Biomimetic synthesis and structural revision of (+/-)-tridachiahydropyrone

A short synthesis of the revised structure of the marine natural product tridachiahydropyrone is described. A novel biomimetic photochemical electrocyclization was employed to construct the bicyclic carbon framework from an open-chain polyene precursor. The spectroscopic data matched that of the isolated natural product, supporting a revised structure of this complex metabolite.     

Total synthesis, structure revision, and absolute configuration of (-)-brevenal

Total synthesis of structure 1 originally proposed for brevenal, a nontoxic polycyclic ether natural product isolated from the Florida red tide dinoflagellate, Karenia brevis, was accomplished. The key features of the synthesis involved (i) convergent assembly of the pentacyclic polyether skeleton based on our developed Suzuki-Miyaura coupling chemistry and (ii) stereoselective construction of the multi-substituted (E,E)-dienal side chain by using copper(I) thiophen-2-carboxylate (CuTC)-promoted modified Stille coupling. The disparity of NMR spectra between the synthetic material and the natural product required a revision of the proposed structure. Detailed spectroscopic comparison of synthetic 1 with natural brevenal, coupled with the postulated biosynthetic pathway for marine polyether natural products, suggested that the natural product was most likely represented by 2, the C26 epimer of the proposed structure 1. The revised structure was finally validated by completing the first total synthesis of (-)-2, which also unambiguously established the absolute configuration of the natural product.     

Enantioselective synthesis of possible diastereomers of heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol; putative structure of a conjugated diyne natural product isolated from Hydrocotyle leucocephala

Enantioselective synthesis of possible diastereomers of heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol, a structure proposed for the natural product isolated from Hydrocotyle leucocephala is accomplished. The reported spectral data of the natural product did not match those of any of the isomers that were synthesized and established that the structure proposed for the natural product is not correct and requires revision.     

Radical carboxyarylation approach to lignans. Total synthesis of (-)-arctigenin, (-)-matairesinol, and related natural products

[reaction: see text] Total syntheses of seven biologically important lignan natural products, including (-)-arctigenin, (-)-matairesinol, and (-)-alpha-conidendrin, by way of a highly stereoselective domino radical sequence is presented. The reported stereochemistry of the natural product 7-hydroxyarctigenin is shown to be erroneous; a diastereoisomeric structure is assigned to the natural product.     

Total synthesis of the proposed structure of cyclic hexadepsipeptide veraguamide A

We have developed a practical method to assemble the proposed structure of natural product veraguamide A (1) by first preparing the three key fragments followed by optimization of the macrocyclization site. Although the synthetic product gave similar optical rotation to that reported for natural product, significant differences in the (1)H and (13)C NMR spectra were observed, especially the proton and carbon signals in the two N-MeVal moieties.     

Synthesis of the enantiomer of the structure assigned to the natural product nobilisitine A

The synthesis of the enantiomer of the structure, 1, assigned to the natural product nobilisitine A has been accomplished using the enantiomerically pure cis-1,2-dihydrocatechol 4 as starting material. The (1)H and (13)C NMR spectral data derived from compound ent-1 do not match those reported for the natural product, thus suggesting its structure has been incorrectly assigned.     

Total synthesis of the proposed structure of brevenal

Total synthesis of the proposed structure of brevenal, a natural marine polycyclic ether product, has been accomplished. The synthesis features (i) convergent synthesis of the pentacyclic polyether skeleton using our developed Suzuki-Miyaura coupling strategy and (ii) construction of the multi-substituted dienal side chain by CuTC-mediated Stille reaction. Comparison of the NMR data of the synthetic compound with those reported for the natural product revealed that the proposed structure of brevenal needs to be revised.     

Total synthesis, structure revision, and absolute configuration of (+)-yatakemycin

The total synthesis of the reported structure 2 for yatakemycin, an exceptionally potent, naturally occurring antitumor agent disclosed in 2003, and its lack of correlation with the natural product are detailed. On the basis of spectroscopic distinctions between 2 and yatakemycin, the natural product structure was reformulated as 3, now bearing a thiomethyl ester versus thioacetate in the left-hand subunit. Total synthesis of 3 provided a compound nearly identical to but still subtly distinct from the natural product. A second reformulation of the yatakemycin structure as 1, incorporating the alternatively substituted right-hand subunit as well as the initial thiomethyl ester reformulation, was confirmed by total synthesis of both (+)- and ent-(-)-1 in studies that also unambiguously established the absolute configuration of the natural product.     

