A Unified Approach to Polycyclic Alkaloids of the Ingenamine Estate: Total Syntheses of Keramaphidin B, Ingenamine, and Nominal Njaoamine I

Abstract

Many polycyclic marine alkaloids are thought to derive from partly reduced macrocyclic alkylpyridine derivatives via a transannular Diels-Alder reaction that forms their common etheno-bridged diaza-decaline core ("Baldwin-Whitehead hypothesis"). Rather than trying to emulate this biosynthesis pathway, a route to these natural products following purely chemical logic was pursued. Specifically, a Michael/Michael addition cascade provided rapid access to this conspicuous tricyclic scaffold and allowed different handles to be introduced at the bridgehead quarternary center. This flexibility opened opportunities for the formation of the enveloping medium-sized and macrocyclic rings. Ring closing alkyne metathesis (RCAM) proved most reliable and became a recurrent theme en route to keramaphidin B, ingenamine, xestocyclamine A, and nominal njaoamine I (the structure of which had to be corrected in the aftermath of the synthesis). Best results were obtained with molybdenum alkylidyne catalysts endowed with (tripodal) silanolate ligands, which proved fully operative in the presence of tertiary amines, quinoline, and other Lewis basic sites. RCAM was successfully interlinked with macrolactamization, an intricate hydroboration/protonation/alkyl-Suzuki coupling sequence, or ring closing olefin metathesis (RCM) for the closure of the second lateral ring; the use of RCM for the formation of an 11-membered cycle is particularly noteworthy. Equally rare are RCM reactions that leave a pre-existing triple bond untouched, as the standard ruthenium catalysts are usually indiscriminative vis-à-vis the different π-bonds. Of arguably highest significance, however, is the use of two consecutive or even concurrent RCAM reactions en route to nominal njaoamine I as the arguably most complex of the chosen targets.

Scheme 1. Key Step of the Proposed Biosynthesis of Keramaphidin B; Representative Alkaloids Thought To Originate from Similar Pathways

Scheme 2. Executive Summary of the “First-Generation” Approach

Scheme 3. Building Blocks (Ingenamine Series)

Reagents and conditions: (a) TBSCl, Et₃N, CH₂Cl₂, quant.; (b) RuO₂ (6 mol %), NaIO₄, EtOAc/H₂O, 55%; (c) LiHMDS, allyl chloroformate, THF, −78 °C, 94%; (d) 4-bromo-1-butene, Cs₂CO₃, DMF, 94%; (e) Pd₂(dba)₃·CHCl₃ (5 mol %), MeCN, reflux, 83%; (f) LiHMDS, allyl chloroformate, toluene, −78 °C → 0 °C, 50% (R = COOMe); (g) NaH, diallyl carbonate, THF, 45% (R = Bn); (h) 1-iodo-3-pentyne, K₂CO₃, acetone, reflux, 36%; (i) 1-iodo-3-pentyne, Cs₂CO₃, DMF, 91%; (j) ClCOOMe, toluene, reflux, quant.; (k) Pd₂(dba)₃·CHCl₃ (5 mol %), MeCN, reflux, 96%

Scheme 4. Michael/Michael Cascade and Further Elaboration

Reagents and conditions: (a) (i) tBuOLi, THF, −50 °C → RT; (ii) Boc₂O, DMAP; (b) NaBH₄, MeOH, 0 °C, 53% (over two steps); (c) MsCl, Et₃N, DMAP, CH₂Cl₂, 0 °C → RT, 91%; (d) (i) 2,6-lutidine, 170 °C; (ii) TBSOTf, CH₂Cl₂, 73%; (e) 1-iodo-5-heptyne, NaH, DMF, 0 °C, 95%; (f) 29 (25 mol %), 30 (30 mol %), toluene, MS 5 Å, 100 °C, 79%; (g) 31 (20 mol %), toluene, MS 5 Å, reflux, 83% (1.3 g scale).

Figure 1

Structure of cycloalkyne 28 in the solid state.

Scheme 5

Reagents and conditions: (a) l-Selectride, THF, 40 °C, 91%; (b) hex-5-enal, NaBH(OAc)₃, CH₂Cl₂, 96%; (c) hex-5-enoyl chloride, Et₃N, CH₂Cl₂, 0 °C → RT, 71%; (d) 36 (50 mol %), toluene, 100 °C, 97% (E/Z = 60:40); (e) see ref (1).

