Synthesis of 6a-hydroxypterocarpans via intramolecular benzoin condensation

Article abstract of DOI:10.1016/j.tetlet.2013.05.121

A novel approach for the syntheses of 6a-hydroxypterocarpans is reported. Its practicality is demonstrated by the synthesis of (±)-glycinol. The main feature is an intramolecular benzoin condensation catalyzed by nucleophilic carbenes to initiate assembly of the benzopyran and establish the 6a-hydroxy center. In addition, a one-pot method was developed to form an epoxide that facilitates subsequent cyclization leading to the benzofuran and direct production of (±)-glycinol.

Full text of DOI:10.1016/j.tetlet.2013.05.121

Tetrahedron Letters 54 (2013) 4121–4124
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Synthesis of 6a-hydroxypterocarpans via intramolecular benzoin
condensation
⇑
Neha Malik, Paul Erhardt
Center for Drug Design and Development, Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 2801 W.
Bancroft Street, Toledo, OH 43606, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach for the syntheses of 6a-hydroxypterocarpans is reported. Its practicality is demon-
strated by the synthesis of ( )-glycinol. The main feature is an intramolecular benzoin condensation cat-
alyzed by nucleophilic carbenes to initiate assembly of the benzopyran and establish the 6a-hydroxy
center. In addition, a one-pot method was developed to form an epoxide that facilitates subsequent cycli-
zation leading to the benzofuran and direct production of ( )-glycinol.
Received 3 May 2013
Accepted 28 May 2013
Available online 6 June 2013
Keywords:
Glyceollins
Ó 2013 Elsevier Ltd. All rights reserved.
Glycinol
6a-Hydroxypterocarpans
Intramolecular benzoin cyclization
Pterocarpans are the second largest group of isoflavonoids.
Derived mostly from legumes, they are potent phytoalexins that
act as plant defensive agents in response to attacking pathogens.1
A distinguishing structural feature of pterocarpans is the presence
of cis-fused benzofuran–benzopyran rings which gives rise to two
asymmetric centers at positions 6a and 11a.2 Several of the 6a-
hydroxypterocarpans are associated with promising medicinal
properties.3 Of particular interest are glycinol (GLO) and the glyce-
ollins (GLYs) (Fig. 1). These intriguing molecules are produced only
in trace amounts when soy plants or seeds are stressed.4
Despite their promising therapeutic potential, complete phar-
macological characterization of the 6a-hydroxypterocarpans re-
mains hampered by limited access to these systems either from
natural or synthetic sources. Only a few routes have been reported
to establish the 6a-hydroxy group.5 The most common method de-
ploys a Sharpless dihydroxylation using OsO4 to produce a benzo-
pyran-diol that can subsequently be closed to the benzofuran cis-
fused system (Scheme 1).
HO
O
O
O
OH
6a
OH
11a
O
O
OH
Glycinol
Glyceollin I
OH
OH
O
O
O
O
O
OH
O
OH
OH
Glyceollin III
Glyceollin II
Figure 1. Soy phytoalexins: glycinol (GLO) and glyceollin isomers (GLYs) I, II, III.
Synthesis of 2 followed our published procedure.6 Masking of
the aldehyde group was then essential to prevent an intramolecu-
lar Aldol condensation which we observed when attempting to
couple 2 and
ation of a reactive enolate in the presence of base. A one-step
approach toward acetalization of that utlilized catalytic
p-toluenesulfonic acid and trimethylorthoformate as a dehydrating
agent,7 resulted in a mixture of starting aldehyde and low yields of
3. Alternatively, the three-step protocol developed by Takikawa
and Suzuki8 proved successful. After acetylation of 2, the aldehyde
group was masked as a 1,3-dioxane acetal using tetrabutylammo-
nium tribromide (TBATB) as a promoter.9 Deprotection of the ace-
tate group provided acetal 3 in 68% overall yield. Ketone 4 was
Herein, we describe a carbene-catalyzed intramolecular ben-
zoin cyclization approach for the synthesis of cis 6a-hydroxyptero-
carpans. This versatile route is delineated using racemic GLO as an
example. Our strategy toward the synthesis of GLO centered on the
3-hydroxy chromanone 12 which can be obtained from commer-
cially available materials through the series of reactions as
depicted in Scheme 2.
a-iodoketone 6, the latter likely being due to gener-
2
⇑
Corresponding author. Tel.: +1 419 530 2167; fax: +1 419 530 7946.
E-mail address: paul.erhardt@utoledo.edu (P. Erhardt).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.121

