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

Article abstract of DOI:10.1021/ol016834j

matrix presented Acyclic ψ[(E)-CH=CMe]- and ψ[(Z)-CH=CMe]-type dipeptide isosteres were efficiently synthesized. In a key reaction, α-alkylation of γ-mesyloxy-β-methyl-α,β-unsaturated esters with organocyanocuprates in diethyl ether or tetrahydrofuran preferentially afforded the ψ[(E)-CH=CMe]- or ψ[(Z)-CH=CMe]-isomer, respectively, via anti-S_N2′ mechanism.

Full text of DOI:10.1021/ol016834j

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1051-1054
Diastereoselective Synthesis of
ψ[(E)-CHdCMe]- and
ψ[(Z)-CHdCMe]-Type Dipeptide
Isosteres by Organocopper-Mediated
anti-SN2′ Reaction
Shinya Oishi,† Takae Kamano,† Ayumu Niida,† 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
Acyclic ψ[(E)-CHdCMe]- and ψ[(Z)-CHdCMe]-type dipeptide isosteres were efficiently synthesized. In a key reaction, r-alkylation of γ-mesyloxy-
â-methyl-r,â-unsaturated esters with organocyanocuprates in diethyl ether or tetrahydrofuran preferentially afforded the ψ[(E)-CHdCMe]- or
ψ[(Z)-CHdCMe]-isomer, respectively, via anti-SN2′ mechanism.
Bioisosteres of natural amino acids and dipeptides are useful
tools for investigation of molecular recognition including
receptor/ligand and enzyme/substrate interactions, and they
represent diverse elements of practical value for constructing
chemical libraries in medicinal chemistry.1 (E)-Alkene dipep-
tide isosteres (EADIs) are examples of structures having
modified peptide backbones, which are designed to provide
resistance to biodegradation2 and conformational restriction
of a â-turn substructures,3 etc. We and others have reported
the stereoselective synthesis of EADIs mediated by organo-
copper reagents4 and their application to bioactive peptides.2,5
For instance, we recently synthesized an EADI-containing
cyclic RGD pseudopeptide 3 and evaluated its biological
activities.6
D-Phe-ψ[(E)-CHdCH]-L-Val isostere was
A
(2) (a) Jenmalm, A. J.; Luthman, K.; Lindeberg, G.; Nyberg, F.; Terenius,
L.; Hacksell, U. Bioorg. Med. Chem. Lett. 1992, 2, 1693. (b) Wai, J. S.;
Bamberger, D. L.; Fisher, T. E.; Graham, S. L.; Smith, R. L.; Gibbs, J. B.;
Mosser, S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Kohl, N. E. Bioorg.
Med. Chem. 1994, 2, 939.
(3) (a) Gardner, R. R.; Liang, G.-B.; Gellman, S. H. J. Am. Chem. Soc.
1995, 117, 3280. (b) Wipf, P.; Henninger, T. C.; Geib, S. J. J. Org. Chem.
1998, 63, 6088.
(4) (a) Ibuka T.; Habashita, H.; Otaka, A.; Fujii, N.; Oguchi, Y.; Uyehara,
T.; Yamamoto, Y. J. Org. Chem. 1991, 56, 4370. (b) Ibuka, T.; Taga, T.;
Habashita, H.; Nakai, K.; Tamamura, H.; Fujii, N.; Chounan, Y.; Nemoto,
H.; Yamamoto, Y. J. Org. Chem. 1993, 58, 1207. (c) Wipf, P.; Fritch, P.
C. J. Org. Chem. 1994, 59, 4875. (d) 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. (e) Wipf, P.; Henninger, T. C. J.
Org. Chem. 1997, 62, 1586. (f) Oishi, S.; Tamamura, H.; Yamashita, M.;
Odagaki, Y.; Hamanaka, N.; Otaka, A.; Fujii, N. J. Chem. Soc., Perkin
Trans. 1 2001, 2445.
† Kyoto University.
‡ Ono Pharmaceutical Co., Ltd.
(1) For recent reviews of peptidomimetics, see: (a) Peptidomimetics
Protocols; Kazmierski, W. M., Ed.; Humana Press: Totowa, NJ, 1999. (b)
Hruby, V. J.; Balse, P. M. Curr. Med. Chem. 2000, 7, 945.
