Stereoselective synthesis of 1-aminocyclopropanecarboxylic acid derivatives via ylide cyclopropanation of dehydroamino acid derivatives

Article abstract of DOI:10.1002/cjoc.201190202

1-Aminocyclopropanecarboxylic acid derivatives are synthesized from readily available dehydroamino acid derivatives via sulfur ylide. A range of different ylides are employed and the corresponding aminocyclopropanes are afforded with reasonable diastereoselection in good yields.

Full text of DOI:10.1002/cjoc.201190202

FULL PAPER
Stereoselective Synthesis of 1-Aminocyclopropanecarboxylic
Acid Derivatives via Ylide Cyclopropanation of Dehydroamino
Acid Derivatives
Zhou, Ruia(周锐)
Deng, Xianmingb(邓贤明)
Zheng, Juncheng*,b(郑君成)
Shen, Qi*,a(沈琪)
Sun, Xiulib(孙秀丽)
Tang, Yonga,b(唐勇)
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Ma-
terials Science, Soochow University, Suzhou, Jiangsu 215123, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 345 Lingling Lu,
Shanghai 200032, China
1-Aminocyclopropanecarboxylic acid derivatives are synthesized from readily available dehydroamino acid de-
rivatives via sulfur ylide. A range of different ylides are employed and the corresponding aminocyclopropanes are
afforded with reasonable diastereoselection in good yields.
Keywords amino acids, enantioselectivity, annulation, ylides, stereoselective synthesis
1-Aminocyclopropanecarboxylic acids (ACCs) have
received considerable attention because of their bio-
logical activity, their potential applications in conforma-
tionally restricted peptides, as well as biosynthetic and
mechanistic probes.1,2 Although ylides proved to be ef-
ficient reagents for preparing enantioselective and di-
astereoselective construction of the cyclopropanes,3,4 the
synthesis of optical 1-aminocyclopropanecarboxylic
acid derivatives via chiral ylide approach have not been
studied systematically.5 Of the synthetic methods de-
veloped for 1-aminocyclopropanecarboxylic acids,5a,6
the reaction between ylide and dehydroamino acid de-
rivatives proved to be a very competitive way, espe-
cially when considering stereoselection.7 In this paper,
we wish to report our efforts on the synthesis of
1-aminocyclopropanecarboxylic acid derivatives via
sulfur ylides.
Our investigation was commenced with the cyclo-
propanation between stabilized sulfonium ylide and eas-
ily available dehydroamino acid derivatives. Fortunately,
we found that amide-stabilized sulfonium salt 1a, after
deprotonation by K2CO3 in CH3CN, could react with
dehydroamino acid derivative 2 to afford cyclopropane
amino acid ester 3a with excellent diastereoselectivity
(＞ 99/1) in 98% yield (Table 1, Entry 1). Under the
same reaction conditions, a range of other stabilized
sulfonium salt was then explored. As shown in Table 1,
less steric amide did not deteriorate the cyclopropana-
tion (Entries 2 and 3). In addition, ester stabilized ylide
was found to be suitable to provide desired amino acid
derivative in excellent yield and unique diastereoselec-
tion (Entries 4 and 5). Although a slight decrease of d.r.
was observed when ketone stabilized sulfonium ylide
was employed, product 3f was obtained in 96% yield
and 30/1 d.r.
Table 1 Cyclopropanation of stable sulfonium ylide with dehy-
droamino acid derivative 2a
Entry
R1
Yieldb/%
d.r.c
＞99/1
＞99/1
＞99/1
＞99/1
＞99/1
30/1
1
2
3
4
5
6
CONiPr2 (1a)
CONEt2 (1b)
CONMe2 (1c)
98
96
95
95
92
96
t
CO2 Bu (1d)
CO2Et (1e)
COPh (1f)
a To a stirred solution of salt 1 (0.3 mmol) and substrate 2 (49 mg,
0.2 mmol) in CH3CN (2 mL) was added K2CO3 (62 mg, 0.3
b
mmol) in one portion at ambient temperature. Isolated yield;
c Determined by 1H NMR.
*
E-mail: tangy@sioc.ac.cn.; Fax: 0086-021-54925078.
Received December 27, 2010; revised January 19, 2011 accepted January 28, 2011.
Project supported by the National Natural Science Foundation of China (Nos. 20821002, 20932008), the Major State Basic Research Development
Program (No. 2009CB825300), and the Science and Technology Commission of Shanghai Municipality (No. Y0D00512E0).
Chin. J. Chem. 2011, 29, 995— 1000
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Zhou et al.
FULL PAPER
The cyclopropanation reaction was extended to aryl
substituted semi-stabilized sulfonium ylide. A brief op-
timization revealed that the combination of Cs2CO3 and
DME was the best, and representative results were
summarized in Table 2. Aryl substituents of sulfonium
salts with diverse electronic and steric properties were
examined, and all worked well to afford products in
yields ranging from 67% to 95% with good to excellent
diastereoselection. For example, salt 1g proceeded this
reaction well to afford desired amino acid derivative in
95% yield and 9/1 d.r. Introducing strong electron-do-
nating or electron-withdrawing group on aryl substituent
led to decreased yield (Entries 1 vs. 5 and 6). Obvious
steric effect could be easily identified in Table 2, and
much better d.r. was delivered with increased hindrance
on orth-position of aryl substituent (Entries 2, 3).
