Stereospecific synthesis of trans-2,3-diaryl substituted 1-aminocyclopropanecarboxylic acid derivatives

Article abstract of DOI:10.1081/SCC-120022177

The stereospecific syntheses of trans-2,3-diaryl-l-aminocyclopropanecarboxylic acid derivatives are reported. They key step is a 1,3-dipolar cycloaddition of phenyldiazomethane to (Z)-2-phenyl-4-arylidene-5(4H)-oxazolones, followed by the extrusion of nitrogen in situ.

Full text of DOI:10.1081/SCC-120022177

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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 16, pp. 2873–2884, 2003
Stereospecific Synthesis of trans-2,3-Diaryl
Substituted 1-Aminocyclopropanecarboxylic
Acid Derivatives
2
2
Guifa Su,1,2,3, Hongtao Mu, DanmingZa,
*
Longmei Zeng,1 Carlos Cativiela,3
Robert P. Hammer,4 and Kaibei Yu5
1College of Chemistry and Chemical Engineering,
Zhongshan University, Canton, P.R. China
2Department of Chemistry and Chemical Engineering,
Guangxi Normal University, Guilin, P.R. China
3Department of Organic Chemistry, ICMA,
University of Zaragoza-CSIC, Zaragoza, Spain
4Department of Chemistry, Louisiana State University,
Baton Rouge, Louisiana, USA
5Chengdu Analysis and Testing Center,
Academia Sinica, Chengdu, P.R. China
ABSTRACT
The stereospecific syntheses of trans-2,3-diaryl-1-aminocyclopro-
panecarboxylic acid derivatives are reported. The key step is a
*Correspondence: Guifa Su, Department of Chemistry, 232 Choppin Hall,
Louisiana State University, Baton Rouge, LA 70803, USA; E-mail: gfsu@lsu.edu.
2873
DOI: 10.1081/SCC-120022177
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2874
Su et al.
1,3-dipolar cycloaddition of phenyldiazomethane to (Z)-2-phenyl-
4-arylidene-5(4H)-oxazolones, followed by the extrusion of nitrogen
in situ.
Key Words: Stereospecific syntheses; trans-2,3-Diaryl-1-amino-
cyclopropanecarboxylic acid; Phenyldiazomethane; Oxazolones;
1,3-Dipolar cycloaddition.
Since the first report on the isolation[1] and identification of 1-
aminocyclopropanecarboxylic acid as an intermediate in the biosynthesis
of ethylene in higher plants,[2] the synthesis of this compound and its
derivatives (ACCs) has been, and currently still is the subject of numer-
ous synthetic efforts.[3] This interest stems from their diverse
documented biological activities, and their potential use in the synthesis
of conformationally constrained peptides. The constrained peptide
analogues are of great value in structure-function relationship studies
aimed at elucidating the biologically active conformations. ACCs
constitute a special class of side-chain conformationally constrained
residues. The rigid cyclopropane ring forces the substituents to adopt a
well-defined orientation withrespect to teh peptide backbone; if a
b-substituent is present on the cyclopropyl ring, the possibility of
choosing the cis (b-substituent to respect nitrogen atom) or trans
stereoisomer allows the evaluation of the substituent effect on the inter-
action between the drug and receptor site.[4]
Among the considerable numbers of ACCs synthesized, most were
2-substituted or 2,2-disubstituted-1-aminocyclopropanecarboxylic amino
[6]
acids,[5] withsome reports on 2,3-disubstituted ACCs,
only several
stereoselective syntheses of 2,3-diaryl ACCs have been reported.[4b,4d]
In the previous report, we described the stereoselective synthesis of
trans-2,3-diphenyl-1-aminocyclopropanecarboxylic acid.[6a] In a conti-
nuation of our studies on the selective synthesis of ACCs,[5l,6a] we
wish to report now the stereospecific synthesis of trans-2,3-diaryl-1-
aminocyclopropanecarboxylic acid derivatives. The key step is a
1,3-dipolar cycloaddition of phenyldiazomethane to (Z)-2-phenyl-4-
arylidene-5(4H)-oxazolones 1, followed by the extrusion of N2 in situ
(Sch. 1).
(Z)-2-Phenyl-4-arylidene-5(4H)-oxazolones 1, readily obtained (yield
vary from 60% to 79%) by condensation of hippuric acid and aromatic
aldehydes following the classical Erlenmeyer procedure employed by
Buck and Ide,[7] reacted with phenyldiazomethane in toluene at room
temperature for 8–48 hto give pure t-1-(4-methoxyphenyl)-c-2, t-5-diphe-
nyl-4-aza-6-oxaspiro[2.4]hept-4-en-r-7-one 2, in 78%–91% yields after

