Chemoenzymatic synthesis of (R)- and (S)-tembamide, aegeline and denopamine by a one-pot lipase resolution protocol

Article abstract of DOI:10.1016/j.tetasy.2004.11.013

An efficient synthesis of optically active β-azido alcohols from their ketoazides by a one-pot reduction and an in situ lipase resolution protocol is described. The synthetic utility of this procedure has been illustrated by its application in the practic

Full text of DOI:10.1016/j.tetasy.2004.11.013

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3939–3944
Chemoenzymatic synthesis of (R)- and (S)-tembamide, aegeline
and denopamine by a one-pot lipase resolution protocol
Ahmed Kamal,* Ahmad Ali Shaik, Mahendra Sandbhor and M. Shaheer Malik
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 30 September 2004; accepted 8 November 2004
Abstract—An efficient synthesis of optically active b-azido alcohols from their ketoazides by a one-pot reduction and an in situ
lipase resolution protocol is described. The synthetic utility of this procedure has been illustrated by its application in the practical
synthesis of both enantiomers of the natural hydroxyamides, tembamide, aegeline and the cardiac drug denopamine, with high
enantioselectivities.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Result and discussion
2.1. Tembamide and aegeline
The importance of enantiopure azido alcohols lies in
their utility as precursors of nonracemic aziridines1
and vicinal amino alcohols.2 The latter compounds are
not only important structural elements in pharmaceuti-
cals such as a- or b-adrenergic blockers3 but also can
be widely used as versatile chiral building blocks and
chiral catalysts4 in organic synthesis. In spite of recent
advances in drug specificity, many chiral drugs are mar-
keted as racemates. Thus, denopamine5 [( )-a,a-(3,4-
dimethoxyphenyl ethyl aminomethyl)-4-hydroxy benzyl
alcohol] 3 is one of the important b-adrenoceptor ago-
nist marketed as racemates of which the (R)-enantiomer
is the active component.
(ꢀ)-Tembamide 1 and (ꢀ)-aegeline 2 are naturally
occurring hydroxyamides isolated from various mem-
bers of the Rutaceae family.6 They have been used in
traditional Indian medicines and have been shown to
have hypoglycemic activity.7 These hydroxyamides pos-
sess a stereogenic centre and have been isolated as total
or partial racemates.8 One of the aims of this investiga-
tion is to develop a one-pot chemoenzymatic synthesis
of both enantiomers of tembamide 1 and aegeline 2.
To date only a few methods for the preparation of these
compounds have been presented, involving resolution of
racemic mixtures9 and multistep synthesis using opti-
cally active cyanohydrins as starting materials.10 Re-
cently enzymatic11 as well as chemical asymmetric
reduction12 of a-azido arylketones have been reported
for the synthesis of 1 and 2. In continuation of our
one-pot synthesis and resolution of various chiral sec-
ondary alcohols,13 we have developed a one-pot reduc-
tion and in situ resolution protocol for the synthesis of
In most of the aryl ethanolamine drugs, the biological
activity resides only in the (R)-enantiomer. The aim of
the present study is to demonstrate that the optically ac-
tive b-azido alcohols can be transformed into chiral nat-
ural and non-natural products of high enantiopurity.
The synthetic targets are the hydroxyamides, tembamide
1, aegeline 2 and denopamine 3.
OH
H
OH
OH
H
H
N
OCH3
OCH3
N
N
O
O
HO
H3CO
H3CO
1
2
3
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189; e-mail: ahmedkamal@iict.res.in
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.013

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A. Kamal et al. / Tetrahedron: Asymmetry 15 (2004) 3939–3944
O
O
O
CH3
N3
OH
N3
N3
i, ii
+
RO
RO
RO
4a R= -CH3
4b R= -CH2 C6H5
(S)-6a, (S)-6b
(R)-5a, (R)-5b
(S)-5a, (S)-5b
iii
Scheme 1. Reagents and conditions: (i) NaBH4, activated alumina, diisopropyl ether; (ii) lipase PS-C, isopropenyl acetate; (iii) anhydrous K2CO3,
MeOH.
enantiopure b-azido alcohols.14 The results encouraged
us to extend the application of the method to the synthe-
sis of chiral b-azido alcohol precursors of tembamide,
aegeline and denopamine. Therefore, the key step in
the synthesis is the one-pot reduction of azidoketone
4a by employing NaBH4 and active neutral aluminum
oxide in diisopropyl ether. The racemic azido alcohol
5a has been resolved in situ by lipase resolution with
Pseudomonas cepacia lipase immobilized on ceramic
particles (PS-C) and isopropenyl acetate as an acyl
donor in 22h at 40ꢁC (Scheme 1). The azido alcohol
(R)-5a was obtained in 98% ee whereas (S)-5a has been
obtained in 96% ee by hydrolysis of (S)-6a with anhy-
drous potassium carbonate in methanol.
duced toxicity, which are important advantages over
many other drugs possessing positive inotropic activity.
