Search

A strategy for the syntheses of pyrrolo [2,1-a] isoquinolines and indolizinoindolones via a Brønsted acid and Lewis acid co-promoted cascade reaction has been developed. The strategy was exemplified in the total synthesis of Erysotramidine.

The first total synthesis of the Euphorbia diterpenoid pepluanol B in both racemic and enantioenriched form involves 20 steps from a known bicyclic diol. This synthesis features an unprecedented bromo-epoxidation to control the eight-membered-ring conformation. In addition, salient reactions for the construction of the tetracyclic backbone include a sterically challenging aldol reaction to establish the quaternary center, a ring closing metathesis (RCM) to forge the eight-membered ring, and a diastereoselective cyclopropanation to assemble the embedded cyclopropane motif.

A concise total synthesis of antitumor and antimalarial marine sponge metabolite (−)-15-oxopuupehenol has been accomplished in 8 steps (longest linear route) with an overall yield of 18% from R-(−)-carvone. Our synthesis involves a Suzuki carbonylative coupling reaction to assemble the compact tetra-substituted α,β-unsaturated aryl ketone and a KOH promoted intramolecular cyclization reaction to construct the unique chromanone core. The antituberculosis drug (+)-puupehenone is obtained via a three-step transformation from the synthetic (−)-15-oxopuupehenol. The formal syntheses of (−)-puupehenol and (+)-puupehedione can also be achieved from the same advanced intermediate 19.

Diquinane or bicyclo[3.3.0]octane is a conspicuous structural unit existing in the carbo-frameworks of a wide range of natural products such as alkaloids and terpenoids. These diquinane-containing molecules not merely exhibit intriguing architectures, but also showcase a broad spectrum of significant bioactivities, which draw widespread attention from the global synthetic community. During the past decade, with an aim to accomplish the total syntheses of such specified cornucopias of natural products, a variety of elegant strategies for construction of the diquinane ring system have been disclosed. In this Minireview, the achievements on this subject in the timeline from 2010 to June 2020 are demonstrated and it is discussed how the diquinane unit is strategically forged in the context of the specific target structure. In addition, impacts of the selected works to the field of natural product total synthesis is highlighted and the particular outlook of diquinane-containing natural product synthesis is provided.

The first total synthesis of Gardneria oxindole alkaloid (-)-gardmultimine A has been achieved in 19 steps from d-tryptophan in a fully stereocontrolled manner. This synthesis features (1) an Ir-catalyzed regioselective C-H borylation/oxidation sequence to introduce the C12 methoxyl group, (2) a stereocontrolled oxidative rearrangement of indole to construct the spirooxindole motif, and (3) an Au(I)-catalyzed transannular Conia-ene-type 6-exo-dig cyclization to establish the azabicyclo[2.2.2]octane skeleton and the exocyclic E-alkene with exclusive stereoselectivity.

The first asymmetric total synthesis of aspidosperma alkaloid (+)-winchinine B was achieved in 12 steps from commercially available materials. A new synthetic strategy which features an efficient aza-Michael addition, a ruthenium-catalyzed transfer dehydrogenation, and an intramolecular palladium-catalyzed oxidative coupling was adopted to install the ABC tricycle system. A one-pot process involving carbonyl reduction/iminium formation/intramolecular conjugate addition developed by our group was utilized to construct the D ring moiety.

An enantioselective total synthesis of the natural chroman-sesquiterpenoid (−)-8-epi-chromazonarol has been accomplished by a unique N2H4·H2O promoted highly diastereo-selective oxa-Michael cyclization to construct the central chroman framework and assemble the unusual C8 stereocenter. The other salient feature of the reported synthesis involves a Stille carbonylative cross-coupling reaction to link the aryl stannane 9 and bicyclic triflate 10.

The first asymmetric total synthesis of gymnothelignan L has been accomplished in 14 steps with 11.2% overall yield. The synthetic approach features an anti Evans aldol reaction, a diastereoselective methylation, a Suzuki–Miyaura coupling and a bioinspired desymmetric transannular Friedel–Crafts reaction. Notably, the synthesis further demonstrated the biogenetic pathway that dibenzocyclooctene-type lignans are generated from eupomatilone-type lignans.

