J. Am. Chem. Soc. 2001, 123, 7725-7726
The Palladium-Catalyzed Oxidative Kinetic
Scheme 1
7725
Resolution of Secondary Alcohols with Molecular
Oxygen
Eric M. Ferreira and Brian M. Stoltz*
The Arnold and Mabel Beckman Laboratories of
Chemical Synthesis, DiVision of Chemistry and
Chemical Engineering, California Institute of Technology
Pasadena, California 91125
using a wide variety of co-oxidants, including allyl carbonates,
aryl halides, CCl , and molecular oxygen. We have investigated
4
a number of these general systems in the presence of chiral ligands
and studied the kinetic resolution of sec-alcohols. Although the
nonenzymatic kinetic resolution of sec-alcohols via acylation has
been extensively studied by the groups of Vedejs, Fu, Miller, and
ReceiVed March 9, 2001
ReVised Manuscript ReceiVed June 19, 2001
7
12
others, oxidative methods for alcohol resolution remain rare.
Furthermore, to our knowledge there are no reported examples
of palladium-catalyzed oxidative kinetic resolutions of sec-
alcohols.
The oxidation of secondary alcohols is one of the most common
and well-studied reactions in chemistry. Although excellent
1
catalytic enantioselective methods exist for a variety of oxidation
2
3
From exploratory studies that focused on chiral phosphine
ligands, it was rapidly established that modest levels of asym-
metric induction were attainable in the presence of organic
oxidants.13 Although initially promising, reactions carried out
under these conditions were plagued by a variety of side reactions
and inconsistencies.14 In an effort to minimize the complexity of
the reaction conditions, we turned our attention toward catalytic
systems that employ oxygen as the stoichiometric oxidant. Using
processes, such as epoxidation, dihydroxylation, and aziridina-
tion,4 it is surprising that there are relatively few catalytic
enantioselective examples of the ubiquitous alcohol oxidation.5
In connection with a general program dealing with the discovery
of new catalytic oxidation systems, we present herein the
development of a catalytic oxidative kinetic resolution of second-
ary alcohols that uses molecular oxygen as the terminal oxidant
see Scheme 1).6
-8
(
1-phenylethanol as a test case, we surveyed a number of variations
Among the many hundred known processes for alcohol
9
of the catalytic reaction and found that the conditions developed
by Uemura1 were particularly suited to the rapid screening of a
variety of chiral ligands. From the structurally diverse set of
ligands explored for the oxidation reaction (see Table 1), (-)-
sparteine quickly emerged as the most selective. Upon further
optimization, the nature of the palladium source was found to be
oxidation, comparatively few metal-catalyzed examples have
1f
10
been developed. One notable exception has been the use of
catalytic palladium(II) systems, which often provide efficient
oxidation of sec-alcohols to ketones in high yield.11 Interestingly,
palladium(II) oxidations have been successfully implemented
(
1) (a) ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
2 2
critical (see Table 2). Thus, substituting PdCl for Pd(OAc)
Pergamon: Oxford, England, 1991. (b) Luzzio, F. A. Org. React. 1998, 53,
1
3b
induced a marked increase in the selectivity factor (s). For
example, oxidative kinetic resolution of 1-phenylethanol using
1
. (c) Tidwell, T. T. Org. React. 1990, 39, 297. (d) Hudlicky, M. Oxidations
in Organic Chemistry; ACS Monograph Series; American Chemical Society:
Washington, DC, 1990.
Pd(OAc)
analogous resolution using PdCl
2
proceeded with a selectivity factor of 8.8, whereas the
was found to have a selectivity
(2) (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; Wiley & Sons: New York, 2000; pp 231-280. (b) Katsuki,
T. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley & Sons: New
York, 2000; pp 287-325.
2
factor of 16.3, thereby providing acetophenone in 62.6% conver-
sion and unreacted alcohol of 98.0% ee. Further evaluation of
(
3) Bolm, C.; Hildebrand, J. P.; Muniz, K. In Catalytic Asymmetric
the palladium source revealed that Pd(nbd)Cl
2
provided the most
Synthesis; Ojima, I., Ed.; Wiley & Sons: New York, 2000; pp 399-428.
4) M u¨ ller, P. In AdVances in Catalytic Processes; JAI Press Inc.:
Greenwich, CT, 1997; Vol. 2, pp 113-151.
5) (a) Ohkubo, K.; Hirata, K.; Yoshinaga, K.; Okada, M. Chem. Lett. 1976,
83. (b) Berti, C.; Perkins, M. J. Angew. Chem., Int. Ed. Engl. 1979, 18, 864.
(
selective catalytic system tested to date (Table 2, entry 7, s )
15,16
23.1).
(
1
(11) For leading references, see: (a) Blackburn, T. F.; Schwartz, J. J. Chem.
(
c) Ishii, Y.; Suzuki, K.; Ikariya, T.; Saburi, M.; Yoshikawa, S. J. Org. Chem.
