A Unified Total Synthesis of the Immunomodulators (-)-Rapamycin and (-)-27-Demethoxyrapamycin: Assembly of the Common C(1-20) Perimeter and Final Elaboration

The potent, naturally occurring immunomodulators (-)-rapamycin (1) and (-)-27-demethoxyrapamycin (2) have been synthesized via a unified and highly convergent strategy. In the preceding paper we discussed the construction of common building blocks A-C and their linkage to provide the C(21-42) segments of 1 and 2. Herein we describe model studies of triene generation and hydroxyl deprotection, the preparation and coupling of building blocks D and E, a two-step protocol for macrocycle formation via union of the ABC and DE subtargets, and completion of the total syntheses. The synthesis of 27-demethoxyrapamycin (2) confirmed the assigned structure. In this two-part full account,1 we present a unified, highly convergent synthetic route to the potent immunosuppressant rapamycin (1)2 and its naturally occurring 27-demethoxy congener 2.3 Our second-generation analysis of the rapamycin problem, discussed in the preceding paper,1 generated the C(2142) ABC perimeters 3 and 4 and the common C(1-20) DE perimeter 5 as key subtargets (Scheme 1). The macrocycles could then be elaborated by intermolecular acylation at C(34) and intramolecular Pd(0)-catalyzed Stille coupling,4,5 or alternatively via initial formation of the triene seco acids followed by macrolactonization. Although we have also made considerable progress in exploring the lactonization strategy,6 it was the former approach which we successfully employed for the total syntheses of 1 and 2.7,8 The previous reports detailed the construction of common subunits A, B, and C9 and the assembly of the ABC segments 3 and 4.1 Herein we describe model studies of triene formation and macrolide deprotection, the X Abstract published in AdVance ACS Abstracts, January 15, 1997. (1) Part 1: Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leahy, J. W.; Leazer, J. L., Jr.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119, 0000 (preceding paper in this issue). (2) (a) Vézina, C.; Kudelski, A.; Sehgal, S. N. J. Antibiot. 1975, 28, 721. (b) Sehgal, S. N.; Baker, H.; Vézina, C. Ibid. 1975, 28, 727. (c) Baker, H.; Sidorowicz, A.; Sehgal, S. N.; Vézina, C. Ibid. 1978, 31, 539. (d) Singh, K.; Sun, S.; Vézina, C. Ibid. 1979, 32, 630. (e) Swindells, D. C. N.; White, P. S.; Findlay, J. A. Can. J. Chem. 1978, 56, 2491. (f) McAlpine, J. B.; Swanson, S. J.; Jackson, M.; Whittern, D. N. J. Antibiot. 1991, 44, 688. (g) McAlpine, J. B.; Swanson, S. J.; Jackson, M.; Whittern, D. N. Ibid. 1991, 44, C-3 (correction). (h) Findlay, J. A.; Radics, L. Can. J. Chem. 1980, 58, 579. (i) Findlay, J. A.; Radics, L. Ibid. 1981, 59, 49 (erratum). (3) (a) Sehgal, S. N.; Baker, H.; Eng, C.; Singh, K.; Vézina, C. J. Antibiot. 1983, 36, 351. (b) Findlay, J. A.; Liu, J. S.; Burnell, D. J.; Nakashima, T. T. Can. J. Chem. 1982, 60, 2046. (c) Caufield, C. E.; Musser, J. H. Annu. Rep. Med. Chem. 1989, 25, 195. (4) To our knowledge, Stille was the first to employ his palladiumcatalyzed coupling for macrolide construction: Stille, J. K.; Tanaka, M. J. Am. Chem. Soc. 1987, 109, 3785. See also: Kalivretenos, A.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1991, 56, 2883. The Nicolaou synthesis of rapamycin5 elegantly extended this methodology by using a Stille-type “stitching-cyclization” to install the C(19,20) vinyl unit and close the macrocycle in 28% yield. (5) (a) Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.; Chakraborty, T. K.; Minowa, N.; Koide, K. Chem. Eur. J. 1995, 1, 318. (b) Nicolaou, K. C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.; Bertinato, P. J. Am. Chem. Soc. 1993, 115, 4419. (6) Condon, S. M. Ph.D. Thesis, University of Pennsylvania, 1995. (7) Preliminary communication: Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1995, 117, 5407. (8) The intramolecular Stille coupling remains an effective protocol for natural product synthesis. See for example: (a) Pattenden, G.; Thom, S. M. Synlett 1993, 215. (b) Barrett, A. G. M.; Boys, M. L.; Boehm, T. L. J. Org. Chem. 1996, 61, 685. (9) Preliminary communications: (a) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leahy, J. W.; Leazer, J. L., Jr.; Maleczka, R. E., Jr. Tetrahedron Lett. 1994, 35, 