Total synthesis and biological activity of neopeltolide and analogues

Combining the core structure of neopeltolide, lactone 16 a, with the oxazole-containing side chain 23 via a Mitsunobu reaction provided the cytotoxic natural product neopeltolide (2). The side chain 23 was prepared from oxazolone 24 via the corresponding triflate. Key steps in the preparation of 23 were a Sonogashira coupling, an enamine alkylation, and a Still-Gennari Horner-Emmons reaction. By changing the Leighton reagent in the allylation step, the 11-epimer of lactone 16 a, compound 50 was prepared. This led to 11-epi-neopeltolide 51. The 5-epimer of neopeltolide, compound 52, could be obtained from the minor isomer of the Prins cyclization. Furthermore, a range of analogues with modifications in the side chain were prepared. All derivatives were checked for toxicity effects on mammalian cell cultures and inhibitory effects on NADH oxidation in submitochondrial particles of bovine heart. Modifications in the lactone part are tolerated to some degree. On the other hand, shortening the distance between the oxazole and the lactone causes a significant drop in activity. Analogue 65 with an additional double bond is equally or even more active than neopeltolide itself.     

Formal total synthesis of neopeltolide

A concise synthesis of the core structure of the macrolide neopeltolide was developed featuring a Prins cyclization to fashion the pyran ring. Key steps in the synthesis of aldehyde 16 were a Leighton allylation and a Feringa-Minnaard asymmetric methyl cuprate addition to an unsaturated thioester. For lactonization, a classical Yamaguchi macrolactonization was used. The longest linear sequence consists of 17 steps providing lactone 26 with an overall yield of 23%.     

Full stereochemical assignment and synthesis of the potent anthelmintic pyrrolobenzoxazine natural product CJ-12662

The structure of the unusual anthelmintic pyrrolobenzoxazine terpenoid natural product CJ-12662 was established by X-ray crystallography and partial synthesis from 2-chloronitrobenzene. An unusual Meisenheimer-type rearrangement was used to provide the core pyrrolobenzoxazine heterocycle, and coupling of a tetracyclic pyrrolobenzoxazine lactone with the terpene alcohol was used to complete the synthesis of CJ-12662.     

Approach toward the total synthesis of griseoviridin: formation of thioethynyl and thiovinyl ether-containing nine-membered lactones through a thioalkynylation-macrolactonization-hydrostannylation sequence

Synthesis of the lactone core 17 of 8-epi-griseoviridin is reported. Thioethynyl derivative 11 was easily prepared via an anionic coupling reaction between acetylenic compound 9 and sulfone 10. After desilylation of 11, saponification of the resulting hydroxy ester 12 followed by a Mitsunobu macrolactonization furnished the unusual triple-bond-containing nine-membered lactone 13 in 50% yield for the last two steps (39% after recrystallization). Stannylation under Magriotis conditions led to the pure regio- and stereocontrolled vinyltin 14 (80% yield). After a Sn/I exchange, palladium-catalyzed carbonylation delivered either the ester lactone 16 in 67% yield or the propargyl amide 17 in 65% yield. Synthesis of propargyl amide 17 of the lactone core of 8-epi-griseoviridin was achieved in 11.9% overall yield from commercial L-cystin dimethyl ester (nine steps).     

Pheromone synthesis. Part 264: Synthesis of the core 3-oxabicyclo[3.3.0]octane structures of gomadalactones A,B and C,the components of the contact sex pheromone of the white-spotted longicorn beetle,Anoplophora malasiaca

The core bicyclic cyclopentanelactone structures of gomadalactones A, B and C with α-hydroxyketone system were synthesized from (R)-pulegone, employing deconjugation of an α,β-unsaturated lactone as the key step. Comparison of the CD spectra of the synthetic compounds with those of the natural products confirmed the absolute configuration of the natural pheromone components as proposed in 2007. X-ray crystallographic analysis of the model compound of gomadalactone B core structure was carried out.     

