Chirality transfer from epoxide to carbanion: Base-induced alkylation of O-carbamoyl cyanohydrins of β-silyl-α,β-epoxy aldehyde

Article abstract of DOI:10.1002/ejoc.200800300

Enantioselective C-C bond formation at an α-position of a nitrile group with an external electrophile can be realized, although in modest ee, with the aid of both the concerted process of an epoxysilane rearrangement and a carbamoyl group. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800300

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800300
Chirality Transfer from Epoxide to Carbanion: Base-Induced Alkylation of
O-Carbamoyl Cyanohydrins of β-Silyl-α,β-epoxy Aldehyde
Michiko Sasaki,[a] Eiji Kawanishi,[a] Yuri Shirakawa,[a] Masatoshi Kawahata,[b]
Hyuma Masu,[b] Kentaro Yamaguchi,[b] and Kei Takeda*[a]
Keywords: Chirality / Carbanions / Rearrangement / Asymmetric synthesis / Alkylation
Enantioselective C–C bond formation at an α-position of a
nitrile group with an external electrophile can be realized,
although in modest ee, with the aid of both the concerted
process of an epoxysilane rearrangement and a carbamoyl
group.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
rearrangement-mediated [3+4] annulation.[5] On the basis
of these findings we became interested to determine
whether a more stable carbanion such as an α-nitrile
carbanion[6] generated by epoxysilane rearrangement
(Scheme 1) could participate in the enantioselective forma-
tion with an electrophile intermolecularly through a con-
certed process involving Brook rearrangement[7] via silicate
intermediate 3 without the involvement of a free α-nitrile
carbanion.
Introduction
Enantioselective formation of a chiral carbanion fol-
lowed by stereospecific reaction with an electrophile is one
of the most powerful and efficient methods in asymmetric
carbon–carbon bond-forming reactions. Although recent
developments in methods for generating a chiral carbanion
by using chiral ligands such as sparteine have provided rela-
tively ready access to chiral carbanions and a better under-
standing of the process, they have usually been applied for
the generation of less-stable carbanions such as benzyl and
allyl anions, which often have α-heteroatoms or dipole-sta-
bilizing and directing groups.[1] Chiral carbanions that are
conjugated with carbon–oxygen or carbon–nitrogen mul-
tiple bonds have been considered to be extremely difficult
to generate due to their high proclivity toward racemiza-
tion. To the best of our knowledge, reports by Walborsky
and coworkers, who found that a chiral cyclopropyl nitrile
derivative could be enantiospecifically deuterated in basic
CH3OD is the only example.[2] They also found that the
corresponding chiral aliphatic nitrile derivative suffered ex-
tensive racemization under the same conditions.
Scheme 1. Epoxysilane rearrangement.
Results and Discussion
We recently reported that epoxide chirality can be trans-
ferred to a carbanion through epoxysilane rearrangement[3]
and trapped intramolecularly almost without racemization
by [2,3]-Wittig rearrangement.[4] We also demonstrated that
the chirality can be transferred to remote positions without
complete racemization through an intramolecular tandem
process that involves epoxysilane rearrangement and Brook
First we examined the reaction of enantiomerically en-
riched epoxysilane 5[8] with a base in the presence of benzyl
bromide (Scheme 2). Unfortunately, benzylated rearrange-
ment products (E)- and (Z)-6[3] obtained under a variety
of conditions were completely racemic. The cause of the
unsuccessful result could be ascribed to several factors, in-
cluding the existence of equilibrium between silicate 3 and
another silicate intermediate involving the siloxy group at
the α-position of the nitrile group. We next examined the
reaction with the use of the corresponding O-benzyl-
cyanohydrin derivative, in which the formation of a chela-
tion structure at the position is impossible; this results in
low chemical yield as well as complete racemization again.
[a] Graduate School of Medical Sciences, Hiroshima University
1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8553, Japan
Fax: +81-82-257-5184
E-mail: takedak@Hiroshima-u.ac.jp
[b] Tokushima Bunri University
1314-1 Shido, Sanuki, Kagawa, 769-2193, Japan
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 3061–3064
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3061

K. Takeda et al.
SHORT COMMUNICATION
yields was obtained with LDA in the presence of benzyl
bromide in Et2O or toluene at –80 °C, which gave benzyl-
ated products (Z)-11 in 23%ee and 35%ee, respectively.[11]
In contrast, reactions in THF, the most common solvent
for carbanion reactions, resulted in complete racemization.
