Resolution of (±)-1-aryl-2-propynylamines via acyltransfer catalyzed by Candida antarctica lipase

Full text of DOI:10.1021/jo982513i

J . Org. Chem. 1999, 64, 3767-3769
3767
In fact, lithium acetylide and ethynylmagnesium bromide
(even in the presence of cerium chloride) failed to react
with enantiopure N-sulfinyl benzaldimine,8 due to their
low nucleophilicity toward carbon-nitrogen double bonds
conjugated with an aromatic ring.9 On the other hand,
synthetic transformations of the carboxyl groups of
R-amino acids mostly involve conversion into N-protected
R-amino aldehydes,10 which are relatively unstable, both
chemically and configurationally,10,11 and whose prepara-
tion from the corresponding acids via esters or active
amides is lengthy.12 In particular, only one laborious
procedure for the preparation of N-protected 2-phenyl-
glycinal has been claimed so far (no experimental data).13
Therefore, in an attempt to provide an easy access to
the required compounds and based on our previous
experience in this field,4a,5 we decided to explore the
possibility of obtaining the title compounds 1 via lipase-
catalyzed resolution of the corresponding racemates.
Some recent papers have described the preparation of
chiral non racemic amines by stereoselective amidation
via acyltransfer reactions using lipases from Candida
antarctica (CAL)14 and Pseudomonas aeruginosa15 or the
protease subtilisin A.16 Schmidt et al.17 have reported the
kinetic resolution of racemic amines by enantioselective
hydrolysis of the corresponding amides catalyzed by CAL,
while Crout et al.18 used the same enzyme to obtain
enantiopure amines by hydrolysis of the corresponding
oxalamic esters. On the basis of these reports, we decided
to test CAL (in the immobilized form Novozym 435 from
Novo Nordisk) in the enantioselective acylation of (()-1.
The racemic starting materials 1a -f were readily
prepared (Scheme 1, Table 1) in 30-70% overall yield
by hydrolysis of the corresponding acetamides 3a -f,
which were in turn obtained from aryl propargylic
alcohols 4a -f4a via Ritter reaction (acetonitrile/sulfuric
acid), using the procedure described by Hacksell for the
preparation of 1a .19 We then investigated the acetylation
Resolu tion of (()-1-Ar yl-2-p r op yn yla m in es
via Acyltr a n sfer Ca ta lyzed by Ca n d id a
a n ta r ctica Lip a se
Flavia Messina,† Maurizio Botta,*,† Federico Corelli,*,†
Manfred P. Schneider,*,‡ and Fabio Fazio‡
Dipartimento Farmaco Chimico Tecnologico, Universita`
degli Studi di Siena, Banchi di Sotto 55, 53100 Siena, Italy,
and FB 9 - Organische Chemie, Bergische Universita¨t,
D-42097 Wuppertal, Germany
Received December 28, 1998
Chiral 1-ethynylbenzylamines (1) are important build-
ing blocks for the stereoselective synthesis of numerous
biologically active compounds, such as conformationally
restricted peptide isosteres,1 oxotremorine analogues,2
and benzo[b]furan compounds of general structure 2 (eq
1), which have been shown to display antifungal and
aromatase inhibiting activities.3
Unlike aryl propargylic alcohols,4 however, no report
on the synthesis of homochiral 1-arylpropargylamines
has appeared up to now in the literature. In view of our
previous studies related to the synthesis of chiral syn-
thons of high enantiomeric purity useful for the prepara-
tion of bioactive compounds in nonracemic form,5 we
turned our attention to the synthesis of enantiomerically
pure propargylamines 1. Our first approaches based
either on the diastereoselective addition of nucleophiles
to the CdN bonds of imines containing removable chiral
auxiliaries,6 or the functional group modification of
enantiopure 2-arylglycines, proved to be unsuccessful.7
(6) (a) Merino, P.; Anoro, S.; Castillo, E.; Merchan, F.; Tejero, T.
Tetrahedron: Asymmetry 1996, 7, 1887. (b) Enders, D.; Schankat, J .
