A Thermodynamic Preference of Chiral N-Methanesulfonyl and N-Arenesulfonyl 2,3-cis-3-Alkyl-2-Vinylaziridines over Their 2,3-Trans-Isomers: Useful Palladium(0)-Catalyzed Equilibration Reactions for the Synthesis of (E)-Alkene Dipeptide Isosteres

J . Org. Chem. 1997, 62, 999-1015

999

A Th er m od yn a m ic P r efer en ce of Ch ir a l N-Meth a n esu lfon yl a n d

N-Ar en esu lfon yl 2,3-cis-3-Alk yl-2-Vin yla zir id in es over Th eir

2,3-Tr a n s-Isom er s: Usefu l P a lla d iu m (0)-Ca ta lyzed Equ ilibr a tion

Rea ction s for th e Syn th esis of (E)-Alk en e Dip ep tid e Isoster es

Toshiro Ibuka,* Norio Mimura, Hiroshi Aoyama, Masako Akaji, Hiroaki Ohno,

Yoshihisa Miwa, Tooru Taga, Kazuo Nakai, Hirokazu Tamamura, and Nobutaka Fujii

Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606, J apan

Yoshinori Yamamoto

Department of Chemistry, Graduate School of Science, Tohoku University, Aoba, Sendai 980, J apan

Received September 13, 1996^X

Palladium(0)-catalyzed reactions of N-methanesulfonyl- or N-(arenesulfonyl)-3-alkyl-2-vinylaziri-

dines reveal that 2,3-cis-isomers are more stable than the corresponding 2,3-trans-isomers in accord

with ab initio calculations. A highly stereoselective synthetic route to (E)-alkene dipeptide isosteres

having desired stereochemistries from 2,3-cis-3-isobutyl-2-vinylaziridine by the use of organocopper

chemistry is also presented.

Sch em e 1

The aziridine ring framework can be found in many

synthetic and natural compounds of biological impor-

tance.¹Currently, there is significant interest in the

synthesis and reaction of aziridines and their N-activated

analogues.²Due to their very high reactivity and ability

to function as carbon electrophiles, activated aziridines,³

notably 2-vinylaziridines⁴and their derivatives,⁵are

versatile synthetic intermediates for the synthesis of

biologically important compounds.

Recently, we proposed that peptides involving (E)-

alkene dipeptide isosteres of type 6 may represent a novel

class of potent bombesin receptor antagonists (Scheme

^XAbstract published in Advance ACS Abstracts, February 1, 1997.

(1) (a) Padwa, A.; Woolhouse, A. D. In Comprehensive Heterocyclic

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Org. Chem. 1990, 55, 4683. (f) Hudlicky, T.; Fan, R.; Reed, J . W.;

Gadamasetti, K. J . In Organic Reactions; Paquette, L. A., Ed.; J ohn

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(i) Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron Lett. 1996, 37, 5473.

(3) For the term activated aziridines, see: Ham, G. E. J . Org. Chem.

1964, 29, 3052.

1).⁶Merck⁷and Dupont Merck⁸groups, Panek,⁹and

Bartlett¹⁰have also reported that peptides containing (E)-

alkene dipeptide isosteres show potent biological activity.

One of the simplest methods for the synthesis of alkene

isosteres such as 5 and 6 via aziridine derivatives of type

3 and 4 involves the use of chiral anti- and syn-amino

alcohols 1 and 2, which in turn could be synthesized from

various chiral amino aldehydes.^11,12However, when a

(5) (a) Scheiner, P. J . Org. Chem. 1967, 32, 2628. (b) Strogryn, E.

L.; Brois, S. J . J . Am. Chem. Soc. 1967, 89, 605. (c) Cardillo, G.; Grena,

M.; Sandri, S.; Tomasini, C. Tetrahedron 1986, 42, 917. (d) Fugami,

K.; Miura, K.; Morizawa, Y.; Oshima, K.; Utimoto, K.; Nozaki, H.

Tetrahedron 1989, 45, 3089. (e) Moran, E. J .; Tellew, J . E.; Zhao, Z.;

Armstrong, R. W. J . Org. Chem. 1993, 58, 7848. (f) A° hman, J .; Somfai,

P. J . Am. Chem. Soc. 1994, 116, 9781. (g) Somfai, P.; A° hman, J .

Tetrahedron Lett. 1995, 36, 1953. (h) Coldham, I.; Collis, A. J .; Mould,

R. J .; Rathmell, R. E. Tetrahedron Lett. 1995, 36, 3557. (i) Viallon, L.;

Reinaud, O.; Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1995, 36,

4787. (j) Li, A.-H.; Dai, L.-X.; Hou, X.-L. J . Chem. Soc., Perkin Trans.

1 1996, 867. (k) A° hman, J .; Somfai, P. Tetrahedron Lett. 1996, 37, 2495.

(6) Wada, M.; Doi, R.; Hosotani, R.; Ibuka, T.; Habashita, H.; Nakai,

K.; Fujii, N.; Imamura, M. Pancreas 1995, 10, 31.

(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.

(4) (a) Aumann, R.; Fro¨hlich, K.; Ring, H. Angew. Chem. 1974, 86,

309. (b) Hassner, A.; Wiegand, N. J . Org. Chem. 1986, 51, 3652. (c)

Spears, G. W.; Nakanishi, K.; Ohfune, Y. Synlett 1991, 91. (d) Tanner,

D.; Somfai, P. Biorg. Med. Chem. Lett. 1993, 3, 2415. (e) A° hman, J .;

Somfai, P.; Tanner, D. J . Chem. Soc., Chem. Commun. 1994, 2785. (f)

Knight, J . K.; Muldowney, M. P. Synlett 1995, 949. (g) A° hman, J .;

Somfai, P. Tetrahedron Lett. 1995, 36, 303. (h) Li, A. H.; Dai, L.-X.;

Hou, X.-L.; Chen, M.-B. J . Org. Chem. 1996, 61, 4641.

(8) Christos, T. E.; Arvanitis, A.; Cain, G. A.; J ohnson, A. L.; Pottorf,

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1035.

(9) Beresis, B.; Panek, J . S. Bioorg. Med. Chem. Lett. 1993, 3, 1609.

(10) Bartlett, P. A.; Otake, A. J . Org. Chem. 1995, 60, 3107.

(11) Fujii, N.; Nakai, K.; Habashita, H.; Hotta, Y.; Tamamura, H.;

Otaka, A.; Ibuka, T. Chem. Pharm. Bull. 1994, 42, 2241 and references

cited.

1000 J . Org. Chem., Vol. 62, No. 4, 1997

Ibuka et al.

Sch em e 2

chiral N-protected amino aldehyde derived from a natural

R-amino acid is reacted with organometallic reagents

such as vinylmagnesium bromide, a mixture of anti- and

syn-amino alcohols 1 and 2 is always obtained.¹²Usually,

N-monoprotected amino aldehydes exhibit low facial

diastereoselectivity.¹³While less stereoselective, the

synthetic procedure involving reactions of N-protected

amino aldehydes with vinylmagnesium halides still

remains the only practical route to amino alcohols 1 and

2.^12,14,15The ratio of isomers is highly dependent on the

structure of the starting material, the reagent, the

solvent, and the temperature of the reaction. Thus, the

highly stereoselective synthesis of either anti- or syn-

amino alcohols 1 or 2 and hence 2,3-trans- or 2,3-cis-3-

alkyl-2-vinylaziridines 3 or 4 from readily available

amino aldehydes has hitherto been difficult. This rather

low stereoselectivity in the reaction of amino aldehydes

with organometallic reagents such as vinylmagnesium

halides frequently hinders their use in many synthetic

applications.^7,12,16

As part of an ongoing program aimed at the synthesis

of biologically active peptides containing (E)-alkene isos-

teres,¹⁷we needed a reliable procedure for the synthesis

of activated cis-3-alkyl-2-vinylaziridines 4 as key syn-

thetic intermediates. In this context, we looked for a

convenient method for the transformation of undesired

2,3-trans-3-alkyl-2-vinylaziridines of general formula 3

into desired 2,3-cis-isomers of type 4. Recently, pal-

ladium(0)-catalyzed carbonylations of vinylaziridines to

â-lactams have been achieved successfully by Ohfune^4c

and Tanner.^4dIt was expected that palladium(0)-

catalyzed isomerization of 2,3-trans-3-alkyl-2-vinylaziri-

dines 3 into the corresponding desired cis-isomers 4 could

occur via π-allyl palladium complexes. Here we detail a

study involving the palladium(0)-catalyzed equilibrated

reaction of chiral N-(methanesulfonyl)- and N-(arene-

sulfonyl)-3-alkyl-2-vinylaziridines and N-(arenesulfonyl)-

4-alkyl-5-vinyloxazolidin-2-ones.¹⁸

(12) Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N.; Oguchi, Y.;

Uyehara, T.; Yamamoto, Y. J . Org. Chem. 1991, 56, 4370. See also:

Spaltenstein, A.; Leban, J . J .; Huang, J . J .; Reinhardt, K. R.; Humberto

Viveros, O.; Sigafoos, J .; Crouch, R. Tetrahedron Lett. 1996, 37, 1343.

For a reaction of amino ketones with vinylmagmesium bromide, see:

Maurer, P. J .; Knudsen, C. G.; Palkowitz, A. D.; Rapoport, H. J . Org.

Chem. 1985, 50, 325.

(13) Beaulieu, P. L.; Wernic, D. J . Org. Chem. 1996, 61, 3635.

(14) Hanson, G. J .; Lindberg, T. J . Org. Chem. 1985, 50, 5399.

(15) For a review, see: J urczak, J .; Golebiowski, A. Chem. Rev. 1989,

89, 149.

Resu lts a n d Discu ssion

Syn t h esis of 2,3-Cis/Tr a n s-P a ir s of Ch ir a l N-

(Meth a n esu lfon yl)- or N-(Ar en esu lfon yl)-3-a lk yl-2-

vin yla zir id in es a n d 4,5-Cis/Tr a n s-P a ir s of Ch ir a l

N -(Ar e n e s u lfo n y l)-4-a lk y l-5-v in y lo x a zo lid in -2-

on es. The requisite homochiral 2,3-cis/trans-pairs of

N-(methanesulfonyl)- and N-tosyl-3-methyl-2-vinylaziri-

dines (10 and 15, and 18 and 21) were prepared in

acceptable yields from the known (2S,3S)-N-trityl-3-

methyl-2-aziridinemethanol (7),^11,17t(D)-allo-threonine

methyl ester hydrochloride (11),¹¹(2S,3S)-N-tosyl-3-

methyl-2-aziridinemethanol (16),¹¹and methyl (2R,3S)-

3-methyl-N-tosylaziridine-2-carboxylate (19),¹¹respec-

tively, according to the usual method as shown in Scheme

2 (for details, see Experimental Section).

The chiral 2,3-cis/ trans-pairs of aziridines (24 and 25,

and 28 and29) were synthesized from the known allyl

alcohols 22 and 23^12,14by a sequence of reactions as

shown in Scheme 3 (for details, see Experimental Sec-

tion). It should be clearly noted that although N-(tert-

butoxycarbonyl)aziridines 24 and 25 are rather labile oily

compounds, the N-(mesitylenesulfonyl)aziridines 28 and

29 are stable crystalline substances.

(16) Franciotti, M.; Mann, A.; Taddei, M. Tetrahedron Lett. 1991,

32, 6783.

(17) (a) 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. (j)

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. (k) Wipf, P.; Fritch, P. C. J . Org. Chem. 1994, 59, 4875. (l)

J enmalm, A. J .; Berts, W.; Li, Y.-L.; Luthman, K.; Cso¨regh, I.; Hacksell,

U. J . Org. Chem. 1994, 59, 1139. (m) McKinney, J . A.; Eppley, D. F.;

Keenan, R. M. Tetrahedron Lett. 1994, 35, 5985. (n) Satake, A.;

Shimizu, I.; Yamamoto, A. Synlett 1995, 64. (o) Wai, J . S.; Fisher, T.

E.; Embrey, M. W. Tetrahedron Lett. 1995, 36, 3461. (p) Daly, M. J .;

Ward, R. A.; Thompson, D. F.; Procter, G. Tetrahedron Lett. 1995, 36,

7545. (q) Daly, M. J .; Procter, G. Tetrahedron Lett. 1995, 36, 7549. (r)

Beresis, R. T.; Masse, C. E.; Panek, J . S. J . Org. Chem. 1995, 60, 7714.

(s) Daly, M. J .; Ward, R. A.; Thompson, D. F.; Procter, G. Tetrahedron

Lett. 1995, 36, 7545. (t) 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. (u) Devadder, S.; Verheyden, P.;

J aspers, H. C. M.; van Binst, G.; Tourwe, D. Tetrahedron Lett. 1996,

37, 703. For (Z)-alkene dipeptide isosteres, see: (v) Bohnstedt, A. C.;

Prasad, J . V. N. V.; Rich, D. H. Tetrahedron Lett. 1993, 34, 5217. (w)

Garro-He´lion, F.; Guibe´, F. J . Chem. Soc., Chem. Commun. 1996, 641.

In a similar manner, the chiral 2,3-cis/trans-pair of

N-(mesitylenesulfonyl)aziridines 38 and 39 bearing a tert-

(18) For a preliminary communication of a portion of this work,

see: Mimura, N.; Ibuka, T.; Akaji, M.; Miwa, Y.; Taga, T.; Nakai, K.;

Tamamura, H.; Fujii, N.; Yamamoto, Y. J . Chem. Soc., Chem. Commun.

1996, 351. In the communication, species I and III in Scheme 1 should

be interchanged. For the corrigendum, see: J . Chem. Soc., Chem.

Commun. 1996, 1399.

Thermodynamics of 2,3-cis-3-Alkyl-2-vinylaziridines

J . Org. Chem., Vol. 62, No. 4, 1997 1001

Sch em e 3

Sch em e 5

in the presence of triethylamine, oxalyl chloride-di-

methyl sulfoxide-N,N-diisopropylethylamine, and vinyl

magnesium bromide to give a separable 53:47 mixture

of allyl alcohols 43 and 44 in 85% combined yield.

Exposure of 43 and 44 to triphenylphosphine-diethyl

azodicarboxylate in THF gave the aziridines 45 and 46,

respectively, in high isolated yields (for details, see

Experimental Section).

Sch em e 4

Finally, as shown in Scheme 6, the 2,3-cis/trans-pairs

of chiral aziridines (62 and 63, 64 and 65, and 68 and

69) and the 4,5-cis/trans-pairs of N-arenesulfonyl 4,5-

disubstituted-oxazolidin-2-ones (54 and 55, and 56 and

57) were prepared from (S)-leucinol 47¹⁹by a sequence

of reactions similar to that described for the synthesis of

the vinylaziridines 45 and 46 (for details, see Experi-

mental Section). The choice of 2,2,5,7,8-pentamethyl-

chroman-6-sulfonyl (Pmc)²⁰and p-nitrobenzenesulfonyl

(PNBS)²¹as both protective and activating groups was

based primarily on their ease of deprotection (for details,

see Experimental Section).

As can be seen from Table 1, the 2,3-cis-aziridines

(Table 1, entries 1-8) show J H_abvalues (J ) 6.8-7.3 Hz)

larger than the J H_abvalues (J ) 4.1-4.5 Hz) of the 2,3-

trans-isomers (Table 1, entries 9-16). In addition, the

H_aprotons in the 2,3-trans-3-alkyl-2-vinylaziridines al-

ways resonate at higher field (δ 3.07-3.23) than those

of the 2,3-cis-isomers (δ 3.28-3.45), respectively. The

data are in agreement with ¹H NMR data for related

compounds.²²It should be clearly noted that the 2,3-cis-

aziridines (Table 1, entries 1-8) show J H_acvalues (J )

6.8-7.1 Hz) smaller than the J H_acvalues (J ) 8.7-9.5

Hz) of the 2,3-trans-isomers (Table 1, entries 9-16).

Although the 2,3-cis- or 2,3-trans stereochemistry of

cis/ trans pairs of the aziridines listed in Table 1 was

1

inferred from H NMR spectral analyses, the structures

of 2,3-cis- and 2,3-trans-N-tosyl-3-methyl-2-vinylaziri-

dines 18 and 21 were unequivocally ascertained by single

crystal X-ray analyses (Figure 1).²³In their solid states

both compounds 18 and 21 are characterized by a well-

(19) McKennon, M. J .; Meyers, A. I.; Drauz, K.; Schwarm, M. J . Org.

Chem. 1993, 58, 3568.

(20) Ramage, R.; Green, J . Tetrahedron Lett. 1987, 28, 2287. Green,

J .; Ogunjobi, O. M.; Ramage, R.; Stewart, A. S. J . Tetrahedron Lett.

1988, 29, 4341.

(21) Fukuyama, T.; J ow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,

36, 6373.

(22) (a) Coutrot, P.; Elgadi, A.; Grison, C. Heterocycles 1989, 28,

1179. (b) Davis, F. A.; Zhou, P. Tetrahedron Lett. 1994, 35, 7525. (c)

Davis, F. A.; Zhou, P.; Reddy, G. V. J . Org. Chem. 1994, 59, 3243. (d)

Ziegler, F. E.; Belema, M. J . Org. Chem. 1994, 59, 7962.

butyldimethylsilyl group was prepared from the known

allyl alcohols 30 and 31¹²by a sequence of reactions as

shown in Scheme 4 (for details, see Experimental Sec-

tion).

The 2,3-cis/trans-pair of chiral aziridines 45 and 46

bearing an isopropyl group was synthesized from (S)-

valinol 40¹⁹as shown in Scheme 5. (S)-Valinol was

treated successively with 2-mesitylenesulfonyl chloride

1002 J . Org. Chem., Vol. 62, No. 4, 1997

Ibuka et al.

