Enantioselective conjugate addition of organomagnesium amides to enamidomalonates: Synthesis of either enantiomer of β-amino acid derivatives [18]

Full text of DOI:10.1021/ja016492c

9708
J. Am. Chem. Soc. 2001, 123, 9708-9709
Scheme 1
Enantioselective Conjugate Addition of
Organomagnesium Amides to Enamidomalonates:
Synthesis of Either Enantiomer of â-Amino Acid
Derivatives
Mukund P. Sibi* and Yasutomi Asano
Department of Chemistry
North Dakota State UniVersity
Fargo, North Dakota 58105-5516
Table 1. Reaction Conditions for Addition to 4a
ReceiVed June 25, 2001
ReVised Manuscript ReceiVed August 17, 2001
Development of new methods for the synthesis of â-amino
acids in enantiomerically pure form continues to attract interest.1
Recently, we2 and others3 have shown that nitrogen nucleophiles
add with high enantioselectivity to enoates to provide access to
â-amino acid derivatives in a straightforward manner. However,
there are drawbacks to this process: (1) the variation in the
nucleophile is generally limited to hydroxylamines and azides,
(2) addition to aryl-substituted enoates is generally inefficient,
and (3) 1,2-addition to the starting material or the product by the
amine nucleophile sometimes interferes.
An alternate and potentially a more general method is shown
in Scheme 1. The process involves the conjugate addition of
readily available carbon nucleophiles to a substrate in which the
nitrogen is pre-installed, as in the enamidomalonates 1. It was
hypothesized that addition of an organometallic reagent to 1 would
produce the amino acid derivative 2, which after decarboxylation
under Krapcho conditions,4 would provide the â-amino acid esters
3. The substrate choice was attractive for several reasons (1) a
doubly activated substrate for efficient conjugate addition, (2) no
E,Z-isomers, and (3) an electron-withdrawing acyl group on the
nitrogen for increased reactivity in conjugate addition. In principle,
introduction of asymmetry in the conversion of 1 to 2 could
require either the acceptor or the nucleophile to be chiral or both.
The addition of chiral nucleophiles to 1 in good chemical
efficiency as well as enantioselectivity is detailed in this work.5
Additionally, a convenient and interesting way to control the
absolute stereochemistry of 2 is also presented.
entry
conditions
1.1 equiv EtMgCl
2.1 equiv EtMgCl
5 R ) Et, 2.2 equiv
4, LiH, then add 1.1 equiv 5 R ) Et
5 R ) i-Pr, then 1.1 equiv EtMgCl
product % yield % ee
1
2
3
4
5
6a R ) Et
6a R ) Et
6a R ) Et
6a R ) Et
6a R ) Et
6b R ) iPr
6a R ) Et
6a R ) Et
46
91
76
86
22
62
39
39
34
79
-
-
79
83
28
78
22
86
89
78
6
7
8
9
4, LiH, 5 RdBr, then 1.1 equiv EtMgCl
4, LiH, 5 RdBr, then 1.3 equiv 5 R ) Et
4, LiH, Ent 5 RdBr, then 1.3 equiv 5 R ) Et 6a R ) Et
4, LiH, add MgI2, then 1.3 equiv 5 R ) Et 6a R ) Et
a For experimental details see Supporting Information.
Increasing the amount of EtMgCl to 2.1 equiv, gave a high yield
of 6a (entry 2). Recently, Nakamura has shown that σ-bound zinc
reagents derived from bisoxazolines are good chiral nucleophiles.8
The chiral organomagnesium amide 5 was prepared similarly by
the treatment of 4,4′-diphenyldihydrobisoxazoline with 1 equiv
of n-BuLi followed by the addition of the Grignard reagent.9
Addition of 4 to 2.1 equiv of 5 gave 6a in excellent chemical
yield and high selectivity (79% ee, entry 3). This established that
the conjugate addition indeed proceeds enantioselectively using
chiral organomagnesium amides. The next experiment was
designed to explore the necessity for a chiral nucleophile. Addition
of 1 equiv of LiH to 4 generated the corresponding lithium salt
to which 5 (R ) Et) was added. The high enantioselectivity in
this experiment suggests that the chiral donor is important (entry
4) and that only a stoichiometric amount of the chiral ligand is
needed. The need for a chiral acceptor was investigated next.
