Synthesis of (-)-terpestacin via catalytic, stereoselective fragment coupling: Siccanol is terpestacin, not 11-epi-terpestacin

Article abstract of DOI:10.1021/ja0373925

(-)-Terpestacin (1a, naturally occurring enantiomer) and (+)-11-epi-terpestacin (1b) were prepared using catalyst-controlled, stereoselective intermolecular reductive couplings of alkyne 4 and aldehyde 5. Related to enantioselective methods developed in o

Full text of DOI:10.1021/ja0373925

Published on Web 08/30/2003
Synthesis of (-)-Terpestacin via Catalytic, Stereoselective Fragment
Coupling: Siccanol Is Terpestacin, Not 11-epi-Terpestacin
Johann Chan and Timothy F. Jamison*
Massachusetts Institute of Technology, Department of Chemistry, Cambridge, Massachusetts 02139
Received July 18, 2003; E-mail: tfj@mit.edu
Scheme 1
The sesterterpene terpestacin (1a) and structurally related
compounds (Scheme 1) have attracted considerable attention from
several scientific communities. Originally isolated in a search for
inhibitors of the formation of syncytia by HIV-infected T cells,
terpestacin also inhibits angiogenesis.1 In 1993 Oka disclosed the
solid-state structure and absolute stereochemistry of terpestacin.2
Fusaproliferin (2), an acetate ester of terpestacin, was isolated
shortly thereafter.3 In 1998 Tatsuta described an enantiospecific
synthesis of terpestacin,4 and Myers recently reported enantiose-
lective total syntheses of both natural products.5 In a thorough series
of investigations, Myers also conclusively established the absolute
configurations of both terpestacin and fusaproliferin. At ap-
proximately the same time, Miyagawa reported that another natural
product, siccanol, is diastereomeric to terpestacin at the allylic
carbinol in the 15-membered ring (C11) and renamed it accord-
ingly: 11-epi-terpestacin (1b).6
Herein we report enantiospecific syntheses of both (-)-terpesta-
cin (1a, naturally occurring enantiomer5) and (+)-11-epi-terpestacin
(1b) using catalyst-controlled, stereoselective intermolecular reduc-
tive couplings of alkyne 4 and aldehyde 5. Related to enantiose-
lective methods developed in our laboratory,7 these stereoselective
fragment couplings were instrumental in confirming that “siccanol”
is not 11-epi-terpestacin, but in fact is (-)-terpestacin itself.
The remaining three stereogenic centers in 1a and 1b are of the
same absolute configuration and were created by relaying the
configuration of C23 to a quaternary carbon stereogenic center (C1)
and its neighbor (C15), which together also comprise the junction
of the 5- and 15-membered rings (eq 1). Conjugate addition to
diastereomers nor any of three other possible regioisomers could
be detected (1H NMR).10
Conjugate addition of a lithium cuprate reagent derived from
iodide 9 occurred with complete diastereoselectivity in the manner
predicted above. To place the triple bond in the position required11
for the catalytic reductive couplings, terminal acetylene 10 was
isomerized with KOt-Bu in DMSO12 in 90-95% yield. The other
coupling partner (aldehyde 5) was prepared from diol 12 (52% yield,
three steps), itself obtained by a site-selective (and enantioselective)
catalytic dihydroxylation of (E,E)-farnesyl acetate.13
Reductive, nickel-catalyzed fragment coupling of alkyne 4 and
aldehyde 5 using Bu3P as a ligand was completely nondiastereo-
selective (1:1). A further challenge presented by this coupling is
that catalytic additions to internal acetylenes of the type RCH2-
CtC-Me, i.e. with substitutents nearly identical in electronic nature
and steric demand, are typically nonregioselective.14 We were
therefore pleased to discover that a catalyst incorporating the
P-chiral ferrocenylphosphine ligand (R)-147a favored the diastere-
omer (3:1) and regioisomer (2:1) corresponding to (-)-terpestacin
in a combined yield of 70%.15 The diastereomer corresponding to
11-epi-terpestacin (11-epi-13, terpestacin numbering) was obtained
with equal regioselectivity and equal and opposite diastereoselec-
tivity simply by using (S)-14, the enantiomer of the ligand used in
the terpestacin-series coupling.
