Total Synthesis of Ingenol课件

1、Total Synthesis of IngenolChem. Rev. 2005, 105, 46614670 IntroductionIn 1991, Hecker published a detailed procedure for the isolation of ingenol from the seeds of E. lathyris . Various esters of ingenol have shown remarkable biological properties to mimic diacylglycerol and function as endogenous ac

2、tivators of protein kinase (PKC). Further, they were found to exhibit antitumor or tumor-promoting, antileukemic, and anti-HIV properties. Because of its biological significance and structural featureingenol has been one of the most challenging targets in synthe-tic organic chemistry for the past 25

3、 years. 1.An unusual trans-fused bicyclo4.4.1undecane ring system, which brings about great strain to the molecule.2.The high degree of oxygenation. 3.The cis-triol segment located on the upper face from C(3) to C(5). J. AM. CHEM. SOC. 2002, 124, 9726-97281. Winklers Total Synthesis of IngenolTotal

4、Synthesis1. The total synthesis of ingenol outlined above proceeds in 43 steps from enone with an 80% average yield per step.2. It is notable for the use of a highly diastereoselective Michael rea -ction to fix the C-11 methyl stereochemistry and the incorporation of the dimethylcyclopropane via dia

5、stereose- lective carbene addition to the C-13,14 olefin. 3. The establishment of the C-8/C-10 trans intrabridgehead stereochemistry serves as a testament to the utility of the intramo-lecular dioxenone photoaddition-fragmentation approach to the synthesis of structurally and stereochemically comple

6、x natural products.Conclusion2. Kigoshis Approach J. Org. Chem.2004, 69, 7802 -780816abRing-Closing Olefin Metathesis in the Synthesis of Ingenol Derivatives The ring-closing olefin metathesis was found to be effective in the synthesis of highly strained ring systems, and to be a key step in synthes

7、izing optically active Winklers alde- hyde.Conclusion3.Woods Total Synthesis of IngenolJ. AM. CHEM. SOC. 2004 , 126 , 16300 -163017%47%40% (47%, 88% based on recovered a )ab A ring-closing metathesis approach has been effectively employed in an efficient total synthesis that delivers the biologicall

8、y important diterpene ingenol in 32 overall steps from 5.ConclusionHypothetical Pathway to Ingenane Carbocycle4. Keiji Taninos Total Synthesis of Ingenol Reaction Pathways Leading to 30 and 31J. AM. CHEM. SOC. 2003 , 125 , 1498 -1500Construction of Ingenane Tetracarbocycle 38Second Approach toward I

9、ngenol Total Synthesis of Ingenol: 1Total Synthesis of Ingenol: 2 Total Synthesis of (-)-Ingenol Total synthesis of ingenol was accomplished on the basis of novel key reactions, namely an intramolecular cyclization reaction of acetylene dicobalt complex, a rearrangement reaction of epoxy alcohol for constructing the ingenane skeleton,and a stereoselective double dihydroxylation reaction of diene. The 45-step transformation from commercially available compound afforded ingenol in ca. 0.1% overall yield.Conclusion J. Am. Chem. SOC. 19