Organocatalytic aldol approach for the protecting group-free asymmetric synthesis of (7R')-parabenzlactone, (-)-hinokinin, (-)-yatein, (-)-bursehernin, (-)-pluviatolide, (+)-isostegane and allied lignans.

A short and efficient catalytic asymmetric protection-free synthesis of dibenzylbutyrolactone lignans, such as (-)-hinokinin, (-)-yatein, (-)-bursehernin, (-)-pluviatolide, and their 7'-hydroxylignans - (7'R)-parabenzlactone, (7'R)-hydroxyyatein, (7'R)-hydroxybursehernin, and (7'R)-hydroxy pluviatolide, respectively, is described. The syntheses of (+)-isostegane and the formal synthesis of (-)-podophyllotoxin and bicubebins are also described. Organocatalytic aldol-reduction-lactonization and Pd/C-catalyzed hydrogenative debromination are two-pot sequential reactions for the enantioselective synthesis of hydroxybutyrolactone 13b with excellent diastereo- and enantioselectivity (dr 33 : 1 and >99% ee). The protecting group-free chemoselective α-alkylation of 13b directly led to 7'-hydroxydibenzylbutyrolactone lignans, followed by hydrogenative dehydroxylation, which led to their (deoxy) dibenzylbutyrolactone lignans, and the syntheses were completed in three to five steps from 6-bromopiperonal.

Stereochemistry of the Benzylidene γ-Butyrolactone Dictates the Reductive Heck Cyclization Mode in the Asymmetric Synthesis of Aryltetralin Lignans: A Detailed Experimental and Theoretical Study.

The reductive Heck cyclization of nonracemic benzylidene γ-butyrolactone is studied toward the asymmetric synthesis of aryltetralin lignans, where the stereochemistry of the benzylidene lactone is found to control the mode of cyclization. The Z-isomer undergoes mostly 6-endo-cyclization and provides the desired (-)-isopodophyllotoxin along with a minor amount of 5-exo-cyclized product, but the E-isomer goes through exclusively 5-exo-cyclization, leading to the undesired dihydroindenolactone compound instead of (-)-podophyllotoxin. The experimental results are well-supported by the DFT studies.

Selective C3-Allylation and Formal [3 + 2]-Annulation of Spiro-Aziridine Oxindoles: Synthesis of 5'-Substituted Spiro[pyrrolidine-3,3'-oxindoles] and Coerulescine.

Brønsted acid- and/or Lewis acid-catalyzed selective C3-allylation and formal [3 + 2]-annulation of spiro-aziridine oxindoles with allylsilanes have been demonstrated to deliver direct access to 3-allyl-3-aminomethyl oxindoles and 5-silyl methyl spiro[pyrrolidine-3,3'-oxindoles], respectively. The acid-catalyzed methods do not provide any stereoselectivity when chiral spiroaziridines are used. However, the reaction of nonracemic sprioaziridines with allyl-Grignard reagent under catalyst-free conditions afforded 3-allyl-3-aminomethyl oxindoles with good stereoselectivity (ee up to 80%). The allylation protocol is utilized for the short synthesis of coerulescine and various 5'-substituted spiro[pyrrolidine-3,3'-oxindoles].

Sequential one-pot synthesis of N-sulfonyl spiroaziridine oxindoles from spiroepoxy oxindoles.

The N-sulfonyl spiroaziridine oxindole is a recently developed versatile precursor in the synthesis of a wide range of 3,3-disubstituted spirooxindoles. It is usually prepared in three steps from isatin and needs costly and hardly available sulfinimides and hazardous peracid. A sequential and one-pot direct strategy for the synthesis of terminal N-sulfonyl spiroaziridine oxindoles has been developed under ambient conditions with excellent yields (up to 95%) from easily accessible spiroepoxy oxindoles by regioselective amination with aqueous ammonia and a subsequent ring enclosure reaction of the resulting 1,2-amino alcohol using easily available sulfonyl chloride and a base. Other salient features of the protocol include inexpensive substrate requirement and the ease of isolation of the desired product by performing single column chromatographic purification after two consecutive steps.

