Synthesis of syn and anti isomers of trans-cyclopropyl arginine

Article abstract of DOI:10.1021/jo016242e

There is currently considerable interest in arginine and its structural analogues in the context of nitric oxide synthase (NOS) substrates and inhibitors. Of particular interest are conformationally constrained arginine analogues used to probe the active sites of the three NOS isoforms. A simple procedure is described for the preparation of syn- and anti-trans-cyclopropyl arginine starting from the α-OBO-protected Cbz-dehydroglutamate. Cyclopropanation is effected by diazomethane addition followed by irradiation of the resulting pyrazoline and gives a 3:1 mixture of syn: anti isomers that can be separated by crystallization. Reduction of the ester to the alcohol followed by guanylation gives the fully protected cyclopropyl arginine analogues. The CBZ protecting groups are removed by hydrogenolysis and the OBO by mild acid treatment followed by base hydrolysis.

Full text of DOI:10.1021/jo016242e

2352
J . Org. Chem. 2002, 67, 2352-2354
The isolation of 3,4-cyclopropyl arginine from natural
Syn th esis of Syn a n d An ti Isom er s of
sources or its synthesis has never been reported. The
availability of syn- and anti-trans-L-cyclopropyl arginine
derivatives will assist the examination of conformational
preferences of enzymes and receptors that recognize
arginine and its derivatives.
tr a n s-Cyclop r op yl Ar gin in e
Dan Fishlock, J . Guy Guillemette, and Gilles A. Lajoie*
Department of Chemistry, University of Waterloo,
Ontario, Canada, N2L 3G1
We recently reported the stereoselective synthesis of
L-cyclopropyl glutamates also known as 2-(carboxycyclo-
propyl)glycines (CCGs)4 via the 1,3-dipolar addition of
diazomethane to a chiral dehydroglutamate derivative,
followed by photolysis of the resultant pyrazoline.5 That
approach made use of the 4-methyl-2,6,7-trioxabicyclo-
[2.2.2] ortho (OBO) ester function, which has been shown
to be a beneficial protecting group of carboxylic acids as
it prevents epimerization at the R-carbon as well as
induces good diastereoselectivities in transformations
performed on serine aldehyde equivalents. The OBO
protection scheme enables access to a variety of nonpro-
teinaceous amino acids.6 In this paper we describe an
extension of this approach for the synthesis of E-3,4-
cyclopropyl L-arginine.
Olefination of Cbz-L-serine aldehyde OBO with Ph3Pd
CHCO2CH3 provided the E-3,4-L-didehydroglutamate
derivative 1 in very good yields (77%) after chromatog-
raphy and recrystallization. Subsequent treatment with
freshly distilled diazomethane provided total conversion
to a pyrazoline intermediate, obtained as a white solid
after evaporation of solvent. Conversion to the cyclopro-
pane by photoirradiation was performed as previously
described, though this photoreactor was constructed from
standard laboratory glassware and a commercially avail-
able 175 W medium-pressure mercury-vapor security
lamp. Under these conditions, longer irradiation times
were required but the yields were similar (82%).
The cyclopropyl glutamate analogues 2 and 3 were
obtained in a 3:1 syn:anti ratio as determined by NMR
and GC-MS analysis. The 3:1 syn:anti ratio vs the 6:1
ratio obtained previously with t-Bu ester5 is likely due
to the use of the less bulky methyl ester. Variation of
irradiation temperatures from -45 to -10 °C did not
have an impact on selectivity or yield.
glajoie@uwo.ca
Received October 26, 2001
Abstr a ct: There is currently considerable interest in argi-
nine and its structural analogues in the context of nitric
oxide synthase (NOS) substrates and inhibitors. Of particu-
lar interest are conformationally constrained arginine ana-
logues used to probe the active sites of the three NOS
isoforms. A simple procedure is described for the preparation
of syn- and anti-trans-cyclopropyl arginine starting from the
R-OBO-protected Cbz-dehydroglutamate. Cyclopropanation
is effected by diazomethane addition followed by irradiation
of the resulting pyrazoline and gives a 3:1 mixture of syn:
anti isomers that can be separated by crystallization. Reduc-
tion of the ester to the alcohol followed by guanylation gives
the fully protected cyclopropyl arginine analogues. The CBZ
protecting groups are removed by hydrogenolysis and the
OBO by mild acid treatment followed by base hydrolysis.
