Knoevenagel reaction, carbon-chain

Another route to create a carbon-carbon double bond on a ketosugar is the Knoevenagel reaction and its variants. It has been applied by Szarek and Ali to prepare olefin 133 (Scheme 45) suitable for the formation of a doubly branched-chain sugar [177] [see Section 1I.D]. 

Hydroformylation-(Knoevenagel reaction)-hydrogenation also allows the prolongation of carbon chains via transient aldehydes (Scheme 5.143) [33]. 

Various methods have been used to lengthen a carbon side chain, in the syntheses of quinuclidyl-3-acetic acid (113) (Scheme 1). The lowest yield is in the sodiomalonic ester synthesis (13.4% ).125 Much better results are afforded by the Reformatsky reaction (40%)125 and Knoevenagel condensation (65-70%).129 The best yield (nearly quantitative) may be obtained by application of the Wittig-Horner reaction.155... 

The first total synthesis of Cet /ojc is that of Masanao Matsui. [228] The starting material is )8-ionone [229] its side-chain double bond can be hydrogenated regioselectively on a copper catalyst. The side-chain is then extended by three carbon atoms by means of a Darzens reaction [230], followed by a Knoevenagel condensation. The (JS/Z)-isomeric mixture (1 1) of acids is separated by fractional distillation of their ethyl esters the ( )-isomer is hydrolysed and cyclised with trifluoroacetic add to sclareolide. Reduction of the latter with Vitride (sodium bis(2-methoxyethoxy)aluminium hydride) and ether formation then produces Cetalo . ... 

Further examples have been reported of the synthesis of aldonic acids by carbon-carbon bond-forming reactions. 2,3 4,5-Di-0-isopropylidene-D-arabinose (3) with methyl acetoacetate gave the Knoevenagel product (4), which is a branched-chain, unsaturated heptonic acid derivative. This rearranged on treatment with trifluoroacetic acid to afford the spiro-product (5) (Scheme 1). This same compound was obtainable from the 2,5-anhydroaldose derivative (6) by similar treatment. The synthesis of destomic acid, 6-amino-6-deoxy-L- /ycew-... 

---