Aza-Darzens asymmetric synthesis of N-(p-toluenesulfinyl)aziridine 2- carboxylate esters from sulfinimines (N-sulfinyl imines)

Article abstract of DOI:10.1021/jo990907j

The one-step aza-Darzens reaction of sulfinimines 2 with lithium α- bromoenolates readily affords diversely substituted cis and trans N- sulfinylaziridine 2-carboxylate esters 3 and 7 in good yield and excellent diastereoselectivity. Higher yields, but lower de's, result when a mixture of the α-bromo ester and 2 are treated with base. The N-sulfinyl group is transformed, nearly quantitatively, without ring opening, into the N-tosyl activating group by oxidation with m-CPBA. Selective removal of the N- sulfinyl group in aziridines 3a and 3h with TFA/H₂O affords 1H-aziridines 21 which are difficult to prepared by other means. However, C(3) activated azirines such as 3b undergo ring-opening under these conditions. Alternatively, the N-sulfinyl group, even in C(3)-activated aziridines, was selectively and efficiently removed by treatment of the aziridine with 2 equiv of MeMgBr.

Full text of DOI:10.1021/jo990907j

J . Org. Chem. 1999, 64, 7559-7567
7559
Aza -Da r zen s Asym m etr ic Syn th esis of
N-(p-Tolu en esu lfin yl)a zir id in e 2-Ca r boxyla te Ester s fr om
Su lfin im in es (N-Su lfin yl Im in es)
Franklin A. Davis,* Hu Liu, Ping Zhou,† Tianan Fang, G. Venkat Reddy, and Yulian Zhang
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, and Department of
Chemistry, Drexel University, Philadelphia, Pennsylvania 19104
Received J une 3, 1999
The one-step aza-Darzens reaction of sulfinimines 2 with lithium R-bromoenolates readily affords
diversely substituted cis and trans N-sulfinylaziridine 2-carboxylate esters 3 and 7 in good yield
and excellent diastereoselectivity. Higher yields, but lower de’s, result when a mixture of the R-bromo
ester and 2 are treated with base. The N-sulfinyl group is transformed, nearly quantitatively,
without ring opening, into the N-tosyl activating group by oxidation with m-CPBA. Selective removal
of the N-sulfinyl group in aziridines 3a and 3h with TFA/H2O affords 1H-aziridines 21 which are
difficult to prepared by other means. However, C(3) activated azirines such as 3b undergo ring-
opening under these conditions. Alternatively, the N-sulfinyl group, even in C(3)-activated aziridines,
was selectively and efficiently removed by treatment of the aziridine with 2 equiv of MeMgBr.
Highly regio- and stereocontrolled ring-opening reac-
tions of aziridines have considerable value in organic
synthesis.1 This is particularly true for aziridine 2-car-
boxylic acids and esters which not only lead to R- and
â-amino acids, but also can be transformed into vinyl
aziridines2 and aziridino alcohols3-5 which themselves are
useful building blocks and auxiliaries.4,5 Methods for the
asymmetric syntheses of aziridine 2-carboxylic acids and
esters include cyclization of synthetic and naturally
occurring â-hydroxy R-amino acids, azide displacement
of chiral oxiranes followed by the Staudinger reaction,
nitrene addition to R,â-unsaturated esters, and kinetic
resolution,5-7 A catalytic method has recently been
introduced.8 Unfortunately, most of these procedures
afford N-substituted derivatives and are lengthy, limited
in scope, and nonstereospecific.1,6 Another key issue is
the difficulty in varying the N-substituent, which plays
a critical role in controlling the ring-opening regiochem-
istry and stereoselectivity.
stereoselective asymmetric syntheses of R-amino acids,7
R-alkyl â-amino acids,9a R-methyl9b and â-substituted
R-amino acids,10 the antibiotic thiamphenacol,11 â-hy-
droxy R-amino acids,12 â-hydroxy R-methyl R-amino
acids,9b the protein kinase C inhibitors D-erythro and
L-threo-sphingosine,12 and the smallest of the unsatur-
ated nitrogen heterocycles 2H-azirine 2-carboxylate es-
ters10 including the cytotoxic antibiotic (R)-(-)-dysidazir-
ine.13 Our synthesis, which appears to be unparalleled
in its simplicity and the ease of incorporating diverse ring
and nitrogen substituents, involves a one-step aza-
Darzens reaction of sulfinimines (N-sulfinyl imines) with
R-bromoenolates.14 This protocol has recently been ex-
tended to the asymmetric synthesis of 2-substituted
N-sulfinylaziridines15,16 and N-sulfinylaziridine 2-phos-
phonates which were used in the first asymmetric
synthesis of azirinyl phosphonates.17 In this paper we
give a full account of our asymmetric synthesis of
N-sulfinylaziridine 2-carboxylate esters from sulfin-
imines.
In preliminary communications we described the syn-
thesis of enantiopure N-sulfinylaziridine 2-carboxylate
esters 1, which were utilized as building blocks in highly
* E-mail: fdavis@astro.ocis.temple.edu.
† Drexel University.
(1) For reviews of aziridines, see (a) Tanner, D. Angew. Chem., Int.
Ed. Engl. 1994, 33, 599. (b) Pearson, W. H.; Lian, B. W. Aziridines
and Azirines: Monocyclic. In Comprehensive Heterocyclic Chemistry
II; Padwa, A., Ed.; Pergamon Press: Oxford, 1996; Vol. 1A, Chapter
1, p 1. (c) Atkinson, R. S. Tetrahedron 1999, 55, 1519.
(2) For leading references, see (a) Ibuka, T.; Nakai, K.; Habashita,
H.; Hotta, Y.; Fujii, N.; Mimura, N.; Miwa, Y.; Taga, T.; Yamamoto,
Y. Angew. Chem., Int. Ed. Engl. 1994, 33, 652. (b) Ibuka, T.; Mimura,
N.; Ohno, H.; Nakai, K.; Akaji, M.; Habashita, H.; Tamamura, H.;
Miwa, Y.; Taga, T.; Fujii, N.; Yamamoto, Y. J . Org. Chem. 1997, 62,
2982.
(3) Ibuka, T.; Nakai, K.; Akaji, M.; Mimura, N.; Ohno, H.; Tama-
mura, Fujii, N. Tetrahedron 1996, 52, 11739.
(4) Andersson, P. G.; Guijarro, D.; Tanner, D. J . Org. Chem. 1997,
62, 7364.
Resu lts a n d Discu ssion
(5) Willems, J . G. H.; Dommerholt, F. J .; Hammink, J . B.; Vaarhost,
A. M.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1995, 36, 603.
(6) For a review, see Osborn, H. M. I.; Sweeney, J . Tetrahedron:
Asymmetry 1997, 8, 1693.
(7) For leading references, see Davis, F. A.; Zhou, P.; Reddy, G. V.
J . Org. Chem. 1994, 59, 3243.
Syn th esis of Azir id in es. The N-sulfinylaziridine
2-carboxylates were prepared by treating sulfinimines (N-
sulfinyl imines 2) with R-haloenolates in the aza-Darzens
reaction outlined in Scheme 1. The lithium enolate of
methyl R-chloroacetate (X ) Cl, R2 ) Me), generated by
(8) Antilla, J . C.; Wulff, W. D. J . Am. Chem. Soc. 1999, 121, 5099.
10.1021/jo990907j CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/16/1999

7560 J . Org. Chem., Vol. 64, No. 20, 1999
Davis et al.
Sch em e 1
Ta ble 1. Asym m etr ic Syn th esis of N-(p-Tolu en esu lfin yl)a zir id in e 2-Ca r boxyla te Ester s 3-8 fr om (S)-2 in THF
R-haloester
R3 R2
Me
% isolated yield [b]
sulfinimine
(S)-2 R1
reaction conditions
base/temp (°C)/time (h)
config dea
of major
entry
)
X
% dea [b]
major
minor
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
2a (Ph)
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
H
LDA/-78/5
decomposition
50
H
H
H
H
H
H
H
H
H
Me
Et
Ph
H
H
H
H
H
H
H
H
H
t-Bu
t-Bu
t-Bu
t-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
t-Bu
Me
Me
Me
Me
Me
LiHMDS/-78/5
(2S,3S)-5a
(2S,3S)-5a
(2S,3S)-5a
(2S,3S)-5a
(2S,3S)-3a
(2S,3S)-3a
(2S,3S)-3a
(2S,3S)-3a
(2S,3S)-3a
(2R,3S)-7a
(2R,3S)-7b
(2R,3S)-7c
(2R,3R)-3a
(2S,3S)-3b
(2S,3S)-3c
(2S,3S)-5c
(2S,3S)-3d
(2S,3S)-3e
(2S,3S)-3f
(2S,3S)-3g
(2S,3S)-3h
54
13
68
68
94[81]
80
76
[44]
[42]
90[46]
90
>95
98
98[90]
98
74
52[41]
98[42]
82[82]
98[73]
98[56]
KHMDS/-78/5
57
63
80
LiHMDS/-78/5
LiHMDS/-78/2.5
LiHMDS/-78/2.5
LiHMDS/-78 to rt/2.5
LiHMDS/-78/2.5c
LiHMDS/-78/2.5d
NaHMDS/-78/2.5
LiHMDS/-78/0.5
LiHMDS/-78/0.5
LiHMDS/-78/0.5
LiHMDS/-78/2.5
LiHMDS/-78/2.5
LiHMDS/-78/2.5
LiHMDS/-78/2.5
LiHMDS/-78/2.5
LiHMDS/-78/2.5
LiHMDS/-78/0.5
LiHMDS/-78/0.5
LiHMDS/-78/3.0
65[89]
77
[8]
60
22[55]
e[55]
85[50]
84
[21]
[22]
2[22]
3
61
70
(R)-2a (Ph)
2b (p-MeOPh)
2c (p-MeSPh)
2c (p-MeSPh)
2d (p-MeSO2Ph)
2e (p-CF3Ph)
2f (3-Pyridyl)
2g (E-PhCHdCH)
2h (i-Pr)
74[93]
68
71
20[55]
22[61]
48[63]
50[78]
64[73]
[15]
[24]
a
b
de’s determined on the crude reaction mixture by 1H NMR. Results using the in situ, one-step procedure for 30 min; see text. c A rt
solution of 2a was added to the -78 °C enolate. Reaction performed in the presence of HMPA. e Decomposition.
d
treatment with LDA at -78 °C, and (S)-(+)-N-(ben-
zylidene)-p-toluenesulfinamide (2a ) resulted in a complex
mixture of products from which no aziridine compound
was identified (Table 1, entry 1). Successful aziridination
was first realized using the enolate of tert-butyl chloro-
acetate which afforded aziridines (2S,3S)-5a and (2S,3R)-
6a in a ratio of 77:23 in 50% yield (Table 1, entry 2). The
yield was improved to 57% by use of the potassium
enolate; however, the diastereoselectivity was reduced
(Table 1, compare entry 3 with entry 2). Use of the
enolate of tert-butyl R-bromoacetate increased the de to
68% (entry 4), and when the reaction time was reduced
to 2.5 h the yield was 80% (entry 5).
