Versatile use of acid-catalyzed ring-opening of β-aziridinyl-α,β-enoates to stereoselective synthesis of peptidomimetics

Article abstract of DOI:10.1016/j.tet.2007.06.029

Treatment of N-arylsulfonylaziridines bearing α,β-unsaturated esters with alcohols, thiols or weak acids such as AcOH in the presence of catalytic amount of Lewis acids affords regio- and stereoselectively ring-opened products, such as δ-aminated γ-alkoxy

Full text of DOI:10.1016/j.tet.2007.06.029

Tetrahedron 63 (2007) 9243–9254
Versatile use of acid-catalyzed ring-opening of b-aziridinyl-a,b-
enoates to stereoselective synthesis of peptidomimetics
a
a
b
Hirokazu Tamamura,a, Tomohiro Tanaka, Hiroshi Tsutsumi, Koji Nemoto,
*
Satoko Mizokami,b Nami Ohashi,a Shinya Oishib and Nobutaka Fujiib,
*
aInstitute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan
bGraduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Received 27 April 2007; revised 11 June 2007; accepted 12 June 2007
Available online 16 June 2007
Abstract—Treatment of N-arylsulfonylaziridines bearing a,b-unsaturated esters with alcohols, thiols or weak acids such as AcOH in the pres-
ence of catalytic amount of Lewis acids affords regio- and stereoselectively ring-opened products, such as d-aminated g-alkoxy-(alkylthio or
acetoxy)-a,b-enoates. In addition, the regio- and stereoselective ring-opening reactions can be performed on solid supports and applied to
stereoselective synthesis of (E)-alkene dipeptide isosteres.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
have been documented to date.1 The regiospecific ring-
opening reactions of N-2,4,6-trimethylphenylsulfonyl
(Mts)-protected (and activated) aziridines possessing a,b-
unsaturated esters by strong acids, such as methanesulfonic
acid (MSA), TFA or HCl (Scheme 1) have been reported by
us.2 The MSA (or HCl)-mediated ring-opening reactions
of N-Mts-g,d-cis-g,d-epimino-(E)-a,b-enoates ((cis-(E)) 2
yield d-aminated g-mesyloxy (or -chloro)-a,b-enoates 3,
which can be converted into (L-amino acid, D-amino acid)-type
Ring-opening reactions of N-activated aziridines have been
widely used for the synthesis of various biological com-
pounds such as b-lactams, alkaloids, dipeptide isosteres
and sphingosines. Ample precedents, in which nucleophilic
reagents, including acids such as HCl, AcOH, TFA and
TsOH, attack either of the two carbon atoms of simple azir-
idines to afford the corresponding ring-opened products,
Scheme 1. R1, R2, R3¼alkyl; Ar¼4-methylphenyl or 2,4,6-trimethylphenyl, Ms¼methanesulfonyl; reagents: (i) Pd(PPh3)4; (ii) MeSO3H in CHCl3; (iii) HCl in
1,4-dioxane; (iv) TFA; (v) R3Cu(CN)MgCl.BF3; (vi) R3Cu(CN)MgCl$2LiCl; (vii) R3Cu(CN)ZnI$2LiCl; (viii) YH (weak acids, alcohols or thiols) and (ix)YH,
TMSOTf.
* Corresponding authors. Tel.: +81 3 5280 8036; fax: +81 3 5280 8039 (H.T.); tel.: +81 75 753 4551; fax: +81 75 753 4570 (N.F.); e-mail addresses: tamamura.
mr@tmd.ac.jp; nfujii@pharm.kyoto-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.029

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H. Tamamura et al. / Tetrahedron 63 (2007) 9243–9254
(E)-alkene dipeptide isosteres (EADIs) 4 via organocopper
(or organozinc-copper)-mediated anti-SN20 reactions.3 On
the other hand, organocopper (or organozinc-copper)-
mediated anti-SN20 reactions of cis-(E) isomers 2 exclu-
sively provide (L,L)-type EADIs 5. The utility of EADIs
as potential biomimics of amide bonds in peptides has
been intensively investigated.4 The above ring-opening reac-
tions are proven to be useful for the stereoselective synthesis
of a set of two diastereomeric EADIs starting from an
L-amino acid, in the combination with the convergently
transforming reactions from four stereoisomeric g,d-
epimino-a,b-enoates 1 into the single cis-(E) isomer 2 by
a Pd(0)-catalyst.5 However, treatment of these b-aziri-
dinyl-a,b-enoates 2 with weak acids such as AcOH, alcohols
or thiols does not yield the corresponding ring-opened prod-
ucts 6. It might be due to insufficient activation of N-arylsul-
fonylaziridines. Thus, in the present study, we investigated
whether the catalytic amount of Lewis acids such as
TMSOTf has an effect on the above ring-opening reactions
of b-aziridinyl-a,b-enoates with weak acids, alcohols or
thiols. In addition, the feasibility of the ring-opening reactions
of b-aziridinyl-a,b-enoates bearing no side-chain group at
the d-position was examined. Furthermore, we investigated
the ring-opening reactions using solid supports and their
application to stereoselective synthesis of EADIs.
the g,d-anti stereochemistry of 10a–e were based on X-
ray analysis of 9a. As a result, the addition of catalytic
TMSOTf was proven to be efficient for the regio- and
stereoselective ring-opening reactions with weak acids,
alcohols or thiols as nucleophiles.
Scheme 2. Ts¼4-methylphenysulfonyl; reagents: (a) AcOH; (b)
BrCH2COOH; (c) EtOH; (d) BnSH and (e) PhSH.
2.2. Ring-opening reactions of N-Mts-g,d-epimino-(E)-
a,b-enoates having no side-chain group at the d-position
2. Results and discussion
Next, the feasibility of the regioselective ring-opening reac-
tions of b-aziridinyl-a,b-enoates having no side-chain group
at the d-position was investivated. b-Aziridinyl-a,b-enoates,
(4R,2E)-enoate 11 and (4S,2E)-enoate 12, were prepared
from Ser and D-Ser, respectively, according to our reported
procedures. As shown in Scheme 3, exposure of 11 or 12 to
several reactants afforded exclusively the corresponding
d-aminated-g-acyloxy (alkoxy, alkylthio, mesyloxy or chlo-
ro,)-a,b-enoates, 13a–h or 14a–h in high yields, via the
regioselective SN2 ring-opening reaction at the g-carbon
position. Regiochemical assignments for products 13a–h
and 14a–h were readily made by 1H NMR. The stereochem-
istry at the g-carbon position of 13a–h and 14a–h was based
on X-ray analysis of 14g and the analysis of 15 and 16 by the
modified Mosher method.7 As a result, the regio- and stereo-
selective ring-opening reactions of b-aziridinyl-a,b-enoates
having no side-chain group at the d-position were achieved
by strong acids or by weak acids, alcohols or thiols in the
addition of catalytic amount of TMSOTf (Table 2).
2.1. Treatment of N-(4-methylphenylsulfonyl) (Ts)-g,d-
epimino-(E)-a,b-enoates with weak acids, alcohols or
thiols in the presence of Lewis acids
b-Aziridinyl-a,b-enoates, cis-(E)-enoate 7 and trans-(E)-
enoate 8, were prepared from Thr and D-allo-threonine,
respectively, as previously reported by us.6 These b-aziri-
dinyl-a,b-enoates 7 and 8 did not react with weak acids
such as AcOH, alcohols or thiols. Thus, examined was the
effect of the addition of catalytic amount of Lewis acids
such as TMSOTf on the ring-opening reactions with weak
acids, alcohols or thiols. Treatment of 7 or 8 with AcOH,
BrCH2COOH, EtOH, BnSH or PhSH in the presence of
catalytic amount of TMSOTf yielded the corresponding
d-aminated-g-acyloxy (alkoxy or alkylthio)-a,b-enoates,
9a–e or 10a–e, exclusively and quantitatively, via the regio-
selective SN2 ring-opening reaction at the g-carbon position
(Scheme 2, Table 1). Regiochemical assignments for prod-
ucts 9a–e and 10a–e were readily made by 1H NMR
(1H–1H COSY). The g,d-syn stereochemistry of 9a–e and
2.3. Synthesis of (Xaa, L-Asp)-type and (Xaa, D-Asp)-
type EADIs
The stereoselective synthesis of a couple of diastereomeric
EADIs from a single substrate of b-aziridinyl-a,b-enoate
has been established as described in Section 1. One potential
limitation to the use of these procedures for the synthesis of
peptide mimetics is the introduction of various functional
groups into the side chain (R3) at the a-position. The
stereoselective synthesis of (Xaa, L-Glu)-type and (Xaa,
D-Glu)-type EADIs has been established by treatment of
b-aziridinyl-a,b-enoates 2 and g-chloro-a,b-enoates 3,
respectively, with organozinc-copper reagents (Scheme
1).3 Next, we attempted to synthesize (Xaa, L-Asp)-type
and (Xaa, D-Asp)-type EADIs. As shown in Scheme 4, or-
thoesterification of allylic alcohol 15, which was obtained
Table 1. Ring-opening reactions of b-aziridinyl-a,b-unsaturated esters by
various nucleophiles in the presence of cat. TMSOTf
Substrate YH
YH/TMSOTf (equiv) Time (h) Product Yield (%)
7
7
7
7
7
8
8
8
8
8
AcOH 20/0.1
BrCH2CO2H 10/0.1
15
15
7
1
1
15
15
7
1
1
9a
9b
9c
9d
90
82
98
95
96
98
86
99
90
99
EtOH
BnSH
PhSH
AcOH
3/0.3
10/0.1
10/0.1
20/0.1
9e
10a
10b
10c
10d
10e
BrCH2CO2H 10/0.1
EtOH
BnSH
PhSH
3/0.3
10/0.1
10/0.1

H. Tamamura et al. / Tetrahedron 63 (2007) 9243–9254
9245
Scheme 3. Mts¼2,4,6-trimethylphenysulfonyl; reagents: (a) AcOH; (b) BrCH2COOH; (c) EtOH; (d) BnSH; (e) PhSH; (f) MeSO3H in CHCl3; (g) HCl in 1,4-
dioxane and (h) TFA.
