Peptidomimetics with tunable tertiary amide bond containing substituted β-proline and β-homoproline

Tunable cis/trans prolyl amide bond configuration in substituted β-proline (β-Pro) and β-homoproline (β-Hpro) homodimers was explored, based on position and nature of the substituent. Tertiary amide bond in β-proline (β^2,3-substituted) dimers show distinct trans configuration and β-homoproline (β³-substituted) dimers preferably exhibited cis configuration.     

Stereoselective synthesis of trans-2,3-disubstituted pyrrolidines via addition to N-acyliminium ions

An efficient and stereoselective synthesis of trans-2,3-disubstituted pyrrolidines is described. The intermolecular alkylation of racemic N-acyliminium ions generated in situ from the corresponding 3-substituted lactams proceeds stereoselectively and in high yield.     

Iodine-mediated ring-closing iodoamination with concomitant N-debenzylation for the asymmetric synthesis of polyhydroxylated pyrrolidines

Treatment of a range of homochiral unsaturated β-amino esters (containing a cis-dioxolane unit) with iodine promotes a novel ring-closing alkene iodoamination reaction which proceeds with concomitant N-debenzylation, providing a simple and stereoselective route to iodomethyl pyrrolidines. Functional group interconversion of the resulting iodomethyl pyrrolidines upon treatment with AgOAc proceeds via the corresponding aziridinium ion, with subsequent deprotection giving access to polyhydroxylated pyrrolidines.     

Stereoselective synthesis of CF3-substituted aziridines by Lewis acid-mediated aziridination of aldimines with diazoacetates

Treatment of trifluoroacetaldehyde N,O-acetal with diazoacetate in the presence of a Lewis acid furnished CF₃-substituted aziridinecarboxylates in good yields. Both cis and trans isomers were obtained stereoselectively by the proper choice of the ester substituents. Use of a chiral diazoacetate derived from (R)-pantolactone led to highly diastereoselective aziridination (94% de).     

Synthesis of 3-Borylated Pyrrolidines by 1,3-Dipolar Cycloaddition of Alkenyl Boronates and Azomethine Ylide

A scalable and efficient process for the preparation of 3-borylated pyrrolidines by 1,3-dipolar cycloaddition of N-benzyl azomethine ylide generated in situ has been developed. The optimized method included the use of LiF in DMSO at 110 °C and was suitable for α-mono-, α,β-di-, and α,β,β-trialkyl-, β,β-(hetera)cycloalkylidene-, CO₂Et-, as well as most β-(het)aryl-substituted alkenyl boropinacolates. The 1,3-dipolar reaction proceeded on a multigram scale providing 3-borylated pyrrolidines with diverse substitution patterns (including fused and spirocyclic ones) in a diastereoselective manner. The Pd(OH)₂-mediated N-debenzylation of pyrrolidine hydrochlorides was successfully performed to give the corresponding bifunctional building blocks on an up to 130 g scale, thus providing a substantial expansion of the synthetic and medicinal chemist's toolbox. Other reactions included the preparation of trifluoroborates, Zweifel-Aggarwal sp³-sp² coupling, and oxidative deborylation as an example of C-heteroatom bond formation.     

A practical approach to the fused β-carboline system. Asymmetric synthesis of indolo[2,3-a]indolizidinones via a diastereoselective intramolecular α-amidoalkylation reaction

Fused β-carboline systems, as indolo[2,3-a]indolizidinones, indolo[2,3-a]quinolizidinones, their 2-oxa analogues, and benzo[a]indolo[2,3-a]indolizidinones are prepared efficiently via an RLi addition-N-acyliminium ion cyclisation sequence on readily available imides. In an enantioselective variant of these α-amidoalkylation reactions, the addition of MeLi to a chiral non-racemic imide derived from tryptophan yielded an oxo amide, which was cyclised diastereoselectively upon treatment with BF₃·OEt₂, to afford 5,11b-trans-indoloindolizidinone in moderate yield and high ee (99%).     

