An easy access to enantio-enriched α-substituted aldehydes by carbolithiation of β-phenyl or β-silyl-α,β-ethylenic aldehydes, protected with the monolithioamide of a chiral diamine

Article abstract of DOI:10.1016/S0040-4039(01)00034-X

Lithium amide derived from N,N,N′-trimethyl-1,2-diphenylethanediamine converts cinnamaldehyde to a lithium alkoxyamide which undergoes a regio- and stereoselective carbolithiation upon addition of various organolithiums. Subsequent hydrolysis or trapping with MeI delivers α-mono-, or α,β-disubstituted 3-phenylpropanals with e.e.s of 76-96%. Extension to a silylated α-enal is possible.

Full text of DOI:10.1016/S0040-4039(01)00034-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1883–1885
An easy access to enantio-enriched a-substituted aldehydes by
carbolithiation of b-phenyl or b-silyl-a,b-ethylenic aldehydes,
protected with the monolithioamide of a chiral diamine
Nathalie Bre´mand, Pierre Mangeney and Jean F. Normant*
Laboratoire de Chimie des Organo-e´le´ments, associe´ au CNRS, Universite´ P. & M. Curie, Tour 44-45, Boˆıte 183,
4 Place Jussieu, 75252 Paris Cedex 05, France
Received 21 December 2000; accepted 5 January 2001
Abstract—Lithium amide derived from N,N,N%-trimethyl-1,2-diphenylethanediamine converts cinnamaldehyde to a lithium
alkoxyamide which undergoes a regio- and stereoselective carbolithiation upon addition of various organolithiums. Subsequent
hydrolysis or trapping with MeI delivers a-mono-, or a,b-disubstituted 3-phenylpropanals with e.e.s of 76–96%. Extension to a
silylated a-enal is possible. © 2001 Published by Elsevier Science Ltd.
The preparation of a,b-disubstituted carbonyl com-
pounds of high optical purity is an important synthetic
objective. Methods involving chiral catalysts or cova-
lently bonded chiral auxiliaries are numerous and deal
mainly with conjugate 1,4-additions, followed by trap-
ping of the intermediate enolate. In this paper we
describe a new carbometalation reaction as a single step
method for such an objective.
We had previously shown that RLi/(−)-sparteine com-
plexes added regio- and enantioselectively to cinnamyl
alcohols, ethers, amines,2 and amides,3 so that we were
interested to know whether intramolecular chirality,
brought into the intermediate 4 by a chiral analog 5 of
the amide 1 would allow a diastereoselective carbolithi-
ation leading to the benzyllithium intermediate 6 and
to the homochiral aldehydes 3 after quenching and
hydrolysis. (R,R) or (S,S) - 1,2 - diphenyl - N,N,N% - tri-
methylethanediamine4 was selected for the preparation
of the chiral reagent 5.
We have recently reported that cinnamaldehyde, once
blocked as a lithium aminoalkoxide, via the amide of
N,N,N%-trimethylethanediamine1 1 undergoes a regiose-
lective addition of alkyllithiums on the carbonꢀcarbon
double bond, which delivers a benzyllithium derivative
2. Various electrophiles reacted with the latter to give
the syn compounds 3 with good yields (49–78%) and
good diastereoselectivities (90% d.e.)1 (Scheme 1).
Two equivalents of the chiral amide 5 are added to 1
equivalent of cinnamaldehyde at −40°C and the temper-
ature is raised to 0°C. The mixture is cooled to −20°C
and 4 equivalents of RLi in different solvents (see Table
1) are added. The mixture is stirred for 3 h at −20°C
Li
N
1)
Me
Li
OLi
E
N
1) E +
1
N
CHO
CHO
Ph
N
Ph
Ph
2) H2O
2) RLi
3
R
R
2
Y. : 49-78%
d.e.: 90%
Scheme 1.
Keywords: aldehyde; carbometalation; diastereoselection.
* Corresponding author. Fax: 00 33-1 44 27 75 67; e-mail: normant@ccr.jussieu.fr
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00034-X

