Enantioselective total syntheses of (-)-palau'amine, (-)-axinellamines, and (-)-massadines

Abstract

Dimeric pyrrole-imidazole alkaloids represent a rich and topologically unique class of marine natural products. This full account will follow the progression of efforts that culminated in the enantioselective total syntheses of the most structurally ornate members of this family: the axinellamines, the massadines, and palau'amine. A bio-inspired approach capitalizing on the pseudo-symmetry of the members of this class is recounted, delivering a deschloro derivative of the natural product core. Next, the enantioselective synthesis of the chlorocyclopentane core featuring a scalable, catalytic, enantioselective Diels-Alder reaction of a 1-siloxydiene is outlined in detail. Finally, the successful divergent conversion of this core to each of the aforementioned natural products, and the ensuing methodological developments, are described.

Figure 1. Structural conformation of 20-deoxymacropalau’amine-N₃ (65) based on the average of 52 interproton distances from a 100 ms ROESY spectrum

Scheme 1. Biosynthesis of pyrrole-imidazole alkaloids

Scheme 2. Bio-inspired retrosynthetic scheme based on an oxidative cyclization from the symmetric seco-sceptrin-N₃ (16)

Scheme 3. Attempt to secure the core of the pyrrole-imidazole alkaloids with an oxidative cascade from a linear precursor (16)

^a Reagents and conditions: (a) Dimethyl fumarate (1.0 equiv), 1,3-dimethylbutadiene (1.0 equiv), neat, 135 °C, 1.5 h; (b) LiAlH₄ (2.0 equiv), THF, 0 °C, 1 h; (c) methanesulfonyl chloride (4.0 equiv), pyridine, 0 → 23 °C, 1 h; (d) sodium azide (6.0 equiv), DMF, 100 °C, 2 h, 78% for four steps; (e) O₃, MeOH, −78 °C, 15 min, then DMS (3.0 equiv), 23 °C, 20 h; (f) diisopropylethylamine (6.0 equiv), TMSOTf (4.0 equiv), 0 → 23 °C, then NBS (2.0 equiv), MeCN, THF, 0 °C, 15 min, 45% for two steps; (g) Boc-guanidine (10 equiv), DMF, 23 °C, 65 h, 14%; (h) TFA:DCM (1:2), 23 °C, 6 h, quant. THF = tetrahydrofuran, DMF = N,N-dimethylformamide, DMS = dimethylsulfide, TMSOTf = trimethylsilyl trifluoromethanesulfonate, NBS = N-bromosuccinimide, TFA = trifluoroacetic acid, DCM = dichloromethane.

Scheme 4. Access to a deschloro core structure 22

^a Reagents and conditions: (a) SiO₂, 23 °C, 12 h, 90%; (b) 2,6-lutidine (4.0 equiv), SOCl₂ (2.0 equiv), DCM, 0 °C, 1 h, 30%; (c) Boc-guanidine (7.0 equiv), THF, 55 °C, 12 h; (d) TFA:DCM (1:1), 23 °C, 1 h, 22% for two steps.

Scheme 5. Revised retrosynthetic analysis of the axinellamines (9–10) and palau’amines (e.g. 13).^a

^a R = H or acyl-2-(4,5-dibromopyrrole).

Scheme 6. Elaboration to a fully substituted cyclopentane core.^a

^a Reagents and conditions: (a) Dodecanethiol (4.4 equiv), n-butyllithium (4.0 equiv), THF, −78 °C → 0 °C, 18 h, 74%; (b) LiAlH₄ (3.0 equiv), Et₂O, 0 °C, 1 h, 86%; (c) methanesulfonyl chloride (4.0 equiv), pyridine, 0 °C → 23 °C, 1 h; (d) sodium azide (6.0 equiv), DMF, 100 °C, 11 h; (e) TBAF (1.1 equiv), THF, 23 °C, 1 h, 81% for three steps; (f) NaH (2.0 equiv), PMBCl (1.1 equiv), TBAI (0.1 equiv), DMF, 0 °C → 23 °C, 2 h; (g) O₃, MeOH, −78 °C, 1 h then DMS (3.0 equiv), 23 °C, 16 h, 86% for two steps; (h) diisopropylethylamine (6.0 equiv), TMSOTf (4.0 equiv), 0 °C → 23 °C, 1.5 h, then NBS (2.0 equiv), THF, MeCN, 0 °C, 15 min, then SiO₂, 50 °C, 16 h, 66%. TBAF = tetra-n-butylammonium fluoride, PMBCl = p-methoxybenzyl chloride, TBAI = tetra-n-butylammonium iodide.

