ARTICLE Received 13 Jan 2015 | Accepted 16 Apr 2015 | Published 21 May 2015 DOI: 10.1038/ncomms8204 OPEN Total synthesis of ( þ )-gelsemine via an organocatalytic Diels–Alder approach Xiaoming Chen1,2, Shengguo Duan1,2, Cheng Tao1, Hongbin Zhai1 & Fayang G. Qiu2 The structurally complex alkaloid gelsemine was previously thought to have no significant biological activities, but a recent study has shown that it has potent and specific antinociception in chronic pain. While this molecule has attracted significant interests from the synthetic community, an efficient synthetic strategy is still the goal of many synthetic chemists. Here we report the asymmetric total synthesis of ( þ )-gelsemine, including a highly diastereoselective and enantioselective organocatalytic Diels–Alder reaction, an efficient intramolecular trans-annular aldol condensation furnishing the prolidine ring and establishing the configuration of the C20 quaternary carbon stereochemical centre. The entire gelsemine skeleton was constructed through a late-stage intramolecular SN2 substitution. The enantiomeric excess of this total synthesis is over 99%, and the overall yield is around 5%. 1 State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China. 2 Laboratory of Molecular Engineering, and Laboratory of Natural Product Synthesis, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Boulevard, The Science Park of Guangzhou, Guangzhou 510530, China. Correspondence and requests for materials should be addressed to H.Z. (email: [email protected]) or to F.G.Q. (email: [email protected]). NATURE COMMUNICATIONS | 6:7204 | DOI: 10.1038/ncomms8204 | www.nature.com/naturecommunications 1 & 2015 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms8204 lthough gelsemine was isolated1 in as early as 1876 from Results Gelsemium Sempervirens Ait., its structure was not Retrosynthetic analysis. Gelsemine may be synthesized from Adetermined until 1959 by means of nuclear magnetic intermediate RS-1 and oxindole via the condensation of the 2,3 resonance (NMR) spectroscopic techniques and X-ray hemiacetal with oxindole followed by an intramolecular SN2 crystallographic analysis4. This indole alkaloid contains a displacement (Fig. 3). Although the condensation may result in hexacyclic cage structure and seven contiguous chiral carbon four stereoisomers, only two of them may undergo the desired centres (Fig. 1). The complex chemical structures of gelsemine SN2 displacement. The other two isomers, however, may either and other members of the alkaloid family5–8 have attracted stay intact or undergo an elimination followed by a Michael considerable attention from synthetic chemists. So far, in addition addition51,52 to regenerate the four stereoisomers. This to the many synthetic efforts9–37, there are eight total syntheses equilibrium is shifted to form the desired product after the 38–49 reported in the literature (Fig. 2), two of which are intramolecular SN2 displacement, which is irreversible under the 44,48 asymmetric . Although gelsemine was thought to have no reaction conditions (Figs 4 and 5). The SN2 displacement may particular biological activities, a recent report indicated that result in two isomers, one of which is the desired product. gelsemine exhibited potent and specific antinociception in Intermediate RS-1 may be obtained from RS-2 following a chronic pain by acting at the three spinal glycine receptors50. sequence of intramolecular aldol condensation, reduction of the Besides, gelsemine was nonaddictive, indicating that the carbonyl group, formation of the sulfonates and then elimination. mechanism of its action is different from that of morphine. The The intramolecular aldol53,54 condensation deserves further complex structure and the potential medicinal applications discussion due to the fact that both the aldehyde and the of gelsemine prompted us to initiate a more efficient ketone functionalities may undergo enolization under the enantioselective total synthesis. reaction conditions, resulting in epimerization of both Herein we wish to report a 12-step, highly enantioselective stereochemical centres attaching the carbonyl groups. Another organocatalytic total synthesis of ( þ )-gelsemine. issue is the direction of the aldol condensation. Since both of the carbonyl groups may be enolized, the aldol condensation from either one may be consequential. However, Cbz is a bulky 55 17 functional group and it will play a significant role in preventing N O the aldehyde from being enolized prior to the ketone enolization. N O 5 In this case, the potential epimerization of the ketone 21 3 R2 functionality is irrelevant. The third issue is the stereochemistry 7 19 of the hydroxyl group even if aldol condensation occurs in the 19 R2 O N desired direction. This difficulty may be overcome when one O N 18 R realizes that the desired product has a more favourable internal 1 56,57 R1 hydrogen bond than the other isomer. Finally, formation of 19-Hydroxydihydrogelsemine