N-benzylhydroxylamine addition to β-aryl enoates. Enantioselective synthesis of β-aryl-β-amino acid precursors

Article abstract of DOI:10.1021/ol006500e

(matrix presented) Chiral Lewis acid catalyzed N-benzylhydroxylamine addition to pyrrolidinone-derived enoates afforded β-aryl-β-amino acid derivatives in high enantiomeric purity with moderate to very good chemical efficiency.

Full text of DOI:10.1021/ol006500e

ORGANIC
LETTERS
2000
Vol. 2, No. 21
3393-3396
N-Benzylhydroxylamine Addition to
â-Aryl Enoates. Enantioselective
Synthesis of â-Aryl-â-amino Acid
Precursors
Mukund P. Sibi* and Mei Liu
Department of Chemistry, North Dakota State UniVersity,
Fargo, North Dakota 58105-5516
mukund_sibi@ndsu.nodak.edu
Received August 24, 2000
ABSTRACT
Chiral Lewis acid catalyzed N-benzylhydroxylamine addition to pyrrolidinone-derived enoates afforded â-aryl-â-amino acid derivatives in high
enantiomeric purity with moderate to very good chemical efficiency.
â-Amino acids are important segments of a variety of
bioactive natural products.1 They also serve as precursors
for the synthesis of â-lactams.2 Given their significance, the
development of efficient methods for their synthesis is
important. A common approach for the synthesis of â-amino
acids is the conjugate addition of nitrogen nucleophiles to
R,â-unsaturated carboxylic acid derivatives (Scheme 1).
Lewis acid catalyzed amine additions have been reported.
We have recently developed a novel catalytic method for
enantioselective synthesis of â-amino acid using O-benzyl-
hydroxylamine as the nucleophile. Good isolated yields and
excellent levels of enantioselectivity were obtained.4 Chiral
(salen)Al(III) complex catalyzed conjugate addition of hy-
drazoic acid (HN3) to R,â-unsaturated imines was recently
described by Jacobson et al.5
â-Aryl-substituted â-amino acids have also received
extensive scrutiny.6 The chiral Lewis acid methodologies
described above are applicable to a variety of alkyl substit-
Scheme 1
(2) For a discussion of the synthesis and biology of â-amino acids, see:
EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997. For comprehensive reviews, see: Cole, D. C.
Tetrahedron 1994, 50, 9517. Juaristi, E.; Quintana, D.; Escalante, J.
Aldrichimica Acta 1994, 27, 3.
(3) (a) Davies, S. G.; Fenwick, D. T. J. Chem. Soc., Chem. Commun.
1995, 1109. (b) Dumas, F.; Mezrhab, B.; d’Angelo, J. J. Org. Chem. 1996,
61, 2293. (c) Enders, D.; Wahl, H.; Bettray, W. Angew. Chem., Int. Ed.
Engl. 1995, 34, 455. (d) Amoroso, R.; Cardillo, G.; Sabatino, P.; Tomasini,
C.; Trere, A. J. Org. Chem. 1993, 58, 5615.
(4) (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.
Stereoselective additions utilizing either chiral nucleophiles
or chiral enoates have been reported in the literature, most
notably from the groups of Davies, d’Angelo, Enders,
Cardillo, and others.3 However, only few examples of chiral
(5) (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959.
Also see: Guerin, D. J.; Horstmann, T. E.; Miller, S. J. Org. Lett. 1999, 1,
1107.
(1) (a) Gellman, S. Acc. Chem. Res. 1998, 31, 173. (b) Seebach, D.;
Abele, S.; Gademann, K.; Jaun, B. Angew. Chem., Int. Ed. 1999, 38, 1596.
10.1021/ol006500e CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/29/2000

