Synthesis pancratistatin analogs

Figure 10.36 Enzyme-catalyzed asymmetric synthesis of a pancratistatin analog using a naphthalene dioxygenase and RhuA-catalyzed aldolization for the creation of four contiguous stereocenters.

Fessner et al. have reported an elegant strategy for the stereospecific synthesis of novel pancratistatin analogs [42]. The pancratistatin alkaloid and its closely related natural congeners, including notably trans-dihydrolycoricidine and the anhydro and deoxy derivatives narciclasine and lycoricidine (Figure 4.2), have attracted considerable attention due to their biological activities [43]. 

Scheme 4.18 Multi-step process for the chemoenzymatic synthesis of pancratistatin analogs.

FDP A was employed in a study of pancratistatin analogs to catalyze the formation of the D-threo stereochemistry (Scheme 5.24). When rhamnulose 1-phosphate aldolase (Rha 1-PA) was used the L-threo stereoisomer was obtained with excellent selectivity. Thus these two enzymes allow the stereoselective synthesis of the two threo-stereoisomers [44]. They were also utilised successfully for the synthesis of different diastereoisomers of sialyl Lewis X mimetics as se-lectin inhibitors. Not only the two threo-selective aldolases RAMA and Rha 1-PA, but also the D-erythro-selective Fuc 1-PA was employed. In this way it was possible to synthesise three of the four diastereoisomers enantioselectively (Scheme 5.25). The L-erythro stereochemistry as the only remaining diastereo-isomer was not prepared [45]. This is because the aldolase that might catalyze its formation, TDP A, is not very stereoselective and therefore often yields mixtures of diastereoisomers. 

Pancratistatin (251), an important anticancer product, is structurally related to carbasugars. In 2004, Kornienko and Nadein reported a synthesis of 1-aryl-1-deoxyconduritols that were used as synthetic intermediates to prepare a series of simplified pancratistatin analogs. Compound 252, prepared from n-xylose, underwent conjugate addition of magnesium diarylcuprates to afford 253. Further steps led to 254 whose RCM catalyzed by [Ruj-I provided aryl deoxyconduritols 255 (Scheme 1.46) [61, 62). 

Entry 23 was part of a synthesis of the pancratistatin structure. The lactone ring was used to control the stereochemistry at the cyclization center. Noncyclic analogs gave a mixture of stereoisomers at this center. In this reaction, triphenylstannane gave much better yields than tri-n-butylstannane. 

Chemoenzymatic synthesis of morphine, pancratistatin, and their analogs 06ARK(7)276. 

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