Modular Synthesis of Novel Macrocycles Bearing α,β‐Unsaturated Chemotypes through a Series of One‐Pot, Sequential Protocols

Abstract

A series of one-pot, sequential protocols was developed for the synthesis of novel macrocycles bearing α,β-unsaturated chemotypes. The method highlights a phosphate tether-mediated approach to establish asymmetry, and consecutive one-pot, sequential processes to access the macrocycles with minimal purification procedures. This library amenable strategy provided diverse macrocycles containing α,β-unsaturated carbon-, sulfur- or phosphorus-based warheads.

Stereoselective Synthesis of Conjugated Polyenes Based on Tethered Olefin Metathesis and Carbonyl Olefination: Application to the Total Synthesis of (+)-Bretonin B

“…The metathesis step then becomes a ring closing metathesis (RCM) reaction. Traceless removal of the tether after the RCM reaction, e.g., by hydrolysis, furnishes acyclic Z -alkenes that cannot be obtained by standard CM reactions. , In our tethered RCM variant, cleavage of the tether is accomplished by a base-induced elimination of the RCM products 2 that generates an additional E -configured double bond conjugated to a Z -double bond. A further difference as compared to other tethered RCM reactions is that the tether is retained in the product as a valuable carboxylate group.…”

Synthesis of the C1−C16 Polyol‐Containing Macrolactone of 13‐Desmethyl Lyngbouilloside, an Unnatural Analog of the Originally Assigned Structure of (−)‐Lyngbouilloside

“…Recently, we have engaged in the synthesis of biologically active natural products using phosphate tether‐mediated approaches, [27,28,29] including the generation of a number of unique P ‐stereogenic bicyclo[n.3.1]phosphate macrocycles, [30] as well as novel macrocyclic variants bearing unsaturated C‐, S‐ and P‐reactive functionality [31] . We now report application of an iterative use of a one‐pot, sequential RCM/CM/ chemoselective diimide reduction protocol for the synthesis of the C1−C16 polyol‐containing macrolactone of 13‐desmethyllyngbouilloside, bearing the originally assigned macrolactone core at the C10/C11 and C13 stereocenters.…”

Synthesis of Benzothiophene‐Containing 10‐ and 11‐Membered Cyclic Phostones

“…However, far less attention has been devoted to the synthesis and biological evaluation of large ring systems of phostines, phostones, and phosphates. Recently, novel macrocyclic phosphates and phosphoramidates, with structural similarities to macrolide polyketides, were reported . Macrocyclic compound 7 (a hapten for raising catalytic antibodies) and antiproliferation and migration agent 8 (an inhibitor of focal adhesion kinase; FAK) are two examples of reported macrocyclic phostones.…”