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1-Aminocyclopropanecarboxylic Acid
2875
Scheme 1.
recrystallization from ethyl acetate/hexane. In the course of the room
temperature addition of a toluene solution of phenyldiazomethane to
(Z)-2-phenyl-4-arylidene-5(4H)-oxazolones 1, a slow evolution of gas
was observed. Presumably the reaction proceeds through a 3 þ 2 cyclo-
addition to form a spiro-pyrazoline A which immediately losses nitrogen
to form the biradical B. In contrast, when diazomethane is used in these
kinds of cycloadditions, the subsequent pyrazolines are stable and can be
isolated. They can only be converted to cyclopropanes by heating at
ꢀ100ꢁC or by photolysis.[3] Apparently in the case of spiro-pyrazoline
A, the 3-phenyl substituent and 5-spirocycle either destabilizes the
pyrazoline sterically or lowers the energy of the presumed diradical
intermediate B so that the nitrogen extrusion takes place at room
temperature. This is in agreement with the studies of Overberger and
Anselme[8] who showed that the addition of phenyl substituent to a
pyrazoline reduced the activation energy for nitrogen loss by over
20 kcal/mol resulting in a 500-fold increase in the rate of cycloproprane
formation.
All new compounds (2, 3, 4) gave satisfactory spectroscopic and
analytical data. GC-MS of the crude reaction mixtures showed the pre-
sence of only one diastereomer of the spirocyclopropanes 2a–2e, indi-
cating that the cycloaddition is diastereoselective and that no loss of
stereochemistry occurs in subsequent formation of the diradical B.[9]
1H NMR analysis of 2 revealed there are two cyclopropyl-H signals at
ꢀ 3.77–3.81 (d) and 3.91–4.03 (d) in compounds 2a–2e and the coupling
constants between the two cyclopropane protons of are quite high

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2876
Su et al.
(J ¼ 9.0, 9.5). This is not definitive evidence for the trans relation of the
aryl group as the range for vicinal cyclopropane couplings is Jcis ¼ 7–13,
Jtrans ¼ 4–9.[10] The trans relationship of the aryl substituents was
confirmed by single crystal X-ray studies of 2b. The crystal structure
(Fig. 1) showed the two aryl groups in a trans relationship with the
p-methoxyphenyl group being cis to the spiro-nitrogen substituent.
Spirocyclopropane derivatives 2 were readily converted into the
corresponding benzamido methyl esters 3 in nearly quantitative yields
by treatment withabsolute methanol containing catalytic amounts of
sodium methoxide. Hydrolysis of esters 3 with hydrochloric acid/acetic
acid furnished the corresponding 2,3-diaryl-1-aminocyclopropane-
carboxylic acid hydrochlorides 4 in 57–67% yields (Sch. 2).
1H NMR analysis of 3 revealed there are two cyclopropyl-H signals
at ꢀ 3.70–3.93 (d) and 3.44–3.69 (d) in compounds 3a–3e, likewise for
compounds 4a–4c, 3.47–3.53 (d) and 3.14–3.21 (d). The vicinal cyclopro-
pane coupling constants for esters 3a–3e and amino acids 4a–4c remain
close to the values for the starting spirocyclopropanes (J ¼ 8.5, 9.0) sug-
Figure 1. X-ray crystal structure of 2b.
Scheme 2.

