A unified total synthesis of the immunomodulators (-)-rapamycin and (-)-27-demethoxyrapamycin: Construction of the C(21-42) perimeters

Article abstract of DOI:10.1021/ja963066w

A total synthesis of the potent, naturally occurring immunomodulators (-)-rapamycin (1) and (-)-27-demethoxyrapamycin (2) has been achieved via a unified, highly convergent synthetic strategy. Both targets were elaborated from common building blocks A-E,

Full text of DOI:10.1021/ja963066w

J. Am. Chem. Soc. 1997, 119, 947-961
947
A Unified Total Synthesis of the Immunomodulators
(-)-Rapamycin and (-)-27-Demethoxyrapamycin: Construction
of the C(21-42) Perimeters
Amos B. Smith, III,* Stephen M. Condon, John A. McCauley,
Johnnie L. Leazer, Jr., James W. Leahy, and Robert E. Maleczka, Jr.
Contribution from the Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
ReceiVed September 3, 1996X
Abstract: A total synthesis of the potent, naturally occurring immunomodulators (-)-rapamycin (1) and (-)-27-
demethoxyrapamycin (2) has been achieved via a unified, highly convergent synthetic strategy. Both targets were
elaborated from common building blocks A-E, the latter available in decagram quantities. Herein we present the
construction of the ABC northern perimeters of 1 and 2. The accompanying paper describes the preparation of the
southern perimeter DE segment, triene and deprotection model studies, and completion of the synthetic venture.
Notable features of the approach include stereoselective σ-bond constructions of trisubstituted olefins and the union
of advanced intermediates via efficient dithiane couplings.
In 1975, researchers at Ayerst Laboratories (Montre´al,
Canada) reported the discovery of rapamycin (1), an antibiotic
produced by Streptomyces hydroscopicus (NRRL 5491) endemic
to Easter Island soil samples.1 Structure elucidation via
degradation and X-ray crystallography revealed a fundamentally
new type of macrocycle, a 31-membered ring containing both
lactam and lactone linkages,2 richly adorned with stereochemical
and functional elements. Notwithstanding its challenging
architecture, rapamycin attracted little interest until 1986, when
the isolation of the structurally related immunosuppressant
FK506 (3)3 sparked investigations of the immunosuppressive
activity of 1. Rapamycin proved to be a potent immuno-
modulator and prospective anti-graft-rejection agent.4,5 In rats,
1 completely suppressed the development of cellular immunity
as well as the formation of an IgE-like antibody.6
rapamycin-FKBP12 complex has recently been identified and
variously designated as mTOR, RAFT and FRAP.10,11 Whereas
the specific roles of 1 and its complexes in signal transduction
and immunosuppression remain unclear, it has been established
that rapamycin interferes with a Ca2+-independent signaling
pathway emanating from the IL-2 receptor.12
Whereas preliminary reports indicated that the naturally
occurring congener13 27-demethoxyrapamycin (2) is 10-fold less
active than 1 in the mixed lymphocyte response assay, 2 is
(7) (a) Bierer, B. E.; Mattila, P. S.; Standaert, R. F.; Herzenberg, L. A.;
Burakoff, G.; Crabtree, G.; Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A.
1990, 87, 9231. (b) Somers, P. K.; Wandless, T. J.; Schreiber, S. L. J. Am.
Chem. Soc. 1991, 113, 8045.
(8) (a) Liu, J. Immunol. Today 1993, 14, 290. (b) Schreiber, S. L.;
Crabtree, G. R. Ibid. 1992, 13, 136. (c) Fruman, D. A.; Klee, C. B.; Bierer,
B. E.; Burakoff, S. J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 3686. (d) Liu,
J.; Albers, M. W.; Wandless, T. J.; Luan, S.; Alberg, D. G.; Belshaw, P. J.;
Cohen, P.; MacKintosh, C.; Klee, C. B.; Schreiber, S. L. Biochemistry 1992,
31, 3896. (e) Liu, J.; Farmer, J. D., Jr.; Lane, W. S.; Friedman, J.; Weissman,
I.; Schreiber, S. L. Cell 1991, 66, 807.
Both rapamycin and FK506 bind to the cytosolic immuno-
philin FKBP12, a strict requirement for the observed physi-
ological responses.7 At this point, however, the immuno-
suppressive mechanisms diverge. The FK506-FKBP12 com-
plex binds calcineurin,8,9 whereas a different target for the
(9) Griffith, J. P.; Kim, J. L.; Kim, E. E.; Sintchak, M. D.; Thomson, J.
A.; Fitzgibbon, M. J.; Fleming, M. A.; Caron, P. R.; Hsiao, K.; Navia, M.
Cell 1995, 82, 507.
X Abstract published in AdVance ACS Abstracts, January 15, 1997.
(1) (a) Ve´zina, C.; Kudelski, A.; Sehgal, S. N. J. Antibiot. 1975, 28,
721. (b) Sehgal, S. N.; Baker, H.; Ve´zina, C. Ibid. 1975, 28, 727. (c) Baker,
H.; Sidorowicz, A.; Sehgal, S. N.; Ve´zina, C. Ibid. 1978, 31, 539. (d) Singh,
K.; Sun, S.; Ve´zina, C. Ibid. 1979, 32, 630.
(2) (a) Swindells, D. C. N.; White, P. S.; Findlay, J. A. Can. J. Chem.
1978, 56, 2491. (b) McAlpine, J. B.; Swanson, S. J.; Jackson, M.; Whittern,
D. N. Ibid. 1991, 44, 688. (c) McAlpine, J. B.; Swanson, S. J.; Jackson,
M.; Whittern, D. N. Ibid. 1991, 44, C-3 (correction). (d) Findlay, J. A.;
Radics, L. Can. J. Chem. 1980, 58, 579. (e) Findlay, J. A.; Radics, L. Ibid.
1981, 59, 49 (erratum).
(3) Kino, T.; Hatanaka, H.; Hashimoto, M.; Nishiyama, M.; Goto, T.;
Okuhara, M.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1987, 40,
1249.
(4) (a) Luo, H.; Chen, H.; Daloze, P.; Chang, J. Y.; St-Louis, G.; Wu, J.
Transplantation 1992, 53, 1071. (b) Henderson, D. J.; Naya, I.; Bundick,
R. V.; Smith, G. M.; Schmidt, J. A. Immunology 1991, 73, 316. (c) Morris,
R. E. Transplant. Proc. 1991, 23, 2722. (d) Sigal, N. H.; Lin, C. S.;
Siekierka, J. J. Ibid. 1991, 23 (Suppl. 2), 1.
(10) (a) Cafferkey, R.; Young, P. R.; McLaughlin, M. M.; Bergsma, D.
J.; Koltin, Y.; Sathe, G. M.; Faucette, L.; Eng, W.-K.; Johnson, R. K.; Livi,
G. P. Mol. Cell. Biol. 1993, 13, 6012. (b) Brown, E. J.; Albers, M. W.;
Shin, T. B.; Ichikawa, K.; Keith, C. T.; Lane, W. S.; Schreiber, S. L. Nature
1994, 369, 756. (c) Sabatini, D. M.; Erdjument-Bromage, H.; Lui, M.;
Tempst, P.; Snyder, S. H. Cell 1994, 78, 35. (d) Chen, Y.; Chen, H.; Rhoad,
A. E.; Warner, L.; Caggiano, T. J.; Failli, A.; Zhang, H.; Hsiao, C.-L.;
Nakanishi, K.; Molnar-Kimber, K. L. Biochem. Biophys. Res. Commun.
1994, 203, 1. (e) Chiu, M. I.; Katz, H.; Berlin, V. Proc. Natl. Acad. Sci.
U.S.A. 1994, 91, 12574. (f) Sabers, C. J.; Martin, M. M.; Brunn, G. J.;
Williams, J. M.; Dumont, F. J.; Wiederrecht, G.; Abraham, R. T. J. Biol.
Chem. 1995, 270, 815.
(11) For the X-ray structure of the rapamycin-FKBP12 complex
interacting with the binding domain of human FRAP, see: Choi, J.; Chen,
J.; Schreiber, S. L.; Clardy, J. Science 1996, 273, 239.
(12) Schreiber, S. L.; Albers, M. W.; Brown, E. J. Acc. Chem. Res. 1993,
26, 412.
(13) Other natural congeners of 1 include (a) 27-desmethylrapamycin:
Ondeyka, J.; Hensens, O.; Liesch, J. U.S. Patent 5,091,389, 1992. (b)
16,27-bis(desmethyl)rapamycin: Byrne, K.; Goegelman, R. T.; Hensens,
O.; Kaplan, L.; Liesch, J. M. U.S. Patent 5,093,338, 1992. (c) 2-norrapa-
mycin: Chan, J. A.; Gerber, R.; Johnson, R. K.; Luengo, J. I. U.S. Patent
5,162,333, May 26, 1994.
(5) Zheng, X. X.; Strom, T. B.; Steele, A. W. Transplantation 1994, 58,
87.
(6) Martel, R. R.; Klicius, J.; Galet, S. Can. J. Physiol. Pharmacol. 1977,
55, 48.
S0002-7863(96)03066-1 CCC: $14.00 © 1997 American Chemical Society

948 J. Am. Chem. Soc., Vol. 119, No. 5, 1997
Smith et al.
of protected aldol linkages and as a tactic for the union of major
synthetic building blocks. Through the investigation of these
key reactions in the rapamycin context, we further developed
several themes which have served to unite the individual projects
within our immunosuppressant program, including most recently
the syntheses of FK50622 and discodermolide.23
The selective generation of E- and Z-disubstitued olefins in
complex targets has traditionally been achieved via π-bond
constructions employing the Wittig reaction and its Horner-
Wadsworth-Emmons variant.24 This approach is not generally
suitable for trisubstituted olefins, as R,R-disubstituted ylides
often furnish unacceptable isomer mixtures. Accordingly, we
were eager to explore the applicability of σ-bond constructions21
to the C(29,30) trisubstituted olefin of rapamycin. We had
successfully installed both the C(19,20) and C(27,28) trisub-
stituted olefins of FK506 in this fashion.22
Although couplings of 1,3-dithianes with electrophiles have
been exploited in the total syntheses of many natural products,25-28
most examples have involved relatively simple reactant struc-
tures.29 In contrast with the parent molecule, which readily
undergoes deprotonation with n-butyllithium, metalation of
substituted dithianes has usually required stronger bases,30
solvent additives, and a myriad of time and temperature regimes.
Moreover, the behavior of highly oxygenated d3 dithiane anions
is often capricious,31,32 consistent with their increased kinetic
basicity.33 In the course of our immunosuppressant synthetic
studies, we have demonstrated the generality of the t-BuLi-
10% HMPA/THF protocol for the rapid metalation of highly
functionalized 2-alkyl-1,3-dithianes,34 as well as their efficient
union with structurally complex epoxides, iodo ethers, and
aldehydes.35
comparable in potency to the clinically important immuno-
modulator cyclosporin A.14 Moreover, the assigned structure
of 2 was derived solely from NMR comparison with 1. These
considerations prompted us to design a single flexible strategy
for the construction of both 1 and 2.
The unique structure and therapeutic potential15 of rapamycin
have stimulated intensive activity within the synthetic com-
munity.16 Three other laboratories have completed total syn-
theses of 1, each representing a significant achievement.17-19
Here and in the accompanying paper, we describe in full the
design and execution of a unified synthetic strategy for (-)-
rapamycin and (-)-27-demethoxyrapamycin.20 Our convergent
and flexible approach should also provide access to rationally
designed analogs of 1 and 2.
Initial Retrosynthetic Analysis of (-)-Rapamycin. In
planning the synthesis of 1, we wished to extend our earlier
work on σ-bond olefin construction21 and dithiane coupling
reactions, the latter of considerable value both for the generation
Beyond these two general objectives, our primary concerns
a priori included (a) stereocontrolled introduction of the C(17-
22) all trans-triene, (b) the lability of the C(16) allylic methoxy
group,36 (c) potential â-elimination of the pipecolinate moiety
(14) (a) Sehgal, S. N.; Baker, H.; Eng, C.; Singh, K.; Ve´zina, 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.
(15) Sehgal, S. N.; Molnar-Kimber, K.; Ocain, T. D.; Weichman, B. M.
Med. Res. ReV. 1994, 14, 1.
(22) For leading references see: Smith, A. B., III; Chen, K.; Robinson,
D. J.; Laakso, L. M.; Hale, K. J. Tetrahedron Lett. 1994, 35, 4271.
(23) Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
Soc. 1995, 117, 12011.
(24) Vedejs, E.; Marth, C. F. J. Am. Chem. Soc. 1988, 110, 3948.
(25) Corey, E. J.; Weigel, L. O.; Chamberlin, A. R.; Cho, H.; Hua, D.
H. J. Am. Chem. Soc. 1980, 102, 6613.
(26) Corey, E. J.; Pan, B.-C.; Hua, D. H.; Deardorff, D. R. J. Am. Chem.
Soc. 1982, 104, 6816.
(27) Park, P.; Broka, C. A.; Johnson, B. F.; Kishi, Y. J. Am. Chem. Soc.
1987, 109, 6205.
(28) (a) Mori, Y.; Asai, M.; Furukawa, H. Heterocycles 1992, 34, 1281.
Also see: (b) Lipshutz, B. H.; Moretti, R.; Crow, R. Tetrahedron Lett. 1989,
30, 15.
(29) (a) Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; Yue, E. W.; La
Greca, S. Angew. Chem., Int Ed. Engl. 1994, 33, 2190. (b) Egbertson, M.;
Danishefsky, S. J. J. Org. Chem. 1989, 54, 11. (c) Barrett, A. G. M.; Capps,
N. K. Tetrahedron Lett. 1986, 27, 5571. (d) Redlich, H.; Francke, W. Angew.
Chem., Int. Ed. Engl. 1980, 19, 630.
(30) Lipshutz, B. H.; Garcia, E. Tetrahedron Lett. 1990, 31, 7261.
(31) Oppong, I.; Pauls, H. W.; Liang, D.; Fraser-Reid, B. J. Chem. Soc.,
Chem. Commun. 1986, 1241.
(32) Konishita, M.; Taniguchi, M.; Morioka, M.; Takami, H.; Mizusawa,
Y. Bull. Chem. Soc. Jpn. 1988, 61, 2147.
(16) Synthetic approaches to 1: (a) Hale, M. R.; Hoveyda, A. H. J. Org.
Chem. 1992, 57, 1643. (b) Eshelman, J. E.; Epps, J. L.; Kallmerten, J.
Tetrahedron Lett. 1993, 34, 749. (c) Sin, N.; Kallmerten, J. Ibid. 1993, 34,
753. (d) Paterson, I.; Tillyer, R. D. J. Org. Chem. 1993, 58, 4182. (e) Rao,
A. V. R.; Desibhatla, V. Tetrahedron Lett. 1993, 34, 7111. (f) Ny, S.;
Kallmerten, J. Ibid. 1993, 34, 753. (g) Pattenden, G.; Tankard, M.; Cherry,
P. C. Ibid. 1993, 34, 2677. (h) Anderson, J. C.; Ley, S. V.; Marsden, S. P.
Ibid. 1994, 35, 2087. (i) Kouklousky, C.; Ley, S. V.; Marsden, S. P. Ibid.
1994, 35, 2091. (j) Ley, S. V.; Norman, J.; Pinel, C. Ibid. 1994, 35, 2095.
(k) Norley, M. C.; Kocienski, P. J.; Faller, A. Synlett 1994, 77. (l) Ley, S.
V.; Kouklovsky, C. Tetrahedron 1994, 50, 835. (m) Bellingham, R.;
Jarowicki, K.; Kocienski, P.; Martin, V. Synthesis 1996, 285.
(17) (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. (c) Piscopio, A. D.; Minowa, N.; Chakraborty,
T. K.; Koide, K.; Bertinato, P.; Nicolaou, K. C. J. Chem. Soc., Chem.
Commun. 1993, 617. (d) Nicolaou, K. C.; Bertinato, P.; Piscopio, A. D.;
Chakraborty, T. K.; Minowa, N. Ibid. 1993, 619.
(18) (a) Romo, D.; Meyer, S. D.; Johnson, D. D.; Schreiber, S. L. J.
Am. Chem. Soc. 1993, 115, 7906. (b) Meyer, S. D.; Miwa, T.; Nakatsuka,
M.; Schreiber, S. L. J. Org. Chem. 1992, 57, 5058. (c) Romo, D.; Johnson,
D. D.; Plamondon, L.; Miwa, T.; Schreiber, S. L. Ibid. 1992, 57, 5060.
(19) (a) Hayward, C. M.; Yohannes, D.; Danishefsky, S. J. J. Am. Chem.
Soc. 1993, 115, 9345. (b) Hayward, C. M.; Fisher, M. J.; Yohannes, D.;
Danishefsky, S. J. Tetrahedron Lett. 1993, 34, 3989. (c) Horvath, R. F.;
Linde, R. G., II; Hayward, C. M.; Joglar, J.; Yohannes, D.; Danishefsky,
S. J. Ibid. 1993, 34, 3993. (d) Fisher, M. J.; Myers, C. D.; Joglar, J.; Chen,
S.; Danishefsky, S. J. J. Org. Chem. 1991, 56, 5826. (e) Chen, S.; Horvath,
R. F.; Joglar, J.; Fisher, M. J.; Danishefsky, S. J. Ibid. 1991, 56, 5834.
(20) 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.
(21) Smith, A. B., III; Hale, K. J.; Laakso, L. M.; Chen, K.; Rie´ra, A.
Tetrahedron Lett. 1989, 30, 6963.
(33) (a) De Brabander, J.; Vandewalle, M. Synthesis 1994, 855. (b)
Hanessian, S.; Pougny, J.-R.; Boessenkool, I. K. Tetrahedron 1984, 40,
1289.
(34) Williams, D. R.; Sit, S.-Y. J. Am. Chem. Soc. 1984, 106, 2949.
(35) For a related coupling of a dithiane anion with a cyclic sulfate, see:
Nicolaou, K. C.; Ajito, K.; Patron, A. P.; Khatuya, H.; Richter, P. K.;
Bertinato, P. J. Am. Chem. Soc. 1996, 118, 3059.
(36) (a) Grinfeld, A. A.; Caufield, C. E.; Schiksnis, R. A.; Mattes, J. F.;
Chan, K. W. Tetrahedron Lett. 1994, 35, 6835. (b) Luengo, J. I.; Konialian-
Beck, A.; Rozamus, L. W.; Holt, D. A. J. Org. Chem. 1994, 59, 6512. (c)
Luengo, J. I.; Yamashita, D. S.; Dunnington, D.; Konialian-Beck, A.;
Rozamus, L. W.; Yen, H.-K.; Bossard, M. J.; Levy, M. A.; Hand, A.;
Newmann-Tarr, T.; Badger, A.; Faucette, L.; Johnson, R. K.; D’Alessio,
K.; Porter, T.; Shu, A. Y. L.; Heys, R.; Choi, J.; Kongsaeree, P.; Clardy,
J.; Holt, D. A. Chem. Biol. 1995, 2, 471.