The use of sodium or potassium amide bases and the ad-
dition of TMEDA were not effective.
Although determination of the absolute configurations
of (Z)-11 and (E)-11 proved difficult and required extensive
investigation, they were eventually determined by chemical
correlation shown Scheme 4. Thus, rac-(E)-11[12] was trans-
formed into diol derivative rac-14 by LiAlH4 reduction fol-
lowed by desilylation and NaBH4 reduction of the resulting
aldehyde. Most attempts at separation of rac-14 after
derivatization to diastereomers as well as separation of rac-
14 itself by using preparative chiral HPLC failed. The only
successful separation was achieved by preparative chiral
HPLC after conversion to diastereomeric camphorsul-
tum[13] derivatives 15a,b. Because suitable crystals of 15a
and 15b for X-ray analysis could not be obtained, they were
Scheme 2. Epoxysilane rearrangement with the use of enantiomer-
ically enriched 5.
These results led us to consider that the concerted alky-
lation from silicate intermediate 3 is not the sole product-
forming reaction pathway and that a pathway via an α-ni-
trile-stabilized carbanion intermediate could also be opera-
tive. Next, we decided to change the siloxy group into a
carbamoyloxy group,[9] which would decelerate the rate of
racemization of the generated α-nitrile allylic carbanion by
its strong chelating ability. Carbamoyl derivatives 10a and
10b were prepared according to the route shown in
Scheme 3. Reaction of cyanohydrin 8, derived from 7 (94%
ee),[3,10] with carbamoyl chloride resulted in ring opening
of the epoxide to chlorohydrins 9a and 9b, which were con-
verted into epoxides 10a and 10b by treatment with DBU
after separation. Stereostructures of 10a and 10b were de-
termined on the basis of X-ray analysis of 9b.
Scheme 3. Synthesis of 10a and 10b. Reagents and conditions: (a)
TMSCl, KCN, nBu4PBr, CH2Cl2; then H2SiF6, room temp., 94%;
(b) ClCONiPr, pyridine, 90 °C, 8 h; then separation; (c) DBU,
CH2Cl2, 0 °C, 1.5 h.
Scheme 4. Determination of the absolute configurations of (Z)-
and (E)-11. Reagents and conditions: (a) LiAlH4, THF, room
temp., 1 h, 52%; (b) nBu4NF, THF, 0 °C, 30 min; EtOH; then
NaBH4, room temp., 1 h, 94%; (c) XsOH, EDC·HCl, DMAP,
CH2Cl2, room temp., 17 h, 85%; 8d) separation with a chiral HPLC
column; 8e) K2CO3, MeOH, room temp.; 8f) p-BrC6H4COCl,
First, exploratory experiments to find conditions al-
lowing the successful chirality transfer shown in Scheme 1
were carried out by using 10a and benzyl bromide as an
electrophile with bases in several solvents for 60 min
(Table 1). The best result in terms of chemical and optical NEt3, DMAP, CH2Cl2.
Table 1. Reaction of enantiomerically enriched 10a with a base in the presence of BnBr.
Solvent
Base
(Z)-11 Yield [%]
(Z)-11 ee [%]
(E)-11 Yield [%]
(Z,E)-12 Yield [%]
THF
Et2O
Et2O
Toluene
Toluene
Et2O
LDA
LDA
LDA (TMEDA)
LDA
LDA (TMEDA)
LHMDS
36
47
25
39
29
35
33
24
0
23
0
35
0
23
4
0
30
8
8
14
25
22
33
50
9
6
21
19
11
7
Et2O
Et2O
NaHMDS
KHMDS
0
0
3062
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3061–3064

Chirality Transfer from Epoxide to Carbanion
Table 2. Reaction of enantiomerically enriched 10a and 10b with LDA in the presence of BnBr.