Organocatalytic Enantioselective Mukaiyama-Mannich Reaction of Isatin-Derived Ketimines for the Synthesis of Oxindolyl-ß3, 3 -Amino Acid Esters.

Mukaiyama-Mannich reactions of ester enolate equivalents with aldimines have been elegantly used for the asymmetric synthesis of ß-amino acids; nevertheless, the corresponding asymmetric reaction employing ketimines are unexplored. Herein, the first organocatalytic enantioselective Mukaiyama-Mannich reaction employing isatin-derived ketimines with unsubstituted silyl ketene acetals is disclosed towards the scalable synthesis of 2-oxoindolinyl-ß3, 3 -amino acid esters at room temperature with excellent enantioselectivities (ee >99.5 %). Ultra-low catalyst loadings (as low as 250 ppm) could be used for the quantitative product formation with high enantiopurity. The synthetic utility of this protocol has been showcased in the short formal synthesis of pharmaceutically demanded (+)-AG-041R, a potent gastrin/CCK-B receptor antagonist.

One-Pot Synthesis of Enantiopure Spiro[3,4-dihydrobenzo[b][1,4]oxazine-2,3'-oxindole] via Regio- and Stereoselective Tandem Ring Opening/Cyclization of Spiroaziridine Oxindoles with Bromophenols.

A highly efficient regio- and stereoselective spiroaziridine ring opening with 2-bromophenols and a subsequent tandem cyclization reaction was developed for the one-pot synthesis of enantiopure 3,4-dihydrospiro[benzo[b][1,4]oxazine-2,3'-oxindole] with excellent enantiopurity (ee up to >99%). It is further extended to asymmetric synthesis of NH-free 3,4-dihydrospiro[benzo[b][1,4]oxazine-2,3'-xindole] retaining the optical activity.

Organocatalytic Domino Reaction of Spiroaziridine Oxindoles and Malononitrile for the Enantiopure Synthesis of Spiro[dihydropyrrole-3,3'-oxindoles].

The first organocatalytic regio- and stereoselective domino reactions of spiroaziridine oxindoles and malononitrile have been developed using DBU as a catalyst without any metal/Lewis acid activation for the enantiopure synthesis of spiro[dihydropyrrole-3,3'-oxindoles] (ee up to >99%). The protocol is also equally effective for the phenyl aziridine with excellent regio- and stereoselectivity.

Reagent-Controlled Reversal of Regioselectivity in Nucleophilic Fluorination of Spiro-epoxyoxindole: Synthesis of 3-Fluoro-3-hydroxymethyloxindole and 3-Aryl-3-fluoromethyloxindole.

A convenient and metal/catalyst-free approach for the reversal of regioselectivity in nucleophilic fluorination of a wide range of spiro-epoxyoxindoles has been reported simply by altering the nucleophilic fluoride reagents. Py·(HF) x-mediated fluorination at the tertiary sp3-C center of spiro-epoxyoxindole furnishes 3-fluoro-3-hydroxymethyloxindoles, whereas TBAF-mediated fluoride addition at the primary sp3-C center renders 3-fluoromethyl-3-hydroxyoxindoles, which have been utilized for the synthesis of 3-aryl-3-fluoromethyloxindole.

Controlling the regioselectivity of the ring opening of spiro-epoxyoxindoles for efficient synthesis of C(3)-N(1')-bisindoles and C(3)-N(1')-diindolylmethane.

An efficient strategy for the construction of both C(3)-N(1') bisindoles and C(3)-N(1') diindolylmethane has been explored via proper tuning of the nucleophilicity of indoline/indole to spiro-epoxyoxindole. Lewis acid-catalyzed highly regio- as well as chemoselective coupling at the C-3 centre of spiro-epoxyoxindoles with indolines furnishes C(3)-N(1') bisindoles whereas base mediated and Lewis acid-catalyzed regioselective coupling at the less hindered site of spiro-epoyoxindoles with indoles via the SN2 mechanism provides C(3)-N(1') diindolylmethane.

