Synthesis of optically active aldol derivatives through chirality transfer type 1,2-Wittig rearrangement of α-alkoxycarboxamides

Article abstract of DOI:10.1016/S0040-4039(01)00868-1

Treatment of chiral α-benzyloxy- or α-propargyloxycarboxamide with tert-BuLi gave β-hydroxycarboxamides (aldol derivatives) in high optical purity through the formation of α-lithiated ethers and the subsquent 1,2-Wittig rearrangement.

Full text of DOI:10.1016/S0040-4039(01)00868-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4865–4868
Synthesis of optically active aldol derivatives through chirality
transfer type 1,2-Wittig rearrangement of a-alkoxycarboxamides
Osamu Kitagawa,a Shu-ichi Momose,a Yoichiro Yamada,a Motoo Shirob and Takeo Taguchia,*
aTokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
bRigaku Corporation, 3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan
Received 23 April 2001; accepted 18 May 2001
Abstract—Treatment of chiral a-benzyloxy- or a-propargyloxycarboxamide with tert-BuLi gave b-hydroxycarboxamides (aldol
derivatives) in high optical purity through the formation of a-lithiated ethers and the subsquent 1,2-Wittig rearrangement. © 2001
Elsevier Science Ltd. All rights reserved.
Isomerization to metal alkoxide through the 1,2-alkyl
migration of a-metalated ethers is well known as the
1,2-Wittig rearrangement.1 A radical pair dissociation–
recombination mechanism is widely accepted as the
most reasonable mechanistic pathway of the 1,2-Wittig
rearrangement.1,2 Furthermore, with substrates having
chiral centers at the migrating carbon (not metal-bear-
ing carbanion center), it has been confirmed that the
reaction proceeds with retention of the migrating car-
bon.3 On the other hand, despite the many reports on
such mechanistic and streochemical studies, 1,2-Wittig
rearrangement of synthetically useful levels has not so
far been reported except for a few examples.4 In this
paper, we report a 1,2-Wittig rearrangement with chiral
a-alkoxycarboxamides which proceeds with a high level
of retention at the migrating center to give optically
active b-hydroxycarboxamides (aldol derivatives)
(Scheme 1).
forms has been also investigated by many groups.5
Asymmetric aldol reaction would be classified as a
diastereoselective version using a chiral auxiliary and
an enantioselective version using a chiral reagent or
catalyst.5c We found a new synthetic method of opti-
cally active aldol derivatives through 1,2-Wittig rear-
rangement with chiral N-phenyl a-alkoxycarboxamides.
When (R)-N-phenyl O-benzylmandelamide 1a derived
from (R)-mandelic acid is treated with 3 equiv. of
tert-BuLi at −78°C, deprotonation of benzyl hydrogen
and subsequent 1,2-Wittig rearrangement of the result-
ing a-lithiated ether smoothly proceeds to give b-
hydroxy-a,b-diphenyl propanamide 2a in good yield
(69%) with relatively high diastereoselectivity (anti-2a/
syn-2a=9.9) (Scheme 2).6 The ee of the major
diastereomer anti-2a was estimated to be 94% by
HPLC analysis using a chiral column.6 Thus, the
present reaction was found to proceed with a high level
of chirality transfer without racemization of 1a. As the
reaction substrate, the use of N-monosubstituted
anilide derivative is essential; for example, in the reac-
tion with the O-benzyl ether of mandelic acid, iso-pro-
Aldol derivatives, b-hydroxy carbonyl compounds, are
a useful synthetic intermediate for the preparation of
various natural products. Accordingly, the development
of asymmetric aldol reactions to get the optically active
Li
O
OH
O
R1
OLi
O
R1
O
H3O+
tert-BuLi
Li
NPh
Li
NPh
R1
NHPh
R1
*
NHPh
R2
*
R2
*
*
*
*
R2
R2
O
O
Scheme 1.
Keywords: hydroxy acids and derivatives; asymmetric reaction; Wittig rearrangement; aldols.
* Corresponding author. Tel./fax: 81-426-76-3257; e-mail: taguchi@ps.toyaku.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00868-1

