JACS: the rawal group of the University of Chicago reported the total synthesis of seven membered ring (−) - ambiguine p

The natural products of ambiguine belong to indole alkaloids (Figure 1) Since smitka et al Reported the indole alkaloids of ambiguine from cyanobacteria in 1992, 18 natural products of hapalindole have been identified These natural products have a wide range of biological activities, including antifungal, anti microbial and anti-cancer Due to the complexity of its structure and wide range of biological activities, the realization of its total synthesis has been the focus of organic chemists for many years In 2007, Baran group reported the total synthesis of tetracyclic a mbiguine H (2) Compared with the synthesis of tetracyclic a mbiguine H (2), the total synthesis of pentacyclic abiguine P (5) is more difficult due to the presence of seven membered indole fused ring Recently, the rawal group of the University of Chicago reported the total synthesis of 5, and successfully realized the construction of 7-membered ring in ambiguines P The results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b01739) (photo source: J am Chem SOC.) inverse synthesis analysis of ambiguine P (5) (scheme 1): the key step in the strategy proposed by the author is to construct the cycloheptano [b] indole structure by [4 + 3] cycloaddition reaction between indole stable TERT carbocation 9 and diene 10 suitable for functionalization The ring was formed by Friedel crafts electrophilic substitution reaction to form a five membered ring intermediate 7 At last, NBS mediated bromination was used to realize the electrophilic bromination / SN1 'substitution and the introduction of key C15 hydroxyl group to realize the full synthesis of ambiguine P (5) (photo source: scheme 2 of [4 + 3] cycloaddition reaction of J am Chem SOC.): firstly, the author determines the feasibility of key [4 + 3] cycloaddition reaction through model study In the reaction, tert alcohol 11 and 2-methylsiloxybutadiene 12 prepared from ethyl indole-2-carboxylic acid ester were used as raw materials After TMSOTf treatment, ternary ring 13 was obtained in 62% yield Under the same reaction conditions, diene-14 derived from 1-acetylcyclohexene with more substituents and tertiary alcohol-11 can obtain [4 + 3] cycloaddition product quaternion ring-15 in 87% yield The experimental results show that [4 + 3] cycloaddition reaction between indole stable intermediate of tertiary carbon cation and diene is feasible (photo source: J am Chem SOC.) construction of ambiguine P (5) pentacyclic skeleton (scheme 3): Based on the results of model study, the author constructs ambiguine pentacyclic skeleton with properly modified diene Firstly, ketone 16 was deprotonated by khmds, then it was treated with Comins reagent to produce its enol trifluoromethane sulfonate 17, and then 18 was obtained by Stille coupling and hydrolysis, after TBS was introduced, diene 19 was obtained Finally, four rings 21 was obtained by [4 + 3] cycloaddition of diene 19 and alcohol 11 However, the author found that the main product of the actual reaction is ketene 23, not cycloaddition product 21, which is inconsistent with the model product The author conjectures that allylic cation 22 will be formed by bonding between benzyl carbon and enol ether, and then seven membered rings will be formed by coupling the inner double bond and indole double bond, so the author hopes to explore several conditions to transform compound 23 into 21 to complete the construction of seven membered rings Finally, it is found that [4 + 3] cycloaddition product 21 can be obtained by treating 23 with naaucl 4 · 2H 2O in 1-propanol 。 Finally, the author treated 21 with BF 3 · OET 2 and MeOH, and formed ambiguine p-skeleton 24 in good yield (photo source: J am Chem SOC.) (−) - ambiguine P synthesis (scheme 4): after the construction of five membered ring 24, the author first oxidizes ketone 24 to enone 26 with DDQ, then protects indole nitrogen with BOC Group, and further reduces carbonyl with lial (OME) 3H to obtain a single enantiomer of enol 28 Then the author dehydrated compound 28 to 29 with Martin reagent, and then removed the BOC Group to obtain diene 7 rich in electrons Finally, the author reacted diene 7 with NBS to obtain a 2.0:1 mixture of C15 hydroxylated enantiomers, from which a pure (−) - ambiguine P (5) was obtained with a yield of 39% (photo source: J am Chem SOC.) the possible mechanism of the formation of − - ambiguine P (5) (scheme 5): the author thinks that 7 is electrophilic brominated at C23 (the terminal carbon of diene), and the intermediate 30 is obtained, and its C15 position loses proton to form diallyl bromide 31 At last, the dissociated carbon ions at C15 site capture H 2O, and the product (- - ambiguine P (5) is obtained (photo source: J am Chem SOC.) Summary: the author has completed the total synthesis of (−) - ambiguine P by a simple method starting from the easily obtained ketone 16 Inspired by the [4 + 3] cycloaddition reaction, the synthesis uses two steps to construct cycloheptyl [b] indole group and Friedel Crafts reaction to construct five membered cycloambiguine skeleton; nbs mediated bromination is used to realize electrophilic bromination / SN1 'substitution to introduce the key C15 hydroxyl group in natural products The strategy is universal, which lays a foundation for the synthesis of other five ring members of the ambiguines alkaloid family.