Asymmetric Synthesis of 2H-Azirine 2-Carboxylate Esters

Article abstract of DOI:10.1021/jo991389f

2H-Azirine 2-carboxylate esters (5), the smallest unsaturated nitrogen heterocycle, are readily prepared in enantiomerically pure form via the base-induced elimination of sulfenic acid (RSOH) from nonracemic N-sulfinylaziridine 2-carboxylate esters (4). Optimum yields were obtained when the aziridine was treated with TMSCl at -95 °C followed by LDA, which was attributed to the improved leaving group ability of an silicon-oxonium species. By using this new methodology the first asymmetric syntheses of the marine cytotoxic antibiotics (R)-(-)- and (S)-(+)-dysidazirine (2) were accomplished.

Full text of DOI:10.1021/jo991389f

J . Org. Chem. 1999, 64, 8929-8935
8929
Asym m etr ic Syn th esis of 2H-Azir in e 2-Ca r boxyla te Ester s
Franklin A. Davis,* Hu Liu, Chang-Hsing Liang, G. Venkat Reddy, Yulian Zhang,
Tianan Fang, and Donald D. Titus
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
Received September 1, 1999
2H-Azirine 2-carboxylate esters (5), the smallest unsaturated nitrogen heterocycle, are readily
prepared in enantiomerically pure form via the base-induced elimination of sulfenic acid (RSOH)
from nonracemic N-sulfinylaziridine 2-carboxylate esters (4). Optimum yields were obtained when
the aziridine was treated with TMSCl at -95 °C followed by LDA, which was attributed to the
improved leaving group ability of an silicon-oxonium species. By using this new methodology the
first asymmetric syntheses of the marine cytotoxic antibiotics (R)-(-)- and (S)-(+)-dysidazirine (2)
were accomplished.
The theoretical, mechanistic and synthetic chemistry
of 2H-azirines, the smallest unsaturated nitrogen het-
erocycle, has been extensively explored.1 Activated by the
high ring strain, the C-N π-bond and nitrogen lone pair
participate in a wide variety of reactions with electro-
philes and nucleophiles, as well as cycloadditions with
dienes. Thermal and photochemical transformations
include rearrangement to vinyl nitrenes and nitrile
ylides. The ability of azirines to serve as precursors of
more complex heterocyclic systems is impressive.1 The
reactivity of 2H-azirines is dictated by the ring substit-
uents, and in this regard 2H-azirine 2-carboxylate acids
(1) are of particular significance because they are found
as naturally occurring antibiotics. For example azirino-
mycin (1, R ) Me)2 was isolated from Streptomyces
aureus, and (R)-(-)-dysidazirine (2) was obtained from
Dysidea fragilis, a marine sponge.3 Dysidazirine (2) is
cytotoxic to L1210 cells and inhibits the growth of Gram
negative bacteria and yeast. Several related azacyclo-
propene analogues, including antazirine (3), a bromine-
containing azirine, have recently been isolated.4 Enan-
tiomerically enriched 2H-azirine carboxylate esters have
been employed in the synthesis of R,R-disubstituted
R-amino acids,5a in cycloaddition reactions,5b and in the
preparation of fully substituted aziridine 2-carboxylate
acids, which on ring-opening lead to â-substituted R-ami-
no acids.6
adaptable, until recently there existed only a single report
of an asymmetric synthesis wherein a diastereoselective
Neber rearrangement was used to prepare a 3-amino-
2H-azirine.11 In 1995 we described the first asymmetric
synthesis of (R)-(-)-dysidazirine (2) and a general method
for the enantioselective synthesis of 2H-azirine 2-car-
boxylate esters involving the base-induced elimination
of sulfenic acid from N-sulfinylaziridine 2-carboxylate
esters.12 After our report, a complementary method was
described by Zwanenburg and co-workers involving the
Swern oxidation of 1H-aziridine 2-carboxylate esters.13
More recently this group reported an alkaloid-mediated
Neber reaction for their synthesis, but the ee’s were
modest (57-82%).14 Other recent methods include a
lipase-catalyzed kinetic resolution of 3-phenyl-2H-azir-
ine15 and the diastereomeric synthesis of 3-amino-2H-
azirines from R-azidoenamies.5a,16 We report here full
Methods for the synthesis of 2H-azirines include the
modified Neber reaction,7 thermolysis and photolysis of
vinyl azides8 and isoxazoles,9 and thermolysis of oxaza-
phospholines.10 Because these procedures are not readily
(7) Nair, V. J . Org. Chem. 1968, 33, 2121. Padwa, A.; Carlsen, P.
H. J . J . Am. Chem. Soc. 1977, 99, 1514. Padwa, A.; Carlsen, P. H. J .
J . Org. Chem. 1978, 43, 2029.
(8) (a) Hassner, A.; Levy, L. A. J . Am. Chem. Soc. 1965, 87, 4203.
(b) Fowler, F. W.; Hassner, A.; Levy, L. A. J . Am. Chem. Soc. 1967,
89, 2077. (c) Hassner, A.; Fowler, F. W. J . Org. Chem. 1968, 33, 2686.
(9) Nishiwaki, T.; Kitamura, T.; Nakano, A. Tetrahedron 1970, 26,
453.
(10) Huisgen, R.; Wulff, J . Tetrahedron Lett. 1967, 917. Bestmann,
H. J .; Kunstmann, R. Angew. Chem., Int. Ed. Engl. 1966, 5, 1039.
(11) Piskunova, I. P.; Eremeev, A. V.; Mishnev, A. F.; Vosekalna, I.
A. Tetrahedron 1993, 49, 4671.
(12) Davis, F. A.; Reddy, G. V.; Liu, H. J . Am. Chem. Soc. 1995,
117, 3651.
(1) For reviews on the chemistry of azirines see: (a) Padwa, A.;
Woolhouse, A. D. In Comprehensive Heterocyclic Chemistry; Lowowski,
W., Ed; Pergamon Press: Oxford, 1984; Vol. 7, Chapter 5, p 47. (b)
Pearson, W. H.; Lian, B. W.; Bergmeier, S. C.; Padwa, A. Comprehen-
sive Heterocyclic Chemistry II; Pergamon Press: Oxford, 1996; Chapter
1, p 1. (c) Nair, V. In Heterocyclic Compounds; Hassner, A., Ed.; J ohn
Wiley & Sons: New York, 1983; Chapter 2, p 215. (d) Fowler, F. W.
Advances in Heterocyclic Chemistry; Academic Press: New York, 1971;
p 45.
(2) Miller, T. W.; Tristram, E. W.; Wolf, F. J . J . Antibiot. 1971, 24,
48.
(3) Molinski, T. F.; Ireland, C. M. J . Org. Chem. 1988, 53, 2103.
(4) Salomon, C. E.; Williams, D. H.; Faulkner, D. J . J . Nat. Prod.
1995, 58, 1463.
(13) Gentilucci, L.; Grijzen, Y.; Thijs, L.; Zwanenburg, B. Tetrahe-
dron Lett. 1995, 36, 4665.
