Regiospecific ring-opening reactions of β-aziridinyl ct, β-enoates with acids: Application to the stereoselective synthesis of a couple of diastereoisomeric (Zi)-alkene dipeptide isosteres from a single β-aziridinyl a, β-enoate and to the convenient preparation of amino alcohols bearing a, β-unsaturated ester groups

Article abstract of DOI:10.1039/a904671b

Regio- and stereo-selective ring-opening reactions of N-(2, 4, 6-trimethylphenylsulfonyl)-γ, δ-cis- or trans-γ, δ-epimino (E)-α, β-enoates with acids such as methanesulfonic acid (MSA) or trifluoroacetic acid (TFA) have been found. These ring-opening reactions are useful for the stereoselective synthesis of a couple of diastereomeric (￡)-alkene dipeptide isosteres from a single substrate of γ, δ-epimino (E)-α, β-enoate, and for the convenient preparation of δ-aminated γ-hydroxy α, β-enoates. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a904671b

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Regiospecific ring-opening reactions of ꢀ-aziridinyl ꢁ,ꢀ-enoates
with acids: application to the stereoselective synthesis of a couple
of diastereoisomeric (E)-alkene dipeptide isosteres from a single
ꢀ-aziridinyl ꢁ,ꢀ-enoate and to the convenient preparation of amino
alcohols bearing ꢁ,ꢀ-unsaturated ester groups
Hirokazu Tamamura,* Masaki Yamashita, Yutaka Nakajima, Kyoko Sakano, Akira Otaka,
Hiroaki Ohno, Toshiro Ibuka and Nobutaka Fujii*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku,
Kyoto 606-8501, Japan
Received (in Cambridge) 11th June 1999, Accepted 12 July 1999
Regio- and stereo-selective ring-opening reactions of N-(2,4,6-trimethylphenylsulfonyl)-γ,δ-cis- or -trans-γ,δ-epimino
(E)-α,β-enoates with acids such as methanesulfonic acid (MSA) or trifluoroacetic acid (TFA) have been found. These
ring-opening reactions are useful for the stereoselective synthesis of a couple of diastereomeric (E)-alkene dipeptide
isosteres from a single substrate of γ,δ-epimino (E)-α,β-enoate, and for the convenient preparation of δ-aminated
γ-hydroxy α,β-enoates.
be extremely valuable (Scheme 1). One advantage of such a
strategy is that three other stereoisomeric enoates 5, 6, and 7
Introduction
The potential of (E)-alkene dipeptide isosteres as backbone
replacements of amide bonds in peptides has been well docu-
mented among various dipeptide isosteres in the past few
years.1 We 2 and others3 have recently reported that peptides
containing (E)-alkene isosteres can exhibit potent biological
activities. In order to facilitate structure–activity relationship
studies on such peptide-lead candidates, development of new
efficient methodology for the synthesis of (E)-alkene isosteres is
needed. Since it has been reported that the stereochemistry at
the α-position and the (E)-configuration are important for
biological activity, the stereocontrolled synthesis of both
isomers of types 2 and 4 from a single substrate of type 1 would
can be convergently transformed into the enoate 1 by exposure
to a palladium(0)-catalyst (Scheme 1).4 We and others reported
previously the two synthetic methods for diastereomerically
pure (E)-alkene isosteres 2 and 8 by employing organocopper-
mediated anti-SN2Ј reactions of β-aziridinyl α,β-enoate 15 and
δ-aminated γ-mesyloxy α,β-enoate 9,6 respectively.
As part of our investigations of peptide scaffold designs
related to structure–activity relationship studies, we are particu-
larly interested in ring-opening reactions of enoates of type 1
for the preparation of key intermediates 3 for the synthesis of
dipeptide surrogates 4. In this paper, we detail the regio- and
stereo-specific ring-opening reactions of β-aziridinyl α,β-
Scheme 1 R1, R2 = alkyl; Ar = 4-methylphenyl or 2,4,6-trimethylphenyl, Ms = methanesulfonyl.
J. Chem. Soc., Perkin Trans. 1, 1999, 2983–2996
This journal is © The Royal Society of Chemistry 1999
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Scheme 2 Reagents: i, CH3SO3H; ii, CF3CO2H; iii, 2,2-dimethoxypropane, pyridinium toluene-p-sulfonate; Mts = 2,4,6-trimethylphenylsulfonyl.
enoates by methanesulfonic acid (MSA) and the stereoselective
synthesis of (E)-alkene dipeptide isosteres by treatment of
the ring-opened products with organocopper reagents.7 In
addition, we also report our finding of similar ring-opening
reactions by trifluoroacetic acid (TFA) and the application
of such reactions to a convenient synthesis of homochiral
δ-aminated γ-hydroxy α,β-enoates, such as a versatile building
block for sphingosine synthesis.
SN2 ring-opening reaction at the γ-carbon position. Further-
more, we investigated the feasibility of the ring-opening
reactions by TFA treatment. The cis-(E)-enoate 10 was exposed
to TFA at rt for 15 h to afford exclusively the δ-aminated
γ-trifluoroacetoxy α,β-enoate 12. Hydrolysis of 12 and silica gel
flash chromatographic purification yielded the δ-aminated
γ-hydroxy α,β-enoate 13 in 93% yield based on 10 (Scheme 2). It
was found that the MSA-mediated ring-opening reaction
proceeded much faster than the reaction involving TFA. In
both cases, ring-opened products generated by nucleophilic
attack at the α- or δ-carbon position could not be detected.
Regiochemical assignments for the mesyl ester 11 and the
trifluoroacetate 12 were readily made by 1H-NMR (1H–1H
COSY). The γ,δ-syn stereochemistry of the ring-opened prod-
uct 13 was confirmed by transformation of 13 into the original
substrate 10 using the Mitsunobu conditions.13 Since the mesyl
compound 11 was prone to regenerate the original substrate 10
during silica gel flash chromatographic purification, it could not
be isolated in an analytically pure form.
Next, ring-opening of three other stereoisomeric enoates 14,
18 and 19, which were previously synthesized from L-valine,4
was investigated. Regiospecific ring-opening was successfully
carried out on the trans-(E)-isomer of the aziridine enoate 14
with MSA or TFA treatment in a similar manner, yielding 15 or
17, respectively (the isolated yield of 17 based on 14: 91%). In
both cases, ring-opened products generated by nucleophilic
attack at the α- or δ-carbon position could not be detected.
Regiochemical assignments for the mesyl ester 15 and the
trifluoroacetate 16 were readily made by 1H–1H COSY. The γ,δ-
anti stereochemistry of the ring-opened product 17 was
confirmed by transformation of 17 into the original substrate
14 using the Mitsunobu conditions.13 Furthermore, stereo-
The focus of this paper deals with regiospecific ring-
opening reactions of β-aziridinyl α,β-enoates and their appli-
cations.
Results and discussion
Ring-opening reactions of N-(2,4,6-trimethylphenylsulfonyl)
(Mts)-ꢂ,ꢃ-epimino ꢁ,ꢀ-enoates with MSA or TFA
Although there exist ample precedents demonstrating that
various nucleophiles,8 containing acids such as acetic acid,9
TFA10 and toluene-p-sulfonic acid in aqueous acetone,11 attack
simple N-activated or inactivated aziridines12 at either of two
carbon atoms, yielding the corresponding ring-opened
products, the practically useful reactions involving γ,δ-epimino
α,β-enoates of type 1 with MSA or TFA have not been reported
heretofore. We initially examined ring-opening reactions by
MSA treatment of N-(2,4,6-trimethylphenylsulfonyl) (Mts)-
protected (and activated) aziridines bearing α,β-unsaturated
esters4,5 (Scheme 2). Exposure of the N-Mts-γ,δ-cis-γ,δ-
epimino (E)-α,β-enoate 10, which was previously synthesized
from -valine,4 to MSA (10 equiv.) in CHCl3 at rt for 20 min
afforded exclusively δ-aminated γ-mesyloxy α,β-enoate 11 in
essentially quantitative yield, presumably via the regioselective
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Scheme 3 (a) Reagents: i, DIBAL; ii, oxalyl dichloride, DMSO, DIPEA; iii, vinylMgCl; iv, TFA; v, Mts-Cl, Et3N; vi, Ph3P, DEAD; vii, O3, dimethyl
sulfide; viii, Ph3P᎐CHCO2Me; ix, Pd(PPh3)4; (b) Reagents: i, TFA; ii, Mts-Cl, Et3N; iii, Ph3P, DEAD; iv, O3, dimethyl sulfide; v, Ph3P᎐CHCO2Bn; vi,
᎐
᎐
Pd(PPh3)4; (c) Reagents: i, Mts-Cl, Et3N; ii, HOBt, WSCD, N,O-dimethylhydroxylamine hydrochloride; iii, DIBAL; iv, vinylMgCl; v, Ph3P, DEAD;
vi, O3, dimethyl sulfide; vii, Ph3P᎐CHCO2Bn; viii, Pd(PPh3)4; (d) Reagents: i, vinylMgCl; ii, TFA, H2O; iii, Mts-Cl, DIPEA; iv, BnBr, NaH; v, Ph3P,
᎐
DEAD; vi, O3, dimethyl sulfide; vii, (EtO)2P(O)CH2CONHMe, DIPEA; viii, Pd(PPh3)4; ix, Ph3P᎐CHCO2Me.
᎐
chemical assignments for diastereomers 13 and 17 were also
easily established by conversion to the acetonide derivatives 20
and 21, respectively. The NOE data by NMR analyses of 20
and 21 are in good agreement with their stereochemistry. On the
other hand, attempted treatment of the cis-(Z)-enoate 18 and
the trans-(Z)-enoate 19 with MSA or TFA failed to afford the
desired ring-opened products and, instead, gave complex
mixtures containing the γ-butenolactones, 22 and 23, respect-
ively. This clearly demonstrates that a slight difference in the
structure of the substituents can significantly change the
reaction route. Since the enoates 18 and 19 can be converted
into the enoate 10 via Pd(0)-catalyzed reactions,4 this ring-
opening reaction incurs no significant problems in terms of
its practical use for the preparation of (E)-alkene isosteres,
although our methodology is not applicable to the synthesis of
(Z)-alkene isosteres.
Synthesis of the other requisite N-Mts-ꢂ,ꢃ-cis-ꢂ,ꢃ-epimino (E)-
ꢁ,ꢀ-enoates (enamides)
As shown in Scheme 3, the diastereomerically pure N-Mts-γ,δ-
cis-γ,δ-epimino (E)-α,β-enoates (enamides) 31, 36, 44, 54 and
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55, which were required for the synthesis of (E)-alkene
dipeptide isosteres (amino alcohols), were readily prepared
according to the known methods.4,5 Boc-D-Phe-OMe 24 was
treated successively with diisobutylaluminium hydride
(DIBAL), oxalyl dichloride– dimethyl sulfoxide (DMSO)–N,N-
diisopropylethylamine (DIPEA) and vinylmagnesium chloride
to give a separable 6:1 mixture of allyl alcohols 27 and 28.
Exposure of 27 to TFA followed by successive treatments with
Mts-Cl in the presence of triethylamine (Et3N), triphenyl-
phosphine–diethyl azodicarboxylate (DEAD), ozone, dimethyl
sulfide and [(methoxycarbonyl)methylene]triphenylphosphor-
ane afforded a mixture of the (2E)- and (2Z)-enoate 31 and 32.
By a palladium(0)-catalyzed reaction,4 a mixture of 31 and 32
was converted into the cis-(E)-enoate 31 (for details, see
Experimental section). Likewise, the allyl alcohol 33, which was
previously synthesized,4 was treated successively with TFA,
Mts-Cl–Et3N, Ph3P–DEAD, ozone, dimethyl sulfide, [(benzyl-
oxycarbonyl)methylene]triphenylphosphorane and Pd(PPh3)4
to give the cis-(E)-enoate 36. Nε-2-Chlorophenylmethoxy-
carbonyl (Cl-Z)-protected Lys 37 was also successively treated
with Mts-Cl–Et3N, 1-hydroxybenzotriazole (HOBt)–3-[3-(di-
methylamino)propyl]-1-ethylcarbodiimide (WSCD)–N,O-di-
methylhydroxylamine hydrochloride, DIBAL, vinylmagnesium
chloride, Ph3P–DEAD, ozone, dimethyl sulfide, [(benzyloxy-
carbonyl)methylene]triphenylphosphorane and Pd(PPh3)4 to
yield the cis-(E)-enoate 44. N-Boc-(S)-serinal acetonide 45 was
successively treated with vinylmagnesium chloride, TFA–H2O,
Mts-Cl–DIPEA, benzyl bromide–sodium hydride and Ph3P–
DEAD to give a diastereomixture of vinylaziridines 52 and 53.
Reaction of the mixture of 52 and 53 with ozone, dimethyl
sulfide, N-methyl(diethylphosphono)acetamide–DIPEA and
Pd(PPh3)4 gave the cis-(E)-enamide 54. Likewise, reaction of
the mixture of 52 and 53 with ozone, dimethyl sulfide,
[(methoxycarbonyl)methylene]triphenylphosphorane and Pd-
(PPh3)4 gave the cis-(E)-enoate 55. The configuration of the
γ- and δ-carbon centers and the (E)-stereochemistry for the
double bonds in the above N-Mts-γ,δ-epimino α,β-enoates
(enamide) were assigned on the basis of the NOE data and the
coupling constants by NMR analyses.5
isosteres were stereoselectively synthesized from either the cis-
or trans-(E)-enoate.
We evaluated the applicability of this synthetic methodology
to diverse aziridine cis-(E)-enoates, such as -amino acid-
derived aziridines and aziridines bearing other functional
groups. In the same manner as described above, the cis-(E)-
enoate 31, which was derived from -Phe, afforded the
corresponding ,-type isostere, Mts--Phe-ψ[(E)-CH᎐CH]-
᎐
L-Leu-OMe, 59 or the ,-type isostere, Mts--Phe-ψ[(E)-
CH᎐CH]--Leu-OMe, 60 by treatment with MSA and
᎐
BuiCu(CN)MgClؒBF3 or BuiCu(CN)MgClؒ2LiCl, respectively.
