Diastereoselective Synthesis of ψ[(E)-CMe=CH]- and ψ[(E)-CMe=CMe]-Type Dipeptide Isosteres Based on Organocopper-mediated anti-SN2′ Reaction

Article abstract of DOI:10.1021/ol016835b

matrix presented A straightforward synthetic route for the synthesis of diastereomerically pure ψ[(E)-CMe=CH]- and ψ[(E)-CMe=CMe]-type dipeptide isosteres was developed on the basis of regio- and stereoselective anti-S_N2′ alkylation of 3-(N-Boc

Full text of DOI:10.1021/ol016835b

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1055-1058
Diastereoselective Synthesis of
ψ[(E)-CMedCH]- and ψ[(E)-CMedCMe]-
Type Dipeptide Isosteres Based on
Organocopper-Mediated anti-SN2′
Reaction
Shinya Oishi,† Ayumu Niida,† Takae Kamano,† Yoshihiko Odagaki,‡
,†
Hirokazu Tamamura,† Akira Otaka,† Nobuyuki Hamanaka,‡ and Nobutaka Fujii*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Sakyo-ku,
Kyoto, 606-8501, Japan, and Minase Research Institute, Ono Pharmaceutical Co. Ltd.,
Mishima-gun, Osaka 618-8585, Japan
nfujii@pharm.kyoto-u.ac.jp
Received September 28, 2001
ABSTRACT
A straightforward synthetic route for the synthesis of diastereomerically pure ψ[(E)-CMedCH]- and ψ[(E)-CMedCMe]-type dipeptide isosteres
was developed on the basis of regio- and stereoselective anti-SN2′ alkylation of 3-(N-Boc-5-methyl-4-substituted-oxazolidin-2-on-5-yl)acrylates
with organocopper reagents.
â-Turn substructures on the surface of bioactive peptides and
proteins very often participate in important molecular
recognition. This motif represents an intensive target for
development of new pharmaceuticals in medicinal chemis-
try.1 Many â-turn mimetics have been developed and
evaluated for restriction and stabilization of active conforma-
tions.2,3 (E)-Alkene dipeptide isosteres (EADIs) correspond-
ing to (L,D)- and (D,L)-type dipeptides are potential mimetics
of the type II and II′ â-turn motifs, respectively. Gellman et
al. previously reported that a Gly-ψ[(E)-CMedCMe]-Gly
type EADI promotes â-hairpin formation in CH2Cl2 in a
flexible linear peptide backbone.4 In addition, Wipf et al.
recently reported that ψ[(E)-CMedCH]-type EADIs promote
the formation of â-turns in the solid state as a result of
restriction of φ,ψ-dihedral angles by A1,2- and A1,3-strains.5
However, synthesis of these agents is likely to be limited to
Ala-ψ[(E)-CMedCH]-Xaa-type EADIs since requisite chiral
epoxides corresponding to diverse amino acids are not easily
(2) (a) Chen, S.; Chrusciel, R. A.; Nakanishi, H.; Raktabutr, A.; Johnson,
M. E.; Sato, A.; Weiner, D.; Hoxie, J.; Saragovi, H. U.; Greene, M. I.;
Kahn, M. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 5872. (b) Etzkorn, F. A.;
Guo, T.; Lipton, M. A.; Goldberg, S. D.; Bartlett, P. A. J. Am. Chem. Soc.
1994, 116, 10412. (c) Gillespie, P.; Cicariello, J.; Olson, G. L. Biopolymers
1997, 43, 191. (d) Fink, B. E.; Kym, P. R.; Katzenellenbogen, J. A. J. Am.
Chem. Soc. 1998, 120, 4334. (e) Johannesson, P.; Lindeberg, G.; Tong,
W.; Gogoll, A.; Karle´n, A.; Hallberg, A. J. Med. Chem. 1999, 42, 601. (f)
Khalil, E. M.; Ojala, W. H.; Pradhan, A.; Nair, V. D.; Gleason, W. B.;
Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1999, 42, 628. (g) Eguchi,
M.; Lee, M. S.; Nakanishi, H.; Stasiak, M.; Lovell, S.; Kahn, M. J. Am.
