The structure and synthesis of penaresidin

Our last example is a natural product called penaresidin A. It was isolated from a Japanese sponge in 1991, and is now known to have the structure shown below. When it was first dis covered, it proved difficult to find out the stereochemistry and, in particular, the relative stereochemistry between the two remotely related groups of chiral centres was not initially known.

What is sure is the relative stereochemistry around the four-membered azetidine ring:

What is also certain is that natural penarisi din A is enantiomerically pure. What Mori and his co-workers set out to do was to make, using unambiguous stereoselective methods, the possible diastereoisomers of penaresidin A to dis cover which was the same as the natural product. The challenge of constructing the three chiral centres at the left-hand end of the molecule can be solved by taking just one of them from a natural source—in this case the amino acid L-serine. The amino group of serine was protected as the Boc derivative, and the hydroxyl and amino groups condensed with the dimethoxyacetal of acetone to form a five-membered ring. Now the free ester could be reduced with LiBH₄ and oxidized to the aldehyde by the Swern method.

How will this aldehyde react with nucleophiles such as lithiated alkynes? Consider a Felkin Anh transition state: again, we know that the substituted nitrogen atom, being electronegative and bulky, will lie perpendicular to the carbonyl group in the most reactive conformation. Looking at the two alternatives shown below, it’s easy to see that the one on the right allows unhindered attack, and in the synthesis an alkynyl anion was used to make the product shown.

The alkyne was then reduced to an E alkene by a dissolving metal reduction, a step which also hydrolysed the five-membered heterocycle. The next step, an epoxidation, is needed to install the third of the chiral centres at the left-hand end of penarisidine. However, hydrogen bond directed epoxidation of this allylic alcohol would be expected to give the syn product shown, which has the wrong relative stereochemistry between the brown OH group and the epoxide.

The solution is to use a large blocking group to prevent this brown OH group hydrogen bonding to the m-CPBA. The t-butyldimethylsilyl group (TBDMS) is the best, and when both OH groups are protected, some of the right diastereoisomer is formed by attack of m-CPBA on the top face of the alkene. Reduction of the epoxide with DIBAL (i-Bu2AlH) now gives the correct diastereoisomer.

To close the ring, the green hydroxyl group was converted to a good leaving group, mesylate (MeSO₃⁻), ready for an attack by the nitrogen with inversion on treatment with base. Make sure you can see how inversion at this centre gives the stereochemistry shown! The chemists knew at this stage they were on the right track with regard to relative stereochemistry because the NMR spectrum of structures containing any long alkyl chain R were very similar to that of the natural compound.

اخر الاخبار

اخبار العتبة العباسية المقدسة

بيان لمكتب المرجعية العليا حول نشر صور السيد السيستاني في الأماكن العامة

متحف الكفيل: إنجاز المرحلة الرابعة من مشروع متحف العتبة العسكرية المقدسة

تضمن عرضًا مسرحيًّا.. شعبةُ الخطابة النسويّة تقيم مجلس عزاء بذكرى شهادة الإمام الحسن (عليه السّلام)

الأمين العام للعتبة العبّاسية المقدّسة يتفقد مجموعة مواكب أمّ البنين (عليها السلام) لخدمة الزائرين

المزيد

الآخبار الصحية

تسارع الشيخوخة.. متى يبدأ وأي الأعضاء أكثر تأثرا؟

9 مسببات شائعة للالتهاب المزمن قد تهدد صحتك

باحثون يطورون علاجا لهشاشة العظام.. النتائج مذهلة

تحمي من أمراض عديدة.. 6 فوائد لتناول البطاطا الحلوة

المزيد

الآخبار التكنلوجية

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

المعلمون في خطر.. خاصية جديدة في "تشات جي بي تي" تشرح الدروس

بشرى لمرضى الشلل.. شريحة في الدماغ قد تتيح التحكم بالأدوات

مدينة غارقة.. هل يخفي قاع البحر الكاريبي سرّ حضارة مفقودة؟

المزيد

مواضيع ذات صلة

The Hammett relationship

Systematic structural variation

Crossover experiments

Labelling experiments reveal the fate of individual atoms

Be sure of the structure of the product

Variation in the structure of the aldehyde

formation of an ester intermediate

formation of an intermediate dimeric adduct

Be sure of the structure of the product

Variation in the structure of the aldehyde

Proposed mechanism C: formation of an ester intermediate

Proposed mechanism B: formation of an intermediate dimeric adduct