Application of the aza-Diels-Alder reaction in the synthesis of natural products.

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REVIEW Application of the aza-Diels-Alder reaction in the synthesis of natural products Received 00th January 20xx, Accepted 00th January 20xx DOI: 10.1039/x0xx00000x www.rsc.org/

a,b

Min-Hui Cao,

c

a

Nicholas J. Green and Sheng-zhen Xu †

Diels-Alder reaction that include a nitrogen atom in the diene or dienophile are termed aza-Diels-Alder reactions. As well as the corresponding all carbon Diels-Alder reaction, aza-Diels-Alder reaction has played an important role in the total synthesis of natural products. Herein, we review the various natural products using an aza-Diels-Alder reaction as a key step to its total synthesis, and divide the syntheses into inter- and intramolecular aza-Diels-Alder reaction and a retroaza-Diels-Alder reaction. Inter- and intramolecular aza-Diels-Alder reaction are further divided into imine as electron deficient dienophile and imine as electron deficient azadiene. The significance of the aza-Diels-Alder reaction for the construction of a six-membered ring containing nitrogen is tremendous, but the development of asymmetric, in particular catalytic enantioselective intramolecular aza-Diels-Alder reaction in the total synthesis of natural products remains highly challenging, and will no doubt see enormous advances in the future.

1. Introduction The Diels–Alder reaction has played an important role in the 1 total synthesis of natural products. Diels–Alder reactions that include a nitrogen atom in the diene or dienophile are termed 2 aza-Diels–Alder reactions. However, compared to the corresponding “all carbon” Diels–Alder reaction, the aza-Diels– Alder reaction has been much less explored and exploited in organic synthesis. Nevertheless, the aza-Diels–Alder reaction, is among the most efficient methods for the synthesis of six membered nitrogen-containing heterocycles, especially in the syntheses of many biologically relevant small molecules and natural products. Natural products have unique features such as high chemical diversity, biochemical specificity and other molecular properties that make them favourable as lead structures for drug discovery. Consequently, natural products have played a major role in the discovery of new active ingredients in the pharmaceutical industry. Since the isolation of morphine, synthetic chemists have busied themselves with the synthesis of this and many other biologically potent targets natural 3 products. During the past several decades, hetero-Diels–Alder have been widely used for the total synthesis of natural products. More

recently, Kumar and Waldmann discussed the applications of asymmetric Hetero-Diels-Alder reactions as key steps in the 2a syntheses of biologically relevant molecules including sugars. Miller described the application of the nitroso Diels–Alder reaction for the syntheses of complex diene-containing natural 4 products. Fochi and Bernardi have highlighted the Povarov reaction for the preparation of various nitrogen-containing 5 compounds. Willis has highlighted the key features and applications of the hetero-Diels–Alder/retro-Diels–Alder 6 reactions for nitrogen heteroaromatic synthesis. Masson described enantioselective aza-Diels–Alder reactions catalysed by chiral transition metal complexes and chiral organic 2b compounds. Quadrelli described the iminium ions as 7 dienophiles in aza-Diels–Alder reaction. And the mechanism of aza-Diels–Alder was generally accepted occure in a concerted manner in the past. However, in most case the aza-Diels–Alder reaction may proceeds through a 2d concert or a step-wise Mannich-Michael reaction. In fact there have been doubts the mechanism involved may not potentially a concerted [4+2]-cycloaddition neatly, Whiting showed some evidence and suggested that it could proceed either be: a) concerted; b) step-wise Mannich-Michael reaction; or c) even occure simultaneously in competition with each 2e other. This is a new area to be discussed. In this review, we focus on the application of aza-Diels–Alder reaction in the synthesis of natural products since 1980 and the mechanism are ignored. Herein, we divide the syntheses into those featuring an intermolecular aza-Diels–Alder reaction, an intramolecular aza-Diels–Alder reaction and a retro-aza-Diels–Alder reaction. Inter- or intramolecular azaDiels–Alder reaction are further divided into those featuring an imine as electron poor dienophile and imine as electron poor azadiene (Figure 1).

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Journal Name aza-Diels-Alder reaction

Intermolecular aza-D-A Reaction R1

R1 N

+ R2

Intramolecular aza-D-A Reaction R1

N

R1

N

N

R2

N


R1

N

N

R2

R2

R1

R1

R1

N

MeO OMe

aza DA

N

N

+

N

O

R2

R2 R1 N

N

aza DA

N

R2

R2

N

O

N

N

O H Me

BnO

3d, reflux 39%

MeO

+

BnO MeO OMe

OMe 4a

4b O

O N

Retro DA -MeCN

xylene

2

R1

Me

Me

N

+

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Ph-Cl-p

O

N

H

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OMe

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imino Diels-Alder reaction R1

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N

Ph-Cl-p

O

Ph-Cl-p N

O

MeO

H N

Me

CO2 Me H2N

3 steps

Me 22 steps

N

N O

BnO

Figure 1. The aza-Diels-Alder reaction.

H2N BnO

Me

KaCO3 MeOH/H 2 O 79%

MeO MeO

OMe

2. Intermolecular aza-Diels–Alder reaction

COOMe

6

5

OMe

O

2.1. Imines as electron deficient dienophiles

MeO

Streptonigrin (1), possessing the tetracyclic aminoquinoline5,8-dione structure, was first isolated from Streptomyces flocculus in 1959 by Rao and Cullen,8 and shows antibiotic activity against both gram-positive and gram-negative bacteria as well as pronounced anticancer activity. The total synthesis of streptonigrin presents a major challenge with its high degree of functionalization and tightly linked array of aromatic rings. An aza-Diels–Alder reaction has been used as a key step at an early stage in a synthesis by Weinreb and coworkers (Scheme 1).9 The successful synthetic strategy involves using an imino Diels–Alder cycloaddition for construction of the pyridine ring system. Diene 2 and methoxyhydantoin 3 under reflux in xylene for three days formed the inseparable ADA adducts 4a and 4b (4a:4b=1:3) in 39% yield. The mixture of 4a and 4b was hydrolysed with aqueous barium hydroxide followed with SOCl2/methanol, then heated with 5% Pd/C in toluene to provide 5 (~20% from adduct mixture 4a and 4b). Installation of the necessary 5-amino substituent and construction of quinoline rings required more than twenty further steps to get pyridine 6. The final stage of the synthesis involved removal of the two protecting groups of 6 by using potassium carbonate afforded synthetic streptonigrin (1).

N

N

H2 N O

COOH

H 2N

Me OH OMe

streptonigrin

1

OMe

Scheme 1. Total Synthesis of Streptonigrin by Weinreb and co-workers Nicholas Green is currently a Ph.D. student at the Research School of Chemistry, the Australian National University (ANU). He studied a Ph.B. (Science) at the ANU and received

an

Honours

degree

with

the

University Medal in 2011, taking up doctoral studies as a Rodney Rickards scholar soon after. His research interests include the use of highly unsaturated molecules in synthesis and the catalytic, enantioselective Diels– Alder reaction. Sheng-Zhen Xu graduated from the Central China Normal University and obtained his Ph. D degree in 2007 under the supervision of Prof. Ming-Wu Ding and Prof. Wen-Jing Xiao. During from Aug. 2014 to Aug. 2015, he studied at the Research School of Chemistry,

Min-Hui Cao graduated from the Central

the Australian National University (ANU). He

China Normal University and obtained her

is

Master degree in 2003 and earned her Ph. D

Huazhong Agricultural University in China.

degree in 2012 under the supervision of Prof

His current research interests cover the

De-Jiang Ni. During from August 2014 to

synthesis and application of natural products.

currently

an

associate

Professor

at

August 2015, she studied at the Research School of Chemistry, the Australian National University (ANU). She is currently an assoc. professor at Huazhong Agricultural University in China. Her current research field cover the synthesis and application of natural products.

Vindoline (7a) and Vindorosine (7b) are among the most complex, highly functionalized, and stereochemically rich natural products within a family of more than 90 alkaloids isolated from the Madagascan periwinkle (Catharanthus 10 roseus (L.) G. Don). Their total synthesis has been achieved 11 by Langlois in 1985 (Scheme 2). The strategy for construction of vindoline and vindorosine was first centered around the preparation of [2,3-a]indoloquinolizidine derivative 13 which

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could lead directly to an intermediate 14 bearing the complete aspidosperma framework. The Indoloquinolizidine synthons 13 could be of interest in the total synthesis of several eburnane alkaloids such as vincamine. The total synthesis begin with an intermolecular imino Diels–Alder reaction between 9methyldihydro-β-carboline derivative 8 and diene 9 conjugated with an electron-withdrawing group, leading to the three aza-Diels–Alder adducts 10, 11, 12, which were directly deprotonated with LDA in THF-HMPA and alkylated with ethyl iodide to afford the compound 13 as a single diastereomer. Acetylation of 14 which was obtained from 13 in seven steps gave rise quantitatively to (±)-vindoline 7a or (±)-vindorosine 7b. The aza-Diels–Alder in this case is an efficient initial step towards generating the densely functionalized structure with high overall yield.

Scheme 3. Total Synthesis of (±)-Ipalbidine by Danishefsky and coworkers.

(±)-Aristeromycin (20), isolated from the ascomycete Streptomyces citricolor nov. sp. as the first naturally occurring pseudo-nucleoside, has been shown to exhibit antibacterial, 14 antiviral, and antitumor activities. A formal synthesis of (±)Aristeromycin with an imino Diels–Alder reaction has been 15 achieved with high overall yield by Prato (Scheme 4). The intermolecular imino Diels–Alder reaction between cyclopentadiene and the N-sulfonylimine 21 was carried out o under the condition (benzene, 0 C) afforded the exo cycloaddition adduct 22 in 84% yield. The isocyanate 23, which can induced from 22 in five steps, trapped with benzyl alcohol to yield benzyl carbamate 24 in 76% yield. Additional hydrogenation and reduction of 24 afforded alcohol 26 in 88% yield from 24. The formation of (±)-aristeromycin 20 from 26 16 by using Sakssena’s method.

Scheme 2. Total Synthesis of Vindorosine and Vindoline by Langlois and coworkers.

(±)-Ipalbidine (15), was isolated from the seeds of Ipomoea alba L., has a relatively simple structure containing a 1azabicyclo-[4.3.0]-non-3-ene system with a phenolic substituent at the 3-position. (±)-Ipalbidine is known to be a non-addictive analgesic, and caused analgesia in mice which 12 was not antagonized by naloxone. Danishefsky have achieved the total synthesis of (±)-Ipalbidine 15 by using an intermolecular imino-Diels–Alder reaction as the key step 13 (Scheme 3). This remarkable rapid synthesis of (±)-Ipalbidine showed the scope of the diene-imine cyclocondensation reaction has been extended to the unstable ∆1-pyrroline 18. It have had a major impact in the synthesis of various alkaloidal syntems, many of which are of considerable current biological interest. The initial reaction of α-aryl-β-methylcrotonate derivative 16 with LDA in THF in the presence of HMPA, followed by quenching of the resultant ester enolate with tertbutyldimethylsilyl chloride afforded the silylketene acetal 17 in quantitative yield. Treatment of 17 with 18 in methylene o chloride under the influence of BF3 etherate (-78 C to rt) affords the [4+2] cycloaddition adduct 19 which is then readily converted to (±)-Ipalbidine 15 after additional reduction with LiAlH4-AlCl3 and subsequent demethylation via boron tribromide in methylene chloride.

Scheme 4. Total Synthesis of (±) – Aristeromycin by Prato and coworkers.

Cuanzine (27), another polyheterocyclic indole alkaloid, was 17 first isolated from the roots of Voacanga chalotiana, Palmisano have achieved the total synthesis of cuanzine (27) 18 by using an imino Diels–Alder reaction (Scheme 5). It offers an alternative approach which allow the stereoselective synthesis of cuanzine in a highly convergent manner. Heating o (120 C, sealed tube) of a degassed solution of 8-methoxy-βcarboline 28 and dihydrofuran 29 in acetonitrile in the presence of 30 as polymerization inhibitor for 6 h delivered diastereomerically pure 31 in 64% isolated yield. The spectral features indicated that the reaction was strongly influenced by the polarity solvents and suggesting it underwent a stepwise mechanism rather than a concerted manner. This is a case that imino Diels–Alder undergoes a step-wise as Whiting report. The regiochemistry depends on the relative ability of the C=N moiety to add to the electron-deficient acceptor 29. Additional homogeneous hydrogenation of the imino Diels–

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Alder reaction adduct 31 followed by oxidation led to aldehyde 32, which condensation with methyl isocyanoacetate to afford 33. Treatment of 33 with N,N’-carbonyldiimidazole and triethylamine in dry THF at room temperature for 15 hours afforded cuanzine 27 in 58% yield. In the meantime, Langlois have also reported the total synthesis of cuanzine (27) by employing an aza-Diels–Alder strategy (Scheme 5). As a slight difference, Langlois using methylpentadienoate as diene reacted with imine 28 gave rise to a mixture of conjugated and unconjugated indoloquinolizidine esters 34 (36%) and 35 (31%) which can 19 also be converted to 33 via a different method. After acetylation and elimination in the presence of DBU, 33 afforded 38 in 45% yield. One pot sequential treatment of Nfomyl enamino ester 38 with hydrogen chloride in anhydrous methanol and excess of sodium carbonate gave rise to cuanzine (23%) and 16-epicuanzine (8%). These two complementary approaches highlight the importance of the aza-Diels–Alder reaction in accessing polycyclic alkaloids via relatively short total syntheses.

followed by acetalization of the resultant enolether led to 43. Removal of the tosyl group by sodium-naphthalenide reduction and acylation with 3-((4-methylphenyl)sulfonamido) propanoyl chloride, preceding LAH reduction gave tertiary amine 44 and 45, obtained from a further seven steps, was hydrolyzed with barium hydroxide to give an amino acid intermediate, which was subjected to macrocyclization at high dilution with Mukaiyama’s reagent (2-chloro-1methylpyridinium iodide) in the presence of a large excess of DMAP to give 46 in 60% yield. Subsequent tosyl and benzyl removal afforded (–)-Cannabisativine 39 in 83% yield. The o synthetic material exhibited an optical rotation [D] of -51 o compared to the reported value +55 for natural (+)cannabisativine, allowing the assignment of the absolute configuration for the natural product.