Construction of C(21-42) Perimeters in Immunomodulators
J. Am. Chem. Soc., Vol. 119, No. 5, 1997 949
in advanced intermediates,37 (d) installation of the C(8-10)
tricarbonyl region, common to both rapamycin and FK506,38
(e) efficient union of the major subtargets, and (f) macro-
cyclization of the 31-membered ring. At the outset of our work,
essentially nothing was known about the relevant chemistry of
rapamycin.
followed by a stoichiometric amount of boron trifluoride etherate
(THF, -78 °C; Scheme 3). Desulfonylation with 6% sodium
Scheme 3
These considerations outlined above guided our initial retro-
synthetic analysis of the rapamycin problem (Scheme 1).
Scheme 1
amalgam in buffered methanol then gave the desired alcohol
(-)-11 in 60% yield. Mesylation allowed for oxirane formation
upon selective removal of the tert-butyldiphenylsilyl (BPS)
protecting group in 12 (NaH, anhydrous HMPA).40 Exposure
of epoxide (-)-13 to LiI and BF3‚Et2O provided iodohydrin
(-)-14, which was protected as PMB ether (-)-15 via the
trichloroacetimidate method of Bundle.41 The stereochemistry
of (-)-15 was confirmed by conversion of (-)-12 to homoallylic
alcohol (-)-16 (Scheme 4), the latter prepared earlier by the
Merck group from a degradation product of natural rapamycin.42
Scheme 4
Disconnection of the macrocyclic lactone followed by excision
of the C(1,9) pipecolinate 7 generated fragments 4, 5, and 6. In
the synthetic direction, σ-bond construction of the C(29,30)
trisubstituted olefin would follow addition of the C(30-42)
sulfone 4 to the C(21-29) aldehyde 5. The triene array would
arise via palladium-catalyzed Suzuki coupling of 5 with dienyl
boronate 6. Installation of the C(8-10) tricarbonyl region and
macrolactonization would then furnish the natural product.
The C(30-42) sulfone 4 would in turn derive from compo-
nents 8-10 (Scheme 2). Sulfone 8 was employed in our recent
The preparation of dithiane 10 began with the conversion of
methyl (R)-3-hydroxy-2-methylpropionate [(-)-17; 97% ee] to
the known alcohol (-)-1843,44 (Scheme 5). Swern oxidation
followed by dithioacetalization of the crude aldehyde furnished
dithiane (+)-10 in 94% yield for the two steps.
Scheme 5
Scheme 2
Invariably we have found that treatment with t-BuLi in 10%
HMPA/THF at -78 °C is the optimum protocol for generation
of 2-substituted dithiane anions (Vide infra).34,45 We routinely
add the precooled electrophile immediately thereafter because
prolonged stirring (ca. 1 h) of the anion solutions at -78 °C
results in loss of reactivity. Kinoshita et al. observed similar
decomposition in their work directed toward the total synthesis
of amphotericin B.32 As expected, alkylation of the 2-lithio
formal synthesis of FK506.22 The butene oxide derivative 9
(90% ee) was also prepared earlier, via Sharpless asymmetric
epoxidation of (E)-crotyl alcohol and in situ derivatization.39
We envisioned the synthesis of dithiane 10 from methyl (R)-
3-hydroxy-2-methylpropionate (Vide infra).
Studies Directed toward the C(30-42) Subunit 4. As our
point of departure, sulfone (-)-8 and epoxide (-)-9 were
coupled by treatment of the admixed components with n-BuLi
(40) Shekhani, M. S.; Khan, K. M.; Mahmood, K.; Shah, P. M.; Malik,
S. Tetrahedron Lett. 1990, 31, 1669.
(41) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun. 1981,
1240.
(42) (a) Goulet, M. T.; Boger, J. Tetrahedron Lett. 1991, 32, 6454
(erratum). (b) Goulet, M. T.; Hodkey, D. W. Ibid. 1991, 32, 4627.
(43) Brandes, E.; Grieco, P. A.; Garner, P. J. Chem. Soc., Chem.
Commun. 1988, 500.
(44) Ley, S. V.; Anthony, N. J.; Armstrong, A.; Brasca, M. G.; Clarke,
T.; Culshaw, D.; Greck, C.; Grice, P.; Jones, A. B.; Lygo, B.; Madin, A.;
Sheppard, R. N.; Slawin, A. M. Z.; Williams, D. J. Tetrahedron 1989, 45,
7161.
(37) Steffan, R. J.; Kearney, R. M.; Hu, D. C.; Failli, A. A.; Skotnicki,
J. S.; Schiksnis, R. A.; Mattes, J. F.; Chan, K. W.; Caufield, C. E.
Tetrahedron Lett. 1993, 34, 3699.
(38) (a) Linde, R. G., II; Jeronic, L. O.; Danishefsky, S. J. J. Org. Chem.
1991, 56, 2534. (b) Batchelor, M. J.; Gillespie, R. J.; Golec, J. M.;
Hedgecock, C. J. R. Tetrahedron Lett. 1993, 34, 167. (c) Meyer, S. D.;
Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(45) For an insightful discussion of the ion pair structures of 2-lithio-
1,3-dithianes in THF and HMPA/THF, see: Reich, H. J.; Borst, J. P.;
Dykstra, R. R. Tetrahedron 1994, 50, 5869.
(39) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.

950 J. Am. Chem. Soc., Vol. 119, No. 5, 1997
Smith et al.
derivative of dithiane (+)-10 with iodohydrin (-)-15 unevent-
steric congestion at C(2) of the dithiane.48 Our efforts to
circumvent this problem by direct conversion of alcohol 24 to
the bromide with dibromotriphenylphosphorane were likewise
unsuccessful (not shown). Ultimately, the observation that
mesylate 25 also rearranged upon exposure to sodium ben-
zenesulfinate or upon heating brought to an end this line of
investigation. Significant differences in the reactiVities of
pendant functional groups in 2-monosubstituted 1,3-dithianes
Vis-a´-Vis related 2,2-disubstituted deriVatiVes, perhaps induced
by conformational changes, resurfaced throughout this synthetic
inVestigation (Vide infra).
fully afforded the C(30-42) fragment 19 in 78% yield (Scheme
6).
Scheme 6
Second-Generation Retrosynthetic Analysis of Rapamycin
and Demethoxyrapamycin. At this juncture we revised our
original synthetic plan in order to circumvent the inaccessible
sulfonyl dithiane 4, retaining insofar as possible the effective
chemistry developed in our initial studies. To this end we
planned to couple the available sulfonyl dithiane (+)-23 with
L-isopropylidene glyceraldehyde, setting the stage for σ-bond
construction of the C(29,30) olefin at an earlier point in the
synthesis. This change in strategy, with retention of the lactone
and C(20,21) disconnections, led to subtargets A, B, and C
(Scheme 9). With the advent of the Golec procedure for
All that remained for completion of subunit 4 was installation
of the C(30) sulfone moiety. To gain experience with the
requisite transformations, we converted dithiane (+)-10 to iodide
(-)-22 via alcohol (-)-20 and tosylate (+)-21 (Scheme 7).
Scheme 7
Scheme 9
Displacement with sodium benzenesulfinate provided sulfone
(+)-23 in excellent yield, accompanied by a small quantity of
the corresponding sulfinate diastereomers. Noteworthy here is
the preparation of 23 in eight steps and 60-65% overall yield
from commercially available methyl (R)-3-hydroxy-2-methyl-
propionate (17; Scheme 5), on a 50-g scale with only two
chromatographic purifications.
Extension of this sequence to the more advanced C(30-42)
intermediate entailed selective removal of the BPS group40 in
19 followed by mesylation of the resultant alcohol (-)-24 (62%
overall yield; Scheme 8). However, standard Finkelstein
Scheme 8
treatment of mesylate (-)-25 failed to generate the desired
1
iodide. Analysis of the crude reaction mixture via H NMR
instead suggested formation of the unstable ring-expansion
product 26.
Similar rearrangements of 2,2-disubstituted 1,3-dithianes
bearing proximal leaving groups have been observed previ-
ously46 and attributed to the Thorpe-Ingold effect,47 reflecting
(46) (a) Marshall, J. A.; Roebke, H. J. Org. Chem. 1969, 34, 4188. (b)
Nickon, A.; Rodriguez, A. D.; Shirhatti, V.; Ganguly, R. Ibid. 1985, 50,
4218. See also: (c) Seebach, D.; Jones, N. R.; Corey, E. J. Ibid. 1968, 33,
300. (d) Tsai, Y.-M.; Cherng, C.-D. Tetrahedron Lett. 1991, 32, 3515. (e)
Li, W. L.; Mao, J.; Li, Y.; Li, Y. OPPI Briefs 1994, 26, 445.
(47) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
107, 1080. (b) Ingold, C. K. Ibid. 1921, 119, 305. (c) Jung, M. E.; Gervay,
J. Tetrahedron Lett. 1988, 29, 2429. (d) Cauwberghs, S.; DeClercq, P.;
Tinant, B.; DeClercq, J. P. Ibid. 1988, 29, 2493.
tricarbonyl formation,38b we could also employ pipecolinate 33,
rather than a C(9) oxygenated derivative (7), as the fifth building
block. For simplicity, we chose to protect C(22) in fragment
(48) Davey, A. E.; Parsons, A. F.; Taylor, R. J. K. J. Chem. Soc., Perkin
Trans. 1 1989, 1853. See also: Keese, R.; Meyer, M. Tetrahedron 1993,
49, 2055.

Construction of C(21-42) Perimeters in Immunomodulators
J. Am. Chem. Soc., Vol. 119, No. 5, 1997 951
C as a dimethyl acetal, deferring elaboration to a suitable Stille
coupling partner until the endgame. We also took advantage
of this opportunity to expand the scope of our effort, previously
focused solely on rapamycin (1), by developing a unified
strategy for the construction of both 1 and the 27-demethoxy
congener 2. The methoxy and demethoxy series would be
differentiated via coupling of suitable electrophiles with dithiane
C.
resultant vinyl triflate (-)-38 (Me2CuLi, Et2O, 0 °C) gave the
C(27-32) B-fragment (+)-30 in 70% yield. Only the Z isomer
1
was detected by H NMR analysis.
Construction of Subunit C (31). The synthesis of 31, the
C(22-26) C fragment, began with the enzymatic desymmetri-
zation of meso diester 39 (Scheme 11).55 Thus, hydrolysis with
Scheme 11
From the retrosynthetic perspective (Scheme 9), we envi-
sioned the elaboration of 1 and 2 from the fully functionalized
northern-perimeter ABC fragments 27 and 28 and a common
southern-perimeter DE element 29, all derived in turn from the
building blocks A-E (15, 30-33).49 This modular approach
would afford considerable flexibility in optimizing the subunit
coupling sequence. Rapid conversion of the ABC and DE
subtargets to the natural products would require minimal
functional group manipulations, with similar endgame chemistry
for both 1 and 2. Final assembly of the macrocycles could in
principle be effected via intermolecular acylation at C(34) and
intramolecular Pd(0)-catalyzed Stille coupling, or alternatively
via initial formation of the triene seco acid followed by
macrolactonization, without major modification of the sub-
targets.
R-chymotrypsin via a modified procedure of Tamm provided
the half acid in 88% yield and 94% ee, and carboxyl reduction
with borane methyl sulfide56 cleanly afforded the primary
alcohol (-)-40. Following protection as the BPS ether (-)-
41, the ester was converted to the corresponding aldehyde (-)-
43 via DIBAL reduction and Swern oxidation of alcohol 42
(86% yield, three steps). Interestingly, 42 displayed negligible
optical rotation. Exposure of 43 to 1,3-propanedithiol and boron
trifluoride etherate then furnished dithiane (+)-44 (99%).
Desilylation to alcohol (+)-45 (94% yield), Swern oxidation,
and dimethyl acetal formation (85%, two steps) generated the
C-fragment (+)-31.
Stereocontrolled σ-Bond Olefin Construction: Assembly
of Fragment B (30). With subtarget A [(-)-15] in hand from
our first-generation investigations, we next undertook the
synthesis of fragment B (30) (Scheme 10), exploiting the
Scheme 10
Fragment Coupling for Demethoxyrapamycin: A + B f
AB + C f ABC. Confident in our ability to prepare large
quantities of the three subtargets, we began to investigate the
assembly of the demethoxyrapamycin backbone. Union of the
A and B-fragments entailed metalation of dithiane (+)-30 with
t-BuLi and alkylation with precooled iodide (-)-15 (10%
HMPA/THF, -78 °C), affording (+)-46 in 87% yield (Scheme
12). Acetonide hydrolysis and selective tosylation of the
Scheme 12
stereocontrolled σ-bond construction of olefins which we also
employed in our FK506 synthesis.22 R-Lithiation of sulfone
(+)-23 (cf. Scheme 7) and addition to isopropylidene L-
glyceraldehyde (34)50 afforded the diastereomeric â-hydroxy
sulfones 35, which furnished a single ketone (-)-37 after
oxidation and desulfonylation.
We anticipated that the C(29,30) trisubstituted olefin could
be installed via coupling of the appropriate vinyl triflate with
lithium dimethyl cuprate.51,52 To our surprise, treatment of
ketone 37 with LDA in 10% HMPA/THF, under the conditions
utilized to great advantage in the FK506 work,22,53 generated
exclusively the undesired enolate regioisomer. After consider-
able experimentation, the requisite (Z)-enolate was secured by
slow addition of 37 to a solution of lithium bis(trimethylsilyl)-
amide (LiHMDS) in 20% HMPA/THF at -78 °C; trapping with
N-phenyltrifluoromethanesulfonimide54 and methylation of the
(49) (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.
(50) (a) MaloneyHuss, K. E. Synth. Commun. 1985, 15, 273. (b)
Hubschwerlen, C.; Specklin, J.-L.; Higelin, J. Org. Synth. 1993, 72, 1.
(51) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1980, 21, 4313.
(52) Synthetic applications of aryl and vinyl triflates have been recently
reviewed: Ritter, K. Synthesis 1993, 735.
(53) Chen, K. Ph.D. Thesis, University of Pennsylvania, 1991.
primary alcohol gave (+)-48; the derived iodohydrin (+)-49