1884
N. Bre´mand et al. / Tetrahedron Letters 42 (2001) 1883–1885
Table 1. Addition of organolithiums to a-aminoalkoxide 4
Entry
RLi
Solvent
7a–f
Yield (%)
e.e. 7a (%)
1
2
3
4
5
6
7
8
n-BuLi
n-BuLi
EtLi
i-PrLi
i-PrLi
s-BuLi
t-BuLi
Et2O
THF
Et2O
Hexane
Et2O
Et2O
Et2O
Et2O
7a
7a
7b
7c
7c
7d
7e
7f
78
65
75
51
77
90
65
49
93
59
92
35
84
84b
76
96c
a Measured from the corresponding alcohol 8.5
b As a mixture of two diastereoisomers (4S/5S).
c After immediate reduction to the alcohol.
Li
Ph
N
2eq.
N
Me
OLi Ph
N
Li
OLi Ph
5
Ph
4 eq.RLi
N
N
CHO
H +
Ph
Ph
N
Ph
4
6
Ph
Ph
R
NaBH4, MeOH
CHO
Ph
OH
8a-f
6
Ph
R
7a-f
R
NaClO2 , buffer
COOH
7a
Ph
9
Bu
Scheme 2.
and 2 h at 0°C. Acidic quench delivers aldehydes 7a–f,
which are reduced to the alcohols 8a–f (Scheme 2). The
enantiomeric purities of the latter are measured from
In THF, the reaction takes place with lower yield (65%)
and lower e.e. (59%) as shown in Table 1. In hexane the
enantioselectivity is worse (compare entries 4 and 5).
Various organolithiums can be used with good yields
and enantioselectivities: primary, secondary and tertiary
alkyllithiums. Even cyclohexenyl lithium, prepared
from 1-chlorocyclohexene reacts in ether (49% yield,
96% e.e.). In this case the reduction of the correspond-
ing aldehyde must be performed immediately after
hydrolysis, in order to avoid epimerization of the labile
allylic Hydrogen atom.
the 31P NMR spectrum of
a
derived chiral
diaminophosphite according to Alexakis et al.5 From
n-BuLi, 2-benzylhexan-1-ol 8a is obtained with 88%
yield and 93% e.e. An excess of chiral amide 5 is
preferable indeed, if 1.3 equiv. are used instead of 2
equiv. the yield is similar (78% for BuLi, entry 1, Table
1), but the e.e. is lowered to 85%.
The raw aldehydes 7a can be isolated after a rapid
filtration on silica gel (78% yield, 93% e.e.). Meanwhile
the chiral diamine used for the preparation of 5 is
retrieved from the acidic aqueous layer. Moreover, the
a-substituted aldehyde 7a has been oxidized6 (NaClO2,
pH 7 buffer) to the corresponding 2-benzylhexanoic
acid 9 with no loss of optical purity (93% e.e.). The
absolute configuration of 9 is determined by compari-
son with the literature data: (R)-2-benzylhexanoic acid7
is formed from (S,S)-1,2-diphenyl-N,N,N%-trimethyl-
ethanediamine. It is worth noting that both enan-
tiomers of the chiral diamine are available, thus both
enantiomers of aldehydes 7a–f can be obtained.
Li
N
Ph
1)
N
Me
Et2O
Ph
CHO
yield= 83%
CHO
Ph
Ph
2) n-BuLi, -20°C to 0°C
3) -78°C, THF, MeI
4) HCl
Bu
10
Me
NaBH4
MeOH
de>95%
ee= 93%
Ph
OH
Contrary to the carbolithiation of cinnamyl derivatives
by RLi/(−)-sparteine, which had to be run in hydrocar-
bons, diethylether as a solvent is used for this reaction.
Bu
11
Scheme 3.