The one pot asymmetric synthesis of 3,3'-pyrrolidonyl spiroxindoles via a regio- and stereoselective domino reaction.

A highly efficient regio- and stereoselective domino aziridine ring opening and lactamization reaction between aziridines and 3-carboxy oxindole esters has been developed for the one pot asymmetric synthesis of 4-aryl-3,3'-spiropyrrolidonyl oxindoles with excellent selectivity (dr >99 : 1 and ee up to >99%). It was further extended to a sequential one pot protocol for the asymmetric synthesis of NH-free 3,3'-pyrrolidonyl spiroxindole, maintaining the same selectivity.

Catalyst-Free Ring Opening of Spiroaziridine Oxindoles by Heteronucleophiles: An Approach to the Synthesis of Enantiopure 3-Substituted Oxindoles.

A simple catalyst-free method was developed for the ring opening of spiroaziridine oxindoles by three different nucleophiles, namely, amines, thiols, and methanol, to produce enantiopure (up to 99%) vicinal diaminooxindoles, ß-aminosulfides, and ß-amino-3-methoxyoxindole, respectively, in good to excellent yields. In contrast to the spiroepoxides, spiroaziridines are opened regio- and stereospecifically through the pseudobenzylic spirocenter under catalyst-free conditions. Moreover, unlike simple 2-substituted aziridines, these spiroaziridines are opened up with retention in configuration at the C3-spirocenter.

An asymmetric acetate-Mannich reaction of chiral isatin derived ketimines and its applications.

A highly efficient TMSOTf-mediated asymmetric acetate-Mannich reaction of isatin derived tert-butylsulfinyl ketimines and S-phenyl thioacetate was developed to afford the direct synthesis of indole-based ß3,3-amino acid thioester with excellent selectivity (dr > 98 : 2). Syntheses of (+)-AG-041R and 3-aminopyrroloindoline have been accomplished utilizing the developed method.

Unified total synthesis of (+)-chinensiolide B and (+)-8-epigrosheimin.

An expedient synthetic approach has been developed for the unified total synthesis of (+)-chinensiolide B and (+)-8-epigrosheimin. The point of divergence was provided by the lactone aldehyde 6, in which four contiguous stereocenters were achieved by a stereocontrolled Evans syn-aldol reaction of a R-carvone derived enantiopure aldehyde and chiral N-succinyl-oxazolidinone. The lactone aldehyde 6 was synthesized in multigram quantity in three steps. Highly optimized chemo- and stereoselective reactions and functional group interconversion enabled us to assemble (+)-chinensiolide B and (+)-8-epigrosheimin from 6.

Dihydrochelerythrine and its derivatives: Synthesis and their application as potential G-quadruplex DNA stabilizing agents.

A convenient route was envisaged toward the synthesis of dihydrochelerythrine (DHCHL), 4 by intramolecular Suzuki coupling of 2-bromo-N-(2-bromobenzyl)-naphthalen-1-amine derivative 5 via in situ generated arylborane. This compound was converted to (±)-6-acetonyldihydrochelerythrine (ADC), 3 which was then resolved by chiral prep-HPLC. Efficiency of DHCHL for the stabilization of promoter quadruplex DNA structures and a comparison study with the parent natural alkaloid chelerythrine (CHL), 1 was performed. A thorough investigation was carried out to assess the quadruplex binding affinity by using various biophysical and biochemical studies and the binding mode was explained by using molecular modeling and dynamics studies. Results clearly indicate that DHCHL is a strong G-quadruplex stabilizer with affinity similar to that of the parent alkaloid CHL. Compounds ADC and DHCHL were also screened against different human cancer cell lines. Among the cancer cells, (±)-ADC and its enantiomers showed varied (15-48%) inhibition against human colorectal cell line HCT116 and breast cancer cell line MDA-MB-231 albeit low enantio-specificity in the inhibitory effect; whereas DHCHL showed 30% inhibition against A431 cell line only, suggesting the compounds are indeed cancer tissue specific.

Enantiopure synthesis of dihydrobenzo[1,4]-oxazine-3-carboxylic acids and a route to benzoxazinyl oxazolidinones.

