Novel stereocontrolled approach to conformationally constrained analogues of L-glutamic acid and L-proline via stereoselective cyclopropanation of 3,4-didehydro-L-pyroglutamic ABO ester

Article abstract of DOI:10.1016/j.tet.2005.06.051

A new stereocontrolled approach to l-(carboxycyclopropyl)glycines (l-CCGs) and 3,4-methano-l-prolines, conformationally constrained analogues of l-glutamic acid and l-proline, respectively, was developed using a 3,4-didehydro-l- pyroglutamate derivative as a common chiral template. The unsaturated l-pyroglutamate derivative employed in this work is a novel chiral synthon in which the carboxyl functionality is protected as a 2,7,8-trioxabicyclo[3.2.1] octyl group (ABO ester). Stereospecific cyclopropanation of the olefin using diazomethane followed by appropriate functional group interconversion gave l-CCG-III and trans-3,4-methano-l-proline with complete stereocontrol. Synthesis of other diastereomers of l-CCG and cis-3,4-methano-l-proline was accomplished by alteration of the 3,4-methanoglutamic acid framework via carboxycyclopropanation of the olefin with sulfur ylide and subsequent Barton decarboxylation reaction of the original γ-carboxyl group included in the pyroglutamate skeleton.

Full text of DOI:10.1016/j.tet.2005.06.051

Tetrahedron 61 (2005) 8456–8464
Novel stereocontrolled approach to conformationally constrained
analogues of L-glutamic acid and L-proline via stereoselective
cyclopropanation of 3,4-didehydro-L-pyroglutamic ABO ester
*
Makoto Oba, Naohiro Nishiyama and Kozaburo Nishiyama
*
Department of Materials Chemistry, Tokai University, 317 Nishino, Numazu, Shizuoka 410-0395, Japan
Received 7 June 2005; revised 20 June 2005; accepted 20 June 2005
Available online 11 July 2005
Abstract—A new stereocontrolled approach to L-(carboxycyclopropyl)glycines (L-CCGs) and 3,4-methano-L-prolines, conformationally
constrained analogues of L-glutamic acid and L-proline, respectively, was developed using a 3,4-didehydro-L-pyroglutamate derivative as a
common chiral template. The unsaturated L-pyroglutamate derivative employed in this work is a novel chiral synthon in which the carboxyl
functionality is protected as a 2,7,8-trioxabicyclo[3.2.1]octyl group (ABO ester). Stereospecific cyclopropanation of the olefin using
diazomethane followed by appropriate functional group interconversion gave L-CCG-III and trans-3,4-methano-L-proline with complete
stereocontrol. Synthesis of other diastereomers of L-CCG and cis-3,4-methano-L-proline was accomplished by alteration of the 3,4-
methanoglutamic acid framework via carboxycyclopropanation of the olefin with sulfur ylide and subsequent Barton decarboxylation
reaction of the original g-carboxyl group included in the pyroglutamate skeleton.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In an effort to overcome the problems encountered by the
above approaches, we opted to explore an alternative chiral
template involving the unsaturated pyroglutamate skeleton.
Recently, Lajoie and co-workers have developed a new
methodology for the synthesis of a wide range of
nonproteinogenic a-amino acids based on the elaboration
of a chiral serine aldehyde in which Corey’s 2,6,7-
trioxabicyclo[2.2.2]octyl group (OBO ester)4 was used as
a protective group for the carboxylic acid.5 The bulky OBO
moiety was found to reduce the acidity of the a-proton
allowing several transformations without racemization and
to induce high diastereoselectivity in the addition reactions
performed on the aldehyde moiety.
L-Glutamic acid is the most widely used a-amino acid in
asymmetric synthesis because of its versatility as a chiral
starting material and its availability at low cost.1 Among a
wide variety of chiral synthons derived from L-glutamic
acid, L-pyroglutamic acid, easily prepared by the intra-
molecular dehydration of L-glutamic acid, occupies an
important place in the field of natural product synthesis.2
For the functionalization at the 3- or 3,4-positions of the
lactam ring, it is necessary to employ 3,4-didehydropyro-
glutamic acid derivatives. Although there are some reports
concerning the reactivity of the unsaturated pyrogluta-
mates,3 they could not be used as a chiral template due to
their tendency to racemize and isomerize via a double-bond
shift. For example, Ezquerra and co-workers reported the
first trapping reaction of the olefin with cyclopentadiene
where the Diels–Alder adduct was obtained only in 50%
ee.3b To circumvent the above problems, the corresponding
pyroglutaminol derivatives are often employed as the chiral
template; however, the procedure necessitates the reduction
of the carboxyl group and its regeneration after the desired
modification has been completed.
In the present work, we adopted a 2,7,8-trioxabicyclo[3.2.1]
octyl group (ABO ester)6 as a protective group for the
carboxyl functionality of the unsaturated pyroglutamate
derivative because the pyroglutamic ABO ester is easier to
prepare than the corresponding OBO ester. During the
course of our investigation, synthesis of an unsaturated
L-pyroglutamic OBO ester has been published;7 however,
the overall yield of the olefin from the starting L-pyro-
glutamic acid was very low (8.4%) and the reaction of the
olefin was limited to Michael additions. In our preliminary
communication,8 we demonstrated an efficient synthesis of
a 3,4-didehydropyroglutamic ABO ester 1 (49.8% overall
yield) and its reactions, such as catalytic hydrogenation,
Diels–Alder reaction, cyclopropanation, dihydroxylation,
Keywords: Amino acids; Asymmetric synthesis; Cyclopropanation; Ortho
ester; Pyroglutamic acid.
Corresponding authors. Tel.: C81 55 968 1111; fax: C81 55 968 1155;
e-mail: makoto@wing.ncc.u-tokai.ac.jp
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.051

M. Oba et al. / Tetrahedron 61 (2005) 8456–8464
8457
and Michael addition, which were found to proceed with
excellent p-facial diastereoselectivity to the olefin without
loss of enantiomeric purity at the a-position. As part of our
ongoing development of the unsaturated orthopyrogluta-
mate methodology for the asymmetric synthesis of unusual
amino acids, we report herein a full account of the synthesis
of L-(carboxycyclopropyl)glycines (L-CCGs) and 3,4-
methano-L-prolines, the conformationally restricted ana-
logues of L-glutamic acid and L-proline, respectively, via
stereoselective cyclopropanation of 3,4-didehydro-L-pyro-
glutamic ABO ester 1. Recently, considerable interest has
been drawn to such conformationally constrained a-amino
acids containing a cyclopropyl ring in their structure on
account of their diverse biological activities.9 In particular,
L-CCGs are recognized as useful pharmacological tools for
analyzing glutamate neurotransmitter systems.10
trans isomers by Fujimoto and co-workers via addition of
carbene to the corresponding dehydroproline derivative.13
Later, several synthetic methods leading to the 3,4-
methanoproline have appeared in the literature;14 however,
most of them were not enantioselective and gave a mixture
of cis and trans isomers. To our knowledge, there are only
two enantioselective routes to cis-3,4-methano-L-proline
using chiral cyclopropane derivatives as starting materials.
