(-)-Teuvcidin

(-)-Teuvcidin

Organic Letters 2012, 14, 2886

X. Liu, C.-S. Lee*

http://pubs.acs.org/doi/abs/10.1021/ol301098s

The retrosynthesis of (-)-teuvcidin beings with the addition of the furan-3-yllithium on the aldehyde group produced by oxonolysis of 14.  The addition of furan-3-yllithum to the aldehyde produces the corresponding hydroxyl anion that closes on the adjacent methyl ester to form the lactone.  Ester 14 was prepared by the oxidation of the aldehyde 13 to the corresponding acid and then esterification under neutral conditions by using diazomethane.  Diazomethane mediated esterfications are the norm in late-stage, acid- or base-sensitive molecules.  Compound 13 was derived from furan 12 by an oxidation protocol utilizing sodium salt of N-chlorobenzenesulfonamide in methanol.  This generates the dimethoxytetrahydrofuran ring initially, which get aromatized under acidic conditions to give the corresponding furan 12.  Compound 12 has an allyl substitution a to the aldehyde – which strongly points to a Claisen rearrangement as the next disconnection.  Thus, compound 12 is derived from 11 by using diisopropylethylamine in 1,2-dichlorobenzene at reflux.  Compound 11 was obtained by the O-alkylation of the enolate of aldehyde 10.  The authors tried direct  a-allylation of aldehyde 10 but failed and had to resort to an initial O-allylation followed by Claisen rearrangement.  Neat trick indeed!  Moving backwards, compound 10 was obtained from ester-epoxide 9 by using TBAF.  In the text, the authors state “Under the reaction conditions, dealkoxycarbonylation of (-)-9 generated an enolate, which underwent epoxide ring opening, acetal formation, and elimination of water to afford the fused furan moiety of (-)-10”. So, first TBAF removes the TMS-ethoxycarbonyl group first, then opens the epoxide, which attacks the carbonyl-carbon to get a hydroxyl group which gets eliminated as water.  Instead, I feel that after removal of the TMS-ethoxycarbonyl group, an enolate gets formed (from the ketone side) and it attacks the epoxide (via the O^‑).  The hydroxyl group that is formed is then eliminated as water.  In any case, whatever the mechanism, this is indeed a nice way to make the furan ring.  The epoxide group in 9 is derived from alkene 8.  The synthesis of compound 8 is the key methodology of this paper – It is formed by a tandem Michael-Coria-Ene-cascade-cyclization reaction.  So, what’s happening here?  The aldehyde enolate formed on 7 by Lewis acid activation attacks in a Michael fashion on the carbon-carbon double bond; this then attack the alkyne in a 6-endo-trig fashion to form the carbocyclic ring in 8.  Compound 7, not surprisingly, was prepared by a Knoevenagle reaction of b-keto-ester 5 on aldehyde 6.  The b-keto-ester 5 was prepared by an insertion of the diazo compound 4 on acid formed from 3 by (a) removal of TIPS group; (b) oxidation of the resulting alcohol to the acid.  Here, it is quite interesting to note the selective deprotection of the TIPS ether in presence of the TES-ether by using 1-chloro-ethylchloroformate (as the source of hydrogen chloride).  This is quite neat as it was quite clean reaction.  Compound 3 was prepared from ester 2 by reduction of the ester group followed by protection as TIPS.  Finally, compound 2 was prepared by the TES protection of the primary alcohol in 1.

Overall, some interesting transformations – (a) selective deprotections of the TIPS ether in presence of TES-ether; (b) unique cyclization protocol to form the carbocyclic ring (methodology which was published earlier by their group); (c) nice way to prepare a furan ring; and (d ) a stepwise Claisen rearrangement.