Collective Synthesis of Natural Products by Means of Organocascade Catalysis

ARTICLE doi:10.1038/nature10232

Collective synthesis of natural products by means of organocascade catalysis

Spencer B. Jones1, Bryon Simmons1, Anthony Mastracchio1 & David W. C. MacMillan1

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.

The field of natural product total synthesis has evolved dramatically over the past 60 years owing substantially to the efforts of strategy- based organic chemists along with remarkable improvements in our bond-forming capabilities. However, two critical challenges that CHO NH remain for this field are those of translating laboratory-level academic 2 OGluc success in total synthesis to the large-scale assembly of biologically N O important molecules1 and building large collections of natural product H Tryptamine MeO2C Secologanin families (or their analogues) for use as biological probes or in medicinal chemistry2. N To address these two fundamental challenges in small-molecule synthesis, we have been inspired by the strategies used in nature to N solve these problems. For example, as chemists, we typically use ‘stop- H Me MeO2C CH2OH and-go’ synthetic protocols, whereby individual transformations are conducted as stepwise processes punctuated by the isolation and Preakuammicine Common tetracyclic core purification of intermediates at each stage of the sequence3. By contrast, in nature the rapid conversion of simple starting materials to N N complex molecular scaffolds is accomplished through the use of trans- formation-specific enzymes, which mediate a continuous series of Et N H highly regulated catalytic cascades in what amounts to be a highly H Me N 4,5 CHO H efficient ‘biochemical assembly line’ . Moreover, biosynthesis in nature CO2Me provides an appealing alternative to the traditional ‘single-target’ Norfluorocurarine Didehydrosecodine approach to chemical synthesis in that it typically involves the construction of natural product collections through the assembly of a common intermediate (Fig. 1).

N Design plan N We recently sought to develop a novel asymmetric approach to total synthesis based on the application of these two nature-inspired con- H N 3,4 H H N Me cepts, namely collective total synthesis and organocascade catalysis . H O CO2Me Whereas syntheses targeting an advanced core structure applicable to H O the synthesis of closely related natural products within a family have Strychnine Vincadifformine been frequently reported6, much less common is the preparation of (Strychnos) (Aspidosperma or Kopsia) an intermediate endowed with functionality amenable to the preparation of structurally diverse natural products in different families—a 7,8 Figure 1 | Cascade catalysis in biosynthesis. In nature, transform-specific strategy we term collective total synthesis . We predicted that the enzymes in continuous catalytic cascades rapidly produce common hybridization of the strategies of collective natural product synthesis biosynthetic intermediates and natural products. Preakuammicine serves as a 9 and enantioselective organocascade catalysis should rapidly give biosynthetic precursor to a range of structurally diverse members of the access to useful quantities of single-enantiomer natural product col- Strychnos, Aspidosperma and Kopsia alkaloid families, including strychnine lections or families with unprecedented levels of ease and efficiency. and vincadifformine. Et, ethyl; Gluc, glucose; Me, methyl.

1Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA.