This paper presents a novel stereocontrolled approach to
L-CCGs and 3,4-methano-L-prolines from a common chiral
olefinic precursor 1 as outlined in Figure 1. In general, an
unsaturated lactam such as compound 1 can become a
precursor only to L-CCG-III and trans-3,4-methano-L-
proline because the cyclopropanation of the olefin is
expected to occur exclusively from trans to the resident
substituent at the 5-position (path A). The present strategy
enables an alteration of the 3,4-methanoglutamic acid
framework by carboxycyclopropanation of the olefin to
introduce a new g-carboxyl group into the cyclopropane
ring as in path B followed by decarboxylation of the original
g-carboxyl group included in the pyroglutamate skeleton.
Consequently, it becomes possible to obtain L-CCG-IV and
cis-3,4-methano-L-proline, which can be formally acces-
sible via cis-selective cyclopropanation of the olefin,
from the endo adduct. Furthermore, it is feasible to obtain
L-CCG-II, an extended derivative of CCGs, provided the
corresponding exo adduct can be isolated in pure form.
Usually, the extended form of CCGs can not be secured
from the cyclopropanation of the cyclic olefin.
2. Results and discussion
2.1. Synthetic strategy
Since the first synthesis of racemic CCG-I by Ohfune and
co-workers,11 several enantioselective syntheses of L-CCGs
have been reported mainly on the basis of cyclopropanation
of chiral olefinic precursors,12 where an appropriate choice
of the geometrical isomer of the olefin or the starting olefin
itself was necessary depending upon the desired dia-
stereomer of CCGs. On the other hand, the first synthetic
3,4-methano-L-proline was obtained as a mixture of cis and
Figure 1. Stereocontrolled approach to L-CCGs and 3,4-methano-L-prolines.

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M. Oba et al. / Tetrahedron 61 (2005) 8456–8464
2.2. Synthesis of unsaturated orthopyroglutamate 1
2.3. Synthesis of L-CCG-III (10) and trans-3,4-methano-
L-proline (14)
Construction of the 2,7,8-trioxabicyclo[3.2.1]octane (ABO)
skeleton relied on zirconocene-catalyzed rearrangement of
the epoxy ester toward the ortho ester reported by Wipf
and co-workers.6 According to the procedure shown in
Scheme 1, the epoxy ester 4 was prepared from L-pyro-
glutamic acid 2 via condensation with 3-methyl-3-buten-1-
ol in the presence of 1,3-dicyclohexylcarbodiimide (DCC)
and a catalytic amount of 4-dimethylaminopyridine
(DMAP) followed by epoxidation with 3-chloroperoxy-
benzoic acid (mCPBA). The obtained epoxy ester 4 was
then treated with zirconocene catalyst, prepared in situ from
zirconocene dichloride and silver perchlorate, to give an
ABO ester 5. Since the epoxidation of the chiral olefin 3 was
non-stereoselective, the orthopyroglutamate 5 was obtained
as a 1:1 mixture of diastereomers. In Scheme 1, only one
enantiomeric form of the ABO skeleton is depicted for
clarity. After protection of the amide proton with a tert-
butoxycarbonyl (Boc) group, the orthopyroglutamate 6 was
converted to a 3,4-didehydro-L-pyroglutamic ABO ester 1
using the well-established procedure involving phenyl-
selenenylation and oxidative deselenenylation by hydrogen
peroxide. The unsaturated orthopyroglutamate 1 was
isolated in 49.8% yield based on the starting L-pyroglutamic
acid (six steps) as a colorless crystalline solid, which was
stable at room temperature for several months.
The synthetic course of (2S,10S,20R)-(carboxycyclopropyl)
glycine (L-CCG-III, 10) and trans-3,4-methano-L-proline
(14) based on stereospecific cyclopropanation of the
unsaturated orthopyroglutamate 1 is illustrated in Scheme
2. First of all, we investigated direct cyclopropanation of the
unsaturated lactam 1 using a sulfoxonium ylide15 as an
alkylidene transfer reagent; however, the desired cyclo-
adduct 9 could be obtained in only 32% yield. The
cyclopropanation of the olefin 1 was next carried out by
1,3-dipolar cycloaddition of diazomethane followed by
photolysis of the resultant pyrazoline 8 in the presence of
benzophenone as a photosensitizer,5b affording the cyclo-
adduct 9 in 61% yield. We could not detect the
corresponding cis adduct in the reaction mixture, suggesting
that exclusive addition of diazomethane to the olefin 1
opposite to the bulky ABO group occurred. In this case, the
Pd(OAc)2-catalyzed cycloaddtion of diazomethane to the
olefin 1 gave no cycloadduct.
Scheme 2. Preparation of L-CCG-III (10) and trans-3,4-methano-L-proline
(14). Reagents and conditions: (a) CH2N2, ether; (b) Hg-lamp (400 W),
benzophenone, MeCN, 0 8C, 64% (two steps); (c) 1 M HCl reflux; then
Dowex 50W-X8, 10: 61%, 14: 89%; (d) HCl–MeOH, 0 8C; (e) (tert-
BuOCO)2O, DMAP, MeCN, 56% (two steps); (f) BH3–THF, 64%. ABOZ
5-methyl-2,7,8-trioxabicyclo[3.2.1]oct-1-yl.
Acidic hydrolysis of the cyclopropane derivative 9 in
refluxing 1 M HCl and subsequent ion exchange operation
afforded 61% yield of enantiomerically pure (O99% ee)
L-CCG-III (10) in a single step, where ring-opening of the
lactam skeleton, deprotection of the N-Boc group, and
regeneration of the carboxyl functionality from the ABO
ester occurred simultaneously. The stereochemistry of
L-CCG-III (10) was determined by comparison of the H
NMR spectrum and specific rotation with the reported
data.12d
Scheme 1. Preparation of 3,4-didehydro-L-pyroglutamic ABO ester (1).
Reagents and conditions: (a) CH2]C(Me)CH2CH2OH, DCC, DMAP,
CH2Cl2, quant; (b) mCPBA, CH2Cl2, 0 8C; (c) Cp2ZrCl2, AgClO4, CH2Cl2;
(d) (tert-BuOCO)2O, DMAP, MeCN, 60% (three steps); (e) NaN(SiMe3)2,
PhSeCl, DMPU–THF, K78 8C; (f) 30% H2O2, THF, 83% (two steps);
(g) H2, 10% Pd/C, MeOH; (h) 1 M HCl reflux; then Dowex 50W-X8, 77%
(two steps).
