Carbonyl derivatives methodology

The treatment AT-carbonyl pyrrolidine derivatives with PhIO/TMSN3 (1 2) leads to a-azidonation of the pyrrolidine ring (Scheme 7) [25]. Similar results were obtained with the piperidine analogs, although product yields were much improved when iodosylbenzene was replaced with o-iodosylbenzoic acid and the reactions were conducted under reflux. Extension of the azidonation methodology to carbonyl derivatives of L-proline methyl ester was successful, although the product mixtures were generally more complex [26]. 

The use of anions derived from a phosphine oxide (132) or a diethyl phosphonate (133) to form al-kenes was originally described by Homer.Although these papers laid the foundations for the use of phosphoryl-stabiliz carbanions for alkene synthesis, it was not until Wadsworth and Emmons published a more detailed account of the general applicability of the reaction that phosphonates bet e widely used. Since the work of Wadsworth and Emmons was significant and crucial to the acceptance of this methodology, the reaction of a phosphonate caibanion with a carbonyl derivative to form an alkene is referred to as a Homer-Wadsworth-Emmons reaction (abbreviated HWE). The phosphine oxide variation of the Wittig alkenation is called the Homer reaction. 

More recently the introduction of low-valent transition metal and lanthanoid based reducing systems, especially those based on titanium, has provided dramatic advances in efficiency and selectivity. It is now possible to select appropriate conditions for efficient coupling of all types of carbonyl compounds, often with high chemo-, regio- and stereo-selectivity. Moreover, imino- and thio-carbonyl derivatives are also coupled via pinacolic methodology. The coupling of imines to 1,2-diamines is particularly effective, with excellent control of vicinal stereochemistry. 

Methodology and stereochemistry of allylation of carbonyl derivatives of heterocycles 00MI9. 

A closely related methodology (route c) involves the dianion from a diketone (R = Me) with the anion of dimethyl malonate (R = Me) (ref.25). The bis-trimethylsilyl ether from methyl acetoacetate has been interacted with the ketalised acid chloride shown (R = CgH ) to furnish the methoxy carbonyl derivative of olivetol (route d) (ref.26). It was also found that pentane-2,4-dione with dimethyl malonate in the presence of sodium hydride afforded methyl orsellinate (ref.26). In a biomimetic approach (route e) a tetraketone has been enzymically cyclised to give the corresponding orsellinic acid (R=H, R = alkyl) (ref. 27). 

The first organocatalyzed enolate-mediated aldol reaction of active carbonyl derivatives with unactivated ketones was reported by Zhao and co-workers [170]. In this methodology, a ketone is deprotonated by the tertiary amine in the quinidine thiourea catalyst backbone and the enolate associates closely with the catalyst through ionic interactions. This method of activation can be used in cases where... 

A dual activation mode based on a network of hydrogen bond interactions is assumed being active in all these methodologies. In particular, the C6 —OH group could activate the carbonyl derivatives, while the quinuclidine tertiary nitrogen atom could modulate the reactivity of the hydroxybenzene (the case of Cinchona alkaloids is reported in Fig. 5.3). 

Snider et al. carried out intensive methodological and synthetic studies in this field. Their synthesis of sesquiter-penoid gymnomitrol by the cyclization of an unsaturated carbonyl derivative 171 with Mn(III) salts to give 172 is depicted in Scheme 25.80. ... 

The direct asymmetric synthesis of a-hydroxy carbonyl derivatives is possible by the use of other methodologies. For instance, the oxidation of silyl enol ethers with oxone (2KHSOj KHSO -KjSO ) in the presence of excess of fructose derivative 62a lead directly to the corresponding chiral a-hydroxy ketones with good enantioselectivities [101]. 

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