The benzyl ester-bearing aziridine 36 gave the corresponding
,-type isostere, Mts--Leu-ψ[(E)-CH᎐CH]--Phe-OBn, 62 or
᎐
the ,-type isostere, Mts--Leu-ψ[(E)-CH᎐CH]--Phe-OBn,
᎐
63 in a similar manner using MSA and BnCu(CN)MgClؒBF3 or
BnCu(CN)MgClؒ2LiCl, respectively. The cis-(E)-enoate 44
derived from -lysine, which possesses the Nε-(Cl-Z)-protected
amino group and the benzyl ester group, was also converted
into the isostere, Mts--Lys(Cl-Z)-ψ[(E)-CH᎐CH]--Ala-OBn,
᎐
65 or Mts--Lys(Cl-Z)-ψ[(E)-CH᎐CH]--Ala-OBn, 66 by treat-
᎐
ment with MSA and MeCu(CN)LiؒLiBrؒBF3 or MeCu(CN)Liؒ
LiBrؒ2LiCl, respectively. The cis-(E)-enamide 54 derived from
-serine, which possesses the benzyl ether group and the N-
methyl amide group, afforded the corresponding amide-type
isostere, Mts--Ser(O-Bn)-ψ[(E)-CH᎐CH]--Ala-NHMe, 68 or
᎐
Mts--Ser(O-Bn)-ψ[(E)-CH᎐CH]--Ala-NHMe, 69 by treat-
᎐
ment with MSA and MeCu(CN)LiؒLiBrؒBF3 or MeCu(CN)Liؒ
LiBrؒ2LiCl, respectively. These results suggest that this syn-
thetic method is widely applicable to various aziridinyl cis-(E)-
enoates and enamides. The (E)-geometry of the double bond in
the obtained isosteres 56, 57, 59, 60, 62, 63, 65, 66, 68 and 69
was assigned on the basis of the coupling constant of the two
olefinic protons by 1H-NMR analyses. The absolute config-
uration of the α-alkylated carbon centers in the above isosteres
was well characterized by circular dichroism (CD) measure-
ments.5,6
Synthesis of a key intermediate compound for the preparation of
sphingosines using the ring-opening reaction with TFA
The sphingosines are important constituents of cell membranes,
which participate in cell recognition phenomena such as growth,
differentiation and immune responses. The sphingosines 72 and
73 are long-chain amino alcohols, and there have been many
Synthesis of (E)-alkene dipeptide isosteres using the ring-opening
reaction with MSA
We examined the feasibility of the stereoselective synthesis of
(E)-alkene dipeptide isosteres by treatment of the ring-opened
products with organocopper reagents. Treatment of the above
mesyl compound 11, which was prepared from the cis-(E)-
enoate 10 by the MSA-mediated ring-opening reaction, with
BnCu(CN)MgClؒBF3 (4 equiv.) in THF at Ϫ78 ЊC for 30 min
yielded the protected (-amino acid, -amino acid)-type
(2S,5S) dipeptide isostere, Mts--Val-ψ[(E)-CH᎐CH]--Phe-
᎐
OMe, 56 in 94% yield based on 10 (diastereoselection > 99:1
from NMR analysis). This reaction occurred by an anti-SN2Ј
mechanism as shown in Scheme 4. In contrast, an anti-SN2Ј
reaction of the cis-(E)-enoate 10 with BnCu(CN)MgClؒ2LiCl
(4 equiv.) in THF at Ϫ78 ЊC for 30 min afforded the ,-type
reports on their syntheses.10b,14 One important factor in the
asymmetric synthesis of -erythro- and -threo-sphingosine 72
and 73 is the stereocontrol in the preparation of the 1,2-amino
alcohol. We investigated the feasibility of the stereocontrolled
preparation of a key intermediate compound for the sphing-
osine synthesis using the TFA-mediated ring-opening reaction
of a β-aziridinyl α,β-enoate. Exposure of the enoate 55 to TFA
at rt for 15 h afforded δ-aminated γ-trifluoroacetoxy α,β-enoate
70 by the regiospecific SN2 ring-opening reaction. The following
hydrolysis of 70 yielded the δ-aminated γ-hydroxy α,β-enoate
71 in 71% yield based on 55 (Scheme 5). The amino alcohol 71
is a key intermediate compound for the -threo-sphingosine 73
synthesis, and can be also converted into -erythro-sphingosine
72 by suitable replacement of the Nα-protecting group and
inversion of stereochemistry of the γ-hydroxy group using
the Mitsunobu reaction.13 This result suggests that the
TFA-mediated ring-opening reaction is useful for the conven-
ient synthesis of the diastereomerically pure δ-aminated
(2R,5S) isostere, Mts--Val-ψ[(E)-CH᎐CH]--Phe-OMe, 57 in
᎐
75% yield as shown in Scheme 4. The most important factor of
the MSA-mediated ring-opening reactions is the inversion of
configuration at the C-γ carbon via an SN2 mechanism. Thus,
cis-(E) enoates lead to syn-(E)-mesyl esters, which are converted
into ,-type isosteres upon treatment with organocopper
reagents. On the other hand, cis-(E)-enoates themselves pro-
duce ,-type isosteres with organocopper reagents. In a com-
parative experiment, the trans-(E)-enoate 14 was treated with
MSA to afford the anti-(E)-mesyl compound 15, which was
converted into the ,-type isostere 57 with the organocopper
reagent in 89% yield based on 14. In contrast, treatment of the
trans-(E)-enoate 14 with the organocopper reagent afforded the
,-type isostere 56 in 77% yield. Taken together, two types of
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Scheme 4 Reagents: i, CH3SO3H; ii, BnCu(CN)MgClؒBF3; iii, BnCu(CN)MgClؒ2LiCl; iv, BuiCu(CN)MgClؒBF3; v, BuiCu(CN)MgClؒ2LiCl; vi,
MeCu(CN)LiؒLiBrؒBF3; vii, MeCu(CN)LiؒLiBrؒ2LiCl.
dipeptide isosteres from a single substrate of either a γ,δ-cis- or
-trans-γ,δ-epimino (E)-α,β-unsaturated ester. ,-Type and ,-
type (E)-alkene dipeptide isosteres are also of comparable use
to ,-type and ,-type isosteres in the field of medicinal
chemistry. γ,δ-Epimino α,β-unsaturated esters can be easily
prepared as a mixture of the cis-(E)-, cis-(Z)-, trans-(E)- and
trans-(Z)-isomers from the corresponding chiral amino alde-
hydes. Pd(0)-catalyzed equilibration reactions of various ster-
eomers of γ,δ-epimino α,β-enoates could afford predominantly
cis-(E)-isomers in high yields.4 Upon treatment with organo-
copper reagents, these would exclusively provide ,-type (or
,-type) (E)-alkene isosteres. Based on the above results, brief
MSA treatment of cis-(E)-γ,δ-epimino α,β-unsaturated esters,
gives γ,δ-syn-δ-aminated γ-mesyloxy (E)-α,β-enoates, which
can be converted into ,-type (or ,-type) (E)-alkene iso-
steres via organocopper–BF3-mediated anti-SN2Ј reactions.
Taken together, the completely stereocontrolled synthetic
process for ,-type, ,-type, ,-type and ,-type (E)-alkene
dipeptide isosteres starting from -amino acid or -amino acid
has been established. Furthermore, the TFA-mediated ring-
opening reactions of cis-(E)-enoates have provided a useful
methodology for the stereoselective synthesis of δ-aminated
γ-hydroxy α,β-enoates such as a key intermediate compound
for the sphingosine synthesis. Many of the existing method-
Scheme 5 Reagents and conditions: i, TFA; ii, hydrolysis.
γ-hydroxy α,β-enoates as the key intermediates for several
bioactive compounds.
In conclusion, regio- and stereo-specific ring-opening reac-
tions of N-Mts-protected aziridines bearing α,β-unsaturated
esters [cis-(E)- and trans-(E)-isomers] by MSA or TFA have
been found. The MSA-mediated ring-opening reactions provide
a useful approach to the stereoselective synthesis of both
,-type (or ,-type) and ,-type (or ,-type) (E)-alkene
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ologies for the synthesis of sphingosines are accompanied by
difficulties in 1,2-amino alcohol stereocontrol.10b,14 However,
our procedure lacks such stereocontrol problems, since TFA-
mediated stereoselective ring-opening reactions of β-aziridinyl
α,β-enoates are unequivocally related to the stereochemistry of
1,2-amino alcohol construction.
5.0, CH᎐) and 6.90 (2 H, s, ArH); m/z (FAB-LRMS) 392
᎐
(MNaϩ), 370 (MHϩ), 254, 183, 167, 119, 91 (base peak) and 72.
Methyl (2E,4R,5S)-6-methyl-4,5-[N-(2,4,6-trimethylphenyl-
sulfonyl)epimino]hept-2-enoate 10 from 13 (confirmation of the
ꢂ,ꢃ-threo stereochemistry of 13)
Ph3P (13.4 mg, 0.0512 mmol) and DEAD (0.0202 cm3 of a 40%
solution in toluene, 0.0512 mmol) were added to a stirred solu-
tion of the alcohol 13 (17.2 mg, 0.0466 mmol) in 0.2 cm3 of
THF at 0 ЊC, and the mixture was stirred at this temperature for
30 min. The mixture was concentrated under reduced pressure
to give an oil, which was purified by flash chromatography over
silica gel with n-hexane–EtOAc (3:1) to yield 11.5 mg (0.0327
mmol, 70%) of compound 10, colourless crystals, mp 76–78 ЊC
[from n-hexane–Et2O (3:1)] (Found: C, 61.26; H, 7.18; N, 3.91.
C18H25NO4S requires C, 61.51; H, 7.17; N, 3.99%); [α]D18 Ϫ78.0
(c 0.407 in CHCl3); δH(270 MHz; CDCl3) 0.79 (3 H, d, J 6.6,
CMe), 0.87 (3 H, d, J 6.9, CMe), 1.42 (1 H, m, 6-H), 2.31 (3 H,
s, CMe), 2.66 (1 H, dd, J 10.2 and 7.3, 5-H), 2.70 (6 H, s, CMe),
3.48 (1 H, t, J 7.1, 4-H), 3.74 (3 H, s, OMe), 6.09 (1 H, dd, J 15.5
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 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 rotations were measured in CHCl3 with a JASCO DIP-
360 digital polarimeter. CD spectra were measured in isooctane
(2,2,4-trimethylpentane) at 24 ЊC with a JASCO J-720 spectro-
polarimeter. IR spectra were obtained on a Shimadzu Model
IR-400 spectrometer. Mps were measured by a hot stage
melting point apparatus and are uncorrected. For flash chrom-
atography, silica gel 60 H (silica gel for thin-layer chrom-
atography, Merck) and Wakogel C-200 (silica gel for column
chromatography) were employed.
and 1.0, CH᎐), 6.72 (1 H, dd, J 15.5 and 6.6, CH᎐) and 6.96
᎐
᎐
(2 H, s, ArH).
Reaction of methyl (2E,4S,5S)-6-methyl-4,5-[N-(2,4,6-tri-
methylphenylsulfonyl)epimino]hept-2-enoate 14 with MSA in
CHCl3
Reaction of methyl (2E,4R,5S)-6-methyl-4,5-[N-(2,4,6-trimeth-
ylphenylsulfonyl)epimino]hept-2-enoate 10 with MSA in CHCl3
By use of a procedure similar to that described for the prepar-
ation of 11 from 10, the trans-(E)-enoate 14 (120 mg, 0.342
mmol) was converted into the γ-mesyloxy-α,β-enoate 15 (col-
ourless oil) by treatment with MSA in CHCl3.
Compound 15, colourless oil (crude), δH(270 MHz; CDCl3)
0.79 (3 H, d, J 6.9, CMe), 0.93 (3 H, d, J 6.9, CMe), 1.85 (1 H,
m, 6-H), 2.30 (3 H, s, CMe), 2.64 (6 H, s, CMe), 2.92 (3 H, s,
SMe), 3.40 (1 H, m, 5-H), 3.76 (3 H, s, OMe), 4.80 (1 H, d, J 9.6,
To a stirred solution of the cis-(E)-enoate 10 (151 mg, 0.430
mmol) in CHCl3 (4.3 cm3) was added dropwise MSA (0.279
cm3, 4.30 mmol) at rt with stirring, and the stirring was con-
tinued for 20 min. The mixture was extracted with EtOAc and
the extract was washed successively with 5% citric acid, water,
5% NaHCO3 and water, and dried over MgSO4. Concentration
under reduced pressure gave the crude mesyl compound 11, as a
colourless oil (crude), δH(270 MHz; CDCl3) 0.85 (3 H, d, J 6.6,
CMe), 0.89 (3 H, d, J 6.6, CMe), 1.88 (1 H, m, 6-H), 2.29 (3 H,
s, CMe), 2.66 (6 H, s, CMe), 3.02 (3 H, s, SMe), 3.40 (1 H, m,
5-H), 3.71 (3 H, s, OMe), 4.83 (1 H, d, J 9.6, NH), 5.27 (1 H, m,
NH), 5.35 (1 H, m, 4-H), 6.07 (1 H, dd, J 15.8 and 1.7, CH᎐),
᎐
6.80 (1 H, dd, J 15.8 and 5.6, CH᎐) and 6.96 (2 H, s, ArH); m/z
᎐
(FAB-LRMS) 448 (MHϩ), 446, 352, 254, 183 (base peak) and
119.