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1-Aminocyclopropanecarboxylic Acid
2877
gesting the trans relationship of the aryl groups is maintained in 3 and 4,
this is in accordance with our previous report.[6a] In fact, the trans stereo-
chemistry of 3a had been confirmed by X-ray diffraction analysis.[6a]
In conclusion, we developed a stereospecific synthesis methodology
of the highly constrained trans-2,3-diaryl-1-aminocyclopropane-
carboxylic acid derivatives. This methodology has significant advantages:
common available materials, mild reaction conditions, simple operations,
high yields and above all the high stereoselectivity. Additional synthesis
of highly constrained ACCs and their incorporation into model peptides
is currently under investigation and will be reported elsewhere.
EXPERIMENTAL
All reagents were obtained from commercial suppliers. All solvents
and liquid reagents were purified by standard procedures, and solvents
were freshly distilled prior to use. (Z)-2-Phenyl-4-arylidene-
5(4H)-oxazolones (1a–e), p-toluenesulfonylhydrazide and benzaldehyde
tosylhydrazone were prepared as previously described.[11] Melting
points were determined on a WRS-IA apparatus without correction.
All elemental analyses were performed by Carlo Erba model 1106
analyzer. 1H spectra were recorded on a Varian INOVA 500 MHz
spectrometer in CDCl3 or in DMSO-d6. Infrared spectra were recorded
on a Nicolet ESP 360 FT-IR spectrometer as KBr pellets. GC-MS spectra
were measured at 70 eV (EI).
Synthesis of Phenyldiazomethane[12]
To a 500 mL two-neck flask was added benzaldehyde tosylhydrazone
(7.0 g, 25 mmol) and toluene (100 mL), then to this solution was added
triethylbenzylammonium chloride (TEBAC, 1.4 g, 6.25 mmol) and 15%
NaOH (100 mL). The mixture was heated under stirring for 2 h. Cooled,
the organic phase was washed by water.
Syntheses of 2a–e
To a mixture of 1a–1e (10 mmol) in toluene (50 mL) was added a
solution of phenyldiazomethane in toluene dropwise over 1 h. The
mixture was stirred at room temperature for another 8–48 h, the progress
of the reaction was monitored by TLC (9/1, hexane/ethyl acetate). After

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2878
Su et al.
the reaction was finished, excess of phenyldiazomethane was decomposed
by addition of glacial acetic acid. The solution was dried over MgSO4,
filtered and the solvent was removed in vacuo to provide a yellow solid.
The crude products were recrystallized from ethyl acetate/hexane to
afford pure 2a–2e, the yields vary from 78% to 91%.
2a. White solid, yield 87%, m.p. 134–135ꢁC, Rf (hexane/ethyl
acetate 4/1, v/v) 0.57. IR (KBr, ꢁ, cmꢂ1): 1800 (C¼O), 1634 (C¼N),
1
695 (Ar-H). H NMR (CDCl3, ꢀ, ppm): 8.0–7.3 (m, 15H, ArH), 3.97
(d, J ¼ 9.5 Hz, 1H, cyclopropyl), 3.78 (d, J ¼ 9.0 Hz, 1H, cyclopropyl).
Anal. calcd. for C23H17NO2: C, 81.40; H, 5.05; N, 4.13. Found: C, 81.12;
H, 5.23; N, 4.16.
2b. White solid, yield 91%, m.p. 144–145ꢁC, Rf (hexane/ethyl acetate
4/1) 0.46. IR (KBr, ꢁ, cmꢂ1): 1796 (C¼O), 1633 (C¼N), 695 (Ar-H).
1H NMR (CDCl3, ꢀ, ppm): 8.0–6.9 (m, 14H, ArH), 3.93 (d, J ¼ 9.5 Hz,
1H, cyclopropyl), 3.82 (s, 3H, CH3O), 3.75 (d, J ¼ 9.5 Hz, 1H, cyclo-
propyl). Anal. calcd. for C24H19NO3: C, 78.03; H, 5.18; N, 3.79.
Found: C, 78.20; H, 5.30; N, 3.83.
The single crystal growth was carried out from a saturated solution
of 2b in ethyl acetate after standing overnight in the refrigerator. X-ray
crystallographic analysis was performed with a Siemens P4 four-circle
diffractometer
(graphite
monochromator,
MoKa
radiation,
ꢂ ¼ 0.71073 A). Crystal data of compound 2b: C24H19NO3,
0.54 ꢃ 0.50 ꢃ 0.44 mm3, Mf ¼ 369.40, monoclinic, Space group P21/n,
a ¼ 11.3462 (2) A, b ¼ 10.464 (2) A, c ¼ 16.557 (3) A, a ¼ 90ꢁ,
b ¼ 105.52 (1)ꢁ, g ¼ 90ꢁ, V ¼ 1894.0 (6) A3, Z ¼ 4, Dc ¼ 1.295 Mg mꢂ3, ꢃ
(MoKa) ¼ 0.086 mmꢂ1, F (000) ¼ 776. T ¼ 292K; 3528 reflections were
ꢁ
independent and unique, I >2 ꢄ (I), and 22 with2.56 <ꢅ<14.96ꢁ were
used for the solution of the structure. R1 ¼ 0.0367, wR2 ¼ 0.0836.
X-ray data for the compound 2b has been deposited at the
Cambridge Crystallographic Data Center. Copies of the data may be
obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, U.K. (Fax: (þ) 44 1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
2c. White solid, yield 85%, m.p. 132–133ꢁC, Rf (hexane/ethyl acetate
4/1) 0.60. IR (KBr, ꢁ, cmꢂ1): 1803 (C¼O), 1631 (C¼N), 693 (Ar-H).
1H NMR (CDCl3, ꢀ, ppm): 8.0–7.3 (m, 14H, ArH), 3.91 (d, J ¼ 9.5 Hz,
1H, cyclopropyl), 3.73 (d, J ¼ 9.0 Hz, 1H, cyclopropyl). Anal. calcd. for
C23H16NO2Cl: C, 73.90; H, 4.31; N, 3.75. Found: C, 74.02; H, 4.34; N, 3.78.
2d. Pale yellow solid, yield 89%, m.p. 181–182ꢁC, Rf (hexane/ethyl
acetate 4/1) 0.52. IR (KBr, ꢁ, cmꢂ1): 1804 (C¼O), 1638 (C¼N), 696
(Ar-H). 1H NMR (CDCl3, ꢀ, ppm): 8.3–7.3 (m, 14H, ArH), 3.98 (d,
J ¼ 9.5 Hz, 1H, cyclopropyl), 3.81 (d, J ¼ 9.0 Hz, 1H, cyclopropyl).

