LETTERS
Pergamon
Tetrahedron TETRAHEDRON Letters 43 (2002) 545548
The synthesis of a key intermediate en route to gelsemine: a program based on intramolecular displacement of the carbon oxygen bond of a strategic oxetane
Fay W. Ng,a Hong Lin,b Qiang Tanb and Samuel J. Danishefskya,b,*
b
Department of Chemistry, Havemeyer Hall, Columbia University, New York, NY 10027, USA Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10021, USA
Received 5 November 2001
a
Abstract--The synthesis of key intermediate 30 en route to gelsemine has been accomplished from known aldehyde 10 via oxetane 19 featuring stereospecific Claisen rearrangement and Lewis acid-catalyzed oxetane ring opening. 2002 Published by Elsevier Science Ltd.
The appearance of the alkaloid gelsemine (1) (isolated from Gelseminium semperverans) in the chemical literature goes back to 1870.1 Its structure was arrived at in 1959 through spectroscopic as well as degradative arguments advanced by Conroy,2a independent of a crystallographic determination conducted concurrently by Lovell and colleagues.2b The keen interest which gelsemine (1) has attracted from the point of view of total synthesis seems incongruous with the rather sketchy and anecdotal suggestions of its potential usefulness.3 Clearly, it is the novel architecture of gelsemine, which has provoked many interesting strategies regarding possible routes for its assembly.4 Any proposal to reach gelsemine (1) must take note of the spiroanilide arising from the quaternary center at C7 (see Scheme 1). Further disconnection of the C7 N2 and O4C3 bonds leads back to structure type 7 (see 781). Progression from 78 requires suprafacial chirality transfer of a carboxyl equivalent with allylic transposition from C14C7. The underside (a face) of 7 is quite hindered and prospects for introduction of a hydroxymethyl group at C16 by late stage joining of a C16 C17 bond were not inviting. Our approach to solving this problem called for an intramolecular displacement of a properly configured oxetane (see sequences 67). In this way the required C17 hydroxymethyl group is released as the pyrrolidine ring is established. It was assumed that overall b
hydroxylation with allylic transposition (en route from 67) could be achieved. The oxetane moiety in 6 would be fashioned from a C5 C16 olefinic linkage by an overall addition of a `formaldehyde' residue in the proper regiochemical and stereochemical sense at the stage of 4. The logic used for adding this formaldehyde element to the C5 C16 olefin in 5 was destined to be the key element of the program (vide infra). It was further proposed that the nucleophilic arm of the projected oxetane displacement reaction (see 67) would have been derived from Curtius degradation of a suitable two carbon carboxylic acid, mounted at C20 (see structure 6). We conjectured about the possibility of concurrent presentation of the C20 vinyl group and the acetic acid residues in 6 via some form of a [3,3] rearrangement. The face selectivity issues in such a transformation would be a question for exploration. Assuming this matter could be resolved favorably, the prospect of reaching the allylic alcohol moiety of 5 from a C20 ketone virtually presented itself (see 45). Finally, in the retrosynthetic sense, it was hypothesized that 4 could have been derived from a divinyl cyclopropanecycloheptadiene rearrangement (34). Compound type 3 might be reached by chain extension (cf. o-nitrobenzylidenation) of the aldehyde linkage of substrate type 2. Depending on the precise nature of the structure, 2 could be a known compound (vide infra). In this and the accompanying paper, the synthesis of
* Corresponding author.
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Scheme 1. Synthetic plan.
