.
Angewandte
Communications
Experimental Section
General procedure for asymmetric hydrogenation of d-aryl d-
ketoester (S/C = 1000): The ketoester substrate 8 (1.0 mmol), a solu-
tion of iridium catalyst (R)-7 in EtOH (0.002 mmolmLÀ1, 0.5 mL,
0.001 mmol), a solution of tBuOK in EtOH (0.08 mmolmLÀ1, 0.5 mL,
0.04 mmol), and 1.0 mL of anhydrous EtOH were added to a 20 mL
hydrogenation vessel in an autoclave. The autoclave was purged with
hydrogen by pressurizing to 5 atm and releasing the pressure. This
procedure was repeated three times and then pressurized to 10 atm of
H2. The reaction mixture was stirred at room temperature (25–308C)
until no obvious hydrogen pressure drop was observed. The solvent
was removed in vacuo and the residue was purified by flash column
chromatography on silica gel with petroleum ether/ethyl acetate (1:2)
as the eluent to afford the chiral diol 9 and the enantioselectivity was
determined by HPLC using a chiral column.
Received: April 11, 2013
Published online: && &&, &&&&
Keywords: asymmetric catalysis · catalyst design ·
.
hydrogenation · iridium · synthetic methods
Scheme 3. Enantioselective synthesis of the optically active 2,2-disub-
stituted piperidine (S,R)-12. Ms=methanesulfonyl.
[1] a) S. N. Ege, Organic Chemistry, D. C. Heath, and Co., Lex-
ington, 1989, p. 596; b) J. seyden-Penne, Reductions by the
Allumino- and Borohydride in Organic Synthesis, 2nd ed., Wiley-
VCH, New York, 1997.
[2] For recent reviews, see: a) M. L. Clarke, G. J. Roff in The
Handbook of Homogeneous Hydrogenation, (Eds.: J. G. de V-
ries, C. J. Elsevier), Wiley, New York, 2007, p. 413; b) M. Ito, T.
92; g) J. Zhang, E. Balaraman, G. Leitus, D. Milstein, Organo-
Matsumoto, O. Ogata, Y. Ino, K. Aoki, S. Tanaka, K. Ishida, T.
k) D. Spasyuk, S. Smith, D. G. Gusev, Angew. Chem. 2012, 124,
Ed. 2012, 51, 2772; l) D. Spasyuk, S. Smith, D. G. Gusev, Angew.
Angew. Chem. Int. Ed. 2013, 52, 2538.
[5] a) J.-H. Xie, X.-Y. Liu, J.-B. Xie, L.-X. Wang, Q.-L. Zhou,
7329; b) J.-H. Xie, X.-Y. Liu, X.-H. Yang, J.-B. Xie, L.-X. Wang,
70, 1427.
disubstituted piperidine (S,R)-12, a lead compound in the
search for orally active NK1 receptor antagonists
(Scheme 3).[8] The chiral N-protected 2-phenylpiperidine
(S)-13 or (S)-14 is a key intermediate for the preparation of
12.[9] With (S)-7 as a catalyst at S/C = 100000, we obtained
(R)-9a in gram-scale quantities in 96% yield with 99.9% ee
by asymmetric hydrogenation of 8a. The (R)-9a was activated
with methanesulfonyl chloride (MsCl) in the presence of
triethylamine (Et3N) in dichloromethane (CH2Cl2) at À208C,
and treated with benzyl amine[10] to produce the N-benzyl-
protected piperidine (S)-13 in 83% yield. The piperidine (S)-
13 was hydrogenated over Pd(OH)2/C under 10 atmospheres
of H2 in the presence of di-tert-butyldicarbonate [(Boc)2O]
and Et3N to afford the N-Boc-protected piperidine (S)-14 in
97% yield with 96% ee (88% yield, 99.9% ee after recrystal-
lization). The piperidine (S)-14 was treated with nBuLi and
tetramethylethylenediamine (TMEDA) in THF at À788C for
1 hour, and the resulting anion was captured with (R)-16[11] to
give (S,R)-15 in 51% yield with 98% de by means of
a literature procedure.[12] Finally, reaction of (S,R)-15 with
ZnBr2 in CH2Cl2 at room temperature for 7 hours yielded the
desired product (S,R)-12 in 98% yield. It is worth mentioning
that (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethanol, the start-
ing material for the chiral intermediate (R)-16, was also
prepared on a large-scale by asymmetric hydrogenation of 1-
(3,5-bis(trifluoromethyl)phenyl)ethanone catalyzed by (S)-
7
[4a] (see the Supporting Information).
In conclusion, we developed a highly efficient iridium-
[6] Optically active 1-arylpentane-1,5-diols (9) are important chiral
building blocks in organic synthesis and the preparation of these
compounds is a challenge: a) A. Kamal, M. Sandbhor, A. A.
catalyzed asymmetric hydrogenation of d-aryl d-ketoesters.
With catalyst Ir-SpiroPAP [(R)-7], we prepared a series of
chiral 1,5-diols in high yields and excellent enantioselectiv-
ities. The key feature of this methodology is that the ester
group of the substrates can be hydrogenated effectively under
mild reaction conditions.
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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