Identification of the binding of sceptrin to MreB via a bidirectional affinity protocol

A bidirectional affinity system was used to screen for marine natural products that bound to Escherichia coli proteins. A system was developed and applied to isolate the natural product sceptrin from an Agelas conifera extract and its affinity partner MreB from E. coli lysate. The use of a dual immunoaffinity fluorescent (IAF) tag permitted this process to co-immunoprecipitate the bacterial equivalent of actin, MreB, from E. coli lysate. MreB was subsequently validated as a target for sceptrin using a resistance mapping approach. The combination of these studies suggests that natural products and their protein targets can be isolated in concert using a melody of forward and reverse affinity matrices. While the structure of sceptrin was elucidated by NMR analysis, the bulk of effort was conducted without knowing the structure of the natural product, thereby elevating a key bottleneck in the development of high-throughput methods for natural product discovery.     

Total synthesis of hectochlorin

Hectochlorin (1) is a marine natural product with significant fungicidal activity. A synthesis effort was initiated to develop a flexible route to hectochlorin which would allow access to analogues with potentially improved activity and/or attributes relative to the natural product. A successful total synthesis of hectochlorin is described. [structure: see text]     

A Concise Total Synthesis of (±)‐Vibralactone

Disclosed is a five‐step synthesis of (±)‐vibralactone, a biologically active terpenoid natural product. A key photochemical valence isomerization of 3‐prenyl‐pyran‐2‐one produces both the all‐carbon quaternary stereocenter and the β‐lactone at an early stage. Cyclopropanation of the resulting bicyclic β‐lactone produces a strained housane structure that is converted to the natural product through a sequential ring expansion and reduction strategy. This concise and modular route to the natural product provides the shortest total synthesis of (±)‐vibralactone reported to date.     

Total synthesis based modification of benzoquinone ansamycin antibiotics: C8 diversification of C5-C15 fragments

Benzoquinone ansamycins are known to be potent Heat shock protein (Hsp90) inhibitors, and total-synthesis-based structure modification of this natural product family may lead to the discovery of novel cancer chemotherapeutics. Described in this paper is a unified synthetic route that gives access to both natural and C-8-modified C5-C15 fragments of this natural product family.     

高通量天然产物化学和毛细管核磁共振探头技术的应用

介绍了近几年为高通量药物筛选构建大型天然产物样品库的高通量天然产物化学,即多通道平行高效液相制备和平行液质联用分析技术;详细介绍了核磁共振新技术即体积小和质量灵敏度高的毛细管核磁共振探头技术,该探头技术的成功应用使得天然产物样品库中活性化合物的结构鉴定所需样品量降低到前所未有的微克级水平;展望了源于中药的天然产物作为小分子探针开展脑功能方面的化学基因组学研究。     

Synthesis and structural reassignment of (+)-epicalyxin F

We have established the structure of (+)-epicalyxin F through chemical synthesis. An acid-promoted rearrangement of synthetic benzopyran 6 led to the identification of the natural product as (3S,5S,7R)-epicalyxin F (22). Comparison with NMR spectra and optical rotation of the natural product confirms our assignment, and the reassigned structure is compatible with the proposed biosynthetic pathway.     

Total synthesis and structural revision of the marine macrolide neopeltolide

The total synthesis and structural revision of the marine natural product neopeltolide is reported. The key bond-forming step involves a Lewis acid-catalyzed intramolecular cyclization to install the tetrahydropyran ring and the macrocycle simultaneously. This type of cyclization is the first of its kind and assembles the carbon backbone of the natural product efficiently. The synthesis of the reported structure revealed differences in the data between the natural and synthetic material. After significant investigation, the diastereomeric molecule with the C11 and C13 configurations inverted was synthesized using the initial route. This compound matches the data reported for neopeltolide (1H, 13C, HRMS, IR, NOESY, [alpha]), thereby establishing the correct overall structure for this potent macrolide natural product, including the relative and absolute stereochemistry.     

