Efficient enzymatic kinetic resolution of 4-hydroxytetralone and 3-hydroxyindanone

Article abstract of DOI:10.1016/S0957-4166(01)00404-9

Both enantiomers of 4-acetoxy- and 4-hydroxytetralone have been obtained with high enantiomeric purity by kinetic resolution using enzymes. 3-Hydroxyindanone was successfully resolved using enzymatic transesterification. The absolute configuration of the products were established by literature precedence.

Full text of DOI:10.1016/S0957-4166(01)00404-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2283–2287
Efficient enzymatic kinetic resolution of 4-hydroxytetralone and
3-hydroxyindanone
S. Joly and Mangalam S. Nair*
Organic Chemistry Division, Regional Research Laboratory (CSIR), Trivandrum 695 019, India
Received 10 June 2001; accepted 11 September 2001
Abstract—Both enantiomers of 4-acetoxy- and 4-hydroxytetralone have been obtained with high enantiomeric purity by kinetic
resolution using enzymes. 3-Hydroxyindanone was successfully resolved using enzymatic transesterification. The absolute
configuration of the products were established by literature precedence. © 2001 Published by Elsevier Science Ltd.
1. Introduction
stituted indane unit is found in indatraline,6 a non-
selective monoamine reuptake inhibitor.
Chiral 4-hydroxytetralone and 3-hydroxyindanone are
important intermediates for the synthesis of biologically
active compounds. The chiral 1,4-disubstituted tetralin
unit is found in the antidepressant molecule, Sertraline.1
Several natural products like catalponol,2 isocatal-
Lipases are extensively used for the synthesis of enan-
tiomerically pure compounds via resolution of racemic
mixtures.7 The high stereoselectivity shown by low cost,
partially purified enzymes combined with high catalytic
activity in organic media make them very useful cata-
lysts for enantiomeric resolution. The great importance
of the two structural units 1 and 3 led us to explore an
enzymatic resolution method for obtaining them in
enantiomerically pure form.
ponol,2 isoshinanolone3 and palmarumycin CP4 also
4
contain the 4-hydroxytetralone unit (Fig. 1). Of these,
palmarumycin CP4 possesses potent antifungal activity.
The chiral 1,2-substituted indane moiety is present in
the anti-HIV agent indinavir5 and the chiral 1,3-disub-
NHMe
OH
O
OH
O
OH
OH
O
Isocatalponol
Catalponol
Isoshinanolone
OH
O
Cl
NHMe
Cl
Sertraline
O
O
OR
O
OH
OR
Cl
Indatraline
Palmarumycin CP4
Cl
1 R = OAc
2 R = OH
3 R = OAc O
4 R = OH
Figure 1.
* Corresponding author. Tel.: 91-471-515257; fax: 91-471-490186; e-mail: msn@csrrltrd.ren.nic.in
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00404-9

2284
S. Joly, M. S. Nair / Tetrahedron: Asymmetry 12 (2001) 2283–2287
Since the hydrolytic activity of the lipases is different
2. Results and discussion
from their transesterification activity, it was of interest
to study the enzymatic transesterification of 4-
hydroxytetralone. Accordingly, the racemic hydroxy
compound ( )-2 was prepared by hydrolysis of the
acetate ( )-1 using K2CO3 in methanol (30°C, 15 min,
94% yield). In enzymatic transesterification studies of
( )-2 using vinyl acetate as the acyl donor, the best
result was obtained on using lipase Amano PS (<15%
conversion was obtained with PPL and CCL even
after 6 days) which showed an enantioselectivity of
E=98 (Scheme 2). Since the enzyme has same prefer-
ence in hydrolysis and transesterification, the products
obtained had complementary stereochemistry leading
to (+)-1 with >96% e.e. and (+)-2 with 67% e.e. In a
typical enzymatic transesterification reaction, the
hydroxy compound ( )-2 was dissolved in an excess of
vinyl acetate and stirred in presence of the enzyme.
When nearly 50% conversion had reached, the enzyme
was filtered off, the solvent was removed under
reduced pressure and the crude product was purified
by column chromatography.
Commercially available 1-tetralone was converted to
the racemic starting material 4-acetoxytetralone ( )-1
in three steps viz. (i) reduction with sodium borohyd-
8
ride (ii) acetylation and (iii) oxidation with KMnO4
as shown in Scheme 1. Following the usual practice
for kinetic resolution, the enzymatic ester hydrolysis of
( )-1 was investigated using the three readily available
enzymes lipase Amano PS, Candida cylindracea lipase
(CCL) and Porcine pancreatic lipase (PPL). Surpris-
ingly, all the three enzymes effected hydrolysis, with
PPL and lipase Amano PS exhibiting high enantiose-
lectivity. The acetate (−)-1 was obtained in >96% e.e.9
The results are shown in Table 1.