()-gelsemine (1) is described. While the proposal presented above was realized in broad terms, reduction to practice involved exposure to many interesting issues in organic synthesis. The synthesis commenced with the epoxidation of 7-tbutoxynorbornadiene (Scheme 2).5 Alumina promoted rearrangement of epoxide 9 afforded the known alde-
hyde 10.6 o-Nitrobenzylidenation7 of this aldehyde, using phosphonate 11, led to 13 presumably via divinylcyclopropane 12. It was envisioned that ketone 15 would be an attractive type of intermediate to construct the critical oxetane moiety (cf. 5). In principle, 15 could be readily obtained from alcohol 14, which might be reached by hydroborationoxida-
Scheme 2. Synthesis of the oxetane ring. Reagents and conditions: (a) 11, NaOMe, DMF, 0C, 74%; (b) BH2ClDMS, Et2O, 0C; NaOH/H2O2, 77%, +7% regioisomer;8 (c) (COCl)2, DMSO, Et3N, CH2Cl2, 98.7%; (d) LiHMDS, TESCl, Et3N, THF, -78 to 0C; Eschenmoser's salt, CH2Cl2, 91%; (e) MeI, CH2Cl2/Et2O; Al2O3, CH2Cl2, 95%; (f) NaBH4, CeCl37H2O, MeOH, 99%; (g) 9-BBN dimer, THF; NaOH/H2O2, 88%; (h) MsCl, Et3N, CH2Cl2, -78C; NaHMDS, THF, -78C, 91%. DMS=dimethyl sulfide; HMDS=hexamethyldisilazane; TESCl=chlorotriethylsilane; Eschenmoser's salt=(CH3)2N CH2I; 9-BBN=9-borabicyclo[3.3.1]nonane.
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tion of 13. Such a hydroboration reaction raised significant questions of chemoselectivity among the two double bonds, regioselectivity at the C5 C16 olefin and face selectivity. The key issue was that of regiopreference, even assuming, as we did, that reaction would be directed to the more strained and more exposed cyclopentene (C5 C16) linkage. Our findings and conjectures on this kind of hydroboration as well as related reactions, in a model closely related to 13, have been discussed elsewhere.8 In the event, treatment of 13 with BH2ClDMS followed by oxidative workup, as shown, afforded a 11:1 ratio of alcohol 14 with the newly introduced alcohol at C5, relative to its isomer where the alcohol is at C16. Oxidation9 of 14 afforded ketone 15. The campaign to install the oxetane commenced with dimethylaminomethylation of the silyl enol ether derived from 15.10 Following quaternization of the nitrogen, and base induced elimination, the amethyleneketone 16 was in hand. At this stage we could take advantage of i-face addition to both sp 2 centers (C5 and C16). Hydride delivery at C5, in the context of a Luche reaction,11 afforded 17. Hydroboration of 17 also occurred from the b-face generating diol 18.12 From this diol intermediate, the a-face oxetane (19) was fashioned in a straightforward way as shown. With the critical oxetane in hand, we entered the next phase of the projected plan hoping to reach a functional version of allylic alcohol 5. We were anticipating a [3,3]-type rearrangement en route to structure type 6. Following the cleavage of t-butyl ether 19,13 the resulting alcohol function in 20 was oxidized to afford ketone 21 (Scheme 3). Emmons-type condensation14 was successful in terms of overall yield, but led to a 3:2 mixture of b,b-disubstituted steroisomers 22. Each compound
was converted by reduction to its allylic alcohol counterpart (23 and 24, respectively).15 These isomers were individually treated with triethylorthoacetate as shown.16 Remarkably, each allylic alcohol gave rise to a single and identical g,d-unsaturated ester 26 (presumably via 25) with the b-vinyl and a-carboxymethyl functions at C20 in the required sense.17 This stereochemical convergence might arise from the tendency of the enolate like component of the Claisen rearrangement step to glide over the five-membered ring fused to oxetane (see 2526). Additional cases must be evaluated to distinguish between possible steric or electronic factors in directing the face of the migration step. Regardless of the reasons for this convergence, it provided smooth access to a key intermediate, 26. Alkaline hydrolysis of the ethyl ester function served to release the free acid 27.18 Subjection of the latter to Curtius degradation, as practiced by Shiori, afforded urethane 28.19 As anticipated, the hitherto robust oxetane linkage, which had survived in the sequence that started with 19, was opened by the urethane nitrogen under Lewis acid activation (BF3 etherate)20 and compound 29 was in hand. In summary, we have shown the viability of a synthetic strategy organized around the central idea of using an oxetane linkage to store molecular functionality in a compact setting. In this case, the logic was used to deliver a highly hindered hydroxymethyl function. Key selectivity issues with potentially broader ramifications in synthesis were resolved favorably in the regioselective hydroboration of 13 and in the stereoconvergent rearrangements of 23 and 2426. The progression of 29 to gelsemine, requiring responses to some difficult and unanticipated challenges, is described in an accompanying paper.
