Chemoenzymatic synthesis of enantiopure geminally dimethylated cyclopropane-based C2- and pseudo-C2-symmetric diamines

Article abstract of DOI:10.1016/j.tetasy.2006.10.030

Enantiopure (-)-(1S,3S)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxamide 2 and (+)-(1R,3R)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxylic acid 3 were easily obtained from a multigram scale biotransformation of racemic amide or nitrile in the presence of Rhodococcus erythropolis AJ270 whole cell catalyst under very mild conditions. Coupled with efficient and convenient chemical manipulations, comprising mainly of the Curtius rearrangement, oxidation, and reduction reactions, chiral C₂-symmetric (1S,2S)-3,3-dimethylcyclopropane-1,2-diamine 6 and ((1R,3R)-3-(aminomethyl)-2,2-dimethylcyclopropyl)methanamine 8 and pseudo-C₂-symmetric (1S,3S)-3-(aminomethyl)-2,2-dimethylcyclopropanamine 11 were prepared. These were also transformed into the corresponding chiral salen derivatives 12, 13, and 14, respectively, in almost quantitative yields.

Full text of DOI:10.1016/j.tetasy.2006.10.030

Tetrahedron: Asymmetry 17 (2006) 2775–2780
Chemoenzymatic synthesis of enantiopure geminally dimethylated
cyclopropane-based C2- and pseudo-C2-symmetric diamines
Guo-Qiang Feng, De-Xian Wang, Qi-Yu Zheng and Mei-Xiang Wang*
Beijing National Laboratory for Molecular Sciences, Laboratory of Chemical Biology, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China
Received 31 August 2006; accepted 10 October 2006
Abstract—Enantiopure (ꢀ)-(1S,3S)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxamide 2 and (+)-(1R,3R)-2,2-dimethyl-3-
(2-methylprop-1-enyl)cyclopropanecarboxylic acid 3 were easily obtained from a multigram scale biotransformation of racemic amide
or nitrile in the presence of Rhodococcus erythropolis AJ270 whole cell catalyst under very mild conditions. Coupled with efficient
and convenient chemical manipulations, comprising mainly of the Curtius rearrangement, oxidation, and reduction reactions, chiral
C2-symmetric (1S,2S)-3,3-dimethylcyclopropane-1,2-diamine 6 and ((1R,3R)-3-(aminomethyl)-2,2-dimethylcyclopropyl)methanamine 8
and pseudo-C2-symmetric (1S,3S)-3-(aminomethyl)-2,2-dimethylcyclopropanamine 11 were prepared. These were also transformed into
the corresponding chiral salen derivatives 12, 13, and 14, respectively, in almost quantitative yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
lytic benzylation of an alanine enolate. These reports5,6
have prompted us to disclose our synthetic study of
enantiomerically pure geminally dimethylated cyclo-
propane-based C2- and pseudo-C2-symmetric diamines.7
Chiral vicinal diamines and their derivatives have been
extensively used as ligands and catalysts in asymmetric
synthesis.1 For example, 1,2-diaminocyclohexane-derived
salen-metal complexes2 and thioureas3 are powerful Lewis
acid catalysts and organocatalysts, respectively, which cat-
alyze a variety of organic reactions. While the effort in
developing new structurally diverse chiral diamine catalysts
and, particularly, in modifying chiral 1,2-diaminocyclo-
hexane-based catalysts is still increasing,1,4 it is surprising
that the design of diamine catalysis based on a chiral cyclo-
propane structure has been overlooked until now. As the
smallest ring, cyclopropane provides a structural scaffold
of unique bond angles and well-defined configurations of
the substituents. Indeed, several cyclopropane-derived chi-
ral phosphorus and phosphorus/sulfur ligands have been
reported,5 and one phosphorus/sulfur ligand has shown
an excellent catalytic activity with a very good enantio-
selectivity in the Pd-catalyzed asymmetric allylic alkylation
of 1,3-diphenylpropenyl acetate with dimethyl malonate.
2. Results and discussion
We have previously found that, when catalyzed by Rhodo-
coccus erythropolis AJ270,8,9 a robust and a highly enantio-
selective nitrile hydratase/amidase containing whole cell
catalyst, racemic chrysanthemic nitriles, and amides under-
go effective hydrolysis to yield the corresponding optically
active chrysanthemic acids and amides.10 Having consid-
ered the polyfunctionality of chrysanthemic acid and amide
structures, we envisioned that these enantiomerically pure
cyclopropane derivatives are ideal chiral pool materials
for the construction of chiral C2- and pseudo-C2-symmetric
diamines.