Helv. Chim. Acta 1995, 78, 970. (c) Denmark, S. E.; Nakajima, N.;
Nicaise, O. J .-C. J . Am. Chem. Soc. 1994, 116, 6, 8797. (d) Inoue, I.;
Shindo, M.; Koga, K.; Tomioka, K. Tetrahedron: Asymmetry 1993, 4,
1603. (e) Enders, D.; Schankat, J . Helv. Chim. Acta 1993, 76, 402.
(7) Fazio, F. Doctorate Thesis, University of Siena, April 1997.
(8) Davis, F. A.; Reddy, R. E.; Portonovo, P. S.; Chiu, Y. J . Org.
Chem. 1996, 61, 440.
(9) (a) Yamazaki, T.; Mizutani, K.; Kitazume, T. J . Org. Chem. 1995,
60, 6046. (b) Denmark, S. E.; Weber, T.; Piotrowski, D. W. J . Am. Chem.
Soc. 1987, 109, 2224.
(10) J urczak, J .; Golebiowski, A. Chem. Rev. 1989, 89, 149.
(11) Luly, J . R.; Dellaria, J . F.; Plattner, J . J .; Soderquist, J . L.; Yi,
N. J . Org. Chem. 1987, 52, 1487.
* Corresponding authors. Maurizio Botta and Federico Corelli.
Phone: +39-577-45393. Fax: +39-577-298183. E-mail: botta@unisi.it.
E-mail: corelli@unisi.it. Manfred P. Schneider. Phone: +49-202-
4392775. Fax: +49-202-4392535. E-mail: schneid@uni-wuppertal.de.
† Universita` degli Studi di Siena.
‡ Bergische Universita¨t.
(1) (a) Reginato, G.; Mordini, A.; Messina, F.; Degl′Innocenti, A.; Poli,
G. Tetrahedron 1996, 52, 10985. (b) J enmalm, A.; Berts, W.; Li, Y. L.;
Luthman, K.; Csoregh, I.; Hacksell, U. J . Org. Chem. 1994, 59, 1139.
(2) Nilsson, B.; Vargas, H. M.; Ringdahl, B.; Hacksell, U. J . Med.
Chem. 1992, 35, 285.
(3) (a) Banting, L. In Progress in Medicinal Chemistry; Ellis, G. P.,
Luscombe, D. K., Eds.; Elsevier Science Publishers: B. V.: Amsterdam,
1996; Vol. 33, pp 147-184. (b) Whomsley, R.; Fernandez, E.; Nicholls,
P. J .; Smith, H. J .; Lombardi, P.; Pestellini, V. J . Steroid Biochem.
Mol. Biol. 1993, 44, 675. (c) Pestellini, V.; Giannotti, D.; Giolitti, A.;
Fanto`, N.; Riviera, L.; Bellotti, M. G. Chemioterapia 1987, 6, 269.
(4) (a) Waldinger, C.; Schneider, M.; Botta, M.; Corelli, F.; Summa,
V. Tetrahedron: Asymmetry 1996, 7, 1485. (b) Elsevier: C. J .; Vermeer,
P. J . Org. Chem. 1989, 54, 3726.
(5) (a) Botta, M.; Summa, V.; Corelli, F.; Di Pietro, G.; Lombardi,
P. Tetrahedron: Asymmetry 1996, 7, 1263. (b) Corelli, F.; Summa, V.;
Brogi, A.; Monteagudo, E.; Botta, M. J . Org. Chem. 1995, 60, 2008. (c)
Botta, M.; Summa, V.; Trapassi, G.; Monteagudo, E.; Corelli, F.
Tetrahedron: Asymmetry 1994, 5, 181. (d) Seemayer, R.; Schneider,
M. P. Tetrahedron: Asymmetry 1992, 3, 827. (e) Schneider, M. P.;
Goergens, U. Tetrahedron: Asymmetry 1992, 3, 525. (f) Schneider, M.
P.; Ader, U. Tetrahedron: Asymmetry 1992, 3, 521. (g) Laumen, K.;
Schneider, M. P. J . Chem. Soc., Chem. Commun. 1988, 598.
(12) Katritzky, A. R.; Cheng, D.; Li, J . J . Org. Chem. 1998, 63, 3438
and references cited therein.
