Aldol condensation lithium anion

Difunctional target molecules are generally easily disconnected in a re/ro-Michael type transform. As an example we have chosen a simple symmetrical molecule, namely 4-(4-methoxyphenyl)-2,6-heptanedione. Only p-anisaldehyde and two acetone equivalents are needed as starting materials. The antithesis scheme given helow is self-explanatory. The aldol condensation product must be synthesized first and then be reacted under controlled conditions with a second enolate (e.g. a silyl enolate plus TiCl4 or a lithium enolate), enamine (M. Pfau, 1979), or best with acetoacetic ester anion as acetone equivalents. 

Addition of lithio alkene 636, a formaldehyde-anion equivalent ( CHO), to 808 at low temperature gives adduct 813 with a diastereomeric excess of 92%. Lithium—bromine exchange, desilation, ketalization, and ozonolysis furnishes aldehyde 814 (> 98% de). The last stereocenter is introduced by aldol condensation with R-HYTRA, thus giving 815 as a 91 9 mixture of isomers. Lactonization to 816 followed by reduction with disiamylborane gives 817, which is separated from the accompanying minor isomer by column chromatography. 

All of the examples shown for the aldol condensation in Sections 22.2 and 22.4 involved an intermolecular reaction (the reaction of two different molecules). If a molecule has two carbonyl units as well as at least one acidic a-hydrogen and is treated with base, an intramolecular aldol condensation can take place. A simple example is 1,6-hexanedial (57), which, when treated with lithium diisopropylamide in THF, gives enolate anion 58 (the carbanion is drawn at C2). This enolate anion reacts with the most available electrophilic center, which in this case is the aldehyde carbonyl on the other end of the molecule (labeled C6). 

Tylonolide hemiacetal (33), the aglycone of the antibiotic tylosin, possesses an anti 14-hydroxymethyl-15-acyloxy stereochemistry conveniently contained in 26, which may be viewed as the western half of 33. In order to prepare the eastern half of 33, an aldol reaction leading to the desired syn stereochemistry at C-3 and C-4 is exploited. The reaction of achiral aldehyde 27 with the S-boron enolate 28 proceeds with the expected diastereofacial selectivity to provide, in a combined yield of 80% after O-silylation, a separable mixture of 29 (derived from the / -enantiomer of 27) and 30 (from the S-enantiomer of 27). Subsequent functional group transformation of 30 ultimately leads to the a-(TMS)methylketone 31. The anion of 31, generated with lithium hexamethylsilazide in THF at — 78 °C, undergoes a Peterson condensation with 26 to afford in 60% yield the seco-diC d 32. Treatment of 32 with 70% acetic acid at 85 °C for one hour affords 33 in 60% yield. The attractive feature of this... 

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