A concise synthesis of rigidified β-amino acids via sulfanyl radical addition-cyclization of oxime ethers and hydrazones

Article abstract of DOI:10.1055/s-1998-1646

A new route to the rigidified cyclic β-amino acids such as cispentacin has been developed by sulfanyl radical addition-cyclization of the alkenyl-tethered-oxime ethers and hydrazones.

Full text of DOI:10.1055/s-1998-1646

March 1998
SYNLETT
271
A Concise Synthesis of Rigidified β-Amino Acids via Sulfanyl Radical Addition-Cyclization
of Oxime Ethers and Hydrazones
Okiko Miyata, Kanami Muroya, Junko Koide, Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658, Japan
FAX 078 441 7556; E-mail: taknaito@kobepharma-u.ac.jp
Received 18 December 1997
Abstract: A new route to the rigidified cyclic β-amino acids such as
cispentacin has been developed by sulfanyl radical addition-cyclization
of the alkenyl-tethered-oxime ethers and hydrazones.
1
The β-amino acids have attracted considerable interest because they are
useful tools in the synthesis of modified peptides with increased activity
and in vivo stability. Although much less abundant than their α-analogs,
β-amino acids are also present in nature. They are found, for instance, in
the anticancer agent taxol, macrocyclic peptides, and antibiotics (β-
2,3
2,4
lactam, cispentacin, etc.). Recently, Seebach's
and Gellman's
groups found that peptide analogs from β-amino acids fold into defined
three-dimensional structures (helical structures) similar to those of
natural peptides and they were much more resistant than the
corresponding α-peptide to cleavage by pepsin and peptidase enzymes.
We report a concise synthesis of the rigidified (cyclic) β-amino acids
After successful cyclization of the oxime ethers 4a-d, we then extended
the sulfanyl radical addition-cyclization to the hydrazones 4e-g.
5
employing the newly developed sulfanyl radical addition-cyclization of
the alkenyl-tethered-oxime ethers and hydrazones. Carbocyclization of
11
11
Cyclization of the hydrazone 4e gave 5e and 6e in 73% combined
yield (entry 5). This represented a much more efficient cyclization than
that of the oxime ether 4a. Similar results were achieved for
heterocyclic systems, although stereoselectivities were lower (entries 6
and 7). The sulfanyl radical addition-cyclization of the alkenyl-tethered-
oxime ethers and hydrazones can be summarized as follows.
(a) Addition of sulfanyl radical to the terminal alkene and subsequent
6
radicals onto C=N bonds has been most studied in halogeno- , carbonyl-
6q,7
6d,8
9
, alkynyl- , and allenic -tethered-oxime ethers and hydrazones. In
10
contrast, little is known about radical cyclization of the alkenyl-
tethered-oxime ethers and hydrazones. Our approach is shown in
Scheme 1. Sulfanyl radical would attack the terminal alkenyl group in
the substrates 1 to provide the alkyl radical species A which is expected
to form to the substituted cyclic amines 2, as a result of 5-exo-trig
cyclization. Subsequent conversion of the phenylsulfanylmethyl group
into the carboxyl group would furnish the desired β-amino acids 3.
cyclization proceeded regioselectively to give the desired products.
12
(b) The cis-isomers were preferentially formed. Beckwith
has
explained that the preferential formation of the cis-product from the 1-
substituted hexenyl radical is ascribed to the effects of orbital symmetry.
13
(c) In spite of existence in a stable zig-zag conformer which is
unfavorable to intramolecular cyclization, the radical cyclization of 4be
proceeded smoothly to give the desired products. Thus, we have now
succeeded in sulfanyl radical addition-cyclization of the alkenyl-
tethered-oxime ethers and hydrazones for preparation of the substituted
cyclic amines.