cyclopropane amino acid with 71% de and 75% ee.7
Guant et al. also documented the asymmetric cyclopro-
panation of dehydroamino acid derivatives using chiral
ammonium ylide in good yield with 97% ee.4g
Table 3 Cyclopropanation of allylic semi-stabilized sulfonium
salt with dehydroamino acid derivative 2a
Table 2 Cyclopropanation of aryl substituted sulfonium ylide
with dehydroamino acid derivative 2a
Entry
Salt
1m
1n
Condition
Yieldb/%
d.r.c
3.9/1
3.5/1
9.3/1
1
2
3
A
B
A
86
72
79
1o
a Condition A: To a stirred solution of salt 1 (0.3 mmol) and sub-
strate 2 (49 mg, 0.2 mmol) in CH2Cl2 (2 mL) was added t-BuOK
(34 mg, 0.3 mmol) in one portion at －20 ℃. Condition B : To a
stirred solution of salt 1 (0.3 mmol) and substrate 2 (49 mg, 0.2
mmol) in DME (2 mL) was added Cs2CO3 (98 mg, 0.3 mmol) in
Entry
R2
C6H5 (1g)
Yieldb/%
d.r.c
b
c
one portion at ambient conditions. Isolated yield; Determined
by 1H NMR.
1
2
3
4
5
6
95
95
86
90
67
71
9/1
o-CH3C6H4 (1h)
2,6-Cl2C6H3 (1i)
m-TBSOC6H4 (1j)
p-CH3OC6H4 (1k)
p-NO2C6H4 (1l)
＞99/1
＞99/1
12/1
We initiated our study by testing reaction of cam-
phor-derived sulfonium salts with dehydroamino acid
derivatives. Under the optimal conditions, we found that
amide substituted sulfonium salt 4a, after deprotonation
by t-BuOK, could react with 2 in CH3CN at －40 ℃
to afford cyclopropane amino acid ester 3a with excel-
lent diastereoselectivity (＞99/1) and good enantiose-
lectivity (92% ee) in 95% overall yield (Table 4, Entry
1).
9/1
＞99/1
a To a stirred solution of salt 1 (0.3 mmol) and substrate 2 (49 mg,
0.2 mmol) in DME (2 mL) was added Cs2CO3 (98 mg, 0.3 mmol)
in one portion at ambient conditions. Isolated yield; Deter-
mined by 1H NMR.
b
c
Further studies showed that the yield and enantiose-
lectivity of the cyclopropanation process were signifi-
cantly influenced by the substituents of chiral sulfonium
salt. When the steric hindrance of the amide substituted
sulfonium salts decreased, the ee of corresponding
products dropped to moderate (Table 4, Entries 1—3).
However, the ester substituted sulfonium salt showed
contradicting behavior, where better ee was achieved
with salt 4e compared with bulky salt 4d (Table 4, En-
tries 4, 5).
Further studies showed that vinylcyclopropanyl
amino acid derivatives could also be synthesized via this
route. As listed in Table 3, the cyclopropanation of
allylic sulfonium salt 1m with substrate 2 proceeded
well to give desired product in 86% yield and 3.9/1 di-
astereoselective ratio (Entry 1). Similar to the steric
effect exhibited in aryl substituted sulfonium salts
(Entries 1—3, Table 2), the introduction of bulky group
on allyl group of sulfonium salts also led to an improved
distereoselection.
The reaction was useful in the synthesis of cyclo-
propane amino aicd derivatives.8 As shown in Scheme 1,
the phthaloyl group of 3g could be easily removed at
room temperature in the presence of hydrazine hydrate,
furnishing 5-Z in 78% yield; Subsequent treatment of
Encouraged by above results, we decided to investi-
gate the enantioselective synthesis of ACCs derivatives
via chiral sulfonium ylide route. To the best of our
knowledge, only two relevant examples have been
documented so far. Aggarwal et al. reported the reaction
of a chiral silylated allylic sulfur ylide which was gen-
erated from diazo compound in situ with
α-aminoacrylate to afford the desired vinyl substituted
5-Z with 4 mol•L－ HCl under the reflux temperature
1
for 24 h provide aminoacid 6-Z in 58% yield.
996
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Chin. J. Chem. 2011, 29, 995— 1000

Stereoselective Synthesis of 1-Aminocyclopropanecarboxylic Acid Derivatives
Table 4 Asymmetric reaction of sulfonium salt 4 with dehy-
droamino acid derivatives 2a
Experimental section
All reactions were carried out under N2 unless other-
wise noted. All solvents were purified according to
standard methods prior to use. H NMR and 13C NMR
1
spectra were recorded in chloroform-d3, d-DMSO or
CD3OD on a VARIAN Mercury 300 MHz or 400 MHz.
All IR (Perkin-Elmer 983, BioRad FTS-185 or
Bruker-Tensor 27), MSLR and MSHR (HP5989A and
Premier CAB088) data were obtained by the analytical
center of Shanghai Institute of Organic Chemistry.
General procedure for synthesis of racemic
1-aminocyclopropanecarboxylic acids (3a— 3o)
To a stirred mixture of sulfonium salt 1 (0.3 mmol)
and subsrate 2 (0.2 mmol) in solvent (2 mL) was added
base (0.3 mmol) at desired temperature in one portion.
The resulting mixture was continuing stirred at the same
temperature until the substrate disappeared (monitored
by TLC). The reaction mixture was passed through a
short pad of silica gel, and eluted with ethyl acetate. The
filtrate was concentrated and the residue was purified by
flash column chromatography to afford cyclopropanes.