N. Bre´mand et al. / Tetrahedron Letters 42 (2001) 1883–1885
1885
OLi
CHO
ee = 0
1
1) 5 + BuLi
Ph
CHO
N
Ph
2) H+
Ph
N
Bu
Scheme 4.
1) 5 (1.2 eq.)
Et2O, -40 to 0˚C
Bu
Y.: 82%
CHO
Me3Si
OH
Me3Si
2) n-BuLi, 2.2 eq.
*
12
3) Hydrolysis (pH 7)
4) NaBH4
e.e. : 92%
αD = + 1.6 (c = 1.5, CHCl3)
Scheme 5.
References
One example of trapping the benzyllithium intermediate
6 (R=n-Bu) has been tested by reacting it with excess
MeI. Aldehyde 10 is then obtained with good yield and
good diastereomeric purity8 (Scheme 3). The e.e. has
been determined from the corresponding alcohol 11.
1. Bre´mand, N.; Normant, J. F.; Mangeney, P. Synlett
2000, 4, 532–534.
2. Norsikian, S.; Marek, I.; Klein, S.; Poisson, J. F.; Nor-
mant, J. F. Chem. Eur. J. 1999, 5, 2055–2067.
3. (a) Bre´mand, N.; Marek, I.; Normant, J. F. Tetrahedron
Lett. 1999, 40, 3379–3382; (b) Bre´mand, N.; Marek, I.;
Normant, J. F. Tetrahedron Lett. 1999, 40, 3383–3386.
4. The amide 5 was prepared from (R,R) or (S,S)-1,2-
diphenylethanediamine (global yield: 88% for the first
two steps), as follows:
Our attempts to trap the intermediate alcoholate 4 by
TBDMSOTf or TMSCl failed,9 and we could not estab-
lish whether it is present as a single diastereomer or not,
which could explain the origin of enantio-enrichment.
However, the intramolecular induction was proven by
adding a mixture of the chiral amide 5 and n-BuLi to
the racemic a-aminoalcoholate derived from 1, whereby
aldehyde 7a was obtained as a racemate (0% e.e.,
Scheme 4).
Ph
N
Ph
N
Ph
NH HN
Ph
NH
Ph
i
ii
Finally, we have shown that the phenyl group present
in the starting cinnamaldehyde was not compulsory,
and could be replaced by other anion-stabilizing
residues. For example, b-trimethylsilylacrolein can be
submitted to the amidation–carbolithiation sequence
(with the chiral amide 5) with success, and leads, after
reduction, to 2-trimethylsilylmethylhexan-1-ol 12 of
92% e.e., in 82% overall yield10 (Scheme 5).
Ph
N
Ph
Ph
iii
N
Li
N
i: (CH2O)n aq. CH2Cl2; ii: NaBH3CN,TFA, MeOH; iii nBuLi
5. Alexakis, A.; Frutos, J.; Mutti, S.; Mangeney, P. J. Org.
Chem. 1994, 59, 3326–3330.
In conclusion, we have designed a new methodology to
synthesize enantio-enriched a,b-substituted aldehydes,
not limited to the a-benzyl ones. Work is under way to
extend the scope of this reaction.
6. Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45,
1175–1176.
7. (R)-2-Benzylhexanoic acid: [h]2D0=−14 (c=2.034, ben-
zene): Watson, M. B.; Youngson, G. W. J. Chem. Soc.
(C) 1968, 258–262.
8. Kato, T.; Marumoto, S.; Sato, T.; Kuwajima, I. Synlett
Acknowledgements
1990, 671–672.
9. (a) Comins, D. L. Synlett 1992, 615–625; (b) Alexakis,
A.; Kanger, T.; Mangeney, P.; Rose-Munch, F.; Perrotey,
A.; Rose, E. Tetrahedron: Asymmetry 1995, 6, 2135–2139;
(c) Corruble, A.; Valnot, J. Y.; Maddaluno, J.; Duhamel,
P. Tetrahedron: Asymmetry 1997, 8, 1519–1523.
10. The absolute configuration is not established as yet.
We acknowledge the funding of N. Bre´mand by the
ORIL Company and we thank Dr A. Renaud, Dr P.
Lecouve´ (ORIL Industrie) for many fruitful discus-
sions.
.