Sch em e 6

NMR spectral analyses (for structures 54-57, see Scheme

6). The 4,5-cis-oxazolidin-2-ones 55 and 57 show J H_4,5

values (J ) 6.9 Hz) larger than the J H_4,5values (J )

2.3-2.5 Hz) of the corresponding 4,5-trans-isomers 54

and 56. In addition, the proton at the C-5 position in

the 4,5-trans-compounds resonates at higher field (δ

4.60-4.70) than those of the 4,5-cis-isomers (δ 4.97-

1

4.98). The data are in agreement with H NMR data for

related compounds.^12,25,26

Ca lcu la tion s of Rela tive Sta bilities of 2,3-Cis-

Disu bstitu ted Azir id in es a n d Th eir 2,3-Tr a n s-Iso-

m er s. Recently, Lewis acid-catalyzed isomerizations of

stereochemistry at the C-2 or C-3 position of aziridines

have been observed for some 2,3-disubstituted aziri-

dines.²⁷Although, the relative thermodynamic stabilities

of 2,3-cis-disubstituted aziridines and their 2,3-trans-

isomers are dependent on the nature of the substituents

at the C-2 and C-3 positions, as well as the N-protecting

or activating group, Huisgen et al. reported experimental

studies on the relative stability of 1,2,3-trisubstituted

aziridines and discovered that 2,3-trans-aziridines are

more stable.²⁸J ørgensen et al. also recently reported that

an N-protected 2,3-cis-aziridine could be transformed into

an N-deprotected 2,3-trans-aziridine.²⁹Accordingly, at

first sight, the isomerization of N-activated 2,3-trans-3-

alkyl-2-vinylaziridines into their 2,3-cis-isomers did not

look promising. In spite of their synthetic utility, the

relative themodynamic stabilities of both unactivated and

activated 2,3-cis- and 2,3-trans-3-alkyl-2-vinylaziridines

are poorly understood.³⁰

In order to gain an understanding of the relative

stabilities of 2,3-cis- and 2,3-trans-disubstituted aziri-

dines, we undertook ab initio molecular orbital calcula-

tions involving full optimizations using the GAUSSIAN

92 quantum mechanical package (revision C).^31,32In

order to reduce the size of the system such that ab initio

calculations could be employed, two model systems of 2,3-

(25) (a) Karlsson, J . O.; Rundblad, A.; Malm, B.; Nilsson, I.;

Nitenberg, T.; Starke, I.; So¨rensen, H.; Westerlund, C. Tetrahedron

Lett. 1989, 30, 2653. (b) Dondoni, A.; Fantin, G.; Fogagnolo, M.;

Pedrine, P. J . Org. Chem. 1990, 55, 1439. (c) Sham, H. L.; Rempel, C.

A.; Stein, H.; Cohen, J . J . Chem. Soc., Chem. Commun. 1990, 904. (d)

Patel, D. V.; R.-Gauvin, K.; Ryono, D. E. Tetrahedron Lett. 1990, 31,

5587.

(26) Cardillo, G.; Gentilucci, L.; Tomasini, C.; Castejon-Bordas, M.

P. V. Tetrahedron: Asymmetry 1996, 7, 755.

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Soc. 1994, 116, 2742. (b) Ku¨hnau, D.; Thomasen, I.; J ørgensen, K. A.

J . Chem. Soc., Perkin Trans. 1 1996, 1167.

(28) (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.

(29) Rasmussen, K. G.; J ørgensen, K. A. J . Chem. Soc., Chem.

Commun. 1995, 1401.

(30) Cromwell, N. H.; Graff, M. A. J . Org. Chem. 1952, 17, 414. We

thank Professor D. Tanner, Denmark, for informing us of ref 30.

(31) All ab initio calculations were performed using the program

GAUSSIAN 92 on a CRAY Y-MP2E/264 at the Supercomputer Labora-

tory, 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.; Ragha-

vachari, 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.

(32) For ab initio calculations of some aziridines derivatives, see:

Rauk, A. J . Am. Chem. Soc. 1981, 103, 1023. Shustov, G. V.; Kadorkina,

G. K.; Kostyanovsky, R. J .; Rauk, A. J . Am. Chem. Soc. 1988, 110,

1719. Shustov, G. V.; Kachanov, A. V.; Kadorkina, G. K.; Kostyanovsky,

R. G.; Rauk, A. J . Am. Chem. Soc. 1992, 114, 8257. Shustov, G. V.;

Kadorkina, G. K.; Varlamov, S. V.; Kachanov, A. V.; Kostyanovsky, R.

G.; Rauk, A. J . Am. Chem. Soc. 1992, 114, 1616. Shustov, G. V.; Rauk,

A. J . Chem. Soc., Chem. Commun. 1993, 1669. Shustov, G. V.;

Kachanov, A. V.; Korneev, V. A.; Kostyanovsky, R. G.; Rauk, A. J . Am.

Chem. Soc. 1993, 115, 10267.

known pyramidal configuration of the ring nitrogen

atom.²⁴X-ray analysis of 2,3-trans-3-methyl-2-vinylaziri-

dine (21) indicates that the p-tosyl group is pointed away

from the vinyl group at the C-2 position (21-A, Figure

1). The origin of this conformation could come from the

repulsion between the vinyl group and the p-tosyl group

in 21. On the other hand, the asymmetric unit of 2,3-

cis-3-methyl-2-vinylaziridine (18) contains two crystal-

lographically independent molecules 18-A and 18-B. The

p-tosyl group in the conformer 18-A is pointed toward

the vinyl group, while it is pointed away from the vinyl

group in the isomeric conformer 18-B. As can be seen

from Figure 1, the p-tosyl groups on the aziridine

nitrogen in the solid state conformations 18-A, 18-B, and

21-A are trans with respect to the methyl group at the

C(3)-position.

Finally, stereochemical assignments for 4,5-trans/ cis-

pairs of 4-alkyl-5-vinyloxazilidin-2-ones (54 and 55, and

56 and 57), which are required for the Pd(0)-catalyzed

1

decarboxylative equilibrated reactions, are based on H

(23) The author has deposited atomic coordinates for this structure

with the Cambridge Crystallographic Data Centre. The coordinates

can be obtained, on request, from the Director, Cambridge Crystal-

lographic Data Centre. 12 Union Road, CB2 1EZ, UK.

(24) Rauk, A.; Allen, L. C.; Mislow, K. Angew. Chem. 1970, 82, 453.

Testa, B. In Principles of Organic Stereochemistry; Katritzky, A. R.,

Rees, C. W., Eds.; Marcel Dekker: New York and Basel, 1979; p 131.

Thermodynamics of 2,3-cis-3-Alkyl-2-vinylaziridines

J . Org. Chem., Vol. 62, No. 4, 1997 1003

Ta ble 1. ¹H NMR Ch em ica l Sh ifts for H_aa n d H_ba n d Sp in -Sp in Cou p lin g Con sta n ts for J H_{a b}a n d J H_{a c}of th e Selected

a

2,3-cis- a n d 2,3-tr a n s-Vin yla zir id in es in CDCl₃

entry

compound

2,3-cis/trans

R¹

R²

Ms

H_a(δ)

H_b(δ)

J H_ab(Hz)

J H_ac(Hz)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

10

18

28

38

45

62

64

68

15

21

29

39

46

63

65

69

cis

trans

Me

3.28

3.32

3.48

3.44

3.41

3.31

3.38

3.45

3.09

3.13

3.20

3.23

3.11

3.07

3.08

3.18

3.01

3.03

3.10

3.07

2.56

2.96

3.13

2.93

2.97

3.14

3.17

2.80

2.94

2.92

3.03

6.8

7.3

6.9

7.0

7.1

6.9

7.2

4.4

4.2

4.1

4.2

4.4

4.2

4.5

6.8

6.9

6.8

6.9

7.0

7.1

6.9

7.0

8.8

8.7

9.1

8.9

9.5

9.1

9.0

Ts

PhCH₂

TBDMSOCH₂

i-Pr

Mts

Ts

Pmc

PNBS

Ms

i-Bu

Me

Ts

PhCH₂

TBDMSOCH₂

i-Pr

Mts

Ts

Pmc

PNBS

i-Bu

a

All ¹H NMR spectra were recorded in CDCl₃at 300 K, and chemical shifts are reported in parts per million downfield from internal

TMS. For designations H_a, H_b, and H_c, see structures A and B. Abbreviations: Mts ) mesitylenesulfonyl; Pmc ) 2,2,5,7,8-

pentamethylchroman-6-sulfonyl; PNBS ) p-nitrobenzenesulfonyl.

Sch em e 7

basis set. The minimum conformations all have positive

frequencies, which is an indication of a true minimum

on the potential surface. Energy calculations for the

aziridines were performed with the second order Møller-

Plesset electron correlation (MP2) on the RHF/6-31**

optimized geometries.³⁴

We initiated our study to determine the relative

stabilities of a 2,3-cis-trans pair of 3-methyl-2-vinylaziri-

dines 70 and 71 (Figure 2). The geometries of 2,3-cis-3-

methyl-2-vinylaziridine 70-A and its nitrogen invertomer

70-B as well as 2,3-trans-3-methyl-2-vinylaziridine 71-A

and its nitrogen invertomer 71-B were located with ab

initio calculations involving full optimizations at the

RHF/6-31G** level. It was found that the energy mini-

mum 71-A of the 2,3-trans-aziridine 71 was predicted to

be 0.25 kcal/mol lower than the energy minimum 70-A

of the 2,3-cis-aziridine 70 at the MP2/6-31G** level.

F igu r e 1. Crystal structures and solid state conformations

The dihedral angle between the C(2)-H(2) bond and

of 18 and 21: 18-A and 18-B, 2,3-cis-N-tosyl-3-methyl-2-

the C(4)-H(4) bond for the most stable conformation

vinylaziridine. 21-A, 2,3-trans-N-tosyl-3-methyl-2-vinylaziri-

71-A of 2,3-trans-3-methyl-2-vinylaziridine (71) was pre-

dine.

dicted to be -177.9°, a spatial arrangement known as

cis-trans pairs (70 and 71, and 72 and 73) were chosen

(Scheme 7). Both theoretical and experimental aspects

were carried out with 2,3-cis- and 2,3-trans-N-(methane-

sulfonyl)-3-methyl-2-vinylaziridines 10 and 15 (Scheme

7).³³All conformational minima were fully optimized up

to the extended 6-31G** basis set. Harmonic frequencies

were calculated for each conformer using the 6-31G**

antiperiplanar. In normal allylic compounds, this con-

formation is favored.^35-37On the other hand, the angle

(34) For references dealing with the 6-31G** basis set and Møller-

Plesset perturbation theory, see: Hehre, W. J .; Radom, L.; Schleyer,

P. v. R.; Pople, J . A. In Ab Initio Molecular Orbital Theory; J ohn Wiley

& Sons: New York, 1986.

(35) For vinylcyclopropanes, see: De Mare, G. R.; Martin, J . S. J .

Am. Chem. Soc. 1966, 88, 5033. de Meijere, A.; Lu¨ttke, W. Tetrahedron

1969, 25, 2047.

(33) For synthesis of some N-mesylaziridines, see: (a) Lygo, B.

Synlett 1993, 764. (b) Bucciarelli, M.; Forni, A.; Moretti, I.; Prati, F.;

Torre, G. J . Chem. Soc., Perkin Trans. 1 1993, 3041.

(36) For vinyloxiranes, see: Marshall, J . A.; Trometer, J . D.; Blough,

B. E.; Crute, T. D. J . Org. Chem. 1988, 53, 4274.

1004 J . Org. Chem., Vol. 62, No. 4, 1997

Ibuka et al.

F igu r e 3. RHF/6-31G** optimized geometries of model

compounds 72 and 73. Energies are relative to the lowest

energy at the MP2/6-31G** level. 72-A and 72-B: 2,3-cis-1,3-

dimethyl-2-vinylaziridine and its nitrogen invertomer, respec-

tively. 73-A and 73-B: 2,3-trans-1,3-dimethyl-2-vinylaziridine

and its nitrogen invertomer.

its 2,3-cis-disubstituted isomer 70 in agreement with the

literature data.^28,29

In N-substituted aziridines, the interactions between

the N-substituent and the substituents at the C(2) and/

or C(3)-positions may have marked conformational con-

sequences. In this context, relative energies of a cis/

trans-pair of N-methyl-2,3-disubstituted aziridines (72

and 73) were investigated (Figure 3). The energy mini-

mum 72-A of 2,3-cis-N-methyl-3-methyl-2-vinylaziridine

(72) was predicted to be ca. 1.80 kcal/mol lower than the

energy minimum 73-A of 2,3-trans-isomer 73, as can be

seen from Figure 3. Interestingly, unlike 2,3-cis- and 2,3-

trans-3-methyl-2-vinylaziridines shown in Figure 2, the

dihedral angle between the C(2)-H(2) bond and the

C(4)-H(4) bond for the optimized geometries 72-A, 72-

B, 73-A, and 73-B were estimated to be 168.5-180°.

Thus, calculations suggest that 2,3-cis-N-methyl-3-meth-

yl-2-vinylaziridine (72) would be more stable than its 2,3-

trans-isomer 73.

F igu r e 2. RHF/6-31G** optimized geometries of model

compounds 70 and 71. Energies are relative to the lowest

energy at the MP2/6-31G** level. 70-A: (1R,2R,3S)-2,3-cis-3-

methyl-2-vinylaziridine. 70-B, 70-C, and 70-D: geometries of

the local energy minima of 2,3-cis-3-methyl-2-vinylaziridines

70. 71-A: the lowest energy geometry of (1R,2S,3S)-2,3-trans-

3-methyl-2-vinylaziridine. 71-B: the lowest energy minimum

of the nitrogen invertomer 71-A. 71-C: geometry of one of the

local energy minima of (1S,2S,3S)-2,3-trans-3-methyl-2-vinyl-

aziridine 71.

Finally, in 2,3-cis/ trans pairs, would 2,3-cis-N-mesyl-

2,3-substituted aziridines or their 2,3-trans-isomers be

expected to be the more stable isomers? The relative

stabilities of a 2,3-cis-trans pair of N-mesyl-3-methyl-

2-vinylaziridines 10 and 15 were investigated (Figure 4).

The energy minimum 10-A of 2,3-cis-N-mesyl-3-methyl-

2-vinylaziridine (10) was predicted to be approximately

1.43 kcal/mol lower than the energy minimum 15-A of

2,3-trans-isomer 15 at the MP2/6-31G** level. Assuming

∆S° ) 0, this energy difference is calculated to give the

equilibrated product ratio of 94:6 (2,3-cis-10:2,3-trans-

15) at 0 °C in the gas phase. As will be described later,

this prediction proved to be quite close to the experimen-

tal results in solution. Optimized geometry 10-B is the

model for estimating the repulsion between the N-mesyl

group and the substituents at the C-2 and C-3 positions.

When compared to conformer 10-A, this amounts ∼6.5

kcal/mol in energy difference.

between the C-H bonds on adjacent carbon atoms C(2)

and C(4) for the energy minimum 70-A of 2,3-cis-3-

methyl-2-vinylaziridine (70) was estimated to be only

45.8°. Likewise, the dihedral angles between the C(2)-

H(2) bond and the C(4)-H(4) bond in the local minima

70-B and 71-B (the nitrogen invertomers of 70-A and 71-

A) were predicted to be only 55.6° and -42.7°, respec-

tively, as shown in Figure 2. It should be clearly noted

that the geometries 70-C, 70-D, as well as 71-C with the

larger dihedral angles (almost antiperiplanar arrange-

ments) were predicated to be less stable.

Thus, as can be seen from Figure 2, 2,3-trans-disub-

stituted aziridine 71 is predicted to be more stable than

(37) (a) Khan, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, A. R. J .

Am. Chem. Soc. 1987, 109, 650. (b) Hoffmann, R. W. Chem. Rev. 1989,

89, 1841. (c) Broeker, J . L.; Hoffmann, R. W.; Houk, K. N. J . Am. Chem.

Soc. 1991, 113, 5006. (d) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl.

1992, 31, 1124.

Thermodynamics of 2,3-cis-3-Alkyl-2-vinylaziridines

J . Org. Chem., Vol. 62, No. 4, 1997 1005

Ta ble 2. P r ed icted Rela tive Sta bilities of 2,3-Cis/

Tr a n s-P a ir s of Com p ou n d s 70 a n d 71, 72 a n d 73, a n d 10

a n d 15

F igu r e 4. RHF/6-31G** optimized geometries of 2,3-cis-N-

mesyl-3-methyl-2-vinylaziridine (10) and its 2,3-trans-isomer

(15). Energies are relative to the lowest energy at the MP2/

6-31G** level. 10-A: the lowest energy geometry of 10. 10-B:

the optimized geometry of the nitrogen invertomer of 10-A.

15-A: the lowest energy geometry of 15. 15-B: the optimized

geometry of the nitrogen invertomer of 15-A.

Ta ble 3. Tota l a n d Rela tive En er gies of th e Cr itica l

P oin ts^a

MP2/6-31G**//RHF/6-31G**

RHF/6-31G**

geometry

E^b

∆E^c

2,3-cis- and 2,3-trans-3-Methyl-2-vinylaziridines 70 and 71

70-A (2,3-cis)

70-B (2,3-cis)

70-C (2,3-cis)

70-D (2,3-cis)

71-A (2,3-trans)

71-B (2,3-trans)

71-C (2,3-trans)

-249.84097

-249.83826

-249.83975

-249.83820

-249.84136

-249.84071

-249.84035

0.25

1.95

1.12

1.98

0.00

0.41

0.63

2,3-cis- and 2,3-trans-N-Methyl-3-methyl-

2-vinylaziridines 72 and 73

72-A (2,3-cis)

72-B (2,3-cis)

73-A (2,3-trans)

73-B (2,3-trans)

-288.00965

-288.00002

-288.00678

-288.00637

0.00

6.04

1.80

2.06

2,3-cis- and 2,3-trans-N-Mesyl-3-methyl-

2-vinylaziridines 10 and 15

F igu r e 5. Solid-state conformation of 2,3-trans-N-mesyl-3-

methyl-2-vinylaziridine (15) (left). One of the local minima of

(1R,2S,3S)-N-mesyl-3-methyl-2-vinylaziridine (15) at the RHF/

6-31G** level (right).

10-A (2,3-cis)

-835.18669

-835.17640

-835.18441

-835.18300

0.00

6.46

1.43

2.19

10-B (2,3-cis)

15-A (2,3-trans)

15-B (2,3-trans)

It is found that one of the local energy minima, 15-B,

shown in Figure 4, is quite similar to the solid-state

conformation²³of 2,3-trans-N-mesyl-3-methyl-2-vinylazir-

idine (15) [compare the solid-state conformation (left)

with the geometry (right) obtained by computations in

Figure 5]. The methyl group in the methanesulfonyl

group is pointed away from the vinyl group presumably

for steric reasons. Although the crystal structure con-

formation and the gas phase geometry need not to be the

same, in the solid state, the methanesulfonyl or arene-

sulfonyl group on the aziridine nitrogen of 3-alkyl-2-

vinylaziridines and their derivatives^17j,tis usually trans

with respect to the alkyl group at the C-3 position (see

also Figure 1).

