Enantioselective Polyene Cyclization Catalyzed by a Chiral Brønsted Acid

The first enantioselective polyene cyclization initiated by a BINOL‐derived chiral N‐phosphoramide (NPA) catalyzed protonation of an imine is described. The ion‐pair formed between the iminium ion and chiral counter anion of the NPA plays an important role for controlling the stereochemistry of the overall transformation. This strategy offers a highly efficient approach to fused tricyclic frameworks containing three contiguous stereocenters, which are widely found in natural products. In addition, the first catalytic asymmetric total synthesis of (?)‐ferruginol was accomplished with an NPA catalyzed enantioselective polyene cyclization, as the key step for the construction of the tricyclic core, with excellent yield and enantioselectivity.     

Total Syntheses of Xiamycins A,C, F,H and Oridamycin A and Preliminary Evaluation of their Anti‐Fungal Properties

Divergent and enantiospecific total syntheses of the indolosesquiterpenoids xiamycins A, C, F, H and oridamycin A have been accomplished. The syntheses, which commence from (R)‐carvone, employ a key photoinduced benzannulation sequence to forge the carbazole moiety characteristic of these natural products. Late‐stage diversification from a common intermediate enabled the first syntheses of xiamycins C and F, and an unexpected one‐pot oxidative decarboxylation, which may prove general, led to xiamycin H. All synthetic intermediates and the natural products were tested for anti‐fungal activity. Xiamycin H emerged as an inhibitor of three agriculturally relevant fungal pathogens.     

Total Synthesis and Stereochemical Revision of Phacelocarpus 2‐Pyrone A

The first total synthesis of phacelocarpus 2‐pyrone A is reported. The original natural compound was tentatively assigned (by NMR spectroscopy) as containing two cis‐alkenes and a trans‐vinyl ether connected to a 2‐pyrone ring motif. Our computational predictions indicated that a cis‐vinyl ether motif was equally feasible. Attempts to prepare the trans‐vinyl ether were met with no success. The all cis‐target compound was synthesised in nine steps, employing key regio‐ and stereoselective reactions including Au^I‐catalysed vinyl etherification, Wittig alkenylation and end‐game Stille macrocyclisation. Analysis of the NMR data enabled identification and confirmation of the correct structure of phacelocarpus 2‐pyrone A, containing a cis‐vinyl ether. Our studies pave the way for future development of methodologies to these structurally distinct pyrone skipped‐polyenyne natural products.     

Highly Efficient Gold‐Catalyzed Synthesis of Dibenzocycloheptatrienes

Dibenzocycloheptatrienes are obtained by a gold‐catalyzed 7‐exo‐dig hydroarylation protocol in a highly efficient manner. The gold‐catalyzed reaction usually gives the products in high yields and excellent selectivity. This procedure provides an easy and efficient access to dibenzocycloheptanoids, which are an interesting and unique class of natural products. This was underlined by the first total synthesis of reticuol.     

Total Synthesis and Bioactivity Mapping of Geodiamolide H

The first total synthesis of the actin-stabilizing marine natural product geodiamolide H was achieved. Solid-phase based peptide assembly paired with scalable stereoselective syntheses of polyketide building blocks and an optimized esterification set the stage for investigating the key ring-closing metathesis. Geodiamolide H and synthetic analogues were characterized for their toxicity and for antiproliferative effects in cellulo, by characterising actin polymerization induction in vitro, and by docking on the F-actin target and property computation in silico, for a better understanding of structure-activity relationships (SAR). A non-natural analogue of geodiamolide H was discovered to be most potent in the series, suggesting significant potential for tool compound design.     

Quinones as Dienophiles in the Diels–Alder Reaction: History and Applications in Total Synthesis

In the canon of reactions available to the organic chemist engaged in total synthesis, the Diels–Alder reaction is among the most powerful and well understood. Its ability to rapidly generate molecular complexity through the simultaneous formation of two carbon? carbon bonds is almost unrivalled, and this is reflected in the great number of reported applications of this reaction. Historically, the use of quinones as dienophiles is highly significant, being the very first example investigated by Diels and Alder. Herein, we review the application of the Diels–Alder reaction of quinones in the total synthesis of natural products. The highlighted examples span some 60 years from the landmark syntheses of morphine (1952) and reserpine (1956) by Gates and Woodward, respectively, through to the present day examples, such as the tetracyclines.     

Substrate‐Controlled Asymmetric Total Syntheses of Microcladallenes A,B, and C Based on the Proposed Structures

Substrate‐controlled asymmetric total syntheses of (+)‐microcladallenes A, B, and C have been accomplished based on the proposed structures. The syntheses of microcladallenes A and B confirmed the structures and absolute configurations of both natural products. However, the synthesis of microcladallene C, which includes seven stereogenic centers and an (R)‐bromoallene in its compact C₁₅ framework, brought the realization that its proposed structure must be revised. The introduction of C12‐bromine into these natural products with retention of configuration relied on TiBr₄‐mediated nucleophile‐assisting leaving group brominations, the stereochemical outcome of which could be attributed, at least in part, to an oxonium or halonium ion formation–fragmentation sequence through intricate neighboring group participation. In addition, the pivotal β‐oriented vicinal cis‐dichloride function in microcladallene C was elaborated through a novel tandem Cl₂‐induced electrophilic cyclization/imidate chlorination process. The positive rotations of these natural products with an (R)‐bromoallene constitute exceptions to Lowe’s rule for reasons yet to be determined.     

