Electrosynthesis of Dihydropyrano[4,3-b]indoles Based on a Double Oxidative [3+3] Cycloaddition

Oxidative [3+3] cycloadditions offer an efficient route for six-membered-ring formation. This approach has been realized based on an electrochemical oxidative coupling of indoles/enamines with active methylene compounds followed by tandem 6π-electrocyclization leading to the synthesis of dihydropyrano[4,3-b]indoles and 2,3-dihydrofurans. The radical–radical cross-coupling of the radical species generated by anodic oxidation combined with the cathodic generation of the base from O₂ allows for mild reaction conditions for the synthesis of structurally complex heterocycles.     

Assembly of the 6/3/5/6 tetracyclic core of rearranged-type C19-diterpenoid alkaloids

A synthetic study toward the structurally complex rearranged-type C₁₉-diterpenoid alkaloids leading to construction of the strained 6/3/5/6 tetracyclic core is presented. The synthesis features an intramolecular Diels–Alder cycloaddition reaction to assemble the highly substituted central cyclopropane motif, which may serve as a key strategy for the total synthesis of relevant natural product molecules.     

Electrosynthesis of Dihydropyrano[4,3‐b]indoles Based on a Double Oxidative [3+3] Cycloaddition

Oxidative [3+3] cycloadditions offer an efficient route for six‐membered‐ring formation. This approach has been realized based on an electrochemical oxidative coupling of indoles/enamines with active methylene compounds followed by tandem 6π‐electrocyclization leading to the synthesis of dihydropyrano[4,3‐b]indoles and 2,3‐dihydrofurans. The radical–radical cross‐coupling of the radical species generated by anodic oxidation combined with the cathodic generation of the base from O₂ allows for mild reaction conditions for the synthesis of structurally complex heterocycles.     

Diversity-oriented regioselective domino Michael/Aldol reaction of 3-ylideneoxindoles: A direct access to indanol-fused 3-oxindoles

A diversity-oriented molecular hybridization strategy has been utilized for the synthesis of 2,3-disubstituted 1-indanol-fused 3-oxindoles through a regioselective domino Michael/Aldol reaction of 3-ylideneoxindoles 1 with malononitrile or cyanacetate ethyle 2. Products bearing consecutive stereocenters consist of an oxindole moiety and an indanol core, were smoothly obtained in high yields (up to 92% yield) with good diastereoselectivity (up to 20:1). This protocol also represents the first construction of indanol-fused 3-oxindole scaffolds, thus leading to new knowledge in the fields of both molecular complexity and diversity-oriented synthesis (DOS) and the lead compound discovery. It is also worth mentioning that the reaction was completely regioselective and the competitive regioisomeric products 4 or 5 were not obtained in any case.     

1,2-Dibromoalkanes into alkynes by elimination reaction under DBU conditions and their application to total synthesis of sapinofuranone B

Treatment of 1,2-dibromoalkanes with DBU effected an elimination reaction, leading to the alkynes. Oxygen substitution at the C3 position plays a critical role to abstract protons by inductive effects. By the application of this protocol, a total synthesis of sapinofuranone B 4 was accomplished.     

Divergent Total Syntheses of (−)‐Daphnilongeranin B and (−)‐Daphenylline

(?)‐Daphnilongeranin B and (?)‐daphenylline are two hexacyclic Daphniphyllum alkaloids, each containing a complex cagelike backbone. Described herein are the first asymmetric total synthesis of (?)‐daphnilongeranin B and a bioinspired synthesis of (?)‐daphenylline with an unusual E ring embedded in a cagelike framework. The key features include an intermolecular [3+2] cycloaddition, a late‐stage aldol cyclization to install the F ring of daphnilongeranin B, and a bioinspired cationic rearrangement leading to the tetrasubstituted benzene ring of daphenylline.     

Total synthesis of (-)-gambierol

The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved. Key features of the successful synthesis include (1) a convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive triene side chain by use of Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille coupling. The ABC ring fragment 5 was synthesized in a linear manner (B --> AB --> ABC), wherein the A ring was formed by intramolecular hetero-Michael reaction and the C ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved synthetic entry to the EFGH ring fragment 6 is also described, in which SmI(2)-induced reductive cyclization methodology was applied to the stereoselective construction of the F and H rings, leading to 6 with remarkable overall efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura coupling with 6 provided endocyclic enol ether 45 in high yield, which was then converted to octacyclic polyether core 4. Careful choice of the global deprotection stage was a key element for the successful total synthesis. Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2. Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (-)-gambierol (1).     

