Concise and Enantioselective Total Synthesis of (−)‐Mehranine, (−)‐Methylenebismehranine,and Related Aspidosperma Alkaloids

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (?)‐mehranine and (+)‐(6S,7S)‐dihydroxy‐N‐methylaspidospermidine. A late‐stage dimerization of (?)‐mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (?)‐methylenebismehranine.     

Total Syntheses of (±)‐Fawcettimine, (±)‐Fawcettidine, (±)‐Lycoflexine,and (±)‐Lycoposerramine‐Q

The total syntheses of four fawcettimine‐related Lycopodium alkaloids, (±)‐fawcettimine, (±)‐fawcettidine, (±)‐lycoposerramine‐Q, and (±)‐lycoflexine, were completed in a highly stereoselective manner. The Pauson–Khand reaction of 4‐methylidene‐6‐siloxyoct‐1‐en‐7‐yne followed by regio‐ and stereoselective hydrogenation led to the short‐step preparation of the bicyclo[4.3.0]nonenone intermediate bearing a methyl group with the required stereochemistry. The subsequent chemical manipulation of the bicyclic compound afforded the 6‐5‐9‐membered tricyclic dioxo compound, which was then transformed into the four targeted alkaloids in an alternative and more efficient fashion.     

Stereoselective total syntheses of three Lycopodium alkaloids, (-)-magellanine, (+)-magellaninone, and (+)-paniculatine, based on two Pauson-Khand reactions

The total syntheses of (-)-magellanine, (+)-magellaninone, and (+)-paniculatine were completed from diethyl l-tartrate via the common intermediate in a stereoselective manner. The crucial steps in these syntheses involved two intramolecular Pauson-Khand reactions of enynes: the first Pauson-Khand reaction constructed the bicyclo[4.3.0] carbon framework, the corresponding A and B rings of these alkaloids in a highly stereoselective manner, whereas the second Pauson-Khand reaction stereoselectively produced the bicyclo[3.3.0]skeleton, which could be converted into the C and D rings of the target natural products.     

Organocatalytic Asymmetric Mannich Cyclization of Hydroxylactams with Acetals: Total Syntheses of (−)‐Epilupinine, (−)‐Tashiromine,and (−)‐Trachelanthamidine

An asymmetric, organocatalytic, one‐pot Mannich cyclization between a hydroxylactam and acetal is described to provide fused, bicyclic alkaloids bearing a bridgehead N atom. Both aliphatic and aromatic substrates were used in this transformation to furnish chiral pyrrolizidinone, indolizidinone, and quinolizidinone derivatives in up to 89 % yield and 97 % ee. The total syntheses of (?)‐epilupinine, (?)‐tashiromine, and (?)‐trachelanthamidine also achieved to demonstrate the generality of the process.     

A Concise Total Synthesis of Diospongins A and B

The total synthesis of the diarylheptanoids (?)‐diospongin A ( 1 ) and B ( 2 ) was achieved stereoselectively via the δ‐lactone intermediate 6 . The key reactions involved are a stereoselective reduction of β‐keto ester and the Horner–Wadsworth–Emmons and intramolecular oxy‐Michael reactions.     

An intramolecular aza-[3+3] annulation approach to azaphenalene alkaloids. Total synthesis of myrrhine

A detailed account on the stereoselective total syntheses of azaphenalene alkaloids via an intramolecular aza-[3+3] annulation strategy is described here. All five members of the Coccinellidae family of defensive alkaloids were prepared from the same common intermediate, which was derived from a stereoselective aza-[3+3] annulation reaction.     

Total Syntheses of (+)‐Grandilodine C and (+)‐Lapidilectine B and Determination of their Absolute Stereochemistry

Enantioselective total syntheses of the Kopsia alkaloids (+)‐grandilodine C and (+)‐lapidilectine B were accomplished. A key intermediate, spirodiketone, was synthesized in 3 steps and converted into the chiral enone by enantioselective deprotonation followed by oxidation with up to 76 % ee. Lactone formation was achieved through stereoselective vinylation followed by allylation and ozonolysis. The total synthesis of (+)‐grandilodine C was achieved by palladium‐catalyzed intramolecular allylic amination and ring‐closing metathesis to give 8‐ and 5‐membered heterocycles, respectively. Selective reduction of a lactam carbonyl gave (+)‐lapidilectine B. The absolute stereochemistry of both natural products was thereby confirmed. These syntheses enable the scalable preparation of the above alkaloids for biological studies.     

A Configurational Switch Based on Iridium‐Catalyzed Allylic Cyclization: Application in Asymmetric Total Syntheses of Prosopis,Dendrobate, and Spruce Alkaloids

A method for the stereoselective synthesis of 2,6‐disubstituted piperidines has been developed that is based on the use of an intramolecular iridium‐catalyzed allylic substitution as a configurational switch. The procedure allows the preparation of 2‐vinylpiperidines with enantiomeric excesses (ee) of greater than 99 %. As applications, total syntheses of piperidine alkaloids have been elaborated, most often by using Ru‐catalyzed cross‐metatheses as a key step for introduction of a side chain. Asymmetric total syntheses of the prosopis alkaloids (+)‐prosopinine, (+)‐prosophylline, (+)‐prosopine, and of the dendrobate alkaloid (+)‐241D and its C6 epimer are described.     

