Tetrahedron Letters 56 (2015) 2133–2140

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Tetrahedron Letters

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Digest Paper of natural and pharmaceutical products powered by organocatalytic reactions

Bing-Feng Sun

Shanghai Institute of Organic , Chinese Academy of Sciences, Shanghai 200032, China article info abstract

Article history: has emerged as the third pillar of modern asymmetric in the past two decades. Received 1 December 2014 Applying organocatalytic reactions in total synthesis is currently a highly dynamic research area. This Revised 5 March 2015 Digest focuses on selected recent examples of total synthesis of natural and pharmaceutical products Accepted 9 March 2015 enabled by organocatalytic reactions, highlighting the importance of organocatalytic reactions in Available online 17 March 2015 fostering structures of biological importance. Ó 2015 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// Keywords: creativecommons.org/licenses/by-nc-nd/4.0/). Total synthesis Organocatalytic reactions Natural products

Contents

Introduction...... 2133 Total syntheses enabled by general catalysis ...... 2134 Dixon’s synthesis of nakadomarin A7 ...... 2134 Fan’s synthesis of lycoramine, galanthamine, and lunarine9 ...... 2134 Zhu’s synthesis of trigonoliimine A10 ...... 2135 Total syntheses powered by catalysis ...... 2135 Hayashi’s and Ma’s syntheses of oseltamivir11,12 ...... 2135 Ma’s synthesis of zanamivir, laninamivir, and CS-895813 ...... 2135 Thomson’s synthesis of GB 1714 ...... 2136 Total syntheses powered by iminium catalysis ...... 2137 MacMillan’s synthesis of diazonamide A15 ...... 2137 Hong’s synthesis of conicol16 ...... 2137 MacMillan’s synthesis of , akuammicine, kopsinine, kopsanone, aspidospermidine, and vincadifformine17 ...... 2137 Wu’s synthesis of kopsinine and aspidofractine18 ...... 2138 Sun and Lin’s synthesis of englerin A/B, orientalol E/F, and oxyphyllol19 ...... 2139 Total syntheses featuring Brønsted catalysis ...... 2139 Zhu’s synthesis of rhazinilam and leucomidine B20 ...... 2139 List’s synthesis of estrone21 ...... 2140 Conclusions and perspectives...... 2140 Acknowledgments...... 2140 References and notes ...... 2140

Introduction process of drug discovery, provides the most transformative power that can build natural or designed Natural products play pivotal roles in drug discovery. of interest. The art and science of organic synthesis have evolved Approximately two thirds of all small- drugs approved tremendously since its inception.2 ‘Can we synthesize the during 1981–2010 have their origins in natural products.1 In the molecule?’ is no longer the question. Nowadays, armed with the strategies and methodologies developed over the past decades, E-mail address: [email protected] synthetic chemists have been endowed with the capability to http://dx.doi.org/10.1016/j.tetlet.2015.03.046 0040-4039/Ó 2015 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 2134 B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140 conquer almost any known if given sufficient contains a synthetically challenging 8/5/5/5/15/6 hexacyclic ring resources, efforts, and time. The ideal synthesis is gaining increas- system containing a quaternary . Prior to Dixon’s synthesis, ing attention from synthetic chemists to confront the demand from the average step count of the three total syntheses of nakadomarin interdisciplinary scientific community as well as industry to pro- A reached 34. In 2009, Dixon’s total synthesis reshaped the land- duce sufficient amount of desired compounds in sustainable ways.3 scape. Pivoting on an organocatalytic diastereoselective Michael Organocatalysis has emerged as the third pillar of modern , Dixon and co-workers amazingly telescoped asymmetric catalysis, along with metal catalysis and .4 the total synthesis of nakadomarin A into less than fifteen steps Organocatalytic reactions usually feature mild reaction conditions, (longest linear sequence) (Scheme 1). The adequate tolerance, insensitivity toward air and between 2 and 3 under the action of 15 mol % of 4 delivered a moisture, as well as their diverse catalytic mechanisms.5 The 91/9 diastereomeric mixture favoring the desired 5 in 57% yield. metal-free nature of organocatalytic reactions meets the demands When LHMDS or KHMDS was employed in the place of the catalyst of . The ability of organocatalysis to effect cascade 4 to promote this reaction, a diastereoselectivity of 1.5/1 was reactions and one-pot tandem transformations is of particular observed. Notably, the configuration of the nascent quaternary importance and has attracted significant attention from the chemi- carbon was dictated by the strong facial bias of the of the cal synthesis community. To combine organocatalysis with metal 5/8 bicyclic framework. It was through the bonding catalysis is a highly dynamic arena. These efforts have culminated interactions between the thiourea catalyst 4 and the nitroalkene in a number of elegant total syntheses of natural products with 3 that the of the newly generated tertiary carbon biological significance. A number of elegant reviews have appeared was effectively controlled. The subsequent nitro-Mannich/ highlighting respective topics in this research area.6 This Digest lactamization cascade formed the piperidone ring of 6. Selective focuses on selected recent examples of total synthesis of natural reductions transformed 6 to aminol which underwent / and pharmaceutical products enabled by organocatalytic reactions. iminium cyclization to pentacyclic 7. The camphorsulfonic acid- These examples are grouped in terms of the mechanisms of the assisted Z-selective RCM reaction annulated the 16-membered organocatalytic reactions applied in the total syntheses, including macrocycle and finalized the total synthesis. This synthesis formed general base catalysis,5a enamine catalysis,5b iminium catalysis,5c the basis of Dixon’s second generation route for nakadomarin and Brønsted .5d A, where the geometric selectivity issue in the formation of the macrocycle was addressed by virtue of metathesis.8 Total syntheses enabled by general base catalysis Fan’s synthesis of lycoramine, galanthamine, and lunarine9 Dixon’s synthesis of nakadomarin A7 Lycoramine (8), galanthamine (9) and lunarine (10) are Construction of an all-carbon quaternary center usually consti- hydrodibenzofuran with biological significance. In par- tutes a significant challenge in total synthesis, especially when the ticular, galanthamine possesses acetylcholinesterase inhibitive quaternary stereogenic carbon is surrounded by ring systems. This activity, and is clinically used for the treatment of mild to moder- is the case in the total synthesis of nakadomarin A (1). ate Alzheimer’s disease and various other memory impairments. In Nakadomarin A was isolated by Kobayashi and co-workers in 2011, Fan and co-workers reported the collective total synthesis of 1997 from a sponge collected off the coast of the Kerama Islands, these three molecules (Scheme 2). The stereochemistry-defining Okinawa, and exhibits significant bioactivities. This molecule step is the asymmetric Michael addition reaction of 11 and 12

