Concise Asymmetric Total Synthesis Research Articles

A Divergent Polyene Cyclization for the Total Synthesis of Greenwayodendrines, Greenwaylactams, Polysin and Polyveoline.

We present a concise asymmetric total synthesis (5-8 steps) of nine sesquiterpenoid alkaloids featuring four different tetra-/pentacyclic scaffolds. To this end, a novel, bioinspired indole N-terminated cationic tricyclization has been developed, enabling the divergent synthesis of greenwayodendrines and polysin. Subtle variation of the C2-substituted indole cyclization precursor allowed switching between indole N- and C-termination. For the latter, a subsequent Witkop oxidation enabled conversion of the cyclopentene-fused indole into the eight-membered benzolactam to directly furnish the family of greenwaylactams. In addition, a diastereomeric C-termination product has been elaborated to provide access to polyveoline.

A Divergent Polyene Cyclization for the Total Synthesis of Greenwayodendrines, Greenwaylactams, Polysin and Polyveoline

AbstractWe present a concise asymmetric total synthesis (5–8 steps) of nine sesquiterpenoid alkaloids featuring four different tetra‐/pentacyclic scaffolds. To this end, a novel, bioinspired indole N‐terminated cationic tricyclization has been developed, enabling the divergent synthesis of greenwayodendrines and polysin. Subtle variation of the C2‐substituted indole cyclization precursor allowed switching between indole N‐ and C‐termination. For the latter, a subsequent Witkop oxidation enabled conversion of the cyclopentene‐fused indole into the eight‐membered benzolactam to directly furnish the family of greenwaylactams. In addition, a diastereomeric C‐termination product has been elaborated to provide access to polyveoline.

Concise Total Synthesis of (-)-Quinocarcin Enabled by Catalytic Enantioselective Reductive 1,3-Dipolar Cycloaddition of Secondary Amides.

A concise asymmetric total synthesis of (-)-quinocarcin has been accomplished with high step economy from commercially available starting materials. A catalytic enantioselective reductive 1,3-dipolar cycloaddition reaction of N-heteroaryl secondary amides with reactive dipolarophile using iridium/copper relay catalysis was developed to prepare the key chiral pyrrolidine intermediate with three stereocenters. This protocol features excellent regio-, exo- and enantioselectivities, broad substrate scope, and good functional group tolerance. The high efficiency was also ensured by a Rh(III)-catalyzed C-H activation/cyclization and a tandem diastereoselective hydrogenation/cyclization to construct the tetrahydroisoquinoline-pyrrolidine tetracyclic core unit of quinocarcin.

Concise Total Synthesis of (−)‐Quinocarcin Enabled by Catalytic Enantioselective Reductive 1,3‐Dipolar Cycloaddition of Secondary Amides

AbstractA concise asymmetric total synthesis of (−)‐quinocarcin has been accomplished with high step economy from commercially available starting materials. A catalytic enantioselective reductive 1,3‐dipolar cycloaddition reaction of N‐heteroaryl secondary amides with reactive dipolarophiles using iridium/copper relay catalysis was developed to prepare the key chiral pyrrolidine intermediate with three stereocenters. This protocol features excellent regio‐, exo‐ and enantioselectivities, broad substrate scope, and good functional group tolerance. The high efficiency was also ensured by a RhIII‐catalyzed C−H activation/cyclization and a tandem diastereoselective hydrogenation/cyclization to construct the tetrahydroisoquinoline‐pyrrolidine tetracyclic core unit of quinocarcin.

Concise Enantioselective Total Synthesis of Isopavine Alkaloids.

Herein, we report a concise asymmetric total synthesis of isopavine alkaloids, which feature a special azabicyclo[3.2.2]nonane tetracyclic skeleton. The key steps include iridium-catalyzed asymmetric hydrogenation of unsaturated carboxylic acids, Curtius rearrangement, and Eschweiler-Clarke methylation, which enable an enantioselective approach to isopavine alkaloids in 6-7 linear steps. Furthermore, for the first time, isopavine alkaloids, especially (-)-reframidine (3), are found to display effective antiproliferative effects on various cancer cell lines.

Intramolecular Rhodium-Catalyzed [(3+2+2)] Carbocyclization Reactions with Dienylidenecyclopropanes: A Concise and Stereoselective Total Synthesis of the Sesquiterpene (+)-Zizaene.

