Epoxides Ritter reaction

Davies and Reider (1996) have given some details of the HIV protease inhibitor CRDCIVAN (INDINAVIR) for which (lS,2R)-c -amino indanol is required. Indene is epoxidized enantioselectively, using the lacobsen strategy (SS-salen Mn catalyst, aqueous NaOH and PiNO), to (lS,2/ )-indene oxide in a two-phase system, in which the OH concentration is controlled. Indene oxide was subjected to the Ritter reaction with MeCN, in the presence of oleum, and subsequent hydrolysis and crystallization in the presence of tartaric acid gives the desired amino indanol. 

Several procedures have been reported using acetonitrile as solvent for Bi(III) salt-catalyzed transformations involving epoxides as substrates [54, 93-95]. However, no reference has been made about the occurrence of the Ritter reaction, even... 

Enantiomerically pure epoxides and diols, readily available through the asymmetric epoxidation and asymmetric dihydroxylation reactions, are ideal precursors to prepare cis-amino alcohols via the Ritter reaction. " " A Merck group has shown that indene oxide 175a can be converted effectively to c/i-l-amino-2-indanol, a key fragment of the HlV-protease inhibitor Indinavir via the cis-... 

Epoxides also participate in the Ritter reaction with nitriles. An investigation of the ring opening of several alkyl-substituted glycidic esters and amides 181 showed that this transformation occurs with inversion and is completely regiospecific. ° Esters appeared to be somewhat more reactive than amides. However, phenyl-substituted glycidic esters and amides 184 are almost totally nonstereoselective. In addition, the oxazolines 186 are isolated in low yield due to the propensity of intermediate 185 to generate an aldehyde byproduct 187 (Scheme 8.53). 

Epoxides also undergo the Ritter reaction in good yields with retention of configuration via a episulfonium intermediate 190a (double-inversion process). For monosubstituted epoxides, the yields of oxazolines are lower due to nondis-criminatory attack of the nitrile on both the primary and the secondary carbon atom of the episulfonium intermediate. Complete retention of configuration is still observed despite the lower yield (Scheme 8.54). 

The chirality conies from the diamine and the oxidation from ordinary domestic bleach (NaOCl), which continually recreates the Mn=0 bond as it is used in the epoxidation. Only 0.7% catalyst is needed to keep the cycle going efficiently. The epoxide is as good as the diol in the Ritter reaction and the whole process gives a 50% yield of enantiomerically pure cis-ami no-indanol on a very large scale. 

Nitriles can react with functionalized oxiranes in a regioselective manner in a tandem epoxide-opening Ritter reaction (Scheme 39) <2005JOC7447>. 

Functionality adjacent to the epoxide can modify its reactivity. For example, 2,3-epoxy sulfides can be converted to a thiiranium species upon treatment with TMS triflate. This intermediate reacts with 0-silyl amides regiospeci-fically to form l-substituted-3-hydroxy-2-thioethers. Simple primary amines undergo polyalkylation, but imines can be used as an indirect amine equivalent <1996T3609>. Nitriles react with functionalized oxiranes in a regioselective manner in a tandem epoxide opening-Ritter reaction (Equation 17) <2005JOC7447>. 

Preparation. A number of methods have been reported for both the racemic and asymmetric preparations of l-amino-2,3-dihydro-lH-inden-2-ol (1), most commonly starting from inexpensive and readily available indene. These methods have been described in detail in recent reviews. The valuable properties of 1 as both a component of a medicinally active compound and as a chirality control element, derive primarily from its rigid and well-defined stereochemical structure. As a result, the compound is most desirable in enantiomerically pure form. One of the most efficient asymmetric syntheses of 1, which may be employed for the synthesis of either enantiomer of the target molecule, involves an asymmetric epoxidation (89% yield, 88% ee) of indene to give epoxide 2 using the well-established Jacobsen catalyst. This is followed by a Ritter reaction using oleum in acetonitrile resulting in conversion to the oxazoline (3) which is subsequently hydrolysed to the amino alcohol. Fractional crystallization with a homochiral diacid permits purification to >99% ee (eq 1). ... 

Merck devised a synthesis that was so efficient that 286 is now available commercially (it was only a rumour that Merck would give it away free as they had so much) and has been used in asymmetric synthesis in many ways. The synthesis is described52 in full by the Merck team in Organic Syntheses. The epoxide 284 is protonated by acid to give the cation 288 that, captures acetonitrile in a Ritter reaction giving the heterocycle 290 that is easily hydrolysed to 286. 

The [Mn(salen)] -catalyzed epoxidation of indene has also proven to be synthetically useful in various contexts. Enantio-enriched indene oxide, produced in 84-86% ee by AE of the corresponding olefin, is a precursor to important building blocks including cfs-aminoindanol through a Ritter reaction (Scheme 10)... 

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