Scheme 6. Total Synthesis of (-) - Cannabisativine by Hamada and coworkers.

Scheme 5. Total Synthesis of Cuanzine by Palmisano and Langlois et al..

(+)-Cannabisativine, contains a 13-membered lactam ring system annulated to a substituted tetrahydropyridine ring, was first isolated from the roots and leaves of the common 20 marijuana plant, Cannibis sativa L. In 1984 and 1985, Natsume and Wasserman reported the first total synthesis of 21 racemic Cannabisativine. In 1991, Hamada has reported the total synthesis of (–)-Cannabisativine (39) by using an imino Diels–Alder reaction as a key step at an early stage (Scheme 22 6). The aza-Diels–Alder reaction of 40 with 41 afforded 42 as a single diastereoisomer in high yield (81%). The homologation of carboxylic butyl-ester by Wittig olefination of the aldehyde analogue of 42 with methoxymethylene phosphorane,

Lasubine (47), is a quinolizidine alkaloid from the Lythraceae family first isolated from the leaves of Lagerstroemia 23 subcostata Koehne in 1978. The total synthesis of the Lythraceae alkaloid (–)-lasubine was achieved by Kündig using a highly diastereoselective aza-Diels–Alder cycloaddition and an intramolecular radical cyclization as key steps to afford a 24 quinolizidinone intermediate (Scheme 7). The aza-Diels– Alder reaction between imine 48 and Danishefsky’s diene 49 mediated by SnCl4 afforded the single diastereoisomer 50 in 48% yield. It was attributed to the steric hindrance by the TMS group in the diene approach to the imine si-face. Mesylate formation and substitution of 50, promoted an intermolecular radical cyclization, which was carried out in refluxing benzene under nitrogen in the presence of tributylstannane and a catalytic amount of AIBN to afford 51. Additional ketone reduction, and desilylation followed by rapid oxidative metal removal afforded enantiomerically pure (–)-lasubine in 84% yield. More recently, a concise enantioselective and stereodivergent synthesis of (+)-Lasubine I and II (52a, 52b) from a common chiral N-tosyl 2,3-dihydro-4-pyridone was reported by 25 Carretero (Scheme 8). The Carretero approach to the Lasubine is very closely related the strategy devised by Kündig. The key intermediate 55 was obtained by application of a

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catalytic asymmetric Cu-mediated aza-Diels–Alder reaction of imine 53 and Danishefsky’s diene 49 in 71% yield and 94% ee. Its excellent activity and enantioselectivity based on the Cu(I)/Fesulphos catalyst at -20°C. After deprotection by activated zinc powder in a THF/saturated aqueous solution of NH4Cl at room temperature, leading to the unprotected N-H pyridine 56 in 97% yield. Initial N-alkylation of 56 with 4chloro-1-iodobutane (NaH, THF) provided N-functionalized chloro-derivative 57 in 75% yield. The iodo derivative prepared by reaction of 57 with NaI in acetone underwent radical cyclization under standard conditions (Bu3SnH, AIBN, benzene, reflux) yielding the quinolizidine ketone 58. Reduction of 58 with L-selectride afforded (+)-Lasubine I in 79% yield. On the other hand, (+)-Lasubine II could also be accessed from 56, first by conversion of 56 to the 4-chlorobutyl amine 59 under Comins conditions. Treatment of 59 by using SnCl4 in EtOAc followed by K2CO3 in CH2Cl2 lead to the quinolizidine ketone 60 which was readily converted to (+)-Lasubine II by L-selectride reduction in 65% yield. This first example of a catalytic enantioslective aza-Diels–Alder in our review highlights the utility of the reaction in quickly generating both structural and stereochemical complexity in alkaloid structures.

Phyllanthine (61)， a tetracyclic compound belong to the securinega alkaloids, was isolated from the bark of roots of P. 26 discoides. The first total synthesis of phyllanthine, featuring a stereoselective imine Diels–Alder reaction catalyzed by Yb(OTf)3 of the hindered and highly functionalized bicyclic imine 62 for efficient annulation of the A ring, has been 27 completed by Weinreb in 2000 (Scheme 9). Imine 62 undergoes an exo-selective aza-Diels–Alder reaction with Danishefsky’s diene under high pressure, producing 63 (yield ca. 70%), or more conveniently and efficiently, with catalysis by ytterbium triflate (Yb(OTf)3) to afford the [4+2] cycloaddition adduct in 84% yield. Treatment of 63 with two equivalents of L-selectride effected both conjugate carboncarbon double bond and ketone reduction. Subsequent Omethylation and removal of the protecting group afforded hydroxyketone 64 which underwent selenation under conditions developed in Sonoda’s group (PhSeSePh, MsOH, 28 SeO2) and then deselenation with NaI/BF3Et2O to provide enone 65 in good yield. Hydroxy-enone 65 was esterified to give phosphonate 66, and cyclization promoted by potassium carbonate/[18]crown-6 eventually afford phyllanthine 61.

Scheme 7. Total Synthesis of (-)-Lasubine by Kündig and co-workers.

Scheme 9. Total Synthesis of Phyllanthine by Weinreb and co-workers.

Scheme 8. Total Synthesis of (+)-Lasubine I & II by Carretero and coworkers.

Coniine (67), a piperidine derivative, has been isolated from one of the most poisonous members of the plant kingdom, 29 Conium macula-tum L. (poisonous hemlock). An asymmetric zirconium complex derived from zirconium and 3,3’,6,6’I4BIBOL was used to catalyze an aza-Diels–Alder reaction for the total synthesis of (+)-coniine by Kobayashi and co-workers 30 (Scheme 10). The synthesis began with an asymmetric ADA reaction between hydrazone 68 and Danishefsky’ diene 1-tertbutyloxy-3-trimethylsilyloxy-1,3-butadine in the presence of a chiral catalyst 69 afforded the desired optically active 2,3dihydro-4-pyridone 70 in 70% yield with 93% ee. Choice of aprotic polar solvents was an important factor to ensure sufficient reactivity, especially in a mixed solvent systems containing aprotic polar solvents. Additional hydrogenation by Pd/C and carbonyl group protection with 1,2-ethanedithiol provided 71. After the N-N bond cleavage followed by Boc-

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yl]methanol stereoisomer or (–)-lupinine. Aoyagi and coworkers developed a novel aza-Diels–Alder reaction of allenyltrimethylsilylthioketene 80 and piperideine 81 to provide unsaturated thiolactams 82, which converted into 35 (±)-lupinine in six steps with high yield (Scheme 12). The [4+2] cycloaddition of allenyltrimethylsilylthioketene 80, generated by the [3,3] sigmatropic rearrangement of trimethylsilylethynyl propargyl sulfide 79 with imine 81, afforded thiolactam 82 as an air-stable compound. 82 was o treated with mCPBA (2.0 equivalents) in CHCl3 at 0 C for 30 min to afford corresponding lactam 83 in 72% yield. Additional desilylation, dehydration, protection, hydrogenation and deprotection led to 84 in good yield. Reduction of 84 by LiAlH4 gave (±)-lupinine in 92% yield.

Scheme 10. Total Synthesis of S-(+)-coniine by Kobayashi and coworkers.

(–)-Anabasine (73), was found in Tree Tobacco (Nicotiana glauca) and has been reported as a nicotinic acetylcholine 32 agonist. The total synthesis of (+)-Anabasine has been completed by Kobayashi through a highly enantioselective aza33 Diels–Alder reaction (Scheme 11). The excellent enantioselectivity rely on the chiral Lewis acid catalyst and ligand 75. The initial imino-Diels–Alder reaction of imine 74 with Danishefsky’s diene, catalyzed by a chiral Nb(V) Lewis acid and ligand 75 was used to synthesize 76 in 74% yield and 92% ee. 76 was transformed to the corresponding methyl ether by o using methyl iodide/NaH in THF at 0 C. Reduction of the conjugated carbon-carbon double bond and carbonyl led to 77, which afforded the (+)-anabasine (73) as a single enantiomer after the protecting group o-methylphenyl was removed by using cerium ammonium nitrate (CAN).

Scheme 11. Total Synthesis of (+)-Anabasine by Kobayashi and coworkers.

Lupinine (78) is an alkaloid first extracted from seeds and herbs of the Lupinus luteus species, a plant of the Fabaceae family. It was later established by chemical methods that the natural product is the [(1R,9aR)-octahydro-1H-quinolizin-1-

Scheme 12. Total Synthesis of (±)-Lupinine by Aoyagi and co-workers.

(+)-Lentiginosine (85) was first isolated by Elbein et. al. upon fractionating the hot methanol extracts from the leaves of 36 Astragalus lentiginosus. Recently, Yang developed a Yb(III)mediated aza-Diels–Alder reaction between a Danishefskytype diene and a chiral aldimine with complete regioselectivity and high degree of diastereoselectivity to complete the total 37 synthesis of (+)-Lentiginosine (Scheme 13). An intermolecular [4+2] cycloaddition reaction between electron-rich Danishefsky-type silyloxydiene 86 (R=H) and oxygenated fivemembered aldimine ring 87 afforded 88 in 73% yield. Additional reduction of the carbon-carbon double bond and the carbonyl group and TBS deprotection of 88 afforded (+)Lentiginosine in high yield. The non-natural laevorotatory enantiomer (–)-Lentiginosine can be synthesized by a similar strategy.

Scheme 13. Total Synthesis of (+)-Lentiginosine by Yang and coworkers.

(+)-Reserpine (90) was first isolated by Schlittler et. al. from 38 Indian snake root R. serpentine Benth. in 1952. Recently, Jacobson has reported the total synthesis of (+)-Reserpine by

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protection and then dithioacetal removal afforded Bocprotected coniine 72 in good yield. All physical data of 31 synthetic 72 completely consistent with the literature.

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Scheme 14. Total Synthesis of (+)-Reserpine by Jacobson and coworkers.

2.2 Imines as electron deficient azadienes Three years after Weinreb reported the total synthesis of streptonigrin, Boger developed another route, this time involving a sequence of two aza-Diels–Alder reactions to achieve the formal total synthesis of streptonigrin (Scheme 51 15). It provides the advanced intermediate 103 in Kende’s total syntehsis of streptongrin in six steps from readily available starting materials. S-methyl thioimidate 97, which was prepared in four steps from commercially available 6methoxyquinoline, reacted with 98 to provid the first azaDiels–Alder reaction adduct 99, and subsequent treatment of 99 with 100 resulted in a second aza-Diels–Alder reaction to furnish a mixture of seperable adducts of 101 and 102 (101:102=2.8:1). With four more synthetic operations from 101, 103 was obtained. An additional four steps using Kende’s 52 method from 103, including the required conversion of the pyridyl-5carboxylate to an amino group and the utilization of a modified Curtius rearrangement on the free 5-carboxylic acid, completed the total synthesis of streptonigrin. If the final steps had followed Kende’s methodology then the synthesis would have been completed in 13 over steps from 97. The strength of this remarkable syntehtic strategy lies in the convergent nature in which Boger assembled the central pyridine core using two aza-Diels–Alder reactions.

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39

employing an imino Diels–Alder reaction (Scheme 14). A highly diastereoselective catalyst-controlled aza-Diels–Alder reaction between imine 91 and α-substituted enone 92 were observed in the presence of 20 mol % chiral amino thiourea 93 providing the desired diasteromer 94 (76% isolated yield) and its isomer. 95 was obtained in two steps from aza-Diels–Alder adduct 94 through cleavage of the primary TBS ether with pyridine-buffered HF and oxidation of the resulting primary alcohol with the Dess-Martin periodinane. Treatment of 95 with piperidine and p-TsOH in toluene resulted in an intramolecular enamine aldol reaction to afford 96 in 86% yield. Additional manipulation of 96 involving aldehyde oxidation/esterification, elimination/reduction of alcohol, deprotection of PMB ether and tosyl amine, and installation of the trimethoxybenzoyl (TMB) ester led to pentacycle (+)Reserpine in a total of 12 steps from 91. In fact 10 more successful total syntheses of reserpine have 40 been developed and reviewed by Chen. The original 41 42 43 approaches of Woodward and those of Pearlman, Stork, 44 45 46 47 Liao, Fraser-reid, Hanessian, and Mehta targeted an appropriate functionalized E-ring precursor in which the requisite stereochemistry was built in. Unlike the initial E-ring 48 49 strategy of Woodward, the approaches of Wender, Martin 50 and Shea targeted a cis-fused DE-ring precursor. Among these, Woodward, Liao, and Mehta employed the Diels-Alder reaction to obtain the E-ring stereochemistry, while Martin and Shea employed intramolecular Diels-Alder reaction as pivotal steps in assembling the cis-hydroisoquinoline framework of the DE-ring. Despite the scope of the effort, Jacobsen reported an alternative to the reserpine framework focused on specifically targeting control over the C3 stereogenic center by means of a stereoselective formal azaDiels–Alder reaction between two fragments of 91 and 92. Compared to other classical methods, such as de Mayo reaction, Michael addition, radical cyclization and cope rearrangement et al., aza-Diels–Alder reaction much simple and the straightforward way of setting C3 stereogenic center relied on chiral catalyst 93 to provide access to coupling component 92.



