Synthetic Strategies Employed for the Construction of Fostriecin and Related Natural Products

Abstract

Fostriecin and related natural products present a significant challenge for synthetic chemists due to their structural complexity and chemical sensitivity. This review will chronicle the successful efforts of synthetic chemists in the construction of these biologically active molecules. Key carbon–carbon bond forming reactions will be highlighted, as well as the methods used to install the numerous stereocenters present in this class of compounds.

Expedient Approach to α,β‐Unsaturated δ‐Lactones through a Catalytic Asymmetric [2+2] Cycloaddition

“…In previous syntheses of this motif, syn-selective aldol reactions, asymmetric allylmetallation reactions of aldehydes, or sigmatropic rearrangements have been successfully used for the synthesis of a stereodefined lactone precursor, with cyclisation to the lactone being achieved by ring-closing metathesis or direct cyclisation from a (Z)-α, -unsaturated acid. [5][6][7][8] Additionally, an elegant approach to the disubstituted lactone motif of pironetin 1 has been described, involving the addition of an acetate enolate to a -acetoxy aldehyde, followed by acyl transfer and subsequent cyclisation. [9] In a project related to the total synthesis of phoslactomycin B (2) and leustroducsin B (3), we planned a synthetic strategy in which the key step would be the coupling of the lactone unit by organometallic addition of an alkenyl or alkynyl anion lactone.…”

“…The presence of two contiguous stereogenic centres with a cis relative configuration means that the issue of control of the relative and absolute configurations must be addressed. In previous syntheses of this motif, syn ‐selective aldol reactions, asymmetric allylmetallation reactions of aldehydes, or sigmatropic rearrangements have been successfully used for the synthesis of a stereodefined lactone precursor, with cyclisation to the lactone being achieved by ring‐closing metathesis or direct cyclisation from a ( Z )‐α,β‐unsaturated acid . Additionally, an elegant approach to the disubstituted lactone motif of pironetin 1 has been described, involving the addition of an acetate enolate to a β‐acetoxy aldehyde, followed by acyl transfer and subsequent cyclisation …”

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

“…8 The most commonly used methods for the total synthesis of polyene natural products are Pd-catalyzed coupling and cross coupling reactions. 2 These methods have been successfully applied in several cases, e.g., very recently for the synthesis of xanthomonadin analogues, 7 in the construction of the Z,Z,Econfigured triene moiety in fostriecin, 9 and in an iterative approach to a truncated amphotericin B fragment. 10 The stereoselective synthesis of the required coupling partners, such as ω-iodoor ω-bromodienes and vinyl metal compounds, can be a drawback because these often start from unstable haloenals 11 that are then subjected to carbonyl olefination reactions in order to furnish iodo-or bromodienes.…”

Lactomycins A–C, Dephosphorylated Phoslactomycin Derivatives that Inhibit Cathepsin B, from the Marine-derived Streptomyces sp. ACT232

“…The C16 and C18 substituents of the cyclohexane ring were both equatorial, as shown by the large coupling constants observed for H16 and H18 to the adjacent axial methylene protons. The structural assignment conducted so far suggested 1 to be a dephospho-25-deamino-25-hydroxy-leustroducsin H (phoslactomycins G) ( 4 ) derivative [ 7 , 8 ]. Although the relative stereochemistry within the three partial structures was identical with that of leustroducsin H [ 9 ], due to the insulation by double bonds and the possible free rotation of the bond between C7 and C8, it was not possible to correlate the relative configurations between the partial structures nor assign that of C8 on the basis of the NOESY data.…”