Toward Efficient and Stereoselective Aromatic and Dearomative Cope Rearrangements: Experimental and Theoretical Investigations of α-Allyl-α'-Aromatic γ-Lactone Derivatives.

The aromatic Cope rearrangement is an elusive transformation that has been the subject of a limited number of investigations compared to those seemingly close analogues, namely the Cope and aromatic Claisen rearrangement. Herein we report our investigations inspired by moderate success observed in the course of pioneering works. By careful experimental and theoretical investigations, we demonstrate that key substitutions on 1,5-hexadiene scaffold allow fruitful transformations. Especially, efficient functionalisation of the heteroaromatic rings results from the aromatic Cope rearrangement, while highly stereoselective interrupted aromatic Cope rearrangements highlight the formation of chiral compounds through a dearomative process.

Divergent and Nucleophile-Assisted Rearrangement in the Construction of Pyrrolo[2,1-b][3]benzazepine and Pyrido[2,1-a]isoquinoline Scaffolds.

Under microwave (MW) irradiation at 150 °C in toluene and in the presence of nucleophiles (DMAP, triphenylphosphine and tetrahydrothiophene) 1-substituted 1-ethynyl-2-vinyldi- and tetrahydroisoquinolines undergo [3,3]-sigmatropic rearrangement providing pyrrolo[2,1-b][3]benzazepines in good yields. The replacement of toluene with acetonitrile directs the rearrangement towards the formation of 7,11b-dihydro-6H-pyrido[2,1-a]isoquinolines.

Design, synthesis and evaluation of bioactivity of peptidomimetics based on chloroalkene dipeptide isosteres.

Ample biologically active peptides have been found, identified and modified for use in drug discovery to date. However, several factors, such as low metabolic stability due to proteolysis and non-specific interactions with multiple off-target molecules, might limit the therapeutic use of peptides. To enhance the stability and/or bioactivity of peptides, the development of "peptidomimetics," which mimick peptide molecules, is considered to be idealistic. Hence, chloroalkene dipeptide isosteres (CADIs) was designed, and their synthetic methods have been developed by us. Briefly, in a CADI an amide bond in peptides is replaced with a chloroalkene structure. CADIs might be superior mimetics of amide bonds because the Van der Waals radii (VDR) and the electronegativity value of a chlorine atom are close to those of the replaced oxygen atom. By a developed method of the "liner synthesis", N-tert-butylsulfonyl protected CADIs can be synthesized via a key reaction involving diastereoselective allylic alkylation using organocopper reagents. On the other hand, by a developed method of the "convergent synthesis", N-fluorenylmethoxycarbonyl (Fmoc)-protected carboxylic acids can be also constructed based on N- and C-terminal analogues from corresponding amino acid starting materials via an Evans syn aldol reaction and the Ichikawa allylcyanate rearrangement reaction involving a [3.3] sigmatropic rearrangement. Notably, CADIs can also be applied for Fmoc-based solid-phase peptide synthesis and therefore introduced into bioactive peptides including as the Arg-Gly-Asp (RGD) peptide and the amyloid ß fragment Lys-Leu-Val-Phe-Phe (KLVFF) peptide, which are correlated with cell attachment and Alzheimer's disease (AD), respectively. These CADI-containing peptidomimetics stabilized the conformation and enhanced the potency of the cyclic RGD peptide and the cyclic KLVFF peptide.

Concise and Free-Metal Access to Lactone-Annelated Pyrrolo[2,1-a]isoquinoline Derivatives via a 1,2-Rearrangement Step.

Here, An efficient approach to obtaining previously unknown furo[2',3':2,3]pyrrolo[2,1-a]isoquinoline derivatives from readily available 1-R-1-ethynyl-2-vinylisoquinolines is described. The reaction features a simple procedure, occurs in hexaflouroisopropanol and does not require elevated temperatures. It has been found that the addition of glacial acetic acid significantly increases the yields of the target spirolactone products. Using trifluoroethanol instead of hexaflouroisopropanol results in the formation of pyrido[2,1-a]isoquinolines.

Stereoselective Synthesis of Polysubstituted Conjugated Dienes Enabled by Photo-Driven Sequential Sigmatropic Rearrangement.