To start our synthesis, we first investigated the preparative
biotransformations of nitrile and amide. After being
incubated with R. erythropolis AJ270 at room temperature,
racemic trans-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclo-
Very recently,
a
(ꢀ)-trans-1,2-diaminocyclopropane-
derived salen-Cu complex has been prepared,6 and no
asymmetric induction was observed, however, in the cata-
propanecarbonitrile
(1S,3S)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropane-
carboxamide and (1R,3R)-2,2-dimethyl-3-(2-methyl-
prop-1-enyl)cyclopropanecarboxylic acid 3 in a high yield
1 (10 mM) was converted into
*
2
Corresponding author. Tel.: +86 10 62565610; fax: +86 10 62564723;
e-mail: mxwang@iccas.ac.cn
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.030

2776
G.-Q. Feng et al. / Tetrahedron: Asymmetry 17 (2006) 2775–2780
with an excellent enantioselectivity (Scheme 1, entry 1 in
Table 1). However, the conversion became sluggish and
incomplete when the substrate concentration was doubled
(Table 1, entries 1–3). When racemic amide ( )-2 was em-
ployed as the substrate, the biocatalytic kinetic resolution
proceeded effectively to afford the desired enantiomerically
pure amide and acid products, even with the substrate con-
centration up to 40 mM (Table 1, entries 4–6). Therefore, a
multigram-scale biocatalytic preparation of pure (1S,3S)-
2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarbox-
upon treatment of 3 with KMnO4 under alkaline condi-
tions at an ambient temperature, a-hydroxy ketone 4 was
obtained as the sole oxidation product in a high yield. Fur-
ther oxidation of 4 using NaIO4 afforded diacid 5 in a good
yield. Following the Curtius rearrangement procedure,
diacid 5 was transformed into enantiomerically pure C2-
symmetric (1S,2S)-3,3-dimethylcyclopropane-1,2-diamine
dihydrochloride 6 in a yield of 68%. The synthesis of
((1R,3R)-3-(aminomethyl)-2,2-dimethylcyclopropyl)methan-
amine 8 was also very straightforward and efficient.
Thus, the reaction of 5 with ClCO2Et in the presence of
Et3N followed by treatment with ammonia produced a
good yield of dicarboxamide intermediate 7 that underwent
reduction with LiAlH4 to furnish ((1R,3R)-3-(amino-
methyl)-2,2-dimethylcyclopropyl)methanamine dihydro-
chloride 8 in a 70% yield (Scheme 2).
amide
2 and (1R,3R)-2,2-dimethyl-3-(2-methylprop-1-
enyl)cyclopropanecarboxylic acid 3 was readily achieved
in our laboratory via the biotransformation of racemic
amide ( )-2 in a parallel fashion.
To synthesize chiral C2-symmetric diamines 6 and 8, C2-
symmetric 3,3-dimethylcyclopropane-1,2-dicarboxylic acid
(1R,3R)-(ꢀ)-5 was chosen as a key intermediate. The syn-
thesis of (1R,3R)-(ꢀ)-5 was then attempted from the direct
oxidation reaction of (1R,3R)-2,2-dimethyl-3-(2-methyl-
prop-1-enyl)cyclopropanecarboxylic acid 3. Interestingly,
Taking the advantage of nitrile and amide biotransforma-
tions, the resulting biotransformation product (1S,3S)-
2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarbox-
amide 2 was directly applied in the synthesis of pseudo-C2-
i
+
EWG
CO2H
CONH2
( )-1 (EWG = CN)
( )-2 (EWG = CONH2)
(1
S
,3
S
)-(-)-amide 2
(1
R,3R
)-(+)-acid 3
Scheme 1. Preparative biotransformations of nitrile and amide. Reagents and conditions: (i) R. erythropolis AJ270, phosphate buffer (0.1 M, pH 7.0),
30 °C.
Table 1. Preparative biotransformations of ( )-1 and ( )-2
Entry
Substrate
Concentration (mM)
Timea (h)
(1S,3S)-2
Yieldb (%)
(1S,3S)-2
eec (%)
(1R,3R)-3
Yieldb (%)
(1R,3R)-3
eec (%)
1
2
3
4
5
6
(
(
(
(
(
(
)-1
)-1
)-1
)-2
)-2
)-2
10
20
20
10
20
40
82
58
95
73
90
48
68
64
48
46
48
>99
37
45
>99
>99
>99
49
27
32
51
50
49
>99
>99
>99
97
99
>99
162
a Racemic nitrile or amide was incubated with R. erythropolis AJ270 (2 g wet weight) in phosphate buffer (0.1 M, pH 7.0, 50 ml).
b Isolated yield.
c Determined by chiral HPLC analysis.
i
ii
CO2H
(1R,3R)-(+)-3
CO2H
R)-(-)-5
CO2H
HO2C
92%
HO
(1
89%
O
(1
R,2
R
,3
R
)-(-)-4
iv
68%
iii
87%
NH2·HCl
NH2·HCl
CONH2
CONH2
v
70%
NH2·HCl
NH2·HCl
(1
S,2S)-(+)-6
(1
R,3
R
)-(-)-8
(1R,2R)-(-)-7
Scheme 2. Synthesis of C2-symmetric diamines 6 and 8. Reagents and conditions: (i) KMnO4, aq KOH (10%), rt, 1 h. (ii) NaIO4, rt, 1 h. (iii) (a) ClCO2Et,
Et3N in acetone, 0 °C, 0.5 h; (b) NaN3, 1 h; (c) toluene, reflux 6 h; (d) HCl, reflux 2.5 h. (iv) (a) ClCO2Et, Et3N in acetone, 0 °C, 0.5 h; (b) concd NH3ÆH2O,
0 °C–rt, 2 h. (v) (a) LiAlH4, THF, under Ar, reflux 12 h; (b) 2 N hydrochloric acid.

