Chiral indenes

A chiral indene derivative, structure K, has been most commonly used.222 The catalyst interacts with the trialkylaluminum to generate a bimetallic species that is the active catalyst. 

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. 

The asymmetric oxidation of indene to the corresponding epoxide (Equation 24) is carried out commercially by Sepracor on a small scale. Chiral indene oxide is an intermediate in the synthesis of crixivan (an HIV protease inhibitor). Reaction is carried out at 5°C with moderately high turnover numbers in the presence of an exotic donor ligand ( P3NO , 3-phenylpropylpyridine N oxide) and sodium hypochlorite as the terminal oxidant. A similar epoxidation of a simple cis olefin (Equation 25) leads to an enantiomerically pure amino-alcohol used in the synthesis of taxol, a potent anticancer drug. 

A novel class of chiral indenes (verbindenes) was prepared from enantiopure verbenone by K.C. Rupert and coworkers who utilized the Shapiro reaction and the Nazarov cyciization as the key transformations. The bicyclic ketone substrate was treated with triisopropylbenzenesulfonyl hydrazide to prepare the trisyl hydrazone that was then exposed to n-BuLi. The resulting vinyllithium intermediate was reacted with various aromatic aldehydes to afford the corresponding allylic alcohols. 

The highest enantioselectivities in the base-catalyzed Michael additions have so far been obtained using achiral bases complexed to chiral crown ethers. The addition of methyl 2,3-dihydro-l-oxo-1//-indene-2-carboxylate (1) to 3-buten-2-one using 4 mol% of a [l,T-binaphthalcnc]-2,2 -diol derived optically active crown ether 3 in combination with potassium AY/-butoxide as the base illustrates this successful method 259 260 It is assumed that the actual Michael donor is the potassium enolate complex of 1 and crown ether 3. 

Jacobsen et al. reported that a different type of dintrogen ligand (48), fe[(2,6-dichlorophenyl)-methylideneaminojcyclohexane, was an efficient chiral ligand for copper-mediated asymmetric aziridination (Scheme 35).154 The reactions of conjugated c/.v-olefins show high enantioselectivity with this catalyst, but enantioselectivity of the reactions of simple olefins such as styrene and indene is moderate. 

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone with methyl chloride in 50% sodium hydroxide/toluene using M-(p-trifluoro-methylbenzyDcinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2--phenyl-l-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation enqploying 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7 dichloro-5-methoxy 2-propyl-l-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3 dihydroxy-5-methoxy-2-propyl-l-inden-l-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an intermediate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. 

By the presence of cyclic monomer units obtained, for example, from cyclic olefins (benzofuran, indene, etc.) (58, 254). The erythro- and threo-diisotactic stractures (26, 27 or in a different representation 77, 78) are chiral. If B is equal to A (cyclobutene or analogous monomers) only the threo-diisotactic structure 27 is chiral. 

An alternate approach has been developed by Charette and coworkers in which chiral iodomethylzinc phosphates were prepared and tested in the cyclopropanation of unfunctionalized alkenes. Although these reagents were not sufficiently reactive to convert aryl-substituted alkenes (such as indene) to the corresponding cyclopropane, they reacted nicely with protected aryl-substituted allylic and homoallylic alcohols (equation 92) °. Several 3,3 -disubstituted binols were tested and ligand 23 stood out as being the most effective with this class of compounds. The active reagent in this case is a chiral iodomethylzinc phosphate. 

Lewis acid-promoted asymmetric addition of dialkylzincs to aldehydes is also an acceptable procedure for the preparation of chiral secondary alcohol. Various chiral titanium complexes are highly enantioselective catalysts [4]. C2-Symmet-ric disulfonamide, chiral diol (TADDOL) derived from tartaric acid, and chiral thiophosphoramidate are efficient chiral ligands. C2-Symmetric chiral diol 10, readily prepared from 1-indene by Brown s asymmetric hydroboration, is also a good chiral source (Scheme 2) [17], Even a simple a-hydroxycarboxylic acid 11 can achieve a good enantioselectivity [18]. 

Research groups at Sepracor53 54 and Merck50-52 independently developed similar strategies to access (lS)-amino-(2R)-indanol. Both processes used Jacobsen s Mn-(salen) catalyst (MnLCl, 2g)42-44,55 for indene epoxidation, followed by chirality transfer of the C-0 bond of indene oxide 26 to obtain enantiopure (15)-amino-(2/f)-indanol (Scheme 24.2). 

The typical technologies used for the preparation of amines have also been used for the synthesis of optically pure (R)- or (S)-l-aminoindane. For example, resolution approaches include the diastereoisomeric salt formation of racemic A-bcnzyl- l -aminoindane with (,S )-mandclic acid41 or (R,R) tartaric acid,42 which resulted in, after hydrogenation, (R)-l-aminoindane with >99% ee. Also, resolutions that use enzymatic acylation concepts have been described.43 44 The maximum theoretic yield of 50% is a clear limitation of these methods. Asymmetric synthetic approaches to chiral 1-aminoindanes have been described, including enantioselective hydrosilylation of l-indanoxime45 46 and hydroboration of indene 47 However, ee values were low to moderate. 

Another type of matrix effect on the properties of the product was described by Doiuchi and Minoura who copolymerized indene with maleic anhydride in the presence of lecithine as a chiral surface active agent [39], The rate of radical copolymerization in benzene is reduced in the presence of lecithine. An optically active copolymer is formed (the asymmetric carbon is marked by the asterisk, )... 

Asymmetric aziridination can also be accomplished via chiral salen ligands. Shi has synthesized a number of axially dissymmetric binaphthyldiimine salen complexes that have shown excellent facility in catalytic asymmetric aziridination reactions <2001TA3105>. Although yields were generally good with acyclic electron-deficient olefins, the chemical yield with electron-rich olefin indene was relatively low (25%). A reasonable enantiomeric excess of 73% was achieved at —20°C over a 24h reaction period (Equation 9). 

Denmark and Matsuhashi achieved only moderate success in the asymmetric epoxidation of phenylcyclohexene and indene catalyzed by novel chiral a-fluoroketones 57 and 58 (Scheme 22) <2002JOC3479>. 

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). ... 

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