High Diastereocontrol Research Articles

Acyl Radical Addition to Activated Olefins: A Stereocontrolled Route to Polysubstituted Tetrahydrofurans and Lactones, and Application to the Total Synthesis of (+)‐No. 2106 A

The addition of acyl radicals to α,β‐unsaturated esters, followed by acetalization and reduction of the resulting hemiacetal was shown to provide a straightforward access to tetrahydrofurans, and fused tetrahydrofuran–lactones in good yield with high 1,3‐stereocontrol. Similar addition reactions to five‐ and six‐membered‐ring α‐methylenelactones led to trisubstituted lactones with high diastereocontrol, using (Me3Si)3SiH as hydrogen‐atom‐transfer agent. This strategy was applied to the first total synthesis of (+)‐No. 2106 A, a fused THF–lactone produced by an endophytic fungus isolated from the seeds of the mangrove Avicennia marina.

Dearomatizing Radical Cyclizations and Cyclization Cascades Triggered by Electron-Transfer Reduction of Amide-Type Carbonyls.

Highly selective dearomatizing radical cyclizations and cyclization cascades, triggered by single electron transfer to amide-type carbonyls by SmI2-H2O-LiBr, provide efficient access to unprecedented spirocyclic scaffolds containing up to five stereocenters with high diastereocontrol. The first dearomatizing radical cyclizations involving radicals derived from amide carbonyls by single electron transfer take place under mild conditions and engage a range of aromatic and heteroaromatic systems present in the barbiturate substrates. The radical cyclizations deliver new polycyclic hemiaminals or enamines selectively, depending on the conditions employed, that are based on a medicinally proven scaffold and can be readily manipulated.

Palladium‐Catalyzed Remote ortho‐CH Alkenylation of Alkyl Aryl Sulfones: Access to Densely Functionalized Indane Derivatives

AbstractA practical method for the palladium‐catalyzed ortho‐olefination of benzyl and phenethyl 2‐pyridyl sulfones with electron‐deficient alkenes using N‐fluoro‐2,4,6‐trimethylpyridinium triflate ([F+]) as the terminal oxidant is described. The chelating auxiliary (2‐pyridyl)sulfonyl unit was demonstrated to be the key to the success of this reaction, which occurs efficiently with excellent regioselectivity and monosubstitution selectivity. A variety of steric and electronic changes to both coupling partners is tolerated, including substitution at the benzylic position of the sulfone compound. Furthermore, no appreciable loss of enantiopurity is observed when using non‐racemic substrates. This method provides access to indane derivatives holding three contiguous stereogenic centers with high diastereocontrol. The indane framework was constructed by intramolecular Michael addition of the α‐sulfonyl carbanion to the electrophilic alkene.magnified image

Copper-Catalyzed Double Additions and Radical Cyclization Cascades in the Re-Engineering of the Antibacterial Pleuromutilin.

A general synthetic sequence involving simply prepared starting materials provides rapid access to diverse, novel tricyclic architectures inspired by pleuromutilin. SmII‐mediated radical cyclization cascades of dialdehydes, prepared using a new, one‐pot, copper‐catalyzed double organomagnesium addition to β‐chlorocyclohexenone, proceed with complete sequence selectivity and typically with high diastereocontrol to give analogues of the target core. Our expedient approach (ca. 7 steps) allows non‐traditional, de novo synthetic access to analogues of the important antibacterial that can′t be prepared from the natural product by semisynthesis.

Formaldehyde as Tethering Organocatalyst: Highly Diastereoselective Hydroaminations of Allylic Amines.

Catalysts possessing sufficient activity to achieve intermolecular alkene hydroaminations under mild conditions are rare, and this likely accounts for the scarcity of asymmetric variants of this reaction. Herein, highly diastereoselective hydroaminations of allylic amines utilizing hydroxylamines as reagents and formaldehyde as catalyst are reported. This catalyst induces temporary intramolecularity, which results in high rate accelerations, and high diastereocontrol with either chiral allylic amines or chiral hydroxylamines. The reaction scope includes internal alkenes. Overall this work provides a new, stereocontrolled route to form complex vicinal diamines.

Gold(I)-catalyzed polycyclization of linear dienediynes to seven-membered ring-containing polycycles via tandem cyclopropanation/Cope rearrangement/C-H activation.

A novel gold(I)-catalyzed polycyclization of easily prepared linear dienediynes has been developed for the construction of fused 5,7,6-tricyclic ring systems in one step with high diastereocontrol. The polycyclization, a formal [4 + 3]/C-H activation reaction, takes place through gold(I)-catalyzed intramolecular cyclopropanation of diene with diyne, Cope rearrangement of cis-alkenylalkynylcyclopropane, aliphatic C-H activation via a seven-membered-ring allene intermediate, and [1,2]-H and -G (H or OAc) shifts.

