A highly convergent synthesis of the C1–C31 polyol domain of amphidinol 3 featuring a TST-RCM reaction: confirmation of the revised relative stereochemistry

Abstract

The concise enantioselective synthesis of the revised C1–C31 fragment of the polyketide amphidinol 3 was accomplished in 16 steps and 12.8% overall yield.

Medium-Ring Stereocontrol in the Temporary Silicon-Tethered Ring-Closing Metathesis Approach to the Synthesis of Polyketide Fragments

“…13 Hence, there is a degree of predictability with this process, which makes it an attractive strategy for applications to target-directed synthesis. 9 The ability to construct contiguous stereogenic centers, especially polypropionate and polyol derivatives, is potentially useful in the preparation of complex synthetic intermediates. In order to illustrate the synthetic utility of the …”

“…These results highlight the generality of the TST-RCM transformation, which facilitates the union of more elaborate fragments relevant to target-directed synthesis. 9 Hence, with the library of silaketals in hand, we elected to examine the stereoselective hydroboration reaction (Table 2). Interestingly, this study demonstrated that silaketals 7a,c reacted with borane-dimethyl sulfide complex to afford the secondary alcohols 8a,c in excellent yield and selectivity (rs ≥19:1, ds ≥19:1) after oxidative work-up (entries 1 and 3); however, the analogous process with silaketals 7b,d resulted in poor regio-and modest diastereocontrol.…”

“…5 In an effort to further extend this methodology, we envisioned that the construction of unsymmetrical medium-ring Z-silaketals would provide an opportunity to stereoselectively functionalize the Z-configured trisubstituted olefin using the propensity for the eight-membered silaketal to adopt a defined conformation and thereby enforce high facial selectivity in the addition. [5][6][7][8][9] Herein, we now describe the highly Scheme 1 Temporary silicon-tethered ring-closing metathesis approach to Z-configured silaketals: a new strategy for the stereoselective construction of polypropionates and polyols [3][4][5] Treatment of the allylic alcohols 5 with excess diisopropyldichlorosilane and imidazole furnished the monochloroalkoxysilane intermediates, which upon removal of the excess reagent and addition of the requisite homoallylic alcohol 4 provided the bis-alkoxysilanes 6 in 77-99% yield. The bis-alkoxysilanes 6 were then subjected to ring-closing metathesis using the second-generation Grubbs catalyst in CH 2 Cl 2 at 40 °C to afford the silaketals 7 in 86-94% isolated yield and with excellent selectivity (Z/E ≥19:1).…”

Synthesis and Stereochemical Revision of the C31–C67 Fragment of Amphidinol 3

“…However, all of them were based on the originally proposed structure reported in 1999. Therefore, there was no argument regarding the stereochemistry of AM3 except for the synthetic study of the C1–C31 polyol fragment, by the group of Evans, based on the revised structure in 2013.…”

Access to the C15–C40 fragment of tetrafibricin via configuration-encoded 1,5-polyol methodology

“…The stereochemical structure elucidation and efforts toward total synthesis have generated significant interest in recent years. [6][7][8][9] Amphidinol 3 has demonstrated potent antifungal activity with submicromolar IC50 values and relatively potent hemolytic activity (EC50 = 0.25 μM/kg), with its mode of action attributed to increasing ion permeability in biomembranes from the formation of pores or lesions. [10][11] The stambomycin family of compounds all contain 1,5,7-triol motifs (Figure 1.4).…”