Concise and Enantioselective Total Synthesis of (−)‐Mehranine, (−)‐Methylenebismehranine,and Related Aspidosperma Alkaloids

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (?)‐mehranine and (+)‐(6S,7S)‐dihydroxy‐N‐methylaspidospermidine. A late‐stage dimerization of (?)‐mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (?)‐methylenebismehranine.     

Stereoselective synthesis of (−)-ara-cyclohexenyl-adenine

A stereoselective synthesis leading to (−)-ara-cyclohexenyl-adenine is described. The synthesis starts from methyl-α-d-glucopyranose and involves an isomerization step, selective protection/deprotection chemistry, a Ferrier rearrangement and a Mitsunobu reaction. This is the first total synthesis of an enantiomeric pure ara-type cyclohexenyl nucleoside.     

PhI(OAc)2 and BF3–OEt2 mediated heterocyclization: metal-free synthesis of pyrimidine-annulated oxazolines

A simple high yielding and highly efficient synthesis of oxazoline ring fused with uracil moiety is reported. Hypervalent iodine (PIDA) in the presence of BF₃–OEt₂ generates an effective electrophile to activate uracil C5–C6 double bond leading to heterocyclization.     

Total synthesis of (+)-zaragozic acid C

A total synthesis of (+)-zaragozic acid C is described. Key features of the synthesis are the use of a double Sharpless asymmetric dihydroxylation reaction of diene 6 to control stereochemistry at four contiguous stereocenters from C3 to C6; the introduction of the C1-side chain by reaction between the anion derived from the dithiane monosulfoxide 27 and the core aldehyde 12; a high yielding, acid-mediated simultaneous acetonide deprotection-dithiane removal-ketalization procedure leading exclusively to the 2, 8-dioxabicyclo[3.2.1]octane core 34; and a novel triple oxidation procedure allowing installation of the tricarboxylic acid.     

The first total synthesis and structural determination of epi-cochlioquinone A

The first total synthesis of epi-cochlioquinone A has been achieved in a highly convergent manner via [3+3] cycloaddition of catechol 2 and oxadecalin 3 as the key reaction. The synthesis of the catechol segment, possessing the side chain with multi stereogenic centers, features the asymmetric vinylogous Mukaiyama aldol reaction, the stereoselective conjugate addition to the nitroalkene, the stereospecific nitro-Dieckmann condensation, and the transformation of 6-nitrocyclohex-2-enone into catechol 2, using two new methodologies, such as (i) the hydrogen-transfer reaction to o-aminophenol and the subsequent auto-redox-catalysis to catechol and (ii) the direct oxidation of 6-nitrocyclohex-2-enone to o-quinone and the subsequent reduction. The oxadecalin segment was synthesized from a glycosyl cyanide by the [3+3] annulation with a ketone and an acetoacetate. These segments were connected by the [3+3] cyclization, and the resulting tetracyclic compound was subjected to a specific oxidation of the protected hydroquinone to provide epi-cochlioquinone A.     

Total synthesis of (+)-phorboxazole A exploiting the Petasis-Ferrier rearrangement.

A highly convergent, stereocontrolled total synthesis of the potent antiproliferative agent (+)-phorboxazole A (1) has been achieved. Highlights of the synthesis include: modified Petasis-Ferrier rearrangements for assembly of both the C(11-15) and C(22-26) cis-tetrahydropyran rings; extension of the Julia olefination to the synthesis of enol ethers; the design, synthesis, and application of a novel bifunctional oxazole linchpin; and Stille coupling of a C(28) trimethyl stannane with a C(29) oxazole triflate. The longest linear sequence leading to (+)-phorboxazole A (1) was 27 steps, with an overall yield of 3%.     

