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International audience; Enantiopure (R) and (S) cyclic α,α-disubstituted amino acid derivatives displaying a δ-valerolactam side chain were prepared from a common isoxazolidine precursor. The (R)-configured δ-valerolactam 11 was converted into diastereoisomeric pseudopeptides to investigate its ability to induce secondary structures in peptidomimetics. Conformational studies of these pseudopeptides were carried out in the solid state (X-ray diffraction), in solution (NMR analyses), and in silico (computer-aided conformational analysis), which demonstrated that such quaternary amino acids induce β-turn conformations stable enough to be retained in polar media (DMSO). Incorporation of this new type of α,α-disubstituted amino acid into a representative pseudopeptidic sequence by N- then C-elongation and N-debenzylation is also described herein and could serve for the synthesis of various structured peptidomimetics

International audience; 3,4‐Dihydro‐2H‐pyrans are present in the skeletons of several natural products, and these versatile synthetic intermediates are readily transformed into tetrahydropyrans, pyridines, or 1,5‐dicarbonyl units. Among the strategies developed to access 3,4‐dihydro‐2H‐pyrans, the hetero‐Diels‐Alder reaction between an oxadiene and a dienophile is particularly valuable because up to three contiguous stereogenic centers can be created diastereo‐ and/or enantioselectively in a single step. This review addresses the mechanism of the reaction and presents methods for preparing the product dihydropyrans enantio‐ and diastereoselectively. Thermal and Lewis acid promoted cycloadditions are discussed, as is the role of activating groups on the oxadiene.

Highly diastereo- and enantioselective 1,3-dipolar cycloadditions between functional ketonitrones and β-substituted enals are promoted by organocatalysis with the imidazolidinium catalyst of MacMillan. Study of the scope of the reaction shows that high selectivities are conserved by varying the N-protecting group or the ester function. However it is sensitive to sterical interaction with the C-substituent of the nitrone. Reaction proceeds in all cases with a high exo selectivity. In most cases, a third diastereomer, not compatible with a concerted mechanism, was observed, although in minute amount. DFT calculations evidence that the cycloaddition proceeds in a non-concerted fashion by a first oxa Michael-type addition of the nitrone to the double bond followed by a cyclization. This mechanism explains the formation of the observed minor diastereomers. In addition, the diastereo- and enantioselectivities of the reaction were shown to be intermediately thermodynamically controlled and the diastereomeric ratio is modulated by the kinetics of iminium hydrolysis.

Copper-catalyzed vinylation of 2- and 4-hydroxy pyridine and quinoline affords exclusively N-vinylation products. However, vinyl ethers of 4-hydroxy pyridine and quinoline can be prepared via a three-step sequence involving copper-catalyzed C-O cross coupling reaction of the corresponding N-heteroaryl bromides with ethylene glycol, chlorination of the terminal alcohol, and dehydrohalogenation of the β-chloro ethers. Although not efficient in 2-hydroxy series, this method can be conveniently applied to the preparation of various aza-aryl vinyl ethers in moderate to good overall yields.

The asymmetric access to unreported trans 4-quinolinoxy oxaproline precursors is investigated here in a comparative way by 1,3-dipolar cycloaddition of vinyloxy quinolines with chiral α-alkoxycarbonyl aldonitrones and chiral cyclic surrogates.

Bicyclic isoxazolidines displaying one or two quaternary stereocenter(s) were formed starting from functional cyclic ketonitrones equipped with a phenyl glycinol chiral auxiliary. The products were engaged in stereocontrolled 1,3-dipolar cycloaddition reactions with a range of electron-rich and electron-poor dipolarophiles. A new reductive removal of the phenyl glycinol chiral auxiliary was introduced and was shown to afford chemoselectively a quaternary isoxazolidine derivative (of oxaprolinol-type) without cleaving the N–O isoxazolidine bond. Keeping the aldehyde function masked as a cyclic pseudo-acetal, the liberated oxy-amine function was shown to be available for a pseudo-peptide coupling with various N-protected amino acids. The isoxazolidine ring was opened by a reductive N–O bond cleavage, giving a pseudo-dipeptide that was C-terminated with an aldehyde function.