Reaction of methyl (2E,4S,5S)-6-methyl-4,5-[N-(2,4,6-tri-
methylphenylsulfonyl)epimino]hept-2-enoate 14 with TFA
4-H), 6.03 (1 H, dd, J 15.5 and 1.3, CH᎐), 6.72 (1 H, dd, J 15.5
᎐
and 6.0, CH᎐) and 6.93 (2 H, s, ArH); m/z (FAB-LRMS) 448
᎐
(MHϩ), 446, 352, 254, 183, 167, 119 and 91 (base peak).
By use of a procedure similar to that described for the prepar-
ation of 12 from 10, the trans-(E)-enoate 14 (139 mg, 0.396
mmol) was converted into the γ-trifluoroacetoxy-α,β-enoate 16
(colourless oil) by treatment with TFA. Hydrolysis, and purifi-
cation by flash chromatography gave the hydrolysate 17 (133.3
mg, 0.361 mmol, 91% yield) as a colourless oil.
Compound 16, colourless oil (crude), δH(270 MHz; CDCl3)
0.83 (3 H, d, J 6.6, CMe), 0.87 (3 H, d, J 7.0, CMe), 1.85 (1 H,
m, 6-H), 2.30 (3 H, s, CMe), 2.59 (6 H, s, CMe), 3.51 (1 H, m,
5-H), 3.77 (3 H, s, OMe), 4.97 (1 H, d, J 9.5, NH), 5.53 (1 H, m,
Reaction of methyl (2E,4R,5S)-6-methyl-4,5-[N-(2,4,6-tri-
methylphenylsulfonyl)epimino]hept-2-enoate 10 with TFA
The cis-(E)-enoate 10 (108 mg, 0.306 mmol) was dissolved in
TFA (1 cm3) at rt and the solution was stirred for 15 h. Concen-
tration under reduced pressure gave a crude product 12 as an
oil. Hydrolysis, and purification by flash chromatography over
silica gel with n-hexane–EtOAc (4:1) afforded the hydrolysate
13 (106 mg, 0.236 mmol, 71% yield based on 10) as a crystalline
mass.
Compound 12, colourless oil (crude), δH(270 MHz; CDCl3)
0.89 (3 H, d, J 6.9, CMe), 0.96 (3 H, d, J 6.9, CMe), 1.83 (1 H,
m, 6-H), 2.29 (3 H, s, CMe), 2.63 (6 H, s, CMe), 3.49 (1 H, m,
5-H), 3.68 (3 H, s, OMe), 4.80 (1 H, d, J 8.9, NH), 5.64 (1 H, m,
4-H), 5.98 (1 H, dd, J 15.5 and 1.3, CH᎐), 6.78 (1 H, dd, J 15.8
᎐
and 5.6, CH᎐) and 6.94 (2 H, s, ArH); m/z (FAB-LRMS) 466
᎐
(MHϩ), 352, 290, 254, 183, 167, 119, 91 (base peak) and 72.
Compound 17, colourless oil [Found (FAB): (M ϩ H)ϩ,
370.1693. C18H27NO5S requires M ϩ H, 370.1688]; [α]D25 Ϫ58.9
(c 1.0 in CHCl3); δH(270 MHz; CDCl3) 0.73 (3 H, d, J 6.6,
CMe), 0.78 (3 H, d, J 7.0, CMe), 1.70 (1 H, m, 6-H), 2.30 (3 H, s,
CMe), 2.64 (6 H, s, CMe), 3.06 (1 H, m, OH), 3.15 (1 H, m, 5-H),
3.75 (3 H, s, OMe), 4.51 (1 H, m, 4-H), 4.97 (1 H, m, NH), 6.16
4-H), 5.77 (1 H, dd, J 15.8 and 1.7, CH᎐), 6.57 (1 H, dd, J 15.8
᎐
and 5.3, CH᎐) and 6.91 (2 H, s, ArH); m/z (FAB-LRMS) 488
᎐
(MNaϩ), 466 (MHϩ), 352, 254, 183, 167, 119 and 91 (base
peak).
(1 H, dd, J 15.5 and 1.7, CH᎐), 6.91 (1 H, dd, J 15.5 and 4.0,
᎐
Compound 13, colourless crystals, mp 157–158 ЊC [from n-
hexane–Et2O (3:1)] (Found: C, 58.51; H, 7.31; N, 3.73.
C18H27NO5S requires C, 58.51; H, 7.37; N, 3.79%); [α]D27 Ϫ42.1
(c 0.569 in CHCl3); δH(270 MHz; CDCl3) 0.76 (3 H, d, J 6.6,
CMe), 0.89 (3 H, d, J 6.9, CMe), 1.88 (1 H, m, 6-H), 2.28 (3 H,
s, CMe), 2.62 (6 H, s, CMe), 2.69 (1 H, m, OH), 3.12 (1 H, m,
5-H), 3.69 (3 H, s, OMe), 4.33 (1 H, m, 4-H), 5.04 (1 H, m, NH),
CH᎐) and 6.96 (2 H, s, ArH); m/z (FAB-LRMS) 392 (MNaϩ),
᎐
370 (MHϩ), 352, 254, 183, 167, 119, 91 (base peak) and 72.
Methyl (2E,4S,5S)-6-methyl-4,5-[N-(2,4,6-trimethylphenyl-
sulfonyl)epimino]hept-2-enoate 14 from 17 (confirmation of the
ꢂ,ꢃ-erythro stereochemistry of 17)
5.94 (1 H, dd, J 15.5 and 1.7, CH᎐), 6.68 (1 H, dd, J 15.5 and
By use of a procedure similar to that described for the prepar-
᎐
2988
J. Chem. Soc., Perkin Trans. 1, 1999, 2983–2996

View Article Online
ation of 10 from 13, the alcohol 17 (32.0 mg, 0.0866 mmol) was
converted into the trans-(E)-enoate 14 (20.8 mg, 0.0592 mmol,
68%) colourless crystals, mp 107–108 ЊC (from n-hexane)
[Found (FAB): (M ϩ H)ϩ, 352.1588. C18H25NO4S requires
M ϩ H, 352.1582]; [α]D26 Ϫ11.0 (c 1.09 in CHCl3); δH(270 MHz;
CDCl3) 0.76 (3 H, d, J 6.9, CMe), 0.89 (3 H, d, J 6.6, CMe),
1.56 (1 H, m, 6-H), 2.30 (3 H, s, CMe), 2.69 (6 H, s, CMe), 2.90
(1 H, dd, J 7.6 and 4.0, 5-H), 3.14 (1 H, dd, J 10.2 and 4.0, 4-H),
5.15 (1 H, m, 4-H), 5.86 (1 H, dd, J 5.6 and 2.0, CH᎐), 6.94
᎐
(2 H, s, ArH) and 7.11 (1 H, dd, J 5.6 and 1.3, CH᎐); m/z (FAB-
᎐
LRMS) 338 (MHϩ), 254, 183 (base peak), 154, 137 and 119.
Reaction of methyl (2Z,4R,5S)-6-methyl-4,5-[N-(2,4,6-trimeth-
ylphenylsulfonyl)epimino]hept-2-enoate 18 with TFA
By use of a procedure similar to that described for the reaction
of 10 with TFA, the cis-(Z)-enoate 18 (146 mg, 0.415 mmol)
was treated with TFA to afford an inseparable complex mixture.
3.75 (3 H, s, OMe), 6.13 (1 H, d, J 15.5, CH᎐), 6.94 (2 H, s, ArH)
᎐
and 7.16 (1 H, dd, J 15.5 and 10.2, CH᎐); m/z (FAB-LRMS)
᎐
374 (MNaϩ), 352 (MHϩ), 320, 296 (base peak), 183, 168, 137
and 119.
Reaction of methyl (2Z,4S,5S)-6-methyl-4,5-[N-(2,4,6-trimeth-
ylphenylsulfonyl)epimino]hept-2-enoate 19 with MSA in CHCl3
and production of (4R,5S)-6-methyl-5-(2,4,6-trimethylphenyl-
sulfonylamino)hept-2-en-4-olide 23
Methyl (2E)-3-[(4S,5S)-2,2-dimethyl-4-methylethyl-N-(2,4,6-
trimethylphenylsulfonyl)oxazolidin-5-yl]prop-2-enoate 20
By use of a procedure similar to that described for the reaction
of 10 with MSA in CHCl3, the trans-(Z)-enoate 19 (256 mg,
0.727 mmol) was treated with MSA (6.55 mmol) in CHCl3 to
yield complex mixtures containing the γ-lactone ring-cyclized
product 23 (142 mg, 0.419 mmol, 58%), which was purified by
flash chromatography over silica gel with n-hexane–EtOAc
(4:1).
To a stirred solution of 149 mg (0.402 mmol) of 13 in a mixture
of 3 cm3 of toluene and 0.148 cm3 (1.21 mmol) of 2,2-
dimethoxypropane at rt was added 1.52 mg (6.03 µmol) of
pyridinium toluene-p-sulfonate, and the mixture was gently
refluxed for 3 h. The mixture was made alkaline with saturated
NaHCO3 solution and extracted with Et2O. The extract was
washed with water and dried over MgSO4. Concentration under
reduced pressure gave a crystalline residue, which was flash
chromatographed over silica gel with n-hexane–EtOAc (3:1) to
yield 139 mg (0.339 mmol, 84%) of compound 20 as colourless
crystals, mp 128–129 ЊC [from n-hexane–Et2O (3:1)] (Found: C,
61.48; H, 7.46; N, 3.39. C21H31NO5S requires C, 61.59; H, 7.63;
N, 3.42%); [α]D28 Ϫ115.6 (c 1.33 in CHCl3); δH(300 MHz; CDCl3)
0.63 (3 H, d, J 6.6, CMe), 0.68 (3 H, d, J 6.9, CMe), 0.93 (1 H,
m, 5-H), 1.81 (3 H, s, CMe), 1.84 (3 H, s, CMe), 2.36 (3 H, s,
CMe), 2.69 (6 H, s, CMe), 3.78 (1 H, t, J 3.8, 4-H), 3.81 (3 H, s,
Compound 23, colourless oil [Found (FAB): (M Ϫ H)Ϫ,
336.1279. C17H23NO4S requires M Ϫ H, 336.1269]; [α]D24 ϩ72.6
(c 0.36 in CHCl3); IR (CHCl3) 3290, 2980, 2360, 1720, 1594,
1499, 1412, 1368, 1328, 1199, 1150, 1108, 1074, 1037, 918, 870,
846, 715, 660 cmϪ1; δH(270 MHz; CDCl3) 0.76 (3 H, d, J 6.9,
CMe), 0.94 (3 H, d, J 6.9, CMe), 1.90 (1 H, m, 6-H), 2.33 (3 H,
s, CMe), 2.65 (6 H, s, CMe), 4.00 (1 H, m, 5-H), 4.03 (1 H, m,
4-H), 4.83 (1 H, d, J 9.6, NH), 5.99 (1 H, dd, J 9.6 and 1.7,
CH᎐), 6.60 (1 H, ddd, J 9.6, 3.3 and 0.7, CH᎐) and 7.00 (2 H, s,
᎐
᎐
ArH); m/z (FAB-LRMS) 338 (MHϩ), 254, 183 (base peak), 149,
OMe), 4.59 (1 H, m, 3-H), 6.07 (1 H, dd, J 15.7 and 1.7, CH᎐),
᎐
119 and 115.
7.00 (2 H, s, ArH) and 7.08 (1 H, dd, J 15.7 and 4.8, CH᎐).
᎐
Reaction of methyl (2Z,4S,5S)-6-methyl-4,5-[N-(2,4,6-trimeth-
ylphenylsulfonyl)epimino]hept-2-enoate 19 with TFA and
production of (4R,5S)-6-methyl-5-(2,4,6-trimethylphenyl-
sulfonylamino)hept-2-en-4-olide 23
Methyl (2E)-3-[(4S,5R)-2,2-dimethyl-4-methylethyl-N-(2,4,6-
trimethylphenylsulfonyl)oxazolidin-5-yl]prop-2-enoate 21
By use of a procedure similar to that described for the prepar-
ation of 20 from 13, the alcohol 17 (120 mg, 0.326 mmol) was
converted into the oxazolidinyl derivative 21 (86.2 mg, 0.211
mmol, 65%) as a colourless oil [Found (FAB): (M ϩ H)ϩ,
410.1994. C21H31NO5S requires M ϩ H, 410.2001]; [α]D28 Ϫ46.8
(c 1.24 in CHCl3); δH(300 MHz; CDCl3) 0.60 (3 H, d, J 7.1,
CMe), 0.65 (3 H, d, J 6.9, CMe), 0.89 (1 H, m, 5-H), 1.83 (3 H,
s, CMe), 1.91 (3 H, s, CMe), 2.34 (3 H, s, CMe), 2.70 (6 H, s,
CMe), 3.68 (1 H, dd, J 5.7 and 3.8, 4-H), 3.78 (3 H, s, OMe),
By use of a procedure similar to that described for the reaction
of 10 with TFA, the trans-(Z)-enoate 19 (130 mg, 0.370 mmol)
was treated with TFA (1 cm3) to yield complex mixtures con-
taining the γ-lactone ring-cyclized product 23 (14.4 mg, 0.0427
mmol, 12%), which was purified by flash chromatography over
silica gel with n-hexane–EtOAc (4:1).
Compound 23, colourless oil [Found (FAB): (M Ϫ H)Ϫ,
336.1268. C17H23NO4S requires M Ϫ H, 336.1270]; [α]D24 ϩ69.4
(c 0.42 in CHCl3); IR (CHCl3) 3350, 2990, 2370, 1720, 1595,
1500, 1414, 1366, 1335, 1202, 1148, 1108, 1074, 1038, 920, 870,
842, 715, 664 cmϪ1; δH(300 MHz; CDCl3) 0.76 (3 H, d, J 6.8,
CMe), 0.94 (3 H, d, J 6.9, CMe), 1.90 (1 H, m, 6-H), 2.33 (3 H,
s, CMe), 2.64 (6 H, s, CMe), 3.97 (1 H, m, 5-H), 3.99 (1 H, m,
4-H), 4.98 (1 H, d, J 9.4, NH), 5.98 (1 H, dd, J 9.8 and 1.7,
4.92 (1 H, m, 3-H), 6.21 (1 H, dd, J 15.6 and 1.8, CH᎐), 6.99
᎐
(2 H, s, ArH) and 7.08 (1 H, dd, J 15.7 and 4.5, CH᎐); m/z
᎐
(FAB-LRMS) 410 (MHϩ), 366, 240, 183, 119 and 112 (base
peak).
