De novo synthesis of gem-dialkyl chlorophyll analogues for probing and emulating our green world.

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De Novo Synthesis of Gem-Dialkyl Chlorophyll Analogues for Probing and Emulating Our Green World Jonathan S. Lindsey* Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204, United States 6.2.1. 6.2.2. 6.2.3. 6.2.4.

Chlorophyll b Analogues Chlorin-Imides Hydrocarbon Skeleton of Chlorophylls Chlorosomal Bacteriochlorophyll Analogues 7. Smorgasbord of Chlorins 7.1. ABCD-Chlorins 7.2. Oxochlorins with Attached Motifs or Extended Conjugation 7.3. Spiroalkyl Group at the Pyrroline Ring 7.4. Facially Encumbered Chlorin−Phosphonates 7.4.1. Aryl Phosphonates for Facial Encumbrance 7.4.2. Swallowtail Phosphonates for Facial Encumbrance 7.5. Amphiphilic Chlorins 7.6. Chlorins with Extended Conjugation 7.6.1. 3,13-Diethynylchlorins 7.6.2. 3-Substituted Chlorins 7.6.3. Chlorin−Chalcones 7.7. 7-Substituted Chlorins 7.8. Chlorophyll f Analogues 7.9. Walking the Formyl Group Around the Ring 7.10. Single-Site Substitution of Chlorins 7.11. Isotopically Substituted Chlorins 7.12. Building Blocks 7.13. Chlorin Dyads 8. Outlook Appendix Traditional vs Index Nomenclature Substituent Abbreviations Distinct Disconnections Linear Heterocycles Abbreviations Author Information Corresponding Author Notes Biography Acknowledgments References

CONTENTS 1. 2. 3. 4.

Introduction Early Landmarks in Chlorin Chemistry Natural Tetrapyrroles with Gem-Dialkyl Motifs Development of de Novo Syntheses of GemDialkylchlorins 4.1. Battersby 4.1.1. Tetrahydrodipyrrin + Dipyrromethane 4.1.2. Tetrahydrodipyrrin + Dipyrrin 4.1.3. Dihydrodipyrrinone + Dipyrromethane 4.1.4. “3 + 1” Cyclization 4.1.5. Photochemical Ring Closure 4.1.6. Dihydrodipyrrin + Dipyrrin 4.1.7. Faktor I Synthesis 4.2. Montforts 4.3. Jacobi 4.4. Lindsey 4.4.1. Precursors to Chlorins 4.4.2. Macrocycle Formation 4.4.3. Sparsely Substituted Chlorins 4.4.4. Metallochlorins 4.4.5. Oxochlorins 5. Importance and Synthetic Challenges of βPyrrole Substituted Chlorins 5.1. β-Substituted Eastern and Western Halves 5.2. β-Bromo Eastern and Western Halves 5.2.1. 10-Mesitylchlorins 5.2.2. Chlorins Without a 10-Mesityl Substituent 6. Bromination of Chlorins 6.1. Neutral Bromination 6.1.1. Quantitative Studies 6.1.2. 131-Oxophorbines 6.1.3. Substitution Patterns for Regioselective Bromination 6.2. Acidic Bromination © 2015 American Chemical Society

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1. INTRODUCTION Chlorophylls are the molecules that absorb sunlight, power the biosphere, and give rise to the familiar verdant landscapes of planet Earth. The chief green pigments of plant photosynthesis, chlorophyll a and chlorophyll b, differ only in the composition

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Received: February 2, 2015 Published: June 12, 2015 6534

DOI: 10.1021/acs.chemrev.5b00065 Chem. Rev. 2015, 115, 6534−6620

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The first and longest thread begins with the isolation of chlorophyll reported in 1817 by Caventou and Pelletier,4−6 who offered the now famous and nearly panlinguistic compound name [χλωρός, chloros (green) and φύλλον, phyllum (leaf)]. Stokes first reported the presence of two forms of chlorophyll, now known to be a and b;7 their fractionation was carried out first by Sorby;8 and their reliable separation and isolation was established by Tswett9 via his eponymous method of chromatography (including a “chemically passive” column of sucrose) at the turn of the 20th century. Willstätter determined the molecular formula of chlorophyll a and of chlorophyll b.10 Fischer carried out incisive studies to determine the molecular structure of chlorophyll a,11−13 which was in hand by 1940 (albeit without stereochemical information),14 and embarked on the synthesis before the structure had been fully deciphered.15 The monumental accomplishments in this era have been reviewed.16−21 The absolute configuration of the six stereocenters of chlorophyll a was finally settled by the late 1960s.22−24 While green plants provide the most demonstrable evidence of photosynthesis, nearly half of photosynthetic production is now believed to occur in aquatic environments including the oceans,25,26 where more diverse photosynthetic organisms (and chlorophylls) are found.27,28 Hence, this first thread has broadened to encompass a wider range of chlorophylls. Chlorophyll d was first isolated in 194329−31 from red algae, and has since been found globally in oceanic and lacustrine environments (Scheme 2).32 [There are two significant nomenclature irregularities in this area: (1) chlorophyll c is a porphyrin, not a chlorin, given the presence of a fully unsaturated macrocycle and (2) whereas bacteriochlorophylls

of one substituent (Scheme 1), yet exhibit distinct and complementary absorption spectra as a consequence (Figure Scheme 1. Structure of Plant Chlorophylls and Nomenclature

Scheme 2. Northern Half of Diverse Chlorophyllsa

Figure 1. Absorption spectra in diethyl ether at room temperature of chlorophylls. Legend from short to long Qy bands: Chl b (blue), Chl a (black), Chl d (red), and Chl f (green).1,2,41−43

1).1,2 The fundamental features that distinguish chlorophylls from porphyrins are the presence of a reduced pyrrole (i.e., pyrroline) ring and an annulated fifth (i.e., isocyclic) ring. The reduction of one pyrrole ring affords the chlorin chromophore; together with the annulated five-membered ring, the macrocycle skeleton is a phorbine.3 Modern chemistry pertaining to chlorophylls is a tapestry formed by integration of at least five distinct threads of research, some of which originated almost two centuries ago.

a

The Southern half in each case is identical with that of chlorophyll a. Auxochromes (vinyl, formyl) are shown in blue or red and are located at positions 2, 3, 7, and 8. See the Appendix, first section, for nomenclature. 6535


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a, b, and g from photosynthetic bacteria are true bacteriochlorins (i.e., tetrahydroporphyrins), bacteriochlorophylls c−f are actually dihydroporphyrins and hence are chlorins.] Bacteriochlorophylls c, d, and e were isolated in the 1960− 70s from photosynthetic bacteria (Scheme 3).33 The “missing”

and facile availability of the natural macrocycles to prepare chlorophyll derivatives for diverse applications. The inherent architectural complexity of chlorophylls also makes semisynthesis (versus total synthesis) attractive for gaining access to rare chlorophylls. Semisynthesis, which continues to flourish and has been extensively reviewed,65−73 typically begins with chlorophyll a and entails a handful of reactions: (1) derivatization at the 3-vinyl group, (2) transesterification of the 173-ester, (3) 132-ester pyrolysis, (4) demetalation and remetalation, (5) 20-bromination and subsequent Pd-mediated coupling, (6) 131-carbonyl modification, and (7) for chlorophyll b, derivatization of the 7-formyl group. The red circles shown in Scheme 4 indicate the chief sites of modification.

Scheme 3. Chlorosomal Bacteriochlorophylls

Scheme 4. Semisynthetic Modification Sites of Chlorophylls

bacteriochlorophyll f was predicted and only produced very recently, by deliberate mutation.34−36 While structurally heterogeneous, bacteriochlorophylls c−f are distinguished from chlorophylls a and b by the presence of the hydrated 3vinyl group and the absence of the 132-carbomethoxy moiety.37 In the past quarter century or so, a more diverse collection of chlorophylls has been identified in oceanic microbes38 (and also in a maize mutant),39 namely divinyl chlorophyll a (also known as chlorophyll a2) and divinyl chlorophyll b (chlorophyll b2). Such research continues to the present with the recent (2010) remarkable discovery of chlorophyll f in stromatolites off the coast of Australia.40,41 The absorption spectra of chlorophylls a, b, d, and f are shown in Figure 1.1,2,41−43 The identification of such chlorophylls expands the known realm of photosynthesis, presents new synthetic challenges, and often raises questions concerning evolutionary biochemistry. The total number of chlorophylls shown in Schemes 2 and 3 is 11, and while these are the chief photosynthetic pigments in nature, a much larger number appears naturally given (1) biosynthetic precursors,44−48 (2) 132-epimers,28,49 (3) allomers (i.e., derivatives due to modification of the isocyclic ring, often by a base, oxidant, or radical),28,50 (4) 173-transesterification (of the phytol or other unit),43 (5) free base or other metal chelates,49,51 (6) products of catabolism52,53 and diagenesis,54 (7) metabolites of dietary chlorophylls,55 (8) photodegradation products,56−58 and combinations thereof. Many such chlorophyll analogues may have limited or no biological function, yet their existence and properties provide insights and raise challenges concerning chemical reactivity and physicochemical properties. A second thread of research, which in the early days was central to and interwoven with structure determination, concerns the total synthesis of the natural pigments. The crowning accomplishment in this area is Woodward’s magisterial synthesis of chlorin e6 trimethyl ester,59−64 a formal precursor to chlorophylls. A third thread of research, the chemical modification of chlorophylls (i.e., semisynthesis), exploits the vast abundance

Further derivatives can be created by dehydrogenation of the pyrroline ring (ring D, magenta ellipse) or by saturation of the distal pyrrole ring (ring B, blue ellipse), to create a porphyrin or bacteriochlorin, respectively. The corpus of knowledge developed from studies of semisynthesis has informed the elaboration of geminal-dialkylchlorins (vide infra). A fourth thread of research entails the conversion of a porphyrin to a chlorin, which has been achieved by a variety of approaches, of which direct hydrogenation is the simplest. More recent methods have employed a wide variety of synthons for cycloaddition with a porphyrin to give the chlorin.74−76 The resulting chlorins typically differ from chlorophylls themselves but contain the requisite reduced ring and are synthetically more accessible, as required for fundamental studies and diverse applications. Given that the porphyrins employed as substrates are invariably synthetic, their hydrogenation or reductive addition comprises a means of de novo synthesis of chlorins. The focus of this review concerns a fifth thread of research, namely the de novo creation of chlorins that contain a geminal dialkyl group in the pyrroline ring and where the geminal (“gem”) dialkyl group is installed in precursors to the chlorin macrocycle. The structural difference between a gemdialkylchlorin (H2C) and a completely unsubstituted chlorin (u-H2C) is shown in Scheme 5. Operationally, the former is stable whereas the latter is susceptible to adventitious dehydrogenation upon handling in an aerobic environment. On the other hand, the preparation of gem-dialkylchlorins requires a significant synthetic investment. Research on gemdialkylchlorins represents the shortest of the five threads, originating around 1980, but synthetic advances for creating gem-dialkylchlorins already present great versatility. Numerous routes to chlorins have been developed, and these approaches 6536


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The conversion of porphyrins to oxochlorins via vicinal dihydroxylation and pinacol rearrangement remains popular, despite the presence of isomers in many cases. One modern example is shown in Scheme 7.94 Treatment of the trans-AB-

Scheme 5. Synthetic Chlorins

Scheme 7. Formation and Separation of Oxochlorin Isomers

have been reviewed over the years15,77−86 yet none treats the gem-dialkylchlorins in significant depth. Methods wherein a porphyrin undergoes cycloaddition or rearrangement of preattached substituents to give a gem-dialkyl group are not treated here. The rationale for preparing gem-dialkylchlorins is multifold: to probe the role of substituents arrayed about the perimeter of the macrocycle in giving rise to the characteristic spectral properties of chlorophylls or the self-assembly properties of chlorophyllous pigments in chlorosomes; to employ chlorophyll-like building blocks in the creation of molecular architectures that support artificial photosynthesis; and to exploit the valuable photophysical and photochemical properties of chlorophyll-like molecules in diverse biomedical areas including use as diagnostic and therapeutic entities. The gemdialkylchlorins constitute an architecture wherein, via de novo synthesis, a stable chlorin (resistant to adventitious dehydrogenation) can be readily accessed yet at the same time can be elaborated in a versatile manner as desired for diverse applications. While the present review touches applications only cursorily, the rich opportunities available from the chemistry described herein may be apparent. For perspective, we begin with an overview of key landmarks in chlorin chemistry.

2. EARLY LANDMARKS IN CHLORIN CHEMISTRY The chemistry of chlorophyll has been extensively reviewed o v e r t h e y e a r s w i t h d i v e r s e p o i n t s o f e m p h asis.10,12,17,65,68,73,80,87 Five advances in the middle half of the 20th century constitute valuable landmarks for the synthesis of chlorins. Understanding such landmarks provides insights and perspective on subsequently developed routes for gaining access to gem-dialkylchlorins. (1) 1927: Fischer first treated a porphyrin bearing a full complement of β-pyrrole substituents (octamethylporphyrin) with hydrogen peroxide in sulfuric acid (Scheme 6),88 and obtained an oxidized product that more than 30 years later was shown to be the corresponding oxochlorin 1.89,90 The use of OsO4 in the presence of pyridine to form the vicinal diol followed by acid-mediated pinacol rearrangement was implemented by Inhoffen87,91 and by Chang.92,93

porphyrin 2 with OsO4 followed by strong acid gave two of the four possible oxochlorin isomers. Apparently the comparative steric bulk of the 2,6-dimethoxyaryl substituent (versus the 6substituted phenyl group) suppressed reactivity in the flanking pyrrole rings. The resulting oxochlorin isomers 3a (26%) and 3b (6%) were separated by chromatography. The oxochlorin obtained in larger yield was taken forward to make triad 4 for studies in artificial photosynthesis of photoinduced electrontransfer reactions. (2) 1943−1949: Calvin and co-workers investigated the Rothemund synthesis of meso-substituted porphyrins and isolated meso-tetraphenylchlorin (H2TPC) as a byproduct from the intended synthesis of the porphyrin H2TPP (Scheme

Scheme 6. Conversion of a Porphyrin to an Oxochlorin

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8).95−97 The presence of the chlorin as an impurity in aldehyde−pyrrole condensations leading to porphyrins is

(not shown). In each case purification was challenging, and the chlorin yield was substantially 10-times the duration for irradiation. The sluggish rate was attributed to the increased steric hindrance at the site of ring closure. 4.1.7. Faktor I Synthesis. A first question in pursuing a route to Faktor I concerns the disconnection, whether longitudinally with Northern and Southern halves (50c and 58), or latitudinally with Western and Eastern halves (50a and 6546


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Scheme 22. Western and Eastern Halves for the Photochemical Ring Closure

59). The two approaches are shown in Scheme 25.165,171 The terminology employed here is at odds with that in the original papers where Faktor I is oriented in a manner consistent with that of vitamin B12, but is done for purposes of comparison with all other chlorin syntheses under discussion (see the Appendix, “Distinct Disconnections” section, for elaboration of this issue). One deciding factor was the availability of the monothioimide required to prepare the dihydrodipyrrin; the Western half requires access to the monothioimide where the thio group flanks a quaternary carbon (60b), whereas in the Southern half the thio group flanks a tertiary carbon (60a). While the Western + Eastern route was preferred, a suitable workaround to gain access to the Western half was not found (60a proved more accessible than 60b), in which case the Northern + Southern route was pursued. Note that in the Southern half 58 the gem-dialkyl group is at the dihydrodipyrrin 2-position, adjacent to the site of imine-enamine tautomerization (red circle in Scheme 25). By contrast, in the Western half 59 the gem-dialkyl group is at the dihydrodipyrrin 3-position, one-

carbon removed from the site of imine-enamine tautomerization (blue circles in Scheme 25). Key features of Battersby’s route to Faktor I are shown in Scheme 26.171 Treatment of imide 62 (a racemic mixture) to Lawesson’s reagent gave the monothioimide 60a, which upon Wittig reaction with pyrrole 61 gave the 5-cyanodihydrodipyrrin 63. Reduction of the latter gave 64, which upon removal of the imine fragment by trapping with 1,2-bis(methylamino)ethane gave the desired dihydrodipyrrin (lactam) 65. Treatment again with Lawesson’s reagent gave the thiolactam 66 but with desultory loss of stereochemical integrity of the propionate group in the pyrroline ring. Subsequent alkylation with di-tertbutyl 2-bromomalonate gave the enamine 67. Dissolution in TFA caused cleavage of the three tert-butyl esters and tautomerization to give the dihydrodipyrrin 58 as a mixture of stereoisomers. Condensation with the dipyrrin 50c gave the seco-chlorin 68, which was treated with DIEA in THF and subjected to irradiation for ring closure. After 22 h of irradiation, the racemic octamethyl ester of Faktor I was 6547


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Scheme 23. Proposal for the Photochemical Ring Closure

