Chiral heterocyclizations

Chiral heterocycles as ligands in asymmetric catalysis 99JHC1437. 

Stereoselective asymmetric synthesis with participation of diazocarbonyl intermediates in the presence of catalysts possessing chiral heterocyclic ligands 97CC983. 

Complexes with chiral heterocycles possessing P-containing substituents as P-mono- andP,N-bidentate ligands and their use in homogeneous asymmetric catalysis 98KK883. 

Table 3 Reaction of chromium alkoxycarbenes with chiral heterocyclic imines ...

Chiral heterocyclic compounds containing vicinal oxygen and nitrogen atoms were achieved by an asymmetric Diels-Alder reaction [111] of chiral acylnitroso dienophiles 111. The latter were prepared in situ from alcohols 110, both antipodes of which are available from camphor, and trapped with dienes (Scheme 2.46). Both the yield (65-94 %i) and diastereoisomeric excess (91-96%) were high. 

In 1996, Fu et al. reported the S3mthesis of the planar chiral heterocycles 64, formally DMAP fused with a ferrocene core [82]. While the original synthesis provided racemic 64a in only 2% overall yield requiring a subsequent resolution by preparative HPLC on a chiral stationary phase, a recently improved synthesis furnished the racemic complexes 64 in 32-40% yield over seven steps. A subsequent resolution with di-p-toluoyltartaric or dibenzoyltartaric acid gave access to the enantiomers with >99% ee (28 14% yield for each isomer in this step) [83]. 

Fu GC (2006) Application of planar-chiral heterocycles as ligands in asymmetric catalysis. Acc Chem Res 39 853-860... 

Asymmetric variants of these reactions are highly interesting since they provide access to chiral heterocycles. A recent comprehensive study by Stahl and coworkers reports the synthesis of various enantiopure [Pd( 4-C1)C1(NHC)]2 complexes and their application in asymmetric aza-Wacker cyclisations. The reactions generally proceed with low yields or enantioselectivity [43]. The best enantio-selectivity (63%) was achieved using complex 28 (Table 10.8). 

Several chiral heterocyclic borylating agents have been found useful for enantio-selective aldol additions. The diazaborolidine 14 is an example.136... 

Several current efforts are focusing on the portability of enzymatic heterocyclization. For example, novel chiral heterocyclic carboxylic acids were produced by using hybrid enzymes [62] (Figure 13.21). Stimulated by biosynthesis pathways, biomimetic heterocyclization methods have also been developed with high efficiency [63]. 

The rhodium complexes with hydroxyphospholane ligand 125663 or 126660 catalyze the asymmetric hydrogenation of a-acetamidoacrylates with ee values in excess of 98%. System 125 is also very effective in the asymmetric hydrogenation of P-acetamidoacrylates (up to 99.6% ee).664 The planar-chiral heterocyclic ligand 127 complexed with rhodium(I) catalyzes the hydrogenation of a-acetamidoacrylates in excellent yields and ee values from 79-96% under mild conditions.665... 

A number of P-N ligands has been reported as efficient ligands for the asymmetric hydrosilylation of ketones. We mention the phosphinooxazolines developed by Helmchen, Pfaltz, and Davis, we have seen before and mixed ligands containing planar-chiral heterocycles such as ferrocene [31] (Figure 18.17). For several ketone and silane combinations e.e. s in the high nineties were obtained. 

The first attempts to develop reactions offering control over the absolute stereochemistry of a chiral center, created by y-selective substitution of an achiral allylic alcohol-derived substrate, involved the use of chiral auxiliaries incorporated in the nucleofuge. The types of stereodirecting groups utilized vary, and have included sulfoximines [15], carbamates [16], and chiral heterocyclic sulfides [17-19]. 

Volume 64 of our series consists of six chapters covering an exciting range of topics in contemporary heterocyclic chemistry. M. TiSler and P. Kolar (Ljubljana, Slovenia) review applications of various amino acids in the synthesis of chiral heterocycles which have become of great importance as synthons for the preparation of a variety of optically active derivatives. 

High diastereofacial selectivities are observed in cycloadditions and Michael additions with ot,(3-unsaturated esters having chiral heterocyclic auxiliary at the p-position, as shown in Schemes 11.20, 11.21, and 11.25, and cannot be well-explained using Kozikowski s awfi-periplanar model (124,125) or Houk s inside alkoxy model (126,127). Both the anti-periplanar conformation and the syn-periplanar conformation of the acceptors participate in the transition structures, depending on nonbonding interactions in the dipole-chiral auxiliary pair (121). 

