Total synthesis of rutamycin B and oligomycin C

Article abstract of DOI:10.1021/jo001767c

The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C (2) is described. The approach relied on the synthesis and coupling of the individual spiroketal fragments 3a and 3b with the C1-C17 polyproprionate fragment 4. The preparation of the spiroketal fragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowed the introduction of the stereogenic centers prior to spiroketalization. The present work details the synthesis of the C19-C28 and C29-C34 subunits as well as their convergent assembly through an alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individual linear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, these advanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41. The requisite polypropionate fragment was assembled in a convergent manner using asymmetric crotylation methodology for the introduction of six of the nine-stereogenic centers. The use of three consecutive crotylation reactions was used for the construction of the C3-C12 subunit 32. A Mukaiyama-type aldol reaction of 35 with the chiral α-methyl aldehyde 39 was used for the introduction of the C12-C13 stereocenters. This anti aldol finished the construction of the C3-C17 advanced intermediate 36. A two-carbon homologation completed the construction of the polypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics was accomplished by the union of two principal fragments that was achieved with an intermolecular palladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of the individual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylic acids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchi reaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin B and oligomycin C.

Full text of DOI:10.1021/jo001767c

J . Org. Chem. 2001, 66, 2747-2756
2747
Tota l Syn th esis of Ru ta m ycin B a n d Oligom ycin C
J ames S. Panek* and Nareshkumar F. J ain†
Department of Chemistry, Metcalf Center for Science and Engineering and Center for Streamlined
Synthesis, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215
Panek@chem.bu.edu
Received December 19, 2000
The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C
(2) is described. The approach relied on the synthesis and coupling of the individual spiroketal
fragments 3a and 3b with the C1-C17 polyproprionate fragment 4. The preparation of the spiroketal
fragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowed
the introduction of the stereogenic centers prior to spiroketalization. The present work details the
synthesis of the C19-C28 and C29-C34 subunits as well as their convergent assembly through
an alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individual
linear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, these
advanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41.
The requisite polypropionate fragment was assembled in a convergent manner using asymmetric
crotylation methodology for the introduction of six of the nine-stereogenic centers. The use of three
consecutive crotylation reactions was used for the construction of the C3-C12 subunit 32. A
Mukaiyama-type aldol reaction of 35 with the chiral R-methyl aldehyde 39 was used for the
introduction of the C12-C13 stereocenters. This anti aldol finished the construction of the C3-
C17 advanced intermediate 36. A two-carbon homologation completed the construction of the
polypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics was
accomplished by the union of two principal fragments that was achieved with an intermolecular
palladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of the
individual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylic
acids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchi
reaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin B
and oligomycin C.
In tr od u ction
from the cultures of Streptomyces aureofaciens in 1984,
respectively. The structure and relative stereochemistry
of the rutamycins were determined by X-ray diffraction
studies.9 The absolute stereochemistry has been deter-
mined by chemical synthesis of the spiroketal fragment
and comparison with the naturally occurring spiroketal
fragment obtained by degradation of the natural prod-
uct.10 The complex structures and stereochemical arrays
associated with these macrolides have created exciting
challenges for chemical synthesis. Indeed, recent syn-
thetic efforts of certain members of this class of natural
products have been carried out using chiral enolate-based
bond construction methodology. In this paper, we report
the convergent asymmetric syntheses of rutamycin B and
oligomycin C. A continuing objective of this program
has been the development and utilization of a class of
The oligomycins are members of a family of macrolide
spiroketal antibiotics.2 Mixtures of the oligomycin anti-
biotics isolated in 19542 from a strain of Streptomyces
diastatochromogesnes consisted of variable proportions
of three major components A, B, and C.3 The structures
and absolute configuration of oligomycin A and C were
established by chemical correlation of their individual
degradation products with those derived from rutamycin
B (Scheme 1). The structure of which had already been
established.4 Oligomycin B was the first of this class of
natural products to have its structure elucidated. This
was accomplished through the combined use of spectro-
scopic and X-ray crystallography experiments.5
Rutamycin A and B are also members of the oligomycin
family.6 These structurally related natural products were
initially isolated in 1961 by Thompson7 from the cultures
of Streptomyces griseus and later by Keller-Schierlein8
(6) For leading references, see: (a) Paterson, I.; Mansuri, M. M.
Tetrahedron 1985, 41, 3569-3624. (b) Boeckman, R. K.; Goldstein, S.
