Total synthesis of oligomycin C

Full text of DOI:10.1021/jo980982e

4572
J . Org. Chem. 1998, 63, 4572-4573
Tota l Syn th esis of Oligom ycin C
J ames S. Panek* and Nareshkumar F. J ain
Department of Chemistry, Metcalf Center for Science and
Engineering, Boston University, Boston, Massachusetts 02215
Received May 22, 1998
Oligomycin C is a polypropionate-derived natural product
that shares a macrolide-spiroketal structure with the
rutamycins (Figure 1). As related members of the oligomy-
cin class of macrolide-antibiotics possessing identical 26-
membered lactones, oligomycin C differs from rutamycin B
by a single methyl group at the C26 position of the
spiroketal. The oligomycin antibiotic complex was first
isolated and characterized in 19541 from a strain of Strep-
tomyces diastatochromogenes. The oligomycins are cytotoxic
macrolides that are reported to inhibit oxidative phospho-
rylation in mitochondria by preventing synthesis of ATP.2
Their mode of action is believed to involve the decoupling of
the F0 and F1 factors, which are responsible for facilitating
proton transfer through the inner mitochondria membrane.
A protein-oligomycin complex is believed to exist between
the oligomycin-sensitivity-conferring protein (OSCP) and the
natural product, which is thought to prevent oxidative
phosphorylation. The OSCP is located in the stalk between
the F0 and F1 factors. As such, these natural products may
serve as potential biological probes and have already been
used in the exploration of oxidative phosphorylation.4 The
structures of oligomycin A, B, and C were assigned on the
basis of degradation products and 1H NMR and 13C NMR
correlation experiments.3 Earlier studies on this class of
antibiotics have resulted in the absolute stereochemical
assignment and total synthesis of rutamycin B.4
Structurally, oligomycin C consists of a synthetically
challenging 26-membered lactone that is linked to the C18-
C34 spiroketal fragment through an ester bond of the C25-
hydroxyl of the spiroketal. The formidable tasks associated
with the synthesis of this class of natural products include
the efficient construction of the C1-C17 polypropionate and
spiroketal fragments and their subsequent coupling. In this
paper, we wish to report the first asymmetric synthesis of
oligomycin C. Since the synthesis of the polypropionate
fragment 4 has been reported,5 the outline of our retrosyn-
thetic analysis emphasizes the asymmetric crotylation strat-
egy6 used in the construction of the spiroketal fragment
(Figure 1). Our synthetic plan for joining these two frag-
ments by the construction of the sp2-sp2 bond at C17-C18
relied on a palladium(0)-based cross-coupling strategy utiliz-
ing a vinylstannane/vinyl iodide combination.7 The syn-
thetic analysis of the spiroketal involved opening of the
spirocycle to give an acyclic precursor bearing seven stereo-
genic centers. Our retrosynthetic plan for the synthesis of
members of this class of macrolides antibiotics allows for a
F igu r e 1.
high degree of convergency and is highlighted by an inter-
molecular Stille coupling to effect the C17-C18 bond
construction.8 Lactonization under Yamaguchi conditions
would complete construction of the macrocycle. The intro-
duction of the stereogenic centers is based on the application
of double-stereodifferentiating crotylation reactions with
chiral (E)-crotylsilanes.9
The synthesis of this subunit of oligomycin C utilizes two
asymmetric crotylation reactions for the introduction of the
C23-C24 and the C25-C26 stereogenic centers. The con-
struction of the C19-C28 subunit of the spiroketal was
initiated by an asymmetric crotylation between the chiral
aldehyde 8 and silane reagent (S)-9a ,10 which established
the C23-C24 stereocenters (Scheme 1). This first addition
proceeds through the intermediacy of an oxocarbenium ion
involving an open transition state where the observed
stereochemistry is consistent with an anti-SE′ mode of
addition. The (E)-olefin of the homoallylic benzyl ether 10
was cleaved by ozonolysis to furnish the R-methyl aldehyde
11. This material was used without further purification in
a chelation-controlled, double-stereodifferentiating crotyla-
tion reaction with chiral â-methylsilane (S)-9b (diastereo-
selection >40:1 anti/syn). The TiCl4-promoted reaction
produced the anti homoallylic alcohol 12 with a high level
of anti-Felkin induction. Presumably, this reaction proceeds
through a Cram chelate transition-state model.11,12 This
material was converted to the hydrazone 13 in a straight-
(1) Smith, R. A.; Peterson, W. H.; McCoy, E. Antibiot. Chemother. 1954,
4, 962-970.
(2) Pederson P. L.; Carafoli, E. Trends Biochem. Sci. 1987, 12, 146-160.
(3) (a) Carter, T. G.; J . Org. Chem, 1986, 51, 4264-4271. (b) Prouty, W.
F.; Thompson, R. M.; Schnoes, H. K.; Strong, F. M. Biochem. Biophys. Res.
Commun. 1971, 44, 619-627.
(4) (a) Evans, D. A.; Ng, H. P.; Rieger, D. L. J . Am. Chem. Soc. 1993,
115, 11446-11459. (b) Gustin, D. J .; VanNieuwenhze, M. S.; Roush, W. R.
Tetrahedron Lett. 1995, 36, 3447-3450.
(5) J ain, N. F.; Panek, J . S. Tetrahedron Lett. 1997, 38, 1345-1348.
(6) Masse, C. E.; Panek, J . S. Chem. Rev. 1995, 95, 1293-1316.
(7) (a) Stille, J . K.; Groh, B. L J . Am. Chem. Soc. 1987, 109, 813-817.
(b) Stille. J . K.; Sweet, M. P. Tetrahedron Lett. 1989, 30, 3645-3648. (b)
Nicolaou, K. C.; Chakraborty, T. K.; Picopio, A. D.; Minowa N.; Bertinato,
P. J . Am. Chem. Soc. 1993, 115, 4419-4420. (c) Stille, J . K. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 508-524.
(8) (a) Evans, D. A.; Rieger, D. L.; J ones, T. K.; Kaldor, S. W. J . Org.
Chem. 1990, 55, 6260-6268. (b) Nakata, M.; Ishiyama, T.; Akamatsu, S.;
Suzuki, R.; Tatsuta, K. Synlett 1994, 601-604. (c) White, J . D.; Porter, W.
J .; Tillre, T. Synlett 1993, 535-538.
(9) (a) J ain, N. F.; Cirillo, P. F.; Pelletier, R.; Panek, J . S. Tetrahedron
Lett. 1995, 36, 8727-8730. (b) J ain, N. F.; Takenaka, N.; Panek, J . S. J .
Am. Chem. Soc. 1996, 118, 12475-12476.
(10) For the preparation of the silane reagents, see: Beresis, R. T.;
Solomon, J . S.; Yang, M. G.; J ain, N. F.; Panek, J . S. Org. Synth. 1997, 75,
78-88.
(11) (a) Cram, D. J .; Kopecky, K. R. J . Am. Chem. Soc. 1959, 81, 2748-
2755. (b) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462-468.
S0022-3263(98)00982-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/20/1998