(5) (a) Bucher, C. B.; Linden, A.; Heimgartner, H. Helv. Chim. Acta
1995, 78, 935. (b) Alves, M. J .; Bickley, J . F.; Gilchrist, T. L. J . Chem.
Soc., Perkin Trans. 1 1999, 1339.
(14) Verstappen, M. M. H.; Ariaans, G. J . A.; Zwanenburg, B. J .
Am. Chem. Soc. 1996, 118, 8, 8491.
(15) Sakai, T.; Kawabata, I.; Kishimoto, T.; Ema, T.; Utaka, M. J .
Org. Chem. 1997, 62, 4906.
(6) Davis, F. A.; Liang, C.-H.; Liu, H. J . Org. Chem. 1997, 62, 3796.
10.1021/jo991389f CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/30/1999

8930 J . Org. Chem., Vol. 64, No. 24, 1999
Davis et al.
details of the asymmetric synthesis of 2H-azirine 2-car-
boxylate esters from N-sulfinylaziridine 2-carboxylate
esters.17
identified when aziridines 4d (R ) 4-MeSO2Ph), 4e (R )
i-Pr), and 11 were treated with LDA (Table 1, entries
10, 11 and 12). In the case of 4d it is likely that
methylsulfonyl protons are removed in preference to the
aziridine C(3) proton, and in 4e the C(3) proton is
considerably less acidic than in the other compounds.
To examine the scope of our 2H-azirine synthesis we
next turned to evaluating the effect of varying the
aziridine ring substituents. trans-(2S,3R)-(+)-N-(p-Tolu-
enesulfinyl)-2-carbomethoxy-3-phenylaziridine (12) gave
only a 9% yield of (S)-5a versus cis-4a , which gave a 47%
yield of the azirine (Scheme 2). The major product was
sulfinamide 13, isolated in 46% yield, resulting from
attack of LDA at the sulfinyl group. Interestingly the NH
aziridine corresponding to 12 was not detected. However,
2-methyl aziridine (2R,3S)-14 gave sulfinamide 13, but
with this example the corresponding aziridine 15 and the
2H-azirine 16 were obtained in 57% and 41% yield,
respectively (Scheme 2).
The new 2H-azirines 2-carboxylate esters (S)-(+)-5a -c
and (R)-(-)-16 gave satisfactory elemental analysis and
had spectral properties consistent with their structures.
The enantiomeric purity was determined to be >95% ee
using the chiral shift reagent Eu(hfc)3. Because it is
reasonable to assume that the C(2) stereocenter in
aziridines 4 and 14 are unaffected by deprotonation at
C(3), the corresponding azirines have the S- and R-
configurations, respectively.
A better nitrogen leaving group was expected to
improve the modest yields of azirines produced in the
base-promoted elimination of sulfenic acid from N-
sulfinylaziridines 4 and 14 (Schemes 1 and 2). However,
when N-tosylaziridines 17, prepared in >95% yield by
m-CPBA oxidation of 4a and 11, were treated at -78 °C
with LDA, amino cinnamates 18a and 18b were obtained
in 61% and 79% yield, respectively (Scheme 3). Hydro-
genation (H2/Pd) of 18a produced a quantitative yield of
the known N-tosyl phenylalanine.21 These results are
consistent with C(2) deprotonation followed by stereospe-
cific ring opening and are similar to the results reported
by Padwa et al. for 1,2-dibenzoyl-3-phenylaziridine
(Scheme 3).22 On the basis of these considerations the
trans structure was assigned to 18 and was confirmed
for 18b by X-ray crystallography.23
Resu lts a n d Discu ssion
Syn th esis of 2H-Azir in es. Treatment of (2S,3S)-(+)-
N-(p-toluenesulfinyl)-2-carbomethoxy 3-phenylaziridine
(4a ) with 1.3-1.5 equiv of lithium diisopropylamide
(LDA) at -78 °C in THF for 20 min and quenching with
H2O afforded a 47% yield of (S)-(+)-2-carbomethoxy-3-
phenyl-2H-azirine (5a ) (Scheme 1). In addition to the
azirine, polar residues were isolated along with a 55%
yield of p-tolyl disulfide (7) and a 26% yield of p-toluene-
p-tolylthiosulfonate (8) (Table 1, entry 1). The latter
products result from disproportionation of the p-toluene-
sulfenic acid (p-TolylSOH)18 generated in formation of the
2H-azirine. When iodomethane was added to trap the
sulfenic acid, methyl p-tolylsulfoxide (9) was isolated in
83% yield (Table 1, entry 2). The yield of azirine 5a
improved to 52%, likely a consequence of easier isolation.
1,2-Elimination of sulfenic acid to produce the known
isomeric 3-carbomethoxy-2-phenyl-2H-azirine (6) was not
1
detected in the H NMR spectrum of the crude reaction
material.19 Attempts to improve the yield by varying the
solvent, temperature, and base were unsuccessful, result-
ing in either no reaction or decomposition, i.e., the
formation of polar oligomeric materials (Table 1, entries
3-7). Indeed only LDA afforded the azirine, and bases
such as NaHMDS, LiHMDS and n-BuLi resulted in
complex mixtures.
Sch em e 1
Significantly, if the C(2) proton is absent, as in aziri-
dine 19a , the yield of (R)-(-)-16 improves from 41% to
87% for elimination of tosic acid. Similar high yields were
observed for the 2-ethyl and 2-phenyl 2H-azirines (R)-
(-)-20 and (R)-(+)-21 prepared from 19b and 19c,
respectively (Scheme 3).
We next turned our attention to increasing the leaving
group ability of the sulfinyl functionality by complexing
it with Lewis acids. These results are summarized in
(16) The in situ generation of optically active azirines from 2-silyl-
aziridines, which were not isolated, has been reported. Atkinson, R.
S.; Coogan, M. P.; Lochrie, I. S. T. J . Chem. Soc., Perkin Trans. 1 1997,
897.
(17) Portions of this work have been reported elsewhere. See
references 6 and 12.
(18) For leading references to the chemistry of sulfenic acids see:
Davis, F. A.; J enkins, L. A.; Billmers, R. L. J . Org. Chem. 1986, 51,
1033.
In a similar way, treatment of the 4-methoxyphenyl
and 4-trifluoromethylphenyl aziridines 4b and 4c with
LDA afforded 2H-azirines 5b and 5c in 55% and 33%
yield, respectively (Table 1, entries 8 and 9). However,
in the latter example methyl N-(4-trifluoromethylben-
zoyl)glycine (10) was also obtained in 30% yield. This
compound was prepared independently from 4-trifluo-
romethylbenzoyl chloride and methyl glycine hydrochlo-
ride salt in 85% yield and likely resulted from hydrolysis
of 5c on workup.20 No characterizable products were
(19) Knittel, D. Synthesis 1985, 186.
(20) Flammang, R.; Lacombe, S.; Laurent, A.; Maquestiau, A.;
Marquet, B.; Novkova S. Tetrahedron 1986, 42, 315.
