Chemoenzymatic synthesis of piperoxan, prosympal, dibozane, and doxazosin

Article abstract of DOI:10.1016/j.tetasy.2012.10.018

The synthesis of both enantiomers of 1,4-benzodioxan-2-carboxylic acid 1, a key synthetic intermediate for the therapeutic agents piperoxan, prosympal, dibozane, and doxazosin was achieved with good yields and high enantioselectivities via the Arthrobacter sp. lipase catalyzed kinetic resolution of ester (±)-17a. The influence of the co-solvents and the immobilization of the lipase upon kinetic resolution demonstrated that immobilized whole cells, in the presence of n-butanol as a co-solvent, resulted in the optimal resolution of the substrate (ee ～99%, E = 535) at 258 mmol (50 g/L) substrate concentration.

Full text of DOI:10.1016/j.tetasy.2012.10.018

Tetrahedron: Asymmetry 23 (2012) 1615–1623
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Tetrahedron: Asymmetry
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Chemoenzymatic synthesis of piperoxan, prosympal, dibozane, and doxazosin
Abdul Rouf, Pankaj Gupta , Mushtaq A. Aga, Brijesh Kumar, Asha Chaubey, Rajinder Parshad,
⇑
Subhash C. Taneja
CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, J&K, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 October 2012
Accepted 26 October 2012
The synthesis of both enantiomers of 1,4-benzodioxan-2-carboxylic acid 1, a key synthetic intermediate
for the therapeutic agents piperoxan, prosympal, dibozane, and doxazosin was achieved with good yields
and high enantioselectivities via the Arthrobacter sp. lipase catalyzed kinetic resolution of ester ( )-17a.
The influence of the co-solvents and the immobilization of the lipase upon kinetic resolution demon-
strated that immobilized whole cells, in the presence of n-butanol as a co-solvent, resulted in the optimal
resolution of the substrate (ee ꢀ99%, E = 535) at 258 mmol (50 g/L) substrate concentration.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
oxan 3, prosympal 4, and dibozane 5, where the (S)-isomers are
more effective then the (R)-isomers.7 Similarly, both enantiomers
The 2-substituted 2,3-dihydro-1,4-benzodioxane ring motif is
present in a large variety of natural products1 and in the structures
of therapeutic agents possessing important biological activities.2 It
has been observed that their respective biological activities are lar-
gely influenced by the absolute configuration at the C2 stereogenic
center of the benzodioxane unit.3 Various 2-substituted 1,4-benzo-
of doxazosin mesylate 6 (antihypertensive drug) have different
biological properties, that is (S)-doxazosin exhibits reduced side ef-
fects (asthenia and dizziness) and improved efficacy over ( )-dox-
azosin for the treatment of benign prostatic hyperplasia8,2b (BPH),
whereas the (R)-enantiomer has a higher selectivity for the lower
urinary tract versus the cardiovascular system and the urinary sys-
tem in the animal experiments.9 It has also been reported that N-
{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-
dioxanes have shown interesting properties as
a- or b-blocking
agents showing antihypertensive properties,4 while others have
affinities with serotonin receptors which are involved in nervous
breakdowns, schizophrenia, and headaches,5 or exhibit antihyper-
glycemic properties.4d Enantiomerically pure 1,4-benzodioxane-2-
carboxylic acid 1 and 2-hydroxymethyl-1,4-benzodioxan 2 deriva-
tives (Fig. 1) are important intermediates for the synthesis of drugs
and biologically active molecules. These compounds are also versa-
tile synthons for a variety of synthetic transformations.6
yl]-ethyl}-2-phenoxy-nicotinamide
7 possesses CNS-penetrant
and selective a2C adrenergic receptor antagonist activities.10
Furthermore, it has been reported that (R)-(+)-1,4-benzodioxan-
2-carboxylic acid is the precursor of (2S)-2-hydroxymethyl-1,4-
benzodioxanes and (2S)-2-aminomethyl-1,4-benzodioxanes which
are the chiral fragments of MKC-242 8,11 an antidepressant and
WB4101 9,12,2a,4b,4d,11b a potent
a-adrenergic antagonist. The (R)-
hydroxymethylbenzodioxane derivative 10 was reported to be
one of a new class of potent, selective, and orally active prostaglan-
din D2 (PGD2) receptor antagonists.13 The natural product flavolig-
nan silybin14 11, a constituent of Silybum marianum Gaertn is
known for antihepatotoxic activities.15 It has been shown that
3,4-dihydroxystyrene dimers 12, 13, and 14 isolated from the mar-
ine sponge Jaspis sp. induce metamorphosis in ascidian Halocynthia
roretzi larvae16 (Fig. 2).
The preparation of a 2-substituted 2,3-dihydro-1,4-benzodiox-
ane ring motif typically involves the use of building blocks from
the chiral pool,17 for example reacting catechol with chiral glyc-
idol18 or epichlorohydrin,11b via Sharpless epoxidation of the sub-
strate 1-aryloxy-4-hydroxy-2-butene,19 or enzymatic resolutions
of racemic 1,4-benzodioxan-2-carboxylic acid,20 its ethyl ester,21,7a
or 2-hydroxymethyl-1,4-benzodioxane,22 or by diastereomeric
crystallization with chiral amines.23 Another approach involves
O
O
O
OH
OH
O
2
O
1
Figure 1. 1,4-Benzodioxane-2-carboxylic acid 1 and 2-hydroxymethyl-1,4-benzo-
dioxan 2 derivatives.
Hydroxymethyl-1,4-benzodioxane 2 derivatives are the direct
intermediates of a-adrenergic receptor antagonists such as piper-
⇑
Corresponding author.
E-mail address: sctaneja@iiim.ac.in (S.C. Taneja).
