Cis- l-Amino-2-indanols

Ricci and co-workers introduced a new class of amino- alcohol- based thiourea derivatives, which were easily accessible in a one-step coupling reaction in nearly quanitative yield from the commercially available chiral amino alcohols and 3,5-bis(trifluoromethyl)phenyl isothiocyanate or isocyanate, respectively (Figure 6.45) [307]. The screening of (thio)urea derivatives 137-140 in the enantioselective Friedel-Crafts reaction of indole with trans-P-nitrostyrene at 20 °C in toluene demonstrated (lR,2S)-cis-l-amino-2-indanol-derived thiourea 139 to be the most active catalyst regarding conversion (95% conv./60h) as well as stereoinduction (35% ee), while the canditates 137, 138, and the urea derivative 140 displayed a lower accelerating effect and poorer asymmetric induction (Figure 6.45). The uncatalyzed reference reaction performed under otherwise identical conditions showed 17% conversion in 65 h reaction time. 

Considering the wide variety of d,v- l -arnino-2-indanol-containing ligands synthesized to date and the numerous applications reported in the literature and detailed in the present section, it is to be expected that novel ligands and methodologies will continue to emerge featuring the remarkable characteristics of cis- l-amino-2-indanol. 

Ghosh et al. reported that the chiral oxazolidinone 87, derived from (1S,2R)-cis-l-amino-2-indanol (86), underwent a highly diastereoselective. vyn-aldol reaction with a variety of aldehydes30 (Scheme 2.1cc). Reaction of the indanolamine 86 with disuccinyl carbonate in acetonitrile gave the oxazolidinone 87, which was deprotonated with -BuLi and reacted with propionyl chloride to provide the N-propionyl derivative 88. Reaction of 88 with n-BioBOTf and... 

Indene Oxide (ChiRex). The epoxidation of indene is an attractive route to cis l-amino-2-indanol, an intermediate in the Crixivan synthesis (HIV protease inhibitor of Merck) and ligand for BH3 reductions of ketones (60a,61). 

Another auxiliary that proved to be useful as a base for enolate alkylations is cis-l-amino-2-indanol 37 developed by researchers at Merck, Sharp, and Dhome. Both enantiomers of the amino alcohol are commercially available in bulk. The alkylation method was elaborated for a synthesis of indinavir, the orally active HIV protease inhibitor that emerged as a major drug for treatment of AIDS. Thus, N-acylated Af,0-acetal 38 was converted into the lithium enolate and subsequently treated with allyl bromide to give the alkene 39 in excellent chemical yield and diastereoselectivity. The conversion into indinavir reveals that the amino alcohol 37 functions both as auxiliary and chiral building block (Scheme 4.8) [26]. 

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-... 

The Sepracor group demonstrated that (l/ ,2S)-indene oxide 26 could be prepared from readily available indene 25 in the presence of 1.5 mol% of (R,R)-MnLCl and 13% NaOCl in dichlo-romethane in 83% yield and 84% ee (Scheme 24.2). Chiral indene oxide 26 was then subjected to nucleophilic opening with ammonia to provide /ram-aminoindanol, which was transformed without isolation to its benzamide under the Schotten-Baumann condition (83% ee, >99.5% ee after recrystallization). The optically pure trans-benzamidoindane was then converted to the optically pure benzaoxazoline 27 by exposure to 80% H2S04, followed by addition of water to give cis-1-amino-2-indanol.53 54 The sequence was demonstrated on multi-kilogram scale to prepare optically pure (IR, 2.S )-1 in 40% yield from indene. 

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. 

Recently, it was suggested by Corey and coworkers [828] that cis-N-sul-fonyl-2-amino-l-indanols can be used to generate titanium complexes that are able to catalyze the asymmetric cycloaddition of 2-bromoacrolein with dienes. 

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