MeOOC 1) Bu SnH N NO 3 H H 2 AIBN Gubbs I H O hex-5-enamine O N O 2 15 mol % 4 HCHO 2) LiAlH4 O (+)-CSA O HN + O2N N N N N 57% 3) Dibal-H 62% HN O 91/9 dr MeOOC N then HCl N 63/37 Z/E N O N O O O F3C CF3 4 O2N 3 5 6 7 nakadomarin A (1)

Scheme 1. Dixon’s synthesis of nakadomarin A (1).

CF R1 3 OMe S O OMe O OMe + H O O N N CF 3 1) NaBH H H CN 1) t-BuONa H 1) glycol, H O 4 N O O 2) LiAlH R Me Me 13 COMe I 2) PTSA 2) Dibal-H 4 2 MeO O O MOMO CN 3) ClCO Me,TEA 98% yield, 80% ee; MOMO 3) NaBH4 3) MeNO2,TEA 2 11a (R1 =H,R2 =OMe) O N 17 (74% yield, 99% ee 4) MsOH CN 4) MsCl, TEA 4) (HCHO)n, TFA 11b (R1 =Br,R2 =H) after one recrystallization) 14 15 MeOOC I NO2 O 16 H 1) TBSOTf, TEA O H O O O L-Selectride, 2) Pd(OAc)2 O 12 O then LiAlH4 3) L-Selectride, then LiAlH4 O H 1) LiOH O NHR O OMe OMe H N O 2) C6F5OH, OH OH O EDCI O O O O NH NH NH Br O OEt NH H H N O NH Heck 3) HCl 4) DIPEA BocHN MeN MeN 18 O OEt NH F3C CF3 N 19 Boc Lycoramine (8) Galanthamine (9) 20 Lunarine (10)

Scheme 2. Fan’s syntheses of lycoramine (8), galanthamine (9), and lunarine (10). B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140 2135

CN COOMe HN HN NC NO2 1) NaN3 1) Ph3P NO2 SeO2Ph NH NO 2) Raney Ni N N N N 23 MeOOC 2) HCl, MeOH 2 POCl3 O H MeOOC 3) PPTS, OH OMe N HC(OMe)3 HN N H N SeO2Ph H N OMe 3) , NaBH(OAc) OMe OMe OMe 25 3 OBu-n N3 22 N 26 27 28 Trigonoliimine A (21) 24 OHC

