Tandem retro-aldol/Wittig/Michael and related cascade processes

A number of novel tandem sequences initiated by a retro-aldol process are described along with preliminary scope and limitation studies. These include (i) retro-aldol/Wittig trapping/intramolecular Michael addition, (ii) retro-aldol/aza-Wittig/intramolecular imine addition, (iii) retro-aldol/Henry/intramolecular Michael addition and (iv) retro-aldol/Knoevenagel/intramolecular Michael addition sequences. A range of novel functionalised cyclopentanes, and related systems, are described which should prove to be useful synthetic building blocks.     

Trimethylsilylated N-alkyl-substituted carbamates : III. Structure of trimethylsilyl-N,N-diisopropyl carbamate in solid phase and in solution

The conformers of trimethylsilyl-N,N-diisopropyl carbamate were studied by ¹H NMR spectroscopy. The barriers to rotation by isopropyl groups and to the rotation around the amide bond, and the population of the conformers were determined from the coalescence temperature of the methyne signal. Single crystal X-ray diffraction studies revealed that the crystal had formed from preferred conformer in solution. The mirror symmetric conformer is stabilized by an intramolecular C---H O hydrogen bond and by an intramolecular O Si donor-acceptor interaction.     

Kinetics and Equilibria of the Thiol/Disulfide Exchange Reactions of Somatostatin with Glutathione

Rate and equilibrium constants are reported for the thiol/disulfide exchange reactions of the peptide hormone somatostatin with glutathione (GSH). GSH reacts with the disulfide bond of somatostatin to form somatostatin-glutathione mixed disulfides (Cys(3)-SH, Cys(14)-SSG and Cys(3)-SSG, Cys(14)-SH), each of which can react with another molecule of GSH to give the reduced dithiol form of somatostatin and GSSG. The mixed disulfides also can undergo intramolecular thiol/disulfide exchange reactions to re-form the disulfide bond of somatostatin or to interconvert to the other mixed disulfide. Analysis of the forward and reverse rate constants indicates that, at physiological concentrations of GSH, the intramolecular thiol/disulfide exchange reactions that re-form the disulfide bond of somatostatin are much faster than reaction of the mixed disulfides with another molecule of GSH, even though the intramolecular reaction involves closure of a 38-membered ring. Thus, even though the disulfide bond of somatostatin is readily cleaved by thiol/disulfide exchange, it is rapidly reformed by intramolecular thiol/disulfide exchange reactions of the somatostatin-glutathione mixed disulfides. By comparison with rate constants reported for analogous reactions of model peptides measured under random coil conditions, it is concluded that disulfide bond formation by intramolecular thiol/disulfide exchange in the somatostatin-glutathione mixed disulfides is not completely random, but rather it is directed to some extent by conformational properties of the mixed disulfides that place the thiol and mixed disulfide groups in close proximity. A reduction potential of -0.221 V was calculated for the disulfide bond of somatostatin from the thiol/disulfide exchange equilibrium constant.     

Construction of the A/B/C core of mexicanolides via a tandem double-aldol reaction

An efficient and concise approach for rapid assembly of the ABC tricyclic carbon skeleton of mexicanolide-type limonoids is described. The acetal/ketal diketoester precursors were prepared from simple starting materials by LiOH-mediated Michael reactions. The ABC tricyclic skeleton bearing multiple stereogenic centers was efficiently constructed by a powerful one-pot cascade reaction, which includes acetal/ketal hydrolysis, double intramolecular aldol condensation, and alkene migration.     

Cationic Iridium/Chiral Bisphosphine‐Catalyzed Enantioselective Hydroacylation of Ketones

A facile and convenient synthesis of the chiral phthalide framework catalyzed by cationic iridium was developed. The method utilized cationic iridium/bisphosphine‐catalyzed asymmetric intramolecular carbonyl hydroacylation of 2‐keto benzaldehydes to furnish the corresponding optically active phthalide products in good to excellent enantioselectivities (up to 98% ee). The mechanistic studies using a deuterium‐labelled substrate suggested that the reaction involved an intramolecular carbonyl insertion mechanism to iridium hydride intermediate. In addition, we investigated the kinetic isotope effect (KIE) of intramolecular hydroacylation with deuterated substrate and determined that the C?H activation step is not included in the turnover‐limiting step.     

