Palladium(0)-Catalyzed Isomerization Reactions of Aziridines Bearing an α,β-Unsaturated Ester Group: A Thermodynamic Preference for Chiral Alkyl (2E)-4,5-cis-4,5-Epimino-N-(alkyl- or arylsvdfonyl) 2-Enoates over the Other Three Stereoisomers

Article abstract of DOI:10.1021/jo962094u

Palladium(0)-catalyzed reactions of five sets of four stereoisomeric 4,5-epimino-N-(methanesulfonyl) or -N-(arylsulfonyl) 2-enoates reveal that 4,5-cis-(2E)-isomers are thermodynamically more stable than other isomers, in accord with calculations. A highly stereoselective synthesis of (E)-alkene dipeptide isosteres having the desired stereochemistries from unwanted stereoisomeric 4,5-epimino-N-(arylsulfonyl) 2-enoates is also presented.

Full text of DOI:10.1021/jo962094u

2982
J . Org. Chem. 1997, 62, 2982-2991
P a lla d iu m (0)-Ca ta lyzed Isom er iza tion Rea ction s of Azir id in es
Bea r in g a n r,â-Un sa tu r a ted Ester Gr ou p : A Th er m od yn a m ic
P r efer en ce for Ch ir a l Alk yl (2E)-4,5-cis-4,5-Ep im in o-N-(a lk yl- or
a r ylsu lfon yl) 2-En oa tes over th e Oth er Th r ee Ster eoisom er s
Toshiro Ibuka,* Norio Mimura, Hiroaki Ohno, Kazuo Nakai, Masako Akaji,
Hiromu Habashita, Hirokazu Tamamura, Yoshihisa Miwa, Tooru Taga, and Nobutaka Fujii
Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo, Kyoto 606, J apan
Yoshinori Yamamoto
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980, J apan
Received November 8, 1996X
Palladium(0)-catalyzed reactions of five sets of four stereoisomeric 4,5-epimino-N-(methanesulfonyl)
or -N-(arylsulfonyl) 2-enoates reveal that 4,5-cis-(2E)-isomers are thermodynamically more stable
than other isomers, in accord with calculations. A highly stereoselective synthesis of (E)-alkene
dipeptide isosteres having the desired stereochemistries from unwanted stereoisomeric 4,5-epimino-
N-(arylsulfonyl) 2-enoates is also presented.
Backbone modification of amide bonds in bioactive
been shown that peptide analogues involving (Z)-alkene
dipeptide isosteres are considerably less bioactive than
peptide mimics involving an (E)-alkene isostere.11 In
addition, it has been reported that the stereochemis
try at the R-carbon center in dipeptide isosteres is one
of the essential factors for enzyme inhibition.4a While
many different synthetic routes to alkene dipeptide
isosteres have been developed,12,13 recently we14 and
Wipf15 have described convenient and highly stereose-
lective synthesis of (E)-alkene dipeptide isosteres 5 and
6 via an organocopper-mediated SN2′ reaction of N-
activated 4,5-epimino 2-enoates (1 and 2) and (3 and 4),
respectively (Scheme 1).
peptides has attracted much attention over the years.1
Among the known isosteric units, the (E)-double bond has
been a topic of continuing interest in the synthetic,2
theoretical,3 and biological4 fields because the (E)-
CHdCH double bond closely resembles the three-
dimensional structure of the parent amide bond in
peptides.5 Recently, we6 and others7-10 have reported
that small peptides containing (E)-alkene isosteres ex-
hibit various types of biological activities. It has also
X Abstract published in Advance ACS Abstracts, April 15, 1997.
(1) According to IUPAC rules, the structure inside the bracket
following ψ is the unit substituting for the amide bond. For nomen-
clature, see: IUPAC-IUB J oint Commission on Biochemical Nomen-
clature Eur. J . Biochem. 1984, 138, 9. Spatola, A. In Chemistry and
Biochemistry of Amino Acids, Peptides and Proteins; Weinstein, B.,
Ed.; Marcel Dekker: New York, 1983; pp 267-358.
(2) (a) For a review of syntheses of (E)-alkene dipeptide isosteres
up to May 1992, see: Ibuka, T. J . Synth. Org. Chem. J pn. 1992, 50,
953. (b) Bol, K. M.; Liskamp, R. M. J . Tetrahedron 1992, 31, 6425. (c)
Li, Y.-L.; Luthman, K.; Hacksell, U. Tetrahedron Lett. 1992, 33, 4487.
(d) Ibuka, T.; Yamamoto, Y. Synlett 1992, 760. (e) Ibuka, T.; Taga, T.;
Habashita, H.; Nakai, K.; Tamamura, H.; Fujii, N.; Chounan, Y.;
Nemoto, H.; Yamamoto, Y. J . Org. Chem. 1993, 58, 1207. (f) Bohnstedt,
A. C.; Prasad, J . V. N. V.; Rich, D. H. Tetrahedron Lett. 1993, 34, 5217.
(g) Yong, Y. F.; Lipton, M. A. Bioorg. Med. Chem. Lett. 1993, 3, 2879.
(h) Fujii, N.; Nakai, K.; Habashita, H.; Yoshizawa, H.; Ibuka, T.;
Garrido, F.; Mann, A.; Chounan, Y.; Yamamoto, Y. Tetrahedron Lett.
1993, 34, 4227. (i) Ibuka, T.; Nakai, K.; Habashita, H.; Bessho, K.;
Fujii, N.; Chounan, Y.; Yamamoto, Y. Tetrahedron 1993, 49, 9479.
(3) Precigoux, G.; Ouvrard, E.; Geoffre, S. In Peptides, Structure and
Fuctions; Deber, C. M., Hruby, V. J ., Kopple, K. D., Eds.; Pierce:
Illinois, 1985; p 763. Gardner, R. R.; Liang, G.-B.; Gellman, S. H. J .
Am. Chem. Soc. 1995, 117, 3280.
(4) (a) Cox, M. T.; Gormley, J . J .; Hayward, C. F.; Petter, N. N. J .
Chem. Soc., Chem. Commun. 1980, 800. (b) Shue, Y.-K.; Tufano, M.
D.; Nadzan, A. M. Tetrahedron Lett. 1988, 29, 4041. (c) Kaltenbronn,
J . S.; Hudspeth, J . P.; Lunney, E. A.; Michniewicz, B. M.; Nicolaides,
E. D.; Repine, J . T.; Roark, W. H.; Steir, M. A.; Tinney, F. J .; Woo, P.
K. W.; Essenburg, A. D. J . Med. Chem. 1990, 33, 838. (d) Scarso, A.;
Degelaen, J .; Viville, R.; De Cock, E.; van Marsenille, M.; van der
Auwera, L.; Tourwe, D.; van Binst, G. Bull. Soc. Chim. Belg. 1991,
100, 381. (e) Touwe, D.; De Cock, E.; van Marsenille, M.; van der
Auwera, L.; van Binst, G.; Viville, R.; Degelaen, J .; Scarso, A. In
Peptides 1988; J ung, G., Bayer, E., Eds.; Walter de Gruyter: Berlin,
New York, 1989; p 562. (f) Tourwe, D.; Couder, J .; Ceusters, M.; Meert,
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I.; Leysen, J . E.; van Binst, B. Int. J . Peptide Protein Res. 1992, 39,
131.
In our continuing synthetic and biological studies, we
required a practical procedure for the synthesis of isos-
teres of type 5 because small peptides containing (E)-
alkene isosteres of type 6 showed undesired and/or low
(7) Wai, J . S.; Smith, D. L.; Gibbs, J . B.; Mosser, S. D.; Oliff, A. I.;
Pompliano, D. L.; Rands, E.; Kohl, N. E. Bioorg. Med. Chem. 1994, 2,
939.
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(11) Kaltenbronn, J . S.; Hudspeth, J . P.; Lunney, E. A.; Michniewicz,
B. M.; Nicolaides, E. D.; Repine, J . T.; Roark, W. H.; Stier, M. A.;
Tinney, F. J .; Woo, P. K. W.; Essenburg, A. D. J . Med. Chem. 1990,
33, 838.
(12) (a) Yong, Y. F.; Lipton, M. A. Bioorg. Med. Chem. Lett. 1993, 3,
2879. (b) J enmalm, A. J .; Berts, W.; Li, Y.-L.; Luthman, K.; Cso¨regh,
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Lett. 1995, 36, 7545. (f) Daly, M. J .; Procter, G. Tetrahedron Lett. 1995,
36, 7549. (g) Beresis, R. T.; Masse, C. E.; Panek, J . S. J . Org. Chem.
1995, 60, 7714. (h) Devadder, S.; Verheyden, P.; J aspers, H. C. M.;
van Binst, G.; Tourwe, D. Tetrahedron Lett. 1996, 37, 703.
(13) For (Z)-alkene dipeptide isosteres, see: (a) Bohnstedt, A. C.;
Prasad, J . V. N. V.; Rich, D. H. Tetrahedron Lett. 1993, 34, 5217. (b)
Garro-He´lion, F.; Guibe´, F. J . Chem. Soc., Chem. Commun. 1996, 641.
(14) (a) Fujii, N.; Nakai, K.; Tamamura, H.; Otaka, A.; Mimura, N.;
Miwa, Y.; Taga, T.; Yamamoto, Y.; Ibuka, T. J . Chem. Soc., Perkin
Trans. 1 1995, 1359. (b) 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. (c) For a recent synthesis of
racemic N-sulfonyl-2-[(E)-2-(alkoxycarbonyl)ethenyl]-3-arylaziridines,
see: Li, A.-H.; Dai, L.-X.; Hou, X.-L. J . Chem. Soc., Perkin Trans. 1
1996, 2725.
(5) (a) Hann, M. M.; Sammes, P. G. J . Chem. Soc., Chem. Commun.
1980, 234. (b) Hann, M. M.; Sammes, P. G.; Kennewell, P. D.; Taylor,
J . B. J . Chem. Soc., Perkin Trans. 1 1982, 307.
(6) Wada, M.; Doi, R.; Hosotani, R.; Ibuka, T.; Habashita, H.; Nakai,
K.; Fujii, N.; Imamura, M. Pancreas 1995, 10, 31.
(15) Wipf, P.; Fritch, P. C. J . Org. Chem. 1994, 59, 4875.
S0022-3263(96)02094-4 CCC: $14.00 © 1997 American Chemical Society

Pd(0)-Catalyzed Isomerization Reactions of Aziridines
J . Org. Chem., Vol. 62, No. 9, 1997 2983
Sch em e 1a
Sch em e 2a
biological activities.16 However, the highly stereoselective
synthesis of 1 or 2 from chiral aldehyde 7 or 8 has
hitherto been difficult. Reaction of aldehydes 7 and 8
with [(alkoxycarbonyl)methylene]triphenylphosphorane
always yields a mixture of enoates (1 and 4) and (2 and
3), respectively. Consequently, development of practical
and facile methods for isomerizing unwanted aziridines
such as 3 and 4 into required stereoisomers is desired.
