Enantioselective synthesis of C-linked spiroacetal-triazoles as privileged natural product-like scaffolds

The enantioselective synthesis of novel C-linked spiroacetal-triazoles 10 is reported. The key step involves reaction of acetylenic spiroacetal 11 with several azides by the Copper-Catalysed Azide-Alkyne Cycloaddition (CuAAC). The biologically privileged spiroacetal scaffold 11 was prepared from silyl-protected Weinreb amide 19 using several reliable Grignard additions and a highly diastereoselective enzymatic kinetic resolution.     

Pyridinyloxazolidines: versatile scaffolds for chiral catalyst construction

Pyridinyloxazolidines are structurally versatile chiral ligand frameworks that are easily made and coordinated to Pd(II); the resulting complexes, which show significant steric and electronic differences from their oxazoline counterparts, as well as intermolecular H-bonding in the solid state, can be isolated in diastereomerically pure form and are remarkably resistant to hydrolysis.     

Enantioselective synthesis of "quaternary" 1,4-benzodiazepin-2-one scaffolds via memory of chirality

Glycine-derived 1,4-benzodiazepine-2-ones such as diazepam are chiral by virtue of the boat-shaped conformation of the diazepine ring and exist as a racemic mixture of conformational enantiomers. However, the presence of a chiral center at C-3 of the benzodiazepine perturbs this equilibrium and preferentially stabilizes one ring conformer. We report that N-i-Pr 1,4-benzodiazepine-2-ones derived from (S)-Ala and (S)-Phe can be deprotonated and alkylated in 86-99% ee, despite the fact that the original chiral center is destroyed in the deprotonation step. We attribute this highly enantioselective alkylation to the chiral memory of the benzodiazepine ring. This protocol provides easy access to the previously unexplored "quaternary" 1,4-benzodiazepine-2-ones.     

Enantioselective approach to indolizidine and quinolizidine scaffolds. Application to the synthesis of peptide mimics

An enantioselective approach to substituted indolizidine and quinolizidine frameworks has been developed. Key steps of the synthesis are the enantioselective, palladium-catalyzed N-allylation of an imide, the nucleophilic allylation of an acyliminium ion and a ring closing metathesis. This general strategy has been applied to the synthesis of indolizidine peptide mimics, starting from a chiral imide derived from l-aspartic acid. It was observed that the preexisting stereogenic center of this substrate has a moderate influence on the stereoselectivity of the electrophilic allylation, which is mainly determined by the sense of chirality of the catalyst.     

Enantioselective copper-catalyzed construction of aryl pyrroloindolines via an arylation-cyclization cascade

An enantioselective arylation-cyclization cascade has been accomplished using a combination of diaryliodonium salts and asymmetric copper catalysis. These mild catalytic conditions provide a new strategy for the enantioselective construction of pyrroloindolines, an important alkaloid structural motif that is commonly found among biologically active natural products.     

Enantioselective construction of quaternary carbon centre catalysed by bifunctional organocatalyst

The bifunctional thiourea-tertiary amine derivatives of simple chiral diamines serve as highly enantioselective catalysts for the Michael addition of alpha-substituted cyanoacetates to vinyl sulfones, giving an efficient protocol for the construction of an all-carbon substituted quaternary stereocentre.     

Enantioselective construction of all-carbon quaternary centers by branch-selective Pd-catalyzed allyl-allyl cross-coupling

The Pd-catalyzed cross-coupling of racemic tertiary allylic carbonates and allylboronates is described. This reaction generates all-carbon quaternary centers in a highly regioselective and enantioselective fashion. The outcome of these reactions is consistent with a process that proceeds by way of 3,3'-reductive elimination of bis(η(1)-allyl)palladium intermediates. Strategies for distinguishing the product alkenes and application to the synthesis of (+)-α-cuparenone are also described.     

Enantioselective construction of biaryl part in the synthesis of stegane related compounds

A Pd-mediated intramolecular aryl-aryl coupling reaction of phenyl benzoate derivatives were examined to form benzo[c]chromen-6-ones, and then enantioselective lactone-opening reaction with a borane-oxazaborolidine combination was carried out. The resulting biphenyl was transformed into a key intermediate for the stegane related compounds. The absolute configuration of the biphenyl is also discussed.     

Enantioselective construction of cyclic quaternary centers: (-)-mesembrine.

The preparation of the crystalline amide 2 is reported. Conjugate addition to 2 proceeded with the expected high diastereocontrol to give 3. This set the stage for subsequent intramolecular alkylidene C-H insertion to give, after ozonolysis and aldol condensation, (-)-mesembrine 1. Amide 2 should be a useful chiron for the enantioselective construction of cyclic quaternary centers.     

Enantioselective synthesis of [1,2]-oxazinone scaffolds and [1,2]-oxazine core structures of FR900482

Several chiral unsaturated [1,2]-oxazinone heterocycles have been synthesized by iridium-catalyzed allylic substitution and ring-closing metathesis (RCM) reaction in high yields with excellent enantiomeric excesses. In addition, the synthesis of [1,2]-oxazine core structures of FR900482 was achieved via iridium-catalyzed allylic substitution, followed by RCM and Heck reactions, respectively.     

