Chiral azole derivatives. 4.1 Enantiomers of bifonazole and related antifungal agents: Synthesis, configuration assignment, and biological evaluation

Full text of DOI:10.1021/jo991937p

4736
J . Org. Chem. 2000, 65, 4736-4739
Ch ir a l Azole Der iva tives. 4.1 En a n tiom er s
of Bifon a zole a n d Rela ted An tifu n ga l
Agen ts: Syn th esis, Con figu r a tion
Assign m en t, a n d Biologica l Eva lu a tion
Maurizio Botta,* Federico Corelli,*
Francesco Gasparrini,† Flavia Messina, and
Claudia Mugnaini
Dipartimento Farmaco Chimico Tecnologico,
Universita` degli Studi di Siena, Via Aldo Moro s.n.c.,
I-53100 Siena, Italy, and Dipartimento di Studi di Chimica
e Tecnologia delle Sostanze Biologicamente Attive,
Universita` “La Sapienza”, P.le Aldo Moro 5,
I-00195 Roma, Italy
botta@unisi.it
F igu r e 1.
Received December 17, 1999
Azole compounds (such as ketoconazole and bifonazole)
have become well-established drugs for the therapy of
superficial mycoses.2 Bifonazole (Mycospor), in particular,
is a broad-spectrum antifungal agent, mainly used by
topical application in the treatment of fungal skin infec-
tions, including nail infections, and also shows antibacte-
rial activity in vitro against some Gram-positive cocci.3
In the wake of the new regulatory policies,4 many efforts
are currently directed toward the development of enan-
tiomerically pure drugs.5 However, there is limited
information in the literature on the preparation of
enantiomers of azole compounds, either by stereoselective
synthesis6 or enantiomeric separation.7 In particular, only
a few examples of enantiopure azole derivatives having
the azole moiety directly linked to the stereogenic center
have as yet been reported, most likely because of dif-
ficulties in their preparation.8 During the course of our
studies on antifungal agents,9 we became interested in
developing methodologies for the preparation of these
compounds in homochiral form for subsequent biological
evaluation following the new regulatory guidelines. We
F igu r e 2.
describe herein the first synthesis, the full stereochemical
characterization, and the biological evaluation of both
enantiomers of bifonazole (1a ) and related compounds
1b-d (Figure 1), which have been previously synthesized
and tested for their antifungal and/or aromatase inhibit-
ing activity in racemic form.10-12
Enantiomerically pure or enriched amines 2a -e (Fig-
ure 2) were used as starting material for the synthesis
of the target compounds. (R)- and (S)-2d were prepared
from (S)- and (R)-1-phenyl-2-propynylamine (3),13 respec-
tively, by heteroannulation with 2-iodophenol (Scheme
1) following a procedure recently described by us for the
preparation of the corresponding alcohols.14 It is impor-
tant to point out that, unlike propargyl alcohols, the
corresponding propargylamines have not found as yet
very extensive application in palladium-mediated het-
* To whom correspondence should be addressed. (M.B.) Phone: +39-
0577-234306. Fax: +39-0577-234333. (F.C.) Phone: +39-0577-234308.
Fax: +39-0577-234333. E-mail: corelli@unisi.it.
† Universita` “La Sapienza”.
(1) For part 3, see: Messina, F.; Botta, M.; Corelli, F.; Mugnaini,
C. Tetrahedron Lett. 1999, 40, 7289-7292.
(2) Polak, A. In Progress in Drug Research; J ucker, E., Ed.;
Birkha¨user Verlag: Basel, 1997; Vol. 49, pp 219-318.
(3) Parfitt, K. Martindale The Complete Drug Reference, 32nd ed.;
Pharmaceutical Press: London, 1999; p 375.
(4) Laganie`re S. In The Impact of Stereochemistry on Drug Develop-
ment and Use; Abdoul-Enein, H. Y., Wainer, I. W., Eds.; J ohn Wiley
& Sons: New York, 1997; pp 545-564.
(5) McCague, R.; Casy, G. In Progress in Medicinal Chemistry; Ellis,
G. P., Luscombe, D. K., Eds.; Elsevier Science Publishers, B. V.:
Amsterdam, 1997; Vol/ 34, pp 203- 261.
