A C2-Symmetric Chiral Pool Based Flexible Strategy: Concise Synthesis of (+)-Valienamine, (+)-Valiolamine, 1-epi-(+)-MK7607, 1-epi-(-)-Streptol, (-)-Hygromycin A, Conduramine B-1, C-1, C-4, D-1, F-1, and F-4, and Key Intermediate of (-)-Laminitol
| Autor: | Hong-Jay Lo, 駱宏杰 |
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| Rok vydání: | 2012 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 100 Herein, we propose a facile and flexible synthetic strategy of chemically challenging and biologically important molecules from C2 symmetric inexpensive chiral pools [L (or) D Tartaric acid]. This expeditious total synthesis includes aminocyclitols [(+)-Valienamine & (+)-Valiolamine], pseudo-carbasugars [1-epi-(+)-MK7607, 1-epi-(-)-streptol], Conduramine series and (-)-Hygromycin A. Aforementioned compounds possess excellent biological activity, such as α- glucosidase inhibitors, antibiotics containing broad spectrum of activity such as peptidyl transferase inhibition activity and high hemaglutination inactivation activity and high antitreponemal activity. On the other hand, the key intermediate could serve as platform for many natural product syntheses. First of all, we utilized Wittig reaction to introduce methylene functional group in 9 steps total synthesis of (+)-Valienamine with 12.4% overall yield. Interestingly, a slightly deviated synthesis from the key intermediate led through asymmetric Sharpless dihydroxylation in 9 steps total synthesis of (+)-Valiolamine, with overall yield of 12.6%. In a concise strategy D-Tartaric acid transformed to Valienamine and Valiolamine. We applied the same procedure to synthesize the enantiomer of same intermediate from L-Tartaric acid and utilized a key step for Heck carbonylation to establish hydroxymethy functional precursor. We achieved an efficient total synthesis of 1-epi-(+)-MK7607 and 1-epi-(-)-streptol in 9 steps with overall yield 11.2% and 12.1% respectively. Similarly, our efforts in devising, simple and flexible strategy to provide an efficient and enantiospecific approach to Hygromycin A. We developed a new platform like 1,4-type azido alcohol aminocyclitol fragment and synthesized through 1,3-transposition from enantiomer L-Tartaric acid. Furanoside fragment was synthesized from different starting materials like D-Tartaric acid or D-Arabinose with short steps and in high yield. Coupling reaction of all key fragments channeled us to complete formal total synthesis of Hygromycin A in 11 steps with overall yield 14.6%. Finally, we efficiently exploited the above mentioned flexible strategy to develop O-isopropylidene protected allylic epoxide, derived from L-Tartaric acid. Other than double bond, diverse stereochemistry of four functional groups in six membered rings achieved from different steps lead rapid high yield synthesis of eight conduramines as its tetraacetates. We achieved total synthesis of Conduramine A-1 and E in 5 steps with overall yield of 30.5% and 36.9% respectively. In addition, Conduramine B-1, C-1 and C-4 were accomplished in 7 steps with overall yield 32.7%, 25.2% and 11.7% respectively. Moreover, we synthesized Conduramine D-1 in 9 steps with overall yield 13.8%. In a similar way, ent-Conduramine F-1 and ent-Conduramine F-4 were completed in 6 steps with overall yield 31.7% and 33.1% respectively. Finally, we also utilized the intermediate for the synthesis of inositol analogues in 8 steps with total yield of 25.2%. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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