Asymmetric Wittig reactions of chiral arsonium ylides. Part 3: Reversal of stereochemistry caused by metal cation in enantioselective olefination of 4-substituted cyclohexanones using a C2-symmetric chiral arsine

Article abstract of DOI:10.1016/S0957-4166(02)00588-8

A novel C₂-symmetric chiral arsine was synthesized from (S)-(-)-1,1′-bi-2-naphthol in three steps. It was employed in the enantioselective olefination of 4-substituted cyclohexanones via a stabilized ylide formed in situ from the corresponding arsonium salt. Enantioselectivity up to 40% was obtained. Moreover, a reversal in the stereochemistry of the product was observed simply by changing the counter cation of the base from lithium to potassium.

Full text of DOI:10.1016/S0957-4166(02)00588-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2187–2191
Asymmetric Wittig reactions of chiral arsonium ylides. Part 3:
Reversal of stereochemistry caused by metal cation in
enantioselective olefination of 4-substituted cyclohexanones using
a C2-symmetric chiral arsine†
Wei-Min Dai,* Anxin Wu and Huafeng Wu
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon,
Hong Kong SAR, China
Received 20 August 2002; accepted 14 September 2002
Abstract—A novel C2-symmetric chiral arsine was synthesized from (S)-(−)-1,1%-bi-2-naphthol in three steps. It was employed in
the enantioselective olefination of 4-substituted cyclohexanones via a stabilized ylide formed in situ from the corresponding
arsonium salt. Enantioselectivity up to 40% was obtained. Moreover, a reversal in the stereochemistry of the product was observed
simply by changing the counter cation of the base from lithium to potassium. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
ylides, we performed a kinetic resolution of axially
chiral N,N-dialkyl 2-formyl-1-naphthamides, giving
diastereomeric ratios of up to 88:12.6b The advantage of
arsonium ylides over the phosphonium counterparts is
the enhanced reactivity toward carbonyl substrates so
that olefinations of arsonium ylides with both alde-
hydes and ketones can be performed at low tempera-
ture. We report here on our results from studies on
enantioselective Wittig reactions of prochiral 4-substi-
tuted cyclohexanones using a chiral arsonium ylide
derived from a novel C2-symmetric chiral tertiary
arsine.
The Wittig and related reactions1 are the most useful
olefination methods using carbonyl compounds as the
starting materials. A variety of phosphorus-derived
reagents including phosphonium ylides (Wittig
reagents), phosphine oxides (Horner reagents), and
phosphonates and other phosphonic acid derivatives
(Horner–Wadsworth–Emmons, HWE reagents) have
been employed. Among them, the HWE reagents pos-
sessing stereogenic sub-unit(s) have been a great success
in the asymmetric versions of the olefination of car-
bonyl compounds.2,3 Moreover, the asymmetric HWE
reactions using external chiral reagents have been
reported very recently.4 Although Wittig-type olefina-
tions of aldehydes can be carried out using a catalytic
amount of n-Bu3As5a or organic tellurides,5b–e a cata-
lytic asymmetric Wittig reaction is still lacking.
2. Results and discussion
In order to avoid creating a stereogenic arsenic atom
after formation of the arsonium salt, we designed the
C2-symmetric chiral tertiary arsine 4 possessing the
1,1%-binaphthyl-2,2%-bis(methylene) backbone (Scheme
1). Similar compounds containing oxygen,7 nitrogen,8
sulfur,9 silicon,10 tin,11 boron,11a and phosphorus12 have
been prepared and used in various asymmetric reactions
and for asymmetric catalysis. We prepared the (S)-2,2%-
dimethyl-1,1%-binaphthyl 3 from (S)-(−)-1 via the bis-
triflate 2 according to the reported procedure.12c,13
Metalation of 3 was carried out using tert-BuLi–
TMEDA in Et2O8k,10,11a to form the dilithio species
In 1997, we reported the first asymmetric Wittig reac-
tion of prochiral 4-substituted cyclohexanones using
chiral arsonium ylides modified by (−)-menthol and
(−)-8-phenylmenthol.6a Diastereomeric ratios of up to
90:10 were achieved. With similar chiral arsonium
* Corresponding author. Tel.: +852-2358-7365; fax: +852-2358-1594;
e-mail: chdai@ust.hk
†
Preliminary results were reported at the World Chemistry Congress,
Brisbane, Australia, 1–6 July 2001, Book of Abstracts, p625–PG77.
14
which reacted with PhAsBr2 to afford 4 in 52% yield.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00588-8