Enantiopure vinyl ethers of Stericol® underwent diastereoselective thermal 1,3 dipolar cycloadditions with N-benzyl, N-benzhydryl, and N-PMB aspartate ester nitrones. Chemoselective N-debenzylation of the resulting cycloadducts afforded diastereomerically and enantiomerically pure crystalline NH-isoxazolidine, the absolute configuration of which was established by X-ray crystallography. N-Protection and N–O cleavage of this isoxazolidine gave enantioenriched quaternary aspartate derivatives bearing functionalized side chains.

Highly enantio- and exo-selective 1,3-dipolar cycloadditions of alanine-derived ketonitrones to E-crotonaldehyde could be realized in a good yield by the use of a chiral imidazolidinone salt without the addition of water. The origin of the stereoselectivity in the reaction was discussed and the absolute configuration of the cycloadduct determined unambiguously.

1,3-Dipolar cycloadditions of nitrones with pentafluorosulfanyl-substituted acrylic ester and amides afforded new trisubstituted pentafluorosulfanylated isoxazolidines in moderate yields as 4-SF5-regioisomers. Theoretical calculations were carried out and the regioselectivity could be explained by the fact that the 5-SF5-regioisomer probably undertook a spontaneous degradation in the reaction medium via the loss of pentafluorosulfanyl anion. Diastereoselectivity of the 1,3-dipolar cycloadditions was also assessed according to NMR and X-ray diffraction analysis.

A new family of analogs of steganacin, an important antimitotic compound, was accessed. It takes advantage of a completely stereoselective sequence of two key steps. The central dihydropyrane core is built by a highly diastereoselective and facially controlled hetero-Diels–Alder reaction. It is followed by a nonphenolic biaryl oxidative coupling with a complete atropo-stereoselectivity. It leads to a quick way to form cyclic biaryl lignans.

A new approach to enantiopure disubstituted oxaprolinol derivatives through diastereoselective [3+2]-cycloaddition of chiral cyclic ketonitrones to electron-rich and electron-poor dipolarophiles is presented.

International audience; 1,3-Dipolar cycloadditions of nitrones with pentafluorosulfanyl-substituted acrylic ester and amides afforded new trisubstituted pentafluorosulfanylated isoxazolidines in moderate yields as 4-SF5-regioisomers. Theoretical calculations were carried out and the regioselectivity could be explained by the fact that the 5-SF5-regioisomer probably undertook a spontaneous degradation in the reaction medium via the loss of pentafluorosulfanyl anion. Diastereoselectivity of the 1,3-dipolar cycloadditions was also assessed according to NMR and X-ray diffraction analysis.

International audience; A short and efficient synthesis of bicyclo[2.2.2]octane-1,4-dicarboxylic acid involving the formation of a semicarbazone is developed, and a reproducible protocol for the reduction of this semicarbazone is described. The use of microwaves significantly shortens the duration of the sequence to the diacid compared to the previously described synthetic method. In addition, by shifting from the use of large amounts of Raney nickel to a solid-phase process, both the safety and cost are improved notably.

The first example of a high facial selective [3 + 2] cycloaddition employing chiral vinyl ethers as dipolarophile and nitrones as dipoles is presented.

C23H27NO3, orthorhombic, P2(1)2(1)2(1) (no. 19), a = 6.054(2) angstrom, b = 11.479(5) angstrom, c = 29.210(3) angstrom, V = 2029.9 angstrom(3), Z = 4, R-gt(F) = 0.047, wR(ref)(F-2) = 0.121, T = 125 K.

A mild and efficient procedure for the selective cleavage of N-benzhydryl protecting group of beta-lactams is described. The protected 2-azetidinones 4, precursors of carbapenems, were treated with a stoichiometric amount of N-bromosuccinimide and a catalytic amount of bromine under sun light irradiation in CH2Cl2-H2O mixture at 20 degreesC for 3 hours. The N-benzhydrol intermediates 6, which could be isolated, were then hydrolyzed with p-TsOH in aqueous acetone to furnish beta-lactams 7 and benzophenone quantitatively.

In the presence of the Ru catalyst (RUC), ketonitrones of type (I) are found to react with methacrolein with high regio-, diastereo-, and enantioselectivity.

The stereoselectivity of the 1,3-dipolar cycloaddition of (E)-ketonitrones (I) bearing a chiral auxiliary on the nitrogen atom with vinyl ethers is studied.