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N. Malik, P. Erhardt / Tetrahedron Letters 54 (2013) 4121–4124
O
O
O
OR3
OR3
R1
OsO4 R1
R1
OH
OH
OH
R2
R2
O
R2
Isoflav-3-ene
6a-Hydroxypterocarpan
Diol
Scheme 1. OsO4 mediated asymmetric dihydroxylation as an entry to 6a-hydroxypterocarpans.
(i) Pyridine, Ac2O, DCM, 0°C to rt
(ii) CH(OMe)3, TBATB, HO
0°C to rt
OH
BnBr, CH3CN
BnO
OH
HO
OH
O
BnO
OH
O
NaHCO3, reflux
O
82%
(iii) K2CO3, MeOH, 0°C to rt
68%, 3 steps
O
1
2
3
+
HO
BnO
BnO
I2, Selectfluor
BnBr, CH3CN
K2CO3,
K2CO3, reflux
84%
CH2Cl2, MeOH, rt
I
Acetone,
OH
O
OBn O
OBn O
6
81%
reflux
4
5
O
7
OBn
O
OBn
NEt3,
MeOH,
BnO
O
O
BnO
O
THF, 11
BnO
O
O
HCl, 0°C
OH
O
90%
76%,
OBn
OBn
2 steps
O
OBn
BnO
( )-12
8
Scheme 2. Preparation of the 3-hydroxy chromanone.
Catalyst (10 mol%)
O
8
OBn
BnO
O
O
Base (20 mol%)
BnO
O
O
Aldol products
12a and 12b
OH
+
Solvent, rt
OBn
OBn
O
BnO
12
BnO
BnO
O
O
O
OBn
OBn
OBn
OBn
OH
12a
12b
Scheme 3. Intramolecular benzoin condensation of keto-aldehyde 8.
protected at both hydroxyl-groups to give dibenzylated product 5.
-Iodination of 5 occurred in an uneventful manner to yield crys-
talline
-iodoketone 6 in high yields.6 Coupling of 3 and 6 was con-
a
BF4
O
a
N
N
F
ducted in refluxing acetone with potassium carbonate as base.
Intermediate 7 was isolated in crude form and used in the next
step without further purification. Hydrolysis of the acetal protect-
ing group in 7 resulted in keto-aldehyde 8 which conveniently pre-
cipitated from the reaction mixture and could be purified by
recrystallization. Keto-aldehyde 8 was then subjected to the key
step in our synthesis, namely, the intramolecular benzoin cycliza-
tion (Scheme 3).8,10
N
N
S
N
S
F
Br
Br
HO
F
HO
F
F
9
10
11
Figure 2. Commercially available catalysts tried during the intramolecular benzoin
condensation.

