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Enzymatic Resolution of Alcohols Coupled with Ruthenium-Catalyzed Racemization of the Substrate Alcohol.

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1161 Crystal structure &ita of (S,S)-14: C,,H,,N,O,. M , = 346.50. colorless plate.
R = 0.074. R, = 0.069. Crystallographic data (excluding structure factors) for
the structures reported in this paper have been deposited with the Cambridge
CryStallOgrdphiC Data Centre as supplementary publication no. CCDC100 106 Copieh of the data can be obtained free ofcharge on application to The
Director, CCDC'. 12 Union Road, Cambridge CBZIEZ, UK (fax: int. code
+ ( 1223j336-033; e-mail depositp
[17] The dihydropyridines 16 were used in the next step without further purification These compounds are apparently sensitive to oxygen.
[18] Y. Toyooka. T Matsuzawa. T Eguchi, K. Kakinuma. Terruliedron 1995, 51.
Catalytic amounts of [ (PPh,),RuCl,] ( I ) epimerized cis-2methylcyclohexanol and racemized enantionierically pure amethylbenzyl alcohol (( +)-(R)-3). For an efficient isomerization it was necessary to use a ketone as a cocatalyst to promote
the ruthenium-catalyzed hydrogen transfer reactions.'"I Consequently, the corresponding ketones, 2-methylcyclohexanone
and acetophenone, were used. The epimerization of cis-2methylcyclohexanol proceeded with a moderate rate.1141whereas the racemization of ( + ) - ( R ) - 3 took only 4 h with 2 moI% of
the catalyst in the presence of base (Scheme 2). The latter reaction was quite sensitive, and in some of the reactions the catalyst
was deactivated and racemization stopped.
Because of the problems with the reproducibility of catalyst 1
we turned our attention to ruthenium catalyst 2." 'I This catalyst
Enzymatic Resolution of Alcohols
Coupled with Ruthenium-Catalyzed
Racemization of the Substrate Alcohol**
Anna L. E . Larsson, B. Anders Person, and
Jan-E. Backvall*
Dedicuted to Professor Henri B. Kagan
The resolution of racemic compounds by enzyme-catalyzed
reactions has become a powerful tool in organic synthesis.["
In particular, processes for hydrolysis of esters and acylation of
alcohols have been successfully employed. One limitation with
classical enzymatic resolution is that the reactions are associated
with a maximum yield of 50% based on the racemate. In order
to overcome this limitation the substrate could be continuously
racemized during the resolution process; this would lead to efficient use of all of the starting material. This approach has attracted some interest recently, and a few applications have been
has been found to be less sensitive and can be used over longer
reaction periods without being deactivated.[9c. Reaction of
( + ) - ( R ) - 3 in the presence of 2 mol% of catalyst 2 and
1 equivalent of acetophenone in tBuOH at 70 "C led to a complete racemization in 45 h (Scheme 2).
1 eqoiv. of acelophenone
96% ee
Argon, 7@c
During our studies on ruthenium-catalyzed hydrogen transfer
Scheme 2. Ruthenium-catalyzed racemization of ( + ) - ( R ) - 3 .Rwction conditions: 2
reactions we observed that alcohols undergo fast isomerization
mol% of 1, 10 mol% of NaOH. 4 h o r 2 mol% of 2.45h
at the r-carbon leading to racemization or e p i m e r i ~ a t i o n . [ ~ - ~ ~
Attempts to use chiral ligands in order to obtain rutheniumcatalyzed asymmetric transfer hydrogenations were hampered
The ruthenium-catalyzed racemization of ( + )-(R)-3 was
by the racemization of the product,["] and this has also been
combined with an enzyme-catalyzed transesterification with
observed by others using the same catalytic system.[' 'I In conCundidu antarctica component B lipase (Novozym 435 = Nnection with previous enzyme studies in our group[121we de435).[16] The use of catalyst 1 in combination with the enzyme
cided to investigate enzyand the acyl donor gave poor results, and the rapid racemization
matic resolution of racemic
with this catalyst could not be reproduced in the presence of the
0' I
alcohol mixtures coupled
enzyme. Combination of catalyst 2 and the enzyme worked
with the above-mentioned
better (Eq. (a) and Table 1). We first tried vinyl acetate as the
racemization. In this comEnzyme
munication we report on
2 molS of 2
the successful enzymatic
resolution of alcohols under
substrate-racemizing condiph
tions (second-order asymmc-3
Scheme 1 Enz>matic resolution under
metric trdnsformation" 31)
Argon. 7OoC
substrate-racemiring conditions
(Scheme 1).
