Diastereoselective epoxidation of allylic alcohols

The titanium compounds CpTiCl3, Cp2TiCl2, and CH2(C5H4)2TiCl2 have been used as catalysts for the diastereoselective epoxidation of allylic alcohols.1932 [TiCp2(LL)]2+ (LL = 1,10-phenantroline, 2,2 -bipyridine) (Scheme 758) have been studied in order to determine the importance of the ancillary chelated ligands versus the metal center for the membrane-permeabilizing action and their effects on lipid epoxidation reactions.1933... 

G. Della Saia, L. Giordano, A. Lattanzi, A. Proto, A. Scettri, Metallocene-catalyzed diastereoselective epoxidation of allylic alcohols. Tetrahedron 56 (2000) 3567. 

The remarkable stereospecificity of TBHP-transition metal epoxidations of allylic alcohols has been exploited by Sharpless group for the synthesis of chiral oxiranes from prochiral allylic alcohols (Scheme 76) (81JA464) and for diastereoselective oxirane synthesis from chiral allylic alcohols (Scheme 77) (81JA6237). It has been suggested that this latter reaction may enable the preparation of chiral compounds of complete enantiomeric purity cf. Scheme 78) ... 

The past thirty years have witnessed great advances in the selective synthesis of epoxides, and numerous regio-, chemo-, enantio-, and diastereoselective methods have been developed. Discovered in 1980, the Katsuki-Sharpless catalytic asymmetric epoxidation of allylic alcohols, in which a catalyst for the first time demonstrated both high selectivity and substrate promiscuity, was the first practical entry into the world of chiral 2,3-epoxy alcohols [10, 11]. Asymmetric catalysis of the epoxidation of unfunctionalized olefins through the use of Jacobsen s chiral [(sale-i i) Mi iln] [12] or Shi s chiral ketones [13] as oxidants is also well established. Catalytic asymmetric epoxidations have been comprehensively reviewed [14, 15]. 

However, styrene and cyclohexene gave complex product mixtures, and 1-octene did not react under the same reaction conditions. Thus, the activity of this catalyst is intrinsically low. Jacobs and co-workers [159,160] applied Veturello s catalyst [PO WCKOj ]3- (tethered on a commercial nitrate-form resin with alkylammonium cations) to the epoxidation of allylic alcohols and terpenes. The regio- and diastereoselectivity of the parent homogeneous catalysts were preserved in the supported catalyst. For bulky alkenes, the reactivity of the POM catalyst was superior to that of Ti-based catalysts with large pore sizes such as Ti-p and Ti-MCM-48. The catalytic activity of the recycled catalyst was completely maintained after several cycles and the filtrate was catalytically inactive, indicating that the observed catalysis is truly heterogeneous in nature. 

The diastereoselectivity of the dimethyldioxirane-mediated epoxidation of allylic alcohols resembles that of the peracid epoxidation4. 

The classical method for the synthesis of epoxy alcohols is the epoxidation of allylic alcohols, the latter accessible by reduction of allylic hydroperoxides or other more traditional methods. One of the most valuable reactions for preparative purposes is the Sharpless method82 83, in which, for chiral allylic alcohols, the epoxy alcohols are produced diastereoselectively and, in the presence of chiral ligands, also in high enantioselectivity (see Section D.4.5.1.). 

Epoxidation of allylic alcohols with peracids or hydroperoxide such as f-BuOaH in the presence of a transition metal catalyst is a useful procedure for the synthesis of epoxides, particularly stereoselective synthesis [587-590]. As the transition metal catalyst, molybdenum and vanadium complexes are well studied and, accordingly, are the most popular [587-590], (Achiral) titanium compounds are also known to effect this transformation, and result in stereoselectivity different from that of the aforementioned Mo- and V-derived catalysts. The stereochemistry of epoxidation by these methods has been compared for representative examples, including simple [591] and more complex trcMs-disubstituted, rrans-trisubstituted, and cis-trisubstituted allyl alcohols (Eqs (253) [592], (254) [592-594], and (255) [593]). In particular the epoxidation of trisubstituted allyl alcohols shown in Eqs (254) and (255) highlights the complementary use of the titanium-based method and other methods. More results from titanium-catalyzed diastereoselective epoxidation are summarized in Table 25. 