(21) Davis, F. A.; Zhou, P.; Reddy, G. V. J . Org. Chem. 1994, 59,
3243.
(22) Padwa, A.; Eisenhardt, W. J . Org. Chem. 1970, 35, 2472.

Synthesis of 2H-Azirine 2-Carboxylate Esters
J . Org. Chem., Vol. 64, No. 24, 1999 8931
Ta ble 1. Syn th esis of 2H-Azir in es 2-Ca r boxyla te Ester s 5 fr om Azir id in es (2S,3S)-4/(2S,3S)-11 a n d (2S,3S)-11
entry
aziridine
conditions
products (% yield)a
1
2
3
(2S,3S)-4a (R ) Ph)
LDA/-78 °C/THF/0.2 h
LDA/-78 °C/THF/0.2 h/MeI
LDA/-78 °C/Et2O/0.5 h
LDA/rt/THF/0.5 h
(S)-5a (47), 7 (55), 8 (26)
(S)-5a (52), 9 (83)
decompositionb
decomposition
4
5
6
7
8
LiHMDS/-78 °C/THF/1 h
NaHMDS/-78 °C/THF/1 h
n-BuLi/-78 °C/THF/1 h
LDA/-78 °C/THF/0.5 h
LDA/-78 °C/THF/0.5 h
LDA/-78 °C/THF/0.5 h
LDA/-78 °C/THF/0.5 h
LDA/-78 °C/THF/0.5 h
(2S,3S)-4a (56)
decomposition
decomposition
(S)-5b (54),
(S)-5c (33), 10 (30)
decomposition
(2S,3S)-4b (R ) 4-MeOPh)
(2S,3S)-4c (R ) 4-CF3Ph)
(2S,3S)-4d (R ) 4-MeSO2Ph)
(2S,3S)-4e (R ) i-Pr)
(2S,3S)-11
9
10
11
12
decomposition
decomposition
a
b
Isolated yields. Complex mixtures.
Sch em e 2
5-12). Improved yields of azirines 5b (4-MeOPh) and 5c
(4-CF3Ph) were also observed using this new protocol
(Table 2, entries 13 and 14). No azirine was detected
using this method with aziridine 4e, in which R ) i-Pr.
Mech a n istic Con sid er a tion s. Generation of sulfenic
acid by removal of the seemingly less acidic C(3) proton
in aziridines 4 was not anticipated because R-deproto-
nation of aziridyl ketones25 and (S)-phenylaziridinecar-
bothiolates26 with C-alkylation has been described. The
available evidence suggests, however, that deprotonation
at the C(2) and C(3) positions in 4 is competitive, i.e.,
generation of aziridine enolates may be hampered by ring
strain (I-strain) and stereoelectronic effects (Scheme 4).27
That both of these protons can be lost in the deprotona-
tion step is supported by the >80% yield of methyl
p-toluene sulfoxide (9) isolated in the presence of MeI
(Table 1, entry 2). Furthermore, this hypothesis is
consistent with the fact that 4e (R ) i-Pr) gives no azirine
because the C(3) proton is not sufficiently acidic to
compete with C(2) proton removal and that 4c (R )
4-CF3Ph) gives higher azirine yields than 4a (R ) Ph),
63% vs 47% (Table 1). Although removal of the C(3)
proton gives the 2H-azirine 5, we speculate that C(2)
deprotonation results in an unstable lithio species 22 that
undergoes stereospecific ring opening to give the amino
cinnamate 23 (Scheme 4). Recall that when an N-tosyl
Sch em e 3
(23) X-ray of methyl trans-2-(p-toluenesulfonyl) amino cinnamate
(18b).
Table 2. Addition of aziridine 4a (R ) Ph) to a trimeth-
ylsilyl chloride (TMSCl)/LDA24 solution at -78 °C pro-
duced no reaction, and the aziridine was recovered, albeit
in 60% yield (Method A) (Table 2, entry 1). Cooling the
reaction mixture to -95 °C gave a 17% yield of azirine
5a , compared to the 33% yield of 5a when the reaction
was carried out at -95 °C without TMSCl (Table 2, entry
2). When 4a was first treated with TMSCl followed by
addition of LDA at -78 °C a 43% yield of 5a was obtained
(Method B) (Table 2, entry 3). However, this yield was
not an improvement over that observed in the absence
of TMSCl. Remarkably, when the reaction temperature
was lowered to -95 °C, the yield of 5a nearly doubled to
77% (Table 2, entry 4). Reducing the number of equiva-
lents of TMSCl, use of trimethylsilyl triflate, phenyldi-
methylsilyl chloride, or boron trifluoride etherate all
resulted in poorer yields of the azirine (Table 2, entries
(24) For a discussion of TMSCl as a Lewis acid see: Fleming, I.;
Barbero, A.; Walter, D. Chem. Rev. 1997, 97, 2063.
(25) Lutz, R. E.; Turner, A. B. J . Org. Chem. 1968, 33, 516.
Tarburton, P.; Chung, A.; Badger, R. C.; Cromwell, N. H. J . Heterocycl.
Chem. 1976, 13, 295. Tarburton, P.; Wall, D. K.; Cromwell, N. H. J .
Heterocycl. Chem. 1978, 15, 1281.
(26) Haner, R.; Olano, B.; Seebach, D. Helv. Chim. Acta 1987, 70,
1676.
(27) For
a discussion of the factors affecting the stability and
structure of aziridine enolates see reference 25.

8932 J . Org. Chem., Vol. 64, No. 24, 1999
Davis et al.
Ta ble 2. Syn th esis of 2H-Azir in e 2-Ca r boxyla te Ester s 5 fr om Azir id in e (2S,3S)-4 Usin g Lew is Acid s in THF
conditions
entry
(2S,3S)-aziridine
4a (R ) Ph)
additive/temp/methodc
products (% yield)a
1
2
6.0 equiv. TMSCl/-78 °C/A
6.0 equiv. TMSCl/-95 °C/A
6.0 equiv. TMSCl/-78 °C/B
6.0 equiv. TMSCl/-95 °C/B
1.5 equiv. TMSCl/-95 °C/B
2.0 equiv. TMSCl/-95 °C/B
2.5 equiv. TMSOTf/-95 °C/B
6.0 equiv. PhSi(Me)2Cl/-95 °C/B
5.0 equiv. BF3‚OEt2/-78 °C/B
5.0 equiv. BF3‚OEt2/-95 °C/B
5.0 equiv. BF3‚OEt2/-78 °C/Bd
5.0 equiv. BF3‚OEt2/-95 °C/Bd
6.0 equiv. TMSCl/-95 °C/B
6.0 equiv. TMSCl/-95 °C/B
6.0 equiv. TMSCl/-95 °C/B
5a (0) [47],b 4a (60) [0]
5a (17) [33], 4a (65) [0]
5a (43) [47], 4a (6) [0]
5a (77) [33], 4a (0) [0]
5a (67), 4a (0)
5a (71), 4a (0)
5a (9), 4a (43)
5a (56), 4a (0)
5a (38), 4a (0)
5a (38), 4a (0)
no reaction
3
4
5
6
7
8
9
10
11
12
13
14
15
no reaction
4b (R ) 4-MeOPh)
4c (R ) 4-CF3Ph)
4e (R ) i-Pr)
5b (78) [53]e
5c (68) [30]e
5d (0) [0]
a
b
Isolated yields. Yield of azirine in the absence of Lewis acid activation at the same temperature, cf. Table 1. c Method A: TMSCl or
d
BF3‚OEt2, LDA followed by addition of the aziridine 4. Method B: (i) aziridine 4, TMSCl or BF3‚OEt2, 15 min. (ii) LDA. Toluene solvent.
e Yield of azirine at -78 °C, cf. Table 1.