Reaction of methyl (2Z,4R,5S)-6-methyl-4,5-[N-(2,4,6-trimeth-
ylphenylsulfonyl)epimino]hept-2-enoate 18 with MSA in CHCl3
and production of (4S,5S)-6-methyl-5-(2,4,6-trimethylphenyl-
sulfonylamino)hept-2-en-4-olide 22
CH᎐), 6.59 (1 H, ddd, J 9.8, 3.2 and 0.7, CH᎐) and 7.00 (2 H, s,
᎐
᎐
ArH); m/z (FAB-LRMS) 336 [(M Ϫ H)Ϫ], 198 (base peak), 183,
153 and 151.
By use of a procedure similar to that described for the reaction
of 10 with MSA in CHCl3, the cis-(Z)-enoate 18 (238 mg, 0.675
mmol) was treated with MSA (6.08 mmol) in CHCl3 to yield
complex mixtures containing the γ-lactone ring-cyclized
product 22 (59 mg, 0.175 mmol, 26%), which was purified by
flash chromatography over silica gel with n-hexane–EtOAc
(4:1).
Compound 22, colourless crystals, mp 217–218 ЊC [from n-
hexane–EtOAc (5:1)] (Found: C, 60.26; H, 6.66; N, 4.11.
C17H23NO4S requires C, 60.53; H, 6.82; N, 4.15%); [α]D19 Ϫ181.4
(c 2.69 in CHCl3); IR (CHCl3) 3410, 3240, 2960, 1752, 1600,
1455, 1408, 1327, 1158, 1100, 1071, 1057, 1028, 910, 850, 815,
650 cmϪ1; δH(270 MHz; CDCl3) 0.87 (3 H, d, J 6.6, CMe), 0.97
(3 H, d, J 6.9, CMe), 1.93 (1 H, m, 6-H), 2.30 (3 H, s, CMe),
2.64 (6 H, s, CMe), 3.43 (1 H, m, 5-H), 4.64 (1 H, d, J 9.6, NH),
(R)-N-(tert-Butoxycarbonyl)phenylalaninol 25
DIBAL in n-hexane (73.8 cm3, 68.6 mmol; 0.93 mol dmϪ3 solu-
tion) was added dropwise to a stirred solution of the ester 24
(5 g, 17.9 mmol) in 20 cm3 of CH2Cl2 at Ϫ78 ЊC under argon.
The mixture was allowed to warm to rt and stirring was
continued for 3 h. The mixture was recooled to Ϫ78 ЊC, and
saturated aq. NH4Cl (10 cm3) was added dropwise with vigor-
ous stirring. The inorganic salts were removed by filtration
through Celite. The filtrate was extracted with EtOAc, and the
extract was washed with water and dried over MgSO4. The
usual work-up and flash chromatography over silica gel with
n-hexane–EtOAc (2:1) gave a crystalline mass. Recrystalliz-
ation from n-hexane–EtOAc (3:1) gave 3.27 g (13.0 mmol,
J. Chem. Soc., Perkin Trans. 1, 1999, 2983–2996
2989

View Article Online
73%) of the title compound 25 as colourless crystals, mp 99 ЊC
[from n-hexane–EtOAc (3:1)] (Found: C, 66.74; H, 8.30; N,
5.53. C14H21NO3 requires C, 66.90; H, 8.42; N, 5.57%); [α]D20
ϩ22.9 (c 1.41 in CHCl3); δH(270 MHz; CDCl3) 1.41 (9 H, s,
CMe), 2.53 (1 H, m, OH), 2.84 (2 H, d, J 6.8, CH2), 3.55 (1 H,
m, CHH), 3.64 (1 H, m, CHH), 3.86 (1 H, m, CH), 4.81 (1 H,
m, NH) and 7.19–7.33 (5 H, m, Ph).
MgSO4. Purification by flash chromatography over silica gel
with n-hexane–EtOAc (3:1) gave 2.12 g (5.91 mmol, 66%) of
the title compound 29 as colourless crystals, mp 95–97 ЊC [from
n-hexane–Et2O (3:1)] (Found: C, 66.65; H, 6.97; N, 3.82.
C20H25NO3S requires C, 66.82; H, 7.01; N, 3.90%); [α]D27 ϩ42.4
(c 0.932 in CHCl3); δH(270 MHz; CDCl3) 1.99 (1 H, d, J 3.6,
OH), 2.28 (3 H, s, CMe), 2.56 (6 H, s, CMe), 2.67 (1 H, dd, J 13.5
and 6.3, CHH), 2.94 (1 H, dd, J 13.5 and 8.3, CHH), 3.44
(1 H, m, 4-H), 4.11 (1 H, m, 3-H), 4.96 (1 H, d, J 8.6, NH), 5.09
(3R,4R)-4-[(tert-Butoxycarbonylamino)-5-phenylpent-1-en-3-ol
27 and (3S,4R)-4-(tert-butoxycarbonylamino)-5-phenylpent-1-
en-3-ol 28
(1 H, m, CHH᎐), 5.21 (1 H, m, CHH᎐), 5.69 (1 H, ddd, J 17.2,
᎐
᎐
10.6 and 5.9, CH᎐), 6.87 (2 H, s, ArH) and 7.00–7.18 (5 H, m,
᎐
Ph).
To a stirred solution of oxalyl dichloride (6.54 cm3, 75 mmol) in
dry CH2Cl2 (70 cm3) at Ϫ78 ЊC under argon was added drop-
wise a solution of DMSO (11.7 cm3, 165 mmol) in CH2Cl2 (20
cm3). After 20 min, a solution of the alcohol 25 (12.6 g, 50
mmol) in CH2Cl2 (20 cm3) was added to the above reagent at
Ϫ78 ЊC, and the mixture was stirred for 1 h. DIPEA (52.3 cm3,
300 mmol) was added dropwise to the above mixture at Ϫ78 ЊC,
and the mixture was stirred for 2 h with warming to 0 ЊC. The
reaction was quenched with 20 cm3 of saturated aq. NH4Cl
at Ϫ78 ЊC with vigorous stirring. The mixture was extracted
with Et2O and the extract was washed successively with 5%
citric acid, water, 5% NaHCO3 and water, and dried over
MgSO4. Concentration under reduced pressure gave the crude
aldehyde 26 as a colourless oil. To a stirred solution of ZnCl2
(27.3 g, 200 mmol) and LiCl (17.0 g, 400 mmol) in 200 cm3 of
Et2O at Ϫ78 ЊC was added via syringe 97.6 cm3 (200 mmol) of
2.05 mol dmϪ3 vinylmagnesium chloride in THF. After being
stirred at this temperature for 10 min, a solution of the above
crude aldehyde 26 in THF (50 cm3) was added dropwise to the
mixture, and the mixture was allowed to warm to Ϫ40 ЊC and
stirred at this temperature for 4 h, followed by quenching with
100 cm3 of aq. 0.05 mol dmϪ3 HCl. The mixture was concen-
trated under reduced pressure and extracted with EtOAc.
Usual work-up led to a mixture of products as a colourless oil,
which was separated by flash chromatography over silica gel
eluting with n-hexane–EtOAc (5:1), yielding, in order of
elution, 27 (6.31 g, 22.8 mmol, 46%) and 28 (1.05 g, 3.79 mmol,
8%).
(2R,3S)-2-Benzyl-N-(2,4,6-trimethylphenylsulfonyl)-3-vinyl-
aziridine 30
Ph3P (0.950 g, 3.62 mmol) and DEAD (0.570 cm3 of a 40%
solution in toluene, 3.62 mmol) were added to a stirred solution
of the alcohol 29 (1.18 g, 3.29 mmol) in 3 cm3 of THF at 0 ЊC,
and the mixture was stirred at this temperature for 30 min. The
mixture was concentrated under reduced pressure to give an oil,
which was purified by flash chromatography over silica gel
with n-hexane–EtOAc (3:1) to yield 1.11 g (3.26 mmol, 99%)
of compound 30 as colourless crystals, mp 72–73 ЊC [from
n-hexane–Et2O (3 : 1)] (Found: C, 70.20; H, 6.82; N, 3.96.
C20H23NO2S requires C, 70.35; H, 6.79; N, 4.10%); [α]D27 ϩ26.2
(c 0.910 in CHCl3); δH(270 MHz; CDCl3) 2.28 (3 H, s, CMe),
2.58 (6 H, s, CMe), 2.64 (1 H, dd, J 14.5 and 7.6, CHH), 2.75
(1 H, dd, J 14.5 and 5.6, CHH), 3.09 (1 H, ddd, J 7.6, 7.6 and
5.6, 2-H), 3.47 (1 H, m, 3-H), 5.37 (1 H, m, CHH᎐), 5.50 (1 H,
m, CHH᎐), 5.78 (1 H, ddd, J 16.8, 10.6 and 6.6, CH᎐), 6.84
(2 H, s, ArH) and 6.94–7.14 (5 H, m, Ph).
᎐
᎐
᎐
Methyl (2E,4S,5R)-6-phenyl-4,5-[N-(2,4,6-trimethylphenyl-
sulfonyl)epimino]hex-2-enoate 31
O3 was bubbled through a solution of the vinylaziridine 30 (1.02
g, 2.98 mmol) in 15 cm3 of MeOH–CHCl3 (3:1) at Ϫ78 ЊC until
a blue colour persisted. Nitrogen was bubbled through the
solution with stirring for 30 min during which time it was
allowed to warm to 0 ЊC. To the solution at 0 ЊC was added
dimethyl sulfide (0.240 cm3, 3.28 mmol), and the mixture was
stirred for 30 min. Concentration under reduced pressure left an
oily residue, which was dissolved in CHCl3 (10 cm3). To the
mixture at 0 ЊC was added [(methoxycarbonyl)methylene]-
triphenylphosphorane (1.99 g, 5.96 mmol), and the mixture was
stirred for 2 h. The mixture was concentrated under reduced
pressure to leave a semisolid, which was extracted with EtOAc
and the extract was washed successively with 1 mol dmϪ3 HCl,
water, saturated aq. NaHCO3 and water, and dried over
MgSO4. Concentration under reduced pressure gave a residue,
which was purified by flash chromatography over silica gel with
n-hexane–EtOAc (5:1) to give a mixture of the enoates 31 and
32, which was dissolved in 10 cm3 of dry THF, and to the
mixture at 0 ЊC under argon was added by syringe with stirring
a solution of Pd(PPh3)4 (147 mg, 0.128 mmol, 5 mol%) in 5 cm3
of dry THF. After 4 h, the mixture was allowed to warm to rt,
and the stirring was continued for a further 15 h. Purification by
flash chromatography over silica gel with n-hexane–EtOAc
(5:1) and recrystallization from n-hexane gave 577 mg (1.44
mmol, 57% yield based on 30) of the cis-(E)-enoate 31 as
colourless crystals, mp 54–55 ЊC (from n-hexane) (Found: C,
65.99; H, 6.24; N, 3.49. C22H25NO4S requires C, 66.14; H,
6.31; N, 3.51%); [α]D19 ϩ64.9 (c 0.575 in CHCl3); δH(270 MHz;
CDCl3) 2.30 (3 H, s, CMe), 2.57 (6 H, s, CMe), 2.64 (1 H,
dd, J 14.6 and 8.4, CHH), 2.76 (1 H, dd, J 14.6 and 5.1,
CHH), 3.19 (1 H, m, 5-H), 3.56 (1 H, m, 4-H), 3.77 (3 H, s,
Compound 27, colourless crystals, mp 93–96 ЊC [from n-
hexane–Et2O (3:1)] (Found: C, 69.12; H, 8.46; N, 5.04.
C16H23NO3 requires C, 69.30; H, 8.36; N, 5.05%); [α]D20 ϩ52.6
(c 0.966 in CHCl3); δH(270 MHz; CDCl3) 1.38 (9 H, s, CMe),
2.30 (1 H, m, OH), 2.92 (2 H, m, CH2), 3.80 (1 H, m, 4-H), 4.11
(1 H, m, 3-H), 4.77 (1 H, m, NH), 5.19 (1 H, ddd, J 10.2, 1.3
and 1.3, CHH᎐), 5.28 (1 H, ddd, J 17.2, 1.3 and 1.3, CHH᎐),
᎐
᎐
5.90 (1 H, ddd, J 17.2, 10.6 and 5.6, CH᎐) and 7.18–7.34 (5 H,
᎐
m, Ph).
Compound 28, colourless crystals, mp 120–122 ЊC [from
n–hexane–Et2O (3:1)] (Found: C, 69.26; H, 8.56; N, 5.02.
C16H23NO3 requires C, 69.30; H, 8.36; N, 5.05%); [α]D20 ϩ25.5 (c
0.964 in CHCl3); δH(270 MHz; CDCl3) 1.36 (9 H, s, CMe), 2.73
(1 H, dd, J 13.9 and 8.9, CHH), 2.85 (1 H, dd, J 14.2 and 5.3,
CHH), 2.96 (1 H, m, OH), 3.97 (1 H, m, 4-H), 4.24 (1 H, m,
3-H), 4.56 (1 H, m, NH), 5.29 (1 H, ddd, J 10.6, 1.3 and 1.3,
CHH᎐), 5.37 (1 H, ddd, J 17.2, 1.3 and 1.3, CHH᎐), 5.94 (1 H,
᎐
᎐
ddd, J 17.2, 10.6 and 5.6, CH᎐) and 7.18–7.42 (5 H, m, Ph).