Table 2. Ring-opening reactions of b-aziridinyl-a,b-unsaturated esters having no side-chain groups at the d-position by various nucleophiles
Substrate
YH or XH
Solvent
YH or XH/TMSOTf (equiv)
Time
Product
Yield (%)
11
11
11
11
11
11
AcOH
CH2Cl2
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
20/0.1
10/0.1
3/0.3
10/0.1
10/0.1
10/—
15 h
15 h
7 h
1 h
1 h
13a
13b
13c
13d
13e
13f
84
62
89
73
87
99
BrCH2CO2H
EtOH
BnSH
PhSH
MeSO3H
10 min
11
11
12
12
12
12
12
12
12
HCl
CF3CO2H
AcOH
BrCH2CO2H
EtOH
BnSH
PhSH
HCl
CF3CO2H
1,4-Dioxane
—
10/—
>20/—
20/0.1
10/0.1
3/0.3
10/0.1
10/0.1
10/—
10 min
15 h
15 h
15 h
7 h
1 h
1 h
10 min
15 h
13g
13h
14a
14b
14c
14d
14e
14g
14h
87
72a
69
69
77
69
81
96
63a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1,4-Dioxane
—
>20/—
a
Isolated yield of 15 or 16.
˚
Scheme 4. Reagents: (i) MeC(OMe)3, cat. PhCOOH, MS4A, o-xylene; (ii) 1 M TMSBr-thioanisole/TFA; (iii) (Boc)2O, Et3N, THF.
by hydrolysis of g-trifluoroacetate 13h in Scheme 3, and the
subsequent Claisen rearrangement8 afforded an EADI, Mts–
Gly–c[(E)-CH]CH]–L-Asp(OMe)–OBn, 19 in 34% yield.
The enantiomeric EADI, Mts–Gly–c[(E)-CH]CH]–D-As-
p(OMe)–OBn, 21 was also obtained from 16 in 19% yield
in a similar way. The optical purities of 19 and 21 were found
to be relatively low based on their HPLC analysis on chiral
column: ee of 19¼33%; ee of 21¼43% on the contrary to our
expectation. This might be attributable to instability of chair-
like transition states. The improvement of these reactions in
yields and optical purities is under investigation.
2.4. Ring-opening reactions of g,d-epimino-(E)-a,b-
enoates by Na-protected amino acids
The feasibility of ring-opening reactions of g,d-epimino-
(E)-a,b-enoates by Na-protected amino acids was in-
vestigated, since Na-protected amino acids are also weak
carboxylic acids. It is thought that introduction of a-amino
acids in the step of opening reactions of aziridine rings might
lead to efficient synthesis of EADI-containing peptidomi-
metics. Treatment of aziridine 7 by Na-Cbz-protected amino
acids, Na-Cbz-phenylalanine and Na-Cbz-valine, in the

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H. Tamamura et al. / Tetrahedron 63 (2007) 9243–9254
Scheme 5. Reagents: (a) Cbz–Phe–OH; (b) Cbz–Val–OH and (c) Fmoc–Pro–OH.
presence of catalytic amount of TMSOTf yielded the corre-
sponding ring-opened products, 23a and b, respectively
(Scheme 5). Ring-opening reaction of 7 with Na-Fmoc-
proline in the presence of TMSOTf obtained 24.
stereoselectivity in usual liquid techniques. Due to low reac-
tivity of resin-bound g-tosylates or basicity of organocopper
reagents, 30 might partially return to the aziridine 7 via ring-
closing, followed by organocopper-mediated alkylation to
produce a diastereomer of 31 [Ts–Ala–c[(E)-CH]CH]–L-
Leu–OMe]. The adjustment of loading amount of toluene-
sulfonic acid on resins and the improvement of linker/spacer
units in these reactions might be required for the develop-
ment of a convenient procedure for the synthesis of EADIs.
Next, this reaction was applied to the synthesis of Fmoc-
Pro–Ala–c[(E)-CH]CH]–D-Leu–OMe 29 in combination
with the O,N-acyl transfer reaction (Scheme 6). An O-
acylated compound 26, which was obtained by treatment
of aziridine 25 with Na-Fmoc-proline in the presence of
TMSOTf, was subjected to deprotection of the Na-Mts group
using 1 M TMSBr-thioanisole/TFA9 to yield 27. Subsequent
treatment of 27 with neutral phosphate buffer gave an
N-acylated compound 28 based on the intramolecular O,N-
acyl transfer.10 O-Mesylation and anti-SN20 type alkylation
mediated by organocopper led to the stereoselective synthe-
sis of a tripeptide mimetic 29. The stereochemistry at the
a-carbon position of 29 was determined by X-ray analysis.
Scheme 7. Reagents: (i) MP–Ts–OH, CH2Cl2 and (ii) iBuCu-
(CN)MgCl$BF3, THF.
3. Conclusion
In summary, the ring-opening reactions of b-aziridinyl-a,b-
enoates with several nucleophiles involving alcohols, thiols
and weak acids such as AcOH and Na-protected amino acids
in the presence of catalytic amount of Lewis acids such as
TMSOTf have been fully investigated. The regio- and
stereoselective SN20 ring-opening at the g-carbon position
was observed. The combination of the ring-opening reac-
tions with the Claisen rearrangement, the O,N-acyl transfer
reaction and the organocopper-mediated anti-SN20 type al-
kylation was efficiently applied to the synthesis of EADI-
containing peptidomimetics. In addition, the ring-opening
reactions of b-aziridinyl-a,b-enoates using solid-phase tech-
niques were applied to the synthesis of EADIs.
Scheme 6. Reagents: (i) Fmoc–Pro–OH, cat. TMSOTf, CH2Cl2; (ii) 1 M
TMSBr-thioanisole/TFA; (iii) pH 7.3 phosphate buffer, MeCN; (iv) MsCl,
Et3N, CH2Cl2 and (v) iBuCu(CN)MgCl$BF3, THF.
2.5. Synthesis of EADIs from g,d-epimino-(E)-a,b-
enoates using solid-phase techniques
To develop a convenient procedure for preparation of
EADIs, simplification of isolation/purification of synthetic
intermediate g-sulfonates might be desirable and critical.
Thus, ring-opening reactions of N-arylsulfonyl-g,d-
epimino-(E)-a,b-enoates mediated by resin-bound sulfonic
acid were applied to the synthesis of EADIs using solid-
phase techniques. Treatment of b-aziridinyl-a,b-enoate 7
with toluenesulfonic acid resin (MP–TsOH, Argonaut Tech-
nologies) yielded a resin-bound g-tosylate 30, which was
converted into an EADI 31 [Ts–Ala–c[(E)-CH]CH]–D-
Leu–OMe] by organocopper reagents in 37% yield (Scheme
7). In this procedure, the resin-bound g-tosylate 30 can
be purified only by washing with solvents, suggesting that
the present solid-phase techniques have the advantage of
manipulation. However, the stereoselectivity of this reaction
is not sufficiently high, compared to exceedingly high
4. Experimental
4.1. General
1
Melting points are uncorrected. H NMR spectra were re-
corded using a JEOL EX-270, a Bruker AC 300, a JEOL
AL-400 or a Bruker AM 600 spectrometer at 270, 300,
400 or 600 MHz 1H frequency in CDCl3, respectively.
Chemical shifts are reported in parts per million downfield
from internal tetramethylsilane. Nominal (LRMS) and exact
mass (HRMS) spectra were recorded on a JEOL JMS-01SG-
2 or JMS-HX/HX 110A mass spectrometer. Optical rota-
tions were measured in CHCl3 or H2O with a JASCO
DIP-360 digital polarimeter (Tokyo, Japan) or a Horiba
high-sensitive polarimeter SEPA-200 (Kyoto, Japan). The

H. Tamamura et al. / Tetrahedron 63 (2007) 9243–9254
9247
X-ray analysis was carried out on a Rigaku AFC5R-RU200
Fourcircle diffractometer or a Rigaku RAXIS-RAPID Imag-
ing Plate diffractometer. For flash column chromatography,
silica gel 60 H (silica gel for thin-layer chromatography,
Merck) and Wakogel C-200 (silica gel for column chroma-
tography) were employed.
4.1.4. Methyl (2E,4S,5S)-5-(((4-methylphenyl)sulfonyl)-
amino)-4-(phenylmethylthio)hex-2-enoate 9d. By use of
a procedure similar to that described for the preparation of
9a from 7, the (E)-enoate 7 (50 mg, 0.169 mmol) was
converted into the g-phenylmethylthio-a,b-enoate 9d
(68.0 mg, 0.162 mmol, 96% yield) by treatment with BnSH
(0.198 cm3, 1.69 mmol) and CF3SO3TMS (0.00306 cm3,
16.9 mmol) in CH2Cl2 (0.5 cm3) at rt for 1 h.
4.1.1. Methyl (2E,4S,5S)-4-acetyloxy-5-(((4-methylphe-
nyl)sulfonyl)amino)hex-2-enoate 9a. To a stirred solution
of the (E)-enoate 7 (50 mg, 0.169 mmol) in CH2Cl2
(0.5 cm3) were added dropwise CH3COOH (0.194 cm3,
3.38 mmol) and CF3SO3TMS (0.00306 cm3, 16.9 mmol) at
rt, and the stirring was continued for 15 h. The mixture was
purified by flash column chromatography over silica gel
with n-hexane–EtOAc (3:1) to yield 54.2 mg (0.152 mmol,
90%) of compound 9a, as colourless crystals, mp 108–
110 ꢀC [from n-hexane–Et2O (3:1)] (Found: C, 53.95; H,
5.94; N, 3.76. C16H21NO6S requires C, 54.07; H, 5.96; N,
3.94%); [a]2D8 ꢁ22.1 (c 1.220 in CHCl3); dH (300 MHz;
CDCl3) 1.09 (3H, d, J 6.8, CMe), 2.05 (3H, s, CMe), 2.43
(3H, s, CMe), 3.59 (1H, m, 5-H), 3.72 (3H, s, OMe), 4.81
(1H, d, J 8.8, NH), 5.33 (1H, m, 4-H), 5.90 (1H, dd, J 15.8
and 1.6, CH]), 6.68 (1H, dd, J 15.8 and 5.5, CH]), 7.29
(2H, d, J 7.9, ArH), 7.74 (2H, d, J 8.3, ArH).
Compound 9d, colourless crystals, mp 100 ꢀC [from n-hex-
ane–Et2O (3:1)] (Found: C, 60.05; H, 6.10; N, 3.32.
C21H25NO4S2 requires C, 60.12; H, 6.01; N, 3.34%); [a]D27
+73.2 (c 3.045 in CHCl3); dH (300 MHz; CDCl3) 1.08
(3H, d, J 6.8, CMe), 2.42 (3H, s, CMe), 3.21 (1H, ddd, J
10.0, 5.2 and 0.5, 4-H), 3.47–3.58 (1H, m, 5-H), 3.49–3.68
(2H, m, SCH2Ph), 3.74 (3H, s, OMe), 4.67 (1H, d, J 7.7,
NH), 5.62 (1H, dd, J 15.5 and 0.7, CH]), 6.67 (1H, dd, J
15.5 and 10.0, CH]), 7.22–7.28 (7H, m, ArH and Ph),
7.66 (2H, d, J 8.3, ArH).
