Control Of Diastereoselectivity Research Articles

Asymmetric Total Syntheses of Kopsane Alkaloids via a PtCl2 -Catalyzed Intramolecular [3+2] Cycloaddition.

A concise and asymmetric total synthesis of five kopsane alkaloids that share a unique heptacyclic caged ring system was accomplished. The key transformation in the sequence involved a remarkable PtCl2 -catalyzed intramolecular [3+2] cycloaddition, which allowed for the rapid assembly of pentacyclic carbon skeletons bearing 2,3-quaternary functionalized indoline. Expeditious construction of diverse indoline scaffolds with excellent control of diastereoselectivity demonstrated the broad scope and versatility of this key transformation.

Asymmetric Total Syntheses of Kopsane Alkaloids via a PtCl2‐Catalyzed Intramolecular [3+2] Cycloaddition

AbstractA concise and asymmetric total synthesis of five kopsane alkaloids that share a unique heptacyclic caged ring system was accomplished. The key transformation in the sequence involved a remarkable PtCl2‐catalyzed intramolecular [3+2] cycloaddition, which allowed for the rapid assembly of pentacyclic carbon skeletons bearing 2,3‐quaternary functionalized indoline. Expeditious construction of diverse indoline scaffolds with excellent control of diastereoselectivity demonstrated the broad scope and versatility of this key transformation.

H-bond donor-directed switching of diastereoselectivity in the Michael addition of α-azido ketones to nitroolefins.

The development of catalyst-controlled stereodivergent asymmetric catalysis is important for providing facile access to all stereoisomers of chiral products with multiple stereocenters from the same starting materials. Despite progress, new design strategies for diastereodivergent asymmetric catalysis are still highly desirable. Here we report the potency of H-bond donors as the governing factor to tune diastereoselectivity in a highly diastereoselective switchable enantioselective Michael addition of α-azido ketones to nitroolefins. While a newly developed bifunctional tertiary amine, phosphoramide, preferentially afforded syn-adducts, an analogous squaramide catalyst selectively gave anti-adducts. The resulting multifunctional tertiary azides can be converted to spiro-pyrrolidines with four continuous stereocenters in a one-pot operation. Mechanistic studies cast light on the control of diastereoselectivity by H-bond donors. While the squaramide-catalyzed reaction proceeded with a transition state with both squaramide N–H bonds binding to an enolate intermediate, an unprecedented model was proposed for the phosphoramide-mediated reaction wherein an amide N–H bond and an alkylammonium ion formed in situ interact with nitroolefins, with the enolate stabilized by nonclassical C–H⋯O hydrogen-bonding interactions.

Diastereoselective Control of Tetraphenylethene Reactivity by Metal Template Self-Assembly.

The reaction of 4,4',4'',4'''-(ethene-1,1,2,2-tetrayl)tetraaniline with 2-pyridinecarboxaldehyde and iron(II) chloride resulted, after aqueous workup, in the diastereoselective formation of an [Fe2 L3 ]4+ triple-stranded helicate structure, irrespective of the stoichiometry employed. The helicate structure was characterized in solution by multinuclear NMR spectroscopy, and in the solid state by single-crystal X-ray crystallography. The reaction of iron(II) tetrafluoroborate or iron(II) bistriflimide with the tetraaniline and 2-pyridinecarboxaldehyde allowed the formation of an [Fe8 L6 ]16+ cube when the appropriate stoichiometry was used, but these structures were unstable with respect to hydrolysis. The pendant amine groups on the helicate can be functionalized by reaction with acid chlorides or anhydrides, and the resulting functionalized tetraphenylethene (TPE) units were isolated by the reaction of the helicate with tris(2-aminoethyl)amine. The emission properties of the TPE units were studied in THF/water mixtures, and they were found by dynamic light scattering to self-assemble into large (av. diameter 250 nm) structures.

Diastereoselective Intramolecular Hydride Transfer under Brønsted Acid Catalysis.

A diastereoselective hydride transfer process has been developed under Brønsted acid-catalyzed reaction conditions using methyl ethers or acetals as hydride donors and tertiary alcohols or alkenes as precursors of carbocation. The method enables construction of complex molecules having multiple stereogenic centers from rather simple and readily available starting materials with predictable diastereoselective control.

A cheap metal for a challenging task: nickel-catalyzed highly diastereo- and enantioselective hydrogenation of tetrasubstituted fluorinated enamides.

Nickel-catalyzed asymmetric hydrogenation of challenging tetrasubstituted fluorinated enamides has been achieved, affording chiral α-fluoro-β-amino esters in high yields with excellent diastereo- and enantioselectivities (up to 98% yield, >99 : 1 dr, up to >99% ee). Deuterium-labeling experiments and control experiments were conducted to probe the mechanism, and the results indicated that the acidity of the solvent plays a critical role in the control of diastereoselectivity by trapping the adduct of nickel hydride to C[double bond, length as m-dash]C bonds via protonolysis, giving the hydrogenation product with stereospecific syn-selectivity. This protocol provides efficient access to chiral α-fluoro-β-amino esters which have important potential applications in organic synthesis and medicinal chemistry.