In a typical experiment, for enzymatic hydrolysis the
racemic acetate was dissolved in acetonitrile (0.5 mL),
phosphate buffer (pH 7.0, ꢀ20 mL) was added and
the mixture was stirred at room temperature in the
presence of the enzyme (1.5 mass equivalents). The
progress of the reaction was followed by tlc analysis
and when approximately 50% conversion was attained,
the products were isolated by extraction with ethyl
acetate and the products viz. chiral acetate (−)-1 and
the enriched 4-hydroxytetralone (−)-2 were separated
by column chromatography. The e.e. of the
The absolute stereochemistry of the products was
confirmed by synthesising (R)-1-acetoxytetralin using
literature procedure12 followed by oxidation with
KMnO4 to give the (4R)-acetoxytetralone. On com-
parison of optical rotation values, it became clear that
enzymatic hydrolysis with all three enzymes led to the
(R)-alcohol, whereas transesterification led to the (R)-
acetate.
1
hydrolysed product was determined by H NMR spec-
tral analysis of the corresponding Mosher’s ester.11 In
the case of acetates, base-catalysed hydrolysis was car-
ried out and the Mosher’s ester was prepared.
OAc
O
OH
OH
OAc
a, b, c
Amano PS
+
OAc
28h
(±)-1
O
O
(±)-2
O
(+)-2
O
(+)-1
38%, > 96% ee
47%, 67% ee
Scheme 1. (a) NaBH4, MeOH, 0°C–rt; (b) Ac2O, DMAP,
Et3N, CH2Cl2 (90% yield for two steps); (c) KMnO4,
MgSO4·7H2O, acetone, water (64% yield).
Scheme 2.
Table 1. Enzymatic hydrolysis of 4-acetoxytetralone 1
OAc
OAc
OH
Enzyme
+
0.1 M
phosphate
buffer
O
O
O
(±)-1
(-)-2
(-)-1
No.
Enzyme
Reaction time (h)
Conversion ca (%)
Acetate
Yieldc (%)
Alcohol
E.e.b (%) Yieldc (%)
Ed
E.e.b (%)
1
2
3
CCL
PPL
Amano PS
25
48
22
58
50
51
92
\96
\96
46
44
48
67
95
91
54
47
54
16
151
69
a c=e.e.s/(e.e.s+e.e.p).
b Determined from 1H NMR of the corresponding Mosher’s ester.
c Isolated yield after column chromatography.
d Ref. 10.

S. Joly, M. S. Nair / Tetrahedron: Asymmetry 12 (2001) 2283–2287
2285
Using the three-step methodology as described already
3.2. KMnO4 oxidation of 1-tetralin acetate
for the synthesis of ( )-1, 3-acetoxyindanone ( )-3 was
prepared starting from indan-1-one. However, enzy-
matic hydrolysis of the acetate in phosphate buffer led
to elimination of acetic acid ultimately giving indenone.
Therefore, 3-hydroxyindanone ( )-4 was synthesised
through acid catalysed hydrolysis of ( )-3. Enzymatic
transesterification was carried out using vinyl acetate as
the acyl donor (Scheme 3). While PPL was unable to
effect transesterification, both CCL and Amano PS
lipases were found to catalyse the reaction. Using lipase
Amano PS, (+)-4 was obtained in 41% yield and >96%
To a cooled solution of 1-acetoxytetralin (0.67 g, 3.54
mmol) in acetone (15 mL) was added MgSO4·7H2O
(2.08 g, 8.43 mmol) and water (5 mL). To this mixture
KMnO4 (2.88 g, 18.30 mmol) was added in small
portions over 1 hour and stirred further for 4 h at room
temperature. The solid was filtered off and the filtrate
was treated with saturated solution of potassium
metabisulphate. The resulting mixture was again
filtered and the filtrate was extracted with
dichloromethane (3×25 mL). The combined extract was
washed with distilled water, saturated brine and dried
over anhydrous Na2SO4. The solvent was removed and
the crude product was chromatographed on silica gel
column. Elution with petroleum ether–ethyl acetate
mixture (85:15) gave the product ( )-1 as an oil (0.46 g,
1
e.e. In this case, the e.e. was determined through H
NMR experiments using Eu(hfc)3 as chiral shift
reagent. The results are summarised in Table 2.