(9) (a) Davis, F. A.; Reddy, G. V.; Liang, C.-H. Tetrahedron Lett.
1997, 38, 5139. (b) Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron
Lett. 1996, 37, 5473.
(10) Davis, F. A.; Liang, C.-H.; Liu, H. J . Org. Chem. 1997, 62, 3796.
(11) Davis, F. A.; Zhou, P. Tetrahedron Lett. 1994, 35, 7525.
(12) Davis, F. A.; Reddy, G. V. Tetrahedron Lett. 1996, 37, 4349.
(13) Davis, F. A.; Reddy, G. V.; Liu, H. J . Am. Chem. Soc. 1995,
117, 3651.
(14) For Darzens-type synthesis of racemic aziridines, see Rosen,
T. In Comprehensive Organic Synthesis; Heathcock, C. H., Ed.;
Pergamon Press: Oxford, 1991; Vol. 2, p 409. Cainelli, G.; Panunzio,
M.; Giacomini, D. Tetrahedron Lett. 1991, 32, 121.
(15) Davis, F. A.; Zhou, P.; Liang, C.-H.; Reddy, R. E. Tetrahedron:
Asymmetry 1995, 6, 1511.
Best results were observed for the lithium enolate of
methyl R-bromo acetate where the de’s were better than
90% (Table 1). Typically, methyl R-bromo acetate (2
mmol) was treated with an equivalent amount of lithium
(16) Ruano, J . L. G.; Fernandez, I.; Catalina, M.; Cruz, A. A.
Tetrahedron: Asymmetry 1996, 7, 3407.
(17) Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999, 40, 249.

Aza-Darzens Asymmetric Synthesis
J . Org. Chem., Vol. 64, No. 20, 1999 7561
Sch em e 2
bis(trimethylsilyl)amide (LiHMDS) in THF at -78 °C.
After 30 min, a THF solution of 1.0 mmol of the
appropriate sulfinimine 2, precooled at -78 °C, was
added to the preformed enolate via cannula. The reaction
mixture was quenched after 2.5 h with H2O, and the
N-sulfinylaziridines were purified by flash chromatog-
1
raphy. The diastereomeric excess was determined by H
NMR based on the integration of C(2) protons (d, 3.18-
3.66 ppm, J cis ) 7.3-7.4 Hz, J trans ) 3.5-4.0 Hz) of the
crude products. For aziridines 7 and 8, the de’s were
determined by integration of the C(3) protons. These
results are summarized in Table 1.
Aziridination with the lithium enolate of methyl R-bro-
moacetate is general for aromatic, aliphatic as well as
R,â-unsaturated sulfinimines 2. The aza-Darzens reaction
takes place readily at -78 °C, affording the corresponding
cis-aziridine products in 50-77% yield and in high
diastereoselectivity (94-98%, Table 1, entries 6, 15, 16,
21, and 22). However, warming the reaction from -78
°C to room temperature reduced the diastereomeric ratio
from 94 to 80%, although the isolated yield was improved
by 12% (Table 1, compare entries 6 and 7). The selectivity
was reduced to 76% de on adding a room temperature
solution of the 2a to the enolate (entry 8). Notable
exceptions were aziridines 3d and 3e, prepared from (S)-
(+)-N-(p-methylsulfonylbenzylidene)-p-toluenesulfina-
mide (2d ) and (S)-(+)-N-(p-trifluoromethylbenzylidene)-
p-toluenesulfinamide (2e), where the yields were 20-22%
(entries 18 and 19). The lithium enolates of methyl
R-bromopropionate, R-bromobutyrate, and R-bromophe-
nylacetate with (S)-(+) 2a gave predominantly the trans-
aziridines (2R,3S)-7a -c (Table 1; entries 11-13). The
diastereoselectivity was 90% and yields were 61-85%.
It should be noted that the configuration of the aziridine
product is controlled by the sulfur stereogenic center in
that (S)-sulfinimines afforded the (2S,3S)-aziridine prod-
uct 3a and the (R)-sulfinimine gave (2R,3R)-3a (Table
1, entries 6 and 14).
The modest yields of aziridines 3 obtained using methyl
R-bromoacetate most likely reflect the instability of this
enolate and its propensity to undergo self-condensation
and dimerization reactions.18 The somewhat better yields
of 7, prepared from substituted R-bromoenolates, which
are more resistant to self-condensation, undoubtedly
reflect this. In an attempt to improve the yields of 3 the
in situ trapping method, which is a useful technique for
dealing with unstable reaction species, was employed.19
In this one-step procedure 2 equiv of methyl bromoac-
etate and 1 equiv of (S)-2a were treated with 1.3 equiv
of LiHMDS at -78 °C. The reaction was complete within
20 min, affording an 89% yield of (2S,3S)-3a (entry 6).
However, the de decreased from 94 to 81%. In the
presence of HMPA the two-pot procedure gave less than
22% yield of 3a , whereas the one-step procedure resulted
in a 55% and 21% isolated yields of cis-(2S,3S)-3a and
trans-(2S,3R)-4a (44% de, entry 9). With NaHMDS,
which gave no aziridine products in the two-step method,
a similar 55% and 22% of cis-(2S,3S)-3a and trans-
(2S,3R)-4a were obtained for the one-step procedure
(entry 10). Dramatic improvement in the yields of aziri-
dines 3d and 3e, prepared from sulfinimines 2d (R )
p-MeSO2Ph) and 2e (p-CF3Ph), was also noted (20-22%
vs 55-61%) (entries 18 and 19). However, with methyl
R-bromopropionate, the one-step method resulted in
reduced yields affording 50 and 22% yields of (2R,3S)-
7a and (2S,3S)-8a , respectively (entry 11). While the in-
situ, one-step, aza-Darzens synthesis of aziridines gen-
erally provides higher yields, the selectivity is lower than
that found in the two-step process. The importance of the
former method is that it makes available useful quanti-
ties of the minor aziridine isomer which are required for
structure determination and mechanistic studies.
We also explored the possibility of preparing N-
sulfinylaziridines (+)-3a and (+)-3f in one pot from the
sulfinimine precursor (1R,2S,5R)-(-)-menthyl (S)-p-tolu-
enesulfinate (9). This was accomplised by treating (-)-9
with 1.2 equiv of lithium bis(trimethylsilyl)amide (LiH-
MDS) at -78 °C followed by the aldehyde to produce the
intermediate sulfinimines 2a and 2f, respectively.20 To
this reaction mixture, at -78 °C, was added 2.0 equiv of
methyl bromoacetate followed by LiHMDS. Flash chro-
matography afforded (+)-3a and (+)-3f in 61 and 50%
overall isolated yields (Scheme 2). While the direct
synthesis of aziridines from 9, the sulfinimine precursor,
eliminates several steps, the cis/trans selectivity was the
lowest of the procedures (Table 1).
Recently we described a new method for the asym-
metric synthesis of 3,3-disubstituted aziridines 2-car-
boxylate esters such as 11 via the addition of Grignard
reagents to 2H-azirine 2-carboxylates, which are other-
wise difficult to prepare.10 As an extension of this
chemistry, we applied our aza-Darzens aziridine synthe-
sis to the acetophenone-derived sulfinimine (S)-(+)-10.21
(2S,3S)-(-)-N-(p-Toluenesulfinyl)-2-carbomethoxy-3-meth-
yl-3-phenylaziridine (11) was isolated as a single isomer
(Scheme 3) in 41% yield. However, the reaction did not
proceed at -78 °C, and warming to 0 °C was necessary.
In addition to 11, a 23% yield of enamine 13 was also
obtained. This material was prepared independently by
(18) (a) Maryanoff, C. A.; Sorgi, K. L.; Zientek, A. M. J . Org. Chem.
1994, 59, 237. (b) Fujisawa, T.; Hayakawa, R.; Shimizu, M. Tetrahedron
Lett. 1992, 33, 7903. (c) Cainelli, G.; Panunzio, M.; Giacomini, D.
Tetrahedron Lett. 1991, 32, 121.
(19) For examples of this technique, see (a) Mori, Y.; Yaegashi, K.;
Iwase, K.; Yamamori, Y.; Furukawa, H. Tetrahedron Lett. 1996, 37,
2605. (b) Campell, J . B.; Dedinas, R. F.; Trumbower-Walsh, S. A. J .
Org. Chem. 1996, 61, 6205. (c) Singer, R. A.; Carreria, E. M.
Tetrahedron Lett. 1997, 38, 927. (d) For a review, see D′Angelo, J .
Tetrahedron 1976, 32, 2979.
(20) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M.; Reddy. G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, T. R.; Zhou, P.; Carroll,
P. J . J . Org. Chem. 1997, 62, 2, 2555.
(21) Davis. F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J . Org. Chem. 1999, 64, 1403.

7562 J . Org. Chem., Vol. 64, No. 20, 1999
Davis et al.
Sch em e 3
Sch em e 4
Sch em e 5
treating 10 with LiHMDS, to generate aza enolate 12,
followed by reaction with methyl bromoacetate. By
contrast, addition of the lithium enolate of methyl acetate
to 10 gave the corresponding â-amino acid N-(p-toluene-
sulfinyl)-3-amino-3-phenylbutanoate, in 84% yield.22 Com-
petitive enolization was not detected.22
of (+)-3a was established by selective removal of the
N-sulfinyl group (vide infra) to give the known methyl
(+)-(2S,3S)-3-phenyl-1H-aziridine-2-carboxylate (21a )29
and hydrolysis to syn-â-phenylserine.7 By analogy, and
on the basis of the similar coupling constants, the major
aziridines 3b-h isomers are assumed to have the cis
geometry.
The minor trans aziridine 4a , isolated as a pair of
invertomers, was oxidized with m-CPBA to give the
N-tosylaziridine as a single isomer 20b (vide infra). This
aziridine had 1H NMR spectra identical to methyl
(2R,3S)-(+)-trans-N-(p-toluenesulfonyl)-3-phenylaziridine-
2-carboxylate prepared by Evans and co-workers28 except
for the sign of optical rotation indicating that the con-
figuration of the minor isomer has the trans (2S,3R)-
configuration.