Scheme 24. Enhanced Enamine Approach (Battersby’s Route VI)

obtained in 26% yield (from 67 + 50c) and the separable 17epimer was isolated as a racemic mixture in 8% yield. The nature of the reacting termini (pyrrole α-position + formyl; enamine + methoxyimine) and oxidation level (dipyrrin) of the Northern and Southern halves as well as the photochemical ring closure thus followed the precedents displayed in Table 1. The penetrating advances wrought by the Battersby group over a decade opened the door to synthetic “C-alkylchlorins” and isobacteriochlorins. In total 10 chlorins (or 16 counting metal chelates, oxochlorins, byproducts, and epimers) were prepared (45 mg total) over this entire effort. While only limited quantities of chlorins were obtained, the amounts dwarfed those available from biosynthetic studies. Indeed, only ∼300 μg of optically active Faktor I was isolated from natural sources over a several year period; a single synthesis would afford some 10-times that amount.171 In addition, the development of routes to diverse hydrodipyrrin reactants and studies of the reactivity of various hydrodipyrrin + dipyrromethane/dipyrrin combinations generated a body of fundamental knowledge of considerable significance and great fecundity. Working contemporaneously with Battersby and of

distinct seminance was Montforts, whose contributions to gemdialkylchlorins we now turn. 4.2. Montforts

The work of Montforts and co-workers concerning de novo syntheses of chlorins205−220 has been deeply influenced and enabled by the prior synthetic studies of Eschenmoser201,202 and Johnson221,222 aimed at corrins (and also isobacteriochlorins) and to some extent that of Jones for the preparation of naturally occurring porphyrins.223,224 The route developed by the Montforts group to chlorins also benefited from their 6548


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other hand, Vilsmeier formylation of 3,4-dimethylpyrrole223 gave 3,4-dimethylpyrrole-2-carboxaldehyde (70), which upon bromination of the lone unsubstituted carbon gave the 2bromopyrrole-5-carboxaldehyde 71a,207 which is destined for ring A of the chlorin. Oxidation of ethyl 3,4,5-pyrrole-2carboxylate (72, available from a modified Knorr synthesis of ethyl acetoacetate, 3-methylacetylacetone, sodium nitrite and zinc dust)224 with Pb(OAc)4 afforded the corresponding pyrrole−carboxaldehyde 73a, destined for ring B.222 Ring D was constructed by reliance on chemistry developed chiefly by Eschenmoser in the synthesis of vitamin B12. The condensation of ethyl 3,3-dimethyllevulinic acid with ammonia afforded ene-lactam 74,202 which upon addition of cyanide gave the racemic aminonitrile 75 (Scheme 28).201 Treatment with P2S5 afforded thiolactam 76.201 The latter was treated to a sequence (and resulting products) of (1) benzoyl peroxide to give disulfide 77; (2) displacement with malonate 78 to give 79; (3) sulfide contraction to give 80; and (4) fluoride treatment to selectively decarboxylate the malonate unit.207 The resulting D unit (81a) was obtained in 46% yield for the four-step sequence. While none of the intermediates (77, 79, and 80) in the sequence needed to be isolated and characterized, the disulfide 77 has been prepared and isolated in 92% yield,201 and 80 (as a mixture of the E/Z diastereomers) has been characterized.207 (A route to an enantiomerically pure ring-D synthon, which bears an acetic acid moiety and a methyl group at the gem-dialkyl site, was developed by Montforts.214) The condensation of pyrrole-carboxaldehyde 73a and 2pyrrolinone 69a afforded the Eastern half 82 containing the B and C rings (Scheme 29).205 Treatment with P2S5 gave the corresponding Eastern half 83 in the thiolactam form. Electrophilic bromination of the enamine 81a gave 84 (as a mixture of imine-enamine tautomers) in the first step of a twostep sequence; the second step entailed reaction with Eastern half 83 to form the sulfide-linked tripyrrin 85. The sulfide contraction procedure then afforded the racemic BCD-tripyrrin unit 86. Tripyrrin 86 is oxygen-sensitive,81 and ester saponification resulted in considerable decyanidation.205 Complexation of nickel (to give Ni-86) overcame both limitations and also facilitated ester hydrolysis (to give Ni-87). Subsequent acidcatalyzed condensation of Ni-87 with bromopyrrole-carboxaldehyde 71a (Scheme 27) resulted in in situ decarboxylation and decomplexation to give the linear tetrapyrrole 88. Treatment of the latter with zinc acetate and base resulted in ring closure, via the putative intermediates Zn-88 and Zn-89, to give the zinc chlorin Zn-90a. Exposure to mild acid liberated the free base chlorin 90a (Scheme 30).207 The resulting chlorin is the deoxo analogue of octamethyloxochlorin, which was first prepared by Fischer upon oxidation/rearrangement of octamethylporphyrin (Scheme 6). As with Battersby’s synthesis, the stereocenter in the pyrroline-containing unit (e.g., compare racemic 13 in Scheme 18 with racemic tripyrrin 86 in Schemes 29 and 30) was necessarily lost upon conversion to the chlorin, showing the inconsequential matter of racemic precursors that are stereoisomeric at the carbon destined to be position 19 in the chlorin. The synthesis of the linear tripyrrolic species requires substantial investment, but once in hand, a variety of substituted chlorin architectures could be prepared by reaction with diverse ring-A synthons. Examples of ring-A pyrrole synthons (71b−h) are shown in Scheme 31. The two enantiomerically pure norbornyl-pyrroles bear ester/nitrile

Scheme 25. Retrosynthetic Analysis for Faktor I

parallel studies of routes to other hydroporphyrins.81,82 The chief route is shown in retrosynthetic fashion in Scheme 27. Three pyrrolic building blocks were synthesized as shown in Scheme 27 (bottom panel). Oxidation of 3,4-dimethylpyrrole with hydrogen peroxide afforded 3,4-dimethylpyrrolin-2-one (69a),221 destined to serve as ring C in the chlorin. On the 6549


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Scheme 26. Synthetic Routes to Faktor I

Reaction of the latter at 130 °C in the presence of a dienophile resulted in extrusion of sulfur dioxide and Diels−Alder addition of the dienophile. Subsequent reaction at elevated temperature (220 °C) affords ring closure to give the chlorin. Thus, the use of dimethyl acetylenedicarboxylate gave annulated chlorin Zn94, which upon aerobic oxidation afforded the benzochlorin Zn-95.213 Other dienophiles that have been employed include C60211,212 and 1,4-naphthoquinone213 (vide infra). While C60 could be added with the sulfone-bilin upon reaction at 220 °C (simultaneous Diels−Alder cycloaddition and chlorin formation), dimethyl acetylenedicarboxylate and 1,4-naphthoquinone were successfully incorporated upon use of the two-stage thermal process.213 This route provides a distinct approach to diversification of chlorin architectures that is not available in any other synthesis. Montforts extended the route to the synthesis of Bonellin.206,208 The synthetic procedures were largely identical with those shown in Schemes 29 and 30 albeit with the use of appropriately substituted A−D constituents 71j, 73b, 69b, and 81b, respectively. The chief challenge resided in the preparation

functionalities in a trans configuration (71b,c),209,215 which afforded the corresponding norbornylchlorins (Zn90b,c). One of the norbornyl-chlorins (Zn90c) was transformed to give chlorin building blocks that contain an amine (Zn-91) or an Nhydroxysuccinimido ester (Zn-92).215 A similar norbornylpyrrole bears a latent naphthoquinone (71d).210 The isomeric β-iodopyrroles (71e,f) provided chlorin building blocks (Zn90e,f) for studies of substituent and architectural effects,219 and an imidazole reactant (71g) provided access to the corresponding 2-azachlorin (not shown).220 Reaction of the sulfonesubstituted pyrrole (71h) afforded the sulfone-chlorin (Zn90h).212 A versatile feature of the sulfone system is the ability to elaborate annulated groups at ring A of the chlorin.211−213 One example is shown in Scheme 32. The nickel tripyrrin Ni-86 was treated to conditions for hydrolysis (forming Ni-87) followed by reaction with sulfone-pyrrole 71i, which contains a blocking benzyloxycarbonyl group at the α-position rather than the more typical α-halo of pyrroles 71 (Schemes 30 and 31). The resulting bilin was isolated as the zinc chelate (Zn-93). 6550


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Scheme 27. Montforts’ Retrosynthesis (Left) and Preparation of Three Constituents (Right)

Scheme 28. Building up the Pyrroline Ring in Montforts’ Synthesis

Scheme 29. Building up the Tripyrrin Unit in Montforts’ Synthesis

vitamin B12 by Woodward225,226 and by Eschenmoser.227 Use of the four constituents shown in Scheme 33 proceeded uneventfully except for epimerization (at the position of the

of an enantiomerically pure ring-D synthon (81b), to be compared with racemic 81a (Scheme 29). An enantiomerically pure lactam precursor to 81b was employed in syntheses of 6551


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Scheme 30. “3 + 1” Ring Closure in Montforts’ Synthesis

methyl propionate attachment) in the ring-D unit during the sulfide-contraction procedure, a process analogous to 85 → 86 (Scheme 29) and operationally akin to 65 → 58 (Scheme 26). Loss of stereochemical integrity during this step resulted in formation of racemic (±)-Bonellin dimethyl ester.206,208 Montforts’ work in chlorin chemistry began around 1980 and has continued to the present. We now turn to consider the contributions of Jacobi, whose work began after that of Battersby was completed.

afforded the enol ether 103, which upon hydrolysis and amination afforded the dihydrodipyrrin 104.230 The latter could be converted with trimethyl orthoformate/TFA to give 101,231 or oxidized with SeO2 to give the dihydrodipyrrin−monoaldehyde 105, the Southern half for formation of unsymmetrically substituted chlorins.231,232 Jacobi prepared alkynoic acids bearing a gem-dimethyl group α or β to the carboxylic acid, as well as alkynoic acids lacking any alkyl substitution.230 The latter afforded dihydrodipyrrins unsubstituted in the pyrroline ring. A generic problem encountered was the tautomerization of the dihydrodipyrrin (106) to give the dipyrromethane (107; Scheme 35). Although conditions were identified to mitigate such ruinous tautomerization, the lability of such dihydrodipyrrins is testament to the virtue of the gem-dialkyl “lock” in securing the reduced ring, as required for formation of the chlorin chromophore. With a dihydrodipyrrin−dialdehyde (e.g., 102) in hand, chlorins could be prepared by reaction with a dipyrromethane1,9-dicarboxylic acid.231 The overall strategy of a “2 + 2” condensation of a diformyl−dipyrrolic species (Southern half) and a dipyrromethane−dicarboxylic acid (Northern half) is akin to the MacDonald route for formation of porphyrins.236,237 The MacDonald route to porphyrins, reported in 1960, relies on condensation of a dipyrromethane (108a) [or dipyrromethane−dicarboxylic acid (108b); decarboxylation occurs in situ] and a dipyrromethane−dicarboxaldehyde (109), as shown in Scheme 36. Two remarkable advances represented by the MacDonald synthesis were (1) reaction proceeded entirely at room temperature and (2) the dipyrromethanes contained alkyl substituents (e.g., acetic acid, propionic acid, or alkyl esters thereof) as required for the synthesis of uroporphyrins and other octaalkylporphyrins (110) rather than more typical deactivating groups (e.g., carboethoxy). On the other hand, a known limitation of the MacDonald synthesis is the lack of control over the orientation of the respective dipyrromethane and dipyrromethane−dicarboxaldehyde reactants; hence, at least one of the dipyrromethane species must be symmetrically substituted about the central methylene, otherwise two porphyrins could form. Regardless, the utilization of dipyrro-

4.3. Jacobi

Jacobi and co-workers developed a handful of de novo syntheses of gem-dialkylchlorins.228−232 Their work grew out of a program aimed at developing synthetic access to the large family of hydroporphyrins including corrins.233,234 The chlorin synthesis entails the joining of Northern + Southern halves. (The Jacobi routes have been displayed here consistent with the chlorophyll nomenclature described in the Appendix, which differs from that published; see “Traditional vs Index Nomenclature” and “Distinct Disconnections” sections for further discussion.) As with all de novo syntheses of chlorins, much methodology development was required for the preparation of the critical pyrroline-containing precursors.228,230−232,234,235 The key methods developed in this regard are shown in Scheme 34.201−203 The Sonogashira-like reaction of an alkynoic acid (96) with an α-iodopyrrole (97) under Pd-mediated coupling conditions afforded the pyrrole−enelactone 98.231 In one route,231 treatment with trimethyl orthoformate in the presence of TFA caused cleavage of the tert-butyl ester, decarboxylation, and formylation of the unsubstituted α-pyrrole position. The resulting 99 upon reaction with two equivalents of methyl lithium underwent ring-opening to give the 1,4diketone 100, which in a Paal-Knorr-like process with an ammonia source formed the pyrroline and thus the dihydrodipyrrin 101. The α-methylpyrrole group of 101 was smoothly oxidized with SeO2 to give dihydrodipyrrin− dialdehyde 102, thereby affording the Southern half for “2 + 2” chlorin-forming reactions.231 Alternatively, reaction with the pyrrole−enelactone 98 and the Petasis reagent TiCp2Me2 6552


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Scheme 31. Diverse Synthons for Use in Montforts’ Synthesis

chlorins.231 The acid-catalysis conditions found most suitable by Jacobi for chlorin formation were TFA (5%) in dichloromethane at room temperature. Such conditions were originally developed by Lash for formation of porphyrins by “3 + 1” reaction of a tripyrromethane−dicarboxylic acid and a pyrrole2,5-dialdehyde.242 By reaction of each member of a set of five dihydrodipyrrin−dicarboxaldehydes (102) with each member in a set of five dipyrromethane-1,9-dicarboxylic acids (108b), a matrix of 25 chlorins (111) was prepared (Scheme 37).231 One representative chlorin (111a) is displayed. The availability of the matrix of chlorins enabled exploration of a supramolecular theme, namely, the effect of localization of the chlorin at various depths in a membrane assembly (due to the length of the alkyl chain) upon photodynamic efficacy.243 Similar studies examined binding of the chlorins to the protein albumin.244 Several features of the synthesis warrant comment. First, the yield of chlorin formation was quite high (47−85%). Second,

methanes, which constituted a significant departure from workhorse methods developed by Fischer for porphyrin synthesis on the basis of dipyrrins,129,238 opened a new route of great importance. Indeed, a decade later Smith remarked (here pyrromethanes refers to dipyrromethanes), “Until recently it was thought that pyrromethanes were unsuitable intermediates for the synthesis of porphyrins, due to their acid lability unless substituted with electron-withdrawing groups. The success of the variations of the MacDonald synthesis has now shown beyond any doubt that pyrromethanes are indeed of great utility.”239 Dipyrromethanes240 have since become central to meso-substituted porphyrin synthesis98,241 and constitute the nonpyrroline-containing half in diverse chlorin syntheses (vide infra). The use of a dipyrromethane−dicarboxylic acid and a dihydrodipyrrin−dicarboxaldehyde in a MacDonald-like synthesis constituted Jacobi’s first method for synthesizing 6553


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Scheme 32. Diversification via Cycloaddition in Montforts’ Synthesis

Scheme 33. Montforts’ Route to Bonellin

contained features for directed reaction to avoid the symmetry limitation of reactants that plagues a MacDonald-like approach.232 The availability of a dipyrromethane bearing one ester and one carboxylic acid (108c) and the dihydrodipyrrin bearing a carboxaldehyde and an ester (105) provided the substrates for Method II, as shown in Scheme 38. Reaction in the presence of 5% TFA resulted in decarboxylation of the dipyrromethane followed by condensation with the dihydrodipyrrin to give the dihydrobilatriene 112. Addition of further TFA (25%) and trimethyl orthoformate resulted in chlorin formation. The latter reaction (from 112 onward) is envisaged as proceeding via (1) loss of the two tert-butyl ester groups to give a presumed intermediate (shown in brackets in Scheme 38) that bears a single formyl group (on the dipyrromethanederived terminus) and a carboxylic acid or no substituent (R = CO2H or H on the dihydrodipyrrin-derived terminus); (2) ring closure concomitant with or following decarboxylation; and (3) dehydration. Three new chlorins (111) were formed in this manner wherein the substituents in rings A and B were nonidentical. Yields were 11 or 12% for R15 = H but 37−59% for R15 = methyl or phenyl; representative chlorin 111b was obtained in 59% yield.232 In method II, the carbon that constitutes position 10 in the chlorin was introduced by formylation with trimethyl orthoformate in the last step of the reaction. The preinstallation of the aldehyde destined to become the C10-carbon was examined through use of a monoformyl dipyrromethane in two rather similar routes (methods III and IV). In method III, Jacobi examined the reaction of an unsymmetrically substituted dipyrromethane (113a) and a dihydrodipyrrin (105a), each of which bears one carboxaldehyde moiety (Scheme 39).232 Decarboxylation of both reactants in the presence of TFA would potentially afford three macrocyclic products: the target chlorin 111c; a porphyrin derived from self-condensation of the dipyrromethane; and a meso-hydroxybacteriochlorin upon selfcondensation of the dihydrodipyrrin−carboxaldehyde (by analogy with condensation of a corresponding dihydrodipyrrin−acetal246). In fact, treatment first with 5% TFA (to decarboxylate the dipyrromethane) and second with 25% TFA

the scale was substantial (∼10−50 mg); indeed, one chlorin was prepared in >300 mg quantity. Third, in each case the substituents R3 and R7 were necessarily identical, given the undifferentiated reactivity of the two pyrrolic α-positions of the dipyrromethane (108b); thus, the resulting chlorins contain identical substituents in the A and B rings. Fourth, each of the pyrroles of the dipyrromethane bears two alkyl substituents. The reactivity of a pyrrole is quite sensitive to the nature of the substituents,245 and pyrroles with two alkyl substituents are highly reactive toward electrophilic aromatic substitution. No comparative studies of pyrroles with other β-substituents (e.g., H, aryl, halo, and carboethoxy) were undertaken. Jacobi next turned to extensions of the “2 + 2” route that would enable access to chlorins without identical substituents in rings A and B. Three methods were developed, each of which 6554


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Scheme 36. MacDonald “2 + 2” Synthesis of Porphyrins

Scheme 34. Synthesis of Dihydrodipyrrins

Scheme 37. MacDonald-Like Synthesis of Chlorins (Jacobi’s Method I)

Scheme 35. Adverse Chemistry in the Absence of the GemDialkyl Group

gave chlorin 111c as the only reported macrocyclic product. The success of this route stems from the difference in reactivity imparted by the pyrroline moiety; in other words, the pyrroline-carboxaldehyde (giving C20) is more reactive than the dipyrromethane-carboxaldehyde (giving C10).