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Scheme 15. Formal total Synthesis of Streptonigrin by Boger and coworkers.

Eight years later, Boger developed another inverse electron demand aza-Diels–Alder reaction of the N-sulfonyl-1-aza-1,3butadiene 105 for introduction of the fully substituted 53 pyridone of streptonigrone 104 (Scheme 16). The initial azaDiels–Alder reaction between azadiene 105 with 1,1dimethoxypropene at room temperature (1h, C6H6) led to the formation of the sensitive [4+2] cycloadduct intermediate, o which upon immediate treatment with t-BuOK(THF, -30 C, 1h) o followed by DDQ (DCM, 25 C, 1h) provided the key intermediate 106. Hydrolysis of the lactone of 106 followed by protection of the free phenol as a methoxymethyl ether and subsequent ester hydrolysis provided 107 in excellent yield. Additional treatment of 107 with Shioiri-Yamada reagent ((PhO)2P(O)N3, benzene/H2O) followed by HBr deprotection of the benzyl ether provided 108. Selective oxidation of 8hydroxyquinoline 108 to provide 109 was accomplished cleanly with potassium nitrosodisulfonate using Kende’s two-phase 54 reaction system. Additional methoxidation in the presence of Ti(O-i-Pr)4, azide installation and reduction, and deprotection of the methyl ether led to the formation of streptonigrone 104. Central to the synthetic strategy was the implementation of a room-temperature, inverse electron demand aza-Diels– Alder reaction of the N-sulfonyl-1-aza-1,3-butadiene 105 for the construction of the central pyridone C ring with completion of the assemblage of the full carbon skeleton of streptonigrone.

Scheme 16. Total Synthesis of Streptonigrone by Boger and coworkers.

Fredericamycin A (110) is a structurally unique and potent 55 antitumor antibiotic isolated from Streptomyces griseus. Its total synthesis was achieved by Boger based on a room temperature inverse electron demand aza-Diels–Alder reaction of a N-sulfonyl-1-aza-1,3-butadiene for the assemblage of a 56 pyridone ring precursor (Scheme 17). The [4+2] cycloaddition of 111 with with 112 to provide the cycloadduct 113 was o o conducted at 25 C and room pressure (CH2Cl2, 25 C, 20 h, 95%). The sensitive cycloadduct 113 was converted directly to pyridine 114 by treatment with DBU (THF, 70, 80-91%). Treatment of 113 with LDA followed by cyclopentenone and EtOH then DDQ oxidation afforded naphthol 115. Protection of 115 of the free phenol as its benzyl ether provided 116 in 8293% yield. Additional manipulation of 116 in order to install the pentadienyl side chain and form the aldehyde afforded 116 within 6 steps. Treatment of the sensitive aldehyde 116 with the lithium acetylide 117 and subsequent protection of the resulting alcohol provided alkyne 118 (54% overall yield from 116). Reaction of 118 with functionalized chromium carbine complex 119 proceeded best in heptane in the presence of Ac2O, providing 120 as a single regioisomer, and a 3:1 mixture of diastereomers. 120 was subjected to protection of the free phenol, deprotection of the benzylic alcohols, and 57 Swern oxidation (TFAA-DMSO, DBU/Net3) to provide 121 with high yield. Two-step deprotection of 121 (BBr3, CH2Cl2, -

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mappcicine. Additionally, reduction of nothapodytine B with (S)-BINAL-H provided (–)-mappicine in 73% yield and 99.9% ee.

EtO2C EtO

OEt


112 EtO2C

N DCM, 25oC SO2Me 20 h, 95%

EtO2C

N CO2Et THF SO2Me 81-91%

111 O

EtO2C

DBU

EtO EtO

O

CO2Et

114

113 TBDMSO

OHC 6 steps

DDQ

N

EtO

Li

117

HO

BnO

LDA N

EtO

CO2Et

EtO

N

115

116

OTBDMS

O MeO

TBDMSCl

O

TBDMSO BnO

O

OMe

O

119

Cr(CO)5

Ac2O, heptane

EtO

N 118

O MeO

O

O

O

OMe OR

R=TBDMS

O

OMe

O

OBn HO

MeO

O

4 steps OH

OR BnO EtO

EtO

N

121

120

BBr3, air TsOH-NaBr 85%

O

OH

O

OH HO

MeO

Scheme 18. Total Synthesis of Nothapodytine B & (–)-Mappicine by Boger and co-workers.

O

N H

O

O

O Fredericamycin A

N H 110

Scheme 17. Total Synthesis of Fredericamycin A by Boger and coworkers.

Nothapodytine B (122) was isolated from Nothapodytes foetida of which the ethanol extract exhibits significant 58 cytotoxity in the human KB cell line. Nothapodytine B is an oxidized derivative of Mappicine (123) (Scheme 18) and an Ering decarboxylated analogue of camptothecin 125 (Scheme 19). The total syntheses of naturally occurring nothapodytine B and (–)-mappicine was achieved by Boger and coworkers based on the implementation of a room temperature azaDiels–Alder reaction of N-sulfonyl-1-azadiene 124 in 1998 59 (Scheme 18). Treatment of 124 with 1,1-dimethoxy-1propene 125 at room temperature (12 h, C6H6) led to the formation of the sensitive cycloaddition adduct 126. o Hydrolysis, subsequent aromatization (t-BuOK, THF, -35 C, 30 o min) and addition of EtMgBr (EtMgBr, Et3N, toluene, -10 C, 4 h, 79%) proceeded to give the corresponding ethyl ketone 127 in good yield. Deprotection both of the benzylic and pyridine o methyl ethers of 127 (HBr(g) in CF3CH2OH, 80 C, 24 h; K2CO3, o 25 C, 1 h) provided nothapodytine B 122 in 88% overall yield. Reduction of nothapodytine B with NaBH4 provided (±)-

(+)-Camptothecin (125) is a pentacyclic alkaloid isolated from the Chinese plant Camptotheca acuminata in 1966 by Wani 60 and Wall. Its total synthesis was completed by Boger using the same strategy as the approach of Nothapodytine B 61 (Scheme 19). The inverse electron demand aza-Diels–Alder cycloaddition between the electron deficient N-sulfonyl-1-aza1,3-butadiene 126 and the electron rich 1,1,3,3o tetraethoxypropene 127 proceeded at 25 C and ambient pressure to give the desired [4+2] cycloaddition adduct 128, which underwent elimination of methanesulfinic acid and o ethanol under mild conditions (NaOEt, 0 C, 1-1.5 h) to provide the highly substituted 2-ethoxypyridine 129. 129 was converted to the corresponding ethyl ether using ZnI2 and Et3SiH which cleanly gave 130 in 92% yield. The ethyl ester 130 was directly converted to ethyl ketone 131 by addition of EtMgBr in the presence of excess Et3N. Additional treatment of 131 involving Wittig-reaction, Sharpless asymmetric dihydroxylation and oxidation afforded the corresponding carboxylic acid 132 which, after ether cleavage in HBr and ring closure catalyzed by potassium carbonate gave (+)Camptothecin 125.

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o

78 C, 1h; TsOH, NaBr, CH3OH, 70 C, 12 h) with air oxidation (3 h) following the BBr3 treatment provided fredericamycin A in 85% yield.



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Scheme 19. Total Synthesis of (+)-Camptothecin by Boger and coworkers.

Pipericidin A1 (133) and Piericidin B1 (134)，are part of an important class of biologically active natural products isolated 62 from Streptomyces mobaraensis. Their total synthesis has been completed by Boger employing an inverse electron demand aza-Diels–Alder reaction of N-sulfonyl-1-azabutadiene 63 136 and tetramethoxyethene 137 (Scheme 20). Treatment of sulfonyimine 136 derived in two steps from 135 with the o electron-rich dienophile 137 (toluene, 50 C, 18h) smoothly afforded the [4+2] cycloaddition adduct 138. Boron trifluoride o diethyletherate complex in CH2Cl2 (0 C, 1h) cleanly affected the transformation from 138 to 139 in 88% yield, and a further six functional interconversion steps yield 140. Palladium catalyzed coupling (Pd(dba)3, t-Bu3P, LiCl, dioxane, 18 h) of 140 with 141 provided 142 in 74% yield. A final deprotection of o the TBS ether 142 (Bu4NF, THF, 50 C, 12 h, 93%) provided pipericidin A1 133; additional O-methylation of the secondary alcohol and pivolate hydrolysis provided piericidin B1 134.

Scheme 20. Total Synthesis of Pipericidin A1 & B1 by Boger and coworkers.

Meridine (143), isolated from the ascidian Amphicarpa 64 meridian and Cystodamine (144), isolated from a 65 mediterranean ascidian Cystodytes delle chiajei, are alkaloids with an interesting fused pentacyclic structure. Kubo achieved the total synthesis of meridine and cystodamine employing an intermolecular aza-Diels–Alder reaction of o66 nitrocinnamaldehyde dimethylhydrazone 145 (Scheme 21). The [4+2] cycloaddition proceeded between azadiene 145 and substituted quinolinedione 146 (R=Cl) or 147 (R=OMe) to afford cycloadduct 148 and 149 respectively. The chloroquinone 149 (R=Cl) was heated with sodium azide in aqueous N,N-dimethylformamide to afford aminoquinone which provided cystodamine 144 in 88% yield after catalytic hydrogenation (H2, Pd-C, MeOH). The pyridoquinolinequinone 149 (R=OMe) was catalytically hydrogenated in methanol to afford pentacyclic compound 150 in 91% yield. Heating 150 in the presence of 57% hydroiodic acid furnished the dimethylated product meridine 143 in 89% yield.

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Scheme 23. Total Synthesis of Calothrixin B by Guingant and coworkers.

Scheme 21. Total Synthesis of Cystodamine & Meridine by Kubo and co-workers.

Sebastianine A (151) was first isolated in Brazil from ascidian 67 Cystodytes delle chiajei. Its total synthesis has been accomplished by Delfourne in 2003 via intermolecular azaDiels–Alder reaction of indole-4,7-dione and trifluoroacetamido-cinnamaldehyde dimethylhydrazone 68 (Scheme 22). The [4+2] cycloaddition reaction between azadiene 152 and indole-4,7-dione 153 in refluxing toluene afforded a mixture of the two regioisomers 154 and 155 in low yield after aromatization by MnO2 (6%). The aza-Diels–Alder adduct 154 was subsequently cyclised under alkaline conditions to give the corresponding pentacyclic compound sebatianine A in 85% yield.

Scheme 22. Total Synthesis of Sebastianine A by Delfourne and coworkers.

Calothrixin B (156) was obtained from the cell extracts of 69 Calothrix cyanobacteria. Its total synthesis was achieved by Guingant employing an aza-Diels–Alder reaction between 2aza-1,3-diene 157 and 3-bromo-9h-carbazole-1,4-dione 158 as a key step to construct the pentacyclic skeleton of the 70 molecule (Scheme 23). Stirring the azadiene 157 and bromoo activated dienophile 158 in acetonitrile at 40 C for 48 hours delivered the [4+2] cycloaddition adduct 159 in 80% yield. Additional aromatization triflate formation and subsequent palladium-mediated reduction afforded calothrixin B.

Phomazarin (160) was isolated by Hansen in 1940 from Phoma 71 terrestris fungus. Its original structure assignment has been 72 revised twice. In 1999, Boger completed the total synthesis of phomazarin employing an inverse electron demand azaDiels–Alder reaction between triethyl 1,2,4-triazine3,5,6tricarboxylate 161 with trimethoxyethylene 162 (Scheme 73 24). The key [4+2] cycloaddition between the 1,2,4-triazine 161 and 1,1,2-trimethoxyethylene 162 provided the fully substituted pyridine 163 in 85% yield. Exhaustive ester hydrolysis of 163 provided the tricarboxylic acid which, when treated with TFAA followed by CH2N2 esterification provided the key cyclic anhydride 164. The remaining addition of the aryllithium reagent 165 to 164 provided 166 with selective uncleophilic addition to the least hindered of the cyclic anhydride carbonyls. Reduction of 166 by NaBH4 followed by hydrogenolysis furnished 167 in excellent yield. Exposure of o 167 to TFAA (50 C, 72 h) provided 168, which was subsequently converted to phomazarin in four steps involving methanolysis, oxidation and deprotection.

Scheme 24. Total Synthesis of Phomazarin by Boger and co-workers.