uents at the â-carbon. However, â-aryl groups fail to pro-
vide adequate results.7 They are considerably less reactive
than the corresponding â-alkyl substrates. This lack of
reactivity intrigued us and alternate pathways were consid-
ered; the successful results from these endeavors are
presented here.
Table 1. N-Benzylhydroxylamime Conjugate Addition. Effect
of Achiral Templates
N-Substituted hydroxylamines are excellent nucleophiles
in conjugate addition to R,â-unsaturated enoates.8 Isoxazo-
lidinones are formed directly in these reactions.9 Zhao et al.
have studied the conjugate addition of N-alkylhydroxylamine
to enoates in some detail and have proposed a concerted
mechanism for the reaction.10
In an effort to improve the reactivity of â-aryl derivatives
in conjugate addition reactions, we hypothesized that the use
of a more reactive achiral template and/or a more reactive
amine nucleophile was necessary. Additionally, the formation
of the same isoxazolidinone irrespective of the starting achiral
template would simplify product analysis. Our experiment
began with the conjugate addition of N-benzylhydroxylamine
to a series of crotonamides 1. Magnesium-based Lewis acids
and a bisoxazoline derived from aminoindanol, a combination
which has been successful in our previous work, were
employed as the catalyst. In contrast to the high selectivity
(96%ee) observed with O-benzylhydroxylamine addition to
3,5-dimethylpyrazole crotonate,4 reactions with N-benzyl-
hydroxylamine (entry 1, Table 1) proceeded only with
moderate selectivity.
We were also interested in exploring other achiral tem-
plates. Oxazolidinone and pyrrolidinone have proven to be
outstanding achiral templates in a variety of enantioselective
transformations.11 Higher levels of selectivity were obtained
for the conjugate addition to pyrrolidinone- and oxazolidi-
none-derived crotonamides 1b-d (entries 2-4, Table 1).
Several other trends are also noteworthy. Pyrrolidinone
substrates 1c and 1d (entries 3 and 4) are more reactive than
the pyrazole substrate 1a. Under the same reaction conditions,
a Isolated yields after chromatography. b ee’s were determined by chiral
HPLC analysis. c The configuration of 3 was established by converting it
to known 3-aminobutyric acid by comparing the sign of rotation of the
product acid with that reported in the literature.3d
reactions with N-benzylhydroxylamine are much faster (entry
1) as compared to addition of O-benzylhydroxylamine.12
Two additional N-substituted hydroxylamines, N-benz-
hydryl- and p-methoxybenzylhydroxylamine, were evaluated.
Pyrrolidinone crotonate (1c) was chosen as the achiral
substrate in this study. The results are tabulated in Table 2.
(6) Isolation of â-DOPA: von Nussbaum, F.; Spiteller, P.; Ru¨th, M.;
Steglich, W.; Wanner, G.; Gamblin, B.; Stievano, L.; Wagner, F. E. Angew.
Chem., Int. Ed. 1998, 37, 3292. (b) Coleman, P. J.; Hutchinson, J. H.; Hunt,
C. A.; Lu, P.; Delaporte, E.; Rushmore, T. Tetrahedron Lett. 2000, 41,
5803. (c) For the use of â-aryl amino acids in Fibrinogen receptor
antagonists, see: Stilz, H. U.; Jablonka, B.; Just, M.; Knolle, J.; Paulus, E.
F.; Zoller, G. J. Med. Chem. 1996, 39, 2118.
Table 2. Conjugate Addition to Pyrrolidinone Crotonate.
Effect of Amine Nucleophiles
(7) For an example of enantioselective catalytic hydrogenation leading
to â-aryl-â-amino acids, see: Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem.
1999, 64, 6907.
(8) (a) Baldwin, S. W.; Aube´, J. Tetrahedron Lett. 1987, 28, 179. (b)
Ishikawa, T.; Nagai, K.; Kudoh, T.; Saito, S. Synlett 1998, 1291. (c)
Ishikawa, T.; Nagai, K.; Senzaki, M.; Tatsukawa, A.; Saito, S. Tetrahedron
1998, 54, 2433. (d) Baldwin, J. E.; Harwood, L. M.; Lombard, M. J.
Tetrahedron 1984, 40, 4363. (e) Stamm, H.; Steudle, H. Tetrahedron Lett.
1976, 3607. (f) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T.
Tetrahedron: Asymmetry 1998, 9, 3945. (g) Keen, S. P.; Weinreb, S. M.
Tetrahedron Lett. 2000, 41, 4307. (h) Jurczak, M.; Socha, D.; Chmielewski,
M. Tetrahedron 1996, 52, 1411. (i) Socha, D.; Jurczak, M.; Chmielewski,
M. Tetrahedron 1997, 53, 739.
R
prod.
time (h)
yield (%)a
ee (%)b
PhCH2
3
4
5
8
21
24
80
90
78
86
85
86
(Ph)2CH
4-MeOC6H4CH2
a Isolated yields after chromatography. b ee’s were determined by chiral
HPLC analysis.
(9) For the conversion of isoxazolidinones to â-amino acids, see: Keirs,
D.; Moffat, D.; Overton, K.; Tomanek, R. J. Chem. Soc., Perkin Trans. 1
1991, 1041.
(10) (a) Niu, D.; Zhao, K. J. Am. Chem. Soc. 1999, 121, 2456. (b) Xiang,
Y.; Gi, H.; Niu, D.; Schinazi, R. F.; Zhao, K. J. Org. Chem. 1997, 62,
7430. (c) Pan, S.; Wang, J.; Zhao, K. J. Org. Chem. 1999, 64, 4.
(11) Ager, D. J.; East, M. B. Asymmetric Synthetic Methodology; CRC
Press: Boca Raton, 1996.
(12) Typical reaction time for O-benzylhydroxylamine additions was 21-
22 h at -60 °C (see ref 4 for details).
We were hoping that the bulkier N-benzhydrylhydroxylamine
would be more sensitive to steric interactions and thus
provide higher levels of selectivity. Additionally, the N-
substituents (benzhydryl and p-methoxybenzyl) would pro-
3394
Org. Lett., Vol. 2, No. 21, 2000