᎐
(3R,4R)-5-Phenyl-4-(2,4,6-trimethylphenylsulfonylamino)pent-
1-en-3-ol 29
TFA (5 cm3) and anisole (0.969 cm3, 8.97 mmol) were added to
2.49 g (8.97 mmol) of the alcohol 27 at 0 ЊC, and the mixture
was stirred for 2 h. The mixture was concentrated under
reduced pressure to give an oily residue, which was washed with
n-hexane. To the oil in 5 cm3 of CHCl3 were added at 0 ЊC
successively 3.7 cm3 (26.9 mmol) of Et3N and 2.35 g (10.8
mmol) of Mts-Cl. After being stirred for 15 h, the mixture was
made acidic with saturated aq. citric acid and extracted with
EtOAc, and the extract was washed with water and dried over
OMe), 6.20 (1 H, dd, J 15.8 and 1.0, CH᎐), 6.85 (1 H, dd,
᎐
J 15.8 and 6.6, CH᎐), 6.86 (2 H, s, ArH) and 6.92–7.12 (5 H, m,
᎐
Ph); m/z (FAB-LRMS) 400 (MHϩ), 216, 183 (base peak), 119
and 91.
2990
J. Chem. Soc., Perkin Trans. 1, 1999, 2983–2996

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(3S,4S)-6-Methyl-4-(2,4,6-trimethylphenylsulfonylamino)hept-
1-en-3-ol 34
Usual work-up and flash chromatography over silica gel with
n-hexane–EtOAc (3:1) gave 3.78 g (7.00 mmol, 74%) of the
title compound 38 as a colourless crystalline mass, mp 111–
113 ЊC [from n-hexane–Et2O (5:1)] (Found: C, 55.64; H, 6.51;
N, 7.58. C25H34ClN3O6S requires C, 55.66; H, 6.35; N,
7.78%); [α]D21 ϩ14.7 (c 1.39 in CHCl3); δH(270 MHz; CDCl3)
1.30 (4 H, m, CH2), 1.57 (2 H, m, CH2), 2.27 (3 H, s, CMe),
2.65 (6 H, s, CMe), 2.98 (3 H, s, NMe), 3.13 (2 H, m, CH2),
3.51 (3 H, s, OMe), 4.16 (1 H, m, 2-H), 4.85 (1 H, m, NH),
5.21 (2 H, s, CH2), 5.59 (1 H, d, J 9.6, NH), 6.92 (2 H, s,
ArH) and 7.24–7.45 (4 H, m, ArH); m/z (FAB-LRMS) 540
(MHϩ), 496, 398, 353 (base peak), 309, 252, 208, 183, 127,
125, 119, 91 and 84.
By use of a procedure identical with that described for the
preparation of 29 from 27, the known alcohol 33 (3.63 g, 14.9
mmol) was converted into 3.99 g (12.3 mmol, 82%) of the
title compound 34, as colourless crystals, mp 137–138 ЊC [from
n-hexane–Et2O (3:1)] (Found: C, 62.77; H, 8.45; N, 4.27.
C17H27NO3S requires C, 62.74; H, 8.36; N, 4.30%); [α]D25 Ϫ14.1
(c 0.951 in CHCl3); δH(270 MHz; CDCl3) 0.69 (3 H, d, J 6.3,
CMe), 0.78 (3 H, d, J 6.6, CMe), 1.23 (1 H, m, CHH), 1.40
(1 H, m, CHH), 1.44 (1 H, m, 6-H), 2.07 (1 H, d, J 4.0, OH),
2.30 (3 H, s, CMe), 2.63 (6 H, s, CMe), 3.29 (1 H, m, 4-H), 4.05
(1 H, m, 3-H), 4.75 (1 H, d, J 9.2, NH), 5.07 (1 H, m, CHH᎐),
᎐
5.20 (1 H, m, CHH᎐), 5.68 (1 H, ddd, J 17.2, 10.6 and 6.6, CH᎐)
and 6.94 (2 H, s, ArH).
᎐
᎐
(3S,4S)-8-(2-Chlorophenylmethoxycarbonylamino)-4-(2,4,6-tri-
methylphenylsulfonylamino)oct-1-en-3-ol 40 and (3R,4S)-8-(2-
chlorophenylmethoxycarbonylamino)-4-(2,4,6-trimethylphenyl-
sulfonylamino)oct-1-en-3-ol 41
(2S,3R)-2-(2-Methylpropyl)-N-(2,4,6-trimethylphenylsulfonyl)-
3-vinylaziridine 35
To a stirred solution of the amide 38 (3 g, 5.56 mmol) in dry
THF (10 cm3) under argon at Ϫ78 ЊC with stirring was added
via syringe 22 cm3 (22.2 mmol) of a 1.01 mol dmϪ3 solution of
DIBAL in toluene, and the stirring was continued for 1.5 h.
EtOAc (2 cm3) and MeOH (2 cm3) were added successively to
the above mixture at Ϫ78 ЊC, and the stirring was continued at
Ϫ78 ЊC for 30 min followed by addition with 1 mol dmϪ3 aq.
HCl (20 cm3). After being stirred at 0 ЊC for 20 min, the mixture
was extracted with EtOAc and the extract was washed with
water and dried over MgSO4. Usual work-up gave the crude
aldehyde 39 (colourless oil). By use of a procedure similar to
that described for the preparation of 27 and 28 from 26, the
above crude aldehyde 39 was converted into allyl alcohols 40
and 41 (diastereomixture 2.71 g, 5.31 mmol, 96%) as a colour-
less oil by treatment with ZnCl2 (22.2 mmol), LiCl (22.2 mmol),
and 1.47 mol dmϪ3 vinylmagnesium chloride (22.2 mmol) in
THF at 0 ЊC for 4 h.
By use of a procedure identical with that described for the
preparation of 30 from 29, the alcohol 34 (1.04 g, 3.18 mmol)
was converted into 0.963 g (3.13 mmol, 98%) of the title com-
pound 35, as a colourless oil [Found (FAB): (M ϩ H)ϩ,
308.1678. C17H25NO2S requires M ϩ H, 308.1684]; [α]D25 Ϫ3.12
(c 0.915 in CHCl3); δH(270 MHz; CDCl3) 0.85 (3 H, d, J 5.3,
CMe), 0.87 (3 H, d, J 5.3, CMe), 1.30 (1 H, m, CHH), 1.38
(1 H, m, CHH), 1.56 (1 H, m, CH), 2.30 (3 H, s, CMe), 2.69
(6 H, s, CMe), 2.96 (1 H, ddd, J 13.5, 7.3 and 0.5, 2-H), 3.35
(1 H, t, J 7.3, 3-H), 5.25 (1 H, m, CHH), 5.34 (1 H, m, CHH),
5.61 (1 H, ddd, J 17.2, 10.2 and 6.9, CH᎐) and 6.94 (2 H, s,
᎐
ArH); m/z (FAB-LRMS) 308 (MHϩ), 306, 183 (base peak), 124
and 119.
Benzyl (2E,4R,5S)-7-methyl-4,5-[N-(2,4,6-trimethylphenyl-
sulfonyl)epimino]oct-2-enoate 36
By use of a procedure similar to that described for the prepar-
ation of 31 from 30, the vinylaziridine 35 (0.928 mg, 3.02 mmol)
was converted into 886 mg (2.01 mmol, 70% yield based on 35)
of the title compound 36 by successive treatments with O3 in
CHCl3–n-hexane (1:1) at Ϫ78 ЊC for 30 min, dimethyl sulfide
(2.21 mmol), [(benzyloxycarbonyl)methylene]triphenylphos-
phorane (6.04 mmol) in CHCl3 at 0 ЊC for 15 h, and Pd(PPh3)4
(0.167 mmol) in THF at rt for 17 h.
Compound 36, colourless crystals, mp 81–82 ЊC (from n-
hexane) (Found: C, 67.90; H, 7.20; N, 2.88. C25H31NO4S
requires C, 68.00; H, 7.08; N, 3.17%); [α]D26 Ϫ2.47 (c 2.41 in
CHCl3); δH(300 MHz; CDCl3) 0.83 (3 H, d, J 6.7, CMe), 0.86
(3 H, d, J 6.8, CMe), 1.32 (2 H, m, 6-H2), 1.53 (1 H, m, 7-H),
2.30 (3 H, s, CMe), 2.68 (6 H, s, CMe), 3.05 (1 H, m, 5-H), 3.43
(1 H, m, 4-H), 5.17 (2 H, s, CH2), 6.08 (1 H, dd, J 15.6 and 0.9,
Compounds 40 and 41, colourless oil (diastereomixture),
[Found (FAB): (M ϩ H)ϩ, 509.1866. C25H33ClN2O5S requires
M ϩ H, 509.1877]; m/z (FAB-LRMS) 509 (MHϩ), 465, 367, 349
(base peak), 252, 208, 183, 167, 125 and 119.
(2S,3R)-2-[4-(2-Chlorophenylmethoxycarbonylamino)butyl]-N-
(2,4,6-trimethylphenylsulfonyl)-3-vinylaziridine 42 and (2S,3S)-
2-[4-(2-chlorophenylmethoxycarbonylamino)butyl]-N-(2,4,6-
trimethylphenylsulfonyl)-3-vinylaziridine 43
By use of a procedure similar to that described for the prepar-
ation of 30 from 29, the diastereomixtures 40 and 41 (2.34 g,
4.60 mmol) were converted into vinylaziridines 42 and 43 (dia-
stereomixture 1.96 g, 3.98 mmol, 87%) as a colourless oil
[Found (FAB): (M ϩ H)ϩ, 491.1775. C25H31ClN2O4S requires
M ϩ H, 491.1772]; m/z (FAB-LRMS) 491 (MHϩ), 349, 308, 252
(base peak), 208, 183, 167, 125, 119 and 91.
CH᎐), 6.72 (1 H, dd, J 15.6 and 6.9, CH᎐), 6.95 (2 H, s, ArH)
᎐
᎐
and 7.32–7.39 (5 H, m, Ph).
(2S)-6-(2-Chlorophenylmethoxycarbonylamino)-N-methoxy-N-
methyl-2-(2,4,6-trimethylphenylsulfonylamino)hexanamide 38
Benzyl (2E,4R,5S)-9-(2-chlorophenylmethoxycarbonylamino)-
4,5-[(2,4,6-trimethylphenylsulfonyl)epimino]non-2-enoate 44
To a stirred solution of Nε-(Cl-Z)-protected (S)-lysine 37 (3 g,
9.53 mmol) and Et3N (3.31 cm3, 23.8 mmol) in H2O (10 cm3) at
0 ЊC was added 2.50 g (11.4 mmol) of Mts-Cl. After being
stirred for 15 h, the mixture was made acidic with saturated aq.
citric acid and extracted with EtOAc and the extract was
washed with water and dried over MgSO4 to give a crude Nα-
and Nε-protected lysine as a colourless oil. To a stirred solution
of the above Nα- and Nε-protected lysine in DMF (10 cm3) at
0 ЊC were added HOBt (1.61 g, 10.5 mmol), WSCD (1.82 cm3,
10.5 mmol) and N,O-dimethylhydroxylamine hydrochloride
(1.02 g, 10.5 mmol). After being stirred at rt for 15 h, the solu-
tion was concentrated under reduced pressure and extracted
with EtOAc. The extract was washed successively with 5% citric
acid, water, 5% NaHCO3 and water, and dried over MgSO4.
By use of a procedure similar to that described for the prepar-
ation of 36 from 35, the diastereomixtures 42 and 43 (1.91 g,
3.90 mmol) were converted into the cis-(E)-enoate 44 [951
mg, 1.52 mmol, 39% (3 steps)] as a colourless oil, [Found
(FAB): (M ϩ H)ϩ, 625.2133. C33H37ClN2O6S requires M ϩ H,
625.2139]; [α]D24 Ϫ43.5 (c 1.51 in CHCl3); δH(300 MHz; CDCl3)
1.24 (2 H, m, CH2), 1.40 (2 H, m, CH2), 1.50 (2 H, m, CH2),
2.28 (3 H, s, CMe), 2.67 (6 H, s, CMe), 2.95 (1 H, m, 5-H), 3.06
(2 H, dd, J 12.9 and 6.4, CH2), 3.46 (1 H, m, 4-H), 4.73 (1 H,
m, NH), 5.16 (2 H, s, CH2), 5.20 (2 H, s, CH2), 6.09 (1 H, dd,
J 15.6 and 1.0, CH᎐), 6.71 (1 H, dd, J 15.6 and 6.7, CH᎐), 6.94
᎐
᎐
(2 H, s, ArH) and 7.21–7.43 (9 H, m, ArH); m/z (FAB-LRMS)
625 (MHϩ), 441, 252 (base peak), 208, 154, 136, 125, 119 and
91.
J. Chem. Soc., Perkin Trans. 1, 1999, 2983–2996
2991

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(1S)-1-[(4S)-N-(tert-Butoxycarbonyl)-2,2-dimethyloxazolidin-4-
yl]prop-2-en-1-ol 46 and (1R)-1-[(4S)-N-(tert-butoxycarbonyl)-
2,2-dimethyloxazolidin-4-yl]prop-2-en-1-ol 47
(2E,4R,5R)-6-Benzyloxy-N-methyl-4,5-[(2,4,6-trimethylphenyl-
sulfonyl)epimino]hex-2-enamide 54
By use of a procedure identical with that described for the
preparation of the corresponding aldehyde from 30, the
mixture of the vinylaziridines 52 and 53 (580 mg, 1.56 mmol)
was converted into the crude diastereomixture of the corre-
sponding aldehydes. To a stirred solution of LiCl (159 mg, 3.75
mmol) in 2 cm3 of CH3CN at 0 ЊC was added via syringe
DIPEA (0.652 cm3, 3.75 mmol) and a CH3CN solution (5 cm3)
of diethoxphosphoryl-N-methylacetamide (791 mg, 3.75
mmol), which was prepared by treatment of ethyl diethyloxy-
phosphorylacetate with methylamine (5 equiv.) in MeOH, and
the mixture was stirred at this temperature for 30 min. To the
mixture at 0 ЊC was added dropwise a solution of the above
crude aldehydes in CH3CN (3 cm3), and the stirring was con-
tinued at rt for 12 h. The mixture was concentrated under
reduced pressure to leave a semisolid, which was extracted with
EtOAc and the extract was washed successively with water, 1
mol dmϪ3 HCl, water, saturated aq. NaHCO3 and water, and
dried over MgSO4. Concentration under reduced pressure gave
a residue, which was purified by flash chromatography over
silica gel with n-hexane–EtOAc (5:1) to give a mixture of
the enamide 54 and its diastereoisomer. The diastereomixture
was treated with Pd(PPh3)4 (0.042 mmol, 5 mol%) by use of a
procedure identical with that described for the preparation of
the cis-(E)-enoate 31 from the mixture of 31 and 32 to give
232 mg [0.541 mmol, 35% (3 steps)] of the cis-(E)-enamide
54 as a colourless oil [Found (FAB): (M ϩ H)ϩ, 429.1841.