Scheme 7. Roadblocks en route to the trihalogenated enone 26.^a

^a Reagents and conditions: (a) LiCl (3.3 equiv), DMF, 23 °C, 1.5 h; (b) TFA:DCM (1:9), anisole (2.0 equiv), 0 °C, 1 h, 72% for two steps; (c) NaOH (1.1 equiv), THF, H₂O, 0 °C, 45 min, 75%; (d) Burgess reagent (5.0 equiv), benzene, 50 °C, 6 h, 95%; (e) 2,6-lutidine (3.0 equiv), SOCl₂ (2.0 equiv), DCM, 0 °C, 2 h, 78%; (f) SO₂Cl₂ (2.0 equiv), 2,6-lutidine (3.0 equiv), DCM, 0 °C, 30 min, 60%.

Scheme 8. Elaboration of enone 22 to the fully substituted core 20.^a

^a Reagents and conditions: (a) NaBH₄ (1.0 equiv), CeCl₃ • 7 H₂O (0.5 equiv), MeOH, 0 °C, 15 min; (b) N,N’-bis-Boc guanidine (1.2 equiv), DBU (1.2 equiv), DMF, −20 °C to 0 °C, 4 h, 55% for two steps; (c) IBX (2.0 equiv), benzene, 83 °C, 16 h, 70%, 1.3:1 57:56; (d) N-Boc guanidine (6.0 equiv), DMF or MeCN, 23 °C, 24–48 h, 5–20%; (e) NaN(CHO)₂ (1.5 equiv), TBAI (0.1 equiv), THF, 23 °C, 3 h; (f) TFA:H₂O (1:1), 50 °C, 24 h, 69% for two steps, 36% 25, 33% 16-epi-25; (g) H₂NCN (40 equiv), pH 5, brine, 70 °C, 4 h, 71%. DBU = 1,8-diazabicycloundec-7-ene, IBX = o-iodoxybenzoic acid.

Scheme 9. Failed biomimetic approaches to the pyrrole-imidazole alkaloids.^a

^a Reagents and conditions: (a) PtO₂ (0.1 equiv), H₂ (1 atm), TFA:H₂O (1:9), 23 °C, 2 h; (b) (trichloroacetyl)pyrrole 59 (3.0 equiv), diisopropylethylamine (3.0 equiv), DMF, 40 °C, 3 h, 26% + 17% mono-acylated product; (c) NBS (1.0 equiv), MeOH, −78 °C, 26 h; (d) neat TFA, 30 °C, 24 h, 34%.

Scheme 10. Non-biomimetic retrosynthesis of the pyrrole-imidazole alkaloids to a common precursor (25)

Scheme 11. Model system for the oxidation of spiro-annulated imidazolines.^a

^a Reactions monitored by HPLC-MS and ¹H-NMR comparison to known standards of 79 and 80.

Scheme 12. Enantioselective total synthesis of (−)-axinellamine A (9) and (−)-axinellamine B (10).^a

^a Reagents and conditions: (a) DMDO (0.35 mL of 0.09 M solution), H₂O, 0 °C, 15 min; (b) TFA:DCM (2:1), 23 °C, 17 h; (c) silver(II) picolinate (3.5 equiv), TFA:H₂O (1:9), 23 °C, 30 min, 43% (3:4 68α:68β); (d) 1,3-propanedithiol (15–20 equiv), Et₃N (11–14 equiv), MeOH, 23 °C, 2 h; (e) (trichloroacetyl)pyrrole 59 (3.0 equiv), diisopropylethylamine (3.0 equiv), DMF, 45 °C, 6–11 h; 9 = 45%, 10 = 24%. DMDO = dimethyldioxirane.

