Narciclasine synthesis

Try to rationalize the following protecting group regime of a narciclasine synthesis [42] ... 

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]. 

Total synthesis of (-l-)-lycoricidine, (—)-lycoricidine and (-l-)-narciclasine via 6-exo cyclization of substituted vinyl radicals with oxime ethers has been reported . Thus, interaction of oxime ether 321 with thiophenol and then with Sml2 and TFA afforded (-l-)-lycoricidine 322 in good overall yield (equation 139). 

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. 

Narciclasine (215) is an antitumor agent which exerts an antimitotic effect during metaphase by immediately terminating protein synthesis in eukaryotic cells at the step of peptide bond formation (97,101,141,142), apparently by interaction with the ansiomycin area of the ribosomal peptidyl transferase center (142). The alkaloid has also been found to inhibit HeLa cell growth and to stabilize HeLa cell polysomes in vivo (97). Although DNA synthesis was retarded by narciclasine, RNA synthesis was practically unaffected (97,142). Sev-... 

The majority of the approaches that have been adopted for the synthesis of narciclasine (215), lycoricidine (214), and related alkaloids have involved the strategy of constructing the ring system in the order A — C —> B. There have also been examples of the A — BC and C —> A —> B type. 

Several syntheses of phenanthridone derivatives related to the aromatization products of narciclasine and lycoricidine and apparently designed to further support the structural revision have been completed. In a photochemical synthesis starting from 368 the compound 360 was obtained yielding on debenzylation narciprimine (356), whereas from 369 in an analogous way arolycoricidine (361) was prepared. Also, starting from the amide 370 through photocyclization to 362 via 363 a compound identical with natural permethylisonarciprimine (357) was obtained (81). 

More recently, a detailed paper discussed the synthetic problems presented by the syntheses of the substituted phenanthridones of the narciprimine-isonarciprimine series along with the synthesis of per-methylisonarciprimine 357 (79). The potential pharmacological interest of narciclasine and other Amaryllidaceae metabolites has been suggested (79a, 79b). 

A number of Amaryllidaceae alkaloids, including haemanthamine, lycorine, narciclasine, and pretazettine, have been shown to inhibit the fundamental step of the formation of a peptide bond in protein synthesis.14... 

The phenanthridine alkaloid lycorine (narcissine, galanthidine) (MD—Phe G5N C6) has a widespread occurrence and inhibits protein synthesis. Like lycorine, the structurally similar alkaloids dihydrolycorinine, haemanthamine, narciclasine, pretazettine and pseudolycorine also inhibit protein synthesis at the level of peptide bond formation. Galanthamine (lycorimine) (Phe C6N C40 C6 ), from daffodil bulbs but also of widespread occurrence, is both a nACh-R allosteric modulator and an inhibitor of AChE. Galanthamine is clinically employed in the treatment of Alzheimer s disease (dementia linked to deficiency in acetylcholine-mediated signalling in the central nervous system). 

In their synthesis of (+)-narciclasine 26, Elango and Yan performed a stereocontrolled epoxide formation via the bromohydrins 25. Following concomitant ring closure and N-piperonylation, treatment with catalytic SnCh affected intramolecular arene-epoxide coupling (Scheme 16) <2002JOC6954>. 

The total synthesis of several amaryllidaceae alkaloids including that of narciclasine was accomplished in the laboratory of T. Hudlicky. The C2 stereochemistry was established by a two-step sequence Luche reduction of the a,(3-unsaturated cyclic ketone followed by a Mitsunobu reaction. The ketone was first mixed with over one equivalent of CeCIs in methanol and then the resulting solution was cooled to 0 °C, and the sodium borohydride was added. In 30 minutes the reaction was done, and the excess NaBH4 was quenched with AcOH. The delivery of the hydride occurred from the less hindered face of the ketone and the allylic alcohol was obtained as a single diastereomer. 

Regarding the synthesis of the narciclasine (lycoricidine)-type alkaloids, an important strategic element is how to construct the functionalized ring C in these alkaloids. Therefore, extensive efforts to explore a new method for preparing a key intermediate have been made. 

This method was used by Hudlicky in a synthesis of the alkaloid narciclasine. The diol 90 was trapped as the usual acetal and reacted as a diene with the nitroso ester Me02C-N0 in a hetero-Diels-Alder reaction to give 91. Suzuki coupling of the vinylic bromide with the right aryl boronic acid gave 92 and the N-0 bond was reduced with Mo(CO)6 to give the advanced intermediate 93 on the way to narciclasine28 94. 

Despite a considerable amount of recent work on reactions of vinyl silanes with various kinds of imines [48,49], scant attention has been paid to N-sulfonyl imi-nes in this area. A single study of a vinyl silane/N-sulfonyl imine reaction has been published by McIntosh and Weinreb in the context of an approach to the total synthesis of [1, 3]-dioxolophenanthrene structural types of Amaryllida-ceae alkaloids such as narciclasine (137), lycoricidine (138) and pancratistatin (139) [50]. The substrate used in this approach was vinyl silane aldehyde 140, prepared enantiomerically pure in a straightforward manner from L-arabinose (Scheme 26). The N-tosyl imine derived from this aldehyde could be generated in two different ways. The first involved combination of 140 with N-sulfinyl-p-toluenesulfonamide at 80 °C, followed by exposure of the imine to BF3 etherate at 0°C, leading to a single cyclization product 142 in 36% yield. The second procedure was to simply react aldehyde 140 with p-toluenesulfonamide and BF3 etherate (-78°C -rt) to afford a 9.5 1 mixture of 142 144 in -80% yield. It was pro-... 