G.-Q. Feng et al. / Tetrahedron: Asymmetry 17 (2006) 2775–2780
2777
NH2·HCl
i
ii
iii
CONH2
HO2C
(1
81%
94%
55%
NHCOPh
NHCOPh
NH2·HCl
11
(1S,3S)-(-)-
10
S,3S)-(-)-
2
)-(-)-
9
(1S,3S)-(-)-
(1
S
,3
S
Scheme 3. Synthesis of pseudo-C2-symmetric diamine 11. Reagents and conditions: (i) (a) LiAlH4, THF, under Ar, reflux 4 h; (b) PhCOCl, Et3N, 0 °C,
2 h. (ii) (a) O3, ꢀ5 °C; (b) 30% aq H2O2, CH3CO2H, 0 °C, 15 min, rt, 1.5 h. (iii) (a) ClCO2Et, Et3N in acetone, 0 °C, 0.5 h; (b) NaN3, 1 h; (c) toluene, reflux
3 h; (d) HCl, reflux 8 h.
symmetric diamine 11. As depicted in Scheme 3, the reduc-
tion of cyclopropanecarboxamide 2 followed by the protec-
tion of the amino group using benzoyl chloride yielded
amide intermediate 9 in a good yield. Ozonolysis of olefin
9 followed by further oxidation with aqueous hydrogen
peroxide solution, led to the formation of amino acid deriv-
ative 10 in an almost quantitative yield. The synthesis of
pseudo-C2-symmetric diamine compound, (1S,3S)-3-(amino-
methyl)-2,2-dimethylcyclopropanamine dihydrochloride 11
was accomplished by performing the Curtius rearrange-
ment of 10 followed by a deprotection reaction.
ical interconversion of (1S,3S)-2 and (1R,3R)-3,
respectively,10 the chemoenzymatic methods developed in
the current study should also be applicable to the synthesis
of all antipodes of chiral diamines 6, 8, and 11 if (1S,3S)-3
and (1R,3R)-2 enantiomers are employed. The C2- and
pseudo-C2-symmetric diamines and their salen derivatives
synthesized provide a set of novel and unique bidentate
ligands with defined structures, and their applications in
asymmetric organic synthesis and chiral recognition
warrant extensive investigation.
Chiral C2-symmetric diamines 6 and 8 and pseudo-C2-
symmetric diamine 11, which are stable in the form of a
dihydrochloride salt, were very efficiently and conveniently
converted into the corresponding salen ligands 12–14
(Fig. 1) in almost quantitative yields when they reacted
with two equivalents of 3,5-di-tert-butyl-2-hydroxy-
benzaldehyde.
4. Experimental
4.1. A multigram-scale preparation of enantiopure amide
(ꢀ)-(1S,3S)-2 and acid (+)-(1R,3R)-3
To each of 14 Erlenmeyer flasks (150 ml) in parallel was
added R. erythropolis AJ270 cells (2 g wet weight), which
can be readily obtained from fermentation,8,9q and potas-
sium phosphate buffer (0.1 M, pH 7.25, 50 ml), and the
resting cells were activated at 30 °C for 0.5 h with orbital
shaking. Racemic amide 2 (4.683 g, 28 mmol) as a fine
powder was added evenly in one portion to each of the
flasks and the mixture (concentration of racemic amide
was 40 mM) was incubated at 30 °C using an orbital shaker
(200 rpm). The reaction was quenched after 162 h by
removing the biomass through a Celite pad via filtration.
The combined filtrate was basified to pH 12 with aqueous
NaOH (2 M). Extraction with ethyl acetate gave, after
drying and concentration, (ꢀ)-(1S,3S)-2,2-dimethyl-3-(2-
3. Conclusion
In conclusion, we have developed a chemoenzymatic syn-
thesis of chiral geminally dimethylated cyclopropane-based
C2- and pseudo-C2-symmetric diamines 6, 8, and 11. The
combination of a highly enantioselective biotransformation
and the straightforward and convenient chemical manipu-
lations using inexpensive reagents under mild conditions
render these syntheses very practical. Since the (1S,3S)-3
and (1R,3R)-2 enantiomers of starting cyclopropanecarb-
oxylic acid and amide are readily available from the chem-
methylprop-1-enyl)cyclopropanecarboxamide 210 as
a
white solid (2.24 g, 48%, ee >99%). The aqueous solution
was then acidified to pH 2 using aqueous HCl (2 M) and
extracted with ethyl acetate. (+)-(1R,3R)-2,2-Dimethyl-3-
(2-methylprop-1-enyl)cyclopropanecarboxylic acid 310
(2.30 g, 49%, ee >99%) was obtained as a colorless oil after
removal of the solvent.
But
But
But
But
But
But
But
But
N
OH
N
N
OH
OH
N
N
OH
OH
4.2. Synthesis of chiral C2-symmetric diamine product 6 and
its salen derivative 12
N
OH
But
4.2.1. Oxidation of (1R,3R)-(+)-3. To a mixture of (+)-
(1R,3R)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropane-
carboxylic acid 3 (1.008 g, 6 mmol, ee >99%, HPLC) with
aqueous KOH solution (10%, 8 ml) and water (50 ml) was
added KMnO4 (3.5 g). The mixture was stirred at room
temperature for 1 h. After filtration through a Celite pad,
the filtrate was first treated with a small amount of dilute
NaHSO3 solution until the purple color had vanished.