The development of an intramolecular rhodium-catalyzed [(3+2+2)] carbocyclization reaction of alkylidenecyclopropanes (ACPs) tethered to 1,4- and 1,5-skipped dienes is described. This transformation offers a new approach for the construction of bridged tricyclic compounds with up to three quaternary centers, which are suitable for the synthesis of challenging bioactive natural products. For instance, the synthetic utility of this transformation is illustrated through a concise asymmetric total synthesis of the sesquiterpene (+)-zizaene in ten steps from a commercially available starting material.

Photocatalytic enantioselective Minisci reaction of β-carbolines and application to natural product synthesis.

A highly efficient enantioselective direct C-H functionalization of β-carbolines via a Minisci-type radical process under a photo-redox and chiral phosphoric acid cooperative catalytic system has been disclosed. Through this protocol, a wide range of C1 aminoalkylated β-carbolines were constructed directly with high levels of enantioselectivities from readily available β-carbolines and alanine-derived redox-active esters. This transformation allows straightforward access to highly valuable enantioenriched β-carbolines, which are an intriguing structural motif in valuable natural products and synthetic bio-active compounds. This protocol has been utilized as a highly efficient synthetic strategy for the concise asymmetric total synthesis of marine alkaloids eudistomin X, (+)-eudistomidin B and (+)-eudistomidin I.

Asymmetric total synthesis of diosniponols A and B.

A concise asymmetric total synthesis of diosniponols A and B has been achieved based on an enantioselective Jacobsen kinetic resolution of racemic epoxide and the important 2,3-dihydro-4H-pyran-4-one moiety being installed by the metal-free δ-hydroxyalkynone rearrangement catalyzed by p-TsOH. A diastereoselective catalytic hydrogenation set the required all-syn stereochemistry leading to diosniponol A, which then, under the Mitsunobu inversion conditions, provided diosniponol B. The structure and absolute stereochemistry of the natural products were further confirmed.

Total Synthesis of (+)-Gilbertine: A Cyclopentanone-Based Approach.

From methyl jasmonate, the concise asymmetric total synthesis of uleine alkaloid gilbertine was reported. The synthesis demonstrated the power of a cyclopentanone-based approach involving the coupling of 2-aminobenzaldehyde and diazo-cyclopentanone for the rapid assembly of the hydrocarbazole natural product.

Asymmetric total synthesis of buprenorphine and dihydroetorphine

The concise asymmetric total synthesis of buprenorphine and dihydroetorphine has been achieved without the consumption of naturally occurring thebaine. Central to the synthesis is the employment of a thebaine-like intermediate, which is easily available through a bioinspired Pd-catalyzed dearomatization arene coupling reaction to forge the morphinan core.

Asymmetric Total Syntheses of (-)-Lycoramine, (-)-Lycoraminone, (-)-Narwedine, and (-)-Galanthamine.

A concise asymmetric total synthesis of naturally occurring Amaryllidaceae alkaloids sharing dihydrobenzofuran scaffolds, (-)-galanthamine (1a), (-)-lycoramine (1b), (-)-narwedine (2a), and (-)-lycoraminone (2b), is reported. Orthoester Johnson-Claisen rearrangement of allyl alcohol (+)-9 (98% ee) in diisopropylethylamine furnished enantioenriched cyclohexene (+)-8 (97.4% ee) with a quaternary stereogenic center.

Asymmetric Total Syntheses of Strychnos Alkaloids via Selective Fischer Indolization.

The complex structures and important biological functions of Strychnos alkaloids have attracted a great deal of attention from synthetic chemists. Herein, we describe the concise asymmetric total syntheses of the Strychnos alkaloids, (-)-dehydrotubifoline, (-)-tubifoline, and (-)-tubifolidine, as well as the formal total synthesis of (-)-strychnine. Our strategy features the construction of the common tetracyclic pyrrolo[2,3-d]carbazole structure using regioselective Fischer indolization on unsymmetrical cyclic ketones and late-stage functionalization for divergent synthesis. We developed a stepwise Fischer indolization featuring selective formation of enol triflate to solve the challenging regioselectivity problem, leading to the common tetracyclic ring skeleton in these Strychnos alkaloids. The regioselectivity of Fischer indolization on unsymmetrical cyclic ketones was studied on the basis of different types of ring systems and supported by density functional theory calculations. Overall, our success in the construction of this tetracyclic ring secured the syntheses of Strychnos alkaloids and may provide a general method for the total syntheses of various alkaloids containing this skeleton.