N. Malik, P. Erhardt / Tetrahedron Letters 54 (2013) 4121–4124
4123
Table 1
catalyst 11 that requires only a mild base to generate the nucleo-
philic carbene species. The weaker base helps minimize the occur-
rence of the Aldol reaction.8 A possibility of conducting this step
stereoselectively was also envisioned due to the chiral nature of
the triazolium catalyst 11. However, the catalyst did not provide
any enantioselectivity and 12 was obtained as a racemic mixture.
Having the 3-hydroxy chromanone intermediate 12, we were
poised to explore the remaining portion of the synthesis as de-
picted in Scheme 4.
Catalysts and bases deployed during the benzoin cyclization step shown in Scheme 3
Entry
Catalyst
Base
Solvent
Time (h)
Products (yield %)
12
12b
1
2
3
4
5
9
9
9
10
11
DBU
THF
THF
THF
Toluene
THF
5
3
12
12
12
—
—
<5
<5
90
91
85
78
83
—
KOtBu
NEt3
NEt3
NEt3
Reduction of 3-hydroxy chromanone 12 was first attempted
using NaBH4 in THF but this resulted in poor yields of diol 13.
Alternatively, LiAlH4 provided the desired diol in 69% yield. Diol
13 was subjected to hydrogenolysis to provide 14 in high yields.
The final intramolecular cyclization step to furnish ( )-glycinol
was accomplished via a quinone methide intermediate using poly-
mer bound 1,3,4,6,7,8-hexahydro-2H-pyrimido(1,2-a)pyrimidine
as base in anhydrous EtOH over molecular sieves.5a,12 Triethylor-
thoformate was added to remove water as a byproduct and drive
the reaction toward product formation. The reaction was per-
formed in dilute conditions to avoid polymerization of the reactive
quinone-methide. The diagnostic shift of the C-11a proton to
5.25 ppm was observed by 1H NMR and is indicative of a cis ring
closure versus trans within these types of fused systems.5a,13 The
1H NMR and 13C NMR spectra were in accordance with our previ-
ously published values for ( )-glycinol.5b Although the yield of
the final step was not as high as expected, we were able to isolate
unreacted starting material 14 which could be then recycled into
subsequent reactions.
All reactions were conducted using 0.2 mmol of 8 with catalysts 9–11 (10 mol %)
and base (20 mol %) at room temperature and were monitored by TLC and 1H NMR.
LiAlH4, THF,
BnO
O
BnO
O
O
0°C to rt
OH
OH
69%
OH
OBn
OBn
BnO
BnO
( )-12
13
Pd/C, H2, rt
94%
Polymeric Base,
CH(OC2H5)3,
EtOH, 80°C
HO
O
HO
O
OH
OH
40%
O
OH
OH
OH
14
OH
( )-Glycinol
The low yields of the final step encouraged us to devise a differ-
ent route for this step. Close examination of the 1H NMR spectra of
diol 13 revealed that the LiAlH4 mediated reduction had taken
place via chelation control resulting in a racemic mixture of anti-
1,2-diols (Scheme 5). There was no sign of the diastereomeric
syn-1,2-diol in the 1H NMR spectra. As a result of chelation, the hy-
dride attacks from the side of the smallest substituent according to
the Cram-chelation model,14 that is, from below and opposite the
phenyl ring. Previous studies5a on a similar system where OsO4
was used to prepare the syn-diol showed that the 2-position
hydrogens appear at d 4.02 and d 4.72 and the 4-position hydrogen
appears at d 5.51 in the 1H NMR spectra. For the anti-diol these pro-
tons appear at d 4.30, d 4.73, and at d 4.88, respectively.
Ms2O, Pyridine
THF, rt
62%,
3 steps
HO
O
HO
O
OH
O
OH
16
OMs
OH
OH
OH
15
Scheme 4. Synthesis of ( )-glycinol.
The anti-arrangement of diol 13 suggested the possibility of
synthesizing ( )-glycinol via epoxide formation from 14 to 16
which can then cyclize intramolecularly to obtain the required
6a-hydroxypterocarpan as shown in Scheme 4. This reaction was
conducted with mesylate as a leaving group to obtain the epoxide
intermediate 16.15 Several attempts to isolate epoxide 16 were
unsuccessful due to the inherent instability of this intermediate.
This transformation was therefore performed in one step from 14
using Ms2O in Pyridine/THF and provided ( )-glycinol in 62% over-
all yield, considerably higher when compared to the quinone-met-
hide closure.
A range of commercially available heterocyclic catalysts 9–11
(Fig. 2) and common bases were tried to enhance this cyclization.
Table 1 summarizes these attempts. Little to no desired product
was formed using catalysts 9 or 10 in the presence of bases like
DBU, KOtBu, and NEt3 (Table 1, entries 1–4).
A major competing reaction in this case is the intramolecular
Aldol condensation due to the presence of a highly enolizable
keto-moiety. This leads to the formation of 12a, b (Scheme 3) dur-
ing reaction (TLC) and eventual isolation of 12b as a side-product.
However, Rovis triazolium catalyst 1111 proved to be very effective
for inducing the benzoin cyclization and provided the desired 3-
hydroxy chromanone 12 in high yields (Table 1, entry 5). We attri-
bute this to the electron withdrawing aryl-substituent present in
In summary, we have devised a novel route to synthesize 6a-
hydroxypterocarpans. Its feasibility has been demonstrated on
( )-glycinol which can be produced in ca. 20% overall yield after
BnO
O
BnO
O
2
BnO
O
O
LiAlH4
OH
Ar
OH
Ar
4
Ar
H
OH
OH
O
H
Li
( )-12
( )-Anti-1,2-diol 13
Scheme 5. LiAlH4 mediated reduction of ( )-12; only one enantiomer is depicted.

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N. Malik, P. Erhardt / Tetrahedron Letters 54 (2013) 4121–4124
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Acknowledgments
This work was supported by a grant from the United States
Department of Agriculture (USDA) and the Southern Regional Re-
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Supplementary data
Supplementary data (experimental details and spectroscopic
data (1H NMR, 13C NMR, COSY) for new intermediates and final
compound are provided) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
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