But
But
But
14
12
13
Figure 1. Salen ligands derived from chiral geminally dimethylated
cyclopropane-based C2- and pseudo-C2-symmetric diamines.

2778
G.-Q. Feng et al. / Tetrahedron: Asymmetry 17 (2006) 2775–2780
The aqueous solution was then acidified to pH 1 using
hydrochloric acid (2 M) and saturated with NaCl. After
extraction with ethyl acetate, drying over anhydrous
MgSO4 and removal of organic solvent, a-hydroxy ketone
(8 ml) was added and the mixture was heated at reflux.
solution of 2-hydroxy-3,5-di-tert-butylbenzaldehyde
A
(93.8 mg, 0.4 mmol) in ethanol (4 ml) was then added drop-
wise to give a bright yellow solution. After another 2 h, the
mixture was cooled to below 5 °C and ice water (10 ml) was
added. The precipitate was filtered, washed with ethanol
(95%), and dried to give pure chiral C2-symmetric salen
ligand 12 (92%) as a pale yellow solid: mp 248–250 °C;
product 4 (1.10 g, yield 92%) was obtained as a colorless
25
solid: mp 144–145 °C; ½aꢁD ¼ ꢀ10 (c 1.0, CH3OH); 1H
NMR (300 MHz, CDCl3) d 6.60 (br s, 1H, COOH), 2.72
(d, 1H, J = 5.7, CH), 2.50 (d, 1H, J = 5.7, CH), 1.48 (s,
3H, CH3), 1.43 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.19 (s,
3H, CH3); 13C NMR (75 MHz, CDCl3) d 209.2, 175.9,
36.7, 34.5, 33.8, 26.5, 25.4, 20.3, 19.8; IR (KBr) 3423
(OH), 2800–3450 (br s, COOH), 1729, 1690 cmꢀ1; MS
(FAB, NBA) m/z 199 (M+ꢀ1). Anal. Calcd for
C10H16O4: C, 59.98; H, 8.05. Found: C, 59.84; H, 8.18.
25
1
½aꢁD ¼ þ560 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3)
d 13.0 (s, 2H, 2OH), 8.48 (s, 2H, 2CH@N), 7.37 (s, 2H,
Ar–H), 7.08 (s, 2H, Ar–H), 3.18 (s, 2H, 2CH), 1.57 (s,
3H, CH3), 1.45 (s, 18H, 6CH3), 1.38 (s, 3H, CH3), 1.31
(s, 18H, 6CH3); 13C NMR (75 MHz, CDCl3) d 164.8
(2C), 157.3 (2C), 140.3 (2C), 136.5 (2C), 126.6 (2C), 125.6
(2C), 118.3 (2C), 61.5 (2C), 35.0 (2C), 34.1 (2C), 31.5
(6C), 29.4 (6C), 29.3 (6C), 20.6 (2C); IR (KBr) 1617,
1465, 1247; MS (EI) m/z 532 (M+, 4%), 517 (2), 299 (5),
289 (22), 288 (100), 270 (15), 244 (50), 219 (16), 216 (28);
MS (FAB, NBA) m/z 533 (M+1)+. Anal. Calcd for
C35H52N2O2: C, 78.90; H, 9.84; N, 5.26. Found: C, 78.93;
H, 9.87; N, 5.23.
4.2.2. Preparation of 5. A mixture of 4 (1.10 g, 5.5 mmol)
with NaIO4 (2.57 g) in water (30 ml) was stirred at room
temperature for 1 h. The resulting mixture was acidified
to pH 1 and saturated with NaCl. Extraction with ethyl
acetate, dried over anhydrous MgSO4, and removal of or-
ganic solvent led to the isolation of crude diacid product 5
(790 mg). Recrystallization from a mixture of ethyl acetate
and petroleum ether gave pure (ꢀ)-(1R,2R)-3,3-dimethyl-
4.3. Synthesis of chiral C2-symmetric diamine product 8 and
its salen derivative 13
cyclopropane-1,2-dicarboxylic acid 5 (770 mg, 89%) as
25
colorless crystals: mp 200–202 °C; ½aꢁD ¼ ꢀ38:7 (c 1.5,
CH3OH); 1H NMR (300 MHz, D2O) d 2.15 (s, 2H,
2CH), 1.18 (s, 6H, 2CH3); 13C NMR (75 MHz, D2O) d
174.3 (2C), 33.5 (2C), 30.5, 19.6 (2C); IR (KBr) 2400–
3600 (br s, COOH), 1688, 1621, 1421; MS (FAB, NBA)
