Total Synthesis and Structural Revision of Callipeltoside C

Abstract

Dedicated to Professor Luigi Minale and co-workersThe continual search for new antitumor and antiviral agents from marine sponge extracts has resulted in the identification of a number of structurally complex and diverse natural products with intriguing biological activity. In 1996 and 1997 Minale and co-workers reported the isolation and structural assignment of callipeltosides A-C (Figure 1), the first three members of a new class of marine macrolides from the lithistid sponge Callipelta sp. indigenous to the shallow waters off New Caledonia. [1] Biological activity, in particular cytotoxicity, varies among the callipeltosides, and their IC 50 values range from 11.3 to 30.0 mg mL À1 against human bronchopulmonary NSCLC-N6 cell lines.[1] These natural isolates were shown to block cell proliferation in the G1 phase, but unfortunately the exact mode of action cannot as yet be determined owing to the prohibitively small quantities of callipeltosides A-C that have been isolated to date ( 3.5 mg).[1] A more detailed annotation of the biological mechanism will await the availability of substantial synthetic quantities of the callipeltosides and their analogues as the natural isolates have been consumed. [1] In terms of structural complexity, the callipeltosides share a common 12-membered macrocycle comprising seven stereocenters and a unique dienyne chlorocyclopropane side chain; this class is differentiated only by the composition of the saccharide moiety. In particular, callipeltosides A and B are characterized by the presence of two unique deoxyamino sugars, while callipeltoside C incorporates the novel deoxy sugar 2-O-methylevalose. Perhaps more notable, the carbohydrate moieties of callipeltosides B and C were reported to exist in the opposite enantiomeric series to that found in callipeltoside A (callipeltosides B and C = d sugar, callipeltoside A = l sugar).Their stereochemical and structural complexity coupled with their unique biological activity make the callipeltoside family an attractive target for total synthesis. Indeed, to date, the groups of Trost, [2] Evans, [3] Paterson, [4] and Panek [5] have completed the asymmetric construction of callipeltoside A, yet surprisingly callipeltosides B and C have remained unchallenged by chemical synthesis. In this communication we describe the first total synthesis of callipeltoside C and present a structural revision with respect to the enantioseries of the pendent 2-O-methylevalose carbohydrate. This synthetic sequence, which is founded upon the use of organocatalytic and organometallic technologies, provides access to useful quantities of callipeltoside C in 18 chemical steps and 12 % overall yield.Our disconnection of callipeltoside C into four components 2-5 of similar complexity (Figure 2) revealed the possibility of a convergent synthesis with broad latitude in the sequence of fragment coupling. Inspection of fragments 2-4 brought to mind the possibility of exploiting three asymmetric organocatalytic transformations that have recently been developed i...

The direct catalytic asymmetric aldol reaction

“…Application of the aldehyde aldol reaction to the syntheses of prelactone B and callipeltoside C. 131, 132 …”

“…Pihko and coworkers used this methodology for a short synthesis of prelactone B (Scheme 11). 131 MacMillan and coworkers also used this method for the synthesis of callipeltoside C. 132 …”

Organocatalysis—after the gold rush

“…47 The first enamine reaction was a double-differentiating aldol reaction between the Roche ester-derived aldehyde 36 and propionaldehydes 37 using L-proline as the catalyst. This reaction proceeds with a high level of stereocontrol and further reaction of this adduct leads to a highly functionalized tetrahydropyran fragment.…”

Survey of marine natural product structure revisions: A synergy of spectroscopy and chemical synthesis

“…Structural motifs misassigned on the basis of NOEs include epoxides (calafianin, 96–98 symbiodinolide 99, 100 ), cyclopropyl rings (clavosolide A, 101, 102 laurentristich-4-ol 103, 104 ), bridges (vannusals A and B 105–107 ), fused ring junctions (itomanallene A, 108, 109 asperdimin, 110, 111 aplysiallene 112, 113 ), polyethers (aplysiol B, 114, 115 azaspiracids 116–119 ), vicinal polyols (amphidinolide H2, 120, 121 hyrtiosterol, 122, 123 pericosine A 124, 125 ), sugars (callipeltoside C; 126, 127 fusapyrone and deoxyfusapyrone, 128, 129 Table 6) and macrolides (palmerolide A, 130–132 neopeltolide 133, 134 ).…”