In conclusion, we have developed an efficient asymmet-
ric synthesis of 4-hydroxy/acetoxytetralone as well as
3-hydroxy and 3-acetoxyindanone by applying an enzy-
matic resolution methodology. As these compounds
bear two useful functional groups, it is expected that
they will serve as chiral building blocks for the synthesis
of natural products and biologically active compounds.
1
64%). IR (neat): 2956, 1736, 1690, 1601 cm−1; H NMR
(CDCl3): l 2.13 (s, 3H), 2.26–2.45 (m, 2H), 2.68 (ddd,
1H, J1=17.5 Hz, J2=6.9 Hz, J3=4.8 Hz), 2.94 (ddd,
1H, J1=17.4 Hz, J2=9.5 Hz, J3=5.1 Hz), 6.14 (dd, 1H,
J1=5.8 Hz, J2=3.8 Hz), 7.44–7.49 (m, 2H), 7.56–7.61
(m, 1H), 8.04–8.07 (m, 1H); 13C NMR (CDCl3): 21.11,
28.37, 34.28, 68.98, 127.09, 128.24, 128.94, 131.89,
133.83, 140.60, 170.37, 196.72; HRMS (M+): 204.0797,
C12H12O3 requires 204.0786.
3. Experimental
3.1. General
3.3. Enzymatic hydrolysis of 4-acetoxytetralone ( )-1
Racemic 1 (243 mg, 1.19 mmol) was dissolved in
CH3CN (0.5 mL). To this was added phosphate buffer
(0.1 M, pH 7.0, 20 mL) and lipase PPL (362 mg). After
stirring the reaction mixture for 2 days at room temper-
ature (30°C), the reaction mixture was treated with
saturated brine (3 mL) and filtered through Celite pad.
The filtrate was extracted with ethyl acetate. The
organic layer was washed with NaHCO3 solution, dis-
tilled water and brine and dried over Na2SO4 and
concentrated in vacuo. The residue was subjected to
column chromatography (petroleum ether–ethyl acetate
85:15–80:20) to get the product acetate (S)-(−)-1 (106
mg, 44%) and alcohol (R)-(−)-2 as a white solid (114
mg, 47%). The spectral characteristics of the acetate
were comparable to that of the racemic acetate. (S)-(−)-
1; e.e. >96%, [h]2D7−80.4 (c, 1.0, CHCl3). (R)-(−)-2; e.e.
95%, [h]2D7−35.5 (c, 1.0, CHCl3); mp: 41–43°C; IR
IR spectra were run on a Bomem MB-Series FT-IR
spectrophotometer. NMR spectra were obtained using
chloroform-d as solvent on Bruker DPX 300. Chemical
shifts are given in l scale with TMS as internal refer-
ence. Optical rotations were recorded on a JASCO
DIP-370 digital polarimeter using sodium vapour lamp
and the rotations were taken in CHCl3. CCL was
purchased from Aldrich, PPL from Sigma and lipase
Amano PS (Pseudomonas cepacia) from Amano phar-
maceutical Co. Enantiomeric ratio E was calculated
using Sih’s method.10 Analytical thin layer chromatog-
raphy was performed on silica gel GF254 TLC plates.
Purification by gravity column chromatography was
carried out using silica gel (100–200 mesh). Mixtures of
ethyl acetate and petroleum ether were used as eluent.
OH
OAc
OH
1
(neat): 3405, 1679, 1601 cm−1; H NMR (CDCl3): 2.13–
Enzyme
2.46 (m, 3H), 2.61 (ddd, J1=17.2 Hz, J2=9.6 Hz,
J3=4.6 Hz), 2.94 (ddd, J1=17.4 Hz, J2=7.4 Hz, J3=
4.5 Hz), 4.99 (dd, J1=5.0 Hz, J2=3.7 Hz), 7.39–7.45
(m, 1H), 7.60–7.61 (m, 2H), 8.02 (d, 1H, J=7.8 Hz);
13C NMR (CDCl3): 32.05, 35.11, 67.82, 126.99, 127.12,
+
OAc
(+)-4
(-)-3
O
O
O
(±)-4
Scheme 3.
Table 2. Enzymatic transesterification of racemic 3-hydroxyindanone 4
No.
