Chiral auxiliaries as docking/protecting groups: Biohydroxylation of selected ketones with Beauveria bassiana ATCC 7159

Article abstract of DOI:10.1016/S0040-4020(01)00803-1

The concept of chiral docking/protecting groups for biohydroxylation was extended from cyclopentanone to other ketones. Reaction of cyclohexanone, (R)-3-methylcyclohexanone, cycloheptanone, 5-methyl-2-hexanone and 4-methyl-2-pentanone with (R)-2-amino-1-propanol and subsequent in situ benzoylation afforded the corresponding N-benzoylated oxazolidine derivatives. All substrates were hydroxylated with the fungus Beauveria bassiana ATCC 7159, one of which was diastereoselectively hydroxylated with a d.e. of 99%. In this manner, access to the corresponding hydroxylated ketones was provided.

Full text of DOI:10.1016/S0040-4020(01)00803-1

TETRAHEDRON
Pergamon
Tetrahedron 57 32001) 8151±8157
Chiral auxiliaries as docking/protecting groups: biohydroxylation
of selected ketones with Beauveria bassiana ATCC 7159
Anna de Raadt,a,p Barbara Fetz,a Herfried Griengl,a Markus Florian Klingler,a Birgit Krenn,a
b
a
a
a
Kurt Mereiter, Dieter Franz Munzer, Peter Plachota, Hansjorg Weber and Robert Saf
c
È
È
a
È È
Spezialforschungsbereich F001 Biokatalyse, Institut fur Organische Chemie der Technischen Universitat Graz,
Stremayrgasse 16, A-8010 Graz, Austria
Institut fur Mineralogie, Kristallographie und Strukturchemie der Technischen Universitat Wien,
b
È
È
Getreidemarkt 9/171, A-1060 Wien, Austria
Institut fur Chemische Technologie organischer Stoffe der Technischen Universitat Graz,
Stremayrgasse 16, A-8010 Graz, Austria
c
È
È
Received 14 March 2001; revised 27 July 2001; accepted 2 August 2001
AbstractÐThe concept of chiral docking/protecting groups for biohydroxylation was extended from cyclopentanone to other ketones.
Reaction of cyclohexanone, 3R)-3-methylcyclohexanone, cycloheptanone, 5-methyl-2-hexanone and 4-methyl-2-pentanone with 3R)-2-
amino-1-propanol and subsequent in situ benzoylation afforded the corresponding N-benzoylated oxazolidine derivatives. All substrates
were hydroxylated with the fungus Beauveria bassiana ATCC 7159, one of which was diastereoselectively hydroxylated with a d.e. of 99%.
In this manner, access to the corresponding hydroxylated ketones was provided. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
the use of whole cell systems 3hence the terms `docking'
and `protecting' groups). The subsequent biotransformation
gives 3a which is then benzylated to improve ®nal product
34) stability. Finally, the d/p group is simply removed to
afford 3R)-ketone derivative 4. In the progress of this work
it was also found that the use of chiral auxiliaries as d/p
groups enhanced hydroxylation stereoselectivity, improved
yield and eased product identi®cation by virtue of the
The regio- and stereoselective hydroxylation of non-
activated carbon atoms in organic compounds remains a
challenge in organic chemistry,1 especially when enantio-
or diastereomerically pure secondary alcohols are desired.
Such compounds are, of course, interesting in their own
right as valuable intermediates for synthetic work. Sur-
prisingly, although the use of microorganisms to hydroxyl-
ate steroids and terpenes has been practised for decades, this
approach has been little exploited in other areas of synthetic
organic chemistry.2 In an effort to change this dissatisfying
situation, the principle of docking/protecting 3d/p) groups
was introduced into the ®eld of biohydroxylation.3 This
concept enables the biohydroxylation of substrate classes
such as carboxylic acids, aldehydes, alcohols and ketones
with a de®ned set of microorganisms.
This approach is demonstrated in Scheme 1 using cyclo-
pentanone 1 as a model compound and the fungus
Beauveria bassiana ATCC 71592 3B. bassiana). Before
the biohydroxylation step, ketone 1 is derivatised to 2a in
order to help facilitate and direct the hydroxylation as well
as prevent undesired transformations which arise through
Keywords: Beauveria bassiana ATCC 7159; biohydroxylation; biotrans-
formations; chiral auxiliaries; ketones.
p
Corresponding author. Tel.: 143-316-873-8751; fax: 143-316-873-
8740; e-mail: deraadt@orgc.tu-graz.ac.at
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020301)00803-1

8152
A. de Raadt et al. / Tetrahedron 57 32001) 8151±8157
Table 1.
Substrate
Product
Substrate
Product
known chiral centre present.4 These ®ndings are also illus-
trated in Scheme 1; whereas substrate 2a was converted to
3a in 60% yield with a low d.e. 340%) with B. bassiana,
substrate 2b was hydroxylated to give 3b in 84% yield and
good d.e. 390%). Moreover, the d.e. of product 3b could be
raised even further to over 99% by recrystallization and,
owing to the presence of a known chiral centre, the absolute
con®guration of all asymmetric centres could be elucidated
by X-ray crystal structure analysis. Bearing these results in
mind, we then endeavoured to investigate the scope and
limitations of the chiral d/p group concept with respect to
other ketone substrates. Our ®ndings in this respect will be
disclosed in this report.
compounds have also been observed to be hydroxylated in
this position by B. bassiana.5 Owing to the stability of the
expected end product, 6 was not benzylated prior to removal
of the d/p group. Subjecting 6 to mildly acidic conditions4
furnished the known6 ketone 4-hydroxy-cyclohexanone in
moderate yield 359%).
Introducing a methyl group into the six-membered ring and
thereby forming an additional chiral centre was not found to
in¯uence the site of hydroxylation. Reacting 3R)-3-methyl-
cyclohexanone with 3R)-2-amino-1-propanol afforded a
mixture of diastereoisomers, whereby major isomer 7 was
isolated by simple crystallisation 367%). The absolute
con®guration of 7 was determined by X-ray crystal structure
analysis. This substrate was hydroxylated 3NMR, X-ray
crystal structure analysis) to give 8 as the sole product in
fair yield 343%, d.e. 95%). D/p removal furnished the
previously unknown ketone, 33S, 4S)-4-hydroxy-3-methyl-
cyclohexanone 343%).
2. Results and discussion
In order to investigate the applicability of the chiral d/p
group concept to other ketones, investigations concentrated
on substances related to model compound cyclopentanone
1. For this purpose the following ketones were chosen;
cyclohexanone, 3R)-3-methylcyclohexanone, cyclohepta-
none, 4-methyl-2-pentanone 313) and 5-methyl-2-hexanone.
