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.

No 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.

No abstract

The total syntheses of (+)-polygalolide A and (+)-polygalolide B have been completed by using a carbonyl ylide cycloaddition strategy. Three of the four stereocenters, including two consecutive tetrasubstituted carbon atoms at C2 and C8, were incorporated through internal asymmetric induction from the stereocenter at C7 by a [Rh(2) (OAc)(4)]-catalyzed carbonyl ylide formation/intramolecular 1,3-dipolar cycloaddition sequence. The arylmethylidene moiety of these natural products was successfully installed by a Mukaiyama aldol-type reaction of a silyl enol ether with a dimethyl acetal, followed by elimination under basic conditions. We have also developed an alternative approach to the carbonyl ylide precursor based on a hetero-Michael reaction. This approach requires 18 steps, and the natural products were obtained in 9.8 and 9.3 % overall yields. Comparison of specific rotations of the synthetic materials and natural products suggests that polygalolides are biosynthesized in nearly racemic forms through a [5+2] cycloaddition between a fructose-derived oxypyrylium zwitterion with an isoprene derivative.