Prior to 1991 only a few methods had been reported for
the enantioselective synthesis of denopamine with max-
imum enantioselectivity of 60%. Corey et al. have syn-
thesized (R)-3 in 97% ee using the CBS-reduction
method. Recently, (R)-3 has been synthesized through
reductive biotransformations.13,17,18 Denopamine (R)-3
have also been synthesized from an optically active
cyanohydrin intermediate.2a,19 The reported methods
however suffer from drawbacks such as high cost
involvement, long reaction times and poor enantioselec-
tivity. Herein we report the synthesis of both (R)- and
(S)-enantiomers of denopamine 3 via optically active
b-azido alcohols obtained by the one-pot reduction
and in situ lipase resolution protocol. As described in
Scheme 1 the azidoketone 4b gives (R)-5b and (S)-6b
under the same conditions described for 4a. The acetate
(S)-6b on hydrolysis with anhydrous potassium carbon-
ate in methanol gives corresponding azido alcohol (S)-
5b. The azido alcohols (R)-5b and (S)-5b have been ob-
tained in >99% ee and in 80% ee, respectively, at 40ꢁC in
24h. The enantiopurities of these products were deter-
mined by chiral HPLC analysis employing chiral col-
umn (Chiralcel OD) with a 5:95; isopropanol/hexane
mobile phase. The reduction of azido alcohol (R)-5b
was carried out under mild conditions with triphenyl-
phosphine and the resulted amine on coupling with
3,4-dimethoxyphenylacetylchloride gives hydroxyamide
(R)-8. The amide group of (R)-8 has been reduced with
BH3–DMS to give benzylated denopamine (R)-9. Final-
ly, the benzyl group deprotection with 10% Pd/C results
in denopamine (R)-3. Denopamine (S)-3 has also been
synthesized following the same reaction sequence from
resolved azido alcohol (S)-5b (Scheme 3).
The enantiomeric excesses of the azido alcohols (R)-5a
and (S)-5a were determined by HPLC analysis employ-
ing chiral column (Chiralcel AD-H) with 5:95; isopropa-
nol/hexane mobile phase. Both (R)- and (S)-tembamide
and aegeline have been synthesized from the corre-
sponding azido alcohol (R)- and (S)-5a by sequential
transformations as described in Scheme 2. The reduction
of azidoalcohol 5a with 10% Pd/C gives amino alcohol
7. Condensation of amine 7 with corresponding acid
chlorides gives tembamide and aegeline in quantitative
yields. The present work represents a chemoenzymatic
synthesis of (R)- and (S)-tembamide and aegeline in
three steps from azidoketone 4a in high
enantioselectivity.
2.2. Denopamine
(ꢀ)-Denopamine 3 is a relatively new b1-receptor ago-
nist,15 which is effective in the treatment of congestive
heart failure.16 It can be administered orally and has re-
OH
H
OH
N
R1
NH2
i
ii
(R)-5a
O
H3CO
(R)-1
H3CO
R1= Ph
Tembamide
Aegeline
(R)-7
(R)-2 R1= (E) -Ph-CH=CH-
OH
H
N
R1
i
ii
(S)-5a
(S)-7
O
H3CO
R1= Ph
R1= (E) -Ph-CH=CH-
Tembamide
Aegeline
(S)-1
(S)-2
Scheme 2. Reagents and conditions: (i) 10% Pd/C, H2, MeOH, rt; (ii) R1COCl, Et3N, CH2Cl2, 0ꢁC.

