Synthese des Makrolid‐Antibiotikums (−)‐A26771B mit Photolactonisierung als Schlüsselreaktion und Computersimulation als effektive Optimierungshilfe

Abstract

Synthesis of the Macrolide Antibiotic (-)-A26771B Using Photolactonization as a Key Reaction and Computer Simulation as an Effective Aid in OptimizationThe title compound has been synthesized in a sequence of 21 steps starting from phenol. The cyclic skeleton has been built up in the earlier part of the synthesis by photolactonization. This reaction supplies C(6) with a functionality, not present in the target structure, but useful for oxygenation at C(4) and generation of the stereogenic center C(5). The BarlonlMcCombie reaction provides a product deoxygenated at C(6), but only after an adjacent oxirane ring has been opened at the cost of an increase in the number of overall steps. X-Ray structural information and computational modelling of appropriate molecules proved to be essential to selection of optimal conditions for various transformations.

Glycal approach to the synthesis of macrolide (−)-A26771B

“…Scheme 1: Retrosynthetic analysis of (-)-A26771B 60 As per the retrosynthesis delineated above, our approach to the total synthesis of 1 was commenced with Ferrier rearrangement of the commercially available peracetylated-D-glucal 7 with benzyl alcohol in the presence of catalytic amount of InCl3 9 to afford 2,3unsaturated pyranoside 11 in 95% yield. Hydrogenation of the double bond and deprotection of the O-benzyl group at anomeric position by H2 in the presence of Pd/C produced the hemiacetal 6 in 98% yield.…”

“…Its in situ 50 prepared Grignard reagent was treated with (R)-propylene oxide 9 in the presence of a catalytic amount of CuCN to deliver the desired (R)-non-8-en-2-ol 4 in 89% yield. 55 Scheme 3: Synthesis of Fragment 4 Reagents and conditions: (a) 47% HBr, toluene, 120 ºC, 12 hrs, 85%; (b) (i) PCC, molecular sieves 4 Å, CH2Cl2, 0 ºC, 4 h; (ii) (Ph)3PCH3Br, t-BuOK, dry THF, 0 ºC to RT, 2 h, 81%; (c) Mg, 60 dry THF, C2H4Br2, 5 h, reflux, then (R)-Propyleneoxide, CuCN, dry THF, -15 ºC, 4 h, 89%. Now we embarked upon synthesis of the title molecule by utilizing the above two fragments (3 and 4).…”

“…55 Optical rotations were determined on an HORIBA, high sensitive polarimeter, SEPA-300 using a 1 dm cell at 17 ºC-32 ºC in chloroform and methanol; concentrations mentioned are in g/100 mL. For IR spectra were recorded on Perkin-Elmer 881 and FTIR-8210 PC Shimadzu 60 Spectrophotometers. Mass spectra were recorded on a JEOL JMS-600H high resolution spectrometer using EI mode at 70 eV.…”

“…The reaction mixture was now added to another RB containing a solution of alcohol 4 (300 mg, 2 mmol) and DMAP (1 g, 8.36 mmol) in toluene (5 ml) and the resulting mixture was heated at reflux for 3 60 h. The reaction mixture was then cooled to room temperature and quenched with saturated NaHCO3 solution. The two layers were separated and the aqueous layer was extracted with EtOAc (3x5 ml).…”

Photochemistry Meets Natural‐Product Synthesis

“…Idealized molecular models of (2E,4Z,17S)-oxo-diene-lactone 102 and (2E,4Z,15R)oxo-diene-lactone 106 revealing unhindered access to the C=O groups within the (Re)-or (Si)-half-space, respectively[114] 114a]* are further deactivated by intersystem crossing to afford the two photoenol conformers 114s and 114a in their electronic ground states. The latter rapidly decay by intersystem crossing into 264 ESSAYS IN CONTEMPORARY CHEMISTRY: Fig.…”