The effect of electronegative atoms

One of the most powerful anticancer agents known is dolastatin, isolated from the sea-hare Dolabella. Dolastatin contains an unusual amino acid, with three stereogenic centres, and chemists in Germany managed to exploit Felkin–Anh control very effectively to make it from the much more widespread amino acid isoleucine. This is the sequence of reactions.

The key step is the aldol reaction of the enolate of methyl acetate with the protected amino aldehyde. To rationalize the stereoselectivity, we fi rst need to draw the two most important conformations of this aldehyde with the large group perpendicular to C=O. The trouble is, which do we choose as ‘large’: the NBn2 group or the branched alkyl group? Since we know which diastereoisomer is produced we can work backwards to find that it must be the NBn2 group that sits perpendicular to C=O in the reactive transition state, and not alkyl. We can draw the best conformation without worrying about alternatives.

Now look at the diastereoselectivity of the reaction: it is much greater than the 3:1 we saw before—more like 20:1. This really does suggest that there is a further factor at work here, and that further factor is the electronegative N atom. Carbonyl groups increase the reactivity of adjacent leaving groups towards nucleophilic substitution by several orders of magnitude. This was an effect that we noted in Chapter 15, where we showed that the ketone below reacts by the SN2 mechanism 5000 times as fast as methyl chloride itself. We explained this effect by saying that the π* of the C=O and the σ* of C–Cl overlap to form a new, lower-energy (and therefore more reactive) LUMO. What we did not note then, because it was not relevant, is that this overlap can only occur when the C–Cl bond is perpendicular to the C=O bond, because only then are the π* and σ* orbitals aligned correctly.

The same thing happens even with electronegative atoms X that are not leaving groups in the SN2 reaction (for example, X=OR, NR2, SR, etc.). The π* and σ* orbitals add together to form a new, lower-energy molecular orbital, more susceptible to nucleophilic attack. But, if X is not a leaving group, attack on this orbital will result not in nucleophilic substitution but in addition to the carbonyl group. Again, this effect will operate only when the C–X and C=O bonds are perpendicular so that the orbitals align correctly.

What does this mean for stereoselectivity? Conformations of the chiral carbonyl compound that place an electronegative atom perpendicular to the C=O bond will be more reactive— size doesn’t matter. So, in the dolastatin amino acid example, the conformations with NBn₂ perpendicular to C=O are the only conformations we need to consider.

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قسم رعاية الصحن الشريف ينهي استعداداته الخاصة بزيارة الأربعين

قسم الإعلام ينظم دورة تخصصية في تقنيات الذكاء الاصطناعي لعددٍ من منتسبيه

القسم النسوي بمجمع أبي الفضل العباس (عليه السلام) ينهي الاستعدادات لاستقبال زائرات الأربعين

قسم الشؤون الفكرية ينظّم ورشة تدريبية عن الالتزام والانضباط في الخدمة لفتية الكفيل

المزيد

الآخبار الصحية

علامات فارقة بين النوبة أو السكتة القلبية.. ماهي؟

الفلفل الأحمر.. سعرات حرارية منخفضة وفوائد صحية عديدة

8 أعراض إذا شعرت بها.. اذهب للطوارئ فورا !

تعرف على أكثر 8 أماكن اتساخا في المنزل

المزيد

الآخبار التكنلوجية

إنتاج الهيدروجين الأخضر في البحر.. هذه أحدث الدراسات

"ناسا" تخطط لبناء مفاعل نووي على سطح القمر !

ابتكار ومواهب وأموال.. مارك زوكربيرغ يعلن الحرب على أبل

عودة التعاون الفضائي بين روسيا وأميركا.. وبحث ملفات "هامة"

المزيد

مواضيع ذات صلة

Non-linear Hammett plots

A complete picture of the transition state from Hammett plots

Using the Hammett ρ values to uncover mechanisms

Reactions with small Hammett ρ values

Reactions with negative Hammett ρ values

Reactions with positive Hammett ρ values

Equilibria with positive Hammett ρ values

The Hammett substituent constant σσ A

The Hammett relationship

Systematic structural variation

Crossover experiments

Labelling experiments reveal the fate of individual atoms