Present address: Department of Chemistry, Govt. Degree College, Kathua, J&K,
India.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.10.018

1616
A. Rouf et al. / Tetrahedron: Asymmetry 23 (2012) 1615–1623
O
O
O
O
O
O
NEt2
N
N
N
O
O
piperoxan 3
prosympal 4
dibozane 5
O
O
N
N
N
OMe
OMe
PhO
O
O
N
N
N
N
O
O
NH2
HCl
O
α2C adrenergic receptor antagonist 7
doxazosin hydrochloride 6
OMe
O
O
O
O
H
N
H
N
O
O
O
HCl
MeO
WB4101 9
MKC-242 8
O
O
O
OH
N
HO
O
O
OMe
OH
COOH
O
O
O
Me
OH
OH
11
prostagladin D2 receptor antagonist 10
OH
O
O
OSO3
O
O
OSO3
O
OH
OH
OH
OH
OH
O3SO
OHC
O3SO
O
OSO3
13
Figure 2. Bioactive molecules containing 1,4-benzodioxane moiety.
12
14
the cycloaddition of a variety of o-quinones with a dienophile,
either directly or via a two-step process involving a hetero-Diels–
Alder reaction followed by a [3,3] sigmatropic rearrangement.24
The most recent examples are the palladium-catalyzed asymmetric
cyclization of benzene-1,2-diol with allylic biscarbonates;25 the
palladium catalyzed intramolecular cyclization of non-racemic 1-
(2-bromophenyl)glycerol;11a and the Cu2O-catalyzed ring-opening
and coupling of epoxides.26 However, most of the reported resolu-
tion techniques are generally either low yielding or has low enanti-
oselectivity; in some cases repeated crystallization is required to
obtain high enantiomeric purity.23a
Numerous reports on the preparation of the 1,4-benzodioxan-2-
carboxylic acid motif signify the importance of this basic unit;
while doxazosin has been the subject of several past investigations,
no satisfactory reports or data are available in the literature espe-
cially related to optically active piperoxan, prosympal, and diboz-
ane, except for a report on the use of chiral shift reagents for
measuring their enantiomeric purity.7 Herein is an attempt toward
the preparation of both enantiomers of these biomolecules with
high enantiomeric purity for their bioactivity evaluation.
other synthetically important molecules.29 In an attempt to devel-
op an efficient kinetic resolution methodology, we herein report
the results of the successful use of whole cells of a versatile indig-
enous lipase Arthrobacter sp.,30 designated as ABL (MTCC No. 5125)
available in the institutional microbial repository for the efficient
resolution of 1,4-benzodioxan-2-carboxylic acid 1, and its syn-
thetic transformation to optically active piperoxan 3, prosympal
4, dibozane 5, and doxazosin 6. The retrosynthetic route to these
molecules is shown in Scheme 1.
2. Results and discussion
We began with the coupling of catechol and alkyl-2,3-dibromo-
propionate (produced by the bromination of an alkyl acrylate) to
produce racemic alkyl-2,3-dihydrobenzo-(1,4)-dioxan-2-carboxyl-
ate 17 in 90% yield (Scheme 2). A kinetic resolution through hydro-
lysis of the ester ( )-methyl-1,4-benzodioxan-2-carboxylate 17a
with ABL (whole cells) was carried out in 0.1 M phosphate buffer;
however good selectivity was not observed. Therefore, the reaction
was carried out in a biphasic system containing different organic
solvents (Scheme 2).
Biocatalysis is increasingly becoming a useful tool for organic
chemists in the synthesis of biologically active natural and unnat-
ural products;27 our group has been actively involved in the che-
moenzymatic synthesis of biologically active compounds28 and
Between the methyl and ethyl derivatives of ( )ꢁ17, ABL
showed both higher selectivity and conversion rate for the methyl

A. Rouf et al. / Tetrahedron: Asymmetry 23 (2012) 1615–1623
1617
O
O
NEt2
3
O
O
N
O
O
O
O
OH
OH
OMe
4
O
O
OH
O
O
O
N
1
17a
N
O
5
O
O
O
N
N
N
OMe
OMe
N
6
NH2
Scheme 1. Retrosynthetic approach for piperoxan, prosympal, dibozane, and doxazosin.
O
O
O
OH
(S)-1
O
O
Br
O
a
O
O
c
b
OR
OR
OR
O
Arthrobacter species
Br
O
15
lipase
OR
(R)-17
16
( )-17
O
17a, R = Methyl,
17b
R = Ethyl,
O
O
O
d
OH
(R)-17a
(R)-1
Scheme 2. Reagents and conditions: (a) Br2, CCl4; (b) Catechol, K2CO3, acetone, reflux; (c) Lipase (ABL), co-solvent, buffer; (d) LiOH, THF:H2O.
Table 1
Effect of alkyl group on hydrolysis
R
Solvent
Time (h)
Conv. (%)
ees (%)
eep (%)
Methyl
Ethyl
n-butanol
n-butanol
4
4
42
49
73
87
99
90
ester (Table 1). Therefore, the optimization of reaction conditions
was carried out on the methyl ester with different co-solvents31
with variations in their concentrations, reaction temperatures,
pH and substrate concentrations, immobilization, etc. to improve
overall time-space yields.
