Stereocontrolled and Versatile Total Synthesis of Bispyrrolidinoindoline Diketopiperazine Alkaloids: Structural Revision of the Fungal Isolate (+)‐Asperdimin

Homo‐ and heterodimeric bispyrrolidinoindoline diketopiperazine alkaloids have been synthesized following a concise, versatile, and stereoselective route. Highlights of the sequence are a diastereoselective construction of the C3a‐bromo‐hexahydropyrrolo[2,3‐b]indole nucleus, its Co^I‐induced C3a? C3a′ dimerization, and the twofold or sequential amide‐bond formation before cyclization to the diketopiperazine of the homo‐ or heterodimeric alkaloids, respectively. Stereochemical diversity is achieved through the choice of the appropriate amino acids combined with the base‐induced epimerization of the C2‐acyl‐hexahydropyrrolo[2,3‐b]indole at C2. According to this strategy, the natural products (+)‐WIN 64821 1 , (+)‐WIN 64745 2 and (+)‐asperdimin 6 as well as analogues ( 5 , 22 , 32 , 44 ) with different relative and absolute configuration have been efficiently synthesized. The flexibility of this synthetic methodology has facilitated the structural revision of the natural product (+)‐asperdimin, whose structure has been corrected to diastereomer 6 .     

Enantioselective Synthesis of Lepadins A–D from a Phenylglycinol‐Derived Hydroquinolone Lactam

The marine alkaloids (?)‐lepadins A–C and (+)‐lepadin D, belonging to two diastereoisomeric series, were synthesized from an (R)‐phenylglycinol‐derived tricyclic lactam via a common cis‐decahydroquinoline intermediate. Crucial aspects of the synthesis are the stereochemical control in the assembly of the cis‐decahydroquinoline platform, in the introduction of the C2 methyl and C3 hydroxy substituents, and in the generation of the C5 stereocenter.     

Synthesis of the azocino[4,3‐b]indole core structure for the synthesis of strychnos alkaloids

The synthesis of compound 12 which has a hexahydro‐1,5‐methanoazocino[4,3‐b]indole structure for the synthesis of pentacyclic strychnos type alkaloids (tubifolin and tubifolidine) is described. Many new compounds 5–12 have also been synthesized.     

Preparation of a stationary phase with quaternary ammonium embedded group for selective separation of alkaloids based on ion‐exclusion interaction

A stationary phase (named QA C10) with quaternary ammonium embedded between a propyl and a decyl chain was synthesized by immobilization of N,N‐dimethyldecylamine on chloropropyl–silica surface. A set of representative neutral, basic, and acidic compounds was employed to evaluate its chromatographic properties. The results illustrated that QA C10 was a mixed‐mode stationary phase possessing both hydrophobic and ionic characteristics. The QA C10 stationary phase was further used for selective separation of alkaloids from Cortex phellodendri. Under acidic condition, alkaloids could be eluted in first 8 min, while other neutral and acidic fractions were retained better on QA C10 column. Then, obtained alkaloid fraction was analyzed by LC‐MS/MS and 22 alkaloids were identified. Our study confirmed the advantages and application potential of the QA C10 stationary phase for alkaloids separation.     

Synthesis of Bis(indole) Alkaloids from Arundo donax: The Ynindole Diels–Alder Reaction,Conformational Chirality,and Absolute Stereochemistry

Bis(indole) alkaloids from Arundo donax were synthesized using the first ynindole Diels–Alder reaction. The alkaloids are chiral, having stable enantiomeric conformations with half‐lives of racemization of t_1/2=4150–25100 seconds at room temperature. Their absolute stereochemistry was determined using the exciton chirality method.     

Divergent Total Synthesis of the Tricyclic Marine Alkaloids Lepadiformine,Fasicularin, and Isomers of Polycitorols by Reagent‐Controlled Diastereoselective Reductive Amination

We describe a flexible and divergent route to the pyrrolo‐/pyrido[1,2‐j]quinoline frameworks of tricyclic marine alkaloids via a common intermediate formed by the ester–enolate Claisen rearrangement of a cyclic amino acid allylic ester. We have synthesized the proposed structure of polycitorols and demonstrated that the structure of these alkaloids requires revision. In addition to asymmetric formal syntheses, stereoselective and concise total syntheses of (?)‐lepadiformine and (?)‐fasicularin were also accomplished from simple, commercially available starting materials in a completely substrate‐controlled manner. The key step in these total syntheses was the reagent‐dependent stereoselective reductive amination of the common intermediate to yield either indolizidines 55 a or 55 b . Aziridinium‐mediated carbon homologation of the hindered C‐10 group to the homoallylic group facilitated the synthesis.     

