Highly efficient chemical kinetic resolution of bishomoallylic alcohols: Synthesis of (R)-sulcatol

Article abstract of DOI:10.1021/ol048608q

(Chemical Equation Presented) A highly efficient chemical kinetic resolution of bishomoallylic alcohols was developed when the alcohols underwent In(OTf)₃-catalyzed 3,5-oxonium-ene-type cyclization with steroidal aldehyde 2. Consistently high e

Full text of DOI:10.1021/ol048608q

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3365-3367
Highly Efficient Chemical Kinetic
Resolution of Bishomoallylic Alcohols:
Synthesis of (R)-Sulcatol
Shui-Ling Chen, Qi-Ying Hu,† and Teck-Peng Loh*
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3,
Singapore 117543
chmlohtp@nus.edu.sg
Received July 20, 2004
ABSTRACT
A highly efficient chemical kinetic resolution of bishomoallylic alcohols was developed when the alcohols underwent In(OTf)3-catalyzed 3,5-
oxonium-ene-type cyclization with steroidal aldehyde 2. Consistently high enantiomeric excess (up to >99%) was obtained.
Optically active allylic, homoallylic, and bishomoallylic
alcohols are valuable intermediates in organic synthesis. The
versatile transformation of their alkenyl functionality provides
access to a variety of enantiomerically enriched compounds.1
Currently, enantioenriched allylic and homoallylic alcohols
can be easily prepared by asymmetric reduction or carbonyl
addition.2 As to bishomoallylic alcohols, enantioselective
synthetic methods are still rarely reported. This is probably
because of the lack of difference between two substituents
of ketone in an asymmetric reduction and the much lower
accessibility of suitable nucleophiles to carbonyl addition.
Therefore, the kinetic resolution of readily available racemic
alcohols3 is an attractive alternative route to optically active
bishomoallylic alcohols. Although enzymatic resolution of
alcohols is well established, most existing chemical methods
for kinetic resolution of alcohols can only be applied to
benzylic or allylic alcohols.4 Herein we present a highly
efficient chemical kinetic resolution of bishomoallylic alco-
hols based on a remarkable remote 1,4-stereocontrol and its
application to a simple synthesis of (R)-sulcatol.
Recently, our group reported that bishomoallylic alcohol
and aldehydes can undergo facile (3,5)-oxonium ene-type
cyclizations in the presence of a catalytic amount of
(3) For some leading references, see: (a) Kimura, M.; Fujimatsu, H.;
Ezoe, A.; Shibata, K.; Shimizu, M.; Matsumoto, S.; Tamaru, Y. Angew.
Chem., Int. Ed. 1999, 38, 397-400. (b) Jang, H.-Y.; Huddleston, R. R.;
Krische, M. J. Angew. Chem., Int. Ed. 2003, 42, 4074-4077. (c) Fu, G. C.
Acc. Chem. Res. 2000, 33, 412-420.
(4) (a) For a review on enzymatic resolution, see: Wong, C.-H.;
Whitesides, G. M. Enzymes in Synthetic Organic Chemistry; Pergamon:
New York, 1994; Chapter 2. (b) For a review on chemical resolution, see:
Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249-330. For some
leading references, see: (c) Miller, S. J.; Copeland, G. T.; Papaioannou,
N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629-
1630. (d) Vedejs, O.; Daugulis, O. J. Am. Chem. Soc. 1999, 121, 5813-
5814. (e) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997,
119, 1492-1493. (f) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001,
123, 7725-7726.
† Current address: Department of Chemistry and Chemical Biology,
Harvard University, Cambridge, MA 02138.
(1) Ikeda, S. I. Angew. Chem., Int. Ed. 2003, 42, 5120-5122 and
references therein.
(2) For reviews, see: (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int.
Ed. 1998, 37, 1986-2012. (b) Denmark, S. E.; Fu, J. Chem. ReV. 2003,
103, 2763-2793. (c) Mikami, K.; Shimizu, M. Chem. ReV. 1992, 92, 1021-
1050. For some of our previous work, see: (d) Loh, T.-P.; Hu, Q.-Y.; Chok,
Y. K.; Tan, K. Y. Tetrahedron Lett. 2001, 42, 9277-9280. (e) Loh, T.-P.;
Zhou, J.-R.; Yin, Z. Org. Lett. 1999, 1, 1855-1857.
10.1021/ol048608q CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/24/2004

