Total Synthesis of Enigmazole A from Cinachyrella enigmatica. Bidirectional Bond Constructions with an Ambident 2,4-Disubstituted Oxazole Synthon

Abstract

The first total synthesis of the cytotoxic marine macrolide enigmazole A has been completed in 22 steps (longest linear sequence). The sensitive, densely functionalized 2,4-disubstituted oxazole fragment was constructed using an efficient Negishi-type coupling of an oxazol-2-ylzinc reagent formed directly from the parent ethyl 2-iodooxazole-4-carboxylate by zinc insertion. Other key steps include a hetero-Diels-Alder cycloaddition to form the central embedded pyran ring, a Wittig reaction to unite Eastern and Western hemispheres, and a ring size-selective Keck macrolactonization.

Concise Total Synthesis of Enigmazole A

“…In the end, it was accomplished in asingle operation using excess TBAF/ HOAc buffer at aslightly elevated temperature to cleave the FmO substituents as well as the remaining silyl ether.T he spectral data of synthetic enigmazole A( 1), which was isolated as the free acid as well as in salt form, matched those reported in the literature (for details see the Supporting Information). [1,5] Overall, the total synthesis of enigmazole A(1)described above is robust, concise and convergent, and provides aplatform for structural modifications.F irst forays are currently being pursued. Although the step count is similar to that of the only previous synthesis of this promising target (23 versus 24 steps for the longest linear route), [5] the new entry is considerably more productive (up to 3.3 %versus 0.41 %) and conceptually different.…”

“…[1,5] Overall, the total synthesis of enigmazole A(1)described above is robust, concise and convergent, and provides aplatform for structural modifications.F irst forays are currently being pursued. Although the step count is similar to that of the only previous synthesis of this promising target (23 versus 24 steps for the longest linear route), [5] the new entry is considerably more productive (up to 3.3 %versus 0.41 %) and conceptually different. It illustrates the power of transannular functionalization, [11,40] aconcept that gains momentum to the extent that macrocycle formation becomes increasingly more facile,n ot least with the help of ever more mature (alkyne) Angewandte Chemie metathesis catalysts.F urthermore,t his project was initially conceived to showcase our growing confidence in p-acid catalysis,w hich still has al ong way to go in terms of applications to elaborate and highly precious substrates.…”

“…An elegant total synthesis of enigmazole A( 1)a sthe parent compound of this series has already been reported, by Molinski and co-workers,b ack-to-back with the isolation paper. [5,6] Their approach hinged upon as elective macrolactonization of an almost fully decorated seco-acid which had to be conformationally biased for cyclization by asupplementary unsaturation in the frame.W es aw the opportunity to develop afundamentally different route which envisaged the concomitant formation of the signature tetrahydropyran ring and the C5-C7 oxygenation pattern in the final stages of the synthesis,o nly after the macrocycle had been closed (Scheme 1). This task might be accomplished by ag oldcatalyzed reaction cascade [7,8] commencing with a [ 3,3]-sigmatropic rearrangement of apropargylic acetate of type C. Theresulting allenyl acetate B is expected to engage with the same catalyst, and an ensuing transannular hydroalkoxylation should lead to the formation of the compound A,f eaturing a cis-disubstituted tetrahydropyran ring and aproperly placed enol acetate as ahandle for the installation of the phosphate at C5.…”

“…[12] If successful, the projected sequence provides opportunities for late-stage modification of the region carrying the distinctive phosphate ester,o nce the project enters into the phase of diverted total synthesis.F rom the purely chemical vantage point, it would help illustrate the prowess of p-acid catalysis,which remains surprisingly underrepresented in total synthesis compared with the overall activity in this topical field of research. [13,14] An oxazole of type H had already been used by the group of Molinski, [5] but our route to this building block represents ac onvenient short cut (Scheme 2). Specifically,acoppermediated anti-carbometalation [15] of the commercial propargyl alcohol 4 terminated by an iodine quench and subsequent O-methylation furnished compound 5,w hich participated in direct coupling with the commercial oxazole-4-carboxylate 6 by palladium-catalyzed C À Hactivation.…”

Update 1 of: Macrolactonizations in the Total Synthesis of Natural Products

“…The potential of this so-called Boden−Keck procedure was rapidly recognized and used in a great number of total syntheses, including those of cytovaricin 598 (where Mukaiyama's reagent failed) (Scheme 44), aplysiatoxin, 599 swhinolide and hemiswhinolide (vide supra), 84 colletodiol, colletol, and grahamimycin A, 600 epothilone derivatives, 601 and various olfactive alkynolides, 602 formal synthesis of apicularen 603 and diazonamide, 604 and synthetic studies of ingenane 605 and enigmazole. 606 This procedure has The main drawback associated with DCC, which is usually used in excess and "quenched" by methanol in acetic acid, is the tricky removal by flash chromatography of the corresponding urea byproduct, DCU. Several modifications of the esterification reagent have therefore appeared, being mainly watersoluble ureas and supported reagents.…”