The first total synthesis of the novel triquinane natural products pleurotellol and pleurotellic acid

The first total synthesis of the triquinane based sesquiterpenoid antibiotics (±)-pleurotellol and (±)-pleurotellic acid isolated from the fermentation broth of Pleurotellus hypnophilus have been accomplished. The triquinane based bis-enone system obtained via photo-thermal metathesis in a caged pentacyclic dione has been elaborated to the natural products through carefully crafted functional group transformations.     

Total synthesis of the anticancer natural product OSW-1

The highly potent anticancer natural saponin OSW-1 has been successfully synthesized from commercially available 5-androsten-3beta-ol-17-one 79 in 10 operations with 28% overall yield. The key steps in the total synthesis included a highly regio- and stereoselective selenium dioxide-mediated allylic oxidation of 80 and a highly stereoselective 1,4-addition of alpha-alkoxy vinyl cuprates 68 to steroid 17(20)-en-16-one 12E to introduce the steroid side chain. This total synthesis demonstrated once again the versatile synthetic applications of alpha-halo vinyl ether chemistry developed in our laboratories.     

Total synthesis of the chlorinated marine natural product dysamide B

[Structure: see text] Two approaches to the synthesis of (2S,4S)-5,5-dichloroleucine are compared, and the parent amino acid was used in the first total synthesis of the polychlorinated marine natural product, dysamide B. A key step was the lead tetraacetate-mediated decarboxylation of an alpha,alpha-dichloro acid in the presence of 1,4-cyclohexadiene to generate the dichloromethyl group.     

Total synthesis of the antibacterial polyketide natural product thailandamide lactone

Stereoselective total synthesis of the structurally intriguing polyketide natural product thailandamide lactone was accomplished, and done so using a convergent approach for the first time to the best of our knowledge. The key features of this synthesis included use of a Crimmins acetate aldol reaction, Evans methylation, Urpi acetal aldol reaction, Sharpless asymmetric epoxidation and subsequent γ-lactonization for the installation of six asymmetric centers and the use of the Negishi reaction, Julia-Kocienski olefination, cross metathesis, HWE olefination and intermolecular Heck coupling for construction of a variety of unsaturated linkages. Pd(i)-based Heck coupling was introduced, for the first time to the best of our knowledge, quite efficiently to couple the major eastern and sensitive western segments of the molecule. The antibacterial activity of thailandamide lactone was also evaluated.

A convergent strategy for the total synthesis of the structurally intriguing polyketide natural product thailandamide lactone has been developed for the first time. The antibacterial activity of the molecule has also been disclosed.     

Total synthesis of the bicyclic marine sesquiterpenoid drechslerine B

The total synthesis of the recently isolated bicyclic sesquiterpenoid drechslerine B (2), isolated from the algicolous fungus Drechslera dematioidearare in the marine red alga Liagora viscida, has been achieved, starting from (S)-carvone (8), via an intramolecular aldol reaction and palladium-catalyzed carbon monoxide insertion as key reactions.     

Total synthesis of the putative structure of the lupin alkaloid plumerinine

[reaction: see text]. A stereocontrolled synthesis of quinolizidine 1, the reported structure of plumerinine, has been accomplished in 10 steps from 4-methoxypyridine. The key step is a highly facial selective intramolecular [2 + 2] photocycloaddition of a 2,3-dihydro-4-pyridone. The reported spectral data for plumerinine did not match that of our synthetic 1.     

Total synthesis approaches to natural product derivatives based on the combination of chemical synthesis and metabolic engineering

Secondary metabolites are an extremely diverse and important group of natural products with industrial and biomedical implications. Advances in metabolic engineering of both native and heterologous secondary metabolite producing organisms have allowed the directed synthesis of desired novel products by exploiting their biosynthetic potentials. Metabolic engineering utilises knowledge of cellular metabolism to alter biosynthetic pathways. An important technique that combines chemical synthesis with metabolic engineering is mutasynthesis (mutational biosynthesis; MBS), which advanced from precursor-directed biosynthesis (PDB). Both techniques are based on the cellular uptake of modified biosynthetic intermediates and their incorporation into complex secondary metabolites. Mutasynthesis utilises genetically engineered organisms in conjunction with feeding of chemically modified intermediates. From a synthetic chemist's point of view the concept of mutasynthesis is highly attractive, as the method combines chemical expertise with Nature's synthetic machinery and thus can be exploited to rapidly create small libraries of secondary metabolites. However, in each case, the method has to be critically compared with semi- and total synthesis in terms of practicability and efficiency. Recent developments in metabolic engineering promise to further broaden the scope of outsourcing chemically demanding steps to biological systems.     

