Asymmetric Nucleophilic Epoxidation

Asymmetric epoxidation of a prochiral alkene is an appealing process because two stereogenic centers are established in the course of the reaction. Often, the starting alkene is inexpensive. There have been several interesting recent advances in the asymmetric nucleophilic epoxidation. 

Keiji Maruoka of Kyoyo University reports (J. Am. Chem. Soc. 2004,126,6844) the development of enantiomerically-pure quaternary ammonium salts (2) that catalyze the epoxidation of enones. The epoxidation of the r-butyl ketone 1 is particularly interesting, as Baeyer-Villiger oxidation would be expected to convert 3 into the ester 4. 

Masakatsu Shibasaki of the University of Tokyo reports (/ Am. Chem. Soc. 2004,126,7559) that use of a BINOL-derived catalyst with cumyl hydroperoxide enables the enantioselective epoxidation of unsaturated N-acyl pyrroles such as 7. The pyrroles 7, prepared from the precursor aldehydes such as 5 with the reagent 6, can be used directly, without further purification. 

The product epoxy pyrroles such as 8 can be efficiently converted to the alcohol 9, the homologated ester 10. and the homologated ketone 11. 

The Julih-Colonna epoxidation uses poly-I.-leucine and hydrogen peroxide to effect enantioselective epoxidation of chalcone derivatives such as 12. In a pair of back-to-back papers Tetrahedron Lett. 2004,45,5065 and 50691, H.-Christian Mililzer of Bayer Healthcare AG, Wuppertal, reports a detailed optimization of thi.s procedure. In the following paper (Tetrahedron Lett. 2004.45, 5073), Stanley Robert.s of the University of Liverpool reports the extension of this procedure to imsaturated sulfones such as 14. 

---

Porco s synthesis of ( )-kinamycin C (3) constituted the first reported route to any of the diazofluorene antitumor antibiotics. This synthesis invokes several powerful transformations, including a modified Baylis-Hillman reaction, a catalyst-controlled asymmetric nucleophilic epoxidation, and a regioselective epoxide opening to establish the D-ring of the kinamycins. The tetracyclic skeleton was constructed by an... 

The synthesis of the spiroisoxazoline natural product (+ )-calafianin 447 has been reported, using asymmetric nucleophilic epoxidation and nitrile oxide cycloaddition as key steps. Syntheses and spectral analyses of all calafianin stereoisomers lead to unambiguous assignments of relative and absolute stereochemistry (494). 

More recently, Tu, Cao, and coworkers revealed that 9-deoxy-9-epi-aminoquinine 33 can catalyze both the asymmetric nucleophilic epoxidation of P-(l-hydroxycyclobutyl)enones and the subsequent semipinacol rearrangement of the resulting epoxide, to afford hydroxy-spirocycloalkane-diones with moderate to good yields and outstanding stereoselectivities (Scheme 40.52) [59]. 

More recently, Tu, Cao, and coworkers revealed that 9-deoxy-9-ept-aminoquinine 33 can catalyze both the asymmetric nucleophilic epoxidation of i-(l-... 

Chiral PTC has been used effectively for making intermediates for drugs. Dolling and coworkers have used 8-R, 9-5, N-(p-trifluoromethylbenzyl) cinchonium bromide to carry out an important asymmetric alkylation, giving 95% ee (Starks, 1987). Nucleophilic epoxidations of enones, Darzens reaction, Michael additions, etc. are some examples of reactions rendered asymmetric through chiral PTCs (Nelson, 1999). 

Asymmetric epoxidation of olefins is an effective approach for the synthesis of enan-tiomerically enriched epoxides. A variety of efficient methods have been developed [1, 2], including Sharpless epoxidation of allylic alcohols [3, 4], metal-catalyzed epoxidation of unfunctionalized olefins [5-10], and nucleophilic epoxidation of electron-deficient olefins [11-14], Dioxiranes and oxazirdinium salts have been proven to be effective oxidation reagents [15-21], Chiral dioxiranes [22-28] and oxaziridinium salts [19] generated in situ with Oxone from ketones and iminium salts, respectively, have been extensively investigated in numerous laboratories and have been shown to be useful toward the asymmetric epoxidation of alkenes. In these epoxidation reactions, only a catalytic amount of ketone or iminium salt is required since they are regenerated upon epoxidation of alkenes (Scheme 1). 

Thiols may be enantioselectiveiy added in a conjugate fashion to a,p-unsaturated carbonyl compounds in the presence of chiral hydroxyamine catalysts e.g. chinchona alkaloids).242,244 249 252-261-269 In some cases ee of up to >80% were achieved e.g. Scheme 77).242-261-262 This methodology was utilized for the kinetic resolution of compound rat-86 Scheme 34) in a multigram scale.94 Related enantioselective 1,4-additions of thioacetates270-271 and selenophenols272 to enones are also known. Epoxidations, based on the asymmetric nucleophilic addition of peroxide anions to enones, are discussed separately.273... 