Tandem intramolecular Diels–Alder/retro-Diels–Alder cycloaddition of 2H-chromen-2-one as dienes with the expulsion of CO_2

To study the intramolecular Diels-Alder cycloadditon of 2H-chromen-2-one as a diene, a series of chiral N-allyl-N-benzylamides that contain a 2H-chromen-2-one moiety were designed for the synthesis of benzo[f]isoindol-1-ones via an intramolecular Diels-Alder and a subsequent retro-Diels-Alder cycloaddition with the expulsion of CO₂. Both the yield (80%-89%) and absolute stereocontrol of the tandem reaction were high when an electron-withdrawing group was attached to the dienophile. The double bond in the styrene substructure remained in the products could be further derivatized by dihydroxylation.     

Total synthesis of (+/-)-strychnine via a [4 + 2]-cycloaddition/rearrangement cascade

A new strategy for the synthesis of the Strychnos alkaloid (+/-)-strychnine has been developed and is based on an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran. The critical D-ring was assembled by an intramolecular palladium-catalyzed enolate-driven cross-coupling of an N-tethered vinyl iodide. [reaction: see text].     

Synthesis of fused imidazo-pyridine and -azepine derivatives by sequential van Leusen/Heck reactions

Fused imidazo-pyridine and -azepine derivatives were synthesized using a sequential van Leusen/intramolecular Heck protocol. The combination of a multicomponent reaction followed by an intramolecular carbon-carbon bond forming reaction generates heterocycles of significant molecular complexity from readily available starting materials in just two steps.     

Synthesis of polycyclic molecules by double C(sp2)-H/C(sp3)-H arylations with a single palladium catalyst

Polycyclic molecules were obtained in good yields by double C(sp(2))-H/C(sp(3))-H arylations mediated by a single palladium/phosphine catalyst. Both double intermolecular/intramolecular and intramolecular/intramolecular C-C couplings were performed successfully, which indicates that this concept has a broad applicability for the rapid construction of molecular complexity.     

Efficient synthesis of the C/D rings of atisine-type C20-diterpenoid alkaloids

A bicyclo[2.2.2]octane C/D ring system,with a lactonic ring at C-8 and C-9,of the atisine-type C₂₀-diterpenoid alkaloids,was successfully synthesized,using an oxidative dearomatization/intramolecular Diels-Alder reaction.     

Construction of novel spiroisoxazolines via intramolecular cyclization/methylation

Improved yields for the syntheses of a variety of spiroisoxazolines were achieved through intramolecular cyclization/methylation reactions of functionalized 5,5-disubstituted isoxazolines in one reaction vessel. Aromatic ring containing nitrile oxides and disubstituted geminal alkenes reacted in a 1,3-dipolar fashion to afford the corresponding 5,5-isoxazoline. A comparison of the relative location of the nucleophile and electrophile on the isoxazoline and two different ester functional groups was performed in order to determine the best isoxazoline system for the intramolecular cyclization/methylation reaction.     

Efficient Synthesis of Quinolines via a Knoevenagel/Staudinger/aza-Wittig Sequence

A simple and efficient method for the construction of quinoline derivatives from 2-azidobenzaldehyde and various carbonyl compounds was developed. The process involves a Knoevenagel condensation of 2-azidobenzaldehyde with carbonyl compound and subsequently an intramolecular normal Staudinger/aza-Wittig reaction to form the quinolone ring in satisfactory yields.     

Intramolecular hydrogen bonding and calixarene-like structures in p-cresol/formaldehyde resins

The nature of the strong hydrogen bonds found in p-cresol/formaldehyde (PCF) resins, compared to ordinary phenolic compounds, is studied. The evidence from FTIR spectroscopy indicates that this strong interaction is due to intramolecular hydrogen bonding from “calixarene-like” structures. The formation of this structure in PCF is enabled by its “linear” (all-ortho-linkage) structure, which is not present in branched resins. Additionally, a transition is observed at around 175 to 200°C where the intramolecular hydrogen bonded structure is lost. This structure cannot be recovered upon cooling or annealing due to restrictions on conformational rotations that are coupled to a new pattern of intermolecular hydrogen bonding. However, the structure is reformed by dissolving the resin in solution and casting new films.     