It was our expectation that palladium(0)-catalyzed
isomerization of undesired enoates 3 and 4 into the
desired 1 could occur via π-allylpalladium complexes.
Taking advantage of recent Pd(0)-catalyzed equilibration
reactions of vinylaziridines 9 and 10,17 we decided to
investigate equilibration reactions of various aziridines
bearing an R,â-unsaturated ester group with Pd(PPh3)4.
We are aware of no systematic investigation of Pd(0)-
catalyzed equilibrations in these systems, although some
N-activated 4,5-epimino 2-enoates are known to undergo
Pd(0)-formic acid-mediated ring-opening reactions yield-
ing alkene isosteres.18,19 We now describe a study involv-
ing the palladium(0)-catalyzed equilibration of five sets
of 4,5-epimino 2-enoates.20
a
Reagents: (a) (i) SOCl2-MeOH, (ii) MsCl-N,N-diisopropyl-
ethylamine, (iii) TBDMSCl-imidazole; (b) HF-MeCN-MeOH-
H2O; (c) PPh3-diethyl azodicarboxylate; (d) (i) DIBAL, (ii)
Ph3PdCHCO2Me.
The requisite homochiral enoates 15 and 16 were
prepared from L-threonine (11) (Scheme 2). Threonine
11 was sequentially treated with thionyl chloride-
methanol, methanesulfonyl chloride in the presence of
diisopropylethylamine, and tert-butyldimethylsilyl chlo-
ride and imidazole to afford the silyl ether 12 in a 45%
yield after the usual extractive workup followed by flash
chromatography over silica gel. Removal of the silyl
group with 48% HF solution in acetonitrile afforded the
hydroxy ester 13. It should be noted that the water-
soluble hydroxy ester 13 poses serious problems with
respect to product isolation. The usual extractive workup
leads to considerable loss of 13. Consequently, after
deprotection of the silyl group in 12, the reaction mixture
was made alkaline with 28% ammonium hydroxide and
concentrated to dryness under reduced pressure to leave
a semisolid, which was directly flash chromatographed
over silica gel. In this way, 13 was obtained in 92% yield
from 12. Cyclization of 13 with PPh3 and diethyl azodi-
carboxylate afforded the aziridine 14, which was succes-
sively reacted with diisobutylaluminum hydride (DIBAL)
and [(methoxycarbonyl)methylene]triphenylphosphorane
to yield a separable mixture of enoates 15 and 16. In a
similar manner, the known aziridine carboxylate 1717
was converted into the two isomeric enoates 18 and 19.
In this way, a set of four stereoisomeric enoates 15 (4,5-
cis-2E), 16 (4,5-cis-2Z), 18 (4,5-trans-2E), and 19 (4,5-
trans-2Z) were synthesized. Other N-tosylaziridine
enoates 20-25 (Scheme 2) were readily prepared follow-
ing literature procedures.14
Resu lts a n d Discu ssion
Syn th esis of F ive Sets of F ou r Ster eoisom er ic
Alk yl 4,5-Ep im in o-N-(a lk yl- a n d a r ylsu lfon yl)-2-a lk -
en oa tes. For the present palladium(0)-catalyzed isomer-
ization study, it seemed that activation by the introduc-
tion of a strong electron-withdrawing group on the
nitrogen atom of the aziridine was desirable. The meth-
anesulfonyl (Ms) or arylsulfonyl [e.g., p-toluenesulfonyl
(Ts) and 2-mesitylenesulfonyl (Mts)] group serves as an
effective activating group. The choice of Mts as a
protecting group was based primarily on its ease of
deprotection.
(16) Takeda, W.; Otaka, A.; Nakai, K.; Ibuka, T.; Fujimoto, K.; Wada,
M.; Doi, R.; Hosotani, R.; Higashide, S.; Imamura, M.; Fujii, N. Peptide
Chemistry; Protein Research Foundation: Osaka, 1995; pp 493-496.
(17) Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.; Miwa,
Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N.; Yamamoto, Y. J . Org.
Chem. 1997, 62, 999.
(18) Satake, A.; Shimizu, I.; Yamamoto, A. Synlett 1995, 64.
(19) For Pd(0)-catalyzed carbonylation reactions of N-activated
2-vinylaziridines, see: (a) Spears, G. W.; Nakanishi, K.; Ohfune, Y.
Synlett 1991, 91. (b) Tanner, D.; Somfai, P. Biorg. Med. Chem. Lett.
1993, 3, 2415.
Synthesis of a set of four stereoisomeric enoates 31-
34 bearing a 2-mesitylenesulfonyl group at the aziridine
nitrogen is shown in Scheme 3. L-Threonine (11) was
sequentially treated with SOCl2-MeOH and 2-mesity-
lenesulfonyl chloride-Et3N to afford the hydroxy mesity-
(20) A preliminary communication of this work has appeared:
Ibuka, T.; Akaji, M.; Mimura, N.; Habashita, H.; Nakai, K.; Tamamura,
H.; Fujii, N.; Yamamoto, Y. Tetrahedron Lett. 1996, 37, 2849.

2984 J . Org. Chem., Vol. 62, No. 9, 1997
Ibuka et al.
Sch em e 3a
Sch em e 4a
a
Reagents: (a) (i) SOCl2-MeOH, (ii) 2-mesitylenesulfonyl
chloride-Et3N; (b) PPh3-diethyl azodicarboxylate; (c) (i) DIBAL,
(ii) Ph3PdCHCO2Me.
lenesulfonamide 26, which on treatment with triphe-
nylphosphine and diethyl azodicarboxylate in tetra-
hydrofuran (THF) yielded the 2,3-cis-aziridine 27. Suc-
cessive treatment of 27 with DIBAL and [(methoxycar-
bonyl)methylene]triphenylphosphorane gave a separable
mixture of two products. Flash chromatographic separa-
tion yielded the enoates 31 (23% yield) and 32 (61% yield)
(Scheme 3). In the same manner, D-allo-threonine (28)
was converted in good overall yields into (2E)- and (2Z)-
enoates 33 and 34 via the hydroxy ester 29 and the
N-(mesitylenesulfonyl) carboxylate 30 (see the Experi-
mental Section).
Starting from the known 2-vinylaziridines17 35, 36, 45,
and 46, three sets of four isomeric enoates (37, 38, 41,
and 42), (39, 40, 43, and 44), and (47, 48, 49, and 50)
bearing an isopropyl or benzyl group on the aziridine ring
were prepared (Scheme 4). Ozonolysis of the 3-isopropyl-
2-vinylaziridine 35 followed by exposure to [(methoxy-
carbonyl)methylene]triphenylphosphorane afforded the
(2E)- and (2Z)-enoates 37 (29%) and 38 (53%) after flash
chromatographic separation. In the same manner, other
requisite enoates shown in Scheme 4 were readily
prepared in good yields.
a
Reagents: (a) (i) ozone, (ii) PPh3, (iii) Ph3PdCHCO2Me; (b)
(i) ozone, (ii) zinc powder, (iii) Ph3PdCHCO2But.
from the viewpoint of relative thermodynamic stabili-
ties.24 Consequently, both theoretical and experimental
aspects of this study were carried out with two sets of
four stereoisomeric 2-enoates, (15, 16, 18, and 19) and
(20, 21, 22, and 23).
We initiated our study to determine the relative
stabilities of four stereoisomeric 2-enoates bearing a
methanesulfonyl group on the nitrogen 15, 16, 18, and
19. Would the enoate 15, 16, 18, or 19 be expected to be
the most thermodynamically stable compound? In order
to gain an understanding of the relative stabilities of
these four isomeric enoates, we undertook calculations
at the PM3, HF/3-21G**, and HF/4-31G** levels.25 The
optimized geometries 15-A, 16-A, 18-A, and 19-A of the
four isomeric enoates 15, 16, 18, and 19 as well as
relative energies are shown in Figure 1. In addition, two
energy minima 18-B and 19-B of the nitrogen inver-
tomers of 18-A and 19-A, respectively, are also shown in
Space restrictions prevent detailed description; how-
ever, the 4,5-cis/trans and E/Z configurations of all of the
required homochiral R,â-enoates shown in Schemes 2-4
(23) For reactions of azirine-3-acrylates, see: Kascheres, A.; Oliveira,
C. M. A.; de Azevedo, M. B. M.; Nobre, C. M. S. J . Org. Chem. 1991,
56, 7.
1
were unambiguously assigned on the basis of H NMR
spectral analyses (see the Experimental Section).
Rela tive Th er m od yn a m ic Sta bilities of Tw o Sets
of F ou r Ster eoisom er ic r,â-En oa tes (15, 16, 18, a n d
19) a n d (20, 21, 22, a n d 23): P a lla d iu m (0)-Ca ta lyzed
Equ ilibr a tion Rea ction s. Despite their potential use-
fulnesses for the synthesis of various natural products
such as alkaloids21 antibiotics,22 and heterocycles,23 to
date 4,5-epimino 2-enoates have scarcely been studied
(24) For relative stability of some aziridines: (a) Huisgen, R.; Scheer,
W.; Huber, H. J . Am. Chem. Soc. 1967, 89, 1753. (b) Huisgen, R.;
Scheer, W.; Ma¨der, H. Angew. Chem. 1969, 81, 619. (c) Cromwell, N.
H.; Graff, M. A. J . Org. Chem. 1952, 17, 414. We thank Professor D.
Tanner, Denmark, for informing us of ref 24c.
(25) For the PM3 level of theory, see: Stewart, J . J . P. J . Comput.
Chem. 1989, 10, 210. All optimizations were carried out by using the
PM3 method, and stationary points were also confirmed by vibrational
analysis on the PM3 potential surface. Single-point energy calculations
were done at the HF/3-21G** and HF/4-31G** levels of theory. All
calculations were performed using the program GAUSSIAN 92 on a
CRAY Y-MP2E/264 at the Supercomputer Laboratory, Institute for
Chemical Research, Kyoto University. GAUSSIAN 92, Revision C:
Frisch, M. J .; Trucks, G. W.; Head-Gordon, M.; Gill, P. M. W.; Wong,
M. W.; Forseman, J . B.; J ohnson, B. G.; Schlegel, H. B.; Robb, M. A.;
Replogle, E. S.; Gomperts, R.; Andres, J . L.; Raghavachari, K.; Binkley,
J . S.; Gonzalez, C.; Martin, R. L.; Fox, D. J .; Defrees, D. J .; Baker, J .;
Stewart, J . J . P.; Pople, J . A. Gaussian Inc., Pittsburgh, PA, 1992.
