Enantioselective synthesis of the excitatory amino acid (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid

Article abstract of DOI:10.1021/jo025892v

An enantioselective synthesis of the α,α-dialkyl-α-amino acid (1S,3R)-ACPD has been achieved using an alkylidene carbene 1,5-CH insertion reaction as a key step. The ketone cyclization precursor was synthesized from Garner's aldehyde in high yield via a Wittig homologation and subsequent catalytic hydrogenation. Treatment of the ketone with 1.2 equiv of lithio(trimethylsilyl)diazomethane in THF resulted in the formation of the corresponding cyclopentene-containing CH-insertion product in 62-69% yield in high enantiomeric excess. Subsequent functional group manipulation allowed the synthesis of the amino acid (1S,3R)-ACPD to be completed.

Full text of DOI:10.1021/jo025892v

En a n tioselective Syn th esis of th e Excita tor y Am in o Acid
(1S,3R)-1-Am in ocyclop en ta n e-1,3-d ica r boxylic Acid
Daniel M. Bradley,† Renameditswe Mapitse,† Nicholas M. Thomson,‡ and
Christopher J . Hayes*,†
The School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, U.K., and
Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ , U.K.
chris.hayes@nottingham.ac.uk
Received May 2, 2002
An enantioselective synthesis of the R,R-dialkyl-R-amino acid (1S,3R)-ACPD has been achieved
using an alkylidene carbene 1,5-CH insertion reaction as a key step. The ketone cyclization precursor
was synthesized from Garner’s aldehyde in high yield via a Wittig homologation and subsequent
catalytic hydrogenation. Treatment of the ketone with 1.2 equiv of lithio(trimethylsilyl)diazomethane
in THF resulted in the formation of the corresponding cyclopentene-containing CH-insertion product
in 62-69% yield in high enantiomeric excess. Subsequent functional group manipulation allowed
the synthesis of the amino acid (1S,3R)-ACPD to be completed.
In tr od u ction
(1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid
(ACPD, 1) is a conformationally restricted analogue of
L-glutamic acid, which is the major neurotransmitter in
the mammalian central nervous system (CNS). Glutamate
receptors can be divided into two major classes: (1) the
ionotropic (iGluRs) and (2) the metabotropic (mGluRs)
glutamate receptors. Compound 1 selectively agonizes the
latter.1 The use of 1 as a tool in the study of glutamate
receptor function and its potential use as a therapeutic
agent for neurodegenerative disorders have led a number
of research groups to develop stereoselective syntheses
of this material (Figure 1).
On the basis of the previously reported route of
Connors and Ross,2a and then later Meister et al.,2b Curry
et al. synthesized all four stereoisomers of 1 from (()-3-
oxocyclopentanecarboxylic acid 3 by brucine salt medi-
ated resolution, followed by construction of the R,R-
dialkyl-R-amino acid moiety using a Bucherer-Bergs/
Strecker-type transformation.2c Azerad et al. subsequently
showed that esters of the key oxocyclopentanecarboxylic
acid 3 could be resolved using a microbial reduction of
the cyclopentanone, followed by separation and oxidation
of the resulting cyclopentanol.2d Using a conceptually
different approach, Ma et al. completed an enantioselec-
tive synthesis of 1 starting from L-malic acid 4.2e In this
F IGURE 1. Previous syntheses of (1S,3R)-ACPD 1.
synthesis, the (1S)-stereocenter was introduced via a
Curtius rearrangement and the 3-carboxylic acid sub-
stituent was installed via a displacement of the mesylate
2 with cyanide, followed by hydrolysis. The fact that the
cyanide displacement only proceeded with 40% de seemed
to indicate that some SN1 substitution or subsequent
epimerization was occurring during this transformation.
Recently, Hodgson et al. used an asymmetric carbamate-
directed hydroboration of 5 to synthesize 2 in moderate
enantiomeric excess2f,g and were able to complete a
synthesis of 1 via a route similar to that described by
Ma.
We have previously reported a method for the con-
struction of the cyclopentane-containing R,R-dialkyl-R-
amino acid (1S,3R)-2,5-methanoleucine based upon an
alkylidene carbene 1,5-CH insertion reaction,3 and we
now wish to report a full account of our studies on the
application of this methodology to a short and novel
enantioselective synthesis of (1S,3R)-ACPD 1.
† University of Nottingham.
‡ Pfizer Global Research and Development.
(1) (a) Kno¨pfel, T.; Kuhn, R.; Allgeier, H. J . Med. Chem. 1995, 38,
1417. (b) Kno¨pfel, T.; Gasparini, F. Drug Discovery Today 1996, 1, 103.
