Total Synthesis of Callystatin A by Titanium‐Mediated Reductive Alkyne–Alkyne Cross‐Coupling

Abstract

Using a modular approach: A concise synthesis of callystatin A has been developed. The modular pathway provides access to the highly unsaturated skeleton of the leptomycin natural products by using a complex titanium‐mediated reductive alkyne–alkyne cross‐coupling reaction as the key transformation (see scheme; TBS=tert‐butyldimethylsilyl).

Total synthesis of antibiotics: recent achievements, limitations, and perspectives

“…(Frantz, 2000) The third precursor was also easily obtained using asymmetric crotylsilylation methodology developed by the same group. The reductive alkyne-alkyne coupling (Reichard, 2008) In the present case, the coupling of 30 and 31 under conditions described above provided diene 37 in 58% yield (Scheme 5). A slightly higher yield of the coupling product can be obtained with alkynamide bearing acetyl protecting group on the C-1 hydroxyl.…”

Alternaric acid: formal synthesis and related studies

“…It began from the known allylic alcohol 21 [46], which was acetylated to afford ester 22 as prelude for reaction as a π-allyl electrophile with the Reformatsky reagent 23 derived from tert -butyl bromoacetate. The TMS-alkyne in 24 was deprotected with buffered TBAF to afford free alkyne 25 , and the vinyl iodide 26 was generated by hydrozirconation/iodination of the free alkyne with Schwartz’s reagent [47]. The vinyl nucleophile 27 could be generated by Knochel’s Mg/I exchange [48] and employed successfully in the three-component-coupling reaction with silyl glyoxylate 1a and aldehyde 16ba to assemble 28 , which contains the bulk of the carbon skeleton of alternaric acid.…”

Metallacycle-mediated cross-coupling in natural product synthesis

“…18 This demonstration appeared in efforts targeting the total synthesis of callystatin A (Figure 4A), a rare and highly cytotoxic member of the leptomycin class of natural products. 19 The Micalizio laboratory reported a highly convergent synthesis that proceeded by way of a coupling reaction that forged the C13–C14 bond and established the accompanying ( E , E )-1,3-diene motif.…”