(13) Braun, M.; Opdenbusch, K. Angew. Chem., Int. Ed. Engl. 1993,
32, 2, 578.
(14) (a) Sa´nchez, V. M.; Rebolledo, F.; Gotor, V. Tetrahedron:
Asymmetry 1997, 8, 37. (b) Reetz, M. T.; Schimossek, K. Chimia 1996,
50, 668. (c) O¨ hrner, N.; Orrenius, C.; Mattson, A.; Norin, T.; Hult, K.
Enzyme Microb. Technol. 1996, 19, 328.
(15) J aeger, K. E.; Liebeton, K.; Zonta, A.; Schimossek, K.; Reetz,
M. T. Appl. Microbiol. Biotechnol. 1996, 46, 99.
(16) (a) Gutmann, A. L.; Meyer, E.; Kalerin, E.; Polyak, F.; Sterling,
J . Biotechnol. Bioeng. 1992, 40, 760. (b) Kitaguchi, H.; Fitzpatrick, P.
A.; Huber, J . E.; Klibanov, A. M. J . Am. Chem. Soc. 1989, 111, 3094.
(17) Schmidt, H.; Fischer, A.; Fischer, P.; Schmid, R. D. Biotechnol.
Tech. 1996, 10, 335.
(18) Chapman, D. T.; Crout, D. H. G.; Mahmoudian, M.; Scopes, D.
I. C.; Smith, P. W. Chem. Commun. 1996, 2415.
(19) Nilsson, B. M.; Hacksell, U. J . Heterocycl. Chem. 1989, 26, 269.
10.1021/jo982513i CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/24/1999

3768 J . Org. Chem., Vol. 64, No. 10, 1999
Notes
Sch em e 1
racemic counterparts afforded amines (R)-1a -e without
loss of enantiomeric purity (Table 3).
In summary, CAL-mediated kinetic resolution of 1-aryl-
2-propynylamines opens up for the first time a very
profitable avenue, both in terms of chemical yield and
stereoselectivity, to (R)- and (S)-propargylamines, valu-
able intermediates for the synthesis of biologically rel-
evant compounds in nonracemic form. Studies in this
area are in progress in our laboratories and will be
reported in due course.
Ta ble 1. P r ep a r a tion of
(()-N-(1-Ar yl-2-p r op yn yl)a ceta m id es 3a -f a n d
(()-1-Ar yl-2-p r op yn yla m in es 1a -f
compd
R
t (h)
yield (%)
mp (°C)
Exp er im en ta l Section
3a
3b
3c
3d
3e
3f
1a
1b
1c
1d
1e
1f
H
4-Cl
4-F
48
18
12
16
18
24
6
17
12
18
72
12
91
60
96
71
60
45
72
65
63
76
77
60
89-90 (lit.a 82.5-84)
Gen er a l. Reagents were obtained from commercial suppliers
and used without further purification. Merck silica gel 60 was
used for both column chromatography (70-230 mesh) and flash
chromatography (230-400 mesh). Melting points are uncor-
116-118
118-119
101-103
105-107
145-148
oil
3-F
3-Me
2-Me
H
4-Cl
4-F
3-F
3-Me
2-Me
1
rected. H NMR spectra were measured at 200 MHz. Chemical
shifts are reported relative to CDCl3 at δ 7.24 ppm and
tetramethylsilane at δ 0.00 ppm. EI low-resolution mass spectra
were recorded with an electron beam of 70 eV. Elemental
analyses (C, H, N) were performed in-house.
oil
oil
oil
oil
Gen er a l P r oced u r e for th e P r ep a r a tion of (()-N-(1-Ar yl-
2-p r op yn yl)a ceta m id es (3b-f). A solution of 96% sulfuric acid
(490 mg, 5 mmol) in dry acetonitrile (2.0 mL) was added to a
stirred mixture of 1-aryl-2-propynyl-1-ol (1 mmol) and anhydrous
sodium sulfate (142.0 mg, 1 mmol) in dry acetonitrile (3.1 mL)
at -20 °C. The mixture was allowed to reach room temperature,
and stirring was continued for the required time. The mixture
was concentrated, poured on ice, and extracted with ether and
dichloromethane. The combined organic layers were dried (Na2-
SO4), filtered, and concentrated. Flash chromatography, using
as eluants hexanes:Et2O 1:1 followed by Et2O, afforded pure
N-(1-aryl-propynyl)acetamides (see Table 1).
oil
a
See reference 19.
