Allyl Alcohol as an Acrolein Equivalent in Enantioselective C–C Coupling: Total Synthesis of Amphidinolides R, J, and S

Abstract

The first systematic study of catalytic enantioselective 1,2-additions to acrolein is described. Specifically, using allyl alcohol as a tractable, inexpensive acrolein proelectrophile, iridiumcatalyzed acrolein allylation is achieved with high levels of regio-, anti-diastereo-, and enantioselectivity. This process delivers 3hydroxy-1,5-hexadienes, a useful compound class that is otherwise challenging to access via enantioselective catalysis. Two-fold use of this method unlocks concise total syntheses of amphidinolide R (9 vs 23 steps, LLS) and amphidinolide J (9 vs 23 or 26 steps, LLS), which are prepared in fewer than half the steps previously possible, and the first total synthesis of amphidinolide S (10 steps, LLS).

O-Acetyl 1,3-Propanediol as an Acrolein Proelectrophile in Enantioselective Iridium-Catalyzed Carbonyl Allylation

“…The corresponding products of acrolein allylation 3a – 3p were all formed in good yields with excellent levels of diastereo-, regio-, and enantioselectivity and were free from contamination by propanal adducts 4 . Adducts 3a – 3p are identical (but enantiomeric) to those prepared in iridium-catalyzed carbonyl allylations allyl alcohol 1a . Reactions of O -acetyl 1,3-propanediol 1b gave slightly lower yields compared to that of allyl alcohol 1a , possibly due to the accumulation of potassium acetate under the highly concentrated reaction conditions in THF (0.5 M), which resulted in poor mixing.…”

“…Recently, in connection with longstanding studies on the use of alcohols as carbonyl proelectrophiles in catalytic enantioselective carbonyl addition, our laboratory described the use of allyl alcohol 1a as a tractable, inexpensive acrolein proelectrophile in asymmetric iridium-catalyzed carbonyl allylations mediated by allylic acetates 2 (Scheme ). Although these reactions were highly effective, delivering 3-hydroxy-1,5-hexadienes 3 with high levels of regio-, anti -diastereo-, and enantioselectivity, in certain cases it was not possible to completely suppress redox isomerization of allyl alcohol to form propanal, which resulted in contamination with inseparable propanal adducts 4 .…”

“…In conclusion, we report diastereo- and enantioselective π-allyliridium- C , O -benzoate-catalyzed acrolein 1,2-additions using acetyl 1,3-propanediol as an acrolein proelectrophile. Unlike corresponding reactions in which allyl alcohol serves as an acrolein proelectrophile, the present method delivers 3-hydroxy-1,5-hexadienes free of propanal allylation adducts. This work adds to the lexicon of catalytic asymmetric methods that transform inexpensive commodity chemicals into value-added products via hydrogen autotransfer. ,, …”

Synthesis of the C28–C41 Side Chain of (Proposed) Neaumycin B: A Contiguous Stereohextet

“…A route to the Southern Fragment via ruthenium-catalyzed butadiene-mediated crotylation and oxazaborolidine-catalyzed vinylogous Mukaiyama aldol reaction was recently disclosed . The Northeast side chain, C28–C41, was deemed accessible through the union of vinyl iodide 3 and aldehyde 6 via substrate-directed aldehyde addition by way of the triorganozincate …”

“…Indeed, attempted vinylation of aldehyde 6 under Nozaki–Hiyama–Kishi conditions provided adduct 7 with only a modest bias (2:1 dr) in favor of the desired isomer. At this stage, inspiration was taken from Williams’ seminal use of vinyl-substituted triorganozincates in additions to chiral α,β-stereogenic aldehydesa method that is highly underutilized . Williams’ example of triorganozincate-mediated vinylation involved an α-benzyloxy aldehyde, and the observed diastereofacial selectivity was consistent with chelation-control.…”