Diastereoselective synthesis of cis-2,6-disubstituted perhydro-4-pyranones using elevated pressure hydrogenation

Article abstract of DOI:10.1007/s00706-005-0317-8

A diastereoselective strategy for the synthesis of γ-pyrons was developed, starting from the Mg diacetonedicarboxylate complex. Initial cyclization with suitable anhydrides or acid chlorides, followed by hydrolytic decarboxylation leads to 2,6-disubstitut

Full text of DOI:10.1007/s00706-005-0317-8

Monatshefte f€ur Chemie 136, 1197–1203 (2005)
DOI 10.1007/s00706-005-0317-8
Diastereoselective Synthesis of cis-2,6-
Disubstituted Perhydro-4-pyranones
Using Elevated Pressure Hydrogenation
Marko D. Mihovilovic1;ꢀ and Helmut Spreitzer2
1
Institute of Applied Synthetic Chemistry, Vienna University of Technology,
A-1060 Vienna, Austria (EU)
2
Institute of Pharmaceutical Chemistry, Vienna University, A-1090 Vienna, Austria (EU)
Received September 21, 2004; accepted November 10, 2004
Published online May 31, 2005 # Springer-Verlag 2005
Summary. A diastereoselective strategy for the synthesis of ꢀ-pyrons was developed, starting from the
Mg diacetonedicarboxylate complex. Initial cyclization with suitable anhydrides or acid chlorides,
followed by hydrolytic decarboxylation leads to 2,6-disubstituted pyrans. Elevated pressure hydroge-
nation using Pd=C affords the title compounds in high diastereoselectivity. Scope and limitations of the
method are outlined on selected examples.
Keywords. Reduction; ꢀ-Pyrons; Magnesium diacetonedicarboxylate complex; Cyclization.
Introduction
In the context of our recent research program aimed at the application of recom-
binant whole-cell biocatalysts in enantioselective Baeyer-Villiger oxidations [1, 2],
we optimized access to various prochiral cyclic ketones, previously [3–5]. As we
became interested in the microbial oxidation of several heterocyclic precursors
[6, 7], we required an efficient strategy for the preparation of an array of 2,6-
disubstituted tetrahydropyran-4-ones.
In recent literature a number of methods are available for the synthesis of
ꢀ-pyrons [8, 9], and this served as a starting point to enter this area. According
to our initial experiences, these approaches lacked generality and simplicity, which
represent key aspects for the generation of a small library of precursors suitable for
subsequent biotransformation studies. Consequently, development of a simple and
robust procedure for the preparation of substituted ꢀ-pyrons was our first goal.
As desymmetrization of prochiral compounds is a most efficient strategy for the
generation of chiral products with a 100% theoretical yield, we focused our interest
ꢀ
Corresponding author. E-mail: mmihovil@pop.tuwien.ac.at

1198
M. D. Mihovilovic and H. Spreitzer
on perhydro-heterocycles with a cis-2,6-substitution pattern. According to our gen-
eral pathway this required a diastereoselective hydrogenation of the ꢀ-pyrons.
Stereoselectivity can be achieved when performing the reaction under conditions
of heterogeneous catalysis [10]. In this case, attack of the hydrogen commences
from the surface of the catalyst, and stereoselectivity is ensured due to the orienta-
tion of the planar substrate vis-ꢀa-vis the catalytic entity.
Results and Discussion
Based on previous work by Yamato et al. [11], a Mg diacetonedicarboxylate
((DADC)2Mg) complex [12, 13] seemed to be a suitable reagent to allow for a
versatile entry into the required heterocyclic system. Yamato and coworkers
reported suitable reaction conditions to favor formation of cyclic compounds
vis-ꢀa-vis open chain products. The one-pot transformation is initiated by an acyla-
tion reaction, followed by cyclization towards the pyrane core using either anhy-
drides 2 or acid chlorides 3 (Scheme 1, Table 1).
Initially, we compared both strategies for the formation of diester 4a with a
slightly modified protocol. When using anhydrides, the reaction of 1 is carried out
in an excess of the reagent simultaneously acting as solvent at reflux temperature.
Conversions with acid chlorides required the presence of a base such as pyridine, with
reagents mixed under ice cooling and subsequent stirring at room temperature. For
the model reaction to 4a no significant difference of both methods was observed and
the pure product was obtained in similar yields after chromatographic purification.
