Asymmetric Total Synthesis of 4-Hydroxy-8-O-methyltetrangomycin, 4-Hydroxytetrangomycin, and 4-Keto-8-O-methyltetrangomycin.

Herein, we report the first asymmetric total synthesis of 4-hydroxy-8-O-methyltetrangomycin (1), 4-hydroxytetrangomycin (2), and 4-keto-8-O-methyltetrangomycin (3), angucyclinones featuring a highly oxidized nonaromatic A ring. A sequential enyne metathesis/Diels-Alder approach was utilized successfully to construct the tetracyclic skeleton of the angucyclinones. Late-stage acetonide deprotection challenges were overcome by A ring functional group manipulation, yielding a dihydroxy intermediate prior to the benzylic photo-oxidation, facilitating the total syntheses of angucyclinones 1-3. The key stereocenter was established through a known Sharpless asymmetric epoxidation/regioselective epoxide opening reaction.

A relay ring-closing metathesis/Diels-Alder approach to sugar-derived pluramycin-hybrids.

Herein, we present a general approach for synthesizing pluramycin hybrids, which are analogous to the pluramycinone carbocyclic skeleton. This method involves a sequence of relay ring-closing enyne metathesis, Diels-Alder and oxidative aromatization reactions to synthesize pluramycinone-sugar hybrids. As part of our ongoing research, we have successfully synthesized two pluramycin hybrid analogues by carefully monitoring the late-stage oxidative aromatization steps, which depend on the stereo-orientation of the Diels-Alder cycloadduct at the C-4 center. The undesired ring-opening product can also serve as a C-glycoside analog, providing a versatile convergent route to access both types of hybrids and highlighting the significance of this strategy.

Total Syntheses of Discoipyrroles A, B, and C, Three Marine Natural Products.

Herein, we describe our efforts culminating in the total syntheses of discoipyrroles A, B, and C in 6, 6, and 7 steps respectively with excellent overall yield. Total syntheses of these unique natural products have been accomplished involving microwave-mediated Paal-Knorr pyrrole synthesis, Pd-catalyzed carbonylative transformation, and MoOPH (Vedejs reagent) oxidation as key reactions to construct the 1,2,3,5-tetrasubstituted pyrrole and oxidative cyclization of highly substituted pyrrole as key steps.

Divergent Synthesis of 6- or 7-Aza-Indazoles via Intramolecular Diels-Alder Cascade of Pyrazines.

Pyrazines are reactive 4π partners in intermolecular Diels-Alder cycloaddition with exceptionally activated dienophiles or in an intermolecular version at elevated temperatures. Herein, it is shown that an intramolecular cascade could occur even at room temperature, delivering a collection of 6- or 7-aza-indazoles. An interesting substituent effect of the cycloaddition precursor on the product distribution was uncovered, and in situ NMR studies were conducted to gain insights into this unexpected selectivity.

A Serendipitous One-Pot Cyanation/Hydrolysis/Enamide Formation: Direct Access to 3-Methyleneisoindolin-1-ones.

A direct, one-pot conversion of 2'-haloacetophenones to 3-methyleneisoindolin-1-one scaffolds using CuCN as the sole reagent without the need for moisture-free or anaerobic conditions is reported. This serendipitously discovered transformation with a broad substrate scope provides a significantly different route towards these important scaffolds. The scope of the method has also been further extended towards the synthesis of three special scaffolds, which are analogous to various bio-active drugs.

Synthetic studies on palmerolide C: synthesis of an advanced intermediate towards the revised structure of palmerolide C.

A stereoselective synthesis of the highly advanced intermediates towards the revised structure of palmerolide C and 10-epi-palmerolide C is described in this paper. The required key fragments C1-C6, C7-C14 and C15-C23 have been successfully assembled in a convergent manner to access the C1-C23 framework bearing all the five stereocenters present in the natural product. The synthesis involves the Julia-Kocienski reaction, Yamaguchi esterification, Takai olefination and regioselective epoxide opening as key steps. The proposed route is flexible and could also be applied to the synthesis of structurally related palmerolides.

