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Organocatalytic Desymmetrization and C-H Bond Activation in Complex Natural Product Synthesis

Final Report Summary - ORDECHASYN (Organocatalytic Desymmetrization and C-H Bond Activation in Complex Natural Product Synthesis)


1.1 Retrosynthetic analysis
Our retrosynthetic analysis resulted in a planned late-stage synthesis of the 6-membered δ-lactone. The pentacyclic core of our natural product target would be synthesized from a vinyl iodide via a palladium coupling as a first key step, and an intramolecular Michael addition of an amide as the second key step allowing for the construction of the tricyclic ketoamide. The key bicyclic intermediate would be simply prepared by a condensation reaction between a spirocyclic aminoenone and an appropriately functionalised carboxylic acid. This acid would be afforded from an optically active iodoalcohol via a Johnson Claisen rearrangement and homologation. The spirocyclic aminoenone would be synthesized from a heavily substituted optically active pyrrolidine via a 1,3-dipolar cycloaddition of its N-oxide analogue with a protected propalgyl alcohol. A subsequent N-O bond cleavage/Horner-Wadsworth-Emmons reaction cascade would efficiently give rise to the synthetically challenging spirocyclic aminoeneone.

1.2 Preparation of model left-hand side spirocyclic aminoenone
As mentioned above, the key reactions in our strategy for the total synthesis of our hexacyclic alkaloid target consisted of an intramolecular Michael addition for the construction of the tricyclic ketoamide and the subsequent cyclization again for the formation of the core pentacyclic system. Therefore, the spirocyclic aminoenone was an essential building block in our synthesis. Aiming to develop a facile route for the preparation of the nitrogen containing spirocycle, we decided to carry out a model study in order to discover the appropriate reaction conditions necessary for this transformation. After various attempts for its synthesis, the model spirocyclic aminoenone was prepared. First of all, proline methyl ester was oxidized by Davis oxaziridine to a nitrone intermediate, and a subsequent 1,3-dipolar cycloaddition between the nitrone and protected propargyl alcohol afforded the cycloadduct regioselectively and in good yield. This bicycle was converted to ketophosphonate quantitatively, which was then treated with LiHMDS and sodium naphthalenide at low temperature to efficiently give rise to the construction of the desired model spirocyclic aminoenone in one step via the designed N-O bond cleavage/Horner-Wadsworth-Emmons reaction cascade.

1.3 Attempts for the construction of the tricyclic core via a Michael addition strategy
A large number of attempts of the Michael addition with various substrates for the formation of the tricyclic core of our natural product target was carried out, and the desired Michael adducts were eventually provided from an alpha cyanoamide and alpha nitroamide in excellent yield respectively. Using an enamine was attractive for us because an amide reduction would not be required in the late stage of the synthesis. However, the enamine was not formed unfortunately by any condition which we attempted. Direct Michael addition of a simple amide did not work either, therefore we decided to attach an electron-withdrawing activating group (ie an ester, bromide, nitro group and nitrile) in order to promote the desired Michael addition. We chose a malonoamate at first, but the desired Michael addition was unsuccessful under any basic conditions, contrary to our expectation. On the other hand, the alpha nitroamide worked very well and afforded the desired Michael adduct in excellent yield. However, the substrate immediately before this cyclization required to be prepared from a bromoamide using sodium nitrite, because the direct amide coupling between spirocyclic amineand alpha nitroacid did not proceed. Incidentally the attempted radical cyclization using this bromoamide was also unsuccessful. Therefore, another substrate was required for this cyclization. To our delight, the performance of this cyanoamide efficiently afforded the cyclized product. In conclusion, the coupling reaction between and alpha cyanoacid proceeded smoothly and the subsequent Michael addition of afforded the cyclized product in excellent yield.

1.4 Preparation of right-hand side carboxyl acid and the Michael addition with model compound
Iodocyclopentenone was reduced to iodoallylic alcohol via Corey-Bakshi-Shibata (CBS) asymmetric reduction in excellent yield with high enantiomeric excess. The optically pure which was afforded after two recrystallizations was treated with triethyl orthoacetate in slightly acidic conditions under reflux, and the designed Johnson-Claisen rearrangement gave the desired iodoester in good yield. Subsequent reduction of ester resulted in primary alcohol which was then protected to tosylate, alkylated with cyanoacetate to afford cyanoester as a diastereomeric mixture in good overall yield from iodoalcohol. Then the desired carboxylic acid was smoothly prepared by hydrolysis of cyanoester with aqueous KOH. This cyanoacid was transformed to cyanoamide by a coupling reaction with the model spirocyclic aminoenone, which was then treated with K2CO3 in acetonitrile under thermal conditions, affording the desired Michael adduct in high yield.

1.5 Preparation of real left-hand side and its Michael addition.
Given the successful result in the model study for intramolecular Michael addition, we moved to the real system. The concise synthesis of a Michael addition precursor has been successfully performed starting from (R)-Roche ester in 11 steps. Firstly, the hydroxy group on the (R)-Roche ester was tosylated and the ester was reduced to the alcohol using DIBAL, which was then reoxidized to aldehyde. Subsequently, the unstable aldehyde was transformed to the oxazoline straightway with isocyanoacetate and catalyst, using a transformation developed previously in the Dixon group. Oxazoline was subsequently hydrolyzed using dry HCl to give aminoalcohol, which was cyclized to afford the highly functionalized pyrrolidine after treatment with base. The pyrrolidine was transformed to the bicyclic ketophosphonate in four steps, including the aforementioned 1,3-dipolar cycloaddition with propargyl alcohol. The desired spirocyclic aminoenone was successfully synthesized in one step from the ketophosphonate via treatment with LiHMDS and sodium naphthalenide successfully. With the real spirocyclic aminoenone in hand, we moved to the proposed coupling reaction and the key intramolecular Michael addition. Pleasingly, both steps proceeded relatively smoothly, thus, affording the tricyclic core of as single diastereomer in excellent overall yield from spirocyclic aminoenone.

1.6 Summary of the progress on the project and future plan
The tricyclic core of our target alkaloid has been synthesized efficiently from known aldehyde in 10 steps. The spirocyclic aminoenone as the key left intermediate was obtained concisely through a catalytic asymmetric aldol reaction, which has been developed in the Dixon group, and N-O bond cleavage/Horner-Wadsworth-Emmons reaction cascade to afford spirocycle. Cyanoacid was afforded from optically pure iodoalcohol concisely through a Johnson Claisen rearrangement and subsequent C2 homologation with malononitrile. The coupling reaction between and proceeded smoothly, and most importantly, the key intramolecular Michael addition afforded the tricyclic core successfully in excellent yield. At this stage, we have to move to the next crucial C-C bond formation, which will afford the seven membered ring and pentacyclic skeleton of the target natural product at the same time. Various attempts on this, and other key C-C bond forming reactions are now in progress.