Synthesis of the tricarbonyl subunit (C8-C19) of rapamycin via tandem chan rearrangement-oxidation

Full text of DOI:10.1021/jo960176c

2600
J . Org. Chem. 1996, 61, 2600-2601
Sch em e 1
Syn th esis of th e Tr ica r bon yl Su bu n it
(C8-C19) of Ra p a m ycin via Ta n d em Ch a n
Rea r r a n gem en t-Oxid a tion
J ames D. White* and Scott C. J effrey
Department of Chemistry, Oregon State University,
Corvallis, Oregon 97331
Received J anuary 29, 1996
The base-induced rearrangement of R-(acyloxy)acetates
1 to R-hydroxy-â-keto esters 4 (Chan rearrangement1
)
is a convenient means for assembling an array of three
contiguous oxygenated carbons. This transformation
played a pivotal role in our routes to aplasmomycin2 and
boromycin,3 but otherwise it has been rarely featured in
natural product synthesis.4 The rearrangement is be-
lieved to proceed via epoxide 2 which subsequently
undergoes fragmentation to 3. Further deprotonation of
this species yields an enediolate 5 which can be trapped
as the bis-silyl ether 6. In principle, oxidation of Chan
products 4 or 6 could afford a 1,2,3-tricarbonyl system,
a subunit present in masked form in the important
immunosuppressant rapamycin (7);5 we now report an
effective means for realizing this construction.6 Specif-
ically, we describe a synthesis of the C8-C19 subunit of
7 via a tandem process involving rearrangement of an
R-(acyloxy)acetate to an enediolate followed by oxidation
of the derived bis-silyl ether with peracid.
Sch em e 2
D-(+)-Xylose (8) was converted via its bis acetonide7
to 9, which was selectively protected as pivalate 10.8
The residual hydroxyl substituent was removed by
(1) Lee, S. D.; Chan, T. H.; Kwon, K. S. Tetrahedron Lett. 1984, 3399.
(2) White, J . D., Vedananda, T. R.; Kang, M.-c.; Choudhry, S. C. J .
Am. Chem. Soc. 1986, 108, 8105.
(3) White, J . D.; Avery, M. A.; Choudhry, S. C.; Dhingra, O. P.; Gray,
B. D.; Kang, M.-c.; Kuo, S.-c.; Whittle, A. J . J . Am. Chem. Soc. 1989,
111, 790.
reduction of xanthate 11 to give 12,9 and hydrolysis of
this tetrahydrofuran derivative in the presence of excess
ethanethiol yielded thioacetal 13.10 After protection of
the diol moiety as its cyclohexylidene derivative 14,11 the
thioacetal was hydrolyzed to afford the unstable aldehyde
1512 (Scheme 1).
(4) However, for a recent example, see: Holton R. A. et al. J . Am.
Chem. Soc. 1994, 116, 1597.
(5) Total syntheses: (a) Nicolaou, K. C.; Chakraborty, T. K.; Piscopio,
A. D.; Minowa, N.; Bertinato, P. J . Am. Chem. Soc. 1993, 115, 4419.
(b) Romo, D.; Meyer, S. D.; J ohnson, D. D.; Schreiber, S. L. J . Am.
Chem. Soc. 1993, 115, 7906. (c) Hayward, C. M.; Yohannes, D.;
Danishefsky, S. J . J . Am. Chem. Soc. 1993, 115, 9345. (d) Smith, A.
B., III; Condon, S. M.; McCauley, J . A.; Leazer, J . L., J r.; Leahy, J .
W.; Maleczka, R. E., J r. J . Am. Chem. Soc. 1995, 117, 5407.
In situ silylation of the ylide prepared from 16,13
followed by coupling with 15, produced cis-olefin 17 which
was immediately deblocked to yield 18.14 Reduction of
this alkene with diimide15 gave 19, and the alcohol was
oxidized with Dess-Martin periodinane16 to 20. Acidic
0022-3263/96/1961-2600$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 8, 1996 2601
Sch em e 3
methanolysis of 20 yielded a cyclic methyl acetal as a
mixture of anomers (â:R ) 2:1) that, after treatment with
diazomethane in the presence of boron trifluoride ether-
ate,17 afforded methyl ether 21. The pivalate was cleaved
reductively, and the resulting alcohol was oxidized16 to
22. This aldehyde was transformed to ketone 23 using
methyllithium-cerium trichloride18 followed by oxida-
tion,16 after hydrolysis-oxidation, 23 was converted to a
single δ-lactone (24, Scheme 2). Comparison of this
substance with material obtained independently by Ley
and co-workers19 established that the two compounds
were identical and thus confirmed the configurational
assignments made to 24.
alcohol 27 was obtained pure after chromatography.
Exposure of 27 to 1,3-propanedithiol in the presence of
a Lewis acid22 yielded dithiane 28 which was then
protected as its bis silyl ether 29.23 Removal of the
dithiane24 furnished aldehyde 30, and this was oxidized25
to carboxylic acid 31. Coupling of the potassium salt of
31 with methyl bromoacetate gave 32 which underwent
Chan rearrangement with excess LDA followed by sily-
lation of the intermediate enediolate to afford 33 as a
single isomer that was unstable to chromatography on
silica. Oxidation of this substance with m-chloroperben-
zoic acid in hexanes led directly to 34, presumably via
rearrangement of an intermediate epoxide,26 in 29%
isolated yield from 32. Final removal of the four silyl
ethers in methanol over an acidic resin produced cyclic
ketal 3527 as a single anomer (Scheme 3).
