Aziridine mediated asymmetric synthesis of α-benzylserine and α-n-butylserine

Article abstract of DOI:10.1016/S0040-4020(01)00500-2

Regioselective hydrogenolysis of enantiopure 2-benzyloxyaziridine 2-carboxylates represents a general method for the asymmetric synthesis of α-substituted serines. The aziridines are readily prepared via an aza-Darzens reaction of the enolate of methyl 3-

Full text of DOI:10.1016/S0040-4020(01)00500-2

TETRAHEDRON
Pergamon
Tetrahedron 57 ,2001) 6345±6352
Aziridine mediated asymmetric synthesis of a-benzylserine
and a-n-butylserine
Franklin A. Davis,p Yulian Zhang, Ashwin Rao and Zhijun Zhang
Department of Chemistry, Temple University, Philadelphia, PA 19122, USA
Received 1 December 2000; revised 12 January 2001; accepted 31 January 2001
AbstractÐRegioselective hydrogenolysis of enantiopure 2-benzyloxyaziridine 2-carboxylates represents a general method for the asym-
metric synthesis of a-substituted serines. The aziridines are readily prepared via an aza-Darzens reaction of the enolate of methyl 3-benzyl-
oxy-2-bromopropanoate with an enantiopure sul®nimine ,N-sul®nyl imine). q 2001 Elsevier Science Ltd. All rights reserved.
The current interest in quaternary, a-alkyl a-amino acids
relates to the important effects they have on biological
activity.1 While a number of these compounds are naturally
occurring and found as substructures of natural products,
most of the recent focus has been on synthetic examples.2
These type of amino acids are useful in studies of enzyme
mechanisms,3 as enzyme inhibitors4 and in the preparation
of peptidomimetics. On incorporation into peptides they
introduce conformational constraints that have been used
to obtain important information on receptor-site structure
and to optimize therapeutic activity.4,5 Furthermore, these
amino acids have been found to increase the metabolic
stability of peptides.6
stituents and the reaction conditions, with the majority of
nucleophiles reacting at C-3.
We recently described a general methodology for the
asymmetric synthesis of a-alkyl a-amino acid derivatives
using N-sul®nyl aziridines carboxylates.12 For example,
E-,SS,2R,3S)-,1)-N-,p-toluenesul®nyl)-2-carbomethoxy-3-
phenylaziridine ,2), prepared via an aza-Darzens reaction of
the lithium enolate of methyl a-bromopropionate with an
enantiopure sul®nimine ,N-sul®nyl imine),13,14 gave, on
treatment with TFA, ,2R,3R)-,1)-a-methyl b-phenylserine
,3) in 75% yields and .96% de ,Scheme 2).15 The N-tosyl
derivative 4, on hydrogenation gave ,R)-,2)-5, and removal
of the N-tosyl group with HBr/PhOH, gave ,R)-,1)-a-
methylphenylalanine ,6) in 73% overall yield. In a related
study the ®rst asymmetric synthesis of ,R)-,1)-a-methyl-
phosphophenylalanine ,9) was accomplished in 92% yield
by transfer hydrogenation of 2-methylaziridine-2-phospho-
nate ,2R,3R)-,1)-8, despite the lack of activation on
nitrogen ,Scheme 2).16 Selective removal of the sul®nyl
group in aziridine ,1)-7 using TFA in acetone±water
afforded ,1)-8 in 76% yield without ring-opening.
The asymmetric synthesis of quaternary a-amino acids has
been reviewed.7 More recent methods include a catalytic8
and a diastereoselective9 asymmetric Strecker synthesis and
others.10 The regio- and stereoselective ring-opening reac-
tions of aziridine 2-carboxylates 1 are valuable sources of
structurally diverse amino acids including a-alkyl examples
,Scheme 1).11 Activation of the aziridine nitrogen by an
electron-withdrawing group ,acyl, sulfonyl), by protona-
tion, or by Lewis acids promotes either C-2 attack to give
b-amino acids or C-3 attack to give a-amino acids. The
stereo- and regioselectivity is determined by the ring sub-
Our aziridine methodology can also be applied to the asym-
metric synthesis of b-substituted a-alkyl amino acids. The
Scheme 1.
Keywords: asymmetric synthesis; aziridines; a-amino acids; N-sul®nyl imines.
Corresponding author. Tel.: 11-215-204-0477; fax: 11-215-204-0478; e-mail: fdavis@astro.ocis.temple.edu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,01)00500-2

6346
F. A. Davis et al. / Tetrahedron 57 &2001) 6345±6352
Scheme 2.
requisite 3-substituted aziridine ,2R,3S)-,2)-11 was
prepared by cis addition of methylmagnesium bromide to
2H-azirine ,R)-,2)-10 ,Scheme 3).17,18 Hydrogenolysis of
11 over Pd,OH)2 occurred primarily with retention of
con®guration in methylene chloride ,90:10 retention:
inversion), but with inversion in hexane ,40:60). The
major isomer ,2R,3R)-12 was isolated in 80% yield.
chiral nonracemic enolates derived from oxazolidines,22,23
oxazinones,24 and bislactam ethers.25 Enzyme kinetic
resolution of a-alkyl-a-aminomalonates26 from azlactones27
and via an asymmetric Strecker synthesis28 have also been
utilized to prepare these compounds. Despite the acknowl-
edged versatility of aziridine carboxylates for the asym-
metric synthesis of amino acids,11 there is only a single
report employing an aziridine generated from a chiral
epoxide, for the preparation of a-methylserine.29 As an
extension of our aziridine methodology we describe here a
general protocol for the aziridine mediated asymmetric
synthesis of a-alkyl serines.