Enolisable aldehydes such as 101 or 103 do not give quite such good yields but the ees are still good and the diastereoselectivity in favour of the trans epoxides 102 and 104 is excellent. The secret of this method is the simple preparation of the reagent 96. In the next chapters you will see that superior catalytic methods are available for asymmetric epoxidation of allylic alcohols and of m-alkenes but they are less good for the trans disubstituted alkenes that would give 97, 102, or 104. You will also see catalytic versions of sulfur ylid epoxidation. 

The previous section described metal catalyzed epoxidation of allylic alcohols by alkyl hydroperoxides, and 193 was proposed as a model to predict the diastereoselectivity of these reactions,. In the cases presented, the reaction was diastereoselective but not enantioselective (sec. 1.4.F) and those epoxidation reactions generated racemic epoxides. To achieve asymmetric induction one must control both the relative orientation of the alkene relative to the peroxide and also the face of the substrate from which the electrophilic oxygen is delivered. Control of this type can be accomplished by providing a chiral ligand that will also coordinate to the metal catalyst, along with the peroxide and the alkene unit. There are two major asymmetric epoxidation reactions, one that can be applied only to allylic alcohols and is the prototype for asymmetric induction in these systems. The other is a procedure that can be applied to simple alkenes. Both procedures use a metal-catalyzed epoxidation that employs alkyl hydroperoxides, introduced in section 3.4.B.ii. 

The diastereoselectivity of the epoxidation of allylic alcohols substituted by polypropionate units is highly dependant upon the nature of the protecting group and on the stereochemistry of the stereogenic centers (eqs 37 and 38). ... 

The Sharpless epoxidation of allylic alcohols by hydroperoxides uses as mediator [45] or as catalyst [46] a chiral titanium complex obtained from the combination Ti(OPr )4/diethyl tartrate (DET) in 1 1 ratio. Kinetic resolution of P-hydroxysulfides was also observed, but without diastereoselectivity for the product P-hydroxysulfoxides [47]. We found that the Sharpless reagent deactivated by 1 equivalent of water allows the enantioselective oxidation of aryl methyl sulfides into sulfoxides to be performed with ee s up to 90% [4S-50]. The best reagent combination proved to be Ti(0Pr )4/DET/H20 = 1 2 1. Independently, Modena et al. obtained similar enantioselectivities with the combination Ti(OPr )4/DET in 1 4 ratio [51]. These two combinations are sometimes referred to as the Kagan reagent and the Modena reagent, respectively. They will be considered successively. 

Sulfonic peracids (66) have also been applied recently to the preparation of acid sensitive oxiranes and for the epoxidation of allylic and homoallylic alcohols, as well as relatively unreactive a, p - unsaturated ketones. These reagents, prepared in situ from the corresponding sulfonyl imidazolides 65, promote the same sense of diastereoselectivity as the conventional peracids, but often to a higher degree. In particular, the epoxidation of certain A -3-ketosteroids (e.g., 67) with sulfonic peracids 66 resulted in the formation of oxirane products (e.g., 68) in remarkably high diastereomeric excess. This increased selectivity is most likely the result of the considerable steric requirements about the sulfur atom, which enhances non-bonded interactions believed to be operative in the diastereoselection mechanism <96TET2957>. 

Scheme 8 summarizes the introduction of the missing carbon atoms and the diastereoselective epoxidation of the C /C double bond using a Sharpless asymmetric epoxidation (SAE) of the allylic alcohol 64. The primary alcohol 62 was converted into the aldehyde 63 which served as the starting material for a Horner-Wadsworth-Emmons (HWE) reaction to afford an E-configured tri-substituted double bond. The next steps introduced the sulfone moiety via a Mukaiyama redox condensation and a subsequent sulfide to sulfone oxidation. The sequence toward the allylic alcohol 64 was com-... 

SCHEME 6. Hydroxy-group directivity in the lAreo-diastereoselective epoxidation of chiral allylic alcohols by DMD... 

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