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The total synthesis of the indole alkaloid (-)-andranginine has been achieved in 10 steps. Key reactions of the synthesis include a nucleophilic addition of acetylenyl anion to chiral

The skeleton of lucidumone was constructed through oxidative dearomatization/intramolecular Diels-Alder reaction, Cu-mediated remote C-H hydroxylation, allyl oxidation, acid-promoted dynamic kinetic resolution cyclization, and benzylic oxidation.

Since 2012, Xu and Zhou have reported the isolation of a series of gymnotheligans, a large group of novel tetrahydrofuran-containing lignan natural products. In the past decade, considerable achievements in the total syntheses of these lignans have been achieved based on a plausible biogenetic pathway proposed by our group in 2014. In this account, we summarize these remarkable synthetic works of the past ten years.1 Introduction2 Biogenetic Pathways to Gymnothelignans3 Total Syntheses of Eupodienones4 Total Syntheses of Eupomatilones5 Total Synthesis of Dibenzocyclooctenes6 Conclusions

An intramolecular anaerobic Mukaiyama hydration-initiated tandem reduction/condensation/acyl migration/aromatization reaction was developed, which enabled the rapid construction of indole-fused 8-10 membered lactones starting from cyclic 2-allyl-2-(2-nitrophenyl)-1,3-diketones. A nitro substituent in the substrates acted as both an oxygen source in the Mukaiyama hydration step and a nitrogen source in a tandem indole ring construction step. Our reaction features mild conditions, atom economy, and inexpensive reagents and it can be conveniently scaled up to a gram scale in modest yields. A rational reaction mechanism was also proposed based on previous reports and control experiments.

It is reported herein that by exploiting the commonly shared bicyclic decahydroquinoline motif, a gold-catalyzed enamide-alkyne cycloisomerization reaction is developed to access tricyclic cores in a simple way. These tricyclic cores further serve as an advanced platform for the divergent enantioselective collective total syntheses of five Lycopodium alkaloids, belonging to three different structural types, in a concise and protecting-group-free fashion. The key transformations in the second phase include: 1) a transannular reductive Heck cyclization for installation of the azepane ring in fawcettidine, fawcettimine, and lycoposerramine Q; 2) a domino Mukaiyama hydration/Grob fragmentation process for construction of the ten-membered lactam system in phlegmariurine B; 3) a Fukuyama one-pot protocol for the construction of the 2-pyridone motif in lycoposerramine R. The newly developed strategy is expected to pave the way for the synthesis of other structurally related Lycopodium alkaloids.

Described herein is a B(C

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.

A direct 1,2-dibromination method of alkenes is realized using 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) as a bromine source. This reaction proceeds under mild reaction conditions without the use of a catalyst and an external oxidant. Various sorts of alkene substrates are transformed into the corresponding 1,2-dibrominated products in good to excellent yields with broad substrate scope and exclusive diastereoselectivity. This method offers a green and practical approach to synthesize vicinal dibromide compounds.

A strategy for the synthesis of cis-hydrocarbazole with a C3 quaternary carbon center has been developed through nickel/Lewis acid dual-catalyzed arylcyanation. A wide array of cis-hydrocarbazoles was accessed with high diastereoselectivities and atom economies in a good yield. The rich chemistry of the installed nitrile group was demonstrated in the preparation of tryptamine- and tryptophol-derived cis-hydrocarbazoles.

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.

An efficient visible light photoredox catalyzed aerobic deprotection of 1,3-oxathiolanes using organic dye Eosin Y as a photocatalyst is disclosed. The deprotection procedure features the use of a metal-free catalyst, mild conditions, a broad range of substrate scope, and good functional group tolerance. 35 examples were tested under the standard conditions and most of them afforded the deprotected products in modest to high yields.

A strategy for the synthesis of 2,3-disubstituted indoles from 2-allyl-2-(2-nitrophenyl)cyclohexane-1,3-dione has been developed. A wide array of 2,3-disubstituted indoles were accessed in modest to good yields via a tandem reduction/condensation/fragmentation/cyclization sequence. The utility of this strategy was exemplified in the formal syntheses of leucomidine A and goniomitine. The mechanism was confirmed by experiments and density functional theory (DFT) calculations. Differential fragmentation made the reaction more complicated.

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.

A double cyclization strategy was developed to construct the common tetracyclic core of calyciphylline B-type alkaloids. Key features of the synthesis included asymmetric Evans alkylation, ring-closing metathesis reaction, intermolecular amidation, intramolecular aza-Michael addition, and aldol condensation reactions. This strategy may be applied to the total syntheses of this type of natural product.

