Collective Synthesis of Lycopodium Alkaloids and Tautomer Locking Strategy for the Total Synthesis of (−)-Lycojapodine A

et al. 2014

Angew Chem Int Ed

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Utilizing a late-stage enamine bromofunctionalization strategy, the twelve-step total synthesis of (-)-huperzine Q was accomplished. Furthermore, the first total syntheses of (+)-lycopladines B and C are described. An unprecedented X-ray crystal structure of an unusual epoxyamine intermediate is also reported, and the synthetic application of this intermediate in natural product synthesis is demonstrated.

Section: Methodsmentioning

confidence: 99%

Total Syntheses of (−)‐Huperzine Q and (+)‐Lycopladines B and C

et al. 2014

Angew Chem Int Ed

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“…Lemieux–Johnson oxidation of 17 afford aldehyde precursor 18 , and subsequent treatment of 18 with SmI 2 in THF afforded two coupling products, 4,5‐ trans diol 19 and 4,5‐ cis diol 20 , in yields of 32 and 30 %, respectively. Oxidation of 19 and 20 by Ley oxidation and Swern oxidation, respectively, provided α‐hydroxy ketone 21 exclusively in both cases without any diol oxidative cleavage byproduct . Deoxygenation of 21 with SmI 2 using t BuOH as the proton source furnished tricyclic ketone 7 in 89 % yield.…”

Section: Resultsmentioning

confidence: 99%

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

Chemistry An Asian Journal

et al. 2017

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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...

“…To rationalize the stereochemical outcome of the formation of 22 and 23 from 5 ,27 a dynamic kinetic epimerization process is suggested (Scheme ): α‐ 5 is in equilibrium with β‐ 5 under acidic conditions. By treatment with NBS, both isomers are converted into the corresponding bromonium ions 26 and 27 , which further undergo sequential ring opening (to form α‐bromoiminium ions), hydration (leading to keto‐amines), and eventually ring–chain tautomerization28 to afford hemiaminals 28 and 29 , respectively. Whereas dehydration of 28 under acidic conditions provided α (C15)‐bromide 22 , hemiaminal 29 underwent an intramolecular S N 2 reaction and afforded β (C15)‐epoxyamine 23 as a single isomer.…”

Section: Methodsmentioning

confidence: 99%

Total Syntheses of (−)‐Huperzine Q and (+)‐Lycopladines B and C

et al. 2014

Angewandte Chemie

Self Cite

Utilizing a late-stage enamine bromofunctionalization strategy, the twelve-step total synthesis of (À)-huperzine Q was accomplished. Furthermore, the first total syntheses of (+)-lycopladines B and C are described. An unprecedented X-ray crystal structure of an unusual epoxyamine intermediate is also reported, and the synthetic application of this intermediate in natural product synthesis is demonstrated.