Ningalin B (169) was isolated from an ascidian of the genus 74 Didemnum collected in Western Australia near Ningaloo reef. Its total synthesis was completed by Boger utilizing a heterocyclic azadiene Diels–Alder reaction between 1,2,4,575 tetrazine and 1,2-diazine (Scheme 25). Boger took the advantage of azadiene Diels–Alder reaction contraction process to quickly and efficiently synthesise its substituted pyrrole core. 1,2-Diazine 172, obtained from the aza-Diels– Alder reaction of the electron-rich acetylene 170 with the electron-deficient 1,2,4,5-tetrazine 171 in excellent yield o (mesitylene, 140 C, 92%), afforded the core pyrrole structure 173 after reductive ring contraction (Zn, HOAc, 62%).

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Additional N-alkylation with phenethyl bromide and subsequent MOM deprotection with concomitant lactonization (HCl-EtOAc, 95%) provided mono-lactone 174, which was converted to ningalin B by selective hydrolysis of the methyl ester using LiI, decarboxylation, and exhaustive demethylation with BBr3.

cycloaddition adduct 183. The bicyclic adduct 183, as the desired exo diastereomer, was isolated in 79% yield. Additional treatment of 183 with Sm(OTf)3 in refluxing MeOH followed by Boc2O/DMAP furnished 184 in excellent yield. Exposure of 184 to n-Bu4NF resulted in fragmentation to nitrile 185 in 81% yield. Enol 185 was subjected to a Krapcho decarboxylation o 79 (DMSO, H2O, 130 C) to provide ketone 186 (99%) which was converted to primary amine 187 in six steps, involving the transposition of nitrogen from the nitrile to a protected amine and reduction of the carbonyl group. Penultimate amine 187 was heated in refluxing CHCl3 for 3 days provided (–)epibatidine in 95% yield. A highly selective synthesis of (–)epobatidine was thus achieved in 13 steps and 13% overall yield from 6-chloropyridine-3-carboxyaldehyde 181, where an aza-Diels-Alder reaction once again served as the lynchpin for installation of both polycyclic complexity and absolute stereochemistry.

Scheme 26. Total Synthesis of (–)-Epibatidine by Evans and coworkers.

Scheme 25. Total Synthesis of Ningalin B by Boger and co-workers.

The product of aza-Diels–Alder reaction, like pyridazine 172, can undergoes a reductive ring contraction reaction to form highly substituted pyrroles. It has been used to synthesise a number of highly complex structures in an efficient manner. This methodology was applied to the synthesis of other structurally interesting and biologically active marine natural products, such as Ningalin A, Lamellarin O, Lukianol A and 76 Ningalin D. (–)-Epibatidine (179) is an alkaloid isolated from the skin of the 77 Ecuadorian frog Epibatidores tricolor. For its total synthesis, a highly exo-selective asymmetric aza-Diels–Alder reaction was 78 employed as a key step by Evans et. al. (Scheme 26). The azaDiels–Alder reaction between azadiene 180 and oxazolidinone 182, prepared from aldehyde 181, produced enantiopure

Martinelline (188) and Martinellic acid (189) were isolated from the medicinal plant Martinella iquitosensis by the Merck 80 group. In 2002, Batey achieved the total synthesis of martinelline and martinellic acid using a protic acid catalyzed 2:1 aza-Diels–Alder coupling reaction between methyl 481 aminobenzoate 190 and N-Cbz 2-pyrroline 191 (Scheme 27). The initial Povarov reaction between substituted aniline 190 and 2 equiv of endocyclic enamine 191 yielded the corresponding tricyclic triamine core 192 in 74% yield as an 89:11 mixture of diastereomers in favor of the desired exo192a. 192a was converted into guianidine 193 via a sequence of protection, hydrogenation and HgCl2-promoted guanidinylation. The installation of the second guanidine was accomplished by deprotection of both Troc groups (Zn, THF, pH=4, rt, 2 h) followed by refluxing in the presence of o isothiourea 194 (MeCN, 75 C, 6 h) to afford the bisguanidine compound 195. Conversion to the free carboxylic acid 196 was attained by reflux of a solution of methyl ester 195 in 3:1

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MeOH/aqueous NaOH (0.2 M) for 16 h. Coupling of fragments 196 and 197 using BOP-Cl and Hunig’s base provided protected martinelline 198 in 78% yield. Global deprotection of the Boc groups (TFA/CH2Cl2, rt) followed by reverse-phase preparative HPLC gave (±)-martinelline 188. Alternatively, deprotection of the remaining two Boc groups of 196 with TFA/CH2Cl2 afforded (±)-martinellic acid 189 in 73% yield. The total synthesis of (±)martinelline and (±)-martinellic acid was completed in nine steps and 10% overall yield.

present in the hexahydropyrroloquinone core were generated in one synthetic operation. A three component aza-Diels–Alder reaction of enamine 200 with the imine which derived from aniline 199 and ethyl 2-oxoacetate provides cycloaddition adducts 201 and 202. Additional regioselective reduction and protection of the diester 202 afforded the alcohol 203. A Swern oxidation of 203 gave the corresponding aldehyde as a mixture of trans- and cis-isomers, which was condensed without purification with (carbethoxymethylene)triphenylphosphorane, giving diester 204 (6% yield) and 205 (85% yield). Following the same procedure, exo-isomer 201 was transformed to the diester 205 in 61% overall yield. Additional transformationt of 205 involving reduction of the carbon-carbon double bond and ethyl ester group, conversion of the hydroxyl to an azide, and reduction of the azide moiety provided 206. Condensation of the triamine 206 with Smethylisothiourea 207 gave the guanylation product 208. After hydrolysis of 208 (NaOH/MeOH), the resultant acid was coupled with 197 mediated with EDCl to provide the ester 198 in 80% yield. Treatment of 198 with 5% TFA under the assistance of anisole afforded (±)-martinelline 188. The total synthesis of (±)-martinelline 188 was achieved in 17 linear steps and 8% overall yield.

Scheme 28. Total Synthesis of Martinelline by Ma and co-workers.

Scheme 27. Total Synthesis of Martinelline & Martinellic acid by Batey and co-workers.

Ma has also reported the total synthesis of (±)-martinelline by employing an imino-Diels–Alder reaction strategy to assemble 82 the core structure of martinelline (Scheme 28). The advantage of this approach was that all three chiral centers

(+)-Alantrypinone (209), first isolated from extracts of the 83 fungus Penicillium thymicola in 1998, possesses an interesting fused, bridged and spirocyclic hexacyclic core. Five years after the isolation, Kende completed the total synthesis of alantrypinone using a novel aza-Diels–Alder reaction as the 84 key step (Scheme 29). The aza-Diels–Alder reaction between azadiene 210 and 3-methyleneoxidole 211 proceeded successfully in chloroform at room temperature to produce a chromatographically separable mixture of exo-isomer 212 in 55% yield and its endo isomer adduct. Mild hydrolysis (1.0N HCl/EtOAc, rt, 5 h) of the [4+2] cycloaddition adduct 212 provided (±)-alantrypinone in 85% yield. Thus, the total synthesis of (±)-alantrypinone (209) was achieved by an aza-

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Diels–Alder reaction starting from anthranilic acid in 8 steps and 13.5% overall yield. Using a similar strategy, Loiseleur and Houk first reported the total synthesis of (±)-lapatin B in only 5 steps and 8% overall 85 yield (Scheme 29). The improvement in the key aza-Diels– Alder reaction step, combiend with a concise synthesis of the 2-azadiene precursor 210, provides an elegant access to diasteromers of (±)-lapatin B. The initial aza-Diels–Alder reaction between the unsubstituted diene 210 (R=H) and 3o methyleneoxidole 211 (TfOH, CH2Cl2, -20 C) provided exoadduct 213 in 32% yield, together with its endo-isomer in 33% yield. Hydrolysis of exo-adduct 213 (2 N HCl, EtOAc, rt) led to the precipitation of water-soluble salt 214, which upon further heating for 1.5 h in EtOAc cyclized to afford (±)-lapatin B in 83% yield.

Scheme 29. A) Total Synthesis of (±)-Alantrypinone by Kende and coworkers.; B) Total Synthesis of (±)-Lapatin B by Loiseleur and Houk et al..

More recently, Ma’s group has achieved the total synthesis of indoline-containing (±)-Spiroquinazoline (216), (–)Alantryphen-one (217)，and (+)-Lapatin A (218) (Scheme 30), the key elements include the formation of aminalembodied 86 olefins and their aza-Diels–Alder reaction with the azadienes. o Heating a mixture of 219 and 220 in xylene at 130 C afforded the desired [4+2] cycloadduct 221, (along with its two isomers), and additional hydrolysis and hydrogenolysis of 221 furnished (±)-Spiroquinazoline (216, R=H), and (–)Alantryphenone (217, R=Bn). The total synthesis of (+)-lapatin A is slightly different from (±)-Spiroquinazoline and (–)Alantryphenone. Cycloaddition of 223 and 224 furnished the desired adduct 225 plus three isomers. Hydrolysis of 225 afforded lactam 226, which was treated with DBU in DMSO at o 110 C to give a mixture of 226 and the desired diastereomer 227. After hydrogenolysis of 227, lapatin A was isolated in 83% yield.

Scheme 30. Total Synthesis of (±)-Spiroquinazoline, (-)-Alantryphenone ，(+)-Lapatin A by Ma and co-workers.

Thiostrepton (228), one of nature’s most intriguing molecules, 87 was first isolated from Streptomyces azureus. The synthesis of its key building block 232 was based on a biosynthetically inspired aza-Diels–Alder dimerization of an appropriate 88 thiazolidine 229 (Scheme 31). Treatment of 229 with silver carbonate in the presence of DBU then benzylamine produced azadiene 230, whose spontaneous aza-Diels–Alder dimerization upon aminolysis afforded the dehydropiperidine core primary amine 232 (5R, 6S) and its isomer (5S, 6R). Additional treatment of 232 involving coupling the (S)-2azidopropanoyl chloride, transesterifcation, azide reduction, primary amine protection and treatment with TFA/DCM led to 233. Coupling the thiazoline containing carboxylic acid 234 to 233 followed by azido reduction and ring closure afforded 235. Finally, coupling of two peptides to 235 followed by oxidation/elimination of PhSe- group, then deprotection/ dehydration, led to thiostrepton.

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CO2Et

S

N S

NH

Ag2CO3, DBU

H N Me

N

O


EtO2C

N

O

CO2Et

N

H2N 5R

Me

NBoc

H

4 steps MeO 2C

S

Me

BocN

O

231 NHAlloc O

COOH

S CO2Me TBSO

N

HN N

N 6S

N

N3

S H

O Me

Me

S OTES

Me

TESO

S

SePh H N

N

6 steps

N

MeO

OH

C Me

TESO

OTBS

HN

OH FmO

S Me

O

235

O H N

N H

O

O

Me

O N

Me OTBS Me NH H

N

H N Me

S

O

NH2

PhSe

Me

S

N

Me

Me HO

N

O

SePh

Me

O

HN

O

N

HN

NH

TBSO

O

NH N H

N

Me

HN

O S

S

O

S

S H S

N

N H

N

N

N

N H NH

S

CO2Me

N

HN

O C

ester hydrolysis

234

233 O

NHAlloc O

OTBS N OH H Me

N

OH

H2N

232

O

NH

N

N Me

S

Me

N

S

O Me

N Boc

230

N

Me

O

S

S

Me

S

OTBS

Me N

N

NBoc

229

S

N

S

S

Me

NBoc

EtO2C

N

aza-Diels-Alder dimerization

N

pyridine -12oC

S

O

CO2Et

S

N

Scheme 32. Total Synthesis of Amythiamicin D by Moody and co-

OTBS

236

HO OTBS O S N

S N H

NH

Me

N

Me O

HN

O N

H N Me

S

O

Me

S

HO HN

O

NH

MeO

2 steps

NH2

O

N N

workers.

O

H N

N H

N H

O O N

NH Me OH

O

O Me

Me NH H

N S Me

O HO OH

OH

thiostrepton 228

Scheme 31. Total Synthesis of Thiostrepton by Nicolaou and coworkers.

Amythiamicin D (237), belong to an increasing class of complex naturally occurring compounds, and was isolated in 1994 by Takeuchi et al. from a strain of Amycolatopsis sp. MI48189 42F4. Its total synthesis was completed by Moody utilizing an aza-Diels–Alder route between enamide dienophile 238 and azadiene 239 to form the pyridine core of the antibiotic as a 90 key step (Scheme 32). Heating the enamide 238 and o azadiene 239 under microwave irradiation in toluene at 120 C for 12 h gave the required pyridine core of the natural product amythiamicin D 240 in a modest 33% yield. Additional steps involving deprotection of N-Boc-group and coupling to N-Bocglycine, removal the benzyl ester using palladium black and coupling of the left-hand bis(thiazole) 241 provided the cyclization precursor 242. Cleaving the terminal N-Boc and tert-butyl ester and the resulting amino acid treated with diphenylphosphoryl azide (DPPA) and Hünig’s base afforded the target molecular amythiamicin D in 73% yield over two steps.

Annomontine (243), was one of the first members of the class of 1-(2’-aminopyrimidin-4-yl)-β-carboline alkaloids. It has been isolated from Annona montama, Annona reticulate, Annona 91 foetida, and Annona purpurea. Recently, Kusurkar has completed the total synthesis of annomontine utilizing an aza92 Diels–Alder reaction as the key step (Scheme 33). Treatment o of the methyl ester 244 with hydrazine hydrate (THF, 150 C, 20 min) gave unstable hydrazide 245, which was immediately o treated with glyoxal (NH4OAc, CH3COOH, 180 C, MW, 10 min). The reaction mixture was further irradiated in a microwave oven for 30 min along with indole to get the desired Cbzprotected aza-Diels–Alder adduct 247. Deprotecting of 247 using H2 and Pd/C furnished annomontine 243 in 78% yield. It was interesting that widely used microwave strategy was successfully applied in the aza-Diels–Alder reaction.

