Organocatalysis

It will not have escaped your notice that most of the reactions we have presented in this chapter have made use of metals. Metals have labile coordination sites that can carry chiral ligands at the same time as they allow substrates and reagents to meet together in a chiral environ ment and then let the products dissociate so that the catalytic cycle can proceed. But in the early years of the 21st century, several chemists around the world realized that it is not always necessary to use a metal to initiate high levels of enantioselectivity in catalytic reactions. Simple chiral and enantiomerically pure organic molecules, many of them amines, can also react reversibly with substrates, providing a chiral environment and simultaneously activating them towards enantio selective attack. Here is an example, which picks up where we left off: a catalytic enantioselective conjugate addition.

aldehydes and ketones react with secondary amines to form enamines, via iminium ions. But this unsaturated aldehyde can’t form an enamine because the iminium ion that is generated by condensation with the cyclic secondary amine cannot lose a proton. The iminium ion is the end of the line for this condensation: it is very reactive towards attack by water (which would reversibly regenerate starting materials), but also towards attack by other nucleophiles. We have just what we want for good asymmetric catalysis—an intermediate species that is reactive, chiral, and enantiomerically pure.

If this condensation is done in the presence of a weak nucleophile—strong enough to attack the positively charged iminium ion but not strong enough to attack the aldehyde itself—an addition reaction takes place. A pyrrole will do: pyrroles react well with cations. The phenyl ring highlighted in green hangs over the front of the molecule so the pyrrole has no choice but to attack diastereoselectively, from behind. The product is an enamine, which in the acid conditions of the reaction is hydrolysed by the water generated in the initial condensation, revealing the aldehyde in enantiomerically enriched form (93% ee) and regenerating the secondary amine catalyst.

This catalyst and strategy were invented by the Glaswegian chemist David MacMillan at the California Institute of Technology (now at Princeton in New Jersey) and given the name ‘organocatalysis’. Organocatalysis makes use of small organic molecules to achieve catalytic asymmetric transformations, and can be distinguished from the more widespread methods of catalysis which typically use metals. We’ll introduce another type of organocatalysis towards the end of the chapter, but before we move on it’s worth looking at this amine catalyst and the way it works in a little more detail. The geminal dimethyl group highlighted in orange above is also important to the function ing of the catalyst. Without it, there is clearly a danger that the pyrrole will add directly to the C=N bond of the iminium ion, a reaction that would kill the catalyst because the product is an amine and not an enamine.

 The methyl groups on both faces of the iminium C=N bond stop this happening. The other thing it ensures is the geometry of the iminium C=N bond. This bond is trans so that the alkene can keep away from the quaternary carbon bearing the two orange groups; the benzyl group with the green phenyl may be bigger in terms of total number of atoms, but there is more space for the alkene on that side because the nearest car bon also carries just an H atom. Why is the geometry of the imine important? Well, if any of it were cis, it would present the other face to the pyrrole and would be likely to give the oppo site enantiomer of product. Catalysts aren’t used in such great quantities as chiral auxiliaries, and so in general their synthesis does not need to be quite so direct. Nonetheless as you can see from the examples here, organocatalysts are still generally used in much greater quantities (10–20 mol%) than some of the best metal catalysts. In this case you should be able to spot that the left-hand portion of the cyclic amine is a derivative of L-phenylalanine. Condensation of its N-methyl amide with an equivalent of acetone gives the catalyst itself. Here’s a related catalyst—as with the Rh- and Ru-catalysed reactions, fine tuning of the catalyst is important—being used in the synthesis of an important pharmaceutical com pound, a COX-2 inhibitor. This time the nucleophile is an indole reacting characteristically at its 3-position.

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الأمين العام للعتبة العباسية المقدسة يتفقد خدمات قسم المضيف لزائري الأربعين

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قد يؤدي إلى فشل القلب.. تحذير من مسكن آلام يستعمله الملايين

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علماء يكتشفون أن نقص عنصر غذائي "شائع" قد يسبب الزهايمر

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المعادن الحيوية قد تنضب خلال 10 سنوات.. دراسة صادمة ؟

"إنستغرام" يستنسخ خاصية شائعة من منافسه "سناب شات"

رواد فضاء يغادرون محطة الفضاء الدولية بعد مهمة استمرت 5 أشهر

"كريساليس".. سفينة فضائية ستسافر بالبشر إلى أعماق النجوم ؟!

المزيد

مواضيع ذات صلة

Cyclic nucleosides and stereochemistry

HIV and AIDS are treated with modifi ed nucleosides Modified nucleosides

The stimulants in tea and coffee are methylated purines

Life begins with nucleic acids

Aldol reactions catalysed by proline

Asymmetric dihydroxylation

Catalytic asymmetric reduction of ketones

Chiral reagents

Enantiomeric excess

Alkylation of enolates

Resolution can be used to separate enantiomers

Nature is asymmetric