Total synthesis and structure confirmation of elatenyne: success of computational methods for NMR prediction with highly flexible diastereomers

Elatenyne is a small dibrominated natural product first isolated from Laurencia elata. The structure of elatenyne was originally assigned as a pyrano[3,2-b]pyran on the basis of NMR methods. Total synthesis of the originally proposed pyrano[3,2-b]pyran structure of elatenyne led to the gross structure of the natural product being reassigned as a 2,2'-bifuranyl. The full stereostructure of this highly flexible small molecule was subsequently predicted by Boltzmann-weighted DFT calculations of (13)C NMR chemical shifts for all 32 potential diastereomers, with the predicted structure being in accord with the proposed biogenesis outlined below. Herein we report two complementary total syntheses of elatenyne, which confirm the computer-predicted stereostructure. Additionally, the total syntheses of (E)-elatenyne and a related 2,2'-bifuranyl, laurendecumenyne B, are reported. This work has not only allowed the full structure determination of all of these natural products but also provides excellent supporting evidence for their proposed biogenesis. The total synthesis of elatenyne demonstrates that DFT calculations of (13)C NMR chemical shifts coupled with biosynthetic postulates, comprise a very useful method for distinguishing among large numbers of highly flexible, closely related molecules.     

Synthesis of putative uniflorine A

A diastereoselective synthesis of the putative structure of the natural product uniflorine A has been achieved by using the Petasis borono-Mannich reaction and ring-closing metathesis as key steps. The NMR data of the synthetic material did not match that reported for the natural product. The structure of the final synthetic product was unequivocally determined by single-crystal X-ray study of its pentaacetate derivative. Thus it was concluded that the proposed structure of uniflorine A is incorrect.     

A concise synthesis of (+)-SCH 351448

[structure: see text] We describe a highly convergent synthetic approach to the natural product (+)-SCH 351448 (1)-a hexane-soluble heptacoordinate monosodium salt of a C(2)-symmetrical macrocyclic dilactone. Our approach implements a photochemical acylation as the key step to combine two nearly identical but orthogonal C1-C29 fragments, followed by a base-induced intramolecular acylation and deprotection to yield the natural product.     

Studies toward diazonamide A: initial synthetic forays directed toward the originally proposed structure

A brief introduction into the chemistry of diazonamide A (1) is followed by first-generation sequences to access the originally proposed structure for this unusual marine natural product. These explorations identified a route capable of delivering a model compound possessing the complete heteroaromatic core of the natural product, highlighting in the process several unanticipated synthetic challenges which led both to new methodology as well as an improved synthetic plan that was successfully applied to fully functionalized intermediates.     

Synthesis of the proposed structure of mucoxin via regio- and stereoselective tetrahydrofuran ring-forming strategies

An enantioselective total synthesis of the proposed structure of mucoxin (1) is described. Mucoxin, an annonaceous acetogenin isolated from bioactive leaf extracts of Rollinia mucosa, is the first acetogenin containing a hydroxylated trisubstituted tetrahydrofuran (THF) ring. This natural product is a highly potent and specific antitumor agent against MCF-7 (breast carcinoma) cell lines (ED50 = 3.7 x 10(-3) microg/mL compared to adriamycin, ED50 = 1.0 x 10(-2) microg/mL). The total synthesis described herein features two regio- and stereoselective THF ring-forming reactions. The 2,3,5-trisubstituted THF portion (C13-C17) was accessed using a highly regioselective cyclization of a methylene-interrupted epoxydiol, and the 2,5-disubstituted THF ring (C8-C12) was conveniently assembled via a 1,2-n-triol cyclization strategy. The spectral data of the synthetic material and two of its diastereomers did not match the reported data for the natural product. On the basis of detailed spectroscopic analysis of the synthesized molecule, we reason that the spectral discrepancies are due to stereochemical misassignment of the natural product.