organic synthesis iiidonohoe.chem.ox.ac.uk/resources/2015handout2.pdf · prof tim donohoe:...

Prof Tim Donohoe: Strategies and Tactics in Organic Synthesis: Handout 2

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Organic Synthesis III 2015 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


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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.


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Regiochemistry of second bromonium ion opening is controlled by sterics and transdiaxial opening of the bromonium ion. See Furst Platner rule (Alicyclic Chemsitry Primer by M. Grossel)


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Potentially, this hydrogen can be switched in acid

Equilibration in acid will FAIL because A is more stable than B.


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R. B. Woodward


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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


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Next for the alkene sidechain

Now to oxidise the alkene


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The concept is simple:

Enantiomers A and B have the same energy; and so the activation energy to form them is the same, and they appear in equal amounts.


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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.


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The catalytic cycle looks like this.

Does the AD reaction work for all types of alkene?


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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.


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Try docking the alkene in another way: usually one way is clearly the best fit


17/35 J. Org. Chem. 1994, 59, 6142-6143


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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.


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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


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What could go wrong?

AND


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The selectivity is encapsulated in a mnemonic

Try it on this!


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To continue with the synthesis

NB: An equilibration of the cis aldehyde to the trans

Two questions 1) Why is trans more stable than cis?

2) Why does the enolate not eliminate?


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Sharpless iterates the sequence


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If we had started the iteration with the other diastereoisomer....

See, Classics in Total Synthesis; Science. 1983, 220, 949


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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


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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


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5) Know common reagents that are equivalent to the following synthons (remember UMPOLUNG)


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6) Stereochemistry gives you a clue


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Or use the shape of the molecule to assist


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7) Know routes to dicarbonyl compounds (it will also help your heteroaromatic chemistry!)


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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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Some problems to think about: Disconnect the following and then devise forward syntheses:

organic synthesis iiidonohoe.chem.ox.ac.uk/resources/2015handout2.pdf · prof tim donohoe:...

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