Zinc(ii)-mediated diastereoselective Passerini reactions of biocatalytically desymmetrised renewable inputs

Abstract

A chiral aldehyde, obtained in both enantiomeric forms from renewable 2,5-Bis(hydroxymethyl)tetrahydrofuran by a chemoenzymatic procedure, was submitted to a modified diastereoselective Passerini reaction employing zinc dicarboxylates.

Synthesis of Polyoxygenated Heterocycles by Diastereoselective Functionalization of a Bio-Based Chiral Aldehyde Exploiting the Passerini Reaction

“…On the previously described similar aldehyde 24 [ 9 ], we reported a model for explaining the stereoselectivity, based on the chelation of the metal by the carbonyl oxygen and the oxygen on carbon β to the aldehyde ( I , Scheme 7 ) [ 30 ]. On the other hand, the outcome of chiral aldehyde 26 [ 10 ] led us to revise our rationale, also because in that case a β-chelation is clearly not possible. In the light of the observation that, performing the Passerini reaction in i Pr 2 O, the initially unsoluble ZnBr 2 is partially dissolved upon addition of the isocyanide, we supposed a zinc coordination by it to give intermediate 28 .…”

“…Based on our recent results on another chiral bio-based aldehyde [10], we also tried a modification of the Passerini reaction using zinc dicarboxylates. Using Zn(OAc)2, the Scheme 5.…”

“…Based on our recent results on another chiral bio-based aldehyde [10], we also tried a modification of the Passerini reaction using zinc dicarboxylates. Using Zn(OAc) 2 , the diastereoselectivity diminished considerably and the reaction became very slow, most likely because the Zn salt is poorly soluble (entry 4).…”

“…In recent years we synthesized enantiopure chiral building blocks by a chemoenzymatic [ 5 , 6 , 7 , 8 , 9 , 10 ] and/or organocatalytic [ 7 , 11 , 12 ] approach, often using bio-based starting materials [ 5 , 6 , 9 , 10 ], and used them for controlling the diastereoselectivity in different isocyanide-based MCRs (Ugi-Joullié [ 5 , 7 ], Passerini [ 6 , 8 , 9 , 10 ], or Ugi [ 11 , 12 ] reactions).…”

The 100 facets of the Passerini reaction

“…The Passerini reaction, performed under standard conditions on a model compound with R 1 = t Bu and R 2 = Ac, was, unlike 139, poorly diastereoselective, affording 166 as a 59 : 41 diastereomeric mixture. 103 Then we applied the previously described protocol with ZnBr 2 as the catalyst and we successfully increased the diastereomeric ratio to 81 : 19 (82% yield), provided that a carefully dried aldehyde was used to prevent the formation of the stabilized hydrated form 165, responsible for not reproducible results. The best results were obtained if a pre-mixed solution of 164 and the carboxylic acid (AcOH) in iPr 2 O was added to the mixture of isocyanide and ZnBr 2 .…”