6372 J. Org. Chem.

1991,56,5372-5375
Practical Chemoenzymatic Synthesis of Both Enantiomers of Propranolol
H. S. Bevinakatti* and A. A. Banerji
Alchemie Research Centre, ZCZ India Limited Site, Thane-Belapur Road, Thane-400 601,Maharashtra, India
Received February 6, 1991

Synthesis of (R)-and (S)-propranolol in high optical and chemical yields was achieved starting from I-naphthol
and epichlorohydrin. Lipase-catalyzed kinetic m l u t i o n of key intermediatea l-chlom3-( l-naphthyloxy)-2-propanol
and its 0-acetyl ester l-chloro-2-acetoxy-3-( 1-naphthy1oxy)propane was studied using four different approaches.

Introduction Scheme I"

As stereochemistry in a drug molecule governs ita bio-
logical activity,' chirality is emerging as a key issue in
pharmaceutical research.2 0-Blockers of the 3-(aryl- OH
oxy)-l-(alkylamino)-2-propanoltype, e.g., propranolol (11, O
Y
-
2 -3 1
are one such class of drugs where the activity resides
mainly in the S isomer^.^" Moreover, (R)-1 is known to 0 Industrial production of (*)-propranolol.
act as a contraceptive. One of the important ways of
meeting the growing needs of the f u t w chiral drug market Scheme 11"
is predicted to be through "environmentally friendly" r 1
biotransformation^.'*^ The ability of enzymes to work in
organic solvents! especially lipases,l0due to their low cost
and stability, now offers an attractive route for industrial
exploitation.
In continuation of our work on lipase catalysis," we
report herein efficient syntheses, of S and R isomers of
propranolol via lipase-catalyzed kinetic resolution of key

(1)(a) Wainer, I. W., Drayer, D. E., Eds. Drug Stereochemistry;

