Angewandte
Chemie
biphenol catalyst and 1.1 equivalents of the acylating agent
(13/14), ester 15 was obtained in up to 95% yield and 92% ee
on a 2.5-mmol scale at room temperature (Table 3, entry 1).
Comparable results but after shorter reaction times were
achieved when the reaction temperature was increased to
608C (Table 3, entry 2). Reactions run on smaller scale were
found to afford slightly lower yields and enantiomeric
excesses (Table 3, entry 3). In the case of 2-octanol (rac-11),
binol appeared to be less effective than 2,2’-biphenol as a
bidentate ligand (Table 3).
We then extended our study to the DKR of the 1-propanol
derivatives 1-phenyl-1-propanol (rac-16) and 3-octanol (rac-
19). Once again, we used “specific” acylating agents that were
synthesized from the corresponding ketones propiophenone
(17) and 3-octanone (20). In these cases, the lipase-catalyzed
acylation, though highly enantioselective, was rather slow.
However, increasing the amount of lipase resulted in almost
quantitative yields and high enantioselectivities after 18 h.
The DKR of the substrates rac-16 and rac-19 gave excellent
results (up to 99% yield and 98% ee) with either binol or 2,2’-
biphenol as ligands (Table 4).
prepared in situ was used as the catalyst for the DKR of 1-
phenylethanol (rac-1), we observed nonenantiospecific chem-
ical esterification at a rate comparable to the racemization of
the alcohol. On the other hand, the Al/binol catalyst, although
it is a Lewis acid, was shown in control experiments to only
weakly promote the direct chemical esterification of 1-
phenylethanol (rac-1). Under these conditions, the substan-
tially higher activity of the lipase towards acylation ensures
high product enantiopurity (Table 1). We also deduce from
the results obtained in the DKR of the other substrates that
such direct “chemical” esterification of the alcohol is not
promoted considerably by the Al/2,2’-biphenol catalyst
either.
In summary, we have demonstrated that chemoenzymatic
DKR of secondary alcohols is possible in high yields and high
enantioselectivity through the use of an inexpensive and
readily available aluminum catalyst generated in situ in
combination with a lipase. We expect that this procedure,
owing to the mild conditions and the simplicity of operation,
will prove useful for the preparation of a variety of optically
pure secondary alcohols, also on larger scale.
We postulate that the bisphenol-type ligands play a dual
role in the DKR. First, they increase the activity of the
aluminum catalyst by impeding aggregation. Second, the
bisphenol aluminum complexes maintain their activity toward
racemization of the alcohol in the presence of the lipase. In
contrast, Al(OtBu)3, prepared in situ from AlMe3 and
tBuOH, is a highly active racemization catalyst, but it loses
its activity almost completely when combined with the lipase.
By the application of bisphenolic ligands, the two processes,
racemization effected by the aluminum catalyst and acylation
mediated by the lipase, become compatible.
Experimental Section
All reactions were performed under argon atmosphere in oven-dried
glassware. Toluene was dried over sodium and distilled under argon
atmosphere. All commercially available chemicals were used without
further purification. GC analysis was performed using a CP-Chirasil-
Dex CB phase column.
DKR of rac-1: A Schlenk tube was charged with binol (72mg,
0.25 mmol, 0.1 equiv), 4 mL of a stock solution of trimethylaluminum
in absolute toluene (62.5 mm, 0.25 mmol, 0.1 equiv) was added, and
the resulting solution was stirred for 15 min at RT. rac-1 (0.302mL,
305 mg, 2.5 mmol, 1 equiv) was added, and the resulting solution was
stirred for a further 5 min. Subsequently, Novozym435 (30 mg),
diphenyl ether (internal standard) (0.397 mL, 2.5 mmol, 1 equiv), and
3 (3 mmol, 1.2equiv) were added. Argon atmosphere was maintained
throughout the reaction. Yields were determined by GC. Samples of
20 mL were withdrawn from the reaction mixture by means of a
syringe, diluted to 1 mL with CH2Cl2/MeOH (1:1), and filtered
through a pad of cotton.
Another remarkable feature of the bisphenol-type ligands
is that they increase the activity of the aluminum catalyst
towards racemization but not acylation. When Al(OtBu)3
Table 4: DKR of rac-16 and rac-19.[a]
DKR of rac-6 on preparative scale: A 50-mL flask was charged
with 2,2’-biphenol (0.29 g, 1.56 mmol, 0.2 equiv), 12.5 mL of a stock
solution of trimethylaluminum in toluene (0.125m, 1.56 mmol,
0.2equiv) was added, and the resulting solution was stirred for
15 min at RT. rac-6 (1.075 mL, 1.00 g, 7.8 mmol, 1 equiv) was added,
and the resulting solution was stirred for a further 5 min. Subse-
quently, Novozym435 (31 mg), dodecane (internal standard)
(1.774 mL, 7.8 mmol, 1 equiv), and 1.34 mL (7.8 mmol, 1 equiv) of
the acylating agent (8/9 ca. 1:2) were added. The resulting mixture was
allowed to stir at RT for 24 h. Argon atmosphere was assured
throughout the reaction. The solution was filtered through a pad of
celite, washed with CH2Cl2, and the solvent was evaporated in vacuo.
The residue was purified by column chromatography on silica gel with
n-hexane/EtOAc (95:5). The product ester 10 (Rf = 0.27) was
obtained as a colorless oil (1.18 g, 90%, 99% ee). The 1H and
13C NMR spectroscopic data obtained from this material were
identical to those in the literature.[4]
Entry Alcohol Ligand
AlMe3
[equiv]
Prod.
Yield [%] ee [%]
1
2
rac-16
rac-16
rac-19
rac-19
binol
0.1
(R)-18 99
(R)-18 97
(R)-21 95
(R)-21 95
98
97
95
94
2,2’-biphenol 0.1
binol 0.2
2,2’-biphenol 0.2
3[b]
4[b]
[a] Unless otherwise noted, reactions were run on a 0.5-mmol scale over
18 h at RT under Ar atmosphere with 1.2 equiv of the acylating agents
(prepared from propiophenone (17) and 3-octanone (20), respectively;
see the Supporting Information for experimental details) and with 80 mg
of Novozym per mmol of alcohol. Yields and ee values were determined
by chiral GC. Bidentate ligand and AlMe3 were added in a 1:1 ratio. The
configuration of the product 18 was assigned by comparison with data in
Ref. [4]. The configuration of the product 21 was assigned in analogy to
the DKR of 2-octanol (rac-11). [b] The reaction was conducted with 40 mg
of Novozym per mmol of alcohol.
Supplementary Information contains all experimental details for
the synthesis and characterization of the racemic acetates used for the
calibrations (rac-5, rac-10, rac-15, rac-18, and rac-21), and acylating
agents (enol acetates of the ketones 2, 7, 12, 17, and 20). Furthermore,
the procedures for the DKR of the alcohols (rac-1, rac-6, rac-11, rac-
Angew. Chem. Int. Ed. 2006, 45, 6567 –6570
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim