Stereoselective synthesis of a set of two functionalized (E)-alkene dipeptide isosteres of L-amino acid-L-Glu and L-amino acid-D-Glu

Article abstract of DOI:10.1039/b103833h

The stereoselective synthesis of a set of two functionalized (E)-alkene dipeptide isosteres of L-amino acid-L-Glu and L-amino acid-D-Glu was carried out. The treatment of N-arylsulfonyl-γ,δ-cis- or -trans-γ,δ-epimino (E)-α,β-enoates with HCl-1,4-dioxane afforded regio- and stereo-selective ring-opened products. The ring-opening reaction provided a useful method for the stereoselective synthesis of a set of diastereomeric (L-Xaa, L-Glu)-type and (L-Xaa, D-Glu)-type (E)-alkene dipeptide isosteres (EADI) from a single substrate of γ,δ-epimino (E)-α,β-enoate using organozinc-copper reagents.

Full text of DOI:10.1039/b103833h

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Stereoselective synthesis of a set of two functionalized (E )-alkene
dipeptide isosteres of L-amino acid-L-Glu and L-amino acid-D-Glu
Shinya Oishi,a Hirokazu Tamamura,*a Masaki Yamashita,a Yoshihiko Odagaki,b
Nobuyuki Hamanaka,b Akira Otakaa and Nobutaka Fujii*a
1
a Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501,
Japan
b Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka 618-8585, Japan
Received (in Cambridge, UK) 27th April 2001, Accepted 30th July 2001
First published as an Advance Article on the web 11th September 2001
Treatment of N-arylsulfonyl-γ,δ-cis- or -trans-γ,δ-epimino (E)-α,β-enoates with HCl–1,4-dioxane affords regio- and
stereo-selective ring-opened products, δ-aminated γ-chloro-α,β-enoates. This ring-opening reaction provides a useful
method for the stereoselective synthesis of a set of diastereomeric (-Xaa, -Glu)-type and (-Xaa, -Glu)-type (E)-
alkene dipeptide isosteres (EADIs) from a single substrate of γ,δ-epimino (E)-α,β-enoate using organozinc–copper
reagents.
Introduction
The utility of (E)-alkene dipeptide isosteres (EADIs)1 as
potential mimics of amide bonds in bioactive peptides has been
intensively investigated by us2 and others.3 Among these
EADIs, ,-type and ,-type EADIs are of comparable value
to ,-type and ,-type EADIs in the field of medicinal
chemistry, since ,-type (or ,-type) EADIs have potentiality
as backbone replacements of the (i ϩ 1)–(i ϩ 2) site in type-II
(or -IIЈ) β-turn structures.4 We recently established a completely
stereocontrolled synthetic process for ,-type, ,-type, ,-
type and ,-type EADIs starting from -amino acids or
-amino acids as chiral pools (Scheme 1).5 In this process,
regio- and stereo-selective ring-opening reactions of N-(2,4,6-
trimethylphenylsulfonyl)-γ,δ-cis-γ,δ-epimino (E)-α,β-enoates
with methanesulfonic acid (MSA) were utilized for the stereo-
selective synthesis of a set of two diastereomeric EADIs from
a single substrate of γ,δ-epimino (E)-α,β-enoate. As shown
in Scheme 1, four stereoisomeric γ,δ-epimino-α,β-enoates 1,
which are obtained from an -amino acid, can be convergently
transformed into the single cis-(E)-isomer 2 by exposure to a
Pd(0)-catalyst.6 The aziridine 2 provides an ,-type EADI 4 by
treatment with organocopper reagents. On the other hand,
MSA treatment of 2 gives the γ-mesylester 3, which can be
converted into an ,-type EADI 5 by treatment with organo-
copper reagents. A -amino acid leads to ,-type and ,-type
EADIs in the same manner. One potential limitation to the use
of these procedures for synthesis of peptide mimetics is the
introduction of functional groups into the side chain (R2) at the
α-position. In our initial effort to prepare an (-Ser, -Glu)-type
EADI, we attempted SN2Ј-substitution of a CH2CH2CO2Me
group onto δ-aminated γ-mesyloxy-α,β-enamide 7, which
was previously synthesized by the ring-opening reaction of
N-Mts-γ,δ-cis-γ,δ-epimino (E)-α,β-enamide 6 with MSA, using
organozinc–copper reagent IZn(CN)CuCH2CH2CO2Meؒ2LiCl
(prepared by the reaction of the soluble copper salt CuCNؒ
2LiCl with zinc organometallic reagent IZnCH2CH2CO2Me)
(Scheme 2).7 However, the reaction quantitatively regenerated
aziridine 6 without forming the desired compound 8. Since
the aziridinyl ring was considered to be formed due to the
basicity of the organocopper reagent, BF3ؒEt2O was added to
Scheme 1 R1, R2 = alkyl; Ms = methanesulfonyl; Mts = 2,4,6-trimethyl-
phenylsulfonyl; reagents: i, Pd(PPh3)4; ii, CH3SO3H in CHCl3; iii, R2Cu-
(CN)MgClؒ2LiCl; iv, R2Cu(CN)MgClؒBF3; -amino acids lead to
,-type and ,-type EADIs in the same way.
DOI: 10.1039/b103833h
J. Chem. Soc., Perkin Trans. 1, 2001, 2445–2451
This journal is © The Royal Society of Chemistry 2001
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Table 1 Ring-opening of N-Ts- or N-Mts-γ,δ-epimino (E)-α,β-enoates with HCl–1,4-dioxane and the following addition of CH2CH2CO2R groups
using organozinc–copper reagents
Entry
Substrate
Ring-opening product (yield %)
Organozinc–copper reagent
Addition product (yield %)
1
2
3
4
5
6
7
8
10
10
11
11
12
12
13
13
14 (92)
15 (92)
16 (96)
17 (91)
IZnCu(CN)CH2CH2CO2Meؒ2LiCl
IZnCu(CN)CH2CH2CO2Bnؒ2LiCl
IZnCu(CN)CH2CH2CO2Meؒ2LiCl
IZnCu(CN)CH2CH2CO2Bnؒ2LiCl
IZnCu(CN)CH2CH2CO2Meؒ2LiCl
IZnCu(CN)CH2CH2CO2Bnؒ2LiCl
IZnCu(CN)CH2CH2CO2Meؒ2LiCl
IZnCu(CN)CH2CH2CO2Bnؒ2LiCl
18 (93)
19 (91)
20 (99)
21 (99)
22 (81)
23 (89)
24 (91)
25 (92)
Exposure of N-Ts-γ,δ-cis-γ,δ-epimino (E)-α,β-enoate 10,
derived from -threonine,6 to 4 M HCl–1,4-dioxane (10 equiv.)
at rt for 30 min afforded exclusively δ-aminated γ-chloro-α,β-
enoate 14 in an essentially quantitative yield (Scheme 3 and
Table 1). Since X-ray analysis of 14 showed that it has (4S)-
configuration, this ring-opening reaction was confirmed to
operate via the regio- and stereo-selective SN2 reaction at the
γ-carbon position. We investigated ring-opening of other
aziridines, N-Mts-γ,δ-cis-γ,δ-epimino (E)-α,β-enoates, 11 and
12, derived from -valine and -phenylalanine, respectively,
according to the reported methods.6 The regiospecific ring-
opening reactions were successfully carried out to yield γ-
chloro-α,β-enoates 15 and 16. The trans-(E)-isomer 13 afforded
the γ,δ-anti-isomer 17 by a similar SN2 ring-opening reaction.