Table 3. Conjugate Addition with N-Benzylhydroxylamine as a Nucleophile. Effect of â-Aryl Substituent
a Isolated yields after chromatography. b ee’s were determined by chiral HPLC analysis. c The configuration of 7a was established by converting it to a
known compound (see Supporting Information). d Reaction was carried out at -45 °C.
vide alternate pathways for deprotection. Similar selectivity
was obtained for all the three N-substituted hydroxylamines.
N-Benzhydrylhydroxylamine was less reactive than N-
benzylhydroxylamine (compare entries 1 and 2, Table 2),
and this was probably due to its bulkiness. Among the three
hydroxylamines examined, N-benzylhydroxylamine showed
the highest reactivity in the conjugate addition reactions.
Taking advantage of the high reactivity of N-benzyl-
hydroxylamine, we then carried out conjugate addition
reactions on cinnamates. A survey of the achiral templates
at 0 °C revealed that pyrrolidinone cinnamate gave the
highest reactivity.13 However, at -60 °C, conjugate addition
of N-benzylhydroxylamine to all three cinnamate substrates
using MgBr2‚Et2O as the Lewis acid were slow; reactions
were incomplete after 48 h. We have also examined several
other Lewis acids: MgI2 and Mg(ClO4)2. At 0 °C, all three
magnesium Lewis acids showed similar reactivity,14 and ee’s
ranging from 66% to 76% were obtained. However, at -60
°C, reactions using MgI2 and Mg(ClO4)2 as the Lewis acid
proceeded much faster than reactions catalyzed by MgBr2‚
Et2O. The best result was obtained for the conjugate addition
of N-benzylhydroxylamine to pyrrolidinone cinnamate (6a)
catalyzed by Mg(ClO4)2 and bisoxazoline ligand 2 (eq 1).
The absolute stereochemistry for 7a was established by
converting it into a known compound (see Supporting
Information).
This constitutes the first example of highly enantioselectiVe
conjugate addition to cinnamates using catalytic amounts
of a chiral Lewis acid. Encouraged by the excellent results
obtained with N-benzylhydroxylamine addition to cinnam-
ates, we then prepared a series of â-aryl-substituted sub-
strates. We wanted to examine electronic effects on substrate
selectivity and reactivity. As illustrated in Table 3, pyrroli-
dinone-derived â-aryl derivatives underwent conjugate ad-
dition with N-benzylhydroxylamine in good yields and
excellent enantioselectivity. The substrate reactivity was
largely dependent on the electronic properties of the â-sub-
stituent. In general, substrates were more reactive when there
was an electron-withdrawing group at the para-position of
the benzene ring, and better enantioselectivity was obtained
(13) At 0 °C, reaction times for oxazolidinone cinnamate, pyrrolidinone
cinnamate and 3,3-dimethylpyrrolidinone cinnamate were 5, 3, and 6 h,
respectively.
(14) Reactions catalyzed by all three Lewis acids were complete in 3 h
at 0 °C.
Org. Lett., Vol. 2, No. 21, 2000
3395

(entries 6c and 6d, Table 3). Substrates were less reactive
when there was an electron-donating group at the para-
position of the benzene ring, and lower enantioselectivity
was obtained (entry 6b). In the case of 3,4-methylenedioxy-
cinnamate, the electron-donating effect at the para-position
was compensated with the electron-withdrawing effect at the
meta-position, and its reactivity was similar to that of the
parent cinnamate (compare entries 6a and 6g). When the
â-substituents were furyl derivatives, the 3-furyl substrate
was much more reactive and selective than the 2-furyl
substrate (compare entries 6e and 6f). However, both furyl
substrates were less reactive than the cinnamates. It is worth
noting that the Mg(ClO4)2 and ligand 2 catalyzed reaction
gave better results for substrates with an electron-withdraw-
ing group on the benzene ring. In contrast, the MgI2 and
ligand 2 catalyzed reaction gave better results for substrates
with an electron-donating group on the benzene ring.
Control experiments analogous to those reported by
Zhao10 using BnNDOD as the nucleophile and 6a or 6c as
the substrate suggest that a concerted addition is also
operative in our experiments.15 We have previously proposed
a cis-octahedral model for conjugate additions with magne-
sium Lewis acids and ligand 2.4 The sense of stereoinduction
in the chemistry presented here is in agreement with this
model. Work is in progress to obtain more conclusive
evidence for our stereochemical models.
In conclusion, we have shown that N-benzylhydroxylamine
is more reactive than O-benzylhydroxylamine in conjugate
addition reactions. Chiral Lewis acid catalyzed N-benzyl-
hydroxylamine addition to pyrrolidinone-derived enoates
afforded â-aryl-â-amino acid derivatives in high enantiomeric
purity. Experiments are underway to apply this methodology
in natural product syntheses.
Acknowledgment. We thank the NSF (CHE-9983680),
the NDSU research foundation, and the DuPont Aid-to-
Education program for financial support.
Supporting Information Available: Experimental pro-
cedures and full characterization data for compounds 1-7
and details for the establishment of absolute stereochemistry
for 7a. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL006500E
(15) The cis stereochemistry of the phenyl group and the deuterium
(overall syn addition) was established by coupling constant analysis.
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Org. Lett., Vol. 2, No. 21, 2000