Total Synthesis of Laulimalide: Synthesis of the Northern and Southern Fragments

Abstract

The first stage of the development of a synthetic route for the total synthesis of laulimalide (1) is described. Our retrosynthetic analysis envisioned a novel macrocyclization route to the natural product using a Ru-catalyzed alkene-alkyne coupling. This would be preceded by an esterification of the C19 hydroxyl group, joining together two equally sized synthons, the northern fragment 7 and the southern fragment 8. Our first generation approach to the northern fragment entailed a key sequential Ru-Pd coupling sequence to assemble the dihydropyran. The key reactions proceeded smoothly, however, the inability to effect a key olefin migration led to the development of an alternative route based on an asymmetric dinuclear Zn-catalyzed aldol reaction of a hydroxyl acylpyrrole. This key reaction led to the desired diol adduct 66 with excellent syn:anti selectivity (10:1), and allowed for the successful completion of the northern fragment 7. The key step for the synthesis of the southern fragment was a chemoselective Rh-catalyzed cycloisomerization reaction to form the dihydropyran ring from a diyne precursor. This reaction proved to be selective for the formation of a six-membered ring, over a seven. The use of an electron-deficient bidentate phosphine allowed for the reaction to proceed with a reduced catalyst loading.

Dinuclear Metal‐ProPhenol Catalysts: Development and Synthetic Applications

“…This transformation was later applied in the total synthesis of laulimalide 29, where the aldol adduct 27 was obtained in 54 % yield and 10:1 dr (Scheme 8). [25] In addition, the stereochemistry of the allylic alcohol of 26 was inconsequential to on the stereo-outcome of the syn-1,2-diol.…”

A Designed Amide as an Aldol Donor in the Direct Catalytic Asymmetric Aldol Reaction

“…[2,3] Since the first report of the intermolecular direct catalytic asymmetric aldol reaction which features in situ or direct generation of nucleophilically active enolates, [4] direct use of aldol donors has gained increasing attention in catalytic asymmetric aldol reactions. [6][7][8][9][10][11][12][13] Only the pioneering example of a direct catalytic asymmetric aldol reaction using amide-based aldol donors (N-Boc amide) has been reported with limited substrate scope and moderate ee values. [5] In this context, direct aldol reactions using less acidic carbonyl compounds, having a carboxylic acid oxidation state, have been much less explored because of their reluctance to form enolates.…”

Total Synthesis of (−)-Lasonolide A

“…12 The particular efficiency of the Ru catalyzed macrocyclization in the laulimalide synthesis stimulates exploration of the Ru catalyzed process making linear rather than branched products. To be applied to the total synthesis of lasonolide A, there are two possible approaches that could afford the desired product (Scheme 2).…”