Stereocontrolled Synthesis of a Cⁿ–Cⁿ⁺⁷Building Block (“Eastern Moiety”) for the Unnatural Enantiomers of Important Polyol,Polyene Antibiotics Based on a Ring‐Closing Metathesis and an Aldol Addition of a Lactone Enolate

Abstract

A stereocontrolled synthesis of epoxide 6, which represents the Cn–Cn+7 or “eastern moiety” building block for the title compounds, has been realized in 19 steps. Our synthesis started from tetrabromoacetone 26 and afforded dibromotriene 33b in six steps. The latter was subjected to a ring‐closing metathesis, which gave the dibromovinyl‐substituted lactone 34 in high yield. A highly stereoselective conjugate addition/enolate aldolization sequence established the additional stereocenters with perfect selectivity. Epoxide 47b was reached in another eight steps, which included a C–SiMe2Ph → C–OH oxidation in the presence of an acetal group. The final structure 6 was completed by hydrostannylation/brominolysis.

Stereocontrolled Synthesis of a C1–C10 Building Block (“Southwestern Moiety”) for the Unnatural Enantiomers of the Polyene Polyol Antibiotics Filipin III and Pentamycin: A Sultone‐Forming Ring‐Closing Metathesis for Protection of Homoallylic Alcohols

“…At –78 °C, the latter added chemoselectively to the C=C bond of the lactone moiety of compound 24 when a stoichiometric amount of Me 3 SiCl was present. Moreover, this addition was perfectly trans ‐selective and in accordance with related observations from our group 14,15. We isolated the resultant silyllactone/unsaturated sultone 26 in 70 % yield.…”

“…At C‐3 (filipin‐ and pentamycin‐numbering) lactone 5 contains an ArR 2 Si substituent, which might be converted into the C‐3‐bound oxygen substituent in lactol “ether” 4 by a Fleming or Tamao oxidation 13. We envisaged derivation of lactone 5 from lactone 7 by an aldol addition, which would hopefully exhibit the desired induced and simple diastereoselectivity 14,15. Lactone 7 would be obtained from lactone 6 by an S N 2 reaction.…”

A thiocyanopalladation/carbocyclization transformation identified through enzymatic screening: stereocontrolled tandem C–SCN and C–C bond formation

“…In this endeavor it was envisioned that the absolute stereochemistry could be set via asymmetric allylation of silyl propiolaldehyde ( 55 ). There was some precedent for such an approach, albeit with modest success, utilizing either Soderquist's chiral B-allyl-borabicyclo[3.3.2]decane reagent 31 (76%, 77% ee) 32 or the Duthaler–Hafner allyl titanium TADDOLate reagent 33 (62%, 85% ee). 32 Accordingly, a range of alternative, asymmetric allylation chemistries were examined here with variation of the metal, the chiral element, the silyl protecting group and the temperature ( Table 4 ).…”

“…There was some precedent for such an approach, albeit with modest success, utilizing either Soderquist's chiral B-allyl-borabicyclo[3.3.2]decane reagent 31 (76%, 77% ee) 32 or the Duthaler–Hafner allyl titanium TADDOLate reagent 33 (62%, 85% ee). 32 Accordingly, a range of alternative, asymmetric allylation chemistries were examined here with variation of the metal, the chiral element, the silyl protecting group and the temperature ( Table 4 ). Absolute configuration was determined using reported optical rotation where possible and ultimately confirmed via X-ray crystallography upon the eventual NP core structure.…”

(Z)-Selective Enol Triflation of α-Alkoxyacetoaldehydes: Application to Synthesis of (Z)-Allylic Alcohols via Cross-Coupling Reaction and [1,2]-Wittig Rearrangement

“…In the case of of (4-methoxyphenyl)methyl ether 3Ca, a specific reaction conditions were required. When the 3Ca was treated with n-BuLi In summary, a useful synthetic scheme for (Z)-allylic alcohols was established based on the novel In a similar manner, 2-alkoxyacetoaldehyde 1A, 26 1C, 27 and 1D 28 were prepared from ethylene glycol. atmosphere.…”