Stereoselective synthesis of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid via C-H insertion of alkylidenecarbene.

Article abstract of DOI:10.1271/bbb.66.887

(1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (ACPD), a potent agonist of metabotropic glutamate receptors, was synthesized from L-serine. The chiral quaternary center was constructed by C-H insertion of the alkylidenecarbene, this being generated by the reaction between lithiotrimethylsilyldiazomethane and the corresponding ketone.

Full text of DOI:10.1271/bbb.66.887

This article was downloaded by: [University of Connecticut]
On: 10 October 2014, At: 05:16
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Bioscience, Biotechnology, and Biochemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/tbbb20
Stereoselective Synthesis of (1S,3R)-1-
Aminocyclopentane-1,3-dicarboxylic Acid via C–H
Insertion of Alkylidenecarbene
Susumu OHIRAa, Megumi AKIYAMAa, Kumiko KAMIHARAa, Yuichi ISODAa & Atsuhito
KUBOKIa
a Department of Biological Chemistry, Faculty of Science, Okayama University of
Science1-1 Ridai-cho, Okayama 700-0005, Japan
Published online: 22 May 2014.
To cite this article: Susumu OHIRA, Megumi AKIYAMA, Kumiko KAMIHARA, Yuichi ISODA & Atsuhito KUBOKI (2002)
Stereoselective Synthesis of (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic Acid via C–H Insertion of Alkylidenecarbene,
Bioscience, Biotechnology, and Biochemistry, 66:4, 887-891, DOI: 10.1271/bbb.66.887
To link to this article: http://dx.doi.org/10.1271/bbb.66.887
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Biosci. Biotechnol. Biochem., 66 (4), 887–891, 2002
Note
Stereoselective Synthesis of (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic
Acid via C–H Insertion of Alkylidenecarbene
Susumu OHIRA,† Megumi AKIYAMA, Kumiko KAMIHARA, Yuichi ISODA, and
Atsuhito KUBOKI
Department of Biological Chemistry, Faculty of Science, Okayama University of Science, 1-1 Ridai-cho,
Okayama 700-0005, Japan
Received October 1, 2001; Accepted November 16, 2001
(1
(ACPD), a potent agonist of metabotropic glutamate
receptors, was synthesized from -serine. The chiral
quaternary center was constructed by C–H insertion of
the alkylidenecarbene, this being generated by the reac-
tion between lithiotrimethylsilyldiazomethane and the
corresponding ketone.
S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid
attacked by lithiotrimethylsilyldiazomethane which is
known to react with esters.12) Some of alcohol 7 and
other products were also observed by thin-layer chro-
matography,13) so the crude reaction products were
treated with potassium carbonate in methanol and
L
then puriˆed. Alcohol 7 was obtained in a 50
z z
–60
yield from 5. The use of (dimethyl)diazomethyl-
phosphonate14) and t-BuOK for generating the car-
bene did not improve the yield.
Key words: metabotropic glutamate agonist; amino
acid; chiral quaternary center; C–H inser-
tion; alkylidenecarbene
1
The H-NMR spectra of the cyclized products (6
and 7) were too complex to assign signals, even at
130
9
C in DMSO-
d
6, due to rotamers attributed to the
1-Aminocyclopentane-1,3-dicarboxylic
acid
(ACPD) is a valuable compound as an agonist for
studying the metabotropic glutamate receptor in the
brain function.1) (1
S,3R)-ACPD (1) has been proved
±
to be an active stereoisomer of ( )-trans-ACPD at
metabotropic excitatory amino acid receptors.2) Syn-
thesis of all the stereoisomers of ACPD has been
achieved based on optical resolution and separation
of a diastereomeric mixture.3,4) Two research groups
have recently reported stereoselective syntheses of
1,5,6) whereby the 3-carboxyl group was introduced by
substitution of the cyanide ion and subsequent
hydrolysis. We describe here the concise stereoselec-
tive synthesis of 1 as an extension of our continuing
studies to construct quaternary chiral centers by C–H
insertion of alkylidenecarbenes.7) A very similar ap-
proach to the simple analogue of 1 emerged in 1999;
however, 1 itself was not attained.8)
Fig. 1.