m/z 157 (M+ꢀ1). Anal. Calcd for C7H10O4: C, 53.16; H,
6.37. Found: C, 53.17; H, 6.46.
4.3.1. Preparation of (ꢀ)-(1R,2R)-3,3-dimethylcyclopro-
pane-1,2-dicarboxamide 7. To a mixture of diacid (ꢀ)-
(1R,2R)-5 (400 mg, 2.53 mmol), triethylamine (820 ll) in
acetone (20 ml), cooled with an ice water bath, was added
slowly ClCO2Et (620 ll) and the mixture was stirred at
0 °C for 0.5 h. The precipitate was filtered off and the
filtrate concentrated. The residue was dissolved in a small
amount of ether and then was added slowly, while stirring,
to a cold ammonia solution. After another 2 h reaction, the
mixture was concentrated to give white solids. Crystalliza-
tion in acetone by adding ether afforded pure (ꢀ)-(1R,2R)-
4.2.3. Preparation of (+)-(1S,2S)-3,3-dimethylcyclopropane-
1,2-diamine dihydrochloride 6. To an ice water bath
cooled solution of (ꢀ)-(1R,2R)-3,3-5 (790 mg, 5 mmol),
Et3N (1.6 ml) in acetone (10 ml) was added ClCO2Et
(1.23 ml) very slowly. A white solid precipitated immedi-
ately from the solution when ClCO2Et was added. After
0.5 h, NaN3 (985 mg, 15.2 mmol) solution in water (4 ml)
was added and the mixture was stirred for 1 h. Ice water
(10 ml) was added and the mixture extracted with ether
and dried with anhydrous MgSO4. The residue, after re-
moval of organic solvent, was refluxed in toluene (6 ml)
for 6 h. After cooling to room temperature, the solvent
was removed and the residue was refluxed again for 2.5 h
with concentrated hydrochloric acid (10 ml) and water
(15 ml) to give a brown solution. Most of the water was
removed under reduced pressure and the resulting residue
was subjected to chromatography using an active carbon
column with water as an eluent to give a colorless solid
product. Recrystallization in a mixture of ethyl acetate
and methanol afforded pure (+)-(1S,2S)-3,3-dimethylcyclo-
propane-1,2-diamine dihydrochloride 6 (590 mg, 68%):
3,3-dimethylcyclopropane-1,2-dicarboxamide 7 (342 mg,
25
87%): mp 249–251 °C; ½aꢁD ¼ ꢀ12 (c 1.0, CH3OH); 1H
NMR (300 MHz, D2O) d 2.09 (s, 2H, 2CH), 1.28 (s, 6H,
2CH3); 13C NMR (75 MHz, D2O) d 177.5 (2C), 35.7
(2C), 30.9, 22.2 (2C); IR (KBr) 3404, 3361, 3199, 1686,
1653, 1627, 1413 cmꢀ1; MS (FAB, NBA) m/z 157
(M++1). Anal. Calcd for C7H12N2O2: C, 53.83; H, 7.74;
N, 17.94. Found: C, 54.11; H, 7.91; N, 17.78.
4.3.2. Preparation of (ꢀ)-((1R,3R)-3-(aminomethyl)-2,2-
dimethylcyclopropyl)methanamine dihydrochloride 8. To
a solution of diamide 7 (230 mg, 1.47 mmol) in anhydrous
THF (40 ml) was added LiAlH4 (300 mg) and the resulting
mixture was refluxed for 12 h under an argon atmosphere.
The reaction was quenched by adding ice after cooling
down to room temperature. The mixture was then filtered
through a Celite pad, washed with THF, and the filtrate
was concentrated. The residue was mixed with hydrochlo-
ric acid (2 N, 15 ml) to give, after removal of the solvent,
a brown solid. The crude product was dissolved in a small
amount of methanol, and acetone was slowly added to pre-
cipitate pure (ꢀ)-((1R,3R)-3-(aminomethyl)-2,2-dimethyl-
cyclopropyl)methanamine dihydrochloride 8 as a pale
25
1
½aꢁD ¼ þ5:5 (c 1.0, CH3OH); H NMR (300 MHz, D2O)
d 2.81 (s, 2H, 2CH), 1.24 (s, 6H, 2CH3); 13C NMR
(75 MHz, D2O) d 35.75 (2C), 21.0 (2C), 17.27 (2C); IR
(KBr) 3445 (–NH3þ), 1637, 1400, 1385 cmꢀ1; MS (FAB,
GLY) m/z 193 (M+ꢀ2HCl+92), 101 (M+ꢀ2HCl).
4.2.4. Preparation of chiral C2-symmetric salen ligand
12.
25
1
A
mixture of
6
(34.6 mg, 0.2 mmol), K2CO3
gray solid (206 mg, 70%): ½aꢁD ¼ ꢀ5 (c 1.0, CH3OH); H
(56 mg), and water (1.5 ml) was stirred for 10 min. Ethanol
NMR (300 MHz, D2O) d 2.98 (m, 4H, 2CH2), 1.03 (s,

G.-Q. Feng et al. / Tetrahedron: Asymmetry 17 (2006) 2775–2780
2779
6H, 2CH3), 0.80 (m, 2H, 2CH); 13C NMR (75 MHz, D2O)
d 39.41 (2C), 26.15 (2C), 21.25, 19.85 (2C); IR (KBr) 3430
(–NH3þ), 1636, 1401, 1385 cmꢀ1. MS (FAB, GLY) m/z 129
(M+ꢀ2HCl).
121 (17), 106 (6), 105 (85), 93 (11), 91 (11), 81 (38), 77
(45). Anal. Calcd for C17H23NO: C, 79.33; H, 9.01; N,
5.44. Found: C, 79.54; H, 9.03; N, 5.52.
4.4.2. Conversion of
9
into (+)-(1S,3S)-3-((benz-
4.3.3. Preparation of C2-symmetric salen ligand 13. Fol-
lowing the procedure for the synthesis of salen 12, diamine
8 (202 mg, 0.1 mmol) was converted into chiral C2-symmet-
ric salen ligand 13 (90%) as pale yellow solids: mp 64–
amido)methyl)-2,2-dimethylcyclopropanecarboxylic acid 10.
