No abstract

A highly selective asymmetric domino allylation of aliphatic ketones is described. When methyl ketones 1 a ± g, the chiral trimethylsilyl ether 2, and allylsilane 3 react in the presence of catalytic amounts of trifluoromethanesulfonic acid, the homoallylic ethers 4 a ± g are produced with up to 24:1 diastereoselectivity and 89 % yield. Cleavage of the obtained tertiary homoallylic ethers 4 using lithium or sodium in liquid ammonia gives the homoallylic alcohols 5 in 75 to 95 % yield and up to 92 % ee. Even ethyl methyl ketone 1 a, the most difficult example, showed a stereoselectivity of 9:1 at À 78 8C and 24:1 at À 109 8C. In addition, the allylation of protected hydroxyalkyl methyl ketones 7 a ± j was investigated to give the corresponding homoallylic ethers 8 a ± j with a diastereoselectivity of up to b 24:1 and 98 % yield. In contrast, ethyl alkyl ketones 1 h ± j have a low selectivity.

Numerous pharmacologically interesting compounds are available by the synthesis of hybrid natural products. Thus, for instance, the estrone-talaromycin hybrid 2, which is synthesized in a few steps from the estrone derivative 1 by a sequence in which a hetero-Diels-Alder reaction is the key step, exhibits notable cytotoxic activity.

Reaction of aliphatic aldehydes 1 and allylsilane 3 at -78 °C in the presence of the norpseudoephedrine derivative 2a and catalytic amounts of trifluoromethanesulfonic acid trimethylsilyl ester gives the homoallylic ethers 4 with >98% diastereoselectivity. The ethers 4 can be transformed into the corresponding homoallylic alcohols 5 having an enantiomeric excess >98% using sodium in liquid ammonia. On-line NMR spectroscopy indicates that the mixed acetal 7 and the oxazolidinium ion 12 are intermediates in the formation of 4. At higher temperature proton transfer occurs to give the oxazolidinium ion 18, which does not react with allylsilane, but gives the oxazolidine 17 on aqueous workup. Protonation of 17 with trifluoromethanesulfonic acid leads to 18 but not to the oxazolidinium ion 12. Thus, an allylation starting from 17 is not possible.

The asymmetric synthesis of enantiomerically pure α‐substituted tertiary homoallylic ethers 4 a, 11 and 12 a–c by the allylation of ethyl methyl ketone (1 a) with γ‐substituted allylsilanes 9 a–h is described. The allylsilanes were obtained by a nickel‐catalysed Grignard cross‐coupling reaction of (E)‐ and (Z)‐(3‐iodoallyl)trimethylsilane with various Grignard reagents. The reaction of the allylsilanes with 1 a in the presence of the trimethylsilyl ether of N‐trifluoroacetylnorpseudoephedrine (3), and catalytic amounts of a mixture of trimethylsilyl triflate and trifluoromethanesulfonic acid led to the homoallylic ethers 4 a, 11 and 12 a–c with two new stereogenic centres, with a selectivity of 1:9 to >20:1 for the homoallylic and of 1:99 to >60:1 for the allylic centre. The facial selectivity does not depend on the configuration of the allylsilane, and in all reactions the anti product is preferentially formed. Interestingly, a pronounced switch of facial selectivity takes place with increasing length of the alkyl group of the allylsilane.