Total synthesis of (+)-gelsemine via an organocatalytic Diels–Alder approach

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 (+)-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%.

A lthough gelsemine was isolated 1 in as early as 1876 from Gelsemium Sempervirens Ait., its structure was not determined until 1959 by means of nuclear magnetic resonance (NMR) spectroscopic techniques 2,3 and X-ray crystallographic analysis 4 . This indole alkaloid contains a hexacyclic cage structure and seven contiguous chiral carbon centres (Fig. 1). The complex chemical structures of gelsemine and other members of the alkaloid family [5][6][7][8] have attracted considerable attention from synthetic chemists. So far, in addition to the many synthetic efforts  , there are eight total syntheses reported in the literature [38][39][40][41][42][43][44][45][46][47][48][49] (Fig. 2), two of which are asymmetric 44,48 . Although gelsemine was thought to have no particular biological activities, a recent report indicated that gelsemine exhibited potent and specific antinociception in chronic pain by acting at the three spinal glycine receptors 50 . Besides, gelsemine was nonaddictive, indicating that the mechanism of its action is different from that of morphine. The complex structure and the potential medicinal applications of gelsemine prompted us to initiate a more efficient enantioselective total synthesis.

Results
Retrosynthetic analysis. Gelsemine may be synthesized from intermediate RS-1 and oxindole via the condensation of the hemiacetal with oxindole followed by an intramolecular S N 2 displacement (Fig. 3). Although the condensation may result in four stereoisomers, only two of them may undergo the desired S N 2 displacement. The other two isomers, however, may either stay intact or undergo an elimination followed by a Michael addition 51,52 to regenerate the four stereoisomers. This equilibrium is shifted to form the desired product after the intramolecular S N 2 displacement, which is irreversible under the reaction conditions (Figs 4 and 5). The S N 2 displacement may result in two isomers, one of which is the desired product. Intermediate RS-1 may be obtained from RS-2 following a sequence of intramolecular aldol condensation, reduction of the carbonyl group, formation of the sulfonates and then elimination. The intramolecular aldol 53,54 condensation deserves further discussion due to the fact that both the aldehyde and the ketone functionalities may undergo enolization under the reaction conditions, resulting in epimerization of both stereochemical centres attaching the carbonyl groups. Another 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 functional group 55 and it will play a significant role in preventing the aldehyde from being enolized prior to the ketone enolization. In this case, the potential epimerization of the ketone functionality is irrelevant. The third issue is the stereochemistry of the hydroxyl group even if aldol condensation occurs in the desired direction. This difficulty may be overcome when one realizes that the desired product has a more favourable internal hydrogen bond 56,57 than the other isomer. Finally, formation of RS-3 and its conversion into RS-2 is straightforward.
Synthesis of the ( þ )-gelsemine. On the basis of the above analysis, the synthetic strategy seemed feasible. If intermediate 3 is made asymmetric, then gelsemine will be made asymmetric. Thus, after a brief literature search 58,59 , an asymmetric Diels-Alder reaction was designed and the synthesis began with dihydropyridine 1 (Fig. 6), which may be prepared from 4-methylpyridine in large scale 60 .    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.
Gratifyingly, the yield of the desired endo product was 47% after reduction of the aldehyde carbonyl group with sodium borohydride, and its enantio excess was determined using chiral high-performance liquid chromatography (HPLC) to be 99.7%, while the exo product was not detected. It was surprising that intermediate 3a was also produced in 30% yield. Since intermediate 3 was stable under the reaction conditions, 3a may be a result of the double-bond isomerization of the enal during the catalytic process 61 , and the rate of the double-bond isomerization was comparable to that of the Diels-Alder cycloaddition (Fig. 7). Fortunately, 3a was converted into 3 with DBU (1,8-diazabicycloundec-7-ene) in refluxing toluene in 97% yield, which brought the total yield of the Diels-Alder cycloaddition to 76%. Intermediate 3 was then further selectively reduced to the hemiacetal 4 using Dibal-H at À 78°C in 94% yield. The subsequent Wittig reaction furnished the methyl enol ether, which was directly treated with trimethyl orthoformate and a catalytic amount of p-toluenesulfonic acid to provide intermediate 5 and 5a (13:1) as a separable mixture in 93% combined yield. Although 5a may be used as well, it was converted into 5 by treating it with pTSOH in methylene chloride (DCM) and only 5 was used for the next step. After a conventional ozonolysis of intermediate 5 in DCM, the 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, the aldol reaction afforded the desired product 6 in 60% combined yield. However, the reaction of 6 with the methanesulfonyl chloride resulted in a complex mixture. Thus, the hydroxyketone intermediate 6 was reduced to diol 7 with sodium borohydride (97%) and the formation of disulfonate 8 with methanesulfonyl chloride was quantitative, the structure of which was confirmed through X-ray crystallographic analysis (Fig. 8)  Finally, acid hydrolysis of the methyl group from the methoxymethyl protective group and removal of the resulting hydroxymethyl with triethylamine converted 13 into ( þ )-gelsemine in 70% combined yield. The synthetic material is identical to the natural product in terms of carbon and proton NMR spectra and optical rotation (see Supplementary Fig. 15).

Discussion
The total synthesis of ( þ )-gelsemine is completed in a highly enantioselective manner from readily accessible starting materials. This synthesis features an enantioselective organocatalytic Diels-Alder reaction, a formidable intramolecular aldol cyclization and a challenging intramolecular S N 2 displacement. The combination of all these features resulted in exceptional overall synthetic efficiency: the enantio excess is over 99%, and the total yield is about 5%.

Methods
General. All reagents were reagent grade and used without purification, unless otherwise noted. All reactions involving air-or moisture-sensitive reagents or intermediates were performed under an inert atmosphere of argon in glassware that was oven dried. Reaction temperatures referred to the temperature of the cooling/heating bath. Chromatography was performed using forced flow (flash chromatography) of the indicated solvent system on 230-400 mesh silica gel (Silicycle flash F60), unless otherwise noted. 1