Total Syntheses of Aurachins A and B

Aurachins A and B are alkaloids having 3-hydroxyquinoline N-oxide cores. An efficient method for the synthesis of 3-hydroxyquinoline N-oxides was established and is amenable to the total syntheses of aurachins A and B. Alkylation of 1-(2-nitrophenyl)butan-2-one with farnesyl bromide took place selectively at the benzylic position, and subsequent treatment of the alkylated product with sodium tert-butoxide in dimethyl sulfoxide gave aurachin B. Alkylation of 1-(2-nitrophenyl)butan-2-one with an epoxy iodide derived from farnesol was used to access aurachin A.     

Total Syntheses of (−)-Minovincine and (−)-Aspidofractinine through a Sequence of Cascade Reactions

We report 8-step syntheses of (−)-minovincine and (−)-aspidofractinine using easily available and inexpensive reagents and catalyst. A key element of the strategy was the utilization of a sequence of cascade reactions to rapidly construct the penta- and hexacyclic frameworks. These cascade transformations included organocatalytic Michael-aldol condensation, a multistep anionic Michael-S_N2 cascade reaction, and Mannich reaction interrupted Fischer indolization. To streamline the synthetic routes, we also investigated the deliberate use of steric effect to secure various chemo- and regioselective transformations.     

Total Syntheses of Kopsaporine,Kopsinol and Kopsiloscine A

Kopsia alkaloids represent a complex class of natural products bearing a polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure-unit-based strategy are an intramolecular Pummerer rearrangement induced nucleophilic cyclization/aza-Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin migration vinylogous alkylation to establish the C20 all-carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α-hydroxyketone moiety, and a bioinspired retro-Aldol/Aldol reaction to convert kopsaporine to kopsiloscine A.     

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.     

Bent π-Conjugation within a Macrocycle: Asymmetric Total Syntheses of Spirohexenolides A and B

Macrocycles with bent π-conjugation motif are extremely rare in nature and synthetically daunting and anticancer haouamines and spirohexenolides were representative of such rare natural products with synthetically challenging bent π-conjugation within a macrocycle. While the total synthesis of haouamines has been elegantly achieved, spirohexenolides remains an unmet synthetic challenge due to the highly strained bent 1,3,5-triene conjugation within C15 macrocycle. Inspired by the chemical synthesis of cycloparaphenylenes (CPPs) and haouamines, herein we devise a synthetic strategy to overcome the highly strained bent 1,3,5-triene conjugation within the macrocycle and achieve the first, asymmetric total synthesis of spirohexenolides A (>20 mg) and B (>50 mg). Our synthesis features strategic design of ring-closing metathesis (RCM) macrocyclization followed by double dehydration to achieve the C15 macrocycle with the deformed nonplanar 1,3,5-triene conjugation. In addition, we have developed a new enantioselective construction of highly functionalized spirotetronate fragment (northeast moiety) through RCM and Ireland–Claisen rearrangement. Our in vitro bioassay studies reveal that both spirohexenolides are cytotoxic against a panel of human cancer cells with IC₅₀ 1.2–13.3 μM and spirohexenolide A is consistently more potent (up to 3 times) than spirohexenolide B, suggesting the importance of alcohol for their bioactivity and for medicinal chemistry development.     

Divergent Total Syntheses of (−)-Daphnezomines A and B and (+)-Dapholdhamine B

The daphnezomine A-type subfamily of Daphniphyllum alkaloids structurally features a unique aza-adamantane core skeleton and anticipates efficient strategies for completing their syntheses to thoroughly investigate their biological activities. Herein, divergent total syntheses of (−)-daphnezomines A and B and (+)-dapholdhamine B have been accomplished in 16–20 steps from a known epoxide via rapid construction of a common core intermediate. The present work features a Ti-mediated radical cyclization to establish the azabicyclo[3.3.1]nonane ring system, an intramolecular Heck reaction to install the bridgehead all-carbon quaternary stereocenter, a tandem deprotection/reduction/keto amine-carbinolamine tautomerization to furnish the aza-adamantane backbone, and an NIS-promoted 6-endo-trig aminocyclization to assemble the (+)-dapholdhamine B backbone.     

