(-)-Merrilactone A [(-)-1], isolated from Illicium merrillianum in 2000, possesses neurite outgrowth activity in cultures of fetal rat cortical neurons, and, therefore, is expected to show therapeutic potential for the treatment of neurodegeneration associated with Alzheimer's and Parkinson's diseases. Apart from its biological aspects, the caged pentacyclic skeleton of 1 poses interesting synthetic challenges. In this account, we describe the total synthesis of (+)- and (-)-merrilactone A, based on two novel strategies. Both strategies employed, as a key step, a transannular aldol reaction of eight membered diketone to construct the core cis-bicyclo [3.3.0] octyl system of 1. In the first generation total synthesis, the 2, 6-bis (trifluoromethyl) benzyl group served as a long-range stereocontrolling element for synthesis of the enantiopure bicyclo [3.3.0] octane frame-work of (-)-1. On the other hand, asymmetric aldol reaction was developed in the second generation synthesis to build the fused core of (+)-1 in a more consice manner. The obtained key intermediates were utilized as a platform for the subsequent functional group manipulations necessary for construction of (-)- and (+)-1. Surprisingly, both the natural and unnatural enantiomers of 1 equally promoted neurite outgrowth in primary neuronal cultures.
Brevetoxin B was isolated from the red tide organism Karenia brevis in 1981 as the first example of marine polycyclic ethers. This compound shows potent neurotoxicity, by binding to sodium channels, causing massive fish kills and human health problems. Since further biological studies are hampered by the limited availability from nature, chemical synthesis has been the sole realistic way to obtain sufficient amounts of brevetoxin B. Moreover, the huge molecular architecture is a particularly attractive target for synthetic chemists. In this account, we describe the highly convergent total synthesis of brevetoxin B based on our methodology, including intramolecular allylation and subsequent ring-closing metathesis.
Based on the concept of bifunctional asymmetric catalysis, chiral ligands containing a carbohydrate scaffold were designed. Rare earth metal complexes of the ligands produced general and practical catalytic enantioselective cyanation of ketones and ketoimines. Structural studies of the asymmetric catalysts revealed that the active catalysts are polymetallic complexes containing higher-order structures. The higher-order structure determines the function (activity and enantioselectivity) of the catalysts. The thus-developed catalytic enantioselective methods for the synthesis of tetrasubstituted carbons were applied to the synthesis of biologically active molecules. Catalytic asymmetric synthesis of fostriecin and its analog, lactacystin, Tamiflu®, and garsubellin A are described.
The first total synthesis of (-) -sordarin 1 has been accomplished by the use of following reactions for key steps : I) Ag (I) -catalyzed oxidative radical cyclization of a cyclopropanol derivative to construct a bicyclo [5.3.0] decan-3-one skeleton, II) Pd (0) -catalyzed intramolecular allylation reaction to prepare the strained bicyclo [2.2.1] heptan-2-one derivative having the whole framework of sordaricin 2, III) selective dihydroxylation reaction of terminal alkenes by the combined use of OsO4 and PhB (OH) 2, and N) β- (1, 2-cis) -selective glycosidation by a 1, 3-neighboring participation of a p-methoxybenzoyl group.
Over the past three decades, a variety of highly functionalized γ-lactam or spiro-heterocyclic γ-lactam natural products have been isolated. These compounds have attracted considerable attention due to their structural uniqueness as well as interesting biological activities. Thus, numerous synthetic organic chemists have established new methodologies for access to the γ-lactam-type compounds. In this review, we summarize completed total syntheses of natural products containing a γ-lactam structure, such as (-) -PI-091, (+) -epolactaene, lucilactaene, (-) -pramanicin, (-) -pseurotin A, (-) -pseurotin F2, (+) -synerazol, and (-) -azaspirene.
