Preparation of chiral secondary

Asymmetric hydrogenolysis of epoxides has received relatively little attention despite the utility such processes might hold for the preparation of chiral secondary alcohol products. Chan et al. showed that epoxysuccinate disodium salt was reduced by use of a rhodium norbornadiene catalyst in methanol/water at room temperature to give the corresponding secondary alcohol in 62% ee (Scheme 7.31) [58]. Reduction with D2 afforded a labeled product consistent with direct epoxide C-O bond cleavage and no isomerization to the ketone or enol before reduction. 

The hydroboration of dienic silyl enol ethers, such as 124, with LItBH leads to organob-oranes which can be converted to new diorganozincs, such as 125 (Scheme 42) . More importantly, this method allows the preparation of chiral secondary alkylzinc reagents. 

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]. 

Asyimnetric hydrogenation of prochiral ketones is an important method for the preparation of chiral secondary alcohols. Until recently, however, such reactions were limited to substrates with pendent metal binding sites, like /3-keto esters. Many of the catalysts that efficiently hydrogenate C-C double bonds exhibit little or no reactivity with isolated ketones. This discrepancy may be ascribed to the different binding modes of alkenes and ketones, and the chemoselectivity of catalysts for these groups. While substrates with C-C double bonds can form metal... 

Asymmetric addition of diorganozincs to aldehydes catalyzed by chiral -amino alcohols provides a general method for the preparation of chiral secondary alcohols. Oguni, Noyori, and co-workers found that the aminoalcohol, (2S)-3-exo-(dimethylamino)isobornenol ((2S)-DAIB), acts as a particularly efficient promoter for this asymmetric reaction [9, 10]. Reaction of benzalde-hyde with diethylzinc in the presence of 2 mol% of (2S)-DAIB gives, after aqueous workup, (S)-l-phenylpropanol in high yield with 99% ee as shown in Scheme 8. Detailed mechanistic and theoretical studies of the (2S)-DAIB-pro-moted asymmetric addition have been reported [11]. 

Hydroboration of simple ketones eatalyzed by proline-derived oxazaborolidine 45 provides a practical method for the preparation of chiral secondary alcohols (Scheme 13). Under this protocol, a key intermediate in the synthesis of MK-0417 (44), a water-soluble carbonic anhydrase inhibitor, has been prepared... 

The enantioselective preparation of chiral secondary alcohols has been achieved through a number of methods with great success. One pathway that is widely used is the asynunetric addition of organometallic compounds R M to aldehydes [1] (retrosynthetic pathway A of Eq. (1). A disconnection involving inversion of polarity [2] is also possible (retrosynthetic pathway B of [Eq. (1)]. 

Yeast ADH has a very narrow substrate specificity and, in general, only accepts aldehydes and methyl ketones [770, 771], Therefore, cyclic ketones and those bearing carbon chains larger than a methyl group are not accepted as substrates. Thus, YADH is only of limited use for the preparation of chiral secondary alcohols. Similarly, other ADHs from Curvularia falcata [772], Mucor javanicus and Pseudomonas sp. [773] are of limited use as long as they are not commercially available. The most conunmily used dehydrogenases are shown in Fig. 2.15, with reference to their preferred size of their substrates [774]. 

Mixed salt-free dialkylzinc species, obtained from the corresponding Grignard reagents by the method described above, display a very useful selectivity in the transfer of alkyl groups in the addition reaction to aldehydes. The presence of a chiral aminoalcohol as a catalyst permits a practical preparation of chiral secondary alcohols with high enantioselectivity. 

More importantly, this method allows the preparation of chiral secondary alkylzinc reagents. Thus, the hydroboration of 1-phenylcyclopentene with (-)-IpcBHj (99% ee) [107] produces, after crystallization, the chiral organoborane 126 with 94% ee. The reaction of 126 with Et2BH replaces the isopinocampheyl group with an ethyl substituent (50 °C, 16h) and provides after the addition of t-Pr2Zn (25 C, 5 h), the mixed diorganozinc 127. Its stereoselective allylation leads to the trans-disubstituted cydopentane 128 in 44% yield (94% ee trans cis= 98 2) Scheme... 

Asymmetric allylic C-H activation of more complex substrates reveals some intrinsic features of the Rh2(S-DOSP)4 donor/acceptor carbenoids [135, 136]. Cyclopropanation of trans-disubstituted or highly substituted alkenes is rarely observed, due to the steric demands of these carbenoids [16]. Therefore, the C-H activation pathway is inherently enhanced at substituted allylic sites and the bulky rhodium carbenoid discriminates between accessible secondary sites for diastereoselective C-H insertion. As a result, the asymmetric allylic C-H activation provides alternative methods for the preparation of chiral molecules traditionally derived from classic C-C bond-forming reactions such as the Michael reaction and the Claisen rearrangement [135, 136]. 

