Enantioselective synthesis of α,β-disubstituted-β-amino acids

Article abstract of DOI:10.1021/ja0372309

Highly diastereoselective and enantioselective addition of N-benzylhydroxylamine to imides 17 and 20-30 produces α,β-trans-disubstituted N-benzylisoxazolidinones 19 and 31-41. These reactions proceed in 60-96% ee with 93-99% de's using 5 mol % of Mg(NTf₂)₂ and ligand 18. The product isoxazolidinones can be hydrogenolyzed directly to provide ∞,β-disubstituted-β-amino acids. Copyright

Full text of DOI:10.1021/ja0372309

Published on Web 09/06/2003
Enantioselective Synthesis of r,â-Disubstituted-â-amino Acids
Mukund P. Sibi,* Narayanasamy Prabagaran, Sandeep G. Ghorpade, and Craig P. Jasperse
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105
Received July 11, 2003; E-mail: mukund.sibi@ndsu.nodak.edu
Scheme 1
We and others have recently reported novel catalytic methods
for the synthesis of â-substituted-â-amino acids.1,2 In contrast, there
are fewer methods that provide access to R-substituted â-amino
acids in high enantiomeric purity,1 especially when both the R-
and â-carbons contain carbon substituents. Since there are several
naturally occurring R,â-disubstituted-â-amino acids, it is important
to develop general methods for their synthesis.3 This work reports
a chiral Lewis acid-mediated conjugate amine addition protocol4
for the synthesis of a variety of R,â-disubstituted-â-amino acids
with high diastereo- and enantioselectivity (Scheme 1).
Successful implementation of 1 f 3 requires rotamer control in
the substrate. Traditional templates such as oxazolidinones experi-
ence poor reactivity due to problematic A1,3 interactions in either
rotamer (Figure 1, 4 and 5).5 To relieve strain the C-C bond of
the enoyl group twists, breaking conjugation which results in
diminished reactivity at the â-carbon. Our hypothesis was that the
use of an imide with an N-H group (6, R3 ) H), a template
pioneered by Jacobsen,2a,6 would eliminate the A1,3 strain present
in 4 and 5 and thus would allow for planar enoyl groups with normal
reactivity. We also thought that s-cis/s-trans rotamer control between
6 and 7 would remain possible and that tunable reactivity should
be available (R4 ) alkyl, aryl). Literature reports and our own work
have shown that N-benzylhydroxylamine adds to enoyl groups in
a concerted fashion.4 We surmised that rotamer control for the
substrate 1 combined with concerted addition of N-benzylhydroxy-
lamine in the presence of a chiral Lewis acid should provide access
to 2 with good relative as well as absolute stereocontrol.
Figure 1.
Table 1. Evaluation of Imides in Conjugate Amine Additiona
Our experiments began with addition of N-benzylhydroxylamine
to tiglates 8-17 with different achiral templates using catalytic
amounts (30 mol %) of a chiral Lewis acid derived from ligand 18
and magnesium salts (eq 1). That the same isoxazolidinone product
formed regardless of template streamlined our assessment of
enantioselectivity. Results from these studies are shown in Table
1. Conjugate amine addition to pyrrolidinone (8) or oxazolidinone
(9) derived tiglate gave low yields, although the diastereoselectivity
and enantioselectivity were good (entries 1 and 2). Reaction with
tertiary imide 10 (R3 ) CH3) was also very slow and low-yielding
and gave 19 with low selectivity (entry 3). By contrast, secondary
imides 11-17 (R3 ) H) lacking the A1,3 strain present in 8-10
were much more reactive and gave good yields. Our initial attempt
with benzimide 11 (entry 4) gave excellent diastereoselectivity and
good enantioselectivity, suggesting that even with R3 ) H, s-cis/
s-trans rotamer control is satisfactory. Increasing the reaction
temperature led to higher yield for 19 with a concomitant decrease
in enantioselectivity (entry 5). In entries 6-8, electron-withdrawing
groups were found to enhance reactivity (reaction time: 1 h for 13
and 8 h for 11 at room temperature) with little impact on selectivity.
Reactions with imides containing alkyl R4 substituents (15-17)
gave higher selectivity as compared to aryl groups (entries 9, 10,
and 14). When the magnesium counterion was varied (entries 11-
13, 15-16), magnesium triflimide gave optimal enantioselectivity.
