Silylated aldols

Transmetalation of 19 by treatment with two equivalents of diethylaluminum chloride generates the aluminum enolate species 23. The latter reacts with acetaldehyde to produce the stable aluminum aldolates 24 which do not undergo the Peterson elimination23. A protic quench then provides the a-silylated aldol adducts of tentative structures (2 R)-25 and (2 V)-25 with little diastereoselectivity. Other diastereomers are not observed. 

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.). 

A stereoselective Mukaiyama-type aldol reaction of bis(trimethylsilyl)ketene acetals produces silyl aldols with syn stereoselectivity, predominantly due to steric effects.23... 

Aldol condensation.1 These O-silyl enol derivatives of amides are available by hydrosilylation of a,P-unsaturated amides catalyzed by Wilkinson s catalyst. A typical reagent of this type, 1, reacts with aldehydes in the absence of a catalyst to form aldol adducts (2) with unusual anti-selectivity. This silyl aldol reaction can be ex-... 

Three-component aldol synthesis.1 This rhodium carbonyl can promote aldol coupling of enol silyl ethers with aldehydes or ketones. It can also effect coupling of an enone, an aldehyde, and a trialkylsilane to provide a silyl aldol. In the case of an enolizable aldehyde, yields are improved by addition of a phosphine ligand such as... 

Thus, according to Scheme 24, diol 149 was converted into protected aldehyde 150 via persilylation and Swem oxidation. Subsequent intramolecular silylative aldolization smoothly provided epimeric bicyclooctanoids 151 and 152 as a separable 92 8 mixture. Bicyclic adducts 151 and 152 were then in parallel elaborated to unmask the hydroxymethyl and the pseudoanomeric functions, leading to 5a-carba-(I-D-gulopyranose (153) and 5a-carba-(3-D-allopyranose (154), respectively. 

The Et3SiH-promoted diastereoselective reductive aldol reaction proceeds by using InBr3 as a catalyst. This three-component reaction affords only silyl aldolates as products without any side-reaction. The //-selectivity obtained here is higher than that of any other reductive aldol reactions (Scheme 111).382 A catalytic amount of In(OAc)3 also promotes... 

The aldol reaction of ketene silyl acetals with several aldehydes (Mukaiyama aldol reaction) assisted by Li has been described briefly by Reetz et al. Wirth 5.0 m LPDE a clean reaction began within 1 h with the sole formation of the silylated aldol 112, whereas the use of a catalytic amount (3 mol %) of LiC104 in Et20 (3 mol % LPDE) required a reaction time of 5 days for 86 % conversion. As observed in the hetero-Diels-Alder reaction of a-alkoxyaldehyde, the higher rate of reaction of 79 compared with that of benzaldehyde can be attributable to chelation. Indeed, the use of 3 mol % LPDE required only 20 h at room temperature for complete uptake of 79 with a diastereoselectivity (syn-113lanti-113) of >96 % (Sch. 55). 

Mukaiyama aldol reactions using a catalytic amount of a Lewis acidic metal salt afford silylated aldols (silyl ethers) as major products, but not free aldols (alcohols). Three mechanistic pathways which account for the formation of the silylated aldols are illustrated in Scheme 10.14. In a metal-catalyzed process the Lewis acidic metal catalyst is regenerated on silylation of the metal aldolate by intramolecular or intermolecular silicon transfer (paths a and b, respectively). If aldolate silylation is slow, a silicon-catalyzed process (path c) might effectively compete with the metal-catalyzed process. Carreira and Bosnich have concluded that some metal triflates serve as precursors of silyl triflates, which promote the aldol reaction as the actual catalysts, as shown in path c [46, 47]. Three similar pathways are possible in the triarylcarbenium ion-catalyzed reaction. According to Denmark et al. triarylcarbenium ions are the actual catalysts (path b) [48], whereas Bosnich has insisted that hydrolysis of the salts by a trace amount of water generates the silicon-based Lewis acids working as the actual catalysts (path c) [47]. Otera et al. have reported that 10-methylacridinium perchlorate is an efficient catalyst of the aldol reaction of ketene triethylsilyl acetals [49]. In this reaction, the perchlorate reacts smoothly with the acetals to produce the actual catalyst, triethylsilyl perchlorate. 

Mukaiyama et al. have shown that a BINOL-derived oxotitanium catalyzes the asymmetric aldol reaction of aldehydes with thioester silyl enolates [147]. In the presence of the chiral complex (20mol%), the TBS enolate of S-t-butyl thioacetate reacts smoothly with aromatic and a,/ -unsaturated aldehydes in toluene to give silylated aldols in high yields with moderate to good enantioselectivity (91-98%, 36-85% ee). The use of the TBS enolate of S-ethyl thioacetate results in lower enantioselectivity. 

