Formal enantioselective synthesis of (+)-estrone

Article abstract of DOI:10.1021/ol063052n

(Chemical Equation Presented) A formal total synthesis of (+)-estrone (4% overall yield; ca. 12 steps) could be achieved via the Torgov diene. An asymmetric allylic substitution is the key step for the construction of the chiral quaternary carbon center of a synthetic intermediate which was converted in four steps to the Torgov diene.

Full text of DOI:10.1021/ol063052n

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1021-1023
Formal Enantioselective Synthesis of
)-Estrone
(+
Darunee Soorukram and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstrasse 5-13, Haus F, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received December 18, 2006
ABSTRACT
A formal total synthesis of (+)-estrone (4% overall yield; ca. 12 steps) could be achieved via the Torgov diene. An asymmetric allylic substitution
is the key step for the construction of the chiral quaternary carbon center of a synthetic intermediate which was converted in four steps to
the Torgov diene.
(+)-Estrone (1) together with estradiol and progesterone are
the most important female sex hormones. (+)-Estrone is only
found as trace in plants and has been isolated from the urine
of pregnant women.1 Several elegant total syntheses of 1
have been reported.2 Our synthetic approach has focused on
the presence of a chiral quaternary center at position 13
(Scheme 1) because we have recently reported a general
intermediate 3 (Scheme 1). We expected that the alkenyl
iodide 3 could be converted into the Torgov diene by using
Heck methodology.7,8 The chiral cycloalkenyl iodide 3 should
be prepared using a copper(I)-mediated anti-SN2′-allylic
substitution3 of the dialkylzinc 4 with the chiral cyclopentene
diol derivative 5. The zinc organometallic 4 will be readily
available from Dane’s diene (6)9 using a hydroboration, B/Zn
exchange sequence.10
We focused first our attention on the preparation of the
cyclopentene diol derivative 5, starting from 4-hydroxy-3-
Scheme 1
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stereoselective synthesis of chiral quaternary centers3,4 using
copper(I)-mediated anti-SN2′-allylic substitutions.5 Our ret-
rosynthetic analysis starting from the Torgov diene (2)6
disconnects the C(8)-C(14) bond leading to the key chiral
10.1021/ol063052n CCC: $37.00
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methyl-2-cyclopent-2-en-1-one (7) which was conveniently
prepared in two steps from 2,5-dimethylfuran.11 Treatment
of the allylic alcohol 7 with TBSCl (1.2 equiv, imidazole
(1.5 equiv), DMF, 25 °C) followed by an oxidative iodolysis
(I2 (2.5 equiv), PDC (0.3 equiv), CH2Cl2) gives the 2-io-
doenone 8 in 73-77% yield. The CBS reduction12 of rac-8
with BH3‚PhNEt2 using the (S)-MeO CBS catalyst (25 °C,
1.5 h)5a affords the two readily separable diastereoisomers,
cis-9 (46%; 84% ee) and trans-9 (49%; 99% ee). The relative
configuration of cis-9 and trans-9 as well as an evaluation
of the reactivity of the corresponding pentafluorobenzoates
cis-5 and trans-5 were established by performing a copper-
(I)-mediated allylic substitution with Pent2Zn (THF, 25 °C,
12 h). As expected, the only substitution products are the
anti-SN2′-cyclopentenyl iodides 10 (54%; 81% ee) and 11
(68%; 99% ee). A complete transfer of the chiral information
was observed for the two substrates as shown by the
enantiomeric excess of the products 10 and 11. The relative
configuration of 10 and 11 was established by NOE
experiments.13 Because the configuration of the carbon
attached to the TBSO substituent in cis- and trans-5 is not
important for the synthesis outcome, we decided to use for
further steps the trans-pentafluorobenzoate (trans-5) which
was available through the CBS reduction in 99% ee14
(Scheme 2).
(3) (a) Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel, F. F.;
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Kneisel, F. F.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 4627. (c)
Soorukram, D.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 3686.
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E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 389. (b) Martin,
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Synlett 2006, 689. (e) Sklute, G.; Marek, I. J. Am. Chem. Soc. 2006, 128,
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E. Org. Lett. 2005, 7, 2795. (g) Jang, D. O.; Kim, D. D.; Pyun, D. K.;
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Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9544. (j) Taber, D.
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Scheme 2
(5) (a) Soorukram, D.; Knochel, P. Org. Lett. 2004, 6, 2409. (b) Calaza,
M. I.; Hupe, E.; Knochel, P. Org. Lett. 2003, 5, 1059. (c) Calaza, M. I.;
Yang, X.; Soorukram, D.; Knochel, P. Org. Lett. 2004, 6, 529. (d) Alexakis,
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Bernardinelli, G. Eur. J. Org. Chem. 2005, 1332. (i) Polet, D.; Alexakis,
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Chapter 3. (c) Link, J. T.; Overman, L. E. In Metal-Catalyzed Cross
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1999, 576, 1. (e) Donde, Y.; Overman, L. E. In Catalytic Asymmetric
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Knochel, P. J. Org. Chem. 1996, 61, 8229.
We have prepared the required zinc reagent 4 starting from
Dane’s diene (6) which was obtained in two steps from
6-methoxytetralone.15 Thus, the treatment of the diene 6 with
Et2BH9 (1 equiv) for 3 h at 0 °C followed by the reaction
with neat Et2Zn (2 equiv) at 25 °C for 16 h affords the
dialkylzinc 4. The reaction was monitored by GC analysis
of hydrolyzed reaction aliquots.16 As the key step, we have
(13) See Supporting Information.
(14) The performance of the CBS reduction on the racemic mixture of
8 affords a mixture of two products, cis-9 and trans-9, of which only the
trans-isomer (trans-9) is obtained with 99% ee. To avoid the formation of
cis-9 (which is obtained only with 84% ee), we performed an enzymatic
kinetic resolution of rac-7 using porcine pancreatic lipase (PPL) and vinyl
acetate at 25 °C. We have obtained both enantiomers (R)-7 and (S)-7 in
91% ee and in excellent yields. See Supporting Information.
(15) 6-Methoxytetralone was treated with vinylmagnesium chloride (1.2
equiv) in THF at reflux for 1 h, and then the resulting allylic alcohol was
subjected to a dehydration reaction (quinoline, I2 (cat.), benzene, reflux, 2
h) to give Dane’s diene (6) in 83% yield.
(11) Adembri, G.; Giorgi, G.; Lampariello, R. L.; Paoli, M. L.; Sega, A.
J. Chem. Soc., Perkin Trans. 1 2000, 2649.
(12) (a) Cho, B. T. Tetrahedron 2006, 62, 7621. For the asymmetric
reduction with the CBS method, see: (b) Corey, E. J.; Helal, C. J. Angew.
Chem., Int. Ed. 1998, 37, 1986.
(16) Whereas the intermediate borane is not protodeborylated under the
quenching conditions of the reaction aliquots, the zinc reagent 4 produces
cleanly 4-ethyl-7-methoxy-1,2-dihydronaphthalene which allows us con-
veniently to monitor the progress of the reaction.
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Org. Lett., Vol. 9, No. 6, 2007