Total synthesis of epoxyquinone meroterpenoid natural product biscognienyne B

1. Download high-res image (82KB)
2. Download full-size image

     

Total synthesis of the novel seco-prezizaane sesquiterpenoid (+)-1S-minwanenone

The first total synthesis of (+)-1S-minwanenone, an archetypical seco-prezizaane sesquiterpene, has been accomplished from a readily available chiral endo-tricyclic synthon following a flexible strategy.     

Total synthesis of anibamine, a novel natural product as a chemokine receptor CCR5 antagonist

The total synthesis of anibamine, the first and only natural product known as a chemokine receptor CCR5 antagonist, is reported herein. Anibamine was synthesized from acetylacetone and cyanoacetamide in 10 steps.     

Total synthesis of a diastereomer of the marine natural product clavosolide A

The first total synthesis of the reported structure of the sponge metabolite clavosolide A is described using a Prins cyclisation to assemble the tetrahydropyran core followed by manipulation of the side-chain, dimerisation and finally glycosidation.     

Total synthesis of the marine natural product (-)-clavosolide A

[Structure: see text] The total synthesis of the marine metabolite clavosolide A is reported which confirms the structure and absolute configuration of the natural product as the symmetrical diolide glycosylated by permethylated D-xylose moieties, 2.     

Total synthesis and stereochemical assignment of the spiroisoxazoline natural product (+)-calafianin

[STRUCTURE: SEE TEXT] Synthesis of the spiroisoxazoline natural product (+)-calafianin is reported using asymmetric nucleophilic epoxidation and nitrile oxide cycloaddition as key steps. Synthesis and spectral analysis of all calafianin stereoisomers led to unambiguous assignment of relative and absolute stereochemistry.     

Total synthesis of the putative structure of stemonidine: the definitive proof of misassignment

[structure: see text] The total synthesis of the putative structure of the Stemona alkaloid stemonidine has been completed. The key transformations include a 1,3-dipolar cycloaddition of a chiral nitrone derived from (S)-prolinol and a spirolactonization process involving the generation of the critical stereocenter. The NMR data of the synthetic material do not match those reported for the natural product. It is concluded that the structure assigned to stemonidine is incorrect, and it must be reassigned as stemospironine.     

Total synthesis of the antiviral marine natural product (-)-hennoxazole A

[structure:see text] The marine natural product hennoxazole A was synthesized by a convergent approach. The diastereoselective Mukaiyama aldol reaction with beta-alkoxy aldehyde was used to construct the tetrahydropyran segment, and the preparation of the nonconjugated triene moiety was accomplished via S(N)2 displacement of allylic bromide with vinyllithium and Takai's iodoolefination followed by palladium-catalyzed cross coupling with MeMgBr. The final steps involve an amide coupling using DEPC and oxazole synthesis via a oxidation/cyclodehydration process.     

Total synthesis of the cytostatic marine natural product dibromophakellstatin via three-component imidazolidinone anellation

The tetracyclic pyrrole-imidazole alkaloid dibromophakellstatin from the marine sponge Phakellia mauritiana has been synthesized within seven steps from pyrrole in an 18% overall yield. The key step is a three-component assembly of a tricyclic enamide, a nitrene, and a carbamoyl building block, affording the imidazolidinone ring of dibromophakellstatin in one step. Notably, it is possible to employ the reagent EtO2CNHOTs in a double function as a source of the electrophilic nitrene and of a dipolar carbamoyl component. Use of debrominated precursor dipyrrolopyrazinones leads to much higher anellation yields and allowed us to develop a second generation synthesis. The cytostatic activity of dibromophakellstatin is confirmed.     

Total synthesis of 1-deoxygulonojirimycin. Revision of the absolute configuration of the natural product

A concise, stereoselective synthesis of 1-deoxygulonojirimycin was achieved and the absolute configuration of the natural product was revised. Key features involve diastereoselective oxazoline formation catalyzed by palladium(0), RCM and dihydroxylation.     

Total synthesis and structural confirmation of the marine natural product Dysinosin A: a novel inhibitor of thrombin and Factor VIIa

The structure and absolute configuration of the marine antithrombotic product dysinosin A was confirmed by total synthesis. The strategy involved disconnections to three subunits, of which two were synthesized from the readily available l-glutamic acid, d-leucine, and d-mannitol. The Grubbs olefin metathesis carbocyclization reaction was utilized to prepare two intermediates.