Cyclization to diethyl substituted 4b via the anhydride method gave a de-
creased yield, which might be attributed to the higher reflux temperature. This
hypothesis is supported to some extent by the excellent yield for the preparation
of 4f using trifluoroacetic anhydride. Hence, conversion to products bearing longer
side chains was performed utilizing the acid chloride protocol. Cyclizations are
summarized in Table 1 and gave acceptable yields of pyranones 4a–4f after
Scheme 1

cis-2,6-Disubstituted Perhydro-4-pyranones
1199
Table 1. Synthetic sequence towards perhydro-pyranones 7
R
Acylation precursor
4
5
6
7
2a
3a
2b
3c
3d
3e
2f
45%
46%
34%
44%
59%
52%
73%
Me
87%
65%
81%
65%
Et
80%
86%
53%
79%
0%
70%
56%a
71%b
76%
n.a.c
n-Pr
i-Pr
n-Bu
CF3
46%
n.a.c
no formation of intermediate ketone 6 observed; b direct hydrolysis to ketone 7; not applicable
a
c
chromatographic purification for a variety of substituents R. The reaction seems
only limited by sterical aspects, as pivaloyl chloride 3g (R ¼ tert.-Bu) gave a spec-
trum of various mono-acylated and acyclic intermediates.
Thermal treatment of pyranones 4 under aqueous acidic conditions has given
the expected products 5a–5e in a hydrolysis=decarboxylation sequence [14]. As a
prerequisite to ensure success of this conversion, diesters 4 are required to allow
formation of a tautomer. Consequently, a proton in ꢁ-position of substituents R
must be present. Such an enol species cannot be formed by CF3-substituted 4f,
which prohibits the decarboxylation reaction. Apart from this limitation, pyranones
5a–5e were obtained in good quality without the need for further purification. It
should be noted, that reaction times increased with chain length and sterical
demands of alkyl substituents.
Initially, the hydrogenation reaction was attempted at ambient or slightly ele-
vated pressure (3–4 bar, Parr apparatus). In contrast to previous reports [10], only
mixtures of partially reduced compounds were obtained. In addition, the stereo-
chemistry of fully reduced products was ambiguous. While initial experiments
were carried out in EtOAc as non-polar solvent, we observed accelerated reductions
when using dry MeOH.
In order to further increase the reaction rate and to improve the diastereoselec-
tivity of the transformation, reactions were carried out at an elevated pressure of
20–25 bar in a steel autoclave. Under these reaction conditions, only cis-substi-
tuted reaction products were obtained and double bonds were generally fully
reduced. However, in some cases ketal 6 was obtained after crude work-up of
the hydrogenation mixture. Usually, this intermediate was not purified, but directly
submitted to a deprotection step using standard conditions in a modified work-up
protocol. The target compounds 7a–7e were finally purified by flash column chro-
matography and obtained in moderate to good yields.
Conclusion
We have developed a facile synthetic route to a variety of prochiral 2,6-disubsti-
tuted tetrahydropyranones 7 starting from (DADC)2Mg complex 1. The reported
high pressure hydrogenation is highly diastereoselective and provides access to
several substrates suitable for subsequent enantioselective Baeyer-Villiger oxida-
tion, as has been demonstrated recently [6].

1200
M. D. Mihovilovic and H. Spreitzer
Experimental
Unless otherwise noted, chemicals were purchased from commercial suppliers and used without
further purification. All solvents were distilled prior to use. Flash column chromatography was per-
formed on silica gel 60 from Merck (40–63 ꢂm). Kugelrohr distillation was carried out using a B€uchi
GKR-51 apparatus. Melting points were determined using a Kofler-type Leica Galen III micro hot
stage microscope and are uncorrected. NMR spectra were recorded from CDCl3 solutions on a Bruker
AC 200 (1H 200 MHz, 13C 50 MHz) spectrometer and chemical shifts are reported in ppm using TMS
as internal standard. Abbreviations, LP¼ light petroleum (bp 40–60ꢁC).
General Procedure for ꢀ-Pyranone Cyclization – Method A
The (DADC)2Mg complex 1 (1 equiv) was dissolved in the corresponding acid anhydride 2 (10%
solution) and heated to reflux for 30–120 min. The heterogeneous reaction mixture was cooled to rt and
concentrated in vacuo. The residue was taken up in CH2Cl2, washed with satd. NaHCO3 solution, and
the aqueous layers were re-extracted with CH2Cl2. The combined organic phases were dried (Na2SO4),
decolorized (charcoal), filtered, and concentrated.