Marcel Dekker: New York, 1988. (b) Sriens, E.J. Med. Res. Reus. 1986,
6,451. (c) Simonyi, M. Med. Res. Reus. 1984,4,369.(d) Witiak, D. T.; -4 5
Inbasekaran, M. N. In Kirk-Othmer Encyclopedia of Chem. Tech. 3rd
ed.; Wiley-Interscience: New York, 1982;Vol. 17,p 311. (e) Ariens, E. 'Key: (a) epichlorohydrin, pyridine, rt 24 h; (b) HC1, 0-5 OC,
J., Sondijn, W., Timmermans, P. B. M. W. M. Eds. Stereochemistry and 94%; (c) CHSCOCl,0-5 OC,rt, 3 h, 93%; (d) AQO-E~N,80-90 OC,
Biological activity; Blackwell Scientific Publications: Amsterdam,1982. 1 h. 92%.
(f) Ariens, E. J. In Chiral Separations by HPLC; Applications to
Pharmaceutical Compounds; Krstulovic,A. M., Ed.; Ellis Horwood La.:
Chichater, 1989; p 31. Table I. Effect of Base Concentration and Temperature on
(2)Borman, S. Chem. Eng. News 1990,68(28),9. the Product Distribution Ratio ( 3 4 ) in the Condensation of
(3)Nelaon, W. L.; Burke, T. R. J. Org. Chem. 1978,43,3641. (b) I-Naphthol (2) with Epichlorohydrino
Howe, R.; Rao, B. S. J. Med. Chem. 1968,II,1118.
(4)For recently reported preparations of (23)-propranolol and related product
compounds by nonenzymatic asymmetric synthesis, see: (a) Takahashi, mol temp time distribution
H.; Sakuraba, S.;Takeda, H.; Achiwa, K. J. Am. Chem. Soc. 1990,112, base % ("'2) (h) 3:4
5876. (b) Klunder, J. M.; KO,S. Y.; Sharplese, K. B. J. Org. Chem. 1986,
52, 3710 and references cited therein. pyridine 1.25 100 10 4555
(5)For the synthesis of (S)-propranolol utilizing enzyme technology, 2.5 100 6 61:39
we: (a) Wang, Y.-F.; Chen, S.T.; Liu, K. K.-C; Wong, C.-H. Tetrahedron 10 rt 24 23:ll
Lett. 1989,30,1917.(b) Terao, Y.; Murata, M.; Achiwa, K.; Nuhino, T.; 25 60 2 65:35
Akamatau, M.; Kamimura, M. Tetrahedron Lett. 1988,29,5173. (c) 25 rt 16 3263
Matauo, M.; Ohno, N. Tetrahedron Lett. 1981,26,5533and references aqueous KzCOt 50 rt 24 2218
cited therein. 100 rt 24 57:43
(6)For the synthesia of chiral &blockers wing chiral building blocka, 250 , rt 24 100:00
e.&, mu"anito1, we: J u r d , J.; Pikul, S.; Bauer, T. Tetrahedron 1986,
42,447and references cited therein. Reactions were carried out with %:epichlorohydrin molar ratio
(7)(a) Sheldon, R.Chem. Ind. (London) 1990,7,212.(b) Roberta,S.; = 15. *In presence of 5 mol % of TEBAC (with respect to 2).
Turner, N. New Sci. 1990,126(1713),38.
(8) For general reviews on biotransformations, see: (a) Jones, J. B.
Tetrahedron 1986,42,3361.(b) Whiteaides, G.M.; Wong, C.-H. Angew. intermediates l-chlor0-3-(l-napthyloxy)-2-propanol(4)and
Chem., Int. Ed. Engl. 1981,24, 617. (c) Kieslich, K., Vol. Ed. Bio- its 0-acetyl ester l-chloro-2-acetoxy-3-(l-naphthyloxy)-
trans/ormations;Biotechnology; Rehm, H., Reed, H., Eds.; Verlag Che-
mie: Weinheim, 1984; Vol. 6A. propane (5).
(9) For some recent review, see: (a) Klibanov, A. M. Acc. Chem. Res.
1990,23,114.(b) Wong, C.-H. Science 1989,244,1146.(c) Akiyama, A.; Results and Discussion
Bednarski, M.; Kim, M. J.; Simon, E. S.; Waldmann, H.; Whiteaides, G.
M. CHEMTECH 1988,16,640. (d) Yamada, H.; Shimizu, S. Angew. While direct resolution of propranolol was reported to
Chem., Int. Ed. En& 1988,27,622. be un~uccessful,1~ successfu1preparation of (a-propranolol
(10)For reviews on the application of lipases alone, see: (a) Chen, via lipase-catalyzed hydrolysis/ transesterification of gly-
C.-S.; Sih, C. J. Angew. Chem., Int. Ed. Engl. 1989,28,695.(b)Sih, C.
J.; Wu, S.-H. In Topic8 in Stereochemistry; Eliel, E. L., Wilen, S. H., W.; cerol derivativessband cyanohydrin intermediates& was
John Wilry and Sons: New York, 1989;Vol. 19,pp 63-125. (c) Schneider, recently r e p ~ r t e d .In
~ spite of the excellent selectivity
M. Perform. Chemicals 1990,5(3),19. (d) Ibid. 1989,4(4),28. shown by lipase toward the intermediates used, these
(11)(a) Bevinakatti, H. S.; Banerji, A. A. Biotechnol. Lett. 1988,10, methods do not show any promise for industrial exploi-
397. (b) Bevinakatti, H. S.; Banerji, A. A.; Newadkar, R. V. J. Org. Chem.
1989,54,2453.(c) Bevinakatti, H. S.; Newadkar, R. V. Biotechnol. Lett. tation because of several disadvantages like multisteps
1989,Jl, 785. (d) Bevinakatti, H. S.; Newadkar, R. V.; Banerji, A. A. J.
Chem. Soc., Chem. Commun. 1990, 1091. (e) Bevinakatti, H. S.;Ne-
wadkar, R. V. Tetrahedron Asym. 1990,583. (f) Bevinakatti, H. S.; (12) Kirchner, G.; Scollar, M. P.; Klibanov, A. M. J. Am. Chem. Soc.
Banerji, A. A.; Newadkar, R. V.; Mukesh, D. Biocatalysis, in press. 1986,107,7072.

