Synthesis of Prostaglandin Analogues, Latanoprost and Bimatoprost, Using Organocatalysis via a Key Bicyclic Enal Intermediate

Abstract

Two antiglaucoma drugs, bimatoprost and latanoprost, which are analogues of the prostaglandin, PGF2α, have been synthesized in just 7 and 8 steps, respectively. The syntheses employ an organocatalytic aldol reaction that converts succinaldehyde into a key bicyclic enal intermediate, which is primed for attachment of the required lower and upper side chains. By utilizing the crystalline lactone, the drug molecules were prepared in >99% ee.

Synergy Between Expert and Machine‐Learning Approaches Allows for Improved Retrosynthetic Planning

“…In the total synthesis of anatural product, seimatopolide A [13] (Figure 4c), popular reactions were ranked among the top five positions by all three methods.I nc ontrast, less frequent ones (zero or one occurrences in the training set) like Prins cyclization constructing at etrahydropyran core,r eductive opening of at etrahydropyran ring, or stereoselective aaminooxylation of an aldehyde followed by reduction, were ranked significantly worse by SW2 + (ranks #173, #100, and #230, respectively) than by both ICHO + and SMALLER. An analogous trend is seen in Aggarwalss ynthesis [14] of ap rostaglandin analogue,b imatoprost (Figure 4d): popular reactions are ranked top ten by both ICHO + and SW2 + but only the former ranks more specialized reactions better (for example,t he ozonolysis of as ilyl enol ether followed by addition of NaBH 4, producing achiral alcohol).…”

“…Average rankings for entire pathways (⟨Rank⟩) are given on the right of each panel. Syntheses of a) BRD 7/9 inhibitor, b) (+)‐synosutine, c) seimatopolide A, and d) bimatoprost . For clarity, and to mimic Chematica's implicit treatment of protections (ref.…”

Synergy Between Expert and Machine‐Learning Approaches Allows for Improved Retrosynthetic Planning

“…In contrast, less frequent ones (zero or one occurrences in the training set) like Prins cyclization constructing a tetrahydropyran core, reductive opening of a tetrahydropyran ring, or stereoselective α‐aminooxylation of an aldehyde followed by reduction, were ranked significantly worse by SW2+ (ranks #173, #100, and #230, respectively) than by both ICHO+ and SMALLER. An analogous trend is seen in Aggarwal's synthesis of a prostaglandin analogue, bimatoprost (Figure d): popular reactions are ranked top ten by both ICHO+ and SW2+ but only the former ranks more specialized reactions better (for example, the ozonolysis of a silyl enol ether followed by addition of NaBH 4, producing a chiral alcohol).…”

Enantio‐ and Diastereoselective Synthesis of Latanoprost using an Organocatalyst

“…4) Excellent 1,3chirali nduction is realized in domino acetalization and oxy-Michael reactions catalyzed by Bi(OTf) 3 and NaClO 4 , developed in our group. The present route possesses several noteworthy features:1 )One of the key reactions is the organocatalyst-mediated [3 + 2]cycloaddition reactiond eveloped by our group fort he construction of the cyclopentane core structure.…”