Entry
R4
Yieldb/%
d.r.c
eed/%
92
1
2
3
4
5
NiPr2 (4a)
NEt2 (4b)
NMe2 (4c)
OtBu (4d)
OEt (4e)
95
88
75
44
65
＞99/1
＞99/1
＞99/1
＞99/1
＞99/1
82
76
10
42
General procedure for synthesis of chiral
1-aminocyclopropanecarboxylic acids (3a— 3e)
a
To a stirred solution of salt 4 (0.25 mmol) in CH3CN (3 mL)
was added t-BuOK (28 mg, 0.25 mmol) at －40 ℃, substrate 2
To a stirred solution of sulfonium salt 4 (0.25 mmol)
in CH3CN (2 mL) was added t-BuOK (0.25 mmol) at
－40 ℃. The resulting mixture was stirred at －40 ℃
for 45 min, and then 2 (0.2 mmol) was added to the ob-
tained solution. The resulting mixture was stirred at
－40 ℃ until the substrate disappeared (monitored by
TLC). The reaction mixture was passed through a short
pad of silica gel, and eluted with ethyl acetate. The fil-
trate was concentrated and the residue was purified by
flash column chromatography to afford cyclopropanes.
(49 mg, 0.2mmol) was added after 45 min. b Isolated yield; De-
c
termined by 1H NMR. d Determined by chiral HPLC.
Scheme 1 Synthesis of 2-arylcyclopropane amino acid
Characterization data of all new synthesized com-
pounds
Dimethyl (diisopropylcarbamoylmethyl)sulfonium
1
bromide (1a) White solid, 75% yield; H NMR
(CDCl3/TMS, 400 MHz) δ: 5.61 (s, 2H), 4.01—3.92 (m,
1H), 3.52—3.43 (m, 1H), 3.37 (s, 6H), 1.36 (d, J＝9.2
Hz, 6H), 1.29 (d, J ＝ 8.4 Hz, 6H); 13C NMR
(CDCl3/TMS, 100 MHz) δ: 161.66, 51.21, 50.72, 46.70,
25.17, 20.84, 20.18; IR (neat) ν: 1627 (s), 1043 (m), 788
Conclusions
－1
(m) cm ; MS (ESI) m/z: 204.0; HRMS (ESI) calcd for
C10H22NOS＋ 204.1417, found 204.1423.
In summary, the cyclopropanation reaction between
sulfonium salts and dehydroamino acid derivatives was
studied, and 1-aminocyclopropanecarboxylic acid de-
rivatives were prepared in moderate to excellent ylieds.
High diastereoselectivities and enantioselectivities could
be obtained under convenient conditions with the use of
optical camphor sulfonium salts. The synthetic proce-
dure is simple, and all starting materials are easily
available. Further studies on the applications of this re-
action in organic synthesis are underway in our labora-
tory.
2-Methyl-benzyl-dimethylsulfonium bromide (1h)
1
White solid, 60% yield; H NMR (CDCl3/TMS, 300
MHz) δ: 7.32—7.16 (m, 4H), 4.52 (s, 2H), 2.42 (s, 3H),
2.12 (s, 6H); 13C NMR (CDCl3/TMS, 100 MHz) δ:
138.26, 132.18, 131.26, 130.15, 126.69, 125.75, 44.65,
24.－57, 19.92; IR (neat) ν: 1006 (m), 780 (s), 740 (m)
1
cm ; MS (ESI) m/z: 167.1; HRMS (ESI) calcd for
C10H15S＋ 167.0889, found 167.0887. Anal. calcd for
C10H15BrS: C 48.59, H 6.12; found C 48.14, H 6.14.
2,6-Dichloro-benzyl-dimethylsulfonium bromide
1
(1i) White solid, 65% yield; H NMR (d-DMSO, 400
Chin. J. Chem. 2011, 29, 995— 1000
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997

Zhou et al.
FULL PAPER
MHz) δ: 7.66—7.64 (m, 2H), 7.56—7.52 (m, 1H), 4.94
(s, 2H), 3.09 (s, 6H); 13C NMR (CD3OD, 100 MHz) δ:
137.94, 133.71, 130.60, 126.38,－44.26, 26.15; IR (neat)
169.15, 167.89, 167.37, 166.34, 134.08, 133.93, 131.96,
131.05, 123.51, 123.13, 62.26, 37.62, 37.05, 35.89,
26.18, 19.64, 13.90; IR (thin film)－ν: 2933 (m), 1783
330 (M , 19.80), 104 (100); HRMS (EI) calcd for
C17H18N2O5 330.1216, found 330.1218.
2-tert-Butyl-1-ethyl 1-(1,3-dioxoisoindolin-2-yl)-
cyclopropane-1,2-dicarboxylate (3d) Colorless vis-
cous liquid, 95% yield; [α]2D0 －7.5 (c＝1.00, CHCl3);
1H NMR (CDCl3/TMS, 400 MHz) δ: 7.85—7.69 (m,
4H), 4.12 (q, J＝6.8 Hz, 2H), 2.80 (t, J＝8.8 Hz, 1H),
2.12—2.08 (m, 2H), 1.31 (s, 9H), 1.16 (t, J＝6.8 Hz,
3H); 13C NMR (CDCl3/TMS, 100 MHz) δ: 168.40,
167.81, 167.54, 167.42, 134.17, 134.10, 131.92, 131.20,
123.53, 123.11, 81.77, 62.34, 37.15, 28.45, 27.61, 20.24,
13.89; IR (thin film) ν: 2980 (m), 2934 (w), 1784 (m),
1
1
ν: 1430 (s), 782 (s), 766 (m) cm ; MS (ESI) m/z: 220.9;
(w), 172＋5 (s), 1649 (m), 718 (m) cm ; MS (EI) m/z (%):
HRMS (ESI) calcd for C9H11Cl2S＋ 220.9953, found
220.9959. Anal. calcd for C9H10BrCl2S: C 35.79, H 3.67;
found C 35.61, H 3.62.