Arginine is involved in a large number of metabolic
processes and is an important component of various
substrates and inhibitors of a variety of enzymes. The
study of conformationally constrained arginine analogues
either alone or incorporated in peptidomimetic inhibitors
is currently an area of active research.1 There are a
number of reports on the synthesis of novel arginine
mimetics.2 Conformational restriction of substrate side
chains facilitates the study of enzyme binding and
mechanism and can result in entropically favorable
binding and improve selectivity.3
Some cyclopropyl amino acids have been synthesized
or isolated from natural sources, and some interesting
biological activities have been observed.3-5 In our study
of nitric oxide synthase isoforms, we needed access to
trans-3,4-cyclopropyl arginine to determine the confor-
mational preference of each isoform and evaluate the
impact of the cyclopropyl moiety on isoform selectivity.
Flash chromatography was performed to obtain the
mixture of esters, but the syn and anti isomers could not
be separated in this manner. Successive recrystallization
provides access to pure syn-2 and anti-3. However, this
time-consuming process can be avoided and the isomers
separated at a later stage. The stereochemistry of cyclo-
propanation was confirmed by acid hydrolysis and puri-
fication of 2 as previously described.5 The optical rotation
of the free amino acid agreed with the literature value
for the syn-cyclopropyl glutamate.4b
* Corresponding author. Phone: 519-663-3054. Fax: 519-663-2936.
(1) (a) Mamai, A.; Hughes, N. E.; Wurthram, A.; Madalengoitia, J .
S. J . Org. Chem. 2001, 66, 6483. (b) Atkinson, R. N.; Moore, L.; Tobin,
J .; King, S. B. J . Org. Chem. 1999, 64, 3467. (c) Lee, Y.; Marletta, M.
A.; Martasek, P.; Roman, L. J .; Masters, B. S. S.; Silverman, R. B.
Bioorg. Med. Chem. 1999, 7, 1097. (d) Eustache, J .; Grob, A.; Lam, C.;
Odile, S.; Shultz, G. Bioorg. Med. Chem. Lett. 1998, 8, 2961. (e) Levy,
O. E.; Semple, J . E.; Lim, M. C.; Reiner, J .; Rote, W. E.; Dempsey, E.
et al. J . Med. Chem. 1996, 39, 4527. (f) Webb, T. R.; Eigenbrot, C. J .
Org. Chem. 1991, 56, 3009.
The mixture of diastereomeric esters 2/3 was reduced
using DIBAL-H, and a mixture of 4 and 5 was obtained
as an oil (81%) after chromatography. Pure samples of
esters 2 and 3 were individually reduced for character-
(2) For a recent review of arginine mimetics, see: Masic, L. P.;
Kikelj, D. Tetrahedron 2001, 57, 7073.
(3) (a) Suckling, C. J . Angew. Chem., Int. Ed. Engl. 1988, 27, 537.
(b) Stammer, C. H. Tetrahedron 1990, 46, 2234. (c) Alamai, A.; Calmes,
M.; Daunis, J .; J acquier, R. Bull. Chem Soc. Chim. Fr. 1993, 130, 5.
(4) CCGs are the most studied of the known cyclopropyl amino acids
since isomers are selective agonists for the N-methyl-D-aspartate or
metabotropic L-glutamate receptor. (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.
(5) Rife, J .; Ortuno, R. M.; Lajoie, G. A. J . Org. Chem. 1999, 64,
8958.
(6) (a) Blaskovich, M. A.; Lajoie, G. A. J . Am. Chem. Soc. 1993, 115,
5021. (b) Blaskovich, M. A.; Lajoie, G. A. Tetrahedron Lett. 1993, 34,
3837. (c) Blaskovich, M. A.; Evindar, G.; Rose, N. G. W.; Lajoie, G. A.
J . Org. Chem. 1998, 63, 3631. (d) Luo, Y.; Blaskovich, M. A.; Lajoie,
G. A. J . Org. Chem. 1999, 64, 6106. (e) Rose, N. G. W.; Blaskovich, M.
A.; Wong, A.; Lajoie, G. A. Tetrahedron 2001, 57, 1497. (f) Ding, Y.;
Wang, J .; Abboud, K. A.; Xu, Y.; Dolbier, W. R., J r.; Richards, N. G. J .