NBoc followed by skeletal rearrangement (Fig. 1). Thus, in a prime example NHBoc CHO of natural economy, a single intermediate is exploited in the construc- Im Im tion of a diverse collection of complex molecular products. N X N P P We expected the preparation of intermediate 1, which incorporates Common tetracycle (1) the requisite functionality for expedient conversion to each of the target natural products (Fig. 2), to be a central element of our design strategy. The key tetracyclic precursor 1 would itself be accessed through a N N one-flask, asymmetric Diels–Alder/elimination/conjugate addition N organocascade sequence commencing with a simple tryptamine- H derived substrate13. N H H N In detail, we hoped that exposure of the 2-(vinyl-1-selenomethyl) N Me H O H H CO Me H O 2 tryptamine system 2 to propynal in the presence of an imidazolidinone 13 Strychnine Aspidospermidine Kopsinine catalyst (3) would set in motion a Diels–Alder [4 1 2] addition (Fig. 3). As a key element of enantiocontrol, the acetylenic functionality N N O N of the catalyst-bound propynal would be expected to partition away from the bulky tert-butyl (t-Bu) group, leaving the naphthyl group effectively to shield the bottom face of the reacting alkyne. The acti- N H Me N Me H H N vated dienophile would then undergo endo-selective Diels–Alder CO Me 2 CO2Me H cycloaddition with the substituted 2-vinyl indole 2. By contrast with Akuammicine Vincadifformine Kopsanone our previous studies using methyl-sulphide-substituted 2-vinyl 13 Strychnos Aspidosperma Kopsia indoles, as demonstrated in our synthesis of minfiensine ,wefelta conceptually unique series of cascade cycles might arise through the incorporation of organoselenide substitution on the diene, leading to a Figure 2 | Collective natural product synthesis: nature-inspired application of cascade catalysis. Synthesis of six structurally diverse Strychnos, novel, architecturally complex system. More specifically, following Aspidosperma and Kopsia alkaloids is expected to proceed from a common the Diels–Alder cycloaddition, the cycloadduct 4 would be poised intermediate tetracycle prepared by means of organocascade catalysis. Boc, to undergo facile b-elimination of methyl selenide to furnish the tert-butoxycarbonyl; Im, iminium catalysis. unsaturated iminium ion 5. We proposed this change in mechanism owing to the higher propensity of selenides to undergo b-elimination To demonstrate this approach, we targeted for total synthesis six well- in comparison with sulphides14. known, structurally complex members of the Strychnos, Aspidosperma In the second cycle, iminium-catalysed 5-exo-heterocyclization of the and Kopsia families of alkaloids, in particular strychnine, the best- pendant carbamate was expected to occur at the d-position to the indo- known member of the Strychnos family, which has been the focus of linium ion (5 R 6;Fig.3,pathA,X5 NR2) to deliver, following hydro- intense synthetic interest for over 50 years. Moreover, this target has lysis, the enantioenriched spiroindoline core (1). We considered the served as a key metric for the success of our nature-inspired dual possibility of an alternative second cycle wherein iminium 5 might techniques10,11. undergo facile cyclization at the indoline carbon to generate pyrroloindo- Importantly, strychnine is believed to share a biosynthetic pre- line 7 transiently (Fig. 3, path B). In this situation, we recognized that cursor with a range of prominent Strychnos, Aspidosperma and amine or Brønsted acid catalysis might thereafter induce the necessary Kopsia alkaloids12. This common intermediate, preakuammicine, 5-exo-heterocyclization of the pendant carbamate to also furnish 6. arises biosynthetically through a controlled enzymatic cascade invol- Importantly, either cascade sequence could allow for the rapid and ving a coupling of the precursors tryptamine and secologanin, enantioselective production of the complex tetracyclic spiroindoline

Boc A Boc Boc Me O N X N N NR2 N NR2 H H Path A 1-Nap t-Bu N H X=NR2 =HNR 3 N SeMe N N 2 P P A P 6 4 5 endo Boc Me O Boc [4+2] N NR2 NH X N X t 1-Nap -Bu N First cycle Second cycle P ′ A MeSe N (Im) NR (Im) or (H+) A N N N P A P P BocHN R′ = Boc 6′

Me O Me O N Path B N 1-Nap 1-Nap t-Bu X = OH t N O -Bu N O H •HA NHBoc H NBoc O 3 •HA 3 NR′ O NHBoc N P N N P P 7 A 8 N SeMe ′ P R = Boc 3•HA Common intermediate (1) 2

Figure 3 | Proposed mechanism of organocascade cycles for the generation organocatalytic Diels–Alder/b-elimination/amine conjugate addition sequence of a common tetracyclic intermediate (1). An organocascade reaction along path A, involving iminium ion catalysis, or path B, involving Brønsted between 2-vinyl indole 2 and propynal is expected to proceed through an acid catalysis. 1-Nap, 1-naphthyl; SeMe, selenomethyl.

O NBoc NH NHBoc CHO a–c 20 mol% 3•TBA d–f N N Boc 63% N SeMe –40 °C to RT, toluene N 61% N H 12 H 9 10 PMB 82%, 97% e.e. 11 PMB PMB CO2Me

N N N N IOH g, h i jk H H H 76% 58% 66% 69% N N N N H H H H H H H H PMB PMB HO O O OH HO O O H 14 15 Wieland–Gumlich (–)-strychnine 12 steps aldehyde (16)

