Asymmetric dihydroxylation

This alternative asymmetric oxidation really is probably the best asymmetric reaction of all. It is an asymmetric version of the syn dihydroxylation of alkenes by osmium tetroxide. Here is an example—although the concept is quite simple, the recipe for the reactions is complicated so we need to approach it step by step.

The active reagent is based on osmium (VIII) and is used in just catalytic amounts. This means that there has to be a stoichiometric quantity of another oxidant to reoxidize the osmium after each catalytic cycle—K₃Fe (CN)₆ is most commonly used. Because OsO₄ is vola tile and toxic, the osmium is usually added as K2OsO₂(OH)₄, which forms OsO₄ in the reaction mixture. The ‘other additives’ include K₂CO₃ and methanesulfonamide (MeSO₂NH₂), which increases the rate of the reaction by regenerating the catalyst at the end of each catalytic cycle. Now for the chiral ligand. Tertiary amines are good ligands for osmium and increase the rate of dihydroxylations: one of the reasons that NMO is used in the racemic version of the reaction is that the by-product, N-methylmorpholine, accelerates the reaction. Sharpless chose some available chiral tertiary amines as ligands, and it turned out that the best ones are based on the alkaloids dihydroquinidine and dihydroquinine, whose structures are shown below. They coordinate to the osmium through the green nitrogen atom.

The alkaloids (usually abbreviated to DHQD and DHQ, respectively) must be attached to an aromatic group Ar, the choice of which varies according to the substrate. The most generally applicable ligands are these two phthalazines in which each aromatic group Ar carries two alkaloid ligands, either DHQ or DHQD.

Dihydroquinine and dihydroquinidine are not enantiomeric (although the chiral centres ringed in orange are of opposite configuration in each of the pairs, those ringed in brown remain the same in both), but they act on the dihydroxylation as though they were. Here, after all that introduction, is a real example, and probably the most remarkable of any in this chapter. trans-Stilbene dihydroxylates more selectively than any other alkene, and this particular example is one of the most enantioselective catalytic reactions ever invented.

We can sum up the usual selectivity of the AD reaction with the diagram shown below. With the substrate arranged as shown, with the largest (RL) and next largest (RM) groups bot tom left and top right, respectively, DHQD-based ligands will direct OsO₄ to dihydroxylate from the top face of the alkene and DHQ-based ligands the bottom face.

The reason for this must come from the way in which the substrate interacts with the osmium–ligand complex. However, the detailed mechanism of the asymmetric dihydroxylation is still far from clear-cut. What is known is that the ligand forms some sort of ‘chiral pocket’, like an enzyme active site, with the osmium sitting at the bottom of it. Alkenes can only approach the osmium if they are correctly aligned in the chiral pocket, and steric hindrance forces the alignment shown in the scheme above. The analogy with an enzyme active

site goes even further, since it appears that part of the pocket is ‘attractive’ to aromatic or strongly hydrophobic groups. This part appears to accommodate RL, part of the reason why the selectivity in the dihydroxylation of trans-stilbene is so high. The asymmetric dihydroxylation is much less fussy about the alkenes it will oxidize than Sharpless’ asymmetric epoxidation. Osmium tetroxide itself is a remarkable reagent, since it oxidizes more or less any sort of alkene, electron-rich or electron-poor, and the same is true of the asymmetric dihydroxylation reagent. The following example illustrates both this and a synthetic use for the diol product.

The chemists at Lilly in Spain who made this diol wanted to turn it into the protected amino acid shown after the dotted arrow as part of the synthesis of an anti-HIV compound. The ease with which diols can be made means that there are a number of reliable methods for trans forming them into derivatives which undergo the sort of substitution needed. The one used here was to make the diol into a cyclic sulfate using sulfuryl chloride, SO₂Cl₂. Cyclic sulfates behave like epoxides, and this one opens easily with azide at the more reactive position adjacent to the carbonyl group. Hydrolysis of the remaining sulfate ester, hydrogenation of the azide to the amine, and protection with Boc gave the target compound.

An alternative way of achieving the same transformation to the cyclic sulfate is to use thionyl chloride (SOCl₂) to give a sulfite, followed by ruthenium-catalysed oxidation to the sulfate. Diols can even be converted with retention of stereochemistry directly to epoxides. Treatment of a diol with trimethyl orthoacetate and acetyl bromide gives firstly the cyclic orthoester, which opens with bromide to a regioisomeric mixture of the bromoacetates. The regiochemistry is irrelevant because treatment with base hydrolyses the ester and closes both of the resulting bromoalcohols to the same epoxide.

It’s no surprise that when chemists from Bristol Myers Squibb needed the epoxide below, they turned to asymmetric dihydroxylation rather than either of the epoxidation methods we have shown you. Sharpless epoxidation works only with allylic alcohols, and Jacobsen epoxidation performs poorly here, giving only 70–74% ee (mainly because the substrate is not a cis alkene). However, asymmetric dihydroxylation saves the day with 98% ee and around 90% yield, and a variant of the reaction we have just shown you gives the epoxide, also in 90% yield—well worth the extra step.

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قسم بين الحرمين الشريفين ينفذ حملات مكثفة لتنظيف الشوارع المحيطة بالعتبة العباسية المقدسة

عبر مفارزه الميدانية.. مستشفى الكفيل يقدّم خدماته الطبّية والإسعافات الأولية لزائري الأربعين

بحضور متوليها الشرعي.. العتبة العباسية المقدسة تقيم مجلس عزاء بذكرى شهادة الإمام الرضا (عليه السلام)

الأمين العام للعتبة العباسية المقدسة يتفقد خدمات قسم المضيف لزائري الأربعين

المزيد

الآخبار الصحية

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

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

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

المزيد

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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

Organocatalysis

Catalytic asymmetric reduction of ketones

Chiral reagents

Enantiomeric excess

Alkylation of enolates

Resolution can be used to separate enantiomers

Nature is asymmetric