General Procedure for ꢀ-Pyranone Cyclization – Method B
The (DADC)2Mg complex (1 equiv) was dissolved in dry pyridine (20% solution) under N2 and
cooled with an external ice=H2O bath. The corresponding acid chloride 3 (4.4 equiv) was added at
0–5ꢁC and the resulting mixture was stirred at room temperature for 1–2 days. After hydrolysis
with ice=HCl (2N) the mixture was extracted repeatedly with CH2Cl2. The combined organic
layers were washed with satd. NaHCO3 solution, dried (Na2SO4), decolorized (charcoal), filtered,
and concentrated.
2,6-Dimethyl-4-oxo-4H-pyran-3,5-dicarboxylic acid diethyl ester (4a)
(DADC)2Mg complex 1 (2.00 g, 4.69 mmol) was converted with acetic anhydride according to method
A to give 1.13 g 4a [11] (45%) as yellow crystals after flash column chromatography (silica gel,
LP=EtOAc¼ 4=1); conversion of 1.00g 1 (2.34 mmol) with acetyl choride following method B gave
0.58g (46%) 4a after chromatographic purification; physical data matching those of Ref. [11]; 13C
NMR (50 MHz, CDCl3): ꢃ ¼ 14.0 (q), 18.4 (q), 61.7 (t), 121.6 (s), 164.0 (s), 165.2 (s), 171.7 (s) ppm.
2,6-Diethyl-4-oxo-4H-pyran-3,5-dicarboxylic acid diethyl ester (4b, C15H20O6)
Complex 1 (2.00 g, 4.69 mmol) was converted with propionic anhydride according to method A to give
0.95g 4b (34%) as yellow oil after flash column chromatography (silica gel, LP=EtOAc¼ 3=1);
1H NMR (200 MHz, CDCl3): ꢃ ¼ 1.20–1.40 (m, 6H), 2.65 (q, J ¼ 7 Hz, 4H), 4.35 (q, J ¼ 7 Hz,
4H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 11.4 (q), 14.0 (q), 25.7 (t), 61.7 (t), 120.9 (s), 163.9 (s),
168.9 (s), 172.2 (s) ppm.
4-Oxo-2,6-dipropyl-4H-pyran-3,5-dicarboxylic acid diethyl ester (4c, C17H24O6)
Complex 1 (3.00 g, 7.03 mmol) was converted with butanoyl chloride according to method B to give
2.00g 4c (44%) as colorless oil after flash column chromatography (silica gel, LP=EtOAc¼ 5=1);
1H NMR (200 MHz, CDCl3): ꢃ ¼ 1.00 (t, J ¼ 6 Hz, 6H), 1.35 (t, J ¼ 6 Hz, 6H), 1.70 (sex, J ¼ 6 Hz,
4H), 2.60 (t, J ¼ 6 Hz, 4H), 4.35 (q, J ¼ 6 Hz, 4H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 13.4 (q), 14.1
(q), 20.6 (t), 33.9 (t), 61.8 (t), 121.6 (s), 164.1 (s), 167.9 (s), 172.2 (s) ppm.

cis-2,6-Disubstituted Perhydro-4-pyranones
1201
2,6-Diisopropyl-4-oxo-4H-pyran-3,5-dicarboxylic acid diethyl ester (4d, C17H24O6)
Complex 1 (5.00 g, 11.7mmol) was converted with isobutanoyl chloride according to method B to give
4.13 g 4d (59%) as yellow oil after flash column chromatography (silica gel, LP=EtOAc¼ 5=1); 1H NMR
(200 MHz, CDCl3): ꢃ ¼ 1.30–1.50 (m, 18H), 2.90–3.10 (m, 2H), 4.35 (q, J ¼ 7 Hz, 4H) ppm; 13C NMR
(50 MHz, CDCl3): ꢃ ¼ 14.0 (q), 19.7 (q), 31.7 (d), 61.8 (t), 120.1 (s), 164.0 (s), 170.8 (s), 172.5 (s) ppm.
