Synthesis of the L‐Acid (C1–C18) Fragment of Pamamycin‐593 and De‐N‐methylpamamycin‐579

Abstract

The L-acid (C1-C18) fragment of pamamycin-593 and de-Nmethylpamamycin-579, strong aerial mycelium-inducers of Streptomyces alboniger, was synthesized using a cis-selective iodoetherification and a nucleophilic addition of a cerium acetylide to an aldehyde as the key steps.

A Reverse Approach to the Total Synthesis of Halichondrin B

“…Thus, hydrolysis of the methoxy acetal on ring E of 50 (PTSA·H 2 O, 86% yield) followed by exposure of the resulting lactol (in equilibrium with its hydroxy aldehyde tautomer, 51′ ) to diazo phosphonate 52 in the presence of SnCl 2 afforded lactol phosphonate 53 (inconsequential lactol isomers) in 67% yield. Coupling of advanced intermediate 53 with fragment A ( A ) as facilitated by Et 3 N and LiBr furnished the expected ( E )-enone 54 in 60% yield . Finally, halichondrin B ( 1 ) was generated from precursor 54 through sequential cleavage of the TBS (TBAF, AcOH) and PMB (DDQ) protecting groups , and subsequent cyclization reactions to cast rings BCDE , respectively, in 38% overall yield as depicted in Scheme .…”

“…The successful cycloetherification and methyl ester hydrolysis of 48 to produce polycyclic carboxylic acid 49 (Scheme 6) proceeded via intermediate polycycle methyl ester 49a (see structure in Table 1) and apparently occurred stepwise from 48 (as evidenced from TLC analysis), first leading to the corresponding polycycle methyl ester (49a) through the expected cycloetherification under the influence of KOH and 18-crown-6 in toluene/MeOH at 60 °C and then hydrolysis of the methyl ester upon addition of 1 M KOH solution in MeOH to afford the desired carboxylic acid (49, Scheme 6). 31 Finally, halichondrin B (1) was generated from precursor 54 through sequential cleavage of the TBS (TBAF, AcOH) and PMB (DDQ) protecting groups 2,30b and subsequent cyclization reactions to cast rings BCDE, respectively, in 38% overall yield as depicted in Scheme 7.…”

A Highly Convergent Total Synthesis of Norhalichondrin B

“…The stage was now set for the coupling of fragments 45 and 32a (initially) or 32b (eventually) (see Scheme for their synthesis) and further elaboration of the so-formed enone coupling products, respectively, toward the ABCD­EFG fragment (C16- epi - 30 ), as shown in Scheme . Thus, reaction of fragment FG ( 45 ) with fragment A [ 32a (first route)] under HWE olefination conditions (Et 3 N, LiBr, THF) furnished ( E )-enone 46a (55% yield), whose deprotection and further elaboration to the targeted ABCD­EFG fragment through 47 is summarized in Scheme . Initially, advanced intermediate 46a was subjected to sequential cleavage of the TES (TBAF, AcOH) and PMB (DDQ, CH 2 Cl 2 /MeOH) protecting groups, which subsequently led to spontaneous ring closures, respectively, to form rings BCDE as depicted in structure 47 (39% overall yield from 46a , 1:3 dr at C16 with the desired product being the minor component).…”

Synthetic studies of biologically active natural products contributing to pesticide development

“…16) In a similar manner, the L-acid and S-acid fragments of pamamycin congeners, aerial hyphal differentiation inducers of Streptomyces alboniger, were synthesized. [17][18][19][20] The proposed structures of spirofungin A and B produced by Streptomyces spp., were revised after synthesis of spiroacetal core fragments as C-15 epimers, 21,22) and the formal total synthesis was also achieved (Fig. 2).…”