Diastereoselective Coupling Research Articles

Nickel-Catalyzed Enantioconvergent and Diastereoselective Allenylation of Alkyl Electrophiles: Simultaneous Control of Central and Axial Chirality.

In recent years, remarkable progress has been described in the development of methods that simultaneously control vicinal stereochemistry, wherein both stereochemical elements are central chirality; in contrast, methods that control central and axial chirality are comparatively rare. Herein we report that a chiral nickel catalyst achieves the enantioconvergent and diastereoselective coupling of racemic secondary alkyl electrophiles with prochiral 1,3-enynes (in the presence of a hydrosilane) to generate chiral tetrasubstituted allenes that bear an adjacent stereogenic center. A carbon-carbon and a carbon-hydrogen bond are formed in this process, which provides good stereoselectivity and is compatible with an array of functional groups.

Strategies for the Catalytic Enantioselective Synthesis of α-Trifluoromethyl Amines.

The exploitation of the α-trifluoromethylamino group as an amide surrogate in peptidomimetics and drug candidates has been on the rise. In a large number of these cases, this moiety bears stereochemistry with the stereochemical identity having important consequences on numerous molecular properties, such as the potency of the compound. Yet, the majority of stereoselective syntheses of α-CF3 amines rely on diastereoselective couplings with chiral reagents. Concurrent with the rapid expansion of fluorine into pharmaceuticals has been the development of catalytic enantioselective means of preparing α-trifluoromethyl amines. In this work, we outline the strategies that have been employed for accessing these enantioenriched amines, including normal polarity approaches and several recent developments in imine umpolung transformations.

Triarylaminium Radical Cation Promoted Coupling of Catharanthine with Vindoline: Diastereospecific Synthesis of Anhydrovinblastine and Reaction Scope.

A new triarylaminium radical cation promoted coupling of catharanthine with vindoline is disclosed, enlisting tris(4-bromophenyl)aminium hexachlororantimonate (BAHA, 1.1 equiv) in aqueous 0.05 N HCl/trifluoroethanol (1-10:1) at room temperature (25 °C), that provides anhydrovinblastine in superb yield (85%) with complete control of the newly formed quaternary C16' stereochemistry. A definition of the scope of aromatic substrates that participate with catharanthine in the BAHA-mediated diastereoselective coupling reaction andsimplified indole substrates other than catharanthine that participate in the reaction are disclosed that identify the key structural features required for participation in the reaction, providing a generalized indole functionalization reaction that bears little structural relationship to catharanthine or vindoline.

Tertiary α-Silyl Alcohols by Diastereoselective Coupling of 1,3-Dienes and Acylsilanes Initiated by Enantioselective Copper-Catalyzed Borylation.

An efficient synthesis of functionalized tertiary α-silyl alcohols by an enantio- and diastereoselective copper-catalyzed three-component coupling of 1,3-dienes, bis(pinacolato)diboron, and acylsilanes is reported. The reaction proceeds well with different 1,3-dienes and a broad range of aryl- as well as alkenyl- but also alkyl-substituted acylsilanes. The target compounds are formed with high regio-, diastereo-, and enantioselectivity (up to 99 % ee and d.r. >20:1) and are highly versatile synthetic building blocks.

Heptamethylindenyl (Ind*) enables diastereoselective benzamidation of cyclopropenes via Rh(iii)-catalyzed C-H activation.

The diastereoselective coupling of O-substituted arylhydroxamates and cyclopropenes mediated by Rh(iii) catalysis was successfully developed. Through ligand development, the diastereoselectivity of this reaction was improved using a heptamethylindenyl (Ind*) ligand, which has been rationalized using quantum chemical calculations. In addition, the nature of the O-substituted ester of benzhydroxamic acid proved important for high diastereoselectivity. This transformation tolerates a variety of benzamides and cyclopropenes that furnish cyclopropa[c]dihydroisoquinolones with high diastereocontrol, which could then be easily transformed into synthetically useful building blocks for pharmaceuticals and bio-active molecules.

Thiophene-Based Double Helices: Syntheses, X-ray Structures, and Chiroptical Properties.

We demonstrate facile and efficient construction of conjugated double helical ladder oligomers from the saddle-shaped cyclooctatetrathiophene (COTh) building blocks. The key step involves deprotonation of tetra[3,4]thienylene (β,β-COTh) with n-BuLi which displays remarkably high ipsilateral selectivity. Three racemic double helical ladder oligomers, rac-DH-1, rac-DH-2, and rac-DH-3, containing two, three, and five COTh annelated moieties are efficiently synthesized by diastereoselective coupling of the racemic precursors. The X-ray crystallographic studies of rac-DH-1, rac-DH-2 and rac-DH-3 unambiguously revealed that each double helical scaffold has two single helices intertwined with each other via the C-C single bonds. Following removal of TMS groups, double helical ladder oligomer rac-DH-1-D had sufficient solubility to be resolved via chiral HPLC, thus enabling determination of its chirooptical properties such as CD spectra and optical rotation. (+)-DH-1-D has a large barrier for racemization, with lower limit of ΔG(‡) > 48 kcal mol(-1), which may be compared to DFT-computed barrier of 51 kcal mol(-1). The enantiomers of DH-1-D show 1 order of magnitude stronger chirooptical properties than the carbon-sulfur [7]helicene, as determined by the anisotropy factor g = Δε/ε = -0.039, based on Δεmax = -11 and ε = 2.8 × 10(2) L mol(-1) cm(-1) in cyclohexane at 327 nm.