We here reported a highly stereoselective method for the synthesis of polysubstituted conjugated dienes from α-aryl α-diazo alkynyl ketones and pyrazole-substituted unsymmetric aminals under mild conditions, which was promoted by photo-irridation and involved with 1,6-dipolar intermediate and quadruple sigmatropic rearrangements, was successfully developed. In this transformation, the cleavage of four bonds and the recombination of five bonds were implemented in one operational step. This protocol provided a modular tool for constructing dienes from amines, pyrazoles and α-alkynyl-α-diazoketones in one-pot manner. The results of mechanistic investigation indicated that the plausible reaction path underwent the 1,6-sigmatropic rearrangement instead of the 1,5-sigmatropic rearrangement.

Mechanistic Study on Selenium- and Sulfur-Mediated Isomerization of Hydroxamic Acids.

An in-depth computational study reveals the intriguing mechanism of the recently reported isomerization of hydroxamic acids into para-aminophenols catalyzed by phenylselenyl bromide under mild conditions. The computations not only align with the reported experimental data, effectively explaining observed phenomena such as para-selectivity but also shed light on crucial aspects of the reaction mechanism that establish limitations on the scope of the studied rearrangement. Additionally, a joint theoretical/experimental study was performed to examine the potency of the phenylsulfenyl bromide to mediate the reaction under the same conditions.

Reductive Asymmetric Aza-Mislow-Evans Rearrangement by 1,3,2-Diazaphospholene Catalysis.

1,3,2-diazaphospholene hydrides (DAP-H) enable smooth conjugate reduction of polarized double bonds. The transiently formed phosphorus-enolate provides a potential platform for reductive α-functionalizations. In this respect, asymmetric C-heteroatom bond forming processes are synthetically appealing but remain elusive. We report a 1,3,2-diazaphospholene-catalyzed three-step cascade reaction of N-sulfinyl acrylamides comprised of conjugate reduction, [2,3]-sigmatropic aza-Mislow-Evans rearrangement and subsequent S-O bond cleavage. The obtained enantio-enriched α-hydroxy amides are formed in good yields and excellent enantiospecificity. The stereo-defined P-bound N,O-ketene aminal ensures an excellent transfer of chirality from the sulfur stereocenter to α-carbon. The transformation operates under mild conditions at ambient temperature. Moreover, DAP-H is a competent reductant for the cleavage of formed sulfenate ester, eliminating the extra step in traditional Mislow-Evans processes.

Copper-Catalyzed Enantioselective Doyle-Kirmse Reaction of Azide-Ynamides via α-Imino Copper Carbenes.

[2,3]-Sigmatropic rearrangement reaction involving sulfonium ylide (Doyle-Kirmse reaction) generated from metal carbenes represents one of the powerful methods for the construction of C(sp3 )-S and C-C bonds. Although significant advances have been achieved, the asymmetric versions via the generation of sulfonium ylides from metal carbenes have been rarely reported to date, and they have so far been limited to diazo compounds as metal carbene precursors. Here, we describe a copper-catalyzed enantioselective Doyle-Kirmse reaction via azide-ynamide cyclization, leading to the practical and divergent assembly of an array of chiral [1,4]thiazino[3,2-b]indoles bearing a quaternary carbon stereocenter in generally moderate to excellent yields and excellent enantioselectivities. Importantly, this protocol represents a unique catalytic asymmetric Doyle-Kirmse reaction via a non-diazo approach and an unprecedented asymmetric [2,3]-sigmatropic rearrangement via α-imino metal carbenes.

Asymmetric Catalytic Ring-Expansion of 3-Methyleneazetidines with α-Diazo Pyrazoamides towards Proline-Derivatives.

We realized a highly efficient formal [1,2]-sigmatropic rearrangement of ammonium ylides generated from 3-methylene-azetidines and α-diazo pyrazoamides. The employ of readily available chiral cobalt(II) complex of chiral N,N'-dioxide enabled the ring-expansion of azetidines, affording a variety of quaternary prolineamide derivatives with excellent yield (up to 99 %) and enantioselectivity (up to 99 % ee) under mild reaction condition. For the rearrangement of ammonium ylides, the installation of a pyrazoamide group as a masked brick to build chiral scaffolds proved successful. The enantioselective ring expansion process was elucidated by DFT calculations.

Sulfonium-aided coupling of aromatic rings via sigmatropic rearrangement.

