Asymmetric Michael-aldol tandem cyclization of ω-oxo-α,β-unsaturated esters with 10-mercaptoisoborneol methyl ether

Article abstract of DOI:10.1016/S0040-4039(03)00253-3

The asymmetric reaction of ω-oxo-α,β-unsaturated esters with lithium chiral thiolates afforded the Michael-aldol tandem cyclization products in high yield and good stereoselectivity. Reductive desulfurization gave the corresponding optically pure 2-hydrox

Full text of DOI:10.1016/S0040-4039(03)00253-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2323–2326
Asymmetric Michael–aldol tandem cyclization of
v-oxo-a,b-unsaturated esters with 10-mercaptoisoborneol
methyl ether
Katsumi Nishimura, Hiroshi Tsubouchi, Masashi Ono, Tomoharu Hayama, Yasuo Nagaoka and
Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 24 December 2002; revised 20 January 2003; accepted 24 January 2003
Abstract—The asymmetric reaction of v-oxo-a,b-unsaturated esters with lithium chiral thiolates afforded the Michael–aldol
tandem cyclization products in high yield and good stereoselectivity. Reductive desulfurization gave the corresponding optically
pure 2-hydroxycycloalkanecarboxylates. © 2003 Elsevier Science Ltd. All rights reserved.
An asymmetric carbonꢀcarbon bond forming cycliza-
tion methodology is of importance in the synthetic
chemistry of chiral carbocycles.1,2 Especially, an aldol-
type reaction of a lithium ester enolate with an alde-
hyde is one of the most powerful process for a
carbonꢀcarbon bond formation. For the constriction of
chiral carbocycles by intramolecular aldol reaction, it is
highly desirable to establish an asymmetric methodol-
ogy for selective generation of lithium enolate of a
chiral ester bearing an enolizable aldehyde in the same
molecule.3,4 Such selective generation of a lithium chiral
ester enolate is possible through the Michael addition
reaction of a lithium chiral thiolate with an enoate
bearing an v-formyl group.5,6 As part of our projects
on an asymmetric reaction of a thiolate,7 we have
recently reported the lithium benzylthiolate-initiated
Michael addition–intramolecular aldol tandem cycliza-
tion of v-oxo-enoates.8,9 We describe herein the exten-
sion of the process into the asymmetric cyclization of
v-oxo-a,b-unsaturated esters 1 with use of 2-Li as an
initiating chiral thiolate, providing a new methodology
for asymmetric construction of chiral carbocycles
(Scheme 1). Furthermore, the cyclization using lithium
thiolate 2-Li gave 4 and 5 in a perfect syn-aldol
stereoselectivity.
as a mixture of two separable diastereomers in 38 and
9% yields, respectively.14,15 The same reaction in THF
at lower temperature, −78°C for 1 h and then −40°C for
0.5 h, gave the Michael addition products only in 77%
combined yield without formation of the tandem aldol
cyclization products, 4, 5 and other stereoisomers. The
reaction in toluene at 0°C for 2 h gave 4aa and 5aa in
17 and 4% yields, together with the Michael addition
products in 19% yield.
Since intra- or intermolecular protonation of 3 by a free
hydroxyl group in 2a may be responsible for the failure
in tandem aldol-cyclization, an alcohol 2a was con-
verted to a methyl ether 2b (R1=Me) (Scheme 2). A
Treatment of 1a10 (n=6) with 1.2 equiv. of a lithium
thiolate of 10-mercaptoisoborneol 2a-Li (R1=H)11,12 in
THF at 0°C for 0.5 h gave 4aa13 and 5aa (n=6, R1=H)
Scheme 1. The Asymmetric Michael–aldol tandem cyclization
of 1 with 2.
* Corresponding author. Tel.: +81-75-753-4553; fax: +81-75-753-4604;
e-mail: tomioka@pharm.kyoto-u.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00253-3

