Stereoselective synthesis of 6/7/6-fused heterocycles with multiple stereocenters via an internal redox reaction/inverse electron-demand hetero-Diels-Alder reaction sequence.

A highly stereoselective synthesis of fused heterocycles with multiple stereocenters via an internal redox reaction/inverse electron-demand hetero-Diels-Alder (IEDHDA) reaction sequence is described. The present reaction sequence has three interesting features: (1) complete control of two potentially competitive processes, i.e., hetero-Diels-Alder reaction and [1,5]-hydride shift; (2) one-shot construction of the complicated 6/7/6-fused heterocyclic structure having multiple stereocenters; and (3) high control of its stereoselectivity. When alkenylidene barbiturates with an allyl benzyl ether moiety were treated with a catalytic amount of Sc(OTf)3 and 2,2'-bipyridine, the internal redox reaction/IEDHDA reaction proceeded successively to afford 6/7/6-fused heterocycles in good chemical yields with good to excellent diastereoselectivities.

Divergent synthesis of multi-substituted phenanthrenes via an internal redox reaction/ring expansion sequence.

We report an effective synthetic route to multi-substituted phenanthrenes via an internal redox reaction/ring expansion sequence. The interesting feature of the present system is that it allows for the divergent synthesis of the target skeleton depending on the selected Lewis acid catalyst. When benzylidene malonates with a cyclic structure at the ortho-position were treated with BF3·OEt2, three sequential processes (internal redox reaction/elimination of the alkoxy group/ring expansion) proceeded to give phenanthrene derivatives in which the alkoxycarbonyl (CO2R) group and the alkyl (R) group were in close proximity to each other, in good chemical yields. In sharp contrast, treatment with Bi(OTf)3 exclusively led to the formation of another type of phenanthrene, whose R group was positioned distal to the CO2R group.

Synthesis of Polysubstituted Naphthalenes by a Hydride Shift Mediated C-H Bond Functionalization/Aromatization Sequence.

A synthetic strategy for forming multisubstituted naphthalenes based on hydride shift mediated C(sp3)-H bond functionalization was developed. This strategy consists of three successive transformations: (1) an intramolecular hydride shift mediated C(sp3)-H bond functionalization; (2) a decarboxylative fragmentation; and (3) an oxidation reaction. When benzylidene malonates having a 2-alkoxyethyl group at the ortho position were treated with a catalytic amount of Al(OTf)3, the hydride shift/cyclization reaction proceeded smoothly to afford tetralin derivatives in good chemical yields. The resulting tetralins were easily converted into naphthalenes by exposing them to modified Krapcho decarboxylation reaction conditions (LiCl, DMSO, and heating under an O2 atmosphere). The one-pot operation of these two reactions was also realized.

Silyl-Group Boosted Internal Redox Reaction: Hydride Shift from an Aliphatic Secondary Position for the Formation of Six- and Seven-Membered Carbocycles.

We report a hydride shift/cyclization reaction at the aliphatic secondary position (methylene group). The key to accomplishing this reaction was the employment of benzylidene malonate having a silyl group ß to the hydride donor carbon. When the corresponding malonates were treated with a catalytic amount of Al(OTf)3, the [1,5]-hydride shift from the simple aliphatic secondary position proceeded smoothly to afford silyl-group substituted tetralin derivatives in excellent chemical yields (up to 98%). This reaction system was applied to the formation of seven-membered carbocycles via the [1,6]-hydride shift mediated process.

Lewis acid-catalyzed formal 1,3-aminomethyl migration.

Here we report a Lewis acid-catalyzed 1,3-aminomethyl migration rection. When δ-amino acid derivatives were treated with a catalytic amount of Sc(OTf)3, 1,3-migration of the aminomethyl group proceeded smoothly to afford ß-amino acid derivatives in moderate to good chemical yields. Detailed investigation suggested that this migration reaction proceeded through the fragmentation/recombination pathway.

Access to ortho-Hydroxyphenyl Ketimines via Imine Anion-Mediated Smiles Rearrangement.

We have achieved a facile access to N-(2-halophenyl)-2-hydroxyphenylimine derivatives via imine anion-mediated Smiles rearrangement. When 2-(2-halophenoxy)benzonitriles were treated with 1.2-1.4 equiv of organolithium reagents, nucleophilic addition to the nitrile group followed by Smiles rearrangement occurred to give various N-(2-halophenyl)-2-hydroxyphenylimine derivatives, which are sometimes difficult to synthesize by the conventional acid-promoted condensation reaction between carbonyl compounds and aniline derivatives, in good to excellent chemical yields (up to 91%).