After suitable functional group manipulation, an intramolecular
allylation constructed the 15-membered ring. Overall, farnesyl
acetate served as a convenient source of an allylic electrophile, 12
carbon atoms and two E alkenes in the 15-membered ring.
Installation of the critical quaternary methyl group (C19) at C1
was best accomplished under rather unusual conditions. Treatment
of 15 with NaH and MeI in toluene gave only recovered starting
oxabicyclo[3.3.0]octenone 6 was expected to occur on the convex
face, but prediction of the major diastereomer in a subsequent
enolate alkylation was less clear (desired approach shown; El )
MeI) since a substituent on this face, adjacent to the site of
alkylation, might strongly influence the stereochemical course of
the reaction. Moreover, since the net stereochemical impact of a
fused 15-membered ring was unclear a priori, we allowed for
flexibility in the order of installation of the C1 Me group (C19)
and the rest of the carbon framework.4 Another benefit of lowering
the oxidation state of C17 and connecting it to the C24 oxygen to
form a tetrahydrofuran ring (e.g., 3a-b, Scheme 1) was concomitant
protection of two otherwise interfering functional groups, the latent
1,2-diketone and the primary hydroxyl group.
An NMO-promoted,8 intermolecular Pauson-Khand reaction
between dihydrofuran 79 and the hexacarbonyldicobalt complex of
trimethylsilylacetylene (8) afforded 6, the oxabicyclo[3.3.0]octenone
discussed above, in 51% yield (Scheme 2). Notably, no other
9
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C O M M U N I C A T I O N S
Scheme 2
material, but added H2O16 (200 mol % relative to 15) afforded the
desired product (16) in >95:5 dr (nOe).
References
(1) (a) Oka, M.; Iimura, S.; Tenmyo, O.; Sawada, Y.; Sugawara, M.; Ohkusa,
N.; Yamamoto, H.; Kawano, K.; Hu, S.-L.; Fukagawa, Y.; Oki, T. J.
Antibiot. 1993, 46, 367. (b) Jung, H. J.; Lee, H. B.; Kim, C. J.; Rho,
J.-R.; Shin, J.; Kwon, H. J. J. Antibiot. 2003, 56, 492.
(2) (a) Iimura, S.; Oka, M.; Narita, Y.; Konishi, M.; Kakisawa, H.; Gao, Q.;
Oki, T. Tetrahedron Lett. 1993, 34, 493. (b) Oka, M.; Iimura, S.; Narita,
Y.; Furumai, T.; Konishi, M.; Oki, T.; Gao, Q.; Kakisawa, H. J. Org.
Chem. 1993, 58, 1875. (c) See also: Schlegel, B.; Schmidtke, M.; Do¨rfelt,
H.; Kleinwa¨chter, P.; Gra¨fe, U. J. Basic Microbiol. 2001, 41, 179.
(3) (a) Randazzo, G.; Fogliano, V.; Ritieni, A.; Mannina, L.; Rossi, E.;
Scarallo, A.; Segre, A. L. Tetrahedron 1993, 49, 10883. (b) Santini, A.;
Ritieni, A.; Fogliano, V.; Randazzo, G.; Mannina, L.; Logrieco, A.;
Benedetti, E. J. Nat. Prod. 1996, 59, 109.
Completion of the synthesis of (-)-terpestacin required three
further transformations, TBAF-mediated removal of the TIPS
protective group and oxidative ring opening of 3a by way of enolate
hydroxylation17 and isomerization of the resulting hemiketal (17)
under mild, basic conditions. Overall, preparation of 1a and 1b
each required 17 steps from 7 (longest linear sequence).18
The spectroscopic data we obtained for our synthetic (-)-
terpestacin are identical in all respects to those previously reported
for natural and synthetic material.19 However, “siccanol” differs
strikingly from our synthetic 11-epi-terpestacin and in fact is
indistinguishable from (-)-terpestacin. A sample of natural material
kindly provided to us by Professor Miyagawa confirmed the
structural reassignments“siccanol” is (-)-terpestacin, not 11-epi-
terpestacin (see Supporting Information). Our hypothesis is that the
Mosher ester analysis used in the original assignment of the C11
configuration of siccanol is ultimately the origin of this discrepancy.
