Deprotecting Dithiane-Containing Alkaloids Fraser F. Fleming,* Lee Funk, Ramazan Altundas, and Yong Tu Duquesne University, Department of Chemistry & Biochemistry, Pittsburgh, Pennsylvania 15282-1530 flemingf@duq.edu Received May 22, 2001 Dithianes are unparalleled as lynchpin carbanions 1 that directly assemble protected ketones. The unrivaled versatility of dithianes 2 is tempered only by the ultimate unmasking of the dithiane to the corresponding ketone, 3 a seemingly trivial conversion for which numerous reagents have been developed. 4 Dithiane deprotection is particularly challenging for dithiane-containing alkaloids since alkylative, oxidative, and Lewis acidic reagents exhibit similar affinities toward the alkaloid as for the dithiane. 5 The dithiane-containing quinolizidine 2a is potentially an excellent alkaloid precursor, being rapidly synthesized by a unique intramolecular conjugate addition reaction. 6 The potential deployment of 2a in alkaloid syntheses hinges on deprotecting the dithiane in the presence of the tertiary amine. Of the few reagents developed for deprotecting dithiane-containing alkaloids, the combina- tion of SbCl 5 -Me 2 S 2 7 is regarded as being particularly mild 8 and well suited for dithiane-containing amines. Quinolizidine 2a reacts readily with the SbCl 5 -Me 2 S 2 reagent resulting in a smooth conversion, not to the anticipated ketone, but rather to the vinyl sulfide 3 (Scheme 1)! The mechanistically challenging formation of vinyl sulfide 3 is surprisingly well precedented. 9 SbCl 5 reacts with MeSSMe to generate SbCl 3 and the powerful thio- methylating 10 reagent 4 7 (Scheme 2) that thiomethylates the more accessible equatorial sulfur atom. Dissociation of the resulting sulfonium salt 5 and addition of excess dimethyl disulfide generates 7 that undergoes sequential thiomethyl transfers to afford 8. Disulfide elimination from 8 cleanly affords 3 (33% yield) accompanied by a polymeric material that presumably arises from self- condensation of intermediate carbocations. Although the dithiane was not hydrolyzed, 11 valuable insight into the precise conditions for hydrolysis was obtained. Specifi- cally, attempts to protect the amine by precomplexing 2a with SbCl 3 , 12 or other transition metals, led to poor mass recovery suggesting that 2a functions as an excel- lent ligand with a pronounced affinity toward transition metals! 13 The inability to hydrolyze 14 or couple the vinyl sulfide 3 15 further indicated the necessity for deprotecting under aqueous conditions to preferentially intercept the sulfonium intermediate 6. Armed with mechanistic insight the dithiane hydroly- sis of 2a was pursued in aqueous media. Alkaloid 2a is readily protonated with aqueous acids (TFA, 16 H 2 SO 4 , 17 HClO 4 ) forming an ammonium salt without perceptible hydrolysis of 2a. Isolation of the perchlorate salt and exposure to trimethyloxonium tetrafluoroborate resulted in the recovery of only a small amount of unreacted 2a, despite this procedure successfully cleaving a closely related dithiane-containing alkaloid. 5c Direct alkylative (1) Smith, Amos B., III; Pitram, Suresh M. Org. Lett. 1999, 1, 2001. (2) (a) Page, P. C. B.; van Niel, M. B.; Prodger, J. C. Tetrahedron 1989, 45, 7643. (b) Gro ¨bel, B.-T.; Seebach, D. Synthesis 1977, 357. (3) Difficulties in unmasking dithianes have often emerged during syntheses with complex intermediates necessitating reagent screening and, in some cases, indirect transacetalization followed by hydrolysis. See, for example: Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 5583. (4) Protective groups in organic synthesis, 3rd ed.; Greene, T. W., Wuts, P. G. M., Eds.; John Wiley & Sons: Chichester, 1999. (5) (a) Forns, P.; Diez, A.; Rubiralta, M. J. Org. Chem. 1996, 61, 7882. (b) Tang, C. S. F.; Morrow, C. J.; Rapoport, H. J. Am. Chem. Soc. 1975, 97, 159. (c) Oishi, T.; Takechi, H.; Kamemoto, K.; Ban, Y. Tetrahedron Lett. 1974, 11. (6) Fleming, F. F.; Hussain, Z.; Weaver, D.; Norman, R. E. J. Org. Chem. 1997, 62, 1305. (7) Weiss, R.; Schlierf, C. Synthesis 1976, 323. (8) Prato, M.; Quintily, U.; Scorrano, G.; Sturaro, A. Synthesis 1982, 679. (9) Kim, J. K.; Pau, J. K.; Caserio, M. C. J. Org. Chem. 1979, 44, 1544. (10) (a) Smallcombe, S. H.; Caserio, M. C. J. Am. Chem. Soc. 1971, 93, 5826. (b) Helmkamp, G. K.; Cassey, H. N.; Olsen, B. A.; Pettitt, D. J. J. Org. Chem. 1965, 30, 933. (11) Similar recalcitrant hydrolyses of vinyl sulfide-containing alkaloids has been noted: Pearson, W. H.; Bergmeier, S. C.; Williams, J. P. J. Org. Chem. 1992, 57, 3977. (12) Treatment of 2a with SbCl3 prior to the addition of 4 causes complete decomposition indicating that complexation between SbCl3 and 2a is precluded during the formation of 3. (13) The use of mercury-based reagents (Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553) resulted in poor mass recovery presumably resulting from strong, irreversible complexation 12 with the amine, dithiane, and nitrile groups that make 2a an excellent metal ligand! Poor mass recovery is observed during the dehydrogenation of quinolizidines with Hg(OAc)2: Kasymov, T. K.; Ishbaev, A. I.; Aslanov, K. A.; Sadykov, A. S. Chem. Nat. Compd. 1969, 5, 383. (14) The following reagents were screened. (a) TFA: Grayson, J. I.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1977, 2263 (b) TiCl4: Sato, M.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1981, 22, 1609. (c) HCl: Chou, W.-C.; Fang, J.-M. J. Org. Chem. 1996, 61, 1473. (15) Luh, T.-Y.; Ni, Z.-J. Synthesis 1990, 89. (16) Grayson, J. I.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1977, 2263. (17) Ho, T.-L.; Ho, H. C.; Wong, C. M. Can. J. Chem. 1973, 51, 153. Scheme 1 Scheme 2 6502 J. Org. Chem. 2001, 66, 6502-6504 10.1021/jo0157829 CCC: $20.00 © 2001 American Chemical Society Published on Web 08/23/2001