Epoxidation of chromenes

SCHEME 92. Mn-catalyzed enantioselective epoxidation of chromene derivatives using H2O2... 

Regardless of the mechanism, the chiral (salen)Mn-mediated epoxidation of unfunctionalized alkenes represents a methodology with constantly expanding generality. Very mild and neutral conditions can be achieved, as illustrated by Adam s epoxidation of chromene derivatives 12 using Jacobsen-type catalysts and dimethyldioxirane as a terminal oxidant [95TL3669]. Similarly, periodates can be employed as the stoichiometric oxidant in the epoxidation of cis- and tram-olefins [95TL319],... 

A somewhat different approach to catalyst separation has been devised by engineering the chiral salen catalyst to have built-in phase-transfer capability, as exemplified by the Mn(III) complex 10 <02TL2665>. Thus, enantioselective epoxidation of chromene derivatives (e.g. 11) in the presence of 2 mol% catalyst 10 under phase transfer conditions (methylene chloride and aqueous sodium hypochlorite) proceeded in excellent yield and very good ee s. The catalyst loading could be reduced to about 0.4% with only marginal loss of efficiency. 

Recently, Wong and Shi have examined the effect of substitution in the 6- or 8-position in the asymmetric epoxidation of chromenes by chiral dioxiranes derived from ketones 52 and 53. Up to 93% ee was achieved, with higher ee s obtained when substrates are substituted at the 6-position <2006JOC3973>. 

Complete conversions and good enantiomeric excesses (64-100%) were achieved in the asymmetric epoxidation of chromenes and indene using UHP as oxidant and a novel dimeric homochiral Mn(III) Schiff base as catalyst. The reactions were carried out in the presence of carboxylate salts and nitrogen and oxygen coordinating co-catalysts. However, the epoxidation of styrene unfortunately proceeded with incomplete conversion and only 23% ee. Modification of the catalyst and use of pyridine 7V-oxide as cocatalyst allowed improvement of the ee to 61% (Scheme 18). ... 

The [Mn(salen)]-catalyzed epoxidation of chromene derivatives was discovered to occur with exceptional enantioselectivity [74]. Chromene derivatives bearing 2,2-disubstitution appear to combine all the important substrate characteristics required for a highly enantioselective epoxidation. The synthetic utility of the enantioenriched epoxychroman products is increased by the predictable regio- and stereochemical outcome of epoxide ring opening with a variety of nucleophiles. These two features were highlighted in the synthesis of the selective potassium channel activator BRL 55834 [78]. Catalyst loadings as low as... 

Scheme 23.1. Asymmetric epoxidation of chromene derivatives mediated by a Mn(salen) complex...

Irie, R., Hosoya, N. and Katsuki, T. (1994). Enantioselective Epoxidation of Chromene Derivatives Using Hydrogen Peroxide as a Terminal Oxidant, Synlett, 4, pp. 255-256. 

There are now many examples of the industrial use of manganese(lll) salen catalyzed asymmetric epoxidations. For example, the as5mmetric epoxidation of a chromene derivative was central to the S5mthesis of the potassium channel activator BRL 55834 (Figure 11.5). ... 

Boyd, D.R., Sharma, N.D., Boyle, R., Evans, T.A., Malone, J.E., McCombe, K.M., Dalton, H. and Chima, J., Chemical and enz3mie-catalysed syntheses of enantiopure epoxide and diol derivatives of chromene, 2,2-dimethylchromene, and 7-methoxy-2,2-dimethylchromene (pre-cocene-1). J. Chem. Soc. Perkin Trans. 1,1996, 1757. 

Fig. 18 The competing transition states for the epoxidation of 6- and 8-substituted chromenes... 

An interesting reversal of chiral induction in chromium(III)-salen complexes using a tartaric derived alicyclic diamine moiety (i.e., 7) has been observed by Mosset, Saalfrank, and co-workers <99T1063>. Thus, epoxidation of the chromene 8 using catalyst 7 and an oxidant consisting of MCPBA/NMO afforded the 3S,4S epoxide 9, whereas the Jacobsen catalyst (1) provided the corresponding 3R,4R enantiomer. A mechanistic rationalization for this curious crossover has not yet been proposed. 