Total Synthesis of (3S, 6S)- ( )-3,7-Dimethyl-3-acetoxy-6-hydroxy-octa-1,7-diene

CompoundI',anovelmonoterpenoid,wasisolatedfromMulisiaspinosa(Compositae).Thestructureofl,determinedbyspectroscopictechniques,correspondedto3,7dimethyl-3-acetoxy-6-hydroxy-cotl,7-diene(thenameof6-hydroxy-7(9)-dehydro-6,7dihydronerylacetateinreferenceIisuncorrect).HowevertheabsoluteconfigurationsatC-3andC-6werenotdetermined.CompoundIwassynthesizedbyphotooxidationoflinalylacetate=,howevertheauthorsobtainedtheisomermixtureof1.Hereinwereportthetotalsynthesisof(3S,6S)-( )-1fromgeraniol2throughsi…     

Preparation of 3-hydroxyoxindoles with dimethyldioxirane and their use for the synthesis of natural products

This work describes a general protocol for the oxidation of indole and oxindole derivatives with dimethyldioxirane to give 3-hydroxyoxindoles present in many natural products. This strategy allowed us to synthesize the natural product 1, to carry out the first total synthesis of 4, a formal total synthesis of donaxaridine (5) and to achieve the synthesis of pyrroloindoline 8, a debromo analogue of the natural product flustraminol B (7).     

Diverted total synthesis of melodorinol analogues and evaluation of their cytotoxicity

A series of melodorinol analogues were synthesized via a diverted total synthesis approach, leading to structural modifications on several regions of the molecule. Their cytotoxicity was evaluated against five human cancer cell lines (KB, HeLa-S3, MCF-7, HT-29 and A549). Structure-activity relationship studies revealed key parameters that affect the cytotoxicity. In particular, the novel 4-bromo-furanone analogues exhibited greater cytotoxicity compared to the corresponding non-brominated analogues. The stereochemistry at C-6 and the nature of acyl substituents on the C-6 and C-7 hydroxyl groups also play an important role. The most potent analogues exhibit approximately 15-fold higher cytotoxicity towards KB and HeLa-S3 than melodorinol and also show exceptionally high potency against MCF-7, HT-29 and A549 cell lines.     

Discovery through total synthesis: a retrospective on the himastatin problem

A total synthesis of a structure proposed for himastatin was accomplished. The non-identity of the fully synthetic material with himastatin necessitated a revision of the assigned structure. Confirmation of the revised stereostructure was subsequently confirmed through total synthesis. Among the achievements during this effort were i) stereospecific routes to both anti-cis and syn-cis pyrrolindoline substructures; ii) a practical synthesis to 5-hydroxypiperazic acid in enantiomerically pure form; iii) a Stille coupling leading to a complex bi-indole moiety, and iv) efficient protecting group management throughout the evolving depsipeptide domain. The outlines for a biological pharmacophore have been delineated. The alternating D- and L-substituents in the 6-mer as well as the biaryl linkage connecting the two identical subunits are critical for maintaining biological activity. This pattern is simulated in another antibiotic, and suggests a possible structural trend for future SAR investigations.     

TBAI-mediated regioselective sulfenylation of indoles with sulfonyl chlorides in one pot

A versatile method for the synthesis of 3-sulfenylated indoles via TBAI promoted sulfenylation of indoles with sulfonyl chlorides in one pot has been presented. This system features highly regioselective, metal-free, easy operation, and shows a broad functional group tolerance leading to excellent yields. And this reaction could be easily conducted in 10?mmol scale with high effectivity. A plausible mechanism is proposed.     

A Highly Convergent Synthesis of 2‐Phenyl Quinoline as Dual Antagonists for NK2 and NK3 Receptors

A novel and highly convergent synthesis leading to 2‐phenyl‐quinolines has been developed. As demonstrated in the preparation of 6‐fluoro‐3‐(3‐oxo‐piperazin‐1‐ylmethyl)‐2‐phenyl‐quinoline‐4‐carboxylic acid [(S)‐1‐cyclohexyl‐ethyl]‐amide (8), the method provides fascile access to this class of analogues via the common intermediate 7.     

Total synthesis of curvulone B and a proposed structure for dothiorelone B; determination of the configuration of curvulone B and structural revision of phomopsin A

The total synthesis of curvulone B was achieved, and its absolute configuration unambiguously established, as had been determined by TD-DFT ECD calculations on the computed solution conformers. Key features of the synthesis were an olefin cross-metathesis of an α,β-unsaturated ketone as a common key building block with (R)-6-triethylsilyloxyhept-1-ene, and an intramolecular oxy-Michael addition of the hydroxyl enone obtained therefrom. An intermolecular metathesis of the enone with (S)-5-benzyloxyhept-ene also enabled us to prepare a proposed structure for dothiorelone B, thus leading to the confirmation of the structural revision of phomopsin A, a novel nine-membered cyclic phenol ether.