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1-Aminocyclopropanecarboxylic Acid
2879
Anal. calcd. for C23H16N2O4: C, 71.87; H, 4.20; N, 7.29. Found: C, 71.72;
H, 4.31; N, 7.39.
2e. White solid, yield 78%, m.p. 155 156ꢁC, Rf (hexane/ethyl acetate
4/1) 0.55. IR (KBr, ꢁ, cmꢂ1): 1803 (C¼O), 1628 (C¼N), 694 (Ar-H).
1H NMR (CDCl3, ꢀ, ppm): 8.0–6.4 (m, 13H, ArH), 4.03 (d, J ¼ 9.0 Hz,
1H, cyclopropyl), 3.77 (d, J ¼ 9.0 Hz, 1H, cyclopropyl). Anal. calcd. for
C21H15NO3: C, 76.58; H, 4.59; N, 4.25. Found: C, 76.51; H, 4.66; N, 4.30.
Syntheses of 3a–e
To a flask containing 40 mL of absolute methanol was added a little
piece of sodium, then to this solution was added 5 mmol of 2a–e under
stirring, the mixture was stirred for another 30 min (monitored by TLC,
hexane/ethyl acetate 3/1). After the reaction was finished, the methanol
was removed in vacuo. The solid was dissolved in ethyl acetate, then
washed by water, brine, dried over MgSO4 overnight. Filtered, the
solvent was removed in vacuo to provide a white solid of 3a–e.
3a. Yield 97%, m.p. 216–217ꢁC, Rf (hexane/ethyl acetate 3/1) 0.28.
IR (KBr, ꢁ, cmꢂ1): 3239 (N-H), 1732 (C¼O), 1645 (C¼O), 697 (Ar-H).
1H NMR (DMSO-d6, ꢀ, ppm): 9.07 (s, 1H, N-H), 7.7–7.1 (m, 15H, Ar-
H), 3.74 (d, J ¼ 9.0 Hz, 1H, cyclopropyl), 3.53 (d, J ¼ 8.5 Hz, 1H, cyclo-
propyl), 3.33 (s, 3H, CO2CH3). Anal. calcd. for C24H21NO3: C, 77.61; H,
5.70; N, 3.77. Found: C, 77.55; H, 5.78; N, 3.82.
3b. Yield 99%, m.p. 169–171ꢁC, Rf (hexane/ethyl acetate 3/1) 0.20.
IR (KBr, ꢁ, cmꢂ1): 3274 (N-H), 1738 (C¼O), 1634 (C¼O), 697 (Ar-H).
1H NMR (CDCl3, ꢀ, ppm): 7.7–6.9 (m, 14H, Ar-H), 6.15 (s, 1H, N-H),
3.83 (s, 3H, OCH3), 3.71 (d, J ¼ 9.0 Hz, 1H, cyclopropyl), 3.48 (s, 3H,
OCH3), 3.44 (d, J ¼ 9.0 Hz, 1H, cyclopropyl). Anal. calcd. for
C25H23NO4: C, 74.49; H, 5.77; N, 3.49. Found: C, 74.45; H, 5.80; N, 3.53.
3c. Yield 98%, m.p. 183ꢁC, Rf (hexane/ethyl acetate 3/1) 0.29. IR
(KBr, ꢁ, cmꢂ1): 3237 (N-H), 1739 (C¼O), 1632 (C¼O), 698 (Ar-H).
1H NMR (CDCl3, ꢀ, ppm): 7.6–7.3 (m, 14H, Ar-H), 6.20 (s, 1H, N-H),
3.74 (d, J ¼ 8.5 Hz, 1H, cyclopropyl), 3.48 (s, 3H, OCH3), 3.46
(d, J ¼ 9.0 Hz, 1H, cyclopropyl). Anal. calcd. for C24H20NO3Cl: C,
71.02; H, 4.97; N, 3.45. Found: C, 70.92; H, 5.01; N, 3.49.
3d. Yield 92%, m.p. 209ꢁC, Rf (hexane/ethyl acetate 3/1) 0.18. IR
(KBr, ꢁ, cmꢂ1): 3249 (N-H), 1741 (C¼O), 1634 (C¼O), 700 (Ar-H).
1H NMR (DMSO-d6, ꢀ, ppm): 9.28 (s, 1H, N-H), 8.1–7.3 (m, 14H,
Ar-H), 3.93 (d, J ¼ 8.5 Hz, 1H, cyclopropyl), 3.69 (d, J ¼ 8.5 Hz, 1H,
cyclopropyl), 3.35 (s, 3H, OCH3). Anal. calcd. for C24H20N2O5:
C, 69.22 ; H, 4.84; N, 6.73. Found: C, 69.31; H, 4.80; N, 6.81.

