Lipase catalyzed resolution of trans-11,12-bis(hydroxymethyl)-9,10-dihydro- 9,10-ethanoanthracene: Facile access to both enantiomers and the synthesis of their amino derivatives

Article abstract of DOI:10.1016/j.tetasy.2011.06.016

The lipase mediated resolution of roof shaped trans-11,12- bis(hydroxymethyl)-9,10-dihydro-9,10-ethanoanthracene using vinyl acetate as an acetylating reagent is achieved. This method gives easy access to both enantiomers of the molecule in very high enantiomeric purity. The chiral diol is converted to diamino and aminoalcohol derivatives by simple chemical transformations.

Full text of DOI:10.1016/j.tetasy.2011.06.016

Tetrahedron: Asymmetry 22 (2011) 1176–1179
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Tetrahedron: Asymmetry
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Lipase catalyzed resolution of trans-11,12-bis(hydroxymethyl)-9,10-
dihydro-9,10-ethanoanthracene: facile access to both enantiomers
and the synthesis of their amino derivatives
⇑
Nilesh Jain, Ashutosh V. Bedekar
Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The lipase mediated resolution of roof shaped trans-11,12-bis(hydroxymethyl)-9,10-dihydro-9,10-ethan-
oanthracene using vinyl acetate as an acetylating reagent is achieved. This method gives easy access to
both enantiomers of the molecule in very high enantiomeric purity. The chiral diol is converted to dia-
mino and aminoalcohol derivatives by simple chemical transformations.
Received 16 May 2011
Accepted 17 June 2011
Available online 19 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to the late Professor Kiyoshi
Tanaka with fond memories and deep
appreciation
1. Introduction
been the subject of various studies.7–9 These basic roof shaped
molecules are precursors of a number of entities with wide appli-
The shape and size of chiral molecules play an important role in
molecular recognition, asymmetric catalysis, and interactions with
bio-receptors and hence are crucial factors in their application in
chemistry and medicine. Depending upon the uses, researchers
have designed molecules with different shapes and with varied
substitutions to provide their desired characteristics. Among such
efforts, Weber introduced the concept of geometrically designed
roof shaped molecules with applications as clathrate hosts and
has studied their inclusion properties.1,2 The roof shaped molecule
consists of two functional groups and a bulky skeleton or base, as
proposed in Figure 1. The diacid 2 and its reduced product diol 3,
are easily prepared by the cycloaddition reaction of anthracene 1
and fumaric acid, with the structure resembling the shape of a roof.
cations, such as in medicinal chemistry,10–12 as ligands in catalytic
transformations,13–19 as mediators for organocatalytic reactions,20
for the preparation of chiral selectors,21 and in the preparation of
functional polymers.22,23
The enantiomerically pure diacid 2 and subsequently non-race-
mic diol 3 can be obtained by a Diels–Alder cycloaddition reaction
of anthracene 1 with the chiral derivatives of fumaric acid. For this
purpose, (À)-menthyl ester of fumaric acid, the (À)-methyl lactate
derivative of fumaric acid, along with similar terpene ester deriva-
tives24,25 or the (S)-benzylprolinate derived diamide of fumaric
acid13 are used as chiral auxiliaries. Another method for obtaining
the pure enantiomers of diacid 2 is by fractional separation of a
racemic mixture using (S)-proline as a chiral resolving agent.26
Although the chiral diacid 2 can be accessed with good enantio-
meric purity, the use of a chiral material in stoichiometric amounts
as an auxiliary or resolving agent is expensive and cumbersome as
it requires extra effort for detachment and reuse; moreover its
availability in both enantiomeric forms is not always feasible.
Hence, we have undertaken the present study to resolve the two
isomers of the C2-symmetric diol 3 by kinetic separation using
bio-catalysis and report our preliminary findings herein. As a part
of an ongoing research project, the chiral trans-diol 3 is then con-
verted to diamines and amino alcohols, which are ligands suitable
for catalytic reactions.
FG
FG
FG
FG
BS
BS
FG = functional group
BS = bulky skeleton
2, R = COOH
3, R = CH2OH
Figure 1. Concept of roof-shaped molecules.