In all cases, ring-opened products generated by nucleophilic
attack at the α-, β- or δ-carbon position could not be detected.
Regiochemical assignments for the γ-chloro-α,β-enoates 14–17
Scheme 2 Reagents: i, CH3SO3H in CHCl3; ii, IZn(CN)CuCH2CH2-
CO2Meؒ2LiCl; iii, IZn(CN)CuCH2CH2CO2MeؒBF3ؒ2LiCl.
1
were readily made by H-NMR spectroscopy (1H–1H COSY).
The γ,δ-syn stereochemistry of 14–16 and the γ,δ-anti stereo-
chemistry of 17 are based on X-ray analysis of 14.
the above organocopper reagent. Unexpectedly, this reaction
afforded δ-aminated γ-chloro-α,β-enamide 9 (the absolute
configuration of the γ-carbon center of 9 was not identified).
Nakamura et al. reported a stereoselective SN2Ј reaction medi-
ated by organometallics of zinc and copper when using allylic
chlorides as substrates.7 Thus, we attempted to utilize γ-chloro-
α,β-enamide 9 as a substrate of the SN2Ј-type organometallic
reaction to yield an (-Ser, -Glu)-type EADI, and initially
to find effective methods for affording diastereomerically pure
δ-aminated γ-chloro-α,β-enoates (enamides). In this paper, we
report the regio- and stereo-selective ring-opening reactions of
N-arylsulfonyl-γ,δ-cis- or -trans-γ,δ-epimino (E)-α,β-enoates
(enamides) with HCl–1,4-dioxane to yield δ-aminated γ-chloro-
α,β-enoates (enamides). Furthermore, we also report the stereo-
selective synthesis of a set of two functionalized (-Xaa,
-Glu)-type and (-Xaa, -Glu)-type diastereomeric EADIs
Synthesis of (L-Xaa, D-Glu)-type and (L-Xaa, L-Glu)-type
EADIs from ꢁ-aminated ꢀ-chloro-ꢂ,ꢃ-enoates
We examined the feasibility of the stereoselective synthesis of
(-Xaa, -Glu)-type and (-Xaa, -Glu)-type EADIs by treat-
ment of the ring-opened products with organozinc–copper
reagents. Treatment of the above γ-chloro-α,β-enoate 14 with
IZnCu(CN)CH2CH2CO2Meؒ2LiCl (4 equiv.) in THF at 0 ЊC
for 30 min yielded the protected (-Ala, -Glu)-type (4S,7S)-
EADI, Ts--Ala-ψ[(E)-CH᎐CH]--Glu(OMe)-OMe, 18 in
᎐
93% yield (diastereoselection > 99 : 1 from NMR analysis)
as shown in Scheme 3 and Table 1. This reaction occurred by a
sole anti-SN2Ј mechanism. In contrast, an anti-SN2Ј reaction
of the cis-(E)-enoate 10 under the same reaction conditions
afforded the protected (-Ala, -Glu)-type (4R,7S)-EADI,
from
a single substrate of γ,δ-epimino (E)-α,β-enoate
Ts--Ala-ψ[(E)-CH᎐CH]--Glu(OMe)-OMe, 24 in 99% yield
᎐
(enamide) using an organozinc–copper reagent IZn(CN)Cu-
CH2CH2CO2R.
as shown in Scheme 3 and Table 2. In a similar way, treat-
ment of 14 with IZnCu(CN)CH2CH2CO2Bnؒ2LiCl yielded
the (4S,7S)-EADI, Ts--Ala-ψ[(E)-CH᎐CH]--Glu(OBn)-
᎐
OMe, 19 whereas treatment of 10 with IZnCu(CN)CH2-
CH2CO2Bnؒ2LiCl afforded the (4R,7S)-EADI, Ts--Ala-
Results and discussion
ψ[(E)-CH᎐CH]--Glu(OBn)-OMe, 25. The most important
᎐
Ring-opening reactions of N-(4-methylphenylsulfonyl) (Ts)- or
N-(2,4,6-trimethylphenylsulfonyl) (Mts)-ꢀ,ꢁ-epimino (E )-ꢂ,ꢃ-
enoates with HCl–1,4-dioxane
point of the HCl-mediated ring-opening reactions is the inver-
sion of configuration at the C-γ carbon via an SN2 mechanism.
Thus, cis-(E)-enoates lead to syn-(E)-chlorides, which are
converted into (-Xaa, -Glu)-type EADIs upon treatment
of organozinc–copper reagents. On the other hand, cis-(E)-
enoates themselves provide (-Xaa, -Glu)-type EADIs with
organozinc–copper reagents. We investigated the applicability
of these synthetic procedures to other aziridine cis-(E)-enoates,
11 and 12. Treatment of the γ-chloride 15 with IZnCu-
(CN)CH2CH2CO2Meؒ2LiCl and IZnCu(CN)CH2CH2CO2Bnؒ
To date, many precedents for aziridine ring-opening, namely,
that several nucleophilic reagents,8 including acids such as
AcOH,9 TFA10 and toluene-p-sulfonic acid in aqueous
acetone,11 attack simple aziridines12 at either of the two carbon
atoms, to yield the corresponding ring-opened products, have
been described. We have also reported TFA- or MSA-mediated
ring-opening reactions of N-Mts-protected (and activated)
aziridines bearing α,β-unsaturated esters as described in the
Introduction.5 Thus, we initially examined ring-opening
reactions of N-Ts- or N-Mts-γ,δ-epimino (E)-α,β-enoates with
HCl–1,4-dioxane to afford δ-aminated γ-chloro-α,β-enoates.
2LiCl yielded the (4S,7S)-EADIs, Mts--Val-ψ[(E)-CH᎐CH]-
᎐
-Glu(OMe)-OMe, 20 and Mts--Val-ψ[(E)-CH᎐CH]--Glu-
᎐
(OBn)-OMe, 21, respectively, whereas treatment of the cis-
(E)-enoate 11 with IZnCu(CN)CH2CH2CO2Meؒ2LiCl and
2446
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Table 2 Direct addition of CH2CH2CO2R groups into N-Ts- or N-Mts-γ,δ-epimino (E)-α,β-enoates using organozinc–copper reagents
Entry
Substrate
Organozinc–copper reagent
Addition product (yield %)
1
2
3
4
5
6
7
8
10
10
11
11
12
12
13
13
IZnCu(CN)CH2CH2CO2Meؒ2LiCl
IZnCu(CN)CH2CH2CO2Bnؒ2LiCl
IZnCu(CN)CH2CH2CO2Meؒ2LiCl
IZnCu(CN)CH2CH2CO2Bnؒ2LiCl
IZnCu(CN)CH2CH2CO2Meؒ2LiCl
IZnCu(CN)CH2CH2CO2Bnؒ2LiCl
IZnCu(CN)CH2CH2CO2Meؒ2LiCl
IZnCu(CN)CH2CH2CO2Bnؒ2LiCl
24 (99)
25 (95)
26 (52)
27 (45)
28 (97)
29 (99)
18 (99)
19 (92)
Scheme 3 Reagents: i, 4 M HCl–1,4-dioxane; ii, IZn(CN)CuCH2CH2CO2Meؒ2LiCl; iii, IZn(CN)CuCH2CH2CO2Bnؒ2LiCl.
