Total Synthesis of Spinosyn A. 2. Degradation Studies Involving the Pure Factor and Its Complete Reconstitution

Abstract

A total synthesis of natural levorotatory spinosyn A (1) has been achieved. The first objective, to confirm the absolute configurational assignment of tricyclic ketone 2 prepared earlier, was accomplished by oxidative degradation of the macrocyclic lactone ring in 1. The route began with the implementation of a four-step one-pot process that resulted in the efficient conversion of 6 into 18. A combination of periodate cleavage and peracid oxidation events then led to 2. In the reconstruction phase, a Pd-catalyzed coupling of a vinylstannane with an acid chloride reestablished the great majority of the structure in an enantiocontrolled manner. Once macrolactonization had been effected, the 2,3,4-tri-O-methylrhamnose unit was introduced first with exceptionally good stereocontrol. The final glycosidation, which involved a 2-mercaptopyrimidine derivative of d-forosamine, was met with an expectedly diminished percentage of the desired β-anomer.

The spinosyn family of insecticides: realizing the potential of natural products research

“…28 Total syntheses of the natural (À)-enantiomer have been subsequently accomplished. 29,30 In addition, studies analyzing methodology for the synthesis of both the natural product and certain analogs have been conducted. [31][32][33][34] FERMENTATION-DERIVED ANALOGS Numerous structurally related compounds from various spinosyn fermentations have now been isolated and identified.…”

Total synthesis of (–)-spinosyn A

“…Kirst et al (3) suggested that the biosynthesis of spinosyn A may involve a transannular Diels-Alder (TDA) (13) reaction of a macrocyclic pentaene to form the C(4)OC (12) and C(7)OC (11) bonds (see 4 3 3; Scheme 1). Kirst also suggested that a transannular cyclization of a 1,3-dicarbonyl nucleophile may generate the C(3)OC (14) bond (3).…”

“…Finally, removal of the PMB group with 2,3-dichloro-4,5-dicyano-1,4-benzoquinone (DDQ) afforded the spinosyn A pseudoaglycon 28, which was identical in all respects to natural 28. Because the published syntheses of (Ϫ)-spinosyn A (1) by Paquette et al (10,11) and (ϩ)-spinosyn A by Evans and Black (9) proceed by way of the pseudoaglycon 28 (or ent-28 in the case of Evans and Black), this synthesis of 28 constitutes a formal synthesis of (Ϫ)-spinosyn A (1).…”

“…This glycosidation proved to be a significant problem in the syntheses of spinosyn A by both Evans and Black (9) and Paquette et al (11). Evans and Black obtained a 70% yield for the installation of the forosamine unit in their synthesis; however, the selectivity for the formation of the required ␤-glycoside was 1:6 ␤͞␣.…”

“…This mixture is currently marketed for use as an insecticide against a variety of insects (6). Total syntheses of spinosyn A have been reported by Evans and Black (9) and Paquette et al (10,11).…”