Ruthenium- and enzyme-catalyzed dynamic kinetic asymmetric transformation of 1,4-diols: Synthesis of γ-hydroxy ketones

Article abstract of DOI:10.1021/jo048511h

Enzymatic kinetic resolution of unsymmetrical 1,4-diols in combination with a ruthenium-catalyzed hydrogen transfer process led to a dynamic kinetic asymmetric transformation (DYKAT) of the least hindered alcohol. Oxidation of the second hydroxy group tak

Full text of DOI:10.1021/jo048511h

Ruthenium- and Enzyme-Catalyzed Dynamic Kinetic Asymmetric
Transformation of 1,4-Diols: Synthesis of γ-Hydroxy Ketones
Bele´n Mart´ın-Matute and Jan-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
Received August 25, 2004
Enzymatic kinetic resolution of unsymmetrical 1,4-diols in combination with a ruthenium-catalyzed
hydrogen transfer process led to a dynamic kinetic asymmetric transformation (DYKAT) of the
least hindered alcohol. Oxidation of the second hydroxy group takes place under the reaction
conditions leading to the formation of γ-acetoxy ketones in high enantiomeric purity.
Introduction
dihydrofurans,8 is well established. These compounds are
also useful in biodegradable polymers and perfumes.9
During the last two decades, the synthesis of enantio-
merically pure, or enriched, compounds has emerged into
one of the most important fields of organic chemistry.1
In particular, the resolution of racemic compounds by
enzyme-catalyzed reactions has become a powerful tool
in organic chemistry.2 However, for the production of a
single enantiomer, kinetic resolution has a maximum
theoretical yield of 50%. By applying dynamic kinetic
resolution (DKR)3,4 this limitation can be overcome since
the unreactive enantiomer is continuously racemized and
the product can be obtained in 100% yield. In the past
few years we3a-c,5 and others3d,e,g,6 have applied DKR to
the preparation of different functionalized alcohols that
are important building blocks for the synthesis of high-
value compounds.
Some approaches for the preparation of enantiopure
γ-hydroxy ketones have been reported. These procedures
include the use of chiral catalysts,9,10 the use of chiral
epoxides,11 and the kinetic resolution of γ-hydroxy ke-
tones.11 To the best of our knowledge, only one study
dealing with the lipase-catalyzed kinetic resolution of
γ-hydroxy ketones has been reported.11 The efficiency of
the kinetic resolution for acyclic γ-hydroxy ketones is
rather low, and the highest ee value obtained was 42%.
The low efficiency of the kinetic resolution of γ-hydroxy
ketones prompted us to develop an alternative dynamic
process for the preparation of enantioenriched γ-hydroxy
ketones. As part of our ongoing program on the combined
enzyme- and transition metal-catalyzed DKR some pro-
cedures for diols have been recently reported.12,13 All diols
tested were transformed into diacetates in excellent
enantiomeric excess. We have now taken advantage of
the very efficient enzymatic resolution of 1,4-diols and
combined it with a Ru-catalyzed hydrogen transfer
process leading to a dynamic kinetic asymmetric trans-
formation (DYKAT)13,14 providing chiral γ-acetoxy ke-
tones. In this process, 1,4-diols, containing one large (RL)
and one small (RS) group, are transformed to enantio-
merically enriched γ-acetoxy ketones (Scheme 1).
The synthesis of γ-hydroxy ketones as precursors of
versatile building blocks, such as tetrahydrofurans7 and
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John
Wiley & Sons: New York, 1994.
(2) (a) Faber, K. Biotransformations in Organic Chemistry; Springer-
Verlag: Berlin, Germany, 2000. (b) Enzyme Catalysis in Organic
Synthesis: A Comprehensive Handbook; Drauz, D., Waldmann, H., Eds.;
Wiley-VCH: Weinheim, Germany, 2002; Vol. 2. (c) Kazlauskas, R. J.;
Bornscheuer, U. T. Hydrolases in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 1999.
