Electrolysis flow reactors based on the filter-press architecture of redox flow batteries have proven to be effective and scalable toward the production of commercially relevant, pharmaceutical quantities of anilines (>500 kg/year) from halogen-, hydroxyl-, and carbonyl-substituted nitroarenes. Turbulent flow through the carbon felts on which the catalysts were supported facilitated scaling toward production levels because it conferred on the reactors scale-independent, plug flow-like residence time distributions and high mass transfer coefficients. Equipping the cells with microreference electrodes made it possible to transfer reaction conditions first developed in batch systems to the continuous flow reactors. The catalysts prepared by incipient wetness impregnation of metal salts into lightly oxidized carbon felt supports were readily generalizable.

We report the first total synthesis of the complex C-aryl glycoside isokidamycin, the epimer of the naturally-occurring pluramycin antibiotic kidamycin. The synthesis features a highly efficientDiels-Alder reaction between a substituted naphthyne and a glycosylatedfuran to form the anthracene core bearing a pendant angolosamine C-glycoside. The regiochemical outcome of the Diels-Alder reaction was controlled by employing a disposable silicon-tether to link the reactive napthyne and the glycosyl furan, rendering the cycloaddition intramolecular. The benzopyranone moietyof the aromatic nucleus was appended by cyclization of a functionalized vinylogous amide onto an advanced anthrol intermediate. The vancosamine amino glycoside was introduced by an O→C-glycoside rearrangement that produced the β-anomer. Subsequent refunctionalizations then led to isokidamycin.

The synthesis of isokidamycin, which represents the first total synthesis of a bis-C-aryl glycoside natural product in the pluramycin family, has been completed. The synthesis features the use of a silicon tether as a disposable regiocontrol element in an intramolecular Diels-Alder reaction between a substituted naphthyne and a glycosyl furan and a subsequent O → C-glycoside rearrangement.Kidamycin (1) is a member of the pluramycin class of C-aryl glycoside antibiotics that was isolated from Streptomyces phaeoverticillatus and displays a broad range of antibacterial, antifungal and anticancer properties.i Like other pluramycins, 1 binds to DNA, leading to single strand cleavage.ii Kidamycin possesses an angular anthrapyranone tetracyclic core that is adorned with a β-angolosaminyl C-glycoside substituent at C(8) and an α-N,Ndimethylvancosaminyl C-glycoside group at C(10).iii Kidamycin (1) is both light and acid sensitive and is easily transformed into isokidamycin (2) upon treatment with acid.iiia , iv No doubt owing to their complex structures and labile functionality, none of the bis-Carylglycoside antibiotics of the pluramycin family have succumbed to total synthesis. Indeed, few have even dared to embark on such a challenging enterprise.v Several years ago we reported a unified strategy for preparing the four major classes of Caryl glycoside antibiotics.vi The approach relies on the ring-opening of glycosyl-substituted oxabicycles that are produced by the Diels-Alder reactions of substituted arynes with glycosyl furans. A significant feature of this novel entry to C-aryl glycosides is that it couples the introduction of the C-aryl glycoside moiety with the annelation of a new aromatic ring, thereby leading to a rapid increase in complexity. We subsequently applied this method to the syntheses of several C-aryl glycoside natural products.vii However, we wished to extend this methodology to the synthesis of a more complex member of the pluramycin family. We now report our efforts in this area that resulted in the total synthesis of isokidamycin (2), the first bis-C-arylglycoside antibiotic to be prepared by total synthesis.The essential elements of our approach to kidamycin are outlined in Figure 1. Given the known propensity for the N,N-dimethylvancosamine moiety at C(10) of 1 to suffer epimerization at the anomeric center to give 2, we favored the late stage introduction of this residue from the advanced intermediate 3 using the O→C-glycoside rearrangement that had been pioneered by Suzuki and had been shown to be applicable to the preparation of some α-C-aryl glycosides.viii We envisioned that anthrol 3 would be accessible from 4 by cleavage of the disposable silicon tether, ring-opening of the oxabicycle, and annelation of the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript substituted pyranone ring. Intermediate 4 would then be formed by the pivotal intramolecular naphthyne-furan cycloaddition that would be initiated by reductive dehalogenation of 5, which would be assem...

[reaction: see text] The total synthesis of (+)-cocaine is described. An extension of the recently reported proline catalyzed intramolecular enol-exo-aldol reaction to a meso-dialdehyde provided the tropane ring skeleton directly with good enantiomeric excess. The meso-dialdehyde was prepared using a 2-azaallyllithium [3 + 2] cycloaddition to generate a cis-2,5-disubstituted pyrrolidine. Overall, the synthesis proceeded in 6.5% yield and 86% ee over 14 linear steps starting from commercially available 3-benzyloxy-1-propanol.

A total synthesis of the aglycone of IB-00208 was accomplished in 22 steps using a newly developed approach towards polycyclic 1,4-dioxygenated xanthones from benzocyclobutenones. The generality of this entry to xanthones was initially established on several model systems before it was successfully applied to the construction of the hexacyclic core of the natural product. A new and potentially general approach towards angularly-fused benzocyclobutenones using ring-closing metathesis (RCM) was also developed.