cis-Fused rings

Almost any cis-fused junction from 3,3 upwards can be made. Even bicyclo [1.1.0] butane exists, although it is not very stable. cis-Fused 4,5, 4,6, and 5,5 systems are common and are much more stable than their trans isomers. Any method of making such bicyclic compounds will therefore automatically form this stereochemistry. Consider this hydrogenation:

The two new hydrogen atoms (shown in black) must, of course, add cis to one another: this is a consequence of the stereospecificity of the reaction. What is interesting is that they have also added cis to the green hydrogen atom that was already there. This approach does give the more stable cis ring junction but the stereochemistry really arises because the other ring hinders approach to the other face of the alkene. Think of it in the way illustrated below: the alkene has two different faces. On one side there is the green hydrogen atom, and on the other the orange parts of the second ring. To get hydrogenated, the alkene must lie more or less flat on the catalyst surface and that is easier on the top face as drawn.

You can think of cis-fused rings as looking like a butterfly or an open book. The key to stereo selectivity in their reactions is that everything happens on the outside (on the cover of the book—the exo face). Nucleophiles add to carbonyl groups from the outside, enolates react with alkyl halides or Michael acceptors on the outside, and alkenes react with peroxyacids on the outside. Notice that this means the same side as the substituents at the ring junction. The rings are folded away from these ring-junction substituents, which that are also on the outside.

A real example comes in the acylation of the enolate from the keto-acetal below. The molecule is folded downwards and the enolate is essentially planar, so the outside face is the top face as drawn. Addition presumably occurs entirely from the outside, although the final stereochemistry of the product is controlled thermodynamically because of reversible enolization of the product, allowing the black ester group to adopt the less hindered outside position.

Reduction of the ketone product also occurs exclusively from the outside and this has the surprising effect of pushing the new OH group into the inside position. Attack from the inside is very hindered in this molecule because one of the acetal oxygen atoms is right on the flight path.

The important metabolite biotin has a cis bicyclic structure in which an alkyl chain lies on the more hindered face of the molecule, and any successful synthesis has to address this particular problem .but the direct alkylation of the sulfide below is no good because the new alkyl group will go exo. Instead, the sulfide was oxidized to a sulfoxide from the exo face, giving an 8:1 ratio of exo:endo sulfoxides. Alkylation of the cyclic sulfoxide results in trans stereochemistry between the new alkyl group and the sulfoxide oxygen atom, forcing formation of the desired (endo) product. The synthesis is diastereoselective—but not enantioselective since there is no way of distinguishing the left and right sides of the symmetrical sulfoxide.

A simple example of epoxidation occurs with a cyclobutene fused to a five-membered ring. This is a very rigid system and attack occurs exclusively from the outside to give a single epoxide in good yield.

Epoxidation is stereospecific and cis—both new C–O bonds have to be on the same face of the old alkene. But Chapter 19 introduced you to several electrophilic additions to alkenes that were stereospecific and trans, many of them proceeding through a bromonium ion. If stereospecific trans addition occurs on a cis-fused bicyclic alkene, the electrophile will fi rst add to the outside of the molecule, meaning the nucleophile will then be forced to add from the inside. A telling example occurs when the 5,4 fused unsaturated ketone below is treated with N-bromoacetamide in water.

The bromonium ion is formed on the outside of the rigid structure and the water is then forced to add from the inside to get trans addition. As well as exhibiting stereospecificity (trans addition) and stereoselectivity (bromonium forms on outside), this reaction also exhibits regio selectivity in the attack of water on the bromonium ion. Water must come from inside, and it attacks the less hindered end of the bromonium ion.

After protection of the OH group, treatment with base closes a three-membered ring to give a remarkably strained molecule. The ketone forms an enolate and the enolate attacks the alkyl bromide intramolecularly to close the third ring. This enolate is in just the right position to attack the C–Br bond from the back, precisely because of the folding of the molecule.

Inside/outside selectivity may allow the distinction between two otherwise similar functional groups. The cis-fused bicyclic diester below may look at fi rst rather symmetrical but ester hydrolysis leaves one of the two esters alone while the other is converted to an acid.

Only the outside ester—on the same side as the ring junction hydrogens—is hydrolysed. In the mechanism for ester hydrolysis, the rate-determining step is the attack by the hydroxide ion so the functional group increases in size in the rate-determining step. This will be much easier for the ester in the outside than for the one inside the half-open book.

The end result is again that the larger of the two groups is on the inside! There are other ways to do this too. If we alkylate the enolate of a bicyclic lactone, the alkyl group (black) goes on the outside as expected. But what will happen if we repeat the alkylation with a different alkyl group? The new enolate will be flat and the stereochemistry at the enolate carbon will be lost. When the new alkyl halide comes in, it will approach from the outside (green) and push the alkyl group already there into the inside.

Should you wish to reverse the positions of the two groups, you simply add them in the reverse order. Whichever group is added first finishes on the inside; the other finishes on the outside.

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تحيي ذكرى شهادة الإمام السجاد (عليه السلام)

العتبة العباسية المقدسة تنشر لافتات خاصة بذكرى شهادة الإمام زين العابدين (عليه السلام)

قسم شؤون المعارف ينظّم دورة مختصة بتحقيق المخطوطات لطلبة الحوزة العلمية النجف الأشرف

قسم التطوير ينظم دورات وورشا تدريبية لطلبة أكاديمية التطوير الإداري

المزيد

الآخبار الصحية

دراسة علمية تكشف مفاجأة حول الأسباب الحقيقية للسمنة

دراسة: الأطباء يتجاهلون "سببا شائعا" لارتفاع ضغط الدم

نظامك الغذائي غني بالبروتين؟.. احذر هذه الآثار الجانبية

لا تتجاهلها.. أعراض تنذرك بأنك مهدد بالإصابة بالسكري

المزيد

الآخبار التكنلوجية

ISOFIX: معيار الأمان الذهبي لمقاعد الأطفال في السيارات

هل المحرك الأكبر دائمًا الأفضل للسيارة؟

اختبارات ناجحة لمحرك "VK-800" الروسي وتطويره لطائرة بايكال الخفيفة

رئيس إنفيديا: الذكاء الاصطناعي الصيني "محفز للتقدم العالمي"

المزيد

مواضيع ذات صلة

Reactions of cis-decalins

Reactions that break open bridged molecules can preserve stereochemistry

Bridged bicyclic rings

Regard five-membered rings with two or more sp3 carbons as flat

Five-membered ketones are flexible

Only axial attack is possible with cyclohexenes

Axial or equatorial attack is possible on a cyclohexanone

Diastereotopic protons in acyclic compounds

Spotting diastereotopic protons in the NMR spectrum

How to tell if protons are homotopic, enantiotopic, or diastereotopic

The size of the geminal coupling constant

Geminal (2J) coupling