Table 2 summarizes the above results obtained by

calculations. Entry 1 shows that 2,3-trans-3-methyl-2-

vinylaziridine (71) is predicted to be more stable than

its 2,3-cis-isomer 70 in accord with precedents.²⁸On the

other hand, entries 2 and 3 show that 2,3-cis-3-methyl-

2-vinylaziridines, bearing a methyl or mesyl group on the

nitrogen atom, are calculated to be more stable. The lone

electron pairs on the nitrogen atom of the stable nitrogen

invertomers of 2,3-cis compounds 72 and 10 are predicted

a

The character of all energy minima and transition states was

confirmed with calculation of force constant analyses at the

Hartree-Fock level. Energy calculations at the MP2 level were

performed on the RHF/6-31G** optimized geometries (single point

calculations). ^bTotal energies in atomic units (Hartree). ^ckcal/mol.

Energies are relative to the lowest energy.

to be on the same side of the aziridine-ring plane as the

C(2)- and C(3)-substituents, presumably for mere steric

reasons. On the contrary, in the stable conformation

15-A (Figure 4) of 2,3-trans-3-methyl-2-vinylaziridine

(15), the N-methanesulfonyl group is predicted to be on

the same side of the plane of the aziridine-ring as the

C(3)-methyl group. Thus, the nitrogen configuration

depends on a subtle balance of stereoelectronic factors.³⁸

Table 3 summarizes total and relative energies of the

critical points.

P a lla d iu m (0)-Ca ta lyzed Equ ilibr a ted Rea ction s

of 2,3-cis- a n d 2,3-tr a n s-3-Alk yl-2-vin yla zir id in es.

Since the energy difference in the gas phase is calculated

(38) For nitrogen configuration of some aziridine derivatives, see:

Ha¨ner, R.; Olano, B.; Seebach, R. Helv. Chim. Acta 1987, 70, 1676.

1006 J . Org. Chem., Vol. 62, No. 4, 1997

Ibuka et al.

Sch em e 9. P d (0)-Ca ta lyzed Equ ilibr a ted

Sch em e 8

Rea ction s

to give the equilibrated product ratio of 94:6 (2,3-cis-10:

2,3-trans-15) at 0 °C, it was our expectation that the

palladium(0)-catalyzed equilibrated reaction of N-acti-

vated 2,3-trans-3-alkyl-2-vinylaziridines B would aid in

producing the desired 2,3-cis-isomers A preferentially via

π-allyl palladium complexes E , D, and C as shown in

Scheme 8. However, we were still apprehensive as to

the possible success of palladium(0)-catalyzed isomer-

izations, because of a recent report disclosing that the

exposure of an N-activated 2-vinylaziridine to palladium-

(0)-catalyst led to the isolation of an aziridine-ring-opened

product.³⁹

To our delight, upon treatment with 5 mol % of Pd-

(PPh₃)₄in THF at 0 °C, 2,3-trans-N-mesyl-3-methyl-2-

vinylaziridine (15) gave a 98:2 mixture of 2,3-cis-N-mesyl-

3-methyl-2-vinylaziridine (10) and its 2,3-trans-isomer

(15) in 90% isolated yield in good agreement with the

computational prediction. So far THF appears to be the

solvent of choice for this equilibrated reaction. An

essentially identical result was obtained following treat-

ment of 2,3-cis-N-mesyl-3-methyl-2-vinylaziridine (10)

under the same reaction conditions (Scheme 9 and entries

1 and 2, Table 4). Thus, a good agreement was observed

between predicted and experimental results, thereby

providing feedback information about the reliability of

the calculation procedure used here.

silica gel flash chromatography. In the presence of PPh₃,

tris(dibenzylideneacetone)dipalladium [Pd₂(dba)₃] could

be used equally well (entries 3, 5, and 7, Table 4).

However, dibenzylideneacetone was found to hinder

product purification by silica gel flash chromatography.

As stated in the calculation section, in order to facili-

tate ab initio calculations, the most simple systems 10

and 15 bearing an N-mesyl group were chosen for

theoretical aspects. We anticipated that the relative

energies of the N-arenesulfonyl 2,3-cis/ trans 3-alkyl-2-

vinylaziridines would not be significantly influenced by

the change of the N-activating group.⁴⁰In this context,

in order to establish the observed equilibria in N-

mesylaziridines 10 and 15 as general trends, the same

chemical analyses were carried out for various 2,3-cis/

trans pairs of N-Boc- and N-(arenesulfonyl)-3-alkyl-2-

vinylaziridines (Scheme 9). Results obtained by exposure

to the palladium(0) catalyst(s) for the 2,3-cis/trans-pairs

of activated aziridines are summarized in Table 4.

Except for the N-Boc-aziridines 24 and 25 (entries 8 and

9, Table 4), it is readily apparent from Table 4 that the

equilibrated reactions give satisfactory results. The low

combined isolated yields in entries 8 and 9 could be

attributed to the low stability of the 24 and 25 toward

At the outset, changing the steric bulk of the N-

activating group and the alkyl group at the C-3 position

was considered to change the 2,3 cis-trans ratio of the

equilibrated products. Interestingly, as can be seen from

Table 4, neither the bulk of the N-activating group (Ms,

Ts, Mts, Pmc, PNBS) nor the 3-alkyl group (Me, isopro-

pyl, isobutyl, tert-butyldimethylsiloxymethyl, or benzyl)

exerts significant influence on the cis-trans ratios of the

reactions at equilibrium. It should be clearly noted that

although we usually stir reaction mixtures for 5-20 h,

reactions described above generally attained equilibrium

at 0 °C in THF within 60 min as can be seen from Figure

6.

Having established conditions for the equilibrated

reactions of cis- and trans-3-alkyl-2-vinylaziridines, the

reaction of five-membered heterocycles 54-57 with Pd-

(PPh₃)₄was briefly investigated (Scheme 10). As ex-

pected, when either the 4,5-trans-oxazolidin-2-one 54 or

the 4,5-cis-isomer 55 was treated with 5 mol % of Pd-

(PPh₃)₄, a 97:3 mixture of the cis-3-isobutyl-2-vinylaziri-

dine 62 and its trans-isomer 63 were formed in good yield

via a decarboxylative ring closure. A similar trend was

(39) Matano, Y.; Yoshimune, M.; Suzuki, H. J . Org. Chem. 1995,

60, 4663.

(40) Reduction of the size of systems for computations. Gung, B. W.;

Fouch, R. A.; Zou, D. J . Org. Chem. 1996, 61, 4200.

Thermodynamics of 2,3-cis-3-Alkyl-2-vinylaziridines

J . Org. Chem., Vol. 62, No. 4, 1997 1007

Ta ble 4. P a lla d iu m (0)-Ca ta lyzed Equ ilibr a ted Rea ction s

Sch em e 10

of N-Activa ted 3-Alk yl-2-vin yla zir id in es^a

combined

isolated

yield %

catalyst^b

product ratio^c

entry reactant (mol %) conditions 2,3-cis:2,3-trans

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

10

15

18

21

24

25

28

29

38

39

45

46

62

63

64

65

68

69

A (5)

B (4)

A (2)

B (4)

A (2)

B (4)

A (4)

A (5)

A (4)

0 °C, 18 h 10:15 ) 98:2

0 °C, 15 h 10:15 ) 98:2

0 °C, 18 h 10:15 ) 98:2

0 °C, 18 h 18:21 ) 96:4

0 °C, 18 h 18:21 ) 95:5

0 °C, 18 h 18:21 ) 96:4

0 °C, 18 h 18:21 ) 95:5

0 °C, 10 h 24:25 ) 91:9

0 °C, 20 h 24:25 ) 90:10

97

90

75

97

80

95

74

46

48

82

94

90

66

99

97

96

97

99

87

88

0 °C, 3 h

0 °C, 1 h

28:29 ) 94.6:5.4

28:29 ) 93.8:6.2

38:39 ) 91.6:8.4

0 °C, 15 h 38:39 ) 92.5:7.5

0 °C, 24 h 45:46 ) 95.5:4.5

0 °C, 24 h 45:46 ) 95.3:4.7

0 °C, 18 h 62:63 ) 97:3

0 °C, 18 h 62:63 ) 96:4

0 °C, 18 h 64:65 ) 96:4

0 °C, 18 h 64:65 ) 97:3

Sch em e 11

0 °C, 5 h

68:69 ) 93:7

a

All reactions were carried out in THF (ca. 0.05 molar solution)

b

under

a positive pressure of argon. A ) Pd(PPh₃)₄; B )

Pd₂(dba)₃‚CHCl₃:PPh₃) 1:8. ^cProduct ratios for entries 1-3 and

4-21 were determined by capillary gas chromatography (0.2 mm

× 50 m) and reverse phase HPLC, respectively.

F igu r e 6. Plot showing the variation in the percentage

composition of a mixture of 2,3-cis-N-Mts-3-isopropyl-2-vinyl-

aziridine (45) and its 2,3-trans-isomer (46) formed by treat-

ment of 46 with 5 mol % of Pd(PPh₃)₄in THF at 0 °C.

noted for the reaction of oxazolidin-2-ones 56 and 57

(Scheme 10).

Syn th etic Ap p lica tion to th e Syn th esis of (E)-

Alk en e Dip ep tid e Isoster es. To demonstrate the

utility of these equilibrated reactions, we have used this

chemistry for the synthesis of (E)-alkene dipeptide isos-

teres such as 77 and 78 (Scheme 11). The importance of

optically active (E)-alkene isosteres as key intermediates

for the synthesis of various types of polypeptides has been

demonstrated by many groups.^6-10,12,41It has also been

disclosed that the stereochemistry at the R-carbon center

in (E)-alkene dipeptide isosteres is one of the essential

factors for enzyme inhibition.⁴²We have also recently

reported that the synthetic isosteric peptide 79, contain-

ing a dipeptide isostere 78, is a potent bombesin receptor

antagonist with no agonist activity.⁶As stated before,

the efficient synthesis of chiral 2,3-cis-3-alkyl-2-vinyl-

aziridines is one of the keys to stereocontrol over the new

chiral centers of the (E)-alkene isosteres.

(41) (a) Shue, Y.-K.; Tufano, M. D.; Nadzan, A. M. Tetrahedron Lett.

1988, 29, 4041. (b) 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 .; P. K. W. Woo, P. K. W.; Essenburg, A. D. J . Med.

Chem. 1990, 33, 838. (c) 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. (d) Touwe, D.; De Cock, E.; van

Marsenille, M.; van der Auwera, L.; van Binst, G.; Viville, R.; Degelaen,

J .; Scarso, A. Peptides 1988; J ung, G., Bayer, E., Eds.; Walter de

Gruyter: Berlin and New York, 1989; p 562. (e) Tourwe, D.; Couder,

J .; Ceusters, M.; Meert, D.; Burks, T. F.; Kramer, T. H.; Davis, P.;

Knapp, R.; Yamamura, H. I.; Leysen, J . E.; van Binst, G. Int. J . Pept.

Protein Res. 1992, 39, 131.

(42) Cox, M. T.; Gormley, C. F.; Hayward, C. F.; Petter, N. N. J .

Chem. Soc., Chem. Commun. 1980, 800. Fujimoto, K.; Doi, R.; Hosotani,

R.; Wada, M.; Lee, J .-U.; Koshiba, T.; Ibuka, T.; Habashita, H.; Nakai,

K.; Fujii, N.; Imamura, M. Life Sci., 1997, 60, 29.

1008 J . Org. Chem., Vol. 62, No. 4, 1997

Ibuka et al.

(2R,3S)-3-Met h yl-N-t r it yl-2-vin yla zir id in e (9). To a

stirred solution of oxalyl chloride (2.5 mL, 26 mmol, 1.5 equiv)

in dry CH₂Cl₂(200 mL) at -78 °C under argon was added

dropwise a solution of DMSO (7.36 mL, 103.8 mmol, 6 equiv)

in CH₂Cl₂(20 mL). After 20 min, a solution of the trityl alcohol

7¹¹(5.7 g, 17.3 mmol) in CH₂Cl₂(20 mL) was added to the

above reagent at -78 °C, and the mixture was stirred for 1 h.

Diisopropylethylamine (21 mL, 0.12 M) was added dropwise

to the above solution at -78 °C, and the mixture was stirred

for 2 h with warming to 0 °C. The reaction was quenched with

40 mL of a saturated aqueous NH₄Cl solution at -78 °C with

vigorous stirring. The mixture was extracted with Et₂O, and

the extract was washed with water and dried over MgSO₄.

Concentration under reduced pressure gave a crude aldehyde

as a colorless oil. To a stirred solution of the above oily

aldehyde in THF (50 mL) at 0 °C was added a THF solution

(200 mL) of methylenetriphenylphosphorane, preprared from

methyltriphenylphosphonium bromide (24.7 g, 69.2 mmol) and

n-BuLi (43.2 mL, 69.2 mmol, 1.6 M in n-hexane), and the

mixture was stirred for 30 min at 0 °C. The reaction was

quenched with 20 mL of a 5% NH₄Cl solution at -78 °C with

vigorous stirring. Usual workup followed by flash chroma-

tography over silica gel with n-hexane-EtOAc (5:1) gave 2.3

The Pd(0)-catalyzed equilibrated reaction has been

successfully applied to the synthesis of (E)-alkene dipep-

tide isosteres. Typically, when a 2:3 mixture of the 2,3-

cis- and 2,3-trans-aziridines 64 and 65 (4.5 g) was allowed

to stand at 0 °C in THF in the presence of 4 mol % of

Pd(PPh₃)₄for 18 h, subsequent flash chromatographic

separation of a 96:4 cis/trans mixture of 64 and 65 led to

the isolation of the desired 2,3-cis-aziridine 64 in an 88%

yield (see Experimental Section). Exposure of 64 to ozone

followed by tert-butyl (triphenylphosphoranylidene)-

acetate yielded a separable 1:12.6 mixture of (Z)- and (E)-

R,â-unsaturated esters 74 and 75 in 83% combined yield.

When tert-butyl (triphenylphosphoranylidene)acetate was

substituted for the anion of tert-butyl diethylphospho-

noacetate,⁴³only the desired (E)-unsaturated ester 75

was obtained in a comparable isolated yield. Reaction

of 75 with isobutyl-Cu(CN)MgCl or isopentyl-Cu(CN)-

MgCl in THF at -78 °C for 30 min yielded stereospecifi-

cally the required (E)-alkene dipeptide isostere 76 or 77

in high isolated yields.^17j,tThe absolute configuration at

the alkylated carbon center in (E)-alkene isosteres can

be determined by a circular dichroism measurement. We

have previously reported that given the sign of the n f

π* Cotton effect, the absolute configuration at the R-posi-

tion in the (E)-alkene isosteres can be determined.⁴⁴The

isostere 76 shows a negative n f π* Cotton effect (∆ꢀ:

-8.78, 222 nm, in isooctane). Similarly, 77 exhibits a

negative Cotton effect (∆ꢀ: -7.82, 222 nm, in isooctane).

Consequently, the absolute configuration at the alkylated

carbon center in the isosteres 76 and 77 was assigned

as R. Deprotection of both the N- and carboxy protecting

groups in 76 followed by tert-butoxycarbonylation yielded

the NH-Boc-isostere 78, which can be used for the

synthesis of the potent bombesin antagonist 79.⁶

In summary, we have developed a reliable procedure

for the isomerization of the undesired 2,3-trans-3-alkyl-

2-vinylaziridines into the desired 2,3-cis-isomers by

means of palladium(0)-catalyzed equilibrated reactions.

2,3-trans-2,3-Disubstituted NH aziridine 71 shown in

Figure 2 is predicted to be more stable than the corre-

sponding cis-isomer 70. On the contrary, as shown in

Figures 3 and 4 and Table 2 (entries 2 and 3), 2,3-cis-

disubstituted aziridines with an N-methyl or mesyl group

are predicted to be more stable than their 2,3-trans-

isomers. Use of Pd(PPh₃)₄has thus overcome the prob-

lematic stereoselectivity in the synthesis of allylic alco-

hols from protected chiral amino aldehydes and has put

the method on a sound synthetic footing.

g (41% yield) of the title compound 9 as a colorless oil. [R]²⁶

D

-70 (c 0.99, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 1.26 (d, J )

5.6 Hz, 3 H), 1.44 (m, 1 H), 1.67 (m, 1 H), 5.18-5.25 (m, 2 H),

5.88 (m, 1 H), 7.17-7.28 (m, 9 H), 7.45-7.49 (m, 6 H). LRMS

(CI, reagent gas: methane) m/z, 326 (MH⁺), 271, 248, 240 (base

peak). HRMS (CI, reagent gas: methane) m/z, calcd for

C₂₄H₂₄N (MH⁺) 326.1909; found: 326.1915.

(2R,3S)-N-(Met h a n esu lfon yl)-3-m et h yl-2-vin yla zir i-

d in e (10). To a solution of the N-tritylaziridine 9 (550 mg,

1.7 mmol) in 3 mL of CHCl₃at 0 °C was added 2 mL of TFA,

and the mixture was stirred for 2 h. Concentration under

reduced pressure gave an oily residue, which was used without

purification for the next step. To a stirred solution of the above

oily residue in 5 mL of CHCl₃at -60 °C were added succes-

sively 2 mL of Et₃N and 0.5 mL of methanesulfonyl chloride

with vigorous stirring, and the whole was stirred for 3 h at 0

°C. It was then cooled to 0 °C, and a saturated NaHCO₃

solution (10 mL) was added with vigorous stirring. The

mixture was extracted with EtOAc, and the extract was

washed successively with 5% citric acid, water, 5% NaHCO₃,

and water and dried over MgSO₄. Usual workup followed by

flash chromatography over silica gel with n-hexane-EtOAc

(3:1) gave 100 mg (37% yield) of the title compound 10 as a

colorless oil. [R]²⁵_D-94.8 (c 0.736, CHCl₃); ¹H NMR (300 MHz,

CDCl₃) δ 1.29 (d, J ) 5.8 Hz, 3 H), 3.01 (m, 1 H), 3.03 (s, 3 H),

3.28 (m, 1 H), 5.38-5.55 (m, 2 H), 5.68 (ddd, J ) 14.1, 10.2,

6.8 Hz, 1 H). LRMS (FAB) m/z, 162 (MH⁺, base peak), 149,

113, 82, 57. HRMS (FAB) m/z, calcd for C₆H₁₂NO₂S (MH⁺)

162.0589; found: 162.0580.

