J. Org. Chem. 1994,59,4875-4886
4875
S#-Reactions of Peptide Aziridines. A Cuprate-Based Approach to (E)-AlkeneIsosterest Peter Wipf“J a n d Paul C. Fritch Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 Received April 28, 1994@
Alkenylaziridines were prepared from allylic alcohols via Sharpless epoxidation, oxirane to aziridine conversion under modified Staudinger conditions, and Wittig chain extension. Alternatively, ,&hydroxy a-amino acids such as threonine can serve as readily available precursors. The corresponding N-acyl, -peptidyl-, -carbamoyl-, and -sulfonylaziridines underwent a high-yielding anti-SN2’ alkylation with organocopper/BF3 complex to give (E)-alkene peptide isosteres in 62 to >98% de. The stereoselectivity of t h e addition process was studied by lH and I9F NMR as well as chemical degradation. Alkene isosteres are important nonhydrolyzable and rigidified analogs of peptide bonds in biologically active peptides. This new methodology considerably facilitates the synthesis and the study of these peptide mimetics, since alkenylaziridines are readily prepared and side-chain modification is simplified by t h e wide range of functionalized organocopper reagents t h a t are available. Peptide analogs are widely employed in elucidating structure-activity relationships, and replacement of the peptide backbone by thiomethylene, hydroxymethylene, ketomethylene, a-aza, and other amino acid isosteres has led to significant increases in bioavailability and oral activity.2 The amide bond i n peptides and proteins is a prime target for enzymatic degradation, and backbone modifications are therefore crucial for improving metabolic stability. Alkenes are ideal isosteric replacements of amides, since the (E)-CR=CH group closely resembles the three-dimensional structure (bond length, bond angle, and rigidity) of the parent amide (Figure 1). The use (E)-alkene isosteres as mimetics of dipeptide units in biologically active peptides requires the preparation of two asymmetric centers at the a- and &positions +Presented in part a t the 25th ACS Central Regional Meeting, Pittsburgh, PA, October 5, 1993. Abstract published in Advance ACS Abstracts, July 15, 1994. (1) Eli Lilly Grantee, 1993-1995; Alfred P. Sloan Research Fellow, 1994-1995; recipient of a n American Cyanamid Faculty Award, 1994. (2) (a) Spatola, A. F. Chem. Biochem. Amino Acids Pept. Proteins 1983, 7, 267. (b) Hirschmann, R. Angew. Chem. Int. Ed. Engl. 1991, 30,1278. (c) Giannis, A.; Kolter, T. Angew. Chem. Int. Ed. Engl. 1993, 32, 1244. (3) (a)Hann, M. M.; Sammes, P. G.; Kennewell, P. D.; Taylor, J. B. J . Chem. SOC.Chem. Comm. 1980,234. (b) Cox, M. T.; Heaton, D. W.; Horbury, J. J . Chem. SOC.Chem. Comm. 1980, 799. (c) Cox, M. T.; Gormley, J. J.; Hayward, C. F.; Petter, N. N. J . Chem. SOC.Chem. Commun. 1980,800. (d) Hann, M. M.; Sammes, P. G.; Kennewell, P. D.; Taylor, J. B. J . Chem. SOC.Perkin Trans. 1 1982, 307. (e) Allan, R. D.; Dickenson, H. W.; Johnston, G. A. R.; Kazlauskas, R.; Tran, H. W. Aust. J . Chem. 1985, 38, 1651. (0 Shue, Y.-K.; Tufano, M. D.; Nadzan, A. M. Tetrahedron Lett. 1988, 29, 4041. (g) Allmendinger, T.; Furet, P.; Hungerbuhler, E. Tetrahedron Lett. 1990,31, 7297. (h) Bol, K. M.; Liskamp, R. M. J . Tetrahedron Lett. 1991, 32, 5401. (i) Callahan, J. F.; Newlander, K. A.; Huffman, W. F. Tetrahedron Lett. 1991,32,7203. (i)Shue, Y.-K.; Tufano, M. D.; Carrera, G. M.; Kopecka, H.; Kuyper, S. L.; Holladay, M. W.; Lin, C. W.; Witte, D. G.; Miller, T. R.; Stashko, M.; Nadzan, A. M. Bioorg. Med. Chem. 1993,1, 161. (4) (a) Spaltenstein, A.; Carpino, P. A.; Miyake, F.; Hopkins, P. B. J . Org. Chem. 1987,52,3759. (b) Lehman de Gaeta, L. S.; Czarniecki, M.; Spaltenstein, A. J . Org. Chem. 1989, 54, 4004. (c) Whitesell, J. K.; Laurence, R. M. Chirality 1989, 1, 89. (d) Ibuka, T.; Habashita, H.; Funakoshi, S.; Fujii, N.; Oguchi, Y.; Uyehara, T.; Yamamoto, Y. Angew. Chem. Int. Ed. Engl. 1990, 29, 801. (e) Allmendinger, T.; Felder, E.; Hungerbuhler, E. Tetrahedron Lett. 1990, 31, 7301. (f) Kempf, D.; Wang, X. C.; Spanton, S. G. Int. J . Pept. Protein Res. 1991, 38, 237. (g) Beresis, R.; Panek, J. S. Bioorg. Med. Chem. Lett. 1993, 3,1609. (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) Bohnstedt, A. C.; Vara Prasad, J. V. N.; Rich, D. H. Tetrahedron Lett. 1993,34, 5217. (i)Yong, Y. F.; Lipton, M. A. Bioorg. Med. Chem. Lett. 1993,3, 2879.
