Total Syntheses of Scabrolide A and Nominal Scabrolide B

Abstract

The marine natural product scabrolide A was obtained by isomerization of the vinylogous 1,4-diketone entity of nominal scabrolide B as the purported pivot point of the biosynthesis of these polycyclic norcembranoids. Despite the success of this maneuver, the latter compound itself turned out not to be identical with the natural product of that name. The key steps en route to the carbocyclic core of these targets were a [2,3]-sigmatropic rearrangement of an allylic sulfur ylide to forge the overcrowded C12-C13 bond, an RCM reaction to close the congested central six-membered ring, and a hydroxy-directed epoxidation/epoxide opening/isomerization sequence to set the "umpoled" 1,4-dicarbonyl motif and the correct angular configuration at C12.

Scheme 1. Structure and Proposed Biosynthesis of Tetracyclic Norcembranoids

Scheme 2. Retrosynthetic Analysis

Scheme 3

Reagents and conditions: (a) TMSCN, NMO, CH₂Cl₂; (b) LiAlH₄, Et₂O, 0 °C; (c) NaNO₂, aq. HOAc, 0 °C, 71% (over three steps); (d) TMSOCH₂CH₂OTMS, TMSOTf (1 mol %), CH₂Cl₂, −78 °C → −20 °C; (e) mCPBA, CH₂Cl₂, −20 °C, 77% (over two steps); (f) nBuLi, 2,2,6,6-tetramethylpiperidine, Et₂AlCl, toluene, 0 °C, quant.; (g) (i) MsCl, Et₃N, CH₂Cl₂, 0 °C; (ii) aq. NaHCO₃, 20 °C, 44%; the scales shown in this and the other Schemes refer to the single largest batch.

Scheme 4

Reagents and conditions: (a) 21 (0.2 mol %); (b) NaH, TBSCl, THF, 65 °C; (c) RuCl₃·H₂O (1 mol %), Mg(OAc)₂·4H₂O, tBuOOH, 55% (over three steps); (d) (i) 1,3-butadiene, AlCl₃, toluene; (ii) l-Selectride, THF, −78 °C, 69% (over two steps); (e) (i) O₃, CH₂Cl₂; (ii) PPh₃; (f) (i) PCC, CH₂Cl₂, 4 Å MS, 0 °C; (ii) NaBH₄, 0 °C, 44% (over three steps); (g) 2-nitrophenylselenocyanate, nBu₃P, THF, 88%; (h) (i) NaOH, MeOH; (ii) TBSCl, DMF, imidazole; (i) 12, DCC, Et₃N, DMAP cat., CH₂Cl₂, 59% (over three steps); (j) KHMDS, Et₃N, TMSCl, THF, −78 °C → 70 °C, or: LiHMDS, TMSCl, THF, −78 °C → 70 °C.

Scheme 5

Reagents and conditions: (a) LiHMDS, MeSSO₂Me, THF, −78 °C → −30 °C, 95%; (b) SOCl₂, pyridine, Et₂O, 0 °C, 89%; (c) (i) 23a (X = Cl), NaI, acetone, reflux; (ii) AgBF₄, 2,6-di-tert-butylpyridine, 22, MeCN; (iii) tBuOK, MeCN; (d) TBAF, THF, reflux, 26 (31%) + 27 (33%) (over three steps)

Figure 1

ORTEP representation of the structure of compound 27 in the solid state.

Scheme 6

Reagents and conditions: (a) (i) Bu₃SnH, AIBN, toluene, 85 °C; (ii) DBU, MeCN, reflux, 79% (28), 66% (13-epi-28); (b) 21 (10 mol %), toluene, 100 °C, 77%; (c) Montmorillonite K-10, CH₂Cl₂; (d) VO(acac)₂ (10 mol %), tBuOOH, MS 4 Å, toluene, 0 °C → 20 °C; (e) Et₃N, CH₂Cl₂, 55% (over three steps) (f) IBX, MeCN, 50 °C, 82%; (g) Et₃N, MeOH; (h) IBX, MeCN, 50 °C, 34% (1) + 35% (34) (over four steps from 29); (i) K₂CO₃, MeCN, 40 °C, 98%; (j) DBU, 0 °C, quant.

Figure 2

ORTEP representation of the structure of compound 33 in the solid state.

Figure 3

Selected NMR data showing the mismatch between the synthetic samples of nominal scabrolide B (and 12-epi-1) and the isolated natural product; for the full data sets, see the Supporting Information.