11244
J. Am. Chem. Soc. 2000, 122, 11244-11245
Scheme 1
Scheme 2
Scheme 3
Highly Stereocontrolled Synthesis of Carbacyclin
from Acyclic Starting Materials via Ti(II)-Mediated
Tandem Cyclization
Sentaro Okamoto, Kandasamy Subburaj, and Fumie Sato*
Department of Biomolecular Engineering
Tokyo Institute of Technology, 4259 Nagatsuta-cho
Midori-ku, Yokohama, Kanagawa 226-8501, Japan
ReceiVed August 10, 2000
Since the discovery of prostaglandin I2 (prostacyclin) which
plays an important role in human physiology, a number of
chemically and metabolically stable prostaglandin I2 analogues
have been developed as clinically effective agents such as
antithrombotic drugs. Among these analogues, carbacyclin (1) is
one of the most attractive agents, and its synthesis has attracted
much interest.1 Available synthetic approaches to 1 usually start
from five-membered cyclic compounds such as the Corey lactone
(or its derivatives) and bicyclo[3.3.0]octan-3-ones.2 Herein we
report a highly stereocontrolled construction of the carbacyclin
framework starting from acyclic hydrocarbons where a titanium-
(II)-mediated multistep sequential transformation in a single
reaction vessel plays a key role.3
Recently, we have developed several synthetically useful
reactions mediated by a divalent titanium reagent, XTi(O-i-Pr)3
(X ) O-i-Pr or Cl)/2 equiv of i-PrMgCl.4 One of these reactions
is a one-pot preparation of bicyclo[3.3.0]octanes 2 having a side
chain by the Ti(II)-mediated tandem cyclization of 2,7-dienoates
3 and subsequent reaction with aldehydes 4, which might proceed
through the reaction mechanism shown in Scheme 1.5 Although
the stereochemistry of 2 thus produced has not been determined
with the exception of the cis-ring junction of 2, we anticipated
that the reaction of the titanabicyclic intermediate with the
aldehyde would proceed through the convex face and, thus, the
relative configuration of three consecutive stereogenic centers on
the ring of 2 would be controlled as depicted in Scheme 1.
With this assumption, we planned one-pot preparation of
carbacyclin intermediate 2a using ethyl (E,E)-5-alkylidene-2,7-
octadienoate (3a) as the starting 2,7-bis-unsaturated ester and (E)-
2-octenal (4a) as an aldehyde. From 2a, carbacyclin was expected
to be prepared readily by stereoselective reduction of the ketone
moiety and isomerization of the allylic alcohol moiety as
summarized in Scheme 2.
As shown in Scheme 3, the starting 3a was readily synthesized
from readily available 56 in 22% overall yield by using the Ti-
(1) Reviews: (a) Schinzer, D. Carbacyclines: Stable Analogs of Prosta-
cyclines. In Organic Synthesis Highlights II; Waldmann, H., Ed.; VCH: New
York, 1995; pp 301-307. (b) Collins, P. W.; Djuric, S. W. Chem. ReV. 1993,
93, 1533.
(2) For syntheses of 1, see: (a) Kojima, K.; Sakai, K. Tetrahedron Lett.
1978, 3743. (b) Nicolaou, K. C.; Sipio, W. J.; Magolda, R. L.; Seitz, S.;
Barnette, W. E. J. Chem. Soc., Chem. Commun. 1978, 1067. (c) Shibasaki,
M.; Ueda, J.; Ikegami, S. Tetrahedron Lett. 1979, 433. (d) Morton, D. R., Jr.;
Brokaw, F. C. J. Org. Chem. 1979, 44, 2880. (e) Aristoff, P. A. J. Org. Chem.
1981, 46, 1954. (f) Shibasaki, M.; Sodeoka, M.; Ogawa, Y. J. Org. Chem.
1984, 49, 4096. (g) Hutchinson, D. K.; Fuchs, P. L. J. Am. Chem. Soc. 1987,
109, 4755. (h) Nagao, Y.; Nakamura, T.; Ochiai, M.; Fuji, K.; Fujita, E. J.
Chem. Soc., Chem. Commun. 1987, 267. (i) Sodeoka, M.; Ogawa, Y.; Kirio,
Y.; Shibasaki, M. Chem. Pharm. Bull. 1991, 39, 309.
(3) An effort to synthesize carbacyclin from acyclic starting materials has
been made by Negishi et al. where the zirconium-mediated enyne cyclization
is a key reaction: Negishi, E.; Pour, M.; Cederbaum, F. E.; Kotora, M.
Tetrahedron 1998, 54, 7057.
(4) Reviews for synthetic reactions mediated by the titanium(II) reagent:
Sato, F.; Urabe, H.; Okamoto, S. Pure Appl. Chem. 1999, 71, 1511. Sato, F.;
Urabe, H.; Okamoto, S. J. Synth. Org. Chem. Jpn. 1998, 56, 424. Sato, F.;
Urabe, H.; Okamoto, S. Synlett 2000, 753. Sato, F.; Urabe, H.; Okamoto, S.
Chem. ReV. 2000, 100, 2835.
(5) Suzuki, K.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 1996, 118, 8729.
Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc. 1997, 119, 10014.
(II)-mediated coupling reaction developed by us recently7 and
the Suzuki-Miyaura coupling reaction8 as the key steps. The
(6) Compound 5 was prepared from 2-buten-1,4-diol through a three-step
reaction in 72-85% yield. See Supporting Information.
(7) Takayama, Y.; Gao, Y.; Sato, F. Angew. Chem., Int. Ed. Engl. 1997,
36, 851. Okamoto, S.; Takayama, Y.; Gao, Y.; Sato, F. Synthesis 2000, 975.
10.1021/ja002974x CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/01/2000