OH
OH
A. Kamal et al. / Tetrahedron: Asymmetry 15 (2004) 3939–3944
3941
H
N
H
N
OCH3
OCH3
OCH3
OCH3
i, ii
iii
(R)-5b
O
BnO
BnO
(R)-9
(R)-8
iv
OH
H
N
OCH3
OCH3
HO
HO
(R)-3, Denopamine
HO
H
i
iv
N
OCH3
OCH3
iii
(S)-9
(S)-5b
(S)-8
ii
(S)-3, Denopamine
Scheme 3. Reagents and conditions: (i) PPh3, THF/H2O (1:1), rt; (ii) 3,4-dimethoxyphenylacetylchloride, dry THF; (iii) BH3–(CH3)2S, THF, rt; (iv)
10% Pd/C, H2, MeOH, rt.
3. Conclusion
geneous addition of 1.1mL water to 10g of neutral
alumina (preheated in oven at 200ꢁC). P. cepacia lipase
immobilized on ceramic particles (PS-C) was purchased
from Amano (Nagoya, Japan).
In summary we have developed a simple and highly effi-
cient synthetic method for optically active b-azido alco-
hols, which have been utilized towards the preparation
of biologically active amino alcohols such as tembamide
1, aegeline 2 and denopamine 3. Reduction of ketoazides
followed by in situ lipase resolution with Pseudomonas
cepacia lipase immobilized on ceramic particles (PS-C)
gives the corresponding b-azido alcohols in high enantio-
selectivity. We have described an alternative chemoen-
zymatic approach for the synthesis of denopamine and
hydroxyamides, which is more efficient than the meth-
ods previously reported.
4.3. General procedure for the one-pot synthesis of
enantiopure azido alcohols 5a,b and acetates 6a,b
To a solution of b-azidoketone (1mmol) in diisopropyl
ether (10mL) was added activated alumina (1.0g) and
NaBH4 (2mmol). The suspension was shaken at
150rpm at 40ꢁC for 3–4h and monitored by TLC for
the complete reduction to racemic azido alcohol. Then
lipase PS-C (1equiv w/w), isopropenyl acetate (6mmol)
were added to the reaction mixture and monitored on
chiral HPLC analysis until it reaches to 50% conversion.
The reaction was filtered and the filtrate was washed
with water, followed by brine. The organic layer was
dried over anhydrous sodium sulfate, concentrated
under reduced pressure and purified by silica gel column
chromatography. The enantiopure products 5 and 6
were analyzed by chiral HPLC and compared with cor-
responding racemic products.
4. Experimental
4.1. Material and methods
Enzymatic reactions were carried out on a ÔLab-line
environ-shakerÕ at 150rpm. Infrared spectra of neat
samples are reported in wave numbers (cmꢀ1). 1H
NMR was recorded as solutions in CDCl3 and chemical
shifts are reported in parts per million (ppm, d) on a
200MHz instrument. Coupling constants are reported
in hertz (Hz). LSIMS mass spectra were recorded on
Autospec M. with 7kV acceleration voltage and 25kV
gun voltage. HPLC analysis was performed on an
instrument that consisted of a Shimadzu LC-10AT sys-
tem controller, SPD-10A fixed wavelength UV monitor
as detector. Optical rotations were recorded on SEPA-
300 Horiba high sensitive polarimeter, fitted with a
sodium lamp of wavelength 589nm.
4.4. Preparation of (R)- and (S)-tembamide 1
4.4.1. (S)-(+)-2-Azido-1-(4-methoxyphenyl)-1-ethyl ace-
tate 6a. One-pot reduction of 4a and in situ lipase res-
olution as described above gave acetate 6a. Yield: 49%;
96% ee [determined by the HPLC analysis using Chiral-
cel AD-H column (hexane/isopropanol, 95:5) with
25
D
0.5mL/min flow rate (tR = 15.29min)]; ½aŠ ¼ þ123:7
(c 1, CHCl3); IR (neat): 2095, 1730cmꢀ1
;
1H
NMR (200MHz, CDCl3): d 2.15 (3H, s), 3.32–3.39
(1H, dd, J = 13.21, 4.15Hz), 3.55–3.63 (1H, dd,
J = 13.21, 8.30Hz), 3.8 (3H, s), 5.80–5.85 (1H, dd,
J = 8.30, 4.15Hz), 6.85 (2H, d, J = 8.68Hz), 7.24 (2H,
d, J = 8.68Hz); LSIMS (m/z): 235 (M+); Anal. Calcd
for C11H13N3O3: C, 56.16; H, 5.57; N, 17.86. Found:
C, 56.11; H, 5.49; N, 17.73%.