Preparative separation of isoquinoline alkaloids from Corydalis impatiens using a middle‐pressure chromatogram isolated gel column coupled with two‐dimensional liquid chromatography

We established a two‐dimensional strong cation exchange/reversed‐phase liquid chromatography protocol to isolate and purify isoquinoline alkaloids from Corydalis impatiens. Isoquinoline alkaloids were first enriched from a C. impatiens extract in which liposoluble components were removed using a medium‐pressure chromatographic tower containing middle chromatogram isolated gel. A strong cation exchange column was employed to separate and obtain 30 fractions. We chose fractions 22–29 for reversed‐phase liquid chromatography purification using characteristic isoquinoline alkaloid ultraviolet absorption spectra. Several isoquinoline alkaloid fractions (22–29) were further separated, and those of low resolution were isolated via two‐dimensional liquid chromatography in the orthogonal plane. A total of eight novel isoquinoline alkaloids with characteristic ultraviolet spectra were obtained from C. impatiens. We thus demonstrate the benefits of off‐line two‐dimensional strong cation exchange/reversed‐phase liquid chromatography to isolate isoquinoline alkaloids from C. impatiens.     

Direct preparation of a graphene oxide modified monolith in a glass syringe as a solid‐phase extraction cartridge for the extraction of quaternary ammonium alkaloids from Chinese patent medicine

Packed cartridges have been widely used in solid‐phase extraction. However, there are still some drawbacks, such as they are blocked easily and the method is time‐consuming. In view of the advantages of monoliths, a monolithic extraction material has been directly synthesized in a glass syringe without any gap between the monolith and syringe inner wall. The monolithic syringe was modified with graphene oxide by loading graphene oxide dispersion onto it. The content of graphene oxide and the surface topography of the monolith have been evaluated by elemental analysis and scanning electron microscopy, respectively, which confirmed the successful modification. This prepared graphene oxide‐modified monolithic syringe was directly used as a traditional solid‐phase extraction cartridge. As expected, it shows good permeability and excellent capability for the extraction of quaternary ammonium alkaloids. The sample loading velocity (1–6 mL/min) does not affect the recovery. Under the optimal conditions, good linearities (R  = 0.9992–0.9998) were obtained for five quaternary ammonium alkaloids, and the limits of detection and quantification were 0.5‐1 and 1–2 μg/L, respectively. The proposed method was successfully applied for the analysis of quaternary ammonium alkaloids in Chinese patent medicine.     

Application of a Palladium‐Catalyzed C−H Functionalization/Indolization Method to Syntheses of cis‐Trikentrin A and Herbindole B

We describe herein formal syntheses of the indole alkaloids cis‐trikentrin A and herbindole B from a common meso‐hydroquinone intermediate prepared by a ruthenium‐catalyzed [2+2+1+1] cycloaddition that has not been used previously in natural product synthesis. Key steps include a sterically demanding Buchwald–Hartwig amination as well as a unique C(sp³)?H amination/indole formation. Studies toward a selective desymmetrization of the meso‐hydroquinone are also reported.     

Synthesis of Bis(indole) Alkaloids from Arundo donax: The Ynindole Diels–Alder Reaction,Conformational Chirality,and Absolute Stereochemistry

Bis(indole) alkaloids from Arundo donax were synthesized using the first ynindole Diels–Alder reaction. The alkaloids are chiral, having stable enantiomeric conformations with half‐lives of racemization of t_1/2=4150–25100 seconds at room temperature. Their absolute stereochemistry was determined using the exciton chirality method.     

Synthesis and spectroscopic studies of optically active n‐acetyl butenoates and n‐acetyl‐2‐alkyl‐pyrrolin‐4‐ones

The synthesis of a series of optically active N‐acetyl butenoates 3–5 is described using a facile methodology. These butenoates undergo cyclization to the corresponding N‐acetyl‐2‐alkyl‐pyrrolin‐4‐ones 6,7 retaining their stereochemical integrity. The structure of the newly synthesized compounds has been elucidated through ¹H‐¹³C NMR, IR spectroscopy and their enantiomeric excesses have been measured by chiral HPLC analysis.     