10.1021/ol016834j CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/05/2002

incorporated as an equivalent to the (i + 1)-(i + 2) position
in the type II′ â-turn substructure of the cyclic RGD
pentapeptide 1 reported by Kessler et al. (Figure 1).7 In the
Scheme 1a
Figure 1. Cyclic RGD peptides 1 and 2 by Kessler et al. and EADI-
containing cyclic RGD pseudopeptides 3 and 4.
inhibition assay of vitronectin-Rvâ3 integrin binding, the
potency of pseudopeptide 3 was higher than that of 1 and
nearly equal to that of the improved cyclic peptide 2.8
a (a) DIBAL-H, CH2Cl2/toluene. (b) CH2dCMeMgCl‚ZnCl2‚LiCl,
THF. (c) (COCl)2, DMSO, DIEA, CH2Cl2. (d) Zn(BH4)2, Et2O. (e)
Ac2O, pyridine, DMAP, CHCl3. (f) O3, EtOAc. (g) DMS. (h)
Ph3PdCHCO2t-Bu, CHCl3, reflux. (i) Na2CO3, MeOH. (j) MsCl,
TEA, THF.
While the reason for the high activity of the pseudopeptide
3 has not been elucidated yet, incorporation of the D-Phe-
ψ[(E)-CHdCH]-L-Val moiety may convert the peptide
backbone to a more active form, as well as N-methylvaline.
Thus, we designed the pseudopeptide 4 containing the D-Phe-
ψ[(E)-CHdCMe]-L-Val moiety in order to rationally inves-
tigate the effect of both the N-methylvaline and the (E)-
alkene moiety. Synthesis of 4 required preparation of this
unique dipeptide isostere. In this communication, we describe
the first unequivocal synthesis of a ψ[(E)-CHdCMe]-type
dipeptide isostere and its ψ[(Z)-CHdCMe]-congener, which
is inherently an unanticipated product, obtained with orga-
nocopper reagents.
reagent (syn:anti ) 80:20). Alternatively, an anti-allyl alcohol
7b was preferentially afforded by reduction of the enone
(obtained by Swern oxidation of a diastereomixture of allyl
alcohols 7a and 7b) with Zn(BH4)2 in Et2O (syn:anti ) 24:
76).9 The diastereomerically pure alcohols 7a and 7b could
be separated by flash chromatography over silica gel fol-
lowed by recrystallization, respectively.
After protection of hydroxyl groups, acetates 8a and 8b
were converted to R,â-unsaturated esters. Ozonolysis of 8a
followed by reductive treatment with dimethyl sulfide and
successive Wittig reaction with Ph3PdCHCO2t-Bu gave
γ-acetoxy-R,â-unsaturated esters. Deprotection of acetyl
groups yielded two isomers of the γ-hydroxy-R,â-unsaturated
esters. Unexpectedly, the resulting minor isomer was not the
(Z)-isomer of syn-R,â-unsaturated esters 9a but rather the
anti-(E)-isomer 9b, which apparently originated as a result
of epimerization at the chiral center of the acetoxy group
(9a:9b ) 90:10). Even in the case of the acetate 8b, both
isomers of R,â-unsaturated esters 9a and 9b were obtained
in similar manner (9a:9b ) 17:83). Each isomer of esters
9a and 9b was readily purified by flash chromatography.
The E geometry and the relative configuration of the hydroxy
groups of R,â-unsaturated esters 9a and 9b were established
Synthesis of ψ[(E)-CHdCMe]-Type Dipeptide Isostere
Precursors. Synthesis of key intermediate, γ-mesyloxy-R,â-
unsaturated esters 10, started from D-phenylalanine derivative
5 or D-phenylalaninol derivative 6. This provided a general-
ized synthetic strategy toward ψ[(E)-CHdCMe]-type dipep-
tide isosteres from chiral amino acids (Scheme 1). A syn-
allyl alcohol 7a was stereoselectively prepared by reduction
of Boc-D-Phe-OMe 5 with DIBAL-H at -78 °C in CH2Cl2/
toluene, followed by treatment with isopropenyl Grignard
(5) (a) Christos, T. E.; Arvanitis, A.; Cain, G. A.; Johnson, A. L.; Pottorf,
R. S.; Tam, S. W.; Schmidt, W. K. Bioorg. Med. Chem. Lett. 1993, 3, 1035.
(b) Beresis, R.; Panek, J. S. Bioorg. Med. Chem. Lett. 1993, 3, 1609. (c)
Bartlett, P. A.; Otake, A. J. Org. Chem. 1995, 60, 3107. (d) Wada, M.;
Doi, R.; Hosotani, R.; Higashide, S.; Ibuka, T.; Habashita, H.; Nakai, K.;
Fujii, N.; Imamura, M. Pancreas 1995, 10, 301. (e) 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. (f) Miyasaka, K.;
Kanai, S.; Masuda, M.; Ibuka, T.; Nakai, K.; Fujii, N.; Funakoshi, A. J.
