Asymmetric Synthesis of O-Protected Acyloins
Scheme 4. Asymmetric synthesis of reference material for (S)-2b, (S)-4b, (S)-5b, and (R)-6b.
XenB, NerA, and EBP1, 60–100 µg, protein concentration in bio-
transformations 75–125 µg/mL) was added to a Tris-HCl buffer
solution (0.8 mL, 50 m, pH 7.5) containing the substrate (10 m)
and the cofactor NADH (15 m). In the case of 6a, the substrate
was solubilized by addition of tBuOMe (v:v 20%). The mixture
was shaken at 30 °C and 120 rpm. After 24 h, the products were
extracted with EtOAc (2ϫ0.5 mL). The combined organic phases
were dried with Na2SO4 and analyzed on achiral GC to determine
the conversion and on chiral GC to determine the enantiomeric
excess. For experiments in the presence of cofactor recycling,
NADH was replaced by the oxidized form of the cofactor (NAD+,
100 µ), the cosubstrate (glucose or formate, 20 m), and the re-
cycling enzyme (glucose dehydrogenase or formate dehydrogenase,
10 U), respectively.
monoether derivative was dissolved in CH2Cl2 (2 mL) and Jones
reagent (2 mL) was added dropwise over 30 min with stirring. Ex-
cess oxidant was quenched by the addition of 2-butanol (2 mL).
Water (10 mL) was added, and the products were extracted with
CH2Cl2 (2ϫ10 mL). The organic phase was filtered through Celite
and dried with Na2SO4, and the solvent was removed in vacuo to
afford (S)-2-(allyloxy)cyclohexanone [(S)-2b], (S)-2-(benzyloxy)-
cyclohexanone [(S)-4b], (S)-2-methoxycyclopentanone [(S)-5b], and
(R)-2-benzyloxycyclopentanone [(R)-6b].
(S)-2-Propoxycyclohexanone [(S)-3b]: (S)-2-(Allyloxy)cyclohexan-
one [(S)-2b] was hydrogenated according to method B (see Support-
ing Information), yielding (S)-2-propoxycyclohexanone [(S)-3b].
The absolute configuration of 1b was determined by co-injection
of enantioenriched reference material obtained by reduction of 1a
with EBP1 [20 mg, 78%ee (R)]. [α]2D0 (CH2Cl2) = +29.5, for (R)-1a
(Scheme 4).[25]
Determination of Absolute Configuration of Products 1b–6b
(1S,2S)-2-(Allyloxy)cyclohexanol and (1S,2S)-2-Methoxycyclopent-
anol: The corresponding (1S,2S)-diol (0.86 mmol) was dissolved in
THF (5 mL) and NaH (40 mg, 1 mmol, 60% in mineral oil) was
added. After 10 min of stirring, allyl or methyl bromide (0.5 mmol)
was added, and the mixture was stirred for 1 h at room tempera-
ture. Then, more NaH was added (40 mg; 1 mmol; 60% in mineral
oil), and the mixture was stirred at room temperature for 16 h.
Then, HCl (5 mL, 1 ) was added, and the mixture was extracted
with ethyl acetate (3ϫ10 mL). The organic phase was dried with
Na2SO4, and the solvent was removed in vacuo to yield a mixture
containing 15% of the desired product monoalkylated diol, which
was used without further purification for the next step.
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis of substrates 1a–8a; synthesis of reference material
for rac-1b–6b, 2c, and 3c; analytical data for the GC-determination
of conversion of substrates 1a–8a and the enantiomeric composi-
tion of products 1b–6b.
Acknowledgments
This study was performed in collaboration with BASF SE (Lud-
wigshafen, Germany) and financial support is gratefully acknowl-
edged. Melanie Bonnekessel and Kai Baldenius are cordially
thanked for inspiring discussions.
(1S,2S)-2-(Benzyloxy)cyclohexanol and (1R,2R)-2-(Benzyloxy)-
cyclopentanol: The corresponding (1S,2S)- and (1R,2R)-diol
(0.86 mmol) and benzyl bromide (152.9 mg, 0.9 mmol) were dis-
solved in CH2Cl2 (5 mL) and silver(I)oxide (1.35 mmol, 310 mg)
was added. The mixture was stirred at room temperature for 24 h
and then HCl (2 mL, 1 ) was added, and the mixture was ex-
tracted with ethyl acetate (2ϫ10 mL). The organic phase was dried
with Na2SO4, and the solvent was removed in vacuo to yield a
mixture containing 80% of the of monobenzylated diol, which was
used without further purification for the next step.[24]
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The absolute configuration of 1b was determined as (R) by com-
parison of the optical rotation value of 1b {[α]2D0 = +29.5 (CH2Cl2)}
obtained by bioreduction of 1a using EBP1 with literature data.[25]
General Procedure for the Oxidation of Monoethers of Cyclopent-
ane- and Cyclohexane-1,2-diols to the Corresponding O-Protected
Acyloins (S)-2b, (S)-4b, (S)-5b, and (R)-6b: (S)-2-(Allyloxy)cyclo-
hexanone [(S)-2b], (S)-2-(benzyloxy)cyclohexanone [(S)-4b], (S)-2-
methoxycyclopentanone [(S)-5b], and (R)-2-benzyloxycyclopent-
anone [(R)-6b] were obtained by Jones oxidation of the correspond-
ing monoether derivatives of 1,2-diols as prepared above: Jones rea-
gent CrO3 (7 g, 70 mmol) was dissolved in water (50 mL) and
H2SO4 (6.1 mL, conc.) was added dropwise under cooling. The
[9] J. Sukumaran, U. Hanefeld, Chem. Soc. Rev. 2005, 34, 530–
542.
[10] For recent studies, see: a) M. Hall, C. Stueckler, W. Kroutil, P.
Macheroux, K. Faber, Angew. Chem. Int. Ed. 2007, 46, 3934–
3937; b) M. Hall, C. Stueckler, H. Ehammer, E. Pointner, G.
Oberdorfer, K. Gruber, B. Hauer, R. Stuermer, W. Kroutil, P.
Macheroux, K. Faber, Adv. Synth. Catal. 2008, 350, 411–418;
c) M. Hall, C. Stueckler, B. Hauer, R. Stuermer, T. Friedrich,
M. Breuer, W. Kroutil, K. Faber, Eur. J. Org. Chem. 2008,
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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