Scheme 3. Zhu’s synthesis of trigonoliimine A (21). catalyzed by thiourea 13. This reaction with 11a resulted in a have glycoproteins on their surfaces that bind to sialic found nearly quantitative yield of 14 with good enantioselectivity which on the surface of human erythrocytes and on the cell membranes could be further enhanced to 99% ee after one recrystallization. of the upper respiratory tract. Widely used anti-influenza drugs Compound 14 was converted to 15 by intramolecular condensation are sialic acid analogs that inhibit the viral neuraminidase, and conjugate addition. The was reduced to and thereby interfering with the proliferation of viruses. Oseltamivir condensed with to give 16. By a sequence involving (29) is the first orally active neuraminidase inhibitor commercially reduction, N-protection and Pictet–Spengler cyclization, nitroalk- developed for the fight against both influenza A and influenza B ene 16 was elaborated into the tetracyclic intermediate 17, which viruses. Efficient synthesis of this molecule containing three could be readily advanced into lycoramine (8) and galanthamine contiguous in short steps with a good overall (9), respectively, via conventional transformations. In the synthesis yield is highly desirable, and challenging. In 2009, Hayashi and of lunarine (10), 11b and 12 was converted to 19 via a similar co-workers achieved this goal by realizing the synthesis of sequence as for the synthesis of 16, except that the catalyst 18 oseltamivir in three one-pot operations with an amazingly high was employed in the starting Michael addition reaction and HWE overall yield (Scheme 4).11 This efficient synthesis relied heavily olefination was used to generate the unsaturated . A Heck on the Michael addition reaction of 30 and 31 catalyzed by coupling reaction between 19 and acrylamide gave 20, from which 5 mol % of 32-ClCH2COOH via an enamine mechanism, which lunarine (10) was readily generated. generated the multi-functional 33 in quantitative yield with 96% ee. The subsequent domino reaction of 33 with vinylphosphonate Zhu’s synthesis of trigonoliimine A10 34 delivered cyclohexenecarboxylate 35 with an undesired Cinchona--based catalysts represent a group of privi- configuration at C5. p-Toluenethiol was then employed to give leged organocatalysts for promoting conjugate addition reactions, the conjugate addition product 36 with the C5 configuration including those generating quaternary . These are powerful rectified. These three steps were integrated into the one-pot catalysts; usually the quinuclidine in the cata- operation which supplied 36 in 70% overall yield. After another lyst activates the , while the functional group OH or two well executed one-pot operations, the total synthesis of osel- thiourea at C60 or C9 activates the , both via hydrogen tamivir was eventually accomplished with 57% overall yield from bonding interactions. Recently, Zhu and co-workers developed a nitroolefin 31. cinchona alkaloid-catalyzed Michael addition reaction. In this reac- In 2010, Ma and co-workers demonstrated their total synthesis tion, various a--a-isocyanoacetates add to vinyl phenylse- of oseltamivir based on a similar strategy (Scheme 5).12 Notably, lenone under the action of 60-OH cinchona alkaloids, providing Ma and co-workers introduced nitroenamides as useful Michael synthetically useful isocyano-bonding quaternary carbons in good acceptors. By applying 38 in their total synthesis of oseltamivir, yields and enantioselectivity. By virtue of this new methodology, they significantly improved the step economy of the synthetic they nicely demonstrated the total synthesis of trigonoliimine A route. Their efforts have laid the basis for development of a practi- (21)(Scheme 3). The Michael addition reaction of 22 and 23 cat- cal industrial process for the production of oseltamivir. alyzed by 24 delivered 25 in 62% yield and 87% ee. This compound was converted to 27 by a sequence involving nucleophilic displace- Ma’s synthesis of zanamivir, laninamivir, and CS-895813 ment of the phenylselenone by azide, acidic of Recently, Ma’s group reported the total synthesis of three rele- the isocyano group, and reductive amination of the resultant vant neuraminidase inhibitors, zanamivir (42), laninamivir (43), with aldehyde 26. The azide and the nitro groups in 27 were and CS-8958 (44)(Scheme 6). This organocatalytic and scalable successively reduced before being transformed to the aza-spiro synthesis relied on a Michael addition reaction involving nitroe- compound 28, which was eventually exposed to POCl3 to effect namide 45. With 5 mol % of thiourea 46, the Michael addition of the Bischler–Napieralski reaction to furnish trigonoliimine A (21). to nitroenamide 45 proceeded smoothly, providing 47 in 72% yield and 98% ee after recrystallization. The subsequent Total syntheses powered by enamine catalysis anti-selective of 47 with 48 was realized with

CuBr2 in the presence of 49. Products 50a and 50b were then Hayashi’s and Ma’s syntheses of oseltamivir11,12 elaborated into zanamivir (42) and laninamivir (43), respectively, Influenza strikes the world in seasonal epidemics, leading to through the same sequence involving functional group trans- hundreds of thousands of annual deaths. The influenza viruses formations. CS-8958 (44) was obtained by esterification of 43.

Ph (EtO)2P(O) COOEt O CHO Ph 6steps 34 TolSH (2 one-pot operations) N OTMS STol 30 H 32 O CHO O COOEt O COOEt 31 O COOEt Cs CO 70% from + 2 3 36 ClCH COOH NO2 5 one-pot operation 82% from 2 t-BuO 2C t-BuO 2C AcHN O2N t-BuO 2C COOBu-t NO2 NH2 NO2 31 33 35 36 Oseltamivir (29)

Scheme 4. Hayashi’s synthesis of oseltamivir (29). 2136 B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140

O CHO Naph STol Naph (EtO) P(O) COOEt 2 O COOEt O COOEt 37 N 39 OTMS O CHO TolSH 2steps + H PhCOOH NO2 AcHN AcHN AcHN AcHN one-pot operation NO 85% NH NO 54% over three steps 2 2 38 2 40 41 Oseltamivir (29)

Scheme 5. Ma’s synthesis of oseltamivir (29).

O OR OR O OMe 1) Zn, HOAc H H OR 2) AcCl, TEA O COOH O O H O COOH n CHO O O HO -C7H15 O NO2 3) SeO2 n-C H C(OMe) O2N 48a/48b (R = MOM / Me) OH 7 15 3 OH 4) NaClO2 O AcHN HCl, MeOH AcHN BocHN O O N NHBoc Me tBu S 2 HN NH HN NH2 N 5) HCl 2 N 47 Ph NHBoc 6) guanidination 45 Bn N N NH H H HO Ph 49 NH O NH2 50a:R=MOM zanamivir (42): R = H 46 F3C OH CS-8958 (44) CuBr2 50b:R=Me laninamivir (43): R = Me

Scheme 6. Ma’s syntheses of zanamivir (42), laninamivir (43), and CS-8958 (44).