J . Org. Chem. 2001, 66, 6381.
10.1021/jo016242e CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/05/2002

Notes
J . Org. Chem., Vol. 67, No. 7, 2002 2353
Sch em e 1a
a
Reaction conditions: (a) (i) CH2N2, EtO; (ii) hv, AcCN, benzophenone; (b) DIBAL-H, CH2Cl2; (c) N′,N,N-tri-Cbz guanidine, Ph3P,
DEAD, THF; (d) (i) H2, Pd/C; (ii) 0.1% TFA/H2O; (iii) 10% Cs2CO3/H2O; (iv) Dowex 50W X4-100.
(dd, J ) 15.8, 1.6 Hz, 1H), 5.14 (d, J ) 9.3 Hz, 1H), 5.11 (s, 2H),
4.55 (ddd, J ) 8.4, 4.3, 1.4 Hz, 1H), 3.88 (s, 6H), 3.71 (s, 3H),
0.79 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 166.6, 157.0, 143.3,
136.3, 128.7, 128.6, 128.3, 122.5, 107.8, 72.9, 67.2, 56.1, 51.7,
30.8, 14.3; Anal. Calcd for C19H23O7N: C, 60.47; H, 6.14; N, 3.71.
Found: C, 60.24; H, 6.16; N, 3.71.
N-Cbz-(O-CH3)-tr a n s-2-(Car boxycyclopr opyl)glycin e OBO
Ester (2/3). The cyclopropanation was performed on 1 (2 g, 5.31
mmol) as previously described.5 The reaction mixture was
evaporated to a thick yellow oil, and flash chromatography
(silica, 2:1 hexane/EtOAc with 0.2% triethylamine) provided a
3:1 mixture of syn- and anti-cyclopropyl derivatives as 1.7 g of
clear oil (82%). Successive recrystallizations from EtOAc/hexane
provided each of the diastereomers in a pure form as fine white
crystals.
N-Cb z-(O-CH 3)-tr a n s-2-(Ca r b oxy-(syn )cyclop r op yl)gly-
cin e OBO Ester 2: mp 130-132 °C; [R]25D +39.9 (c 1.05, EtOAc);
TLC (1:1 EtOAc/hexane) Rf ) 0.5; 1H NMR (CDCl3, 300 MHz) δ
7.32 (m, 5H), 5.08 (m, 2H), 5.03 (m, 1H), 3.88 (s, 6H), 3.63 (s,
3H), 3.47 (m, 1H), 1.68 (m, 2H), 1.22 (m, 1H), 0.96 (m, 1H), 0.78
(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 136.3, 128.7, 128.6, 128.1,
108.3, 72.8, 67.1, 57.0, 51.8, 30.7, 23.0, 16.9, 14.6, 14.4; GC-MS
Rt ) 17.8 min, m/z 283 (6, M+ - Cbz),8 225 (22), 185 (19), 154
(39), 86 (64), 55 (100). Anal. Calcd for C20H25O7N: C, 61.37; H,
6.44; N, 3.58. Found: C, 61.52; H, 6.40; N, 3.62.
ization of each alcohol. Mitsunobu reaction of the mixture
with N′,N,N-tri-Cbz guanidine7 gave a mixture of fully
protected cyclopropyl arginine derivatives 6 and 7 (74%).
This mixture can be conveniently separated by flash
chromatography, and each diastereomer 6 and 7 was
obtained in a pure form. Derivatization of pure 4 provided
6 with identical characteristics.
The removal of protecting groups was performed under
standard conditions,6a and lyophilization following cation
exchange chromatography provided syn-3,4-cyclopropyl
L-arginine 8 and anti-3,4-cyclopropyl L-arginine 9 as fine
white powders in 67 and 70% yields, respectively. An
efficient and practical method for the stereoselective
synthesis of both syn and anti-trans-3,4-cyclopropyl L-
arginine (18 and 8%, respectively) from a chiral serine
aldehyde equivalent has been described. The biological
evaluation of each diastereomer with NOS isoforms will
be described in due course.