C23H28N2O4S requires M ϩ H, 429.1848]; [α]D21 Ϫ54.4 (c 1.06 in
CHCl3); δH(300 MHz; CDCl3) 2.29 (3 H, s, CMe), 2.68 (6 H, s,
CMe), 2.86 (3 H, d, J 4.9, NMe), 3.22 (1 H, m, 5-H), 3.45 (1 H,
dd, J 11.1 and 6.5, CHH), 3.52 (1 H, m, 4-H), 3.53 (1 H, dd,
J 11.1 and 5.5, CHH), 4.36 (2 H, s, CH2), 5.52 (1 H, d, J 4.7,
By use of a procedure similar to that described for the prepar-
ation of 27 and 28 from 26, the aldehyde 45 (3.95 g, 17.2 mmol)
was converted into allyl alcohols 46 and 47 (diastereo-
mixture 2.91 g, 11.3 mmol, 59%) as a colourless oil by treat-
ment with ZnCl2 (51.6 mmol), LiCl (51.6 mmol), and 1.60 mol
dmϪ3 vinylmagnesium chloride (51.6 mmol) in THF at 0 ЊC for
4 h.
Compounds 46 and 47, colourless oil (diastereomixture)
[Found (FAB): (M ϩ H)ϩ, 258.1710. C13H23NO4 requires
M ϩ H, 258.1705]; m/z (FAB-LRMS) 258 (MHϩ), 202, 200,
189, 184 (base peak), 144, 131, 100 and 57.
(2S,3S)-2-(2,4,6-Trimethylphenylsulfonylamino)pent-4-ene-1,3-
diol 48 and (2S,3R)-2-(2,4,6-trimethylphenylsulfonylamino)pent-
4-ene-1,3-diol 49
TFA (15 cm3) and H2O (2.11 cm3, 117 mmol) were added to
3.02 g (11.7 mmol) of the allyl alcohols 46 and 47 (diastereo-
mixture) at 0 ЊC, and the mixture was stirred for 1 h. The mix-
ture was concentrated under reduced pressure to give an oily
residue, which was washed with n-hexane. To the oil in 10 cm3
of CHCl3 were added at 0 ЊC successively 3.99 cm3 (23.5 mmol)
of DIPEA and 4.62 g (21.1 mmol) of Mts-Cl. After being
stirred for 15 h, the mixture was made acidic with saturated
aq. citric acid and extracted with EtOAc and the extract was
washed with water and dried over MgSO4. Purification by flash
chromatography over silica gel with n–hexane–EtOAc (2:3)
gave 1.86 g (6.21 mmol, 53%) of the diastereomixture of 48 and
49 as a colourless oil [Found (FAB): (M ϩ H)ϩ, 300.1263.
C14H21NO4S requires M ϩ H, 300.1269]; m/z (FAB-LRMS) 300
(MHϩ), 282, 252 (base peak), 242, 183 and 119.
NH), 6.04 (1 H, dd, J 15.2 and 0.9, CH᎐), 6.57 (1 H, dd, J 15.2
᎐
and 6.9, CH᎐), 6.94 (2 H, s, ArH) and 7.10–7.33 (5 H, m, Ph);
᎐
m/z (FAB-LRMS) 429 (MHϩ), 154 (base peak), 119 and 91.
(3S,4S)-5-Benzyloxy-3-hydroxy-4-(2,4,6-trimethylphenylsulfon-
ylamino)pent-1-ene 50 and (3R,4S)-5-benzyloxy-3-hydroxy-4-
(2,4,6-trimethylphenylsulfonylamino)pent-1-ene 51
Methyl (2E,4R,5R)-6-benzyloxy-4,5-[(2,4,6-trimethylphenyl-
sulfonyl)epimino]hex-2-enoate 55
Sodium hydride (198 mg of 60% dispersion in mineral oil, 4.94
mmol) was added to a stirred solution of the diastereomixture
of 48 and 49 (672 mg, 2.42 mmol) in 3 cm3 of THF at Ϫ40 ЊC,
and the mixture was stirred for 30 min with warming to 0 ЊC. To
the above mixture at 0 ЊC was added dropwise benzyl bromide
(0.294 cm3, 2.47 mmol), and the mixture was stirred for 2 h. The
reaction was quenched with 5 cm3 of saturated NaHCO3 at
0 ЊC. The mixture was extracted with EtOAc and the extract
was washed successively with water, 1 mol dmϪ3 HCl, water, 5%
NaHCO3 and water, and dried over MgSO4. Concentration
under reduced pressure gave a residue, which was purified by
flash chromatography over silica gel with n-hexane–EtOAc
(2:1) to give 483 mg (1.24 mmol, 55%) of the diastereomixture
of the alcohols 50 and 51.
By use of a procedure identical with that described for the
preparation of 31 from 30, the mixture of the vinylaziridines 52
and 53 (1.27 g, 3.42 mmol) was converted into the cis-(E)-
enoate 55 [(526 mg, 1.23 mmol, 36% (3 steps)] as a colourless oil
[Found (FAB): (M ϩ H)ϩ, 430.1691. C23H27NO5S requires
M ϩ H, 430.1688]; [α]D24 Ϫ66.9 (c 0.352 in CHCl3); δH(300 MHz;
CDCl3) 2.29 (3 H, s, CMe), 2.68 (6 H, s, CMe), 3.27 (1 H, m, 5-
H), 3.49 (2 H, m, CH2), 3.51 (1 H, m, 4-H), 3.73 (3 H, s, OMe),
4.36 (1 H, d, J 12.0, CHH), 4.41 (1 H, d, J 12.0, CHH), 6.08
(1 H, dd, J 15.6 and 0.9, CH᎐), 6.67 (1 H, dd, J 15.6 and 6.8,
᎐
CH᎐), 6.95 (2 H, s, ArH) and 7.13–7.33 (5 H, m, Ph); m/z (FAB-
᎐
LRMS) 430 (MHϩ), 400, 246, 217, 183, 167 (base peak), 119
and 91.
Compounds 50 and 51, colourless oil (diastereomixture)
[Found (FAB): (M ϩ H)ϩ, 390.1747. C21H27NO4S requires
M ϩ H, 390.1739]; m/z (FAB-LRMS) 390 (MHϩ), 242 (base
peak), 183, 149, 119 and 91.
Mts-L-Val-ꢀ[(E)-CH᎐CH]-D-Phe-OMe 56 prepared from 10
᎐
To a stirred slurry of CuCN (154 mg, 1.72 mmol) in 3 cm3 of
dry THF under argon at Ϫ78 ЊC was added by syringe 1.37 cm3
(1.72 mmol) of 1.25 mol dmϪ3 BnMgCl in THF, and the
mixture was allowed to warm to 0 ЊC and was stirred at this
temperature for 15 min. BF3ؒEt2O (0.211 cm3, 1.72 mmol) was
added to the above mixture at Ϫ78 ЊC and the mixture was
stirred for 5 min. A solution in dry THF (1 cm3) of the crude
mesyl compound 11, which was prepared from the cis-(E)-
enoate 10 (151 mg, 0.430 mmol) by the MSA treatment, was
added dropwise to the above reagent at Ϫ78 ЊC with stirring,
and the stirring was continued for 30 min followed by quench-
ing with 2 cm3 of a 1:1 saturated aq. NH4Cl–28% NH4OH
solution. The mixture was extracted with Et2O and the extract
was washed with water and dried over MgSO4. Concentration
(2R,3R)-2-(Benzyloxymethyl)-N-(2,4,6-trimethylphenylsulfon-
yl)-3-vinylaziridine 52 and (2R,3S)-2-(benzyloxymethyl)-N-
(2,4,6-trimethylphenylsulfonyl)-3-vinylaziridine 53
By use of a procedure identical with that described for
the preparation of 30 from 29, the mixture of the alcohols
50 and 51 (760 mg, 1.95 mmol) was converted into 640 mg
(1.72 mmol, 88%) of the diastereomixture of the vinylaziridines
52 and 53 as a colourless oil [Found (FAB): (M ϩ H)ϩ,
372.1626. C21H25NO3S requires M ϩ H, 372.1634]; m/z
(FAB-LRMS) 372 (MHϩ), 302, 264 (base peak), 188, 183, 119
and 91.
2992
J. Chem. Soc., Perkin Trans. 1, 1999, 2983–2996

View Article Online
under reduced pressure gave a colourless oil, which was purified
by flash chromatography over silica gel with n-hexane–EtOAc
(3:1) to yield 179 mg (0.404 mmol, 94% yield based on 10) of
56 as a colourless oil [Found (FAB): (M Ϫ H)Ϫ, 442.2056.
C25H33NO4S requires M Ϫ H, 442.2052]; [α]D27 ϩ14.3 (c 1.0 in
CHCl3); ∆ε ϩ2.95 (217 nm, isooctane); δH(270 MHz; CDCl3)
0.69 (3 H, d, J 7.3, CMe), 0.72 (3 H, d, J 7.3, CMe), 1.66 (1 H,
m, 6-H), 2.28 (3 H, s, CMe), 2.53 (1 H, dd, J 13.5 and 7.6,
CHH), 2.59 (6 H, s, CMe), 2.90 (1 H, dd, J 13.5 and 7.6, CHH),
3.05 (1 H, dd, J 15.2 and 7.6, 2-H), 3.48 (1 H, m, 5-H), 3.60
(3 H, s, OMe), 4.49 (1 H, d, J 7.6, NH), 5.06 (1 H, ddd, J 15.5,
treatment with BnCu(CN)MgClؒ2LiCl (0.640 mmol) in THF at
Ϫ78 ЊC for 30 min.
Compound 56, colourless oil [Found (FAB): (M Ϫ H)Ϫ,
442.2050. C25H33NO4S requires M Ϫ H, 442.2052]; [α]D24 ϩ16.8
(c 2.22 in CHCl3); ∆ε ϩ4.21 (214 nm, isooctane); δH(270 MHz;
CDCl3) 0.69 (3 H, d, J 7.3, CMe), 0.72 (3 H, d, J 7.3, CMe),
1.64 (1 H, m, 6-H), 2.28 (3 H, s, CMe), 2.53 (1 H, dd, J 13.5 and
7.6, CHH), 2.59 (6 H, s, CMe), 2.90 (1 H, dd, J 13.5 and 7.6,
CHH), 3.05 (1 H, dd, J 15.2 and 7.6, 2-H), 3.47 (1 H, m, 5-H),
3.60 (3 H, s, OMe), 4.51 (1 H, d, J 6.9, NH), 5.06 (1 H, ddd,
J 15.5, 7.6 and 0.5, CH᎐), 5.35 (1 H, ddd, J 15.5, 8.3 and 0.8,
᎐
7.6 and 1.5, CH᎐), 5.35 (1 H, ddd, J 15.5, 8.3 and 1.1, CH᎐),
CH᎐), 6.91 (2 H, s, ArH) and 7.01–7.38 (5 H, m, Ph); m/z (FAB-
᎐
᎐
᎐
6.91 (2 H, s, ArH) and 7.01–7.38 (5 H, m, Ph); m/z (FAB-
LRMS) 442 [(M Ϫ H)Ϫ], 308 (base peak), 198, 183, 153 and
151.
LRMS) 442 [(M Ϫ H)Ϫ], 308, 198, 183, 153 and 151 (base
peak).
Methyl (2E,4R,5R)-4-(methylsulfonyloxy)-6-phenyl-5-(2,4,6-tri-
methylphenylsulfonylamino)hex-2-enoate 58
Mts-L-Val-ꢀ[(E)-CH᎐CH]-L-Phe-OMe 57 prepared from 10
᎐
To a stirred solution of CuCN (358 mg, 4 mmol) and LiCl (339
mg, 8 mmol) in dry THF (8 cm3) under argon at Ϫ78 ЊC was
added via syringe 7.27 cm3 (4 mmol) of 0.55 mol dmϪ3 BnMgCl
in THF, and the mixture was allowed to warm to 0 ЊC and was
stirred at this temperature for 15 min. A solution of the cis-(E)-
enoate 10 (351 mg, 1 mmol) in dry THF (2 cm3) was added
dropwise to the above reagent at Ϫ78 ЊC with stirring, and the
stirring was continued for 30 min followed by quenching with 5
cm3 of a 1:1 saturated aq. NH4Cl–28% NH4OH solution. The
mixture was extracted with Et2O and the extract was washed
with water and dried over MgSO4. Concentration under
reduced pressure gave an oily residue, which was purified by
flash chromatography over silica gel with n-hexane–EtOAc
(3:1) to yield 333 mg (0.75 mmol, 75%) of 57 as colourless
crystals, mp 85–87 ЊC (from Et2O) (Found: C, 67.65; H, 7.53; N,
3.08. C25H33NO4S requires C, 67.69; H, 7.50; N, 3.16%); [α]D26
Ϫ69.2 (c 0.697 in CHCl3); ∆ε Ϫ11.09 (219 nm, isooctane);
δH(270 MHz; CDCl3) 0.74 (3 H, d, J 6.6, CMe), 0.79 (3 H, d,
J 6.9, CMe), 1.69 (1 H, m, 6-H), 2.27 (3 H, s, CMe), 2.52 (1 H,
dd, J 13.5 and 6.3, CHH), 2.62 (6 H, s, CMe), 2.87 (1 H, dd,
J 13.5 and 8.6, CHH), 3.07 (1 H, m, 2-H), 3.51 (1 H, m, 5-H),
3.55 (3 H, s, OMe), 4.43 (1 H, d, J 7.9, NH), 5.19 (1 H, ddd,
By use of a procedure similar to that described for the prepar-
ation of 11 from 10, the cis-(E)-enoate 31 (42.3 mg, 0.106
mmol) was converted into the γ-mesyloxy-α,β-enoate 58 by
treatment with MSA in CHCl3.