Sch em e 4
Sch em e 5
sulfinyl group, the reason for the impressive improve-
ment in yields at -95 °C (77%) vs -78 °C (43%) is not
readily apparent (Table 2, entries 3 and 4). Perhaps the
seemingly enhanced kinetic acidity of the C(3) proton in
4 is due to a more favorable arrangement of leaving
groups or to the fact that 24 is more stable at the lower
temperature.
group is present the amino cinnamate, i.e., 18, was
isolated, but an N-sulfinyl group apparently results in
elimination of sulfenate ion, resulting in the formation
of oligomeric materials. Consistent with this hypothesis
is the observation that when the C(2) proton is absent,
as in 14 and 19, the yields of 2H-azirines are much higher
(Scheme 3).
For steric reasons the N-sulfinyl aziridine invertomers
likely adopt structure 4 in which the bulky p-toluene-
sulfinyl group is anti to the aziridine ring substituents.28
This syn-periplanar arrangement of leaving groups re-
sults in a syn elimination of sulfenic acid to afford 2H-
azirine 5 (Scheme 4). Furthermore, it is nearly impossible
in the aziridine for the leaving groups to obtain the
dihedral angle of 180° necessary for anti-elimination. It
is probably for this reason that aziridine 12 reacts with
LDA, primarily at the sulfinyl sulfur, to give sulfinamide
13 (Scheme 2).
Treatment of N-sulfinyl aziridine 4 with TMSCl results
in formation of the silicon-oxonium species 24, which is
well precedented in the silicon-induced Pummerer-type
rearrangements29 and in the conversion of alcohols to
chlorides by TMSCl and DMSO.30 Indeed, if the aziridine-
TMSCl mixture is quenched prior to addition of LDA, an
85:15 epimeric mixture at sulfur of (SS)-4a and (RS)-4a
is formed. Although the silicon-oxonium species 24 is
undoubtedly a better leaving group than the p-toluene-
Syn th esis of 3-Ca r bom eth oxy-2-m eth yl-2-p h en yl-
2H-a zir in e. As mentioned earlier the isomeric azirine 6
was not detected in the LDA-induced elimination of
sulfenic acid from aziridine 4a (Scheme 1). However,
Swern oxidation of (2S,3R)-(+)-25,6 which lacks a C(3)
proton, at -60 °C afforded a >90% yield of (R)-(+)-3-
carbomethoxy-2-methyl-2-phenyl-2H-azirine (26) (Scheme
5) and is the first enantiomerically enriched example of
an azirine in which the carboxyl group is conjugated with
the CdN bond. Unfortunately all attempts to purify 26
chromatographically resulted in intractable mixtures. In
26 the C(2) methyl and carbomethoxy protons appear at
δ 1.83 and 4.0 ppm, and the imine carbon is observed at
δ 159.4 ppm in the 13C NMR. This absorption is upfield
from the imine carbon 2H-azirine (R)-(-)-16 (δ 163.5
ppm) and is consistent with its conjugated nature.
Furthermore, the imine and carbonyl infrared absorption
frequencies at 1715 and 1750 cm-1, respectively, are
nearly identical to those reported for the related 3-car-
boethoxy-2-(2,6-dichlorophenyl)-2H-azirine.31 The diffi-
culty in purifying this azirine may be as result of the
enhanced electrophilicity of the CdN bond, due to its
conjugation with the carbomethoxy group, making it
more susceptible to hydrolysis.
Syn th esis of (R)-(-) a n d (S)-(+)-Dysid a r izin e.
Employing our 2H-azirine synthesis, the marine cytoxic
antibiotic (R)-(-)-dysidazirine (2) was prepared as out-
lined in Scheme 6. Aziridine (2R,3R)-(-)-28 was synthe-
sized in 86% yield via the in situ one-pot aza-Darzens
reaction of the lithium enolate of methyl bromoacetate
with (R)-(-)-27.28 With LDA/MeI/-78 °C a 42% yield of
(28) Davis, F. A. Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang,
Y. J . Org Chem. 1999, 94, 7559.
(29) Kita, Y.; Shibata, N. Synlett 1996, 289. Kita, Y.; Shibata, N.;
Fukui, S.; Bando, M.; Fujita, S. J . Chem. Soc., Perkin Trans 1 1997,
1763.
(30) Snyder, D. C. J . Org. Chem. 1995, 60, 2638.
(31) Bhullar, P.; Gilchrist, T. L.; Maddocks, P. Synthesis 1997, 271.

Synthesis of 2H-Azirine 2-Carboxylate Esters
J . Org. Chem., Vol. 64, No. 24, 1999 8933
Syn t h esis of (S)-(+)-2-Ca r b om et h oxy-3-p h en yl-2H -
a zir in e (5a ). Typ ica l P r oced u r e. 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
0.14 g (0.45 mmol) of (2S,3S)-(+)-N-(p-toluenesulfinyl)-2-
carbomethoxy-3-phenylaziridine (4a )21,28 in THF (10 mL). The
solution was cooled to -78 °C, and 0.56 mL (0.56 mmol, 1.0 M
in THF) of LDA was added slowly. The reaction was stirred
at -78 °C for 15 min, quenched with H2O (2 mL), and diluted
with EtOAc (10 mL). The organic phase was separated, and
the aqueous layer was washed with EtOAc (2 × 20 mL). The
combined organic extracts were washed with brine (10 mL),
dried (MgSO4), and concentrated. Purification by flash chro-
matography (EtOAc/hexane, 10:90) gave 0.04 g (47%) of (S)-
(+)-5a , 0.02 g (26%) of p-TolylSO2STolyl-p (8), 0.03 g (55%) of
p-TolylSSTolyl-p (7), and 0.04 g of polar material from the
baseline as a yellow oil. When 0.14 g (1.0 mmol) of io-
domethane was added after the addition of LDA, 5a was
isolated in 52% yield and methyl p-toluenesulfoxide (9) was
obtained in 83% yield following chromatography. (S)-(+)-2-
Sch em e 6
Ca r bom eth oxy-3-p h en yl-2H-a zir in e (5a ): yellow wax; [R]20
D
1
(R)-(-)-2 was obtained following flash chromatography
and was improved to 62% using the LDA/TMSCl/-95 °C
protocol. (R)-(-)-Dysidazirine (2) had spectral properties
identical with literature values, confirming the structure
and absolute configuration of (R)-(-)-2 established by
Molinski and Ireland on the basis of chemical correlation
and circular dichroism studies.3 However, our synthetic
sample, determined to be >95% ee by chiral shift reagent
289.3 (c 1.8, CHCl3); H NMR (CDCl3) δ 7.89 (m, 2H), 7.69-
7.54 (m, 3H), 3.75 (s, 3H), 2.87 (s, 1H); 13C NMR (CDCl3) δ
172.1, 158.5, 133.9, 130.5, 129.3, 122.1, 52.3, 29.4; (S)-(+)-5a
has other physical and spectroscopic properties identical to
literature values.19,36 The optical purity of (+)-5a was deter-
mined using the chiral shift reagent Eu(hfc)3 and monitoring
the C-2 proton. In the racemic material this proton was split
by >25 Hz using Eu(hfc)3.
