organic synthesis iii
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Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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Organic Synthesis III 8 x 1hr Lectures: Michaelmas Term
Weeks 5-8 Tues; Thrs at 10am
Dyson Perrins lecture theatre
Copies of this handout will be available at http://donohoe.chem.ox.ac.uk/page16/index.html
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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Prelude FOR centuries, the Indian snake-root, Rauwolfia serpentina Benth., has enjoyed a favorable reputation in its habitat as a valuable medicinal agent. The problem of defining the scope of its utility in terms of modern Western medical standards was complicated by the fact that the plant produces a very large number of closely related alkaloids, of which those present in larger relative measure are not those with the more interesting physiological properties. Only five years ago, Schlittler first isolated reserpine, and demonstrated that this new alkaloid was largely responsible for the hypotensive activity associated with crude Rauwolfia extracts. This discovery, and the remarkable effect which reserpine was subsequently found to exert upon the central nervous system, rapidly won for the alkaloid an important place in the treatment of hypertensive, nervous, and mental disorders.
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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Potentially, this hydrogen can be switched in acid
Equilibration in acid will FAIL because A is more stable than B.
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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Camptothecin A cyctotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I. First discovered in 1966 from the bark of Camptotheca acuminate (native to China) Showed excellent levels of anti-cancer activity, but this was coupled to poor solubility in water.
Note: two water soluble derivatives of camptothecin are currently used in cancer chemotherapy: Topotecan (GSK) for ovarian and lung cancer Irinotecan (Pfizer) for colon cancer
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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Next for the alkene sidechain
Now to oxidise the alkene
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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The concept is simple:
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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The chiral ligands themselves are complicated; they come from the chiral pool.
The most active catalysts have TWO chiral amine units attached via a linker; they bind to Os independently.
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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The catalytic cycle looks like this.
Does the AD reaction work for all types of alkene?
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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It is very difficult to model the transition structure with such a complex ligand; So Sharpless developed a MNEMONIC to predict enantioselectivity.
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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Try docking the alkene in another way: usually one way is clearly the best fit
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
17/35 J. Org. Chem. 1994, 59, 6142-6143
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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Synthesis of L-hexose sugars (K. B. Sharpless) A useful application of the Sharpless Asymmetric Epoxidation; utilises reagent control Amenable to the synthesis of 8 different sugars (and their enantiomers)
The Sharpless Asymmetric Epoxidation (SAE) is extremely powerful and general way of epoxidising allylic alcohols with high enantioselectivity (which enantiomer simply depends on the use of (+)- or (-) DET ligands.
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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Mechanism Sharpless noted: 1) Ligand exchange on Ti is very rapid. 2) Reaction is first order in Ti complex, TBHP and allylic alcohol 3) Extensive solution studies showed that a dimer is present
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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What could go wrong?
AND
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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The selectivity is encapsulated in a mnemonic
Try it on this!
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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To continue with the synthesis
NB: An equilibration of the cis aldehyde to the trans
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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Sharpless iterates the sequence
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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If we had started the iteration with the other diastereoisomer....
See, Classics in Total Synthesis; Science. 1983, 220, 949
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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1) Make the synthesis as short as possible!
Use convergent rather than linear sequences- it cuts down the step count (and the risk)
2) Disconnect C-X bonds wherever possible (this includes RCO-X)
3) Use FGIs to make the chemistry easier
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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4) Disconnect bonds by using nearby functional groups
Also, it makes more sense to disconnect in the middle of a molecule
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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5) Know common reagents that are equivalent to the following synthons (remember UMPOLUNG)
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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6) Stereochemistry gives you a clue
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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Or use the shape of the molecule to assist
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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7) Know routes to dicarbonyl compounds (it will also help your heteroaromatic chemistry!)
Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2
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8) The Diels Alder reaction is a VERY general one
9) Dont forget about the link between aromatic and non-aromatic compounds
Two reactions illustrate this point
1) The Birch reduction
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2) Hydrogenation
10) Don’t panic- explore more than one disconnection for each target
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