The Total Synthesis of (±)‐Naupliolide: A Tetracyclic Sesquiterpene Lactone

The first total synthesis of (±)‐naupliolide has been achieved. The synthetic method includes a Simmons–Smith cyclopropanation of an allyl alcohol, diastereoselective cleavage of a benzylidene acetal group, radical cyclization of an aldehyde with a cyclopropane ring, and construction of an eight‐membered ring by ring‐closing metathesis.     

Total Synthesis of (−)‐Pepluanol B: Conformational Control of the Eight‐Membered‐Ring System

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.     

Enantioselective Total Synthesis of (+)‐Ophiobolin A

The enantioselective total synthesis of (+)‐ophiobolin A is described. This total synthesis features the construction of the spiro CD ring of (+)‐ophiobolin A through a stereoselective intramolecular Hosomi–Sakurai cyclization reaction, the joining of the A ring to the CD ring by using a reaction reported by Utimoto, and the construction of the ophiobolin eight‐membered carbocyclic ring through ring‐closing metathesis (RCM), which was performed for the first time in this study. This successful RCM reaction required the use of a substrate that contained either a benzyloxy or a methoxymethoxy group at the C5 position and either an isopropenyl group or its hydroxylated form at the C6 position.     

Total Synthesis of 1‐Hydroxytaxinine

1‐Hydroxytaxinine ( 1 ) is a cytotoxic taxane diterpenoid. Its central eight‐membered B‐ring possesses four oxygen‐functionalized centers (C1, C2, C9, and C10) and two quaternary carbon centers (C8 and C15), and is fused with six‐membered A‐ and C‐rings. The densely functionalized and intricately fused structure of 1 makes it a highly challenging synthetic target. Reported here is an efficient radical‐based strategy for assembling 1 from A‐ and C‐ring fragments. The A‐ring bearing an α‐alkoxyacyl telluride moiety underwent intermolecular coupling with the C‐ring fragment by a Et₃B/O₂‐promoted decarbonylative radical formation. After construction of the C8‐quaternary stereocenter, a pinacol coupling reaction using a low‐valent titanium reagent formed the B‐ring with stereoselective installation of the C1,C2‐diol. Subsequent manipulations at the A‐ and C‐rings furnished 1 in 26 total steps.     

Total Synthesis of Marine Eicosanoid (−)‐Hybridalactone

(?)‐Hybridalactone ( 1 ) is a marine eicosanoid isolated from the red alga Laurencia hybrida. This natural product contains cyclopropane, cyclopentane, 13‐membered macrolactone and epoxide ring systems incorporating seven stereogenic centers. Moreover, this compound has an acid‐labile skipped Z,Z‐diene motif. In this paper, we report on the total synthesis of (?)‐hybridalactone ( 1 ). The unique eicosanoid (?)‐hybridalactone ( 1 ) was synthesized starting from optically active γ‐butyrolactone 2 in a linear sequence comprising 21 steps with an overall yield of 21.9 %. A key step in the synthesis of (?)‐hybridalactone ( 1 ) is the methyl phenylsulfonylacetate‐mediated one‐pot synthesis of the cis‐cyclopropane‐γ‐lactone derivative. This reaction provided an efficient and stereoselective access to cis‐cyclopropane‐γ‐lactone 12 . Further elaboration of the latter compounds through desulfonylation, epoxidation, oxidation, Wittig olefination and Shiina macrolactonization afforded (?)‐hybridalactone.     

Efficient Synthesis of (±)‐Horsfiline through the MgI2‐Catalyzed Ring‐Expansion Reaction of a Spiro[cyclopropane‐1,3′‐indol]‐2′‐one

We report a short synthetic route to (±)‐horsfiline that provides the racemate in five steps from commercially available, substituted isatin in 41% overall yield. Efficient entry into the spiro[oxindole‐pyrrolidine] ring system is possible through the application of the cyclopropane opening/ring expansion chemistry we have described with MgI₂ as a bifunctional catalyst.     