952 J. Am. Chem. Soc., Vol. 119, No. 5, 1997
Smith et al.
was then smoothly protected as the TBS ether (+)-50. Lithia-
tion of the C-subunit dithiane 31 and alkylation with the AB
iodide 50 generated a three-component mixture in good yield
(ca. 80%). The desired ABC segment (+)-51 predominated in
all of our experiments, but formation of the elimination products
(+)-52 and (+)-53 in significant amounts precluded further
development of this route.
analysis57 and supported by literature precedent for dithiane
additions to D-isopropylideneglyceraldehyde (Vide infra).58
Selective protection of 47 as pivaloate (+)-56 followed by
silylation and reduction of the ester in (+)-57 readily afforded
primary alcohol (+)-58. Unfortunately, a variety of oxidation
protocols all failed to provide aldehyde 59. Suspecting that an
unfavorable conformation imparted by the 2,2-disubstituted 1,3-
dithiane might be responsible, we unmasked the C(34) ketone
by exposure of 58 to MeI in 4:1:1 MeCN/THF/H2O.59 In
support of our hypothesis, keto alcohol (-)-60 underwent facile
Swern oxidation to aldehyde (-)-61. However, coupling of
dithiane (+)-31 with 61 not unexpectedly furnished a complex
mixture of products (not shown).
We turned instead to the epoxide (+)-54, available quanti-
tatively from hydroxy tosylate 48 (Scheme 13). The very acid-
Scheme 13
An Alternative Coupling Sequence for 1: B + C f BC
+ A f ABC. The flexibility of our synthetic scheme allowed
for the ready pursuit of an alternative strategy, involving initial
union of fragments B and C and subsequent alkylation with
subunit A. In this approach the C(27) hydroxyl would be
installed via the B-C coupling step; the reduced complexity
of the latter products (vis-a´-vis ABC intermediates) was
expected to facilitate stereochemical analysis. Preliminary
investigations began with the conversion of (+)-30 (B) to a
suitable electrophile, aldehyde 66 (Scheme 15). By analogy
Scheme 15
sensitive epoxide was used without purification. Coupling with
the lithio derivative of dithiane (+)-31 (t-BuLi, 10% HMPA/
THF) and silylation afforded the advanced ABC intermediate
(+)-51, isolated in 72% yield overall from 48. Completion of
the demethoxyrapamycin C(21-42) backbone (i.e., 28) merely
entailed installation of the vinyl stannane moiety (Vide infra).
An Initial Approach to the Rapamycin AB Aldehyde 59.
In seeking to extend the successful strategy employed for the
27-demethoxy intermediate (i.e., A + B f AB + C f ABC)
to the corresponding segment of rapamycin, we planned to
establish the C(27) stereocenter by adding the lithio derivative
of dithiane (+)-31 to AB aldehyde 59 (Scheme 14). The
with the attempted preparation of aldehyde 59, the acetonide
moiety in 30 was hydrolyzed and the resultant diol (+)-62
selectively protected as pivaloate (+)-63. A minor bispivaloate
by-product (5-15%) could be reconverted to 62 with DIBAL.
Silylation of 63 and DIBAL reduction of (+)-64 then provided
alcohol (+)-65. Under Swern conditions 65 uneventfully
furnished aldehyde (+)-66, providing further support for the
contention that the unsuccessful oxidation of alcohol 58 was
specifically attributable to the 2,2-disubstituted dithiane moiety,
and not simply to the presence of sulfur. Single-crystal X-ray
analysis confirmed the stereochemistry and olefin geometry of
(+)-66.49a
Scheme 14
The reaction of aldehyde 66 with the lithio derivative of
dithiane 44 was complicated by competitive proton transfer from
the 1,3-dithiane moiety in 66. This problem was overcome by
addition of the precooled aldehyde to 5 equiv of preformed
dithiane anion at -78 °C; a 5:1 mixture of C(27) epimers (+)-
67 and 68 was isolated in 75% yield, with 76% recovery of
unreacted 44 (Scheme 16). The Felkin-Anh model,57 with the
R-carbon-oxygen bond orthogonal to the carbonyl group,
indicated that the requisite (R)-alcohol should predominate (Vide
infra).
For elucidation of the C(27) stereochemistry, we recognized
that comparison of NMR coupling constants would be incon-
clusive. Mosher analysis of hindered alcohols can likewise be
(54) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979.
(55) Mohr, P.; Waespe-Sarcevic, N.; Tamm, C.; Gawronska, K.;
Gawronski, J. K. HelV. Chim. Acta 1983, 66, 2501.
(56) Seebach, D.; Maestro, M. A.; Sefkow, M.; Neidlein, A.; Sternfeld,
F.; Adam, G.; Sommerfeld, T. HelV. Chim. Acta 1991, 74, 2112.
(57) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chem. 1977, 1, 61. (c) Ahn,
N. T. Top. Curr. Chem. 1980, 88, 145.
(58) David, S.; Estramareix, B.; Fischer, J.-C.; The´risod, M. J. Chem.
Soc., Perkin Trans. 1 1982, 2131.
aldehyde in turn was expected to derive from diol 47 via
standard manipulations, whereas the requisite â-configuration
of the C(27) hydroxyl was both predicted by Felkin-Anh
(59) Fetizon, M.; Jurion, M. J. Chem. Soc., Chem. Commun. 1972, 382.

Construction of C(21-42) Perimeters in Immunomodulators
J. Am. Chem. Soc., Vol. 119, No. 5, 1997 953
Scheme 16
Scheme 17
Apparently, the bulkier OBPS moiety led to enhanced discrimi-
nation between conformers I and II, with the vinyl side chain
perpendicular to the carbonyl. This hypothesis suggested that
a smaller protecting group would result in diminished R-selec-
tivity. Indeed, coupling of dithiane 44 with the MOM ether 76
furnished a 2:1 mixture of 79 and 80, albeit in low yield.64
We also determined the X-ray structure of aldehyde 66
(Figure 2), which revealed that the solid-state conformation most
problematic;60 moreover, generation of the diastereomeric
Mosher esters was not straightforward.61 These considerations
prompted us to prepare a crystalline derivative; the major epimer
67 was thus converted to tris(3,5-dinitrobenzoate) (+)-70 via
triol (+)-69 (Scheme 16). X-ray analysis of (+)-70 revealed
that the major product was, in fact, the undesired (S)-alcohol.
Stereoselectivity of Dithiane Additions to Aldehyde 66.
Preferential formation of the R-epimer (+)-67 is consistent with
the Felkin-Anh model57 only if the vinyl moiety is oriented as
the large group (conformers I and II, Figure 1). We had
Figure 2. Solid-state conformation of aldehyde (+)-66.
closely resembles conformation I. Thus, the olefin moiety is
orthogonal to the carbonyl plane both in crystalline 66 and
apparently in the reactive solution conformation. Presumably,
the steric influence of the trisubstituted olefin overrides the
stereoelectronic effect of the R-alkoxy substituent.65
The substitution of dithiane (+)-31 for (+)-44 in the coupling
reaction with 66 had little effect on the yield and selectivity,
(63) The stereochemistry of (+)-77 was determined by conversion to
(+)-69.
Figure 1. Felkin-Anh analysis of dithiane additions to C(27)
aldehydes.
(64) The stereochemistry of (+)-81 was elucidated by conversion to (+)-
83, identical to an authentic sample prepared from (+)-67.
anticipated that both steric and stereoelectronic interactions
involving the OTBS group would control the stereochemistry
of addition, as illustrated in conformers III and IV.62 Variation
of the R-hydroxyl protecting group did yield some interesting
results (Scheme 17). The very bulky tert-butyldiphenylsilyl
(BPS) moiety caused a marked increase in selectivity: only the
undesired epimer (+)-7763 was detected! Whereas we expected
a larger OR group to give predominantly the â-alcohol via
conformer III, the observed effect was just the opposite.
(60) (a) Kusumi, T.; Fujita, Y.; Ohtani, I.; Kakisawa, H. Tetrahedron
Lett. 1991, 32, 2923. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,
H. J. Org. Chem. 1991, 56, 1296. (c) Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
(61) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
(62) Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353.
(65) See ref 62 for a discussion of steric vs stereoelectronic effects in
nucleophilic addition reactions of R-substituted aldehydes.

954 J. Am. Chem. Soc., Vol. 119, No. 5, 1997
Smith et al.
affording the desired alcohol (+)-8566 as the minor component
of a separable 5:1 epimer mixture (Scheme 18). Nonetheless,
Scheme 20
Scheme 18
the problematic oxidation of an advanced intermediate (e.g.,
58) by protecting aldehyde 66 as an acetal. Alkylation of (+)-
96 with the A-fragment iodide (-)-15 was effected under our
standard conditions in excellent yield. Hydrolysis of acetal (-)-
97 then furnished the elusive aldehyde (+)-59 (70%).
it seemed prudent to test the viability of our strategy by coupling
this intermediate with fragment A. Following O-methylation,
alkylation of dithiane (+)-86 with iodide (-)-15 gave the
rapamycin ABC segment (+)-87 in 61% yield.
To explore further the dominant influence of the C(29,30)
trisubstituted olefin on the stereoselectivity of dithiane additions
to aldehydes 66, 75, and 76, we coupled the lithio derivative of
dithiane (+)-31 with D-isopropylideneglyceraldehyde [(+)-89],67
obtaining an inseparable 2.4:1 mixture of epimeric alcohols 90
and 91 in good yield (Scheme 19). The derived methyl ethers
In the event, addition of the lithio derivative of fragment-C
dithiane (+)-31 to the AB aldehyde (+)-59 generated a 1.2:1
mixture of alcohols (+)-98 and (+)-99 in 65% yield, with the
undesired R-epimer in slight excess (Scheme 21). This result
offered a significant improvement in material throughput.
O-Methylation of (+)-99 then afforded (+)-87 (88%), identical
to the material prepared earlier (Scheme 18). It is noteworthy
that our modular synthetic design furnished the rapamycin
(66) The stereochemistry of (+)-84 was determined by conversion to
(+)-88, identical to a sample prepared from (+)-83.
Scheme 19
(67) Schmid, C. R.; Bryant, J. D. Org. Synth. 1993, 72, 6.
(68) The stereochemistry of (+)-94, a derivative of (+)-92,69 was
elucidated via conversion to (+)-95, identical to a sample prepared from
(+)-86.
(+)-92 and (+)-93 were readily purified by chromatography,
and the C(27) â-configuration of the major product 92 was
established by conversion of 92 to a substance of known
stereochemistry.68 The anticipated predominance of 90 is in
accord with a perpendicular orientation of the R-carbon-oxygen
bond and the carbonyl moiety as well as literature precedent.58
Efforts to convert 92 to the rapamycin intermediate 86 were
unsuccessful.69
Assembly of the Rapamycin ABC Backbone Segment:
Aldehyde 59 Revisited. At this point we recalled the markedly
divergent behavior of alcohols 58 and 65 toward oxidizing
reagents (cf. Schemes 14 and 15) and wondered whether the
2,2-disubstituted dithiane moiety in aldehyde 59 might influence
the stereochemical outcome of dithiane addition as well. In
devising an alternate route to 59 (Scheme 20), we circumvented
(69) McCauley, J. A. Ph.D. Thesis, University of Pennsylvania, 1996.

Construction of C(21-42) Perimeters in Immunomodulators
J. Am. Chem. Soc., Vol. 119, No. 5, 1997 955
Scheme 21
yields. DDQ-induced oxidative removal of the PMB group gave
the C(34) alcohols (+)-106 and (+)-107 (92-94%);71 dithiane
cleavage with bis(trifluoroacetoxy)iodobenzene then led to aldols
(-)-108 and (-)-109 (86-90%).72 Finally, palladium-mediated
hydrostannylation73 produced the requisite ABC vinylstannanes
(-)-27 and (-)-28 in 91 and 87% yields.74
Summary. We have presented herein a unified synthetic
approach to the complete C(21-42) ABC segments of rapa-
mycin and its 27-demethoxy congener [(-)-27 and (-)-28,
respectively], poised for union with a common DE fragment.
The successful strategy exploited and extended our earlier
investigations of σ-bond olefin construction to generate the
C(29,30) trisubstituted alkene in stereocontrolled fashion. We
have again efficiently coupled highly functionalized dithiane
anions with diverse electrophilic subunits in the assembly of
complex structures. In addition, we have discovered that a
second C(2) appendage in a substituted dithiane can exert
dramatic effects on the reactivity of ꢀ side-chain functionalities,
five bonds removed. In the following paper we describe the
preparation of the DE segment and completion of the rapamycin
synthetic venture.
C(22-42) ABC segment 87 via two different assembly strate-
gies without significant modifications of the initial building
blocks.
Completion of the Rapamycin and 27-Demethoxyrapa-
mycin ABC Vinylstannanes. Final elaboration of the methoxy
and 27-demethoxy intermediates 87 and 51 to the targeted
C(21-42) northern perimeters proceeded along parallel lines
(Scheme 22). Unmasking of the C(22) aldehydes and homolo-
Experimental Section75
Alcohol (-)-11. A solution of sulfone (-)-822 (18.0 g, 40.8 mmol)
and epoxide (-)-939 (13.0 g, 40.8 mmol) in THF (250 mL) was cooled
Scheme 22
(71) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(72) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(73) Zhang, H. X.; Guibe´, F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857.
(74) Minor amounts (ca. 5% total) of internal stannanes 110 and 111
were formed in the hydrostannylation reaction.
(75) Materials and Methods. Reactions were carried out in oven- or
flame-dried glassware under an argon atmosphere, unless otherwise noted.
All solvents were reagent grade. Diethyl ether and tetrahydrofuran (THF)
were freshly distilled from sodium/benzophenone under argon. Dichlo-
romethane, benzene, diisopropylamine, and hexamethylphosphoramide
(HMPA) were freshly distilled from calcium hydride. Triethylamine and
diisopropylethylamine were distilled from calcium hydride and stored over
potassium hydroxide. Anhydrous pyridine, N,N-dimethylformamide, and
dimethyl sulfoxide were purchased from Aldrich and used without purifica-
tion. n-Butyllithium and tert-butyllithium were purchased from Aldrich and
standardized by titration with diphenylacetic acid. Except as otherwise
indicated, all reactions were magnetically stirred and monitored by thin
layer chromatography with Whatman 0.25-mm precoated silica gel plates.
Flash chromatography was performed with silica gel 60 (particle size 0.023-
0.040 mm) supplied by E. Merck. Radial chromatography was performed
with a Chromatotron (Harrison Research, Inc., Palo Alto, CA) and silica
gel rotors supplied by Analtech (Newark, DE). High-performance liquid
chromatography (HPLC) was performed with a Ranin component analytical/
semiprep system. Yields refer to chromatographically and spectroscopically
pure compounds, unless otherwise stated. Melting points were determined
on a Bristoline heated-stage microscope or a Thomas-Hoover apparatus and
are corrected. Infrared spectra were recorded on a Perkin-Elmer Model 283B
spectrometer with polystyrene as external standard. Proton NMR spectra
were recorded on a Bruker AM-500 spectrometer. Carbon-13 NMR spectra
were recorded on a Bruker AM-500 or AM-250 spectrometer. Chemical
shifts are reported relative to internal tetramethylsilane (δ 0.00) for 1H and
chloroform (δ 77.0) or benzene (δ 128.0) for 13C. Optical rotations were
measured with a Perkin-Elmer Model 241 polarimeter. High-resolution mass
spectra were obtained at the University of Pennsylvania Mass Spectrometry
Service Center with either a VG Micromass 70/70H or VG ZAB-E
spectrometer. Microanalyses were performed by Robertson Laboratories,
Madison, NJ. Single-crystal X-ray structure determinations were performed
at the University of Pennsylvania with an Enraf Nonius CAD-4 automated
diffractometer.
gation via a modification of the two-step Corey-Fuchs proto-
col70 provided acetylenes (+)-104 and (+)-105 in good overall
(70) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.