(6) (a) Kitazaki, T.; Tasaka, A.; Hosono, H.; Matsushita, Y.; Itoh,
K. Chem. Pharm. Bull. 1999, 47, 360-368 and references therein. (b)
Saksena, A. K.; Girijavallabhan, V. M.; Lovey, R. G.; Pike, R. E.; Desai,
J . A.; Ganguly, A. K.; Hare, R. S.; Loebenberg, D.; Cacciapuoti, A.;
Parmegiani, R. M. Bioorg. Med. Chem. Lett. 1994, 4, 2023-2028.
(7) Tucker, R. P.; Fell, A. F.; Berridge, J . C.; Coleman, M. W.
Chirality 1992, 4, 316-322.
(8) (a) Corelli, F.; Summa, V.; Brogi, A.; Monteagudo, E.; Botta, M.
J . Org. Chem. 1995, 60, 2008-2015. (b) Botta, M.; Summa, V.;
Trapassi, G.; Monteagudo, E.; Corelli, F. Tetrahedron: Asymmetry 1994,
5, 181-184.
(9) Tafi, A.; Anastassopoulou, J .; Theophanides, T.; Botta, M.;
Corelli, F.; Massa, S.; Artico, M.; Costi, R.; Di Santo, R.; Ragno, R. J .
Med. Chem. 1996, 39, 1227-1235 and references therein.
(10) 1b: J ones, C. D.; Winter, M. A.; Hirsch, K. S.; Stamm, N.;
Taylor, H. M.; Holden, H. E.; Davenport, J . D.; Krumkalns, E. V.; Suhr,
R. G. J . Med. Chem. 1990, 33, 416-429.
(11) 1c: Artico, M.; Stefancich, G.; Silvestri, R.; Massa, S.; Apuzzo,
G.; Artico, M.; Simonetti, G. Eur. J . Med. Chem. 1992, 27, 693-699.
(12) 1d : (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) Riviera, L.; Bellotti, M.
G.; Pestellini, V.; Giannotti, D.; Giolitti, A.; Fanto`, N. Chemioterapia
1987, 6, 272-276. (c) Pestellini, V.; Giannotti, D.; Giolitti, A.; Fanto`,
N.; Riviera, L.; Bellotti, M. G. Chemioterapia 1987, 6, 269-271.
(13) Messina, F.; Botta, M.; Corelli, F.; Schneider, M. P.; Fazio, F.
J . Org. Chem. 1999, 64, 3767-3769.
(14) Botta, M.; Summa, V.; Corelli, F.; Di Pietro, G.; Lombardi, P.
Tetrahedron: Asymmetry 1996, 7, 1263-1266.
10.1021/jo991937p CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/29/2000

Notes
J . Org. Chem., Vol. 65, No. 15, 2000 4737
Sch em e 1a
Ta ble 1. P r ep a r a tion of Com p ou n d s 4, 5, a n d 1 (see
Sch em e 3)
c
yielda
(%)
eeb
(%)
[R]23
(c)
D
compd
R1
mp (°C)
(R)-4a 4-biphenylyl
(R)-4b 4-chlorophenyl
(R)-4c 1-naphthalenyl
(R)-4d 2-benzofuranyl
(S)-4a 4-biphenylyl
(S)-4b 4-chlorophenyl
(S)-4c 1-naphthalenyl
(S)-4d 2-benzofuranyl
(R)-5a 4-biphenylyl
(R)-5b 4-chlorophenyl
(R)-5c 1-naphthalenyl
(R)-5d 2-benzofuranyl
(S)-5a 4-biphenylyl
(S)-5b 4-chlorophenyl
(S)-5c 1-naphthalenyl
(S)-5d 2-benzofuranyl
(R)-1a 4-biphenylyl
(R)-1b 4-chlorophenyl
(R)-1c 1-naphthalenyl
(R)-1d 2-benzofuranyl
(S)-1a 4-biphenylyl
(S)-1b 4-chlorophenyl
(S)-1c 1-naphthalenyl
(S)-1d 2-benzofuranyl
83
70
83
69
78
70
89
72
94
94
87
88
92
79
70
86
68
65
73
64
65
71
71
60
yellow oil
yellow oil
yellow oil
yellow oil
yellow oil
yellow oil
yellow oil
yellow oil
NDd
ND
+7.9 (1.90)
+9.3 (6.92)
ND -25.5 (4.17)
ND -20.1 (1.00)
ND
ND
ND +26.1 (4.22)
ND +21.3 (1.10)
ND
ND +11.0 (2.73)
ND -32.8 (3.20)
ND +29.0 (0.88)
ND +14.9 (2.02)
ND -10.3 (2.73)
ND +40.2 (3.23)
ND -27.4 (0.63)
>97
>98
78
-7.6 (1.90)
-8.9 (6.90)
a
Reaction conditions: (a) 2-iodophenol, PdCl2(PPh3)2, CuI,
TMG, DMF.