Exp er im en ta l Section
Gen er a l. All chemicals were purchased from Aldrich and
used directly. CH2Cl2 was distilled from CaH2 and THF from
Na/benzophenone. Melting points are uncorrected. All reactions
were performed under an argon atmosphere in oven-dried
glassware. TLC was performed using Merck aluminum-backed
silica gel 60 F254 and visualized using 5% (NH4)6MoO24/0.2% Ce-
(SO4)2/5% H2SO4. Chromatography was performed using silica
gel (230-400 mesh). NMR spectra were recorded in D2O or
CDCl3 prefiltered through basic alumina to remove traces of acid.
Elemental analyses were performed by MHW Laboratories,
Phoenix, AZ. HRMS-FAB was performed by Tim J ones at Brock
University, Ontario. GC-MS was performed on a 30 m × 0.25
mm HP5 column. Temperature program: initial, 70 °C for 2 min;
heating rate, 10 °C/min for 18 min; final, 250 °C for 10 min.
N-Cb z-(O-CH3)-E-2,3-L-Deh yd r oglu t a m a t e OBO E st er
(1). Cbz-L-Ser(ald)-OBO ester6c (6 g, 18.58 mmol) and Ph3Pd
CHCO2CH3 (6.52 g, 1.05 eq) were dissolved in dry CH2Cl2 (250
mL) and stirred for 15 min at room temperature. The reaction
was quenched with 3% NH3Cl (100 mL) and the organic layer
washed with 3% NH3Cl (3 × 50 mL) and brine (50 mL), dried
(MgSO4), and evaporated to dryness. Purification by flash
column chromatography (silica gel, 3:2 EtOAc/hexane with 0.2%
triethylamine) yielded 5.39 g (77%) of clear oil. Crystallization
N-Cb z-(O-CH3)-tr a n s-2-(Ca r b oxy-a n ti)cyclop r op yl)gly-
cin e OBO Ester 3: mp 124-127 °C; [R]25 -38.78 (c 1.065,
D
EtOAc); TLC (1:1 EtOAc/hexane) Rf ) 0.5; 1H NMR (CDCl3, 300
MHz) δ 7.32 (m, 5H), 5.12 (m, 2H), 4.97 (m, 1H), 3.86 (s, 6H),
3.64 (s, 3H), 3.61 (m, 1H), 1.64 (m, 2H), 1.05 (m, 1H), 0.97 (m,
1H), 0.77 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 136.4, 128.7,
128.2, 128.1, 108.3, 72.8, 67.0, 56.3, 51.8, 30.7, 22.1, 18.7, 14.4,
11.6; GC-MS Rt ) 17.9 min, m/z 283 (8, M+ - Cbz),8 225 (23),
185 (38), 154 (35), 86 (77), 55 (100). Anal. Calcd for C20H25O7N:
C, 61.37; H, 6.44; N, 3.58. Found: C, 61.61; H, 6.49; N, 3.49.
N-Cbz-(tr a n s)-2-(Cyclopr opyl)pen tah om oser in e OBO Es-
ter 4/5. The mixture of cyclopropyl esters 2/3 (3:1, 1.5 g, 3.84
mmol) was dissolved in dry CH2Cl2 (50 mL) under argon and
cooled to -78 °C. DIBAL-H (1 M in hexanes) (8.45 mL, 2.2 equiv)
was added dropwise over 1 h while maintaining the solution at
-78 °C. The solution was stirred for an additional 2 h at -78
°C, followed by addition of methanol (3 mL), and allowed to
warm to 0 °C. A saturated solution of KNa tartrate (20 mL) was
added, and the suspension stirred vigorously for l6 h at room
temperature. The layers were separated and the aqueous layer
washed with additional CH2Cl2 (20 mL). The organic fractions
were combined and washed with brine (20 mL), then dried
(MgSO4). The solution was concentrated to a yellowish clear oil
that was purified by flash chromatography (silica, 3:1 EtOAc/
provided fine white crystals: mp 109-112 °C; [R]25 -32.9 (c
D
1.0, EtOAc); TLC (1:1 EtOAc/hexane) Rf ) 0.49; 1H NMR (CDCl3,
300 MHz) δ 7.32 (m, 5H), 6.97 (dd, J ) 15.8, 5.1 Hz, 1H), 5.98
(8) Cbz-protected amino acids decomposed during GC-MS analysis
to the corresponding isocyanate. Thus, under these conditions, benzyl
alcohol also elutes at Rt ) 6.08 min.
(7) Feichtinger, K.; Sings, H. L.; Baker, T. J .; Matthews, K.;
Goodman, M. J . Org. Chem. 1998, 63, 8432.