For the optimization study with methyl ester, a variety of polar
and non-polar solvents ranging from 10 to 50% (v/v) in buffer were
used and their effects on the rate of hydrolysis, as well as enanti-
oselectivity, were measured. It was found that the addition of
20–30% of co-solvent markedly improved the enantioselectivity
Figure 3. Effect of the percentage of the co-solvent n-butanol on eep and
conversion.
as well as the rate of hydrolysis (Fig. 3). During the screening of
the co-solvents as depicted in Table 2, only two solvents, n-butanol

1618
A. Rouf et al. / Tetrahedron: Asymmetry 23 (2012) 1615–1623
Table 2
Effect of co-solvents (20%) on the hydrolysis of ( )-17a at 20 g/L using Arthrobacter species lipase (ABL)
Entry
Enzyme
Co-solvent
Conv.(%)
Time (h)
eep (%)
ees (%)
E
1
2
3
4
5
6
7
8
Cells
Cells
Cells
Nil
50
47
42
46
37.3
41
47
68
65
44
79
70
55
44
40
52
42
36.6
4
7
4
24
18
24
6
0
45
88
73
87
40
71
81
97
79
73
87
99
99
71
60
99
65
33
—
n-butanol
n-butanol
n-butanol
n-butanol
n-butanol
Toluene
Dioxane
Isopropanol
CH3CN
DMSO
DIE
DIE
DIE
93
99
99
67
99
89
45
41.5
91.5
23
41
79
89
90
88
90
60
79.6
429.2
535.6
7.3
411.9
41
9.1
5.27
48
3.8
8.1
33
35.9
34.9
58.8
37.2
5.5
Immobilized Cellsa
Free enzyme
Immobilized enzyme
Cells
Cells
Cells
Cells
Cells
Cells
Cells
Cells
Cells
Cellsb
Cellsc
Cellsd
6
9
12
12
12
4
10
11
12
13
14
15
16
17
18
2
20 min
4
n-butanol
n-butanol
n-butanol
n-butanol
5 h
5 h
5 h
Letters in bold indicate the best results.
E = ln[1-c(1+eep)]/ln[1-c(1-eep)],33 p = product.
The ees were determined by chiral HPLC column OJ-H using a triflouroacetic acid/isopropyl alcohol/hexane; (0.1:5:95) solvent system at a 0.5 ml/min flow rate.
a
Experimental conditions: cells entrapped in sol–gel supports.
Substrate adsorbed on Celite.
Substrate adsorbed on silica.
b
c
d
Substrate adsorbed on alumina, all the reactions were performed at 25 °C in a shaker at 320 rpm, ee (%) was measured by chiral HPLC and the conversion was calculated
using the formula c = (ees ꢂ 100)/(eep + ees)%, DIE—diisopropylether.
and diisopropylether (DIE) were found to be suitable. Finally, the
addition of 20% n-butanol or DIE (v/v) in a phosphate buffer
(0.1 M, pH 7.0) proved to be the best choice for an efficient kinetic
resolution.
During the kinetic resolution studies, we observed that the
enantiomeric excess was strongly dependent on the extent of
hydrolysis and so it was important to carry out the reaction beyond
50% hydrolysis (ꢀ58%) in order to obtain the enantiopure ester (R)-
17a (ee >99%) in good yields when diisopropyl ether was used as
the co-solvent. In order to obtain its enantiomer, (S)-1, the reaction
was stopped at ꢀ42% for >99% enantioselectivity using n-butanol
as the co-solvent. The results of these investigations are repre-
sented in Figure 4.
Attempts were also made to observe the effect of immobilized
substrates on hydrolysis, a methodology found to be highly useful
in the kinetic resolution of spiro-b-lactams.32 The substrate was
adsorbed on different supports such as Celite, silica, and neutral
alumina. However, it was observed that adsorption of the substrate
on Celite and silica had no significant advantage (ee ꢀ88–90%),
whereas in the alumina adsorbed substrate, the ee% decreased fur-
ther (Table 2).
In order to assess the effect of the immobilized enzyme (ABL),
hydrolytic reactions were performed using a sol–gel entrapped iso-
lated enzyme as well as entrapped whole cells (see Section 4). It
was observed that the selectivity as well as conversion increased
by immobilizing whole cells (E = 535.6) whereas a very significant
increase in enantioselectivity was recorded with immobilized en-
zyme compared to unimmobilized lipase (entries 5 and 6, Table 2).
However, the whole cell immobilization displayed slight advanta-
ges over the immobilized isolated enzyme (entries 4 and 6, Table 2).
Figure 4. Enantioselective hydrolysis of ( )-17a using Arthrobacter species lipase in
It should be noted that the time of hydrolysis increased signifi-
n-butanol and DIE as co-solvents.
cantly (24 h) when using immobilized biocatalysts. Moreover, the
immobilized whole cells/enzymes could be reused after washing
with organic solvent/sodium bicarbonate/distilled water to remove
Keeping all other reaction parameters constant, the substrate
any traces of the substrate/product (results not shown).
concentration was also varied from 10 to 50 g/L (51–258 mmol)
Upon varying the ratios of the substrate and whole cell mass,
and we observed that the lipase remained quite active up to
the best results were observed with a substrate/whole cell ratio
50 g/L (258 mmol) with no effect on the enantiomeric excess,
of 1:3, as shown in Table 3.

A. Rouf et al. / Tetrahedron: Asymmetry 23 (2012) 1615–1623
1619
Table 3
coupled with mono-Boc piperazine to form (S)-18 in high yields;
an improvement over earlier reported methods,8a followed by cou-
pling with amine 20 to obtain the (S)-doxazosin 6 (Scheme 3). The
(R)-doxazosin was then prepared from ester (R)-1 by following the
same procedure (see Section 4).
Effect of substrate/whole cell ratio on conv. and ee of acid 1
S. no.
Subs/whole cell ratio
Conv. (%)
eep (%)
1
2
3
4
5
1:1
1:2
1:3
1:4
1:5
34
40
42
52
53
87
93
99
91
80
3. Conclusion
In conclusion, immobilized whole cells of an indigenous micro-
organism Arthrobacter species (MTCC no. 5125) bearing lipase have
been successfully used for the kinetic resolution of ( )-1,4–benzo-
dioxan-2-carboxylic acid, which was then converted into enantio-
merically enriched enantiomers of bioactive molecules such as
piperoxan, prosympal, dibozane, and doxazosin.