4.2. Chemicals and enzymes
Sodium borohydride, neutral alumina and solvents were
obtained commercially and used without purification.
Activated neutral alumina was prepared by homo-

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A. Kamal et al. / Tetrahedron: Asymmetry 15 (2004) 3939–3944
4.4.2.
(R)-(ꢀ)-2-Azido-1-(4-methoxyphenyl)-1-ethanol
70.83; H, 6.32; N, 5.16. Found: C, 70.79; H, 6.28; N,
5.09%.
5a. Prepared from 4a by above general procedure.
Yield: 47%; 98% ee [determined by the HPLC analysis
using Chiralcel AD-H column (hexane/isopropanol,
95:5) with 0.5mL/min flow rate (tR = 42.32min)];
4.4.7. (S)-(+)-Tembamide 1. Prepared from the amino
alcohol (S)-7 by the same procedure described for (R)-
1 to give 0.7g of (S)-1 in pure form. Yield: 87%; White
25
24
D
½aŠ ¼ ꢀ116:9 (c 1.2, CHCl3), {lit12 ½aŠ ¼ ꢀ117:4 (c
D
1.3, CHCl3), ee 99%}; IR (neat): 3449, 2930,
crystalline solid; mp 150–151ꢁC (lit.11 154–155ꢁC);
25
2105cmꢀ1; H NMR (200MHz, CDCl3): d 2.20 (1H,
½aŠ ¼ þ56:9 (c 0.54, CHCl3).
1
D
d, J = 2.97Hz), 3.29–3.5 (2H, m), 3.8 (3H, m), 4.72–
4.85 (1H, m), 6.85 (2H, d, J = 8.17Hz), 7.25 (2H, d,
J = 8.17Hz); Anal. Calcd for C9H11N3O2: C, 55.95; H,
5.74; N, 21.75. Found: C, 55.89; H, 5.63; N, 21.69%.
4.5. Preparation of (R)- and (S)-aegeline 2
4.5.1. (R)-(ꢀ)-Aegeline 2. Acylation of (R)-7 with (E)-
cinnamoyl chloride under similar above mentioned con-
ditions gave 0.75g of aegeline (R)-2. Yield: 85%; White
crystalline solid; mp 194–195ꢁC (lit.11 196–197ꢁC);
4.4.3. (S)-(+)-2-Azido-1-(4-methoxyphenyl)-1-ethanol 5a.
Prepared from (S)-6a by deacetylation procedure using
anhydrous K2CO3 in methanol at room temperature
for 2h to give (S)-5a. Yield: 100%, 96% ee [deter-
mined by the HPLC analysis using Chiralcel AD-H
column (hexane/isopropanol, 95:5) with 0.5mL/min flow
rate (tR = 41.48min)]; ½aŠ ¼ þ114:3 (c 1.3, CHCl3).
25
D
24
D
½aŠ ¼ ꢀ35:9 (c 0.48, CHCl3) {lit.7a ½aŠ ¼ ꢀ35:6
(c 0.4, CHCl3)}; IR (neat): 3460, 3340, 1630, 1093cmꢀ1
;
1H NMR (500MHz, CDCl3): d 3.17–3.25 (1H, m),
3.36–3.43 (1H, m), 3.72 (3H, s), 4.6 (1H, m), 5.44 (1H,
d, J = 4.40Hz), 6.72 (1H, d, J = 15.74Hz), 6.89 (2H, d,
J = 8.18Hz), 7.26 (2H, d, J = 8.18Hz), 7.33–7.43 (3H,
m), 7.54 (2H, d, J = 6.92Hz), 8.14 (1H, m); 13C NMR
(50MHz, DMSO-d6) 46.9, 54.9, 70.9, 113.3, 122.3,
127.0, 127.3, 128.7, 129.2, 134.8, 135.6, 138.4, 158.2,
165.0; LSIMS (m/z): 298 (M++1); Anal. Calcd for
C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.68; H, 6.38, N, 4.66%.
