Total Synthesis and Absolute Stereochemistry of Polygalolides A and B

Abstract

In 2003, Wei and co-workers reported the isolation and structural elucidation of the polygalolides A (1) and B (2) obtained from Polygala fallax Hemsl., a medicinal plant from which extracts are used as tonics and antihepatitis drugs in China.[1] The structure and relative configuration of the polygalolides were determined on the basis of NMR spectroscopic data. However, the issue of the absolute stereochemistry of the molecules has not been resolved. The structural complexity of these molecules, which include an unprecedented trioxatetracyclic ring system and contiguous quaternary stereogenic centers at C2 and C8, poses a considerable synthetic challenge. Herein, we describe the first total synthesis of (À)-polygalolides A (1) and B (2). The synthesis takes advantage of a transformation consisting of a tandem carbonyl ylide formation/1,3-dipolar cycloaddition, which has been extensively studied, especially in the research group of Padwa. [2][3][4][5] Our retrosynthetic analysis of the polygalolides is illustrated in Scheme 1. We elected to introduce the arylmethylidene moiety at a late stage in the synthesis, and the scission of the lactone ring provided 3 as a common intermediate. The tricyclic compound 3 was assumed to arise from an intramolecular 1,3-dipolar cycloaddition of carbonyl ylide 5, generated from a-diazoketone 6 in the presence of a Rh II catalyst. Compound 6 arises from homologation of the tert-butyl ester 7, which would be elaborated from the known alcohol 8, [6] which in turn can readily be obtained from d-arabinose.We initiated the synthesis by alkylating alcohol 8 with (Z)-1-bromo-4-(tert-butyldiphenylsilyl)oxy-2-butene [7] to provide the allyl ether 9 in 98 % yield (Scheme 2). The oxidative hydrolysis of the dithioacetal with iodine was followed by oxidation with NaClO 2 and esterification with (Boc) 2 O[8] to give tert-butyl ester 10 in 70 % yield over three steps. Catalytic hydrogenation of alkene 10 provided the TBDPS ether 11 in 95 % yield, and 11 was then treated with Bu 4 NF in the presence of AcOH to give alcohol 12 in 96 % yield. Installation of the C2=C3 bond was accomplished by employing a modification of the procedure reported by Ogasawara and co-workers, [9] and subsequent reduction with NaBH 4 gave alcohol 13 in 81 % yield over both steps. A two-step sequence involving mesylation and nucleophilic substitution with pmethoxyphenol was used to convert the allyl alcohol 13 into the PMP ether 14 in 78 % overall yield. The acetonide was Scheme 1. Retrosynthetic analysis of polygalolides A and B. PMP = p-methoxyphenyl, TBDPS = tert-butyldiphenylsilyl.

Stereochemical Control by an Ester Group or Olefin Ligand in Platinum‐Catalyzed Carboalkoxylation of 6‐(1‐Alkoxyethoxy)‐ hex‐2‐ynoates

“…The reaction of 2,2,2-trichloroethyl ester 1a in the presence of 10 mol% PtCl 2 and 40 mol% 1,5-hexadiene in toluene at 25 8C gave (Z)-2a, which was derived from the transaddition of the acetal C À O bond to the alkynyl moiety, in 84% yield with exclusive Z stereoselectivity (entry 1). Interestingly, the reaction of substrates 1a, 1b, 1c, and 1d having an electron-deficient ester group afforded Z isomers as the major product (entries 1-4), while the reaction of substrates having a relatively electron-rich ester, such as 1f, 1g, and 1h, proceeded slowly to give the E isomers, which were derived from the formal cis-addition of the acetal C À O bond (entries [6][7][8]. Particularly, the reaction of phenyl ester 1h gave (E)-2h in good yield with exclusive E stereoselectivity (entry 8).…”

“…For example, the platinum-catalyzed reaction of 1h using 1,5-hexadiene as the olefin ligand gave E-2h as the major product, while that using 1,5-cyclooctadiene produced mainly the Z isomer. Lewis acidic transition metal-catalyzed cyclization of ortho-alkynylanilines, [3,4] ortho-alkynylphenyl ethers, [3a,b,5,6] and ortho-alkynylphenyl sulfides [7] having a carbon migrating group (CR 3 ), such as allyl, acyl, p-methoxyphenyl (MPM), or a-alkoxylalkyl group, attached to the heteroatom (Y), which proceeds through carbon-heteroatom bond addition, was developed for the synthesis of 2,3-disubstituted indoles, benzofurans, and benzothiophenes [Scheme 1, Eq. (2)].…”

Total Syntheses of Zaragozic Acids A and C by a Carbonyl Ylide Cycloaddition Strategy

“…While the carbonyl ylide cycloaddition methodology with rhodium( II ) catalysts is rapidly becoming recognized as a powerful means for the construction of highly substituted oxygen‐containing polycycles, a limited number of examples of the successful application of this chemistry to the complete, total synthesis of natural products, especially in optically pure form, have been reported to date 19c,j,n,o. The present synthesis attests to the power and vitality of the tandem reaction sequence in natural product synthesis.…”

Copper-Catalyzed Skeletal Rearrangements ofO-Propargylic Oximes via Cleavage of a Carbon-Oxygen Bond

“…Subsequent carbodemetalation of the resulting vinylplatinum intermediate 4 involved the 1,3-migration of the α-alkoxyalkyl group on the oxygen atom to give benzofuran 3. This methodology was successfully extended to the synthesis of other heteroarenes such as indoles, [16] benzo[b]thiophenes, [17] and benzo[b]selenophenes (Scheme 5). [18] Moreover, we also demonstrated that the migrating group can be composed of various carbon-based functional moieties, including α-alkoxyalkyl (acetal), acyl, allyl, p-methoxyphenylmethyl, α-phenethyl, ester, or carbamoyl groups, and also various heteroatom-based functional groups, such as sulfonyl and silyl groups, which would lead to intramolecular heteroatom-heteroatom addition reactions.…”