Studies On The Construction Of "5, 6" Bisbenzannelated Spiroketals And Base-Oriented Chemoselective Tandem Wacker Cyclizations

[5,6]-bisbenzannelated spiroketal exists in biologically significant natural product rubromycins. Spiroketal moiety is an important pharmacophore and core skeleton of the rubromycins, so it is of major importance to construct this unit in total synthesis of rubromycins. This thesis aims at exploring novel conveneient method for the construction of bis-benzannelated [5,6]-spiroketal core of rubromycins. During the investigation, tandem Wacker cyclizations and NBS induced electrophilic cyclization were found to be efficient for this conversion, and a base-oreinted chemoselective Wacker aerobic cyclization to spiroketals or benzopyrans were found. It consists of the following four parts:Chapter 1. Review on the Structure, Biological Activities of the Rubromycins Family and the Construction methods of the Bis-benzannelated [5,6]-Spiroketal Core (review).The isolation, structural identification, bioactivity of Rubromycins were summarized. The basic structural motif of these natural products consists of an aliphatic [5,6]-spiroketal core fused to aromatic naphthoquinone and isocoumarin moieties. Spiroketal moiety is an important pharmacophore and core skeleton of the rubromycins, and it is of major importance to construct this unit in total synthesis of rubromycins. The methods for the construction of the bis-benzannelated [5, 6]-spiroketal skeleton were reviewed. It contains spirocyclization of bis-phenolic ketones under the catalysis of acid, etherification of benzofurans under the activation of halogen, Mitsunobu reaction, cycloaddition reaction, aromatic Pumerer type reaction and transition metal catalyzed intramolecular addition between hydroxy and unsaturated bond.Chapter 2. Palladium-Catalyzed Intramolecular Tandem Wacker Cyclization: Synthesis of Bisbenzannelated Spiroketals.The syntheses of oxo-heterocyclic compounds via palladium-catalyzed intramolecular Wacker cyclizations were introduced briefly and a new method was designed and investigated based on Intramolecular Tandem Wacker cyclization of bisphenol olefins. Firstly, the substrates 2-9 were synthesized using the readily available o-hydroxybenzaldehyde and allyloxybenzene as starting materials.2-9a was then used as substrate to explore the conditions and gave a bis-benzannelated [5, 6]-spiroketal products successfully. The experiments showed that 10 mol% PdCl2/20 mol% CuCl/1 atm O2/MeOH/reflux was the optimal reactive condition, under which various bisbenzannelated [5,6]-spiroketals 2-10 were obtained in 36～71% yields along with benzofuran 2-11. We also found the electro-donating group at the ortho or para position of phenolic hydroxyl group of phenyl ring A could increase the reaction activity. Deeply investigation proved that 2-11 are intermediates of 2-10, so the mechanism was proposed. Pd chelated with the double bond and the cyclization proceeded through 5-endo-trig and 6-exo-trig in turn to form the [5,6]-spiroketal core. It was the first report about the application of palladium-catalyzed intramolecular tandem Wacker cyclization for the construction of bisbenzannelated spiroketal skeleton. The process would serve as a good complement to the existing methodologies.Chapter 3. Palladium-Catalyzed Intramolecular Wacker Cyclizations-Micheal Additions:Synthesis of 2-Substituted Chromans.As the modification of the result in chapter 2, research in chapter found that the Wacker reactions gave different results in the presence of base, where 1, 2-difuncationalization happened to the olefins and benzopyran formed. Compared to chapter 2, a base-oriented chemoselective Wacker cylcization were discussed. Firstly, 1,2-difunctionalization reactions of olefin were reviewed including Prevost reaction, Sharpless Asymmetric Dihydroxylation and Sharpless Asymmetric Aminohydroxylation. Then,2-9 was used as model substrate to explore the conditions of the palladium-catalyzed intramolecular Wacker cyclization-Micheal addition and various 2-substituted chromans 3-1 were obtained with high chemoselective and good yields (56～95%) under the condition similar to the chapter 2 in the presence of base. The presence base could be responsible for the high chemoselective. Hence a palladium-catalyzed intramolecular tandem Wacker cyclization-Micheal Addition mechanism was proposed. The syn configuration of major product was determined by the NMR spectral analysis as well as the literature data. It was not only the first report about base-oriented chemoselective tandem Wacker cyclizations, but also for the first report about synthesis of 2-substituted chromans via Wacker cyclization-Micheal addition.Chapter 4. NBS induced Electrophilic Cyclization:construct of Bisbenzannelated Spiroketals.Halogen induced electrophilic cyclizations were introduced briefly. Using the readily available o-iodophenols and allyloxybenzene as starting materials, a series of alkynyl diphenols 4-5 were obtained after several effective steps.4-5a gave a bisbenzannelated [5,6]-spiroketal 4-6 successfully via electrophilic cyclization. The experiments showed that 2.4 equiv NBS/2.4 equiv K2CO3/CH2Cl2/MeOH (1: 1)/reflux was the optimal reactive condition. Various bisbenzannelated [5, 6]-spiroketals 4-6 were obtained with moderate yields (40～56%) under this condition. A contrastive study on the formation of aromatic spiroketals has also been conducted, which showed that alcohol perfom the reaction smoothly.