Total synthesis and structural revision of vannusals A and B: synthesis of the originally assigned structure of vannusal B

Abstract

The total synthesis of the originally assigned structure of vannusal B (2) and its diastereomer (d-2) are described. Initial forays into these structures with model systems revealed the viability of a metathesis-based approach and a SmI(2)-mediated strategy for the key cyclization to forge the central region of the molecule, ring C. The former approach was abandoned in favor of the latter when more functionalized substrates failed to enter the cyclization process. The successful, devised convergent strategy based on the SmI(2)-mediated ring closure utilized vinyl iodide (-)-26 and aldehyde fragment (+/-)-86 as key building blocks, whose lithium-mediated coupling led to isomeric coupling products (+)-87 and (-)-88 (as shown in Scheme 17 in the article). Intermediate (-)-88 was converted, via (-)-89 and (-)-90/(+)-91, to vannusal B structure 2 (as shown in Scheme 18 in the article), whose spectroscopic data did not match those reported for the natural product. Similarly, intermediate (+)-25, obtained through coupling of vinyl iodide (-)-26 and aldehyde (+/-)-27 (as shown in Scheme 13 in the article) was transformed via intermediates (-)-97 and (+)-98 (as shown in Scheme 19 in the article) to diastereomeric vannusal B structure (+)-d-2 (as shown in Scheme 19 in the article) which was also proven spectroscopically to be non-identical to the naturally occurring substance. These investigations led to the discovery and development of a number of new synthetic technologies that set the stage for the solution of the vannusal structural conundrum.

Figure 1

Originally assigned structures of vannusals A (1) and B (2).

Figure 2

X-ray derived ORTEP of triol (±)-41.

Figure 3

NOEs observed for compounds (+)-95 and (+)-98.

Figure 4

Stereocontrolling steric interactions within transition states 12-TSa-d leading from substrate (±)-12 to cyclization product (±)-11 on exposure to SmI₂ (see Scheme 5).

Figure 5

Stereocontrolling steric interactions within transition states (73-TSa-d) from cyclization precursor (−)-73 leading to formation of products (−)-77 and (+)-78 (see Table 2).

Figure 6

Stereocontrolling steric interactions within transition states 89-TSa-d leading to products (−)-90 and (+)-91 from cyclization precursor (−)-89 on exposure to SmI₂ (see Scheme 17).

Figure 7

Stereocontrolling steric interactions within transition states 97-TSa-d leading from cyclization precursor (−)-97 to cyclization product (+)-98 on exposure to SmI₂ (see Scheme 19).

Scheme 1

Biosynthetic Hypotheses for Vannusals A and B

Scheme 2

Ring Closing Metathesis-based Strategy to Vannusal Model System 7

Scheme 3

Samarium Diiodide Cyclization-based Strategy to Vannusal Model System 11

Scheme 4

Construction of Model Aldehyde (±)-13a ^aReagents and conditions: (a) bromocatecholborane (3.5 equiv), CH₂Cl₂, 50 °C, 3 h; (b) PPTS (1.0 equiv), 2,2-dimethoxypropane:DMF (1:1), 50 °C, 12 h, 84% for the two steps; (c) TBDPSCl (1.5 equiv), imidazole (3.0 equiv), CH₂Cl₂, 25 °C, 6 h, 92%; (d) O₃, py (1.0 equiv), CH₂Cl₂:MeOH (1:1), −78 °C; then Ph₃P (5.0 equiv), −78 → 25 °C, 1 h, 82%; (e) KH (10 equiv), allyl chloride (30 equiv), HMPA (10 equiv), DME, 25 °C, 12 h, 85%; (f) 1,2-dichlorobenzene, 200 °C (µ-wave), 20 min; then NaBH₄ (10 equiv), MeOH, 1 h, 25 °C, 82% for the two steps; (g) BOMCl (5.0 equiv), i-Pr₂NEt (15 equiv), n-Bu₄NI (1.0 equiv), CH₂Cl₂, 50 °C, 12 h; (h) O₃, py (1.0 equiv), CH₂Cl₂:MeOH (1:1), −78 °C; then Ph₃P (5.0 equiv), −78 → 25 °C, 1 h, 81% for the two steps; (i) TBSCl (10 equiv), DBU (20 equiv), CH₂Cl₂, 25 °C, 12 h; (j) O₃, py (1.0 equiv), CH₂Cl₂:MeOH (1:1), −78 °C; then Ph₃P (5.0 equiv), −78 → 25 °C, 1 h, 80% for the two steps.