25
D
4.4.4. (R)-(ꢀ)-2-Amino-1-(4-methoxyphenyl)-1-ethanol
7. The azido alcohol (R)-5a (0.579g, 3mmol) was dis-
solved in methanol (10mL) and stirred under a hydro-
gen atmosphere (1atm) in the presence of 10% Pd/C
(50mg) at room temperature for 3h. The catalyst was re-
moved by filtration on a Celite pad and the filtrate was
concentrated to give 0.5g amino alcohol 7. Yield: 99%;
4.5.2. (S)-(+)-Aegeline 2. Prepared from amino alcohol
(S)-7 under above mentioned conditions to give 0.69g
of (S)-2. Yield: 78%; White crystalline solid; mp 194–
25
20
D
½aŠ ¼ ꢀ38:2 (c 1, EtOH) {lit.12 ½aŠ ꢀ39.9 (c 1.03,
D
EtOH)}; IR (neat): 3348, 3078, 1615, 1509cmꢀ1 1H
;
NMR (200MHz, CDCl3): d 1.68–2.10 (3H, br s), 2.70–
3.0 (2H, m), 3.82 (3H, s), 4.60 (1H, br s), 6.89 (2H, d,
J = 8.68Hz), 7.28 (2H, d, J = 8.68Hz); LSIMS (m/z):
137 (M+ꢀ30); Anal. Calcd for C9H13NO2: C, 64.65;
H, 7.84; N, 8.38. Found: C, 64.59; H, 7.78; N, 8.35%.
25
195ꢁC (lit.11 196–197ꢁC); ½aŠ ¼ þ34:1 (c 0.4, CHCl3).
D
4.6. Preparation of (R)- and (S)-denopamine 3
4.6.1. (S)-(+)-2-Azido-1-(4-benzyloxyphenyl) ethyl ace-
tate 6b. Prepared by using the general procedure of
one-pot reduction of 4b and in situ lipase resolution to
give acetate (S)-6b. Yield: 49%; 80% ee [determined
by the HPLC analysis using Chiralcel OD column
4.4.5. (S)-(+)-2-Amino-1-(4-methoxyphenyl)-1-ethanol
7. Prepared from azido alcohol (S)-5a by the same
procedure described for (R)-7. Yield: 99%;
25
D
½aŠ ¼ ꢀ37:8 (c 1.1, EtOH).
(hexane/isopropanol, 95:5) with 0.5mL/min flow rate
25
(tR = 25.56min)]; ½aŠ ¼ þ80:2 (c 0.9, CHCl3); IR
D
1
4.4.6. (R)-(ꢀ)-Tembamide 1. To a solution of amino
alcohol (R)-7 (0.5g, 3mmol) in dry CH2Cl2 (10mL) in
the presence of Et3N (0.42mL, 4mmol) was added ben-
zoyl chloride (0.38mL, 3.3mmol) dropwise at 0ꢁC and
the mixture was stirred at the same temperature for
2h. The reaction mixture was diluted with water and ex-
tracted with CH2Cl2. The organic layer was separated
and washed with brine and dried over anhydrous
Na2SO4. The solvent was evaporated and the residue
was chromatographed on silica gel to give pure 0.73g
(neat): 2120, 1740cmꢀ1; H NMR (200MHz, CDCl3):
d 2.12 (3H, s), 3.31–3.43 (1H, dd, J = 12.63, 3.71Hz),
3.54–3.68 (1H, dd, J = 12.63, 8.17Hz), 5.06 (2H, m),
5.8–5.89 (1H, dd, J = 8.17, 3.71Hz), 6.93 (2H, d,
J = 8.92Hz) 7.26–7.44 (7H, m); LSIMS (m/z): 255
(M+ꢀ56); Anal. Calcd for C17H17N3O3: C, 65.58; H,
5.50, N, 13.50. Found: C, 65.49; H, 5.48; N, 13.46%.
