Biogenetically Inspired Total Synthesis of (+)‐Liphagal: A Potent and Selective Phosphoinositide 3‐Kinase α (PI3Kα) Inhibitor from the Marine Sponge Aka coralliphaga

Abstract

A biologically attractive and structurally unique marine natural product, (+)-liphagal, was biomimetically synthesized in 29 % overall yield in a longest linear sequence of 13 steps from commercially available (+)-sclareolide. This synthesis involved the following crucial steps: (i) stereocontrolled hydrogenation of an endo-olefinic decalin to install the C8 stereogenic centre present in the requisite decalin segment;[a]

Total Synthesis and Structure Revision of (−)-Siphonodictyal B and Its Biomimetic Conversion into (+)-Liphagal

“…12 The Katoh group indirectly achieved a similar transformation via a three step sequence involving a protected substrate. 8 We started our synthesis of 3 (Scheme 2) from (+)-sclareolide (8), an inexpensive chiral pool starting material that has found wide application in the synthesis of terpenoid natural products. 13 Conversion of 8 into aldehyde 9 was achieved in six steps according to published procedures.…”

“…13 Conversion of 8 into aldehyde 9 was achieved in six steps according to published procedures. 6,8 Addition of the aryllithium species derived from aryl bromide 10 14 to aldehyde 9 then gave benzylic alcohol 11 in 74% yield as a single diastereomer, although the C-15 relative configuration was not determined. Dehydration of 11 by treatment with POCl 3 and pyridine gave alkene 12 in 54% yield.…”

Total Syntheses of Liphagal: A Potent and Selective Phosphoinositide 3-Kinase α (PI3Kα) Inhibitor from the Marine Sponge Aka coralliphaga

“…2a → 1 in Scheme 36), appears to be the most elegant methodology for the synthesis of the natural product. Relative to the enantioselective syntheses, the main advantage of our method is the higher overall yield [our synthesis (2014): 29.7% overall yield in 13 steps; 18 Andersen's synthesis (2010): 1.2% overall yield in 16 steps; 15 George's syntheses (2010, 2015): 9.2% overall yield in 13 steps, 12 4.6% overall yield in 11 steps; 11 Alvarez-Manzaneda's synthesis (2010): 15.9% overall yield in 12 steps; 16 Stoltz's synthesis (2011): 0.36% overall yield in 19 steps 17 ]. These syntheses are promising for the preparation of additional analogs of 1 in enantiomerically pure forms with the aim of exploring their structure-activity relationships, which will be useful for the design and development of novel therapeutic agents that target the inhibition of PI3Kα.…”

“…(17), which has already been converted to (±)-1, can be produced from brominated dienylbenzofuran 6 by biomimetic polyene cyclization followed by formylation on the aromatic ring (6 → 5 → 17). The key cyclization precursor 6 can be elaborated through the S N 2-type coupling reaction between acetylbenzofuran 19 and commercially available geranyl bromide (18). Intermediate 19 can be accessed from 2,4,5-trimethoxybenzaldehyde (11).…”

“…In 2006, the first total synthesis of racemic (±)-1 was presented by Andersen et al 6 Subsequently, the formal total syntheses of (±)-1 were reported by Mehta et al (2009) 13 and Kumar et al (2011), 17 and our group (2014). 18 Recently, the formal total synthesis of (±)-1 was reported by Ferreira et al (2017). 19 Related synthetic studies have also been reported by several other research groups.…”