Regio- and stereoselective ring-opening of chiral 1,3-oxazolidin-2-one derivatives by organocopper reagents provides novel access to di-, tri- and tetra-substituted alkene dipeptide isosteres

Article abstract of DOI:10.1039/b203482d

Organocopper-mediated alkylation of β-(N-Boc-2-oxo-1,3-oxazolidin-5-yl)-α,β-enoates has been intensively investigated. Alkylation proceeded regio- and stereoselectively by anti-S_N2′ ring-opening to provide a new route to the synthesis of Ψ[(E)-

Full text of DOI:10.1039/b203482d

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Regio- and stereoselective ring-opening of chiral 1,3-oxazolidin-2-
one derivatives by organocopper reagents provides novel access to
di-, tri- and tetra-substituted alkene dipeptide isosteres†
1
Shinya Oishi,a Ayumu Niida,a Takae Kamano,a Yoshihisa Miwa,a Tooru Taga,a
Yoshihiko Odagaki,b Nobuyuki Hamanaka,b Mikio Yamamoto,c Keiichi Ajito,c
Hirokazu Tamamura,a Akira Otakaa and Nobutaka Fujii*a
a Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501,
Japan
b Minase Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, 618-8585,
Japan
c Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama, 222-0002,
Japan
Received (in Cambridge, UK) 9th April 2002, Accepted 7th June 2002
First published as an Advance Article on the web 27th June 2002
Organocopper-mediated alkylation of β-(N-Boc-2-oxo-1,3-oxazolidin-5-yl)-α,β-enoates has been intensively
investigated. Alkylation proceeded regio- and stereoselectively by anti-SN2Ј ring-opening to provide a new route to
the synthesis of ψ[(E)-CH᎐CH]-, ψ[(E)-CMe᎐CH]- and ψ[(E)-CMe᎐CMe]- type alkene dipeptide isosteres from
᎐
᎐
᎐
chiral amino acid derivatives. These resulting agents are potential mimetics of type II and type IIЈ β-turn
substructure.
Introduction
Determination of bioactive conformations of peptides often
allows identification of the spatial requirements involved in
pharmacophore activities. This in turn provides valuable
information for rational drug design of non-peptidic pharma-
ceuticals. For restriction of local and/or global conformation of
bioactive peptides, a number of peptidomimetics have been
developed, to aid in conformational structure–activity relation-
ship studies.1,2 Mimicry of the peptide backbone by replace-
ment with functional units or addition of secondary-structure-
promoting motifs represent effective strategies for conforma-
tional restriction of peptides. This can also be achieved through
cyclization via covalent bond formation between side chains of
neighbouring or distant residues. E-Alkene dipeptide isosteres
(EADIs), based on the concept of ω-angle planarity, have been
used as amide bond mimetics which are stable against specific/
non-specific degradation and which serve as mechanistic probes
Scheme 1 R1, R2, R3 = alkyl; L = OMs or Cl; Ms = methanesulfonyl.
lacking amide polarity.3,4 In particular, (,)-type and (,)-
type EADIs are thought to be potential surrogates of (i ϩ 1)–
(i ϩ 2) dipeptides in type II and type IIЈ β-turns, respectively.
Wipf et al. recently reported that, due to rigidity of φ- and ψ-
Reagents: i, R3Cu(CN)MgClؒBF3; ii, R3Cu(CN)MgClؒ2LiCl; iii,
MsOH or HCl.
dihedral angles, Xaa1-ψ[(E)-CMe᎐CH]-Xaa2- and Xaa1-ψ[(Z)-
the construction of side chain functionality at the α-position,
utilize organocopper-mediated alkylation of α,β-enoates with
a leaving group at the γ-position, to afford E-isomers of α-
alkylated products regio- and stereoselectively. For example,
treatment of γ-mesyloxy-α,β-enoates A7,8 and N-activated
γ,δ-epimino-α,β-enoates C9,10 with organocopper reagents gives
only anti-SN2Ј products B and D, respectively. In addition,
alkylation of γ-mesyloxy- or γ-chloro-α,β-enoates E, which can
be obtained by MsOH- or HCl-treatment of N-activated γ,δ-
epimino-α,β-enoates C, can also give anti-SN2Ј products DЈ,
which are diastereomers of D.11 As such, 1,3-chirality transfer
by organocopper-mediated alkylation offers an efficient
approach for the synthesis of molecules having two remote
᎐
CCF ᎐CH]-Xaa2 -type EADIs having trisubstituted alkenes
᎐
3
are more effective β-turn promoters in the solid state than
Xaa1-ψ[(E)-CH᎐CH]-Xaa2-type EADIs having disubstituted
᎐
alkenes, which lack heavy atoms corresponding to a carbonyl
oxygen.5 Gardner et al. have also shown that peptides contain-
ing a tetrasubstituted alkene such as a Gly-ψ[(E)-CMe᎐CMe]-
᎐
Gly-type EADI, induce β-hairpin formation.6
We and others have developed practical methodologies for
the stereoselective synthesis of EADIs starting from chiral
amino acid derivatives (Scheme 1).7–12 Herein, key reactions for
† Electronic supplementary information (ESI) available: synthetic pro-
cedures and characterization for 4a,b, 5a,b, 7b, 8a,b, 9a,b, 10b, 11a,b,
12b,c, 13b, 14a,b, 15, 16a,b, 17a,b, 18, 19b, 20b. See http://www.rsc.org/
suppdata/p1/b2/b203482d/
chiral centres adjacent to an olefin such as Xaa1-ψ[(E)-CH᎐
᎐
CH]-Xaa2-type EADIs.13 We assumed that ψ[(E)-CMe᎐CH]-
᎐
and ψ[(E)-CMe᎐CMe]-type EADIs could be synthesized
᎐
1786
J. Chem. Soc., Perkin Trans. 1, 2002, 1786–1793
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b203482d

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utilizing the same strategy as that used for the synthesis of
isopropenyl Grignard addition in the presence of anhydrous
ψ[(E)-CH᎐CH]-type EADIs. On the other hand, we inferred
CeCl3 to a methyl ketone, which was prepared by treatment of
Weinreb amide 1 with MeMgCl, preferentially afforded the syn-
allyl alcohols 4a and 5a (4a : 4b = 79 : 21 and 5a : 5b = 80 : 20),
