Divergent Total Syntheses of (−)‐Huperzine Q, (+)‐Lycopladine B, (+)‐Lycopladine C, and (−)‐4‐epi‐Lycopladine D

Abstract

We report herein our synthetic efforts towards the divergent syntheses of (À)-huperzine Q( 1), (+ +)-lycopladine B (2), (+ +)-lycopladine C( 3), and (À)-lycopladine D( 4). The 10-step total synthesis of (À)-huperzine Q( 1)a nd the first total syntheses of (+ +)-lycopladines B( 2)a nd C( 3)w ere accomplished through as eries of cascade reactions. Our approach involved aM ichael addition/aldol/intramolecular C-alkylation sequence to forge the 6/9 spirocycle ring, and this was followed by an ethylene-accelerated carbonyl-olefin metathesis to construct the common 6/5/9 ring system.F inally,l atestage enamine bromofunctionalization enabled us to access (À)-huperzine Q( 1), (+ +)-lycopladine B( 2), and (+ +)-lycopladine C( 3), and at andem C4-epimerization/retro-Claisenc ondensation furnished (À)-4-epi-lycopladine D( 63). IntroductionThe Lycopodium alkaloids are al arge family of complex natural products.N early 300 compounds have been isolated so far. [1] Owing to their intricate polycyclic skeletons andd iverse bioactivities, the total syntheses of these alkaloids have attracted broad attention from the synthetic community in recent years. [2] Among these compounds, (À)-huperzine Q( 1), (+ +)-lycopladine B( 2), (+ +)-lycopladine C( 3), and (À)-lycopladine D( 4) are four structurally relatedf awcettimine-type alkaloids (Figure 1). HuperzineQ (1)w as isolatedf rom Huperzia serrata by Zhu and co-workersi n2 002, and it possessesa nu nprecedented pentacyclic ring system and an aminal moiety. [3] The Takayama group [4] and the Zhao group [5] reported the total syntheseso f1 in 2011a nd 2015, respectively.( + +)-Lycopladine B (2), (+ +)-lycopladine C( 3), and (À)-lycopladine D( 4)w ere isolated from Lycopodium complanatum by Kobayashi and co-workers in 2006. [6] Whereasb oth (+ +)-lycopladines B( 2)a nd C( 3) contain au nique tetracyclic skeleton with ad ienamine moiety, (À)-lycopladine D( 4)c onsists of ap entacyclic core structure with ac arbinolamine lactone core. In 2013, Zhao and co-workers achievedt he first total synthesis of (À)-lycopladine D( 4). [7] Herein, we describe af ull account of our divergents yntheses of (À)-huperzine Q( 1), (+ +)-lycopladine B( 2), and (+ +)-lycopladine C( 3) [8] as wella so ur synthetic efforts towards (À)-lycopladine D( 4). Retrosynthetic analysisOur retrosynthetic analysisf or (À)-huperzine Q( 1), (+ +)-lycopladine B( 2), (+ +)-lycopladine C( 3), and (À)-lycopladine D( 4)i s outlined in Scheme 1. We envisioned that the aminal moietyi n 1 and the dienamine moieties in 2 and 3 could be derived from enamine intermediates 5 and 6,r espectively.W hereas both 5 and 6 could arise from 7 by aC 4-epimerization/cyclization sequence, diketone 7 could also potentially serve as ac ommon synthetic intermediate for the synthesis of (À)-lycopladine D( 4)t hrough aldehyde 10.T he cyclopentanone ring in 7 could be constructedf rom spirocyclic diketone 8,w hich could be readily accessed from enone 9 through our previously developed Michael addition/aldol/C-alkylation method.Initial synthe...

Chiral Tetrahydropyridines via FeCl3-Catalyzed Carbonyl-Olefin Metathesis

“…We recently reported a distinct design principle for catalytic carbonyl-olefin ring-closing metathesis reactions for the synthesis of cyclic systems such as spirocyclic lactones, indenes, polyaromatic hydrocarbons and 3-pyrrolines. [11][12][13] Upon reaction with FeCl3 as a Lewis acid catalyst, aryl ketones bearing prenyl or styrenyl fragments undergo a concerted, asynchronous [2+2]-cycloaddition to form intermediate oxetanes. A subsequent Lewis acid-catalyzed retro [2+2]-cycloreversion results in the desired ring-closing metathesis product.…”

Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of α,β-Unsaturated Aldehydes

“…A similar method was recently reported by the Lei group [121] who used an iminium-catalyzed Robinson annulation reaction to build up the required skeleton enone 174 of Lycopodium alkaloids, namely, (−)-huperzine Q, (+)-lycopladine B, (+)-lycopladine C, and (−)-4- epi -lycopladine D (Scheme 44) starting from the common precursor 175 .…”

Fawcettimine‐Type Lycopodium Alkaloids as a Driving Force for Discoveries in Organic Synthesis

“…Our group finished the second synthesis of (−)‐ 13 in 2015 . As shown in Scheme b, an organocatalytic annulation provided enantioenriched enone ( 143 ).…”

“…In 2017, our group also disclosed our synthetic efforts which ultimately accumulated into the synthesis of (−)‐4‐ epi ‐lycopladine D ( 181 ) . As shown in Scheme b, upon treatment with K 2 CO 3 /MeOH, diketo‐aldehyde ( 176 ) underwent tandem C 15 epimerization/intramolecular aldol reaction to generate tetracyclic intermediate ( 177 ).…”

“…Lycopladines B ( 18 ) and C ( 19 ) were also isolated from Lycopodium complanatum by Kobayashi group in 2006 . In 2015, our group finished the first total synthesis of (+)‐ 18 and (+)‐ 19 . As shown in Scheme , an ethylene‐accelerated, selective carbonyl‐olefin metathesis generated desired tricyclic product ( 146 ) in 48 % isolated yield.…”