(3) For reviews on DKR, see: (a) Pa`mies, O.; Ba¨ckvall, J.-E. Trends
Biotechnol. 2004, 22, 130-135. (b) Pa`mies, O.; Ba¨ckvall, J.-E. Chem.
Rev. 2003, 103, 3247-3262. (c) Huerta, F. F.; Minidis, A. B. E.;
Ba¨ckvall, J.-E. Chem. Soc. Rev. 2001, 30, 321-331. (d) Kim, M.-J.; Ahn,
Y.; Park, J. Curr. Opin. Biotechnol. 2002, 13, 578-587. Kim, M.-J.;
Ahn, Y.; Park, J. Curr. Opin. Biotechnol. 2003, 14, 131. (e) El Gihani,
M. T.; Williams, J. M. J. Curr. Opin. Chem. Biol. 1999, 3, 11-15. (f)
Stu¨rmer, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 1173-1174. (g)
Reetz, M. T.; Schimossek, K. Chimia 1996, 50, 668-669. (h) Noyori,
R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36-
56. (i) Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475-1490.
(4) For dynamic thermodynamic resolutions see: Beak, P.; Ander-
son, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel, D. J.; Weisenburger,
G. A. Acc. Chem. Res. 2000, 33, 715-727.
(7) Harmange, J. C.; Figade`re, B. Tetrahedron: Asymmetry, 1993,
4, 1711-1754.
(8) See, for example: (a) Shao, X.; Tamm, C. Tetrahedron Lett. 1991,
32, 2891-2892. (b) Reissig, H.-U.; Holzinger, H.; Glomsda, G. Tetra-
hedron 1989, 45, 3139-3150. (c) Roussis, V.; Gloer, K. B.; Wiemer, D.
F. J. Org. Chem. 1988, 53, 2011-2015.
(9) Seiji, W.; Shigeru, M.; Kidenori, K. European Patent Appl. 18,
1997.
(10) (a) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1989, 30, 6275-
6278. (b) Watanabe, M.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1994,
837-842.
(11) Crotti, P.; Bussolo, V. D.; Favero, V.; Minutolo, F.; Pineschi,
M. Tetrahedron: Asymmetry, 1996, 7, 1347-1356.
(12) Persson, B. A.; Huerta, F. F.; Ba¨ckvall, J.-E. J. Org. Chem. 1999,
64, 5237-5240.
(13) Edin, M.; Steinreiber, J.; Ba¨ckvall, J.-E. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5761-5766.
(14) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1-14.
(5) Mart´ın-Matute, B.; Edin, M.; Boga´r, K.; Ba¨ckvall, J.-E. Angew.
Chem., Int. Ed. 2004, in press.
(6) (a) Choi, J. H.; Kim, Y.-H.; Nam, S. H.; Shin, S. T.; Kim, M.-J.;
Park, J. Angew. Chem., Int. Ed. 2002, 41, 2373-2376. (b) Choi, J. H.;
Choi, Y. K.; Kim, Y. H.; Park, E. S.; Kim, E. J.; Kim, M.-J.; Park, J. J.
Org. Chem. 2004, 69, 1972-1977.