Solvent
Time
[min]
(Z)-11
Yield [%]
(Z)-11
(E)-11
Yield [%]
(E)-11
ee [%]
12
Yield [%]
ee [%][a]
10a
10a
10a
10a
10b
10b
10b
10b
Et2O
Et2O
toluene
toluene
Et2O
Et2O
toluene
toluene
1
60
1
60
1
60
1
60
22
47
39
39
–
5
5
39 (R)
23 (R)
29 (R)
35 (R)
–
10 (S)
9 (S)
5
8
40 (R)
35 (R)
21 (R)
20 (R)
7 (R)
5 (R)
10 (R)
11 (R)
47
6
21
19
44
7
13
14
27
45
47
42
16
18
6
15 (S)
[a] Corrected for the ee of the starting material (94%ee).
further transformed into p-bromobenzoate derivatives 16a ically enriched products by change in the O-substituent of
and 16b. Absolute configurations of 16b, whose crystal was the cyanohydrin from TBS to carbamoyl seems to be con-
suitable for X-ray analysis, were determined by X-ray crys- sistent with a pathway that involves an α-nitrile carbanion.
tallographic analysis by using the anomalous dispersion Carlier also predicted increased configurational stabiliza-
technique. Comparison of chiral HPLC of (–)-14b derived tion of an α-nitrile carbanion by a directing group such
from 15b with 14 derived from (E)-11 and (Z)-11 obtained as a carbamoyl group based on calculation for lithiated β-
in the reaction of 10a, respectively, showed that both of the formylcyclopropylnitriles.
absolute configurations of the major enantiomers of (E)-
To examine the possibility of the intermediacy of a dis-
and (Z)-11 are R.
crete chiral α-nitrile carbanion in the reaction of 10a,b, we
Having established the absolute configurations, we next decided to perform benzylation reaction of O-carbamoyl
decided to examine the reactions of 10a and 10b with LDA cyanohydrin 17,[18] which was prepared from O-acetyl cya-
in the presence of BnBr in Et2O and toluene with reaction nohydrin of 3-phenylpropanal by lipase-mediated kinetic
times of 60 min and 1 min (Table 2). The latter reaction resolution[19] followed by carbamoylation. When LDA was
time was selected by considering the possibility of a rela- added to a solution of 17 and benzyl bromide in Et2O at
tively slow reaction rate of the silicate intermediate and/or –80 °C and then quenched for 1 min, benzylated product
the chiral carbanion with benzyl bromide. In Et2O, the ee 18[20] was obtained in 35% chemical yield and 5%ee
values of (R,Z)-11 and (R,E)-11 were improved by quench- (Table 3). Although prolongation of the reaction time to
ing for 1 min, but at the expense of the chemical yield, 60 min gave almost the same ee value, the use of toluene as
whereas in toluene the chemical and optical yields were not a solvent gave a somewhat higher ee value (11%).[21] These
greatly affected by the reaction time. The result can be inter- results suggest the intermediacy of a discrete chiral α-nitrile
preted in terms of a relatively slow reaction rate of the sili- carbanion that can be trapped intermolecularly with an
cate intermediate and/or the chiral carbanion with benzyl
bromide in Et2O. The optical yields in the reaction of 10b
were lower than those in the reaction of 10a.
Table 3. Reaction of enantiomerically enriched 17 with LDA in the
presence of BnBr.
Although a mechanistic rationalization of the observed
partial asymmetric induction and of the stereochemical out-
come cannot be made at the present time and must await
further studies, it is noteworthy, considering the fact that a
chiral α-nitrile carbanion has never been generated due to
its low inversion barrier except Walborsky’s substrate,[14]
that a chiral carbanion in an α-position of the nitrile group
can be generated and trapped by an intermolecular process
without complete racemization, with a maximum ee value
of 40%, regardless of whether a discrete chiral α-nitrile
carbanion is involved. Carlier reported that the calculated
inversion barrier for lithioacetonitirile is 0.45 kcal/mol,[15,16]
and X-ray analysis of lithiophenylacetonitrile indicated that
Solvent
Time [min]
Yield [%]
ee [%][c]
Et2O
Et2O
Toluene
Toluene
THF
1
60
1
60
1
35[a]
84
5
3
11
9
0
0
40[b]
71
85
80
THF
60
[a] 39% of 17 was recovered. [b] 27% of 17 was recovered. [c] Cor-
the geometry is planar.[17] The formation of enantiomer- rected for the ee of the starting material (98%ee).