2,6-Dibutyl-4-oxo-4H-pyran-3,5-dicarboxylic acid diethyl ester (4e, C19H28O6)
Complex 1 (5.14 g, 12.0mmol) was converted with pentanoyl chloride according to method B to give
8.14g 4e (52%) as yellow oil after flash column chromatography (silica gel, LP=EtOAc¼ 7=1);
1H NMR (200 MHz, CDCl3): ꢃ ¼ 0.95 (t, J ¼ 7 Hz, 6H), 1.20–1.45 (m, 10H), 1.55–1.70 (m, 4H),
2.60 (t, J ¼ 7 Hz, 4H), 4.35 (q, J ¼ 7 Hz, 4H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 14.0 (q), 22.0 (t),
22.1 (q), 29.1 (t), 31.8 (t), 61.7 (t), 121.4 (s), 164.0 (s), 168.1 (s), 172.1 (s) ppm.
2,6-Trifluoromethyl-4-oxo-4H-pyran-3,5-dicarboxylic acid diethyl ester (4f)
Complex 1 (3.00 g, 7.03mmol) was converted with trifluoroacetic anhydride according to method A to
give 3.86 g 4f [15] (73%) as colorless crystals after flash column chromatography (silica gel,
1
LP=EtOAc¼ 7=1); mp 92–94ꢁC; H NMR (200MHz, CDCl3): ꢃ ¼ 1.37 (t, J ¼ 7 Hz, 6H), 4.42 (q,
J ¼ 7 Hz, 4H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 13.8 (q), 63.6 (t), 117.5 (q, JCF ¼ 275 Hz), 124.7
(q, JCF ¼ 1.5 Hz), 149.0 (q, JCF ¼ 41Hz), 158.9 (s), 170.5 (s) ppm.
General Procedure for the Decarboxylation
Diester 4 was dissolved in a 5=1 mixture of 2N HCl and acetic acid (5%) and refluxed for 5–30h until
TLC indicated complete conversion. The reaction was hydrolyzed with satd. NaHCO3 solution and
extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, and evaporated to
give 5 without further purification.
2,6-Dimethyl-4H-pyran-4-one (5a)
Decarboxylation of 0.50g 4a (1.86 mmol) gave 0.20 g 5a [16] (87%) as colorless crystals; physical
data matching those of Ref. [16].
2,6-Diethyl-4H-pyran-4-one (5b)
Decarboxylation of 0.50 g 4b (1.67 mmol) gave 0.20 g 5b [8] (87%) as colorless oil; physical data
matching those of Ref. [8]; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 10.5 (q), 26.4 (t), 111.7 (d), 170.0 (s),
180.4 (s) ppm.
2,6-Dipropyl-4H-pyran-4-one (5c)
Decarboxylation of 2.00 g 4c (6.17 mmol) gave 0.95 g 5c [9] (86%) as colorless crystals; mp 56–58ꢁC;
1H NMR (200 MHz, CDCl3): ꢃ ¼ 1.10 (t, J ¼ 7 Hz, 6H), 1.60–1.80 (m, 4H), 2.45 (t, J ¼ 7 Hz, 4H), 6.05
(s, 2H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 13.3 (q), 20.5 (t), 35.3 (t), 113.1 (d), 168.9 (s), 180.4 (s)
ppm.
2,6-Diisopropyl-4H-pyran-4-one (5d, C11H16O2)
Decarboxylation of 2.23g 4d (6.80 mmol) gave 0.64 g 5d (53%) as colorless oil; 1H NMR (200 MHz,
CDCl3): ꢃ ¼ 1.25 (d, J ¼ 7 Hz, 12H), 2.70–2.80 (m, 4H), 6.05 (2H, s) ppm; 13C NMR (50 MHz,
CDCl3): ꢃ ¼ 20.0 (q), 32.6 (d), 110.7 (d), 173.5 (s), 181.0 (s) ppm.

1202
M. D. Mihovilovic and H. Spreitzer
2,6-Dibutyl-4H-pyran-4-one (5e, C13H20O2)
Decarboxylation of 4.10g 4e (11.60mmol) according to the above procedure gave 1.89 g 5e (79%) as
1
colorless oil; H NMR (200MHz, CDCl3): ꢃ ¼ 0.95 (t, J ¼ 7 Hz, 6H), 1.30–1.40 (m, 4H), 1.50–1.70
(m, 4H), 2.45 (t, J ¼ 7 Hz, 4H), 6.05 (s, 2H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 13.6 (q), 22.1 (t),
29.1 (t), 31.8 (t), 112.9 (s), 169.1 (s), 180.4 (s) ppm.