W. The Total Synthesis of Natural Products; Apsimon, J ., Ed.; Wiley:
New York, 1988; Vol.7, pp 1-139 (c) Kobayashi, K.; Nishino, C.; Ohya,
J .; Sato, S.; Shiobara, Y.; Nishimoto, N. J . Antibiot. 1987, 40, 1053-
1057
† Current address: The R. W. J ohnson Pharmaceutical Research
Institute, Raritan NJ .
(1) For leading references, see: Macrolide Antibiotics; Omura, S.,
Ed.; Academic Press: Orlando, Florida, 1984.
(2) Smith, R. A.; Peterson, W. H.; McCoy, E. Antibiot. Chemother.
1954, 4, 962-970.
(3) Vissser, J .; Weinaurer, D. E.; Davis, R. C.; Peterson, Nazarewicz,
W.; Ordway H, J . Biochem. Microbiol. Technol. Eng. 1960, 2, 31-48
(4) Carter, G. T. J . Org. Chem. 1986, 51, 4264-4271.
(5) Sakurai, T.; Kihara, T.; Isono, K. Acta Crystallogr. 1983, C39,
295-297.
(7) Thompson, R. Q.; Hoehn, M. M.; Higgens, C. E. Antimicrob.
Agents Chemother. 1961, 474-480.
(8) (a) Wuthier, D.; Keller-Schierlein, W. Helv. Chim. Acta 1984,
67, 1208-1216. (b) Szilagyi, L.; Feher, K. J . Mol. Struct. 1998, 471,
195-207.
(9) Arnoux, B.; Garcia-Alvarez, M. C.; Marazano, C.; Bhupesh, C.
D.; Pascard, C. J . Chem. Soc., Chem. Commun 1987, 318-319.
(10) Evans, D. A.; Rieger, D. L.; J ones, T. K.; Kaldor, S. W. J . Org.
Chem. 1990, 55, 6260-6268.
10.1021/jo001767c CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/23/2001

2748 J . Org. Chem., Vol. 66, No. 8, 2001
Panek and J ain
Sch em e 1
chiral silicon reagents bearing C-centered chirality.
We had hoped that these reagents might someday be
used as a reliable complement to the well-developed
chiral metal enolate-based and aldol surrogate method-
ologies for the construction of polypropionate-like sub-
units. The synthetic approach for the introduction of the
stereogenic centers is based largely on the development
and application of chiral allylsilane bond construction
methods. In the context of acyclic stereocontrol, these
reaction processes rely on the use and proper choice of
silane reagent and Lewis acid type to deliver the antici-
pated relative and absolute stereochemical relation-
ship(s).
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.16
The conformational resemblance encountered between
rutamycins/oligomycins and cytovarycins has been used
to explain their similar bioactivity. Despite the similari-
ties shared between these natural products, the oligo-
mycins pose a different set of synthetic challenges from
cytovaricin. The most prominent feature of the oligomy-
cins is the 26-membered macrocyclic lactone, in which
nine stereocenters are located in the propionate derived
region of the molecule (C4-C14) while the remaining
eight stereocenters (seven for rutamycin B) are located
in the spiroketal fragment (C20-C34).
Retr osyn th etic An a lysis of Ru ta m ycin B a n d
Oligom ycin C. Following the successful use of a Suzuki
cross coupling reaction employed by Evans17 and White18
in their syntheses of rutamycin B, the natural products
were dissected into their individual spiroketal and identi-
cal polypropionate fragments. Our approach to the
synthesis of rutamycin and oligomycin is shown in
Scheme 1, which has been successfully employed in our
synthesis of oligomycin C.19 Disconnection at the C1-ester
linkage and at the C17-C18 (E,E)-diene gives the
spiroketal fragments 3a and 3b and the polypropionate
fragment 4. The regeneration of the (E,E)-diene unit,
employing a palladium (0)-mediated cross coupling be-
tween the vinylstannane of the spiroketals and the vinyl
Oligomycins and rutamycins share a common 1,7-
dioxaspiro[5.5]undecanyl ring system displayed off of a
26-membered macrolide. The macrolide portions of these
natural products share an identical polypropionate frag-
ment bearing nine stereogenic centers. Several members
of the oligomycin family are structurally closely related
and differ by the carbon oxidation state at C28 and by
the substitutions at C26 and C12. Other members of the
oligomycin group include cytovaricin,11 phthoramycin,12
kaimonolide A,13 NK86-0279I, and NK86-0279II.14
Biologica l Activity. The oligomycins are cytotoxic
molecules that have been shown to inhibit oxidative
phosphorylation in mitochondria by preventing synthesis
of ATP.15 Their mode of action is believed to involve the
decoupling of the F0 and F1 factors, which are respon-
sible for facilitating proton transfer through the inner
mitochondria membrane. Although not documented ex-
perimentally, a protein-oligomycin complex is thought
to exist between the oligomycin-sensitivity-conferring
protein (OSCP) and the natural product. It is this “drug-
protein” complex which is thought to prevent oxidative
(16) (a) Lardy, H. A.; J ohnson D.; McMurray, W. C. Arch. Biochem.