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W.-M. Dai et al. / Tetrahedron: Asymmetry 13 (2002) 2187–2191
The chemical structure of 4 was unambiguously con-
firmed by X-ray crystal structural analysis of its arson-
ium salt 5, as shown in Scheme 2 and Fig. 1.15
Formation of the arsonium salt 5 was effected by
microwave irradiation of a mixture of 4 and methyl
bromoacetate in xylene in a pressure tube. The salt was
collected by precipitation in 71% yield (Scheme 2).
Deprotonation of 5 using n-BuLi in THF at −78°C6a
formed the arsonium ylide, which was reacted without
isolation with the 4-substituted cyclohexanones 6a–d at
−10°C by standing in a freezer for 5 days. The products
(R)-7a–d were isolated through flash column chro-
matography over silica gel in 53–92% yields (entries
1–4, Table 1). The enantioselectivity of the reactions
(25.4–40.0% ee) was determined by HPLC analysis
using a chiral stationary phase. The absolute stereo-
chemistry of (R)-7a–c was assigned by comparing the
sign of the specific rotations with the reported values.16
The absolute configuration of (R)-7d was assigned by
its similar specific rotation data to 7c.
Scheme 1. Synthesis of novel C2-symmetric chiral arsine 4.
In an attempt to examine the effect of counter ion of
the base on enantioselectivity, we found that the abso-
lute stereochemistry of the product reversed from R to
S when NaHMDS and KHMDS were used for the
formation of the ylide (entries 5–7, Table 1). For 4-
phenylcyclohexanone 6a, (R)-7a of 29.7% ee was
obtained using LiHMDS as the base. In contrast, (S)-
7a of 25.8% and 40.4% ee was obtained when NaH-
MDS and KHMDS were used for ylide formation,
respectively. The counter ion effect was also observed
for KH, KOtBu, ZnEt2, and CsCO3 to form (S)-7a with
enantioselectivities in the range of 5.7–42.3% ee (entries
11–15, Table 1). It is interesting to note that a similar
level of enantioselectivity was achieved for the Wittig
reaction at room temperature (entry 15, Table 1). For
other 4-substituted cyclohexanones 6b–d, (S)-products
Scheme 2. Enantioselective Wittig reaction of chiral arsonium
ylide.
Figure 1. X-Ray crystal structure of chiral arsonium salt 5.

W.-M. Dai et al. / Tetrahedron: Asymmetry 13 (2002) 2187–2191
2189
Table 1. Enantioselective Wittig reaction of 4-substituted cyclohexanones 6 with the chiral arsonium ylide in situ formed
from the chiral arsonium salt 5a
Entry
Substrate
Base
Product (%)b
ee (%)c
Entry
Substrate
Base
Product (%)b
ee (%)c
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6a
6a
6a
6b
6c
6d
nBuLi
(R)-7a: 92
(R)-7b: 53
(R)-7c: 60
(R)-7d: 77
(R)-7a: 76
(S)-7a: 65
(S)-7a: 76
(S)-7b: 55
(S)-7c: 48
(S)-7d: 63
25.4
33.5
40.0
39.2
29.7
25.8
40.4
27.7
36.2
30.4
11
12
13
14
15
16
17
18
19
6a
6a
6a
6a
6a
6a
6a
6a
6a
KH
(S)-7a: 55
(S)-7a: 62
(S)-7a: 36
(S)-7a: 50
(S)-7a: 41
(S)-7a: 42
(S)-7a: 48
(S)-7a: 40
36.0
34.7
5.7
42.3
38.4
43.5
39.7
44.6
8.5
nBuLi
KOtBu
nBuLi
ZnEt2
nBuLi
CsCO3 (THF, 4°C)
CsCO3 (THF, rt)
CsCO3 (PhH, rt)
CsCO3 (8, PhH, rt)
CsCO3 (9, PhH, rt)
LiHMDS
NaHMDS
KHMDS
KHMDS
KHMDS
KHMDS
9
10
CsCO3 (CH3CN, rt) (S)-7a: 34
a Reactions were carried out in THF at −10°C for entries 1–13.
b Isolated yield and not optimerized. Loss of materials during sample drying may occur due to the low molecular weights of the liquid products
7b–d.
c Determined by HPLC analysis over one or two Chiralcel OD column(s) eluted with hexane–2-propanol (98:2) at 0.5 mL/min using UV detector
at 230 nm.
were also produced in the ees of 27.7 (Me), 36.2 (tert-
Bu), and 30.4% (tert-Amyl) (entries 8–10, Table 1).
However, it should be emphasized that the counter ion
effect on enantioselectivity was not observed in the
reactions of the menthol-modified chiral arsonium
ylides.6b
seen for Ph–Asd+–CH–C(OMe)–Od− in II. Attack of the
ylide should occur from the equatorial position of the
cyclohexanones to form a 1,4-diequatorial cyclohexane
species which undergoes syn elimination of As=O to
give the olefin.6a In the absence of strong chelating
metal ions, the Wittig reaction should take place
through pathway I, where the ketone substrate is
bisected by the Ph–Asd+–CH plane. (R)-7a–d are
We investigated solvent effects on the Wittig reaction of
6a carried out at room temperature in the presence of
CsCO3. A slight enhancement in the enantioselectivity
was obtained in benzene over THF, whereas the use of
acetonitrile resulted in a dramatic loss in the asymmet-
ric induction (entries 16 and 19 versus entry 15, Table
1). The results imply that a tight association of the
counter ion with the reagent(s) is favored for maintain-
ing a rigid transition state, leading to better stereo-
differentiation. We tried two chiral phase transfer cata-
lysts 8 and 94d in the reactions of 6a. However, no
significant improvement in enantioselectivity was
observed (entries 17–18, Table 1). This reflects the
different structural features of arsonium ylides com-
pared to HWE reagents.4d
We suggest a mechanism for the enantioselective Wittig
reactions of the chiral arsonium ylide, as depicted in
Fig. 2. Among various possible isomers and conforma-
tions of the ylide, two low energy structures are
assumed on the basis of the X-ray crystal structure of
its precursor salt 5. As shown in I and II, the ylide
possesses Z configuration as a consequence of coulom-
bic interaction between the oppositely charged arsenic
and oxygen atoms.6,17 The Asd+–CH–C(OMe)–Od− moi-
ety in I is perpendicular to the plane of Ph–Asd+–CH
which bisects the 1,1%-binaphthyl-2,2%-bis(methylene)
backbone. On the other hand, a coplanar alignment is
Figure 2. Proposed pathways for the enantioselective Wittig
reaction.