Synthesis of the C1 -C10 Fragment of Muamvatin.

This report delineates our efforts towards the synthesis of a stereochemically well-defined ketone, the C1 -C10 fragment of muamvatin, the first example of a 2, 4, 6-trioxaadamantane ring skeletal polypropionate marine natural product, using two non-aldol variants. i) The Shimizu reaction, a Pd(0) mediated stereoselective epoxy-ring opening of alkenyl oxiranes, was employed for the stereoselective installation of methyl groups in syn-fashion and ii) Bode's protocol, a NHC-mediated reaction on ß-epoxy aldehydes, was utilized for stereoselective construction of methyl and hydroxyl groups in anti-fashion.

Synthetic approaches towards cortistatins: evolution and progress through its ages.

Cortistatins are a family of steroidal alkaloids with a unique pentacyclic skeleton, having immensely potent anti-angiogenetic activities. Given the scarcity in the natural availability of these compounds, their syntheses became major attractions in organic chemistry. Along with total synthesis of the most potent congeners in the family: cortistatins A and J, the synthesis of two other members have been successfully completed, while various other analogues have also been designed with variable degrees of biological activities. This review is an exhaustive coverage of the significant attempts towards constructing this highly challenging molecule and also aims to highlight the deep understanding of the structure-activity relationships of these compounds, which have been garnered over time.

Serendipitous Synthesis of Pyridoquinazolinones via an Oxidative C-C Bond Cleavage.

A direct one-pot copper-catalyzed oxidative C-C bond cleavage route to the synthesis of pyridoquinazolinones is described. This one-pot strategy involves a copper-catalyzed C-N coupling followed by concomitant C(sp3)-H oxidation and amidation via oxidative C-C bond cleavage under an O2 atmosphere to deliver the target molecules in high yields.

Construction of key building blocks towards the synthesis of cortistatins.

This work reports the construction of key building blocks towards the synthesis of cortistatins; a family of steroidal alkaloids. Cortistatin A, being a primary target due to its superior biological properties over other congeners, has been prepared by two different synthetic routes. Synthesis of the precursor to the heavily substituted A-ring starting from d-glucose and construction of the DE-ring junction employing a Hajos-Parrish ketone as a chiral pool have been demonstrated. Efforts are underway to assemble these key fragments and build towards the total synthesis of cortistatin A.

Copper Catalyzed Oxidative C-C Bond Cleavage of 1,2-Diketones: A Divergent Approach to 1,8-Naphthalimides, Biphenyl-2,2'-dicarboxamides, and N-Heterocyclic Amides.

We report here a simple and efficient copper catalyzed oxidative C-C bond cleavage of stable aromatic cyclic-fused and acyclic 1,2-diketones to deliver amides and imides in high yields. This newly developed protocol provides an excellent tool to transform structurally different 1,2-diketones into different products under the same reaction conditions. The key synthetic features of this methodology are the formation of 1,8-naphthalimides and biphenyl-2,2'-dicarboxamide motifs in high yields. The fluorescent studies of 1,8-naphthalimide derivatives were also carried out in order to show the potential application of these scaffolds.

An Unprecedented, Lewis Acid-Mediated, Metal-Free Iodoannulation Strategy to Aromatic Iodides.

A direct transformation of ortho-alkynylated aromatic vinyl ethers to 1-iodonaphthalenes and other iodo-heterocycles under mild Lewis acidic conditions in the presence of iodide as an external nucleophile is reported. The first example of an iodoannulation strategy using a nucleophilic source of iodine, coupled with good to excellent yields, exclusive alpha regioselectivity and a broad substrate scope makes this work an attractive avenue towards the construction of aromatic iodides.

Transition-Metal-Free Multicomponent Approach to Stereoenriched Cyclopentyl-isoxazoles through C-C Bond Cleavage.