(21) Hudlicky, T.; Luna, H.; Price, J . D.; Rulin, F. J . Org. Chem.
1990, 55, 4683. Pearson, W. H. Bergmeier, S. C.; Degan, S.; Lin, K.-
C.; Poon, Y.-F.; Schkeryantz, J . M.; Williams, J . P. J . Org. Chem. 1990,
55, 5719.
(22) Moran, E. J .; Tellew, J . E.; Zhao, Z.; Armstrong, R. W. J . Org.
Chem. 1993, 58, 7848.

Pd(0)-Catalyzed Isomerization Reactions of Aziridines
J . Org. Chem., Vol. 62, No. 9, 1997 2985
Sch em e 5. Rela tive Sta bilities of Tw o sets of F ou r
Ster eoisom er ic r,â-En oa tes (15, 16, 18, a n d 19) a n d
(20, 21, 22, a n d 23)a
a
The order of decreasing relative thermodynamic stabilities of
four stereoisomeric R,â-enoates (15, 16, 18, and 19) and (20, 21,
22, and 23) were predicted as follows: 4,5-cis-(2E) (15) > 4,5-trans-
(2E) (18) > 4,5-cis-(2Z) (16) > 4,5-trans-(2Z) (19). 4,5-cis-(2E) (20)
> 4,5-trans-(2E) (22) > 4,5-cis-(2Z) (21) > 4,5-trans-(2Z) (23). Our
results of an earlier study of the relative stabilities of vinylaziri-
dines 51 and 52 are included for comparison (see ref 17).
F igu r e 1. PM3 optimized geometries of four stereoisomeric
methyl 4,5-epimino-N-(methanesulfonyl)hex-2-enoates 15, 16,
18, and 19. Energies are relative to the lowest energy at the
PM3, HF/3-21G**, and HF/4-31G** levels, respectively.25 15-
A, 16-A, 18-A, and 19-A: the lowest energy geometries of 15,
16, 18, and 19, respectively. 18-B and 19-B: the lowest energy
geometries of the nitrogen invertomers of 18-A and 19-A,
respectively.
to be close to the experimental results obtained in
solution. The relative stabilities of the four stereoisomers
are summarized in Scheme 5.
In accord with calculations, the 4,5-trans-(2Z)-enoate
19 did give an 88.89:7.67:3.45:<0.01 equilibrium mixture
of 15, 18, 16, and 19 by exposure to 4 mol % of Pd(PPh3)4
(entry 4, Table 1). The rather low combined isolated yield
can be attributed to competing decomposition of products,
since the isolated yield of an equilibrated mixture of
products is maximized within 24 h or less at 0-25 °C.
To establish the observed equilibration results from 19
as a general trend, the same Pd(0)-catalyzed reactions
were carried out for the other stereoisomers 15, 16, and
18. It is found that the enoates 15, 16, and 18 gave
comparable results (entries 1-3, Table 1).
From the above results, it is evident that palladium-
(0)-catalyzed reactions lead to equilibrium ratios of all
possible stereoisomers as a function of their relative
stabilities. The stereochemical outcomes of these pal-
ladium-catalyzed isomerizations could be rationalized by
considering π-allylpalladium complexes A, B, C, and D
generated by oxidative addition of 4,5-epimino-N-(meth-
anesulfonyl) 2-enoates 15, 16, 18, and 19 to the Pd(0)
complex shown in Figure 2.
Next, both theoretical and experimental studies were
carried out with the four stereoisomeric 2-enoates 20-
23 bearing a tosyl group as an activating moiety. Figure
3 shows optimized geometries 20-A, 21-A, 22-A, and 23-A
for the four stereoisomeric methyl 4,5-epimino-N-(4-
methylbenzenesulfonyl)hex-2-enoates 20, 21, 22, and 23.
The calculations suggest that the energy minimum 20-A
of 4,5-cis-(2E)-enoate 20 is favored by 0.67 kcal mol-1 over
the energy minimum 22-A of the 4,5-trans-(2E)-isomer
22 at the HF/4-31G** level. Likewise, the optimized
geometry 21-A of 4,5-cis-(2Z) enoate 21 was predicted to
Figure 1. As one might expect, for 4,5-cis enoates 15-A
and 16-A, the methanesulfonyl group is trans with
respect to substituents at the C-4 and C-5 positions, for
presumably steric reasons.
From the calculations it is apparent that among the
four stereoisomers 15, 16, 18, and 19 the most stable and
unstable enoates are predicted to be 4,5-cis-(2E)-enoate
15 and 4,5-trans-(2Z)-enoate 19, respectively (Figure 1).
Calculations also suggest that the energy minimum 15-A
of 4,5-cis-(2E) enoate 15 is favored by 1.05 kcal mol-1 over
the global energy minimum 18-A of the 4,5-trans-(2E)-
isomer 18 at the HF/4-31G** level. Generally, it is well
documented that in disubstituted alkenes the (E)-isomer
is more stable than the (Z).26 In accord with this, the
(E)-enoates 15 and 18 are calculated to be more stable
than the corresponding (Z)-enoates 16 and 19.
As can be seen from Figure 1, the order of decreasing
relative thermodynamic stabilities for the four stereoi-
someric R,â-enoates 15, 16, 18, and 19 were predicted to
be as follows: 4,5-cis-(2E) (15) > 4,5-trans-(2E) (18) >
4,5-cis-(2Z) (16) > 4,5-trans-(2Z) (19). The relative
energy differences among the four isomeric enoates are
calculated to give an approximately 87:11:2:0.1 mixture
of 15, 18, 16, and 19 at 0 K at equilibrium in the gas
phase. As will be described below, this prediction proved
(26) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of
Organic Compounds; J ohn & Wiley & Sons: New York, 1994; pp 574-
577.

2986 J . Org. Chem., Vol. 62, No. 9, 1997
Ibuka et al.
Ta ble 1. P d (P P h 3)4-Ca ta lyzed Equ ilibr a ted Rea ction s of N-(Meth a n esu lfon yl)- or N-(Ar ylsu lfon yl)-γ,δ-ep im in o
r,â-En oa tesa
Pd(PPh3)4
(mol %)
product ratio
cis-(E):cis-(Z):trans-(E):trans-(Z)
combined
isolated yield (%)
conds (T (°C), time (h))
entry
substrate
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
15
16
18
19
20
21
22
23
31
32
33
34
37
38
41
42
47
48
49
50
4
4
4
4
2
2
2
2
2
2
2
2
4
4
2
2
4
4
4
4
0
25
25
25
15
15
15
15
20
20
20
20
0
0
0
0
30
30
30
28
16
16
16
16
15
15
15
15
15
15
15
15
24
24
24
24
3
15:16:18:19 ) 89.17:3.39:7.43:<0.01
15:16:18:19 ) 89.00:3.24:7.75:<0.01
15:16:18:19 ) 88.23:3.46:8.30:<0.01
15:16:18:19 ) 88.89:3.45:7.67:<0.01
20:21:22:23 ) 85.74:5.02:9.24:<0.01
20:21:22:23 ) 87.00:4.70:8.30:<0.01
20:21:22:23 ) 85.09:5.12:9.79:<0.01
20:21:22:23 ) 87.86:5.70:6.44:<0.01
31:32:33:34 ) 90.40:3.89:5.71:<0.001
31:32:33:34 ) 91.23:3.17:5.60:<0.001
31:32:33:34 ) 90.91:3.57:5.52:<0.001
31:32:33:34 ) 90.54:3.85:5.61:<0.001
37:38:41:42 ) 94.13:0.43:5.44:<0.001
37:38:41:42 ) 94.12:0.51:5.47:<0.001
37:38:41:42 ) 94.03:0.50:5.47:<0.001
37:38:41:42 ) 94.06:0.56:5.38:<0.001
47:48:49:50 ) 90.22:4.04:4.79:0.95
47:48:49:50 ) 89.40:3.70:5.79:1.11
47:48:49:50 ) 88.51:3.42:5.44:2.63
47:48:49:50 ) 88.61:3.62:6.32:1.45
87%
65%
56%
64%
93%
86%
84%
88%
87%
90%
96%
96%
97%
98%
97%
96%
90%
70%
94%
93%
3
3
3
a
All reactions were carried out in dry THF (ca. 0.05 M solution) under slight positive argon pressure. Except for entries 17-20,
product ratios were determined by reverse phase HPLC (Cosmosil 5C18-AR, MeOH:H2O ) 42-10:58-90). Product ratios (entries 17-
20) were determined by HPLC (Cosmosil 10SL, hexane:THF ) 92:8).
F igu r e 2. Palladium(0)-catalyzed equilibrated reaction.
be more stable by 1.29 kcal mol-1 than the energy
minimum 23-A of the isomeric 4,5-trans-(2Z)-enoate 23.
Optimized conformations 22-B and 23-B are the nitrogen
F igu r e 3. PM3-optimized geometries of four stereoisomeric
invertomers of 22-A and 23-A. It is evident that 22-A
methyl 4,5-epimino-N-(4-methylbenzenesulfonyl)hex-2-enoates
and 23-A are energetically favored over these nitrogen
20-23. Energies are relative to the lowest energy at the PM3
invertomers 22-B and 23-B. The order of decreasing
and HF/4-31G** levels, respectively.25 20-A, 21-A, 22-A, and
relative thermodynamic stabilities for the four 2-enoates
23-A: the lowest energy geometries of 20, 21, 22, and 23,
20-23 was predicted to be as follows: 4,5-cis-(2E) (20)
> 4,5-trans-(2E) (22) > 4,5-cis-(2Z) (21) > 4,5-trans-(2Z)
(23). These trends are in good accord with the results
depicted in Figure 1.
In actuality, the N-tosyl 2-enoate 23 did afford an
87.86:6.44:5.70:<0.01 mixture of 20, 22, 21, and 23 in
respectively. 22-B and 23-B: the lowest energy geometries of
the nitrogen invertomers of 22-A and 23-A, respectively.
88% combined isolated yield upon exposure to Pd(PPh3)4
(2 mol %) in THF at 15 °C (entry 8, Table 1). Within the
limits of experimental error, essentially identical results

Pd(0)-Catalyzed Isomerization Reactions of Aziridines
J . Org. Chem., Vol. 62, No. 9, 1997 2987
Sch em e 6a
were obtained following treatment of the isomeric enoates
20-22 under the same reaction conditions (entries 5-7,
Table 1).
