Auxiliary induced asymmetric Michael-aldol reaction under kinetic and thermodynamic conditions

Article abstract of DOI:10.1016/S0040-4039(00)00101-5

Asymmetric intramolecular Michael-aldol reaction of (-)-phenylmenthyl enoates 1 affords tricyclic cyclobutanes 2 in excellent diastereoselectivity. It is made clear that Michael-aldol reaction is reversible under conditions using trimethylsilyl iodide (TM

Full text of DOI:10.1016/S0040-4039(00)00101-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2145–2148
Auxiliary induced asymmetric Michael-aldol reaction under
kinetic and thermodynamic conditions
Kiyosei Takasu,∗ Megumi Ueno and Masataka Ihara ∗
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama,
Sendai 980-8578, Japan
Received 16 December 1999; revised 6 January 2000; accepted 7 January 2000
Abstract
Asymmetric intramolecular Michael-aldol reaction of (−)-phenylmenthyl enoates 1 affords tricyclic cyclo-
butanes 2 in excellent diastereoselectivity. It is made clear that Michael-aldol reaction is reversible under conditions
using trimethylsilyl iodide (TMSI) in the presence of hexamethyldisilazane (HMDS) at ambient temperature. The
difference of stereoselectivity under kinetic or thermodynamic conditions are reported. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: asymmetric reactions; isomerism; cyclobutanes; Michael-aldol reactions.
We have described the convenient construction of polycyclic cyclobutanes from α,β-unsaturated esters
having ketocarbonyl group by intramolecular Michael-aldol reaction,1 which can highly control the
relative configuration of four or five stereogenic centers. The asymmetric modification of the reaction
would provide an extremely potent synthetic methodology to obtain optically pure cyclobutanes.2 Now,
we report the asymmetric Michael-aldol reaction induced by chiral auxiliary. Since 8-arylmenthols had
been utilized as effective chiral inducer in the conjugate addition and cycloaddition reactions,3,4 we
planned to use (−)-8-phenylmenthol for asymmetric Michael-aldol reaction.
The substrates 1a and 1b were easily prepared from the corresponding ketoaldehyde1b by Wittig
reaction. Intramolecular Michael-aldol reaction was carried out under TMSI–HMDS conditions,5,6
which have been established by us for non-asymmetric version.1b,1d The treatment of ketoesters 1a
and 1b with TMSI–HMDS or TMSOTf–HMDS in CH2Cl2 afforded tricyclo[5.4.0.03,7]undecane and
tricyclo[5.3.0.03,7]decane compounds, respectively (Scheme 1 and Table 1).7 At ambient temperature,
Michael-aldol reaction of 1a afforded a mixture of diastereomers 2a and 3a, which were separable by
column chromatography on silica gel (entries 1 and 2). After the elimination of auxiliary of 2a and
3a by DIBAL-H, the resulting diols were characterized as 5 and its antipode. The specific rotations,
∗
Corresponding authors. Tel: +00 81 22 217 6887; fax: +00 81 22 217 6877; e-mail: mihara@mail.pharm.tohoku.ac.jp (M.
Ihara)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00101-5
tetl 16381

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[α]D (c 1.0, CHCl3), of the diols derived from 2a and 3a were −26.6 and +26.1, respectively.
The relative stereochemistry was identical with the known diol.1b The absolute configuration of 2a
was determined by circular dichroism of the spiro cyclohexanone 68 ([θ]=+886, λ=308.6 nm). The
application of the octant rule suggested (R)-configuration of the spiro carbon. Accordingly, 2a has
(1S,2R,3R,7R)-tricyclo[5.4.0.03,7]undecane structure. At the lower temperature, the diastereoselectivity
of 2a remarkably improved and the yield of the silyl enol ether 4 decreased (entries 3–5). Especially,
the reaction, carried out at −78°C, resulted in 85% yield of 2a with perfect selectivity. When 1a was
treated with TMSOTf–HMDS, although the diastereoselectivity was not different, the reaction rate was
remarkably slow at lower temperature (entries 6 and 7). The cyclopentanone 1b also furnished the
Michael-aldol adducts 2b and 3b and excellent selectivity was achieved at −78°C (entries 8 and 9).
Scheme 1.
Table 1
Asymmetric Michael-aldol reactions of 1
The results of the experiments at room temperature (Table 1, entries 1 and 2) indicated that
TMSI–HMDS conditions afforded thermodynamic equilibrium between 2a and 3a. The correlation
between the diastereomeric proportion and the reaction time at room temperature was investigated to
throw light on the thermodynamic behavior of the reaction (Fig. 1). After 1 h, 2a was populated by about
seven times more than 3a. As the reaction time was longer, the ratio of 3a increased, and finally the
diastereomeric ratio equilibrated (2a:3a 11:9).

