Titanium mediated epoxidation

The original titanium-mediated epoxidation is a stoichiometric reaction.27 However, the epoxidation can be carried out with a catalytic amount (5-10 mol.%) of titanium-tartrate complex in the presence of molecular sieves.29 The advantages of the catalytic procedure are ease of product isolation, increased yield, economy, and a high substrate concentration. 

The proposed dinuclear transition-state model (1) has been supported by the observation of nonlinear relationship between enantiomeric excess (ee) of the epoxide and ee of DAT.33 The use of simple diol instead of tartrate vitiates stereoselectivity of the reaction.34,35 The ester group of DAT is indispensable for the construction of the desired catalyst. It is noteworthy that 1,2-di(o-methoxy-phenyl)ethylenediol is an efficient chiral auxiliary for titanium-mediated epoxidation, while 1,2-diphenylethylenediol is a poor one.36... 

Keywords Epoxidation, Epoxy alcohol, Allylic alcohol. Titanium-mediated epoxidation. Titanium tartrate complex. Kinetic resolution. Ligand acceleration... 

Table 1. List of functional groups tolerable to the titanium-mediated epoxidation ...

Following the success with the titanium-mediated asymmetric epoxidation reactions of allylic alcohols, work was intensified to seek a similar general method that does not rely on allylic alcohols for substrate recognition. A particularly interesting challenge was the development of catalysts for enantioselective oxidation of unfunctionalized olefins. These alkenes cannot form conformationally restricted chelate complexes, and consequently the differentiation of the enan-tiotropic sides of the substrate is considerably more difficult. 

Studies of bis-tartrate esters and other tartrate ligands for titanium-mediated asymmetric epoxidation have provided evidence against the sole intermediacy of monomeric titanium-tartrate species in the parent system329,330. Other tartrate ligands have been studied in attempts to gain a better understanding of the mechanism of the Sharpless epoxidation330. 

Cyclic voltammetry, kinetic studies, and DFT calculations using a BP functional and the TZVP basis set showed that the major pathway of the non-regiospeciflc zinc-reduced titanocene-mediated ring opening of epoxides was initiated by a titanium dimer-epoxide compound that reacted in a rate-determining electron transfer mechanism 25 The calculations showed that the transition state is early so the stereoselectivity is determined by steric effects rather than by the stability of intermediate radicals. This was confirmed by studies with more sterically crowded catalysts. 

The first enantioselective total synthesis of (- -)-l 1,12-epoxycembrene C (28) has been accomplished via a macro-olefination strategy by employing titanium-mediated McMurry coupling as a key step and the Sharpless asymmetric epoxidation for the introduction of chiral epoxide. Based on the enantioselective Sharpless asymmetric epoxidation, Li et al. assumed the configuration of natural 28 to be (115,125) (Scheme 6-21). ... 

Starting from the chiral pool (/f-(+)-hmonene), the total synthesis of natural (-f)-3,4-epoxycembrene A (56) has been achieved by Liu et al. with the low-valent titanium-mediated intramolecular pinacol couphng of the corresponding sec-keto aldehyde precursor 171 (Scheme 6-25). A more general and efficient enantioselective synthesis of (+)-3,4-epoxy-cembrene A (56) with a chiral pool protocol and Sharpless asymmetric epoxidation for the introduction of three chiral centers has also been reported by the same authors in 2001 (Scheme 6-26). ... 

In an investigation related to the total synthesis of (-i-)-3a-hydroxyreynosin, Cuerva and Oltra discovered that the products of a Ti(III)-mediated epoxide-opening/cycUzation cascade varied with the presence or absence of water. In dry THF they obtained the product originally desired, with an exocyclic A [3,14] double bond, but the addition of water resulted in the formation of the reductively cychzed product in Scheme 1.4. Apparently H is transferred from the titanium-water complex to the cyclized radical [35-37]. 

Hatakeiyama et have also reported a highly s yn-diastereoselective epoxidation of MBH adducts using both Weitz-Scheffer and titanium-mediated oxidation procedures. As shown in Scheme 4.60, Ti(OPr )4-mediated epoxidation of 200 was found to proceed with complete diastereoselectivity to furnish the 5y -epoxy alcohol 201 in 73% yield. 

Catalytic turn-over [59,60] in McMurry couplings [61], Nozaki-Hiyama reactions [62,63], and pinacol couplings [64,65] has been reported by Fiirst-ner and by Hirao by in situ silylation of titanium, chromium and vanadium oxo species with McaSiCl. In the epoxide-opening reactions, protonation can be employed for mediating catalytic turn-over instead of silylation because the intermediate radicals are stable toward protic conditions. The amount of Cp2TiCl needed for achieving isolated yields similar to the stoichiometric process can be reduced to 1-10 mol% by using 2,4,6-collidine hydrochloride or 2,6-lutidine hydrochloride as the acid and Zn or Mn dust as the reduc-tant (Scheme 9) [66,67]. 

The scope of metal-mediated asymmetric epoxidation of allylic alcohols was remarkably enhanced by a new titanium system introduced by Katsuki and Sharpless epoxidation of allylic alcohols using a titanium(IV) isopropoxide, dialkyl tartrate (DAT), and TBHP (TBHP = tert-butyl-hydroperoxide) proceeds with high enantioselectivity and good chemical yield, regardless of... 

A silastannation product bearing an epoxide moiety undergoes titanium(m)-mediated cyclization with the vinyl-stannane moiety (Equation (109)).268... 

Chemistry of low-valent titanium and zirconium has produced a number of powerful methods for the transformation of carbohydrates to carbocyclic compounds. The Ti(III)-mediated generation of a radical from epoxides and its subsequent cyclization [32] was discussed earlier under free radical methods (see Scheme 9). As shown in Scheme 12,... 

Diastereoselective epoxidation of an allylic alcohol. Epoxidation of either a cis-or Irons-allylic alcohol substituted in the y-position by an alkoxy function by either m-ehloroperbenzoic acid or r-butyl hydroperoxide/VO(acac), results mainly in the anti-cpoxide (9, 109). Epoxidation of the allylic alcohol 1 with m-chloroperbenzoic acid conforms to this pattern, but epoxidation with f-butylhydroperoxide and VO(acac)2 mediated by titanium (IV) isopropoxide favors formation of the jyn-epoxide by a (actor of 10 1. The methyl group attached to the double bond is necessary for this unusual syn-selectivity when it is lacking, epoxidation with f-butyl hydroperoxide/ Ti(l V) is anti-sclcctivc, but less so than epoxidation with the peracid.1... 

Sharpless asymmetric epoxidation of allylic alcohols, asymmetric epoxidation of conjugated ketones, asymmetric sulfoxidations catalyzed, or mediated, by chiral titanium complexes, and allylic oxidations are the main classes of oxidation where asymmetric amplification effects have been discovered. The various references are listed in Table 4 with the maximum amplification index observed. 

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