Atropselective syntheses of (−) and (+) rugulotrosin A utilizing point-to-axial chirality transfer

Abstract

Chiral, dimeric natural products containing complex structures and interesting biological properties have inspired chemists and biologists for decades. A seven step total synthesis of the axially chiral, dimeric tetrahydroxanthone natural product rugulotrosin A is described. The synthesis employs a one-pot Suzuki coupling/dimerization to generate the requisite 2,2'-linked biaryl linkage. Highly selective point-to-axial chirality transfer was achieved using palladium catalysis with achiral phosphine ligands. Single X-ray crystal diffraction data was obtained to confirm both the atropisomeric configuration and absolute stereochemistry of rugulotrosin A. Computational studies are described to rationalize the atropselectivity observed in the key dimerization step. Comparison of the crude fungal extract with synthetic rugulotros in A and its atropisomer verified that nature generates a single atropisomer of the natural product.

Unusual dimeric tetrahydroxanthone derivatives from Aspergillus lentulus and the determination of their axial chiralities

“…3), due to the similar NOEs of H-5/OCH 3 -12, H-5′/OCH 3 -12′, H-5′/H-6′, OCH 3 -12′/H-6′, and CH 3 -14′/CH 3 -13′16. However, the contrary optical rotations ( –210.2 for 1 ; +276.1 for 2 ) suggested the distinction of their axial chiralities1920. More importantly, the different long range NOE correlations between units A and B (Fig.…”

A twist of nature – the significance of atropisomers in biological systems

“…Comparison of CD spectra from the synthesized ±(M) and ±(P) forms of 20 indicated the natural product was exclusively (6R,6ʹR,7R,7ʹR) with regards to the stereogenic carbons, with (P) axial chirality. 46 A B3LYP/6-31G(d) level of theory calculated a barrier of rotation of 47.7 kcal.mol -1 for 20; the fact no (M) atropisomer was observed following heating of 20 in toluene up to 150 °C for 3 h indicates the thermodynamic stability of the (P) conformation. 46 For the aforementioned atropselective synthesis of 20, Qin.…”

Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium‐Sized Lactones and Lactams

“…Pleasingly,aniline-based lactam 11 u was formed in quantitative yield;p resumably,t his system did not suffer from competing intermolecular reaction in view of the lower nucleophilicity of the aniline nucleophile relative to aliphatic amines.F inally,wefound that primary-amine-derived lactam 11 v could be formed in 52 %y ield using the standard conditions. [11] Atropisomerism can play av ital role in mediating ligand-target interactions in biology, [15] but while synthetic methods able to impart exquisite levels of control over stereogenic centres on asingle atom (usually referred to as point chirality) are very well established, methods designed to control other chirality elements (e.g.,p lanar, axial, and helical chirality) [16] are less well developed. The utility of the cyclisation/ring expansion cascade has therefore been well demonstrated by the synthesis of 34 medium-sized lactones or lactams using asimple and mild synthetic method, without requiring high dilution conditions.…”

“…However,t he thermodynamic model cannot be ruled out either,e specially as DFT calculations of the relative free energies of the two possible atropisomers in each case correlate well with the observed atroposelectivity;alarge difference in free energy was calculated for the atroposelective examples (11 a,11 za,11 zb, kJ mol À1 )whereas the least selective examples can be considered isoenergetic at this level of theory (11 x,11 y,DG = 2kJmol À1 ). However,t he thermodynamic model cannot be ruled out either,e specially as DFT calculations of the relative free energies of the two possible atropisomers in each case correlate well with the observed atroposelectivity;alarge difference in free energy was calculated for the atroposelective examples (11 a,11 za,11 zb, kJ mol À1 )whereas the least selective examples can be considered isoenergetic at this level of theory (11 x,11 y,DG = 2kJmol À1 ).…”