Iñaki Ganboa

Asymmetric Synthesis of β-Lactams by Staudinger Ketene-Imine Cycloaddition Reaction

[2 + 2] Cycloaddition reactions between ketenes, bearing amino-, oxy-, or halo- groups, and imines are recognized as being amongst the most important and direct routes to β-lactams. Alkyl-substituted ketenes also furnished the corresponding β-lactams upon reaction with activated imines (iminoesters). In general, ketenes are generated from the appropriate acid chloride and a tertiary amine. The major or sole product of the cycloaddition is usually the cis-β-lactam, although a few exceptions showing trans selectivity are known. In this way β-lactams with a widely varying substitution pattern at the C-3 and C-4 positions of the ring are constructed stereoselectively. The diastereoselection of the cycloaddition process can be controlled with variable success from chiral groups attached to either the ketene or the imine component, or alternatively to both. This method, in turn, has proved to be valuable for the synthesis of precursors of important β-lactam antibiotics, and new successful applications can be expected in the near future.

Fromβ-lactams toα- andβ-amino acid derived peptides

SummaryThe potential ofβ-lactams as intermediates for the access toα- andβ-amino acid-derived peptides is shortly reviewed, with major focus on the technologies developed in our group. The two general strategies lie, on one side, in the oxidative ring expansion of 3-hydroxyβ-lactams toN-carboxyα-amino acid anhydrides or Leuchs anhydrides and subsequent coupling withα-amino acid esters and, on the other side, in the nucleophilic ring opening ofN-Boc-β-lactams. Both approaches have been successfully applied to the synthesis ofα,β-diamino acid,α-amino-β-hydroxy acid, polyhydroxylatedα-amino acid,α,α-disubstitutedα-amino acid,β-amino acid,β-amino-α-hydroxy acid andβ,β-disubstitutedβ-amino acid derived peptides. Because of the mild reaction conditions needed for the above transformations and the highly stereoselective procedures employed for the construction of the startingβ-lactam ring, the whole process allows the production of optically pure final products.

N,N-Dimethylphosphoramidic dichloride: a convenient reagent for the preparation of β-lactams from acetic acids and imines

Abstract A convenient reagent for the preparation of β-lactams from acetic acids and imines is described. A new route to α-keto-β-lactams from 3-bis(ethylthio)β-lactams is also reported. Reaction of 4-acethyl-β-lactams with diazomethane is also made.

Versatility of β-lactams in synthesis. Studies directed toward the synthesis of complex nucleoside antibiotics and some macrocyclic peptides

The diastereoselective [2+2] cycloaddition of α-hydroxyketene equivalents with chiral α,ω-oxyaldehyde-derived imines followed by the 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO)-promoted ring expansion of the resulting α-hydroxy β-lactam adducts provides an unconventional and short route to α-amino acid N-carboxy anhydrides (NCAs). The required enantiopure α,ω-oxyaldehydes were obtained either from the chiral pool or through the Sharpless AD methodology. Following the present strategy, several nonproteinogenic NCAs were synthesized, which were further coupled with α-amino acid esters giving rise to key fragments of some nucleoside antibiotics and macrocyclic peptides.

A concise synthesis of piperazine-2-carboxylic acids via β-lactam-derived α-amino acid N-carboxy anhydrides

Abstract A route to piperazine-fused 3-hydroxy β-lactams was accomplished via [2+2] cycloaddition of alkoxyketenes with imines derived from chiral α-amino aldehydes and chiral β-aminoalcohols. The resulting β-lactams on exposure to 0.55M NaOCl and a catalytic amount of 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) afforded α-amino acid N-carboxy anhydrides formally derived from piperazine-2-carboxylic acids.

Triphenylphosphine dibromide and dimethylsulfide dibromide as versatile reagents for beta-lactam synthesis

Abstract Triphenylphosphine dibromide and dimethylsulfide dibromide are efficient reagents for the direct synthesis of beta-lactams from carboxylic acids and imines avoiding the use of acid halides as starting materials. Synthesis of 4-imino-beta-lactams are also briefly described. A potential synthesis of N-unsubstituted beta-lactams is made.

Synthesis of (S)- and (R)- tert Leucine Enabling Direct Coupling with α-Amino Acid Esters via β-Lactam-Derived α-Amino Acid N-Carboxy Anhydrides.

Abstract (3S, 4R)- and (3R, 4S)-3-hydroxy-4- tert -butyl β-lactams on exposure to 1M NaOCl and a catalytic amount of 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) afforded α-amino acid N-carboxy anhydrides formally derived from both (S)- and (R)- tert -leucine amino acids.

A concise synthesis of α-amino acid N-carboxy anhydrides of (2S,3S)-β-substituted serines

A general access to 3-hydroxy-4-(1-hydroxyalkyl)--lactams with a C4-C1 relative configuration unlike is provided. The subsequent oxidative ring expansion of the corresponding 3-hydroxy -lactam smoothly affords an -amino acid N-carboxy anhydride (NCA) formally derived from (2S,3S)--substituted serine, which upon sequential peptide coupling furnishes the tripeptide segment 2, present in lysobactin.

Concise synthesis of α-alkyl α-amino acids and their incorporation into peptides viaβ-lactam-derived α-amino acid N-carboxy anhydrides

α-Hydroxy β-lactams in which C4 exists as a quaternary carbon are transformed in a single one-pot operation into α,α-dialkyl α-amino acid N-carboxy anhydrides providing a new approach to conformationally restricted peptide segments from non α-amino acid precursors.

A β-lactam framework as a β-alanyl dication equivalent: new synthesis of α-amino acid N-carboxy anhydrides (NCAs) derived from β-substituted alanines

Optically pure 4-formyl-3-hydroxy β-lactams are transformed into 4-methylaryl and 4-(2-ethylaryl) derivatives and converted into β-substituted alanine-derived NCAs through oxidation and Baeyer–Villiger rearrangement of the resulting α-keto β-lactams.