A facile approach to chiral 1,4-benzodioxane toward the syntheses of doxazosin, prosympal, piperoxan, and dibozane

Article abstract of DOI:10.1016/j.tetlet.2013.09.040

The process describes the concise synthesis of (R/S)-enantiomers of doxazosin, an antidepressant drug and α-adrenergic receptor antagonists like prosympal, piperoxan, and dibozane in practical yields from easily available (R)-2,3-O-cyclohexylidene-d-glyce

Full text of DOI:10.1016/j.tetlet.2013.09.040

Tetrahedron Letters 54 (2013) 6420–6422
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Tetrahedron Letters
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A facile approach to chiral 1,4-benzodioxane toward the syntheses of
doxazosin, prosympal, piperoxan, and dibozane
⇑
⇑
Abdul Rouf , Mushtaq A. Aga, Brijesh Kumar, Subhash Chandra Taneja
CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The process describes the concise synthesis of (R/S)-enantiomers of doxazosin, an antidepressant drug
and -adrenergic receptor antagonists like prosympal, piperoxan, and dibozane in practical yields from
easily available (R)-2,3-O-cyclohexylidene-
Received 10 August 2013
Revised 4 September 2013
Accepted 11 September 2013
Available online 21 September 2013
a
D
-glyceraldehyde and (S)-3-(benzyloxy)propane-1,2-diol.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2,3-Dihydro-1,4-benzodioxane
Doxazosin
Prosympal
Piperoxan
Dibozane
The 1,4-benzodioxane derivatives are found in a wide variety of
natural products1 and therapeutic agents possessing important
biological activities.2 They are known to possess the interesting
the enantiomers into diastereoisomers.17 Another approach used
the cycloaddition of a variety of O-quinones with dienophiles,
either directly or via a two-step process involving a hetero-Diels–
Alder reaction, followed by a [3,3]-sigmatropic rearrangement.18
The most recent examples are the palladium-catalyzed asymmetric
cyclization of benzene-1,2-diol with allylic biscarbonates,19 the
palladium catalyzed intramolecular cyclization of non-racemic 1-
(2-bromophenyl)glycerol,20 and Cu2O-catalyzed ring-opening and
coupling of epoxides.21
Recently our group has also reported the chemoenzymatic ap-
proach toward the synthesis of enantiomerically pure isomers of
doxazosin, piperoxan, prosympal, and dibozane containing 1,4-
benzodioxane unit.22 Even though the enzymatic processes are
environment friendly and mild, the maximum yield of an enantio-
mer is only 50%. In this Letter an efficient and facile alternative for
the preparation of these bioactive molecules from a cheap and eas-
ily available raw material that is, (R)-2,3-cyclohexylideneglyceral-
dehyde 8 and (S)-3-(benzyloxy)propane-1,2-diol 11 is described.
Earlier, 1,4-benzodioxanes have also been chemically synthesized
by various methods using chiral glyceraldehydes23,9 or epoxides,12
the present method offers a more facile and practical approach to
the preparation of chiral 1,4-benzodioxanes.
biological properties like
a
-adrenergic blocking,3 antigastric,4
spasmolytic,5 antipsychotic,6 anxiolytic,7 and hepatoprotective8
properties. These activities are influenced by the absolute
configuration of the 1,4-benzodioxane unit.9 Enantiomerically pure
1,4-benzodioxan-2-carboxylic acid 1 and 2-hydroxymethyl-1,4-
benzodioxane 2 derivatives (Fig. 1) are important intermediates
of various drug molecules. These compounds could also be used
as intermediates for very useful synthetic transformations.10
The reported methods for the synthesis of benzodioxane con-
taining molecules typically involve the use of chiral building blocks
from the ‘chiral pool’, such as glycerol or glycidol derivatives,11 via
condensation of catechol with chiral glycidol,12 by Sharpless
epoxidation of 1-aryloxy-4-hydroxy-2-butene substrate13and
chemoenzymatic methods, involving kinetic resolutions of 1,4-
benzodioxan-2-carboxylic acid,14 its ethyl ester,15 2-hydroxy-
methyl-1,4-benzodioxane,16 or accomplished after conversion of
O
O
O
O
OH
OH
O
2
The syntheses of chiral 1,4-benzodiaxane and the downstream
products that is, doxazosin 3, piperoxan 4, prosympal 5, and diboz-
ane 6 are based upon commercially available and inexpensive
(R)-824 and (S)-11.25
1
Figure 1. 1,4-Benzodioxan-2-carboxylic acid 1 and 2-hydroxymethyl-1,4-benzodi-
oxane 2 derivatives.
For the synthesis of (S)-hydroxymethyl-1,4-benzodioxane 2, the
methodology initiated was the reduction of (R)-2,3-O-cyclohexy-
lidene-D-glyceraldehyde 8 (obtained via protection of D-mannitol
⇑
Corresponding authors.
E-mail addresses: roufiiim@rediffmail.com (A. Rouf), drsctaneja@gmail.com,
sctaneja@iiim.ac.in (S.C. Taneja).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.040