A Divergent Enantioselective Total Synthesis of Post-Iboga Indole Alkaloids

Divergent enantioselective total syntheses of five naturally occurring post-iboga indole alkaloids, dippinine B and C, 10,11-demethoxychippiine, 3-O-methyl-10,11-demethoxychippiine, and 3-hydroxy-3,4-secocoronaridine, as well as the two analogues 11-demethoxydippinine A and D, are presented for the first time. The enantioenriched aza[3.3.1]-bridged cycle, a common core intermediate to the target molecules, was constructed through an asymmetric phase-transfer-catalyzed Michael/aldol cascade reaction. The challenging azepane ring fused around the indole ring and the [3.3.1]-bridged cycle were installed through an intramolecular S_N2′-type reaction. These cyclization strategies enabled rapid construction of the [6.5.6.6.7]-pentacyclic core at an early stage. Highlights of the late-stage synthetic steps include a Pd-catalyzed Stille coupling and a highly stereoselective catalyst-controlled hydrogenation to incorporate the side chain at C₂₀ with both R and S configurations in the natural products.     

Total Synthesis of (+)-Gelsedine

A novel iodide-promoted, allene-terminated cyclization of an N-acyliminium ion, a stereoselective Heck spirocyclization, and a chemoselective demethylation at the nitrogen atom of an oxindole are the key transformations in the first total synthesis of the indole alkaloid (+)-gelsedine ( 1 ). This dextrorotatory form of natural gelsedine was formed as a single enantiomer in 21 steps from (S)-malic acid.     

用大孔吸附树脂分离利血平

以利血平的吸附量和解吸率为指标,筛选大孔吸附树脂.研究吸附和解吸的优化条件,并考察选定树脂的吸附等温线、吸附动力学、吸附和解吸性能.结果表明,将催吐萝芙木根粉浸提液蒸去乙醇且不调pH(pH 1)进行吸附,HZ-818型大孔吸附树脂对利血平的吸附量可达到9.34mg/mL.使用工业乙醇-水(80:20,pH 1.0)为解吸剂,解吸率可达99.3%.该树脂的吸附符合Langmuir吸附等温方程.吸附前期,吸附速度较快,以后速度减慢.HZ-818型树脂对利血平的吸附量大,解吸率高,通过大孔树脂吸附和解吸,利血平浓度提高50倍以上,适宜于工业化生产.     

One-Pot Synthesis of Metastable 2,5-Dihydrooxepines through Retro-Claisen Rearrangements: Method and Applications

A one-pot methodology to synthesize metastable bicyclic 2,5-dihydrooxepines from cyclic 1,3-diketones and 1,4-dibromo-2-butenes through the retro-Claisen rearrangement of syn-2-vinylcyclopropyl diketone intermediates is reported. DFT calculations were performed to understand the reaction selectivity and mechanisms towards [1,3]- or [3,3]-sigmatropic rearrangements, highlighting the crucial influence of the temperature. The reaction was successfully applied to a short protecting group-free total synthesis of radulanin A, a natural 2,5-dihydrobenzoxepine. Moreover, the strong herbicidal potential of this natural product is demonstrated for the first time.     

Total Synthesis and Biological Evaluation of the Antibiotic Lysocin E and Its Enantiomeric,Epimeric, and N‐Demethylated Analogues

Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid‐phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N‐demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action.     

Regio- and Enantioselective Prenyl Anion Transfer: Application to the Total Synthesis of (−)-Rosiridol

At elevated temperature (refluxing THF) prenyl anion adds regio- and enantioselectively to aldehyde 1 when a chiral, borneol-derived ligand is present. This reaction is the key stepin the first total synthesis of the monoterpene (−)-rosiridol (retrosynthesis is shown on the right). In addition, the absolute configuration of this natural product has been assigned conclusively. M=Zn, R=tBuMe₂Si.     

Enantioselective Divergent Syntheses of Several Polyhalogenated Plocamium Monoterpenes and Evaluation of Their Selectivity for Solid Tumors

The family of polyhalogenated monoterpenes from Plocamium counts over a hundred known members. Using glyceraldehyde acetonide as a chiral‐pool precursor, an enantioselective and divergent strategy was developed that provides a blueprint for the synthesis of many of the small yet complex acyclic members of this family. The broad applicability of this approach is demonstrated with the short, eight‐step synthesis of four natural products and three analogues. These syntheses are the first of any members of the acyclic polyhalogenated Plocamium monoterpenes and permitted the evaluation of their selectivity against a range of tumor cell lines.     