3-((tert-Butyldimethylsilyl)oxy)-benzyl-dimethyl-
1
sulfonium bromide (1j) White solid, 80% yield; H
NMR (CDCl3/TMS, 300 MHz) δ: 7.31—7.27 (m, 1H),
7.19—7.16 (m, 1H), 6.97—6.90 (m, 2H), 5.21 (s, 2H),
3.22 (s, 6H), 0.98 (s, 9H), 0.218 (s, 3H), 0.217 (s, 3H);
13C NMR (CDCl3/TMS, 75 MHz) δ: 155.99, 130.14,
128.06, 123.67, 121.97, 121.34, 45.50, 25.25, 24.10,
17.－77, －4.68; IR (neat) ν: 1291 (w), 841 (s), 782 (m)
1
cm ; MS (ESI) m/z: 283.1; HRMS (ESI) calcd for
C15H27OSiS＋ 283.1546, found 283.1548. Anal. calcd
for C15H27BrOSSi: C 49.57, H 7.49; found C 49.34, H
7.64.
1728 (s), 721 (m) cm ; MS (ESI) m/z (%): 382.4 (M
＋Na); HRMS (ESI) calcd for C19H21NO6Na (M＋Na):
382.1267, found 382.1261.
＋
－1
Ethyl 2-(diisopropylcarbamoyl)-1-(1,3-dioxoiso-
indolin-2-yl)cyclopropanecarboxylate (3a) Colour-
less viscous liquid, 98% yield; [α]2D0 －43.3 (c＝1.00,
Diethyl 1-(1,3-dioxoisoindolin-2-yl)cyclopropane-
1,2-dicarboxylate (3e) Colorless viscous liquid, 92%
yield; [α]2D0 － 28.5 (c ＝ 1.00, CHCl3); 1H NMR
(CDCl3/TMS, 300 MHz) δ: 7.87—7.71 (m, 4H), 4.18—
4.03 (m, 4H), 2.89 (t, J＝8.7 Hz, 1H), 2.17 (d, J＝8.7
Hz, 2H), 1.24—1.15 (m, 6H); 13C NMR (CDCl3/TMS,
75 MHz) δ: 168.54, 168.12, 167.71, 167.38, 134.17,
134.08, 131.72, 131.00, 123.42, 123.29, 62.36, 61.29,
37.20, 27.20, 20.23, 13.80, 13.78.
1
CHCl3); H NMR (CDCl3/TMS, 300 MHz) δ: 7.87—
7.69 (m, 4H), 4.43—4.30 (m, 1H), 4.19 (q, J＝7.2 Hz,
2H), 3.62—3.52 (m, 1H), 3.03 (t, J＝7.8 Hz, 1H), 2.51
—2.47 (m, 1H), 2.02—1.97 (m, 1H), 1.44 (d, J＝6.6 Hz,
3H), 1.31 (d, J＝6.6 Hz, 3H), 1.25 (d, J＝6.6 Hz, 3H),
1.19 (t, J＝7.2 Hz, 3H), 1.10 (d, J＝6.3 Hz, 3H); 13C
NMR (CDCl3/TMS, 100 MHz) δ: 169.18, 167.33,
167.03, 164.41, 133.68, 131.83, 130.92, 123.29, 122.44,
61.91, 48.37, 45.55, 37.05, 27.33, 21.27, 20.16, 19.89,
19.63, 19.37, 13.69; IR (thin film)－ν: 2969 (m), 1783
Ethyl 2-benzoyl-1-(1,3-dioxoisoindolin-2-yl)cyclo-
propanecarboxylate (3f) Colorless viscous liquid,
96% yield; 1H NMR (CDCl3/TMS, 300 MHz) δ: 8.02—
7.47 (m, 9H), 4.23 (q, J＝6.9 Hz, 2H), 3.90 (t, J＝7.8
Hz, 1H), 2.54 (dd, J＝5.1, 7.5 Hz, 1H), 2.25 (dd, J＝5.4,
9.3 Hz, 1H), 1.21 (t, J＝6.9 Hz, 3H); 13C NMR
(CDCl3/TMS, 75 MHz) δ: 193.67, 168.58, 167.65,
167.45, 137.52, 134.15, 134.05, 133.06, 131.74, 130.93,
128.40, 128.31, 123.46, 123.36, 62.52, 39.92, 30.09,
21.04, 13.90; IR－(thin film) ν: 2925 (m), 1781 (w＋), 1726
1
(w), 1727 (s), 1634 (m), 722 (m) cm ; MS (EI) m/z (%):
386 (M＋ , 13.07), 43 (100); HRMS (EI) calcd for
C21H26N2O5 386.1842, found 386.1848.