Concerning the choice of chiral d/p group, previous studies
had shown4 that the highest yields and biohydroxylation
selectivities could be obtained with the chiral d/p group
present in substrate 2b. Consequently, the aforementioned
ketones were reacted with 3R)-2-amino-1-propanol in a
similar manner to that described4 for compound 2b to give
the corresponding derivatives. With respect to the con-
ditions employed for the biohydroxylation, for preliminary
experiments it was thought appropriate to take the same
conditions which had been found for the optimal conversion
of derivative 2b.
Homologation of the six-membered ring by an additional
carbon atom resulted in a pronounced loss in hydroxylation
selectivity, lowered isolated yield and promoted ketone
formation via biooxidation of the initially formed alcohol.
Substrate 9, obtained from cycloheptanone in modest yield
325%), afforded an inseparable mixture of alcohols 10a and
10b 329%, a waxy solid), in addition to small amounts 37%)
of the corresponding ketone derivative. Due to the com-
plexity of the NMR data obtained for alcohols 10a and
10b, structure elucidation could only be achieved by
X-ray crystal structure analysis of the corresponding crystal-
line N-phenylurethane derivative.7 In strong contrast to the
®ve-membered ring analogue 3b 3d.e. 90%), products 10a
and 10b were formed in only equal amounts 3HPLC).
Ketone formation and yield reduction upon ring expan-
sion has also been observed for similar compounds,
namely cycloheptyl-N-phenylcarbamates.8 Due to these
discouraging results d/p group removal was not carried out.
2.1. Biohydroxylation of cycloalkanones
Taking cyclohexanone as the ®rst example, reaction of this
ketone with 3R)-2-amino-1-propanol gave product 5 in
moderate yield 3Table 1, 70%). Treatment of 5 with B.
bassiana under standard conditions4 gave 6 in 44% yield.
NMR experiments and X-ray crystal structure analysis
con®rmed that hydroxylation had taken place as shown.
At this point it should be mentioned that structurally similar
It is interesting to note that in all of the examples above 36,
8, 10a and 10b) hydroxylation always occurred anti to the
nitrogen moiety. This observation has been frequently made
with B. bassiana employing other N-benzoylated spiro-
oxazolidines4 as well as related compounds.2

A. de Raadt et al. / Tetrahedron 57 32001) 8151±8157
8153
Scheme 2.
2.2. Biohydroxylation of acyclic derivatives
ever reported for this fungus. After benzylation of product
21 to afford 22, the d/p group was removed to give 3R)-5-
benzyloxy-4-methylpentan-2-one 24 in an e.e. of 99%.
Derivatives of acyclic ketones were also found to be suitable
candidates for B. bassiana, as can be seen from substrates 11
3Table 1), 14 and 15 3Scheme 2). Derivatising 5-methyl-2-
hexanone with 3R)-2-amino-1-propanol produced a mixture
of diastereoisomers in low yield 334%, 2.4:1). Subjecting
major isomer 11 to B. bassiana gave compound 12 in good
yield 367%). Because the expected end product from 12,
5-hydroxy-5-methyl-2-hexanone, can be prepared more
ef®ciently by chemical means,9 12 was not further investi-
gated.
3. Conclusion
In conclusion, we have shown that the concept of chiral
docking/protecting groups can be successfully extended to
acyclic and cyclic ketones other than cyclopentanone. In
this manner, depending on the substrate employed, a
hydroxyl moiety could be selectively introduced into the
substrate to give the corresponding alcohol derivative. In
addition, through `®ne tuning' of the fermentation con-
ditions, hydroxylated product yields could be improved, if
desired.11
As can be seen from Scheme 2, reacting 4-methyl-2-penta-
none 13 with 3R)-2-amino-1-propanol and subsequent
benzoylation afforded a mixture of diastereoisomers 14
and 15 31.8:1). Subjecting major isomer 14 to B. bassiana
gave a mixture of three hydroxylated products. While
hydroxylation at the tertiary carbon 3C-20) of substrate 14
furnished 16, hydroxylation of the primary carbon 3C-30 or
C-40) of this starting material afforded two diastereoisomers
17 and 19 by virtue of the newly formed chiral centre at
C-20. Because the hydroxy ketone end product was expected
to be in equilibrium with the corresponding hemiacetal,
compounds 17 and 19 were benzylated to give 18 and 20,
respectively, prior to d/p group removal. Subsequently,
cleavage of the d/p group from 18 and 20 gave rise to 3S)-
5-benzyloxy-4-methylpentan-2-one 23 and 3R)-5-benzyl-
oxy-4-methylpentan-2-one 24, respectively.
4. Experimental
4.1. General methods
All chemicals were purchased from either Aldrich or Fluka.
If required, chemicals and solvents were puri®ed according
to Perrin and Armarego.12 Optical rotations were measured
on a DIP-370 Digital Polarimeter 3Japan Spectroscopic
Company). Melting points 3uncorrected) were determined
in open capillaries using a BuÈchi 530. 1H and 13C NMR were
recorded on either a Gemini 200 BB 3Varian), INOVA 300
3Varian) or INOVA 500 3Varian). HETCOR, DEPT and
COSY experiments were carried out as required. CDCl3
was used as solvent and as internal standard unless other-
wise stated. Before use, the CDCl3 was ®ltered through a
short plug of basic alumina to remove traces of acid. Mass
spectra 3HRMS, EI, 70 eV) were recorded on a Kratos
Pro®le HV-4 double focussing magnetic sector instrument
In contrast, minor isomer 15 was diastereoselectively
hydroxylated by B. bassiana at only one of the primary
carbon atoms to afford product 21 in 60% isolated yield,
this outcome being con®rmed by X-ray crystal structure
analysis. Indeed, this compound was furnished in a d.e. of
99%. To the best of our knowledge,10 this is the highest d.e.