[*) Prof J -E. Backvall, A L E. Larsson, B. A. Person
Depariment of Organic Chemistry
Uppsala ~JrIiVcX'Sity
Box 531. S-75121 Uppsala (Sweden)
Fax: Int. code +(18)-508-542
e-mail: jeh!(l
We would like to thank Dr. Ratan. L. Chowdhury who performed the initial
studies o n the racemization of alcohols. Cundidu unturctica component B Lipase (Novorym 435) was a gift from Novo Nordisk A/S, Denmark. Financial
support by the Swedish National Science Research Council is gratefully acknowledged
acyl donor. Although a complete conversion of the alcohol took
place, only about 50% of the acetate was obtained, because the
acetaldehyde formed when using this acyl donor reacts as a
hydrogen acceptor and oxidizes the substrate alcohol to ketone." 1'
The use of isopropenyl acetate, from which acetone is formed
in the acylation step, showed the same phenomenon but to a
lesser extent than for vinyl acetate. In this case 72% of the
substrate was converted into (R)-a-methylbenzyl acetate ((R)4), and the remaining 28 O/O was oxidized (Table 1, entry 2). The
Table 1. Results of the enzymatic resolution of 2-methylbenzyl alcohol (rue-3)
coupled with ruthenium-catalyzed racemization with catalyst 2 [a].
ROAc (equiv)
ee of (R)-4 [%]
>99.5 [cJ
>99.5 [d]
n o A c ( 3 )
> 99.5 Id]
[h] (R)-4:3:5 [b]
Recerved. December 30, 1996 (Z99451EI
German version: Angew. Chem 1997, 109, 1256-1258
Keywords: alcohols - asymmetric catalysis . chiral resolution
enzyme catalysis * ruthenium
>99.5 [d]
92% yield of isol. (R)-4
[a] The reactions were performed on a 2 mmol scale with 2 moI% of complex 2,
1 equiv of acetophenone, 50mg of Novozym435 and the acyl donor (ROAc) in
tBuOH (5 mL) at 70°C under argon. [b] The conversion and ratio of products were
determined by 'H NMR and GC. The relative amount of acetophenone (5)formed
has been corrected for the amount of added acetophenone. [c] The ee value was
determined directly on (R)-4 by chiral HPLC on a Chiralcel OD-H column with 5%
iPrOH in hexane (0.5 m l m i n- '). [d] The ee value was determined on the corresponding alcohol to (R)-4 (namely, (+)-(R)-3),by chiral HPLC under the same
conditions as for the acetate [el The reaction was run on half the scale as in [a]
(1 mmol).
production of 2-propanol was confirmed by GC analysis. The
product was hydrolyzed, and the enantiomeric excess of the
alcohol was determined and found to be greater than 99.5%.
To further improve the efficiency of the resolution, an acyl
donor that does not interfere with the ruthenium catalyst was
required. Alkenyl acetates should therefore not be used, since
they produce carbonyl compounds. Also esters producing an
alcohol with protons in the c( position should be avoided,
since such an alcohol will compete with the substrate for the
ruthenium catalyst. We therefore considered the use of an aryl
acetate, which should be reasonably activated to favor acyl
transfer from the phenol to the alcohol substrate. The phenol
produced from this acyl donor should not interfere with the
ruthenium. Phenyl acetate was not active enough in the transesterification reaction, but halogenated derivatives, p-chlorophenyl acetate and 2,4,5-trichlorophenyl acetate were excellent
acyl donors in the enzyme-catalyzed acylation of rac-3 with
enzyme N-435.
The combination of ruthenium catalyst 2, p-chlorophenyl acetate, and enzyme N-435 in the reaction of rac-3 gave enantiomerically pure (R)-4 ( > 99.5 O h ee) and in high conversion
(Table 1, entries 3 and 4). In the best case the conversion of ruc-3
into enantiomerically pure acetate (R)-4 was greater than 99 %
(>99.5% ee).
In preliminary studies racemic 1-indanol (rac-6) was allowed
to react with p-chlorophenyl acetate in the presence of the enzyme and ruthenium catalyst 2. An 81 YOconversion into the
acetate (R)-7 with > 99.5 % ee took place [Eq. (b)].
2%Complex 2
Novozym 435
3 eqmv. p-C1-PhOAc
1 equiv.
During the course of our work on this project Williams et al.
reported a related study on metal-catalyzed racemization of
alcohols combined with enzymatic resolution.[6b1They used another lipase (from Pseudomonasjluorescens) and a rhodium-catalyst for their second order asymmetric transformation. Their
best results were 76 % conversion with 80 % ee and 60 % conversion with 98% ee. We obtained a high conversion of enantiomerically pure product, and in addition explored alternative
acyl donors that are compatible with the racemization catalyst.
a) A.M. Kilbanov, Acc. Chem. Res. 1990, 23, 114; b) M. Ohno, M Otsaka,
Org. React. 1990,37, 1 ; c) K. Faber, Biorrunsformationsin Orgunic Chemi.stry,
Springer. Heidelberg 1992; d) C. H. Wang, G. M. Whitesides, Enzymes in
Synthetic Organic Chemistry, Elsevier, Amsterdam, 1994; e) E. Schoffers,
A. Golebiowski, C. R. Johnson, Tetrahedron, 1996, 52, 3769.
a) C. J. Sih, S . H. Wu. Top. Srereochem. 1989, 19,63; b) C.-S. Chen, C. J. Sih,
Angen. Chem. 1989,101, 71 1 ; Angeu. Chem. Int. Ed. Engl. 1989,28, 695.
a) R. L. Gu, I. S . Lee, C J. Sih, Tetruhedron Lett. 1992,33. 1953; b) J. 2. Crich,
R. Brieva, P. Marquart, R. L Gu, S. Flemming, C. J. Sih, J Org. Chem. 1993,
58, 3252, c) G. Fulling, C. J. Sih, J. Am. Chem. Soc. 1987, 109, 2845.
a) R. S . Ward, Tetrahedron Asymmetry 1995, 6. 1475; b) K. Yokozeki, S.