A. Rouf et al. / Tetrahedron Letters 54 (2013) 6420–6422
6421
OH
O
and C–C bond scissoring) by sodium borohydride followed by
benzyl protection to generate (S)-2-((benzyloxy)methyl)-1,4-diox-
aspirodecane 10. The deprotection of the cyclohexylidene group of
(S)-10 with p-toluenesulfonic acid (PTSA) led to the formation of
(R)-3-(benzyloxy)propane-1,2-diol 11. An attempt was made to di-
rectly couple the optically active diol-11 with catechol under Mits-
unobu conditions. However, the reaction was unsuccessful,
therefore the hydroxyl groups were substituted by bromine
through Appel reaction (CBr4/triphenylphosphine)26 to form (R)-
((2,3-dibromopropoxy)methyl)benzene 12 in 95% yields. Under
the basic conditions, the coupling of catechol and dibromo (R)-12
was successfully accomplished to yield the intermediate (S)-2-
(benzyloxymethyl)-1,4-benzodioxane 13 in 60% yield, which was
hydrogenated (H2/Pd-C, MeOH) to form the intermediate (S)-
hydroxymethyl-1,4-benzodioxane 2 in ꢀ42% overall yield from
(R)-8, which was thereafter used for further transformations
(Scheme 1).
O
Scheme 3
Scheme 1
O
(R)-doxazosin 3
H
O
~17% overall yield
O
(S)-2
(R)-8
Scheme 4. Synthesis of (R)-doxazosin.
OH
OBn
Tf2O, NEt3
CHCl3
,
O
HO
Scheme 2
HO
O
(R)-2
(S)-11
O
O
NHEt2, CHCl3
NEt2
4
(R)-piperoxan
OTf
O
O
O
piperidine, CHCl3.
piperazine, CHCl3
N
95%
O
(R)-prosympal 5
(S)-isomer
O
O
N
The nature provides only
zodioxane 2 with the (S)-configuration can be obtained from
-mannitol through (R)-aldehyde 8. However, for the preparation
D-sugars and hydroxymethyl-1,4-ben-
N
O
(RR)-dibozane 6
O
D
∼52% overall yield
of (R)-hydroxymethyl-1,4-benzodioxane 2, the synthesis was initi-
ated from the commercially available (S)-benzyl-l,2-propanediol
11,27 by following the same reaction sequence described for (S)-2
isomer (bromination, coupling and deprotection) in ꢀ55% overall
yield from (S)-11 (Scheme 2).
For the preparation of (S)-doxazosin 3, (R)-hydroxymethyl-1,4-
benzodioxane 2 [obtained from (S)-11] was oxidized with perman-
ganate (KMnO4) to form the enantiomerically pure acid (S)-1, and
coupled with mono-Boc-piperazine to form (S)-14 in 95% yield.
The earlier reported methods15b used unprotected piperazine in
which side product diamide is formed, while the present method
afforded the desired amide in higher yields. The deprotection of
Scheme 5. Synthesis of (R)-isomers of 4, 5 and 6.
OH
O
O
4,
(S)-piperoxan
(S)-prosympal 5,
(SS)-dibozane 6
Scheme 5
Scheme 1
O
H
O
O
(R)-8
∼39% overall yield
(S)-2
Scheme 6. Synthesis of (S)-isomers of 4, 5 and 6.
the tert-butoxy carbonyl group (Boc) was accomplished by trifluo-
roacetic acid in dichloromethane furnishing piprazinamide (S)-15,
which was then coupled with 4-amino-2-chloro-6,7-dimethoxy-