(2) (a) Connors, T. A.; Ross, W. C. J . J . Chem. Soc. 1960, 2119. (b)
Stephani, R. A.; Rowe, W. B.; Gass, J . D.; Meister, A. Biochemistry
1972, 11, 4094. (c) Curry, K.; Peet, M. J .; Magnuson, D. S. K.;
McLennan, H. J . Med. Chem. 1988, 31, 864. (d) Trigalo, F.; Buisson,
D.; Azerad, R. Tetrahedron Lett. 1988, 29, 6109. (e) Ma, D.; Ma, J .;
Dai, L. Tetrahedron: Asymmetry 1997, 8, 825; (f) Hodgson, D. M.;
Thompson, A. J .; Wadman, S. Tetrahedron Lett. 1998, 39, 3357. (g)
Hodgson, D. M.; Thompson, A. J .; Wadman, S.; Keats, C. J . Tetrahe-
dron 1999, 55, 10815.
Resu lts a n d Discu ssion
Our retrosynthetic analysis of 1 is shown in Scheme
1. Based upon our previous studies, we planned to access
(3) Gabaitsekgosi, R.; Hayes, C. J . Tetrahedron Lett. 1999, 40, 7713.
10.1021/jo025892v CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/05/2002
J . Org. Chem. 2002, 67, 7613-7617
7613

Bradley et al.
SCHEME 1
allowed 14 to be isolated in good overall yield. With
multigram quantities of 14 in hand, the synthesis of the
phosphorane 16 was completed using a standard two-
step procedure involving displacement of the bromide
with triphenylphosphine, followed by generation of the
ylide with KOH.7
Pleasingly, the phosphorane 16 underwent smooth
Wittig-type olefination with Garner’s aldehyde to afford
the unsaturated ketone 15 (>20:1, E/Z) in excellent yield.
Catalytic hydrogenation over palladium on carbon then
afforded the hydroxymethyl ketone 18. We found that
reduction of the olefin in 15 was much faster than
hydrogenolysis of the benzyloxy group, and the interme-
diate saturated benzyloxymethyl ketone 17 could be
isolated if desired. For the synthesis of ACPD, exchange
of the benzyl protecting group was deemed necessary as
the benzylic methylene present in 17 would provide a
competitive site for 1,5-CH insertion of the alkylidene
carbene intermediate. To complete the synthesis of the
cyclization precursor 19, all that remained was TBS-
protection of the hydroxymethyl ketone 18. To our
chagrin, TBS-protection of 18 proved to be a nontrivial
operation and a number of alternative procedures had
to be examined before suitable conditions were found. For
example, treatment of a solution of 18 in DMF with
TBSCl in the presence of imidazole followed by aqueous
workup resulted in the isolation of only small amounts
of 19, with the starting material 18 accounting for the
mass balance. Deprotonation of the R-hydroxy ketone 18
with LDA in THF or DMF before addition of TBS-Cl and
aqueous workup resulted in the same low yield of 19.
Fortunately, the desired cyclization precursor 19 could
be accessed conveniently by using TBSOTf in the pres-
ence of Et3N and DMAP. We found that after stirring
for 1 h at room temperature, the crude reaction mixture
could be loaded directly onto a SiO2 gel flash column, and
the desired product 19 could be isolated in high yield and
purity by elution with petroleum ether/Et2O (6:1). Sub-
sequent investigations revealed that the silyloxymethyl
ketone 19 was very susceptible to mildly basic hydrolysis,
and the nature of this reactivity is currently being
investigated.
Although we were able to access the desired cyclization
precursor 19 using the chemistry described above, we
were somewhat unhappy with several aspects of the route
and we decided to address these by developing a more
efficient second-generation synthesis. Upon examination
of the synthesis of 19 (vide supra), it was clear that both
the effort required to synthesize the phosphorane 16 on
large scale, and a rather frustrating benzyl to TBS
protecting group swap, were making it difficult to access
multigram quantities of 19. We felt it would be much
better if we could synthesize an ylide (e.g., 21) with the
desired TBS protecting group already in place and to do
this in a much more convergent manner. We therefore
decided to examine methods for the synthesis of the
revised ylide 21. We felt that the route used to synthesize
the phosphorane 16 would be unsuitable, as it was quite
lengthy and the TBS-protecting group required was
unlikely to survive the harshly acidic conditions used.