Auton. NerV. Syst. 1997, 63, 179.
(6) Oishi, S.; Kamano, T.; Niida, A.; Kawaguchi, M.; Hosotani, R.;
Imamura, M.; Yawata, N.; Ajito, K.; Tamamura, H.; Otaka, A.; Fujii, N.
In Peptide Science 2000; Shioiri, T., Ed.; The Japanese Peptide Society:
Osaka, 2001; pp 249-250.
1
by H NMR analysis of the corresponding acetonides.10
Esters 9a and 9b were converted into the respective mesylates
10a and 10b.
(9) Zinc borohydride was widely utilized for the stereoselective synthesis
of peptide isosteres: (a) Wasserman, H. H.; Xia, M.; Petersen, A. K.;
Jorgensen, M. R.; Curtis, E. A. Tetrahedron Lett. 1999, 40, 6163. (b)
Travins, J. M.; Bursavich, M. G.; Veber, D. F.; Rich, D. H. Org. Lett. 2001,
3, 2725.
(10) Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.; Zlatoidzky, P. J.
Org. Chem. 1997, 62, 9348.
(7) For reviews of cyclic RGD peptides, see: Haubner, R.; Finsinger,
D.; Kessler, H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1374.
(8) Dechantsreiter, M. A.; Planker, E.; Matha¨, B.; Lohof, E.; Ho¨lzemann,
G.; Jonczyk, A.; Goodman, S. L.; Kessler, H. J. Med. Chem. 1999, 42,
3033.
1052
Org. Lett., Vol. 4, No. 7, 2002

Table 1. Alkylation of syn-γ-Mesyloxy-â-methyl-R,â-unsaturated Ester 10a with Organocyanocuprates
product ratioc
11a :11b:11c+11d d:12
yielde
(%)
entry
reagenta
additiveb
solvent
THF
THF
THF
THF
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O/THFf
condition
0 °C, 0.5 h
-78 °C, 0.5 h
-78 °C, 0.5 h
-78 °C, 0.5 h
-78 °C, 0.5 h
0 °C, 3 h
-78 °C, 0.5 h
-78 °C, 0.5 h, then 0 °C, 0.5 h
-78 °C, 0.5 h
-78 °C, 0.5 h
-78 °C, 0.5 h
-78 °C, 0.5 h
1
2
3
4
5
6
7
8
9
i-PrCu(CN)MgCl‚BF3
i-Pr2Cu(CN)(MgCl)2‚BF3
i-Pr2Cu(CN)(MgCl)2‚BF3
i-Pr2Cu(CN)(MgCl)2‚BF3
i-Pr2Cu(CN)(MgCl)2
i-PrCu(CN)MgCl‚BF3
i-Pr2Cu(CN)(MgCl)2‚BF3
i-Pr2Cu(CN)(MgCl)2‚BF3
i-Pr2Cu(CN)(MgCl)2‚BF3
i-Pr2Cu(CN)(MgCl)2
40:51: -g:9
35:64: -g:1
28:71: -g:1
27:72: -g:1
25:73: -g:1
36:63: -g:1
46:27:26:1
70:27: -g:3
44:25:28:3
14:84: -g:2
43:42:12:3
37:62: -g:1
82
94
91
92
86
15h
90
93
81
93
97
87
HMPA
TMEDA
18-crown-6
HMPA
TMEDA
18-crown-6
THF
10
11
12
i-Pr2Cu(CN)(MgCl)2‚BF3
i-Pr2Cu(CN)(MgCl)2‚BF3
1
a All reactions were carried out with 4 molar equiv of reagent. b 4 molar equiv. c Product ratios were determined by HPLC and H NMR. d Containing
a small amount of an unknown product. e Combined yield. f Et2O/THF ) 7:3. g Although we cannot conclusively rule out its presence, we failed to isolate
the corresponding product. h The starting material was recovered (77%).