Ph t H S Ph H S 1) BuOK (15 mol %) O S H S O MeOH O N OTMS O H7 H S H Boc S 2) CF3COOH Boc S TFA Boc S Ph3P=CHCOOMe Me N 3) Cs CO Me N ent-32 Me N 2 3 6 H16 H H N H O 99% O 52 53 MeOOC 54' Me O 55' H (CF3CH2O)2P(O)CH2COOMe OH 1) Tf2NPh, LiCl, DIPEA H S H S S O NaHMDS H H O H S 2) HCOOH O 1) CF COOH H H S H H S S 3 7 Pd (0) 1) Selectfluor H Me Boc S 2) MeONa 2) NaBH N Me N 6 16 H 4 H H 3) NaHMDS, 52' N N 3) NMO, O H 3-bromo-2- Me O NaIO , O methylprop-1-ene 4 COOMe Me O Me O OsO 54 55 56 4 GB 17 (51)

Scheme 7. Thomson’s synthesis of GB17 (51).

Me O O O O H H N MeN N Me NH HN HN H SEt H SEt H HN B(pin) Me TIPSO N O N Ph N O N NH O COOMe TIPSO H TIPSO O TIPSO O Me TCA O O O + O Me 61 O O HO SEt N OBn 1) DDQ PMB CHO I OBn 2) TFAA NPMB 3) O3 OH 59 86%, >20/1 dr OBn NTFA OBn OH O NPMB 4) MgBr2 O 58 60 62 63

1) Dess-Martin 2) DAST 3) AgTFA, RNH2 HO TIPSO HN H HN NH HN NH HN H N NTf N N NH N N TIPSO N N TIPSO HN O N O N O O O Cl O O O O O O O O O O O O Cl 1) NBS Br Br 2) LiOH (Bpin)2,[Pd] 1) Ph3P, C2Cl6 NH 3) NCS NTf OTf 2) BBr3 OBn O NH O NH O NTFA 3) PhNTf O NTFA 4) H2,Pd(OH)2 2 5) TASF Diazonamide A (57) 66 65 64

Scheme 8. MacMillan’s synthesis of diazonamide A (57).

Thomson’s synthesis of GB 1714 obtained with 520. Through the intramolecular Michael addition Organocatalytic intramolecular Michael addition reactions can reaction of (Z)-olefin 54, compound 53 could be elaborated into be powerful tools for construction of cyclic compounds with two 55 and 7-epi-55 as a 1/1 mixture diastereomeric at C7. The geome- contiguous stereogenic centers. Thomson and co-workers demon- try of the olefin played a critical role in determining the stereo- strated this strategy in their total synthesis of GB 17 (51) chemistry of the addition product; with the (E)-olefin 540 as the (Scheme 7). In the presence of 5 mol % ent-32-TFA, 52 underwent substrate, the Michael addition proceeded with the undesired an annulating Michael addition reaction, affording 53 in a nearly sense of stereochemistry at C16 and the C6 - quantitative yield. This highly effective stereocontrol was exerted ized under the conditions, leading to formation of 550.7-epi-55 by the catalyst, not the substrate, as evidenced by the similar result could be equilibrated upon exposure to base to give a 3/2 mixture B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140 2137

Ph OH Me Ph MeO OMe NO OMe 2 N OTMS O N O N CHO CHO H 2 O 2 1) RhCl(PPh3)3 1) AcCl, TEA H ent 32 O MeO H HO - H 71 H 2) H2,Pd/C HO 2) Li/NH3 HO HO HO Me Me H H HOAc H H 3) Amberlyst 15 OH 55% yield from 69 O O 69 4) DABCO O 99% ee O 5) Dibal-H 68 70 72 73 Conicol (67)

