Homoallylic Alcohols via a Chemo-Enzymatic One-Pot Oxidation–Allylation Cascade
most likely due to steric hindrance. Fortunately, the compound 9c) to clarify the solution and products were ex-
tracted with EtOAc (3ꢃ20 mL). Phase separation was con-
ꢀ
slimꢁ cinnamic alcohol (12a) was smoothly converted.
The recovery of the whole-cell biocatalyst by
ducted in 50-mL Sarstedt tubes, which were centrifuged in
order to facilitate phase seperation. The combined organic
phases were dried over Na SO , filtered and concentrated
simple centrifugation allows one to circumvent
enzyme deactivation caused by the allylation reagents
in the second step. Depending on the substrate con-
centration, three to five oxidation cycles could be per-
formed before the activity started to decline.
2
4
under reduced pressure. The crude product was purified
using column chromatography (silica gel, petroleum ether/
EtOAc) to furnish the products in >95% NMR purity and
>
99% GC-MS purity.
In conclusion, we have established a one-pot, two-
step procedure for the chemo-enzymatic synthesis of
homoallylic alcohols. All reactions were conducted at
room temperature in aqueous buffer without require- Acknowledgements
ment of cosolvents. The cascade starts from a benzylic
alcohol, which is enzymatically oxidized by galactose This study was financed by Evonik Degussa GmbH and the
oxidase in a clean fashion at the expense of O to fur- BMBF (Germany). We would like to thank Klaus Zangger
2
and his group for NMR measurements, Markus Pichler for
the construction of the oxygen-pressure apparatus and Ma-
thias Pickl for technical assistance. Markus Damm, Toma
from an allylboronic ester in a metal-free variant. A
Glasnov and C. Oliver Kappe are acknowledged for stimulat-
special feature of this method is the functional group
ing discussions.
nish the corresponding aldehyde, which is coupled to
an allyl moiety derived from allyl bromide/In(0) or
tolerance, which includes unprotected phenolic hy-
droxy groups and – in the case of In(0)/allyl bromide
–
basic heteroaromatic moieties. Overall, the reaction
References
sequence is carried out under mild (aqueous) condi-
tions and avoids the handling of moisture-sensitive
and flammable organometallics.
[
1] C. J. Li, Chem. Rev. 2005, 105, 3095.
[
2] L. F. Tietze, F. Stecker, J. Zinngrebe, K. M. Sommer,
Chem. Eur. J. 2006, 12, 8770; L. F. Tietze, K. M.
Sommer, J. Zinngrebe, F. Stecker, Angew. Chem. 2005,
117, 262; Angew. Chem. Int. Ed. 2005, 44, 257.
Experimental Section
[
[
3] C. J. Li, T. H. Chan, Tetrahedron Lett. 1991, 32, 7017.
4] B. Zhao, X. Peng, S. Cui, Y. Shi, J. Am. Chem. Soc.
General Procedure for the One-Pot Preparation of
Homoallylic Alcohols 1c–12c
2
010, 132, 11009.
[
5] J. S. Yadav, B. V. Subba Reddy, G. G. K. S. Narayana
Whole cells of E. coli containing overexpressed galactose
oxidase (40 mg lyophilized dry weight) were rehydrated in
phosphate buffer (2 mL, 100 mM, pH 7.0, 10 mM
CuSO ·5H O) by shaking at 308C and 120 rpm in a horizon-
tal position for 20 min. The rehydrated cells were trans-
ferred to a 10-mL round-bottom flask equipped with a mag-
netic stirring bar. Horseradish peroxidase (0.300 mg in 60 mL
buffer), 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)
Kumar, T. Swamy, Tetrahedron Lett. 2007, 48, 2205.
[6] D. T. Hung, J. B. Nerenberg, S. L. Schreiber, J. Am.
Chem. Soc. 1996, 118, 11054; A. B. Smith, C. M.
Adams, S. A. L. Barbosa, A. P. Degnan, J. Am. Chem.
Soc. 2003, 125, 350; J. D. White, P. R. Blakemore, N. J.
Green, E. B. Hauser, M. A. Holoboski, L. E. Keown,
C. S. Nylund Kolz, B. W. Phillips, J. Org. Chem. 2002,
67, 7750.
4
2
(
0
0.300 mg in 60 mL buffer) and substrate 1a–12a (method A:
.4 mmol; method B: 0.2 mmol) was added, the reaction
[7] S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763; C. J.
Li, Tetrahedron 1996, 52, 5643; J. Podlich, T. C. Maier,
Synthesis 2003, 633; Y. Yamamoto, N. Asao, Chem.
Rev. 1993, 93, 2207.
[8] L. Blackburn, R. J. K. Taylor, Org. Lett. 2001, 3, 1637;
B. Gnanaprakasam, J. Zhang, D. Milstein, Angew.
Chem. 2010, 122, 1510; Angew. Chem. Int. Ed. 2010, 49,
1468; S. Imm, S. Baehn, L. Neubert, H. Neumann, M.
Beller, Angew. Chem. Int. Ed. 2010, 49, 8126; M. S.
Kwon, S. Kim, S. Park, W. Bosco, R. K. Chidrala, J.
Park, J. Org. Chem. 2009, 74, 2877; D. Pingen, C. Muel-
ler, D. Vogt, Angew. Chem. Int. Ed. 2010, 49, 8130;
V. P. Srivastava, R. Patel, L. D. S. Yadav, Adv. Synth.
Catal. 2011, 353, 695.
mixture was placed in an oxygen-pressurizing apparatus (see
Supporting Information) using a rack for round-bottom
flasks. After the apparatus had been primed with oxygen
(
technical grade) for 1–2 min, the cylinder was closed and
pressurized to 4 bar. The reaction mixture was shaken at
room temperature and 170 rpm for 20 h. After careful de-
pressurization, the flask was removed and subjected to the
allylation step.
Method A: Indium powder (54 mg, 0.48 mmol, 100 mesh)
and allyl bromide (70 mL, 96 mg, 0.8 mmol) were added, the
flask was closed with a glass stopper and the mixture was
stirred at room temperature for 20 h.
Method B: Allylboronic acid pinacol ester (45 mL, 40 mg,
.24 mmol) was added, the flask was closed with a glass
stopper and the mixture was stirred at room temperature
for 6 h.
[9] F. Escalettes, N. J. Turner, ChemBioChem 2008, 9, 857;
B. Yuan, A. Page, C. P. Worrall, F. Escalettes, S. C. Wil-
lies, J. J. W. McDouall, N. J. Turner, J. Clayden, Angew.
Chem. Int. Ed. 2010, 49, 7010.
0
For work-up, the mixture was treated with saturated
NH Cl solution (10 mL; saturated K CO solution in case of
[10] L. Sun, T. Bulter, M. Alcalde, I. P. Petrounia, F. H.
Arnold, ChemBioChem 2002, 3, 781.
4
2
3
Adv. Synth. Catal. 2011, 353, 2354 – 2358
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2357