Amparo Asensio

Synthesis of Nonracemic α-Trifluoromethyl α-Amino Acids from Sulfinimines of Trifluoropyruvate

We describe a novel and useful method for the synthesis of nonracemic α-trifluoromethyl α-amino acids (α-Tfm-AAs). Key building blocks are the sulfinimines (S)-1a and (S)-1b, prepared by Staudinger reaction from trifluoropyruvate esters and the chiral N-sulfinyl iminophosphorane (S)-8, which were treated with benzyl, allyl, and alkylmagnesium halides. The resulting diastereomeric N-sulfinyl α-Tfm α-amino esters, 12 and 13, were produced with moderate to good stereoselectivity and yields. When alkyl Grignard reagents were used, stereocontrol became progressively higher with increasing steric bulk, while reversed, though poor, stereocontrol was achieved with benzyl/allyl Grignard reagents. An explanation for the observed stereochemical outcome is proposed, on the basis of the exclusive E geometry (N-sulfinyl and CF3trans about the C=N bond) of the chiral sulfinimines 1. This assignment is the product of structural correlation and is supported by ab initio calculations and NOE experiments. Sulfinamides 12 and 13 were transformed into a series of nonracemic α-Tfm-AAs 16−22. The sulfinyl auxiliary can be regenerated and recycled.

Cross-Metathesis Reactions as an Efficient Tool in the Synthesis of Fluorinated Cyclic β-Amino Acids§

The synthesis of enantiomerically pure, cyclic, gamma,gamma-difluorinated beta-amino acids with various ring sizes has been carried out with a cross-metathesis (CM) reaction being one of the key steps, followed by a Dieckmann-type condensation to bring about the cyclization. Subsequent catalytic hydrogenation under microwave irradiation with (-)-8-phenylmenthol as a chiral auxiliary led to the successful chemo- and diastereoselective chemical reduction of the resulting cyclic beta-enamino esters. The efficiency and scope of the CM reaction with different types of fluorinated imidoyl chlorides and unsaturated esters has also been studied in order to determine the optimal reaction conditions with regard to selectivity and reactivity.

Intramolecular Michael Reaction of tert-Butylsulfinyl Ketimines: Asymmetric Synthesis of 3-Substituted Indanones

Aromatic tert-butylsulfinyl ketimines bearing a suitable Michael acceptor at the ortho position readily undergo an intramolecular conjugate addition achieving indanone derivatives in good yields and complete diastereoselectivity.

An efficient entry to optically active anti- and syn-beta-amino-alpha-trifluoromethyl alcohols.

The reaction of chiral 5,6-dihydro-2H-1,4-oxazin-2-ones with TMSCF3 in the presence of a suitable activator leads to trifluoromethyl lactols, which can be selectively reduced to anti-beta-amino-alpha-trifluoromethyl alcohols. The corresponding syn diastereoisomers are obtained when the starting imines are reduced and the nitrogen atom is conveniently protected. In addition, a novel rearrangement of the CF3 group in the lactol intermediates has been observed. This represents a formal CF3 addition to the imine function in the starting substrates.

Comparison of some dispersion-corrected and traditional functionals as applied to peptides and conformations of cyclohexane derivatives.

We compare the energetic and structural properties of fully optimized α-helical and antiparallel β-sheet polyalanines and the energetic differences between axial and equatorial conformations of three cyclohexane derivatives (methyl, fluoro, and chloro) as calculated using several functionals designed to treat dispersion (B97-D, ωB97x-D, M06, M06L, and M06-2X) with other traditional functionals not specifically parametrized to treat dispersion (B3LYP, X3LYP, and PBE1PBE) and with experimental results. Those functionals developed to treat dispersion significantly overestimate interaction enthalpies of folding for the α-helix and predict unreasonable structures that contain Ramachandran φ and ψ and C = O...N H-bonding angles that are out of the bounds of databases compiled the β-sheets. These structures are consistent with overestimation of the interaction energies. For the cyclohexanes, these functionals overestimate the stabilities of the axial conformation, especially when used with smaller basis sets. Their performance improves when the basis set is improved from D95∗∗ to aug-cc-pVTZ (which would not be possible with systems as large as the peptides).

Novel strategy for the synthesis of fluorinated β-amino acid derivatives from Δ2-oxazolines

Abstract Racemic and chiral non-racemic β-fluoroalkyl-β-amino acid derivatives have been prepared in two steps starting from 2-alkyl-Δ2-oxazolines and fluorinated imidoyl chlorides. Subsequent chemoselective reduction of the C-masked β-enamino acid derivatives initially formed provided the target β-amino acids. The process takes place with total chemoselectivity, high yields and satisfactory diastereoselectivity.

An efficient synthesis of new fluorinated uracil derivativesElectronic supplementary information (ESI) available: general procedures for the preparation of compounds 3, 6 ,7, 8 and 9. See http://www.rsc.org/suppdata/cc/b3/b300796k/

A series of potentially biologically active fluorinated uracil derivatives has been prepared in three steps from oxazolines and fluorinated nitriles with good chemical yields.

Synthesis and C-alkylation of C-protected β-enamino acid derivatives from oxa- thia- and imidazolines

Abstract Various heterocycles 3a-h can be readily metallated and condensed with a variety of organic nitriles to afford C-protected β-enamino acid derivatives 1 (or 2). Procedures for alkylation of compounds 1 to obtain 2 as well as a “one-pot” preparation of 2 from 3 are also described.

Triazolopyridines. Part 9. The synthesis of7-amino(1,2,3)triazolo(1,5-a)pyridines☆

Abstract Regiospecific lithiation of (1,2,3) triazolo(1,5-a)pyridines (1) and (4) with subsequent reaction with styryl azide gave small yields of the 7-aminotriazolopyridines (6) and (7). A longer larger scale synthesis of compounds (6) and (7) is described giving overall yields of 17 and 25%, starting from 2-amino-6-methyl (9) or 2-amino-6-ethyl pyridine (19).

Triazolopyridines. 14. Substitution reactions of 7-amino[1,2,3]triazolo[1,5-a]pyridines. ☆

Abstract Reaction between 7-aminotriazolopyridines 1 or 2 and sulphuric acid gives hydroxyalkylpyridines 3 and 4 ; bromination gives brominated pyridine 5 or triazolopyridine 6. The anions from amines 1 or 2 are ambident, acylating on N but alkylating on N or on C6; in the latter case triazolylalkenylcyanides 16 – 20 or the 6,6-dialkylated derivative 19 are obtained. An X-ray diffraction study has confirmed structure 19.