Stereoselective synthesis of 1-2-(carboxycyclopropyl)glycines via stereocontrolled 1,3-dipolar cycloadditions of diazomethane on Z- and E-3,4- L-didehydroglutamates OBO esters

Full text of DOI:10.1021/jo991066j

8958
J . Org. Chem. 1999, 64, 8958-8961
the fruits of Blighia unijugata.8 These compounds are
Ster eoselective Syn th esis of
L-2-(Ca r boxycyclop r op yl)glycin es via
Ster eocon tr olled 1,3-Dip ola r
also of interest as useful synthetic intermediates9 and
as conformationally restricted analogues in peptide mi-
metics.10
Cycloa d d ition s of Dia zom eth a n e on Z- a n d
E-3,4-L-Did eh yd r oglu ta m a tes OBO Ester s
CCG-I-CCG-IV (Figure 1) were first synthesized as
diastereomeric mixtures by Ohfune et al. by cyclopropa-
nation of chiral olefinic precursors through palladium-
catalyzed cycloaddition of diazomethane.6 Later, other
enantioselective syntheses of CCG derivatives were
described on the basis of cyclopropanation of chiral
precursors by means of rhodium-catalyzed cycloaddition
of diazomethane11 or by using sulfoxonium ylides.12
J oan Rife´ and Rosa M. Ortun˜o*
Departament de Quı´mica, Universitat Auto`noma de
Barcelona, 08193 Bellaterra, Barcelona, Spain
Gilles A. Lajoie*
Department of Chemistry, University of Waterloo,
Waterloo, ON, Canada, N2L 3G1
Received J uly 2, 1999
In tr od u ction
Due to the importance of metabotropic glutamate
receptor (mGluR) and the crucial role of L-glutamate (L-
Glu) as the major excitatory neurotransmitter in the
mammalian central nervous system, the search for new
structures with activity as agonists or antagonists is very
intense. Several structural analogues of L-glutamic acid
have been synthesized and found to be more specific
agonists than L-Glu which not only activates mGluRs but
also the ionotropic glutamate receptors.1-3 Some confor-
mationally constrained analogues of L-Glu recognize and
bind to the various types of glutamate receptors in
exclusive or preferential manner. Among them, the 2,3-4
and 3,4-methano derivatives of L-Glu are most promi-
nent;5 the latter compounds are also referred to as
carboxycyclopropylglycines (CCGs). The four isomeric
CCG-I-CCG-IV were found to be agonists for either the
N-methyl-D-aspartic acid (NMDA) or the metabotropic
L-glutamate receptor.6 The neurophysiological assays
suggested that the extended conformer of L-Glu, which
is equivalent to CCG-I and -II, activates the metabotro-
pic L-Glu receptor and that the NMDA receptor is
activated by the folded conformer of L-Glu, which is
equivalent to CCG-III and -IV.6 Interestingly, both
amino acids CCG-I and -III were also isolated as natural
products by Fowden from the green fruits of Aesculus
parviflora and Blighia sapida,7 and CCG-I was found in
F igu r e 1.
One of our laboratories has previously investigated the
1,3-dipolar cycloaddition of diazomethane to chiral amino
enoates followed by photolysis of the resultant pyrazo-
lines as a convenient protocol to prepare enantiopure
cyclopropane amino acids with high stereoselectivity.4,13
The bulky 4-methyl-2,6,7-trioxabicyclo[2.2.2] ortho (OBO)
ester function has been shown to be a useful protecting
group of carboxylic acids for preventing epimerization at
the R-carbon and to induce good diastereoselectivities in
the transformations performed on serine aldehyde or
threonine ketone equivalents, i.e. carbonyl addition reac-
tions,14 reductions of ketones to secondary alcohols,15,16
and substitution reactions,17 leading to a wide range of
amino acids.
In this paper we describe a concise and stereoselective
syntheses of CCG-I and CCG-III based on the highly
(8) Fowden, L.; MacGibbon, C. M.; Mellon, F. A.; Sheppard, R. C.