4866
O. Kitagawa et al. / Tetrahedron Letters 42 (2001) 4865–4868
Li
O
OH
O
3 equiv.
tert-BuLi
Ph
O
Ph
Li
NPh
Ph
NHPh
+ syn-2a
NHPh
Ph
Ph
THF, -78 ˚C
Ph
anti-2a (94 %ee)
(69 %, anti / syn = 9.9)
O
O
(≥ 98 %ee)
1a
Li
O
3 equiv.
tert-BuLi
OH
O
OH
O
Ph
Me
O
Ph
Me
Li
NPh
+
NHPh
NHPh
Ph
Ph
NHPh
THF, -78 ˚C
Me
Me
O
O
syn-2b (79 %ee)
anti-2b (95 %ee)
1b (≥ 98 %ee)
(77 %, anti / syn = 2.2)
Scheme 2.
pyl mandelate or N,N-diethyl mandelamide, recovery
of the starting material or formation of a complex
mixture resulted without the formation of the 1,2-Wit-
tig product. Although a decrease in diastereoselectivity
was observed (anti-2b/syn-2b=2.2), under the same
conditions, 1,2-Wittig rearrangement of (S)-N-phenyl
O-benzyllactamide 1b derived from (S)-lactic acid also
proceeded to give the product 2b in good yield (77%)
(Scheme 2). Similar to mandelamide 1a, the ee of major
diastereomer anti-2b was found to be 95% which indi-
cates a high level of chirality transfer, while for minor
diastereomer syn-2b, a decrease in the ee was observed
(79% ee).7 These reactions would be equivalent to an
asymmetric aldol reaction of phenylacetic acid and
propionic acid derivatives with benzaldehyde.
The relative and absolute stereochemistries of the prod-
ucts 2a and 2b were determined after conversion to
known diols 4a8 and 4b9 in accordance with Scheme 3.
On the basis of the results of Scheme 2 and Scheme 3,
the stereochemical course of the present reaction may
be rationalized as Scheme 4. The high ee and absolute
OH
TBSO
Ph
O
1) TBSOTf
2,6-lutidine
3) LiAlH4
Ph
OH
anti-2a
NPh
Ph Ts
anti-3a
THF
(70 %)
2) n-BuLi
then TsCl
(76 %)
Ph
(94 %ee)
anti-4a
[α]D = -64.4 (c=0.9, acetone)
lit. [α]D = -81.8 (c=0.21, acetone)
OH
OH
1) - 3)
syn-2b
1) - 3)
anti-2b
Ph
OH
Ph
OH
(74 %)
(67 %)
(79 %ee)
Me
syn-4b
Me
anti-4b
[α]D = -46.1 (c=1.45, CH3Cl)
(95 %ee)
[α]D = +44.2 (c=0.38, CH3Cl)
lit. [α]D = +52.6 (c=0.57, CH3Cl)
lit. [α]D = -44.3 (c=1.04, CH3Cl)
Scheme 3.
Li
3equiv.
tert-BuLi
Bn
Ph
Li
NPh
Li
Li
O
Ph
O
Ph
O
tert-BuLi
tert-BuLi
1a
NPh
NPh
X
Ph
+
Ph
6A
O
OLi
O
5A
Li
Li
NPh
OLi
O
Li
H
NPh
anti-2a
+
H
Ph
H
Ph
Ph
NPh
Ph
OLi
Ph
O
O
7A
Ph Li
10A
O
8A
9A
7A (retention)
retention
Scheme 4.

