Synthetic strategies toward hetidine and hetisine-type diterpenoid alkaloids.

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REVIEW

Cite this: Org. Biomol. Chem., 2014, 12, 1846

Received 19th December 2013, Accepted 31st January 2014 DOI: 10.1039/c3ob42541j www.rsc.org/obc

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Synthetic strategies toward hetidine and hetisine-type diterpenoid alkaloids Amy M. Hamlin, Jessica K. Kisunzu and Richmond Sarpong* Within the diterpenoid alkaloid family of natural products, the hetidine and hetisine structural types have been the targets of a number of synthetic studies. Various strategies have been pursued to access the azacyclic moiety of these natural products as well as the characteristic [2.2.2] bicyclic structural motif. This perspective article examines the different disconnections and approaches that have been applied to the synthesis of these natural products to date.

University of California, Berkeley, Department of Chemistry, Berkeley, CA 94704, USA. E-mail: [email protected]; Fax: +1 510 642 8369; Tel: +1 510 643 6312

of all three categories have been studied with respect to their biological activity, synthesis, and medicinal properties, and many of these findings have been reviewed previously.1–3 Of the three classes, synthetic studies toward the C20-diterpenoid alkaloids are of added importance due to their role as biosynthetic precursors to the related structural classes,4 as well as the C20-specific biological activity that has been found for these congeners.5 Several compounds in the C20-atisane and kaurane structural classes (see Fig. 1) have been synthesized.6 The close architectural relationships between the atisanes, kauranes and the hetidine and hetisine-type diterpenoid alkaloids makes the existing syntheses significant as a starting point for the synthesis of related structural classes. Given that even small structural differences have an impact on biological activity,7 the ability to easily access multiple structural frameworks would be beneficial and facilitate further biological

Amy Hamlin was born and raised in the suburbs of Detroit, MI. She received her B.S. in chemistry from the University of Detroit Mercy in 2009 where she performed undergraduate research with Prof. Matthew Mio. That same year she began her doctoral studies with Prof. Richmond Sarpong at the University of California, Berkeley where her research focuses on the synthesis of hetidine and hetisineAmy M. Hamlin type C20-diterpenoid alkaloids. Upon completion of her PhD in 2014, she will be joining Ash Stevens (Riverview, MI) as a senior scientist in process development.

Jessica Kisunzu was raised in Cary, IL. She received her B.S. in chemistry from Southern Adventist University in 2008. After studying abroad for a year at the Campus Adventiste du Salève in France, Jessica began her doctoral studies in 2009 with Prof. Richmond Sarpong at the University of California, Berkeley. Her research has focused on the synthesis of C20-diterpenoid alkaloids, specifically those Jessica K. Kisunzu containing the hetisine-type framework. Upon completion of her PhD in 2014, she will be moving to conduct postdoctoral research with Prof. Helma Wennemers at ETH Zurich.

Introduction C20-diterpenoid alkaloids For many years, plants belonging to the Ranunculaceae family have been used for a variety of purposes—from medicine to poison. Meticulous extractions, structure elucidation through chemical conversion and derivatization, and pharmacological studies have identified many diterpenoid alkaloids as the principle components of the plants responsible in large part for their bioactivity. Efforts to study and synthesize the diterpenoid alkaloids have thus been increasing steadily. Natural products in this family are classified as either C18-, C19-, or C20diterpenoid alkaloids based on their core structure. Members

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Organic & Biomolecular Chemistry

Fig. 1 Representative core for two C20-diterpenoid alkaloid structural classes and sub-types of interest.

study. This perspective article examines the strategies toward the syntheses of C20-diterpenoid alkaloids possessing a hetisine or hetidine core (see Fig. 1). Degradation studies An analysis of compounds in the C20-diterpenoid alkaloid family reveals many potential opportunities for structural interconversion, and it is conceivable that one type of structural framework could be converted to another if the reactivity of these densely functionalized molecules was better understood. Seminal work in this area was accomplished by Okamoto and coworkers.8,9 Starting from kobusine (1, Scheme 1), a hetisine-type alkaloid, they investigated the cleavage and reformation of the C14–C20 and N–C6 bonds, as these are key bonds that establish the relationship between the hetidine, hetisine, and atisine cores. Subjection of kobusine to reducing conditions (sodium in n-propanol) followed by acylation gave acetate 2

Richmond Sarpong was born in Ghana, West Africa in 1974. He received his B.A. degree from Macalester College (St. Paul, Minnesota, USA) in 1995. During that time he carried out research with Professor Rebecca Hoye. He conducted his Ph.D. research with Professor Martin F. Semmelhack at Princeton University (Princeton, New Jersey, USA) and completed his degree in 2000. After three and a half Richmond Sarpong years as a postdoctoral fellow with Professor Brian Stoltz at Caltech (Pasadena, California, USA) he began his independent career at the University of California, Berkeley where he is currently an Associate Professor. His current research interests include the development of new strategies for the synthesis of complex natural products including the diterpenoid alkaloids.