Phytochemistry 1972, 11, 1105.
* Corresponding author. E-mail: glajoie@uwaterloo.ca. Tel.: 519-
888-4620. Fax: 519-746-0435.
(9) For reviews on the synthesis of cyclopropane amino acids, see:
(a) Stammer, C. H. Tetrahedron 1990, 46, 2234. (b) Alamai, A.; Calmes,
M; Daunis, J .; J acquier, R. Bull. Chem Soc. Chim. Fr. 1993, 130, 5.
(10) Burgess, J . K.; Ho, K. K. Synlett 1994, 575 and references
therein.
(11) Pellicciari, R., Natalini, B.; Marinozzi, M. Tetrahedron Lett.
1990, 31, 139
(12) (a) Ma, D.; Ma, Z. Tetrahedron Lett. 1997, 38, 7599. (b) Demir,
A. S.; Tanyeli, C.; Cagir, A.; Tahir, M. N.; Ulku, D. Tetrahedron:
Asymmetry 1998, 9, 1035.
(1) (a) J ohnson, R. L.; Koerner, J . K. J . Med. Chem. 1988, 31, 2057.
(b) Shimamoto, K.; Ohfune, Y. J . Med. Chem. 1996, 39, 407.
(2) Kno¨pfel, T.; Kuhn, R.; Allgeier, H. J . Med. Chem. 1995, 38, 1417.
(3) (a) Ornstein, P. L.; Bleisch, T. J .; Arnold, M. B.; Wright, R. A.;
J ohnson, B. G.; Schoepp, D. D. J . Med. Chem. 1998, 41, 346. (b)
Ornstein, P. L.; Bleisch, T. J .; Arnold, M. B.; Kennedy, J . H., Wright,
R. A.; J ohnson, B. G.; Tizzano, J . P.; Helton, D. R.; Kallman, M. J .;
Schoepp, D. D. J . Med. Chem. 1998, 41, 358.
(4) There is only one enantioselective synthesis of (-)-(Z)-2,3-
methano-L-glutamic acid: J ime´nez, J . M.; Ortun˜o, R. M. Tetrahe-
dron: Asymmetry 1996, 7, 3203. Results on its biological activity are
not yet available.
(5) Conformational analysis of some of these derivatives has been
done: Evrard-Todeschi, N.; Gharbi-Benarous, J .; Cosse-Barbi, A.;
Thirot, G.; Girault, J . P. J . Chem. Soc., Perkin Trans. 2 1997, 2677.
(6) (a) Yamanoi, K.; Ohfune, Y. Tetrahedron Lett. 1988, 29, 1181.
(b) Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y. J . Org. Chem.
1991, 56, 4167.
(13) (a) J ime´nez, J . M.; Rife´, J .; Ortun˜o, R. M. Tetrahedron:
Asymmetry 1996, 7, 537. (b) Mart´ın-Vila`, M.; Hanafi, N,; J ime´nez, J .
M.; Alvarez-Larena, A.; Piniella, J . F.; Branchadell, V.; Oliva, A.;
Ortun˜o, R. M. J . Org. Chem. 1998, 63, 3581.
(14) Blaskovich, M. A.; Lajoie, G. A. J . Am. Chem. Soc. 1993, 115,
5021.
(15) Blaskovich, M. A.; Lajoie, G. A. Tetrahedron Lett. 1993, 34,
3837.
(16) Blaskovich, M. A.; Evindar, G.; Rose, N. G. W.; Wilkinson, S.;
Luo, Y.; Lajoie, G. J . Org. Chem. 1998, 63, 3631.
(17) Luo, Y.; Blaskovich, M.; Lajoie, G. A. J . Org. Chem. 1999, 64,
6106.
(7) Fowden, L.; Smith, A.; Millington, D. S.; Sheppard, R. C.
Phytochemistry 1969, 8, 437.
