Marine Puupehenone and Puupehedione: Synthesis and Future Perspectives

Abstract

Puupehenone and puupehedione are natural products isolated from marine organisms. These compounds display a broad spectrum of biological activities, the in vitro antitubercular activity of puupehenone being a stand out, and are equipped with an interesting structural complexity. These products have served to stimulate the continual interest of the synthetic community. The first part of this article is a review of their total synthesis, using natural compounds which have the potential to be transformed into these marine compounds as starting materials; the synthetic routes employed to generate the basic skeleton; and the advances made to synthesize the pyran C ring with the required diastereoselectivity to obtain the natural products. Finally, this perspective shows a personal reflection of the authors on a possible unified and efficient retrosynthetic route that could allow easy access to these natural products, as well as their epimers at the C8 carbon and which could be used to address future biological issues in the production of pharmacologically active compounds.

Keywords: marine natural products; meroterpenoids; puupehedione; puupehenone.

Figure 1

Selected members of puupehenone-type natural compounds (C₈-Me_α). (Rings and atoms labels drawn only in 1).

Scheme 1

Starting materials employed in the previous synthesis of puupehenone (1) and puupehedione (2) [11,12,13,14,15,16,17,18,19,20,21,22,23].

Scheme 2

Barrero’s enantioselective synthesis of (+)-puupenhenone (1) from (-)-sclareol (8). Reagents and conditions: (I) Ref. [27]; (II) 15, t-BuLi, Et₂O, −78 °C, 88%; (III) (i) Cl₂SO, Py, rt, 1 h, 94%; (ii) TBAF, THF, rt, 15 min, 81%; (iii) NaBH₄, EtOH, rt, 20 min, 91%; (IV) NPSP, SnCl₄, CH₂Cl₂, −78 °C, 2 h, 91%; (V) (i) Raney Ni, THF, rt, 20 h, 75%; (ii) PDC, CH₂Cl₂, rt, 3 h, 70%. TBAF = tetrabutylammonium fluoride; NPSP = N-phenylselenophtalimide; PDC = pyridinium dichromate.

Scheme 3

Barrero’s enantioselective synthesis of puupehedione (2) from (-)-sclareol (8). Reagents and conditions: (I) Ref. [28]; (II) (i) t-BuLi, 15, Et₂O, −78 °C, 50 min, Ar; 20 Et₂O, −78 °C, 40 min; (ii) Et₃SiH, TFA, CH₂Cl₂, −78 °C, 45 min, 79%, two steps; (iii) TBAF, THF, rt, 15 min, 95%; (III) (i) Ac₂O, NaAcO, reflux, 2 h, 98%; (ii) mCPBA, NaHCO₃, CH₂Cl₂, −20 °C, 2 h, 98%; (IV) (i) 2N KOH-MeOH, rt, 48 h, 95%; (ii) H₂, 10% Pd/C, MeOH, rt, 1 h, 91%; (V) (i) silica gel, 45%; (ii) NaIO₄, EtOH-H₂O, rt, 15 min, 80%. TFA = trifluoroacetic acid; TBAF = tetrabutylammonium fluoride; mCPBA = meta-chloroperbenzoic acid.

Scheme 4

Álvarez-Manzaneda’s enantioselective synthesis of (+)-puupehenone (1) and (+)-puupehedione (2) from (-)-sclareol (8). Reagents and conditions: (I) Ref. [13]; (II) t-BuLi, 26, THF, −80 °C, 30 min, Ar; 25, THF, −80 °C, 30 min, 87%; (III) Raney Ni, THF, rt, 30 min, 98%; (IV) PdCl₂, Pd(OAc)₂ (cat), MeOH-H₂O (99:1), 40 °C, 48 h, 91%, (V) H₂, Pd/C, EtOH, rt, 48%, 99%; (VI) Ag₂O, THF, rt, 90 min, 95%; (VII) DDQ, dioxane, reflux, 2 h, 80%. DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone.

Scheme 5

Álvarez-Manzaneda’s enantioselective formal synthesis of (+)-puupehenone (1) from (-)-sclareol (8). Reagents and conditions: (I) Ref. [14]; (II) Amberlyst A-15, 4 Å molecular sieves, CH₂Cl₂, reflux, 12 h, 94%; (III) (i) MeMgBr, Et₂O, 0 °C, 30 min, 94%; (ii) H₂, Pd/C, MeOH, rt, 1 h, 93%; (IV) (i) (TfO)₂O, CH₂Cl₂, iPrNEt₂, 0 °C, 5 min, 83%; (ii) Pd(OAc)₂ (cat), DPPF, NaOtBu, toluene, 100 °C, 14 h, 76%; (V) (i) BBr₃, CH₂Cl₂, 0 °C, 80 min, 82%; (ii) Ref. [13]. DPPF = 1,1′-bis(diphenylphosphanyl)ferrocene.

Scheme 6

Quideau’s enantiospecific synthesis of (+)-puupehenone (1) from (+)-sclareolide (9). Reagents and conditions: (I) Ref. [15]; (II) (i) 36, t-BuLi, THF, −78 °C, 20 min; then 35 THF, −78 °C, 15 min, 73%; (ii) H₂, Pd/C (10%), THF, rt, overnight, 87%; (III) BTI, CH₂Cl₂, 45 min, −25 °C, 67%; (IV) KH, dioxane, rt, 1h; then 20 min at 45 °C, 27%. BTI = [bis(trifluoroacetoxy)-iodo]benzene.