(Hetero)arylboration of alkynes: a strategy for the synthesis of α,α-bis(hetero)arylketones.

A method for (hetero)arylboration of alkynes is presented. The reaction allows for the synthesis of densely functionalized tetrasubstituted alkenes with control of regioselectivity and diastereoselectivity. The conversion of the products to the corresponding α,α-bis(hetero)arylketones is also shown.

1,2-Addition versus homoconjugate addition reactions of indoles and electron-rich arenes to α-cyclopropyl N-acyliminium ions: synthetic and computational studies.

An investigation of the reactivity of α-cyclopropyl N-acyliminium ions towards indoles has resulted in the unprecedented synthesis of 5-cyclopropyl-5-(3-indoyl)pyrrolidin-2-ones via 1,2-addition reactions and, in the case of highly electron deficient indoles and electron rich arenes, spiroheterocycles via sequential homoconjugate and 1,2-addition reactions with often high diastereoselective control at the C-5 quaternary stereocentres. Computational studies provided support for the proposed mechanisms and stereochemical outcome of these reactions, clearly showing that the 1,2-addition pathway is kinetically controlled. In reactions where the 1,2-adduct is destabilised, for example when the arene ring is less nucleophilic, the 1,2-addition is reversible and the thermodynamically preferred homoconjugate addition and subsequent rearrangement and cyclisation reactions become the major pathway.

Chiral Syn-1,3-diol Derivatives via a One-Pot Diastereoselective Carboxylation/ Bromocyclization of Homoallylic Alcohols

SummaryChiral syn-1,3-diols are fundamental structural motifs in many natural products and drugs. The traditional Narasaka-Prasad diastereoselective reduction from chiral β-hydroxyketones is an important process for the synthesis of these functionalized syn-1,3-diols, but it is of limited applicability for large-scale synthesis because (1) highly diastereoselective control requires extra explosive and flammable Et2BOMe as a chelating agent under cryogenic conditions and (2) only a few functional syn-1,3-diol scaffolds are available. Those involving halogen-functionalized syn-1,3-diols are much less common. There are no reported diastereoselective reactions involving chemical fixation of CO2/bromocyclization of homoallylic alcohols to halogen-containing chiral syn-1,3-diols. Herein, we report an asymmetric synthesis of syn-1,3-diol derivatives via direct diastereoselective carboxylation/bromocyclization with both relative and absolute stereocontrol utilizing chiral homoallylic alcohols and CO2 in one pot with up to 91% yield, > 99% ee, and >19:1 dr. The power of this methodology has been demonstrated by the asymmetric synthesis of statins at the pilot plant scale.

Directed Cu(I)-Catalyzed Carbomagnesiation of 1-Arylcycloprop-2-ene-1-carboxamides En Route to Densely Substituted Functionalized Cyclopropanes.

Copper-catalyzed, directed addition of Grignard reagents across the strained C═C bond of cyclopropene-3-carboxamides was developed. It was demonstrated that the amide functionality serves as an ultimate directing group allowing for highly efficient control of diastereoselectivity of addition including stereoselectivity of electrophilic trapping with prochiral aldehydes. Also, regioselectivity of carbomagnesiation of cyclopropenes with a monosubstituted double bond is investigated. It was shown that in many cases this selectivity is controlled by steric factors and allows for preparation of products with a "reversed" regiochemistry.

Asymmetric Synthesis of Functionalized trans-Cyclopropoxy Building Block for Grazoprevir.

A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular SN2 displacement-ring closure, followed by a Baeyer-Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH2)2NEt2. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.

Diols as Dienophiles: Bridged Carbocycles via Ruthenium(0)-Catalyzed Transfer Hydrogenative Cycloadditions of Cyclohexadiene or Norbornadiene.

Highly exo-selective ruthenium(0) catalyzed transfer hydrogenative cycloadditions of 1,2-diols with cyclohexadiene or norbornadiene are described. Novel bridged bicyclic ring systems are accessible from the diol, α-ketol or 1,2-dione oxidation levels with complete control of diastereoselectivity.

Diols as Dienophiles: Bridged Carbocycles via Ruthenium(0)‐Catalyzed Transfer Hydrogenative Cycloadditions of Cyclohexadiene or Norbornadiene

AbstractHighly exo‐selective ruthenium(0) catalyzed transfer hydrogenative cycloadditions of 1,2‐diols with cyclohexadiene or norbornadiene are described. Novel bridged bicyclic ring systems are accessible from the diol, α‐ketol or 1,2‐dione oxidation levels with complete control of diastereoselectivity.

Oxazolidinones and 2,5-Dihydrofurans via Zinc-Catalyzed Regioselective Allenylation Reactions of l-α-Amino Aldehydes.

The simultaneous control of diastereoselectivity and regioselectivity in Zn-catalyzed allenylation reactions of N-protected l-α-amino aldehydes is reported. A reversal in diastereoselectivity could be realized by variation of the α-amino aldehyde protecting groups. A range of 1-allenyl-2-amino alcohols were obtained with excellent regioselectivity and converted to oxazolidinones and dihydrofurans. Many of which could be isolated as single diastereoisomers and without significant erosion of ee, making this a practical catalytic synthesis of highly functionalized heterocycles.