Compound 4 was treated with 1.1 equiv of 5 (R ) iPr) followed
by another 1.1 equiv of EtMgCl (entry 5). The ee for 6a in entry
5 is much lower than in entry 4, suggesting that the chiral
nucleophile is the primary determinant of product stereochemistry.
The formation of 6b implied that deprotonation is marginally
competitive with conjugate addition. A more unambiguous
experiment to ascertain the role of chiral acceptor is shown in
Our experiments began with the establishment of reaction
conditions for the conversion 1 to 2. Grignard reagents were
chosen as the nucleophile. Addition of 1.1 equiv of EtMgCl to
the trifluoroacetamide derivative 46 at -78 °C furnished the
conjugate addition product 6a in 46% yield (entry 1, Table 1).7
This indicated that deprotonation was competitive with addition.
(1) For synthesis and biology of â-amino acids see: EnantioselectiVe
Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997.
(2) (a) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc.
1998, 120, 6615. (b) Also see: Sibi, M. P.; Liu, M. Enantiomer 1999, 4, 575.
(c) Sibi, M. P.; Liu, M. Org. Lett. 2000, 2, 3393. (d) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033.
(3) (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959.
(b) Also see: Guerin, D. J.; Horstmann, T. E.; Miller, S. J. Org. Lett. 1999,
1, 1107.
(4) Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E.,
Jr.; Lovey, A. J.; Stephen, W. P. J. Org. Chem. 1978, 43, 138.
(5) Selected examples of conjugate addition using chiral nucleophiles:
Organolithiums: (a) Tomioka, K.; Shinda, M.; Koga, K. Tetrahedron Lett.
1993, 34, 681. (b) Asano, Y.; Iida, A.; Tomioka, K. Chem. Pharm. Bull. 1998,
46, 184. (c) Park, Y. S.; Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc.
1997, 119, 10537. (d) Curtis, M. D.; Beak, P. J. Org. Chem. 1999, 64, 2996.
Heterobimetallic catalysts: (e) Vogl, E. M.; Gro¨ger, H.; Shibasaki, M.; Angew.
Chem., Int. Ed. 1999, 38, 1570. (f) Arai, T.; Sasai, H.; Yamaguchi, K.;
Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 441. (g) Chiral malonates:
Christoffers, J.; Ro¨ssler, U.; Werner, T. Eur. J. Org. Chem. 2000, 701. (h) Ji,
J.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenberger, S. J.; Morton, H. E.
J. Am. Chem. Soc. 1999, 121, 10215. For the addition of neutral nucleophiles
to alkylidene malonates see: (i) Evans, D. A.; Rovis, T.; Kozlowski, M. C.;
Downey, C. W.; Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134.
(6) See Supporting Information for the synthesis of 4 and other details.
(7) The choice of the methyl group for an ester substituent and the
trifluoroacetyl group for nitrogen protection was based on ease of preparation.
The benzamide analogue reacted similarly (entry 3, Table 1) with 85% yield
and 79% ee. A full account will discuss the effect of variations of these groups
on chemical as well as selectivity efficiency.
(8) (a) Nakamura, M.; Hirai, A.; Sogi, M.; Nakamura, E. J. Am. Chem.
Soc. 1998, 120, 5846. (b) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am.
Chem. Soc. 1996, 118, 8489. (c) Schulze, V. V.; Hoffmann, R. W. Chem.
Europ. J. 1999, 5, 337. (d) Hanessian, S.; Yang, R.-Y. Tetrahedron Lett. 1996,
37, 8997. (e) Bandini, M.; Cozzi, P. G.; Negro, L. Umani-Ronchi, A. Chem.
Commun. 1999, 39.
(9) See Supporting Information for experimental details. For formation of
organomagnesium amides from lithium amides and Grignard reagents see:
Henderson, K. W.; Molvey, R. E.; Clegg, W.; O’Neil, P. A. J. Organomet.
Chem. 1992, 439, 237.