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W.-M. Dai et al. / Tetrahedron: Asymmetry 13 (2002) 2187–2191
expected to form as the major products, as observed in
the Wittig reactions using n-BuLi and LiHMDS as the
base. Alternatively, chelating metal ions such as Na, K,
and Cs favor the reaction pathway II, where the ketone
substrate suffers from a minimum steric interaction
with the 1,1%-binaphthyl-2,2%-bis(methylene) backbone,
leading to the formation of (S)-7a–d as the major
enantiomers. The observed solvent effect on the enan-
tioselectivity, in the order of PhH (43.5% ee)>THF
(38.4% ee)>CH3CN (8.5% ee), is consistent with the
chelation model shown in II. Less polar solvents pro-
mote chelation and lead to higher enantioselectivity. It
should be emphasized that the above discussion is
based on the assumption that the addition of the chiral
arsonium ylide to the ketone is the rate-determining
step. Other possibilities cannot be ruled out at this
stage.
3. Selected recent reports on asymmetric Wittig-type reac-
tions and applications, see: (a) Pedersen, T. M.; Hansen,
E. L.; Kane, J.; Rein, T.; Helquist, P.; Norrby, P.-O.;
Tanner, D. J. Am. Chem. Soc. 2001, 123, 9738–9742; (b)
Nagao, T.; Suenage, T.; Ichihashi, T.; Fujimoto, T.;
Yamamoto, I.; Kakehi, A.; Iriye, R. J. Org. Chem. 2001,
66, 890–893; (c) Bedekar, A. V.; Watanabe, T.; Tanaka,
K.; Fuji, K. Tetrahedron: Asymmetry 2002, 13, 721–727;
(d) Yamazaki, J.; Bedekar, A. V.; Watanabe, T.; Tanaka,
K.; Watanabe, J.; Fuji, K. Tetrahedron: Asymmetry 2002,
13, 729–734.
4. Enantioselective
Wittig–Horner
and
Horner–
Wadsworth–Emmons reactions using external chiral
reagents, see: (a) Toda, F.; Akai, H. J. Org. Chem. 1990,
55, 3446–3447; (b) Kumamoto, T.; Koga, K. Chem.
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K.; Tomioka, K. Angew. Chem., Int. Ed. 1998, 37, 515–
517; (d) Arai, S.; Hamaguchi, S.; Shioiri, T. Tetrahedron
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2002, 43, 281–284.
In summary, we have designed and synthesized the first
example of a C2-symmetric chiral tertiary arsine pos-
sessing the 1,1%-binaphthyl-2,2%-bis(methylene) back-
bone and applied it in the enantioselective Wittig
reactions of prochiral 4-substituted cyclohexanones.
The change in enantioselectivity and the reversal of
stereochemistry caused by metal cations are discussed
in terms of the conformational flexibility of the chiral
arsonium ylide derived from 5. Future work should be
aimed at increasing the conformational rigidity of the
arsonium ylide in order to improve the enantioselectiv-
ity of the Wittig reactions.
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We thank the Department of Chemistry, HKUST and
the Research Grants Council of the Hong Kong Special
Administrative Region, China (HKUST6068/98P) for
financial support. We also thank Professor Ian D.
Williams and Dr. Samuel M. F. Lo of HKUST for
assistance with the X-ray crystallographic analysis.
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