The structures of trans-(2R,3S)-(+)-N-(p-toluenesulfi-
nyl)-2-methyl-2-carbomethoxy-3-phenylaziridine (7a ),
its cis isomer (2S,3S)-(+)-8a , and cis-(2S,3S)-(-)-N-(p-
toluenesulfinyl)-2-carbomethoxy-3-methyl-3-phenylaziri-
dine (11) are based on 1H NOE experiments and their
transformations into known compounds. It was not
possible to directly establish the stereochemistry of 7a
and 8a by NOE experiments because they exist as cis
and trans invertomers. This problem was overcome by
m-CPBA oxidation (vide infra) of the N-p-toluenesulfinyl
group to the bulky tosyl derivatives 14 and 15 which exist
as single invertomers (Scheme 5). The fact that irradia-
tion of the C(2) Me protons in 14 and 15 produces NOE
enhancements of 3% and 10% at the C(3) phenyl and C(3)
hydrogen, respectively, is consistent with the trans
nature of the ring substitutes in (2R, 3S)-(+)-7a and the
cis nature in (2S,3S)-(+)-8a . As reported earlier, the
absolute stereochemistry of (2R,3S)-(+)-14 was deter-
mined by ring-opening hydrogenolysis and removal of
the tosyl group to give the known (R)-(+)-R-methyl-
phenylalanine.9b
Sulfinimines (S)-2a -h and (S)-10 were prepared in
one-pot from commercially available (1R,2S,5R)-(-)-
menthyl (S)-p-toluenesulfinate (9), LiHMDS, and the
aldehydes20 or by the direct condensation of (S)-(+)-p-
toluenesulfinamide (p-tolyl-S(O)NH2) with the aldehyde
or ketone in the presence of Ti(OEt)4.21 This latter
procedure avoids separation of the menthol byproduct
which is sometimes problematic. Sulfinimines 2, devel-
oped in our laboratory, are widely used chiral building
blocks for the asymmetric synthesis of amine derivatives,
because the N-sulfinyl auxiliary activates the CdN bond
for addition, is highly stereodirecting and is easily
removed from the product under mild acid or base
conditions, problems that plague other imine auxilia-
ries.23,24
Str u ctu r e a n d F or m a tion of Azir id in es. The bar-
rier to syn/anti inversion in N-sulfinylaziridines is low
(∆G‡ ) 10-14 kcal/mol)25 and, as a consequence, several
of the aziridines 3a , 7a , etc., were initially produced as
mixtures of invertomers as indicated by a doubling of the
C(2) and C(3) proton resonances. However, within min-
utes to hours a single invertomer was generally formed
which presumably has the sterically favored trans-
orientation, i.e., 3.26
The stereochemical assignments for aziridines 3 and
4 are based on the large ring proton coupling constants
observed for cis-3 vs trans-4, (e.g., J ) 7.3-7.4 Hz vs 3.5-
3.6 Hz, respectively).27,28 The absolute stereochemistry
(22) Davis, F. A.; Reddy, T. R.; Reddy, R. E. J . Org. Chem. 1992,
57, 6387.
(23) For a review on the chemistry of sulfinimines, see Davis, F. A.;
Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13.
The relative stereochemistry of (2S,3S)-(-)-N-(p-tolu-
enesulfinyl)-2-carbomethoxy-3-methyl-3-phenylaziri-
dine (11) is based on the difference in its spectral
properties compared to the trans-(2S,3R) isomer which
(24) For recent reviews on the chemistry of imines, see (a) Volk-
mann, R. A. In Comprehensive Organic Synthesis; Schreiber, S. L., Ed.;
Pergamon Press: Oxford, 1991; Vol. 1, Chapter 12, p 355. (b) Kleinman,
E. F. In Comprehensive Organic Synthesis; Heathcock, C. H., Ed;
Pergamon Press: Oxford, 1991; Vol. 2, Chapter 4, p 893. Bloch, R.
Chem. Rev. 1998, 98, 1407. Enders, D.; Reinhold, U. Tetrahedron:
Asymmetry 1997, 8, 1895.
(25) Anet, F. A. L.; Trepka, R. D.; Cram, D. J . J . Am. Chem. Soc.
1967, 89, 357. Raban, M.; Kost, D. J . Am. Chem. Soc. 1972, 94, 3234.
(26) Methyl N-(phenylsulfinyl)-2-aziridinecarboxylate is reported to
prefer the trans-configuration. Chervin, I. I.; Fomichev, A. A.; Mosk-
alenko, A. S.; Zaichenko, N. L. Aliev, A. E.; Prosyanik, A. V.;
Voznesenskii, V. N.; Kostyanovskii, R. G. Izv. Akad. Nauk SSSR, Ser.
Khim. 1988, 1110. Chem. Abstr. 1989, 110, 56755g.
(27) The coupling constants for cis- and trans-2-(methoxycarbonyl)-
3-phenylaziridines are 6.5 and 2.3 Hz, respectively. Ploux, O.; Caruso,
M.; Chassaing, G.; Marquet, A. J . Org. Chem. 1988, 53, 3154.
(28) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Andersopn, B. A.;
Barnes, D. M. J . Am. Chem. Soc. 1993, 115, 5328.
(29) Thijs, L.; Porskamp, J . J . M.; van Loon, A. A. W. M.; Derks, M.
P. W.; Feenstra, R. W.; Legters, J .; Zwanenburg, B. Tetrahedron 1990,
46, 2611.

Aza-Darzens Asymmetric Synthesis
J . Org. Chem., Vol. 64, No. 20, 1999 7563
Sch em e 6
was prepared independently by addition of methylmag-
nesium bromide to (S)-(+)-3-phenyl-2H-azirine 2-car-
boxylate.10 The absolute stereochemistry of (-)-11 was
determined by m-CPBA oxidation of the tosyl derivative
16 and subsequent conversion into erythro-(2S,3S)-(-)-
3-methylphenylalanine (18), previously prepared by Hru-
by et al. (Scheme 4).30 Transfer hydrogenation of (-)-16
gave mainly the inversion product (2S,3S)-(-)-2-N-(p-
toluenesulfonyl)amino-3-phenylbutyrate (17) in 74% de.
The diastereoisomers were separated by flash chroma-
tography affording (-)-17 in 82% yield. The N-tosyl
protecting group was removed by refluxing in 48% HBr
in the presence of phenol to produce a 78% yield of
(2S,3S)-(-)-18 (Scheme 4).
In the aza-Darzens reactions of sulfinimines 2 with
R-bromoenolates, two new stereocenters are created at
C(2) and C(3) producing, in principle, four stereoisomeric
aziridines. However, only the cis and trans aziridines are
formed with cis-3/5 predominating for the enolate of
R-bromoacetate and trans-7 for the substituted R-bro-
moacetate enolates. The high cis-selectivity for 3/5 is
consistent with a six-membered chairlike transition
containing a four-membered metallocycle, TS-1. It is
assumed that the enolate of methyl R-bromoacetate has
the E-geometry as has been proposed by others.31,32 It is
also assumed that in solution the sulfinimines also adopt
the same sterically favored E-geometry as they have in
the solid state.20 Furthermore, 2 may be locked into this
geometry as a consequence of the metal cation of the
enolate being coordinated with both nitrogen and oxygen
atoms of the sulfinimine. A similar transition state, TS-
2, provides a rational for the trans-selectivity of aziridines
7 observed with substituted R-bromoenolates. Here the
Z-geometry for the enolate is required and is supported
by the Ireland six-membered transition state for kinetic
enolate formation.32 However, attempts to verify this by
TMS-Cl trapping of the enolate were unsuccessful.
highly efficient and versatile method for preparing
structurally diverse C(2)- and C(3)-substituted aziridines
(Scheme 1). Equally important is being able to vary the
nitrogen substituent, because aziridine ring-opening
requires activation at nitrogen which determines regio-
and stereoselectivity.1,32 As mentioned earlier, many of
the methods used to prepare aziridines produce N-
substituted derivatives where it is difficult or impossible
to remove or alter the nitrogen substituent.
Many aziridine N-activating groups have been studied
with N-tosyl activation, often affording superior reactivity
and regiospecificity.1,33 However, attempts to tosylate 1H-
3-arylaziridine-2-carboxylate esters with tosyl chloride
lead predominantly to ring-opened products.33 By con-
trast, this key activating group is readily installed, prior
to ring opening, by oxidation of N-sulfinylaziridines
(Scheme 5). Thus, treatment of aziridines (2S,3S)-3a , 4a ,
(2R,3S)-7a , (2S,3S)-8a , and (2S,3S)-11 with 1.5 equiv of
57% m-CPBA in CHCl3 gave nearly quantitative yields
of the corresponding N-tosyl aziridines, respectively
(Table 2).
Another advantage of the N-sulfinyl group in aziridines
is that it can be removed under comparatively mild
conditions, affording enantiopure 1H-aziridines. 1H-
Aziridines are precursors of N-substituted aziridines and
can be elaborated into 2H-azirines.34 Reaction of aziri-
dines 3a and 3h with 5 equiv of TFA in 50% aqueous
acetone for 15-20 min afforded 1H-aziridines 21a and
21h in 83 and 80% yield, respectively (Scheme 6).
However, under the same conditions the 3-(p-methox-
yphenyl)aziridine 3b gave a 1:1 mixture of the erythro
and threo â-hydroxy R-amino acids 22. The p-methoxy
phenyl group in 3b, under these acidic conditions, ap-
parently activates aziridine ring-opening by stabilizing
a carbocation at C(3). To circumvent this problem, a
procedure was developed for removing the sulfinyl group
under basic, nucleophilic conditions. With 2.0 equiv of
Va r ia tion of th e Azir id in e Nitr ogen Su bstitu en t.
We have seen that the aziridination of sulfinimines is a
(30) Dharanipragada, R.; VanHulle, K.; Bannister, A.; Bear, S.;
Kennedy, L.; Hruby, V. J . Tetrahedron 1992, 48, 4733.
(31) Cainelli, G.; Panunzio, M. Tetrahedron Lett. 1991, 32, 121.
(32) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J . Am. Chem.
Soc. 1976, 98, 2868. (b) Ireland, R. E.; Wipf, P.; Armstrong, J . D. J .
Org. Chem. 1991, 56, 650. (c) Oare, D. A.; Heathcock, C. H. J . Org.
Chem. 1990, 55, 157.
(33) Legters, J .; Willems, J . G. H.; Thijs, L.; Zwanenburg, B. Recl.
Trav. Chim. Pays-Bas 1992, 111, 59.
(34) Gentilucci, L.; Grijzen, Y.; Thija, L.; Zwanenburg, B. Tetrahe-
dron Lett. 1995, 36, 4665.