Elevated Pressure Hydrogenation
Starting material 5 was dissolved in dry MeOH (5% solution) and charged into a B€uchi steel autoclave
with mechanical stirring. Pd catalyst (10% on C, 5%-w=w) was added and hydrogenation was accom-
plished at room temperature and 25 bar H2 pressure. After complete conversion (18–48 h) the reaction
mixture was filtered through a pad of Celite+ and concentrated.
cis-Tetrahydro-4,4-dimethoxy-2,6-dimethyl-2H-pyrane (6a, C9H18O3)
1
Hydrogenation of 5.00 g 5a (40.3mmol) gave 4.53 g 6a [10] (65%) as colorless liquid; H NMR
(200 MHz, CDCl3): ꢃ ¼ 1.20 (d, J ¼ 7 Hz, 6H), 1.85–2.00 (m, 4H), 3.15 (s, 3H), 3.20 (s, 3H),
3.50–3.70 (m, 2H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 21.5 (q), 39.8 (t), 46.9 (q), 47.3 (q),
69.7 (d), 98.7 (s) ppm.
cis-2,6-Diethyltetrahydro-4,4-dimethoxy-2H-pyrane (6b, C11H22O3)
Hydrogenation of 4.50g 5b (29.6 mmol) gave 4.85g 6b (81%) as colorless liquid; 1H NMR (200 MHz,
CDCl3): ꢃ ¼ 0.95 (t, J ¼ 7 Hz, 6H), 1.11–1.30 (m, 2H), 1.32–1.65 (m, 4H), 1.89–2.12 (m, 2H), 3.19
(s, 3H), 3.23 (s, 3H), 3.26–3.41 (m, 2H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 10.0 (q), 28.8 (t), 38.4
(t), 47.2 (q), 47.5 (q), 75.3 (d), 99.3 (s) ppm.
cis-Tetrahydro-2,6-dipropyl-4H-pyran-4-one (7c, C11H20O2)
Hydrogenation of 0.90g 5c (5.3mmol) gave 0.68 g 7c (56%) as beige oil after flash column chroma-
1
tography (silica gel, LP=EtOAc¼ 10=1); H NMR (200MHz, CDCl3): ꢃ ¼ 0.90 (t, J ¼ 7 Hz, 6H),
1.30–1.80 (m, 8H), 2.15–2.40 (m, 4H), 3.60–3.75 (m, 2H) ppm; 13C NMR (50 MHz, CDCl3):
ꢃ ¼ 14.3 (q), 19.0 (t), 38.9 (t), 48.4 (t), 77.1 (d), 207.9 (s) ppm.
cis-Tetrahydro-2,6-diisopropyl-4H-pyran-4-one (7d, C11H20O2)
Hydrogenation of 1.59 g 5d (8.8mmol) gave a mixture of ketal and ketone, which was treated with
THF=2N HCl (5=1, 25 cm3) at rt overnight. The deprotection was hydrolyzed with satd. NaHCO3 and
extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, and concentrated.
Pure 7d (1.16 g, 71%) was obtained as colorless oil after Kugelrohr distillation; bp 90–95ꢁC=0.1 mbar
(KRD); 1H NMR (200 MHz, CDCl3): ꢃ ¼ 0.90 (d, J ¼ 6 Hz, 6H), 0.95 (d, J ¼ 6 Hz, 6H), 1.60–1.80 (m,
2H), 2.10–2.45 (m, 4H), 3.20–3.30 (m, 2H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 18.1 (q), 33.4 (d),
45.2 (t), 81.8 (d), 208.8 (s) ppm.
cis-2,6-Dibutyltetrahydro-4,4-dimethoxy-2H-pyrane (6e, C15H30O3)
1
Hydrogenation of 1.89 g 5e (9.09 mmol) gave 1.07g 6e (46%) as yellow oil; H NMR (200 MHz,
CDCl3): ꢃ ¼ 0.85 (t, J ¼ 7 Hz, 6H), 1.20–1.60 (m, 12H), 1.85–2.00 (m, 4H), 3.15 (s, 3H), 3.20 (s, 3H),
3.32–3.47 (m, 2H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 13.9 (q), 22.5 (t), 27.7 (t), 35.6 (t), 38.7 (t),
47.1 (q), 47.4 (q), 73.8 (d), 99.1 (s) ppm.

