Synthesis Of Boronic Acid Derivatives Of Quindoline Total Synthesis Of DHDA, And Study Of Samarium Diiodide-Mediated Intramolecular Cyclization

Natural products-based drugs (parent compounds, derivatives, analogues, and mimics) are major entities among the FDA-approved drugs (57.7% of all drugs). However, bioactive natural products may not be readily available in substantial quantities from natural sources, as would be needed for drug manufacturing or even for investigational studies. The difficulty to get substantial bioactive natural products through extraction and isolation restricting the development of clinic studies and drug manufacturing can be solved by means of chemical synthesis fortunately. Meanwhile, chemical modification of highly promising lead compounds arising from natural sources furnishes a powerful tool for innovative drug discoveryFor some functional molecules, especially natural products with complicated chemical structures and susceptible groups, selectivity and functional-group tolerance are highly required. As a result of this potent combination of useful reactivity and tunable selectivity, samarium diiodide (SmI2) is widely employed and recognized as one of the premier single-electron reducing agents in synthetic chemistry. Many functional molecules have been furnished by SmI2, and an array of cyclization protocols induced by SmI2 has been employed successfully in the construction of hundreds of challenging and complicated natural products, as well as many other functional molecules.1. Synthesis and Antitumor Activity Study of Arylboronic Acid Derivatives of QuindolineQuindoline is an alkaloid isolated from West African shrub Cryptolepis sanguinolenta. Synthesis and biological studies of indoloquinoline compounds were interest-focused areas of this series of natural products. A simple and efficient synthetic approach to a series of indoloquinoline acids and their arylboronic acid derivatives was established here, employing polyphosphoric acid (PPA) mediated cyclization, aromatization and amidation as key steps. Most of the derived molecules possessing boronic acid functional group synthesized exhibit higher proliferation inhibitory activity than the parent skeleton molecules against the human breast cancer cell line (MDA-MB-231). Interaction between some carbohydrates (sialic acid, fucose, etc) over-expressed on the surface of cancer cells and these molecules were studied by mass spectrometry. We found saccharides did form diboronate with synthesized arylboronic acid derivatives of quindoline in alkaline aqueous solution. This result is of help for us to understand the target selectivity decided by boronic acid on tumor cells might be a reason for the improved antitumor activity.2. Total Synthesis of Dihydrodehydrodiconiferyl Alcohol (DHDA)An efficient synthesis of natural product DHDA, in twelve linear steps and 17% yield, was established, although attenuated by partial C3-epimerisation in the final step. Key advantages of the described route are the formation of a 2, 3-dihydrobenzo[b]furan core via high-yielding diazo transfer and C-H insertion, and a late-stage Pd0 catalyzed functionalization which permits synthesis of analogues with varying C5-substitution. This method is supposed to be an efficient way to establish the library of 2,3-dihydrobenzofuran molucules used for future test of their biological activity.3. Intramolecular Cyclization ofα,β-Unsaturated Carbonyl Compounds Mediated by Samarium DiiodideAs a result of the potent combination of useful reactivity and tunable selectivity, samarium diiodide (SmI2) is widely employed and recognized as one of the premier single-electron reducing agents in synthetic chemistry. We established a new chemical methodology to the synthesis of different-sized spirocyclic ethers by intramolecular conjugate addition mediated with samarium diiodide. First of all, we synthesized ten bis-a,β-unsaturated carbonyl compounds with different-sizedα,β-unsaturated carbonyl side chains as terminal by a facile method, involving generation of cyclic a,β-unsaturated enone with alkene as side chain, oxidation, Horner-Wadsworth-Emmons olefination. Then these synthesized bis-a,β-unsaturated carbonyl coumpounds ungerwent cyclization upon treatment with SmI2 in THF/MeOH. Theα,β-unsaturated cyclic enones withα,β-unsaturated enone as terminal had not gone as what we supposed. Butα,β-unsaturated enoates as terminals ungergone Michael-type addition as what we designed. Furthermore experiments showed that only a,β-unsaturated cyclic enones withα,β-unsaturated enoate and proper length ofα,β-unsaturated carbonyl side chain could accompany this reaction. The reaction condition is mild, and has high yield with satisfied diastereoselectivity. This methodology should be an advisable choice for the synthesis of natural products, drugs or other molecules with spirocyclic ether cores.