An efficient synthesis of optically active (2R,3R)-2-methyl-3-[(1R)-1-methylprop-2-enyl]cyclopentanone, a useful chiral building block for synthesis of vitamin D and steroids

Article abstract of DOI:10.1016/S0040-4039(03)00152-7

An efficient synthesis of optically active (2R,3R)-2-methyl-3-[(1R)-1-methylprop-2-enyl]cyclopentanone, a useful chiral building block for synthesis of vitamin D and steroids, has been developed starting from readily accessible optically active secondary propargyl phosphate (R)-2, where the asymmetric Michael addition of a chiral allenyltitanium to alkylidenemalonate 3 is a key reaction.

Full text of DOI:10.1016/S0040-4039(03)00152-7

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Tetrahedron Letters 44 (2003) 2113–2115
An efficient synthesis of optically active (2R,3R)-2-methyl-3-
[(1R)-1-methylprop-2-enyl]cyclopentanone, a useful chiral
building block for synthesis of vitamin D and steroids
Yongcheng Song, Sentaro Okamoto† and Fumie Sato*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259, Nagatsuta-cho, Midori-ku, Yokohama,
Kanagawa 226-8501, Japan
Received 24 December 2002; revised 14 January 2003; accepted 16 January 2003
Abstract—An efficient synthesis of optically active (2R,3R)-2-methyl-3-[(1R)-1-methylprop-2-enyl]cyclopentanone, a useful chiral
building block for synthesis of vitamin D and steroids, has been developed starting from readily accessible optically active
secondary propargyl phosphate (R)-2, where the asymmetric Michael addition of a chiral allenyltitanium to alkylidenemalonate
3 is a key reaction. © 2003 Elsevier Science Ltd. All rights reserved.
3-Substituted-2-methylcyclopentanones of the type 1
shown in Figure 1, which have a stereodefined side-
chain at the 3-position, or their acetal derivatives have
been accepted as useful CD ring synthons of vitamin D,
steroids and their derivatives. Among these compounds,
those having a functionalized side-chain, such as 1b and
1c, have been considered to be versatile since the func-
tionality could be derivatized to a variety of side-
chains.1 Therefore, much effort has been paid to
develop new efficient methodology to synthesize these
cyclopentanones. However, to date, only a limited num-
ber of methods have been reported which allow access
to these cyclopentanones with high optical purity due
to the difficulty in asymmetric construction of the rela-
tive and the absolute stereochemistries with respect to
the side-chain, which correspond to the C-17 and C-20
of steroids, respectively. These synthetic methods
include selective cleavage of bicyclic compounds,2
asymmetric conjugated addition to cyclopentenones,3
and other processes.4 Thus, new efficient methodology
to prepare such cyclopentanones is still highly desirable.
In line with our continuing interest in vitamin D syn-
thesis,5 we report herein an efficient and practical syn-
thesis of optically active (2R,3R)-2-methyl-3-
[(1R)-1-methylprop-2-enyl]cyclopentanone (1c) from an
acyclic compound.
Recently, we have reported that the Michael addition
of chiral allenyltitaniums, generated from readily acces-
sible optically active secondary propargyl phosphates
and a Ti(O-i-Pr)4/2i-PrMgCl reagent,6,7 to alkylidene-
malonates proceeds with excellent diastereo- and enan-
tioselectivity.6a With these results, we expected that the
reaction could be used to synthesize cyclopentanone 1c
efficiently, as shown in Scheme 1 by a retrosynthetic
way.
Figure 1.
Keywords: Michael addition; chiral allenyltitanium; vitamin D;
steroids.
* Corresponding author. Tel.: +81-(0)45-924-5787; fax: +81-(0)45-
924-5826; e-mail: fsato@bio.titech.ac.jp
The allenyltitanium, prepared from (R)-1-methyl-3-
trimethylsilylprop-2-ynyl phosphate (2) with 98.0% e.e.8
and Ti(O-i-Pr)4/2i-PrMgCl, reacted smoothly with
diethyl 3-(tert-butyldimethylsilyloxy)propylidenemalo-
† Present address: Department of Applied Chemistry, Kanagawa Uni-
versity, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686,
Japan. E-mail: okamos10@kanagawa-u.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00152-7