4.6.2. (R)-(ꢀ)-2-Azido-1-(4-benzoyloxyphenyl)-1-ethanol
5b. Prepared by using the general procedure of one-
pot reduction of 4b and in situ lipase resolution to give
azido alcohol (R)-5b. Yield: 46%; >99% ee [determined
by the HPLC analysis using Chiralcel OD column
of (R)-1. Yield: 90%; White crystalline solid; mp 150–
25
D
151ꢁC (lit.11 154–155ꢁC); ½aŠ ¼ ꢀ58:7 (c 0.6, CHCl3)
24
{lit.7a ½aŠ ¼ ꢀ59:8 (c 0.4, CHCl3)}; IR (neat): 3498,
D
3390, 1632, 1545, 1243cmꢀ1
;
1H NMR (200MHz,
(hexane/isopropanol, 95:5) with 0.5mL/min flow rate
25
D
CDCl3): d 3.42–3.6 (1H, m), 3.8 (3H, s), 3.81–3.95
(1H, m), 4.9 (1H, dd, J = 8.17, 2.97Hz), 6.6 (1H, m),
6.9 (2H, d, J = 8.17Hz), 7.32 (2H, d, J = 8.92Hz), 7.44
(3H, m), 7.75 (2H, d, J = 8.92Hz); 13C NMR
(50MHz, DMSO-d6) 47.7, 55.0, 70.8, 113.4, 127.22,
127.25, 128.2, 131.1, 134.6, 135.8, 158.4, 166.5; LSIMS
(m/z): 272 (M++1); Anal. Calcd for C16H17NO3: C,
(tR = 61.57min)]; ½aŠ ¼ ꢀ72:5 (c 1.3, CHCl3),
20
D
{lit.12 ½aŠ ¼ ꢀ72:2 (c 1.1, CHCl3), ee 99%}; IR (neat):
1
3345, 3142, 2890cmꢀ1; H NMR (200MHz, CDCl3): d
3.42–3.52 (2H, m), 4.81 (1H, m) 5.05 (2H, s), 6.95
(2H, d, J = 8.78Hz), 7.25–7.45 (7H, m); LSIMS (m/z):
213 (M+ꢀ56); Anal. Calcd for C15H15N3O2: C, 66.90;
H, 5.61; N, 15.60. Found: C, 66.79; H, 5.56; N, 15.56%.

A. Kamal et al. / Tetrahedron: Asymmetry 15 (2004) 3939–3944
3943
4.6.3. (S)-(+)-2-Azido-1-(4-benzyloxyphenyl)-1-ethanol
5b. Prepared from 6b by the deacetylation procedure
using anhydrous K2CO3 in MeOH at room temperature
for 2h to give 5b. Yield: 98%; 80% ee [determined by the
HPLC analysis using Chiralcel OD column (hexane/
4.6.8. Denopamine (R)-3. Benzylated denopamine (R)-9
(0.83g, 2.07mmol) was dissolved in MeOH (10mL) and
stirred under hydrogen atmosphere (1atm) in the pres-
ence of 10% Pd/C (80mg) at room temperature for 6h.
The catalyst was removed by filtration on a Celite pad
and the filtrate was concentrated and recrystallized from
ethyl acetate/hexane to give 0.661g of denopamine (R)-3
isopropanol, 95:5) with 0.5mL/min flow rate (tR =
25
D
68.67min)]; ½aŠ ¼ þ69:4 (c 0.9, CHCl3).
in pure form. Yield: 96%; White crystalline solid;
25
D
mp 160–161ꢁC (lit.11 164–165ꢁC) ½aŠ ¼ ꢀ27:9 (c 1,
4.6.4. Preparation of hydroxyamide (R)-8. The azido
alcohol (R)-5b (0.807g, 3mmol) was dissolved in THF/
H2O (10:10mL) and added triphenylphosphine
(0.917g, 3.5mmol) at room temperature. The resulting
mixture was evaporated to remove THF and the residue
was extracted with ethyl acetate. The organic layer was
separated and washed with brine and dried over anhy-
drous Na2SO4. The solvent was evaporated under re-
duced pressure to give crude amino alcohol, which was
dissolved in 10mL of dry THF and Et3N (0.487mL,
3.5mmol) and was added dropwise to the solution of
3,4-dimethoxyphenacetyl chloride21 in dry THF. The
resulting solution was stirred at ꢀ78ꢁC for 30min and
it was allowed to warm to room temperature. After 3h
the reaction mixture was quenched with saturated
solution of NH4Cl and extracted with ethyl acetate
(2 · 10mL). The organic layers were combined, washed
with brine, dried over anhydrous sodium sulfate and
evaporated. The residue was chromatographed on silica
24
MeOH), {lit.20 ½aŠ ¼ ꢀ27:5 (c 0.95, MeOH)} IR
D
(neat): 2935, 1620, 1583cmꢀ1
;
1H NMR (200MHz,
CDCl3): d 3.02–3.36 (6H, m), 3.79 (3H, s), 3.81 (3H,
s), 4.53 (1H, m), 5.16 (1H, m), 6.68–6.88 (5H, m), 7.21
(2H, d, J = 8.78Hz); 13C NMR (50MHz, CDCl3)
34.88, 50.90, 52.75, 56.09, 72.48, 111.28, 114.43,
119.85, 126.96, 132.08, 134.29, 147.85, 149.18, 158.40,
159.31; LSIMS (m/z): 318 (M++1); Anal. Calcd for
C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C,
68.08; H, 7.23; N, 4.39%.
