Asymmetric synthesis of β-substituted α-amino acids using 2H-azirine-2-carboxylate esters. Synthesis of 3,3-disubstituted aziridine-2-carboxylate esters

Full text of DOI:10.1021/jo9702610

3796
J . Org. Chem. 1997, 62, 3796-3797
Sch em e 1
Asym m etr ic Syn th esis of â-Su bstitu ted
r-Am in o Acid s Usin g
2H-Azir in e-2-ca r boxyla te Ester s. Syn th esis
of 3,3-Disu bstitu ted Azir id in e-2-ca r boxyla te
Ester s†
Franklin A. Davis,* Chang-Hsing Liang, and Hu Liu
Department of Chemistry, Temple University,
Philadelphia, Pennsylvania 19122-2585
Sch em e 2
Received February 12, 1997
The asymmetric synthesis of nonprotein â-substituted
R-amino acids is an area of considerable current interest
because these amino acids are constituents of antibiotics
and peptides.1 Moreover, incorporation of these amino
acids, along with their R-alkylated analogs, into peptides
results in modification of the peptide’s steric, conforma-
tional, and stereoelectronic properties.2 One method for
the asymmetric syntheses of â-substituted R-amino acids
is the conjugate addition of organometallic reagents to
R,â-unsaturated chiral amides with subsequent incorpo-
ration of the R-amino functionality.3,4 Methylphenyla-
lanine was prepared by conjugate addition of a chiral
glycine unit to a vinyl sulfone,5 and addition of phenyl-
magnesium bromide to an oxazolidinone methyl ester
afforded diphenylalanine.6 A few other methods have
also been described.7
N-Activated aziridine-2-carboxylate esters undergo ste-
reoselective ring opening with nucleophiles to give â-sub-
stituted R-amino acids.8,9 However, most of these ex-
amples were with heteronucleophiles,10 and the few
studies with organometallic reagents employed unsub-
stituted aziridines.10a,11 In this paper, we report that
addition of Grignard reagents to 2H-azirine-2-carboxylate
esters results in new methodology for the asymmetric
synthesis of 3,3-disubstituted aziridine-2-carboxylate
esters, which on stereoselective hydrogenolysis afford
â-substituted R-amino acid esters (Scheme 1).
N-Sulfinylaziridine-2-carboxylate esters such as 1 and
2 are important chiral building blocks for the asymmetric
synthesis of R-amino acids and their derivatives.9,12-14
Furthermore, treatment of 1a with LDA/MeI affords
enantiomerically pure 2H-azirine-2-carboxylate ester 3a
and resulted in the first asymmetric synthesis of the
cytotoxic antibiotic (R)-(-)-dysidazirine (3a, Ph ) n-C13H27-
CH)CH-) (Scheme 2).15 However, an attempt to extend
this methodology to the synthesis of the 2-methyl-3-
phenyl analog 4 by reaction of the corresponding N-
sulfinyl derivative of 2a with LDA resulted in a complex
mixture of products consisting of 4, diisopropyl-p-tolyl-
sulfinamide (p-tolylS(O)NPri ), and the N-unsubstituted
2
aziridine 2. Significantly, treatment of the N-tosylaziri-
dine 2a 12 with 1.25 equiv of LDA at -78 °C afforded (R)-
† This paper is dedicated to Professor Carl R. J ohnson on the
occasion of his 60th birthday.
(-)-4a , [R]20 -163.2 (c, 0.434 CHCl3), in 87% isolated
D
(1) (a) Yoshioka, H.; Aoki, T.; Goko, H.; Nakatsu, K.; Noda, T.;
Sakakibara, H.; Take, T.; Nagata, A.; Abe, J .; Wakamiya, T.; Shiba,
T.; Kaneko, T. Tetrahedron Lett. 1971, 2043. (b) Takita, T.; Muraola,
Y.; Yoshioka, T.; Fuji, A.; Naeda, K.; Umezawa, H. J . Antibiot. 1972,
25, 755. (c) Barrett, G. C. Amino Acids, Peptides and Proteins; The
Chemical Society: London, 1980; Vol. 13, p 1.
yield following flash column chromatography. The tert-
butyl ester derivatives 3b and 4b were prepared in a
similar manner from the corresponding aziridines 1b and
2b 16 in 54 and 74-80% yield, respectively.17
We next turned our attention to the reaction of orga-
nometallic reagents to azirines 3 and 4. The few reports
of the addition of Grignard reagents to 2H-azirines
revealed that the aziridine product is formed by attack
at the least hindered face.18 Since there are no reports
of the reaction of organometallic reagents to 2H-azirine-
2-carboxylate esters, it was unclear whether the C-N
bond or the ester functionality would be the more reactive
site. Moreover, there was the possibility that deproto-
(2) For leading references see: (a) Kazmierski W. M.; Yamamura,
H. I.; Hruby, V. J . J . Am. Chem. Soc. 1991, 113, 2275. (b) Holladay,
M. W.; Nadzan, A. M. J . Org. Chem. 1991, 56, 3900. (c) Kamierski, W.
M.; Urbanczyk-Lipkowska, Z.; Hruby, V. J . J . Org. Chem. 1994, 59,
1789.