8154
A. de Raadt et al. / Tetrahedron 57 32001) 8151±8157
equipped with direct insertion 3DI) and GC 3Shimadzu GC-
14A, column HP-5MS). GC-MS was measured on a HP
6890 Series GC system equipped with a HP 5 column
325 m) and a HP 6890 series mass detector. Helium was
used as carrier gas. Relative intensities are given in brackets
for all mass spectral data. HPLC was determined with a
JASCO system containing pump 880-PU, UV-detector
875-UV 3detection at 238 nm) and AXXIOM Model 727
chromatography software. The chiral column used was a
CHIRALCEL OD-H. LC was performed on Silica gel 60
3Merck, 70±230 mesh) using mixtures of ethyl acetate and
petroleum ether unless otherwise stated. TLC was
performed on Silica gel 60 F254 aluminium plates
3Merck) and compounds detected with UV 3254 nm) and
spraying with either reagent A 35% vanillin in concen-
4.1.3. 4-Hydroxycyclohexanone. Removal of the d/p from
6 355.9 mg) afforded the title compound as a clear syrup
313.6 mg, 59% yield) after column chromatography. 1H
and 13C NMR data were in agreement with reported values.6
4.1.4. .3R,5S,7R)-4-Benzoyl-3,7-dimethyl-1-oxa-4-aza-
spiro[4.5]decane 7. Reacting 3R)-3-methylcyclohexanone
31.40 g) with 3R)-2-amino-1-propanol 30.78 g) afforded a
syrupy mixture of diastereoisomers 33.4:1, HPLC, n-hep-
tane/IPA; 95:5; ¯owˆ0.5 mL/min) in 94% yield 32.68 g)
after column chromatography. The major isomer 7 was
isolated as a single isomer 3d.e. 93%, HPLC) by crystal-
lisation to give white crystals in 67% isolated yield; mp
20
91.0±92.08C 3from pet. ether/CH2Cl2); [a]D ˆ245.08 3c
1.4, CH2Cl2); 1H NMR d 0.82±1.16 36H, m, 2£Me),
1.43±1.87 and 2.46 39H, m, 6-H, 7-H, 8-H, 9-H, 10-H),
3.61 31H, m, 2-H), 4.01 32H, m, 2-H, 3-H), 7.38 35H, s,
benzoyl); 13C NMR d 20.9, 22.6 32£Me), 23.0, 30.3, 33.5
3C-8, C-9, C-10), 30.0 3C-7), 43.5 3C-6), 54.7 3C-3), 69.6
3C-2), 97.6 3C-5), 126.3, 128.7, 129.4, 138.8, 168.4 3Bz);
MS 370 eV): m/z 3%) 273 328) [M]1, 258 32) [M2CH3]1,
230 336) [M2C3H7]1, 216 318) [M2C4H9]1, 105 3100)
[Bz]1, 77 325) [Ph]1; HRMS 3C17H23NO2): calcd
273.1729, found 273.1745; The absolute con®guration
of compound 7 was obtained by X-ray crystallographic
analysis 3CCDC 159176).
trated H2SO4) or reagent
B
310% H2SO4, 10%
3NH4)6Mo7O24´4H2O and 0.8% Ce3SO4)2´4H2O in water).
The TLC plates were then developed on a hot plate. Unless
otherwise stated, mixtures of petroleum ether/ethyl acetate
were used as eluent. Solvents needed for recrystallization
were always ®ltered through basic alumina 3ALDRICH,
Basic Brockmann I, 150 mesh) prior to use. All crystallo-
graphic data have been deposited at the Cambridge Crystal-
lographic Data Centre. The respective CCDC numbers are
given with the compound under consideration.
General procedures for substrate preparation and bio-
hydroxylation as well as d/p removal have been published
elsewhere.4
4.1.5.
.3R,5R,7S,8S)-4-Benzoyl-3,7-dimethyl-1-oxa-4-
azaspiro[4.5]decan-8-ol 8. Treatment of substrate 7
30.715 g) with B. bassiana furnished compound 8 as the
sole product, a white crystalline solid, after column chroma-
tography 30.325 g, 43% yield); mp 219.5±220.58C 3from
4.1.1. .R)-4-Benzoyl-3-methyl-1-oxa-4-azaspiro[4.5]decane
5. The title compound 5 was prepared as a white crystalline
solid from cyclohexanone 33.40 g) and 3R)-2-amino-1-
propanol 32.00 g) in 70% isolated yield 34.83 g) after
column chromatography; mp 108.0±109.08C 3from pet.
pet. ether/CH2Cl2); [a]D ˆ233.28 3c 0.5, CH2Cl2); 1H
20
NMR d 0.98 and 1.03 36H, 2£d, Jˆ6.7 and 6.4 Hz,
2£Me), 1.54±1.95 and 2.63 36H and 2H, m and bm, 6-H,
7-H, 9-H, 10-H, OH), 3.31 31H, ddd, J8,9axˆJ8,7axˆ10.8 Hz,
J8,9eqˆ4.2 Hz, 8-H), 3.63 31H, m, 2-H), 4.02 32H, m, 2-H,
3-H), 7.37 35H, s, Bz); 13C NMR d 18.5, 20.8 32£Me), 29.4
3C-9), 31.9 3C-10), 36.9 3C-7), 41.3 3C-6), 54.8 3C-3), 69.6
3C-2), 75.0 3C-8), 96.5 3C-5), 126.2, 128.7, 129.5 138.5,
168.7 3Bz); MS 370 eV): m/z 3%) 289 38) [M]1, 230 337)
[M2C3H7O]1, 216 331) [M2C4H9O]1, 202 36), 105 3100)
[Bz]1, 77 324) [Ph]1; HRMS 3C17H23NO3): calcd 289.1678,
found 289.1692; The absolute con®guration of compound 8
was determined by X-ray crystallographic analysis 3CCDC
159177).
ether/EtOAc); [a]D ˆ258.38 3c 0.6, CH2Cl2); H NMR13
1.11 33H, d, Jˆ5.7 Hz, Me), 1.11±1.80, 2.49 and 2.72 38H,
1H and 1H, bm and 2£bs, 6-H, 7-H, 8-H, 9-H, 10-H), 3.59
31H, m, 2-H), 4.00 32H, m, 2-H, 3-H), 7.34 35H, s, benzoyl);
13C NMR 20.8 3Me), 23.4, 23.5, 24.8, 31.1, 35.1 3C-6, C-7,
C-8, C-9, C-10), 54.7 3C-3), 69.5 3C-2), 97.2 3C-5), 126.3,
128.7, 129.4, 138.8, 168.3 3Bz); MS 370 eV): m/z 3%) 259
332) [M]1, 216 336) [M2C3H7]1, 105 3100) [Bz]1, 77 326)
[Ph]1; HRMS 3C16H21NO2): calcd. 259.1572, found
259.1587.