1
In order to evaluate the chiral integrity at the a-position of
the unsaturated orthopyroglutamate 1, the olefin 1 was
hydrogenated in the presence of 10% palladium on carbon
followed by acidic hydrolysis in refluxing 1 M HCl to give
L-glutamic acid in 77% yield. The enantiomeric purity of the
obtained L-glutamic acid was found to be O99% ee by
HPLC analysis using a chiral stationary column (MCIGEL
CRS10W), suggesting that no racemization at the a-position
occurred during the chemical transformations shown in
Scheme 1.
To access the trans-3,4-methano-L-proline (14), we next
investigated the chemoselective reduction of the lactam
carbonyl moiety. Several attempts to reduce directly the
carbonyl group of the bicyclic lactam 9 by borane or
LiEt3BH were unsuccesfull. We eventually found that the
corresponding methyl ester 12, prepared by methanolysis of
the ABO ester 9 followed by reprotection with the Boc
group, underwent chemoselective reduction by borane–THF

M. Oba et al. / Tetrahedron 61 (2005) 8456–8464
8459
Scheme 3. Preparation of L-CCG-II (21) and L-CCG-IV (19). Reagents and conditions: (a) Me2S]CHCO2R, DMSO, 15a: 56%, 16a: 40%, 15b: 54%, 16b:
29%; (b) 1 M LiOH, THF; (c) 4-methylmorpholine, ClCO2Bui, THF; then 2-mercaptopyridine N-oxide, Et3N, THF; (d) tert-BuSH, W-lamp (100 W), 18: 85%
(three steps), 20: 51% (three steps); (e) 1 M HCl reflux; then Dowex 50W-X8, 19: 86%, 21: 84%. ABOZ5-methyl-2,7,8-trioxabicyclo[3.2.1]oct-1-yl.
to afford 3,4-methanoproline derivative 13 in 63% yield.
Deprotection of compound 13 in refluxing 1 M HCl
followed by treatment with Dowex 50W-X8 gave enantio-
merically pure (O99% ee) trans-3,4-methano-L-proline
(14) in 89% yield; and the structure was also confirmed
With the basic and nucleophilic reaction conditions
employed in the succeeding processes in mind, only the
tert-butyl ester derivatives 15b and 16b were adopted in this
synthesis. The obtained endo and exo adducts 15b and 16b
were chromatographically separable and were isolated in 54
and 29% yields, respectively. The chemoselective ring-
opening of the lactam 15b was carried out with 1 M LiOH to
give crude carboxylic acid 17. The acid 17 was then
subjected to Barton decarboxylation reaction20 using
mercatopyridine N-oxide as a derivatizing reagent of the
carboxyl group to afford fully protected (carboxycyclo-
propyl)glycine derivative 18 in 85% yield for the three
steps. Finally, deprotection of compound 18 in refluxing
1 M HCl followed by the standard ion exchange operation
afforded 86% yield of enantiomerically pure (99% ee)
L-CCG-IV (19).
1
by H NMR data and specific rotation.13
The present protocol provides an extremely facile and
straightforward approach to L-CCG-III and trans-3,4-
methano-L-proline with unprecedented complete
stereocontrol.
2.4. Synthesis of L-CCG-IV (19) and L-CCG-II (21)
Scheme 3 shows the synthetic course of (2S,10R,20S)-
(carboxycyclopropyl)glycine (L-CCG-IV, 19) and (2S,10R,
20R)-(carboxycyclopropyl)glycine (L-CCG-II, 21) via
alteration of the 3,4-methanoglutamic acid framework by
a combination of carboxycyclopropanation of the olefin
with sulfur ylides16 and Barton decarboxylation reaction.
When a solution of the unsaturated pyroglutamate 1
and ethyl dimethylsulfuranylideneacetate17 in dimethyl
sulfoxide was stirred at room temperature overnight, a
mixture of endo and exo adducts, 15a and 16a, respectively,
was obtained in a 57:42 ratio. Similar treatment of the olefin
1 with tert-butyl dimethylsulfuranylideneacetate18 slightly
improved the endo selectivity, giving a 67:33 mixture of
15b and 16b. This stereochemical outcome observed in the
conjugate addition of sulfur ylides toward the unsaturated
lactam 1 can be rationalized by considering a synclinal-like
transition state proposed by Meyers and co-workers.19 We
also investigated the cyclopropanation using ethyl and tert-
butyl diazoacetate in the presence or absence of a catalytic
amount of Pd(OAc)2; however, the expected cycloadducts
could not be detected in the reaction mixture. The reason for
the lower reactivity of the diazoacetates compared to
diazomethane itself is probably due to the steric hindrance.
Several efforts to obtain either diastereomer as a major
product utilizing thermodynamic equilibration of the two
products by treatment with a weak base or kinetic
protonation of the corresponding enolate were unsuccessful.
While the addition of the sulfur ylides across the carbon–
carbon double bond is stereospecific, we could not obtain
either an endo or exo adduct as a major product with
overwhelming selectivity.
In order to obtain the corresponding extended form, similar
treatment of the exo adduct 16b, even though it was
obtained as a minor product in the carboxycyclopropanation
reaction, was carried out and afforded L-CCG-II (21) in 43%
yield based on the adduct 16b (four steps). The structures of
L-CCG-IV (19) and L-CCG-II (21) were established by
comparing their physical and spectral data with those
reported in the literature.12d
2.5. Synthesis of cis-3,4-methano-L-proline (25)
Since the cis-3,4-methano-L-proline (25) is regarded as a
cyclic analogue of L-CCG-IV (19), it is reasonable to
employ a common precursor to these amino acids. There has
been only one enantioselective route to N-Boc derivatives of
L-CCG-IV and cis-3,4-methano-L-proline from a common
key intermediate.14b In this work, we planned to prepare the
methanoproline 25 via intramolecular cyclization of
compound 18, the precursor of L-CCG-IV, as shown in
Scheme 4. Treatment of compound 18 with dry hydrogen
chloride in methanol gave a crude dimethyl ester of L-CCG-
IV as the hydrochloride salt 22. The obtained hydrochloride
22 was neutralized to effect intramolecular cyclization
reaction and subsequent protection of the resultant
pyroglutamate derivative with the Boc group afforded
3,4-methano-L-pyroglutamate 23 in 40% yield based on
compound 18 (three steps). According to the procedure for
the synthesis of trans-3,4-methanoproline (14), the bicyclic

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2,3,3-D4]propionate (dH 0.00), or the central peak of
deuteriochloroform (dC 77.0). High-resolution mass spectra
(HRMS) were determined using perfluorokerosene as an
internal standard. Optical rotations were measured on a
HORIBA SEPA-200 polarimeter. Solvents and reagents
were of commercial grade and were purified if necessary.
