Solid-State Isomerization of Atropodiastereomers: Effective Diastereoselection through Polymorphic Transformations

Abstract

The  re Á se Averbuch, and Jacques Einhorn* Polymorphism is a fascinating phenomenon accompanied by a lot of strange manifestations. [1] It is generally defined as the existence of a given compound in more than one crystalline form. In conformational polymorphs, [2] a given molecular compound adopts different conformations in different polymorphs. But, at a molecular level, conformational changes may involve quite high energy barriers, allowing in some cases the isolation of separate stereoisomers (atropisomers) which do not interconvert rapidly in solution at room temperature, but do so if enough energy is supplied. Herein we report solid-state thermal isomerizations of compounds 1, which present such a type of atropisomerism. These isomerizations have features reminiscent of polymorphic transformations, although not involving polymorphs in the usual sense of the word. [3] As depicted in Scheme 1, the synthesis of 1 has been achieved by Diels ± Alder reactions between isobenzofuran 2 and maleimide or N-benzylmaleimide, giving adducts 3 a or 3 b in good yields. Their aromatization under strongly acidic conditions furnished 1 a and 1 b quantitatively. Demethylation of 1 a and 1 b gave diphenols 1 c and 1 d in high yields. Scheme 1. Reagents, conditions, and yields: a) for 3 a: 1 equiv maleimide, toluene, RT, 6 h, 96 %; for 3 b: 1 equiv N-benzylmaleimide, toluene, RT, 6 h, 81 %; b) 6 equiv MeSO 3 H, CH 2 Cl 2 , RT, 12 h, b 99 % for 1 a, b 99 % for 1 b; c) 3 equiv BBr 3 , CH 2 Cl 2 , À 78 8C to RT, 15 h, 98 % for 1 c, 99 % for 1 d. Full details can be found in the Supporting Information. RT room temperature.16: m.p. 81 ± 83 8C (hexane). A referee proposed that we examine the reaction of S 8 O with trapping reagents, with regard to the mechanism of the reactions reported here. The reaction of S 8 O, prepared by a reported method, [4b] with 2,3dimethyl-1,3-butadiene in dichloromethane at room temperature for 1 h gave 2 in only 1.4 % yield, while that carried out under reflux gave 2 in 25 % yield. At present we do not have direct evidence for the existence of free S 2 O in solution, so that ªS 2 Oº should be read as ªS 2 O equivalentº throughout this paper.

Variable C2‐Symmetric Analogues of N‐Hydroxyphthalimide as Enantioselective Catalysts for Aerobic Oxidation: Kinetic Resolution of Oxazolidines

“…These analogues exhibited modest enantioselectivities in some representative asymmetric oxidation reactions, such as the desymmetrization of 2‐substituted indanes and the kinetic resolution of racemic acetals 4. Herein we report a straightforward approach to the synthesis of variable C 2 ‐symmetric analogues of NHPI from diphenol 1 , which can be obtained in high diastereomeric purity by thermal isomerization in the solid state 5. We reported previously an efficient resolution of (±)‐ 1 via the corresponding N (α)‐Boc‐tryptophan diesters; each enantiomer of 1 is now readily available with >99 % ee .…”

“…The precatalysts 4 a and 4 b were thus obtained from 1 in 90 and 88 % overall yield, respectively (Scheme ). The whole sequence was carried out at room temperature, thus avoiding thermal atropisomerization of configurationally fragile compounds 5. 6 Compounds ( aS , aS )‐ 4 a and ( aS , aS )‐ 4 b were obtained from ( aS , aS )‐ 1 (>99 % ee ) with no loss of enantiomeric purity.…”

Assessing Atropisomer Axial Chirality in Drug Discovery and Development

“…Consequences for the higher barrier of rotation for these compounds can be found in both the analytics and the crystal/polymorph forms of the substances. 52 Due care needs to be taken to control the crystallization of these substances in order to consistently produce the desired polymorph, 53 which in turn is dependent on the atropisomeric ratios. Also, chiral formulations may perturb atropisomeric ratios.…”

Architecture and function of atropisomeric molecular triads

“…Selective solid-state isomerization of ambienttemperature stable atropisomeric imides 12 was recently reported by Einhorn et al 14 In boiling toluene either of atropisomers 12 equilibrated to a mixture syn and anti in the ratio 45:55. However, microcrystalline pure syn-12, m.p.…”

“…The use of C and S labels, although common, [8][9][10] is apparently limited to the cases where there is unambiguous correspondence between the shape of the letter and the shape of the B-A-B molecule. Occasionally, the stereoisomers of a B-A-B triad are referred to as cis and trans isomers [11][12][13][14] ; however, the use of these stereochemical labels should be restricted to the differentiation of stable configurational isomers (disubstituted alkenes or saturated cyclic compounds). In the case of meso-disubstituted porphyrin triads syn and anti atropisomers are also labeled ␣␣ and ␣␤, respectively.…”