4.1.5. Methyl (2E,4S,5S)-5-(((4-methylphenyl)sulfonyl)-
amino)-4-phenylthiohex-2-enoate 9e. By use of a proce-
dure similar to that described for the preparation of 9a
from 7, the (E)-enoate 7 (50 mg, 0.169 mmol) was converted
into the g-phenylthio-a,b-enoate 9e (66.0 mg, 0.163 mmol,
96%) by treatment with PhSH (0.174 cm3, 1.69 mmol)
and CF3SO3TMS (0.00306 cm3, 16.9 mmol) in CH2Cl2
(0.5 cm3) at rt for 1 h.
4.1.2. Methyl (2E,4S,5S)-4-(2-bromoacetyloxy)-5-(((4-
methylphenyl)sulfonyl)amino)hex-2-enoate 9b. By use
of a procedure similar to that described for the preparation
of 9a from 7, the (E)-enoate 7 (50 mg, 0.169 mmol) was con-
verted into the g-bromoacetyloxy-a,b-enoate 9b (60.2 mg,
0.139 mmol, 82% yield) by treatment with BrCH2COOH
(235 mg, 1.69 mmol) and CF3SO3TMS (0.00306 cm3,
16.9 mmol) in CH2Cl2 (0.5 cm3) at rt for 15 h.
Compound 9e, colourless crystals, mp 99–101 ꢀC [from
n-hexane–Et2O (3:1)] (Found: C, 59.07; H, 5.49; N, 3.17.
C20H23NO4S2 requires C, 59.23; H, 5.72; N, 3.45%); [a]D28
+1.38 (c 3.610 in CHCl3); dH (300 MHz; CDCl3)
1.16 (3H, d, J 6.8, CMe), 2.42 (3H, s, CMe), 3.58–3.68
(1H, m, 5-H), 3.70 (3H, s, OMe), 3.74 (1H, ddd, J
10.3, 5.6 and 0.8, 4-H), 4.80 (1H, d, J 7.8, NH), 5.63 (1H,
dd, J 15.5 and 0.8, CH]), 6.75 (1H, dd, J 15.5 and 9.5,
CH]), 7.26–7.32 (7H, m, ArH and Ph), 7.68 (2H, d,
J 8.3, ArH).
Compound 9b, colourless oil [Found (FAB): (M+H)+,
434.0278. C16H21BrNO6S requires M+H, 434.0273]; [a]D25
ꢁ42.7 (c 0.445 in CHCl3); dH (300 MHz; CDCl3) 1.12 (3H,
d, J 6.8, CMe), 2.43 (3H, s, CMe), 3.60–3.67 (1H, m, 5-H),
3.74 (3H, s, OMe), 3.79 (2H, s, CCH2Br), 4.59 (1H, d, J
8.8, NH), 5.37 (1H, m, 4-H), 5.98 (1H, dd, J 15.8 and 1.5,
CH]), 6.70 (1H, dd, J 15.7 and 5.6, CH]), 7.31 (2H, d, J
7.9, ArH), 7.74 (2H, d, J 8.3, ArH); m/z (FABLRMS) 436,
434 (MH+, base peak), 391, 296, 259, 198, 167, 149 and 136.
4.1.6. Methyl (2E,4R,5S)-4-acetyloxy-5-(((4-methylphe-
nyl)sulfonyl)amino)hex-2-enoate 10a. By use of a proce-
dure identical with that described for the preparation of 9a
from 7, the (E)-enoate 8 (50 mg, 0.169 mmol) was converted
into the g-acetyloxy-a,b-enoate 10a (58.8 mg, 0.165 mmol,
98% yield).
4.1.3. Methyl (2E,4S,5S)-4-ethoxy-5-(((4-methylphenyl)-
sulfonyl)amino)hex-2-enoate 9c. By use of a procedure
similar to that described for the preparation of 9a from 7,
the (E)-enoate 7 (50 mg, 0.169 mmol) was converted into
the g-ethoxy-a,b-enoate 9c (56.4 mg, 0.165 mmol, 98%
yield) by treatment with EtOH (0.0296 cm3, 0.508 mmol)
and CF3SO3TMS (0.00919 cm3, 50.8 mmol) in CH2Cl2
(0.5 cm3) at rt for 7 h.
Compound 10a, colourless crystals, mp 99–101 ꢀC [from n-
hexane–Et2O (3:1)] (Found: C, 54.03; H, 5.87; N, 3.85.
C16H21NO6S requires C, 54.07; H, 5.96; N, 3.94%); [a]D29
ꢁ8.80 (c 1.590 in CHCl3); dH (300 MHz; CDCl3) 1.06
(3H, d, J 6.9, CMe), 2.02 (3H, s, CMe), 2.43 (3H, s,
CMe), 3.61–3.67 (1H, m, 5-H), 3.73 (3H, s, OMe), 5.11
(1H, d, J 8.9, NH), 5.26 (1H, m, 4-H), 5.93 (1H, dd, J 15.8
and 1.7, CH]), 6.74 (1H, dd, J 15.8 and 5.1, CH]),
7.29–7.32 (2H, d, J 8.0, ArH), 7.74 (2H, d, J 8.4, ArH).
Compound 9c, colourless oil [Found (FAB): (M+H)+,
342.1384. C16H24NO5S requires M+H, 342.1375]; [a]D25
ꢁ20.8 (c 2.662 in CHCl3); dH (300 MHz; CDCl3) 1.10–
1.17 (6H, m, 2ꢂCMe), 2.42 (3H, s, CMe), 3.26–3.41 (1H,
m, 5-H and OCHHMe), 3.43–3.57 (1H, m, OCHHMe),
3.72 (3H, s, OMe), 3.77 (1H, m, 4-H), 4.87 (1H, d, J 7.5,
NH), 5.93 (1H, dd, J 15.8 and 1.3, CH]), 6.64 (1H, dd, J
15.8 and 6.2, CH]), 7.28 (2H, d, J 7.9, ArH), 7.72 (2H, d,
J 8.3, ArH); m/z (FABLRMS) 342 (MH+), 296 (base peak),
279, 198, 184, 155 and 154.
4.1.7. Methyl (2E,4R,5S)-4-(2-bromoacetyloxy)-5-(((4-
methylphenyl)sulfonyl)amino)hex-2-enoate 10b. By use
of a procedure identical with that described for the prepara-
tion of 9b from 7, the (E)-enoate 8 (50 mg, 0.169 mmol) was
converted into the g-bromoacetyloxy-a,b-enoate 10b
(63.6 mg, 0.146 mmol, 87% yield).

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H. Tamamura et al. / Tetrahedron 63 (2007) 9243–9254
Compound 10b, colourless oil [Found (FAB): (M+H)+,
434.0262. C16H21BrNO6S requires M+H, 434.0273]; [a]D26
ꢁ18.5 (c 3.085 in CHCl3); dH (300 MHz; CDCl3) 1.06
(3H, d, J 6.9, CMe), 2.44 (3H, s, CMe), 3.64–3.70 (1H, m,
5-H), 3.73 (3H, s, OMe), 3.81 (2H, d, J 2.6, CCH2Br),
5.27 (1H, d, J 9.0, NH), 5.32 (1H, m, 4-H), 6.02 (1H, dd, J
15.8 and 1.7, CH]), 6.75 (1H, dd, J 15.8 and 5.1, CH]),
7.32 (2H, d, J 7.9, ArH), 7.74 (2H, d, J 8.3, ArH); m/z
(FABLRMS) 436, 434 (MH+), 391, 296, 264, 250 (base
peak), 198, 167, 155 and 110.
(FABLRMS) 406 (MH+), 391 (base peak), 374, 296, 235,
198, 175, 155 and 149.
4.1.11. Phenylmethyl (2E,4S)-4-acetyloxy-5-(((2,4,6-tri-
methylphenyl)sulfonyl)amino)pent-2-enoate 13a. By use
of a procedure similar to that described for the preparation
of 9a from 7, the (E)-enoate 11 (50 mg, 0.130 mmol) was
converted into the g-acetyloxy-a,b-enoate 13a (48.3 mg,
0.108 mmol, 84%) by treatment with CH3COOH
(0.149 cm3, 2.60 mmol) and CF3SO3TMS (0.00235 cm3,
13.0 mmol) in CH2Cl2 (0.5 cm3) at rt for 15 h.
4.1.8. Methyl (2E,4R,5S)-4-ethoxy-5-(((4-methylphenyl)-
sulfonyl)amino)hex-2-enoate 10c. By use of a procedure
identical with that described for the preparation of 9c from
7, the (E)-enoate 8 (50 mg, 0.169 mmol) was converted
into the g-ethoxy-a,b-enoate 10c (57.4 mg, 0.168 mmol,
99% yield).
Compound 13a, colourless crystals, mp 106 ꢀC [from n-hex-
ane–Et2O (3:1)] (Found: C, 62.14; H, 6.10; N, 2.84.
C23H27NO6S requires C, 62.00; H, 6.11; N, 3.14%); [a]D26
+1.65 (c 1.208 in CHCl3); dH (300 MHz; CDCl3) 2.03
(3H, s, CMe), 2.29 (3H, s, CMe), 2.60 (6H, s, 2ꢂCMe),
3.08–3.17 (1H, m, CHH), 3.19–3.28 (1H, m, CHH), 4.75
(1H, t, J 6.4, NH), 5.17 (2H, s, OCH2Ph), 5.33–5.39 (1H,
m, 4-H), 5.96 (1H, dd, J 15.8 and 1.6, CH]), 6.72 (1H,
dd, J 15.8 and 5.1, CH]), 6.94 (2H, s, ArH), 7.33–7.39
(5H, m, Ph).
Compound 10c, colourless oil [Found (FAB): (M+H)+,
342.1367. C16H24NO5S requires M+H, 342.1375]; [a]D23
ꢁ24.2 (c 2.768 in CHCl3); dH (300 MHz; CDCl3) 0.98
(3H, d, J 6.8, CMe), 1.13 (3H, t, J 7.0, CMe), 2.43 (3H, s,
CMe), 3.19–3.29 (1H, m, OCHHMe), 3.39–3.52 (2H, m,
OCHHMe and 5-H), 3.74 (3H, s, OMe), 3.85 (1H, m, 4-
H), 4.91 (1H, d, J 8.9, NH), 5.95 (1H, dd, J 15.8 and 1.5,
CH]), 6.70 (1H, dd, J 15.8 and 5.6, CH]), 7.30 (2H, d,
J 7.9, ArH), 7.76 (2H, d, J 8.3, ArH); m/z (FABLRMS)
342 (MH+), 310, 296, 282, 264, 256 (base peak), 198, 186,
155, 144 and 110.