Ethyl
2-(diethylcarbamoyl)-1-(1,3-dioxoisoin-
dolin-2-yl)cyclopropanecarboxylate (3b) Colorless
viscous liquid, 96% yield; [α]2D0 － 63.7 (c ＝ 1.00,
1
1
CHCl3); H NMR (CDCl3/TMS, 400 MHz) δ: 7.87—
(s), 726 (w) cm ; MS (ESI) m/z (%): 364.5 (M ＋H);
7.70 (m, 4H), 4.22—4.18 (m, 2H), 3.88—3.82 (m, 1H),
3.53—3.48 (m, 1H), 3.37—3.34 (m, 1H), 3.00—2.96
(m, 2H), 2.51—2.47 (m, 1H), 2.05—2.02 (m, 1H), 1.31
(t, J＝7.6 Hz, 3H), 1.19 (t, J＝7.2 Hz, 3H), 0.94 (t, J＝
6.8 Hz, 3H); 13C NMR (CDCl3/TMS, 100 MHz) δ:
169.21, 167.70, 167.18, 165.18, 133.98, 133.84, 132.00,
131.03, 123.48, 122.78, 62.14, 42.22, 40.85, 37.14,
26.40, 19.72, 14.30, 13.86, 11.98; IR (thin film) ν: 2978
HRMS (ESI) calcd for C21H18NO5 (M＋H) 364.1185,
found 364.1180.
Ethyl 1-(1,3-dioxoisoindolin-2-yl)-2-phenylcyclo-
propanecarboxylate (3g) Colorless viscous liquid,
95% yield; 1H NMR (CDCl3/TMS, 400 MHz) δ: 7.93—
7.61 (m, 4.37H), 7.37—7.33 (m, 0.28H), 7.17—7.11 (m,
4.37H), 4.27—4.13 (m, 1.80H), 3.82—3.77 (m, 0.21H),
3.38 (t, J＝9.2 Hz, 0.88H), 3.18 (t, J＝9.6 Hz, 0.12H),
2.53—2.49 (m, 0.12H), 2.45—2.41 (m, 0.88H), 2.27 (dd,
J＝10, 6.8 Hz, 0.88H), 1.90 (dd, J＝10, 6.4 Hz, 0.12H),
1.21 (t, J＝7.2 Hz, 2.68H), 0.76 (t, J＝7.2 Hz, 0.32H);
13C NMR (CDCl3/TMS, 100 MHz) δ: 169.71, 168.50,
166.76, 134.24, 133.97, 131.76, 130.71, 127.87, 127.80,
127.03, 123.23, 61.94, 39.05, 31.52, 18.99, 13.99; IR
(thi－n film) ν: 2929 (m), 1782 (w), 1＋724 (s), 723 (w)
－1
(m), 1782 (w), 1726 (s), 1641 (m), 724 (m) cm ; MS
(EI) m/z (%): 358 (M＋, 49.87), 211 (100); HRMS (EI)
calcd for C19H22N2O5 358.1529, found 358.1522.
Ethyl 2-(dimethylcarbamoyl)-1-(1,3-dioxoisoindo-
lin-2-yl)cyclopropanecarboxylate (3c)
Colorless
viscous liquid, 95% yield; [α]2D0 － 47.6 (c ＝ 1.00,
1
CHCl3); H NMR (CDCl3/TMS, 400 MHz) δ: 7.82—
1
7.67 (m, 4H), 4.18—4.12 (m, 2H), 3.27 (s, 3H), 3.04
(dd, J＝8.8, 7.6 Hz, 1H), 2.83 (s, 3H), 2.43 (dd, J＝5.6,
7.6 Hz , 1H), 2.01 (dd, J＝5.2, 9.2 Hz, 1H), 1.60 (t, J＝
7.2 Hz, 3H); 13C NMR (CDCl3/TMS, 100 MHz) δ:
cm ; MS (ESI) m/z: 358.3 (M＋H ); HRMS (ESI)
calcd for C20H17NO4 (M ＋ Na) 358.1055, found
358.1050.
Ethyl 1-(1,3-dioxoisoindolin-2-yl)-2-o-tolylcyclo-
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Chin. J. Chem. 2011, 29, 995— 1000

Stereoselective Synthesis of 1-Aminocyclopropanecarboxylic Acid Derivatives
propanecarboxylate (3h) Colourless viscous liquid,
95% yield; 1H NMR (CDCl3/TMS, 400 MHz) δ: 7.83—
7.64 (m, 4H), 7.15 (d, J＝6.8 Hz, 1H), 7.01 (dt, J＝7.6
Hz, 1.2 Hz, 1H), 6.84 (t, J＝7.6 Hz, 1H), 6.62 (d, J＝
7.6 Hz 1H), 4.25—4.19 (m, 2H), 3.46—3.42 (m, 1H),
2.60—2.56 (m, 4H), 2.21 (dd, J＝12.5, 6.8 Hz 1H), 1.21
(t, J＝7.2 Hz, 3H); 13C NMR (CDCl3/TMS, 75 MHz) δ:
169.85, 168.42, 166.68, 139.60, 133.86, 131.86, 131.64,
130.58, 129.89, 126.89, 124.93, 123.74, 123.06, 61.80,
38.93, 28.87, 19.80, 17.97, 13.96; IR (thin film) ν: 2917
(ESI) m/z: 388.1 (M＋Na＋); HRMS (ESI) calcd for
C21H19NO5 (M＋Na＋) 388.1161, found 388.1155.