Scheme 33. Total Synthesis of Annomontine by Kusurkar and coworkers.

More than forty kinds of natural products with excellent biological activities have been synthesized ultilizing

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intermolecular aza-Diels–Alder reaction in this first and largest part. The basic strategy outlined above have been proved to be very useful synthetic methods and can be extended to achieve the total synthesis of some kinds of other alkaloids. Resperine (90), one of the earliest total synthesis, first successful total synthesis by Woodward in 1956, was synthesized again by Jacobson in 2013 by using an imino Diels– Alder reaction as a key step. Thiostrepton (228), one of the nature’s most intriguing molecules, was also synthesized by Nicolaou ten years ago. This strategy is still playing an 93 increasingly important role in organic synthesis. And although there has been significant progress in expanding the utility of aza-Diels–Alder reaction, there is still work that remains in increasing the yields and expanding its application range of these processes. 3. Intramolecular aza-Diels–Alder reaction 3.1 Imines as electron deficient dienophiles δ-Coniceine (248) is a semisynthetic alkaloid derived from 94 coniine. Weinreb et. al. used an intramolecualr aza-Diels– Alder cycloaddition of acetate 250 to form the bicyclic 95 A toluene solution of 4,6framework. (Scheme 34). dienamidomethyl acetate 250 was rapidly passed through a o 15-cm column of glass helices maintained at 370-390 C afforded bicyclic lactam 252, which was reduced (5% Pd-C, EtOAc, 1 atm) to afford lactam 253. Additional reduction of 253 with diborane gave racemic δ-Coniceine. Tylophorine 96 (249), isolated from Tylophora indica (Asclepiadaceae). was synthesized by a similar strategy (Scheme 34). Pyrolysis of the o acetate 254 in bromobenzene at 220 C for 5 h yielded the pentacyclic lactam 256 in 50% yield. The lactam carbonyl 256 was reduced with LiAlH4 in THF at room temperature to produce racemic tylophorine 249 in 64% yield.

Elaeokanine A (257), was isolated from Ekaeocarous kaniensis 97 Schltr., a large rain forest tree found in New Guinea. Its total synthesis was completed by Weinreb utilizing the intramolecular imino-Diels–Alder reaction as the key ring98 forming step (Scheme 35). A dilute toluene solution of 258 was slowly passed through a 15-cm column of glass helices o maintained at 370-390 C providing 260 in 68% yield which probably occurs via the unisoable diene-acylimine 259. Hydrolysis of 260 (MeOH/H2O/HCl) led to alcohol 261 which gave amino alcohol 262 in 91% yield upon reduction with DIBAL-H in THF. Additional treatment of 262 with o DMSO/trifluoroacetic anhydride in CH2Cl2 at -78 C gave racemic elaeokaine A in 62% yield.

Scheme 35. Total Synthesis of Elaeokanine A by Weinreb and coworkers.

Epi-lupinine (263), isolated from the seeds of Lupinus varius L. 99 (Leguminosae) and Cryptopleurine (264), was isolated by 100 Saifah et. al. from Cissus rbeifolia Planch, were also synthesized by Weinreb utilizing an intramolecular iminoDiels–Alder reaction to construct the quinolizidine ring system 101 (Scheme 36). Upon heating in refluxing o-dichlorobenzene, methylol acetate 265 cleanly cyclized to afford a single bicyclic lactam 268 in 93% yield. Additional hydrogenation with (H2/Pd-C, MeOH) and reduction with (diborane/THF) provided racemic epi-lupinine 263. Cryptopleurine 264 was synthesized from methylol acetate 270 by a similar strategy.

Scheme 36. Total Synthesis of Epi-lupinine and Cryptopleurine by Weinreb and co-workers.

Scheme 34. Total Synthesis of δ-Coniceine and Tylophorine by Weinreb and co-workers.

In 1988, Grieco et. al. have also reported the total synthesis of (±)-Lupinine (78), (±)-Epi-lupinine (263), (±)-Cryptopleurine (264), and (±)-Julandine (272) (Scheme 37), it is much more efficient employing an intramolecular aza-Diels–Alder reaction 102 for the construction of the quinolizidine alkaloids. When a 0.1 M aqueous solution of the hydrochloride salt of 273 was

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treated with 3.0 equiv of 37% aqueous formaldehyde solution o at 65 C for 28 h, the desired [4+2] cycloadduct 275 and 276 (275:276=1.6:1) were isolated in 82% yield. Additional hydrogenation and reduction of 275 and 276 provided racemic lupinine and epi-lupinine. (±)-Cryptopleurine 264 was synthesized in a similar manner but slightly different of equiv of formaldehyde and refluxing temperature. Isojulandine 281 was also synthesized using this strategy, with double-bond isomerization employing p-toluenesulfonic acid in refluxing benzene ultimately affording (±)-julandine 272 in 86% yield.

Scheme 38. Total Synthesis of (-)-8a-Epipumiliotoxin C by Grieco and co-workers.

(±)-Eburnamonine (287), a new class of pentacyclic indole 105 alkaloid, was isolated from Hunteria eburnean Pichon. Its total synthesis was completed by Grieco via an intramolecular imino Diels–Alder reaction of vinyl indole imine (Scheme 106 The cycloaddition of Vinyl indole imine 288 could be 39). performed in 5.0 M lithium perchlorate-diethyl ether containing 0.1 equiv of camphorsulfonic acid afford the azaDiels–Alder reaction adduct 289 in a remarkable yield (96%). The subsequent conversion of 289 into (±)-Eburnamonine 287 required an additional isomerization using deoxygenated 6.0 M sulfuric acid in refluxing ethanol.

Scheme 37. Total Synthesis of (±)-Lupinine, (±)-Epi-lupinine, (±)-

Scheme 39. Total Synthesis of (±) – Eburnamonine by Grieco and coworkers.

Cryptopleurine, (±)-Julandine by Grieco and co-workers.

Pumiliotoxin C was isolated from the skin secretions of the 103 brightly colored Panamanian frog Dendrobates pumilio. The total synthesis of (-)-8a-epi-pumiliotoxin C (282) was completed by Grieco utilizing an intramolecular immonium ion 104 based Diels–Alder reaction (Scheme 38). The strategy for elaborating octahydroquinoline systems centered around intramolecular cyclodondensation of the immonium ion derived from aldehyde and ammonium, shows the ability of immonium ions to function as aza-dienophiles in aza-Diels– Alder reaction carried out under Mannich-like condition holds considerable promise for the construction of nitrogencontaining ring systems. Treatment of dienyl aldehyde 283 in ethanol with an equal volume of aqueous ammonium chloride o at 75 C for 48 h provided 285 and 286 in a ratio of 2.2:1. 285 converted into (-)-8a-Epipumiliotoxin C upon reduction (H2, 10% Pd/C, MeOH) in 98% yield.

Quinolizidine (–)-217A (290), is an amphibian alkaloid isolated by Daly in 1993 from skin extracts of the Medagascan frog 107 Mantella baroni. Its synthesis was achieved by Danheiser using an intramolecular iminoacetonitrile [4+2] cycloaddition reaction as the key step in an efficient assembly of the quinolizidine core of the alkaloid (–)-217A, more efficient and enabling the total synthesis of this natural product in only 12 108 steps (Scheme 40). Exposure of 291 to cesium carbonate led to the elimination of trifluoromethanesulfinate and formation of [4+2] adduct iminoacetonitrile 292, which produced the o desired -amino nitrile 293 after heating at 130 C for 36 hours. Alkylation of 293 with (Z)-3-bromo-1-chloropropene and reductive decyanation of the crude alkylation product afforded the desired quinolizidine 294 in 74-77% overall yield. Treatment of silyl enol ether 294 with 1.1 equiv of n-Bu4NF in THF generated ketone 295 as a single diastereomer with the C1 methyl group in the desired equatorial orientation. Additional treatment of 295 involving reductive excision of the

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Scheme 42. Total Synthesis of (±)-Coniceine by Jung and co-workers.


112

Scheme 40. Total Synthesis of Quinolizidine (–)-217A by Danheiser and co-workers.

Sedum alkaloid sedridine was isolated from Sedum acre. In 1991, Yamamoto completed the total synthesis of (±)Sedridine (302) using an intramolecular aza-Diels–Alder reaction of an N-acyl derivative of 1-aza-1,3-butadiene as the 113 key step (Scheme 43). A solution of acrolein was treated o o with lithium hexamethylsilazide (THF, -78 C to 20 C, 1 h) and o o o TMSCl (0 C to 20 C, 1 h) and chloroformate 305 (THF, 20 C, 30 min). The reaction mixture was diluted with xylene, THF was removed and the xylene solution was heated to reflux for 63 h. Removal of the solvent gave the desired [4+2] cycloaddition adduct 307 in 30% yield. After hydrogenation and treatment with a boiling aqueous KOH solution, diluted hydrochloric acid, and 10% NaOH, (±)-Sedridine was obtained.

Tricyclic alkaloid lepadiformine A was isolated from the 109 tunicate Clavelina lepadiformis in 1994. Recently, Lygo has completed the total synthesis of (±)-Lepadiformine A (297) via intramolecular aza-Diels–Alder reaction of ester imine 110 (Scheme 41). Simply heating the tert-butyl ester imine 298 o in hexafluoroisopropanol at 60 C produced the tricyclic acid 299 in 53% yield. 299 was readily converted into (±)Lepadiformine A (52% over two steps) by hydrogenation of the alkene followed by reduction of the carboxylic acid using lithium aluminium hydride. Scheme 43. Total Synthesis of (±) – Sedridine by Yamamoto and coworkers.

Scheme 41. Total Synthesis of (±)-Lepadiformine A by Lygo and coworkers.

3.2 Imines as electron deficient azadienes In 1991, Jung also reported the total synthesis of (±)-Coniceine (248) utilizing intramolecular aza-Diels–Alder reaction of 1111 acyl-1-azabutadiene as the key step (Scheme 42). Refluxing azabutadiene 300 in benzene for 28 h produced the enamide 301 in 46% yield. Hydrogenation of 301 followed by hydride reduction afforded (±)-Coniceine. Compare to Weinreb’s approach, Jung get the same result by different means. The same point is that they all need high temperature to get the precusor 251 and 300 of the intramolecular aza-Diels–Alder reaction, and the different point is that the construction for the bicyclic framework 252 and 301. Weinreb’s approach using an imine as dienophile and a diene, Jung’s approach using alkene as dienophile and a 1azadiene in one molecule.

Fused pentacyclic alkaloid (–)-Normalindine (309) was first isolated from the root bark of Strychnos johnsonii 114 (Loganiaceae) in 1987. Its total synthesis was completed by Ohba using an intramolecular aza-Diels–Alder reaction as the 115 key step (Scheme 44). Reduction of a 3:1 mixture of 310a o and 310b (diisobutylaluminum hydride, CH2Cl2, -78 C, 20min) provided the corresponding aldehyde which reacted with ethyl- (triphenylphosphoranylidene)acetate (CH2Cl2, rt, 3 h) affording a 3:1 mixture of the (E)-esters 311a and 311b and a 3:1 mixture of the (Z)-esters 313a and 313b in 59% and 26% yield, respectively. When the 3:1 mixture of (E)-esters 311a and 311b was heated in boiling toluene for 24 h, the adducts 312 (53% yield) and an iaomer (5% yield) were formed. Similarly, the 3:1 mixture of (Z)-esters 313a and 313b underwent the intramolecular aza-Diels-Alder to give the adduct 314 in 40% yield. Treatment with AcOH-xylene (1:5, reflux, 8h), 312 and 314 was converted into the aromatic ester 315, which was converted into (-)-Normalindine 309 after removal the ester group.

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carbonyl group and Sonogashira coupling trimethylsilylacetylene afforded quinolizidine (–)-217A.

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hydrobromic acid to afford ethyl ester 330. Ethyl ester 330 reacted with methanol in the presence of conc. H2SO4 to afford methyl ester nothapodytine B 325, which was converted into 119 mappicine 123 by Kametani’s method.

Scheme 44. Total Synthesis of (–)-Normalindine by Ohba and coworkers.

Lycorine alkaloids, such as anhydrolycorinone (317) and hippadine (318), belong to the Amaryllidaceae family of 116 alkaloids. Their total syntheses were achieved by Boger employing two sequential intramolecular azadiene Diels–Alder 117 reactions (Scheme 45). The first intramolecular aza-Diels– Alder reaction was accomplished at room temperature in superb yield upon N-acylation of 319 with Boc2O and catalytic DMAP, affording the intramolecular [4+2] cycloaddition adduct 320 in 96% yield. 322 can be easily obtained from 320 in two steps. Simply heating 323 converts it into anhydrolycorinone precursor 324, which provided anhydrolycorinone by reductive o desulfurization with Raney nickel (EtOH, 25 C, 5 h, 97%). Anhydrolycorinone could subsequently converted to o hippadine by oxidation (DDQ, 80 C, 24 h, 65%).

Scheme 45. Total Synthesis of Hippadine & Anhydrolycorinone by Boger and co-workers.

