Total Synthesis of Jadomycin A and a Carbasugar Analogue of Jadomycin B

Abstract

The first syntheses of Jadomycin A and the carbosugar analogue of Jadomycin B have been achieved in 6 and 20 longest linear steps respectively. The key ring system of the aglycone was prepared by a 6π-electron electrocyclic ring closure and subsequent hemi-aminal ring closure. Acid sensitivity of the glycosidic bond in Jadomycin B precluded its synthesis but led to the synthesis of the carbasugar analogue.

Eight-Membered Ring-Containing Jadomycins: Implications for Non-enzymatic Natural Products Biosynthesis

“…20 Compelling evidence for the cyclization process has been demonstrated through the chemical synthesis of jadomycin A by O'Doherty and later by Yu in the total syntheses of a key series of fully glycosylated jadomycins. 21,22 If this biosynthetic step could be exploited to react with an amine other than the α- amine of an amino acid, it could yield a unique opportunity to expand the structural diversity of these natural products. Since L-ornithine contains α-and δ-amino groups, we hypothesized that either could act as a nucleophile forming imine intermediates and potentially undergo spontaneous cyclization with the free carboxylic acid forming either a five-membered, or eight-membered heterocyclic ring (Scheme 1).…”

Bioreductively Activated Reactive Oxygen Species (ROS) Generators as MRSA Inhibitors

“…This scaffold contained the amide adjoining the quinone of deoxynyboquinone and the aryl ring-like jadomycins, 14 another class of natural products that are known to cleave DNA in the presence of metal ions such as Cu(II) 15 presumably through the generation of hydroxyl radical (Chart 1). 16 1 is predicted to undergo bioreduction to its semiquinone, 17 which then is reoxidized by molecular oxygen, forming O 2 −• (Scheme 2).…”

“…14 The addition of an amine to 2 would result in the formation of an imine, which sets up the molecule for an intramolecular 6π-electrocyclic ring closure to afford the alcohol 3; subsequent oxidation of 3 should give the desired lactams of structure 1 ( Table 1). 14 When 2 was reacted with methylamine in an open container, we found 1a as the major product in 73% yield implying that the intermediate alcohol (3a, R = Me, Scheme S2, Supporting Information) was oxidized during the reaction (Table 1). Using this one-pot procedure, compounds 1b−1g were prepared from 2 ( Table 1, entries 2−7).…”

“…The overall yield of 1f could thus be improved to 24% in two steps from commercially available 2-bromo-1,4-naphthoquinone. In contrast, jadomycins are synthesized in >20 steps 14 while deoxynyboquinone was prepared in seven linear steps. 9 Cyclic voltammetry analysis revealed that 1e − reduction potentials (E red ) of 1f was −1.00 V (Table S1, Supporting Information), which appears appropriate for metabolism by bioreductive enzymes.…”

Synthesis and Structure–Activity Relationship Study of 5a-Carbasugar Analogues of SL0101

“…We have been developing practical and generalizable approaches to both pyranose 18−26 and 5a-carbasugar 16,17,27,28 and have reported synthetic approaches to SL0101 and its derivatives. The general approach to these analogues is outlined in Scheme 1.…”