7564 J . Org. Chem., Vol. 64, No. 20, 1999
Davis et al.
Ta ble 2. Oxid a tion of N-Su lfin yl Azir id in e 2-Ca r boxyla te Ester s to N-Tosyl Azir id in e 2-Ca r boxyla te Ester s w ith
m -CP BA a t 25 °C in CHCl3
entry
N-sulfinyl aziridine
N-tosyl aziridine
R1
R2
R3
R4
(% yield)a
1
2
2
3
4
(2S,3S)-3a
(2S,3R)-4a
(2R,3S)-7a
(2S,3S)-8a
(2S,3S)-11
(2S,3S)-19
(2S,3R)-20
(2R,3S)-14
(2S,3S)-15
(2S,3S)-16
Ph
H
Ph
Ph
Ph
H
Ph
H
H
Me
CO2Me
CO2Me
Me
CO2Me
CO2Me
H
H
(94)
(95)
(98)
(95)
(95)
CO2Me
Me
H
a
Isolated yields.
SO (M + H) 312.0670, found 312.0671. Anal. Calcd for C15H12
-
MeMgBr aziridine 3a gave 21a in 83% yield in addition
to methyl p-toluene sulfoxide (23). The latter product
indicates that the Grignard reagent efficiently attacks
at the aziridine sulfinyl sulfur. With more than 2.0 equiv
of MeMgBr, yields were lower. The (p-methoxyphenyl)-
aziridine 3b with 2.0 equiv of MeMgBr gave the corre-
sponding 1H-aziridine 21b in 71% isolated yield and
sulfoxide 23 in 98% yield (Scheme 5).
Con clu sion s. The aza-Darzens aziridination of sulfin-
imines with R-bromo enolates represents a versatile one-
step method for the asymmetric synthesis of structurally
diverse N-sulfinylaziridine 2-carboxylate esters, valuable
building blocks for the enantioselective synthesis of R-
and â-amino acids. Furthermore, the N-sulfinyl group is
easily transformed, without ring-opening, into the N-tosyl
activating group, which often provides for superior aziri-
dine ring-opening regio- and stereoselectivities. 1H-
Aziridines, which are difficult to prepare by other meth-
ods, are easily available because the N-sulfinyl group can
be efficiently removed under mild acid or base conditions.
NF3SO: C, 57.88; H, 3.86; N, 4.50. Found: C, 57.77; H, 3.94;
N, 4.38.
P r ep a r a tion of cis- a n d tr a n s-N-(p-Tolu en esu lfin yl)-
2-ca r bo-ter t-bu toxy-3-p h en yla zir id in es 5a a n d 6a : Typ i-
ca l Tw o-Step P r oced u r e. In a 50 mL oven-dried, two-necked,
round-bottomed flask fitted with a magnetic stirring bar,
rubber septum, and an argon-filled balloon was placed 2.0 mL
(2.0 mmol, 1.0 M in THF) of lithium bis(trimethylsilyl)amide
(LiHMDS) in THF (5 mL). The solution was cooled to -78 °C,
and 0.33 mL (2.0 mmol) of tert-butyl R-bromoacetate was
added. The reaction was stirred at -78 °C for 30 min, and
0.243 g (1.0 mmol) of (S)-(+)-2a in THF (5 mL) precooled to
-78 °C was added to the enolate via a double-ended needle
over a period of 30 min. The reaction mixture was stirred for
2.5 h at -78 °C, quenched with H2O (2 mL), and diluted with
EtOAc (20 mL). The organic layer was separated, washed with
brine (10 mL), dried (MgSO4), filtered, and concentrated to give
a crude 84:16 ratio mixture of diastereomers by 1H NMR. The
crude mixture was purified by chromatography (EtOAc/hex-
anes, 2:8) to afford 0.29 g (81%) of cis-(2S,3S)-5a and 0.03 g
(7%) of trans-(2S,3R)-6a .
cis-(Ss,2S,3S)-(+)-N-p-Tolu en esu lfin yl-2-ca r bo-ter t-bu -
toxy-3-p h en yla zir id in e (5a ): mp 79-80 °C; [R]20D 24.6 (c 1.6,
CHCl3); IR (KBr) cm-1 2976, 1742, 1596, 1072; 1H NMR
(CDCl3) δ 7.74 (d, 2H, J ) 8.2 Hz), 7.49-7.30 (m, 7H), 3.85 (d,
1H, J ) 7.4 Hz), 3.39 (d, 1H, J ) 7.4 Hz), 2.43 (s, 3H), 1.07 (s,
9H); the 13C NMR could not be obtained because this aziridine
exists as a slowly interconverting mixture of invertomers at
nitrogen. Anal. Calcd for C20H23NO3S: C, 67.20; H, 6.49.
Found: C, 67.05; H, 6.64.
Exp er im en ta l Section
Gen er a l P r oced u r e. Column chromatography was per-
formed on silica gel, Merck grade 60 (230-400 mesh). Analyti-
cal and preparative thin-layer chromatography was performed
on precoated silica gel plates (250 and 1000 µm) purchased
from Analtech Inc. TLC plates were visualized with UV, in
an iodine chamber or with phosphomolybdic acid unless noted
otherwise. THF was freshly distilled under nitrogen from a
purple solution of sodium and benzophenone.
tr a n s-(Ss,2S,3R)-(+)-N-(p-Tolu en esu lfin yl)-2-ca r bo-ter t-
bu toxy-3-p h en yla zir id in e (6a ): mp 84-86 °C; [R]20D 60.1 (c
1
2.0, CHCl3); IR (KBr) cm-1 2978, 1720, 1230, 1155; H NMR
Unless stated otherwise, all reagents were purchased from
commercial sources and used without additional purification.
Sulfinimines were prepared as previously described.20,21
(Ss)-(-)-N-(p -Met h ylt h iob en zylid en e)-p -t olu en esu lfi-
n a m id e (2c): eluant, EtOAc:hexanes (3:7); yield 2.30 g (80%);
(CDCl3) δ 7.71 (d, 2H, J ) 8.1 Hz), 7.27-7.10 (m, 7H), 3.81 (d,
1H, J ) 3.5 Hz), 3.24 (d, 1H, J ) 3.5 Hz), 2.38 (s, 3H), 1.53 (s,
9H); the 13C NMR could not be obtained because this aziridine
exists as a slowerly interconverting mixture of invertomers
at nitrogen. Anal. Calcd for C20H23NO3S: C, 67.20; H, 6.49.
Found: C, 67.38; H, 6.71.
mp 132-134 °C; [R]20 -40.2 (c 1.1, CHCl3); IR (KBr) cm-1
D
1587, 1548, 1495, 1405, 1089; 1H NMR (CDCl3) δ 8.68 (s, 1H),
7.72 (d, 2H, J ) 8.3 Hz), 7.62 (d, 2H, J ) 8.3 Hz), 7.30 (d, 2H,
J ) 8.3 Hz), 7.25 (d, 2H, J ) 8.3 Hz), 2.50 (s, 3H), 2.39 (s,
3H); 13C NMR (CDCl3) δ 159.3, 144.9, 141.5, 141.2, 129.8,
129.4, 124.9, 124.4, 21.2, 14.6. Anal. Calcd for C15H15NOS2:
C, 62.25; H, 5.22. Found: C, 62.48; H, 5.28.
P r epar ation of cis-(Ss,2S,3S)-(+)-N-(p-Tolu en esu lfin yl)-
2-ca r bom eth oxy-3-p h en yla zir id in e (3a ): Typ ica l On e-
Step P r oced u r e. In a 100 mL, two-necked, round-bottomed
flask fitted with a magnetic stirring bar, a rubber septum, and
an argon-filled balloon was placed 2.00 g (8.24 mmol) of (S)-
(+)-2a in THF (50 mL). The solution was cooled to -78 °C,
and 1.56 mL (16.5 mmol) of methyl R-bromoacetate was added.
After 3 min, 10.7 mL (10.7 mmol, 1.0 M in THF) of LiHMDS
was added slowly. The reaction was stirred at -78 °C for 20
min, quenched with H2O (5 mL), and diluted with EtOAc (15
mL). The organic layer was separated, and the aqueous phase
was washed with EtOAc (2 × 15 mL). The combined organic
phases were washed with brine (15 mL), dried (MgSO4), and
concentrated to give a crude 91:9 mixture of diastereomers.
Purification by flash chromatography (EtOAc/hexanes, 2:8)
afforded 2.32 g (89%) of (2S,3S)-(+)-3a and 0.20 g (8%) of
(2S,3R)-(+)-4a .
(Ss)-(+)-N-(p -Met h ylsu lfon ylb en zylid en e)-p -t olu en e-
su lfin a m id e (2d ): crystallization from EtOAc; yield 1.11 g
(80%); mp 139-140 °C; [R]20D 35.2 (c 1.1, CHCl3); IR (KBr) cm-1
1
3006, 1606, 1566, 1310, 1290, 1146; H NMR (CDCl3) δ 8.80
(s, 1H), 8.03 (s, 4H), 7.63 (d, 2H, J ) 8.1 Hz), 7.33 (d, 2H, J )
8.1 Hz), 3.06 (s, 3H), 2.40 (s, 3H); 13C NMR (CDCl3) δ 158.7,
143.4, 142.0, 140.8, 138.1, 130.1, 129.9, 127.9, 127.8, 124.6,
44.3, 21.3; HRMS calcd for C15H16NS2O3 (M + H) 322.0572,
found 322.0569. Anal. Calcd for C15H15NS2O3: C, 56.07; H,
4.67; N, 4.36. Found: C, 56.11; H, 4.75; N, 4.25.