IZnCu(CN)CH2CH2CO2Bnؒ2LiCl yielded the (4R,7S)-EADIs,
Mts--Val-ψ[(E)-CH᎐CH]--Glu(OMe)-OMe, 26 and Mts--
chloro-α,β-enamide 30, which was converted into the protected
(-Ser, -Glu)-type (4S,7S)-EADIs, Mts--Ser(O-Bn)-ψ[(E)-
᎐
Val-ψ[(E)-CH᎐CH]--Glu(OBn)-OMe, 27, respectively. In the
CH᎐CH]--Glu(OMe)-NHMe, 8 and Mts--Ser(O-Bn)-ψ[(E)-
᎐
᎐
same manner, the γ-chloride 16 provided the corresponding
(4S,7S)-EADIs, 22 and 23, whereas the cis-(E)-enoate 12
afforded the corresponding (4R,7S)-EADIs, 28 and 29, respec-
tively. In a comparative study, the anti-(E)-chloride 17, derived
from the trans-(E)-enoate 13, was converted into the protected
CH᎐CH]--Glu(OBn)-NHMe, 31 with IZnCu(CN)CH CH -
᎐
2 2
CO2Meؒ2LiCl and IZnCu(CN)CH2CH2CO2Bnؒ2LiCl, respec-
tively, as shown in Scheme 4. In contrast, treatment of the
cis-(E)-enamide
6 with IZnCu(CN)CH2CH2CO2Bnؒ2LiCl
afforded the protected (-Ser, -Glu)-type (4R,7S)-EADI,
(-Ala, -Glu)-type (4R,7S)-EADIs, Ts--Ala-ψ[(E)-CH᎐CH]-
Mts--Ser(O-Bn)-ψ[(E)-CH᎐CH]--Glu(OBn)-NHMe, 32.
᎐
᎐
-Glu(OMe)-OMe, 24 and Ts--Ala-ψ[(E)-CH᎐CH]--Glu-
In conclusion, we have found regio- and stereo-specific
ring-opening reactions of N-Ts- or N-Mts-protected aziridines
bearing α,β-unsaturated esters (amides) [cis-(E)- and trans-
(E)-α,β-enoates (enamides)] by HCl–1,4-dioxane. The HCl-
mediated ring-opened products (γ,δ-syn-δ-aminated γ-chloro-
α,β-enoates or enamides) yield (-Xaa, -Glu)-type EADIs by
the addition with organozinc–copper reagents. On the other
hand, aziridines [cis-(E)-α,β-enoates (enamides)] afford (-Xaa,
-Glu)-type EADIs with organozinc–copper reagents. The
present ring-opening reactions provide useful methodology
for stereoselective synthesis of both (-Xaa, -Glu)-type and
(-Xaa, -Glu)-type EADIs from a single substrate of
either a γ,δ-cis- or -trans-γ,δ-epimino (E)-α,β-unsaturated ester
(amide). Four stereoisomers of γ,δ-epimino-α,β-unsaturated
esters (amides), which can be prepared from the corresponding
chiral amino aldehydes, are converted into cis-(E)-isomers by
Pd(0)-catalyzed equilibration.6 Taken together, a completely
stereocontrolled synthetic process for a set of (-Xaa, -Glu)-
type and (-Xaa, -Glu)-type EADIs starting from -amino
acids has been established.
᎐
(OBn)-OMe, 25 with IZnCu(CN)CH2CH2CO2Meؒ2LiCl and
IZnCu(CN)CH2CH2CO2Bnؒ2LiCl, respectively. On the other
hand, treatment of the trans-(E)-enoate 13 with IZnCu-
(CN)CH2CH2CO2Meؒ2LiCl and IZnCu(CN)CH2CH2CO2Bnؒ
2LiCl afforded the protected (-Ala, -Glu)-type (4S,7S)-
EADIs, Ts--Ala-ψ[(E)-CH᎐CH]--Glu(OMe)-OMe, 18 and
᎐
Ts--Ala-ψ[(E)-CH᎐CH]--Glu(OBn)-OMe, 19, respectively.
᎐
Thus, two types of EADIs were stereoselectively synthesized
from either the cis- or trans-(E)-enoate. These synthetic pro-
cedures are applicable to aziridinyl cis- or trans-(E)-enoates.
The (E)-geometry of the double bond in the synthesized
EADIs was assigned based on the coupling constant of the
1
two olefinic protons on H-NMR analysis. The absolute con-
figuration of the α-alkylated carbon center in the EADI 22 was
confirmed by X-ray analysis as 4S.
Next, we attempted to synthesize highly functionalized
(-Ser, -Glu)-type and (-Ser, -Glu)-type EADIs, our initial
synthetic targets. The ring-opening reaction of the cis-(E)-
enamide 6 with HCl–1,4-dioxane yielded the corresponding γ-
J. Chem. Soc., Perkin Trans. 1, 2001, 2445–2451
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HCl–1,4-dioxane. Representative: methyl (2E,4S,5S)-4-chloro-
5-(4-methylphenylsulfonylamino)hex-2-enoate 14
The cis-(E)-enoate 10 (295 mg, 1.00 mmol) was dissolved in
4 M HCl solution in 1,4-dioxane (10.0 mmol, 2.5 cm3) at rt
and the mixture was stirred for 30 min at this temperature.
Concentration under reduced pressure gave an oily residue,
which was purified by flash chromatography over silica gel with
n-hexane–EtOAc (4 : 1) to yield 306 mg (0.922 mmol, 92%) of
the title compound 14 as colorless crystals, mp 168–169 ЊC
[from n-hexane–EtOAc (1 : 1)] (Found: C, 50.74; H, 5.54; N,
4.17. C14H18ClNO4S requires C, 50.68; H, 5.47; N, 4.22%);
[α]2D1 Ϫ78.75 (c 0.965); δH(300 MHz) 1.16 (3 H, d, J 6.7, CMe),
2.43 (3 H, s, CMe), 3.69 (1 H, m, 5-H), 3.74 (3 H, s OMe), 4.51
(1 H, ddd, J 7.4, 3.5 and 1.2, 4-H), 4.85 (1 H, d, J 8.5, NH), 6.02
(1 H, dd, J 15.4 and 1.2, CH᎐), 6.80 (1 H, dd, J 15.4 and 7.4,
᎐
CH᎐), 7.30 (2 H, m, ArH), 7.74 (2 H, m, ArH).
᎐
Crystal structure determination of compound 14†
Crystal data. C14H18ClNO4S, M = 331.81, orthorhombic,
a = 9.685(4), b = 21.585(5), c = 7.745(4) Å, V = 1619(1) Å3, T =
296 K, space group P212121 (no. 19), Z = 4, µ(Cu-Kα) = 34.27
mmϪ1, 1580 reflections measured, 1484 [I > 3σ(I )] were used in
all calculations. The final wR was 0.066.
Methyl (2E,4S,5S)-4-chloro-6-methyl-5-(2,4,6-trimethylphenyl-
sulfonylamino)hept-2-enoate 15
By use of a procedure identical with that described for the
preparation of 14 from 10, the cis-(E)-enoate 11 (351 mg,
1.00 mmol) was converted into the title compound 15 (360 mg,
0.928 mmol, 92%) as colorless crystals, mp 111–113 ЊC [from
n-hexane–EtOAc (2 : 1)] (Found: C, 55.71; H, 6.95; N, 3.56.
