Synthesis and structure revision of nakiterpiosin

Abstract

This manuscript describes a convergent synthesis and the revision of the relative stereochemistry of nakiterpiosin, a marine C-nor-D-homosteroid. Our synthesis features a late-stage carbonylative Stille cross-coupling reaction and a photo-Nazarov cyclization reaction that deliver the complete nakiterpiosin skeleton efficiently.

Figure 1

The C-nor-D-homosteroids.

Figure 2

Our synthetic approach to 1.

Scheme 1

The synthesis of 6^{a a}Reaction conditions: (a) CDI, NH(OMe)Me•HCl, CH₂Cl₂, 23 °C, 74%. (b) 2 mol % RuCl[(S,S)-TsDPEN](p-cymeme), HCOONa, H₂O, 40 °C, 87%, 91% ee. (c) H₂C=C(Me)MgBr, THF, 0 to 23 °C, 84%. (d) Me₂AlCl, CH₂Cl₂, −78 to −30 °C, 71%. (e) DMAP, ArSO₂Cl, CH₂Cl₂, 0 to 23 °C, 100%; Ar = 2-(MeOOC)Ph. (f) 20 mol % OsO₄, NMO, acetone, H₂O, 23 °C, 89%. (g) LiBr, acetone, 70 °C, 62%. (h) KHMDS, PhNTf₂, THF, −78 °C, 96%.

Scheme 2

Synthesis of 7 and completion of the synthesis of 1^{a a}Reaction conditions: (a) 15 mol % Ti(OⁱPr)₄, 18 mol % (−)-diethyl tartrate, ^tBuOOH, 4Å MS, CH₂Cl₂, −20 °C, 98%, 92% ee. (b) TBSCl, imidazole, DMF, 23 °C, 97%. (c) (Ar′O)₂AlMe, CH₂Cl₂, −78 °C, 79%, 71% ee; Ar′ = 4-Br-2,6-^tBu₂-Ph. (d) 10 mol % Bi(OTf)₃, 3-Me-2-TIPSO-furan, CH₂Cl₂, −40 °C, 76% (56% conversion), dr 11:1, 60% ee. (e) H₂, 10 mol % [(cod)Ir(PCy₃)(Py)]PF₆, CH₂Cl₂, 23 °C, 97%, dr 6:1. (f) Dess-Martin periodinane, H₂O, CH₂Cl₂, 23 °C, 98%. (g) NaBH₄, THF, EtOH, −78 °C, 93%. (h) TBSOTf, 2,6-lutidine, CH₂Cl₂, 40 °C, 93%. (i) 1) HOAc, THF, H₂O, 60 °C, 76%. (j) Dess-Martin periodinane, H₂O, CH₂Cl₂, 23 °C, 91%. (k) Cl₂, P(OPh)₃, NEt₃, CH₂Cl₂, −78 °C, 83%. (l) 45 mol % Pd(PPh₃)₄, Me₃Sn–SnMe₃, dioxane, 100 °C, 50%. (m) 1 atm CO, Pd(PPh₃)₄, CuCl, DMSO, 55 °C, 62%. (n) hν (350 nm), CH₃CN, 23 °C. (o) ⁱPr₂NH, MeOH, 50 °C, 60% for two steps. (p) TFA, CH₂Cl₂, H₂O, 23 °C. (q) NaIO₄, acetone, pH 7.4 buffer, 23 °C. (r) BF₃•OEt₂, Et₃SiH, CH₂Cl₂, 0 to 23 °C, 44% for three steps. (s) TBAF, THF, 23 °C, 79%.