In(OTf)3.5 In conjunction with our ongoing project, we
investigated the stereoinduction of chiral aldehydes in this
reaction. In an initial experiment, a solution of the bisho-
moallylic alcohol 1b6 (0.3 mmol) and the commercially
available steroidal aldehyde 27 (0.3 mmol) in CH2Cl2 (1 mL)
was stirred with a catalytic amount of In(OTf)3 (10 mol %)
at room temperature (Scheme 1). After 3-4 h, TLC analysis
Table 1. Kinetic Resolution of Various Bishomoallylic
Alcohols Using In(OTf)3
a
Scheme 1. Kinetic Resolution of Bishomoallylic Alcohol 1b
entry
1
R
yield (3)b yield (4)c
ee (4)
1
2
3
4
5
a
b
c
d
e
BnOCH2CH2
(CH3)2CH
c-C6H11
44%
49%
47%
40%
49%
28%
27%
22%
23%
37%
>99%d (S)
>99%d (S)
>99%e (S)
>99%d (S)
92%d (S)
Ph
PhCH2CH2
a Strem Chemicals, Inc. b Purified yield. c Resolved alcohol 4 was
converted to its corresponding 3,5-dinitrobenzoic ester directly after the
reaction. Purified yield. d Ee was determined using an OD chiralcel chiral
HPLC column. e Ee was determined using an AD chiralpak chiral HPLC
column.
The stereochemistry of the cyclization product 3 was fully
established by a series of spectroscopic analyses, as well as
single-crystal X-ray diffraction analysis of 3c (Figure 1).9
indicated that approximately half of the substrates have been
consumed. No significant progress of the reaction was
observed even with an elongation of the reaction time to 16
h. Furthermore, only one cyclization product was observed
1
by TLC and crude H NMR, which indicated a kinetic
resolution of racemate alcohol. After chromatography puri-
fication, the recovered alcohol was found to have an
enantiomeric purity of >99% ee.8
Encouraged by this preliminary result, we investigated the
reaction conditions for the kinetic resolution of bishomoal-
lylic alcohol 1b. It was found that the enantiomeric excess
of the alcohol 1b was increased from 44, 80, 98 to >99%
ee with increases in reaction times from 0.5, 1, 2, 3 to 4 h,
respectively. This series of data indicated that the kinetic
resolution is very rapid and reached maximum conversion
in 4 h at room temperature. In turn, we also investigated the
catalytic ability of different acids. Among them, In(OTf)3
was found to have the best catalytic activity (Scheme 1).
With the optimized reaction conditions, we examined the
applicability of this new kinetic resolution method for various
substrates. The results are summarized in Table 1. This
method worked very well with different R groups (from
linear and bulky aliphatic substituents to aromatic substitu-
ents) and gave consistently high enantiomeric excesses
ranging from 92 to >99% ee.
Figure 1. Structure of 3c.
To rationalize the stereochemical course of this reaction,
a transition state assembly was proposed as shown in Figure
2. First, the addition of alkene to oxonium at C-22 followed
(5) Loh, T.-P.; Hu, Q.-Y.; Tan, K.-T.; Cheng, H.-S. Org. Lett. 2001, 3,
2669-2672.
(6) Loh, T. P.; Song, H. Y.; Zhou, Y. Org. Lett. 2002, 4, 2715-2717
and references therein.
(7) Steroids Catalog, 12th ed.; Q3720-000 (CAS: 66289-21-2), US15/
gm.
(8) Recovered alcohol was converted to its 3,5-dinitrobenzoic ester and
then subjected HPLC analysis by using OD chiralcel chiral column (n-
hexane/isopropanol ) 99:1; flow rate ) 1 mL/min, Rt ) 7.52 and 8.38
min).
Figure 2. Transition state of the 3,5-oxonium-ene cyclization.
Org. Lett., Vol. 6, No. 19, 2004
3366