quinazoline 16 in n-butanol to give (S)-doxazosin 3 in 65% yield
with 99% ee (23% overall yield, Scheme 3).
For the synthesis of (R)-doxazosin 3, (S)-hydroxymethyl-1,4-
benzodioxane 2 [obtained from aldehyde (R)-8, Scheme 1] was oxi-
dized to (R)-1,4-benzodioxan-2-carboxylic acid 1, and thereafter
converted to (R)-doxazosin 3 (99% ee) following the same reaction
sequence described for (S)-doxazosin with ꢀ17% overall yield
(Scheme 4).
OH
O
OBn
1. cyclohexanone, PTSA,
DMSO, 86%
BnBr, NaH,
THF
NaBH4,
MeOH
O
O
O
H
D-Mannitol
O
O
O
95%
2. NaIO4, Ether:H2O (5:3)
90%
90%
7
8
(R)-
(S)-10
9
(S)-
OBn
OH
OBn
OBn
H2/Pd-C,
MeOH
PTSA,
MeOH
Catechol, K2CO3,
acetone, reflux
CBr4, Ph3P,
DCM
95%
O
O
O
Br
HO
60%
92%
98%
O
(S)-2
Br
(R)-12
HO
11
(R)-
13
(S)-
~42% overall yield
The synthesis of target bioactive molecules 4,5,6 by the substi-
tution of the hydroxyl group with respective nucleophiles was
optimized via triflation. Thus, the hydroxyl group was reacted with
trifluoromethane sulfonic anhydride (triflic anhydride-Tf2O) in
chloroform to form activated triflates and then substituted with
respective amines, that is, diethyl amine for piperoxan 4, piperi-
dine for prosympal 5, and piperazine for dibozane 6 in one step.
The reaction occurred cleanly in high yields (95%) without any
by-product formation (Scheme 5). The preparation of (R)-isomers
of 4, 5, and 6 from (R)-hydroxymethyl-1,4-benzodioxane 2 is de-
picted in Scheme 5 with ꢀ52% overall yields.
Scheme 1. Synthesis of (S)-hydroxymethyl-1,4-benzodioxane.
OBn
OH
OBn
OBn
H2/Pd-C,
MeOH
Catechol, K2CO3,
acetone, reflux
CBr4, Ph3P,
DCM
O
O
Br
Br
HO
HO
60%
O
O
(R)-2
98%
95%
(S)-11
(R)-13
(S)-12
∼55% overall yield
Scheme 2. Synthesis of (R)-hydroxymethyl-1,4-benzodioxane.
While the (S)-isomers of 4,5,6 were prepared from the (S)-
hydroxymethyl-1,4-benzodioxane 2 by the procedure discussed
for (R)-isomers in ꢀ39% overall yield (Scheme 6).
EDC, HOBt,
O
OH
O
mono-Boc-
piperazine,
OBn
Scheme 2
KMnO4
acetone
,
O
O
O
O
O
HO
N
OH
In conclusion an efficient and facile methodology has been
demonstrated for the synthesis of (R/S)-isomers of doxazosin 3,
piperoxan 4, prosympal 5, and dibozane 6 from the (R/S)-3-(ben-
zyloxy)propane-1,2-diol via a common intermediate 2.
NBoc
Et3N,
THF:DCM (9:1)
95%
70%
HO
O
14
(S)-11
(S)-
2
(R)-
(S)-1
MeO
MeO
N
Cl
O
O
N
O
N
O
NH2
N
N
OMe
OMe
Acknowledgment
TFA, DCM
96%
16
N
O
NH
N
NH4OH, n-butanol,
reflux, 65%
O
3
(S)-doxazosin
~23% overall yield
NH2
The authors (AR, MAA and BK) thank CSIR and UGC, New Delhi
for the award of senior research fellowships. The authors are
declaring the institutional publication number IIIM/1600/2013.
15
(S)-
Scheme 3. Synthesis of (S)-doxazosin.

6422
A. Rouf et al. / Tetrahedron Letters 54 (2013) 6420–6422
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