Enantioselective indanone

A novd example of a catalytic enantioselective domino process1201 is the inter-intramolecular nitro-aldol reaction described by Shibasaki et al which generates substituted indanones. As catalyst a praseodym-heterobimetallic complex with binaph-thol as chiral ligand is employed. Treatment of keto-aldehyde 41 with nitromethane in the presence of the catalyst 46 at -40 °C and successive warming to room temperature affords diredly the produd 42 in an overall yield of 41 % and 96 % ee after several recrystallizations (scheme 9). As intermediates the nitromethane adduct 43 and the hemiacetal 44 can be proposed. In a second aldol reaction 44 leads to 45 which isomerizes to the thermodynamically more stable epimer 42. 

D. L. Hughes, U.-H. Dolling, K M Ryan, R F. Schoene-waldt, E. I. J. Grabowski, A Kinetic and Mechanistic Study of the Enantioselective Phase-Transfer Methyla-tion of 6,7-Dichloro-5-methoxy-2-phenyl-l-indanone , J. Org. Chem. 1987, 52, 4745-4752... 

There are only a few reports on chiral phase transfer mediated alkylations". This approach, which seems to offer excellent opportunities for simple asymmetric procedures, has been demonstrated in the catalytic, enantioselective alkylation of racemic 6,7-dichloro-5-methoxy-2-phenyl-l-indanone (1) to form ( + )-indacrinone (4)100. /V-[4-(tnfluoromethyl)phenylmethyl]cinchoninium bromide (2) is one of the most effective catalysts for this reaction. The choice of reaction variables is very important and reaction conditions have been selected which afford very high asymmetric induction (92% cc). A transition state model 3 based on ion pairing between the indanone anion and the benzylcinchoninium cation has been proposed 10°. 

The indanone substrate was methylated in 94% enantiomeric excess, by the use of a chiral catalyst, N-(/>-(trifluoromethyl)benzyl)cinchoninium bromide, under phase transfer conditions.1468 In another method enantioselective alkylation can be achieved by using a chiral base to form the enolate.1469... 

Enantioselective Robinson annelation Alkylation of indanone 2 with 1,3-dichloro-2-butene (E/Z = 4 1) catalyzed by 1 gives (S)-3 in 92% ee. The enantiomer, (R)-3, is obtained by the same alkylation but catalyzed by N-(/ -trifluoro-methylbenzyl)cinchonidinium bromide in 78% ee and 99% yield. Optically pure 3 undergoes hydrolysis and cyclization in high yield. Demethylation and alkylation provides the desired tricyclic enone 4 in 83% overall yield from (R)-3. 

Polymer catalysts containing cinchona alkaloids were re-examined by d Angelo for the reaction of l-indanone-2-carboxylate and methyl vinyl ketone, in which the structure of the spacer connecting the base moiety to the Merri-field resin dramatically influenced the enantioselectivity (Scheme 5) [12]. Catalyst 4 (n=7) with a 7-atom-length spacer to quinine exhibits 87% ee, while 4 (n=3) with a 5-atom spacer and 4 ( =9) with an 11-atom spacer gave only 13% and 31% ee, respectively. 

Asymmetric phenylation of carbanions with chiral iodonium salts has recently been reported [70]. The chiral diiodonium salt 93 selectively reacts with potassium enolate of l-oxo-2-indancarboxylate 92 to give the a-phenylated indanone 94 with moderate enantioselectivity (Scheme 42). 

An important issue is the right choice of substrate 1 which functions as an anion precursor. Successful organocatalytic conversions have been reported with indanones and benzophenone imines of glycine derivatives. The latter compounds are, in particular, useful for the synthesis of optically active a-amino acids. Excellent enantioselectivity has been reported for these conversions. In the following text the main achievements in this field of asymmetric organocatalytic nucleophilic substitutions are summarized [1, 2], The related addition of the anions 2 to Michael-acceptors is covered by chapter 4. 

The first examples of asymmetric Michael additions of C-nudeophiles to enones appeared in the middle to late 1970s. In 1975 Wynberg and Helder demonstrated in a preliminary publication that the quinine-catalyzed addition of several acidic, doubly activated Michael donors to methyl vinyl ketone (MVK) proceeds asymmetrically [2, 3], Enantiomeric excesses were determined for addition of a-tosylnitro-ethane to MVK (56%) and for 2-carbomethoxyindanone as the pre-nudeophile (68%). Later Hermann and Wynberg reported in more detail that 2-carbomethoxy-indanone (1, Scheme 4.3) can be added to methyl vinyl ketone with ca 1 mol% quinine (3a) or quinidine (3b) as catalyst to afford the Michael-adduct 2 in excellent yields and with up to 76% ee [2, 4], Because of their relatively low basicity, the amine bases 3a,b do not effect the Michael addition of less acidic pre-nucleophiles such as 4 (Scheme 4.3). However, the corresponding ammonium hydroxides 6a,b do promote the addition of the substrates 4 to methyl vinyl ketone under the same mild conditions, albeit with enantioselectivity not exceeding ca 20% [4],... 

