Ketones 3-Ketophosphonates. preparation

Of course, the use of tris(trimethylsilyl) phosphite213 214 provides facile access to the free a-hydroxyphosphonic acids. These silyl reagents have been used for the preparation of a wide range of a-substituted phosphonates and -phosphonic acids, starting with ketene,215 a-ketophosphonates,216 ketoesters,217 218 and a,P-unsaturated carbonyl compounds,207/219-221 as well as simple aldehydes and ketones.205 210/219 224 Their use for the preparation of compounds of significant biological interest has been reviewed.125... 

As outlined in Scheme 28, the synthesis of the P-ketophosphonate 131 began with a one-pot anh -aldol/reduction step between ethyl ketone 101 and aldehyde 133, giving the 1,3-syn diol 134 (>30 ldr) [130, 132-136, 145, 146], The diol 134 was then converted into the carboxylic acid 135 in six steps. Completion of the subunit 131 required conversion into the acid chloride and reaction with the lithium anion of methyl-(di-l,l,l-trifluoroethyl)-phosphonate. The C9-C24 aldehyde 132 was prepared in two steps from 136, an intermediate from previous routes [55-58], The Still-Gennari-type coupling of 131 and 132 was readily achieved via treatment with... 

Protocol 2 produces the protected fi-formylphosphonate 12 f)-ketophospho-nates may also be synthesized by other methods,23 however, they may not be prepared in unprotected form by the Michaelis-Arbuzov reaction because the Perkow reaction, in which an a-haloaldehyde or ketone and a trialkyl phosphite yield an enol phosphate (e.g. 13, Scheme 5,24 i.e. [P—O] bond formation), competes and frequently dominates (see Section 4). Conversely halocarboxylic acid derivatives (e.g. see Table 7.1, entry 3) and acyl halides (see Protocol 3) react well in the Michaelis-Arbuzov reaction to yield useful functionalized phosphonates. fi-Ketophosphonates are useful reagents for the synthesis of a,fi-unsaturated carbonyl compounds by the Horner-Wadsworth-Emmons reaction,3,4 25 and have other applications.23... 

Other procedures for the synthesis of P-ketophosphonates based on the use of a phosphorus electrophile have been explored. For example, the reaction of dialkyl chlorophosphates with the dilithium derivatives of a-bromo ketones has been described,but the yields of isolated products remain modest. The Lewis acid-catalyzed reaction of oc-hydroxy ketones with dialkyl chlorophosphites constitutes an efficient synthesis of P-ketophosphonates in high yields (92-96%, Scheme 7.42). This reaction is of special value for the preparation of oc-fully substituted P-keto-phosphonates. ... 

The catalytic enantioselective reduction of 1-ketophosphonates has recently been developed. This approach takes advantage of a development in the enantioselective reduction of prochiral ketones to chiral alcohols by means of catalytic amounts of oxazaborolidines with borane as reducing agent. Thus, the enantioselective reduction of 1-ketophosphonates is accomplished by treatment with different boranes, BH. THF (0.9 eq), BII3Me2S (0.66 eq),5 545 qj- catccholborane (1.1 eq)5° 5 6 in different solvent systems in the presence of a catalytic amount of freshly prepared B-n-butyloxazaborolidine, (5) or (R) (Scheme 7.93). The reaction is complete in about 5 h and produces the expected dialkyl 1-hydroxyalkylphosphonates in satisfactory yields (53-98%). 

Chiral allylic acetates 426 can be prepared using a similar j5-ketophosphonate (425), also derived from lactic acid. The desired 425 is formed via reaction of lithiated diphenylphos-phonate with 401. Reduction of the ketone gives an intermediate alcohol which, upon treatment with base, forms the ( )-Wittig olefin. Removal of the silyl protecting group followed by acetylation gives the product 426 (> 98% ee) [133]. 

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