Serine, a b-hydroxy a-amino acid,19 is found in a number of
biologically active molecules20 and is a useful chiral build-
ing block for asymmetric synthesis.21 Methods for the asym-
metric synthesis of a-alkyl analogs include alkylation of
Scheme 3.
Scheme 4.

F. A. Davis et al. / Tetrahedron 57 &2001) 6345±6352
6347
1. Results and discussion
on NOE experiments and conversion to known compounds
,see below). In ,2S,3S)-14b no NOE was observed between
the C-3 proton and the C-2 methylene group whereas in
,2R,3S)-14b the value was 20%. As was noted earlier the
possibility exists for the formation of four stereoisomeric
aziridines, but only the Z and E-aziridines are formed.12 It
was found in these studies that substituted bromo enolates
gave aziridines having predominantly the E-geometry and
this ®nding is consistent with chair-like transition state TS-1
containing a four-membered metallocycle. A reasonable
assumption is that in solution the sul®nimine adopts the
thermodynamically favored E-geometry32,33 and that the
bromo enolate has the Z-geometry. The reason that the
crotonaldehyde-derived sul®nimine ,S)-,1)-13b affords
the Z-aziridine ,2R,3S)-14b is not readily apparent. A
change in the geometry of the sul®nimine from E to Z is
one possibility, but seems unlikely due to the strong thermo-
dynamic preference for the former. A more probable expla-
nation is that the geometry of the sodium enolate is E; i.e. TS-
2. It is worth recalling that the lithium and sodium enolates
give a 1:1 and 85:15 ratios of the Z/E aziridines 14b, respec-
tively ,Table 1: compare entries 4 with 7). The fact that E-14a
was obtained regardless of the counterion could re¯ect the
larger size of phenyl verses propenyl. Open transitions states
can also not be excluded for the sodium enolates.
To prepare a-alkyl serines via our aziridine methodology a
2-benzyloxymethylaziridine 2-carboxylate is required that
on C-3 ring-opening would give the desired product. The
requisite N-sul®nylaziridines carboxylates 14 were prepared
by treating sul®nimines ,N-sul®nyl imines 13)13 with the
enolate generated from methyl 3-benzyloxy-2-bromopro-
panoate30 in the aza-Darzens reaction outlined in Scheme
4. The lithium enolate of 3-benzyloxy-2-bromopropanoate
was generated by treatment with LiHMDS and ,S)-,1)-N-
,benzylidene)-p-toluenesul®namide ,13a) was added at
2788C. However, work-up resulted in recovery of starting
material in ca. 60% yield. Under these conditions ,S)-,1)-
N-,crotonylidene)-p-toluenesul®namide ,13b) gave similar
results ,Table 1). In an earlier study with other bromo
enolates we encountered modest yields in the sul®nimine-
mediated aza-Darzens synthesis, which we attributed to
their instability and propensity to self-condense.31 To
improve the yields we developed an in situ trapping method
that involves treating a mixture of the a-haloester and the
sul®nimine with base. The idea was to trap the reactive
enolate with the sul®nimine before it could self-condense.
Yields improved, but the selectivity suffered.12 In a similar
fashion 1.0 equiv. of ,1)-13a and 3.0 equiv. methyl 3-
benzyloxy-2-bromopropanoate at 2788C followed by addi-
tion of 2.5 equiv. of LiHMDS gave an overall 90% yield of
the E- and Z-aziridines 14a in a 95:5 ratio ,Table 1, entry 2).
With the sodium enolate the ratio dropped to 80:20 ,Table 1,
entry 3). The major aziridine diastereoisomer E-,2S,3S)-
,1)-14a was isolated in 70% yield by chromatography.
There was no selectivity observed under these conditions
with the crotonaldehyde-derived sul®nimine ,S)-,1)-13b
and the lithium enolate afforded E,Z 14b in an 1:1 ratio in
42% yield ,Table 1, entries 4±7). However, the sodium
enolate improved the selectivity to 70% de, but unexpect-
edly gave the Z aziridine ,2R,3S)-,1)-14b as the major
diastereoisomer in 79% isolated yield ,Table 1, entry 8).
Attempts to further improve the selectivity by varying the
solvent and base equivalents resulted in reduced yields and
selectivity ,Table 1).
The stereochemical assignments for aziridines 14 are based
Table 1. Aza-Darzens synthesis of 2-benzyloxymethyl aziridines 14 at 2788C in THF
Entry
Sul®nimine 13 Rˆ
,S)-,1)-13a, Ph
Reaction conditionsa
13:base:bromopropionate
Con®guration of
major diastereomer
Dr ,% de)b
% Isolated yield of
major diastereomer
1
2
3
4
5
6
7
8
1:2 LiHMDS:2c
No reactiond
70
70
No reactiond
1:2.5 LiHMDS:3 ,in situ)e
1:2.5 NaHMDS
E-,2S,3R)-,1)-14a
E-,2S,3R)-,1)-14a
95:5 ,90)
80:20 ,60)
,S)-,1)-13b, E-MeCHvCH22
1:2 LiHMDS:2c
1.3 LiHMDS:2 ,in situ)e
2.0 LiHMDS:2
Z-,2R,3S)-,1)-14b
Z-,2R,3S)-,1)-14b
Z-,2R,3S)-,1)-14b
Z-,2R,3S)-,1)-14b
Z-,2R,3S)-,1)-14b
Z-,2R,3S)-,1)-14b
Z-,2R,3S)-,1)-14b
Z-,2R,3S)-,1)-14b
1:1 ,0)
1:1 ,0)
1:1 ,0)
15:85 ,70)
15:85 ,70)
33:67 ,34)
33:67 ,34)
40:60 ,20)
42
44
40
79
40
44
48
20
6.0 LiHMDS:2 ,Et2O)
1.3 NaHMDS:2
6.0 NaHMDS:2
2.0 NaHMDS:2 ,PhMe)
2.0 NaHMDS:2 ,Et2O)
1.3 KHMDS:2
9
10
11
12
a
Equivalents of 13/base/bromoproponate used.
b
c
d
e
Drs determined on the crude reaction mixture by 1H NMR.