4.1.12. Phenylmethyl (2E,4S)-4-(2-bromoacetyloxy)-5-
(((2,4,6-trimethylphenyl)sulfonyl)amino)pent-2-enoate
13b. By use of a procedure similar to that described for the
preparation of 9b from 7, the (E)-enoate 11 (200 mg,
0.519 mmol) was converted into the g-bromoacetyloxy-
a,b-enoate 13b (167.7 mg, 0.320 mmol, 62%) by treatment
with BrCH2COOH (1.44 g, 10.4 mmol) and CF3SO3TMS
(0.00940 cm3, 51.9 mmol) in CHCl3 (5 cm3) at rt for 15 h.
4.1.9. Methyl (2E,4R,5S)-5-(((4-methylphenyl)sulfonyl)-
amino)-4-(phenylmethylthio)hex-2-enoate 10d. By use
of a procedure identical with that described for the prepara-
tion of 9d from 7, the (E)-enoate 8 (50 mg, 0.169 mmol)
was converted into the g-phenylmethylthio-a,b-enoate 10d
(64.1 mg, 0.153 mmol, 90% yield).
Compound 13b, colourless crystals, mp 91–93 ꢀC [from
n-hexane–Et2O (3:1)] (Found: C, 52.70; H, 5.07; N, 2.69.
C23H26BrNO6S requires C, 52.68; H, 5.00; N, 2.67%);
[a]2D9 +3.29 (c 4.250 in CHCl3); dH (300 MHz; CDCl3)
2.29 (3H, s, CMe), 2.60 (6H, s, 2ꢂCMe), 3.13–3.22 (1H,
m, CHH), 3.26–3.34 (1H, m, CHH), 3.78 (2H, s, CCH2Br),
4.91 (1H, t, J 6.6, NH), 5.18 (2H, s, OCH2Ph), 5.39–5.45
(1H, m, 4-H), 6.04 (1H, dd, J 15.8 and 1.6, CH]), 6.73
(1H, dd, J 15.8 and 5.2, CH]), 6.95 (2H, s, ArH), 7.36–
7.38 (5H, m, Ph).
Compound 10d, colourless oil [Found (FAB): (M+H)+,
420.1298. C21H26NO4S2 requires M+H, 420.1303]; [a]D27
ꢁ144.2 (c 3.210 in CHCl3); dH (300 MHz; CDCl3) 1.06
(3H, d, J 6.7, CMe), 2.42 (3H, s, CMe), 3.13 (1H, ddd, J
9.4, 4.3 and 0.5, 4-H), 3.44–3.67 (2H, m, SCH2Ph), 3.47–
3.54 (1H, m, 5-H), 3.73 (3H, s, OMe), 4.90 (1H, d, J 9.0,
NH), 5.68 (1H, dd, J 15.4 and 0.9, CH]), 6.65 (1H, dd, J
15.4 and 9.4, CH]), 7.21–7.34 (7H, m, ArH and Ph), 7.66
(2H, d, J 8.3, ArH); m/z (FABLRMS) 420 (MH+), 391,
249, 222 (base peak), 198, 155, 149 and 109.
4.1.13. Phenylmethyl (2E,4S)-4-ethoxy-5-(((2,4,6-trime-
thylphenyl)sulfonyl)amino)pent-2-enoate 13c. By use of
a procedure similar to that described for the preparation
of 9c from 7, the (E)-enoate 11 (50 mg, 0.130 mmol) was
converted into the g-ethoxy-a,b-enoate 13c (49.9 mg,
0.117 mmol, 89%) by treatment with EtOH (0.0227 cm3,
0.390 mmol) and CF3SO3TMS (0.00235 cm3, 13.0 mmol)
in CH2Cl2 (0.5 cm3) at rt for 7 h.
4.1.10. Methyl (2E,4R,5S)-5-(((4-methylphenyl)sulfonyl)-
amino)-4-phenylthiohex-2-enoate 10e. By use of a proce-
dure identical with that described for the preparation of 9e
from 7, the (E)-enoate 8 (50 mg, 0.169 mmol) was con-
verted into the g-phenylthio-a,b-enoate 10e (68.6 mg,
0.169 mmol, 99%).
Compound 13c, colourless oil [Found (FAB): (M+H)+,
432.1859. C23H30NO5S requires M+H, 432.1844]; [a]D25
+14.66 (c 1.705 in CHCl3); dH (300 MHz; CDCl3) 1.16
(3H, t, J 7.0, CMe), 2.29 (3H, s, CMe), 2.62 (6H, s,
2ꢂCMe), 2.74–2.83 (1H, m, CHH), 3.07–3.16 (1H, m,
CHH), 3.21–3.31 (1H, m, OCHHMe), 3.44–3.54 (1H, m,
OCHHMe), 3.91 (1H, m, 4-H), 4.95 (1H, br, NH), 5.16
(2H, dd, J 13.7 and 12.4, OCH2Ph), 6.00 (1H, dd, J 15.8
and 1.3, CH]), 6.69 (1H, dd, J 15.8 and 6.0, CH]), 6.94
(2H, s, ArH), 7.31–7.38 (5H, m, Ph); m/z (FABLRMS) 432
(MH+), 324 (base peak), 302, 261, 212, 183, 149 and 119.
Compound 10e, colourless oil [Found (FAB): (M+H)+,
406.1133. C20H24NO4S2 requires M+H, 406.1147]; [a]D28
ꢁ117.7 (c 3.730 in CHCl3); dH (300 MHz; CDCl3) 1.15
(3H, d, J 6.8, CMe), 2.41 (3H, s, CMe), 3.59 (1H, ddd, J
8.8, 4.0 and 1.0, 4-H), 3.66–3.77 (1H, m, 5-H), 3.70 (3H,
s, OMe), 5.07 (1H, d, J 9.2, NH), 5.66 (1H, dd, J 15.4 and
1.1, CH]), 6.76 (1H, dd, J 15.4 and 8.8, CH]), 7.19–
7.27 (7H, m, ArH and Ph), 7.73 (2H, d, J 8.3, ArH); m/z

H. Tamamura et al. / Tetrahedron 63 (2007) 9243–9254
9249
4.1.14. Phenylmethyl (2E,4S)-4-(phenylmethylthio)-5-
(((2,4,6-trimethylphenyl)sulfonyl)amino)pent-2-enoate
13d. By use of a procedure similar to that described
for the preparation of 9d from 7, the (E)-enoate 11
(50 mg, 0.130 mmol) was converted into the g-phenyl-
methylthio-a,b-enoate 13d (48.0 mg, 0.0942 mmol, 73%)
by treatment with BnSH (0.152 cm3, 1.30 mmol) and
CF3SO3TMS (0.00235 cm3, 13.0 mmol) in CH2Cl2
(0.5 cm3) at rt for 1 h.
4.1.17. Reaction of phenylmethyl (2E,4R)-3-(2-((2,4,6-tri-
methylphenyl)sulfonyl)-2-aziridinyl)prop-2-enoate 11
with HCl-1,4-dioxane.
4.1.17.1. Phenylmethyl (2E,4S)-4-chloro-5-(((2,4,6-tri-
methylphenyl)sulfonyl)amino)pent-2-enoate 13g. The
(E)-enoate 11 (50 mg, 0.130 mmol) was dissolved in 4 M
HCl-1,4-dioxane (0.325 cm3, 1.30 mmol) at rt, and the solu-
tion was stirred for 10 min followed by extraction with
EtOAc. The extract was washed successively with aq 5% cit-
ric acid, brine, aq 5% NaHCO3, brine and dried over MgSO4.
Concentration under reduced pressure gave a crystalline res-
idue, which was purified by chromatography over silica gel
with n-hexane–EtOAc (3:1) to yield 47.5 mg (0.113 mmol,
87%) of compound 13g as colourless crystals, mp 78–
79 ꢀC [from n-hexane–Et2O (3:1)] (Found: C, 59.60; H,
5.92; N, 3.21. C13H17NO4S requires C, 59.78; H, 5.73; N,
3.32%); [a]2D5 ꢁ26.2 (c 1.185 in CHCl3); dH (300 MHz;
CDCl3) 2.29 (3H, s, CMe), 2.62 (6H, s, 2ꢂCMe), 3.14–
3.23 (1H, m, CHH), 3.30–3.38 (1H, m, CHH), 4.45–4.52
(1H, m, 4-H), 4.97 (1H, t, J 5.8, NH), 5.18 (2H, s, OCH2Ph),
6.04 (1H, dd, J 15.4 and 1.2, CH]), 6.77 (1H, dd, J 15.4 and
7.4, CH]), 6.95 (2H, s, ArH), 7.33–7.39 (5H, m, Ph).
Compound 13d, colourless oil [Found (FAB): (M+H)+,
510.1765. C28H32NO4S2 requires M+H, 510.1772]; [a]D25
+81.8 (c 1.198 in CHCl3); dH (600 MHz; CDCl3) 2.28
(3H, s, CMe), 2.55 (6H, s, 2ꢂCMe), 3.00–3.13 (2H, m,
CH2), 3.23 (1H, br, 4-H), 3.53 (1H, d, J 13.6, SCHHPh),
3.53 (1H, d, J 13.5, SCHHPh), 4.83 (1H, t, J 6.3, NH),
5.17 (2H, dd, J 15.2 and 12.3, OCH2Ph), 5.63 (1H, d, J
15.5, CH]), 6.64 (1H, dd, J 15.5 and 9.0, CH]), 6.90
(2H, s, ArH), 7.20–7.30 (5H, m, Ph), 7.34–7.40 (5H, m,
Ph); m/z (FABLRMS) 531, 510 (MH+), 402, 298, 282, 256
(base peak), 207, 183, 154 and 119.
4.1.15. Phenylmethyl (2E,4S)-4-phenylthio-5-(((2,4,6-tri-
methylphenyl)sulfonyl)amino)pent-2-enoate 13e. By use
of a procedure similar to that described for the preparation
of 9e from 7, the (E)-enoate 11 (50 mg, 0.130 mmol) was
converted into the g-phenylthio-a,b-enoate 13e (55.7 mg,
0.112 mmol, 87%) by treatment with PhSH (0.133 cm3,
1.30 mmol) and CF3SO3TMS (0.00235 cm3, 13.0 mmol) in
CH2Cl2 (0.5 cm3) at rt for 1 h.
4.1.18. Reaction of phenylmethyl (2E,4R)-3-(2-((2,4,6-tri-
methylphenyl)sulfonyl)-2-aziridinyl)prop-2-enoate 11
with TFA.