Condensation of 23 with the anion of phosphonate 2520
gave a 14:1 mixture of (E)-R,â-unsaturated ester 26 and
its (Z) isomer. The mixture was reduced,21 and (E)-
In summary, the chemistry outlined in Schemes 1-3
defines a new route to a key segment of rapamycin.
Improvement of the Chan rearrangement-oxidation28 of
32 and incorporation of this sequence into a total
synthesis of 7 will be the subject of further studies.
(6) Approaches to the tricarbonyl segment of rapamycin and FK-
506: (a) Kocienski, P.; Stocks, M.; Donald, D.; Cooper, M.; Manners,
A. Tetrahedron Lett. 1988, 29, 4481. (b) Williams, D. R.; Benbow, J .
W. J . Org. Chem. 1988, 53, 4643. (c) Egbertson, M.; Danishefsky, S. J .
J . Org. Chem. 1989, 54, 11. (d) Wasserman, H. H.; Rotello, V. M.;
Williams, D. R.; Benbow, J . W. J . Org. Chem. 1989, 54, 2785. (e) Rama
Rao, A. V.; Chakraborty, T. K.; Laxma Reddy, K. Tetrahedron Lett.
1990, 31, 1439. (f) Linde, R. G., II; J eroncic, L. O.; Danishefsky, S. J .
J . Org. Chem. 1991, 56, 2534. (g) Hoffman, R. V.; Huizenga, D. J . J .
Org. Chem. 1991, 56, 6435. (h) Batchelor, M. J .; Gillespie, R. J .; Golec,
J . M. C.; Hedgecock, C. J . R. Tetrahedron Lett. 1993, 34, 167. (i)
Pattenden, G.; Tankard, M. Tetrahedron Lett. 1993, 34, 2677. (j) Rama
Rao, A. V.; Desibhatla, V. Tetrahedron Lett. 1993, 34, 7111.
(7) Matsuda, F.; Terashima, S. Tetrahedron 1988, 44, 4721.
(8) (a) Greene, T. W.; Wuts, P. G. Protective Groups in Organic
Synthesis; Wiley-Interscience: New York, 1991. (b) Schuda, P. F.;
Heimann, M. R. Tetrahedron Lett. 1983, 24, 4267.
Ack n ow led gm en t. We are indebted to Professor
Steven Ley and Michael Willis, Cambridge University,
1
for H and 13C NMR spectra of 24. This research was
assisted financially by the National Institutes of Health
through Grant No. GM50574.
Su p p or tin g In for m a tion Ava ila ble: Preparative proce-
dures and characterization data for all new compounds (21
pages).
J O960176C
(9) Nicolaou, K. C.; Daines, R. A.; Uenishi, J .; Li, W. S.; Papahatjis,
D. P.; Chakraborty, T. K. J . Am. Chem. Soc. 1988, 110, 4672.
(10) Zinner, H.; Brandner, H.; Rembarz, G. Chem. Ber. 1956, 89,
800.
(21) Wilson, K. E.; Seidner, R. T.; Masamune, S. J . Chem. Soc.,
Chem. Commun. 1970, 213.
(11) White, J . D.; Engebrecht, J . R.; Theramongkol, P.; Kuroda, C.
J . Org. Chem. 1986, 51, 956.
(12) Corey, E. J .; Erickson, B. W. J . Org. Chem. 1971, 36, 3553.
(13) Kozikowski, A. P.; Chen, Y.-Y. Tetrahedron 1984, 40, 2345.
(14) White, J . D.; Amedio, J . C.; Gut, S.; J ayasinghe, L. J . Org.
Chem. 1989, 54, 4268.
(15) Hamersma, J . W.; Snyder, E. I. J . Org. Chem. 1965, 30, 3985.
(16) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.
(17) White, J . D.; Toske, S. G.; Yakura, T. Synlett 1994, 591.
(18) Imamoto, T.; Sugiura, Y.; Takijama, N. Tetrahedron Lett. 1984,
25, 4233.
(19) Ley, S. V.; Norman, J .; Pinel, C. Tetrahedron Lett. 1994, 35,
2095.
(22) Honda, Y.; Ori, A.; Tsuchihashi, G.-i. Chem. Lett. 1987, 1259.
(23) Corey, E. J .; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455.
(24) Takano, S.; Hatakeyama, S.; Ogasawara, K. J . Chem. Soc.,
Chem. Commun. 1977, 68.
(25) Dalcanale, E.; Montanari, F. J . Org. Chem. 1986, 51, 567.
(26) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron
Lett. 1974, 4319.
(27) Corey, E. J .; Ponder, J . W.; Urlich, P. Tetrahedron Lett. 1980,
21, 137.
(28) Chan rearrangement of 32 to 33 is accompanied by the
formation of carboxylic acid 31, particularly when bases other than
LDA are employed. Although the epoxidation of 33 takes place in high
yield, major losses are incurred in the purification of 34 by chroma-
tography on silica.
(20) Wadsworth, W. S.; Emmons, W. D. J . Am. Chem. Soc. 1961,
83, 1733.