Tetrachlorovancomycin: Total Synthesis of a Designed Glycopeptide Antibiotic of Reduced Synthetic Complexity.

A technically straightforward total synthesis of a new class of vancomycin analogues of reduced synthetic complexity was developed that provided tetrachlorovancomycin (1, LLS = 15 steps, 15% overall yield) and its precursor aglycon 29 (nearly 20% overall yield). The class retains all the intricate vancomycin structural features that contribute to its target binding affinity and selectivity, maintains the antimicrobial activity of vancomycin, and achieves the simplification by an unusual addition, not removal, of benign substituents to the core structure. The modification, accomplished by addition of two aryl chloride substituents to provide 1, permitted a streamlined total synthesis of the new glycopeptide antibiotic class by removing the challenges associated with CD and DE ring system atropisomer stereochemical control. This also enabled their simultaneous and further-activated SNAr macrocyclizations that establish the tricyclic skeleton of 1. Key elements of the approach include catalyst-controlled diastereoselective formation of the AB biaryl axis of chirality (>30:1 dr), an essentially instantaneous macrolactamization of the AB ring system free of competitive epimerization (>30:1 dr), racemization free coupling of the E ring tetrapeptide, room temperature simultaneous CD and DE ring system cyclizations, a highly refined 4-step conversion of the cyclization product to the aglycon, and a protecting-group-free one-pot enzymatic glycosylation for disaccharide introduction. In addition to the antimicrobial evaluation of tetrachlorovancomycin (1), the preparation of key peripherally modified derivatives, which introduce independent and synergistic mechanisms of action, revealed their exceptional antimicrobial potency and provide the foundation for future use of this new class of synthetic glycopeptide analogues.

Divergent Total Synthesis and Characterization of Maxamycins.

A new streamlined and scaled divergent total synthesis of pocket-modified vancomycin analogs is detailed that provides a common late-stage intermediate [Ψ[C(═S)NH]Tpg4]vancomycin (LLS = 18 steps, 12% overall yield, >5 g prepared) to access both existing and future pocket modifications. Highlights of the approach include an atroposelective synthesis of [Ψ[C(═S)NH]Tpg4]vancomycin aglycon (11), a one-pot enzymatic glycosylation for direct conversion to [Ψ[C(═S)NH]Tpg4]vancomycin (12), and new powerful methods for the late-stage conversion of the embedded thioamide to amidine/aminomethylene pocket modifications. Incorporation of two peripheral modifications provides a scalable total synthesis of the maxamycins, all prepared from aglycon 11 without use of protecting groups. Thus, both existing and presently unexplored pocket-modified analogues paired with a range of peripheral modifications are accessible from this common thioamide intermediate. In addition to providing an improved synthesis of the initial member of the maxamycins, this is illustrated herein with the first synthesis and examination of maxamycins that contain the most effective of the pocket modifications (amidine) described to date combined with two additional peripheral modifications. These new amidine-based maxamycins proved to be potent, durable, and efficacious antimicrobial agents that display equipotent activity against vancomycin-sensitive and vancomycin-resistant Gram-positive organisms and act by three independent synergistic mechanisms of action. In the first such study conducted to date, one new maxamycin (21, MX-4) exhibited efficacious in vivo activity against a feared and especially challenging multidrug-resistant (MRSA) and vancomycin-resistant (VRSA) S. aureus bacterial strain (VanA VRS-2) for which vancomycin is inactive.

Intramolecular Singlet Fission in Pentacene Oligomers via an Intermediate State.

Intramolecular singlet fission (iSF) is an efficient strategy of multiexciton generation via a singlet exciton splitting into a correlated triplet pair in one organic molecule with more than two chromophores. Propeller-shaped iptycene-linked triisopropylsilyl(TIPS)-ethynyl functionalized pentacene oligomers (pent-monomer, pent-dimer, and pent-trimer) were synthesized, and the iSF dynamics of pent-dimer and -trimer were monitored by a visible-near-IR transient absorption (TA) spectroscopy. Quantum yields of the triplet pair, ∼80%, of both estimated by near-IR TA spectral analysis are in good agreement with the results of global analysis and triplet sensitization experiments. The iSF rate of pent-trimer is slightly faster than that of pent-dimer even with one more chromophore site. The unexpectedly weak difference indicates the existence of an intermediate process to realize iSF. The intermediate process might be determined by through-bond electronic coupling of the homoconjugation bridge in the pentacene oligomers. Our results suggest the importance of the rigid bridge to the fast iSF rate and the elongated lifetime of the correlated triplet pair in pentacene oligomers.

Didehydroisobenzofuran: A New Reactive Intermediate for Construction of Isoacenofuran.

An efficient generation method of didehydroisobenzofuran, a new heteroaryne species, was developed by bromine/lithium exchange of the dibromoisobenzofuran. The reactive intermediate, thus generated, was trapped by appropriate arynophile to give the [2+2], [2+3], and [2+4] cycloadducts, respectively. Moreover, the reaction could be applied to the syntheses of isoanthracenofurans (anthra[2,3-c]furans), a new class of heteroacenes, with isoelectoronic structure to the corresponding acenoheteroles (anthra[2,3-b]furans).