Asymmetric Synthesis

Asymmetric Epoxidation of Allylic Alcohols

The catalytic asymmetric epoxidation of olefins has become the reaction of choice to generate diverse chiral building blocks used in the synthesis of natural products and biologically active molecules. The development of catalysts based on bis(hydroxamic acid) ligands for the vanadium-catalyzed asymmetric epoxidation of allylic alcohols was based on a desire to reduce the deceleration effect observed in some cases in related epoxidations with hydroxamic acid ligands. The deceleration observed was predicted to be a result of the formation of inactive species, which were formed from the binding of more than one ligand to the metal. It was predicted that since the bidentate ligand (bis(hydroxamic acid)) would be chelating to the metal, this deceleration effect could be resolved. Additionally, it was hypothesized that a larger R group would prevent the carbonyl oxygen coordination to the metal by favoring a conformation in which the carbonyl group was directed towards the cyclohexane (Figure 1). Thus, an ideal catalyst system was designed via control of the coordination number as well as the steric environment.

Figure 1.

The use of bis(hydroxamic acid) based ligands in combination with VO(O-iPr)3 proved effective in the efficient asymmetric epoxidation of various allylic alcohols (Scheme 1). Using only 1 mol% of the catalyst, Yamamoto and co-workers demonstrated a variety of allylic alcohols could be converted to the enantiopure epoxides with excellent enantioselectivity.

Scheme 1.

This methodology was also applied in the kinetic resolution of allylic alcohol 1, which resulted in high enantioselectivities of the epoxy alcohol as well as the allylic alcohol (Scheme 2).1

Scheme 2.

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Asymmetric Epoxidation of Homoallylic Alcohols

While there are various efficient catalytic systems for the asymmetric epoxidation of allylic alcohols, the extension to homoallylic alcohols had not been demonstrated. While the catalytic system reported above allowed for the desired transformations, the enantioselectivities achieved were a major limitation. After tuning the ligand, Zhang and Yamamoto discovered that the (2,4,6-triethyl)-substituted biphenyl bis(hydroxamic acid) ligand (2) provided the desired epoxide products in excellent yields and enantioselectivities (Scheme 3). In addition, the kinetic resolution of substrate 3 was facilitated by the same catalyst system to afford excellent enantioselectivities of both the chiral homoallylic alcohol as well as the epoxidation product (Scheme 4).2

Scheme 3.

Scheme 4.

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Asymmetric Transfer Hydrogenation

The use of transfer hydrogenation to reduce alkenes, carboxyl groups, ketones, or imines has become very popular. Hashiguchi et al. reported the asymmetric transfer hydrogenation of ketones using a catalyst system comprised of ruthenium complexed with a chiral diamine ligand (RuCl(p-cymene)[(S,S)-Ts-DPEN], Scheme 5).3 Subsequently, this methodology was extended to include transfer hydrogenation of imines with low catalyst loadings, good yields, and excellent enantioselectivities of the desired products observed (Schemes 6 and 7). A variety of imines were subjected to these reaction conditions, with slight variations in the catalyst-ligand composition and/or solvent, leading to excellent yields and enantioselectivities of the functionalized amine heterocycles.4

Scheme 5.

Scheme 6.

Scheme 7.

Matsumura and co-workers also accomplished the asymmetric transfer hydrogenation of α,β-acetylenic ketones using the RuCl(p-cymene) [(R,R)-Ts-DPEN] catalyst system. As shown in Scheme 8, the reduction to the propargylic alcohols occurs selectively without any competitive reaction with the alkynes.5

Scheme 8.

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Asymmetric Ketone Hydrogenation

Mikami and co-workers reported an asymmetric ketone hydrogenation that utilizes an achiral benzophenone ligand (2,2’-bis(diphenylphosphino)benzophenone, DPBP) chelated to a ruthenium catalyst, followed by addition of (1S,2S)-(-)1,2- diphenylethylenediamine (S,S-DPEN). The levels of enantioselectivity observed with the benzophenone-based catalyst are superior to those observed with BINAP-based catalytic systems. When the hydrogenation of 1’-acetonaphthone was examined with 2,2’-bis(diphenylphosphino) benzhydrol as the ligand in place of benzophenone, the enantioselectivity observed was lower than that observed with 2,2’-bis(diphenylphosphino)benzophenone) (Table 1).6

Table 1.

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  1. Zhang, W. et al. Angew. Chem., Int. Ed. 2005, 44, 4389.
  2. Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286.
  3. Hashiguchi, S. et al. J. Am. Chem. Soc. 1995, 117, 7562.
  4. Uematsu, N. et al. J. Am. Chem. Soc. 1996, 118, 4916.
  5. Matsumura, K. et al. J. Am. Chem. Soc. 1997, 119, 8738.
  6. Mikami, K. et al. Org. Lett. 2006, 8, 1517.

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