Review

(Scheme 1). Treatment of 2 with phenyl chloroformate in o-dichlorobenzene at reflux delivered carbamate 3 in 90% yield, where the N–C6 bond has been cleaved. Interestingly, it was observed that hydrolysis of the carbamoyl group resulted in reformation of the N–C6 bond (to yield 2) when the C6–C7 double bond was in place as in 3. Therefore, reduction of the C6–C7 double bond was necessary in order to achieve further manipulation. This observation is of note because forming the strained azabicycle of the hetisines from the hetidines is a significant challenge. Synthetic planning could therefore benefit from mimicking this type of innate reactivity. From carbamate 3, sequential reductions of the tri- and disubstituted double bonds resulted in a fully saturated framework (not shown). Removal of the acetyl group proceeded without complication, and cleavage of the carbamate was accomplished in two steps to arrive at amine 4. In order to cleave the C14–C20 bond (see 4 for numbering) to arrive at the atisine-type core, polycycle 4 was first converted to the chloramine, then treated with sodium methoxide in methanol at reflux to deliver chloroimine 6 in 38% yield. Among the compounds isolated from the crude mixture was 5 in which the N–C6 bond was reformed, presumably under a Hoffman–Löffler– Freytag-type mechanism. This transformation again provides insight into the importance of proximity and potential reactivity of key atoms that could be exploited in the synthesis of hetisine-type natural products (i.e., 4→5). Imine 6 could then be reduced to the secondary amine (not shown) or treated with activated magnesium to reform the C14–C20 bond (4). Through these chemical conversion studies, Okamoto and coworkers were able to learn about the intrinsic reactivity of kobusinederived caged structures that may be applied to the synthesis of related hetisine and hetidine-type diterpenoid alkaloids. Model studies toward the hetidine/hetisine core Retrosynthetic analysis of the C20-diterpenoid alkaloid core often focuses on deconstructing two structural units: the nitrogen-containing rings and the all-carbon [2.2.2] bicycle containing an exomethylene on the right hand portion (Fig. 1, bold). In most of the existing studies and syntheses of hetidine and hetisine-type alkaloids, the azabicycle is often constructed first, with the [2.2.2] bicycle formed at a later stage. This overview of the synthetic work toward these compounds therefore begins with a discussion of the strategies employed to form the azabicycle, followed by C–C bond formation to construct the [2.2.2] bicycle, and completion of the core. The general tetracyclic structure 7 (see Fig. 2) was identified by Pelletier10 as a versatile intermediate that was used in various early synthetic studies toward diterpenoid alkaloids in the atisane or kaurane class.11–15 While this seminal work was not directed specifically at the hetidine or hetisine frameworks, much of the work that followed from other investigators adopted similar intermediates (e.g., 8) as targets (vide infra). Bickelhaupt One of the earliest reported model studies toward the hetisinetype diterpenoid alkaloids was reported by van der Baan and

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Review


Scheme 1

Degradation and chemical conversion studies by Okamoto and coworkers.

Scheme 2

Bickelhaupt tricycle formation via a cyanopyridinediol.

Bickelhaupt in 1975.16 In studying the reactivity of cyanopyridinediols such as 11 (Scheme 2), which they could easily prepare from ethyl cyclohexanone-2-carboxylate (9) and malononitrile or cyanoacetamide (10),17 they observed that alkylation of these diols (e.g., with allyl bromide) occurred exclusively at the carbon atom bearing the cyano group to give compounds such as 12. Protection of the imide nitrogen followed by Cope rearrangement delivered imide 13 in which the quaternary center at C10 was now in place. Bromohydroxylation of the terminal olefin group and subsequent protection of the secondary hydroxyl as a tetrahydropyran ether gave 14, which was now poised for cyclization. Treatment of 14 with NaH in DMF gave the cyclized product (15) via initial deprotonation of the vinyl nitrile. Imide 16, bearing an additional carbonyl group, was accessed by THP-cleavage and oxidation. This compound maps closely onto 8 (Fig. 2), and contains the 2 C–N bonds present in the hetidine structural core, with a functional handle at C6, should the hetisine-type alkaloids be of interest as targets.

Fig. 2

Key tricyclic intermediates.

Kwak began with vinylogous amide 17, which was used to access 1,5-diene 18 in 3 steps (Scheme 3). Irradiation of amide 18 gave “crossed” photoadduct 19 in good yield. Heating 19 in ethanol followed by the addition of catalytic pyridinium p-toluenesulfonate delivered tricycle 21 via sequential retroMannich/Mannich reactions. This azabicyclic[3.2.1]octanone has the same decalin system as the Bickelhaupt model system (i.e., 16), but with the pyrrolidine ring in place rather than the piperidine (compare 16 to 21). Superimposed onto the hetisine core, the C–N bonds resident in 21 correspond to the N–C6 and N–C20 bonds of the hetisines.