Enantioselective Catalysis Coupled with Stereodivergent Cyclization Strategies Enables Rapid Syntheses of (+)‐Limaspermidine and (+)‐Kopsihainanine A

Enantioselective Pd‐catalyzed allylic alkylations of dihydropyrido[1,2‐a ]indolone (DHPI) substrates were used to construct the C20‐quaternary stereocenters of multiple monoterpene indole alkaloids. Stereodivergent Pictet–Spengler and Bischler–Napieralski cyclization/reduction cascades furnish the cis‐ and trans ‐fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively, en route to highly efficient syntheses of (+)‐limaspermidine and (+)‐kopsihainanine A.     

14‐Membered Cyclopeptides from Paliurus ramosissimus and P. hemsleyanus

Six 14‐membered cyclopeptide alkaloids, i.e., ramosines A–C, mucronine J, and lotusines A and D, were isolated from the roots of Paliurus ramosissimus, and an additional four, hemsines A–D, from the roots of P. hemsleyanus. Among these, ramosines A–C ( 1, 5 , and 6 , resp.) and hemsines A and B ( 7 and 8 , resp.) are new bases of the amphibine‐B type, and hemsines C and D ( 9 and 10 , resp.) are new integerrine‐type alkaloids. Additionally, ramosine C ( 6 ) represents the first 14‐membered cyclopeptide alkaloid possessing a substitution (? OH) at C(13′). Their structural elucidations were based on spectral analysis and molecular‐modeling studies. Pronounced solvent effects in the ¹H‐ and ¹³C‐NMR spectra of these two types of alkaloids were observed.     

Biomimetic Total Synthesis of Hyperjapones A–E and Hyperjaponols A and C

Hyperjapones A–E and hyperjaponols A–C are complex natural products of mixed aromatic polyketide and terpene biosynthetic origin that have recently been isolated from Hypericum japonicum. We have synthesized hyperjapones A–E using a biomimetic, oxidative hetero‐Diels–Alder reaction to couple together dearomatized acylphloroglucinol and cyclic terpene natural products. Hyperjapone A is proposed to be the biosynthetic precursor of hyperjaponol C through a sequence of: 1) epoxidation; 2) acid‐catalyzed epoxide ring‐opening; and 3) a concerted, asynchronous alkene cyclization and 1,2‐alkyl shift of a tertiary carbocation. Chemical mimicry of this proposed biosynthetic sequence allowed a concise total synthesis of hyperjaponol C to be completed in which six carbon–carbon bonds, six stereocenters, and three rings were constructed in just four steps.     

Total Synthesis of (+)‐trans‐Trikentrin A

Several syntheses have already been reported for cis‐trikentrins and herbindoles, which are indole alkaloids unsubstituted at the C2 and C3 positions that bear a trans‐1,3‐dimethylcyclopentyl unit. Herein, we describe the first asymmetric and stereoselective synthesis of the more challenging trans‐trikentrin A as its naturally occurring isomer. Different approaches were investigated and the strategy of choice was a combination of an enzymatic kinetic resolution and a thallium(III)‐mediated ring contraction. The antiproliferative activities of the natural product and related intermediates have been tested against human tumor cell lines, leading to the discovery of new compounds with potent antitumor activity.     

pH‐Zone‐refining counter‐current chromatography for two new lipo‐alkaloids separated from refined alkaline extraction of Kusnezoff monkshood root

