Enantiospecific formal total synthesis of (+)-dihydrokawain-5-ol

Abstract

Formal total synthesis of dihydrokawain-5-ol is accomplished starting from tartaric acid. Key reactions include Horner–Wadsworth–Emmons olefination, sodium borohydride mediated stereoselective reduction, orthogonal protection and deprotection of alcohols and ring closing metathesis.     

A formal total synthesis of eleutherobin using the ring-closing metathesis (RCM) reaction of a densely functionalized diene as the key step: investigation of the unusual kinetically controlled RCM stereochemistry

Asymmetric oxyallylation reactions and ring-closing metathesis have been used to synthesize compound 3, a key advanced intermediate used in the total synthesis of eleutherobin reported by Danishefsky and co-workers. The aldehyde 6, which is readily prepared from commercially available R-(-)-carvone in six steps in 30 % overall yield on multigram quantities, was converted into the diene 5 utilizing two stereoselective titanium-mediated Hafner-Duthaler oxyallylation reactions. The reactions gave the desired products (8 and 12) in high yields (73 and 83 %, respectively) as single diastereoisomers, with the allylic alcohol already protected as the p-methoxyphenyl (PMP) ether, which previous work has demonstrated actually aids ring-closing metathesis compared to other protective groups and the corresponding free alcohol. Cyclization under forcing conditions, using Grubbs' second-generation catalyst 13, gave the ten-membered carbocycle (E)-14 in 64 % yield. This result is in sharp contrast to similar, but less functionalized, dienes, which have all undergone cyclization to give the Z stereoisomers exclusively. A detailed investigation of this unusual cyclization stereochemistry by computational methods has shown that the E isomer of the ten-membered carbocycle is indeed less thermodynamically stable than the corresponding Z isomer. In fact, the selectivity is believed to be due to the dense functionality around the ruthenacyclobutane intermediate that favors the trans-ruthenacycle, which ultimately leads to the less stable E isomer of the ten-membered carbocycle under kinetic control. During the final synthetic manipulations the double bond of enedione (E)-16 isomerized to the more thermodynamically stable enedione (Z)-4, giving access to the advanced key-intermediate 3, which was spectroscopically and analytically identical to the data reported by Danishefsky and co-workers, and thereby completing the formal synthesis of eleutherobin.     

Novel total synthesis of anserinone A and B

Anserinones A and B are natural products that have been shown to have potential anticancer, antifungal, and antibacterial properties. This work entails the novel synthesis of these natural products.     

Efficient and versatile stereoselective synthesis of cryptophycins

The cryptophycins are a family of cyclic depsipeptides with four retrosynthetic units A to D which correspond to the respective amino acids and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres by introducing two of them in a catalytic asymmetric dihydroxylation, followed by substrate-controlled diastereoselective reactions. The diol also serves as the epoxide precursor. This approach provides selective access to stereoisomers of unit A (enantiomers, epimers) for structure-activity relationship studies. The unit A derivatives were incorporated into cryptophycin-1, cryptophycin-52 and a novel epimer of cryptophycin-52.