Total Synthesis and Determination of Absolute Configuration of Cryptorigidifoliol G.

The first asymmetric total synthesis of (1S,5R,7S)-cryptorigidifoliol G and (1S,5R,7R)-cryptorigidifoliol G of the proposed natural product was achieved. The key steps in the synthesis involved Keck-Maruoka allylation, our own developed protocol for the construction of the trans-2,6-disubstituted dihydropyran, iodolactonization, cross-metathesis, Prins cyclization, and cis-Wittig olefination reaction. A comparison of the NMR as well as analytical data and thorough analysis of the 2D NMR suggested that the absolute stereochemistry of the proposed natural product is (1S,5R,7S)-cryptorigidifoliol G.

BF3·OEt2-Catalyzed Unexpected Stereoselective Formation of 2,4-trans-Diallyl-2-methyl-6-aryltetrahydro-2H-pyrans with Quaternary Stereocenters.

The present manuscript describes a convenient, mild, and highly stereoselective method for the allylation of δ-hydroxy-α,ß-unsaturated ketones having a benzylic hydroxyl group at the δ-position using allyltrimethylsilane mediated by BF3·OEt2, leading to 2,4-diallyl-2-methyl-6-aryltetrahydro-2H-pyran ring systems with quaternary carbon stereogenic centers. This represents the first example of a tandem isomerization followed by one C-O and two C-C bond-forming reactions in one pot. The isolation of TMS-protected lactol as an intermediate from the reaction strongly supports the proposed mechanistic pathway.

Total Synthesis and Structural Revision of Greensporone F and Dechlorogreensporone F.

The first asymmetric total syntheses of the real isolation product (2S,5R,8R)-greensporone F and (2S,5R,8R)-dechlorogreensporone F, 14-membered resorcylic acid lactones with a cis-2,5-disubstituted tetrahydrofuran ring system, was accomplished. The synthesis features a late-stage Lewis acid-catalyzed stereoselective intramolecular oxa-Michael reaction, E-selective ring-closing metathesis, De Brabander's esterification, and Jacobsen's hydrolytic kinetic resolution as the key steps. Synthesis of both real isolation and erroneously proposed structure necessitated the revision of the absolute configuration of greensporone F and dechlorogreensporone F. The erroneous representation of (2S,5S,8S)-configuration in greensporone F and dechlorogreensporone F was assigned to be (2S,5R,8R) by comparison with the NMR data and specific rotation of the synthetic compounds with that of the reported data.

Stereoselective Synthesis of the C1-C16 Fragment of the Purported Structure of Formosalide B.

The first stereoselective synthesis of the C1-C16 fragment possessing stereo-enriched fully substituted tetrahydropyran (THP) along with tetrahydrofuran (THF) rings of the proposed structure of formosalide B is described in 12 longest linear steps with 22% overall yield, starting from two cheap and commercially available 1,5-pentanediol and l-glutamic acid, following a convergent approach. The key steps involve in this synthesis are Horner-Wadsworth-Emmons reaction, Sharpless asymmetric dihydroxylation, and acid-mediated ketalization to assemble the substituted THP ring, one-pot Sharpless dihydroxylation-SN2-type cyclization, and Wittig homologation to construct the THF derivative.

CuBr2-catalyzed diastereoselective allylation: total synthesis of decytospolides A and B and their C6-epimers.

An efficient CuBr2-catalyzed diastereoselective allylation of a cyclic hemiacetal with allyltrimethylsilane as a nucleophile has been developed. The protocol offers a cost effective, protecting group tolerant, and operationally simple approach to 2,6-trans-disubstituted tetrahydropyran with excellent diastereoselectivity. Furthermore, the application of this methodology has been demonstrated in the total synthesis of decytospolides A and B and their C6-epimers.

[3,3]-Acyloxy Rearrangement-Triggered Regioselective Hydration of δ-Acetoxy-α,ß-Alkynoates/Halo Alkynes.