respectively. Meanwhile, Swern oxidation of allyl alcohols 2
and 3 followed by addition of MeMgCl in the presence of
CeCl3 predominantly yielded anti-allyl alcohols 4b and 5b
(4a : 4b = 14 : 86 and 5a : 5b = 4 : 96), respectively. The ratio of
isomers formed can be explained by chelation control during
addition of alkenyl or methyl groups to methyl ketones or
enones (Fig. 1). Each isomer of the allyl alcohols 4b and 5a,b
᎐
that γ-methylated γ-mesyloxy-α,β-enoates or γ-methylated γ,δ-
epimino-α,β-enoates might not be obtainable through known
synthetic schemes owing to difficulties in derivatization of the
tertiary hydroxy group. As an example of this, a -Ala-ψ[(E)-
CMe᎐CH]--Ala-type EADI was prepared only in low overall
᎐
yield by Wipf et al. from a chiral epoxide, wherein derivatiza-
tion of the epoxide to a γ-methylated γ,δ-epimino-α,β-enoate
was not efficient. Therefore, we sought to develop a new general
synthesis of diverse ψ[(E)-CMe᎐CH]- and ψ[(E)-CMe᎐CMe]-
᎐
᎐
type EADIs using organocopper-mediated alkylation of new
key intermediates.14
Accordingly, 5-vinyl-1,3-oxazolidin-2-ones, having hydroxy
groups protected and activated as cyclic carbamates, were sub-
jected to various modifications using organometallic reagents
with accompanying ring-opening and decarboxylation.15–18
We had previously reported that alkylation of 5-vinyl-1,3-oxa-
zolidin-2-ones with various organocopper reagents proceeds
regio- and stereoselectively to give vinylglycine derivatives.15 We
further thought to examine the alkylation of β-(N-Boc-2-oxo-
1,3-oxazolidin-5-yl)-α,β-enoates as an approach to precursors
for the synthesis of EADIs. In this article, we report the
organocopper-mediated alkylation of β-(N-Boc-2-oxo-1,3-
oxazolidin-5-yl)-α,β-enoates to afford ψ[(E)-CH᎐CH]-type
᎐
EADIs having disubstituted alkenes. We further report its
Fig. 1
application to the synthesis of ψ[(E)-CMe᎐CH]- and ψ[(E)-
᎐
CMe᎐CMe]-type EADIs having multisubstituted alkenes.
᎐
was obtained as a single diastereomer following purification by
flash chromatography and repeated recrystallization. The syn-
allyl alcohol 4a containing the minor isomer 4b was used for
next step without further purification.
Results and discussion
Sodium hydride-mediated cyclization of allyl alcohols 6a,b,19
4a,b and 5a,b followed by N-protection with (Boc)2O efficiently
gave the respective 1,3-oxazolidin-2-ones 7a,b, 8a,b and 9a,b.
Removal of the minor isomer 8b from 8a was carried out
at this step by repeated recrystallization. Ozone–dimethyl
sulfide treatment of the 5-vinyl derivatives 7a,b, 8a,b followed
by modified Horner–Wadsworth–Emmons reaction (HWE
reaction)21 gave α,β-enoates 10a,b and 11a,b E-selectively. β-
Methylated analogues 12a,b were also obtained E-selectively
Synthesis of diastereomerically pure ꢀ-(N-Boc-2-oxo-1,3-
oxazolidin-5-yl)-ꢁ,ꢀ-enoates
In the synthesis of EADIs based on the anti-SN2Ј reaction of
organocopper reagents, the chirality of the leaving group at
the γ-position and the geometry of the olefin are responsible
for the chirality of alkyl groups introduced at the product
α-position. As such, the efficient synthesis of enantio- and
diastereomerically pure substrates is critical. We therefore
investigated the preparation of chiral β-(N-Boc-2-oxo-1,3-
oxazolidin-5-yl)-α,β-enoates, including mono- and dimethyl-
ated derivatives. These were selected as chiral key intermediates
for the preparation of diverse EADIs from α-amino alcohol or
α-amino acid derivatives 1–316,19,20 (Scheme 2 and 3). Vinyl and
following Wittig reaction with Ph P᎐CHCO But in CHCl of
᎐
3
2
3
methyl ketones prepared by ozonolysis and successive reductive
treatment of 5-isopropenyl derivatives 9a,b. Peterson olefina-
tion of the methyl ketone derived from 9b gave an unexpected
Z-isomer of α,β-enoates 12c, although in low yield.
The 2E-geometry of 10a,b and 11a,b was established based
1
on the large H-coupling constants between the two olefinic
protons (15.5–15.6 Hz). The geometry of 12a,b was established
by the absence of NOESY cross-peaks between the olefinic pro-
ton and the β-methyl protons, while the 2Z-geometry of 12c
was established by NOE enhancement (19%) of the olefinic
proton resonance upon irradiation of the β-methyl protons.
Relative configurations of 1,3-oxazolidin-2-ones 11a,b were
established by NOE experiments. No NOE enhancement of the
4-H resonance was observed by irradiation of the 5-methyl pro-
tons in the trans-isomer 11a, while an NOE enhancement in
the cis-isomer 11b was observed (12%). The trans-configuration
of 12a was established by a NOESY cross-peak between the
5-methyl protons and one benzyl proton, while the cis-con-
figuration of 12b was established by cross-peaks between the
4-H proton and the 5-methyl protons.
Synthesis of ꢀ[(E )-CH᎐CH]-type EADIs by alkylation with
᎐
ring-opening of ꢀ-(N-Boc-2-oxo-1,3-oxazolidin-5-yl)-ꢁ,ꢀ-enoates
using organocopper reagents
For β-(N-Boc-2-oxo-1,3-oxazolidin-5-yl)-α,β-enoates, at least
four alkylation sites are possible: SN2-type substitution sites
(Fig. 2, sites a and b) and a likely SN2Ј-type substitution site
Scheme 2 Reagents: i, MeMgCl, THF; ii, CH2᎐᎐CH–MgCl, CeCl3,
THF; iii, CH2᎐᎐CMe–MgBr, CeCl3, THF; iv, (COCl)2, DMSO,
(Pri)2NEt, CH2Cl2; v, MeMgCl, CeCl3, THF.
J. Chem. Soc., Perkin Trans. 1, 2002, 1786–1793
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Scheme 3 Reagents: i, NaH, THF; ii, (Boc)2O; iii, O3 gas, EtOAc or CH2Cl2; iv, Me2S; v, (EtO)2P(O)CH2CO2But, LiCl, (Pri)2NEt, MeCN; vi, Ph3P᎐
᎐
CHCO2But, CHCl3; vii, Me3SiCH2CO2But, (Cy)2NLi, THF.
