Cyclization asymmetric

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

Hydrosilylation of dienes accompanied by cyclization is emerging as a potential route to the synthesis of functionalized carbocycles. However, the utility of cycliza-tion/hydrosilylation has been Umited because of the absence of an asymmetric protocol. One example of asymmetric cycUzation/hydrosilylation has been reported very recently using a chiral pyridine-oxazoUne ligand instead of 1,10-phenanthroline of the cationic palladium complex (53) [60]. As shown in Scheme 3-21, the pyridine-oxazoUne Ugand is more effective than the bisoxazoUne ligand in this asymmetric cyclization/hydrosilylation of a 1,6-diene. 

Asymmetric Cyclizations of 1,6-Heptadiene and of Diallyl Ether Using Catalyst Modified with Epimers of MENTHYL-rerf-BuTYLMETHYLPHospHiNE... 

Asymmetric cyclization was also successful in the rhodium-catalyzed hydrosilylation of silyl ethers 81 derived from allyl alcohols. High enantioselectivity (up to 97% ee) was observed in the reaction of silyl ethers containing a bulky group on the silicon atom in the presence of a rhodium-BINAP catalyst (Scheme 23).78 The cyclization products 82 were readily converted into 1,3-diols 83 by the oxidation. During studies on this asymmetric hydrosilylation, silylrhodation pathway in the catalytic cycle was demonstrated by a deuterium-labeling experiment.79... 

Asymmetric cyclization-hydrosilylation of 1,6-enyne 91 has been reported with a cationic rhodium catalyst of chiral bisphosphine ligand, biphemp (Scheme 30).85 The reaction gave silylated alkylidenecyclopentanes with up to 92% ee. A mechanism involving silylrhodation of alkyne followed by insertion of alkene into the resulting alkenyl-rhodium bond was proposed for this cyclization. 

The asymmetric cyclization-hydrosilylation of 1,5-dienes has been also reported by use of a chiral yttrocene complex (Scheme 32).87 Highest enantioselectivity (50% ee) was observed for 3,3-dimethyl-l,5-hexadiene with diphenylsilane. 

Effect of 18-crown-6 [31 on the asymmetric cyclization of 11481 with t-BuOK° in chlorobenzene6... 

Recently, an asymmetric version of this reaction has been reported by Gong and co-workers, allowing an efficient access to highly enantiomerically enriched 4-aryl-substituted 1,4-DHPs [152]. Thus, the use of chiral phosphoric acids as catalysts allowed the preparation of the desired products with enantiomeric excesses up to 97% (Scheme 53). To illustrate the importance of this asymmetric cyclization reaction, the authors developed the synthesis of some optically active heterocycles... 

Widenhoefer and co-workers have developed an effective protocol for the asymmetric cyclization/hydrosilylation of functionalized 1,6-enynes catalyzed by enantiomerically enriched cationic rhodium bis(phosphine) complexes. For example, treatment of dimethyl allyl(2-butynyl)malonate with triethylsilane (5 equiv.) and a catalytic 1 1 mixture of [Rh(GOD)2] SbF6 and (i )-BIPHEMP (5 mol%) at 70 °G for 90 min gave the silylated alkylidene cyclopentane 12 in 81% yield with 98% de and 92% ee (Table 4, entry 1). A number of tertiary silanes were effective for the rhodium-catalyzed asymmetric cyclization/hydrosilylation of dimethyl allyl(2-butynyl)malonate with yields ranging from 71% to 81% and with 77-92% ee (Table 4, entries 1-5). Although the scope of the protocol was limited, a small number of functionalized 1,6-enynes including A-allyl-A-(2-butynyl)-4-methylbenzenesulfonamide underwent reaction in moderate yield with >80% ee (Table 4, entries 6-8). 

Bercaw has investigated the application of the 6 2-symmetric, enantiomerically pure lanthanide metallocene derivative (i ,A)-BnBpYH 34 as a catalyst for the asymmetric cyclization/hydrosilylation of 1,5- and 1,6-dienes. Although 34 displayed high activity for the reaction of a number of dienes, asymmetric induction was low. In the best case, reaction of 3,3-dimethyl-1,5-hexadiene with phenylsilane catalyzed by 34 gave silylated cyclopentene 35 in 95% yield with 50% ee (Equation (25)). 

Widenhoefer and co-workers have developed an effective Pd-catalyzed protocol for the asymmetric cyclization/ hydrosilylation of functionalized 1,6-dienes that employed chiral, non-racemic pyridine-oxazoline ligands." " " Optimization studies probed the effect of both the G(4) substituent of the pyridine-oxazoline ligand (Table 7, entries 1-6) and the nature of the silane (Table 7, entries 6-15) on the yield and enantioselectivity of the cyclization/ hydrosilylation of dimethyl diallylmalonate. These studies revealed that employment of isopropyl-substituted catalyst (N-N)Pd(Me)Gl [N-N = (i )-( )-4-isopropyl-2-(2-pyridinyl)-2-oxazoline] [(i )-43f and a stoichiometric amount of benzhydryldimethylsilane provided the best combination of asymmetric induction and chemical yield, giving the corresponding silylated cyclopentane in 98% yield as a single diastereomer with 93% ee (Table 7, entry 15). 

