Cryptopleurine, synthesis

Silicon (iv) chloride is an effective Lewis acid in the cyclization and subsequent dehydration steps of Herbert s synthesis of julandine and of cryptopleurine (cf. Vol. 10, p. 72).27 An early cryptopleurine synthesis has been improved.28... 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

The anti-tumour properties of cryptopleurine (33) continue to stimulate synthetic work in this area, and two new syntheses have been reported this year. Snieckus and co-workers25 have described a short, efficient synthesis of the alkaloid, utilizing a benzamide-directed metallation reaction (Scheme 6). In the other synthesis,26 the piperidine derivative (35), prepared by a nitrone cycloaddition reaction, is cyclized... 

TTie lithiation of a l,6-methano[10]annulenamide occurs selectively at the peri position, but the lithiation of fused ring aromatics t es place preferentially at the ortho (rather than peri) position,as shown by the examples in Scheme 12. Subsequent transformations of the phthalides obtained in the naphthalene example also illustrate the usefulness of this method for the annelation of aromatic rings. The preference for ortho over peri lithiation holds true for phenanthrenes as well. The selective metd-ation of trimethoxyphenanthrenamide (15) followed by phthalide synthesis as above constitute the key steps in the synthesis of the phenanthroquinolizidine alkaloid cryptopleurine and the phenanthroindoli-zidine alkaloid antofme (Scheme 13). ... 

The asymmetric total synthesis of the phenanthroquinolizidine alkaloid (-)-cryptopleurine was reported by S. Kim et al. One of the key steps in the sequence was the thermai Overman rearrangement which took place in refluxing toluene in nearly quantitative yield and without any loss of the optical purity of the allyl trichloroimidate substrate. 

Returning to phenol ether-phenol ether coupling, synthetic septicine (59) gave ( )-tylophorine (60) on treatment with thallium trifluoroacetate, and the same reagent converted synthetic julandine (61) to ( )-cryptopleurine (62 69%). In another synthesis of tylophorine the lactam (63) was transformed with va-... 

Lebrun and coworkers reported a convenient synthesis to a range of phenanthroindo- and quinolizidine natural products [62]. In this approach, the alkaloids (+)-antofine [( )-3] (n-1) and (+)-cryptopleurine [(+)-5] (n=2), were synthesized by Pictet-Spengler cyclization of 72 [2-arylmethyl-piperidine (n=2) and -pyrrolindine (n=l)], Scheme (7). The intermediate compounds were obtained by sequential iV-deprotection-reduction of the parent enecarbamates 71, which were obtained from Homer reaction of phosphorylated carbamates 70 with the appropriate aldehyde (69). 

The tylophorine (phenanthroindolizidine alkaloid) nucleus was first synthesized by Govindachari et al. in 1958 [48] followed by the synthesis of cryptopleurine (6-membered E ring, phenanthroquinolizidine alkaloid) by Bradsher and Berger [49] as well as Marchini and Belleau [50]. Many naturally occurring tylophorine alkaloids (e.g., tylophorine, tylophrinine and tylocrebine) have been synthesized, and the earlier routes before 1985 were well summarized in a comprehensive review by M. Suffness [5]. In this paper, only the more recently reported synthetic methods will be described. 

A novel synthesis of antofine 22, an indolizidine alkaloid, and cryptopleurine 23, a quinolizidine alkaloid, involves lithiation of trimethoxy-fihenanthrene-carbox mide. The key step in both these cases is the generation of substituted phthalides 92)... 

The Weinreb group has also applied intramolecular imino Diels-Alder chemistry to the synthesis of the phenanthroindolizidine antitumor alkaloid tylophorine (42) (Scheme 2-XIV).85 86 In this example, a diene incorporated into a phenanthrene unit proved sufficiently reactive in an intramolecular cyclization to provide the pentacyclic alkaloid ring system. A similar strategy was later used to synthesize the phenanthroquinolizidine alkaloid cryptopleurine.89... 

Cryptopleurine (45) has been prepared (Scheme 4) by a modification of an earlier synthesis. The key step is anodic oxidation of the known quinolizidone (42) to a mixture of compounds (43) and (44). The spiro-compound (43) was transformed in high yield into (44), which was reduced to cryptopleurine. 

Intramolecular amide formation is also a useful route to quinolizines. Thus, a very efficient synthesis of the phenanthroquinolizidine alkaloid cryptopleurine (189) described by Snieckus and... 

A new and efficient synthesis of ( )-cryptopleurine (Scheme 1) has been reported. " The piperidylacetophenone (30) was prepared from the benzoylacetic acid derivative (29) and A -piperideine, which was generated in situ from cadaverine and pea-seedling diamine oxidase. The enamine (31) undergoes cyclization and subsequent dehydration in the presence of a Lewis acid, and biaryl coupling is then effected with thallium trifluoroacetate. 

The tin hydride-mediated C(sp )-C(sp )-bond formation has successfully been applied as key step in the synthesis of various natural products. Amaiyttidacaea alkaloids [39], glaucine [40], cryptopleurine ]41] and an anticancer benzo]c]phenanthridine alkaloid [42] were each successfully prepared using this approach. 

Method 1. The first reported synthesis in the field gave racemic cryptopleurine (45). 

An improved synthesis employs anodic oxidation of the diaryl quinolizi-done derivative to give the corresponding 0,0-dimethylspirodienone, which is converted to cryptopleurine by essentially the same sequence of reactions as that shown above 51). 

Sydnes MO, Bezos A, Bums C, Kruszelnicki I, Parish CR, Su S, Rae AD, Willis AC, Banwell MG (2008) Synthesis and biological evaluation of some enantiomerically pure C8c-C15 monoseco analogues of the phenanthroquinolizidine-type alkaloids cryptopleurine and julandine. Aust J Chem 61(7) 506-520. doi 10.1071/ch08190... 

Eagle s 9 KB carcinoma in cell culture (ED50 = 7-8 x 10 Pg/ml), but is inactive in vivo against a number of experimental neoplasms [41]. A bio-genetically-based synthesis of cryptopleurine has recently been described [42]. A number of analogues of (IV) have been synthesized for antitumour studies [42a]. 

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