Method IV constituted a slight extension of method III. Here, Jacobi employed an unsymmetrically substituted dipyrro6555


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Scheme 38. Chlorins via Jacobi’s Method II

Scheme 39. Differential Reactivity of a Carboxaldehyde on Two Reactants (Jacobi’s Methods III and IV)

methane (113b) and a dihydrodipyrrin (105a), each of which bears one carboxaldehyde and one tert-butyl ester moiety (Scheme 39).232 Method III, by contrast, employed a monocarboxy/monoester substituted dipyrromethane. Here, treatment with 25% TFA again resulted in a single chlorin (111d). The subtle difference in reactivity of the carboxaldehyde group attached to a pyrroline or pyrrole moiety was predicted and remains a striking finding of this fundamental study in methodology.

The rationale for the observed regioselectivity in the condensation of method IV is 2-fold: the dipyrromethane ester is cleaved preferentially versus the dihydrodipyrrin ester, and the dihydrodipyrrin-carboxaldehyde is more reactive than the dipyrromethane-carboxaldehyde. Indeed, decarboxylation of α-carboxy pyrroles247 (and analogous dipyrromethanes)248 is more favorable with pyrroles that are more electron-rich, because the first step in the process is believed to entail protonation of the pyrrole.249 In this case, the pyrrole in the 6556


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halves are joined regioselectively on the Western side. Subsequent treatment with 25% TFA caused deesterification (labeled (iii)) and ring closure with the pyrrolic carboxaldehyde of the dihydrodipyrrin (labeled (iv)) on the Eastern side. The reaction order of the four functional groups is displayed as i− ii−iii−iv in Scheme 40. In this manner, six unsymmetrically substituted chlorins (111) were prepared in yields of 22− 87%.232 Two representative chlorins (111c,e) are shown. The route combines the simplicity of the MacDonald approach to porphyrins with insights concerning subtle differences in reactivity of like functional groups to achieve a directed and efficient synthesis of chlorins. In summary, Jacobi’s routes constitute a milestone in chlorin chemistry. The chlorin is formed in the absence of metals and with precursors at the same oxidation state as the macrocycle product−hence an oxidant is not required in the macrocycleforming step. The new routes to hydrodipyrrins augur well for rich exploitation in the synthesis of diverse chlorins and related hydroporphyrins. All of the target chlorins contain a full complement of alkyl substituents at the six β-pyrrole positions. In this regard, the chlorins represent a limiting (albeit widely useful) form, to be compared with chlorophyll a, for example, which at the β-pyrrole positions contains four alkyl, one vinyl, and one carbonyl group. The effect of electron-withdrawing groups, which diminish the reactivity (toward electrophiles) of pyrroles245 and dipyrrolic species,251−253 has not been explored in Schemes 37−40 but introduction of such groups appears feasible given the methodology developed by Jacobi and coworkers. We now turn to the work of the author and his research group concerning chlorins, which began in earnest in 1995.

dihydrodipyrrin is deactivated owing to the conjugating formyl−pyrroline unit. Conversely, the electron-withdrawing effect of the pyrroline unit (in the neutral form or even more so in the protonated form) increases the electrophilicity of the adjacent formyl group whereas the formyl group in the dipyrromethane is attached to an electron-rich pyrrole. The pyrroline unit is undoubtedly protonated under the reaction conditions; indeed, protonated 2-methylpyrrole250 has pKa = −0.21 whereas protonated 2,4,4-trimethyl-Δ1-pyrroline180 has pKa = 7.6. While methods III and IV were each used to prepare only one chlorin, the experimental proof of differential reactivity of the carboxaldehyde group on the pyrroline (dihydrodipyrrin) versus pyrrole (dipyrromethane) pointed the way to a new synthetic method: in method V, the dihydrodipyrrin was substituted with two carboxaldehyde units (Scheme 40).232 Scheme 40. Concise Synthesis of Chlorins (Jacobi’s Method V)

4.4. Lindsey

The objectives of the Lindsey group in chlorin chemistry originated in the field of artificial photosynthesis. A central goal has been to create stable chlorin macrocycles that contain diverse substituents in specific patterns (including the isocyclic ring) or that contain no substituents at all. The substitution sites include all 6 β-pyrrole-, 2 β-pyrroline-, and 4 mesopositions. The substituents of interest encompass auxochromes to tune spectral properties, reactive functional groups for covalent building block applications (e.g., ethyne, iodo, and boronic ester), polar or nonpolar groups for self-assembly (e.g., affording amphiphilic character), ionizable groups for watersolubilization, and reactive groups for bioconjugation (e.g., iodoacetamide). Such objectives constitute a clean break from the constraints imposed by the substitution patterns present in naturally occurring chlorin macrocycles. Efforts to fulfill such objectives over the past 20 years have been described in 45 papers (including >1200 pages of Supporting Information).254−300 For stability of the synthetic chlorins, the gem-dimethyl group was chosen, which is a chief structural element in diverse hydroporphyrins (Scheme 16) including Bonellin but not present in chlorophylls. In this regard, the chlorin chemistry of the Lindsey group has been deeply influenced by (1) the chlorin syntheses of Battersby (including that of Bonellin) and (2) prior studies of routes to meso-patterned porphyrins.241 The latter have relied on the development of (1) facile routes to dipyrromethanes (114),301 (2) methods of derivatization of dipyrromethanes including acylation of the dipyrromethane αpositions,302−305 (3) methods for the gentle (nonscrambling; vide infra) acid-catalyzed condensation of dipyrromethane-

Thus, dihydrodipyrrin−dicarboxaldehyde 102 was reacted with dipyrromethane 108c bearing a carboxylic acid and a tert-butyl ester at the respective α-positions. Treatment with 5% TFA caused decarboxylation (labeled (i)) thereby opening the corresponding lone α-pyrrole position of the dipyrromethane for reaction. Of the two carboxaldehyde groups of dihydrodipyrrin 102, that attached to the pyrroline moiety is more reactive (labeled (ii)). Hence, the Northern and Southern 6557


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carbinols (114-diol) to give porphyrinogens (115),306−310 and (4) scalable routes with little or no chromatography across all steps of the tetrapyrrole synthesis.311,312 A route to porphyrins bearing four distinct meso-substituents (116) is shown in Scheme 41.241 On face value the routes to chlorins that are

stituent was present in the dipyrrin Eastern half (18); such groups are typically constructed by treatment (of an αmethypyrrole or α-methyldipyrrin) at some point with Br2,199 a feature that also would be incompatible with various desired substituents as well as use of β-unsubstituted pyrroles. Moreover, all of Battersby’s routes typically have employed a full complement of β-pyrrole alkyl substituents (which activate the remaining open α-sites for electrophilic substitution and block the β-sites toward side reactions) and few if any mesosubstituents. A broadly generic limitation across all of the routes concerned the small quantity of chlorins obtained. Ultimately, the first route that was developed departed from the Battersby thermal route156,162 by employing (1) a dipyrromethane Eastern half with carbinol (instead of bromomethyl) and bromo substituents (119-Br9/OH) rather than a dipyrrin, (2) Zn(II) rather than Cu(II) for templating, (3) reactants with no β-pyrrole substituents, and (4) introduction of two meso-aryl substituents (Scheme 42, panel C). The resulting chlorins could be obtained in workable (e.g., 10−100 mg) quantities. Relevant distinctions concerning the reacting functional groups and substrate oxidation states in panel C versus those in panels A and B might appear slight but only emerged over a painstaking five-year period of exploration (initiated in 1995) as described in the Supporting Information of ref 254. A family of hydrodipyrrins was created as part of this exploratory research.268 For route C, the Western half employed initially was a dihydrodipyrrin (117),254,255 but a tetrahydrodipyrrin (118) Western half was found to afford greater stability and more efficacious reactivity.256 Moreover, the use of a carbinol-substituted Eastern half has required R5 ≠ H, in which case all resulting chlorins have contained a 5-aryl (or occasionally, 5-alkyl) substituent. Route D was subsequently developed wherein an Eastern half bears a carboxaldehyde (120-Br9) in lieu of the carbinol moiety, providing access to 5-unsubstituted chlorins (Scheme 42).265 By analogy with the exploratory studies that led to route C, for route D a handful of other reacting functional groups (and substrate oxidation states) also was examined but none was found to be superior to that of the 9-bromo/1carboxaldehyde combination.269 The development and virtues of such routes are described below; we first turn to consideration of the synthesis of the requisite precursors. 4.4.1. Precursors to Chlorins. The synthesis of the Eastern half begins with the one-flask synthesis of a dipyrromethane (114) from pyrrole and an aldehyde (Scheme 43).240,301 The dipyrromethane undergoes 1-acylation313 upon conversion to the bis(pyrrole Grignard reagent) and treatment with an S-(2-pyridyl) thioate (Mukaiyama reagent, 121; Scheme 43) or phenyl formate (Scheme 44).302,303,305 The acyl substituent (B or H) and the aldehyde substituent (A) of the acyldipyrromethane (119, 120) are destined to become the chlorin 5- and 10-substituents, respectively. Bromination occurs selectively at the α-position of the nonacylated (and hence nondeactivated) pyrrole ring, affording 119-Br9 or 120Br9.254,265,269 Synthesis of the Eastern half is completed by reduction of the ketone to give the dipyrromethane-carbinol (119-Br9/OH)254 whereas the dipyrromethane-carboxaldehyde (120-Br9) is used directly.265,269 It warrants mention that dipyrromethane-carbinol 119-Br9/OH contains two stereocenters (R5,10 ≠ H) and is employed directly as a mixture of four stereoisomers, whereas dipyrromethane-carboxaldehyde 120-Br9 contains one stereocenter (R10 ≠ H) and is used directly as a mixture of enantiomers. The use of the mesityl-

Scheme 41. Rational Synthesis of ABCD-Porphyrins

described in this section may appear simpler than those of Battersby: the chlorin architecture is less elaborate and is devoid of stereocenters. The greater simplicity has enabled a host of spectroscopic and photochemical questions to be posed, and perhaps to some extent answered, that are not accessible with the more complex natural macrocycles. In this regard, simplicity is a virtue. Despite the enormous inspiration and specific examples provided by the work of Battersby and co-workers, a slew of problems required resolution to develop a robust synthesis compatible with the aforementioned objectives in artificial photosynthesis. Paradoxically perhaps, the chief challenges associated with adopting Battersby’s routes concerned identification of the appropriate Eastern half (e.g., 18, 50), not the structurally more complex (pyrroline-containing) Western half (e.g., 13, 43). The Western half chosen was nearly identical to that employed in Battersby's synthesis of Bonellin. Among the various routes developed by Battersby, the two shown in Scheme 42 (panels A and B) were most influential. Both rely on dipyrrin Eastern halves. The photochemical route (Schemes 22-26; Table 1) was employed most extensively by Battersby, but did not appear suited to scale up, and moreover, was likely incompatible with various types of desirable substituents. The thermal route156,162 shown in Scheme 19, while intriguing, had multiple drawbacks. The drawbacks include the following: (1) the route was abandoned by the Battersby group after a single chlorin was prepared, (2) copper chelation was employed in the macrocycle-forming step, and (3) an α-bromomethyl sub6558


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Scheme 42. Battersby (A, B) and Lindsey (C, D) Routes, Different Approaches for Different Objectives

ation of the dialkylboron unit occurs in situ (Scheme 43). The reduction and accompanying decomplexation has been demonstrated for 1-acyldipyrromethanes (e.g., 119-BR2) with good results but has not yet been implemented for those bearing a 9-bromo substituent (dashed arrow, Scheme 43). The synthesis of the Western half begins with a pyrrole-2carboxaldehyde and largely follows the route developed by Battersby (Scheme 17).156,162 The example shown in Scheme 45 is for the β-unsubstituted pyrrole (destined to be ring A of the chlorin). Thus, aldol condensation with nitromethane (i.e., the Henry reaction176) afforded the nitrovinylpyrrole 122, which upon reduction gave 2-(2-nitroethyl)pyrrole (123). Michael addition with the α,β-unsaturated ketone mesityl oxide (10) gave the γ-nitrohexanone 124, which was then subjected to metal-mediated ring closure. The metal-mediated ring closure could be achieved with TiCl3 to form the dihydrodipyrrin 117 or with Zn to form the tetrahydrodipyrrin 118. The tetrahydrodipyrrin is racemic, as is the case in Battersby’s synthesis (e.g., 13, Scheme 17) but the stereocenter, destined for position 19 of the chlorin, is necessarily lost upon aromatization during chlorin formation. The formation of the

substituted dipyrromethane stemmed from prior use of the mesityl group in porphyrin chemistry, where (1) the facial encumbrance provided by the ortho-methyl groups imparts significant solubility of the resulting tetrapyrrole macrocycle in organic solvents314,315 and (2) such dipyrromethanes are known to be quite resistant to acid-induced scrambling processes (vide infra).316 1-Acyldipyrromethanes (119, 120) typically streak extensively upon chromatography and upon isolation exist as oils or solid foams. On the other hand, complexation with a dialkylboron triflate (e.g., Bu2B−OTf, 9-BBN−OTf) affords the 1-acyldipyrromethane−dialkylboron complex (119-BR2) as a highly crystalline substance, whereas the nonacylated dipyrromethane does not afford such a complex.303 Accordingly, dialkylboron complexation provides a simple means to facilitate purification of the 1-acyldipyrromethane from the crude acylation reaction mixture.288 The 1-acyldipyrromethane−dialkylboron complex (119-BR2) undergoes 9-bromination to give (119-BR2-Br9).288 Treatment of a 1-acyldipyrromethane−dialkylboron complex with NaBH 4 gives the corresponding dipyrromethane-1-carbinol, where decomplex6559


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Scheme 43. Synthesis of a Carbinol-Substituted Eastern Half

Scheme 44. Synthesis of a Formyl-Substituted Eastern Half

tetrahydrodipyrrin could be achieved via the N-oxide intermediate 125 or directly without isolation of any intermediates.264 Streamlined procedures have enabled the synthesis of several grams of 118 from pyrrole-2-carboxaldehyde in a few days time with almost no chromatography.264 The chemistry underlying the conversion of a γ-nitrohexanone (e.g., 124) to a pyrroline unit (e.g., 117, 118) is quite rich and has a long history. Here, four salient features concerning such transformations and related hydrodipyrrin chemistry are presented. (1) The Nef reaction, which dates to 1894, entails the treatment of a nitroalkane first with base (to form the nitronate) and second with aqueous acid (to hydrolyze the nitronate).317 The organic product is the carbonyl compound (e.g., ketone or aldehyde). McMurry and Melton reported that

treatment of a nitroalkane with TiCl3 in aqueous acid (pH 7,8 > 20; under acidic bromination conditions, the order of reactivity is 15 > 20 > 7,8. The ramifications of this externally controlled inversion of order are profound, given that the 15-position is integral to the isocyclic ring and the 7-position is the site that distinguishes chlorophylls a and b. Four major examples that exploit acidic versus neutral bromination are described in the next sections. The examples include the synthesis of chlorophyll b analogues, chlorin-imides, the core hydrocarbon skeleton of chlorophylls, and chlorosomal bacteriochlorophyll analogues. It deserves comment, however, that the use of acidic bromination conditions dates to the work of Fischer with porphyrins.384 A number of prior studies of bromination of chlorins employed similar acidic conditions 6577


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Scheme 69. Thwarted Regioselective 15-Brominationa

Scheme 68. Steric and Electronic Interplay in Neutral Bromination of Chlorinsa

a

Reprinted with permission from ref 283. Copyright 2009 American Chemical Society.