Some other molecules, such as iptacene,3,4 triptacene,5 and
molecular tweezers6 are structurally similar to the aforementioned
roof shaped compounds and have found several useful applica-
tions. The diacid 2 and its diol 3 in enantiomerically form have
2. Results and discussions
Our efforts to obtain enantiomerically pure diol 3 began
with the synthesis of the required diacid 2 by the established
Diels–Alder reaction of anthracene 1 and fumaric acid.27 The diacid
⇑
Corresponding author. Tel.: +91 265 2795552.
E-mail address: avbedekar@yahoo.co.in (A.V. Bedekar).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.016

N. Jain, A. V. Bedekar / Tetrahedron: Asymmetry 22 (2011) 1176–1179
1177
COOH
COOH
HOOC
OH
HO
I2-NaBH4
COOH
THF, 18 h, 87%
dioxane
reflux
72 h
1
2
3
90 %
Scheme 1. Synthesis of diol ( )-3.
HO
OH
*
OAc
OH
*
*
HO
lipase
acyl donor
solvent
HO
*
+
(R,R)-4
( )-3
(S,S)-3
KOH, MeOH
r.t., 3 h, 90%
HO
OH
*
*
(R,R)-3
Scheme 2. Resolution of diol ( )-3.
Table 1
Conditions for the kinetic resolution of diol ( )-3
Entry
Conditions
Solvent
DME
Et2O
THF
THF
Dioxane
THF
THF
THF
THF
THF
% ee of acetate 4a
% ee of diol 3a
Cb
Ec
Acyl donor
Temp (°C)
Time (h)
1
2
3
4
5
5
6
7
8
9
Vinyl acetated
Vinyl acetated
Vinyl acetated
Vinyl acetated
Vinyl acetated
Ethyl acetated
Ethyl acetatee
Ethyl acetatee
Butyl acetated
Isopropyl acetated
rt
rt
rt
8–9
8–9
rt
rt
8–9
rt
48
48
48
48
60
120
96
96
96
96
93.2
64.1
94.1
96.6
97.8
No reaction
78.2
>99
>99
57.1
90.0
37.6
99.6
56.5
38
58
28
51
37
49
13
46
>200
176
39.8
15.3
10.9
16.7
34
14
20
15
12
>200
>200
>200
rt
99
a
b
c
Enantiomeric purity was determined by chiral phase HPLC analysis using Chiralcel-OD and OD-H columns.
Conversion, C = ee3/(ee3 + ee4).
E = {In [ee4(1 À ee3)]/(ee4 + ee3)}/{In [ee4(1 + ee3)]/(ee4 + ee3)}; Ref. 34.
d
e
1.5 equiv.
6.0 equiv.
2 was efficiently converted to diol 3 by a mild reduction using
NaBH4–I2 (Scheme 1).28
to give monoester (R,R)-4. Ether solvents were found to be compat-
ible and gave better conversion and selectivity. The effect of low
temperatures on the biocatalysis is well documented.35 The reac-
tion in THF, or dioxane, was performed at 8–9 °C with vinyl acetate
in tetrahydrofuran and the selectivity and conversion both im-
proved (Table 1, entries 3–5). Out of the different acetylating re-
agents screened, vinyl acetate was found to give the best
conversion and selectivity (Table 1, entries 5–9). Although other
reagents were quite selective, the conversions were poor even if
used in excess (Table 1, entries 7–9). We next studied the ratio
of the lipase to the substrate (Table 2). A 1:1.33 w/w ratio of diol
3 to the granular sample of lipase was the most effective (Table 2,
entries 5 and 6).
Bio-catalytic and enzyme assisted organic transformations are
fast becoming attractive and efficient methods. In addition to their
mild nature of the bio-promoters, the additional advantage of
being highly selective in their actions has established them as pre-
cious tools in modern synthesis.29–33 The separation of enantio-
mers of alcohols by the selective acetylation of one isomer while
not affecting the other kinetic resolution, is one of the more stud-
ied biocatalyzed reactions. Hence, we have screened commercially
available immobilized lipases as biocatalysts for the enantioselec-
tive acetylation of racemic trans-diol 3. Diol ( )-3 was treated with
an appropriate acetylating reagent in the presence of a commercial
sample of the immobilized steapsin lipase, purchased from Sisco
Research Laboratories (SRL), Mumbai under different conditions
(Scheme 2; Table 1).