O. Kitagawa et al. / Tetrahedron Letters 42 (2001) 4865–4868
4867
O
O
OH O
OH
O
3equiv.
tert-BuLi
Me
Me
NPh
Li
+
NHPh
NHPh
NHPh
O
Li
O
Me
syn-2c (80 %ee)
Me
anti -2c (80 %ee)
1c (91 %ee)
(55 %, anti / syn = 1 / 1.2)
Scheme 5.
O
O
O
Li
2equiv.
n-BuLi
Me
Me
Me
NHAr
N Ar
Ot-Bu
NHAr
Ph
NH
Ph
Li
N
Ph
NBoc
DME, -78 °C
CO2t-Bu
(single diastereomer)
O
(Ar = 2-methoxyphenyl)
1d
11d (56 %, 98 %ee)
Scheme 6.
References
configurations of 2a and 2b indicate that the reaction
proceeds with a high level of retention at the inherent
chiral center (the migrating center). That is, the forma-
tion of dianionic lithium enolate by deprotonation of
a-hydrogen and racemization of a radical intermediate
such as 7A should hardly occur. As far as we know,
since no example of 1,2-Wittig rearrangement involving
the formation of a carbonyl a-radical fragment has so
far been reported, the high level of the chirality transfer
in such reaction system should be noteworthy.
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1,2-Wittig rearrangement using an a-alkoxy carbox-
amide derivative can be applied to not only O-benzyl
ether derivatives 1a and 1b but also O-propargyl
ether derivative 1c (Scheme 5). Under the similar con-
ditions, the reaction of (S)-O-propargyllactamide 1c
(91% ee) gave the product anti-2c and syn-2c in 55%
yield, while decrease in the diasteroselectivity and the
level of chirality transfer was observed in comparison
with O-benzyl derivatives 1a and 1b (anti-2c/syn-2c=1/
1.2, syn-2c and anti-2c: 80% ee).7,10
4. (a) Yadav, J. S.; Ravishankar, R. Tetrahedron Lett. 1991,
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An aza-version of 1,2-Wittig rearrangement with N-Boc
N-benzyl alanine derivative 1d was further investigated.
However, in this case, migration of the Boc group to
the resulting N-benzyl carbanion takes place, leading to
the isolation of 11d as a single stereoisomer without the
formation of an aza-Wittig product (aza-aldol deriva-
tive) (Scheme 6).10
5. For recent reviews: (a) Nelson, S. G. Tetrahedron: Asym-
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917–947.
6. General procedure of 1,2-Wittig rearrangement. Under Ar
atmosphere, to a solution of 1a (159 mg, 0.5 mmol) in THF
(3 ml) was added pentane solution of tert-BuLi (1.47 M,
1.02 ml, 1.5 mmol) at −78°C. After being stirred for 1 h
at −78°C, the reaction mixture was poured into 2% HCl
In conclusion, we have succeeded in the development of
1,2-Wittig rearrangement with chiral a-alkoxycarbox-
amides which proceeds with a high level of chirality
transfer to give optically active b-hydroxycarboxamides
(aldol derivatives). The present reaction should provide
new methodology for the synthesis of optically active
aldol derivatives from inexpensive chiral a-hydroxy
acids.

4868
O. Kitagawa et al. / Tetrahedron Letters 42 (2001) 4865–4868
and extracted with CH2Cl2. The CH2Cl2 extracts were
7.65 (1H, d, J=8.0 Hz), 6.98–7.32 (14H, m), 5.67 (1H, d,
J=4.4 Hz), 5.17 (1H, dd, J=4.4, 10.3 Hz), 3.91 (1H, d,
J=10.3 Hz). 13C NMR (CDCl3): l 171.0, 143.5, 139.6,
137.4, 128.9, 128.1, 127.8, 127.2, 127.1, 126.9, 123.3,
119.1, 75.1, 61.1.
washed with brine, dried over MgSO4, and evaporated to
dryness. Purification of the residue by column chro-
matography (CHCl3) gave a mixture of anti-2a and syn-
2a (110 mg, 69%). The ratio of syn-2a and anti-2a was
1
determined by 300 MHz H NMR. Further purification
7. The ee was determined on the basis of Mosher’s analysis.
8. Berova, N.; Boyadzhiv, S.; Rakovska, R. Izv. Khim. 1981,
14, 487–497.
9. (a) Abiko, A.; Liu, J.; Masamune, S. J. Am. Chem. Soc.
1997, 119, 2586–2587; (b) Davies, S. G.; Edwards, A. J.;
Evans, G. B.; Mortlock, A. A. Tetrahedron 1994, 50,
6621–6642.
of the mixture by MPLC (CHCl3) gave anti-2a (less
polar) and syn-2a (more polar). The ee of anti-2a was
determined on the basis of HPLC analysis using CHI-
RALPAK AS column [25 cm×0.46 cm; solvent, 10%
i-PrOH in hexane; flow rate; 0.8 ml/min; major-enan-
tiomer, tR=9.2 min, minor-enantiomer, tR=11.8 min].
anti-2a: colorless solid; mp 218–220°C; [h]D=−66.9 (c=
10. The stereochemistries of syn-2c and 11d were determined
on the basis of X-ray analysis.
1
0.60, acetone); H NMR (DMSO-d6): l 10.14 (1H, brs),
.