Stereoselective Synthesis of C3-C12 Dihydropyran Portion of Antitumor Laulimalide Using Copper-Catalyzed Oxonium Ylide Formation-[2,3] Shift

Abstract

Tetrahydropyran and dihydropyran rings are structural components of a large number of natural products.1,2) Therefore, considerable attention has recently been directed toward their stereoselective synthesis. [3][4][5][6][7][8] The microtubule-stabilizing agent (Ϫ)-laulimalide, 9-18) also known as fijianolide B, which was isolated from several sponges (Cacospongia mycofijiensis,19) Hyattella sp., 20) Fasciospongia rimosa 21) ), contains 2,6-trans disubstituted 5,6-dihydro-2H-pyran as its C5-C9 portion. Stereoselective construction of thermodynamically less stable 2,6-trans substituted pyrans is one of most important subjects in synthesis of this attractive antitumor agent and its analogues.Metal catalyzed carbenoid reactions 22,23) have become a powerful tool for the synthesis of functionalized cyclic compounds including oxacycles. In 1994, Clark and co-workers reported that a copper-catalyzed reaction of 5-allyoxy-1-diazo-2-hexanone predominantly gave 2,6-trans-2-allyl-6-methy-3-dihydropyranone in good yield.24) This result stimulated us to investigate the metal catalyzed stereoselective synthesis of 2,6-trans disubstituted 3-pyranone (2) from adiazoketone (3) as a feasible method for synthesis of the C5-C9 portion of laulimalide and its analogues because 3 would be converted easily into the key intermediate (1) of the Mulzer's laulimalide synthesis, 11,25) as outlined in Chart 1. Herein, we describe the synthesis of 2 in high yield with excellent stereoselectivity by the copper-catalyzed oxonium ylide formation-[2,3] shift of 3 and conversion of 2 into 1 and its derivatives.a-Diazoketone (3) was prepared readily from the known alcohol (4) 11) as shown in Chart 2. Homoallylic alcohol (4) was converted to diol by hydroboration-oxidation process with borane-tetrahydrofuran (THF) complex and subsequent treatment with hydrogen peroxide and sodium hydroxide. Then the resulting primary hydroxyl group was protected as a tert-butyldimethylsilyl (TBDMS) ether to give the secondary alcohol (5) in high yield. O-Allylation of 5 was troublesome. Under usual allylation conditions, such as reaction with sodium hydride (NaH) and allyl bromide in THF, no reaction occurred. Several examinations revealed that treatment of 5 with NaH and allyl iodide in the presence of 15-crown-5 in THF at room temperature afforded allyl ether (6) in 96% yield. Deprotection of TBDMS group with tetrabutylammonium fluoride (TBAF), followed by two stepoxidation with Dess-Martin periodinane and oxone in dimethylformamide (DMF) 26) gave carboxylic acid (7) in 80% overall yield. Conversion of 7 into a-diazoketone (3) was achieved by the usual procedure, 27) formation of mixed acid anhydride with ethyl chloroformate and treatment with diazomethane, thereby providing 3 in 85% yield in two steps.With a-diazoketone (3) in hand, we turned our attention to cyclization of 3 by the metal catalyzed reaction (Eq. 1).(1)Formation of 2,6-disubstituted 3-pyranone using oxonium ylide formation-[2,3] shift of a-diazoketone has already been examined. Clark and co-worke...

Application of a Stereoselective Rhodium(II)-Catalyzed Oxonium Ylide Formation–[2,3]-Sigmatropic Rearrangement of an α-Diazo-β-keto Ester to the Synthesis of 2-epi-Cinatrin C1 Dimethyl Ester

“…8 The X-ray analysis of 10 confirmed the trans relationship between the 5-silyloxymethyl and 2-allyl groups and showed the 3,4-cis stereochemistry. This indicated that the rhodium(II)-catalyzed reaction proceeds via oxonium ylide A, which is apparently a more stable intermediate than B, and that the subsequent [2,3]-sigmatropic rearrangement of the allyl group from oxygen to carbon formed 3, consistent with our previously reported stereoselectivity for the reaction of 5-allyloxy-2-diazo-3-ketoesters (Scheme 4). In the subsequent reduction, the hydride should attack the carbonyl group from the α-side to avoid the adjacent bulky α-TBDMSO group of ketone to give β-hydroxy compound 9.…”

“…However, the deprotection was achieved by the treatment of 17 with iodine in methanol 11 under reflux to give 2-epi-cinatrin C 1 dimethyl ester 2 12,13 in 84% yield. In conclusion, the Rh 2 (OAc) 4 -catalyzed oxonium ylide formation- [2,3]-sigmatropic rearrangement reaction of α-diazo-β-keto ester 4 derived from D-glucose stereoselectively proceeded to give tetrahydrofuran-3-one 3 as a single diastereomer in high yield. The resulting 3 was converted into 2-epi-cinatrin C 1 dimethyl ester 2.…”

“…When the resulting ylide has an allylic substituent at the proper position, a subsequent [2,3]sigmatropic rearrangement takes place. Such metal-catalyzed carbenoid reactions have become a powerful tool for the synthesis of functionalized cyclic compounds including oxacycles.…”

“…The stereoselective construction of substituted γ-lactones with three continuous stereocenters is one of the most important issues for the synthesis of these attractive bioactive compounds. 5 Here we report the stereoselective rhodium(II)-catalyzed oxonium ylide formation- [2,3]-sigmatropic rearrangement of α-diazo-β-keto ester 4 derived from D-glucose and its application to the synthesis of 2-epi-cinatrin C 1 dimethyl ester 2.…”

“…Cinatrins are generated from a key intermediate, a substituted tetrahydrofuran-3-one 3, by (a) oxidation to a lactone, (b) introduction of the C1 unit, and (c) extension of the side chain. Furanone 3 is stereoselectively synthesized from α-diazo-β-keto ester 4 by using the rhodium(II)-catalyzed oxonium ylide formation- [2,3]sigmatropic rearrangement. The diazoketo ester 4 is easily prepared from D-glucose.…”