Highly Stereocontrolled Total Syntheses of Cedrane Sesquiterpenes via Cascade [5+2] Cycloaddition/Etherification

Comprehensive SummaryCedrane sesquiterpenes possess common tricyclo[5.3.1.01,5]undecane core structure. The varied oxa‐five‐membered ring decorating their core structure to form 8‐oxa‐tetracyclo[7.2.2.01,5.06,13]tridecane framework, containing six consecutive chiral centers (including two all‐carbon quaternary centers and one oxygenated quaternary carbon center), has proven to be a synthetic challenge and a biosynthetic mystery to date. Herein, we reported a distinct and biomimetic strategy to these sesquiterpenes resulting in the concise asymmetric total syntheses of three cedrane sesquiterpenes from simple commercially available building blocks. Key feature is exploitation of a cascade oxidative dearomatization‐induced [5+2] cycloaddition/etherification to highly stereocontrolled construct 8‐oxa‐tetracyclo[7.2.2.01,5.06,13]tridecane framework with five contiguous chiral centers in one step. In addition, a metal‐free I2‐catalyzed and DMSO‐mediated oxidative dehydroaromatization was applied to prepare curcuphenol and its derivatives from the highly functionalized cyclohexenones with minimal manipulations.

Total Synthesis of (-)-Canadine, (-)-Rotundine, (-)-Sinactine, and (-)-Xylopinine Using a Last-Step Enantioselective Ir-Catalyzed Hydrogenation.

A concise asymmetric total synthesis of a group of tetrahydroprotoberberine alkaloids, (-)-canadine, (-)-rotundine, (-)-sinactine, and (-)-xylopinine, has been accomplished in three steps from the commercially available corresponding disubstituted phenylethylamine and disubstituted benzaldehyde. Our synthesis toward these four alkaloids took advantage of the following strategy: in the first step, we achieved an efficient and sustainable synthesis of secondary amine hydrochlorides via a fully continuous flow; in the second step, we developed a Pictet-Spengler reaction/Friedel-Crafts hydroxyalkylation/dehydration cascade for the construction of the dihydroprotoberberine core structure (ABCD-ring); and in the last step, Ir-catalyzed enantioselective hydrogenation was employed for the introduction of the desired stereochemistry at the C-14 position in the tetrahydroprotoberberine alkaloids. This work significantly expedites the asymmetric synthesis of the entire tetrahydroprotoberberine alkaloid family as well as a more diverse set of structurally related non-natural analogues.

Recent advances in the total synthesis of vinigrol

(−)-Vinigrol, a unique, novel, and biologically significant diterpenoid, was isolated from fungal strain Virgaria nigra F-5408 in 1987 by Ando and co-workers. Initial biological studies found that vinigrol possesses both antihypertensive and platelet aggregation-inhibitory properties. More recent studies have identified vinigrol as a tumor necrosis factor (TNF) antagonist. In addition, vinigrol has also been shown to be effective in the treatment of human immunodeficiency virus (HIV) and inflammation. Structurally, the 1,5-butanodecahydronaphthalene core with eight contiguous stereocenters located in vinigrol represents the unprecedented and unique motif found in natural product small molecules. This promising biological activities of vinigrol combined with its unique terpene framework have attracted significant attention from the synthetic community. However, the total synthesis of vinigrol has been regarded as one of the most challenging tasks in the synthesis community for more than two decades. Numerous research efforts have been oriented toward the total synthesis of vinigrol, including Paquette, Corey, Hanna and other groups before 2008. Until now, four elegant total syntheses have been reported. In 2009, Baran and co-workers completed the first total synthesis of (±)-vinigrol, and the challenging 1,5-butanodecahydronaphthalene core was constructed by a way of intermolecular Diels-Alder and intramolecular Diels-Alder reactions followed by Grob fragmentation. Key salient features including an unusual dipolar cycloaddition for establishing the cis -orientation of the C8-methyl and C8a-hydroxy groups, and a later stage of Shapiro reaction via the tri-anionic species to deliver the final target. The synthesis was completed in a 23-step route with 3% overall yield from commercially available materials. This work represented a landmark achievement in the vinigrol synthesis. In 2013, Njardarson and co-workers completed another remarkable total synthesis of (±)-vinigrol, and the challenging 1,5-butanodecahydronaphthalene core was established with an elegant oxidative dearomatization/intramolecular Diels-Alder reaction followed by a Wharton fragmentation. In 2019, Luo and co-workers reported the first asymmetric total synthesis of (−)-vinigrol, with an impressive transannular Diels-Alder reaction as the key step. This scalable synthesis of (−)-vinigrol was completed in a 20-step route with 1.4% overall yield from commercially available materials, and provided over 600 mg of natural product in one operation. It should be noted that the Diels-Alder reaction was a crucial element in the synthetic strategy toward vinigrol in all these noteworthy achievements. Later, our group reported another asymmetric total synthesis of (−)-vinigrol using a unique Type II [5+2] cycloaddition and a novel ring contraction cascade as the key reactions. This synthetic work represents the first example of an intramolecular [5+2] cycloaddition to construct eight-membered ring system in natural product synthesis. Furthermore, the linear sequence of our concise asymmetric total synthesis of (−)-vinigrol was only 14 steps from commercially available material and without the need for protecting groups during the whole synthesis. The goal of this review is to provide a survey of advances in the total synthesis of vinigrol and discuss the synthetic strategies and tactics in each synthesis. The authors also hope that this review will serve a useful guidance for organic chemists who involved in total synthesis of natural products and provide a stimulus for inventions and further advances in this exciting area.