10.1021/jo048511h CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/11/2004
J. Org. Chem. 2004, 69, 9191-9195
9191

Mart´ın-Matute and Ba¨ckvall
SCHEME 1. Dynamic Kinetic Asymmetric
Transformation of 1,4-Diols to γ-Acetoxy Ketones
(RL * Me, Et, RS ) Me)
SCHEME 3. One-Pot Procedure for the Synthesis
of γ-Acetoxy Ketones
SCHEME 2. Two-Step Procedure for the
Synthesis of Enantiomerically Pure γ-Acetoxy
Ketones
TABLE 1. DYKAT of 1,4-Diolsa
acyl donor
(equiv)
enzyme
yield of
ee
entry substrate
(mg/mmol)b
4 (%)c (%)d
1
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
3
3
CALB (30)
CALB (30)
CALB (30)
CALB (30)
CALB (30)
CALB (30)
CALB (30)
CALB (60)
CALB (30)
PS-C “Amano II”
CALB (60)
57 (53)e 90
2f
75
84
77
71
81
76
90
93
75
75
89
83
71
75
51
86
3f
10
20
40
20
20
20
3j
4f
5f
6f,g
7f,h
8
9i
10
11
20
10
63e
83
a Conditions unless otherwise noted: 0.14 mmol of 1, CALB,
isopropenyl acetate and 5 mol % of 3 in 0.5 mL of toluene at 70 °C
for 12 h. b Milligrams of enzyme per millimole of diol. c % yield
measured by GC. d Enantiomeric excess determined by GC. e Iso-
lated yield. f Freshly distilled isopropenyl acetate. g In cyclohexane
at 65°C. h In tert-butyl methyl ether at 65°C. i Reaction time was
4 days. j p-Chlorophenyl acetate as acyl donor.
Results and Discussion
For an unsymmetrical 1,4-diol with a large and a small
group only one of the alcohol groups (the least sterically
hindered) will be accessible to the enzyme. Treatment of
1-phenyl-1,4-pentanediol (1a) with isopropenyl acetate
in the presence of Candida antarctica lipase B (CALB)
in toluene at 70 °C afforded diol monoacetate 2a in 45%
yield.15 After purification by chromatography (38% iso-
lated yield) oxidation16 of 2a in the presence of Shvo’s
catalyst (3)17 and 2,6-dimethoxy-1,4-benzoquinone af-
forded the known γ-acetoxy ketone 4a11 enantiomerically
pure (>99% ee) (Scheme 2). This result prompted us to
develop conditions for a one-pot synthesis of compounds
4 starting from the diols precursors.
In the very first attempts to combine the DYKAT of
the least hindered alcohol and the oxidation of the inner
alcohol, we used CALB, isopropenyl acetate, and Shvo’s
ruthenium catalyst 3. Subjecting diol 1b (R ) i-Pr) to
the reaction conditions at 70 °C with use of 5 mol % of
catalyst 3 led to consumption of all the starting material
after 12 h. Surprisingly, 57% of acetoxy ketone 4b was
obtained in 90% ee and the remainder of the converted
starting material was diketone 5b (Scheme 3).
donor the yield improved and the ee remained the same
(compare entries 2 and 3, Table 1). When 20 equiv of
isopropenyl acetate were employed the ee was improved
to 89% and 4b was obtained in good yield (entry 4, Table
1). Running the reaction in the presence of 40 equiv of
acyl donor did not increase either the ee or the yield
(entry 5, Table 1). The reaction was also tried in different
solvents. Thus, in cyclohexane at 65 °C 4b was obtained
in 81% yield (71% ee) (entry 6, Table 1). Using tert-butyl
methyl ether as the solvent at 65 °C did not improve the
process (entry 7, Table 1). Increasing the amount of
enzyme to 60 mg per mmol of diol gave 4b in high yield
but low ee (entry 8, Table 1). When p-chlorophenyl
acetate was employed as acyl donor, 4b was obtained in
93% yield and 86% ee. However, prolonged reaction times
were needed (entry 9, Table 1). The use of Pseudomonas
cepacia lipase (PS-C “Amano II”) gave only decomposition
products (entry 10, Table 1). Diol 1a gave acetoxy ketone
4a by using CALB and 10 equiv of isopropenyl acetate
(entry 11, Table 1).
Scope and Limitations of the DYKAT. To study the
scope of the reaction, a variety of substrates were
resolved (Table 2). Aliphatic substrates were tested by
using the best reaction conditions of Table 1. Thus,
substrates 1b,c gave the corresponding γ-hydroxy ke-
tones 4b,c in good yields and high enantiomeric excess
(entries 2-4, Table 2). Substrate 1d was also converted
to the corresponding acetoxy ketone in a high yield but
with low enantiomeric excess. A plausible explanation
is that the readdition of hydrogen to the inner ketone
might simply be very slow because of steric hindrance
Before turning to other substrates, studies were un-
dertaken to improve the synthesis of γ-acetoxy ketones
in one pot (Table 1). The yield was improved by using
freshly distilled isopropenyl acetate, but in this case 4b
was obtained in lower ee (compare entries 1 and 2, Table
1). By increasing the amount of freshly distilled acyl
(15) Yield determined by 1H NMR.