yellowish oil
yellowish oil
yellowish oil
yellowish oil
colorless oil
colorless oil
colorless oil
yellowish oil
147-149e
127-130f
-9.9 (2.01)
Sch em e 2a
-2.8 (1.00)
+8.2 (1.39)
+17.0 (1.77)
+22.0 (0.60)
+3.2 (1.00)
-7.9 (1.13)
-17.0 (1.76)
-24.1 (0.66)
81-82g
203-205 dech 90
148-150e
126-129f
80-83g
>97
>98
78
a
Reaction conditions: (a) phenylboronic acid, Pd(OAc)2, PPh3,
Na2CO3, PrOH, H2O.
201-203 dech 92
Sch em e 3a
a
b
Yields refer to isolated and purified materials. Determined
by enantioselective HPLC (see the Experimental Section). c Meas-
ured in CHCl3 solution. ND ) not determined. e Lit.20 mp 142
d
°C. f As nitrate salt (lit.10 mp 129-131 °C). Lit.11 mp 82-83 °C.
g
h
As hydrochloride salt (lit.12c mp 205-207 °C dec).
rotamers in the ratio 2:1. Finally, ring closure by heating
in the presence of ammonium acetate/acetic acid provided
the final compounds 1a -d in good chemical yield and
with high stereoselectivity (Table 1).
The enantiomeric excess was determined by enantio-
selective HPLC on chiral columns Chiralpak AD (1a , 1c,
1d ) and Chiralcel OD (1b) using multiple detections: UV/
CD and polarimetric (see the Experimental Section for
details). An example for compound 1a is reported in
Figure 3.
The enantiomers of compounds 1a -d were tested
against Candida albicans strains in comparison with the
corresponding racemates as well as to fluconazole and
amphotericin B as reference standards using the micro-
broth dilution method.17 In particular, one laboratory
strain of C. albicans and two clinical isolates, one of
which (L3107 strain) fluconazole-resistant, were used.
The results, expressed as minimal inhibitory concentra-
tion (MIC, µM), are reported in Table 2. All the tested
compounds showed essentially the same antimycotic
profile and, quite unexpectedly, in no case was a dif-
ferential activity between the two enantiomers of each
compound observed.18 This lack of stereoselectivity is not
due to racemization of the compounds in the test me-
dium,19 nor necessarily reflects the insensitivity of the
putative fungal target (cytochrome P-450-dependent
a
Reaction conditions: (a) BrCH2 CH(OMe)2, K2CO3, DMF; (b)
BuOCHO, reflux; (c) AcONH4, AcOH. For simplicity, only the (S)-
enantiomers are shown. R1: a , 4-biphenylyl; b, 4-cholorophenyl;
c, 1-naphthalenyl; d , 2-benzofuranyl (see Table 1).
eroannulation reactions, and to the best of our knowledge,
the reaction here reported is the first example involving
a chiral nonracemic R-arylpropargylamine. (R)-2d and
(S)-2d were obtained with only a slight decrease in
enantiomeric purity (93% and 94% ee, respectively, as
determined by enantioselective HPLC) with respect to
the starting amine 3. Both enantiomers of homochiral
amines 2b (>98% ee), 2c (80% ee), and 2e (>98% ee) were
prepared according to the literature.15 The knowledge of
the absolute configurations15b of (S)-(+)-2c and (R)-(-)-
2c allowed us to infer the absolute configuration of 2b
and 2e, by means of the comparison of their circular
dichroism (CD) curves (see the Supporting Information).