4.1.1. (5S)-2-Pyrrolidone-5-carboxylic acid 3-methyl-3-
butenyl ester (3). To a solution of 1,3-dicyclohexylcarbo-
diimide (DCC, 12.3 g, 59.7 mmol), 4-dimethylamino-
pyridine (DMAP, 610 mg, 5.00 mmol) and 3-methyl-3-
buten-1-ol (5.17 g, 60.1 mmol) in dichloromethane
(150 mL) was added L-pyroglutamic acid (2, 6.45 g,
50.0 mmol) at 0 8C and the reaction mixture was stirred at
room temperature overnight. After removal of the precipi-
tated 1,3-dicyclohexylurea, the filtrate was washed with
saturated aqueous NH4Cl and concentrated. The residue was
dissolved in ether and extracted several times with water.
The combined aqueous extracts were evaporated and the
residue was dissolved in chloroform. The organic layer was
dried over MgSO4 and concentrated to give quantitative
yield of the title compound 3 (9.85 g, 50.0 mmol) as an oil.
1H NMR (CDCl3) d 1.75 (s, 3H), 2.17–2.51 (m, 6H), 4.21–
4.32 (m, 3H), 4.73 (br s, 1H), 4.82 (br s, 1H), 6.15 (s, 1H).
13C NMR (CDCl3) d 21.4, 24.1, 28.5, 35.8, 54.9, 62.4,
111.7, 140.5, 171.6, 177.9. HRMS (EI, 70 eV) m/z 197.1052
(MC, calcd for C10H15NO3 197.1031).
Scheme 4. Preparation of cis-3,4-methano-L-proline (25). Reagents and
conditions: (a) HCl–MeOH, 0 8C; (b) aqueous NaHCO3–THF; (c) (tert-
BuOCO)2O, DMAP, MeCN, 40% (three steps); (d) BH3–THF, 31%;
(e) 1 M HCl reflux; then Dowex 50W-X8, 70%.
lactam 23 was converted to the corresponding cis-3,4-
methano-L-proline (25) via chemoselective reduction of the
lactam carbonyl group followed by the standard deprotec-
tion protocol. The structure and enantiomeric purity (O99%
ee) of the final product 25 were determined by comparison
1
of their H NMR data and the specific rotation with those
reported.13
3. Conclusion
In this paper, we have demonstrated a novel approach to
some pharmacologically important cyclopropane amino
acids, such as L-CCGs and 3,4-methano-L-prolines, via
stereoselective cyclopropanation of 3,4-didehydro-L-pyro-
glutamic ABO ester 1.
4.1.2. (5S)-1-tert-Butoxycarbonyl-5-(5-methyl-2,7,8-
trioxabicyclo[3.2.1]oct-1-yl)-2-pyrrolidone (6). To a solu-
tion of 3-chloroperoxybenzoic acid (mCPBA, 13.0 g,
75.0 mmol) in dichloromethane (150 mL) was added a
solution of ester 3 (9.85 g, 50.0 mmol) in dichloromethane
(50 mL) at 0 8C and the reaction mixture was stirred for 4 h.
After removal of the solvent, the residue was chromato-
graphed on silica gel (chloroform/methanolZ90:10) to give
epoxide 4 (10.7 g) in quantitative yield. Although the
Among the four possible diastereomers of L-CCGs, two
folded and one extended forms, L-CCG-III, -IV, and -II,
respectively, were prepared from a common starting olefin 1
in a stereodivergent way using a combination of cyclo-
propanation with diazomethane or sulfur ylides and Barton
decarboxylation reaction. The trans- and cis-3,4-methano-L-
prolines, which are considered to be cyclic derivatives of
the folded L-CCGs, were also prepared from the precursors
of L-CCG-III and -IV, respectively.
obtained epoxide
4 was still contaminated with
3-chlorobenzoic acid, the sample could be used in the
next step without further purification.
To a suspension of bis(cyclopentadienyl)zirconium
dichloride (1.47 g, 5.03 mmol) and AgClO4 (1.10 g, 5.
31 mmol) in dichloromethane (60 mL) was added a solution
of the obtained crude epoxide 4 in dichloromethane (40 mL)
and the mixture was stirred for 2 days. After addition of
saturated aqueous NaHCO3, the insoluble materials were
filtered off. The filtrate was washed with brine, dried over
MgSO4, and concentrated to afford crude orthopyrogluta-
mate 5.
As expected, the ABO group serves as an efficient protective
group, which completely prevents racemization at the
a-position. Furthermore, the bulky ABO group provides
steric hindrance that limits the approach of reagents from
the b-face of the olefin, thus realizing stereospecific
cyclopropanation. The ABO moiety can resist various
reaction conditions employed in the present work and is
amenable to regeneration of the carboxyl functionality
through acidic treatment in the final stage of the synthetic
processes.
The obtained orthoester 5 was then treated with di-tert-butyl
dicarbonate (13.2 g, 60.6 mmol) and DMAP (6.20 g,
50.8 mmol) in acetonitrile (80 mL) at room temperature
for 1.5 h. After removal of the solvent, the residue was
extracted with ethyl acetate. The organic layer was washed
successively with aqueous KHSO4 and brine, dried over
MgSO4, and concentrated. The residue was purified by
flash column chromatography on silica gel (hexane/ethyl
acetateZ50:50) to afford 9.40 g (60%, three steps) of the
title compound 6 as an oil. 1H NMR (CDCl3) d 1.34 and 1.35
(2s, 3H), 1.43–1.48 (m, 1H), 1.51 (s, 9H), 1.98–2.35 (m,
4H), 2.74–2.84 (m, 1H), 3.45–3.49 (m, 1H), 3.85–3.91 (m,
4. Experimental
4.1. General
1
Melting points are uncorrected. H and 13C NMR spectra
were measured at 400 and 100 MHz, respectively. All
chemical shifts are reported as d values (ppm) relative to
residual chloroform (dH 7.26), sodium 3-(trimethylsilyl)[2,

M. Oba et al. / Tetrahedron 61 (2005) 8456–8464
8461
1H), 3.97–4.14 (m, 2H), 4.44 and 4.48 (2d, JZ9 Hz, 1H).
13C NMR (CDCl3) d 19.2 and 19.6, 21.2, 27.1 and 27.2,
31.2, 33.05 and 33.08, 57.9 and 58.5, 58.75 and 58.83, 72.9
and 73.2, 78.5 and 78.6, 81.59 and 81.61, 119.6 and 119.7,
149.09 and 149.12, 174.6. HRMS (EI, 30 eV) m/z 313.1525
(MC, calcd for C15H23NO6 313.1556).
27.8, 33.8, 59.4 and 59.5, 60.0, 73.6 and 73.8, 79.0 and 79.3,
82.3, 119.3, 150.3, 174.3. HRMS (EI, 70 eV) m/z 326.1604
[(MC1)C, calcd for C16H24NO6 326.1648].
4.1.5. (2S,10S,20R)-2-(Carboxycyclopropyl)glycine (10,
L-CCG-III). A mixture of compound 9 (318 mg,
0.978 mmol) and 1 M HCl (30 mL) was heated to reflux
for 3 h. The cooled solution was washed with chloroform
and concentrated to dryness. The residue was submitted to
ion-exchange column chromatography on Dowex 50W-X8
and elution with 1 M NH4OH to give the ammonium salt
of compound 10. The salt was then dissolved in water and
the solution was acidified to pH 3 with 1 M HCl. The
precipitated solids were collected by filtration and recrys-
tallized from water–acetone to give the title compound 10
(95.0 mg, 61%) as colorless crystals, mp 205–207 8C (lit.12d
mp 192–197 8C dec). [a]2D3 C20.7 (c 0.54, H2O) (lit.12d
4.1.3. (5S)-1-tert-Butoxycarbonyl-5-(5-methyl-2,7,8-
trioxabicyclo[3.2.1]oct-1-yl)-5H-2-pyrrolinone (1). A solu-
tion of 1 M sodium bis(trimethylsilyl)amide in THF
(61 mL, 61 mmol) was treated with N,N0-dimethylpropyl-
eneurea (8.2 mL, 68 mmol) at 0 8C under an argon
atmosphere for 20 min, cooled to K78 8C, and treated
with a solution of compound 6 (7.90 g, 25.2 mmol) in THF
(50 mL). After 0.5 h, a solution of phenylselenenyl chloride
(5.30 g, 27.7 mmol) in THF (50 mL) was added and the
mixture was stirred for 2 h. The reaction was quenched with
saturated aqueous NH4Cl and the mixture was extracted
with ethyl acetate. The organic layer was dried over MgSO4
and the solvent was evaporated to give 3-phenylseleno-2-
pyrrolidone derivative 7.
[a]2D2 C20.8 (c 0.52, H2O)). H NMR (D2O) d 1.37 (ddd,
1
JZ6, 6, 7 Hz, 1H), 1.52 (ddd, JZ6, 9, 9 Hz, 1H), 1.77
(dddd, JZ7, 8, 9, 11 Hz, 1H), 1.99 (ddd, JZ6, 8, 9 Hz, 1H),
4.21 (d, JZ11 Hz, 1H).
To a solution of the obtained crude phenylselenide 7 in THF
(300 mL) was added dropwise 30% H2O2 (15 mL,
132 mmol) at 0 8C and the reaction mixture was stirred at
room temperature for 2 h. The mixture was extracted with
ethyl acetate and the organic layer was washed with
saturated aqueous NaHCO3 and dried over MgSO4. After
removal of the solvent, the residue was chromatographed on
silica gel. Elution with a mixture of hexane and ethyl acetate
(50:50) afforded 6.48 g (83%, two steps) of the title
compound 1 as a colorless solid, mp 110–112 8C. 1H
NMR (CDCl3) d 1.34 and 1.35 (2s, 3H), 1.43–1.48 (m, 1H),
1.52 (s, 9H), 1.99 and 2.08 (2m, 1H), 3.45 and 3.47 (2d, JZ
2 Hz, 1H), 3.84–4.1 (m, 3H), 4.97 and 5.03 (2dd, JZ2,
2 Hz, 1H), 6.11 (m, 1H), 7.19 (m, 1H). 13C NMR (CDCl3) d
21.6 and 21.7, 27.7 and 27.8, 33.6, 59.4 and 59.5, 63.3 and
63.9, 73.4 and 73.5, 79.1 and 79.5, 82.6 and 82.7, 117.9 and
118.0, 127.3, 146.1, 149.1, 169.8. HRMS (EI, 30 eV) m/z
312.1447 [(MC1)C, calcd for C15H22NO6 312.1485].
4.1.6. (1R,4S,5S)-3-tert-Butoxycarbonyl-4-methoxy-
carbonyl-3-azabicyclo[3.1.0]hexan-2-one (12). A solution
of compound 9 (534 mg, 1.64 mmol) in methanol (40 mL)
was cooled in an ice bath and a slow stream of HCl was
introduced with stirring to saturation. After being stirred at
room temperature for 3 h, the solution was concentrated and
the residue was extracted with ethyl acetate. The organic
layer was washed with brine, dried over MgSO4, and
concentrated to give crude methyl pyroglutamate derivative
11 (187 mg).
The obtained ester 11 was treated with di-tert-butyl
dicarbonate (640 mg, 2.94 mmol) and DMAP (310 mg,
2.54 mmol) in acetonitrile (20 mL) at room temperature
overnight. After removal of the solvent, the residue was
extracted with ethyl acetate. The organic layer was washed
successively with aqueous KHSO4 and brine, dried over
MgSO4, and concentrated to give 233 mg (56%, two steps)
of the title compound 12 as an oil. 1H NMR (CDCl3) d 0.84
(ddd, JZ4, 4, 5 Hz, 1H), 1.24 (ddd, JZ5, 8, 9 Hz, 1H), 1.45
(s, 9H), 1.95 (ddd, JZ4, 6, 8 Hz, 1H), 2.06 (dddd, JZ1, 4, 6,
9 Hz, 1H), 3.79 (s, 3H), 4.51 (s, 1H). 13C NMR (CDCl3) d
12.0, 14.9, 20.4, 27.8, 52.7, 60.2, 83.4, 149.5, 170.6, 172.6.
HRMS (EI, 70 eV) m/z 255.1107 (MC, calcd for
C12H17NO5 255.1124).
4.1.4. (1R,4S,5S)-3-tert-Butoxycarbonyl-4-(5-methyl-2,7,
8-trioxabicyclo[3.2.1]oct-1-yl)-3-azabicyclo[3.1.0]hexan-
2-one (9). To a solution of olefin 1 (3.11 g, 10 mmol) in
ether (50 mL) was added an excess ethereal solution of
diazomethane (ca. 8.3 equiv) at 0 8C and the mixture was
stirred at room temperature in the dark for 3.5 h. The
reaction was quenched by addition of anhydrous CaCl2 and,
after filtration, evaporation of the solvent gave very unstable
pyrazoline derivative 8 (3.53 g).