Meth yl O-(ter t-Bu tyld im eth ylsilyl)-N-(m eth a n esu lfo-

n yl)-^D-a llo-th r eon in a te (12). To a stirred solution of D-allo-

threonine methyl ester hydrochloride (11) (5.7 g, 33.6 mmol)

in a mixture of 20 mL of CHCl₃and 20 mL of DMF at -78 °C

were added successively N,N-diisopropylethylamine (14.6 mL,

0.168 M) and methanesulfonyl chloride (3.12 mL, 40.3 mmol),

and then the mixture was allowed to warm to 0 °C. After 2 h,

imidazole (9.13 g, 134 mmol) and tert-butyldimethylsilyl

chloride (6.088 g, 40.3 mmol) were added to the mixture with

stirring at 0 °C, and stirring was continued for 48 h, followed

by quenching with aqueous 5% NaHCO₃(20 mL). The mixture

was extracted with Et₂O, and the extract was washed succes-

sively 5% citric acid, water, 5% NaHCO₃, and water and then

dried over MgSO₄. Concentration under reduced pressure

gave an oily residue, which was purified by flash chromatog-

raphy over silica gel with n-hexane-EtOAc (3:1) to give 7.5 g

Exp er im en ta l Section

Gen er a l Meth od s. 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. All NMR spectra were recorded in

CDCl₃unless otherwise specified. 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. The enantiomeric excess (ee) was determined using

chiral HPLC columns (Chiralcel OD or Chiralcel OB, Daicel,

or ChiraSpher, Merck).

(69% yield) of the title compound 12 as a colorless oil. [R]²⁵

D

-8.3 (c 1.77, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 0.092 (s, 3

H), 0.10 (s, 3 H), 0.89 (s, 9 H), 1.20 (d, J ) 6.3 Hz, 3 H), 3.01

(s, 3 H), 3.79 (s, 3 H), 4.12-4.21 (m, 2 H), 5.09 (d, J ) 7.7 Hz,

1 H). LRMS (FAB) m/z, 326 (MH⁺), 310, 268 (base peak), 266,

208, 194, 159. HRMS (FAB) m/z, calcd for C₁₂H₂₈NO₅SSi

(MH⁺) 326.1457; found: 326.1444.

(43) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;

Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,

2183.

(44) Ibuka, T.; Habashita, H.; Funakoshi, S.; Fujii, N.; Baba, K.;

Kozawa, M.; Oguchi, Y.; Uyehara, T.; Yamamoto, Y. Tetrahedron:

Asymmetry 1990, 1, 389.

Thermodynamics of 2,3-cis-3-Alkyl-2-vinylaziridines

J . Org. Chem., Vol. 62, No. 4, 1997 1009

Meth yl N-(Meth a n esu lfon yl)-D-a llo-th r eon in a te (13).

To a stirred solution of the silyl ether 12 (2.5 g, 7.67 mmol) in

a mixture of MeCN (18 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, which was purified by

flash chromatography over silica gel eluting with n-hexane-

EtOAc (1:2) to give 1.55 g (96% yield) of the title compound

13 as a colorless syrup. [R]²⁵_D-0.86 (c 1.72, CHCl₃); ¹H NMR

(270 MHz, CDCl₃) δ 1.21 (d, J ) 6.3 Hz, 3 H), 2.74 (d, J ) 7.0

Hz, 1 H), 3.04 (s, 3 H), 3.82 (s, 3 H), 4.16-4.26 (m, 2 H), 5.63

(d, J ) 8.3 Hz, 1 H). LRMS (FAB) m/z, 212 (MH⁺, base peak),

194, 152, 134. HRMS (FAB) m/z, calcd for C₆H₁₄NO₅S (MH⁺)

212.0593; found: 212.0596.

Meth yl (2R,3S)-N-(Meth an esu lfon yl)-3-m eth ylazir idin e-

2-ca r boxyla te (14). Triphenylphosphine (2.34 g, 8.93 mmol)

and diethyl azodicarboxylate (1.2 mL, 7.56 mmol) were added

to a stirred solution of the alcohol 13 (1.45 g, 6.87 mmol) in

20 mL of THF at 0 °C, and the mixture was allowed to warm

to room temperature and stirred at this temperature for 1 h.

The mixture was concentrated under reduced pressure to an

oil, which was flash chromatographed on a silica gel column.

Elution with n-hexane-EtOAc (3:2) gave 1.28 g (96% yield)

of the title compound 14 as a colorless oil. Kugelrohr distil-

lation, 115 °C (1 Torr); [R]²⁵_D+102.6 (c 1.16, CHCl₃); ¹H-NMR

(300 MHz, CDCl₃) δ 1.67 (d, J ) 6.0 Hz, 3 H), 3.08-3.16 (m,

1 H), 3.14 (s, 3 H), 3.29 (d, J ) 4.0 Hz, 1 H), 3.79 (s, 3 H).

Anal. Calcd for C₆H₁₁NO₄S: C, 37.3; H, 5.74; N, 7.25.

Found: C, 37.21; H, 5.80; N, 7.24.

31% yield): colorless crystals from n-hexane-Et₂O (5:1); mp

83 °C; [R]²⁶-87.4 (c 0.633, CHCl₃); ee > 98% (Chiralcel OB,

D

2-PrOH: n-hexane ) 85:15); ¹H NMR (300 MHz, CDCl₃) δ 1.45

(d, J )5.8 Hz, 3 H), 2.44 (s, 3 H), 2.97 (m, 1 H), 3.13 (dd, J )

8.7, 4.4 Hz, 1 H), 5.29-5.32 (m, 1 H), 5.41-5.48 (m, 1 H), 5.91

(ddd, J ) 17.1, 10.2, 8.7 Hz, 1 H), 7.27-7.33 (m, 2 H), 7.80-

7.84 (m, 2 H). Anal. Calcd for C₁₂H₁₅NO₂S: C, 60.73; H, 6.37;

N, 5.90. Found: C, 60.78; H, 6.40; N, 5.86.

(2R,3S)-3-Ben zyl-N-(ter t-bu toxyca r bon yl)-2-vin yla zir i-

d in e (24). Triphenylphosphine (262 mg, 1 mmol, 2 equiv) and

diethyl azodicarboxylate (0.326 mL of a 40% solution in

toluene, 0.75 mmol, 1.5 equiv) were added to a stirred solution

of the alcohol 22 (139 mg, 0.5 mmol) in 4 mL of THF at 0 °C,

and the mixture was stirred at this temperature for 5 h. The

mixture was concentrated under reduced pressure to an oil,

which was flash chromatographed on a silica gel column.

Elution with n-hexane-EtOAc (5:1) gave 100 mg (77% yield)

of the title compound 24 as a colorless oil. [R]²⁵_D-42.9 (c 0.81,

CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 1.43 (s, 9 H), 2.67-2.79

(m, 2 H), 2.84-2.96 (m, 1 H), 3.05 (dddd, J ) 6.4, 6.4, 0.8, 0.8

Hz, 1 H), 5.36 (ddd, J ) 10.4, 1.7, 0.8 Hz, 1 H), 5.41 (ddd, J )

17.1, 1.7, 0.8 Hz, 1 H), 5.79 (ddd, J ) 17.1, 10.4, 6.4 Hz, 1 H),

7.18-7.31 (m, 5 H). LRMS (FAB) m/z, 260 (MH⁺), 259, 204

(base peak), 160, 143, 91, 57. HRMS (FAB), m/z, calcd for

C₁₆H₂₂NO₂(MH⁺) 260.1650; found: 260.1643.

(2S,3S)-3-Ben zyl-N-(ter t-bu toxyca r bon yl)-2-vin yla zir i-

d in e (25). By use of a procedure similar to that described for

the synthesis of the vinylaziridine 24 from 22, 277 mg (1 mmol)

of 23 was converted into 200 mg (77% yield) of the title

compound 25 as a colorless oil by treatment with PPh₃(262

mg) and diethyl azodicarboxylate (0.434 mL of a 40% solution

in toluene) in THF (5 mL) at 0 °C for 5 h followed by usual

(2S ,3S )-N -(Me t h a n e su lfon yl)-3-m e t h yl-2-vin yla zir i-

d in e (15). Diisobutylaluminum hydride in toluene (4.8 mL,

4.8 mmol; 1.0 M solution) was added dropwise to a stirred

solution of the ester 14 (744 mg, 4 mmol) in 13 mL of toluene

at -78 °C under argon. After 1 h, a saturated NH₄Cl solution

(2 mL) was added dropwise with vigorous stirring. The

mixture was made acidic with 15% citric acid at 0 °C and

extracted with CHCl₃. The extract was washed with water

and dried over MgSO₄. Concentration under reduced pressure

gave a crude aldehyde as a colorless oil. To a stirred solution

of the above oily aldehyde in THF (10 mL) at 0 °C was added

a THF solution (30 mL) of methylenetriphenylphosphorane,

preprared from methyltriphenylphosphonium bromide (4.11

g, 11.5 mmol) and n-BuLi (7.19 mL, 11.5 mmol, 1.6 M in

n-hexane), and the mixture was stirred for 30 min at 0 °C.

The reaction was quenched with 2 mL of a 5% NH₄Cl solution

at 0 °C with vigorous stirring. The mixture was concentrated

under reduced pressure to a semisolid, which was flash

chromatographed on a silica gel column. Elution with n-hex-

ane-EtOAc (2:1) gave 100 mg of a colorless solid, which was

recrystallized from cold n-hexane-Et₂O (4:1) to give the title

compound 15 (80 mg, 12.4% yield) as colorless crystals: mp

workup and flash chromatography over silica gel with n-hex-

1

ane-EtOAc (5:1). [R]²⁵-16 (c 0.84, CHCl₃); H NMR (300

D

MHz, CDCl₃) δ 1.45 (s, 9 H), 2.61-2.71 (m, 2 H), 2.88 (dd, J )

7.3, 3.0 Hz, 1 H), 3.05 (m, 1 H), 5.23-5.50 (m, 3 H), 7.19-7.36

(m, 5 H). LRMS (FAB) m/z, 260 (MH⁺), 259, 204 (base peak),

158, 143, 91, 57. HRMS (FAB), m/z, calcd for C₁₆H₂₂NO₂

(MH⁺) 260.1650; found: 260.1652.

(3S,4S)-5-P h en yl-4-[N-(2,4,6-t r im et h ylb en zen esu lfo-

n yl)a m in o]-1-p en ten -3-ol (26). Trifluoroacetic acid (15 mL)

was added to 1.385 g (5 mmol) of the alcohol 22^12,14at 0 °C,

and the mixture was stirred for 1 h. The solution was

concentrated under reduced pressure to an oily residue, which

was made alkaline with 28% NH₄OH and extracted with

CHCl₃. The extract was washed with brine and concentrated

under reduced pressure to leave a colorless oil. To the oil in

50 mL of CHCl₃were added successively 15 mL of Et₃N and

1.31 g (6 mmol) of mesitylenesulfonyl chloride. After being

stirred for 1 h at 0 °C, 10 mL of 10% NaHCO₃was added to it,

and the mixture was stirred for 30 min. The mixture was

made acidic with 20% citric acid and extracted with EtOAc

and the extract was washed with water and dried over MgSO₄.

Concentration followed by flash chromatography over silica

gel with n-hexane-EtOAc (2:1) gave 1.493 g (83% yield) of the

48 °C; [R]²⁵-40.5 (c 0.682, CHCl₃); ¹H NMR (300 MHz,

D

CDCl₃) δ 1.50 (d, J ) 5.8 Hz, 3 H), 2.93 (ddd, J ) 11.6, 5.8, 4.4

Hz, 1 H), 3.05 (s, 3 H), 3.09 (dd, J ) 8.8, 4.4 Hz, 1 H), 5.34-

5.38 (m, 1 H), 5.50-5.56 (m, 1 H), 5.86 (ddd, J ) 17.1, 10.2,

8.8 Hz, 1 H). LRMS (CI: reagent gas, methane) m/z, 162

(MH⁺, base peak), 146, 120, 106, 84, 83, 82. HRMS (CI:

reagent gas, methane) m/z, calcd for C₆H₁₂NO₂S (MH⁺)

162.0589; found: 162.0589.

title compound 26. Colorless crystals from n-hexane-Et₂O (2:

1

1); mp 92-93 °C; [R]²⁷-42.0 (c 1.02, CHCl₃); H NMR (270

D

MHz, CDCl₃) δ 1.99 (d, J ) 3.8 Hz, 1 H), 2.28 (s, 3 H), 2.56 (s,

6 H), 2.65 (dd, J ) 13.8, 6.5 Hz, 1 H), 2.93 (dd, J ) 13.8, 8.6

Hz, 1 H), 3.43 (m, 1 H), 4.10 (m, 1 H), 4.96 (d, J ) 8.6 Hz, 1

H), 5.05-5.25 (m, 2 H), 5.69 (ddd, J ) 17.3, 10.5, 5.7 Hz, 1 H),

7.00-7.21 (m, 5 H); LRMS (FAB) m/z, 360 (MH⁺), 302, 183,

119 (base peak), 91. HRMS (FAB), m/z, calcd for C₂₀H₂₆NO₃S

(MH⁺) 360.1633; found: 360.1631.

(2R,3S)-3-Met h yl-N-(4-m et h ylb en zen esu lfon yl)-2-vi-

n yla zir id in e (18). By use of a procedure similar to that

described for the preparation of 9 from 7, the known 2-aziri-

dinemethanol 16¹¹(2.892 g, 12 mmol) was converted into the

title compound 18 (300 mg, 11% yield): colorless crystals from

(3R,4S)-5-P h en yl-4-[N-(2,4,6-t r im et h ylb en zen esu lfo-

n yl)a m in o]-1-p en ten -3-ol (27). By use of a procedure identi-

cal with that described for the preparation of 26 from 22, the

known alcohol 23^12,14(730 mg, 2.635 mmol) was converted into

677 mg (72% yield) of the title compound 27. Colorless crystals

from n-hexane-Et₂O (2:1); mp 72-73 °C; [R]²⁷_D-43.9 (c 1.00,

n-hexane-Et₂O (4:1); mp 84 °C; [R]²⁶-1.0 (c 1.05, CHCl₃);

D

ee > 99% (Chiralcel OB, 2-PrOH: n-hexane ) 85:15); ¹H NMR

(300 MHz, CDCl₃) δ 1.19 (d, J ) 5.8 Hz, 3 H), 2.44 (s, 3 H),

3.03 (ddd, J ) 11.7, 7.3, 5.8 Hz, 1 H), 3.32 (m, 1 H), 5.27-5.31

(m, 1 H), 5.60 (ddd, J ) 17.2, 10.3, 6.9 Hz, 1 H), 7.31-7.34

(m, 2 H), 7.80-7.84 (m, 2 H). Anal. Calcd for C₁₂H₁₅NO₂S:

C, 60.73; H, 6.37; N, 5.90. Found: C, 60.45; H, 6.47; N, 5.82.

(2S,3S)-3-Meth yl-N-(4-m eth ylben zen esu lfon yl)-2-vin yl-

a zir id in e (21). By use of a procedure similar to that described

for the preparation of 15 from 14, the known ester 19¹¹(1.8 g,

6.69 mmol) was converted into the title compound 21 (500 mg,

1

CHCl₃); H NMR (270 MHz, CDCl₃) δ 1.72 (d, J ) 6.8 Hz, 1

H), 2.27 (s, 3 H), 2.43 (s, 6 H), 2.61 (dd, J ) 14.5, 8.9 Hz, 1 H),

2.68 (m, 1 H), 2.77 (dd, J ) 14.5, 5.7 Hz, 1 H), 3.48 (m, 1 H),

4.38 (m, 1 H), 4.86 (m, 1 H), 5.30 (ddd, J ) 10.5, 1.5, 1.5 Hz,

1 H), 5.39 (ddd, J ) 17.5, 1.5, 1.5 Hz, 1 H), 5.89 (ddd, J )

17.5, 10.5, 5.7 Hz, 1 H), 6.70-7.26 (m, 5 H). Anal. Calcd for

1010 J . Org. Chem., Vol. 62, No. 4, 1997

Ibuka et al.

C₂₀H₂₅NO₃S: C, 66.82; H, 7.01; N, 3.90. Found: C, 66.56; H,

7.04; N, 3.87.

+72.3 (c 1.15, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 0.12 (s, 3

H), 0.14 (s, 3 H), 0.87 (s, 9 H), 2.30 (s, 3 H), 2.64 (s, 6 H), 4.00

(s, 1 H), 4.02 (s, 1 H), 4.21 (m, 1 H), 4.96 (m, 1 H), 5.32 (d, J

) 10.5 Hz, 1 H), 5.39 (d, J ) 17.3 Hz, 1 H), 5.88 (ddd, J )

17.3, 10.5, 5.1 Hz, 1 H), 6.97 (s, 2 H). Anal. Calcd for

C₂₁H₃₃NO₅SSi: C, 57.38; H, 7.57; N, 3.19. Found: C, 57.10;

H, 7.56; N, 3.12.

(2R,3S)-3-Ben zyl-N-(2,4,6-tr im eth ylben zen esu lfon yl)-

2-vin yla zir id in e (28). By use of a procedure similar to that

described for the synthesis of 24 from 22, 213 mg (0.593 mmol)

of the allyl alcohol 26 was converted into 141 mg (70% yield)

of the title compound 28 by treatment with PPh₃(187 mg, 1.1

mmol) and 0.098 mL (0.622 mmol) of diethyl azodicarboxylate

in THF (2 mL) at 0 °C for 5 h followed by usual workup and

flash chromatography over silica gel with n-hexane-EtOAc

(9:1). Colorless crystals from n-hexane-Et₂O (2:1); mp 73-

74 °C; [R]²⁶_D-25.7 (c 1.01, CHCl₃); ¹H NMR (270 MHz, CDCl₃)

δ 2.29 (s, 3 H), 2.58 (s, 6 H), 2.65 (dd, J ) 14.6, 7.8 Hz, 1 H),

2.75 (dd, J ) 14.6, 5.7 Hz, 1 H), 3.10 (m, 1 H), 3.48 (dd, J )

7.3, 6.8 Hz, 1 H), 5.37 (m, 1 H), 5.50 (m, 1 H), 5.79 (ddd, J )

17.0, 10.5, 6.8 Hz, 1 H), 6.80-7.20 (m, 5 H). Anal. Calcd for

C₂₀H₂₃NO₂S: C, 70.35; H, 6.79; N, 4.10. Found: C, 70.19; H,

6.78; N, 3.98.

(4S,5R)-4-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-N-(2,4,6-

tr im eth ylben zen esu lfon yl)-5-vin yloxa zolid in -2-on e (35).

By use of a procedure identical with that described for the

synthesis of the oxazolidin-2-one 34 from 32, 500 mg (1.945

mmol) of the oxazolidin-2-one 33 was converted into 573 mg

(67% yield) of the title compound 35. Colorless crystals from

n-hexane-EtOAc (3:1); mp 133 °C; [R]²⁷+129 (c 0.952,

D

1

CHCl₃); H NMR (270 MHz, CDCl₃) δ 0.12 (s, 3 H), 0.15 (s, 3

H), 0.92 (s, 9 H), 2.30 (s, 3 H), 2.68 (s, 6 H), 3.86 (d, J ) 11.5

Hz, 1 H), 4.13 (dd, J ) 11.5, 3.2 Hz, 1 H), 4.40 (dd, J ) 7.6,

2.7 Hz, 1 H), 4.98 (t, J ) 7.6 Hz, 1 H), 4.46 (d, J ) 10.3 Hz, 1

H), 5.50 (d, J ) 17.5 Hz, 1 H), 6.13 (ddd, J ) 17.6, 10.3, 7.6

Hz, 1 H), 6.98 (s, 2 H). Anal. Calcd for C₂₁H₃₃NO₅SSi: C,

57.38; H, 7.57; N, 3.19. Found: C, 57.53; H, 7.65; N, 3.12.