Methyl ester 2, derived from
L
-serine,9) was
reduced with diisobutylaluminum hydride, and the
crude aldehyde was treated with 2-oxo-3-(triphenyl-
l
a
5-phosphanylidene)propyl acetate (3).10) Resulting
, b-unsaturated ketone 4 was hydrogenated over
palladium on charcoal to give saturated ketone 5 in a
high yield. The reaction between lithiotrimethylsilyl-
diazomethane and 5 gave cyclized product 6 via the
generation of the alkylidenecarbene, this being fol-
lowed by intramolecular 1,5 C–H insertion.11) It is
noteworthy that the keto group of 5 was selectively
Scheme 1. (a) DIBAL-H, CH2Cl2, „78
60–70 C, 10 h (88 in 2 steps); (c) H2, Pd C, EtOAc (92
TMS(Li)CN2, THF, „78–0
(50–60 in 2 steps).
9
C; (b) 3, benzene,
); (d)
C, 2 h; (e) K2CO3, MeOH, rt,
9
z
z
W
9
z
†
To whom correspondence should be addressed. Fax: +81-86-256-9425; E-mail: sohira
＠
dbc.ous.ac.jp

888
S. OHIRA et al.
the optical rotation of synthetic ACPD was also
satisfactory. We could not determine the enantiomer-
ic excess of the synthetic intermediates,15) although
the 1H-NMR spectra of 10, 11 and the dimethyl ester
of 1 with [Eu(hfc)3] did not indicate the presence of
other enantiomers.
Scheme 2. (a) H2, 4 atm, PtO2, EtOAc (75
z); (b) AcCl, MeOH,
Experimental
rt; (c) (Boc)2O, 1
M NaOH (96z in 2 steps).
Melting points (mp) values are uncorrected. Opti-
cal rotation data were measured with a Horiba
SEPA-200 polarimeter at ambient temperature. IR
spectra were recorded by a Perkin-Elmer 1720 FT-IR
spectrometer. 1H- and 13C-NMR spectra were record-
ed by either a Jeol JNM-GSX400 or Bruker ARX-400
spectrometer. Mass spectra (MS) and exact mass de-
terminations were obtained with a JMX-700 MSta-
tion mass spectrometer. Analytical TLC was done on
Scheme 3. (a) AcCl, MeOH, rt; (b) Ac2O, Py, rt (65
steps); (c) KOH, MeOH, rt (66 ); (d) CrO3, H2SO4, acetone, rt,
5 h; (e) CH2N2, Et2O (42 in 2 steps); (f) 6 HCl, re‰ux
(86 ).
z in 2
z
z
M
z
×
1.5 5-cm precoated TLC plates (silica gel 60 F-254,
0.2 mm layer thickness) manufactured by E. Merck.
Column chromatography was carried out with E.
Merck silica gel 60 (230–400 mesh ASTM).
Boc group. We tried to remove the Boc group at this
stage, but obtained only a complex mixture, because
of the eminent instability of allylic alcohol 7 under a-
cidic conditions.
tert-Butyl (R)-4-(4-acetoxy-3-oxo-1-(E)-butenyl)-
2,2-dimethyloxazolidine-3-carboxylate (4). To a solu-
Hydrogenation of 7 proceeded under 4.0 atom to
aŠord saturated compound 8. The stereoselectivity of
this hydrogenation was not clear at this stage due to
the presence of rotamers, although it was assumed
that the hydrogen molecule came from the opposite
side to that of the bulky Boc group. The stereoche-
mistry of 8 became clear after it had been converted
to compound 10. After removing all the protecting
groups, the amino group was again protected as a
carbamate. Transformation of the diol to a diacid
was attempted under various reaction conditions
(conversion of diol 9 to the corresponding dialdehyde
and then further oxidation, for example), but was
unsuccessful due primarily to the lability of the Boc
group under acidic conditions.
