Total Synthesis of Aspergillide A and B Based on the Transannular Oxy‐Michael Reaction

Abstract

The aspergillides A, B, and C (1, 2, and 3) comprise a novel class of 14-membered macrolides that were isolated by Kusumi and co-workers from the marine-derived fungus Aspergillus ostianus strain 01F313 that was cultured in a medium composed of bromine-modified artificial sea water. [1] Their structures were determined by extensive spectroscopic studies, and their absolute configurations were established by X-ray crystallography (for 1 and 2) and the modified Mosher method (for 3).[2] These compounds contain tri-substituted tetrahydro and dihydropyran units and exhibit cytotoxicity against mouse lymphocytic leukemia cells (L1210) with LD 50 values of 2.1, 71.0, and 2.0 mg mL À1 , respectively. Because of their intriguing structural features and biological profile, these polyketides have attracted much attention in the synthetic community as targets for total synthesis. To date, four total syntheses of 1, [3] six of 2, [3c, 4] and two of 3 [5] have been reported. Herein, we describe our total synthesis of the aspergillides A (1) and B (2) from a common macrolide intermediate by employing an interesting transannular oxyMichael reaction [6] as the key step. Our strategy for the synthesis of the aspergillides A and B, illustrated in Scheme 1, proposes the formation of the trisubstituted pyran moiety through a base-mediated transannular oxy-Michael reaction from the 14-membered macrolactone 4. It was thought that stereochemical control at the newly generated stereogenic center at C3 could be achieved by the choice of reaction conditions. The macrolactone 4 could be assembled by using a sequential cross-metathesis and intramolecular Horner-Wadsworth-Emmons reaction of the acyclic precursors 5, which could be accessed from the chiral building block 7 [7] and compound 6, which was known in the literature.[8] Two stereogenic centers at the future C4 and C7 positions in 5 would be created by taking advantage of the convex nature of 7.The optically pure enone 7 with a bicyclo[3.2.1]octane framework, prepared from 2-furfural by a six-step sequence, served as the starting material for the synthesis of the alkenyl alcohol 14 (Scheme 2). Attempted transformation of 7 into 10 using the Wharton transposition [7,9] gave unsatisfactory results ( % 20 % yield), prompting us to find another route. Reduction with NaBH 4 followed by the Hata reaction [10] of Scheme 1. Retrosynthetic analysis. Bn = benzyl, HWE = Horner-Wadsworth-Emmons, TBS = tert-butyldimethylsilyl. then TESCl, DMAP, CH 2 Cl 2 , RT, 1 h; k) LiBH 4 , THF, 0 8C, 3 h, 96 % (over 2 steps, based on recovered diol 13). DMAP = 4-dimethylaminopyridine, mCPBA = m-chloroperoxybenzoic acid, Ms = methanesulfonyl, Piv = pivaloyl, TES = triethylsilyl, THF = tetrahydrofuran.

Efficient access to a dihydropyran-containing macrolide via a transannular oxy-Michael reaction: total synthesis of (+)-aspergillide C

“…To date, three total syntheses, 2 one of which is a formal synthesis, 2b have been reported. Herein we describe the secondgeneration total synthesis of the natural enantiomer (+)-aspergillide C (1) from the bicyclic acetal 5 that was prepared from 6 3 via a 4-step sequence and used for the syntheses of aspergillides A and B, 4 the key step of which employs an interesting 6-exo-trig transannular oxy-Michael reaction providing the tetrahydropyran moiety. 5 Since such a process has not yet been reported, the pivotal transannular cyclization of 2 to afford the dihydropyran incorporated in the macrolide 1 could prove to be challenging.…”

“…In summary, the second-generation enantioselective total synthesis of aspergillide C (1) has been accomplished in a longest linear sequence of 15 steps from the bicyclic chiral building block 6 in 19% overall yield. It was revealed that the 6-exo-trig transannular oxy-Michael reaction of the macrolide 2 with the non-protected Z-allylic diol and the enoate functionalities proceeded smoothly to produce the substituted dihydropyran-containing macrolide, namely aspergillide C (1), in a shorter period of time compared to the corresponding dihydro-substrate, 4 which was used previously for the synthesis of aspergillides A and B. We also completed the first, efficient enantioselective synthesis of 3-epi-aspergillide C (15) from the common substrate 2, and demonstrated the successful conversion of 15 to aspergillide C (1).…”

Diastereoseletive Transannular Oxa-Conjugate Addition Generates the 2,6-cis-Disubstituted Tetrahydropyran of Neopeltolide

“…A stock solution of 0.1 M DBU in C 6 D 6 was prepared and used as the reaction solvent for both diastereomers 21 and 14 . Contrary to the successful use of DBU in the oxa-conjugate additions observed for both linear and transannular systems by Fuwa and Shishido, , respectively, 21 and 14 were unreactive at room temperature and completely consumed at reflux without observable formation of the desired THP product. Elimination, leading toward formation of sorbate containing compounds, predominated.…”

Bioinspired synthesis and biological evaluation of ent-protulactones A and B

“…To access the trans -disubstituted tetrahydropyran skeleton, we considered base-promoted cyclization according to a stereoselectivity model proposed by Shishido. 13 After investigating a number of bases and reaction conditions, it was found that a one-pot sequential CM/oxa-Michael addition process in the presence of 1,8-diazabicyclo-[5,4,0]-undec-7-ene (DBU) at ambient temperature initiated a rapid and clean intramolecular cyclization of intermediate 12 to give trans -3,7-disubstituted tetrahydropyran 16 in 63% yield, along with the cis -disubstituted tetrahydropyran lactone 17 (16%) as a side product. One-pot tandem acetonide deprotection and lactonization of 16 was accomplished with 50% TFA and afforded the desired bicyclic dioxabicyclo[3.3.1]nonane lactone 6 in a good yield of 79%.…”