A concise route to (+)-estrone

Article abstract of DOI:10.1021/ol005988g

(Formula presented) A concise route to the Torgov diene, the key intermediate of estrone, has been devised using a chiral dioxycyclopentenone as the starting material by employing a sequence of five steps of reactions involving a Lewis acid-mediated Diels-Alder reaction with Dane's diene.

Full text of DOI:10.1021/ol005988g

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1915-1917
A Concise Route to (+)-Estrone
Keigo Tanaka, Hiromi Nakashima, Takahiko Taniguchi, and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
konol@mail.cc.tohoku.ac.jp
Received April 26, 2000
ABSTRACT
A concise route to the Torgov diene, the key intermediate of estrone, has been devised using a chiral dioxycyclopentenone as the starting
material by employing a sequence of five steps of reactions involving a Lewis acid-mediated Diels−Alder reaction with Dane’s diene.
We previously reported a facile six-step synthesis1 of estrone
(+)-5, starting from enantiopure ketodicyclopentadiene2,3
(-)-1. In this synthesis, the Lewis acid-mediated Diels-
Alder reaction between the chiral enone (-)-1 and Dane’s
diene4 2 proceeded diastereoselectively in an exo-mode (A),
alleviating the steric repulsion between the diene and the
dienophile, to give rise to adduct 3 having trans-C9-C14
stereochemistry (steroid numbering) matching that of (+)-
estrone 5. Moreover, the following introduction of the
quaternary 18-methyl functionality occurred diastereoselec-
tively from the convex face of adduct 3 to give the requisite
trans C-D product 4 from which the cyclopentene blocking
group on the D ring could be removed on thermolysis
(Scheme 1). Since we recently developed an efficient
preparation of the enantiopure bicyclic dioxycyclopentenone
6 in both enantiomeric forms,6,7 we planned to use it as a
synthetic equivalent of ketodicyclopentadiene 1 in the above
estrone synthesis, making use of the 1,3-dioxolane moiety
of the former enone as the cyclopentene moiety of the latter
enone both in a steric and a functional sense. We wish to
report here the outcome of the reaction between 6 and 2,
generating the adduct with the undesired cis-C9-C14 stere-
ochemistry and leading eventually to a new enantiocontrolled
synthesis of Torgov diene8,9 13, the key intermediate of
estrone 5, by modification on the basis of the stereochemical
outcome observed.
To determine the regio- and stereochemistry of the key
Diels-Alder reaction, a reaction of racemic enone (()-6 and
Dane’s diene 2 was first examined in the presence of a Lewis
(7) For previous syntheses, see: (a) Cocu, F. G.; Posternak, T. HelV.
Chem. Acta 1972, 55, 2838. (b) Bestmann, H. J.; Moenius, T. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 994. (c) Johnson, C. R.; Penning, T. D. J. Am.
Chem. Soc. 1986, 108, 5655. (d) Ohrui, H.; Konno, M.; Meguro, H. J. Agric.
Biol. Chem. 1987, 51, 625. (e) Borcherding, D. R.; Scholtz, S. A.; Borchardt,
R. T. J. Org. Chem. 1987, 52, 5457. (f) Deardorff, D. R.; Shambayati, S.;
Myles, D. C.; Heerding, D. J. Org. Chem. 1988, 53, 3416. (g) Flann, C. J.;
Mash, E. A. Synth. Commun. 1988, 18, 391. (h) Belanger, P.; Prasit, P.
Tetrahedron Lett. 1988, 29, 5521. (i) Johnson, C. R.; Penning, T. D. J.
Am. Chem. Soc. 1988, 110, 4726. (j) Hudlicky, T.; Luna, H.; Barbieri, G.;
Kwart, L. D. J Am. Chem. Soc. 1988, 110, 4735. (k) Takano, S.; Inomata,
K.; Ogasawara, K. Chem. Lett. 1989, 359. (l) Ali, S. M.; Ramesh, K.;
Borchardt, R. T. Tetrahedron Lett. 1990, 31, 1509.
(8) Anachenko, S. N.; Torgov, I. V. Tetrahedron Lett. 1963, 1553.
(9) For previous chiral syntheses of the Torgov diene, see: (a) refs 5b
and 5c. (b) Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 1996, 37, 7403.
(10) For recent syntheses of estrone steroids, see: (a) Tietze, L. F.; No¨bel,
T.; Spescha, M. J. Am. Chem. Soc. 1998, 120, 8971. (b) Rigby, J. H.;
Warshakoon, N. C.; Payen, A. J. J. Am. Chem. Soc. 1999, 121, 8237.
(1) Takano, S.; Moriya, M.; Ogasawara, K. Tetrahedron Lett. 1992, 1909.
(2) For a review, see: Ogasawara, K. J. Synth. Org. Chem. Jpn. 1996,
54, 29.
(3) Sugahara, T.; Kuroyanagi, Y.; Ogasawara, K. Synthesis 1996, 1101.
(4) Dane, E. Angew Chem. 1939, 52, 655. Dane, E.; Schmitt. Leibigs
Ann. Chem. 1938, 536.
(5) For extensive studies on steroid synthesis using Dane’s diene, see:
(a) Quinkert, G.; del Grosso, M.; Bucher, A.; Bats, J. W.; Du¨rner, G.
Tetrahedron Lett. 1991, 32, 3357. (b) Quinkert, G.; del Grosso, M.; Bucher,
A.; Bauch, M.; Do¨ring, W.; Bats, J, W.; Du¨rner, G. Tetrahedron Lett. 1992,
33, 3617. (c) Quinkert, G.; del Grosso, M.; Do¨ring, A.; Do¨ring, W.;
Schenkel, R. I.; Bauch, M.; Dambacher, G. T.; Bats, J. W.; Zimmermann,
G.; Du¨rner, G. HelV. Chim. Acta 1995, 78, 1345. (d) Schuster, T.; Bauch,
M.; Du¨rner, Go¨bel, M. W. Org. Lett. 2000, 2, 179.
(6) Nakashima, H.; Sato, M.; Taniguchi, T.; Ogasawara, K. Synthesis
2000, 817.
10.1021/ol005988g CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/01/2000