Polymers derived from natural sources such as proteins, DNA, and polyhy-droxyalkanoates are optically pure, making the biocatalysts responsible for their synthesis highly appealing for the preparation of chiral synthetic polymers. In recent years, enzymes have been explored successfully as catalysts for the preparation of polymers from natural or synthetic monomers. Moreover, the extraordinary enantioselectivity of lipases is exploited on an industrial scale for kinetic resolutions of secondary alcohols and amines, affording chiral intermediates for the pharmaceutical and agrochemical industry. It is therefore not surprising that more recent research has focused on the use of lipases for synthesis of chiral polymers from racemic monomers. 

Epoxides from ic-diols. The reaction if secondary, primary v/c-diols with a mixture of 6 M hydrogen bromide in HOAc n suits in a vR -2-acetoxy-l-bromoalkane, which is converted into an alkyloxirane on treaiment with base. The method is suitable for preparation of chiral alkyloxiranes. 

Treatment of a primary aliphatic amine with nitrous acid or its equivalent produces a diazonium Ion which results in the formation of a variety of products through solvent displacement, elimination and solvolysis with 1,2-shift and concurrent elimination of nitrogen. The stereochemistry of the deamination-substitution reaction of various secondary amines was investigated as early as 1950, when an Swl-type displacement was suggested. Thus, the process can hardly be utilized for the preparation of alcohols except in cases where additional factors controlling the reaction course exist. Deamination-substitution of a-amino acids can be utilized for the preparation of chiral alcohols. 

Carboxylic acids. Primary alcohols are oxidized to acids (secondary alcohols to ketones) using catalytic amount of CrOj and excess HjIOg in wet MeCN. By this procedure there is very little racemization of the products bearing a chirality center adjacent to the emerging carbonyl group. Therefore this method is useful for the preparation of chiral a-amino acids. 

Arylamines. Primary," secondary, and tertiary arylamines have been prepared by Pd(0)-catalyzed IV-arylation methods. The most common and effective catalytic system contains (dbaljPd, r-BuONa, and a tertiary phosphine such as BINAP. The nucleophilic species for the synthesis of primary anilines is a Ti-N complex formed from (i-PrO) Ti, Li, and McjSiCl in THF under nitrogen at room temperature (8 h). N-Arylation of chiral secondary amines proceeds without affecting the stereocenters. Arylation with Arl is facile because it can be carried out at room temperature. More recent development indicates that employment of 2-dimethylamino-2 -dicyclohexylphosphinobiphenyl as ligand in the amination of unactivated chloroarenes under mild conditions is also possible. 

FIGURE 3.24. Use of an immobilized TADDOL reagent to prepare a chiral secondary alcohol... 

Using the optimum conditions (Table 28, entry 6), a variety of chiral secondary amines have been investigated. The results are shown in Table 29. The most effective auxiliary for preparation of the enantiomeric aldol (242b) is the phenylglycine-derived amine (Table 29, entry 8). 

Thionyl chloride is used extensively for the preparation of chlorides. In the absence of base, retention of configuration is always observed. This has been rationalized by an SNi mechanism or by participation of the solvent46. Thionyl chloride in hexamethylphosphoric triamide46 or chloroform47 gives clean SN2 chlorinations of chiral secondary alcohols. Allylic silyl ethers are chlorinated with thionyl chloride in an SN2 reaction48. 

Ring cleavage. Diastereoselective cleavage of C2-symmetrical 1,3-dioxanes has been effected by reagents prepared from organoaluminums. For example, reduction with a species obtained from Me Al and C6F5OH is useful for synthesis of chiral secondary alcohols. ... 

The synthesis of 2-aminobutadienes from ketones is somewhat limited due to difficult control of /Z-stereochemistry. [27] Therefore, the catalytic aminomercuration of3-alkenyl-l-ynes 4 was a significant improvement of the synthesis of 2-amino-l,3-butadienes 5 (yields 49-75 %). [28] The catalytic aminomercuration of 4-ethoxy-3-alkenyl-1-ynes even leads to electronrich and highly reactive 1,3-diamino-1,3-butadiens which undergo a great variety of cycloadditions. [29] Scheme 2 shows the reaction for a general example (for R = H two secondary amines can add to the enine 4 to yield 6). The method can easily be extended to the preparation of chiral 2-amino-1,3-butadienes by addition of chiral amines [e. g. (5)-2-methoxymethylpyr-rolidine (SMP) [27]]. 

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