Scheme 9. Hong’s synthesis of conical (67). of 55 and 7-epi-55 and recycled. Compound 55 was transformed to undesired functionalities, compound 72 was transformed to 56 by conversion of the carbonyl to the olefin and the subsequent 73, which was further subjected to acylation and deacetoxylation allylation, before being further advanced into GB 17 (51). to give (+)-conicol (67). This asymmetric total synthesis determined the absolute configuration of (+)-conicol, which had Total syntheses powered by iminium catalysis previously been a mystery due to the lack of an efficient analytical method. MacMillan’s synthesis of diazonamide A15 Diazonamides are a structurally unique family of marine natu- MacMillan’s synthesis of strychnine, akuammicine, kopsinine, ral products isolated by Fenical and co-workers. Among these, kopsanone, aspidospermidine, and vincadifformine17 diazonamide A (57) was identified to be a potent antimitotic agent, In nature, simple building blocks could be assembled rapidly to exhibiting cytotoxicity toward a variety of human cancer cell lines form highly complex and diverse molecular architectures via through interaction with ornithine d-amino-transferase, a enzyme-catalyzed cascade reactions, as exemplified by the biosyn- mitochondrial matrix protein. Total synthesis of this molecule thesis of terpenoids. These biological pathways are distinctive from has been intensely explored in the past two decades, with the general where ‘stop-and-go’ protocols are pre- original structure being corrected by Harren and co-workers vailing with significantly lower efficiency. Therefore, to mimic nat- through synthetic studies. One of the major synthetic challenges ure’s strategies has been a constant attraction for synthetic lies in the construction of the C10 quaternary carbon. In 2011, chemists. In 2011, MacMillan and co-workers marked a milestone MacMillan’s group contributed the total synthesis of 57 covering in this arena. By realizing an organocatalytic cascade reaction, they twenty steps from commercial materials (Scheme 8). Thus, seg- achieved the collective synthesis of six structurally complex ter- ments 58 and 59 were assembled via Suzuki coupling and further pene alkaloids, strychnine (74), akuammicine (75), kopsi- converted to 60. Under the action of 61-TCA, the Michael addition nine (76), kopsanone (77), aspidospermidine (78) and reaction of 60 and propynal went on efficiently, providing 62 with vincadifformine (79), each with high step economy (Scheme 10). a diastereoselectivity of over 20/1. This reaction established the In particular, they accomplished the shortest asymmetric synthesis C10 quaternary center and the complete benzofuranoindoline core. of strychnine (74), the best-known strychnos alkaloid Notably, when rac-61 was tested for this reaction, 1/1 dr was (Scheme 10A). This collective total synthesis was centered on a resulted, indicating the formation of the C10 stereocenter was one-flask, asymmetric Diels–Alder/elimination/conjugate addition dominated by the catalyst. Compound 62 was subjected to protect- organocascade reaction that coined the key tetracyclic core of the ing group manipulations, oxidative cleavage, and macrocyclization targets. In this reaction, by forming the corresponding iminium by intramolecular , furnishing 63, which was further species with catalyst 81, propynal was activated toward the advanced into 64 via oxidative aromatization and Ag+ promoted Diels–Alder [4+2] cycloaddition with 2-vinyl indole 80, engender- amidation. Formation of the second oxazole ring followed by ing iminium 83. The ensuing elimination and hydrolysis provided debenzylation and triflation generated 65, which was subjected 84, which underwent intramolecular conjugate addition to deliver to a tandem borylation/annulation to yield 66. After initial bromi- 82 in 82% yield and 97% ee. Employment of the selenide-substi- nation of the activated indoline E-ring and hydrolysis of the indolyl tuted 2-vinyl indole, such as 80, as the diene component was triflate, a sequence involving chlorination/debromination/desilyla- critical for the success. Use of the corresponding methyl-sulfide- tion was then carried out to furnish diazonamide A (57). This substituted 2-vinyl indole as the diene component would to synthesis elegantly blended organocatalysis and transition-metal a different product due to the mitigated propensity of the sulfide catalysis to attain unprecedented synthetic efficiency. to undergo elimination. Treatment of 82 with Wilkinson’s catalyst to effect decarbonylation followed by introduction of a car- 16 Hong’s synthesis of conicol bomethoxy group with COCl2/MeOH and reduction with Dibal-H In the past century, total synthesis has been playing an indis- resulted in 85 as an inconsequential mixture of olefin . pensible role in determining the structure of natural products. In N-alkylation and ester reduction gave 86 as a proper Heck sub- 2010, Hong and co-workers accomplished the catalytic enantiose- strate. The Heck cyclization- formation and the subsequent lective total synthesis of conicol (67) and settled the stereochemi- debenzylation gave the Wieland–Gumlich aldehyde, which was cal issue of this molecule (Scheme 9). Hong’s approach to this converted to strychnine (74) following the know procedure. This molecule features a domino oxa-Michael–Michael–Michael-aldol total synthesis delivered strychnine in 12 steps and 6.4% overall reaction sequence. By employing ent-32-AcOH as the catalyst, the yield from commercially available materials, constituting the first stage of this one-pot sequence involved the oxa-Michael shortest route to enantioenriched strychnine to date. Notably, in addition of 68 and 69 and the ensuing intramolecular Michael the Heck cyclization, the PMB was believed criti- addition, furnishing compound 70. In the second stage, enal 71 cal in facilitating regioselective b-hydride elimination away from was introduced and the Michael-aldol cascade reaction proceeded the indoline ring methine since formation of the N-PMB-substi- to give tricyclic 72. This one-pot sequence delivered 72 in 55% tuted enamine would accompany destabilizing allylic . This overall yield with 99% ee. The stereochemistry of this tandem destabilizing factor was envisioned in the synthesis of akuam- reaction was established unambiguously through X-ray micine (75). Thus, compound 85 was subjected to cleavage of the crystallographic analysis of relevant products, thus certifying the PMB group with concomitant isomerization of the in stereochemistry of the target molecule. By trimming off the conjugation with the ester group. After installation of the iodoallyl 2138 B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140

NBoc NH A) 1) Wilkinson cat. N 1) [Pd] N O CHO N NHBoc 2) COCl2,MeOH 1) -allylation I OH 2) PhSH, 3) Dibal-H; TFA 2) Dibal-H TFA H O N N N SeMe H N N H H H H PMB MeN 1-Nap PMB 82 PM B COOMe PMB 80 HO OH O 82%, 97% ee 85 86 87 t-Bu N H TCA 1) PhSH, TFA 81 Boc Boc 2) N-allylation NH NH N N NHR2 N Me CHO I [Pd] H N N H H H N SeMe N N H Me H H COOMe PMB PMB COOMe O H O 88 akuammicine (75) 83 84 strychnine (74)

1) TMSI, TEA N B) 1) COCl N NBoc 2) CH =CHPPh Br N 2 R 2 3 MeOH NHBoc CHO MeOH; then 2) H ,Pd/C CH2=CHSO2Ph propynal t-BuOK 2 N 81 N N SeMe N N Bn COOMe Bn Bn Bn COOMe 83%, 97% ee Bn 91 R=SO Ph 80' 82' 89 90 2 H Raney Ni O N N N HN o neat, 200 C HCl

N N N N H - H H H COO COOMe COOH 92 kopsanone (77) 93 kopsinine (76)

C) I NBoc N N N N CHO 1) Ph3P=CH2 1) DMSO, Pd(PPh ) 2) NaCNBH3 3 4 H2,Pd(OH)2 (COCl)2 N 3) TFA N Me 2) n-BuLi, N Me N N N Bn 4) -allylation H H H H NCCO2Me H Bn 94 Bn COOMe ent-82' 95 aspidospermidine (78) vincadifformine (79)

Scheme 10. MacMillan’s syntheses of indole alkaloids 74–79.