Asymmetric Total Synthesis of Asperversin A.

Asperversin A represents the first example of a steroid-sterigmatocystin heterodimer. We report the concise asymmetric total synthesis of this natural product in 11 steps (the longest linear sequence). The polycyclic ring system was constructed by a cascade dialdehyde cyclization and the late stage xanthene formation by a phenol-assisted reductive alkylation and a SNAr reaction. The acetal linkage with ergosterol peroxide was furnished by a glycosylation-inspired approach.

Stereoselective Synthesis of Oxazolidin-2-Ones via an Asymmetric Aldol/Curtius Reaction: Concise Total Synthesis of (-)-Cytoxazone.

Herein, we are reporting an efficient approach toward the synthesis of 4,5-disubstituted oxazolidin-2-one scaffolds. The developed approach is based on a combination of an asymmetric aldol and a modified Curtius protocol, which uses an effective intramolecular ring closure to rapidly access a range of oxazolidin-2-one building blocks. This strategy also permits a straightforward and concise asymmetric total synthesis of (−)-cytoxazone. Consisting of three steps, this is one of the shortest syntheses reported to date. Ultimately, this convenient platform would provide a promising method for the early phases of drug discovery.

Concise asymmetric total syntheses of (−)-nuciferol, (−)-nuciferal, and (−)-dihydrocurcumene via Rh(I)-catalyzed boronic acid addition

A general catalytic asymmetric total synthesis of aromatic bisabolane sesquiterpenes, (−)-nuciferol (ent-1c), (−)-nuciferal (ent-1d), and (−)-dihydrocurcumene (ent-1h) have been achieved in 5–6 steps in high chemical yields from commercially available (E)-ethylcrotonate. A key catalytic enantioselective boronic acid addition onto (E)-crotonate in the presence of Rh(I)-(S)-BINAP afforded enantioenriched product with benzylic stereogenic center in 93% yield with up to >99% ee.

A concise asymmetric total synthesis of (+)-fawcettimine

A straightforward and stereocontrolled total synthesis of (+)-fawcettimine was accomplished from the known (R)-5-methyl-2-cyclohexen-one in 11 steps. The synthesis features a palladium mediated cycloalkenylation of a silyl enol ether for assembling the 6/5-hydrindane system and generating a quaternary carbon center in one step; an oxa-Diels-Alder reaction followed by a Mitsunobu reaction to construct the Heathecock intermediate, i.e., the 6–5-9 tricycle skeleton.

Asymmetric total synthesis of dihydroisocoumarins: 6-methoxymellein, kigelin and fusarentin 6, 7 dimethyl ether by employing proline catalysed asymmetric α-aminoxylation

A concise asymmetric total synthesis of dihydroisocoumarins such as 6-methoxymellein, kigelin and fusarentin 6,7-dimethyl ether in high enantiopurity have been achieved from non-chiral aldehydes by employing proline catalysed asymmetric α-aminoxylation reaction. The required stereochemistry of hydroxyl group have been generated by alternating L or D proline as a organocatalyst in α-aminoxylation step and lactone ring is assembled by oxa-Pictet-Spengler cyclisation reaction as the key steps.