De Novo Asymmetric Synthesis of C-linked and O-linked Aryl Natural Products.

摘要

The carbohydrate portion of many natural products play an important role in their biological activities, such as target binding, solubility, tissue targeting, and membrane transportation. A review of carbohydrate containing natural products leads to the realization that nature uses a myriad of rare carbohydrate structural motifs. In order to explore and exploit these structural motifs for medicinal chemistry structure-activity relationship (SAR) studies, chemists have desired new synthetic approaches that allow for the preparation of unnatural rare sugars and analogous structural motifs. In this regard, the O'Doherty group has developed a divergent de novo methodology to build the desired sugar functionality and stereochemistry from simple achiral 2-keto-furanyl starting materials, which stands in contrast to the traditional method that use the limited number of known carbohydrates as starting materials. Outlined in Chapter 1 Section I is the O'Doherty approach to carbohydrates, which relies on a highly enantioselective Noyori asymmetric reduction reaction, a highly diastereoselective palladium (0)-catalyzed glycosylation reaction to install the stereochemistry. Subsequent post-glycosylation transformations are then used to introduce the remaining sugar functionality.;Digitoxin is a naturally occurring cardiac glycoside, which has been used for the treatment of congestive heart failure, via enhancing cardiac contraction. More recently, digitoxin has been shown to possess anticancer activity. Chapter 1 Section II shows our synthetic and biological studies into the structure activity relationship (SAR) effects on C5'-alkyl substitution on the &agr;-L-sugar (steric effect). The results revealed an inverse relationship between size of the group and cytotoxicity.;The natural product SL0101 is the first specific inhibitor of p90 ribosomal kinase (RSK). We corporately developed a diastereoselective approach for the synthesis of both L- and D-sugar analogues with different degree of acylation. Further, studies involved substitution of the C5' position (methyl, ethyl, n-propyl, i-butyl). In this regard, a series of analogues were synthesized and evaluated for biological activity. Based on the success of the C5'-alkyl substitution of SL0101, we continued our investigation of C4'-amido and C4'-keto modifications to improve the resistance to ester hydrolysis. Four targets of C4'-amido analogues were made. The C4'-keto series is still undergoing.;The nanaomycins and griseusins are structurally related antibiotic natural products from a family of pyranonaphthoquinone. This family contain a naphtho[2,3-c]pyran-5,10-dione core, with griseusins possessing an additional spiroketal 1,7-dioxa-spiro[5,5]undecane ring. The nanaomycins displayed biological activity against a variety of gram-positive bacteria, pathogenic fungi, yeasts, as well as, antiviral activity. A 12-step synthesis of nanaomycin A was completed starting from simple achiral 1,5-dihydroxynaphthalene. Several typical reactions such as Claisen rearrangement of the allyl group, quinone-dimethoxy quinonol interconversion, Sharpless dihydroxylation to install the first stereocenter, 1,3-trans pyran ring formation, nitrile hydrolysis were researched and utilized to finish the total synthesis of natural product (-)-nanaomycin A and (-)-nanaomycin D. Griseusin A was envisioned as resulting from the coupling of a key intermediate beta-hydroxy nitrile from the nanaomycin synthesis with a carboxylic acid with protected 1,3-cis-diol. This carboxylic acid was made via a 9-step sequence starting from achiral ethyl sorbate. The route began with a Sharpless dihydroxylation to secure a 1,2-cis-diol, which was converted into a cyclic carbonate and then reduced to give an allylic alcohol. A second Sharpless dihydroxylation provided the 1,3,4-cis-triol. Benzylidene protection of the 1,3-cis-diol allowed the subsequent Mitsunobu inversion of the C4 stereochemistry. Mom-protection of the hydroxyl and a final saponification should give the desired carboxylic acid for coupling. The practical routes for completing the total synthesis of enantiomeric griseusin A and B are still under investigation.