A General Strategy for the Construction of Calyciphylline A‐Type Alkaloids: Divergent Total Syntheses of (−)‐Daphenylline and (−)‐Himalensine A

Abstract

An efficient general strategy for the synthesis of the Daphniphyllum alkaloids via the rapid construction of a common core intermediate has been established, based on which a divergent total synthesis of (−)‐daphenylline and (−)‐himalensine A has been accomplished in 16 and 19 steps, respectively. The present work features an enantioselective Mg(ClO4)2‐catalyzed intramolecular amidocyclization to construct the aza‐bridged core structure; a Cu‐catalyzed intramolecular cyclopropanation and subsequent phosphine‐catalyzed Cope‐type rearrangement to furnish the himalensine A scaffold; and a one‐pot Diels–Alder/aromatization method to assemble the aromatic skeleton of daphenylline.

Facile Generation of Fused Seven-Membered Polycyclic Systems via Ring Expansion and Application to the Total Synthesis of Sesquiterpenoids

“…Molecules with fused seven-membered ring systems have attracted considerable attention due to their extensive presence in biologically active natural products and small molecule drugs, such as daphenylline, aplyviolene, pepluanol A, and ingenol (Figure 1). [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] For this reason, methods with high efficiency for the 2 synthesis of fused ring systems is in great demand. However, those seven-membered ring systems are particularly difficult to prepare due to their typically higher strain barrier than other sized rings.…”

Total Synthesis of Daphniphyllum Alkaloids: (+)-Daphlongamine E, (+)-Calyciphylline R, and (–)-10-Deoxydaphnipaxianine A

“…The next step was a seemingly straightforward transformation, selective amide reduction in presence of ketones, as several similar examples have well proved the power and feasibility of selective amide reduction. 5` c d , 10b 11 16a However, attempts to convert our substrate, tricarbonyl compound 25 , into target molecule (–)-10-deoxydaphnipaxianine A through selective amide reduction in presence of two ketone motifs proved extremely difficult. Attempts using Vaska’s conditions 25 yielded only a trace amount of desired product, while global reductions of all three carbonyls gave only messy and irreproducible results.…”

“…Interestingly, the amide moiety in compound 30 behaved drastically different than the one in compound 25 . Under selective amide reduction conditions using Vaska’s catalyst, 5c 10b 11 16a 25 compound 30 was smoothly reduced to yield (+)-daphlongamine E in 66% yield. Lastly, further oxidation ( m- CPBA, 90%) of (+)-daphlongamine E afforded its N -oxide congener, (+)-calyciphylline R. In addition, we also attempted to convert daphlongamine E into its other natural congeners, such as daphniyunnine B, 31 calyciphylline S, 30 and 17- O -acetyldaphniyunnine B 28 (Scheme 5 ) by functionalization of its terminal alkene moiety.…”

Synthesis of the [6.6.7.5] Tetracyclic Core of Calyciphylline N via a Boc-Mediated Oxidative Dearomatization/Diels–Alder Approach

“…2 After that, a series of elegant total syntheses and constructive studies on the skeleton of Daphniphyllum alkaloids constantly updated our understanding of these molecules. 3 Kobayashi and co-workers successfully reported the isolation of five novel hexacyclic daphniphyllum alkaloids: Daphmanidin A (1), 4 E (3), and F (4), 5 Daphtenidine C ( 5), 6 and Calyciphylline N (2) 7 from 2002 to 2009, composing as a new subtype of Daphmanidin Atype (Figure 1). Structurally, these members possess a dihydropyrrole, a unique bicyclo[2.2.2]octane core, and a tricyclic dodecahydrocyclopenta[cd]azulene.…”