Novel reactions of oxabicyclic compounds and reductive aldol cyclizations of activated alkynes

by Leung, Sze-kar

(Uncorrected OCR) Abstract of thesis entitled NOVEL REACTIONS OF OXABICYCLIC COMPOUNDS AND REDUCTIVE ALDOL CYCLIZATIONS OF ACTIVATED ALKYNES Submitted by Leung Sze Kar for the degree of Doctor of Philosophy at The University of Hong Kong in August 2004 Transition metal catalysed cyclopropanation using diazocarbonyl compounds was demonstrated for the first time for oxabicyclic alkene substrates. Compounds 2.4 and 2.7 were prepared and used as the oxabicyclic substrates. Diazocompounds 2.9, 2.10, 2.11 and 2.12 were prepared for the cyclopropanation reactions. Exo, exo-cyclopropanated products 2.13a, 2.14, 2.15, 2.16, 2.17a, 2.18, 2.19 and 2.20 were the sole or major diastereomeric products in all cases. Exo, e?o-cyclopropanated products 2.13b and 2.17b were the minor products from the reactions of 2.4 and 2.7 with 2.8. Catalysts, reaction temperature, addition rate of the diazo compounds and the concentration of the substrate were factors that have been examined to optimize the reaction conditions. In general, dirhodium tetraacetate was an effective catalyst at room temperature, and a slow addition of the diazo compound and high concentrations of the alkene substrates gave the highest yields of cyclopropanated products. Reductive ring cleavage of the cyclopropane ring in the meso cyclopropanated oxabicyclic compound 2.16 occurred at the Ca-Cp bond to afford desymmetrized oxabicyclic compound 2.22 bearing six stereocenters. Compound 3.11 was prepared to explore the possibility of intramolecular cyclopropanation; however, the reaction failed to occur for this substrate, presumably due to strain in the cyclopropanated product. Stoichiometric and catalytic reductive aldol cyclizations of activated alkynes mediated by Stryker's reagent were studied. Alkynones 5.12, 5.16, 5.20, 5.27, 5.33, 5.39, 5.44 were prepared and underwent successful reductive intramolecular aldol reactions using stoichiometric or catalytic amounts of Stryker's reagent to give five-and six-membered cyclic aldols 5.45a, 5.46a, 5.47a, 5.48a, 5.49a, 5.50a and 5.51a within hours in good yields. Cw-fused products were the sole or major diastereomers in all cases. Only in the reaction of 5.27 was frans-fused 5.48b also obtained as a minor product. Asymmetric catalytic reductive aldol cyclizations using the chiral bisphosphine ligand BINAP have been attempted on substrates 5.39 and 5.44. Good yields of reductive aldol products were obtained but low enantioselectivities (6% and 18% ee respectively) were observed. Further functionalizations of the products are possible, such as the epoxidation of 5.49a which generated a single diastereomeric oxirane product 5.53 with four contiguous stereocenters. Notably, the p-hydroxycycloalkenone products are complementary to those obtained from intramolecular Baylis-Hillman reactions. The achievement of the reductive aldol reaction of alkynones provide an alternative methodology to access such p-hydroxy-a,P-unsaturated ketone compounds. The epoxidation of P-hydroxycycloalkenone is an example which serves to highlight the synthetic potential of this reductive cyclization to generate highly functionahzed intermediates for organic synthesis, which may find applications in the synthesis of pharmaceutical or other biologically active compounds. Alkynoates' 6.6 and 6.8 were prepared to examine their reductive aldol cyclizations using Stryker's reagent. However, these substrates did not undergo cyclization and only conjugate reduction via cw-hydrocupration occurred. Deuterium-labelling studies were performed to investigate the reaction mechanism. J^/"- OTIPS IL^J-?otips 2.7 2.13a OCH3 2.13b ^CH O OEt N O OO 2.8 R=OEt "R 2.9 R = Ph N2 2.10R=/-Pr 2.11R=f-Bu' ~OTIPS EtCY?\ -OTIPS L-rP~-7^^OTIPS 2 2.12 EtO 2.17a otips q OTIPS OCH3 2.14 R = Ph 2.15 R = /-Pr 2.16 R = f-Bu 2.18 R = Ph 2.19 R =/-Pr 2.20'R = /-Bu \l^~J-?TIPS 2.17b OCH3___p OBn 2.22 0=\ ^> 3.11 N2 n=l 5.12 n = 2 5.16 C02Et n=l 5.47a n = 2 5.45a R = H 5.48a R = CH3 5.49a c^ 0 5.50a 5.51a 5.53