To a solution of 9 (80 mg, 0.31 mmol) in ethyl acetate
(30 ml) was bubbled into O3 at ꢀ5 °C. After consumption
of the starting material (about 20 min), which was moni-
tored by TLC, oxygen was bubbled into the solution to re-
move O3 in the system. Acetic acid (200 ll) and aqueous
hydrogen peroxide (30%, 200 ll) were added, and the mix-
ture was stirred at 0 °C for 15 min and then at room tem-
perature for 1.5 h. After reaction, the mixture was poured
into ice water (20 ml), extracted with ethyl acetate, and
dried over anhydrous MgSO4. Removal of solvent under
vacuum gave the crude product as a glass solid. Precipita-
tion from acetone solution by adding ether afforded pure
(+)-(1S,3S)-3-((benzamido)methyl)-2,2-dimethylcyclopro-
25
1
66 °C; ½aꢁ ¼ ꢀ40 (c 1.0, CH2Cl2); H NMR (300 MHz,
CDCl3) dD14.04 (s, 2H, 2OH), 8.39 (s, 2H, 2CH@N), 7.41
(d, 2H, J = 2.25, Ar–H), 7.11 (d, 2H, J = 2.2, Ar–H),
3.77 (dd, 2H, J = 5.18, 13.4, 2NCHH), 3.57 (dd, 2H,
J = 7.4, 13.2, 2NCHH), 1.48 (s, 18H, 6CH3), 1.34 (s, 3H,
CH3), 1.34 (s, 18H, 6CH3), 1.23 (s, 6H, 2CH3), 0.88 (dd,
2H, J = 5.58, 5.59, 2CH); 13C NMR (75 MHz, CDCl3) d
165.3 (2C), 158.2 (2C), 139.8 (2C), 136.6 (2C), 126.7 (2C),
125.7 (2C), 117.9 (2C), 59.1 (2C), 35.0 (2C), 34.1 (2C),
31.5 (6C), 29.9 (6C), 29.4 (6C), 21.7 (2C), 20.5 (1C); IR
(KBr) 3437, 1632, 1597, 1470, 1441; MS (EI) m/z 561
(M++1, 24), 560 (M+, 54%), 545 (10), 327 (11), 315
(23), 314 (100), 294 (15), 293 (19), 266 (15), 265 (28), 248
(19), 247 (95), 246 (25), 244 (10), 232 (37), 219 (21), 218
(31), 190 (51), 57 (97). Anal. Calcd for C37H56N2O2: C,
79.24; H, 10.06; N, 4.99. Found: C, 79.16; H, 10.11; N,
4.95.
panecarboxylic acid 10 (72 mg, 94%) as a white solid: mp
25
162–164 °C; ½aꢁD ¼ þ46 (c 1.0, CH3OH); 1H NMR
(300 MHz, CD3OD) d 8.56 (br s, 1H, COOH), 7.70 (d,
2H, J = 7.47, Ar–H), 7.32–7.43 (m, 3H, Ar–H), 4.82 (br
s, 1H, NH), 3.32–3.40 (m, 2H, CH2), 1.59 (m, 1H, CH),
1.38 (d, 1H, J = 5.4, CH), 1.18 (s, 3H, CH3), 1.14 (s, 3H,
CH3); 13C NMR (75 MHz, CD3OD) d 174.4, 168.7,
134.1, 131.1 (2C), 128.0 (2C), 126.7, 38.4, 32.0, 31.6, 26.8,
20.5, 19.5; IR (KBr) 3337 (NH), 2600–3600 (COOH),
1705, 1628, 1601, 1575, 1555, 1183; MS (EI) m/z 247
(M+, 10%), 229 (5), 202 (7), 147 (16), 146 (10), 134 (13),
122 (8), 105 (100), 96 (3), 77 (46). Anal. Calcd for
C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C, 68.14;
H, 6.96; N, 5.62.
4.4. Synthesis of chiral pseudo-C2-symmetric diamine
product 11 and its salen derivative 14
4.4.1. Preparation of (+)-N-(((1S,3S)-2,2-dimethyl-3-(2-
methylprop-1-enyl)cyclopropyl)methyl)benzamide 9. To a
solution of (ꢀ)-(1S,3S)-2,2-dimethyl-3-(2-methylprop-1-
enyl)cyclopropanecarboxamide 2 (334 mg, 2 mmol, ee
>99%) in anhydrous THF (10 ml) was added slowly
LiAlH4 (200 mg), and the resulting mixture gently refluxed
for 4 h under argon. Ice was added to quench the reaction
after cooling to room temperature and the mixture was
filtered through a basic aluminum pad. The filtrate was
mixed with cold water (25 ml) and extracted with ether.
The combined organic phase was dried with anhydrous
MgSO4 and then concentrated to a volume of about
10 ml. After cooling with an ice water bath, the resulting
solution was consecutively mixed with triethylamine
(350 ll) and benzoyl chloride (290 ll) slowly while stirring.
The reaction was stopped after 2 h by adding ice water, and
the mixture was basified with 2 M NaOH solution. Extrac-
tion with ether, drying over anhydrous MgSO4, and
concentration under vacuum gave an oily residue.