Nakamori, C. Eguchi, K Ymada, K. Mitsugi, Agric. Biol. Chem. 1987. 109,
a) D. S. Tan, M. M. Giinther, D. G. Drueckhdmrner. J Am. Chem. SOC.
117,9093;b) H. van der Deen, A. D. Cuiper, R. P. Hof, A. van Oeveren. B. L.
Feringa, R. M. Kellog, ibid. 1996, 118, 3801.
a) J. V. Allen, J. M. J. Williams, TerruhedronLett. 1996,37,1859;h) P. M. Dinh,
1. A. Howarth, A. R. Hudnott, J. M J. Williams, W. Harris, ibrd. 1996,37,7623.
a) R. L. Chowdhury, J. E. Backvall, J. Chem. Soc. Chem. Cornmun. 1991,1063;
h) J. E. Backvall, U. Andreasson, Tetrahedron Lett. 1993,34, 5459.
J. E. BPckvall, R. L. Chowdhury, U. Karlsson. G . 2 . Wang in Perspectives in
Coordinurion Chemistry (Eds.. A. F, Williams, C. Floriani, A. E. Merbach),
Verlag Helvetica Chimica Acta, Basel, 1992. p. 463.
Wang, J. E. Bdckvall, J. Chem. Sor. Chem. Commun. 1992, 337;
b) G.-Z. Wang, U. Andreasson, J. E. Bdckvall, ibid. 1994, 1037; c) M. L. S.
Almeida, P. KoEovsky, J. E. Backvall, J: Org. Chem. 1996,61,6587;d) M. L. S.
Almeida, M. Beller. G.-Z. Wang. J. E BBckvall. Chem Eur. J 1996, 2,1533.
a) R. L. Chowdhury, unpublished results; b) U. Andreasson, J. E. Backvall,
R. L. Chowdhury, G. 2. Wang, Abstr. OMCOS 7 1993, Kobe, Japan, p. 68.
J. P Genet, V. Ratovelomanana-Vidal, C. Pinel, Synletr. 1993, 478.
a) H. E. Schink, J. E. Backvall, J. Org. Chem. 1992.57, 1588. Correction: ihid.
1992, 57, 6082. b) I. E. Backvall, R. Gatti, H. E. Schink. Synrhesis 1993, 343;
C) R. P. G. Gatti, A. L E. Larsson, and J. E. Backvall, J: Chem. Sot. Perkin
Trans. 1, 1997, 577.
E. L. Eliel, S . H. Wilen, L. N. Mander, Srereochemi.~tryofOrgunieCompounds.
Wiley-Interscience, New York, 1994, pp. 315.
Starting from (f)-cis-2-methylcyclohexanol a crs/trans ratio of 46: 54 was obtained in 14 h at 8O'C with 2 mol% of 1, 10 mol% NaOH, and 1 equiv of
2-methylcyclohexanone in 2 mL of tBuOH.
This catalyst is readily prepared from [Ru,CO,,] and tetraphenylcyclopentadienone. Y Shvo, N Menashe, Orgunometullics 1991, 10, 3885.
a) C. R. Johnson, H. Sakaguchi, Synlett 1992,813; b) C. Orrenius, A. Mattson.
T. Norin, N. Ohrner, K. Hult, Tetruhedron Asymmetry 1994, 5, 1363; c) C.
Orrenius, N. Ohmer, D. Rotticci, A. Mattson, K. Huh, T. Norin, hid. 1995,6,
1217;d) A. Mattson, C. Orrenius, N. Ohrner, C. R. Unelius. K. Hu1t.T. Norin,
Acta Chem. Scund. 1996.50.918; e) C. R. Johnson, S J. Bis, Tetrahedron Lett.
1992, 33. 7287; f) M. Arroyo, J. V. Sinisterra, J Org. Chem. 1994, 59, 4410;
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6975; h) M. Pozo, R. Pulido, V. Gotor, Tetrahedron 1992, 48. 6477.
In this process the acetaldehyde is reduced to ethanol, which is rapidly acylated,
and the process becomes irreversible.
tBuOH, 70°C
Argon' 69b
81 % conv.
An advantage with these chlorophenyl acetates is that the rate
of the transesterification can be adjusted by varying the number
of halogen atoms to match the rate of a metal-catalyzed racemization of a given alcohol.
VCH Verlugsgesellschufi mbH. 0-69451 Weinheim. 1997
17.50+ SO10
Angew. Chem. In/. Ed. Engl. 1997.36. No. 11
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resolution, enzymatic, substrate, ruthenium, coupled, alcohol, racemization, catalyzed
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