Ethyl 2-(4-nitrophenyl)-1-(1,3-dioxoisoindolin-2-
yl)cyclopropanecarboxylate (3l) Colourless viscous
1
liquid, 71% yield; H NMR (CDCl3/TMS, 300 MHz) δ:
8.04 (d, J＝8.7 Hz, 2H), 7.87—7.63 (m, 4H), 7.30 (d,
J＝8.4 Hz, 2H), 4.24—4.17 (m, 2H), 3.45 (t, J＝12 Hz,
1H), 2.48 (t, J＝11.2 Hz, 1H), 2.41—2.35 (m, 1H), 1.21
(t, J＝7.2 Hz, 3H); 13C NMR (CDCl3/TMS, 75 MHz) δ:
169.04, 168.31, 166.87, 146.87, 142.39, 134.41, 131.57,
130.47, 128.90, 128.62, 128.34, 123.54, 123.11, 62.39,
39.66, 30.73, 19.54, 13.97; IR (thin film) ν: 1715 (s),
－1
(m), 1717 (s), 717 (w) cm ; MS (ESI) m/z: 372.1
(M＋Na＋); HRMS (ESI) calcd for C21H19NO4 (M＋
Na＋) 372.1212, found 372.1206.
1522 (w), 709 (m) cm ; MS (ESI) m/z: 403.1 (M＋
－1
Ethyl
2-(2,6-dichlorophenyl)-1-(1,3-dioxoiso-
Na＋); HRMS (ESI) calcd for C20H16N2O6 (M＋Na＋)
indolin-2-yl)cyclopropanecarboxylate
(3i)
403.0906, found 403.0901.
Colourless viscous liquid, 86% yield; 1H NMR
(CDCl3/TMS, 400 MHz) δ: 7.73—7.67 (m, 4H), 7.16 (d,
J＝7.6 Hz, 2H), 7.02—6.97 (m, 2H), 4.24—4.18 (m,
2H), 3.82—3.74 (m, 2H), 2.32—2.39 (m, 1H), 1.20 (t,
J＝6.8 Hz, 3H); 13C NMR (CDCl3/TMS, 100 MHz) δ:
169.7, 167.5, 134.1, 131.4, 129.1, 129.0, 128.3, 123.3,
62.1, 37.7, 31.0, 21.2, 14.1; IR (thin film) ν: 1720 (s),
Ethyl
1-(1,3-dioxoisoindolin-2-yl)-2-vinylcyclo-
propanecarboxylate (3m) Colorless viscous liquid,
1
86% yield; H NMR (CDCl3/TMS, 300 MHz) δ:
7.87—7.85 (m, 2.01H), 7.76—7.73 (m, 2.10H), 6.00—
5.88 (m, 0.20H), 5.65—5.47 (m, 1.04H), 5.27 (d, J＝
10.2 Hz, 0.22H), 5.15 (d, J＝17.1 Hz, 0.88H), 5.03 (d,
J＝9.9 Hz, 1H), 4.21—4.05 (m, 2.17H), 2.78 (q, J＝8.4
Hz, 0.80H), 2.51—2.42 (m, 0.20H), 2.09—2.04 (m,
1.09H), 1.86—1.81 (m, 0.87H), 1.76—1.71 (m, 0.24H),
1.19—1.12 (m, 3.09H); 13C NMR (CDCl3/TMS, 100
MHz) δ: 169.8, 134.2, 132.7, 123.5, 119.1, 117.9, 61.9,
37.－7, 29.9 19.6, 14.0; IR (thin film) ν:＋1717 (s), 717 (s)
－1
＋
712 (m) cm ; MS (ESI) m/z: 426.0 (M＋Na ); HRMS
(ESI) calcd for C20H15Cl2NO4 (M＋Na＋ ) 426.0276,
found 426.0270.
Ethyl 2-(3-((tert-butyldimethylsilyl)oxy)phenyl)-
1-(1,3-dioxoisoindolin-2-yl)cyclopropane carboxylate
1
1
(3j) Colourless viscous liquid, 90% yield; H NMR
cm ; MS (ESI) m/z: 286.1 (M＋H ); HRMS (ESI)
(CDCl3/TMS, 300 MHz) δ: 7.92—7.61 (m, 4.05H),
7.18—7.13 (m, 0.26H), 7.00 (t, J＝7.8 Hz, 0.94H), 6.77
(d, J＝7.8 Hz, 1.01H), 6.58 (d, J＝7.8 Hz, 0.89H), 6.51
(s, 0.90H), 4.261—4.10 (m, 1.92H), 3.84—3.77 (m,
0.18H), 3.34—3.28 (m, 0.92H), 3.15—3.09 (m, 0.08H),
2.47—2.35 (m, 1.07H), 2.22 (dd, J＝9.6, 6.6 Hz, 0.94H),
1.84 (dd, J＝9.9, 6.0 Hz, 0.09H), 1.19 (t, J＝7.2 Hz,
2.75H), 0.99 (s, 0.83H), 0.84 (s, 8.07H), 0.23 (s, 0.21H),
0.22 (s, 0.23H), －0.00 (s, 2.39H), －0.069 (s, 2.33);
13C NMR (CDCl3/TMS, 75 MHz) δ: 169.8, 155.2, 135.8,
134.0, 134.0, 133.9, 128.9, 123.4, 121.7, 119.3, 118.9,
62.0, 39.1, 31.4, 25.5, 19.1, 18.0, 14.1, －4.63, －4.81;
calcd for C16H15NO4 (M ＋ Na ＋ ) 308.0899, found
308.0893.
