Total Synthesis of Callyspongiolide: An Anticancer Marine Natural Product

Abstract

The stereoselective total synthesis of cytotoxic marine macrolide callyspongiolide has been reported. The 14-membered macrolactone ring along with Z -olefin in the molecule was constructed via an intramolecular Horner–Wadsworth–Emmons olefination in a Z -selective fashion. The other E -olefinic moiety as well as the C9 stereocenter was introduced via stereoselective addition of the methyl group in an S N 2′ fashion. The C5 stereocenter was installed via Sakurai allylation, whereas the C7 center was fixed by Jacobsen hydrolytic kinetic resolution. The C12 methyl and C13 hydroxy centers were fixed via Macmillan coupling reaction. The macrolactone core with a vinyl iodide side chain was coupled with the known alkyne fragment to complete the synthesis.

The Synthesis and Bioactivity of the Marine Macrolide Callyspongiolide

“…Similar to Xu and Ye's [26] approach, their synthetic strategy used carbamate formation as the final step, with their Sonogashira cross‐coupling joining the free alcohol‐containing macrocycle ent ‐ 3 with alkyne 4 (Scheme 22). [49] …”

“…Protecting group manipulations, followed by DMP oxidation and Takai olefination formed vinyl iodide 118 (Scheme 23). [49] …”

“… Synthesis of vinyl iodide 118 by S. Ghosh et al [49] . Reagents and conditions: i) allylSiMe 3 , TiCl 4 , CH 2 Cl 2 , −78 °C, 94 %; ii) LiBH 4 , Et 2 O, 0 °C–rt; iii) Et 3 N, TBDPSCl, DMAP, CH 2 Cl 2 , 0 °C–rt, 89 % (2 steps); iv) m CPBA, CH 2 Cl 2 , 0 °C–rt, 93 %; v) ( R , R )‐ 131 , H 2 O, 40 % ( 127 ) 44 % ( 126 ); vi) Et 3 N, PivCl, DMAP, CH 2 Cl 2 , 0 °C–rt, 87 %; vii) Et 3 N, MsCl, DMAP, CH 2 Cl 2 , 0 °C–rt, 92 %; viii) K 2 CO 3 , MeOH, 0 °C–rt, 74 %; ix) TMS acetylene, n BuLi, THF, BF 3 ⋅ OEt 2 , then 127 −78 °C–rt, 89 %; x) 2,6‐lutidine, TBSOTf, CH 2 Cl 2 , 0 °C–rt, 87 %; xi) K 2 CO 3 , MeOH, 0 °C–rt, 85 %; xii) NaBH 4 , MeOH, 0 °C, 93 %; xiii) TBAF, THF, 0 °C, 91 %; xiv) 2,2‐dimethoxypropane, p TSA, CH 2 Cl 2 , 0 °C–rt, 71 %; xv) DMP, CH 2 Cl 2 , 0 °C–rt, 94 %; xvi) n BuLi, THF, −78 °C then 123 , 83 %; xvii) DMP, NaHCO 3 , CH 2 Cl 2 , 0 °C–rt, 84 %; xviii) ( S , S )‐ 33 , i PrOH, 88 %, de >95 %; xix) H 2 , Pd/BaSO 4 , EtOAc/py/1‐octene, rt, 93 %; xx) 2‐picolinic acid, DMAP, EDCI (1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide), CH 2 Cl 2 , rt, 88 %; xxi) Me 2 S ⋅ CuBr, MeMgBr, THF, 40 °C, 95 %; xxii) ZnBr 2 , CH 2 Cl 2 , 0 °C, 92 %; xxiii) PPTS, PMP ( p ‐methoxyphenyl)‐acetal, CH 2 Cl 2 , 0 °C–rt, 85 %; xxiv) DIBAL‐H, CH 2 Cl 2 , −78 °C, 92 %; xxv) DMP, NaHCO 3 , CH 2 Cl 2 , 0 °C–rt, 95 %; xxvi) CrCl 2 , CHI 3 , THF, 0 °C–rt, 87 %.…”

A Ring Closing Metathesis Approach to the Formal Synthesis of (+)‐Callyspongiolide

“…Further total syntheses of (+)‐callyspongiolide ( 1 a ) by Fürstner et al [24,25] and the natural enantiomer (−)‐callyspongiolide ( 2 ) by Harran et al [26] . and S. Ghosh et al [27] . were reported in 2018.…”

“…Further total syntheses of (+)-callyspongiolide (1 a) by Fürstner et al [24,25] and the natural enantiomer (À )-callyspongiolide (2) by Harran et al [26] and S. Ghosh et al [27] were reported in 2018. Partial syntheses of this natural product have also been reported, with the synthesis of the macrocyclic core of (+)-callyspongiolide (1 a) by S. Ghosh [28] and the synthesis of the unsaturated side-chain of (À )-callyspongiolide (2) by Kotora [29] both reported in 2016, and a further synthesis of C3-C15 fragment of the macrocyclic core of (+)-callyspongiolide (1 a) published by Mohapatra in 2018.…”