Figure 4 | Twelve-step enantioselective total synthesis of (2)-strychnine. Et3N, toluene, 245 uC to RT, then MeOH, 230 uCtoRT.f, DIBAL-H, CH2Cl2, Reagents and conditions are as follows. a, NaH, PMBCl, dimethylformamide 278 uC to RT, then trifluoroacetic acid (TFA), 278 uC to RT. g, 1,8- (DMF), 0 uC. PMB, para-methoxybenzyl. b,SeO2, dioxane, H2O, 100 uC. diazabicyclo[5.4.0]undec-7-ene (DBU), K2CO3,DMF,(Z)-4-bromo-3- c, (EtO)2P(O)CH2SeMe, 18-crown-6, potassium bis(trimethylsilyl)amide iodobut-2-enyl acetate (13), RT. h, DIBAL-H, CH2Cl2, 278 uC. i, 25 mol% (KHMDS), tetrahydrofuran (THF), 278 uC to room temperature (RT, 23 uC). Pd(OAc)2,Bu4NCl, NaHCO3, EtOAc, RT. j, PhSH, TFA, 45 uC. k, NaOAc, e.e., enantiomeric excess. d, (Ph3P)3RhCl, toluene, PhCN, 120 uC. e,COCl2, Ac2O, AcOH, malonic acid, 120 uC. Ac, acetyl.

1 from simple tryptamine-derived and ynal substrates in a single formation, using vinyl iodide 14 to form the PMB-protected operation. Wieland–Gumlich aldehyde 15 in 58% yield18. Early studies showed that the PMB protecting group was critical in facilitating regioselective Experimental results b-hydride elimination away from the indoline ring methine (and pro- The feasibility of the proposed organocascade sequence was first ductively towards the alcohol). Such a high degree of regiocontrol pre- evaluated in the context of a total synthesis of strychnine. The requisite sumably arises from the allylic strain that accompanies formation of the 2-vinyl indole 10 was prepared in three steps from 9 according to the N-PMB-substituted enamine, a destabilizing element that is absent standard procedures outlined in Fig. 4 (ref. 15). The crucial organo- from the corresponding enol formation step. cascade addition–cyclization was accomplished with the use of Finally, the synthetic sequence was completed by TFA-mediated 1-naphthyl-substituted imidazolidinone catalyst 3 in the presence of removal of the PMB group13 to furnish the Wieland–Gumlich aldehyde 20 mol% tribromoacetic acid (TBA) co-catalyst, forming the complex (16), which, on heating in a mixture of malonic acid, acetic anhydride and spiroindoline 11 in 82% yield and with excellent levels of enantioin- sodium acetate18, delivered enantioenriched (2)-strychnine in 12 steps duction (97% e.e.). Notably, we have now gathered evidence that path B and 6.4% overall yield from commercial materials. To our knowledge, of the cascade sequence is operational. Specifically, when the same this asymmetric organocascade-based sequence is the shortest route to protocol was performed in the presence of stoichiometric catalyst at enantioenriched strychnine that has been accomplished so far19–22. 278 uC and quenched after 10 min with Et3N, an 84% yield of pyrro- We next turned to the construction of related alkaloids of the loindoline 7 (protecting group, PMB) was obtained. Moreover, expo- Strychnos, Aspidosperma, and Kopsia families based on the strategy sure of pyrroloindoline 7 (protecting group, PMB) to catalytic 3?TBA of collective total synthesis outlined above. The total synthesis of (2)- and, separately, N-methyl 3?TBA (incapable of undergoing iminium akuammicine11 (Fig. 5) was achieved starting with unsaturated ester formation) facilitates the conversion to the spiroindoline 11 at com- 12 (prepared in the course of the synthesis of strychnine; see Fig. 4). parable rates. Treatment of the PMB-protected spiroindoline 12 with TFA and The product of the key organocascade sequence, tetracyclic thiophenol at 60 uC resulted in the cleavage of the PMB protecting spiroindoline 11, was advanced to strychnine in only eight additional group as well as isomerization of the alkene into conjugation with the steps (Fig. 4). In detail, decarbonylation was achieved through the use of Wilkinson’s catalyst. Subsequent treatment with phosgene and NH NH 16 methanol served to introduce a carbomethoxy group at the diena- a b mine a-position. Next, on exposure to DIBAL-H, the enamine unsa- turation was reduced and the requisite tertiary indoline stereocentre N 91% N 76% was installed to provide the unsaturated ester 12 (existing as an incon- H H H 12 PMB CO2Me 17 CO2Me sequential mixture of alkene isomers) in 62% overall yield for the three steps. We converted intermediate 12 to vinyl iodide 14 through a two-step 76%-yield protocol involving allylation with the substituted allyl bromide 13 and concomitant alkene isomerization, fol- N Me N lowed by DIBAL-H-mediated reduction of both ester functionalities. I c As a second key step, we predicted direct conversion of the vinyl 47% N N Me iodide 14 to the protected Wieland–Gumlich aldehyde 15 through a H H H H 19 cascade Jeffery–Heck cyclization/lactol formation sequence17. CO2Me CO2Me Insertion of palladium into the vinyl iodide and subsequent carbo- (–)-akuammicine palladation would forge the six-membered ring and produce an alkyl 10 steps, 10% overall yield palladium intermediate, which would then undergo b-hydride elimination to provide an enol that would rapidly engage in lactol forma- Figure 5 | Ten-step enantioselective synthesis of (2)-akuammicine. tion with the proximal alcohol-bearing side chain. Reagents and conditions are as follows. a, TFA, PhSH, 60 uC. b,(Z)-1-bromo-2- Following extensive investigations, we discovered an optimized iodobut-2-ene (18), K2CO3, DMF, RT. c, 20 mol% Pd(OAc)2, NaHCO3, set of conditions to allow successful Jeffery–Heck cyclization/lactol Bu4NCl, MeCN, 65 uC.

