LETTER
Asymmetric Transfer Hydrogenation of Ketones
2621
new polymeric ligand exhibited similar to 6 catalytic per-
formance in terms of the activity and enantioselectivity
giving the product of the opposite chirality, 1-(S)-phenyl-
ethanol. These findings show that the chirality of the re-
mote polypeptide main chain does not interfere with the
chiral induction in the rhodium-catalyzed ATH of aromat-
ic ketones. The catalyst operates under mild reaction con-
ditions giving the products in a very high yield and
enantioselectivity. The polymeric catalysts can be recy-
cled several times with only a slight drop in activity. The
covalent linkage of the catalyst to the block copolymer
provides higher conversions and better recyclability than
regular micellar mixtures.
O2
S
N
NH2
Rh
Cl
7
Figure 1 Monomeric analogue of catalyst 6
In addition, the use of the common surfactant sodium do-
decyl sulfate (SDS) was even less efficient as only 17% of
the secondary alcohol was obtained under the same condi-
tions. The conversion further dropped to 6% upon the at- In conclusion, we have reported the first example of an
tempted recycling. Therefore, although good conversions amphiphilic block polypeptide based metal system for ef-
can be achieved using the combination of a monomeric ficient catalytic asymmetric transfer hydrogenation in
catalyst and surfactant, the chemical attachment of the pure water. The catalyst operates under mild reaction con-
catalyst units to the micellar core provides the benefits of ditions giving the products in a very high yield and enan-
the efficient recycling.
tioselectivity. The polymeric catalysts can be recycled
several times with only a slight drop in activity. The cova-
lent linkage of the catalyst to the block copolymer pro-
vides higher conversions and better recyclability than
regular micellar mixtures.
Interestingly, although the structurally similar to aceto-
phenone 4-fluoroacetophenone showed similar reactivity
and recycling features under ATH with 6, more hydropho-
bic 4-n-butylacetophenone was a poor substrate giving the
product in a very low yield (Table 2). It is possible that the
increased hydrophobicity of the product leads to a slower
exchange with the substrate outside the micelle. A similar
effect was observed in the release of micelle-encapsulated
Acknowledgment
We acknowledge the support from the Israel Science Foundation.
We thank Prof. Moshe Portnoy for valuable discussion. We also
thank Mrs. Dvora Reshef for technical assistance.
1
3
drugs. In addition, our results are in agreement with the
recently reported considerable electronic effect of simple
1
4
alkyl groups on the reduction of aromatic ketones. Both
factors can be responsible for the low reactivity of 4-n-bu-
tylacetophenone.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. SnuIpofoipmngr irtSatnoIuipfog
r
t
iornat
Table 2 Catalytic ATH of Substituted Acetophenonesa
References and Notes
Entry Ketone
Conversion
ee (%)c
(abs. config.)
(1) Sun, Y.; Liu, G.; Gu, H.; Huang, T.; Zhang, Y.; Li, H. Chem.
Commun. 2011, 47, 2583.
b
(
%)
(
2) (a) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68.
st
1
4-fluoroacetophenone
100 (1 cycle)
99 (R)
99 (R)
98 (R)
59 (R)
n.d.d
(
b) Sinou, D. Adv. Synth. Catal. 2002, 344, 221. (c) Eckl, R.
W.; Priermeier, T.; Herrmann, W. A. J. Organomet. Chem.
997, 532, 243.
(3) Wu, X.; Vinci, D.; Ikariya, T.; Xiao, J. Chem. Commun.
005, 4447.
(4) (a) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem.
1
1
00 (2nd cycle)
00 (3rd cycle)
1
2
8
3 (4th cycle)
2
2
006, 4, 393. (b) Gladiali, S.; Albericob, E. Chem. Soc. Rev.
006, 35, 226. (c) Morris, R. H. Chem. Soc. Rev. 2009, 38,
st
2
4-n-butylacetophenone
8 (1 cycle)
0 (2nd cycle)
3 (3rd cycle)
2282. (d) Samec, J. S. M.; Bäckvall, J. E.; Andersson, P. G.;
Brandt, P. Chem. Soc. Rev. 2006, 35, 237. (e) Wu, X.; Wang,
C.; Xiao, J. Platinum Metals Rev. 2010, 54, 3. (f) Dimroth,
J.; Keilitz, J.; Schedler, U.; Schomäcker, R.; Haag, R. Adv.
Synth. Catal. 2010, 352, 2497.
1
1
n.d.
n.d.
a
Reaction conditions: sodium formate (10 equiv), catalyst (1 mol%),
degassed H O (2 mL), r.t., 1.5 h.
2
(5) (a) Li, X.; Chen, W.; Hems, W.; King, F.; Xiao, J.
Tetrahedron Lett. 2004, 45, 951. (b) Li, X.; Wu, X.; Chen,
W.; Hancock, F. E.; King, F.; Xiao, J. Org. Lett. 2004, 6,
b
Determined by NMR.
c
The ee was determined by HPLC, using a Chiralpak OD column.
d
n.d. = not determined.
3
321.
(
6) (a) Kotre, T.; Zarka, M. T.; Krause, J. O.; Buchmeiser, M.
R.; Weberskirch, R.; Nuyken, O. Macromol. Symp. 2004,
Finally, we were interested to examine the effect of the
chirality of the polypeptide backbone on the stereoselec-
tivity of the ATH reaction. To test this, we synthesized
and attached the (1S,2S)-cyclohexane-1,2-diamine-based
ligand to block copolymer 2. The rhodium complex of the
2
17, 203. (b) Persigehl, P.; Jordan, R.; Nuyken, O.
Macromolecules 2000, 33, 6977. (c) Schonfelder, D.;
Fischer, K.; Schmidt, M.; Nuyken, O.; Weberskirch, R.
Macromolecules 2005, 38, 254. (d) Zarka, M. T.; Nuyken,
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Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2619–2622