10.1021/jo991066j CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/03/1999

Notes
J . Org. Chem., Vol. 64, No. 24, 1999 8959
Sch em e 1a
Reaction conditions: (a) (Ph)3PdCH2CO2tBu, CH2Cl2, 15 min; (b) (CF3CH2O)2P(O)CHCO2Me, NaH, THF, -78 °C, 45 min; (c) CH2N2,
Et2O, 1 h; (d) hν, CH2Cl2 (or acetonitrile), benzophenone, -45 °C, 1 h; (e) 6 N HCl, 90 °C, 5 h.
a
efficient stereochemical control of the 1,3-dipolar cycload-
dition of diazomethane provided by the presence of the
OBO function on the chiral E- or Z-3,4-L-didehydro-
glutamate used as substrates.
(didehydroglutamate 5) was obtained and little of the
desired cyclopropane could be isolated. Various conditions
for the photolysis reaction were then examined. Lower
temperatures or change of photosensitizer to acetone gave
similar results. We eventually found that increasing the
amount of benzophenone to 30 mol % gave good yields
(60% for both steps) of cis-cyclopropane 9. Removal of the
methyl or tert-butyl ester, the OBO, and Cbz protecting
groups from the fully protected cyclopropanes 5, 6, and
9 was achieved in a single step by acid hydrolysis (6 N
HCl, 90 °C, 5 h). After evaporation, the crude amino acids
were treated with propylene oxide, filtered through a
reverse phase cartridge and recrystallized from H2O/
EtOH to give CCG-I, -II and -III in their pure form in
91-96% yields. The stereochemistry of CCG-I, -II and
-III and their precursors was determined by comparison
of the NMR and optical rotation of CCGs of each isomers
reported by Ohfune et al.6
The observed syn π-facial diastereoselectivity in the
cycloaddition reactions can be rationalized by consider-
ation of the active conformers for dehydroglutamates 2
and 7. Figure 2 shows the conformers 2A and 2B leading
to the same syn-pyrazoline 3 from Z-precursor 2, through
the preferential attack of diazomethane to the less
hindered face of the double bond. On the contrary,
conformer 2C leads to the anti adduct 4 which is the
minor isomer. Thus the diastereoselection observed can
be explained on the basis of the serious steric congestion
in 2C. The exclusive production of syn-pyrazoline 8 from
Z-didehydroglutamate 7 can be explained in a similar
manner. The facial stereoselectivity can, in part, be
explained by the allylic 1-3 strain arguments.18 Notable
is the effectiveness of the bulky OBO group to achieve
Resu lts a n d Discu ssion
Preparation of the E-3,4-L-didehydroglutamate 2 was
performed as described previously14 for the Fmoc deriva-
tive by the olefination of the Cbz-L-Ser-aldehyde-OBO 1
with Wittig-Horner reagent15 (Scheme 1). Optically pure
2 was obtained after chromatography and no Z-isomer
was detected by NMR. Addition of etheral diazomethane
to 2 gave a mixture of pyrazoline 3 and 4 in excellent
yields but proved to be too unstable to be separated by
chromatography. Thus, the mixture of pyrazoline 3 and
4 was subjected to optimized photolysis conditions to give
a 86% yield of a 6:1 mixture of syn- and anti-trans-
cylopropane derivatives 5 and 6, as determined by NMR
analysis. The use of acetonitrile as solvent was critical
as the usual solvent, CH2Cl2, led to partial ring opening
of the OBO ester. Pure diastereomers 5 and 6 were
obtained after by flash chromatography and recrystalli-
zation.
The Z-3,4-L-didehydroglutamate 7 was obtained from
the OBO serine aldehyde 1 by olefination with Na(CF3-
CH2O)2PdCHCO2Et as 9:1 mixture of Z:E isomer (Scheme
1) which were separated by flash chromatography. Ad-
dition of etheral diazomethane to 7 gave the correspond-
ing pyrazoline 8 exclusively. The pyrazoline 8 is even
more unstable than 3 and 4. In fact when the crude
pyrazoline 8 was irradiated under the same conditions
used for 3 and 4, large amount of cycloreversion product

8960 J . Org. Chem., Vol. 64, No. 24, 1999
Notes
lized from EtOAc and hexane to yield 510 mg of 2 (78%). Mp:
147-148 °C. [R]25 ) -24.0 (c ) 1.00, AcOEt). IR (KBr): 3312,
D
2974, 2935, 2885, 1722, 1704, 1686 cm-1
.
