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.

Construction of Fused‐oxa‐[n.2.1] Skeletons by Tandem Intramolecular [3+2] Cycloaddition/O‐H Insertion/Ester Exchange of Cyclopropanes with Diazocarbonyls

“…The product was not detected when catalysts Cu(OTf) 2 , CuCl, and BF 3 ·Et 2 O were used, respectively (entries [7][8][9]. When the methyl on the substrate 1 a was replaced by ethyl, benzyl, and trifluoroethyl, the reactions could smoothly proceed to form the desired products in moderate to good (62-84%) yields (entries [2][3][4]. In apolar solvents dichloroethane (DCE) and toluene (PhMe), the yields of the reactions catalyzed by Sc(OTf) 3 increased lightly.…”

“…4, 165.9, 133.0, 131.4, 130.0, 129.1, 125.9, 122.0, 89.6, 76.0, 70.6, 68.9, 53.1, 38.7, 35.2;IR (KBr, neat): 2960, 2924, 1773, 1745, 1255 Ethyl 3-oxo-1,3,3 a,4,5,6-hexahydro-5,10 165.5, 133.0, 131.4, 129.9, 129.0, 125.8, 122.2, 89.5, 75.9, 70.5, 68.9, 62.4, 38.7, 35.3, 13.8;IR (KBr, neat): 3059, 2964, 1783, 1749, 1263 4, 165.3, 134.4, 132.8, 131.1, 129.8, 128.9, 128.7, 128.6, 128.5, 125.9, 122.2, 89.6, 75.9, 70.4, 68.9, 68 Methyl 8-fluoro-3-oxo-1,3,3 a,4,5,6-hexahydro-5,10 b-epoxybenzo [3,4] 3, 75.6, 70.3, 68.9, 53.3, 38.5, 35.4; 19 F NMR (100 MHz, CDCl 3 ) δ -112.0 (F); IR (KBr, neat): 3063, 2960(KBr, neat): 3063, , 2924(KBr, neat): 3063, , 1781(KBr, neat): 3063, , 1745(KBr, neat): 3063, , 1259 9, 165.7, 133.1, 131.6, 131.4, 131.3, 129.1, 122.4, 89.1, 75.9, 70.5, 68.8, 53.4, 38.5, 34.6;IR (KBr, neat): 3060, 2968, 1745, 1257 2, 75.8, 70.6, 68.8, 53.2, 38.7, 35.2; 19 F NMR (100 MHz, CDCl 3 ) δ -62.5 (CF 3 ); IR (KBr, neat): 2956,2912,1785,1749,1269,869,736, 672 cm À 1 ; HRMS (ESI) m/z calcd for C 16 H 13 F 3 NaO 5 [M + Na] + : 365.0607, found: 365.0598. The product 2 was afforded by silica gel column chromatography (petroleum ether/EtOAc).…”

Asymmetric Domino Reactions Based on the Use of Chiral Substrates

“…This chiral domino product was further converted into zaragozic acids A and C. In addition, an intramolecular version of a comparable strategy was applied by the same authors to synthesise biologically active natural products (-)-polygalolides A and B. 67 Later, Schaus et al developed a nice intermolecular domino carbonyl ylide formation-1,3-dipolar cycloaddition reaction of a chiral dihydropyrimidone with a maleimide which afforded, in the presence of rhodium(II) acetate, the corresponding cycloadduct in 90-93% yield as a single stereoisomer, as shown in Scheme 1.44. 68 The process evolved through the in situ formation of dipole 31 by treatment of substrate with rhodium(II) acetate dimer in refluxed benzene.…”

Inverse electron demand asymmetric cycloadditions of cyclic carbonyl ylides catalyzed by chiral Lewis acids—Scope and limitations of diazo and olefinic substrates

“…Tandem Rh(II)-catalyzed intramolecular carbonyl ylide formation followed by 1,3-dipolar cycloaddition of -diazocarbonyl compounds with dipolarophiles, 1 which can efficiently provide epoxybridged complex polycyclic products in a one-pot reaction (Scheme 1), has been applied toward the syntheses of various biologically important oxygen-containing polycyclic natural products, such as brevicomin, 2 zaragozic acids, 3 komaroviquinone, 4 polygalolides, 5 pseudolaric acid A, 6 and aspidophytine 7 ( Figure 1). To improve the asymmetric synthesis of optically active oxygen-containing polycyclic compounds, Hodgson 8 and Hashimoto 9 have independently developed a highly enantioselective variant of this methodology featuring a chiral Rh(II)-associated carbonyl ylide in the transition state.…”