Biophys. 1958, 78, 587-597. (b) Lardy, H. A.; Witocky P.; J onhson, D.
Biochem. 1965, 4, 552-554.
(17) Rutamycin B studies: (a) Evans, D. A.; Ng, H. P.; Rieger, D. L.
J . Am. Chem. Soc. 1993, 115, 11446-11459. (b) White, J . D.; Tiller,
T.; Ohba, Y.; Porter, W. Tetrahedron Lett. 1997, 38, 3167-3170. (c)
Gustin, D. J .; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron Lett.
1995, 36, 3447-3450. (d) Nakata, M.; Ishiyama, T.; Akamatsu, S.;
Hirose, Y.; Marukoa, H.; Suzuki, R.; Tatsuta, K. Bull. Chem. Soc. J pn.
1995, 68, 967-989.
(18) (a) White, J . D.; Tiller, T.; Ohba, Y.; Porter, W.; J ackson, R.
W.; Wang, S.; Hanselmann, R. Chem. Commun. 1998, 1, 79-80. (b)
White, J . D.; Porter, W. J .; Tiller, T. Synlett 1993, 535-538.
(19) (a) Synthesis of oligomycin C: Panek, J . S.; J ain, N. F. J . Org.
Chem. 1998, 63, 4572-4573. (b) J ain, N. F.; Panek, J . S. Tetrahedron
Lett. 1997, 38, 1345-1348. (c) J ain, N. F.; Panek, J . S. Tetrahedron
Lett. 1997, 38, 1349-1352.
(11) (a) Kihara, T.; Kusakabe, H.; Nakamura, G.; Sakurai, T.; Isono,
K. J . Antibiot. 1981, 34, 1073-1074. (b) Total synthesis: Evans, D.
A.; Kaldor, S. W.; J ones, T. K.; Clardy, J .; Stout, T. J . J . Am. Chem.
Soc. 1990, 112, 7001-7031.
(12) Nakagawa, A.; Miura, S.; Imai, H,.; Imamura, N.; Omura, S.
J . Antibiot. 1989, 42, 1324-1327.
(13) Hirota, A.; Okada, H.; Kanza, T.; Nakayama, M,; Hirota, H.;
Osagai, A. Agric. Biol. Chem. 1989, 53, 2831-2833.
(14) Yamazaki, M.; Yamashita, T.; Harda, T.; Nishikiori, T.; Saito,
S.; Shimada, N.; Fujii, A. J . Antibiot. 1992, 45, 171-179.
(15) Pederson P. L.; Carafoli, E. Trends Biochem. Sci. 1987, 12, 146-
160.

Total Synthesis of Rutamycin B and Oligomycin C
J . Org. Chem., Vol. 66, No. 8, 2001 2749
Sch em e 2
Sch em e 3
Sch em e 4
iodide of 4 precedes ring closure by macrolactonization
at C1 with the C25-hydroxyl.20
Th e Sp ir ok eta l F r a gm en ts of Ru ta m ycin B a n d
Oligom ycin C. Retrosynthetic analysis of the spiroketal
fragment of rutamycin B and oligomycin C gave the C18-
C34 subunit bearing E-vinylstannanes, which was de-
rived from the corresponding E-vinyl iodide through a
palladium(0)-catalyzed halogen/trialkyl stannane ex-
change. Opening of the individual spiroketals 3a and 3b
gave an advanced intermediate 5a bearing seven stereo-
centers for rutamycin B and eight for oligomycin C
(Scheme 2). In both cases, disconnection at C28-C29
furnished their respective C19-C28 left-hand sub-
units 6 and 8 and an identical C29-C34 right-hand
subunit 7.