(S)-(+)-2-Ca r bom eth oxy-3-(4-m eth oxyp h en yl)-2H-a zir -
in e (5b). Purification by flash chromatography (EtOAc/hex-
anes, 1:4) gave 0.03 g (54%) of (S)-(+)-5b as an oil: [R]20D 295.2
(c 0.90, CHCl3); IR (neat) cm-1 2954, 1772, 1734, 1507, 1260;
1H NMR (CDCl3) δ 7.84 (d, 2H, J ) 8.7 Hz), 7.08 (d, 2H, J )
8.7 Hz), 3.91 (s, 3H), 3.75 (s, 3H), 2.81 (s, 1H); 13C NMR (CDCl3)
δ 172.4, 164.1, 157.1, 132.5, 114.9, 114.5, 55.6, 52.2, 29.2;
HRMS calcd for C11H12NO3 (m + H) 206.0817, found 206.0813.
Anal. Calcd for C11H11NO3: C, 64.39; H, 5.37; N, 6.83. Found:
C, 64.80; H, 5.32; N, 7.01.
studies with Eu(hfc)3, had a specific rotation of [R]20
D
-186.4, whereas the naturally occurring material had a
rotation of [R]20 -165, suggesting that the latter is less
D
than 89% optically pure. In a similar manner the
epimeric dysidazirine, (S)-(+)-2, was prepared in 46%
yield using the LDA method.
In summary, the base-induced elimination of p-tolu-
enesulfenic acid from readily available N-sulfinylaziri-
dine 2-carboxylate esters affords stereodefined enan-
tiopure 2H-azirine 2-carboxylate esters in good yield. The
optimum conditions for the elimination were at -95 °C
in the presence of TMSCl.
P r ep a r a tion of (S)-(+)-2-Ca r bom eth oxy-3-(4-tr iflu o-
r om et h ylp h en yl)-2H -a zir in e (5c) a n d Met h yl N-(4-t r i-
flu or om eth ylben zoyl)glycin e (10). Purification by flash
chromatography (EtOAc/hexanes, 15:85) gave 0.015 g (33%)
of (S)-(+)-5c as an oil and 0.015 g (30%) of 10 as a yellow solid.
(S)-(+)-2-Ca r bom eth oxy-3-(4-tr iflu or om eth ylp h en yl)-2H-
Exp er im en ta l Section
a zir in e (5c): oil; [R]20 70.3 (c 0.40, CHCl3); IR (neat) cm-1
D
2958, 1775, 1737, 1325, 1132; 1H NMR (CDCl3) δ 8.04 (d, 2H,
J ) 7.9 Hz), 7.86 (d, 2H, J ) 8.6 Hz), 3.76 (s, 3H), 2.94 (s,
1H); 13C NMR (CDCl3) δ 171.5, 158.5, 135.2 (q, J ) 129.5 Hz,
CF3), 130.7, 126.4, 126.4, 125.6, 52.5, 29.9; HRMS calcd for
Gen er a l P r oced u r es. 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 microns) pur-
chased 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.
C
11H9F3NO2 (m + H) 244.0585, found 244.0589. Anal. Calcd
for C11H8F3NO2: C, 54.32; H, 3.29. Found: C, 54.00; H, 3.44.
Meth yl N-(4-tr iflu or om eth ylben zoyl)glycin e (10): mp 60-
1
61 °C; IR (KBr) cm-1 3273, 1747, 1648, 1573, 1337; H NMR
(CDCl3) δ 7.94 (d, 2H, J ) 8.1 Hz), 7.73 (d, 2H, J ) 8.1 Hz),
6.80 (bs, 1H), 4.28 (d, 2H, J ) 5.1 Hz), 3.84 (s, 3H); 13C NMR
(CDCl3) δ 170.3, 166.1, 136.9, 133.5 (q, J ) 129.5 Hz, CF3),
127.6, 125.7, 124.7, 122.5, 52.6, 41.8; HRMS calcd for C11H11F3-
NO3 (m + H) 262.0691, found 262.0695. Anal. Calcd for
Unless stated otherwise, all reagents were purchased from
commercial sources and used without additional purification.
Enantiomerically pure N-sulfinylaziridines 2-carboxylates
(2S,3S)-4,21 (2S,3S)-11,28 (2S,3R)-12,21 and (2R,3S)-1421 were
prepared using the aza-Darzens reaction of R-bromoenolates
with sulfinimines (N-sulfinyl imines) as previously described.28
Sulfinimines were prepared by the one-step32 or two-step33
procedures as previously reported.34 N-Tosyl aziridines 17a ,6
17b,27 19a ,6,35 and 19b,c28 were prepared by oxidation of the
corresponding N-sulfinylaziridines with m-CPBA.28
C
11H10F3NO3: C, 50.58; H, 3.83; N 5.36. Found: C, 50.25; H,
3.80; N 5.11.
Syn th esis of Meth yl N-(4-tr iflu or om eth ylben zoyl)gly-
cin e (10) fr om th e Hyd r och lor id e Sa lt of Meth yl Glycin e.
In a 15 mL oven-dried two-necked round-bottomed flask fitted
with a magnetic stirring bar, a rubber septum, and an argon-
filled balloon was placed 0.06 g (0.47 mmol) of the hydrochlo-
ride salt of methyl glycine (Aldrich) in THF (5 mL). The
solution was cooled to 0 °C, and 0.20 mL (1.41 mmol) of Et3N
was slowly added. The reaction mixture was stirred at 0 °C
for 10 min, and 0.14 mL (0.94 mmol) of 4-trifluoromethylben-
zoyl chloride (Aldrich) was added. The reaction mixture was
stirred at 0 °C for 1 h, warmed to room temperature for 1 h,
(32) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M.; Reddy. G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Thimma Reddy, R.; Zhou, P.;
Carroll, P. J . J . Org. Chem. 1997, 62, 2555.
(33) Davis. F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J . Org. Chem. 1999, 64, 1403.
(34) For a review on the chemistry of sulfinimines see: Davis, F.
