Diastereoselective Michael reactions of (1R)-(+)-camphor methyl ketone enolates with nitro olefins

Article abstract of DOI:10.1016/S0040-4039(01)00885-1

The reaction of the sodium enolate of the methyl ketone 2 with a range of nitro olefins proceeds readily to give the corresponding Michael adducts in good yields and diastereoselectivities. Subsequent oxidative cleavage of the acyloin moiety provides γ-nitroalkanoic acids along with (1R)-(+)-camphor, the chiral auxiliary of the process, which can be recovered and reused.

Full text of DOI:10.1016/S0040-4039(01)00885-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4829–4831
Diastereoselective Michael reactions of (1R)-(+)-camphor methyl
ketone enolates with nitro olefins
Claudio Palomo,a,* Jesu´s M. Aizpurua,a M. Oiarbide,a Jesu´s M. Garc´ıa,b Alberto Gonza´lez,b
I. Odriozolaa and Anthony Lindenc
aDepartamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, Universidad del Pa´ıs Vasco, Apdo 1072,
20080 San Sebastia´n, Spain
bDepartamento de Qu´ımica Aplicada, Universidad Pu´blica de Navarra, Campus de Arrosad´ıa, E-31006 Pamplona, Spain
cOrganisch-chemisches Institut der Universitat Zu¨rich, Winterthurerstrasse 190, CH-8057 Zu¨rich, Switzerland
Received 23 January 2001; revised 9 February 2001; accepted 13 April 2001
Abstract—The reaction of the sodium enolate of the methyl ketone 2 with a range of nitro olefins proceeds readily to give the
corresponding Michael adducts in good yields and diastereoselectivities. Subsequent oxidative cleavage of the acyloin moiety
provides g-nitroalkanoic acids along with (1R)-(+)-camphor, the chiral auxiliary of the process, which can be recovered and
reused. © 2001 Elsevier Science Ltd. All rights reserved.
The asymmetric Michael addition of enolizable car-
bonyl compounds to electron deficient olefins is a fun-
damental process for the stereoselective construction of
CꢀC bonds.1,2 Nitroalkenes are of special interest as
powerful Michael acceptors due to the strong anion-
stabilizing effect of the nitro group which causes the
reaction to proceed with very high efficiency.3 On the
other hand, the nitro group can be transformed into
other functionalities such as the carbonyl group via Nef
reaction or an amino group by reduction.4 However,
despite the recent advances in this area,5 there are very
few examples of diastereoselective Michael reactions
with nitro olefins.6 One important problem associated
with this process is the usual lack of stereoselection
with enolates of a-unsubstituted carboxylic acid deriva-
tives.7 Recently we have reported on the use of the
methyl ketone 2 in ‘acetate’ aldol8 and Mannich9 reac-
tions. Herein we report on the reaction of 2 with
aromatic nitro olefins10 as the key-step for a highly
stereoselective synthesis of g-nitroalkanoic acids and
their g-lactam derivatives. These compounds are pre-
cursors of g-amino acids which have potent activity on
the central nervous system.11
As Scheme 1 illustrates, the methyl ketone 2, readily
available from (1R)-(+)-camphor 1 and acetylene,8
upon treatment with NaHMDS and subsequent reac-
tion with nitrostyrene in THF at −78°C provided the
adduct 3a in good yield and acceptable diastereoselec-
tivity. Under similar reaction conditions, the lithium
enolate of 2, generated from either LDA or LiHMDS,
worked without efficiency in terms of diastereoselectiv-
ity, and the potassium enolate of 2 did not provide the
expected adduct. Results are listed in Table 1 to illus-
1. B- (1.5 equiv.)
2. RCH=CHNO2
1. C2HLi
2. HgO, H+
OR1
R
(2 equiv.)
OTMS
THF
3. XSiMe3
NO2
ref 7
O
O
O
2
1
R1: SiMe3
R1: H
3
TBAF, MeOH
a
b
R: C6H5
c R: 4-ClC6H4
r.t., 15min
98%
4
R: 4-MeOC6H4 d R: 2,4-Me2C6H3
Scheme 1.
* Corresponding author. E-mail: qoppanic@sc.ehu.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00885-1

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C. Palomo et al. / Tetrahedron Letters 42 (2001) 4829–4831
Table 1. Diastereoselective Michael reactions of 2 with
nitro olefins
equivalent with nitro olefins that formally involves the
use of acetylene as the elementary source of carbonyl
(acetyl) and (1R)-(+)-camphor as the source of chiral
information. In addition, from an economical point of
view, such a process with (1S)-(+)-camphor would also
be viable as a route to the biologically active (R)-g-
amino acids, since the chiral controller, with no loss of
chiral integrity, might be recovered at the final stage
and could be reused.
Product
Base
t (h)
d.r.a
Yield %b
3a
LDA
16
75:25
70:30
93:7
65:35
94:6
nd
nd
67
LiHMDS
NaHMDS
LDA
NaHMDS
NaHMDS
NaHMDS
0.5
0.5
16
0.5
0.5
0.5
3b
nd
65
4c
4d
93:7
94:6
64c
53c
Acknowledgements
a Determined by 1H NMR (500 MHz) and by HPLC (Lichorsorb Si
60, 5 mm, 20°C; eluant: ethyl acetate:hexane 1:99).
b Yield of isolated, pure products. nd: not determined.
c Overall from 2.
This work was financially supported by Gobierno
Vasco (Project EX-1999-128) and in part by Universi-
dad del Pa´ıs Vasco (Project UPV 170.215-G47/98) and
by Diputacio´n Foral de Guipu´zcoa. A grant from
Gobierno Vasco to I.O. is gratefully acknowledged.
trate the excellent diastereofacial selection observed for
the reaction of the sodium enolate of 2 with some
representative aromatic nitro olefins.
These adducts are of particular interest in that they
provide, through oxidative cleavage of the acyloin moi-
ety, g-nitroalkanoic acids. For example, Scheme 2,
compounds 5 and 6 were produced along with (1R)-(+)-
camphor 1 by exposure of the adducts 4a and 4c to a
threefold excess of ammonium cerium nitrate (CAN) in
acetonitrile/water. From each crude mixture, the chiral
auxiliary 1 was isolated by extraction with pentane in
95–97% yield12 and the resulting g-nitroalkanoic acids
were isolated as their methyl esters 7 and 8 in 85 and
89% yields, over the two steps, respectively. The stereo-
chemical assignments for the major products were
established primarily by conversion of 8 into the g-lac-
tam 9. The observed optical rotation of 9 was then
compared with that of 10. In addition, a single-crystal
X-ray analysis of the Michael adduct 4c13 corroborated
its assigned configuration.
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8 R: 4-ClC6H4
O
O
Raney Ni
H2(10bar)
NH
Cl
NH
EtOH, 70%
Cl
9
10
[α]D25= -39.0
(c=1.0, EtOH)
[α]D25= +37.9
(c=0.42, EtOH)
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C. Palomo et al. / Tetrahedron Letters 42 (2001) 4829–4831
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optical rotation value of [h]2D5=+41.5/+42.0 (c=1.0,
EtOH) ([h]2D5=+42.2 (c=1.0, EtOH) for the starting
camphor, purchased from Aldrich).
13. The X-ray crystal structure analysis has been performed
by one of us (A.L.) at the Organisch-chemisches Institut
der Universita¨t Zu¨rich. Crystallographic data (excluding
structure factors) for compound 4c have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 156554. Copies of
the data can be obtained free of charge on application
to the CCDC, 12 Union Road, Cambridge, CB2, 1EZ,
UK. E-mail: deposit@ccdc.cam.ac.uk.
.