ozonolysis conditions (O3/DMS) yielded R-methyl alde-
hyde 12. This material was then subjected to a TiCl4-
promoted allylation with 2-methylallyl dimethylphenyl
silane 10b to afford 13 in 71% yield (dr ) 6:1 anti/syn)
with the (S)-stereochemistry of the emerging hydroxyl
group being preferred presumably by chelation of a
bidentate Lewis acid with the â-hydroxyl group and the
aldehyde. This reaction resulted in the construction of
the C19-C28 subunit of the rutamycin spiroketal (Scheme
4). In a similar fashion, aldehyde 12 was subjected to
TiCl4-promoted double-stereodifferentiating crotylation
reaction using the methyl-substituted silane 10c to give
14 as a single diastereomer (71% yield).23 This crotylation
product, comprising anti stereochemistry between the
newly installed methyl and hydroxyl groups, occurred
with anti-Felkin induction (Scheme 4). The use of silane
10c permitted the introduction of a trisubstituted olefin,
which was intended for use as a methyl ketone synthon
through an oxidative cleavage. This transformation
completed the construction of the C19-C28 left-hand
subunit of oligomycin C bearing five stereogenic centers.
Once again, the stereochemistry can be rationalized by
the addition of the chiral silane to the si face of the
aldehyde preferred by the use of a bidentate Lewis acid
which chelates to the aldehyde oxygen and C23 oxygen.
The following section describes the detailed synthesis
and coupling of the spiroketal subunits of rutamycin B
and oligomycin C. In an effort to avoid any late stage
stereochemical adjustments or oxidation state changes,
a stereocontrolled route was designed that planned for
the introduction of all the stereocenters prior to spiroket-
alization. Chiral aldehyde 9, which was synthezised in
seven steps starting from the commercially available
ethyl diethyl malonate21 underwent an in situ acetaliza-
tion followed by an asymmetric crotylation to the derived
oxonium ion to give the C23-24 syn stereochemistry of
the benzyl protected homoallylic alcohol 11 (Scheme 3).
This three component crotylation proceeded with useful
levels of diastereoselection (syn/anti 6:1) and in 76%
yield.22 Oxidation of the trans-olefin under standard
Once an efficient preparation of the left-hand subunits
of rutamycin B and oligomycin C had been achieved, the
next objective was aimed at the synthesis of the right-
hand subunit of the individual spiroketals. Those experi-
ments are summarized in Scheme 5. In that regard, the
primary iodide 18 which is the same for both the
synthesis of rutamycin B and oligomycin C was prepared
by an initial TiCl4 promoted crotylsilane addition of 10a
(20) (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.
(21) See Supporting Information for experimental procedures for the
synthesis of aldehyde 9.
(22) (a) Panek, J . S.; Yang, M.; Xu, F. J . Org. Chem. 1992, 57, 5790-
5792. (b) Masse, C. E.; Panek, J . S. Chem. Rev. 1995, 95, 1293-1316.
(23) J ain, N. F.; Takenaka, N.; Panek, J . S. J . Am. Chem. 1996,
118, 12475-12476.

2750 J . Org. Chem., Vol. 66, No. 8, 2001
Panek and J ain
Sch em e 5
to the known â-alkoxy chiral aldehyde 15.24 The antici-
pated syn homoallylic alcohol was obtained in 79% yield
with a selectivity greater than 15:1 (syn/anti), introducing
a 1,3-anti relationship between C31-C33 stereogenic
centers.25 Presumably, this crotylation reaction using a
bidentate Lewis acid (TiCl4) proceeds through a Cram
chelate transition-state model. Protection of the second-
ary-hydroxyl as its TBS ether was followed by standard
ozonolysis (O3/Me2S). The crude aldehyde was reduced
with NaBH4 to produce primary alcohol 17 in 73% yield
over two steps. The resulting alcohol was directly con-
verted to the primary iodide 18 in 70% yield using
triphenoxy phosphomium iodide,26 which completed the
synthesis of the right-hand subunit and was used directly
in the alkylation reaction with the left-hand subunit.