(CN)MgClؒBF3ؒ2LiCl (R = Pri and Bn)] also provided the
respective α-alkylated products, -Phe-ψ[(E)-CH᎐CH]--Xaa
᎐
14a and 16a (Xaa = Val and Phe, respectively), in excellent
yields (entries 4 and 6). Interestingly, unforeseen formation of
the Z-isomer of the anti-S 2Ј product, -Phe-ψ[(Z)-CH᎐CH]-
᎐
N
-Val 15, was observed only in the reaction of 10a with
PriCu(CN)MgClؒBF3ؒ2LiCl (entry 4), although the reason for
this is unclear.22 An α-alkylated product 14a and Z-isomer 15
were also afforded in moderate yields using a “higher-order”
organocyanocuprate–BF3 complex [Pri2Cu(CN)(MgCl)2ؒBF3ؒ
2LiCl, entry 5). This is an inappropriate reagent for alkylation
of N-activated β-aziridinyl-α,β-enoates, owing to the formation
of unwanted reductive products.9 Alkylation of cis-1,3-oxa-
zolidin-2-one 10b with the “lower-order” methyl cyanocuprate–
BF3 complex [MeCu(CN)LiؒBF3ؒLiBr] derived from methyl-
lithium in THF–Et2O, resulted in the production of small
amounts of α-alkylated product 13b with recovery of starting
material 10b (entry 7), whereas use of a “higher-order” complex
[Me2Cu(CN)Li2ؒBF3ؒ2LiBr] gave a number of uncharacterized
products (entry 8). In contrast, alkylation of 10b proceeded
favourably using organocyanocuprate–BF3 complexes [RCu-
(CN)MgClؒBF3ؒ2LiCl, R = Me, Pri and Bn] derived from
Fig. 2
(site d) with ring-opening, and a 1,4-addition site (site c).
Alkylation of α,β-enoates having a leaving group at the γ-
position is known to proceed principally via an SN2Ј mechan-
ism. However, we were afraid that 1,4-adducts might be
obtained without ring-opening, due to the poor leaving-group
ability of cyclic carbamates. Therefore we next investigated in
detail alkylations of β-(N-Boc-2-oxo-1,3-oxazolidin-5-yl)-α,β-
enoates 10a,b by various organocopper reagents (Scheme 4 and
Grignard reagents, to afford -Phe-ψ[(E)-CH᎐CH]--Xaa 13b,
᎐
14b and 16b (Xaa = Ala, Val and Phe), respectively, in excellent
yields (entries 9–11). This was similar to reactions of the trans-
isomer 10a. In contrast to the trans-isomer 10a (entry 4),
reaction of cis-1,3-oxazolidin-2-one 10b with PriCu(CN)MgClؒ
BF3ؒ2LiCl gave exclusively the E-isomer of the α-alkylated
product 14b without production of the Z-isomer (entry 10).
The regiochemistry of the resulting EADIs, 13a,b, 14a,b and
16a,b was readily assigned by 1H–1H COSY spectra, large
coupling constants between the olefinic protons (15.4–15.7 Hz)
and/or comparison with the 1H NMR spectrum of an authentic
sample.8 The stereochemical assignments of the α-alkyl
groups in 13a,b, 14a,b and 16a,b could be deduced from
well-established organocopper-mediated anti-SN2Ј alkylations.
Additionally, the 1H NMR spectrum of 14a was in good
accordance with that of the enantiomer8 derived from another
precursor. Based both on a 220 nm negative Cotton effect in its
CD spectrum23 and on regiochemical assignment by 1H NMR
spectroscopy, the α-adduct 15 was proved to be the Z-isomer
Scheme 4
Table 1). Here, expected α-alkylations of 10a,b by an anti-SN2Ј
mechanism should give ψ[(E)-CH᎐CH]–type EADIs.
᎐
Treatment of trans-1,3-oxazolidin-2-one 10a with either
a methyl copper reagent (MeCuؒLiIؒLiBr) or Gilman-type
reagent (Me2CuLiؒLiIؒ2LiBr) in THF gave a complex mixture
of products (Table 1, entries 1 and 2). On the other hand,
“lower-order” organocyanocuprate–BF3 complexes prepared
from methyl Grignard reagents [MeCu(CN)MgClؒBF3ؒ2LiCl]
in THF at Ϫ78 ЊC for 30 min gave an α-alkylated product,
of an anti-S 2Ј product, -Phe-ψ[(Z)-CH᎐CH]--Val-type iso-
᎐
N
stere. As such, except for the formation of a Z-isomer 15 from
10a, each reaction using organocopper reagents derived from
Grignard reagents yielded the respective single diastereomers
-Phe-ψ[(E)-CH᎐CH]--Ala 13a, regio- and stereoselectively
(entry 3). Other organocyanocuprate–BF3 complexes [RCu-
᎐
1788
J. Chem. Soc., Perkin Trans. 1, 2002, 1786–1793

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Table 1 Alkylation of β-(N-Boc-2-oxo-1,3-oxazolidin-5-yl)-α,β-enoates 10a and 10b by organocopper reagents
Entry
Substrate
Reagent (4 eqiuv.)
Solvent
Conditions
Products (Yield %)
a
1
2
3
4
5
6
7
8
9
10a
10a
10a
10a
10a
10a
10b
10b
10b
10b
10b
MeCuؒLiIؒLiBr
Me2CuLiؒLiIؒ2LiBr
THF–Et2O (10 : 1)
THF–Et2O (5 : 1)
THF
THF
THF
Ϫ78 ЊC, 30 min, then 0 ЊC, 1 h
Ϫ78 ЊC, 1 h
Ϫ78 ЊC, 30 min
Ϫ78ЊC, 30 min
Ϫ78 ЊC, 30 min
Ϫ78 ЊC, 30 min
Ϫ78 ЊC, 30 min, then 0 ЊC, 3 h
Ϫ78 ЊC, 30 min
Ϫ78 ЊC, 30 min
Ϫ78 ЊC, 30 min
—
—
a
MeCu(CN)MgClؒBF3ؒ2LiCl
PriCu(CN)MgClؒBF3ؒ2LiCl
Pri2Cu(CN)(MgCl)2ؒBF3ؒ2LiCl
BnCu(CN)MgClؒBF3ؒ2LiCl
MeCu(CN)LiؒBF3ؒLiBr
Me2Cu(CN)Li2ؒBF3ؒ2LiBr
MeCu(CN)MgClؒBF3ؒ2LiCl
PriCu(CN)MgClؒBF3ؒ2LiCl
BnCu(CN)MgClؒBF3ؒ2LiCl
13a (77)
14a (85) ϩ 15 (14)b
14a (50) ϩ 15 (27)b
16a (99)
THF
THF–Et2O (10 : 1)
THF–Et2O (5 : 1)
THF
THF
THF
13b (24)c
a
—
13b (90)
14b (96)
16b (99)
10
11
Ϫ78 ЊC, 30 min
a α-Alkylated products were not isolated. b The product ratios were determined by reverse phase HPLC. c The starting material was recovered (58%).
