Cyanohydrins 2-aminoalcohols

Another fruitful investigation was based upon the cyanohydrin of ketone 60. This substance (75) undergoes hydride reduction to the corresponding aminoalcohol, which forms cyclic carbamate 76 on... 

A different approach involving cyanohydrin formation from the 3-keto sugar was also explored in the D-Fru series (Scheme 17). A mixture of epimeric cyanohydrins was quantitatively formed by reaction with sodium cyanide in methanol, albeit without stereoselectivity. Chromatographic separation of (R)- and (A)-isomers was straightforward and the former epimer was selected to exemplify the two-step transformation into an OZT. Reduction of this nitrile by lithium aluminum hydride led to the corresponding aminoalcohol, which was further condensed with thiophosgene to afford the (3i )-spiro-OZT in ca. 30% overall yield. Despite its shorter pathway, the cyanohydrin route to the OZT was not exploited further, mainly because of the disappointing yields in the last two steps. 

Another notable new advance is the development of hydroxynitrile lyases for the synthesis of enantiomerically active aromatic and aliphatic cyanohydrins. For instance, an S-specific hydroxynitrile lyase has been obtained from Hevea brasiliensis and the resulting fS)-cyanohydrin can be used to obtain both hydroxy acids and aminoalcohols. 

In general, the method of enzymatic cyanohydrin synthesis promises to be of considerable value in asymmetric synthesis because of the synthetic potential offered by the rich chemistry of enantiomerically pure cyanohydrins, including their stereoselective conversion into other classes of compounds such as a-hydroxy carboxylic acids or respective esters, w c-diols, / -aminoalcohols, aziridins, a-azido(amino/fluoro)nitriles, and acyloins [501, 516]. 

Scheme 12 Option. The oxynitrilase-catalyzed HCN addition to the aldehyde Xin appeared to offer an attractive prospect presuming that the R-cyanohydrin (XIV) could be formed, and this then converted to dilevalol via intermediates XV and XVI. Although the oxynitrilase-catalyzed formation of chiral aromatic and aliphatic cyanohydrins and their reduction to chiral aminoalcohols has been known for some time,16 the selective reduction of XIV to XV and the likelihood of 100% induction in the reduction of the Schiff base XVI raised many questions.

Asymmetric cyanosilylation of ketones and aldehydes is important because the cyanohydrin product can be easily converted into optically active aminoalcohols by reduction. Moberg, Haswell and coworkers reported on a microflow version of the catalytic cyanosilylation of aldehydes using Pybox [5]/lanthanoid triflates as the catalyst for chiral induction. A T-shaped borosilicate microreactor with channel dimensions of 100 pm X 50 pm was used in this study [6]. Electroosmotic flow (EOF) was employed to pump an acetonitrile solution of phenyl-Pybox, LnCl3 and benzal-dehyde (reservoir A) and an acetonitrile solution of TMSCN (reservoir B). LuC13-catalyzed microflow reactions gave similar enantioselectivity to that observed in analogous batch reactions. However, lower enantioselectivity was observed for the YbCl3-catalyzed microflow reactions than that observed for the batch reaction (Scheme 4.5). It is possible that the oxophilic Yb binds to the silicon oxide surface of the channels. 

Recently, it has been demonstrated that the enzymatic synthesis of (S)-cyanohydrins was possible using an oxynitrilase isolated from Sorghum biocolor (95,96), These optically active cyanohydrins can be subsequently converted chemically to chiral ot-hydroxyadds, aminoalcohols, and acyloins. 

Enantiomerically pure cyanohydrins can easily be modified chemically or enzymatically (Scheme 4.12B), providing access to chiral a-hydroxy acids, a-hydroxy amides, 2-aminoalcohols, and epoxides. Replacement of the hydroxyl functionahty by a better leaving group, such as a sulfonyl moiety (e.g. tosylate), allows the introduction of various other nucleophiles with inversion at the stereocenter [51a]. The structures of some bioactive molecules that have been synthesized using a biotransformation step with a hydroxynitrile lyase are depicted in Scheme 4.12B [51a, 52]. 

Amines from nitriles s. 1, 53 a-Aminoalcohols from cyanohydrins s. 1, 54 Hydrogenation of the isoquinoline ring s. 2, 839 1,2,3 4-T etrahydroquinoxalines Removal of catalyst poisons s. 4, 65 CN —CH2NH2 [Pg.274]

Reduction of a cyanohydrin with lithium aluminum hydride gives a j8-aminoalcohol ... 

Asymmetric cyanosilylation of ketones and aldehydes is highly important, since the cyanohydrin product can easily be converted into optically active aminoalcohols... 

Another example dealing with a, 3-unsaturated ketones was reported by Gems et al. [110], Ketones 327 were smoothly converted to cyanohydrins by treatment with TMSCN, which on reduction with LiAlH, afforded the aminoalcohols 328. Acid catalyzed intramolecular cyclization gave 329, which by dehydration gave the pyrroles 330 generally in good yields. 

Trimethylsilyl [ C]cyanide is conveniently accessible from trimethylsilyl chloride, Na CN and Nal in the presence of lutidine or pyridine ". In carbon-14 synthesis it is normally generated in situ and used immediately in subsequent Lewis acid catalyzed chemical transformations. It is useful for some reactions in which alkah metal [ " C]cyanides normally fail, such as cyanide addition to acetals and aromatic and heteroaromatic aldehydes and ketones. Examples include the Znl2-catalyzed addition of TMS " CN to 2-furaldehyde followed by hydride reduction of the resultant silylated cyanohydrin to the aminoalcohol 96 " and the SnCLj-catalyzed formation of D-[l- " C]allonitrile 98, obtained from reaction of TMS " CN to the 0-acetylated hemiacetal 97 (Figure 7.26). Subsequent addition of H2Se to the nitrile group, cyclocondensation of the intermediate selenoamide in situ with ethyl bromopymvate and deprotection yielded 99, precursor to [2- " C]CI-935, a compound with... 

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