Winkler In 2001, the Winkler group reported a methodology that they posited could be used to access a different portion of the hetisine azabicycle.18 To demonstrate their strategy, Winkler and

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Mander Mander and coworkers investigated several model systems of the hetisine and hetidine structural cores. Herein we highlight


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Scheme 3

Winkler’s photochemical approach.

two—one that contains the desired N–C20 bond (forming a piperidine ring) and one that has the N–C6 bond forged (to access the requisite pyrrolidine ring).19,20 The first of these sequences was published by Williams and Mander in 200321,22 and utilized a silver(I)-promoted bridgehead arylation. Starting from azabicycle 22, which was accessed via a double Mannich reaction, they were able install the piperidine ring at the onset (Scheme 4). The addition of aryl acetylide 23 to 22 provided access to the desired diastereomer of the adduct (24) in 64% yield. From this adduct, they were able to access cyclization precursor 25 in 3 steps. At this point, numerous silver(I) salts and solvents were screened to effect bridgehead arylation. Ultimately, silver 2,4,6-trinitrobenzenesulfonate (26) in nitromethane emerged as the optimal combination for delivering arylated product 27. This substrate contains the 6–6–6 tricycle present in the natural product core and is analogous to the tetracyclic intermediate utilized by Pelletier (for example see 7, Fig. 2).

Scheme 4

Review

Several years later, Mander and Hutt reported another approach to the hetisine structural core, this time focusing on the installation of the pyrrolidine ring containing the N–C6 bond.23 Key to this sequence was a reductive acylation as well as a Lewis acid-catalyzed 1,6-addition of a carbamate to form the N–C6 bond. Enone 28 was accessed in 8 steps from commercial starting materials using known procedures (Scheme 5). At this juncture, reducing metal conditions were employed to reduce the enone, followed by quenching with methyl cyanoformate, to afford a β-ketoester (not shown). Subsequent protection of the β-ketoester gave MOM enol ether 29. Vinylogous carbonate 29 was reduced to methylene alcohol 30 using lithium and NH3 with complete diastereoselectivity. From this point, Mander and Hutt were able to install the requisite nitrogen atom in 3 steps through oxime formation and subsequent dehydration to the nitrile (31). Enone 32 was accessed in a 6-step sequence, which left them poised to test a conjugate addition to form the C–N bond. While basic and strongly acidic conditions resulted in no reaction or decomposition of 32, it was found that milder Lewis acidic conditions— namely, FeCl3 and TMSCl—delivered the desired pyrrolidine (33), albeit in 21% yield. In this way, Hutt and Mander were able to demonstrate the utility of a 1,6-conjugate addition strategy, as well as highlight the use of methyl cyanoformate in the context of a reductive acylation that provided a critical substituent for the natural product scaffold. Okamoto In 1985, Shibanuma and Okamoto reported an approach to the hetisine core with kobusine (1) as the specific target.24 Starting from tetrahydrophenanthol (34, Scheme 6), they were able to access amine 35 in 7 steps. This compound was used to access the azabicycle. The first key step was the formation of the N–C6 bond. This was accomplished by treatment of amine 35 with lead tetraacetate, which resulted in aziridine 36. Without purification, aziridine 36 could be treated with benzyl chloroformate to effect a regioselective ring opening to provide

Williams and Mander’s approach.


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Review


Scheme 5

Hutt and Mander’s approach.

Scheme 6

Shibanuma and Okamoto’s HLF approach to the azabicycle.

benzyl carbamate 37. Reduction of chlorocarbamate 37 with RANEY® Ni gave secondary amine 38. At this stage, Shibanuma envisioned forming the N–C19 bond (see 38) using a Hofmann–Löffler–Freytag (HLF) reaction. The HLF transformation is often used to form 5-membered azacycles via an N-halo intermediate. Treatment of amine 38 with NCS provided the requisite N-chloro compound (not shown) that was then submitted to photoirradiation under acidic conditions (400 W high-pressure Hg lamp, trifluoroacetic acid) to provide 40 via alkyl chloride intermediate 39. Sarpong In 2013, the Sarpong group reported a synthesis of the hetidine core that could potentially be used to also access hetisine targets.25 They proposed that the hetisine core could arise from the hetidine core through a formal dehydrogenative C–N bond forming reaction (Fig. 3) as suggested by the degradation studies published by Okamoto (see 4→5, Scheme 1).8,9 Within the hetidine framework, the Sarpong group recognized a fused 6–7–6 carbocycle (see bolded bonds, Fig. 3) and

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Fig. 3

Proposed formation of hetisines from hetidines.

proposed that tetracycle 41, which is representative of the hetidine core, could be accessed from cycloheptadiene 42 (Scheme 7). Cycloheptadiene 42 could arise from an appropriately functionalized indenyl alkyne (43) using a gallium(III)catalyzed cycloisomerization reaction. The cycloisomerization of indenyl alkyne 43 (Scheme 8) proceeded in the presence of gallium(III) iodide to provide 6–7–6 fused carbocycle 42 in 89% yield. Cycloheptadiene 42 was elaborated to Boc-protected amino alcohol 44 over a sequence of 7 steps. Exposure of 44 to thionyl chloride effected cyclization to form the piperidine ring (45). Demethylation of methoxy arene 45 and subsequent oxidative dearomatization of the resulting phenol with PIFA ([bis(trifluoroacetoxy)iodo]benzene)


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Review

particular scaffolds and the strategies that can be employed for C–N bond formation.