In principle we felt it should be possible to access 21
directly by acylation of methylenetriphenylphosphorane
SCHEME 2a
a
Reagents: (i) HgSO4, H2SO4, MeOH/H2O (65%); (ii) Br2,
MeOH; (iii) TFA/H2O (90%, two steps); (iv) PPh3, PhMe, then KOH,
H2O (60%); (v) 9, CH2Cl2 (91%); (vi) Pd/C, H2, EtOAc, 2 h (95%);
(vii) Pd/C, H2, 18 h (82%); (viii) TBSOTf, Et3N, DMAP, DMF (83%).
the dicarboxylic acid from the protected diol 6 using
standard functional group interconversions. The desired
(3R)-stereochemistry in 1 could be introduced by catalytic
hydrogenation of 6, with the bulky Boc protecting group
blocking one face of the cyclic olefin. We anticipated that
the key cyclopentene 6 could be accessed via a 1,5-CH
insertion reaction of a suitably functionalized alkylidene
carbene 7, which in turn could be generated from the
corresponding ketone 11 by treatment with lithio(trim-
ethylsilyl)diazomethane 8.4 The cyclization precursor 11
was further disconnected to reveal Garner’s aldehyde 9
and the phosphorane 10 as possible starting materials.
As multigram quantities of Garner’s aldehyde 95a were
readily available using the modified procedure as de-
scribed by Taylor et al.,5b our synthetic attention first
turned to the elaboration of the alkoxy-substituted phos-
phorane 10. Following literature precedent,6 alkylation
of benzyl alcohol with propargyl bromide gave the desired
ether 12, and mercuric ion-mediated hydrolysis of the
alkyne then afforded the corresponding methyl ketone
13 in acceptable yield (Scheme 2). Bromination of 13
afforded the desired bromomethyl ketone 14 along with
significant amounts of its dimethoxy ketal derivative, but
acid-mediated hydrolysis of the crude reaction mixture
(4) (a) Taber, D. F.; Neubert, T. D. J . Org. Chem. 2001, 66, 143. (b)
Taber, D. F.; Han, Y.; Incarvito, C. D.; Rheingold, A. L. J . Am. Chem.
Soc. 1998, 120, 13285. (c) Taber, D. F.; Meagley, R. P.; Walter, R. J .
Org. Chem. 1994, 59, 6014. (d) Taber, D. F.; Meagley, R. P.; Doren, D.
J . J . Org. Chem. 1996, 61, 5723. (e) Ohira, S.; Ishi, S.; Shinohara, K.;
Nozaki, H. Tetrahedron Lett. 1990, 31, 1039. (f) Gilbert, J . C.;
Giamalva, D. H.; Baze, M. E. J . Org. Chem. 1985, 50, 2557.
(5) (a) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361 (b)
Campbell, A. D.; Raynham, T. M.; Taylor, R. J . K. Synthesis 1998, 1707.
(6) Boger, D. L.; Palanki, M. S. S. J . Am. Chem. Soc. 1992, 114,
9318.
(7) For details of the synthesis of 16 see the Supporting Information.
7614 J . Org. Chem., Vol. 67, No. 22, 2002

Synthesis of (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic Acid
SCHEME 3
SCHEME 4a
with methyl glycolate 20.8 To test this new route, methyl
glycolate was first protected (TBSCl, imidazole, DMF) to
afford 20.9 Pleasingly, we found that the desired stabi-
lized ylide 21 could be accessed in good yield (50-69%)
on a 60-70 g scale, by the dropwise addition of 20 to 2
equiv of a cool (0 °C) solution of methylenetriphenylphos-
phorane in THF. The ylide 21 could be purified by flash
column chromatography if required, but we found that
on a large scale, washing the solid product with EtOAc
was sufficient to provide material of adequate purity for
further transformations. We also found that the benzy-
loxy-substituted phosphorane 16 could be accessed in a
similar manner by treatment of methylenetriphenylphos-
phorane with the commercially available acid chloride
23 or the methyl ester derivative 22 (Scheme 3).