4. Experimental
4.1. General
1H NMR spectra in CDCl3 were recorded on Bruker 200, 400, and
500 MHz spectrometers with TMS as the internal standard. Chem-
ical shifts are expressed in parts per million (d ppm). Reagents and
solvents used were mostly of LR grade. Silica gel coated aluminum
plates coated on alumina from M/s Merck were used for TLC. MS
were recorded on a High Resolution Mass Spectrometer MS Q-
TOF LC/MS, Agilent Technologies 6540. Optical rotations were
measured on a Perkin–Elmer 241 polarimeter at 25 °C using so-
dium D light. Melting points were determined on a Buchi B-542
apparatus by the open capillary method and are uncorrected.
Enantiomeric excesses (ee%) were determined by chiral HPLC on
OJ-H and ADH chiral columns. Chemicals were purchased from
M/s Aldrich Chemicals, Mumbai.
Figure 5. Effect of concentration on conv. and ee using 20% n-butanol as a co-
solvent after 4 h.
4.2. Preparation and immobilization of whole cells/isolated ABL
The biomass from Arthrobacter sp. (MTCC 5125) was grown in
1% peptone, 0.5% beef extract, and 0.5% NaCl, at pH 7.0 followed
by isolation of the enzyme as previously described.28b Microbial
cells/isolated enzyme were entrapped in sol–gel supports using a
tetraethylorthosilicate precursor as previously reported.34 ABL
cells/isolated enzyme were added to the homogenized solution of
tetraethylorthosilicate during the polymerization process to allow
for gelation. The gel containing entrapped cells/isolated enzyme
was filtered and washed several times with buffer to remove any
free enzyme and dried in air. The dried powder was then directly
used for the biotransformations.
Figure 6. Effect of temperature variation on the enantioselectivity and hydrolytic
activity of ABL.
however, as expected, the rate of hydrolysis decreased with higher
concentrations (Fig. 5).
The influence of reaction temperature was studied in the range
of 15–35 °C; the optimum range recorded as 15–25 °C. At a higher
temperature (35 °C), there was a significant decrease in the enanti-
oselectivity (Fig. 6).
The phosphate buffer concentration (0.1 M) and pH parameters
(pH 7–8) were also optimized for the kinetic resolution (Table 4).
For the preparation of (S)-piperoxan 3, (S)-prosympal 4, and
(S,S)-dibozane 5, the optically active ester (R)-17a was first re-
duced with LAH and then substituted with the desired amines
(diethylamine, piperidine, and piperazine) to yield the target mol-
ecules through a triflate intermediate (Scheme 3). A similar route
was followed for the preparation of the (R)-isomers of 3, 4, and 5
by reducing acid (S)-1 (see Section 4). For the preparation of (S)-
doxazosin 6, the enantiomerically pure acid (S)-1 isomer was first
4.3. Synthesis of methyl 2,3-dibromopropionate 16a
A solution of 1.2 mol of Br2 in carbon tetrachloride was added
dropwise to a stirred solution of methyl acrylate 1 mol in CCl4 at
0 °C and the mixture was allowed to reflux at 60 °C for two hours.
After the completion of the reaction as indicated by TLC, the sol-
vent was removed under reduced pressure to yield ethyl 2,3-dib-
romopropionate (yield 99%). 1H NMR: d 3.6–4.2 (m, 2H); 3.8 (s,
3H), 4.4 (dd, J = 4.4, 1.2 Hz, 1H); 13C NMR: d 29.5, 40.9, 51.2,
168.8; HRMS (ESI) Calcd for C4H6Br2NaO2 (M+Na): 266.8632.
Found: 266.8636.
Table 4
Influence of pH on the hydrolytic activity and enantioselectivity
4.4. Synthesis of ethyl 2,3-dibromopropionate 16b
S. no.
pH
Conv. (%)
eep (%)
1
2
3
4
5
5
6
23
28
42
47
51
80
91
99
95
90
Compound 16b was prepared from ethyl acrylate (1 mmol) fol-
lowing the procedure described for methyl 2,3-dibromopropionate
(yield 99%). 1H NMR: d 1.28 (t, 3H), 3.7 (dd, J = 4.4, 2H), 3.9 (t, J = 10,
1H), 4.28 (m, 2H), 4.4 (dd, J = 4.4, 1.4 Hz, 1H); 13C NMR: d 14.1, 29.5,
7–7.5
8
9

1620
A. Rouf et al. / Tetrahedron: Asymmetry 23 (2012) 1615–1623
O
NEt2
i
O
3
(S)-
OTf
OH
O
O
O
O
a
b
c
N
ii
(R)-17a
O
O
O
(S)-4
(S)-2
(R)-isomer
O
O
iii
N
N
O
(S)-5
O
N
O
O
O
d
O
O
e
N
1
(S)-
NBoc
O
NH
(S)-18
(S)-19
O
O
f
N
N
N
OMe
OMe
MeO
MeO
N
Cl
N
N
NH2
NH2
20
(S)-6
Scheme 3. Reagents and conditions: (a) LAH, THF, 0 °C; (b) Triflic anhydride, Et3N, CHCl3; (c) (i) Et2NH, CHCl3, (ii) piperidine, CHCl3, (iii) piperazine, CHCl3; (d) EDC, HOBT,
Boc-piperazine, Et3N, THF:DCM; (e) TFA, CHCl3; (f) NH4OH, n-butanol, reflux, 1.5 h.
41.2, 60.2, 168.8; HRMS (ESI) Calcd for C5H8Br2NaO2 (M+Na):
280.8789. Found: 280.8794.
The reaction was stirred for 3 h until hydrolysis was complete.