Chem. Soc. 1999, 121, 12204. (h) Kim, H.-O.; Nakanishi, H.; Lee, M. S.;
Kahn, M. Org. Lett. 2000, 2, 301. (i) Estiarte, M. A.; Rubiralta, M.; Diez,
A.; Thormann, M.; Giralt, E. J. Org. Chem. 2000, 65, 6992. (j) Golebiowski,
A.; Klopfenstein, S. R.; Shao, X.; Chen, J. J.; Colson, A.-O.; Grieb, A. L.;
Russell, A. F. Org. Lett. 2000, 2, 2615. (k) Smith, A. B., III; Wang, W.;
Sprengeler, P. A.; Hirschmann, R. J. Am. Chem. Soc. 2000, 122, 11037. (l)
Alonso, E.; Lo´pez-Ortiz, F.; Del Pozo, C.; Peralta, E.; Mac´ıas, A.; Gonza´lez,
J. J. Org. Chem. 2001, 66, 6333.
† Kyoto University.
‡ Ono Pharmaceutical Co., Ltd.
(1) Rose, G. D.; Gierasch, L. M.; Smith, J. A. AdVances in Protein
Chemistry; Academic Press: New York, 1985; pp 1-109.
10.1021/ol016835b CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/05/2002

available. In this communication, we describe an alternative
practical synthesis of ψ[(E)-CMedCH]- and ψ[(E)-CMed
CMe]-type dipeptide isosteres from a chiral amino acid
utilizing organocopper-mediated regio- and stereoselective
anti-SN2′ alkylation of oxazolidinone derivatives.
Scheme 1a
We and others previously reported that ψ[(E)-CHdCH]-
type EADIs are efficiently synthesized via organocopper-
mediated regio- and stereoselective alkylation of R,â-
unsaturated esters containing a leaving group at the γ-position.
This includes γ-mesyloxy-R,â-unsaturated esters6 and N-
activated â-aziridino-R,â-unsaturated esters,5,7 which are
easily constructed from chiral amino alcohol derivatives. On
the other hand, if γ-methylated R,â-unsaturated esters are
to be used in the same manner for the synthesis of ψ[(E)-
CMedCX]-type EADIs (X ) H or Me), activation of tertiary
alcohols for the construction of key SN2′ substrates as the
corresponding mesylates or N-activated aziridines is poten-
tially problematic. Thus, we attempted to develop a new
process for the synthesis of ψ[(E)-CMedCX]-type EADIs
based on organocopper-mediated SN2′ reactions of â-oxazo-
lidinonyl-R,â-unsaturated esters as key substrates.
To make our synthetic methodology generally applicable
to diverse ψ[(E)-CMedCX]-type EADIs, we chose chiral
amino acid derivatives 1 and 6 as the starting materials
(Scheme 1).8 Initially, ester 1 was converted to allyl alcohols
2 or 3 by successive treatment with DIBAL-H and vinyl or
isopropenyl Grignard reagents. Swern oxidation of 2 and 3
followed by treatment with methyl Grignard reagent in the
presence of CeCl3 yielded anti-isomers of the respective allyl
alcohols 4a and 5a as major products (4a:4b ) 86:14; 5a:
5b ) 96:4).9 Their syn-isomer 4b or 5b was preferentially
obtained by treatment of the methyl ketone, which was
prepared from Weinreb’s amide 7, with vinyl or isopropenyl
Grignard reagent in the presence of CeCl3 (4a:4b ) 21:79;
5a:5b ) 20:80).9 Cyclization by sodium hydride of allyl
a (a) DIBAL-H, CH2Cl2/toluene. (b) CH2dCRMgBr‚ZnCl2‚LiCl,
THF. (c) (COCl)2, DMSO, DIEA, CH2Cl2. (d) MeMgCl, CeCl3,
THF. (e) MeONHMe‚HCl, DCC, DIEA, DMF. (f) MeMgCl, THF.
