Indan, oxidation

The Jones reagent851 and < rt-BuOOH in the presence of chromium(VI) complexes852,853 were found to be particularly useful in the oxidation of tetralins and indans. Oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) occurs with an exceptional mechanism.854 In contrast with the radical processes observed in other oxidations DDQ generates a carbocation by hydride abstraction that is trapped by water to form an alcohol ... 

In the case of 1,4-dimethylbenzene epoxide (181), incursion of intermediates like l,4-dimethyl-l,4-dihydroxydihydrobenzene (182)91,92 or intermediates like 4,8- and 4,5-indane oxides (183 and 184), respectively, by oxygen walk8,93-96 does not allow prediction of the product of epoxide opening on... 

In KYI, more than 95% of indene substrate is oxidized by a monooxygenase to indane oxide, which in turn is hydrolyzed to undesired trans-(lK,2K)-indanediol and cis-(lS,2J )-indanediol, as was verified by steady-state metabolite balancing and labeling with 14C-tracers. 

As a result of the flux analysis, the most promising target for pathway modification to augment the yield of desired trans- (lK,2K)-indanediol is enhanced selective hydrolysis of indane oxide to trans-(lR,2J )-indanediol, either by modification of the culture conditions or by overexpression of an epoxide hydrolase. 

One noteworthy example of the aromatization of an arene oxide to yield different phenols by the A h (acid-catalyzed) and ko (spontaneous) pathways is indan oxide The mechanisms for the aromatization reaction of arene oxide 7... 

Dihydrodiols have not been obtained from hydrolysis reactions of benzene oxides however, evidence for the formation of 1,4-dihydrodiols has been obtained from acid-catalysis studies on 1,4-dimethylbenzene oxide 63 ° and 8,9-indan oxide 7. The mechanism of acid-catalyzed rearrangement and hydrolysis of benzene oxide has been investigated theoretically using the semiempirical allvalence electron MINDO/3 method and the perturbational MO method, both from the viewpoint of product stabilities and reaction pathways. The aromatization reaction was found to be much more exothermic than the hydrolysis and thus would be the preferred reaction, as was found experimentally. 

Indane oxide (109) undergoes a pH-independent reaction to form 4-indanol (115), and part of this product is formed by a 1,2-alkyl migration.96 However, most of the 4-indanol is formed as a result of the isomerization of 8,9-indane oxide to 4,9-indane oxide (111) via an oxygen walk. 96a,b A minor amount of 5-indanol (116) is... 

The spontaneous oxepin-benzene oxide isomerization proceeds as a thermally allowed, disrotatory process according to the Woodward-Hoffmann rules. Because of eclipsing interactions, 2,7-substituents destabilize the benzene oxide structure and favour oxepin formation. If the 2,7-positions are bridged, the size of the bridge influences the oxepin-benzene oxide equilibrium. This is shown by studies of the 2,7-methylene-bridged systems 7 and 8 If n = 3, only the indane oxide is present if n = 4, tetrahydronaphthalene oxide predominates in the equilibrium mixture if n = 5, oxepin and benzene oxide are present in a ratio of 1 1 [4]. 

Indan oxide hydrolysis rate constant to cis-(IS,2i )-indandiol... 

C]-Metabolite concentration czs-(lS,2R)-Indandiol excretion rate czs-(lR,2S)-Indandiol excretion rate Indene uptake rate Indan oxide excretion rate l-Keto-2-hydroxy-indan excretion rate frans-(lR,2R)-Indandiol excretion rate [ -fra s-( lR,2R)-Indandiol concentration Indan oxide hydrolysis flux to czs-(lS,2R)-indandiol Dioxygenase flux Flux for enzyme i... 

Indan oxide hydrolysis flux to fraMS-(lR,2R)-indandiol... 

Protease inhibitors are well-characterized chiral drugs in terms of their mechanism of action. An important new class of protease inhibitors comprises molecules designed to treat HIV infection. In particular, indinavir sulfate (CRIXIVAN, Merck and Co., Inc.) contains five chiral centers that must be of a specific orientation for the molecule to have the desired therapeutic effect. Manufacturing processes for these compounds involving chemical synthesis steps can be quite inefficient, due to yield reduction caused by racemization at each step where a chiral center is formed. A key intermediate in the synthesis of CRIXIVAN is cis-(lS,2R)-l-amino-2-indanol [(-)-CAI], an indene derivative that contributes two chiral centers to indinavir sulfate (Fig. 1). To circumvent the technically demanding chemical synthesis of (-)-CAI and reduce product loss, Merck scientists conceptualized a bioconversion process in which indene is oxidized to one of three derivatives that can serve as precursors to (-)-CAI cis-(lS,2R)-indandiol, trans-(lR,2R)-indandiol, or (lS,2R)-indan oxide. Oxygenases that have been identified in isolates of the genus Pseudomonas and Rhodococcus can catalyze this transformation. 

Fig. 2. Indene bioconversion network in Rhodococcus strain 124 proposed by Chartrain et al. [8]. Indene is converted to the indandiol enantiomers shown through specific oxygenase activities. Dioxygenases produce the cis enantiomers of indandiol while the monooxygenase converts indene to indan oxide. The indandiols are then converted to l-keto-2-hydroxy-indan through the action of dehydrogenase enzymes and a proposed undetectable 1,2-indenediol intermediate...

A suitably designed chiral analog of NHPI can be used as an enantioselective oxidation catalyst. Einhorn reported the synthesis of axially chiral NHPI analogs (Scheme 6.21). These NHPI derivatives can be used in several catalytic asymmetric oxidation reactions, such as indane oxidation and oxidative deprotection of acetal. 

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