Eur. J. Org. Chem. 2008, 3061–3064
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3063

K. Takeda et al.
SHORT COMMUNICATION
[3]
a) K. Takeda, E. Kawanishi, M. Sasaki, Y. Takahashi, K. Yama-
guchi, Org. Lett. 2002, 4, 1511–1514; b) M. Sasaki, E. Kawan-
ishi, Y. Nakai, T. Matsumoto, K. Yamaguchi, K. Takeda, J.
Org. Chem. 2003, 68, 9330–9339; c) M. Sasaki, K. Takeda, J.
Synth. Org. Chem. Jpn. 2006, 64, 1148–1158.
M. Sasaki, M. Higashi, H. Masu, K. Yamaguchi, K. Takeda,
Org. Lett. 2005, 7, 5913–5915.
Y. Nakai, M. Kawahata, K. Yamaguchi, K. Takeda, J. Org.
Chem. 2007, 72, 1379–1387.
For α-nitrile carbanions, see: a) F. F. Fleming, B. C. Shook,
Tetrahedron 2002, 58, 1–23; b) S. Arseniyadis, K. S. Kyler, D. S.
Watt, Org. React. 1984, 31, 1–364; c) F. F. Fleming, S. Gudi-
pati, Z. Zhang, W. Liu, O. W. Steward, J. Org. Chem. 2005, 70,
3845–3849.
For reviews on the Brook rearrangement, see: a) M. A. Brook,
Silicon in Organic, Organometallic, and Polymer Chemistry,
Wiley & Sons, New York, 2000; b) A. G. Brook, A. R. Bassind-
ale in Rearrangements in Ground and Excited States (Ed.: P.
de Mayo), Academic Press, New York, 1980, pp. 149–221; c)
A. G. Brook, Acc. Chem. Res. 1974, 7, 77–84. For the use of
the Brook rearrangement in tandem bond-formation strategies,
see: d) W. H. Moser, Tetrahedron 2001, 57, 2065–2084. Also
see: e) A. Ricci, A. Degl’Innocenti, Synthesis 1989, 647–660; f)
P. C. Bulman Page, S. S. Klair, S. Rosenthal, Chem. Soc. Rev.
1990, 19, 147–195; g) H. Qi, D. P. Curran in Comprehensive
Organic Functional Group Transformations (Eds.: A. R. Ka-
tritzky, O. Meth-Cohn, C. W. Rees, C. J. Moody), Pergamon,
Oxford, 1995, pp. 409–431; h) P. F. Cirillo, J. S. Panek, Org.
Prep. Proc. Int. 1992, 24, 553–582; i) A. F. Patrocinio, P. J. S.
Moran, J. Braz. Chem. Soc. 2001, 12, 7–31; j) E. Schaumann,
A. Kirschning, Synlett 2007, 177–190.
electrophile without complete racemization, although the ee
values were low. Consequently, the partial chirality transfer
observed in the above epoxysilane rearrangement should be
based on both a concerted alkylation process from the sili-
cate intermediate and the presence of the carbamoyl group,
although the former process should be mainly responsible
for the chirality transfer.
[4]
[5]
[6]
Conclusions
The overall stereochemical process of the chirality trans-
fer through an epoxysilane rearrangement is much more
complicated than it may appear and involves subtle inter-
play of many factors that are not easy to estimate. Thus, at
least the mode of ring opening of the epoxide (syn/anti),
stereochemistry of the Brook rearrangement (retention/in-
version), and the stereochemistry (syn/anti) of the SEЈ reac-
tion in silicate intermediate 3 should be clarified. Further
work along these lines is currently under way, and the re-
sults will be the subject of a forthcoming full paper.
[7]
Experimental Section
To a cooled (–80 °C) solution of 10a (100 mg, 0.294 mmol) and
benzyl bromide (0.175 mL, 1.47 mmol) in Et2O (2.4 mL) was added
dropwise a solution of lithium diisopropylamide (0.4  in Et2O,
0.808 mL, 0.323 mmol) over a period of 2 min. After stirring at the
same temperature for 1 min, the reaction mixture was poured into
saturated ammonium chloride solution (5 mL) and then extracted
with Et2O (3ϫ10 mL). The combined organic phase was washed
with water (10 mL) and saturated brine (10 mL), dried, and con-
centrated. The residual oil was subjected to column chromatog-
raphy (silica gel 15 g; hexane/Et2O, 5:1) to give a mixture of (E)-
11, (Z)-11, (E)-12, and (Z)-12 (81.1 mg).