Scheme 70. Acidic Bromination of Chlorins

a

Adapted with permission from ref 283. Copyright 2009 American Chemical Society.

convenient handle for tailoring the absorption spectrum of synthetic chlorins. An in-depth analysis of the effects of the 7-formyl and other 7-substituents has been performed.291 The fact that introduction of a conjugative substituent (e.g., formyl) can shift the long-wavelength absorption band to shorter wavelength is at odds with the organic chemist’s traditional “one-electron particle-in-a-box” view. Moroever, the fact that a conjugative substituent at one position can cause a bathochromic/ hyperchromic shift but at another position a hypsochromic/

group shifts the position of the Qy band from 656 to 653 nm and the B band from 413 to 442 nm. In addition, the ratio of the intensities of the B:Qy band increases from 1.7 to 4.5, reflecting the respective relative greater/lesser absorption in the blue/red region of the 7-formyl-substituted macrocycle. In summary, modification of the 7-substituent provides a 6578


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Scheme 71. Synthesis of Pheophytin b Analogues

Figure 6. Absorption spectra at room temperature of natural versus synthetic 131-oxophorbines. (A) Absorption spectra of pheophytin a (Pheo a, red) and H2OP-M10 (blue). (B) Absorption spectra of pheophytin b (Pheo b, red) and H2OP-F7M10 (blue). The pheophytins are in diethyl ether whereas the synthetic analogues are in toluene. Adapted with permission from ref 283. Copyright 2009 American Chemical Society.

sequence in the left panel, carbamoylation of H2C-M10Br3,13 afforded the 3,13-bis(carbamoyl) derivative 161. Acidic bromination proceeded regioselectively at the 15-position to give bromochlorin 162; again, neutral bromination would proceed in ring B (for the molecules shown, at the 7-position). The juxtaposition of the 13-amide and 15-bromo groups enabled carbonylation followed by intramolecular imidation to create the chlorin-imide 163, which also bears a carbamoyl group at the 3-position. (2) In the reaction sequence in the right panel, carbonylation of H2C-M10Br3,13 afforded the 3,13diester chlorin H2C-M10Es3,13. Again, acidic bromination of H2C-M10Es3,13 afforded the corresponding 15-bromochlorin 164. Carbamoylation of the latter afforded the chlorin-imide 165, which also bears an ester group at the 3-position. The results show that the carbamoylation can be carried out successfully with an aryl or benzyl amine. Moreover, the chlorin-13,15-dicarboximide bearing a 3-carbomethoxy substituent (165) illustrates the ability to install distinct groups in the 3- and 13-positions while creating the 13−15-spanning imide group.286 The long-wavelength (Qy) absorption band of members of the family of synthetic zinc and free base (gem-dimethyl) chlorins (including 131-oxophorbines) resides in the range of 598−687 nm, whereas the chlorin-imides absorb in a longer wavelength region, from 660−714 nm. The chlorin-imides thus fill the gap in the spectral progression of synthetic free base and

hypochromic shift requires more nuanced usage of the term “auxochrome”291 − the effect of an auxochrome is not an intrinsic functional group property given that augmentation, diminution, or modification of the color can arise depending on the position of attachment to the π-system. 6.2.2. Chlorin-Imides. Chlorin-imides (previously often termed purpurinimides) have traditionally been prepared by ring expansion of naturally occurring or naturally derived chlorophylls.65,68 Such modifications represent one of the earliest and most common methods for semisynthesis with chlorophylls, dating to the work of Conant388 and of Fischer.12,389 The imide unit spans positions 13 and 15 on the chlorin macrocycle. The virtues of such chlorin-imides are as follows: (1) bathochromic shift of the long-wavelength absorption band, (2) versatile synthetic handle at the nitrogen of the imide, and (3) stability toward oxidation. The de novo synthesis begins with a 3,13-dibromochlorin (Scheme 72).286 Two pathways are possible: (1) In the reaction 6579


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Scheme 72. De Novo vs Semisynthetic Routes to Chlorin-13,15-dicarboximides

mediated acetylation gave the 13-acetylchlorin H2C-A13. Acidic bromination of the latter proceeded regioselectively at the 15position (neutral bromination would proceed at both the 7- and 8-positions) to give H2C-A13Br15. The juxtaposition of the 13acetyl and 15-bromo groups enabled intramolecular α-arylation to create ring E and give the 131-oxophorbine (H2OP). Subsequent deoxygenation afforded the phorbine H2P. H2OP and H2P constitute the fundamental skeletons of all naturally occurring chlorophylls, with the gem-dimethyl group present to ensure aerobic stability. Comparison of the absorption spectra of four synthetic chlorins illuminates the requisite structural features to give the characteristic green of chlorophyll in solution (Figure 7).289 (A conceptual framework for understanding the origin of the

zinc chlorins lacking imides (598−687 nm; Figures 5 and 6), chlorin-imides (660−714 nm)300 and synthetic bacteriochlorins (709 to nearly 900 nm).348,390 6.2.3. Hydrocarbon Skeleton of Chlorophylls. The Pdmediated α-arylation route for installation of the isocyclic ring was first developed with a 5,10-diarylchlorin (Scheme 67),267 extended to a 10-monoarylchlorin (Scheme 71) and culminated with a chlorin lacking the aryl substituents as shown in Scheme 73.289 Acidic bromination in conjunction with α-arylation enabled preparation of the core molecular skeleton of chlorophylls. Thus, reaction of 8,9-dibromodipyrromethane-1carboxaldehyde (120a-Br8,9, see Scheme 60) with Western half 118 afforded the 13-bromochlorin ZnC-Br13. Demetalation with TFA gave the free base 13-bromochlorin H2C-Br13. Pd6580


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Scheme 73. Synthesis of the Core Skeleton of Chlorophylls

Figure 7. Absorption spectra of synthetic phorbine, chlorins, and 131-oxophorbine versus a naturally derived 131-oxophorbine (normalized at the Bband maxima). The solvent is diethyl ether (Zn-Pheo a) or toluene (all other compounds).289 The λmax (in nm) are as follows: ZnP (402, 601), ZnC (398, 602), ZnC-A13 (412, 628), ZnOP (420, 637), Zn-Pheo a (423, 653). Adapted with permission of The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC (http://pubs.rsc.org/en/Content/ArticleLanding/2011/NJ/ c0nj00652a#!divAbstract).

allows the long-wavelength transition; and second, auxochromes positioned at peripheral sites along the y-axis (e.g., the 3- and 13-positions) to potentiate the Qy transition. While this point perhaps could have been gleaned from studies via semisynthesis or reduction of porphyrins, the distinct spectra provided by the systematic set of compounds shown in Figure 7 provide for stark and unambiguous comparison. The availability of the set of unsubstituted chlorin, phorbine, 131-oxophorbine and other unsubstituted (17-oxochlorin) or sparsely substituted (13-bromochlorin, 13-acetylchlorin) macrocycles enabled an in-depth analysis via single-crystal Xray studies of the structural properties of this family of molecules. Selected results of the structural studies are shown in Figure 8.287 A key parameter of interest is the architecture of the four nitrogen atoms. In this regard, the porphyrin is essentially a square, the chlorin (or oxochlorin) is more kiteshaped, and the phorbine or 131-oxophorbine more resembles a right-angle trapezoid. A comprehensive review of the structural chemistry of chlorophyll and other substituted chlorins has been prepared by Senge and MacGowan.391

intrinsic spectral properties of tetrapyrrole macrocycles is provided by Gouterman’s four-orbital model,346 which is outside the scope of the present review.) Zinc chelates were employed for comparison with the zinc chelate of chlorophyll a (zinc pheophytin a, abbreviated Zn-Pheo a) given the greater chemical stability of zinc versus magnesium chelates. The chlorin lacking any substituents other than the gem-dimethyl group (ZnC) exhibits the long-wavelength (Qy) absorption band at 602 nm. The core skeleton of chlorophyll, namely the phorbine ZnP (which includes the annulated hydrocarbon ring) absorbs at nearly the same wavelength (602 nm) as ZnC albeit with somewhat diminished relative intensity. Installation of a 13-acetyl group to give chlorin ZnC-A13 provides a strong bathochromic and hyperchromic effect (Qy = 627 nm), which is further accentuated by inclusion of the keto moiety to give the 131-oxophorbine ZnOP; the latter exhibits Qy = 637 nm and essentially the same B:Qy band intensity ratio as that of ZnPheo a. The far-reaching conclusion from this work is that the structural features that imbue a chlorophyll with the characteristic “color” are, first, the dihydroporphyrin chromophore, which breaks the symmetry (versus that of the porphyrin) and 6581


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Figure 8. Left panel shows the adjacent-nitrogen distances and angles along the progression from porphyrin to chlorin to phorbine (for porphine, H2C, and H2P). The right panel shows the general changes in macrocycle structure along the series from porphine to chlorin (H2C), chlorin to phorbine (H2P), and phorbine to 131-oxophorbine (H2OP). The gem-dimethyl groups are omitted for clarity. Adapted from ref 287. Copyright 2010, with permission from Elsevier.

Scheme 74. Chlorosomal Bacteriochlorophylls Compared with Chlorophyll a

74).37 Ancillary differences include various hydrocarbon substituents about the perimeter of the macrocycle (including in some cases a 20-methyl group) and hydrocarbon analogues of the phytyl chain. The key structural features believed to underpin the selfassembly of the chlorin macrocycles include the 3-(αhydroxy)ethyl group, the central magnesium, and the 131keto group. Pioneering and extensive research, particularly by the Tamiaki group and also by Balaban, has been devoted to explore the spontaneous formation of chlorosomal-like assemblies.69,394,395 The work by Tamiaki has relied almost exclusively on semisynthesis. To complement the semisynthetic approaches, a de novo synthesis of chlorosomal bacteriochlorophylls was developed (Scheme 75).290 A 3,13-diacetylchlorin was treated to acidic bromination to introduce the bromine

6.2.4. Chlorosomal Bacteriochlorophyll Analogues. In green plants, the antenna chlorophylls (e.g., chlorophyll a) are organized in protein complexes. On the other hand, the antenna chlorophylls of green bacteria largely self-assemble in the absence of a protein superstructure. The self-assembled antenna, which can encompass some 105 pigment molecules, is termed the chlorosome.392,393 The chlorophylls of green bacteria differ from chlorophylls a and b in several key respects and also suffer from the misnomer “bacteriochlorophyll” even though the chromophore is a dihydroporphyrin (i.e., a chlorin) not a tetrahydroporphyrin characteristic of true bacteriochlorins. The key structural differences of the chlorosomal bacteriochlorophylls versus chlorophyll a include (1) an αhydroxyethyl group rather than a vinyl group at the 3-position, and (2) the absence of the 132-carbomethoxy group (Scheme 6582


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Scheme 75. Synthesis of Chlorosomal Bacteriochlorophyll Analogues

Scheme 76. Synthesis of Oxochlorin Analogues of Bacteriochlorophyll c

atom at the 15-position. Subsequent Pd-mediated α-arylation created the 131-oxophorbine. Selective reduction of the 3-acetyl group in the presence of the 13-keto group proved challenging; selectivity eventually was achieved with tert-butylamine·BH3 at room temperature. Subsequent zinc insertion completed the synthesis. The ability to carry distinct 10-substituents (phenyl, mesityl, pentafluorophenyl) through the synthesis was considered of value for possibly altering the stacking and solubility of the macrocycles in a putative chlorosomal-like assembly. Chlorosomal-like assembly processes of ZnOP-He3M10 (He is an abbreviation for α-hydroxyethyl; see the Appendix, "Substituent Abbreviations" section, for nomenclature) were suggested by the characteristic spectral changes upon dissolution at increasing concentration or by use of a only a trace amount of a coordinating solvent (THF) in the nonpolar solvent n-hexane.290 To investigate an assembly wherein the coordinating groups are aligned along the chlorin x-axis instead of the y-axis (i.e., an antioriented chlorosomal model), the synthesis shown in Scheme 76 was carried out. Here, the keto group is provided by a 17-oxochlorin and the α-hydroxyethyl group is located at

the 7-position. The zinc 10-phenylchlorin ZnC-P10 was converted smoothly to the oxochlorin ZnC-P10O17. The interplay of electronic and steric factors in dictating the regioselectivity of bromination of chlorins and oxochlorins has been discussed at length earlier in this section. Thus, treatment of the zinc oxochlorin with NBS gave, as expected, the 20bromo product ZnC-P10O17Br20. On the other hand, the free base oxochlorin H2C-P10O17, like a free base chlorin, gave preferential bromination at the 7-position, affording the chlorin H2C-Br7P10O17. This latter result−for a free base 10-aryloxochlorin−stands in contrast to the result for a free base 5,10diaryl-oxochlorin, which gave a mixture of products with no 6583


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clear preferential site of bromination.263 While a deep understanding of the origin of the regiochemistry for chlorin bromination remains obscure, the operational results are clear: for neutral bromination of the 10-phenyl-substituted macrocycles, the bromination pattern for the free base oxochlorin (7 > 15, 20) is distinct from that of the zinc oxochlorin (20 > 15, 7) and the free base chlorin (15 > 7 > 20). Introduction of the 7-bromo atom in the 17-oxochlorin set the desired substituent pattern, hence the remainder of the synthesis would appear unremarkable given the precedent of the chlorosomal bacteriochlorophyll model shown in Scheme 75. However, attempts to reduce the corresponding 7-acetyl17-oxochlorin resulted in selective reduction to the 17-hydroxy product. A successful recourse was to ketalize the 7-bromo-17oxochlorin, install and reduce the 7-acetyl group to the 7-(αhydroxyethyl) moiety, hydrolyze the ketal protecting group, and insert zinc to finish the synthesis of the zinc chlorin ZnCHe7P10O17 for studies of chlorosomal-like assembly (Scheme 76).290 In summary, the development of the acidic bromination conditions enables regioselective bromination of chlorins in high yield at the 15-position even when sterically hindered and the 7,8-positions are sterically unhindered. This ostensibly small change in reaction conditions has opened the door to effective de novo syntheses of four classes of chlorins, namely realistic mimics of chlorophyll b (i.e., 7-substituted derivatives of the 131-oxophorbine), the hydrocarbon skeleton of chlorophylls (i.e., phorbine), chlorin-imides (previously only available by derivatization of chlorophylls), and bacteriochlorophyll c model compounds. The next section describes chlorins that have been designed and prepared by making extensive use of the synthetic methods described in this and previous sections.

typically are left unsubstituted, given that the resulting mesosubstituted porphyrins can be exploited in rich applications including use as modular building blocks. The meso-substituted porphyrins are conveniently accessible and complement the naturally occurring or naturally derived porphyrins, which largely are β-substituted macrocycles. While it was clear for chlorins that the optical properties in the red region of the spectrum are accentuated by introduction of auxochromes at the β-positions of rings A and C rather than the meso-positions, for completion of the synthetic routes to chlorins, analogous meso-substituted ABCD-chlorins were sought. The introduction of meso-substituents flanking the gemdialkyl position of chlorins via de novo syntheses of chlorins has not been well developed. Battersby reported the route shown in Scheme 77 to install a flanking methyl group. Reductive Scheme 77. Meso-Substituted Hydrodipyrrins

7. SMORGASBORD OF CHLORINS The work described in Schemes 42−76 illustrates the ability to circumambulate the ring with placement of specific substituents at designated sites. Indeed, access to the 2,255,296,298,299 3, 265,290,298,299 5, 254,256,269 7, 277,283,2908,277 10, 254,256,269 12,255,284,299 13,265,286,289,299 15,263,270,283,286,299 17,257,270,299 18,257 and 20263,283 positions has been achieved, as has installation of the isocyclic ring267,289 (and 6-membered imide analogues286,300) characteristic of native chlorophylls. The following sections describe novel chlorin architectures obtained chiefly by application of aforementioned methodology for (1) precursor synthesis, (2) macrocycle formation, and (3) bromination of the chlorin macrocycle under neutral or acidic conditions. In a few cases, however, the fulfillment of synthetic objectives has motivated the development of new methodology. 7.1. ABCD-Chlorins