Sul®nimine added to the enolate at 2788C.
Starting material recovered.
Base added to a mixture of the bromopropionate and sul®nimine.

6348
F. A. Davis et al. / Tetrahedron 57 &2001) 6345±6352
Scheme 5.
Table 2. Hydrogenolysis of aziridine 15 to a-alkyl serines 16 and 17
Entry
Aziridine
Catalyst
Solvent
Products ,% isolated yield)
1
2
3
5
6
7
8
,2)-15a
,2)-15a
,2)-15a
,2)-15b
,2)-15b
,2)-15b
,2)-15b
Pd,OH)2
THF
,S)-,1)-16 ,100)
,S)-,2)-17 ,99)
,S)-,2)-17 ,90)
,2R,3S)-,2)-21 ,30)
,R)-,2)-19 ,25)
,R)-,2)-19 ,65)
,R)-,2)-20 ,60)
Pd,OH)2/TFA
Pd,OH)2
Pd,OH)2
Pd,OH)2/TFA
Pd/C
Pd,OH)2
3:1 EtOH:THF
MeOH
THF
3:1 EtOH:THF
THF
MeOH
Reaction time: 18 h.
The N-sul®nyl group in ,2S,3S)-14a was selectively
removed, without ring-opening, by treatment with 50%
aqueous TFA in acetone to give ,2S,3S)-15a in 76% yield
,Scheme 5). Similarly 14b gave a ca. 40% yield of 15b, but
was dif®cult to purify because of numerous side products.
These products may result from generation of carbocations
following protonation of the alkene by the acid. Fortunately,
the NH aziridine ,2)-15b was obtained in 86% yield on
reaction of 14b with 9.0 equiv. of methylmagnesium
bromide.
The results for the low-pressure ,balloon) hydrogenolysis of
aziridines 15 using various catalyst/solvent systems are
summarized in Table 2. With Pearlman's catalyst,
Pd,OH)2, in THF, aziridine E-15a gave a quantitative
yield of ,S)-,1)-benzyloxy a-benzylserine methyl ester
,16) ,Scheme 6). The inhibition of O-debenzylation by
amines has been reported and appears to be related to the
preferential af®nity of the palladium surface for the more
basic nitrogen atom.34 Both ring-opening and debenzylation
can be readily accomplished by hydrogenolysis of E-15a in
Scheme 6.

F. A. Davis et al. / Tetrahedron 57 &2001) 6345±6352
6349
the presence of 4 equiv. of TFA or in MeOH affording a
nearly quantitative yields of ,S)-,2)-a-benzylserine methyl
ester ,17) ,Table 2, entries 2 and 3).
THF and Et2O were freshly distilled under an inert
atmosphere from a purple solution of sodium/benzophenone
ketyl. Anhydrous CH2Cl2 was obtained by re¯uxing over
calcium hydride followed by distillation under an inert
atmosphere. Sul®nimines ,S)-,1)-13a and ,S)-,1)-13b13
and 3-benzyloxy-2-bromopropanoate30 were prepared
according to literature procedures. All other reagents were
obtained from commercial sources and used without further
puri®cation. Reactions were performed under an inert
atmosphere of argon unless otherwise stated and all glass-
ware was vacuum or oven dried prior to use.
The situation is more complex for the hydrogenolysis of the
crotonaldehyde-derived aziridine Z-,2)-15b. On hydro-
genolysis with Pd,OH)2 the aziridine failed to open and a
low, ca. 30%, yield of aziridine 21 was obtained ,Scheme 6).
With Pd,OH)2/TFA ring-opening occurred to give ,R)-,2)-
19, but the yield was only 25% along with many uncharac-
terizable products. Here again protonation of the alkene by
the acid may be responsible for these undesirable products.
Hydrogenolysis over Pd/C in THF, however, gave ,R)-,2)-
19 in 65% isolated yield ,Table 2, entry 7). Both ring-
opening, and debenzylation was accomplished using
Pd,OH)2 in MeOH affording ,R)-,2)-a-n-butylserine
methyl ester ,20) in 60% isolated yield ,Table 2, entry 8).
We speculate that the different reactivities of the two
aziridines are associated with the af®nities of the alkene
and aromatic p-systems for the catalysts, with the former
having the greater af®nity.
2.1.1. Preparation of E-(SS,2S,3S)-(1)-N-p-toluenesul-
®nyl-2-benzyloxymethyl-2-carbomethoxy-3-phenylaziri-
dine (14a). In a 250 mL oven-dried two-necked round-
bottomed ¯ask ®tted with a magnetic stirring bar, a rubber
septum and an argon balloon was placed 1.0 g ,4.09 mmol)
of ,SS)-,1)-N-,benzylidene)-p-toluenesul®namide ,13a) in
THF ,60 mL). The solution was cooled to 2788C and
2.24 mL ,12.3 mmol) of methyl 2-bromo-3-,phenylmethoxy)-
propionate was added. After 3 min, 11.1 mL ,10.3 mmol,
1.0 M in THF) of LiHMDS was added slowly via syringe.
The reaction was stirred at 2788C for 2 h, quenched with
water ,4 mL) at 2788C, and diluted with EtOAc ,2£20 mL).
