Total Synthesis of Jiadifenolide

Total Synthesis of Jiadifenolide

Ian Paterson,* Mengyang Xuan, and Stephen M. Dalby*

DOI: http://dx.doi.org/10.1002/anie.201404224

As promised months ago here is the write-up of the second Jiadifenolide synthesis published this year. The main features of this synthesis from the Paterson group consist of a boron-aldol reaction and a neat SmI2 mediated radical cyclization. Though a racemic synthesis (like in the good old days) this route provides an efficient and highly selective access to Jiadifenolide.

The synthesis started with Luche reduction of cyclopentenone 1 which in turn was treated with mCPBA followed by TBS protection to give oxirane 2. In the presence of BF3 the epoxide rearranged to the corresponding ketone with excellent diastereocontrol. HWE reaction, LiAlH4 reduction and acylation then delivered allyl acetate 5. Silylketene acetal formation and subsequent heating in benzene resulted in Ireland-Claisen rearrangement to yield after another LiAlH4 reduction alcohol 6 in moderate yield. Hydrolysis of the TBS ether and global Swern oxidation finally furnished 7.

Scheme 1

 scheme_1_17102014

The remaining carbon skeleton was attached utilizing the boron enolate of lactone 8 followed by TES protection. Upon treatment with samarium diiodide the last quaternary center was formed giving tricycle 10 in good yield. A possible transition state is depicted below. Deprotection and PCC oxidation then delivered ketone 11. The hydroxyl group at the ring junction was then introduced by a Rubottom oxidation, the ketone subsequently reduced and protected. All that remained was dihydroxylation of the double bond, oxidation to the pyruvate and deprotection of the TES group to complete the synthesis.

 

Scheme 2

 scheme_2_17102014

An Enantiospecific Synthesis of Jiadifenolide

An Enantiospecific Synthesis of Jiadifenolide

David A. Siler, Jeffrey D. Mighion, and Erik J. Sorensen

DOI: http://dx.doi.org/10.1002/anie.201402335

jiadifenolide

In a recent communication the Sorensen group disclosed a short synthesis of Jiadifenolide isolated by the Fukuyama group in 2009. Only one synthesis has been reported to date from the Theodorakis group. The latest disclosure comprises just one major scheme proving the efficiency of this approach. As a last introductory remark it should be noted that Jiadifenolide exhibits some promising neurotrophic activity potentiating neurite outgrowth in rats.

 

As can be found in an older JOC paper pulegone 1 can be converted into ketone 2 in three steps consisting of bromination, Favorskii rearrangement and subsequent ozonolysis. A two-step Robinson annulation then provided Hajos-Parrish ketone 3 in good yield. One-pot double methylation of the a-position of the ketone furnished 4 with the olefin shifted into the five-membered ring. Protection of the ketone with ethylene glycol and DIBAL reduction to alcohol 5 set the stage for an interesting one-carbon homologation to nitrile 6. A mechanistic rationale will be discussed later.

Scheme 1

scheme_1_27042014

With this nitrile in hand an intramolecular Ritter reaction was utilized to produce tricyclic lactone 7. Condensation with hydroxylamine set the stage for a directed C-H oxidation developed by the Sanford group functionalizing selectively only one of the neighboring methyl groups. Although in low yield this transformation allowed a straightforward access to the core structure of Jiadifenolide. Reductive cleavage of the oxime to ketone 9 was followed by vinyl triflate formation and methoxycarbonylation to ester 10. Lactone formation and Scheffer-Weitz epoxidation then provided epoxide 11.

 Scheme 2

scheme_2_27042014

 

To conclude α-halogenation was directly followed by an interesting DMDO mediated oxidation and hydrolysis of the epoxide to finally yield Jiadifenolide in moderate yield over 3 steps.

Scheme 3

 scheme_3_27042014

A mechanistic proposal can be found in the JOC paper cited below. After oxidation to the aldehyde the carbonyl is attacked by TosMIC to form an oxazoline ring. This undergoes an inter- or intramolecular proton shift giving rise to the stabilized oxazoline with the negative charge located next to the tosylgroup. Ring opening then forms an intermediate vinyl formamide which presumably is attacked by methanol to furnish after elimination of methylformate and tolylsulfinic acid the desired nitrile in fairly good yield.

 Scheme 4

scheme_4_27042014

The problem set will be provided within this week and will also discuss the recent total synthesis from Paterson et al.

New section

To all of you who like to work yourself through a total synthesis rather then just reading the write-up I created a new section which contains a problem of the total synthesis as well as the solution. I will add bit by bit all the older syntheses as well so you can learn even more from this page. I hope you enjoy it and leave me a comment about your thoughts. Stay tuned…