0022-3263/91/1956-5372$02.50/0 0 1991 American Chemical Society

Synthesis of Both Enantiomers of Propranolol J. Org. Chem., Vol. 56, No. 18, 1991 5373

Table 11. Lipam-Catalyzed Kinetic Resolution of Acetate 5 and Chlorohydrin 4 O

-OH (4) -0Ac (5)
[al%D [a]%D
convn (1-5%. eeb (1-5%, el?
sub. lipase reaction medium time (%) EtOHj isomer (%I EtOH) isomer (%)
5 PPLd BuOH-DIPE' 20d 26 +3.3 S 37 -2.8 S 14 3
BuOH 14 d 22 t3.2 S 35 -2.2 S 11 3
HZ0 51 h 16 +4.2 S 47 -1.7 S 9 3
CCU BuOH-DIPE 2d 41 -5.0 R 56 +8.2 R 41 6
3d 58 -3.6 R 40 +11.8 R 59 4
OctOH-DIP@ 5d 58 -3.4 R 38 +10.8 R 54 4
LPSA" BuOH-DIPE 9d 50 +9.0 S >95 -19.9 S >95 >loo
BuOH 5d 47 +9.0 S >95 -18.0 S 90 >loo
HZOi 52 h 48 +8.7 S >95 -17.5 S 88 >lo0
4 PPL VAi 2d -
LPSA VA 46 h 47 -8.1 R 90 +19.1 R >95 >lo0
VA' 13 d 50 -8.7 R >95 +18.5 R 93 >loo
AcZO-DIPE' 41 h 51 -8.3 R 92 +17.5 R 88 53
a Reactions were carried out on 5-25-mmol scale of substrate 5 or 4 at ambient temperature. Unless otherwise mentioned, the ratio used
for substrate-solvent (DIPE or BuOH or HzO or VA)-lipase was 5 mmoLl0 mL:500 mg. bSee ref 21. CSeeref 20. dPorcine pancreatic
lipase. 10 mmol of 1-BuOH in 10 ,mL of DIPE. 'Lipase from C. cylindracea. 10 mmol of 1-OctOH in 10 mL of DIPE. Lipase PS
J

'Amano" isolated from P.cepacia. Substratdipase = 5 mmoL100 mg. 1 Vinyl acetate. 10 mmol of AczO in 10 mL of DIPE.