Total Syntheses of (−)-Secologanin, (−)-5-Carboxystrictosidine,and (−)-Rubenine

The first enantioselective total syntheses of (−)-secologanin ( 1 ), (−)-5-carboxystrictosidine ( 2 ), and (−)-rubenine ( 3 ) were accomplished in 10, 9, and 14 steps, respectively. The key transformation in the synthesis of 1 was a sequential anti-selective organocatalytic Michael reaction/Fukuyama reduction/spontaneous cyclization to form an optically active dihydropyran ring. In addition, the secologanin tetraacetate ( 16 ), which is a potential key intermediate for the bioinspired divergent syntheses of monoterpenoid indole alkaloids, was prepared in gram-scale in seven steps. The total syntheses of 2 and 3 , which are classified as glycosylated monoterpenoid indole alkaloids, were achieved through bioinspired transformations such as a diastereoselective Pictet–Spengler reaction, a site- and stereoselective epoxidation, and a site-selective epoxide ring-opening followed by a lactonization reaction.     

Synthesis and Biological Activity of 7,8,9‐Trideoxy‐ and 7R DesTHP‐Peloruside A

The stereoselective syntheses of 7,8,9‐trideoxypeloruside A ( 4 ) and a monocyclic peloruside A analogue lacking the entire tetrahydropyran moiety ( 3 ) are described. The syntheses proceeded through the PMB‐ether of an ω‐hydroxy β‐keto aldehyde as a common intermediate which was elaborated into a pair of diastereomeric 1,3‐syn and ‐anti diols by stereoselective Duthaler–Hafner allylations and subsequent 1,3‐syn or anti reduction. One of these isomers was further converted into a tetrahydropyran derivative in a high‐yielding Prins reaction, to provide the precursor for bicyclic analogue 4 . Downstream steps for both syntheses included the substrate‐controlled addition of a vinyl lithium intermediate to an aldehyde, thus connecting the peloruside side chain to C15 (C13) of the macrocyclic core structure in a fully stereoselective fashion. In the case of monocyclic 3 macrocyclization was based on ring‐closing olefin metathesis (RCM), while bicyclic 4 was cyclized through Yamaguchi‐type macrolactonization. The macrolactonization step was surprisingly difficult and was accompanied by extensive cyclic dimer formation. Peloruside A analogues 3 and 4 inhibited the proliferation of human cancer cell lines in vitro with micromolar and sub‐micromolar IC₅₀ values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for nM biological activity.     

Further Syntheses of Optically Active Verrucarinic Acid, 43rd Communication of Verrucarins and Roridins

Two new syntheses of verrucarinic acid (2S, 3R-dihydroxy-3-methylpentanoic acid) and its derivatives, suitably protected for the further conversion to macrocyclic trichothecenes, are described. The first one makes use of a diastereoselective alkylation of a (?)-(S)-malic acid ester and the regioselective reductin of one carboxyl function toa methyl group. The second approach involves a stereoselective addition of an allylsilane to a chiral glyoxylate.     

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (?)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO₄)₂‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (?)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.     

Rapid Syntheses of (−)‐FR901483 and (+)‐TAN1251C Enabled by Complexity‐Generating Photocatalytic Olefin Hydroaminoalkylation

We report a common strategy to facilitate the syntheses of the polycyclic alkaloids (?)‐FR901483 ( 1 ) and (+)‐TAN1251C ( 2 ). A divergent synthetic strategy provides access to both natural products through a pivotal spirolactam intermediate ( 3 ), which can be accessed on a gram‐scale. A photocatalytic olefin hydroaminoalkylation brings together three readily available building blocks and forges the majority of the carbon framework present in 1 and 2 in a single operation, leading to concise total syntheses. The complexity‐generating photocatalytic process also provides direct access to novel non‐racemic spirolactam scaffolds that are likely to be of interest to early‐stage drug discovery programs.     

Enantioselective Syntheses of Strychnos and Chelidonium Alkaloids through Regio‐ and Stereocontrolled Cooperative Catalysis

We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α‐alkylation. This provides products containing indole‐bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N‐substituent. This led to concise syntheses of (?)‐akuammicine and (?)‐strychnine. In the second case, the poor performance of ortho‐substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α‐alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)‐chelidonine, (+)‐norchelidonine, and (+)‐chelamine.     

Redox Divergent Synthesis of Fawcettimine‐Type Lycopodium Alkaloids

A new approach for synthesis of fawcettimine‐type Lycopodium alkaloids is described. A divergent strategy was achieved by applying stereoselective Diels–Alder reaction followed by redox‐controlled elaboration. Eventually, (?)‐8‐deoxyserratinine, (+)‐fawcettimine, (?)‐lycopoclavamine‐A, (?)‐serratine, (?)‐lycopoclavamine‐B and (?)‐serratanidine were successfully accessed.     