This review focuses on total syntheses of antitumor antibiotic FR 900482. After a brief discussion of synthetic problems of this compound, the first racemic total synthesis of FR 900482 by Fukuyama is described, which provided some important insights for the designing synthetic route through the 8-membered N-hydroxybenzazocinone key intermediate. Then, recently disclosed total syntheses as well as formal total syntheses and synthesis of derivatives were described including Martin's formal total synthesis utilizing the Grubbs' olefin metathesis for the formation of benzazocin ring, Ciufolini's characteristic formation of benzazocin ring by a sequential reaction (intramolecular [1, 3] -dipolar cycloaddition of azide, photomediated conversion of triazorine to aziridine, and a fragmentation initiated by a homo-Brook rearrangement), Williams' total synthesis employing an intramolecular reductive amination to construct the benzazocin ring and an unusual deprotective oxidation of N-PMB group to form hydroxylamine, Paleo and Rapoport's formal synthesis taking convergent route using an epoxy α-amino acid segment derived from vinylglycin, and Fukuyama's synthetic approach using intramolecular [3+2] cycloaddition of nitrone and enantiospecific total synthesis utilizing a novel ketone synthesis and reductive intramolecular hydroxyamination.
The pathways of prostaglandin (PG) and thromboxane (TX) biosynthesis starting from arachidonic acid are shown in Scheme 1. It is well known that PGs and TX play an important role in maintaining homeostatsis. Since the discovery of these agents, much attention has been paid to their therapeutic potential. Massive efforts have been made to achieve their efficient chemical synthesis because a sufficient supply of these rare local hormones is exclusively dependent on their synthesis. Among the many synthetic methods described in the literature, Corey's and Noyori's are representative ones because both of these approaches are highly efficient and allow the production of all the naturally occurring PGs and a wide range of structural analogues. Discovery of a stereoselective method for the reduction of prochiral 15-ketone was another challenge in relation to the highly efficient synthesis of PGs. In this review, we describe methods for the synthesis of PGs and TX, including stereoselective reduction of 15-ketone.
Tetrodotoxin, a toxic principle of puffer fish poisoning, is one of the most famous marine natural products because of the complex structure and its potent biological activity. Since the structure elucidation in 1964, the toxin has been recognized as a formidable target molecule for total synthesis. We achieved the first asymmetric total synthesis commencing from 2-acetoxy-tri-O-acetyl-D-glucal as a chiral starting material. Highly hydroxylated cyclohexane was constructed by intramolecular aldol condensation of a precursor having methyl ketone with dihydroxyacetone, which was synthesized through Sonogashira coupling, Claisen rearrangement and regioselective hydroxylations of acetone moiety. Since installation of nitrogen functionality by the attempted Overman rearrangement was unsuccessful, we employed intramolecular conjugate addition of carbamate to unsaturated ester for the purpose. The α-hydroxyl lactone moiety was synthesized by epoxide opening with enolate of aldehyde followed by oxidation-reduction of the resulting cyclic vinylether. The lactone was then protected as ortho ester, and guanidinylation followed by cleavage of the 1, 2-glycol gave a fully protected tetrodotoxin. Protective group elaboration furnished the total synthesis of tetrodotoxin in an enantiomerically pure form.
If a ring-closing olefin metathesis (RCM) reaction is employed for the synthesis of a naturally occurring medium-ring ether, stereoselective construction of the acyclic di-sec-alkyl ether part of the RCM precursors is a problem. Therefore, we have developed a process including C-glycosidation of a hexopyranose and ring-cleavage of the resulting C-glycoside as a solution for the problem. In fact, the combined use of the C-glycoside-cleavage process and RCM was very effective for the synthesis of the medium-ring ether parts of ciguatoxins, the principal causative toxins of ciguatera seafood poisoning, as well as for the total synthesis of prelaureatin and laurencin, which originated from Laurencia red alga.
It sometimes happens that the synthetic compound of the proposed structure is not identical with the natural product due to the misassignment of its stereochemistry. Fudecalone 17 and kaitocephalin 49 are the examples of that case and their stereostructures were revised by our syn-theses. Fudecalone was clarified to be a 6 a-epimer of the proposed structure and the absolute stereochemistry was also established by the asymmetric synthesis. Kaitocephalin was found to be a 2-epimer of the proposed structure.