956 J. Am. Chem. Soc., Vol. 119, No. 5, 1997
Smith et al.
to -78 °C. n-BuLi (1.7 M in hexanes, 24.0 mL, 40.8 mmol) was added
dropwise from an addition funnel and the resultant yellow solution
stirred for 30 min. Boron trifluoride etherate (5.00 mL, 40.8 mmol)
was then introduced dropwise via a syringe. After an additional 2 h at
-78 °C, the reaction was quenched with saturated aqueous NH4Cl (100
mL), warmed to ambient temperature, and partitioned between ether
(300 mL) and water (300 mL). The organic phase was washed with
brine (250 mL), dried over MgSO4, filtered, and concentrated. Fol-
lowing flash chromatography (hexanes/ethyl acetate, 5:1), the fractions
containing the diastereomeric sulfones were combined and concentrated.
This material was used without further purification.
high-resolution mass spectrum (CI, NH3) m/z 499.2086 [(M + H)+;
calcd for C21H44IO3Si, 499.2104].
C(33-42) Subtarget (-)-15 (A). A solution of iodohydrin (-)-14
(536 mg, 1.07 mmol) and p-methoxybenzyl trichloroacetimidate (350
mg, 1.23 mmol) in dichloromethane (6 mL) was cooled to -78 °C
and boron trifluoride etherate catalyst (ca. 10 µL) was added. After
30 min the white, heterogeneous mixture was diluted with ether (100
mL) and water (50 mL) and warmed to ambient temperature. The
organic phase was washed with brine (50 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes/ethyl
acetate, 15:1) provided (-)-15 (A) (560 mg, 84% yield) as a colorless
oil: [R]2D3 -18° (c 0.5, CHCl3); H NMR (500 MHz, CDCl3) δ 7.29
1
Dibasic sodium phosphate (83 g, 0.58 mol) was added to a solution
of the sulfones in methanol (750 mL), and the white, heterogeneous
mixture was stirred for 30 min at ambient temperature. Na(Hg) (6%)
(80 g, 0.19 mol) was added in 5-g portions over 15 min, and the reaction
was monitored closely by TLC. Upon completion (ca. 30 min), the
mixture was filtered through Celite and the solids were washed with
ethyl acetate (300 mL). The clear filtrate was concentrated until it
became cloudy and then partitioned between ethyl acetate (300 mL)
and water (300 mL). The organic phase was washed with brine (250
mL), dried over MgSO4, filtered, and concentrated. Flash chromatog-
raphy (hexanes/ethyl acetate, 10:1) followed by HPLC (Waters Prep
500; hexanes/ethyl acetate, 10:1, 0.2 L/min) provided (-)-11 (15 g,
(d, J ) 8.6 Hz, 2 H), 6.87 (d, J ) 8.6 Hz, 2 H), 4.50 (ABq, JAB ) 11.1
Hz, ∆νAB ) 65.6 Hz, 2 H), 3.80 (s, 3 H), 3.53 (ddd, J ) 10.9, 8.4, 4.8
Hz, 1 H), 3.40 (s, 3 H), 3.32-3.20 (m, 3 H), 2.89 (ddd, J ) 11.2, 8.4,
4.5 Hz, 1 H), 2.09-2.05 (m, 1 H), 1.95-1.88 (m, 2 H), 1.57-1.54
(m, 1 H), 1.38-1.24 (m, 4 H), 1.16-1.00 (m, 22 H), 0.86 (d, J ) 6.8
Hz, 3 H), 0.72 (q, J ) 11.6 Hz, 1 H); 13C NMR (62.8 MHz, CDCl3)
δ 130.1, 129.5, 113.7, 84.7, 82.5, 75.4, 71.9, 57.6, 55.2, 38.5, 35.7,
34.2, 33.6, 33.3, 31.8, 18.1, 15.5, 12.6, 7.3; high-resolution mass
spectrum (CI, NH3) m/z 636.2911 [(M + NH4)+; calcd for C29H55INO4-
Si, 636.2945].
â-Hydroxy Sulfones 35. A solution of sulfone (+)-23 (33.3 g, 110
mmol) in THF (400 mL) was cooled to -78 °C, and n-BuLi (1.6 M in
hexanes, 75.6 mL, 121 mmol) was added dropwise from an addition
funnel. After 30 min, the brilliant yellow reaction mixture was warmed
to -55 °C and treated dropwise with a solution of freshly distilled
L-isopropylideneglyceraldehyde (34) (21.5 g, 166 mmol) in THF (75
mL), premixed, and stored for 1 h over activated 4 Å molecular sieves.
After 1 h, the reaction mixture was quenched with saturated aqueous
NH4Cl (200 mL) and extracted with ether (1 L). The organic phase
was washed with water (500 mL) and brine (500 mL), dried over
MgSO4, filtered, and concentrated. Following flash chromatography
(hexanes/ethyl acetate, 4:1) the fractions containing the diastereomeric
products were combined, concentrated, and carried forward without
further purification.
â-Keto Sulfones 36. A solution of oxalyl chloride (5.2 mL, 60
mmol) in dichloromethane (400 mL) was cooled to -78 °C, and
dimethyl sulfoxide (9.2 mL, 119 mmol) in dichloromethane (50 mL)
was added dropwise via a syringe. After 15 min, a solution of the
â-hydroxy sulfones 35 (21.5 g, 49.6 mmol) in dichloromethane (150
mL) was introduced at a moderate rate. After an additional 15 min
triethylamine (34.6 mL, 248 mmol) was added, and the mixture was
warmed to 0 °C and partitioned between ether (1 L) and water (1 L).
The organic phase was washed with water (500 mL) and brine (500
mL), dried over MgSO4, filtered, and concentrated. Flash chromatog-
raphy (hexanes/ethyl acetate, 3:1) furnished 36 (17.6 g, 82% from 23)
as a mixture of diastereomers. An analytical sample of the S isomer
was obtained by washing the crude solid with cold ether followed by
recrystallization from ether to yield clear crystals: mp 124-126 °C;
[R]D23 -121° (c 1.9, CHCl3); IR (CHCl3) 1720 (s) cm-1; 1H NMR (500
MHz, CDCl3) δ 7.87 (d, J ) 7.1 Hz, 2 H), 7.70 (t, J ) 7.5 Hz, 1 H),
7.59 (t, J ) 7.5 Hz, 2 H), 5.56 (d, J ) 9.2 Hz, 1 H), 4.69 (d, J ) 3.1
Hz, 1 H), 4.46 (dd, J ) 7.8, 5.0 Hz, 1 H), 4.16 (dd, J ) 8.8, 8.0 Hz,
1 H), 4.06 (dd, J ) 8.8, 5.0 Hz, 1 H), 2.97 (td, J ) 11.7, 1.7 Hz, 1 H),
2.86-2.79 (m, 2 H), 2.73 (td, J ) 12.0, 2.3 Hz, 1 H), 2.65-2.61 (m,
1 H), 2.10-2.07 (m, 1 H), 1.79 (qt, J ) 14.1, 2.3 Hz, 1 H), 1.52 (s, 3
H), 1.36 (s, 3 H), 1.02 (d, J ) 7.0 Hz, 3 H); 13C NMR (62.8 MHz,
CDCl3) δ 202.7, 137.5, 134.3, 129.4, 129.0, 111.3, 80.6, 69.4, 66.1,
52.1, 37.7, 31.2, 30.3, 26.1, 25.7, 24.4, 14.3; high-resolution mass
spectrum (CI, NH3) m/z 431.1013 [(M + H)+; calcd for C19H27O5S3,
431.1020].
60% yield) as a colorless oil: [R]2D3 -12° (c 0.6, CHCl3); H NMR
1
(500 MHz, CDCl3) δ 7.72-7.63 (m, 4 H), 7.48-7.33 (m, 6 H), 3.64
(dd, J ) 9.8, 3.9 Hz, 1 H), 3.58 (d, J ) 9.8 Hz, 1 H), 3.57-3.48 (m,
2 H), 3.36 (s, 3 H), 2.88 (ddd, J ) 11.3, 8.2, 4.4 Hz, 1 H), 2.38 (br s,
1 H), 2.03 (qd, J ) 13.0, 4.1 Hz, 1 H), 1.88 (qd, J ) 13.1, 4.5 Hz, 1
H), 1.67-1.58 (m, 1 H), 1.57-1.52 (m, 1 H), 1.39-1.16 (m, 4 H),
1.14-1.01 (m, 31 H), 0.83 (d, J ) 6.7 Hz, 3 H), 0.68 (q, J ) 12.0 Hz,
1 H); 13C NMR (62.8 MHz, CDCl3) δ 135.5, 133.1, 129.8, 127.7, 84.7,
75.4, 74.9, 66.2, 57.4, 39.9, 35.8, 34.2, 32.9, 32.2, 31.5, 26.8, 19.1,
18.0, 14.4, 12.6; high-resolution mass spectrum (CI, NH3) m/z 627.4296
[(M + H)+; calcd for C37H63O4Si2, 627.4264]. Anal. Calcd for
C37H62O4Si2, C, 70.92; H, 10.03. Found: C, 70.76; H, 10.11.
Epoxide (-)-13. A solution of mesylate (-)-12 (392 mg, 0.55
mmol) in HMPA (2 mL) was added to a mixture of sodium hydride
(60% oil dispersion; 0.11 g, 2.77 mmol) and HMPA (2 mL) at 5 °C.
The reaction mixture was stirred at ambient temperature for 6 h and
then recooled to 5 °C and quenched by the cautious addition of water
(2 mL). The reaction mixture was partitioned between ether (100 mL)
and water (100 mL), and the organic phase was washed with 1 N HCl
(100 mL), water (100 mL), and brine (100 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (gradient elution,
hexanes f hexanes/ethyl acetate, 50:1) afforded (-)-13 (181 mg, 87%
yield) as a colorless oil: [R]2D3 -29° (c 0.7, CHCl3); H NMR (500
1
MHz, CDCl3) δ 3.53 (ddd, J ) 10.9, 8.4, 4.8 Hz, 1 H), 3.38 (s, 3 H),
2.92 (ddd, J ) 11.2, 8.4, 4.5 Hz, 1 H), 2.71-2.66 (m, 2 H), 2.45 (dd,
J ) 4.7, 3.0 Hz, 1 H), 2.05 (dq, J ) 12.7, 4.1 Hz, 1 H), 1.91 (dq, J )
13.1, 4.6 Hz, 1 H), 1.73-1.66 (m, 1 H), 1.57-1.48 (m, 1 H), 1.47-
1.31 (m, 3 H), 1.26-1.18 (m, 1 H), 1.10-1.00 (m, 22 H), 0.91 (d, J
) 6.7 Hz, 3 H), 0.78 (q, J ) 12.0 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 84.7, 75.5, 57.4, 57.1, 45.4, 41.7, 36.4, 34.2, 33.5, 33.2, 31.2,
18.0, 16.2, 12.6; high-resolution mass spectrum (CI, NH3) m/z 371.2981
[(M + H)+; calcd for C21H43O3Si, 371.2981].
Iodohydrin (-)-14. At -78 °C a solution of epoxide (-)-13 (270
mg, 0.72 mmol) in ether (5 mL) was treated with LiI (0.32 g, 2.39
mmol) in one portion. Boron trifluoride etherate (90 µL, 0.72 mmol)
was then added dropwise, and after an additional 5 min the reaction
was quenched with water (5 mL), warmed to ambient temperature, and
partitioned between ether (100 mL) and water (100 mL). The organic
phase was washed with brine (100 mL), dried over MgSO4, filtered,
and concentrated. Flash chromatography (hexanes/ethyl acetate, 20:
1) furnished (-)-14 (285 mg, 78% yield) as a colorless oil: [R]D23
-25° (c 0.9, CHCl3); IR (CHCl3) 3600-3300 (br) cm-1; 1H NMR (500
MHz, CDCl3) δ 3.56 (ddd, J ) 10.6, 8.4, 4.7 Hz, 1 H), 3.45-3.39 (m,
4 H), 3.38-3.34 (m, 1 H), 3.28 (dd, J ) 9.8, 7.6 Hz, 1 H), 2.92 (ddd,
J ) 11.1, 8.3, 4.5 Hz, 1 H), 2.14-2.06 (m, 1 H), 1.98 (d, J ) 5.0 Hz,
1 H), 1.96-1.90 (m, 1 H), 1.81-1.73 (m, 1 H), 1.66-1.59 (m, 2 H),
1.47-1.31 (m, 4 H), 1.17-1.05 (m, 21 H), 0.90 (d, J ) 6.7 Hz, 3 H),
0.76 (q, J ) 11.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 84.7, 75.6,
75.3, 57.5, 38.7, 35.9, 35.5, 34.0, 33.3, 31.9, 18.1, 15.7, 14.6, 12.6;
Desulfonylated Ketone (-)-37. A solution of mercury(II) chloride
(60.3 g, 222 mmol) in water (1.2 L) was added to a vigorously stirred
suspension of aluminum powder (11.9 g, 449 mmol) in water (50 mL).
The supernatant was decanted and the amalgam washed with methanol
(3 × 50 mL) followed by THF (3 × 50 mL). A suspension of the
amalgam in THF (50 mL) was poured through a funnel into a solution
of the â-keto sulfones 36 (4.80 g, 11.1 mmol) in THF (70 mL). A
reflux condenser was then fitted, and water (5 mL) was added. After
ca. 5 min, the reaction mixture began to reflux. Stirring was continued
for 1 h, and the mixture was then filtered through a pad of Celite and