4.1.18.1. Phenylmethyl (2E,4S)-4-hydroxy-5-(((2,4,6-
trimethylphenyl)sulfonyl)amino)pent-2-enoate 15. The
(E)-enoate 11 (1 g, 2.60 mmol) was dissolved in TFA
(10 cm3) at rt, and the solution was stirred for 15 h. Concen-
tration under reduced pressure gave a crude product 13h as
an oil. Hydrolysis and purification by flash chromatography
over silica gel with n-hexane–EtOAc (4:1) afforded the
hydrolyzate 15 (752 mg, 1.86 mmol, 72% yield based on
11) as an oil.
Compound 13e, colourless crystals, mp 96–97 ꢀC [from
n-hexane–Et2O (3:1)] [Found (FAB): (M+H)+, 496.1629.
C27H30NO4S2 requires M+H, 496.1616]; [a]2D5 +42.8 (c
1.495 in CHCl3); dH (300 MHz; CDCl3) 2.28 (3H, s,
CMe), 2.59 (6H, s, 2ꢂCMe), 3.06–3.24 (2H, m, CH2),
3.59–3.66 (1H, m, 4-H), 5.08 (1H, t, J 6.4, NH), 5.56 (2H,
s, OCH2Ph), 5.58 (1H, dd, J 15.6 and 1.0, CH]), 6.71
(1H, dd, J 15.6 and 8.7, CH]), 6.92 (2H, s, ArH), 7.22–
7.29 (5H, m, Ph), 7.29–7.39 (5H, m, Ph); m/z (FABLRMS)
496 (MH+), 444, 388, 386, 330, 296 (base peak), 284, 256,
207, 183, 149 and 119.
Compound 13h, colourless oil (crude), dH (300 MHz;
CDCl3) 2.29 (3H, s, CMe), 2.59 (6H, s, 2ꢂCMe), 3.26–
3.32 (2H, br, CH2), 5.14 (1H, t, J 6.7, NH), 5.17 (2H, s,
OCH2Ph), 5.47–5.53 (1H, m, 4-H), 6.03 (1H, dd, J 15.8
and 1.5, CH]), 6.74 (1H, dd, J 15.8 and 5.8, CH]), 6.95
(2H, s, ArH), 7.31–7.38 (5H, m, Ph); m/z (FABLRMS) 500
(MH+), 404, 302 (base peak), 212, 183, 137 and 119.
4.1.16. Reaction of phenylmethyl (2E,4R)-3-(2-((2,4,6-tri-
methylphenyl)sulfonyl)-2-aziridinyl)prop-2-enoate 11
with MSA in CHCl3.
Compound 15, colourless oil [Found (FAB): (M+H)+,
404.1527. C21H26NO5S requires M+H, 404.1532]; [a]D22
ꢁ2.59 (c 3.855 in CHCl3); dH (300 MHz; CDCl3) 2.28
(3H, s, CMe), 2.60 (6H, s, 2ꢂCMe), 2.83 (1H, m, CHH),
3.13 (1H, m, CHH), 4.12 (1H, m, 4-H), 5.16 (2H, s,
OCH2Ph), 5.22 (1H, t, J 5.8, NH), 6.13 (1H, dd, J 15.7
and 1.8, CH]), 6.82 (1H, dd, J 15.6 and 4.4, CH]), 6.94
(2H, s, ArH), 7.31–7.36 (5H, m, Ph); m/z (FABLRMS) 404
(MH+), 302, 212, 183, 167, 149 (base peak) and 119.
4.1.16.1. Phenylmethyl (2E,4S)-4-(methylsulfonyl-
oxy)-5-(((2,4,6-trimethylphenyl)sulfonyl)amino)pent-2-
enoate 13f. To a stirred solution of (E)-enoate 9 (7 mg,
0.0182 mmol) in CHCl3 (0.182 cm3) was added dropwise
MSA (0.0118 cm3, 0.182 mmol) at rt, and the stirring was
continued for 10 min. The mixture was extracted with
EtOAc and the extract was washed successively with aq
5% citric acid, brine, aq 5% NaHCO3, brine, and dried
over MgSO4. Concentration under reduced pressure gave
the crude mesyl compound 13f, as a colourless oil (crude),
dH (300 MHz; CDCl3) 2.29 (3H, s, CMe), 2.61 (6H, s,
2ꢂCMe), 3.07 (3H, s, SMe), 3.13–3.30 (2H, m, CH2), 5.04
(1H, t, J 6.7, NH), 5.18 (2H, s, OCH2Ph), 5.22–5.30 (1H,
m, 4-H), 6.13 (1H, dd, J 15.7 and 1.5, CH]), 6.78 (1H,
dd, J 15.7 and 5.7, CH]), 6.95 (2H, s, ArH), 7.33–7.39
(5H, m, Ph); m/z (FABLRMS) 482 (MH+), 391, 363, 296
(base peak), 279, 261, 212, 167 and 149.
4.1.19. Phenylmethyl (2E,4R)-4-acetyloxy-5-(((2,4,6-tri-
methylphenyl)sulfonyl)amino)pent-2-enoate 14a. By use
of a procedure identical with that described for the prepara-
tion of 13a from 11, the (E)-enoate 12 (50 mg, 0.130 mmol)
was converted into the g-acetyloxy-a,b-enoate 14a
(39.9 mg, 0.0896 mmol, 69%).
Compound 14a, colourless crystals, mp 84–86 ꢀC [from
n-hexane–Et2O (3:1)] (Found: C, 61.73; H, 6.05; N, 2.95.

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H. Tamamura et al. / Tetrahedron 63 (2007) 9243–9254
C23H27NO6S requires C, 62.00; H, 6.11; N, 3.14%); [a]D26
ꢁ2.00 (c 0.998 in CHCl3); dH (270 MHz; CDCl3) 2.03
(3H, s, CMe), 2.29 (3H, s, CMe), 2.60 (6H, s, 2ꢂCMe),
3.10–3.23 (2H, m, CH2), 4.92 (1H, m, NH), 5.16 (2H, s,
CH2), 5.35 (1H, m, 4-H), 5.96 (1H, dd, J 15.8 and 1.7,
CH]), 6.72 (1H, dd, J 15.8 and 5.3, CH]), 6.94 (2H, s,
ArH), 7.37 (5H, m, ArH).
4.1.23. Phenylmethyl (2E,4R)-4-phenylthio-5-(((2,4,6-tri-
methylphenyl)sulfonyl)amino)pent-2-enoate 14e. By use
of a procedure similar to that described for the preparation
of 13e from 11, the (E)-enoate 12 (50 mg, 0.130 mmol)
was converted into the g-phenylthio-a,b-enoate 14e
(55.7 mg, 0.112 mmol, 87%).
Compound 14e, colourless crystals, mp 99 ꢀC [from n-
hexane–Et2O (3:1)] (Found: C, 65.19; H, 5.71; N, 2.82.
C27H29NO4S2 requires C, 65.43; H, 5.90; N, 2.83%); [a]D26
ꢁ41.2 (c 2.575 in CHCl3); dH (400 MHz; CDCl3) 2.29
(3H, s, CMe), 2.60 (6H, s, 2ꢂCMe), 3.08–3.20 (2H, m,
CH2), 3.62 (1H, m, 4-H), 5.02 (1H, t, J 6.4, NH), 5.14
(2H, s, OCH2Ph), 5.59 (1H, dd, J 15.5 and 1.0, CH]),
6.71 (1H, dd, J 15.4 and 8.8, CH]), 6.93 (2H, s, ArH),
7.24–7.27 (5H, m, Ph), 7.35 (5H, m, Ph).
4.1.20. Phenylmethyl (2E,4R)-4-(2-bromoacetyloxy)-5-
(((2,4,6-trimethylphenyl)sulfonyl)amino)pent-2-enoate
14b. By use of a procedure similar to that described for the
preparation of 13b from 11, the (E)-enoate 12 (100 mg,
0.260 mmol) was converted into the g-bromoacetyloxy-
a,b-enoate 14b (93.6 mg, 0.178 mmol, 69%) by treatment
with BrCH2COOH (721 mg, 5.19 mmol) and CF3SO3TMS
(0.00470 cm3, 26.0 mmol) in CH2Cl2 (1 cm3) at rt for 15 h.
Compound 14b, colourless crystals, mp 87–88 ꢀC [from n-
hexane–Et2O (3:1)] (Found: C, 52.70; H, 5.26; N, 2.75.
C23H26BrNO6S requires C, 52.68; H, 5.00; N, 2.67%);
[a]2D8 ꢁ2.56 (c 3.905 in CHCl3); dH (270 MHz; CDCl3)
2.29 (3H, s, CMe), 2.60 (6H, s, 2ꢂCMe), 3.16–3.28 (2H,
m, CH2), 3.79 (2H, s, CCH2Br), 5.17 (2H, s, OCH2Ph),
5.29 (1H, br, NH), 5.43 (1H, m, 4-H), 6.04 (1H, dd, J 15.8
and 1.7, CH]), 6.74 (1H, dd, J 15.8 and 5.3, CH]), 6.94
(2H, s, ArH), 7.36 (5H, m, Ph); m/z (FAB-LRMS) 432
(MH+), 324, 302, 250 (base peak), 212, 183, 149 and 119.
4.1.24. Reaction of phenylmethyl (2E,4S)-3-(2-((2,4,6-tri-
methylphenyl)sulfonyl)-2-aziridinyl)prop-2-enoate 12
with HCl-1,4-dioxane.
4.1.24.1. Phenylmethyl (2E,4R)-4-chloro-5-(((2,4,6-
trimethylphenyl)sulfonyl)amino)pent-2-enoate 14g. By
use of a procedure identical with that described for the
preparation of 13g from 11, the (E)-enoate 12 (50 mg,
0.130 mmol) was converted into the g-chloro-a,b-enoate
14g (52.7 mg, 0.125 mmol, 96%).
Compound 14g, colourless crystals, mp 80–81 ꢀC [from n-
hexane–Et2O (3:1)] (Found: C, 59.53; H, 5.73; N, 3.40.
C13H17NO4S requires C, 59.78; H, 5.73; N, 3.32%); [a]D25
+25.9 (c 1.390 in CHCl3); dH (270 MHz; CDCl3) 2.30
(3H, s, CMe), 2.62 (6H, s, 2ꢂCMe), 3.13–3.23 (1H, m,
CHH), 3.28–3.38 (1H, m, CHH), 4.46 (1H, m, 4-H), 5.03
(1H, t, J 7.3, NH), 5.18 (2H, s, CH2), 6.04 (1H, dd, J 15.5
and 1.0, CH]), 6.78 (1H, dd, J 15.5 and 7.6, CH]), 6.95
(2H, s, ArH), 7.37 (5H, m, ArH).
4.1.21. Phenylmethyl (2E,4R)-4-ethoxy-5-(((2,4,6-trime-
thylphenyl)sulfonyl)amino)pent-2-enoate 14c. By use of
a procedure identical with that described for the preparation
of 13c from 11, the (E)-enoate 12 (50 mg, 0.130 mmol) was
converted into the g-ethoxy-a,b-enoate 14c (43.1 mg,
0.0999 mmol, 79%).
