Simple, Catalytic Enantioselective Syntheses of Estrone and Desogestrel

Article abstract of DOI:10.1021/ja048808x

Highly enantioselective and very short syntheses of the bioactive forms of estrone (3) and desogestrel (4) are described using a chiral oxazaborolidinium catalyst (2) in the key initial step. Enantiomerically pure estrone was synthesized in eight steps from the readily available starting materials diene 5 and α,β-enal 6 via intermediates 8 and 9. Desogestrel was synthesized using a similar strategy from diene 5 and α,β-enal 11 via intermediates 12-17. The efficient syntheses of the chiral catalyst 2 and its enantiomer are also presented. Copyright

Full text of DOI:10.1021/ja048808x

Published on Web 04/22/2004
Simple, Catalytic Enantioselective Syntheses of Estrone and Desogestrel
Qi-Ying Hu, Pankaj D. Rege, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received March 2, 2004; E-mail: corey@chemistry.harvard.edu
Recent studies have demonstrated that the oxazaborolidinium salt
1 and the corresponding triflate are exceptionally potent and
versatile chiral Lewis acids for many enantioselective Diels-Alder
reactions.1-6 Using a wide variety of dienes and dienophiles, many
reactions have been demonstrated to proceed with excellent yield,
enantioselectivity, and structure selectivity. We report in this paper
a number of important further developments in this area, including
(1) efficient synthesis of the catalyst 2 and its enantiomer and (2)
the application of 2 to the enantioselective synthesis of estrone (3)
and the important third-generation oral contraceptive desogestrel
(4).
Because the amino alcohol precursor of catalyst 2 can be
recovered easily for reuse from the initial Diels-Alder step, we
believe that the process shown in Scheme 1 is also practical and
economical.
The key Diels-Alder reaction 5 + 6 f 7 for the above synthesis
of estrone was predicted to proceed in the required way using
catalyst 2 on the basis of previous studies and the mechanistic model
that these investigations had produced.1-5 The catalyst-dienophile
complex 10 when attacked by diene 5 from the sterically less
shielded front side directs the [4+2]-cycloaddition to the observed
product 7. There are several reasons for the strong preference for
[4+2]-cycloaddition to complex 10. Oxazaborolidinium-catalyzed
Diels-Alder reactions of R,â-enals are generally much faster than
those of the corresponding R,â-unsaturated esters, so that the formyl
complexation route via 10 is preferred. The formyl complex is
further stabilized by a formyl C-H‚‚‚O hydrogen bond as indicated
in 10 and as described in detail previously.16 The strong electron-
The new synthesis of estrone (3) commenced with 5 (Dane’s
diene) and followed the pathway that is summarized in Scheme 1.
The use of Dane’s diene for the synthesis of steroids, first discussed
almost 70 years ago,7,8 has a long and convoluted history,9,10 but
for the most part had been disappointing until the more modern
studies of Quinkert’s group.11 Although the Quinkert synthesis
proceeds from 5 with modest yields and enantioselectivity, it is
limited practically by the need for large quantities of Ti(IV)-
TADDOL catalyst (2 equiv), long reaction times (several days) at
-80 °C, and a not easily available dienophile component. As shown
in Scheme 1, the reaction of Dane’s diene12 with the readily
available ester aldehyde 613 under catalysis by 0.2 equiv of 2 affords
the Diels-Alder adduct 7 with 97:3 enantioselectivity and in 92%
isolated yield. Enantiomerically pure 7, mp 121-122 °C, was
obtained from this product simply by one recrystallization from
CH2Cl2-hexanes.14 Reaction of 7 with methylmagnesium bromide
(2 equiv in THF at -40 °C for 1 h) afforded a γ-hydroxy ester
which was directly reduced (LiAlH4 in THF at 0 °C for 1 h) to the
corresponding 1,4-diol, which in turn was oxidized by the Swern
reagent from Me2SO and oxalyl chloride in CH2Cl2 (-78 °C for
30 min and -78 °C to 20 °C over 30 min) to give the keto aldehyde
8 in 78% overall yield from 7. Base-catalyzed aldol cyclization
followed by acid treatment provided the dienone 9 (Torgov diene)15
in 80% yield. The synthesis of estrone from 9 proceeds by the
known sequence: (1) stereospecific reduction of the 14,15-double
bond of 9 (H2, Pd-C) to form the C/D trans-fused dihydro
derivative of 9, (2) reduction of the 8,9-double bond (Et3SiH-CF3-
CO2H) to form the B/C/D trans-anti-trans tetrahydro derivative of
9, and (3) HBr-catalyzed methyl ether cleavage.11b The synthesis
