2756 J . Org. Chem., Vol. 66, No. 8, 2001
Panek and J ain
palladium(0) cross-coupling methodology (Stille coupling)
could then be carried out. In individual procedures, a
solution containing the spiroketal fragments bearing
vinylstannanes 3a and 3b and polypropionate fragment
4 in DMF, Pd(CH3CN)2Cl2 was added at 0 °C and stirred
for 15 min. After workup, the mixture yielded the
protected seco acids 46 and 47, respectively, which were
immediately subjected to macrolactonization. The most
effective procedures for cyclization of the seco acid was
carried out using the Yamaguchi36 and Yonemitsu37
procedures. Accordingly, the seco acids were treated with
DMAP, Et3N, and trichlorobenzoyl chloride in dry ben-
zene and was stirred at ambient temperature for 48 h
affording the macrocyclic lactones 50 and 51 in 45% and
47% yield, respectively. Final deprotection of the mac-
rocyclic lactones with HF/CH3CN38 completed the total
syntheses of rutamycin B (1) and oligomycin C (2),
respectively.
Our objectives in the design and excecution of the
synthesis of these macrolide antibiotics were to demon-
strate (i) the reliability of our chiral silane reagents in
the synthesis of polypropionate-like subunits and (ii) the
use of mild transition-metal-catalyzed cross coupling
strategies for the union of these subunits and principal
fragments. The reliable and flexible nature of the chiral
silane reagents have facilitated the subunit assembly and
subsequent coupling and as such one can imagine other
members of this class of natural products may be ac-
cessed in similar convergent approachs.
Ack n ow led gm en t. We are grateful to Ms. J . V.
Schaus (Boston University), Professor D. A. Evans, and
Drs. A. S. Kim, J . L. Duffy, M. Dart, and M. Yang
(Harvard University) for helpful discussions. Financial
support was obtained from the NIH (GM55740).
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental procedures and spectral data for all compounds includ-
ing the preparation of aldehydes 9 and 39. Stereochemical
correlation of intermediates 27, 29, and 33 is also described.
Except for the slightly lower [R]23 of rutamycin B (1),
D
the spectroscopic properties of 1 and 2 were identical in
all respects (1H, 13CNMR, [R]23D, MS, (HRMS) with those
previously reported; for rutamycin B ([R]23 ) -61.0 (c
1
For comparison, this section also contains a table of H and
D
13C NMR assignments between natural and synthetic ruta-
mycin B and oligomycin C. This material is available free of
) 0.01 CHCl3); lit.7 [R]23 ) -70.0 (c ) 1.22, CHCl3); for
D
oligomycin C [R]23D ) -82.7 (c ) 0.15, dioxane); lit.4 [R]23
) -80.7 (c ) 3.7, dioxane).
D
The total synthesis of rutamycin B and oligomycin C
has been completed in 43 and 44 steps, respectively,
using chiral silane-based bond construction methods for
the introduction of the majority of the stereogenic centers.
From a historical perspective, synthetic programs aimed
at the stereocontrolled synthesis of polypropionate de-
rived macrolide natural products were based on applica-
tions of two methodologies of great significance in syn-
thetic chemistry: the use of conformationally biased ring
systems as templates for the assembly of contiguous
arrays of stereocenters, as exemplified in Woodward’s
synthesis of erythromycin B39 as well as in the total
synthesis of erythronolide B by Corey40 and (+)-9S-
dihydroerythronolide A by Stork.41 Subsequently the
application of chiral metal enolate based aldol (or aldol
surrogoates) methodology was used to assemble propi-
onate subunits.42 The application of chiral silane-based
methodology represents a complementary approach to
these complex macrolides while underscoring the opera-
tional ease of the crotylation experiments.
J O001767C
(39) (a) Woodward, R. B.; Logush, E.; Nambiar, K. P.; Sakan, K.;
Ward, D. E.; Au-Yeung, B.-W.; Balaram, P.; Browne, L. J .; Card, P.
J .; Chen, C. H.; Cheˆnevert, R. B.; Fliri, A.; Frobel, K.; Gais, H.-J .;
Garratt, D. G.; Hayakawa, K.; Heggie, W.; Hesson, S. P.; Hoppe, D.;
Hoppe, I.; Hyatt, J . A.; Ikeda, D.; J acobi, P. A.; Kim, K. S.; Kobuke,
Y.; Kojima, K.; Krowicki, K.; Lee, V. J .; Leutert, T.; Malchenko, S.;
Martens, J .; Matthews, R. S.; Ong, B. S.; Press: J . B.; Rajan Babu, T.
V.; Rousseau, G.; Sauter, H. M.; Suzuki, M.; Tatsuta, K.; Tolbert, L.
M.; Truesdale, E. A.; Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella, A. T.;
Vladuchick, W. C.; Wade, P. A.; Williams, R. M.; Wong, H. N.-C. J .
Am. Chem. Soc. 1981, 103, 3211-3213. (b) Woodward, R. B.; et al. J .
Am. Chem. Soc. 1981, 103, 3213-3215. (c) Woodward, R. B.; et al. J .
Am. Chem. Soc. 1981, 103, 3215-3217.
(40) (a) Corey, E. J .; Trybulski, E. J .; Melvin, L. S., J r; Nicolaou, K.
C.; Secrist, J . A.; Lett, R.; Sheldrake, P. W.; Falck, J . R.; Brunelle, D.
J .; Haslanger, M. F.; Kim, S.; Yoo, S. J . Am. Chem. Soc. 1978, 100,
4618-4619. (b) Corey, E. J .; Kim, S.; Yoo, S.; Nicolaou, K. C.; Melvin,
L. S., J r.; Brunelle, D. J .; Falck, J . R.; Trybulski, E. J .; Lett, R.;
Sheldrake, P. W. J . Am. Chem. Soc. 1978, 100, 4620-4621.
(41) (a) Stork, G.; Rychnovsky, S. D. J . Am. Chem. 1987, 109, 1564-
1565. (b) Stork, G.; Rychnovsky, S. D. J . Am. Chem. 1987, 109, 1565-
1567.
(42) Selected examples: (a) X-206: Evans, D. A.; Bender, S. L.;
Morris, J . J . Am. Chem. Soc. 1988, 110, 2506-2526. (b) Cytovaricin:
Evans, D. A.; Kaldor, S. W.; J ones, T. K.; Clardy, J .; Stout, T. J . J .
Am. Chem. Soc. 1990, 112, 7001-7031. (c) Oleandolide: Paterson, I.;
Norcross, R. D.; Ward, R. A.; Remea, P.; Lister, M. A. J . Am. Chem.
Soc. 1994, 116, 12287-12314. (d) (-)-Calyculin A: Tanimoto, N.;
Gerritz, S. W.; Sawbe, A.; Noda, T.; Filla, S. A.; Masamune, S. Angew.
Chem., Int. Ed. Engl. 1994, 33, 673-675. (e) Rifamycin ansa chain:
Roush, W. R.; Palkowitz, D. A.; Ando, K. A.; J . Am. Chem. Soc. 1990,
112, 6348-6349.
(36) Inanagana, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(37) (a) Hikota, M.; Sakurai, Y.; Horita, K.; Yonemitsu, O. Tetra-
hedron Lett. 1990, 31, 6367-6370. (b) Hikota, M.; Tone, H.; Horita,
K.; Yonemitsu, O. J . Org. Chem. 1990, 55, 7-9.
(38) Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.;
Roberts, S. M. Tetrahedron Lett. 1979, 3981-3982.