Ketones synthon representing

Methyl deoxypodocarpate 127 (Scheme 1) 129) represents a simple problem since the ketone 132 is well-known and readily available from Hagemann s ester in three steps. The problem of geminal alkylation of this ketone stems from its existence as an EjZ mixture of ring fusion isomers. Recognizing that decarbonylation of aldehydes occurs readily with Wilkinson s catalyst creates a structural equivalence of an acetaldehyde chain and a methyl group as in 128. This simple relationship immediately establishes several options, a simple one uses a thioacetal such as 129 as a synthon for the aldehyde. The presence of a carbonyl group three carbons away... 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

The metalation of vinyl ethers, the reaction of a-lithiated vinyl ethers obtained thereby with electrophiles and the subsequent hydrolysis represent a simple and efficient method for carbonyl umpolung. Thus, lithiated methyl vinyl ether 56 and ethyl vinyl ether 54, available by deprotonation with t- or n-butyllithium, readily react with aldehydes, ketones and alkyl halides. When the enol ether moiety of the adducts formed in this way is submitted to an acid hydrolysis, methyl ketones are obtained as shown in equations 72 and 73 . Thus, the lithiated ethers 56 and 54 function as an acetaldehyde d synthon 177. The reactivity of a-metalated vinyl ethers has been reviewed recently . 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

The synthetic principle of olefinating an a,co-bisfunctional synthon A, representing the later molecular centre of the carotenoid, with two reaction partners B, the future molecular ends, can easily be described by the equation A + 2B -> B—A—B. This method was used by Mayer et al.265> in the synthesis of rhodoxanthin 550, a ketonic carotenoid, which was isolated for the first time from the red berrys of the yew-tree Taxus baccata. The authors describe the conversion of two equivalents of the stable phosphorane 548 with one equivalent of the C12-dialdehyde 549 265) (Scheme 93). The analogous reaction of crocetindial 552 with substituted benzylidenephospho-ranes such as 551 gives carotenoids such as isorenieratene 553266,267) and related compounds 266> (Scheme 93). Condensation of the phosphoranes 554 and 555 with the Cjo-dialdehyde 539 yields carotenoids of the dihydro type 556 268) and such like 557 269), respectively (Scheme 93). 

The last steps of the synthesis, en route to synthon 157, consisted of chain elongation at C6 using a suitable carbanion. An acetylenic carbanion, representing C2-C3 of 151, was chosen because of a known propensity to add stereoselectively but also because they are good precursors of ketones. A brief study showed that the chelation controlled addition, that is, the use of magnesium derivatives, led to the required stereochemistry at C6. Other examples of such chelation controlled addition will be given in the following sections. 

Chromans. - 2,4-Diethoxychromans (78) (mainly cis) represent a new type of chroman and have been prepared in high yield from a phenol (but not a deactivated phenol) and malonaldehyde bis(diethyl acetal) in the presence of SnCU they are converted into the benzopyrylium salts (79), in excellent yield, by treatment with perchloric acid. A Wittig-Horner reaction of the chiral phosphoryl ( S)-sulphoxide (81) and the ketone (80) gave the chiral sulphoxide (82), which was cyclized by aqueous alkali to a mixture which contained 22% diastereoisomeric excess of (25 )-chroman (i )-sulphoxide. This was converted, in three steps, into the aldehyde (83), which is a useful synthon for a-tocopherol. ... 

The cyclic ketone (4) is best disconnected where ring and chain meet and synthon (5) is best represented by malonate. 

Synthon (23) was represented by an enamine and the vinyl ketone (24) could be made by the Mannich reaction (see Chapter 20) if required, as discussed in the next section. 

Cross-aza-benzoin reactions of aldehydes with imines have also been developed to afford a-amido ketones. The difference in reactivity between aldehydes and imines is inherently greater but also tunable because of the trivalency of nitrogen. Furthermore, a-amido ketones represent an important class of medicinal agents and are an important synthon for the ubiquitous 1,2-amino alcohol motif. 

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