1H NMR (250 MHz,
CDCl3): 0.78 (s, 3H), 1.45 (s 9H), 3.88 (s, 6 H), 4.52 (dd, J ) 8.0,
5.1 Hz, 1H), 5.10 (br m, 3H), 5.88 (dd, J ) 16.1, 1.4 Hz, 1H),
6.85 (dd, J ) 16.1, 5.1 Hz, 1H), 7.33 (br m., 5 H). 13C NMR (62.5
MHz, CDCl3): 14.24, 28.07, 30.73, 55.96, 66.05, 72.84, 80.41,
107.71, 124.51, 128.12, 128.48, 136.27, 141.62, 155.90, 165.43.
Anal. Calcd for C22H29NO7: C, 62.99; H, 6.97; N; 3.34. Found:
C, 62.98; H, 6.94; N, 3.41.
N-Cbz-(O-Me)-Z-2,3-L-d eh yd r oglu ta m a te OBO Ester (7).
A dispersion of NaH 60% in oil (124 mg, 3.1 mmol) was added
to THF (2 mL) in a round-bottom flask under nitrogen. (CF3-
CH2O)2P(O)CH2CO2Me (0.98 g, 650 µL, 3.1 mmol) was added
and the mixture cooled to -78 °C. In another flask Cbz-L-Ser
OBO ester 1 (400 mg, 1.2 mmol) was dissolved in THF (5 mL)
under nitrogen and cooled to -78 °C. This solution was trans-
ferred to the first flask and was stirred at this temperature for
45 min. The solution is then poured in 2:1 CH2Cl2/5% NH4Cl
and extracted with EtOAc. The organic layer was separated,
washed with 10% NaCl, dried (MgSO4), filtered, and evaporated
to dryness. The resulting oil was purified by flash column
chromatography (silica gel, 1:3 EtOAc/hexane with 1% Et3N) to
give the Z-2,3-L-dehydroglutamate 7 (438 mg, 74%) and the
corresponding E isomer (38 mg, 8%) both as oils for a combined
F igu r e 2.
these highly diastereoselective cycloadditions of diazo-
methane. The OBO substituent is much better than the
chiral dioxolane ring used as the selectivity-directing
group in the reactions on related substrates.13b
yield of 82%. Da ta for 7: [R]25 ) -47.5 (c ) 0.80, AcOEt). IR
Con clu sion
D
(film): 3352, 2951, 2882, 1728, 1659 cm-1. 1H NMR (CDCl3, 250
MHz): 0.73 (s, 3H), 3.68 (s, 3H), 3.85 (s, 6 H), 5.04 (s, 1H), 5.28
(m, 1H), 5.68 (t, J ) 8.7, 8.7 Hz, 1H), 5.84-6.01 (br m, 2H), 7.28,
(br m, 5 H). 13C NMR (CDCl3, 62.5 MHz): 14.07, 30.51, 51.21,
551.69, 66.60, 72.70, 107.74, 122.27, 127.82, 127.95, 128.23,
136.27, 141.20, 155.29, 165.66. Anal. Calcd for C22H29NO7: C,
62.99; H, 6.97; N, 3.34. Found: C, 63.12; H, 7.05; N, 3.13.