Molecular structure and fluorescence behaviour of a benzoquinone/porphyrin/benzoquinone sandwich-molecule

For the benzoquinone/porphyrin/benzoquinone sandwich-molecule 1 a highly symmetrical structure with parallel ring planes and interplanar distances of 342 pm was derived from X-ray analysis. 1 shows, in comparison to 2, a very strong quenching of fluorescence indicating intramolecular electron transfer.     

ortho-Mercuration of ferrocenylimines

The mercuration of a series of aryliminomethylferrocenes occurred predominantly in an ortho-position of the substituted ferrocenyl ring to yield 2-mercurated ferrocenylimines. The regiospecificity of this reaction suggests that the mercury is directed into the ortho-position by coordination of the mercury to imino nitrogen with subsequent electrophilic substitution. The chromatographic and spectral properties of the 2-mercurated products show the presence of an intramolecular N → Hg coordination via the five-membered ring in these molecules, which was further confirmed by the single-crystal structure analysis of 2-chloromercuro-1-[(4-methoxyphenylimino)methyl]ferrocene.     

Highly stereoselective Michael reduction/intramolecular Michael reaction cascade to synthesize trans-stereodiad comprising an all-carbon quaternary stereogenic center

A highly stereoselective Michael reduction/intramolecular Michael reaction cascade is described. The cascade is initiated by the regioselective Michael reduction of an α-methylidene ester with L-Selectride. This is followed by the highly stereoselective intramolecular Michael reaction which efficiently constructs a six-membered carbocyclic ring with formation of the trans-stereodiad, composed of an all-carbon quaternary center and a tertiary stereogenic center. The stereoselectivity is perfectly controlled by the choice of alkene geometry in the Michael acceptor.     

Synthesis of regioisomeric difluoro- and 8-chloro-9- fluorobenz [g] isoquinoline-5,10-diones and SNAr displacements studies by diamines: bis(aminoalkyl)aminobenz[g] isoquinoline-5,10-diones

Convenient pathways have been developed for the synthesis of 6,7−, 6,8-, 7,9- and 8,9-difluorobenz[g] isoquinoline-5,10-diones and 8-chloro-9-fluorobenz [g] isoquinoline-5,10-dione. The crucial step in these synthesis involved the Ni-catalyzed coupling of the difluoro- or chlorofluorobenzylic zinc bromides with ethyl 3-chloroisonicotinate or ethyl 4-chloronicotinate. The reactions of the 6,7- or 8,9-difluoro regioisomers with N,N-dimethylethylenediamine led to quaternary salts which were formed by intramolecular displacements from the initial mono displacement products. These cyclizations could be obviated with the use of 3-dimethylaminopropylamine in the displacements which led to the desired bis (aminoalkyl) amino substitution products. Treatment of 8-chloro-9-fluorobenz [g] isoquinoline-5,10-dione with N,N-dimethylethylenediamine led to the regioselective displacement of fluoride. Treatment of this mono substitution product with excess N,N-dimethylethylenediamine led only to the intramolecular cyclization product which was also obtained by reaction of 8,9-difluorobenz[g] isoquinoline-9,10-dione with N,N-dimethylethylenediamine. The 6,8- and 7,9-difluoro analogues on treatment with N,N-dimethylethylenediamine or 3-dimethylaminopropylamine led to the expected bis substitution products.     

Pd/Cu-catalyzed cascade Sonogashira coupling/cyclization reactions to highly substituted 3-formyl furans

An efficient palladium/copper-catalyzed approach to the synthesis of highly substituted 3-formyl furans from the reactions of readily available α-bromoenaminones with terminal alkynes has been developed. This methodology was realized by the cascade reactions of Sonogashira coupling and the subsequent intramolecular cyclization.     

Synthesis of 3-alkyl-5-hydroxycyclohex-2-enones via aldolic addition/sulfinate elimination tandem reactions

The first synthesis of 3-alkyl-5-hydroxycyclohex-2-enones is reported. An intramolecular cyclization by means of an aldolic addition/sulfinate elimination tandem reactions, performed under mild basic conditions was the key step.     

An efficient synthesis of thiopyrano[5,6-c]coumarin/[6,5-c]chromones through intramolecular domino Knoevenagel hetero Diels-Alder reactions

The synthesis of novel polycyclic thiopyrano coumarin/chromone frameworks through intramolecular domino Knoevenagel hetero Diels-Alder reactions of 4-hydroxy coumarin and its benzo-analogous with S-prenylated aromatic aldehydes was studied. A high degree of chemoselectivity was achieved by the application of microwave irradiation and a solid support.