Divergent Access to Seven/Five-Membered Rings Based on [1,6]-Hydride Shift/Cyclization Process.

We have achieved a divergent access to seven/five-membered rings based on a [1,6]-hydride shift/cyclization process from benzylidenemalonate with an o-alkoxymethyl group. Whereas Yb(OTf)3 afforded benzoxepines (with a seven-membered ring) selectively, indanes (with a five-membered ring) were the main products when Sc(OTf)3 was employed.

Rapid access to 3-indolyl-1-trifluoromethyl-isobenzofurans by hybrid use of Lewis/Brønsted acid catalysts.

We report herein a rapid access to 3-indolyl-1-trifluoromethyl-isobenzofurans via a [1,4]-hydride shift/cyclizatin/intermolecular nucleophilic addition reaction sequence. In this process, a Lewis acid promoted internal redox reaction ([1,4]-hydride shift/cyclization) followed by a Brønsted acid promoted intermolecular reaction (generation of cyclic oxonium cation/intermolecular Friedel-Crafts reaction) occurred to give various 3-indolyl-1-trifluoromethyl-isobenzofurans in good chemical yields.

Highly Stereoselective Synthesis of Fused Tetrahydropyrans via Lewis-Acid-Promoted Double C(sp3)-H Bond Functionalization.

We have achieved a sequential hydride-shift-triggered double C(sp3)-H bond functionalization at a position adjacent to an oxygen atom and a benzylic/aliphatic position through the employment of substrates with a dialkyl group in the alkyl chain, which enabled the highly diastereoselective synthesis of fused tetrahydropyrans.

Genome Mining-Based Discovery of Fungal Macrolides Modified by glycosylphosphatidylinositol (GPI)-Ethanolamine Phosphate Transferase Homologues.

Through genome mining for fungal macrolide natural products, we discovered a characteristic family of putative macrolide biosynthetic gene clusters that contain a glycosylphosphatidylinositol-ethanolamine phosphate transferase (GPI-EPT) homologue. Through the heterologous expression of two clusters from Aspergillus kawachii and Colletotrichum incanum, new macrolides, including those with phosphoethanolamine or phosphocholine moieties, were formed. This study is the first demonstration of the tailoring steps catalyzed by GPI-EPT homologues in natural product biosynthesis, and it uncovers a new gene resource for phospholipid-resembling fungal macrolides.

Expeditious Synthesis of Multisubstituted Quinolinone Derivatives Based on Ring Recombination Strategy.

We achieved a concise construction of 3-substituted quinolinone derivatives based on a ring recombination strategy. In this process, seven transformations involving two types of cyclization proceeded in one pot to afford various quinolinone derivatives in good to excellent chemical yields (up to 98%).

Construction of seven- and eight-membered carbocycles by Lewis acid catalyzed C(sp3)-H bond functionalization.

We achieved a concise construction of seven- and eight-membered carbocycles via Lewis acid catalyzed C(sp3)-H bond functionalization. In these reactions, a quite rare [1,6 (or 7)]-hydride shift/cyclization process proceeded smoothly to afford seven- and eight-membered carbocycles with good chemical yields starting from substrates with high conformational freedom.

Highly Diastereoselective Synthesis of Medium-Sized Carbocycle-Fused Piperidines via Sequential Hydride Shift Triggered Double C(sp3)-H Bond Functionalization.

Herein we report a diastereoselective synthesis of medium-sized carbocycle-fused piperidines via [1,n (n = 6, 7)]-[1,5]-sequential hydride shift triggered double C(sp3)-H bond functionalization. When cinnamylidene malonates having N,N-dibenzyl propylamine moiety were treated with 5 mol % of Yb(OTf)3, a [1,6]-[1,5]-sequential hydride shift/cyclization process proceeded to afford seven-membered carbocycle-fused piperidines with excellent diastereoselectivities. This sequential system was applicable to the synthesis of eight-membered carbocycle-fused piperidines by an unprecedented [1,7]-[1,5]-sequential hydride shift/cyclization process.

The Discovery of Fungal Polyene Macrolides via a Postgenomic Approach Reveals a Polyketide Macrocyclization by trans-Acting Thioesterase in Fungi.