Next, THF was evaporated and the residue acidified with 10%
HCl. DCM was used for extraction. The organic layers were dried
in vacuo to give ( )-1,4-benzodioxan-2-carboxylic acid 1 in 91%
yield as a white solid; mp 117–119 °C; [lit.23b 125.4]; 1H NMR: d
4.44 (d, J = 4.8 Hz, 2H), 4.90 (t, J = 3.7, 7.6 Hz, 1H), 6.88–6.97 (m,
3H), 6.99–7.02 (m, 1H); 13C NMR: d 64.63, 71.61, 117.34, 122.38,
141.97, 142.87 173.59; HRMS (ESI) Calcd for C9H8NaO4 (M+Na):
203.0320. Found: 203.0317.
4.5. Synthesis of ( )-methyl 1,4-benzodioxan-2-carboxylate 17a
A mixture of 12 g (0.11 mol) of catechol, 17.9 (0.1 mol) of
methyl 2-bromopropionate, and 41.4 g (0.3 mol) of anhydrous
K2CO3 was refluxed in 200 ml of dry acetone for 18 h. After the ace-
tone was removed, the residue was taken up in methylene chlo-
ride, extracted with water, 5% NaOH, 5% HCl, and saturated NaCl
solutions, and finally dried over anhydrous Na2SO4. Evaporation
of the solvent and distillation of the residue afforded 15.4 g (74%)
of 17a. Mp 60–62 °C [lit.23b mp 53 °C]; 1H NMR: d 3.81 (s, 3H),
4.38 (d, J = 4.0 Hz, 2H,), 4.85 (t, J = 3.8, 7.6 Hz, 1H), 6.86–6.92 (m,
3H), 6.99–7.02 (m, 1H); 13C NMR: d 52.78, 64.90, 72.05, 117.40,
4.8. Lipase catalyzed hydrolysis of ( )-methyl 1,4-benzodioxan-
2-carboxylate
Racemic methyl 1,4-benzodioxan-2-carboxylate 17a (50 mg),
aqueous phosphate buffer (2.5 mL, 0.1 M, pH. 7.1), n-butanol
121.98, 142.28, 169.48; HRMS (ESI) Calcd for
(M+Na): 217.0477. Found: 217.0474.
C
10H10NaO4
(500 ll), and wet whole cells of Arthrobacter sp. lipase (100 mg)
were shaken (320 rpm) continuously at 25 1 °C. After a certain
degree of conversion (ꢀ42%) as indicated by chiral high perfor-
mance liquid chromatography (HPLC), the reaction was terminated
by adding ethyl acetate and centrifuging the mixture at 10,000–
15,000 g to remove the enzyme and the suspended particles. The
clear solution was decanted and the centrifuged mass was ex-
tracted separately with ethyl acetate (3 ꢂ 25 mL). The organic lay-
ers were combined, washed with water, and treated with 2 M
NaOH solution to give (S)-2,3-hydrobenzo[1,4]dioxane-2-carbox-
ylic acid as its salt. The salt was neutralized with dilute HCl to give
enantiomerically pure (S)-2,3-dihydrobenzo[1,4]dioxane-2-car-
4.6. Synthesis of ( )-ethyl 1,4-benzodioxan-2-carboxylate 17b
Compound 17b was prepared from ethyl 2-bromopropionate
(10.0 g, 0.1 mmol) following the procedure described for 17a
(11.0 g, 76%), colorless oil; 1H NMR: d 2.25 (t, 3H), 4.25(q, 2H),
4.38 (d, J = 4.0 Hz, 2H), 4.85 (t, J = 4.0 Hz, 1H), 6.86–6.92 (m, 3H),
6.99–7.02 (m, 1H); 13C NMR: d 14.6, 61.6, 65.33, 72.53, 115.40,
121.02, 146.74, 170.48; HRMS (ESI) Calcd for
(M+Na): 231.0633. Found: 231.0628.
C11H12NaO4
boxylic acid (yield 42%). ee = 99%; mp = 102–103 °C;
½
a 2D5
ꢃ
¼
4.7. Synthesis of ( )-1,4-benzodioxan-2-carboxylic acid 1
ꢁ61:0 (c 1, CHCl3); Abs, config. (S); {lit.23b
½
a 2D5
ꢃ
¼ ꢁ63:8 (c 1,
CHCl3); ee = 99.0%; mp 97.5 °C}; HPLC conditions {OJ-H chiral col-
umn, eluent 2-propanol-hexane-triflouroacetic acid (5:95:0.1),
flow rate: 0.5 mL/min, t1 = 20.78 and t2 = 22.87 min}. The organic
Methyl 1,4-benzodioxan-2-carboxylate ( )-17a was dissolved
in THF/H2O (1:1 ratio) after which lithium hydroxide was added.

A. Rouf et al. / Tetrahedron: Asymmetry 23 (2012) 1615–1623
1621
layer was dried and evaporated under reduced pressure to furnish
the optically active unhydrolyzed ester. ee = 73%; mp = 58–61 °C;
½
a 2D5
ꢃ
¼ ꢁ11:2 (c 0.5, CHCl3); HPLC conditions {ADH chiral column,
eluent 3-propanol-hexane; flow rate: 0.8 mL/min, t1 = 16.2,
20.5 min}; 1H NMR: d 1.24–1.28 (m, 6H), 2.57–2.66 (m, 5H),
2.73–2.74 (dd, J = 5.44, 13.67 Hz, 1H), 3.46 (s, NH) 3.96–4.00 (m,
1H), 4.24–4.33 (m, 2H), 6.82–6.87 (m, 4H); 13C NMR: d 14.78,
48.16, 53.54, 66.96, 72.00, 117.07, 117.37, 121.20, 121.46, 143.47,
143.77; HRMS (ESI) Calcd for C13H20NO2 (M+H): 222.1494. Found:
222.1497.