Gratifyingly, the new phosphorane 21 underwent
smooth Wittig reaction with Garner’s aldehyde to afford
the corresponding enone 24, and catalytic hydrogenation
proceeded cleanly to complete the new route to the
desired cyclization precursor 19. To our pleasure, and in
accord with our previously reported model study,3 reac-
tion of 19 with lithio(trimethylsilyl)diazomethane in THF
(-78 f 0 °C) gave the desired cyclopentene product 27
in 62-69% yield. We were unable to determine the
enantiomeric excess of 27 directly and further derivati-
zation was required. Thus dihydroxylation of 27 using
the Upjohn conditions10 afforded the corresponding diol
(+)-25 (94%) in high diasteromeric excess (>95% de by
1HNMR of the crude reaction mixture). A racemic sample
of 25 was prepared from (()-Garner’s aldehyde 9 using
an identical synthetic route to that described above, and
this was used as a reference sample for subsequent % ee
determinations. Using this sample, the diol (+)-25 was
shown to have >95% ee by chiral HPLC analysis (Chiral-
pak AD, 8:92 IPA/hexane), thus confirming the stereo-
chemical integrity of the quaternary stereocenter in the
insertion product 27. Having installed the (1S)-quater-
nary center, the remaining (3R)-stereochemistry was
then introduced via catalytic hydrogenation (Pd, 10% on
carbon) to afford 26 as the predominant diastereoisomer
(10:1, 3R/3S) (Scheme 4). Unfortunately we were unable
to separate the minor diasteroisomer from this mixture,
and the 10:1 mixture of (3R/3S) isomers was carried
through the remaining transformations.
a
Reagents: (i) CH2Cl2, rt (87%); (ii) Pd/C, H2, EtOAc (80%);
(iii) TMSCHN2, BuLi, THF (-78 °C), then 19 (-78 f 0 °C) (69%);
(iv) OsO4, NMO, Me2CO/H2O (94%); (v) Pd/C, H2, EtOAc; (vi) HF/
MeCN (81%, two steps); (vii) RuCl3, NaIO4, CCl4, MeCN, H2O; (viii)
HCl, EtOAc (49%, two steps).
selective deprotection of 26 with HF/MeCN afforded the
corresponding diol 28 in good yield. Oxidation of this diol
with RuCl3/NaIO411 next afforded N-Boc-protected ACPD
29, which was sufficiently pure to use in the final
deprotection step without further purification. Exposure
of 29 to HCl in EtOAc effected removal of the Boc
protecting group, and evaporation of the volatiles resulted
in the production of (1S,3R)-ACPD as its HCl salt (49%,
from 28). Ion exchange chromatography (Dowex 50 ×
8-200, 2 M NH3(aq)), of this salt then afforded (1S,3R)-
ACPD 1 as a white solid. The data recorded (mp, 1H
NMR, 13C NMR) for our synthetic material matched that
previously reported for ACPD 1, and copies of the 1H and
13C NMR data are provided in the Supporting Informa-
tion.12
In summary, we have shown that the excitatory amino
acid (1S,3R)-ACPD 1 can be synthesized from Garner’s
aldehyde 9 in seven steps using a conceptually novel
approach. An alkylidene carbene 1,5-CH insertion reac-
tion was used as a key step to introduce the (1R)-
quaternary center with a high degree of stereocontrol,
and the cyclopentene-containing CH-insertion product 27
should prove to be a valuable building block in the
synthesis of other glutamate analogues. These and other
studies in this area will be reported in due course.
Exp er im en ta l Section
Starting materials were obtained from commercial suppliers
and used without further purification unless otherwise stated.
All reactions were performed in flame-dried apparatus under
an atmosphere of nitrogen at room temperature unless oth-
erwise stated. CH
Na/benzophenone ketyl under nitrogen. Flash chromatography
With all of the C-C bond formations completed, all
that remained to finish the synthesis of 1 was a series of
standard functional group interconversions. First of all,
2Cl2 was distilled from CaH2, and THF from
(8) (a) Wittig, G.; Scho¨llkopf, U. Chem. Ber. 1954, 87, 1318. (b)
Bestmann, H. J . Tetrahedron Lett. 1960, (4), 7. (c) Bestmann, H. J .;
Arnason, B. Tetrahedron Lett. 1961, 455. (d) Trippett, S.; Walker, D.
M. J . Chem. Soc. 1961, 1266. (e) Bestmann, H. J . Angew. Chem., Int
Ed. Engl. 1962, 1, 270. (f) Chopard, P. A.; Searle, R. J . G.; Devitt, F.
H. J . Org. Chem. 1965, 30, 1015.
(9) Mukaiyama, T.; Teruaki, I.; Iwadare, H.; Saitoh, M.; Toshihiro,
N.; Naoto, O.; Sakoh, H.; Nishmura, K.; Tani, Y.-I.; Hasegawa, M.;
Yamada, K.; Saitoh, K. Chem. Eur. J . 1999, 5, 121.
(11) (a) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K.
B. J . Org. Chem. 1981, 46, 3936. (b) Chakraborty, T. K.; Ghosh, S.;
J ayaprakash, S.; Sharma, J . A. R. P.; Ravikanth, V.; Diwan, P. V.;
Nagaraj, R.; Kunwar, A. C. J . Org. Chem. 2000, 65, 6441.