Finally, (R)- and (S)-2a were obtained in high enantio-
meric purity (>98% ee) from (R)- and (S)-2e via Suzuki
coupling with phenylboronic acid (Scheme 2) and proved
to be identical with the compounds obtained through the
tedious resolution of the racemic base by means of L-(+)-
tartaric acid.16 Elaboration of 2a -d was carried out
through a reaction sequence (Scheme 3) involving N-
alkylation with bromoacetaldehyde dimethyl acetal to
give 4a -d , followed by N-formylation of 4a -d with butyl
formate to afford intermediates 5a -d as a mixture of
(17) Biologica l Assa y. The antimycotic activity against C. albicans
was evaluated by means of the minimal inhibitory concentration (MIC)
using the serial dilution test in a liquid nutrient medium. MIC is
defined as the lowest concentration (µg/mL) of tested substance at
which there is no macroscopic colonial growth in comparison with a
blank experiment after the preset incubation time. Samples were
dissolved in a mixture of DMSO/water (1/9, v/v). The medium used
was RPMI 1640 broth at pH 7. Inoculum was 10-4 CFU/mL from deep
frozen yeast stock suspension. Visual reading was performed after 20-
24 h of incubation at 35 °C, in humid air.
(15) (a) 2b and 2e: Clemo, G. R.; Gardner, C.; Raper, R. J . Chem.
Soc. 1939, 1958-1960. (b) 2c: Annunziata, R.; Cinquini, M.; Cozzi, F.
J . Chem. Soc., Perkin Trans. 1 1982, 339-343.
(16) Hsu¨, S. K.; Ingold, C. K.; Wilson, C. L. J . Chem. Soc., Perkin
Trans. 2 1935, 1778-1785.
(18) Analogues of 1d have proven to inhibit aromatase in enantio-
selective way (see ref 1).

4738 J . Org. Chem., Vol. 65, No. 15, 2000
Notes
Ta ble 3. Th er m od yn a m ic P a r a m eter s a n d Elu tion Or d er
for th e Sep a r a tion of Com p ou n d s 1a -d by
En a n tioselective HP LC
a
compd
k′1
Rb
Pol.c
CDd
1a
1b
1c
1d
3.96
3.21
2.10
3.55
(-) 1.52
(-) 1.14
(+) 1.70
(+) 1.18
-
-
+
+
(+)
(+)
(-)
(-)
a
b
Capacity factor of the first eluted enantiomer. Enantioselec-
tivity factor. c Sign of polarimetric detector. Sign of CD detector.
d
from uptake by the cells to inhibition of the fungal target
enzyme.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise stated, all reactions
were carried out under an argon atmosphere. 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 uncorrected. 1H 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.
(R)-(+)-r-(4-Bip h en ylyl)b en zyla m in e [(R)-2a ]. Phenyl-
boronic acid (659 mg, 5.4 mmol) was added in one portion to a
solution of (R)-2e (1.35 g, 5.1 mmol) in PrOH (10 mL). The
resulting solution was stirred for 30 min at room temperature.
Next, Pd(OAc)2 (3.5 mg, 0.016 mmol), Ph3P (12.3 mg, 0.047
mmol), and 2 N aqueous Na2CO3 (3.1 mL, 6.2 mmol) were added
successively, and the yellow reaction mixture was refluxed for
6 h. After cooling, the mixture was diluted with water (10 mL)
and extracted with EtOAc. The combined extracts were washed
with brine and dried (Na2SO4). The solvent was removed in
vacuo, and the residue was purified by flash chromatography
(EtOAc as eluent) to give 1.21 g (91%) of (R)-2a as white
crystals: mp 74-76 °C (from cyclohexane) (lit.16 mp 78 °C (from
F igu r e 3. HPLC resolution of the enantiomers of 1a at 25
°C: column, Chiralpak-AD (250 × 4.6 mm); eluent, n-hexane/
i-PrOH (90/10, v/v); flow rate, 1.0 mL/min. Top: CD spectra
of the two enantiomers of 1a in MeOH. Traces a and b: CD
and UV detection, respectively, of racemic 1a . Traces c and
d : UV detection of (-)-1a (97.4% ee) and (+)-1a (97.5% ee),
respectively.
diethyl ether)); [R]22 +13.6 (c 2.58, CHCl3). Anal. Calcd for
D
C
19H17N: C, 87.99; H, 6.61; N, 5.41. Found: C, 88.22; H, 6.57;
N, 5.20.
(S)-(-)-r-(4-Bip h en ylyl)ben zyla m in e [(S)-2a ]. Prepared in
90% yield from (S)-2e following the same procedure described
above: [R]22D -12.8 (c 2.50, CHCl3). Physical and chemical data
were identical with those described above for the opposite
enantiomer.