Construction of C(21-42) Perimeters in Immunomodulators
J. Am. Chem. Soc., Vol. 119, No. 5, 1997 957
sand on a sintered-glass funnel. The solids were rinsed with ethyl
acetate (300 mL), and the filtrate was washed with water (200 mL)
and brine (200 mL), dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 3:1) provided (-)-37 (1.9 g,
60% yield) as a colorless oil: [R]2D3 -15° (c 1.7, CHCl3); IR (CHCl3)
(CI, NH3) m/z 220.0931 [M+; calcd for C10H20OS2, 220.0956]. Anal.
Calcd for C10H20OS2, C, 54.50; H, 9.15. Found: C, 54.58; H, 9.47.
C(22-26) Subtarget (+)-31 (C). A solution of oxalyl chloride (0.14
mL, 1.6 mmol) in dichloromethane (4 mL) was cooled to -78 °C, and
dimethyl sulfoxide (0.23 mL, 3.21 mmol) in dichloromethane (1 mL)
was added dropwise. After 15 min, a solution of alcohol (+)-45 (295
mg, 1.33 mmol) in dichloromethane (2 mL) was introduced at a
moderate rate. The mixture was stirred for 15 min further, treated with
triethylamine (0.93 mL, 6.69 mmol), warmed to 0 °C for 15 min, and
partitioned between ether (50 mL) and water (50 mL). The organic
phase was washed with 1 N HCl (25 mL), water (25 mL), and brine
(25 mL), dried over MgSO4, filtered, and concentrated. The crude
aldehyde was dried azeotropically with benzene (20 mL) and used
without further purification.
1
1715 (s) cm-1; H NMR (500 MHz, CDCl3) δ 4.41 (dd, J ) 7.7, 5.5
Hz, 1 H), 4.16 (dd, J ) 8.6, 7.7 Hz, 1 H), 4.07 (d, J ) 4.8 Hz, 1 H),
3.97 (dd, J ) 8.6, 5.5 Hz, 1 H), 2.95 (dd, J ) 17.7, 4.6 Hz, 1 H), 2.81
(m, 4 H), 2.58 (dd, J ) 17.7, 7.9 Hz, 1 H), 2.55 (m, 1 H), 2.06 (m, 1
H), 1.82 (m, 1 H), 1.46 (s, 3 H), 1.36 (s, 3 H), 1.07 (d, J ) 6.7 Hz, 3
H); 13C NMR (62.8 MHz, CDCl3) δ 209.2, 110.9, 80.2, 66.3, 53.9,
42.9, 33.1, 30.4, 30.2, 26.0, 24.9, 17.6; high-resolution mass spectrum
(CI, NH3) m/z 291.1063 [(M + H)+; calcd for C13H23O3S2, 291.1088].
Enol Triflate (-)-38. A mixture of HMPA and THF (1:4, 20 mL)
was cooled to -78 °C, and LHMDS (1.0 M in THF, 3.84 mL, 3.84
mmol) was added. A solution of ketone (-)-37 (860 mg, 2.96 mmol)
in 1:4 HMPA/THF (6 mL), precooled to -78 °C, followed by a solution
of N-phenyltrifluoromethanesulfonimide (1.27 g, 3.55 mmol) in 1:4
HMPA/THF (6 mL) was then introduced dropwise via a cannula. After
5 min the reaction mixture was quenched with saturated aqueous
NaHCO3 (10 mL) and partitioned between water (100 mL) and ether
(100 mL). The organic phase was washed with water (2 × 50 mL)
and brine (50 mL), dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 20:1) gave (-)-38 (937 mg,
75% yield) as a pale yellow oil: [R]2D3 -19° (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 5.81 (d, J ) 10.5 Hz, 1 H), 4.65 (t, J ) 6.5 Hz,
1 H), 4.15 (ABq, JAB ) 6.6 Hz, ∆νAB ) 8.5 Hz, 1 H), 4.01 (d, J ) 6.0
Hz, 1 H), 3.89 (ABq, JAB ) 6.5 Hz, ∆νAB ) 8.5 Hz, 1 H), 3.09-3.04
(m, 1 H), 2.86-2.83 (m, 4 H), 2.10-2.06 (m, 1 H), 1.88-1.84 (m, 1
H), 1.49 (s, 3 H), 1.38 (s, 3 H), 1.23 (d, J ) 6.8 Hz, 3 H); 13C NMR
(62.8 MHz, CDCl3) δ 144.8, 125.5, 118.4 (q, JCF ) 319 Hz), 110.8,
74.4, 67.4, 52.7, 35.7, 30.2, 30.1, 25.9, 25.7, 25.2, 17.6; high-resolution
mass spectrum (CI, NH3) m/z 422.0513 [M+; calcd for C14H21F3O5S3,
422.0503].
A solution of the above aldehyde and p-TsOH (1 mg) in trimethyl
orthoformate (3 mL) and MeOH (3 mL) was stirred for 1 h at ambient
temperature and then quenched with saturated aqueous NaHCO3 (2 mL).
The mixture was extracted with ether (50 mL), and the organic phase
was washed with brine (25 mL), dried over MgSO4, filtered, and
concentrated. Flash chromatography (hexanes/ethyl acetate, 10:1,
containing 1% triethylamine) furnished (+)-31 (C) (302 mg, 85%yield)
as a clear, colorless oil: [R]2D3 +2.6° (c 3.2, CHCl3); H NMR (500
1
MHz, CDCl3) δ 4.15 (d, J ) 3.5 Hz, 1 H), 4.01 (d, J ) 5.7 Hz, 1 H),
3.37 (s, 3 H), 3.36 (s, 3 H), 2.94-2.83 (m, 4 H), 2.12-2.03 (m, 2 H),
1.87-1.80 (m, 4 H), 1.10 (d, J ) 6.7 Hz, 3 H), 0.92 (d, J ) 6.7 Hz,
3 H); 13C NMR (62.8 MHz, CDCl3) δ 108.8, 54.5, 54.4, 54.0, 36.4,
35.7, 33.2, 31.1, 30.6, 26.3, 17.7, 14.7; high-resolution mass spectrum
(CI, CH4) m/z 264.1206 [M+; calcd for C12H24O2S2, 264.1218].
Alkylated Dithiane (+)-46. A solution of dithiane (+)-30 (B) (200
mg, 0.69 mmol) in 10% HMPA/THF (3 mL) was cooled to -78 °C,
and t-BuLi (1.5 M in pentane, 0.46 mL, 0.69 mmol) was added
dropwise. Immediately thereafter a precooled (-78 °C) solution of
iodide (-)-15 (A) (320 mg, 0.51 mmol) in 10% HMPA/THF (3 mL)
was added dropwise via a cannula. The reaction was immediately
quenched with saturated aqueous NH4Cl (2 mL), diluted with ether
(50 mL), and warmed to ambient temperature. The layers were
separated, and the organic phase was washed with water (25 mL) and
brine (25 mL), dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 20:1) gave (+)-46 (350 mg,
C(27-32) Subtarget (+)-30 (B). At -15 °C a suspension of CuI
(1.7 g, 9.0 mmol) in ether (200 mL) was treated with MeLi (1.1 M in
ether, 15.0 mL, 18.0 mmol). The resultant clear, colorless solution
was cooled to -78 °C, and a solution of vinyl triflate (-)-38 (1.9 g,
4.5 mmol) in ether (50 mL) was added dropwise. After 10 min the
reaction mixture was quenched with saturated aqueous NH4Cl (20 mL)
and 10% aqueous NH4OH (20 mL), and the organic phase was washed
with 10% aqueous NH4OH (30 mL), water (30 mL), and brine (30
mL), dried over MgSO4, filtered, and concentrated. Flash chromatog-
raphy (hexanes/ethyl acetate, 10:1) afforded (+)-30 (B) (0.91 g, 70%
87% yield) as a white foam: [R]2D3 +14° (c 3.5, CHCl3); H NMR
1
(500 MHz, CDCl3) δ 7.27 (d, J ) 8.5 Hz, 2 H), 6.84 (d, J ) 8.5 Hz,
2 H), 5.70 (d, J ) 9.6 Hz, 1 H), 4.52 (t, J ) 7.0 Hz, 1 H), 4.46 (ABq,
JAB ) 10.3 Hz, ∆νAB ) 37.7 Hz, 2 H), 4.03 (t, J ) 7.2 Hz, 1 H), 3.78
(s, 3 H), 3.66-3.63 (m, 2 H), 3.55 (ddd, J ) 10.9, 8.4, 4.7 Hz, 1 H),
3.40 (s, 3 H), 3.16 (dq, J ) 9.6, 6.9 Hz, 1 H), 2.94-2.70 (m, 5 H),
2.11-1.88 (m, 7 H), 1.66-1.59 (m, 1 H), 1.61 (s, 3 H), 1.46-1.20
(m, 2 H), 1.45 (s, 3 H), 1.36 (s, 3 H), 1.19-0.85 (m, 24 H), 1.13 (d,
J ) 6.9 Hz, 3 H), 0.90 (d, J ) 6.7 Hz, 3 H), 0.77 (q, J ) 12.0 Hz, 1
H); 13C NMR (62.8 MHz, CDCl3) δ 158.8, 131.9, 131.1, 130.1, 129.5,
113.4, 108.9, 84.7, 81.4, 80.3, 75.5, 70.7, 67.6, 57.5, 57.2, 55.1, 39.7,
38.7, 36.2, 36.0, 34.1, 33.3, 32.5, 31.6, 26.4, 26.2, 25.9, 25.2, 24.9,
18.0, 15.8, 14.2, 12.5, 10.9; high-resolution mass spectrum (FAB, NBA)
m/z 777.4583 [(M - H)+; calcd for C43H73O6S2Si, 777.4618]. Anal.
Calcd for C43H74O6S2Si, C, 66.28; H, 9.57. Found: C, 65.94; H, 9.43.
Diol (+)-47. A solution of acetonide (+)-46 (450 mg, 0.57 mmol)
in methanol (15 mL) was treated with camphorsulfonic acid (13 mg,
0.05 mmol), stirred at ambient temperature for 2 h, quenched with
saturated aqueous NaHCO3 (10 mL), and partitioned between ether (50
mL) and water (50 mL). The organic phase was washed with brine
(20 mL), dried over MgSO4, filtered, and concentrated. Flash chro-
matography (hexanes/ethyl acetate, 4:1) gave recovered (+)-46 (57 mg,
13% yield) in addition to (+)-47 (312 mg, 73% yield), a white foam:
yield) as a colorless oil: [R]2D3 +15° (c 2.7, CHCl3); H NMR (500
1
MHz, CDCl3) δ 5.50 (d, J ) 10.0 Hz, 1 H), 4.51 (t, J ) 7.0 Hz, 1 H),
4.08 (dd, J ) 8.2, 6.8 Hz, 1 H), 4.01 (d, J ) 6.8 Hz, 1 H), 3.67 (dd,
J ) 8.0, 7.8 Hz, 1 H), 2.85-2.78 (m, 5 H), 2.09-2.06 (m, 1 H), 1.85-
1.75 (m, 1 H), 1.66 (d, J ) 1.3 Hz, 3 H), 1.45, (s, 3 H), 1.38 (s, 3 H),
1.15 (d, J ) 6.8 Hz, 3 H); 13C NMR (62.8 MHz, CDCl3) δ 133.3 (s),
130.2 (d), 109.0 (s), 80.9 (d), 67.8 (t), 54.3 (d), 37.3 (d), 30.7 (t), 30.5
(t), 26.2 (t), 25.9 (q), 25.3 (q), 18.1 (q), 11.3 (q); high-resolution mass
spectrum (CI, NH3) m/z 288.1218 [M+; calcd for C14H24O2S2, 288.1234].
Anal. Calcd for C14H24O2S2, C, 58.29; H, 8.38. Found: C, 58.59; H,
8.74.
Dithiane Alcohol (+)-45. At 0 °C a solution of silyl ether (+)-44
(1.80 g, 3.92 mmol) in THF (30 mL) was treated slowly with TBAF
(1.0 M in THF, 4.7 mL, 4.7 mmol). After removal of the cooling bath,
the reaction mixture was stirred for 16 h at ambient temperature and
then poured into a mixture of water and ether (1:1, 100 mL). The
organic phase was washed with 1 N HCl (50 mL), water (50 mL), and
brine (50 mL), dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 4:1, then 1:1) provided (+)-
45 (816 mg, 94% yield) as a colorless oil: [R]2D3 +11° (c 0.3, CHCl3);
[R]2D3 +19° (c 0.8, CHCl3); IR (CHCl3) 3600-3100 (br, w) cm-1; H
1
NMR (500 MHz, CDCl3) δ 7.23 (d, J ) 8.6 Hz, 2 H), 6.82 (d, J ) 8.6
Hz, 2 H), 5.66 (d, J ) 9.7 Hz, 1 H), 4.43 (ABq, JAB ) 10.4 Hz, ∆νAB
) 19.4 Hz, 2 H), 4.12 (t, J ) 6.2 Hz, 1 H), 3.76 (s, 3 H), 3.60 (m, 1
H), 3.55-3.48 (m, 2 H), 3.38 (s, 3 H), 3.06 (m, 1 H), 2.91-2.65 (m,
5 H), 2.29 (m, 1 H), 2.14-1.83 (m, 7 H), 1.71-1.60 (m, 2 H), 1.59 (d,
J ) 1.1 Hz, 3 H), 1.42-1.28 (m, 2 H), 1.20-0.85 (m, 4 H), 1.11 (d,
J ) 6.8 Hz, 3 H), 1.05 (s, 21 H), 0.89 (d, J ) 6.7 Hz, 3 H), 0.75 (q,
J ) 11.8 Hz, 1 H); 13C NMR (62.8 MHz, CDCl3) δ 158.9, 134.1, 131.0,
129.5, 128.8, 113.6, 84.7, 80.3, 77.5, 75.5, 70.7, 64.5, 57.6, 55.2, 39.9,
1
IR (CHCl3) 3630 (m), 3590-3320 (br) cm-1; H NMR (500 MHz,
CDCl3) δ 4.12 (d, J ) 3.7 Hz, 1 H), 3.49 (dd, J ) 10.5, 4.8 Hz, 1 H),
3.40 (dd, J ) 10.5, 6.0 Hz, 1 H), 2.87 (dq, J ) 14.1, 2.5 Hz, 1 H),
2.82 (m, 3 H), 2.08 (m, 1 H), 1.97 (m, 1 H), 1.80 (m, 1 H), 1.70 (m,
2 H), 1.43 (br s, 1 H), 1.10 (m, 1 H), 1.07 (d, J ) 6.8 Hz, 3 H), 0.93
(d, J ) 6.5 Hz, 3 H); 13C NMR (62.8 MHz, CDCl3) δ 67.8, 55.0, 37.7,
35.9, 33.2, 31.1, 30.7, 26.3, 17.7, 17.3; high-resolution mass spectrum

958 J. Am. Chem. Soc., Vol. 119, No. 5, 1997
Smith et al.
1
38.5, 36.2, 34.1, 33.3, 32.4, 31.6, 26.4, 25.8, 25.0, 18.0, 15.7, 14.2,
12.6, 11.7; high-resolution mass spectrum (FAB, NBA) m/z 737.4281
[(M - H)+; calcd for C40H69O6S2Si, 737.4305].
CHCl3); IR (CHCl3) 3440 (br) cm-1; H NMR (500 MHz, C6D6) δ
7.40 (d, J ) 8.6 Hz, 2 H), 6.85 (d, J ) 8.6 Hz, 2 H), 6.01 (d, J ) 9.7
Hz, 1 H), 4.79 (d, J ) 9.0 Hz, 1 H), 4.66 (ABq, JAB ) 10.5 Hz, ∆νAB
) 80.8 Hz, 2 H), 4.06 (d, J ) 5.7 Hz, 1 H), 3.96 (d, J ) 7.9 Hz, 1 H),
3.77 (d, J ) 1.6 Hz, 1 H), 3.67 (ddd, J ) 10.9, 8.4, 4.8 Hz, 1 H), 3.35
(m, 1 H), 3.32 (s, 3 H), 3.30 (s, 3 H), 3.20 (s, 3 H), 3.17 (s, 3 H), 2.95
(ddd, J ) 11.1, 8.3, 4.4 Hz, 1 H), 2.75-2.69 (m, 2 H), 2.64-2.55 (m,
3 H), 2.46 (d, J ) 14.2 Hz, 1 H), 2.45-2.41 (m, 2 H), 2.36 (dd, J )
15.3, 7.1 Hz, 1 H), 2.24-2.13 (m, 2 H), 2.10 (d, J ) 14.2 Hz, 1 H),
1.96 (m, 1 H), 1.92 (d, J ) 1.1 Hz, 3 H), 1.55-1.40 (m, 6 H), 1.39 (d,
J ) 6.9 Hz, 3 H), 1.34 (d, J ) 6.7 Hz, 3 H), 1.33-1.24 (m, 2 H),
1.24-1.21 (m, 29 H), 1.04 (d, J ) 6.8 Hz, 3 H), 1.02 (d, J ) 6.9 Hz,
3 H), 0.83 (apparent q, J ) 11.9 Hz, 1 H); 13C NMR (62.8 MHz, C6D6)
δ 159.6, 138.4, 131.9, 129.7, 126.7, 113.9, 109.5, 85.0, 80.5, 75.9, 74.7,
71.0, 59.2, 58.5, 57.0, 54.7, 54.6, 53.4, 42.0, 40.2, 39.2, 38.5, 36.8,
36.5, 36.4, 35.2, 34.7, 33.7, 33.1, 31.8, 26.6, 26.3, 25.6, 25.4, 18.5,
17.1, 16.7, 15.5, 14.8, 13.0, 12.2. Anal. Calcd for C52H92O7S4Si, C,
63.37; H, 9.41. Found: C, 63.08; H, 9.42.
Tosylate (+)-48. A solution of alcohol (+)-47 (272 mg, 0.36 mmol),
triethylamine (0.5 mL, 3.67 mmol), and DMAP (5 mg, 0.03 mmol) in
dichloromethane (5 mL) was cooled to 0 °C. TsCl (70 mg, 0.36 mmol)
was added in one portion, and the reaction mixture was warmed to
ambient temperature, stirred for 16 h, and then poured into a mixture
of ether and water (1:1, 40 mL). The organic phase was washed with
1 N HCl (10 mL), water (10 mL), and brine (10 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes/ethyl
acetate, 4:1) provided starting material (+)-47 (30 mg, 11% yield) and
tosylate (+)-48 (279 mg, 85% yield), a white foam: [R]2D3 +10° (c
1
0.3, CHCl3); IR (CHCl3) 3650-3100 (br), 1740 (s) cm-1; H NMR
(500 MHz, CDCl3) δ 7.80 (d, J ) 8.3 Hz, 2 H), 7.33 (d, J ) 8.1 Hz,
2 H), 7.26 (d, J ) 8.2 Hz, 2 H), 6.84 (d, J ) 8.6 Hz, 2 H), 5.69 (d, J
) 9.8 Hz, 1 H), 4.45 (ABq, JAB ) 10.3 Hz, ∆νAB ) 27.1 Hz, 2 H),
4.23 (dd, J ) 8.1, 2.8 Hz, 1 H), 4.08 (dd, J ) 10.3, 3.2 Hz, 1 H), 3.96
(dd, J ) 10.2, 8.2 Hz, 1 H), 3.78 (s, 3 H), 3.62 (m, 1 H), 3.55 (ddd, J
) 10.9, 8.2, 4.7 Hz, 1 H), 3.40 (s, 3 H), 3.11 (dd, J ) 9.7, 6.9 Hz, 1
H), 2.91 (ddd, J ) 11.1, 8.3, 4.4 Hz, 1 H), 2.84-2.82 (m, 1 H), 2.74-
2.71 (m, 3 H), 2.43 (s, 3 H), 2.07-1.80 (m, 10 H), 1.64 (m, 1 H),
1.43-1.08 (m, 3 H), 1.07 (s, 27 H), 0.89 (d, J ) 6.8 Hz, 3 H), 0.77 (q,
J ) 11.9 Hz, 1 H); 13C NMR (62.8 MHz, CDCl3) δ 158.9, 144.9, 132.9,
131.7, 131.1, 130.0, 129.8, 129.5, 127.9, 113.5, 84.7, 80.3, 75.5, 74.7,
72.7, 70.6, 57.7, 57.2, 55.2, 39.8, 38.5, 36.3, 36.1, 34.2, 33.4, 32.4,
31.6, 26.5, 25.9, 24.9, 21.6, 18.0, 15.8, 14.2, 12.6, 12.5; high-resolution
mass spectrum (FAB, NBA) m/z 894.4460 [M+; calcd for C47H76O8S3-
Si, 894.4472]. Anal. Calcd for C47H76O8S3Si, C, 63.19; H, 8.57.
Found: C, 63.34; H, 8.38.
Alcohols (+)-84 and (+)-85. A solution of dithiane (+)-31 (C)
(280 mg, 1.06 mmol) in 10% HMPA/THF (5 mL) was cooled to -78
°C, and t-BuLi (1.5 M in pentane, 0.61 mL, 0.92 mmol) was added
dropwise. A precooled (-78 °C) solution of aldehyde (+)-66 (100
mg, 0.28 mmol) in 10% HMPA/THF (3 mL) was immediately added
dropwise via a cannula. The reaction was then immediately quenched
with saturated aqueous NH4Cl (5 mL), diluted with ether (20 mL), and
warmed to ambient temperature. The organic phase was washed with
water (2 × 10 mL) and brine (10 mL), dried over MgSO4, filtered,
and concentrated. Flash chromatography (hexanes/ethyl acetate, 15:
1, containing 1% triethylamine) furnished a 5:1 mixture of (+)-84 and
(+)-85 (128 mg, 74% yield). Radial chromatography (silica; 1-mm
layer, hexanes/ethyl acetate, 15:1, containing 1% triethylamine) then
gave pure (+)-84 (95 mg, 55% yield) and (+)-85 (20 mg, 12% yield)
as colorless oils.
Epoxide (+)-54. A solution of tosylate (+)-48 (0.90 g, 1.0 mmol)
in anhydrous MeOH (30 mL) was treated with K2CO3 (0.40 g, 3.2
mmol). The heterogeneous mixture was stirred at ambient temperature
for 1 h and then partitioned between ether (100 mL) and water (100
mL). The organic phase was washed with brine (50 mL), dried over
MgSO4, filtered, and concentrated. The crude epoxide was dried
azeotropically with benzene (50 mL) and used without further purifica-
tion in the next reaction. Flash chromatography (hexanes/ethyl acetate,
20:1, containing 1% triethylamine) provided an analytical sample of
(+)-84: [R]2D3 +39.2° (c 1.37, CHCl3); IR (CHCl3) 3450 (br) cm-1
;
1H NMR (500 MHz, CDCl3) δ 5.39 (d, J ) 9.6 Hz, 1 H), 4.53 (s, 1
H), 4.11 (d, J ) 5.7 Hz, 1 H), 4.00 (d, J ) 6.0 Hz, 1 H), 3.99 (m, 1
H), 3.81 (d, J ) 6.6 Hz, 1 H), 3.39 (s, 6 H), 3.36 (d, J ) 4.4 Hz, 1 H),
3.19 (br m, 1 H), 3.04 (apparent t, J ) 9.7 Hz, 1 H), 2.86-2.67 (series
of m, 7 H), 2.43 (dd, J ) 8.0, 6.3 Hz, 1 H), 2.13 (apparent t, J ) 6.9
Hz, 1 H), 2.06 (dt, J ) 13.8, 3.5 Hz, 1 H), 2.04-1.95 (m, 2 H), 1.84-
1.75 (m, 2 H), 1.66 (d, J ) 1.2 Hz, 3 H), 1.15 (d, J ) 6.8 Hz, 3 H),
1.11 (d, J ) 6.8 Hz, 3 H), 0.94 (d, J ) 6.9 Hz, 3 H), 0.91 (s, 9 H),
0.20 (s, 3 H), 0.07 (s, 3 H); 13C NMR (62.8 MHz, CDCl3) δ 138.3 (s),
129.8 (d), 109.4 (d), 79.5 (d), 76.3 (d), 62.4 (s), 54.8 (q), 54.6 (d),
54.2 (q), 37.4 (d), 37.2 (t), 37.1 (d), 35.1 (d), 30.7 (t), 30.5 (t), 27.6 (t),
26.6 (t), 26.1 (t), 25.9 (q), 25.2 (t), 18.2 (q), 17.6 (s), 16.3 (q), 15.8
(q), 11.4 (q), -4.1 (q), -4.6 (q); high-resolution mass spectrum (CI,
NH3) m/z 647.2753 [(M + Na)+; calcd for C29H56O4S4Si, 647.2729].
(+)-54 as a colorless oil: [R]2D3 +12° (c 0.7, CCl4); H NMR (500
1
MHz, C6D6) δ 7.37 (d, J ) 8.6 Hz, 2 H), 6.80 (d, J ) 8.6 Hz, 2 H),
6.07 (d, J ) 9.7 Hz, 1 H), 4.64 (ABq, JAB ) 10.4 Hz, ∆νAB ) 67.9
Hz, 2 H), 3.92 (d, J ) 8.2 Hz, 1 H), 3.67 (ddd, J ) 10.9, 8.3, 4.8 Hz,
1 H), 3.33 (dd, J ) 9.8, 6.9 Hz, 1 H), 3.30 (s, 3 H), 3.29 (s, 3 H), 3.15
(dd, J ) 3.9, 2.7 Hz, 1 H), 2.95 (ddd, J ) 11.1, 8.4, 4.5 Hz, 1 H), 2.56
(ddd, J ) 9.7, 8.0, 3.6 Hz, 1 H), 2.43-2.37 (m, 5 H), 2.34 (dd, J )
15.5, 7.4 Hz, 1 H), 2.17-2.10 (m, 2 H), 2.08 (dd, J ) 15.5, 1.5 Hz, 1
H), 1.97 (dq, J ) 13.1, 4.5 Hz, 1 H), 1.58-1.47 (m, 3 H), 1.45 (d, J
) 1.3 Hz, 3 H), 1.42-1.33 (m, 2 H), 1.30 (d, J ) 6.9 Hz, 3 H), 1.25-
1.22 (m, 24 H), 1.02 (d, J ) 6.8 Hz, 3 H), 0.83 (q, J ) 11.2 Hz, 1 H);
13C NMR (62.8 MHz, C6D6) δ 159.6 (s), 131.9 (s), 131.8 (s), 131.7
(d), 129.8 (d), 113.9 (d), 85.0 (d), 80.5 (d), 75.8 (d), 71.2 (t), 57.8 (s),
57.0 (q), 56.0 (d), 54.7 (q), 45.5 (t), 40.3 (t), 39.5 (d), 36.8 (t), 36.4 (t),
34.7 (t), 33.7 (d), 33.0 (d), 31.8 (t), 26.6 (t), 26.2 (t), 25.3 (t), 18.5 (q),
16.4 (q), 14.7 (q), 13.0 (d), 10.2 (q); high-resolution mass spectrum
(FAB, NBA) m/z 743.4152 [(M + Na)+; calcd for C40H68O5S2SiNa,
743.4175]. Anal. Calcd for C40H68O5S2Si, C, 66.62; H, 9.50. Found:
C, 66.83; H, 9.54.
Dithiane Alcohol (+)-55. At -78 °C a solution of dithiane (+)-
31 (C) (1.7 g, 6.4 mmol) in 10% HMPA/THF (17 mL) was treated
with t-BuLi (1.7 M in pentane, 3.0 mL, 5.3 mmol). Immediately
thereafter a precooled (-78 °C) solution of crude epoxide (+)-54 in
10% HMPA/THF (7 mL) was added via a cannula. The reaction
mixture was rapidly warmed to -55 °C and then quenched with
saturated aqueous NH4Cl (10 mL). At ambient temperature the mixture
was partitioned between ether (30 mL) and water (30 mL), and the
organic phase was washed with water (3 × 20 mL) and brine (20 mL),
dried over MgSO4, filtered, and concentrated. A second reaction was
performed on the same scale, and the combined products were subjected
to flash chromatography (hexanes/ethyl acetate, 20:1, containing 1%
triethylamine, then 4:1, containing triethylamine), affording (+)-55 (1.8
g, total yield 86% from 48) as a white foam: [R]2D3 +16° (c 0.8,
(+)-85: [R]2D3 +29° (c 0.44, CHCl3); IR (CHCl3) 3680 (w), 3500
(br) cm-1; H NMR (500 MHz, CDCl3) δ 5.36 (d, J ) 9.9 Hz, 1 H),
1
4.49 (d, J ) 6.1 Hz, 1 H), 4.15 (dd, J ) 6.1, 2.9 Hz, 1 H), 4.08 (d, J
) 5.3 Hz, 1 H), 4.02 (d, J ) 6.9 Hz, 1 H), 3.36 (s, 6 H), 3.34 (m, 1
H), 3.10 (ddd, J ) 13.6, 10.0, 3.4 Hz, 1 H), 2.87-2.79 (m, 5 H), 2.70-
2.62 (m, 3 H), 2.40 (apparent t, J ) 6.8 Hz, 1 H), 2.14 (dd, J ) 12.1,
6.4 Hz, 1 H), 2.08 (dt, J ) 13.8, 3.7 Hz, 1 H), 2.01 (m, 1 H), 1.90-
1.81 (m, 3 H), 1.76 (d, J ) 1.2 Hz, 3 H), 1.26 (d, J ) 6.8 Hz, 3 H),
1.16 (d, J ) 6.7 Hz, 3 H), 1.08 (ddd, J ) 14.4, 7.8, 6.3 Hz, 1 H), 0.93
(d, J ) 6.8 Hz, 3 H), 0.88 (s, 9 H), 0.13 (s, 3 H), 0.04 (s, 3 H); 13C
NMR (125 MHz, CDCl3) δ 138.0, 132.1, 108.8, 80.8, 79.3, 62.6, 55.1,
54.1, 54.0, 37.8, 37.2, 35.6, 35.2, 30.7, 30.3, 27.7, 26.7, 26.1, 26.0,
24.7, 18.2, 17.7, 17.4, 15.6, 12.7, -4.4 (2 C); high-resolution mass
spectrum (CI, NH3) m/z 647.2741 [(M + Na)+; calcd for C29H56O4S4-
Si, 647.2729].
Methyl Ether (+)-86. At ambient temperature a solution of alcohol
(+)-85 (16 mg, 0.03 mmol) in THF (1 mL) was treated with sodium
hydride (60% oil dispersion; 5 mg, 0.13 mmol), 15-crown-5 (5 µL,
0.03 mmol), and methyl iodide (25 µL, 0.26 mmol). The reaction
mixture was stirred for 4 h and then partitioned between ether (10 mL)
and saturated aqueous NH4Cl (10 mL). The organic layer was washed
with water (5 mL) and brine (5 mL), dried over MgSO4, filtered, and
concentrated. Flash chromatography (hexanes/ethyl acetate, 15:1,
containing 1% triethylamine) afforded (+)-86 (14 mg, 85% yield) as

