Brønsted Acid Catalyzed Addition of Enamides to ortho‐Quinone Methide Imines—An Efficient and Highly Enantioselective Synthesis of Chiral Tetrahydroacridines

The direct and highly enantioselective synthesis of tetrahydroacridines was achieved through the phosphoric acid catalyzed addition of enamides to in situ generated ortho‐quinone methide imines and subsequent elimination. This novel one‐step process constitutes a very efficient, elegant, and selective synthetic approach to valuable N‐heterocycles with a 1,4‐dihydroquinoline motif. By subsequent highly diastereoselective hydrogenation and N‐deprotection the reaction products were easily converted into free hexahydroacridines with a total of three new stereogenic centers.     

Highly cis‐Diastereoselective Synthesis of Coumarin‐Based 2,3‐Disubstituted Dihydrobenzothiazines by Organocatalysis

An efficient and organocatalyzed asymmetric reaction of phenacyl halides with coumarin‐based dihydrobenzothiazoles was developed to afford cis‐2,3‐disubstituted 3,4‐dihydro‐2H‐benzothiazines. This method provides a one‐step and highly diastereoselective route to a wide variety of coumarin‐based 3,4‐dihydro‐2H‐benzothiazines using the cheap and commercially available Cinchona alkaloid quinine hydrochloride.     

A Highly Diastereoselective Three‐component Domino Reaction in Water Yielding Poly‐substituted 4,5‐Dihydropyrroles

An efficient methodology for highly diastereoselective synthesis of poly‐substituted 4,5‐dihydropyrrole derivatives from readily available common reactants in water has been developed. During domino processes, the formation of pyrrole skeleton and its C2‐hydroxylation and C3‐arylamination were readily achieved via metal‐free [3+2] heterocyclization in a one‐pot operation.     

Total Synthesis and Absolute Configuration Assignment of MRSA Active Garcinol and Isogarcinol

A short total synthesis of (±)‐garcinol and (±)‐isogarcinol, two endo‐type B PPAPs with reported activity against methiciline resistant Staphylococcus aureus (MRSA), is presented. The separation of framework‐constructing from framework‐decorating steps and the application of two highly regio‐ and stereoselective Pd‐catalysed allylations, that is, the Pd‐catalysed decarboxylative Tsuji–Trost allylation and the diastereoselective Pd‐catalysed allyl–allyl cross‐coupling, are key elements that allowed the total synthesis to be accomplished within 13 steps starting from acetylacetone. After separation of the enantiomers the absolute configurations of the four natural products (i.e., (?)‐garcinol, (+)‐guttiferone E (i.e., ent‐garcinol), (?)‐isogarcinol, and (+)‐isoxanthochymol (i.e., ent‐isogarcinol)) were assigned based on ECD spectroscopy.     

Expedient Construction of the Hexacycle of Franchetine

Franchetine, a unique 7,17‐seco type of norditerpenoid alkaloid, possesses a highly congested polycyclic architecture coupled with nine stereogenic centers. Here we present an efficient synthetic approach for the intact hexacyclic framework of franchetine from the known tricyle 16 in 20 steps. The synthesis features a diastereoselective 6‐exo‐tet radical cyclization for construction of ring A and a unique oxidative Wagner–Meerwein‐type rearrangement to realize the functionalized [3.2.1] bridging ring CD.     

Total Synthesis of the Isodon Diterpene Sculponeatin N

The total synthesis of sculponeatin N, a bioactive polycyclic diterpene isolated from Isodon sculponeatus, is reported. Key features of the synthesis include diastereoselective Nazarov and ring‐closing metathesis reactions, and a highly efficient formation of the bicyclo[3.2.1]octane ring system by a reductive radical cyclization.     

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.     

Experimental and Theoretical Investigations of the Stereoselective Synthesis of P‐Stereogenic Phosphine Oxides

An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides has been developed, incorporating the use of (1S,2S)‐2‐aminocyclohexanol as the chiral auxiliary. The method relies on three key steps: 1) Highly diastereoselective formation of P^V oxazaphospholidine, rationalized by a theoretical study; 2) highly diastereoselective ring‐opening of the oxazaphospholidine oxide with organometallic reagents that takes place with inversion of configuration at the P atom; 3) enantioselective synthesis of phosphine oxides by cleavage of the remaining P?O bond. Interestingly, the use of a P^III phosphine precursor afforded a P‐epimer oxazaphospholidine. Hence, the two enantiomeric phosphine oxides can be synthesized starting from either a P^V or a P^III phosphine precursor, which constitutes a clear advantage for the stereoselective synthesis of sterically hindered phosphine oxides.     

