Tertiary alcohols, aldol reactions

A domino reduction-aldol reaction of ketones with methyl acrylate produces tertiary alcohols bearing an ester group (51) in high ee and de.151 Using a diphosphine- modified copper fluoride complex in the presence of phenylsilane, the method avoids having to preactivate the nucleophile prior to the C—C bond-forming step. 

Since the preparation of enantiomerically pure tertiary aldols remains a challenge, aldolase antibody 38C2 was investigated as a catalyst for the kinetic resolution of racemic tertiary aldols. Ab38C2 was demonstrated to be an efficient catalyst for the retro-aldol reaction of the fluorogenic tertiary aldol /m-methodol (Scheme 5.68) and exhibited an E value of >159 50. At 50% conversion, (R)-terMnethodol is obtained with an enantiomeric excess of >99% ee. Consequently the ability of Ab38C2 to resolve tertiary alcohol was exploited in the enantioselective synthesis of ( )-frontalin (Scheme 5.69).125... 

Once again, ( )-carvone was chosen as starting material (Scheme 48) (727). Aldol reaction with formaldehyde led to 6-hydroxymethylcarvone. The primary alcohol was protected as silylether 415 to permit addition of (cyanomethyl)lithium. The 5 1 mixture of epimeric tertiary alcohols was separated and the main product, 416, the alcohol generated by axial attack, was protected stereoselectively as bromoether 417 utilizing pyridinium hydrobromide perbromide. To introduce the necessary alkyne, the nitrile was reduced to the aldehyde with diisobutylaluminum hydride and subsequent hydrolysis. Addition of the alkyne led to a 2 1 mixture of... 

Nucleophilic addition to less reactive ketone carbonyls by Lewis acid activation is also possible. Evans and co-workers have reported enol silane addition to pyruvate esters mediated by chiral copper Lewis acids (Sch. 36) [72]. The aldol reactions proceed with high facial selectivity to provide the tertiary alcohol products 153. The chemical efficiency is, however, reduced when a bulky alkyl group is present at the ketone carbonyl. Addition of more functionalized enol silanes (155) to keto esters enables the establishment of two contiguous chiral centers, a substitution pattern present in a variety of natural products. The stereochemistry of the major product is syn, irrespective of the enol silane geometry. Once again, bidentate coordination of the substrate to the Lewis acid was essential for obtaining high selectivity. 

Akiyama, Y, Ishikawa, K, OzaM, S, Asymmetric synthesis of functionalized tertiary alcohols by diastereoselective aldol reaction of silyl enol ether and ketene silyl acetals with a-keto esters bearing an optically active cyclitol as a chiral auxihary, Synlett, 275-276, 1994. 

Representative examples of the reactions of various carbonyl compounds with Grignard reagents under these conditions are listed in Table 5. It is emphasized that enolization, aldol reaction, ester condensation, reduction and 1,4-addition are remarkably suppressed by the use of cerium chloride. Various tertiary alcohols, which are difficult to prepare by the conventional Grignard reaction, can be synthesized by this method. 

Condensations. Reaction of tertiary alcohols with cyclic anhydrides, Baylis-Hillman reaction, aldol reaction involving bis(trimethylsilyl) ketene acetals, reaction of R(XIH(CN)2 with activated imines, and the [2+2]cycloaddition between isocyanates and enol ethers are assisted by high pressure. 

Chiral auxiliary-bound substrates have also been used for the asymmetric process. The aldol reaction of chiral pyruvates such as 46 is a reliable method for highly enantioselective synthesis of functionalized tertiary alcohols (Scheme 10.38) [112]. The Lewis acid-catalyzed aldol-type reactions of chiral acetals with silyl enolates are valuable for the asymmetric synthesis of -alkoxy carbonyl compounds ]113, 114]. 

This is a reversal of the aldol (or ketol) condensation it assumes preparative importance in the fission of citral which, as an, / -unsaturated aldehyde, is cleaved by boiling potassium carbonate solution into methylheptenone and acetaldehyde,77 a reaction in which addition of water to give a tertiary alcohol must be assumed ... 

The preparation of 76 began with phenol 65. A key TiCLj-mediated coupling with isatin 67 afforded a tertiary alcohol, which was reduced to form 78 via the chloride. Ester reduction followed by p-TsOH-catalyzed reaction with 2,2-dimethoxypropane afforded acetonide 79. Oxindole silylation and an aldol reaction with HCHO provided an equimolar mixture of both CIO stereoisomers 80. A two-step protection followed by 9-BBN reduction of the lactam gave fragment 76 in good yield (Scheme 13). 

The r-BuOK-catalyzed reaction of a terminal alkyne with cyclohexanone in DMSO to give a tertiary alcohol in 91% yield (eq 47) provides a straightforward illustration of an addition to a carbonyl compound. The same type of addition takes place in the nonpolar solvent benzene but the rate is slower and the yield lower. Treatment of cyclohexanone with ethynylbenzene under the same reaction conditions yields l-(phenylethynyl)cyclohexanol in 83% yield when the reaction is carried out using 1.0 equiv of r-BuOK in the absence of solvent the yield of the tertiary alcohol is 93%. Other aliphatic and aromatic ketones give similar results. Ketones with relatively acidic a hydrogens are capable of undergoing intermolecular aldol additions in the presence of the base but, apparently, the reversibility of this reaction allows the irreversible addition of the acetyUde anion to compete favorably. ... 

Introduction of the ethylidene moiety was next achieved via a two-step sequence consisting of an aldol reaction of lactam 126 with acetaldehyde, followed by dehydration employing N, N-dicyclohexylcarbodiimide (DCC) and copper(I) chloride in benzene at reflux (Scheme 8). Methanolysis of the lactam in indohne 127, followed by reduction with DIBAL—H, next furnished aUyl alcohol 128. Conversion to an aUyl halide then permitted a base-mediated cyclization to form the tertiary amine 129, a substrate containing the carbon skeleton ofvincorine (18). 

The aldol reaction between acetone (3a) and a-phenoxy and phenylsulfanylm-ethyl ketones 87 was possible by using catalyst 79c (Scheme 4.28) affording tertiary alcohols 88 albeit in moderated yields and enantioselectivities, with acetone acting both as nucleophile and solvent. Also, compounds 87 reacted as source of the nucleophile with different aromatic aldehydes using (S)-profine (20 mol%) as catalyst in DMSO at 25°C. Whereas a-phenoxy ketones gave the legioisomer from the reaction... 

Componnd 94f (R=OSiPhjBu , 15 mol%) was able to catalyzed the reaction between aromatic a,P-unsaturated keto esters 38 and cyclic ketones such compounds 3b, 14 and 48 (5-10 equiv.) in water at 25°C, yielding the corresponding tertiary alcohols in good results (41-99% yield, 98-99% de, 81-99% ee). Although the reaction was performed with acetone giving the expected aldol product in 85% yield and 45% ee, other aliphatic ketones failed [191]. 

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