- A formal total synthesis of the macrolactone pyrolizidine alkaloid (-)-integerrimine (2), from R-(+)-citronellal (93) is described. Aldehyde 93 was converted to exo methylene derivative 94 which was reduced to allylic alcohol 95. The epoxides 96 and 98, obtained in a ratio of 3:1 respectively by Sharp less epoxidation of 95 with diisopropyl (-)-tartrate, were separated as their 3,5-dinitrobenzoates 97 and 99 . Diol 100, derived from hydride opening of the major epoxide 97, was protected as the bis-3,5-dinitrobenzoate 101, which was oxidatively cleaved at the isopropylidene terminus. Methanolysis of the dinitrobenzoates and acid catalyzed lactonization provided 3-lactone 102, the structure of which was confirmed by X-ray crystallographic analysis. Oxidation of the primary alcohol of 102, followed by introduction of the E-ethylidene group, furnished 31 which has been previously converted to (-)-2 . The Sharpless epoxidation of 95 employing (+)-tartrate furnished 98 and 96 in 96:4 ratio respectively. Epoxide 98 was converted to 102 and hence to 31. Epoxide 98 was also protected as its silyl ether 109 and the olefin was oxidatively cleaved. The resulting carboxylic acid was converted to 110, acid catalyzed opening of which was anchimerically assisted by the ester function to give δ-lactone 112. The primary alcohol of 112 was reduced to a methyl group via iodide 113 and removal of the silyl blocking group from 114 then yielded 102. An approach to the chiral synthesis of (+)-usaramine (5) began from epoxide 98 . The diol 121, derived from opening of 98 with pivalic acid, was protected as the acetonide 122 and the pivalate ester was reduced to give 123. Alcohol 123 was oxidized to carboxylic acid 124 which was converted to methyl ester 125. The latter provided 120, via acid 126, by truncation of the isopropylidene group. Since introduction of the E-ethylidene substituent could not be accomplished on 120, δ-lactone 137 was used as the substrate for the aldol reaction with acetaldehyde. This lactone was prepared from 126 by cleavage of the acetonide, selective protection of the primary hydroxyl of the derived diol as 136, and subsequent lactonization with Mukaiyama's reagent. Introduction of the ethylidene group and deprotection of 138 provided 139. The first chiral synthesis of (-)-140, the dimethyl ester of naturally occurring (+)-retronecic acid (117), was achieved by methanolysis of 139. The ester 130 was prepared by titanate-mediated transesterification of 125 with 2-(trimethylsilyl)ethanol and subsequent oxidative cleavage of the olefin. This carboxyl terminus of 130 was coupled with the retronecine derivative 26 via anhydride 150 to yield 143. A nucleophilic macrolactonization protocol was attempted on 151, which was obtained by selective desilylation of 143, but this unexpectedly provided 153 instead of the macrolactone 149. Further treatment of 153 with excess fluoride at elevated temperature yielded the macrolactone 149, which contains the carbon skeleton and stereochemistry of (+)-usaramine (5) but lacks the ethylidene side chain.