Conversion of the cyclopentylamines 5be and 6be to the β-amino acid 9
was very readily achieved as shown in Scheme 2. (1R,2S)-2-
14
Aminocyclopentanecarboxylic acid (9b), cispentacin is an antifungal
15
antibiotic isolated by Konishi et al. from the culture broth of a
Scheme 1
Bacillus cereus strain. A mixture of 5b and 6b was converted step by
step into the exo-methylene 8 via reduction of the methoxyamino group,
t-butoxycarbonylation of the resulting amine, and oxidative elimination
of the phenylthio group in the N-Boc-sulfide 7. The exo-methylene 8
We first investigated the radical cyclization of the readily available
oxime ethers 4a-d (Table 1). The oxime ether 4a was treated with
thiophenol (1 equiv.) and AIBN (0.5 equiv.) in refluxing benzene. The
reaction proceeded smoothly to give a mixture of the cis- and trans-
cyclopentylamines 5a and 6a in good yield, although with modest
cis/trans selectivity (entry 1). Under the same reaction conditions,
sulfanyl radical addition-cyclization of the simple substrate 4b gave a
mixture of the desired products 5b and 6b in 49 % combined yield
(entry 2). Sulfanyl radical addition-cyclization of the oxime ethers 4c
and 4d having the hetero atoms (X=NTs, O) as a X group, proceeded
also was obtained readily from
hydrogenolysis, t-butoxycarbonylation, and oxidative elimination.
a mixture of 5e and 6e via
16
11
11
Stereoselective hydroboration-oxidation of 8 with 9-BBN-H O from
2
2
the convex face followed by oxidation of the resulting alcohol gave the
17
cis-N-Boc-amino acid 9a. The spectral data of 9a were identical with
11
11
14e
those reported in the literature.
(±)-9a had previously been
transformed into (-)-cispentacin (9b) via the optical resolution and
18
removal of t-butoxycarbonyl protecting group.
11
11
11
11
smoothly to give the cyclized products 5c and 6c , and 5d and 6d
in 88 and 72 % yields, respectively (entries 3 and 4).
In conclusion, a general method for the sulfanyl radical addition-
cyclization of the alkenyl-tethered-oxime ethers and hydrazones has
been developed. This method was successfully applied to the practical
synthesis of the rigidified cyclic β-amino acid, cispentacin.

272
LETTERS
SYNLETT
(n) Kim, S.; Cheong, J. H.; Yoon, K. S. Tetrahedron Lett. 1995, 36,
6069. (o) Kim, S. Pure Appl. Chem. 1996, 68, 623. (p) Brinza, I. M.;
Fallis, A. G. J. Org. Chem. 1996, 61, 3580. (q) Marco-Contelles, J.;
Gallego, P.; Rodríguez-Fernández, M.; Khiar, N.; Destabel, C.;
Bernabé, M.; Martínez-Grau, A.; Chiara, J. L. J. Org. Chem. 1997,
62, 7397. (r) Grové, J. J. C.; Holzapfel, C. W. Tetrahedron Lett.
1997, , 7429. (s) Noya, B.; Alonso, R.
38
1997,
Tetrahedron Lett.
38,
2745. (t) Clive, D. L. J.; Zhang, J. Chem. Commun. 1997, 549.
(u) Kim, S.; Kim, Y.; Yoon, K. S. Tetrahedron Lett. 1997, 38, 2487.
(7) (a) Corey, E. J.; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821.
(b) Kim, S.; Kee, I. S. Tetrahedron Lett. 1993, 34, 4213. (c) Naito,
T.; Tajiri, K.; Harimoto, T.; Ninomiya, I.; Kiguchi, T. Tetrahedron
1994, , 2205. (d) Chiara J. L.; Marco-Contelles, J.; Khiar, N.;
35
Lett.
Scheme 2
Gallego, P.; Destabel, C.; Bernabé, M. J. Org. Chem. 1995, 60,
6010.
(8) (a) Enholm, E. J.; Burroff, J. A.; Jaramillo, L. M. Tetrahedron Lett.
Acknowledgments. This work was supported in part by Grant-in-Aid
for scientific research (No. 09672293) from the Ministry of Education,
Science, Sports and Culture, Japan and the Science Research Promotion
Fund of the Japan Private School Promotion Foundation for a research
grants.