(g) CH2dCHMgBr, CeCl3, THF. (h) CH2dCMeMgBr, CeCl3, THF.
(i) NaH, THF. (j) Boc2O. (k) O3 gas, EtOAc. (l) DMS. (m)
(EtO)2P(O)CH2CO2t-Bu, LiCl, DIEA, MeCN. (n) Ph3PdCHCO2t-
Bu, CHCl3.
(3) For recent reviews of peptidomimetics, see: (a) Peptide Secondary
Structure Mimetics. Tetrahedron (Symposia-in-print, no. 50; Kahn, M., Ed.)
1993, 49, 3444. (b) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-
G.; Lubell, W. D. Tetrahedron 1997, 53, 12789. (c) Peptidomimetics
Protocols; Kazmierski, W. M., Ed.; Humana Press: Totowa, NJ, 1999. (d)
Hruby, V. J.; Balse, P. M. Curr. Med. Chem. 2000, 7, 945. (e) Kim, H.-O.;
Kahn, M. Comb. Chem. High Throughput Screening 2000, 3, 167.
(4) Gardner, R. R.; Liang, G.-B.; Gellman, S. H. J. Am. Chem. Soc. 1995,
117, 3280.
(5) (a) Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4875. (b) Wipf,
P.; Henninger, T. C.; Geib, S. J. J. Org. Chem. 1998, 63, 6088.
(6) (a) Ibuka, T.; Habashita, H.; Funakoshi, S.; Fujii, N.; Oguchi, Y.;
Uyehara, T.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1990, 29, 801.
(b) Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N.; Oguchi, T.; Uyehara, T.;
Yamamoto, Y. J. Org. Chem. 1991, 56, 4370.
(7) (a) 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. (b) 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. (c) Wipf, P.; Henninger, T. C. J. Org. Chem. 1997, 62, 1586.
(d) Tamamura, H.; Yamashita, M.; Nakajima, Y.; Sakano, K.; Otaka, A.;
Ohno, H.; Ibuka, T.; Fujii, N. J. Chem. Soc., Perkin Trans. 1 1999, 2983.
(e) Oishi, S.; Tamamura, H.; Yamashita, M.; Odagaki, Y.; Hamanaka, N.;
Otaka, A.; Fujii, N. J. Chem. Soc., Perkin Trans. 1 2001, 2445.
(8) D-Phenylalanine derivatives 1 and 6 were utilized for the synthesis
of D-Phe-ψ[(E)-CMedCX]-D/L-Val-type EADIs as a model case in this
communication. A dipeptide, D-Phe-L-Val, accommodates in the (i + 1)-
(i + 2) position in the type II′ â-turn substructure of the cyclic RGD
pentapeptide, cyclo(-Arg-Gly-Asp-D-Phe-Val-), previously reported: Haub-
ner, R.; Finsinger, D.; Kessler, H. Angew. Chem., Int. Ed. Engl. 1997, 36,
1374.
alcohols 4a,b and 5a,b, followed by N-protection by a Boc
group, afforded oxazolidin-2-ones 8a,b and 9a,b, respec-
tively, in which the hydroxy groups of 4a,b and 5a,b were
converted to leaving groups with apparent protecting groups
as carbamates. After ozonolysis of 5-vinyloxazolidin-2-ones
8a,b and subsequent reductive treatment with dimethyl
sulfide, Horner-Wadsworth-Emmons reaction (HWE reac-
tion) of the resulting aldehydes yielded R,â-unsaturated esters
10a,b in E-selective manner. The â-methylated derivatives
11a,b were prepared by Wittig reaction of the ketones in
moderate yields, which were obtained following ozonolysis
and consecutive reductive treatment of 5-isopropenyloxazo-
(9) The diastereomerically pure allyl alcohols 4a and 5a,b were readily
purified by recrystallization from the diastereomixture, respectively. The
syn-allyl alcohol 4b could not be isolated in this step, and thus the
diastereomixture, which contained the syn-allyl alcohol 4b as a major isomer,
was converted into the corresponding oxazolidin-2-one derivative 8b. The
diastereomerically pure oxazolidin-2-one 8b was purified by recrystalliza-
tion.