Katsuki has extended his earlier work on asymmetric induction using achiral catalysts such as 13. In these systems, the stereochemical bias is imbued by a chiral non-racemic axial ligand, such as (+)-3,3 -dimethyl-2,2 -bipyridine A2,A -dioxide (14), which was purified by crystallization with (5)-binaphthol. Epoxidation using these conditions resulted in good ee s and fair yields, as exemplified by the preparation of chromene epoxide 16 <99SL783>. 

Examples of epoxidation (95SL197,95TL3669) and aziridination (95JA5889) of chromenes with high enantioselectivity have been reported. 

Likewise, as it has been studied in the chromenes (21), we examined the possible relationship between precocene-like activity and chemical shifts of C-3 and C-4 in several 3,4-epoxides of active and inactive chromenes. In all cases observed, these chemical shifts differed too slightly, within the range of 0.5 ppm for C-3 and 0.7 ppm for C-4, to be of any diagnostic value. 

Katsuki and co-workers have investigated asymmetric epoxidation reactions mediated by achiral Mn(salen) complexes in the presence of chiral additives the combination of tetramethyl diamine-derived complex 37 and (—)-sparteine 38 can mediate the oxidation of chromenes with up to 73% ee (Table 2, entry 1) however, the yields were low <1997T9541>. More successful was ethylene diamine-derived complex 39, which promoted the asymmetric epoxidation of several chromenes in good to excellent yields and good levels of ee in combination with chiral... 

Due to the demand for inexpensive anti-HIV agents, several reactions for the synthesis of Indinavir (70, an HIV protease inhibitor of Merck Co.) have been reported. Enantioselective epoxidation of simple alkenes with bleach is achievable in the presence of the Mn " complex 69 possessing a well-designed chiral salen ancillary [69]. Scheme 20 exemplifies its application to the synthesis of Indinavir (70), by way of indene oxide (68) in 88 % ee [69]. This method is also useful for the asymmetric synthesis of a chromene epoxide in 97 % ee serving as an intermediate for Lemakalim, a K" -channel opening agent [70]. 

Scheme 9.15 Homochiral Salen-Mn metal-organic framework for the asymmetric epoxidation of 2,2-dimethyl-2H-chromene.

Dinuclear or polynuclear manganese complexes of salen-type ligands were also tested in the epoxidation of olefins with H2O2 as oxidant. Enantioselective epoxidation of several olefins with urea-H202 and a dinuclear Mn-salen type of complex has been reported by Kureshy and co-workers (130). Conversions of more than 99 % ee were obtained with chromenes and... 

The rate of Jacobsen-Katsuki epoxidation can be enhanced in the presence of additives such as pyridine A-oxide or related aromatic A-oxides. For example, in a synthesis of the potassium channel activator BRL-55834, only 0.1 mol% of the (5,5)-(salen)Mn(III)Cl catalyst 58 was required for efficient epoxidation of the chromene 62 in the presence of 0.1 mol% isoquinoline A-oxide (5.68). In the... 

Framework structure of [Zn2(bpdc)2L]- (guest). (c) Plots of total turnover number (TON) vs time for the enantioselective epoxidation of 2,2-dimethyl-2H-chromene catalysed by [Zn2(bpdc)2L]- (guest) (squares) and the free ligand L (circles). Reprinted with S.H. Cho, B.Q. Ma, S.T. Nguyen, J.T. Hupp and T.E. Albrecht-Schmitt, Chem. Commun., 2563-2565. Copyright (2006) Royal Society of Chemistry... 

When appHed in the asymmetric epoxidation of 2,2-dimethyl-2H-chromene, this MOF was less active than the homogeneous salen complex, but more stable over time, as the immobihzation of the Mn(salen) complexes precludes oxidation of one metal center by another. Immobilization decreases the flexibility of the hgands, explaining the slight decrease in enantioselectivity compared to the free complex. While a small loss of catalytically inactive Mn was observed after each ran, the enantioselectivity remained constant however, upon prolonged use of this catalyst, the outer layers of the MOF crystals were gradually damaged by oxidation. This... 

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