cis-2,6-Disubstituted Perhydro-4-pyranones
1203
Deketalization
A solution of ketal 6 in THF=2N HCl (5=1, 10%) was stirred at rt overnight. The mixture was
hydrolyzed with satd. NaHCO3 solution and extracted with Et2O. The combined organic layers were
dried (Na2SO4), filtered, and concentrated.
cis-Tetrahydro-2,6-dimethyl-4H-pyran-4-one (7a)
Deketalization of 4.53g 6a (23 mmol) gave 2.17 g 7a [10] (65%) as colorless liquid after extraction
with CH2Cl2 and vacuum distillation; bp 62–65ꢁC=12mbar; 1H NMR (200MHz, CDCl3): ꢃ ¼ 1.35 (d,
J ¼ 7 Hz, 6H), 2.10–2.45 (m, 4H), 3.61–3.80 (m, 2H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 21.9 (q),
48.8 (t), 72.9 (d), 207.2 (s) ppm.
cis-2,6-Diethyltetrahydro-4H-pyran-4-one (7b, C9H16O2)
Deketalization of 4.78 g 6b (23.6mmol) gave 2.59g 7b (70%) as colorless liquid after vacuum
1
distillation; bp 81–83ꢁC=11 mbar; H NMR (200MHz, CDCl3): ꢃ ¼ 1.00 (t, J ¼ 7 Hz, 6H), 1.43–
1.81 (m, 4H), 2.11–2.45 (m, 4H), 3.39–3.55 (m, 2H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 9.6
(q), 29.3 (t), 47.5 (t), 78.2 (d), 207.7 (s) ppm.
cis-2,6-Dibutyltetrahydro-4H-pyran-4-one (7e, C13H24O2)
Deketalization of 1.07 g 6e (4.1mmol) gave 0.66g 7e (76%) as beige oil after flash column chroma-
1
tography (silica gel, LP=EtOAc¼ 10=1); H NMR (200 MHz, CDCl3): ꢃ ¼ 0.90–1.00 (m, 6H), 1.20–
1.80 (m, 12H), 2.10–2.40 (m, 4H), 3.40–3.55 (m, 2H) ppm; 13C NMR (50 MHz, CDCl3): ꢃ ¼ 14.4 (q),
22.9 (t), 27.9 (t), 36.5 (t), 48.8 (t), 77.4 (d), 208.4 (s) ppm.
Acknowledgement
€
Financial support for this project by the Hochschuljubilaumsfond=City of Vienna (project no.:
H-40=98) is gratefully acknowledged.
References
€
[1] For general reviews on Baeyer-Villiger oxidations see: Mihovilovic MD, Rudroff F, Grotzl B
(2004) Curr Org Chem 8: 1057; Renz M, Meunier B (1999) Eur J Org Chem 737
[2] For recent reviews on enzymatic Baeyer-Villiger oxidations see: Kamerbeek NM, Janssen DB,
€
van Berkel WJH, Fraaije MW (2003) Adv Synth Catal 345: 667; Mihovilovic MD, Muller B,
Stanetty P (2002) Eur J Org Chem 3711
€
[3] Mihovilovic MD, Adelwohrer C, Stanetty P (2001) Arkivoc 2: 1082
[4] Mihovilovic MD, Muller B, Kayser MM, Stanetty P (2002) Synlett 700
€
€
[5] Mihovilovic MD, Muller B, Schulze A, Stanetty P, Kayser MM (2003) Eur J Org Chem 2243
[6] Mihovilovic MD, Rudroff F, Kandioller W, Grotzl B, Stanetty P, Spreitzer H (2003) Synlett 1973
€
€
[7] Mihovilovic MD, M€uller B, Kayser MM, Stewart JD, Frohlich J, Stanetty P, Spreitzer H (2001)
J Mol Catal B Enzym 11: 349
[8] Yates P, Hand ES, Singh P, Roy SK, Still IWJ (1969) J Org Chem 34: 4046
[9] Sear RP, Frenkel D (1996) J Chem Phys 105: 10632
[10] Sato M, Kuroda H, Kaneko C, Furuya T (1994) J Chem Soc Chem Commun 687
[11] Yamato M, Kusunoki Y (1981) Chem Pharm Bull 29: 1214
[12] Yamato M, Uenishi J-I, Hashigaka K (1978) Chem Pharm Bull 26: 1973
[13] Yamato M, Uenishi J-I, Hashigaka K (1978) Chem Pharm Bull 26: 1459
[14] Feist F (1890) Liebigs Ann Chem 257: 253
[15] Lee LF, Miller ML (1986) Eur Pat Appl EP 182769, Chem Abstr 105: 190960
[16] Gold V, Mah T (1981) J Chem Soc Perkin Trans 2, 812