(16) Csjernyik, G.; EÄ ll, A. H.; Fadini, L.; Pugin, B.; Ba¨ckvall, J.-E.
J. Org. Chem. 2002, 67, 1657-1662.
(17) Menasche, N.; Shvo. Y. Organometallics 1991, 10, 3885-3891.
9192 J. Org. Chem., Vol. 69, No. 26, 2004

Synthesis of γ-Hydroxy Ketones
TABLE 2. DYKAT of a Variety of 1,4-Diolsa
SCHEME 4. Proposed Mechanism for the Easy
[Ru]-Catalyzed Oxidation of the Inner Alcohola
acyl
donor time
yieldd eee
(%) (%)
entry
1f,g Ph
R
CALBb (equiv)c (h) product
8
30
30
30
30
30
15
8
10
20
20
18
96
17
16
17
18
24
36
8
4a
4b
4b
4c
4d
4e
4f
4g
4h
4i
75 (69)h 84
77 89
93 (89)h 86
73 90
82 (77)h 48
2
3
4
5
6
i-Pr
i-Pr
Cy
3i
20
20
20
10
10
10
10
pentyl
benzyl
70
82
81
74
79
88
7f,g 2-naphthyl
8f,g p-Br
9f,g p-F
8
75 (72)h 86
10f,g p-OMe
8
96h
21
a Conditions unless otherwise noted: 0.43 mmol of 1, CALB,
isopropenyl acetate and 5 mol % of 3 in 1.5 mL of toluene at 70
°C. b Milligrams of enzyme per millimole of diol. c Freshly distilled
isopropenyl acetate. d % yield measured by GC. e Enantiomeric
excess determined by GC. f Reaction run in 3 mL of toluene. g 2.5
a The phenyl groups on the ring are omitted for clarity.
i
mol % of 3. h Isolated yield. p-Chlorophenyl acetate as the acyl
donor.
giving rise to the formation of a significant amount of
hydroxy ketone, and as observed before,11 the enantio-
selectivity of CALB for this kind of substrates is rather
low (vide infra). For aromatic substrates 2.5 mol % of
Shvo’s catalyst gave good results, and the use of 8 mg of
CALB per mmol of diol and 10 equiv of isopropenyl
acetate gave the best ee. Electron-donating groups on the
phenyl ring significantly decreased the enantioselectivity
(entry 10, Table 2), which is a result of the high redox
potential of phenyl ketones/benzylic alcohols with electron-
donating groups in the 4-position.18 Running the reaction
under a hydrogen gas (1 bar) atmosphere19 gave the same
result. Electron-withdrawing groups on the ring do not
have a significant effect on the outcome of the reaction.
Mechanistic Considerations. The least sterically
hindered alcohol function is acylated under DYKAT
conditions. This acylation leads to acetate formation in
strict agreement with Kazlauskas’ rule.20 The second
alcohol function, the most hindered, cannot lead to the
acylated product because both substituents at the stereo-
center are too big to be placed in the small pocket of the
enzyme. However, under the reaction conditions, the
most hindered alcohol is easily oxidized to the ketone.
In this transformation there is a hydrogen loss process.