4.1.7. (1S,2S,5R)-3-tert-Butoxycarbonyl-2-methoxy-
carbonyl-3-azabicyclo[3.1.0]hexane (13). To a solution
of compound 12 (83.0 mg, 0.325 mmol) in THF (10 mL)
was added a 1 M solution of borane in THF (1 mL, 1 mmol)
under an argon atmosphere and the mixture was stirred at
room temperature overnight. The reaction was quenched by
addition of methanol and, after being stirred for 1 h, the
mixture was diluted with dichloromethane. The organic
layer was then dried over MgSO4 and concentrated. The
crude product was purified by flash column chromatography
on silica gel (hexane/ethyl acetateZ50:50) to afford the title
compound 13 (50.0 mg, 64%) as an oil. 1H NMR (CDCl3) d
0.319 (ddd, JZ5, 9, 9 Hz, 1H), 0.742 (ddd, JZ5, 7, 15 Hz,
1H), 1.39 and 1.44 (2s, 9H), 1.49–1.56 (m, 1H), 1.57–1.62
(m, 1H), 3.54 (d, JZ2 Hz, 1H), 3.58 (d, JZ4 Hz, 1H), 3.74
An acetonitrile solution (500 mL) of the obtained pyrazoline
8 in the presence of benzophenone (1.87 g, 10.3 mmol) was
irradiated with a 400 W medium-pressure mercury lamp at
0 8C under an argon atmosphere for 20 min. After removal
of the solvent, the crude product was purified by flash
column chromatography on silica gel (hexane/ethyl
acetateZ50:50) to afford the title compound 9 (2.09 g,
1
64%) as an oil. H NMR (CDCl3) d 0.65–0.69 (m, 1H),
1.08–1.13 (m, 1H), 1.35 and 1.37 (2s, 3H), 1.45–1.50 (m,
1H), 1.47 and 1.48 (2s, 9H), 1.93–2.14 (m, 3H), 3.47–3.51
(m, 1H), 3.88–4.13 (m, 3H), 4.38 and 4.42 (2s, 1H). 13C
NMR (CDCl3) d 10.8, 12.0 and 12.3, 20.2, 21.7 and 21.8,

8462
M. Oba et al. / Tetrahedron 61 (2005) 8456–8464
and 3.75 (2s, 3H), 4.27 and 4.39 (2s, 1H). 13C NMR (CDCl3)
d 8.84 and 9.13, 14.9 and 15.4, 18.9 and 19.8, 28.3 and 28.4,
48.3 and 48.4, 52.0 and 52.1, 60.9 and 61.5, 80.0, 154.7 and
155.2, 172.7 and 172.9. HRMS (EI, 70 eV) m/z 241.1314
(MC, calcd for C12H19NO4 241.1313).
in THF (40 mL) were added 4-methylmorpholine (250 mg,
2.47 mmol) and isobutyl chloroformate (337 mg,
2.47 mmol) at K15 8C under an argon atmosphere. After
5 min, a solution of 2-mercaptopyridine N-oxide (326 mg,
2.56 mmol) and triethylamine (259 mg, 2.56 mmol) in THF
(20 mL) was added and the mixture was stirred in the dark
for 1 h. After removal of the precipitated triethylamine
hydrochloride, the filtrate was concentrated and the residue
was chromatographed on silica gel in the dark. Elution with
a mixture of hexane and ethyl acetate (50:50) gave
quantitative yield (1.14 g) of the corresponding ester,
which was very unstable and used immediately in the next
step.
4.1.8. (2S,3S,4R)-3,4-Methanoproline (14). A mixture of
compound 13 (255 mg, 1.06 mmol) and 1 M HCl (26 mL)
was heated to reflux for 3 h. The cooled solution was
washed with chloroform and concentrated to dryness. The
residue was submitted to ion-exchange column chromato-
graphy on Dowex 50W-X8 and elution with 1 M NH4OH to
give the title compound 14 (120 mg, 89%) as colorless
crystals (water–acetone), mp 263–265 8C (lit.13 mp 245–
250 8C). [a]D20 K94.8 (c 0.5, H2O) (lit.13 [a]2D0 K94 (c 1.0,
H2O)). 1H NMR (D2O) d 0.38–0.42 (m, 1H), 0.93–0.99 (m,
1H), 1.80–1.86 (m, 1H), 1.99–2.04 (m, 1H), 3.45 (d, JZ
11 Hz, 1H), 3.58 (dd, JZ4, 12 Hz, 1H), 4.13 (s, 1H).
A solution of the obtained ester and 2-methyl-2-pro-
panethiol (1.88 g, 20.8 mmol) in THF (40 mL) was
irradiated with a 100 W tungsten lamp at room temperature
under an argon atmosphere for 1 h. After removal of the
solvent, the residue was extracted with ethyl acetate, washed
successively with 0.1 M aqueous NaHCO3, 0.5 M aqueous
KHSO4, and brine, dried over MgSO4, and concentrated.
The crude product was purified by flash column chroma-
tography on silica gel (hexane/ethyl acetateZ70:30) to
afford the title compound 18 (701 mg, 85%, three steps) as
4.1.9. (1S,4S,5R,6R)-3,6-Di-tert-butoxycarbonyl-4-(5-
methyl-2,7,8-trioxabicyclo[3.2.1]oct-1-yl)-3-azabicyclo-
[3.1.0]hexan-2-one (15b) and (1S,4S,5R,6S)-isomer (16b).
A solution of olefin 1 (5.07 g, 16.3 mmol) and tert-butyl
dimethylsulfuranylideneacetate (5.70 g, 32.4 mmol) in
DMSO (100 mL) was stirred at room temperature overnight.
The mixture was diluted with ethyl acetate, washed with
brine, and dried over MgSO4. After removal of the solvent,
the residue was chromatographed on silica gel (hexane/ethyl
acetateZ50:50) to give compound 16b (1.99 g, 29%) as
colorless crystals, mp 173–178 8C. 1H NMR (CDCl3) d 1.35
and 1.37 (2s, 3H), 1.43 (s, 9H), 1.47 (s, 9H), 1.57–1.67
(m, 1H), 1.71 (dd, JZ3, 3 Hz, 1H), 2.00–2.14 (m, 1H), 2.41
(d, JZ3 Hz, 1H), 2.45 and 2.47 (2d, JZ3 Hz, 1H), 3.46–
3.51 (m, 1H), 3.88–4.13 (m, 3H), 4.44 and 4.48 (2s, 1H). 13C
NMR (CDCl3) d 20.0 and 20.3, 21.7, 25.6, 27.7, 27.9, 28.4
and 28.5, 33.7, 59.3 and 59.4, 59.6 and 59.9, 73.6 and 73.8,
79.2 and 79.4, 81.8, 82.7 and 82.8, 118.8, 149.5, 168.7 and
168.8, 171.3. HRMS (EI, 70 eV) m/z 426.2128 [(MC1)C,
calcd for C21H32NO8 426.2169].
1
an oil. H NMR (CDCl3) d 0.86–0.91 (m, 1H), 1.16–1.22
(m, 1H), 1.35 and 1.36 (2s, 3H), 1.40–1.42 (dd, JZ4, 4 Hz,
1H), 1.45 (s, 18H), 1.60–1.70 (m, 2H), 1.99–2.08 (m, 1H),
3.44–3.50 (m, 1H), 3.82–3.88 (m, 1H), 3.99–4.08 (m, 2H),
4.26 (br s, 1H), 4.85 (br s, 1H). 13C NMR (CDCl3) d 10.4,
20.3 and 20.4, 21.8, 21.9, 28.2, 28.3, 33.8, 51.4, 59.1 and
59.2, 73.7, 73.9, 78.9, 79.9, 119.6, 155.4, 171.4. HRMS (EI,
70 eV) m/z 399.2257 (MC, calcd for C20H33NO7 399.2291).