This Pd(0)-catalyzed reaction was successfully carried
out on three other sets of four stereoisomeric 2-enoates
(31, 32, 33, and 34), (37, 38, 41, and 42), and (47, 48,
49, and 50). The desired 4,5-cis-(2E)-products 31, 37, and
47 were obtained with a selectivity as high as ca. 9:1 [31:
(32 + 33 + 34), 37:(38 + 41 + 42), and 47:(48 + 49 +
50)] when a catalytic amount of Pd(PPh3)4 was employed
in the equilibrated reactions (entries 9-20, Table 1).
Thus, good agreement was observed between computa-
tionally predicted and experimental results, thereby
providing feedback about the reliability of the calculation
procedure.
Clearly the thermodynamic stabilities of the 4,5-cis-
4,5-epimino (2E)-enoates 15, 20, 31, 37, and 47 are higher
than those of the corresponding 4,5-trans-4,5-epimino
(2E)-enoates 18, 22, 33, 41, and 49. In addition, it is
apparent from entries 9-12 and 13-16 in Table 1 that
the greater steric bulk of the nitrogen protecting group
(Mts) and the alkyl group (i-Pr) on the aziridine ring
tended to afford considerably higher ratios of the desired
4,5-cis-4,5-epimino (2E)-enoates 31 and 37.
Although the actual basis for the thermodynamic
preference of 4,5-cis-(2E)-enoates over the other corre-
sponding stereoisomers is still not clear, we speculate
that the origin of this energy difference might lie in a
delicate balance of steric and electronic factors. Steric
interaction between the alkyl group and the R,â-enoate
group at the aziridine-ring carbons would be of less
importance because the 4,5-cis-(2E)-enoate 37 bearing a
bulky isopropyl group and a relatively large 2-mesityle-
nesulfonyl group on the nitrogen atom was obtained in
higher ratios (entries 13-16, Table 1).
a
Reagents: (a) Pd(PPh3)4 (4 mol %); (b) Pd(PPh3)4 (2 mol %);
(c) i-BuCu(CN)MgCl; (d) i-PrCu(CN)MgCl.
Syn th etic Ap p lica tion to th e Syn th esis of (E)-
Alk en e Dip ep tid e Isoster es. The equilibrated reac-
tions illustrated below demonstrate how the undesired
2-enoates 24, 40 and 43, and 49 were transformed into
the desired 2-enoates 25, 39, and 47 (Scheme 6). Thus,
chiral cis-(Z)-enoate 24 bearing a phenyl group can be
converted into diastereomerically pure cis-(E)-enoate 25
as follows. Exposure of 24 to Pd(PPh3)4 (4 mol %) in dry
THF at 20 °C for 18 h was followed by filtration through
a short pad of silica gel with n-hexane-EtOAc (1:1).
Concentration under reduced pressure gave a crystalline
residue. Recrystallization from MeOH gave essentially
pure cis-(E)-enoate 25 as silky needles in 75% yield. The
mother liquor was concentrated to a semisolid, which was
again treated with Pd(PPh3)4 (4 mol %) in dry THF.
Workup as described above gave additional 25 in 6%
yield. The total combined yield of 25 amounted to 81%.
In the same manner, both cis-(Z)- and trans-(E)-enoates
40 and 43 were converted into the desired enoate 39
having a cis-(E)-configuration in 84 and 87% isolated
yields. Reaction of 39 with i-BuCu(CN)MgCl in THF at
-78 °C for 30 min gave the required isostere 53 in 95%
isolated yield as a single isomer. Likewise, the enoate
49 gave an isomeric enoate 47 in 78% isolated yield by
treatment with a catalytic amount (4 mol %) of Pd(PPh3)4
followed by flash chromatography or recrystallization
from n-hexane-Et2O (9:1). Space restrictions prevent
detailed descriptions of all results; however, it is apparent
that the Pd(0)-catalyzed reactions give very satisfactory
results. Exposure of the enoates 47 and 49 to i-PrCu-
(CN)MgCl gave the Phe-Ψ[(E)-CHdCH]-Val isosteres 54
and 55, respectively, in high yields.
In summary, it has been shown herein that palladium-
catalyzed equilibrated reactions of various 4,5-epimino
2-enoates afford mixtures of four possible stereoisomers
in which the desired cis-(E)-isomers predominate over
other stereoisomers. Ready access to desired R,â-enoates
from unwanted R,â-enoates and subsequent transforma-
tion into highly useful dipeptide isosteres in a regio- and
stereoselective manner are attractive features of this
approach.
Exp er im en ta l Section
Gen er a l Meth od s. The instrumentation has already been
described.2e,17 All reactions were carried out under a positive
pressure of argon. All glassware and syringes were dried in
an electric oven at 100 °C prior to use. All melting points are
uncorrected. For flash chromatographies, silica gel 60 H (silica
gel for thin-layer chromatography, Merck) or silica gel 60 (finer
than 230 mesh, Merck) was employed. For HPLC, Cosmosil-
5SL (10 × 200 mm, Nacalai Tesque) was employed.
Met h yl (2S,3R)-O-(ter t-Bu t yld im et h ylsilyl)-N-(m et h -
a n esu lfon yl)-L-th r eon in a te (12). Thionyl chloride (14.64
mL, 0.2 M) was added dropwise to a stirred solution of (2S,3R)-
threonine 11 (16 g, 0.134 M) in MeOH (160 mL) at -78 °C,
and the mixture was allowed to warm to rt and stirred at this
temperature for 18 h. Concentration under reduced pressure
gave an oily residue. To a solution of the oily residue in a
mixed solvent of DMF (20 mL) and CHCl3 (30 mL) at -78 °C
were added N,N-diisopropylethylamine (81.5 mL, 0.469 M) and
methanesulfonyl chloride (15.6 mL, 0.2 M) with stirring, and
stirring was continued for 5 h at 0 °C. Imidazole (36.48 g,
0.536 M) and tert-butyldimethylsilyl chloride (24.13 g, 0.161
M) were added to the mixture at 0 °C with stirring, and
stirring was continued for 18 h, followed by quenching with
aqueous 5% NaHCO3 (40 mL). The mixture was extracted

2988 J . Org. Chem., Vol. 62, No. 9, 1997
Ibuka et al.
with EtOAc-Et2O (3:1), and the extract was washed succes-
sively with water, 10% citric acid, water, saturated NaHCO3,
and water and dried over MgSO4. Usual workup followed by
flash chromatography over silica gel with n-hexane-EtOAc
(2:1) gave 19.6 g (45% yield) of the title compound 12 as a
colorless oil: [R]31D -31.8 (c 0.886, CHCl3); 1H NMR (270 MHz,
CDCl3) δ -0.01 (s, 3 H), 0.10 (s, 3 H), 0.84 (s, 9 H), 1.29 (d, J
) 6.2 Hz, 3 H), 3.00 (s, 3 H), 3.78 (s, 3 H), 3.99 (dd, J ) 10.5,
1.5 Hz, 1 H), 4.45 (ddd, J ) 10.5, 4.3, 1.5 Hz, 1 H), 5.06 (d, J
) 10 Hz, 1 H); LRMS (FAB) m/z 326 (MH+), 310, 268 (base
peak), 208, 194, 159, 73.
converted into the enoates 18 (435 mg, 39% yield) and 19 (220
mg, 20% yield). 18: colorless oil; [R]28D +49.2 (c 1.19, CHCl3);
1H NMR (270 MHz, CDCl3) δ 1.58 (d, J ) 5.9 Hz, 3 H), 2.96
(m, 1 H), 3.08 (s, 3 H), 3.20 (dd, J ) 8.9, 4.3 Hz, 1 H), 3.76 (s,
3 H), 6.20 (d, J ) 15.4 Hz, 1 H), 6.83 (dd, J ) 15.4, 8.9 Hz, 1
H); LRMS (FAB) m/z 220 (MH+), 219 (M+), 188, 140 (base
peak), 110, 109, 99; HRMS (FAB) m/z calcd for C8H14NO4S
(MH+) 220.0643, found 220.0641. 19: colorless oil; [R]28
D
-113.6 (c 0.83, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.55 (d,
J ) 5.7 Hz, 3 H), 2.97 (m, 1 H), 3.77 (s, 3 H), 3.08 (s, 3 H),
4.36 (dd, J ) 8.9, 3.8 Hz, 1 H), 6.07 (d, J ) 11.6 Hz, 1 H), 6.19
(dd, J ) 11.6, 8.9 Hz, 1 H); LRMS (FAB) m/z 220 (MH+), 219
(M+), 188, 140 (base peak), 110, 109, 99; HRMS (FAB) m/z
calcd for C8H14NO4S (MH+) 220.0643, found 220.0647.
Meth yl (2S,3R)-N-(Meth an esu lfon yl)-L-th r eon in ate (13).
To a stirred solution of 12 (2.5 g, 7.67 mmol) in a mixed solvent
of MeCN (8 mL), MeOH (3 mL), and water (0.6 mL) was added
1.5 mL of 46% aqueous HF, and the mixture was stirred at 50
°C for 1 h. The mixture was made basic with 28% NH4OH at
0 °C and concentrated under reduced pressure to leave a
colorless semisolid. The semisolid was purified by flash
chromatography over silica gel eluting with n-hexane-EtOAc
(1:2.5) to give 1.49 g (92% yield) of the title compound 13 as a
colorless crystalline mass. Recrystallization from Et2O-
Meth yl (2S,3R)-N-[(2,4,6-Tr im eth ylp h en yl)su lfon yl]th -
r eon in a te (26). Thionyl chloride (8.65 mL, 0.12 M) was added
dropwise to a stirred solution of (S)-threonine (11) (11.9 g, 0.1
M) in MeOH (100 mL) at -78 °C, and the mixture was allowed
to warm to rt and stirred at this temperature for 18 h.
Concentration under reduced pressure gave an oily residue.
To a solution of the residual oil in a mixed solvent of DMF (30
mL) and CHCl3 (50 mL) at 0 °C were added Et3N (40 mL) and
2,4,6-trimethylbenzenesulfonyl chloride (21.87 g) with stirring,
and stirring was continued for 2 h followed by quenching with
5% NaHCO3 (50 mL). The mixture was extracted with EtOAc,
and the extract was washed successively with water, 10% citric
acid, water, saturated NaHCO3, and water and dried over
MgSO4. Usual workup followed by recrystallization from
Et2O-CHCl3 (10:1) gave 15 g (48% yield) of the title compound
EtOAc (3:1) gave colorless crystals: mp 117 °C; [R]25 -38.3
D
(c 0.99, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.35 (d, J ) 6.5
Hz, 3 H), 2.12 (d, J ) 5.7 Hz, 1 H), 3.01 (s, 3 H), 3.84 (s, 3 H),
4.02 (dd, J ) 9.7, 2.7 Hz, 1 H), 4.36 (dddd, J ) 11.9, 6.2, 6.2,
2.4 Hz, 1 H), 5.38 (d, J ) 9.5 Hz, 1 H). Anal. Calcd for C6H13
-
NO5S: C, 34.12; H, 6.20; N, 6.63. Found: C, 33.95; H, 6.00;
N, 6.58.