Table 2 Alkylation of mono- and dimethylated β-(N-Boc-2-oxo-1,3-oxazolidin-5-yl)-α,β-enoates 11a,b and 12a,b by organocopper reagents
Entry
Substrate
Reagent
Conditions
Products (Yield %)
1
2
3
4
5
6
7
8
9
11a
11a
11a
11a
11b
11b
12a
12a
12b
12b
12b
12b
PriCu(CN)MgClؒBF3 (4.2 equiv.)
Ϫ78 ЊC, 30 min
Ϫ78 ЊC, 30 min
Ϫ78 ЊC, 30 min
Ϫ78 ЊC, 30 min
Ϫ78 ЊC, 30 min
Ϫ78 ЊC, 30 min
Ϫ78 ЊC, 30 min, then 0 ЊC, 3 h
Ϫ78 ЊC, 30 min, then 0 ЊC, 3 h
Ϫ78 ЊC, 30 min, then 0 ЊC, 3 h
Ϫ78 ЊC, 30 min, then 0 ЊC, 3 h
Ϫ78 ЊC, 30 min, then 0 ЊC, 3 h
Ϫ78 ЊC, 30 min, then 0 ЊC, 3 h
17a (70) ϩ 18 (22)a
17a (38) ϩ 18 (26)a
17a (68) ϩ 18 (31)a
17a (58) ϩ 18 (27)a
17b (95)
Pri2Cu(CN)(MgCl)2ؒBF3 (4.2 equiv.)
PriCu(CN)MgClؒBF3ؒ2LiCl (4.2 equiv.)
Pri2Cu(CN)(MgCl)2ؒBF3ؒ2LiCl (4.2 equiv.)
PriCu(CN)MgClؒBF3ؒ2LiCl (4 equiv.)
Pri2Cu(CN)(MgCl)2ؒBF3ؒ2LiCl (4 equiv.)
PriCu(CN)MgClؒBF3ؒ2LiCl (4 equiv.)
Pri2Cu(CN)(MgCl)2ؒBF3ؒ2LiCl (4 equiv.)
PriCu(CN)MgClؒBF3ؒ2LiCl (4 equiv.)
Pri2Cu(CN)(MgCl)2ؒBF3ؒ2LiCl (4 equiv.)
Pri2Cu(CN)(MgCl)2ؒBF3ؒ2LiCl (6 equiv.)
Pri3Cu(CN)(MgCl)3ؒBF3ؒ2LiCl (4 equiv.)
17b (95)
b
—
19a (75) ϩ 20a (20)a
b
—
10
11
12
19b (37) ϩ 20b (11)a
19b (55) ϩ 20b (19)a
19b (52) ϩ 20b (25)a
a The product ratios were determined by reverse phase HPLC. b The starting material was recovered.
regio- and stereoselectively out of four possible α-alkylated
syntheses of -Phe-ψ[(E)-CMe᎐CH]--Val-, -Phe-ψ[(E)-
᎐
products.
CMe᎐CMe]--Val-type EADIs and their diastereomers were
᎐
attempted. Such structures represent a potential (i ϩ 1)–(i ϩ 2)
scaffold of type IIЈ β-turn found in the cyclic RGD peptide,
cyclo(-Arg-Gly-Asp--Phe-Val-).24 As employed for the syn-
Synthesis of ꢀ[(E )-CMe᎐CH]- and ꢀ[(E )-CMe᎐CMe]-type
alkene dipeptide isosteres via organocopper-mediated alkylation
᎐
᎐
thesis of ψ[(E)-CH᎐CH]-type EADIs from 1,3-oxazolidin-
᎐
To extend the application of regio- and stereoselective alkyl-
ation of β-(N-Boc-2-oxo-1,3-oxazolidin-5-yl)-α,β-enoates by
2-ones 10a,b, isopropylcyanocuprate–BF3 complexes were
prepared from PriMgCl and used for alkylations.
organocopper reagents, we sought to synthesize ψ[(E)-CMe᎐
᎐
Similarly to the reaction of trans-1,3-oxazolidin-2-one 10a,
treatment of monomethylated (γ-methylated) trans-1,3-oxa-
zolidin-2-one 11a with PriCu(CN)MgClؒBF3 in THF at Ϫ78 ЊC
for 30 min afforded α-alkylated products as both the E-isomer,
CH]- and ψ[(E)-CMe᎐CMe]-type EADIs having multisubsti-
᎐
tuted alkenes (Scheme 5 and Table 2). As a model system,
-Phe-ψ[(E)-CMe᎐CH]--Val 17a, and the Z-isomer, -Phe-
᎐
ψ[(Z)-CMe᎐CH]--Val 18 (17a : 18 = 76 : 24, Table 2, entry 1).
᎐
Additionally, reaction of 11a with Pri2Cu(CN)(MgCl)2ؒBF3
also gave α-alkylated products 17a and 18 in low selectivity
(entry 2). The use of LiCl-containing complexes such as PriCu-
(CN)MgClؒBF3ؒ2LiCl and Pri2Cu(CN)(MgCl)2ؒBF3ؒ2LiCl in
the reaction of 11a somewhat improved the combined yield of
α-alkylated products (entries 3 and 4).25 From the cis-isomer
11b, only the E-isomer of the α-alkylated product, -Phe-
ψ[(E)-CMe᎐CH]--Val 17b, was obtained in excellent yields
᎐
both by treatment with PriCu(CN)MgClؒBF3ؒ2LiCl and with
Pri2Cu(CN)(MgCl)2ؒBF3ؒ2LiCl in THF at Ϫ78 ЊC for 30 min
(entries 5 and 6).
