Cyanohydrins silyl-protected

A. Van der Gen, Synthesis of optically active silyl protected cyanohydrins, Tetrahedron 1990, 46, 979-986. 

The most systematically investigated acyl anion equivalents have been the IMS ethers of aromatic and heteroaromatic aldehyde cyanohydrins, TBDMS-protected cyanohydrins, - benzoyl-protected cyanohydrins, alkoxycaibonyl-protected cyanohydrins, THP-protected cyanohydrins, ethoxyethyl-protect cyanohydrins, a-(dialkylamino)nitriles, cyanophosphates, diethyl l-(trimethylsiloxy)-phenyimethyl phosphonate and dithioacetals. Deprotonation di these masked acyl anions under the action of strong basie, usually LDA, followed by treatment with a wide varies of electrophiles is of great synthetic value. If the electrophUe is another aldehyde, a-hydroxy ketones or benzoins are formed. More recently, the acyl caibanion equivalents formed by electroreduction of oxazolium salts were found to be useful 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. - - ... 

The other route uses a silyl-protected cyanohydrin anion for the formation of the ketoester. The corresponding bromoester, prepared as shown in Scheme 21, reacts with the anion of a cyanohydrin to give, after hydrolysis, an ester which was transformed into trichostatin A in 4.8% overall yield. 

An important role for Znl2 has been found in the catalysis of RsSiCN addition to ketones and aldehydes to afford silyl protected cyanohydrins. This is a very general reaction that is effective even with very hindered carbonyl compounds (eq 7). Diastere-oselective cyanohydrin formation has been reported when these reaction conditions are applied to asymmetric carbonyl substrates (eq... 

Silylated cyanohydrins have also been prepared via silylation of cyanohydrins themselves and by the addition of hydrogen cyanide to silyl enol ethers. Silylated cyanohydrins have proved to be quite useful in a variety of synthetic transformations, including the regiospecific protection of p-quinones, as intermediates in an efficient synthesis of a-aminomethyl alcohols, and for the preparation of ketone cyanohydrins themselves.The silylated cyanohydrins of heteroaromatic aldehydes have found extensive use as... 

The hydroxyl group was usually protected, because cyanohydrins have tendency to racemization or even decomposition. Vinyl ethers or acetal and acid catalysts furnish acetals [62]. Trialkylsilyl chlorides and imidazole are used to give silyl ethers [63]. Commonly used protective groups are silyl ether, ester, methoxy isopropyl (MIP) ether, and tetrahydro-pyranyl ether. ( -Protected cyanohydrins are tolerant to a wider range of cyanide/nitrile transformations and are utilized widely in the synthesis of compounds of synthetic relevance in organic chemistry. 

Me3SiCN reacts with both saturated and unsaturated aldehydes and ketones to given silylated cyanohydrines. This reaction has been particularly useful for the regioselective protection of a carbonyl in p. quinones and p. quinol antibiotic metabolite has been prepared. 

Cyclic cyanohydrin ethers, 6-alkyl-2,2-dimethyl-l,3-dioxane-4-carbonitriles 1, are easily available from silylated aldols. Deprotonation of 1 and subsequent alkylation gives, v+ -4,6-disubsti-tuted 2,2-dimethyl-l,3-dioxane-4-carbonitriles 2 in good yields in a highly diastereoselective reaction48. Primary bromoalkanes and oxiranes have been used as alkylating reagents. Reduction of the alkylation products 2 afforded the protected, vj. -l,3-diols 3 with complete retention of configuration (see Section D.2.I.). 

Compound 1 has also been prepared by the following methods. Addition of ethylmagnesium bromide to the protected cyanohydrin of acetone, followed by hydrolysis and silylation provides 1 1n 40t yield (eq 2).2 Metallation of 1-methoxypropene by butyllithium in pentane gives 1-lithio-l-methoxypropene, which reacts with acetone to give, after hydrolysis and silylation, ketone 1... 