(3S,4S)-5-(ter t-Bu tyldim eth ylsiloxy)-4-[N-(2,4,6-tr im eth -

ylben zen esu lfon yl)a m in o]-1-p en ten -3-ol (36). To a stirred

solution of the oxazolidin-2-one 34 (2 g, 4.56 mmol) in 15.3

mL of MeOH-H₂O (2:1) at 0 °C was added 2.3 g of KOH, and

the mixture was stirred for 15 h at room temperature. The

solution was concentrated under reduced pressure and ex-

tracted with Et₂O. The extract was washed with brine and

dried over MgSO₄. Usual workup and flash chromatography

over silica gel with n-hexane-EtOAc (7:3) gave 947 mg (50%

yield) the title compound 36 as a crystalline mass. Recrys-

(2S,3S)-3-Ben zyl-N-(2,4,6-t r im et h ylb en zen esu lfon yl)-

2-vin yla zir id in e (29). By use of a procedure identical with

that described for the synthesis of 28 from 26, 655 mg (1.825

mmol) of the allyl alcohol 27 was converted into 488 mg (78%

yield) of the title compound 29. Colorless crystals from

n-hexane-Et₂O (2:1); mp 109-110 °C; [R]³¹-32.8 (c 0.993,

D

1

CHCl₃); H NMR (300 MHz, CDCl₃) δ 2.30 (s, 3 H), 2.54 (s, 6

H), 2.67 (dd, J ) 14.3, 7.0 Hz, 1 H), 2.99 (dd, J ) 14.3, 5.1 Hz,

1 H), 3.14 (m, 1 H), 3.20 (dd, J ) 9.1, 4.2 Hz, 1 H), 5.35 (m, 1

H), 5.50 (m, 1 H), 6.07 (ddd, J ) 17.0, 10.2, 9.1 Hz, 1 H), 6.80-

7.14 (m, 5 H). Anal. Calcd for C₂₀H₂₃NO₂S: C, 70.35; H, 6.79;

N, 4.10. Found: C, 70.51; H, 6.90; N, 4.10.

(4S,5S)-4-[(ter t-Bu t yld im et h ylsiloxy)m et h yl]-5-vin yl-

oxa zolid in -2-on e (32). To a stirred suspension of sodium

hydride (435 mg, 9 mmol) in a mixture of THF (25 mL) and

DMF (15 mL) at 0 °C was added 3 g (9 mmol) of the alcohol

30¹²in 10 mL of THF. The stirring was continued for 18 h at

rt followed by quenching with 15 mL of 20% citric acid at -78

°C with vigorous stirring. The mixture was extracted with

Et₂O and the extract was washed successively with brine, 5%

NaHCO₃, and water and dried over MgSO₄. Usual workup

and flash chromatography over silica gel with n-hexane-

EtOAc (3:1) gave 960 mg (42% yield) of the title compound 32

tallization from n-hexane-Et₂O (2:1) gave colorless crystals;

1

mp 104 °C; [R]³¹-21 (c 0.944, CHCl₃); H NMR (270 MHz,

D

CDCl₃) δ 0.018 (s, 3 H), 0.021 (s, 3 H), 0.87 (s, 9 H), 2.30 (s, 3

H), 2.63 (s, 6 H), 2.99 (d, J ) 2.2 Hz, 1 H), 3.17 (m, 1 H), 3.59

(dd, J ) 10.3, 4.6 Hz, 1 H), 3.70 (dd, J ) 10.3, 2.4 Hz, 1 H),

4.32 (m, 1 H), 5.05 (ddd, J ) 10.5, 1.5, 1.5 Hz, 1 H), 5.20 (d, J

) 8.6 Hz, 1 H), 5.25 (ddd, J ) 17.2, 1.5, 1.5 Hz, 1 H), 5.54

(ddd, J ) 17.2, 10.5, 5.7 HZ, 1 H), 6.94 (s, 2 H). Anal. Calcd

for C₂₀H₃₅NO₄SSi: C, 58.07; H, 8.53; N, 3.39. Found: C, 57.96;

H, 8.45; N, 3.37.

as a colorless oil. [R]³⁰-42.0 (c 0.948, CHCl₃); ¹H NMR (300

(3R ,4S )-5-(t er t -Bu t yld im e t h ylsiloxy)-4-[N -(2,4,6-t r i-

m eth ylben zen esu lfon yl)a m in o]-1-p en ten -3-ol (37). By

use of a procedure similar to that described for the synthesis

of the amino alcohol 36 from 34, 395 mg (0.9 mmol) of the

oxazolidin-2-one 35 was converted into 207 mg (56% yield) of

D

MHz, CDCl₃) δ 0.08 (s, 6 H), 0.89 (s, 9 H), 3.60-3.67 (m, 3 H),

4.74 (m, 1 H), 5.30 (ddd, J ) 10.5, 1.0, 1.0 Hz, 1 H), 5.41 (ddd,

J ) 17.0, 1.0, 1.0 Hz, 1 H), 6.02 (broad s, 1 H), 5.92 (ddd, J )

17.0, 10.5, 6.5 Hz, 1 H); LRMS (FAB) m/z, 258 (MH⁺, base

peak), 200, 156, 115, 73. HRMS (FAB) m/z, calcd for C₁₂H₂₄

-

the title compound 37 as a colorless oil. [R]²⁸+23.0 (c 1.087,

D

NO₃Si (MH⁺) 258.1525; found: 258.1530.

CHCl₃); H NMR (270 MHz, CDCl₃) δ 0.01 (s, 6 H), 0.86 (s, 9

1

H), 2.30 (s, 3 H), 2.66 (s, 6 H), 2.97 (d, J ) 8.6 Hz, 1 H), 3.21

(m, 1 H), 3.53 (dd, J ) 10.3, 3.8 Hz, 1 H), 3.82 (dd, J ) 10.3,

3.0 Hz, 1 H), 4.11 (m, 1 H), 5.21 (ddd, J ) 10.5, 1.5, 1.5 Hz, 1

H), 5.30 (ddd, J ) 17.2, 1.5, 1.5 Hz, 1 H), 5.37 (d, J ) 8.6 Hz,

1 H), 5.80 (ddd, J ) 17.2, 10.5, 5.1 Hz, 1 H), 6.96 (s, 2 H).

LRMS (FAB) m/z, 414 (MH⁺), 396, 356, 213, 173, 167, 119,

89, 73 (base peak). HRMS (FAB) m/z, calcd for C₂₀H₃₆NO₄-

SSi (MH⁺) 414.2134; found: 414.2144.

(4S,5R)-4-[(ter t-Bu t yld im et h ylsiloxy)m et h yl]-5-vin yl-

oxa zolid in -2-on e (33). By use of a procedure identical with

that described for the synthesis of the oxazolidin-2-one 32 from

30, 1.0 g (3.02 mmol) of the alcohol 31¹²was converted into

265 mg (34.1% yield) of the title compound 33. Colorless

crystals from n-hexane; mp 78 °C; [R]²⁹_D-53.8 (c 1.05, CHCl₃);

¹H NMR (300 MHz, CDCl₃) δ 0.059 (s, 3 H), 0.062 (s, 3 H),

0.89 (s, 9 H), 3.53 (dd, J ) 10.5, 7.3 Hz, 1 H), 3.59 (dd, J )

10.5, 4.9 HZ, 1 H), 3.89 (ddd, J ) 12.1, 7.6, 4.6 Hz, 1 H), 5.09

(dddd, J ) 8.1, 6.8, 1.1, 1.1 Hz, 1 H), 5.34 (broad s, 1 H), 5.37

(ddd, J ) 10.5, 1.0., 1.0 Hz, 1 H), 5.49 (ddd, J ) 17.2, 1.0, 1.0

Hz, 1 H), 5.90 (ddd, J ) 17.2, 10.5, 6.8 Hz, 1 H). Anal. Calcd

for C₁₂H₂₃NO₃Si: C, 55.99; H, 9.01; N, 5.44. Found: C, 56.12;

H, 9.25; N, 5.39.

(2R,3R)-2-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-N-(2,4,6-

tr im eth ylben zen esu lfon yl)-3-vin yla zir id in e (38). By use

of a procedure similar to that described for the synthesis of

the vinylaziridine 24 from 22, 413 mg (1 mmol) of the allyl

alcohol 36 was converted into 379 mg (96% yield) of the title

compound 38 as a colorless oil. [R]²⁸+0.12 (c 1.04, CHCl₃);

D

¹H NMR (270 MHz, CDCl₃) δ -0.09 (s, 3 H), -0.06 (s, 3 H),

0.79 (s, 9 H), 2.30 (s, 3 H), 2.69 (s, 6 H), 3.07 (m, 1 H), 3.44

(dddd, J ) 6.9, 6.9, 1.0, 1.0 Hz, 1 H), 3.58 (dd, J ) 17.0, 1.5

Hz, 1 H), 3.61 (dd, J ) 17.0, 1.5 Hz, 1 H), 5.28 (m, 1 H), 5.41

(m, 1 H), 5.66 (ddd, J ) 17.0, 10.0, 6.5 Hz, 1 H), 6.940 (s, 1 H),

6.942 (s, 1 H). LRMS (FAB) m/z, 396 (MH⁺), 338, 308, 241,

212, 177, 154, 119, 89, 73 (base peak), 59. HRMS (FAB) m/z,

calcd for C₂₀H₃₄NO₃SSi (MH⁺) 396.2028; found: 396.2026.

(2R,3S)-2-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-N-(2,4,6-

tr im eth ylben zen esu lfon yl)-3-vin yla zir id in e (39). By use

of a procedure similar to that described for the preparation of

24 from 22, 187 mg (0.453 mmol) of the allyl alcohol 37 was

converted into 174 mg (97% yield) of the title compound 39 as

a colorless oil. [R]²⁸_D+0.12 (c 1.04, CHCl₃); ¹H NMR (270 MHz,

(4S,5S)-4-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-N-(2,4,6-

tr im eth ylben zen esu lfon yl)-5-vin yloxa zolid in -2-on e (34).

Mesitylenesulfonyl chloride (3.4 g, 15.6 mmol) in 10 mL of THF

and 32 (2.0 g, 7.8 mmol) in 15 mL of THF were successively

added to a stirred suspension of sodium hydride (0.588 g, 23.4

mmol) in THF (2 mL) at 0 °C. The stirring was continued for

1 h followed by quenching with 10 mL of 20% citric acid at

-78 °C with vigorous stirring. The mixture was made alkaline

with 5% NaHCO₃and extracted with EtOAc. The extract was

successively washed with brine and water and dried over

MgSO₄. Usual workup and flash chromatography over silica

gel with n-hexane-EtOAc (9:1) gave 2.73 g (70% yield) of the

title compound 34 as a crystalline mass. Recrystallization

from n-hexane gave 34 as colorless crystals; mp 99 °C; [R]³⁰

D

Thermodynamics of 2,3-cis-3-Alkyl-2-vinylaziridines

J . Org. Chem., Vol. 62, No. 4, 1997 1011

CDCl₃) δ -0.13 (s, 3 H), -0.10 (s, 3 H), 0.78 (s, 9 H), 2.84 (s,

3 H), 2.69 (s, 6 H), 3.17 (m, 1 H), 3.22 (dd, J ) 8.9, 4.1 Hz, 1

H), 3.60 (dd, J ) 11.5, 5.4 Hz, 1 H), 3.75 (dd, J ) 11.5, 3.8 Hz,

1 H), 5.36 (dd, J ) 10.2, 1.0 Hz, 1 H), 5.56 (dd, J ) 17.0, 1.0

Hz, 1 H), 6.12 (ddd, J ) 17.0, 10.2, 9.6 Hz, 1 H), 6.919 (s, 1

H), 6.922 (s, 1 H). LRMS (FAB) m/z, 396 (MH⁺), 338, 308,

241, 212, 177, 154, 119, 89, 73 (base peak), 59. HRMS (FAB)

m/z, calcd for C₂₀H₃₄NO₃SSi (MH⁺) 396.2028; found: 396.2034.

(S)-N-(2,4,6-Tr im eth ylben zen esu lfon yl)va lin ol (41). To

a stirred solution of (S)-valinol 40 (11.74 g, 0.114 M) and Et₃N

(63 mL, 0.456 M) in THF (30 mL) at 0 °C was added 2,4,6-

trimethylbenzenesulfonyl chloride (25 g, 0.114 M), and the

mixture was stirred for 1 h. The reaction was quenched with

20 mL of 5% NaHCO₃at 0 °C with stirring. The mixture was

extracted with EtOAc, and the extract was washed succes-

sively with 5% citric acid, water, 5% NaHCO₃, and brine and

dried over MgSO₄. Usual workup followed by flash chroma-

tography over silica gel with n-hexane-EtOAc (4:1) gave 29 g

(89% yield) of the title compound 41 as a colorless crystalline

mass. Recrystallization from n-hexane-Et₂O (2:1) gave color-

less crystals: mp 71 °C; [R]²⁰_D-37.8 (c 1.13, CHCl₃); ¹H NMR

(270 MHz, CDCl₃) δ 0.75 (d, J ) 6.6 Hz, 3 H), 0.80 (d, J ) 6.9

Hz, 3 H), 1.76 (m, 1 H), 2.30 (s, 3 H), 2.35 (m, 1 H), 2.66 (s, 6

H), 2.98 (m, 1 H), 3.60 (m, 2 H), 5.14 (m, 1 H), 6.95 (s, 2 H).

Anal. Calcd for C₁₄H₂₃NO₃S: C, 58.92; H, 8.12; N, 4.91.

Found: C, 58.84; H, 8.42; N, 4.90.

1.2 equiv) were added to a stirred solution of the alcohol 43

(4.79 g, 15.4 mmol) in 40 mL of THF at 0 °C, and the mixture

was allowed to warm to room temperature and stirred at this

temperature for 1 h. The mixture was concentrated under

reduced pressure to an oil, which was flash chromatographed

on a silica gel column. Elution with n-hexane-EtOAc (5:1)

gave 4.3 g (95% yield) of the title compound 45 as a crystalline

mass. Recrystallization from cold n-hexane gave 45 as color-

less prisms; mp 46 °C; [R]²⁰-11.1 (c 1.37, CHCl₃); ee > 99%

D

(Chiralcel OB, n-hexane-i-PrOH ) 98:2); ¹H NMR (270 MHz,

CDCl₃) δ 0.78 (d, J ) 6.9 Hz, 3 H), 0.88 (d, J ) 6.6 Hz, 3 H),

1.43 (m, 1 H), 2.30 (s, 3 H), 2.56 (dd, J ) 9.9, 7.0 Hz, 1 H),

2.70 (s, 6 H), 3.41 (t, J ) 7.0 Hz, 1 H), 5.25-5.44 (m, 2 H),

5.65 (ddd, J ) 17.2, 10.2, 7.0 Hz, 1 H), 6.95 (s, 2 H). Anal.

Calcd for C₁₆H₂₃NO₂S: C, 65.49; H, 7.90; N, 4.77. Found: C,

65.25; H, 8.13; N, 4.73.

(2S,3S)-3-Isopr opyl-N-(2,4,6-tr im eth ylben zen esu lfon yl)-

2-vin yla zir id in e (46). By use of a procedure identical with

that described for the preparation of 45 from 43, the alcohol

44 (4.26 g, 13.7 mmol) was converted into the title compound

46 (3.81 g, 95% yield). 46: colorless prisms from n-hexane-

Et₂O (2:1); mp 67 °C; [R]²⁰-89.1 (c 2.10, CHCl₃); ee > 99%

D

(Chiralcel OB, n-hexane-i-PrOH ) 98:2); ¹H NMR (270 MHz,

CDCl₃) δ 0.70 (d, J ) 6.6 Hz, 3 H), 0.87 (d, J ) 6.6 Hz, 3 H),

1.51 (m, 1 H), 2.29 (s, 3 H), 2.70 (s, 6 H), 2.80 (dd, J ) 7.6, 4.2

Hz, 1 H), 3.11 (dd, J ) 9.5, 4.2 Hz, 1 H), 5.34 (d, J ) 9.5 Hz,

1 H), 5.50 (d, J ) 17.0 Hz, 1 H), 6.17 (triplets of d, J ) 17.0,

9.5 Hz, 1 H), 6.93 (s, 2 H). Anal. Calcd for C₁₆H₂₃NO₂S: C,

65.49; H, 7.90; N, 4.77. Found: C, 65.35; H, 8.01; N, 4.52.

(S)-N-(ter t-Bu toxyca r bon yl)leu cin ol (48). To a stirred

solution of (S)-leucinol 47 (23.4 g, 0.2 M) in dry DMF (250 mL)

and Et₃N (55.8 mL, 0.4 M) under argon was added Boc₂O (43.6

g, 0.2 M) with stirring at 0 °C. After 18 h, water (60 mL) was

added, and the mixture was stirred for 1 h. The mixture was

extracted with Et₂O, and the extract was washed successively

with 5% citric acid, water, 5% NaHCO₃, and brine and dried

over MgSO₄. Concentration under reduced pressure gave 46

g (96% yield) of the title compound 48 as a colorless oil.

(3S,4S)-5-Met h yl-4-[N-(2,4,6-t r im et h ylb en zen esu lfo-

n yl)a m in o]-1-h exen -3-ol (43) a n d (3R,4S)-5-Meth yl-4-[N-

(2,4,6-tr im eth ylben zen esu lfon yl)am in o]-1-h exen -3-ol (44).