2114
Y. Song et al. / Tetrahedron Letters 44 (2003) 2113–2115
nate (3)9 to afford the expected product anti-4 as the
only detectable isomer in 93% yield, as shown in
Scheme 2. Compound 4 was methylated with NaH and
MeI to give 5 in high yield, which was subsequently
subjected to the decarbethoxylation reaction. To our
satisfaction, in addition to removal of one of the ester
groups, both silyl protective groups of 5 were simulta-
neously removed to afford d-lactone
6
as
a
diastereomeric mixture with respect to the a-stereogenic
center of the carbonyl group in 87% yield. Lactone 6
was then treated with N,O-dimethylhydroxyamine
hydrochloride/AlMe3 reagent10 to give amide 7, which
was successively subjected to partial hydrogenation of
the terminal triple bond and conversion of the hydroxy
to an iodo group by conventional reactions to furnish
iodoamide 8. Compound 8 was smoothly cyclized by
treatment with 2.4 equiv. of tert-butyllithium at −78°C
to afford, after epimerization, the title compound 1c in
60% overall yield from 6.
Scheme 1.
The enantiomeric excess (e.e.) of cyclopentanone 1c
1
thus obtained was determined to be 97.5% by H NMR
analysis after derivatization to 2-methoxy-2-tri-
fluoromethyl-2-phenylacetyl (MTPA) ester 9, as shown
in Scheme 3, indicating the overall enantiospecificity
from 2 to 4 is >99%. Meanwhile, the absolute configu-
ration of 1c was determined after derivatization to a
pair of diastereomeric MTPA ester 10, as shown in
Scheme 3, among which 10 with the (R)-MTPA moiety
displayed identical NMR spectra to those of its known
enantiomer, (S)-MTPA ester of (2S,3S)-2-methyl-3-
[(1R)-1-methyl-2-hydroxyethyl]cyclopentanone.11
Cyclopentanones 1a and 1b have been converted to
hydrindenone, the CD ring portion of vitamin D,
steroids, and their derivatives, by Robinson annulation.
However, the corresponding Robinson annulation of 1c
has not been reported, and thus, we carried out this
transformation. Treatment of 1c with methyl vinyl
ketone in the presence of KOH furnished hydrindenone
11 in 62% yield with 17% recovery of 1c, as shown in
Eq. (1). Compound 11 might serve as a key intermedi-
ate for synthesizing vitamin D derivatives having a
variety of side-chains,12 thanks to the versatility of the
vinyl moiety present in 11.13
Scheme 2. Reagents and conditions: (i) NaH, MeI, THF; (ii)
LiCl, H2O, DMSO, reflux, 8 h, then 1N HCl; (iii) AlMe3 (3
equiv.), Me(OMe)NH·HCl (3 equiv.), THF–CH2Cl2; (iv)
Lindlar’s cat., H2; (v) MsCl, NEt3, THF; (vi) NaI, acetone;
(vii) t-BuLi (2.4 equiv.), −78°C, THF, then 1N NaOH.
(1)
In conclusion, an efficient entry to optically active
(2R,3R)-2-methyl-3-[(1R)-1-methylprop-2-enyl]cyclo-
pentanone, a useful chiral building block for synthesis
of vitamin D and steroids, has been developed starting
from readily accessible propargyl phosphate (R)-2. Fur-
ther applications of this compound for the synthesis of
novel vitamin D analogs are currently being carried out
in this laboratory.
Scheme 3. Reagents and conditions: (i) PTS, HC(OMe)3,
MeOH, 90%; (ii) O3, MeOH, then NaBH4, 86%; (iii) (R)-/(S)-
MTPACl, py., 84%; (iv) TFA, CH2Cl2, H2O.

Y. Song et al. / Tetrahedron Letters 44 (2003) 2113–2115
2115
Acknowledgements
1999, 40, 3737; (e) An, D. K.; Okamoto, S.; Sato, F.
Tetrahedron Lett. 1998, 39, 4555; (f) Okamoto, S.; An, D.
K.; Sato, F. Tetrahedron Lett. 1998, 39, 4551.
Y.S. thanks the Japan Society for the Promotion of
Science (JSPS) for financial support.
7. For reviews for reactions mediated by a Ti(O-i-Pr)4/2i-
PrMgX reagent, see: (a) Sato, F.; Urabe, H. In Titanium
and Zirconium in Organic Synthesis; Marek, I., Ed.;
Wiley-VCH: Weinheim, 2002; Chapter 9; (b) Sato, F.;
Okamoto, S. Adv. Synth. Catal. 2001, 343, 759; (c) Sato,
F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100, 2835.
8. Compound 2 was prepared in 60% overall yield from
methyl (R)-lactate in a five-step reaction. See Refs. 6a
and 6d for the synthesis and the determination of optical
purity.
9. Compound 3 was prepared in 75% yield from 3-(tert-
butyldimethylsilyloxy)propionaldehyde and diethyl mal-
onate according to the literature procedure in: Lehnert,
W. Tetrahedron Lett. 1970, 11, 4723.
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