When temperature, imide R4, and chiral Lewis acid were all
c
ent
SM
R
R
Lewis acid
Mg(ClO4)2 -40 10 95 70
95 40
T, °C yldb
de
eed
3
4
1
2
3
4
5
6
7
8
9
8
9
-CH2CH2CH2-
-CH2CH2O-
Mg(ClO4)2 -40
8
10 Me Ph
Mg(ClO4)2 -40 10 60 18
Mg(ClO4)2 -40 47 94 75
11
11
12
13
14
15
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Mg(ClO4)2
Mg(ClO4)2
25 66 90 45
25 70 92 40
25 66 90 44
25 62 94 46
25 45 92 57
25 64 88 67
3,5-(CF3)2Ph
3,5-(NO2)2Ph Mg(ClO4)2
4-NO2Ph
tert-butyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
isopropyl
isopropyl
isopropyl
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
10 16
11 16
12 16
13 16
14 17
15 17
16 17
Mg(ClO4)2 -40 76 92 88
Mg(NTf2)2 -40 66 90 96
MgI2
Mg(ClO4)2
-40 62 90 70
25 78 94 54
Mg(ClO4)2 -40 76 96 90
Mg(NTf2)2 -40 72 96 96
a For details on the synthesis and characterization of starting materials
and products, and reaction conditions, see the Supporting Information.
b Isolated yield after column chromatography. c Diastereomeric excess
determined by H NMR (500 MHz). d Determined by chiral HPLC.
1
optimized (entries 9-16), the optimal substrate was determined to
be 17, which gave 19 with outstanding levels of selectivity (96%
ee and 96% de, entry 16) using magnesium triflimide as a Lewis
9
11796
J. AM. CHEM. SOC. 2003, 125, 11796-11797
10.1021/ja0372309 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Breadth and Scope Studies
c
entry
SM
R
1
R
2
product
yield (%)a
deb
ee %
Figure 2. Stereochemical model for amine addition.
1d
2
3
4
5
17
20
21
22
23
24
25
26
27
28
29
30
methyl
methyl
methyl
methyl
ethyl
n-propyl
isopropyl
isobutyl
n-heptyl
ethyl
methyl
ethyl
19
31
32
33
34
35
36
37
38
39
40
41
95
70
76
90
82
92
28
64
73
72
38
49
96
98
99
95
96
95
95
95
96
96
95
93
96
86
76
90
90
89
81
77
87
60
76
84
the addition of the nitrogen occurs on the re face of the â-carbon,
as is also the case for additions of both amines4a and radicals8 to
oxazolidinone crotonates and cinnamates when activated by MgX2/
18. This suggests by analogy that even in the case of tiglates,
reaction still occurs from s-cis rotamers 6 rather than s-trans
rotamers 7. The high diastereoselectivity results from the fact that
protonation of the R-carbon is concerted with addition of nitrogen
to the â-carbon.4
In conclusion, we have developed a novel and practical chiral
catalytic method for the synthesis of R,â-disubstituted-â-amino acids
in good overall yields and enantioselectivity. The availability of
highly enantioenriched isoxazolidinones provides access to syn
disubstituted as well as R,R,â-trisubstituted compounds by base-
mediated inversion or alkylation protocols.9 Experiments along these
lines as well as extension of the methodology to the synthesis of
more complex amino acids and optimization of the protocol for
less reactive substrates is underway.
bromo
phenyl
methyl
methyl
methyl
methyl
methyl
ethyl
6
7e
8f
9
10
11e
12e
phenyl
phenyl
methyl
phenyl
a Isolated yield after chromatography. b Diastereomeric excess determined
by 1H NMR (500 MHz). c Determined by chiral HPLC. d 5 g scale.
e Reactions at 0 °C using 30 mol % of catalyst. f 10 mol % of catalyst
acid.7 These results clearly demonstrate that a highly enantiose-
lectiVe method for the synthesis of disubstituted-â-amino acids is
at hand.
The results from breadth and scope studies for the preparation
of a variety of isoxazolidinones (19, 31-41) using 5 mol % of the
catalyst and isopropyl-substituted imides are shown in Table 2 (eq
2). As illustrated earlier, amine addition to the tiglate 17 gave 19
with 96% ee (entry 1). Reaction with a bulkier R-ethyl group was
equally effective (entry 2). Bromo (entry 3) as well as phenyl
substituents (entry 4) at the R-position are also well tolerated in
the reaction, leading to products 32 and 33 with good and high
selectivity, respectively. Reactions with several substrates with
changes in the â-substituent were examined next (entries 5-9).