Synthesis of ψ[(E)-CHdCMe]- and ψ[(Z)-CHdCMe]-
Type Dipeptide Isosteres. Alkylation of γ-Mesyloxy-â-
methyl-r,â-unsaturated Esters with Organocyanocu-
prates. In the synthesis of chiral R-alkyl-â,γ-unsaturated
esters11a and chiral R,R-dialkyl-â,γ-unsaturated esters11b and
its application to the synthesis of ψ[(E)-CHdCH]-type
dipeptide isosteres,4a the regio- and stereochemical outcomes
of organocopper-mediated alkylation of γ-mesyloxy-R,â-
unsaturated esters are fully documented. Alkylation proceeds
through an anti-SN2′ mechanism, and all products are
exclusively of E-geometry. As such, it was our expectation
that ψ[(E)-CHdCMe]-type dipeptide isosteres would be
easily prepared from γ-mesyloxy-â-methyl-R,â-unsaturated
esters such as 10a and 10b.
Next, we investigated conditions using only Et2O as
solvent. We originally thought this to be unsuitable for the
alkylation because of sluggishness.4,11 Treatment with i-PrCu-
(CN)MgCl‚BF3 afforded a mixture of SN2′-alkylated products
in low yield (15%), and the substrate 10a was recovered
(77%, entry 6). The more reactive “higher-order” reagent
i-Pr2Cu(CN)(MgCl)2‚BF3 in Et2O gave alkylated products
in excellent yield (90%) with concomitant formation of anti-
and syn-SN2′ products4b (anti-SN2′:syn-SN2′ ) 74:26), and
the E-ratio of the isomers was remarkably increased (11a:
11b ) 63:37) compared with the reaction in THF (entry 7).
In addition, various additives were examined (entries 8-10),
including HMPA, which proved to suppress formation of
syn-SN2′ products, 11c and 11d, and apparently improved
the overall yield of the D-Phe-ψ[(E)-CHdCMe]-L-Val-type
dipeptide isostere 11a (11a:11b ) 72:28, entry 8). In contrast,
addition of 18-crown-6 decreased the formation of the
E-isomer 11a (entry 10).
To evaluate solvent effects on selectivity, alkylation in
mixed solvents of Et2O and THF was examined (entries 11
and 12). Addition of 4 equiv of THF in Et2O decreased
E-selectivity (11a:11b ) 51:49), and a 7:3 mixture of Et2O
and THF yielded a ratio of 11a and 11b products similar to
that using THF alone (11a:11b ) 37:63). Taken together,
cyclic ethers such as THF and 18-crown-6 probably affected
the Z-selectivity in alkylation for reasons that are unclear.
Alkylation of the anti-isomer 10b with organocyanocu-
prates was also investigated similarly (Table 2). In THF, both
i-PrCu(CN)MgCl‚BF3 and i-Pr2Cu(CN)(MgCl)2‚BF3 pro-
vided 11c and 11d Z-selectively (entries 1 and 2). Whereas
treatment of 10b with i-PrCu(CN)MgCl‚BF3 in Et2O resulted
in recovered substrate with no conversion to products (entry
3), i-Pr2Cu(CN)(MgCl)2‚BF3 in Et2O gave a D-Phe-ψ[(Z)-
CHdCMe]-L-Val-type dipeptide isostere 11d as a main
However, treatment of 10a with a “lower-order” organo-
cyanocuprate-BF3 complex, i-PrCu(CN)MgCl‚BF3, in THF,
which is the usual condition for preparation of ψ[(E)-CHd
CH]-type dipeptide isosteres, gave D-Phe-ψ[(Z)-CHdCMe]-
D-Val-type dipeptide isostere 11b as a major product, along
with the expected D-Phe-ψ[(E)-CHdCMe]-L-Val-type dipep-
tide isostere 11a (11a:11b ) 44:56, Table 1, entry 1).12
A
“higher-order” cyanocuprate-BF3 complex, i-Pr2Cu(CN)-
(MgCl)2‚BF3 (which gave only reductive products in the case
of alkylation of â-aziridinyl-R,â-unsaturated esters4d), also
yielded 11b with higher Z-selectivity (11a:11b ) 35:65, entry
2). Several additives (HMPA, TMEDA, 18-crown-6), which
were intended to improve E-selectivity, further increased
Z-selectivity (entries 3-5).
(11) (a) Ibuka, T.; Tanaka, M.; Nishii, S.; Yamamoto, Y. J. Am. Chem.