Herein, we report a simple, efficient, highly regioselective, and broad-scope hydration method that is facilitated by an unusual interception of an electrophilic intermediate by water generated via acetate group participation during [3,3]-acyloxy rearrangement. Various carboxylate-directing groups including acetate, acrylates, pivalates, benzoate or its derivatives, and those derived from bioactive natural products were successfully implemented to direct the regioselective hydration for various functionalized δ-acyloxy-ß-ketoester synthesis. The reaction pathway was further confirmed by 18O labeling experiments, and to the best of our knowledge, this is the first report of hydration through an electrophilic intermediate generated during [3,3]-acyloxy rearrangement. Synthetic application includes the synthesis of a modifiable C5-carbon chain, five-, six-, and seven-membered heterocycles, and natural product diversification.

Total Synthesis of (-)-Citreoisocoumarin, (-)-Citreoisocoumarinol, (-)-12-epi-Citreoisocoumarinol, and (-)-Mucorisocoumarins A and B Using a Gold(I)-Catalyzed Cyclization Strategy.

A unified and concise first asymmetric total synthesis of (-)-citreoisocoumarin (2), (-)-citreoisocoumarinol (3), 12-epi-citreoisocoumarinol (4), and (-)-mucorisocoumarins A (5) and B (6) have been accomplished from the common intermediate (-)-6-O-methyl-citreoisocoumarin (1). Central to the synthetic approach is a regioselective gold(I)-catalyzed 6-endo-dig cyclization strategy for the construction of the isocoumarin skeleton. The other key steps in this approach included Sonogashira coupling, Tsuji-Wacker oxidation, Evans-Saksena's 1,3-anti-reduction, and Narasaka-Prasad's 1,3-syn-reduction. The synthetic results unambiguously confirmed the absolute configuration of the natural products mucorisocoumarins A and B as (-)-(10R,12S)-5 and (+)-(10S,12S)-6, respectively.

The Mukaiyama type aldol reaction for the synthesis of trans-2,6-disubstituted tetrahydropyrans: synthesis of diospongin A and B.

An efficient synthesis protocol for the preparation of trans-2,6-disubstituted tetrahydropyrans by the reaction of 1-phenyl-1-triemthylsiloxyethylene with six membered cyclic hemiacetals in the presence of iodine is developed. This reaction proceeds smoothly under mild conditions employing a catalytic amount of molecular iodine. The feature of this novel conversion includes milder reaction conditions, broader substrate scope, functional group tolerance and good diastereoselectivity. The efficiency and practicality of the current method were successfully displayed in the total synthesis of diospongin A and B in good yields.

Total Synthesis and Structural Revision of Monocillin VII.

The first asymmetric total synthesis of macrolactone monocillin VII and its C-10' epimer was achieved starting from a known chiral pure epoxide in 16 longest linear sequences. The present synthesis highlights the macrolactone formation involving an alkyne-dicobalt carbonyl complex under De Brabander's conditions followed by an unexpected regioselective hydration. The asymmetric total synthesis resulted in the revision of the configuration at C10' and reassignment of the absolute configuration of the natural product.

Total synthesis and stereochemical revision of relgro and 10'-oxorelgro.

The first asymmetric total synthesis and stereochemical assignments of 10-membered macrolactones relgro and 10'-oxorelgro are disclosed. To this end, palladium-catalyzed Stille coupling, the Mitsunobu reaction, ring-closing metathesis, EDCI promoted coupling and the Jacobsen hydrolytic kinetic resolution are used as key steps. The total synthesis followed by thorough evaluation of the optical rotation and CD spectral data led to the revision of the absolute configuration at C-6' for both relgro and 10'-oxorelgro. Moreover, the 1H as well as 13C NMR data are reported for the first time for relgro.

Correction: A synthetic study toward the core structure of (-)-apicularen A.

Correction for 'A synthetic study toward the core structure of (-)-apicularen A' by Tapas R. Pradhan et al., Org. Biomol. Chem., 2018, 16, 8810-8818.

A synthetic study toward the core structure of (-)-apicularen A.