tion of methyl ester 2 (13.55 g, 52.3 mmol) in
dichloromethane was added a 1.0 solution of
diisobutylaluminum hydride in toluene (94.1 ml,
94 mmol) at „78 C under nitrogen. After stirring
for 1 h, 10 aqueous sodium hydroxide was added
to the reaction mixture at 0 C. The mixture was
M
9
z
9
stirred for 15 min at rt and then extracted with
dichloromethane. The organic layer was dried over
anhydrous sodium sulfate and evaporated. The crude
aldehyde thus obtained was dissolved in anhydrous
benzene, and the solution stirred with 2-oxo-3-
(triphenyl-
27.54 g, 73.2 mmol) at 65–70
l
5-phosphanylidene)propyl acetate (3;
9
C overnight. The reac-
tion was quenched with water, and the mixture was
extracted with dichloromethane. The organic layer
was dried over anhydrous sodium sulfate and evapo-
rated. Puriˆcation by column chromatography on
silica gel with hexane–ethyl acetate (3:1) as the eluent
We therefore decided to change the protecting
group of the amine. Treatment of 8 with acidic
methanol and subsequent acetylation gave triacetate
1
10 as a single isomer. All signals of the H-NMR
gave pure product 4 (11.87 g, 69
z
) as a mixture of
26
spectrum could now be clearly assigned to structure
10. It was disclosed here that the hydrogenation of 7
to 9 was highly stereoselective. Removal of two acetyl
groups by basic hydrolysis gave diol 11. Oxidation of
11 was attempted under many reaction conditions,
the crude product being treated with diazomethane
and puriˆed as a dimethyl ester. Among the several
conditions attempted, Jones oxidation employed at
room temperature with subsequent esteriˆcation gave
a moderate yield of 12. Finally, the esters and
acetamide of 12 were hydrolyzed with re‰uxing
hydrochloric acid. Puriˆcation with ion-exchange
rotamers. Oil; [
a
]
„40 (c 0.84, CHCl3); IR nmax
9
D
(CHCl3) cm„1: 1750 (O–C O), 1694 (C O and
＝
＝
＝
＝
O–(C O)–O), 1638 (C C); NMR dH (CDCl3): 1.42
and 1.49 (9H, each s, –C(C 3)3), 1.52 and 1.54 (3H,
each s, one of –C(C 3)2), 1.60 and 1.65 (3H, each s,
one of –C(C 3)2), 2.17 and 2.18 (3H, each s,
OCOC 3), 3.816 and 3.821 (1H, each d,
one of N–CH–C 2–O), 4.10–4.14 (1H, m, one of
N–CH–C 2–O), 4.44 and 4.56 (1H, each brs,
N–C –CH2–O), 4.85 (2H, s, C
and 6.29 (1H, each d,
H
H
H
＝
9.2 Hz,
H
J
H
H
H
H
2–OCOCH3), 6.22
＝
J
15.9 and 16.3 Hz, CO–C
H
＝
＝
CH
CH–), 6.80–6.84 (1H, m, CO–CH
–); NMR
resin gave (1
S
,3
R
)-ACPD, whose physical properties
dC (CDCl3): 20.4, 23.4, 24.5, 26.4, 27.2, 28.3, 30.8,
were identical with those reported.3,5) The value for
58.2, 66.9, 67.1, 80.3, 80.8, 94.0, 94.6, 125.8, 145.2,

Synthesis of (1
S
,3
R
)-ACPD
889
145.8, 151.4, 151.9, 170.1, 192.1, 206.8; MS m z
24.4, 25.5, 25.9, 27.0, 28.4, 30.7, 33.9, 34.9, 61.6,
72.7, 73.6, 73.8, 74.2, 79.2, 79.9, 94.2, 94.8, 126.2,
W
(
z
): 327 (M+, 1), 312 (17), 271 (25), 256 (7), 254 (3),
212 (100), 194 (4), 170 (26), 152 (18), 96 (28), 57 (44);
z
127.1, 145.0, 146.5, 151.4, 151.9; MS m z ( ): 283
W
HRMS m z (M+): calcd. for C16H25O6N, 327.1682;
(M+, 28), 268 (87), 225 (100), 210 (97), 194 (14), 166
W
found, 327.1681.
(15), 150 (4), 83 (7), 57 (3); HRMS m z (M+): calcd.
W
for C15H25O4N, 283.1784; found, 283.1783.
tert-Butyl
dimethyloxazolidine-3-carboxylate
presence of 10 Pd C (0.12 g), a solution of
(R)-4-(4-acetoxy-3-oxobutyl)-2,2-
(
5
). In the
tert-Butyl (5S,7R)-7-hydroxymethyl-2,2-dimethyl-
1-aza-3-oxaspiro[4.4]nonane-1-carboxylate (8). In
z
a
,
b
-
W
unsaturated ketone 4 (6.02 g, 18.17 mmol) in ethyl
acetate was treated overnight with hydrogen under
atmospheric pressure. After ˆltration to remove the
catalyst, the solvent was evaporated. The residue was
chromatographed on silica gel using hexane–ethyl
the presence of platinum oxide (6.0 mg), a solution of
allylic alcohol 7 (299 mg, 1.054 mmol) in ethyl
acetate (10.5 ml) was stirred under hydrogen at
400 kPa and rt for 6 h. After removing the catalyst
by ˆltration, column chromatography on silica gel
using hexane–ethyl acetate (2:1) as the eluent gave
acetate (3:1) to give saturated ester 5 (5.97 g, 99
z
).