Scheme 3. Construction of quaternary C7 and the pyrollidine ring. Reagents and conditions: (a) TFA/CH2Cl2, 0C, 81%; (b) (COCl)2, DMSO, Et3N, CH2Cl2, -78C, 81%; (c) triethylphosphonoacetate, NaH, THF, 0C, 3:2, 92%; (d) DIBAL, CH2Cl2, -78C, 88%; (e) cat. propionic acid, H3CC(OEt)3, toluene, reflux, 64%; (f) NaOH/THF/EtOH, 86%; (g) diphenylphosphoryl azide, Et3N, benzene, 25C, reflux; MeOH, reflux; 89%; (h) BF3Et2O, CH2Cl2, -78 to 12C, 64%; (i) PivCl, Et3N, DMAP, CH2Cl2, 025C, 92%. DIBAL=diisobutylaluminum hydride; PivCl=2,2,2-trimethylacetyl chloride; DMAP=N,N-dimethylaminopyridine.
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Acknowledgements This work was supported by grants from the National Institute of Health (grant HL25848). H.L. would like to thank the Texaco Foundation for a postdoctoral fellowship. We thank Dr. George Sukenick and Ms. Sylvi Rusli of the MSKCC NMR Core Facility for NMR and MS spectral analyses (NIH Grant CA08748).
References
1. Saxton, J. E. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1965; Vol. 8, pp. 93117. 2. (a) Conroy, H.; Chakrabarti, J. K. Tetrahedron Lett. 1959, 613; (b) Lovell, F. M.; Pepinsky, R.; Wilson, A. J. C. Tetrahedron Lett. 1959, 15. 3. Liu, Z.-J.; Lu, R.-R. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1988; Vol. 33, pp. 83140. 4. (a) Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767768; (b) Sheikh, Z.; Steel, R. W.; Tasker, A. S.; Johnson, A. P. J. Chem. Soc., Chem. Commun. 1994, 763764; (c) Dutton, J. K.; Steel, R. W.; Tasker, A. S.; Popsavin, V.; Johnson, A. P. J. Chem. Soc., Chem. Commun. 1994, 765766; (d) Atarashi, S.; Choi, J.-K.; Ha, D.-C.; Hart, D. J.; Kuzmich, D.; Lee, C.-S.; Ramesh, S.; Wu, S. C. J. Am. Chem. Soc. 1997, 119, 62266241; (e) Kuzmich, D.; Wu, S. C.; Ha, D.-C.; Lee, C.-S.; Ramesh, S.; Atarashi, S.; Choi, J.-K.; Hart, D. J. J. Am. Chem. Soc. 1994, 116, 69436944; (f) Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 74267427; (g) Madin, A.; O'Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem., Int. Ed. Engl. 1999, 38, 29342936. 5. 7-t-Butoxynorbornadiene is commercially available. It can be prepared by the method of Story: Story, P. R. J. Org. Chem. 1961, 26, 287290. 6. (a) Klumpp, G. W.; Barnick, J. W. F. K.; Veefkind, A. H.; Bickelhaupt, F. Recl. Trav. Chim. Pays-Bas 1969, 88, 766778; (b) Cupas, C.; Watts, W. E.; Schleyer, P.; von, R. Tetrahedron Lett. 1964, 5, 25032507.