½
a 2D5
ꢃ
¼ þ46:4 (c 1, CHCl3) [lit.23b
½
a 2D5
ꢃ
¼ 57:0 (c 1, CHCl3), mp
78.1]; Abs. config. (R); HPLC conditions {OJ-H chiral column, eluent
2-propanol-hexane-triflouroacetic acid (5:95:0.1), flow rate:
0.5 mL/min, t1 = 31.74 and t2 = 33.34 min}. The enantiomerically
pure ester with ee = 99%; mp = 73–76 °C;
½
a 2D5
ꢃ
¼ þ55:4 (c 1,
CHCl3); Abs. config. (R); {lit.23b
½
a 2D5
ꢃ
¼ þ57:0 (c 1, CHCl3);
ee = 99.4%; mp 78.5 °C}, was obtained in the case of hydrolysis
with diisopropylether as the co-solvent (Table 2, entry 13).
4.13. (2R)-2-Diethylaminomethyl-1,4-benzodioxane [(R)-piper-
oxan] (R)-3
4.9. (R)-(+)-1,4-Benzodioxan-2-carboxylic acid (R)-1
(R)-Piperoxan was prepared from (2R)-2-hydroxymethyl-1,4-
(R)-(+)-1,4-Benzodioxan-2-carboxylic acid was prepared from
(R)-methyl 1,4-benzodioxan-2-carboxylate 17a (1 mmol) by lith-
ium hydroxide hydrolysis, following the same procedure as de-
scribed for ( )-1,4-benzodioxan-2-carboxylic acid 1 in 95% yield
benzodioxane-2 (1 mmol) following the procedure as described
for the (S)-3 isomer. Semi solid; ee = 92%; ½a D25
¼ þ11:6 (c 0.5,
ꢃ
CHCl3); HPLC condition {ADH chiral column, eluent 3-propanol-
hexane; flow rate: 0.8 mL/min, t1 = 14.2, 21.3 min}; HRMS (ESI)
Calcd for C13H20NO2 (M+H): 222.1494. Found: 222.1499. Spectro-
scopic data are the same as for the (S)-3 isomer.
as a white solid; mp 93–95 °C, ½a D25
ꢃ
¼ þ59:1 (c 1, CHCl3); [lit.2a
=
+62.1 (c 1, CHCl3), mp 98–99 °C]; 1H NMR: d 4.38 (dd, J = 2.9 Hz,
11.4 Hz, 1H), 4.44 (dd, J = 4.4 Hz, 11.4 Hz, 1H), 4.90 (dd, J = 2.9 Hz,
4.4 Hz, 1H), 6.88–6.97 (m, 3H), 6.99–7.02 (m, 1H). 13C NMR: d
64.63, 71.61, 117.34, 122.38, 141.97, 173.59; HRMS (ESI) Calcd
for C9H8NaO4 (M+Na): 203.0320. Found: 203.0325.
4.14. (2S)-2-Piperidinomethyl-l,4-benzodioxane [(S)-prosympal]
(S)-4
A catalytic amount of triethylamine was added to a solution of
(2S)-2-hydroxymethyl-1,4-benzodioxane (1 mmol) in chloroform
(30 mL). At 0 °C triflic anhydride (1 mmol) was added dropwise
over 10 min under nitrogen. The reaction was then stirred until
the starting material was consumed as indicated by TLC (2 h); after
the reaction, piperidine was added and the reaction stirred for 8 h.
After completion of the reaction as indicated by TLC, the reaction
was extracted with chloroform and water, and the organic layer
was dried and purified by column chromatography to give the final
product (2S)-prosympal-4 in 95% yield as a semi solid; ee = 90%;
4.10. Synthesis of (S)-(ꢁ)-2-(hydroxymethyl)-1,4-benzodioxane
(S)-2
A solution of (R)-methyl 1,4-benzodioxan-2-carboxylate (R)-
17a (1 mmol) in anhydrous THF (10 mL) was slowly added under
a nitrogen atmosphere, to a suspension of LiAlH4 (2 mmol) in anhy-
drous THF (50 mL). The mixture was stirred at room temperature
until the completion of the reaction as indicated by TLC. After
hydrolysis with small amounts of water, the suspension obtained
was filtered and the THF removed. The residue was diluted with
water and extracted with ether. The organic layers were dried, fil-
tered, and concentrated to obtain pure alcohol (S)-2 after recrystal-
lization from diethyl ether, in 85% yield as a white solid; mp
½
a 2D5
ꢃ
¼ ꢁ14:3 (c 0.25, CHCl3); HPLC condition {ADH chiral column,
eluent 3-propanol-hexane; flow rate: 0.8 mL/min, t1 = 18.3,
22.6 min}; 1H NMR: d 1.54–1.60 (m, 6H), 2.46–2.56 (m, 5H),
2.62–2.66 (dd, J = 5.7, 13.23 Hz, 1H), 3.95–3.99 (q, J = 7.6, 11.7 Hz,
1H), 4.25–4.33 (m, 2H), 6.81–6.87 (m, 4H); 13C NMR: d 23.95,
25.65, 55.15, 59.17, 66.96, 71.16, 116.90, 117.25, 121.09, 121.27,
70.5 °C; ½a 2D5
ꢃ
¼ ꢁ33:4 (c 0.1, ethanol); {lit.2a
½
a 2D5
ꢃ
¼ ꢁ34:7 (c 0.1,
EtOH); mp 69–71 °C}; 1H NMR: d 3.84–3.90 (qq, J = 5.14, 12.0 Hz,
2H), 4.08–4.12 (m, 1H), 4.25–4.30 (m, 2H), 6.84–6.90 (m, 4H);
13C NMR: d 61.30, 64.98, 73.25, 116.94, 117.07, 121.23, 121.36,
142.87, 142.94; HRMS (ESI) Calcd for C9H10NaO3 (M+Na):