4907. (b) Smith, A. B., III; Maleczka, R. E., Jr.; Leazer, J. L., Jr.; Leahy, J. W.; McCauley, J. A.; Condon, S. M. Ibid. 1994, 35, 4911. Scheme 1 962 J. Am. Chem. Soc. 1997, 119, 962-973 S0002-7863(96)03067-3 CCC: $14.00 © 1997 American Chemical Society preparation and union of fragments D and E to furnish 5, and completion of the synthetic venture. Preparation of Subunit D. The key element of the common DE fragment 5 was building block D, the enyne ortho ester 9. Retrosynthetically, 9 was expected to derive from organometallic addition of an enyne moiety to aldehyde 12, the latter readily available from alkene (+)-11 (Scheme 2), an intermediate in our latrunculin synthesis.10 Hydrostannylation of the known silyl diyne 1311 was viewed as an expedient approach to vinylstannane 14, precursor to the desired lithio derivative.12 In the event, reaction of 13 with conventional stannyl cuprates afforded unacceptable mixtures of regioand stereoisomers, but both the (E)and (Z)-enynes 14 and 15 could be selectively generated in quantity via higher-order cuprates (Scheme 3).13 For installation of the all trans-triene of rapamycin, we initially focused on the (E)-vinylstannane 14. Transmetalation (n-BuLi, THF, -78 °C) and addition to aldehyde (+)-12 (Scheme 4) afforded a 1.3:1 mixture of the diastereomeric alcohols (+)-16 and (+)-17 in 69% yield. Fortuitously, we observed that the (Z)-organolithium, present in minor amounts, reacted with much higher diastereoselectivity; substitution of 15 (>98% Z) for 14 led to epimers (+)-25 and (+)-26 in a 5.6:1 ratio (65%, Scheme 6). At this juncture, however, it was unclear whether the (Z)-enyne could serve as a viable precursor to the triene moiety in 1; the configurations of the new carbinol stereocenters in both pairs of adducts also remained to be elucidated. Following chromatographic separation, the E isomers 16 and 17 were O-methylated with concurrent removal of the trimethylsilyl groups, affording ethers (+)-9 and (+)-20 in good yield. Single-crystal X-ray analysis revealed that 20 embodied the undesired (R) stereochemistry. We then optimized the formation of (+)-16 via an oxidation/asymmetric reduction sequence, employing the Corey chiral oxaborolidine catalyst14 to provide the pure (S)-alcohol in 30% yield overall from aldehyde 12. Triene Formation: Model Studies with Fragments C and D. Including N-acetylpipecolinic acid (E), a known compound,15 we now had in hand all five subunits.1 As outlined above, we envisioned from the outset that palladium-mediated σ-bond coupling of the ABC and DE subtargets would install the potentially sensitive (E,E,E)-triene in regioand stereocontrolled fashion.16 Before proceeding with elaboration of the subtargets, we decided to model the Stille cross-coupling with partners derived from fragments C with D. To generate the desired dienylstannane, we first investigated palladium-catalyzed hydrostannylation. Reaction of 9 with tributyltin hydride in the presence of (Ph3P)2PdCl2 (5 mol %) gave exclusively the internal stannane (+)-21 (Scheme 5). In contrast, treatment of 9 with n-Bu3SnH and AIBN in toluene at reflux furnished the (10) The (-)-antipode of 11, obtained by resolution, was required for the latrunculins: (a) Zibuck, R.; Liverton, N. J.; Smith, A. B., III J. Am. Chem. Soc. 1986, 108, 2451. (b) Smith, A. B., III; Leahy, J. W.; Noda, I.; Remiszewski, S. W.; Liverton, N. J.; Zibuck, R. Ibid. 1992, 114, 2995. (11) Holmes, A. B.; Jones, G. E. Tetrahedron Lett. 1980, 21, 3111. (12) (a) Zweifel, G.; Leong, W. J. Am. Chem. Soc. 1987, 109, 6409. (b) Stacker, E. C.; Zweifel, G. Tetrahedron Lett. 1991, 32, 3329. (13) (a) Piers, E.; Chong, J. M.; Morton, H. E. Tetrahedron Lett. 1981, 22, 4905. (b) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Reuter, D. C. Ibid. 1989, 30, 2065. (c) Singer, R. D.; Hutzinger, M. W.; Oehlschager, A. C. J. Org. Chem. 1991, 56, 4933. (14) (a) Corey, E. J.; Cheng, X.-M.; Cimprich, K. A.; Sarshar, S. Tetrahedron Lett. 1991, 32, 6835. (b) Corey, E. J.; Bakshi, R. K. Ibid. 1990, 31, 611. (15) (a) Rodwell, V. W. Methods Enzymol. 1971, 17, Part B, 174. (b) Toone, E. J.; Jones, J. B. Can. J. Chem. 1987, 65, 2772. (c) Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 5583. (16) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813. (17) Zhang, H. X.; Guibé, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857. Scheme 2