Scheme 46. Total Synthesis of Mappicine & Nothapodytines B by Toyota & Ihara et al..

Camptothecin is a naturally occurring alkaloid possessing potent antitumor activities and clinical applications. Recently, Yao has also reported the total synthesis of camptothecin (125) utilizing an intramolecular aza-Diels–Alder reaction of 120 amide 333 as the key step (Scheme 47). Amide 333 was synthesized from known chloro-pyridine 331 in five steps. Treatment with bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate at room temperature produced [4+2] cycloaddition adduct 335 in 96% yield. Additional treatment of 335 involving a modified Sharpless asymmetric dihydroxylation and an I2/CaCO3-based hemiacetal oxidation afforded (+)-camptothecin 125 in 83% yield (2 steps) and 95% ee. Compare to Boger’s inverse electron demand aza-Diels–Alder reaction of 126 with electron-rich olefin 127 to construct the pyridone CDE ring of the polycyclic quinoline alkaloid or any 121 other C-ring construction approach, BC rings construction 122 123 approach, B-ring construction approach, D-ring 124 125 construction approach and biomimetic synthesis. Yao developed a mild and efficient cascade methodology to construct indolizino[1,2-b]quinolinone BC rings, and an eightstep total syntehsis of comptothecin was accomplished from a known pyridine derivative in direct fashion with an overall yield of 47%.

In 2000, Toyota and Ihara also reported the total synthesis of mappicine (123), and nothapodytine B (325) via an intramolecular aza-Diels–Alder reaction of an unsaturated 118 amide 328 as the key step (Scheme 46). Reduction of 326 with triphenylphosphine followed by condensation with fumaric acid monoethyl ester 327 (BOP, i-Pr2Net, MeCN) gave the unsaturated amide 328 in 67% overall yield. Intramolecular aza-Diels–Alder reaction of 328 led to the [4+2] cycloaddition adduct 329 in 76% yield, which was treated with aqueous

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Luotonin A (336) is a new pyrroloquinazolinoquinoline alkaloid isolated from the aerial parts of Peganum nigellasterum 126 (Chinese Bunge). Its total synthesis was completed by Toyota and Ihara using an intramolecular aza-Diels–Alder reaction of an aryl imino ether (diene) with an aryl nitrile 127 (dienophile) as the key step in 2003 (Scheme 48). The nitrile 339 was synthesized from the commercially available amine 337 in 2 steps in high yield. Heating 339 with o chlorotrimethylsilane (TMSCl, ZnCl2, NEt3, Toluene, 150 C) produced luotonin A in 46% yield.

Scheme 49. Total Synthesis of Luotonin A by Batey and co-workers.

Scheme 48. Total Synthesis of Luotonin A by Ihara & Toyota et al..

In 2004, Batey has also reported the total synthesis of Luotonin A (336), using a late stage three component Povarov reaction as the key step for the construction of pyrrolo[3,4128 b]quinoline CD ring (Scheme 49). Ring-opening of commercially available isatoic anhydride 341 with propargylamine gave 2-amino benzamide 342. N-Acylation of 342 with acetoxyacetyl chloride (AcOCH2COCl, Et3N, benzene, o 40 C-rt, 16 h) proceeded to give 343 in 68% yield. Reaction of 343 with triphenylphosphine (PPh3, I2, i-PrNEt, CH2Cl2, 5 h, rt, 89%) afforded 344 in excellent yield. One-pot rearrangement of 344 using piperidine followed by silica gel gave 345 in 85% yield. Treatment of 345 with 1 M NaOH in THF/H2O and subsequent oxidation using the Dess-Martin periodinane gave the aldehyde 346 in good yield over two steps. Intramolecular Povarov reaction between 346 and aniline occurred in the presence of 10 mol % Dy(OTf)3 in acetonitrile for 24 hours to give luotonin A. Toyota and Ihara’s approach using an aryl nitrile as dienophile and a 1-azadiene, and Batey’s approach using alkyne derivative as dienophile and a 2-azadiene derived from aldehyde 346 and aniline for the construction of CD ring. This Povarov approach was also applied to the formal synthesis of lavendamycin methyl ester and nitramarine by 129 Nagarajan featured inexpensive catalyst with good yield.

Recently, Boger has also reported the total synthesis of Vindoline (7a) and Vindorosine (7b) utilizing intramolecular 130 aza-Diels–Alder reaction as the key step (Scheme 50). Coupling of 2-(1-methylindol-3-yl)acetic acid 347 with (Z)-348 and (E)-348 provided 349 and 350 respectively. Cyclization of Z-isomer 349 provided the desired cycloadduct 353 as the major diastereomer (6-10:1 dr) when heated in o-Cl2C6H4 o (140 C, 20 h). Additional reduction (NaCNBH3, HCl, THF/i-PrOH, o 0 C, 1 min, 99%) of 353 provided 355 in quantitative yield. The cycloadduct 356 was obtained by the similar strategy. The two cycloadducts 355 and 356 were converted to the same key intermediate 359 by hydrogenation and alcohol acetylation or oxidation/ketone reduction then alcohol acetylation. 359 was duly converted to vindoline and vindorosine in 9 steps. Boger’s cascade approach is initiated by an intramolecular inverse electron demand aza-Diels–Alder reaction of an electron-rich dienophile tethered to the 1,3,4-oxadiazole and is followed by the loss of N2 and a subsequent intramolecular 1,3-dipole cycloaddition of a tethered indole that proceeds with exclusive endo diastereoselectivity. It is much more efficient for the construction of the pentacyclic skeleton of vindorosine and introduces all the requisite substituents and functionality. At the same time, it sets each of the six stereocenters in a single step.

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Scheme 47. Total Synthesis of Camptothecin by Yao and co-workers.

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Scheme 51. Total Synthesis of (+)-Fendleridine Acetylaspidoalbidine by Boger and co-workers.

Scheme 50. Total Synthesis of Vindoline & Vindorosine by Boger and co-workers.

(+)-Fendleridine (Aspidoalbidine) (361) and (+)-1Acetylaspidoalbidine (362) are the parent members of the aspidoalbine family of alkaloids. Fendleridine was first isolated from the Venezuelan tree Aspidoserma fendleri WOODSON by 131 Burnell and 1-Acetylaspidoalbidine has been isolated from Vallesia dichotoma RUIZ et PAV by Djerassi in Peru in the early 132 60s. Recently, Boger completed the total synthesis of (+)Fendleridine and (+)-1-Acetylaspidoalbidine utilizing intramolecular [4+2]/[3+2] cycloaddition as the key step 133 (Scheme 51). Coupling of 1,3,4-oxadiazole 363 with carboxylic acid 364 was effected by treatment with 1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCl) and DMAP to provide 365 in 47% yield. Simply heating o 365 in o-dichlorobenzene (180 C) afforded 367 as a single isomer in 71% yield. 367 was transformed into 368 in a further five steps. Additional treatment of 368 with Lawesson’s reagent, then desulfurization and debenzylation gave (+)fendleridine. Further treatment of (+)-fendleridine with Ac2O in pyridine afforded (+)-1-Acetylaspidoalbidine.

&

(+)-1-

Malbrancheamide (370) and malbrancheamide B (371), were isolated from Malbranchea aurantiaca RRC1813, a fungus 134 collected on bat detritus in a cave in Mexico. Williams has achieved the total synthesis of malbrancheamide and malbrancheamide B using an intramolecular aza-Diels–Alder 135 reaction as the key step (Scheme 52). Treatment of the enamide 372 with aqueous KOH in MeOH gave intermediate hydroxy-azadiene 373 by enolization and tautomerization. Subsequent intramolecular [4+2] cycloaddition provided adduct 374 and 375 in ratio of (2-1.6):1. Additional reduction of 375 by excess DIBAL-H (20 eq) afforded the natural product Malbrancheamide (X=Y=Cl) and malbrancheamide B (X=H, Y=Cl). Recently another approach of the synthesis of 136 malbrancheamide B was reported by Scheerer (Scheme 52). The mixture of the N-benzyloxymethyl (BOM) protected indole 376 and diketopiperazine 377 in the presence of o MeONa/MeOH at 65 C afforded 380a-c in nearly quantitative combined yield. Both 380a and 380b can be easily converted to oxo-malbrancheamide B which after reduction by DIBAL-H afforded the desired malbrancheamide B.

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Scheme 53. Total Synthesis of (±) – Lysergic acid by Oppolzer and coworkers.

Scheme 52. A) Total Synthesis of Malbrancheamide and Malbrancheamide B by Williams and co-workers; B) Total Synthesis of malbrancheamide B by Scheerer and co-workers.

More than twenty kinds of natural products with excellent biological activities have been synthesized employing intramolecular aza-Diels–Alder reaction as key steps in this second part. Some of them were even synthesized by intermolecular aza-Diels–Alder reaction, such as Vindoline (7a), Vindorosine (7b) and (±)-Lupinine (78). It shows that the azaDiels–Alder reaction play very important role in the total synthesis of nitrogen-containing natural products. Whether intra- or intermolecular aza-Diels–Alder reaction, they have their own advantages in organic synthesis. With the development of synthetic methods, the intramolecular azaDiels–Alder reaction will play an increasingly important role in the total synthesis of alkaloids. 4. Retro-Diels–Alder/aza-Diels–Alder Reaction Lysergic acid is a typical representative of ergot alkaloids, Oppolzer has completed the total synthesis of (±)-Lysergic acid (382) utilizing an intramolecular (Retro-Diels–Alder)-(Diels– 137 Alder) reaction as the key step (Scheme 53). This is a pioneer work based upon a brilliant combination of a retroDiels–Alder release a diene unit and then react another Diels– Alder reaction. In fact professor Oppolzer has already focused on the area very eary. The key step of this reaction, a solution of 383 in 1,2,4-trichlorobenzene was added over 5 h into o preheated (200 C) 1,2,4-trichlorobenzene undergoes a retroDiels–Alder reaction to produce 384, which furnished the 8ergolene 385 as a 2:3 mixture of diastereoisomers in 67%

Stemoamide is a member of the stemona class of alkaloid that 138 was isolated from Stemona tuberose. Jacobi has completed the total synthesis of (±)-stemoamide (386) using an intramolecular (Diels–Alder)-(retro-Diels–Alder) reaction as the 139 key step (Scheme 54). In refluxing diethylbenzene, the nonactivated alkyne oxazole 387 underwent the sequence to give 50-55% of 390 on gram scale. Treatment of butenolide 390 with the nickel boride catalyst derived from NiCl2 and o NaBH4 at -30 C in MeOH afforded (±)-stemoamide in 73% yield together with a small amount of cis-lactone isomer (15%). This key ring forming process involved an alkyne oxazole (Diels– Alder)-(retro-Diels–Alder) reaction, which established the tricyclic skeleton of (±)-Stemoamide in a single step. The total synthesis of (–)-stemoamide has also been reported.

Scheme 54. Total Synthesis of (±)-Stemoamide by Jacobi and coworkers.

This smallest part only have two examples for the total synthesis of two natural products by using retro-Diels– Alder/aza-Diels–Alder reaction as key steps, but it show a real efficient way to the syntehsis of (±)-Lysergic acid and (±)stemoamide.

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yield, via Diels-Alder reaction. Additional methylation and hydrogenolysis led to the precipitation of crystalline (±)lysergic acid in 33% yield.