A concise synthetic strategy towards the core structure of (-)-apicularen A has been described in an 11-step synthetic sequence from a known intermediate. The key steps include tandem isomerization followed by C-O and C-C bond-forming reactions and iodocyclization strategies for the synthesis of a bicyclic ether embedded in the macrolactone ring. The applied reagent-controlled Keck-Maruoka allylation, Lin Pu alkynylation and Ricket-Diels-Alder reactions were used to simplify the synthetic sequence of related natural products. An intramolecular Yamaguchi lactonization constructed the macrolactone core, while the attempt to install the C11 hydroxyl chiral centre either under catalytic hydrogenation conditions or oxidative conditions was not successful.

A General Diastereoselective Strategy for Both cis- and trans-2,6-Disubstituted Tetrahydropyrans: Formal Total Synthesis of (+)-Muconin.

A protocol for general diastereoselective tandem dihydroxylation followed by SN2 cyclization was developed for the convenient and efficient synthesis of cis- and trans-2,6-disubstituted tetrahydropyrans from ζ-mesyloxy α,ß-unsaturated esters. The application of this novel method was demonstrated through the concise formal synthesis of (+)-muconin, a nonclassical acetogenin, with sequential THP-THF ring formation.

Total Synthesis of Four Isomers of the Proposed Structures of Cryptorigidifoliol K.

The first asymmetric convergent total synthesis of four isomers of proposed structures of cryptorigidifoliol K (1a, 1b, 1c, and 1d) has been achieved from commercially available starting materials. The key steps in this synthesis involve tandem isomerization followed by a C-O and C-C bond-forming reaction for the construction of trans-2,6-disubstituted dihydropyran, iodolactonization, isomerization of terminal alkene, and cross-metathesis reaction. The large discrepancies in the spectroscopic data (1H NMR) of synthetic cryptorigidifoliol K from the natural product suggest that the structure of the natural cryptorigidifoliol K requires revision.

Genetic Validation of Leishmania donovani Lysyl-tRNA Synthetase Shows that It Is Indispensable for Parasite Growth and Infectivity.

Leishmania donovani is a protozoan parasite that causes visceral leishmaniasis. Increasing resistance and severe side effects of existing drugs have led to the need to identify new chemotherapeutic targets. Aminoacyl-tRNA synthetases (aaRSs) are ubiquitous and are required for protein synthesis. aaRSs are known drug targets for bacterial and fungal pathogens. Here, we have characterized and evaluated the essentiality of L. donovani lysyl-tRNA synthetase (LdLysRS). Two different coding sequences for lysyl-tRNA synthetases are annotated in the Leishmania genome database. LdLysRS-1 (LdBPK_150270.1), located on chromosome 15, is closer to apicomplexans and eukaryotes, whereas LdLysRS-2 (LdBPK_300130.1), present on chromosome 30, is closer to bacteria. In the present study, we have characterized LdLysRS-1. Recombinant LdLysRS-1 displayed aminoacylation activity, and the protein localized to the cytosol. The LdLysRS-1 heterozygous mutants had a restrictive growth phenotype and attenuated infectivity. LdLysRS-1 appears to be an essential gene, as a chromosomal knockout of LdLysRS-1 could be generated when the gene was provided on a rescuing plasmid. Cladosporin, a fungal secondary metabolite and a known inhibitor of LysRS, was more potent against promastigotes (50% inhibitory concentration [IC50], 4.19 µM) and intracellular amastigotes (IC50, 1.09 µM) than were isomers of cladosporin (3-epi-isocladosporin and isocladosporin). These compounds exhibited low toxicity to mammalian cells. The specificity of inhibition of parasite growth caused by these inhibitors was further assessed using LdLysRS-1 heterozygous mutant strains and rescue mutant promastigotes. These inhibitors inhibited the aminoacylation activity of recombinant LdLysRS. Our data provide a framework for the development of a new class of drugs against this parasite. IMPORTANCE Aminoacyl-tRNA synthetases are housekeeping enzymes essential for protein translation, providing charged tRNAs for the proper construction of peptide chains. These enzymes provide raw materials for protein translation and also ensure fidelity of translation. L. donovani is a protozoan parasite that causes visceral leishmaniasis. It is a continuously proliferating parasite that depends heavily on efficient protein translation. Lysyl-tRNA synthetase is one of the aaRSs which charges lysine to its cognate tRNA. Two different coding sequences for lysyl-tRNA synthetases (LdLysRS) are present in this parasite. LdLysRS-1 is closer to apicomplexans and eukaryotes, whereas LdLysRS-2 is closer to bacteria. Here, we have characterized LdLysRS-1 of L. donovani. LdLysRS-1 appears to be an essential gene, as the chromosomal null mutants did not survive. The heterozygous mutants showed slower growth kinetics and exhibited attenuated virulence. This study also provides a platform to explore LdLysRS-1 as a potential drug target.