now reacted the zinc organometallic 4 (2.4 equiv)17 with the
allylic pentafluorobenzoate trans-5 in the presence of CuCN‚
2LiCl (2.4 equiv) in THF (25 °C, 48 h) leading to the anti-
SN2′-substitution product 12 in 66% yield. Removal of the
TBS group provides the alcohol 13 which has allowed us to
determine its enantiopurity by HPLC analysis as well as to
confirm the relative stereochemistry of the adjacent methyl
and hydroxyl groups by NMR analysis (NOE experiments;
Scheme 3).
and oxidation with sodium perborate (NaBO3‚4H2O, 10
equiv, 25 °C, 24 h) affording the ketone 15 in 45% yield.
An acid-mediated ring closure19 (p-TsOH, benzene, 25 °C,
12 h) followed by the removal of the TBS group by using
TBAF (2 equiv, THF, 25 °C, 12 h) and subsequent oxidation
with CrO3 on Celite20 furnished Torgov diene (2) in 61%
overall yield and 99% ee, mp ) 141-144 °C (lit. mp )
20
20
144-145 °C),2h,i [R]D ) -95.6 (c 0.5, CHCl3) (lit. [R]D
) -102.6 (c 0.904, CHCl3)2h,i (Scheme 5).21 The conversion
Scheme 5
Scheme 3
We had planned to complete the synthesis of the Torgov
diene (2) by performing a Heck ring-closure reaction.8
However, the reaction of the unsaturated iodide 12 with Pd-
(OAc)2 (15 mol %), PPh3 (30 mol %), and Ag2CO3 (1.1
equiv) in THF at 65 °C for 12 h18 leads only to the
unexpected pentacyclic product 14 in 57% yield (Scheme
4).7i,j
of the diene 2 into (+)-estrone (1) has been previously
reported by Quinkert and Ogasawara in three steps and 32-
37% yield.2h,i
Thus, we have performed, using a Cu(I)-mediated anti-
SN2′-substitution, an enantioselective synthesis of the Torgov
diene (2) in nine steps and 12% yield starting from
4-hydroxy-3-methylcyclopent-2-en-1-one (7). This represents
a formal total synthesis of (+)-estrone (1) in 12 steps and
4% overall yield. It demonstrates the utility of the Cu-
catalyzed SN2′-substitution for constructing quaternary cen-
ters with high enantioselectivity.
Scheme 4
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the DFG, and Merck Research Laboratories (MSD)
for financial support. We also thank Chemetall GmbH
(Frankfurt) and BASF AG (Ludwigshafen) for the generous
gift of chemicals and Schering AG (Berlin) for providing
the racemate Torgov diene to us.
Supporting Information Available: Experimental pro-
cedures and characterization of the compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
However, we achieved the desired ring closure by convert-
ing the cyclopentenyl iodide 12 to the corresponding ketone
15 by a method previously developed in our laboratory.3c
Thus, in a one-pot procedure, the iodide 12 was reacted with
t-BuLi (2 equiv, -78 °C, 0.5 h) in THF followed by the
addition of B(OMe)3 (2.5 equiv, -78 °C to 25 °C, 24 h)
OL063052N
(19) (a) Windholz, T. B.; Fried, J. H.; Patchett, A. A. J. Org. Chem.
1963, 28, 1092. (b) Kuo, C. H.; Taub, D.; Wendler, N. L. J. Org. Chem.
1968, 33, 3126. (c) Enev, V. X.; Mohr, J.; Harre, H.; Nickisch, K.
Tetrahedron: Asymmetry 1998, 9, 2693.
(17) The zinc organometallic 4 was used as an excess to obtain the
product 12 with a short reaction time under mild reaction conditions.
(18) Fox, M. E.; Li, C.; Marino, J. P., Jr.; Overman, L. E. J. Am. Chem.
Soc. 1999, 121, 5467.
(20) Gilchrist, T. L.; Summersell, R. J. J. Chem. Soc., Perkin Trans. 1
1988, 2603.
(21) The racemic Torgov diene was generously obtained from Schering
AG (Berlin, Germany).
Org. Lett., Vol. 9, No. 6, 2007
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