Ethyl 1-(1,3-dioxoisoindolin-2-yl)-2-styrylcyclo-
propanecarboxylate (3n) Colorless viscous liquid,
72% yield; 1H NMR (CDCl3/TMS, 400 MHz) δ: 7.90—
7.69 (m, 4.39H), 7.41—7.29 (m, 1.58H), 7.23—7.13 (m,
3.84H), 6.67 (d, J＝16.0 Hz, 0.30H), 6.50 (d, J＝16.0
Hz, 0.69H), 6.37 (dd, J＝16.0, 8.4 Hz, 0.32H), 5.96 (dd,
J＝16.0, 7.2 Hz, 0.69H), 4.20—4.07 (m, 2.17H), 2.97—
2.91 (m, 0.69H), 2.64 (q, J＝9.2 Hz, 0.34H), 2.23—2.17
(m, 1.05H), 1.97—1.93 (m, 0.74H), 1.84 (dd, J＝9.6,
6.0 Hz, 0.33H); 13C NMR (CDCl3/TMS, 100 MHz) δ:
169.8, 136.7, 134.2, 131.7, 132.7, 128.4, 127.4, 126.2,
124.4, 123.5, 62.0, 38.0,－29.9, 20.2, 14.0; IR (thin film)
－1
IR (thin film) ν: 1722 (s), 1281 (m), 717 (m) cm ; MS
(ESI) m/z: 466.3 (M＋H＋); HRMS (ESI) calcd for
C26H31NO5 (M＋Na＋) 488.1869, found 488.1864.
Ethyl 2-(4-methoxyphenyl)-1-(1,3-dioxoisoindo-
1
ν: 1724 (s), 722 (m) cm ; MS (ESI) m/z: 384.3 (M＋
Na＋); HRMS (ESI) calcd for C22H19NO4 (M＋H＋)
lin-2-yl)cyclopropanecarboxylate (3k)
Colourless
362.1392, found 362.1387.
1
viscous liquid, 67% yield; H NMR (CDCl3/TMS, 400
MHz) δ: 8.03—7.61 (m, 4.32H), 7.51 (d, J＝8.8 Hz,
0.21H), 7.43—7.39 (m, 0.09H), 7.18—7.14 (m, 0.10H),
7.03 (d, J＝8.8 Hz, 1.77H), 6.86 (d, J＝8.0 Hz, 0.27H),
6.67 (d, J＝8.4 Hz, 1.75H), 4.24—4.10 (m, 1.87H),
3.82—3.77 (m, 0.59H), 3.67 (s, 2.58H), 3.31 (t, J＝8.8
Hz, 0.90H), 3.10 (t, J＝9.2 Hz, 0.10H), 2.46—2.43 (m,
0.12H), 2.38—2.34 (m, 0.88H), 2.24—2.20 (m, 0.91H),
1.87—1.83 (m, 0.10H), 1.18 (t, J＝7.2 Hz, 2.82H), 0.81
(t, J＝8.8 Hz, 0.32H); 13C NMR (CDCl3/TMS, 100
MHz) δ: 169.9, 158.6, 134.2, 134.0, 130.7, 129.0, 126.2,
123.5, 123.3, 113.4, 61.9, 55.0, 38.9, 31.1, 19.0, 14.0;
Ethyl 2-((E)-2-(trimethylsilyl)vinyl)-1-(1,3-dioxo-
isoindolin-2-yl)cyclopropanecarboxylate
(3o)
Colorless viscous liquid, 79% yield; 1H NMR
(CDCl3/TMS, 400 MHz) δ: 7.87—7.84 (m, 2.06H),
7.75—7.72 (m, 2.11H), 6.21—6.06 (m, 0.17H), 5.90 (dd,
J＝18.8, 6.0 Hz, 0.92H), 5.60 (d, J＝18.8 Hz, 1H),
4.21—4.08 (m, 2.10H), 2.83 (q, J＝8.4 Hz, 0.92H),
2.54—2.47 (m, 0.08H), 2.13—2.03 (m, 1.03H), 2.00—
1.96 (m, 0.94H), 1.76—1.72 (m, 0.11H), 1.82 (t, J＝7.2
Hz, 3.15H), 0.09 (s, 0.78H), －0.2 (s, 8.31H); 13C NMR
(CDCl3/TMS, 100 MHz) δ: 169.58, 168.18, 167.56,
139.33, 134.07, 132.03, 131.69, 131.19, 123.29, 123.06,
61.74, 38.10, 31.48, 18.81, 13.95; IR (thin film) ν: 1720
－1
IR (thin film) ν: 1716 (s), 1284 (m), 717 (m) cm ; MS
Chin. J. Chem. 2011, 29, 995— 1000
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
999

Zhou et al.
FULL PAPER
＋
－1
11, 741.
For reviews, see:
(s), 717 (s) cm ; MS (ESI) m/z: 358.3 (M＋H＋);
3
HRMS (ESI) calcd for C19H23NO4Si (M ＋ Na
)
(a) Sun, X.-L.; Tang, Y. Acc. Chem. Res. 2008, 41, 937.
(b) McGarrigle, E. M.; Myers, E. L.; Illa, O.; Shaw, M. A.;
Riches, S. L.; Aggarwal, V. K. Chem. Rev. 2007, 107, 5841.
(c) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37,
611.
(d) Lebel, H.; Marcouxv, J. F.; Molinnaro, C.; Charatte, A.
B. Chem. Rev. 2003, 103, 977.
(e) Tang, Y.; Ye, S.; Huang, Z.-Z.; Huang, Y.-Z.
Heteroatom. Chem. 2002, 13, 463.
(f) Huang, Y.-Z.; Tang, Y.; Zhou, Z.-L. Tetrahedron 1998,
53, 1667.