Two explanations can account for this ruthenium-
mediated oxidation (Scheme 4). Catalyst 3 is activated
by heat to ruthenium species A (16 electrons) and B (18
electrons). The alcohol function reacts with complex A
giving rise to the oxidized product and complex B (cycle
A, Scheme 4). This process is in principle reversible, thus
the ketone can react with species B and the alcohol is
obtained. However, if this ruthenium-mediated reduction
is slow (cycle B, Scheme 4), complex B can lose hydrogen
and be converted to ruthenium-species A.21 As a conse-
quence, the ketone would be accumulated in the reaction
mixture. The second explanation that can account for this
oxidation has to do with the acyl donor. Since isopropenyl
acetate was employed as the acyl donor, acetone will be
formed from the tautomerization of the corresponding
enol formed after the acylation reaction. Probably acetone
is reduced faster than the oxidized substrate, and, once
again, the ketone would be accumulated in the system.
To test this hypothesis two control experiments were
carried out. In the first one a mixture of 1-phenylethanol
and 2.5 mol % of 3 in toluene was stirred at 70 °C. After
15 h 6% of acetophenone had been formed. In the second
experiment, a mixture of 1-phenylethanol and 2.3 mol %
of 3 in a mixture of toluene/acetone (4:1) was stirred at
70 °C. After 15 h 97% of acetophenone had been formed.22
These results strongly suggest that the oxidation of the
inner alcohol in the diols occurs mainly via hydrogen
transfer to acetone and to a lesser extent via loss of
molecular hydrogen from the catalyst.
Despite the excellent enantiomeric excess reported in
dynamic kinetic asymmetric transformation of sym-
metrical 1,4-diols12 it was of interest to measure the
selectivity of CALB for unsymmetrical 1,4-diols. The E
value (enantiomeric ratio)23 is applied only to enanti-
omers. In this case, this does not apply since the starting
substrate is a mixture of rac-/diastereomeric diols. How-
ever, it was found that the stereochemistry of the inner
alcohol does not affect the enzyme-catalyzed acylation of
the least hindered alcohol (Scheme 5). Therefore, the
selectivity of the enzyme was tested for different dia-
(21) (a) Casey, C. P.; Vos, T. E.; Singer, S. W.; Guzei, I. A.
Organometallics 2002, 21, 5038-5046. (b) Choi, J. H.; Kim, N.; Shin,
Y. J.; Park, J. H.; Park. J. Tetrahedron Lett. 2004, 45, 4607-4610.
(22) For oxidations employing acetone as the hydrogen acceptor
see: Almeida, M. L. S.; Beller, M.; Wang, G.-Z.; Ba¨ckvall, J.-E. Chem.
Eur. J. 1996, 2, 1533-1536.
(23) (a) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, G. C. J. J.
Am. Chem. Soc. 1982, 104, 7294-7299. (b) Chem, C.-S.; Wu, S.-H.;
Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1987, 109, 2812-2817.
(18) Electronic effects in ruthenium-catalyzed asymmetric transfer
hydrogenation reactions: (a) Hashiguchi, S.; Fujii, A.; Takehara, J.;
Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562-7563. (b)
Jiang, Y.; Jiang, Q.; Zhu, G.; Zhang, X. Tetrahedron Lett. 1997, 38,
215-218.
(19) Pa`mies, O.; Ba¨ckvall, J.-E. J. Org. Chem. 2002, 67, 1261-1265.
(20) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656-2665.
J. Org. Chem, Vol. 69, No. 26, 2004 9193

Mart´ın-Matute and Ba¨ckvall
SCHEME 5. Enzyme-Catalyzed Kinetic
Asymmetric Transformation of Diastereomeric
Mixtures of Unsymmetrical 1,4-Diols
SCHEME 7. Kinetic Resolution of Hydroxy
Ketone 6
TABLE 4. Sequential KAT/DYKATa
ii
iii
TABLE 3. CALB-Catalyzed Acylation of Rac-/
Diastereomeric Mixtures of 1,4-Diolsa
entry product
R
yieldb (%) eec yieldd (%) eec
1
2
3
4
4c
4d
4e
4f
Cy
65
60
56
49d
90 66
99 63
99 58
90 nd
89
99
93
nd
pentyl
Bn
2-naphthyl
yield of
substrate
2 (%)b
2-(2R):2-(2S)c 1-(2R):1-(2S)c pseudo-E
1a
1b
27
35
>99:<1
>99:<1
32.5:67.5
22:78
285
350
a Conditions unless otherwise noted: (i) 0.43 mmol of 1, CALB
(30 mg/mmol of diol), isopropenyl acetate (10 equiv) in 1.5 mL of
toluene at 70 °C under argon for 3 h; (ii) 5 mol % of 3 for 12 h; (iii)
under hydrogen gas (1 bar) for an additional 12 h. b Yield
measured by GC. c Enantiomeric excess determined by GC. d Iso-
lated yield.