N-Cbz-(O-tBu )-tr a n s-2-(car boxycyclopr opyl)glycin e OBO
Ester (5). Excess ethereal solution of diazomethane (ca. 15
equiv) was distilled onto a solution of E-2,3-L-dehydroglutamate
2 (1.00 g, 2.38 mmol) dissolved in ether (30 mL) at 0 °C. The
resulting solution was protected from light and stirred at room
temperature for 1 h. Anhydrous CaCl2 (1.0 g) was then added
to destroy the excess diazomethane and, after filtration, evapo-
rated under vacuum to give an oil. The mixture of pyrazolines
3 and 4 obtained was very unstable (purification attempts by
chromatography or crystallization gave decomposition products)
and was used without purification. The mixture of pyrazolines
3 and 4 and benzophenone (50 mg, 0.27 mmol) was dissolved in
acetonitrile (500 mL) and transferred into a Pyrex reactor under
nitrogen atmosphere, cooled at -45 °C and irradiated with a
125 W medium-pressure mercury-lamp for 10 min. The solvent
was removed under vacuum and the crude was purified by flash
chromatography (silica gel, 1:1 EtOAc:hexane, with 1% of
triethylamine), to give 903 mg (2.08 mmol, 87% yield) of a
mixture of the two possible isomers in a ratio 6:1 as determined
by NMR analysis. Recrystallization (EtOAc/pentane) provided
600 mg (58%) of the major isomer 5 in a pure form. Mp: 145-
145.5 °C. [R]25D ) +38.0 (c ) 2.00, EtOAc). IR (KBr): 3380, 2974,
2932,1730, 1522 cm-1. 1H NMR (250 MHz) (CDCl3) 0.77 (s, 3H),
0.83 (m, 1 H), 1.09 (m, 1 H), 1.39 (br m, 10H), 1.55 (m, 1 H),
3.48 (m, 1 H), 3.87 (s, 6 H), 5.00 (d, J ) 10.2 Hz, 1 H), 5.07, (d,
J ) 10.2 Hz, 1 H), 7.32 (br s, 5H). 13C NMR (CDCl3, 62.5 MHz):
13.68, 14.32, 17.95, 22.22, 28.12, 30.62, 56.68, 66.80, 72.70, 79.94,
108.33, 127.97 (2 × C), 128.14, 136.52, 156.29, 173.28. Anal.
Calcd for C23H31NO7: C, 63.73; H, 7.21; N, 3.23. Found: C, 63.77;
H, 7.21; N, 3.32. Additional recrystallization gave a small
quantity of the minor diastereomer 6 in a pure form. Mp 115-
In summary, we described a very efficient method for
the stereoselective synthesis of two of the carboxycyclo-
propylglycines CGC-I or -III. The major advantages of
this new approach for the preparation of CCGs are the
ease of preparation of the starting enoates; the high
diastereoselectivity in the diazomethane cycloaddtion
induced by the OBO ester; and the minimal manipulation
necessary to convert the cyclopropane intermediates to
the deprotected cyclopropyl amino acids, which is effected
by the simultaneous removal of the protecting groups.
As part of our joint program, we are currently examining
the cycloaddition of other dipoles to more substituted 3,4-
didehydroglutamate OBO derivatives. We also envisage
carrying out theoretical calculations of the ground and
transition states involved in these reactions to rationalize
their stereochemical outcome. Results of these studies
will be published in due course.
Exp er im en ta l Section
Gen er a l. All chemicals were purchased from Aldrich, Fluka,
or Sigma and used directly. CH2Cl2 was distilled from CaH2,
and THF from Na/benzophenone. Melting point are uncorrected.
Mass spectra were determined at a ionizing voltage of 70 eV.
Most reactions were carried out under dry argon in glassware
dried overnight at 120 °C or flame-dried before use. TLC was
carried out on Merck aluminum-backed silica gel 60 F254, with
visualization by UV or 5% (NH4)6MoO24/0.2% Ce(SO4)2/5% H2-
SO4 or ninhydrin solution (2% in EtOH). TLC solvent systems
commonly used are A, 5:1 CH2Cl2/EtOAc; B, 10:1 CH2Cl2/EtOAc;
C, 3:1 CH3OH/EtOAc; and D, 10:1 CH3OH/EtOAc. Column
chromatography was done on a silica gel (230-400 mesh)
column. IR spectra were recorded in the 4000-625 cm-1 range.