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Su et al.
3e. Yield 94%, m.p. 212–213ꢁC, Rf (hexane/ethyl acetate 3/1) 0.28.
IR (KBr, ꢁ, cmꢂ1): 3253 (N-H), 1737 (C¼O), 1645 (C¼O), 696 (Ar-H).
1H NMR (DMSO-d6, ꢀ, ppm): 9.14 (s, 1H, N-H), 7.7–6.2 (m, 13H, Ar-
H), 3.70 (d, J ¼ 8.5 Hz, 1H, cyclopropyl), 3.47 (d, J ¼ 9.0 Hz, 1H, cyclo-
propyl), 3.33 (s, 3H, OCH3). Anal. calcd. for C22H19NO4: C, 73.12;
H, 5.30; N, 3.88. Found: C, 73.21; H, 5.36; N, 3.92.
Syntheses of 4a–c
To a flask containing glacial acetic acid (25 mL) and 4 M HCl
(25 mL) was added 1 mmol of 3a–3c under stirring, the mixture was
heated under reflux for 24 h. The liquid was evaporated in vacuo, the
white residue was dissolved in 0.5 M HCl (40 mL), then washed with
CHCl3 (3 ꢃ 15 mL), the water phase was filtered and the water removed
in vacuo. Recrystallization from hot water furnished the products 4a–4c
as white solids.
4a. M.p. 204–205ꢁC, yield 57%. IR (KBr, ꢁ, cmꢂ1): 3001 (br, OH),
1773 (C¼O), 1595 (NH3), 1505 (C¼O), 1445 (NH3), 698 (Ar-H).
1H NMR (DMSO-d6, ꢀ, ppm): 7.5–7.2 (m, 10H, Ar-H), 3.54
(d, J ¼ 8.5 Hz, 1H, cyclopropyl), 3.21 (d, J ¼ 9.0 Hz, 1H, cyclopropyl).
Anal. calcd. for C16H16NO2Cl: C, 66.32; H, 5.57; N, 4.83. Found:
C, 66.41; H, 5.51; N, 4.87.
4b. M.p. 180–182ꢁC, yield 67%. IR (KBr, ꢁ, cmꢂ1): 2936 (br, OH),
1727 (C¼O), 1610 (NH3), 1515 (C¼O), 1448 (NH3), 699 (Ar-H).
1H NMR (DMSO-d6, ꢀ, ppm): 7.4–6.9 (m, 9H, Ar-H), 3.76 (s, 3H,
OCH3), 3.47 (d, J ¼ 8.5 Hz, 1H, cyclopropyl), 3.14 (d, J ¼ 9.0 Hz, 1H,
cyclopropyl). Anal. calcd. for C17H18NO3Cl: C, 63.85; H, 5.67; N, 4.38.
Found: C, 63.72; H, 5.73; N, 4.44.
4c. M.p. 216ꢁC, yield 60%. IR (KBr, ꢁ, cmꢂ1): 3001 (br, OH), 1737
1
(C¼O), 1600 (NH3), 1503 (C¼O), 1441 (NH3), 699 (Ar-H). H NMR
(DMSO-d6, ꢀ, ppm): 7.5–7.2 (m, 9H, Ar-H), 3.53 (d, J ¼ 8.5 Hz, 1H,
cyclopropyl), 3.20 (d, J ¼ 8.5 Hz, 1H, cyclopropyl). Anal. calcd. for
C16H15NO2Cl2: C, 59.28; H, 4.66; N, 4.32. Found: C, 59.38; H, 4.58;
N, 4.39.
ACKNOWLEDGMENT
Financial support from the Foundation of Science and Technology
Bureau of the Guangxi Zhuang Autonomous Region, People’s Republic
of China is gratefully acknowledged.