A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13. For a leading
reference to the applications of enantiopure sulfinimines in asymmetric
synthesis, see reference 33.
(35) Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron Lett. 1996, 37,
5473.
(36) Hassner, A.; Fowler, F. W. J . Am. Chem. Soc. 1968, 90, 2869.

8934 J . Org. Chem., Vol. 64, No. 24, 1999
Davis et al.
and quenched with saturated aqueous NH4Cl (2 mL). The
reaction mixture was diluted with EtOAc (10 mL), the organic
phase was separated, and the aqueous layer was washed with
EtOAc. The combined organic phases were washed with brine,
dried (Na2SO4), and concentrated to give 0.11 g (90%) of 10 as
a yellow solid, mp 60-61 °C.
(c 0.43, CHCl3); IR (neat) cm-1 2930, 1760, 1726, 1273, 1128;
1H NMR (CDCl3) δ 7.85 (d, 2H, J ) 7.8), 7.68-7.51 (m, 3H),
3.68 (s, 3H), 1.64 (s, 3H); 13C NMR (CDCl3) δ 173.5, 163.5,
133.6, 130.1, 129.6, 129.3, 122.4, 52.4, 35.4, 17.7; HRMS calcd
for C11H12NO2 (m + H) 190.0868, found 190.0869. Anal. Calcd
for C11H11NO2: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.71;
H, 5.65; N, 7.54.
Tr eatm en t of (2R,3S)-N-(p-Tolu en esu lfin yl)-2-car bom e-
th oxy-2-m eth yl-3-p h en yla zir id in e (14) w ith LDA. Treat-
ment of aziridine (2R,3S)-14 under the standard conditions
followed by flash chromatography (EtOAc/n-pentane, 30:70)
gave 0.12 g of an inseparable mixture of (R)-(-)-16, (2R,3S)-
2-carbomethoxy-2-methyl-3-phenylaziridine (15),28 and 0.07 g
(46%) of N,N-bis(isopropyl)-p-toluenesulfinamide (13).37 The
(R)-(-)-2-Ca r b om et h oxy-2-et h yl-3-p h en yl-2H -a zir in e
(20). The compound was prepared from (2R,3S)-19b; purifica-
tion by flash chromatography (EtOAc/hexanes, 10:90) gave
0.04 g (81%) of (R)-(-)-20: oil; [R]20 -87.6 (c 0.8, CHCl3); IR
D
(neat) cm-1 2930, 1760, 1726, 1273, 1128; H NMR (CDCl3) δ
1
7.91-7.84 (m, 2H), 7.67-7.54 (m, 3H), 3.68 (s, 3H), 2.23-2.05
(m, 2H), 0.87 (t, 3H, J ) 7.5 Hz); 13C NMR (CDCl3) δ 173.2,
163.2, 133.6, 130.1, 129.6, 129.3, 123.1, 52.4, 40.6, 23.6, 10.5;
HRMS calcd for C12H14NO2 (m + H) 204.1025, found 204.1025.
Anal. Calcd for C12H13NO2: C, 70.94; H, 6.40; N, 6.90. Found:
C, 71.22; H, 6.75; N, 6.52.
1
yields of 16 and 1H-aziridine 15 were estimated by H NMR
integration (1:1.39) to be 41% and 57%, respectively.
P r ep a r a tion of Meth yl tr a n s-2-(p-Tolu en esu lfon yl)-
a m in o Cin n a m a te (18a ). In a 25 mL oven-dried two-necked
round-bottomed flask fitted with an argon-filled balloon, a
rubber septum and a magnetic stirring bar was placed 0.19 g
(0.58 mmol) of (2S,3S)-(+)-17a in THF (10 mL). The reaction
flask was cooled to -78 °C, and 0.62 mL of LDA (0.62 mmol,
1.0 M in THF) was slowly added. The reaction mixture was
stirred at -78 °C for 10 min, quenched by the addition of H2O
(2 mL), and diluted with CH2Cl2. The organic phase was
separated, washed with brine, dried (MgSO4), and concen-
trated. Purification by flash chromatography (EtOAc/n-pen-
tane, 20:80) afforded 0.12 g (61%) of 18a as a yellow solid: mp
138-142 °C; IR (KBr) cm-1 3246, 3070, 2952, 2851, 1716, 1439,
1338, 1252, 1165, 1091; 1H NMR (CDCl3) δ 7.87-7.84 (m, 2H),
7.66 (d, 2H, J ) 8.3 Hz), 7.53 (s, 1H), 7.38-7.33 (m, 3H), 7.23
(d, 2H, J ) 8.3 Hz), 6.25 (bs, 1H), 3.52 (s, 3H), 2.39 (s, 3H);
13C NMR (CDCl3) δ 165.4, 143.9, 137.7, 136.3, 132.7, 131.0,
130.3, 129.3, 128.4, 127.8, 122.7, 52.5, 21.5; HRMS calcd for
(R)-(+)-2-Ca r b om et h oxy-2-p h en yl-3-p h en yl-2H -a zir -
in e (21). The compound was prepared from (2R,3S)-(+)-19c;28
purification by flash chromatography (EtOAc/hexanes, 10:90)
gave 0.05 g (61%) of (R)-(+)-21; mp 70-71 °C; [R]20 83.5 (c
D
0.64, CHCl3); IR (KBr) cm-1 2945, 1759, 1725, 1450; 1H NMR
(CDCl3) δ 7.93 (d, 2H, J ) 8.2 Hz), 7.63-7.48 (m, 5H), 7.35-
7.27 (m, 3H), 3.74 (s, 3H); 13C NMR (CDCl3) δ 171.6, 160.7,
136.2, 133.9, 130.4, 129.4, 128.2, 128.1, 127.7, 121.9, 52.7, 41.0;
HRMS calcd for C16H14NO2 (m + H) 252.1025, found 252.1026.
Anal. Calcd for C16H13NO2: C, 76.19; H, 5.18; N, 5.56. Found:
C, 75.67; H, 5.37; N, 5.27.
P r ep a r a tion of (S)-(+)-2-Ca r bom eth oxy-3-p h en yl-2H-
a zir in e (5a ) in th e P r esen ce of TMSCl. Typ ica l P r oce-
d u r e (Meth od A). 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 0.12 mL (0.94
mmol) of TMSCl in THF (6 mL). The solution was cooled to
-95 °C (MeOH/liquid N2), and 0.35 mL (0.53 mmol, 1.5 M in
cyclohexane) of LDA was added slowly. The reaction was
stirred at -95 °C for 10 min, and a solution of 0.09 g (0.28
mmol) of (2S,3S)-(+)-4a in THF (8 mL) was added via cannula.
The reaction was stirred at -95 °C for another 20 min,
quenched with saturated aqueous NH4Cl (5 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 phases were washed with brine (10 mL),
dried (Na2SO4), and concentrated. The crude reaction mixture
was purified by flash chromatography (EtOAc/hexanes, 10: 90)
to give 0.01 g (17%) of (S)-(+)-5a and 0.06 g (65%) of aziridine
4a .