Compound 14c, colourless oil [Found (FAB): (M+H)+,
432.1856. C23H29NO5S requires M+H, 431.1766]; [a]D25
ꢁ14.51 (c 2.205 in CHCl3); dH (270 MHz; CDCl3) 1.16 (3H,
t, J 6.9, CMe), 2.29 (3H, s, CMe), 2.62 (6H, s, 2ꢂCMe), 2.77
(1H, m, CHH), 3.11 (1H, m, CHH), 3.22–3.28 (1H, m,
OCHHMe), 3.46–3.52 (1H, m, OCHHMe), 3.91 (1H, m, 4-
H), 4.98 (1H, m, NH), 5.16 (2H, s, OCH2Ph), 6.00 (1H, dd,
J 15.8 and 1.3, CH]), 6.69 (1H, dd, J 15.8 and 6.3,
CH]), 6.95 (2H, s, ArH), 7.37 (5H, m, Ph); m/z (FABLRMS)
432 (MH+), 324, 302, 250 (base peak), 212, 183, 149 and 119.
4.1.25. Reaction of phenylmethyl (2E,4S)-3-(2-((2,4,6-tri-
methylphenyl)sulfonyl)-2-aziridinyl)prop-2-enoate 12
with TFA.
4.1.25.1. Phenylmethyl (2E,4R)-4-hydroxy-5-(((2,4,6-
trimethylphenyl)sulfonyl)amino)pent-2-enoate 16. By
use of a procedure identical with that described for the
preparation of 13h from 11, the (E)-enoate 12 (200 mg,
0.519 mmol) was converted into the hydrolyzate 16
(131 mg, 0.325 mmol, 63% yield based on 12) via the
g-trifluoroacetoxy-a,b-enoate 14h.
4.1.22. Phenylmethyl (2E,4R)-4-(phenylmethylthio)-5-
(((2,4,6-trimethylphenyl)sulfonyl)amino)pent-2-enoate
14d. By use of a procedure similar to that described for the
preparation of 13d from 11, the (E)-enoate 12 (50 mg,
0.130 mmol) was converted into the g-phenylmethylthio-
a,b-enoate 14d (45.9 mg, 0.0901 mmol, 69%).
Compound 14h, colourless oil (crude), dH (300 MHz;
CDCl3) 2.29 (3H, s, CMe), 2.59 (6H, s, 2ꢂCMe), 3.20–
3.38 (2H, m, CH2), 4.99 (1H, t, J 6.7, NH), 5.18 (2H, s,
CH2), 5.46–5.52 (1H, m, 4-H), 6.03 (1H, dd, J 15.8 and
1.5, CH]), 6.73 (1H, dd, J 15.8 and 5.8, CH]), 6.94
(2H, s, ArH), 7.32–7.40 (5H, m, ArH); m/z (FABLRMS)
500 (MH+), 404, 398, 302, 273 (base peak), 212, 183, 167
and 119.
Compound 14d, colourless oil [Found (FAB): (M+H)+,
510.1760. C28H32NO4S2 requires M+H, 510.1772]; [a]D25
ꢁ74.2 (c 1.145 in CHCl3); dH (400 MHz; CDCl3) 2.28
(3H, s, CMe), 2.55 (6H, s, 2ꢂCMe), 3.01–3.12 (2H, m,
CH2), 3.20–3.26 (1H, m, 4-H), 3.52–3.67 (2H, m, SCH2Ph),
4.84 (1H, t, J 6.3, NH), 5.18 (2H, s, OCH2Ph), 5.63 (1H, d, J
15.4, CH]), 6.64 (1H, dd, J 15.6 and 8.8, CH]), 6.90 (2H,
s, ArH), 7.21–7.29 (5H, m, Ph) 7.38 (5H, m, Ph); m/z
(FABLRMS) 510 (MH+), 408, 402 (base peak), 311, 302,
221, 207, 183, 149 and 119.
Compound 16, colourless oil [Found (FAB): (M+H)+,
404.1521. C21H26NO5S requires M+H, 404.1532]; [a]D22
+2.56 (c 2.340 in CHCl3); dH (300 MHz; CDCl3) 2.29
(3H, s, CMe), 2.62 (6H, s, 2ꢂCMe), 2.85 (1H, m, CHH),
3.16 (1H, m, CHH), 4.42 (1H, m, 4-H), 4.98 (1H, s, NH),
5.17 (2H, s, CH2), 6.13 (1H, dd, J 15.7 and 1.7, CH]),

H. Tamamura et al. / Tetrahedron 63 (2007) 9243–9254
9251
6.82 (1H, dd, J 15.6 and 4.5, CH]), 6.95 (2H, s, ArH), 7.32–
7.38 (5H, m, ArH); m/z (FABLRMS) 426, 404 (MH+), 391,
302, 222 (base peak), 212, 183, 149 and 119.
Boc–Gly–c[(E)-CH]CH]–L-Asp(OMe)–OH 20 accompa-
nied with its enantiomer 22 as a colourless oil [Found
(CI): (M+H)+, 288.1453. C13H22NO6 requires M+H,
288.1447]; dH (600 MHz; CDCl3) 1.27 (9H, s, 3ꢂCMe),
2.54–2.58 (1H, dd, J¼16.6 and 5.2, CHH), 2.82–2.86 (dd,
J¼16.7 and 8.2, CHH), 3.55 (1H, m, 2-H), 3.69 (3H, s,
OMe), 3.70 (2H, br, CH2), 4.63 (1H, br, NH), 5.63–5.67
(2H, m, 2ꢂCH]); m/z (CILRMS), 288 (MH+, base peak),
260, 242, 232, 214, 188, 171.
4.1.26. Mts-Gly–c[(E)-CH]CH]–L-Asp(OMe)–OBn
[methyl phenylmethyl (1E,2R)-2-(3-(((2,4,6-trimethyl-
phenyl)sulfonyl)amino)prop-1-enyl)butane-1,4-dioate]
19. Allylic acetate 15 (2.30 g, 5.69 mmol), trimethyl ortho-
acetate (7.25 cm3, 56.9 mmol), benzoic acid (139 mg,
˚
1.14 mmol), and dried molecular sieves (4 A, powder,
2.85 g) were mixed in 75 cm3 o-xylene and then refluxed
for 3 days. The mixture was cooled to rt and purified by chro-
matography over silica gel with n-hexane–EtOAc (3:1) to
give 896 mg (1.95 mmol, 34%) of the mixture of Mts–
Gly–c[(E)-CH]CH]–L-Asp(OMe)–OBn 19 and its enan-
tiomer 21 (66.5: 33.5) as a colourless oil [Found (FAB):
(M+H)+, 460.1802. C24H30NO6S requires M+H, 460.1794];
dH (400 MHz; CDCl3) 2.29 (3H, s, CMe), 2.37–2.43 (1H, dd,
J 16.6 and 5.9, CHH), 2.60 (6H, s, 2ꢂCMe), 2.63–2.76 (1H,
dd, J 16.6 and 8.5, CHH), 3.45–3.51 (3H, m, CH and CH2),
3.62 (3H, s, OMe), 4.44 (1H, t, J 6.1, NH), 5.11 (2H,
s, OCH2Ph), 5.45–5.50 (1H, m, CH]), 5.57–5.63 (1H, dd,
J 15.6 and 7.6, CH]), 6.94 (2H, s, ArH), 7.33 (5H, m,
Ph); m/z (FABLRMS), 460 (MH+), 352 (base peak), 183,
136, 119.
4.1.29. Boc–Gly–c[(E)-CH]CH]–D-Asp(OMe)–OH
[(3E,2S)-5-((tert-butoxy)carbonylamino)-2-((methoxy-
carbonyl)methyl)pent-3-enoic acid] 22. By use of a proce-
dure identical with that described for the preparation of 20
from 19, the allylic dioate 21 (58.1 mg, 0.126 mmol, the
enantiomixture with 19, ee¼43%) was converted into
Boc–Gly–c[(E)-CH]CH]–D-Asp(OMe)–OH 22 accompa-
nied with its enantiomer 20 (16.0 mg, 0.0557 mmol, 44%)
as a colourless oil [Found (CI): (M+H)+, 288.1442.
C13H22NO6 requires M+H, 288.1447]; dH (270 MHz;
CDCl3) 1.45 (9H, s, 3ꢂCMe), 2.52–2.60 (1H, dd, J¼16.8
and 5.9, CHH), 2.80–2.89 (1H, dd, J¼16.8 and 8.2, CHH),
3.53 (1H, m, 2-H), 3.69 (3H, s, OMe), 3.74 (2H, br, CH2),
4.63 (1H, br, NH), 5.65–5.67 (2H, m, 2ꢂCH]); m/z
(CILRMS), 288 (MH+, base peak), 272, 260, 242, 232,
214, 188, 171.
4.1.27. Mts–Gly–c[(E)-CH]CH]–D-Asp(OMe)–OBn
[methyl phenylmethyl (1E,2S)-2-(3-(((2,4,6-trimethyl-
phenyl)sulfonyl)amino)prop-1-enyl)butane-1,4-dioate]
21. By use of a procedure identical with that described for the
preparation of 19 from 15, the allylic acetate 16 (1.88 g,
4.64 mmol) was converted into the mixture (398 mg,
0.866 mmol, 19%) of Mts–Gly–c[(E)-CH]CH]–D-Asp-
(OMe)–OBn 21 and its enantiomer 19 (71.5: 28.5) as a col-
ourless oil [Found (FAB): (M+H)+, 460.1801. C24H30NO6S
requires M+H, 460.1794]; dH (300 MHz; CDCl3) 2.29 (3H,
s, CMe), 2.41 (1H, dd, J 16.6 and 5.8, CHH), 2.60 (6H, s,
2ꢂCMe), 2.73 (1H, dd, J 16.7 and 8.7, CHH), 3.43–3.47 (1H,
m, CH), 3.48–3.52 (2H, t, J 6.3, CH2), 3.62 (3H, s, OMe),
4.41 (1H, t, J 6.4, NH), 5.12 (2H, s, OCH2Ph), 5.42–5.51
(1H, m, CH]), 5.61 (1H, dd, J 15.5 and 7.6, CH]), 6.95
(2H, s, ArH), 7.29–7.39 (5H, m, Ph); m/z (FABLRMS), 460
(MH+, base peak), 307, 289, 243, 154, 136.