Chromatography on a silica gel column yielded pure (+)-
N-(((1S,3S)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopro-
pyl)methyl)benzamide 9 (415 mg, 81%) as a colorless oil:
4.4.3. Preparation of (ꢀ)-(1S,3S)-3-(aminomethyl)-2,2-di-
methylcyclopropanamine dihydrochloride 11. To a solution
of 10 (124 mg, 0.5 mmol) in acetone (3 ml) were added con-
secutively triethylamine (0.16 ml) and ClCO2Et (0.125 ml)
while stirring. After 0.5 h, a solution of NaN3 (100 mg) in
water (0.35 ml) was added and the mixture kept stirring at
0 °C for 1 h. The reaction was quenched by the addition
of ice water (10 ml), extracted with ether, and dried with
anhydrous MgSO4. After removal of the solvent, the resi-
due was refluxed in toluene (3 ml) for 3 h. The solvent
was then removed again under vacuum and the residue re-
fluxed for 8 h in a mixture of concentrated hydrochloric
acid (2 ml) and water (3 ml). After cooling to room temper-
ature, ice water (5 ml) was added and the resulting brown
solution washed with ethyl acetate. The aqueous solution
was concentrated to dryness under vacuum, and the solid
residue dissolved in a small amount of methanol. The slow
addition of acetone, while stirring, gave pure product (ꢀ)-
(1S,3S)-3-(aminomethyl)-2,2-dimethylcyclopropanamine
25
1
½aꢁD ¼ þ16 (c 2.5, CH3OH); H NMR (300 MHz, CDCl3)
d 7.77 (d, 2H, J = 7.5, Ar–H), 7.39–7.48 (m, 3H, Ar–H),
6.34 (br s, 1H, NH), 4.86 (d, 1H, J = 7.9, =CH), 3.45–
3.56 (m, 2H, CH2N), 1.70 (s, 3H, CH3), 1.68 (s, 3H,
CH3), 1.17 (s, 3H, CH3), 1.16 (d, 1H, J = 9.9, CH), 1.05
(s, 3H, CH3), 0.81 (m, 1H, CH); 13C NMR (75 MHz,
CDCl3) d 167.4, 134.8, 133.3, 131.3, 128.5, 126.9, 123.3,
40.8, 32.0, 29.2, 25.7, 22.6, 22.2, 21.6, 18.3; IR (KBr)
3310, 3064, 1635, 1603, 1578, 1541, 1295, 694; MS (EI)
m/z 257 (M+, 5%), 214 (2), 134 (13), 124 (10), 123 (100),
dihydrochloride 11 (51 mg, 55%) as a pale gray precipi-
25
tate: ½aꢁ ¼ ꢀ6 (c 1.0, CH3OH); 1H NMR (300 MHz,
D2O) d D2.91 (d, 2H, J = 7.5, CH2), 2.29 (d, 2H, J = 4.0,
CH), 1.10 (m, 1H, CH), 1.06 (s, 3H, CH3), 0.97 (s, 3H,
CH3); 13C NMR (75 MHz, D2O) d 37.79, 36.99, 25.48,
20.74, 18.87, 18.09; IR (KBr) 3430 (NH3þ), 1636, 1401,
1385; MS (FAB, GLY) m/z 207 (M+ꢀ2HCl+92), 115
(M+ꢀ2HCl).

2780
G.-Q. Feng et al. / Tetrahedron: Asymmetry 17 (2006) 2775–2780
3. For recent examples, see: (a) Fuerst, D. E.; Jacobsen, E. N. J.
Am. Chem. Soc. 2005, 127, 8964; (b) Yoon, T. P.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2005, 44, 466; (c) Joly, G. D.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102; (d)
Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed.
2005, 44, 4032; (e) Berkessel, A.; Cleemann, F.; Mukherjee,
S.; Mueller, T. N.; Lex, J. Angew. Chem., Int. Ed. 2005, 44,
807; (f) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.;
Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
4. For recent examples, see: (a) Rondot, C.; Zhu, J. Org. Lett.
2005, 78, 1641; (b) Hong, Y.-W.; Izumi, K.; Xu, M.-H.; Lin,
G.-Q. Org. Lett. 2004, 6, 4747; (c) Ooi, T.; Sakai, D.;
Takeuchi, M.; Tayama, E.; Maruoka, K. Angew. Chem., Int.
Ed. 2003, 42, 5868; (d) Kitagawa, O.; Yotsumoto, K.;
Kohriyama, M.; Dobashi, Y.; Taguchi, T. Org. Lett. 2004,
6, 3605.
5. Molander, G. A.; Burke, J. P.; Carroll, P. J. J. Org. Chem.
2004, 69, 8062.
6. Belokon, Y. N.; Fuentes, J.; North, M.; Steed, J. W.
Tetrahedron 2004, 60, 3191.
7. This work is taken partly from Feng’s doctorial thesis. Feng,
G.-Q. Ph.D. Thesis, Institute of Chemistry, Chinese Academy
of Sciences, 2003.
8. Rhodococcus erythropolis AJ270, formerly called Rhodococcus
sp. AJ270, is a nitrile hydratase/amidase containing microbial
strain. (a) Blakey, A. J.; Colby, J.; Williams, E.; O’Reilly, C.