C18H26ClNO4S requires C, 55.73; H, 6.76; N, 3.61%); [α]2D7 Ϫ13.3
(c 0.822); δH(300 MHz) 0.97 (6 H, m, 2 × CMe), 1.88–2.05 (1 H,
m, 6-H), 2.28 (3 H, s, CMe), 2.61 (6 H, s, 2 × CMe), 3.45 (1 H,
ddd, J 9.5, 7.8 and 2.4, 5-H), 3.64 (3 H, s, OMe), 4.66 (1 H, ddd,
J 6.4, 2.4 and 1.5, 4-H), 4.73 (1 H, d, J 9.5, NH), 5.87 (1 H, dd,
Scheme 4 Reagents: i, 4 M HCl–1,4-dioxane; ii, IZn(CN)CuCH2-
CH2CO2Meؒ2LiCl; iii, IZn(CN)CuCH2CH2CO2Bnؒ2LiCl.
Experimental
General
1H-NMR spectra were recorded using a JEOL EX-270 or a
Bruker AC 300 spectrometer at 270 or 300 MHz 1H frequency
for samples in CDCl3. Chemical shifts (δ) are reported in parts
per million downfield from internal tetramethylsilane. J-Values
are in Hz. Nominal (LRMS) and exact mass (HRMS) spectra
were recorded on a JEOL JMS-01SG-2 or JMS-HX/HX 110A
mass spectrometer. Optical rotations were measured in CHCl3
with a JASCO DIP-360 digital polarimeter (Tokyo, Japan)
or a Horiba high-sensitive polarimeter SEPA-200 (Kyoto,
Japan). [α]D-Values are given in units of 10Ϫ1 deg cm2 gϪ1.
X-Ray analyses were made on a Rigaku AFC5R diffractometer
with graphite-monochromated Cu-Kα radiation and a rotating
anode generator. Mps were measured by a hot-stage melting-
point apparatus and are uncorrected. For flash chroma-
tography, silica gel 60 H (silica gel for TLC, Merck) and
Wakogel C-200 (silica gel for column chromatography) were
employed.
J 15.2 and 1.5, CH᎐), 6.56 (1 H, dd, J 15.2 and 6.4, CH᎐), 6.90
᎐
᎐
(2 H, s, ArH).
Methyl (2E,4S,5S)-4-chloro-6-phenyl-5-(2,4,6-trimethylphenyl-
sulfonylamino)hex-2-enoate 16
By use of a procedure identical with that described for the
preparation of 14 from 10, the cis-(E)-enoate 12 (399 mg,
1.00 mmol) was converted into the title compound 16 (422 mg,
0.967 mmol, 96%) as colorless crystals, mp 108–109 ЊC [from
n-hexane–EtOAc (2 : 1)] (Found: C, 60.59; H, 6.07; N, 3.20.
C22H26ClNO4S requires C, 60.61; H, 6.01; N, 3.21%); [α]2D8 Ϫ57.8
(c 0.570); δH(300 MHz) 2.27 (3 H, s, CMe), 2.53 (6 H, s,
2 × CMe), 2.79 (1 H, dd, J 13.7 and 6.8, CHH), 3.04 (1 H, dd,
J 13.7 and 8.2, CHH), 3.65 (1 H, m, 5-H), 3.70 (3 H, s, OMe),
4.59 (1 H, J 6.4, 2.5 and 1.5, 4-H), 4.86 (1 H, d, J 8.6, NH), 5.95
(1 H, dd, J 15.3 and 1.5, CH᎐), 6.67 (1 H, dd, J 15.3 and 6.4,
᎐
Methyl (2E,4R,5S)-6-phenyl-4,5-[N-(2,4,6-trimethylphenyl-
sulfonyl)epimino]hex-2-enoate 12
CH᎐), 6.85 (2 H, m, ArH), 7.01–7.07 (2 H, m, ArH), 7.17–7.23
᎐
(3 H, m, ArH).
According to our previous procedure,6 the cis-(E)-enoate 12
(2.23 g, 5.58 mmol, 93%) was prepared from the known vinyl-
aziridine6 (2.04 g, 6.00 mmol) as colorless crystals, mp 51–53 ЊC
[from n-hexane–Et2O (3 : 1)] (Found: C, 66.26; H, 6.46; N, 3.51.
Calc. for C22H25NO4S: C, 66.14; H, 6.31; N, 3.51%); [α]D26
Ϫ63.75 (c 1.19); δH(300 MHz) 2.30 (3 H, s, CMe), 2.56 (6 H, s,
2 × CMe), 2.64 (1 H, dd, J 14.5 and 8.0, CHH), 2.76 (1 H, dd,
J 14.5 and 5.3, CHH), 3.18 (1 H, ddd, J 7.9, 7.2 and 5.3, 5-H),
3.55 (1 H, m, 4-H), 3.76 (3 H, s, OMe), 6.19 (1 H, dd, J 15.5 and
Methyl (2E,4R,5S)-4-chloro-5-(4-methylphenylsulfonylamino)-
hex-2-enoate 17
By use of a procedure identical with that described for the
preparation of 14 from 10, the cis-(E)-enoate 13 (295 mg,
1.00 mmol) was converted into the title compound 17 (303 mg,
0.913 mmol, 91%) as a colorless crystalline mass, mp 69–71 ЊC
(from n-hexane) (Found: C, 50.63; H, 5.60; N, 3.95. C14H18-
ClNO4S requires C, 50.68; H, 5.47; N, 4.22%); [α]2D5 Ϫ7.92
1.0, CH᎐), 6.84 (1 H, dd, J 15.5 and 6.6, CH᎐), 6.85 (2 H, s,
᎐
᎐
ArH), 6.94 (2 H, m, ArH), 7.04–7.15 (3 H, m, ArH).
† CCDC reference number(s) 166365 and 166366. See http://
www.rsc.org/suppdata/p1/b1/b103833h/ for crystallographic files in .cif
or other electronic format.
General procedure for the ring-opening reaction of N-Ts- or N-
Mts-ꢀ,ꢁ-epimino (E )-ꢂ,ꢃ-enoates (enamides) by treatment with
2448
J. Chem. Soc., Perkin Trans. 1, 2001, 2445–2451

View Article Online
(c 1.00); δH(300 MHz) 1.07 (3 H, d, J 6.6, CMe), 2.43 (3 H,
s, CMe), 3.69 (1 H, m, 5-H), 3.74 (3 H, s, OMe), 4.59 (1 H, ddd,
J 6.6, 3.3 and 1.4, 4-H), 4.94 (1 H, d, J 9.1, NH), 6.06 (1 H, dd,
J 15.3 and 1.4, CH᎐), 6.77 (1 H, dd, J 15.3 and 6.7, CH᎐), 7.32
6.90 (2 H, s, ArH); m/z (FAB-LRMS) 440 (MHϩ), 396 (base
peak), 364, 254, 241, 209, 183, 181, 177, 167, 149, 119.
Mts-L-Val-ψ[(E )-CH᎐CH]-D-Glu(OBn)-OMe 21
᎐
᎐
᎐
(2 H, m, ArH), 7.76 (2 H, m, ArH).