Figure 1.
@
0022-3263/94/1959-4875$04.50/0
of 5-amino-3-pentenoic acids. Among the reported synthetic procedures for this class of compound^,^ stereocontrolled protocols4 are relatively rare, and a general stereoselective synthesis of alkene isosteres would considerably increase their application in drug discovery and development. We have recently reported on the preparation of peptide aziridines by the Mitsunobu r e a ~ t i o n . As ~ an extension of these studies, we were interested in the use of aziridines of type 1 as peptide mimetics. Specifically, SN2’-reaction of cuprates with 1 would provide a versatile route to (E)-alkene dipeptide isosteres (Figure 2). In the past years, reactions of allylic derivatives with organocuprate reagents have been extensively studied.6 Al( 5 )(a) Wipf, p.; Miller, C. P. Tetrahedron Lett. 1992,33, 6267. (b) Mitsunobu, 0. Synthesis 1981, 1. (6) For reviews see: (a) Yamamoto, Y. Angew. Chem. Int. Ed. Engl. 1986,25, 947. (b) Nakamura, E. Synlett 1991, 539. (c) Lipshutz, B. H.; Sengupta, S. Org. React 1992,41; 135. (d)Wipf, P. Synthesis 1993, 537. (7) After the completion of our studies, Ibuka et al. reported that alkenylaziridines were inert toward vinylzinc or vinylcopper reagents: Ibuka, T.; Nakai, K.; Habashita, H.; Bessho, K.; Fujii, N.; Chounan, Y.; Yamamoto, Y. Tetrahedron 1993, 42, 9479. Very recently, this group also reported the successful addition of alkylcopper/ zincate reagents to N-tosylated /3-aziridinyl a,p-enoates: 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.
0 1994 American Chemical Society
4876
J. Org. Chem., Vol.59,No. 17,1994
Wipf and Fritch
Scheme 1 d
t-BuOOH, Ti(O-i-Pr), L-(+)-DIPT,4 A MS
a
1. Swern Ox.
(carbalkoxymethy1ene)triphenylphosphorane (69-88% yield for two steps, Scheme 1). Stereoselective epoxide ring opening a t C(4) of 5 was achieved in 45-85% yield by treatment with 3.0 equiv of sodium azide and 3.0 equiv of ammonium chloride in refluxing ethanol1' for 3 h or less. Under these reaction conditions, generally less than 5% of the epimeric azide 7 was isolated. Any increase (8) (a) Curran, D. P.; Chen, M.-H.; Leszczweski, D.; Elliot, R. L.; Rakiewicz, D. M. J. Org. Chem. 1986,51,1612. (b)Tseng, C. C.; Yen, S.; Goering, H. L. J. Org. Chem. 1986,51,2892. (c)Underiner, T. L.; Goering, H. L. J . Org. Chem. 1988, 53, 1140. (d) Underiner, T. L.; Paisley, S. D.; Schmitter, J.;Lesheski, L.; Goering, H. L. J.Org. Chem.