Enantiomerically pure mono-acetate (R,R)-4 was converted to
diol (R,R)-3 by alkaline hydrolysis without any loss of enantiomeric
purity. The conditions standardized for both steps are extremely
mild. The separation of products is straightforward and is obtained
in very high enantiomeric and chemical yields. As a part of an
Under the present conditions, the (S,S)-isomer of 3 remained
unchanged while the (R,R)-isomer underwent mono acetylation

1178
N. Jain, A. V. Bedekar / Tetrahedron: Asymmetry 22 (2011) 1176–1179
Table 2
Effect of the substrate to enzyme ratio on the kinetic resolution of ( )-3
Entry
Conditions with vinyl acetate (1.5 equiv) in THF
% ee of acetate 4a
% ee of diol 3a
Cb
Ec
Ratio (W/W) substrate 3: lipase
Temp (°C)
Time (h)
1
2
3
4
5
6
1: 0.33
1: 0.33
1: 0.6
1: 1.0
1: 1.3
1: 1.3
rt
40
8–9
8–9
rt
36
48
48
48
48
48
58.5
53.8
62.8
72.8
94.1
96.5
55.1
30.2
43.1
39.6
37.6
>99
49
36
41
35
28
50
6
4
6
9
46
8–9
>200
a
b
c
Enantiomeric purity was determined by chiral phase HPLC analysis using Chiralcel-OD and OD-H columns.
Conversion, C = ee3/(ee3 + ee4).
E = {In [ee4(1 À ee3)]/(ee4 + ee3)}/{In [ee4(1 + ee3)]/(ee4 + ee3)}; Ref. 34.
HN
N
TsO
OTs
N
*
*
*
OH
*
OTs
*
*
*
*
HO
TsO
Na2CO3, DMF
70 C, 50 h
TsCl, Py
36 h
º
53 %
74 %
(R,R)-7
(R,R)-5
(S,S)-3
(S,S)-5
TsO
HN
O
HO
OH
OTs
*
N
N
N
*
*
*
*
OTs
*
*
N
TsO
TsO
TsO
*
O
O
Na2CO3, DMF
70 C, 50 h
TsCl, Py
36 h
º
74 %
62 %
(R,R)-3
(R,R)-5
TsO
(S,S)-5
(S,S)-8
HO
OAc
OAc
*
*
*
HN
*
*
*
OTs
OTs
*
*
N
TsCl, Py
36 h
Na2CO3, DMF
70 C, 50 h
º
70 %
(R,R)-4
(R,R)-6
59 %
(S,S)-5
(S,S)-9
Scheme 3. Conversion of optically pure alcohols to tosylates.
HN
NMe
*
*
*
*
N
MeN
NMe
Na2CO3, DMF
70 C, 50 h
ongoing project, we are in need of converting the chiral diol 3 to chi-
ral diamines. The two isomers of the diol 3 are converted to the cor-
responding ditosylate 5 by treatment with freshly crystallized p-
toluene sulfonyl chloride in presence of pyridine; similarly alcohol
(R,R)-4 is also converted to mono-tosylate (R,R)-6 (Scheme 3). Chiral
compound 6 possesses two different reactive functional groups
which offer opportunities for dissimilar manipulations.
The three substrates were then converted to the corresponding
diamines 7–10 and monoamine 11 by substitution of the tosyl
group by a number of cyclic amines (Scheme 4). The reaction
was carried out in DMF at 70 °C with sodium carbonate and the
corresponding products were isolated by column chromatography
over neutral alumina.
º
53 %
(S,S)-5
(S,S)-10
HN
O
N
TsO
OAc
OAc
*
*
O
*
*
Na2CO3, DMF
70 C, 50 h
º
30 %
(R,R)-11
(R,R)-6
Scheme 4. Synthesis of diamines and amino ester.