Biaryl synthesis continues to occupy a central role in chemical synthesis. From blockbuster drug molecules to organic electronics, biaryls present numerous possibilities and new applications continue to emerge. Transition-metal-catalyzed coupling reactions represent the gold standard for biaryl synthesis and the mechanistic steps, such as reductive elimination, are well established. Developing routes that exploit alternative mechanistic scenarios could give unprecedented biaryl structures and expand the portfolio of biaryl applications. We have developed metal-free C-H/C-H couplings of aryl sulfoxides with phenols to afford 2-hydroxy-2'-sulfanylbiaryls. This cascade strategy consists of an interrupted Pummerer reaction and [3,3] sigmatropic rearrangement. Our method enables the synthesis of intriguing aromatic molecules, including oligoarenes, enantioenriched dihetero[8]helicenes, and polyfluorobiaryls. From our successes in aryl sulfoxide/phenol couplings and a deeper understanding of sigmatropic rearrangements for biaryl synthesis, we have established related methods, such as aryl sulfoxide/aniline and aryl iodane/phenol couplings. Overall, our fundamental interests in underexplored reaction mechanisms have led to various methods for accessing important biaryl architectures.

Expeditious and Efficient ortho-Selective Trifluoromethane-sulfonylation of Arylhydroxylamines.

A metal- and oxidant-free, practical and efficient method for the synthesis of highly versatile and synthetically useful ortho-trifluoromethanesulfonylated anilines from arylhydroxylamines and trifluoromethanesulfinic chloride was developed. This rapid transformation proceeded smoothly with good yields and excellent ortho-selectivity in the absence of any metals or ligands. Mechanistically, the reaction comprised a noncanonical O-trifluoromethanesulfinylation of the arylhydroxylamine, and the subsequent [2,3]-sigmatropic rearrangement to afford ortho-trifluoromethanesulfonylated aniline derivatives. The practical application of this reaction was demonstrated by further conversion into a series of functional molecules under different reaction conditions.

Sigmatropic [1,5] Carbon Shift of Transient C3 Ammonium Enolates.

The stereospecific sigmatropic [1,5] carbon shift of C3 ammonium enolates is discovered. According to mechanistic, kinetic and computational experiments, this new rearrangement proceeds via the catalytic generation of a transient C3 ammonium enolate by intramolecular aza-Michael addition. This intermediate rapidly undergoes [1,5] sigmatropic carbon migration to furnish the respective tetrahydroquinoline-4-ones with excellent diastereoselectivities of d.r. >99 : 1 and in 61-98 % yield.

Aryne 1,4-Disubstitution and Remote Diastereoselective 1,2,4-Trisubstitution via a Nucleophilic Annulation-[5,5]-Sigmatropic Rearrangement Process.

Both aryne 1,4-disubstitution and 1,2,4-trifunctionalization were accomplished from tertiary amines bearing a penta-2,4-dien-1-yl moiety. These transformations could directly incorporate a C-N and a C-C bond para to each other on an aryne intermediate via a sequential nucleophilic addition and [5,5]-sigmatropic rearrangement. When arynes bearing 3-tethered electrophiles were employed, a cascade regioselective nucleophilic addition, intramolecular cyclization, and remote diastereoselective [5,5]-sigmatropic rearrangement process was observed. Our density functional theory (DFT) calculations revealed that hydrogen-bonding interactions between two C-H hydrogens on the penta-2,4-dien-1-yl chain and the oxygen anion generated upon N-nucleophilic annulation reaction in the [5,5]-sigmatropic rearrangement step is responsible for the remote diastereoselective control in this reaction system.

Mechanistic Investigation of a Synthetic Route to Biaryls by the Sigmatropic Rearrangement of Arylsulfonium Species.

A comprehensive mechanistic investigation was conducted on the coupling reaction of aryl sulfoxides with phenols by using trifluoroacetic anhydride to yield biaryls. NMR experiments revealed that our previously proposed mechanism, which consists of a cascade of an interrupted Pummerer reaction and a rate-determining [3,3] sigmatropic rearrangement, is reasonable. The electronic effects of the substrates were also evaluated to elucidate the nature of the rearrangement step. Based on experimental observations and theoretical calculations, we conclude that the rearrangement is highly asynchronous and stepwise rather than concerted when electron-rich phenols are employed for the reaction.

Copper-Catalyzed Synthesis of Axially Chiral Biaryls with Diaryliodonium Salts as Arylation Reagents.

