Synthesis of (Z)‐Trisubstituted Olefins by Decarboxylative Grob‐Type Fragmentations: Epothilone D, Discodermolide, and Peloruside A

Abstract

Methyl-branched (Z)-trisubstituted olefins are found in many polyketides with interesting biological activity, such as epothilone D (1), discodermolide (3), and peloruside A (2). Despite the employment of numerous different strategies, this motif has often been the weak point in total synthesis. Thus, we present a novel hydroxide- induced Grob-type fragmentation as an easy access to trisubstituted olefins. In our case, beta-mesyloxy delta-lactones with three stereogenic centers were chosen whose fragmentation underlies a high stereoelectronic control. Major challenges in the syntheses were the installation of quaternary stereocenters, achieved by enzymatic desymmetrization of meso-diesters and by aluminium-promoted stereoselective rearrangement of chiral epoxides, respectively. Different aldol strategies were developed for the formation of the fragmentation precursors. Additionally a short survey about nucleophilic additions to aldehydes with quaternary alpha-centers is presented.

Total Synthesis of Leupyrrins A1 and B1, Highly Potent Antifungal Agents from the Myxobacterium Sorangium cellulosum

“…As shown in Scheme , its synthesis started from dimethyl malonate 73 , which was hydroxyalkylated and then underwent a PLE‐catalyzed (PLE=pig liver esterase) resolution giving monoacid acid 74 in 91 % yield and an ee of 82 % following a known procedure . The acid was then converted into the corresponding anhydride, reduced to the respective alcohol, and then selectively oxidized to the desired aldehyde 75 with IBX . To avoid potential disadvantages of the tert ‐butyl protecting group due to its Lewis acid lability, we also prepared the corresponding TBS‐protected aldehyde 76 .…”

6.19 Fragmentation Reactions

“…3 An illustrative example of a related decarbonylative fragmentation for the stereocontrolled synthesis of a trisubstituted alkene is provided in equation 20. 23 Eschenmoser's seminal fragmentation method (cf. equation 5, above) was limited in scope to five-membered rings because of competition from other pathways (i.e., cyclization).…”

The Chelation-controlled Mukaiyama Aldol Reaction of Chiral α- and β-Alkoxy Aldehydes

“…36 For example, the addition of enol silane 59 to aldehyde 58 with formation of 60 occurs with essentially complete chelation control (Scheme 14). Another example from the same study concerns β-chelation of aldehyde 61 having a stereocenter at the α-position leading to exclusive formation of aldol adduct 63 (although with moderate yield).…”

“…Another example from the same study concerns β-chelation of aldehyde 61 having a stereocenter at the α-position leading to exclusive formation of aldol adduct 63 (although with moderate yield). 36 Efficient syntheses of cryptophycin-52 and novel analogs of the p-alkoxymethyl unit A were reported by Sewald et al in which chelation-controlled Mukaiyama aldol reactions as well as allyl stannane additions play key roles. 37 An example is the MgBr 2 -mediated vinylogous Mukaiyama aldol addition of enol silane 65 to aldehyde 64 leading to a single diastereomer 66 (Scheme 15).…”