Phenanthroquinolizidine

Scheme 4.4. Steps toward the synthesis of phenanthroquinolizidine alkaloids.

In 2004, Banwell and Sydnes reported an unintentional but intriguing result of intermolecular pseudodimer formation as a result of carbon-carbon bond formation during their efforts toward the synthesis of phenanthroquinolizidine alkaloids (Scheme 4.18).13... 

Although the detection and isolation of bicyclic, tricyclic, and tetracyclic quinolizidine alkaloids and stereochemical studies, increasingly aided by X-ray analysis, proceeds apace, the main emphasis this year is on synthesis of the Nuphar, azaphenalene, and phenanthroquinolizidine alkaloids. 

Phenanthroindolizidine and phenanthroquinolizidine alkaloids involve a phenanthrene (Phe ] Phe Phe (angular)) fused with an indolizidine or quinolizidine, respectively. The phenanthroindolizidines tylophorine (phenanthrene G5N G4N ) and tylocrebrine (phenanthrene G5N C4N ) and the phenanthroquinolizidine crypto-pleurine (phenanthrene G5N C5N ) are toxic, cytotoxic protein synthesis inhibitors. The phenanthroindolizidines tylophorine and pergularinine are thymidylate synthase inhibitors. 

The phenanthroquinolizidine alkaloid cryptopleurine (149), which is a homologue of tyrophorine (119), was synthesized by the Weinreb group via the methylol acetate derivative (146) of an inseparable mixture of ( )- and (Z)-... 

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. 

Gupta et al. [72] performed an extensive structure-activity comparison regarding cross-resistance in two emetine-resistant CHO cell variants. This study showed that phenanthroindolizidine alkaloids, phenanthroquinolizidine alkaloids, and emetine-related benzoquinolizidines may have the same site of action. The conformation of emetine was suggested to have a close spatial relationship to the other three compound classes, and thus, they could bind to the same hypothetical binding site, Fig. (7). 

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. 

The intermediate diarylquinolizidinone (40) was also reduced by means of lithium aluminium hydride to give the related tertiary amine (44), which was shown to be identical with the seco-phenanthroquinolizidine alkaloid isolated from Boehmeria platyphylla Don. ° The identity of the synthetic material with the natural base, for which [a]o +4.6° was reported, suggests that the latter is largely racemic. ... 

The pandemic nettle family, Urticaceae, was hardly known as a source of alkaloids until the isolation of the phenanthroquinolizidine base cryptopleurine (31) from two Boehmeria spp., together with certain others such as the seco-base, julandine (32), that appear to be biosynthetically related to it 47. The latter had not been recorded previously, but cryptopleurine was already known, having been obtained from a lauraceous plant referred to later apart from these examples, another genus of the Urticaceae, Cypholophus, produced cypholophine (33), a new type of imidazole alkaloid [48. ... 

Isolation, total synthesis, and biological activity of phenanthroindolizidine and phenanthroquinolizidine alkaloids 01S2365. 

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... 

Phenanthroindolizidine and phenanthroquinolizidine alkaloids have similar pentacyclic structures however, the latter compounds contain a 6-membered piperidine E ring rather than the 5-membered pyrrolidine E ring found in the former compounds. Cryptopleurine (5), Fig. (2), is a representative and important phenanthroquinolizidine alkaloid. It is isolated primarily from Cryptocarya pleurosperma [20], but also from Cryptocarya laevigata [21], Boehmeria cylindrica [22, 23], Boehmeria platyphylla [24], Boehmeria caudate [21], and Cissus rheifolia [25], and is known as a highly toxic skin irritant and vesicant. 

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... 

The phenanthroindolizidine alkaloid (-)-tylocrebrine has been shown to have the S configuration, like (-)-tylophorine, from a study of the o.r.d. and c.d. spectra of these two alkaloids and of the phenanthroquinolizidine alkaloid cryptopleurine. ... 

---