Cyclohexanols diastereoselectivity

The ring closures of cis- and fra/t5-2-aminomethyl-l-cyclohexanols and frani-2-hydroxymethyl-l-cyclohexylamine with aromatic aldehydes are highly diastereoselective. After recrystallization of the reaction products, the presence of single diastereomers 31-33 was observed [72ACH(73)81 80ACH(105)293, 800MR204 87JOC3821],... 

Interestingly, the reduction shown in Figure 17.53 is highly diastereoselective. Only the tranr-configured cyclohexanol is formed, that is, the equatorial alcohol. Such a level of diastereoselectivity cannot he achieved with hydride transfer reagents (cf. Figure 10.11). 

In contrast, sterically undemanding hydride donors such as NaBH4 or LiAlH4 reduce 4-fert-butylcyclohexanone preferentially through an axial attack. This produces mainly the cyclohexanol with the equatorial OH group (Figure 8.8, middle and bottom reactions). This difference results from the fact that there is also a stereoelec-tronic effect which influences the diastereoselectivity of the reduction of cyclohexanones. 

The Birch reduction has been applied to electron-deficient pyrroles substituted with a chiral auxiliary at the C(2)-position <1999TL435>. Using either (—)-8-phenylmenthol or (- -)-/ra /-2-(ot-cumyl)cyclohexanol as auxiliaries, high levels of stereoselectivity were obtained. Pyrrole 911, prepared from the l/7-pyrrole-2-carboxylic acid 910 in 90% yield, was reduced under modified Birch conditions (Scheme 176). The best conditions involved lithium metal (3 equiv), liquid ammonia and THE at —78°C. The addition of A, A -bis(2-methoxyethyl)amine (10 equiv) helped to reduce side reactions caused by the lithium amide formed in the reaction <1998TL3075>. After 15 min, the Birch reductions were quenched with a range of electrophiles and in each case 3,4-dehydroproline derivatives 912 were formed in excellent yields and with good diastereoselectivities. 

Addition of BuiSnLi to cyclohex-2-enone followed by enolate trapping with n-decyl iodide proceeded with high diastereoselectivity to provide the 2,3-rrdiR5-stannyl ketone (16), which could be equilibrated with the cis diastereomer (17) upon treatment with base. LAH reduction, followed by separation of the diasteteomers, afforded samples of the 2-alkyl-3-stannylcyclohexanols as shown in Scheme 17. Iodine(III)-mediated fragmentation was shown to proceed in a stereospecific anti manner, with either of the rrdiRr-2,3-cyclohexanols affording ( )-enal (18), and the cir-2,3-alcohol the (Z)-enal (19 Scheme 17). Enal (18) was then utilized in a stereoselective synthesis of the mosquito pheromone, erythro-6-asx-toxyhexadiecan-S-olide (20 Scheme 18). ... 

Allylic azides, e.g., 1, were produced by treatment of the triisopropylsilyl enol ethers of cyclic ketones with azidotrimethylsilane and iodosobenzene78, but by lowering the temperature and in the presence of the stable radical 2,2,6,6-tetramethylpiperidine-/V-oxyl (TEMPO), 1-triso-propylsilyloxy-l,2-diazides, e.g., 2, became the predominant product79. The radical mechanism of the reaction was demonstrated. A number of 1,2-diazides (Table 4) were produced in the determined optimum conditions (Method B 16h). The simple diastereoselectivity (trans addition) was complete only with the enol ethers of unsubstituted cycloalkanones or 4-tert-butylcy-clohexanone. This 1,2-bis-azidonation procedure has not been exploited to prepare a-azide ketones, which should be available by simple hydrolysis of the adducts. Instead, the cis-l-triiso-propylsilyloxy-1,2-diazides were applied to the preparation of cw-2-azido tertiary cyclohexanols by selective substitution of the C-l azide group by nucleophiles in the presence of Lewis acids. 

