Total synthesis of TAK-kinase inhibitor LL-Z1640-2 via consecutive macrocyclization and transannular aromatization

The biomimetic total synthesis of LL-Z1640-2 (3) is reported without the use of phenol protection. The aromatic unit was constructed via the transannular aromatization of macrocyclic triketo-ester 2, which in turn was synthesized by macrolactonization using an intramolecular trapping of a triketo-ketene derived from dioxinone 1.     

Fast and efficient synthesis of the complete LL-Z1640-2 framework

The convergent synthesis of the complete LL-Z1640-2 framework has been completed. This fast and efficient approach provides flexible access into the resorcyclic lactones.     

Total synthesis of echinopines A and B: exploiting a bioinspired late-stage intramolecular cyclopropanation

Total synthesis of echinopine A and B have been accomplished, based on a strategy that involved two transition-metal-mediated ene-yne cycloisomerizations. A modified Pd-catalyzed enyne cycloisomerization/intramolecular Diels-Alder cascade rendered a more streamlined synthesis of tricyclic ketone 15, and a Ru-catalyzed ene-yne cycloisomerization/cyclopropanation resembled the late-stage [5/7] → [3/5/5/7] ring-forming sequence in the proposed biosynthetic pathway.     

Total synthesis of acosamine and daunosamine utilizing a diastereoselective intramolecular [3+2] cycloaddition

A total synthesis of daunosamine (3) and acosamine (4) has been accomplished via a diastereoselective intramolecular nitrone-olefin cyclization. In the key step the chiral nitrone 12a cyclized to give two isoxazolidines 13a and 14a in an 82:18 ratio. Further elaboration of 13a led to daunosamine and acosamine. The effects of olefin substitution on the diastereoselectivity of the cycloaddition was also examined.     

Total synthesis of anhydrolycorinone utilizing sequential intramolecular Diels-Alder reactions of a 1,3,4-oxadiazole

A convergent total synthesis of anhydrolycorinone is detailed, enlisting sequential intramolecular Diels-Alder reactions of a suitably substituted 2-amino-1,3,4-oxadiazole defining a novel oxadiazole --> furan --> benzene Diels-Alder strategy.     

Total synthesis of (+/-)-taiwaniaquinol B via a domino intramolecular friedel-crafts acylation/carbonyl alpha-tert-alkylation reaction

The first synthesis of taiwaniaquinol B, a 6-nor-5(6-->7)abeoabietane-type diterpenoid exhibiting the uncommon fused 6-5-6 tricyclic carbon skeleton, was accomplished in 15 steps. A Lewis acid-promoted tandem intramolecular Friedel-Crafts/carbonyl alpha-tert-alkylation reaction was exploited as the core strategy for the synthesis of the sterically congested 1-indanone-containing tricyclic structure. This multiple carbon-carbon bond forming reaction exploits the unique reactivity of Meldrum's acid. The facile precursor synthesis makes this a useful methodology for the expedient modification and assembly of sterically congested 1-indanone-containing ring systems.     

Total synthesis of suaveoline and norsuaveoline via intramolecular oxazole-olefin Diels-Alder reaction

Total synthesis of two Rauwolfia alkaloids, suaveoline (1) and norsuaveoline (2), has been achieved through a highly stereoselective route starting from l-tryptophan methyl ester (9) and exploiting the intramolecular Diels-Alder reaction of the oxazole-olefin 16.     

Total synthesis of Elisabethin A: intramolecular Diels-Alder reaction under biomimetic conditions

We describe the first total synthesis of the marine diterpenoid elisabethin A. The synthesis uses (S)-hydroxy-2-methyl-propionate as the chiral starting material, which is elaborated into a dienyl-iodide and added to an aryl acetic acid ester via enolate alkylation. The hydroquinoid system is oxidized to the quinone which serves as the dienophile in a highly stereocontrolled intramolecular Diels-Alder addition. This IMDA reaction, which to our knowledge is the first one to employ a terminal (Z)-diene, proceeds under biomimetic conditions (water, ferrichloride as the oxidant, room temperature) with high yield and stereoselectivity. The Diels-Alder adduct is transformed into the natural product via a three-step sequence including selective hydrogenation, base-catalyzed epimerization of the cis- into the trans-decalin system and O-demethylation.     

Total synthesis of 6-epiprelactone-V via a syn-selective oxygen tethered intramolecular Michael reaction

The intramolecular protective group (benzylidene acetal) assisted syn-1,3-diol synthesis has been efficiently utilized in a short synthesis of 6-epiprelactone-V starting from (S)-malic acid.     