In contrast, dimethylated (β,γ-dimethylated) 1,3-oxazolidin-
2-ones 12a,b displayed different reactivity to organocopper
reagents than those of the non-methylated 10a,b and mono-
methylated ones 11a,b. For both isomers of 1,3-oxazolidin-2-
ones 12a,b, no reaction was observed with the “lower-order”
cyanocuprate–BF3 complex [PriCu(CN)MgClؒBF3ؒ2LiCl],
rather, starting materials were recovered (entries 7 and 9). This
was probably due to the low reactivity of the reagent. Alter-
natively, alkylation of trans-1,3-oxazolidin-2-one 12a with the
“higher-order” cyanocuprate–BF3 complex [Pri2Cu(CN)(Mg-
Cl)2ؒBF3ؒ2LiCl] at Ϫ78 ЊC for 30 min then at 0 ЊC for 3 h,
afforded two isomeric α-alkylated products, -Phe-ψ[(E)-
Scheme 5
J. Chem. Soc., Perkin Trans. 1, 2002, 1786–1793
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CMe᎐CMe]--Val 19a and -Phe-ψ[(Z)-CMe᎐CMe]--Val
᎐
᎐
20a. The selectivity of this reaction was similar to that in reac-
tions of trans-1,3-oxazolidin-2-ones 10a and 11a (19a : 20a =
79 : 21, entry 8). On the other hand, treatment of the cis-isomer
12b with four equivalents of Pri2Cu(CN)(MgCl)2ؒBF3ؒ2LiCl
gave both the expected E-isomer, -Phe-ψ[(E)-CMe᎐CMe]--
᎐
Val 19b, as well as the Z-isomer, -Phe-ψ[(Z)-CMe᎐CMe]--
᎐
Val 20b, in low yield (19b : 20b = 76 : 24). Substrate 12b was
recovered in 13% yield (entry 10). Using six equivalents of the
same reagent or four equivalents of Pri3Cu(CN)(MgCl)3ؒBF3ؒ
2LiCl improved the combined yields of the reaction to 74 or
77%, respectively, although trace amounts of reactant 12b still
remained (entries 11 and 12).
Regiochemical assignments of EADIs 17a,b, 18, 19a,b and
1
20a,b were accurately established by H NMR (1H–1H COSY,
NOE experiments and NOESY). For example, an NOE
enhancement of the olefinic proton signal upon irradiation of
the 5-H resonance in the 3E-isomer 17a (7%) as well as by
irradiation of the 4-methyl proton signal in the 3Z-isomer 18
(15%) were observed. The presence of a cross-peak between the
olefinic proton and the 5-H proton and the absence of a cross-
peak between the olefinic proton and the 4-methyl protons in
the NOESY spectrum of 17b, suggested 3E-geometry. The
lack of NOE enhancement of the 5-H proton signal of 19b
following irradiation of the 2-H proton signal, along with an
NOE enhancement of the same signal of 20b (14%), suggested
that 19b and 20b had 3E- and 3Z-geometries, respectively.
The stereochemistry of the α-alkyl groups of 17a,b, 18, 19a,b
and 20a,b was established by the CD spectra.23 EADIs 17a, 19a
and 20b, which showed negative Cotton effects, were regarded
as 2R-isomers, while 17b, 18, 19b and 20a, which showed
positive Cotton effects around 220 nm, were regarded as 2S-
isomers. Crystal structures of 18,‡ 19a‡ and 19b also
supported these assignments. Based on the above, it was
concluded that all α-alkylated products 17a,b, 18, 19a,b and
20a,b were obtained by organocopper-mediated anti-SN2Ј-type
alkylation.
A feasible mechanism for organocopper-mediated alkyl-
ation of β-(N-Boc-2-oxo-1,3-oxazolidin-5-yl)-α,β-enoates was
inferred based on the precedence of γ-mesyloxy-α,β-enoates7
or N-activated γ,δ-epimino-α,β-enoates9 as shown in Fig. 3.
Assuming direct alkylation by the organocopper reagents,
examination of two possible conformers during the reaction
facilitates interpretation of the diastereoselective formation
of E- and Z-isomers. For example, alkylation of conformers
10a,b-A, 11a,b-A and 12a,b-A can yield only E-isomers 13a,b,
14a,b, 16a,b, 17a,b and 19a,b, while conformers 10a,b-B, 11a,b-
B and 12a,b-B would yield only Z-isomers such as 15, 18 and
20a,b. It might be supposed that the product ratios of E- and Z-
isomers depend on the proportions of these two conformers,
the stability of which is based on the cis/trans-configuration of
the 1,3-oxazolidin-2-ones and the presence of methyl groups.26
In addition, the unlikely formation of reactive conformers 12b-
A and 12b-B of dimethylated cis-1,3-oxazolidin-2-one 12b due
to 1,3-allylic strain, may cause low reactivity to organocopper
reagents. This could result in the production of Z-isomer 20b,
which does not occur with the non- and monomethylated sub-
strates 10b and 11b. On the other hand, the formation of
copper-π-allyl complexes as reactive intermediates such as 21a–
d cannot be ruled out. In such a mechanism, two complexes 21a
and 21b, which can afford E- and Z-isomers of α-alkylated
products, respectively, would be required to form from
trans-1,3-oxazolidin-2-ones 10–12a in a ratio dependent on
their stability. Similarly, two complexes 21c and 21d should be
formed from cis-1,3-oxazolidin-2-ones 10–12b. In fact, in the
alkylation of the non-methylated trans-1,3-oxazolidin-2-one
10a, formation of the Z-isomer 15 of the α-alkylated product
Fig. 3 Feasible reaction mechanism in the alkylation of β-(N-Boc-2-
oxo-1,3-oxazolidin-5-yl)-α,β-enoates. R1, R2 = H or Me.27
was observed only by treatment with PriCu(CN)MgClؒBF3ؒ
2LiCl (but not the methyl and benzyl counterparts). Bulky
alkyl groups such as an isopropyl group, may lead to favour-
able formation of other copper-π-allyl complexes such as 21b,
which can provide the Z-isomer 15. In both mechanisms,
organocopper-mediated alkylation of 1,3-oxazolidin-2-ones
10a,b, 11a,b and 12a,b can afford only anti-SN2Ј-type
products.