Methyl-a-D-galactopyranoside (13) was used for the synthesis of suitable intermediates for the synthesis of (+)-pancratistatin (3) and (+)-narciclasine (9) (Scheme 1). Protection of the primary hydroxyl group in 13 as the TIPS ether followed by per-benzylation afforded 14, and then removal of the TIPS group followed by Swern oxidation afforded 15. Reaction of 15 with 16 gave a mixture of diastereomers 17, which underwent bromination with Ph3PBr2 to produce 18. Heating of 18 in dry pyridine afforded 19 as an and Z mixture in 75%... 

Compound 47 from the former scheme was also used for the synthesis of the narciclasine alkaloids (Scheme 5). Its treatment with excess ethanethiol and magnesium bromide afforded the dithioacetal 54 in 86% yield. Protection of the hydroxyl groups in 54 followed by hydrolysis of the dithioacetal afforded the corresponding aldehyde, which was treated with nitromethane to give a mixture of diastereomers 55 (1.8 1 ratio) in 80% yield. Treatment of the mixture with excess TBSOTf resulted in the silylation of the hydroxyl group. Subsequent selective deprotection of the phenolic TBS group afforded 56. Oxidation of the mixture of diastereomers 56 with silver(I) oxide afforded 57, whose treatment with DMAP afforded 60 and 61 in 29 and 57% yield, respectively. The minor product 60 possesses five of the six stereogenic centers of pancratistatin (3). 

Keck has reported a short, enantioselective synthesis of lycoricidine as outlined in Scheme 10 [70]. The synthesis began with the acetonide of D-gulonolactone (104). This material was converted in 6 steps to oxime ether 105. Irradiation of 105 with thiophenol in toluene gave a 90% yield of 106, resulting from addition of a thio-phenoxy radical to the alkyne and cyclization of the resulting vinyl radical onto the oxime ether. It is notable that tri- -butylstannyl radicals failed to mediate this ad-dition-cyclization sequence. The synthesis of lycoricidine was completed from 106 in two steps. Keck also reported that the enantiomer of lycoricidine could be prepared in a similar manner starting from D-lyxose [71], and also described a modification of this route that provided (+)-narciclasine [70]. 

A simple modification of the reaction sequence shown above has allowed for the synthesis of e f-narciclasine (cnt-188). Thus, as shown in Scheme 20, Suzuki-Miyaura cross-coupling of the previously prepared 2-bromocyclohex-2-enamine 209 with the readily synthesised aryl boronic acid 212 afforded the expected lactam 213 (63%). Once again, treatment of the last compound with TMS-Br resulted in exhaustive cleavage of the MOM ether residues and, this time, the formation of the target compound cnt-188 (48%). 

The same group also disclosed the synthesis of epz-7-deoxypaneratistatin via an aza-Payne rearrangement (254) (Scheme 7). Analogues of narciclasine (68), pan-crastistatin, and 7-deoxypancratistatin have been synthesized using modifications of the reported procedures as well as new methodologies (e.g. addition of indoles to oxiranes and aziridines derived from cyclohexadiene diols) (255-258). 

Rigby s studies on the synthesis of alkenylisocyanates fostered the preparation of a suitable substituted aryl enamide, which on photocyclization yielded the polysubstituted pentacyclic system. Key to the success of this process is the hydrogen bond between the phenolic OH and the carbonyl group, which restricts the rotation around the aryl-amide bond and directs the cyclization. Further functionalization allowed the total synthesis of pancratistatin (272) and narciclasine (68) (275) (Scheme 11). The [4-1-1] cycloaddition of bis(alkylthio)carbenes with vinyl isocyanates was the key process in a recent synthesis of (+)-mesembrine (92) 274). 

Taking advantage of the availability of narciclasine (68) from plant extracts, Pettit used the compound as a starting material in an efficient synthesis of pan-cratistatin (77). The same group has also described related approaches for the preparation of a pancratistatin phosphate prodrug (291), as well as for the natural product 7-deoxy-trfl/J5-dihydronarciclasine and related derivatives (292). In another context, an improved protocol for the synthesis of (—)-galanthamine (75), based on the spontaneous resolution of either of the enantiomers of narwedine (83), has been reported (293). 

Narciclasine (22) halts protein synthesis by blockage of peptide-bond formation on the 60-S ribosomal subunit. The effect is specific for eucaryotic cells. Narciclasine inhibits Rauscher virus NIH/3T3 (Wink, 1993). Lycorine (8) blocks mitosis in the broad bean (Viciafaba). The mechanism appears to be related to inhibition of protein synthesis (Suffness and Cordell, 1985). Pretazettine (15) has been used in combination with DNA-binding and alkylating agents in the treatment of the Rauscher leukemia virus (Cordell, 1981 Martin, 1987). This alkaloid inhibits purified RNA-dependent DNA polymerase (reverse transcriptase) from avian myelo-... 

Chapleur Y, Chretien F, Ibn Ahmed S, Khaldi M (2006) Chemistry and synthesis of highly oxygenated alkaloids from Amaryllidaceae lycoricidine, narciclasine, pancratistatin and analogues. Curr Org Synth 3 341... 

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