Scheme 6

Reagents and conditions: (a) TBAF, THF, 0 °C, quant.; (b) Martin’s sulfurane, toluene, 100 °C, 97%; (c) NaBH₃CN, TFA, CH₂Cl₂, 0 °C → RT, 73%; (d) 36 (50 mol %), 1,2-dichloroethane, 83% (E/Z = 1:1); (e) Ni(OAc)₂·4H₂O, NaBH₄, ethylenediamine, H₂ (1 bar), EtOH, 37% (over two steps, pure isomer); (f) Dibal-H, Et₂O/hexane, 38%.

Figure 2

Structure of compound 42 in the solid state.

Figure 3

Representative members of the njaoamine family (* stereocenters of unknown configuration).

Scheme 7

Reagents and conditions: (a) (i) NaIO₄, MeOH/H₂O; (ii) aq. HCl, MeOH, 81%; (b) toluene, reflux, then SiO₂, 94%; (c) Tf₂O, pyridine, 0 °C → RT, 88%; (d) 49, Pd(PPh₃)₄ (5 mol %), THF, reflux, 73%; (e) (i) PhNTf₂, KHMDS (excess), THF, −78 °C; (ii) Boc₂O, DMAP, MeCN; (f) TBAF, THF, 0 °C → RT, 72% (over three steps); (g) pyridine·SO₃, DMSO, Et₃N, 0 °C → RT, 77%.

Scheme 8. Failed First Foray

Reagents and conditions: (a) (i) Bn₂NLi, DMPU, – 50 °C → 0 °C; (ii) Boc₂O, DMPU; (b) NaBH₄, MeOH, 0 °C, 42% (over two steps); (c) MsCl, Et₃N, DMAP, CH₂Cl₂, 85%; (d) 2,6-lutidine, 170 °C, 81%; (e) (i) NaH, 1-iodo-4-pentene, DMF; (ii) TBAF, 98%; (f) (i) ClCH₂SO₂Cl, Et₃N, DMAP, CH₂Cl₂; (ii) DBU, 77% (over two steps); (g) NaBH₃CN, TFA, CH₂Cl₂, 0 °C → RT, 60%; (h) l-Selectride, THF, 40 °C; (i) 52, NaBH(OAc)₃, CH₂Cl₂, 73% (over two steps); (j) 29 (30 mol %), 30 (30 mol %), MS 5 Å, toluene, reflux, 77%.

Scheme 9

Reagents and conditions: (a) I₂, PPh₃, imidazole, CH₂Cl₂, 0 °C, 99%; (b) 61, Cs₂CO₃, DMF, 67%; (c) ClCOOMe, toluene, 100 °C, 97%; (d) Pd₂(dba)₃ (5 mol %), MeCN, reflux, 92%; (e) (i) 53, tBuOLi, THF, −50 °C → RT; (ii) Boc₂O, DMAP; (f) NaBH₄, MeOH, 0 °C, 55% (over two steps); (g) MsCl, Et₃N, DMAP, CH₂Cl₂, 0 °C → RT, 94%; (h) (i) 2,6-lutidine, 170 °C; (ii) TBSOTf, CH₂Cl₂, 78%; (i) 61, NaH, DMF/THF, 0 °C → RT; (j) TBAF, THF, 92% (over two steps); (k) Martin’s sulfurane, toluene, 100 °C, quant.; (l) NaBH₃CN, TFA, CH₂Cl₂, 0 °C → RT, 66%; (m) TMSI, CH₂Cl₂; (n) 52, NaBH(OAc)₃, CH₂Cl₂, 67% (over two steps); (o) 29 (30 mol %), 30 (30 mol %), MS 5 Å, toluene, reflux, 77%; (p) 31 (30 mol %), MS 5 Å, toluene, reflux, 77%; (q) H₂ (1 bar), Pd/CaCO₃, THF, 52%; (r) Dibal-H, Et₂O, 0 °C → RT; (s) Zn, THF, HOAc, 44% (over two steps); (t) 29 (30 mol %), 30 (30 mol %), MS 5 Å, toluene, reflux, 73%; (u) 31 (30 mol %), MS 5 Å, toluene, reflux, 98%; (v) HCl in 1,4-dioxane, EtOAc, quant.

Figure 4

Originally assigned and revised structure of njaoamine I.

Scheme 10. Two Concurrent RCAM Reactions

Reagents and conditions: (a) l-Selectride, THF, 40 °C; (b) 52, NaBH(OAc)₃, CH₂Cl₂, HOAc, 67% (over two steps); (c) 29 (60 mol %), 30 (60 mol %), MS 5 Å, toluene, reflux, 35% (73 + 17% (isomer), see text).