4.1.11. (2S,10R,20S)-2-(Carboxycyclopropyl)glycine (19,
L-CCG-IV). A mixture of compound 18 (219 mg,
0.549 mmol) and 1 M HCl (30 mL) was heated to reflux
for 3 h. The cooled solution was washed with chloroform
and concentrated to dryness. The residue was submitted to
ion-exchange column chromatography on Dowex 50W-X8
and elution with 1 M NH4OH to give the ammonium salt of
compound 19. The salt was then dissolved in water and the
solution was acidified to pH 3 with 1 M HCl. The
precipitated solids were collected by filtration and recrys-
tallized from water–acetone to give the title compound 19
(75.0 mg, 86%) as colorless crystals, mp 180–182 8C (lit.12d
mp 178–180 8C). [a]2D2 C103.7 (c 0.2, H2O) (lit.12d [a]2D6
C103.4 (c 0.5, H2O)). 1H NMR (D2O) d 1.13 (ddd, JZ6, 6,
7 Hz, 1H), 1.29 (ddd, JZ6, 9, 9 Hz, 1H), 1.66 (dddd, JZ7,
9, 9, 10 Hz, 1H), 2.02 (ddd, JZ6, 9, 9 Hz, 1H), 3.83 (d, JZ
10 Hz, 1H).
Further elution with a mixture of hexane and ethyl acetate
(50:50) afforded the compound 15b (3.75 g, 54%) as an oil.
1H NMR (CDCl3) d 1.31 and 1.32 (2s, 3H), 1.36 (s, 9H),
1.42 (s, 9H), 1.45–1.47 (m, 1H), 1.94–2.08 (m, 2H), 2.19–
2.27 (m, 2H), 3.45–3.46 (m, 1H), 3.83–4.09 (m, 3H), 4.51
and 4.54 (2s, 1H). 13C NMR (CDCl3) d 18.9 and 19.1, 21.4,
24.7, 25.9 and 26.0, 27.4 and 27.5, 27.6, 33.5, 56.9 and 57.4,
59.1 and 59.3, 73.2 and 73.5, 77.2, 78.8 and 79.1, 81.4
and 81.8, 118.9 and 119.0, 149.0, 166.1 and 166.2, 170.3.
HRMS (EI, 70 eV) m/z 425.2050 (MC, calcd for
C21H31NO8 425.2056).
4.1.12. (2S,10R,20R)-N-tert-Butoxycarbonyl-2-((tert-
butoxycarbonyl)cyclopropyl)glycine ABO ester (20).
According to the procedure for the preparation of compound
18, ring-opening of lactam 16 (504 mg, 1.14 mmol)
followed by the Barton decarboxylation reaction afforded
51% (three steps) yield of the title compound 20 (233 mg) as
4.1.10. (2S,10R,20S)-N-tert-Butoxycarbonyl-2-((tert-
butoxycarbonyl)cyclopropyl)glycine ABO ester (18). To
a solution of compound 15b (2.37 g, 5.58 mmol) in THF
(60 mL) was added a solution of 1 M aqueous LiOH
(20 mL) and the mixture was stirred at room temperature
overnight. The solution was then acidified to pH 4 with 10%
aqueous citric acid and extracted with chloroform. The
organic layer was dried over MgSO4 and concentrated to
give compound 17 (2.47 g) in quantitative yield.
1
an oil. H NMR (CDCl3) d 0.86–0.91 (m, 1H), 0.96–1.02
(m, 1H), 1.20–1.26 (m, 1H), 1.35 and 1.37 (2s, 3H), 1.42 (s,
9H), 1.43 (s, 9H), 1.51–1.62 (m, 2H), 1.99–2.08 (m, 1H),
3.45–3.51 (m, 1H), 3.67–3.73 (m, 1H), 3.84–3.91 (m, 1H),
4.01–4.09 (m, 2H), 4.65–4.76 (br s, 1H). 13C NMR (CDCl3)
d 10.9, 19.5 and 19.7, 21.8, 28.1, 28.3, 29.6, 33.8, 54.8, 59.3,
To a solution of the obtained acid 17 (912 mg, 2.06 mmol)

M. Oba et al. / Tetrahedron 61 (2005) 8456–8464
8463
73.9 and 74.0, 79.0 and 79.1, 79.5, 79.9, 119.6, 155.9, 173.3.
HRMS (EI, 70 eV) m/z 400.2335 [(MC1)C, calcd for
C20H34NO7 400.2341].
0.419 mmol) gave the title compound 25 (37.0 mg, 70%) as
colorless crystals (water–acetone), mp 224–230 8C (lit.13
mp 235–245 8C). [a]2D0 K130 (c 0.12, H2O) (lit.13 [a]2D0
K131 (c 0.1, H2O)). 1H NMR (D2O) d 0.508 (ddd, JZ4, 5,
6 Hz, 1H), 0.804 (ddd, JZ6, 7, 8 Hz, 1H), 1.83–1.89 (m,
1H), 2.01–2.05 (m, 1H), 3.51 (d, JZ2 Hz, 2H), 4.32 (d, JZ
5 Hz, 1H).
4.1.13. (2S,10R,20R)-2-(Carboxycyclopropyl)glycine (21,
L-CCG-II). According to the procedure for the preparation
of compound 19, hydrolysis and deprotection of compound
20 (293 mg, 0.734 mmol) gave the title compound 21
(98.0 mg, 84%) as colorless crystals (water–acetone), mp
265–270 8C dec (lit.12d mp 255–258 8C dec). [a]2D3 K20.0 (c
1
0.1, H2O) (lit.12d [a]D25 K20.2 (c 0.51, H2O)). H NMR
(D2O) d 1.04 (ddd, JZ5, 7, 9 Hz, 1H), 1.21 (ddd, JZ5, 5,
9 Hz, 1H), 1.67 (dddd, JZ4, 7, 9, 9 Hz, 1H), 1.80 (ddd, JZ
4, 5, 9 Hz, 1H), 3.39 (d, JZ9 Hz, 1H).
References and notes
1. Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis.
Construction of Chiral Molecule Using Amino Acids; Wiley:
New York, 1987.
4.1.14. (1S,4S,5R)-3-tert-Butoxycarbonyl-4-methoxy-
carbonyl-3-azabicyclo[3.1.0]hexan-2-one (23). A solution
of compound 18 (1.32 g, 3.31 mmol) in methanol (300 mL)
was cooled in an ice bath and a slow stream of HCl was
introduced with stirring to saturation. After being stirred at
room temperature overnight, the solution was concentrated
and the residue was dissolved in water. The aqueous layer
was washed with chloroform and concentrated to give
quantitative yield of crude methyl ester 22.