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1-Aminocyclopropanecarboxylic Acid
REFERENCES
2881
1. Burroughs, L.F. 1-Aminocyclopropane-1-carboxylic acid: a new
amino acid in perry pears and cider apples. Nature 1957, 179,
360–361.
2. Adams, D.O.; Yang, S.F. Ethylene biosynthesis: Identification of
1-aminocyclopropane-1-carboxylic acid as an intermediate in the
conversion of methionine to ethylene. Proc. Natl. Acad. Sci. USA
1979, 76 (1), 170–174.
3. For recent reviews on ACCs, see: (a) Salaun, J. Cyclopropane
derivatives and their diverse biological activities. Top. Curr. Chem.
2000, 207, 1–67; (b) Cativiela, C.; Diaz-de-Viellgas, M.D.
Stereoselective synthesis of quaternary a-amino acids. Part 2: cyclic
compounds. Tetrahedron: Asymmetry 2000, 11 (3), 645–732; (c)
Salaun, J.; Baird, M.S. Biologically active cyclopropanes and cyclo-
propenes. Curr. Med. Chem. 1995, 2 (1), 511–542; (d) Burgess, K.;
Ho, K.-K.; Moye-Sherman, D. Asymmetric syntheses of
2,3-methanoamino acids. Synlett 1994, 8, 575–583.
4. For some researches about ACCs were used in conformationally
constrained peptides, see: (a) Jimenez, A.I.; Cativiela, C.; Marraud,
M. A g-turn induced by a highly constrained cyclopropane analog of
phenylalanine (c3diPhe) in the solid state. Tetrahedron Lett. 2000,
41 (28), 5353–5356; (b) Moye-Sherman, D.; Jin, S.; Li, S.; Welch,
M.B.; Reibenspies, J.; Burgess, K. Cyclopropane amino acids
that mimic two ꢆ1-conformations of phenylalanine. Chem. Eur.
J. 1999, 5 (9), 2730–2739; (c) Jimenez, A.I.; Cativiela, C.;
Aubry, A.; Marraud, M. b-Turn preferences induced by 2,3-metha-
nophenylalanine chirality. J. Am. Chem. Soc. 1998, 120 (37),
9452–9459; (d) Moye-Sherman, D.; Jin, S.; Ham, I.; Burgess, K.
Conformational preferences of RNase A C-peptide derivatives con-
taining a highly constrained analog of phenylalanine. J. Am. Chem.
Soc. 1998, 120 (37), 9435–9443; (e) Lim, D.; Burgess, K. Spirocyclic
peptidomimetics featuring 2,3-methanoamino acids. J. Am. Chem.
Soc. 1997, 119 (41), 9632–9640; (f ) Jimenez, A.I.; Vandersse, R.;
Marraud, M.; Aubry, A.; Cativiela, C. Folding types of dipeptides
containing the diastereoisomeric cyclopropanic analogs of phenyla-
lanine. Tetra. Lett. 1997, 38 (43), 7559–7562; (g) Burgess, K.; Ke, C.-
Y. On the conformational bias of F((2R,3S)-cyclo-M)RFa induced
by the cis-2,3-methanomethionine residue. J. Org. Chem. 1996, 61
(24), 8627–8631; (h) Burgess, K.; Ho, K.-K.; Pal, B. Comparison of
the effects of (2S,3S)-2,3-methanomethionine, (2R,3R)-2,3-methano-
methionine, and (2R,3R)-2,3-methanophenylalanine on the

