organic synthesis iii - university of...

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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All reagents approach from the less hindered CONVEX face (ie below- syn to H)


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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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There is a problem. We have the WRONG stereochemistry


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Potentially, this hydrogen can be switched in acid

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

Change the shape of the molecule and change the rules! Join OH and COOH to form a lactone- see how close they are in B.


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Shape changed dramatically

Equilibration now lies the OTHER way, ie more stable when H is trans!

R. B. Woodward

Tetrahedron, P1, 1958


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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

Initial target is a 2,3,4 trisubstituted pyridine


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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.

HOWEVER, OsO4 is a 16 e complex, and likes to form 18 e complexes with amines. Imagine using a chiral and enantiopure amine ligand, L*.

Complexes A and B are now DIASTEREOISOMERS and need not have the same energy; and so the activation energy to form them need not be the same, and they appear in unequal 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.

The ligand actually makes the dihydroxylation FASTER (ligand accelerated catalysis). Means that background dihydroxylation with free osmium tetroxide (racemic product) is SLOW.


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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

AD mix a and b are commercially available:


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Now, to complete the synthesis of camptothecin

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.

Only works for allylic alcohols. Sometimes Di-isopropyl tartrate (DIPT) gives higher ees.


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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?

Both of these would predict the Formation of the other enantiomer

AND


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◼ Draw allylic alcohol as though it resembles the letter “L”. ◼ D-(-)-DET delivers “O” down onto the alkene – conversely L-(+)-DET delivers “O” from below. ◼ Applicable to most alkene types - remember (Z)-alkenes are less reactive/selective than (E)-alkenes.

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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The SAE tartrate reagent controls the relative stereochemistry

The Payne rearrangement

Sharpless iterates the sequence

1,2-diol protection


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The Pummerer rearrangement

Equilibrate to invert stereochemistry→

Equilibrate to invert stereochemistry→


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

So, all eight L sugars have been made using this sequence; Of course using (-) DET would give all eight D-sugars as well

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)

X


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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

The stereochemistry of BOTH components is transfered to the products

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 iii - university of...

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