Construction of C(21-42) Perimeters in Immunomodulators
J. Am. Chem. Soc., Vol. 119, No. 5, 1997 959
a colorless oil: [R]2D3 +9.8° (c 0.25, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 5.43 (d, J ) 9.3 Hz, 1 H), 4.45 (d, J ) 5.4 Hz, 1 H), 4.12
(d, J ) 5.6 Hz, 1 H), 4.07 (d, J ) 5.4 Hz, 1 H), 3.77 (d, J ) 5.5 Hz,
1 H), 3.58 (s, 3 H), 3.37 (s, 3 H), 3.36 (s, 3 H), 3.24 (apparent t, J )
9.7 Hz, 1 H), 3.15 (apparent t, J ) 10.6 Hz, 1 H), 2.88 (dq, J ) 11.8,
2.3 Hz, 1 H), 2.85-2.79 (m, 4 H), 2.63 (t, J ) 4.4 Hz, 1 H), 2.60 (t,
J ) 4.5 Hz, 1 H), 2.33 (m, 1 H), 2.11-2.00 (m, 3 H), 1.87-1.81 (m,
3 H), 1.79 (d, J ) 1.2 Hz, 3 H), 1.23 (d, J ) 6.7 Hz, 3 H), 1.15 (d, J
) 6.8 Hz, 3 H), 1.04 (ddd, J ) 15.5, 8.7, 6.8, 1 H), 0.92 (d, J ) 6.9
Hz, 3 H), 0.87 (s, 9 H), 0.10 (s, 3 H), 0.03 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 137.6, 131.1, 108.6, 91.7, 81.0, 63.5, 61.6, 55.2, 54.6,
53.8, 37.7, 37.5, 35.7, 34.7, 31.1, 30.6, 27.7, 27.2, 26.2, 26.0, 24.6,
18.2, 17.7, 17.1, 15.5, -4.5 (2 C).
with benzene (2 × 20 mL) was dissolved in 10% HMPA/THF (4 mL);
the precooled (-78 °C) solution was immediately added via a cannula
to the dark orange anion mixture, and the flask and cannula were rinsed
with 10% HMPA/THF (2 × 0.5 mL). The reaction was quenched with
saturated aqueous NH4Cl (5 mL) and extracted with ether (20 mL).
The organic layer was washed with water (10 mL), saturated aqueous
Na2S2O3 (10 mL), water (10 mL), and brine (10 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes/ethyl
acetate, 30:1) gave recovered (+)-96 (32 mg, 16% yield) and dithiane
(-)-97 (337 mg, 91% yield), a pale yellow oil: [R]2D3 -1.6° (c 0.87,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.28 (d, J ) 8.6 Hz, 2 H),
6.38 (d, J ) 8.6 Hz, 2 H), 5.54 (d, J ) 9.6 Hz, 1 H), 4.48 (ABq, JAB
) 10.4 Hz, ∆υAB ) 69.1 Hz, 2 H), 4.21 (d, J ) 6.7 Hz, 1 H), 3.96 (d,
J ) 6.7 Hz, 1 H), 3.79 (s, 3 H), 3.68 (d, J ) 5.4 Hz, 1 H), 3.55 (ddd,
J ) 10.8, 6.2, 3.8 Hz, 1 H), 3.41 (s, 3 H), 3.40 (s, 3 H), 3.29 (s, 3 H),
3.22 (dd, J ) 9.6, 6.9 Hz, 1 H), 2.92 (ddd, J ) 12.8, 8.4, 4.4 Hz, 1 H),
2.82-2.70 (m, 4 H), 2.09-1.89 (m, 6 H), 1.85 (d, J ) 14.6 Hz, 1 H),
1.64 (d, J ) 1.0 Hz, 3 H), 1.49-1.45 (m, 1 H), 1.35 (dq, J ) 10.9, 3.5
Hz, 1 H), 1.25-1.12 (m, 3 H), 1.10 (d, J ) 6.9 Hz, 3 H), 1.08 (s, 21
H), 1.02-0.94 (m, 1 H), 0.90 (d, J ) 6.7 Hz, 3 H), 0.86 (s, 9 H), 0.77
(q, J ) 12.0 Hz, 1 H), 0.05 (s, 3 H), 0.00 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 158.9 (s), 134.4 (s), 131.4 (s), 129.5 (d), 129.5 (d),
113.5 (d), 105.7 (d), 84.8 (d), 80.2 (d), 79.1 (d), 75.6 (d), 70.6 (t), 57.6
(q), 57.5 (s), 55.7 (q), 55.2 (q), 52.8 (q), 39.8 (t), 38.7 (d), 36.4 (t),
36.3 (t), 34.3 (t), 33.4 (d), 32.7 (d), 31.7 (t), 26.6 (t), 25.9 (t), 25.8 (q),
25.0 (t), 18.2 (s), 18.1 (q), 16.0 (q), 14.4 (q), 12.6 (d), 11.9 (q), -4.7
(q), -4.9 (q); high-resolution mass spectrum (FAB, NBA) m/z 919.5421
[(M + Na)+; calcd for C48H88O7S2Si2Na, 919.5408]. Anal. Calcd for
C48H88O7S2Si2: C, 64.31; H, 9.78. Found: C, 64.52; H, 10.12.
AB Aldehyde (+)-59. At ambient temperature a solution of
dimethyl acetal (-)-97 (220 mg, 0.24 mmol) in acetone (10 mL) was
treated with trichloroacetic acid (1.5 g, 9.6 mmol). The reaction mixture
was stirred for 16 h, quenched with saturated aqueous NaHCO3 (25
mL), and extracted with ether (50 mL). The organic layer was washed
with water (2 × 20 mL) and brine (20 mL), dried over MgSO4, filtered,
and concentrated. Flash chromatography (hexanes/ethyl acetate, 10:
1) provided (+)-59 (141 mg, 70% yield) as a pale yellow oil: [R]D23
+27.2° (c 1.14, CHCl3); IR (CHCl3) 2970 (s), 2920 (s), 2860 (s), 1730
Methoxy-Alkylated Dithiane (+)-87. A. From (+)-86. A solu-
tion of dithiane (+)-86 (15 mg, 0.024 mmol) in 10% HMPA/THF (1.5
mL) was cooled to -78 °C, and t-BuLi (1.1 M in pentane, 44 µL,
0.068 mmol) was added dropwise. Immediately thereafter a precooled
(-78 °C) solution of iodide (-)-15 (A) (42 mg, 0.048 mmol) in 10%
HMPA/THF (2 mL) was introduced dropwise via a cannula. The
reaction mixture was immediately quenched with saturated aqueous
NH4Cl (10 mL), diluted with ether (20 mL), and warmed to ambient
temperature. The layers were separated, and the organic phase was
washed with saturated aqueous Na2S2O3 (10 mL), water (2 × 10 mL)
and brine (10 mL), dried over MgSO4, filtered, and concentrated. Flash
chromatography (hexanes/ethyl acetate, 10:1) gave (+)-87 (16.3 mg,
61% yield) as a colorless oil: [R]2D3 +12° (c 0.38, CHCl3); H NMR
1
(500 MHz, CDCl3) δ 7.27 (d, J ) 8.6 Hz, 2 H), 6.82 (d, J ) 8.6 Hz,
2 H), 5.55 (d, J ) 9.2 Hz, 1 H), 4.50 (ABq, JAB ) 10.5 Hz, ∆υAB
)
69.2 Hz, 2 H), 4.42 (d, J ) 8.1 Hz, 1 H), 4.03 (d, J ) 6.5 Hz, 1 H),
3.78 (s, 3 H), 3.74 (d, J ) 6.4 Hz, 1 H), 3.73 (m, 1 H), 3.55 (s, 3 H),
3.55 (m, 1 H), 3.40 (s, 3 H), 3.34 (s, 3 H), 3.33 (s, 3 H), 3.32-3.25
(m, 2 H), 3.16 (m, 1 H), 2.92 (ddd, J ) 11.2, 8.4, 4.5 Hz, 1 H), 2.87-
2.79 (m, 3 H), 2.68 (m, 1 H), 2.61-2.56 (m, 2 H), 2.38 (apparent t, J
) 6.6 Hz, 1 H), 2.12-1.80 (complex series of m, 10 H), 1.79 (d, J )
1.0 Hz, 3 H), 1.64 (dq, J ) 10.2, 2.9 Hz, 1 H), 1.40 (m, 1 H), 1.35
(dq, J ) 10.9, 3.6 Hz, 1 H), 1.26 (d, J ) 6.7 Hz, 3 H), 1.21 (m, 1 H),
1.14 (d, J ) 6.9 Hz, 3 H), 1.12-1.03 (m, 4 H), 1.08 (s, 21 H), 0.91 (d,
J ) 6.8 Hz, 3 H), 0.90 (d, J ) 6.8 Hz, 3 H), 0.87 (s, 9 H), 0.77 (q, J
) 12.0 Hz, 1 H), 0.11 (s, 3 H), 0.04 (s, 3 H); 13C NMR (62.8 MHz,
CDCl3) δ 158.9, 136.2, 131.5, 130.6, 129.5, 113.5, 108.6, 90.7, 84.9,
82.1, 80.2, 75.6, 70.8, 63.6, 61.5, 57.7, 57.6, 55.2, 55.1, 53.8, 39.7,
38.7, 37.8, 36.4, 36.3, 36.0, 34.3, 33.5, 33.1, 31.7, 28.0, 27.2, 26.5,
26.3, 26.1, 25.0, 24.6, 18.2, 18.1 (2 C), 17.9, 16.1, 15.5, 14.7, 13.1,
12.7, -4.1, -4.3; high-resolution mass spectrum (FAB, NBA) m/z
1151.6336 [(M + Na)+; calcd for C59H108O8S4Si2Na, 1151.6364]. Anal.
Calcd for C59H108O8S4Si2: C, 64.51; H, 9.52. Found: C, 64.89; H,
9.66.
1
(s) cm-1; H NMR (500 MHz, CDCl3) δ 9.33 (d, J ) 1.6 Hz, 1 H),
7.27 (d, J ) 8.7 Hz, 2 H), 6.38 (d, J ) 8.7 Hz, 2 H), 5.87 (d, J ) 9.9
Hz, 1 H), 4.46 (ABq, JAB ) 10.4 Hz, ∆υAB ) 50.4 Hz, 2 H), 4.34 (s,
1 H), 3.79 (s, 3 H), 3.65 (dd, J ) 7.4, 2.7 Hz, 1 H), 3.55 (ddd, J )
10.9, 8.4, 4.8 Hz, 1 H), 3.40 (s, 3 H), 3.20 (dd, J ) 9.8, 6.9 Hz, 1 H),
2.91 (ddd, J ) 11.2, 8.4, 4.4 Hz, 1 H), 2.85 (dt, J ) 14.9, 6.4 Hz, 1
H), 2.78-2.73 (m, 4 H), 2.12-2.00 (m, 4 H), 1.96-1.88 (m, 4 H),
1.67-1.61 (m, 1 H), 1.55 (d, J ) 1.2 Hz, 3 H), 1.51-1.41 (m, 1 H),
1.35 (ddd, J ) 24.1, 13.5, 3.8 Hz, 1 H), 1.20-1.14 (m, 1 H), 1.12 (d,
J ) 6.8 Hz, 3 H), 1.07 (s, 21 H), 0.93 (d, J ) 6.6 Hz, 3 H), 0.90 (s,
9 H), 0.77 (q, J ) 12.0 Hz, 1 H), 0.07 (s, 3 H), 0.06 (s, 3 H); 13C
NMR (125 MHz, CDCl3) δ 199.9, 158.9, 131.3, 131.0, 129.8, 129.5,
113.5, 84.8, 83.2, 80.3, 75.6, 70.7, 57.6, 57.4, 55.2, 39.9, 38.9, 36.3,
36.2, 34.3, 33.5, 32.6, 31.7, 26.5, 26.0, 25.8, 25.0, 18.3, 18.1, 16.1,
14.3, 12.7, 12.5, -4.8, -5.1; high-resolution mass spectrum (FAB,
NBA) m/z 873.4981 [(M + Na)+; calcd for C46H82O6S2Si2Na, 873.4989].
Anal. Calcd for C46H82O6S2Si2: C, 64.89; H, 9.71. Found: C, 65.14;
H, 9.72.
Alcohols (+)-98 and (+)-99. Via the procedure described above
for the preparation of (-)-97, a solution of aldehyde (+)-59 (31 mg,
0.036 mmol) in 10% HMPA/THF (1.5 mL) was added to the lithio
derivative generated by the reaction of dithiane (+)-31 (C) (80 mg,
0.30 mmol), dissolved in 10% HMPA/THF (1.5 mL) with t-BuLi (1.0
M in pentane, 0.25 mL, 0.25 mmol). Work-up and flash chromatog-
raphy (hexanes/ethyl acetate, 10:1, containing 1% triethylamine)
furnished a mixture of (+)-98 and (+)-99 (26 mg, 65% yield). Radial
chromatography (silica; 1-mm layer, hexanes/ethyl acetate, 10:1) then
gave pure (+)-98 (14 mg, 35% yield) and (+)-99 (12 mg, 30% yield).
Dimethyl Acetal (+)-96. At ambient temperature a solution of
aldehyde (+)-66 (200 mg, 0.55 mmol) in methanol (6 mL) and trimethyl
orthoformate (6 mL) was treated with p-toluenesulfonic acid mono-
hydrate (20 mg, 0.11 mmol). The reaction mixture was stirred for 30
min, quenched with saturated aqueous Na2CO3 (5 mL), and partitioned
between ether (50 mL) and water (50 mL). The organic layer was
washed with water (20 mL) and brine (20 mL), dried over MgSO4,
filtered, and concentrated. Flash chromtography (hexanes/ethyl acetate,
20:1) afforded (+)-96 (202 mg, 90% yield) as a colorless oil: [R]D23
1
+2.8° (c 0.88, CHCl3); H NMR (500 MHz, CDCl3) δ 5.37 (d, J )
9.6 Hz, 1 H), 4.18 (d, J ) 6.7 Hz, 1 H), 4.01 (d, J ) 6.5 Hz, 1 H),
3.92 (d, J ) 6.7 Hz, 1 H), 3.42 (s, 3 H), 3.33 (s, 3 H), 2.88-2.76 (m,
5 H), 2.10-2.04 (m, 1 H), 1.86-1.77 (m, 1 H), 1.65 (d, J ) 1.3 Hz,
3 H), 1.13 (d, J ) 6.8 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 3 H), 0.01 (s,
3 H); 13C NMR (125 MHz, CDCl3) δ 135.8 (s), 130.2 (d), 106.2 (d),
79.0 (d), 55.6 (q), 54.6 (d), 54.0 (q), 37.4 (d), 30.8 (t), 30.5 (t), 26.1
(t), 25.8 (q), 18.2 (s), 18.0 (q), 12.3 (q), -4.8 (q), -4.9 (q); high-
resolution mass spectrum (CI, NH3) m/z 375.1858 [(M - OMe)+; calcd
for C18H35O2S2Si, 375.1848]. Anal. Calcd for C19H38O3S2Si, C, 56.11;
H, 9.42. Found: C, 56.27; H, 9.53.
(+)-98: white foam; [R]D23 +26° (c 0.37, CHCl3); IR (CHCl3) 3460
(w), 2960 (s), 2940 (s), 2880 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ
7.26 (d, J ) 8.7 Hz, 2 H), 6.83 (d, J ) 8.7 Hz, 2 H), 5.56 (d, J ) 9.7
Hz, 1 H), 4.64 (s, 1 H), 4.46 (ABq, JAB ) 10.5 Hz, ∆νAB ) 55.4 Hz,
2 H), 4.08 (d, J ) 5.8 Hz, 1 H), 3.91 (d, J ) 7.5 Hz, 1 H), 3.79 (s, 3
H), 3.78 (m, 1 H), 3.65 (d, J ) 4.8 Hz, 1 H), 3.55 (ddd, J ) 11.0, 8.4,
AB-Alkylated Dithiane (-)-97. Dithiane (+)-96 (200 mg, 0.49
mmol) was dried azeotropically with benzene (2 × 20 mL) and
dissolved in 10% HMPA/THF (4 mL). The solution was cooled to
-78 °C and treated with t-BuLi (1.6 M in pentane, 0.31 mL, 0.49
mmol). Iodide (-)-15 (A) (256 mg, 0.41 mmol), dried azeotropically