20
1
4.1.2. cis-.3R)-4-Benzoyl-3-methyl-1-oxa-4-azaspiro[4.5]-
decan-8-ol 6. Treatment of substrate 5 31.04 g) with B.
bassiana furnished the title compound 6 30.46 g, 44%) as
the sole product, a white crystalline solid, after column
chromatography; mp 212.0±213.08C 3from n-heptane/
CH2Cl2); [a]D ˆ255.08 3c 1.0, CH2Cl2); H NMR d 0.96
33H, d, Jˆ5.7 Hz, Me), 1.53±1.99 and 2.51±2.99 37H and
2H, 2£bd, 6-H, 7-H, 9-H, 10-H, OH), 3.53±3.85 32H, bm,
2-H, 8-H), 4.03 32H, m, 2-H, 3-H), 7.35 35H, s, Bz); 13C
NMR d 20.7 3Me), 29.1, 32.3, 32.4, 32.8 3C-6, C-7, C-9,
C-10), 54.8 3C-3), 69.4, 69.6 3C-2, C-8), 96.0 3C-5), 126.2,
128.7, 129.6, 138.5, 168.7 3Bz); MS 370 eV): m/z 3%) 275
311) [M]1, 216 362) [M2C3H7O]1, 202 36), 105 3100)
[Bz]1, 77 323) [Ph]1; HRMS 3C16H21NO3): calcd
275.1521, found 275.1527; The absolute con®guration of
compound 6 was obtained by X-ray crystallographic analy-
sis 3CCDC 159175).
4.1.6. .3S,4S)-4-Hydroxy-3-methylcyclohexanone. Removal
of the d/p from 8 357 mg) afforded the title compound as a
clear syrup 319 mg, 77% yield) after column chroma-
20
tography; [a]D ˆ122.08 3c 0.6, CH2Cl2); 1H NMR d
20
1
1.05 33H, d, Jˆ6.1 Hz, Me), 1.68±2.59 38H, m, 2-H, 3-H,
5-H, 6-H, OH), 3.69 31H, ddd, J4,5axˆJ4,3axˆ8.1 Hz, J4,5eq
ˆ
3.7 Hz, 4-H); 13C NMR d 18.6 3Me), 32.4, 38.4, 39.5 3C-2,
C-5, C-6), 45.7 3C-3), 72.8 3C-4), 210.5 3C-1); MS 370 eV):
m/z 3%) 128 3100) [M]1, 113 318) [M2CH3]1, 110 320)
[M2H2O]1, 69 390); HRMS 3C7H12O2): calcd 128.0837,
found 128.0830.
4.1.7.
.R)-4-Benzoyl-3-methyl-1-oxa-4-azaspiro[4.6]-
undecane 9. Cycloheptanone 34.48 g) was reacted with
3R)-2-amino-1-propanol 32.0 g) to afford the title compound
9 32.0 g, 27% yield) as colourless crystals after column

A. de Raadt et al. / Tetrahedron 57 32001) 8151±8157
8155
20
chromatography; mp 86.0±89.08C; [a]D ˆ260.28 3c 1.5,
obtained by X-ray crystallographic analysis 3CCDC
159784).
1
CH2Cl2); H NMR d 0.96 33H, d, Jˆ5.9 Hz, Me), 1.50±
1.98, 2.51 and 2.69 310H, 1H and 1H, 3£m, 6-H, 7-H,
8-H, 9-H, 10-H, 11-H), 3.60 31H, dd, J2,2ˆ6.2 Hz, J2,3ˆ
0.9 Hz, 2-H), 4.03 32H, m, 2-H, 3-H), 7.38 35H, s, Bz);
13C NMR d 20.7 3Me), 23.0, 28.9, 29.2, 36.4, 39.6 3C-6,
C-7, C-8, C-9, C-10, C-11), 54.5 3C-3), 69.6 3C-2), 100.8
3C-5), 126.3, 128.6, 129.4, 138.8, 168.4 3Bz); MS 370 eV):
m/z 3%) 273 332) [M]1, 216 342) [M2C4H9]1, 105 3100)
[Bz]1, 77 322) [Ph]1; HRMS 3C17H23NO2): calcd 273.1729,
found 273.1747.
4.1.10.
.2J,4R)-3-Benzoyl-2,4-dimethyl-2-.30-methyl-
butyl)oxazolidine 11. Reacting 5-methyl-2-hexanone
32.28 g) with 3R)-2-amino-1-propanol 31.00 g) produced a
mixture of diastereoisomers which were separated by
column chromatography 3major isomer 11: 0.86 g, 24%,
colourless oil; minor isomer: 0.35 g, 10%, white crystalline
20
solid). Experimental data for 11: [a]D ˆ227.38 3c 1.2,
1
CH2Cl2); H NMR d 0.92 39H, m, 40-H, 50-H, 70-H), 1.24
33H, m, 20-H, 30-H), 1.58 33H, s, 60-H), 2.10 32H, m, 10-H),
4.1.8. .3R,5R,8S) and .3R,5S,8R)-4-Benzoyl-3-methyl-1-
oxa-4-azaspiro[4.6]undecan-8-ol 10a and 10b. Treatment
of substrate 9 30.720 g) with B. bassiana and column
chromatography furnished an inseparable mixture of com-
pounds 10a and 10b 30.2 g, 29% yield; 1:1, HPLC,
n-heptane/IPA; 7:3; ¯owˆ0.5 mL/min), a white waxy
solid, as well as the corresponding ketone derivative14 as a
waxy solid 30.050 g, 7%). Experimental data for 10a and
3.59 31H, d, J5,4 ˆ6.5 Hz, 5-H), 4.09 32H, m, 4-H, 5-H), 7.40
13
35H, s, Bz); C NMR d 20.1, 22.0, 22.7, 22.8 3C-40, C-50,
C-60, C-70), 28.2 3C-30), 33.1, 35.9 3C-10, C-20), 54.1 3C-4),
69.4 3C-5), 97.9 3C-2), 125.9, 128.4, 129.1, 138.4, 168.1
3Bz); MS 370 eV): m/z 3%) 260 37) [M2CH3]1, 204 397)
[M2C5H11]1, 105 3100) [Bz]1, 77 316) [Ph]1; HRMS 3[M2
CH3]1; C16H22NO2): calcd 260.1651, found 260.1671.