[8]
This compound (94%ee) was prepared from 7 according to the
procedure described in the literature.[3b]
[9]
[10]
D. Hoppe, Angew. Chem. Int. Ed. Engl. 1984, 23, 932–948.
F. Le Bideau, F. Gilloir, Y. Nilsson, C. Aubert, M. Malacria,
Tetrahedron 1996, 52, 7487–7510.
[11]
The relative yields of (E)-11 and (Z,E)-12 were determined
1
from the H NMR spectrum of the crude product mixture, as
they were inseparable. The ee of (Z)-11 was determined by chi-
ral HPLC analysis with a chiral column.
[12]
[13]
[14]
rac-(E)-11 was obtained from the reaction of 10b with
NaHMDS in THF as the sole product in 89% yield.
N. Harada, T. Nehira, T. Soutome, N. Hiyoshi, F. Kido, En-
antiomer 1996, 1, 35–39.
Carlier has recently reported that magnesiated cyclopropyl ni-
trile anions possess macroscopic configurational stability. P. R.
Carlier, Y. Zhang, Org. Lett. 2007, 9, 1319–1322.
P. R. Carlier, Chirality 2003, 15, 340–347.
a) E. Buncel, J. M. Dust, Carbanion Chemistry: Structures and
Mechanisms, American Chemical Society, Washington DC,
2003; b) J. Kaneti, P. R. von Schleyer, T. Clark, A. J. Kos, G. W.
Spitznagel, J. G. Andrade, J. B. Moffat, J. Am. Chem. Soc.
1986, 108, 1481–1492.
W. Zarges, M. Marsch, K. Harms, G. Boche, Angew. Chem.
Int. Ed. Engl. 1989, 28, 1392.
We have tried to prepare cyanohydrin derivatives of α,β-unsatu-
rated aldehydes, but O-carbamoylation of the cyanohydrin gave
back the starting aldehyde.
a) S. Yokoshima, T. Ueda, S. Kobayashi, A. Sato, T. Kubo-
yama, H. Tokuyama, T. Fukuyama, J. Am. Chem. Soc. 2002,
124, 2137–2139; b) J. Casas, C. Nájera, J. M. Sansano, J. M.
Saá, Tetrahedron 2004, 60, 10487–10496.
The absolute configuration of 18 was not determined.
We believe that the ee values are meaningful because they were
reproducible.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details and spectroscopic data.
Acknowledgments
This research was partially supported by the Ministry of Educa-
tion, Culture, Sports, Science and Technology (MEXT) through a
Grant-in-Aid for Scientific Research (B) (15390006, 19390006) and
[15]
[16]
a
Grant-in-Aid for Scientific Research on Priority Areas
(17035054, 18032049). We thank the Research Center for Molecu-
lar Medicine, Faculty of Medicine, Hiroshima University and N-
BARD, Hiroshima University for the use of their facilities.
[17]
[18]
[1] a) D. Hoppe, T. Hense, Angew. Chem. Int. Ed. Engl. 1997, 36,
2282–2316; b) P. Beak, A. Basu, D. J. Gallagher, Y. S. Park, S.
Thayumanavan, Acc. Chem. Res. 1996, 29, 552–560; c) A.
Basu, S. Thayumanavan, Angew. Chem. Int. Ed. 2002, 41, 716–
738; d) V. K. Aggarwal, Angew. Chem. Int. Ed. Engl. 1994, 33,
175–177. Also see: e) D. C. Kapeller, L. Brecker, F. Ham-
merschmidt, Chem. Eur. J. 2007, 13, 9582–9588, and references
therein.
[2] a) H. M. Walborsky, J. M. Motes, J. Am. Chem. Soc. 1970, 92,
2445–2450; b) H. M. Walborsky, A. A. Youssef, J. M. Motes,
J. Am. Chem. Soc. 1962, 84, 2465–2466; c) H. M. Walborsky,
F. M. Hornyak, J. Am. Chem. Soc. 1955, 77, 6026–6029.
[19]
[20]
[21]
Received: March 20, 2008
Published Online: May 8, 2008
3064
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3061–3064