FEMS Microbiol. Lett. 1995, 129, 57; (b) O’Mahony, R.;
Doran, J.; Coffey, L.; Cahill, O. J.; Black, G. W.; O’Reilly, C.
Antonie Leeuwenhoek 2005, 87, 221.
4.4.4. Preparation of chiral pseudo-C2-symmetric salen
ligand 14. Following the procedure for the synthesis of
salen 12, diamine 11 (20.1 mg, 0.1 mmol) was converted
into chiral pseudo-C2-symmetric salen ligand 14 (51.6 mg,
25
92%) as a pale yellow solid: mp 82–84 °C; ½aꢁD ¼ þ16 (c
1.5, CH2Cl2); 1H NMR (300 MHz, CDCl3) d 13.90 (s,
1H, OH), 13.14 (s, 1H, OH), 8.48 (s, 1H, CH@N), 8.40
(s, 1H, CH@N), 7.39 (d, 1H, J = 1.68, Ar–H), 7.34 (d,
1H, J = 1.29, Ar–H), 7.08 (s, 2H, Ar–H), 3.74 (dd, 2H,
J = 6.42, 6.86, CH2), 2.69 (d, 1H, J = 3.3, CH), 1.59 (s,
3H, CH3), 1.46 (s, 9H, 3CH3), 1.44 (s, 9H, 3CH3), 1.34
(s, 3H, CH3), 1.32 (d, 1H, J = 7.7, CH), 1.31 (s, 9H,
3CH3), 1.309 (s, 9H, 3CH3), 1.27 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d 165.9, 164.0, 158.2, 157.3, 140.1,
140.0, 136.6, 136.4, 126.9, 126.3, 125.8, 125.4, 118.3,
117.9, 57.8, 57.2, 35.1, 35.0, 34.7, 34.1, 31.5 (6C), 29.4
(6C), 25.2, 22.2, 20.4; IR (KBr) 3435, 1630, 1469, 1441,
1390, 1362, 1273, 1251; MS (EI) m/z 546 (M+, 22%), 531
(3), 461 (3), 434 (5), 357 (4), 315 (24), 314 (100), 313 (72),
303 (14), 302 (64), 301 (22), 300 (81), 298 (21), 274 (11),
258 (16), 244 (32), 234 (52), 233 (36), 232 (10), 218 (21),
190 (16), 69 (14), 57 (95), 41 (20), 32 (50). Anal. Calcd
for C36H54N2O2: C, 79.07; H, 9.95; N, 5.12. Found: C,
78.79; H, 9.96; N, 4.95.
9. For examples of Rhodococcus erythropolis AJ270-catalyzed
enantioselective biotransformations, see: (a) Wang, M.-X.;
Deng, D.; Wang, D.-X.; Zheng, Q.-Y. J. Org. Chem. 2005, 70,
2439; (b) Wang, M.-X.; Liu, J.; Wang, D.-X.; Zheng, Q.-Y.
Tetrahedron: Asymmetry 2005, 16, 2409; (c) Wang, M.-X.;
Lin, S.-J.; Liu, J.; Zheng, Q.-Y. Adv. Synth. Catal. 2004, 346,
439; (d) Wang, M.-X.; Feng, G.-Q.; Zheng, Q.-Y. Tetra-
hedron: Asymmetry 2004, 15, 347; (e) Wang, M.-X.; Feng,
G.-Q.; Zheng, Q.-Y. Adv. Synth. Catal. 2003, 345, 695;
(f) Wang, M.-X.; Lin, S.-J.; Liu, C.-S.; Zheng, Q.-Y.; Li, J.-S.
J. Org. Chem. 2003, 68, 4570; (g) Wang, M.-X.; Lin, S.-J.
J. Org. Chem. 2002, 67, 6542; (h) Wang, M.-X.; Zhao, S.-M.
Tetrahedron Lett. 2002, 43, 6617; (i) Wang, M.-X.; Zhao,
S.-M. Tetrahedron: Asymmetry 2002, 13, 1695; (j) Wang,
M.-X.; Feng, G.-Q. New J. Chem. 2002, 1575; (k) Wang,
M.-X.; Feng, G.-Q. J. Mol. Catal. B: Enzym. 2002, 18, 267;
(l) Wang, M.-X.; Li, J.-J.; Ji, G.-J.; Li, J.-S. J. Mol. Catal. B:
Enzym. 2001, 14, 77; (m) Wang, M.-X.; Lin, S.-J. Tetrahedron
Lett. 2001, 42, 6925; (n) Wang, M.-X.; Liu, C.-S.; Li, J.-S.
Tetrahedron: Asymmetry 2001, 12, 3367; (o) Wang, M.-X.;
Liu, C.-S.; Li, J.-S.; Meth-Cohn, O. Tetrahedron Lett. 2000,
41, 8549; (p) Wang, M.-X.; Feng, G.-Q. Tetrahedron Lett.
2000, 41, 6501; (q) Wang, M.-X.; Lu, G.; Ji, G.-J.; Huang,
Z.-T.; Meth-Cohn, O.; Colby, J. Tetrahedron: Asymmetry
2000, 11, 1123.
Acknowledgments
We thank the State Major Fundamental Research Program
(2003CB716005), the Ministry of Science and Techno-
logy, the National Natural Science Foundation of
China, and the Chinese Academy of Sciences for financial
support.
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