By use of a procedure identical with that described for the
preparation of 18 from 14, treatment of the ester 15 (100 mg,
0.257 mmol) with IZn(CN)CuCH2CH2CO2Bnؒ2LiCl in THF
gave the title compound 21 (132 mg, 0.255 mmol, 99%) as a
colorless oil [Found (FAB): (M ϩ H)ϩ, 516.2408. C28H38NO6S
requires M ϩ H, 516.2420]; [α]2D9 Ϫ13.3 (c 1.04); δH(300 MHz)
0.80 (3 H, d, J 6.7, CMe), 0.83 (3 H, d, J 6.8, CMe), 1.53–1.79
(2 H, m, CHH and CH), 1.84–1.97 (1 H, m, CHH), 2.20 (2 H,
m, CH2), 2.25 (3 H, s, CMe), 2.58 (6 H, s, 2 × CMe), 2.82 (1 H,
m, 4-H), 3.53 (1 H, m, 7-H), 3.64 (3 H, s, OMe), 4.56 (1 H, d,
J 7.7, NH), 5.09 (2 H, s, OCH ), 5.14–5.33 (2 H, m, 2 × CH᎐),
General procedure for the preparation of (L-Xaa, D-Glu)-type
EADIs from ꢀ-chloro-ꢂ,ꢃ-enoates. Representative: Ts-L-Ala-
ψ[(E )-CH᎐CH]-D-Glu(OMe)-OMe 18
᎐
To a supension of zinc dust (157 mg, 2.41 mmol) in dry THF
(0.20 cm3), which was subjected to treatment for activation, was
added methyl 3-iodopropionate (257 mg, 1.20 mmol) [obtained
by treatment of methyl 3-bromopropionate in acetone with
sodium iodide followed by distillation] in dry THF (1.00 cm3) at
rt, and the mixture was stirred for 1 h at this temperature. The
organozinc reagent was added to a stirred suspension of CuCN
(107 mg, 1.20 mmol) and LiCl (102 mg, 2.41 mmol) in dry THF
(1.20 cm3) under argon at Ϫ78 ЊC, and the mixture was allowed
to warm to 0 ЊC and was stirred at this temperature for 10 min.
To the solution of organozinc–copper reagent was added
dropwise a solution of the ester 14 (100 mg, 0.301 mmol) in
dry THF (1.00 cm3) at Ϫ78 ЊC with stirring, and the mixture
was stirred at 0 ЊC for 30 min followed by quenching with 1 : 1
saturated aq. NH4Cl–28% NH4OH (2 cm3). The mixture was
extracted with Et2O, and the extract was washed with water,
and dried over MgSO4. Concentration under reduced pressure
gave a colorless oil, which was purified by flash chromatography
over silica gel with n-hexane–EtOAc (3 : 1) to yield the title
compound 18 (108 mg, 0.282 mmol, 93%) as a colorless oil
[Found (FAB): (M ϩ H)ϩ, 384.1470. C18H26NO6S requires
M ϩ H, 384.1481]; [α]2D7 Ϫ4.06 (c 1.47); δH(300 MHz) 1.16 (3 H,
d, J 6.7, CMe), 1.70 (1 H, dq, J 13.8 and 7.6, CHH), 1.89–2.03
(1 H, m, CHH), 2.21 (2 H, t, J 7.6, CH2), 2.41 (3 H, s, CMe),
2.91 (1 H, m, 4-H), 3.65 (3 H, s, OMe), 3.66 (3 H, s, OMe), 3.84–
3.96 (1 H, m, 7-H), 4.84 (1 H, d, J 7.6, NH), 5.34–5.50 (2 H, m,
᎐
2
6.87 (2 H, s, ArH), 7.29–7.40 (5 H, m, ArH); m/z (FAB-LRMS)
516 (MHϩ, base peak), 472, 440, 332, 317, 285, 263, 254, 209.
Mts-L-Phe-ψ[(E )-CH᎐CH]-D-Glu(OMe)-OMe 22
᎐
By use of a procedure identical with that described for the
preparation of 18 from 14, treatment of the ester 16 (100 mg,
0.229 mmol) with IZn(CN)CuCH2CH2CO2Meؒ2LiCl in THF
gave the title compound 22 (97 mg, 0.200 mmol, 81%) as color-
less crystals, mp 98–100 ЊC [from n-hexane–EtOAc (5 : 1)]
(Found: C, 63.88; H, 6.87; N, 2.65. C26H33NO6S requires C,
64.04; H, 6.82; N, 2.87%); [α]2D3 ϩ12.1 (c 1.64); δH(300 MHz)
1.54–1.67 (1 H, m, CHH), 1.81–1.94 (1 H, m, CHH), 2.09 (2 H,
m, CH2), 2.27 (3 H, s, CMe), 2.48 (6 H, s, 2 × CMe), 2.70–2.91
(3 H, m, PhCH2 and 4-H), 3.65 (6 H, m, 2 × OMe), 3.92 (1 H,
m, 7-H), 4.51 (1 H, d, J 6.4, NH), 5.34 (2 H, m, 2 × CH᎐),
᎐
6.87 (2 H, s, ArH), 7.00–7.05 (2 H, m, ArH), 7.15–7.25 (3 H, m,
ArH).
Crystal structure determination of compound 22†
2 × CH᎐), 7.28 (2 H, m, ArH), 7.73 (2 H, m, ArH); m/z (FAB-
᎐
Crystal data. C26H33NO6S, M = 487.61, orthorhombic, a =
11.780(8), b = 35.92(1), c = 6.24(1) Å, V = 2639(4) Å3, T = 296
K, space group P212121 (no. 19), Z = 4, µ(Cu-Kα) = 14.14
mmϪ1, 2628 reflections measured, 869 [I > 3σ(I )] were used in
all calculations. The final wR was 0.101.
LRMS) 384 (MHϩ, base peak), 213, 198, 181, 155, 149, 121, 91.
Ts-L-Ala-ψ[(E )-CH᎐CH]-D-Glu(OBn)-OMe 19
᎐
By use of a procedure identical with that described for the
preparation of 18 from 14, treatment of the ester 14 (100 mg,
0.301 mmol) with IZn(CN)CuCH2CH2CO2Bnؒ2LiCl [benzyl
3-iodopropionate was obtained by successive treatment of
3-bromopropionic acid with benzyl alcohol–benzene–cat.
TsOH and sodium iodide–acetone] in THF gave the title com-
pound 19 (127 mg, 0.276 mmol, 91%) as a colorless oil [Found
(FAB): (M ϩ H)ϩ, 460.1785. C24H30NO6S requires M ϩ H,
460.1794]; [α]2D6 Ϫ3.62 (c 1.38); δH(300 MHz) 1.14 (3 H, d, J 6.7,
CMe), 1.65–1.79 (1 H, m, CHH), 1.91–2.04 (1 H, m, CHH),
2.25 (2 H, m, CH2), 2.39 (3 H, s, CMe), 2.91 (1 H, m, 4-H), 3.65
(3 H, s, OMe), 3.88 (1 H, m, 7-H), 4.59 (1 H, d, J 7.6, NH), 5.10
(2 H, s, OCH ), 5.33 (1 H, dd, J 15.5 and 5.2, CH᎐), 5.43 (1 H,
Mts-L-Phe-ψ[(E )-CH᎐CH]-D-Glu(OBn)-OMe 23
᎐
By use of a procedure identical with that described for the
preparation of 18 from 14, treatment of the ester 16 (100 mg,
0.229 mmol) with IZn(CN)CuCH2CH2CO2Bnؒ2LiCl in THF
gave the title compound 23 (115 mg, 0.204 mmol, 89%) as a
colorless oil [Found (FAB): (M ϩ H)ϩ, 564.2415. C32H38NO6S
requires M ϩ H, 564.2420]; [α]2D9 ϩ12.2 (c 1.22); δH(300 MHz)
1.54–1.69 (1 H, m, CHH), 1.81–1.95 (1 H, m, CHH), 2.12 (2 H,
m, CH2), 2.25 (3 H, s, CMe), 2.47 (6 H, s, 2 × CMe), 2.68–2.89
(3 H, m, PhCH2 and 4-H), 3.63 (3 H, s, OMe), 3.90 (1 H, m,
7-H), 4.54 (1 H, d, J 6.4, NH), 5.09 (2 H, s, OCH2), 5.30 (2 H,
᎐
2
m, CH᎐), 7.23–7.29 (2 H, m, ArH), 7.31–7.38 (5 H, m, ArH),
m, 2 × CH᎐), 6.84 (2 H, s, ArH), 6.99 (2 H, m, ArH), 7.13–7.23
᎐
᎐
7.69–7.75 (2 H, m, ArH); m/z (FAB-LRMS) 460 (MHϩ, base
(3 H, m, ArH), 7.31–7.39 (5 H, m, ArH); m/z (FAB-LRMS)
586 (MNaϩ), 564 (MHϩ, base peak), 472, 440, 392, 365, 333,
315, 302, 289, 257, 225, 183.