Dumas et al. noted the good yields and syn diastereoselectivities obtained in a high-pressure aldol reaction of bis-silyl ketene acetals 154 with benzaldehyde (155) (Scheme 7.39). The syn aldol 156 was obtained with a diastereoselectivity that was significantly correlated with the steric bulkiness of the R-substituent in the acetals 154. The preference for syn bis-silyl aldols 156 has been attributed to the reaction pathway that involves compact transition states in which steric interactions between the R substituent of 154 and the phenyl group of benzaldehyde are minimized. The authors also studied the condensation of unsaturated bis-silyl ketene acetal as a model for the synthesis of retinoid compounds. ... 

Preliminary examples of catalytic enantioselective aldol additions using rhodium complexes with chiral phosphine ligands attached, e.g. (42), have been disclosed by Reetz and Vougioukas (equation 15) although the low level of asymmetric induction so far obtain in the silylated aldol adduct (43) requires substantial enhancement before this reaction has any synthetic value. However, there is ample scope for future improvement by the use of more effective chiral diphosphine- odium complexes. 

Dehydration of aldols. Dehydration of j8-silyl aldols with pyridinium tosylate (PPTS) and MsCI-EtjN give very different results. The PPTS reaction is regioselec-tive and stereoselective, affording mainly the (Z)-isomers. 

The carbonyl group of a-silylated aldols can be reduced stereoselectively with hydride reagents to yield 2-silylated 1,3-diols [e.g. (95)]. Diols which are configured syn,anti [such as (95)] undergo highly regio- and stereo-selective Peterson olefination. 

An intramolecular silylative aldol reaction has been effectively employed as a key step in the synthesis of a variety of carbasugars (eq 19). The TBDMS triflate plays a dual role in this chemistry, forming an enol silane and activating the aldehyde toward nucleophilic attack. 

Group transfer-type of Mukaiyama aldol addition to aldehydes or ketones affords the isolable 0-silylated aldol adducts, which can be hydrolyzed under acidic conditions to provide a-keto esters in high yield (eq 2) In the case of aldehydes the initial products are 0-silyl-protected reductones. ... 

Silylated aldol adducts can be reached by using a nonaldol rearrangement promoted by treatment of bulky epoxy bis-silyl ethers with TMSOTf/i-Pr2NEt in methylene chloride at —50 °C (eq 95). Bulky mesylated epoxy silyl ethers also undergo this transformation however, a silyl triflate-promoted Payne rearrangement was observed as a side reaction depending on the stereochemistry of the starting epoxide. ... 

A few years ago, Riant and co-workers had already presented a fine example of a copper(l)-catalyzed domino silylative aldol reaction. The stereochemical outcome was controlled by the use of a chiral oxazolidinone auxiliary attached to a Michael acceptor (Scheme 37) [88], The copper(l)-enolate formed by the conjugate silylation of acryloyloxazolidinone 143 was trapped with different aldehydes to yield aldol structures 145d and 145g-i diastereoselectively (Scheme 37, upper). 

Scheme 37 Domino silylative aldol reactions by Riant...

Scheme 11.23 Cu(I)-catalyzed diastereoselective silylative aldol reaction.

Welle, A., Petrignet, J., Tinanf B., Wonters, J. Riant, O. (2010). Copper-catalysed domino silylative aldol reaction leading to stereocontrolled chiral quaternary carbons. Chemistry - A European Journal, 16, 10980-10983. 

A solution of ketene silyl acetal 74 (146 mg, 0.84 mmol) in DMF (0.8 mL) was added to a solution of lithium pyrrolidone in DMF (0.1 m, 0.6 mL, 0.06 mmol) at —45 °C and a solution of aldehyde (89.5 mg, 0.60 mmol) in DMF (1.6 mL) was then added. The reaction mixture was stirred at the same temperature for 1 h and the reaction was then quenched by adding saturated NH4CI. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated. The crude product was purified by preparative TLC (hexane-ethylacetate, 3 1) to give the silylated aldol adduct 75 (187 mg, 96%). 

Treatment of ketone (69) with excess amounts of t-BuMe2SiOTf and bis[(k)-l-phenylethyl]amine ((i )-BPEA) gives tricyclic silyl aldolate (70) with moderate enantioselectivity [104]. The formation of (70) can be explained by the enol silylation to (71) followed by a tandem Michael-aldol reaction. The asymmetric induction by the chiral amine occurs in the enol silylation (Scheme 9.40). The combined use of silyl triflates and amines has been applied to an intramolecular aldol reaction for natural product synthesis [105]. 

The asymmetric Mukaiyama-type aldol reaction is a representative example of ammonium fluoride-catalyzed reactions (Scheme 14.7) (25). In the first step, silyl enol ether 10 reacts with ammonium fluoride to produce ammonium enolate 11 with generation of trialkylsilyl fluoride. The ammonium enolate 11 then reacts with aldehyde to produce ammonium alkoxide 12. Attack of this alkoxide anion on silyl enol ether 10 leads to the regeneration of ammonium enolate 11 and the formation of silylated aldol product 13. 

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