The first asymmetric total synthesis of the structurally unique Lycopodium alkaloid (-)-lycospidine A, containing an unprecedented five-membered ring, has been accomplished in only 10 steps with 21.6% overall yield from the known conveniently available sulfoxide. This protecting-group-free short synthesis relied on the use of a key amidation/aza-Prins domino cyclization reaction to rapidly construct the tricyclic skeleton and two continuous stereocenters (one of which is a bridged quaternary stereocenter). An intramolecular aldol condensation was successfully utilized to establish the unique five-membered ring, and a late-stage oxidation inspired by biosynthesis pathway was adopted to synthesize the diosphenol ring of (-)-lycospidine A.

A protecting-group-free route for the total synthesis of (-)-lycopodine was demonstrated in only 8 steps from Wade's fawcettimine enone (12 steps from commercial availiable (R)-(+)-pulegone). The key core of this alkaloid was constructed through a phosphoric acid promoted and highly stereocontrolled alkyne aza-Prins cyclization reaction, synchronously establishing the bridged B-ring and the C13 quaternary stereocenter. Importantly, the synthesis further features a new efficient approach for the preparation of other lycopodine-type alkaloids.

The first enantioselective total synthesis of the bisnorditerpene (+)-(5,8,10)-8-hydroxy-13-methylpodocarpa-9(11),13-diene-3,12-dione (1) was accomplished in 7 steps with 18.5% overall yield from known aldehyde and chiral epoxide. Key steps of the synthesis include a cationic domino cyclization used to construct the [6,6,6] fused framework, and an oxidative dearomatization reaction used to form the 1,4-quinoid moiety.

The first bioinspired total syntheses of (-) kravanhins A and C were accomplished from a labdane diterpenoid derivative. The key reactions involve a photooxidation and a one-pot sequential aldol cyclization and lactonization, which provide a new plausible biosynthetic pathway for the kravanhins and other symbiotic members.

The first total synthesis of conosilane A, a densely oxygenated nonisoprenoid sesquiterpene, has been achieved through stereoselective intramolecular radical cyclization and double utilization of site-selective C–H functionalization as key steps, thus simplifying the synthetic endeavors in natural product synthesis.

The first asymmetric total synthesis of kravanhin B has been accomplished with a linear reaction sequence of 13 steps starting from (R)-(-)-carvone. The synthesis features an intramolecular aldol cyclization to construct the desired cis-fused decalin skeleton and an acid-catalyzed dehydration and olefin isomerization to install the γ-butenolide ring.

(±)-Aspidospermidine (1) has been synthesized from the commercially available 2,3-dihydro-1H-carbazol-4(9H)-one 6 in 10 steps with 20% overall yield. The key step of the strategy is a one-pot carbonyl reduction/iminium formation/intramolecular conjugate addition reaction that may be applied for the synthesis of other kinds of Aspidosperma alkaloids.

The first total synthesis of isospongian diterpenoid (+/-)-polyrhaphin D has been accomplished in 9 steps with 19% overall yield starting from the Wieland-Miescher ketone derivative. The key features of our synthesis include a sequential reduc-tion/Michael addition/aldol condenzation to assemble the A ring and an intramolecular dehydrative cyclization/olefin isomerization reaction to install the gamma-butenolide D ring.

Bioinspired total synthesis of gymnothelignan N was accomplished in 13 steps and 6.7% overall yield. The synthesis features a syn Evans aldol reaction, an intramolecular hydrogenative dehydration reaction, and a phenol oxidative dearomatization/Friedel-Crafts reaction, which provides a new plausible biosynthetic pathway for the gymnothelignans and other symbiotic members. Meanwhile, another tetrahydrofuran-type lignan beilschmin A was also synthesized.

A scalable, efficient total synthesis of mupirocin H was accomplished in 7 longest linear steps with 39% overall yield. The developed strategy is great progress for the construction of pseudomonic acid analogues and all steps in our strategy could be conducted on a gram scale. The strategy is also suitable for other related molecules.

A concise asymmetric total synthesis of (12S)-12-hydroxymonocerin (1) and (12R)-12-hydroxymonocerin (2) were efficiently achieved from the known 4-bromo-2,6-dimethoxyphenol. The synthetic approach was inspired by our biomimetic synthesis of (+)-monocerin (3) and 7-O-demethylmonocerin (4). The cis-fused furobenzopyranones of 1 and 2 was efficiently constructed via an intramolecular nucleophilic trapping of a quinonemethide intermediate, which was obtained by benzylic oxidation of compound 10 using 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

The first total synthesis of the Myrioneuron alkaloids (±)-α,β-myrifabral A and B has been accomplished in only four steps from conveniently available starting materials. This short synthesis relied on the use of a key tandem Mannich/amidation reaction to rapidly construct the core framework and two carbon stereocenters. The synthetic route allows for large scale preparation of these promising natural products against the hepatitis C virus (HCV).