1989,54,2369. (9) (a)Hutchinson, D. K.; Fuchs, P. L. J.Am. Chem. SOC. 1986,107, 6137. (b) Ibuka, T.; Nakao, T.; Nishii, S.; Yamamoto, Y. J.Am. Chem. Soc. 1986,108,7420. (c)Ibuka, T.; Tanaka, M.; Nishii, S.; Yamamoto, Y. J. Am. Chem. SOC. 1989, 111, 4864. (d) Ibuka, T.; Tanaka, M.; Yamamoto,Y. J. Chem. SOC.,Chem. Comm. 1989, 967. (e) Pan, V.; Hutchinson, D. K.; Nantz, M. H.; Fuchs, P. L. Tetrahedron 1989,45, 467. (0 Ibuka, T.; Taga, T.; Habashita, H.; Nakai, K.; Tamamura, H.; Fujii, N.; Chounan,Y.; Nemoto, H.; Yamamoto, Y. J . Org. Chem. 1993, 58, 1207. (10) (a)For a review see: Marshall J. A. Chem. Rev. 1989,89,1503. (b) Marshall, J. A.; Blough, B. E. J. Org. Chem. 1991,56, 2225. (c) Marshall, J. A.; Crute, T. D.; Hsi, J. D. J. Org. Chem. 1992, 57, 115. (d)Anderson, R. J. J . Am. Chem. Soc. 1970,92,4978. (e)Herr, R. W.; Johnson, C. R. J. Am. Chem. SOC.1970, 92, 4979. (0 Staroscik, J.; Rickborn,B. J . Am. Chem. Soc. 1971,93,3046. (g)Marino, J. P.; Floyd, D. M. Tetrahedron Lett. 1979,20, 675. (h) Marino, J. P.; Jaen, J. C. J. Am. Chem. SOC.1982,104, 3165. (11) (a) Yanagisawa, A.; Noritake, Y.; Nomura, N.; Yamamoto, H. Synlett 1991,251. (b)Arai, M.; Nakamura, E.; Lipshutz, B. H. J. Org. Chem. 1991,56, 5489. (12) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Maruyama, K. J. Am. Chem. SOC. 1980, 102, 2318. (13) Kang, S.-K.; Lee,D.-H.; Sim,H.-S.; Lim,J.-S. TetrahedronLett. 1993, 34, 91. (14)For a recent excellent review on the synthesis of chiral aziridines, see: Tanner, D. Angew. Chem. Int. Ed. E&. 1994,33,599. (15) Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, pp 389-436. (16) Mancuso, A. J.; Swern, D. Synthesis 1981, 165. (17) (a) Guthrie, R. D.; Murphy, D. J. Chem. Soc. 1965, 5288. (b) Shaw, K. J.; Luly,J. R.; Rapoport, H. J. Org. Chem. 1988,60, 4515. (c) Chid, M.; Crotti, P.; Flippin,L. A.; Macchia,F. J.Org. Chem. 1991, 56, 7043. (d) Legters, J.;Thijs, L.; Zwanenburg, B. R e d . Trau. Chim. Pays-Bas 1992, 111, 1.
*,,
HO R3
EOH. reflux * R2@O&yI N, k1 6
L
X = imidazole,
CI, OPFP, OCQCBu
0
+ R Z ~ O a l k y l
R'
k3
'
(19:l)
0
R3
R4COX
SR,
R 2 w O a l k y !
HQ R3
NaN3, NH4Cl
though S~a'-alkylationof alkenyl aziridines has escaped this a t t e n t i ~ nthere , ~ is ample precedence for this transformation in a highly stereoselective a n t i - S ~ 2 'fashion with allylic esters,8 sulfonates: oxiranes,l0 phosphates,ll halides,6aJ2 and ~ a r b 0 n a t e s . l ~ Preparation of Alkenyl Aziridines. A variety of routes to scalemic aziridines is a ~ a i 1 a b l e . l ~We envisioned several synthetic schemes for the preparation of peptidyl aziridines 1. Epoxy alcohols 4, obtained by Sharpless asymmetric epoxidation15 of allylic alcohols 3 in the presence of (+)-diisopropyl tartrate (DIP"), were oxidized under Swern conditions,16 and the resulting aldehydes were subjected to a Wittig chain extension with
,Ik'OH 4
2. Ph3P=CHC02alkyl
Figure 2.
