Study And Applications Of Cope Rearrangements And Prins Cyclizations Based On Cross-Dimerization Between Carbonyl Compounds And Aldehydes Or Imines

The motivation of scientific research is to explore the mysteries of nature and science, to improve human life and protect our survival environment. In the process of exploration, organic synthesis plays an important role. It’s our mission as an organic chemist to explore and discover new organic synthetic methods under the concept of green chemistry, thus providing new solutions for the synthesis of novel structures and complex organic compounds.As efficient methods for construction of C-C bond, both Cope rearrangement and Prins cyclization have been widely applied in the total synthesis of many complex natural products and biochemical active drugs. Albeit these reactions are established over half a century, finding useful strategies to build the achievable reaction sequences of Cope rearrangement or Prins cyclization are still an active area and quite attractive in organic chemistry. Initiated by Lewis acid mediated cross-dimerization of unsaturated carbonyl compounds and aldehydes or imines, novel oxy-2-oxonia (azonia)-Cope rearrangement and oxonia-Prins cyclization are illustrated in this thesis. And further theoretical study and their applications in natural product synthesis highlighted the applicability of these new reactions. These "addition" reactions have high efficiency in atom utilization in terms of the green chemistry. Additionally, these reactions can be achieved by using widely available and inexpensive starting materials in the presence of catalytic amount of Lewis acid in high concentration. The main contents of this thesis are described as follows.The background of the Cope rearrangement is introduced in Chapter 1. Subsequently, the strategies of 2-oxonia (azonia)-Cope rearrangements and their applications are described in details. The reaction mechanism of Prins cyclization, its current progress and application in natural product synthesis are illustrated.Serendipitous discovery is an important way to prompt the human’s recognition of the world. With the mastery of knowledge by a wise brain, serendipity can be converted into necessity. A new oxy-2-oxonia-Cope rearrangement based on cross-dimerization of β,γ-unsaturated carbonyl compounds and aldehydes has been unraveled during our efforts on design and synthesis of new odorants. In chapter 2, the scope of this novel reaction is investigated. This reaction has wide substrate compatibility as homoallylic esters can be synthesized by reaction of a series of β,γ-unsaturated ketones or aldehydes with aliphatic aldehydes or aromatic aldehydes in moderate to high yields. The compound 113i was selected to study the [n+4] ring-enlargement oxy-2-oxonia-Cope rearrangement, leading to the structures of 10-membered lactones. Their structures were further confirmed by the X-ray diffraction analysis for a selected product 1181. The complete chirality transfer during the ring enlargement of substrate (R)-113i was observed. A postulated mechanism was given to account for the chirality transfer. Chiral Bronsted acid catalyzed enantioselectively oxy-2-oxonia-Cope rearrangement could also be performed and an optimal enantioselectivity of 63% ee was achieved. In the application of this novel reaction, phoracantholid I was synthesized using a simple procedure in high overall yield (23%) from cheap and easily available starting material cyclohexanone.Inspired by oxy-2-oxonia-Cope rearrangement, a cascade oxy-2-azonia-Cope rearrangement is developed in Chapter 3, resulting from the cross-dimerization of P,y-unsaturated carbonyl compounds and imines. This discovery opens a new route to amide derivatives in an atom economic way, a top-priority research area in organic chemistry. After screening the reaction condition, the scope of reaction was examined. Moderate to high yield of homoallylic amides were obtained by reaction of a series of P,y-unsaturated carbonyl compounds with oximes and imines (12 examples, yields ranging from 29% to 97%). Interestingly,1H-indole reacted equally well with P,y-unsaturated ketones via its tautomeric form 3H-indole. The scope of the reaction was then extended to [n+4] ring-enlarging oxy-2-azonia-Cope rearrangement and 9-16-membered medium to large ring lactams were synthesized (25 examples, yields ranging from 26% to 96%). The structures of the lactams were further verified by the X-ray analysis for (E)-155d, (E)-155g and (Z)-155s. Examining the E/Z selectivity of the reaction indicates that 9-membered latams have excellent Z selectivity, while 10-to 12-membered lactams display good E selectivity. For the 16-membered lactams, the E/Z selectivities depend on the substitution patterns of imines. The reaction of 113e with 150b in the presence of EtAlCl2 was investigated both experimentally and computationally. The density functional theory (DFT) study reveals that the reaction occurs via the chair-like transition state intermediate TS (5)-113e, and the Cope rearrangement step constitutes the selectivity-determining step. Finally, we applied this [n+4] ring-enlargement reaction to the short synthesis and structural verification of the natural occurring alkaloid motuporamine G (53% yield for 4 steps). The key step is to establish the 13-membered lactam 168 from 9-membered ring substrate via oxy-2-azonia-Cope rearrangement. This reaction also exemplifies the application of oxy-2-azonia-Cope rearrangement in organic synthesis.With more understanding about strategy of cross-dimerization of β,γ-unsaturated compounds and aldehyde (or imines), a further extension is illustrated in chapter 4. A novel cascade γ,δ-unsaturated carbonyl compounds and aldehydes cross-dimerization/oxonia-Prins cyclization is investigated by inserting one more carbon atom to the position between carbonyl group and double bond of β,γ-unsaturated carbonyl compounds. Catalyzed by a low toxic Lewis acid FeCl3, a series of novel [2.2.2] bridged cyclic acetals were synthesized (15 examples, yields ranging from 19% to 85%). The structure of product 198k has been undoubtly confirmed by X-ray diffraction analysis. Endo selectivity is highly dominated in oxonia-Prins cyclization, so the reaction mechanism is discussed in terms of these results. Finally, enantioselective oxonia-Prins cyclization is preliminarily examined and 32% ee in the enantioselectivity was observed.