The first asymmetric total syntheses of cladosporin and isocladosporin were accomplished in 8 steps with 8% overall yield and 10 steps with 26% overall yield, respectively. The relative configuration of isocladosporin was determined via this total synthesis.

(-)-Delta(8)-trans-Tetrahydrocannabinol was synthesized with high regio- and stereoselectivity through S(N)2' addition of an arylcyanocuprate to the optically pure enol silyl ether of alpha,beta-epoxy-cyclohexanone.

An efficient total synthesis of (+)-aspergillide B has been achieved, which features the C-glycosylation reaction for constructing the 2,6-trans-substituted pyran core, a highly effective four-step sequence without purification to produce the key intermediate 13 and an advantegous E-selective Julia-Kocienski olefination on a highly elaborate substrate. The synthesis confirmed the revised structure of aspergillide B by Uenishi.

An enantioselective total synthesis of (−)-cladospolide B was described. The key steps in this synthesis include(a) a Sharpless asymmetric dihydroxylation to elaborate syn diol at C-4 and C-5 positions; (b) a Mitsunobu esterification to reverse the configuration at C-11 from (S) to (R); and (c) a ring-closing metathesis to access the 12-membered macrocyclic ring.

The facile total synthesis of the antimalarial nonenolide 1 is reported. The convergent strategy features the use of reactions such as Sharpless asymmetric dihydroxylation, aldol addition, Mitsunobu reaction, and ring-closing metathesis (RCM).

The first total synthesis of hydramicromelin B is described. An AuCl3/AgOTf-catalyzed intramolecular reaction was used as key step for the construction the coumarin ring.

The facile total synthesis of the (−)-Heliconol A (ent-1) as well as its diastereoisomer 18 is described, in which different reaction sequences lead to different results. The osmylation of 15 followed by hydrolysis afforded a single isomer 18, otherwise, a mixture of ent-1 and 18 resulted. Other important processes include the catalytic asymmetric CBS reduction and induced osmylation. The synthesis proceeded with a sequence of 11 steps, affording ent-1 in 9.0% and 18 in 22% overall yield, respectively.

The facile enantioselective synthesis of the di-O-methyl ethers of (-)-agatharesinol (1b), (-)-sugiresionl (2b), (+)-nyasol (3b) and (+)-tetrahydronyasol (4) were achieved in high yield. The absolute configuration of (+)-3a was confirmed via first total synthesis of (+)-3b and (+)-4.

The first efficient asymmetric total syntheses of xestodecalactones B and C have been accomplished in 10 steps with an overall yield of 22 and 20.2%, respectively. The key steps involve the utility of Evans oxazolidinone-mediated syn-aldol condensations to establish the C-9 configuration and the macrolide ring formation by intramolecular acylation. The absolute configurations of xestodecalactones B and C have been determined via these syntheses.

A general and efficient route for the synthesis of 5,6- seco -hexahydrodibenzopyran and trans -hexahydrodibenzopyran analogues was established, via a highly regio- and stereoselective S N 2′ reaction of arylcyanocuprates to enol silyl ether of α,β-epoxycyclohexanone. It was applied to the first facile total synthesis of (+)-Machaeridiol B and (+)-Machaeriol B.

(±)-Aspidospermidine (1) has been synthesized from the commercially available 2,3-dihydro-1H-carbazol-4(9H)-one 6 in 10 steps with 20% overall yield. The key step of the strategy is a one-pot carbonyl reduction/iminium formation/intramolecular conjugate addition reaction that may be applied for the synthesis of other Aspidosperma alkaloids.

The total synthesis of the title compound (I) is accomplished in 13 steps and 6.7% overall yield via syn Evans aldol reaction, an intramolecular hydrogenative dehydration reaction, and a phenol oxidative dearomatization/Friedel-crafts reaction.

An efficient, convergent approach for the total synthesis of aigialomycin D 1 is described. Key features of the synthetic strategy include (a) a Sharpless asymmetric epoxidation reaction and selective opening of a 2,3-epoxy alcohol to elaborate the two hydroxy-bearing stereogenic centers at the C5′ and C6′ positions; (b) a Kocienski modified Julia protocol to construct the two E-configured double bonds; and (c) Yamaguchi macrolactonization to acccess the 14-membered macrocyclic ring.

