Total Synthesis and Structure−Activity Investigation of the Marine Natural Product Neopeltolide

Abstract

The total synthesis and biological evaluation of neopeltolide and analogs are reported. The key bondforming step utilizes a Lewis acid-catalyzed intramolecular macrocyclization that installs the tetrahydropyran ring and macrocycle simultaneously. Independent of each other, neither the macrolide nor the oxazole side chain substituents of neopeltolide can inhibit the growth of cancer cell lines. The biological data of the analogs indicate that alterations to either the ester side chain or the stereochemistry of the macrolide result in a loss of biological activity.

The Vinylogous Aldol and Related Addition Reactions: Ten Years of Progress

“…Optimized Enantioselective VMAR in the Total Synthesis of Marine Polyketides 23, 436, 437, and 440 34,[187][188][189][190] Scheme 79. Further Use of BINOL-Ti(IV) Catalyst System in Asymmetric VMAR 191,192 copper(II) catalyst variant, ent-398, was conveniently exploited by Evans himself in the VMAR reaction between dienolate 444 and protected hydroxyacetaldehyde 445 during the debut of (-)-callipeltoside A synthesis (Scheme 80, eq 1). 35,36 In the event, (S)-configured aldol compound 446 was generated in high yield (93%), with almost complete E selectivity (E/Z > 50:1) and excellent enantioselectivity (95% ee).…”

Total Synthesis of Bryostatin 9

“…This is the most step economical and convergent total synthesis of a potent bryostatin (PKC K i < 10 nM), underscoring the strategic value of this functionality-tolerant macrocyclization reaction. 38 Recent notable examples of Prins macrocyclizations have also been described by the Scheidt, 39 Lee, 40 Rychnovsky, 41 and Yadav groups. 42 …”

Strategies and Methods for the Synthesis of Anticancer Natural Product Neopeltolide and its Analogs

“…[11] Their synthesis features a Mitsunobu reaction to install the side chain and a Prins-type macrocyclization to synthesize the THP-containing macrolactone core in one operation. As delineated in Scheme 2, a Ti(IV)-( S )-BINOL-catalyzed asymmetric aldol reaction was employed to introduce the C 3 stereocenter in intermediate 18 .…”