Meth yl (2S,3S)-N-(Meth a n esu lfon yl)-3-m eth yl-2-a zir i-
d in eca r boxyla te (14). Triphenylphosphine (484 mg, 1.84
mmol) and diethyl azodicarboxylate (0.338 mL, 2.12 mmol)
were added to a stirred solution of the ester 13 (300 mg, 1.42
mmol) in 10 mL of CHCl3 at 0 °C, and the mixture was stirred
at this temperature for 6 h. The mixture was concentrated
under reduced pressure to an oil, which was flash chromato-
graphed on a silica gel column. Elution with n-hexane-
EtOAc-CHCl3 (2:1:3) gave 207 mg (75%) of the title compound
26 as colorless crystals: mp 120 °C; [R]20 -20.3 (c 1.82,
D
1
CHCl3); H NMR (270 MHz, CDCl3) δ 1.22 (d, J ) 6.3 Hz, 3
H), 2.29 (s, 3 H), 2.64 (s, 6 H), 3.52 (s, 3 H), 3.74 (dd, J ) 9.6,
3.3 Hz, 1 H), 4.10 (m, 1 H), 5.58 (d, J ) 9.6 Hz, 1 H), 6.95 (s,
2 H). Anal. Calcd for C14H21NO5S: C, 53.32; H, 6.71; N, 4.44.
Found: C, 53.20; H, 6.91; N, 4.37.
Met h yl (2S,3S)-3-Met h yl-N-[(2,4,6-t r im et h ylp h en yl)-
su lfon yl]-2-a zir id in eca r boxyla te (27). By a procedure
identical with that described for the preparation of the
aziridine 14 from 13, the ester 26 (8.1 g, 25.7 mmol) was
14 as a colorless oil: [R]30 -84.2 (c 1.04, CHCl3); 1H NMR
D
(270 MHz, CDCl3) δ 1.40 (d, J ) 5.9 Hz, 3 H), 3.04-3.14 (m,
1 H), 3.13 (s, 3 H), 3.40 (d, J ) 7.6 Hz, 1 H), 3.81 (s, 3 H);
LRMS (FAB) m/z 194 (MH+, base peak), 162, 134, 114; HRMS
(FAB) m/z calcd for C6H12NO4S (MH+) 194.0487, found 194.0489.
Meth yl (4R,5S,2E)-4,5-Ep im in o-N-(m eth a n esu lfon yl)-
h ex-2-en oa te (15) a n d Meth yl (4R,5S,2Z)-4,5-Ep im in o-N-
(m eth a n esu lfon yl)h ex-2-en oa te (16). To a stirred solution
of 14 (1.30 g, 6.73 mmol) in toluene (8 mL) at -78 °C under
argon was added dropwise diisobutylaluminum hydride (1 M
solution in toluene; 6.73 mL, 6.73 mmol). After 2 h, saturated
aqueous NH4Cl (2 mL) and [(methoxycarbonyl)methylene]-
triphenylphosphorane (4.5 g, 13.46 mmol) were added to the
solution with stirring at -78 °C. The mixture was stirred for
1 h, during which time it was allowed to warm to room
temperature. The mixture was made acidic with 20% citric
acid and extracted with EtOAc-CHCl3 (4:1). The extract was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure to an oil, which was flash chromatographed
on silica gel eluting with n-hexane-EtOAc (2:3) to give the
cis-enoate 16 (770 mg, 52% yield). Continued elution gave the
trans-enoate 15 (278 mg, 19% yield). 15: colorless crystals
converted into the aziridine 27 (6.2 g, 81% yield): mp 76-77
1
°C (n-hexane-Et2O ) 1:1) ; [R]20 -41.6 (c 2.74, CHCl3); H
D
NMR (270 MHz, CDCl3) δ 1.30 (d, J ) 5.9 Hz, 3 H), 2.31 (s, 3
H), 2.70 (s, 6 H), 3.13 (m, 1 H), 3.79 (d, J ) 7.3 Hz, 1 H), 3.73
(s, 3 H), 6.97 (s, 2 H). Anal. Calcd for C14H19NO4S: C, 56.55;
H, 6.44; N, 4.71. Found: C, 56.52; H, 6.62; N, 4.65.
Meth yl (2R,3R)-N-[(2,4,6-Tr im eth ylp h en yl)su lfon yl]a -
lloth r eon in a te (29). By a procedure identical with that
described for the preparation of 26 from (2S,3R)-threonine (11),
D-allothreonine (28) (8 g, 67 mmol) was converted into the title
compound 29 (17 g, 81% yield): colorless prisms from EtOAc-
CHCl3 (2:1); mp 143 °C; [R]20 +3.2 (c 0.754, CHCl3); 1H NMR
D
(270 MHz, CDCl3) δ 1.17 (d, J ) 6.6 Hz, 3 H), 2.29 (s, 3 H),
2.53 (d, J ) 8.6 Hz, 1 H), 2.64 (s, 6 H), 3.52 (s, 3 H), 3.84 (dd,
J ) 8.9, 4.3 Hz, 1 H), 4.03 (m, 1 H), 5.69 (d, J ) 8.9 Hz, 1 H),
6.96 (s, 2 H). Anal. Calcd for C14H21NO5S: C, 53.32; H, 6.71;
N, 4.44. Found: C, 53.20; H, 6.87; N, 4.41.
Met h yl (2R,3S)-3-Met h yl-N-[(2,4,6-t r im et h ylp h en yl)-
su lfon yl]-2-a zir id in eca r boxyla te (30). By a procedure
identical with that described for the preparation of the
aziridine 27 from the hydroxy ester 26, the hydroxy ester 29
(7.635 g, 24.2 mmol) was converted into the title compound
30 (6.15 g, 88% yield) by treatment with PPh3 (7.6 g, 29 mmol)
and diethyl azodicarboxylate (4.6 mL, 29 mmol) in THF (50
mL) followed by flash chromatography over silica gel with
n-hexane-EtOAc (3:1): colorless prisms from n-hexane-Et2O
from Et2O; mp 56 °C; [R]20 -180 (c 1.09, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 1.30 (d, J ) 5.8 Hz, 3 H), 3.05 (s, 3 H),
3.11 (m, 1 H), 3.38 (ddd, J ) 7.5, 6.8, 1.0 Hz, 1 H), 3.77 (s, 3
H), 6.21 (dd, J ) 15.6, 1.0 Hz, 1 H), 6.74 (dd, J ) 15.6, 6.8 Hz,
1 H). Anal. Calcd for C8H13NO4S: C, 43.82; H, 5.98; N, 6.39.
Found: C, 43.70; H, 6.03; N, 6.36. 16: colorless oil; [R]30
D
-96.5 (c 0.904, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.31 (d,
J ) 5.9 Hz, 3 H), 3.06 (s, 3 H), 3.17 (m, 1 H), 3.77 (s, 3 H),
4.32 (ddd, J ) 7.8, 7.8, 1.0 Hz, 1 H), 5.97 (dd, J ) 11.6, 8.1
Hz, 1 H), 6.12 (dd, J ) 11.6, 1.0 Hz, 1 H). LRMS (FAB) m/z
220 (MH+), 219 (M+), 188, 140 (base peak), 110, 109, 99; HRMS
(FAB) m/z calcd for C8H14NO4S (MH+) 220.0643, found 220.0637.
Meth yl (4S,5S,2E)-4,5-Ep im in o-N-(m eth a n esu lfon yl)-
h ex-2-en oa te (18) a n d Meth yl (4S,5S,2Z)-4,5-Ep im in o-N-
(m eth a n esu lfon yl)h ex-2-en oa te (19). By a procedure iden-
tical with that described for the preparation of the enoates 15
and 16 from 14, the aziridine 17 (0.98 g, 5.07 mmol) was
(2:1); mp 71 °C; [R]20 +18.8 (c 1.52, CHCl3); 1H NMR (270
D
MHz, CDCl3) δ 1.70 (d, J ) 5.9 Hz, 3 H), 2.29 (s, 3 H), 2.72 (s,
6 H), 3.12 (m, 1 H), 3.34 (d, J ) 4.0 Hz, 1 H), 3.69 (s, 3 H),
6.95 (s, 2 H). Anal. Calcd for C14H19NO4S: C, 56.55; H, 6.44;
N, 4.71. Found: C, 56.58; H, 6.51; N, 4.76.
Meth yl (4R,5S,2E)-4,5-Ep im in o-N-[(2,4,6-tr im eth ylp h e-
n yl)su lfon yl]h ex-2-en oa te (31) a n d Meth yl (4R,5S,2Z)-4,5-
E p im in o -N -[(2,4,6-t r im e t h y lp h e n y l)s u lfo n y l]h e x -2-
en oa te (32). By a procedure identical with that described for
the preparation of the enoates 15 and 16 from 14, the aziridine
27 (4.35 g, 14.64 mmol) was converted into the enoates 31 (1.1

Pd(0)-Catalyzed Isomerization Reactions of Aziridines
J . Org. Chem., Vol. 62, No. 9, 1997 2989
g, 23% yield) and 32 (2.91 g, 61% yield). 31: colorless oil; [R]20
stirred for 30 min, during which time it was allowed to warm
to 0 °C. To the mixture at 0 °C was added [(tert-butoxycar-
bonyl)methylene]triphenylphosphorane (3.3 g, 8.87 mmol, 2.0
equiv), and the mixture was stirred for 1 h. The mixture was
concentrated under reduced pressure to leave a semisolid,
which was purified by flash chromatography over silica gel
eluting with n-hexane-EtOAc (4:1) to give the (Z)-enoate 40
(760 mg, 44% yield). Continued elution gave the (E)-enoate
39 (950 mg, 55% yield). 39: colorless crystals; mp 118 °C (n-
D
-68.8 (c 1.44, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.20 (d, J
) 5.9 Hz, 3 H), 2.31 (s, 3 H), 2.68 (s, 6 H), 3.12 (m, 1 H), 3.43
(t, J ) 7.3 Hz, 1 H), 6.05 (d, J ) 15.8 Hz, 1 H), 6.68 (dd, J )
15.8, 6.6 Hz, 1 H), 6.91 (s, 2 H); LRMS (FAB) m/z 324 (MH+),
183, 167, 140 (base peak), 119; HRMS (FAB) m/z calcd for
C16H22NO4S (M+) 324.1269, found 324.1261. 32: colorless
crystals from n-hexane-Et2O (1:1); mp 97 °C; [R]20 +23.3 (c
D
1
1.51, CHCl3); H NMR (270 MHz, CDCl3) δ 1.22 (d, J ) 5.9
Hz, 3 H), 2.30 (s, 3 H), 2.68 (s, 6 H), 3.18 (m, 1 H), 3.74 (s, 3
H), 4.38 (t, J ) 7.6 Hz, 1 H), 5.88 (dd, J ) 11.9, 7.6 Hz, 1 H),
5.98 (d, J ) 11.9 Hz, 1 H), 6.95 (s, 2 H). Anal. Calcd for
C16H21NO4S: C, 59.42; H, 6.55; N, 4.33. Found: C, 59.19; H,
6.48; N, 4.12.
