Phospho-aldol reaction

This reaction (6.297) is proving to be useful in obtaining P-C bonds [28]. 

Some acyl phosphonates such as phosphonoformic acid (6.298a) have valuable anti-viral or antibiotic properties (Chapter 12.12). Phosphono acetic acid (6.298b) has similar properties. The diethyl compound (6.298c) can serve as a useful source of other P compounds [29]. 

Phosphonoformic acid is obtainable from dialkyl phosphites by the route (6.299) [30]. 

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Kee TP, Nixon TD (2003) The Asymmetric Phospho-Aldol Reaction. Past, Present, and Future. 223 45-65... 

The Asymmetric Phospho-Aldol Reaction. Past, Present, and Future... 

Kawai K, Majima T (2004) Hole Transfer in DNA by Monitoring the Transient Absorption of Radical Cations of Organic Molecules Conjugated to DNA. 236 117-137 Kee TP, Nixon TD (2003) The Asymmetric Phospho-Aldol Reaction. Past, Present, and Future. 223 45-65... 

Early-on it was discovered that these Salen compounds, and the related six-coordinate cations [6], were useful as catalysts for the polymerization of oxiranes. These applications were anticipated in the efforts of Spassky [7] and in the substantial work of Inoue [8]. Subsequently, applications of these compounds in organic synthesis have been developed [9]. Additional applications include their use in catalytic lactide polymerization [10], lactone oligomerization [11], the phospho-aldol reaction [12], and as an initiator in methyl methacrylate polymerization [13]. 

The phospho-aldol reaction has been known for many years within the phosphorus-chemistry community, under many names (including the Abramov and Pudovik reactions) and is one of the most valuable and powerful synthetic processes for the construction of phosphorus-carbon bonds [1]. The reaction, illustrated in its usual form, is outlined in Scheme 1 a. It involves an addition reaction between a hydrogen-phosphonate ester and a carbonyl substrate to afford an alpha-(a)-functionalised phosphonate ester. Whilst alternative methods or activation have been explored [2], the phospho-aldol reaction is most commonly performed under conditions of base catalysis [3]. 

Since the 1950s there have been many variants of the basic phospho-aldol reaction published for the stoichiometric synthesis of a-functionalised phos-phonates. For example, the widely studied Abramov reaction outlined in Scheme 1 b (when R = SiMej, this process can be considered to be a close relative of the Mukaiyama aldol reaction) has been used as a method of building a-functionalised phosphonates both without [4], and more recently with, control over stereochemistry at the a-carbon atom [5]. 

This report summarises the developments in asymmetric catalytic variants of the phospho-aldol reaction tracing their evolution from early studies in the 1980s to the current day whilst attempting to suggest future advances within the context of growing applications in biomedical science. 

The products of the phospho-aldol reaction, a-functionalised phosphonate esters such as a-hydroxy- and a-aminophosphonates, find widespread application directly or indirectly as precursors to enzyme inhibitors (such as the enzymes renin [6], thrombin [7],EPSP synthase [8], HIV protease [9] and various classes of PTK and PTPs [10]) and phosphate analogues [11], antibiotics [ 12], antiviral agents [ 13], and in nucleotide technology [ 14]. Within each application stereochemistry of the phosphonate is crucial to eliciting the required properties [15]. 

Consequently, chemists must have at their disposal simple, effective, efficient, and stereoselective synthetic methods to construct the necessary frameworks. Development of catalytic asymmetric variants of the phospho-aldol reaction provides, arguably, the most versatile such process for the simultaneous construction of the [P-C] bond and associated a-carbon functionality with control over the stereochemistry at the newly generated alpha-carbon site. 

Surprisingly, it took a considerable time for Wynberg and co-workers initial breakthrough to be extended but when that extension did eventually take place in the early 1990s it was to open up the whole field of asymmetric catalytic hydrophosphonylation and the phospho-aldol reaction in particular. 

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