Studies On The Synthesis Of The Bis-benzannelated [5,6]-Spiroketal Core Of Rubromycins With HDA Reaction

The thesis aims at the studies on the synthesis of the bis-benzennated[5,6] spiroketal skeleton of antibiotic Rubromycins.Systematic studies on the Hetero-Diels-Alder reaction between the o-Quinone methides(o-QMs)and different enol ether dienophiles for the construction of the spiroketal skeleton was described.It mainly consists of the following three chapters:Chapter 1.Structure identification,biologically valuable and research towards the synthesis of Rubromycins family(review)The sources,structure identification,bioactivity and synthesis of Rubromycins were presented.They are characterized to have highly functionalized naphthalene and isocoumarin.A special central spiroketal unit connects the two hemispheres together as the key feature and possess highly attractive antitumor,HIV reverse transcriptase inhibitority and inhibitority of DNA helicases.The synthesis research always focus on the synthesis of the special bis-benzannelated[5,6]-spiroketal core.The methods for the construction of the bis-benzannelated[5,6]-spiroketal skeleton were reviewed in according to the reaction type.It contains spirocyclization of bis-phenolic ketones under the catalysis of acid,etherification of benzofurans under the activation of halogen,transition metal catalyzed intramolecular addition between hydroxy and unsaturated bond,Mitsunobu reaction,aromatic Pumerer type reaction and[3+2] cycloaddition type reaction.Strongly emphasized two methods for the successful total synthesis of Rubromycins:the total synthesis of the racemic Heliquinomycinone from Danishefsky group with Mitsunobu reaction and the total synthesis of the racemicγ-Rubromycin form Kita group with two Pumerer type reactions.Chapter 2.Studies about the construction of the bis-benzannelated spiroketal core with the Hetero-Diels-Alder reactionDesigned and synthesized a series of 3,4-Dihydro-2-methylene-2H-l-benzopyrans and the o-Quinone methides precursors using the readily available salicylaldehyde derivatives and coumarins.Under the sealed tube conditions,they gave a series of bis-benzannelated[6,6]-spiroketal products successfully.It was the first report about the application of Hetero-Diels-Alder reaction for the construction of bis-benzannelated spiroketal skeleton.It was found that the substituents on the benzene ring of the vinyl ether have no effect on the reaction activity,7 examples,yield from 46%～60%.And the electro-donating group on the o-Quinone methides precursor can increase the reaction activity.We also found that the addition of TiCl₄ as catalyst improved the yield.More research revealed that the best equivalent of TiCl₄ is 5 mmol%,yield increased to 70%～60%.When the same condition was used for the construction of the bis-benzannelated[6,6]-spiroketal,methylenation of 2(3H)benzofuranones gave only 2-methylbenzofuran as the isomer of 2,3-dihydro-2-methylene-benzofuran, which can not construct the bis-benzannelated spiroketal with Hetero-Diels-Alder reaction.Chapter 3.Studies on the construction of the bis-benzannelated[5,6]-spiroketal of RubromycinsIn order to construct the bis-benzannelated[5,6]-spiroketal skeleton with Hetero-Diels-Alder reaction,the 2-methylene-3(2H)benzo-furanone was synthesized from readily available material.The isomerization of 2,3-dihydro-2-methylene-benzofuran to 2-methylbenzofuran was resolved.The Hetero-Diels-Alder reaction between the 2-methylene-3(2H)benzofuranone and the o-Quinone methides precursor gave the carbonyl bis-benzannelated[5,6]-spiroketal successfully.This model compounds can be used for the synthesis of the spiroketal in 3'-Hydroxy-β-rubromycin,β-Rubromycin,γ-Rubromycin and δ-Rubromycin.On the base of this model,another highly functionalized bis-benzannelated [5,6]-spiroketal was designed.Starting with readily available material,a series of key intermediate vinyl sulfoxides were synthesized in six steps. The Hetero-Diels-Alder reaction between the vinyl sulfoxides and the o-Quinone methides precursor gave the spiroketal products.The sulfoxides in the cycloadducts eliminated automatically under the same condition and gave a series of highly functionalized bis-benzannelated [5,6]-spiroketals in good yield.This model can be used for the synthesis of all of the Rromycins family.It was found that both the electro-withdraw and electro-donating substituents have no effect on reaction activity and the electro-withdraw substituents can increase the reaction activity.