hexane-Et2O ) 2:1); [R]20 -54.7 (c 1.64, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 0.77 (d, J ) 6.6 Hz, 3 H), 0.87 (d, J ) 6.6
Hz, 3 H), 1.36-1.50 (m, 1 H), 1.47 (s, 9 H), 2.31 (s, 3 H), 2.63
(dd, J ) 10.0, 7.2 Hz, 1 H), 2.70 (s, 6 H), 3.47 (ddd, J ) 7.2,
7.2, 1.0 Hz, 1 H), 6.02 (dd, J ) 15.6, 1.0 Hz, 1 H), 6.59 (dd, J
) 15.6, 7.2 Hz, 1 H), 6.96 (s, 2 H). Anal. Calcd for C21H31
-
Meth yl (4S,5S,2E)-4,5-Ep im in o-N-[(2,4,6-tr im eth ylp h e-
n yl)su lfon yl]h ex-2-en oa te (33) a n d Meth yl (4S,5S,2Z)-4,5-
E p im in o -N -[(2,4,6-t r im e t h y lp h e n y l)s u lfo n y l]h e x -2-
en oa te (34). By a procedure identical with that described for
the preparation of the enoates 31 and 32 from 27, the aziridine
30 (5.91 g, 20 mmol) was converted into the enoates 33 (2.4 g,
37.3% yield) and 34 (1.9 g, 30% yield) by treatment with
diisobutylaluminum hydride (1 M solution in n-hexane; 24.5
mL, 24 mmol, 1.2 equiv) followed by [(methoxycarbonyl)-
NO4S: C, 63.93; H, 8.18; N, 3.55. Found: C, 63.65; H, 8.06;
N, 3.38. 40: colorless oil; [R]20D -54.2 (c 1.84, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 0.81 (d, J ) 6.6 Hz, 3 H), 0.88 (d, J ) 6.8
Hz, 3 H), 1.37 (m, 1 H), 1.50 (s, 9 H), 2.30 (s, 3 H), 2.69 (s, 6
H), 2.70 (dd, J ) 9.9, 7.6 Hz, 1 H), 4.42 (dd, J ) 7.6, 6.4 Hz,
1 H), 5.82 (dd, J ) 11.6, 6.4 Hz, 1 H), 5.88 (d, J ) 11.6 Hz, 1
H), 6.941 (s, 1 H), 6.943 (s, 1 H); LRMS (FAB) m/z 394 (MH+),
338, 320, 254 (base peak), 154, 119; HRMS (FAB) m/z calcd
for C21H32NO4S (MH+) 394.2052, found 394.2057.
methylene]triphenylphosphorane (7.45 g, 22 mmol, 1.1 equiv).
1
33: colorless oil; [R]20 +25.6 (c 1.70, CHCl3); H NMR (270
Meth yl (4S,5S,2E)-4,5-Ep im in o-6-m eth yl-N-[(2,4,6-tr i-
m eth ylp h en yl)su lfon yl]h ep t-2-en oa te (41) a n d Meth yl
(4S,5S,2Z)-4,5-Ep im in o-6-m eth yl-N-[(2,4,6-tr im eth ylp h e-
n yl)su lfon yl]h ep t-2-en oa te (42). By a procedure identical
with that described for the preparation of the enoates 37 and
38 from 35, the 2-vinylaziridine 36 (2.4 g, 8.19 mmol) was
converted into the enoates 41 (2.15 g, 75% yield) and 42 (740
mg, 19% yield). 41: colorless oil; [R]20D -12.8 (c 1.10, CHCl3);
1H NMR (270 MHz, CDCl3) δ 0.76 (d, J ) 6.6 Hz, 3 H), 0.88
(d, J ) 6.9 Hz, 3 H), 1.57 (m, 1 H), 2.30 (s, 3 H), 2.69 (s, 6 H),
2.89 (dd, J ) 7.6, 4.0 Hz, 1 H), 3.14 (dd, J ) 9.9, 4.0 Hz, 1 H),
3.74 (s, 3 H), 6.13 (d, J ) 15.8 Hz, 1 H), 6.94 (s, 2 H), 7.16 (dd,
J ) 15.8, 9.9 Hz, 1 H); LRMS (FAB) m/z 352 (MH+), 350, 254,
183, 168 (base peak), 153, 119; HRMS (FAB) m/z calcd for
D
MHz, CDCl3) δ 1.52 (d, J ) 5.9 Hz, 3 H), 2.30 (s, 3 H), 2.68 (s,
6 H), 3.00 (m, 1 H), 3.20 (dd, J ) 8.9, 4.0 Hz, 1 H), 3.71 (s, 3
H), 6.04 (d, J ) 15.5 Hz, 1 H), 6.86 (dd, J ) 15.5, 8.9 Hz, 1 H),
6.94 (s, 2 H); LRMS (FAB) m/z 324 (MH+), 322, 183, 167, 140
(base peak), 119, 109; HRMS (FAB) m/z calcd for C16H22NO4S
(MH+) 324.1269, found 324.1270. 34: colorless oil; [R]20D -18.8
(c 0.84, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.48 (d, J ) 5.6
Hz, 3 H), 2.29 (s, 3 H), 2.68 (s, 6 H), 3.00 (m, 1 H), 3.73 (s, 3
H), 4.43 (dd, J ) 9.6, 4.0 Hz, 1 H), 5.98 (d, J ) 11.6 Hz, 1 H),
6.22 (dd, J ) 11.6, 9.6 Hz, 1 H), 6.94 (s, 2 H); LRMS (FAB)
m/z 324 (MH+), 322, 183, 167, 140, 119 (base peak), 109; HRMS
(FAB) m/z calcd for C16H22NO4S (MH+) 324.1269, found
324.1268.
C18H26NO4S (MH+) 352.1582, found 352.1589. 42: colorless
Meth yl (4R,5S,2E)-4,5-Ep im in o-6-m eth yl-N-[(2,4,6-tr i-
m eth ylp h en yl)su lfon yl]h ep t-2-en oa te (37) a n d Meth yl
(4R,5S,2Z)-4,5-Ep im in o-6-m eth yl-N-[(2,4,6-tr im eth ylp h e-
n yl)su lfon yl]h ept-2-en oate (38). Ozone was bubbled through
a solution of the vinylaziridine 35 (2.0 g, 6.82 mmol) in CH2-
Cl2 (30 mL) at -78 °C until a blue color persisted. The solution
was stirred for 30 min, during which time it was allowed to
warm to 0 °C. To the mixture at 0 °C were added triph-
enylphosphine (893 mg, 3.41 mmol) and [(methoxycarbonyl)-
methylene]triphenylphosphorane (3.41 g, 10.23 mmol, 1.5
equiv), and the mixture was stirred for 18 h. The mixture was
concentrated under reduced pressure to leave a semisolid,
which was purified by flash chromatography over silica gel
eluting with n-hexane-EtOAc (5:1) to give the (Z)-enoate 38
(1.26 g, 53% yield). Continued elution gave the (E)-enoate 37
1
oil; [R]20 -121 (c 0.975, CHCl3); H NMR (270 MHz, CDCl3)
D
δ 0.73 (d, J ) 6.6 Hz, 3 H), 0.88 (d, J ) 6.9 Hz, 3 H), 1.58 (m,
1 H), 2.30 (s, 3 H), 2.69 (s, 6 H), 2.85 (dd, J ) 7.7, 4.3 Hz, 1
H), 4.50 (dd, J ) 10.0, 4.3 Hz, 1 H), 6.03 (d, J ) 11.6 Hz, 1 H),
6.61 (dd, J ) 11.6, 10.0 Hz, 1 H), 6.94 (s, 2 H); LRMS (FAB)
m/z 352 (MH+), 350, 254, 183, 168 (base peak), 153, 119; HRMS
(FAB) m/z calcd for C18H26NO4S (MH+) 352.1582, found
352.1581.
ter t-Bu tyl (4S,5S,2E)-4,5-Ep im in o-6-m eth yl-N-[(2,4,6-
tr im eth ylp h en yl)su lfon yl]h ep t-2-en oa te (43) a n d ter t-
Bu t yl (4S,5S,2Z)-4,5-E p im in o-6-m et h yl-N-[(2,4,6-t r im e-
th ylp h en yl)su lfon yl]h ep t-2-en oa te (44). By a procedure
identical with that described for the preparation of the enoates
39 and 40 from 35, 36 (760 mg, 2.59 mmol) was converted into
the enoates 43 (800 mg, 79% yield) and 44 (180 mg, 18% yield).
(690 mg, 29% yield). 37: colorless crystals from n-hexane-
1
Et2O (2:1); mp 78 °C; [R]20 -80.8 (c 1.17, CHCl3); H NMR
43: colorless oil; [R]20 +6.0 (c 1.90, CHCl3); 1H NMR (300
D
D
(270 MHz, CDCl3) δ 0.79 (d, J ) 6.6 Hz, 3 H), 0.87 (d, J ) 6.9
Hz, 3 H), 1.40 (m, 1 H), 2.31 (s, 3 H), 2.66 (dd, J ) 9.9, 7.3 Hz,
1 H), 2.70 (s, 6 H), 3.48 (t, J ) 7.2 Hz, 1 H), 3.73 (s, 3 H), 6.09
(dd, J ) 15.5, 1.0 Hz, 1 H), 6.72 (dd, J ) 15.5, 6.9 Hz, 1 H),
6.96 (s, 2 H). Anal. Calcd for C18H25NO4S: C, 61.51; H, 7.17;
N, 3.99. Found: C, 61.53; H, 7.19; N, 3.94. 38: colorless oil;
[R]20D -41.7 (c 1.08, CHCl3); 1H NMR (270 MHz, CDCl3) δ 0.82
(d, J ) 6.6 Hz, 3 H), 0.87 (d, J ) 6.9 Hz, 3 H), 1.39 (m, 1 H),
2.30 (s, 3 H), 2.70 (s, 6 H), 2.74 (dd, J ) 9.9, 7.6 Hz, 1 H), 3.75
(s, 3 H), 4.46 (t, J ) 7.3 Hz, 1 H), 5.93 (dd, J ) 11.9, 7.3 Hz,
1 H), 6.00 (d, J ) 11.9 Hz, 1 H), 6.95 (s, 2 H); LRMS (FAB)
m/z 352 (MH+), 350, 254 (base peak), 183, 168, 153, 119; HRMS
(FAB) m/z calcd for C18H26NO4S (MH+) 352.1582, found
352.1574.