The combined extracts were washed with brine ,20 mL),
dried ,NaSO4), and concentrated to give the crude product
,90% de). Puri®cation by ¯ash chromatography ,EtOAc/
pentane, 20:80) afforded 1.13 g ,70%) of E-,2S,3S)-14a;
Treatment of ,S)-,2)-17 and ,R)-,2)-20 with LiOH in THF,
neutralization with 1N HCl, and isolation by Dowex
50WX8-100 ion exchange column gave ,S)-,1)-a-benzyl-
serine ,18)28b and ,R)-,2)-a-n-butylserine ,22)35 in 91 and
75% yields, respectively ,Scheme 6). Their properties were
in agreement with literature values, which indicates the %
ee, as expected, was .95 because at no time in the reaction
sequence are any bonds to the stereogenic carbon broken.
colorless oil; [a]20 ˆ170.8 ,c 3.9, CHCl3); IR ,neat)
D
1
1738, 1453, 1102, 553 cm21; H NMR ,CDCl3) d 7.72 ,d,
2H, Jˆ8.5 Hz), 7.2 ,m, 12H), 4.48 ,s, 1H), 4.16 ,d, 2H,
Jˆ3.5 Hz), 3.85 ,s, 3H), 3.82 ,d, 1H, Jˆ10 Hz), 3.08 ,d,
1H, Jˆ10 Hz), 2.42 ,s, 3H); 13C NMR ,CDCl3) d 168.4,
143.0, 142.1, 138.2, 133.6, 130.3, 126.0, 73.6, 68.0, 53.7,
52.4, 46.2, 22.2. HRMS: calcd for C25H25NO4S ,M1H)
436.1583; found: 436.1564.
In summary, general methodology for the asymmetric
synthesis of a-substituted serines via the regioselective
hydrogenolysis of 2-benzyloxyaziridine-2-carboxylates is
described. Either the O-benzyloxy serine, which can be
used for further elaboration of the amino acid, or the depro-
tected serine can be readily obtained by varying the reaction
conditions.
2.1.2. Methyl E-(SS,2S,3S)-(2)-2-benzyloxymethyl-3-
phenyl-1H-aziridine-2-carboxylate (15a). In a 25 mL
round-bottom ¯ask equipped with a magnetic stirring bar
were placed 0.44 g ,1.0 mmol) of ,1)-14a and 0.40 mL
,5 mmol) of TFA in acetone ,5 mL) and water ,5 mL).
The solution was stirred vigorously for 15 min at rt, conc.
NH4OH was added to adjust the pH to 10, and concentrated.
The residue was washed with CH2Cl2 ,3£15 mL), dried
,Na2SO4), and concentrated to give a residue that was puri-
®ed by ¯ash chromatography ,EtOAc/n-hexane, 3:7) afford-
2. Experimental
2.1. General procedure
Column chromatography was performed on silica gel,
Merck grade 60 ,230±400 mesh). Analytical and prepara-
tive thin-layer chromatography was performed on precoated
silica gel plates ,250 and 400 mm) purchased from Analtech
Inc. TLC plates were visualized by quenching of UV ¯uo-
rescence ,lmax 254 nm), staining with iodine or with 0.5%
ninhydin in ethanol. IR spectra were obtained using NaCl
plates or KBr discs and recorded on a Mattson 4020 FTIR
spectrometer. 1H- and 13C NMR were recorded on a General
Electric Omega 500, operating at 500 and 125 MHz, respec-
tively. The spectra were referenced to solvent residues as
internal standards. HRMS analyses were performed in the
Department of Chemistry, Drexel University, Philadelphia,
PA using a Fissions ZAB HF double-focusing mass spectro-
meter. Melting points were recorded on a MEL-TEMP
apparatus and are uncorrected. Optical rotations were
measured on a Perkin±Elmer 341 polarimeter and elemental
analyses were performed in the Department of Chemistry,
University of Pennsylvania, Philadelphia, PA.
ing 0.264 g ,89%) of an oil; [a]20 ˆ296.2 ,c 4.8, CHCl3);
D
1
IR ,neat) 3282, 1726, 1437, 1219, 1097 cm21; H NMR
,CDCl3) d 7.231 ,m, 10H), 4.54 ,d, 1H, Jˆ12 Hz), 4.38
,d, 1H, Jˆ12 Hz), 3.86 ,s, 3H), 3.82 ,d, 1H, Jˆ10.5 Hz),
3.55 ,s, 1H), 3.15 ,d, 1H, Jˆ10.5 Hz), 2.35 ,bs, 1H); 13C
NMR ,CDCl3) d 173.8, 138.8, 135.9, 128.9, 128.7, 128.5,
128.4, 128.2, 73.9, 68.4, 53.8, 45.2, 45.0. Anal. Calcd for
C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C, 72.33; H,
6.68; N, 4.63.