(12) For NMR data of an authentic sample of 1, see: Larue, V.;
Gharbi-Benarous, J .; Acher, F.; Valle, G.; Crisma, M.; Toniolo, C.;
Azerad, R.; Girault, J .-P. J . Chem. Soc., Perkin Trans. 2 1995, 1111.
We believe that the slight difference between our observed optical
rotation for 1 ([R]29 -5.6 (c 1.3, H2O)) and that previously reported
D
(10) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973
in the literature2c ([R]29 -6.9 (c 1.0, H2O)) is due to the presence of
D
5-10% of the (1S,3S)-diasteroisomer of 1 ([R]20 +8.4 (c 1.0, H2O)).
D
J . Org. Chem, Vol. 67, No. 22, 2002 7615

Bradley et al.
was carried out using Merck silica gel 60, 35-70µ as the
stationary phase and the solvents used were either of analyti-
cal grades or were distilled before use. Chiral HPLC was
carried out using a Chiralpak AD column with appropriate
mixtures of HPLC grade 2-propanol and hexane being used
as eluent. Unless otherwise stated, Infrared spectra were
obtained of dilute chloroform solutions. NMR spectra were
obtained at the indicated spectrometer frequency as dilute
solutions in CDCl3 at room temperature unless is otherwise
stated. All coupling constants are reported in hertz (Hz). High-
resolution mass spectra were obtained using either chemical
ionization (CI, methane), fast atom bombardment (FAB),
electron ionization (EI), or electrospray (ES) techniques.
1-(ter t-Bu tyld im eth ylsila n yloxy)-3-(tr ip h en ylp h osp h a -
n ylid en e)p r op a n -2-on e 21. n-Butyllithium (172 mL; 2.5 M
in hexanes; 431 mmol) was added dropwise in four portions
(3 × 50 mL and 1 × 22 mL), each over 5 min (with a 10 min
interval between each addition), to a cool (0 °C) stirring
suspension of Ph3PCH3‚Br (156 g; 437 mmol) in THF (1 L),
and the resulting yellow/orange solution was stirred at 0 °C
for a further 40 min. (O-TBS)methyl glycolate 209 (39.7 g 194
mmol) was added dropwise over 1 min, and the resulting
mixture was then warmed to room temperature and stirred
for a further 2 h. Water (600 mL) was added, and the mixture
was stirred for 10 min before removal of the THF in vacuo.
The resulting aqueous residue was partitioned between ethyl
acetate (1.2 L) and water (600 mL), and the separated organic
phase was dried (MgSO4) and concentrated in vacuo, giving a
pale yellow solid. This material was purified by trituration
with minimal ethyl acetate (×4), giving 21 as a white solid
(61.0 g; 69%): mp 118-122 °C; δH (400 MHz) 0.14 (6H, s), 0.95
(9H, s), 4.14 (2H, s), 4.34 (1H, d, J 26.0), 7.42-7.46 (6H, m),
7.51-7.55 (3H, m), 7.65-7.70 (6H, m); δC (101 MHz, 303K)
192.1 (d, J 4.0), 133.0 (d, J 10.1), 132.0 (d, J 3.0), 128.7 (d, J
13.1), 127.1 (d, J 90.5), 68.2 (d, J 13.1), 49.0 (d, J 109.6), 26.3,
18.7, -4.9; δP (162 MHz, 303K) 17.5; m/z (ES+) 449.2070 (M
+ H, C27H34O2PSi requires 449.2066). Anal. Calcd for C27H33O2-
PSi: C, 72.3; H, 7.4. Found: C, 72.4; H, 7.3.