Total Syntheses of AF-2785 and Gamendazole—Experimental Male Oral Contraceptives

Both AF-2785 and gamendazole are experimental male oral contraceptives. The total syntheses of these two compounds are achieved in good yields.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Synthesis of Terpenoids. III. Total Syntheses of α-Bisabololone and α-Trans-Atlantone

Recently, anions of “protected” cyanohydrins have been introduced as useful acyl carbanions equivalents in organic synthesis². Continuing with our interest in the use of these reagents for natural product syntheses³, we wish to report a short total synthesis of the sesquiterpene α-bisabololone 1 ^4,5, whose salient feature is a novel application of “protected” cyanohydrins to the synthesis of β-hydroxy ketones.     

Enantioselective Total Syntheses of Lyconadins A–E through a Palladium-Catalyzed Heck-Type Reaction

A novel palladium-catalyzed Heck-type reaction of thiocarbamates has been designed to construct bridged seven-membered-ring systems that are otherwise challenging to prepare. Taking advantage of this newly developed method, enantioselective syntheses of lyconadins A–E ( 1 – 5 ), lycopecurine ( 6 ), and dehydrolycopecurine ( 7 ) have been realized in a divergent fashion. Our synthetic strategy also features an intramolecular cyclization of a N-chloroamine to forge the C6−N bond, a transannular Mannich-type reaction of a cyclic nitrone to stitch the C4 and C13 together, and a cyclocondensation to deliver the (dihydro-)pyridone motif.     

Total Syntheses of (−)-Conidiogenone B, (−)-Conidiogenone,and (−)-Conidiogenol

Cyclopianes are novel diterpenes featuring a highly strained 6/5/5/5 tetracyclic core embedded with 6–8 consecutive stereocenters. The concise total syntheses of (−)-conidiogenone B, (−)-conidiogenone, and (−)-conidiogenol have been accomplished in 14–17 steps. The present work features a HAT-mediated alkene–nitrile cyclization to access the cis-biquinane, a Nicholas/Pauson–Khand reaction to construct the linear triquinane, and a Danheiser annulation to afford the congested angular triquinane skeleton.     

Divergent Total Syntheses of (+)-Vulgarisins A–E

The asymmetric total syntheses of (+)-vulgarisins A–E, which share a rare and highly oxygenated [5-6-4-5] tetracyclic core structure that were isolated from P. vulgaris Linn., have been described for the first time in a divergent manner. Key transformations include: 1) a catalytic asymmetric intramolecular cyclopropanation to forge the A ring bearing desired stereochemistry at C14; 2) a one-pot borylation/conjugate addition process for creation of the C1−C11 bond; 3) a Wolff ring contraction to assemble the bicyclo[3.2.0]heptane subunit (CD rings); and 4) a stereocontrolled pinacol cyclization for construction of the central B ring of the natural products.     

Syntheses of Iso-Condensed Heteroaromatic Pyrroles and the Application to the Total Synthese of Natural Products

A novel method, namely the intramolecular 1,3-dipolar cycloaddition and cycloreversion ofazido-alkylidene malonates, for the preparation of iso-condensed heteroaromatic pyrroles has beendeveloped. The application of this method for the synthesis of 2,4-dihydropyrrolo[3,4-b]indole ringsystem, as well as the application of this ring system for the total syntheses of ellipticine alkaloids arereported.     