the Cram-Felkin-Anh model.10,11 Second, the nucleophilic
alkene was tethered through a six-membered chair comfor-
mation, which set all substituents to be equatorial so as to
minimize axial steric interactions. The above two principles
posed by this rigid transition assembly nicely linked the chiral
center at C-20 to all prochiral centers or the chirality of rac-
1. Thus, the chiral centers at C-22 and C-23 were established
via 1,2- and 1,3-stereocontrol. Meanwhile, the remote 1,4-
stereocommunication12 successfully distinguished the chiral-
ity of rac-1, and the highly efficient kinetic resolution was
realized. As a result, in a single oxonium-ene reaction, the
stereocenter at C-20 of chiral aldehyde substrate 2 determined
all three other chiral centers in cyclization product 3.
Scheme 2. Synthesis of (R)-Sulcatol
Having established the kinetic resolution method and the
remote 1,4-stereocontrol mechanism, we examined its ap-
plicability and predictability in the synthesis of natural
products. Sulcatol 5 is the male-produced aggregation
pheromone, which was first isolated from Gnathotrichus
Sulcatus.13 Its important biological activity for the insect pest
control, together with its biochemical and chemical synthetic
relation with another important pest attractant, pityol 6,14
stimulated extensive interests in its enantioselective synthe-
sis.15 By using our kinetic resolution, we successfully
resolved the commercially available racemic alcohol in a
single step, obtaining (R)-sulcatol in 98% ee (Scheme 2).
In summary, a remarkable remote 1,4-stereocommunica-
tion in In(OTf)3-catalyzed oxonium-ene cyclization was
unveiled. On the basis of this stereochemical feature, an
efficient kinetic resolution of useful bishomoallylic alcohols
was established.16 Finally, the power of the resolution method
was successfully demonstrated in a one-step synthesis of (R)-
sulcatol with over 98% ee.
Acknowledgment. We are grateful to Singapore Millen-
nium Foundation, Ltd., for a research scholarship to S.L.C.
and National University of Singapore for generous financial
grants. Thanks are also due to Prof. Koh Lip Lin and Ms.
Tan Geok Kheng for the X-ray determination of structure
3c.
(9) X-ray data for 3c: Empirical formula C35H54O2; formula weight
506.78; crystal system orthorhombic; space group P2(1)2(1)2(1); unit cell
dimensions a ) 6.2915(10) Å, b ) 16.082(3) Å, c ) 30.679 Å; volume
3104.1(9) Å3; Z ) 4; GOF on F2 1.102; R1 ) 0.0830, wR2 ) 0.1702.
(10) (a) Ann, N. T.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61-70. (b)
Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199-2204.
(11) For an anti-Cram addition example, see: Cheng, H.-S.; Loh, T.-P.
J. Am. Chem. Soc. 2003, 125, 4990-4991.
(12) For reviews, see: (a) Mikami, K.; Shimizu, M.; Zhang, H.-C.;
Maryanoff, B. E. Tetrahedron 2001, 57, 2917-2951. (b) Mikami, K.;
Shimizu, M. J. Synth. Org. Chem. Jpn. 1993, 51, 3-13.
Supporting Information Available: Experimental de-
tails, characterization data for all new compounds (PDF) and
X-ray crystal data for 3c (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) (a) Byrne, K. J.; Swigar, A. A.; Silverstein, R. M.; Borden, J. H.;
Stokkink, E. J. Insect Physiol. 1974, 20, 1895. (b) Borden, J. H.; Chong,
L.; McLean, J. A.; Slessor, K. N.; Mori, K. Science 1976, 192, 894-896.
(14) (a) Mori, K.; Puapoomchareon, P. Liebigs Ann. Chem. 1987, 271-
272. (b) Mori, K.; Puapoomchareon, P. Liebigs Ann. Chem. 1989, 1261-
1262.
OL048608Q
(15) (a) Mori, K. Tetrahedron 1975, 31, 3011-3012. (b) Mori, K.
Tetrahedron 1981, 37, 1341-1342. (c) Davies, S. G.; Smyth, G. D.
Tetrahedron: Asymmetry 1996, 7, 1005-1006. (d) Arnone, A.; Bravo, P.;
Panzeri, W.; Viani, F.; Zanda, M. Eur. J. Org. Chem. 1999, 117, 7-127.
(16) Scope and limitation: (1) A stoichiometric amount of chiral source
is required. (2) Due to the limitation of the chiral source, only one
enantiomer of the bishomoallylic alcohol is obtained. Currently, we are
searching for other suitable chiral aldehydes for the kinetic resolution.
Org. Lett., Vol. 6, No. 19, 2004
3367