NBoc NBoc NBoc 98 NHBoc O 1) ,TCA, 1) CH2=CHSO2Ph 2) NaBH4 2) Raney Ni CO2Me N Ar N N OH N OH H H H H Ar CO2Me COOMe COOMe 97 99 N OTMS 64%, 93% ee 102 103 H 1) MsCl, TEA 98 (Ar = 3,5-(CF3)2C6H3) 2) TFA TCA 3) Na2CO3 Boc NH N N NHR2 NBoc HCOOH, Ac O CHO 2

N N N N H H H CHO COOMe COOMe CO2Me CO2Me kopsinine (76) 100 101 aspidofractine (96)

Scheme 11. Wu’s synthesis of kopsinine (76) and aspidofractine (96). , the Heck cyclization of 88 was set in motion to produce Heck cyclization was also featured in the synthesis of the last akuammicine (75). two natural products (Scheme 10C). From ent-820, 94 was obtained The total synthesis of kopsinine (76) and kopsanone (77) via a sequence involving Wittig reactin, enamine saturation, N-Boc employed a slightly modified precursor 820 obtained from 800 via deprotection and N-allylation. The subsequent Heck cyclization the organocascade reaction (Scheme 10B). Conjugate addition of provided 95, the precursor for both aspidospermidine (78) and the revealed amine to the vinylphosphonium bromide produced vincadifformine (79). This accomplishment of the collective the corresponding ylide that underwent olefination with the syntheses of six complex natural products in 6.4–24% yields with vicinal aldehyde to furnish 89. Compound 89 was converted via 9–12 steps have highlighted the capability of organocatalysis, conventional procedures to 90, and the latter was further subjected which combined with metal catalysis may provide rapid access to [4+2] cycloaddition reaction with vinylsulfone to access 91 with to complex molecular architectures. a [2.2.2] bicyclic framework. After desulfurization with Raney nickel, the total synthesis of kopsinine (76) was accomplished in Wu’s synthesis of kopsinine and aspidofractine18 14% overall yield spanning 9 steps from commercial materials. Indole alkaloids comprise a rich source of appealing targets that Further, kopsinine was demethylated to give 92, which was form a test base for new synthetic methodologies. Recently, Wu converted to kopsanone (77) simply by heating without solvent. selected kopsinine (76) and aspidofractine (96) as the synthetic B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140 2139

61 m TFA 1) CPBA O 1) EtMgBr 2) Dibal-H HO H ,Pd/C HO MeNO 1) LDA, PhNTf 2 2 O 2) DMP O 2 O O O + 109 O O 3) NaBH4 OTMS 63% O 3) CH2CHMgBr O 2) Pd(Ph P) , H 3 4 4) TPAP, NMO 111 112OHC 4) Ac2O H H H / OHC H TEA CHO = 2.4/1 5) HCOONH4 112 111 115 116 orientalol F (106) Pd(Ph3P)4 114 110 H2, Crabtree's cat. 1) 9-BBN, H2O2 N N dr 7/1 O N O O 2) H2,Pfaltzcat. (dr 1/2.5) O N N N α-face 1) Ac2O 1) AcOCH2COCl 2) CrO O approach HO 3 HO HO 2) Yamaguchi's Bu4NIO4 conditions H O OR H O H O H O OH Ph endo addition O O 3) K2CO3 O O O 3) K2CO3 H H H MeOH HO H MeOH 104 104/105 = 1.2/1 englerin A ( ): Si Si Si 117 R = HOCH CO orientalol E (108) oxyphyllol (107:R=H) 2 113 TS2 TS1 englerin B (105): R = H