Total Synthesis of Gelsedilam by Means of a Thiol‐Mediated Diastereoselective Conjugate Addition–Aldol Reaction

The total synthesis of gelsedilam, which features a highly diastereoselective thiol conjugate addition–intramolecular aldol reaction to install the strained and caged [3.2.2] bridged ring system and highly efficient NiCl₂/NaBH₄‐mediated four‐step transformation in one‐pot to construct its five‐membered lactam ring is reported. The synthesis requires only 18 linear steps from the known compounds, providing useful strategies for the construction of the intricate ring system in the synthesis of related gelsedine‐type alkaloids.     

Synthesis of Functionalized 2‐Aminopyrroles by Lewis Acid Catalyzed Ring‐opening of 1,1,2,3‐Tetrasubstituted Cyclopropanes with Arylamines

Under the catalysis of Lewis acid Co(ClO₄)₂ the reaction of the sterically hindered 1,1,2,3‐tetrasubstituted cyclopropanes with arylamines in refluxing THF gave the functionalized 2‐aminopyrroles with sequential ring‐opening of cyclopropane, nucleophilic substitution, nucleophilic addition of cyano group and recyclization processes.     

Total Synthesis of Diterpenoid Steenkrotin A

A concise and diastereoselective total synthesis of the diterpenoid (±)‐steenkrotin A is described for the first time. The strategy mainly features three key ring formations: 1) a rhodium‐catalyzed O? H bond insertion followed by an intramolecular carbonyl‐ene reaction to build up the tetrahydrofuran subunit; 2) sequential SmI₂‐mediated Ueno–Stork and ketyl–olefin cyclizations to construct the [5,7] spirobicyclic skeleton; and 3) an intramolecular aldol condensation/vinylogous retro‐aldol/aldol sequence to form the final six‐membered ring with inversion of the relative configuration at the C7 position.     

A Vinyl Cyclopropane Ring Expansion and Iridium‐Catalyzed Hydrogen Borrowing Cascade

A vinyl cyclopropane rearrangement embedded in an iridium‐catalyzed hydrogen borrowing reaction enabled the formation of substituted stereo‐defined cyclopentanes from Ph* methyl ketone and cyclopropyl alcohols. Mechanistic studies provide evidence for the ring‐expansion reaction being the result of a cascade based on oxidation of the cyclopropyl alcohols, followed by aldol condensation with the pentamethyl phenyl‐substituted ketone to form an enone containing the vinyl cyclopropane. Subsequent single electron transfer (SET) to this system initiates a rearrangement, and the catalytic cycle is completed by reduction of the new enone. This process allows for the efficient formation of diversely substituted cyclopentanes as well as the construction of complex bicyclic carbon skeletons containing up to four contiguous stereocentres, all with high diastereoselectivity.     

Total Synthesis and Biological Evaluation of (+)‐Gambieric Acid A and Its Analogues

In this study, we report the first total synthesis and complete stereostructure of gambieric acid A, a potent antifungal polycyclic ether metabolite, in detail. The A/B‐ring exocyclic enol ether 32 was prepared through a Suzuki–Miyaura coupling of the B‐ring vinyl iodide 18 and the alkylborate 33 and subsequent closure of the A‐ring by using diastereoselective bromoetherification as the key transformation. Suzuki–Miyaura coupling of 32 with acetate‐derived enol phosphate 49 , followed by ring‐closing metathesis of the derived diene, produced the D‐ring. Subsequent closure of the C‐ring through a mixed thioacetalization completed the synthesis of the A/BCD‐ring fragment 8 . The A/BCD‐ and F′GHIJ‐ring fragments (i.e., 8 and 9 ) were assembled through Suzuki–Miyaura coupling. The C25 stereogenic center was elaborated by exploiting the intrinsic conformational property of the seven‐membered F′‐ring. After the oxidative cleavage of the F′‐ring, the E‐ring was formed as a cyclic mixed thioacetal (i.e., 70 ) and then stereoselectively allylated by using glycosylation chemistry. Ring‐closing metathesis of the diene 3 thus obtained closed the F‐ring and completed the polycyclic ether skeleton. Finally, the J‐ring side chain was introduced by using a Julia–Kocienski olefination in the presence of CeCl₃ to complete the total synthesis of gambieric acid A ( 1 ), thereby unambiguously establishing its complete stereostructure. The present total synthesis enabled us to evaluate the antifungal and antiproliferative activities of 1 and several synthetic analogues.     