Compound 58, colourless oil (crude), δH(300 MHz; CDCl3)
2.27 (3 H, s, CMe), 2.43 (6 H, s, CMe), 2.54 (1 H, dd, J 14.1 and
8.8, CHH), 3.03 (1 H, dd, J 14.1 and 6.2, CHH), 3.07 (3 H, s,
SMe), 3.69 (1 H, m, 5-H), 3.76 (3 H, s, OMe), 4.88 (1 H, d, J 7.3,
NH), 5.47 (1 H, m, 4-H), 6.09 (1 H, dd, J 15.8 and 1.5, CH᎐),
᎐
6.80 (2 H, s, Ph), 6.91 (1 H, dd, J 15.8 and 5.8, CH᎐) and 6.94–
᎐
7.18 (5 H, m, Ph); m/z (FAB-LRMS) 496 (MHϩ), 400, 302,183,
149 (base peak), 119 and 91.
Mts-D-Phe-ꢀ[(E)-CH᎐CH]-L-Leu-OMe 59
᎐
By use of a procedure similar to that described for the prepar-
ation of 56 from 11, the crude mesyl derivative 58, which was
prepared from the cis-(E)-enoate 31 (42.3 mg, 0.106 mmol), was
converted into Mts--Phe-ψ[(E)-CH᎐CH]--Leu-OMe 59 (41.7
᎐
mg, 0.091 mmol, 86% yield based on 31) by treatment with
BuiCu(CN)MgClؒBF3 (0.424 mmol) in THF at Ϫ78 ЊC for 30
min.
J 15.5, 7.3 and 1.0, CH᎐), 5.36 (1 H, ddd, J 15.5, 7.6 and 1.0,
Compound 59, colourless crystals, mp 74–75 ЊC [from n-
hexane–Et2O (5:1)] (Found: C, 67.95; H, 7.63; N, 2.86.
C26H35NO4S requires C, 68.24; H, 7.71; N, 3.06%); [α]D18 Ϫ11.2 (c
0.624 in CHCl3); ∆ε Ϫ5.97 (221 nm, isooctane); δH[270 MHz;
CDCl3 containing tris-{3-[heptafluoropropyl(hydroxy)methyl-
ene]-d-camphorato}europium()] 0.77 (3 H, d, J 6.6, CMe),
0.81 (3 H, d, J 6.3, CMe), 1.18 (1 H, m, CHH), 1.29 (1 H, m,
CHH), 1.48 (1 H, m, CH), 2.29 (3 H, s, CMe), 2.54 (6 H, s,
CMe), 2.77 (1 H, dd, J 13.5 and 7.3, CHH), 2.85 (1 H, dd,
J 13.5 and 6.3, CHH), 2.99 (1 H, dd, J 15.2 and 7.6, 2-H), 3.72
(3 H, s, OMe), 3.98 (1 H, m, 5-H), 4.56 (1 H, d, J 6.3, NH), 5.36
᎐
CH᎐), 6.93 (2 H, s, ArH) and 7.04–7.29 (5 H, m, Ph); m/z
᎐
(FAB-LRMS) 442 [(M Ϫ H)Ϫ], 308 (base peak), 198, 183 and
153.
Mts-L-Val-ꢀ[(E)-CH᎐CH]-L-Phe-OMe 57 prepared from 14
᎐
By use of a procedure similar to that described for the prepar-
ation of 56 from 11, the crude mesyl derivative 15, which was
prepared from the trans-(E)-enoate 14 (120 mg, 0.342 mmol)
by MSA treatment, was converted into Mts--Val-ψ[(E)-
CH᎐CH]--Phe-OMe 57 (135 mg, 0.305 mmol, 89% yield based
᎐
(1 H, dd, J 15.7 and 5.9, CH᎐), 5.42 (1 H, dd, J 15.7 and 7.8,
᎐
on 14) by treatment with BnCu(CN)MgClؒBF3 (1.37 mmol) in
THF at Ϫ78 ЊC for 30 min.
CH᎐), 6.90 (2 H, s, ArH) and 7.02–7.27 (5 H, m, Ph); m/z (FAB-
᎐
LRMS) 480 (MNaϩ), 458 (MHϩ), 456 (MHϪ), 398 (base peak),
366, 259, 227, 199, 183, 129, 119 and 91.
Compound 57, colourless crystals, mp 82 ЊC [from n-hexane–
Et2O (5:1)] (Found: C, 67.77; H, 7.73; N, 3.07. C25H33NO4S
requires C, 67.69; H, 7.50; N, 3.16%); [α]D19 Ϫ64.8 (c 0.603 in
CHCl3); ∆ε Ϫ7.16 (221 nm, isooctane); δH(270 MHz; CDCl3)
0.73 (3 H, d, J 6.9, CMe), 0.79 (3 H, d, J 6.9, CMe), 1.69 (1 H,
m, 6-H), 2.27 (3 H, s, CMe), 2.52 (1 H, dd, J 13.5 and 6.3,
CHH), 2.62 (6 H, s, CMe), 2.86 (1 H, dd, J 13.5 and 8.6, CHH),
3.07 (1 H, m, 2-H), 3.51 (1 H, m, 5-H), 3.55 (3 H, s, OMe), 4.45
Mts-D-Phe-ꢀ[(E)-CH᎐CH]-D-Leu-OMe 60
᎐
By use of a procedure similar to that described for the prepar-
ation of 57 from 10, the cis-(E)-enoate 31 (53.3 mg, 0.133
mmol) was converted into Mts--Phe-ψ[(E)-CH᎐CH]--Leu-
᎐
OMe 60 (56.0 mg, 0.122 mmol, 92%) by treatment with
BuiCu(CN)MgClؒ2LiCl (0.534 mmol) in THF at Ϫ78 ЊC for 30
min.
Compound 60, colourless crystals, mp 109–110 ЊC [from
n-hexane–Et2O (5:1)] (Found: C, 67.97; H, 7.70; N, 3.06.
C26H35NO4S requires C, 68.24; H, 7.71; N, 3.06%); [α]D18 ϩ56.0
(c 0.603 in CHCl3); ∆ε ϩ5.64 (216 nm, isooctane); δH(270 MHz;
CDCl3) 0.81 (3 H, d, J 6.3, CMe), 0.83 (3 H, d, J 6.3, CMe),
1.14 (1 H, m, CHH), 1.36 (1 H, m, CHH), 1.46 (1 H, m, CH),
2.28 (3 H, s, CMe), 2.50 (6 H, s, CMe), 2.80 (2 H, d, J 6.6, 6-H2),
(1 H, d, J 7.9, NH), 5.19 (1 H, ddd, J 15.5, 7.6 and 1.0, CH᎐),
᎐
5.35 (1 H, ddd, J 15.5, 7.9 and 1.0, CH᎐), 6.93 (2 H, s, ArH) and
᎐
7.04–7.29 (5 H, m, Ph).
Mts-L-Val-ꢀ[(E)-CH᎐CH]-D-Phe-OMe 56 prepared from 14
᎐
By use of a procedure similar to that described for the prepar-
ation of 57 from 10, the trans-(E)-enoate 14 (56.2 mg, 0.160
mmol) was converted into Mts--Val-ψ[(E)-CH᎐CH]--Phe-
᎐
OMe 56 (54.4 mg, 0.123 mmol, 77%) as a colourless oil by
J. Chem. Soc., Perkin Trans. 1, 1999, 2983–2996
2993

View Article Online
2.89 (1 H, dd, J 15.2 and 7.6, 2-H), 3.60 (3 H, s, OMe), 3.90
(1 H, m, 5-H), 4.46 (1 H, d, J 6.6, NH), 5.27 (1 H, dd, J 15.5 and
was converted into the γ-mesyloxy-α,β-enoate 64 by treatment
with MSA in CHCl3.
7.6, CH᎐), 5.35 (1 H, dd, J 15.2 and 6.6, CH᎐), 6.88 (2 H, s,
Compound 64, colourless oil (crude), δH(300 MHz; CDCl3)
1.09 (2 H, m, CH2), 1.32 (2 H, m, CH2), 1.44 (1 H, m, CHH),
1.60 (1 H, m, CHH), 2.25 (3 H, s, CMe), 2.60 (6 H, s, CMe),
3.00 (3 H, s, SMe), 3.04 (2 H, m, CH2), 3.51 (1 H, m,
5-H), 4.88 (1 H, t, J 5.9, NH), 5.15 (2 H, s, CH2), 5.17 (1 H,
m, 4-H), 5.20 (2 H, s, CH2), 5.56 (1 H, d, J 8.2, NH), 6.02 (1 H,
᎐
᎐
ArH) and 7.00–7.27 (5 H, m, Ph); m/z (FAB-LRMS) 480
(MNaϩ), 458 (MHϩ), 456 (MHϪ), 398 (base peak), 366, 259,
227, 199, 183, 129, 119 and 91.
Benzyl (2E,4S,5S)-7-methyl-4-(methylsulfonyloxy)-5-(2,4,6-tri-
methylphenylsulfonylamino)oct-2-enoate 61
dd, J 15.7 and 1.4, CH᎐), 6.83 (1 H, dd, J 15.7 and 5.5,
᎐
CH᎐), 6.90 (2 H, s, ArH) and 7.24–7.44 (9 H, m, ArH); m/z
᎐
By use of a procedure similar to that described for the prepar-
ation of 11 from 10, the cis-(E)-enoate 36 (94.9 mg, 0.215
mmol) was converted into the γ-mesyloxy-α,β-enoate 61 by
treatment with MSA in CHCl3.
(FAB-LRMS) 721 (MHϩ), 625 (base peak), 307, 289, 252, 208,
119 and 91.
Mts-L-Lys(Cl-Z)-ꢀ[(E)-CH᎐CH]-D-Ala-OBn 65
᎐
Compound 61, colourless oil (crude), δH(270 MHz; CDCl3)
0.64 (3 H, d, J 5.9, CMe), 0.82 (3 H, d, J 5.9, CMe), 1.24 (2 H,
m, 6-H2), 1.43 (1 H, m, 7-H), 2.28 (3 H, s, CMe), 2.62 (6 H, s,
CMe), 3.01 (3 H, s, SMe), 3.59 (1 H, m, 5-H), 4.56 (1 H, d, J 8.6,
NH), 5.18 (2 H, s, CH2), 5.24 (1 H, m, 4-H), 6.05 (1 H, dd,
J 15.8 and 1.7, CH᎐), 6.82 (1 H, dd, J 15.8 and 5.9, CH᎐), 6.93
To a stirred slurry of CuCN (390 mg, 4.34 mmol) in 12 cm3 of
dry THF under argon at Ϫ78 ЊC was added by syringe 2.89 cm3
(4.34 mmol) of 1.5 mol dmϪ3 MeLiؒLiBr in Et2O, and the mix-
ture was allowed to warm to 0 ЊC and was stirred at this temper-
ature for 15 min. BF3ؒEt2O (0.533 cm3, 4.34 mmol) was added
to the above mixture at Ϫ78 ЊC and the mixture was stirred for
5 min. A solution in dry THF (3 cm3) of the crude mesyl com-
pound 64, which was prepared from the cis-(E)-enoate 44 (678
mg, 1.08 mmol), was added dropwise to the above reagent at
Ϫ78 ЊC with stirring, and the stirring was continued for 30 min
followed by quenching with 6 cm3 of a 1:1 saturated aq.
NH4Cl–28% NH4OH solution. The mixture was extracted with
Et2O and the extract was washed with water and dried over
MgSO4. Concentration under reduced pressure gave a colour-
less oil, which was purified by flash chromatography over silica
gel with n-hexane–EtOAc (3:1) to yield 502 mg (0.782 mmol,
72% yield based on 44) of compound 65 as a colourless oil,
[Found (FAB): (M Ϫ H)Ϫ, 639.2300. C34H41ClN2O6S requires
M Ϫ H, 639.2295]; [α]D19 Ϫ5.64 (c 2.20 in CHCl3); ∆ε ϩ2.83 (223
nm, isooctane); δH(270 MHz; CDCl3) 1.01 (3 H, d, J 5.3, CMe),
1.26 (2 H, m, CH2), 1.41 (4 H, m, CH2), 2.25 (3 H, s, CMe), 2.58
(6 H, s, CMe), 2.89 (1 H, m, 2-H), 3.11 (2 H, m, CH2), 3.69 (1 H,
m, 5-H), 4.78 (1 H, d, J 7.3, NH), 4.88 (1 H, m, NH), 5.07 (2 H,
᎐
᎐
(2 H, s, ArH) and 7.39 (5 H, m, Ph); m/z (FAB-LRMS) 538
(MHϩ), 536 (MHϪ), 442, 352 (base peak), 268, 183, 152, 119
and 91.
Mts-L-Leu-ꢀ[(E)-CH᎐CH]-D-Phe-OBn 62
᎐
By use of a procedure similar to that described for the prepar-
ation of 56 from 11, the crude mesyl derivative 61, which was
prepared from the cis-(E)-enoate 36 (94.9 mg, 0.215 mmol), was
converted into Mts--Leu-ψ[(E)-CH᎐CH]--Phe-OBn 62 (103
᎐
mg, 0.192 mmol, 89% yield based on 36) by treatment
with BnCu(CN)MgClؒBF3 (0.860 mmol) in THF at Ϫ78 ЊC for
30 min.
