Conversion of Torgov's synthesis of estrone into a highly enantioselective and efficient process

Article abstract of DOI:10.1021/ja0742434

A very direct and efficient conversion of the achiral Torgov diketone into the natural form of O-methyl estrone is described. Copyright

Full text of DOI:10.1021/ja0742434

Published on Web 08/02/2007
Conversion of Torgov’s Synthesis of Estrone into a Highly Enantioselective
and Efficient Process
Ying-Yeung Yeung, Rong-Jie Chein, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received June 11, 2007; E-mail: corey@chemistry.harvard.edu
Scheme 1
In 1963 Torgov and Ananchenko disclosed a remarkably short
synthesis of (()-estrone which was based on the high-yielding
thermal coupling of the readily available components 1 and 2 to
form 3 (Scheme 1).1,2
Although this route provides facile access to racemic estrone,
its modification to a simple enantioselective version has been pro-
blematic.3 We describe herein an effective solution to this classic
unsolved problem, the key to which was the development of a new
method for the enantioselective and diastereoselective reduction of
the achiral Torgov diketone 3. In addition to this route, we have
recently developed a different short and highly enantioselective
synthesis of estrone from 3-methoxy-8-vinyl-5,6-dihydronaphtha-
lene (4), using a catalytic enantioselective Diels-Alder reaction
as the key step.4
Scheme 2
The pathway of synthesis of the natural form of estrone methyl
ether from the Torgov diketone 3 is summarized in Scheme 2. The
initial chirogenic step, the reduction 3 f 5, could not be effected
enantioselectively using oxazaborolidine catalysis with various
boranes as reductants under any of the standard conditions.5
Typically, the reductions were very slow and the enantiomer of 5
was obtained with an enantiomeric purity of only ca. 20-50%.
However, it was possible to modify the process in such a way as
to accelerate the reaction, create a new pathway, and control
absolute stereochemistry. The reduction was best carried out
by the slow addition of 1.8 equiv of catecholborane to a cold
(-50 °C) toluene solution of diketone 3, 0.2 equiv of catalyst 6,
and 0.4 equiv of N,N-diethylaniline. After a reaction time of 3 h at
-50 °C the reaction mixture was quenched in the CH3OH and the
product 5 was isolated by extraction and flash chromatography on
silica in a yield of 86% and enantiomeric purity of 92%. A single
crystallization from ethyl acetate-hexane afforded 5 of 99% ee,
mp 99-101 °C; the structure of 5 was confirmed by X-ray analysis.
Treatment of 5 with methanolic HCl at 65 °C for 2 h generated the
tetracycle 7 which was oxidized without purification by 1-hydroxy-
1,2-benziodoxol-3(1H)-one 1-oxide (IBX) in DMSO at 23 °C for
4 h to give the pure dienone 8, mp 138-140 °C, in 97% yield
overall from 5. Exposure of dienone 8 to 20 equiv of Et3SiH, H2
(1 atm) and Pd-C in C6H6 at 3 °C generated enone 9 which, after
filtration, was directly treated with CF3CO2H and Bu4NI to give
of this new reduction process is due to a number of factors,
including that (1) significant amounts of the catecholborane-
PhNEt2 complex exist in the reaction mixture, (2) there is also free
catecholborane available for activation of the oxazaborolidine by
coordination to the nitrogen of 6, (3) the pre-transition state
assembly 10 is of lower energy than the various alternative
geometries. In the assembly 10 boron is complexed with the
pure estrone methyl ether, mp 163-165 °C, [R]25 +155 (c 1.0,
D
CHCl3), in 88% overall yield from 8. The conversion of the achiral
Torgov intermediate 3 into the natural chiral form of estrone is
remarkably efficient and expeditious.
The key enantioselective reduction 3 f 5 clearly proceeds by a
different pathway from the standard CBS reduction5 since it follows
the opposite stereocourse and since the known variants of the CBS
reduction are not useful with 3, as mentioned above. We believe
that the reversal caused by PhNEt2 can be explained by the pre-
transition-state assembly 10 in which the hydride donor is the
catecholborane-PhNEt2 complex and the ketone is activated by