ChemInform Abstract: Hydrogen Bond Directed Epoxidation: Diastereoselective Olefinic Oxidation of Allylic Alcohols and Amines

AbstractReview: [26 refs.

Isothiourea-Catalyzed Asymmetric Synthesis of β-Lactams and β-Amino Esters from Arylacetic Acid Derivatives and N-Sulfonylaldimines

The isothiourea HBTM-2.1 (5 mol %) catalyzes the asymmetric formal [2 + 2] cycloaddition of both arylacetic acids (following activation with tosyl chloride) and preformed 2-arylacetic anhydrides with N-sulfonylaldimines, generating stereodefined 2,3-diaryl-β-amino esters (after ring-opening) and 3,4-diaryl-anti-β-lactams, respectively, with high diastereocontrol (up to >95:5 dr) and good to excellent enantiocontrol. Deprotection of the N-tosyl substituent within the β-lactam framework was possible without racemization by treatment with SmI2.

Asymmetric addition of chiral boron-ate complexes to cyclic iminium ions

Boron-ate complexes derived from enantioenriched secondary benzylic boronic esters and aryl lithiums have been reacted with quinolinium, pyridinium and dihydroisoquinolinium salts to give enantioenriched heterocyclic structures with very high diastereocontrol over two contiguous stereogenic centres (87: 1 3–99 : 1 dr; >95 : 5 es). The salts were derived from the corresponding heterocycle and Troc-Cl or dimethylTroc-Cl. In the case of the quinolinium and pyridinium salts, the presence of a 3-carboxyamide group increased both reactivity and diastereoselectivity. The unusually high diastereoselectivity observed is thought to originate from strong cation–π interactions between the cationic heterocycle and the electron rich benzylic boronate complex with minimisation of steric interactions between the substituents on the ate complex and the non-planar substituents on the heterocycle.

Hydrogen bond directed epoxidation: diastereoselective olefinic oxidation of allylic alcohols and amines.

This article compares the diastereoselective epoxidation of acyclic and cyclic allylic alcohols, with the chemo- and diastereoselective olefinic oxidation of a range of acyclic and cyclic allylic amines. The diastereoselectivity in these systems is compared and a discussion about the origin of this high diastereocontrol is also presented. The ammonium directed epoxidation methodology has been extended to more complex substrates and representative applications of this protocol in natural product synthesis are also summarised.

ChemInform Abstract: A Diastereocontrolled Route to 10‐Arylpyrrolo[1,2‐b]isoquinolines.

The diastereocontrolled preparation of a series of 10-aryl-substituted pyrroloisoquinolines is achieved through a synthetic design that involves two key cyclization steps. First, the iodine(III)-mediated reaction of a series of N-benzylpentynamides leads to the generation of the 5-aroylpyrrolidinone skeletons. Finally, after reduction of the generated ketone group into the corresponding carbinol, the effect of a number of different acidic conditions was studied to assist the second cyclization step that occurs through an aromatic electrophilic substitution process. The study of the stereochemical course of this step led us to conclude that it takes place through a SN1 mechanism with very high (>95% anti) diastereocontrol.

Cover Picture: Total Synthesis of (+)-Pleuromutilin (Chem. Eur. J. 21/2013)

The first enantiospecific total synthesis of (+)-pleuromutilin is reported. A SmI2-mediated cyclisation cascade allows access to the tricyclic core of the antibacterial natural product, constructing the five- and eight-membered rings in a single step, with high diastereocontrol. For more details, see the Full Paper by D. J. Procter et al. on page 6718 ff.

A Diastereocontrolled Route to 10-Arylpyrrolo[1,2-b]isoquinolines

The diastereocontrolled preparation of a series of 10-aryl-substituted pyrroloisoquinolines is achieved through a synthetic design that involves two key cyclization steps. First, the iodine(III)-mediated reaction of a series of N-benzylpentynamides leads to the generation of the 5-aroylpyrrolidinone skeletons. Finally, after reduction of the generated ketone group into the corresponding carbinol, the effect of a number of different acidic conditions was studied to assist the second cyclization step that occurs through an aromatic electrophilic substitution process. The study of the stereochemical course of this step led us to conclude that it takes place through a S(N)1 mechanism with very high (>95% anti) diastereocontrol.

The combined C-H functionalization/Cope rearrangement: discovery and applications in organic synthesis.

