Synthesis of Enantiopure Tertiary Skipped Diynes via One-Pot Desymmetrizing TMS-Cleavage

Enantiopure tetrasubstituted skipped diynes were readily synthesized from N-protected amino esters upon addition of lithium TMS-acetylide which was found to be desymmetrizing through one-pot selective TMS-cleavage. The deprotection of the TMS group was realized through a one-pot silicon atom attack by the liberated methoxide, which was diastereoselective due to a conformational favorable chelate

Raman Optical Activity of Enantiopure Cryptophanes

Raman optical activity (ROA) and density functional theory (DFT) calculations were used to determine the absolute configuration of enantiopure cryptophane molecules and to obtain conformational information about their three ethylenedioxy linkers. ROA spectra recorded in chloroform solution for the two resolved enantiomers of cryptophanes derivatives bearing five (<b>2</b>), six (<b>1</b>), nine (<b>3</b> and <b>4</b>), and 12 (<b>5</b>) methoxy substituents are presented for the first time. The number of methoxy substituents (cryptophanes <b>1</b>, <b>3</b>, and <b>5</b>) and the arrangement of the three linkers (anti for <b>3</b> and syn for <b>4</b>) are two important parameters that significantly affect the ROA spectra. DFT calculations, at the B3PW91/6-31G** level, for cryptophane bearing six methoxy substituents establish, besides the absolute configuration, the preferential all-trans conformation of the ethylenedioxy linkers of the chloroform–cryptophane complex. This study shows that the ROA/DFT approach exhibits a higher selectivity for the conformation of the linkers than vibrational circular dichroism (VCD) associated with theoretical calculations

Synthesis and Chiroptical Properties of a Chiral Isotopologue of <i>syn</i>-Cryptophane‑B

We report the synthesis and absolute configuration (AC) of a chiral isotopologue of syn-cryptophane-B. Low chiral signatures were measured by polarimetry and electronic circular dichroism, whereas most significant chiroptical effects were observed by vibrational circular dichroism (VCD) and Raman optical activity (ROA). The comparison of experimental VCD and ROA spectra with those predicted by DFT calculations allows the determination of the AC of the two enantiomers as (−)589-MP-syn-2 and (+)589-PM-syn-2

Steric Scale of Common Substituents from Rotational Barriers of <i>N</i>‑(<i>o</i>‑Substituted aryl)thiazoline-2-thione Atropisomers

A steric scale of 20 recurrent groups was established from comparison of rotational barriers on <i>N</i>-(<i>o</i>-substituted aryl)­thiazoline-2-thione atropisomers. The resulting energy of activation Δ<i>G</i>^⧧_rot reflects the spatial requirement of the ortho substituent borne by the aryl moiety, electronic aspects and external parameters (temperature and solvent) generating negligible contributions. Concerning divergent rankings reported in the literature, the great sensitivity of this model allowed us to show unambiguously that a methyl appears bigger than a chlorine and gave the following order in size: CN > OMe > OH. For the very bulky CF₃ and <i>i</i>Pr groups, constraints in the ground state decreased the expected Δ<i>G</i>^⧧_rot values resulting in a minimization of their apparent sizes

Atropisomerism in Amidinoquinoxaline <i>N-</i>Oxides: Effect of the Ring Size and Substituents on the Enantiomerization Barriers

The atropisomerism of novel 2,3-dihydro-1<i>H</i>-pyrimido­[1,2-<i>a</i>]­quinoxaline 6-oxides <b>1</b> bearing dissymmetric (<i>ortho</i>-substituted) 5-aryl residues and the homologous 1,2-dihydroimidazo­[1,2-<i>a</i>]­quinoxaline 5-oxides <b>2</b> was investigated. The existence of a chiral axis was demonstrated for compound <b>1a</b> by X-ray diffraction and by DFT calculations of the ground state geometry. The resolution of the atropisomeric enantiomers on chiral stationary phases is reported. The barriers to enantiomerization were determined by off-line racemization studies and/or by treatment of the plateau-shaped chromatograms during chromatography on chiral support. A clear ring size effect was evidenced. In all cases, six-membered amidine derivatives <b>1</b> showed higher barriers than the corresponding lower homologues <b>2</b>, which also display lower sensitivity to the substituent size. Transition states for the interconversion of the atropisomers were located using DFT calculations, and involved the interaction of the <i>ortho</i> substituent with the formally sp² nitrogen in the amidine moiety. In contrast, in the most favored enantiomerization transition state of the 2-nitro derivative the <i>ortho</i> substituent is close to the <i>N</i>-oxide group

Atropisomerization in <i>N</i>‑aryl-2(1<i>H</i>)‑pyrimidin-(thi)ones: A Ring-Opening/Rotation/Ring-Closure Process in Place of a Classical Rotation around the Pivot Bond