I O NBoc N NHBoc CHO a–c 20 mol% ent-3 •TBA d–f N N Boc N SeMe N N H 61% –40 °C to RT, toluene 73% H 9 20 Bn 21 Bn 23 Bn 83%, 97% e.e.

N N N N

g h i j

65% N 98% N Me 65% N Me 57% N Me H H H H 24 Bn 25 CO2Me (+)-aspidospermidine (+)-vincadifformine 9 steps, 24% overall yield 11 steps, 8.9% overall yield

Figure 6 | Enantioselective total syntheses of (1)-aspidospermidine and THF, 0 uC, then AcOH, NaCNBH3,0uC. Bn, benzyl. e,TFA,CH2Cl2,RT.f,(Z)- (1)-vincadifformine. Reagents and conditions are as follows. a, NaH, DMF, 3-bromo-1-iodoprop-1-ene (22), K2CO3, DMF, RT. g,(Ph3P)4Pd, Et3N, BnBr, RT. b, SeO2, dioxane, H2O, 100 uC. c, (EtO)2P(O)CH2SeMe, 18-crown-6, toluene, 80 uC. h, Pd(OH)2,H2 (200 p.s.i.), MeOH, EtOAc, RT. i,CH2Cl2, KHMDS, THF, 278 uCtoRT.ent-, enantio-. d,Ph3PCH3I, n-butyllithium, DMSO, (COCl)2. j, n-butyllithium, NCCO2Me, THF, 278 uCtoRT. ester to give diamine 17 in 91% yield. Allylation of the pyrrolidine sequence30. Indeed, Swern oxidation of aspidospermidine leads to the nitrogen with functionalized allyl bromide 18 (ref. 23) gave vinyl formation of imine 25, which can be treated with n-butyllithium fol- iodide 19, a precursor to akuammicine, by means of a Heck cycliza- lowed by methyl cyanoformate to obtain (1)-vincadifformine (Fig. 6) tion11. We expected insertion of palladium into the vinyl iodide fol- in 11 steps and 8.9% overall yield31. lowed by carbopalladation of the a,b-unsaturated ester to give an alkyl We further extended our strategy of collective total synthesis to the palladium intermediate. b-hydride elimination would then furnish synthesis of kopsinine32–35 and the related compound kopsanone33,36. the natural product. In the event, treatment of vinyl iodide 19 with A unified approach to producing both alkaloids was implemented, palladium acetate under Jeffery conditions24 gave (2)-akuammicine, allowing for a two-step conversion of kopsinine to kopsanone by prepared in a total of ten steps and 10% overall yield. means of a biomimetic thermocyclization33,37 (Fig. 7). Kopsinine The alkaloids aspidospermidine25 and vincadifformine26 are among was synthesized by first treating enantio-21 with trimethylsilyl iodide the most highly sought Aspidosperma alkaloid targets. Aspidospermidine, and then by vinyl triphenylphosphonium bromide to induce a depro- in particular, has been the subject of extensive investigation, having tection/conjugate addition. Further treatment with KOt-Bu promoted been synthesized by over 30 research groups27,28. Application of our a Wittig olefination to form the cyclic alkene found in triene 26.An cascade catalysis approach allowed access to both of these alkaloids enamine a-carbomethoxylation was then accomplished with phos- according to the following sequence. Conversion of the cascade product gene–methanol16 to afford an intermediate ester, which was selec- 21 into the vinyl iodide 23 was achieved in a three-step sequence as tively reduced to diene 27 by treatment with palladium on carbon outlined in Fig. 6. After optimization, we found that a Heck cyclization (Pd/C) and H2 in 69% over two steps. of the vinyl iodide onto the tri-substituted double bond could be used to Dienes such as 27 can undergo [4 1 2] cycloadditions with a range form triene 24 in 65% yield, thus completing the pentacyclic core of of dienophiles, including vinyl sulfones33,38. We were able to obtain aspidospermidine. We achieved a simultaneous global hydrogenation/ cycloadduct 28 in 83% yield through treatment of diene 27 with debenzylation of triene 24 using palladium hydroxide on carbon under phenylvinyl sulfone in refluxing benzene. Furthermore, we were able hydrogen pressure, to afford (1)-aspidospermidine in nine linear steps to obtain (2)-kopsinine by performing a simultaneous desulfonyla- and 23% overall yield (Fig. 6), which constitutes the shortest enantio- tion, benzyl hydrogenolysis and diastereoselective alkene reduction of selective synthesis of aspidospermidine reported so far29,30. Finally, we sulfone 28 with Raney nickel33 to give (2)-kopsinine in only nine recognized the potential to synthesize (1)-vincadifformine from (1)- steps, which is a significant improvement over the previous 19-step aspidospermidine by means of an oxidation and carbomethoxylation chiral-auxiliary-mediated approach32. Our attempts to directly