The first total synthesis of (-) and (+)-2-hydroxy-24-oxooctacosanolide using an effective lactonization

[structure: see text] An effective method for the total synthesis of 2-hydroxy-24-oxooctacosanolide, a defensive salivary secretion of the African termite Pseudacanthotermes spiniger, has been developed. The key lactonization to form a 29-membered ring lactone core is performed using 2-methyl-6-nitrobenzoic anhydride with a catalytic amount of 4-(dimethylamino)pyridine N-oxide.     

Synthesis of N,N-Disubstituted Lactone Hydrazones via (Sulfonylimino)-ethers

The dihydropyran 3 reacts with sulfonyl azides to give the known (sulfonylimino)-ethers ( = lactone sul-fonylimines) 4 and 18 . Reaction of 4 with NH₂NH₂ · H₂O leads to the aminoiriazole-dibulanol 5 , characterized as its tetraacetate 8 , and not, as previously claimed, to 6 or 7 . Similarly, the dihydrofuran-derived (tosylimino)-ether 10 yields 11 The structure of 5 was established by X-ray analysis, and a mechanism for its formation is proposed. Reaction of 4 with NH₂NMe₂ afforded the lactone hydrazone 16 and the hydrazidine 17. Catalysis by imidazole suppressed the formation of 17 similarly, the [(trifluoromethyl)sulfonyl]imine 18 yielded 16, and, by reaction with NH₂N(Me)Ph or 4-amino-4H-1,2,4-triazole, the lactone hydrazone 19 and the adduct 20 , respectively. The 1,4-lactone hydrazone 21 was obtained from 10 or from 22 . The structure of 20 was established by X-ray analysis. Treatment of 16 with BuLi followed by BnBr yielded the α-alkylated lactone hydrazone 23 .     

The synthesis of carnosol derivatives

In this paper we report on the development of an efficient and flexible synthetic strategy towards the synthesis of carnosol type derivatives. The strategy involves the construction of the required trans-decalin structure with a carboxylic functionality in the angular position as well as the elaboration of the lactone ring to afford the tetracyclic core structure of the natural compound 1.     

An efficient synthesis of 9-anthrone lactone derivatives via the Knoevenagel condensation and intramolecular cyclization

One-step synthesis of 9-anthrone lactone derivatives from 1-acetyloxyanthraquinone with a variety of dicarbonyl substrates in the presence of K₂CO₃ by Knovenagel condensation and intramolecular cyclization is developed. Possible reaction mechanisms have been investigated using the density functional theory (DFT), which has been widely used in the study of reaction mechanism. The strategy could be useful for the synthesis of the core structure of marine natural product aspergiolide.     

Novel strategies to construct the gamma-hydroxy lactone moiety of the CP molecules. Synthesis of the CP-225,917 core skeleton

[formula: see text] The array of challenging structural lineaments embodied in the CP molecules (1 and 2, Figure 1) offers synthetic chemists uncharted realms of exploration and discovery. In this communication, we focus on the chemical hurdies posed by the gamma-hydroxy lactone moiety of these exciting targets. Thus, the examination of the general reactivity of these systems, the development of a novel tandem oxidation sequence to construct the gamma-hydroxy lactone moiety, and the successful construction of the complete polycyclic core of 2 (compound 28, Scheme 5) is enumerated within.     

Dyotropic rearrangement facilitated proximal functionalization and oxidative removal of angular methyl groups: efficient syntheses of 23'-deoxy cephalostatin 1 analogues

Oxidative functionalization (or removal) of a steroidal C18 methyl group is possible using a previously unknown dyotropic rearrangement of a seven-membered fused C-ring lactone to a 6-ring spiro lactone. Spiroketal equilibration led to the 23-deoxy South analogue of cephalostatin 1 (1) in only 12 steps (23% overall yield) from hecogenin acetate 4, and to strained diene South 1 analogue 30 in 11 steps (28% overall). Total synthesis of 23'-deoxy cephalostatin 1 (3) was accomplished in 16 operations from 4 (9% overall; average 86% yield per operation), and that of 16',17'-dehydro-23'-deoxy cephalostatin 1 (36) in 15 operations from 4 (8% overall; av 84%/op).     