-
R3
R 2 w O a l k y l R4-$
-
R'
Table 1. Preparation of Alkenylaziridines 9 from Epoxy Alcohols 4 According to Scheme 1
entry
alkenylaziridines 9 R3 R4 H Ph H EtOzCCHzCHz H PhCH20C(O)NHCHz H t-BuO CH3 t-BuO
R2 no. yielda(%) CH3 9a 27 CHs 9b 42 2 3 CH3 QC 39 4 CH3 9d 47 5 H 9e 24 Yields are not optimized and are based on epoxy alcohol 4 and aziridines 9. Aziridines were purified by column chromatography on silica gel; 9a-d contained 65% of the corresponding (2s)diastereomer. 1
R' H H H H CH3
in reaction time led to a significant decrease in the ratio of 6:7, possibly a s a consequence of a nonstereoselective [3,3lsigmatropic allylic azide shift.la Staudinger reactionlg of ,&azido alcohol 6 proceeded in 6 5 8 2 % yield and resulted in aziridine formation via inversion of the configuration a t C(5).20 Subsequent N-acylation of 8 with acylimidazoles, acid chlorides, pentafluorophenyl esters (OPFP), or mixed anhydrides yielded 57-98% of the desired alkenylaziridines 9. A summary of the Nacylaziridines that were prepared via this route and the overall yield from epoxy alcohol 4 are given in Table 1. The Sharpless asymmetric epoxidation protocol provides epoxy alcohols 4 in various degrees of optical purity, depending on the substitution pattern of the alkene.15 Crystallization of appropriate derivatives can also be used to improve the enantiomeric excess.21 We used epoxy alcohols 4a and 4e in 84% and 60% ee, a s with literature data determined by comparison of [ a l ~ (18) Biffin, M. E. C.; Miller, J.; Paul, D. B. In The Chemistry of the Azido Group; Patai, S., Ed.; Interscience: London, 1985; p 84. (19) Gololobov,Y. G.; Zhmurova, I. N.; Gsukhin, I. F. Tetrahedron 1981, 37, 437. (20) (a) Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org. Chem. 1978, 43, 4271. (b) Tanner, D.; Somfai, P. Tetrahedron Lett. 1987, 28, 1211. (c) Legters, J.; Thijs, L.; Zwanenburg, B. R e d . Trau. Chim. Pays-Bas 1992,111, 16. (21) Klunder, J. M.; Onami, T.; Sharpless, K. B. J . Org. Chem. 1989, 54, 1295.
J . Org. Chem., Vol. 59, No. 17, 1994 4877
S~2’-Reactionsof Peptide Aziridines
Scheme 2 1. MsCI, (i-Pr)2NEt,CH2C12 2. LiBH4, Et20
10
NHBoc
73%
NHBoc
11
17
reduction
0
a-alkylation
-
Ph3P=CHC&Et CH2CI2 71%
0
I
H
w
O E 9f
BOC‘
t y-alkylation
Scheme 3 TsCI, pyridine 37% 14
Tso 15Y
cyclization
NaBH,, LiCl O NHTs M
NHz
e
&ai ky lation
THF-EtOH87%
1. Dess-Martin Periodinane
2. Ph3P=CHC02Me, CHZCIZ
33%
Ts’
R4bO
9g
Figure 3.