A detailed analysis of the data in the literature relevant to this issue,
and a full account of the syntheses summarized above will be
reported in due course.
(4) Tatsuta, K.; Masuda, N. J. Antibiot. 1998, 51, 602.
(5) Myers, A. G.; Siu, M.; Ren, F. J. Am. Chem. Soc. 2002, 124, 4230.
(6) Nihashi, Y.; Lim, C.-H.; Tanaka, C.; Miyagawa, H.; Ueno, T. Biosci.
Biotechnol. Biochem. 2002, 66, 685.
(7) (a) Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156. (b) Miller,
K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442.
(c) Chan, J.; Huang, W.-S.; Jamison, T. F. Org. Lett. 2000, 2, 4221.
(8) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett. 1990,
31, 5289.
(9) Botteghi, C.; Consiglio, G.; Ceccarelli, G.; Stefani, A. J. Org. Chem. 1972,
37, 1835. Resolved with (+)-(Ipc)2BH (>99% ee; 55% conversion).
(10) Kerr, W. J.; McLaughlin, M.; Pauson, P. L.; Robertson, S. M. J.
Organomet. Chem. 2001, 630, 104.
(11) Direct installation of the methylpropargyl group by conjugate addition of
allenylstannane reagents to 6 was unsuccessful: Haruta, J.; Nishi, K.;
Matsuda, S.; Akai, S.; Tamura, Y.; Kita, Y. J. Org. Chem. 1990, 55, 4853.
(12) (a) Takano, S.; Sekiguchi, Y.; Sato, N.; Ogasawara, K. Synthesis 1987,
139. (b) Recent application in total synthesis: Thompson, C. F.; Jamison,
T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2000, 122, 10482.
(13) (a) Crispino, G. A.; Ho, P. T.; Sharpless, K. B. Science 1993, 259, 64.
(b) Corey, E. J.; Noe, M. C.; Lin, S. Tetrahedron Lett. 1995, 36, 8741.
(14) Notable exceptions: (a) Et vs Me (2:1): Larock, R. C.; Yum, E. K. J.
Am. Chem. Soc. 1991, 113, 6689. (b) i-Bu vs Me (7.3:1): Molander, G.
A.; Retsch, W. H. Organometallics 1995, 14, 4570. (c) n-Undecyl vs Me
(2.4:1): Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726.
(15) R)-P-phenyl-P-(p-xylyl)-ferrocenylphosphine provided a higher overall
yield (85%; 2.1:1 dr, 2.6:1 regioselectivity); see Supporting Information.
(16) Sodium hydroxide, finely dispersed in toluene, is likely the operative base,
and it should be noted that the use of solvents other than toluene led to
nearly exclusive O-alkylation of the enolate.
Acknowledgment. We are grateful to Professor Hisashi Miya-
gawa, Kyoto University, for a generous supply of natural 1a. We
thank Mr. Ryan K. Zeidan (Pfizer SURF) and Mr. Jianlong Tan
for experimental assistance. This work was supported by the
National Institute of General Medical Sciences (GM-063755) and
by Bristol Myers-Squibb and Boehringer-Ingelheim (research
assistantships to J.C.). We also thank the NSF (CAREER CHE-
0134704), Merck Research Laboratories, Johnson & Johnson,
Amgen, and MIT for generous financial support. The NSF (CHE-
9809061 and DBI-9729592) and NIH (1S10RR13886-01) provide
partial support for the MIT Department of Chemistry Instrumenta-
tion Facility.
(17) Hartwig, W.; Born, L. J. Org. Chem. 1987, 52, 4352.
(18) epi-Terpestacin (1b) was prepared by the same sequence from 11-epi-13.
The same nOe shown for 16 (Scheme 2) was observed in 11-epi-16.
(19) That is, refs 2c and 5, and all data in refs 1a, 2a,b, and 4, except [R]D,
which Myers demonstrated to be artifactual (see ref 5).
Supporting Information Available: Experimental procedures and
data; tabulated NMR data and spectra of natural and synthetic 1a and
of 1b (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
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