Pancratistatin (PST) is a natural compound initially extracted from spider lily, a Hawaiian native plant of the family Amaryllidaceae (AMD).
Occurrence Pancratistatin occurs naturally in Hawaiian spider lily, a flowering plant within the family Amaryllidaceae. Pancratistatin is mostly found in the bulb tissues of spider lilies. It has been shown that the enrichment of atmospheric CO2 can enhance the production of antiviral secondary metabolites, including pancratistatin, in these plants. Pancratistatin can be isolated from the tropical bulbs of Hymenocallis littoralis in the order of 100 to 150 mg/kg when bulbs are obtained from the wild type in Hawaii. However, the compound has to be commercially extracted from field- and greenhouse-grown bulbs or from tissue cultures cultivated, for example, in Arizona, which generate lower levels of pancratistatin (a maximum of 22 mg/kg) even in the peak month of October. After October, when the bulb becomes dormant, levels of pancratistatin drop, down to only 4 mg/kg by May. Field-grown bulbs, which show monthly changes in pancratistatin content, generate somewhat smaller amounts (2–5 mg/kg) compared to those grown in greenhouses cultivated over the same period. There are about 40 different spider lily species worldwide and they are mainly native to the Andes of South America.
Pharmaceutical research Pancratistatin is thought to have potential as a basis for the development of new pharmaceuticals, particularly in the field of cancer treatment.
Biosynthesis
Although there may not be a precise elucidation of pancratistatin biological synthesis, there have been speculations on biosynthesis of narciclasine and lycoricidine that are very similar to pancratistatin in terms of structure. The biosynthesis is accomplished via synthesis from O-methylnorbelladine by para-para phenol coupling to obtain vittatine as an intermediate. Subsequent elimination of two carbon atoms and hydroxylations of vittatine then leads to narciclasine.
Total synthesis The first total synthesis of racemic (+/-)-pancratistatin was reported by Samuel Danishefsky and Joung Yon Lee, which involved a very complex and long (40 steps) total synthesis. According to Danishefsky and Joung, there were several weak steps in this synthesis that gave rise to a disappointing low synthetic yield. Amongst the most challenging issues, the Moffatt transposition and the orthoamide problem, which required a blocking maneuver to regiospecifically distinguish the C, hydroxyl group for rearrangement were considered to be the severe cases. However, both Danishevsky and Yon Lee stated that their approach towards the PST total synthesis was not without merit and believed that their work would interest other medicinal scientists to construct a much more practical and efficient way for PST total synthesis.
The work of Danishevsky and Joung provided the foundation for another total synthesis of PST, which was propounded by Li, M. in 2006. This method employed a more sophisticated approach, starting out with pinitol that has stereocenters which are exactly the same as the ones in the C-ring of pancratistatin. Protection of the diol functions of compound 30 gave compound 31. The free hydroxyl of this was subsequently substituted by an azide to give 32. After removal of the silyl function, a cyclic sulfate was installed to obtain product 33. The Staudinger reaction gave the free amine 34 from azide 33. The coupling reaction between 34 and 35 gave compound 36 with a moderate yield. Methoxymethyl protection of both the amide and the free phenol gave compound 37. Treatment of this latter product with t-BuLi followed by addition of cerium chloride gave compound 38. Full deprotection of 38 by BBr3 and methanol afforded pancratistatin 3 in 12 steps from commercially available pinitol with an overall yield of 2.3% 20.
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