coordination to the complex of 6 with catecholborane. The success
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J. AM. CHEM. SOC. 2007, 129, 10346-10347
10.1021/ja0742434 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Enantioselective Three Component Reduction of Cyclic 1,3-Diketones
a Based on 90% conversion. b The B-H oxazaborolidine was used as catalyst rather than the B-n-Bu reagent 6. c Based on 85% conversion.
sterically less screened lone electron pair of the carbonyl oxygen,
steric repulsion is minimized, and the nucleophilic hydride is at-
tached to the carbonyl carbon at the sterically more accessible face.
Our new reduction method is more broadly applicable to the
enantioselective reduction of achiral 1,3-diketones, which previously
had only been realized by the use of enzymic processes such as
fermenting yeast reduction.6 Five examples of the enantioselective
reduction of cyclic 1,3-diketones are summarized in Table 1.
Excellent enantioselectivities were observed with 5, 6, and 8-mem-
bered substrates, and yields of chiral â-hydroxyketone generally
were good (entries 1-3 and 5).7 The principal byproduct in each
case was the 1,3-diol produced by further reduction of the initially
formed â-hydroxyketone. The reduction of 2,2-dimethylcyclohep-
tan-1,3-dione (entry 4) was both slower and less enantioselective
than that of the other substrates in Table 1. The absolute configura-
tions of the products of entries 28 and 39 were determined by
comparison of optical rotation of each product with the value
reported previously. The absolute configurations for the products
of entries 1, 4, and 5 were assigned by analogy with the three
examples reported (3 f 5 and Table 1, entries 2 and 3) and from
the application of mechanistic model implicit in the pre-transition-
state assembly 10.
Acknowledgment. R.-J. Chein is the recipient of a Taiwan Merit
Scholarship.
Supporting Information Available: Experimental procedures and
characterization data for all compounds; X-ray crystal structure of 5.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Ananchenko, S. N.; Torgov, I. V. Tetrahedron Lett. 1963, 4, 1553-1558.
(2) See, also: Ananchenko, S. N.; Limanov, V. Y.; Leonov, V. N.;
Rzheznikov, V. N.; Torgov, I. V. Tetrahedron 1962, 18, 1355-1367.
(3) For total syntheses of estrogens see: (a) Zeelen, F. J. Nat. Prod. Rep.
1994, 11, 607-612. (b) Groen, M. B.; Zeelen, F. J. Recl. TraV. Chim.
Pays-Bas 1986, 105, 465-487. For recent examples, see: (c) Rigby, J.
H.; Warshakoon, N. C.; Payen, A. J. J. Am. Chem. Soc. 1999, 121, 8237-
8245. (d) Tietze, L. F.; Nobel, T.; Spescha, M. J. Am. Chem. Soc. 1998,
120, 8971-8977. (e) Tanaka, K.; Nakashima, H.; Taniguchi, T.; Ogasawara,
K. Org. Lett. 2000, 2, 1915-1917. (f) Hanada, K.; Miyazawa, N.;
Ogasawara, K. Chem. Pharm. Bull. 2003, 51, 104-106. (g) Tsogoeva, S.
B.; Durner, G.; Bolte, M.; Gobel, M. W. Eur. J. Org. Chem. 2003, 1661-
1664. (h) Enev, V. S.; Mohr, J.; Harre, M.; Nickisch, K. Tetrahedron:
Asymmetry 1998, 9, 2693-2699. (i) Soorukram, D.; Knochel, P. Org.
Lett. 2007, 9, 1021-1023.
(4) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 5984-
5986.
(5) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-2012.
(6) See: Jones, J. B. Tetrahedron 1986, 42, 3351-3403.
(7) Enantioselectivities for the reduction products of Table 1 were determined
by 1H NMR analysis of the Mosher MTPA esters except for entry 1 which
was analyzed by HPLC using a Chiral Technologies OD column. Full
details appear in the Supporting Information.
The new methodology for the enantioselective reduction of cyclic
achiral 1,3-diketones provides an alternative to the use of fermenting
yeast reduction which suffers from a number of drawbacks,
including the need to use large reaction volumes, troublesome
foaming and copious evolution of CO2 and, finally, difficulties in
extracting water-soluble products.
(8) Lee, S.-F.; Barth, G.; Djerassi, C. J. Am. Chem. Soc. 1981, 103, 295-
301.
(9) Ema, T.; Yagasaki, H.; Okita, N.; Takeda, M.; Sakai, T. Tetrahedron 2006,
62, 6143-6149.
We are currently exploring other applications of the new three-
component process.
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