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K. Nishimura et al. / Tetrahedron Letters 44 (2003) 2323–2326
Scheme 3. 1H NMR and conversion of 4ab and 5ab to 8.
Scheme 2. Synthesis of chiral thiol 2b from 2a.
hydroxythiol 2a was initially converted to a disulfide 6
and then methylated to 7, and finally reduced back with
lithium aluminum hydride to 2b in 71% overall yield
from 2a.
The reaction of 1a (n=6) with 2b-Li (R1=Me), pre-
pared by treating 2b with butyllithium, in THF at 0°C
for 0.5 h gave chromatographically separable two iso-
mers 4ab and 5ab (n=6, R1=Me) in 77 and 18% yields
(81:19 dr), respectively. It is important to note that only
syn-aldol cyclization products were obtained without
formation of anti-aldol products. The diastereomer
ratio was improved by lowering reaction temperature at
−40°C, giving 4ab and 5ab in 77 and 13% yields (86:14
dr).
Scheme 4. Synthesis of an optically pure five-membered car-
bocycle 9.
thus established the absolute stereostructure of 4ab.
Similarly, 5ab was also determined by converting to
(+)-8 as shown. The structures of 4aa and 5aa were also
determined by the same way.
The reaction efficiency highly depends on the solvent
used to give 4ab and 5ab in 69 and 26% in DME at
0°C, 23 and 14% in ether, 46 and 17% in acetonitrile
(Table 1). In methylene chloride, 4ab was an only
isolable product although in 30% yield. Additives,
HMPA, Dabco, and trimethylaluminium in a THF
solvent were not factors improving efficiency to afford
4ab and 5ab in 75 and 19%, 65 and 21%, 46 and 11%,
respectively.
Five-membered carbocycle is also a good target. The
reaction of 1b (n=5) with 1.2 equiv. of 2b-Li in THF at
−20°C for 0.5 h gave 4bb and 5bb (n=5, R1=Me) in
78:22 dr and 96% combined yield. Direct Raney-nickel
reduction of a mixture gave (−)-(1S,2R)-methyl 2-
hydroxycyclopentanecarboxylate 917 of [h]D23 −8.2 (c 1.2,
CHCl3) with 49% ee in 73% yield, establishing the
stereochemistry of a major product 4bb (Scheme 4). A
78:22 mixture was converted to their carbamates and
fractionally recrystallized from ether–hexane to give
pure 10, which was then reduced via 11 to optically
pure 9 in 45% overall yield from 1b.18
The stereochemical structures of 4ab and 5ab were
1
determined based on H NMR and conversion to cis-8
and its enantiomer of the established absolute configu-
ration. Coupling constants, 2.4 Hz and 11.3 Hz
between methine protons at 4.16, 3.17 and 2.55 ppm of
4ab indicate the chair stereostructure, where SR* and
CO2Me are equatorial, OH is axial, as shown in
Scheme 3. Reductive removal of a sulfanyl group SR*
with Raney-nickel in methanol afforded optically pure
(−)-(1S,2R)-816 of [h]D20 −32.8 (c 4.6, ether) in 82% yield,
The stereochemistry of the tandem reaction is rational-
ized by the model 12, which is sterically favorable much
more than 13 (Scheme 5). The oxo-ester 1a reacts in
s-cis form to generate cis-enolate 3,19,20 which then
reacts intramolecularly with lithium-coordinated car-
bonyl group shown in 14 to result in the observed
major syn-only aldol product 4ab. In this context it is
interesting to examine the reaction of 2b without activa-
tion by lithium.
Table 1. Solvent dependency of the reaction of 1a with
2b-Li giving 4ab and 5ab
Entry
Solvent
Temp. (°C)
Yield (%)
Dr
1
2
3
4
5
6
THF
THF
DME
Ether
CH3CN
CH2Cl2
−40
90
95
95
37
63
30
86:14
81:19
73:27
62:38
73:27
99:1
0
0
0
0
0
The reaction of 1a with 2b in THF was catalyzed by 0.1
equiv. of Triton B at rt for 0.5 h to give a mixture of
possibly all four cyclization products, syn-aldols 4ab
(48%) and 5ab (22%), anti-aldols 15 and 16 (ca 1:1,
26%) in 96% combined yield (Fig. 1). It is also impor-

K. Nishimura et al. / Tetrahedron Letters 44 (2003) 2323–2326
2325
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Figure 1. Structures of 15 and 16.
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In summary, a new methodology has been developed
for the construction of chiral carbocycles by employing
an asymmetric Michael–aldol tandem cyclization of
v-oxo-a,b-unsaturated esters with a lithium chiral
thiolate.
Acknowledgements
We gratefully acknowledge financial support from the
Ministry of Education, Science, Sports and Culture,
Japan.
10. The v-oxo-a,b-unsaturated esters 1 were prepared by the
Wittig reaction of the corresponding dialdehyde
equivalents.
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