(3) Nicolas, E.; Russell, K. C.; Knollenberg, J .; Hruby, V. J . J . Org.
Chem. 1993, 58, 7565.
(4) Oppolzer, W.; Tamura, O.; Deerberg, J . Helv. Chim. Acta 1992,
75, 1965.
(5) Shapiro, G.; Buechler, D.; Marzi, M.; Schmidt, K.; Gomez-Lor,
B. J . Org. Chem. 1995, 60, 4978.
(6) Sibi, M. P.; Deshpande, P. K.; LaLoggia, A. J .; Christensen, J .
W. Tetrahedron Lett. 1995, 36, 8961.
(7) (a) Belokon, Y. N.; Sagyan, A. S.; Djamgaryan, S. M. Bakhmutov,
V. I.; Belikov, V. M. Tetrahedron 1988, 44, 5507. (b) Hanessian, S.;
Yang, R.-Y.; Tetrahedron Lett. 1996, 37, 5273.
(8) For a review on optically active aziridines see: Tanner, D. Angew.
Chem., Int. Ed. Engl. 1994, 33, 599.
(9) For leading references to optically active aziridine-2-carboxylic
acids see: Davis, F. A.; Zhou, P.; Reddy, G. V. J . Org. Chem. 1994, 59,
3243.
(10) (a) Baldwin, J . E.; Spivey, A. C.; Schofield, C. J .; Sweeney, J .
B. Tetrahedron 1993, 45, 6309 and references cited therein. (b) Legters,
J .; Willems, J . G. H.; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim. Pays-
Bas 1992, 111, 59.
(11) Tanner, D.; Birgersson, C.; Dhaliwa, H. K. Tetrahedron Lett.
1990, 31, 1903. Church, N. J .; Young, D. W. Tetrahedron Lett. 1995,
36, 151. Lim, Y.; Lee, W. K. Tetrahedron Lett. 1995, 36, 8431. Burgaud,
B. G. M.; Horwell, D. C.; Padova, A.; Pritchard, M. C. Tetrahedron
1996, 52, 13035.
(12) Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron Lett. 1996, 37,
5473.
(13) Davis, F. A.; Zhou, P. Tetrahedron Lett. 1994, 35, 7525.
(14) Davis, F. A.; Reddy, G. V. Tetrahedron Lett. 1996, 37, 4349.
(15) Davis, F. A.; Reddy, G. V.; Liu, H. J . Am. Chem. Soc. 1995,
117, 3651.
(16) N-Sulfonylaziridines were prepared as previously described. See
refs 12 and 13.
(17) Selected physical properties: 1b mp 79-80 °C, [R]20 +24.6 (c
D
1.6, CHCl3); 2b, oil, [R]20D +43.4 (c 1.32, CHCl3); 3b, mp 72-3 oC, [R]20
D
+219.9 (c 0.7, CHCl3); 4a , oil, [R]20 -163.2 (c 0.434, CHCl3); 4b, oil,
D
[R]20 -139.4 (c 0.71, CHCl3); 5a , oil, [R]20 +206.2 (c 0.31, CHCl3);
D
D
5b, oil, [R]20 +165.2 (c 0.51, CHCl3); 6a , mp 55-56 °C, [R]20 -142.0
D
D
(c 1.26, CHCl3); 6b, mp 35-36, [R]20 -135.0 (c 0.30, CHCl3); 7b, oil,
D
[R]20 +4.54 (c 1.04, CHCl3); 8b, oil, [R]20 +11.0 (c 0.51, CHCl3).
D
D
(18) Carlson, R. M.; Lee, S. Y. Tetrahedron Lett. 1969, 4001 and
references cited therein.
S0022-3263(97)00261-2 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 12, 1997 3797
Sch em e 3
Sch em e 4
Ta ble 1. Hyd r ogen a tion of Azir id in es 5 a n d 6 over 20%
P a lla d iu m Hyd r oxid e on Ca r bon
86 and 95% isolated yield, respectively, and >96% ee.
Attempts to separate the isomers of 7a /8a (R ) Me) by
preparative TLC were unsuccessful. Diastereomerically
pure (2R,3S)-(-)-2,3-dimethylphenylalanine2c was ob-
tained in 52% yield from (2R,3S)-8a (Table 1, entry 3)
by hydrolysis with 6 N HCl and crystallization of the
hydrochloride salts.
