Luca Banfi

Solid-phase synthesis of modified oligopeptides via Passerini multicomponent reaction

A Passerini multicomponent reaction of N-protected-α-aminoaldehydes, carboxylic acids and solid-supported isocyanides has been successfully performed on Lantern™. The initially formed N-protected-β-amino-α-acyloxyamides gave, by piperidine-promoted deprotection and concomitant acyl migration, β-acylamino-α-hydroxyamides which, by OH-oxidation and cleavage off the solid support, provided β-acylamino-α-oxoamides. Formation and disappearance of the isocyano group has been followed using photoacoustic IR spectroscopy, a fast, reliable and non-disruptive technique that has been successfully applied for the first time to macroscopic solid supports.

Chemoenzymatic approach to the AB ring system of aklavinone

Abstract Both enantiomers of compound 3 , a possible intermediate for the AB ring system 2 of Aklavinone 1 , were obtained in optically active form from diol 7 . Key steps were the preparation of both enantiomers of monoacetate 8d , via enzymatic reactions that utilize PPL as catalyst, and the construction of ring A in a totally regioselective manner.

Beyond Ugi and Passerini Reactions: Multicomponent Approaches Based on Isocyanides and Alkynes as an Efficient Tool for Diversity Oriented Synthesis

The reaction of isocyanides with electron deficient alkynes has been first reported in 1969, about ten years after the first reports on the famous Ugi four component reaction. However it took about thirty years to realise that the zwitterionic intermediate originating from interaction of the two species could be trapped by a third component, thus giving the start to a novel class of isocyanide-based multicomponent reactions. From that first report dated 1996 there has been an ongrowing interest that has produced, so far, about 150 distinct scientific papers. This review is aimed at rationalising and cathegorising these reports and at offering an overview of all the possible applications of this novel methodology.

Passerini reaction--amine deprotection--acyl migration (PADAM): A convenient strategy for the solid-phase preparation of peptidomimetic compounds.

Abstractβ-Acylamino-α-hydroxyamides andβ-acylamino-α-oxoamides, compounds known to be potent protease inhibitors, can be conveniently prepared with a highly convergent strategy involving a Passerini multicomponent reaction between a N-protected α-aminoaldehyde, a carboxylic acid and an isocyanide. After N-deprotection and concomitant acyl migration the desired β-acylamino-α-hydroxyamide moiety is obtained and can be further elaborated, for exampleviaoxidation of the secondary alcohol group. In this paper we report the studies that have been carried out in order to transfer this synthetic methodology onto polystyrene resin, using a photocleavable linker and a N-Boc protecting strategy.

Protecting group controlled diastereoselective reduction of diprotected α,α-bis(hydroxymethyl)ketones derived from THYM*, using the DIBALH / MgBr2 system

Abstract The reduction of diprotected α,α- bis (hydroxymethyl)ketones 5 , derived from the novel chiral building blocks THYM* 1 and BHYMA* 2 has been realized with good to excellent stereoselectivity (from 85:15 to 97:3), through a appropriate choice of the two protecting groups and by employing the combination of DIBALH and MgBr 2 ·Et 2 O.

OPHA (Oxidation–Passerini–Hydrolysis–Alkylation) Strategy: a Four-Step, One-Pot Improvement of the Alkylative Passerini Reaction

Multicomponent reactions are often recognized for their efficiency and convergency, if compared with multistep organic synthesis. Nevertheless, we here demonstrate that a four-step-one-pot approach (named OPHA strategy for the initials of the four steps involved) is not only able to afford compounds that could not be obtained by an alkylative Passerini reaction but also capable of generating them with minimal loss of atoms and high operational simplicity, as in a typical multicomponent approach.

Ugi and Passerini reactions of biocatalytically derived chiral aldehydes: application to the synthesis of bicyclic pyrrolidines and of antiviral agent telaprevir.

Lipase mediated desymmetrization of a meso-diol (1,2-cyclopentanedimethanol) allows the synthesis of both enantiomers of some chiral aldehydes, whose behavior in Passerini and Ugi reactions has been explored. Exploiting these two complementary multicomponent reactions and coupling them with a subsequent cyclization process, we observed that 6 out of all 8 possible stereoisomers of peptidomimetic pyrrolidines can be obtained in good yields. The potential of these protocols has been proved by the development of a new efficient synthesis of antiviral drug telaprevir.

Enzymatic Resolution of Acetoxyalkenylphosphonates and Their Exploitation in the Chemoenzymatic Synthesis of Phosphonic Derivatives of Carbohydrates

The resolution of racemic α-, β-, and γ-hydroxy-ω-alkenylphosphonates was achieved by enzymatic hydrolysis of the corresponding acetates. The optically active alcohols were transformed into β-hydroxyaldehydes and allowed to react with dihydroxyacetone phosphate (DHAP) via enzymatic aldol addition catalyzed by rabbit muscle fructose 1,6-bisphosphate aldolase (FruArab). After enzymatic dephosphorylation, a set of novel sugar phosphonates was obtained.

Enantio- and Diastereoselective Synthesis of Highly Substituted Benzazepines by a Multicomponent Strategy Coupled with Organocatalytic and Enzymatic Procedures

Enantiomerically pure 4,5-dihydro-1H-benzo[c]azepines with three contiguous stereogenic centers have been assembled by convergent strategy with a good control of diastereoselectivity. The two steps are as follows: an asymmetric organocatalytic Mannich reaction performed on Boc-imines of o-(azidomethyl)benzaldehydes, followed by a one-pot Staudinger/aza-Wittig/Ugi-Joullié sequence. The latter reaction represents one of the first examples of diastereoselective Ugi three-component reaction on a seven-membered cyclic imine. The o-azidomethylbenzaldehydes have been synthesized employing a simple and efficient chemoenzymatic strategy from commercially available building blocks.

Chemoenzymatic preparation of a key intermediate for carbapenem synthesis starting from asymmetrized bis(hydroxymethyl)acetaldehyde (BHYMA

Abstract 4-Unsubstituted 2-azetidinones 3a,b, which are useful intermediates for the synthesis of carbapenem antibiotics, have been enantiospecifically and diastereoselectively prepared starting from asymmetrized bis(hydroxymethyl)acetaldehyde (BHYMA*)4, a new chiral building block obtained through biological methods. The key steps are the highly diastereoselective addition of Me2CuLi to 4 (diast. ratio = 95 : 5), and the regioselective deblocking of tBuMe2Si ether in the presence of a (tPr)3Si ether, by using a novel methodology.