Lactone synthesis oxidative addition processes

In 1988, an improved synthesis of orlistat (1) was reported by the Hoffmann-La Roche discovery chemistry. The scheme involved a pivotal P-lactone 14. In the approach, an aldol condensation of aldehyde 7 with the dianion generated from octanoic acid and two equivalents of LDA. After tosylic acid-facilitated lactonization and Jones oxidation, the resultant lactone 14/14 was hydrogenated to establish two additional chiral centers. A battery of somewhat tedious protections and deprotections transformed 15 to P-lactone 19 via the intermediacy of 16,17, and 18. Six additional steps then converted P-lactone 19 to orlistat (1). This route may provide better overall yield in comparison to the previous scheme. However, too many protections and deprotections render this approach less elegant and not very practical for large-scale process. 

The synthesis of some 2,4-dioxahydrindans is illustrated in Scheme 6. Oxidation of 4-C-hydroxymethyl-2,3,4-trideoxy-D-cryfAro-hex-2-enopyranose with silver carbonate on Celite produced 4-C-hydroxymethyl-2,3,4-trideoxy-D-r/ireo-hex-2-eno-l,5-lactone together with the expected D-erythro lactone." Michael addition of various nitroalkanes to levoglucosenone under cathodic electrolysis conditions (circumstances that were found to be milder and higher yielding than the base-catalysed version) resulted in products 42. Phthalimide, succinimide and saccharin were also nucleophiles in this process. ... 

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