Total Syntheses of Tubulysins

The total syntheses of tetrapeptides tubulysins D ( 1 b ), U ( 1 c ), and V ( 1 d ), which are potent tubulin polymerization inhibitors, are described. The synthesis of Tuv ( 2 ), an unusual amino acid constituent of tubulysins, includes an 1,3‐dipolar cycloaddition reaction of chiral nitrone D ‐ 6 derived from D ‐gulose with N‐acryloyl camphor sultam (?)‐ 9 employing the double asymmetric induction, whereas the synthesis of Tup ( 20 ), another unusual amino acid, involves a stereoselective Evans aldol reaction of (Z)‐boron enolate generated from (S)‐4‐isopropyl‐3‐propionyl‐2‐oxazolidinone with N‐protected phenylalaninal and a subsequent Barton deoxygenation protocol. We accomplished the total syntheses of tubulysins U ( 1 c ) and V ( 1 d ) by using these methodologies, in which the isoxazolidine ring was used as the effective protective group for γ‐amido alcohol functionality. Furthermore, to understand the structure‐activity relationship of tubulysins, we synthesized tubulysin D ( 1 b ) and cyclo‐tubulysin D ( 1 e ) from 2 ‐Me and 20 , and ent‐tubulysin D (ent‐ 1 d ) from ent‐ 2 ‐Me and ent‐ 20 , respectively. The preliminary results regarding their biological activities are also reported.     

Total Syntheses of (−)‐Strictosidine and Related Indole Alkaloid Glycosides

A collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet–Spengler reaction with α‐cyanotryptamine and secologanin tetraacetate as substrates, followed by a reductive decyanation reaction, was developed for the synthesis of (?)‐strictosidine, which is an important intermediate in biosynthesis. This two‐step chemical method was established as an alternative to the biosynthetically employed strictosidine synthase. Furthermore, after carrying out chemical and computational studies, a transition state for induction of diastereoselectivity in our newly discovered Pictet–Spengler reaction is proposed. Having achieved the first enantioselective total synthesis of (?)‐strictosidine in just 10 steps, subsequent bioinspired transformations resulted in the concise total syntheses of (?)‐strictosamide, (?)‐neonaucleoside A, (?)‐cymoside, and (?)‐3α‐dihydrocadambine.     

Total Syntheses of Crinipellins Enabled by Cobalt‐Mediated and Palladium‐Catalyzed Intramolecular Pauson–Khand Reactions

Efficient total syntheses of the naturally occurring, potent antibiotic compounds (?)‐crinipellin A and (?)‐crinipellin B are described. The key advanced intermediate, a fully functionalized tetraquinane core, was constructed by a novel thiourea/palladium‐catalyzed Pauson–Khand reaction. This intermediate can serve as a common intermediate for the collective total synthesis of other members of the crinipellin family.     

Stereocontrolled Total Synthesis of (+)‐trans‐Dihydronarciclasine

A highly stereoselective and efficient total synthesis of trans‐dihydronarciclasine from a readily available chiral starting material was developed. The synthesis defines two of the five stereogenic centers of the natural product by an amino acid ester–enolate Claisen rearrangement. The other three stereogenic centers are created in a highly stereocontrolled fashion via a six‐ring vinylogous ester intermediate, which is generated from the γ,δ‐unsaturated ester functional group of the Claisen rearrangement product in an efficient three‐step sequence. This concise total synthesis exemplifies the use of a highly regioselective Friedel–Crafts‐type cyclization to form the B ring via an isocyanate intermediate derived from an N‐Boc group, which is superior to the conventional method using an imino triflate intermediate. This same N‐Boc group is employed to give high selectivity in the Claisen rearrangement earlier in the sequence.     

Total Syntheses and Biological Evaluation of Both Enantiomers of Several Hydroxylated Dimeric Nuphar Alkaloids

Herein, we describe the first total syntheses of five members of the dimeric nuphar alkaloids: (+)‐6,6′‐dihydroxythiobinupharidine (+)‐ 1 a , (+)‐6‐hydroxythiobinupharidine (+)‐ 1 b , (?)‐6,6′‐dihydroxythionuphlutine (?)‐ 2 a , (?)‐6,6′‐dihydroxyneothiobinupharidine (?)‐ 3 a , and (+)‐6,6′‐dihydroxyneothionuphlutine (+)‐ 4 a . The latter two have not been found in nature. We have also made each of their enantiomers (?)‐ 1 a – b , (+)‐ 2 a , (+)‐ 3 a , and (?)‐ 4 a . The key step in these syntheses was the dimerization of an α‐aminonitrile (a hydrolytically stable surrogate for its corresponding hemiaminal) with chiral Lewis acid complexes. We have also reassigned the literature structures of (+)‐ 1 a – 1 b —for those instances in which the NMR spectra were obtained in CD₃OD—to their corresponding CD₃O‐adducts. Our efforts provide for the first time apoptosis data for (?)‐ 3 a , (+)‐ 4 a , and all five non‐natural enantiomers prepared. The data indicate high apoptotic activity regardless of the enantiomer or relative stereochemical configuration at C7 and C7′.