and integration of the 19FNMR of the Mosher esterz2 product was trans-oxazoline 22; this compound was derivatives. Alternatively, optically pure peptide aziriformed as the only detectable product with PhCu-BF3 in dines can be obtained from j3-hydroxy amino a ~ i d s . ~ ~ , ~ ~ Etz0.26 No &alkylation or conjugate addition products Sequential treatment of Boc-threonine methyl ester (10) 21 or 19 were observed. Table 2 summarizes the results with 1 equiv of mesyl chloride in CHzClz and lithium of organocuprate additions to alkenylaziridines. borohydride in Et20 provided alcohol 11 in 73% overall The balance between S~2‘-reactionproducts of alkenyield (Scheme 2). Cyclization of 11 in hot CH3CN in the ylaziridines and side products of this process depends presence of potassium carbonate was followed by Parikhstrongly on the type of cuprate reagent used. The best Doering oxidation24to aldehyde 13. The Wittig reaction results were obtained with alkylcopper reagents derived with (carbethoxymethy1ene)triphenylphosphorane gave from CUI or CuCN and alkyl lithium in the presence of the N-Boc protected alkenylaziridines 9f in 71% yield. boron trifluoride-diethyl ether (Yamamoto-typeGacuI n a related sequence of reactions, the N-tosylated prates). The nature of the electron-withdrawing acyl derivative 9g was prepared in four steps from threonine group (R4CO) on the aziridine ring nitrogen was also methyl ester (14) (Scheme 3). Reduction of N,O-ditosyfound to have a profound effect on the efficiency and the lated ester 15 with NaBH4 in the presence of LiClZ5 regioselectivity of the addition reaction. The yield of resulted in concomitant aziridine ring formation. dipeptide isosteres 17 was highest (70-90%) with NCuprate Additions to Alkenylaziridines. Several sulfonated or Boc-protected azirdines 9g, 9f, and 9e electrophilic sites on alkenylaziridines of type 9 are (Table 1, entries 17-22). Nucleophilic attack on the potential points of attack for organocuprate reagents N-benzoylated substrate 9a a s well a s the succinate (Figure 3). The desired a-alkylation product 17 was derivative 9b and the Cbz-glycyl tripeptide 9c led to obtained by S~2’-reactionof the organocuprate. Genersignificant amounts of y-alkylation and, consequently, ally, the formation of 17 was accompanied by sN2-(ydecreased amounts (< 70%) of a-alkylation products. alkylation) and reduction products 20 and 18. Single The stereoselectivity of the S~2’-alkylationof alkenylelectron transfer from the copper(1) species followed by aziridines 9 appeared, according to high-field NMR, H abstraction or enolization of the transient a-Cu(II1) uniformly high in favor of anti attack. This result is in species could account for the reduction product t h a t is a agreement with the vast majority of allylic displacements frequent side product in organocuprate substitution and involving organocopper reagents.6J0 Corey and Boaz addition reactions.6c Another generally observed side suggested orbital symmetry, e.g. the interaction of a filled dl0copper orbital with both the n* and the a* antibonding (22)Dale, J. A.;Mosher, H. S. J.Am. Chem. Soc. 1973,95,512. orbitals of the allylic leaving group, to be the reason for (23)Nakagawa, Y.;Tsuno, T.; Nakajima, K.; Iwai, M.; Kawai, H.; this p r e f e r e n ~ e .I~n~order to obtain NMR-independent Okawa, I(.Bull. Chem. SOC.Jpn. 1972,45,1162. quantitative information on the degree of anti-selectivity (24)Parikh, J.R.;von E. Doering, W. J.Am. Chem. SOC.1967,89, 5505. of the sN2’ process, alkene peptide isosteres 17 were (25)Hamada, Y.;Shibata, M.; S u g i u a , T.; &to, S.; Shioiri, T. J. chemically degraded t o short-chain alcohols (Scheme 4). Org.Chem. 1987,52,1252. (26)For the acid-catalyzed rearrangement of N-acylaziridine to Reduction of the ester 17 to the primary alcohol 23 with oxazoline, see ref 20c and Heine, H.W.; Fetter, M. E.; Nicholson, E. LiB& was followed by O-benzylation, Johnson-Lemieux M. J.Am. Chem. SOC.1969,81, 2202. Single electron transfer to a n
N-acylaziridine can lead to oxazoline formation: Archier-Jay, D.; Besbes, N.; Laurent, A.; Laurent, E.; Stamm,H.; Tardivel, R. Tetrahedron Lett. 1989,30,2271.
(27)(a)Corey, E.J.; Boaz, N. W. Tetrahedron Lett. 1984,25,3063. (b) Hamon, L.; Levisalles, J. Tetrahedron 1989, 45,489.
J. Org. Chem., Vol. 59,No. 17, 1994
4878
Wipf and Fritch
Table 2. Product Distribution and Yield of Organocuprate Additions to Alkenylaziridines 9
cuprate (additive)
entry 1 2
aziridine 9a 9a
ND ND
products [% yieldP 18 20 20aa (21) 18a (53) 18a (44) 20aa (7)
22 ND ND
Me Me
17
RE
4
9a 9a
ND 17aa (24)
18a (46) 18a (43)
20aa (3) 20aa (4)
ND ND
Me Me
5
9a
17aa (62)
18a ( ~ 1 )
20aa (6)
3
Me
6
9a
l7aa (60)
18a (
