Aldehyde-ketophosphonate condensation

The next sequence of steps was directed towards generating a handle for attachment of this pyridine CD system to a quinoline AB framework. Compound (108) was therefore transformed to P-ketophosphonate (110) in five additional steps via aldehyde (109). Condensation of the anion derived from (110) with nitroaldehyde (111) gave an intermediate chalcone, which on reductive cyclization with sodium hydrosulfite afforded the tetracyclic system (112). 

Scheme 5. Ketophosphonate-aldehyde condensation in the total synthesis of a tylosin system.

Intramolecular ketophosphonate-aldehyde condensation has been used by Nicolaou and co-workers as a cyclization release strategy to form macrocycles in the muscone series of natural products (Scheme 5). A highlight of this work was development of a unique phosphonate resin. 

Regioselective reduction of the C-1 carboxylate of dimethyl (R)-malate (203) with BMS-NaBH4 followed by protection of the diol with either triethylsilyl groups or an acetonide furnishes 978. Condensation of the ester group with the anion of dimethyl methylphosphonate produces j -ketophosphonate 979 in high yield. Coupling of 979 with (2 S)-3-hydroxy-2-methylpropionate-derived aldehyde 980 under Homer—Emmons conditions affords 981, which contains the basic skeletal requirements for the C-16 to C-26 subunit (982) of hali-chondrin B (Scheme 144) [213]. 

The synthetic plan followed by the authors is presented in Scheme 24 which shows strategic bond formations in the retrosynthetic sense. For the construction of 181, a ketophosphonate aldehyde condensation was used as the macrocyclization step which led to compound 182, an ester derived from hydroxyaldehyde 183 and ketophosphonate acid 184. The remaining C-C bond formations are indicated on 183 and 184, which then conducted to the key building blocks 127,185-188. The authors took advantage of hidden symmetry elements which led them to select both enantiomers of xylose and tartaric acid as chiral starting materials and/or chiral auxiliaries. 

The C1-C20 segment (184) The construction started by condensation of ketophosphonate 187 and aldehyde 186 leading to a conjugated enone, hydrogenated to ketone 209 (Scheme 29). The desired configuration at Cg was... 

Muscone (40) is a sex pheromone of the musk deer and a chemical component of cosmetics. A 12-member library of racemic muscone analogs was synthesized by Nicolaou et al.," who anployed a cyclorelease method on solid support to form the macrocycle scaffold (Figure 11.17). A phosphonate-functionalized resin loaded on encoded SMART microreactors 36 was coupled to olelinic esters 35 to form the p-ketophosphonates 37. Sorting and cross olefin metathesis of 37 with two alkenols followed by oxidation with Dess-Martin reagent gave aldehydes 38. An intramolecular ketophosphonate-aldehyde condensation (Homer-Emmons-Wadsworth reaction) of 38 caused smooth cyclorelease of macrocyclic enones 39. Parallel solution-phase chemistry completed the sequence. 

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