The Synthesis Of Spirooxindole Skeletons Of Natural Products

The main task of this Ph D thesis is the synthesis of spirooxindole skeletons of important natural products from oxindole derivatives via different types of reactions. The contents of this thesis could be divided into the following four parts:Chapter 1. The Synthesis of Spirooxindole Skeletons（Review）This chapter focused on the introduction of the progress on the synthesis of spirooxindole moieties. We classified and summarized these reactions respectively, based on the ring size（3-7-member） and different types of cyclization methods. We also reviewed some examples of the total synthesis of natural products containing these spirooxindole structures. The spirooxindole skeletons represent ubiquitous structural motifs in a broad range of alkaloids and bioactive compounds. Most of these alkaloids have been found to exhibit remarkable biological and pharmacological activities. In this context, the development of flexible synthetic methods for the synthesis of spirooxindole skeletons would thus be beneficial and important for the synthesis of those bioactive alkaloids.Chapter 2. Mg（Cl O₄）₂-Promoted [4 + 3] Cycloaddition Reaction: Concise Synthesis of Spirocycloheptane Oxindole DerivativesThe spirocycloheptane oxindole skeletons are important bioactive cores existing in a broad range of natural products and bioactive compounds. However, there has been limited work on the direct construction of spirocycloheptane oxindole frameworks from oxindole derivatives. We have developed a novel and convenient approach for the construction of spirocycloheptane oxindole skeletons through a Mg（Cl O₄）₂-promoted [4 + 3] cycloaddition of 2-methyl-3-furyloxindole derived allylic cations with conjugated dienes in DCM at room temperature. After optimizing the conditions and investigating the substrates of the reactions, this method could achieve the concise synthesis of a series of spirocycloheptane oxindoles in moderate yields（35-74%） and with high diastereoselectivities（dr > 20:1）. A possible mechanism was proposed, we expected that the intermolecular [4 + 3] cycloaddition reactions might point to a two-step cationic cyclization process, and result in the spirocycloheptane oxindole skeleton via a special endo-cycloaddition transition state. We believe that the strategy demonstrated here may be utilized in the further synthesis of natural products and potential bioactive compounds containing spirocycloheptane oxindole skeletons, such as Gelsemine et al.Chapter 3. Tandem Elimination-Michael-Michael Addition Process: The Synthesis of Spirocyclohexane Oxindole MoietiesThe spirocyclohexane oxindole skeletons have drawn tremendous attention among synthetic and medicinal chemists during the past few years due to their functional diversity and their significance in organic synthesis as crucial intermediates. We have developed a novel approach for the construction of spirocyclohexane oxindole moieties through a tandem elimination-Michael-Michael addition process. We investigated the reaction with simple substrates 3-methyleneindolinone 3-1 and N-benzyloxy α-haloamides 3-2. After optimizing the conditions, this method could be employed to synthesize a series of spirocyclohexane oxindoles containing up to three stereocenters under the mild reaction conditions（K2CO3 as the base, DCM as the solvent, room temperature, 24 h）, in high yields（up to 95%） and with high diastereoselectivities（dr > 20:1）, and a possible mechanism was proposed.Furthermore, the applications of the tandem elimination-Michael-Michael addition reaction are undergoing in our lab. We set this novel method as a key step to synthesize the bioactive compounds Lapatin B, which belongs to the Spiroquinazoline alkaloids family. Starting with readily available material, a key intermediate 3-3b was synthesized in four steps.Chapter 4. Tandem Intramolecular Cyclization-Michael Addition Reaction: The Synthesis of Oxazolyl-Oxindole CompoundsBoth oxindole skeletons and 5H-oxazol-4-ones represent ubiquitous structural motifs in a broad range of alkaloids and bioactive compounds. However, there has been limited research on the construction of the oxazolyl-oxindole frameworks from oxindole derivatives. We have designed a novel tandem intramolecular cyclization-Michael addition reaction to construct oxazolyl-oxindole moieties. We investigated the reaction with simple substrates 3-methyleneindolinone 3-1 and N-benzoyl α-haloamides 4-9. This new strategy provides an approach to the construction of a series of oxazolyl-oxindole derivatives, with moderate to good yields（up to 92%） and high diastereoselectivities（dr > 20:1）. This reaction demonstrated high functional group tolerance and a broad range of oxazolyl-oxindole derivatives could be synthesized efficiently, under the mild reaction conditions（K2CO3 as the base, DCM as the solvent, room temperature, 24 h）, and a plausible mechanism was proposed.Furthermore, incorporated with the results of Chapter 3, we have achieved the highly selective control of the two novel tandem reactions under the same reaction conditions, with almost the same substrate, via changing the substituents at the nitrogen atoms of α-bromoamides: the spirocyclohexane oxindole skeletons were constructed via elimination-Michael-Michael addition from N-benzyloxy α-bromoamides; while oxazolyl-oxindoles were achieved via cyclization-Michael addition from N-benzoyl α-bromoamides. This novel substituent-controlled selective synthetic strategy was developed to accomplish two kinds of oxindole derivatives via two sorts of simple but efficient tandem reactions.Besides, we also developed an asymmetric version of the cyclization-Michael addition reactions to construct chiral oxazolyl-oxindole derivatives. We have synthesized five kinds of bifunctional cinchona alkaloid-thiourea type catalysts, and tested a series of conditions to optimize the enantioselectivity. So far, in the optimal conditions, the ee value can reach 65%, and this work is undergoing in our laboratory.