2.1.3. (S)-(1)-2-Amino-2-benzyloxymethyl-3-phenylpro-
pionic acid methyl ester (16). In a 25 mL round-bottomed
¯ask equipped with magnetic stirring bar and hydrogen
balloon was placed with 0.050 g ,0.17 mmol) of ,2)-15a,
0.05 g of Pd,OH)2 in THF ,8 mL). The solution was stirred
at rt for 8 h, ®ltered, and concentrated to give 0.049 g ,98%)

6350
F. A. Davis et al. / Tetrahedron 57 &2001) 6345±6352
of a white solid, mp 66±678C; [a]20 ˆ15.37 ,c 2.14,
1H), 7.37 ,m, 7H), 7.64 ,d, 2H, Jˆ8.1 Hz); 13C NMR
,CDCl3) d 18.6, 22.2, 46.0, 51.3, 53.5, 68.5, 73.7, 123.5,
126.0, 128.4, 128.5, 128.9, 130.1, 133.8, 138.4, 142.4,
142.7, 168.7. Anal. Calcd for C22H25NO4S: C, 66.14; H,
6.31; N, 3.51. Found: C, 65.97; H, 6.30; N, 3.32.
D
1
CHCl3); IR ,KBr) 3362, 1741 cm21; H NMR ,CDCl3) d
7.25 ,m, 10H), 4.57 ,d, 1H, Jˆ12.5 Hz), 4.52 ,d, 1H,
Jˆ12.5 Hz), 3.85 ,d, 1H, Jˆ9 Hz), 3.69 ,s, 3H), 3.49 ,d,
1H, Jˆ9 Hz), 3.06 ,d, 1H, Jˆ13 Hz), 2.75 ,d, 1H,
Jˆ13 Hz), 1.92 ,s, 2H); 13C NMR ,CDCl3) d 176.2,
138.5, 136.0, 130.5, 129.1, 129.0, 128.4, 128.3, 127.8.
Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 4.68.
Found: C, 71.96; H, 7.27; N, 4.59.
2.1.7. (2R,3S)-(2)-2-Benzyloxymethyl-2-carbomethoxy-
3-propenylaziridine (15b). In a 50 mL round-bottomed
¯ask equipped with a magnetic stirring bar, a rubber septum,
and an argon balloon was placed 0.068 g ,0.17 mmol) of cis-
,SS,2R,3S)-,1)-14b in THF ,15 mL). The solution was
cooled to 2788C and 0.17 mL ,3.0 M in ethyl ether,
1.53 mmol, 9.0 equiv.) of methyl magnesium bromide was
added dropwise via a syringe. The reaction mixture was
stirred for 4 h, quenched with saturated NH4Cl ,10 mL),
and diluted with ethyl acetate ,10 mL). The organic phase
was separated and the aqueous phase was washed with
EtOAc ,2£15 mL). The organic phases were combined,
dried ,Na2SO4), and concentrated to give an oil. Puri®cation
by preparative TLC ,50% EtOAc/hexanes) afforded 0.038 g
2.1.4. (S)-(1)-2-Amino-2-hydroxymethyl-3-phenylpro-
pionic acid methyl ester (17). In a 25 mL round-bottomed
¯ask ®tted with magnetic stirring bar and hydrogen balloon
were placed 0.05 g ,0.17 mmol) of ,1)-16 and 0.05 g of
Pd,OH)2 in EtOH ,6 mL), THF ,2mL), and 0.05 mL
,0.68 mmol, 4 equiv.) of TFA. The solution was stirred at
rt for 8 h, ®ltered, and concentrated to give 0.034 g ,97%) of
,2)-17 as a white solid, mp 110±1118C; [a]20 ˆ11.57 ,c
D
1
1.27, CHCl3); IR ,KBr) 3254, 1743, 1601, 1422 cm21; H
NMR ,CDCl3) d 7.21 ,m, 10H), 3.87 ,d, 1H, Jˆ10.5 Hz),
3.74 ,s, 3H), 3.59 ,d, 1H, Jˆ10.5 Hz), 3.09 ,d, 1H,
Jˆ13.5 Hz), 2.79 ,d, 1H, Jˆ13.5 Hz), 2.23 ,bs, 3H); 13C
NMR ,CDCl3) d 176.2, 135.9, 130.5, 129.3, 127.9, 68.6,
64.3, 53.0, 42.6. Anal. Calcd for C11H15NO3: C, 63.14; H,
7.23; N, 6.69. Found: C, 62.79; H, 7.49; N, 6.51.
,86%) of ,2R,3S)-,2)-15b: [a]20 ˆ264.1 ,c 1.5, CHCl3);
D
IR ,neat) 3683, 1737, 1521 cm21; 1H NMR ,CDCl3) d 1.69
,d, 3H, Jˆ6.6 Hz), 2.07 ,s, broad, 1H), 2.83 ,d, 1H,
Jˆ5.0 Hz), 3.49 ,d, 1H, Jˆ10.0 Hz), 3.77 ,s, 3H), 3.93 ,d,
1H, Jˆ10.0 Hz), 4.59 ,dd, 2H, Jˆ12.0, 71 Hz), 5.2 ,m, 1H),
5.84 ,m, 1H), 7.28 ,m, 5H); 13C NMR ,CDCl3) d 18.6, 44.2,
53.5, 68.9, 74.0, 126.6, 128.2, 128.5, 128.6, 128.9, 173.8.
HRMS calcd for C15H19NO3 ,M1Na) 284.1263. Found:
284.1252.