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Fig. 1. Time course for the diastereomeric proportion of 2a (ꢀ) and 3a (ꢀ)
The reaction mechanism and the stereoselectivities can be explained as follows. Initially the thermo-
dynamically stable silyl enol ether 4 was generated from 1 under TMSI–HMDS conditions.5 Then,
Mukaiyama-type Michael addition and successive aldol reaction were promoted to give 2 and/or 3. At
low temperatures the diastereofacial selection was controlled by π-stacking effect of phenylmenthol,9 as
expected, to give 2 (Fig. 2). Even at ambient temperature, the kinetic product 2 was initially preferred.
However, retro-Michael-aldol reaction was gradually promoted by TMSI–HMDS, and consequently the
isomerization of Michael-aldol adducts occurred via the silyl enol ether 4 to provide a mixture of 2 and
3. Actually, the treatment of isolated 2a with TMSI and HMDS at room temperature afforded a mixture
of 2a, 3a and 4a.
Fig. 2. Diastereofacial selection of 1a
Exposure of cyclopentanone 7 to TMSI–HMDS at room temperature gave tricyclo-undecane 8 and
the mono-Michael adduct 9 in 15% and 76% yield, respectively (Scheme 2). Though the yield of 8
was unsatisfactory, the pseudo-antipode of 8 was not detected. The formation of 9 provides supporting
evidence that the cyclization is promoted through a stepwise mechanism.
Scheme 2.
In summary, we have developed an effective method for the construction of optically pure tricyclic
cyclobutanes via asymmetric Michael-aldol reaction. We found that Michael-aldol reaction is reversible
under TMSI–HMDS conditions at ambient temperature; the stereoselectivities are dependent on the
reaction temperature and time. It is noteworthy that the four stereogenic centers can be entirely controlled
by 8-phenylmenthol chiral auxiliary at −78°C.

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Acknowledgements
This work was partly supported by a Grant-in-Aid for scientific Research on Priority Areas (11119206
and 11147202) from the Ministry of Education, Science, Sports and Culture of Japan.
References
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27
adduct 2a: colorless oil; [α]D (c 1.1, CHCl3) −23.4; IR (neat) ν 2950, 1715, 1250, 1200, 840 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.30–7.23 (m, 4H), 7.19–7.12 (m, 1H), 4.85 (ddd, 1H, J=10.8, 10.8, 4.4 Hz), 2.36 (d, 1H, J=7.7 Hz), 2.26 (dd, 1H,
J=8.0, 4.0 Hz), 2.22 (m, 1H), 2.00–1.85 (m, 3H), 1.78–0.72 (m, 18H), 1.33 (s, 3H), 1.23 (s, 3H), 0.86 (d, 3H, J=6.6 Hz), 0.16
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 171.9, 151.1, 128.0, 125.6, 125.3, 75.1, 74.2, 52.7, 52.6, 50.3, 41.9, 40.1, 39.4, 34.7,
34.5, 34.3, 31.7, 31.3, 30.3, 28.5, 27.0, 25.1, 25.0, 22.5, 21.7, 19.8, 1.7. HRMS calcd for C31H48O3Si (M+): 496.3370, found
496.3369.
8. Cyclohexanone 6 was obtained by the treatment of 2a with TBAF, followed by hydrolysis with NaOMe.
9. For a review of π-stacking effects in asymmetric synthesis, see: Jones, G. B.; Chapman, B. J. Synthesis 1995, 475–497.