Total syntheses: nominine

Scheme 7

Retrosynthetic analysis of the Sarpong intermediate.

provided 46, where the Boc carbamate engaged as the nucleophile. To form the last two C–C bonds and complete the [2.2.2] bicycle, a Michael addition followed by an aldol reaction was enlisted. Thus, the allyl group was converted to an aldehyde (not shown) that cyclized through a Michael addition reaction to provide 47. Finally, reduction of enone 47 to a ketone (not shown) and an aldol reaction formed the final C–C bond and provided the hetidine framework (41). The Sarpong group proposes to use this intermediate to access natural products of both the hetidine and hetisine-type. As previously stated, structural classifications of the diterpenoid alkaloids are partially guided by the presence or absence of specific C–N bonds. Particularly pertinent to this review, the N–C6 bond differentiates the hetidine and hetisine cores. Therefore, structural analyses and methodologies that address the formation of the azabicycle in different ways are important to understanding the reactivity and conformations of these compounds. Although the strategies and model studies presented thus far have not led to completed natural product syntheses, they provide insight into the reactivity of these

Scheme 8

Muratake and Natsume. Muratake and Natsume reported their first approach toward the natural product nominine (48) in 2002.26 In this first approach, they sought to use a strategy similar to a previous approach by Shibanuma and Okamoto where the azabicycle is constructed early in the synthesis. They envisioned accessing the [2.2.2] bicycle at a late stage from functional handles present on hexacyclic compound 49 (Scheme 9) where all 3 bonds to the basic amine are already installed. Azabicycle 49 could arise from functionalization of tricycle 50, where the amine is installed over a series of steps. Tricycle 50 could be obtained from a palladium-catalyzed intramolecular arylation, a method previously developed in their group. Using this initial approach, Muratake and Natsume were able to access azabicycle 49 (where R = CH2CH2OBz), but were unable to use this intermediate to access the [2.2.2] bicycle of the hetisine core. The synthesis of azabicycle 49 (where R = CH2CH2OBz) began with the palladium-catalyzed α-arylation of aldehyde 51 (Scheme 10) to arrive at tricycle 50. The tricycle was elaborated through a sequence of 6 steps to provide 52. Treatment of 52 with boron trifluoride effected an acetal–ene cyclization to forge a key C–C bond between C14 and C20. Transposition of the ketone in 53 followed by installation of the methyl group at C4 gave 54 over 4 steps. A Nagata reaction with Et2AlCN was used to install a cyano group (see 55), which provided the nitrogen atom that would be used to construct the azabicycle. The MOM and 2-hydroxyethyl protecting groups at C20 were then removed over a three-step sequence to reveal a hydroxyl group that would be used to form the third and final C–N

Sarpong’s synthesis of the hetidine framework.


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Review

Natsume’s first generation retrosynthesis.


Scheme 9


Scheme 10

Natsume’s first generation synthesis of the azabicyclic core.

bond. To access the N–C6 bond and form the pyrrolidine ring, the carbonyl was first protected as a silyl enol ether and the nitrile group was reduced to a primary amine. The primary amine immediately condensed with the incipient ketone generated upon cleavage of the silyl group. Protection of the resulting imine with Boc anhydride gave 57. Reduction of the enamine and selective protection of the primary alcohol provided 58, which on exposure to trifluoroacetic acid revealed a secondary amine. Treatment of the secondary amine with thionyl chloride led to cyclization by displacement of the secondary hydroxyl group at C20 (see 58) to complete the azabicycle. Hexacyclic compound 49 is composed of almost the entire skeleton of the hetisines, except for the 6-membered ring bearing the exomethylene. Unfortunately, because of the basicity of the tertiary amine, Muratake and Natsume were unable

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to advance this intermediate any further toward the hetisine core. In 2004, Muratake and Natsume reported a revised approach to the hetisine core that involved formation of the N–C20 bond last, thus avoiding the need to carry a basic amine through several steps in the synthesis.27 In this approach, the [2.2.2] bicycle would be constructed before completion of the azabicycle to enable the basic amine to be carried through the majority of the synthesis protected as an amide (Scheme 11). Herein we analyze the key insights that led to the first total synthesis of nominine. The initial report was published 2004 and was followed by a series of full papers which were published in 2006.28–30 In the revised approach to the hetisine core, Muratake and Natsume first explored ways to access the [2.2.2] bicycle directly


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Scheme 11

Review

Second generation Natsume retrosynthesis.

