Stereoselective coupling of alkyne and dicarbonyl system to form high oxygen carbon ring

The high oxygen carbon ring is very challenging in chemical synthesis Generally, a series of rings can be synthesized to form a multi ring system, but the most advanced synthesis method is also difficult to build new rings and assemble multiple adjacent SP 3 centers (quaternary carbon or tertiary alcohol) at the same time The defects of the synthesis method make the synthesis of oxycarbon ring need to go through two different stages, that is, to build a high-density functionalization system first, and then to form a ring In spite of the rapid development of cyclization and functionalization reactions, it is still difficult to prepare carbon ring systems (as shown in Figure 1a, 1-3) with multiple / continuous total substitution of SP 3 carbon Figure 1 High oxygen carbon ring molecule (a) and synthesis design (B & C) source: J am Chem SOC Recently, Glenn C from Dartmouth College Professor micalizio's team has established a reaction mode that can realize the simultaneous formation of rings and the construction of high-density oxygen-containing molecular structure Through this mode, five or six membered rings can be isolated or in a multi ring system (Figure 1b) The research begins with the realization of the formation of a series of keys in Fig 1C The oxidation of cyclopentene (I I), an intermediate of carbonyl addition, was obtained by the formation of cyclopropene (I) Subsequently, the complexation of terminal carbonyl oxygen with metal center promotes stereocontrolled nucleophilic addition to form a bridged metal alkyl oxide system (III) Although the chain reaction of metal cyclopropane / olefine intermediates is considered to be the core feature of the fourth group of metals involved in the cyclization reaction, the stereospecific diols studied in this paper are first reported Professor Glenn C micalizio source: Dartmouth College reaction feasibility study design is shown in Figure 2 First of all, the author tried to react TMS phenylacetylene (4) with methyl 4-oxobutyrate (5) under the action of Ti, but did not get the target cyclization product (Fig 2 (1)) After replacing ester (5) with ketone (7), the reaction was successfully carried out to obtain cyclohexene glycol 8, and no regio isomeric and stereoisomeric products were found (Fig 2 (2)) The reactions (3) and (4) in Fig 2 show that TMS alkynes containing aromatic heterocycles (9) and aliphatic branched chains (11) are also compatible with this reaction The cyclohexene products from the reaction all contain secondary alcohol and allyl tertiary alcohol structures, which have not been obtained by other cyclization methods before Further experiments show that TMS alkyne and 1,3-diketone can also have the target cyclization reaction The key to success is to replace the reductant n-BuLi with i-prmgcl, but the mechanism is not clear (Fig 3 (5)) Fig 2 Source of intermolecular alkyne dicarbonyl coupling reaction: J am Chem SOC In order to obtain dense functionalized polycyclic, the author began to study the intramolecular transformation The reactions (6) and (7) in Fig 3 show that 1,3-diketones containing alkynes can be cyclized in stereoselective molecules successfully, and the efficiency is higher than that of intermolecular cyclization Cyclopentene products from cyclization of 1,3-diketone and alkyne can be further oxidized to obtain five completely substituted SP 3 carbons As shown in Fig 3 (8), adding t-BuOOH to terminate the cyclization reaction, an epoxy glycol compound 20 containing a bicyclic [3.3.0] octane structure can be obtained γ - diketone can undergo the same process of cyclization and oxidation For example, compound 16 can react to get high oxygen octahydroindene 22 Its structure was characterized by X-ray diffraction The cyclization process also has some limitations It is found that none of methyl ketone 23, conjugated alkyne 24 and propyne ether 25 can react smoothly without steric hindrance (Fig 3b) Although the reaction is limited, this synthesis strategy has application value It is very important to realize stereoselectivity of cyclization process by substrate control for the synthesis of complex structures Figure 3 Cyclization source of diketone: J am Chem SOC Finally, in order to verify the application value of alkyne and diketone cyclization strategy, the author synthesized ryanodol core structure IV (Figure 4a) Starting from the simple raw material cyclohexanone 26, through alkylation, hydrolysis, acylation, methylation and other reactions, as well as the key cyclization process, the author has also obtained the structure 29 and 30 of the high oxygen containing multi carbon ring (Fig 4b) Figure 4 Application source of alkyne dicarbonyl cyclization: J am Chem SOC Conclusion: Professor Glenn C micalizio's team developed a cyclization strategy with alkyne and dicarbonyl as substrates to generate dense functionalized and high oxygen-containing carbon rings The products of 4-5 consecutive completely substituted SP 3 carbons and stereoselective tertiary alcohols can be obtained by the reaction, which is difficult to obtain by traditional cyclization Although the reaction substrate is limited, it is a very effective method to construct multi substituted carbon ring system.