Type II Intramolecular [5+2] Cycloaddition: Facile Synthesis of Highly Functionalized Bridged Ring Systems

A type II intramolecular oxidopyrylium‐mediated [5+2] cycloaddition reaction allows the efficient and diastereoselective formation of various highly functionalized and synthetically challenging bridged seven‐membered ring systems (such as bicyclo[4.4.1]undecane, bicyclo[4.3.1]decane, bicyclo[5.4.1]dodecane, and bicyclo[6.4.1]]tridecane). This simple, thermal, direct transformation has a broad substrate scope and is high yielding, with high functional‐group tolerance and unique endo selectivity. The highly strained tricyclic cores of ingenol mebutate (picato) and cyclocitrinol are synthesized efficiently and diastereoselectively using this methodology.     

Catalytic Asymmetric Alkylation Reactions for the Construction of Protected Ethylene‐Amino and Propylene‐Amino Motifs Attached to Quaternary Stereocentres

An efficient catalytic and stereoselective method for the direct construction of protected ethylene‐amino and propylene‐amino scaffolds attached to quaternary stereocentres is reported. Preliminary investigations revealed a mild base catalysed nucleophilic ring opening of N‐sulfonyl aziridines using the commercially available phosphazene base 2‐tert‐butylimino‐2‐diethylamino‐1,3‐dimethyl‐perhydro‐1,3,2‐diazaphosphorine (BEMP) was possible and resulted in highly efficient alkylation reactions with a range of methine carbon acids. This reaction could be rendered highly asymmetric (up to 97 % ee) by employing phase‐transfer catalysis to control stereoinduction. Incorporation of alkyl substituents onto the aziridine electrophile, resulted in a highly diastereoselective (up to 30:1 d.r.) variant of this methodology. A further extension using N‐protected cyclic sulfamidates as the electrophilic component was successful with a range of pro‐nucleophiles (up to 96 % ee and 45:1 d.r.) and allowed a range of nitrogen protecting groups (carbamate, sulfonyl, phosphonyl, benzyl) to be incorporated into the alkylation adducts. Finally, the utility of the products have been demonstrated in the synthesis of useful heterocycles and compounds bearing structural components of natural products.     

Ring‐Closing Metathesis and Photo‐Fries Reaction for the Construction of the Ansamycin Antibiotic Kendomycin: Development of a Protecting Group Free Oxidative Endgame

Two convergent total syntheses of the ansa‐polyketide (?)‐kendomycin ( 1 ) are described. The syntheses benefit from the use of readily available and cheap starting materials. Highly complex diastereoselective Claisen–Ireland rearrangements were used to introduce the (E)‐double bond and the C16‐Me group. The ring closure of the strained ansa macrocycle was achieved by ring‐closing metathesis and a highly efficient combination of macrolactonization and photo‐Fries reaction. A protecting group free endgame via an unstable o‐quinone is presented. Additionally some unsuccessful synthetic efforts towards the total synthesis of 1 are described.     

Dearomative Indole [5+2] Cycloaddition Reactions: Stereoselective Synthesis of Highly Functionalized Cyclohepta[b]indoles

The first dearomative indole [5+2] cycloaddition reaction with an oxidopyrylium ylide resulted in efficient and diastereoselective construction of some highly functionalized and synthetically challenging oxacyclohepta[b]indoles. The protocol proceeds under very mild reaction conditions, thus enabling high functional‐group tolerance and unique endo selectivity.     

Catalytic Asymmetric Crotylation of Aldehydes: Application in Total Synthesis of (−)‐Elisabethadione

A new, highly efficient Lewis base catalyst for a practical enantio‐ and diastereoselective crotylation of unsaturated aldehydes with E‐ and Z‐crotyltrichlorosilanes has been developed. The method was employed as a key step in a novel asymmetric synthesis of bioactive serrulatane diterpene (?)‐elisabethadione. Other strategic reactions for setting up the stereogenic centers included anionic oxy‐Cope rearrangement and cationic cyclization. The synthetic route relies on simple, high yielding reactions and avoids use of protecting groups or chiral auxiliaries.     

Enantiodivergent Synthesis of (+)‐ and (−)‐Pyrrolidine 197B: Synthesis of trans‐2,5‐Disubstituted Pyrrolidines by Intramolecular Hydroamination

A highly efficient, diastereoselective, iron(III)‐catalyzed intramolecular hydroamination/cyclization reaction involving α‐substituted amino alkenes is described. Thus, enantiopure trans‐2,5‐disubstituted pyrrolidines and trans‐5‐substituted proline derivatives were synthesized by means of a combination of enantiopure starting materials, easily available from l ‐α‐amino acids, with sustainable metal catalysts such as iron(III) salts. The scope of this methodology is highlighted in an enantiodivergent approach to the synthesis of both (+)‐ and (?)‐pyrrolidine 197B alkaloids from l ‐glutamic acid. In addition, a computational study was carried out to gain insight into the complete diastereoselectivity of the transformation.     