Silylated cyanohydrins have found considerable utility in the regioselective protection of p-qui-nones, as intermediates for the preparation of 3-amino alcohols and as precursors to acyl anion equivalents. Such compounds are typicdly prepared in high yield by either thermal or Lewis acid catalyzed addition of TMS-CN across the carbonyl group. This cyanosilylation has a variety of disadvantages and modified one-pot cyanosilylation procedures have been reported. - The carbonyl group can be regenerated by treatment with acid, silver fluoride or triethylaluminum hydrofluoride followed by base. ... 

Diketones often are protected as enol ethers or enamines and these selectively functionalized compounds may be subjected to complementary transformations (Scheme 94). Also silylenes can be prepared from diketones and -hydroxycarbonyl compounds by reaction with dimethyldicyanosilane. Naturally, these blocking groups are relatively sensitive to hydrolysis. On the other hand, partial solvolysis can open a route to monoprotected derivatives (e.g. 101), usually blocked at the sterically less demanding carbonyl function as 0-silyl cyanohydrins (see Scheme 95). Deprotection is finally achieved with silver fluoride in THF. 

Heteroatom-stabilized Carbanions. Heteroatom-stabilized and allylic carbanions serve as homoenolate anions and acyl anion equivalents, e.g. a-anions of protected cyanohydrins of aldehydes and Q ,/3-unsaturated aldehydes are intermediates in general syntheses of ketones and Q ,/3-unsaturated ketones (eq 36). Allylic anions of cyanohydrin ethers may be a-alkylated (eq 37) or, if warmed to —25°C, may undergo 1,3-silyl migration to cyanoenolates which may be trapped with TMSCl. Metalated Q -aminonitriles of aldehydes are used for the synthesis of ketones and enamines (eq 38). Similarly, allylic anions from 2-morpholino-3-alkenenitriles undergo predominantly a-C-alkyl-ation to give, after hydrolysis, a,/3-unsaturated ketones (eq 39). ... 

The hard silicon atom forms strong bonds with oxygenated compounds. This property has been exploited in the direct preparation of cyanohydrin trimethyl-silyl ethers (15-17). Strikingly the carbonyl group of p-benzoquinones can be protected by this method (18). 

Silyl ketene imines 21.126 (Scheme 21.18) developed by Denmark represent another group of useful nucleophilic reagents. These compounds are derived from protected cyanohydrins and thus can be viewed as acyl anion equivalents. They allow enantio- and diastereoselective construction of highly functionalised adducts 21.127, which can be further converted into useful synthetic intermediates, e.g. upon hydrolysis they produce crossbenzoin condensation products 21.128. ... 

The protection of carbonyl functions by reaction with trimethylsilyl cyanide to form the cyanohydrin trimethylsilyl ethers is subject to catalysis by potassium cyanide in the presence of 18-crown-6, tetrabutylammonium cyanide or resin bound tetraalkyl-ammonium cyanide [27, 29]. The nucleophilic cyanide ion is believed to attack the carbonyl yielding a cyanohydrin anion. This anion is silylated by trimethylsilyl cyanide with generation of an equivalent of cyanide anion. The sequence is shown in equation 7.13. Accordingly, 3-pentanone and 4- -butylcyclohexanone are cyanosil-... 

An interesting extension of this method involves the reaction of Af-silyl oxyketene imines derived from cyanohydrins (Scheme 19) [81]. By judicious selection of the protecting group on the oxygen, highly functionalized (3-hydroxy cyanohydrins can be accessed with high levels of enantio- and diastereoselectivity. These products can then be transformed into a diversity of structural motifs (amines, aldehydes, imines, ketones) important for the synthesis of polyketide and other classes of natural products. In addition, the ethers can be easily converted to enantiomerically enriched unsymmetrical benzoins, thus revealing the synthetic equivalency of A-silyl oxyketene imines as acyl anions (Scheme 19). 

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