7. Le Corre, M.; Hercouet, A.; Le Stanc, Y.; Le Baron, H. Tetrahedron 1985, 41, 53135320. 8. Ng, F. W.; Chiu, P.; Danishefsky, S. J. Tetrahedron Lett. 1998, 767770. 9. Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem. 1979, 44, 41484150. 10. (a) Kleinman, E. F. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Press: New York, USA, 1991; Vol. 2, p. 899; (b) Danishefsky, S.; Kitahara, T.; Schuda, P. F.; Etheredge, S. J. J. Am. Chem. Soc. 1976, 98, 30283030. 11. Luche, J.-L.; Gemal, A. J. L. Chem. Soc., Chem. Comm. 1978, 976977. 12. It was unlikely for the hydroboration to occur on the endo-face because the free hydroxyl group reacted with the boron reagent to give the boronate ester, which is a poor chelating partner, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 13071370. 13. Beyerman, H. C.; Heiszwolf, G. L. J. Chem. Soc. 1963, 755756. 14. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863927. 15. Winterfeldt, E. Synthesis 1975, 617630. 16. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brosksom, T. J.; Li, T.-T.; Faulkner, D. J.; Perterson, M. R. J. Am. Chem. Soc. 1970, 92, 741743. For an overview of Claisen reaarangement see: (a) Ziegler, F. E. Chem. Rev. 1988, 88, 14231452; (b) Ziegler, F. E. Acc. Chem. Res. 1977, 10, 227232. 17. After this discovery, the 3:2 mixture of allylic alcohols 23 and 24 were subjected to the above variant Claisen rearrangement conditions without further separation of the two isomers. 18. Honda, M.; Hirata, K.; Sueoka, H.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1981, 22, 26792682. 19. (a) Shiori, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 62036205; (b) Ninomiya, K.; Shiori, T.; Yamada, S. Tetrahedron 1974, 30, 21512152. 20. Boron trifluoride was the superior Lewis acid for the activation of oxetane derivatives with intramolecular etheral oxygen participation. See: Itoh, A.; Hirose, Y.; Kashiwagi, H.; Masaki, Y. Heterocycles 1994, 38, 2165 2169. Boron trifluoride catalyzed the nucleophilic ring opening of oxetane derivatives, see: Xianming, H.; Kellogg, R. M. Tetrahedron: Asymmetry 1995, 6, 13991408.
TETRAHEDRON LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 549551
The synthesis of ()-gelsemine
Hong Lin,a Fay W. Ngb and Samuel J. Danishefskya,b,*
a
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10021, USA b Department of Chemistry, Havemeyer Hall, Columbia University, New York, NY 10027, USA
Received 5 November 2001
Abstract--The synthesis of ()-gelsemine has been completed from tetracyclic intermediate 2 via a stereospecific [3,3]-rearrangement followed by a one carbon excision to convert a d-lactam (13) to a g-lactam (19). 2002 Published by Elsevier Science Ltd.
In the preceding paper1 we reported on a synthesis of compound 2 in furtherence of a proposed total synthesis of gelsemine (1).2 Before describing how gelsemine was reached via 2, we must place our study in context. It was possible in several settings to accomplish overall isomerization of the non conjugated D3(14) double bond to the conjugated D3(7) series, in which the aromatic amino function is also presented (see Scheme 1, structure type 3). With this capability, a number of possibilities for introduction of a one carbon residue between C7 and the anilino nitrogen group were surveyed (cf. 34, with or without concurrent participation from the primary hydroxy function). These attempts were uniformly unsuccessful. Instead, those reactions that could be achieved, were initiated by attack of a one carbon moiety at C3 (in a Markovnikov sense) rather at C7 as would be required for spirocyclization to a 5-membered anilide.3 A key element in the overall isomerization (ie. conjugation) of the double bond to the D3(7) series was allylic bromination of a D3(14) double bond isomer to introduce a b-bromine at C14 with reappearance of the double bond at the D3(7) position.4 This reaction was now conducted on pivaloate 2, thereby affording 5 (Scheme 2).5 Debromination of 5 (tri-n-butyltin hydride) in the presence of O2, followed by the reduction of the resulting hydroperoxide with sodium borohydride afforded 6 with high stereoselectivity.6 Alternatively, acetolysis of 5 was accomplished, with silver acetate in acetic acid, to provide 7.7 The overall stereochemical retention result in this reaction attests to the highly hindered nature of the a-face of the `balllike' surface of 5, and species derived therefrom. Reduc* Corresponding author.
tion of the nitro group afforded the amine, which was protected with CbzCl to provide 8. Deprotection of the acetate afforded 9. Major efforts were directed to the goal of using the C14 b-OH group to introduce a b-one carbon fragment at C7 by suprafacial allylic transposition (cf. 1011, Scheme 3). Such attempts were uniformly unsuccessful. A particularly disappointing case is seen in the high
Scheme 1.