Experimental data for the minor isomer: mp 63.5±66.08C;
1
20
1
10b; H NMR d 0.96 33H, m, Me), 1.50±2.08 and 2.20±
[a]D ˆ287.38 3c 1.2, CH2Cl2); H NMR d 0.88 39H, m,
40-H, 50-H, 70-H), 1.27 32H, m, 20-H), 1.51 31H, m, 30-H),
1.69 33H, s, 60-H), 2.10 32H, m, 10-H), 3.62 31H, dd,
J5,4ˆ3.6 Hz, J5,5ˆ7.9 Hz, 5-H), 4.10 32H, m, 4-H, 5-H),
2.80 311H, 2£bm, 6-H, 7-H, 9-H, 10-H, 11-H, OH), 3.63
31H, dd, J2,2ˆ6.1 Hz, J2,3ˆ2.5 Hz, 2-H), 3.82±4.13 33H, m,
2-H, 3-H, 8-H), 7.38 35H, s, Bz); 13C NMR d 20.4 3Me),
18.4, 31.1, 37.4, 37.9, 39.9 3C-6, C-7, C-9, C-10, C-11), 54.4
3C-3), 69.5 3C-2), 72.0 3C-8), 102.5 3C-5), 126.0, 128.5,
129.4, 138.1, 168.2 3Bz); MS 370 eV): m/z 3%) 289 332)
[M]1, 216 354) [M2C4H9O]1, 202 38) [M2C5H11O]1,
105 3100) [Bz]1, 77 323) [Ph]1; HRMS 3C17H23NO3):
calcd 289.1678, found 289.1685.
13
7.40 35H, s, Bz); C NMR d 20.4, 22.7, 24.9 3C-40, C-50,
C-60, C-70), 28.2 3C-30), 32.6, 34.5 3C-10, C-20), 54.6 3C-4),
70.4 3C-5), 97.8 3C-2), 126.4, 128.5, 129.6, 138.2, 164.2
3Bz); GC-MS, m/z 3%) 274 3M1, 1), 260 32), 204 333),
162 32), 105 3100), 77 330).
4.1.11. .2J,4R)-3-Benzoyl-2,4-dimethyl-2-.30-hydroxy-
30-methylbutyl)oxazolidine 12. Treating substrate 11
30.869 g) with B. bassiana furnished compound 12
30.619 g, 67%) as a colourless oil after chromatography:
[a]D ˆ217.48 3c 1.7, CH2Cl2); H NMR d 0.93 33H, d,
Jˆ8.6 Hz, 70-H), 1.22 36H, s, 40-H, 50-H), 1.60 35H, m,
20-H, 60-H), 2.21 32H, m, 10-H), 3.60 31H, d, J5,4ˆ7.9 Hz,
5-H), 4.07 32H, m, 4-H, 5-H), 7.35 35H, s, Bz); 13C NMR d
20.5 3C-70), 22.2 3C-60), 29.1, 29.8 3C-40, C-50), 32.7, 38.0
3C-10, C-20), 54.0 3C-4), 69.4 3C-30), 70.3 3C-5), 97.8 3C-2),
125.8, 128.2, 129.3, 138.1, 168.1 3Bz); MS 370 eV): m/z 3%)
276 33) [M2CH3]1, 204 373) [M2C5H11O]1, 162 318), 105
3100) [Bz]1, 77 319) [Ph]1; HRMS 3[M2CH3]1;
C16H22NO3): calcd 276.1600, found 276.1604.
20
Experimental data for the ketone by-product14. [a]D
ˆ
1
265.78 3c 1.8, CH2Cl2); H NMR d 0.98 33H, Jˆ6.3 Hz,
Me), 1.70±2.20 and 2.30±3.20 310H, 2£bm, 6-H, 7-H, 9-H,
10-H, 11-H), 3.65 31H, d, J2,2ˆ6.1 Hz, 2-H), 4.08 32H, m,
2-H, 3-H), 7.38 35H, s, Bz); 13C NMR d 20.5 3Me), 19.0,
31.1, 37.2, 38.9, 37.9, 43.4 3C-6, C-7, C-9, C-10, C-11), 54.6
3C-3), 69.8 3C-2), 97.7 3C-5), 126.0, 128.6, 129.5, 138.0,
168.2 3Bz), 213.9 3C-8); GC-MS, m/z 3%) 287 3M1, 11),
216 38), 182 39), 154 323), 105 3100), 77 343).
20
1
4.1.9. .3R,5S,8R)- and .3R,5R,8S)-4-Benzoyl-3-methyl-8-
phenylcarbamoyloxy-1-oxa-4-azaspiro[4.6]undecane 25a
and 25b.14 Alcohols 10a and 10b 30.330 g), an inseparable
mixture, were derivatised with phenylisocyanate 30.160 g)
according to a known procedure15 to give the title
compounds 25a and 25b, also an inseparable mixture, as
colourless crystals 30.47 g, 28% yield): mp 70.0±70.58C
3from n-hexane/CH2Cl2); 1H NMR d 0.97 33H, d, Jˆ
6.5 Hz, Me), 1.60±2.34 and 2.40±2.83 310H, 2£bm, 6-H,
7-H, 9-H, 10-H, 11-H), 3.64 31H, d, J2,2ˆ6.4 Hz, 2-H), 4.18
32H, m, 2-H, 3-H), 5.01 31H, bs, 8-H), 7.03 31H, t, Jˆ
7.1 Hz, OCONHPh), 7.28 32H, t, Jˆ8.3 Hz, OCONHPh),
7.39 37H, m, Bz, OCONHPh); 13C NMR d 20.6 3Me), 18.5,
27.4, 34.4, 37.2, 39.7 3C-6, C-7, C-9, C-10, C-11), 54.4
3C-3), 69.5 3C-2), 75.5 3C-8), 99.7 3C-5), 118.6, 123.2,
126.1, 128.6, 129.0, 129.4, 138.2, 138.3, 153.2, 168.4
3OCONHPh; Bz); MS 370 eV): m/z 3%) 408 36) [M]1, 289
39) [M2PhNCO]1, 271 317) [M2C7H7NO2]1, 216 324)
[M2C11H14NO2]1, 162 320), 119 335) [PhNCO]1, 105
3100) [Bz]1, 91 315), 77 325) [Ph]1; HRMS 3C24H28N2O4):
calcd 408.2049, found 408.2042; The absolute con®gu-
rations of compounds 25a and 25b 3mixed crystals) were
4.1.12.