(more than six steps), low overall yields (less than lo%), methods (Ac20-EhN), interestingly the mixture of 4 and
use of hazardous and expensive reagents like sodium 3 (77:23) as obtained above, when stirred with acetyl
cyanide, lithium aluminium hydride, sodium borohydride, chloride (<5 "C), directly gave 5 (93% yield with <1%
etc., and lastly, noncompatibility with the existing in- other isomer"), thus avoiding an extra step of isolating 4
dustrial process for racemic propranolol13(Scheme I). for the preparation of 5 (Scheme 11).
To overcome these drawbacks, our obvious choices of Lipase-catalyzeddeacylation of 5 was studied using our
the key intermediates for lipase-catalyzed studies were 4 approach with 1-butanol1lb as well as with water (con-
and 5, which not only can be obtained in a single step from ventional hydrolysis). Studies on acylation of 4 were
1-naphthol (2) and epichlorohydrin but can also be con- carried out using cheap and readily available acylating
verted easily to propranolol. agents such as vinyl acetatel8 and acetic anhydride.Ig
Condensation of 2 with epichlorohydrin, following Trihaloethyl butyrates, though found to be excellent
known procedure," in presence of 2.5 M % pyridine at 100 acylating agents,cJ2 were not tried because of cost and
"C yielded a mixture of chlorohydrin 4 and glycidyl 1- operability problems.
naphthyl ether (3) in ca. 4060 ratio. Treatment of this Transesterification/ hydrolysis of acetate 5 with l-bu-
mixture with HCl at room temperature, however, yielded tanol (or 1-octanol)/water using a lipase either from por-
the required 4 contaminated with 2-3% of the unwanted cine pancreas (PPL) or Candida cylindracea (CCL)
regiomer 2-chloro-3-(l-naphthyloxy)-l-propanol, Cl&,O- showed poor selectivity (E = 3+1).~ A purif~edlipase from
CH2CH(C1)CH20H;4a (detected only by GC) obviously Pseudomonas cepacia (Lipase PS "Ammo"; LPSA), how-
was generated after the ring opening of epoxide 3. This ever, was found to show excellent selectivity toward the
was confirmed by treatment of pure glycidyl 1-naphthyl S isomer. A 50% conversion using 1-butanol in diisopmpyl
etherls separately with HCl to give 5 and 2.5% of 4a at ether (DIPE) resulted in (59-4 and (R)-5 in >95% ee21(E
room temperature and <5 "C,respectively. As 4a, being = >loo). Similar results were obtained with neat butanol
primary alcohol, interfered in the lipase-catalyzed reac- or water (Table 11). While hydrolysis worked faster than
tions, it was necessary to suppress/minimize its formation, transesterification, the ease of workup and isolated yields
which, in turn, was possible by suppressing the formation were in favor of the latter.
of epoxide 3 itself in the first step. With systematic op- In the acylation studies of 4, though PPL showed no
timization of temperature and amount of pyridine, it was reaction, LPSA once again showed excellent selectivity
possible to reduce the formation of epoxide from 60 to 23% toward the S isomer. Whether the acylating agent used
(23:77of 3:4). While aqueous K&O3 in the presence of was vinyl acetate (used in excess as solvent also) or acetic
triethylbenzylammonium chloride (TEBAC) gave similar
results, NaOH or KOH gave poorer resultale (see Table I). (17) Treatment of pure glycidyl 1-naphthylether with acetyl chloride
The ease of workup, however, makes pyridine-catalyzed at room temperature gave l-chloro-2-acetoxy-3-(1-naphthy1oxy)propane
condensation a better choice for large-scale reactions. (6) with 4-7% of other regiomer l-acetoxy-2-chloro-3-(l-naphthyloxy)-
The 77:23 mixture of 4 and 3 as obtained above, after propane.
treatment with HCl (either concd or gaseous) below 5 "C (18) (a) Degueil-Casting, M.;DeJesco, B.; Drouillnrd, S.; MaiUard, B.
Tetrahedron Lett. 1987,28,953. (b) Wang, Y.-F.; Lnlonde, J. J.; Mom-
yielded the required chlorohydrin 4 in excellent overall ongan, M.;Bergbreiter, D. E.; Wong, C.-H. J.Am. Chem. Soc. 1988,110,
yields (94% with <1%of the other isomer). While 4 could 7200. (c) Wang, Y.-F.; Wong, C.-H. J. Org. Chem. 1988,53,3127.