product: retention/inversion
(% isolated yield)a in solvent
entry
aziridine
CH2Cl2
hexane
1
2
3
4
5a (R ) Me)
5b (R ) t-Bu)
6a (R ) Me)
6b (R ) t-Bu)
7a : 86:14b (88)
7b: 96:4 (84)
65:35 (85)
79:21 (90)
10:90 (90) [52]c
40:60 (95)
In related experiments, hydrogenation of optically
active 2-methyl-2-phenylaziridine over Pd(OH)2 occurs
predominately with inversion of configuration (86:14), but
with retention in the presence of NaOH.21 These results
were interpreted by Mitsui and Sugi in terms of the
affinity of the catalysts for the nitrogen atom with a low
affinity leading to inversion. As can be seen from the
results summarized in Table 1, the stereoselectivity for
the hydrogenolysis of aziridines 5 and 6 is highly de-
pendent upon the solvent and the substitution pattern
of the substrate. For aziridines 5 hydrogenation gives 7
primarily with retention of configuration regardless of
the solvent (Table 1, entries 1 and 2). On the other hand,
the presence of the C-2 methyl group in 6 results in
addition of hydrogen with retention in methylene chloride
but inversion of configuration in n-hexane (see Table 1,
entries 3 and 4). The carbonyl groups in 5 and 6, which
may provide an additional site for palladium chelation,
and the added complication of steric factors make inter-
pretation of these results difficult and is under active
investigation.
8a : 67:33 (97)
8b: 90:10 (88) [80]d
a
b
Combined yields of isomers. Retention/inversion as deter-
mined by 1H NMR. c Isolated yield of pure major amino acid.
d
Isolated yield of pure major isomer.
nation at C-2 in (+)-3 could result in lower yields and
loss of enantiomeric purity.
Attempts to add methyllithium to the azirine 3 and 4
gave complex mixtures of products resulting mainly from
reaction at the carbonyl group. Gratifyingly, reaction of
(+)-3a and (-)-4a with methylmagnesium bromide
(MeMgBr) in THF at -78 °C gave (+)-5a and (-)-6a in
60-65% and 75-80% yield, respectively (Scheme 3). The
yields of 5b and 6b were 75 and 90% when the bulky
tert-butoxy ester derivatives, (+)-3b and (-)-4b, were
employed. No other isomers could be detected in the
1
crude mixture by H NMR. For 5a and 6a , irradiation
at the C-3 methyl groups resulted in 2% and 1% NOE’s
with the carbomethoxy groups, respectively, but no
NOE’s were detected for the corresponding C-2 hydrogen
and C-2 methyl groups. Since NOE experiments on 5b/
6b were inconclusive, assignment of their stereochemis-
In summary, the highly stereoselective addition of
MeMgBr to 2H-azirines 3 and 4 results in the first
asymmetric synthesis of unsymmetrical 3,3-disubstituted
aziridine-2-carboxylate esters and is a potentially general
route to these valuable materials. Selective hydrogena-
tion of the aziridines 5 and 6 results in new methodology
for the enantioselective synthesis of â-substituted R-ami-
no acid esters 7 and 8.
1
try was based on the fact that their H NMR spectra were
nearly identical to aziridines 5a /6a ; e.g., the CMe and
CH are shielded to the same extent by the adjacent
phenyl group. Thus, addition of MeMgBr occurs syn to
the carbomethoxy group or from the more hindered face
of the azirine. These results, which contradict previous
reports,18 are likely a consequence of prechelation of the
Grignard reagent with the carboxyl ester group.
Hydrogenation of aziridines 5 and 6 was accomplished
under an atmosphere of H2 (balloon) over 20% palladium
hydroxide on carbon for 3 h (Table 1, Scheme 4). The
ratio of retention/inversion products was determined by
1H NMR of the crude reaction mixtures before purifica-
tion by flash chromatography. The assignment of ster-
eochemistry to the isomers of 7a (R ) Me) was based on
the fact that the erythro product has the larger coupling
constant (7.5 vs 7.1 Hz)19 and for (2R,3S)-8a by compari-
son with literature values.2c These assignments were
confirmed by 6 N HCl hydrolysis of the major isomers of
7b/8b (R ) CMe3), purified by ion-exchange column
(Dowex, H+), to give erythro-(2S,3S)-(-)-3-methylphenyl-
alanine20 and (2R,3R)-(+)-2,3-dimethylphenylalanine2c in
Ack n ow led gm en t. We thank Mr. George Kemmer-
er, director of NMR facilities at Temple University, for
help with the NOE experiments. Financial support of
this work by the National Science Foundation and the
National Institutes of Health is gratefully acknowl-
edged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of compounds 3-8 and spectral data
for aziridines 1b, 2b, 5a ,b, and 6a ,b, aziridines 3b and 4a ,
and amino acid esters 7b and 8b (4 pages).
J O9702610
(20) Dharanipragada, R.; VanHulle, K.; Bannister, A.; Bear, S.;
Kennedy, L.; Hruby, V. J . Tetrahedron 1992, 48, 4733.
(21) Mitsui, S.; Sugi, Y. Tetrahedron Lett. 1969, 1287. Mitsui, S.;
Sugi, Y. Tetrahedron Lett. 1969, 1291.
(22) For the synthesis of unsymmetrical 3,3-disubstituted N-ami-
doaziridine-2-carboxylic acids see: Hogale, M. B.; Chavan, P. B. Indian
J . Chem. B 1993, 581.
(19) Kataoka, Y.; Seto, Y.; Yamamoto, M.; Yamada, T.; Kuwata, S.;
Wantanabe, H. Bull. Chem. Soc. J pn. 1976, 49, 1081.