(Ss)-(+)-N-(p-Tr iflu or om eth ylben zylid en e)-p-tolu en e-
su lfin a m id e (2e): eluant, EtOAc:n-pentane (1:9); yield 3.80
g (67%); mp 92-93 °C; [R]20D 85.0 (c 0.4, CHCl3); IR (KBr) cm-1
cis-(Ss,2S,3S)-(+)-N-(p-Tolu en esu lfin yl)-2-car bom eth oxy-
1
2923, 1608, 1324, 1170; H NMR (CDCl3) δ 8.79 (s, 1H), 7.96
3-p h en yla zir id in e (3a ): mp 72-73 °C; [R]20 51.4 (c 1.5,
D
(d, 2H, J ) 8.1 Hz), 7.71 (d, 2H, J ) 8.3 Hz), 7.64 (d, 2H, J )
8.2 Hz), 7.33 (d, 2H, J ) 8.3 Hz), 2.41 (s, 3H); 13C NMR (CDCl3)
δ 159.1, 141.8, 141.1, 136.6, 133.6 (q, J ) 132 Hz, CF3), 129.8,
129.6, 125.7, 124.6, 121.3, 21.2; HRMS calcd for C15H13NF3-
CHCl3); IR (KBr) cm-1 3031, 1754, 1596, 1204, 1074; 1H NMR
(CDCl3) δ 7.72 (d, 2H, J ) 8.2 Hz), 7.50-7.20 (m, 7H), 3.88 (d,
1H, J ) 7.4 Hz), 3.50 (d, 1H, J ) 7.4 Hz), 3.39 (s, 3H), 2.43 (s,
3H); 13C NMR (CDCl3) δ 165.8, 141.9, 140.6, 132.3, 129.5,

Aza-Darzens Asymmetric Synthesis
J . Org. Chem., Vol. 64, No. 20, 1999 7565
128.1, 127.9, 127.6, 125.0, 51.9, 42.1, 34.8, 21.5. Anal. Calcd
for C17H17NO3S: C, 64.74; H, 5.43. Found: C, 64.72; H, 5.50.
t r a n s-(Ss,2S ,3R )-(+)-N -(p -Tolu e n e su lfin yl)-2-ca r b o-
NNaO3S (m+Na) 406.0701, found 406.0699. Anal. Calcd for
C
18H16NF3SO3: C, 56.40; H, 4.18; N, 3.66. Found: C, 56.00;
H, 4.27; N, 3.21.
m eth oxy-3-p h en yla zir id in e (4a ): oil; [R]20 38.3 (c 0.2,
cis-(Ss,2S,3S)-(+)-N-(p-Tolu en esu lfin yl)-2-car bom eth oxy-
3-(3-p yr id yl)a zir id in e (3f). The typical one-step procedure
was followed; 82% de; eluant, Et2O:EtOAc (1:1); yield 63%; mp
74-76 °C; [R]20D 51.9 (c 1.1, CHCl3); IR (KBr) cm-1 1718, 1576,
D
CHCl3); IR (neat) cm-1 2952, 1735, 1438, 1206, 1109; 1H NMR
(CDCl3) δ 7.70 (d, 2H, J ) 8.0 Hz), 7.30-7.24 (m, 5H), 7.17-
7.13 (m, 2H), 3.90 (d, 1H, J ) 4.0 Hz), 3.84 (s, 3H), 3.31 (d,
1H, J ) 3.5 Hz), 2.39 (s, 3H); 13C NMR (CDCl3) δ 167.7, 142.7,
141.9, 134.0, 129.7, 128.4, 126.9, 125.3, 52.9, 45.1, 44.0, 21.5.
Anal. Calcd for C17H17NO3S: C, 64.74; H, 5.43; N, 4.44.
Found: C, 64.61; H, 5.50; N, 4.67.
1
1424, 1096; H NMR (CDCl3) δ 8.71 (d, 1H, J ) 1.5 Hz), 8.57
(dd, 1H, J ) 1.5 Hz, 5.0 Hz), 7.84 (dt, 1H, J ) 1.5 Hz, 8.0 Hz),
7.71 (d, 2H, J ) 8.5 Hz), 7.36 (d, 2H, J ) 8.5 Hz), 7.30-7.27
(m, 1H), 3.88 (d, 1H, J ) 7.0 Hz), 3.52 (d, 1H, J ) 7.0 Hz),
3.42 (s, 3H), 2.44 (s, 3H); 13C NMR (CDCl3) δ 166.5, 150.3,
150.2, 143.2, 141.1, 136.3, 130.5, 129.3, 125.8, 123.7, 52.9, 40.7,
35.1, 22.2. Anal. Calcd for C16H16N2O3S: C, 60.74; H, 5.10; N,
8.85. Found: C, 60.53; H, 5.13; N, 8.71.
ci s-(S R ,2R ,3R )-(-)-N -(p -T o lu e n e s u lfin y l)-2-c a r b o -
m eth oxy-3-p h en yla zir id in e (3a ). The typical two-step pro-
cedure was followed using (R)-(-)-2a ; 98% de; eluant, EtOAc/
hexanes (2:8); yield 70%; oil; [R]20 -50.8 (c 1.5, CHCl3); its
D
spectral properties were identical to (Ss,2S, 3S)-(+)-3a .
cis-(Ss,2S,3S)-(+)-N-(p-Tolu en esu lfin yl)-2-car bom eth oxy-
3-(p-m eth oxyp h en yl)a zir id in e (3b). The typical two-step
procedure was followed; 98% de; eluant, EtOAc/n-pentane (3:
cis-(Ss,2S,3S)-(+)-N-(p-Tolu en esu lfin yl)-2-car bom eth oxy-
3-[(2-p h en yl)-E-1-eth en yl]a zir id in e (3g). The typical two-
step procedure was followed; 98% de; eluant, EtOAc:n-pentane
(3:7); yield 0.43 g (50%); mp 107-109 °C; [R]20 109.0 (c 1.0,
D
7); yield 0.23 g (74%); oil; [R]20 26.4 (c 1.7, CHCl3); IR (neat)
CHCl3); IR (KBr) cm-1 1735, 1593, 1210, 1095, 1074; 1H NMR
(CDCl3) δ 7.64 (d, 2H, J ) 8.1 Hz), 7.42-7.25 (m, 7H), 6.85 (d,
1H, J ) 16.0 Hz), 6.23 (dd, 1H, J ) 8.3 Hz, 16.0 Hz), 3.61 (s,
3H), 3.50-3.39 (m, 2H), 2.42 (s, 3H); 13C NMR (CDCl3) δ 166.9,
142.0, 140.5, 136.4, 135.6, 129.5, 128.4, 128.1, 126.4, 124.6,
121.2, 52.3, 42.6, 32.7, 21.5. Anal. Calcd for C19H19NO3S: C,
66.83; H, 5.61. Found: C, 66.38; H, 5.65.
D
cm-1 3001, 1752, 1596, 1204, 1074; H NMR (CDCl3) δ 7.54
1
(d, 2H, J ) 8.2 Hz), 7.22 (d, 2H, J ) 8.8 Hz), 7.16 (d, 2H, J )
8.2 Hz), 6.69 (d, 2H, J ) 8.8 Hz), 3.66 (d, 1H, J ) 7.3 Hz),
3.62 (s, 3H), 3.28 (d, 1H, J ) 7.3 Hz), 3.23 (s, 3H), 2.25 (s,
3H); 13C NMR (CDCl3) δ 166.0, 159.4, 142.0, 140.6, 129.6,
128.9, 125.1, 124.4, 113.5, 55.2, 52.1, 42.0, 34.9, 21.6. Anal.
Calcd for C18H19NO4S: C, 62.59; H, 5.54. Found: C, 62.48; H,
5.28.
cis-(Ss,2S,3S)-(+)-N-(p-Tolu en esu lfin yl)-2-car bom eth oxy-
3-isop r op yla zir id in e (3h ). The typical one-step procedure
was followed; 56% de; eluant, EtOAc/n-pentane (1:9); yield 0.55
cis-(Ss,2S,3S)-(-)-N-(p-Tolu en esu lfin yl)-2-car bom eth oxy-
3-(p-m eth ylth iop h en yl)a zir id in e (3c). The typical two-step
procedure was followed; 98% de; eluant, EtOAc/n-pentane (3:
7); yield 64%; mp 86-88 °C; [R]20D -2.3 (c 0.5, CHCl3); IR (KBr)
g (73%); mp 52-55 °C; [R]20 110.7 (c 1.3, CHCl3); IR (neat)
D
cm-1 2964, 1752, 1597, 1203, 1074; H NMR (CDCl3) δ 7.62
1
(d, 2H, J ) 8.1 Hz), 7.29 (d, 2H, J ) 8.1 Hz), 3.61 (s, 3H), 3.21
(d, 1H, J ) 7.3 Hz), 2.49 (dd, 1H, J ) 7.4 Hz, 9.8 Hz), 2.40 (s,
3H), 1.89-1.71 (m 1H), 1.17 (d, 3H, J ) 6.6 Hz), 0.93 (d, 3H,
J ) 6.6 Hz),. 13C NMR (CDCl3) δ 167.2, 141.5, 140.9, 129.2,
124.5 51.8, 47.4, 31.6, 26.7, 21.2, 20.4, 19.1. Anal. Calcd for
1
cm-1 1751, 1592, 1495, 1437, 1095; H NMR (CDCl3) δ 7.70
(d, 2H, J ) 8.1 Hz), 7.39 (d, 2H, J ) 8.2 Hz), 7.33 (d, 2H, J )
8.1 Hz), 7.20 (d, 2H, J ) 8.2 Hz), 3.82 (d, 1H, J ) 7.3 Hz),
3.47 (d, 1H, J ) 7.3 Hz), 3.41 (s, 3H), 2.47 (s, 3H), 2.42 (s,
3H); 13C NMR (CDCl3) δ 166.1, 142.3, 140.8, 138.9, 129.8,
129.3, 128.3, 126.1, 125.2, 52.1, 41.9, 34.9, 21.5, 15.6. Anal.
Calcd for C18H19NO3S2: C, 59.82; H, 5.30. Found: C, 60.12;
H, 5.52.
C
14H19NO3S: C, 59.76; H, 6.80. Found: C, 59.77; H, 6.95.
t r a n s-(Ss,2S ,3R )-(+)-N -(p -Tolu e n e su lfin yl)-2-ca r b o-
m et h oxy-3-isop r op yla zir id in e (4h ). The typical one-step
procedure was followed; yield 0.18 g (24%); oil; [R]20 30.7 (c
D
1
cis-(Ss,2S,3S)-(-)-N-(p -Tolu en esu lfin yl)-2-ca r b o-ter t-
bu toxy-3-(p-m eth ylth iop h en yl)a zir id in e (5c). The typical
two-step procedure was followed; 74% de; eluant, EtOAc/n-
pentane (2:8); yield 0.58 g (71%); oil; [R]20D -16.6 (c 1.2, CHCl3);
IR (KBr) cm-1 2978, 1744, 1368, 1153; 1H NMR (CDCl3) δ 7.43
(d, 2H, J ) 8.2 Hz), 7.41-7.20 (m, 6H), 3.79 (d, 1H, J ) 7.4
Hz), 3.36 (d, 1H, J ) 7.4 Hz), 2.47 (s, 3H), 2.43 (s, 3H), 1.10 (s,
9H); 13C NMR (CDCl3) δ 164.2, 141.4, 140.8, 138.1, 129.3,
129.1, 127.9, 125.5, 124.9, 81.4, 41.3, 35.4, 27.3, 21.2, 15.5.