960 J. Am. Chem. Soc., Vol. 119, No. 5, 1997
Smith et al.
4.7 Hz, 1 H), 3.40 (s, 3 H), 3.37 (s, 6 H), 3.36 (m, 1 H), 3.14 (dd, J )
9.7, 7.0 Hz, 1 H), 3.03 (m, 1 H), 2.93-2.68 (m, 8 H), 2.44-2.40 (m,
2 H), 2.22 (m, 1 H), 2.07-1.73 (series of m, 12 H), 1.63 (d, J ) 0.9
Hz, 3 H), 1.43-1.15 (m, 5 H), 1.13 (d, J ) 6.8 Hz, 3 H), 1.12 (d, J )
6.9 Hz, 3 H), 1.08 (s, 21 H), 0.93 (d, J ) 6.9 Hz, 3 H), 0.91 (s, 9 H),
0.90 (d, J ) 6.7 Hz, 3 H), 0.77 (q, J ) 12.1 Hz, 1 H), 0.20 (s, 3 H),
0.06 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 158.9, 137.7, 131.5,
129.5, 128.8, 113.6, 109.5, 84.9, 80.2, 76.2, 75.6, 70.7, 62.9, 57.9, 57.6,
55.2, 54.7, 54.1, 39.8, 38.8, 37.9, 37.5, 36.4, 36.3, 35.2, 34.3, 33.5,
32.9, 31.7, 26.5, 26.2, 26.0, 25.2, 25.0, 18.2, 18.1 (2 C), 16.5, 16.0,
15.7, 14.7, 12.7, 11.3, -3.9, -4.5; high-resolution mass spectrum (FAB,
NBA) m/z 1137.6235 [(M + Na)+; calcd for C58H106O8S4Si2Na,
1137.6206].
(+)-99: white foam; [R]D23 +28° (c 0.42, CHCl3); IR (CHCl3) 3480
(w), 2960 (s), 2930 (s), 2860 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ
7.27 (d, J ) 8.6 Hz, 2 H), 6.83 (d, J ) 8.6 Hz, 2 H), 5.63 (d, J ) 9.9
Hz, 1 H), 4.57 (d, J ) 6.9 Hz, 1 H), 4.46 (ABq, JAB ) 10.5 Hz, ∆νAB
) 52.8 Hz, 2 H), 4.06 (m, 1 H), 4.05 (d, J ) 5.5 Hz, 1 H), 3.78 (s, 3
H), 3.64 (br d, J ) 5.1 Hz, 1 H), 3.55 (ddd, J ) 10.9, 8.5, 4.8 Hz, 1
H), 3.40 (s, 3 H), 3.35 (s, 3 H), 3.34 (s, 3 H), 3.26 (apparent t, J ) 9.7
Hz, 1 H), 3.15 (dd, J ) 9.7, 6.8 Hz, 1 H), 3.03 (m, 1 H), 2.91 (ddd, J
) 11.2, 8.3, 4.4 Hz, 1 H), 2.84-2.70 (series of m, 4 H), 2.68 (d, J )
4.0 Hz, 1 H), 2.63 (dt, J ) 13.7, 4.2 Hz, 1 H), 2.44 (apparent t, J )
6.6 Hz, 1 H), 2.20 (dd, J ) 12.0, 3.8 Hz, 1 H), 2.13-1.86 (series of
m, 7 H), 1.81 (quintet, J ) 6.4 Hz, 1 H), 1.74 (d, J ) 1.0 Hz, 3 H),
1.66-1.52 (m, 2 H), 1.35 (dq, J ) 11.4, 3.9 Hz, 1 H), 1.28 (d, J ) 6.8
Hz, 3 H), 1.25-1.02 (series of m, 6 H), 1.14 (d, J ) 6.9 Hz, 3 H),
1.08 (s, 21 H), 0.93 (d, J ) 6.6 Hz, 3 H), 0.92 (d, J ) 6.1 Hz, 3 H),
0.88 (s, 9 H), 0.78 (q, J ) 12.0 Hz, 1 H), 0.14 (s, 3 H), 0.04 (s, 3 H);
13C NMR (125 MHz, CDCl3) δ 158.9, 136.9, 131.6, 131.3, 129.4, 113.6,
108.9, 84.9, 82.0, 80.0, 78.3, 75.5, 70.7, 62.9, 57.6, 55.2, 54.9, 53.9,
39.7, 38.5, 38.0, 36.4, 36.3, 35.9, 35.3, 34.3, 33.5, 32.9, 31.7, 26.6,
26.5, 26.1, 26.0, 25.0, 24.8, 18.2, 18.1 (2 C), 17.9, 15.6, 15.0, 14.6,
12.7, 12.2, -4.2 (2 C); high-resolution mass spectrum (FAB, NBA)
m/z 1137.6239 [(M + Na)+; calcd for C58H106O8S4Si2Na, 1137.6206].
Anal. Calcd for C58H106O8S4Si2: C, 62.43; H, 9.57. Found: C, 62.65;
H, 9.54.
Methoxy-Alkylated Dithiane (+)-87. B. From (+)-99. At
ambient temperature a solution of alcohol (+)-99 (11 mg, 0.01 mmol)
in THF (0.3 mL) at ambient temperature was treated with sodium
hydride (60% oil dispersion; 4 mg, 0.1 mmol), 15-crown-5 (4 µL, 0.02
mmol), and methyl iodide (18 µL, 0.20 mmol). The reaction mixture
was stirred for 6 h and partitioned between ether (10 mL) and saturated
aqueous NH4Cl (10 mL). The organic phase was washed with saturated
aqueous Na2S2O3 (10 mL), water (10 mL), and brine (10 mL), dried
over MgSO4, filtered, and concentrated. Flash chromatography (hex-
anes/ethyl acetate, 10:1, containing 1% triethylamine) provided (+)-
87 (9.7 mg, 88% yield) identical to the material prepared from (+)-86.
Methoxy Aldehyde (+)-100. At ambient temperature a solution
of dimethyl acetal (+)-87 (15 mg, 0.013 mmol) in acetone (4 mL) was
treated with a catalytic amount of p-toluenesulfonic acid (ca. 1 mg).
The reaction mixture was stirred for 5 h and then partitioned between
ether (20 mL) and water (20 mL). The organic phase was washed
with water (10 mL), and brine (10 mL), dried over MgSO4, filtered,
and concentrated. Flash chromatography (hexanes/ethyl acetate, 10:
1) gave (+)-100 (14 mg, 97% yield) as a white foam: [R]2D3 +21° (c
0.23, CHCl3); IR (CHCl3) 1725 (m) cm-1; 1H NMR (500 MHz, CDCl3)
δ 9.58 (d, J ) 1.9 Hz, 1 H), 7.28 (d, J ) 8.6 Hz, 2 H), 6.83 (d, J )
8.6 Hz, 2 H), 5.52 (d, J ) 9.2 Hz, 1 H), 4.48 (ABq, JAB ) 10.4 Hz,
∆νAB ) 60.0 Hz, 2 H), 4.46 (d, J ) 5.3 Hz, 1 H), 3.80 (d, J ) 5.3 Hz,
1 H), 3.79 (s, 3 H), 3.71 (br d, J ) 6.8 Hz, 1 H), 3.59 (s, 3 H), 3.55
(ddd, J ) 10.9, 8.4, 4.7 Hz, 1 H), 3.40 (s, 3 H), 3.26 (dd, J ) 9.0, 6.7
Hz, 1 H), 3.20-3.15 (m, 2 H), 2.92 (ddd, J ) 11.3, 8.4, 4.5 Hz, 1 H),
2.88-2.82 (m, 2 H), 2.77-2.72 (m, 1 H), 2.64-2.57 (m, 3 H), 2.37-
2.30 (m, 2 H), 2.15 (apparent t, J ) 11.3 Hz, 1 H), 2.09 (br d, J )
12.0 Hz, 1 H), 2.04-1.82 (m, 6 H), 1.81 (s, 3 H), 1.79-1.60 (m, 2 H),
1.48-1.20 (m, 7 H), 1.19 (d, J ) 6.5 Hz, 3 H), 1.12 (d, J ) 6.9 Hz,
3 H), 1.08 (s, 21 H), 1.03 (d, J ) 7.0 Hz, 3 H), 0.92 (d, J ) 6.8 Hz,
3 H), 0.86 (s, 9 H), 0.78 (q, J ) 12.0 Hz, 1 H), 0.08 (s, 3 H), 0.03 (s,
3 H); 13C NMR (125 MHz, CDCl3) δ 205.3, 158.9, 136.0, 131.6, 131.0,
129.6, 113.5, 92.1, 84.9, 81.4, 79.9, 75.6, 70.5, 62.4, 62.0, 57.6, 55.3,
44.4, 39.7, 38.1, 37.1, 36.3, 36.0, 34.3, 33.5, 33.0, 31.7, 27.5, 27.2,
26.4, 26.2, 26.1, 25.0, 24.4, 18.2, 18.1 (2 C), 16.4, 16.0, 15.2, 14.6,
13.1, 12.7, -4.3, -4.4; high-resolution mass spectrum (FAB, NBA)
m/z 1105.5922 [(M + Na)+; calcd for C57H102O7S4Si2Na, 1105.5945].
Anal. Calcd for C57H102O7S4Si2: C, 63.17; H, 9.48. Found: C, 63.47;
H, 9.60.
Methoxy Vinylidene Dibromide (+)-102. A solution of carbon
tetrabromide (215 mg, 0.65 mmol) in THF (10 mL) was cooled to -25
°C, and hexamethylphosphortriamide (HMPT) (0.24 mL, 1.3 mmol)
was added. After 5 min the yellow heterogeneous mixture turned beige.
A solution of aldehyde (+)-100 and its C(27) epimer (1:1 mixture,
140 mg, 0.13 mmol) in THF (3 mL) was then introduced via a cannula.
The reaction mixture was stirred for 30 min further, quenched with
saturated aqueous NaHCO3 (10 mL), and extracted with ether (30 mL).
The organic layer was washed with saturated aqueous Na2S2O3 (10
mL), water (10 mL), and brine, dried over MgSO4, filtered, and
concentrated. A second reaction was performed on the same scale,
and the combined products were purified by flash chromatography
(hexanes/ethyl acetate, 10:1), furnishing a 1:1 mixture of (+)-102 and
its C(27) epimer (250 mg, 78% total yield) as a white foam. Radial
chromatography (silica; 2-mm layer, hexanes/ether, 10:1) afforded (+)-
102 (120 mg, 36%) as a white foam: [R]2D3 +12° (c 0.40, CHCl3); IR
1
(CHCl3) 2980 (s), 2930 (s), 2860 (s), 1720 (w) cm-1; H NMR (500
MHz, CDCl3) δ 7.28 (d, J ) 8.6 Hz, 2 H), 6.82 (d, J ) 8.6 Hz, 2 H),
6.17 (d, J ) 9.4 Hz, 1 H), 5.57 (d, J ) 9.4 Hz, 1 H), 4.49 (ABq, JAB
) 10.5 Hz, ∆νAB ) 67.3 Hz, 2 H), 4.37 (d, J ) 5.8 Hz, 1 H), 3.78 (s,
3 H), 3.72 (br d, J ) 4.6 Hz, 1 H), 3.64 (d, J ) 6.9 Hz, 1 H), 3.58-
3.52 (m, 2 H), 3.55 (s, 3 H), 3.40 (s, 3 H), 3.26 (dd, J ) 8.1, 7.1 Hz,
1 H), 3.12 (apparent t, J ) 10.0 Hz, 1 H), 3.04 (apparent t, J ) 10.0
Hz, 1 H), 2.92 (ddd, J ) 11.0, 7.8, 4.8 Hz, 1 H), 2.86-2.77 (m, 3 H),
2.69-2.52 (m, 4 H), 2.23 (br m, 1 H), 2.09-2.05 (m, 2 H), 1.97-1.81
(m, 5 H), 1.86 (d, J ) 14.4 Hz, 2 H), 1.78 (s, 3 H), 1.72 (d, J ) 15.4
Hz, 1 H), 1.65 (d, J ) 13.1 Hz, 1 H), 1.43-1.31 (m, 3 H), 1.24 (d, J
) 6.7 Hz, 3 H), 1.23-1.16 (m, 2 H), 1.15 (d, J ) 6.8 Hz, 3 H), 1.08
(s, 21 H), 1.04 (d, J ) 6.7 Hz, 3 H), 0.91 (d, J ) 6.8 Hz, 3 H), 0.89
(s, 9 H), 0.77 (q, J ) 12.1 Hz, 1 H), 0.11 (s, 3 H), 0.05 (s, 3 H); 13C
NMR (125 MHz, CDCl3) δ 158.9, 144.1, 135.9, 131.6, 130.9, 129.8,
129.5, 113.5, 90.2, 88.2, 84.9, 81.7, 80.2, 75.6, 70.7, 62.8, 61.8, 57.9,
57.6, 55.2, 39.7, 38.8, 37.5, 37.0, 36.4, 36.3, 34.3, 33.5, 33.1, 31.7,
27.4, 26.8, 26.5, 26.3, 26.1, 25.0, 24.4, 20.5, 18.3, 18.1 (2 C), 16.5,
16.2, 14.7, 12.7, -4.1, -4.3. Anal. Calcd for C58H102Br2O6S4Si2: C,
56.20; H, 8.29. Found: C, 55.81; H, 8.04.
Methoxy Alkyne (+)-104. A solution of vinylidene dibromide (+)-
102 (103 mg, 0.83 mmol) in THF (5 mL) was cooled to -78 °C and
treated dropwise with n-BuLi (1.6 M in hexanes, 0.25 mL, 0.40 mmol).
The reaction mixture was stirred for 5 min further, quenched with
saturated aqueous NH4Cl (5 mL), and extracted with ether (30 mL).
The organic phase was washed with water (10 mL), and brine (10 mL),
dried over MgSO4, filtered, and concentrated. Flash chromatography
with (hexanes/ethyl acetate, 15:1) gave (+)-104 (81 mg, 90% yield)
as a white foam: [R]2D3 +19° (c 0.51, CHCl3); IR (CHCl3) 3300 (w)
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.29 (d, J ) 8.5 Hz, 2 H), 6.83
(d, J ) 8.5 Hz, 2 H), 5.65 (d, J ) 8.9 Hz, 1 H), 4.49 (ABq, JAB ) 10.6
Hz, ∆νAB ) 79.1 Hz, 2 H), 4.46 (d, J ) 4.0 Hz, 1 H), 3.90 (d, J ) 4.0
Hz, 1 H), 3.79 (s, 3 H), 3.69 (d, J ) 4.5 Hz, 1 H), 3.66 (s, 3 H), 3.55
(ddd, J ) 10.9, 8.3, 2.6 Hz, 1 H), 3.40 (s, 3 H), 3.32-3.20 (m, 3 H),
2.92 (ddd, J ) 12.6, 8.4, 4.4 Hz, 1 H), 2.87-2.76 (m, 3 H), 2.65-
2.61 (m, 2 H), 2.57-2.45 (m, 3 H), 2.24 (d, J ) 2.2 Hz, 1 H), 2.08-
1.91 (m, 8 H), 1.85 (s, 3 H), 1.79 (d, J ) 14.9 Hz, 2 H), 1.70 (m, 1 H),
1.64 (m, 2 H), 1.56-1.25 (series of m, 4 H), 1.23 (d, J ) 6.5 Hz, 3
H), 1.19 (d, J ) 6.8 Hz, 3 H), 1.10 (d, J ) 7.0 Hz, 3 H), 1.08 (s, 21
H), 0.89 (s, 9 H), 0.88 (d, J ) 6.8 Hz, 3 H), 0.76 (q, J ) 12.0 Hz, 1
H), 0.11 (s, 3 H), 0.03 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 158.8,
136.3, 131.6, 130.7, 129.6, 113.4, 96.5, 87.8, 84.9, 80.3, 80.0, 75.6,
70.7, 70.5, 62.1, 60.7, 57.7, 57.5, 55.2, 39.7, 38.1, 38.0, 37.4, 36.3,
36.2, 34.3, 33.5, 33.1, 31.7, 27.5, 26.5, 26.2, 26.1, 25.0, 24.5, 24.1,
22.0, 18.1 (2 C), 15.7, 15.5, 14.6, 14.1, 13.2, 12.8, -4.1, -4.3; high-
resolution mass spectrum (FAB, NBA) m/z 1101.5985 [(M + Na)+;
calcd for C58H102O6S4Si2Na, 1101.5996]. Anal. Calcd for
C58H102O6S4Si2: C, 64.51; H, 9.52. Found: C, 64.89; H, 9.66.
Methoxy Alcohol (+)-106. A solution of PMB ether (+)-104 (31
mg, 0.03 mmol) in dichloromethane (4 mL) was treated with water
(0.2 mL) and the biphasic mixture cooled to 0 °C. DDQ (7 mg, 0.03