peak), 391, 352, 304, 289, 257, 239, 198, 181, 167, 155, 149.
Mts-L-Val-ψ[(E )-CH᎐CH]-D-Glu(OMe)-OMe 20
᎐
General procedure for the preparation of (L-Xaa, L-Glu)-type
EADIs from N-Ts- or N-Mts-ꢀ,ꢁ-epimino (E )-ꢂ,ꢃ-enoates.
By use of a procedure identical with that described for the
preparation of 18 from 14, treatment of the ester 15 (100 mg,
0.257 mmol) with IZn(CN)CuCH2CH2CO2Meؒ2LiCl in THF
gave the title compound 20 (113 mg, 0.257 mmol, 99%) as a
colorless oil [Found (FAB): (M ϩ H)ϩ, 440.2100. C22H34NO6S
requires M ϩ H, 440.2107]; [α]2D9 ϩ20.4 (c 1.07); δH(300 MHz)
0.82 (3 H, d, J 6.7, CMe), 0.85 (3 H, d, J 6.8, CMe), 1.53–1.66
(1 H, m, CHH), 1.69–1.81 (1 H, m, CH), 1.82–1.96 (1 H, m,
CHH), 2.16 (2 H, m, CH2), 2.28 (3 H, s, CMe), 2.60 (6 H, s,
2 × CMe), 2.83 (1 H, m, 4-H), 3.55 (1 H, m, 7-H), 3.65 (6 H, s,
Representative: Ts-L-Ala-ψ[(E )-CH᎐CH]-L-Glu(OMe)-OMe 24
᎐
prepared from 10
To a suspension of zinc dust (177 mg, 2.70 mmol) in dry THF
(0.60 cm3), which was subjected to treatment for activation, was
added methyl 3-iodopropionate (288 mg, 1.35 mmol) in dry
THF (0.75 cm3) at room temperature, and the mixture was
stirred for 1 h at this temperature. The organozinc reagent was
added to a stirred suspension of CuCN (121 mg, 1.35 mmol)
and LiCl (114 mg, 2.70 mmol) in dry THF (1.35 cm3) under
2 × OMe), 4.63 (1 H, d, J 7.7, NH), 5.20–5.35 (2 H, m, 2 × CH᎐),
᎐
J. Chem. Soc., Perkin Trans. 1, 2001, 2445–2451
2449

View Article Online
argon at Ϫ78 ЊC, and the mixture was allowed to warm to 0 ЊC
and was stirred at this temperature for 15 min. To the solution
of organozinc–copper reagent was added dropwise a solution
of the cis-(E)-enoate 10 (100 mg, 0.338 mmol) in dry THF
(1.00 cm3) at Ϫ78 ЊC with stirring, and the mixture was stirred
at 0 ЊC for 30 min followed by quenching with 1 : 1 saturated
aq. NH4Cl–28% NH4OH (2 cm3). The mixture was extracted
with Et2O, and the extract was washed with water, and dried
over MgSO4. Concentration under reduced pressure gave a
colorless oil, which was purified by flash chromatography over
silica gel with n-hexane–EtOAc (3 : 1) to yield the title com-
pound 24 (129 mg, 0.336 mmol, 99%) as a colorless oil [Found
(FAB): (M ϩ H)ϩ, 384.1488. C18H26NO6S requires M ϩ H,
384.1481]; [α]2D4 Ϫ74.3 (c 1.38); δH(300 MHz) 1.16 (3 H, d, J 6.7,
CMe), 1.71 (1 H, dq, J 13.9 and 7.5, CHH), 1.88–2.02 (1 H,
m, CHH), 2.19–2.27 (2 H, m, CH2), 2.42 (3 H, s, CMe), 2.92
(1 H, m, 4-H), 3.64 (3 H, s, OMe), 3.66 (3 H, s, OMe), 3.81–3.93
(1 H, m, 7-H), 4.78 (1 H, d, J 7.4, NH), 5.35–5.49 (2 H, m,
Mts-L-Phe-ψ[(E )-CH᎐CH]-L-Glu(OMe)-OMe 28
᎐
By use of a procedure identical with that described for the
preparation of 24 from 10, treatment of the cis-(E)-enoate 12
(100 mg, 0.250 mmol) with IZn(CN)CuCH2CH2CO2Meؒ2LiCl
in THF gave the title compound 28 (119 mg, 0.244 mmol, 97%)
as a colorless oil [Found (FAB): (M ϩ H)ϩ, 488.2123. C26H34-
NO6S requires M ϩ H, 488.2107]; [α]2D7 Ϫ56.4 (c 0.957); δH(300
MHz) 1.59–1.73 (1 H, m, CHH), 1.83–1.97 (1 H, m, CHH),
2.19 (2 H, m, CH2), 2.27 (3 H, s, CMe), 2.48 (6 H, s, 2 × CMe),
2.78 (2 H, d, J 6.7, PhCH2), 2.88 (1 H, m, 4-H), 3.61 (3 H,
s, OMe), 3.66 (3 H, s, OMe), 3.89 (1 H, m, 7-H), 4.57 (1 H, d,
J 6.6, NH), 5.30 (1 H, dd, J 15.5 and 7.8, CH᎐), 5.41 (1 H, dd,
᎐
J 15.5 and 6.8, CH᎐), 6.87 (2 H, s, ArH), 6.98–7.04 (2 H, m,
᎐
ArH), 7.15–7.27 (3 H, m, ArH); m/z (FAB-LRMS) 488 (MHϩ,
base peak), 396, 364, 302, 289, 257, 225.
Mts-L-Phe-ψ[(E )-CH᎐CH]-L-Glu(OBn)-OMe 29
᎐
2 × CH᎐), 7.29 (2 H, m, ArH), 7.74 (2 H, m, ArH); m/z (FAB-
By use of a procedure identical with that described for the
preparation of 24 from 10, treatment of the cis-(E)-enoate 12
(100 mg, 0.250 mmol) with IZn(CN)CuCH2CH2CO2Bnؒ2LiCl
in THF gave the title compound 29 (141 mg, 0.250 mmol,
99%) as a colorless oil [Found (FAB): (M ϩ H)ϩ, 564.2432.