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Scheme 2. Reagents and conditions: (a) NBS, AIBN, hw, CCl4/CH2Cl2, reflux, 60% based on recovered starting material; (b) AIBN, Bu3SnH, dry air, hw, toluene, 60C; NaBH4, 0C; 55% based on recovered starting material; (c) AgOAc, HOAc, 52%; (d) zinc dust, THF/HOAc; (e) CbzCl, NaHCO3 (aq.), CH2Cl2, 94% for two steps; (f) K2CO3, MeOH, 90%. NBS=N-bromosuccinimide, AIBN=2,2%-azobisisobutyronitrile, CbzCl=benzyl chloroformate.
Scheme 3. Reagents and conditions: (a) CH3C(OMe)2NMe2, m-xylene, silica gel purification, 3040%; (b) NaOMe, MeOH, 74%.
yielding transformation of 10128 by apparent [1,2] transposition,9 in the context of a projected StillWittig rearrangement.10 Apparently, formidable steric forces are arrayed against carbon carbon bond formation even on the b-face of C7, and even by intramolecular means. Fortunately, it was found that the Eschenmoser amide acetal version of the Claisen rearrangement took place in the desired [3,3] sense.11 Subjection of 9 to the conditions shown, led to 13 and, following deprotection of the pivaloate group, 14.12 We now faced the challenging prospect of shrinking the 6-membered lactam to a 5-membered spiroanilide for purposes of reaching gelsemine (1). The sequence to accomplish this goal began with reduction of the imidelike functionality of 13 to afford aminal 15 (Scheme 4). Dehydration of this aminal, as shown, furnished enamide 16 (50% yield over two steps). Dihydroxylation of 16, across the more electron-rich enamide double bond, provided a trihydroxy intermediate, which was subjected to oxidative cleavage, as shown. This degradation provided a 45% yield of 17, containing an all-important b-face aldehyde at C7. Protection of the hydroxy group of 17 led to silyl ether 18. Methanolysis of this compound served to accomplish N-deformylation and, concurrently, ring closure to a cyclic hemiaminal. The latter, following oxidation, gave rise to oxindole 19. Desilylation of 19, as shown, led to 20 in
which the extremely hindered free hydoxymethyl group on a-face (initially derived by intramolecular oxetane opening)1 was now poised to close the tetrahydropyran ring. Oxymercruation of 20 with Hg(OTf)2 N,N-dimethylaniline complex in CH3NO213,14 afforded the desired mercuric cyclization product which, following reductive demercuration (using Fukuyama's protocol),15 furnished hydropyran 21 in 60% yield. Hydrolysis of the Cbz protected oxindole in 21,16 with 10% of NaOH in THF afforded a 90% yield of 22. Finally, the methyl carbamate of 22 was reduced to an N-methyl group with LiAlH4,17 thereby affording 1 whose spectroscopic and chromatographic properties matched those of naturally derived gelsemine. In summary, we had set out to explore some novel synthetic constructions using the synthesis of gelsemine (1) as an orienting, clearly defined, goal. Many interesting issues of selectivity, both at regiochemical and stereochemical levels, were resolved in favorable ways.1,18 Our findings as to reaction specificities in subtle cases merit continuing study. While confident application of these findings to new cases would require broadening of our database as to scope and limitations, the finding reported here as part of the synthesis, already invite potentially important interpretations.
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Scheme 4. Reagents and conditions: (a) DIBAL, CH2Cl2, -78C; (b) TsOHH2O, CH2Cl2, reflux, 50% for two steps; (c) OsO4, THF, -25C; Na2SO3 (aq.); (d) NaIO4, THF/H2O, 45%; (e) TESOTf, Et3N, CH2Cl2, 0C, 80%; (f) NaOMe, MeOH; (g) TPAP, , NMO, CH2Cl2, 4 A MS, 50% for two steps; (h) TBAF/HOAc 1:1, THF, 80%; (i) Hg(OTf)2C6H5NMe2, CH3NO2; NaBH4, 10% NaOH, Et3BnNCl, CH2Cl2, 60%; (j) 10% NaOH, THF, 90%; (k) LiAlH4, THF, 025C, 81%. DIBAL=diisobutylaluminum hydride, TESOTf=triethylsilyltrifluoromethanesulfonate, TPAP=tetrapropylammonium perruthenate, NMO=N-methylmorpholine N-oxide.
