Aldol reactions catalysed by proline

A variety of catalytic ways of doing asymmetric aldol reactions have also been invented, but space prevents us discussing all but one. This one we highlight firstly because it illustrates the use of a supremely simple biologically derived compound to catalyse a complex reaction, and secondly because this discovery was part of the revolution in catalytic thinking which launched the field of organocatalysis in the early years of the 21st century. The catalyst we will use is the amino acid L-proline—no derivatization or protection required. It was actually back in 1971 that it was first noted that L-proline will catalyse asymmetric aldols, but until the year 2000 examples were limited to this one cyclization. Treatment of a triketone with proline leads to selective cyclization onto one of the two enantiotopic carbonyl groups. A molecule of proline must condense with the least hindered ketone, and in this case an enamine (rather than an iminium ion) can form. The chiral enamine can select to react with only one of the two other carbonyl groups, and it turns out that it chooses with rather high selectivity the one coloured green in the scheme below. Cyclization, in the manner of a Robinson annelation, and hydrolysis of the resulting iminium ion follow on, releasing the molecule of L-proline to start another catalytic cycle. The isolated product is the bicyclic ketone, in 93% ee.

This remained an oddity of a reaction until 2000, when chemists at the Scripps Institute in California, and then others around the world, took the simple expedient of adding L-proline to many other aldol reactions, with considerable success. With care, excellent results can be obtained. Here is an example.

usually need one of the reagents to be converted to an enolate equivalent to ensure selective reaction. Here, the acetone is in excess, but the components are just stirred together at room temperature in DMSO! The key to success is that one of the two components must be more able to form a reactive enamine with proline than the other. In the case above, the acetone-derived enamine is favoured because (1) enamine formation is reversible, (2) the acetone is in excess, and (3) the enamine from acetone is less hindered and more reactive than the enamine that would arise from the aldehyde.

In the aldol reaction itself, proline’s carboxyl group has a key role to play because it can participate in a hydrogen bond that organizes the six-membered transition state in such a way that only one of the possible enantiomeric products can form. The diagram below shows how. Water generated in the initial condensation hydrolyses the iminium product of the aldol and regenerates the proline catalyst.

Organocatalytic aldol reactions also work well with hydroxylated ketones—the reaction below, for example. In this case, the enamine forms with an E double bond, which means that the hydroxyl group has to be equatorial on the six-membered transition state. You should be able to work out from this that the anti-aldol has to form.

اخر الاخبار

اخبار العتبة العباسية المقدسة

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المزيد

الآخبار الصحية

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

هل الجري يساعد على فقدان الوزن؟.. إليك ما يقوله الخبراء

ماذا يحدث لجسمك عند شرب عصير البطيخ بانتظام؟

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

المزيد

الآخبار التكنلوجية

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"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

Organocatalysis

Asymmetric dihydroxylation

Catalytic asymmetric reduction of ketones

Chiral reagents

Enantiomeric excess

Alkylation of enolates

Resolution can be used to separate enantiomers

Nature is asymmetric