2354 J . Org. Chem., Vol. 67, No. 7, 2002
Notes
hexane with 0.2% triethylamine). Concentration of pure fractions
provided a mixture of 4 and 5 as 1.13 g (81%) of clear oil.
N-Cbz-(tr a n s)-2-((syn )Cyclopr opyl)pen tah om oser in e OBO
Ester 4: [R]25D -6.01 (c 1.015, EtOAc); TLC (3:1 EtOAc/hexane)
Rf ) 0.34; 1H NMR (CDCl3, 300 MHz) δ 7.32 (m, 5H), 5.09 (d, J
) 12.21, 1H), 5.03 (d, J ) 12.22 Hz, 1H), 4.93 (d, J ) 8.77 Hz,
1H), 3.88 (s, 6H), 3.70 (dd, J ) 6.0, 9.45 Hz, 1H), 3.66 (m, 1H),
3.08 (dd, J ) 8.52, 10.62 Hz, 1H), 1.80 (br s), 1.08 (m, 1H),
0.93 (m, 1H), 0.78 (s, 3H), 0.56 (m, 1H), 0.46 (m, 1H); 13C
NMR (CDCl3, 75 MHz) δ 136.6, 128.6, 128.2, 128.1, 108.8,
72.8, 66.9, 66.7, 55.9, 30.7, 17.1, 17.1, 14.4, 7.9; Anal. Calcd for
hexane) Rf ) 0.53; 1H NMR (CDCl3, 300 MHz) δ 7.36 (m, 20H),
5.0 (m, 9H), 3.98 (dd, J ) 5.1, 14.2, 1H), 3.71 (s, 6H), 3.64 (m,
1H), 3.10 (m, 2H), 1.29 (m, 1H), 1.09 (m, 1H), 0.69 (s, 3H), 0.59
(m, 1H), 0.36 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 155.9, 136.7,
134.6, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 108.6,
72.7, 69.3, 68.2, 66.8, 58.65, 50.2, 30.5, 18.6, 17.7, 14.4, 8.3. Anal.
Calcd for C44H46O11N4: C, 65.50; H, 5.75; N, 6.94. Found: C,
65.62; H, 5.81; N, 7.09.
Rem ova l of P r otectin g Gr ou p s. A sample of pure, fully
protected arginine analogue was dissolved in 1:1 EtOH/EtOAc
with an equal mass of Pd/C. The suspension was stirred
vigorously under a pure H2 atmosphere for 16 h. The mixture
was filtered and the solvent evaporated. The clear oil was
dissolved in 0.1% TFA in distilled deionized water and stirred
for 10 min, and then the solvent was removed in vacuo. The clear
oil was suspended in 10% Cs2CO3, stirred for 16 h, and then
lyophilized. The residue was dissolved in minimal H2O (distilled),
acidified with doubly distilled 6 N HCl to pH 3, and then loaded
onto Dowex 50W X4-100 cation-exchange resin. After being
washed with pure H2O, the product was eluted with a gradient
to 0.5 N NH4OH. Fractions were combined and lyophilized to
provide the free amino acid as a fine white powder.
C
19H25O6N: C, 62.80; H, 6.93; N, 3.85. Found: C, 62.85; H, 6.84;
N, 3.90.
N-Cb z-(tr a n s)-2-((a n ti)Cyclop r op yl)p en t a h om oser in e
OBO Ester 5: [R]25 -23.16 (c 1.075, EtOAc); TLC (3:1 EtOAc/
D
1
hexane) Rf ) 0.34; H NMR (CDCl3, 300 MHz) δ 7.30 (m, 5H),
5.17 (d, J ) 9.35 Hz, 1H), 5.09 (d, J ) 12.01 Hz, 1H), 5.03 (d, J
) 12.01 Hz, 1H), 3.86 (s, 6H), 3.75 (m, 1H), 3.30 (app br t, J )
9.66 Hz, 1H, 2.97 (t, J ) 9.67 Hz, 1H), 2.28 (br s), 1.15 (m, 1H),
0.86 (m, 1H), 0.75 (s, 3H), 0.67 (m, 1H), 0.37 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 156.4, 136.6, 128.5, 128.2, 128.1, 109.0, 72.8,
66.9, 66.6, 58.2, 30.7, 21.3, 18.5, 14.4, 7.3; Anal. Calcd for
C
19H25O6N: C, 62.80; H, 6.93; N, 3.85. Found: C, 62.82; H, 6.95;
N, 3.96.