10.1021/ja016492c CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/07/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 39, 2001 9709
Table 2. Conjugate Addition of Different Nucleophiles to 4a
a For experimental details see Supporting Information.
entry 6. Formation of a magnesium diamide by treatment of 4-Li
with 5 (R ) Br) followed by the addition of EtMgCl gave 6a in
low yield and ee (entry 6), suggesting that a chiral nucleophile is
required for high selectivity. Further corroboration for this
requirement is shown in entry 7, where addition of 5 (R ) Et) to
a chiral acceptor gave high selectivity for 6a. The next experiment
used enantiomeric 5 (R ) Br) to prepare the chiral acceptor and
addition of 5 (R ) Et) (entry 8). The sense of stereoinduction
for 6a suggests that the chirality in the nucleophile controls the
stereochemical outcome. The last control experiment involved
conjugate addition to the N-Mg salt of 4. Treatment of 4 with
LiH followed by addition of MgI2 gave the N-Mg salt (entry 9).
Addition of 5 (R ) Et) furnished 6a with similar levels of
selectivity as the Li salt (compare entry 4 with 9). It should be
noted that the ligand could be recovered (∼80%) after the
experiment. Compound 6 (R ) Et) could be monodecarboxylated4
to the corresponding amino acid ester uneventfully (3, R ) Et,
R1 ) CF3, R2 ) Me).6
Having established that conjugate addition of chiral donors to
4 is feasible, we then undertook a brief study on the variation of
its structure as well as the chiral ligand. Results from these
experiments are tabulated in Table 2. Addition of a variety of
nucleophiles derived from 5 to 4 either using the Li or Mg salt
gave products 6a-g in very good yield and selectivity (entries
1-7). There was very little variation in the yield or selectivity
using the two methods. Examination of Table 2 indicates that
alkyl, vinyl, and aryl nucleophiles are all compatible in this
method.
Figure 1.
outcome from reactions with 7 was that products 6a-g had the
opposite configuration as compared to reactions with 5. Thus
enantiomeric series of products are available with a simple change
of the chiral ligand.
A working model for the sense of stereoinduction is presented
in Figure 1. The absolute stereochemistry for 6a (entry 3, Table
1) was determined to be R by converting it to a known
compound.11 The control experiments suggest that deprotonation
is not required and thus the chiral nucleophile12 is the stereo-
determining factor. Coordination of the ester carbonyl to the
magnesium allows for alkyl transfer through a six-membered
transition state (Figure 1). However, the inversion of stereochem-
istry with 7 is not easily rationalized using this model.
In conclusion, a general methodology for the preparation of
â-amino acid esters has been developed. Experiments to gain a
better understanding of the structure for the reactive complex,
development of catalytic variants, and evaluation of copper and
zinc nucleophiles in conjugate additions are underway.
We have shown previously10 that bisoxazolines prepared from
aminoindanol and phenylglycinol possessing the same sense of
stereochemistry provide enantiomeric products in conjugate radical
additions. On the basis of this precedence, we evaluated nucleo-
philes 7 in conjugate addition reactions to 4. In contrast to
reactions with 5, conjugate addition using 7 (R ) Et) was not
very efficient (1.3 equiv 15% yield, 68% ee; 2.1 equiv, 35% yield,
63% ee). Addition of 7 (R ) Et) to 4-Li was also not possible.
However, 7 added with good efficiency to the corresponding Mg
salt (4-MgI). These results are also shown in Table 2. In general,
the chemical yield as well as selectivity for 6a-g in reactions
with 7 were slightly lower than using 5. The most interesting
Acknowledgment. This work was supported by a grant from the
National Science Foundation (CHE-9983680).
Supporting Information Available: Characterization data for com-
pounds 3-6 and experimental procedures (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA016492C
(11) Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 1996, 7, 2911.
(12) For structural characterization of a bis-isopropyl-derived EtMg complex
see: Singh, R. P. Spectrochim. Acta, Part A. 1997, 53, 1713. Also see Gibson,
V. C.; Segal, J. C.; White, A. J. P.; Williams, D. J. J. Am. Chem. Soc. 2000,
122, 7120.
(10) Sibi, M. P.; Ji, J. J. Org. Chem. 1997, 62, 3800.