be smoothly converted to its 0-acetate 5 using conventional (19) Bianchi, D.; Cati, P.; Battistel, E.J. Org. Chem. 1988,53,5631.
(20) Enantiomericratio, E, was calculated according to the method of:
Chen, C. S.;Fujimoto, Y.;Girdaukas, G.; Sih,C. J. J.Am. Chem. SOC.
~ ~ ~~
1982,104,7294.
(13) (a) Sittig, M.,Ed. Phiarmoceutical Manufacturing Encyclopedia, (21) Attempta to determine ee of chual4 and 5 or ita other derivativm
Noyes Publications: Park Ridge, 1988, Vol. 2, p 1314. (b) Crowther, A. using chiral HPLC (Pickle,DNBPG column) or NMR with Eu(dcm)sno
F.; Smith, L. H. (IC1 Chem. Ind. Ltd.). US. Patent 3,337,628, 1967. chiral shift reagent were not successful. Hence, the ee (and absolute
(14) Stephenson, 0. J. Chem. SOC. 1964, 1571. configurations) were determined by one of the following methods. (a)
(15) Prepared according to the known method;13now commercially HPLC analysis of (-)-MTPA ester of 4 prepared according to: Dale, J.
available from Aldrich Chem. Co. A.; Dull, D. 4.; Moeher,,H. S: J. Org. Chem. 1969,36, 2643. (b) Con-
(16) (a) Lafon, V. (Orsymonde S.A.). Ger. Offen. 2,166,869, 1976; version of chiral 4/5 to ita chiral epoxide 3 or to chiral propranolol (1)
Chem. Abstr. 1976,85,6zBM1. (b)Beasley, Y.M.; Petrow, V.; Stephenson, and comparing the observed rotation with that of literature reported
0. J. Pharm. Pharmacol. 1958,10,47. values.
5374 J. Org. Chem., Vol. 56, No.18, 1991 Bevinakatti and Banerji
Scheme IIP and DIPE used in lipase reactions were dried overnight over 3A
molecular sieves. Ambient temperature fluctuated between 25-35
"C.
l-Chloro-3-( l-naphthyloxy)-2-propanol(4). (a) Using
Pyridine. Modification of Stephenson's method:" A solution
of l-naphthol(2 28.8 g, 0.2 mol), epichlorohydrin (78 mL, 1mol),
and pyridine (1.6 mL, 0.02 mol) was stirred at ambient temper-
ature until GC/TLC analysis showed completion (24 h). Removal
of excess epichlorohydrin and pyridine under reduced pressure
around 80-100 "C yielded 47.2 g of a crude mixture of 3 and 4
(ratio 23:77 by GC).
The crude mixture was stirred with CHCl, (100 mL) and concd
HCl(50 mL) for 1h below 5 "C. After ambient temperature was
attained, water (100 mL) was added and layers were separated.
Extraction of the aqueous layer again with CHC1, (100 mL)
followed by washing of the combined organic layers with water
(t1-L (Rb(-)-i ISt.l*l-5 (50 mL), drying, and removal of solvent yielded 49 g of crude 4,
filtration of which through a silica gel column (CHCl,) to remove
"Key: (a) Lipase PS, n-BuOH or HzO, rt; (b) Lipase PS, vinyl colored impurities gave 44.5 g (94%) of pure 4 as oil: IR (neat)
acetate or Acz0-DIPE, rt; (c) (CH3)2CHNHz,aqueous NaOH; (d) v (cm-l) 3400 (OH); 'H NMR (CDC13,80 MHz) b 2.6 (d, 1 H, J
aqueous NaOH, i-PrOH; (e) (CH&CHNH1. = 5.5 Hz, OH), 3.85 (d, 2 H, J = 4 Hz, CH2Cl),4.2-4.4 (m, 3 H,
OCH2CH), 6.7-8.2 (m, 7 H, aromatic).
anhydride (2 equiv in DIPE),both these acylations at- (b)Using Aqueous K&O,-TEBAC. A mixture Of l-mphthol
tained ca.50% conversions in less than 48 h. These results (21.6 g, 0.15 mol), epichlorohydrin (57 mL, 0.75 mol), K2C03(10.35
show the excellent substrate selectivity exhibited by a g, 0.075 mol), triethylbenzylammonium chloride (1.68 g, 7.5 mmol),
and water (15 mL) was stirred at ambient temperature for 24 h.
lipase toward both forward (acylation)as well as backward After water (50 mL) and CHC1, (50 mL) were added, the reaction
(deacylation) reactions without getting affected by the mixture was further stirred for 30 min. Separation of layers
medium used. Another notable factor about all the followed by removal of solvent afforded 36 g of crude mixture
LPSA-catalyzed reactions, in favor of excellent selectivity, containing 3 and 4 (2278). Treatment of this crude mixture with
was that the initial rate of reaction drastically dropped concd HCl following the procedure described previously gave 33
down after 40% conversion, coming to a practical halt g (93% ) of pure 4.
around 50% conversion (after consumption of all the S 1-Chloro-2-acetoxy-3-(l-naphthy1oxy)propane (5). (a)
isomer). From a Mixture of 3 and 4. A solution of 47.2 g of crude mixture