4.1.30. Methyl (2E,2S,4S,5S)-5-(((4-methylphenyl)sulfo-
nyl)amino)-4-(3-phenyl-2-((phenylmethoxy)carbonyl-
amino)propanoyloxy)hex-2-enoate 23a. By use of a
procedure similar to that described for the preparation of
9a from 7, the (E)-enoate 7 (50 mg, 0.169 mmol) was con-
verted into the g-acyloxy-a,b-enoate 23a (59.7 mg,
0.100 mmol, 59%) by treatment with Cbz–L-Phe–OH
(507 mg, 1.69 mmol) and CF3SO3TMS (0.00920 cm3,
50.8 mmol) in CH2Cl2 at rt for 15 h.
Compound 23a, colourless crystals, mp 60–62 ꢀC [from
n-hexane–Et2O (3:1)] (Found: C, 62.33; H, 5.77; N, 4.50.
C31H34N2O8S requires C, 62.61; H, 5.76; N, 4.71%); [a]D29
+17.9 (c 0.335, CHCl3); dH (600 MHz; CDCl3) 0.87–0.89
(3H, m, CMe), 2.41 (3H, s, CMe), 3.09 (2H, d, J 6.4,
CCH2Ph), 3.47 (1H, br, 5-H), 3.71 (3H, s, OMe), 4.63
(1H, q, J 7.2, 2-H), 4.72 (1H, d, J 8.7, NH), 5.06–5.12
(2H, m, OCH2Ph), 5.25 (1H, d, J 8.0, NH), 5.33 (1H, br,
4-H), 5.84 (1H, d, J 15.8, CH]), 6.62 (1H, dd, J 15.8 and
5.5, CH]), 7.22–7.35 (12H, m, ArH and 2ꢂPh), 7.71
(2H, d, J 8.2, ArH).
4.1.28. Boc–Gly–c[(E)-CH]CH]–L-Asp(OMe)–OH
[(3E,2R)-5-((tert-butoxy)carbonylamino)-2-((methoxy-
carbonyl)methyl)pent-3-enoic acid] 20. Mts–Gly–c[(E)-
CH]CH]–L-Asp(OMe)–OBn 19 (48.7 mg, 0.106 mmol,
the enantiomixture with 21, ee¼33%) was treated with
1 M TMSBr-thioanisole/TFA (2.5 cm3) in the presence of
m-cresol (0.122 cm3, 1.17 mmol) and 1,2-ethanedithiol
(0.050 cm3, 0.595 mmol) at 0 ꢀC with warming to rt for
15 h. After concentration with N2 gas, ice-cold Et2O was
added. The resulting precipitate was collected by centrifuga-
tion, and the precipitate was washed three times with Et2O,
and dissolved with H2O (0.150 cm3). The solution was
treated with 3 M (Boc)2O in THF (0.050 cm3) in the pres-
ence of Et3N (0.0334 cm3, 0.240 mmol) at 0 ꢀC with warm-
ing to rt for 15 h. The mixture was extracted with EtOAc, and
the extract was washed with saturated aq citric acid, brine
and dried over MgSO4. Concentration under reduced pres-
sure followed by chromatography over silica gel with
CH3Cl–MeOH (9:1) gave 14.0 mg (0.0487 mmol, 46%) of
4.1.31. Methyl (2E,2S,4S,5S)-4-(3-methyl-2-((phenyl-
methoxy)carbonylamino)butanoyloxy)-5-(((4-methyl-
phenyl)sulfonyl)amino)hex-2-enoate 23b. By use of a
procedure similar to that described for the preparation of
9a from 7, the (E)-enoate 7 (100 mg, 0.339 mmol) was con-
verted into the g-acyloxy-a,b-enoate 23b (83.2 mg,
0.152 mmol, 45%) by treatment with Cbz–L-Val–OH
(852 mg, 3.39 mmol) and CF3SO3TMS (0.0184 cm3,
0.102 mmol) in CH2Cl2 at rt for 15 h.
Compound 23b, colourless crystals, mp 51–52 ꢀC [from n-
hexane–Et2O (3:1)] (Found: C, 59.52; H, 6.44; N, 4.85.
C27H34N2O8S requires C, 59.32; H, 6.27; N, 5.12%); [a]D29
ꢁ49.0 (c 0.490, CHCl3); dH (600 MHz; CDCl3) 0.89 (3H,

9252
H. Tamamura et al. / Tetrahedron 63 (2007) 9243–9254
d, J 6.6, CMe), 1.00 (3H, d, J 6.8, CMe), 1.05 (3H, d, J 6.7,
CMe), 2.17–2.24 (1H, m, 3-H), 2.42 (3H, s, CMe), 3.61 (1H,
m, 5-H), 3.72 (3H, s, OMe), 4.30 (1H, dd, J 8.6 and 4.6, 2-H),
4.67 (1H, d, J 8.7, NH), 5.09–5.16 (2H, m, OCH2Ph), 5.19
(1H, m, NH), 5.37 (1H, br, 4-H), 5.92 (1H, d, J 15.7,
CH]), 6.66 (1H, dd, J 15.7 and 5.5, CH]), 7.29 (2H, d,
J 8.1, ArH), 7.32–7.36 (5H, m, Ph), 7.73 (2H, d, J 8.2, ArH).
Na2HPO4 (3.4 cm3) at 0 ꢀC, and the mixture was allowed
to warm to rt for 30 min. Concentration under reduced pres-
sure gave an oily residue, which was purified by chromato-
graphy over silica gel with n-hexane–EtOAc (1:3) to yield
152 mg (0.318 mmol, 84%) of compound 28 as colourless
crystals, mp 85–87 ꢀC [from n-hexane–Et2O (3:1)] (Found:
C, 67.50; H, 6.25; N, 5.67. C27H30N2O6 requires C, 67.77; H,
6.32; N, 5.85%); [a]2D3 ꢁ21.9 (c 1.097, CHCl3); dH
(600 MHz; CDCl3) 1.25–1.27 (3H, m, CMe), 1.91–1.96
(3H, br, CH2 and CHH), 2.28 (1H, br, CHH), 3.32 (2H, m,
CH2), 3.70 (3H, s, OMe), 3.87 (1H, br, 5-H), 4.25 (3H, br,
2-H, 4-H and 9-H), 4.33 (2H, br, CH2), 6.12 (1H, d, J
11.0, CH]), 6.82 (1H, br, NH), 6.90 (1H, d, J 12.7,
CH]), 7.30–7.34 (2H, m, ArH), 7.41 (2H, t, J 5.7, ArH),
7.60 (2H, d, J 7.0, ArH), 7.77 (2H, d, J 7.5, ArH).
4.1.32. Methyl (2E,2S,4S,5S)-4-(1-((fluoren-9-ylmethyl)-
oxycarbonyl)pyrrolidin-2-ylcarbonyloxy)-5-(((4-meth-
ylphenyl)sulfonyl)amino)hex-2-enoate 24. By use of a
procedure similar to that described for the preparation of
9a from 7, the (E)-enoate 7 (50 mg, 0.169 mmol) was
converted into the g-acyloxy-a,b-enoate 24 (73.9 mg,
0.117 mmol, 69%) by treatment with Fmoc–L-Pro–OH
(852 mg, 3.39 mmol) and CF3SO3TMS (0.0184 cm3,
0.102 mmol) in CH2Cl2 at rt for 6 h.
4.1.35. Fmoc–L-Pro–L-Ala–c[(E)-CH]CH]–D-Leu–
OMe 29. To a stirred solution of the g-hydroxy-a,b-enoate
28 (53.1 mg, 0.111 mmol) in CH2Cl2 (2 cm3) were added
dropwise MsCl (0.0859 cm3, 1.11 mmol) and Et3N
(0.153 cm3, 1.11 mmol) at 0 ꢀC, and the mixture was stirred
at this temperature for 3 h. To ice-cold saturated aq citric
acid was added the mixture followed by stirring for
10 min. The mixture was extracted with EtOAc, and the ex-
tract was washed successively with aq 5% citric acid and
brine and dried over MgSO4. Concentration under reduced
pressure gave an oily residue of the crude g-mesyloxy-
a,b-enoate, which was utilized for the next reaction without
purification.
Compound 24, colourless amorphous semisolid [Found
(FAB): (M+H)+, 633.2261. C34H37N2O8S requires M+H,
633.2270]; [a]2D0 ꢁ38.6 (c 1.346, CHCl3); dH (600 MHz;
CDCl3) 1.03 (3H, d, J 6.8, CMe), 1.93–2.32 (4H, m,
2ꢂCH2), 2.39 (3H, s, CMe), 3.51–3.66 (2H, m, CH2),
3.59–3.66 (1H, m, 5-H), 3.72 (3H, s, OMe), 4.29–4.38
(2H, m, CH2), 4.46 (1H, dd, J 8.6 and 3.9, 2-H), 4.58 (1H,
dd, J 10.4 and 6.5, 9-H), 5.04 (1H, d, J 9.1, NH), 5.42
(1H, m, 4-H), 5.96 (1H, dd, J 15.7 and 1.4, CH]), 6.72
(1H, dd, J 15.8 and 5.2, CH]), 7.20–7.43 (6H, m, ArH),
7.63–7.78 (6H, m, ArH); m/z (FABLRMS), 633 (MH+),
411, 296, 292 (base peak), 225, 179, 178 and 91.
To a stirred slurry of CuCN (79.9 mg, 0.888 mmol) in THF
i
4.1.33. Methyl (2E,2S,4S,5S)-4-(1-((fluoren-9-ylmethyl)-
oxycarbonyl)pyrrolidin-2-ylcarbonyloxy)-5-(((2,4,6-tri-
methylphenyl)sulfonyl)amino)hex-2-enoate 26. By use
of a procedure similar to that described for the preparation
of 9a from 7, the (E)-enoate 25 (723 mg, 2.24 mmol) was
converted into the g-acyloxy-a,b-enoate 26 (657 mg,
0.994 mmol, 44%) by treatment with Fmoc–L-Pro–OH
(5.20 g, 15.5 mmol) and CF3SO3TMS (0.121 cm3,
0.669 mmol) in CH2Cl2 at rt for 15 h.
(1 cm3) was added a solution of BuMgCl in THF (1.3 M,
0.683 cm3, 0.888 mmol) at ꢁ78 ꢀC under argon, and the
mixture was stirred at 0 ꢀC for 15 min. BF3$Et2O
(0.109 cm3, 0.888 mmol) was added to the above mixture
at ꢁ78 ꢀC. After 10 min of stirring at ꢁ78 ꢀC, a solution
of the crude g-mesyloxy-a,b-enoate in dry THF (2 cm3)
was added to the above mixture at ꢁ78 ꢀC under argon.
