Tethered functional groups can reach only one side of the molecule

The proverbial donkey starved to death in the field with two heaps of hay because it could not decide which one to go for first. If the donkey had been tethered to a stake near one heap it would have been able to reach that heap alone and it could have feasted happily. This principle can be applied to molecules. If a nucleophile is joined to the group, it is to attack by a short chain of covalent bonds, it may be able to reach only one side.

: iodolactonization. To remind you, iodolactonization involves treating a non-conjugated unsaturated acid with iodine in aqueous NaHCO₃. The product is an iodolactone.

The cyclization reaction is a typical two-stage electrophilic addition to an alkene with attack by the nucleophile at the more substituted end of the intermediate iodonium ion. The ring opening is a stereospecific SN2 and the stereochemistry of the alkene will be reproduced in the product.

The starting acid contains an E alkene, giving a trans iodonium ion. Inversion occurs in the attack of the carboxylate anion on the iodonium ion and we have shown this by bringing the nucleophile in at 180° to the leaving group, with both bonds in the plane of the paper. A single diastereoisomer of the iodolactone results from a stereospecific reaction. Things get more interesting again when the starting material is cyclic. The iodolactonization below gives only one diastereoisomer.

The relationship between the two stereogenic centres on the old alkene is not an issue— inversion during opening of the iodonium ion means that the I and the O must lie trans. But during the cyclization the carboxylic acid can attack only the nearer side of what was the double bond—in other words the bridge in black has no choice but to be cis across the red six membered ring. The reason for this is that, while formation of the iodonium ion is reversible, only the iodonium ion with the I and CO₂H groups trans to each other can cyclize. Tethering the nucleophilic CO₂H group to the alkene dictates the stereochemistry of the product.

This reaction can be used to solve a general problem in the synthesis of steroids: the construction of a diketone with trans-fused 6,5 rings and a quaternary carbon atom at the ring junction. One solution to this problem uses the lactone just made. The lactone makes a good temporary tether because it can be hydrolysed or reduced to break the ring at the C–O bond and reveal new stereogenic centres on the old structure. In this sequence the lactone ring controls all the subsequent stereochemistry of the molecule in two ways: it fixes the conformation rigidly in one chair form—hence forcing the iodide to be axial—and it blocks one face of the ring. From the lactone above, an alkene is introduced by E2 reaction on the iodide. This stereospecific reaction requires an anti-periplanar H atom so it has to take the only available neighbouring axial hydrogen atom, shown in green. The brown and orange hydrogens are not anti-periplanar and anyway elimination with the brown one would produce a bridgehead alkene.

The resulting alkene has its top face blocked by the lactone bridge so epoxidation occurs entirely from the bottom face.

Now the epoxide is opened with HBr. Only the trans diaxial opening product is possible, so the bromide ion is forced to attack from the top face.

Do you see how the functional groups are being pushed round the ring? This process is extended further by a second elimination, after protection, which again seeks out the only neighbouring axial hydrogen.

The protecting silyl group is removed in acid, ready for the next important reaction: a Michael addition requiring the alcohol to be oxidized to a ketone. Allylic (or benzylic) alco hols can be oxidized by manganese dioxide, and with three atoms now trigonal the ring becomes even further flattened. But-3-enyl Grignard reagent is added with Cu(I) catalysis to make sure that conjugate addition occurs. Conjugate addition normally gives the axial pro duct, as we saw earlier, and fortunately this is not the direction blocked by the bridge.

The bridge has now done its work and is removed by zinc metal reduction. This reaction removes leaving groups on the atoms next to carbonyl groups. In this case it is the axial carboxylate that is driven out by the zinc. The released carboxyl group is esterified.

The last stages are shown below. The ketone is protected, and the alkene oxidized to a car bonyl group by ozonolysis. The diester can be cyclized by a Claisen ester condensation The stereogenic centres in the ring are not affected by any of these reactions so a trans ring junction must result from this reaction. After ester hydrolysis, HCl decarboxylates the product and removes the protecting group.

It is not easy to set up a trans-fused 5,6 system. In this sequence the molecule is effectively tricked into making the trans ring junction by the work done with the lactone tether.

اخر الاخبار

اخبار العتبة العباسية المقدسة

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