Investigation on Synthetic Methods toward Homoallylic Amines from Alkyl Azides by Allylation of N-Unsubstituted Imines

Abstract

Homoallylic amines are important intermediates in synthetic organic chemistry due to their versatile transformation. Furthermore, they are found in numerous bioactive natural product derivatives. The addition of allylic metal reagent to N-substituted imines have been widely used to access homoallylic amines. In the light of synthetic viewpoint, this strategy has limitations in the requirement of additional reaction steps such as preparation of N-substituted imines and removal of the substituent for further transformation. In this thesis, the synthetic methods toward homoallylic amines via allylation of N-unsubstituted imines by using allylic boron/zinc species are demonstrated. In addition, stereoselective synthesis of highly substituted α-silylamines bearing multiple stereocenters from α-silylimines and their synthetic application as diversity-generating elements are also described. Finally, desilylative [1,3]-sigmatropic rearrangement of homoallylic α-silylamines is demonstrated. First, the allylation of N-unsubstituted imine with allyl boron and allyl boronates was investigated. Homoallylic amines were afforded in high yield via 6-membered chairlike transition state. Excellent substrate- or reagent-controlled diastereoselectivity was noted. Enantioenriched homoallylic amine was also produced by using chiral allyl borane reagent. We then developed an operationally simple and inexpensive protocol for zinc-mediated allylation of N-unsubstituted imines. Highly substituted allyl halides gave homoallyilc amines in high yield with excellent γ-regioselectivity and moderate to high diastereoselectivity. In addition, N-unsubstituted imines were compatible with highly reactive allylic zinc reagent. The triethylborane-imine complex are reactive species in zinc-mediated allylation. The diastereoselectivity depends on the size of substituent at terminal olefin and the reaction temperature. Small size of substituent and low reaction temperature promoted forming syn-product via synclinal transition state. Allyl halide possessing large substituent and high reaction temperature led anti-product via antiperiplanar transition state. Next, stereoselective synthesis of highly substituted α-silylamines bearing multiple stereocenters were developed. Chiral α-silylamines were also obtained by chiral borane and boronates. The synthetic utility of α-silylamine as a diversity generating element was described to synthesize quinolizine structures. The oxidative Pictet-Spengler reaction of silyl group is key transformation to increase the complexity of molecule. During the purification of homoallylic α-silylamines, we discovered an unprecedented desilylative formal [1,3]-sigmatropic rearrangement. From the optimization study, we found that the reaction was performed with acid additive in methanol solvent. The high levels of chirality transfer of substrate is highlighted. In addition, the olefin geometry of product was determined by the structure of substrates. Though mechanism is unclear, this transformation probably includes [2,3]-sigmatropic rearrangement at initial stage followed by desilylative [1,2]-allyl migration or desilylative [1,3]-sigmatropic rearrangement. Divergent synthesis of homoallylic amines are realized from α-silyamine by simple desilylation or by desilylative formal [1,3]-sigmatropic rearrangement. It represents γ-and α-addition of allyl moiety to formimine, the simplest imine species.