986, 51, 2822. (d) Ma, Z.; Huang, Q.; Bobbitt, J. M. J. Org. Chem. 1993,
8, 4837. (e) Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, H. J. Org.
Soc., Chem. Commun. 1977, 157. (b) Tamaru, Y.; Yamamoto, Y.; Yamada,
Y.; Yoshida, Z. Tetrahedron Lett. 1979, 20, 1401. (c) Nagashima, H.; Tsuji,
J. Chem. Lett. 1981, 1171. (d) A ¨ı t-Mohand, S.; H e´ nin, F.; Muzart, J.
Tetrahedron Lett. 1995, 36, 2473. (e) Peterson, K. P.; Larock, R. C. J. Org.
Chem. 1998, 63, 3185. (f) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J.
Org. Chem. 1999, 64, 6750. (g) ten Brink, G.-J.; Arends, I. W. C. E.; Sheldon,
R. A. Science, 2000, 287, 1636.
1
5
Chem. 1996, 61, 1194. (f) Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura,
K.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 288. (g)
Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M. Organometallics 1999,
1
8, 2291. (h) Kashiwagi, Y.; Kurashima, F.; Kikuchi, C.; Anzai, J.; Osa, T.;
Bobbitt, J. M. Tetrahedron Lett. 1999, 40, 6469. (i) Masutani, K.; Uchida,
T.; Irie, R.; Katsuki, T. Tetrahedron Lett. 2000, 41, 5119. (j) Kuroboshi, M.;
Yoshihisa, H.; Cortona, M. N.; Kawakami, Y.; Gao, Z.; Tanaka, H.
Tetrahedron Lett. 2000, 41, 8131.
(12) Three noteworthy examples include the ruthenium system of Noyori
(ref 5f), Rychnovsky’s nitroxyl radical system (ref 5e), and the use of baker’s
yeast, see: Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.; Poli, S.;
Sinigaglia, M. Tetrahedron Lett. 1993, 34, 883.
(6) For excellent discussions on kinetic resolution, see: (a) Martin, V. S.;
(13) (a) For example, racemic 1-cyclohexylethanol could be resolved to
65.5% ee at 58.0% conversion (selectivity ) s ) 5.3) by exposure to (-)-
Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am.
Chem. Soc. 1981, 103, 6237. (b) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.;
Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294. (c) Kagan, H. B.; Fiaud, J. C.
In Topics in Stereochemistry; Eliel, E. L., Ed.; Wiley & Sons: New York,
2 2 2
Me-DUPHOS, Pd(OAc) , NaOt-Bu, and iodobenzene in CH Cl at 30 °C. (b)
The selectivity factor (s) was determined using the equation: s ) krel(fast/slow)
6
c
) ln[(1 - C)(1 - ee)]/ln[(1 - C)(1 + ee)], where C ) conversion. Kagan
has defined s as the chemical stereoselectivity factor, while the biochemical
stereoselectivity factor (solved by an equivalent equation) is defined as E.
Additionally, this distinction in terminology was recently adopted by Eliel
and Wilen, see; Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley & Sons: New York, 1994; pp 395-415. For a full account
of the nomenclature used in this communication, see ref 6c.
1
988; Vol. 18, pp 249-330.
(
7) For leading references describing outstanding nonenzymatic catalytic
acylation approaches to the kinetic resolution of sec-alcohols, see: (a) Ruble,
J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492. (b) Miller,
S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J.
Am. Chem. Soc. 1998, 120, 1629. (c) Vedejs, E.; Daugulis, O. J. Am. Chem.
Soc. 1999, 121, 5813.
(14) (a) In particular, control experiments indicated that treatment of a
mixture of either acetophenone and 1-cyclohexylethanol or 1-phenylethanol
and 1-cyclohexylethanone with NaOt-Bu in CH Cl resulted in a Meerwein-
2 2
(8) For a recent monograph describing enzymatic approaches to kinetic
resolution, see: Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic Organic
Chemistry; Pergamon: Oxford, U.K., 1994.
Ponndorf-Verley reduction/Oppenauer oxidation cycle to yield a mixture of
all four compounds in each case. For a review, see: Djerassi, C. Org. React.
1951, 6, 207. (b) Adding to the complexity of these conditions was an observed
oxygen dependence; thus, experiments performed with rigorous exclusion of
oxygen were found to result in low catalyst turnover and hence almost no
conversion to the ketone.
(
9) Larock, R. C. ComprehensiVe Organic Transformations; Wiley &
Sons: New York, 1999; pp 1234-1248.
(
10) For example, of the 297 examples listed in ref 9, only 67 are metal-
catalyzed. Some notable examples include the use of catalytic Ru, Co, Cr,
W, Mo, Fe, Os, Ir, Yb, Zr, V, Ce, and Pd.
1
0.1021/ja015791z CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/12/2001