TMS-cyanohydrins

The synthesis of the furan-imidazole derivatives, shown in Scheme 2, were also described by Wang et al. [34]. Reaction of 4-(dimethylamino)benzalde-hyde (20) with trimethylsilylcyanide (TMS)-CN in the presence of Znl2 produced the TMS cyanohydrin 21. Compound 21 was treated with LDA followed by the addition of 3,4,5-trimethoxybenzaldehyde to give the benzoin intermediate 22. Oxidation with CUSO4 in aqueous pyridine, followed by reaction with 3-furaldehyde in acetic acid, produced the substituted imidazole 23. 

TMS cyanohydrins. Aliphatic aldehydes react smoothly, aromatic and a,0-unsaturated aldehydes react very slowly, with ketones being unreactive. 

Our first approach to 1 is based on a retrosynthetic analysis depicted in Fig (8). The crucial step to construct the cw-fused bicyclic ring skeleton of 1 is the intramolecular allylic amination of a cw-allylic carbonate 25. The paUadium-catalyzed allylation takes place with retention of the configuration [76] and requires the c/s-isomer 25 for the ring closure. Compound 25 may be derived from keto acid 24 through a sequence of reactions including esterification, O-methoxycarbonylation, removal of the Boc and benzylidene groups, dehydrative cyclization, reductive alkylation and ureido formation. The last five transformations are to be conducted in a successive manner, i.e., without isolation of the intermediates. The 4-carboxybutyl chain of 1 may be installed by the reaction of O-trimethylsilyl (TMS) cyanohydrin 23 with a di-Grignard... 

A highly anti-selective hydrocyanation of (7 )-jV-Boc-2, 2-dimethylthia-zolidine-4-carbaldehyde (Gamer s aldehyde) with hydrogen cyanide in the presence of a Lewis acid has been reported [78]. In the initial study, we applied the procedure to the synthesis of anti-O-TMS cyanohydrin 23. However, the cyanosilylation of 22 in the presence of Lewis acid such as zinc iodide (Znl2), zinc bromide (ZnBr2) or boron trifluoride (BFy) diethyl ethcrate was problematic, leading only to traces of 23. 

Enantioselective TMS cyanohydrin formation with aldehydes can be achieved using a variety of chirally-modified titanium catalytic systems chiral modifiers include Schiff bases, including salen ligands and sulphoximines. A chirally-modified yttrium complex has been employed for the same purpose (equation 8) here, the chiral modifier was a ferrocene-derived 1,3-diketone. This general area has been reviewed recently . 

Alkylation reactions of (207) are not so promising. In general, a-hydroxyamides are best prepared from carbonyls by cyanohydrin formation and subsequent hydrolysis of the nitrile function. However, this approach is usually not feasible with aryl ketones as the equilibrium between ketone and cyanohydrin lies far to the left. This problem can be overcome by using trimethylsilyl cyanide acid hydrolysis of the resulting O-TMS cyanohydrin gives a-hydroxyamides in >70% yield. Some ketones however, still cannot be satisfactorily transformed by this method. Treatment of bis-NO-trimethylsilylacetamide or iV-trimethylsilyl-acetamide with n-BuLi results in the formation of anions (209) and (210), respectively, which condense with carbonyls to give /8-hydroxyamides or their iV-methyl derivatives in fair to excellent yields. " ... 

The N,N -dioxide 98 has been reported to catalyze the formation of TMS-cyanohydrins ent-96 apparently without the need for dual activation (Scheme 15.21). However, the reaction requires a rather long time (80h) to reach completion at acceptable enantioselectivity (<73% ee) [90]. 

In 2000, Kagan et al. presented the addition of trimethylsilylcyanide (TMSCN) (99) to aldehydes catalyzed by the monolithium salt of (5)-(-)-BINOL (106) [118]. The proposed mechanism includes a hypervalent silicon intermediate. In an initial attack of the anionic chiral catalyst, a pentavalent silicon complex is formed (100). The complex acts as Lewis acid and is supposed to coordinate the carbonyl group of the aldehyde (101) to a hexavalent species (102). The next step is the enantioselective transfer of cyanide (103), followed by elimination of the anionic catalyst. Consequently, the TMS cyanohydrin (104) is formed (Scheme 7.18). 

The addition of trimethylsilyl (TMS) cyanide to aldehydes produces TMS-protected cyanohydrins. In a recent investigation a titanium salen-type catalyst has been employed to catalyse trimethylsilylcyanide addition to benzaldehyde at ambient temperature1118]. Several other protocols have been published which also lead to optically active products. One of the more successful has been described by Abiko et al. employing a yttrium complex derived from the chiral 1,3-diketone (41)[119] as the catalyst, while Shibasaki has used BINOL, modified so as to incorporate Lewis base units adjacent to the phenol moieties, as the chiral complexing agent11201. 

Utihzing the readily accessible diastereomeric atropoisomeric thioureas (aR/ aR)-(R,R)-88 as the catalyst (10mol%) various (hetero)aromatic and aliphatic aldehydes could be cyanosilylated to the corresponding TMS-protected cyanohydrins... 

Scheme 6.95 TMS-protected cyanohydrins prepared from the cyanosilylation of aidehydes in the presence of atropoisomeric thiourea catalyst (aR/aR)-(R,R)-ZZ. Desilylation and acetylation to the respective more stable acetates.

Scheme 12.12. Synthesis of isoclavukerin using a three-component nucleophilic addition/cyanohydrin breakdown/ conjugate addition, by Trost and Higushi [34]. TMS = trimethylsilyl, LDA = lithium diisopropylamide, THF = tetrahydrofuran, PMB = p-methoxybenzyl, Ac = acetyl.

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. 

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... 

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). 

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). ... 

Acetals prepared from chiral diols and carbonyl compounds serve as a chiral synthetic equivalent of aldehydes or ketones. 1,3-Dioxanes synthesized from chiral 2,4-pentanediols are especially useful, and high asymmetric inductions are observed in the Lewis acid promoted reactions of a variety of organometallic compounds. After the removal of the chiral auxiliary by the oxidation and -elimination procedures, optically active alcohols are obtained. Optically active propargylic alcohols and cyanohydrins are synthesized from organosilane compounds, TMS-C CR or TMS-CN in the presence of TiCU (Scheme 24). 1 6-138 Reactive wganometals such as alkyl-lithiums, -magnesiums or -coppers also react with chiral... 

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-... 

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. ... 

Oxidation of a cyanohydrin derived from a conjugated aldehyde (as the 0-TMS derivative) using py-ridinium dichromate (PE)C) in DMF gave an a,3-unsaturated lactone (5 -butenolide) as the major product (equation 12). Simple nonconjugated cyanohydrins are not satisfactory substrates for the synthesis of acyl cyanides using PDC, because they seem to add to the initially formed acyl cyanides, leading ultimately to cyanohydrin esters. Oxidation of cyanohydrin to acyl cyanides can be carried out either by means of manganese dioxide, ruthenium-catdyzed oxidation with t-butyl hydroperoxide or NBS. ... 

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). ... 

A system analogous to a cyanohydrin is a siloxyalkylphosphonate. Thus, the diethyl 1-phenyl-1-tri-methylsiloxymethylphosphonate carbanion derived from (61) on treatment with LDA acts as an effective acyl anion equivalent in the preparation of a-hydroxy ketones and ketones. The phosphonate (61) is formed from triethyl phosphite, benzaldehyde and TMS-Cl in excellent yield. 

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