Expeditious construction of a carbobicyclic skeleton via sp3-C-H functionalization: hydride shift from an aliphatic tertiary position in an internal redox process

Described herein is the first example of an aliphatic, nonbenzylic hydride shift/cyclization sequence that contains two types of novel sp(3)-C-H functionalization: (1) construction of a tetraline skeleton via [1,5]-hydride shift/cyclization and (2) [1,6]-hydride shift/cyclization to form a five-membered ring (indane derivatives).     

Enantioselective organocatalytic Michael-Wittig-Michael-Michael reaction: dichotomous construction of pentasubstituted cyclopentanecarbaldehydes and pentasubstituted cyclohexanecarbaldehydes

Michael addition of carbethoxymethylenetriphenylphosphorane (a Wittig reagent) to nitroalkenes, followed by a reaction with ethyl formylformate and cinnamaldehydes, or formaldehyde and cinnamaldehydes, provided the respective pentasubstituted cyclopentanecarbaldehydes bearing a quaternary carbon center and pentasubstituted cyclohexanecarbaldehydes having five contiguous stereocenters with excellent enantioselectivities (up to >99% ee).     

Enantioselective construction of highly functionalized bicyclo[4.3.0] system through Diels-Alder cycloaddition

The Diels-Alder reaction of chiral 2-alkylsulfinyl-1-nitroalkene 4 with Danishefsky's diene afforded adducts 9a and 10a in good chemical yield with a high enantiomeric excess, while diastereomeric nitroalkene 5 gave 9b and 10b, enantiomeric to 9a and 10a, respectively. The synthesis of the chiral dienophiles and mechanism of the chiral induction in the cycloaddition are discussed.     

Enantioselective synthesis of erythro-4-deoxyglycals as scaffolds for target- and diversity-oriented synthesis: new insights into glycal reactivity

An efficient, enantioselective synthesis of erythro-4-deoxyglycals has been developed using asymmetric aldehyde allylation and tungsten-catalyzed alkynol endo-cycloisomerization as the key steps. These versatile synthetic scaffolds have been elaborated to a variety of products using stereoselective transformations that are complementary to those available using the corresponding threo glycals. This work has provided valuable insights into the relationships between glycal structure and reactivity. In addition, a new diene-forming side reaction during tungsten-catalyzed alkynol cycloisomerization has been discovered.     

Stereoselective construction of azepine-containing bridged scaffolds via organocata-lytic bicyclization of yne-allenone esters with nitrones

A new organocatalytic double annulation cascade involving scission/recombination of N-O bonds of nitrones is reported for the first time, and used to produce a range of hitherto unprecedented tricyclic bridged-fused benzo[d]azepines bearing three stereogenic centers with moderate to good yields and complete diastereoselectivity. A quinine-catalyzed reaction of yne?allenone esters with nitrones worked well and provided a convergent and regioselective pathway to access these three-dimensional scaffolds from the planar conjugated system. Density functional theory (DFT) calculations have been applied to understand the key process for forming diradical intermediates.     

Pestalotiopsin a. Enantioselective construction of potential building blocks derived from antipodal cyclobutanol intermediates

D-Glyceraldehyde acetonide has been used as the starting point for accessing the enantiomeric cyclobutanols 11 in optically pure condition. The dextrorotatory enantiomer has been transformed in five steps into the [3.2.0] bicyclic lactone 22. While the deoxygenation of 22 proved to be problematical, the uncyclized variant 25 underwent the Barton process smoothly. These findings guided the related conversion of (-)-11 into 34. Use was also made of ring-closing metathesis to bring about the conversion of (+)-11 into [4.2.0] bicyclic lactone building blocks. In general, all three pathways are efficient and offer the prospect of practical side-chain appendage for the purpose of installing the nine-membered ring of pestalotiopsin A (1).     

Synthesis of carbobicyclic compounds via palladium-catalyzed cyclization/hydrosilylation: evidence for reversible silylpalladation

Cyclization/hydrosilylation of substituted 1-vinyl-1-(3-butenyl)cycloalkanes catalyzed by a 1:1 mixture of (phen)Pd(Me)Cl (1) and NaBAr(4) [phen = 1,10-phenanthroline; Ar = 3,5-C(6)H(3)(CF(3))(2)] formed silylated spirocycles in high yield with excellent regio and diastereoselectivity. Cyclization/hydrosilylation of substituted 3-(3-butenyl)cycloalkenes or 2,3-diallyl-5,6-dimethyl-1,4-hydroquinone diacetate (16) formed silylated fused bicyclic complexes in good yield. Reaction of substituted 1,6,11-nonatrienes with silane catalyzed by 1/NaBAr(4) led to cascade cyclization with hydrosilylation. This latter procedure was employed in the synthesis of silylated bicyclopentanes and a linear triquinane.