High Diastereoselectivity Research Articles

Organocatalytic Asymmetric [2 + 4] Cycloadditions of 3-Vinylindoles with ortho-Quinone Methides.

Catalytic asymmetric [2 + 4] cycloadditions of 3-vinylindoles with ortho-quinone methides and their precursors were carried out in the presence of chiral phosphoric acid to afford a series of indole-containing chroman derivatives with structural diversity in overall high yields (up to 98%), good diastereoselectivities (up to 93:7 dr) and moderate to excellent enantioselectivities (up to 98% ee). This approach not only enriches the chemistry of catalytic asymmetric cycloadditions involving 3-vinylindoles but is also useful for synthesizing chiral chroman derivatives.

Stereoselective Synthesis of Oxacycles via Ruthenium-Catalyzed Atom-Economic Coupling of Propargyl Alcohols and Michael Acceptors.

Synthesis of β-hydroxyenones and its application toward development of tetrahydro-4H-pyran-4-one in an atom-economic fashion is limited. This manuscript describes a ruthenium-catalyzed atom-economic coupling of pent-2-yne-1,5-diols and Michael acceptors as an efficient route for the synthesis of β-hydroxyenones with excellent yields and high regioselectivity. The β-hydroxyenones further undergo a 6-endo trig cyclization under acid-catalyzed conditions to deliver the tetrahydro-4H-pyran-4-ones with high diastereoselectivity. An intramolecular aldol condensation under mild basic conditions and palladium-catalyzed oxidative aromatization was developed for the synthesis of hexahydro-6H-isochromen-6-ones and isochromanols, respectively, from highly substituted tetrahydro-4H-pyran-4-ones with excellent yield and diastereoselectivity. Overall, this work demonstrates the synthetic potential toward the synthesis of oxacycles like tetrahydro-4H-pyran-4-ones, hexahydro-6H-isochromen-6-ones, and isochromanols via an atom-economic catalysis.

Synthesis of Pentacoordinated Spiro[4.4]phosphoranes by Reaction of Cyclic Phosphazenyl Anions with Epoxides: Study of their P-Remote Functionalization and Hydrolysis

AbstractThe synthesis of a new family of pentacoordinated spiro[4.4]phosphoranes stabilized by the ortho-benzamide bidentate ligand (oBA, -C6H4-2-C(O)NH-) through reaction of Cα,C ortho -dilithiated phosphazenes with oxiranes is reported. Mixtures of epimers that differ in configuration at the phosphorus atom were obtained with moderate to high yields and diastereoselectivities. C3-Disubstituted derivatives could be separated, which provided access to enantiopure products arising from the reaction with (R)-2-phenyloxirane. Stereomutation was observed by heating the spirophosphoranes at 100 °C. Directed ortho-lithiation of spirophoshoranes followed by electrophilic quench reactions including carbon-based and heteroatom-based electrophiles afforded derivatives functionalized in a remote position with respect to the phosphorus atom. Benzoic acid catalyzed hydrolysis of spirophosphoranes furnished ortho-(γ-hydroxyalkylphosphoryl)benzamides by cleavage of the P–O and P–N bonds with retention of the phosphorus configuration. In contrast, alkaline hydrolysis led to the formation of γ-hydroxyphosphinic acids and benzamide.

Functionalized Polyhydroquinolines from Amino Acids Using a Key One-Pot Cyclization Cascade and Application to the Synthesis of (±)-Δ7-Mesembrenone.

Substituted polyhydroquinolines are ubiquitous skeletal cores found in drugs and bioactive natural products. As a new route to access this motif, we successfully developed a one-pot cyclization cascade with high chemocontrol and diastereoselectivity. The sequence generates two cycles, three carbon-carbon bonds, and an all-carbon quaternary center in a highly convergent process. Functionalized polyhydroquinolines and congeners can be accessed from commercially available amino acids. This versatile and robust strategy was applied to the synthesis of (±)-Δ7-mesembrenone.

The Electrochemical cis-Chlorination of Alkenes.

The first example for the electrochemical cis‐dichlorination of alkenes is presented. The reaction can be performed with little experimental effort by using phenylselenyl chloride as catalyst and tetrabutylammoniumchloride as supporting electrolyte, which also acts as nucleophilic reagent for the SN2‐type replacement of selenium versus chloride. Cyclic voltammetric measurements and control experiments revealed a dual role of phenylselenyl chloride in the reaction. Based on these results a reaction mechanism was postulated, where the key step of the process is the activation of a phenylselenyl chloride‐alkene adduct by electrochemically generated phenylselenyl trichloride. Like this, different aliphatic and aromatic cyclic and acyclic alkenes were converted to the dichlorinated products. Thereby, throughout high diastereoselectivities were achieved for the cis‐chlorinated compounds of >95 : 5 or higher.