NOBIN and BINAM derivatives harboring biaryl frameworks are recognized as a class of important atropisomers with versatile applications. Here, we present an efficient synthetic route to access such compounds through copper-catalyzed domino arylation of N-arylhydroxylamines or N-arylhydrazines with diaryliodonium salts and [3,3]-sigmatropic rearrangement. This reaction features mild conditions, good substrate compatibility, and excellent efficiency. The practicality of this protocol was further extended by the synthesis of biaryl amino alcohols.

Asymmetric Total Syntheses of 8,9-Seco-ent-kaurane Diterpenoids Enabled by an Electrochemical ODI-[5+2] Cascade.

An electrochemical ODI-[5+2] cascade reaction was developed which enables the rapid assembly of diversely functionalized bicyclo[3.2.1]octadienones from sensitive ethynylphenols. By combining a directed retro-aldol/aldol process, a [2,3]-sigmatropic rearrangement, and an Al(O-iPr)3 -promoted reductive 1,3-transposition, the asymmetric total syntheses of five 8,9-seco-ent-kauranoids-(-)-shikoccin, (-)-O-methylshikoccin, (-)-epoxyshikoccin, (+)-O-methylepoxyshikoccin, and (+)-rabdo-hakusin-have been achieved in a concise and efficient manner.

Seven-Step Synthesis of All-Nitrogenated Sugar Derivatives Using Sequential Overman Rearrangements.

All-nitrogenated sugars (ANSs), in which all hydroxy groups in a carbohydrate are replaced with amino groups, are anticipated to be privileged structures with useful biological activities. However, ANS synthesis has been challenging due to the difficulty in the installation of multi-amino groups. We report herein the development of a concise synthetic route to peracetylated ANSs in seven steps from commercially available monosaccharides. The key to success is the use of the sequential Overman rearrangement, which enables formal simultaneous substitution of four or five hydroxy groups in monosaccharides with amino groups. A variety of ANSs are available through the same reaction sequence starting from different initial monosaccharides by chirality transfer of secondary alcohols. Transformations of the resulting peracetylated ANSs such as glycosylation and deacetylation are also demonstrated. Biological studies reveal that ANS-modified cholesterol show cytotoxicity against human cancer cell lines, whereas each ANS and cholesterol have no cytotoxicity.

Nitrone and Alkyne Cascade Reactions for Regio- and Diastereoselective 1-Pyrroline Synthesis.

The synthesis of 1-pyrrolines from N-alkenylnitrones and alkynes has been explored as a retrosynthetic alternative to traditional approaches. These cascade reactions are formal [4+1] cycloadditions that proceed through a proposed dipolar cycloaddition and N-alkenylisoxazoline [3,3']-sigmatropic rearrangement. A variety of cyclic alkynes and terminal alkynes have been shown to undergo the transformation with N-alkenylnitrones under mild conditions to provide the corresponding spirocyclic and densely substituted 1-pyrrolines with high regio- and diastereoselectivity. Mechanistic studies provide insight into the balance of steric and electronic effects that promote the cascade process and control the diastereo- and regioisomeric preferences of the 1-pyrroline products. Diastereoselective derivatization of the 1-pyrrolines prepared by the cascade reaction demonstrate the divergent synthetic utility of the new method.

C-F Arylation of Polyfluorophenols by Means of Sigmatropic Dearomatization/Defluorination Sequence.

Selective C-F arylation of polyfluorophenols with aryl sulfoxides has been accomplished by means of a sigmatropic dearomatization/defluorination sequence. This sequence consists of three processes: 1) interrupted Pummerer reaction to form S-O-tethered sulfonium salt; 2) C-C-forming [3,3] sigmatropic rearrangement with dearomatization; and 3) Zn-mediated defluorinative rearomatization. The present biaryl construction provides a facile access to polyfluorinated biaryls that is difficult to synthesize by other methods. The synthetic utility of the strategy is clearly demonstrated by the synthesis of a fluorinated analogue of Maxipost, a potassium channel modulator.

Construction of Biaryls from Aryl Sulfoxides and Anilines by Means of a Sigmatropic Rearrangement.

An unprecedented S-N variant of the benzidine rearrangement for construction of biaryls has been developed. Aryl sulfoxides underwent dehydrogenative coupling with anilines by successive treatment with trifluoromethanesulfonic anhydride and trifluoromethanesulfonic acid to provide the corresponding 2-amino-2'-sulfanyl- and/or 4-amino-4'-sulfanylbiphenyls. Mechanistic studies indicate that the C-C-bond-forming sigmatropic rearrangement proceeds intramolecularly from dicationic S-N-tethered species.