An efficient and refined method for the separation of six aconitine‐type alkaloids from the alkaline prepared “Kusnezoff monkshood root” was established. It is the first study that two new lipo‐alkaloids were successfully isolated from refined sample by pH‐zone‐refining counter‐current chromatography rather than synthetic method. It was of interest that a great deal of lipo‐alkaloids was produced in crude extract from the alkalization of “Kusnezoff monkshood root.” A refined sample method was proposed to enrich two types of alkaloids by liquid–liquid extraction, i.e. lipo‐alkaloids and monoester‐diterpenoid alkaloids. The pH‐zone‐refining counter‐current chromatography was performed with an optimized two‐phase solvent system composed of n‐hexane‐ethyl acetate–methanol–water (3:5:4:5, v/v), where upper organic phase was added to 3 mmol/L triethylamine as a retainer and lower aqueous mobile phase was added to 3 mmol/L hydrochloric acid as an eluter. As a result, six aconitum alkaloids, including two lipo‐alkaloids (8‐lino‐14‐benzoylaconine, 8‐pal‐14‐benzoylaconine), three monoester‐diterpenoid alkaloids (14‐benzoylmesaconine, 14‐benzoylaconine, beyzoyldeoxyaconine), and one aconine alkaloid (neoline) were acquired from the plant at the same time. The anti‐inflammatory activities of the two new lipo‐alkaloids were compared to the six alkaloids in vitro, in cyclo‐oxygen‐ase‐2 inhibition assays. The separation mechanism of six alkaloids by pH‐zone‐refining counter‐current chromatography was illustrated.     

Oxazepines and thiazepines. 41 . Synthesis of 4‐aryl‐2,3‐dihydro‐2‐styryl‐1,5‐benzothiazepines by the reaction of (E,E)‐cinnamylideneacetophenones with 2‐aminothiophenol and their conversion into 2,2‐disubstituted 3‐acetyl‐2,3‐dihydrobezothiazoles

New 4‐aryl‐2,3‐dihydro‐2‐styryl‐1,5‐benzothiazepines 8–13 have been synthesized by an acid catalyzed reaction of 2‐arninothiophenol ( 1 ) and (E,E)‐cinnamylideneacetophenones 2–7. Ring contraction of 1,5‐benzothiazepines 8–13 provided 2,2‐disubstituted 3‐acetyl‐2,3‐dihydrobenzothiazoles 14–19 under acetylating conditions.     

Studies of a Diazo Cyclopropanation Strategy for the Total Synthesis of (−)‐Lundurine A

The bioactive Kopsia alkaloids lundurines A–D are the only natural products known to contain indolylcyclopropane. Achieving their syntheses can provide important insights into their biogenesis, as well as novel synthetic routes for complex natural products. Asymmetric total synthesis of (?)‐lundurine A has previously been achieved through a Simmons–Smith cyclopropanation strategy. Here, the total synthesis of (?)‐lundurine A was carried out using a metal‐catalyzed diazo cyclopropanation strategy. In order to avoid a carbene C?H insertion side reaction during cyclopropanation of α‐diazo‐ carboxylates or cyanides, a one‐pot, copper‐catalyzed Bamford–Stevens diazotization/diazo decomposition/cyclopropanation cascade was developed, involving hydrazone. This approach simultaneously generates the C/D/E ring system and the two chiral quaternary centers at C2 and C7.     

Synthesis and Reactivity of 3‐oxoprop‐1‐en‐1‐olate Derivative as a Building Block for the Synthesis of Azole and Azine Derivatives

Several new heterocyclic compounds such as 7‐substituted pyrazolo[1,5‐a ]pyrimidine ( 5a–e ) derivatives have been synthesized by the reactions of the versatile unreported sodium 3‐(4‐methyl‐2‐(4‐methylphenylsulfonamido)thiazol‐5‐yl)‐3‐oxoprop‐1‐en‐1‐olate (2) with amino heterocyclic ( 3a–e ) derivatives. Reaction of (2) with hydrazonyl halide ( 7a–d ) and hydroximoyl chloride ( 11a,b ) derivatives followed by reaction with hydrazine hydrate afforded pyrazolo[3,4‐d ]pyridazine and isoxazolo[3,4‐d ]pyridazine derivatives, respectively incorporating a thiazole moiety have been described. All newly synthesized compounds were elucidated by considering the data of both elemental and spectral analysis.     

2,2,2‐triaryl‐4‐oxo‐1,3,2‐benzoxazastibinines

The hitherto unreported 4‐oxo‐1,3,2‐benzoxazastibinines 2 have been synthesized by the cyclization of disodium salt of salicylanilide ( 1 ) with Ar₃SbBr₂ (Ar = Ph, p‐tolyl, or mesityl). These compounds have been characterized by elemental analyses, molecular weight determination, and by IR, far IR, ¹H, and ¹³C NMR spectral studies. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:622–624, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10202