With cyclic alkenes, fairly high diastereoselectivity can be achieved. Hydrozirconation of norbomene, followed by TBHP oxidation, gives the exo-alcohol in 95% yield, while the more complex bicyclics camphene (37) and P-pinene (38) give the mixtures shown in equations (39) and (40), respectively. TTie hafnium analog shows the opposite preference with P-pinene and does not react with camphene at all, attributed to significantly greater steric demand. Diastereoselectivity in cyclohexanols obtained by hydrozirconation of ketones has also been examined. ... 

In order to obtain an insight into the diastereoselectivity in the Diels-Alder reaction of acetylenic sulfinates, chiral (+)-trans-2-phenylcyclohexanol [35] was used in place of cyclohexanol in the synthesis of the dienophile. A 1 1 dia-stereoisomeric mixture of acetylenic sulfinates 69 and 70 was obtained. After separation, each diastereoisomer was subjected to a Diels-Alder reaction with cyclopentadiene. Although the reaction once again occurred readily at room temperature, to our disappointment an inseparable mixture of diastereomeric adducts (3 2 by NMR) was obtained for each sulfinate. Apparently, a more spatially demanding chiral auxiliary needs to be incorporated into the dienophile in order to generate chiral sulfinates which cycloadd with prominent diastereoselectivity. 

The use of chiral chloroformates, such as that derived from tranx-2-(a-cumyl)cyclohexanol, allows diastereoselective additions to 4-methoxypyridine. The introduction of a tri-ixo-propylsilyl group at C-3 greatly enhances the diastereoselectivity. The products of these reactions are multifunctional chiral piperidines which have found use in the asymmetric synthesis of natural products. ... 

Summary rac-l-(4-Fluorophenyl)-l-methyl-l-sila-2-cyclohexanone (rac-1) and rac-(SiS, C/ /Sii ,CS)-2-acetoxy-l-(4-fluorophenyl)-l-methyl-l-silacycIohexane [rac-(Si5,Ci /Siiil,C5)-3a] were synthesized as substrates for stereoselective microbial transformations. Resting free cells of the yeast Saccharomyces cerevisiae (DSM 11285) and growing cells of the yeasts Trigonopsis variabilis (DSM 70714) and Kloeckera corticis (ATCC 20109) were found to reduce rac- diastereoselectively to yield mixtures of the enantiomers (S S,CR)- and (SLR,C5)-l-(4-fluorophenyl)-l-methyl-1-sila-2-cyclohexanol [(Si5,C/ )-2a and (SLR,CS)-2a]. In the case of Kloeckera corticis (ATCC 20109), diastereoselective reduction of rac-1 gave a quasi-racemic mixture of (Si5,CR)-2a and (SiR,CS)-2a (diastereomeric purity 95 % de, yield 95 %). Enantioselective ester hydrolysis (kinetic resolution) of the 2-acetoxy-l-silacyclohexane rac-(Si5,CR/Si/ ,C5)-3a yielded the optically active l-sila-2-cyclohexanol (Si/ ,C5)-2a [enantiomeric purity >99% ee yield 56 % (relative to (Si, C5)-3a)]. 

In addition to the Bamford-Stevens/Claisen sequence, the same group investigated a number of cascade reactions, wherein a third chemical step occurs after the initial tandem process. For instance, Lewis acid promotion of neryl ether 30 induces a cascade terminating in a carbonyl-ene reaction to produce cyclohexanol 31 with excellent diastereoselectivity. 

The domino Henry-Michael reaction of CH3NO2 with 7-oxo-hept-5-en-l-als RC0CH=CH(CH2)3CH=0, catalysed by the quinine-derived thiourea (288b) (<96% ee), followed by the tetramethyl guanidine (TMG)-catalysed retro-Henry-Henry reaction of the initially formed disubstituted cyclohexanols, led to a refinement of diastereoselectivity (to >99 1 dr) ... 

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