| In Part I, through total synthesis, we prepared and evaluated several panaxytriol analogs, each of which exhibited enhanced cytotoxicity relative to panaxytriol. We have begun to chart the first SAR map for panaxytriol, which suggests C3 hydroxyl functionality is not critical for biological activity and engagement of the C9-C10 diol as an acetonide actually leads to notably enhanced cytotoxicity. We revealed that panaxytriol and its derivatives are not substrates for the P-glycoprotein. Through in vivo investigations, we demonstrated that panaxytriol and panaxytriol acetonide (12) moderately suppress tumor growth with little or no toxicity. In addition, it may indeed be used synergistically with fludelone (15) to lower the toxicity and dosage of existing cancer drugs while continuing to maintain their antitumor properties. Finally, preliminary in vitro evaluation of panaxytriol indicates that it possesses neurotrophic activity.; In Part II, a sequence which prepares cycloheptadienones by ring-expansion of fused cyclohexenones has been developed and applied to improved synthesis of a key intermediate in the total synthesis of guanacastepene A. Following the routes documented in the racemic series, 39 could be converted to enantiopure guanacastepene A. The computational study revealed that the origin of stereoselective beta-attack in the epoxidation of 67 is a strong torsional control of stereoselectivity. We hope to evaluate how Homo-Robinson protocol can be put to good use in the target-oriented synthesis contexts. We have begun synthesis of tricholomalide A.; In Part III, through the first generation synthesis of xestocyclamine A, double Michael reaction followed by B-alkyl Suzuki macrocyclization reaction afforded 51. In the mean while, mechanism of double Michael reaction was addressed regarding protecting group and substitution effect. To resolve a mediocre selectivity of double Michael reaction, direct aza Diels-Alder reaction was explored. However, this aza Diels-Alder reaction was not compatible with more advanced substrate. Through the second generation, hydroboration followed by B-alkyl Suzuki coupling reaction afforded coupling product 85. Macrocyclization of 86 influenced by NaH generated 87. To generate isoquinuclidine core, imino Diels-Alder reaction was proposed. After chain elongation, several attempts to induce imino Diels-Alder reaction were discussed but currently they have not been successful. |