Determination of the electron density in methyl (±)‐(1S,2S,3R)‐2‐methyl‐1,3‐diphenylcyclopropanecarboxylate using refinements with X‐ray scattering factors from wavefunction calculations of the whole molecule

The molecule of the title compound, C₁₈H₁₈O₂, is a substituted cyclopropane ring. The electron density in this molecule has been determined by refining single‐crystal X‐ray data using scattering factors derived from quantum mechanical calculations. Topological analysis of the electron densities in the three cyclopropane C—C bonds was carried out. The results show the effects of this substitution on these C—C bonds.     

Total Synthesis of (−)‐Glaucocalyxin A

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)₃‐mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (?)‐glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels–Alder reaction to assemble the A/B ring system.     

Total Synthesis of (±)‐Aspidophylline A

A total synthesis of aspidophylline A, a pentacyclic akuammiline‐type monoterpene indole alkaloid, is described. The synthesis features: 1) rapid access to a fully functionalized dihydrocarbazole through the desymmetrization of readily available 2‐allyl‐2‐(o‐nitrophenyl)cyclohexane‐1,3‐dione; 2) an intramolecular azidoalkoxylation of an enecarbamate to install both the furoindoline ring and the azido functionality; and 3) an intramolecular Michael addition for the construction of the 2‐azabicyclo[3.3.1]nonane ring system.     

Stereospecific and Stereoselective Rhodium(I)‐Catalyzed Intramolecular [2+2+2] Cycloaddition of Allene‐Ene‐Ynes: Construction of Bicyclo[4.1.0]heptenes

Treatment of the allene‐ene‐yne substrates with [{RhCl(CO)₂}₂] effected the intramolecular [2+2+2]‐type ring‐closing reaction to produce various of tri‐ and tetracyclic derivatives containing a cyclopropane ring. The reaction is highly stereoselective as well as stereospecific with good to excellent yields.     

Total Synthesis of (−)‐Lundurine A and Determination of its Absolute Configuration

A 15‐step total synthesis of (?)‐lundurine A ( 1 ) from easily accessible (S)‐pyrrolidinone 18 is reported. A Simmons‐Smith reaction allows the efficient, simultaneous assembly of the cyclopropyl C ring, the six‐membered D ring, the seven‐membered E ring, and the quaternary carbon stereocenters at C2 and C7. The absolute configuration of natural (?)‐lundurine A was deduced to be 2R,7R,20R based on the stepwise construction of the stereocenters during the total synthesis.     

trans‐(1R,2R)‐1‐Benzyl‐2‐phenylcyclopropanecarboxylic acid

The cyclopropane ring of the title compound, C₁₇H₁₆O₂, shows a high level of substituent‐induced bond‐length asymmetry. The carboxyl group adopts a conformation that prompts electron‐density transfer from the ring towards the carbonyl π system.     

Enantioselective Total Synthesis of (+)‐Plumisclerin A

The first and enantioselective total synthesis of (+)‐plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring‐formation protocol was adopted to generate the characteristic tricycle[4.3.1.0^1,5]decane and trans‐fused dihyrdopyran moiety. Scalable enantioselective La^III‐catalyzed Michael reaction, palladium(0)‐catalyzed carbonylation and SmI₂‐mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D‐ring system having six continuous stereogenic centers and two all‐carbon quaternary centers. The trans‐fused dihyrdopyran moiety with an exo side‐chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)‐plumisclerin A.     

Silylium‐Ion‐Promoted (5+1) Cycloaddition of Aryl‐Substituted Vinylcyclopropanes and Hydrosilanes Involving Aryl Migration

A transition‐metal‐free (5+1) cycloaddition of aryl‐substituted vinylcyclopropanes (VCPs) and hydrosilanes to afford silacyclohexanes is reported. Catalytic amounts of the trityl cation initiate the reaction by hydride abstraction from the hydrosilane, and further progress of the reaction is maintained by self‐regeneration of the silylium ions. The new reaction involves a [1,2] migration of an aryl group, eventually furnishing 4‐ rather than 3‐aryl‐substituted silacyclohexane derivatives as major products. Various control experiments and quantum‐chemical calculations support a mechanistic picture where a silylium ion intramolecularly stabilized by a cyclopropane ring can either undergo a kinetically favored concerted [1,2] aryl migration/ring expansion or engage in a cyclopropane‐to‐cyclopropane rearrangement.