2.1.5. (S)-(1)-a-Benzylserine (18). In a 25 mL round-
bottom ¯ask equipped with a magnetic stirring bar was
place 0.035 g ,0.167 mmol) ,2)-17 in THF ,5 mL). The
solution was treated with 0.006 g ,0.25 mmol, 1.5 equiv.)
of LiOH in H2O ,5 mL). The reaction mixture was re¯uxed
for 10 h, concentrated, and the pH adjusted to 1±2 with 1N
HCl. The solution was evaporated to dryness and the residue
was puri®ed through a DOWEX 50WX8-100 column
eluting with 15% NH4OH ,200 mL) to give 0.03 g ,91%)
2.1.8. (R)-(2)-2-Amino-2-benzyloxymethylhexanoic acid
methyl ester (19). In a 25 mL two-necked round-bottomed
¯ask equipped with a magnetic stirring bar and a rubber
septum was placed 0.030 g ,0.11 mmol) of ,2)-15b and
0.030 g of Pd black in THF ,5 mL). After two vacuum/H2
cycles to remove air from the reaction vessel, the stirred
mixture was hydrogenated at ordinary pressure ,balloon)
at rt for 18 h. The solution was ®ltered, concentrated, and
puri®ed by preparative TLC ,50% EtOAc/hexanes) to give
of a white solid, mp 157±1588C ,dec); [a]20 ˆ116.6 ,c 0.9,
D
H2O) [lit.28b [a]20 ˆ116.4 ,c 0.81, H2O)]. Spectral
D
properties of ,2)-18 were consistent with literature
values.28b
0.020 g ,65%) of an oil: [a]20 ˆ229.6 ,c 0.55, CHCl3); IR
D
2.1.6. Z-(1)-N-p-Toluenesul®nyl-2-benzyloxymethyl-2-
carbomethoxy-3-propenylaziridine (14b). In a 50 mL
round-bottomed ¯ask equipped with a magnetic stirring
bar, a rubber septum, and an argon balloon was placed
0.1 g ,0.48 mmol) of ,S)-,1)-13b in THF ,15 mL). The
solution was cooled to 2788C and 0.16 mL ,0.96 mmol,
2.0 equiv.) of methyl 2-bromo-3-,phenylmethoxy)propio-
nate was added. After 5 min, 0.63 mL ,1.0 M solution in
THF, 0.63 mmol, 1.3 equiv.) of NaHMDS was introduced
dropwise via a syringe. The reaction mixture was stirred at
2788C for 3 h and quenched with saturated NH4Cl ,10 mL).
Ethyl acetate ,10 mL) was added, the organic phase was
separated, and the aqueous phase was washed with ethyl
acetate ,2£10 mL). The organic phases were combined,
washed with brine ,10 mL), dried ,Na2SO4), and concen-
trated to give an 85:15 mixture of diastereomers. Puri®ca-
tion by ¯ash chromatography ,15% EtOAc/hexanes)
afforded 0.150 g ,79%) of ,2R,3S)-,1)-14b; mp 66±708C;
,neat) 3385, 2954, 1733, 1208, 1104 cm21
;
1H NMR
,CDCl3) d 0.86 ,t, 3H, Jˆ7.3 Hz), 1.07 ,m, 1H), 1.27 ,m,
4H), 1.49 ,m, 1H), 1.62 ,m, 1H), 1.93 ,s, broad, 2H), 3.42 ,d,
1H, Jˆ9.5 Hz), 3.71 ,s, 3H), 3.74 ,d, 1H, Jˆ9.5 Hz), 4.52
,dd, 2H, Jˆ12.5, 29.0 Hz), 7.31 ,m, 5H); 13C NMR ,CDCl3)
d 14.5, 23.5, 26.2, 36.8, 52.8, 62.7, 73.9, 76.7, 128.2, 128.3,
128.4, 129.0, 138.7, 177.1. HRMS calcd for C15H23NO3
,M1H) 266.1748. Found: 266.1756.
2.1.9. (R)-(2)-2-Amino-2-hydroxymethylhexanoic acid
methyl ester (20). In a 25 mL two-necked round-bottomed
¯ask equipped with a magnetic stirring bar and a rubber
septum was placed 0.030 g ,0.11 mmol) of ,2)-15b and
0.1 g of Pd,OH)2 in MeOH ,5 mL). The reaction mixture
was hydrogenated at rt for 18 h and the product was puri®ed
as described above to give a 0.012 g ,60%) of ,2)-20 as an
oil; [a]20 ˆ213.3 ,c 0.33, CHCl3); IR ,neat) 3745, 3683,
D
1699, 1521 cm21
;
1H NMR ,CDCl3) d 0.95 ,t, 3H,
[a]20 ˆ165.5 ,c 4.3, CHCl3); IR ,KBr pellet) 1745, 1444,
Jˆ7.2 Hz), 1.35 ,m, 4H), 1.5 5 ,m, 1H), 1.7 2 ,m, 1H),
3.53 ,d, 1H, Jˆ10.8 Hz), 3.81 ,s, 3H), 3.87 ,d, 1H,
Jˆ10.5 Hz); 13C NMR ,CDCl3) d 14.5, 23.5, 26.3, 36.7,
53.2, 63.3, 68.6, 175.4. HRMS calcd for C8H17NO3
,M1H) 176.1284. Found 176.1287.
D
1220, 1096 cm21
;
1H NMR ,CDCl3) d 1.67 ,d, 3H,
Jˆ6.6 Hz), 2.42 ,s, 3H), 3.37 ,d, 1H, Jˆ10.2 Hz), 3.69 ,d,
1H, Jˆ6.9 Hz), 3.78 ,s, 3H), 3.94 ,d, 1H, Jˆ10.5 Hz), 4.45
,dd, 2H, Jˆ12.3 Hz, Jˆ33.9 Hz), 5.26 ,m, 1H), 5.82 ,m,

F. A. Davis et al. / Tetrahedron 57 &2001) 6345±6352
6351
Sprengeler, P. A.; Guzman, M. C.; Wood, J. L.; Carroll,
P. J.; Hirschmann, R. J. Am. Chem. Soc. 1992, 114, 10672.
,c) Burgess, K.; Ho, K.-K.; Pettitt, B. M. J. Am. Chem. Soc.