Described herein is a novel and efficient copper-catalyzed oxidative phosphonation of α-tert-hydroxylalkenes. This protocol displays a broad scope with good functional group compatibility and gives efficient access to diverse β-oxophosphine oxides from simple allylic alcohols and H-phosphine oxides. The mechanism is proposed to be an unprecedented three-component radical coupling/fragmentation cascade reaction of α-tert-hydroxylalkenes, HP(O)R1R2 and tert-butyl hydroperoxide (TBHP), in which the excess TBHP acts as not only a radical initiator but also a coupling partner.

A concise and efficient strategy for the synthesis of the common 6,6-dimethyltricyclic[5.4.0.02,8]undecane framework of longipinane- and ent-longipinane-type sesquiterpenoids has been developed. This approach features an intramolecular Diels–Alder reaction to construct the 6/7 cis-fused ring system and a Ti(III)-mediated reductive radical cyclization reaction to access the highly strained bridged cyclobutane moiety.

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.

A strategy for the synthesis of

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.

A double cyclization strategy was developed to construct the common tetracyclic core of calyciphylline B-type alkaloids. Key features of the synthesis included asymmetric Evans alkylation, ring-closing metathesis reaction, intermolecular amidation, intramolecular aza-Michael addition, and aldol condensation reactions. This strategy may be applied to the total syntheses of this type of natural product.

A novel photocatalyst-free visible-light-mediated dithioacetalization of aldehydes and thiols has been developed. This protocol is operationally simple, mild and atom-economical, which provides an environmental benign access to dithioacetals at room temperature under aerobic conditions.

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 construction of the ABC tricyclic skeleton of malabanone A with the required 4 stereocenters was accomplished in a concise route starting from R-carvone. The synthesis featured an intramolecular [3 + 2] cycloaddition reaction to assemble its A ring and an intramolecular Diels-Alder reaction to construct its C ring.

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.

A strategy for the synthesis of multisubstituted hydrocarbazoles has been developed through (3 + 2)-annulation of p-quinamines and arynes. In this way, new analogs of hydrocarbazoles with quaternary carbon center can be synthesized in satisfactory yield under mild conditions. Furthermore, this (3 + 2)-annulation can be easily scaled-up, and the products can be modified through simple transformation.

A tandem radical cyclization reaction towards the 6/6/5 fused tricyclic skeleton, which exists in numerous natural products, was developed in modest to good yields. In this transformation, two C–C bonds and two rings were formed successively via a tandem 5-exo-trig/6-endo-trig cyclization reaction. 5-epi-7-deoxy-Isoabietenin A was also synthesized efficiently via this strategy.

An efficient synthesis of complex tetracyclic compounds is developed which relies on a gold(I)-catalyzed tandem 1,2-acyloxy migration/[3 + 2] cycloaddition/Friedel–Crafts type cyclization reaction of linear enynyl esters. The reaction proceeds under extremely mild conditions in good to excellent yields (54%–88%) with a dr value of up to 20 : 1.

A rapid construction of the tricyclic scaffold of annotinine hydrate has been accomplished in only four steps from conveniently available starting materials. This short synthesis featured an efficient Lewis acid-catalyzed Diels–Alder reaction to construct the 4a, 8a-cis-hydroquinoline skeleton and a 5-exo-trig radical cyclization reaction to assemble the γ-butylrolactone motif.

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.

An efficient approach for the synthesis of the 9/6/6 tricyclic structure of Lycopodium alkaloid palhinine A has been accomplished. The developed synthetic route features oxidative dearomatization and tandem hydroxyl oxidation/intramolecular Diels–Alder (IMDA) reactions to assemble the A/C/D tricyclic ring system. Most importantly, the protocol can undergo ring constriction to rapidly construct the highly strained nine-membered azonane ring of palhinine A.

An efficient method for the 1,3-dipolar cycloaddition of azomethine imines with active esters under thermal conditions has been described in good to high yields. This method offers a straightforward pathway to synthesize bioactive pyrazolidinones.

A sequential reaction combining N-heterocyclic carbene (NHC) and N-hydroxyphthalimide (NHPI) catalysis allowed for the upstream by-product NHPI, which was generated in the NHC-catalyzed cycloaddition reaction, to act as the catalyst for a downstream nitrogen-to-carbon sulfonyl migration reaction. Enantiomeric excess of the major product in the cycloaddition reaction remained intact in the follow-up sulfonyl migration reaction.

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.

An efficient method to build various multisubstituted polycyclic indoline-annulated normal to medium-size rings through dearomatization of indole via a tandem 1,2-acyloxy migration/intramolecular [3 + 2] cycloaddition process is described. The pentacyclic skeleton of strychnine could be synthesized via this tandem cycloaddition and a further Mannich reaction. This approach would provide a novel strategy to the synthesis of strychons alkaloids.

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.