Lycoricidine, synthesis

The Michael addition of the copper-zinc reagent derived from ethyl 4-bromobntyrate to the plperonal-derived nitroalkene proceeds cleaniy to give the nitre ester, which is an intermediate for the synthesis of lycoricidine alkaloids fEq. 4.85. ... 

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). 

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. 

The total synthesis of ( )-lycoricidine (214) from the aryl cyclohexene 272, which was accessed by a Diels-Alder reaction of the carbinol 46, has been... 

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). 

Many further important natural product syntheses are covered by the aforementioned review. Particularly noteworthy amongst them are Hudlicky s syntheses of conduramines [522] and (+)-lycoricidine [523] since they employ enantioselective microbial oxidations of halobenzenes as source of chirality. Racemic lycoricidine has also been prepared by Martin et al. this synthesis exhibits an interesting Heck cyclisation as key step in addition to the hetero Diels-... 

Chida, N, Ohtsuka, M, Ogawa, S, Stereoselective total synthesis of (+)-lycoricidine. Tetrahedron Lett., 32, 4525-4528, 1991. 

The stereoselective total synthesis of antimitotic alkaloid (+)-lycoricidine was accomplished by S. Ogawa and coworkers by utilizing the catalytic version of the Type II Ferrier rearrangement for the synthesis of the optically active... 

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. 

Following this report, a total synthesis of optically active (+)-lycoricidine (204) 150) and (+)-2-ep/-lycoricidine (224) 150b) starting from o-glucose was described in the literature (Scheme 21). 

A sequence of reactions similar to those noted previously has been applied to l,2-cw-dihydroxycyclohexa-3,5-diene, constituting a formal synthesis of ( )-lycoricidine (204) (154). 

Since the isolation and discovery of the significant biological activity of 7-deoxypancratistatin (210) and pancratistatin (211), which have more oxygenated functional substituents than lycoricidine (204), synthetic studies have been performed extensively. The total synthesis of optically active (-1-)-7-deoxypancratistatin (210) and (+)-pancratistatin (211) has been reported independently by four research groups. 

Furthermore, this methodology was developed to afford the synthesis of e t-lycoricidine (248) using photolysis instead of a chemically mediated radical reaction (160). Photolysis of 4-(4/ )-hydroxy-6-[(2-methoxycar-bonyl-4,5-methylenedioxy)phenyl]-25,35-0-isopropylidenehex-5-ynal O-benzyloxime 245 (derived from D-glucose) in the presence of thiophenol under went intramolecular cyclization to produce l-(A-benzyloxy-amino)-5-phenylthiocyclohex-5-ene 246. Cleavage of the N-O bond and reductive elimination of the phenylthio group in 246 with Sml2 in THF... 

The synthesis of (-l-)-7-deoxy-fra s-dihydronarciclasine (208) and (-1-)-7-deoxypancratistatin (210) employing the key intermediate 221 previously reported in the synthesis of (-l-)-lycoricidine (204) 150) has been published by a fourth group 162) (Schemes 28 and 29). Catalytic hydrogenation of the protected 7-deoxylycoricidine 221, followed by conversion of the 2/3-0-(p-methoxy)phenylmethyl (MPM) group into a 2a-acetoxy substituent, produced the protected (-l-)-7-deoxy-rranj-dihydronarciclasine 254. Stepwise deprotection of 254 afforded (-t-)-7-deoxy-trans-dihydronarciclasine (208) (Scheme 28). 

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-... 

Isocyanates and isothiocyanates have been used as precursors to formamidyl and thioformamidyl cation equivalents. The reaction shown in equation (25), catalyzed by boron trifluoride etherate, was used in a synthesis of the alkaloid lycoricidine, and proceeded in 89% yield. This type of reaction also works efficiently using other -phenethyl isocyanates. 

Various schemes have been developed for the synthesis of phenanthridene ring systems from D-glucose. Thus, a synthesis of (-l-)-lycoricidine (8) has been reported (Scheme starting from D-glucose by conversion into 22, which upon protection with MOMCl... 

L-Arabinose has also been used for the synthesis of (-l-)-lycoricidine (8) (Scheme 7). Condensation of 71 with the aldehyde 70, prepared from 2,3,4-tri-C-benzyl-L-arabinose 69, afforded the adduct 72, as a complex mixture of diastereomers. Desilylation of 72 with TBAF followed by treatment with CSA in benzene furnished the lactone 73, whose immediate esterification and oxidation afforded the ketone 74 in 87% yield. Oxidative... 

Coupling of amino cyclohexene derivative 100 with 6-bromopiperonylic acid (101) provides amide 102, which is a key intermediate for the synthesis of phenanthridone alkaloid lycoricidine (103).39... 

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