The feasibility of a deprotonation of cyclohexanone derivatives bearing a chiral heterocyclic substituent in the 4-position with the C2-symmetric base lithium bis[(/f)-l-phenylethyl]amide with internal quenching of the lithium enolate formed with chlorotrimethylsilane is shown in entries 32 and 33 of Table 229,25a. The silyl enol ethers are obtained in a diastereomeric ratio of 79.5 20.5. By using lithium bis[(1S)-l-phenylethyl]amide the two diastereomers are formed in a ratio of 20 80 indicating that the influence of the chirality of the substituent is negligible. 

The creation of all-carbon quaternary chiral centers by asymmetric conjugate addition is a challenging task. A chiral heterocyclic carbene 199 has been used as a ligand for this reaction. Chiral 3,3-disubstituted cyclohexanones 200 were obtained by this method with up to 85% ee (equation 126) . ... 

Transformations shown in Schemes 12-14 constitute the first examples of catalytic AROM reactions ever reported. Meso-triene 50 is converted to chiral heterocyclic triene 32 in 92% ee and 68% yield in the presence of 5 mol % 4a (Scheme 12) [21]. Presumably, stereoselective approach of the more reactive cy-clobutenyl alkene in the manner shown in Scheme 12 (II) leads to the enantioselective formation of Mo-alkylidene III, which in turns reacts with an adjacent terminal olefin to deliver 51. Another example in Scheme 12 involves the net rearrangement of meso-bicycle 52 to bicyclic structure 54 in 92% ee and 85% yield. The reaction is promoted by 5 mol % 4a and requires the presence of di-... 

Nitrogen based heterocycles are present in an array natural products, thousands of which have been mentioned in clinical or preclinical studies.1 Thus, the synthesis of piperidine-2 and pyrrolidine-3 derivatives have attracted much attention from the modem day organic chemists. Of particular interest are strategies that lead to chiral heterocyclic derivatives.4... 

A pyrrolidine-thiourea organocatalyst (69) facilitates Michael addition of cyclohexanone to both aryl and alkyl nitroalkenes with up to 98% de and ee 202 The bifunctional catalyst (69) can doubly hydrogen bond to the nitro group, leaving the chiral heterocycles positioned for cyclohexyl enamine formation over one face of the alkene. 

Heterocycles are very important in pharmaceutical research [49,50] and the stereo-controlled synthesis of chiral heterocyclic compounds is therefore a major task in modem organic chemistry. Besides catalytic methods, auxiliaries are valuable for asymmetric syntheses of chiral heterocycles. Carbohydrates have been used as auxiliaries in the stereoselective formation of heterocycles, as well as in the stereoselective introduction of functionalities into the heterocyclic framework. 

An alternative stereoselective synthesis of chiral heterocycles based on carbohydrate-induced stereodifferentiation includes nucleophilic addition reactions on heterocyclic systems already bound to the carbohydrate auxiliary. An example of this strategy has been shown by stereoselective addition of Grignard reagents to carbohydrate-linked 4-pyridones [61]. For this purpose, trimethylsiloxypyridine was glycosylated regioselectively using pivaloyl-protected glycosyl fluorides. 

This methodology opens up an efficient stereoselective access to chiral piperidi-none derivatives 60 which have opposite configuration compared to compounds 46 obtained by the tandem Mannich-Michael reaction sequence described in Section 4.3.2. The high diasteroselectivity and regioselectivity in these reactions once again illustrate the stereodifferentiating potential of carbohydrates in the synthesis of chiral heterocyclic systems. 

Carbohydrate-derived auxiliaries exhibit an efficient stereoselective potential in a number of nucleophilic addition reactions on prochiral imines. a-Amino acids, P amino acids and their derivatives can be synthesized in few synthetic steps, and with high enantiomeric purity. A variety of chiral heterocycles can readily be obtained from glycosyl imines by stereoselective transformations, providing evidence that carbohydrates have now been established as useful auxiliaries in stereoselective syntheses of various interesting classes of chiral compounds. 

Chiral heterocycles as reagents for NMR determination of enantiomeric purity 91CRV1441. 

Chiral heterocycles as ligands and auxiliaries for enantioselective catalysts 92CRV935. 

The chiral heterocycle (81) is deprotonated by trityl sodium and the resulting anion trapped with methyl formate giving the hydroxymethylene derivative (82) <92JCS(P1)517>. 

The thiopyranopyrandione derivative (92) is reduced by lithium borohydride yielding the product (93) in moderate yield <88JCS(Pl)663>, and the chiral heterocycle (94) gives the chiral 2-pyranone derivative (95) when treated with nickel boride <9iH(32)i875>. 

The THP derivatives (130 X = H, Cl) have been deprotected and the resulting alcohols (131) oxidized with PCC yielding the chiral heterocycles (132) <92JOC1930>. Dehydration of a 1 1 mixture of the diastereoisomers (133) with phosphorus oxychloride gives the thiopyrano[4,3-c]thiopyran derivative (134) (48% yield) <84J0C5136>. 

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