R = H, R = OH RS-3 and its conversion into RS-2 is straightforward. Gelsemine R1 = H, R2 = H, H 1 2 19-Hydroxydihydrogelsevirine Gelsevirine R1 = OMe, R2 = H, H 21-Oxogelsemine R = H, R = O R1 = OMe, R2 = OH 1 2 Synthesis of the ( þ )-gelsemine. On the basis of the above 21-Oxogelsevirine R = OMe, R = O 19-Acetroxydihydrogelsevirine 1 2 analysis, the synthetic strategy seemed feasible. If intermediate 3 R1 = OMe, R2 = OAc is made asymmetric, then gelsemine will be made asymmetric. Figure 1 | The structures of gelsemium alkaloids. The difference between Thus, after a brief literature search58,59, an asymmetric the members of the gelsemium alkaloids is the presence of the functional Diels–Alder reaction was designed and the synthesis began with groups in the unique carbon skeleton. The major difference appeared in dihydropyridine 1 (Fig. 6), which may be prepared from C-19 and C-21. 4-methylpyridine in large scale60. O This work, 2015 Speckamp,1994 Asymmetric Racemic N Cbz N 12 steps, 5% 19 steps, 0.83% O Ts Qin, 2012 Johnson, 1994 N OH MeO C CO Me O Asymmetric 2 2 Racemic N 25 steps 1% 29 steps, 0.58% TBSO Cl OtBu Fukuyama 1996 Danishefsky, 2002 OMe O N Racemic H Racemic 32 steps 0.67% 36 steps, 0.019% O O Gelsemine Fukuyama, 2000 O Hart, 1997 Asymmetric Overman,1999 Racemic 31 steps, 0.86% O Racemic O 23 steps, 0.25% N 26 steps, 1.2% Cl N O OMe O Bn Figure 2 | Schematic summary of the previous total syntheses of gelsemine. Among the seven total syntheses completed so far, two of them were asymmetric and the overall yields were around 1%. This molecule has been an active target of total synthesis during the past two decades. 2 NATURE COMMUNICATIONS | 6:7204 | DOI: 10.1038/ncomms8204 | www.nature.com/naturecommunications & 2015 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms8204 ARTICLE Gratifyingly, the yield of the desired endo product was 47% 97% yield, which brought the total yield of the Diels–Alder after reduction of the aldehyde carbonyl group with sodium cycloaddition to 76%. Intermediate 3 was then further selectively borohydride, and its enantio excess was determined using chiral reduced to the hemiacetal 4 using Dibal-H at À 78 °C in 94% high-performance liquid chromatography (HPLC) to be 99.7%, yield. The subsequent Wittig reaction furnished the methyl enol while the exo product was not detected. It was surprising that ether, which was directly treated with trimethyl orthoformate and intermediate 3a was also produced in 30% yield. Since a catalytic amount of p-toluenesulfonic acid to provide intermediate 3 was stable under the reaction conditions, 3a intermediate 5 and 5a (13:1) as a separable mixture in 93% may be a result of the double-bond isomerization of the enal combined yield. Although 5a may be used as well, it was during the catalytic process61, and the rate of the double-bond converted into 5 by treating it with pTSOH in methylene chloride isomerization was comparable to that of the Diels–Alder (DCM) and only 5 was used for the next step. After a cycloaddition (Fig. 7). Fortunately, 3a was converted into 3 conventional ozonolysis of intermediate 5 in DCM, the with DBU (1,8-diazabicycloundec-7-ene) in refluxing toluene in resulting dicarbonyl intermediate was directly treated with sodium methoxide in methanol at 0 °C due to the fact that the dicarbonyl intermediate was unstable for storage. To our delight, Cbz N O the aldol reaction afforded the desired product 6 in 60% N O combined yield. However, the reaction of 6 with the + methanesulfonyl chloride resulted in a complex mixture. Thus, N O OH O N H X the hydroxyketone intermediate 6 was reduced to diol 7 with H Gelsemine RS-1 sodium borohydride (97%) and the formation of disulfonate 8 with methanesulfonyl chloride was quantitative, the structure of Cbz which was confirmed through X-ray crystallographic analysis N O CHO Cbz CbzN O + N (Fig. 8). Treatment of intermediate 8 with DBU (1,8- OH CO R diazabicycloundec-7-ene) in refluxing toluene led to the O 2 OH 9 O RS-3 formation of alkene (85%) and reduction of the Cbz RS-2 protective group to methyl with lithium aluminium hydride in Figure 3 | Retrosynthetic analysis of gelsemine. In principle, gelsemine THF afforded 10 in 86% yield. Subsequent acid hydrolysis of the may be constructed from oxindole and intermediate RS-1, where X is a acetal with aqueous hydrochloric acid in THF provided leaving group. After a few transformations, RS-1 may be synthesized from hemiacetal 11 (96%). intermediate RS-2, which inturn may be obtained from RS-3 following With the key intermediate in hand, we began to test the several reaction steps including ozonolysis. Finally, RS-3 may be condensation of 11 with methoxymethyl oxindole and the synthesized from readily accessible starting materials. subsequent SN2 displacement, another key reaction for Me N O Me Me N O Me N O N OH O N 13 H Me OMs NH NH OMs NH N O OMs O O O O 12b 12a 12 NH 13a Figure 4 | Cyclization of intermediate 9 to form the gelsemine framework.