189.0528. Found: 189.0520.
143.06, 143.23; HRMS (ESI) Calcd for
234.1494. Found: 234.1488.
C14H20NO2 (M+H):
4.15. (2R)-2-Piperidinomethyl-l,4-benzodioxane [(R)-prosympal]
(R)-4
4.11. (R)-(+)-2-(Hydroxymethyl)-1,4-benzodioxane (R)-2
(R)-Prosympal was prepared from (2R)-2-hydroxymethyl-1,4-
Compound (R)-2 was prepared from (S)-1,4-benzodioxan-2-car-
boxylic acid 1 (1 mmol) following the procedure as described for
benzodioxane (1 mmol) following the same procedure as described
for (S)-4 isomer. Semi solid; ee = 90%; ½a D25
¼ þ13:6 (c 0.25, CHCl3);
ꢃ
the (S)-2 isomer. Mp 83.5 °C; ½a D25
ꢃ
¼ þ35:5 (c 0.1, ethanol); {lit.18
HPLC condition {ADH chiral column, eluent 3-propanol-hexane;
½
a 2D0
ꢃ
¼ þ36:2 (c 0.1 EtOH)}; HRMS (ESI) Calcd for C9H10NaO3
flow rate:0.8 mL/min, t1 = 20.3, 23.3 min}; HRMS (ESI) Calcd for
C14H20NO2 (M+H): 234.1494. Found: 234.1490. Spectroscopic data
(M+Na): 189.0528. Found: 189.0523. Spectroscopic data are the
same as for the (S)-2 alcohol.
are the same as for the (S)-4 isomer.
4.12. (2S)-2-Diethylaminomethyl-1,4-benzodioxane [(S)-piper-
oxan] (S)-3
4.16. (2S)-2-(l-Piperazinylmethyl)-1,4-benzodioxane [(S,S)-dibo-
zane] (S,S)-5
A catalytic amount of triethylamine was added to a solution of
(2S)-2-hydroxymethyl-1,4-benzodioxane (1 mmol) in chloroform
(30 mL). At 0 °C triflic anhydride (1 mmol) was added dropwise
over 10 min under nitrogen. The reaction was then stirred until
the starting material was consumed as indicated by TLC (2 h), after
which diethyl amine was added and the reaction stirred for 6 h.
After completion of the reaction as indicated by TLC, the mixture
was extracted with chloroform and water, and the organic layer
was dried and purified by column chromatography to give the final
product (S)-piperoxan 3 in 95% yield as a semi solid; ee = 93%;
A catalytic amount of triethylamine was added to a solution of
(2S)-2-hydroxymethyl-1,4-benzodioxane (1 mmol) in chloroform
(30 mL). At 0 °C triflic anhydride (1 mmol) was added dropwise
over 10 min under nitrogen conditions. The reaction was then stir-
red until the starting material was consumed as indicated by TLC
(2 h), after which piperazine was added and the reaction stirred
at 60 °C for 8 h. After the reaction is complete as indicated by
TLC, the solution was extracted with chloroform and water, and
the organic layer was dried and purified by column chromatogra-
phy to give the final product (S,S)-dibozane 5 in 95% yield as a

1622
A. Rouf et al. / Tetrahedron: Asymmetry 23 (2012) 1615–1623
white solid; mp 158–163; ee = 94%; HPLC condition {ADH chiral
C13H16N2NaO3 (M+Na): 271.1059. Found: 271.1054. Spectroscopic
column, eluent 3-propanol-hexane; flow rate:0.8 mL/min, t1 =
data are the same as for the (S)-19 isomer.
35.5, 37.5 min; ½a D25
ꢃ
¼ ꢁ16:2 (c 0.5, CHCl3)}; 1H NMR d 2.54–2.90
(m, 8H), 3.51–3.77 (m, 4H), 3.98 (dd, J = 11.3, 7.1 Hz, 2H), 4.26 (d,
J = 2.3 Hz, 1H), 4.29 (d, J = 2.3 Hz, 1H), 4.38–4.41 (m, 2H), 6.85
(m, 8H); 13C NMR d 53.85, 58.45, 66.90, 71.23, 117.07, 117.39,
121.32, 121.49, 143.10, 143.30; HRMS (ESI) Calcd for
4.22. Synthesis of (S)-doxazosinꢄHCl
4-Amino-2-chloro-6,7-dimethoxyqunizoline 20 (1.27 g) and N-
(1,4-benzodioxan-2-carbonyl)piperazine (S)-2 (1.4 g) were sus-
pended in n-butanol (30 mL). The mixture was then heated at re-
flux for 4 h. The reaction mixture was then cooled to 60 °C. The
slurry was collected by filtration. The wet cake was washed with
ethylacetate (500 mL) and dried at 50 °C under vacuum to give
the product (2.5 g) in 70% yield.
C22H26N2NaO4 (M+Na): 405.1790. Found: 405.1794.