Anal. Calcd for C21H25NO3S2: C, 65.50; H, 6.24. Found: C,
65.10; H, 6.46.
1.2, CHCl3); IR (neat) cm-1 2962, 1745, 1440, 1228, 1093; H
NMR (CDCl3) δ 7.59 (d, 2H, J ) 8.0 Hz), 7.27 (d, 2H, J ) 8.5
Hz), 3.63 (s, 3H), 3.15 (d, 1H, J ) 4.0 Hz), 2.77 (dd, 1H, J )
4.0 Hz, 9.5 Hz), 2.38 (s, 3H), 1.95-1.85 (m, 1H), 1.06 (d, 3H,
J ) 7.0 Hz), 0.98 (d, 3H, J ) 7.0 Hz); 13C NMR (CDCl3) δ 168.9,
142.7, 141.7, 129.5, 124.9, 52.4, 51.1, 34.1, 27.9, 22.1, 21.4, 21.3;
HRMS calcd for C14H20NSO3 (M + H) 282.1164, found 282.1166.
Anal. Calcd for C14H19NSO3: C, 59.79; H, 6.76; N, 4.98.
Found: C, 59.36; H, 6.51; N, 4.90.
P r ep a r a tion of tr a n s- a n d cis-N-(p-Tolu en esu lfin yl)-
2-m eth yl-2-ca r bom eth oxy-3-p h en yla zir id in e (7a a n d 8a ).
Typ ica l P r oced u r e. In a 250 mL, two-necked, round-bot-
tomed flask fitted with a magnetic stirring bar, a rubber
septum, and an argon-filled balloon was placed 11.1 mL (11.1
mmol, 1.0 M in THF) of LiHMDS in THF (60 mL). The solution
was cooled to -78 °C, and 1.24 mL (11.1 mmol) of methyl
R-bromopropionate was slowly added. After 35 min 1.00 g (4.11
mmol) of (S)-(+)-2a in THF (40 mL) precooled to -78 °C was
added to the enolate via a cotton-wrapped, double-ended needle
over a period of 30 min. The reaction mixture was stirred for
0.5 h, quenched with H2O (4 mL), and diluted with EtOAc (40
mL). The organic phase was separated, and the aqueous phase
was washed with EtOAc (2 × 20 mL). The combined organic
extracts were washed with brine (20 mL), dried (MgSO4), and
concentrated to give a crude 95:5 mixture of diastereomers.
Purification by flash chromatography (EtOAc:n-pentane, 1:4)
afforded 1.14 g (85%) of trans-(2R,3S)-7a and 0.04 g (2%) of
cis-(2S,3S)-8a .
cis-(Ss,2S,3S)-(+)-N-(p-Tolu en esu lfin yl)-2-car bom eth oxy-
3-(4-m eth ylsu lfon ylp h en yl)a zir id in e (3d ). The typical one-
step procedure was followed; 41% de; eluant, EtOAc/hexanes
(presaturated with ammonia, 4:6); yield 0.34 (55%); mp 139-
140 °C; [R]20 14.0 (c 0.4, CHCl3); IR (KBr) cm-1 3006, 1746,
D
1
1315, 1206, 1146, 1092; H NMR (CDCl3) δ 7.86 (d, 2H, J )
8.4 Hz), 7.64 (d, 4H, J ) 8.4 Hz), 7.29 (d, 2H, J ) 8.1 Hz),
3.85 (d, 1H, J ) 7.5 Hz), 3.48 (d, 1H, J ) 7.5 Hz), 3.34 (s, 3H),
3.30 (s, 3H), 2.37 (s, 3H); 13C NMR (CDCl3) δ 165.6, 142.5,
140.3, 138.9, 129.9, 129.8, 129.0, 128.9, 127.3, 127.1, 125.1,
124.9, 52.2, 44.4, 41.4, 34.7, 21.5; HRMS calcd for C18H20NS2O5
(M + H) 394.0783, found 394.0774. Anal. Calcd for C18H19
-
NS2O5: C, 54.96; H, 4.83; N, 3.56. Found: C, 55.21; H, 4.87;
N, 3.39.
cis-(Ss,2S,3S)-(+)-N-(p-Tolu en esu lfin yl)-2-car bom eth oxy-
3-(4-tr iflu or om eth ylp h en yl)a zir id in e (3e). The typical one-
step procedure was followed; 42% de; eluant, EtOAc/hexanes
(2:8); yield 0.35 g (61%); mp 89-90 °C; [R]20 42.1 (c 0.4,
tr a n s-(Ss,2R,3S)-(+)-N-(p-Tolu en esu lfin yl)-2-m eth yl-2-
D
CHCl3); IR (KBr) cm-1 2954, 1752, 1325, 1167, 1125; 1H NMR
(CDCl3) δ 7.72 (d, 2H, J ) 8.0 Hz), 7.61 (s, 4H), 7.34 (d, 2H, J
) 8.0 Hz), 3.90 (d, 1H, J ) 7.0 Hz), 3.53 (d, 1H, J ) 7.0 Hz),
3.40 (s, 3H), 2.43 (s, 3H); 13C NMR (CDCl3) δ 165.8, 142.5,
140.5, 136.7, 130.4 (q, J ) 129 Hz, CF3), 129.8, 128.4, 125.8,
125.1, 122.2, 52.1, 41.6, 34.7, 21.4; HRMS calcd for C18H16F3-
ca r bom eth oxy-3-p h en yla zir id in e (7a ): yield 85%; oil; [R]20
D
99.6 (c 0.22, CHCl3); IR (neat) cm-1 2950, 1732, 1284, 1154,
1
1102; H NMR (CDCl3) δ 7.75 (d, 2H, J ) 8.1 Hz), 7.31-7.16
(m, 7H), 4.23 (s, 1H), 3.83 (s, 3H), 2.38 (s, 3H), 1.19 (s, 3H);
13C NMR (CDCl3) δ 169.3, 142.1, 142.0, 133.1, 129.4, 128.0,
127.8, 127.3, 125.1, 52.8, 49.6 47.5, 21.3, 15.6; HRMS calcd

7566 J . Org. Chem., Vol. 64, No. 20, 1999
Davis et al.
for C18H20NO3S (M + H) 330.1164, found 330.1164. Anal. Calcd
for C18H19NO3S: C, 65.65; H, 5.78; N, 4.26. Found: C, 65.00;
H, 5.70; N, 4.35.
by flash chromatography (EtOAc:n-pentane, 5: 95) to give 0.23
g (41%) of cis-(Ss,2S,3S)-(-)-11 and 0.13 g (23%) of enamine
13.
cis-(Ss,2S,3S)-(-)-N-p-Tolu en esu lfin yl-2-car bom eth oxy-
3-m eth yl-3-ph en ylazir idin e (11): mp 91-92 °C; [R]20D -12.40
(c 1.0, CHCl3); IR (KBr) cm-1 2955, 1756, 1448, 1232, 1179,
1060; 1H NMR (CDCl3) δ 7.76 (d, 2H, J ) 8.0 Hz), 7.44 (d, 2H,
J ) 8.5 Hz), 7.35-7.26 (m, 5H), 3.65 (s, 1H), 3.33 (s, 3H), 2.42
(s, 3H), 2.01 (s, 3H); 13C NMR (CDCl3) δ 166.9, 142.2, 141.8,
139.1, 129.6, 128.3, 127.7, 126.7, 125.5, 53.1, 51.9, 39.1, 21.4,
21.2; HRMS calcd for C18H20NO3S (M + H) 330.1164, found
330.1167. Anal. Calcd for C18H19NO3S: C, 65.65; H, 5.78; N,
4.26. Found: C, 65.14; H, 5.84; N, 4.13.
cis-(Ss,2S,3S)-(+)-N-(p-Tolu en esu lfin yl)-2-m eth yl-2-ca r -
bom eth oxy-3-p h en yla zir id in e (8a ): yield 2%; oil; [R]20
D
23.37° (c 0.95, CHCl3); IR (neat) cm-1 1730, 1452, 1239, 1147,
1
1099; H NMR (CDCl3) δ 7.84 (d, 2H, J ) 6.5 Hz), 7.39-7.26
(m, 7H), 3.92 (s, 1H), 3.35 (s, 3H), 2.43 (s, 3H), 1.70 (s, 3H);
13C NMR (CDCl3) δ 168.3, 141.7, 141.4, 133.5, 129.6, 128.1,
128.0, 127.3, 127.2, 125.8, 125.0, 54.9, 51.9, 46.5, 21.4, 15.6;
HRMS calcd for C18H20NO3S (M + H) 330.1164, found 330.1164.
Anal. Calcd for
C18H19NO3S: C, 65.65; H, 5.78; N,4.26.
Found: C, 65.95; H, 5.43; N, 4.00.
Com p ou n d 13: oil; IR (neat) cm-1 3066, 2951, 1754, 1436,
1205, 1097; 1H NMR (CDCl3) δ 7.71-7.63 (m, 4H), 7.48-7.36
(m, 5H), 4.97 (s, 1H), 4.90 (s, 1H), 4.08 (d, 1H, J ) 17.4 Hz),
3.70 (d, 1H, J ) 17.4 Hz), 3.64 (s, 3H), 2.46 (s, 3H); 13C NMR
(CDCl3) δ 169.3, 149.3, 142.0, 139.7, 137.3, 129.7, 129.0, 128.6,
tr a n s-(Ss,2R,3S)-(+)-N-(p -Tolu en esu lfin yl)-2-et h yl-2-
ca r bom eth oxy-3-p h en yla zir id in e (7b): 90% de; eluant,
EtOAc/hexanes (1:4); yield 1.16 g (84%); mp 95-96 °C; [R]20
D
150.0 (c 0.80, CHCl3); IR (KBr) cm-1 2971, 1729, 1449, 1241,
1160; 1H NMR (CDCl3) δ 7.72 (d, 2H, J ) 10.1 Hz), 7.33-7.25
(m, 7H), 4.29 (s, 1H), 3.82 (s, 3H), 2.41 (s, 3H), 1.65-1.54 (m,
1H), 1.43-1.26 (m, 1H), 0.67 (t, 3H, J ) 7.4 Hz); 13C NMR
(CDCl3) δ 168.8, 141.9, 141.8, 133.1, 129.3, 128.0, 127.8, 127.4,
128.1, 125.7, 102.3, 52.1, 44.2, 21.4; HRMS calcd for C18H20
NO3S (M + H) 330.1164, found 330.1163. Anal. Calcd for
18H19NO3S: C, 65.65; H, 5.78; N, 4.26. Found: C, 65.18; H,
-
C
5.94; N, 4.40.
