Integrated synthesis of 3,4-carbazoquinone alkaloids N-Me-carbazoquinocin A, B and D-F.

Carbazole alkaloids carbazoquinocin A-F possessing a 1-alkyl-2-methyl-3,4-ortho-carabazoquinone framework were isolated from the microorganism Streptomyces violaceus 2448-SVT2 in 1995. Furthermore, they were found to exhibit strong inhibitory activity against lipid peroxidation. Herein, we report the integrated synthesis of N-Me-analogues of 5 members of the carbazoquinocin family of natural products, namely, N-Me-carbazoquinocin A, B and D-F. We employed an acid-catalyzed, intramolecular benzannulation of indole-appended Z-enoate propargylic alcohols, which was developed earlier in our laboratory, for the construction of the required carbazole framework. All five natural products were obtained in an overall yield of 50-60%, starting from a commercially available indole.

The Bis(indolylmethyl) ethers: Design, Prototypical Synthesis, and Scope Studies.

The design, prototypical synthesis, isolation, and characterization of bis(indolylmethyl) ethers from corresponding indolylcarbinols is described. This approach involves very mild conditions and exhibits good scope for indolylcarbinols (both N-electron withdrawing group and N-electron donating group). Cross etherification between two electronically different indolylcarbinols is also demonstrated for the generation of unsymmetrical ethers. For the first time, the intermediacy of the bis(indolylmethyl) ethers for the formation of bis(indolyl)methanes from indolylcarbinols is proved experimentally and by 1H NMR analysis.

Diastereoselective Biomimetic Synthesis of Dimeric Tetrahydrocarbazoles via a Copper(II)-Catalyzed Cycloisomerization-[3+2] Cyclodimerization Cascade.

The cyclodimerization (homochiral- and heterochiral-) of monomeric units for the construction of stereodefined polycyclic systems is a powerful strategy in both biosynthesis and biomimetic synthesis. Herein we have discovered and developed a CuII - catalyzed, biomimetic, diastereoselective tandem cycloisomerization-[3+2] cyclodimerization of 1-(indol-2-yl)pent-4-yn-3-ol. This novel strategy operates under very mild conditions, providing access to structurally unprecedented dimeric tetrahydrocarbazoles fused to a tetrahydrofuran unit in excellent yields of the products. Several fruitful control experiments, isolation of the monomeric-cycloisomerized products and their subsequent conversion into the corresponding cyclodimeric products supported their intermediacy and the possible mechanism as a cycloisomerization-diastereoselective [3+2] cyclodimerization cascade. The cyclodimerization involves a substituent controlled, highly diastereoselective homochiral [3+2] annulation or heterochiral [3+2] annulation of in situ generated 3-hydroxytetrahydrocarbazoles. The key and important features of this strategy are: a) construction of three new C-C bonds & one new C-O bond; b) creation of two new stereocenters, and c) construction of three new rings, in a single operation; d) low catalyst loading (1-5 mol %); e) 100 % atom economy; and f) rapid construction of structurally unprecedented natural product like polycyclic frameworks. A chiral pool version using an enantio- and diastereopure substrate was also demonstrated.

An approach to functionalized carbazoles from Z-enoate propargylic alcohols. A unified total synthesis of N-Me-carazostatin, N-Me-carbazoquinocin C and N-Me-lipocarbazole A4.

Development of an acid catalyzed, intramolecular benzannulation of indoles for the synthesis of functionalized carbazoles has been reported. The indole appended Z-enoate propargylic alcohols have been employed. The N-EDG-indoles involve the 5-exo-dig cyclization followed by 1,2-migration to give the carbazole-butenoates, whereas the N-EWG-indoles undergo the Z-enoate assisted Meyer-Schuster rearrangement to give the dihydrocarbazole-4-oxo-butanoates. Utilizing one of the 2-methyl-carbazole-butyraldehyde (obtained from the corresponding carbazole-butanoate) as the key intermediate, we have developed a simple approach for an efficient synthesis of N-Me-carazostatin, N-Me-carbazoquinocin C and N-Me-lipocarbazole A4.

An Approach for the Generation of γ-Propenylidene-γ-butenolides and Application to the Total Synthesis of Rubrolides.

Design and synthesis of a new class of γ-butenolides, viz. ß-aryl-γ-propenylidene-γ-butenolides, have been reported from ß-aryl-Z-enoate propargylic alcohols in the presence of acid. Isolation of ß-aryl-γ-propenylidene-γ-butenolides and their O18-isomer confirmed the intermediacy of the allenyl-lactonium ion as well as the cyclic-hemiacetal during the proposed mechanism. By utilizing the ß-aryl-γ-methylenecyclohexenylidene-γ-butenolides as starting materials, a highly stereoselective and efficient approach has been developed for the syntheses of frameworks of rubrolide natural products. This strategy was further extended for the total synthesis of rubrolide E.

Evidence for Atropisomerism in Polycyclic γ-Butenolides: Synthesis, Scope, and Spectroscopic Studies.

Design and development of a domino cyclative approach for the synthesis of new polycyclic γ-butenolides from ß-aryl-Z-enoate propargylic alcohols, through the interception of an intermediate of the Z-enoate-assisted Meyer-Schuster rearrangement, has been reported. A systematic NMR analysis of various derivatives of this class revealed and supported the potential atropisomerism associated with them. These molecules represent first examples of butenolide ring-based atropisomeric compounds in organic chemistry. The synthetic process involves a synchronous construction of both rings with concurrent creation of the potential stereogenic rotational axis.

A Rationally Designed Thymidine-Based Self-Assembled Monolayer on a Gold Electrode for Electroanalytical Applications.

A self-assembled monolayer (SAM) of 1-(3,5-epidithio-2,3,5-trideoxy-ß-D-threo-pentofuranosyl)thymine (EFT) on a gold electrode was prepared and characterized by Raman spectral and electrochemical measurements. Voltammetric and electrochemical impedance measurements show that the SAM of EFT on a Au electrode impedes the electron-transfer reaction. The SAM of EFT was successfully used for the voltammetric sensing of urate in neutral solution. The coexisting ascorbate anion does not interfere and therefore the EFT-based electrode was able to quantify urate at the micromolar level in the presence of a large excess amount of ascorbate. To demonstrate the practical applications, the amount of urate in two different human serum samples was quantified by using the EFT-based electrode; the results are in good agreement with those determined by the clinical method. DFT calculations show that both ascorbate and urate have noncovalent interactions including hydrogen-bonding interactions with EFT.