name and it’s molecular

structure is really

interesting. Let me

introduce you spiro-

noraristeromycin:

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.

Ortho strategy has been chosen to construct such trisubstituted pyridines. 4-substituted pyridine seems to be a good starting material in such strategy. Let’s see strategic disconnection in retrosynthetic plan:

Total synthesis should be quick.

As you can see it starts with 4-cyanopyridine 2. First and second step are of course halogenations steps which go through ortho-lithiations. In first step bromine is introduced into molecule (through nucleophilic attack on CBr₄) and in second step – iodine. LTMP is lithium 2,2,6,6-tetramethylpiperide, a strong and sterically hindered base:

Next steps allow to construct five-membered ring:

Conversion 5 to unsaturated ester 6 is Heck reaction. Unsaturated ester 6 can be then hydrogenated on Adam’s catalyst to 7. 7 in turn is cyclized to 8 under basic conditions (enolisation and nucleophilic attack on CN group) and subsequent hydrolysis.

From ketone 8 both louisianins can be prepared under Stille coupling reaction conditions.

The only difference between those two reactions is adition of base (DBU = 1,8-diazabicycloundec-7-ene) which causes isomerisation to more stable (trans and disubstituted) alkene.

That’s all. Happy New Year and see:

Chang, C. -Y. et al., Tetrahedron (2009), doi:10.1016/j.tet.2008.11.075