Scheme 7

Wu’s enantiospecific synthesis of puupehenone (1) and puupehedione (2) from (+)-sclareolide (9). Reagents and conditions: (I) Ref. [15]; (II) 39, LDA, THF, −78 °C, 30 min; then 35, 1h, 67%; (III) HCl, MeOH, rt, 30 min, 92%; (IV) (i) KHDMS, THF, −78 °C, 30 min; (ii) then P(OMe)₃, O₂, −78 °C, 1 h, 42 (19%), 1 (38%); (V) tBuOK, tBuOH rt, 1 h, 86%; (VI) (i) NaBH₄, EtOH, rt, 20 min, 92%; (ii) DDQ, 1,4-dioxane, reflux, 2h, 71%. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Scheme 8

Wu’s enantiospecific synthesis of puupehenone (1) and puupehedione (2) from (+)-sclareolide (9). Reagents and conditions: (I) Ref. [15]; (II) pTsNHNH₂, MeOH, rt, 12 h, 88%; (III) 44, Pd(PPh₃)₄ (cat), K₂CO₃, toluene, 110 °C, 8 h, 85%; (IV) CAN, MeCN-H₂O, rt, 47%; (V) Pd/C, H₂, MeOH, 40 °C, 62%; (VI) CAN, MeCN-H₂O, −5 °C to rt, 84%; (VII) pTsOH, CH₂Cl₂, rt; (VIII) K₂CO₃, CH₃CN, rt, 92% from 48. CAN = ceric ammonium nitrate.

Scheme 9

Banerjee’s enantiospecific synthesis of puupehedione (2) from (-)-carvone (10). Reagents and conditions: (I) Ref. [18]; (II) n-BuLi, −78 °C (3 h) to −5 °C (6 h), to rt (2 h); then 50, −78 °C, 5 h, 59%; (III) silica gel, CH₂Cl₂, rt, 3–4 h; (IV) RhCl₃·3H₂O, EtOH, reflux, 7 h, quantitative.

Scheme 10

Xie’s enantiospecific and concise synthesis of (+)-puupehenone (1) and (+)-puupehedione (2) from (-)-carvone (10). Reagents and conditions: (I) Ref. [19]; (II) 55, 56, PdCl₂ (cat), PPh₃, K₂CO₃, CO (1 atm), DMF, 80 °C, 2h, rt; then 12 h at 80 °C, 73%; (III) AlCl₃, CH₃CN, reflux, 4 h, 90%; (IV) DEG, KOH, 120 °C, 12 h, 86 °C; (V) (i) LiAlH₄, THF; (ii) TFA/H₂O = 6/10 equiv, CH₂Cl₂, 86% two steps; (VI) Ref. [20]; (VII) BBr₃, 0 °C, CH₂Cl₂, 99%; (VIII) (i) DIPEA, MOMCl, CH₂Cl₂, 93%; (ii) LiBH₄, THF, 0 °C at rt, overnight; (iii) THF/H₂O: 10/1, p-TsOH, 40 °C, 2 h, 56% two steps, based on the recycled starting material. DMF = Dimethylformamide; DEG = Diethylene glycol; TFA = trifluoroacetic acid; DIPEA = N,N-diisopropylethyl amine; MOMCl = chloromethyl methyl ether.

Scheme 11

Armstrong’s stereoselective synthesis of puupehedione (2) from (-)-drimenol (11). Reagents and conditions: (I) PCC, CH₂Cl₂ THF (yield was not reported in the original publication); (II) (i) n-BuLi, −78 °C, 61, Et₂O, 25; (ii) TBAF, THF; (III) p-TsOH, benzene, rt, 16 h, 90% from 25; (IV) AgO/HNO₃, THF (yield was not reported in the original publication); (V) n-BuLi, 61, Et₂O, 25, p-TsOH, benzene. PCC = pyridinium chlorochromate; TBAF = tetrabutylammonium fluoride.

Scheme 12

Trammell’s stereoselective synthesis of (±)-puupehenone (1) from farnesol bromide. Reagents and conditions: (I) Ac₂O, pyridine; (II) (i) BF₃·Et₂O, CH₂Cl₂; (ii) KOH, MeOH, 40% overall yield; (III) β-naphthalenesulfonic acid, CH₂Cl₂; (IV) (i) PCl₅, CH₂Cl₂, reflux; (ii) H₂O, MeOH, reflux; (V) KOH, MeOH, O₂, quantitative yield.

Scheme 13

Gansäuer’s diastereoselective synthesis of (±)-puupehedioine (2) from farnesol 68. Reagents and conditions: (I) Ref. [44]; (II) Li₂CiCl₄ (cat), 13, THF, 0 °C; then 69, 3 h at 0 °C, then overnight at rt, 60%; (III) Cp₂TiCl (cat), Mn, 2,4,6-collidine, Me₃SiCl, THF, rt, overnight, 41%; (IV) (i) DMAP, C₆F₅OCSCl, CH₂Cl₂, 2h, rt, 76%; (ii) HSnBu₃, AIBN, benzene, reflux, 1 h, 77%; (iii) p-TsOH, MeOH, 48 h, rt, 85%; (V) (i) N-(phenylseleno)phthalimide, SnCl₄, CH₂Cl₂, 0 °C, 30 min, 80%; (ii) HSnBu₃, AIBN, benzene, reflux, 1 h, 86%; (VI) Ref. [12]. DMAP = 4-Dimethylaminopyridine; C₆F₅OCSCl = O-pentafluorophenyl chlorothioformate; AIBN = Azobisisobutyronitrile.

Scheme 14

Unified retrosynthetic analysis of puupehenone-type natural and unnatural products.