ter t-Bu t yl (4R,5S,2E)-4,5-E p im in o-6-m et h yl-N-[(2,4,6-
tr im eth ylp h en yl)su lfon yl]h ep t-2-en oa te (39) a n d ter t-
Bu tyl (4R,5S,2Z)-4,5-Ep im in o-6-m eth yl-N-[(2,4,6-tr im e-
th ylph en yl)su lfon yl]h ept-2-en oate (40). Ozone was bubbled
through a solution of the vinylaziridine 35 (1.3 g, 4.436 mmol)
in AcOEt (15 mL) at -78 °C until a blue color persisted. Zinc
powder (0.7 g) was added to the solution, and the mixture was
MHz, CDCl3) δ 0.80 (d, J ) 6.7 Hz, 3 H), 0.90 (d, J ) 6.8 Hz,
3 H), 1.48 (s, 9 H), 1.59 (m, 1 H), 2.29 (s, 3 H), 2.69 (s, 6 H),
2.90 (dd, J ) 7.6, 4.1 Hz, 1 H), 3.08 (dd, J ) 10.0, 4.1 Hz, 1
H), 6.00 (dd, J ) 15.4, 0.4 Hz, 1 H), 6.93 (s, 2 H), 7.01 (dd, J
) 15.4, 10.0 Hz, 1 H); LRMS (FAB) m/z 394 (MH+), 338, 320,
210, 154, 119 (base peak); HRMS (FAB) m/z calcd for C21H32
-
NO4S (MH+) 394.2052, found 394.2044. 44: colorless oil; [R]20
D
-94.0 (c 0.723, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.73 (d,
J ) 6.7 Hz, 3 H), 0.89 (d, J ) 6.8 Hz, 3 H), 1.48 (s, 9 H), 1.58
(m, 1 H), 2.30 (s, 3 H), 2.70 (s, 6 H), 2.82 (dd, J ) 7.4, 4.2 Hz,
1 H), 4.48 (ddd, J ) 10.0, 4.2, 1.0 Hz, 1 H), 5.92 (dd, J ) 11.6,
1.0 Hz, 1 H), 6.46 (dd, J ) 11.6, 10.0 Hz, 1 H), 6.94 (s, 2 H);
LRMS (FAB) m/z 394 (MH+), 338, 320, 282, 254 (base peak),
154, 119; HRMS (FAB) m/z calcd for C21H32NO4S (MH+)
394.2052, found 394.2045.
ter t-Bu t yl (4R,5S,2E)-4,5-E p im in o-6-p h en yl-N-[(2,4,6-
t r im et h ylp h en yl)su lfon yl]h ex-2-en oa t e (47) a n d ter t-
Bu tyl (4R,5S,2Z)-4,5-Ep im in o-6-p h en yl-N-[(2,4,6-tr im e-
th ylp h en yl)su lfon yl]h ex-2-en oa te (48). By a procedure
identical with that described for the preparation of the enoates
39 and 40 from 35, the 2-vinylaziridine 45 (570 mg, 1.67 mmol)

2990 J . Org. Chem., Vol. 62, No. 9, 1997
Ibuka et al.
was converted into the enoates 47 (256 mg, 35% yield) and 48
The product 39 thus obtained amounts to 920 mg (83.6%
(332 mg, 45% yield). 47: colorless crystals (n-hexane-Et2O
yield): mp 118 °C (from n-hexane); [R]26 -54.8° (c 0.945,
D
1
1
) 4:1); mp 92 °C; [R]35 -52.9 (c 0.85, CHCl3); H NMR (270
CHCl3); H NMR (300 MHz, CDCl3) δ 0.77 (d, J ) 6.6 Hz, 3
D
MHz, CDCl3) δ 1.50 (s, 9 H), 2.30 (s, 3 H), 2.56 (s, 6 H), 2.62
(dd, J ) 14.3, 8.1 Hz, 1 H), 2.77 (dd, J ) 14.3, 5.1 Hz, 1 H),
3.15 (m, 1 H), 3.55 (ddd, J ) 7.0, 7.0, 1.1 Hz, 1 H), 6.10 (dd, J
) 15.7, 1.1 Hz, 1 H), 6.73 (dd, J ) 15.7, 6.5 Hz, 1 H), 6.85 (s,
2 H), 6.91-7.14 (m, 5 H); LRMS (FAB) m/z 442 (MH+), 386,
368, 258, 202, 186, 156, 119 (base peak), 91; HRMS (FAB) m/z
calcd for C25H32NO4S (MH+) 442.2052, found 442.2054. 48:
colorless oil; [R]31D -73.6 (c 0.78, CHCl3); 1H NMR (2700 MHz,
CDCl3) δ 1.50 (s, 9 H), 2.29 (s, 3 H), 2.57 (s, 6 H), 2.60 (dd, J
) 14.8, 8.1 Hz, 1 H), 2.80 (dd, J ) 14.8, 4.9 Hz, 1 H), 3.22
(ddd, J ) 8.1, 8.1, 4.9 Hz, 1 H), 4.49 (m, 1 H), 5.97 (m, 2 H),
6.85 (s, 2 H), 6.90-7.14 (m, 5 H); LRMS (FAB) m/z 442 (MH+),
386, 368, 302 (base peak), 202, 186, 156, 119, 91; HRMS (FAB)
m/z calcd for C25H32NO4S (MH+) 442.2052, found 442.2046.
ter t-Bu tyl (4S,5S,2E)-4,5-Ep im in o-6-p h en yl-N-[(2,4,6-
t r im et h ylp h en yl)su lfon yl]h ex-2-en oa t e (49) a n d ter t-
Bu t yl (4S,5S,2Z)-4,5-E p im in o-6-p h en yl-N-[(2,4,6-t r im e-
th ylp h en yl)su lfon yl]h ex-2-en oa te (50). By a procedure
identical with that described for the preparation of the enoates
43 and 44 from 36, the 2-vinylaziridine 46 (450 mg, 1.32 mmol)
was converted into the enoates 49 (427 mg, 73% yield) and 50
H), 0.87 (d, J ) 6.6 Hz, 3 H), 1.36-1.50 (m, 1 H), 1.47 (s, 9 H),
2.31 (s, 3 H), 2.63 (dd, J ) 10.0, 7.2 Hz, 1 H), 2.70 (s, 6 H),
3.47 (ddd, J ) 7.2, 7.2, 1.0 Hz, 1 H), 6.02 (dd, J ) 15.6, 1.0
Hz, 1 H), 6.59 (dd, J ) 15.6, 7.2 Hz, 1 H), 6.96 (s, 2 H). Anal.
Calcd for C21H31NO4S: C, 63.93; H, 8.18; N, 3.55. Found: C,
64.00; H,8.11; N, 3.59.
ter t-Bu t yl (4R,5S,2E)-4,5-E p im in o-6-m et h yl-N-[(2,4,6-
tr im eth ylp h en yl)su lfon yl]h ep t-2-en oa te (39) fr om ter t-
Bu t yl (4S,5S,2E)-4,5-E p im in o-6-m et h yl-N-[(2,4,6-t r im e-
th ylp h en yl)su lfon yl]h ep t-2-en oa te (43). By a procedure
identical with that described for the preparation of the enoates
39 from 40, the 4,5-trans-enoate 43 was converted into the
enoate 39 (86.7% yield): mp 118 °C (from n-hexane); [R]26
D
1
-55.1° (c 1.05, CHCl3); H NMR (300 MHz, CDCl3) δ 0.77 (d,
J ) 6.6 Hz, 3 H), 0.87 (d, J ) 6.6 Hz, 3 H), 1.36-1.50 (m, 1
H), 1.47 (s, 9 H), 2.31 (s, 3 H), 2.63 (dd, J ) 10.0, 7.2 Hz, 1 H),
2.70 (s, 6 H), 3.47 (ddd, J ) 7.2, 7.2, 1.0 Hz, 1 H), 6.02 (dd, J
) 15.6, 1.0 Hz, 1 H), 6.59 (dd, J ) 15.6, 7.2 Hz, 1 H), 6.96 (s,
2 H). Anal. Calcd for C21
H31NO4S: C, 63.93; H, 8.18; N, 3.55.
Found: C, 64.01; H,8.21; N, 3.60.
ter t-Bu tyl (2R,5S,3E)-6-Meth yl-2-(2-m eth ylp r op yl)-5-
[[(2,4,6-t r im et h ylp h en yl)su lfon yl]a m in o]-3-h ep t en oa t e
(53) fr om 39. To a stirred solution of CuCN (916 mg, 10.2
mmol) and LiCl (860 mg, 20.4 mmol) in 20 mL of dry THF
under argon was added by syringe isobutylmagnesium chloride
(1.1 M solution in THF; 9.27 mL, 10.2 mmol) at -78 °C, and
the mixture was allowed to warm to 0 °C and stirred at this
temperature for 10 min. The enoate 39 (1.0 g, 2.544 mmol) in
10 mL of dry THF was added dropwise to the above reagent
at -78 °C with stirring, and the stirring was continued for 30
min followed by quenching with 20 mL of a 1:1 saturated NH4-
Cl-28% NH4OH solution. The mixture was extracted with
Et2O, and the extract was washed with water and dried over
MgSO4. Concentration under reduced pressure gave an oily
residue, which was flash chromatographed on silica gel eluting
with n-hexane-EtOAc (4:1) to give the title compound 53
(1.091g, 95% yield) as a crystalline mass. Recrystallization
from n-hexane gave colorless crystals: mp 108 °C; [R]20D -42.1
(c 1.35, CHCl3); ∆ꢀ -4.75 (219 nm in isooctane); 1H NMR (300
MHz, CDCl3) δ 0.81 (d, J ) 6.4 Hz, 3 H), 0.82 (d, J ) 6.7 Hz,
3 H), 0.83 (d, J ) 6.6 Hz, 3 H), 0.87 (d, J ) 6.8 Hz, 3 H), 0.98
(m, 1 H), 1.28-1.48 (m, 2 H), 1.38 (s, 9 H), 1.74 (m, 1 H), 2.28
(s, 3 H), 2.61 (s, 6 H), 2.69 (m, 1 H), 3.47 (m, 1 H), 4.48 (d, J
) 7.8 Hz, 1 H), 5.18 (m, 2 H), 6.91 (s, 2 H). Anal. Calcd for
C25H41NO5S: C, 66.48; H, 9.15; N, 3.10. Found: C, 66.43; H,
9.09; N, 3.14.