With the required spiroketal subunits in our posses-
sion, the elaboration to the individual spiroketals 40 and
41 was investigated. In a parallel format, Scheme 6
summarizes the spiroketal syntheses of rutamycin B and
oligomycin C, path A and B, respectively. In that regard,
the spiroketal synthesis of rutamycin B (path A) was
initiated with the protection of the C25 hydroxyl group
(TBSCl/imidazole) yielding the protected homoallylic
alcohol 20 in 95% yield. Osmium tetraoxide catalyzed
dihydroxylation of the terminal olefin followed by lead
tetraacetate promoted cleavage of the resulting diol
yielded methyl ketone 20. Our initial attempts to couple
the ketone enolate derived from 20 with iodide 18 proved
unsuccessful as only small amounts of the desired alkyl-
ation product could be obtained. Due to the low reactivity
of the methyl ketone enolate, the lithiated N,N-dimethyl
hydrazone derived from the methyl ketones 20 and 22
were used to provide for a more efficient subunit coupling
in the assembly of the spiroketal fragments. Hydrazone
formation was accomplished using N,N-dimethyl hydra-
zine and TMSCl27 which was converted to the lithiated
hydrazone by treatment with LDA (1.5 equiv) in THF.
This intermediate participated in a smooth alkylation
with the primary iodide 18 to give the coupled product
23 that was directly subjected to hydrazone hydrolysis
without further purification. The hydrazone was hydro-
lyzed using silica gel and dichloromethane for 2 days
providing the ketone in 80%. Removal of the benzyloxy
protecting group by hydrogenolysis followed by depro-
tection of the silyl enol ethers with HF in acetonitrile
gave the spiroketal fragment 40 of rutamycin B in 89%
yield.
The synthesis plan for the construction of the spiroket-
al of oligomycin C is also summarized in Scheme 6, path
B. Overall, the plan closely follows the one which was
implemented in the synthesis of the rutamycin spiroketal
fragment. Deprotection of the C23 benzyl group of 14 was
followed by ketalization with dimethoxypropane yielded
the acetonide 21 in 71% yield for two steps. Ozonolysis
of the trisubstituted olefin gave aldehyde 22, which was
converted to the N,N-dimethylhydrazone using 1,1-dim-
ethyl hydrazine and TMSCl. Deprotonation of the hy-
drazone (LDA/THF) followed by alkylation with iodide
18 gave the coupled product 24 in 78% yield. Deprotection
of both silyl protecting groups and cyclization using HF
in acetonitrile followed by debenzylation by hydrogenoly-
sis yielded the spiroketal fragment of oligomycin C 41 in
65% over two steps. At this stage, the synthesis of both
spiroketals of rutamycin and oligomycin were completed.
The assignment of stereochemistry of the spiroketals was
secured by comparison with literature values. Accord-
ingly, a careful comparison of the published spectroscopic
data, including 1H and 13C NMR spectra of the sprioketal
of rutamycin B, a known degradation product, with our
synthetic material was shown to be identical.10
Retr osyn th etic An a lysis of th e C1-C17 P olyp r o-
p ion a te F r a gm en t of Ru ta m ycin B a n d Oligom ycin
C. The plan for the synthesis of the polypropionate
fragment of rutamycin B and oligomycin C is outlined in
Scheme 7 and relied extensively on the use of our chiral
silane reagents for the introduction of the stereochemical
relationships. In fact, six of the nine stereogenic centers
were introduced using the asymmetric crotylations.
Disconnection of the polypropionate fragment at C12-
C13 bond yields two components: the C1-C12 ethyl
ketone subunit and the C13-C17 R-methyl aldehyde 39.
This bond construction relies on a double-stereodifferen-
tiating anti aldol reaction with Felkin selectivity,28
employing a Mukaiyama-like aldol involving a (Z)-(O)-
silyl enol ether. We had anticipated that the C3-C12
subunit maybe constructed by three consecutive double-
stereodifferentiating syn crotylation reactions at C5-C6,
C7-C8, and C9-C10. The C13-C17 subunit 9 could be
(24) Reetz, M. T.; J ung, A. J . Am. Chem. Soc. 1983, 105, 4833-
4835.
(25) (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.
(26) Maguire, A. R.; Meng, W.; Roberts, S. M.; Whilletts, A. J . J .
Chem. Soc., Perkin Trans. 1 1993, 24, 1795-1808.
(27) Evans, D. A.; Bender, S. L.; Morrisy J . J . Am. Chem. Soc. 1988,
110, 2506-2526.
(28) (E)-Lithium enolates and (E)-boron enolates are known to give
propionate aldol products with anti stereochemistry and Felkin induc-
tion; see: (a) Evans, D. A.; Yang, M. G.; Dart, M. J .; Duffy, J . L.