.2R,4R)-3-Benzoyl-2,4-dimethyl-2-.20-methyl-
propyl)oxazolidine 14 and .2S, 4R)-3-Benzoyl-2,4-di-
methyl-2-.20-methylpropyl)oxazolidine 15. Reacting
4-methyl-2-pentanone 13 37.22 g) with 3R)-2-amino-1-pro-
panol 33.60 g) afforded a mixture 31.8:1, HPLC, n-heptane/
IPA; 95:5; Tˆ108C; ¯owˆ0.5 mL/min) of diastereoisomers
14 and 15 34.03 g, 32% combined yield). These were sepa-
rated with careful column chromatography to give major
isomer 14 as a clear syrup and the minor isomer 15 as a
white crystalline solid. Experimental data for the major
20
1
isomer 14: [a]D ˆ242.28 3c 1.5, CH2Cl2); H NMR d
0.96 39H, 30-H, 40-H, 60-H), 1.65 33H, s, 50-H), 1.87 and
2.21 33H, 2£m, 20-H, 10-H), 3.62 31H, bd, 5-H), 4.06 32H,
m, 4-H, 5-H), 7.36 35H, s, Bz); 13C NMR d 20.7, 24.0, 24.6,
24.9, 46.2 3C-10, C-20, C-30, C-40, C-50, C-60), 54.2 3C-4),
69.7 3C-5), 98.4 3C-2), 126.1, 128.6, 129.4, 138.6, 163.0
3Bz); MS 370 eV): m/z 3%) 261 3,0.1) [M]1, 246 35)
[M2CH3]1, 204 364) [M2C4H9]1, 105 3100) [Bz]1, 77

8156
A. de Raadt et al. / Tetrahedron 57 32001) 8151±8157
319) [Ph]1; HRMS 3[M2CH3]1; C15H20NO2): calcd
[M2CH3]1, 204 396) [M2C11H15O]1, 162 38), 105 3100)
[Bz]1, 91 319) [C7H7]1, 77 317) [Ph]1; HRMS 3C23H29NO3):
calcd. 367.2147, found 367.2152.
246.1494, found 246.1511; HRMS 3[M]1; C16H23NO2):
calcd 261.1729, found 261.1708. 3very low intensity).
20
Experimental data for 15; mp 56.0±57.08C; [a]D
ˆ
277.58 3c 1.1, CH2Cl2); H NMR12 d 0.95 39H, m, 30-H,
40-H, 60-H), 1.73 33H, s, 50-H), 1.77±2.15 33H, m, 20-H,
10-H), 3.62 31H, bd, 5-H), 4.08 32H, m, 4-H, 5-H), 7.38
4.1.16. .2R,4R,20R)-3-Benzoyl-2,4-dimethyl-2-.30-hydroxy-
20-methylpropyl)oxazolidine 19. Subjecting major isomer
14 30.917 g) to B. bassiana afforded three hydroxylated
products 16 30.103 g), 17 30.126 g) and 19 30.047 g,
HPLC indicated that 19 was contaminated with both 16
and 17) after chromatography. Experimental data for 19: a
colourless syrup; 5% yield; d.e. 23%; HPLC, n-heptane/
1
13
35H, s, Bz); C NMR d 20.7, 24.0, 24.7, 25.3, 44.1 3C-10,
C-20, C-30, C-40, C-50, C-60), 54.6 3C-4), 70.1 3C-5), 98.3
3C-2), 126.5, 128.7, 129.7, 138.5, 169.0 3Bz); MS 370 eV):
m/z 3%) 261 30.1) [M]1, 246 37) [M2CH3]1, 204 359)
[M2C4H9]1, 105 3100) [Bz]1, 77 318) [Ph]1; HRMS
3[M2CH3]1; C15H20NO2): calcd 246.1494, found 246.1506.
20
IPA; 90:10; Tˆ108C, ¯owˆ0.5 mL/min; [a]D ˆ222.98
1
3c 0.9, CH2Cl2); H NMR d 1.00 36H, m, 40-H, 60-H),
1.68 33H, s, 50-H), 1.73±2.43 33H, m, 10-H, 20-H), 2.90
31H, bs, OH), 3.35±3.80 33H, bm, 5-H, 30-H), 4.10 32H,
m, 4-H, 5-H), 7.39 35H, s, Bz); 13C NMR d 19.5, 20.7,
22.2, 32.4, 42.6 3C-10, C-20, C-40, C-50, C-60), 54.2 3C-4),
68.6, 69.6 3C-5, C-30), 98.3 3C-2), 126.1, 128.7, 129.5,
138.0, 168.7 3Bz); MS 370 eV): m/z 3%) 262 36) [M2
CH3]1, 204 368) [M2C4H9O]1, 162 38), 105 3100) [Bz]1,
77 319) [Ph]1; HRMS 3[M2CH3]1; C15H20NO3): calcd
262.1443, found 262.1425.
4.1.13. .2R,4R)-3-Benzoyl-2,4-dimethyl-2-.20-hydroxy-
20-methylpropyl)oxazolidine 16. Subjecting major isomer
14 30.917 g) to B. bassiana afforded three hydroxylated
products 16 30.103 g), 17 30.126 g) and 19 30.047 g) after
chromatography. Experimental data for 16: a colourless
syrup; 12% yield; 1H NMR d 1.06 33H, d, Jˆ6.0 Hz,
60-H), 1.32 and 1.40 32£3H, 2£s, 30-H, 40-H), 1.61 31H,
bs, OH), 1.80 33H, s, 50H), 2.25 and 2.70 32£1H, 2£d, Jˆ
14.9 Hz, 10-H), 3.77 31H, d, Jˆ8.4 Hz, 5-H), 4.13 32H, m,
3C-50), 30.5 and 31.6 3C-30, C-40), 50.7 3C-10), 54.3 3C-4),
70.1 3C-5), 70.9 3C-20), 98.2 3C-2), 126.1, 128.8, 129.6,
138.1, 168.4 3Bz); MS 370 eV): m/z 3%) 262 37) [M2
CH3]1, 204 369) [M2C4H9O]1, 162 314), 140 312), 105
3100) [Bz]1, 77 317) [Ph]1; HRMS 3[M2CH3]1;
C15H20NO3): calcd 262.1443, found 262.1437.
13
4-H, 5-H), 7.40 35H, s, Bz); C NMR d 20.6 3C-60), 24.1
4.1.17. .2R,4R,20R)-3-Benzoyl-2,4-dimethyl-2-.30-benzyl-
oxy-20-methylpropyl)oxazolidine 20. Benzylation of 19
30.061 g) under standard conditions16 afforded the title
compound 30.067 g) as a colourless syrup: 83% yield;
20
1
[a]D ˆ222.78 3c 1.2, CH2Cl2); H NMR d 0.95 and 1.10
32£3H, 2£m, 40-H, 60-H), 1.66 33H, s, 50-H), 2.06 33H, m,
10-H, 20H), 3.28 31H, m, 30H), 3.40±3.72 32H, m, 5-H,
30-H), 4.06 32H, m, 4-H, 5-H), 4.53 32H, s, CH2Ph), 7.35
310H, m, CH2Ph, Bz); 13C NMR d 19.7, 20.5, 22.8, 30.0,
41.2 3C-10, C-20, C-40, C-50, C-60), 54.1 3C-4), 69.6, 73.1,
76.1 3C-5, C-30, CH2Ph), 98.2 3C-2), 126.1, 127.5, 127.7,
128.4, 128.6, 129.4, 138.4, 139.1, 168.3 3CH2Ph, Bz); MS
370 eV): m/z 3%) 367 32) [M]1, 352 36) [M2CH3]1, 204
392) [M2C11H15O]1, 162 320), 105 3100) [Bz]1, 91 322)
[C7H7]1, 77 319) [Ph]1; HRMS 3C23H29NO3): calcd
367.2147, found 367.2165.