N-Cbz-(tr a n s)-2-((syn /a n ti)-Cyclop r op yl)-δ,ω,ω′-tr i-Cbz-
syn -3,4-Cyclop r op yl L-Ar gin in e 8. The deprotection proce-
dure above was applied to 6 (289 mg) to provide 44.5 mg of 8
(67%) as a white pwoder: mp 196-200 °C dec; [R]25 +40.0 (c
a r gin in e OBO Ester 6/7. The unresolved mixture of cyclopropyl
alcohols 4/5 (600 mg, 1.65 mmol) was dissolved in dry THF (20
mL) under argon, to which was added Ph3P (649 mg, 1.5 equiv)
and N′,N,N-tri-Cbz guanidine7 (1.264 g, 1.66 equiv). This mixture
was cooled to 0 °C, and DEAD (0.39 mL, 1.5 equiv) was added
dropwise over 1 h. The reaction was allowed to warm to room
temperature and continue to stir for 16 h. The solvent was
evaporated in vacuo and the residue purified by flash chroma-
tography (silica, 1:1 EtOAc/hexane with 0.2% triethylamine)
providing 6 (687 mg) and 7 (292 mg) (74% combined yield).
N-Cbz-(tr a n s)-2-((syn )-Cyclop r op yl)-δ,ω,ω′-tr i-Cbz-a r gi-
n in e OBO Ester 6: [R]25D -3.6 (c 1.0, EtOAc); TLC (1:1 EtOAc/
hexane) Rf ) 0.48; 1H NMR (CDCl3, 300 MHz) δ 7.36 (m, 20H),
5.0 (m, 9H), 4.08 (m, 1H), 3.77 (s, 6H), 3.54 (m, 1H), 3.53 (m,
1H), 1.18 (m, 2H), 0.69 (s, 3H), 0.50 (m, 2H); 13C NMR (CDCl3,
75 MHz) δ 136.8, 134.7, 128.8, 128.7, 128.6, 128.5, 128.2, 128.0,
108.7, 72.7, 69.3, 68.2, 66.0, 56.36, 50.9, 30.6, 17.7, 14.4, 13.9,
9.52; Anal. Calcd for C44H46O11N4: C, 65.50; H, 5.75; N, 6.94.
Found: C, 65.38; H, 5.53; N, 7.00.
D
1
1.0, H2O); H NMR (D2O, 300 MHz) δ 2.97 (dd, J ) 7.03, 13.82
Hz, 1H), 2.88 (dd, J ) 7.26, 13.83 Hz, 1H), 2.54 (d, J ) 8.67 Hz,
1H), 0.88 (m, 1H), 0.75 (m, 1H), 0.52, 0.37 (m, 2 × 1H); 13C NMR
(D2O, 75 MHz) δ 178.59, 156.64, 58.51, 44.43, 20.44, 15.89, 8.71;
HR-MS (FAB) calcd for C7H15N4O2 187.1195, found 187.1161.
a n ti-3,4-Cyclop r op yl L-Ar gin in e 9. The deprotection pro-
cedure above was applied to 7 (100 mg) to provide 16.1 mg of 9
(70%): mp 198-201 °C dec; [R]25D +30.67 (c 0.6, H2O); 1H NMR
(D2O, 300 MHz) δ 3.12 (dd, J ) 6.63, 13.91, 1H), 2.97 (d, J )
10.28 Hz, 1H), 2.89 (dd, J ) 7.71, 13.91, 1H), 1.23 (m, 1H), 0.95
(m, 1H), 0.62 (m, 2H); 13C NMR (D2O, 75 MHz) δ 173.88, 156.60,
58.44, 44.17, 18.32, 17.01, 8.90; HR-MS (FAB) calcd for C7H15N4O2
187.1195, found 187.1158.
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada for finan-
cial support.
N-Cbz-(tr a n s)-2-((a n ti)-Cyclop r op yl)-δ,ω,ω′-tr i-Cbz-a r gi-
n in e OBO Ester 7: [R]25D -1.5 (c 1.0, EtOAc); TLC (1:1 EtOAc/
J O016242E