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Su et al.
conformations of small peptides. J. Am. Chem. Soc. 1995, 117 (13),
3808–3819; (i) Burgess, K.; Ho, K.-K.; Pettitt, B.M. J. Am. Chem.
Soc. Conformational effects of substituting methionine with
(2S,3S)-2,3-methanomethionine in Phe-Met-Arg-Phe-NH2. 1995,
117 (1), 54–65; ( j) Balaji, V.N.; Ramnarayan, K.; Chan, M.-F.;
Rao, S. Conformational studies on model peptides with1-
aminocyclopropane-1-carboxylic acid residues. Pep. Res. 1994, 7
(2), 60–71; (k) Burgess, K.; Ho, K.-K.; Pettitt, B.M. A g-turn
structure induced by 2S,3S-2,3-methanomethionine. J. Am. Chem.
Soc. 1994, 116 (2), 799–800; (l) Mapelli, C.; Newton, M.G.;
Ringold, C.E.; Stammer, C.H. Cyclopropane amino acid ester
dipeptide sweeteners. Int. J. Peptide Protein Res. 1987, 30 (4),
498–510.
5. For some selected recent examples about the synthesis of
2-substituted or 2,2-disubstituted ACCs, see: (a) Abellan, T.;
Mancheno, B.; Najera, C.; Sansano, J.M. Asymmetric synthesis of
a-amino acids from a,b-(Z)-didehydroamino acid derivatives with
1,2,3,6-tetra-hydropyrazin-2-one structure. Tetrahedron 2001,
57 (30), 6627–6640; (b) Clerici, F.; Gelmi, M.L.; Pocar, D.; Pilati,
T. Masked constrained cysteines: diastereoselective and enantio-
selective synthesis of 1-amino-2-mercaptocyclo-propanecarboxylic
acid derivatives. Tetrahedron: Asymmetry 2001, 12 (19), 2663–
2669; (c) Salgado, A.; Huybrechts, T.; Eeckhaut, A.; Van der
Eycken, J.; Szakonyi, Z.; Fulop, F.; Tkachev, A.; De Kimpe, N.
Synthesis of (1S)-1-amino-2,2-dimethylcyclopropane-1-carboxylic
acid via PLE mediated hydrolysis of bis(2,2,2-trifluoroethyl)-
2,2-dimethylcyclopropane-1,1-dicarboxylate. Tetrahedron 2001,
57 (14), 2781–2786; (d) Debache, A.; Collet, S.; Bauchat, P.;
Danion, D.; Euzenat, L.; Hercouet, A.; Carboni, B. Belokon’s
Ni(II) complex as a chiral masked glycine for the diastereoselective
synthesis of 2-substituted 1-aminocyclo-propane carboxylic acids.
Tetrahedron: Asymmetry 2001, 12 (5), 761–764; (e) Racouchot, S.;
Ollivier, J.; Salaun, J. Titanium-mediated diastereoselective form-
ation of (Z)-1-(1-alkenyl)-2-substituted-cyclopropyl esters efficient
precursors of (Z)-2,3-methanoamino acids. Synlett 2000,
12, 1729–1732; (f ) Abellan, T.; Chinchilla, R.; Galindo, N.; Najera,
C.; Sansano, J.M. New oxazinone and pyrazinone derivatives as
chiral reagents for the asymmetric synthesis of a-amino acids.
J. Heterocyclic Chem. 2000, 37 (3), 467–479; (g) Katagiri, T.;
Irie, M.; Minoru, U.K. Syntheses of optically active trifluoro-
norcoronamic acids. Org. Lett. 2000, 2 (16), 2423–2425; (h) Donkor,
I.O.; Zheng, X.; Han, J.; Miller, D.D. Asymmetric synthesis of