Total Synthesis,Proof of Absolute Configuration,and Biosynthetic Origin of Stylopsal,the First Isolated Sex Pheromone of Strepsiptera

The asymmetric total synthesis of the diastereomers of stylopsal establishes the absolute configuration of the first reported sex pheromone of the twisted‐wing parasite Stylops muelleri as (3R,5R,9R)‐trimethyldodecanal. The key steps for the diastereo‐ and enantiodivergent introduction of the methyl groups are two different types of asymmetric conjugate addition reactions of organocopper reagents to α,β‐unsaturated esters, whereas the dodecanal skeleton is assembled by Wittig reactions. The structure of the natural product was confirmed by chiral gas chromatography (GC) techniques, GC/MS and GC/electroantennography (EAD) as well as field tests. An investigation into the biosynthesis of the pheromone revealed that it is likely to be produced by decarboxylation of a 4,6,10‐trimethyltridecanoic acid derivative, which was found in substantial amounts in the fat body of the female, but not in the host bee Andrena vaga. This triple‐branched fatty acid precursor thus seems to be biosynthesized de novo through a polyketide pathway with two consecutive propionate‐propionate‐acetate assemblies to form the complete skeleton. The simplified, motionless and fully host‐dependent female exploits a remarkable strategy to maximize its reproductive success by employing a relatively complex and potent sex pheromone.     

Total Synthesis of Camptothecin and Related Natural Products by a Flexible Strategy

A flexible strategy for constructing natural products containing indolizinone or quinolizinone scaffolds and their analogues was developed, which was based on a cascade exo hydroamination followed by spontaneous lactamization. This method was applied in the total synthesis of camptothecin in nine steps in a new ring‐forming approach. It was also used to efficiently prepare five biogenetically or structurally related natural alkaloids, including 22‐hydroxyacuminatine, oxypalmatine, norketoyobyrine, naucleficine, and nauclefine, as well as 35 natural‐product‐like molecules. We believe that this method and the small‐molecule library prepared with it can open new avenues for studying the bioactivity of camptothecin and Nauclea natural products.     

Stereocontrolled Synthesis of (−)-5,11-Dideoxytetrodotoxin

New derivatives of an intriguing marine natural product are now accessible. The first asymmetric synthesis of the simple tetrodotoxin analogue, 5,11-dideoxytetrodotoxin ( 3 ), was achieved. Hydroxylation at position C8 of the key intermediate 1 relied on the neighboring trichloroacetamide group, and stereoselective elaboration of the vinyl group gave α-hydroxylactone 2 , which was transformed into the title compound through a new guanidylation method.     

Quantitative densitometric determination of reserpine and ajmaline in Rauwolfia Vomitoria by HPTLC

A direct densitometric method for the quantitative measurement of reserpine and ajmaline in whole roots and bark of roots of Rauwolfia Vomitoria, after extraction and separation by thin-layer chromatography, is described. The emission and excitation spectra of the reserpine and the absorption spectrum of the ajmaline were scanned. The linear range between peak area and concentration is given.     

Synthesis of Morpholine-Based Analogues of (−)-Zampanolide and Their Biological Activity

We describe the convergent synthesis of three prototypical examples of a new class of analogues of the complex, cytotoxic marine macrolide (−)-zampanolide that incorporate an embedded N-substituted morpholine moiety in place of the natural tetrahydropyran ring. The final construction of the macrolactone core was based on a high-yielding intramolecular HWE olefination, while the hemiaminal-linked side chain was elaborated through a stereoselective, BINAL-H-mediated addition of (Z,E)-sorbamide to a macrocyclic aldehyde precursor. The synthesis of the common functionalized morpholine building block involved two consecutive epoxide openings with tosylamide and the product of the first opening reaction, respectively, as nucleophiles. Of the three morpholino-zampanolides investigated, the N-acetyl and the N-benzoyl derivatives both exhibited nanomolar antiproliferative activity, thus being essentially equipotent with the natural product. In contrast, the activity of the N-tosyl derivative was significantly reduced.     

Total synthesis of cassane-type diterpenoid pikrosalvin

This paper presents the first successful total synthesis of pikrosalvin, a compound naturally derived from Salvia officinalis, grounded on the structural framework delineated by Brieskorn and Fuchs. Our synthetic approach was underpinned by a biomimetic strategy inspired by the Stork–Eschenmoser hypothesis for the biosynthesis of terpenes via polyene cyclization. Starting with commercially available vanillic acid and geraniol, we strategically assembled pikrosalvin's structural core, consisting of a decalin A/B ring, an aromatic C ring, and a butyrolactone D ring. Challenges related to protective groups and specific catalytic conditions were effectively addressed, resulting in high product yields. We further demonstrated the efficacy and broad applicability of a combined-acid-catalyzed polyene cyclization methodology in the context of complex natural product synthesis. This study sets the stage for future biological and pharmacological investigations of pikrosalvin.