after the acetal–ene reaction (Scheme 12). Allylic oxidation of acetal–ene product 61 with chromium trioxide provided a mixture of enones (62 and 63). Each enone was used as a model substrate to study how the [2.2.2] bicycle could be formed. Enone 62 was advanced to keto-aldehyde 64 over a threestep sequence (not shown). Homologation of aldehyde 64 with the Ohira–Bestmann reagent provided the desired alkyne (66) along with a small amount of aldol product 67 where the [2.2.2] bicycle had been formed, but in a low 7% yield (Scheme 13). Treatment of keto-alkyne 66 with LDA and TMSCl followed by carbomercuration with mercuric triflate-N,N,N′,N′tetramethylurea complex [Hg(OTf )2(TMU)2] led to an aldol reaction upon acidic workup. This sequence provided access to

Scheme 12

Allylic oxidation of acetal–ene product 61.

Scheme 13

Functionalization of keto-aldehyde 64.


69 where the [2.2.2] bicycle was in place as well as the exomethylene group at C16. Enone 63 was converted to keto-aldehyde 70 through the same 3-step sequence used to prepare 64 (not shown). Exposure of aldehyde 70 to K2CO3 in refluxing methanol effected an aldol cyclization to give 71 as a mixture of epimers at the hydroxyl bearing C16 position (Scheme 14). Aldehyde 70 could also be converted to alkyne 72 through an Ohira–Bestmann homologation. Carbomercuration of alkyne 72 with [Hg(OTf )2(TMU)2] followed by an aldol cyclization of the resulting ketone (73) in the presence of LDA provided access to a [2.2.2] bicycle as a single diastereomer (74, stereochemistry was not determined).

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Review

Scheme 14


Functionalization of keto-aldehyde 70.

With several strategies to access the [2.2.2] bicycle in hand, Muratake and Natsume next explored ways to install the amine before formation of the [2.2.2] bicycle. The pyrrolidine was installed using a strategy similar to their first reported approach beginning with intermediate 55. In this new approach, the hydroxyl group at C20 remained protected with the MOM and 2-hydroxyethyl protecting groups until the final stages of the synthesis. The N–C6 bond was forged using the same sequence previously described to access 57 and the resulting enamine was protected with either a Boc group or a Cbz group to provide 75 and 76, respectively (Scheme 15). Reduction of the enamine and protection of the primary hydroxyl group as a benzoate provided 77 and 78 over 2 steps. Allylic oxidation of the Bocprotected amine substrate (77) in the presence of chromium trioxide as before gave a mixture of enones 79 and 81 in 45%

Scheme 15

and 28% yield, respectively. Using the Cbz protected substrate (78), the yields for the chromium trioxide oxidation were even lower with only 12% of 80 and 6% of 82 obtained with a 50% recovery of 78. Because of the low yields associated with the oxidation of Cbz-protected amine substrate 78, only enone 79 was carried forward. Enone 79 was converted to keto-aldehyde 83 using a 3-step sequence (not shown) and treatment of keto-aldehyde 83 with Ohira–Bestmann homologation conditions gave 34% yield of the desired alkyne (84) as well as 55% of aldol product 85 as a mixture of diastereomers at C16 (Scheme 16). Oxidation of 85 to yield diketone 86 occurred in the presence of PCC–Al2O3 but unfortunately, attempts at a Wittig reaction to install the exomethylene group only returned starting material. Because the aldol reaction approach to form the [2.2.2] bicycle was low yielding, the use of a radical-mediated

Installation of the nitrogen and C–N bond formation.

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Scheme 16

[2.2.2] Bicycle formation via an Aldol reaction.

methodology to form a similar [2.2.2] bicycle was explored. It was proposed that a radical intermediate obtained from a xanthate-containing compound in the presence of a tethered alkyne (see 87) could be used to access the desired [2.2.2] bicycle containing the exomethylene group. Xanthate 87 was obtained from 75 through a 5-step sequence (Scheme 17). Treatment of xanthate 87 with tributyltin hydride in the presence of catalytic AIBN generated a radical intermediate that cyclized with the alkyne group to provide 88 in 85% yield. Generation of a radical intermediate to access the [2.2.2] bicycle proved to be an effective strategy. Unfortunately, following the cyclization, the MOM and Boc protecting groups could not be removed because of the unexpected instability of the methylene-[2.2.2]bicycle moiety to acidic conditions. The synthesis of the xanthate (not shown) from olefin 75 was also low yielding. With these challenges in mind, Muratake and Natsume next explored an enyne radical cyclization from enyne 89 where the secondary amine was protected with a Cbz group and the MOM group was removed before the cyclization. This final approach would not require the use of a xanthate to generate the radical intermediate and would avoid the acidic conditions required to cleave the protecting groups. Enyne radical cyclization substrate 89 was obtained from 76 over a 4-step sequence (Scheme 18). Treatment of enyne 89 with