a Conditions: 0.68 mmol of 1, CALB (30 mg/mmol of diol),
freshly distilled isopropenyl acetate (20 equiv) in 2 mL of toluene
at 70 °C for 1 h. b % yield measured by NMR. c Ratio determined
on diacetate by GC.
SCHEME 6. Reaction Intermediates
ee after 10 min. This gave an E value of 2.2 for the kinetic
resolution of 6a (Scheme 7).
To minimize the oxidation of the inner alcohol at the
very early stage of the DYKAT, and therefore avoid path
ii (Scheme 6), a different procedure was investigated.
Thus, diols 1c-f were first treated with the enzyme and
the acyl donor in a kinetic asymmetric transformation
(KAT). After 3 h the Ru catalyst was added. This
sequential KAT/DYKAT led to the products in moderate
yields but in good to excellent ee. Several attempts to
increase the efficiency of the process by reducing the
amount of diketone formed as byproduct have been
carried out. The use of hydrogen gas (1 bar)19 after
running the reaction for 17 h in the presence of Shvo’s
catalyst slightly improved the yield, but the ee dropped
for some substrates (Table 4).
stereomeric substrates and the measured kinetic param-
eter was called the pseudo-E value (Table 3).
Despite the excellent pseudo-E value measured for
substrates 1a and 1b, under DYKAT conditions acetate
2a could be obtained in only 84% ee and 2b in 90% ee.
Scheme 6 shows the two different pathways leading to
the products. If the kinetic asymmetric transformation
takes place before the oxidation of the inner alcohol (path
i) one might expect to obtain, after the oxidation, the
enantiomerically pure product based on the pseudo-E
values measured. However, if the oxidation of the inner
alcohol takes place before the enzyme-catalyzed reaction
(path ii), hydroxy ketones are formed and, as pointed out
before,11 the kinetic resolution of acyclic γ-hydroxy
ketones has been shown to proceed in low enantio-
selectivity.
It was therefore of interest to determine the relative
rate of the CALB-catalyzed acylation of (4R)- and (4S)-
4-hydroxy-1-phenyl-1-pentanone (6a) under the reaction
conditions employed for our system. Thus, reaction of
racemate 6a in the presence of CALB and isopropenyl
acetate (20 equiv) gave acetoxy ketone 4a (12%)24 in 35%
Conclusion
We have taken advantage of the higher selectivity of
CALB for 1,4-diols than for γ-hydroxy ketones to develop
a new dynamic kinetic asymmetric transformation. This
process allows a one-pot transformation of 1,4-diols into
enantiomerically enriched γ-acetoxy ketones. Despite the
fact that CALB is among the most enantioselective
lipases toward secondary alcohols, the efficiency of the
kinetic resolution of 4-hydroxy-1-phenyl-1-pentanone (6a)
catalyzed by this enzyme is rather low. The interaction
of CALB with 1,4-diols and γ-hydroxy ketones is cur-
rently being investigated in our laboratories.
Experimental Section
General Procedure for the Synthesis of 1,4-Diols:
1-Phenyl-1,4-pentanediol (1a).25,26 A solution of 3-butyn-2-
ol (1.5 g, 21.4 mmol) in THF (60 mL) was cooled to -50 °C.
(24) Yield of 4a determined by 1H NMR.
9194 J. Org. Chem., Vol. 69, No. 26, 2004

Synthesis of γ-Hydroxy Ketones
MeLi (28 mL, 44.94 mmol; 1.6 M in Et2O) was added slowly.