(g) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997,
97, 2341.
380.1294, found 380.1288.
(R)-[2-(Diisopropylamino)-2-oxoethyl][(2R,3S,4R)-
3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]me-
thylsulfonium bromide (4a) White solide; [α]D20
1
＋92.3 (c＝1.00, CHCl3); H NMR (CDCl3/TMS, 300
MHz) δ: 5.71 (d, J＝6.9 Hz, 1H), 5.50 (d, J＝15.3 Hz,
1H), 5.17 (d, J＝15.6 Hz, 1H), 4.39 (d, J＝7.2 Hz, 1H),
4.16 (t, J＝7.2 Hz, 1H), 4.09—4.03 (m, 1H), 3.46—
3.37 (m, 1H), 3.11 (s, 3H), 2.01 (d, J＝4.8 Hz, 1H),
1.89—1.81 (m, 1H), 1.54—1.46 (m, 1H), 1.33 (dd, J＝
6.3, 2.1 Hz, 6H), 1.24 (t, J＝6.3 Hz, 6H), 1.15 (s, 3H),
0.92 (s, 3H), 0.81 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ: 161.4, 76.1, 62.0, 51.0, 50.1, 49.9, 47.2, 47.1, 46.2,
31.6, 27.5, 22.6, 20.8, 20.7, 20.5, 20.3, 20.0, 19.7, 11.1;
IR (neat) ν: 3185 (w), 2963 (w), 2920 (w), 1738 (w),
4
For recent examples, see:
(a) Riches, S. L.; Saha, C.; Filgueira, N. F.; Grange, E.;
McGarrigle, E. M.; Aggarwal, V. K. J. Am. Chem. Soc.
2010, 132, 7626.
(b) Zhu, B.-H.; Zhou, R.; Zheng, J.-C.; Deng, X.-M.; Sun,
X.-L.; Tang, Y. J. Org. Chem. 2010, 75, 3454.
(c) Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.;
Li, K.; Tang, Y.; Wu, Y.-D.; Da, L.-X. J. Am. Chem. Soc.
2006, 128, 9730.
(d) Kunz, R. K.; Macmillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 3240.
(e) Huang, K.; Huang, Z.-Z. Synlett 2005, 1621.
(f) Bremeyer, N.; Smith, S. C.; Ley, S. V.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2004, 43, 2681.
(g) Papageorgious, C. D.; Cubillo de Dios, M. A.; Ley, S.
V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 43, 4641.
(h) Papageorgious, C. D.; Ley, S. V.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2003, 42, 828.
(i) Ye, S.; Huang, Z.-Z.; Xia, C.-A.; Tang, Y.; Dai, L.-X. J.
Am. Chem. Soc. 2002, 124, 2432.
(a) Brackmann, F.; Meijere, A. D. Chem. Rev. 2007, 107,
4493.
(b) Wurz, R. P.; Charette, A. B. Org. Lett. 2003, 5, 2327.
(c) Abellan, T.; Mancheno, B.; Najera, C.; Sansano, J. M.
Tetrahedron 2001, 57, 6627.
(d) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Najera, C. J.
Org. Chem. 2000, 65, 3034.
(e) Czombos, J.; Aelterman, W.; Tkachev, A.; Martins, J. C.;
Tourwe, D.; Peter, A.; Toth, G.; Fulop, F.; DeKimpe, N. J.
Org. Chem. 2000, 65, 5469.
(f) Liu, W.-Q.; Carreaux, F.; Meudal, H.; Roques, B. P.;
GarbayJaureguiberry, C. Tetrahedron 1996, 52, 4411.
(g) Bruncko, M.; Crich, D. J. Org. Chem. 1994, 59, 4239.
(h) Williams, R. M.; Fegley, G. J. J. Org. Chem. 1993, 58,
6933.
－1
1630 (s), 1448 (w), ＋1124 (s), 800 (m) cm ; MS (ESI)
m/z: 342.3 (M－Br) . Anal. calcd for C19H36BrNO2: C
54.02, H 8.59, N 3.32; found C 53.8, H 8.64, N 2.96.
(R)-[2-(tert-Butoxy)-2-oxoethyl][(2R,3S,4R)-3-
hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]meth-
ylsulfonium bromide (4d) White solide; [α]2D0 ＋48.2
(c＝1.00, CHCl3); 1H NMR (CDCl3/TMS, 300 MHz) δ:
5.74 (d, J＝6.9 Hz, 1H), 5.28—5.10 (m, 3H), 4.23 (t,
J＝7.2 Hz, 1H), 3.18 (s, 3H), 2.03 (d, J＝4.8 Hz, 1H),
1.96—1.84 (m, 1H), 1.58—1.51 (m, 11H), 1.25—1.22
(m, 4H), 1.01 (s, 3H), 0.86 (s, 3H); 13C NMR
(d-DMSO/TMS, 100 MHz) δ: 163.1, 84.6, 76.7, 63.7,
49.9, 47.1, 46.3, 45.8, 31.5, 27.5, 27.4, 22.3, 20.9, 20.1,
11.2; IR (film) ν: 3186 (w), －2982 (w), 2881 (w), 1719
1
(m), 1147 (s), 844 (m) cm ; MS (ESI) m/z: 315.3
(M－Br)＋. Anal. calcd for C17H31BrO3S: C 51.35, H
8.10.
5
References
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For reviews, see:
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7
8
(E1012271 Cheng, F.; Lu, Z)
1000
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 995— 1000