Total Synthesis of (±)-Streptonigrin: De Novo Construction of a Pentasubstituted Pyridine using Ring-Closing Metathesis

Total Synthesis of (±)-Streptonigrin: De Novo Construction of a Pentasubstituted Pyridine using Ring-Closing Metathesis

Timothy J. Donohoe, Christopher R. Jones, and Luiz C. A. Barbosa


Streptonigrin is a rather interesting natural product because of its axial chirality between rings C and D which was determined to be M. It contains a highly substituted quinoline dione system connected to a pentasubstituted pyridine ring. Only a handful of total syntheses are known to date and none of them, as it is true for this one, devises an enantioselective route towards the target compound. Nevertheless, compared to the previously described routes this one furnished (±)-Streptonigrin in a respectable yield of 11% over 14 steps (LLS).

The problem was reduced as shown below:

Scheme 1

The group planned an iterative route in which the main fragments were coupled using standard palladium chemistry. By using this approach three fragments are retrosynthetically received.

The synthesis of the green fragment commenced with benzaldehyde 1 which was nitrated ipso with respect to the carbonyl and reduced to give aniline 2. Acylation and subsequent cyclization was followed by chlorination to give quinoline 4. After some experimentation the group found stannane 5 to be the most reliable intermediate for the crucial C-C-bond forming step. The resulting stannane was used without further purification.

 Scheme 2


Next the orange fragment was synthesized starting from ethyl glyoxalate 6. Oxime formation was followed by regioselective crotylated to give methoxyamino ester 7. Amidation with phthalimide A after acid chloride formation gave amide 8. RCM employing Hoveyda-Grubbs II worked uneventfully to give pyridone 9. The presence of benzoquinone was necessary to prevent isomerization of the double bond by quenching the Ru-H species formed in situ. After elimination of methanol and triflate formation the resulting pyridine was brominated with NBS to give 11.

 Scheme 3

The last fragment was completed within 3 steps. Bromination of phenol 12 with NBS was followed by benzylation and boronate formation to give 14.

 Scheme 4


Fragments 5 and 11 were then coupled under old school conditions using tetrakis to give 15 which was reacted with 14 to give 16 again in the presence of tetrakis. Oxidation of the quinoline fragment then gave quinoline dione 17 in very good yield.

 Scheme 5


All previous syntheses relied on the endgame of the Weinreb paper published in 1980 going on from intermediate 17. Nevertheless the Donohoe group decided to construct their own endgame.

 Scheme 6


Bromination of 17 produced a dibrominated product 18 which was directly reacted with sodium azide to give compound 19 which in turn was converted into pyridine 20 through hydrogenation with palladium on charcoal. In the latter step the azide was reduced to the amine, the bromine reductively removed, and the benzyl protecting group cleaved off. After saponification racemic Streptonigrin was obtained.

Very nice stuff and no polyketides anywhere.

THX to Bobby for proofreading.

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