Diastereoselective Coupling of Chiral Acetonide Trisubstituted Radicals with Alkenes.

The stereochemical outcome of reactions of chiral nucleophilic trisubstituted acetonide radicals with electron-deficient alkenes is dictated by a delicate balance between destabilizing non-bonding interactions and stabilizing hydrogen-bonding between substituents on the α and β carbons.

ChemInform Abstract: Copper‐Catalyzed Diastereoselective Aerobic Intramolecular Dehydrogenative Coupling of Hydrazones via sp3 C—H Functionalization.

AbstractThe title reaction gives substituted pyrazolines as the products and it is the first example of Cu‐catalyzed intramolecular diastereoselective coupling reaction via an iminium ion intermediate.

Silver-Catalyzed Diastereoselective Coupling

Silver-Catalyzed Diastereoselective Coupling

Copper-catalyzed diastereoselective aerobic intramolecular dehydrogenative coupling of hydrazones via sp3 C-H functionalization.

Transition metal-catalyzed cross dehydrogenative coupling is an important tool for functionalization of the α Csp3-H bond of amines. Among this reaction category, copper-catalyzed selective C-C bond formation under atmospheric O2 is of considerable research interest and significant progress has been achieved in recent years. In comparison, development of the intramolecular version of this transformation is still in its infancy. Furthermore, diastereoselective cyclization with this transformation has not been achieved. Here, we describe the highly diastereoselective intramolecular dehydrogenative cyclization of N,N-disubstituted hydrazones by a copper-catalyzed sp3 C-H bond functionalization process. The reaction protocol utilizes O2 as the oxidant and shows great functional group compatibility. Computational studies suggest that a 5-center/6-electron disrotatory cyclization mechanism is probably involved in the process for controlling the diastereoselectivity. This work represents the first example of a copper-catalyzed, direct intramolecular diastereoselective coupling reaction via an iminium ion intermediate. Additionally, it provides an environmentally friendly and atom efficient approach to access substituted pyrazolines, an important structural unit in many biologically active compounds.

A Practical Synthesis of Chiral Oxazolines through a Highly Diastereoselective Coupling–Cyclization Reaction of N‐(Buta‐2,3‐dienyl)amides and Aryl Iodides

AbstractA highly trans diastereoselective synthesis of 2,4,5‐trisubstituted oxazoline derivatives is described that proceeds through a palladium‐catalyzed coupling–cyclization reaction of N‐(buta‐2,3‐dienyl)amides with aromatic iodides. The reaction with optically active substrates provides convenient access to highly enantioenriched oxazoline derivatives with excellent 1,2‐induction.

Enantioselective Synthesis of 2-Substitued-Tetrahydroisoquinolin-1-yl Glycine Derivatives via Oxidative Cross-Dehydrogenative Coupling of Tertiary Amines and Chiral Nickel(II) Glycinate

The asymmetric synthesis of 2-substituted-tetrahydroisoquinolin-1-yl glycines was achieved by an oxidative cross-dehydrogenative coupling (CDC) reaction. This method for activation of the α-C-H bonds of amines with chiral nickel(II) glycinate using o-chloranil as the sole oxidant afforded highly diastereoselective coupling adducts. The decomposition of coupling adducts readily afforded 2-substituted-tetrahydroisoquinolin-1-yl glycine derivatives.

Synthesis of a Long Acting HIV Protease InhibitorviaMetal or Enzymatic Reduction of the Appropriate Chloro Ketone and Selective Zinc Enolate Condensation with an Amino Epoxide

This paper describes a new convergent approach to the synthesis of an HIV protease inhibitor which was designed to be suitable in long acting formulations. Unique features in the synthesis include an asymmetric hydrogenation as well as enzymatic reduction of a key chloro ketone intermediate, to set the threo stereochemistry in the corresponding epoxide and the diastereoselective coupling of the latter with the zinc enolate of a suitable functionalized amide derivative.

ChemInform Abstract: Diastereoselective Coupling of N‐(tert‐Butyl)sulfinyl Imines and Dimethyl Malonate. Synthesis of Enantiomerically Enriched β‐Amino Esters and β‐Lactams.

AbstractHigher yields of the target compounds (III) are obtained in the presence of NaI compared to NaHCO3.

ChemInform Abstract: Nickel‐Catalyzed Diastereoselective Alkyl—Alkyl Kumada Coupling Reactions.