1990, , 3727. (b) Grissom, J.W.; Klingberg, D.
31
J. Org. Chem.
1993, , 6559. (c) Pattenden, G.; Schulz, D. J.
58
Tetrahedron Lett.
1993, , 6787. (d) Marco-Contelles, J.; Destabel, C.; Chiara, J. L.;
34
Bernabé, M. Tetrahedron: Asymmetry 1995, 6, 1547.
(e) Hollingworth, G. J.; Pattenden, G.; Schulz, D. J. Aust. J. Chem.
1995, , 381. (f) Marco-Contelles J.; Destabel, C.; Gallego, P.;
Chiara, J. L.; Bernabé, M. J. Org. Chem. 1996, 61, 1354. (g) Keck,
G. E.; Wagen, T. T. J. Org. Chem. 1996, 61, 8366.
48
References and Notes
(1) (a) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1997, 26, 117.
(b) Cole, D. C. Tetrahedron 1994, 50, 9517.
(9) (a) Hatem, J.; Henriet-Bernard, C.; Grimaldi, J.; Maurin, R.
(2) (a) Borman, S.; Chem. Eng. News 1997, 75, 32. (b) Koert, U. Angew.
1992,
Tetrahedron Lett.
33, 1057. (b) Bernard-Henriet, C. D.;
1997, , 1836.
36
Chem. Int. Ed. Engl.
Grimaldi, J. R.; Hatem, J. M. Tetrahedron Lett. 1994, 35, 3699.
(c) Marco-Contelles, J.; Balme, G.; Bouyssi, D.; Destabel, C.;
Henriet-Bernard, C. D.; Grimaldi, J.; Hatem, J. M. J. Org. Chem.
(3) (a) Seebach, D.; Overhand, M.; Kühnle, F. N. M.; Martinoni, B.;
Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta. 1996, 79,
913. (b) Seebach, D.; Ciceri, P. E.; Overhand, M.; Jaun, B.; Rigo, D.;
Oberer, L.; Hommel, U.; Amstutz, R.; Widmer, H. Helv. Chim. Acta.
1997, , 1202.
62
(10) A known example of radical cyclization of the alkenyl-tethered-
1996, , 2043. (c) Hintermann, T.; Seebach, D.
79
1997, 437.
Synlett
oxime ethers: Parker, K. A.; Spero, D. M.; Epp, J. V. J. Org. Chem.
1988, , 4628.
53
(4) (a) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.;
Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 13071. (b) Appella, D.
H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.; Huang, X.;
Barchi, J. J. J.; Gellman, S. H. Nature 1997, 387, 381.
(11) The each stereoisomer was isolated and their relative
stereochemistries were established by NOE measurements.
(12) (a) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073. (b) Spellmeyer,
D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959.
(5) Sulfanyl radical addition-cyclization of dienes: (a) Naito, T.; Honda,
Y.; Miyata, O.; Ninomiya, I. Heterocycles 1992, 32, 2319. (b) Naito,
T.; Honda, Y.; Miyata, O.; Ninomiya, I. Chem. Pharm. Bull. 1993,
41, 217. (c) Naito,T.; Honda, Y.; Miyata, O.; Ninomiya, I. J. Chem.
(13) Substituent effects on intramolecular cyclization: (a) Jung, M. E.;
Vu, B. T. Tetrahedron Lett. 1996, 37, 451. (b) Jung, M. E.; Marquez,
R. Tetrahedron Lett. 1997, 38, 6521.
1995, 19. (d) Miyata, O.; Nishiguchi, A.;
Soc. Perkin Trans. 1
Ninomiya, I.; Naito, T.; Aoe, K.; Okamura K. Tetrahedron Lett.
1996, , 229. (e) Miyata, O.; Nishiguchi, A.; Ninomiya, I.; Naito, T.
(14) Previous syntheses of cispentacin: (a) Plieninger, H.; Schneider, K.
1959, , 1594. (b) Bernáth, G.; Láng, K. L.; Göndös,
92
Chem. Ber.
