Highly trans‐Selective Arylation of Achmatowicz Rearrangement Products by Reductive γ‐Deoxygenation and Heck–Matsuda Reaction: Asymmetric Total Synthesis of (−)‐Musellarins A–C and Their Analogues

Abstract

Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans-2,6-dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two-step trans arylation of AR products to access 2,6-trans-dihydropyranones. This new trans-arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier-type and Tsuji-Trost-type reactions, was finally enabled by an unprecedented, highly regioselective γ-deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck-Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (-)-musellarins A-C and 12 analogues in 11-12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three-to-six times greater potency than the musellarins as promising new leads.

Oxidative Ring‐Expansion of a Chitin‐Derived Platform Enables Access to Unexplored 2‐Amino Sugar Chemical Space

“…Having accessed a series of glycosides based on the l ‐rednose scaffold, attention turned to accessing further 2‐amino sugars by synthetic manipulation of the β‐aminoenone unit (Scheme ). Subjecting 4 to standard hydrogenation conditions did not reduce the C=C double bond, instead leading to the 3‐aminopyranone 8 resulting from reductive deoxygenation . In contrast, hydrogenation of the double bond in α‐ 5 was successful, giving α‐ 9 as a single diastereomer.…”

Unexpected cytotoxicity of a triisopropylsilylated syringaldehyde derived cinnamic acid amide

“…Reaction (Scheme 1) of syringaldehyde (1, 4hydroxy-3,5-dimethoxy-benzaldehyde) with triisopropylsilyl chloride (TIPS-Cl) gave 93% of TIPS-protected 2 30 . Its reaction with malonic acid under Knoevenagel-Doebner conditions furnished (E) configurated cinnamic acid 3.…”

Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure-Activity Relationship (SAR) of SGLT2 Inhibition

“…The allylic electrophiles 16 and 17 were prone to β-elimination which led to the formation of diene side products. A literature search revealed that allyl-aryl coupling reactions in cyclic systems are rare and challenging 30–32 , while those in acyclic systems often necessitate elevated reaction temperatures 33–35 . Thus, a mild reaction condition for cyclic substrates is highly sought-after.…”