4.17. (2R)-2-(l-Piperazinylmethyl)-1,4-benzodioxane [(R,R)-dibo-
zane] (R,R)-5
(RR)-Dibozane 5 was prepared from (2R)-2-hydroxymethyl-1,4-
benzodioxane (1 mmol) following the procedure as described for
the (S,S)-5 isomer. White solid; mp 158–160; ee = 93.6%; HPLC
condition {ADH chiral column, eluent 3-propanol-hexane; flow
4.23. Preparation of (S)-doxazosin free base (S)-6
The (S)-doxazosinꢄHCl salt was dissolved in DMF and water and
then heated at 50 °C followed by the addition of K2CO3 (40% aq) to
give a clear solution. The solution was diluted with water to pre-
cipitate the (S)-doxazosin free base from the solution. The free base
was collected by filtration and dried under vacuum to afford the
rate:0.8 mL/min, t1 = 31.2, 35.5 min; ½a D25
¼ þ16:0 (c 0.5, CHCl3)};
ꢃ
HRMS (ESI) Calcd for C22H26N2NaO4 (M+Na): 405.1790. Found:
405.1796. Spectroscopic data are the same as for the (S,S)-5 isomer.
4.18. (S)-N-Boc-(1,4-benzodioxan-2-carbonyl)piperazine (S)-18
product 94% yield as a white solid, mp 249–251 °C; ½a D25
¼ þ25:4
ꢃ
(c 1, DMSO); 1H NMR: d 3.66 (m, 8H), 3.79 (s, 3H), 3.83 (s, 3H),
4.21 (m, 1H), 4.41 (d, J = 11.6 Hz,1H), 5.24 (m, 1H), 6.84 (m, 4H),
7.17 (s, 1H), 7.44 (s, 1H); 13C NMR: d 41.57, 43.38, 43.99, 45.14,
55.44,55.84, 64.79, 69.52, 103.04, 103.67, 105.28, 116.90, 117.10,
121.40, 121.51, 142.89, 143.08, 145.09, 148.77, 154.26, 158.29,
161.20, 164.91; HRMS (ESI) Calcd for C23H25N5NaO5 (M+Na):
474.1753. Found: 474.1758.
Triethylamine (2 mmol) and HOBT (1 mmol) were added to acid
(S)-1 (1 mmol) dissolved in THF/DCM (9:1 ratio) at 0 °C. After
10 min of mixing, Boc-piperazine was slowly added. The reaction
was then left to stir overnight. After completion of the reaction,
the mixture was dissolved in ethyl acetate and extracted with
10% HCl to remove the basic reagents. The organic layer was
washed with water, dried in vacuo, and purified by column chro-
matography to give the desired compound in 95% yield as a white
4.24. Preparation of (R)-doxazosin free base
solid, mp. 134 °C; ½a D20
ꢃ
¼ þ51:5 (c 1, CHCl3); 1H NMR: d 1.46 (m,
9H), 3.31–3.45 (m, 5H), 3.52–3.60 (m, 2H), 4.32–4.45 (dd, J = 4,
8 Hz, 1H), 4.47–4.51 (dd, J = 2.6, 12 Hz, 1H), 4.81–4.83 (q, J = 2.4,
8 Hz, 1H), 6.82–6.91 (m, 4H); 13C NMR: d 28.09, 41.84, 45.45,
64.78, 70.45, 80.62, 110.57, 117.15, 121.44, 122.16, 142.11,
(R)-Doxazosin was prepared from acid (R)-1 (1 mmol) following
the procedure as described for (S)-doxazosin. White solid, mp
250 °C;
½
a 2D5
ꢃ
¼ ꢁ25:0 (c 1, DMSO); HRMS (ESI) Calcd for
C23H25N5NaO5 (M+Na): 474.1753. Found: 474.1759. Spectroscopic
143.01, 154.56, 165.31; HRMS (ESI) Calcd for
(M+Na): 371.1583. Found: 371.1589.
C
18H24N2NaO5
data are the same as for the (S)-6 isomer.
Acknowledgements
4.19. (R)-N-Boc-(1,4-benzodioxan-2-carbonyl)piperazine (R)-18
The authors (A.R., M.A.A. and B.K.) are highly thankful to CSIR
and UGC, New Delhi for financial support and the award of SRFs.
Compound (R)-18 was prepared from acid (R)-1 (1 mmol) fol-
lowing the procedure as described for (S)-18 isomer. White solid,
mp 130–132 °C; ½a D25
ꢃ
¼ ꢁ52:0 (c 1, CHCl3); HRMS (ESI) Calcd for
References
C
18H24N2NaO5 (M+Na): 371.1583. Found: 371.1586. Spectroscopic
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4.20. (S)-N-(1,4-Benzodioxan-2-carbonyl)piperazine (S)-19
Triflouroacetic acid was slowly added to (S)-18 dissolved in
DCM at 0 °C. The reaction was stirred for 1 h and quenched with
water. Extraction was carried out with DCM and 10% bicarbonate.
The organic layer was dried to give the desired product in 96% as a
white powder, mp 85 °C; ½a D25
ꢃ
¼ þ85:4 (c 1, MeOH); 1H NMR: d
2.40 (s, 1H), 2.90–2.96 (m, 4H), 3.53–3.55 (q, J = 3.95, 6.88, 2H),
3.74–3.76 (t, J = 4.43, 8.60, 2H), 4.30–4.34 (dd, J = 8.08, 11.98 Hz,
1H), 4.47–4.50 (dd, J = 2.44, 11.90, 1H), 4.81–4.83 (dd, J = 2.51,
8.08, 1H), 6.85–6.92 (m, 4H); 13C NMR: d 43.2, 45.8, 46.4, 47.1,
65.2, 70.5, 117.2, 117.3, 121.5, 122.2, 142.5, 143.2, 164.8; HRMS
(ESI) Calcd for C13H16N2NaO3 (M+Na): 271.1059. Found: 271.1051.
4.21. (R)-N-(1,4-Benzodioxan-2-carbonyl)piperazine (R)-19
Compound (R)-19 was prepared from acid (R)-18 (1 mmol) fol-
lowing the procedure as described for the (S)-19 isomer. White so-
lid, mp 83 °C; ½a 2D5
¼ ꢁ80:2 (c 1, CHCl3); HRMS (ESI) Calcd for
ꢃ

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