One of the first synthetic chlorins (H2TPC) was obtained by hydrogenation of H2TPP (Scheme 10). Thus, chlorin H2TPC contains a phenyl group at each meso-position but no substituents at the β-pyrrole sites. One longstanding objective was to develop chemistry for preparing substituted chlorins that is comparable to methods for the preparation of ABCDporphyrins (116, Scheme 41). The latter methodology enables relatively rapid conversion of pyrrole and carbonyl compounds to the corresponding meso-patterned porphyrins.241 Alternatively, in chemistry pioneered by Senge, sparsely substituted porphyrins (including the fully unsubstituted porphyrin, “porphine”) undergo nucleophilic substitution to give ABCDporphyrins.396,397 In both cases, the β-pyrrole positions

alkylation of 166 (a homologue of 8, Scheme 17) installed the methyl group at the α-position of the 2-alkylpyrrole 167, which upon reaction with 10 gave the meso-methyl tetrahydrodipyrrin 168. The resulting tetrahydrodipyrrin (mixture of diastereomers) was employed in syntheses of isobacteriochlorins but not chlorins.172 The availability of meso-cyano dihydrodipyrrinone 169a, constructed via Wittig reaction in the Faktor I synthesis (see Scheme 25), led to studies of reductive transformations. 6584


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Scheme 78. Synthesis of a 20-Substituted Chlorin and ABCD-Chlorins

examination of the spectral parameters of the chlorin wherein the meso-aryl substituent flanks the gem-dimethyl group. The position of the respective B and Qy bands for the 20-phenylsubstituted chlorins (ZnC-P20, H2C−P20) were nearly identical with those for the 15-phenyl-substituted chlorins (ZnC-P15, H2C−P15) where the phenyl group is on the opposite side of the pyrroline ring. Access to the meso-substituted Western half opened the door to the synthesis of ABCD-chlorins (Scheme 78, right panel), where the meso-substituent is destined to occupy the 20position of the chlorin. Thus, reaction of dipyrromethanecarbinol 119a-Br9/OH with the meso-substituted Western half 172 gave the 5,10,20-triarylchlorin ZnC-T5M10P20, again in lower yield (11%) by several-fold versus that of the unsubstituted Western half (Scheme 50). Demetalation and

After lengthy study, conditions were identified for conversion to the aminomethyl (169b) or methyl group (169c, Scheme 77). Related transformations are shown in Scheme 26. The key step in the synthesis of 20-substituted chlorins entailed preparation of a meso-substituted Western half. Thus, reaction of β-nitrostyrene with pyrrole afforded the nitroethylpyrrole (170) substituted with a phenyl group, which is ultimately destined for the 20-position of the chlorin (Scheme 78, left panel). Reaction with mesityl oxide (10) afforded the diastereomeric nitrohexanone-pyrrole 171, which upon reductive cyclization gave the diastereomeric phenyl-substituted Western half 172. Condensation of the latter with bromodipyrromethane-carboxaldehyde 120a-Br9 gave the 20-phenylsubstituted chlorin ZnC-P20, albeit in only 5% yield.294 Regardless, the route demonstrated the scope and enabled 6585


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bromination at the lone remaining meso-site (15-position) gave the 15-bromochlorin H2C-T5M10Br15P20. Subsequent Suzuki coupling with three aryl boronates afforded the corresponding 5,10,15,20-tetraarylchlorins 173a−c. The spectral properties of such ABCD-chlorins (173a−c) are nearly identical to that of H2TPC (Figure 2). The two types of chlorins differ only in the presence of an 18,18-dimethyl versus 18,18-dihydro moiety; hence, the presence of the gem-dimethyl group has an inconsequential effect on the chlorin spectral properties. The nearly identical spectral properties with the presence or absence of the gem-dimethyl group hold for the free base as well as the corresponding zinc chlorins. The availability of the ABCD-chlorin synthesis as well as the other chlorin synthesis methodologies described herein enabled the synthesis of chlorins bearing 0−4 meso-aryl substituents. A set of such structures is shown in Scheme 79.294 The Figure 9. Absorption spectra of free base chlorins with 0−4 meso-aryl substituents in toluene at room temperature: H2C (a, black), H2C-T5 (b, blue), H2C-T5M10 (c, purple), H2C-T5M10P20 (d, green), and 173c (e, red).294 Reproduced by permission of The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC (http://pubs.rsc. org/en/Content/ArticleLanding/2013/PP/c3pp50240f#!divAbstract).

Scheme 79. Chlorins with 0−4 Meso-Aryl Substituents294

meso-aryl substituents) to 4.2 (4 meso-aryl substituents). Analogous spectral changes were observed in the zinc chelates of the same series of chlorins. A further comparison entails “walking a phenyl group around the ring”, in other words, comparing the set of four chlorins each containing a single phenyl substituent (5-phenyl, 10-phenyl, 15-phenyl, or 20phenyl). The Qy band exhibited at most 3 nm variation in position among the four chlorins.294 The relatively weak Qy band of the meso-arylchlorins suggests such chlorins to be of lesser utility for (solar) light harvesting versus 3,13-disubstituted chlorins. On the other hand, the synthesis may be of value, for example, in creating trans-AB architectures wherein substitution is required at the 10- and 20positions, leaving the 5- and 15-positions or any of the βpyrrole positions available for incorporation of other substituents. Regardless, the synthesis shown in Scheme 78 brings chlorin chemistry full circle as it were, given that mesotetraarylchlorins can now be prepared by reduction of a porphyrin (Scheme 10) or by de novo synthesis. 7.2. Oxochlorins with Attached Motifs or Extended Conjugation

The 17-position might be regarded as the Achilles’ heel of the gem-dialkylchlorins given the lability of the methylene unit toward oxidation. On the other hand, the presence of the 17hydroxy group provided a convenient handle for elaboration. Battersby prepared a mixture of oxochlorins by vicinal dihydroxylation of porphyrin 174 followed by pinacol rearrangement to give the resulting oxochlorins; subsequent reduction gave a diastereomeric mixture of 17-hydroxy-18,18dimethylchlorins (175a-OH, 175b-OH, Scheme 80). The mixture ensues despite the nominal C2v symmetry (ignoring NH-positions) of porphyrin 174. Subsequent elaboration provided a panoply of 17-substituted chlorins, illustrating another method for possible installation of the propionate chain in the pyrroline ring, a structural feature of Bonellin (Schemes 14 and 33).175 Elaboration of the oxo/keto moiety of an oxochlorin has been used previously398,399 and remains popular323 although typically beset with isomeric products.

corresponding absorption spectra are shown in Figure 9.294 The addition of each meso-aryl group causes a progressive bathochromic shift in the position of both bands but also (and perhaps surprisingly) a decrease in the relative intensity of longwavelength absorption. Indeed, the chlorin with four aryl substituents exhibits the B and Qy absorption at 420 and 651 nm, respectively, to be compared with 389 and 633 nm for the unsubstituted chlorin H2C. The progressive hypochromicity of the Qy band is given by the increase in IB/IQy ratio from 2.4 (0 6586


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Scheme 80. Elaboration of a Mixture of Oxochlorins

Scheme 81. Elaboration of an Oxochlorin

Reaction with the mesityl/p-tolyl-substituted Eastern half 119aBr9/OH proceeded smoothly to give the spirohexyl-chlorin Zn182, which also was converted by oxidation to the corresponding spirohexyl-oxochlorin Zn-183.257 The oxidation at the 17-methylene position in the presence of the 18,18spirohexyl substituent indicates tolerance toward substituents other than 18,18-dimethyl groups, although the yield was 20%. Use of the spirohexyl group demonstrates the ability to install an alternative to the gem-dimethyl group while maintaining the “dialkyl lock” and thereby precluding adventitious dehydrogenation, yet further studies are required to expand the scope and delineate the accessibility of this site for creation of diverse chlorin architectures. Such chemistry has been explored for analogous dihydrodipyrrin precursors to bacteriochlorins, but with only limited success.401 The demonstration in Scheme 82 notwithstanding, the synthetic manipulation of the gem-dialkyl unit at the 17-position remains a significant lacuna in chlorin chemistry.

The preparation of chlorins with extended conjugation is of great interest to understand the effects of such substituents on spectral and photophysical properties. Montforts employed oxochlorin 1, available from octamethylporphyrin (Scheme 6), as a substrate for installing extended conjugation (Scheme 81).217 Olefination of such sterically hindered ketones via Wittig or Wittig−Horner approaches has proved problematic. Thus, nickel insertion of 1 gave Ni-1 (essential to block the nitrogen atoms), which upon reaction with Lawesson’s reagent gave the nickel thiochlorin Ni-176. Barton olefination via thiadiazoline intermediates was employed with considerable success, affording the ethylidene (Ni-177a), diphenylethylidene (Ni-177b), and fluorenylidene (Ni-177c) derivatives. 7.3. Spiroalkyl Group at the Pyrroline Ring

The gem-dimethyl group has proved invaluable in gaining access to stable synthetic chlorins. A symmetric structural alternative to the gem-dimethyl unit is the spirohexyl unit shown in Scheme 82.257 The synthesis proceeded in the standard way but with use of the elaborated α,β-unsaturated ketone cyclohexylidene-acetone (178)257,400 instead of mesityl oxide (10) with 2-(2-nitroethyl)pyrrole (123, Scheme 45) to give the Michael addition product 179. The reductive cyclization of 179 was carried out under early conditions (Zn, AcOH/EtOH),256 which gave the tetrahydrodipyrrin-Noxide 180; deoxygenation of the latter with TiCl4/LiAlH4 gave the spirohexyl-tetrahydrodipyrrin Western half 181. (Subsequent refinement264 of tetrahydrodipyrrin formation gave rise to a single-step transformation by use of Zn/HCO2NH4.)

7.4. Facially Encumbered Chlorin−Phosphonates

A design strategy for imparting solubility to tetrapyrrole macrocycles entails projection of groups above and below the π-plane. The strategy is designed to suppress cofacial aggregation of the disk-shaped, tetrapyrrole macrocycles. meso-Aryl groups have torsional mobility about the singlebond connection to the tetrapyrrole macrocycle. Even though the corresponding (sp2−sp2 biphenyl-type)402 torsional potential may be shallow, the aryl groups are not coplanar with the tetrapyrrole macrocycle (Figure 10). The hindrance to rotation is greatest for ortho-substituted aryl groups, but even metasubstituted aryl groups present steric obstacles to cofacial aggregation. The groups that have been attached to meso-aryl 6587


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Scheme 82. Synthesis of a Spiroalkyl (Oxo)Chlorin

Figure 10. Illustration of facial encumbrance of a porphyrin by hindered meso-aryl ring rotation. The blue spheres are located at the 2,6-positions of the aryl ring.

Figure 11. Illustration of facial encumbrance of a zinc porphyrin by a meso-swallowtail (i.e., symmetrically branched alkyl) substituent. A Newman projection is shown at left. Adapted from ref 410.

groups project above and below the plane of the tetrapyrrole thereby providing facial encumbrance.410 Polar groups can be placed at the termini of the swallowtails to afford aqueous solubilization.412−414 Both aryl phosphonates and swallowtail phosphonates have been incorporated in chlorins, as described next. 7.4.1. Aryl Phosphonates for Facial Encumbrance. One example of facial encumbrance with chlorins entails use of a 2,6-bis(phosphonomethoxy)phenyl group. Two routes to a chlorin bearing a bis(phosphonomethoxy)phenyl group at the 10-position are shown in Scheme 83.279 The synthesis in the left panel proceeded in the standard fashion. The dipyrromethane 114d was derived from 2,6-dimethoxybenzaldehyde and then was formylated; treatment with dibutyltin dichloride gave the dibutyltin complex of the diformyldipyrromethane but not of the monoformyldipyrromethane or any unreacted dipyrromethane. The diformyldipyrromethane−tin complex was easily removed, thereby facilitating isolation of the monoformyldipyrromethane 120d. Reaction with the tetrahydrodipyrrin Western half 118 led to the 10-(2,6dimethoxyphenyl)chlorin Zn-184. Demetalation with TFA gave 184, and demethylation with BBr3 followed by alkylation with (EtO2)P(O)CH2OTf gave the diethyl-protected bis(phosphono)chlorin 185. Subsequent treatment with trimethylsilyl bromide removed the ethyl groups to give the swallowtail chlorin 186. The synthesis also was carried out with preinstallation of the two phosphono groups (Scheme 83, right panel).279 The requisite benzaldehyde 187 was formed and converted to dipyrromethane 114e in high yield. The inability to formylate the delicate dipyrromethane 114e led to reversal in the choice

groups of porphyrins include 3,5-di-tert-butyl groups403,404 and a variety of substituents at the 2,6-positions.98,405,406 Representative examples of the latter include methyl (e.g., tetramesitylporphyrin),314 methoxy,315 benzyloxy,407 methoxymethyl,408 (N-pyridinium)methyl,408 and ethynyl;409 more elaborate examples include perylenyl-ethynyl groups.406 An example that does not employ an aryl group instead relies on a symmetrically branched alkyl (termed “swallowtail”) group at the meso-position; an example is the 7-tridecyl group (Figure 11).410,411 Spectroscopic studies show that the C−H group is coplanar with the tetrapyrrole plane; hence, the two heptyl 6588


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Scheme 83. Two Routes to Chlorin−Phosphonates

of the Western half and Eastern half functional groups. The Western half (e.g., 118) typically contains an unsubstituted pyrrole and α-methylpyrroline groups (both nucleophilic), while the Eastern half (e.g., 120-Br9) is substituted with αformyl and α-bromo groups (both electrophilic). Here, the Western half (188)269 was substituted with α-formylpyrrole (electrophilic) and α-methylpyrroline (nucleophilic) groups whereas the Eastern half (114e-Br9) contained an unsubstituted pyrrole (nucleophilic) and an α-bromopyrrole (electrophilic). This reversal from the typical strategy for chlorin formation was employed previously.269,277 Thus, dipyrromethane 114e was treated to 1 equiv of NBS to give an expected mixture of the non-, mono-, and dibrominated

products. The mixture was used in situ on considering (1) that only the monobromodipyrromethane (114e-Br9) could serve as a functional Eastern half, and (2) the practical difficulty of separating the mixture. The reaction with the Western half (9-formyltetrahydrodipyrrin, 188) under standard chlorinforming conditions gave the diethyl-protected bis(phosphono)chlorin Zn-189 in a satisfactory 42% yield from dipyrromethane 114e. The two routes illustrate the versatility of the general route to chlorins for accommodating substituents. The aqueous solubility of the resulting bis(phosphono)chlorins with mesoaryl or meso-swallowtail groups provided further examples of facial encumbrance as a design tactic for solubilization in desired media. 6589


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and wavelength tunability has hardly been explored for tetrapyrrole macrocycles.418 While filling this nexus may require considerable work, the challenge to doing so resides perhaps as much in molecular design as in synthetic development and implementation. 7.4.2. Swallowtail Phosphonates for Facial Encumbrance. Swallowtail groups have been used to impart solubility to porphyrins (e.g., Figure 11)410−414,419,420 and peryleneimides.421 A similar approach was pursued with chlorins to impart aqueous solubility (Scheme 85). The swallowtail

Chlorin 185 was derivatized to install a bioconjugatable handle (Scheme 84).299 Thus, bromination under neutral Scheme 84. Water-Soluble Bioconjugatable Chlorina

Scheme 85. Swallowtail Chlorin−Phosphonatea

a

Reprinted with permission from ref 279. Copyright 2008 American Chemical Society.

a

Reprinted with permission from ref 299. Copyright 2015 World Scientific Publishing Co. Pte. Ltd.

substituent was introduced via dipyrromethane Eastern half 120e-Br9, employing benzyl protection of the terminal hydroxy substituents. Chlorin formation proceeded in the standard way with Western half 118, thereby illustrating applicability with a branched meso-alkyl substituent. Following formation of zinc chlorin Zn-194a, the benzyl groups were removed with concomitant demetalation to give free base chlorin 194b. Replacement of the resulting hydroxy groups with terminal bromides gave 194c, which in turn enabled installation of dimethyl phosphonate groups by Michaelis-Arbuzov reaction422 with trimethyl phosphite. The methyl ester units of 195 were finally cleaved with trimethylsilyl bromide to give the free phosphonic acid group of the chlorin−swallowtail phosphonate

conditions gave the 15-bromo-10-arylchlorin 190 in 96% yield. Suzuki coupling of 190 with arylboronic ester 191 under standard conditions employed for porphyrins,415,416 chlorins263 and bacteriochlorins417 afforded chlorin 192 in 50% yield. Saponification with KOH followed by deprotection of the ethyl phosphonate groups led to the water-soluble bioconjugatable chlorin 193. In summary, the approach shown in Schemes 83 and 84 offers a rational route to a chlorin bearing a facially encumbering bis(phosphonate) group and a single bioconjugatable tether. The nexus of water-solubility, bioconjugatability, 6590


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Scheme 86. Synthesis of Amphiphilic Chlorins292