The mixture was stirred at the same temperature for 2 h and
then benzaldehyde (2.5 g, 23.54 mmol) was added. The reaction
mixture was slowly allowed to reach 0 °C and stirred overnight
at room temperature. After extractive workup (NH4Cl/EtOAc)
1-phenyl-2-pentyn-1,4-diol (3.77 g, 100%) was obtained as a
yellowish oil. 1-Phenyl-2-pentyn-1,4-diol (1.5 g, 8.5 mmol), PtO2
(150 mg, 0.68 mmol), and methanol (40 mL) together with a
magnetic stirrer bar were placed in an autoclave. The auto-
clave was evacuated and then charged with hydrogen. The
hydrogen pressure was adjusted to 100 psi. After being stirred
for 12 h the solution was filtered and the solvent was
evaporated. Purification by chromatography (SiO2, 2:1 pen-
tane/EtOAc) yielded 1a (780 mg, 51%) as a colorless thick oil;
1H NMR (400 MHz, CDCl3) δ 7.35-7.24 (m, 5H), 4.74-4.68
(m, 1H), 3.87 (quint, J ) 6.2 Hz, 1H, one isomer), 3.84 (quint,
J ) 6.2 Hz, 1H, one isomer), 2.95-2.0 (br s, 2H), 1.91-1.79
(m, 2H), 1.65-1.43 (m, 2H), 1.19 (d, J ) 5.7 Hz, 3H, one
isomer), 1.18 (d, J ) 6.2 Hz, 3H, one isomer); 13C NMR (100
MHz, CDCl3; DEPT) δ 144.8 (C), 144.7 (C), 128.4 (2 × CH),
127.5 (CH), 127.5 (CH), 125.8 (CH), 125.8 (CH), 74.8 (CH), 74.4
(CH), 68.2 (CH), 67.9 (CH), 36.0 (CH2), 35.9 (CH2), 35.2 (CH2),
35.1 (CH2), 23.7 (CH3), 23.5 (CH3).
General Procedure for the DYKAT of 1,4-Diols: 1-Phen-
yl-4-(acetyloxy)-1-pentanone (4a).11 In a typical experiment
a solution of the diol (1a) (77 mg, 0.43 mmol) in toluene (1.5
mL) was added to a mixture of CALB (3.5 mg) and 3 (0.012
mmol, 13 mg) in a Schlenk-type flask under argon atmosphere.
Then isopropenyl acetate (4.3 mmol, 430 mg) was added. The
mixture was stirred at 70 °C for 20 h under Ar. After filtration
through Celite and purification by chromatography (SiO2, 20:1
pentane/EtOAc) 4a (65 mg, 69%) was obtained as a colorless
thick oil: 1H NMR (300 MHz, CDCl3) δ 7.97-7.90 (m, 2H),
7.56 (tt, J ) 7.4, 1.4 Hz, 1H), 7.49-7.43 (m, 2H), 5.00 (sext, J
) 6.3 Hz, 1H), 3.11-2.93 (m, 2H), 2.00 (s, 3H), 2.05-1.97 (m,
2H), 1.28 (d, J ) 6.1 Hz, 3H); 13C NMR (75 MHz, CDCl3; DEPT)
δ 199.3 (C), 170.7 (C), 136.8 (C), 133.1 (CH), 128.6 (CH), 128.0
(CH), 70.4 (CH), 34.5 (CH2), 30.2 (CH2), 21.3 (CH3), 20.1 (CH3).
Acknowledgment. Financial support from the Swed-
ish Foundation for Strategic Research, the Swedish
Research Council, and the Spanish Ministerio de Edu-
cacio´n y Ciencia is gratefully acknowledged.
Supporting Information Available: General experimen-
tal procedure and spectral data and 1H and 13C NMR spectra
of compounds 1a-i, 3, and 4a-i. This material is available
free of charge via the Internet at http://pubs.acs.org.
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