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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Synthesis of N-Alkyl Substituted Benzimidazoquinazolinones.

Aromatic N-heterocycles, especially benzimidazoquinazolinones featuring alkyl chains, hold significant pharmaceutical relevance. Here, we introduce a streamlined one-pot, 2-fold Cu-catalyzed C-N bond formation protocol for the efficient synthesis of diverse N-alkyl benzimidazoquinazolinone derivatives. This method showcases a broad substrate scope, leveraging readily accessible alkyl halides and delivers the desired cyclized products in excellent yields. Additionally, the methodology enabled the synthesis of an antitumor agent with satisfactory yield, highlighting its utility in medicinal chemistry endeavors.

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.

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.

Recent developments on domino metathesis reactions in India.

This review summarizes research work carried out in India on domino metathesis reactions using ruthenium-carbene complexes. This reaction has been widely used by synthetic chemists in India for the synthesis of polycyclic systems and complex molecular architectures.

A radical cyclization approach to the formal total syntheses of platencin.

Two different strategies leading to formal total syntheses of platencin are described. The first strategy involving Claisen rearrangement and radical cyclization provides a rapid access to the core structure of platencin, and also use minimum protective-group operations. The second strategy, a protecting group-free route, utilizes a 6-exo-trig radical cyclization and aldol condensation as key steps leading to the formal synthesis of platencin.

A flexible and unified strategy for syntheses of cladospolides A, B, C, and iso-cladospolide B.

A simple, efficient and flexible strategy for the syntheses of cladospolides A-C and iso-cladospolide B is reported here. This strategy involves Julia-Kocienski olefination and Yamaguchi macrolactonization as key steps, starting from either d-ribose or suitable tartaric acid esters. Although our initial efforts towards cladospolide A involving a ring closing metathetic approach were not successful, changing the mode of ring closure and the use of Julia-Kocienski olefination for the construction of the key intermediate solved this issue and paved the way for the completion of total syntheses of this class of natural products.

Application of an enyne metathesis/Diels-Alder cycloaddition sequence: a new versatile approach to the syntheses of C-aryl glycosides and spiro-C-aryl glycosides.

An efficient approach for the synthesis of a variety of C-aryl and spiro-C-aryl glycosides is described. This diversity-oriented strategy employed here relies on a sequential enyne metathesis to generate the 1,3-diene moiety and Diels-Alder reaction with different dienophiles followed by aromatisation. Whereas cross-enyne metathesis with ethylene gas is used to install the 1,3-diene moiety at the anomeric centre for the synthesis of C-aryl glycosides, an intramolecular enyne metathesis on the sugar enyne is performed to generate the 1,3-diene moiety for the synthesis of spiro-C-aryl glycosides. Efforts to extend this strategy to the synthesis of the core structure of natural C-aryl glycoside gilvocarcin are also described. A combination of both C-aryl and spiro-C-aryl glycosides in the same moiety to combine the features thereof has also been accomplished. A tandem enyne metathesis/Diels-Alder reaction/aromatisation has also been attempted to directly access the C-aryl glycosides in one pot albeit in low yield.

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.

A versatile access to calystegine analogues as potential glycosidases inhibitors.

An efficient metathetic strategy and nitrone chemistry have been suitably tethered to construct 8-azabicyclo[3.2.1]octanes as versatile precursors for the synthesis of several calystegine analogues. This synthetic strategy relies on the ability of mannose-derived nitrone to undergo a highly stereoselective nucleophilic addition of various Grignard reagents to access syn orientation of alkenes, which then smoothly undergo ring-closing metathesis (RCM) to provide this framework. These RCM products 18 and 20 have been successfully used as advance precursors to synthesize many calystegine analogues (27, 36, 38, 40, 43, and 44) either by syn-dihydroxylation or by hydrogenation and followed by global deprotection. Interestingly, both compounds 36 and 40 exhibited significant noncompetitive inhibition against alpha-mannosidase and N-acetyl-beta-D-glucosaminidase.