Scheme 12. Sun and Lin’s syntheses of 7,10-epoxy guaianoids 104–108. targets to demonstrate their organocatalytic method (Scheme 11). orientation. The could be rationalized by the In this exquisite Michael addition/aza-Michael addition/cyclization preference of the postulated transition state TS1 over TS2. cascade reaction, 97 reacted with propynal under the catalysis of Compound 111 was subjected to a sequence to give 114, which 98 to deliver the key tetracyclic 99 directly, presumably via the was triflated before undergoing Heck cyclization to furnish guaiane intermediacy of 100 and 101. In the second catalysis by 98, the triene 115. Selective epoxidation of the trisubstituted olefin 0 conjugate addition of compound 99 to acrolein proceeded to fur- followed by SN2 -type hydride delivery provided allylic nish, after reduction, dienamine 102, which underwent the [4+2] 116, which after with Pd/C gave orientalol F (106). cycloaddition/desulfurization sequence to give 103. After forma- Formal hydration of the disubstituted olefin via the hydrob- tion of the last ring by nucleophilic substitution, the total synthesis oration/oxidation procedure generated 117, which was of kopsinine (76) was accomplished in a concise manner. The end- readily converted into englerin A (104) and englerin B (105) game N-formylation of kopsinine provided aspidofractine (96). by esterification and saponification. The directed hydrogenation of 116 with Crabtree’s catalyst resulted in oxyphyllol (107). Sun and Lin’s synthesis of englerin A/B, orientalol E/F, and Eventually, a three-step sequence involving acylation, chemoselective oxyphyllol19 and stereospecific C–H oxidation, and saponification produced 7,10-Epoxy guaianoids represent a small group of sesquiterpene orientalol E (108). natural products. These structurally exquisite natural products have aroused significant attention from the synthesis community Total syntheses featuring Brønsted acid catalysis since englerin A and englerin B were disclosed by Beutler and co- workers to possess potent cytotoxicity toward renal cell carci- Zhu’s synthesis of rhazinilam and leucomidine B20 noma. In early 2013, Sun, Lin, and co-workers demonstrated how Desymmetrization represents an effective strategy for generat- an organocatalytic [4+3] cycloaddition reaction could be tamed ing chiral all-carbon quaternary centers. The desymmetrization of for the production of a collection of natural products including prochiral diesters via enzymatic hydrolysis has been a powerful englerin A (104), englerin B (105), orientalol F (106), oxyphyllol method. Nevertheless, it is less efficient for long-chain-bridged (107), and orientalol E (108)(Scheme 12). The [4+3] cycloaddition diesters, such as dimethyl 118 (Scheme 13), which is the key reaction catalyzed by 61-TFA involved the unsymmetrically substi- precursor in several syntheses accomplished tuted furan 109 and dienal 110, affording two regioisomers in a by Kuehne. Recently, Zhu and co-workers developed a catalytic ratio of 2.4/1 favoring the desirable 111. The TMS group was desymmetrization method to access 119 enantioselectively deemed to play a critical role in the stereochemical guidance: the (Scheme 13). This desymmetrization was realized by the alcoholy- and t- of catalyst 61 occupy the a face sis of bicyclic bislactone 120 catalyzed by the chiral Brønsted acid of iminium 113, while the even bulkier TMS group blocks its b face, 121. Aldehyde 119 was secured in 95% yield and 84% ee, and was forcing 109 to approach from the a face through the endo utilized for the total synthesis of rhazinilam (122) and leucomidine

O RO MeO Et 1) ethanedithiol Et 1) H ,Pd/C O O MeOOC Et 2 MeOH 2) LiBH4 1) IBX COOMe MeOOC 2) KOH O 121 3) TMSCHN 126 Ag CO 3) EDC, (0.1 eq.) 2 2) Ph3P Et 2 3 Et H + N Et Et NO2 N - O RT 4) MsCl S DMF Br N OHC HN 5) NaN 100 oC O 3 N O 95%, 84% ee S NO2 Rhazinilam (122) 120 for 119 O N3 125 127 128 MeO 124 118 (R = Me) 129 COOMe Me 119 (R = H) COOMe toluene Et MeOOC H2,Pd/C o Et R R NO2 NO2 90 C then 110 oC H H N O OH O O N 70% 40% for 123 P P N N H 1/1 dr plus 40% N O O O O2N O COOMe O COOMe O2N HO O H 123 R 121 R 126 Br 129 131 130 Leucomidine B ( )

Scheme 13. Zhu’s synthesis of rhazinilam (122) and leucomidine B (123). 2140 B.-F. Sun / Tetrahedron Letters 56 (2015) 2133–2140

O O O O H ,Pd/C; O 1) BrMgCH=CH 136 2 2 (5 mol %) TFA, Et3SiH BBr 3 H H 75% 2) 95%, 93% ee 71% MeO O O O H H H H MeO HO 133 134 MeO 135MeO 139 132 dehydration olefin isomerization & O olefin isomerization O O2N NO2 Prins

cyclization O S SO 2 N 2 F S SF O OH 6 H 6 MeO MeO SF6 F6S 136 137 138

Scheme 14. List’s synthesis of estrone (132).

B(123). Compound 119 was converted to 124 before being elabo- are still underdeveloped, and some of the organocatalytic reactions rated into tetrahydropyridine 125, the common precursor to the are far from being satisfactory. Therefore, further development of two natural products. The N-allylation of 125 by 126 produced imi- organocatalytic reactions in both breadth and depth is anticipated. nium 127, which upon heating in toluene in the presence of