Synthesis of highly functionalized 2,5-disubstituted pyrrolidines via an aza-Morita-Baylis-Hillman-type reaction

An aza-Morita-Baylis-Hillman-type reaction of Michael acceptors with 5-substituted cyclic N,O-acetals derived from pyrrolidines has been investigated. It has been found that the combination of Me₂S and TMSOTf work well with unhindered and reactive enals and enones whilst the use of quinuclidine and TMSOTf is superior for more hindered Michael acceptors. The reactions lead to 2,5-trans-disubstituted pyrrolidines with good to excellent diastereoselectivity. The origin of the selectivity is discussed.     

Ag/ThioClickFerrophos catalyzed highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides with alkenes

A silver(I)/ThioClickFerrophos complex catalyzed the endo selective asymmetric 1,3-dipolar cycloaddition reaction of methyl N-benzylideneglycinate (the source of azomethine ylides) with α,β-unsaturated esters and maleimides to give the endo-2,4,5- and 2,3,4,5-substituted pyrrolidines in good yields with high enantioselectivities (up to 99% ee). The complex also effectively catalyzed the endo selective reactions with β-nitrostyrene to give the 4-nitropyrrolidine in a high enantioselectivity.     

Addition of carbon nucleophiles to cyclic N-acyliminium and oxocarbenium ions under solvent-free conditions

The InCl₃-catalyzed addition of carbon nucleophiles to cyclic N-acyliminium and oxocarbenium ions under solvent-free conditions at room temperature is described. The corresponding α-substituted heterocycles were obtained in moderate to excellent yields.     

Reductive allylation of pyrrole with allylboranes. Synthesis oftrans- andcis-2,5-disubstituted pyrrolidines

Pyrrole undergoes reductive mono- and diallylation on successive treatment with β,γ-unsaturated organoboron derivatives (triallylborane, allyl(dipropyl)borane, and triprenylborane) and alcohols to give 2-allylated 3-pyrrolines andtrans-2,5-diallylated pyrrolidines. The addition of both the first and second boron-allylic fragment to the heterocycle proceeds with rearrangement. A method for transformation of thetrans-2,5-diallylpyrrolidine into thecis-isomer (heating with triallylborane at 190 °C) was developed and a series ofN-substituted derivatives of these pyrrolidines was synthesized. A method for the preparative synthesis of nonsymmetrically substitutedtrans- andcis-2-alkyl(phenyl)-5-allylpyrrolidines, based on reductive allylboration of pyrrole followed by 1,2-addition of RLi to the 5-allyl-1-pyrroline that formed, was also developed. A direct confirmation of intermediate formation of 2H- and 3H-pyrrole tautomers under the action of allylboranes was obtained. The adduct of 2H-pyrrole with BF₃ was detected by NMR spectroscopy. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1718–1728, September, 1999.     

Facile stereoselective synthesis of cis- and trans-3-alkoxyazetidin-2-ones

A highly stereoselective synthesis of cis- and trans-3-alkoxy-3-phenyl/benzylthioazetidin-2-ones is described. The reaction of α-chlorosulfide-β-lactams with various alcohols catalyzed by a Lewis acid such as ZnCl₂ in the presence of molecular sieves (3-4 Å) leads to cis-3-alkoxy-3-phenyl/benzylthio-β-lactams whereas treatment of potassium 2-alkoxy-2-phenylthioethanoate with appropriate Schiff's base using POCl₃ in the presence of triethylamine leads to the formation of trans-3-alkoxy-3-phenylthioazetidin-2-ones as major products.     

