Chromenes epoxidation

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>. 

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]. 

Hydroxymethyl-4,8-dimethylfuro[2,3-/z]chromen-2-one was realized in an efficient manner via a Claisen rearrangement of 4-(hydroxybut-2-ynyloxy)-4-methylchromen-2-one as depicted in the following scheme. Other examples with substitution of hydroxyl and with other substituents, such as chloro, amino, acetoxy were also reported <06JHC763>. A new approach for the synthesis of oxygenated benzo[fe]furans was developed via epoxidation and cyclization of 2 -hydroxystilbene <06T4214>. 

Dimethylchromene has also proven to be a useful substrate for the assessment of various transition metal complexes as epoxidation catalysts. Chiral Mn(III)-salen complexes are efficient <00CC615 00T417> and can be recycled when used in an ionic liquid <00CC837>. The enantioselective aziridination of a chromene has been achieved using a chiral biaryldiamine-derived catalyst (Scheme 22) <00JA7132>. 

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... 

Various other chromene derivatives 176a-d could be epoxidized with Katsuki s Mn-salen catalyst 173d using either H2O2 or TMS2O2 as oxidant. With this catalytic system several axial ligands (none, 7V-methylimidazole, pyridine TV-oxide) and additives (none. 

NH4CIO4, NELtPFe) have been tested and the best results were obtained in acetonitrile as solvent in the presence of Ai-methylimidazole using H2O2 as terminal oxidant (Scheme 92). Under these conditions chromene derivatives could be converted into the corresponding epoxides 177 in yields between 55 and 98% and ee values of 88-95%. 

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

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. 

The photoinduced cleavage of 217-pyrans to a,/ ,y,8-unsaturated ketones, as reported for 2/f-chromene, has already been discussed. The formation of the 2/f-pyran system from such an unsaturated ketone is also known and has been reported for cis-/3-ionone411 and for the substituted o-vinylbenzophenone (395) which on irradiation at low temperature yields the unstable pyran (396).412 On prolonged photolysis, however, this benzophenone is converted in benzene solution into the epoxide (397) and in methanol solution into the methoxyisochroman (398). It seems probable that a common intermediate exists and that this has the structure 399. A close analogy, therefore, exists between this conversion and the photolysis of o-divinylbenzene in which a similar intermediate is postulated.413,414... 

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],... 

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

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. 

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. 

Two of the better known "anti-juvenile "Hormone" agents, preco-cenes (9) and fluoromevalonate (10) are inhibitors of JH biosynthesis. The mode of action of fluoromevalonate at the molecular level is unknown. Elucidation of the mode of action of precocenes indicates that these plant chromene derivatives reach the site of JH biosynthesis, the corpora allata (CA), where they undergo a lethal epoxidation leading to extensive macromolecular alkylation and ultimately cause cell death (11, 12). Bioactivation of precocenes to the highly reactive precocene epoxide (13) in the corpora allata is almost certainly catalyzed by methyl farnesoate (MF) epoxidase (14), a cytochrome P-450 sonooxygenase (15) tdtich is the last enzyme of the JH biosynthetic pathway (at least in locusts and cockroaches). 

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... 

Related dimeric Mn(salen) complexes have also been examined by the group of Ning 6-cyano-2,2-dimethyl-chromene was epoxidized in 92-93% yield and 92-94% ee <2004JM0353>. 

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>. 

Dimethyl-2//-chromenes have been epoxidized enantioselectively with DMD in the presence of chiral Mn(III)salen catalysts <95TL3669>. 

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). ... 

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