8290
J . Org. Chem. 1997, 62, 8290-8291
Sch em e 1
Tota l Syn th esis of (+)-Mycotr ien ol a n d
(+)-Mycotr ien in I
J ames S. Panek* and Craig E. Masse†
Department of Chemistry, Metcalf Center for
Science and Engineering, Boston University,
Boston, Massachusetts 02215
Received September 29, 1997
In 1985, Umezawa and co-workers reported the isola-
tion of five novel ansamycin antibiotics, trienomycins
A-E, from the culture broth of Streptomyces sp. No. 83-
16.1 These molecules exhibited strong cytotoxicity in
vitro against HeLa S3 cells.2 Their relative and absolute
stereochemistry has been determined by Smith through
careful degradative and spectroscopic methods.3 The (+)-
mycotrienins I and II, which have previously been
isolated from the fermentation broth of Streptomyces
rishiriensis T-23, have displayed potent antifungal activ-
ity.4 Stereochemical correlation studies have extended
the absolute stereochemical assignments of the trieno-
mycins to the (+)-mycotrienins I and II, and therefore to
the mycotrienols (Scheme 1).5 To date, Smith and co-
workers have reported the only total synthesis of mem-
bers of this class of compounds, specifically the synthesis
of trienomycins A and F.6
Sch em e 2
Our retrosynthetic plan for the synthesis of members
of this class of antitumor antibiotics, illustrated in
Scheme 1, allows for a high degree of convergency and
is highlighted by a tandem inter/intramolecular Stille
coupling to effect macrocyclization. Analysis of the myco-
trienol skeleton reveals two distinct subunits: (i) the C9-
C16 polypropionate subunit 3 whose stereochemical
issues are readily accessible through chiral allylsilane
bond construction methodology;7 (ii) the aromatic subunit
4 whose single stereocenter at C3 can also be addressed
using a chiral (E)-crotylsilane reagent.
The construction of the C9-C16 subunit was initiated
by an asymmetric crotylation between the R-keto-diben-
zylacetal 5 and silane reagent (S)-6 to establish the C12-
C13 centers (Scheme 2). This first addition proceeds
through an antiperiplanar transition state where the
observed stereochemistry is consistent with an anti-SE′
† Recipient of a Graduate Fellowship from the Organic Chemistry
Division of the American Chemical Society 1996-1997, sponsored by
Organic Syntheses, Inc.
(1) (a) Funyama, S.; Okada, K.; Komiyama, K.; Umezawa, I. J .
Antibiot. 1985, 38, 1107-1109. (b) Funyama, S.; Okada, K.; Iwasaki,
K.; Komiyama, K.; Umezawa, I. J . Antibiot. 1985, 38, 1677-1683. (c)
Katasumata, S.; Takahashi, K.; Funayama, S.; Komiyama, K.; Umeza-
wa, I. Omura, S. J . Antibiot. 1989, 24, 479-481.
(2) Umezawa, I.; Funayama, S.; Okada, K.; Iwasaki. K.; Satoh, J .;
Masuda, K.; Komiyama, K. J . Antibiot. 1985, 38, 699-705.
(3) Smith, A. B., III; Wood, J . L.; Wong, W.; Gould, A. E.; Rizzo, C.
J . J . Am. Chem. Soc. 1990, 112, 7425-7426.
(4) (a) Sugita, M.; Natori, Y.; Sasaki, T.; Furihata, K.; Shimazu, A.;
Seto, H.; Otake, N. J . Antibiot. 1982, 35, 1460-1466. (b) Sugita, M.;
Sasaki, T.; Furihata, K.; Shimazu, A.; Seto, H.; Otake, N. J . Antibiot.
1982, 35, 1467-1473. (c) For (+)-mycotrienol see: Sugita, M.; Natori,
Y.; Sueda, N.; Kazuo, F.; Seto, H.; Otake, N. J . Antibiot. 1982, 35,
1474-1479.
(5) Smith, A. B., III; Wood, J . L.; Wong, W; Gould, A. E.; Rizzo, C.
J .; Barbosa, J .; Funayama, S.; Komiyama, K, Omura, S. J . Am. Chem.
Soc. 1996, 118, 8308-8315.
(6) Smith, A. B., III; Barbosa, J .; Wong, W.; Wood, J . L. J . Am. Chem.
Soc. 1996, 118, 8316-8328. For other synthetic approaches to the
trienomycins and related mycotrienins see: (a) Yadav, J . S.; Praveen
Kumar, T. K.; Maniyan, P. P. Tetrahedron Lett. 1993, 34, 2965-2968.
(b) Fu¨rstner, A.; Baumgartner, J . Tetrahedron 1993, 49, 8541-8560.
For preliminary work conducted in our laboratories see: Panek, J . S.;
Yang, M. Y.; Solomon, J . Tetrahedron Lett. 1995, 36, 1003-1006.
(7) Masse, C. E.; Panek, J . S. Chem. Rev. 1995, 95, 1293-1316.
mode of addition. Homologation of the homoallylic ether
7 by treatment with the ester enolate of benzyl acetate
gave a â-tertiary alcohol which was immediately con-
verted to the tertiary acetate under DMAP-catalyzed
acetylation conditions. Oxidative cleavage of the (E)-
olefin by ozonolysis furnished aldehyde 8. This was
followed by a chelation controlled asymmetric allylsilane
addition reaction to install the C11 hydroxyl stereocenter
(diastereoselection ) 28:1 anti/syn). The 1,3-anti rela-
tionship is believed to arise from nucleophilic addition
to a titanium chelate between the C13 benzyloxy group
and the aldehyde carbonyl.8 Elaboration of the C14-C15
(Z)-double bond was initiated by cleavage of the terminal
olefin to give the â-(silyloxy) aldehyde which was masked
as the dimethyl acetal 9. Cleavage of the benzyl groups
via hydrogenation and simultaneous cyclization of the
derived hydroxy acid gives the lactone, which upon
elimination of the tertiary â-acetoxy group with DBU
gave the R,â-unsaturated lactone 10. Subsequently, the
(8) For a discussion of chelation-controlled carbonyl addition see:
Reetz, M. T. Acc. Chem. Res 1993, 26, 462-468.
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