(4R)-4-[4-(ter t-Bu t yld im et h ylsila n yloxy)-3-oxob u t -1-
en yl]-2,2-d im eth yloxa zolid in e-3-ca r boxylic Acid ter t-Bu -
tyl Ester 24. (S)-Garner’s aldehyde 9 (2.16 g; 9.42 mmol) was
added dropwise over 2 min to a stirring solution of the ylide
21 (8.6 g; 19.2 mmol) in dichloromethane (20 mL), and the
mixture was stirred at room temperature for 3 days. Removal
of the solvent in vacuo left the crude product, which was
purified by column chromatography (4:1 pentane/diethyl ether)
to give the enone 24 as a colorless oil (3.28 g; 87%): [R]D -60
(c 1.04, CHCl3) >95% ee (Chiralpak AD, hexane/i-PrOH (95:
5), 1 mL/min); νmax(film)/cm-1 1698, 1631; δH (400 MHz, C6D6,
343K) 0.15 (6H, s), 0.92 (9H, s), 1.36 (9H, s), 1.47 (3H, s), 1.61
(3H, s), 3.42 (1H, dd, J 9.0, 2.7), 3.65 (1H, dd, J 9.0, 6.5), 4.09-
4.26 (1H, m), 4.13 (2H, app s), 6.46 (1H, d, J 15.8), 6.83 (1H,
dd, J 15.8, 6.8); δC (101 MHz, C6D6, 343K) 197.6, 152.4, 145.6,
126.5, 95.2, 80.6, 69.8, 68.1, 59.3, 29.1, 27.6, 26.7, 24.9, 19.1,
-4.7; m/z (ES+) 422.2357 (M + Na, C20H37NNaO5Si requires
422.2339). Anal. Calcd for C20H37NO5Si: C, 60.11; H, 9.33; N,
3.51. Found: C, 60.03; H, 9.36; N, 3.49.
(4R)-4-[4-(tert-Butyldimethylsilanyloxy)-3-oxobutyl]-2,2-di-
m eth yl-oxa zolid in e-3-ca r boxylic Acid ter t-Bu tyl Ester
19. Palladium (341 mg, 10% on carbon) was added in one
portion to a stirring solution of the enone 24 (301 mg; 0.75
mmol) in ethyl acetate (126 mL). The reaction vessel was
purged with hydrogen by four evacuate/fill cycles, and the
resulting mixture was stirred under an atmosphere of hydro-
gen (balloon) for 17 h. The catalyst was removed by filtration
through a pad of Celite, and the filtrate was concentrated in
vacuo to afford a yellow oil (2.17 g), which was purified by
column chromatography (3:1 pentane/diethyl ether) to give 19
as a colorless oil (2.03 g; 80%): [R]D -18.1 (c 4.55, CHCl3) >95%
m), 1.96-2.04 (1H, m), 2.27-2.42 (2H, m), 3.44 (1H, d, J 8.8),
3.62 (1H, dd, J 8.8, 6.0), 3.81 (1H, br s), 4.00 (2H, app s); δC
(125 MHz, 1:1 mixture of rotamers) 210.0, 152.5, 151.9, 93.9,
93.4, 80.0, 79.7, 69.2, 67.0, 56.6, 34.9, 34.6, 28.4, 27.0, 25.8,
24.4, 23.1, 18.3, -5.5; m/z (FAB positive ion) 402.2646 (MH+,
C20H40NO5Si requires 402.2676). Anal. Calcd for C20H39NO5-
Si: C, 59.8; H 9.8; N, 3.5. Found: C, 59.5; H, 9.5; N, 3.2.
(4S)-2,2-Dim eth yl-7-(ter t-bu tyld im eth ylsila n yloxym e-
th yl)-1-oxa -3-a za sp ir o[4.4]n on -6-en e-3-ca r boxylic Acid
ter t-Bu tyl Ester 27. n-Butyllithium (6.17 mL, of a 2.1 M
solution in hexanes, 13.0 mmol) was added dropwise over 11
min to a cold (-78 °C) stirring solution of trimethylsilyldiaz-
omethane (7.50 mL of a 2 M solution in hexanes, 15.0 mmol)
in THF (20 mL), and the resulting mixture was stirred for 1 h
at -78 °C. The ketone 19 (3.92 g, 13.6 mmol) in THF (13 mL)
was then added, dropwise over 20 min, and the mixture was
stirred for another 70 min. The reaction mixture was warmed
to 0 °C and stirred for 15 min. The reaction was quenched with
NH4Cl (20 mL of a saturated solution diluted with water (25
mL)), extracted with ether (250 mL), dried (MgSO4), and
concentrated in vacuo to give the crude product. Column
chromatography [petroleum ether (40-60 °C)/Et2O (10:1)]
afforded the pure product 27 (2.68 g, 69%) as a colorless oil:
[R]D -49.0 (c 1.24, CHCl3); νmax/cm-1 1682; δH (400 MHz, C6D6,
340K) 0.28 (6H, s), 1.17 (9H, s), 1.62 (9H, s), 1.83 (3H, s), 1.87
(3H, s), 2.15 (1H, ddd, J 12, 8.7, 3.0), 2.30-2.40 (1H, m), 2.50-
2.70 (2H, m), 3.83 (1H, d, J 8.7), 3.87 (1H, d, J 8.7), 4.31 (1H,
d, J 13.8), 4.36 (1H, d, J 13.8), 5.63 (1H, s); δC (125 MHz, 2.3:1
mixture of rotamers) 152.1, 151.1, 146.3, 145.3, 126.6, 125.8,
94.8, 94.1, 79.4, 79.1, 74.3, 73.9, 73.7, 73.2, 62.4, 62.2, 35.0,
33.3, 30.7, 28.5, 26.9, 25.9, 24.5, 18.4, -5.3; m/z (ES+) 420.2523
(M + Na, C12H39NNaO4Si requires 420.2546). Anal. Calcd for
C
21H39NO4Si: C, 63.43; H, 9.89; N, 3.52. Found: C, 63.31; H,
9.82; N, 3.45.