125.2, 54.1, 52.6, 46.6, 22.6, 21.3, 9.0; HRMS calcd for C19H22
NO3S (M + H) 344.1253, found 344.1250. Anal. Calcd for
19H21NO3S: C, 66.47; H, 6.12; N, 4.08. Found: C, 66.08; H,
-
P r ep a r a tion of 13. In a 25 mL, oven-dried, two-necked,
round-bottomed flask fitted with a magnetic stirring bar, a
rubber septum, and an argon-filled balloon was placed 0.10 g
(0.41 mmol) of (S)-10 in THF (10 mL). The solution was cooled
to 0 °C, and 0.49 mL (0.49 mmol, 1.0 M in THF) of LiHMDS
was slowly added. The reaction mixture was stirred for 15 min,
and 0.05 mL (0.49 mmol) of methyl R-bromoacetate was added.
The mixture was stirred for 30 min at 0 °C, warmed to room
temperature for 20 min, and cooled to 0 °C. The solution was
quenched by addition of H2O (1 mL) and diluted with EtOAc
(5 mL). The organic phase was separated and the aqueous
phase was washed with EtOAc (2 × 5 mL). The combined
organic phases were washed with brine (10 mL), dried
(MgSO4), and concentrated to give a brown oil. Purification
by flash chromatography (EtOAc:n-pentane, 5:95) afforded 0.08
g (56%) of 13 and 0.03 g (24%) of sulfinimine 10.
C
6.54; N, 3.87.
tr a n s-(Ss,2R,3S)-(+)-N-(p-Tolu en esu lfin yl)-2-p h en yl-2-
ca r bom eth oxy-3-p h en yla zir id in e (7c): 95% de; eluant,
EtOAc/hexanes (1:9); yield 0.99 g (61%); mp 68-72 °C; [R]20
D
40.4 (c 1.1, CHCl3); IR (KBr) cm-1 2952, 1738, 1433, 1264,
1099; 1H NMR (CDCl3) δ 7.81 (d, 2H, J ) 8.2 Hz), 7.36 (d, 2H,
J ) 8.1 Hz), 7.12-6.95 (m, 10 H), 4.55 (s, 1H), 3.74 (s, 3H),
2.44 (s, 3H); 13C NMR (CDCl3) δ 168.3, 142.3, 141.3, 132.8,
132.4, 129.5, 128.6, 127.8, 127.7, 127.5, 125.4, 56.5, 52.9, 47.1,
21.5; HRMS calcd for C23H22NO3S (M + H) 392.1320, found
392.1323. Anal. Calcd for C23H21NO3S: C, 70.59; H, 5.37; N,
3.58. Found: C, 70.40; H, 5.22; N, 3.59.
Syn th esis of Azir id in e 3a fr om (1R,2S,5R)-(-)-Men th yl
(S)-p-Tolu en esu lfin a te (9). Typ ica l P r oced u r e. In a 100
mL, two-necked, round-bottomed flask equipped with a mag-
netic stirring bar, a rubber septum, and an argon-filled balloon
was placed 0.92 g (3.1 mmol) of (S)-(-)-9 in THF (30 mL). The
solution was cooled to -78 °C, and 3.8 mL (3.8 mmol, 1.0 M
in THF) of LiHMDS was added dropwise. The reaction was
warmed to room temperature, stirred for 1.5 h, and monitored
by TLC for the disappearance of 9. The mixture was then
cooled to -78 °C, and 0.35 mL (3.4 mmol) of benzaldehyde was
added. The reaction mixture was stirred for 1 h at -78 °C and
1 h at room temperature and cooled to -78 °C, and 0.59 mL
(6.2 mmol) of methyl bromoacetate was added. After 10 min,
4.7 mL (4.7 mmol, 1.0 M in THF) of LiHMDS was added. After
another 30 min, the solution was warmed to -45 °C for 10
min, quenched by addition of H2O (5 mL), and diluted with
EtOAc (150 mL). The organic phase was separated, washed
with brine (30 mL), dried (MgSO4), and concentrated to give
a 85:15 mixture of diastereomers. Flash chromatography
(EtOAc/n-pentane, 1:9) afforded 0.60 g (61%) of 3a .
Oxid a tion of (2R,3S)-7a to tr a n s-(2R,3S)-(+)-N-(p-Tolu -
en esu lfon yl)-2-m et h yl-2-ca r b om et h oxy-3-p h en yla zir i-
d in e (14). Typ ica l P r oced u r e. In a 25 mL, single-necked,
round-bottomed flask equipped with a magnetic stirring bar
was placed 0.59 g (1.79 mmol) of (2R,3S)-(+)-7a in CHCl3 (10
mL). m-Chloroperbenzoic acid (1.03 g, 3.59 mmol, 60%, Ald-
rich) was added to the reaction in small portions. The reaction
mixture was stirred for 25 min and diluted with CH2Cl2 (10
mL). The organic phase was washed with saturated Na2S2O3
(2 × 10 mL) and saturated NaHCO3 (10 mL), dried (MgSO4),
and concentrated to give a crude product which was purified
by flash chromatography (EtOAc/n-pentane, 20:80) to give 0.61
g (98%) of (2R,3S)-(+)-14 as a colorless oil; [R]20D 44.14 (c 0.28,
CHCl3); IR (neat) cm-1 2952, 1741, 1336, 1163; 1H NMR
(CDCl3) δ 7.88 (d, 2H, J ) 8.4 Hz), 7.35-7.26 (m, 5H), 7.18-
7.17 (m, 2H), 4.94 (s, 1 H), 3.90 (s, 3H), 2.45 (s, 3H), 1.23 (s,
3H); 13C NMR (CDCl3) δ 168.1, 144.2, 137.1, 132.2, 129.5,
128.3, 128.1, 127.3, 127.1, 53.9, 53.1, 50.1, 21.5, 15.4; HRMS
calcd for C18H20NO4S (M + H) 346.1113, found 346.1113. Anal.
Calcd for C18H19NO4S: C, 62.61; H, 5.51; N, 4.06. Found: C,
62.59; H, 5.80; N, 3.70.
P r epar ation of cis-(Ss,2S,3S)-(-)-N-p-(Tolu en esu lfin yl)-
2-ca r bom eth oxy-3-m eth yl-3-p h en yla zir id in e (11). In a 50
mL, oven-dried, two-necked, round-bottomed flask fitted with
a magnetic stirring bar, a rubber septum, and an argon-filled
balloon was placed 3.4 mL (3.4 mmol, 1.0 M in THF) of
LiHMDS in THF (10 mL). The solution was cooled to -78 °C,
and 0.32 mL (3.42 mmol) of methyl R-bromoacetate was slowly
added. The reaction misture was stirred for 30 min, and a
solution of 0.44 g (1.72 mmol) of (S)-(+)-N-(R-methylben-
zylidene)-p-toluenesulfinamide (10)21 in THF (20 mL) was
added to the enolate via cannula. The mixture was stirred for
1 h at -78 °C, warmed to 0 °C for 15 min, cooled to -78 °C,
quenched by addition of H2O (3 mL), and diluted with EtOAc
(10 mL). The organic phase was separated, and the aqueous
phase was washed with EtOAc (2 × 10 mL). The combined
organic extracts were washed with brine (10 mL), dried
(MgSO4), and concentrated to give an oil which was purified
cis-(2S,3S)-(+)-N-(p -Tolu en esu lfon yl)-2-m et h yl-2-ca r -
bom eth oxy-3-p h en yla zir id in e (15): eluant, EtOAc/hexanes
(2:8); yield 0.05 g (95%); mp 105-106 °C; [R]20 17.10 (c 1.05,
D
CHCl3); IR (neat) cm-1 2952, 1752, 1735, 1331, 1091; 1H NMR
(CDCl3) δ 7.93 (d, 2H, J ) 6.7 Hz), 7.32 (d, 2H, J ) 8.1 Hz),
7.22-7.18 (m, 3H), 7.11-7.07 (m, 2H), 4.11 (s, 1H), 3.41 (s,
3H), 2.43 (s, 3H), 2.11 (s, 3H); 13C NMR (CDCl3) δ 167.4, 144.4,
137.2, 132.3, 129.6, 128.2, 128.1, 127.5, 126.8, 54.8, 52.4, 52.2,
21.6, 16.3; HRMS calcd for C18H20NO4S (M + H) 346.1113,
found 346.1108. Anal. Calcd for C18H19NO4S: C, 62.61; H, 5.51;
N, 4.06. Found: C, 62.57; H, 5.54; N, 4.04.
cis-(2S,3S)-(-)-N-(p-Tolu en esu lfon yl)-2-ca r bom eth oxy-
3-m eth yl-3-p h en yla zir id in e (16): eluant, EtOAc/hexanes (2:
8); yield 0.13 g (95%); mp 114-115 °C; [R]20 -9.54 (c 0.43,
D
CHCl3); IR (KBr) cm-1 2961, 1758, 1328, 1158, 1091; 1H NMR
(CDCl3) δ 8.01 (d, 2H, J ) 8.4 Hz), 7.41-7.25 (m, 7H), 3.86 (s,

Aza-Darzens Asymmetric Synthesis
J . Org. Chem., Vol. 64, No. 20, 1999 7567
1H), 3.43 (s, 3H), 2.49 (s, 3H), 2.18 (s, 3H); 13C NMR (CDCl3)
δ 165.7, 144.5, 138.1, 137.1, 129.7, 128.4, 128.0, 127.5, 126.6,
56.8, 52.2, 49.8, 22.1, 21.7; HRMS calcd for C18H20NO4S (M +
H) 346.1113, found 346.1113. Anal. Calcd for C18H19NO4S: C,
62.61; H, 5.51. Found: C, 62.21; H, 5.53.
extracts were washed with brine (20 mL), dried (Na2SO4), and
concentrated. Flash chromatography (EtOAc/n-pentane, 3:7)
gave 0.16 g (89%) of 21a as a solid: mp 58 °C [lit.29 mp 51-57
°C]; [R]20 20.9 (c 1.98, EtOH) [lit.29 [R]20 22.2 (c 1.0, EtOH)];
D
D
1H NMR (CDCl3) δ 7.32-7.26 (m, 5H), 3.52 (s, 3H), 3.50 (d,
1H, J ) 6.4 Hz), 3.04 (d, 1H J ) 6.3 Hz), 1.73 (bs, 1H); 13C
NMR (CDCl3) δ 160.3, 134.7, 128.0, 127.6, 127.3, 52.0, 40.2,
37.2.