A Biomimetic Synthesis of (±)‐Basiliolide B

A highly diastereoselective and practical biomimetic total synthesis of (±)‐basiliolide B has been achieved through the study of the two proposed biosynthetic pathways (O‐methylation and O‐acylation) for the unprecedented 7‐methoxy‐4,5‐dihydro‐3H‐oxepin‐2‐one (C ring). The synthesis featured a cyclopropanation/ring opening strategy for establishing the stereogenic centers at C8 and C9, a biomimetic 2‐pyrone Diels–Alder cycloaddition for the synthesis of the ABD ring system, and finally a highly efficient biomimetic intramolecular O‐acylation for the C ring formation. This result provides an important perspective on the biosynthetic origin of the unprecedented 7‐membered acyl ketene acetal moiety of the C ring.     

Total Synthesis of (−)‐Caprazamycin A

Caprazamycin A has significant antibacterial activity against Mycobacterium tuberculosis (TB). The first total synthesis is herein reported and features a) the scalable preparation of the syn‐β‐hydroxy amino acid with a thiourea‐catalyzed diastereoselective aldol reaction, b) construction of a diazepanone with an unstable fatty‐acid side chain, and c) global deprotection with hydrogenation. This report provides a route for the synthesis of related liponucleoside antibiotics with fatty‐acid side chains.     

Single‐Electron/Pericyclic Cascade for the Synthesis of Dienes

The highly efficient and diastereoselective synthesis of E dienes has been accomplished through radical cyclization of bromoallyl hydrazones. This methodology has been further extended to generate these products through a one‐pot condensation/radical cyclization/cycloreversion cascade from simple aldehyde starting materials in high yields (>75 %) and high diastereoselectivities (>95:5). Mechanistic investigations suggest that the cascade reaction proceeds through a cyclic diazene intermediate prior to the cycloreversion.     

Highly Efficient Asymmetric Synthesis of Vinylic Amino Alcohols by Zn‐Promoted Benzoyloxyallylation of Chiral N‐tert‐Butanesulfinyl Imines: Facile and Rapid Access to (−)‐Cytoxazone

An efficient and convenient α‐hydroxyallylation approach for the asymmetric synthesis of a variety of β‐amino‐α‐vinyl alcohols has been successfully developed. A wide range of vinylic amino alcohol derivatives could be obtained in very good yields and with excellent diastereomeric ratios of up to 99:1 in favor of anti isomers by highly diastereoselective Zn‐promoted benzoyloxyallylation of chiral N‐tert‐butanesulfinyl imines with 3‐bromopropenyl benzoate at room temperature. In particular, excellent enantioinduction of the two new stereogenic centers was observed, with up to 98 % ee. The method provides a new route for the direct α‐hydroxyallylation of imines in a highly stereoselective manner. Moreover, the synthetic value of the method has also been demonstrated by the most concise and straightforward synthesis of (?)‐cytoxazone yet reported.     

Highly Diastereoselective Synthesis of α‐Difluoromethyl Amines from N‐tert‐Butylsulfinyl Ketimines and Difluoromethyl Phenyl Sulfone

The first highly efficient and stereoselective difluoromethylation of structurally diverse N‐tert‐butylsulfinyl ketimines has been achieved with an in situ generated PhSO₂CF₂^? anion, which provides a powerful synthetic method for the preparation of a variety of structurally diverse homochiral α‐difluoromethyl tertiary carbinamines, including α‐difluoromethyl allylic amines and α‐difluoromethyl propargylamines. The stereocontrol mode of the present diastereoselective difluoromethylation of ketimines was found to be different from that of other known fluoroalkylations of N‐tert‐butylsulfinyl aldimines, which suggests that a cyclic six‐membered transition state may be involved in the reaction.     

Stereoselective Total Synthesis of Eburnane‐Type Alkaloids Enabled by Conformation‐Directed Cyclization and Rearrangement

Controlling the cis C20/C21 relative stereochemistry remains an unsolved issue in the synthesis of eburnane‐type indole alkaloids. Provided herein is a simple solution to this problem by developing a unified and diastereoselective synthesis of four representative members of this class of natural products, namely, eburnamonine, larutensine, terengganensine B, and melokhanine E. The synthesis features the following key steps: a) an α‐iminol rearrangement transforming the 3‐hydroxyindolenine into spiroindolin‐3‐one, b) a highly diastereoselective conformation‐directed cyclization leading to the melokhanine skeleton with the desired C20/C21 cis stereochemistry, and c) either an aza‐pinacol or an unprecedented α‐aminoketone rearrangement converting spiroindolinone back into the indole skeleton.