Construction of C(21-42) Perimeters in Immunomodulators
J. Am. Chem. Soc., Vol. 119, No. 5, 1997 961
mmol) was added portionwise over 5 min. The yellow-brown reaction
mixture was stirred at 0 °C for 30 min and then directly subjected to
flash chromatography (hexanes/ethyl acetate, 6:1), affording (+)-106
(26 mg, 94% yield) as a white foam: [R]2D3 +9.1° (c 0.64, CHCl3); IR
mass spectrum (FAB, NBA) m/z 801.5491 [(M + Na)+; calcd for
C44H82O7Si2Na, 801.5496].
Methoxy ABC Vinylstananne (-)-27. A solution of alkyne (-)-
108 (7.5 mg, 10 µmol) and bis(triphenylphosphine)palladium(II)
dichloride (1 mg, 20 mol %) in THF (1.5 mL) was cooled to 0 °C, and
tri(n-butyl)tin hydride (13 µL, 50 µmol) was added dropwise. After 5
min, the reaction mixture was directly subjected to flash chromatography
(hexanes/ethyl acetate, 10:1, containing 1% triethylamine). The
resultant impure stannane was rechromatographed (hexanes/ethyl
acetate, 10:1, containing 1% triethylamine), affording (-)-27 (9.4 mg,
91% yield) as a colorless oil: [R]2D3 -62° (c 0.56, CHCl3); IR (CHCl3)
1710 (m) cm-1; 1H NMR (500 MHz, C6D6) δ 6.07 (d, J ) 19.0 Hz, 1
H), 5.96 (dd, J ) 19.0, 7.5 Hz, 1 H), 5.34 (d, J ) 9.4 Hz, 1 H), 4.49
(d, J ) 6.9 Hz, 1 H), 3.97 (m, 1 H), 3.88 (d, J ) 7.0 Hz, 1 H), 3.66
(ddd, J ) 11.1, 6.2, 4.1 Hz, 1 H), 3.29 (s, 3 H), 3.28-3.20 (m, 2 H),
3.20 (s, 3 H), 2.93-2.87 (m, 3 H), 2.52 (dd, J ) 17.2, 2.3 Hz, 1 H),
2.42 (dd, J ) 17.2, 9.8 Hz, 1 H), 2.31 (m, 1 H), 2.14 (m, 1 H), 1.96
(dq, J ) 12.9, 3.5 Hz, 1 H), 1.85 (ddd, J ) 13.8, 8.4, 4.3 Hz, 1 H),
1.72 (d, J ) 1.3 Hz, 3 H), 1.67-1.51 (m, 9 H), 1.44-1.26 (m, 10 H),
1.24-1.15 (complex series of m, 36 H), 1.14 (d, J ) 6.6 Hz, 3 H),
1.12 (d, J ) 6.4 Hz, 3 H), 1.05-0.89 (m, 6 H), 0.95 (s, 9 H), 0.77 (q,
J ) 12.0 Hz, 1 H), 0.11 (s, 3 H), 0.03 (s, 3 H); 13C NMR (125 MHz,
C6D6) δ 211.6, 211.1, 154.5, 137.8, 128.5, 126.8, 85.6, 85.0, 78.4, 75.9,
71.9, 58.0, 56.9, 47.1, 44.1, 42.6, 39.7, 39.5, 38.9, 36.0, 35.9, 34.7,
33.7, 32.3, 29.6, 27.6, 26.1, 21.5, 18.5, 18.4, 15.8, 15.3, 13.9, 13.1,
12.4, 9.8, -4.3, -4.7; high-resolution mass spectrum (FAB, NBA) m/z
1093.6736 [(M + Na)+; calcd for C56H110O7Si2SnNa, 1093.6709].
1
(CHCl3) 3620 (w), 3440 (br), 3310 (w) cm-1; H NMR (500 MHz,
CDCl3) δ 5.77 (d, J ) 9.7 Hz, 1 H), 4.49 (d, J ) 3.3 Hz, 1 H), 3.95
(d, J ) 3.3 Hz, 1 H), 3.86 (m, 1 H), 3.68 (s, 3 H), 3.54 (ddd, J ) 12.3,
8.5, 3.6 Hz, 1 H), 3.45 (br s, 1 H), 3.39 (s, 3 H), 3.31 (apparent t, J )
11.0 Hz, 1 H), 3.22 (br t, J ) 10.9 Hz, 1 H), 3.14 (ddd, J ) 7.4, 7.0,
7.0 Hz, 1 H), 2.97-2.83 (m, 3 H), 2.77-2.70 (m, 2 H), 2.65 (dt, J )
13.5, 4.2 Hz, 1 H), 2.58-2.54 (m, 2 H), 2.43 (ddd, J ) 9.8, 6.6, 6.6
Hz, 1 H), 2.32 (d, J ) 1.8 Hz, 1 H), 2.21 (dd, J ) 15.4, 9.3 Hz, 1 H),
2.11 (br d, J ) 9.5 Hz, 1 H), 2.06 (d, J ) 15.4 Hz, 1 H), 2.03-1.97
(m, 2 H), 1.93-1.88 (m, 2 H), 1.84 (s, 3 H), 1.81 (m, 1 H), 1.69-1.62
(m, 3 H), 1.57 (d, J ) 2.5 Hz, 1 H), 1.52 (dt, J ) 12.2, 4.2 Hz, 1 H),
1.43-1.29 (m, 4 H), 1.27 (d, J ) 6.5 Hz, 3 H), 1.22 (d, J ) 7.3 Hz,
3 H), 1.11 (d, J ) 7.0 Hz, 3 H), 1.07 (s, 21 H), 0.94 (d, J ) 6.8 Hz,
3 H), 0.90 (s, 9 H), 0.73 (q, J ) 12.0 Hz, 1 H), 0.12 (s, 3 H), 0.04 (s,
3 H); 13C NMR (125 MHz, CDCl3) δ 137.7, 130.2, 87.8, 84.9, 79.9,
75.6, 72.4, 70.6, 65.8, 62.3, 60.3, 57.8, 57.4, 39.0, 38.8, 38.7, 37.5,
36.8, 35.9, 34.3, 33.4, 32.1, 28.3, 27.5, 26.3, 26.0, 24.8, 24.5, 24.1,
22.0, 18.1 (2 C), 15.5, 15.1, 13.3, 12.7, -4.1, -4.3; high-resolution
mass spectrum (CI, NH3) m/z 981.5415 [(M + Na)+; calcd for
C50H94O5S4Si2Na, 981.5421].
Methoxy Aldol (-)-108. A solution of dithiane (+)-106 (9.9 mg,
0.01 mmol) in THF/MeOH/H2O (10:9:1, 2 mL) was cooled to 0 °C
and treated with PhI(O2CCF3)2 (21 mg, 0.05 mmol). After 30 min,
the reaction was quenched with saturated aqueous NaHCO3 (2 mL),
and the resultant mixture was partitioned between ether (10 mL) and
water (5 mL). The organic phase was washed with saturated aqueous
Na2S2O3 (5 mL), water (5 mL), and brine (5 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (hexanes/ethyl
acetate, 6:1) gave (-)-108 (6.9 mg, 86% yield) as a colorless oil:
[R]2D3 -106° (c 0.53, CHCl3); IR (CHCl3) 3680 (w), 3510 (br), 3310
Acknowledgment. Financial support was provided by the
National Institutes of Health (Institute of General Medical
Sciences) through Grant GM-29028. S.M.C., J.A.M., J.L.L., and
R.E.M. gratefully acknowledge a Carolyn Hoff Lynch Graduate
Fellowship, a University of Pennsylvania School of Arts and
Sciences Dissertation Fellowship, a Merck Type II Fellowship,
and an American Cancer Society Postdoctoral Fellowship,
respectively. In addition, we thank Drs. George T. Furst and
Patrick J. Carroll and Mr. John Dykins of the University of
Pennsylvania Spectroscopic Service Center for assistance in
securing and interpreting high-field NMR spectra, X-ray crystal
structures, and mass spectra, respectively.
1
(w), 1720 (m) cm-1; H NMR (500 MHz, CDCl3) δ 5.32 (d, J ) 9.9
Hz, 1 H), 4.24 (d, J ) 7.0 Hz, 1 H), 3.93 (d, J ) 7.0 Hz, 1 H), 3.84
(m, 1 H), 3.53 (ddd, J ) 11.0, 8.4, 4.8 Hz, 1 H), 3.41 (dd, J ) 9.7, 6.8
Hz, 1 H), 3.38 (s, 3 H), 3.29 (s, 3 H), 3.11 (ddd, J ) 11.0, 6.7, 3.1 Hz,
1 H), 2.95 (d, J ) 4.1 Hz, 1 H), 2.90 (ddd, J ) 11.2, 7.4, 4.5 Hz, 1 H),
2.58 (dd, J ) 17.4, 2.2 Hz, 1 H), 2.56 (m, 1 H), 2.46 (dd, J ) 17.4,
9.9 Hz, 1 H), 2.09 (d, J ) 2.4 Hz, 1 H), 2.07 (m, 1 H), 1.91 (dq, J )
13.1, 4.7 Hz, 1 H), 1.77-1.71 (m, 1 H), 1.75 (d, J ) 1.3 Hz, 3 H),
1.67-1.58 (m, 2 H), 1.36-1.13 (m, 4 H), 1.23 (d, J ) 6.8 Hz, 3 H),
1.15 (d, J ) 6.8 Hz, 3 H), 1.08 (d, J ) 6.6 Hz, 3 H), 1.07 (s, 21 H),
0.98-0.88 (m, 2 H), 0.87 (d, J ) 6.8 Hz, 3 H), 0.85 (s, 9 H), 0.69 (q,
J ) 11.6 Hz, 1 H), 0.01 (s, 3 H), -0.02 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 212.8 (s), 212.6 (s), 137.8 (s), 127.9 (d), 87.5 (d), 84.9 (d),
84.8 (d), 78.7 (d), 75.5 (d), 71.7 (d), 69.4 (s), 58.1 (q), 57.4 (q), 46.9
(d), 43.5 (t), 42.9 (d), 39.0 (t), 38.7 (t), 35.7 (t), 35.4 (d), 34.3 (t), 33.3
(d), 32.0 (t), 25.8 (q), 23.7 (d), 21.5 (q), 18.1 (s), 18.1 (q), 15.6 (q),
15.3 (q), 14.0 (q), 12.7 (d), 12.2 (q), -4.6 (q), -5.0 (q); high-resolution
Supporting Information Available: Experimental proce-
dures and characterization data for 10, 12, 16, 19-25, 41-44,
49-53, 56-58, 60-67, 69-77, 79-83, 88, 90-93, 95, 101,
103, 105, 107, 109, and 28 and X-ray data for (+)-66 and (+)-
70 (51 pages). See any current masthead page for ordering and
Internet access instructions.
JA963066W