Studies on the synthesis of (-)-spinosyn a: application of the steric directing group strategy to transannular Diels-Alder reactions

A highly diastereoselective and enantioselective synthesis of the decahydro-as-indacene nucleus 12 of (-)-spinosyn A (1) is reported. By implementing the steric directing group strategy, tricyclic lactone 37 was produced from a remarkably diastereoselective transannular Diels-Alder reaction of lactone 9. The tricyclic core of the natural product was then obtained by using an Ireland-Claisen ring contraction of 37. Reversal of the order of these two steps resulted in an almost complete loss of diastereoselectivity.     

An efficient, stereoselective synthesis of the hydroxyethylene dipeptide isostere core for the HIV protease inhibitor A-792611

A stereoselective synthesis of the hydroxyethylene dipeptide isostere 1 is described. The route employs a substrate-directed kinetic protonation of an alpha/gamma-substituted lactone to afford the desired stereochemistry. A method for converting the diastereomerically enriched intermediate lactone to the ring-open form with retention of stereochemistry is demonstrated. A novel procedure for utilizing N,N-dibromo-5,5-dimethylhydantoin in Hofmann rearrangements is disclosed. This route was used to prepare amino alcohol 1, the core portion of the HIV protease inhibitor A-792611, in 46% yield from phenylalanine-derived epoxide 2.     

Thapsigargin的全合成研究进展

Thapsigargin是一类从地中海植物毒胡萝卜(thapsia garganica)中分离得到的结构复杂的高氧化态倍半萜内酯,其对肌浆-内质网Ca~(2+)-ATP泵(SERCAs)具有不可逆的抑制作用,抑制浓度达纳摩尔级别(KD=0.4 nmol/L)。Thapsigargin因其独特的结构和良好的生物活性而备受有机合成化学家的广泛关注。在合成中,立体选择性地构建该分子cis-5/7/5稠环体系以及多个手性中心是极具挑战性的。本文综述了该分子近二十年来的全合成研究进展。     

Asymmetric synthesis of (+)-stagonolide C and (−)-aspinolide A via organocatalysis

A new enantioselective synthesis of two important fungal metabolites, (+)-stagonolide C and (?)-aspinolide A, has been described from readily available raw materials. Proline catalyzed asymmetric α-aminooxylation and Jorgensen’s epoxidation of aldehydes are the key reactions employed in the introduction of chirality. The formation of the 10-membered lactone core structure was finally accomplished via Steglich esterification and ring closing metathesis reactions.     

Identification of the absorptive constituents and their metabolites in vivo of Ziziphi Spinosae Semen by UPLC–ESI–Q-TOF–MS/MS

In this research, ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC–ESI–Q-TOF–MS/MS) was used for detection and identification of the absorptive constituents and their metabolites in rat plasma, urine and feces following oral administration of Ziziphi Spinosae Semen alcohol extract. After structure elucidation, a total of 12 compounds in rat plasma, comprising seven prototypes and five metabolites, 28 compounds in urine, comprising 17 prototypes and 11 metabolites, and 23 compounds in feces, comrpising 17 prototypes and six metabolites, have been tentatively identified by comparison with standard compounds and reference literature information. To the best of our knowledge, this is the first comprehensive and systematical metabolic study on the seed. Mostly importantly, we propose that gastric acid could convert jujubosides into an absorbable form of ebelin lactone oligosaccharides, which may be responsible for the low bioavailability and specific bioactivities of these compounds. Additionally, we deduced that the absorption site of ebelin lactone oligosaccharides is located in the stomach, and that the ebelin lactone form of jujubosides may be more suitable for absorption than its hydrolysis product. Our investigation will be helpful to narrow the scope for potentially active ingredients of the seed, and pave the way for determination of the pharmacological mechanism of the seed.     

