A systematic investigation of radical haloacetal cyclizations (Ueno-Stork reaction) where the acetal center is the unique stereogenic element is reported. This highly diastereoselective reaction can be used for the preparation of polysubstituted tetrahydrofurans and gamma-lactones. We report herein the full experimental details of reactions where up to three new chiral centers are created. To demonstrate the potential of this approach, short syntheses of (+)-eldanolide and of tricyclic acetals related to biologically active lignans have been achieved.

An approach for the synthesis of lignans related to the podophyllotoxin family is reported. The key reaction is a highly diastereoselective iodoacetal cyclization under iodine atom transfer conditions followed by a homolytic aromatic substitution. The second aromatic ring is introduced at a later stage via addition of aryllithium to an aryl ketone. A novel and very mild method for the deoxygenation of the intermediate tertiary benzylic alcohols is described. Podophyllotoxins are naturally occurring lignans that are found in plants of the genus podophyllum. 1,2 This class includes several closely related chemical structures such as podophyllotoxin (1), 3-5 deoxypodophyllotoxin (2) 6 and isodeoxypodophyllotoxin (iso-2) ( Figure 1). 7 They also include some semi-synthetic compounds such as etoposide and teniposide, which are used in cancer therapy. [8][9][10][11] Podophyllotoxin itself serves as the starting material for the synthesis of both compounds as well as for the treatment of angogenital warts. 12 Podophyllotoxin causes inhibition of tubulin polymerization. 13 The binding sites on tubulin for colchicine and podophylloxin were found to overlap significantly. Deoxypodophyllotoxin is a cytotoxic and antineoplastic agent. 14,15 Finally, polygamain (3) and 1b-polygamain (1b-3) (Figure 1), two structurally closely related lignans isolated from Polygala polygama were found to have interesting antibacterial effect on Staphylococcus aureus and E. coli. [16][17][18][19] Here, we report the total synthesis of racemic deoxypodophyllotoxin (2), 20-22 isodeoxypodophyllotoxin (iso-2) 23-31 and dehydrodeoxypodophyllotoxin (15). 32 A mixture of diastereomeric polygamain (3) and 1b-polygamain (1b-3) 33 has also been prepared according to the same synthetic strategy to illustrate its flexibility.The retrosynthetic analysis is described in Scheme 1. The aromatic substituent at C-7¢ will be introduced by nucleophilic addition to the ketone 4 followed by deoxygenation of the benzylic alcohol. We plan to prepare the keto lactone 4 via a 5-exo-trig radical cyclization of the iodoacetal 5 under iodine atom transfer conditions (Ueno-Stork cyclization) 34 followed by a radical aromatic substitution 35,36 and oxidation of the acetal to the corresponding lactone. The formation of the five-and six-membered rings in a single radical cascade process will be investigated. Based on previous studies with related systems, we expect that the 5-exo-trig cyclization should deliver the desired isomer having a trans relationship between the substitutents at C-8 and C-8¢. 37,38 Moreover, a related cascade process involving a radical aromatic substitution was recently used by Zard in an elegant synthesis of lycorane. 39 The iodoacetal 5 should be easily prepared from commercially available piperonyloyl chloride (6).Conversion of piperonyloyl chloride (6) into the desired iodide 9 is achieved according to standard procedures (Scheme 2) by first converting the acyl chloride 6 into the Weinreb amide 7, followed by its reaction with the Z-lithiated en...

A systematic investigation of radical haloacetal cyclizations (Ueno ± Stork reaction) where the acetal center is the unique stereogenic element is reported. This highly diastereoselective reaction can be used for the preparation of polysubstituted tetrahydrofurans and g-lactones. We report herein the full experimental details of reactions where up to three new chiral centers are created. To demonstrate the potential of this approach, short syntheses of ()-eldanolide and of tricyclic acetals related to biologically active lignans have been achieved.