1994, 116, 799.
2.1.10. (2R,2S)-(2)-2-Benzyloxymethyl-2-carbomethoxy-
3-propylaziridine (21). In a 10 mL two-necked round-
bottomed ¯ask equipped with a magnetic stirring bar and
a rubber septum was placed 0.014 g ,0.05 mmol) of
,2)-15b and 0.014 g of Pd,OH)2 in THF ,5 mL) and hydro-
genated at room temperature for 18 h. The reaction mixture
was ®ltered and the ®ltrate was concentrated and puri®ed by
preparative TLC ,50% EtOAc/hexanes) to give 0.0042 g
6. Toniolo, C.; Crisma, M.; Pegoraro, S.; Valle, G.; Bonora,
G. M.; Becker, E. L.; Polinelli, S.; Boesten, W. H. J.;
Schoemaker, H. E.; Meijer, E. M.; Kamphuis, J.; Freer, R.
Peptide Res. 1991, 4, 66.
,30%) of ,2)-21 as a yellow oil, [a]20 ˆ260.0 ,c 0.2,
7. For a reviews on the synthesis of quaternary a-alkylated
a-amino acids see: ,a) Wirth, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 225. ,b) Cativiela, C.; Diaz-de-Villegas,
M. D. Tetrahedron: Asymmetry 1998, 9, 3517. ,c) Cativiela,
C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000,
11, 645.
D
1
CHCl3); IR ,neat) 3677, 2955, 1728, 1516 cm21; H NMR
,CDCl3) d 0.92 ,t, 3H, Jˆ3.4 Hz), 1.45 ,m, 4H), 1.9 ,s,
broad, 1H), 2.3 ,m, 1H), 3.5 ,d, 1H, Jˆ10.26 Hz), 3.8 ,s,
3H), 3.9 ,d, 1H, Jˆ10.27 Hz), 4.5 ,d, 1H, Jˆ12.47 Hz), 4.7
,d, 1H, Jˆ12.1 Hz), 7.3 ,m, 5H); 13C NMR ,CDCl3) d 13.8,
20.9, 31.3, 42.6, 43.2, 52.8, 68.5, 73.4, 127.6, 127.8, 128.2,
138.1, 174.3. HRMS calcd for C15H21NO3 ,M1H)
264.1600. Found: 264.1605.
8. Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867.
9. Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem.
2000, 65, 8704.
10. For leading reference see Ref. 9.
2.1.11. (R)-(2)-2-n-Butylserine (22). In a 10 mL round
bottom ¯ask equipped with a magnetic stirring bar was
placed 0.007 g ,0.039 mmol) in THF ,1 mL). The solution
was treated with 0.0024 g ,0.057 mmol, 1.5 equiv.) of LiOH
in H2O ,1 mL). The reaction mixture was stirred at room
temperature for 12 h, concentrated and the pH adjusted to
1±2 with 1N HCl. The solution was evaporated to dryness
and the residue was puri®ed through a DOWEX 50WX8-
100 column eluting with 10% NH4OH ,20 mL) to give
0.0048 g ,75%) as a white solid, mp 226±2328C ,dec)
11. For a review on the synthetic application of chiral aziridines
see: McCoull, W.; Davis, F. A. Synthesis 2000, 1347.
12. Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang,
Y. J. Org. Chem. 1999, 64, 7559.
13. ,a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.;
Fanelli, D. L.; Zhang, H. J. Org. Chem. 1999, 64, 1403.
,b) Fanelli, D. L.; Szewczyk, J. M.; Zhang, Y.; Reddy, G. V.;
Burns, D. M.; Davis, F. A. Org. Synth. 1999, 77, 50.
14. For a reviews on the chemistry of sul®nimines see: ,a) Zhou,
P.; Chen, B.-C.; Davis, F. A. Syntheses and Reactions of
Sul®nimines. Advances in Sulfur Chemistry; Rayner, C. M.,
Ed.; JAL: Stamford, 2000; Vol. 2, pp 249. ,b) Hua, D. H.;
Chen, Y.; Millward, G. S. Sulfur Rep. 1999, 21, 211. ,c) Davis,
F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13.
15. Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron Lett. 1996,
37, 5473.
[lit.35 mp 225±2328C ,dec)]; [a]20 ˆ211.6 ,c 0.23, H2O)
D
[lit.35 [a]20 ˆ211.8 ,c 0.3, H2O)]. Spectral properties of
D
,2)-22 were consistent with literature values.35
Acknowledgements
16. Davis, F. A.; McCoull, W.; Titus, D. D. Org. Lett. 1999, 1,
1053.
This work was supported by the National Institutes of
Health ,GM51982 and GM57807).
17. Davis, F. A.; Liang, C.-H.; Liu, H. J. Org. Chem. 1997, 62,
3796.
18. For the asymmetric synthesis of 2H-azirine 2-carboxylates
see: Davis, F. A.; Liu, H.; Liang, C.-H.; Reddy, G. V.;
Zhang, Y.; Fang, T.; Titus, D. D. J. Org. Chem. 1999, 64,
8929.
References
1. ,a) Barrett, G. C. Amino Acids, Peptides and Proteins; The
Chemical Society: London, 1980; Vol. 13, pp 1. ,b) Hunt, S. In
Chemistry and Biochemistry of the Amino Acids; Barrett, G. C.,
Ed.; Chapman and Hall: London, 1985; pp 55.