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Org. Lett., Vol. 4, No. 7, 2002

Table 1. Organocyanocuprate-Mediated Alkylation of â-(Oxazolidin-2-on-5-yl)-R,â-unsaturated Esters 10a,b and 11a,b
entry
substrate
reagent
condition
-78 °C, 30 min
-78 °C, 30 min
-78 °C, 30 min
yield (%)a
product ratiob
1
2
3
4
5
6
7
8
9
10a
10a
10b
10b
11a
11a
11a
11a
11b
11b
i-PrCu(CN)MgCl‚BF3‚2LiCl (4 equiv)
i-Pr2Cu(CN)(MgCl)2‚BF3‚2LiCl (4 equiv)
i-PrCu(CN)MgCl‚BF3‚2LiCl (4.2 equiv)
i-Pr2Cu(CN)(MgCl)2‚BF3‚2LiCl (4.2 equiv)
i-PrCu(CN)MgCl‚BF3‚2LiCl (4 equiv)
i-Pr2Cu(CN)(MgCl)2‚BF3‚2LiCl (4 equiv)
i-Pr2Cu(CN)(MgCl)2‚BF3‚2LiCl (6 equiv)
i-Pr3Cu(CN)(MgCl)3‚BF3‚2LiCl (4 equiv)
i-PrCu(CN)MgCl‚BF3‚2LiCl (4 equiv)
i-Pr2Cu(CN)(MgCl)2‚BF3‚2LiCl (4 equiv)
95
95
99
85
c
48
73
77
c
12a :13a ) 100:0
12a :13a ) 100:0
12b:13b ) 68:32
12b:13b ) 79:21
-78 °C, 30 min
-78 °C, 30 min, then 0 °C, 3 h
-78 °C, 30 min, then 0 °C, 3 h
-78 °C, 30 min, then 0 °C, 3 h
-78 °C, 30 min, then 0 °C, 3 h
-78 °C, 30 min, then 0 °C, 3 h
-78 °C, 30 min, then 0 °C, 3 h
14a :15a ) 76:24
14a :15a ) 75:25
14a :15a ) 68:32
10
95
14b:15b ) 79:21
a Combined isolated yields. b Ratio was determined by RP-HPLC. c The starting material was recovered.
lidin-2-ones 9a,b. Relative configurations of 10a,b and 11a,b
were determined by H NMR measurements.
CMe]-D-Val) 14a but also its Z-isomer (D-Phe-ψ[(Z)-CMed
CMe]-L-Val) 15a in low combined yield (48%, entry 6). The
chemical yield was significantly improved by use of 6 equiv
of the same reagent or 4 equiv of i-Pr3Cu(CN)(MgCl)3‚BF3‚
2LiCl, although a trace amount of the starting material 11a
still remained and the production of Z-isomer 15a was not
suppressed (entries 7 and 8). The trans-isomer 11b was
converted by i-Pr2Cu(CN)(MgCl)2‚BF3‚2LiCl to D-Phe-
ψ[(E)-CMedCMe]-L-Val 14b as a major product with
concomitant formation of a small amount of D-Phe-ψ[(Z)-
CMedCMe]-D-Val 15b (14b:15b ) 79:21, entry 10). All
products were purified by flash chromatography over silica
gel, and the optical purity of each product was estimated as
>99% by 1H NMR spectra. Olefinic geometry of all products
1
The leaving-group ability of carbamate functionality in
â-(oxazolidin-2-on-5-yl)-R,â-unsaturated esters 10a,b and
11a,b is presumed to be insufficient for alkylation with
organocyanocuprates as compared to that of mesylates or
N-activated aziridines in key intermediates for ψ[(E)-CHd
CH]-type EADIs. In practice, MeCu(CN)Li‚LiBr or its BF3
complex was not effective for the alkylation of 5-vinylox-
azolidin-2-one. However, the alkylation by more active
“higher-order” cyanocuprates, Me2Cu(CN)Li2‚BF3‚LiBr, pro-
ceeded excellently.10 On the basis of precedent investigations,