Diastereoselective synthesis of spiro[chromane-3,3′-indolines] and spiro[chromane-3,2′-indenes] via DBU promoted formal [4 + 2]cycloaddition reaction

A new DBU-catalyzed formal [4 ​+ ​2] cycloaddition between ortho-hydroxyphenyl-substituted para-quinone methides and electron-deficient dienophiles including 3-methyleneoxindoles and 2-aryldeneindene-1,3-diones was established. A wide range of functionalized spiro[chromane-3,3′-indolines] and spiro[chromane-3,2′-indenes] were successfully synthesized in good yields and with high diastereoselectivity. The features of the reaction included readily available substrates, mild reaction conditions, convenient methodology and good functional group tolerance.

Diastereoselective Pd-Catalyzed Decarboxylative Allylation To Construct Quaternary Stereocenters Using Sulfinimine as the ­Directing Group

AbstractA robust Pd(0)-catalyzed decarboxylation alkylation has been developed to construct quaternary stereocenters through the use of chiral tert-butanesulfinamide as the directing group. This strategy provides a simple and efficient route to the construction of quaternary chiral centers at the α-position of chiral sulfinamides, with high diastereoselectivities and high yields.

Selective Synthesis of Diverse Spiro-oxindole-fluorene Derivatives via a DABCO-Promoted Annulation Reaction of Bindone and 3-Methyleneoxindoles.

A DABCO-promoted annulation reaction of bindone ([1,2'-biindenylidene]-1',3,3'-trione) and 3-methyleneoxindoles showed very interesting molecular diversity under different reaction conditions. The base-promoted annulation reaction of bindone and 3-phenacylideneoxindoles in DCM at room temperature afforded spiro[indeno[1,2-a]fluorene-5,3'-indoline] derivatives in good yields and with high diastereoselectivity. However, the similar reaction of 2-(2-oxoindolin-3-ylidene) acetates resulted in Z/E-isomeric spiro[indeno[1,2-a]fluorene-5,3'-indolines] with diastereomeric ratios of 2:1 to 10:1. On the other hand, the DABCO-promoted annulation reaction of bindone and 3-methyleneoxindoles in acetonitrile at different temperatures selectively gave spiro[benzo[5,6]pentaleno[1,6a-b]naphthalene-7,3'-indoline] derivatives and complex dispiro[indoline-3,6'-[4b,6a]ethanoindeno[1,2-a]fluorene-14',3″-indolines] in satisfactory yields.

Unnatural biosynthesis by an engineered microorganism with heterologously expressed natural enzymes and an artificial metalloenzyme.

Synthetic biology enables microbial hosts to produce complex molecules that are otherwise produced by organisms that are rare or difficult to cultivate, but the structures of these molecules are limited to those formed by chemical reactions catalyzed by natural enzymes. The integration of artificial metalloenzymes (ArMs) that catalyze unnatural reactions into metabolic networks could broaden the cache of molecules produced biosynthetically by microorganisms. We report an engineered microbial cell expressing a heterologous biosynthetic pathway, which contains both natural enzymes and ArMs, that produces an unnatural product with high diastereoselectivity. To create this hybrid biosynthetic organism, we engineered Escherichia coli (E. coli) with a heterologous terpene biosynthetic pathway and an ArM containing an iridium-porphyrin complex that was transported into the cell with a heterologous transport system. We improved the diastereoselectivity and product titer of the unnatural product by evolving the ArM and selecting the appropriate gene induction and cultivation conditions. This work shows that synthetic biology and synthetic chemistry can produce, together with natural and artificial enzymes in whole cells, molecules that were previously inaccessible to nature.

Dual C(sp3)-H Functionalization of Cyclic Ethers via Singlet Oxygen-Mediated Ring Opening and Ring Closing.

A metal-free dual C(sp3)-H bond functionalization of saturated cyclic ethers via photooxidative singlet oxygen-mediated ring opening and ring closing has been developed, providing a method for generating hydrobenzofurans/pyrans/dioxins. Mechanistic studies have confirmed that ring-opening intermediates were effectively generated by singlet oxygen-mediated C(sp3)-H activation and efficiently reacted with aldehydes and activated methylene compounds to form a wide array of products with high diastereoselectivities (up to >95:5 dr). This study is a rare example of α,β-dual C(sp3)-H bond functionalization of ethers.

Directed Nickel-Catalyzed Diastereoselective Reductive Difunctionalization of Alkenyl Amines.