196. All of the facially encumbered chlorin−phosphonates (186, 193, 196) were soluble in water.279,299

chelation of palladium by the tetrahydrodipyrrin. The resulting chlorin bears a single substituent (other than the gem-dimethyl group), the phenylethynyl group at the 3-position. Subsequent 15-bromination (neutral conditions) gave versatile chlorin H2C-PE3Br15, which upon Suzuki coupling enabled introduction of the benzoic acid or pyridyl moiety. The pyridyl group was then quaternized with methyl iodide. Zinc insertion constituted the final step of the synthesis to give chlorins ZnC-PE3BA15 and ZnC-PE3MePy15. The 5,15-disubstituted chlorins also were prepared in a rational manner. The 5-p-tolylchlorin H2C-T5 (derived from 118 and 119b-Br9)269 was subjected to 15-bromination (neutral conditions) to give bromochlorin277 H2C-T5Br15. Subsequent Suzuki coupling was employed in similar manner to install the benzoic acid or pyridyl moiety.292 Quaternization of the pyridine unit and zincation of both chlorins gave the two amphiphilic 5,15-disubstituted chlorins ZnC-T5BA15 and ZnCT5MePy15. The 5,15-disubstituted zinc chlorin exhibits the long-wavelength absorption maximum at 610 nm (benzoic

7.5. Amphiphilic Chlorins

Four amphiphilic chlorins were prepared for studies of selfassembly in an organized environment, such as at the aqueouslipid interface (Scheme 86).292 The pattern of substitution includes a hydrophobic group at the 3- or 5-position and a polar group at the 15-position. The synthesis of 3,15disubstituted chlorins relied on condensation of phenylethyne-substituted Western half 197 and the unsubstituted Eastern half 120a-Br9 to give the 3-(phenylethynyl)chlorin H2C-PE3. The phenylethyne-substituted Western half was prepared by Sonogashira coupling with the 3-bromo-Western half 152-Ts followed by deprotection of the N-p-tosyl-Western half 197-Ts. Two points concerning the Pd-mediated ethynylation warrant mention: (1) copper cocatalysis can be employed given that the copper can be removed prior to chlorin formation (where copper insertion must be assiduously avoided), and (2) the N-p-tosyl protecting group prevents 6591


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Scheme 87. Assorted Amphiphilic Chlorins

by hydrogenation of the corresponding porphyrin (200);427 and (3) a chlorin derived by semisynthesis from the porphyrin heme (201).428 The chlorins in Scheme 87 that contain a gem-dimethyl group include the following: (1) the naturally occurring Bonellin; (2) 111f, prepared by Jacobi243 (see Schemes 37-40 for other examples); (3) 202, which bears an isophthalic acid moiety designed for incorporation in solar cells;275,276 (4) 203a, which bears a single benzoic acid unit (10-position) and a p-tolyl group (5-position);299 and (5) 203b, which bears a single phosphonic acid unit (10-position) and a p-tolyl group (5-position).261 Chlorin 202 was prepared from H2C-T5M10 by 15-bromination (neutral conditions) followed by Sonogashira coupling. Chlorin 203a was prepared from the parent protected (TMS-ethyl) ester by cleavage in the presence of KF.299 Chlorin 203b was prepared from the parent protected (di-tertbutyl) ester by cleavage with TMSCl and TEA.261 The chlorins in this set prepared by de novo synthesis (111f, 202, 203a,b)

acid) or 614 nm (pyridinium) whereas the 3-phenylethynyl-15substituted chlorins each absorb at 633 nm (benzoic acid or pyridinium), highlighting the wavelength tunability of the synthetic chlorins via the auxochromic effect of the 3phenylethynyl moiety. All four synthetic chlorins were incorporated in micellar media and characterized spectroscopically.292 The four amphiphilic chlorins shown in Scheme 86 are additions to a sizable family of amphiphilic chlorins that have been prepared over the years. A representative selection is shown in Scheme 87. The amphiphilic chlorins that lack gemdimethyl groups include the following: (1) derivatives of chlorophylls such as pheophorbide a (obtained upon acidic demagnesiation and hydrolysis of the phytyl ester),65 chlorin e6423 and p6424 (derived by saponification, opening of the isocyclic ring, and oxidation), a chlorin-imide (198) derived from chlorophyll a,425 and the semicarbazone of chlorophyll b and Girard’s T reagent (199);426 (2) a tetraarylchlorin prepared 6592


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7.6.2. 3-Substituted Chlorins. A set of 3-substituted chlorins (Zn-205a-c) bearing electron-rich groups (N,Ndimethylamino, methoxy, methylthio) was prepared to examine the effects of these groups on spectral properties (Scheme 88).

again illustrate the molecular control afforded by synthesis, albeit requiring greater investment of resources than those chlorins obtained from naturally occurring macrocycles. 7.6. Chlorins with Extended Conjugation

7.6.1. 3,13-Diethynylchlorins. A collection of 3,13disubstituted chlorins was prepared and individual members examined for the spectral effects of auxochromes (e.g., vinyl,265 acetyl,265 formyl,274 TIPS-ethynyl,265 phenylethynyl278,280). The synthesis relied on derivatization of 3,13-dibromo-10mesitylchlorin H2C-Br3,13M10.265 The analogous 3,13-dibromo10-p-tolylchlorin H2C-Br3,13T10 was derivatized via the Sonogashira reaction to install more extended conjugated moieties via the ethyne linker. The resulting 3,13-bis(ethynyl)chlorins (204) are shown in Table 3 along with the peak position of the long-wavelength absorption band.299

Scheme 88. 3-Substituted Chlorins

The synthesis relied on Pd-mediated derivatization of the 3bromo-10-mesitylchlorin ZnC-Br3M10 (Scheme 57). In each case the spectral effects were marginal, however, particularly compared with those imparted by electron-withdrawing groups.299 7.6.3. Chlorin−Chalcones. In seeking ways to bathochromically shift the absorption of the chlorins, 3- or 13acetylchlorins were employed in aldol condensations with aldehydes, given that the former were available by de novo synthesis and the latter are readily available commercially. The aldol condensation was carried out under microwave conditions, with repetition of 20 min stages of heating until the starting material was consumed. In this manner, the 13acetylchlorin H2C-A13M10 was derivatized with benzaldehyde, cinnamaldehyde, or all-trans-retinal to give the corresponding chlorin−chalcone 206a−c in yield of 92%, 90%, or 53%, respectively (Scheme 89).282 The term “chalcone” (chalkos, copper ore) was chosen by Kostanecki and Tambor at the turn of the 20th century to describe the colored condensation product of benzaldehyde and acetophenone (i.e., benzylideneacetophenone) in keeping with the names of other colored aryl ketones such as flavone and xanthone.429 The enone benzylideneacetophenone is the parent member of the family of chalcones.430 The literature concerning chalcones is now vast given the importance of this motif in plant biochemistry (polyketides, flavonoids, anthocyanines) and medicinal chemistry.431 The long-wavelength absorption band of the chlorin− chalcones 206a−c is shifted only slightly versus that of the parent 13-acetylchlorin H2C-A13M10, but the absorption is increased substantially in the 420−500 nm region.297 The simplicity of the synthetic chemistry and the resulting spectral properties suggests the chalcone route may offer significant attractions in chlorin-based light-harvesting architectures.

Table 3. Spectral Properties of 3,13-Diethynyl-Chlorins

7.7. 7-Substituted Chlorins

a

Chlorophyll b differs from chlorophyll a in the composition of one functional group: a 7-formyl group rather than a 7-methyl group (Scheme 1). A route to 7-substituted chlorins was developed that relied on placement of a bromine atom at the appropriate location in the Eastern half (Scheme 90).277 To accommodate the 2-bromo group in the dipyrromethane (destined to be the 7-bromochlorin) required shifting the pyrrole-carboxaldehyde functional group from the 1-position of the Eastern half (e.g., 120-Br9, Scheme 50) to the 9-position of the Western half (188). The same strategy was employed in Scheme 83. The challenge then resided in constructing the 2bromodipyrromethane equipped for chlorin formation.

Prepared by deprotection of the TMS-analogue (not shown). 6593


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Scheme 89. Chlorin−Chalcone Syntheses

Scheme 90. 7-Substituted Chlorins to Mimic Chlorophyll b

Two approaches were investigated. Both began with bromination of 2-p-toluoylpyrrole (207) to give the 4bromopyrrole derivative 208. One approach employed αdecylthio protected pyrrole 209; the decyl group blocks the pyrrole 2-position without altering the preferred reaction of the incoming electrophile at the pyrrole 5-position (most α-pyrrole protecting groups are deactivating and direct electrophilic substitution to the β′-position).432 Reaction of 2-(decylthio)-

pyrrole (209) with the 4-bromopyrrole-2-carbinol (derived from 208) gave the desired dipyrromethane 210. Alternatively, reaction of the 4-bromopyrrole-2-carbinol with excess pyrrole gave the monobromodipyrromethane 211 (compare with 154 in Scheme 60). Treatment of 211 with NBS gave reaction preferentially at the α-position of the unsubstituted pyrrole, affording dipyrromethane 211-Br9. The two dipyrromethanes each bear a bromine atom destined for the chlorin 7-position and a displaceable group at the dipyrromethane 9-position (decylthio for 210, bromo for 211-Br9). 6594


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Scheme 91. Regioselective Bromination of a Western Half−Dialkylboron Complex (Left)296 and Examples of Related Complexes (Right)303,304,433

7.8. Chlorophyll f Analogues

Reaction of each dipyrromethane (210, 211-Br9) with the formyl-Western half 188 was successful in each case, but the αbromo-substituted dipyrromethane 211-Br9 gave >5-times greater yield of chlorin than that with the decylthio-dipyrromethane 210. The resulting 7-bromochlorin ZnC-Br7T10 was a viable substrate for introduction of several auxochromes (acetyl, formyl, and TIPS-ethynyl), affording analogues of chlorophyll b for spectroscopic examination. The rational synthesis of 7substituted chlorins via use of bromo-Eastern half precursors complements the approach wherein 10-aryl-substituted chlorins are treated to regioselective bromination (Schemes 68, 71, and 76).

The recently discovered chlorophyll f absorbs at longer wavelength than any other naturally occurring chlorophyll and is now known to contain the unusual combination of 2formyl and 3-vinyl groups (Scheme 2).40−42 The previous record holder for long-wavelength absorption among native chlorophylls, chlorophyll d, contains 3-formyl and 2-methyl groups. By contrast concerning substituent placement, chlorophyll b contains 7-formyl, 3-vinyl and 2-methyl groups. Clearly, the placement of conjugative groups at distinct sites provides a potent means to tune spectral and photophysical properties. Earlier syntheses and spectroscopic studies of chlorins containing carbonyl groups (acetyl and/or formyl) 6595


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Scheme 92. Routes to Monoformyl-Chlorins

had been carried out at the 3-position265,274,286,290,291 but not the 2-position (Schemes 57 and 58; Figure 5). The availability of the 2-formylchlorin lacking any other substituents was sought for comparison with the analogous 3-formylchlorin, thereby enabling fundamental studies to perhaps understand the origin of the spectral and photophysical properties of the more highly substituted chlorophyll f.296 The synthesis of 2- and 3-formyl chlorins is shown in Scheme 91.296 Retrosynthetic analysis for a 2-formylchlorin led to the corresponding 7-bromo-tetrahydrodipyrrin Western half 213. The origin of the methodology employed to prepare the required 7-bromotetrahydrodipyrrin has a long if not tortuous history, here summarized in brief. (1) Dialkylboron complexation was initially found to facilitate handling of 1-acyldipyrromethanes (Schemes 43 and 91, right panel, A and C), rendering poorly behaved foam-like substances into readily crystalline solids, thereby enabling laborious chromatography to be replaced by simple crystallization.303,304 The boron−dipyrromethane complex contains a covalent B−N bond and a dative B−O bond embedded in a 5-membered ring. (2) Analogous results were obtained with meso-imidazolyldipyrromethanes, which contain one covalent and one dative B−N bond embedded in a 6-membered ring (Scheme 91, right panel, B and C).433 (3) Given the similar structural features in the hydrodipyrrins (e.g., 118) and the imidazolyldipyrromethanes,

similar complexation of the hydrodipyrrins with dialkylboron was examined (Scheme 91, left panel).296 Dibutylboroncomplexation with the tetrahydrodipyrrin 118 afforded the corresponding complex 118-BBu2, but no noticeable improvement in purification was achieved. (4) The availability of the complex 118-BBu2 was exploited to explore any behavioral distinctions upon electrophilic substitution versus the unsubstituted species. Electrophilic bromination of 118-BBu2 gave three detectable products, with the 7-bromo product 213-BBu2 dominant, accompanied by smaller amounts of the 7,8-dibromo product 214-BBu2 and the 8-bromo product 152-BBu2 (Scheme 91).296 No α-brominated tetrahydrodipyrrin was detected, which was considered remarkable given that in the absence of complexation, the α-bromination of 118 proceeded in high yield to give 212. The effect of the dibutylboron unit in altering the position of substitution was not restricted to bromination, as Vilsmeier formylation of 118-BBu2 gave the 7-, 8-, and 9- monoformyl isomers in 10:1:1 ratio (not shown). Moreover, the regiochemical outcome for electrophilic substitution of the dibutylboron−tetrahydrodipyrrin (7-position) is in contrast with that of the dibutylboron−dihydrodipyrrin (7- and 8positions) and that of difluoroboron−5-aryldipyrrin dyes (8position).296 While the 7-formyltetrahydrodipyrrin proved ineffective in chlorin-forming reactions, the 7-bromotetrahy6596


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Table 4. Single-Site Positional Access for Chlorinsa

drodipyrrin was employed instead. Thus, 213-BBu2 (readily isolated in 53% yield) was decomplexed in refluxing methanol that contained K3PO4. The resulting 7-bromotetrahydrodipyrrin 213 was condensed in the usual way to give the 7bromochlorin, which upon Pd-mediated formylation gave the desired 2-formylchlorin H2C−F2.296 The 3-formylchlorin counterpart H2C−F3 was prepared similarly by reaction of the 8-bromo-substituted Western half 152 and subsequent derivatization (Scheme 91, bottom left).296 The absorption spectra of the 2-formylchlorin H2C-F2, 3formylchlorin H2C-F3, and the unsubstituted chlorin H2C reveal subtle distinctions.296 The 3-formylchlorin H2C-F3 exhibits B and Qy bands at 416 and 664 nm, respectively, to be compared with that of the 2-formylchlorin H2C-F2 (404, 654 nm) and the unsubstituted chlorin H2C (389, 634 nm). Similar spectral trends were observed for the zinc chelates of this series of formylchlorins.298 The slightly larger bathochromic shift and hyperchromic effect of the 3-formylchlorin versus the 2-formylchlorin provide data for comparison with native chlorophylls such as chlorophyll f, which contains the 2formyl-3-vinyl substituent pattern (Scheme 2). A deeper understanding of the origin of the substituent effects that engender the spectral properties of chlorophyll f likely will require synthesis of chlorins bearing combinations of multiple auxochromes, including not only the 2-formyl and 3-vinyl groups (and vice versa) but also the isocyclic ring.

site

scheme

substituent (refs)

none 2 3

50 91 91 86 b 50 b NDc NDc 50,52 b b b 83 85 61 61,73 68 55 NDc 78

none265,269 formyl296 formyl296 phenylethynyl292 phenyl294 p-tolyl269 3,5-di-tert-butylphenyl269

5

7 8 10

12 13 15 17 18 20

7.9. Walking the Formyl Group Around the Ring

One objective of recent research has been to understand the effects of specific groups at designated sites about the perimeter of the chlorin macrocycle. The potent effect of the formyl group as an auxochrome (Scheme 2, Figure 1) prompted the synthesis and spectroscopic characterization of a family of formylchlorins. Chlorins with the formyl group at position 2,296 3,296 5,274 7,277 13,274 or 15274 are shown in Scheme 92. The key precursor wherein the position for formyl installation is set is shown in each case. The 5-formyl group was installed by use of a 1,3-dioxacyclohex-2-yl substituent (an isopropylidene acetal) attached to the Eastern half 119c-Br9, which was treated to acidic hydrolysis following chlorin formation, ultimately yielding ZnC-F5P10. It warrants emphasis that there is at present no other means to introduce a formyl group at the 5-position.274 All other formylchlorins were prepared by Pd-mediated carbonylation with the corresponding bromochlorin to give the 2-formylchlorin ZnC-F2 and 3-formylchlorin ZnC-F3 (Scheme 91), 7-formylchlorin ZnC-F7T10 (Scheme 90), 13-formylchlorins ZnC-M10F13 and ZnC-T5M10F13 (Schemes 57 and 67 show the bromochlorin precursors), and 15-formylchlorin (ZnCT5M10F15; Scheme 65). Other formylchlorins in this general family also were prepared from the bromochlorin and include (1) 3,13-diformylchlorin ZnC-F3,13M10 (Schemes 57 and 58) and (2) 7-formyl-10-mesityl-131-oxophorbine ZnOP-F7M10 (Scheme 71). The spectral effects are profound, as the 7formylchlorin ZnC-F7T10 absorbs at 598 nm,277 whereas the 13-formylchlorin ZnC-M10F13 absorbs at 634 nm274 (the nature of the 10-aryl group has an insignificant effect in this regard).

