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

Abstract

The temporary silicon-tethered ring-closing metathesis of chiral non-racemic allylic and homoallylic alcohols affords unsymmetrical Z-configured trisubstituted olefins that readily undergo stereoselective hydroboration and dihydroxylation to provide a novel approach to masked polypropionate and polyol fragments present in an array of biologically important natural products. For example, this strategy provides a convenient method for the construction of polyol fragments relevant to the secondary metabolites amphidinol 3 and lophodiol A, which have antifungal and cytotoxic activity, respectively.The stereoselective construction of structurally diverse polyketides is of particular interest due to their ubiquity in biologically important natural products ( Figure 1). 1 In this context, the development of new methodology that provides complementary routes for the preparation of these challenging motifs is of great synthetic importance since it can lead to the development of new strategies that expedite the synthesis of these types of agents. 2 In a program directed toward the exploration of new synthetic methodologies based on the temporary silicon-tethered ring-closing metathesis (TST-RCM), we have developed a novel approach for the synthesis of protected C 2 -symmetrical 1,4-diols using chiral non-racemic allylic alcohols (Scheme 1A). 3,4 The inherent advantage of this approach is the ability to couple a variety of allylic alcohols and functionalize the newly formed geometrically defined Z-olefin to enable the rapid construction of molecular complexity. 4-6 In a related study, we developed a new strategy for controlling long-range asymmetric induction using a bis-alkoxysilane that contains a prochiral bis-allylic alcohol (Scheme 1B). 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. 5-9 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 O Si O R R O Si O R R O Si O R R OH HO + cat.

A Modular Synthesis of Antitumor Macrolide (–)‐Lasonolide A†

“…[ 27 ] In a recent solution reported by the Evans group, the hydroboration of Z ‐alkene with ThexBH 2 via a bis‐alkoxysilane medium 7‐membered ring resulted in syn , syn ‐1,3‐triols with excellent diastereoselectivity ( ds ≥19 : 1). [ 28 ] We thus envisioned that a possible boron‐ate complex to chelate 1,4‐diol may also promote the hydroboration of Z ‐alkene to favor a syn , syn ‐isomer through mimicking the conformation of the silyl‐templated medium ring (the chelation model in Figure 3). [ 29 ]…”

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

“…20 In concurrent work, we focused on the preparation of the fragments required for the key TST-RCM cross-coupling reaction (Scheme 4). 21 Conversion of the allylic alcohol 14 22 to the corresponding primary allylic bromide and concomitant Sharpless asymmetric dihydroxylation, 23 afforded the required a-hydroxy epoxide 15 in 75% overall yield and with 92% enantiomeric excess (by 1 H NMR analysis of the Mosher's ester). Protection of the secondary alcohol 15 as the tertbutyldimethylsilyl ether and regioselective ring-opening of the terminal epoxide with isopropenylmagnesium cuprate at À78 C furnished 7 in 79% yield over two steps.…”

Diastereoselective synthesis of trisubstituted olefins using a silicon-tether ring-closing metathesis strategy

“…4 Silicon-tether ring-closing metathesis (RCM) reactions with O-Si-O linkages have been widely used for the formation of alkenes, when the corresponding CM reactions are not high yielding or/and diastereoselective. 5 Previous works by Kobayashi et al 6 and Evans et al 7 illustrate the use of such linkage for the formation of E and Z trisubstituted olefins, respectively, via eight-membered rings (Scheme 2).…”