Im p r oved P r ep a r a tion of (S)-(+)-2-Ca r bom eth oxy-3-
p h en yl-2H-a zir in e (5a ) in th e P r esen ce of TMSCl. Typ i-
ca l P r oced u r e (Meth od B). 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
0.15 g (0.46 mmol) of aziridine (2S,3S)-4a in THF (12 mL).
The solution was cooled to -95 °C, and 0.35 mL (2.76 mmol)
of TMSCl was added. The reaction mixture was stirred at -95
°C for 15 min, and 0.60 mL (0.90 mmol, 1.5 M in cyclohexane)
of LDA was slowly added. The solution was stirred at -95 °C
for 15 min, quenched with saturated aqueous NH4Cl (5 mL),
and diluted with EtOAc (10 mL). The organic phase was
separated, and the aqueous phase was washed with EtOAc.
The combined organic phases were washed with brine, dried
(MgSO4), and concentrated. Purification by flash chromatog-
raphy (EtOAc/hexanes, 1: 9) gave 0.06 g (76%) of (S)-(+)-5a
as a yellow wax identical to that prepared above.
C
17H18NSO4 (m + H) 332.0957, found 332.0954. Anal. Calcd
for C17H17NSO4: C, 61.63; H, 5.14. Found: C, 61.53; H, 5.35.
Hyd r ogen a tion of 18a to N-Tosyl P h en yla la n in e. In a
25 mL two-necked round-bottomed flask equipped with a
hydrogen filled balloon, a glass stopper, and a magnetic
stirring bar was placed 0.10 g (0.30 mmol) of 18a in methanol
(10 mL). Palladium (0.03 g, 10% on activated carbon) was
added, and the reaction mixture was stirred at room temper-
ature for 1.5 h, diluted with CH2Cl2 (10 mL), and filtered
through a short silica gel column. Concentration of the filtrate
afforded 0.10 g (99%) of N-tosyl phenylalanine as a white solid,
mp 93 °C [lit.21 mp 92-93 °C], which had spectrometric
properties identical with an authentic sample.21
Meth yl tr a n s-2-(p-Tolu en esu lfon yl)am in o-3-m eth yl Cin -
n a m a te (18b). Purification by flash chromatography (EtOAc/
hexanes, 50:50) gave 0.05 g (79%) of 18b: mp 159-160 °C; IR
1
(KBr) cm-1 3261, 3051, 1721, 1405, 1172; H NMR (CDCl3) δ
7.76 (d, 2H, J ) 8.1 Hz), 7.42-7.22 (m, 5H), 7.12-7.04 (m,
2H), 6.20 (bs, 1H), 3.10 (s, 3H), 2.41 (s, 3H), 2.29 (s, 3H); 13C
NMR (CDCl3) δ 164.6, 153.5, 143.9, 141.1, 136.2, 129.5, 128.1,
127.8, 127.6, 126.4, 121.4, 104.3, 51.5, 24.1, 21.5; HRMS calcd
for C18H19NSO4 (m) 345.1035, found 345.1033. Anal. Calcd for
C
18H19NSO4: C, 62.61; H, 5.51; N, 4.06. Found: C, 62.63; H,
5.55; N, 3.83.
P r ep a r a tion of (R)-(-)-2-Ca r bom eth oxy-2-m eth yl-3-
p h en yl-2H-a zir in e (16) fr om (2R,3S)-N-(p-Tolu en esu lfo-
n yl)-2-ca r bom eth oxy-2-m eth yl-3-p h en yla zir id in e (19a ).
Typ ica l P r oced u r e. In a 25 mL oven-dried two-necked round-
bottomed flask fitted with a magnetic stirring bar, rubber
septum, and an argon-filled balloon was placed 0.09 g (0.27
mmol) of (2R,3S)-(+)-19a in THF (9 mL). The solution was
cooled to -78 °C, and 0.37 mL (0.37 mmol, 1.0 M in THF) of
LDA was added slowly. The reaction was stirred at -78 °C
for 20 min, quenched with H2O (3 mL), and diluted with EtOAc
(10 mL). The organic phase was separated, and the aqueous
phase was washed with EtOAc. The combined organic phases
were washed with brine, dried (MgSO4), and concentrated.
Purification by flash chromatography (EtOAc/hexanes, 30:70)
(R)-(+)-3-Ca r b om et h oxy-2-m et h yl-2-p h en yl-2H -a zir -
in e (26). 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 0.05 mL (0.56 mmol) of
oxalyl chloride in CH2Cl2 (2 mL). The solution was cooled to
-60 °C, and 0.1 mL (1.4 mmol) of DMSO was added. After 10
min, 0.04 g (0.21 mmol) of aziridine (2S,3R)-(+)-256 in CH2-
Cl2 (1.0 mL) was added dropwise at -60 °C followed by 0.3
mL (2.15 mmol) of triethylamine. The reaction mixture was
warmed to room temperature. After 3 h the solution was
gave 0.04 g (87%) of (R)-(-)-16 as an oily solid: [R]20 -163.2
D
(37) Solladie, G.; Zimmermann, R. J . Org. Chem. 1985, 50, 4062.

Synthesis of 2H-Azirine 2-Carboxylate Esters
J . Org. Chem., Vol. 64, No. 24, 1999 8935
concentrated to give a residue to which diethyl ether (25 mL)
was added. The precipitated salts were filtered, and the filtrate
was washed with brine (2 × 10 mL), dried (MgSO4), and
concentrated to give 0.036 g (90%) of crude (R)-(+)-26 in 95%
purity as indicated by 1H NMR. Attempts to purify 26 by flash
chromatography (silica gel, neutral and basic alumna oxide)
tion by flash chromatography (EtOAc/n-Pentane, 7: 93) gave
0.10 g (86%) of (2R,3R)-(-)-28 as a low melting solid: mp 40-
42 °C; [R]20D -86.9 (c 1.6, CHCl3); IR (CHCl3) cm-1 2924, 2852,
1751, 1735, 1664, 1596, 1490, 1437, 1369, 1281, 1200, 1175
1
1098, 969, 809; H NMR (CDCl3) δ 7.61 (d, 2H, J ) 8.3 Hz),
7.30 (d, 2H, J ) 8.2 Hz), 6.02 (dt, 1H, J ) 15.5, 6.6 Hz), 5.51-
resulted in decomposition. Compound (R)-(+)-26: [R]20 303
5.42 (m, 1H), 3.61 (s, 3H), 3.29 (m, 2H), 2.41 (s, 3H), 2.06 (m,
D
(c 0.66, CHCl3); IR (neat) cm-1 2960, 2925, 1750, 1715, 1260,
1027; 1H NMR (CDCl3) δ 7.36-7.17 (m, 5H), 4.00 (s, 3H), 1.83
(s, 3H); 13C NMR (CDCl3) δ 169.1, 159.4, 141.6, 128.3, 127.4,
126.2, 53.5, 43.1, 21.4.