phenyl269 mesityl269 p-tolyl277 pentyl277 2,6-dialkoxyaryl279 branched alkyl279 acetyl284 acetyl289 phenyl270 oxo269 phenyl294

a

Other than the gem-dimethyl group at position 18. M = Zn and/or H,H in most cases. bDemonstrated but not shown here. cNot demonstrated.

substituted Eastern half (blue square), substituted Western half (red circle), or via derivatization of an intact chlorin (magenta cross). Also provided is the scheme number where the structures and synthesis route are displayed. Inspection of Table 4 shows that the phenyl group has been walked around the four meso-positions of the chlorin macrocycle. The 7- and 8-positions are noticeable lacunae. Substitution at such sites has been achieved, albeit in chlorins that bear additional substituents. Such routes include bromination of chlorins that bear 10- or 5-aryl groups, respectively (Schemes 68, 69, 71, and 76); use of an aryl-substituted Eastern half (Scheme 56); and use of a bromo-substituted Eastern half (Scheme 90). The latter two routes appear amenable for preparing chlorins bearing a single 7- or 8-substituent although this capability has not yet been demonstrated. 7.11. Isotopically Substituted Chlorins

Isotopically substituted chlorins have been prepared over the years for diverse purposes, including to elucidate biosynthetic pathways and to label macrocycles for spectroscopic studies (for an overview, see ref 288). Labeling of tetrapyrroles by biosynthetic procedures is, to date, a blunt hammer that typically gives a rich distribution of isotopomers and isotopologues. Traditional syntheses of chlorin isotopologues with skeletal atoms replaced with isotopes have been restricted to routes to isotopically substituted tetraphenylporphyrin or octaethylporphyrin, which upon diimide reduction give the corresponding chlorin. Examples include meso-tetraphenylchlorin (H2TPC) containing four meso-13C atoms,434 and

7.10. Single-Site Substitution of Chlorins

The demonstrated installation of a single substituent (other than the gem-dimethyl group at position 18) at a designated site is summarized in Table 4. The code superposed on the chlorin macrocycle indicates substituent installation via a 6597


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octaethylchlorin (H2OEC) containing four 15N atoms.435−437 Other examples of chlorin isotopologues include those with incorporation of deuterium in the meso-tetraphenylchlorin family (e.g., β-d8 and phenyl-d20)434 or in the octaethylchlorin family (e.g., meso-d4354,435,438,439 5,10-d2,354,436−438 and 15,20d2354,438,440). A single 13C atom was sought at a given site in one constituent of a chlorin−chlorin dyad so that the hyperfine interactions in the electron paramagnetic resonance spectrum of the singly oxidized dyad could be used as a clock of the ground-state hole/electron-transfer process. The choices for the location of the 13C atom included the α-positions wherein significant hole/electron density resides (4/11-, 6/9-, and 16/ 19-), of which the 16/19-positions exhibited highest density, and among these the 19-position appeared most tractable synthetically. The 13C isotope was introduced via the standard synthesis, employing 13 CH 3 NO 2 for formation of the tetrahydrodipyrrin Western half 216 as shown in Scheme 93.288 The synthesis proceeded routinely upon use of the

synthesis and utilization of chlorins with site-specific isotopic incorporation has hardly been explored. 7.12. Building Blocks

The methodology described herein has been exploited to prepare a wide variety of chlorins. Chlorins that contain 1−3 reactive functional groups are particularly valuable building blocks. The reactive functional groups include those for Pdmediated coupling reactions (I, Br, and ethyne);343,344,441 various such chlorins are displayed throughout this review. Additional notable chlorin building blocks are shown in Scheme 94. The set includes the following: (1) chlorins with a single halo or ethyne (217,292 218,272 219,442 220,442 221,256 and 222256); (2) oxochlorins with a single halo or ethyne (223,259 224258); (3) chlorins with two halo or two ethynes (225,284 226284); (4) chlorins with one halo and one ethyne (227,284 228299); and (5) a chlorin with two bromo substituents and one ethyne (229278). Neutral bromination of H2C-T5 afforded chlorin 217 (also termed H2C-T5Br15, Scheme 86), and 218 was obtained similarly upon neutral bromination of H2C-M10 followed by Sonogashira coupling with TMS-acetylene. Chlorin 219 was prepared by reaction of an 8,9-dibromodipyrromethane bearing a 5-p-tolyl group (120f-Br8,9;442 analogue of 120c-Br8,9, Scheme 57) with Western half 118; subsequent Sonogashira coupling led to ethynylchlorin 220. Chlorins 221 and 222 were prepared with a suitably diaryl-substituted Eastern half 119Br9/OH and Western half 118 (Scheme 50); oxochlorins 223 and 224 were prepared likewise followed by oxidation of the 17-methylene unit (Scheme 54). Dibromochlorin 225 was prepared from bromo-Western half 152 and bromo-Eastern half 120a-Br8,9 (Schemes 57, 60, and 61); subsequent Sonogashira coupling gave diethynylchlorin 226. Ethynyl/ bromochlorin 227 was prepared from TIPS-ethynyl Western half 153 and bromo-Eastern half 120a-Br8,9 (Schemes 57 and 61). Iodophenyl/ethynylphenylchlorin 228 is an analogue of 147 (Scheme 56) and was prepared in similar fashion, where the iodophenyl and ethynylphenyl functional groups were installed upon formation of the pyrrole precursors.299 Finally, chlorin 229 was prepared from bromo-Western half 152 and Eastern half278 120g-Br8,9 (analogue of 120c-Br8,9, Scheme 57); the Eastern half contained a 4-(TIPS-ethynyl)phenyl group at the dipyrromethane meso-position and the requisite 8,9-dibromo and 1-formyl groups. Another set of chlorin building blocks is suited for amidation reactions. The chlorins contain amino and/or carboxylic acid functional groups (Scheme 95).443,444 The set is less fleshed out than that with halo/ethyne functionalities but holds much promise particularly for applications in the life sciences. The set includes chlorin 230,443 231,444 and 232.444 A subset of the various chlorin building blocks described in this and preceding sections has been employed in the rational synthesis of dyads, examples of which are shown in the next section.

Scheme 93. Retrosynthesis for a Chlorin Bearing a Single 13 C Atom

7.13. Chlorin Dyads 9

13

The synthesis of dyads containing one or two tetrapyrroles has played a central role in fundamental studies in artificial photosynthesis and molecular photonics, yet most such constructs are built around porphyrins445−447 rather than chlorins.448,449 The availability of gem-dimethylchlorin building blocks has enabled the rational synthesis of a variety of molecular architectures that contain one or two chlorins. Each of the examples shown in Scheme 96 contains a single chlorin.

Eastern half 119d-Br /OH to afford the C-substituted chlorin building block 215. The chlorin building block was incorporated in a dyad, as described in the next two subsections. The de novo synthesis enabled the placement of a single isotope at a designated site, and thus complements the labeling methods used previously.288 This synthetic strategy has been deployed recently to prepare diverse bacteriochlorins with pairwise site-specific isotopic substitution,322 yet the broader 6598


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Scheme 94. Diverse Halo/Ethynyl-Chlorin Building Blocks (and Selected Precursors)

Scheme 95. Diverse Amino/Carboxy-Chlorin Building Blocks

The dyads that contain an ethyne linker were prepared via Pd-

than the perylene-diimide. Perylene-monoimide oxochlorin (Dyad-1, prepared from bromo-oxochlorin 224) is an energytransfer model compound,258 whereas members of the perylene-diimide oxochlorin series (Dyad-2a-c, prepared from

mediated Sonogashira coupling chemistry. The perylene dyes have absorption complementary to that of chlorins. The perylene-monoimide is less electron-deficient 6599


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Scheme 96. Dyads from One Chlorin Building Block

ethynyl-oxochlorin 223) are potent light-driven chargeseparation units.259 Dyad-2c, for example, exhibits fast forward excited-state electron transfer (150 nm. Moreover, the emission lifetime of the lanthanide is >100 ns, enabling temporal as well as spectral selectivity (Scheme 97).444 Dyad-8 and Dyad-9 were prepared from chlorin 231 and 232, respectively (Scheme 95).

The dyads shown in Scheme 98 elegantly demonstrate the synthetic diversification enabled by the approaches developed in the Montforts group (Schemes 27−33). Each dyad contains a chlorin and an attached redox-active unit for studies of lightinduced electron-transfer reactions relevant to artificial photosynthesis. The redox-active units include a naphthoquinone (Dyad-10a,b),210 fullerene (Dyad-11),211 or anthraquinone (Dyad-12, Dyad-13).213 The naphthoquinone-containing dyad was prepared by incorporation of naphthoquinone reactant 71d into linear tetrahydrobilatriene Ni-86, which subsequently underwent cyclization (Scheme 31). In the case of the fullerene (or anthraquinone), sulfone-substituted linear tetrahydrobilatriene Zn-93 underwent extrusion of sulfur dioxide in the presence of C60 (or naphthoquinone) to give both adduct attachment and ring closure (as shown for dimethyl acetylenedicarboxylate in Scheme 32). Dyad-13 contains an anthraquinone joined via an amide linker and was prepared by condensation of a chlorin building block containing an N6601


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Scheme 99. Dyads from Two Chlorin Building Blocks

ethynylchlorin 220. Both the butadiynyl- and ethynyl-linked dyads show altered absorption spectra compared with those of the monomeric constituents.442 In summary, the smorgasbord displayed in this section illustrates the richness of current synthetic methodology for preparing and tailoring gem-dialkylchlorins. Synthetic access to each position about the perimeter of the chlorin macrocycle has been achieved, numerous chlorin building blocks have been prepared that bear one or more functional groups in specific patterns, and diverse molecular architectures containing gemdialkylchlorins have been created. A subset of gem-dimethylchlorin building blocks has been used in the rational synthesis of chlorin-containing dyads. Chlorin dyads of a generation ago were built entirely around semisynthetic chlorophyll derivatives448,449 or necessarily relied on statistical reactions for creation of the chlorin.94,118 In this regard, the gemdimethylchlorin-containing dyads prepared to date−while necessarily limited in number and variety due to the recent advent of the chlorin building blocks−herald a substantial advance in molecular design.

hydroxysuccinimido-activated ester (Zn-92, Scheme 31) with 2-aminomethylanthraquinone. Architectures that contain two chlorins were prepared from Montforts-type building blocks (Scheme 99). The dyads are distinguished by the molecular architecture (distance, orientation) of the constituents with respect to each other as well as the nature of the intervening linker. Examples include two chlorins joined via an amide linkage (Dyad-14)215 and two chlorins joined via ethynyl groups to a biphenylene spacer (Dyad-15).219 The former was prepared by condensation of amino-chlorin Zn-91 and N-hydroxysuccinimidocarbonylchlorin Zn-92 (Scheme 31). The latter was prepared by use of the two iodochlorins Zn-90e and Zn-90f (Scheme 31). Tetrapyrrole macrocycles joined via ethynyl groups are known to have considerably more conformational motion than might be suggested by the linear display of the triple bond; the motion originates from the large degree of “s” character of the carbons of the alkyne.451 Architectures that contain two chlorins also were prepared (Scheme 100). Several dyads (Dyad-16−20) contain an ethyne linkage and were prepared via Sonogashira coupling reactions of an ethynylchlorin and a halochlorin, whereas Dyad-21 contains a butadiyne linkage and was prepared via dimerization of an ethynylchlorin. Chlorin dyads Dyad-16a-c (prepared from 221 and 222, Scheme 94) and oxochlorin dyads Dyad17a-c (prepared from 140d and 140e, Scheme 55) containing a zinc and a free base macrocycle (joined by a diphenylethyne linker) were employed for studies of excited-state energy transfer, whereas the corresponding all zinc dimers were employed for studies of ground-state hole hopping.260 The chlorin Dyad-18 bearing a single site of 13C substitution was derived by coupling of ethynylchlorin 215 (Scheme 93) with iodophenylchlorin 221 (Scheme 94).288 The oxochlorins joined via a phenylethynyl linker (Dyad-19a,b) were prepared from 10-(4-ethynylphenyl)oxochlorin 140e (Scheme 55) and 20-bromooxochlorin ZnC-T5M10O17Br20 (Scheme 64). The phenylethynyl linker results in more extensive electronic coupling than a diphenylethyne linker (Dyad-17a-c); moreover, the ethynyl group typically functions as an auxochrome on the macrocycle to which it is attached.262,263 The ethynyl-linked chlorin dyad (Dyad-20) was prepared from building blocks bromochlorin 219 and ethynylchlorin 220 (Scheme 94). The butadiynyl-linked dyads containing free base (Dyad-21a) or zinc (Dyad-21b) constituents were prepared by dimerization of

8. OUTLOOK The tapestry of chlorin chemistry is composed of at least five major threads−identification of natural chlorophylls and chlorins, total syntheses of natural chlorophylls, semisynthesis of chlorophyll derivatives, derivatization of porphyrins to make chlorins, and de novo syntheses of gem-dialkylchlorins. The discovery of gem-dialkylchlorins in the late 1970s motivated the invention of new synthetic methods and de novo synthetic routes, the scope of which now encompasses the naturally occurring gem-dialkylchlorins as well as a far larger and increasingly diverse collection of non-natural chlorins. The present review has aimed to provide a comprehensive treatment of the past 35 years of research concerning the synthesis of gem-dialkylchlorins, place such research in the broader context of nearly two centuries of research on chlorophylls, and highlight the suitability of gem-dialkylchlorins as readily accessible and versatile synthetic surrogates for chlorophylls. The development of methodology, at least in tetrapyrrole chemistry, is an endeavor that seems to advance significantly on the time scale of a generation. The routes developed by Montforts and by Battersby beginning in the 1980s were clearly enabled by (1) the landmark syntheses of vitamin B12 (and hydrodipyrrin constituents contained therein) pioneered in the 6602


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Scheme 100. Dyads from Two Chlorin Building Blocks

1960s by Woodward225,226 and by Eschenmoser;227 (2) earlier fundamental studies of pyrroline chemistry by Todd and coworkers;180−194 and (3) the robust foundation of dipyrrin (dipyrromethene) chemistry and general strategies for porphyrin formation established by Hans Fischer125−128 a generation even earlier. In tracing the broad arc of chlorin synthesis methodology over the past 3/4 of a century, several distinct themes are evident. (1) An early approach that employed hydrogenation of (or addition to) porphyrins remains prevalent. The simplicity of this approach is attractive only when the formation of isomeric products is not possible, or when the target study can be performed indifferently to the presence of such isomers. (2) The de novo synthesis of target tetrapyrrole macrocycles in its earliest guises, as in the Fischer era of porphyrin

chemistry125−127 or even in Woodward’s synthesis of chlorin e6 trimethyl ester,64 relied heavily on condensation chemistry. Almost all substituents (or robust latent analogues thereof) were installed prior to macrocycle construction, or rather demanding conditions were employed to introduce substituents to the intact macrocycle. The comments of Kenner and coworkers from 1967 are illustrative:452 “The preparation of porphyrins bearing vinyl substituents (e.g., protoporphyrin IX, porphyrin-a) presents a number of problems, chief among which is the necessity of introducing such a labile group at a fairly late stage of the synthesis. Two main methods have been described in the literature, viz., (i) acetylation of a β-free porphyrin followed by reduction and dehydration (as in Fischer’s classical synthesis of haemin) and (ii) Hofmann degradation of a β-aminoethyl side chain.” Lwowski, a coworker with Woodward,59,64 upon reviewing both the 6603


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role of oxidation state of the precursors (e.g., Western half = dihydrodipyrrin or tetrahydrodipyrrin; Eastern half = dipyrrin or dipyrromethane) in reactivity and macrocycle formation. Examples of capabilities that would be well received but have not been developed include (1) methods for selective derivatization of sparsely substituted chlorins at the 5- and 10-positions and (2) tactics that enable a stable pyrroline ring to be constructed/installed on an intact macrocycle in a highly regioselective manner without the creation of stereoisomers. While pyrroline ring construction is integral to de novo chlorin synthesis, the other three rings are pyrroles. In this regard, ongoing advances in methodology to construct substituted pyrroles453−456 are expected to expand the scope of accessible chlorins with desired substitution patterns. The assessment of what remains to be done is informed with granular definition by previously encountered challenges yet undoubtedly will be influenced generically as the scientific understanding of the natural world deepens. Chlorophyll f, for example, was unknown five years ago,457 and only in the past two decades or so has the nature of the divinyl chlorophylls and their role in aquatic photosynthesis become apparent. The question of “why chlorophyll” has been posed and addressed more than once;458,459 the issue of “why plants are green”460,461 or at least a modern variant concerning whether viable exoplanets would be green462 remains under discussion; and the naturalist’s perspective of “Earth−a little-known planet”463 reflects how little is thought to be known about extant biodiversity. All of this taken together would suggest that Nature has many secrets yet to give up concerning the physics, chemistry, biology, ecology, and evolution of chlorins. The synthetic advances sparked by the discovery of gemdialkylchlorins in the late 1970s have enriched our understanding of some of the physicochemical properties of the chlorophyll-like “great ring” (a felicitous term apparently first used by Linstead324). The methodology for working with tetrapyrrole macrocycles has changed profoundly since Woodward’s iconic synthesis of chlorin e6 trimethyl ester. Scheer’s pungent observation78 in 1978 “in spite of the straightforward reactions now available to prepare the common model chlorins like [H2OEC] and [H2TPC], there is still no generally applicable set of conditions to obtain chlorins with sensitive substituents” can now surely be revised on the basis of the methodological advances described herein. Given the generational nature of methodology, perhaps the intellectual framework and advances described in this review will provide a foundation for the invention of powerful new routes in the future, where the magic wizardry of synthesis enables even more facile creation of chlorins and chlorin-containing architectures to obtain a deeper understanding of our green world.