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Conclusions

10 a) B.K. Moza, J. Trojanek. Collect. Czech. Chem. Commun., 1963, 28, 1419; b) M. Gorman, N. Neuss, K. Biemann. J. Am. Chem. Soc., 1962, 84, 1058; c) J. W. Moncrief, W. N. Lipscomb. J. Am. Chem. Soc., 1965, 87, 4963. 11 R. Z. Andriamialisoa, N. Langlois, Y. Langlois. J. Org. Chem., 1985, 50, 961. 12 J. M. Gourley, R. A. Heacock, A. G. McInnes, B. Nikolin, D. G. Smith. J. Chem. Soc. Chem. Commun., 1969, 709. 13 S. J. Danishefsky, C. Vogel. J. Org. Chem., 1986, 51, 3915. 14 a) T. Kishi, M. Muroi, T. Kusaka, M. Nishikawa, K. Kamiya, K. Mizuno. J. Chem. Soc. Chem. Commun., 1967, 17, 852; b) T. Kishi, M. Muroi, T. Kusaka, M. Nishikawa, K. Kamiya, K. Mizuno. Chem. pharm. Bull., 1972, 20, 940; c) D. M. Houston, E. K. Dolence, B. T. Keller, U. P. Thombre, R. T. Borchardt. J. Med. Chem., 1985, 28, 471; d) P. Herdewijn, J. Balzarini, E. D. Clercq, H. Vanderhaeghe. J. Med. Chem., 1985, 28, 1385. 15 M. Maggini, M. Prato, G. Scorrano. Tetrahedron Lett., 1990, 31, 6243. 16 A. K. Sakssena. Tetrahedron Lett., 1980, 21, 133. 17 E. Bombardelli, A. Bonati, B. Gabetta, E. M. Martinelli, G. Mustich, B. Danieli. Tetrahedron, 1974, 30, 4141. 18 G. Palmisano, B. Danieli, G. Lesma, D. Passarella, L. Toma. J. Org. Chem., 1991, 56, 2380. 19 J. C. Ortuno, Y. Langlois. Tetrahedron Lett., 1991, 32, 4491. 20 a) H. L. Latter, D. J. Abraham, C. E. Turner, J. E. Knapp, P. L. Schiff, D. J. Slatkin. Tetrahedron Lett., 1975, 16, 2815; b) C. E. Turner, M. F. H. Hsu, J. E. Knapp, P. L. Schiff, D. L. J. Slatkin, Pharm. Sci., 1976, 65, 1084. 21 a) M. Ogawa, N. Kuriya, M. Natsume. Tetrahedron Lett., 1984, 25, 969; b) H. H. Wasserman, B. C. Pearce. Tetrahedron Lett., 1985, 26, 2237. 22 T. Hamada, T. Zenkoh, H. Sato, O. Yonemitsu. Tetrahedron Lett., 1991, 32, 1649. 23 K. Fuji, T. Yamada, E. Fujita, H. Murata. Chem. Pharm. Bull., 1978, 26, 2515. 24 H. Ratni, E. P. Kündig. Org. Lett., 1999, 1, 1997. 25 O. G. Mancheno, R. G. Arrayas, J. Ardrio, J. C.Carretero. J. Org. Chem., 2007, 72, 10294. 26 J. Parello. Bull. Soc. Chim. Fr., 1968, 3, 1117. 27 a) G. Han, M. G. Laporte, J. J. Fplmer, K. M. Werner, S. M. Weinreb. J. Org. Chem., 2000, 65, 6293; b) G. Han, M. G. Laporte, J. J. Fplmer, K. M. Werner, S. M. Weinreb. Angew. Chem. Int. Ed., 2000, 39, 237; Angew. Chem. 2000, 112, 243. 28 N. Miyoshi, T. Yamamoto, N. Kambe, S. Murai, N. Sonoda. Tetrahedron Lett., 1982, 23, 4813. 29 a) J. Vetter. Food and Chemical Toxicology, 2004, 42, 1373; b) N. Radulović, N. Đorđević, M. Denić, M. M. Pinheiro, P. D. Fernandes, F. Boylan. Food and Chemical Toxicology, 2012, 50, 274. 30 Y. Yamashita, Y. Mizuki, S. Kobayashi. Tetrahedron Lett., 2005, 46, 1803. 31 D. Enders, J. Tiebes, Liebigs Ann. Chem., 1993, 2, 173. 32 I. Schmeltz, Hoffmann, D. Chem. Rev., 1977, 77, 295. 33 V. Jurčík, K. Arai, M. M. Salter, Y. Yamashita, S. Kobayashi, Adv. Synth. Catal., 2008, 350, 647. 34 N. J. Chapter 14, (Editor: Manske, R. H. F.) Academic Press: New York, 1960, pp 254. 35 S. Aoyagi, M. Hakoshi, M. Suziki, Y. Nakanoya, K. Shimada, Y. Takikawa. Tetrahedron Lett., 2006, 47, 7763. 36 I. Pastuszak, R. J. Molyneux, L. F. James, A. D. Elbein. Biochemistry, 1990, 29, 1886. 37 J. Shao, J. S. Yang. J. Org. Chem., 2012, 77, 7891. 38 J. M. Muller, E. Schlittler, H. J. Bein. Experientia, 1952, 8, 338. 39 N. S. Rajapaksa, M. A. McGowan, M. Rienzo, E. N. Jacobson. Org. Lett., 2013, 5, 706. 40 F. E. Chen, J. Huang. Chem. Rev., 2005, 105, 4671. 41 a) R. B. Woodward, F. E. Bader, H. Bickel, A. J. Frey, R. W. Kierstead. Tetrahedron, 1958, 2, 1; b) R. B. Woodward, F. E.

The aza-Diels–Alder reaction has played an important part in modern organic synthesis, especially in the field of natural product synthesis. The significance of the aza-Diels–Alder reaction for the construction of six-membered ring containing nitrogen is tremendous. In many cases, intermolecular azaDiels–Alder reactions have unpredictable region, endo/exoand stereo- selectivity. These problems are less apparent using intramolecular approaches. This review has systematically summarized a number of recent publications concerning aza-Diels–Alder reaction based natural product synthesis. The strategic incorporation of an aza-Diels– Alder reaction in the synthesis of natural product may be complicated, and together with the reactivity and selectivity problems may frequently be encountered. In general, the development of asymmetric, in particular catalytic enantioselective intramolecular aza-Diels–Alder reaction in the total synthesis of natural products remains highly challenging, and will no doubt see enormous advances in coming years.

Acknowledgements This project is supported by Natural Science Foundation of China (Grant No. 31500562), Fundamental Research Funds for the Central Universities (Grant No. 2662016PY122) and Hubei 2011 Cooperative Innovation Center Foundation (Grant No. 2011JH-2014CXTT02).

Notes and references 1

2

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a) J. G. Han, A. Jones, X. G. Lei. Synthesis, 2015, 47, 1519; b) E. Mackay, M. S. Sherburn. Synthesis, 2015, 47, 1; c) M. Juhl, D. Tanner, Chem. Soc. Rev., 2009, 38, 2983; d) K. C. Nicolaou, S. A. Snyder, T. Montagnon, G. E. Vassilikogiannakis. Angew. Chem. Int. Ed., 2002, 41, 1668; Angew.Chem., 2002, 114, 1742. a) V. Eschenbrenner-Lux, K. Kumar, H. Waldmann. Angew. Chem. Int. Ed., 2014, 53, 11146; b) G. Masson, C. Lalli, M. Benohoud, G. Dagousset. Chem. Soc. Rev., 2013, 42, 902; c) V. V. Kouznetsov. Tetrahedron, 2009, 65, 2721; d) P. R. Girling, A. S. Batsanov, A. D. J. Calow, H. C. Shen, A. Whiting. Tetrahedron, 2016, 72, 1105; e) P. R. Girling, T. Kiyoi, A. Whiting. Org. Biomol. Chem., 2011, 9, 3105. For recent reviews on natural product synthesis, see a) M. Wang, M. H. Feng, B. Q. Tang, X. F.Jiang. Tetrahedron Lett., 2014, 55, 7147; b) J. Shimokawa. Tetrahedron Lett., 2014, 55, 6156; c) Y. Zhang, T. P. Luo, Z. Yang. Nat. Prod. Rep., 2014, 31, 489; d) T. Kuranaga, Y. Sesoko, M. Inoue. Nat. Prod. Rep., 2014, 31, 514; e) J. C. Morris. Nat. Prod. Rep., 2013, 30, 783; f) P. M. Tadross, B. M. Stoltz. Chem. Rev., 2012, 112, 3550. a) S. Carosso, M. J. Miller. Org. Biomol. Chem., 2014, 12, 7445; b) B. S. Bodnar, M. J. Miller. Angew. Chem. Int. Ed., 2011, 50, 5630. Angew. Chem., 2011, 123, 9010. M. Fochi, L. Caruana, L. Bernardi. Synthesis, 2014, 46, 135. R. A. A. Foster, M. C. Willis, Chem. Soc. Rev., 2013, 42, 63. M. G. Memeo, P. Quadrelli. Chem. Eur. J., 2012, 18, 12554. K. V. Rao, W. P. Cullen. Antibiot. Annu., 1959-1960, 7, 950. S. M. Weinreb, F. Z. Basha, S. Hibino, N. A. Khatri, D. Kim, W. E. Pye, T. Wu. J. Am. Chem. Soc., 1982, 104, 536.

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56 57 58 59 60 61 62

63

64 65 66 67 68 69 70

Journal Name

Bader, H. Bickel, A. J. Frey, R. W. Kierstead. J. Am. Chem. Soc., 1956, 78, 2023. B. A. Pearlman. J. Am. Chem. Soc., 1979, 101, 6404. G. Stork. Pure and Appl. Chem., 1989, 61, 439. C. S. Chu, C. C. Liao, P. D. Rao. Chem. Commun., 1996, 1537. a) A. M. Gomez, J. C. Lopez, B. Fraser-Reid. J. Org. Chem., 1994, 59, 4048; b) A. M. Gomez, J. C. Lopez, B. Fraser-Reid. J. Org. Chem., 1995, 60, 3859. S. Hanessian, J. Pan, A. Carnell, H. Bouchard, L. Loibner. J. Org. Chem., 1997, 62, 465. a) G. Mehta, D. S. Reddy. Synlett., 1997, 612; b) G. Mehta, D. S. Reddy. J. Chem. Soc. Perkin Trans., 1 2000, 1399. P. A. Wender, J. M. Schaus, A. W. White. J. Am. Chem. Soc., 1980, 102, 6157. a) S. F. Martin, S. A. Williamson, R. P. Gist, K. M. Smith. J. Org. Chem., 1983, 48, 5170; b) S. F. Martin, B. Benage, S. A. Williamson, S. P. Brown. Tetrahedron, 1986, 42, 2903. a) S. M. Sparks, K. J. Shea. Org. Lett. 2001, 3, 2265; b) S. M. Sparks, A. J. Gutierrez, K. J. Shea. J. Org. Chem., 2003, 68, 5274. D. L. Boger, J. S. Panek. J. Am. Chem. Soc., 1985, 107, 5745. A. S. Kende, D. P. Lorah, R. J. Boatman. J. Am. Chem. Soc., 1981, 103, 1271. D. L. Boger, K. C. Cassidy, S. Nakahara. J. Am. Chem. Soc., 1993, 115, 10733. A. S. Kende, F. H. Ebetino. Tetrahedron Lett., 1984, 25, 923. a) R. C. Pandey, M. W. Toussaint, R. M. Stroshane, C. C. Kalita, A. A. Aszalos, A. L. Garretson, T. T. Wei, K. M. Byrne, R. F. Jr. Geoghegan, R. J. White. J. Antibiot., 1981, 34, 1389; b) K. M. Byrne, B. D. Hilton, R. J. White, R. Misra, R. C. Pandey. Biochemistry, 1985, 24, 478. a) D. L. Boger, O. Huter, K. Mbiya, M. S. Zhang. J. Am. Chem. Soc., 1995, 117, 11839; b) D. L. Boger, J. Heterocyclic Chem., 1996, 33, 1519. A. J. Mancuso, D. Swern. Synthesis, 1981, 3, 165. T. S. Wu, Y. Y. Chan, Y. L. Leu, C. F. Chern, C. F. Chen, phytochemistry, 1996, 42, 907. a) D. L. Boger. J. Heterocyclic Chem., 1998, 35, 1003; b) D. L. Boger, J. Y. Hong. J. Am. Chem. Soc., 1998, 120, 1218. M. E. Wall, M. C. Wani, C. E. Cook, K. H. Palmer, A. T. McPhail, G. A. Sim, J. Am. Chem. Soc., 1966, 88, 3888. B. S. J. Blagg, D. L. Boger. Tetrahedron, 2002, 58, 6343. a) N. Takahashi, A. Suzuki, S. Tamura. J. Am. Chem. Soc., 1965, 87, 2066; b) N. Takahashi, A. Suzuki, Y. Kimura, S. Miyamoto, S. Tamura, T. Mitsui, J. Fukami. Agr. Biol. Chem., 1968, 32, 1115. a) M. J. Schnermann, D. L. Boger. J. Am. Chem. Soc., 2005, 127, 15704; b) M. J. Schnermann, F. A. Romero, I. Hwang, E. Nakamaru-Ogiso, T. Yagi, D. L. Boger. J. Am. Chem. Soc., 2006, 128, 11799. F. J. Schmitz, F. S. DeGuzman, M. B. Hossain, D. V. Helm. J. Org. Chem., 1991, 56, 804. N. Bontemps, I. Bonnard, B. Banaigs, G. Combaut, C. Francisco. Tetrahedron Lett., 1994, 35, 7023. a) Y. Kitahara, F. Tamura, A. Kubo. Tetrahedron Lett., 1997, 38, 4441; b) Y. Kitahara, F. Tamura, M. Nishimura, A. Kubo. Tetrahedron, 1998, 54, 8421. Y. R. Torres, T. S. Bugni, R. G. S. Berlinck, C. M. Ireland, A. Magalhaes, A. G. Ferreira, R. Mareira Rocha, J. Org. Chem., 2002, 67, 5429. L. Legentil, J. Bastide, E. Delfourne. Tetrahedron Lett., 2003, 44, 2473. R. W. Rickards, J. M. Rothschild, A. C. Willis, N. M. Chazal, J. Kirk, K. Kirk, K. J. Saliba, G. D. Smith. Tetrahedron, 1999, 55, 13513. a) D. Sissouma, S. Collet, A. Guingant. Synlett., 2004, 14, 2612; b) D. Sissouma, L. Maingot, S. Collet, A. Guingant, J. Org. Chem., 2006, 71, 8384.

