Cyanohydrin TMS ethers

As summarized in Scheme 6.7, several a-acetal ketones were converted to the corresponding cyanohydrin TMS-ethers with 90-98% ee at catalyst loadings of 2-20 mol%. 

In 2000, Kagan and Holmes reported that the mono-lithium salt 10 of (R)- or (S)-BINOL catalyzes the addition of TMS-CN to aldehydes (Scheme 6.8) [52]. The mechanism of this reaction is believed to involve addition of the BI NO Late anion to TMS-CN to yield an activated hypervalent silicon intermediate. With aromatic aldehydes the corresponding cyanohydrin-TMS ethers were obtained with up to 59% ee at a loading of only 1 mol% of the remarkably simple and readily available catalyst. Among the aliphatic aldehydes tested cyclohexane carbaldehyde gave the best ee (30%). In a subsequent publication the same authors reported that the salen mono-lithium salt 11 catalyzes the same transformation with even higher enantioselectivity (up to 97% Scheme 6.8) [53], The only disadvantage of this remarkably simple and efficient system for asymmetric hydrocyanation of aromatic aldehydes seems to be the very pronounced (and hardly predictable) dependence of enantioselectivity on substitution pattern. Furthermore, aliphatic aldehydes seem not to be favorable substrates. 

In 1993 Corey et al. [60] reported a new enantioselective method for synthesis of chiral cyanohydrins [61] from aldehydes and trimethylsilyl cyanide (TMSCN) by the use of a pair of synergistic chiral reagents. Reaction of cyclohexane carbaldehyde 78 and trimethylsilyl cyanide (TMSCN) 79 in the presence of 20 mol % chiral magnesium complex 80 afforded the cyanohydrin TMS ether 81 in 85 % yield with 65 % ee. This modest enantioselectivity was fiirther enhanced to 94 % ee by addition of a further 12 mol % of the bis(oxazoline) 70 (Sch. 34). 

To explain this catalytic system it was proposed that the active CN source is not TMSCN but HCN, which can be expected to be present in reaction mixtures containing TMSCN as a result of hydrolysis caused by an adventitious trace of water. The chiral Lewis acid catalyst in turn captures the aldehyde and subsequent reaction proceeds with a chiral cyanide donor derived from the bis(oxazoline) 70 and HCN as shown in XXX. Finally, the cyanohydrin, produced as primary product is converted to the cyanohydrin TMS ether and HCN (Sch. 35). 

Me2AlCl has unique character in the discrimination of reaction pathways in Lewis acid-promoted reactions of aldehydes with organosilicon reagents (Scheme 10.235) [609]. The Me2AlCl-promoted reaction of benzaldehyde and cyclohexanecarbalde-hyde with a ketene silyl acetal and TMSCN affords the corresponding aldol adduct of benzaldehyde and the cyanohydrin TMS ether of cyclohexanecarbaldehyde, exclusively. 

The Lewis acid-Lewis base bifunctional catalyst 178a, prepared from Ti(Oi-Pr)4 and diol 174 (1 1), realizes highly enantioselective cyanosilylation of a variety of ketones to (R)-cyanohydrin TMS ethers (Scheme 10.241) [645]. The proposed mechanism involves Ti monocyanide complex 178b as the active catalyst this induces reaction of aldehydes with TMSCN by dual activation. Interestingly, the catalyst prepared from Gd(Oi-Pr)3 and 174 (1 2) serves for exclusive formation of (S)-cyanohy-drin TMS ethers [651]. The catalytic activity of the Gd complex is much higher than that of 178a. The results of NMR and ESI-MS analyses indicate that Gd cyanide complex 179 is the active catalyst. It has been proposed that the two Gd cyanide moieties of 179 play different roles - one activates an aldehyde as a Lewis acid and the other reacts with the aldehyde as a cyanide nucleophile. 

A recent variation of this strategy is due to Ziegler, who used TMS ethers of cyanohydrins of (x, -unsaturated aldehydes as substrates. Alkylation with an allylic halide, such as crotyl bromide in equation... 

The most systematic y investigated acyl anion equivalents have been the TMS ethers of aromatic and heteroaromatic aldehyde cyanohydrins, TBDMS-protected cyanohydrins, benzoyl-protected cyanohydrins, alkoxycarbonyl-protected cyanohydrins, THP-protected cyanohydrins, ethoxyethyl-protected cyanohydrins, a-(dialkylamino)nitriles, cyanophosphates, diethyl l-(trimethylsiloxy)-phenylmethyl phosphonate and dithioacetals. Deprotonation of these masked acyl anions under the action of strong base, usually LDA, followed by treatment with a wide variety of electrophiles is of great synthetic value. If the electrophile is another aldehyde, a-hydroxy ketones or benzoins are formed. More recently, the acyl carbanion equivalents formed by electroreduction of oxazolium salts were found to be useM for the formation of ketones, aldehydes or a-hydroxy ketones (Scheme 4). a-Methoxyvinyl-lithium also can act as an acyl anion equivalent and can be used for the formation of a-hydroxy ketones, a-diketones, ketones, y-diketones and silyl ketones. 42... 

Subsequently, the Feng group developed an enantioselective cyanosilylation of ketones by a catalytic double-activation catalyst system composed of chiral (J ,J )-salen 16-triethylaluminium complex and N-oxide 17 (Scheme 19.10). High catalytic turnovers (200 for aromatic ketones, 1000 for aliphatic ones) with high enantioselectivity (up to 94% enantiomeric excess for aromatic ketones, up to 90% enantiomeric excess for aliphatic ones) were achieved under mild reaction conditions. Based on the control experiments, a double-activation model was suggested (Scheme 19.10). The chiral aluminium complex performed as a Lewis acid to activate the ketone, whereas the N-oxide acted as a Lewis base to activate trimethylsilyl cyanide and form an isocyanide species. The activated nucleophile and ketone attracted and approached each other, and so the transition state was formed. The intramolecular transfer of cyanide to the carbonyl group gives the product cyanohydrin O-TMS ether. 

In the presence of a Lewis acid such as SnCh, BF3 OEt2, ot TiC104, TMS-CN reacts with acetals to give cyanohydrin ethers. o-Ribofuranosyl cyanide, an important intermediate of C-nucleoside synthesis, is prepared from a furanosyl acetate (Scheme 23). ... 

In catalytic processes with enzymes such as D-oxynitrilase and (R) xynitrilase (mandelonitrilase) or synthetic peptides such as cyclo[(5)-phenylalanyl-(5)-histidyl], or in reaction with TMS-CN pro-mot by chiral titanium(IV) reagents or with lanthanide trichlorides, hydrogen cyanide adds to numerous aldehydes to form optically active cyanohydrins. The optically active Lewis acids (8) can also be used as a catalyst. Cyanation of chiral cyclic acetals with TMS-CN in the presence of titanium(IV) chloride gives cyanohydrin ethers, which on hydrolysis lead to optically active cyanohydrins. An optically active cyanohyrMn can also be prepared from racemic RR C(OH)CN by complexation with bru-... 

The condensation of cyanohydrin ethers with aldehydes or ketones provides a-hydroxy ketones. 0-Benzoyl-protected cyanohydrins react with aldehydes to give a-hydroxy ketones via intramolecular deprotective benzoylation analogous to TMS-protect cyanohydrins (Scheme 10). ... 

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