Communications
J . Org. Chem., Vol. 63, No. 14, 1998 4573
Sch em e 1
Sch em e 2
The completion of the synthesis was accomplished by
selective oxidation of the C19 primary hydroxyl group with
15
Ru(PPh3)3Cl2 to afford aldehyde 17, which was homolo-
gated using the Takai protocol16 to yield vinyl iodide 18
(Scheme 2). Selective protection of the C33 hydroxyl with
TBSCl/imidazole and conversion of the vinyl iodide to the
vinylstannane using the Stille protocol7a gave the fully
elaborated C18-C34 spiroketal fragment 3. Fragment
coupling was accomplished by using a palladium(0)-cata-
lyzed cross-coupling reaction between the stannylated
spiroketal and vinyl iodide 4 to give hydroxy acid 19.
Finally, macrocyclization of hydroxy acid 19 using the
Yamaguchi protocol17 followed by removal of the silicon
protecting groups with aqueous HF furnished synthetic
oligomycin C (1). Its spectroscopic and physical properties
were identical in all respects (1H, 13C NMR, [R]D, and MS)
forward four-step sequence: (i) deprotection of the C23
secondary benzyl group (BCl3‚SMe2), (ii) protection of the
anti-1,3-diol as its acetonide, (iii) oxidative cleavage of the
(E)-double bond with O3/Me2S, and (iv) hydrazone formation
in 62% overall yield.
The C29-C34 right-hand subunit of oligomycin C (14) is
identical to that of rutamycin B, and its synthesis has been
previously reported from our laboratory.13 It was envisioned
that the most efficient subunit coupling would involve an
alkylation reaction of the ketone enolate of 13 with primary
iodide 14 to construct the C28-C29 bond (Scheme 1). Thus,
the lithium enolate of N,N-dimethylhydrazone 13 was
formed and reacted with primary iodide 14 to afford the
alkylated hydrazone 15.14 The synthesis of the spiroketal
fragment was completed in two steps and was initiated by
deprotection and cyclization with aqueous HF in MeCN/CH2-
Cl2 (1:1) at room temperature. The resulting crude product
was subjected to hydrogenolysis to remove the benzylic ether
at C33 [H2 (1 atm) over 10% Pd/C in EtOH at 25 °C/36 h],
providing the C19-C34 fragment 16 as the fully elaborated
carbon framework of the spiroketal of oligomycin C.
with those previously reported [[R]23 ) -82.7° (c ) 0.15,
D
dioxane) (lit.3a [R]23 ) -80.7° (c ) 3.70, dioxane))]. In
D
summary, the total synthesis of oligomycin C has been
completed in 44 steps. Overall, the approach represents an
interesting application of chiral crotylsilane-based bond
construction methodology and easily complements the well-
developed chiral enolate methodology.
Ack n ow led gm en t. Financial support was obtained
from NIH (GM55740).
Su p p or tin g In for m a tion Ava ila ble: General experimental
data as well as spectral data for all products (39 pages).
J O980982E
(12) (a) Panek, J . S.; Cirillo, P. F. J . Org. Chem. 1993, 58, 294-296. (b)
Mikami, K.; Kawamoto, K.; Loh, T.-P.; Nakai, T. J . Chem. Soc., Chem.
Commun. 1990, 1161-1163 (c) Fleming, I. Chemtracts 1991, 4, 21-25.
(13) J ain, N. F.; Panek, J . S. Tetrahedron Lett. 1997, 38, 1349-1352.
(14) Evans, D. A.; Bender, S. L.; Morris, J . J . Am. Chem. Soc. 1988, 110,
2506-2526.
(15) Tomioka, H.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1981, 22, 1605-1608.
(16) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108, 7408-
7410.
(17) Inanagana, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.