C32H38NO6S requires M ϩ H, 564.2420]; [α]2D8 Ϫ40.8 (c 1.29);
δH(300 MHz) 1.60–1.74 (1 H, m, CHH), 1.85–1.98 (1 H, m,
CHH), 2.20–2.27 (5 H, m, CH2 and CMe), 2.46 (6 H, s,
2 × CMe), 2.77 (2 H, d, J 6.7, PhCH2), 2.88 (1 H, m, 4-H), 3.60
(3 H, s, OMe), 3.88 (1 H, m, 7-H), 4.50 (1 H, d, J 6.7, NH), 5.11
᎐
LRMS) 384 (MHϩ, base), 228, 213, 198, 181.
Ts-L-Ala-ψ[(E )-CH᎐CH]-L-Glu(OBn)-OMe 25 prepared from
᎐
10
By use of a procedure identical with that described for the
preparation of 24 from 10, treatment of the cis-(E)-enoate 10
(100 mg, 0.338 mmol) with IZn(CN)CuCH2CH2CO2Bnؒ2LiCl
in THF gave the title compound 25 (148 mg, 0.322 mmol,
95%) as a colorless oil [Found (FAB): (M ϩ H)ϩ, 460.1804.
C24H30NO6S requires M ϩ H, 460.1794]; [α]2D8 Ϫ52.0 (c 1.17);
δH(300 MHz) 1.14 (3 H, d, J 6.7, CMe), 1.66–1.79 (1 H, m,
CHH), 1.90–2.23 (1 H, m, CHH), 2.26 (2 H, m, CH2), 2.38 (3 H,
s, CMe), 2.91 (1 H, m, 4-H), 3.63 (3 H, s, OMe), 3.85 (1 H, m,
7-H), 4.69 (1 H, d, J 7.4, NH), 5.10 (2 H, m, OCH2), 5.31–5.47
(2 H, m, OCH ), 5.25–5.41 (2 H, m, 2 × CH᎐), 6.84 (2 H, s,
᎐
2
ArH), 6.98–7.03 (2 H, m, ArH), 7.15–7.24 (3 H, m, ArH), 7.31–
7.38 (5 H, m, ArH); m/z (FAB-LRMS) 564 (MHϩ, base peak),
474, 472, 440, 391, 365, 333, 315, 302, 289, 257, 225, 183.
(2E,4S,5S)-6-Benzyloxy-4-chloro-N-methyl-5-(2,4,6-trimethyl-
phenylsulfonylamino)hex-2-enamide 30
(2 H, m, 2 × CH᎐), 7.23–7.28 (2 H, m, ArH), 7.29–7.39 (5 H, m,
᎐
ArH), 7.72 (2 H, m, ArH); m/z (FAB-LRMS) 460 (MHϩ), 304,
By use of a procedure identical with that described for the
preparation of 14 from 10, the cis-(E)-enamide 6 (11.5 g,
26.7 mmol) was converted into the title compound 30 (9.53 g,
20.5 mmol, 77%) as colorless crystals, mp 131–133 ЊC (from
Et2O) (Found: C, 59.18; H, 6.17; N, 5.79. C23H29ClN2O4S
requires C, 59.41; H, 6.29; N, 6.02%); [α]2D8 Ϫ26.0 (c 0.50);
δH(300 MHz) 2.29 (3 H, s, CMe), 2.58 (6 H, s, 2 × CMe), 2.85
(3 H, d, J 4.9, NMe), 3.45 (1 H, m, 5-H), 3.53–3.64 (2 H,
m, OCH2), 4.39 (2 H, s, OCH2Ph), 4.81 (1 H, ddd, J 7.4, 3.4
and 1.2, 4-H), 5.08 (1 H, d, J 8.6, NH), 5.53 (1 H, br s, CONH),
289, 257, 239 (base peak), 198, 181, 167, 155, 149.
Mts-L-Val-ψ[(E )-CH᎐CH]-L-Glu(OMe)-OMe 26
᎐
By use of a procedure identical with that described for the
preparation of 24 from 10, treatment of the cis-(E)-enoate 11
(100 mg, 0.284 mmol) with IZn(CN)CuCH2CH2CO2Meؒ2LiCl
in THF gave the title compound 26 (65 mg, 0.149 mmol, 52%)
as a colorless oil [Found (FAB): (M ϩ H)ϩ, 440.2103. C22H34-
NO6S requires M ϩ H, 440.2107]; [α]2D2 Ϫ43.2 (c 2.17); δH(300
MHz) 0.80 (3 H, d, J 6.7, CMe), 0.85 (3 H, d, J 6.8, CMe), 1.54–
1.93 (3 H, m, CH2 and CH), 2.17 (2 H, m, CH2), 2.28 (3 H,
s, CMe), 2.61 (6 H, s, 2 × CMe), 2.85 (1 H, m, 4-H), 3.49 (1 H,
m, 7-H), 3.63 (3 H, s, OMe), 3.67 (3 H, s, OMe), 4.56 (1 H, d,
5.94 (1 H, dd, J 15.1 and 1.2, CH᎐), 6.56 (1 H, dd, J 15.1 and
᎐
7.4, CH᎐), 6.91 (2 H, s, ArH), 7.19–7.38 (5 H, m, Ph).
᎐
Mts-L-Ser(O-Bn)-ψ[(E )-CH᎐CH]-D-Glu(OMe)-NHMe 8
᎐
J 7.9, NH), 5.19–5.34 (2 H, m, 2 × CH᎐), 6.92 (2 H, s, ArH);
᎐
By use of a procedure identical with that described for the
preparation of 18 from 14, treatment of the enamide 30 (2.32 g,
4.98 mmol) with IZn(CN)CuCH2CH2CO2Meؒ2LiCl in THF
gave the title compound 8 (2.40 g, 4.64 mmol, 93%) as a
colorless oil [Found (FAB): (M ϩ H)ϩ, 517.2368. C27H37N2O6S
requires M ϩ H, 517.2372]; [α]2D8 Ϫ28.0 (c 0.50); δH(300 MHz)
1.70 (1 H, m, CHH), 2.19 (1 H, m, CHH), 2.23–2.26 (2 H, m,
CH2), 2.30 (3 H, s, CMe), 2.56 (6 H, s, 2 × CMe), 2.75 (3 H, d,
J 4.7, NMe), 2.83 (1 H, m, 4-H), 3.33–3.43 (2 H, m, OCH2),
3.62 (3 H, s, OMe), 3.69 (1 H, m, 7-H), 4.40 (2 H, s, OCH2Ph),
m/z (FAB-LRMS) 440 (MHϩ, base peak), 396, 364, 254, 241,
209.
Mts-L-Val-ψ[(E )-CH᎐CH]-L-Glu(OBn)-OMe 27
᎐
By use of a procedure identical with that described for the
preparation of 24 from 10, treatment of the cis-(E)-enoate 11
(100 mg, 0.284 mmol) with IZn(CN)CuCH2CH2CO2Bnؒ2LiCl
in THF gave the title compound 27 (66 mg, 0.129 mmol, 45%)
as a colorless oil [Found (FAB): (M ϩ H)ϩ, 516.2439. C28H38-
NO6S requires M ϩ H, 516.2420]; [α]2D7 Ϫ35.5 (c 1.68); δH(300
MHz) 0.79 (3 H, d, J 6.7, CMe), 0.84 (3 H, d, J 6.8, CMe), 1.54–
1.77 (2 H, m, CHH and CH), 1.80–1.94 (1 H, m, CHH), 2.18–
2.28 (5 H, m, CH2 and CMe), 2.59 (6 H, s, 2 × CMe), 2.84 (1 H,
m, 4-H), 3.47 (1 H, m, 7-H), 3.61 (3 H, s, OMe), 4.52 (1 H, d,
5.22 (1 H, d, J 4.4, NH), 5.47 (1 H, dd, J 15.4 and 8.2, CH᎐),
᎐
5.55 (1 H, dd, J 15.5 and 7.2, CH᎐), 6.30 (1 H, br s, CONH),
᎐
6.92 (2 H, s, ArH), 7.19–7.38 (5 H, m, ArH); m/z (FAB-LRMS)
539 (MNaϩ), 517 (MHϩ), 485, 318, 228 (base peak), 196, 183,
119, 91.