NBoc N N N R CHO a b, c d e

N 58% N 69% N 86% N 83% Ent- Bn CO Me 21 Bn 26 Bn 27 Bn CO2Me 28 2

R = SO2Ph

H O N N HN B: N H f 200 °C

N Neat N 74% N H H H (two steps) N CO2Me 29 H CO2 HO O (–)-kopsinine (–)-kopsanone 9 steps, 14% overall yield 11 steps, 10% overall yield

Figure 7 | Enantioselective total syntheses of (2)-kopsinine and (2)- b, COCl2,Et3N, toluene, 245 uC to RT, then MeOH, 230 uC to RT. c, Pd/C, H2, kopsanone. Reagents and conditions are as follows. a,Et3N, CH2Cl2,Me3SiI, EtOAc, EtOH, 0 uC. d,H2C5CHSO2Ph, benzene, 100 uC. e, Raney Ni, EtOH, 0 uC, then MeOH, H2C5CHPPh3Br, 40 uC, then CH2Cl2, THF, KOt-Bu, 0 uC. 78 uC. f,1NHCl,130uC.

Table 1 | Enantioselective synthesis of six well-known indole member of the Strychnos alkaloid family. We hope to describe the alkaloids value of this approach in terms of other natural product and medicinal

NBoc O agent families in the near future. Enantioselective syntheses of Strychnos, Aspidosperma METHODS SUMMARY Synthetic and Kopsia alkaloids N elaboration All reactions were performed under an inert atmosphere using dry solvents in P ≤8 steps anhydrous conditions, unless otherwise noted. Full experimental details and Common intermediate (1) characterization data for all new compounds are included in Supplementary Information. Compound No. steps Overall PSAC PSCA here* yield (%) steps steps Received 4 February; accepted 26 May 2011. N 1. Walji, A. & MacMillan, D. W. C. Strategies to bypass the Taxol problem. Enantioselective cascade catalysis, a new approach for the efficient construction of H 12 6.4 25 (refs 19, 20) 16 (ref. 21) molecular complexity. Synlett 1477–1489 (2007). N H H 2. Va, P., Campbell, E. L., Robertson, W. M. & Boger, D. L. Total synthesis and evaluation of a key series of C5-substituted vinblastine derivatives. J. Am. Chem. O H O Soc. 132, 8489–8495 (2010). 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