(50 mg, 9% yield). 49: colorless crystals from n-hexane-
1
EtOAc (2:1); mp 100 °C; [R]35 27.9 (c 0.96, CHCl3); H NMR
D
(270 MHz, CDCl3) δ 1.46 (s, 9 H), 2.30 (s, 3 H), 2.57 (s, 6 H),
2.84 (dd, J ) 14.3, 5.9 Hz, 1 H), 3.02 (dd, J ) 14.3, 5.7 Hz, 1
H), 3.22 (m, 2 H), 6.01 (d, J ) 15.4 Hz, 1 H), 6.87 (dd, J )
15.4, 9.2 Hz, 1 H), 6.89 (s, 2 H), 6.95-7.19 (m, 5 H). Anal.
Calcd for C25H31NO4S: C, 67.00; H, 7.08; N, 3.17. Found: C,
67.30; H, 7.04; N, 3.19. 50: colorless oil; [R]35 -34.1 (c 0.50,
D
1
CHCl3); H NMR (270 MHz, CDCl3) δ 1.53 (s, 9 H), 2.30 (s, 3
H), 2.67 (dd, J ) 14.0, 7.3 Hz, 1 H), 3.04-3.19 (m, 2 H), 4.64
(ddd, J ) 9.7, 3.5, 0.5 Hz, 1 H), 5.94 (dd, J ) 11.3, 0.5 Hz, 1
H), 6.34 (dd, J ) 11.3, 10, 0 Hz, 1 H), 6.85 (s, 2 H), 6.90-7.14
(m, 5 H); LRMS (FAB) m/z 442 (MH+), 386, 302 (base peak),
202, 183, 119, 91, 57; HRMS (FAB) m/z calcd for C25H32NO4S
(MH+) 442.2052, found 442.2055.
Meth yl (4S,5R,2E)-4,5-Ep im in o-5-p h en yl-N-[(4-m eth -
ylp h en yl)su lfon yl]p en t-2-en oa te (25) fr om 24. To a stirred
solution of cis-(Z)-enoate 24 (107 mg, 0.3 mmol) in THF (3 mL)
at 20 °C under argon was added by syringe a solution of Pd-
(PPh3)4 (13.9 mg, 4 mol %) in 2 mL of THF. After 18 h, the
mixture was filtered through a short pad of silica gel with
n-hexane-EtOAc (1:1). Concentration under reduced pressure
gave a crystalline residue. Recrystallization from MeOH gave
80 mg (75% yield) of pure cis-(E)-enoate 25 as silky needles.
The mother liquor was concentrated to a semisolid, which was
treated with Pd(PPh3)4 (4 mol %) in dry THF. The same
workup as described above gave 7 mg (6% yield) of 25. The
total yield of 25 amounted to 81%: colorless silky needles from
MeOH; mp 146 °C; [R]20D -44.3 (c 1.40, CHCl3); 1H NMR (300
MHz, CDCl3) δ 2.44 (s, 3 H), 3.63 (s, 3 H), 3.68 (m, 1 H), 6.09
(dd, J ) 15.7, 0.6 Hz, 1 H), 6.33 (dd, J ) 15.7, 7.7 Hz, 1 H),
7.19-7.36 (m, 5 H), 7.86-7.87 (m, 2 H). Anal. Calcd for
C19H19NO4S: C, 63.85; H, 5.36; N, 3.92. Found: C, 63.95; H,
5.33; N, 3.69.
ter t-Bu t yl (4R,5S,2E)-4,5-E p im in o-6-m et h yl-N-[(2,4,6-
tr im eth ylp h en yl)su lfon yl]h ep t-2-en oa te (39) fr om ter t-
Bu tyl (4R,5S,2Z)-4,5-Ep im in o-6-m eth yl-N-[(2,4,6-tr im e-
t h ylp h en yl)su lfon yl]h ep t -2-en oa t e (40). To a stirred
solution of the enoate 40 (1.1 g, 2.8 mmol) in 7 mL of dry THF
at 0 °C under argon was added by syringe a solution of Pd-
(PPh3)4 (64.6 mg, 0.056 mmol, 2 mol %) in 3 mL of dry THF,
and the mixture was stirred at 15 °C for 15 h. Concentration
under reduced pressure at 0 °C followed by flash chromatog-
raphy over silica gel with n-hexane-EtOAc (4:1) gave 1.08 g
of a crystalline mass. Recrystallization from n-hexane gave
690 mg (62.7% yield) of the (2E)-isomer 39 as colorless crystals.
The mother liquor was concentrated under reduced pressure
to leave 410 mg of a colorless semisolid. The semisolid was
treated with 24 mg of Pd(PPh3)4 in 5 mL of dry THF for 16 h
at 15 °C. Usual workup followed by flash chromatography over
silica gel with n-hexane-EtOAc (5:1) and recrystallization
from n-hexane gave 230 mg (20.9% yield) of the enoate 39.
ter t-Bu t yl (4R,5S,2E)-4,5-E p im in o-6-p h en yl-N-[(2,4,6-
tr im eth ylp h en yl)su lfon yl]h ex-2-en oa te (47) fr om ter t-
Bu t yl (4S,5S,2E)-4,5-E p im in o-6-p h en yl-N-[(2,4,6-t r im e-
th ylp h en yl)su lfon yl]h ex-2-en oa te (49). By a procedure
identical with that described for the preparation of the enoate
39 from 40, the enoate (49) was converted into the isomeric
enoate 47 (78% yield). 47: colorless crystals from n-hexane-
1
Et2
O (2:1); mp 92 °C; [R]35 -46.2 (c 1.17, CHCl3); H NMR
D
(270 MHz, CDCl3) δ 1.50 (s, 9 H), 2.30 (s, 3 H), 2.56 (s, 6 H),
2.62 (dd, J ) 14.3, 8.1 Hz, 1 H), 2.77 (dd, J ) 14.3, 5.1 Hz, 1
H), 3.15 (m, 1 H), 3.55 (ddd, J ) 7.0, 7.0, 1.1 Hz, 1 H), 6.10
(dd, J ) 15.7, 1.1 Hz, 1 H), 6.73 (dd, J ) 15.7, 6.5 Hz, 1 H),
6.85 (s, 2 H), 6.91-7.14 (m, 5 H). Anal. Calcd for C25H31
-
NO4S: C, 67.99; H, 7.08; N, 3.17. Found: C, 67.80: H, 7.15:
N, 3.14.
ter t-Bu t yl (2S,5S,3E)-2-(2-Met h ylet h yl)-6-p h en yl-5-
[[(2,4,6-tr im eth ylph en yl)su lfon yl]am in o]-3-h exen oate (55).
To a stirred solution of CuCN (81 mg, 0.89 mmol) and LiCl
(76.5 mg, 1.81 mmol) in 2 mL of dry THF under argon was
added by syringe isopropylmagnesium chloride (0.89 M solu-
tion in THF; 1.0 mL, 0.89 mmol) at -78 °C, and the mixture
was allowed to warm to 0 °C and stirred at this temperature
for 10 min. The enoate 49 (100 mg, 0.226 mmol) in 2 mL of
dry THF was added dropwise to the above reagent at -78 °C
with stirring, and the stirring was continued for 30 min
followed by quenching with 2 mL of a 1:1 saturated NH4Cl-
28% NH4OH solution. The mixture was extracted with EtOAc,

Pd(0)-Catalyzed Isomerization Reactions of Aziridines
J . Org. Chem., Vol. 62, No. 9, 1997 2991
and the extract was successively washed with water, 5% citric
acid, 5% NaHCO3, and brine and dried over MgSO4. Concen-
tration under reduced pressure gave an oily residue, which
was flash chromatographed on silica gel eluting with n-hex-
ane-EtOAc (4:1) to give the title compound 55 (88 mg, 80%
yield) as a colorless oil: [R]33D +2.65 (c 1.08, CHCl3); ∆ꢀ +3.37
(219 nm in isooctane); 1H NMR (270 MHz, CDCl3) δ 0.66 (d, J
) 6.8 Hz, 3 H), 0.81 (d, J ) 6.5 Hz, 3 H), 1.43 (s, 9 H), 1.75 (m,
1 H), 2.25 (s, 3 H), 2.41 (t, J ) 8.4 Hz, 1 H), 2.49 (s, 6 H), 2.80
(m, 2 H), 3.92 (m, 1 H), 4.46 (d, J ) 6.2 Hz, 1 H), 5.27-5.50
(m, 2 H), 6.88 (s, 2 H), 7.01-7.26 (m, 5 H); LRMS (FAB) m/z
486 (MH+), 484, 470, 384, 338, 302, 231, 185, 129, 119 (base
peak), 91, 57; HRMS (FAB) m/z calcd for C28H40NO4S (MH+)
486.2678, found 486.2669.
(m, 5 H); LRMS (FAB) m/z 486 (MH+), 484, 470, 384, 338, 302,
231, 185, 129, 119 (base peak), 91, 57; HRMS (FAB) m/z calcd
for C28H40NO4S (MH+) 486.2678, found 486.2661.
Ackn owledgm en t. We thank Dr. Terrence R. Burke,
J r., NCI, NIH, Bethesda, MD, for reading the manu-
script and providing useful comments. We are grateful
to Professor Tamio Hayashi, Kyoto University, for the
helpful discussion. This work was supported in part by
Grant-in-Aid for Scientific Research (B) and (C) from
the Ministry of Education, Science and Culture of
J apan, to which the authors’ thanks are due.
ter t-Bu t yl (2R,5S,3E)-6-P h en yl-2-(2-m et h ylet h yl-5-
[[(2,4,6-tr im eth ylph en yl)su lfon yl]am in o]-3-h exen oate (54).
By a procedure identical with that described for the prepara-
tion of the enoate 55 from 49, the enoate 47 was converted
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of compounds 12, 14, 16, 18, 19, 31, 33, 34, 38, 40-
44, 47, 48, 50, 54, and 55 are available (19 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
into the title compound 54 as a colorless oil (90% yield): [R]33
D
-64.0 (c 0.85, CHCl3); ∆ꢀ -4.89 (227 nm in isooctane); 1H NMR
(270 MHz, CDCl3) δ 0.73 (d, J ) 6.5 Hz, 3 H), 0.85 (d, J ) 6.5
Hz, 3 H), 1.40 (s, 9 H), 1.80 (m, 1 H), 2.28 (s, 3 H), 2.39-2.48
(m, 1 H), 2.49 (s, 6 H), 2.81 (m, 2 H), 3.91 (m, 1 H), 4.46 (d, J
) 7.0 Hz, 1 H), 5.30-5.47 (m, 2 H), 6.87 (s, 2 H), 7.00-7.26
J O962094U