Diamines 7–10 and the amino alcohol prepared from 11 are
currently being tested in catalytic reactions and the findings will
be published shortly.
4. Experimental
3. Conclusion
4.1. Standard procedure for resolution of diol ( )-3 (Table 2,
entry 6)
The resolution of trans-11,12-bis(hydroxymethyl)-9,10-dihy-
dro-9,10-ethanoanthracene has been achieved by an alcohol being
selectively acetylated using vinyl acetate and immobilized lipase
as bio-catalyst. The mono acetate obtained in optically pure form
is converted to the other isomer of diol by simple alkaline hydroly-
sis. The easily accessible two isomers of diol 3 are converted to
chiral diamines and mono amine.
To a solution of diol ( )-3 (0.30 g, 1.12 mmol) in dry THF
(10 mL) SRL made immobilized granular steapsin lipase enzyme
(0.40 g) and vinyl acetate (0.15 g, 1.69 mmol) were added and reac-
tion mixture was stirred for 48 h at 8–9 °C. The reaction was fol-
lowed by TLC (48 h). The material was filtered and the filtrate
was concentrated in vacuo. Separation was carried out by column

N. Jain, A. V. Bedekar / Tetrahedron: Asymmetry 22 (2011) 1176–1179
1179
chromatography over silica gel using light petroleum ether (60–80)
and ethyl acetate as the eluent. The mono-acetate 4 was isolated
with a 4:1 ratio (0.15 g, 43.1%) and diol 3 with a 3:2 ratio (0.14 g,
46.7%).
1.51–1.53 (m, 2H), 1.83–1.96 (m, 4H), 2.29–2.32 (br signal, 4H),
2.43–2.46 (broad signal, 4H), 3.70 (s, 8H), 4.34 (s, 2H), 7.08–7.14
(m, 4H), 7.26–7.29 (m, 4H). 13C NMR (CDCl3, 100 MHz) d 41.7,
46.7, 54.1, 63.4, 67.2, 123.6, 125.2, 125.5, 125.7, 141.6, 144.0. IR
(KBr)
m 3014.7, 2952.3, 2918.7, 2845.9, 1647.5, 1454.5, 1278.32,
4.1.1. trans-11,12-Bis(hydroxymethyl)-9,10-dihydro-9,10-ethano-
anthracene (S,S)-3
1138.4, 998.6, 864.4, 758.3, 632.16, 553.84 cmÀ1 Mass (DIP-EI)
404.1(4), 386.1(2), 215.0(2), 203.0(2), 202.0(2), 178.0(8),
139.0(100), 100.0(37).
White solid, mp = 125–7 °C (Lit.24 131–2 °C); [
a]D = +11.0 (c 0.9,
MeOH), (Lit.21 +11.1 (c 0.9, MeOH). HPLC conditions: Chiracel OD
column; 15% IPA in hexane, flow = 0.3 mL/min; 22.2 min (R,R)
and 26.1 min (S,S). 1H NMR (400 MHz; CDCl3) d 1.81–1.84 (m,
2H), 2.80–2.86 (dd, J = 1.9, 11.6 Hz, 2H), 3.23–3.19 (m, 2H), 4.45
(d, J = 1.8 Hz, 2H), 7.11–7.18 (m, 4H), 7.30–7.34 (m, 4H). 13C NMR
(CDCl3, 100 MHz) d 46.1, 46.3, 66.1, 123.3, 125.0, 125.7, 126.1,
Acknowledgments
We thank the Council of Scientific and Industrial Research
(CSIR) New Delhi for the award of Research Fellowship (JRF) to
N.J. We are grateful to Professor B.V. Kamath, Head of the Depart-
ment for his support and Dr. Nitin W. Fadnavis of Indian Institute
of Chemical Technology, Hyderabad for his help in the analysis
and discussions.
143.5, 140.6. IR (KBr)
m 3289.0, 3070.4, 2951.4, 2896.4, 1610.1,
1464.0, 1385.4, 1211.9, 1167.7, 1076.4, 998.0, 624.4, 555.2 cmÀ1
Mass (DIP-EI) 266.1(2), 202.1(4), 179.1(15), 178.1(100), 177.07(6).