(4S,6R,7R)-6,7-Dih yd r oxy-2,2-Dim eth yl-7-(ter t-bu tyld i-
m eth ylsila n yloxym eth yl)-1-oxa -3-a za sp ir o[4.4]n on a n e-3-
ca r boxylic Acid ter t-Bu tyl Ester 25. N-Methylmorpholine-
N-oxide (1.34 g; 9.91 mmol) was added in one portion to a room
temperature stirring solution of the alkene 27 (1.31 g; 3.30
mmol) in acetone/water (10:1; 143 mL). K2OsO4‚2H2O (121 mg;
0.33 mmol) was added in one portion to the stirring mixture,
and the resulting stirred at room temperature for a further
4.5 days. The reaction was quenched with Na2SO3 (1.26 g) and
concentrated in vacuo, and the residue was adsorbed onto silica
gel by evaporation from ethyl acetate (∼500 mL) to form a free-
flowing powder. The dry powder was slurried in ethyl acetate
and filtered through Celite, and the eluent was concentrated
in vacuo, giving a dark yellow oil (1.47 g). This was purified
by column chromatography (3:1 petrol/ethyl acetate), giving
25 as a colorless oil (1.34 g; 94%): [R]25D 41 (c 3.3, CHCl3) (97%
ee, Chiralpak AD, 8:92 IPA/hexane); νmax(film)/cm-1 3454,
1694; δH (400 MHz, CD3C6D5, 368K) 0.07 (6H, s), 0.95 (9H, s),
1.47 (9H, s), 1.61 (3H, s), 1.67-1.56 (1H, m (obscured)), 1.67
(3H, s), 1.73-1.83 (1H, m), 1.96-2.06 (1H, m), 2.22 (1H, d (br),
J 5.5 Hz), 2.33-2.43 (1H, m), 2.49 (1H, s), 3.55 (1H, d, J 9.8
Hz), 3.59 (1H, d, J 9.8 Hz), 3.72 (1H, d, J 9.2 Hz), 4.51 (1H, d,
J 9.2 Hz), 4.80 (1H, s (br)); δC (126 MHz, C6D6, 340 K) 151.9,
94.3, 79.7, 78.5, 75.8, 71.2, 69.7, 31.4, 30.7, 30.2, 28.7, 26.5,
26.1, 18.5, -4.3; m/z (ES+) 454.2629 (M + Na, C21H41NNaO6-
Si requires 454.2601).
(1S,3R)-1-ter t-Bu t oxyca r b on yla m in o-1,3-d ih yd r oxy-
m eth ylcyclop en ta n e 28. Palladium (109 mg, 10% on carbon)
was added to a solution of the unsaturated spirocycle 27 (870
mg, 2.19 mmol) in EtOAc (44 mL). The reaction vessel was
purged with hydrogen by three evacuate/fill cycles, and the
resulting mixture was stirred under an atmosphere of hydro-
gen (balloon) for 19 h. The catalyst was removed by filtration
through a pad of Celite, and the filtrate was concentrated in
vacuo to afford 26 (928 mg), which was used in the following
reaction without further purification. HF (0.57 mL of 48%
aqueous solution) was added in one portion to a stirring
solution of crude 26 (927 mg) in CH3CN (23 mL), and the
ee (Chiralpak AD, hexane/i-PrOH (99:1), 0.5 mL/min); νmax
/
cm-1 1713, 1682; δH (400 MHz, C6D6, 340 K) 0.03 (6H, s), 0.94
(9H, s), 1.42 (9H, s), 1.46 (3H, s), 1.65 (3H, s), 1.85-1.94 (1H,
7616 J . Org. Chem., Vol. 67, No. 22, 2002

Synthesis of (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic Acid
resulting solution was stirred for 15 min at room temperature
before being quenched with excess NaHCO3 (30 mL of a
saturated solution). The aqueous layer was extracted with
Et2O (3 × 100 mL), dried (MgSO4), and concentrated in vacuo.