Abstract1,4‐Cyclohexyl halides (Br, I) undergo a coupling reaction with alkyl or aryl Grignard reagents in the presence of nickel pincer complex TAN to give trans‐1,4‐disubstituted cyclohexanes as major products.

Computational tools for mechanistic discrimination in the reductive and metathesis coupling reactions mediated by titanium(IV) isopropoxide

A theoretical study has been carried out at the B3LYP/LANL2DZ level to compare the reactivity of phenyl isocyanate and phenyl isothiocyanate towards titanium(IV) alkoxides. Isocyanates are shown to favour both mono insertion and double insertion reactions. Double insertion in a head-to-tail fashion is shown to be more exothermic than double insertion in a head-to-head fashion. The head-to-head double insertion leads to the metathesis product, a carbodiimide, after the extrusion of carbon dioxide. In the case of phenyl isothiocyanate, calculations favour the formation of only mono insertion products. Formation of a double insertion product is highly unfavourable. Further, these studies indicate that the reverse reaction involving the metathesis of N,N′-diphenyl carbodiimide with carbon dioxide is likely to proceed more efficiently than the metathesis reaction with carbon disulphide. This is in excellent agreement with experimental results as metathesis with carbon disulphide fails to occur. In a second study, multilayer MM/QM calculations are carried out on intermediates generated from reduction of titanium(IV) alkoxides to investigate the effect of alkoxy bridging on the reactivity of multinuclear Ti species. Bimolecular coupling of imines initiated by Ti(III) species leads to a mixture of diastereomers and not diastereoselective coupling of the imine. However if the reaction is carried out by a trimeric biradical species, diastereoselective coupling of the imine is predicted. The presence of alkoxy bridges greatly favours the formation of the d,l (±) isomer, whereas the intermediate without alkoxy bridges favours the more stable meso isomer. As a bridged trimeric species, stabilized by bridging alkoxy groups, correctly explains the diastereoselective reaction, it is the most likely intermediate in the reaction. Computational studies carried out at the B3LYP/LANL2DZ level throw light on the contrasting reactivity of isocyanates and isothiocyanates towards titanium(IV) alkoxides. While both mono and double insertion reactions are feasible with isocyanates, only the mono insertion reaction appears to be thermodynamically feasible with isothiocyanates. Multilayer calculations are also performed on multinuclear titanium intermediates in diastereoselective coupling reactions initiated by low valent titanium species. These studies clearly predict that the coupling of a trinuclear titanium complex involvng alkoxy bridges gives rise to diastereoselective coupling. Non bridged forms and dimeric species would not result in the observed diastereoselectivity.

Diastereoselective Coupling of N‐(tert‐Butyl)sulfinyl Imines and Dimethyl Malonate. Synthesis of Enantiomerically Enriched β‐Amino Esters and β‐Lactams

AbstractA diastereoselective coupling of dimethyl malonate with N‐(tert‐butyl)sulfinyl imines under solvent‐free conditions was developed, using NaHCO3 or NaI as base promoters. The resulting dimethyl 2‐(1‐aminoalkyl)malonates could be easily transformed successively to β‐amino esters and the corresponding β‐lactams with high optical purity.

Samarium Iodide-Mediated Reformatsky Reactions for the Stereoselective Preparation of β-Hydroxy-γ-amino Acids: Synthesis of Isostatine and Dolaisoleucine

The synthesis of β-hydroxy-γ-amino acids via SmI(2)-mediated Reformatsky reactions of α-chloroacetyloxazolidinones with aminoaldehydes is reported. Diastereoselective coupling is demonstrated to depend on the absolute configuration of the Evans chiral auxiliary employed in the reaction, allowing erythro or threo products to be obtained selectively. The potential utility of the methodology is exemplified by the facile synthesis of biologically relevant N-Boc-isostatine (2b) and N-Boc-dolaisoleucine (3c).

Diastereoselective Rhodium-Catalyzed Switchable Three-Component Couplings

Diastereoselective Rhodium-Catalyzed Switchable Three-Component Couplings

Catalytic enantioselective dehydrogenative Si–O coupling of oxime ether-functionalized alcohols

Asymmetric silylation of alcohols is an unusual but effective approach to their kinetic resolution, and the Cu–H-catalyzed dehydrogenative Si–O coupling is particularly noteworthy as dihydrogen is formed as the sole by-product. Our laboratory had previously reported on diastereoselective (with silicon-stereogenic silanes) and enantioselective (with achiral silanes) Si–O couplings of azine donor-functionalized alcohols. The limitation, that is, the requirement of a nitrogen donor atom, prompted us to seek equally useful donor groups. Oxime ethers were identified as a suitable alternative, and we describe herein the preparation of a series of oxime ether-functionalized alcohols. To assess different substitution patterns in their kinetic resolution, these were tested in the reagent-controlled Si–O coupling using a silicon-stereogenic silane. The optimal substituents at the oxime carbon atom (dr=85:15 in the diastereoselective coupling) were then chosen for the related catalyst-controlled Si–O coupling but selectivity factors were only moderate.