Enantioselective Oxidative Spirocyclization of Biaryl Hydroxy Carboxylic Acids: Enantioselective Synthesis of
Kirara Saeda1, Muhammet Uyanik1, Kazuaki Ishihara1
1Graduate School of Engineering, Nagoya University, Chikusa, Nagoya, 464-8603, Japan.
Abstract:
The first metal-free, catalytic, and highly enantioselective total synthesis of the natural product (-)-arnottin II is described. The central challenge of this synthesis lies in the oxidative spirolactonization of a conformationally rigid biaryl hydroxy carboxylic acid (BHCA), an intrinsically unstable intermediate that is prone to an unwanted intramolecular dehydrative condensation that regenerates the thermodynamically stable aromatic lactone arnottin I. To overcome this issue, we have developed a one-pot strategy in which BHCA is generated in situ from arnottin I and immediately subjected to an enantioselective oxidative spirolactonization, catalyzed by a chiral hypervalent iodine. The use of a phosphate buffer (pH = 6.3) proved essential to suppress re-lactonization and competing side reactions. Under the optimized conditions, (-)-arnottin II was obtained in up to 83% isolated yield with 91% enantiomeric excess, establishing a practical and sustainable solution to a long-standing synthetic challenge.
Related Concept Videos
Alkylation of β-Diester Enolates: Malonic Ester Synthesis
Synthesis of α-Substituted Carbonyl Compounds: The Stork Enamine Reaction
Oxidation of Alkenes: Syn Dihydroxylation with Osmium Tetraoxide
Alkylation of β-Ketoester Enolates: Acetoacetic Ester Synthesis
Thermal Electrocyclic Reactions: Stereochemistry
Selection Rules: Thermal Activation
Conjugated systems containing an even number of π-electron pairs undergo a conrotatory ring closure. For example, thermal electrocyclization of (2E,4E)-2,4-hexadiene, a conjugated diene containing two π-electron pairs, gives trans-3,4-dimethylcyclobutene.
Regioselectivity and Stereochemistry of Hydroboration
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.


![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)