Tetrahedron Lett. 1996, 37, 1957-1960 and references therein. (b)
Paterson, I.; Perkin, M. V. J . Am. Chem. Soc. 1993, 115, 1608-1610.

Total Synthesis of Rutamycin B and Oligomycin C
J . Org. Chem., Vol. 66, No. 8, 2001 2751
Sch em e 6
Sch em e 7
synthesized from the chiral R-methyl aldehyde using
Takai’s protocol to introduce the (E)-vinyl iodide.29
Syn th esis of th e C1-C17 P olyp r op ion a te F r a g-
m en t. Our synthesis of this fragment was initiated with

2752 J . Org. Chem., Vol. 66, No. 8, 2001
Panek and J ain
Sch em e 8
Sch em e 9
the reaction of the chiral aldehyde 26 and was condensed
with crotylsilane 11a in the presence of TiCl4 in CH2Cl2
at -78 °C to yield homoallylic alcohol 27 with 30:1 syn/
anti ratio (Scheme 8). Deprotection of the primary
hydroxyl group using aqueous HF was followed by cyclic
silylene formation using di-tert-butyl-silylditriflate in the
presence of 2,6-lutidine afforded the protected 1,3-diol.
Oxidative cleavage of the olefin under standard ozonoly-
sis conditions (O3/DMS) gave aldehyde 28. Condensation
of aldehyde 28 with (R)-11a was again promoted by TiCl4
to yield homoallylic alcohol 29 with excellent levels of
diastereoselctivity, dr >30:1 syn: anti.
At this crucial point in the synthesis of the polypropi-
onate fragment we were nearly ready for the third
crotylation, which is used for the introduction of the final
two stereocenters of the C3-C12 ethyl ketone synthon.
Accordingly, homoallylic alcohol 29, was converted to
aldehyde 30 with the anticipation that this material could
be used in the final crotylation reaction with the ethyl
substituted silane (R)-11d (Scheme 9). Disappointingly,
after a considerable number of experiments were carried
out, we were unable to achieve an efficient condensation
for the formation of homoallylic alcohol 32. We concluded
that the low reactivity of aldehyde 30 was brought about
from a stereic and/or conformational change associated
with the terminal silylene. We have learned that this
particular 1,3-diol protecting group results in the forma-
tion of a Lewis acid-aldehyde complex that is unreactive
and resistant to the crotylation with 11d . Indeed, we
could obtain the desired homoallylic alcohol 32 in yields
no higher than 10% along with the recovery of the start-
ing aldehyde (ca. 45%). Accordingly, this poor efficiency
of this crotylation forced us to reconsider the silicon-based
hydroxyl protecting group strategy. The terminal cyclic
silylene was removed with HF in acetonitrile, the pri-
mary alcohol was protected as a silyl ether with tert-butyl
dimethylsilyl chloride and imidazole followed by con-
comitant formation of the internal cyclic silylene with
diisopropyl dichlorosilane.30 This one-pot operation af-
forded the fully protected intermediate, which was con-
verted to the R-methyl aldehyde 31 by ozonolysis. In
direct contrast, aldehyde 31, bearing the internal cyclic
silylene smoothly participated in the double-stereodif-
ferentiation reaction with (R)-silane 11d to afford the
desired homoalylic alcohol 33 in 82% and as a single
diastereomer. Although a case for a steric argument can
be made, the precise nature of the reactivity difference
resulting from the repositioning of the silicon protecting
group (aldehydes 30 and 31) cannot at this time be
explained. However, the movement of the 1,3-diol pro-
tecting group to an internal position certainly provided
enhanced reactivity in this paticular double-stereodiffer-
entiating crotylation reaction.
Protection of the secondary hydroxyl of 33 as a TBS
ether, followed by cleavage of the substituted olefin under
(30) Attempts to effect silylene formation using di-tert-butyldichlo-
rosilane proved to be unsuccessful, presumably from severe steric
destabilizing interactions.
(29) Takai, K.; Nitta, K.; Ulimoto, K. J . J . Am. Chem. Soc. 1986,
108, 7408-7410.

Total Synthesis of Rutamycin B and Oligomycin C
J . Org. Chem., Vol. 66, No. 8, 2001 2753
Sch em e 10
standard ozonolysis conditions (O3/DMS) yielded ethyl
ketone 34 in 83% yield. The (Z)-O-silyl-enol ether 35 was
formed in 92% yield by the selective enolization of 34 with
lithium bis(trimethyl)disilazide31 and subsequent trap-
ping with dimethylphenylsilyl chloride in the presence
of triethylamine (Scheme 10), whose stereochemistry was
assigned by the measurements of NOEs.