To a stirred solution of oxalyl chloride (5.68 mL, 59.3 mmol,

1.3 equiv) in dry CH₂Cl₂(70 mL) at -78 °C under argon was

added dropwise a solution of DMSO (9.7 mL, 137 mmol, 3

equiv) in CH₂Cl₂(20 mL). After 20 min, a solution of the

alcohol 41 (13 g, 45.6 mmol) in CH₂Cl₂(20 mL) was added to

the above reagent at -78 °C, and the mixture was stirred for

1 h. Diisopropylethylamine (39.6 mL, 228 mmol, 5 equiv) was

added dropwise to the above solution at -78 °C, and the

mixture was stirred for 2 h with warming to 0 °C. The reaction

was quenched with 20 mL of a saturated aqueous NH₄Cl

solution at -78 °C with vigorous stirring. The mixture was

extracted with Et₂O and the extract was washed successively

with 5% citric acid, water, 5% NaHCO₃, and brine, and dried

over MgSO₄. Concentration under reduced pressure gave a

crude aldehyde as a colorless oil. To a stirred solution of CuCN

(410 mg, 4.56 mmol) and LiCl (386 mg, 9.12 mmol) in 40 mL

of THF at -78 °C was added via syringe vinylmagnesium

bromide (96 mL; 1 M solution in THF; 96 mmol, 2.1 equiv).

After being stirred at this temperature for 10 min, a solution

of the above crude aldehyde in THF (50 mL) was added

dropwise to it, and the mixture was allowed to warm to -40

°C and stirred at this temperature for 30 min, followed by

quenching with 30 mL of a mixture of 5% NH₄Cl-28% NH₄-

OH (1:1). The mixture was concentrated under reduced

pressure and extracted with Et₂O. Usual workup led to a

mixture of products as a colorless oil, which was separated by

flash chromatography over silica gel eluting with n-hexane-

EtOAc 4:1, yielding, in order of elution, 44 (5.673 g, 40% yield)

and 43 (6.38 g, 45% yield). 43: Colorless needles from

n-hexane-Et₂O (2:1); mp 119 °C; [R]²⁰_D-36.2 (c 0.918, CHCl₃);

¹H NMR (270 MHz, CDCl₃) δ 0.75 (d, J ) 6.9 Hz, 3 H), 0.83

(d, J ) 6.5 Hz, 3 H), 1.85 (m, 1 H), 2.14 (d, J ) 4.0 Hz, 1 H),

2.29 (s, 3 H), 2.64 (s, 6 H), 3.06 (m, 1 H), 4.15 (m, 1 H), 4.94

(m, 1 H), 4.95-5.02 (m, 1 H), 5.16-5.22 (m, 1 H), 5.63 (ddd, J

Kugelrohr distillation, 141 °C (5 Torr); [R]²⁰-28.36 (c 0.952,

D

CHCl₃); IR (CHCl₃) cm^-1: 3500 (NH and OH), 1709, 1690 (CO);

¹H NMR (200 MHz, CDCl₃) δ 0.930 (d, J ) 6.3 Hz, 3 H), 0.933

(d, J ) 6.8 Hz, 3 H), 1.25-1.35 (m, 2 H), 1.45 (s, 9 H), 1.55-

1.80 (m, 1 H), 2.30 (broad s, 1 H), 3.40-3.75 (m, 3 H), 4.55

(broad s, 1 H). Anal. Calcd for C₁₁H₂₃NO₃: C, 60.80; H, 10.67;

N, 6.45. Found: C, 60.85; H, 10.83; N, 6.39.

(4S,5S)-4-(2-Meth ylpr opyl)-5-vin yloxazolidin -2-on e (52)

a n d Its (4S,5R)-Isom er (53). To a stirred solution of oxalyl

chloride (25 mL, 0.26 M, 1.3 equiv) in dry CH₂Cl₂(300 mL) at

-78 °C under argon was added dropwise a solution of DMSO

(56.7 mL, 0.8 M) in CH₂Cl₂(100 mL). After 20 min, a solution

of the alcohol 48 (46 g, 0.2 M) in CH₂Cl₂(100 mL) was added

to the above reagent at -78 °C, and the mixture was stirred

for 1 h. Diisopropylethylamine (139 mL, 0.8 M) was added

dropwise to the above solution at -78 °C, and the mixture was

stirred for 2 h with warming to 0 °C. The reaction was

quenched with 200 mL of a saturated aqueous NH₄Cl solution

at -78 °C with vigorous stirring. The mixture was extracted

with Et₂O, and the extract was washed with water and dried

over MgSO₄. Concentration under reduced pressure gave a

crude aldehyde as a colorless oil. To a stirred mixture of

vinylmagnesium chloride (300 mL, 2 M solution in THF; 0.6

M) and zinc chloride (54.4 g, 0.4 mol) in THF (350 mL) at -78

°C was added a solution of the above crude aldehyde in 200

mL of THF, and the mixture was stirred for 1 h with warming

to 0 °C. The reaction was quenched with 100 mL of 5% citric

acid at -78 °C with vigorous stirring. The mixture was

concentrated under reduced pressure and extracted with Et₂O.

The extract was washed successively with 5% citric acid, water,

5% NaHCO₃, and water and then dried over MgSO₄. The

usual workup and flash chromatography over silica gel with

n-hexane-EtOAc (4:1) gave 35.5 g (74% yield) of an insepa-

rable mixture of the alcohols 50 and 51 as a colorless oil. To

a stirred suspension of sodium hydride (4.3 g, 180 mmol) in a

mixture of THF (300 mL) and DMF (100 mL) at 0 °C was

added 23.2 g (95.5 mmol) of a mixture of alcohols (50 and 51)

in 50 mL of THF. The stirring was continued for 18 h at rt

) 16.8, 10.2, 6.3 Hz, 1 H), 6.93 (s, 2 H). Anal. Calcd for C₁₆H₂₅

-

NO₃S: C, 61.71; H, 8.09; N, 4.50. Found: C, 61.54; H, 8.14;

N, 4.44. 44: Colorless prisms from n-hexane-Et₂O (1:1); mp

103 °C; [R]²⁰-24.9 (c 2.56, CHCl₃); ¹H NMR (270 MHz,

D

CDCl₃) δ 0.77 (d, J ) 6.6 Hz, 3 H), 0.78 (d, J ) 6.6 Hz, 3 H),

3.12 (m, 1 H), 2.30 (s, 3 H), 2.52 (d, J ) 6.6 Hz, 1 H), 2.65 (s,

6 H), 3.12 (ddd, J ) 9.9, 6.3, 3.6 Hz, 1 H), 4.25 (m, 1 H), 4.78

(d, J ) 9.5 Hz, 1 H), 5.23-5.37 (m, 2 H), 5.82 (ddd, J ) 17.2,

10.6, 5.3 Hz, 1 H), 6.95 (s, 2 H). Anal. Calcd for C₁₆H₂₅NO₃S:

C, 61.71; H, 8.09; N, 4.50. Found: C, 61.52; H, 8.34; N, 4.47.

(2R,3S)-3-Isopr opyl-N-(2,4,6-tr im eth ylben zen esu lfon yl)-

2-vin yla zir id in e (45). Triphenylphosphine (4.8 g, 18.5 mmol,

1.2 equiv) and diethyl azodicarboxylate (2.9 mL, 18.5 mmol,

1012 J . Org. Chem., Vol. 62, No. 4, 1997

Ibuka et al.

followed by quenching with 100 mL of 5% citric acid at -78

°C with vigorous stirring. The mixture was extracted with

Et₂O, and the extract was washed successively with 5% HCl,

5% NaHCO₃, and water and dried over MgSO₄. Usual workup

and flash chromatography over silica gel with n-hexane-

EtOAc (2:1) gave 13.7 g (85% yield) of 52, and further elution

gave 2.1 g (13% yield) of 53. 52: a colorless oil; Kugelrohr

¹H NMR (300 MHz, CDCl₃) δ 1.01 (d, J ) 6.5 Hz, 3 H), 1.02

(d, J ) 6.5 Hz, 3 H), 1.32 (s, 3 H), 1.33 (s, 3 H), 1.69-1.89 (m,

4 H), 2.08-2.17 (m, 1 H), 2.11 (s, 3 H), 2.52 (s, 3 H), 2.54 (s, 3

H), 2.64 (m, 2 H), 4.22 (ddd, J ) 7.2, 3.1, 2.3 Hz, 1 H), 4.69

(dddd, J ) 5.8, 2.3, 1.3, 1.3 Hz, 1 H), 5.31-5.43 (m, 2 H), 5.87

(ddd, J ) 17.1, 10.5, 5.8 Hz). Anal. Calcd for C₂₃H₃₃NO₅S:

C, 63.42; H, 7.64; N, 3.22. Found: C, 63.43; H, 7.74; N, 2.93.

(4S,5R)-4-(2-Meth ylp r op yl)-N-(2,2,5,7,8-p en ta m eth yl-6-

ch r om a n su lfon yl)-5-vin yloxa zolid in -2-on e (57). By use of

a procedure similar to that described for the synthesis of 56

from 52, 950 mg (5.6 mmol) of the oxazolidin-2-one 53 was

converted into 2.34 g (96% yield) of the title compound 57 by

treatment with 2,2,5,7,8-pentamethyl-6-chromansulfonyl chlo-

ride (2.04 g, 6.72 mmol) and NaH (0.202 g, 8.4 mmol) in a

mixture of THF (15 mL) and DMF (60 mL) at room temper-

ature for 18 h followed by usual workup and flash chroma-

tography over silica gel with n-hexane-EtOAc (9:1). Recrys-

distillation, 185 °C (1 mmHg); [R]²⁰-54 (c 1.12, CHCl₃); IR

D

(CHCl₃) cm^-1: 3500-3250 (NH and OH), 1743 (CO); ¹H NMR

(200 MHz, CDCl₃) δ 0.92 (d, J ) 6.4 Hz, 3 H), 0.94 (d, J ) 6.6

Hz, 3 H), 1.30-1.80 (m, 3 H), 3.61 (m, 1 H), 4.53 (m, 1 H),

5.32 (dt, J ) 10.3, 1.0 Hz, 1 H), 5.42 (dt, J ) 17.1, 1.0 Hz, 1

H), 5.91 (ddd, J ) 17.1, 10.3, 6.8 Hz, 1 H). Anal. Calcd for

C₉H₁₅NO₂: C, 63.88; H, 8.93; N, 8.26. Found: C, 64.08; H,

8.97; N, 8.12. 53: a colorless oil; Kugelrohr distillation, 180

°C (1 mmHg); [R]²⁰-24 (c 0.846, CHCl₃); IR (CHCl₃) cm^-1

:

D

3500-3250 (NH and OH), 1740 (CO); ¹H NMR (200 MHz,

CDCl₃) δ 0.90 (d, J ) 6.6 Hz, 3 H), 0.95 (d, J ) 6.6 Hz, 3 H),

1.21 (ddd, J ) 13.4, 9.3, 3.4 Hz, 1 H), 1.43 (ddd, J ) 13.4,

10.3, 4.9 Hz, 1 H), 1.45-1.70 (m, 1 H), 3.97 (ddd, J ) 10.3,

8.1, 4.2 Hz, 1 H), 5.04 (m, 1 H), 5.34-5.49 (m, 2 H), 5.89 (ddd,

J ) 17.0, 10.3, 6.8 Hz, 1 H), 6.24 (broad s, 1 H). Anal. Calcd

for C₉H₁₅NO₂: C, 63.88; H, 8.93; N, 8.26. Found: C, 63.80;

H, 8.97; N, 8.26.

tallization from n-hexane-Et₂O (10:1) gave 57 as colorless

1

crystals, mp 131 °C; [R]³⁰+123.2 (c 1.45, CHCl₃); H NMR

D

(300 MHz, CDCl₃) δ 0.95 (d, J ) 6.3 Hz, 3 H), 1.01 (d, J ) 6.3

Hz, 3 H), 1.32 (s, 3 H), 1.33 (s, 3 H), 1.75-1.86 (m, 5 H), 2.13

(s, 3 H), 2.56 (s, 3 H), 2.58 (s, 3 H), 2.67 (m, 2 H), 4.49 (m, 1

H), 4.97 (dddd, J ) 6.9, 6.9, 1.0, 1.0 Hz, 1 H), 5.47 (ddd, J )

10.5, 1.0, 1.0 Hz, 1 H), 5.54 (ddd, J ) 17.1, 1.0, 1.0 Hz, 1 H),

(4S,5S)-N-(4-Meth ylben zen esu lfon yl)-4-(2-m eth ylp r o-

p yl)-5-vin yloxa zolid in -2-on e (54). To a stirred suspension

of sodium hydride (0.48 g, 20 mmol) in a mixture of THF (10

mL) and DMF (25 mL) at 0 °C were added successively 1.69 g

(10 mmol) of 52 in 5 mL of THF and 2.48 g (13 mmol) of

p-toluenesulfonyl chloride. The stirring was continued for 18

h at room temperature followed by quenching with 10 mL of

10% NH₄Cl at -78 °C with vigorous stirring. The mixture

was extracted with Et₂O, and the extract was washed succes-

sively with 5% HCl, 5% NaHCO₃, and water and dried over

MgSO₄. Usual workup and flash chromatography over silica

gel with n-hexane-EtOAc (5:1) gave 2.49 g (77% yield) of the

title compound 54 as a crystalline mass. Recrystallization

from n-hexane-Et₂O (2:1) gave 54 as colorless crystals; mp

5.88 (ddd, J ) 17.1, 10.5, 6.9 Hz, 1 H). Anal. Calcd for C₂₃H₃₃-

NO₅S: C, 63.42; H, 7.64; N, 3.22. Found: C, 63.56; H, 7.79;

N, 3.11.

(3S,4S)-6-Meth yl-4-[(4-m eth ylben zen esu lfon yl)a m in o]-

1-h ep ten -3-ol (58). To a stirred solution of the oxazolidin-

2-one 54 (1.371 g, 4.24 mmol) in 25 mL of MeOH-H₂O (4:1)

was added 1.90 g (34 mmol, 8 equiv) of KOH at 0 °C, and the

mixture was stirred under reflux for 4 h. The mixture was

made acidic with 5% citric acid and concentrated under

reduced pressure to leave an oily residue. This oily residue

was extracted with CHCl₃, and the extract was washed with

water and dried over MgSO₄. The usual workup and flash

chromatography over silica gel with n-hexane-EtOAc (3:1)

gave 1.05 g (83% yield) of the title compound 58. Colorless

109 °C; [R]²⁰-30.36 (c 1.05, CHCl₃); ¹H NMR (300 MHz,

crystals from n-hexane-Et₂O (1:1); mp 89 °C; [R]²⁰-37.9 (c

D

1

CDCl₃) δ 0.98 (d, J ) 6.5 Hz, 3 H), 0.99 (d, J ) 6.4 Hz, 3 H),

1.62-1.77 (m, 2 H), 1.88-1.99 (m, 1 H), 2.45 (s, 3 H), 4.15

(ddd, J ) 10.3, 3.5, 2.5 Hz, 1 H), 4.60 (dddd, J ) 6.1, 2.5, 1.2,

1.2 Hz, 1 H), 5.23-5.33 (m, 3 H), 5.75 (ddd, J ) 17.0, 10.5, 6.1

Hz, 1 H), 7.32-7.36 (m, 2 H), 7.89-7.92 (m, 2 H). Anal. Calcd

for C₁₆H₂₁NO₄S: C, 59.42; H, 6.55; N, 4.33. Found: C, 59.24;

H, 6.64; N, 4.04.

0.71, CHCl₃); H NMR (270 MHz, CDCl₃) δ 0.68 (d, J ) 6.3

Hz, 3 H), 0.79 (d, J ) 6.6 Hz, 3 H), 1.19 (m, 1 H), 1.34-1.52

(m, 2 H), 2.11 (d, J ) 4.3 Hz, 1 H), 2.23 (s, 3 H), 3.32 (ddd, J

) 12.9, 5.3, 4.0 Hz, 1 H), 4.06 (m, 1 H), 4.73 (d, J ) 8.6 Hz, 1

H), 5.09-5.25 (m 2 H), 5.73 (ddd, J ) 17.2, 10.6, 6.6 Hz, 1 H),

7.27-7.31 (m, 2 H), 7.74-7.77 (m, 2 H). Anal. Calcd for

C₁₅H₂₃NO₃S: C, 60.58; H, 7.79; N, 4.71. Found: C, 60.42; H,

7.98; N, 4.55.

(4S,5R)-N-(4-Meth ylben zen esu lfon yl)-4-(2-m eth ylp r o-

p yl)-5-vin yloxa zolid in -2-on e (55). By use of a procedure

similar to that described for the preparation of the tosylate

54 from 52, the oxazolidin-2-one 53 (0.66 g, 4 mmol) was

converted into the title compound 55 (1.2 g, 85% yield).

(3R,4S)-6-Meth yl-4-[(4-m eth ylp h en ylsu lfon yl)a m in o]-

1-h ep ten -3-ol (59). By use of a procedure similar to that

described for the preparation of the allyl alcohol 58 from 54,

the oxazolidin-2-one 55 (0.72 g, 2.23 mmol) was converted into

the title compound 59 (0.64 g, 97% yield) by treatment with

Colorless crystals from CHCl₃-Et₂O (1:1); mp 156 °C; [R]²⁵

D

+39.7 (c 1.21, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 0.91 (d, J

) 6.3 Hz, 3 H), 0.99 (d, J ) 6.7 Hz, 3 H), 1.56-1.72 (m, 3 H),

2.45 (s, 3 H), 4.48 (m, 1 H), 4.98 (dddd, J ) 6.9, 6.9, 1.0, 1.0

Hz, 1 H), 5.44 (ddd, J ) 10.5, 1.0, 1.0 Hz, 1 H), 5.50 (ddd, J )

17.1, 1.0, 1.0 Hz, 1 H), 5.82 (ddd, J ) 17.1, 10.5, 6.9 Hz, 1 H),

7.33-7.37 (m, 2 H), 7.93-7.98 (m, 2 H). Anal. Calcd for

C₁₆H₂₁NO₄S: C, 59.42; H, 6.55; N, 4.33. Found: C, 59.15; H,

6.60; N, 4.32.

O (2:1) under reflux for

1.93 g of KOH in 30 mL of MeOH-H₂

2 h followed by usual workup and flash chromatography over

silica gel with n-hexane-EtOAc (3:1). Colorless needles from

n-hexane-Et₂O (3:1); mp 60 °C; [R]²⁵_D-21.9 (c 0.858, CHCl₃);

¹H NMR (300 MHz, CDCl₃) δ 0.58 (d, J ) 6.6 Hz, 3 H), 0.78

(d, J ) 6.6 Hz, 3 H), 1.17 (m, 2 H), 1.43 (m, 1 H), 2.43 (s, 3 H),

2.50 (d, J ) 6.6 Hz, 1 H), 3.76 (m, 1 H), 4.11 (m, 1 H), 4.74 (d,

J ) 9.6 Hz, 1 H), 5.21-5.32 (m, 2 H), 5.78 (ddd, J ) 17.2,

10.6, 5.3 Hz, 1 H), 7.27-7.33 (m, 2 H), 7.78-7.81 (m, 2 H).

Anal. Calcd for C₁₅H₂₃NO₃S: C, 60.58; H, 7.79; N, 4.71.

