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Total synthesis of eudesmane terpenes by site-selective C–H oxidations
Ke Chen, Phil S. Baran
Department of Chemistry, The Scripps Research Institute
Nature, 2009, 459, 824
dihydroxyeudesmane
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(A) Traditional approach to organic synthesis by means of FG
(B) Synthesis by means of C–H bond functionalization.
C-H Functionalization:
(1) Transition metal catalyzed C-H bond functionalization
Godula, K.; Sames, D. Science, 2006, 312, 67.
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C–H functionalization by metal carbenoid and nitrenoid insertion
Davis, H. M. L.; Manning, J. R. Science, 2008, 451, 417.
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(2) C-H bond functionalization through radical reactions
Hofmann, A. W. Ber. 1883, 16, 558.
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1,3-Diol Synthesis via Controlled, Radical-Mediated C-H Functionalization
Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247.
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Figure 1. 1,3-Diol synthesis using a modified HLF reaction.
Two Challenge:
1, 6-H transfer vs 1, 5-H transfer
Oxygen attack vs Nitrogen attack
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Figure 2. Relative efficiency of selected N-bromocarbamates
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Competition experiment
The application of this mothod in some simple natural products
Isopulegol hydrate has been synthesized many times in from 1 to 5 steps and 4.8 to 35% yield as mixtures of regioisomers.
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Unique chemo- and regioselectivity
White catalyst (Fe-based) selective for Ha
(Chen, M. S.; White, M. C. Science 2007, 318, 783.)
Curci [O] (dioxirane) non-selective
(Curci, R. J. Am. Chem. Soc. 1989, 111, 6749.)
This work selective for Hc
Figure 3. Comparison of selectivity of tertiary C-H bond activation
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Total synthesis of eudesmane terpenes by site-selective C–H oxidations
(From menthol to cholesterol to Taxol, terpenes are a ubiquitous group of
molecules and over 55,000 members are isolated so far)
Biosynthesis of terpenes (two phase process)
1. Cyclase phase
“ simple linear hydrocarbon phosphate building blocks are stitched together by means of ‘prenyl coupling’, followed by enzymatically controlled molecular cyclizations and rearrangements. ”
2. Oxidase phase
“oxidation of alkenes and carbon–hydrogen bonds results in a large array of structural diversity. ”
Maimone, T. J.; Baran, P. S. Nature Chem. Biol. 2007, 3, 396.
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Figure 4. Outline of the ‘two-phase’ approach to terpene total synthesis.
H
(eudesmane)
Chen, K.; Baran, P. S. Nature, 2009, 459, 824.
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Figure 5. Simple, enantioselective total synthesis of dihydrojunenol (4).
“ Equivalent to the cyclase phase”
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13C NMR analysis of the reactivity of five tertiary C-H bonds
relative electronegativity:
X-ray crystallography and modelling studies
H1 adopts an equatorial orientation
H5 is populated by multiple conformers
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Figure 6. Total syntheses of 4-epiajanol (5) and dihydroxyeudesmane (6)
“ Equivalent to the oxidase phase”
16Figure 7. Total syntheses of pygmol (7) and eudesmantetraol (8)
17Figure 8. Pyramid diagram for the retrosynthetic planning of terpene
synthesis using a ‘two-phase’ approach
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Characteristics of this terpene biosynthesis:
This work presents an example of a linear C-H activation strategy featuringmultiple consecutive site-selective oxidation in total synthesis
Installation of functional groups (oxidation) onto the carbon framwork usually occurs near the end of the sequence which leads to the minimization of protecting group chemistry
This biomimetic approach can naturally lead to the synthesis of relatedfamily members, closely related analogues
This work provides a set of rules and logic for the use of C-H oxidation in terpene synthesis
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Chen, M. S.; White, M. C. Science 2007, 318, 783
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Curci, R. J. Am. Chem. Soc. 1989, 111, 6749