cis-(2S,3S)-(+)-N-(p-Tolu en esu lfon yl)-2-ca r bom eth oxy-
3-p h en yla zir id in e (19): eluant, EtOAc/n-pentane (2:8); yield
94%; mp 85-87 °C; [R]20 18.2 (c 1.0, CHCl3); IR (KBr) cm-1
D
1
3033, 1757, 1598, 1334, 1210, 1164, 1092; H NMR (CDCl3)
δ
Meth yl (2S,3S)-(+)-3-isop r op yl-1H-a zir id in e-2-ca r box-
7.92 (d, 2H, J ) 8.3 Hz), 7.35 (d, 2H, J ) 8.4 Hz), 7.32-7.20
(m, 5H), 4.12 (d, 1H, J ) 7.6 Hz), 3.71 (d, 1H, J ) 7.7 Hz),
3.49 (s, 3H), 2.44 (s, 3H); 13C NMR (CDCl3) δ 164.5, 145.0,
133.8, 130.9, 129.7, 128.3, 128.0, 127.9, 127.2, 52.3, 45.3, 43.3,
21.6. Anal. Calcd for C17H17NO4S: C, 61.61; H, 5.17. Found:
C, 61,43; H, 5.17.
yla te (21h ): eluant, EtOAc/hexanes (3:7); yield 85%; oil; [R]20
D
50.2 (c 2.9, CHCl3); IR (neat) cm-1 3266, 2960, 1734, 1208; 1H
NMR (CDCl3) δ 3.77 (s, 3H), 2.72 (d, 1H, J ) 6.3 Hz), 2.02-
1.96 (m, 1H), 1.52-1.42 (m, 2H), 1.11 (d, 3H, J ) 6.6 Hz), 0.91
(d, 3H, J ) 6.7 Hz); 13C NMR (CDCl3) δ 171.2, 52.2, 45.5, 34.7,
28.0, 21.1, 20.4. Anal. Calcd for C7H13NO2: C, 58.72; H, 9.15.
Found: C, 58.40; H, 8.86.
t r a n s-(2S ,3R )-(-)-N -(p -T o lu e n e s u lfo n y l)-2-c a r b o -
m eth oxy-3-p h en yla zir id in e (20): eluant, EtOAc/n-pentane
Meth yl (2S,3R)- a n d (2S,3S)-2-Am in o-3-h yd r oxy-3-(p-
m eth oxyp h en yl)p r op a n oa te (22). Using the standard con-
ditions, aziridine (2S,3S)-3b gave a 68% yield of a 1:1 mixture
of (2S,3R)- and (2S,3S)-22. The diastereomers were separated
by preparative TLC (MeOH/CH2Cl2, 5:95).
(2:8); yield 95%; mp 42-44 °C; [lit.28 mp 44.2-44.6 °C]; [R]20
D
-29.4 (c 0.92, CH2Cl2); [lit.28 [R]20 33.1 (c 1.0, CH2Cl2) for the
D
(2R,3S)-20.
Met h yl (2S,3S)-(-)-2-N-(p -Tolu en esu lfon yl)a m in o-3-
p h en ylbu tyr a te (17). In a 25 mL, single-necked, round-
bottomed flask equipped with a magnetic stirring bar was
placed 0.05 g (0.14 mmol) of (-)-16 in ethanol (12 mL). Formic
acid (2 mL) was added followed by Pd black (0.10 g, Aldrich).
The solution was stirred at room temperature for 2 h, filtered
through a short silica column, and concentrated to give a crude
87:13 ratio mixture of diastereomers. Flash chromatography
(EtOAc/hexanes, 1:9) afforded 0.04 g (82%) of 17 as a white
Meth yl (2S,3R)-(+)-2-a m in o-3-h yd r oxy-3-(p-m eth oxy-
p h en yl)p r op a n oa te (22): yield 34%; oil; [R]20 26.74 (c 2.3,
D
CHCl3); IR (neat) cm-1 3367, 3303, 3032, 1737; 1H NMR
(CDCl3) δ 7.24 (d, 2H, J ) 8.6 Hz), 6.86 (d, 2H, J ) 8.6 Hz),
4.72 (d, 1H, J ) 5.3 Hz), 3.78 (s, 3H), 3.62 (s, 3H), 3.53 (d, 1H,
J ) 5.4 Hz); 13C NMR (CDCl3) δ 174.0, 159.1, 132.7, 127.2,
113.7, 73.8, 60.7, 55.2, 52.1. Anal. Calcd for C11H15NO4: C,
58.66, H, 6.71, N, 6.22. Found C, 58.32, H, 6.57, N, 6.06.
Meth yl (2S,3S)-(+)-2-a m in o-3-h yd r oxy-3-(p-m eth oxy-
p h en yl)p r op a n oa te (22): yield 34%; mp 107 °C; [R]20D 18.54
(c 1.3, CHCl3); IR (neat) cm-1 3447, 3401, 3322, 3062, 1734;
1H NMR (CDCl3) δ 7.18 (d, 2H, J ) 8.8 Hz), 6.85 (d, 2H, J )
8.8 Hz), 4.84 (d, 1H, J ) 5.8 Hz), 3.78 (s, 3H), 3.75 (d, 1H, J
) 5.8 Hz), 3.66 (s, 3H); 13C NMR (CDCl3) δ 173.5, 159.2, 131.8,
127.4, 113.6, 73.9, 59.9, 55.1, 51.9.
solid: mp 101-102 °C; [R]20 -35.2 (c 0.89, CHCl3); IR (KBr)
D
cm-1 3458, 2980, 1740, 1344, 1166; H NMR (CDCl3) δ 7.66
1
(d, 2H, J ) 8.4 Hz), 7.32-7.27 (m, 5H), 7.12-7.10 (m, 2H),
4.86 (d, 1H, J ) 9.6 Hz), 4.08 (dd, 1H, J ) 5.1 Hz, 9.9 Hz),
3.47 (s, 3H), 3.32-3.27 (m, 1H), 2.45 (s, 3H), 1.43 (d, 3H, J )
7.2 Hz); 13C NMR (CDCl3) δ 170.9, 143.6, 139.8, 136.4, 129.5,
128.6, 127.7, 127.5, 127.2, 61.0, 52.2, 42.2, 21.5, 17.6; HRMS
calcd for C18H22NO4S (M + H) 348.1270, found 348.1272. Anal.
Calcd for C18H21NO4S: C, 62.25; H, 6.05; N, 4.03. Found: C,
61.95; H, 5.96; N, 3.98.
Rem ova l of th e N-Su lfin yl Gr ou p Usin g MeMgBr .
Typ ica l P r oced u r e. In a 25 mL, one-necked, round-bottomed
flask fitted with an argon balloon and magnetic stirring bar
was placed 0.07 g (0.21 mmol) of aziridine (2S,3S)-3a in THF
(4.2 mL). The reaction mixture was cooled to -78 °C, and 0.14
mL (0.42 mmol, 3.0 M in Et2O) of MeMgBr was added. The
mixture was stirred for 30 min at -78 °C and quenched with
H2O (1 mL). The mixture was warmed to room temperature
and diluted with EtOAc (50 mL), and the aqueous phase was
extracted with EtOAc (2 × 5 mL). The combined organic
phases were washed with brine (20 mL), dried (MgSO4), and
concentrated. The crude aziridine was purified by preparative
TLC (EtOAc/n-pentane, 1:1) to afford 0.03 g (83%) of 21a and
0.03 g (97%) of (S)-(-)-methyl p-tolyl sulfoxide (23) in >96%
ee.
er yth r o-(2S,3S)-(-)-3-Meth ylp h en yla la n in e (18). In a 15
mL, single-necked, round-bottomed flask equipped with a
magnetic stirring bar and a reflux condenser were placed 0.04
g (0.12 mmol) of (2S,3S)-(-)-17, 0.15 g (1.59 mmol) of phenol,
and 5 mL of 48% HBr. The reaction mixture was refluxed at
100 °C for 1 h and then stirred at room temperature for 1 h.
The solution was diluted with EtOAc (10 mL) and H2O (15
mL). The aqueous phase was extracted with EtOAc (2 × 5 mL)
and loaded into a distilled H2O packed ion-exchange column
(Dowex 50 × 8-100, H+). The column was first washed with
distilled H2O (350 mL) until pH 6 and then with 1.5 M NH4-
OH (200 mL). The NH4OH fractions were collected. Removal
of water gave a light brown solid which was dissolved in
distilled H2O (2 mL) and filtered through a cotton filter twice
to remove insoluble impurities. The filtrate was concentrated
to afford 0.016 g (78%) of 18: mp 184-186 °C [lit.30 mp 182-
184 °C]; [R]20 -26.6 (c 0.35, H2O), [lit.30 [R]20 -26.7 (c 1.0,
Meth yl (2S,3S)-(+)-3-(p-Meth oxyp h en yl)-1H-a zir id in e-
2-ca r boxyla te (21b). Preparative TLC (EtOAc/n-pentane,
1:1): yield 71%; mp 56-57 °C; [R]20 14.4 (c 0.93, CHCl3); IR
D
(KBr) cm-1 3458, 3311, 1740; 1H NMR (CDCl3) δ 7.24 (bs, 2H),
6.83 (d, 2H, J ) 8.8 Hz), 3.78 (s, 3H), 3.54 (s, 3H), 3.43 (bs,
1H), 2.98 (bs, 1H), 1.68 (bs, 1H); 13C NMR (CDCl3) δ 170.4,
159.8, 129.2, 127.5, 114.2, 55.9, 52.8, 40.8, 37.8; HRMS calcd
for C11H13NO3 (M + H) 207.0895, found 207.0889. Anal. Calcd
for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.36;
H, 6.09; N, 6.56.
D
D
H2O)]. Compound (2S,3S)-(-)-18 has other physical and
spectroscopic properties identical with reported values.30
P r ep a r a tion of Meth yl (2S,3S)-(+)-3-P h en yl-1H-a zir i-
d in e-2-ca r boxyla te (21a ). Typ ica l P r oced u r e. In 25 mL,
round-bottomed flask equipped with a magnetic stirring bar
was placed 0.32 g (1.0 mmol) of aziridine (2S,3S)-3a in acetone/
H2O (1:1, 15 mL). Trifluoroacetic acid (0.4 mL, 5.2 mmol) was
added dropwise. After 15 min, concentrated NH4OH was added
until the aqueous layer was brought to pH 10. The solution
was concentrated, H2O (7 mL) was added, and the pH was
again adjusted to 10 with concentrated NH4OH. The solution
was extracted with CH2Cl2 (3 × 15 mL), and the organic
Ack n ow led gm en t. We thank Dr. William McCoull
for helpful discussions. This work was supported by
grants from the National Institutes of Health (GM
51982) and the National Science Foundation.
J O990907J