Found: C, 60.55; H, 7.77; N, 4.60.

(4S,5S)-4-(2-Meth ylp r op yl)-N-(2,2,5,7,8-p en ta m eth yl-6-

ch r om a n su lfon yl)-5-vin yloxa zolid in -2-on e (56). To a

stirred suspension of sodium hydride (0.72 g, 30 mmol) in a

mixture of THF (50 mL) and DMF (80 mL) at 0 °C were added

successively 3.38 g (20 mmol) of 52 in 10 mL of THF and 6.66

g (22 mmol) of 2,2,5,7,8-pentamethyl-6-chromansulfonyl chlo-

ride. The stirring was continued for 18 h at room temperature

followed by quenching with 100 mL of 10% citric acid at -78

°C with vigorous stirring. The mixture was concentrated

under reduced pressure followed by extracted with Et₂O. The

extract was washed successively with 5% HCl, 5% NaHCO₃,

and water and dried over MgSO₄. Usual workup and flash

chromatography over silica gel with n-hexane-EtOAc (9:1)

gave 7.58 g (87% yield) of the title compound 56 as a crystalline

mass. Recrystallization from n-hexane-Et₂O (10:1) gave pure

56 as colorless crystals, mp 134 °C; [R]²⁵_D+124 (c 1.54, CHCl₃);

(3S,4S)-6-Meth yl-4-[(2,2,5,7,8-p en ta m eth yl-6-ch r om a n -

su lfon yl)a m in o]-1-h ep ten -3-ol (60). By use of a procedure

identical with that described for the preparation of the allyl

alcohol 58 from 54, the oxazolidin-2-one 56 (5.65 g, 13 mmol)

was converted into the title compound 60 (4.9 g, 92% yield) as

a colorless oil by treatment with 5.82 g of KOH in 70 mL of

MeOH-H₂O (5:2) followed by usual workup and flash chro-

matography over silica gel with n-hexane-EtOAc (3:1). [R]³⁰

D

-24.1 (c 0.755, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 0.66 (d,

J ) 6.2 Hz, 3 H), 0.75 (d, J ) 6.4 Hz, 3 H), 1.10-1.52 (m, 5

H), 1.31 (s, 6 H), 1.83 (t, J ) 6.8 Hz, 2 H), 2.13 (s, 3 H), 2.28

(d, J ) 4.2 Hz, 1 H), 2.54 (s, 3 H), 2.56 (s, 3 H), 2.64 (t, J ) 6.9

Hz, 2 H), 3.32 (m, 1 H), 4.06 (m, 1 H), 4.70 (d, J ) 8.9 Hz, 1

Thermodynamics of 2,3-cis-3-Alkyl-2-vinylaziridines

J . Org. Chem., Vol. 62, No. 4, 1997 1013

H), 5.10 (ddd, J ) 11.7, 1.3, 1.3 Hz, 1 H), 5.22 (ddd, J ) 17.0,

1.3, 1.3 Hz, 1 H), 5.43 (ddd, J ) 17.0, 10.4, 6.4 Hz, 1 H). LRMS

(FAB) m/z, 410 (MH⁺), 352, 267, 251, 219, 203 (base peak),

147, 126. HRMS (FAB) m/z, calcd for C₂₂H₃₆NO₄S (MH⁺)

410.2365; found: 410.2368.

similar to that described for the synthesis of the vinylaziridine

62 from 58, 1.28 g (3.12 mmol) of the allyl alcohol 61 was

converted into 1.20 g (98% yield) of the title compound 65 as

a colorless oil by treatment with PPh₃(1.06 g, 4.06 mmol) and

diethyl azodicarboxylate (0.64 mL, 4.06 mmol) in THF (10 mL)

at room temperature for 30 h followed by usual workup and

flash chromatography over silica gel with n-hexane-EtOAc

(5:1). [R]³⁰_D-57.1 (c 0.963, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

δ 0.87 (d, J ) 6.5 Hz, 3 H), 0.88 (d, J ) 6.6 Hz, 3 H), 1.311 (s,

3 H), 1.316 (s, 3 H), 1.39 (dt, J ) 13.1, 7.7 Hz, 1 H), 1.52-1.74

(m, 2 H), 1.82 (t, J ) 6.8 Hz, 2 H), 2.12 (s, 3 H), 2.58 (s, 3 H),

2.60 (s, 3 H), 2.64 (t, J ) 6.8 Hz, 1 H), 2.92 (ddd, J ) 7.5, 5.3,

4.7 Hz, 1 H), 3.08 (dd, J ) 9.1, 4.2 Hz, 1 H), 5.25-5.29 (m, 1

H), 5.40-5.46 (m, 1 H), 6.01 (ddd, J ) 17.0, 10.2, 9.1 Hz, 1 H).

LRMS (FAB) m/z, 392 (MH⁺), 390, 267, 251, 219, 203, 147,

124 (base peak). HRMS (FAB) m/z, calcd for C₂₂H₃₄NO₃S

(MH⁺) 392.2259; found: 392.2250.

(3R,4S)-6-Meth yl-4-[(2,2,5,7,8-p en ta m eth yl-6-ch r om a n -

su lfon yl)a m in o]-1-h ep ten -3-ol (61). By use of a procedure

similar to that described for the preparation of the allyl alcohol

58 from 54, the oxazolidin-2-one 57 (1.5 g, 3.44 mmol) was

converted into the title compound 61 (1.35 g, 96% yield).

Colorless needles from n-hexane; mp 105 °C; [R]²⁵-14.9 (c

D

1

1.04, CHCl₃); H NMR (300 MHz, CDCl₃) δ 0.61 (d, J ) 6.5

Hz, 3 H), 0.77 (d, J ) 6.7 Hz, 3 H), 1.09-1.26 (m, 2 H), 1.32

(s, 6 H), 1.36-1.53 (m, 1 H), 1.83 (t, J ) 6.8 Hz, 2 H), 2.13 (s,

3 H), 2.55 (m, 1 H), 2.57 (s, 3 H), 2.58 (s, 3 H), 2.65 (t, J ) 6.8

Hz, 2 H), 3.39 (m, 1 H), 4.18 (m, 1 H), 4.58 (d, J ) 9.2 Hz, 1

H), 5.24 (ddd, J ) 10.6, 1.6, 1.6 Hz, 1 H), 5.31 (ddd, J ) 17.2,

1.6, 1.6 Hz, 1 H), 5.78 (ddd, J ) 17.2, 10.5, 5.1 Hz, 1 H). Anal.

Calcd for C₂₂H₃₅NO₄S: C, 64.51; H, 8.61; N, 3.42. Found: C,

64.24; H, 8.57; N, 3.33.

(3S,4S)-4-[N-(4-Nitr oben zen esu lfon yl)a m in o]-6-m eth -

yl-1-h ep ten -3-ol (66). To a stirred solution of the oxazolidin-

2-one 52 (1.69 g, 10 mmol) in 30 mL of MeOH-H₂O (1:1) at 0

°C was added KOH (1.68 g, 30 mmol), and the mixture was

refluxed for 5 h. The mixture was concentrated under reduced

pressure followed by extraction with CHCl₃(30 mL). The

extract was washed with brine and dried over MgSO₄. To a

stirred dried chloroform extract were added successively Et₃N

(3 mL) and p-nitrobenzenesulfonyl chloride (2.43 g, 11 mmol)

at 0 °C, and the stirring was continued for 30 min at room

temperature. It was then cooled to 0 °C, and a saturated

NaHCO₃solution (10 mL) was added with vigorous stirring.

The mixture was extracted with EtOAc, and the extract was

washed successively with 5% citric acid, water, 5% NaHCO₃,

and water and dried over MgSO₄. Usual workup followed by

flash chromatography over silica gel with n-hexane-EtOAc

(3:1) gave 2.3 g (70% yield) of the title compound 66. Colorless

(2R,3S)-N-(4-Meth ylben zen esu lfon yl)-3-(2-m eth ylp r o-

p yl)-2-vin yla zir id in e (62). By use of a procedure similar to

that described for the synthesis of the vinylaziridine 45 from

the N-protected amino alcohol 43, 0.75 g (2.52 mmol) of 58

was converted into 675 mg (96% yield) of the title compound

62 by treatment with PPh₃(858 mg, 3.28 mmol) and diethyl

azodicarboxylate (0.52 mL, 3.28 mmol) in THF (15 mL) at room

temperature for 1 h followed by usual workup and flash

chromatography over silica gel with n-hexane-EtOAc (5:1).

1

62: a colorless oil; [R]²⁵-7.1 (c 0.70, CHCl₃); H NMR (300

D

MHz, CDCl₃) δ 0.87 (d, J ) 6.7 Hz, 3 H), 0.88 (d, J ) 6.7 Hz,

3 H), 1.34 (m, 2 H), 1.59 (m, 1 H), 2.43 (s, 3 H), 2.96 (ddd, J )

7.1, 6.2, 6.2 Hz, 1 H), 3.31 (tt, J ) 7.1, 0.7 Hz, 1 H), 5.26 (ddd,

J ) 10.2, 0.7, 0.7 Hz, 1 H), 5.39 (ddd, J ) 17.1, 0.7, 0.7 Hz, 1

H), 5.59 (ddd, J ) 17.1, 10.2, 7.1 Hz, 1 H), 7.28-7.32 (m, 2 H),

7.78-7.84 (m, 2 H). LRMS (FAB) m/z, 280 (MH⁺, base peak),

155, 139, 124 (base peak), 91. HRMS (FAB) m/z, calcd for

C₁₅H₂₂NO₂S (MH⁺) 280.1371; found: 280.1377.

crystals from Et₂O, mp 82 °C; [R]¹⁰-25.2 (c 2.02, CHCl₃); ¹H

D

NMR (300 MHz, CDCl₃) δ 0.79 (d, J ) 6.2 Hz, 3 H), 0.84 (d, J

) 6.4 Hz, 3 H), 1.26-1.37 (m, 1 H), 1.41-1.58 (m, 2 H), 1.84

(d, J ) 3.7 Hz, 1 H), 3.44 (dddd, J ) 14.5, 9.0, 5.7, 3.4 Hz, 1

H), 4.10 (m, 1 H), 4.92 (d, J ) 9.1 Hz, 1 H), 5.07 (ddd, J )

10.4, 1.2, 1.2 Hz, 1 H), 5.21 (ddd, J ) 17.2, 1.2, 1.2 Hz, 1 H),

5.67 (ddd, J ) 17.2, 10.4, 6.1 Hz, 1 H), 8.02-8.07 (m, 2 H),

8.32-8.36 (m, 2 H). Anal. Calcd for C₁₄H₂₀N₂O₅S: C, 51.21;

H, 6.14; N, 8.53. Found: C, 51.10; H, 6.10; N, 8.52.

(2S,3S)-N-(4-Meth ylben zen esu lfon yl)-3-(2-m eth ylp r o-

p yl)-2-vin yla zir id in e (63). By use of a procedure similar to

that described for the synthesis of the vinylaziridine 62 from

58, 560 mg (1.88 mmol) of the allyl alcohol 59 was converted

into 411 mg (78% yield) of the title compound 63 by treatment

with PPh₃(640 mg, 2.44 mmol) and diethyl azodicarboxylate

(0.387 mL, 2.44 mmol) in THF (10 mL) at rt for 1 h followed

by usual workup and flash chromatography over silica gel with

(3R,4S)-4-[N-(4-Nitr oben zen esu lfon yl)a m in o]-6-m eth -

yl-1-h ep ten -3-ol (67). By use of a procedure similar to that

described for the preparation of 66 from 52, the oxazolidin-2-

one 53 (1.69 g, 10 mmol) was converted into the title compound

n-hexane-EtOAc (5:1). Colorless crystals from n-hexane, mp

67 (2.595 g, 79% yield) as a colorless semisolid. [R]¹⁰-20.6

1

61 °C; [R]²⁵-71 (c 0.60, CHCl₃); H NMR (300 MHz, CDCl₃)

D

(c 1.03, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 0.69 (d, J ) 6.5

Hz, 3 H), 0.83 (d, J ) 6.6 Hz, 3 H), 1.14-1.34 (m, 2 H), 1.38-

1.54 (m, 1 H), 2.11 (d, J ) 5.3 Hz, 1 H), 3.50 (m, 1 H), 4.17 (m,

1 H), 5.00 (d, J ) 9.1 Hz, 1 H), 5.77 (ddd, J ) 17.2, 10.6, 5.2

Hz, 1 H), 5.26 (ddd, J ) 10.5, 1.5, 1.5 Hz, 1 H), 5.27 (ddd, J )

17.2, 1.5, 1.5 Hz, 1 H), 8.08-8.12 (m, 2 H), 8.33-8.38 (m, 2

H). LRMS (FAB) m/z, 329 (MH⁺), 311 (base peak), 295, 271,

255, 215, 186. HRMS (FAB) m/z, calcd for C₁₅H₂₁N₂O₅S:

(MH⁺) 329.1171; found: 329.1162.

(2R,3S)-3-(2-Meth ylpr opyl)-N-(4-n itr oben zen esu lfon yl)-

2-vin yla zir id in e (68). By use of a procedure similar to that

described for the synthesis of the vinylaziridine 45 from 43,

2.20 g (6.7 mmol) of the allyl alcohol 66 was converted into

1.9 g (91% yield) of the title compound 68 as a colorless oil by

treatment with PPh₃(2.11 g, 8.04 mmol) and diethyl azodi-

carboxylate (1.27 mL, 8.04 mmol) in THF (10 mL) at 0 °C for

δ 0.89 (d, J ) 6.7 Hz, 6 H), 1.39 (m, 1 H), 1.60 (m, 2 H), 2.43

(s, 3 H), 2.94 (ddd, J ) 8.7, 5.6, 4.4 Hz, 1 H), 3.07 (dd, J ) 9.1,

4.4 Hz, 1 H), 5.32 (dd, J ) 10.2, 1.0 Hz, 1 H), 5.45 (dd, J )

17.0, 1.0 Hz, 1 H), 6.01 (ddd, J ) 17.0, 10.2, 9.1 Hz, 1 H), 7.28-

7.32 (m, 2 H), 7.80-7.84 (m, 2 H). Anal. Calcd for C₁₅H₂₁

-

NO₂S: C, 64.49; H, 7.58; N, 5.02. Found: C, 64.54; H, 7.72;

N, 4.90.

(2R,3S)-3-(2-Meth ylp r op yl)-N-(2,2,5,7,8-p en ta m eth yl-6-

ch r om a n su lfon yl)-2-vin yla zir id in e (64). By use of a pro-

cedure similar to that described for the synthesis of the

vinylaziridine 62 from 58, 230 mg (0.562 mmol) of the allyl

alcohol 60 was converted into 216 mg (98% yield) of the title

compound 64 as a colorless oil by treatment with PPh₃(191

mg, 0.73 mmol) and diethyl azodicarboxylate (0.115 mL, 0.73

mmol) in THF (10 mL) at room temperature for 30 h followed

by flash chromatography over silica gel with n-hexane-EtOAc

(5:1). [R]³⁰+5.3 (c 0.68, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

18 h followed by flash chromatography over silica gel with

D

1

δ 0.83 (d, J ) 6.6 Hz, 3 H), 0.87 (d, J ) 6.6 Hz, 3 H), 1.24-

1.44 (m, 5 H), 1.31 (s, 3 H), 1.57 (m, 1 H), 1.82 (t, J ) 6.8 Hz,

2 H), 2.12 (s, 3 H), 2.59 (s, 3 H), 2.61 (s, 3 H), 2.65 (t, J ) 6.8

Hz, 1 H), 2.96 (m, 1 H), 3.38 (tt, J ) 6.9, 0.7 Hz, 1 H), 5.26

(ddd, J ) 10.3, 0.7, 0.7 Hz, 1 H), 5.37 (ddd, J ) 17.1, 0.7, 0.7

Hz, 1 H), 5.63 (ddd, J ) 17.1, 10.3, 6.9 Hz, 1 H). LRMS (FAB)

m/z, 392 (MH⁺), 390, 267, 251, 219, 203, 147, 124 (base peak).

HRMS (FAB) m/z, calcd for C₂₂H₃₄NO₃S (MH⁺) 392.2259;

found: 392.2248.

n-hexane-EtOAc (4:1). [R]¹⁰+9.4 (c 1.64, CHCl₃); H NMR

D

(300 MHz, CDCl₃) δ 0.91 (d, J ) 6.6 Hz, 3 H), 0.92 (d, J ) 6.7

Hz, 3 H), 1.30-1.49 (m, 2 H), 1.57-1.71 (m, 1 H), 3.12 (m 1

H), 3.45 (m, 1 H), 5.30 (ddd, J ) 10.2, 0.7, 0.7 Hz, 1 H), 5.39

(ddd, J ) 17.1, 0.7, 0.7 Hz, 1 H), 5.59 (ddd, J ) 17.1, 10.2, 7.0

Hz, 1 H), 8.12-8.16 (m, 2 H), 8.35-8.40 (m, 2 H). LRMS (FAB)

m/z, 311 (MH⁺), 295, 186, 124 (base peak). HRMS (FAB) m/z,

calcd for C₁₄H₁₉N₂O₄S (MH⁺) 311.1065; found: 311.1064.

(2S,3S)-3-(2-Meth ylpr opyl)-N-(4-n itr oben zen esu lfon yl)-

2-vin yla zir id in e (69). By a procedure similar to that de-

scribed for the synthesis of the vinylaziridine 45 from 43, 2.5

(2S,3S)-3-(2-Meth ylp r op yl)-N-(2,2,5,7,8-p en ta m eth yl-6-

ch r om a n su lfon yl)-2-vin yla zir id in e (65). By a procedure

1014 J . Org. Chem., Vol. 62, No. 4, 1997

Ibuka et al.

g (8.06 mmol) of 67 was converted into 1.9 g (80% yield) of the

title compound 69 as a colorless oil by treatment with PPh₃

(2.1 g, 8.06 mmol) and diethyl azodicarboxylate (1.27 mL, 8.06

mmol) in THF (10 mL) at 0 °C for 30 min followed by flash

chromatography over silica gel with n-hexane-EtOAc (4:1).

[R]¹⁰_D-68.9 (c 1.21, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 0.90

(d, J ) 6.4 Hz, 3 H), 0.92 (d, J ) 5.9 Hz, 3 H), 1.37-1.48 (m,

1 H), 1.56-1.73 (m, 2 H), 3.03 (m, 1 H), 3.18 (dd, J ) 9.0, 4.5

Hz, 1 H), 5.38 (m, 1 H), 5.50 (m, 1 H), 5.95 (ddd, J ) 19.2,

10.2, 9.0 Hz, 1 H), 8.11-8.15 (m, 2 H), 8.34-8.39 (m, 2 H).

