Conformational analysis of phorboxazole bis‐oxazole oxane fragment analogs by NMR spectroscopy and molecular modeling simulations

Abstract

We present a detailed conformational study of a simplified synthetic analog of the bis-oxazole oxane fragment found in the cytostatic agents phorboxazole A and B based on results from NMR spectroscopy and molecular modeling simulations. Complete 1H and 13C resonance assignments for the bis-oxazole oxane system were carried out through the use of COSY, HSQC, HMBC, TOCSY, and HSQC-TOCSY experiments, and its conformational preferences in solution were investigated by analysis of 3J(HH) coupling constants and NOE enhancements obtained from 1D and 2D NOESY experiments. In order to solve inconsistencies from our preliminary structural studies, simulated annealing studies were performed to thoroughly sample the phase space available to the molecule. Our results reveal that the six-membered oxane ring, which constitutes the most important moiety regarding the three-dimensional (3D) structure and flexibility of the analog, exists in rapid equilibrium between its two accessible chair conformers in an approximate ratio of 70:30. The information gathered from these studies will be of critical importance in our efforts to prepare novel compounds with phorboxazole-like structure and activity.

Polyoxygenated Diterpenes from the Sponge Phorbas sp.

“…An aliquot (1.73 g) of the fraction eluted with 10% MeOH(aq) was dried and separated by reversed-phase HPLC (YMC-ODS-A column, 20% MeOH(aq)) to afford, in the order of elution, compounds 13, 11,6,3,8,5,4,15,9,7,12,14,2, and 1 as white solids. An aliquot (1.75 g) of the fraction eluted with 100% MeOH was dried and separated by reversed-phase HPLC (YMC-ODS-A column, 15% MeOH(aq)) to afford, in the order of elution, compounds 4, 12, 2, 1, 16, 10, and 17 as white solids.…”

Interconversion Study in 1,4-Substituted Six-Membered Cyclohexane-Type Rings. Structure and Dynamics of trans-1,4-Dibromo-1,4-dicyanocyclohexane

“…This small six-membered ring has excellent stability, so it occurs in many organic molecules, ,,, perhaps most famously in steroids. , Heteroatoms do not disturb this stability very much, so carbohydrates in their pyranose ring forms, with one oxygen atom in the ring, also adopt chair conformations, − and there are many more examples. − Common network solids, such as diamond, quartz, and silicon carbide, , are also based on tetrahedral coordination, so the structures can be viewed as fused six-membered rings. This is a small sample of the vast literature on these six-membered ring systems.…”

Insights into the stereoselective BF3-catalyzed hetero Diels–Alder reaction of Garner’s aldehyde with Danishefsky’s diene

“…6,14 Apart from being an effective tool for the generation of large conformer ensembles, simulated annealing is particularly well suited to overcome the energy barriers that may preclude adequate sampling of the phase space in cyclic systems. The most populated family of conformers obtained following this approach, comprising of 50% of the low energy structures, corresponds with the chair conformation postulated earlier (Fig.…”

“…The low-energy conformers for compound 9a, 9b, and 10 were generated with a simulated annealing protocol. 6,14 The MM2-based MM+ force field was employed for the simulations, 18 using no non-bonded cutoffs and bond dipoles to compute electrostatic interactions. Each simulated annealing cycle consisted of 1 ps of equilibration at 800 K and annealing to 200 K for a 0.8 ps period, followed by minimization of the resulting structures to an energy gradient below 0.001 Kcal/mol.…”

“…As part of our ongoing efforts aimed toward the design of naturally inspired biologically active compounds through novel methodologies, we have recently detailed the synthesis and conformational evaluation of analogues of the C15-C32 bis-oxazole oxane fragment of the phorboxazoles. 6,7 Herein we report a high-yielding and stereoselective route for the preparation of key intermediates in the synthesis of analogues of the C3-C17 oxazole oxane fragment of these molecules (Scheme 1). The approach relies on the BF 3 -catalyzed hetero Diels-Alder (HDA) reaction between Danishefsky's diene and Garner's aldehyde, 8,9 and leads to a trans-2,6-disubstituted tetrahydropyranone as the major product.…”