In conclusion, we have found that alkylation of β-(N-Boc-
2-oxo-1,3-oxazolidin-5-yl)-α,β-enoates with organocyano-
cuprates derived from Grignard reagents proceeds with ring-
opening and decarboxylation to afford α-alkylated products in
a regio- and stereoselective fashion. The stereochemistry at the
α-positions of the α-alkylated products depends on the chirality
of the 5-position of the 1,3-oxazolidin-2-one derivatives. The
reactions proceed with complete anti-SN2Ј-type chirality trans-
fer regardless of E/Z-products. Finally, we have achieved the
first synthesis of ψ[(E)-CMe᎐CH]- and ψ[(E)-CMe᎐CMe]-
᎐
᎐
type alkene dipeptide isosteres starting from chiral amino
acid derivatives by application of organocopper-mediated
alkylation. To summarize, the reaction of 1,3-oxazolidin-2-one
derivatives with organocopper reagents yields (,)-/(,)-type
E- and (,)-/(,)-type Z-alkene isosteres from trans-starting
material, while cis-isomers yield (,)-/(,)-type E- and (,)-/
(,)-type Z-alkene isosteres.
‡ The crystal structures of 18 and 19a were presented in the preliminary
communication.14
1790
J. Chem. Soc., Perkin Trans. 1, 2002, 1786–1793

View Article Online
n-hexane–Et2O (3 : 1)] (Found: C, 65.44; H, 7.21; N, 3.34.
Experimental
C22H29NO6 requires C, 65.49; H, 7.24; N, 3.47%); [α]2D0 Ϫ74.7
(c 0.976 in CHCl3); δH (300 MHz; CDCl3) 1.44 (9 H, s, CMe3),
1.59 (9 H, s, CMe3), 2.82 (1 H, dd, J 13.4 and 9.8, CHH), 3.37
(1 H, dd, J 13.4 and 3.6, CHH ), 4.22 (1 H, ddd, J 9.8, 3.5 and
2.9, NCH), 4.74 (1 H, ddd, J 4.5, 2.8 and 1.7, OCH), 5.86 (1 H,
General
1H NMR spectra were recorded using a JEOL EX-270, a
Bruker AC 300 or a Bruker AM 600 spectrometer at 270, 300 or
600 MHz. Chemical shifts are reported in parts per million
downfield from internal tetramethylsilane and coupling con-
stants (J) are given in Hz. Nominal (LRMS) and exact mass
(HRMS) spectra were recorded on a JEOL JMS-01SG-2 or
JMS-HX/HX 110A mass spectrometer. Optical rotations were
measured for samples in CHCl3 with a Horiba high-sensitivity
polarimeter SEPA-200 (Kyoto, Japan). CD spectra were
recorded on a JASCO J-720 spectropolarimeter. The X-ray
analysis was carried out on a Rigaku AFC5R-RU200 four-
circle diffractometer. Melting points were measured on a
hot stage melting point apparatus and are uncorrected.
For flash chromatography, Silica Gel 60 H (silica gel for
thin-layer chromatography, Merck) and Wakogel C-200 (silica
gel for column chromatography) were employed. For HPLC
separations, a Cosmosil 5C18-ARII analytical (4.6 × 250 mm)
column was employed, and eluting products were detected by
UV at 220 nm. A solvent system consisting of 0.1% TFA
aqueous solution (v/v) and 0.1% TFA in MeCN (v/v) was used
for HPLC elution.
dd, J 15.6 and 1.7, CH᎐), 6.42 (1 H, dd, J 15.6 and 4.5, CH᎐),
᎐
᎐
7.15–7.40 (5 H, m, Ph).
tert-Butyl (2E )-3-[(4R,5R)-4-benzyl-N-(tert-butoxycarbonyl)-5-
methyl-2-oxo-1,3-oxazolidin-5-yl]but-2-enoate 12a
By use of a procedure similar to that described for the succes-
sive treatment of the 1,3-oxazolidin-2-one 7a with ozone gas
and Me2S, the 1,3-oxazolidin-2-one 9a (3.33 g, 10.0 mmol) was
converted into the corresponding ketone. To a solution of the
above ketone in CHCl (20 cm3) was added Ph P᎐CHCO But
᎐
3
3
2
(11.3 g, 30.1 mmol), and the mixture was gently refluxed for
24 h. Concentration under reduced pressure followed by flash
chromatography over silica gel with n-hexane–EtOAc (6 : 1)
gave the title compound 12a (3.08 g, 7.13 mmol, 71%) as colour-
less crystals, mp 158–159 ЊC [from n-hexane–Et2O (3 : 1)];
(Found: C, 66.82; H, 7.71; N, 3.24. C24H33NO6 requires C,
66.80; H, 7.71; N, 3.25%); [α]2D4 ϩ78.3 (c 1.06 in CHCl3); δH (300
MHz; CDCl3) 1.40 (3 H, s, CMe), 1.45 (9 H, s, CMe3), 1.47
(9 H, s, CMe3), 1.90 (3 H, d, J 1.2, CMe), 2.98 (1 H, dd, J 14.3
and 9.1, CHH), 3.18 (1 H, dd, J 14.3 and 4.5, CHH ), 4.48 (1 H,
(4S,5S)-4-Benzyl-N-(tert-butoxycarbonyl)-5-ethenyl-1,3-oxa-
zolidin-2-one 7a
dd, J 9.1 and 4.5, CH), 5.95 (1 H, m, CH᎐), 7.23–7.38 (5 H,
᎐
m, Ph).