C1-C17 polypropionate fragment of rutamycin an oli-
gomycin, we had anticipated that the chiral enolsilane
35 would control the stereochemistry of the emerging C12
methyl bearing center while the R-methyl aldehyde 39
provides dominat control over the C13-hydroxyl stereo-
center. Finally, the 1,3-relationship across the carbonyl
is predetermined by the chirality of the R-methyl ketone
and the configuration of the enolsilane. Thus, the ste-
reocontrolling elements for the 1,3-induction of the meth-
yl groups across the carbonyl reside within the chiral
ethyl ketone coupling partner.
Mu k a iya m a Ald ol Cou p lin g. With the required
advanced intermediates now available, the crucial double-
stereodifferentiating aldol reaction between the C3-C12
and the C13-C17 subunits was investigated.32 This aldol-
based fragment coupling reaction described here was
designed on the basis of an extensive study by Evans and
co-workers whose careful systematic analysis of this
reaction-type laid the ground for our route.33 In previous
syntheses of rutamycin B, this particular C12-C13 aldol
bond construction was not reported. In considering the
predicted stereochemical outcome of the Mukaiyama
aldol, it has been well established that the configuration
of the silyl enol ether will determine the relative stereo-
chemistry of the emerging vicinal stereocenters. Further,
this chiral reaction partner primarily influences the
absolute stereochemical outcome of the methyl bearing
stereocenter, while the carbonyl facial selectivity is
primarily determined by inherent chirality of the alde-
hyde. In other words, for aldol processes proceeding
through an open transition state, the strereochemical
determinants for the emerging methyl and secondary
hydroxyl stereogenic centers are contained within the
chiral enolsilane and chiral aldehyde reaction compo-
nents, respectively. Thus, in experiments designed to find
a workable solution to this bond construction, we have
learned that the type of Lewis acid and the size of the
silicon group has significant effect on the level of induc-
tion. Table 1 summarizes the important findings con-
cerning this aldol based coupling. Accordingly, in the
double-stereodifferentiating aldol used to construct the
These experiments underscore the sensitive nature of
the open transition-state models to steric influences of
the Lewis acids and trialkylsilicon group. Among the
Lewis acids surveyed, BF3‚OEt2, SnCl4, and TiCl4 gener-
ally provided clean reaction products. Also surveyed was
the size of the silicon group. In that regard, three
different trialkylsilyl groups representing considerably
different steric environments have been screened: Me3-
Si, Me2PhSi, and t-BuMe2Si. The combination of BF3‚
OEt2 and a sterically bulky silyl enol ether (M )
SiMe2Ph) were found to be most effective with respect to
the level of diastereoselectivity and reaction yield (entry
2). The reaction diastereoselection can be rationalized
with the open transition state model that orientates the
chiral reaction partners in an anti/staggered transition
state. After considerable experimentation, this critical
bond construction was achieved with useful levels of
selectivity. The (Z)-O-silyl enol ether 35 derived from
ethyl ketone 34, and aldehyde 39 were treated with BF3‚
OEt2 (1.1 equiv) at -78 °C for 24 h to furnish the required
anti aldol product 36a with good selectivity (dr ) 7:1). It
is believed the Me2PhSi (Z)-O-silyl enol ether sterically
reinforces Felkin induction by stabilizing the transition
state allowing the aldehyde substituent (H) to adopt the
sterically most demanding position. This organization of
reactive π-partners results in an anti aldol with the
methyl groups positioned anti across the C11 carbonyl.
An open transition-state model that can be used to
rationalize the stereochemical course of this bond con-
struction is shown in Scheme 11.
(31) Masamune, S.; Ellingboe, J . W.; Choy, W. J . Am. Chem. Soc.
1982, 104, 5526-5528.
(32) Double-stereodifferentiating aldol reactions: (a) Masamune, S.;
Choy, W.; Petersen, J . S.; Sita; L. R. Angew. Chem., Int. Ed. Engl. 1985,
24, 1-30.
(33) (a) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J . J .