A two step protocol is developed for the efficient synthesis of enantiopure N-Boc-dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids 4 from serine derived cyclic sulfamidate via intramolecular arylamination. The RuPhos Palladacycle along with additional RuPhos ligand is found to be an efficient catalyst for the arylamination of ß-(2-bromoaryloxy)amino acids 3 to provide easy and direct access to a variety of dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids 4 with complete retention of enantiopurity in moderate to high yields. Dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids are not only important unnatural amino acids, but are key precursors for the synthesis of important compounds such as benzoxazinyl oxazolidinones. A general approach for the synthesis of benzoxazinyl oxazolidinone is presented.

Efficient asymmetric synthesis of N-protected-ß-aryloxyamino acids via regioselective ring opening of serine sulfamidate carboxylic acid.

First regioselective ring opening of serine derived cyclic sulfamidate by hard nucleophiles like ArONa is developed, where ß-elimination of serine sulfamidate ester by stronger nucleophiles is overcome by reversal of the electronic effect of the carboxylate anion. This method provides easy and direct access to a variety of N-Boc- and N-PMB protected ß-aryloxy-α-amino acids with complete retention of enantiopurity in moderate to high yields.

Asymmetric total synthesis of (+)-propolisbenzofuran B.

The first asymmetric total synthesis of (+)-propolisbenzofuran B is accomplished in 11 steps with an overall yield of 11.9%. The key steps are tandem deacetylative Sonogashira coupling-annulation reaction to synthesize the 2-substituted benzofuran core, stereoselective syn-aldol reaction and Friedel-Crafts cyclization to install the desired stereocenters & third-ring, and Stille coupling for C-acetylation.

Asymmetric Total Synthesis of Eupalinilide E, a Promoter of Human HSPC Expansion.

A concise and scalable asymmetric total synthesis of eupalinilde E from (R)-(-)-carvone in 12 steps is reported with an overall yield of 20%. The key steps of the synthesis are a tandem Favorskii rearrangement-elimination reaction in the chromatography-free synthesis of carvone-derived 2-cyclopentene carbaldehyde and its catalyst-free stereospecific tandem allylboration-lactonization using recyclable trifluoroethanol as a promoter and solvent affording ß-hydroxymethyl-α-methylene-γ-butyrolactone.

Catalytic enantioselective aziridoarylation of aryl cinnamyl ethers toward synthesis of trans-3-amino-4-arylchromans.

Catalytic enantioselective one-pot aziridoarylation reaction of aryl cinnamyl ethers has been demonstrated in detail. Combination of suitable copper catalyst and chiral bis-oxazoline ligand was found to be very efficient for asymmetric aziridination followed by intramolecular arylation (Friedel-Crafts) reaction to provide a general and direct method for the synthesis of trans-3-amino-4-arylchromans with high regio-, diastereo- (dr > 99:1), and enantioselectivity (up to 95% ee) with moderate yield. trans-3-Amino-4-arylchroman is an advanced intermediate for the synthesis of chromenoisoquinoline compounds such as doxanthrine, a potent and selective full agonist for the dopamine-D(1) receptor.

Efficient chemical fixation and defixation cycle of carbon dioxide under ambient conditions.

Chemical fixation of CO2 as a C1 feedstock for producing value-added products is an important post-combustion technology reducing the CO2 emission. As it is an irreversible process, not considered for the CO2 capture and release. Overall, these chemical transformations also do not help to mitigate global warming, as the energy consumed in different forms is much higher than the amount of CO2 fixed by chemical reactions. Here we describe the development of re-generable chemical fixation of CO2 by spiroaziridine oxindole, where CO2 is captured (chemical fixation) under catalyst-free condition at room temperature both in aqueous and non-aqueous medium even directly from the slow stream of flue gas producing regioselectively spirooxazolidinyl oxindoles, a potential drug. The CO2-adduct is reversed back to the spiroaziridine releasing CO2 under mild conditions. Further both the fixation-defixation of CO2 can be repeated under near ambient conditions for several cycles in a single loop using a recyclable reagent.