37
Chem. Pharm. Bull.
G.; Márai, P.; Kovács, K. Acta. Chim. Acad. Sci. Hung. 1972, 74,
479. (c) Mierke, D. F.; Nößner, G.; Schiller, P. W.; Goodman, M.
1996, , 1285. (f) Miyata, O.; Ozawa, Y.;
44
Ninomiya, I.; Naito, T. Synlett 1997, 275.
1990, , 35. (d) Evans, C.; McCague,
35
Int. J. Peptide Protein Res.
(6) (a) Marco-Contelles, J.; Martínez-Grau, A.; Bernabé, M.; Martín, N.;
Seoane, C. Synlett 1991, 165. (b) Booth, S. E.; Jenkins, P. R.; Swain,
C. J. J. Chem. Soc. Chem. Commun. 1991, 1248. (c) Marco-
Contelles, J.; Martínez, L.; Martínez-Grau, A.; Rozuelo, C.; Jimeno,
M. L. Tetrahedron Lett. 1991, 32, 6437. (d) Marco-Contelles, J.;
Martínez, L.; Martínez-Grau, A. Tetrahedron: Asymmetry 1991, 2,
961. (e) Kim, S.; Kee, I. S.; Lee, S. J. Am. Chem. Soc. 1991, 113,
9882. (f) Marco-Contelles, J.; Martínez-Grau, A.; Martinez-Ripoll,
M.; Cano, H.; Foces-Foces, C. J. Org. Chem. 1992, 57, 403.
(g) Marco-Contelles, J.; Pozuelo, C.; Jimeno, M. L.; Martínez, L.;
Martínez-Grau, A. J. Org. Chem. 1992, 57, 2625. (h) Booth, S. E.;
Jenkins, P. R.; Swain, C. J.; Sweeney, J. B. J. Chem. Soc. Perkin
R.; Roberts, S. M.; Sutherland, A. G.; Wisdom, R. J. Chem. Soc.
1991, 2276. (e) Konosu, T.; Oida, S.
Perkin Trans. 1
Chem. Pharm.
1993, , 1012. (f) Davies, S. G.; Ichihara, O.; Walters, I. A. S.
Bull.
41
1993, 461. (g) Davies, S. G.; Ichihara, O.; Lenoir, I.; Walters,
Synlett
I. A. S. J. Chem. Soc. Perkin Trans. 1 1994, 1411. (h) Theil, F.;
Ballschuh, S. Tetrahedron: Asymmetry 1996, 7, 3565.
(15) Konishi, M.; Nishio, M.; Saitoh, K.; Miyaki, T.; Oki, T.; Kawaguchi,
H. J. Antibiot. 1989, 42, 1749.
(16) The application of conventional methods (10%Pd-C/H2/HCl,6t
10%Pd-C/H2/dl-10-camphorsulfonic acid,6k 5%Rh on Al2O3/ H2
)
16
to the cleavage of N-N bond was unsuccessful. Overberger, C. G.;
Palmer, L. C.; Marks, B. S.; Byrd, N. R. J. Am. Chem. Soc. 1955, 77,
4100.
1994, 3499. (i) Della, E. W.; Knill, A. M.
Trans.1
Aust. J. Chem.
1994, , 1833. (j) Grissom, J. W.; Klingberg, D.; Meyenburg, S.;
47
(17) The attempted conversion of cis-7 into 9a via Pummerer reaction
Stallman, B. L. J. Org. Chem. 1994, 59, 7876. (k) Sturino, C. F.;
Fallis, A. G. J. Am. Chem. Soc. 1994, 116, 7447. (l) Sturino, C. F.;
Fallis, A. G. J. Org. Chem. 1994, 59, 6514. (m) Keck, G. E.;
McHardy, S. F.; Murry, J. A. J. Am. Chem. Soc. 1995, 117, 7289.
was unsuccessful.
(18) Yamazaki, T.; Zhu, Y.-F.; Probstl, A.; Chadha, R. K.; Goodman, M.
1991, , 6644.
56
J. Org. Chem.