International audience; A catalytic 1,3-dipolar cycloaddition between carboalkoxy ketonitrones and methacrolein under the effect of chiral ruthenium Lewis acid (R,R-1) was developed with high regio-, diastereo-, and enantiocontrol. The diastereochemical outcome of the cycloaddition reaction is marked by a significant solvent effect, and a divergent endo or exo control can be tuned by an appropriate choice of both the solvent and the N- and O-substituents of the ketonitrone. A rationale of the solvent effect, based on the computational study of the interactions between the methacrolein–Ru complex and its counteranion (SbF6–), is proposed to explain the selectivities obtained.

Original acyclic (E)-α,α-dialkylketonitrones bearing a chiral auxiliary on their nitrogen atom were synthesized and successfully employed for the asymmetric synthesis of α,α-disubstituted amino acids using regio- and stereocontrolled 1,3-dipolar cycloaddition reactions with vinyl ethers. N-Glycosyl chiral auxiliaries were found to provide excellent exo- and π-facial stereocontrol. The obtained enantiopure cycloadducts were selectively transformed into functional α,α-disubstituted amino acids and related β-peptides through the highly regioselective opening of an intermediate quaternary anhydride.

A series of para-substituted benzhydrylamines 6 were obtained by substitution of the corresponding benzhydrol precursors 1 with phenyl carbamate 2 under acidic conditions, followed by basic hydrolysis of the carbamate intermediates 3. One unsymmetrical intermediate 3i has been resolved by preparative chiral chromatography. Subsequent deprotection of the carbamate function led to the recovery of enantiomerically pure (+)- and (-)-4-chlorobenzhydryl amines.

C23H27NO3, monoclinic, P1211 (no. 4), a = 8.669(3) Å, b = 22.880(5)Å, c = 10.220(3)Å, β = 96.04(2)°, V = 2015.9Å3, Z = 4, Rgt(F) = 0.039, wRref(F2) = 0.106, T = 125 K.

Efficient access to masked β-amino-aldehydes was performed starting from 6-alcoxy tetrahydrooxazinone 6a–d (6-ATO). Transacetalization leads to the opening of the cycle to form either unsymmetric acetal 7 or symmetric acetals 16–18. These amino acetals are key compounds, obtained with 99% ee, which can be engaged in efficient peptide coupling. This method could easily provide peptides aldehydes or small amido aldehydes as exemplified with the formal synthesis of ent-Maraviroc.

A series of para-substituted benzhydrylamines 6 were obtained by substitution of the corresponding benzhydrol precursors 1 with phenyl carbamate 2 under acidic conditions, followed by basic hydrolysis of the carbamate intermediates 3. One unsymmetrical intermediate 3i has been resolved by preparative chiral chromatography. Subsequent deprotection of the carbamate function led to the recovery of enantiomerically pure (+)- and (-)-4-chlorobenzhydryl amines.

Amino acid derived nitrones were conveniently synthesized in good-to-excellent yields by condensation of α-ketoesters with N-benzylhydroxylamine. The cycloaddition reactions of these nitrones with different alkenes were investigated under thermal solvent-free conditions. Considering conversions, yields, and selectivities, alkyl vinyl ethers have proven to be valuable partners to achieve this transformation, which creates a tetrafunctionalized stereogenic quaternary center. From the adducts derived from vinyl ethers, a three-step access to highly functionalized α-substituted amino acid derivatives is described.

Amino acid derived nitrones were conveniently synthesized in good-to-excellent yields by condensation of alpha-ketoesters with N-benzylhydroxylamine. The cycloaddition reactions of these nitrones with different alkenes were investigated under thermal solvent-free conditions. Considering conversions, yields, and selectivities, alkyl vinyl ethers have proven to be valuable partners to achieve this transformation, which creates a tetrafunctionalized stereogenic quaternary center. From the adducts derived from vinyl ethers, a three-step access to highly functionalized alpha-substituted amino acid derivatives is described.

A mild and efficient procedure for the selective cleavage of N-benzhydryl protecting group of beta-lactams is described. The protected 2-azetidinones 4, precursors of carbapenems, were treated with a stoichiometric amount of N-bromosuccinimide and a catalytic amount of bromine under sun light irradiation in CH2Cl2-H2O mixture at 20 degreesC for 3 hours. The N-benzhydrol intermediates 6, which could be isolated, were then hydrolyzed with p-TsOH in aqueous acetone to furnish beta-lactams 7 and benzophenone quantitatively.