Total Synthesis and Stereochemical Revision of 4,8-Dihydroxy-3,4-dihydrovernoniyne.

The first asymmetric total synthesis of two possible diastereomers (4S,5R)-4,8-dihydroxy-3,4-dihydrovernoniyne 5 and (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a is accomplished. Salient features of the synthesis involve Cadiot-Chodkiewicz coupling and Sonogashira cross-coupling of terminal acetylenes. Detailed comparison of the 1H and 13C NMR data and specific rotation with that of the natural product led to the revision of the absolute stereochemistry of the natural product as (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a.

Gold(I)-Catalyzed Cyclization for the Synthesis of 8-Hydroxy-3- substituted Isocoumarins: Total Synthesis of Exserolide F.

A highly regioselective gold(I)-catalyzed 6-endo-dig cyclization of 2,2-dimethyl-5-(alkynyl)-4H-benzo[d][1,3]dioxin-4-ones for the synthesis of 8-hydroxy-3-substituted isocoumarins is described. Key features of the reaction include the broad substrate scope, scalability, and tolerance for protecting groups. The synthetic utility of this novel method is demonstrated by the first total synthesis of exserolide F, an isocoumarin-containing polyol natural product.

Asymmetric Total Synthesis of the Putative Structure of Diplopyrone.

The first asymmetric total synthesis of the putative structure of diplopyrone was achieved in 17 linear steps starting from cis-1,4-butene-diol. The synthetic route features iodine-catalyzed tandem isomerization followed by C-O and C-C bond formation reaction strategy developed by our own group to construct the trans-2,6-disubstituted dihydropyran ring, asymmetric α-aminoxylation reaction, and Still-Gennari (Z)-selective olefination reactions. Careful comparison of 1H and 13C NMR spectroscopic data as well as investigation of the UV and circular dichroism spectrum in trifluoroethanol for compound 2 suggest that the putative structure for diplopyrone {6-[(1S)-1-hydroxyethyl]-2,4a(S),6(R),8a(S)-tetrahydropyran[3,2-b]pyran-2-one} requires revision.

First asymmetric total synthesis of aspergillide D.

The first asymmetric total synthesis of a 16-membered macrolide, aspergillide D, is described. The chiral centers of the acid are derived from d-ribose and the alcohol subunit from 1,8-octane diol through Sharpless kinetic resolution, respectively. The other key reactions include Yamaguchi esterification, ring-closing metathesis reaction, and Shiina macrolactonization to construct the fully functionalized macrocycle.

Asymmetric Total Syntheses of Two Possible Diastereomers of Gliomasolide E and Its Structural Elucidation.

The first total syntheses of two possible diastereomers of gliomasolide E, a 14-membered macrolides isolated from the marine sponge Phakellia fusca Thiele, which was collected from the South China Sea, is reported. Highlights of the synthesis include macrolactonization through intramolecular Horner-Wadsworth-Emmons olefination, Yamaguchi-Hirao alkynylation, and base-induced elimination reactions for propargyl alcohol synthesis as the key reactions. Detailed comparison of their 1H and 13C NMR (1D and 2D NMR data) and specific rotation with those of the natural product revealed that the absolute stereochemistry of gliomasolide E should be (2E,5R,7R,9R,13R).