4.1.14. .2R,4R, 20S)-3-Benzoyl-2,4-dimethyl-2-.30-hydroxy-
20-methylpropyl)oxazolidine 17. Subjecting major isomer
14 30.917 g) to B. bassiana afforded three hydroxylated
products 16 30.103 g), 17 30.126 g) and 19 30.047 g) after
chromatography. Experimental data for 17: a colourless
syrup; 14% yield; d.e. 99% 3HPLC, n-heptane/IPA; 90:10;
20
Tˆ108C, ¯owˆ0.5 mL/min); [a]D ˆ223.98 3c 1.0,
1
CH2Cl2); H NMR d 1.01 36H, m, 40-H, 60-H), 1.64 33H,
s, 50-H), 1.88 31H, m, 20-H), 2.19 32H, d, Jˆ5.4 Hz, 10-H),
2.53 3H, bs, OH), 3.47 32H, d, Jˆ6.6 Hz, 30-H), 3.65 31H, d,
Jˆ8.8 Hz, 5-H), 4.09 32H, m, 4-H, 5-H), 7.38 35H, s, Bz);
13C NMR d 18.5, 20.6, 22.7, 32.0, 41.6 3C-10, C-20, C-40,
C-50, C-60), 54.0 3C-4), 69.3, 69.6 3C-5, C-30), 98.1 3C-2),
126.0, 128.6, 129.3, 138.3, 168.3 3Bz); MS 370 eV): m/z 3%)
262 38) [M2CH3]1, 204 372) [M2C4H9O]1, 162 36), 105
3100) [Bz]1, 77 320) [Ph]1; HRMS 3[M2CH3]1;
C15H20NO3): calcd 262.1443, found 262.1443.
4.1.18. .2S,4R,20R)-3-Benzoyl-2,4-dimethyl-2-.30-hydroxy-
20-methylpropyl)oxazolidine 21. Treatment of substrate 15
30.927 g) with B. bassiana furnished the title compound 21.
After column chromatography, compound 21 was afforded
as a clear syrup which later solidi®ed 30.529 g, 60% yield,
d.e. 99%, HPLC, n-heptane/IPA; 90:10; Tˆ108C, ¯owˆ
0.5 mL/min). Recrystallisation furnished white needles
20
3CH2Cl2/pet. ether); mp 66.5±67.08C; [a]D ˆ287.48 3c
1
1.4, CH2Cl2); H NMR d 0.84 and 0.96 36H, 2£d, Jˆ4.4
4.1.15.
.2R,4R,
20S)-3-Benzoyl-2,4-dimethyl-2-.30-
and 6.6 Hz, 40H, 60-H), 1.70 33H, s, 50H), 1.74±2.06 and
2.39 32H and 1H, m and bd, 10H, 20-H), 2.62 31H, bs, OH),
3.53 33H, bm, 30H, 5-H), 4.16 32H, m, 4-H, 5-H), 7.44 35H,
benzyloxy-20-methylpropyl)oxazolidine 18. Benzylation
of 17 30.071 g) under standard conditions16 afforded the
title compound 30.073 g) as a colourless syrup: 78% yield;
13
s, Bz); C NMR d 18.8, 20.2, 24.8, 32.2, 40.6 3C-10 C-20,
20
1
[a]D ˆ219.58 3c 1.1, CH2Cl2); H NMR d 0.97 and 1.09
32£3H, 2£d, Jˆ5.7 and 6.2 Hz, 40-H, 60-H), 1.64 33H, s,
50-H), 1.95 and 2.31 32H and 1H, 2£m, 10-H, 20-H), 3.24 and
3.47 32£1H, 2£dd, Jˆ5.3, 7.0 and 8.8 Hz, 30-H), 3.62 31H,
dd, Jˆ2.0 and 8.1 Hz, 5-H), 4.06 32H, m, 4-H, 5-H), 4.52
32H, s, CH2Ph), 7.35 310H, m, CH2Ph, Bz); 13C NMR d
18.8, 20.5, 22.8, 30.0, 41.0 3C-10, C-20, C-40, C-50, C-60),
54.1 3C-4), 69.6, 73.1, 76.5 3C-5, C-30, CH2Ph), 98.1 3C-2),
126.1, 127.5, 127.8, 128.4, 128.6, 129.3, 138.4, 138.9, 168.3
3CH2Ph, Bz); MS 370 eV): m/z 3%) 367 32) [M]1, 352 37)
C-40, C-50 C-60 54.7 3C-4), 69.0, 70.5 3C-5, C-30), 98.1
3C-2), 126.7, 128.9, 130.2, 138.1, 169.1 3Bz); MS 370 eV):
m/z 3%) 262 312) [M2CH3]1, 204 368) [M2C4H9O]1, 162
39), 140 36), 105 3100) [Bz]1, 77 325) [Ph]1; HRMS 3[M2
CH3]1; C15H20NO3): calcd 262.1443, found 262.1452. The
absolute con®guration of compound 21 was obtained by
X-ray crystallographic analysis 3CCDC 164173).
4.1.19. .2R,4S,20R)-3-Benzoyl-2,4-dimethyl-2-.30-benzyl-
oxy-20-methylpropyl)oxazolidine 22. Benzylation of 21

A. de Raadt et al. / Tetrahedron 57 32001) 8151±8157
8157
30.152 g) under standard conditions16 afforded the title
compound 30.131 g) as a colourless syrup: 65% yield;
4. de Raadt, A.; Fetz, B.; Griengl, H.; Klingler, M. F.; Kopper, I.;
Krenn, B.; MuÈnzer, D. F.; Ott, R. G.; Plachota, P.; Weber, H.;
Braunegg, G.; Mosler, W.; Saf, R.; Eur J. Org. Chem. 2000,
3835±3847.