Scheme 17

Review

tributyltin hydride and catalytic AIBN in refluxing toluene provided the [2.2.2] bicycle bearing the exomethylene (90) in 50% yield. With the [2.2.2] bicycle in place, oxygenation at C15 was introduced and the 2-hydroxyethyl protecting group was removed over a 6-step sequence to give 59 (where PG = Cbz). The Cbz group was removed with triethylsilane in the presence of a catalytic amount of palladium(II) acetate and the resulting amino alcohol was treated with thionyl chloride to form the final C–N bond. Cleavage of the acetyl protecting group provided nominine (48) in a total of 40 steps from commercially available starting materials. Muratake and Natsume completed the first total synthesis of nominine using several key steps including a palladiumcatalyzed α-arylation to access a 6–6–6 ring system, an acetal– ene reaction to form the bonds between C14 and C20 and a radical cyclization to access the [2.2.2] bicycle. Peese and Gin. The Peese and Gin total synthesis of nominine, first reported in 2006,31 used a convergent, dual-cycloaddition approach to access the hetisine core. They envisioned accessing the bridged pyrrolidine ring of 48 using a 1,3-dipolar cycloaddition from an aza-dipole and dipolarophile to form bonds between C5–C6 and C10–C20 simultaneously (Scheme 19). The [2.2.2] bicycle could then be assembled using a Diels–Alder reaction between an appropriately placed

Radical cyclization to form the [2.2.2] bicycle.


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Scheme 18

Completion of the first total synthesis of nominine.

Scheme 19

Cycloaddition approach to the hetidine core.

diene and dienophile to form the final two C–C bonds. Because functional group incompatibility would most likely thwart a tandem cycloaddition, the 1,3-dipolar cycloaddition was explored first, and was then followed by the Diels–Alder from a latent diene and dienophile pair. Peese and Gin first explored the feasibility of using a 1,3dipolar cycloaddition to access the azabicycle found in the hetisine core.32 They ultimately decided to use a 3-oxidopyridinium betaine as the aza-dipole because it is significantly more stable than other aza-dipoles, such as azomethine ylides, but still moderately reactive in cycloadditions. Initial investigations began with a 3-oxidopyridinium betaine tethered to a 2-enenitrile dipolarophile (93, Scheme 20). Betaine 93 was accessed from furan 92 through an aza-Achmatowicz reaction in the presence of bromine. However, heating oxidopyridinium 93 to effect the dipolar cycloaddition was unsuccessful. Instead, an intramolecular conjugate addition of the oxidopyridinium followed by rearomatization occurred to provide 94 in 73% yield. In order to suppress the 1,4-conjugate addition pathway, Gin and Peese envisioned a cycloaddition substrate bearing a removable electron deficient group (Z) at C5 rather than at C10 of the dipolarophile (see Fig. 4). Conjugate addition would then occur at the C10 position leading to a strained bridged [3.3.1] bicycle. It was anticipated that the high barrier associated with the generation of a strained bicycle would possibly suppress the 1,4-conjugate addition pathway and instead favor the 1,3-dipolar cycloaddition pathway.

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Scheme 20

Fig. 4

Initial cycloaddition investigations.

[3 + 2] cycloaddition vs. conjugate addition pathways.

Cycloaddition precursor 96 (bearing a phenyl sulfone at C5) was obtained in racemic form in 5 steps from 2-cyano-2methylcyclohexanone (95, Scheme 21). An enantioselective synthesis of 96 was also reported starting from 2-oxo-cyclohexanecarboxylic acid ethyl ester (98). An asymmetric α-methylation of the (S)-t-butylvaline enamine derivative of 98 provided


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Scheme 21

Review

Racemic and enantioselective synthesis of the core azabicycle.

cyclohexanone 99 (98 : 2 er). Enantioenriched 96 could then be obtained from 99 in 6 additional steps. Heating cycloaddition precursor 96 in toluene at reflux provided cycloadduct 97 in 70% yield with no trace of a 1,4-conjugate addition product. With the cycloaddition successfully accomplished, the sulfone group could then be removed by reduction of enone 97 to olefin 100 over 2 steps followed by desulfurization with sodium/mercury amalgam to provide 101. The 1,3-dipolar cycloaddition strategy proved to be an effective strategy to generate the azabicycle found in the hetisine-type natural products and Gin and Peese ultimately provided the first example of accessing the azabicycle moiety enantioselectively.32 From azabicycle 101, installation of the diene group could be envisioned through various annulation strategies at C8–C14 but unfortunately, accessing the dienophile at C10 remained a challenge. Given the challenge of installing the dienophile after the cycloaddition, Gin and Peese next explored the use of an appropriate functional group handle at C10, which would be installed before the cycloaddition.33 For this purpose, they chose to introduce a nitro group at C10 (102). Heating the nitro containing oxidopyridinium betaine in the microwave gave only one regioisomer of cycloadduct 103 with no trace of the conjugate addition product. However, the reaction did not proceed past 14% conversion (Scheme 22). Furthermore, resubmission of cycloadduct 103 to the microwave reaction conditions provided a ∼6 : 1 ratio of betaine 102 to cycloadduct 103 suggesting that the dipolar cycloaddition reaction is under thermodynamic control. To address the unfavourable equilibrium observed in the dipolar cycloaddition of 3-oxidopyridinium substrate 102 to give pyrrolidine adduct 103, Gin and Peese once again decided to redesign the cycloaddition substrate. The use of a


Scheme 22

Nitro containing cycloaddition substrate.