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1-Aminocyclopropanecarboxylic Acid
2883
2,3-methanoleucine stereoisomers from common intermediates.
Chirality 2000, 12, 551–557; (i) Chinchilla, R.; Falvello, L.R.;
Galindo, N.; Najera, C. New chiral didehydroamino acid derivatives
from a cyclic glycine template with3,6-dihydro-2H-1,4-oxazin-2-one
structure: applications to the asymmetric synthesis of nonproteino-
genic a-amino acids. J. Org. Chem. 2000, 65 (10), 3034–3041;
( j) Kordes, M.; Winsel, H.; de Meijere, A. Cyclopropyl building
blocks for organic synthesis 58; A new short access to amino acids
incorporating an aminocyclopropyl moiety from N,N-dibenzyl-
carboxamides. Eur. J. Org. Chem. 2000, 18, 3235–3245;
(k) Kozyrkov, Y.; Pukin, A.; Kulinkovich, O.; Ollivier, J.; Salaun,
J. A convenient approachto substituted 1-(1-alkenyl)cyclopropanols:
a new preparation of 2,3-methano amino acids. Tetrahedron Lett.
2000, 41 (33), 6399–6402; (l) Dorizon, P.; Su, G.; Ludvig, G.;
Nikitina, L.; Paugam, R.; Ollivier, J.; Salaun, J. Stereoselective
synthesis of highly functionalized cyclopropanes. Application to the
asymmetric synthesis of (1S,2S)-2,3-methanoamino acids. J. Org.
Chem. 1999, 64 (13), 4712–4724.
6. (a) Jimenez, A.I.; Lopez, P.; Laureano, O.; Cativiela, C. Facile
synthesis and highly efficient resolution of a constrained cyclo-
propane analogue of phenylalanine. Tetrahedron 2001, 57 (28),
6019–6026; (b) Anisimova, N.A.; Deiko, L.I.; Berkova, G.A.
Synthesis of 1-aminocyclopropane-1,2-dicarboxylic acid derivatives.
Russ. J. Org. Chem. 1999, 35, 155–156; (c) Koskinen, A.M.P.;
Munoz, L. Intramolecular cyclopropanation: stereospecific synthesis
of (E)- and (Z)-1-amino-cyclopropane-1-carboxylic acids. J. Org.
Chem. 1993, 58 (4), 879–886; (d) Lalitha, N.; Bhalerao, U.T.;
Iyengar, D.S. Stereospecific synthesis of gem-diphenylcyclopro-
panecarboxamides: aminolysis of spiro cyclopropano lactones by
acetonitrile and triethylamine. J. Org. Chem. 1992, 57 (24),
6684–6686; (e) Zhu, Y.F.; Yamazaki, T.; Tsang, J.W.; Lok, S.;
Goodman, M. Synthesis and taste properties of L-aspartyl-
methylated 1-aminocyclopropanecarboxylic acid methyl esters.
J. Org. Chem. 1992, 57 (4), 1074–1081. (f ) Lalitha, N.; Iyengar,
D.S.; Bhalerao, U.T. Cyclopropanation of 2-ylidene-oxazol-5-one
with diphenyldiazomethane. Stereospecific synthesis of novel
gem-diphenylcyclopropyl amino acid derivatives. J. Org. Chem.
1989, 54 (7), 1771–1773; (g) Schollkopf, U.; Hupfeld, B.; Gull, R.
Angew. Chem. Int. Ed. Engl. Simple synthesis of 1-aminocyclo-
propanecarboxylic acids from tert-butyl isocyanoacetate and
epoxides. Synthesis of 5,6-dihydro-4-H-1,3-oxazine-4-carboxylic
acid esters. 1986, 25 (8), 754–755.

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©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2884
Su et al.
7. Buck, J.S.; Ide, W.S. Organic Synthesis; Blatt, A.H., Ed.; Wiley:
New York, 1943; Collect. Vol. II, 55–57.
8. Overberger, C.G.; Anselme, J.-P. Azo compounds. XLIII. Five-
membered cyclic azo compounds. Their stereospecific decom-
position. J. Am. Chem. Soc. 1964, 86 (4), 658–660.
9. (a) Arai, S.; Nakayama, K.; Hatano, K.; Shioiri, T. Stereoselective
synthesis of cyclopropane rings under phase-transfer-catalyzed
conditions. J. Org. Chem. 1998, 63 (25), 9572–9575;
(b) Overberger, C.G.; Anselme, J.-P.; Hall, J.R. Azo compounds.
XLII. Dipole moments and spectral data. J. Am. Chem. Soc.
1963, 85 (18), 2752–2754; (c) Overberger, C.G.; Anselme, J.-P. A
five-membered ring azo compound. A stereoselective decom-
position. J. Am. Chem. Soc. 1962, 84 (5), 869–870.
10. Silverstein, R.M.; Webster, F.X. Spectrometric Identification of
Organic Compounds, 6thEd.; Jonh Wiley & Sons, Inc.: New
York, 1998; Chapter 4, 212.
11. (a) Vogel, A.I. Vogel’s Textbook of Practical Organic Chemistry, 5th
Ed.; Longman: London, 1989; 1156; (b) Albert, A.; Boyer, R. J.
Chem. Soc. 1949, 1148–1152; (c) Farnum, D.G. Preparation of
aryldiazoalkanes by the Bamford-Stevens reaction. J. Org. Chem.
1963, 28 (3), 870–872.
12. Wulfman, D.S.; Yousefian, S.; White, J.M. Metal salt-catalyzed
carbenoids. XIX. The synthesis of aryldiazomethanes. Synth.
Commun. 1988, 18 (18), 2349–2352.
Received in Japan November 20, 2002

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