Am. Chem. Soc. 1998, 120, 5921-5942. (b) Evans, D. A.; Dart, M. J .;
Duffy, J . L.; Yang, M.; G.; Livingston, A. B.; J . Am. Chem. Soc. 1995,
117, 6619-6620. (c) Dart, M. J . Ph.D. Thesis, Harvard University, May
1995.
The synthesis of the C1-C17 fragment was completed
in five steps from 36a and was initiated with the selective
removal of the C5-C7 silylene protecting group using
HF‚Py/Py in THF at 0 °C. The resulting crude triol was
selectively protected at the C5 and C13 hydroxyls with

2754 J . Org. Chem., Vol. 66, No. 8, 2001
Panek and J ain
Ta ble 1
36a :36b
diastereoselectivity
entry
Lewis acid (equiv)
(Z)-enolsilane (M)a
anti/syn/∑ othersb
% yieldc
1
2
3
4
5
6
7
BF3‚OEt2 (1.1)
BF3‚OEt2 (1.1)
BF3‚OEt2 (1.1)
SnCl4 (1.1)
TiCl4 (1.1)
TiCl4 (1.1)
Me3Si
2:1:1
7:1:0
not determined
2:1:0
1:1:3
43
73
<10
32.5
71
21
43-53
Me2PhSi
tBuMe2Si
Me2PhSi
Me3Si
Me2PhSi
5:1:0
20:1:0
TiCl4 (1.1)
tBuMe2Si
a
b
Assignment of enol stereochemistry was accomplished by NOE experiments. Ratio of diastereomers was determined by 1H NMR
experiments on the crude reaction products. c Refers to purified material (single major diastereomer) after chromatography on SiO2.
Sch em e 11
TBSOTf (2.2 equiv), 2,6-lutidine (3 equiv) at -78 °C. This
material was selectively deprotected at the C3 TBS ether
using HF‚Py/Py in THF at room temperature to give diol
37 in high yield. A Swern oxidation of the resulting C3-
C7 diol provided the keto-aldehyde. This advanced in-
termediate was subjeted to a phosphorus based olefina-
tion with an (E)-selective Horner-Emmons reaction using
tert-butyldiethylphophonoacetate and LiN(TMS)2 to com-
plete the assembly of the C1-C17 polypropionate frag-
ment of rutamycin B and oligomycin C.
Syn th esis of th e C18-C34 Sp ir ok eta l F r a gm en ts
of Ru ta m ycin B a n d Oligom ycin C. At this stage of
the synthesis, the individual spiroketal subunits were
further functionalized to prepare them for cross-coupling
with the polypropionate fragment. In that regard, the
conversion of the spiroketal individual intermediates 39
and 40 to the required coupling partners was completed
in four steps. These transformations were accomplished
by selective oxidation of the C19 primary hydroxyl group
in the presence of the C25 and C33 secondary hydroxyl
groups. In that context, the oxidation was successfully
carried out using Ru(PPh3)3Cl2 to afford aldehydes 41
34
and 42. However, these aldehydes proved to be unstable
toward purification on SiO2, which resulted in their use
in the next olefination reaction without further purifica-
tion. Accordingly, homologation to the E-vinyl iodide
using the Takai protocol,29 selective protection of the C33
hydroxyl with TBSCl/imidazole provided E-vinyl iodides
44 and 45 in 70% and 79% yield, respectively (Scheme
12). The vinyl iodides were converted to the E-vinylstan-
nane using the Stille protocol. This halogen f stannane
conversion completed the assembly of the fully elaborated
C18-C34 spiroketal fragments 3a and 3b, which were
used separately in the transition metal mediated frag-
ment coupling with the polypropionate fragment 4.
(34) Tomioka, H.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron
Lett. 1981, 22, 1605-1608.

Total Synthesis of Rutamycin B and Oligomycin C
J . Org. Chem., Vol. 66, No. 8, 2001 2755
Sch em e 12
Sch em e 13
Com p letion of Syn th esis of of Ru ta m ycin B a n d
Oligom ycin C. The following discussion describes the
final stages of the synthesis of rutamycin B and oligo-
mycin C. Prior to actual fragment coupling exeperiments,
the tert-butyl ester of 4 was converted to the correspond-
ing carboxylic acid 47, by treatment with TMSOTF in
the presence of 2,6-lutidine35 (Scheme 13). Coupling of
the polypropionate with the spiroketal fragment using
(35) Trzeciak, A.; Bannwarth, W.; Synthesis 1996, 1433.

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
charge via the Internet http://pubs.acs.org.
) 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.