Scheme 13. Attempts to secure both the 2-aminoimidazole and the C20 hemiaminal en route to the massadines (11–12).^a

^a Reagents and conditions: (a) silver(II) picolinate (2.5 equiv), TFA:H₂O (1:9), 23 °C, 30 min, 58%. ^b TFA:H₂O (2:1), 50 °C, 20 h, 65%.

Scheme 14. Total synthesis of (−)-massadine (11) and (−)-massadine chloride (12).^a

^a Reagents and conditions: (a) silver(II) picolinate (2.5 equiv), TFA:H₂O (1:9), 23 °C, 30 min, 69%; (b) H₂NCN (40 equiv), pH 5, brine, 70 °C, 4 h, 65%; (c) DMDO (1.3 equiv), TFA:H₂O (1:9), 0 °C, 1 h; (d) neat TFA, 23 °C, 3 h, 71% (1:3.7 d.r. at C6/C10); (e) PtO₂ (0.3 equiv), H₂ (1 atm), TFA:H₂O (1:19), 1 h, 23 °C; (f) (trichloroacetyl)pyrrole 59 (16 equiv), diisopropylethylamine (16 equiv), DMF, 23 °C, 14 h, 60% from 70α (2:1 9:8), 55% from 70β (4:1 88:89); (g) H₂O, 60 °C, 4 h, quant.

Scheme 15. Initial investigations into the generation of an N-coupled pyrrole.^a

^a 90 (1.0 equiv), TFA:H₂O, 60 °C, 24 h, 82%. ^b 90 (1.0 equiv), Neat pyrrole, 60 °C, 2 h, 71%. ^c 90 (1.0 equiv), AcOH (3.0 equiv), pyrrolidine (3.0 equiv), 40 °C, 3 h, 48%. ^d 90 (1.0 equiv), AcOH (3.0 equiv), benzylamine (3.0 equiv), 40 °C, 3 h, 72%.

Scheme 16. Synthesis of deoxypalau’amine azide 66.^a

^a Reagents and conditions: (a) TFAA:TFA (1:1), 1 h, then Br₂ (2.0 equiv), 1 h, then TFA:H₂O (1:1), 1 h, 38 °C, 58% (b) AcOH (3.0 equiv), 97 (3.0 equiv), THF, 38 °C, 6 h; (c) TFA:DCM (1:30 to 1:1), 23 °C, 12 h, 48%; (d) EDC (1.5 equiv), DMAP (2.0 equiv), thiol 99 (1.2 equiv), MeCN, 23 °C, 2 h, 48%; (e) DABCO (7.5 equiv), THF, 60 °C, 6 h, 20%; (f) neat TFA, 70 °C, 23 h, 38% (ca. 75% conversion). TFAA = trifluoroacetic anhydride, EDC = 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine, DMAP = 4-(N,N-dimethylamino)pyridine, DABCO = 1,4-diazabicyclo[2.2.2]octane.

Scheme 17. Enantioselective total synthesis of (−)-palau’amine (13).^a

^a Reagents and Conditions: (a) TFAA:TFA (1:1), 1 h, then Br₂ (2.0 equiv), 1 h, then TFA:H₂O (1:1), 38 °C, 1 h, 54%; (b) AcOH (3.0 equiv), 97 (3.0 equiv), THF, 38 °C, 6 h, then TFA:DCM (1:30 to 1:1), 23 °C, 12 h, 44%; (c) Pd(OAc)₂ (1.6 equiv), H₂ (1 atm), TFA:H₂O (1:9), 23 °C; (d) EDC (3.0 equiv), DMF, 23 °C, 3 h; (e) neat TFA, 70 °C, 24 h, 17% for three steps.