Synthesis of 1,19-Aza-1,19-desoxy-avermectin B_1a:  The First Avermectin Macrolactam

Abstract

The first synthesis of 1,19-aza-1,19-desoxy-avermectin B(1a) (2) is described. This new macrolactam, prepared efficiently from avermectin B(1a) (1a) in seven steps, was designed to form an intramolecular hydrogen bond between the amide carbonyl and the adjacent C7 tertiary hydroxyl via a six-center hydrogen bonding network. The presence of this intramolecular hydrogen bond is anticipated to confer additional conformational rigidity to the 16-membered macrocycle.

Polyvalent Iodine in Organic Chemistry

“…Its synthetic applications have been highlighted in two recent overviews. 205,206 The unique oxidizing properties of 108 in key oxidation steps in the total synthesis of several natural products is best illustrated by such recent examples as the synthesis of CP-molecules, [207][208][209][210][211][212][213][214] cyclotheonamide B, 215 (()-deoxypreussomerin A, 216 racemic brevioxime, 217 erythromycin B, 218 (+)-discodermolide, 219 (+)-cephalostatin 7, 220 (+)-cephalostatin 12, 220 (+)-ritterazine K, 220 3-Ogalloyl-(2R,3R)-epicatechin-4β,8-[3-O-galloyl-(2R,3R)-epicatechin], 221 fredericamycin A, 222 indolizidine alkaloids (-)-205A, (-)-207A, and (-)-235B, 223 1,19-aza-1,19-desoxyavermectin B, 224 angucytcline antibiotics, 225 tricyclic β-lactam antibiotics, 226 and the platelet aggregationinhibiting γ-lactam PI-09. 227 These are but the most recent and significant examples of the many continuing uses of the Dess-Martin periodinane 108 since its discovery and report by Dess and Martin.…”

Rearrangement of a Cyclohexyl Radical to a Cyclopentylmethyl Radical on the Avermectin Skeleton

“…The proposed rearrangement is energetically feasible with a formyl substituent at R 1 and a vinyl substituent at R . The highly stabilizing vinyl substituent lowers the activation enthalpy of ring-cleavage by 8−9 kcal/mol.…”

“…The highly potent avermectin macrolides, discovered more than two decades ago at Merck, , continue to elicit considerable interest for the treatment of parasitic diseases. Synthetic derivatives of avermectins have also been found to be effective against parasitic infections, and many total syntheses of avermectin and its derivatives have been reported .…”

A New Method for the Synthesis of Iminoquinones via DMP-Mediated Oxidative Reaction

“…3 Its unique oxidizing properties and convenience of use have ensured the advance DMP to a widely employed reagent in the synthesis of biologically important natural products. Recently DMP was used in the key oxidation steps in the total syntheses of cyclotheonamide B, 4 (±)-deoxypreussomerin A, 5 racemic brevioxime, 6 erythromycin B, 7 (+)-discodermolide, 8 (+)-cephalostatin 7, 9 (+)-cephalostatin 12, 9 (+)ritterazine K, 9 3-O-galloyl-(2R,3R)-epicatechin-4b,8-[3-O-galloyl-(2R,3R)-epicatechin], 10 fredericamycin A, 11 indolizidine alkaloids (-)-205A, (-)-207A, and (-)-235B, 12 1,19-aza-1,19-desoxy-avermectin B1a, 13 angucytcline antibiotics, 14 tricyclic b-lactam antibiotics, 15 and the platelet aggregation-inhibiting g-lactam PI-091. 16 The iminoquinone moiety is important in a large number of antineoplastic drugs and plays a significant role in the nucleus of actinomycins, which are powerful, highly toxic, natural antibiotics that target DNA as intercalating agents.…”