Chiral 4 or 5 was then smoothly converted, in one step, of 3 and 4 (obtained by method a) in CHC18 (50 mL) and freshly
to chiral propranolol by treating with aqueous iso- distilled acetyl chloride (50 mL) was stirred for 1 h a t <5 "C
followed by 1-2 h a t ambient temperature until TLC (CHClJ
propylamine in the presence of NaOH (>W%yield). The showed complete conversion to 5. Removal of CHCl, and excess
reaction works without using NaOH, albeit sluggish. As acetyl chloride under vacuum followed by filtration through silica
an alternative process, chiral 4 or 5 could &o be converted gel column (CHCl,) to get rid of colored impurities provided pure
to corresponding chiral epoxide 3 by simply stirring with 5 as an oil (52 g, 93%): IR (neat) v (cm-I) 1740 (CO); 'H NMR
NaOH in isopropyl alcohol. Comparison of the rotation (CDCIB) 6 2.13 (8, 3 H, CHJ, 3.91 (d, 2 H, J = 5.0 Hz, CHZCl),
of the isolated epoxides with that of known values also 4.36 (d, 2 H, J = 5.0 Hz,OCH&,5.5 (pentet, 1H, J = 5.1 Hz,CHI,
helped us in establishing the absolute stereochemistry and 6.8-8.3 (m, 7 H aromatic). Anal. Calcd for ClsHlsC103: C, 64.64;
optical purity of the resolved products 4 and 5.21 Chiral H, 5.42; C1, 12.72. Found C, 64.60; H, 5.43; C1, 12.61.
epoxides, on treatment with isopropylamine, readily gave (b) From 4. A solution of 4 (4.73g, 20 mmol), AczO (5 mL),
propranolol (Scheme 111). and E b N (5 mL) was stirred a t 80-90 "C for 1h. Addition of
cold water (25 mL) followed by CHC13 extraction (2 X 25 mL),
To summarize our results, we have shown that chiral water wash (20 mL), drying, removal of solvent, and purification
propranolol with high optical purity (>95% ee) and on silica gel column gave 5.1 g (92%) of 5.
chemical yields (>30% overall) can be obtained in essen- General P r o c e d u r e for Lipase-Catalyzed T r a n s -
tially three steps by incorporating a single lipase-catalyzed esterification of 5. A solution of 5 (1.4 g, 5 "01) and l-butanol
kinetic resolution step into the existing two-step process (1 mL, 10 mmol) in DIPE (10 mL; or alternatively 5 in excess
for the preparation of propranolol. The "robust" selectivity l-butanol(10 mL) used both as a nucleophile and solvent) was
of the enzyme was proved by carrying out kinetic resolu- stirred at ambient temperature with lipase (0.7 g). After a certain
tion of the intermediates (4 or 5) using four different ap- degree of conversion (GC)was attained (seeTable 11),the reaction
proaches. As other important &blockers like practolol, was stopped by filtration. Removal of the solvent followed by
oxprenolol, metaprolol, acebutolol, atenolol, moprolol, etc. separation on a column (CH2C12)yielded optically active 4 and
5 (90 f 2% of theoretical expected yields).
are all closely related to propranolol and are made by the Lipase-Catalyzed Hydrolysis of 5. A mixture of 5 (2.8 g,
same basic route,22our present route should serve as a 10 mmol), LPSA (0.28g), water (20 mL), and phosphate buffer
protocol for all these chiral drugs. (pH 7,lO mL) was magnetically stirred a t ambient temperature
while pH was maintained a t 7 by slow addition of 0.5 M NaOH
Experimental Section solution. After consumption of required amount of NaOH solution
'H NMR spectra were recorded in CDCl, using TMS as an (10 mL) to hydrolyze 50% of 5 (52 h), the reaction mixture was
internal standard. GLC analyses were carried out by using an extracted with CHCl, (2 X 50 mL). Drying and removal of solvent
H P 101 capillary column (methyl silicone; 25 m X 0.2 mm gave a mixture of 4 and 5 (47% conversion by GC), which, after
thickness). Optical rotations were measured on a JAW0 DIP-140 separation on column (CH2Clp), gave 1.28 g (86%) of (-)-5 and
digital polarimeter. PPL (12 u/mg) and CCL (665 u/mg) were ~ , Table II). IR and NMFt spectra
0.93 g (83%)of (+)-4(for [ a ] see
purchased from Sigma Chemical Co. LPSA from P.cepacia (30 of (-)-5 and (+)-4 were identical with those of racemic 5 and 4
u/mg) was a gift from Amano Pharmaceutical Co., Japan. All described previously.
lipases were used straight from the bottle. Prior to use, 1-butanol General Procedure for Lipase-Catalyzed Acylation of 4.