attempted Fischer synthesis and the successful Woodward synthesis, similarly commented about “the special problems associated with the reactivity of the vinyl group in position 2” and pointed out that one of Woodward’s four main premises on which the formal synthesis of chlorophyll a was based was that “the 2-vinyl group should be formed only at a late stage in the synthesis because of its high reactivity.”15 Now a bromo-chlorin can be converted via Heck coupling to the vinyl-chlorin (or any number of other auxochrome-substituted chlorins) under mild conditions with broad functional group tolerance. Indeed, the de novo approach at present augments the prior classical chemistry with (a) preinstallation of halogens or (b) regioselective halogenation of the chlorin macrocycle followed by organometallic coupling reactions to install the desired peripheral substituents. The strategy of pre- or postinstallation of halogens followed by Pd-mediated coupling, while only in extensive use for less than two decades, is exceptionally fecund for gaining access to diverse chlorin target compounds. Such an approach also has profoundly altered the synthetic chemistry of porphyrins and phthalocyanines.441 The ability to derivatize the intact tetrapyrrole macrocycle by organometallic coupling procedures enables late-stage diversification of building blocks. By contrast, Woodward’s landmark synthesis of chlorin e6 trimethyl ester64 employed metals in only 5 of the 46 steps, and these were solely for hydrogenation and acylation, not organometallic coupling processes. (3) The de novo synthesis of gem-dialkylchlorins complements semisynthesis approaches that begin with natural chlorophylls; while the latter may be more expedient, the former provides greater versatility of substituent type and placement. Moroever, the gem-dimethyl group in particular affords chlorins lacking stereocenters in the pyrroline ring. Access to each site about the perimeter of the chlorin macrocycle is now available via de novo synthesis approaches. The synthetic methods described herein to prepare gemdialkylchlorins provide a platform technology for diverse studies. The studies to date in artificial photosynthesis include understanding how substituents alter spectral properties, understanding how to cover the red region of the spectrum, probing issues concerning the flow of energy among multiple chromophores, and examining interfacial photoinduced electron-transfer reactions. The studies in photomedicine include use as therapeutic agents and/or as diagnostic markers. Much has been learned by preparation and study of the synthetic gem-dialkylchlorins. While presentation of the resulting insights is beyond the scope of this review, one point that bears on molecular design warrants statement: the increasing number of meso-aryl groups in a chlorin causes a bathochromic shift of both the B and Qy bands but a relative hypochromic shift of the Qy band. In other words, meso-aryl groups to some extent render the chlorin more like a porphyrin.294 This trend is observed in Figure 9. Accordingly, there is great value in the de novo synthesis of chlorins that lack the full complement of meso-aryl groups (as accrues upon derivatization of mesotetraarylporphyrins). While much has been learned about chlorins via synthesis, much remains to be done. The synthetic advances to date are thrown into sharp relief by unresolved limitations and many facets of chlorin chemistry that are poorly understood or undeveloped. The most apparent limitations include low yields of macrocycle formation and lengthy syntheses. Examples of issues that are poorly understood include (1) the nature of the intermediates accompanying macrocycle formation and (2) the

APPENDIX The nomenclature employed herein is well suited for describing chlorins yet is at odds with several CAS and IUPAC rules. The rationale for the departure from such rules is outlined first. Then the terminology for labeling and numbering chlorins and chlorin precursors is delineated. The rationale for a fixed nomenclature regardless of the “2 + 2” route (Eastern + Western vs Northern + Southern) is described. The section finishes with review of (standard) terminology for heterocycles relevant to chlorins including pyrroles, pyrrolines, and bilin intermediates, as well as abbreviations commonly employed in synthetic chemistry. 6604


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Scheme 101. Chlorin and Phorbine Nomenclaturea

a

Numbering of the α-carbons is largely omitted for visual clarity.

Scheme 102. Abbreviations Used Herein for Chlorins and Substituents

Traditional vs Index Nomenclature

also would force the N−H protons on the lowest numbered rings, which corresponds to the less stable tautomer of the chlorin464 (the chlorin shown at left in Scheme 101 is from ref 3, Figure 7 in TP-4.1). Accordingly, the numbering system adopted herein (1) coheres with the chlorophyll numbering tradition, (2) places the NH units consistent with the most stable chlorin tautomer, (3) is invariant with appended substituents, and (4) is invariant with structural modification. The consequence of the latter two points is that regardless of what substituents are appended (e.g., a carboxylic acid) or framework alterations occur (e.g., installation of the isocyclic ring converting a chlorin to a phorbine), the core numbering system is fixed. Given that “the only real requirement for conventional nomenclature is that it provide unambiguous and understandable names for the audience being addressed”465 this departure from index nomenclature is justified. Accordingly, the structures formally derived from the parent macrocycle have been named 17,18-dihydro-18,18-dimethylporphyrins (Scheme 101).255

The nomenclature concerning synthetic chlorins understandably relies very heavily on trivial names for derivatives and degradation products of chlorophyll. In the chemistry of chlorophylls, a universal convention is to display the reduced ring in the lower left corner.3 The rings are then labeled in clockwise fashion beginning in the upper left corner; the reduced ring is thus labeled D (Scheme 1). The numbering system is fixed accordingly such that the β-positions of ring A take 2,3 and so on until those in ring D are numbered 17,18. No such convention exists in the literature concerning nonchlorophyll chlorins. For clarity in comparison across a very broad range of syntheses, all chlorins presented herein are displayed in the same, consistent, chlorophyll-like format; substituent positions are numbered accordingly. By contrast, IUPAC nomenclature would begin the numbering system such that the β-positions of the reduced ring take 2,3 and so on.3 Not only does this system disregard the thoughtful considerations developed over generations in the chlorophyll field, but IUPAC nomenclature 6605


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Scheme 103. Retrosynthetic Analysis for de Novo Chlorin Syntheses

BBu2; Scheme 91), or combinations thereof (e.g., 119a-Br8,9; Scheme 67). The use of combination names is well established in the chlorin field as illustrated by descriptive names such as H2OECd4 (Scheme 63). The terminology described in Scheme 102 has been employed for most of the synthetic chlorins in sections 4.4−7.12, and is particularly suited to identify specific substituents and their locations in sparsely substituted chlorins. The compounds numbered 1−233 are typically those where common names are absent and/or calling out such substituent patterns is unnecessary. While perhaps no method of nomenclature is perfect, the mixed use of the three labeling schemes reflects the multiple facets examined in this review. A subtle feature of chlorin nomenclature is described next, which entails fixing the gem-dimethyl group at the 18-position.

Similarly, the ring system for phorbine is recognized by IUPAC and CAS,466 yet both the IUPAC and CAS definitions for phorbine adhere to numbering systems that are at odds with the widely accepted numbering system for porphyrins and chlorins.267 (An earlier nomenclature system for phorbine relied on Fischer’s numbering system.467) The IUPAC and CAS definitions for phorbine are shown in Scheme 101. In this review, the phorbine ring system shown as the parent hydrocarbon has been adopted for naming purposes but with use of the more directly understandable chlorophyll-derived numbering system (Scheme 101 at right). We now turn to a convenient shorthand for labeling chlorins and phorbines with their appended substituents. Substituent Abbreviations

While traditional chlorin nomenclature has attractive features, fixed rings A−D and fixed numbering system, the panoply of names for macrocycles with ostensibly capricious substituent patterns can be uninformative and even offputting particularly to non-aficionados. The abbreviations used in the present review meld the traditional chlorin numbering scheme with labels for specific substituents. This approach has a long history, beginning with use of AMe and PMe to denote methyl acetate (AMe) and methyl propionate (PMe), respectively, which are typically present in native tetrapyrroles (e.g., Schemes 22, 24−26, and 80; Table 1). Such labels have been supplemented with those employed for diverse synthetic chlorins, as shown in Scheme 102. The substituents employed with the sparsely substituted, non-natural chlorins appear beginning in Scheme 50 and through the remainder of the review. The fictive chlorin shown in the lower right corner of Scheme 102 illustrates the utility of the substituent terminology. In many respects, this shorthand is similar to CAS index nomenclature albeit in conjunction with the traditional (and superior) chlorophyll numbering system. Thus, the present review chiefly employs three main labeling schemes: (1) traditional names and abbreviations for well known compounds (e.g., Chl a, H2TPC), (2) labels specific for the gem-dimethylchlorin skeleton with a given pattern of substituents (Scheme 102), and (3) numbers for distinctive starting materials, intermediates, and products (e.g., 1−233) with, where appropriate, accompanying alphabetical labels (e.g., 71a−j; Schemes 30−33), substituent descriptors (e.g., 118-

Distinct Disconnections

Two disconnections for the chlorin macrocycle are shown in Scheme 103. Both build the chlorin macrocycle from dipyrrolic fragments. In the illustration, the fragments are shown (1) in the same oxidation state as present in the chlorin, (2) as the free base, (3) and without specification of the nature of peripheral substituents or a−d joining groups, each pair of which must include one carbon (which together give rise to the linking meso-carbons). In the Western half + Eastern half route, the a−b and d−c groups are joined whereas in the Northern half + Southern half route, the c−b and d−a groups are joined. In the absence of defining substituents in a given ring, such as ring D (e.g., the gem-dimethyl group), the two routes differ only by 90° rotation, whereupon the Southern and Western halves are equivalent, as are the Northern and Eastern halves (Scheme 103, left panel). Here, the gem-dialkyl group is arbitrarily located at position 18 of the chlorin regardless of other substituents in the macrocycle. On that basis, the two routes (Western half + Eastern half; Northern half + Southern half) are distinct because the Southern and Western halves are not equivalent (Scheme 103, right panel). Said differently, in the Western half the gem-dimethyl group is at the 3-position of the dihydrodipyrrin, whereas in the Southern half the gem-dimethyl group is at the 2-position of the dihydrodipyrrin. Given the consistent placement of the pyrroline ring in the ring-D position, and the arbitrary fixed location of a gem-dialkyl group (if any) at position 18, many of the displays of structures in the 6606


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Scheme 104. Nomenclature of Heterocyclic Constituents

Scheme 105. Bilin Nomenclature and Oxidation Levels versus a Chlorin

prior sections have been recast versus those in the original publications. Indeed, the display of Faktor I (Scheme 15) as well as siroheme, heme d, and Tolyporphin A (Scheme 16) are reoriented here versus those typically employed in the scientific literature. The advantages of doing so include systematic comparisons of syntheses and the effects of substituents located

at particular sites (relative to a constant substitution pattern in the pyrroline ring). Linear Heterocycles

The remainder of the terminology employed herein is standard for the heterocyclic field as shown in Scheme 104. Pyrrole, Δ1pyrroline, Δ3-pyrroline, and pyrrolidine share a common 6607


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Biography

numbering system, as do the four diheterocyclic systems. Unsaturation of the dipyrromethane gives the dipyrrin (formerly dipyrromethene).3 Progressive saturation of the dipyrrin gives the 2,3-dihydrodipyrrin and the 2,3,4,5tetrahydrodipyrrin. Note that a dipyrromethane and a dihydrodipyrrin are at the same oxidation level and, in the absence of any gem-dialkyl locks, are potential tautomers (Scheme 35). Numerous routes have been developed to create the chlorin macrocycle. The routes differ in the oxidation level of the reactants (e.g., dihydrodipyrrin or tetrahydrodipyrrin; dipyrromethane or dipyrrin), nature of the end groups, modular assembly (e.g., “2 + 2”, “3 + 1”), and disconnection (Western− Eastern, Northern−Southern). The distinct oxidation level of various bilin reactants256 is shown in Scheme 105. As a general rule, the development of routes to the pyrroline-containing moiety (Western or Southern half) has entailed considerably more work than that for the all-pyrrole containing species (Eastern or Northern half)although the identif ication of suitable reactant pairs to form chlorins has entailed a commensurate challenge. The disparity stems from the large body of prior work concerning dipyrromethane (or dipyrrin) species for synthesis of porphyrins, versus the less-explored chemistry for creating pyrroline-containing reactants.

Jonathan S. Lindsey (b. 1956) grew up in Rockport, Indiana and did his undergraduate studies at Indiana University in Bloomington (1974−1978) where he worked with Profs. Frank R. N. Gurd and Lawrence K. Montgomery. His graduate and postdoctoral studies (1978−1984) were at The Rockefeller University with Prof. David C. Mauzerall. He was on the faculty at Carnegie Mellon University for 12 years before joining North Carolina State University in 1996. His passions concern the science and creation of tetrapyrrole macrocycles and their roles in photosynthesis and diverse photochemical phenomena.

Abbreviations

AgOTf aq 9-BBN-OTf BBu2-OTf Bn Boc dba DCC DDQ DIEA DBN DBU DMF i-Pr mCPBA Mes NBS rt t-Bu or tBu TFA THF TIPS TMS TosMIC p-TsOH·H2O p-TsNHNH2 Xantphos

silver(I) triflate aqueous 9-borabicylo[3.3.1]nonane triflate dibutylboron triflate benzyl tert-butoxycarbonyl dibenzylideneacetone N,N-dicyclohexylcarbodiimide 2,3-dichloro-5,6-dicyano-1,4-benzoquinone N,N-diisopropylethylamine 1,5-diazabicyclo[4.3.0]non-5-ene 1,8-diazabicyclo[5.4.0]undec-7-ene N,N-dimethylformamide isopropyl meta-chloroperoxybenzoic acid mesityl (2,4,6-trimethylphenyl) N-bromosuccinimide room temperature tert-butyl trifluoroacetic acid tetrahydrofuran triisopropylsilyl trimethylsilyl p-toluenesulfonylmethyl isocyanide p-toluenesulfonic acid monohydrate p-toluenesulfonyl hydrazide 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

ACKNOWLEDGMENTS The author wishes to express deep gratitude to the many individuals who contributed to the work concerning gemdialkylchlorins from the author’s group (1995−2014) that has been described in sections of this review. First, to the many coworkers (graduate students, postdoctoral fellows, and visiting scholars) cited herein who worked tirelessly in developing the chemistry. Second, to Drs. David Bocian and Dewey Holten, whose longstanding interests in fundamental chlorophyll spectroscopy and photophysics have driven the development and application of new synthetic routes to chlorins. Third, to Dr. David Mauzerall, in whose lab the author, as a graduate student many years ago, synthesized chlorins118 (by diimidemediated hydrogenation of porphyrins) and from across the hall gazed enviously at illuminated suspensions of Chlorella vulgaris, greening naturally with comparative ease. Finally, to Dr. Masahiko Taniguchi and Ms. Ann Norcross for assistance in manuscript preparation. Funding agencies played an essential enabling role, including initially the NIH (GM36238) and subsequently the Division of Chemical Sciences, Geosciences, and Biosciences, Office of Basic Energy Sciences of the U.S. Department of Energy (DE-FG02-96ER14632). REFERENCES (1) Smith, J. H. C.; Benitez, A. Chlorophylls: Analysis in Plant Materials. In Modern Methods of Plant Analysis; Paech, K., Tracey, M. V., Eds.; Springer-Verlag: Berlin, 1955; Vol. IV, pp 142−196. (2) Dixon, J. M.; Taniguchi, M.; Lindsey, J. S. PhotochemCAD 2: A Refined Program with Accompanying Spectral Databases for Photochemical Calculations. Photochem. Photobiol. 2005, 81, 212−213. (3) Moss, G. P. Nomenclature of Tetrapyrroles. Pure Appl. Chem. 1987, 59, 779−832. (4) Pelletier; Caventou. Sur La Matière Verte Des Feuilles. J. Pharm. Sci. Accessories 1817, 3, 486−491. (5) Pelletier; Caventou. Sur La Matière Verte Des Feuilles. Ann. Chim. Phys. 1818, 9, 194−196.

AUTHOR INFORMATION Corresponding Author

*Phone: 919-515-6406. Fax: 919-513-2830. E-mail: jlindsey@ ncsu.edu. Notes

The author declares no competing financial interest. 6608


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