Sch em e 2
(()-N-[1-(4-Ch lor oph en yl)-2-pr opyn yl]acetam ide (3b): 1H-
NMR (CDCl3) δ 7.43-7.26 (4H, m, J ) 8.3 Hz), 6.19 (1H, br d,
J ) 8.2 Hz), 5.95 (1H, dd, J ) 8.2, 2.0 Hz), 2.47 (1H, d, J ) 2.0
Hz), 1.98 (3H, s). MS: 210/208 (M + H)+, 209/207 (M+), 130
(100%). Anal. Calcd for C11H10ClNO: C, 63.62; H, 4.85; N 6.75.
Found: C, 63.88; H, 4.80; N, 6.66.
of (()-1 using CAL as the catalyst, ethyl acetate as acyl
donor, and diethyl ether as solvent (Scheme 2, Table 2).
The reaction was monitored by GC on a chiral column,
allowing the simultaneous determination of (a) conver-
sion and (b) the enantiomeric purities of both educt and
product. The transformations were terminated as soon
as the desired conversion (ca. 50%) was achieved. Fol-
lowing usual workup, compounds (R)-3 and (S)-1 were
easily purified by flash chromatography and their ee
determined again by chiral GC. In no case was observed
a loss of ee due to the workup and silica gel chromatog-
raphy. As can be seen from the data reported in Table 2,
CAL proved to be an effective catalyst (E > 100)20 in the
enantioselective acetylation of (()-1a -e. On the contrary,
(()-1f proved to be resistant to bioconversion under these
conditions, and even after 120 h reaction both (R)-3f and
(S)-1f were obtained only in negligible chemical yield and
low enantiomeric purity. To assign the absolute configu-
rations of 1 and 3, the propargylamine (+)-1a was
hydrogenated (H2, 10% Pd/C, 30 psi) leading to (-)-1-
phenylpropylamine. Comparison of its specific rotation
with reported data for (R)-(+)-1-phenylpropylamine21
established the S-configuration for 1 and, consequently,
the R-configuration for the amides 3. This result is in
perfect agreement with the reported preference of CAL
for the acylation of (R)-amines.14,22
(()-N-[1-(4-Flu or oph en yl)-2-pr opyn yl]acetam ide (3c): 1H-
NMR (CDCl3) δ 7.49 (2H, dd J ) 5.5, 2.3 Hz), 7.02 (2H, m), 6.42
(1H, d, J ) 8.6 Hz), 5.93 (1H, dd, J ) 8.2, 1.8 Hz), 2.48 (1H, d,
J ) 1.6 Hz), 2.00 (3H, s). MS: 191 (M+, 100%). Anal. Calcd for
C
11H10FNO: C, 69.10; H, 5.27; N 7.33. Found: C, 68.91; H, 5.33;
N, 7.50.
(()-N-[1-(3-Flu or oph en yl)-2-pr opyn yl]acetam ide (3d): 1H-
NMR (CDCl3) δ 7.29-7.15 (3H, m), 6.99-6.95 (1H, m), 6.51 (1H,
br d, J ) 8.3 Hz), 5.96 (1H, dd, J ) 8.4, 2.2 Hz), 2.47 (1H, d, J
) 2.4 Hz). MS: 192 (M + H)+, 148 (100%). Anal. Calcd for C11H10
-
FNO: C, 69.10; H, 5.27; N 7.33. Found: C, 69.29; H, 5.38; N,
7.19.
(()-N-[1-(3-Meth ylph en yl)-2-pr opyn yl]acetam ide (3e): 1H-
NMR (CDCl3) δ 7.27-7.07 (4H, m), 6.32 (1H, d, J ) 7.6 Hz),
5.93 (1H, dd, J ) 8.2, 1.9 Hz), 2.44 (1H, d, J ) 1.9 Hz), 2.33
(3H, s), 1.96 (3H, s). MS: 187 (M+, 100%). Anal. Calcd for C12H13
-
NO: C, 76.98; H, 7.00; N 7.48. Found: C, 77.19; H, 6.88; N, 7.32.