A mixture of 4 (1.18 g, 5 mmol), vinyl acetate (10 mL, or alter-
natively 10 mmol of AcpO and 10 mL of DIPE), and lipase PS
(22) Ladnicer, D.; Mitscher, L. A. The Organic Chemistry of Drug %mano" (0.5 g or 0.1 g; see Table 11) was magnetically stirred
Syntherb; John Why and Sons: New York, 1980; Vol. 2, p 109. at ambient temperature until the desired conversion was achieved.
 J. Org. Chem. 1991,56,5375-5380 6375
Filtration and removal of solvents under vacuum followed by for S-(+)-3,[a]IID +31.4' (1.5, MeOH)).
separation on column (CHICIJ gave (-1-4 and (+)-5 (oitS; 90435% (-)-6 ([a]=D -19.9 (2.4, EtOH), obtained from BuOH-DIPE
yield). reaction, see Table 11) gave (+)-3,[ a ] %+32.9'
~ (1, MeOH) (lit.=
A reaction using 25 mmol of 4 (5.9 g), vinyl acetate (50 mL), [CX]~'D+ 31.4' (1.5, MeOH)).
and lipase PS (0.5 g) gave, after 13 d, 2.78 g (94%) of (-)-4 and 'H NMR (CDClJ data for 3 6 2.8 (m, 2 H, epoxide CHI),
3.16 g (91%) of (+)-5 (both oils; for [a]~y see Table 11). IR and 3.1-4.6 (m, 3 H, ArOCH2CH), 6.75-8.5 (m, 7 H, aromatic).
NMR spectra of (-)-4 and (+)-5 were identical with those of Chiral Propranolol (1) from Chiral3. A solution of chiral
racemic 4 and 5. 3 (1mmol) in excess isopropylamine (2.5 mL) and two drops of
General Procedure for Direct Conversion of C h i r a l 4 or water was stirred at ambient temperature until TLC (CH2C12-
5 to Chiral Propranolol (1). A mixture of chird 4 or 5 (1mmol), MeOH) showed completion (16-20 h). Removal of solvent yielded
excess isopropylamine (2.5 mL), and 10% aqueous NaOH (0.44 crude propranolol (free base), which could be either purified by
mt, 1.1"01) was stirred at ambient temperature for 16 h. After recrystallization in hexane or, more conventiently, converted
excess isopropylamine was removed, water (2 mL) was added and directly to ita hydrochloride as described earlier ( 8 5 4 % ) .
the mixture was extracted with ether (2 X 10 mL). After the ether (-1-3 ([ala6D -33.9' (1.55, MeOH) as obtained previously) gave
layer was dried over Na2S04, dry HCl was bubbled into the R-(+)-1, [ a ] % D +9.82' (1.6, EtOH) (lit.% [ a ] " ~+10.6' (1.02,
solution for ca. 15 min to give colorless chiral propranolol hy- EtOH), mp 70 "C (lit.% 73 'C).
drochloride in quantitative yields. (+)-3 ([a]%D +32.9 (1, MeOH) as obtained previously) gave
For example, ( 4 - 4 obtained from the vinyl acetate reaction as S-(-)-l,[a]%D -9.7' (1.5, EtOH) (lit.u [alZ1D -10.2' (1.02, EtOH),
described earlier ([a]lbD -8.7'; 0.95 g, 4 "01) after reaction with mp 71 'C (lit.% 73 'c).
isopropylamine (10 mL) and 10% aqueous NaOH (1.76 mL) gave Spectral data for 1: IR (KBr) v (cm-') 3425 (OH), 3280 (NH);
1.2 g (100%) of crude (S)-(-)-propranolol hydrochloride, [.]%D lH NMR (CDClJ d 1.1(6 H, J = 6.2 Hz), 1.9 (2 H, br 8 ) 2.9 (3
-22.9' (1.15, EtOH); mp 188-190 'C. A single crystallization in H, m), 6.8-8.3 (7 H, m).
MeOH-Et20 provided optically pure (S)-1HCl, mp 194-196 'C;
[a]%, -25.5' (1.05, EtOH) (lit? -25.9' (1.06, EtOH)). Acknowledgment. Financial assistance for this work
General Procedure for Conversion of Chiral 4 or 5 to was provided b y IC1 India Limited. We thank Dr. B. N.
Chiral Glycidyl 1-Naphthyl Ether (3). To a solution of chiral Roy for encouragement and Amano Pharmaceutical Co.
4 or 5 (1 mmol) in isopropyl alcohol (5 mL) was added 20% (Japan) for providing a free sample of Lipase PS.
aqueous NaOH (0.24 mL, 1.2 mmol for 4 or 0.5 mL, 2.5 mmol for
5), and the mixture was stirred at ambient temperature until TLC Supplementary Material Available: 'H NMR spectra of
(CHIClI) showed complete conversion to 3 (ca.1-2 h). Removal 1and 3-5 (4 pages). Ordering information is given on any current
of solvent followed by CHzCII (10 mL) extraction, water (2 mL) masthead page.
wash, drying, and removal of solvent afforded chiral3 (77-85%
yield) as an oil. (23) Tucker, H.(IC1Ltd.). German Offen. 1975,2,453,324; Chem.
(+)-4 ( [ ( u ] l b D +9.0° (1.9, EtOH), obtained from BuOH-DIPE Abstr. 1976,83,96993.
reaction, see Table ID gave (-)-a, [@D -33.9' (1.55, MeOH) (litB (24) Howe, R.;Shanks, R. G. Noture 1966,210, 1336.