4.1.2. trans-9,10-Dihydro-9,10-ethanoanthracene-11-acetoxy-
methyl-12-methanol (R,R)-4
References
White solid, mp = 113–4 °C; [
a
]
D = À14.1 (c 0.9, MeOH). HPLC
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conditions: Chiracel OD-H column; 5% IPA in hexane, 0.3 mL/
min; 32.6 min (R,R) and 37.3 min (S,S). 1H NMR (400 MHz; CDCl3)
d 1.58–1.67 (m, 2H), 2.07 (s, 3H), 3.13–3.17 (m, 1H), 3.34–3.38
(m, 1H), 3.56–3.61 (m, 1H), 3.78–3.82 (m, 1H), 4.22–4.23 (d,
J = 2.0 Hz, 1H), 4.30–4.34 (d, J = 2.0 Hz, 1H), 7.09–7.12 (m, 4H),
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m
3561.3, 3066.0, 3022.0, 2962.1, 2881.6, 1735.8, 1458.1, 1363.7,
1239.3, 1045.8, 1022.9, 969.6, 755.4, 556.76 cmÀ1 Mass (DIP-EI)
308.0(1), 215.0(2), 203.0(2), 202.0(3), 179.0(19), 178.0(100).
4.1.3. Preparation of trans-9,10-dihydro-9,10-ethanoanthra-
cene-11,12-bis-p-toluenesulfonate (S,S)-5
To a stirred solution of diol (S,S)-3 (0.30 g, 1.12 mmol) in dry
pyridine (5 ml), freshly crystallized p-toluenesulfonyl chloride
(0.52 g, 2.70 mmol) was added at 0 °C under an N2 atmosphere.
After stirring for 36 h, the reaction mixture was poured into ice
cold water and extracted with ethyl acetate and washed with di-
lute HCl. The organic phase was concentrated under vacuum. The
solid was further purified by column chromatography over silica
gel to give a white material (0.480 g, 74.15% yield). Mp 143–
145 °C, [a]
D = +28.1 (c 1.0, CHCl3). 1H NMR (400 MHz; CDCl3) d
11.57–1.60 (m, 1H), 2.47 (s, 3H), 3.32–3.37 (m, 1H), 3.68–3.72
(m, 1H), 4.23 (s, 1H), 6.96–7.02 (m, 2H), 7.07–7.11 (m, 1H), 7.20–
7.22 (d, J = 7.2 Hz, 1H), 7.35–7.37 (d, J = 8.0 Hz, 2H), 7.75–7.77 (d,
J = 8.0 Hz, 2H). 13C NMR (CDCl3, 100 MHz) d 21.7, 42.9, 44.7, 71.3,
123.7, 125.6, 126.1, 126.5, 128.0, 130.0, 132.5, 139.1, 142.1,
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145.1. IR (KBr)
m
3069.9, 2955.2, 1627.7, 1596.0, 1360.9, 1176.2,
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1095.4, 949.9, 857.9, 750.3, 662.3, 555.08. Mass (DIP-EI) 574.1(3),
402.2(2), 368.3(2), 230.1(3), 202.1(4), 178.1(100).
4.1.4. Preparation of (S,S)-trans-11,12-bis(morpholine)-9,10-
dihydro-9,10-ethanoanthracene 8
A mixture of ditosylate (S,S)-5 (0.30 g, 0.52 mmol), morpholine
(0.45 g, 5.2 mmol) and Na2CO3 (0.28 g, 2.6 mmol) was heated at
70 °C in dry DMF (5 mL) under an N2 atmosphere. The reaction
mixture was quenched with water and extracted with ethyl ace-
tate. The organic extract was washed with water and dried over
anhydrous sodium sulfate. The crude product was purified by col-
umn chromatography over neutral alumina by eluting with petro-
leum ether–ethyl acetate. White solid (0.13 g; 61.6% Yield), mp
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182–4 °C. [a]
D = +6.8 (c 0.9, CHCl3). 1H NMR (400 MHz; CDCl3) d