Ta ble 2. In Vitr o An tim ycotic Activity of Com p ou n d s
1a -d a ga in st C. a lbica n s Str a in s17
MIC (µg/mL)
(R)-(-)-r-(2-Ben zofu r a n yl)ben zyla m in e [(R)-2d ]. To the
orange solution obtained by mixing 2-iodophenol (220 mg, 1.0
mmol) and TMG (345 mg, 3.0 mmol) were added successively
PdCl2(PPh3)2 (35.1 mg, 0.05 mmol), CuI (19.0 mg, 0.1 mmol),
and dry DMF (1.0 mL). After 5 min, a solution of (S)-3 (131 mg,
1.0 mmol) in dry DMF (2 mL) was added, and the reaction
mixture was stirred at 40 °C for 16 h. After cooling, the reaction
was diluted with EtOAc and washed with water (6 × 3 mL).
Washings were reextracted with EtOAc, and the combined
organic layers were washed with brine and dried (Na2SO4). The
solvent was removed in vacuo, and the residue was purified by
flash chromatography (EtOAc/hexanes, 3:1 as eluent) to provide
(R)-2d (156 mg, 70%) as a yellow oil. An analytical sample was
prepared by TLC: [R]23D -10.1 (c 1.15, CHCl3); 1H NMR (CDCl3)
δ 7.47-7.15 (m, 9H), 6.48 (s, 1H), 5.39 (br s, 1H), 1.68 (br s, 2H,
exchangeable with D2O). Anal. Calcd for C15H13NO: C, 80.69;
H, 5.87; N, 6.28. Found: C, 80.44; H, 5.96; N, 6.10.
C. albicans
C. albicans
C. albicans
ATCC90028 clinical isolate clinical isolate
compd
L3023
L145
L3107a
(R)-1a
(S)-1a
1
1
1
1
1
2
2
1
2
2
2
1
0.5
0.5
1
1
1
1
2
1
2
2
1
2
2
2
0.5
0.5
>64
>64
>64
32
32
64
32
32
8
16
(R,S)-1a (bifonazole)
(R)-1b
(S)-1b
(R,S)-1b
(R)-1c
(S)-1c
(R,S)-1c
(R)-1d
(S)-1d
16
32
>64
1
(R,S)-1d
fluconazole
amphotericin B
(S)-(+)-r-(2-Ben zofu r a n yl)ben zyla m in e [(S)-2d ]. Prepared
in 75% yield from (R)-3 following the same procedure described
a
Fluconazole-resistant strain.
(19) Samples dissolved in DMSO/water (1/9, v/v) at pH 7 (phosphate
buffer), and stored at 35 °C for 24 h did not show any decrease of the
ee value.
(20) The Merck Index, 12th ed.; Merck & Co., Inc.,: Whitehouse
Station, NJ , 1996; p 1257.
lanosterol 14R-demethylase) to the stereochemistry of the
inhibitors, but might be the consequence of other phe-
nomena occurring somewhere in the mechanism of action,

Notes
J . Org. Chem., Vol. 65, No. 15, 2000 4739
above: [R]23D +12.0 (c 1.22, CHCl3). Physical and chemical data
were identical with those described above for the opposite
enantiomer.
(9 mmol) in glacial acetic acid (20 mL) was refluxed for 3 h and
then evaporated in vacuo. A saturated aqueous solution of
Na2CO3 (5 mL) was added to the residue, and the mixture was
extracted with EtOAc (3 × 5 mL). The combined extracts were
washed with brine and dried (Na2SO4). The solvent was removed
in vacuo, and the residue was purified by flash chromatography
(EtOAc as eluent) to give 1 (Table 1). As an example, the
spectroscopic and analytical data of (R)-1a are reported below.
For data referring to the other compounds 1, see the Supporting
Information.
(R)-(-)-1-[r-(4-Bip h en ylyl)ben zyl]-1H-im id a zole [(R)-1a ]:
1H NMR (CDCl3) δ 7.55-7.11 (m, 16H), 6.87 (s, 1H), 6.54 (s,
1H); EIMS m/z 311 (M + H)+. Anal. Calcd for C22H18N2: C, 85.12;
H, 5.84; N, 9.03. Found: C, 85.27; H, 5.79; N, 8.94.
Assa y of En a n tiom er ic P u r ity. Enantiomers of compounds
1a -d were separated by enantioselective HPLC employing the
following conditions. Mobile phase: n-hexane/i-PrOH (90/10,
v/v); flow rate, 1.0 mL/min; T ) 25 °C. Detectors: UV/CD (1a :
λ ) 221 nm; 1b, 1c: λ ) 225 nm; 1d : λ ) 245 nm) and ORD in
series. Columns: Chiralpak-AD (250 × 4.6 mm) for compounds
1a , 1c, and 1d , Chiralcel-OD (250 × 4.6 mm) for compound 1b.