Enzymes in Organic Synthesis. 48.'~~Pig Liver Esterase and Porcine

Pancreatic Lipase Catalyzed Hydrolyses of
3,4-(Isopropylidenedioxy)-2,5-tetrahydrofuranylDiesters
Philip G. Hultin, Franz-Josef Mueseler, and J. Bryan Jones*
Department of Chemistry, University of Toronto, 80 S t . George Street, Toronto, Ontario, Canoda M5S 1Al
Received February 8, 1991

Pig liver esterase (PLE) and porcine pancreatic lipase (PPL) catalyzed hydrolysea of 2,bbis(methoxycarhnyl)
and 2,5-bis(acetoxymethyl)meso-diester derivatives of 3,4-(isopropy1idenedioxy)tetrahydrofuranproceed with
enantiotopic selectivity to give monoester products of up to 72% ee. Transesterification of the 2,5-bis(hy-
droxymethyl) derivative with trifluoroethyl laurate promoted by PPL in ether also proceeds stereoselectively
but in the opposite stereochemical sense from the hydrolysis of the corresponding diacetate. The data provide
further examples of heteroatom and ester moiety induced reversals of stereoselectivity for the two enzymes.

Introduction E.C. 3.1.1.3)6 have proven particularly valuable in this

T h e use of enzymes as catalysts for the production of regard, particularly with respect to their abilities to dis-
a broad structural range of chiral synthons is well-docu-
menteda3 Hydrolytic enzymes such as pig liver esterase
(PLE, E.C. 3.1.1.1)'$ and porcine pancreatic lipase (PPL, (4) (a) Ohno, M.; Otauka, M. Org. React. 1989,97,1. (b) Zhu, L A . ;
Tedford, C. Tetrahedron 1990,46,6587.
(5) Some recent references are: (a) Naemura, K.; Mataumura, T.;
(1) Part 47: Toone, E.J.; Werth, M. J.: Jones. J. B. J. Am. Chem. SOC. Komatau, M.; Himse, Y.; Chikamatsu, H.Bull. Chem. Soc. Jpn. 1989,62,
1990, 112, 4946. 3523. (b) Ganey, M. V.; Padykula, R. E.; Berchtold, G. A. J. Org. Chem.
(2) Abstracted largely from the Ph.D. thesis of Philip G. Hultin, 1989,54, 2787. (c) Fouque, E.; Rouaseau, G. Synthesis .l989,661. (d)
Univenity of Toronto, 1988. Santaniello, E.;Ferraboechi, P.; Grisenti, P.; Manzocclu, A.; Trave, 9.
(3) (a) Daviers, H.G.; Green. R. H.; Kelly. D. R.;Roberts. S.M. Bio- Gozz. Chim. Ital. 1989,119,581. (e) Luytan, M.;Muller, 5.;H e m , B.;
transforations in Reparatiue Orgonic chemistry; Academic Press: K e w , R. Helu. Chim. Acta 1987,70,1250. (f) Sabbioni, 0.;Jones, J. B.
London, 1990. (b) Klibanov, A. M. Acc. Chem. Res. 1990,23, 114. (c) J. Og. Chem. 1987,52,4565. (g) Tschamber, T.;Waespe-Sarcevic, N.;
&M,S.Synthesis ISSO, 1. (d) Toone, E.J.; Simon, E. S.; Bednarski, M. Tamm, C. Helu. Chim. Acto 1986,69,621. (h) Lam, L.K. P.; Hu, R. A.
B.; Whitesidea, G. M. Tetrahedron 1989, 45, 5365. (e) Wong, C.-H. H. F.; Jones, J. B. J . Org. Chem. 1986,51,2047. (i) Jones, J. B.; Hinka,
Science 1989,244, 1145. (f) Crout, D. H. G.; Christen, M. In Modern R. S.; Hultin, P. G. Can. J. Chem. 1985,63,452. (j) Sabbioni, G.;Shea,
Synthetic Methods; Scheffold, R., Ed.;Springer-Verlag: Berlin, 1989; M. L.;Jones, J. B. J. Chem. SOC.,Chem. Commun. 1984, 236. (k)
Vol. 5, pp 1-114. (8) Akiyama, A.; Bednareki, M.; Kim, M. J.; Simon, E. Schneider, M.; Engel, N.; Hoenicke, P.; Heinemann, G.; Goerisch, H.
S.;Waldmann, H.; Whitesides, G. M. Chem. Brit. 1987,23,645. (h) Jones, Angew. Chem., Int. Ed. Engl. 1984,23,67. (1) Mohr, P.; Waeape&rcevic,
J. B. Tetrahedron 1986,42,3351. (i) Klibanov, A. M. Chem. Tech. 1986, N.; Ta", C.; Gawroneka, K.; Gawronski, J. K. Helu. Chim. Acta lSN,
354. 66,2501.

0022-3263/91/ 1956-5375$02.50/0 0 1991 American Chemical Society