The stirring was continued at ꢁ78 ꢀC for 30 min followed
by quenching with saturated aq NH4Cl at 0 ꢀC. The mixture
was extracted with Et2O, and the extract was washed with
water and dried over MgSO4. Concentration under reduced
pressure gave a colourless oil, which was purified by chro-
matography over silica gel with n-hexane–EtOAc (1:1) to
yield 40.2 mg (0.0775 mmol, 70%) of 29 as colourless crys-
tals, mp 158–159 ꢀC [from EtOAc] (Found: C, 71.53; H,
7.38; N, 5.33. C31H38N2O5 requires C, 71.79; H, 7.16; N,
5.40%); [a]2D3 ꢁ22.8 (c 0.832, CHCl3); dH (600 MHz;
CDCl3) 0.87–0.89 (6H, br, 2ꢂCMe), 1.18 (3H, d, J 5.8,
CMe), 1.36 (1H, br, CH), 1.50 (1H, br, CHH), 1.60 (1H,
br, CHH), 1.92 (2H, br, CH2), 2.17 (2H, m, CH2), 3.07
(1H, br, 2-H), 3.43 (1H, br, CHH), 3.54 (1H, br, CHH),
3.64 (3H, s, OMe), 4.22–4.45 (4H, br, CH2, 2-H and 9-H),
4.52 (1H, br, 5-H), 5.45–5.54 (2H, br, 2ꢂCH]), 6.57 (1H,
br, NH), 7.30–7.33 (2H, m, ArH), 7.40 (2H, t, J 7.4, ArH),
7.59 (2H, d, J 3.8, ArH), 7.76 (2H, d, J 7.4, ArH).
Compound 26, colourless crystals, mp 77–79 ꢀC [from n-
hexane–Et2O (3:1)] (Found: C, 63.80; H, 6.11; N, 4.20.
C36H40N2O8S$H2O requires C, 63.70; H, 6.24; N, 4.13%);
[a]2D2 +14.88 (c 0.739, CHCl3); dH (600 MHz; CDCl3) 1.08
(3H, d, J 6.8, CMe), 1.92–2.17 (4H, m, 2ꢂCH2), 2.27 (3H,
s, CMe), 2.61 (6H, s, 2ꢂCMe), 3.50–3.57 (2H, m, CHH
and 5-H), 3.61–3.67 (1H, m, CHH), 3.70 (3H, s, OMe),
4.27–4.56 (4H, m, CH2, 2-H and 9-H), 5.08 (1H, d, J 9.3,
NH), 5.42 (1H, m, 4-H), 5.91 (1H, dd, J 15.7 and 1.5,
CH]), 6.64 (1H, dd, J 15.8 and 5.0, CH]), 6.89 (2H, s,
ArH), 7.30–7.33 (2H, m, ArH), 7.36–7.42 (2H, m, ArH),
7.65 (2H, t, J 7.2, ArH), 7.73–7.78 (2H, m, ArH).
4.1.34. Methyl (2E,2S,4S,5S)-5-((1-((fluoren-9-ylmethyl)-
oxycarbonyl)pyrrolidin-2-yl)carbonylamino)-4-hydroxy-
hex-2-enoate 28. The g-acyloxy-a,b-enoate 26 (250 mg,
0.378 mmol) was treated with 1 M TMSBr-thioanisole/
TFA (12.5 cm3) in the presence of m-cresol (0.610 cm3,
5.83 mmol) at 0 ꢀC with warming to rt for 15 h. After
thorough concentration under reduced pressure, the residue
27 was dissolved with CH3CN (20 cm3). To the solution
was added dropwise PBS (20 cm3) and saturated aq
4.1.36. Methyl (2E,4S,5S)-5-(((4-methylphenyl)sulfonyl)-
amino)-4-(phenylsulfonyloxy)hex-2-enoate resin 30. The
(E)-enoate 7 (1.05 g, 3.56 mmol) was treated with MP–
Ts–OH resin (Argonaut Technologies, California, U.S.A.,
1.27 mmol/g, 933 mg, 1.19 mmol) in CH2Cl2 (12 cm3) at
rt, and the mixture was stirred for 15 h. The resin was filtered

H. Tamamura et al. / Tetrahedron 63 (2007) 9243–9254
9253
and washed with dried THF (1 cm3ꢂ7) to give resin-bound
enoate 30 (1.26 g). The filtrate was concentrated under re-
duced pressure and chromatographed by flash column over
silica gel with n-hexane–EtOAc (4:1) to recover excess of
7 (0.84 g, 2.84 mmol).
1986, 1133–1136; (c) Tanner, D.; Somfai, P. Tetrahedron Lett.
1987, 28, 1211–1214; (d) Matsubara, S.; Kodama, T.; Utimoto,
K. Tetrahedron Lett. 1990, 31, 6379–6380; (e) Legters, J.;
Willems, J. G. H.; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim.
Pays-Bas 1992, 111, 59–68; (f) Tanner, D.; He, H. M.; Somfai,
P. Tetrahedron 1992, 48, 6069–6078; (g) Kawabata, T.; Kiryu,
Y.; Sugiura, Y.; Fuji, K. Tetrahedron Lett. 1993, 34, 5127–
5130; (h) Church, N. J.; Young, D. W. Tetrahedron Lett. 1995,
36, 151–154 and references cited therein; (i) Burgaud,
B. G. M.; Horwell, D. C.; Padova, A.; Pritchard, M. C.
Tetrahedron 1996, 52, 13035–13050; (j) Rayner, C. M. Synlett
1997, 11–21; (k) Ohno, H.; Mimura, N.; Otaka, A.;
Tamamura, H.; Fujii, N.; Ibuka, T.; Shimizu, I.; Satake, A.;
Yamamoto, Y. Tetrahedron 1997, 53, 12933–12946; (l)
Cantrill, A. A.; Osborn, H. M. I.; Sweeney, J. Tetrahedron
1998, 54, 2181–2208; (m) Fleming, I.; Frackenpohl, J.; Ila, H.
J. Chem. Soc., Perkin Trans. 1 1998, 1229–1235; (n) Bongini,
A.; Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. J. Chem.
Soc., Perkin Trans. 1 1986, 1339–1344; (o) Bongini, A.;
Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. J. Chem.
Soc., Perkin Trans. 1 1986, 1345–1349; (p) Evans, D. A.; Faul,
M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M.
J. Am. Chem. Soc. 1993, 115, 5328–5329; (q) Coldham, I.;
Collis, A. J.; Mould, R. J.; Rathmell, R. E. J. Chem. Soc.,
Perkin Trans. 1 1995, 2739–2745; (r) Davis, F. A.; Reddy,
G. V. Tetrahedron Lett. 1996, 37, 4349–4352; (s) Davis, F. A.;
Zhou, P. Tetrahedron Lett. 1994, 35, 7525–7528.
4.1.37. Ts–L-Ala–c[(E)-CH]CH]-D-Leu–OMe [methyl
(2E,2S,5S)-5-(((4-methylphenyl)sulfonyl)amino)-2-(2-
methylpropyl)hex-3-enoate] 31. To a stirred slurry of
CuCN (122 mg, 1.35 mmol) in THF (3 cm3) was added a so-
lution of iBuMgCl in THF (1.2 M, 1.13 cm3, 1.35 mmol) at
ꢁ78 ꢀC under argon, and the mixture was stirred at 0 ꢀC for
15 min. BF3$Et2O (0.167 cm3, 1.35 mmol) was added to the
above mixture at ꢁ78 ꢀC. After 10 min of stirring at ꢁ78 ꢀC,
the dried resin-bound enoate 30 (180 mg) was added to the
above mixture at ꢁ78 ꢀC. The stirring was continued at
ꢁ78 ꢀC for 30 min and then at 0 ꢀC for 15 h followed by
quenching with 2 cm3 of saturated aq NH4Cl-aq 28%
NH4OH (1:1 (v/v)). The mixture was extracted with Et2O,
and the extract was washed with water and dried over
MgSO4. Concentration under reduced pressure gave a col-
ourless oil, which was purified by chromatography over
silica gel with n-hexane–EtOAc (5:1) to yield 22.4 mg
(0.0634 mmol, 37% based on 7) of 31 accompanied with
its 2R-isomer.
Compound 31, colourless oil [Found (FAB): (M+H)+,
354.1746. C18H28NO4S requires M+H, 354.1739]; [a]D27
ꢁ7.14 (c 1.680, CHCl3); D3+2.833 (227 nm, isooctane);
dH (600 MHz; CDCl3) 0.81–0.86 (6H, m, 2ꢂCMe), 1.17
(3H, d, J 6.8, CMe), 1.19–1.24 (1H, m, CHH), 1.37–1.42
(1H, m, CH), 1.48–1.55 (1H, m, CHH), 2.43 (3H, s, CMe),
2.95 (1H, q, J 7.9, 2-H), 3.65 (3H, s, OMe), 3.85–3.95
(1H, m, 5-H), 4.40 (1H, d, J 7.6, NH), 5.33–5.37 (1H, m,
CH]), 5.40–5.45 (1H, m, CH]), 7.23–7.30 (2H, m,
ArH), 7.72–7.74 (2H, m, ArH); m/z (FABLRMS), 354
(MH+, base peak), 352, 338, 322, 294, 198, 183, 155, 123.
2. (a) Tamamura, H.; Yamashita, M.; Muramatsu, H.; Ohno, H.;
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4. (a) Kaltenbronn, J. S.; Hudspeth, J. P.; Lunney, E. A.;
Michniewicz, B. M.; Nicolaides, E. D.; Repine, J. T.; Roark,
W. H.; Stier, M. A.; Tinney, F. J.; Woo, P. K. W.; Essenburg,
A. D. J. Med. Chem. 1990, 33, 838–845; (b) Tourwe, D.;
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Bioorg. Med. Chem. Lett. 1993, 3, 1609–1614; (e) Wai, J. S.;
Bamberger, D. L.; Fisher, T. E.; Graham, S. L.; Smith, R. L.;
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947; (f) Bartlett, P. A.; Otake, A. J. Org. Chem. 1995, 60,
3107–3111; (g) Tamamura, H.; Hiramatsu, K.; Miyamoto,
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Chem. Lett. 2002, 12, 923–928; (h) Tamamura, H.; Koh, Y.;
Ueda, S.; Sasaki, Y.; Yamasaki, T.; Aoki, M.; Maeda, K.;
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Hiramatsu, H.; Ueda, S.; Wang, Z.; Kusano, S.; Terakubo, S.;
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Acknowledgements
The authors thank Prof. Yoshihisa Miwa, Faculty of Pharma-
ceutical Sciences, Hiroshima-International University, and
Dr. Motoo Shiro, Rigaku International Corporation, for X-
ray analysis. This work was supported in part by a 21st
Century COE Programme ‘Knowledge Information Infra-
structure for Genome Science’ a grant-in-aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan, the Japan Health Science
Foundation and the Mochida Memorial Foundation for
Medical and Pharmaceutical Research.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.06.029.
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