71 a) F. Kögl, F. W. Quackenbush. Recl. Trav. Chim. Pays-Bas 1944, 63, 251; b) F. Kögl, G. C. Wessem, O. I. Elsbach, Recl. Trav. Chim. Pays-Bas 1945, 64, 23. 72 a) A. J. Birch, D. N. Butler, R. W. Rickards. Tetrahedron Lett., 1964, 5, 1853; b) A. J. Birch, R. Effenberger, R. W. Rickards, T. J. Simpson. Tetrahedron Lett., 1976, 17, 2371; c) A. J. Birch, D. N. Butler, R. Effenberger, R. W. Rickards, T. J. Simpson, J. Chem. Soc., Perkin Trans., 1 1979, 807. 73 D. L. Boger, J. Y. Hong, M. Hikota, M. Ishida. J. Am. Chem. Soc., 1999, 121, 2471. 74 H. Kang, W. Fenical. J. Org. Chem., 1997, 62, 3254. 75 a) D. L. Boger, D. R. Soenen, C. W. Boyce, M. P. Hedrick, Q. Jin. J. Org. Chem., 2000, 65, 2479; b) A. Hamasaki, J. M. Zimpleman, I. Hwang, D. L. Boger. J. Am. Chem. Soc., 2005, 127, 10767. 76 a) D. L. Boger, C. W. Boyce, M. A. Labroli, C. A. Sehon, Q. Jin. J. Am. Chem. Soc., 1999, 121, 54. (b) A. Hamasaki, J. M. Zimpleman, I. Hwang, D. L. Boger. J. Am. Chem. Soc., 2005, 127, 10767. 77 a) T. F. Spande, H. M. Garraffo, M. W. Edwards, H. J. C. Yeh, L. Pannell, J. W. Daly. J. Am. Chem. Soc., 1992, 114, 3475; b) J. W. Daly, H. M. Garraffo, T. F. Spande, M. W. Decker, J. P. Sullivan, M.Williams. Nat. Prod. Rep., 2000, 17, 131. 78 D. A. Evans, K. A. Scheidt, C. Wade Downey, Org. Lett., 2001, 3, 3009. 79 A. P. Krapcho. Synthesis, 1982, 10, 805. 80 K. M. Witherup, R. W. Ransom, A. C. Graham, A. M. Bernard, M. J. Salvatore, W. C. Lumma, P. S. Anderson, S. M. Pitzenberger, S. L. Varga. J. Am. Chem. Soc., 1995, 117, 6682. 81 D. A. Powell, R. A. Batey. Org. Lett., 2002, 4, 2913. 82 C. F. Xia, L. S. Heng, D. W. Ma. Tetrahedron Lett., 2002, 43, 9405. 83 T. O. Larsen, K. Frydenvang, J. C. Frisvad, C. Christophersen. J. Nat. Prod., 1998, 61, 1154. 84 a) A. S. Kende, J. F. Fan, Z. C. Chen. Org. Lett., 2003, 5, 3205. b) Z. C. Chen, J. F. Fan, A. S. Kende. J. Org. Chem., 2004, 69, 79. 85 D. Leca, F. Gaggini, J. Cassayre. O. Loiseleur, S. N. Pieniazek, J. A. R. Luft, K. N. Houk. J. Org. Chem., 2007, 72, 4284. 86 M. Y. Wu, D. W. Ma. Angew. Chem. Int. Ed., 2013, 52, 9759. 87 M. C. Bagley, J. W. Dale, E. A. Merritt, X. Xiong. Chem. Rev., 2005, 105, 685. 88 a) K. C. Nicolaou, B. S. Safina, M. Zak, A. A. Estrada, S. H. Lee. Angew. Chem. Int. Ed., 2004, 43, 5087; Angew. Chem., 2004, 116, 5197; b) K. C. Nicolaou, M. Zak, B. S. Safina, S. H. Lee, A. A. Estrada. Angew. Chem. Int. Ed., 2004, 43, 5092; Angew. Chem., 2004, 116, 5202; c) K. C. Nicolaou, B. S. Safina, M. Zak, S. H. Lee, M. Nevalainen, M. Bella, A. A. Estrada, C. Funke, F. J. Zecri, S. Bulat. J. Am. Chem. Soc., 2005, 127, 11159; d) K. C. Nicolaou, M. Zak, B. S. Safina, A. A. Estrada, S. H. Lee, M. Nevalainen. J. Am. Chem. Soc., 2005, 127, 11176. 89 K. Shimanaka, Y. Takahashi, H. Iinuma, H. Naganawa, T.Takeuchi. Journal of antibiotics, 1994, 47, 1153. 90 a) R. A. Hughes, S. P. Thompson, L. Alcaraz, C. J. Moody. J. Am. Chem. Soc., 2005, 127, 15644; b) R. A. Hughes, S. P. Thompson, L. Alcaraz, C. J. Moody. Chem. Commu., 2004, 8, 946. 91 a) M. Leboeuf, A. Cave, P. Forgacs, J. Provost, A. Chiaroni, C. Riche. J. Chem. Soc. Perkin Trans., 1 1982, 5, 1205; b) T. H. Yang, M. Y. Cheng. Taiwan yaoxue zazhi, 1987, 39, 195; c) E. V. Costa, M. L. B. Pinheiro, C. M. Xavier, J. R. A. Silva, A. C. F. Amaral, A. D. L. Souza, A. Barison, F. R. Campos, A. G. Ferreira, G. M. C. Machado, L. L. P. Leon. J. Nat. Prod., 2006, 69, 292; d) J. C. Rejón-Orantes, A. R. González-Esquinca, M. Perez de la Mora, G. R. Roldan, D. Cortes. Planta Med., 2011, 77, 322. 92 N. H. Naik, A. K. Sikder, R. S. Kusurkar. Tetrahedron Lett., 2013, 54, 3715.

24 | J. Name., 2012, 00, 1-3




ARTICLE

Page 25 of 25


DOI: 10.1039/C6OB02761J

ARTICLE

93 J. C. Castillo, J. Quiroga, R. Abonia, J. Rodriguez, Y. Coquerel. Org. Lett., 2015, 17, 3374. 94 K. Damodar, M. Lingaiah, N. Bhunia, B. Das. Synthesis, 2011, 15, 2478. 95 S. M. Weinreb, N. A. Khatri, J. Shringarpure. J. Am. Chem. Soc., 1979, 101, 5073. 96 E. Gellert. The Alkaloids: Chemical and Biological Perspectives. Vol V (Editor: Pelletier S. W.) New York: Academic Press, 1987, pp 55. 97 N. K. Hart, S. R. Johns, J. A. Lamberton. Aust. J. Chem., 1972, 25, 817. 98 H. F. Schmitthenner, S. M. Weinreb. J Org. Chem., 1980, 45, 3373. 99 W. D. Crow, N. V. Riggs. Aust, J. Chem., 1955, 8, 136. 100 E. Saifah, C. J. Kelley, J. D. Leary. J. Nat. Prod., 1983, 46, 353. a) M. L. Bremmer, S. M. Weinreb. Tetrahedron Lett., 101 1983, 24, 261; b) M. L. Bremmer, N. A. Khatri, S. M. Weinreb. J. Org. Chem., 1983, 48, 3661. 102 P. A. Grieco, D. T. Parker, J. Org. Chem., 1988, 53, 3325. 103 J. W. Daly, T. Tokuyama, G. Habermehl, I. L. Karle, B. Witkop. Justus Liebigs Ann. Chem., 1969, 729, 198. 104 P. A. Grieco, D. T. Parker, J. Org. Chem., 1988, 53, 3658. M. F. Bartlett, R. Sklar, A. F. Smith, W. I. Taylor. J. Org. 105 Chem., 1963, 28, 2197. a) M. D. Kaufman, P. A. Grieco. J. Org. Chem., 1994, 59, 106 7197; b) P. A. Grieco, M. D. Kaufman. J. Org. Chem., 1999, 64, 7586. 107 H. M. Garraffo, J. Caceres, J. W. Daly, T. F. Spande, N. R. Andriamaharavo, M. Andriantsiferana. J. Nat. Prod., 1993, 56, 1016. 108 K. M. Maloney, R. L. Danheiser. Org. Lett., 2005, 7, 3115. J. F. Biard, S. Guyot, C. Roussakis, J. F. Verbist, J. 109 Vercauteren, J. F. Weber, K. Boukef. Tetrahedron Lett., 1994, 35, 2691. B. Lygo, E. H. M. Kirton, C. Lumley. Org. Biomol. Chem., 110 2008, 6, 3085. M. E. Jung, Y. M. Choi. J. Org. Chem., 1991, 56, 6729. 111 112 a) H. C. Beyerman, Y. M. F. Muller. Rec. Tra. Chim. PaysBas, 1955, 74, 1568; b) B. Franck. Angew. Chem., 1958, 70, 269. 113 T. Uychara, N. Chiba, I. Suzuki, Y. Yamamoto. Tetrahedron Lett., 1991, 32, 4371. 114 G. Massiot, P. Thépenier, M. J. Jacquier, L. Le MenOlivier, R. Verpoorte, C. Delaude. Phytochemistry, 1987, 26, 2839. 115 a) M. Ohba, H. Kubo, T. Fujii, H. Ishibashi, M. V. Sargent, D. Arbain. Tetrahedron Lett., 1997, 38, 6696; b) M. Ohba, H. Kubo, H. Ishibashi. Tetrahedron, 2000, 56, 7751. a) N. Unver. Phytochem. Rev., 2007, 6, 125; b) A. 116 Evidente, A. Kornienko. Phytochem. Rev., 2009, 8, 449-459; c) Z. Jin. Nat. Prod. Rep., 2007, 24, 886. 117 D. L. Boger, S. E. Wolkenberg. J. Org. Chem., 2000, 65, 9120. 118 M. Toyota, C. Komori, M. Ihara. J. Org. Chem., 2000, 65, 7110. 119 T. Kametani, H. Takeda, H. Nemoto, K. Fukumoto. J. Chem. Soc., Perkin Trans., 1, 1975, 1825. 120 H. B. Zhou, G. S. Liu, Z. J. Yao. Org. Lett., 2007, 9, 2003. 121 a) D. L. Comins, M. F. Baevsky, H. Hong. J. Am. Chem. Soc., 1992,114, 10971; b) M. L. Bennasar, C. Juan, J. Bosch. Chem. Commun., 2000, 2459; c) M. L. Bennasar, E. Zulaica, C. Juan, Y. Alonso, J. Bosch. J. Org. Chem., 2002, 67, 7465; d) N. Murata, T. Sugihara, Y. Konda, T. Sakamoto. Synlett., 1997, 298. 122 D. P. Curran, H. Liu. J. Am. Chem. Soc., 1992, 114, 5863. 123 M. E. Wall, M. C. Wani, S. M. Natschke, A. W. Nicholas. J. Med. Chem., 1986, 29, 1553.

a) M. A. Ciufolini, F. Roschangar. Angew. Chem. Int. Ed., 124 1996, 35, 1692. Angew. Chem., 1996, 108, 1789; b) M. A. Ciufolini, F. Roschangar. Tetrahedron, 1997, 53, 11049. R. T. Brown, J. Liu, C. A. M. Santos, Tetrahedron Lett., 125 2000, 41, 859. 126 a) Z. Z. Ma, Y. Hano, T. Nomura, Y. J. Chen. Heterocycles, 1997, 46, 541-546; b) Z. Z. Ma, Y. Hano, T. Nomura, Y. J. Chen. Phytochemistry, 2000, 53, 1075. 127 M. Toyota, C. Komori, M. Ihara. Arkivoc, 2003, viii, 15. H. Twin, R. A. Batey. Org. Lett., 2004, 6, 4913. 128 129 S. Ramesh, R. Nagarajan. J. Org. Chem., 2013, 78, 545. 130 a) G. I. Elliott, J. Velcicky, H. Ishikawa, Y. K. Li, D. L. Boger. Angew. Chem. Int. Ed., 2006, 45, 620; Angew. Chem., 2006, 118, 636; b) D. Kato, Y. Sasaki, D. L. Boger. J. Am. Chem. Soc., 2010, 132, 3685; c) Y. Sasaki, D. Kato, D. L. Boger. J. Am. Chem. Soc., 2010, 132, 13533. 131 R. H. Burnell, J. D. Medina, W. A. Ayer. Can. J. Chem., 1966, 44, 28. a) K. S. Brown, H. Budzikiewicz, C. Djerassi. Tetrahedron 132 Lett., 1963, 4, 1731; b) A. Walser, C. Djerassi. Helv. Chim. Acta, 1965, 48, 391. E. L. Cambell, A. M. Zuhl, C. M. Liu, D. L. Boger. J. Am. 133 Chem. Soc., 2010, 132, 3009. S. Martínez-Luis, R. Rodríguez, L. Acevedo, M. C. 134 González, A. Lira-Rocha, R. Mata. Tetrahedron, 2006, 62, 1817. 135 K. A. Miller, T. R. Welch, T. J. Greshock, Y. S. Ding, D. H. Sherman, R. M. Williams. J. Org. Chem., 2008, 73, 3116. 136 S. W. Laws, J. R. Scheerer. J. Org. Chem. 2013, 78, 2422. W. Oppolzer, E. Francotte, K. Bättig. Helvetica Chimica 137 Acta., 1981, 64, 478. 138 W. H. Lin, Y. Ye, R. S. Xu, J. Nat. Prod., 1992, 55, 571. P. A. Jacobi, K. Lee. J. Am. Chem. Soc., 2000, 122, 4295. 139

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Journal Name

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Strategies for the construction of tetrahydropyran rings in the synthesis of natural products.

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Strategic innovation in the total synthesis of complex natural products using gold catalysis.

Cu-mediated enamide formation in the total synthesis of complex peptide natural products.

Total synthesis of resveratrol-based natural products using a palladium-catalyzed decarboxylative arylation and an oxidative Heck reaction.

Application of a modification of the Polonovski reaction to the synthesis of vinblastine-type alkaloids.

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Double trouble--the art of synthesis of chiral dimeric natural products.

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Biosynthesis and Total Synthesis Studies on The Jadomycin Family of Natural Products.