20
1
[a]D ˆ292.68 3c 1.1, CH2Cl2); H NMR d 0.92 and 1.07
32£3H, 2 £ d, Jˆ5.3 and 6.2 Hz, 40H, 60-H), 1.74 33H, s,
50H), 2.05 33H, m, 10-H, 20-H), 3.23 31H, m, 30-H), 3.49 and
3.61 32£1H, 2£m, 5-H, 30H), 4.06 32H, m, 4-H, 5-H), 4.53
32H, s, CH2Ph), 7.35 310H, m, CH2Ph, Bz); 13C NMR d
18.9, 20.5, 25.1, 30.1, 39.3 3C-10, C-20, C-40, C-50, C-60),
54.5 3C-4), 70.1, 73.1, 76.5 3C-5, C-30, CH2Ph), 98.0 3C-2),
126.4, 127.5, 127.8, 128.4, 128.6, 129.7, 138.3, 138.9, 168.3
3CH2Ph, Bz); MS 370 eV): m/z 3%) 367 32) [M]1, 352 318)
[M2CH3]1, 204 396) [M2C11H15O]1, 162 316), 105 3100)
[Bz]1, 91 324) [C7H7]1, 77 321) [Ph]1; HRMS 3C23H29NO3):
calcd 367.2147, found 367.2145.
5. 3a) Johnson, R. A.; Murray, H. C.; Reineke, L. M.; Fonken,
G. S. J. Org. Chem. 1969, 34, 2279±2284. 3b) Aitken, S. J.;
Grogan, G.; Chow, C. S.-Y.; Turner, N. J.; Flitsch, S. L. J.
Chem. Soc., Perkin Trans. 1 1998, 3365±3370.
6. Majewski, M.; MacKinnon, J. Can. J. Chem. 1994, 72, 1699±
1704.
7. This structure determination showed that the N-phenyl-
urethane derivatives 25a and 25b of diastereomers 10a and
10b enter a single crystal lattice of monoclinic symmetry,
space group P21, with two independent molecules in the
asymmetric unit. In context with the pseudo-enantiomeric
nature of the two diastereomers 25a and 25b, they are able
to mimic, in the crystalline state, a lattice with pseudo-inver-
sions and pseudo-symmetry P21/n thus forming a crystalline
pseudo-racemate.
4.1.20. .S)-5-Benzyloxy-4-methylpentan-2-one 23.17
Removal of d/p group4 from 18 30.059 g) afforded the title
compound 30.030 g) as a colourless syrup; 91% yield; e.e.
20
99% 3GC); [a]D ˆ23.2 3c 1.0, CH2Cl2); 1H NMR data was
in agreement with the values published for the correspond-
ing racemate.17
È
8. Pietz, S.; Wolker, D.; Haufe, G. Tetrahedron 1997, 50,
17067±17078.
9. DesMarteau, D. D.; Petrov, V. A.; Monatanari, V.; Pregnolato,
M.; Resnati, G. Tetrahedron Lett. 1992, 33, 7245±7248.
10. For examples where high selectivities were observed for B.
bassiana please see: Archelas, A.; Fourneron, J. D.; Furstoss,
R. J. Org. Chem. 1988, 53, 1797±1799 and reference 8.
11. Kraemer-Schafhalter, A.; Domenek, S.; Boehling, H.;
Feichtenhofer, S.; Griengl, H.; Voss, H. Appl. Microbiol.
Biotechnol. 2000, 53, 266±271.
4.1.21. .R)-5-benzyloxy-4-methylpentan-2-one 24.17
Removal of d/p group4 from either 20 30.054 g) or 22
30.077 g) provided the title compound in 67% 30.020 g,
23% e.e.) and 73% 30.031 g, 99% e.e.) yield, respectively.
20
Experimental data for 24 399% e.e.): [a]D ˆ13.1 3c 1.5,
1
CH2Cl2); H NMR 3500 MHz) d 0.96 33H, d, Jˆ6.8 Hz,
6-H), 2.13 33H, s, 1-H), 2.27 31H, dd, Jˆ7.9 and 16.2 Hz,
3-H), 2.37 31H, m, 4-H), 2.62 31H, dd, Jˆ5.8 and 16.2 Hz,
3-H), 3.27 31H, dd, Jˆ7.1 and 9.4 Hz, 5-Ha) 3.37 31H, dd,
Jˆ5.2 and 7.1 Hz, 5-Hb), 4.49 32H, s, 7-H), 7.33 35H, m,
Ph); 13C NMR d 17.2 3C-6), 30.0 3C-4), 30.5 3C-1), 48.1
3C-3), 73.1 3C-7), 75.1 3C-5), 127.7, 128.5, 138.6 3Ph),
208.8 3C-2); MS 370 eV): m/z 3%) 206 31) [M]1, 164 318)
[M2C2H2O]1, 148 38), 115310), 107 322) [C7H7O]1, 99
316), 91 3100) [C7H7]1, 43 313); HRMS 3C13H18O2): calcd
206.1307, found 206.1282.
12. Perrin, D. D.; Armarego, W. L. F. Puri®cation of Laboratory
Chemicals; 3rd ed.; Pergamon: Oxford, 1988.
13. The numbering of the cyclic and acyclic derivatives is
depicted below for substrates 5, 11 and 15:
Acknowledgements
14. The structures of the ketone by-product as well as of deriva-
tives 25a and 25b are shown below:
The authors wish to thank C. Illaszewicz for the measure-
ment of NMR spectra, W. Mosler for conducting XRD
structural measurements, M. Ortner and J. Kern for their
È
preparative help as well as R. F. G. Frohlich, M. Kaube
and W. Schmid for their technical assistance.
References
1. 3a) Barton, D. H. R. Tetrahedron 1998, 54, 5805±5817.
Matsunaka, K.; Iwahama, T.; Sakaguchi, S.; Ishii, Y.
Tetrahedron Lett. 1999, 40, 2165±2168. 3b) Asensio, G.;
Mello, R.; Gonzalez-Nunez, M. E.; Castellano, G.; Corral, J.
Angew. Chem. 1996, 108, 196±198.
È
15. Pietz, S.; Frohlich, R.; Haufe, G. Tetrahedron 1997, 53,
17055±17066.
2. 3a) Holland, H. L. Organic Synthesis with Oxidative Enzymes;
VCH: New York, 1992. 3b) Grogan, G. J.; Holland, H. L. J.
Mol. Catal. 2000, 9, 1±32 and references cited therein.
3. 3a) Braunegg, G.; de Raadt, A.; Feichtenhofer, S.; Griengl, H.;
Kopper, I.; Lehmann, A.; Weber, H. Angew. Chem., Int. Ed.
Engl. 1999, 38, 2763±2765. 3b) de Raadt, A.; Griengl, H.;
Weber, H. Chem. Eur. J. 2001, 7, 27±31.
16. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; 3rd ed.; Wiley: New York, 1999.
17. This compound was previously reported as a racemate:
Tone, H.; Hikota, M.; Hamada, T.; Nishi, T.; Oikawa, Y.;
Yonemitsu, O. Chem. Pharm. Bull. 1989, 37, 1155±1159.