of estrone outlined in Scheme 1 is short, efficient, and enantio-
and stereocontrolled.
donating effect of the methoxy substituent of diene 5 enhances the
nucleophilicity of the endocyclic diene terminus of 5 over that of
the terminal methylene carbon. It is this interesting property of diene
5 that is responsible for the high regioselectivity that characterizes
the catalytic Diels-Alder reaction of 5 with 6 to give adduct 7.
Related work in these laboratories has shown that the tert-
butyldimethylsilyl analogue of 5 shows the same type of regiose-
lectivity, but to an even greater degree than the methyl ether 5.6
The enantioselective total synthesis of desogestrel 4 was carried
out by a series of early steps that paralleled those shown in Scheme
1 for the synthesis of estrone. The synthetic pathway for desogestrel
is outlined in Scheme 2. The catalytic enantioselective [4+2]-
cycloaddition of 5 and R,â-enal 11 proceeded efficiently to form
the required adduct 12 with 66:1 enantioselectivity, and enantio-
merically pure 12 was obtained by a single recrystallization. The
transformation of 12 to the tetracyclic dienone 14 via 13 also
occurred smoothly, as with 7 f 9 and using essentially the same
procedures. The conversion of 14 to desogestrel (4) can be
9
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10.1021/ja048808x CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
Scheme 2
Scheme 3 a
conducted by a number of previously described routes, one of which
is summarized in Scheme 2. Catalytic hydrogenation of 14 to the
14,15-dihydro derivative followed by acid-catalyzed transposition
of the 8,9-double bond to the 9,11-position generates 1517 which
has been converted by reaction with BH3-THF and protection of
hydroxyl at C(17) to the 17R-alcohol 16.18 Oxidation of 16 to the
11-keto derivative and Peterson methyleneation leads to 17,18 a late-
stage intermediate in our recently published route to desogestrel
(4).19
The syntheses of estrone and desogestrel described herein
demonstrate the advances in multistep synthesis that can be realized
with the widespread use of oxazaborolidinium cationic catalysts
of the class represented by 1 and 2. Catalysts 1 and 2 provide
enantiomeric Diels-Alder adducts with similar enantioselectivities,
although one may be somewhat more effective than the other
depending on the substrates. Catalyst 2 and its enantiomer are
readily prepared from (S)- and (R)-2-cyclopentenylacetic acid, 18
and 19, respectively, by the route summarized in Scheme 3.20 We
have also developed an expedient and practical process for the
synthesis of both (S)- and (R)-2-cyclopentenylacetic acid from (()-
trans-2-iodocyclopentanol21 which is described in detail in the
Supporting Information and flowcharted in Scheme 4. Enantio-
selective acetylation (Amano lipase AH), reaction with diphenyl-
methylsilylimidazole, followed by DBU, all in hexanes (one pot),
a (a) SOCl2, 60 °C, 1 h. (b) BnNH2, Et3N, THF, 0 °C, 3 h (98% overall).
(c) LAH, THF, reflux, 4 h (100%). (d) NBS, pentane, 0 °C, 2 h; then CuBr,
CH2Cl2, 0 °C, 3 h (78%). (e) LiOH, DME-H2O, reflux, 1 h (85%). (f)
Me2SO, ClCOCOCl, CH2Cl2, -78 °C, then substrate and Et3N at -78 °C,
1 h (83%). (h) H2 (1 atm), Pd(OH)2-C, AcOH, CH3OH, 2 h (94%). (i)
(o-tolBO)3, C7H8, reflux, 4 h; then concentration and addition of CH2Cl2
and (CF3SO2)2NH.
gave after separation by distillation in vacuo the volatile acetate
(R)-21 (80% over three steps, >95% ee) and undistilled 20. These
were then efficiently transformed into 19 and 18, respectively, as
shown in Scheme 4.
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C O M M U N I C A T I O N S
Scheme 4
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reaction of 1,1-dimethoxyacetone and ethyl 2-(diethoxyphosphoryl)acetate
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times (min): 24.71 for 7 and 18.38 for the enantiomer).
It is hoped that the synthetic methodology described above will
be broadly useful for the synthesis of many complex chiral targets.
Further illustrations are now being developed in our laboratory.
Acknowledgment. We thank Pfizer Inc. for generous financial
support.
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Supporting Information Available: Experimental procedures for
the synthetic sequences described herein, together with characterization
data for reaction products. X-ray diffraction data (CIF) are provided
for the product 7. This material is available free of charge via the
Internet at http://pubs.acs.org.
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