Ring-closing iodoamination of homoallylic amines for the synthesis of polysubstituted pyrrolidines: application to the asymmetric synthesis of (−)-codonopsinine

Ring-closing iodoamination of (E)-configured, N-α-methyl-p-methoxybenzyl protected homoallylic amines upon treatment with I₂ and NaHCO₃ in MeCN occurs with concomitant loss of the N-α-methyl-p-methoxybenzyl group to give 3-iodopyrrolidines in >99:1 dr. This transformation was used as one of the key steps in the total asymmetric synthesis of (?)-codonopsinine, which was achieved in seven steps (from commercially available tert-butyl crotonate) in 5% overall yield and >99:1 dr.     

Trading N and O: asymmetric syntheses of β-hydroxy-α-amino acids via α-hydroxy-β-amino esters

Both diastereoisomers of 2-amino-3-hydroxybutanoic acid and 2-amino-3-hydroxy-3-phenylpropanoic acid have been prepared from enantiopure α-hydroxy-β-amino esters via the intermediacy of the corresponding cis- and trans-aziridines. Aminohydroxylation of two α,β-unsaturated esters produced enantiopure 2,3-anti-α-hydroxy-β-amino esters in >99:1 dr. Subsequent epimerisation at the C(2)-position via a sequential oxidation/diastereoselective reduction protocol gave the corresponding enantiopure 2,3-syn-α-hydroxy-β-amino esters in >99:1 dr. These syn- and anti-substrates were then converted into the corresponding N-Boc protected cis- and trans-aziridines, respectively, via a three step reaction sequence: (i) hydrogenolysis and in situ N-Boc protection; (ii) OH-activation; and (iii) aziridine formation. Subsequent regioselective ring-opening of the C(3)-methyl-aziridines with Cl₃CCO₂H proceeded with inversion of configuration to give the corresponding 2-amino-3-trichloroacetate esters, whereas the analogous reaction with the C(3)-phenyl-aziridines resulted in rearrangement to the corresponding oxazolidin-2-ones with retention of configuration. In each case, hydrolysis of the products from these ring-opening reactions produced the corresponding enantiopure β-hydroxy-α-amino acids as single diastereoisomers.     

Kinetic versus thermodynamic access to imidazoisoindolones, benzimidazoisoindolones, and [1,4]diazepinoisoindolones: intramolecular nitrogen and π-aromatic trapping of N-acyliminium cation

Efficient assembly of substituted imidazo[2,1-a]isoindolones I is reported from suitable α,β-diamine IV (or corresponding β-nitroamine) and phthalic anhydride (1) in a three- or four-step sequence in good yields. The key step of this methodology is based on an intramolecular α-aza-amidoalkylation of the N-acyliminium species. Furthermore, when R₂ is an aromatic moiety a competing α-amidoalkylation took place and imidazo[2,1-a]isoindolones (or benzimidazo[2,1-a]isoindolones) I and/or isoindolo[1,4]benzodiazepines III were obtained under kinetic or thermodynamic control. The chemoselectivity of these transformations is also discussed.     

Creation of quaternary stereocenters by the addition of allyltributyltin to chiral cyclic N-acyliminium ions

5,5-Disubstituted pyrrolidinones and 5-substituted pyrrolidinones were obtained with moderate to good diastereoisomeric excess through the cis addition of allyltributyltin and triethylsilane, respectively, to the 4-OTBS group in the N-acyliminium ion prepared from the corresponding 5-hydroxy lactams. Cyclization of an N-allyl-5-propargyl pyrrolidinone and N-allyl-5-allyl-5-substituted pyrrolidinones using Grubbs’ catalyst led to the preparation of a dehydropyrrolizinone and dehydroindolizinones containing a quaternary stereocenter.     

Solution-phase synthesis of novel seven-membered cyclic dipeptides containing α- and β-amino acids

A convenient synthetic procedure for the preparation of seven-membered cyclic α,β-dipeptides is described. Following coupling of N-protected α-amino acids with N-substituted β-amino acid tert-butyl esters, that affords linear α,β-dipeptides, the protecting groups at the terminal functionalities were removed and the open-chain dipeptides were cyclized with phenylphosphonic dichloride, PhP(O)Cl₂, to give the desired cyclic α,β-dipeptides in good yields. NMR studies, X-ray diffraction analysis, and DFT calculations provided evidence for the conformation adopted by these cyclic dipeptides in solution, in the solid-state, and in the gas phase.     