Purification by column chromatography [petroleum (40-60
°C)/Et2O/MeOH gradient; (30:5:2)-(8:15:1)] afforded the diol
28 (451 mg; 81%) as a colorless oil: [R]D +6.9 (c 1.78, CHCl3);
mixture was concentrated in vacuo until a white precipitate
formed. The solid was removed by filtration and washed with
cold (0 °C) EtOAc, giving a white powder (49 mg; 49%, 2 steps);
δH (500 MHz, MeOH) 2.04-2.14 (2H, m), 2.19 (1H, dd, J 14.3,
8.3), 2.37-2.43 (1H, m), 2.61 (1H, dd, J 14.3, 8.3); δC (126 MHz;
MeOH) 176.6, 174.0, 65.5, 45.1, 40.1, 36.7, 30.3. The hydro-
chloride salt was dissolved in NaOH (2M; 5 mL), washed with
diethyl ether (4 mL, then 8 mL), and the aqueous acidified
(HCl, 1M) to pH 5. Concentration in vacuo gave a white solid,
which was purified by ion exchange chromatography (Dowex
50X8 200; 2M NH3 aq), giving ACPD 1 (24.9 mg; 30%, 2 steps
from 28) as a white solid: mp 248 °C dec (lit.2c mp 246-250
°C dec); [R]29 -5.6 (c 1.3, H2O) (lit.2c [R]29 -6.9 (c 1.0, H2O));
ν
max /cm-1 3625, 3439, 1693; δH (400 MHz, C6D6, 343 K) 1.30-
1.42 (2H, m), 1.39 (9H, s), 1.43-1.52 (1H, m), 1.54-1.63 (1H,
m), 1.68-1.76 (1H, m), 1.78-1.89 (2H, m), 3.05 (1H, br s, OH),
3.21 (2H, app s), 3.47-3.60 (2H, m), 4.79 (1H, br s); δC (100
MHz) 156.0, 79.9, 68.8, 66.3, 64.9, 40.2, 38.5, 34.9, 28.4, 27.0;
m/z (EI positive ion) 246.1688 (MH+, C12H24NO4 requires
246.1705). Anal. Calcd for C12H23NO4: C, 58.75; H, 9.45; N,
5.71. Found: C, 58.33; H, 9.56; N, 5.57.
(1R,3S)-1-Am in ocyclop en ta n e-1,3-d ica r boxylic Acid 1.
CCl4 (0.48 mL), CH3CN (0.72 mL), and H2O (0.48 mL) were
added successively to a mixture of NaIO4 (240 mg, 1.12 mmol)
and RuCl3‚xH2O (62 mg, 0.30 mmol). After being stirred for
35 min, the mixture was added dropwise over 30 s to a cool (0
°C) stirring solution of the diol 28 (118 mg). After the mixture
was stirred at 0 °C for 45 min, NaIO4 (534 mg, 2.54 mmol)
was added in one portion, and the resulting mixture stirred
at 0 °C for a further 3 h. The mixture was adsorbed onto silica,
D
D
δH (400 MHz, D2O) 1.93-2.07 (2H, m), 2.14 (1H, dd, J 14.5,
4.7), 2.21-2.36 (2H, m), 2.42 (1H, dd, J 14.5, 8.6), 3.03-3.11
(1H, m); δC (101 MHz, D2O) 186.7, 180.1, 69.7, 49.3, 42.5, 38.5,
32.8.
Ack n ow led gm en t. We thank The University of
Botswana for the provision of a Scholarship (R.M.), the
EPSRC and Pfizer Central Research for provision of a
studentship (D.M.B.), and also AstraZeneca and the
School of Chemistry, University of Nottingham, for
additional financial support.
filtered through
a pad of silica (EtOAc as eluent), and
concentrated in vacuo giving the N-Boc-bis-carboxylic acid 29
as a colorless oil (111 mg) in crude form. HCl (concd, 2.5 mL)
was added in one portion to a stirring solution of the crude
N-Boc bis-carboxylic acid 29 in EtOAc (7.5 mL) and after 7 h
at room temperature, the solution was concentrated in vacuo
giving a yellow oil (106 mg). The crude material was dissolved
in methanol (0.6 mL), and ethyl acetate (24 mL) and the
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of 15, 16, 18, and 19. Copies of
the 1H (500 MHz) and 13C (125 MHz) NMR spectra for our
synthetic sample of 1. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O025892V
J . Org. Chem, Vol. 67, No. 22, 2002 7617