Palladium-catalyzed asymmetric cyclization/hydrosilylation tolerated a number of functional groups including benzyl and pivaloyl ethers as well as benzyl and methyl esters (Table 8, entries 1-4). Furthermore, the protocol tolerated substitution at one of the two /ra/zi -terminal alkenyl positions and at one of the two allylic positions of the 1,6-diene (Table 8). As was the case with diene cyclization/hydrosilylation catalyzed by achiral palladium... 

Table 7 Asymmetric cyclization/hydrosilylation of dimethyl diallyl malonate catalyzed by palladium pyridine-oxazoline complexes...

Table 8 Asymmetric cyclization/hydrosilylation of functionalized dienes catalyzed by (R)-43f/NaBAr4...

Suisse and co-workers have studied the asymmetric cyclization/silylformylation of enynes employing catalytic mixtures of a rhodium(i) carbonyl complex and a chiral, non-racemic phosphine ligand. Unfortunately, only modest enantioselectivities were realized.For example, reaction of diethyl allylpropargylmalonate with dimethylphenyl-silane (1.2 equiv.) catalyzed by a 1 1 mixture of Rh(acac)(GO)2 and (i )-BINAP in toluene at 70 °G for 15 h under GO (20 bar) led to 90% conversion to form a 15 1 mixture of cyclization/silylformylation product 67 and cyclization/ hydrosilylation product 68. Aldehyde 67 was formed with 27% ee (Equation (46)). 

Most workers in the field have investigated the asymmetric cyclization of 2-methyl-2-(3-oxobutyl)-l,3-cyclopentadione (29). The resulting enedione (30) was used as the C,D-unit in the total syntheses of steroids having a natural configuration 67). With (S)-proline, (30) was obtained with an enantiomeric excess of 95 % in almost quantitative chemical yield 67d). 

Synthesis of a m-decalin system by the asymmetric cyclization[38] has been carried out with high enantioselectivity[142,143,147,148], Using BINAP as a chiral ligand, 91% ee was achieved in the asymmetric cyclization of 177 to give 178. In order to achieve an efficient asymmetric cyclization, selection of the reaction conditions is crucial, and sometimes added Ag salts play an important role[148], A catalytic asymmetric cyclization of 179 to prepare the key intermediate enone 180 for vernolepin synthesis has been carried out[149]. Highly efficient asymmetric cyclization of 181 to give the tetralin system 182 has been applied to the synthesis of (-)-eptazocine (183)[150], Hydrindans are synthesized in 86% ee[151]. 

Asymmetric cyclization of nerol and famesol.1 A biomimetic cyclization of nerol to limonene can be effected with an aluminum reagent 2 and a chiral leaving group. Thus the neryl ether 3 of R-( + )-2,2 -dihydroxy-1,1 -binaphthyl is cyclized... 

Asymmetric cyclization to apyrrolizuline. Treatment of the secondary amine 2 with methanolic HC1 followed by reduction of the Mannich base 3 gives the alkaloid (+ )-trachelanlhamidine (4) in about 40% yield. Use of the chiral salt 1 results in asymmetric cyclization to give (+ )-4 in 33% enantiomeric excess. Unfortunately the chemical yield is low. 

Rhodium-catalysed asymmetric cyclization/hydroboration followed either by Pd-catalysed arylation or by oxidation was applied to the synthesis of a number of chiral, non-racemic carbocycles and heterocycles. Thus, reaction of enyne (28) with catecholborane, catalysed by a 1 1 mixture of [Rh(COD)2]+ Sbly,- and (S)-BINAP (5 mol%), followed by Pd-catalysed arylation with /7-IC6H4CF3, afforded benzyli-denecyclopentane (29) in 65% yield with 88% ee.46... 

Asymmetric cyclization-hydrosilylation, examples, 10, 833 Asymmetric [3+2]-Cycloaddition reactions, via silver catalysts, 9, 566... 

Asymmetric cyclization using chiral ligands offers powerful synthetic methods for the preparation of optically active compounds [39]. After early attempts [40,41], satisfactory optical yields have been obtained in a number of cases. Synthesis of the optically active cA-decalin system [42] was carried out with high enantioselectivity based on the differentiation of enantiotopic C=C double bonds [43]. The cyclization of the triflate 93 gave the cA-decalin 94 with 95% ee in 78% yield using (i )-BINAP. A mixture of 1,2-dichloroethane and f-BuOH is the best solvent, and the asymmetric synthesis of vemolepin (96) via Danishefsky s key intermediate 95 has been achieved [44]. 

The highly efficient asymmetric cyclization of 97 using (i )-BINAP as a chiral ligand based on the differentiation of enantiotopic faces gave the tetralin system 98 with 93% ee and has been applied to the synthesis of (—)-eptazocine (99) [45]. 

The choice of solvents is crucial in the asymmetric cyclizations. In this case, DMSO gives the best results. 

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