2H), 1.36 (m, 2H), 1.26 (bs, 20 H), 0.88 (t, 3H, J ) 6.4 Hz); 13
C
NMR (CDCl3) δ 167.0, 142.1, 139.4, 129.6, 124,8, 121.8, 52.1,
42.3, 32.4, 31.8, 29.6, 29.5, 29.4, 29.3, 29.0, 28.7, 22.6, 21.4,
14.2. Anal. Calcd for C26H41NO3S: C, 69.76; H, 9.23. Found:
C, 69.63; H, 9.29. (2S,3S)-(+)-N-(p-Tolu en esu lfin yl)-2-ca r -
bom eth oxy-3-(1-p en ta d ecen yl)a zir id in e (28): mp 40-42
(R)-(-)-N-(E-2-Hexa d ecen ylid en e)-p-tolu en esu lfin im -
id e (27). In
a 50 mL two-necked round-bottomed flask
equipped with a magnetic stirring bar, a rubber septum, and
an argon-filled balloon was placed 0.30 g (1.0 mmol) of
(1S,2R,5S)-(+)-menthyl-(R)-p-toluenesulfinate in THF (10 mL).
The solution was cooled to -78 °C, and 2.0 mL (2.0 mmol, 1.0
M in THF) of LiHMDS was added. The mixture was warmed
to room temperature, stirred for 5 h, and cooled to 0 °C. Cesium
fluoride (0.30 g, 2.0 mmol) was added, and the reaction was
stirred for 30 min prior to addition of 0.19 g (0.80 mmol) of
(2E)-hexadecenal.38 After an additional 2 h, the reaction
mixture was quenched with H2O (3 mL). The organic phase
was separated, and the aqueous phase was washed with
EtOAc (2 × 40 mL). The combined organic phases were washed
with brine, dried (MgSO4), and concentrated to give the crude
sulfinimine, which was purified by column chromatography
(EtOAc/hexanes, 10:90) to afford 0.24 g (79%) of (R)-(-)-27 as
°C; [R]20 86.3 (c 1.8, CHCl3).
D
(R)-(-)-2-Ca r b om et h oxy-3-(1-p en t a d ecen yl)-2H -a zir -
in e [Dysid a zir in e] (2). In a 50 mL two-necked round-
bottomed flask equipped with a magnetic stirring bar, a rubber
septum, and an argon-filled balloon was placed 0.45 g (1.0
mmol) of (2R,3R)-(-)-28 in THF (7 mL), which was cooled to
-78 °C. Freshly prepared lithium diisopropylamide39 (1.3 mL,
1.3 mmol, 1.0 M in THF) was added via syringe to the reaction
mixture, and stirring was continued for 15 min, at which time
0.28 g (2.0 mmol) of iodomethane was added. After stirring
for 20 min the reaction mixture was quenched at -78 °C with
H2O (5 mL). The organic phase was separated, and the
aqueous phase was washed with ether. The combined ether
extracts were washed with brine, dried (MgSO4), and concen-
trated to give an oil that was purified by column chromatog-
raphy (EtOAc/hexanes, 7:93) to afford 0.13 g (85%) of methyl
p-tolyl sulfoxide (9) and 0.13 g (42%) of azirine (R)-(-)-2 as a
low melting solid: [R]20 -186.3 (c 2.53, MeOH) [lit.3 [R]20
a low melting solid: mp 38-40 °C; [R]20 -393.3 (c 1.87,
D
CHCl3); IR (neat) cm-1 2958, 2915, 2848, 1639, 1579, 1094,
809; 1H NMR (CDCl3) δ 8.33 (d, 1H, J ) 9.1 Hz), 7.57 (d, 2H,
J ) 8.0 Hz), 7.30 (d, 2H, J ) 8.1 Hz), 6.58 (dt, 1H, J ) 15.5,
6.7 Hz), 6.40 (m, 1H), 2.40 (s, 3H), 2.25 (q, 2H, J ) 6.8, 13.7
D
D
1
-165 (c 0.5, MeOH)]; the IR and H NMR data were identical
with literature values;3 13C NMR (CDCl3) δ 172.2, 156.6, 155.8,
112.9, 52.2, 33.2, 31.9, 29.6, 29.5, 29.3, 29.1, 28.3, 27.8, 22.7,
14.1. Anal. Calcd for C19H33NO2: C, 74.22; H, 10.82; Found:
C, 73.92; H, 10.99. (S)-(+)-2-Ca r bom eth oxy-3-(1-p en ta d e-
cen yl)-2H-a zir in e [Dysid a zir in e] (2): Low melting solid;
[R]20 183.7 (c 2.23, MeOH), 191.5 (c 1.77, CHCl3) [(lit.4 [R]20
Hz), 1.46 (m, 2H), 1.25 (bs, 20 H), 0.88 (t, 3H, J ) 6.3 Hz); 13
C
NMR (CDCl3) δ 162.0, 152.5, 142.0, 141.6, 129.8, 128.5, 124.6,
33.0, 31.9, 29.6, 29.5, 29.3, 29.1, 28.1, 22.6, 21.4, 14.1. Anal.
Calcd for C23H37NOS: C, 73.55; H, 9.93. Found: C, 73.47; H,
10.02. (S)-(+)-N-(E-2-Hexa d ecen ylid en e)-p-tolu en esu lfin -
D
D
im id e (27): low melting solid; mp 38-40 °C; [R]20 394.1 (c
D
47.2 (c 1.08, CHCl3)].
2.23, CHCl3).
(2R,3R)-(-)-N-(p -Tolu en esu lfin yl)-2-ca r b om et h oxy-3-
(1-p en ta d ecen yl)a zir id in e (28). In a 50 mL oven-dried two-
necked round-bottomed flask equipped with a magnetic stir-
ring bar, a rubber septum, and an argon-filled balloon was
placed 0.10 g (0.27 mmol) of sulfinimine (R)-(-)-27 in THF
(18 mL). The solution was cooled to -78 °C, and 0.10 mL (1.1
mmol) of methyl bromoacetate was added. After 2 min, 0.49
mL (0.49 mmol, 1.0 M in THF) of LiHMDS was added, and
the solution was stirred at -78 °C for 1 h, warmed to -45 °C
for 1.5 h, and quenched with saturated aqueous NH4Cl (5 mL).
The organic phase was separated, and the aqueous phase was
washed with EtOAc. The combined organic phases were
washed with brine, dried (NaSO4), and concentrated. Purifica-
Ack n ow led gm en t. We thank Drs. David Dalton
and William McCoull for helpful discussions. This work
was supported by grants from the National Institutes
of Health (GM 51982) and the National Science Foun-
dation.
Su p p or tin g In for m a tion Ava ila ble: X-ray data for 18b
and spectra for (2R)-(+)-26. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O991389F
(39) Ireland, R. E.; Mueller, R. H.; Willard, A. J . J . Am. Chem. Soc.
1976, 98, 2868.
(38) Cavallo, A. S.; Koessler, J . L. J . Org. Chem. 1994, 59, 3240.