Soc. 1989, 111, 4864. (b) Ibuka, T.; Akimoto, N.; Tanaka, M.; Nishii, S.;
Yamamoto, Y. J. Org. Chem. 1989, 54, 4055.
(12) Unusual formation of the Z-isomer of anti-SN2′ products by
organocopper-mediated alkylation was previously reported: Yang, H.;
Sheng, X. C.; Harrington, E. M.; Ackermann, K.; Garcia, A. M.; Lewis,
M. D. J. Org. Chem. 1999, 64, 242.
Org. Lett., Vol. 4, No. 7, 2002
1053

Table 2. Alkylation of anti-γ-Mesyloxy-â-methyl-R,â-
unsaturated Ester 10b with Organocyanocuprates
product ratioc
yieldd
(%)
entry
reagenta,b
solvent
11c:11d :11a +11b:12
1
2
3
4
e
f
e
f
THF
THF
Et2O
Et2O
27:69: -g:4
41:54: -g:5
65
87
h
7:41:26:26
68
a Reactions in entries 1, 3, and 4 were carried out at -78 °C, 0.5 h then
0 °C, 3 h with 4 molar equiv of reagent. b Reaction in entry 2 was carried
out at -78 °C, 0.5 h with 4 molar equiv of reagent. c Product ratios were
determined by HPLC and 1H NMR. d Combined yield. e i-PrCu(CN)-
MgCl‚BF3. f i-Pr2Cu(CN)(MgCl)2‚BF3. g Although we cannot conclusively
rule out its presence, we failed to isolate the corresponding product. h The
starting material was recovered.
Figure 2. Plausible mechanism for the stereoselective alkylation
of syn-γ-mesyloxy-â-methyl-R,â-unsaturated ester 10a.
â-unsubstituted substrates.4,11 The products 11a and 11b are
presumably formed via conformer 10a-A and conformer 10a-
B, respectively. The ratio of products is assumed to be
determined by the population of these conformers in the
transition state.14
product with a considerable amount of a D-Phe-ψ[(Z)-CHd
CMe]-Gly-type dipeptide isostere 12 (entry 4).
The olefinic geometries of 11a-d were established by
NOE experiment, and the stereochemistry of 11a-d was
determined by circular dichroism in a fashion analogous to
the determination of the R-alkyl group configuration in
acyclic R-alkyl-â,γ-unsaturated esters.13 Whereas 11a and
11d had negative Cotton effects around 220 nm, 11b and
11c exhibited positive Cotton effects as expected. Thus, the
alkylated products 11a-d were identified as the (2R,3E)-,
(2S,3Z)-, (2S,3E)-, (2R,3Z)-isomers, respectively. The abso-
lute configuration of 11d was also confirmed by X-ray
analysis.
A plausible reaction mechanism is depicted in Figure 2.
The predominant formation of the (2R,3E)-isomer 11a and
(2S,3Z)-isomer 11b from 10a and of (2S,3E)-isomer 11c and
(2R,3Z)-isomer 11d from 10b suggested that the products
were obtained via anti-SN2′ alkylation as in the case of
In conclusion, we have accomplished the synthesis of
ψ[(E)-CHdCMe]- and ψ[(Z)-CHdCMe]-type dipeptide
isosteres via organocopper-mediated alkylation with solvent-
dependent geometric selectivity. These isosteres may afford
valuable tools for restriction of peptide bonds to trans- and
cis-conformation, respectively. They may be vital for the
evaluation of effects of N-methylamino acids on conforma-
tion of peptides.
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.
Supporting Information Available: Selected experi-
mental procedures, 1H NMR spectra for all new compounds,
CD spectra of 11a-d, and crystal structure of 11d. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Ibuka, T.; Habashita, H.; Funakoshi, S.; Fujii, N.; Baba, K.; Kozawa,
M.; Oguchi, Y.; Uyehara, T.; Yamamoto, Y. Tetrahedron: Asymmetry 1990,
1, 389.
(14) Though we cannot rule out the formation of copper-π-allyl complex
as a reactive intermediate, it is assumed that the alkylation of the mesylates
10a and 10b predominantly proceeded via direct alkylation by organocopper
reagents because the alkylation mainly gave E- and Z-isomers of the anti-
SN2′ products.
OL016834J
1054
Org. Lett., Vol. 4, No. 7, 2002