26
Oil; [
a
]
„13
9
(
c
1.45, CHCl3); IR nmax (CHCl3)
saturated alcohol 8 (225.3 mg, 75 ) as a mixture of
z
D
cm„1: 1734 (O–C O and O–(C O)–O), 1685 (C
O); NMR dH (CDCl3): 1.48 (9H, s, –C(C 3)3), 1.49
and 1.56 (6H, each s, –C(C 3)2), 1.92–1.97 (2H, m,
N–CH–C 2), 2.16 (3H, s, OCOC 3), 2.47–2.62
(2H, m, CO–C 2–CH2), 3.58–4.09 (3H, m,
N–C –C 2), 4.68 (2H, s, C 2–OCOCH3); NMR dC
rotamers. Oil; [
a
]
„14
9(
c
1.40, CHCl3); IR nmax
26
＝
＝
＝
D
(CHCl3) cm„1: 3441 (–OH), 1682 (C O); NMR dH
＝
H
H
(CDCl3): 1.48, 1.49, 1.52, and 1.55 (15H, each s,
H
H
–C(CH3
)
and –C(C
2–CH2 and O
2–O and C 2–OH); NMR dC (CDCl3):
H
3)2), 1.67–2.45 (7H, m,
3
H
–C
H
2–C–C
H
H
), 3.60–4.09 (4H, m,
H
H
H
N–C–C
H
H
(CDCl3): 20.4, 23.0, 24.3, 24.6, 26.6, 27.1, 27.3,
27.7, 28.4, 35.0, 35.4, 56.3, 65.3, 67.0, 67.4, 67.9,
24.4, 24.6, 25.9, 26.1, 26.5, 27.1, 27.4, 28.35, 28.44,
28.7, 32.9, 36.8, 39.0, 40.6, 41.3, 65.3, 66.7, 67.0,
80.2, 93.5, 94.1, 170.2, 203.2; MS m z
z
( ): 314
z
69.7, 76.2, 79.9, 94.1, 94.3, 151.4; MS m z ( ): 285
W
W
(M+-15, 8), 269 (15), 254 (3), 228 (4), 214 (100), 198
(10), 169 (7), 154 (11), 138 (5), 112 (17), 83 (13), 57
(M+, 0.5
z
), 270 (6), 214 (13), 200 (5), 184 (4), 170
(59), 152 (76), 144 (56), 116 (83), 100 (43), 57 (100);
(51); HRMS m z (M+-15): calcd. for C15H24O6N,
HRMS m z (M+-15): calcd. for C14H24O4N,
W
W
314.1604; found, 314.1603.
270.1705; found, 270.1705.
tert-Butyl
aza-3-oxaspiro[4.4]non-6-ene-1-carboxylate (
solution of trimethylsilyldiazomethane (a 2.0
tion in hexane, 2.48 ml, 4.96 mmol) in THF (11 ml)
was added a 1.54 solution of butyllithium (3.21 ml,
4.95 mmol) at „78 C. After stirring for 1 h, a solu-
tion of ketone 5 (1.10 g, 3.3 mmol) in THF (5.5 ml)
was added, and the mixture was stirred 0 C for 2 h.
(S)-7-hydroxymethyl-2,2-dimethyl-1-
). To a
solu-
(1S,3R)-(3-Acetoxymethyl-1-acetylaminocyclopen-
tyl)methyl acetate (10). To a solution of alcohol 8 in
methanol (7.7 ml) was added acetyl chloride
7
M
(0.39 ml, 5.51 mmol) at 09C. The mixture was stirred
M
at rt for 0.5 h, and the solvent was evaporated. The
residue was successively treated with acetic anhydride
(1.30 ml, 13.8 mmol), pyridine (1.11 ml, 13.7 mmol),
and 4-dimethylaminopyridine (17 mg, 0.14 mmol) at
9
9
The reaction was quenched with aqueous ammonium
chloride, and the solvent was evaporated. The aque-
ous residue was extracted with dichloromethane, and
the organic layer was dried over anhydrous sodium
sulfate. Evaporation of the solvent gave a crude mix-
ture (1.51 g) which was used in the next reaction.