The first efficient asymmetric synthesis of obolactone 1 has been accomplished in 11 steps and with a 15% overall yield in which Brown's enantioselective allylation reactions and ring-closing metathesis reaction are key steps.

The enantioselective synthesis of 7-butyl-6,8-dihydroxy-(3R)-pentylisochroman-1-one has been achieved for the first time in which Sharpless asymmetric dihydroxylation is the key step.

An asymmetric total synthesis of Mansonone P and R was achieved. The synthesis highlights an OH substituent at position 2 by Sharpless dihydroxylation of silyl enol ether.

A facile total synthesis of (′)-nimbiol 1 has been achieved. In order to decrease the dioxo byproduct 2a, an improved oxidation system of CrO 3 /H 2 O/HOAC/NaOAc was used.

The stereoisomers of 3,4-dihydroxy-6-methoxy-2,2-dimethyl-chroman 1a–c and 3,4,7-trihydroxy-6-acetyl-2,2-dimethyl-chroman 2a–c were conveniently prepared for the first time via a synthesis in which Sharpless asymmetric dihydroxylation and Jacobsen’s catalytic asymmetric epoxidation are the key steps.

The first total synthesis of (+)-cryptocaryanone A is described. The synthesis features a Mukaiyama aldol reaction, one-pot saponification/lactonization sequences, and TsOH-assisted dihydropyrone formation as key steps.

A concise construction of the 6/6/5 tricyclic core of Lycopodium alkaloid palhinine A (1) has been accomplished. The developed synthetic strategy featured a tandem oxidative dearomatization/intramolecular Diels-Alder reaction to construct C/D rings and an intramolecular 5-exo-trig radical cyclization to install the B ring of palhinine A (1). The developed approach paves the way for the total synthesis of palhinine A (1).

The first and efficient total synthesis of (±)-dasyscyphin D was achieved in 9 steps with 22.6% overall yield. The key steps involved a PtCl(2)-catalyzed pentannulation reaction and acid-catalyzed double Robinson annulations.

The first enantioselective total synthesis of the structurally unique nortriterpenoid (−)-walsucochin B has been accomplished through the cationic polyolefin cyclization initiated by chiral epoxide. The core framework and the stereocenters in the natural product were all constructed in this step. A site-selective, late-stage free-radical halogenation and Seyferth–Gilbert homologation was adopted to install the acetylene moiety to synthesize the phenylacetylene. The absolute configuration of walsucochin B was confirmed through enantioselective total synthesis.

A concise asymmetric total synthesis of (12S)-12-hydroxymonocerin (1) and (12R)-12-hydroxymonocerin (2) were efficiently achieved from the known 4-bromo-2,6-dimethoxyphenol. The synthetic approach was inspired by our biomimetic synthesis of (+)-monocerin (3) and 7-O-demethylmonocerin (4). The cis-fused furobenzopyranones of 1 and 2 was efficiently constructed via an intramolecular nucleophilic trapping of a quinonemethide intermediate, which was obtained by benzylic oxidation of compound 10 using 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

The first enantioselective total synthesis of the structurally unique nortriterpenoid (−)-walsucochin B has been accomplished through the cationic polyolefin cyclization initiated by chiral epoxide. The core framework and the stereocenters in the natural product were all constructed in this step. A site-selective, late-stage free-radical halogenation and Seyferth–Gilbert homologation was adopted to install the acetylene moiety to synthesize the phenylacetylene. The absolute configuration of walsucochin B was confirmed through enantioselective total synthesis.

A concise asymmetric total synthesis of (+)-monocerin has been accomplished. The cis-fused furobenzopyranone of monocerin was efficiently constructed via a Lewis acid-mediated stereoselective cyclization of 1,2,4-triols intermediate.

Daphenylline is a recently isolated Daphniphyllum alkaloid with an unprecedented novel hexacyclic scaffold. In this study, the synthesis of the fused all-carbon DEF tricyclic skeleton of daphenylline has been accomplished. Key steps of the reported sequence involve Evans asymmetric allylation, aldol condensation, Diels-Alder reaction, and oxidative aromatization reactions. The developed strategy might lead to the total synthesis of daphenylline.

The first total synthesis of (-)-Przewalskin B has been accomplished with an intramolecular nucleophilic acyl substitution (INAS) reaction and an intramolecular aldol condensation as key steps.