We report herein an intermolecular syn-arylalkylation and alkenylalkylation of alkenyl amines with two different organohalides (iodides and bromides) using Ni(II) catalyst. The cleavable bidentate quinolinamide is utilized after extensive directing group screening to enable olefin difunctionalization with high levels of regio-, chemo-, and diastereocontrol. This general and practical protocol is compatible with α- or β-substituted terminal alkenes and internal alkenes, providing rapid access to branched aliphatic amines bearing two skipped and vicinal stereocenters with high diastereoselectivities that would otherwise be difficult to synthesize.

O2‐Assisted Four‐Component Reaction of Vinyl Magnesium Bromide with Chiral N‐tert‐Butanesulfinyl Imines To Form syn‐1,3‐Amino Alcohols

An O2 -assisted, four-component reaction has been developed to synthesize a wide range of syn-1,3-amino alcohols in one step. The reaction proceeds by oxygenation of vinyl magnesium bromide (component-I) with O2 (component-II) to give a magnesium enolate of acetaldehyde, which undergoes addition to a chiral N-tert-butanesulfinyl imine (component-III) followed by a sequential addition with excess vinyl magnesium bromide (component-IV). The approach allows diastereoselective synthesis of anti/syn- and syn/syn-3-amino-1,5-diols in good yields with high diastereoselectivity. The method was illustrated in an efficient, four-step synthesis of piperidine alkaloid (-)-2'-epi-ethylnorlobelol.

O2‐Assisted Four‐Component Reaction of Vinyl Magnesium Bromide with Chiral N‐tert‐Butanesulfinyl Imines To Form syn‐1,3‐Amino Alcohols

AbstractAn O2‐assisted, four‐component reaction has been developed to synthesize a wide range of syn‐1,3‐amino alcohols in one step. The reaction proceeds by oxygenation of vinyl magnesium bromide (component‐I) with O2 (component‐II) to give a magnesium enolate of acetaldehyde, which undergoes addition to a chiral N‐tert‐butanesulfinyl imine (component‐III) followed by a sequential addition with excess vinyl magnesium bromide (component‐IV). The approach allows diastereoselective synthesis of anti/syn‐ and syn/syn‐3‐amino‐1,5‐diols in good yields with high diastereoselectivity. The method was illustrated in an efficient, four‐step synthesis of piperidine alkaloid (−)‐2′‐epi‐ethylnorlobelol.

A Molecular Replication Process Drives Supramolecular Polymerization.

Supramolecular polymers are materials in which the connections between monomers in the polymer main chain are non-covalent bonds. This area has seen rapid expansion in the last two decades and has been exploited in several applications. However, suitable contiguous hydrogen-bond arrays can be difficult to synthesize, placing some limitations on the deployment of supramolecular polymers. We have designed a hydrogen-bonded polymer assembled from a bifunctional monomer composed of two replicating templates separated by a rigid spacer. This design allows the autocatalytic formation of the polymer main chain through the self-templating properties of the replicators and drives the synthesis of the bifunctional monomer from its constituent components in solution. The template-directed 1,3-dipolar cycloaddition reaction between nitrone and maleimide proceeds with high diastereoselectivity, affording the bifunctional monomer. The high binding affinity between the self-complementary replicating templates that allows the bifunctional monomer to polymerize in solution is derived from the positive cooperativity associated with this binding process. The assembly of the polymer in solution has been investigated by diffusion-ordered NMR spectroscopy. Both microcrystalline and thin films of the polymeric material can be prepared readily and have been characterized by powder X-ray diffraction and scanning electron microscopy. These results demonstrate that the approach described here is a valid one for the construction of supramolecular polymers and can be extended to systems where the rigid spacer between the replicating templates is replaced by one carrying additional function.

Stereochemistry and chiroptical properties of bimetallic single helicates of hexapyrrole-α,ω-dicarbaldimines with high diastereoselectivity