(()-N-[1-(2-Meth ylph en yl)-2-pr opyn yl]acetam ide (3f): 1H-
NMR (CDCl3) δ 7.63-7.59 (1H, m), 7.24-7.14 (3H, m), 6.04 (1H,
dd, J ) 8.1, 2.1 Hz), 5.79 (1H, bs), 2.43 (1H, d, J ) 2.6 Hz), 2.35
(3H, s), 1.98 (3H, s). MS: 188 (M + H)+, 128 (100%). Anal. Calcd
for C12H13NO: C, 76.98; H, 7.00; N 7.48. Found: C, 77.23; H,
7.10; N, 7.21.
Gen er a l P r oced u r e for th e P r ep a r a tion of (()-1-Ar yl-
2-p r op yn yla m in es (1b-f). A suspension of N-(1-aryl-2-propyn-
yl)acetamide (1 mmol) and 3.0 N aqueous HCl (5.7 mL) was
heated to 70 °C for the required time. The resulting solution
was extracted with Et2O (5 mL). The aqueous layer was
alkalinized by addition of solid NaHCO3 to pH 8.5 and extracted
with Et2O (4 × 5 mL). The combined organic solution was dried
(K2CO3), filtered, and concentrated in vacuo. The oily residue
was subjected to flash chromatography using as eluants hexanes:
Et2O 1:1, followed by Et2O, affording pure 1-aryl-2-propynyl-
amine (see Table 1).
Chemical hydrolysis of acetamides (R)-3a -e under the
same experimental conditions as described for their
(20) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 104, 7294.
(21) (a) Wu, M.-J .; Pridgen, L. N. J . Org. Chem. 1991, 56, 1340. (b)
Rossi, D.; Calcagni, A.; Romeo, A. J . Org. Chem. 1979, 44, 2222.
(22) Graf, M.; Brunella, A.; Kittelmann, M.; Laumen, K.; Ghisalba,
O. Appl. Microbiol. Biotechnol. 1997, 47, 650.

Notes
J . Org. Chem., Vol. 64, No. 10, 1999 3769
Ta ble 2. CAL-Ca ta lyzed Resolu tion of (()-1-Ar yl-2-p r op yn yla m in es 1a -f
(S)-1
(R)-3
c
c
compd
time (h)
conversion (%)
yield (%)a
ee (%)b
[R]23
yield (%)a
ee (%)b
[R]23
E
D
D
1a
1b
1c
1d
1e
1f
17
25
25
47
48
48.0
49.8
48.0
49.0
49.7
31
40.3
39.8
40.3
46.0
32.9
NDd
97
98
88
93
98
22
+30.4
+28.6
+8.65
+22.5
+27.3
NDd
45.2
42.6
38.2
38.9
40.8
NDd
>98
>98
98
>98
98
+61.6
+80.3
+51.3
+59.1
+58.9
NDd
>100 (310)
>100 (420)
>100 (310)
>100 (360)
>100 (410)
4.7
120
57
a
b
d
Yield refer to isolated and purified materials. Determined by chiral GC. c Measured in CHCl3 solution (c 1.0). ND ) not determined.
Ta ble 3. P r ep a r a tion of (R)-1 by Hyd r olysis of (R)-3
(2 mmol), EtOAc (0.78 mL, 8 mmol), and lipase B from Candida
antarctica (immobilized form NOVOZYM 435) (100 mg) in Et2O
(5 mL) was strirred at room temperature, and the reaction was
monitored by GC on a FS-cyclodex BETA I/P column. After the
desired conversion was reached, the reaction mixture was diluted
with Et2O and filtered to remove the enzyme. The organic layer
was washed twice with 3.0 N HCl, and the two phases were
separated. The organic layer, containing the amide was washed
once with brine, dried over Na2SO4, filtered, and evaporated to
give the crude (R)-3.
The aqueous phase containing (S)-1 hydrochloride was alka-
linized with solid NaHCO3 to pH 7-8 and then extracted three
times with Et2O. The organic layer was washed with brine, dried
over Na2SO4, filtered, and evaporated to give the crude (S)-1.