The enol formed by irradiation of a-disubstituted indanones and tetralones bearing at least one hydrogen in the y-position undergoes enantioselective tautomerization to ketone in the presence of catalytic amounts of optically active aminoalcohols [74]. 

Muzart and coworkers have reported a new catalytic enantioselective protonation of prochiral enolic species generated by palladium-induced cleavage of p-ketoesters or enol carbonates of a-alkylated 1-indanones and 1-tetralones [21 ]. Among the various (S)-p-aminocycloalkanols examined, 17 and 18 were effective chiral catalysts for the asymmetric reaction and (J )-enriched a-alkylated 1-indanones and 1-tetralones were obtained with up to 72% ee. In some cases, the reaction temperature affected the ee. 

In 1993, Bolm reported that these reactions could be performed using catalytic quantities (10 mol%) of the chiral P-hydroxy sulfoximine.132 The enantiomeric purities of the product alcohols ranged from 52% (1-indanone) to 93% (PhCOCHjOSiRj). In many cases the enantiomeric purities were enhanced using sodium borohydride as reductant in the presence of chlorotrimethylsilane.133 These methods have been extended to the asymmetric reductions of imines.134 /V-SPh-substituted imines gave the highest enantioselectivities and these reductions proceeded in the same stereochemical sense as the reductions of ketones. 

The groups of Pete and Rau also employed chiral amino alcohols for the enantioselective protonation of simple enols 23a-c that were photochemically generated from 2-/-butyl indanones and tetralones 22a-c by a Norrish type II photoelimination (Scheme 9) [41,42]. Best enantioselectivities were obtained at — 40°C in acetonitrile with 0.1 equivalent of the chiral amino alcohol. In the case of indanone 22a, the selectivity reached 49% ee with (— )-ephedrine ent-18) and could not be further enhanced by the camphor derived inductor 20. With this amino alcohol, enantioselectivities over 80% ee were induced in the case of tetralone 22b. A benzyl substituent in place of the methyl group led to substantial decrease of the selectivity to 47% ee. Linear ketones gave low yields and enantioselectivities around 9% ee. 

D. The use of chiral oxazaborolidines as enantioselective catalysts for the reduction of prochiral ketones, imines, and oximes, the reduction of 2-pyranones to afford chiral biaryls, the addition of diethylzinc to aldehydes, the asymmetric hydroboration, the Diels-Alder reaction, and the aldol reaction has recently been reviewed.15b d The yield and enantioselectivity of reductions using stoichiometric or catalytic amounts of the oxazaborolidine-borane complex are equal to or greater than those obtained using the free oxazaborolidine.13 The above procedure demonstrates the catalytic use of the oxazaborolidine-borane complex for the enantioselective reduction of 1-indanone. The enantiomeric purity of the crude product is 97.8%. A... 

Among the several screened cinchona derivatives, (DHQ)2AQN 6 was selected for a full optimization of the conditions (solvent and temperature). The reaction was carried out in DMF with a combination of benzoyl fluoride and ethanol as a latent source of HF. Enantioselectivities up to 92% ee were obtained with tetralones trimethylsilyl enol ethers Sa-d using 10 mol% of organocatalyst 6 (Table 7.1, entries 1-4). Indanone silyl enol ethers Se-g afforded the corresponding ketones 7e-g with lower selectivities (64—74% ee, Table 7.1, entries 5-7) while the 2,2,6-trimethyl-cyclohexanone was obtained with only 58% ee, the reaction being conducted at — 10 °C (data not shown in Table 7.1). 

In 2008, Jorgensen and coworkers reported the first example of the asymmetric conjugate addition of (5-ketoesters 184 to the vinyl bisphosphonate esters 183 catalyzed by the parent cinchona alkaloids (20 mol%) such as dihydroquinine and dihydroqui-nidine [57]. High yields and enantioselectivities (up to 99% ee) were achieved for a wide range of indanone-based (3-ketoesters as well as various 5-tert-butyloxycarbonyl... 

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