A-Silyloxy aldehydes

Addition of silyl phosphites to a-alkoxy and a-silyloxy aldehydes, carried out under various conditions, gives the products in good yields and with high diastereoselectivity54-55. 

Diastereoselective synthesis of p-substituted a-hydroxyphosphinates (252) and (253) by hydroxyphosphinylation of a-silyloxy aldehydes (254) and a-amino aldehydes (255) with ethyl allylphosphinate (256), catalysed with lithium phenoxide, has been reported (Figure 47). ... 

Felkin-Anh addition in the case of the a-silyloxy aldehyde 35 leads to the anti stereochemistry in the homoallylic alcohol 36 as depicted in the antiperiplanar arrangement 37 (Scheme 5.2.8)d ... 

Scheme 5.2.8 Felkin-Anh addition of allyltributyltin to the a-silyloxy aldehyde 35...

Additionally, the employment of enantiopure a-silyloxy aldehydes in these reactions provided a general entry to anti-, 2-diols 88 in high diastereoselectivities [92] (Scheme 5.68). 

Nucleophilic phosphonylations of a-silyloxy aldehydes (e.g. 77) with phosphite 78 give a mixture of 79 and 80 with moderate to good diastereoselectivity (equation 36)55. ratio of 79/80 depends greatly upon the size of the silyl groups in 77, according to the order shown in entry 42 of Table 1. 

Chelation-controlled diastereoselective addition to a-silyloxy aldehydes has been achieved using dialkylzincs and chlorotrimethylsilane the chelation is promoted by in situ ethyl zinc chloride. This autocatalysis means that stoichiometric amounts are not needed. 

Other important molecules that are useful intermediates in the synthesis of natural products are chiral diols. anli-l,2-Diols of type 30 were obtained in good yields (75-85%) and moderate to good diastereoselectivity (76-96% de) by a nickel-catalyzed three-component addition of a-silyloxy aldehydes 27, alkynyl silanes 28a, and reduction with triisopropyl silane (29a) (Scheme 11.11) [31]. The diastereoselectivity of this process could be explained by the Felkin model. Alternatively, a chiral alkynyl derivative can control the outcome of the reaction. Thus, the coupling of optically active, oxazolidinone-derived ynamides, aldehydes, and silane as reducing agent led to the formation of y-siloxyenamide derivatives with diastereoselectivities up to 99% [32]. 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

In a cross-coupling benzoin condensation of two different aldehydes, usually a mixture of products is obtained, with the ratio being determined by the relative stabilities of the four possible coupling products under thermodynamic control. If, however, an acyl silane, e.g. 5, is used as the donor component, the a-silyloxy-ketone 6 is obtained as a single product " ... 

Our group has exploited 4-phenylthio-l,3-dioxanes as convenient precursors to 4-lithio-l,3-dioxanes [45,65-69]. 4-Phenylthio-l,3-dioxanes 184 were originally prepared from -silyloxy aldehydes 183 [65] (Eq. 28). Lewis acid-promoted addition of phenylthiotrimethylsilane gave an unstable thioacetal intermediate, which could be converted in situ to the corresponding 1,3-dioxane. Yields for this process are variable, as the product is unstable under the conditions of its formation. The reaction slowly evolves to a mixture of the desired product, the phenylthio acetal of 183, the phenylthio acetal of acetone, and a variety of other unidentified products. 

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

Oxidation of silyl enol ethers. Oxidation of silyl enol ethers to a-hydroxy aldehydes or ketones is usually effected with w-chloroperbenzoic acid (6, 112). This oxidation can also be effected by epoxidation with 2-(phenylsulfonyl)-3-( p-nitrophenyl) oxaziridine in CHC1, at 25-60° followed by rearrangement to a-silyloxy carbonyl compounds, which are hydrolyzed to the a-hydroxy carbonyl compound (BujNF or H,0 + ). Yields are moderate to high. Oxidation with a chiral 2-arene-sulfonyloxaziridine shows only modest enantioselectivity. 

Addition to carbonyl compounds. In the presence of ZnCl2 or SnCl2, N,Si(CH,), adds to aldehydes or ketones to form gem-di azides. Reactions catalyzed by NaN and 15-crown-5 provide a-silyloxy azides exclusively. The adducts of aldehydes in both reactions are obtained in higher yield than the adducts of ketones. 