4-oxidoisoquinolinium betaine as the dipole was explored. It was proposed that lowering the energetic cost of breaking aromaticity of the dipole during the cycloaddition would allow for a more thermodynamically favored dipolar cycloaddition. The 4-oxidoisoquinolinium betaine (106) was accessed using a Staudinger–aza-Wittig reaction between dipole precursor 105 and dipolarophile 104 followed by a TFA-promoted extrusion of methanol (Scheme 23). Heating betaine 106 in toluene at 90 °C in the microwave for 30 min provided a mixture of 3 isomeric products: cycloaddition products 107 and 108 and intramolecular conjugate addition product 109, in a 4 : 2 : 3 ratio (Scheme 24). Unfortunately, longer reaction times lead to exclusive formation of 109. Because of the reversibility of the cycloaddition reaction, the reversion of cycloaddition products 107 and 108 to betaine 106 enabled eventual funnelling of all the material to the conjugate addition product 109, which is the thermodynamic sink of the reaction.

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Scheme 23


Synthesis of the oxidoisoquinolinium betaine.

In order to suppress the competing irreversible conjugate addition of 106, one last modification of the dipolarophile component was made. The use of a less activated ene–nitrile as the dipolarophile was re-investigated using the 4-oxidoisoquinolinium as the dipole component. Dipolarophile precursor 110 was accessed from cyclohexenone in 3 steps (not shown). The Staudinger–aza-Wittig reaction followed by subsequent extrusion of methanol was used to couple aldehyde 110 to azide 105 giving access to betaine 111. Heating cycloaddition precursor 111 to 180 °C provided two cycloadducts (112 and 113) as the only products with the undesired regioisomer (113) being the major product in a ratio of

Scheme 24

Cyclization results with the nitro substrate.

Scheme 25

Final cycloaddition substrate bearing a cyano group.

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1 : 3.6 (desired : undesired) (Scheme 25). This ratio remained unchanged over extended reaction times and no conjugate addition products were detected. The observations indicate that the cycloaddition reaction was exothermic and the undesired conjugate addition pathway had been completely suppressed. Because the cycloaddition was under thermodynamic control, the undesired diastereomer (113) could be isolated and re-equilibrated using the same reaction conditions to give the same ratio of the desired to undesired diastereomer, which allowed for accumulation of ∼20% of 112 per re-equilibration of 113 with very little loss of material. To complete the synthesis of nominine from cycloadduct 112, the benzylic ketone group was removed and the cyano group was converted to the vinyl group that would serve as the dienophile in the [4 + 2] cycloaddition reaction (Scheme 26). To access the diene, a reductive dearomatization using standard Birch reduction conditions was performed on the methoxy arene followed by hydrolysis of the resulting methyl enol ether. It was expected that isomerization of the double bond into conjugation with the ketone would subsequently lead to formation of the requisite diene. All attempts to isomerize 115 to a conjugated enone under both acidic and basic conditions led only to returned starting material or decomposition suggesting that 115 is thermodynamically favoured. In an attempt to form the diene using iminium/enamine intermediates, it was found that by treating 115 with pyrrolidine in refluxing methanol, the [4 + 2] cycloaddition product (118)


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Scheme 26

Formation of the [2.2.2] bicycle and total synthesis of nominine.

Scheme 27

Enantioselective synthesis of nominine.

could be obtained as the sole product. Although several dienamine species are possible, diene 116 is the only one poised for the intramolecular Diels–Alder cycloaddition. Thus, the equilibrating intermediates could be funnelled to the irreversible cycloaddition adduct (117). Ketone 118 could then be obtained from 117 following enamine hydrolysis. Finally, Wittig olefination of ketone 118 followed by allylic oxidation with SeO2 provided nominine in a total of 15 steps from commercially available materials. Gin and Peese also completed an enantioselective synthesis of nominine by setting the stereocenter at C4 of 120 using an enantioselective 1,4 conjugate addition of a dialkylzinc reagent into enone 120 in the presence CuOTf and chiral N-heterocyclic carbene ligand complex 121 (Scheme 27). The resulting zinc enolate was then trapped as vinyl triflate 122. A two-step sequence from vinyl triflate 122 provided enantioenriched dipolarophile 110, which was then used to access dipolar cycloaddition product 112 in enantioenriched form. Recrystallization of 112 further increased the enantiopurity to provide material which was used to complete the first enantioselective synthesis of nominine (48).