4.6.9. Denopamine (S)-3. Prepared from (S)-9 under
similar above mentioned conditions to give 0.647g of
denopamine (S)-3. Yield: 98%; White crystalline solid;
25
D
mp 160–161ꢁC (lit.11 164–165ꢁC) ½aŠ ¼ þ25:4 (c 0.8,
MeOH).
Acknowledgements
gel to give 0.985g of (R)-8 in pure form. Yield: 78%;
25
D
Authors (A.A.S., M.S. and M.S.M.) are thankful to
CSIR, New Delhi for the award of research fellowships.
½aŠ ¼ ꢀ29:8 (c 1.1, CHCl3); IR (KBr): 3475, 3362,
1639cmꢀ1
;
1H NMR (200MHz, CDCl3): d 3.06–3.40
(2H, m), 3.5–3.64 (2H, m) 3.86 (3H, s), 3.89 (3H, s),
4.70–4.77 (1H, m) 5.0 (2H, s) 6.74–6.85 (2H, m), 6.92
(2H, d, J = 8.68), 7.19 (2H, d, J = 8.68Hz), 7.32–7.45
(6H, m); LSIMS (m/z): 421 (M+); Anal. Calcd for
C25H27NO5: C, 71.24; H, 6.46; N, 3.32. Found: C,
71.15; H, 6.39; N, 3.25%.
References
1. For reviews, see: (a) McCoull, W.; Davis, F. A. Synthesis
2000, 1347; (b) Osborn, H. M. L.; Sweeney, J. Tetrahe-
dron: Asymmetry 1997, 8, 1693; (c) Tanner, D. Angew.
Chem., Int. Ed. Engl. 1994, 33, 599.
2. For reviews, see: (a) Bergmeier, S. C. Tetrahedron 2000,
56, 2561; (b) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem.
Rev. 1996, 96, 835.
3. Powell, J. R.; Waimer, I. W.; Drayer, D. E. Drug
Stereochemistry Analytical Methods and Pharmacology;
Marcel Dekker: New York, 1998.
4.6.5. Preparation of hydroxyamide (S)-8. Prepared
from the azido alcohol (S)-5b by the above mentioned
conditions to give 0.871g of (S)-8 in pure form. Yield:
25
69%; ½aŠ ¼ þ25:6 (c 1.1, CHCl3).
D
4. For a review see: Noyori, R.; Suga, S.; Kawai, K.; Okada,
S.; Kitamura, M.; Oguni, N.; Hayashi, M.; Kaneko, T.;
Matsuda, Y. J. Organomet. Chem. 1990, 382, 19–37.
5. Elks, J.; Ganellin, C. R. Dictionary of Drugs, Chemical
Data, Structure and Bibliographies, first ed.; University
Press: Cambridge, GB, 1990; p 358.
6. (a) Kuck, A. M.; Albonico, S. M.; Deulofeu, V. Chem.
Ind. 1996, 945–946; (b) Chatterjee, A.; Bose, S. J. Ind.
Chem. Soc. 1952, 29, 425; (c) Johns, S. R.; Lamberton, J.
A.; Price, J. R. Aust. J. Chem. 1967, 20, 2795–2797; (d)
Johns, S. R.; Lamberton, J. A.; Tweeddale, H. J.; Willing,
R. I. Aust. J. Chem. 1969, 22, 2233–2236.
4.6.6. Benzylated denopamine (R)-9. To a solution of
hydroxyamide (R)-8 (0.9g, 2.13mmol) in dry THF
(10mL) a solution of BH3–DMS (2.43mL, 2.5mmol)
was added. The resulting mixture was stirred at room
temperature for 2h. The reaction mass was quenched
with methanol, upon solvent evaporation to give
0.849g of (R)-9 in pure form. Yield: 98%;
25
20
½aŠ ¼ ꢀ34:8 (c 1.2, CHCl3), {lit.18 ½aŠ ¼ ꢀ34:3
D
(c 1.0, CHCl3)}; IR (KBr): 3275, 2920, 1600,
D
1450cmꢀ1 1H NMR (200MHz, CDCl3): d 2.70–3.10
;
(6H, m), 3.74 (3H, s), 3.77 (3H, s), 4.77 (1H, m), 4.94
(2H, s), 6.66 (2H, d, J = 5.12Hz), 6.83 (2H, d,
J = 8.78), 7.1–7.38 (8H, m); LSIMS (m/z): 408 (M++1);
Anal. Calcd for C25H29NO4: C, 73.69; H, 7.17; N,
3.44. Found: C, 73.57; H, 7.01; N, 3.35%.
7. (a) Brown, R. F. C.; Jackson, W. R.; McCarthy, T. D.