Asymmetric Total Syntheses of Di- and Sesquiterpenoids by Catalytic C−C Activation of Cyclopentanones

To show the synthetic utility of the catalytic C−C activation of less strained substrates, described here are the collective and concise syntheses of the natural products (−)-microthecaline A, (−)-leubehanol, (+)-pseudopteroxazole, (+)-seco-pseudopteroxazole, pseudopterosin A–F and G—J aglycones, and (+)-heritonin. The key step in these syntheses involve a Rh-catalyzed C−C/C−H activation cascade of 3-arylcyclopentanones, which provides a rapid and enantioselective route to access the polysubstituted tetrahydronaphthalene cores presented in these natural products. Other important features include 1) the direct C−H amination of the tetralone substrate in the synthesis of (−)-microthecaline A, 2) the use of phosphoric acid to enhance efficiency and regioselectivity for problematic cyclopentanone substrates in the C−C activation reactions, and 3) the direct conversion of serrulatane into amphilectane diterpenes by an allylic cyclodehydrogenation coupling.     

Unified Asymmetric Total Syntheses of (−)-Alotaketals A–D and (−)-Phorbaketal A

The novel tricyclic spiroketal alotane-type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (−)-alotaketals A–D and (−)-phorbaketal A were accomplished [29–31 steps from (−)-malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy δ-keto-alcohols to forge the common tricyclic spiroketal intermediate, 2) a late-stage allylic C−H oxidation, and 3) olefin cross-metathesis to install the different side chains.     

Syntheses of Benzoxepinoquinolinone and Benzothiepinoquinolinone

l-Benzoxepino(3, 4-b)quinolin-l3(6H)-one and its halogen,alkyl, alkoxy derivatives Va'-d' and 1-benzothiepino(3,4-b}-quinolin- 13 ( 6H)-one Vf, and its alkyl derivatives Vg, weresynthesized through cyclization of 2-(substituted phenoxymethyl)-3-quinolinecarboxylic acids Va-d and 2-[ (un)substituted phen-ylthiomethyll-3-quinolinecarboxylic acids IVf-g in the presence ofpolyphosphoric acid.The acids IV were obtained from the corresponding ethyl-esters @ whcih were prepared through refluxing ethyl 2-bromo-methyl-3-quinolinecarboxylate(1) with substituted phenol or (un)substituted thiophenol in the presence of NaOEt.The compound Vg, was allowed to react with NBS, KaBH4, NH2OH-HCl to give compounds VII , VIII, and IX, respectively.The structures of 24 new compounds have been confirmed by elemental analysis, IR and 1H NMR.     

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.     

Total Syntheses of the Chlorinated β‐Carboline Alkaloids Bauerine A,B, and C

The first total synthesis of the chlorinated 1‐oxo‐β‐carboline alkaloid bauerine C based on a Japp–Klingemann reaction is reported. An intermediate of this synthesis was converted to the fully aromatic β‐carboline bauerine B, and the related alkaloid bauerine A was prepared in an analogous manner.     

Is There No End to the Total Syntheses of Strychnine? Lessons Learned in Strategy and Tactics in Total Synthesis

From the 19th century to the present, the complex indole alkaloid strychnine has engaged the chemical community. In this Review, we examine why strychnine has been and remains today an important target for directed synthesis efforts. A selection of the diverse syntheses of strychnine is discussed with the aim of identifying their influence on the evolution of the strategy and tactics of organic synthesis.     

Total Syntheses of Norrisolide-Type Spongian Diterpenes Cheloviolene C,Seconorrisolide B,and Seconorrisolide C

The first total syntheses of three unusual norrisolide-type rearranged spongian diterpenes, cheloviolene C, seconorrisolide B, and seconorrisolide C, have been accomplished via a common intermediate through late-stage ring-scissoring. The synthesis features a Wolff ring contraction for the synthesis of the trans-hydrindane system, and a crucial retro Diels–Alder reaction/intramolecular ene cyclization for the rapid stereoselective construction of the furo[2,3-b]furan system, which is commonly seen in rearranged spongian diterpenes.     

The First Total Synthesis of 16-Hydroxygeranylgeraniol

Facile synthesis of 16-hydroxygeranylgeranio 1,a naturally occurring alicyclic diterpene,by alkylation reaction of allylic iodide 3 with phenyl sulfone 4,is described.