The oil which contained acetate 6 was dissolved in
methanol (16.5 ml) and treated with potassium car-
rt overnight. The reaction was quenched with 1
M
hydrochloric acid, and the mixture was extracted
with ethyl acetate. The organic layer was successively
washed with brine and aqueous saturated sodium
hydrogen carbonate, and dried over anhydrous sodi-
um sulfate. Evaporation of the solvent and column
chromatography on silica gel, using ethyl acetate as
the eluent, gave triacetate 10 (244 mg, 65
z
). Oil;
2.25, CHCl3); IR nmax (CHCl3) cm„1
3445 (N–H), 1735 (O–C O), 1676 (N–C O); NMR
dH (CDCl3): 1.56–2.03 (7H, m, –C 2–C–C 2–CH2
and C 2–O), 1.95 (3H, s, OCOC
3), 2.07 (3H, s, OCOC
–CH2–O), 4.00 (1H, dd,
2–O), 4.05 (1H, dd,
one of –CH–C 2–O), 4.25 (2H, s, one of
–C–C 2–O), 5.77 (1H, s, N–H); NMR dC (CDCl3):
20.8, 20.9, 24.0, 27.4, 34.5, 37.3, 38.2, 63.0, 66.6,
67.7, 169.8, 170.9, 171.1; MS m z
): 256 (M+-15,
14), 228 (14), 211 (12), 198 (91), 185 (13), 156 (58),
26
bonate (2.28 g, 16.5 mmol) at 0
9C for 1.5 h. After
[a
]
„3
9(c
:
D
ˆltration and evaporation, the residue was chro-
matographed on silica gel using hexane–ethyl acetate
＝
＝
H
H
(3:1) to give alcohol 7 (528 mg, 56
z
) as a mixture of
H
H3), 2.06 (3H, s,
26
rotamers. Oil; [
a
]
„33
9
(c
1.00, CHCl3); IR nmax
OCOC
m, –C
H
H
3), 2.08–2.34 (1H,
D
(CHCl3) cm„1: 3447 (–OH), 1682 (C O); NMR dH
H
J
10.9, 6.8 Hz,
＝
＝
(CDCl3): 1.40 and 1.46 (9H, s, –C(C
1.51 (3H, each s, one of –C(C 3)2), 1.54 and 1.58
(3H, each s, one of –C(C 3)2), 2.05–2.57 (4H, m,
–C 2–C 2), 3.69 and 3.72 (2H, each brs,
N–CH–C 2–O), 3.71 (2H, brs, –C 2OH), 5.40 and
5.46 (1H, each brs, C ); NMR dC (CDCl3):
H
3)3), 1.49 and
one of –CH–C
H
J 10.9, 7.2 Hz,
＝
H
H
H
H
H
H
H
H
(z
W
＝
CH

890
S. OHIRA et al.
138 (93), 129 (19), 110 (27), 96 (100), 92 (28), 60 (37),
57 (28).
CH–C
–CH2–CH2–), 2.37 (1H, dd,
CH–C 2–C–N), 2.99–3.06 (1H, m, C
C (CDCl3): 31.3, 36.9, 41.0, 48.0, 68.1, 178.5,
H2–C–N), 2.23–2.33 (2H, m, two of
＝
J
8.5, 14.5 Hz, one of
–COOH);
H
d
H
N-[(1S,3R)-1,3-Bis(hydroxymethyl)cyclopentyl]
acetamide (11). To a suspension of dry potassium
carbonate (186 mg, 1.35 mmol) in methanol (2.3 ml)
was added a solution of acetate 10 in methanol
NMR
185.9.