Enzyme
Reaction time
Conversion, c (%)
Acetate
Yield (%)
Alcohol
Yield (%)
E
E.e. (%)
E.e. (%)
1
2
3
CCL
PPL
Amano PS
35 h
7 days
25 h
41
–
53
73
–
85
29
–
43
51
–
\96
63
91
41
16
–
48

2286
S. Joly, M. S. Nair / Tetrahedron: Asymmetry 12 (2001) 2283–2287
128.33, 131.12, 134.08, 145.32, 197.49. Anal. calcd for
C10H10O2: C, 74.06; H, 6.21. Found: C, 74.41; H, 6.13.
3.8. Acid-catalyzed hydrolysis of ( )-3
To a solution of acetoxyindanone ( )-3 (286 mg, 1.50
mmol) in acetone (10 mL), 20% HCl (10 mL) was
added and stirred at room temperature for 24 h. The
reaction mixture was treated with NaHCO3 solution
and extracted with CH2Cl2 (3×10 mL). The extract was
finally dried over anhydrous Na2SO4. After removal of
the solvent and purification by column chromatography
(petroleum ether:ethyl acetate, 80:20) yielded ( )-4 as a
colorless oil (189 mg, 85%). IR (neat): 3393, 1699, 1601
3.4. Enzymatic transesterification of 4-hydroxytetralone
To a solution of ( )-2 (133 mg, 0.65 mmol) in vinyl
acetate (7 mL) was added lipase Amano PS (203 mg)
and the mixture stirred at room temperature for 28 h.
The enzyme was then filtered off and the solvent was
evaporated. The crude product was subjected to
column chromatography to get acetate (R)-(+)-1 (64
mg, 38%), e.e. >96%, [h]2D7 77.1 (c, 0.9, CHCl3) and
alcohol (S)-(+)-2 (62 mg, 47%), e.e. 67%, [h]2D7 23.5 (c,
0.7, CHCl3).
1
cm−1; H NMR (CDCl3:CCl4, 7:3): 2.49 (dd, 1H, J1=
18.9 Hz, J2=2.7 Hz), 2.99 (dd, 1H, J1=18.9 Hz, J2=
6.8 Hz), 3.28 (brs, 1H), 5.29 (m, 1H), 7.38 (m, 1H), 7.59
(m, 3H); 13C NMR (CDCl3:CCl4, 7:3): 47.07, 68.38,
123.23, 125.94, 129.37, 135.24, 136.29, 155.30, 203.40;
HRMS (M+): 148.0539, C9H8O2 requires 148.0524.
3.5. Hydrolysis of (−)-1 using K2CO3
The following procedure is representative: acetate (−)-1
(60 mg, 0.29 mmol) was dissolved in methanol (5 mL)
containing a few drops of water and K2CO3 (46 mg,
0.33 mmol) was added and the mixture stirred at rt for
10 min. The reaction mixture was concentrated to
remove methanol, diluted with water and extracted
with dichloromethane. The crude product was purified
by column chromatography to yield the product (42
mg, 88%). The spectral data was identical with that
prepared earlier.
3.9. Enzymatic transesterification of 3-hydroxyindanone
To a solution of 3-hydroxyindanone ( )-4 (58 mg, 0.39
mmol) in vinyl acetate (5 mL) was added lipase Amano
PS (89 mg). After stirring for 25 h, the reaction mixture
was filtered and concentrated in vacuo. Purification by
column chromatography gave acetate (R)-(−)3 (32 mg,
43%) e.e. 85%; [h]2D7 −8.9 (c, 1.2, CHCl3) and alcohol
(S)-(+)-4 (24 mg, 41%), e.e. >96%; [h]2D7 99.5 (c, 0.9,
CHCl3).
3.6. Determination of the e.e. of alcohol 2 by making
the corresponding Mosher’s ester
3.10. Determination of the e.e. of 3 by using the chiral
shift reagent, Eu(hfc)3
To a solution of ( )-2 (31 mg, 0.19 mmol) in dry
CH2Cl2 (1.5 mL) was added DMAP (4 mg, 0.03 mmol)
and Mosher’s acid (52 mg, 0.22 mmol). The mixture
was cooled in an ice bath and DCC (58 mg, 0.28 mmol)
was added. The reaction mixture was allowed to warm
to room temperature and stirring was continued until
the alcohol was completely converted to the ester as
evident from tlc (28 h). The reaction mixture was
worked up by filtering out the dicyclohexyl urea formed
in the reaction and the filtrate was concentrated and
purified by column chromatography (eluent petroleum
ether–ethyl acetate 95:5). The chromatography yielded
Good separation of the methyl signals (OCOCH3) of
the two enantiomers were achieved by the sequential
addition of Eu(hfc)3 (5 mg) to a solution of racemic
( )-3 (5 mg) in CDCl3 (0.5 mL). Baseline separation of
the methyl signals were obtained with 25 mg of shift
reagent. The difference in chemical shifts of the CH3 of
acetate ( )-3 was found to be 0.118 ppm. The hydroxy
compound (+)-4 was converted to the acetate (using
Ac2O, Et3N, and DMAP) and its e.e. determined by
NMR as above.