Optical rotations were measured on a digital polarimeter using
a cuvette of 0.5 cm in length. Elemental analyses were performed
by MHW laboratories in Phoenix, AZ, or by Institut de Qu´ımica
Bio-Orga`nica de Barcelona, Spain.
N-Cbz-(O-tBu )-E-2,3-L-d eh yd r oglu ta m a te OBO Ester (2).
Cbz-L-Ser OBO13 ester 1 (500 mg, 1.55 mmol) and Ph3PdCHCO2-
tBu (700 mg, 1.86 mmol) were dissolved in anhydrous CH2Cl2
(30 mL) under nitrogen and stirred for 15 min at room temper-
ature. The solution was then washed with 3% NH4Cl (2 × 20
mL), dried (MgSO4), and evaporated to dryness. The yellowish
oil was purified by flash chromatography (silica gel, 3:2 EtOAc/
hexane with 1% Et3N) to give a white solid that was recrystal-
117 °C (AcOEt/hexane). [R]25 ) -45.5 (c ) 1.00, EtOAc). IR
D
(KBr): 3387, 2972, 2930, 2881, 1726 cm-1. 1H NMR (CDCl3, 250
MHz): 0.78 (s, 3H), 0.83 (m, 1 H), 0.96 (m, 1 H), 1.41 (s, 9H),
1.42 (m, 10H), 1.58 (m, 1 H), 3.61 (dd, J ) 10.2, 6.6 Hz, 1H),
3.86 (s, 6H), 5.07 (br m, 1H), 7.33 (m, 5 H). 13C NMR (CDCl3,
62.5 MHz): 10.85, 14.24, 15.74, 21.53, 28.06, 30.56, 56.03, 66.82,
72.65, 79.88, 108.26, 127.99, 128.41, 136.23, 155.85, 173.20. Anal.
Calcd for C23H31NO7: C, 63.73; H, 7.21; N, 3.23. Found: C, 63.52;
H, 7.34; N, 3.58.
N-Cbz-(O-Me)-Z-2-(ca r bocycyclop r op yl)glycin e OBO es-
ter (9) was synthesized as for 6, with Z-dehydroglutamate 7
(162 mg, 0.4 mmols), except the reaction was completed in 2 h.
The irradiation of the resulting pyralozine 8 was performed in
(18) Hoffmann. R. W. Chem Rev. 1989, 89, 1841.

Notes
J . Org. Chem., Vol. 64, No. 24, 1999 8961
the presence of a larger concentration of benzophenone (24 mg,
30 mol % instead of 10 mol %). Under these conditions, the cis-
cyclopropane 9 was isolated after flash column chromatography
(1:1 EtOAc:hexane) as a white solid (101 mg, 0.3 mmol, 60%).
Mp 90-92 °C (AcOEt/hexane). [R]25D ) +14.0 (c ) 2.00, AcOEt).
IR (KBr): 3600-3300 (br), 2953, 2881, 1724, 1727 cm-1. 1H NMR
(CDCl3, 250 MHz): 0.77 (s, 3H), 1.10 (m, 1 H), 1.33 (m, 1 H),
1.45 (m, 1H), 1.64 (m, 1 H), 3.56 (s, 3H), 3.86 (s, 6H), 3.95 (m, 1
H), 5.03 (br m, 2H), 5.23 (d, NH, J ) 9.5 Hz), 7.31 (Br m, 5 H).
13C NMR (CDCl3, 62.5 MHz): 12.74, 14.36, 19.24, 22.21, 30.63,
51.82, 53.59, 66.47, 72.68, 108.88, 127.78, 127.96, 128.31, 136.87,
155.66, 172.92. Anal. Calcd for C20H25NO7: C, 61.37; H, 6.44;
N, 3.58. Found: C, 61.19; H, 6.58; N, 3.71.