References
9
(1.1 ml) at 0 C. The mixture was stirred at rt for 1.5
1) McLennan, H. and Liu, J. R., The action of six
antagonists of the excitatory amino acids on neurons
of the rat spinal cord. Exp. Brain Res., 45, 151–156
(1982); Schoepp, D. D. and Conn, P. J., Metabotrop-
ic glutamate receptors in brain function and patholo-
gy. Trends Pharmacol. Sci., 14, 13–20 (1993).
h and then ˆltered. Evaporation of the solvent and
column chromatography on silica gel, using acetone
26
as the eluent, gave diol 11 (83 mg, 66
z). Oil; [a]
D
„109(c
0.60, CHCl3); IR nmax (CHCl3) cm„1: 3445
＝
(N–H), 3339 (O–H), 1653 (N–C O); NMR dH
(CDCl3): 1.56–1.66 and 1.74–1.85 (each 2H, each m,
2) Schoepp, D. D., Johnson, B. G., True, R. A., and
–C
(2H, m, C–C
–CH2–O), 3.58 (1H, d,
N–C–CH2–O), 3.62 (1H, dd,
H2–CH2–), 1.98 (3H, s, N–COCH3), 2.00–2.03
Mon, J. A., Comparison of (1
clopentane-1,3-dicaroxylic acid (1
,3 -ACPD-stimulated brain phosphoinositide
hydrolysis. European Journal of Phar-
S
,3
R
)-1-aminocy-
H
2–CH), 2.30–2.33 (1H, m,
S
,3
R
-ACPD) and
＝
＝
＝
J
C
H
J
11.4 Hz, one of
9.8, 4 Hz, one of
9.8, 4.6 Hz, one of
1
R R
J
macology—Molecular Pharmacology Section, 207,
351–353 (1991).
CH–C
CH–C
H
H
2–O), 3.65 (1H, dd,
2–O), 3.75 (1H, d,
J
＝
11.4 Hz, one of
3) Curry, K., Peet, M. J., Magnuson, D. S. K., and
McLennan, H., Synthesis, resolution, and absolute
conˆguration of the isomers of the neuronal excitant
1-amino-1,3-cyclopentanedicarboxylic acid. J. Med.
Chem., 31, 864–867 (1988).
N–C–CH2–O), 5.26 (1H, br, OH), 6.71 (1H, brs,
NH); NMR dC (CDCl3): 23.8, 26.4, 35.0, 39.0, 39.2,
65.4, 66.8, 69.3, 171.7; MS m z (
z
): 156 (M+-29,
W
72), 128 (7), 126 (7), 114 (100), 96 (41), 79 (13), 72
(16), 59 (26); HRMS m z (M+-29): calcd. for
W
4) Trigalo, P., Buisson, D., and Azerad, R., Chemoen-
zymatic synthesis of conformationally rigid glutamic
acid analogues. Tetrahedron Lett., 47, 6109–6112
(1988).
C8H14 O2N, 156.1025; found, 156.1024.
Dimethyl (1S,3R)-1-Acetylaminocyclopentane-1,3-
5) Ma, D., Ma, J., and Dai, L., Stereospeciˆc synthesis
dicarboxylate (12). Jones reagent (2.75 ) was added
M
of
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic
to a solution of diol 11 (30 mg, 0.16 mmol) in acetone
(0.8 ml) until the red color persisted (ca. 0.5 ml). The
mixture was stirred at rt for 5 h, and then the reaction
was quenched with solid sodium hydrogen sulˆte.
The top clear layer was treated with diazomethane in
ether, and evaporated. Column chromatography on
acid, a selective agonist of metabotropic glutamate
receptors. Tetrahedron Asymmetry
(1997).
, 8, 825–827
6) Hodgson, D. M., Thompson, A. J., Waldman, S.,
and Keats, C. J., On the Possibility of carbamate-
directed hydroboration. An approach to the asym-
metric synthesis of 1-aminocyclopentane-1,3-dicar-
boxylic acid. Tetrahedron, 55, 10815–10834 (1999).
7) Ohira, S., Yoshihara, N., and Hasegawa, T., Synthe-
sis of („)-gleenol via C–H insertion reaction of
silica gel using ethyl acetate as the eluent, gave diester
26
12 (16 mg, 42
z
). Oil; [
a
]
„3.7
9
(
c
1.50, CHCl3);
O),
1675 (N–C O); NMR dH (CDCl3): 1.98 (3H, s,
N–COCH3), 2.14–2.38 (6H, m, C 2–C–C 2C 2),
D
IR nmax (CHCl3) cm„1: 3446 (N–H), 1734 (O–C
＝
＝
alkylidenecarbene. Chem. Lett.