Scheme 1
acid. It was found that the reaction proceeded stereo- and
regioselectively without double bond migration in the pres-
ence of diethylaluminum chloride1,5a-c (1.3 molar equiv) in
dichloromethane at -78 °C to give the single adduct (()-7
in 89% yield after 2 h. As expected, the dioxolane moiety
of enone (()-6 served as an excellent stereocontrolling
element similar to the cyclopentene moiety of ketodicyclo-
pentadiene 1 in the reaction with Dane’s diene 2. However,
NOE examination revealed that the adduct 7 obtained has
the undesired cis-C9-C14 stereochemistry, indicating that the
cycloaddition proceeded diastereoselectively by following the
orbital-controlled endo rule from the opposite face of the
dioxolane moiety (B) (Scheme 2).
CHCl3), in 83% yield on exposure to iodine in a pyridine-
carbon tetrachloride (1:1) solution at 0 °C to room temper-
ature for 2 h.11 To replace the iodine with a methyl
functionality, (-)-8 was treated with tetramethylstannane (3
equiv) in the presence of dichlorobis(benzonitrile)palladium-
(II) (5 mol %), copper(I) iodide (10 mol %), and tripheny-
larsine (10 mol %) in N-methylpyrrolidinone12 to give the
R-methyl enone (+)-9, [R]24D +17.0 (c 0.44, CHCl3), in 76%
yield after 2 h at 75 °C. Reaction of 9 with Dane’s diene 2
(1.3 equiv) in the presence of diethylaluminum chloride1 (1.2
equiv) in dichloromethane at -78 °C for 2 h furnished the
single adduct (+)-10, [R]28 +142.8 (c 0.88, CHCl3),
D
diastereoselectively, in 92% yield. The product was found
to have cis-C9-C14 stereochemistry by NOE experiment,
indicating that the cycloaddition occurred in an endo-mode
(C) as the nonmethylated enone 6 (Scheme 3).
Scheme 2
Scheme 3
Moreover, as adduct 7 was found to be unstable under
the strongly basic conditions required for the introduction
of the quaternary 18-methyl functionality,1 we chose an
alternative route to reach (+)-estrone10 5. Thus, to avoid
diastereoselective construction of the trans-C9-C14 stereo-
chemistry in the cycloaddition stage as well as to avoid
introduction of the quaternary stereogenic center in the later
stage, we changed our target to the Torgov diene8 (+)-13,
having a single chiral quaternary stereogenic center, which
has been used as the key intermediate in industrial synthesis
of estrone 5.
To obtain the Torgov diene (+)-13, adduct (+)-10 was
first treated with an aluminum amalgam7i,13 in aqueous
(11) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.
Tetrahedron Lett. 1992, 33, 917.
(12) Bellina, F.; Carpita, A.; Ciucci, D.; DeSantis, M.; Rossi, R.
Tetrahedron 1993, 49, 4677.
(13) Nakashima, H.; Sato, M.; Taniguchi, T.; Ogasawara, K. Tetrahedron
Lett. 2000, 41, 2639.
Thus, enantiopure enone6 (+)-6 was first transformed into
the R-iodide (-)-8, mp 85.5 °C, [R]28 -10.4 (c 0.74,
D
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Org. Lett., Vol. 2, No. 13, 2000

in HCl-AcOH (0.7 N) at room temperature for 3 h, ketol
11 afforded in one step the Torgov diene (+)-13, mp 142-
143 °C, [R]25D -96.5 (c 0.20, CHCl3) [lit. mp 145-146 °C,
[R]20 -102.6 (c 0.904, CHCl3);9a mp 141-144 °C, [R]24
Scheme 4
D
D
-98.46 (c 0.9, CHCl3)],9b in 83% yield presumably via
transient diene 12. Conversion of the Torgov diene (+)-13
into estrone (+)-5 has been carried out in three steps without
difficulty9 (Scheme 4).
In short, we have devised a concise route to (+)-estrone
5 via the Torgov diene 13 starting from chiral dioxycyclo-
pentenone building block (+)-6 which exhibited endo-
selectivity in the convex-face selective Diels-Alder reaction
with Dane’s diene 2 in the presence of a Lewis acid.
Acknowledgment. The authors thank the Ministry of
Education, Science, Sports and Culture, Japan, for financial
support.
ethanol (75%) to give â-ketol (+)-11, mp 135-137 °C,
[R]27D +241.6 (c 0.36, CHCl3), in 84% yield. Upon stirring
OL005988G
Org. Lett., Vol. 2, No. 13, 2000
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