Uncatalyzed racemization processes in atropisomeric diphenyl-like frameworks are classically described as the result of the rotation around the pivotal single bond linking two planar frameworks. Severe constraints leading to more or less distorted transition states account for the experimental barrier to atropenantiomerization. In 1988, one of us hypothesized that, in <i>N</i>-aryl-2­(1<i>H</i>)-pyrimidin-(thi)­ones, a ring-opening/ring-closure process was contributing to the observed racemization process accounting for the lower barriers in the sulfur analogues than in oxygen analogues. Now, a series of six novel 6-amino-5-cyano-1,4-disubstituted-2­(1<i>H</i>)-pyrimidinones <b>5a</b>–<b>5f</b> and two 6-amino-5-cyano-4-<i>p</i>-tolyl-1-substituted-2­(1<i>H</i>)-pyrimidinethiones <b>6a</b> and <b>6b</b> were synthesized and characterized through spectroscopic and X-ray diffraction studies. Semipreparative HPLC chiral separation was achieved, and enantiomerization barriers were obtained by thermal racemization. The rotational barriers of 6-amino-5-cyano-1-<i>o</i>-tolyl-4-<i>p</i>-tolyl-2­(1<i>H</i>)-pyrimidinone (<b>5b</b>) and 6-amino-5-cyano-1-(naphthalen-1-yl)-4-<i>p</i>-tolyl-2­(1<i>H</i>)-pyrimidinone (<b>5e</b>) were found to be 120.4 and 125.1 kJ·mol^–1 (<i>n</i>-BuOH, 117 °C), respectively, and those of the corresponding thiones were 116.8 and 109.6 kJ·mol^–1 (EtOH, 78 °C), respectively. DFT calculations of the rotational barriers clearly ruled out the classical rotation around the pivotal bond with distorted transition states in the case of the sulfur derivatives. Instead, the ranking of the experimental barriers (sulfur versus oxygen, and <i>o</i>-tolyl versus 1-naphthyl in both series) was nicely reproduced by calculations when the rotation occurred via a ring-opened form in <i>N</i>-aryl-2­(1<i>H</i>)-pyrimidinethiones

1,2,3- versus 1,2-Indeno Ring Fusions Influence Structure Property and Chirality of Corannulene Bowls

Annulated corannulenes <b>3</b>–<b>5</b> form via distinct synthetic pathways: (i) Pd-catalyzed sp³ CH insertion, (ii) Pd-catalyzed aryl coupling, and (iii) silyl cation-promoted C–F activation/CH insertion. Crystal structure, redox, and photophysical studies elucidate the differing influence of 1,2,3- versus 1,2-indeno ring fusions. Mono and dianions of <b>3</b>–<b>5</b> are characterized. Resolution of <b>4</b> gives enantiopure forms, allowing assessment of the bowl-inversion barrier

Atropisomerization in <i>N</i>‑aryl-2(1<i>H</i>)‑pyrimidin-(thi)ones: A Ring-Opening/Rotation/Ring-Closure Process in Place of a Classical Rotation around the Pivot Bond

Uncatalyzed racemization processes in atropisomeric diphenyl-like frameworks are classically described as the result of the rotation around the pivotal single bond linking two planar frameworks. Severe constraints leading to more or less distorted transition states account for the experimental barrier to atropenantiomerization. In 1988, one of us hypothesized that, in <i>N</i>-aryl-2­(1<i>H</i>)-pyrimidin-(thi)­ones, a ring-opening/ring-closure process was contributing to the observed racemization process accounting for the lower barriers in the sulfur analogues than in oxygen analogues. Now, a series of six novel 6-amino-5-cyano-1,4-disubstituted-2­(1<i>H</i>)-pyrimidinones <b>5a</b>–<b>5f</b> and two 6-amino-5-cyano-4-<i>p</i>-tolyl-1-substituted-2­(1<i>H</i>)-pyrimidinethiones <b>6a</b> and <b>6b</b> were synthesized and characterized through spectroscopic and X-ray diffraction studies. Semipreparative HPLC chiral separation was achieved, and enantiomerization barriers were obtained by thermal racemization. The rotational barriers of 6-amino-5-cyano-1-<i>o</i>-tolyl-4-<i>p</i>-tolyl-2­(1<i>H</i>)-pyrimidinone (<b>5b</b>) and 6-amino-5-cyano-1-(naphthalen-1-yl)-4-<i>p</i>-tolyl-2­(1<i>H</i>)-pyrimidinone (<b>5e</b>) were found to be 120.4 and 125.1 kJ·mol^–1 (<i>n</i>-BuOH, 117 °C), respectively, and those of the corresponding thiones were 116.8 and 109.6 kJ·mol^–1 (EtOH, 78 °C), respectively. DFT calculations of the rotational barriers clearly ruled out the classical rotation around the pivotal bond with distorted transition states in the case of the sulfur derivatives. Instead, the ranking of the experimental barriers (sulfur versus oxygen, and <i>o</i>-tolyl versus 1-naphthyl in both series) was nicely reproduced by calculations when the rotation occurred via a ring-opened form in <i>N</i>-aryl-2­(1<i>H</i>)-pyrimidinethiones

1,2,3- versus 1,2-Indeno Ring Fusions Influence Structure Property and Chirality of Corannulene Bowls

Annulated corannulenes <b>3</b>–<b>5</b> form via distinct synthetic pathways: (i) Pd-catalyzed sp³ CH insertion, (ii) Pd-catalyzed aryl coupling, and (iii) silyl cation-promoted C–F activation/CH insertion. Crystal structure, redox, and photophysical studies elucidate the differing influence of 1,2,3- versus 1,2-indeno ring fusions. Mono and dianions of <b>3</b>–<b>5</b> are characterized. Resolution of <b>4</b> gives enantiopure forms, allowing assessment of the bowl-inversion barrier

1,2,3- versus 1,2-Indeno Ring Fusions Influence Structure Property and Chirality of Corannulene Bowls

Annulated corannulenes <b>3</b>–<b>5</b> form via distinct synthetic pathways: (i) Pd-catalyzed sp³ CH insertion, (ii) Pd-catalyzed aryl coupling, and (iii) silyl cation-promoted C–F activation/CH insertion. Crystal structure, redox, and photophysical studies elucidate the differing influence of 1,2,3- versus 1,2-indeno ring fusions. Mono and dianions of <b>3</b>–<b>5</b> are characterized. Resolution of <b>4</b> gives enantiopure forms, allowing assessment of the bowl-inversion barrier