, 739–740 (1998);
H
H
H
Ohira, S., Ida, T., Moritani, M., and Hasegawa, T.,
Synthesis of („)-malyngolide using reactions of
3.08 (1H, m, CO–CH), 3.71 (3H, s, COOCH3), 3.73
(3H, s, COOCH3), 6.62 (1H, s, NH); NMR dC
(CDCl3): 23.0, 28.5, 35.9, 39.8, 42.0, 52.2, 52.6,
alkylidenecarbenes. J. Chem. Soc., Perkin Trans. I
,
293–297 (1998); Ohira, S., Noda, I., Mizobata, T.,
and Yamato, M., Synthesis of tertiary alcohol from
secondary alcohol via intramolecular C–H insertion
65.7, 169.8, 173.3, 177.3; MS m z (z
): 243 (M+,
W
12), 212 (7), 184 (76), 170 (26), 142 (100), 124 (20), 82
(72); HRMS m z (M+): calcd. for C11H17O5N,
W
of alkylidenecarbene. Tetrahedron Lett.
,
36,
243.1107; found, 243.1106.
3375–3376 (1995); Ohira, S., Ishi, S., Shinohara, K.,
and Nozaki, H., C–H Insertion method for the chiral
tertiary alcohol: Formal synthesis of („)-frontalin.
Tetrahedron Lett., 31, 1039–1040 (1990).
(1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic
acid (
1). Diester 12 (18 mg, 0.074 mmol) was treated
8) Gabaitsekgosi, R. and Hayes, C. J., Alkylidene car-
bene C–H insertion strategy for the enantioselective
with 6
M
hydrochloric acid under the re‰uxing condi-
tion for 5 h. After evaporating the water, the residue
was puriˆed by ion-exchange chromatography on
synthesis of
a,a-dialkyl-a-amino acids. Tetrahedron
aqueous NH36) to
Lett., 40, 7713–7716 (1999).
Dowex 50WX8-100 eluted with 2
M
9) Garner, P. and Park, J. M., 1,1-Dimethylethyl (S)-
give dicarboxylic acid 1 (11 mg, 86
z
). White solid;
or (R)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxy-
23
20
[
a
]
„8.5
9
(
c
1.65, H2O)
s
lit.3)
[
a
]
9
„6.9 (c 1.0,
D
D
late: a useful serinal derivative. Org. Synth., 70,
H2O)
t
; NMR dH (D2O): 1.96–2.03 (2H, m, two of
18–26 (1992).
–CH2–CH2–), 2.11 (1H, dd,
J
＝
4.2, 14.5 Hz, one of

Synthesis of (1
S
,3
R
)-ACPD
891
10) Kim, K. S. and Szarek, W. A., Synthesis of 3
?
,7
?
-an-
13) We presume that those byproducts were produced by
the reaction between the excess reagent and the acetyl
group of 6.
hydrooctose nucleosides related to the ezomycins and
the octosyl acids. Can. J. Chem., 59, 878–888 (1981).
11) Shioiri, T. and Aoyama, T., Trimethyldiazomethane:
a useful reagent for generating alkylidene carbenes
and its application to organic synthesis. Synth. Org.
Chem., Jpn., 54, 918–928 (1996); Ohira, S., Okai, K.,
and Moritani, T., Generation of alkylidenecarbenes
by the alkenation of carbonyl compounds with
lithiotrimethylsilyldiazomethane. J. Chem. Soc.,
Chem. Commun., 721–722 (1992).
14) Gilbert, J. C., Giamalva, D. H., and Weerasooriya,
U., Intramolecular carbon-hydrogen insertions of
alkylidenecarbenes. 1. Selectivity. J. Org. Chem., 26,
5251–5256 (1983); Ohira, S., Methanolysis of
dimethyl(1-diazo-2-oxopropyl)phosphonate: genera-
tion of dimethyl(diazomethyl)phosphonate and reac-
tion with carbonyl compounds. Synth. Commun., 19,
561–564 (1989).
12) Aoyama, T. and Shioiri, T., New methods and rea-
gents in organic synthesis. 31. Lithium trimethylsilyl-
diazomethane: a new synthon for the preparation of
15) Scince all intermediates except 10, 11 and the
dimethyl ester of 1 were rotameric mixtures, we did
not examine their optical purity. Attempts to convert
10 to the bis MTPA ester under various conditions
were unsuccessful.
tetrazoles. Chem. Pharm. Bull.
, 30, 3450–3452
(1982).