Gin and Peese reported a very elegant synthesis of nominine, which stands as the shortest and most efficient approach to these molecules to date. By using a convergent dual cycloaddition strategy, they were able to rapidly and efficiently access the hetisine core and thereby set the standard for future syntheses of the hetisines and related frameworks.

Conclusions In the analysis of synthetic studies toward the hetidine and hetisine-type C20-diterpenoid alkaloids, we see a variety of strategies employed to construct the core framework, with most centering on formation of the azabicycle and the allcarbon [2.2.2] bicycle. These studies, as well as chemical conversion and degradation studies, provide insight into reactivity in these frameworks and continue provide a full understanding of the interplay of functional groups in these densely functionalized molecules. Despite the major advances that have been made, challenges still exist in developing and executing efficient sequences that allow for divergence and diversity.

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These shortcomings provide opportunities for future syntheses of these structurally alluring natural products.


Notes and references 1 F. P. Wang, Q. H. Chen and X. T. Liang, in The Alkaloids: Chemistry and Biology, ed. G. A. Cordell, Elsevier Science, New York, 2009, vol. 67, p. 1. 2 F. P. Wang and Q. H. Chen, in The Alkaloids: Chemistry and Biology, ed. G. A. Cordell, Elsevier Science, New York, 2010, vol. 69, p. 1. 3 F. P. Wang and X. T. Liang, in The Alkaloids: Chemistry and Biology, ed. G. A. Cordell, Elsevier Science, New York, 2002, vol. 59, p. 1. 4 See ref. 3. 5 F. P. Wang, Q. H. Chen and X. Y. Liu, Nat. Prod. Rep., 2010, 27, 529. 6 See ref. 3 and 5 and references therein. 7 See ref. 3 and 5 and references therein. 8 T. Yatsunami, T. Isono, I. Hayakawa and T. Okamoto, Chem. Pharm. Bull., 1975, 23, 3030. 9 T. Yatsunami, S. Furuya and T. Okamoto, Chem. Pharm. Bull., 1978, 26, 3199. 10 S. W. Pelletier and S. W. Page, in The Alkaloids, ed. M. F. Grundon, The Royal Society of Chemistry, London, 1979, vol. 9, p. 221. 11 W. L. Meyer, T. E. Goodwin, R. J. Hoff and C. W. Sigel, J. Org. Chem., 1977, 42, 2761. 12 W. L. Meyer, C. W. Sigel, R. J. Hoff, T. E. Goodwin, R. A. Manning and P. G. Schroeder, J. Org. Chem., 1977, 42, 4131. 13 T. Kametani, Y. Kato, T. Honda and K. Fukumoto, J. Am. Chem. Soc., 1976, 98, 8185.

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14 F. Satoh, T. Kametani, Y. Kato, T. Honda and K. Fukumoto, Heterocycles, 1977, 6, 1757. 15 S. W. Pelletier and P. C. Parthasarathy, Tetrahedron Lett., 1963, 4, 205. 16 J. L. van der Baan and F. Bickelhaupt, J. R. Neth. Chem. Soc., 1975, 94, 109. 17 J. L. van der Baan and F. Bickelhaupt, Tetrahedron, 1974, 30, 2447. 18 Y.-S. Kwak and J. D. Winkler, J. Am. Chem. Soc., 2001, 123, 7429. 19 For Mander’s first approach, see: B. S. Balgir, L. N. Mander and R. H. Prager, Aust. J. Chem., 1974, 27, 1245. 20 For Hutt and Mander’s most recent approach, see: O. E. Hutt and L. N. Mander, Aust. J. Chem., 2008, 61, 204. 21 C. M. Williams and L. N. Mander, Org. Lett., 2003, 5, 3499. 22 C. M. Williams, L. N. Mander, P. V. Bernhardt and A. C. Willis, Tetrahedron, 2005, 61, 3759. 23 O. E. Hutt and L. N. Mander, J. Org. Chem., 2007, 72, 10130. 24 Y. Shibanuma and T. Okamoto, Chem. Pharm. Bull., 1985, 33, 3187. 25 A. M. Hamlin, F. de J. Cortez, D. Lapointe and R. Sarpong, Angew. Chem., Int. Ed., 2013, 52, 4854. 26 H. Muratake and M. Natsume, Tetrahedron Lett., 2002, 43, 2913. 27 H. Muratake and M. Natsume, Angew. Chem., Int. Ed., 2004, 43, 4646. 28 H. Muratake and M. Natsume, Tetrahedron, 2006, 62, 7056. 29 H. Muratake and M. Natsume, Tetrahedron, 2006, 62, 7071. 30 H. Muratake and M. Natsume, Tetrahedron, 2006, 62, 7093. 31 K. M. Peese and D. Y. Gin, J. Am. Chem. Soc., 2006, 128, 8734. 32 K. M. Peese and D. Y. Gin, Org. Lett., 2005, 7, 3323. 33 K. M. Peese and D. Y. Gin, Chem.–Eur. J., 2008, 14, 1654.


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