The a-silyloxy alkyl radical generated by the addition of (TMS)3Si radical to the aldehyde moiety of 45 has been employed in radical cyclization of (3-aminoacrylates (Reaction 7.53) the trans-hydroxy ester and the lactone in a 2.4 1 ratio were the two products [62]. 

Normant and Poisson prepared allenylzinc bromide reagents from TMS acetylenes along the lines of Epsztein and coworkers5, by sequential lithiation with s-BuLi to yield a lithiated species, and subsequent transmetallation with ZnBr2 (equation 35)27,28. Additions to racemic /J-silyloxy aldehydes proceed with low diastereoselectivity to afford mixtures of the anti,anti and anti,syn adducts (Table 17). The latter adducts are formed via an anti Felkin-Anh transition state. Additions to the racemic IV-benzylimine analogs, on the other hand, proceed with nearly complete Felkin-Anh diastereoselectivity to yield the anti,anti amino alcohol adducts (Table 18). 

The key observation was that L-proline would catalyze the addition of a-hetero aldehydes to a-branched aldehydes such as 2 to give the aldol product 3 with high cnantio- and diastereocontrol. Even more exciting, in the absence of other acceptors the a-hetero aldehydes dimerize with high relative and absolute stereocontrol. Both alkoxy and silyloxy aldehydes worked efficiently. 

The chiral imidazolidinone 45 also catalyzes the Mukaiyama-Michael reaction between 2-silyloxy furans and a,/ -unsaturated aldehydes, affording enantiomeri-cally highly enriched y-butenolides (Scheme 4.18) [33]. For optimum catalytic performance, hydroxyl additives are necessary, and addition of 2 equiv. water proved best. 

In a synthesis of (+)-hyptolide Marco exploited the Carreira procedure for alky-nylation of a /3-silyloxy aldehyde to afford the product proparyl alcohol as a single isomer [28], Subsequent semireduction of the alkyne furnished the requisite Z double bond to complete the synthesis (Eq. 23). 

Hydroxyketones are versatile intermediates in the synthesis of pharmaceutical intermediates and heterocyclic molecules. a-Aryl hydroxyketones have been prepared by reaction of aryl aldehydes with 1,4-dioxane followed by reduction with lithium aluminum hydride (LAH) and by the selective LAH reduction of a-silyloxy a,P-unsaturated esters." WissneC has shown that treatment of acid chlorides with tris(trimethylsilyloxy)ethylene affords alkyl and aryl hydroxymethyl ketones. 1-Hydroxy-3-phenyl-2-propanone (3) has been generated by the osmium-catalyzed oxidation of phenylpropene and by the palladium-catalyzed rearrangement of phenyl epoxy alcohoP both in 62% yield. 

Importantly, with a-silyloxy acetaldehyde, the syn aldol is the major dimer (threose derivative). Thus, applying Mukaiyama condensations with 27 (see O Scheme 23), hexoses such as idose, gulose, and galactose can be prepared. A highly stereoselective protocol for the cross coupling of aldehydes and ketones with a-thioacetal aldehydes has been developed... 

Deprotonation of a-silyloxy ketones with LDA furnishes (Z)-lithium enolates, whereas treatment of ketones with n-Bu2BOTf in the presence of /-Pr2EtN gives the corresponding (Z)-(0)-boron enolates. Interestingly, reaction of the Li-enolates with r-PrCHO proceeds with opposite facial preference to that of the boron enolates. Thus, the Si face of the Li-enolate adds to the Si face of the aldehyde and the Si face of the boron enolate adds to the Re face of the aldehyde to furnish the chiral P-hydroxy ketone enantiomers shown below. The reason for the different face selectivity between the lithium enolate and the boron enolate is that lithium can coordinate with three oxygens in the aldol Zimmerman-Traxler transition state, whereas boron has only two coordination sites for oxygen. 

The relative ease of pinacolization is primarily determined by the reduction potential of the carbonyl group involved. Many reductants are therefore selective for aromatic and other electronically activate systems. Moreover, as a result of this ready reduction, pinacolization of such carbonyls can be effected by either anionic or radical routes. For example, treatment of aromatic aldehydes or ketones with Mg/TMSCl in HMPA promotes pinacolization via formation of an a-silyloxy carbanion - and nucleophilic attack on a second carbonyl group (equation 2). Furthermore, with benzaldehyde the reaction is stereodirecting with a preference for /it-coupling. Whilst an alternate coupling metht using the milder... 

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