Antonia Mielgo

α,α-Diarylprolinol Ethers: New Tools for Functionalization of Carbonyl Compounds

Alpha,alpha-diaryl(dialkyl)prolinol ethers constitute a potent organocatalyst family which has been shown to be very general for a broad range of reactions involving enamine and iminium ion activation or a combination of both. The reactions are characterized by an efficient steric control approach and can lead to a variety of alpha-, beta-, gamma-, and alpha,beta-functionalized carbonyl compounds with excellent stereocontrol. As a full expression of their catalytic activity, these compounds are also excellent promoters of elegant cascade processes and valuable catalysts in water-compatible systems.

Highly stereoselective synthesis of α-hydroxy β-amino acids through β-lactams: application to the synthesis of the taxol and bestatin side chains and related systems.

Abstract Formation of α-hydroxy β-lactams, followed chemical elaboration at C 4 and further βlactam cleavage afforded functionalised α-hydroxy β-amino acids or their derivatives in a highly stereoselective manner.

Catalytic asymmetric α-alkylation of aldehydesvia a SN2′-type addition-elimination pathway

A novel method for the direct, amine-catalyzed, highly enantioselective α-alkylation of aldehydes is described that is founded upon the use of electrondeficient allylic halides as alkylating agents and DABCO or DMAP as coadyuvant. Both experimental observations and DFT calculations, in support of a SN2′-type addition-elimination pathway involving ammonium salt intermediates, are provided.

Asymmetric synthesis of α-keto β-lactams via [2+2] cycloaddition reaction : a concise approach to optically active α-hydroxy β-lactams and β-alkyl(aryl)isoserines

Abstract The cycloaddition reaction of the Evans-Sjogren ketenes to imines, followed by α-hydroxylation of the resulting cycloadducts provides an efficient general asymmetric synthesis of α-keto β-lactams and derivatives.

Catalytic Enantioselective Synthesis of Tertiary Thiols From 5H‐Thiazol‐4‐ones and Nitroolefins: Bifunctional Ureidopeptide‐Based Brønsted Base Catalysis

reactions of a-sulfanyl lactones.Accordingly, whilst many methodologies for the enantiose-lective synthesis of secondary thiols exist, approaches for theasymmetric synthesisoftertiarythiolsareclearlynecessarytohelp fill this important gap in organic chemistry. The inherentdifficulty associated with the stereoselective construction ofquaternary stereogenic centers is probably the reason for thelimited number of studies.

Brønsted Acid Assisted Regio- and Enantioselective Direct O-Nitroso Aldol Reaction Catalysed by α,α-Diphenylprolinol Trimethylsilyl Ether

In the presence of p-nitrobenzoic acid, the O-nitroso aldol reaction of nitrosobenzene with enolisable aldehydes may be promoted by commercially available alpha,alpha-diphenylprolinol trimethylsilyl ether. The reaction proceeds with good yields and essentially complete enantioselectivity, with catalyst loadings in the 5-10 mol % range. The resulting alpha-oxyaldehyde adducts may be transformed in situ into alpha-oxyimines, which provide 1,2-amino alcohols upon treatment with Grignard reagents, in good overall yield (45-59%) and with typical diastereomeric ratios > or = 95:5.

A mild method for the alcoholysis of β-lactams

Abstract Ring opening reaction of N-Boc-azetidinones using alcohols is greatly enhanced by NaN3 or KCN. Extremely mild and neutral reaction conditions are described favouring the reaction with hindered alcohols and precluding epimerization of enolizable substrates.

A 4‐Hydroxypyrrolidine‐Catalyzed Mannich Reaction of Aldehydes: Control of anti‐Selectivity by Hydrogen Bonding Assisted by Brønsted Acids

An anti-selective Mannich reaction of aldehydes with N-sulfonyl imines has been developed by using a 4-hydroxypyrrolidine in combination with an external Brønsted acid. The catalyst design is based on three elements: the alpha-substituent of the pyrrolidine, the 4-hydroxy group, and the Brønsted acid, the combination of which is essential for high chemical and stereochemical efficiency. The reaction works with aromatic aldehyde-derived imines, which have rarely been employed in previously reported enamine-based anti-Mannich reactions. Additionally, both N-tosyl and N-nosyl imines can be successfully used and the Mannich adducts can be easily reduced or oxidized, and after N-deprotection the corresponding beta-amino acids and beta-amino alcohols can be obtained with good yields. The results also show that this ternary catalytic system may be practical in other enamine-based reactions.

Combined α,α-dialkylprolinol ether/Brønsted acid promotes Mannich reactions of aldehydes with unactivated imines. An entry to anti-configured propargylic amino alcohols

The first enamine mediated anti-selective and highly enantioselective Mannich reaction of aldehydes and unactivated imines is reported. The key for success is the combined use of a Bronsted acid with an α,α-dialkylprolinol ether catalyst that leads to adducts with good yields (typically 70–75%), anti : syn ratios greater than 90 : 10, and ee values usually above 95%. The method works particularly well with propargylic imines and, unlike previous catalytic routes to optically active propargylamines, provides adducts featuring two contiguous stereocenters and a functionalized side chain amenable for ulterior synthetic applications.

Asymmetric synthesis of propargylic alcohols via aldol reaction of aldehydes with ynals promoted by prolinol ether–transition metal–Brønsted acid cooperative catalysis

A catalytic and highly stereoselective entry to propargylic alcohols and products derived thereof is reported based on an unprecedented cross-aldol coupling between unmodified aldehydes and ynals. The method requires an amine–metal salt–Bronsted acid ternary catalyst system and implies synergistic activation of the donor aldehyde via enamine and of the acceptor carbonyl via unique and reversible metal–alkyne complexation. Specifically, by using a combined a,a-dialkylprolinol silyl ether–CuI–PhCO2H catalyst system, remarkably high levels of diastereo- and enantioselectivity (anti/syn up to >20 : 1, ee up to >99%) are achieved.