Compound 62, colourless crystals, mp 81 ЊC [from n-hexane–
Et2O (3:1)] (Found: C, 71.97; H, 7.43; N, 2.38. C32H39NO4S
requires C, 72.01; H, 7.36; N, 2.62%); [α]D28 0 (c 2.682 in CHCl3);
∆ε ϩ2.74 (210 nm, isooctane); δH(270 MHz; CDCl3) 0.74 (3 H,
d, J 6.3, CMe), 0.76 (3 H, d, J 6.3, CMe), 1.20 (2 H, m, 6-H2),
1.35 (1 H, m, 7-H), 2.25 (3 H, s, CMe), 2.52 (1 H, dd, J 13.5 and
7.3, CHH), 2.57 (6 H, s, CMe), 2.88 (1 H, dd, J 13.5 and 8.3,
CHH), 3.10 (1 H, dd, J 15.5 and 7.6, 2-H), 3.68 (1 H, m, 5-H),
4.29 (1 H, m, NH), 5.03 (2 H, s, CH2), 5.05 (1 H, dd, J 15.5 and
s, CH ), 5.12 (1 H, ddd, J 15.5, 7.3 and 1.5, CH᎐), 5.21 (2 H, s,
᎐
2
CH ), 5.45 (1 H, dd, J 15.5 and 6.9, CH᎐), 6.88 (2 H, s, ArH)
᎐
2
and 7.22–7.44 (9 H, m, ArH); m/z (FAB-LRMS) 639
[(M Ϫ H)Ϫ], 497, 471, 305, 198, 183, 168, 153, 151 and 122 (base
peak).
7.3, CH᎐), 5.42 (1 H, dd, J 15.5 and 8.2, CH᎐), 6.89 (2 H, s,
᎐
᎐
ArH) and 6.99–7.35 (10 H, m, Ph).
Mts-L-Lys(Cl-Z)-ꢀ[(E)-CH᎐CH]-L-Ala-OBn 66
᎐
Mts-L-Leu-ψ[(E)-CH᎐CH]-L-Phe-OBn 63
᎐
To a stirred solution of CuCN (32.3 mg, 0.359 mmol) and LiCl
(30.4 mg, 0.718 mmol) in dry THF (1 cm3) under argon at
Ϫ78 ЊC was added via syringe 0.240 cm3 (0.359 mmol) of 1.5
mol dmϪ3 MeLiؒLiBr in THF, and the mixture was allowed to
warm to 0 ЊC and was stirred at this temperature for 15 min. A
solution of the cis-(E)-enoate 44 (56.1 mg, 0.0897 mmol) in dry
THF (1 cm3) was added dropwise to the above reagent at
Ϫ78 ЊC with stirring, and the stirring was continued for 30 min
followed by quenching with 1 cm3 of a 1:1 saturated aq.
NH4Cl–28% NH4OH solution. The mixture was extracted with
Et2O and the extract was washed with water and dried over
MgSO4. Concentration under reduced pressure gave an oily
residue, which was purified by flash chromatography over silica
gel with n-hexane–EtOAc (3:1) to yield 55.8 mg (0.0870 mmol,
97%) of compound 66 as a colourless oil, [Found (FAB):
(M Ϫ H)Ϫ, 639.2292. C34H41ClN2O6S requires M Ϫ H,
639.2296]; [α]D21 Ϫ14.1 (c 1.34 in CHCl3); ∆ε Ϫ6.00 (216 nm,
isooctane); δH(270 MHz; CDCl3) 1.01 (3 H, d, J 6.9, CMe), 1.26
(2 H, m, CH2), 1.41 (4 H, m, CH2), 2.25 (3 H, s, CMe), 2.59
(6 H, s, CMe), 2.89 (1 H, m, 2-H), 3.11 (2 H, m, CH2), 3.66 (1 H,
m, 5-H), 4.67 (1 H, d, J 7.3, NH), 4.82 (1 H, m, NH), 5.05 (2 H,
By use of a procedure similar to that described for the prepar-
ation of 57 from 10, the cis-(E)-enoate 36 (71.3 mg, 0.161
mmol) was converted into Mts--Leu-ψ[(E)-CH᎐CH]--Phe-
᎐
OBn 63 (78.6 mg, 0.147 mmol, 91%) by treatment with
BnCu(CN)MgClؒ2LiCl (0.646 mmol) in THF at Ϫ78 ЊC for 30
min.
Compound 63, colourless crystals, mp 102–104 ЊC [from
EtOAc–Et2O (1:5)] (Found: C, 71.71; H, 7.32; N, 2.41.
C32H39NO4S requires C, 72.01; H, 7.36; N, 2.62%); [α]D29 Ϫ0.392
(c 2.04 in CHCl3); ∆ε Ϫ1.11 (214 nm, isooctane); δH(300 MHz;
CDCl3) 0.76 (3 H, d, J 1.8, CMe), 0.78 (3 H, d, J 1.8, CMe),
1.24 (2 H, m, 6-H2), 1.47 (1 H, m, 7-H), 2.99 (3 H, s, CMe),
2.53 (1 H, dd, J 13.6 and 6.1, CHH), 2.60 (6 H, s, CMe), 2.87
(1 H, dd, J 13.6 and 9.1, CHH), 3.09 (1 H, m, 2-H), 3.71 (1 H,
m, 5-H), 4.28 (1 H, d, J 7.5, NH), 4.98 (2 H, s, CH2), 5.15
(1 H, ddd, J 15.5, 7.6 and 0.7, CH᎐), 5.41 (1 H, ddd, J 15.5, 8.2
᎐
and 0.7, CH᎐), 6.91 (2 H, s, ArH) and 7.01–7.33 (10 H, m,
᎐
Ph).
Benzyl (2E,4S,5S)-9-[(2-chlorophenyl)methoxycarbonylamino]-
4-(methylsulfonyloxy)-5-(2,4,6-trimethylphenylsulfonylamino)-
non-2-enoate 64
s, CH ), 5.13 (1 H, dd, J 15.5 and 7.6, CH᎐), 5.22 (2 H, s, CH ),
᎐
2
2
5.36 (1 H, dd, J 15.5 and 7.6, CH᎐), 6.89 (2 H, s, ArH) and
᎐
By use of a procedure similar to that described for the prepar-
7.23–7.45 (9 H, m, ArH); m/z (FAB-LRMS) 639 [(M Ϫ H)Ϫ],
ation of 11 from 10, the cis-(E)-enoate 44 (678 mg, 1.08 mmol)
497, 471, 310, 305 (base peak), 198, 183, 168, 153 and 122.
2994
J. Chem. Soc., Perkin Trans. 1, 1999, 2983–2996

View Article Online
6-Benzyloxy-(2E,4S,5S)-N-methyl-4-(methylsulfonyloxy)-5-
(2,4,6-trimethylphenylsulfonylamino)hex-2-enamide 67
Methyl (2E,4S,5S)-6-benzyloxy-4-hydroxy-5-(2,4,6-trimethyl-
phenylsulfonylamino)hex-2-enoate 71
By use of a procedure similar to that described for the prepar-
ation of 11 from 10, the cis-(E)-enamide 54 (85 mg, 0.198
mmol) was converted into the crude γ-mesyloxy-α,β-enamide
67 (colourless oil) by treatment with MSA in CHCl3.
Compound 67, colourless oil (crude), δH(300 MHz; CDCl3)
2.29 (3 H, s, CMe), 2.58 (6 H, s, CMe), 2.85 (3 H, d, J 4.9,
NMe), 3.00 (3 H, s, SMe), 3.26 (1 H, dd, J 9.7 and 5.2, CHH),
3.46 (1 H, dd, J 9.7 and 4.0, CHH), 3.52 (1 H, m, 5-H), 4.20
(1 H, m, 4-H), 4.35 (2 H, s, CH2), 5.32 (1 H, d, J 8.9, NH), 5.76
Purification of the above crude trifluoroacetate 70 by flash
chromatography over silica gel with n-hexane–EtOAc (4:1)
afforded the hydrolysate 71 (106 mg, 0.236 mmol, 71% yield
based on 55) as a colourless oil, [Found (FAB): (M ϩ H)ϩ,
446.1653. C23H29NO6S requires M ϩ H, 446.1638]; [α]D28 Ϫ36.4
(c 0.0714 in CHCl3); δH(300 MHz; CDCl3) 2.31 (3 H, s, CMe),
2.53 (6 H, s, CMe), 3.55 (1 H, m, 5-H), 3.74 (3 H, s, OMe), 3.80
(2 H, m, CH2), 3.97 (1 H, d, J 8.8, 4-H), 4.56 (1 H, d, J 10.2,
NH), 4.58 (1 H, d, J 13.8, CHH), 4.68 (1 H, d, J 13.8, CHH),
(1 H, m, CONH), 6.07 (1 H, dd, J 15.4 and 1.2, CH᎐), 6.62
5.84 (1 H, dd, J 15.8 and 0.6, CH᎐), 6.95 (2 H, s, ArH), 7.12
᎐
᎐
(1 H, dd, J 15.4 and 6.5, CH᎐), 6.91 (2 H, s, ArH) and 7.19–7.36
(1 H, dd, J 15.8 and 8.7, CH᎐) and 7.01–7.29 (5 H, m, Ph); m/z
᎐
᎐
(5 H, m, Ph); m/z (FAB-LRMS) 525 (MHϩ), 475 (base peak),
(FAB-LRMS) 446 (MHϪ), 428, 306, 239 (base peak), 199, 183,
168, 153 and 122.
429, 391, 279, 167, 149, 119 and 91.
Mts-L-Ser(O-Bn)-ꢄ[(E)-CH᎐CH]-D-Ala-NHMe 68
Acknowledgements
᎐
By use of a procedure identical with that described for the
preparation of 65 from 64, the above crude mesyl compound
67, which was prepared from the cis-(E)-enamide 54 (85 mg,
0.198 mmol), was converted into Mts--Ser(O-Bn)-ψ[(E)-
This work was supported in part by a Grant-in-Aid for
Scientific Research (B) and (C) from the Ministry of Education,
Science, Sports and Culture, Japan and the Japan Health
Science Foundation. We are grateful to Dr Terrence R. Burke,
Jr., NCI, NIH, for helpful discussions during the preparation
of this manuscript.
CH᎐CH]--Ala-NHMe 68 (79 mg, 0.178 mmol, 90% based on
᎐
54) by treatment with MeCu(CN)LiؒLiBrؒBF3 (0.792 mmol) in
THF at Ϫ78 ЊC for 30 min.
Compound 68, colourless oil [Found (FAB): (M ϩ H)ϩ,
445.2156. C24H32N2O4S requires M ϩ H, 445.2161]; [α]D21 Ϫ29.7
(c 1.04 in CHCl3); ∆ε ϩ0.945 (221 nm, isooctane); δH(300 MHz;
CDCl3) 1.18 (3 H, d, J 7.1, CMe), 2.32 (3 H, s, CMe), 2.57 (6 H,
s, CMe), 2.74 (3 H, d, J 4.7, NMe), 2.89 (1 H, m, 2-H), 3.39
(2 H, d, J 5.9, CH2), 3.69 (1 H, m, 5-H), 4.41 (2 H, s, CH2), 5.20
References
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Mts-L-Ser(O-Bn)-ꢄ[(E)-CH᎐CH]-L-Ala-NHMe 69
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By use of a procedure identical with that described for the
preparation of 66 from 44, the cis-(E)-enamide 54 (39 mg, 0.091
mmol) was converted into Mts--Ser(O-Bn)-ψ[(E)-CH᎐CH]--
᎐
Ala-NHMe 69 (35 mg, 0.079 mmol, 87%) by treatment with
MeCu(CN)LiؒLiBrؒBF3 (0.364 mmol) in THF at Ϫ78 ЊC for 30
min.
Compound 69, colourless oil [Found (FAB): (M ϩ H)ϩ,
445.2165. C24H32N2O4S requires M ϩ H, 445.2161]; [α]D21 Ϫ35.1
(c 2.71 in CHCl3); ∆ε Ϫ6.96 (208 nm, isooctane); δH(300 MHz;
CDCl3) 1.21 (3 H, d, J 7.1, CMe), 2.30 (3 H, s, CMe), 2.57 (6 H,
s, CMe), 2.71 (3 H, d, J 4.8, NMe), 2.88 (1 H, m, 2-H), 3.37
(1 H, d, J 1.3, CHH), 3.39 (1 H, s, CHH), 3.72 (1 H, m, 5-H),
4.40 (2 H, s, CH2), 5.24 (1 H, d, J 4.7, NH), 5.47 (1 H, ddd,
J 15.6, 7.2 and 1.0, CH᎐), 5.75 (1 H, ddd, J 15.6, 7.5 and 0.9,
᎐
CH᎐), 6.20 (1 H, m, CONH), 6.93 (2 H, s, ArH) and 7.18–7.38
᎐
(5 H, m, Ph); m/z (FAB-LRMS) 445 (MHϩ), 246, 167 (base
peak), 156, 149, 119 and 91.
Methyl (2E,4S,5S)-6-benzyloxy-4-trifluoroacetoxy-5-(2,4,6-
trimethylphenylsulfonylamino)hex-2-enoate 70
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2.57 (6 H, s, CMe), 3.34 (1 H, m, 5-H), 3.73 (3 H, s, OMe),
3.79 (2 H, m, CH2), 4.38 (2 H, s, CH2), 5.32 (1 H, m, NH),
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᎐
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᎐
(5 H, m, Ph); m/z (FAB-LRMS) 566 (MNaϩ), 544 (MHϩ), 470,
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J. Chem. Soc., Perkin Trans. 1, 1999, 2983–2996
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