The development of methods for the stereoselective functionalization of sp(3) C-H bonds is a challenging undertaking. This Account describes the scope of the combined C-H functionalization/Cope rearrangement (CHCR), a reaction that occurs between rhodium-stabilized vinylcarbenoids and substrates containing allylic C-H bonds. Computational studies have shown that the CHCR reaction is initiated by a hydride transfer to the carbenoid from an allyl site on the substrate, which is then rapidly followed by C-C bond formation between the developing rhodium-bound allyl anion and the allyl cation. In principle, the reaction can proceed through four distinct orientations of the vinylcarbenoid and the approaching substrate. The early examples of the CHCR reaction were all highly diastereoselective, consistent with a reaction proceeding via a chair transition state with the vinylcarbenoid adopting an s-cis conformation. Recent computational studies have revealed that other transition state orientations are energetically accessible, and these results have guided the development of highly stereoselective CHCR reactions that proceed through a boat transition state with the vinylcarbenoid in an s-cis configuration. The CHCR reaction has broad applications in organic synthesis. In some new protocols, the CHCR reaction acts as a surrogate to some of the classic synthetic strategies in organic chemistry. The CHCR reaction has served as a synthetic equivalent of the Michael reaction, the vinylogous Mukaiyama aldol reaction, the tandem Claisen rearrangement/Cope rearrangement, and the tandem aldol reaction/siloxy-Cope rearrangement. In all of these cases, the products are generated with very high diastereocontrol. With a chiral dirhodium tetracarboxylate catalyst such as Rh(2)(S-DOSP)(4) or Rh(2)(S-PTAD)(4), researchers can achieve very high levels of asymmetric induction. Applications of the CHCR reaction include the effective enantiodifferentiation of racemic dihydronaphthalenes and the total synthesis of several natural products: (-)-colombiasin A, (-)-elisapterosin B, and (+)-erogorgiaene. By combining the CHCR reaction into a further cascade sequence, we and other researchers have achieved the asymmetric synthesis of 4-substituted indoles, a new class of monoamine reuptake inhibitors.

Radical Cyclization Cascades of Unsaturated Meldrum’s Acid Derivatives

Unsaturated, differentially substituted Meldrum's acid derivatives undergo cascade cyclizations upon ester reduction with SmI(2)-H(2)O. The cascade cyclizations proceed in good yield and with high diastereocontrol and convert simple, achiral starting materials to complex molecular architectures, bearing up to four stereocenters, in a single operation. The cascades are triggered by the generation and trapping of unusual radical-anions formed by electron transfer to the ester carbonyl.

Synthesis of Enantiopure Substituted Piperidines via an Aziridinium Ring Expansion

Herein we report a novel methodology for the asymmetric synthesis of 3-substituted piperidines from readily available chiral building blocks. This method, which features a novel irreversible dihydropyrole-tetrahydropyridine ring expansion, allows the introduction of a large variety of substituents at the 3-position and permits substitution at the 2- and 6-position giving mono-, di-, or trisubstituted piperidines with high diastereocontrol.

Visible‐Light‐Induced Photoreductive Generation of Radicals from Epoxides and Aziridines

It's a trap! Both epoxides and aziridines substituted by an aryl ketone can be reduced efficiently using visible-light photoredox catalysts. The radicals generated were trapped by allyl sulfones, and formed α-branched β-hydroxy or amino derivatives with high diastereocontrol (see scheme; dtbbpy=4,4′-di-tert-butyl-2,2′-bipyridine, ppy=2-phenylpyridine). Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

SmI 2-mediated dialdehyde ‘radical then aldol’ cyclization cascades: a feasibility study

Dialdehydes undergo ‘radical then aldol’ cyclization cascades upon treatment with SmI 2, generating four contiguous stereocenters with high diastereocontrol. The scope of the process has been explored and the cascade has been extended to also include lactone reduction.

Functionalized fluoroalkyl heterocycles by 1,3-dipolar cycloadditions with γ-fluoro-α-nitroalkenes

Differently fluorinated γ-fluoro-α-nitroalkenes 1a– d are effective dipolarophiles in 1,3-dipolar cycloadditions with nitrones and azomethine ylides, respectively, providing fluoroalkyl isoxazolidines 3– 12 and pyrrolidines 13– 14 in good to excellent yields, with nearly complete regiocontrol and total diastereocontrol in favor of the isomers having anti-configuration of the nitro- and fluoroalkyl-substituted carbon centers. The 3,4-cis-cycloadducts were generally produced in higher ratios. In the case of chiral nitrones, such as 2e, very high diastereocontrol in favor of the endo bicyclic cycloadduct 11 was observed. Interestingly, in most cases the chlorodifluoro nitroalkene 1b was found to afford the best diastereocontrol.

SmI 2-mediated dialdehyde cyclization cascades

Dialdehydes undergo sequenced SmI 2-mediated cyclization cascades generating four contiguous stereocenters with high diastereocontrol.