The crude products were purified by flash chromatography on
silica gel (EtOAc:hexanes 1:1). The enantiomeric excess of
purified products was determined by GC on the above-mentioned
chiral column (for yields, ee and conversion, see Table 2).
Amines (R)-1a -e were prepared by hydrolysis (see Table 3)
of the corresponding amides (R)-3a -e following the same
procedure described for the hydrolysis of their racemic counter-
parts.
c
product
yield (%)a
ee (%)b
[R]23
D
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1e
60
65
83
70
54
98
98
97
98
97
-31.3
-27.5
-32.8 (c 0.8)
-19.7
-29.7 (c 0.7)
a
b
Yield refer to isolated and purified materials. Determined
by chiral GC. c Measured in CHCl3 solution (c 1.0, unless otherwise
stated).
(()-1-(4-Ch lor op h en yl)-2-p r op yn yla m in e (1b): 1H-NMR
(CDCl3) δ 7.48-7.29 (4H, m), 4.72 (1H, d, J ) 1.9 Hz), 2.48 (1H,
d, J ) 1.9 Hz), 1.75 (2H, br d). MS: 167/165 (M+), 166/164 (M -
H)+, 130 (100%). HRMS calcd for C9H8ClN 165.03452, found
165.03470.
(()-1-(4-F lu or op h en yl)-2-p r op yn yla m in e (1c): 1H-NMR
(CDCl3) δ 7.50 (2H, dd, J ) 8.7, 5.7 Hz), 7.01 (2H, m), 4.74 (1H,
d, J ) 2.2), 2.48 (1H, d, J ) 1.9), 1.78 (2H, bs). MS: 148 [(M -
H)+, 100%]. HRMS calcd for C9H8FN 149.06408, found 149.06369.
(()-1-(3-F lu or op h en yl)-2-p r op yn yla m in e (1d ): 1H-NMR
(CDCl3) δ 7.36-7.24 (3H, m), 7.03-6.91 (1H, m), 4.75 (1H, d, J
) 2.3 Hz), 2.49 (1H, d, J ) 2.3 Hz), 1.78 (2H, s). MS: 149 (M+),
[148 (M - H)+, 100%]. HRMS calcd for C9H8FN 149.06408, found
149.06444.
Ack n ow led gm en t. We thank Novo Nordisk S/A,
Denmark, for a generous gift of Novozym 435. Some of
the optical activity measurements were run in Dipar-
timento di Chimica Organica “U. Schiff”, Firenze, Italy.
The authors from Siena gratefully acknowledge finan-
cial support from “Progetto Finalizzato Biotecnologie”
(CNR Target Project on “Biotechnology”) and from the
University of Siena (60% funds). M.P.S. is grateful to
the Fonds der Chemischen Industrie for financial sup-
port. M.B. wishes to thank the Merck Research Labo-
ratories for the 1998 Academic Development Program
(ADP) Chemistry Award.
(()-1-(3-Meth ylp h en yl)-2-p r op yn yla m in e (1e): 1H-NMR
(CDCl3) δ 7.33-7.24 (3H, m), 7.10 (1H, d, J ) 7.1 Hz), 4.73 (1H,
d, J ) 2.0 Hz), 2.47 (1H, d, J ) 2.0 Hz), 2.35 (3H, s), 1.88 (2H,
s). MS: 145 (M+), 128 (100%). HRMS calcd for C10H11
145.08915, found 145.08870.
N
(()-1-(2-Meth ylp h en yl)-2-p r op yn yla m in e (1f): 1H-NMR
(CDCl3) δ 7.64-7.61 (1H, m), 7.23-7.17 (3H, m), 4.92 (1H, d, J
) 2.0 Hz), 2.44 (1H, d, J ) 2.0 Hz), 2.43 (3H, s), 1.75 (1H, bs).
MS: 145 (M+), 128 (100%). HRMS calcd for C10H11N 145.08915,
found 145.08945.
Gen er a l P r oced u r e for th e CAL-Ca ta lyzed Resolu tion
of (()-1-Ar yl-2-p r op yn yla m in es (1a -f). A mixture of (()-1
J O982513I