we evaluated alkylation of oxazolidin-2-ones 10a,b and 11a,b
by cyanocuprates prepared from copper cyanide and available
Grignard reagents (Table 1). Treatment of cis-isomer 10a
with i-PrCu(CN)MgCl‚BF3‚2LiCl or i-Pr2Cu(CN)(MgCl)2‚
BF3‚2LiCl in THF at - 78 °C for 30 min gave only the
E-isomer of an anti-SN2′ product (D-Phe-ψ[(E)-CMedCH]-
D-Val) 12a in excellent yield (entries 1 and 2). In the case
of trans-isomer 10b, the expected anti-SN2′ products, D-Phe-
ψ[(E)-CMedCH]-L-Val 12b and D-Phe-ψ[(Z)-CMedCH]-
D-Val 13b, were obtained by i-PrCu(CN)MgCl‚BF3‚2LiCl
(12b:13b ) 68:32, entry 3). Employment of the more active
reagent, i-Pr2Cu(CN)(MgCl)2‚BF3‚2LiCl, similarly yielded
12b and 13b with higher E-selectivity (12b:13b ) 79:21,
entry 4).
1
12a-15a and 12b-15b were established by H NMR, and
stereochemistries of the R-alkyl groups of the products were
determined by circular dichroism measurements.11 X-ray
analyses of 13b and 14b also supported these analyses.
In summary, we have found that alkylation of â-(oxazo-
lidin-2-on-5-yl)-R,â-unsaturated esters by several organo-
copper reagents proceeds regio- and stereoselectively via
anti-SN2′ mechanisms to give mainly E-isomers of the
R-alkylated products. The alkylation was successfully applied
to the stereoselective synthesis of ψ[(E)-CMedCH]- and
ψ[(E)-CMedCMe]-type EADIs from a chiral amino acid.
Interestingly, the reactivities of â-methylated substrates
11a,b to organocopper reagents were more sluggish than
those of 10a,b. Each reaction of 11a or 11b by the “lower-
order” i-PrCu(CN)MgCl‚BF3‚2LiCl gave no product, and the
starting material was recovered (entries 5 and 9). Alkylation
of the cis-isomer 11a with 4 equiv of the higher-order reagent
i-Pr2Cu(CN)(MgCl)2‚BF3‚2LiCl yielded not only the ex-
pected E-isomer of anti-SN2′ product (D-Phe-ψ[(E)-CMed
Acknowledgment. We thank Dr. Terrence R. Burke, Jr.,
NCI, NIH, for valuable discussions. This work was supported
by Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan, and the Japan Health Science Foundation. S.O. is
grateful for Research Fellowships of the JSPS for Young
Scientists.
(10) Ibuka, T.; Suzuki, K.; Habashita, H.; Otaka, A.; Tamamura, H.;
Mimura, N.; Miwa, Y.; Taga, T.; Fujii, N. J. Chem. Soc., Chem. Commun.
1994, 2151.
(11) Ibuka, T.; Habashita, H.; Funakoshi, S.; Fujii, N.; Baba, K.; Kozawa,
M.; Oguchi, Y.; Uyehara, T.; Yamamoto, Y. Tetrahedron: Asymmetry 1990,
1, 389.
Org. Lett., Vol. 4, No. 7, 2002
1057

Supporting Information Available: Selected experi-
mental procedures, 1H NMR spectra for all new compounds,
CD spectra of 12a-15a and 12b-15b, and crystal structure
of 13b and 14b. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL016835B
1058
Org. Lett., Vol. 4, No. 7, 2002