Total synthesis of (+)-brasilenyne. Application of an intramolecular silicon-assisted cross-coupling reaction

The first enantioselective total synthesis of (+)-brasilenyne (1) has been achieved in 19 linear steps, with 5.1% overall yield from l-(S)-malic acid. The construction of the oxonin core containing a 1,3-cis,cis diene unit was accomplished with a tandem ring-closing metathesis/silicon-assisted intramolecular cross-coupling reaction. In addition, a key propargylic stereogenic center was created through a novel, highly diastereoselective ring opening of a 1,3-dioxolanone promoted by TiCl(4). This reaction proceeded through an oxocarbenium ion intermediate and the asymmetric induction was fully controlled by l-malic acid residue. The C(8) stereogenic center was set by a reagent-controlled asymmetric allylboration.     

Stereoselective synthesis of (−)-gabosine C using a Nozaki-Hiyama-Kishi reaction and RCM

An efficient synthesis of (−)-gabosine C 3 and a formal synthesis of (−)-COTC 4 are described using the Nozaki-Hiyama-Kishi (NHK) reaction and RCM as the key steps.     

Efficient synthesis of isoplagiochin D, a macrocyclic bis(bibenzyls), by utilizing an intramolecular Suzuki-Miyaura reaction

Isoplagiochin D, a highly strained macrocyclic bis(bibenzyls) with two biaryl units isolated from the liverwort Pladiochila fruticosa, was prepared in 10.6% overall yield for the 11 steps by an efficient synthetic approach involving the construction of two bibenzyl and one biaryl units using Horner-Wadsworth-Emmons and Suzuki-Miyaura protocols.     

A novel synthesis of 2-aryl-2H-indazoles via a palladium-catalyzed intramolecular amination reaction

[reaction: see text] A variety of 2-aryl-2H-indazoles were synthesized by the palladium-catalyzed intramolecular amination of the corresponding N-aryl-N(o-bromobenzyl)hydrazines. Of several sets of reaction conditions surveyed, the combination of Pd(OAc)2/dppf/tBuONa gave the best results. This method applies to a wide scope of substrates containing electron-donating and electron-withdrawing substituents.     

Pd-catalyzed intramolecular Heck reaction for the synthesis of 2-methylbenzofurans

A new strategy for the synthesis of 2-Methylbenzofurans via the intramolecular Heck reaction has been developed. This efficient palladium-catalyzed system showed good catalytic activity. Various substituted 2-methylbenzofurans could be afforded in good to excellent yields.     

Total synthesis of Amaryllidaceae alkaloids utilizing sequential intramolecular heterocyclic azadiene Diels-Alder reactions of an unsymmetrical 1,2,4,5-tetrazine

Convergent total syntheses of anhydrolycorinone, hippadine, and anhydrolycorinium chloride are detailed, enlisting sequential inverse electron demand Diels-Alder reactions of an unsymmetrical N-acyl-6-amino-1,2,4,5-tetrazine.     

Total synthesis of the marine alkaloids (-)-lepadins a, b, and c based on stereocontrolled intramolecular acylnitroso-Diels-Alder reaction

The first syntheses of (-)-lepadins A and C, as well as a new synthesis of (-)-lepadin B, have been achieved from commercially available (S)-malic acid. The methodology is based on an intramolecular hetero-Diels--Alder reaction of the acylnitroso compound, affording the bicyclic oxazino lactam with trans selectivity, which was converted to the cis-decahydroquinoline via asymmetric enolate hydroxylation followed by intramolecular aldol cyclization. The total syntheses proceed by employing cis-decahydroquinoline bearing the (E)-iodoalkenyl group as the common key intermediate, which underwent a convergent coupling with the (E)-hexenyl unit via a palladium-catalyzed Suzuki cross-coupling reaction for the elaboration of the octadienyl side chain at the C5 position.     

Total synthesis of Akuammiline alkaloid (-)-vincorine via intramolecular oxidative coupling

An asymmetric total synthesis of the Akuammiline alkaloid (-)-vincorine (18 steps from 5-methoxytryptamine, 5% overall yield) is described. The key steps include Pd-catalyzed direct C-H functionalization of indole derivatives, organocatalyzed asymmetric Michael addition of aldehydes to alkylidene malonates, and intramolecular oxidative coupling between indole and malonate moieties.     

Total synthesis of (-)-kainic acid via intramolecular Michael addition: a second-generation route

A total synthesis of (-)-kainic acid starting from the commercially available 2-azetidinone is described. The key delta-lactone intermediate was concisely prepared from the commercially available azetidinone through the Reformatsky-type reaction and an introduction of a glycine moiety. The construction of the functionalized pyrrolidine ring was executed by a one-pot sequential elimination-Michael addition protocol of a beta-amino-delta-lactone intermediate with high diastereoselectivity.