LRMS (FAB) m/z, 311 (MH⁺), 303, 186, 124 (base peak).

HRMS (FAB) m/z, calcd for C₁₄H₁₉N₂O₄S (MH⁺) 311.1065;

found: 311.1069.

P d (P P h ₃)₄. To a stirred solution of the 2,3-trans-aziridine 69

(236 mg, 0.761 mmol) in 3 mL of dry THF under a positive

pressure of argon at 0 °C was added by syringe a solution of

Pd(PPh₃)₄(35.1 mg, 4 mol %) in 2 mL of dry THF, and the

mixture was stirred at 0 °C for 5 h. Concentration under

reduced pressure at 0 °C followed by flash chromatography

on a short silica gel column with n-hexane-EtOAc (3:1) gave

a mixture of 68 and 69 (68:69 ) 93:7) as a colorless oil. The

mixture was flash chromatographed on a silica gel column.

Elution with n-hexane-EtOAc (6:1) gave 195 mg (82% yield)

of the 2,3-cis-aziridine 68 as a colorless oil, and further elution

gave 14 mg (6% yield) of the 2,3-trans-aziridine 69 as a

colorless oil.

Gen er a l P r oced u r e for E q u ilib r a t ed R ea ct ion of

N-(Ar en esu lfon yl)-3-alkyl-2-vin ylazir idin es with Tetr akis-

(tr ip h en ylp h osp h in e)p a lla d iu m (0). Equ ilibr a ted Rea c-

tion of (2S,3S)-3-Meth yl-N-(4-m eth ylben zen esu lfon yl)-2-

vin yla zir id in e (21). To a stirred solution of the 2,3-trans-

vinylaziridine 21 (237 mg, 1 mmol) in 5 mL of dry THF at 0

°C under argon was added by syringe a solution of Pd(PPh₃)₄

(23 mg, 0.02 mmol, 2 mol %) in 3 mL of dry THF, and the

mixture was stirred at 0 °C for 18 h. Concentration under

reduced pressure at 0 °C followed by flash chromatography

over silica gel with n-hexane-EtOAc (5:1) gave 225 mg (95%

yield) of a mixture of 18 and 21 (18:21 ) 96:4) as a crystalline

mass. Recrystallization from n-hexane-Et₂O (4:1) gave 191

mg (80.6% yield) of 2,3-cis-vinylaziridine 18 as colorless

crystals. The mother liquor was concentrated under reduced

pressure to leave 32.3 mg of a colorless semisolid. The residual

semisolid was treated with 3 mg of Pd(PPh₃)₄in 4 mL of dry

THF for 16 h at 0 °C. Usual work up followed by flash

chromatography over silica gel with n-hexane-EtOAc (5:1) and

recrystallization from n-hexane-Et₂O (4:1) gave 24 mg (10.1%

yield) of pure 18. The product 18 thus obtained amounts to

215 mg (90.7% yield).

P a lla d iu m (0)-Ca t a lyzed E q u ilib r a t ed R ea ct ion of

(2S,3S)-3-Isop r op yl-N-(2,4,6-tr im eth ylben zen esu lfon yl)-

2-vin yla zir id in e (46). By use of a procedure similar to that

described for the preparation of 18 from 21, the 2,3-trans-

aziridine 46 (293 mg, 1 mmol) was converted into the 2,3-cis-

aziridine 45 by treatment with Pd(PPh₃)₄(46.2 mg, 0.04 mmol,

4 mol %) in 15 mL of dry THF at 0 °C for 24 h followed by

usual workup and flash chromatography over silica gel with

n-hexane-EtOAc (5:1). Recrystallization from cold n-hexane

gave 45 (219 mg, 75% yield) as colorless crystals. The mother

liquor was concentrated under reduced pressure to leave 60

mg of a colorless semisolid. This residual semisolid was

treated with 9.5 mg of Pd(PPh₃)₄in 5 mL of dry THF for 16 h

at 0 °C. Usual workup followed by flash chromatography over

silica gel with n-hexane-EtOAc (5:1) and recrystallization

from cold n-hexane gave 45 mg (15.3% yield) of pure 45. The

product 45 thus obtained amounts to 264 mg (90% yield). Mp

46 °C; [R]²⁰_D-11.6 (c 1.09, CHCl₃); ¹H NMR (270 MHz, CDCl₃)

δ 0.78 (d, J ) 6.9 Hz, 3 H), 0.88 (d, J ) 6.6 Hz, 3 H), 1.43 (m,

1 H), 2.30 (s, 3 H), 2.56 (dd, J ) 9.9, 7.0 Hz, 1 H), 2.70 (s, 6

H), 3.41 (t, J ) 7.0 Hz, 1 H), 5.25-5.44 (m, 2 H), 5.65 (ddd, J

ter t-Bu tyl (4R,5S,2Z)-4,5-Epim in o-7-m eth yl-N-(2,2,5,7,8-

p en ta m eth yl-6-ch r om a n su lfon yl)-2-octen oa te (74) a n d

ter t-Bu tyl (4R,5S,2E)-4,5-Ep im in o-7-m eth yl-N-(2,2,5,7,8-

pen tam eth yl-6-ch r om an su lfon yl)-2-octen oate (75). Ozone

was bubbled through a solution of the vinylaziridine 64 (2.7

g, 6.92 mmol) in EtOAc (30 mL) at -78 °C until a faint blue

color persisted. To the mixture at -78 °C were added 2 g of

triphenylphosphine and tert-butyl (triphenylphosphoranili-

dene)acetate (5.20 g, 13.84 mmol), and the mixture was stirred

for 3 h with warming up to 0 °C. The mixture was concen-

trated 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 74 (782 mg, 23%

yield). Continued elution gave the (E)-enoate 75 (1.35 g, 40%

yield). Compound 74, colorless crystals from Et₂

O, mp 113

°C; [R]³⁰-1.4 (c 0.997, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ

D

0.84 (d, J ) 6.6 Hz, 3 H), 0.87 (d, J ) 6.6 Hz, 3 H), 1.32 (s, 6

H), 1.34-1.64 (m, 3 H), 1.82 (t, J ) 6.8 Hz, 2 H), 2.12 (s, 3 H),

2.58 (s, 3 H), 2.60 (s, 3 H), 2.64 (t, J ) 6.8 Hz, 2 H), 3.10 (dd,

J ) 7.4, 6.7 Hz, 1 H), 4.40 (dd, J ) 7.6, 6.7 Hz, 1 H), 5.80 (dd,

J ) 11.6, 6.7 Hz, 1 H), 5.87 (d, J ) 11.6 Hz, 1 H). LRMS (FAB)

m/z, 492 (MH

⁺), 436, 352, 267, 251, 203, 168 (base peak), 147.

HRMS (FAB) m/z, calcd for C₂₇H₄₂NO₅S (MH⁺) 492.2783;

found: 492.2791. Compound 75, a colorless oil; [R]³⁰-38.3

D

(c 0.737, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 0.83 (d, J )

6.6 Hz, 3 H), 0.86 (d, J ) 6.6 Hz, 3 H), 1.20-1.60 (m, 3 H),

1.32 (s, 6 H), 1.47 (s, 9 H), 1.83 (t, J ) 6.8 Hz, 2 H), 2.13 (s, 3

H), 2.59 (s, 3 H), 2.60 (s, 3 H), 2.65 (t, J ) 6.8 Hz, 2 H), 3.02

(dd, J ) 7.3, 5.9 Hz, 1 H), 3.42 (td, J ) 7.3, 1.0 Hz, 1 H), 5.97

(dd, J ) 15.6, 1.0 Hz, 1 H), 6.57 (dd, J ) 15.6, 7.1 Hz, 1 H).

LRMS (FAB) m/z, 492 (MH⁺), 490, 434, 267, 251, 224 (base

peak), 203, 168, 147. HRMS (FAB) m/z, calcd for C₂₇H₄₂NO₅S

(MH⁺) 492.2783; found: 492.2782.

ter t-Bu tyl (4R,5S,2E)-4,5-Epim in o-7-m eth yl-N-(2,2,5,7,8-

pen tam eth yl-6-ch r om an su lfon yl)-2-octen oate (75). Ozone

was bubbled through a solution of the vinylaziridine 64 (0.80

g, 2.046 mmol) in CH₂Cl₂(15 mL) at -78 °C until a faint blue

color persisted. To the mixture at -78 °C was added 0.5 g of

zinc powder, and the mixture was stirred for 1 h with warming

up to 0 °C. The inorganic precipitates were removed by

filtration through a short column of silica gel. The filtrate was

concentrated under reduced pressure to leave a crude aldehyde

as a colorless oil. To a stirred suspension of LiCl (173 mg,

4.092 mmol) in MeCN (10 mL) under argon at room temper-

ature were added tert-butyl diethylphosphonoacetate (0.96 mL,

4.092 mmol), diisopropylethylamine (0.71 mL, 4.092 mmol),

and finally the above oily aldehyde in 5 mL of MeCN. The

mixture was stirred for 1 h at room temperature. Usual

workup followed by flash chromatography over silica gel

eluting with n-hexane-EtOAc (3:1) afforded the (E)-enoate 75

) 17.2, 10.2, 7.0 Hz, 1 H), 6.95 (s, 2 H). Anal. Calcd for C₁₆H₂₃

-

NO₂S: C, 65.49; H, 7.90; N, 4.77. Found: C, 65.32; H, 7.83;

N, 4.65.

P a lla d iu m (0)-Ca ta lyzed Equ ilibr a ted Rea ction of a 2:3

Mixtu r e of (2R,3S)-3-(2-Meth ylp r op yl)-N-(2,2,5,7,8-p en -

ta m eth yl-6-ch r om a n su lfon yl)-2-vin yla zir id in e (64) a n d

Its (2S,3S)-Isom er (65). To a stirred solution of a 2:3 mixture

of the 2,3-cis- and 2,3-trans-aziridines 64 and 65 (4.5 g, 11.45

mmol) in 15 mL of dry THF at 0 °C was added by syringe a

solution of Pd(PPh₃)₄(529 mg, 0.458 mmol, 4 mol %) in 5 mL

of dry THF, and the mixture was stirred at 0 °C for 18 h.

Concentration under reduced pressure at 0 °C followed by flash

chromatography on a short silica gel column with n-hexane-

EtOAc (5:1) gave 4.46 g (99% yield) of a mixture of 64 and 65

(64:65 ) 96:4, HPLC) as a colorless oil, which was flash

chromatographed on silica gel eluting with n-hexane-EtOAc

to give the desired compound 64 (3.96 g, 88% yield) as a

colorless oil.

(860 mg, 85.6% yield) as a colorless oil. [R]³⁰

-38.5 (c 1.64,

D

1

CHCl₃); H NMR (300 MHz, CDCl₃) δ 0.83 (d, J ) 6.6 Hz, 3

H), 0.86 (d, J ) 6.6 Hz, 3 H), 1.20-1.60 (m, 3 H), 1.32 (s, 6 H),

1.47 (s, 9 H), 1.83 (t, J ) 6.8 Hz, 2 H), 2.13 (s, 3 H), 2.59 (s, 3

H), 2.60 (s, 3 H), 2.65 (t, J ) 6.8 Hz, 2 H), 3.02 (dd, J ) 7.3,

5.9 Hz, 1 H), 3.42 (td, J ) 7.3, 1.0 Hz, 1 H), 5.97 (dd, J ) 15.6,

1.0 Hz, 1 H), 6.57 (dd, J ) 15.6, 7.1 Hz, 1 H). Anal. Calcd for

C₂₇

H₄₁NO₅S: C, 65.96; H, 8.41; N, 2.85. Found: C, 65.93; H,

8.48; N, 2.85.

ter t-Bu tyl (2R,5S,3E)-7-Meth yl-2-(2-m eth ylp r op yl)-5-

[N-(2,2,5,7,8-p en ta m eth yl-6-ch r om a n su lfon yl)a m in o]-3-

octen oa te (76). To a stirred solution of CuCN (954 mg, 10.6

mmol) and LiCl (896 mg, 21.2 mmol) in 20 mL of dry THF

Equ ilibr a ted Rea ction of (2S,3S)-3-(2-Meth ylp r op yl)-

N-(4-n it r ob en zen esu lfon yl)-2-vin yla zir id in e (69) w it h

Thermodynamics of 2,3-cis-3-Alkyl-2-vinylaziridines

J . Org. Chem., Vol. 62, No. 4, 1997 1015

under argon was added by syringe isobutylmagnesium chloride

(1.1 M solution in THF; 9.64 mL, 10.6 mmol) at -78 °C, and

the mixture was allowed to warm to 0 °C and stirred at this

temperature for 10 min. The enoate 75 (1.3 g, 2.65 mmol) in

5 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 76 (1.40

(2R,5S,3E)-5-[N-(ter t-Bu tyloxycar bon yl)am in o]-7-m eth -

yl-2-(2-m eth ylp r op yl)-3-octen oic Acid (78). To a stirred

solution of the N-Pmc derivative 76 (840 mg, 1.53 mmol) in

10 mL of TFA under argon was added by syringe 0.5 mL of

thioanisole at room temperature, and the mixture was stirred

at this temperature for 24 h. The mixture was concentrated

under reduced pressure to leave an oily residue. To a solution

of the oily residue in 15 mL of CHCl₃were added diisopropyl-

ethylamine (4 mL) and Boc₂O (1.0 g) under stirring at 0 °C,

and the mixture was stirred for 3 h. The mixture was made

acidic with 20% citric acid and extracted with EtOAc. Usual

workup followed by flash chromatography over silica gel with

n-hexane-EtOAc gave the title compound 78 (280 mg, 56%

yield) as a crystalline mass. Colorless crystals from cold

g, 96% yield) as a colorless oil. [R]²⁰-39.8 (c 1.22, CHCl₃);

D

∆ꢀ -8.72 (222 nm in isooctane); ¹H NMR (300 MHz, CDCl₃) δ

0.79 (d, J ) 6.6 Hz, 3 H), 0.80 (d, J ) 6.6 H, 3 H), 0.81 (d, J

) 6.5 Hz, 3 H), 0.83 (d, J ) 6.7 Hz, 3 H), 1.00 (m, 1 H), 1.17-

1.60 (m, 6 H), 1.31 (s, 6 H), 1.39 (s, 9 H), 1.83 (t, J ) 6.8 Hz,

2 H), 2.12 (s, 3 H), 2.535 (s, 3 H), 2.538 (s, 3 H), 2.65 (t, J )

6.8 Hz, 2 H), 2.74 (m, 1 H), 3.71 (m, 1 H), 4.33 (d, J ) 7.4 Hz,

1 H), 5.25 (m, 2 H). LRMS (FAB) m/z, 549 (M⁺), 492, 448,

284, 267 (base peak), 203, 147. HRMS (FAB) m/z, calcd for

C₃₁H₅₁NO₅S (M⁺) 549.3488; found: 549.3495.

n-hexane; mp 97 °C; [R]²⁰-61.0 (c 0.95, CHCl₃); ∆ꢀ -4.19

D

(219 nm in isooctane); ¹H NMR (300 MHz, CDCl₃) δ 0.87 (d, J

) 6.2 Hz, 3 H), 0.90 (d, J ) 6.6 Hz, 3 H), 0.91 (d, J ) 6.4 Hz,

6 H), 1.22-1.42 (m, 2 H), 1.44 (s, 9 H), 1.48-1.69 (m, 3 H),

3.07 (m, 1 H), 4.11 (m, 1 H), 4.39 (broad s, 1 H), 5.45 (dd, J )

15.5, 6.0 Hz, 1 H), 5.56 (dd, J ) 15.5, 8.3 Hz, 1 H). Anal. Calcd

for C₁₈H₃₃NO₄: C, 66.02; H, 10.16; N, 4.28. Found: C, 65.85;

H, 9.97; N, 4.21.

ter t-Bu tyl (2R,5S,3E)-7-Meth yl-2-(3-m eth ylbu tyl)-5-[N-

(2,2,5,7,8-p e n t a m e t h yl-6-ch r om a n su lfon yl)a m in o]-3-

octen oa te (77). By use of a procedure similar to that

described for the reaction of 75 with i-BuCu(CN)MgCl, the R,â-

enoate 75 (391 mg, 0.8 mmol) was converted into the â,γ-

enoate 77 (430 mg, 96%) as a colorless oil by treatment with

isopentyl-Cu(CN)MgCl (3.2 mmol, 4 equiv) in 7.5 mL of THF

Ack n ow led gm en t. We thank Dr. T. R. Burke, J r.,

NCI, NIH, Bethesda, MD, for reading the manuscript

and providing useful comments. This work was sup-

ported in part by Grant-in-Aid for Scientific Researches

(B and C) from the Ministry of Education, Science and

Culture of J apan, to which the authors’ thanks are due.

at -78 °C for 30 min. [R]²⁰-42.6 (c 1.13, CHCl₃); ∆ꢀ -7.82

D

1

Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR

(222 nm in isooctane); ¹H NMR (300 MHz, CDCl₃) δ 0.79 (d, J

) 6.5 Hz, 6 H), 0.85 (d, J ) 6.6 Hz, 3 H), 0.86 (d, J ) 6.6 Hz,

3 H), 0.97-1.61 (m, 8 H), 1.32 (s, 6 H), 1.40 (s, 9 H), 1.83 (t, J

) 6.8 Hz, 2 H), 2.12 (s, 3 H), 2.53 (s, 3 H), 2.55 (s, 3 H), 2.60

(dd, J ) 8.1, 6.3 Hz, 1 H), 2.65 (t, J ) 6.8 Hz, 2 H), 3.71 (m, 1

H), 4.31 (d, J ) 7.3 Hz, 1 H), 5.22 (dd, J ) 15.5, 7.2 Hz, 1 H),

5.33 (dd, J ) 15.5, 8.0 Hz, 1 H). LRMS (FAB) m/z, 563 (M⁺),

506, 462, 267 (base peak), 203, 147, 57.

spectra of compounds 9, 10, 12, 13, 15, 24-26, 32, 37-39, 60,

62, 64, 65, 67-69, 74-77 are available (23 pages). This

material is contained in libraries on microfiche, immediately

follows this article in the microfilm version of the journal, can

be ordered from the ACS; see any current masthead page for

ordering information.

J O961760O

Article Doi

A Thermodynamic Preference of Chiral N-Methanesulfonyl and N-Arenesulfonyl 2,3-cis-3-Alkyl-2-Vinylaziridines over Their 2,3-Trans-Isomers: Useful Palladium(0)-Catalyzed Equilibration Reactions for the Synthesis of (E)-Alkene Dipeptide Isosteres

DOI: 10.1021/jo961760o

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