Addition reactions of chloro- or iodomethyllithium to imines. Synthesis of enantiopure aziridines and beta-chloroamines.

We report a novel, simple, and efficient synthesis of aziridines and 1-chloroalkan-2-amines by the reaction of imines derived from various aldehydes and p-toluenesulfonamide or benzenesulfonamide with iodo- or chloromethyllithium, respectively. Both halogenated anions were generated in situ by treatment of diiodo- or chloroiodomethane with methyllithium at -78 or 0 degrees C. The reaction of in situ generated iodo- or chloromethyllithium could also be performed from chiral 2-aminoaldimines to yield enantiopure aziridines or (2S,3S)-2,3-diamino-1-chloroalkanes with high stereoselectivity.

Reactive trityl derivatives: stabilised carbocation mass-tags for life sciences applications.

The rational design of novel triarylmethyl (trityl)-based mass tags (MT) for mass-spectrometric (MS) applications is described. We propose a "pK(R+) rule" to correlate the stability of trityl carbocations with their MS performance: trityls with higher pK(R+) values ionise and desorb better. Trityl blocks were synthesised that have high pK(R+) values and are stable in conditions of MS analysis; these MTs can be ionised by matrix as well as irradiation with a 337 nm nitrogen laser. (13)C-Labelled tags were prepared for MS quantitation applications. Moreover, the tags were equipped with a variety of functional groups allowing conjugation with different functionalities within (bio)molecules to enhance the MS characteristics of the latter. The MS behaviour of model polycationic trityl compounds with and without the matrix was studied to reveal that poly-trityl clusters are always singly charged under the (MA)LDI-TOF conditions. Several peptide-trityl conjugates were prepared and comparisons revealed a beneficial effect of trityl tags on the conjugate detection in MS. Trityl compounds containing para-methoxy- and dimethylamine groups, as well as a xanthene fragment, showed considerable enhancement in MS detection of model peptides; thus they are promising tools for proteomic applications. Dimethoxytrityl derivatives allow one to distinguish between Arg- and Lys-containing peptides. Maleimido trityl derivatives are suitable for the efficient derivatisation of thiol-containing peptides in pyridine.

S(O)-pixyl protecting group as efficient mass-tag.

We report herein the design, preparation and first applications of novel trityl tags with adjustable stability, efficient as protecting groups or MS analytes.

Stereoselective synthesis of functionalized gamma-amino esters: azetidinium salts and epoxy esters.

Addition of several lithium ester enolates to chiral 1-aminoalkyl chloromethyl ketones 1 affords enantiomerically pure 3-hydroxyazetidinium salts 3 or 3-(1'-aminoalkyl)-3,4-epoxy esters 4, depending on the reaction conditions. [reaction: see text]

Synthesis of different chiral amino gamma-butyrolactones and amino gamma-butenolides.

Different transformations of chiral epoxy esters 1 afford two different amino gamma-butyrolactones 2 and 6, and amino gamma-butenolides 8, by different nucleophilic opening-closing processes. [reaction: see text]

Synthesis of Isotopically Labeled (E)-ß,γ-Unsaturated Esters with Total or High Diastereoselectivity by Using Samarium Diiodide.

A simple, efficient, highly diastereoselective method for preparing (E)-α,δ-dideuterio-ß,γ-unsaturated esters: SmI2 -promoted reduction/elimination of α-halo-ß-hydroxy-γ,δ-unsaturated esters in the presence of D2 O. This provides the desired products in which the C-C double bond is generated with total or high diastereoselectivity.

SNP detection using trityl mass tags.

A new method suitable for single nucleotide polymorphism (SNP) detection using differential oligonucleotide probe extension has been developed. Sulfur-linked laser-cleavable trityl labels are implemented in this protocol. The method is based on mass spectrometry and utilizes a single surface for affinity purification of extended probes and matrix-independent desorption-ionization of the cleavable labels. The usefulness of this method for SNP genotyping is demonstrated.

Novel mass tags for single nucleotide polymorphism detection.

A new method suitable for single nucleotide polymorphism detection and other applications based on oligonucleotide probe extension has been developed. The method is based on mass spectrometry and utilizes a single surface for affinity purification of extended probes and matrix-independent desorption/ionization of the cleavable labels. A new family of sulfur-linked laser-cleavable trityl labels with vastly improved flying abilities is implemented in this study. Corresponding reagents compatible with automated oligonucleotide synthesis are presented. Utility of this method for SNP genotyping is demonstrated.

A convenient samarium-promoted synthesis of aliphatic (E)-nitroalkenes under mild conditions.