,c) Coppala, G. M.; Schuster, H. F. Asymmetric Synthesis:
Construction of Chiral Molecules using Amino Acids;
Wiley: New York, 1987. ,d) Williams, R. M. In Organic
Chemistry Series Volume 7: Synthesis of Optically Active
a-Amino Acids; Baldwin, J. E., Magnus, P. D., Eds.;
Pergamon: Oxford, 1989.
19. For leading references see: Davis, F. A.; Srirajan, V.; Fanelli,
D. L.; Portonovo, P. J. Org. Chem. 2000, 65, 7663.
20. ,a) Yoshimoto, T.; Walter, R.; Tsuru, D. J. Biol. Chem. 1980,
255, 4786. ,b) Masaki, T.; Fujihashi, T.; Nakamura, K.;
Soejima, M. Biochim. Biophys. Acta 1981, 660, 51.
,c) Mickos, H.; Sundberg, K.; Luning, B. Acta Chem. Scand.
1992, 46, 989. ,d) Hatakeyama, S.; Yoshida, M.; Esumi, T.;
Iwabuchi, Y.; Irie, H.; Kawamoto, T.; Yamada, H.;
Nishizawa, M. Tetrahedron Lett. 1997, 38, 7887.
21. For some recent applications of serine in asymmetric synthesis
see: ,a) Boulton, L. T.; Stock, H. T.; Raphy, J.; Horwell, D. C.
J. Chem. Soc., Perkin Trans. 1 1999, 1421. ,b) Gabaitsekgosi,
R.; Hayes, C. J. Tetrahedron Lett. 1999, 40, 7713. ,c) Corey,
E. J.; Li, W.-D. Chem. Pharm. Bull 1999, 47, 1. ,d) Sakai, N.;
Ohfune, Y. Tetrahedron Lett. 1990, 31, 4151.
2. ,a) Hanessian, S.; Haskell, T. H. Tetrahedron Lett. 1964, 2451.
,b) Kluepfel, D.; Bagli, J.; Baker, H.; Charest, M. P.; Kudelski,
A.; Sehgal, S. N.; Vezina, C. J. Antibiot. 1972, 25, 109.
,c) Fenteany, G.; Standaert, R. F.; Lane, W. S.; Choi, S.;
Corey, E. J.; Schreiber, S. L. Science 1995, 268, 726.
3. Walsh, J. J.; Metzler, D. E.; Powell, D.; Jacobson, R. A. J. Am.
Chem. Soc. 1980, 102, 7136.
22. ,a) Seebach, D.; Aebi, J. D. Tetrahedron Lett. 1984, 25, 2545.
,b) Seebach, D.; Aebi, J. D.; Gander-Coquoz, M.; Naef, R.
Helv. Chim. Acta 1987, 70, 1194. ,c) Seebach, D.; Sting, A. R.;
Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708.
23. Alezra, V.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.;
Husson, H.-P. Tetrahedron Lett. 2000, 41, 1737.
4. Jung, H. J. In Chemistry and Biochemistry of the Amino Acids;
Barrett, G. C., Ed.; Chapman and Hall: London, 1985; pp 227.
5. ,a) For recent examples see Heimgartner, H. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 238 and references cited therein.
,b) Smith III, A. B.; Keenan, T. P.; Holcomb, R. C.;

6352
F. A. Davis et al. / Tetrahedron 57 &2001) 6345±6352
24. Williams, R. M.; Im, M.-N.; Cao, J. J. Am. Chem. Soc. 1991,
113, 6976.
30. Anelli, P. L.; Beltrami, A.; Lolli, M.; Uggeri, F. Synth.
Commun. 1993, 23, 2639.
25. Sano, S.; Takebayashi, M.; Miwa, T.; Ishii, T.; Nagao, Y.
Tetrahedron: Asymmetry 1998, 9, 3611.
31. ,a) Cainelli, G.; Panunzio, M.; Giacomini, D. Tetrahedron
Lett. 1991, 32, 121. ,b) Fujisawa, T.; Hayakawa, R.; Shimizu,
M. Tetrahedron Lett. 1992, 33, 7903. ,c) Maryanoff, C. A.;
Sorgi, K. L.; Zientek, A. M. J. Org. Chem. 1994, 59, 237.
32. Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Thimma Redd, R.;
Zhou, P.; Carroll, P. J. J. Org. Chem. 1997, 62, 2555.
33. Bharatam, P. V.; Uppal, P.; Kaur, A.; Kaur, D. J. Chem. Soc.,
Perkin Trans. 2 2000, 43.
26. ,a) Sano, S.; Hayashi, K.; Miwa, T.; Ishii, T.; Fujii, M.; Mima,
H.; Nagao, Y. Tetrahedron Lett. 1998, 39, 5571. ,b) Honda,
T.; Koizumi, T.; Komatsuzaki, Y.; Yamashita, R.; Kanai, K.;
Nagase, H. Tetrahedron: Asymmetry 1999, 10, 2703.
27. ,a) Obrecht, D.; Altorfer, M.; Lehmann, C.; Schoenholzer, P.;
Mueller, K. J. Org. Chem. 1996, 61, 4080. ,b) Ruble, J. C.; Fu,
G. C. J. Am. Chem. Soc. 1998, 120, 11532.
34. Czech, B. P.; Bartsch, R. A. J. Org. Chem. 1984, 49, 4076.
35. Carda, M.; Murga, J.; Rodriguez, S.; Gonzalez, F.; Castillo,
E.; Marco, J. A. Tetrahedron: Asymmetry 1998, 9, 1703.
28. ,a) Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116,
7405. ,b) Horikawa, M.; Nakajima, T.; Ohfune, Y. Synlett
1997, 253.
29. Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron Lett.
1995, 36, 3639.