Bimetallic complexes of hexapyrrole-[Formula: see text],[Formula: see text]-dicarbaldimines consisting of a pair of four-coordinate metal sites adopt a helical closed [Formula: see text]-symmetric form or sigmoidal open forms depending on whether the 2,2[Formula: see text]-bipyrrole subunit at the center of the hexapyrrole chain takes cis- or trans-conformation. X-ray crystallography of a bisNi complex having N-[([Formula: see text]-1-cyclohexylethyl]carbaldimine units at both ends of the hexapyrrole chain revealed a non-symmetric heterohelical open form where the metal coordination sites of opposite helical sense sit on opposite sides of the central 2,2[Formula: see text]-bipyrrole subunit. BisPd complexes preferred a closed [Formula: see text] form and a steric bulk at the 3,3[Formula: see text]-position of the 2,2[Formula: see text]-bipyrrole subunit improved the helical sense bias. A bisPd complex with N-[([Formula: see text]-1-cyclohexylethyl]carbaldimine units adopts a helical closed [Formula: see text] form exclusively with full bias for a [Formula: see text]-helical sense. These bimetallic single stranded helicates were reversibly oxidized to [Formula: see text]-cation radicals at 0.1∼0.3 V vs. a ferrocene/ferrocenium couple and spectroelectrochemistry revealed remarkable absorption and CD spectral changes in the Vis-NIR region.

Highly Stereoselective Aldol Reactions by Memory of Chirality: Synthesis of Quaternary β‐Hydroxy α‐Amino Acids

AbstractWe describe here an asymmetric aldol reaction based on the principle of Memory of Chirality. From α‐amino acids such as leucine and methionine, we have synthesized in two steps quaternary α‐amino acid derivatives with high diastereoselectivity and enantioselectivity, using the chirality of the initial α‐amino acid as the only chirality source. Furthermore, we were able to determine the relative and absolute configurations of the aldol products thanks to crystallographic structures and thus showed that the relative configuration depended on the aldehyde employed. We proposed a stereoselectivity explanation and obtained also quaternary β‐hydroxy α‐amino acids after acidic hydrolysis.

Development of a Chiral N-Alkoxyamide Strategy and Application to the Asymmetric Total Synthesis of Fasicularin

AbstractThe asymmetric total synthesis of fasicularin by a chiral N-alkoxyamide strategy is reported. Incorporation of the chiral alkoxy group onto an amide nitrogen changes the original reactivity of the amide, enabling two key transformations: aza-spirocyclization and the reductive Strecker reaction. DFT calculations indicate that pyramidalization of the N-alkoxyamide nitrogen is crucial to produce a cyclic hemiaminal in equilibrium, which undergoes aza-spirocyclization. The chiral alkoxy group is also used as a stereocontrol element to establish two consecutive stereocenters. The iridium-catalyzed reductive Strecker reaction of the N-alkoxylactam provides the aminonitrile with high diastereoselectivity.

Phase-Transfer Catalyzed Asymmetric [4 + 1] Annulations for the Synthesis of Chiral 2,2-Disubstituted Tetrahydrothiophenes.

An efficient catalytic asymmetric [4 + 1] reaction, which features the use of simple β-keto esters as one-carbon nucleophiles and 5-succinimidothio-pent-2-enoates as four-atom bielectrophiles, has been developed in the presence of a bifunctional chiral phase-transfer catalyst. The new annulation provides a distinct protocol to access the functionalized 2-acyl-2-carboxyl tetrahydrothiophenes bearing consecutive quaternary and tertiary carbon stereocenters in high diastereoselectivities and enantioselectivities. Moreover, the prepared products could be readily transformed into the chiral 2-alkyl-2-carboxyl tetrahydrothiophenes via two steps of debenzoylation and alkylation reactions.

Diastereoselective Formal [5+2] Cycloaddition of Diazo Arylidene Succinimides-Derived Rhodium Carbenes and Aldehydes: A Route to 2-Benzoxepines

We report on a facile method for the preparation of 2-benzoxepine derivatives as a result of Rh(II)-catalyzed decomposition of diazo arylidene succinimides in the presence of aldehydes. The process is thought to involve the formation of styryl carbonyl ylide which undergoes 1,7-electrocyclization and subsequent 1,5-hydrogen shift. In some cases, the competition of the target reaction and [3+2] dipolar cycloaddition of the intermediate carbonyl ylide to another molecule of diazo substrate was observed. Generally, the desired 2-benzoxepines were isolated in good to high yields and high diastereoselectivity. The developed original approach toward a 2-benzoxepine core via formal [5+2] cycloaddition of styryl carbenoids and aldehydes significantly expands the arsenal of synthetic methods for producing this scaffold.

A Mild and Highly Diastereoselective Preparation of N-Alkenyl-2-Pyridones via 2-Halopyridinium Salts and Aldehydes.

An experimentally simple one-pot preparation of N-alkenyl-2-pyridones is reported. The reaction features mild conditions using readily available 2-halopyridinium salts and aldehydes. N-Alkenyl-2-pyridone formation proceeds with high diastereoselectivity, and a wide range of aldehyde reaction partners is tolerated. Pyridone products are also amenable to further manipulation, including conversion to N-alkyl pyridones and polycyclic ring systems.