Diastereoselectivity of Azido-Ugi Reaction with Secondary Amines. Stereoselective Synthesis of Tetrazole Derivatives.

The diastereoselectivity of azido-Ugi reaction with cyclic amines was investigated. It was found that the reaction with α-substituted five- to seven-membered cyclic amines proceeds very efficiently to provide high control of diastereoselectivity (≤100% de) under mild conditions. Target tetrazole-derived products were isolated in excellent yields (≤98%). The reaction has a broad scope in terms of its amine, aldehyde, and isocyanide nature. It was found that the diastereoselectivity of the reaction depends on the ring size of the starting cyclic amines. More rigid piperidines provided the highest selectivity of the reaction. Using benzyl isocyanide, the prepared N-benzyl tetrazoles can be deprotected by hydrogenolysis to form the corresponding NH tetrazoles in high yields.

Ortho-Nitro Effect on the Diastereoselective Control in Sulfa-Staudinger and Staudinger Cycloadditions.

The ortho-nitro effect was discovered in sulfa-Staudinger cycloadditions of ethoxycarbonylsulfene with linear imines. When an ortho-nitro group is present at the C-aryl substituents of linear imines, the sulfa-Staudinger cycloadditions deliver cis-β-sultams in considerable amounts, together with the predominant trans-β-sultams. In other cases, the above sulfa-Staudinger cycloadditions give rise to trans-β-sultams exclusively. Further mechanistic rationalization discloses that the ortho-nitro effect is attributed to its strong electron-withdrawing inductive effect. Similarly, the ortho-nitro effect also exists in Staudinger cycloadditions of ethoxycarbonyl ketene with the imines. The current research provides further insights into the diastereoselective control in sulfa-Staudinger and Staudinger cycloadditions.

Asymmetric Synthesis of Octahydroindoles via a Domino Robinson Annulation/5-Endo Intramolecular Aza-Michael Reaction

A straightforward, two-step asymmetric synthesis of octahydroindoles has been developed on the basis of two complementary strategies: (i) an organocatalyzed Michael reaction followed by a tandem Robinson-aza-Michael double cyclization catalyzed by PS-BEMP, and (ii) a diastereoselective cyclization, which formally constitutes a remote 1,6 asymmetric induction mediated by PS-BEMP. This allowed the construction of complex octahydroindoles with up to four stereocenters, excellent enantioselectivities (up to 95% ee), and complete diastereoselective control in a single-pot operation. DFT calculations were performed to understand the origin of this effect.

Photoinduced "Double Click" Cascade Offers Access to Complex Polyheterocycles from Readily Available Isatin-Based Photoprecursors.

The cascade photoassisted synthetic strategy for accessing complex N,O-polyheterocycles of unprecedented molecular architecture is developed. It is based on intramolecular cycloadditions of aza-o-xylylenes formed in situ via excited-state intramolecular proton transfer (ESIPT) of o-acylanilides. The photoprecursors are synthesized via a two-step one-pot method from readily available starting materials. The photochemical cascade (one experimentally simple step) results in the formation of four new heterocyclic rings with high control of diastereoselectivity.

Enantiopure Ferrocene-Based Planar-Chiral Iridacycles: Stereospecific Control of Iridium-Centred Chirality.

Reaction of [IrCp*Cl2 ]2 with ferrocenylimines (Fc=NAr, Ar=Ph, p-MeOC6 H4 ) results in ferrocene C-H activation and the diastereoselective synthesis of half-sandwich iridacycles of relative configuration Sp *,RIr *. Extension to (S)-2-ferrocenyl-4-(1-methylethyl)oxazoline gave highly diastereoselective control over the new elements of planar chirality and metal-based pseudo-tetrahedral chirality, to give both neutral and cationic half-sandwich iridacycles of absolute configuration Sc ,Sp ,RIr . Substitution reactions proceed with retention of configuration, with the planar chirality controlling the metal-centred chirality through an iron-iridium interaction in the coordinatively unsaturated cationic intermediate.

Insights into the diastereoselective control in the sulfa-Michael addition of thiols to nitroalkenes: stereoelectronic effect in the cyclic chelated transition state

The diastereoselective control in the sulfa-Michael addition of nitroalkenes and lithium thiolates followed by protonation was investigated. Lithium thiolates first added to nitroalkenes to afford cyclic lithium-chelated nitronates. The subsequent kinetic protonation of nitronates was proved to be the stereochemical determinant through the chelate-controlled six-membered half-chair transition state bearing two approximately 1,2-diaxial substituents due to stereoelectronic effect control. The stereoelectronic effect in the cyclic chelated transition state was probed and verified by tuning the steric bulkiness of the corresponding substituents. The reaction involving 1-nitrocyclohexene provided perfect support for the proposed diastereoselective control model. The current investigation provided not only comprehensive insights into the diastereoselective control in the sulfa-Michael addition of nitroalkenes and thiolates, but also an important role of the stereoelectronic effect in certain organic reactions involving cyclic chelate transition states.