1
the ester (67 mg, 93%). H NMR (CDCl3): 2.36–2.82
(m, 4H), 3.47, 3.52 (s, 3H, -OMe of the two
diastereomeric ester), 6.31–6.33 (m, 1H), 7.29–7.61 (m,
8H), 8.05 (uneven triplet, 1H).
Acknowledgements
The authors thank Dr. A. T. Anilkumar for a gift of
the lipase Amano PS. S.J. thanks the CSIR, New Delhi
for research fellowship.
The same procedure was used for making Mosher’s
ester of optically enriched alcohols.
3.7. KMnO4 oxidation of 1-acetoxyindane
Procedure was the same as in the case of ( )-1. The title
compound was prepared from acetoxyindane in 80%
yield as a yellow oily liquid. IR (neat): 2937, 1738,
References
1. Williams, M.; Quallich, G. Chem. Ind. 1990, 315.
2. Inoue, K.; Inouye, H.; Taga, T.; Fujita, R.; Osaki, K.;
Kuriyama, K. Chem. Pharm. Bull. 1980, 28, 1224.
3. Anh, N. H.; Ripperger, H.; Porzel, A.; Sung, T. V.;
Adam, G. Phytochemistry 1997, 44, 549.
1
1723, 1606 cm−1; H NMR (CDCl3:CCl4, 7:3): 2.13 (s,
3H), 2.78 (dd, 1H, J1=19.2 Hz, J2=2.6 Hz), 3.18 (dd,
J1=19.2 Hz, J2=7.1 Hz), 6.36 (dd, J1=6.9 Hz, J2=2.4
Hz), 7.59 (m, 1H), 7.68 (m, 2H), 7.79 (d, 1H, J=7.6
Hz); 13C NMR (CDCl3:CCl4, 7:3): 20.92, 43.72, 69.77,
123.34, 126.77, 129.90, 135.09, 137.08, 151.36, 170.64,
201.56; HRMS (M+): 190.0618, C11H10O3 requires
190.0630.
4. Wipf, P.; Jung, J.-K.; Rodr´ıguez, S.; Laso, J. S. Tetra-
hedron 2001, 57, 283.
5. Dorsey, B. D.; Levin, R. B.; McDaniel, S. L.; Vacca, J.
P.; Guare, J. P.; Darke, P. L.; Zugay, J.; Emini, E. A.;

S. Joly, M. S. Nair / Tetrahedron: Asymmetry 12 (2001) 2283–2287
2287
Schleif, W. A.; Quintero, J. C.; Lin, J. H.; Chen, I.-W.;
Oxford, 1994.
Holloway, M. K.; Fitzgerald, P. M. D.; Axel, M. G.;
Ostovic, D.; Anderson, P. S.; Huff, J. R. J. Med. Chem.
1994, 37, 3443.
8. US Patent 5,422,116.
9. The other isomer is not seen in 300 MHz NMR. Since NMR
technique is used for the determination of e.e., an accuracy
of only >96% is claimed.
6. Bøgesø, K. P.; Christensen, A. V.; Hyttel, J.; Liljefors, T.
J. Med. Chem. 1985, 28, 1817.
10. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am.
7. (a) Drauz, K.; Waldmann, H. Enzyme Catalysis In Organic
Synthesis; VCH: Weinheim, 1995; Vols. I and II; (b)
Whitesides, G. M.; Wong, C.-H. Angew. Chem., Int. Ed.
Engl. 1985, 24, 617; (c) Wong, C.-H.; Whitesides, G. M.
Enzymes In Synthetic Organic Chemistry; Pergamon:
Chem. Soc. 1982, 104, 7294.
11. Dale, A. J.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543.
12. Naemura, K.; Fukuda, R.; Murata, M.; Konishi, M.;
Hirose, K.; Tobe, Y. Tetrahedron: Asymmetry 1996, 6, 2385.