Binding Mode-Based Physicochemical Screening Method Using d-Ala-d-Ala Silica Gel and Chemical Modification Approach to Facilitate Discovery of New Macrolactams, Banglactams A and B, from Nonomuraea bangladeshensis K18-0086.

Utilizing a binding mode-based physicochemical screening method using d-Ala-d-Ala silica gel, two new macrolactams, named banglactams A (1) and B (2), were discovered from the culture broth of Nonomuraea bangladeshensis K18-0086. In the course of our investigation, we found that d-Ala-d-Ala silica gel precisely differentiated the chemical structures of banglactams and separated them. However, we were not able to obtain enough of 1 to elucidate the structure due to its instability and insolubility. To overcome this challenge, we chemically modified 1 to improve solubility, enabling us to obtain a sufficient material supply for the indirect determination of the structure. Antibacterial activity evaluation of banglactams revealed that 1 binding to d-Ala-d-Ala silica gel exhibited antibacterial activity against Staphylococcus aureus; however, this was not the case with 2. This research indicates the utility of our original binding mode-based PC screening method, and the combination strategy of PC and chemical modifications led us to discover novel antibacterial compounds.

Design and Synthesis of d-Ala-d-Ala Silica Gel for a Binding Mode-Based Physicochemical Screening Method.

Vancomycin is a potent and broad-spectrum antibiotic that binds to the d-Ala-d-Ala moiety of the growing bacterial cell wall and kills bacteria. This fascinating binding model prompted us to design and synthesize d-Ala-d-Ala silica gels for the establishment of a new physicochemical (PC) screening method. In this report, we confirmed that vancomycin binds to d-Ala-d-Ala silica gel and can be eluted with MeOH containing 50 mM TFA. Finally, d-Ala-d-Ala silica gel enables to purify vancomycin from the culture broth of a vancomycin-producing strain, Amycolatopsis orientalis.

Dipyrimicin A and B, microbial compounds isolated from Amycolatopsis sp. K16-0194.

In a search for compounds interacting with ergosterol resin, a new compound named dipyrimicin B was isolated from a rare actinomycete strain, Amycolatopsis sp. K16-0194. In addition, another analog, dipyrimicin A, which does not interact with the resin, was also discovered. The structures of the two dipyrimicins were established by comprehensive 1D and 2D NMR and MS analyses and found to contain a unique core structure, a 2,2'-bipyridine skeleton. Dipyrimicin A showed strong antimicrobial and cytotoxic activity, whereas dipyrimicin B displayed distinctly poor antimicrobial and cytotoxic activities.

Synthesis of fused and linked bicyclic nitrogen heterocycles by palladium-catalyzed domino cyclization of propargyl bromides.

The palladium(0)-catalyzed direct construction of bicyclic heterocycles is described. Treatment of propargyl bromides that have nucleophilic functional groups connected by two or three carbon atoms with catalytic [Pd(PPh(3))(4)] affords bis-cyclization products in good yields. The desired bicyclic heterocycles can be obtained selectively when using substrates with appropriate nucleophilic groups. We also describe the reaction of a 2-alkynylazetidine derivative with a catalytic amount of [Pd(PPh(3))(4)] under base-free conditions, which affords the same fused heterocycles as the corresponding propargyl bromides.

Direct construction of bicyclic heterocycles by palladium-catalyzed domino cyclization of propargyl bromides.

The palladium-catalyzed domino cyclization of propargyl bromides having two nucleophilic functional groups is described. Treatment of 1,7-diamino-5-bromohept-3-yne derivatives with catalytic Pd(PPh3)4 in the presence of NaH in MeOH gives the 2,7-diazabicyclo[4.3.0]non-5-enes in good yields. Interestingly, the regioselectivity of the reaction is completely controlled by the relative reactivity of the amine functional groups, irrespective of the position of the nucleophiles. The malonate derivative also undergoes domino cyclization to produce a hexahydroindole derivative.

Bromoallenes as allyl dication equivalents in the presence or absence of palladium(0): direct construction of bicyclic sulfamides containing five- to eight-membered rings by tandem cyclization of bromoallenes.

A highly regioselective synthesis of bicyclic sulfamides is described. Based on our recent discovery that bromoallenes can act as allyl dication equivalents in the presence of a palladium catalyst and alcohol, we investigated tandem cyclization of bromoallenes bearing a sulfamide group. It is found that some bromoallenes act as allyl dication equivalents even in the absence of a palladium(0) catalyst to afford cyclosulfamides containing five- or six-membered rings. While the palladium-free cyclization is dependent on the substrate structure affording the bicyclic sulfamides through the first cyclization onto the proximal or central carbon atom of the bromoallenes, the palladium-catalyzed reaction strongly promotes the first cyclization onto the central allenic carbon atom to afford bicyclic sulfamides containing a seven- or eight-membered ring. Formation of two types of bicyclic sulfamides from single bromoallenes by simply changing the reaction conditions is also described.

Palladium(0)-catalyzed synthesis of medium-sized heterocycles by using bromoallenes as an allyl dication equivalent.

We have developed a highly regio- and stereoselective synthesis of medium-sized heterocycles containing one or two heteroatoms via cyclization of bromoallenes bearing an oxygen, nitrogen, or carbon nucleophilic functionality in the presence of a palladium(0) catalyst and alcohol. In this reaction, bromoallenes act as an allyl dication equivalent, and the intramolecular nucleophilic attack takes place exclusively at the central carbon atom of the allene moiety. Interestingly, bromoallenes having a carbon nucleophile with a five-atom tether afford eight-membered rings with trans-configuration, while those having an oxygen or a nitrogen nucleophile give the corresponding cis-rings selectively. This is the first example that demonstrates the synthesis of medium-sized rings via cyclization of bromoallenes, and this reaction provides a very useful method for a catalytic synthesis of seven- and eight-membered heterocycles without using high dilution conditions.