Total Synthesis of Muconin by Efficient Assembly of Chiral Building Blocks

Abstract

Muconin (1) is a novel tetrahydropyran-bearing acetogenin isolated from Rollinia mucosa that has exhibited potent and selective in vitro cytotoxicities against pancreatic and breast tumor cell lines. 1 We considered the possibility of preparing 1 by the convergent assembly of readily accessible chiral units (Scheme 1). We describe herein the total synthesis of muconinsthe first of any THP-bearing Annonaceous acetogenin 2 sby taking advantage of such a chiral building block approach.Our laboratories uncovered recently a highly effective method for the hydrolytic kinetic resolution (HKR) of terminal epoxides catalyzed by cobalt complex 8 (eq 1). 3 The HKR provides practical access to both terminal epoxides and 1,2-diols in highly enantioenriched form. The commercial availability on a bulk scale of racemic terminal epoxides such as tetradecene oxide, epichlorohydrin, and propylene oxide render these attractive starting materials for the synthesis of muconin. The fourth requisite building block, dihydropyran 5, is also readily accessed in enantioenriched form using the recently discovered hetero-Diels-Alder condensation of 1-methoxy-3-[(trimethylsilyl)oxy]-1,3-butadiene with aldehydes catalyzed by chromium complex 9 (eq 2). 4 To synthesize fragment 2, the HKR of (()-tetradecene oxide using 0.5 mol % of complex (S,S)-8 in TBME and 0.5 equiv of H 2 O afforded (R)-tetradecane-1,2-diol 4 in >99% ee and in 90% of the theoretical yield. 5 Selective protection of the secondary hydroxyl group was effected by the method of Yamamoto using trimethyl orthoformate and DIBALH. 6 The resulting primary alcohol 10 was transformed to the corresponding aldehyde without detectable epimerization by means of TEMPO-catalyzed oxidation with hypochlorite. 7 Chelation-controlled addition of vinylmagnesium bromide in CH 2 Cl 2 with MgBr 2 ‚OEt 2 8 at -78°C provided the desired allylic alcohol in 74% yield and >100:1 diastereoselectivity. This material was converted to acid 11 in 92% yield by alkylation with sodium iodoacetate in THF.Pyranol 12 was constructed by the hetero-Diels-Alder condensation of 1-methoxy-3-[(trimethylsilyl)oxy]-1,3-butadiene with p-bromobenzyloxyacetaldehyde catalyzed by 2 mol % (S,S)-9 followed by diastereoselective Luche reduction. 9 The moderate enantioselectivity of the catalytic reaction (80% ee) was reconciled by recrystallization of the dihydropyranone condensation product to 99% ee and in good yield. Esterification of 12 with acid 11 was effected cleanly under EDC coupling conditions. The corresponding silyl ketene acetal was generated with LDA in 4:1 THF/ HMPA and in situ trapping with TMSCl. 10 Ireland-Claisen rearrangement 11 occurred upon elevation of the reaction temperature to 50°C, with formation of the 2,6-cis-disubstituted dihydropyran isolated as the methyl ester in 81% yield and 5:1 diastereoselectivity at C(18). The observed preferential formation of the threo stereoisomer is attributable to sigmatropic rearrangement of the Z-silyl ketene acetal through a boatlike transition state. 12 The methyl...

Functional Molecules for Grafting onto Ionic Surfaces

“…1,2-Bis(prop-2-ynyloxy)benzene, [22] methyl 2-amino-4-bromobutanoate, [18] methyl 4-bromo-2-(tert-butoxycarbonylamino)butanoate, [19] hexyl azide, [23] azidomethyl pivalate, [24] and (6-bromohex-1ynyl)triisopropylsilane [25] were obtained according to the published procedures. HHTP [26] was obtained from hexamethoxytriphenylene (HMTP) [27] according to literature procedure.…”

Catalytic Asymmetric Epoxide Ring‐opening Chemistry

“…The use of water as the resolving agent, low loadings of a recyclable catalyst, and ease of separation of resolved epoxide from diol have made the HKR a widely used method for preparing enantioenriched terminal epoxides. Examples of natural products synthesized with the aid of the HKR include muconin [76], amphidinolide T1 [77], cytochalasin B [78], (-)-indolizidine 223AB [79], and (+)-allosedamine [80]. The high enantioselectivity and broad substrate scope of the HKR are accompanied by an intriguing mechanistic framework involving cooperative catalysis between different catalyst species.…”

Synthesis and biological evaluation of analogs of the tetrahydropyran acetogenin, muconin

“…The ketone derivative (7) showed apparently decreased activity, indicating that the hydroxyl groups adjacent to the THP ring play a critical role for cytotoxic activity. The fact that the hydroxyl-protected analogs (9,10,11,12) exhibited the lowest potency also proves that the number of hydroxyl groups is an important factor. The saturated lactone compound (8) having almost the same activity as muconin, is about 5-fold more potent than the unsaturated counterpart (7).…”

“…The remarkable antitumor activity and the unique structure of muconin have consequently stimulated synthetic efforts toward 1. 10 We have reported a convergent synthesis of (+)-muconin recently.ll '12 Most of the work thus far on annonaceous acetogenins has focused on isolation of new natural products and total synthesis. Some information regarding the structure-activity relationships (SAR) of THE-bearing acetogenins has been summarized by investigation of the isolated natural products,2 but very little research on the SAR of synthetic analogs has been pursued until now,l3~-15) probably due to the complex structure of acetogenins.…”