´
2. Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10,
2245–2303.
3. (a) Baldwin, J. E.; Cha, J. K.; Kruse, L. I. Tetrahedron 1985,
41, 5241–5260. (b) Ezquerra, J.; Pedregal, C.; Collado, I.;
Yruretagoyena, B.; Rubio, A. Tetrahedron 1995, 51,
´
10107–10114. (c) Guillena, G.; Manchen˜o, B.; Najera, C.;
Ezquerra, J.; Pedregal, C. Tetrahedron 1998, 54, 9447–9456.
4. Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571–5574.
5. (a) Blaskovich, M. A.; Lajoie, G. A. J. Am. Chem. Soc. 1993,
The obtained ester was then dissolved in a mixture of water
(100 mL) and THF (100 mL) and the pH was adjusted to 8
by adding NaHCO3. After being stirred at room temperature
overnight, the mixture was extracted with ethyl acetate and
the organic layer was dried over MgSO4 and concentrated to
give a crude lactam (372 mg). The obtained lactam was then
treated with di-tert-butyl dicarbonate (631 mg, 2.89 mmol)
and DMAP (297 mg, 2.43 mmol) in acetonitrile (30 mL) at
room temperature overnight. After removal of the solvent,
the residue was extracted with ethyl acetate. The organic
layer was washed successively with aqueous KHSO4 and
brine, dried over MgSO4, and concentrated. The crude
product was purified by column chromatography on silica
gel (hexane/ethyl acetateZ50:50) to give 341 mg (40%,
´
115, 5021–5030. (b) Rife, J.; Ortun˜o, R. M.; Lajoie, G. A.
J. Org. Chem. 1999, 64, 8958–8961. (c) Rose, N. G. W.;
Blaskovich, M. A.; Wong, A.; Lajoie, G. A. Tetrahedron 2001,
57, 1497–1507. (d) Fishlock, D.; Guillemette, J. G.; Lajoie, G.
A. J. Org. Chem. 2002, 67, 2352–2354. (e) Rose, N. G. W.;
Blaskovich, M. A.; Evindar, G.; Wilkinson, S.; Luo, Y.;
Fishlock, D.; Reid, C.; Lajoie, G. A. Org. Synth. 2003, 79,
216–227.
6. Wipf, P.; Xu, W.; Kim, H.; Takahashi, H. Tetrahedron 1997,
53, 16575–16596.
7. Herdeis, C.; Kelm, B. Tetrahedron 2003, 59, 217–229.
8. Oba, M.; Nishiyama, N.; Nishiyama, K. Chem. Commun.
2003, 6, 776–777.
1
9. Stammer, C. H. Tetrahedron 1990, 46, 2231–2254.
10. (a) Shinozaki, H.; Ishida, M.; Shimamoto, K.; Ohfune, Y. Br.
J. Pharmacol. 1989, 98, 1213–1224. (b) Kawai, M.; Horikawa,
Y.; Ishihara, T.; Shimamoto, K.; Ohfune, Y. Eur. J.
Pharmacol. 1992, 211, 195–202. (c) Ishida, M.; Akagi, H.;
Shimamoto, K.; Ohfune, Y.; Shinozaki, H. Brain Res. 1990,
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three steps) of the title compound 23 as an oil. H NMR
(CDCl3) d 0.98 (ddd, JZ5, 8, 9 Hz, 1H), 1.14 (ddd, JZ5, 6,
6 Hz, 1H), 1.37 (s, 9H), 2.02 (ddd, JZ4, 6, 9 Hz, 1H), 2.12
(dddd, JZ4, 6, 6, 8 Hz, 1H), 3.72 (s, 3H), 4.61 (d, JZ6 Hz,
1H). 13C NMR (CDCl3) d 8.8, 14.6, 21.2, 27.7, 52.4, 58.5,
83.4, 149.1, 169.8, 172.4. HRMS (EI, 70 eV) m/z 255.1107
(MC, calcd for C12H17NO5 255.1101).
11. Kurokawa, N.; Ohfune, Y. Tetrahedron Lett. 1985, 26, 83–84.
12. (a) Yamanoi, K.; Ohfune, Y. Tetrahedron Lett. 1988, 29,
1181–1184. (b) Shimamoto, K.; Ohfune, Y. Tetrahedron Lett.
1989, 30, 3803–3804. (c) Pellicciari, R.; Natalini, B.;
Marinozzi, M.; Monahan, J. B.; Snyder, J. P. Tetrahedron
Lett. 1990, 31, 139–142. (d) Shimamoto, K.; Ishida, M.;
Shinozaki, H.; Ohfune, Y. J. Org. Chem. 1991, 56, 4167–4176.
(e) Ma, D.; Ma, Z. Tetrahedron Lett. 1997, 38, 7599–7602.
(f) Demir, A. S.; Tanyeli, C.; Cagir, A.; Tahir, M. N.; Ulku, D.
Tetrahedron: Asymmetry 1998, 9, 1035–1042.
4.1.15. (1R,2S,5S)-3-tert-Butoxycarbonyl-2-methoxy-
carbonyl-3-azabicyclo[3.1.0]hexane (24). According to
the procedure for the preparation of compound 13, reduction
of lactam 23 (341 mg, 1.34 mmol) afforded the title
1
compound 24 (101 mg, 31%) as an oil. H NMR (CDCl3)
d 0.62 (m, 1H), 0.72 (m, 1H), 1.35 and 1.40 (2s, 9H), 1.56–
1.61 (m, 1H), 1.77–1.83 (m, 1H) 3.49–3.58 (m, 2H), 3.71
and 3.72 (2s, 3H), 4.30 and 4.34 (2d, JZ5 Hz, 1H). 13C
NMR (CDCl3) d 8.26 and 8.38, 15.8 and 16.5, 19.7 and 20.6,
28.1 and 28.3, 49.7, 51.8 and 51.9, 60.3 and 60.5, 80.0 and
80.1, 154.2, 171.8. HRMS (EI, 70 eV) m/z 241.1314 (MC,
calcd for C12H19NO4 241.1355).
13. Fujimoto, Y.; Irreverre, F.; Karle, J. M.; Karle, I. L.; Witkop,
B. J. Am. Chem. Soc. 1970, 93, 3471–3477.
14. (a) Milewska, M. J. Pol. J. Chem. 2000, 74, 447–467 and
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36, 3149–3152. (c) Tverezovsky, V. V.; Baird, M. S.; Bolesov,
I. G. Tetrahedron 1997, 53, 14773–14792.
4.1.16. (2S,3R,4S)-3,4-Methanoproline (25). According to
the procedure for the preparation of compound 14,
hydrolysis and deprotection of compound 24 (101 mg,

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M. Oba et al. / Tetrahedron 61 (2005) 8456–8464
15. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87,
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