Heterologous expression of a unique biosynthetic gene cluster (BGC) comprising a highly reducing polyketide synthase and stand-alone thioesterase genes in Aspergillus oryzae enabled us to isolate a novel 34-membered polyene macrolide, phaeospelide A (1). This is the first isolation of a fungal polyene macrolide and the first demonstration of fungal aliphatic macrolide biosynthetic machinery. In addition, sequence similarity network analysis demonstrated the existence of a large number of BGCs for novel fungal macrolides.

Diastereoselective Synthesis of CF3-Substituted Spiroisochromans by [1,5]-Hydride Shift/Cyclization/Intramolecular Friedel-Crafts Reaction Sequence.

Developed herein is a diastereoselective synthesis of CF3-substituted spiroisochromans via C(sp3)-H bond functionalization involving sequential transformations ([1,5]-hydride shift/cyclization/elimination of MeOH/intramolecular Friedel-Crafts reaction).

Highly diastereoselective synthesis of tricyclic fused-pyrans by sequential hydride shift mediated double C(sp3)-H bond functionalization.

Described herein is the Brønsted acid-catalyzed double C(sp3)-H bond functionalization of alkyl phenethyl ether derivatives. In this process, a [1,5]-[1,5]-hydride shift occurred successively to afford tricyclic fused pyran derivatives in excellent chemical yields with excellent diastereoselectivities (up to >20 : 1). The key to achieve this reaction was the introduction of two methyl groups at the benzylic position, which was effective in both hydride shift processes: (1) the Thorpe-Ingold effect for the first hydride shift and (2) conformational control in the second hydride shift.

Expeditious synthesis of multisubstituted indoles via multiple hydrogen transfers.

Described herein is the expeditious construction of multi-substituted indole skeletons via multiple hydrogen transfers. When ortho-amino ketoesters were treated with a catalytic amount of TiCl4 in the presence of 1.0 equivalent of dehydrating reagent, three types of hydrogen transfer processes ([1,5]-hydride shift, proton transfer, and [1,2]-hydride shift) occurred to give various 3-alkoxycarbonylindoles. Further study revealed that a [1,2]-alkyl shift instead of a [1,2]-hydride shift proceeded to afford 3-alkylindoles from the substrates with an amino group having tertiary carbons adjacent to a nitrogen atom.

Construction of 1,3-Dithio-Substituted Tetralins by [1,5]-Alkylthio Group Transfer Mediated Skeletal Rearrangement.

A novel skeletal rearrangement involving a [1,5]-alkylthio group transfer/cyclization sequence is described. Treatment of benzylidene malonates having a thioketal moiety at the homobenzyl position with a catalytic amount of Sc(OTf)3 afforded alkylthio group rearranged adducts in good chemical yields. Detailed investigation of the reaction mechanism revealed that an intramolecular conjugate addition/ring opening sequence (not through-space transfer) is the key to achieving this reaction.

Divergent synthesis of CF3-substituted polycyclic skeletons based on control of activation site of acid catalysts.

We report a divergent synthesis of CF3-substituted fused skeletons based on precise control of the activation site through the selection of acid catalysts. When trifluoromethyl ketones with an ortho-phenethyl ether group were treated with a catalytic amount of Sc(OTf)3, a hydride shift triggered C(sp3)-H bond functionalization proceeded to give CF3-substituted isochromene derivatives by selective activation of the carbonyl group. In sharp contrast, CF3-substituted bicyclo[3.3.1]nonanes were obtained exclusively via the activation of ether oxygen initiated sequential reactions (nucleophilic attack of carbonyl oxygen, and intramolecular Friedel-Crafts reaction) under strong Brønsted acid catalysis (Tf2NH).

Chiral Magnesium Bisphosphate-Catalyzed Asymmetric Double C(sp3)-H Bond Functionalization Based on Sequential Hydride Shift/Cyclization Process.

Described herein is a chiral magnesium bisphosphate-catalyzed asymmetric double C(sp3)-H bond functionalization triggered by a sequential hydride shift/cyclization process. This reaction consists of stereoselective domino C(sp3)-H bond functionalization: (1) a highly enantio- and diastereoselective C(sp3)-H bond functionalization by chiral magnesium bisphosphate (first [1,5]-hydride shift), and (2) a highly diastereoselective C(sp3)-H bond functionalization by an achiral catalyst (Yb(OTf)3, second [1,5]-hydride shift).