Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of Δ12 -Prostaglandin J3.

Andrejs Pelšs,James R Smith,Damien Mailhol,Narasimhulu Gandhamsetty,Isabel Perez‐Powell,Varinder K Aggarwal,Mattia Silvi,Andrew J A Watson,Nina Schützenmeister,Peter R Moore,Sébastien Prévost

doi:10.1002/chem.201802498

Andrejs Pelšs, James R Smith + Show 9 more

Open Access

https://doi.org/10.1002/chem.201802498

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Journal: Chemistry	Publication Date: Jun 6, 2018
Citations: 33	License type: CC BY 4.0

Affiliation: University of Bristol, AstraZeneca (United Kingdom)

Abstract

Re‐investigation of the l‐proline catalyzed double aldol cascade dimerization of succinaldehyde for the synthesis of a key bicyclic enal intermediate, pertinent in the field of stereoselective prostaglandin synthesis, is reported. The yield of this process has been more than doubled, from 14 % to a 29 % isolated yield on a multi‐gram scale (32 % NMR yield), through conducting a detailed study of the reaction solvent, temperature, and concentration, as well as a catalyst screen. The synthetic utility of this enal intermediate has been further demonstrated through the total synthesis of Δ12‐prostaglandin J3, a compound with known anti‐leukemic properties.

Highlights

Bimatoprost,[10] and alfaprostol.[11] The key step in our synthesis is the double aldol dimerization of succinaldehyde with proline and dibenzylammonium trifluoroacetate (DBA) as catalysts to give the bicyclic enal intermediate (1) in high enantioselectivity (Scheme 1).[12] Whilst this single step converts a simple starting material into a complex intermediate[13] fully primed to enable rapid attachment of the two side chains required, its Achilles’ heel is its low yield (caused by the extensive oligomerization of succinaldehyde under the reaction conditions)
We describe a full re-investigation of this key step, which has culminated in an increase in yield from 14 %[9a] to a 29 % isolated yield on a multi-gram scale, thereby enabling the enal 1 to be used not just in further, more efficient prostanoid syntheses, and as a highly functionalized and useful building block more generally
We demonstrate its application to the concise synthesis of D12-PGJ3, a prostanoid of considerable contemporary interest due to its high activity against cancer stem cells, a class of cells that are notoriously resistant toward conventional chemical therapies.[14]

Summary

Introduction

Bimatoprost,[10] and alfaprostol.[11] The key step in our synthesis is the double aldol dimerization of succinaldehyde with proline and dibenzylammonium trifluoroacetate (DBA) as catalysts to give the bicyclic enal intermediate (1) in high enantioselectivity (Scheme 1).[12] Whilst this single step converts a simple starting material into a complex intermediate[13] fully primed to enable rapid attachment of the two side chains required, its Achilles’ heel is its low yield (caused by the extensive oligomerization of succinaldehyde under the reaction conditions). The yield was further increased to 19 % (NMR) by reducing the initial concentration to 1 m (entry 3), but under these reaction conditions, the enal was isolated in only 9 % yield.

Results

Conclusion