Unfortunately, the focused gelsemine target goal became quite complicated in that its solution required excision of a one carbon unit from a six-membered lactam to a five-membered spiroanilide (see 1319). In the end, this ring contraction was accomplished. A full account of these experiments and other interesting excursions directed to gelsemine (1) is planned. Acknowledgements This work was supported by grants from the National Institute of Health (grant HL25848). H.L. would like to thank the Texaco Foundation for a postdoctoral fellowship. We thank Dr. George Sukenick and Ms. Sylvi Rusli of the MSKCC NMR Core Facility for NMR and MS spectral analyses (NIH Grant CA08748). References
1. Ng, F. W.; Lin, H.; Tan, Q.; Danishefsky, S. J. Tetrahedron Lett. 2002, 43, 545548. 2. Saxton, J. E. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1965; Vol. 8, pp. 93117. 3. For specific examples of this effect see: Ng, F.W. Ph.D. Thesis, Columbia Unversity, 1997, 70, and 74. 4. For free radical benzylic bromination of substituted nitrotoluene derivatives with NBS, see: Mataka, S.; Kurisu, M.; Takahashi, K.; Tashiro, M. Chem. Lett. 1984, 19691972. 5. Following precedents, methylene chloride was used to minimize double bromination, see: Offermann, W.; Vogtle, F. Angew. Chem., Int. Ed. Engl. 1980, 19, 464465. 6. Nakamura, E.; Inubushi, T.; Aoki, S.; Machii, D. J. Am. Chem. Soc. 1991, 113, 89808982. For additional examples of free radical initiated oxygenation, see: Mayer, S.; Prandi, J. Tetrahedron Lett. 1996, 37, 31173120; Moutel, S.; Prandi, J. Tetrahedron Lett. 1994, 35, 81638166. The yield was based on the recovered starting material.
7. Cf: Winstein, S.; Buckles, R. E. J. Am. Chem. Soc. 1942, 64, 27872790. 8. Ng, F. W. Ph.D. Thesis, Columbia University, 1997, 54. The stereochemistry at C14 of the rearrangement product (12) was not determined. 9. Cf: Still, C. W.; Mitra, A. J. Am. Chem. Soc. 1978, 100, 1927. 10. For an overview of [2,3]-Wittig rearrangements see: (a) Mikami, K.; Nakai, T. Org. React. 1994, 46, 105; (b) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885902. 11. Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv. Chim. Acta 1969, 52, 10301042. 12. Compound 14 was prepared to clarify the stereo outcome of the Claisen rearrangement as shown in Scheme 3. The most conclusive signal was the NOE between one of the a-protons in the lactam and H19 (the methine proton of the terminal alkene). 13. Nishizawa, M.; Takenaka, H.; Hayashi, Y. J. Org. Chem. 1986, 51, 806813. 14. Newcombe, N. J.; Ya, F.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767768. 15. Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 74267427. 16. Reductive demercuration was capricious when conducted on small scale. It is currently under optimization. Hydrolysis of 21 was performed on the material that was degraded from commercially available gelsemine (1) in three steps: demethylation of 1 with PhOCOCl and Hunig's base provided the phenyl carbamate, which was converted to methyl carbamate (which is identical to 22) with NaOMe in MeOH at reflux. Protection of the free oxindole with CbzCl, Et3N and DMAP in CH2Cl2 provided 21 whose spectroscopic and chromatographic properties were identical to those of its synthetic counterpart. 17. Confalone, P. N.; Huie, E. M. J. Org. Chem. 1985, 52, 7983. 18. Ng, F. W.; Chiu, P.; Danishefsky, S. J. Tetrahedron Lett. 1998, 39, 767770.