A samarium-promoted synthesis of (E)-nitroalkenes from 1-bromo-1-nitroalkan-2-ols in high yields and with total selectivity is reported. This reaction together with the easy and efficient preparation of the 1-bromo-1-nitroalkan-2-ols constitutes a simple and advantageous alternative toward nitroalkenes with total E-stereoselectivity. A mechanism is proposed to explain the E-stereoselectivity of the beta-elimination reaction.

Synthesis of enantiopure (alphaS,betaS)- or (alphaR,betaS)-beta-amino alcohols by complete regioselective opening of aminoepoxides by organolithium reagents LiAlH4 or LiAlD4.

The reaction of chiral (2R,1'S)- or (2S,1'S)-2-(1-aminoalkyl)epoxides, 1 or 2 with a variety of organolithium compounds to obtain the corresponding (alphaS,betaS)- or (alphaR,betaS)- beta-amino alcohols in enantiopure form is reported. In both cases, the opening of the oxirane ring at C-3 proceeded with total regioselectivity. Moreover, the ring opening of aminoepoxides 1 or 2 by hydride (utilizing LiAlH4) to obtain the corresponding (2S,3S)- or (2R,3S)-3-aminoalkan-2-ols is also described. The reaction of 1 or 2 with LiAlD4 in place of LiAlH4 gave the corresponding (2S,3S)- or (2R,3S)-3-amino-1-deuterioalkan-2-ols.

Stereoselective functionalization of 2-(1-aminoalkyl)aziridines via lithiation of aziridine-borane complexes.

Highly selective functionalization of the aziridine ring of (2S,1'S)-2-(1'-aminoalkyl)aziridines 1, through successive formation of aziridine-borane complexes, lithiation, treatment with a variety of electrophiles and final decomplexation is described. The influence of the structure of the starting complexes 2 and of the electrophiles in the stereoselectivity of this process has been studied. Finally, successive double lithiation-electrophile reactions were carried out affording enantiopure 1,2,3,3-tetrasubstituted aziridine-borane complexes with high selectivity.

Selective ring-opening of nonactivated amino aziridines by thiols and unusual nucleophilic substitution of a dibenzylamino group.

[Reaction: see text]. The reaction of chiral 2-(1-aminoalkyl)aziridines 1 with different thiols, in the presence of BF3*Et2O, is reported. The obtained products were dependent on the structure of the starting amino aziridines 1. Thus, enantiopure (2S,3S)-2-(alkylthio)alkane-1,3-diamines 2 were obtained from aziridines with C-2 substituents with lower steric congestion and partially racemized (2S,3S)-2,3-bis(alkylthio)alkan-1-amines 3 (ee = 56-66%) from aziridines with larger C-2 subtituents. In both cases, the opening of the nonactivated aziridine ring at C-2 took place with retention of configuration and proceeded with regio- and stereoselectivity at C-2. In the synthesis of 3, 2 equiv of thiol reacts with 1 and the opening of aziridine ring at C-2 was followed by an unusual displacement of the dibenzylamino group by a second equivalent of thiol. The regiochemistry and relative configuration of compounds 3 was established by single-crystal X-ray analysis. A mechanism is proposed to explain the results obtained.

Synthesis of (E)-alpha-hydroxy-beta,gamma-unsaturated amides with high selectivity from alpha,beta-epoxyamides by using catalytic samarium diiodide or triiodide.

The highly stereoselective synthesis of (E)-alpha-hydroxy-beta,gamma-unsaturated amides starting from alpha,beta-epoxyamides, by using catalytic SmI2 or SmI3, was achieved. This transformation can also be carried out by using SmI2 generated in situ from samarium powder and diiodomethane. The starting compounds 1 are easily prepared by the reaction of enolates derived from alpha-chloroamides with ketones at -78 degrees C. A mechanism to explain this transformation has been proposed. Cyclopropanation of (E)-alpha-hydroxy-beta,gamma-unsaturated amides has been performed to demonstrate their synthetic applications.

Addition reaction of vinylic reagents, derived from alpha-chloroenones, to carbonyl compounds promoted by samarium diiodide.

A new samarium diiodide-promoted addition reaction of vinylsamarium reagents, derived from (Z)-alpha-chloro-alpha,beta-unsaturated phenones 1, to both ketones (in THF) and aldehydes (in acetonitrile) led to (Z)-2-(1-hydroxyalkyl)-2,3-unsaturated ketones in good yield. These transformations took place with total or very high inversion of the stereochemistry of the C-C double bond of the starting chloroenone, producing the Z diastereoisomer. A new methodology to prepare SmI(2) in acetonitrile by sonic treatment of 1,2-diiodoethane with Sm powder is also described. A mechanism to explain this transformation is proposed.