Gen er a l P r oced u r e for th e P r ep a r a tion of 4a -d . Bromo-
acetaldehyde dimethyl acetal (1.5 mmol) and anhydrous K2CO3
(1.5 mmol) were added to a solution of the appropriate amine 2
(1 mmol) in dry DMF (2 mL). After being stirred overnight at
120 °C, the reaction mixture was cooled to room temperature,
diluted with water, and extracted with EtOAc. The combined
extracts were washed with water (4 × 5 mL) and brine and then
dried (Na2SO4). The solvent was removed in vacuo, and the
residue was purified by flash chromatography (Et2O/hexanes,
1:1 as eluent) to give 4 (Table 1). As an example, the spectro-
scopic and analytical data of (R)-4a are reported below. For data
referring to the other compounds 4, see the Supporting Informa-
tion.
(R)-(+)-r-(4-Bip h en ylyl)-N-(2,2-d im eth oxyeth yl)ben zyl-
a m in e [(R)-4a ]: 1H NMR (CDCl3) δ 7.61-7.24 (m, 14H), 4.90
(s, 1H), 4.58 (t, J ) 5.6 Hz, 1H), 3.38 (s, 6H), 2.78 (d, J ) 5.6
Hz, 2H), 1.86 (s, 1H, exchangeable with D2O); EIMS m/z 348
(M + H)+. Anal. Calcd for C23H25NO2: C, 79.50; H, 7.25; N, 4.04.
Found: C, 79.26; H, 7.20; N, 3.94.
Gen er a l P r oced u r e for th e P r ep a r a tion of 5a -d . A
solution of the appropriate compound 4 (1 mmol) in butyl
formate (20 mL) was refluxed overnight and then evaporated
in vacuo. The resulting oily residue was purified by flash
chromatography (Et2O/hexanes, 3:1 as eluent) to provide 5 (Table
1) as a mixture of rotamers in the ratio 2:1 (1.5:1 for 5d ). As an
example, the spectroscopic and analytical data of (R)-5a are
reported below. For data referring to the other compounds 5,
see the Supporting Information.
Ack n ow led gm en t. We thank Dr. Stefania Stefanelli
(Biosearch Italia spa, Gerenzano, Varese, Italy) for
biological tests and Prof. Mario Barteri (Department of
Chemistry, University of Rome “La Sapienza”, Rome,
Italy) for CD spectra. This work was supported by the
University of Siena (60% funds-1998) and Italian CNR.
M.B. wishes to thank the Merck Research Laboratories
for the 1998 Academic Development Program (ADP)
Chemistry Award.
(R)-(-)-N-[r-(4-Bip h en ylyl)ben zyl]-N-(2,2-d im eth oxyeth -
yl)for m a m id e [(R)-5a ]: 1H NMR (CDCl3) δ 8.40 (s, 0.3H), 8.12
(s, 0.7H), 7.58 (d, J ) 7.8 Hz, 4H), 7.46-7.20 (m, 10H), 6.99 (s,
0.3H), 6.04 (s, 0.7H), 4.62 (t, J ) 5.2 Hz, 0.7H), 3.52 (d, J ) 5.3
Hz, 2 × 0.7H), 3.44 (s, 6 × 0.7H), 3.36 (d, J ) 5.2 Hz, 2 × 0.3H),
3.12-3.10 (superimposed signals: s, 6 × 0.3H and t, 0.3H); IR
Su p p or tin g In for m a tion Ava ila ble: CD curves for com-
pounds (R)-(+)-2b, (R)-(-)-2c, (S)-(+)-2c, (R)-(+)-2e, and (S)-
(-)-2e as well as spectroscopic and analytical data for com-
pounds 4, 5, and 1 (for simplicity, only R-enantiomers). This
material is available free of charge via the Internet at
http://pubs.acs.org.
1665 cm-1; EIMS m/z 376 (M + H)+. Anal. Calcd for C24H25
-
NO3: C, 76.77; H, 6.71; N, 3.73. Found: C, 76.90; H, 6.79; N,
3.61.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1a -d . A
solution of the appropriate compound 5 (1 mmol) and AcONH4
J O991937P