All of these gave isoxazolidinones with high selectivity. The
chemical efficiency with the bulky â-isopropyl group (25) was low
(entry 7). Amine addition to 28, containing R,â-diethyl groups, gave
39 in good yield. However, the enantioselectivity was modest (entry
10). Reactions with a â-phenyl substituent were also examined
(entries 11 and 12). These are relatively unreactive substrates, and
reactions were carried out at 0 °C to get modest yields. However,
the enantioselectivity for 40 and 41 remained good. The results
from these studies demonstrate that a variety of substituted
isoxazolidinones can be prepared with high diastereo- and enantio-
selectivity.
Acknowledgment. This work was supported by the National
Science Foundation (NSF-CHE-9983680 and CHE-0316203).
Supporting Information Available: Characterization data for
compounds 8-42 and experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) For a recent review on synthesis, see: Liu, M.; Sibi, M. P. Tetrahedron
2002, 58, 7991.
(2) (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959. (b)
Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964. (c)
Horstmann, T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem., Int. Ed. 2000,
39, 3635. (d) Falborg, L.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans.
1 1996, 2823. (e) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka,
K. J. Am. Chem. Soc. 2003, 125, 2886. (f) Sibi, M. P.; Shay, J. J.; Liu,
M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615. (g) Sibi, M. P.;
Asano, Y. J. Am. Chem. Soc. 2001, 123, 9708.
(3) Ulongamides A.-F.: (a) Luesch, H.; Williams, P. G.; Yoshida, W. Y.;
Moore, R. E.; Paul, V. J. J. Nat. Prod. 2002, 65, 996. Dolastatins 11 and
12: (b) Pettit, G. R.; Kamano, Y.; Kizu, H.; Dufresne, C.; Herald, C. L.;
Bontems, R.; Schmidt, J. M.; Boettner, F. E.; Nieman, R. A. Heterocycles
1989, 28, 553. Majusculamide C: (c) Mynderse, J. S.; Hunt, A. H.; Moore,
R. E. J. Nat. Prod. 1988, 51, 1299.
(4) (a) Sibi, M. P.; Liu, M. Org. Lett. 2000, 2, 3393. (b) Sibi, M. P.; Liu, M.
Org. Lett. 2001, 3, 4181. For mechanistic information, see: (c) Niu, D.;
Zhao, K. J. Am. Chem. Soc. 1999, 121, 2456. (d) Moglioni, A.; Muray,
E.; Castillo, J. A.; AÄ lvarez-Larena, AÄ .; Moltrasio, G. Y.; Branchadell,
V.; Ortun˜o, R. M. J. Org. Chem. 2002, 67, 2402.
The product isoxazolidinones can be easily converted to the
corresponding amino acids by a simple hydrogenolysis. Catalytic
hydrogenolysis of 19 using Pd/C on a 5 g scale gave (2R,3R)-3-
amino-2-methylbutanoic acid 42 in 90% yield. Compounds 31, 36,
37, and 40 were also converted to the corresponding amino acids
by hydrogenolysis. Thus R,â-disubstituted-â-amino acids can be
synthesized in four steps from the unsaturated acids in good overall
yields and high enantiopurity using chiral catalysis.
(5) Sibi, M. P.; Sausker, J. B. J. Am. Chem. Soc. 2002, 124, 984.
(6) Goodman, S. N.; Jacobsen, E. N. AdV. Synth. Catal. 2002, 344, 953.
(7) Metal triflimides have seen limited use in chiral catalysis. They possess
several important properties such as solubility in nonpolar organic solvents,
stability, and good Lewis acidity. Several other Lewis acids and ligands
have also been examined in conjugate amine additions. These results will
be reported in a full account.
(8) Sibi, M. P.; Chen, J. J. Am. Chem. Soc. 2001, 123, 9472.
(9) Ishikawa, T.; Nagai, K.; Kudoh, T.; Saito, S. Synlett 1995, 1171.
We have a tentative cis octahedral model (43) for the observed
stereochemistry based on the identity of 42 (Figure 2). Interestingly,
JA0372309
9
J. AM. CHEM. SOC. VOL. 125, NO. 39, 2003 11797