Spiro-noraristeromycin is an analog of naturally occuring aristeromycin. That one was isolated from Streptomyces citricolor bacteria and exhibits antiviral activity.

Let’s see how spiro-noraristeromycin has been synthesised.

Core compound 5 can be synthesised by alkylation of cyclopentadiene anion with dichloride 3 wich in turn can be obtained from commercially avaiable amine 2.

Diene 5 is used in hetero-Diels-Alder reaction where acyl nitroso compound 7 is a dienophile. Compound 7 is unstable but it can be prepared in situ by oxidation of Boc-protected hydroxylamine 6. Such an oxidation of hydroxamic acids (Boc-NHOH has hydroxamic acid motif) is well-known reaction. Anyway – hetero-Diels-Alder reaction leads to adduct 8.

Now, bicyclic system can be cleavaged by molybdenum hexacarbonyl in the presence of reducing agent – sodium borohydride. This allows to get syn-amino alcohol 9 in 90% yield. Hydroxyl group of compund 9 is then protected as acetate ester and in next step Boc group is removed under standard conditions (TFA) which leads to compound 11.

Free NH2 group of amine 11 can be now utilized in aromatic nucleophilic substitution reaction with pyrimidine 12. The yield is high and only one chlorine atom is substituted by an amine. Nitro group of compound 13 is reduced to amine 14 in the presence of indium metal in acidic environment. Now, synthesis of purine can be acomplished. Reaction with ethyl orthoformate and camphorosulphonic acid leads to compound 15.

In next step, UpJohn dihydroxylation is undergone and diol 16 is formed. Diol 16 reacts with ammonia in sealed tube and chlorine atom is substituted and also – acetate hydrolyses. In this way triol 17 is formed. Hydrogenolysis of compound 17 leads to spiro-noraristeromycin 1.

For more – please see here.

Radulanin H exhibits inhibitory activity aganist cyclooxygenase. It has no stereocentres but contains seven-membered heterocyclic ring with trisubstituted double bond and highly-substituted aromatic ring. Concise synthesis of this aromatic ring is the challange.

So how this synthesis was planned?

It’s not a surprise that ring-closing metathesis was used in contruction of heterocyclic ring. This simplification reveals compound A which can be prepared from phenol B by introduction of two allyl groups in Claisen and Williamson reactions. Now, question arises – in which way aromatic ring B (with all substituents on their places) can be synthesised? Well, for such complex system authors of paper have chosen synthesis from acyclic substrates:

It’s not very obvious how this can be done by using ethyl acetoacetate and benzyl bromide – so let’s see how this synthesis has been acomplished.

The answer is – dianions! They acted on ethyl acetoacetate 2 with a little bit more than 1 eq NaH and they got of course anion 2a. For this moment it sounds like simple synthesis from acetoacetates. But they didn’t add to reaction mixture  electrophile but another equivalent of strong base instead! In this way they got dianion 2b. When in next step they added benzyl bromide more reactive anion reacted with electrophile and ketoester 3 was formed. That’s not standard procedure of alkylate ethyl acetoacetate Ketoester 3 was in next step protected as acetal 4. Yield after two steps is good.

Well, next step involves also dianion strategy but this time dianion 2b is acylated with previously formed ketoester 4 (that’s why carbonyl group in 3 had to be protected) and we have compound 5.

Ok, now 5 should make some aromatic ring It can be done by deprotection of acetal 5 to polycarbonyl compound 5a which forms 5c by some aldol-like intramolecular reaction. Now – by using weak base sodium perchlorate – 5c is converted to 6. Yield is only 48% but in one step you get highly-substituted aromatic ring.

Now 6 is converted to its allyl ethers mixture 7a and 7b. These compounds aren’t isolated and in high temperature, under Claisen rearrangement reaction conditions, allylbenzene 8 is formed.

Next step is second Williamson reaction and in this way allyl ether 9 is formed. Regioselectivity of this reaction is quite obvious because other OH group between two substituent is of course less reactive. Cyclisation of 9 to 10 probably is not very easy because paper’s authors used 20% mol Grubbs’ catalyst. It’s a quite big amount, but yield after two steps (RCM and deprotection step) was very good.

For more details see: M. Yoshida, K. Nakatani, K. Shishido, Tetrahedron, 2009, 65, 5702–5708.

For Polish version of this post please see here.

For  more see:

(-)-Adaline – J. Am. Chem. Soc., 2009, 3, 876-877.

iso-Duocarmycin SA and iso-Yatakemycin – J. Am. Chem. Soc., 2009, 3, 1187-1194.

(-)-Deoxoprosophylline – Tetrahedron: Asymmetry, 2009, 23, 2731-2734.

(-)-Cernuine and (+)-Cermezine – Tetrahedron, 2009, 8, 1607-1617.

This week following total syntheses have been published:

For fullpapers please see:

(-)-Penifulvin A – J. Am. Chem. Soc., 2009(2), 452-453.

Cucurbitoside A – Tetrahedron Lett., 2009(8), 939-942.

Kalasinamide, Geovanine and Marcanine A – Angew. Chem., 2009(5), 911-913.

Bottromycin A – Angew. Chem., 2009(5), 914-917.

For fullpapers see below, please:

(+)-Carissone – Org. Lett., 2009, 289-292.

(+)-Cassiol – Org. Lett., 2009, 293-295.

Brevetoxin A - Org. Lett., 2009, 489-492.

(+)-Monomorine – J. Org. Chem., 2009, 590-596.

Cyrmenin B₁ – J. Org. Chem., 2009, 844-849.

Halicylindramide A - J. Org. Chem., 2009, 906-909.