Enantio- and Diastereoselective Synthesis of Latanoprost using an Organocatalyst.

An enantioselective total synthesis of latanoprost was achieved. Its chiral cyclopentane core structure was constructed through an organocatalyst-mediated [3+2]-cycloaddition reaction, and chirality in the ω-side chain was generated by prolinate-anion-mediated α-aminoxylation of an aldehyde. Highly diastereoselective domino acetalization and an oxy-Michael reaction were key steps for the generation of C9 chirality.

Two-Pot Synthesis of Chiral 1,3-syn-Diols through Asymmetric Organocatalytic Aldol and Wittig Reactions Followed by Domino Hemiacetal/Oxy-Michael Reactions.

A two-pot synthetic method to construct the chiral syn-1,3-diol unit has been developed from three aldehydes and either Wittig or Horner-Wadsworth-Emmons reagents. In the first pot, chiral δ-hydroxy α,ß-unsaturated ketones are synthesized with excellent enantioselectivity by the organocatalyst-mediated asymmetric direct aldol reaction of two different aldehydes, followed by either Wittig or Horner-Wadsworth-Emmons reactions. In the second pot, domino acetalization with an aldehyde and subsequent oxy-Michael reaction proceeds in the presence of NaClO4 and a catalytic amount of Bi(OTf)3 (OTf=trifluoromethanesulfonate) to provide the chiral 1,3-syn-diol derivative with excellent diastereoselectivity. Diospongin C and yashabushidiol A have been synthesized efficiently by using the present method as a key step.

Organocatalyst-mediated, pot-economical total synthesis of latanoprost.

The enantioselective total synthesis of latanoprost, an antiglaucoma agent, has been accomplished with excellent diastereo- and enantioselectivities in a pot-economical manner using six reaction vessels. An enantioselective Krische allylation was conducted in the first pot. In the second pot, olefin metathesis, silyl protection, and hydrogenolysis proceeded efficiently. In the third pot, an organocatalyst-mediated Michael reaction proceeded with excellent diastereoselectivity. The fourth pot involved a substrate-controlled Mukaiyama intramolecular aldol reaction and elimination of HNO2 to afford a methylenecyclopentanone, also with excellent diastereoselectivity. The fifth pot involved a Michael reaction of vinyl cuprate. In the sixth pot, three reactions, a cis-selective olefin metathesis, diastereoselective reduction, and deprotection, afforded latanoprost. Nearly optically pure latanoprost was obtained, and the total yield was 24%.

Prolinate Salt as a Catalyst in the syn-Selective, Asymmetric Mannich Reaction of Alkynyl Imine.

Prolinate salt is an efficient catalyst in the Mannich reaction of alkynyl imine and aldehyde, to afford synthetically useful chiral propargyl amine derivatives with excellent syn-selectivity and nearly perfect control of the absolute configuration. The counterion of the prolinate salt does not affect the enantioselectivity. This is a rare example, in which proline alkali metals, alkaline-earth metals, or ammonium salt show higher reactivity and better stereoselectivity than the parent proline.

Enantioselective Total Synthesis of Beraprost Using Organocatalyst.

A convergent and enantioselective total synthesis of the most active isomer of beraprost was achieved in 17 pots. A unique tricyclic core in beraprost was synthesized efficiently by utilizing the asymmetric organocatalyst-mediated formal [3 + 2] cycloaddition reaction of succinaldehyde with nitroalkene as a key step. The synthesis of the optically active Horner-Wadsworth-Emmons reagent for the construction of the ω-side chain was also established by means of the enantioselective Michael reaction of crotonaldehyde with nitromethane catalyzed by the organocatalyst developed by our group.