To a stirred suspension of NaH (1.58 g, 66.0 mmol) in dry THF
(40 cm3) was added dropwise a solution of the known allyl
alcohol 6a19 (4.58 g, 16.5 mmol) in dry THF (60 cm3) at 0 ЊC
under argon, and the mixture was heated under reflux for
15 min. (Boc)2O (7.20 g, 33.0 mmol) was added to the mixture
at 0 ЊC, and the mixture was stirred for 1.5 h with warming to
room temperature. The mixture was poured into a saturated
NH4Cl solution at 0 ЊC, and the whole was extracted with
EtOAc. The extract was washed successively with water,
saturated NaHCO3 and brine, and dried over MgSO4. Concen-
tration under reduced pressure followed by flash chroma-
tography over silica gel with n-hexane–EtOAc (4 : 1) gave the
title compound 7a (4.36 g, 14.3 mmol, 87%) as colourless
crystals, mp 89–91 ЊC [from n-hexane–Et2O (3 : 1)] (Found: C,
67.39; H, 6.96; N, 4.50. C17H21NO4 requires C, 67.31; H, 6.98;
N, 4.62%); [α]2D1 Ϫ33.8 (c 0.708 in CHCl3); δH (300 MHz; CDCl3)
1.58 (9 H, s, CMe3), 2.84 (1 H, dd, J 13.4 and 9.6, CHH), 3.34
(1 H, dd, J 13.4 and 3.6, CHH ), 4.17 (1 H, dt, J 9.6 and 3.1,
NCH), 4.62 (1 H, m, OCH), 5.10–5.21 (2 H, m, CH ᎐), 5.62
General procedure for the synthesis of ꢀ[(E )-CH᎐CH]- and
ꢀ[(E )-CMe᎐CH]-type alkene dipeptide isosteres via “lower-
᎐
᎐
order” cyanocuprate-mediated alkylation: synthesis of tert-butyl
(2S,5S,3E )-5-(tert-butoxycarbonylamino)-2-methyl-6-phenyl-
hex-3-enoate (Boc-L-Phe-ꢀ[(E )-CH᎐CH]-D-Ala-OBut) 13a
᎐
To a stirred suspension of CuCN (44.4 mg, 0.496 mmol) and
LiCl (42.0 mg, 0.992 mmol) in dry THF (1.5 cm3) was added
MeMgCl in dry THF (2.92 mol dmϪ3, 0.169 cm3, 0.496 mmol)
under argon at Ϫ78 ЊC, and the mixture was stirred for 10 min
at 0 ЊC. BF3ؒEt2O (0.0628 cm3, 0.496 mmol) was added to the
above mixture at Ϫ78 ЊC, and the mixture was stirred for 5 min.
To the solution of organocopper reagent was added dropwise
a solution of the ester 10a (50.0 mg, 0.124 mmol) in dry THF
(1.8 cm3) at Ϫ78 ЊC. After being stirred for 30 min, the reaction
mixture was quenched with a 1 : 1 saturated NH4Cl-28%
NH4OH solution (2 cm3). The mixture was extracted with Et2O,
and then the extract was washed with water, and dried over
MgSO4. Concentration under reduced pressure followed by
flash chromatography over silica gel with n-hexane–EtOAc (15 :
1) yielded the title compound 13a (36.1 mg, 0.0961 mmol, 77%)
as colourless crystals, mp 64–66 ЊC [from n-hexane–Et2O (10 :
1)]; (Found: C, 70.63; H, 8.83; N, 3.66. C22H33NO4 requires C,
70.37; H, 8.86; N, 3.73%); [α]2D5 ϩ19.2 (c 0.987 in CHCl3);
δH (600 MHz; CDCl3) 1.14 (3 H, d, J 6.9, CMe), 1.40 (9 H, s,
CMe3), 1.41 (9 H, s, CMe3), 2.79 (1 H, dd, J 13.3 and 6.9,
CHH), 2.82–2.88 (1 H, m, CHH ), 2.97 (1 H, dd, J 14.2 and 7.1,
2-H), 4.38 (1 H, m, 5-H), 4.45 (1 H, m, NH), 5.47 (1 H, dd,
᎐
2
(1 H, ddd, J 17.2, 10.4 and 5.6, CH᎐), 7.15–7.38 (5 H, m, Ph).
᎐
tert-Butyl (2E )-3-[(4S,5S)-4-benzyl-N-(tert-butoxycarbonyl)-2-
oxo-1,3-oxazolidin-5-yl]prop-2-enoate 10a
Ozone gas was bubbled through a stirred solution of the 1,3-
oxazolidin-2-one 7a (4.26 g, 14.0 mmol) in EtOAc (150 cm3) at
Ϫ78 ЊC until a blue colour persisted. Me2S (20.6 cm3, 280
mmol) was added to the solution at Ϫ78 ЊC. After being stirred
for 30 min at 0 ЊC, the mixture was dried over MgSO4, and
concentrated under reduced pressure to give the crude aldehyde,
which was used for the next reaction without further purifica-
tion. To a stirred suspension of LiCl (1.48 g, 35.1 mmol) in
MeCN (50 cm3) was added tert-butyl diethyl phosphonoacetate
(8.34 cm3, 35.1 mmol) and (Pri)2NEt (6.11 cm3, 35.1 mmol) at
0 ЊC under argon. After 1 h, the above aldehyde in MeCN
(35 cm3) was added to the mixture at 0 ЊC, and the stirring was
continued for 2 h. The mixture was concentrated under reduced
pressure and extracted with EtOAc. The extract was washed
successively with saturated citric acid, brine, 5% NaHCO3 and
brine, and dried over MgSO4. Concentration under reduced
pressure followed by flash chromatography over silica gel with
n-hexane–EtOAc (6 : 1) gave the title compound 10a (3.98 g,
9.86 mmol, 70%) as colourless crystals, mp 157–159 ЊC [from
J 15.5 and 5.5, CH᎐), 5.57 (1 H, dd, J 15.5 and 7.5, CH᎐),
7.13–7.30 (5 H, m, Ph).
᎐
᎐
General procedure for the synthesis of ꢀ[(E )-CMe᎐CMe]-type
᎐
alkene dipeptide isosteres via “higher-order” cyanocuprate-
mediated alkylation: tert-butyl (2R,5R,3E )-5-(tert-butoxy-
carbonylamino)-2-isopropyl-3,4-dimethyl-6-phenylhex-3-enoate
(Boc-D-Phe-ꢀ[(E )-CMe᎐CMe]-L-Val-OBut) 19a and tert-butyl
᎐
(2S,5R,3Z )-5-(tert-butoxycarbonylamino)-2-isopropyl-3,4-
dimethyl-6-phenylhex-3-enoate (Boc-D-Phe-ꢀ[(Z )-CMe᎐CMe]-
᎐
D-Val-OBut) 20a
To a stirred solution of LiCl (32.2 mg, 0.760 mmol) and CuCN
(34.0 mg, 0.380 mmol) in dry THF (1.5 cm3) was added drop-
J. Chem. Soc., Perkin Trans. 1, 2002, 1786–1793
1791

View Article Online
wise PriMgCl (1.50 mol dmϪ3, 0.506 cm3, 0.760 mmol) in dry
THF at Ϫ78 ЊC under argon, and the mixture was stirred for
10 min at 0 ЊC. BF3ؒEt2O (0.0481 cm3, 0.380 mmol) was added
to the mixture at Ϫ78 ЊC. After 5 min, to the above reagent was
added dropwise a solution of the ester 12a (41.0 mg, 0.0950
mmol) in dry THF (1.5 cm3) at Ϫ78 ЊC, and stirring was con-
tinued for 30 min at Ϫ78 ЊC. The reaction was quenched with
saturated NH4Cl-28% NH4OH (1 : 1, 2 cm3), and the whole was
extracted with Et2O. The extract was washed with water, and
dried over MgSO4. Concentration under reduced pressure fol-
lowed by flash chromatography over silica gel with n-hexane–
EtOAc (25 : 1) gave the title compound 20a (8.1 mg, 0.0187
mmol, 20%) and 19a (30.8 mg, 0.0713 mmol, 75%), in order of
elution.