Ag2CO3 under an inert atmosphere delivered 128. Reduction of Acknowledgments the nitro group and lactamization engendered rhazinilam (122). On the other hand, heating the mixture of 125 and 129 resulted Financial supports from the National Natural Science in 130 as a 1/1 diastereomeric mixture, probably via the inter- Foundation of China (Grant Nos. 21172246, 21290180, mediacy of 131, before further proceeding to leucomidine B (123). 21472210) and the Youth Innovation Promotion Association, Chinese Academy of Sciences are gratefully appreciated. List’s synthesis of estrone21 have captured the imagination of synthetic chemists References and notes for decades owing to their appealing molecular architecture as well as their biological significance. While the female sex hormone 1. Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311–335. 2. Nicolaou, K. C.; Vourloumis, D.; Winssinger, M.; Baran, P. S. Angew. Chem., Int. estrone (132) has been the target of numerous syntheses, the Ed. 2000, 39, 44–122. synthesis developed by Torgov in 1963, albeit racemic, appeared 3. Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657–4673. particularly efficient. Recently, List and co-workers achieved the 4. List, B. Chem. Rev. 2007, 107, 5413–5415. 5. (a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743; (b) asymmetric synthesis of 132 by virtue of a catalytic enantioselec- Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471– tive Torgov cyclization (Scheme 14). The substrate 134 was readily 5569; (c) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416– prepared from 133 via a two-step procedure. Torgov cyclization 5470; (d) Akiyama, T. Chem. Rev. 2007, 107, 5744–5758; (e) Enders, D.; entails strong acidic conditions. In List’s work, a highly Brønsted Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606–5655; (f) Maruoka, K.; Hashimoto, T. Chem. Rev. 2007, 107, 5656–5682. acidic disulfonimide was selected out as the catalyst. Thus, in the 6. (a) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167–178; (b) Abbasov, presence of only 5 mol % of 136 at low temperature for 4 days, M. E.; Romo, D. Nat. Prod. Rep. 2014, 31, 1318–1327; (c) Yoshimura, T. the Torgov cyclization of 134 went on smoothly to deliver 135 in Tetrahedron Lett. 2014, 55, 5109–5118; (d) Sánchez-Rosello, M.; Aceña, J. L.; Simón-Fuentes, A.; Pozo, C. Chem. Soc. Rev. 2014, 43, 7430–7453; (e) Marqués- 95% yield and 93% ee. After one recrystallization, 135 could be López, ; Herrera, R. P.; Christmann, M. Nat. Prod. Rep. 2010, 27, 1138–1167; (f) isolated in 88% yield with 99.8% ee. The Torgov cyclization of 134 Marqués-López, E.; Herrera, R. P. In Comprehensive Enantioselective presumably involves these consecutive reactions: (1) isomeriza- Organocatalysis: Catalysts, Reactions, and Applications; Dalko, P. I., Ed.; Wiley- VCH Verlag GmbH & Co. KGaA, 2013; pp 1359–1383. Chapter 44; (g) Ying, Y.; tion of 134–137; (2) Prins reaction of 137 that ends in depro- Jiang, X. In Stereoselective Organocatalysis: Bond Formation Methodologies and tonation furnishing 138 as an olefin mixture; and (3) Activation Modes; Torres, R. R., Ed.; John Wiley & Sons, 2013; pp 587–628. dehydration and olefin isomerization. The strong acidic conditions Chapter 17. 7. Jacubec, P.; Cockfield, D. M.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 16632– are necessary that ensure the final product as the desired 16633. thermodynamically most stabilized one. Torgov diene was then 8. Kyle, A. F.; Jakubec, P.; Cockfield, D. M.; Cleator, E.; Skidmore, J.; Dixon, D. J. hydrogenated to give 139, which furnished estrone (132) after Chem. Commun. 2011, 10037–10039. 9. Chen, P.; Bao, X.; Zhang, L.-F.; Ding, M.; Han, X.-J.; Li, J.; Zhang, G.-B.; Tu, Y.-Q.; demethylation. Fan, C.-A. Angew. Chem., Int. Ed. 2011, 50, 8161–8166. 10. Buyck, T.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2013, 52, 12714–12718. 11. Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304–1307. Conclusions and perspectives 12. Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem., Int. Ed. 2010, 49, 4656–4660. 13. Tian, J.; Zhong, J.; Li, Y.; Ma, D. Angew. Chem., Int. Ed. 2014. http://dx.doi.org/ Organocatalytic reactions generally involve convenient, mild, 10.1002/anie.201408138. 14. Larson, R. T.; Clift, M. D.; Thomson, R. J. Angew. Chem., Int. Ed. 2012, 51, 2481– and metal-free conditions, and are amenable to the construction 2484. of molecular architectures with complexity and diversity in 15. Knowles, R. R.; Carpenter, J.; Blakey, S. M.; Kayano, A.; Mangion, I. K.; Sinz, C. J.; enantioselective manner. These virtues bestow them an edge in MacMillan, D. W. C. Chem. Sci. 2011, 2, 308–311. 16. Hong, B.-C.; Kotame, P.; Tsai, C.-W.; Liao, J.-H. Org. Lett. 2010, 12, 776–779. synthesis of natural and pharmaceutical products. Selected con- 17. Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011, 475, tributions summarized in this Digest highlight the importance of 183–188. organocatalytic reactions in fostering structures of interest, 18. Wu, X.; Huang, J.; Guo, B.; Zhao, L.; Liu, Y.; Chen, J.; Cao, W. Adv. Synth. Catal. 2014, 356, 3377–3382. particularly quaternary stereogenic carbons and polycyclic sys- 19. Wang, J.; Chen, S.-G.; Sun, B.-F.; Lin, G.-Q.; Shang, Y.-J. Chem. Eur. J. 2013, 19, tems embedded in complex molecules with biological significance. 2539–2547. We hope this Digest will inspire more efforts in applying 20. Gualtierotti, J. B.; Pasche, D.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2014, 53, 9926–9930. organocatalytic transformations in total synthesis of complex 21. Prévost, S.; Dupré, N.; Leutzsch, M.; Wang, Q.; Wakchaure, V.; List, B. Angew. natural products. On the other hand, organocatalytic reactions Chem., Int. Ed. 2014, 53, 8770–8773.