An efficient multicomponent reaction for the synthesis of stereoenriched cyclopentyl-isoxazoles from camphor-derived α-oximes, alkynes, and MeOH is reported. Our method involved a series of cascade transformations, including the in situ generation of an IIII catalyst, which catalyzed the addition of MeOH to a sterically hindered ketone. Oxidation of the oxime, and rearrangement of the α-hydroxyiminium ion generated a nitrile oxide in situ, which, upon [3+2] cycloaddition reaction with an alkyne, delivered the regioselective product. This reaction was very selective for the syn-oxime. This multicomponent approach was also extended to the synthesis of a new glycoconjugate, camphoric ester-isoxazole C-galactoside.

A new and informative [a,b,c,d] nomenclature for one-pot multistep transformations: a simple tool to measure synthetic efficiency.

Domino, cascade and tandem reactions constitute the most efficient and creative chemical transformations with a huge domain of synthetic utility and applications. A number of reactions may be achieved in a single pot, accompanied by the formation of new rings and new bonds, leading towards higher molecular complexity. A lack of one unified, yet informative descriptor often understates the synthetic ingenuity of certain highly creative transformations. In this review, we propose a new tetra-coordinated [a,b,c,d] nomenclature which takes into account and displays the basic parameters which generally indicate the level of efficiency of a chemical transformation. An almost exhaustive set of one-pot multistep reactions may be described by this system and this review is an attempt to display the one-pot multistep transformations reported from our group and to classify them based on our proposed descriptor.

Copper-Catalyzed Cascade Amination Route to N-Aryl Benzimidazoquinazolinones.

An efficient one-pot Cu-catalyzed C-H functionalization/two-fold C-N bond formation protocol for the syntheses of N-aryl benzimidazoquinazolinones is being reported. This strategy involves a Cu-catalyzed C-N bond coupling reaction between N-anilinoquinazolinones and aryl/heteroaryl halides followed by acetate ligand-assisted intramolecular C-H amination.a This reaction is high-yielding and straightforward for the synthesis of anti-cancer drug analogues of benzimidazoquinazolinones.

Recent Trends in Copper-Catalyzed C-H Amination Routes to Biologically Important Nitrogen Scaffolds.

Nitrogen-containing heterocycles have found remarkable applications in natural product research, material sciences, and pharmaceuticals. Although the synthesis of this interesting class of compounds attracted the interest of generations of organic chemists, simple and straightforward assembly methods based on transition-metal catalysis have regularly been elusive. The recent advancements in the development of C-H functionalization have helped in accomplishing the synthesis of a variety of complex heterocycles from simple precursors. This Focus Review summarizes the recent advances in one particular field: the copper-catalyzed C-N bond formation reactions via C-H bond functionalization to furnish a comprehensive range of nitrogen heterocycles. Applicability and synthetic feasibility of a particular reaction represent major requirements for the inclusion in this review.

An enantioselective total synthesis of Sch-725674.

An enantioselective total synthesis of Sch-725674, a unique 14-membered macrolactone, has been accomplished in 13 steps. The step-wise dithiane alkylation served as a strategic step to assemble the upper and lower fragments of the molecule, whereas cross metathesis reaction, Yamaguchi macrolactonization and a substrate controlled stereoselective reduction are used as key steps to complete the total synthesis.

A one-pot copper catalyzed biomimetic route to N-heterocyclic amides from methyl ketones via oxidative C-C bond cleavage.

A direct one-pot Cu-catalyzed biomimetic oxidation of methyl ketones to pharmaceutically important N-heterocyclic amides is reported. The scope of the method is broad, scalable, and mild, and the reaction is tolerant with various acid, base sensitive functionalities with multiple heteroatoms and aryl halides. The extensive mechanistic studies suggest that this reaction follows the Luciferin-Luciferase-like pathway.

A domino enyne/IMDA approach to the core structure of (-) vinigrol.

We report here an enantioselective formal synthesis of vinigrol involving a 1-2-3 strategy: one pot and two reactions with the formation of three rings leading to the core structure of vinigrol from its stereochemically well-defined acyclic precursor.

An iterative Shimizu non-aldol approach for the stereoselective synthesis of C13-C22 fragment of callystatin A.

An efficient synthesis of the polypropionate framework of callystatin A has been achieved by utilizing the Shimizu reaction in an iterative fashion.