High Throughput Screening, 2000, 3, 167; M. G. Bursavich and
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Compound 19a. colourless crystals, mp 128–130 ЊC (from
n-hexane); (Found: C, 72.40; H, 9.85; N, 3.26. C26H41NO4
requires C, 72.35; H, 9.57; N, 3.25%); ∆ε = Ϫ36.54 (229 nm,
isooctane); [α]2D6 Ϫ176.3 (c 0.726 in CHCl3); δH (300 MHz;
CDCl3) 0.32 (3 H, d, J 6.2, CMe), 0.87 (3 H, d, J 6.3, CMe),
1.38 (9 H, s, CMe3), 1.39 (9 H, s, CMe3), 1.55 (3 H, s, CMe),
1.68 (3 H, m, CMe), 1.93 (1 H, m, CH), 2.66 (1 H, dd, J 13.3
and 8.8, CHH), 2.86–2.97 (2 H, m, CHH and 2-H), 4.70 (1 H,
m, NH), 4.89 (1 H, m, 5-H), 7.12–7.28 (5 H, m, Ph).
Compound 20a. colourless crystals, mp 59–61 ЊC (from
n-hexane); (Found: C, 72.25; H, 9.56; N, 3.12. C26H41NO4
requires C, 72.35; H, 9.57; N, 3.25%); ∆ε = ϩ32.47 (228 nm,
isooctane); [α]2D6 ϩ182.9 (c 1.72 in CHCl3); δH (300 MHz;
CDCl3) 0.31 (3 H, d, J 6.1, CMe), 0.85 (3 H, d, J 6.3, CMe),
1.38 (9 H, s, CMe3), 1.39 (9 H, s, CMe3), 1.59 (3 H, d, J 0.9,
CMe), 1.66 (3 H, d, J 0.9, CMe), 2.03 (1 H, m, CH), 2.78 (1 H,
dd, J 13.3 and 7.4, CHH), 2.95–3.05 (2 H, m, CHH and 2-H),
4.53 (1 H, m, NH), 4.92 (1 H, m, 5-H), 7.12–7.28 (5 H, m, Ph).
Crystal structure determination of tert-Butyl (2S,5R,3E )-5-
(tert-butoxycarbonylamino)-2-isopropyl-3,4-dimethyl-6-phenyl-
4 M. M. Vasbinder, E. R. Jarvo and S. J. Miller, Angew. Chem., Int.
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6088.
hex-3-enoate (Boc-D-Phe-ꢀ[(E )-CMe᎐CMe]-D-Val-OBut) 19b:
᎐
crystal data§
C26H41NO4, M = 431.62, monoclinic, a = 10.483(3), b =
10.019(2), c = 13.104(4) Å, β = 90.12(2)Њ, U = 1376.3(5) Å3, T =
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1997, 45, 1259.
8 S. Oishi, T. Kamano, A. Niida, M. Kawaguchi, R. Hosotani,
M. Imamura, N. Yawata, K. Ajito, H. Tamamura, A. Otaka and
N. Fujii, in Peptide Science 2000, ed. T. Shioiri, The Japanese
Peptide Society, Osaka, 2001, p. 249.
9 T. Ibuka, K. Nakai, H. Habashita, Y. Hotta, N. Fujii, N. Mimura,
Y. Miwa, T. Taga and Y. Yamamoto, Angew. Chem., Int. Ed. Engl.,
1994, 33, 652; N. Fujii, K. Nakai, H. Tamamura, A. Otaka, N.
Mimura, Y. Miwa, T. Taga, Y. Yamamoto and T. Ibuka, J. Chem.
Soc., Perkin Trans. 1, 1995, 1359; T. Ibuka, N. Mimura, H. Ohno,
K. Nakai, M. Akaji, H. Habashita, H. Tamamura, Y. Miwa,
T. Taga, N. Fujii and Y. Yamamoto, J. Org. Chem., 1997, 62, 2982.
10 P. Wipf and P. C. Fritch, J. Org. Chem., 1994, 59, 4875; P. Wipf and
T. C. Henninger, J. Org. Chem., 1997, 62, 1586.
295 K, space group P21 (No. 4), Z = 2, µ(Cu-Kα) = 0.55 mmϪ1
,
2229 reflections measured, 1897 [I > 3.00σ(I )] were used in all
calculations. The final R(F 2) was 0.061.
Acknowledgements
We thank Dr Terrence R. Burke, Jr., NCI, NIH, for reading
the manuscript and for valuable discussions. This work was
supported by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan, and the Japan Health Science Foundation. S. O.
is grateful for Research Fellowships from the JSPS for Young
Scientists.
§ The crystal data have been deposited at the Cambridge Crystallo-
graphic Data Centre. CCDC reference number 183665. See http://
www.rsc.org/suppdata/p1/b2/b203482d/ for these data in .cif or other
electronic format
11 H. Tamamura, M. Yamashita, H. Muramatsu, H. Ohno, T. Ibuka,
A. Otaka and N. Fujii, Chem. Commun., 1997, 2327; H. Tamamura,
M. Yamashita, Y. Nakajima, K. Sakano, A. Otaka, H. Ohno,
T. Ibuka and N. Fujii, J. Chem. Soc., Perkin Trans. 1, 1999, 2983;
S. Oishi, H. Tamamura, M. Yamashita, Y. Odagaki, N. Hamanaka,
A. Otaka and N. Fujii, J. Chem. Soc., Perkin Trans. 1, 2001, 2445.
12 N. Fujii, H. Habashita, N. Shigemori, A. Otaka, T. Ibuka,
M. Tanaka and Y. Yamamoto, Tetrahedron Lett., 1991, 32,
4969; A. Otaka, H. Watanabe, E. Mitsuyama, A. Yukimasa,
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26 In this plausible mechanism, the nearly equal rates in the direct
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27 Enantiomers of 10a,b are depicted for easy understanding.
J. Chem. Soc., Perkin Trans. 1, 2002, 1786–1793
1793