J 7.9, NH), 5.11 (2 H, m, OCH ), 5.21–5.26 (2 H, m, 2 × CH᎐),
᎐
2
Mts-L-Ser(O-Bn)-ψ[(E )-CH᎐CH]-D-Glu(OBn)-NHMe 31
᎐
6.88 (2 H, s, ArH), 7.31–7.39 (5 H, m, ArH); m/z (FAB-LRMS)
516 (MHϩ, base peak), 514, 472, 440, 408, 380, 332, 317, 289,
285, 254, 209, 183, 167, 149.
By use of a procedure identical with that described for the
preparation of 18 from 14, treatment of the enamide 30 (600
2450
J. Chem. Soc., Perkin Trans. 1, 2001, 2445–2451

View Article Online
1995, 1359; M. J. Daly, R. A. Ward, D. F. Thompson and G. Procter,
Tetrahedron Lett., 1995, 36, 7545; P. Wipf and T. Henninger, J. Org.
Chem., 1997, 62, 1586.
mg, 1.29 mmol) with IZn(CN)CuCH2CH2CO2Bnؒ2LiCl in
THF gave the title compound 31 (595 mg, 1.01 mmol, 78%) as a
colorless oil [Found (FAB): (M Ϫ H)Ϫ, 591.2547. C33H39N2O6S
requires M Ϫ H, 591.2528]; [α]2D8 Ϫ11.9 (c 0.50); δH(270 MHz)
1.73 (1 H, m, CHH), 2.23 (1 H, m, CHH), 2.28 (2 H, m, CH2),
2.29 (3 H, s, CMe), 2.54 (6 H, s, 2 × CMe), 2.73 (3 H, d, J 4.7,
NMe), 2.80 (1 H, m, 4-H), 3.30–3.40 (2 H, m, OCH2), 3.62 (1 H,
m, 7-H), 4.37 (2 H, s, OCH2Ph), 5.07 (2 H, s, OCH2Ph), 5.21
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60, 29; K. Miyasaka, S. Kanai, M. Masuda, T. Ibuka, K. Nakai,
N. Fujii and A. Funakoshi, J. Auton. Nerv. Syst., 1997, 63, 179.
3 T. E. Christos, A. Arvanitis, G. A. Cain, A. L. Johnson,
R. S. Pottorf, S. W. Tam and W. K. Schmidt, Bioorg. Med. Chem.
Lett., 1993, 3, 1035; B. Beresis and J. S. Panek, Bioorg. Med. Chem.
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(1 H, d, J 4.0, NH), 5.43 (1 H, dd, J 15.1 and 7.0, CH᎐), 5.51
᎐
(1 H, dd, J 15.1 and 7.0, CH᎐), 6.30 (1 H, br s, CONH), 6.92
᎐
(2 H, s, ArH), 7.18–7.39 (10 H, m, 2 × Ph); m/z (FAB-LRMS)
591 [(M Ϫ H)Ϫ], 483 (base peak), 305, 199, 168, 153, 122.
Mts-L-Ser(O-Bn)-ψ[(E )-CH᎐CH]-L-Glu(OBn)-NHMe 32
᎐
4 R. B. Gardner, G.-B. Liang and S. H. Gellman, J. Am. Chem.
Soc., 1995, 117, 3280; U. Schopfer, M. Stahl, T. Brandl and
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6088.
By use of a procedure identical with that described for the
preparation of 24 from 10, treatment of the cis-(E)-enamide 6
(327 mg, 0.763 mmol) with IZn(CN)CuCH2CH2CO2Bnؒ2LiCl
in THF gave the title compound 32 (255 mg, 0.430 mmol,
56%) as a colorless oil [Found (FAB): (M ϩ H)ϩ, 593.2700.
C33H41N2O6S requires M ϩ H, 593.2685]; [α]2D8 Ϫ54.0 (c 0.50 in
CHCl3); δH(270 MHz) 1.74 (1 H, m, CHH), 2.13 (1 H, m,
CHH), 2.28 (3 H, s, CMe), 2.34 (2 H, t, J 7.5, CH2), 2.55 (6 H,
s, 2 × CMe), 2.70 (3 H, d, J 4.7, NMe), 2.80 (1 H, m, 4-H),
3.28–3.40 (2 H, m, OCH2), 3.69 (1 H, m, 7-H), 4.36 (2 H, s,
OCH2Ph), 5.10 (2 H, s, OCH2Ph), 5.15 (1 H, d, J 4.7, NH), 5.43
5 H. Tamamura, M. Yamashita, H. Muramatsu, H. Ohno, T. Ibuka,
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K. Nakai, M. Akaji, H. Habashita, H. Tamamura, Y. Miwa,
T. Taga, N. Fujii and Y. Yamamoto, J. Org. Chem., 1997, 62, 2982.
7 E. Nakamura, S. Aoki, K. Sekiya, H. Oshino and I. Kuwajima,
J. Am. Chem. Soc., 1987, 109, 8056; H. Ochiai, Y. Tamaru,
K. Tsubaki and Z. Yoshida, J. Org. Chem., 1987, 52, 4418; M. C. P.
Yeh and P. Knochel, Tetrahedron Lett., 1988, 29, 2395; P. Knochel,
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8 M. E. Duggan and D. S. Karanewsky, Tetrahedron Lett.,
1983,24,2935;S.Itsuno,K.TanakaandK.Ito,Chem.Lett.,1986,1133;
D. Tanner and P. Somfai, Tetrahedron Lett., 1987, 28, 1211;
S. Matsubara, T. Kodama and K. Utimoto, Tetrahedron Lett., 1990,
31, 6379; J. Legters, J. G. H. Willems, L. Thijs and B. Zwanenburg,
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and P. Somfai, Tetrahedron, 1992, 48, 6069; T. Kawabata, Y. Kiryu,
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references cited; B. G. M. Burgaud, D. C. Horwell, A. Padova and
M. C. Pritchard, Tetrahedron, 1996, 52, 13035; C. M. Rayner,
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N. Fujii, T. Ibuka, I. Shimizu, A. Satake and Y. Yamamoto,
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J. Sweeney, Tetrahedron, 1998, 54, 2181; I. Fleming, J. Frackenpohl
and H. Ila, J. Chem. Soc., Perkin Trans. 1, 1998, 1229.
(1 H, dd, J 15.5 and 8.7, CH᎐), 5.70 (1 H, dd, J 15.5 and 6.7,
᎐
CH᎐), 6.07 (1 H, m, CONH), 6.91 (2 H, s, ArH), 7.17–7.38 (10
᎐
H, m, 2 × Ph); m/z (FAB-LRMS) 593 (MH)ϩ, 485 (base peak),
465, 394, 332, 196, 183, 119, 91.
Acknowledgements
This work was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan and the Japan Health
Science Foundation.
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