A polymeric binaphthyl zinc complex has been used for related epoxidation reactions <1999JOC8149>.A bimetallic samarium-based Lewis acid complex catalyzes the nucleophilic epoxidation of unsaturated carbonyl compounds very efficiently <2002JA14544>. The use of amino acids has organocatalysts for asymmetric epoxidations of enones and enals has been investigated <2005OL2579, 2005JA6964>. 

Hansen, K. B., Leighton, J. L., Jacobsen, E. N. On the Mechanism of Asymmetric Nucleophilic Ring-Opening of Epoxides Catalyzed by (Salen)Crlll Complexes. J. Am. Chem. Soc. 1996,118,10924-10925. 

Reactions of chiral allylic boranes with carbonyl compounds Reactions of chiral allyl boranes with imines Asymmetric Addition of Carbon Nucleophiles to Ketones Addition of alkyl lithiums to ketones Asymmetric epoxidation with chiral sulfur ylids Asymmetric Nucleophilic Attack by Chiral Alcohols Deracemisation of arylpropionic acids Deracemisation of a-halo acids Asymmetric Conjugate Addition of Nitrogen Nucleophiles An asymmetric synthesis of thienamycin Asymmetric Protonation... 

Some of the most pertinent virtues of asymmetric epoxidations and dihydroxylations were already present in their classical versions. Both reactions are highly chemo-selective and can be carried out in the presence of many other functional groups. More important with respect to stereochemistry, each reaction is stereospecific in that the product faithfully reflects the E or Z configuration of the starting olefin (the nucleophilic epoxidation of a,P-unsaturated carbonyl compounds is an important exception). And one should not underestimate the importance of experimental simplicity in most cases, one can carry out these reactions by simply adding the often commercially available reagents to a substrate in solvent, without extravagant precautions to avoid moisture or air. 

Hansen KB, Leighton JL, Jacobsen EN (1996) On the mechanism of asymmetric nucleophilic ring-opening of epoxides catalyzed by (salen)Crlll complexes. J Am Chem Soc 118 10924-10925... 

Sun BE, Hong R, Kang YB, Deng L (2009) Asymmetric Total Synthesis of (-)-Plicatic Acid via a Highly Enantioselective and Diastereoselective Nucleophilic Epoxidation of Acyclic Trisubstitued Olefins. J Am Chem Soc 131 10384... 

The asymmetric epoxidation of alkenes constitutes a powerful approach to enantiomerically enriched epoxides, a class of highly versatile intermediates in organic synthesis [1]. Various effective epoxidation systems have been developed, including epoxidation of allylic [2, 3] and homoallylic [4] alcohols, metalunfunctionalized alkenes [5-7], and the nucleophilic epoxidation of electron-deficient alkenes [8]. During the past 10-15 years, much effort has been devoted to chiral ketone-catalyzed asymmetric epoxidation (Scheme 3.1). The subject has been described in great detail in the first edition [9] and other reviews [10]. This chapter provides an update on progress in this area since the first edition [9]. 

The mechanism of the a,a-L-diarylprolinol-catalysed asymmetric epoxidation of enones with TBHP has been studied by second-order Moller-Plesset perturbation theory and DFT calculations. Non-covalent activation of the reactants is shown to initiate an energetically viable pathway, thereby a two-step nucleophilic epoxidation mechanism, with the first oxa-Michael addition being the rate- and stereoselectivity-determining step. Consistent with the experimental findings, the formation of the (2/ ,35)-enantiomer of the epoxide, derived from trani -chalcone, is energetically favoured." ... 

Epoxides are very versatile intermediates, and asymmetric epoxidation of olefins is an effective approach to the synthesis of enantiomericaUy enriched epoxides [1-3]. Great success has been achieved for the epoxidation of allyhc alcohols [1], the metal-catalyzed epoxidation of unfunctionalized olefins (particularly conjugated cis- and tri-substituted) [2], and the nucleophilic epoxidation of electron-deficient olefins [3]. In recent years, chiral dioxiranes have been shown to be powerful agents for asymmetric epoxidation of olefins. Dioxiranes can be isolated or generated in situ from Oxone (potassium peroxymonosulfate) and ketones (Scheme 3.1) [4,5]. When the di-oxirane is used in situ, the corresponding ketone is regenerated upon epoxidation. Therefore, in principle, a catalytic amount of ketone can be used. When a chiral ketone is used, asymmetric epoxidation should also be possible [6]. Extensive studies have been carried out in this area since the first chiral ketone was reported by Curd in 1984 [7]. This chapter describes some of the recent progress in this area. 

---