Total Synthesis of Cyclothialidine

A total synthesis of cyclothialidine ( 1 ), a new DNA gyrase inhibitor isolated from Streptomyces filipinensis, is described. The synthetic concept was tested by preparing the lactone 13 (Scheme 2) which contains the characteristic bicyclic core entity of 1 . Key features of the synthesis of 1 are: preparation of 3,5-dihydroxy-2,6-dimethylbenzoic acid ( 23 ) from 3,5-dihydroxybenzoic acid ( 19 ) by two consecutive Mannich aminomethylation/hydrogenation sequences; benzylic N-bromosuccinimide bromination of an ester derivative 25 thereof and its subsequent coupling with Boc-Ser-Cys-OMe ( 11 ); cyclization of the ω-hydroxy acid 29 29 to the 12-membered lactone 30 using preferably Mitsunobu conditions; completion of the peptidic side chains of 1 using Boc strategy (Scheme 4). Optically pure cis-N-(tert-butoxycarbonyl)-3-hydroxy-L -proline ((–)- 14 ) was obtained by resolution of the racemate via an efficient reaction sequence containing a lipase-catalyzed enantiospecific acetate hydrolysis (Scheme 3). The structure of natural 1 was confirmed by comparison with the synthetic material. The synthetic route described provides also easy access to analogues of 1 , e.g., via the intermediate 30 .     

Guianolactones A and B,Two Rearranged Pentacyclic Limonoids from the Seeds of Carapa guianensis

Two novel rearranged limonoids, guianolactones A ( 1 ) and B ( 2 ), were isolated from Carapa guianensis Aubl. (Meliaceae) seeds. The structures of 1 and 2 with their absolute configurations were elucidated in detailed examinations using single‐crystal X‐ray diffraction analyses and 2D NMR spectra. Guianolactone A ( 1 ) has a novel 5/6/6/6/6 pentacyclic core including two δ ‐lactone and a tetrahydropyran ring, while guianolactone B ( 2 ) is a novel limonoid with a 6/6/5/6/6 pentacyclic core featuring a δ ‐lactone and a tetrahydrofuran ring.     

Rearranged lanostane triterpenoids from Abies sachalinensis (III)

To isolate more rearranged lanostane-type triterpenes from Abies sachalinensis, continuous chemical investigation of the ethyl acetate soluble fraction of the methanol extract of A. sachalinensis afforded two new rearranged lanostane-type triterpenes (1, 2). Their structures were elucidated to be 3,4-seco-4(28),7,12,24-mariesatetraen-26,23-olide-23-hydroxy-3-oic acid (1) and ethyl 3,4-seco-8(14-->13R)abeo-17,13-friedo-4(28),7,14,24-lanostatetraen-26,23-olide-23-hydroxy-3-oate (2), respectively. The structure of these compounds was determined by spectral studies, especially by two-dimensional (2D)-NMR and high-resolution (HR)-MS. Compounds 1 and 2 have a tautomeric lactone structure in the side chain.     

An x-ray crystallographic,mass spectroscopic,and NMR study of the limonoid insect antifeedant azadirachtin and related derivatives

The limonoid insect antifeedant azadirachtin (1) may be partially hydrogenated at the C22-C23 position and subsequently treated with an excess of sodium periodate and potassium permanganate in the presence of a base to give detigloyldihydroazadirachtin (4). This compound was examined by X-ray crystallographic techniques which revealed key structural fragments and together with detailed n.m.r. and mass spectroscopic studies allowed the complete unambiguous structure assignment to the parent azadirachtin molecule. Two further compounds, 3-deacetyl-11-desoxyazadirachtin (2), and 3-acetoxy-7-tigloyl-vilasinin lactone (3) were also isolated and characterised from a Senegal sample of neem seed.