Pancratistatin synthesis

Rinner U, Hudlicky T, Gordon H, Pettit GR (2004) A p-Carbolinc-l-onc Mimic of the Anticancer Amaryllidaceae Constituent Pancratistatin Synthesis and Biological Evaluation. Angew Chem Int Ed 43 5342... 

Scheme 10.12. Retrosynthetic analysis of Danishefsky s pancratistatin synthesis.

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.

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. 

The 1,4- addition of an ortho-] i th iated benzamide to 1-nitrocyclohexene has been used for synthesis of pancratistatin models (Eq. 4.75).95... 

Acetylene equivalent of P-sulfonylnitroalkene in the Diels-Alder reaction is used in part for total synthesis of pancratistatin (Eq. 7.114). Pancratistatin is isolated from the root of the plant... 

Cleavage of aziridines has been employed in the asymmetric total synthesis of pancratistatin 57 [47], a compound that is the object of considerable attention thanks to its broad spectrum of antineoplastic activities [48]. The chemistry of vinylaziridines has for the most part been confined to their use in rearrangement sequences resulting in functionalized pyrrolines. Hence, because of the lack of data concerning the ring-opening of vinylaziridines with carbon nucleophiles,... 

In an alternative synthesis of pancratistatin (57) by Trost et al. [52], (Scheme 9.15) addition of the Grignard reagent 63 [53] to a mixture of the azide 62 and copper cyanide reproducibly gave the desired adduct 64. Because of the difficulties associated with purification of adduct, the overall yield of the two steps (the next being dihydroxylation of the olefin) was 62%. 

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.

Pancratistatin (15) (Figure 7.4) was isolated by Pettit and co-workers from the roots of Pancratium littorale, which exhibits anticancer activity against murine P-5076 ovarian sarcoma and P-388 lymphocytic leukemia [10]. Rigby and coworkers performed photocycHzation as a key step in the total synthesis of 15,... 

Hudlicky, T., Tian, X., Konigsberger, K., Mauiya, R., Rouden, J. and Fan, B. (1996c) Toluene-dioxygenase-mediated as-dihydroxylation of aromatics in enantioselective synthesis. Asymmetric total syntheses of pancratistatin and 7-deoxypancratistatin, promising antitumor agents. J. Am. Chem. Soc., 118, 10752-10765. 

Few applications of cyclizations to form fused ring 8-lactones or tetrahydropyrans are found. Two consecutive bromolactonizations were used to effect stereoselective dihydroxylation of a cyclohexadi-enone system in a total synthesis of erythronolide B (Scheme S).64 Iodolactonization of an NJV-di-ethylbenzamide derivative to form a ds-fused benzolactone was a key step in a recent synthesis of pancratistatin.641 A di-fused tetrahydropyran was produced in good yield by intramolecular oxymercura-tion as shown in equation (17),59 although attempts to cyclize a more highly functionalized system have been reported to fail.65 Formation of a fused ring tetrahydropyran via an anti-Markovnikov 6-endo sel-enoetherification has been reported in cases where steric and stereoelectronic factors disfavor a 5-exo cyclization to a spirocyclic structure.38... 

Scheme 8E.14. Allylic azidation and synthesis of pancratistatin and epibatidine.

Pancratistatln. The first total synthesis of ( )-pancratistatin (94) (Scheme 14), the structurally most complex of narciclasine alkaloids, was achieved by Danishefsky [27]. The requisite starting material, the substituted benzaldehyde 95 prepared from pyrogallol in six steps in 18% overall yield, was converted via the homoallylic alcohol 96 into the diene 97. Reaction of 97 with 2-nitrovinylsulphone yielded the cycloadduct 98, which on treatment with tributyltinhydride and 2,2 -azobisisobutyronitrile furnished the cyclohexadiene 99. Whilst the cyclisation of the silylether 99 or the derived phenol, under the influence of iodine, could not be accomplished, the more nucleophilic stannylether did participate in the desired ring closure and provided via the iminium salt, the iodolactone 100 on aqueous work-up. 

Scheme 14. Synthesis of ( )-pancratistatin (continued next page).

Pancralistatin, [29], The first asymmetric total synthesis of (+)-pancratistatin (94) was reported by Hudlicky 130,26], Thus the bromo olefin 114 (Scheme 15), obtained by a-addition of copper nitrenoid generated from (N-tosyiimino) phenyliodinane to 45, was debrominated to the olefinic aziridine 117. The latter underwent Irons 1,2-ring opening with diarylcyancuprate... 

The elegant asymmetrization methodology of a meso compound, achieved in high enantioexcess under chiral environment, was the highlight of the total synthesis of (+)-pancratistatin (94) reported by Trost and Pulley (31]. The synthesis commenced with ( )-conduritol-A (130), obtained from p-benzoquinone, (Scheme 18) which was converted into the acetonide 131 and thence, via the dialkoxide to the cis-bis carbonate 132 (Scheme 19). The chiral n-ailyl palladium complex A formed on treatment erf 132 with the catalyst generated from chiral bis-amide 133 and n-allyl palladium chloride underwent azide substitution from the less hindered face of the molecule to provide the monocarbonate 134 in excellent yield and with high optical induction. 

The /J-azido triisopropylsilyl (TIPS) enol ether (96) functionalization developed by Magnus et al. from TIPS-enol ether (95) using iodosobenzene (Phl=0)-TMSN3 [70-73] provides a unique strategy for the total synthesis of an antitumor agent, (+)-pancratistatin (97) [Eq. (21)]. 

Unique total synthesis of antitumor alkaloid, pancratistatin (97), which was isolated from the roots of the Hawaiian Pancratium littorale Jacq., by / -azido-nation reaction of triisopropylsilylenol ether (183) with Phl=0-TMSN3 as the key reaction has been accomplished by Magnus and Sebhat [138] (Scheme 47). 

The synthesis of pancratistatin [37] (65, Scheme 15), involving anionic ortho-Fries (62 —> 63) and further DoM (—> 64) is a pertinent showcase of anionic chemistry for preparation of a pentasubstituted aromatic using the conceptual framework 66. 

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. 

Methyl 2-indolecarboxylate 560 was found to react on the silica gel surface with iV-tosylvinylaziridine in 68% yield. The solid-phase aziridine opening constituted a key step in the synthesis of the P-carbolin-l-one mimic of Pancratistatin (Equation 135) <2005JOC3490>. 

The additional key transformation in a nine-step synthesis of the Pancratistatin mimic involved silica gel-catalyzed opening of an epoxide and hydrolysis of an acetonide (Scheme 112) <2005JOC3490>. The yields of condensation products depend on reaction conditions that were used (1) silica gel surface at 70 °C (2) 0.1 equiv of InCh in CH2CI2 (3) InCh-doped silica at 70 °C (4) 10% aq InCh-treated silica at 70 °C (5) rt, TLC plate silica. 

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