Heteroatoms acylation with aldehydes

An unexpected reactivity in the functionalization of 2-acyl-l,3-dithianes has been reported by Mioskowski and co-workers. They found that 2-acyl-l,3-dithianes with no further heteroatom at the acyl side chain react with aldehydes to give 2-acyl-2-hydroxyalkyl-l,3-dithianes, whereas a silyl-protected hydroxy group in the side chain of the 2-acyl-l,3-dithiane led to formation of the aldol product at the opposite site of the carbonyl group. Acyl chlorides always react with 2-acyl-l,3-dithianes to give the enol esters (Scheme 81) <2003TL213>. 

Many types of reactive molecules are well known to medicinal chemists acyl halides, aldehydes, aliphatic esters, aliphatic ketones, alkyl halides, anhydrides, alpha-halocarbonyl compounds, aziridines, 1,2-dicarbonyl compounds, epoxides, halopyrimidines, heteroatom-heteroatom single bonds, imines, Michael acceptors and (l-heterosubstituted carbonyl compounds, perhalo ketones, phosphonate esters, thioesters, sulfonate esters, and sulfonyl halides, to name a few [14]. This is not to say that these functionalities are not useful - some even appear in approved drugs -but all of these can react covalently with proteins, and thus should be regarded with suspicion. However, molecules can react covalently with proteins even if they do not contain functionalities that raise alarm. Jonathan Baell has referred to these as pan assay interference compounds, or PAINS, and has published a list of moieties to watch out for, as well as strategies to detect them [15, 16]. 

The most important reactions of alkyl substituents a and y to the ring heteroatom are those which proceed via base-catalyzed deprotonation. Treatment of 2- and 4-alkyl heterocycles with strong bases such as sodamide and liquid ammonia, alkyllithiums, LDA, etc., results in an essentially quantitative deprotonation and formation of the corresponding carbanions. These then react normally with a wide range of electrophiles such as alkyl halides and tosylates, acyl halides, carbon dioxide, aldehydes, ketones, formal-dehyde/dimethylamine, etc., to give the expected condensation products. Typical examples of these transformations are shown in Scheme 17. Deprotonation of alkyl groups by the use of either aqueous or alcoholic bases can also be readily demonstrated by NMR spectroscopy, and while the amount of deprotonation under these conditions is normally very small, under the appropriate conditions condensations with electrophiles proceed normally (Scheme 18). 

In chapter 10 we compared C-C disconnections with related two-group C-X disconnections, mainly at the alcohol oxidation level. In this chapter we deal more fully with carbonyl compounds, chiefly aldehydes and ketones, by two related disconnections. We start by comparing the acylation of heteroatoms by acid derivatives such as esters (a 1,1-diX disconnection 1 that can also be described as a one-group C-X disconnection) with the acylation of carbon nucleophiles and move on to compare the 1,2-diX disconnection 3 with the alkylation of enolates 6. Here we have reversed the polarity. We mention regioselectivity—a theme we shall develop in chapter 14. 

The SN reaction under consideration is not terminated until water, a dilute acid, or a dilute base is added to the crude reaction mixture. The tetrahedral intermediate B is then protonated to give the compound E. Through an El elimination it liberates the carbonyl compound C (cf. discussion of Figure 6.4). Fortunately, at this point in time no overreaction of this aldehyde with the nucleophile can take place because the nucleophile has been destroyed during the aqueous workup by protonation or hydrolysis. In Figure 6.32 this process for chemoselective acylation of hydride donors, organometallic compounds, and heteroatom-stabilized carbanions has been included as strategy 1. ... 

Heteroatom-stabilized Carbanions. Heteroatom-stabilized and allylic carbanions serve as homoenolate anions and acyl anion equivalents, e.g. a-anions of protected cyanohydrins of aldehydes and Q ,/3-unsaturated aldehydes are intermediates in general syntheses of ketones and Q ,/3-unsaturated ketones (eq 36). Allylic anions of cyanohydrin ethers may be a-alkylated (eq 37) or, if warmed to —25°C, may undergo 1,3-silyl migration to cyanoenolates which may be trapped with TMSCl. Metalated Q -aminonitriles of aldehydes are used for the synthesis of ketones and enamines (eq 38). Similarly, allylic anions from 2-morpholino-3-alkenenitriles undergo predominantly a-C-alkyl-ation to give, after hydrolysis, a,/3-unsaturated ketones (eq 39). ... 

Carbon-heteroatom double bonds can also participate in this reaction. These include both carbonyl compounds (Scheme 11.37) and imines (Scheme 11.38). Addition to aldehydes is co-catalysed by tin(II) or indium(III) salts. Under these conditions, tetrahydrofiirans are obtained. The presence or absence of the co-catalyst can also switch the reaction from one mode to another (Scheme 11.39). An indium cocatalysed cycloaddition to a 7-pyrone aldehyde 11.117 was used in a synthesis of aureothin 11.122 and A-acetylaureothamine 11.123 (Scheme 11.40). Cross-metathesis of the exo-cyc ic alkene 11.118 allowed a subsequent Suzuki coupling with a gem-dibromide 11.120 that showed the expected selectivity (Section 2.1.4.2). This reaction required the use of thallium ethoxide as the Lewis base to suppress the formation of side products. A Negishi coupling completed the synthesis of aureothin 11.122. Reduction and acylation of the nitro group yielded A-acetylaureothamine 11.123. The latter compound is active digainst Helicobacter pylori, a bacterium behind stomach ulcers. 

An alternative to 138 and 122 is (R)- or (5)-2-hydroxy-l,2,2-triphenylethyl acetate ((/ )-or (5)-HYTRA) (14.3). a chiral acetate which does not need an auxiliary heteroatomic substituent. Compound 143 is readily available through acylation of 1,2,2-triphenyl-1,2-ethandiol with acetyl chloride or acetic anhydride. Its dianion, generated by double deprotonation with LDA and transmetallation with MgBr2 or Mgl2, reacts with aliphatic and aromatic aldehydes to give )8-hydroxy acid derivatives with diastereomeric ratios ranging from 92 8 to 98 2 . The crude adducts can be readily purified by crystallization. Removal of the auxiliary can be accomplished either hydrolytically (KOH, aq. MeOH) or transesterification (MeONa, MeOH/THF) to provide the respective j8-hydroxy acid/ester in enantiomerically pure form. 

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