Gen er a l P r oced u r e for th e Rem ova l of th e P r otectin g
Gr ou p s. The suitable amount of the fully protected product was
introduced in a round-bottom flask followed by the addition of
6 M HCl. The solution was stirred at 90 °C for 5 h. The solvent
was then evaporated to dryness and the resulting crude amino
acid was dissolved in EtOH. Propylene oxide was added until
cloudiness appears. After sedimentation the precipitate was
filtered, dissolved in water, and eluted through a reverse phase
C-18 cartridge. After removal the water under vacuum, the solid
was recrystallized from H2O/EtOH.
J ) 10.2 Hz, 1H). 13C NMR (D2O, 62.5 MHz): 15.10, 20.13, 23.37,
58.33, 173.65, 178.53.
Dep r otection of 6: (2S,1′R,2′R)-2-(Ca r boxycyclop r op yl)-
glycin e, CCG-II. The protected cyclopropane 6 (77 mg, 0.2
mmol) was treated as described above with 6 M HCl (4 mL).
The reaction yielded (2S,1′R,2′R)-2-(carboxycyclopropyl)glycine,
CCG-II (25 mg, 0.2 mmol, 90%). Mp: 253-256 °C dec (lit. 255-
258 °C dec). [R]25 ) -20.3 (c ) 1.50, H2O) (lit. -20.2, c ) 0.5,
D
H2O). 1H NMR (D2O, 250 MHz): 1.04 (ddd, J ) 8.8, 5.7, 5.0 Hz,
1H), 1.22 (ddd, J ) 9.1, 5.1, 5.0 Hz, 1H), 1.70-1.82 (br m, 2H),
3.35 (d, J ) 9.1 Hz, 1H). 13C NMR (D2O, 62.5 MHz): 14.81, 21.14,
24.42, 59.15, 174.28, 177.94.
Dep r otection of 9: (2S,1′S,2′R)-2-(Ca r boxycyclop r op yl)-
glycin e, CCG-III. The protected cis-cyclopropane 9 (100 mg,
0.2 mmol) was treated as described above with 6 M HCl (5 mL).
The reaction yielded (2S,1′S,2′R)-2-(carboxycyclopropyl)glycine,
CCG-III (37 mg, 0.2 mmol, 93%). Mp: 190-193 °C dec (lit. 192-
197 °C dec). [R]25 ) +20.4 (c ) 1.50, H2O) (lit. +20.8, c ) 0.5,
D
H2O). 1H NMR (D2O, 250 MHz): 1.24 (ddd, J ) 6.8, 5.7, 5.0 Hz,
1H), 1.37 (ddd, J ) 9.3, 9.1, 5.0 Hz, 1H), 1.59 (m, 1H), 1.85 (ddd,
J ) 9.1, 7.7, 5.7 Hz, 1H), 3.86 (d, J ) 10.8 Hz, 1H). 13C NMR
(D2O, 62.5 MHz): 16.91, 19.94, 24.76, 60.01, 175.15, 178.61.
Dep r otection of 5: (2S,1S′,2S′)-2-(ca r boxycyclop r op yl)-
glycin e (CCG-I). The protected cyclopropane derivative 5 (200
mg, 0.5 mmol) was dissolved in 6 M HCl (10 mL). The reaction
yielded (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine, CCG-I (70
mg, 0.4 mmol, 96%). Mp: 243-245 °C dec (lit. 243-247 °C dec).
Ack n ow led gm en t. Financial support from NSERC
(Canada) to G.L. and from DGESIC (Spain, PB97 0214)
to R.O. is gratefully acknowledged. J .R. also thanks
CIRIT, Generalitat de Catalunya, Spain, for a travelling
research grant.
[R]25 ) +101.3 (c ) 0.50, H2O) (lit. +102, c ) 0.5, H2O). 1H
D
NMR (D2O, 250 MHz): 1.19 (ddd, J ) 8.4, 5.9, 5.1 Hz, 1H), 1.30
(ddd, J ) 9.5, 5.1, 5.1 Hz, 1 H), 1.62-1.77 (br m, 2 H), 3.20 (d,
J O991066J