Synthesis and analysis of compounds having the skeleton of ergot alkaloids with the nitrogen atom in the D-ring transposed

Alkylation-amination of the enamine 2 in the presence of ethyl α,α-bis(dibromomethyl)acetate, triethyl-amine, and methylamine lead to the construction of the aza-transposed ergoline 3 . Sequential reduction, hydrolysis, reesterification, and indolization of 3 , produced three diastereomers of 6 . The structure of these three diastereomers was assigned on the basis of nmr and ir spectral analysis to be (α-cis) syn, (β-cis) anti, and (α-trans) syn. The isomer (β-cis) anti was reduced with lithium aluminum hydride to the corresponding alcohol.     

Influence of the cavity size of cyclodextrins on the photochromism of azoimidazoles

1-Alkyl-2-(arylazo)imidazole (RaaiR^/) exists in trans configuration about the –NN- bond. Upon optical excitation in UV region the trans-configuration isomerises to cis-RaaiR^/. The photochromism is very susceptible to internal substituents and external environment like solvent polarity, viscosity and presence of innocent foreign species. In this work, the trans-to-cis photoisomerisation of RaaiR^/has been studied in DMF solution of cyclodextrin (α/β/γ-CD). The rate of trans-to-cis isomerisation is decreased in presence of CD compared to native form of RaaiR^/. The quantum yield of the photoisomerisation is decreased by 35–55% in inclusion phase, [email protected]^/, than free photochrome and follows the rate sequence: free state > γ-cyclodextrin > β-cyclodextrin > α-cyclodextrin. The cis-to-trans isomerisation proceeds slowly in visible light irradiation while it is appreciably fast with increasing temperature. The activation energy (E_a) of cis → trans thermal isomerisation is also diminished compared to free state of photochrome. The absorption spectral studies have been used in case of Pai-C₁₈H₃₇ with β-CD and inclusion constant is K_b ?= ?0. 121 M^?1. The ¹H NMR spectral measurement also suggests interaction of aryl protons with cavity protons of β-CD. DFT computation is also attempted to examine the inclusion of RaaiR^/with CD and the negative values of binding energy show that the process of inclusion is spontaneous and complexes formed are stable.     

Synthesis of 1,2,4-trisubstituted-1,2,5,6-tetrahydropyridines

A novel method for the synthesis of 1,2,4-trisubstituted- or 1,2,3,4-tetrasubstituted-1,2,5,6-tetrahydropyridine is presented. The process was carried out by the bromomethoxylation of 4-substituted-1,2,5,6-tetrahydropyridines 1 with N-bromosuccinimide (NBS) in methanol, dehydrobromination with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and boron trifluoride etherate (BF₃-OEt₂)-catalyzed cross coupling of the corresponding enamine with trimethylsilyl-based nucleophiles. Homokainoid analogs were also synthesized via the protocol.     

Synthesis of dihydroxylated prolines and iminocyclitols from five-membered endocyclic enecarbamates. Total synthesis of the potent glycosidase inhibitor (2R,3R,4R,5R)-2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP)

cis- and trans-3,4-Dihydroxylated prolines and the iminocyclitol 1,4-dideoxy-1,4-imino ribitol were synthesized employing a strategy involving the Heck arylation of five-membered endocyclic enecarbamates with aryldiazonium salts followed by oxidative cleavage of the electron-rich aromatic ring. The total synthesis of the potent α- and β-glucosidase inhibitor (2R,3R,4R,5R)-2,5-hydroxymethyl-3,4-dihydroxypyrrolidine (DMDP) was also achieved by the same strategy in ten steps from a chiral five-membered enecarbamate in 12% overall yield.