Tetrahedron: Asymmetry 1993, 4, 205–206; (b) Brown, R.
F. C.; Donohue, A. C.; Jackson, W. R.; McCarthy, T. D.
Tetrahedron 1994, 50, 13739–13752.
8. Kuck, A. M.; Albonico, S. M.; Deulofeu, V. J. Chem.
Soc., Sect. C 1967, 1327–1328.
9. Kappe, T.; Armstrong, M. D. J. Med. Chem. 1964, 7, 569–
571.
10. (a) Pamies, O.; Backvall, J. E. J. Org. Chem. 2001, 66,
4022–4025; (b) Foelsche, E.; Hickel, A.; Honig, H.;
4.6.7. Benzylated denopamine (S)-9. Prepared from
hydroxyamide (S)-8 by above procedure to give 0.85g
of (S)-9. Yield: 94%; ½aŠ ¼ þ30:4 (c 0.8, CHCl3).
25
D

3944
A. Kamal et al. / Tetrahedron: Asymmetry 15 (2004) 3939–3944
Seufer-Wasserthal, P. J. Org. Chem. 1990, 55, 1749–
1753.
11. Yadav, J. S.; Reddy, P. T.; Nanda, S.; Rao, A. B.
Tetrahedron: Asymmetry 2001, 12, 3381–3385.
K.; Nagao, K.; Ono, Y.; Otsuka, M.; Harigaya, S.;
Nakajima, H. Jpn. J. Pharmacol. 1985, 39, 541.
16. Ikeo, T.; Nagao, T.; Suzuki, T.; Yabana, H. Jpn. J.
Pharmacol. 1985, 39, 191.
12. Cho, B. T.; Kang, S. K.; Shin, S. H. Tetrahedron:
Asymmetry 2002, 13, 1209–1217.
17. Xin-Jian, G.; Zu-Yi, L.; Guo-Qiang, L. Tetrahedron 1993,
49, 5805–5816.
13. (a) Kamal, A.; Sandbhor, M.; Ramana, K. V. Tetrahe-
dron: Asymmetry 2002, 13, 815; (b) Kamal, A.; Sandbhor,
M.; Shaik, A. A.; Sravanthi, V. Tetrahedron: Asymmetry
2003, 14, 2839; (c) Kamal, A.; Sandbhor, M.; Shaik, A. A.
Tetrahedron: Asymmetry 2003, 14, 1575; (d) Kamal, A.;
Sandbhor, M.; Ahmad, K.; Adil, S. F.; Shaik, A. A.
Tetrahedron: Asymmetry 2003, 14, 3861.
14. Kamal, A.; Shaik, A. A.; Sandbhor, M.; Malik, M. S.
Tetrahedron: Asymmetry 2004, 15, 935–938.
15. (a) Naito, K.; Nagao, T.; Otsuka, M.; Harigaya, S.;
Nakajima, H. Jpn. J. Pharmacol. 1985, 38, 235; (b) Naito,
18. Goswami, J.; Bezbaruah, R. L.; Goswami, A.; Borthakur,
N. Tetrahedron: Asymmetry 2001, 12, 3343–3348.
19. Brown, R. F. C.; Jackson, W. R.; McCarthy, T. D.
Tetrahedron: Asymmetry 1993, 4, 2149–2150.
20. Corey, E. J.; Link, J. O. J. Org. Chem. 1991, 56, 442–
447.
21. 3,4-Dimethoxyphenacetyl chloride was prepared by add-
ing pivaloyl chloride (0.383mL, 3.15mmol) dropwise to a
stirred and cooled (ꢀ78ꢁC) solution of 3,4-dimethoxy-
phenyl acetic acid (0.588g, 3mmol) and Et3N (0.48mL,
3.5mmol) in dry THF (15mL).