Scheme 5

Synthesis of Vannusal Model System (±)-11 Through Shapiro Coupling and SmI₂-Mediated Cyclizationa ^aReagents and conditions: (a) 14 (2.0 equiv), n-BuLi (2.5 M hexanes, 4.0 equiv), THF, −78 → −20 °C, 30 min; then (±)-13 (1.0 equiv), THF, −40 → 0 °C, 20 min; (b) TBAF (1.0 M in THF), THF, 25 °C, 12 h, 88% for the two steps; (c) TESCl (2.0 equiv), imidazole (5.0 equiv), CH₂Cl₂, 25 °C, 1 h; (d) KHMDS (0.5 M in toluene, 5.0 equiv), ClCO₂Me (10 equiv), Et₃N (10 equiv), THF, −78 → 25 °C, 20 min; (e) PPTS (1.0 equiv), MeOH, 25 °C, 6 h, 90% for the three steps; (f) PhI(OAc)₂ (2.0 equiv), TEMPO (1.0 equiv), CH₂Cl₂, 25 °C, 16 h, 90%; (g) SmI₂ (0.1 M in THF, 5.0 equiv), HMPA (15 equiv), THF, 25 °C, 0.5 h, 33%; (h) Ac₂O (10 equiv), 4-DMAP (1.0 equiv), Et₃N (10 equiv), CH₂Cl₂, 5 h, 92%.

Scheme 6

Retrosynthetic Analysis of the Originally Assigned Structure of Vannusal B (2) and Its Diastereomer (d-2)

Scheme 7

Stereoselective Installation of the C₂₁ Stereocenter Through a Ketone–Ketone Aldol Reactiona ^aReagents and conditions: (a) Br-catecholborane (3.5 equiv), CH₂Cl₂, 50 °C, 3 h; (b) TIPSCl (2.0 equiv), imidazole (6.0 equiv), DMF, 25 °C, (±)-35: 70% for the two steps, (+)-36: 85% for the two steps; (c) IBX (3.0 equiv), DMSO, 50 °C, 4 h, (±)-37: 90%, (+)-38: 81%; (d) TiCl₄ (1.0 M in CH₂Cl₂, 1.2 equiv), Et₃N (3.0 equiv), CH₂Cl₂, −78 → −30 °C, 30 min; then acetone (10 equiv), −92 °C, 12 h (9:1 dr); (e) TESOTf (3.0 equiv), 2,6-lut. (5.0 equiv), −78 → −40 °C, 1 h, (±)-39: 81% for the two steps, (+)-40: 73% for the two steps.

Scheme 8

Construction of the Completed “Northeastern” Fragment of the Originally Assigned Structure of Vannusal B in Racemic [(±)-27] and Enantiopure [(+)-27] Formsa ^aReagents and conditions: (a) NaBH₄ (20 equiv), THF:MeOH (1:1), −10 → 25 °C, 4 h; (b) PPTS (0.2 equiv), EtOH, 25 °C, 2 h, (±)-41: 85% for the two steps, (+)-42: 71% for the two steps; (c) 2-methoxypropene (20 equiv), CSA (0.1 equiv), CH₂Cl₂, −78 → −40 °C, 2 h, (±)-43: 82%, (+)-44: 91%; (d) SEMCl (3.0 equiv), i-Pr₂NEt (10 equiv), n-Bu₄NI (1.0 equiv), CH₂Cl₂, 50 °C, 24 h; (e) O₃, py (1.0 equiv), CH₂Cl₂:MeOH (1:1), −78 °C; then Ph₃P (5.0 equiv), −78 → 25 °C, 1 h, 88% for the two steps; (f) KH (10 equiv), allyl chloride (20 equiv), HMPA (5.0 equiv), DME, −10 → 25 °C, 5 h, 88%; (g) i-Pr₂NEt (1.0 equiv), 1,2-dichlorobenzene, 200 °C (µ-waves), 20 min; then NaBH₄ (20 equiv), MeOH, 1 h, 25 °C, 91% for the two steps; (h) BOMCl (10 equiv), i-Pr₂NEt (20 equiv), n-Bu₄NI (1.0 equiv), CH₂Cl₂, 50 °C 12 h; (i) O₃, py (1.0 equiv), CH₂Cl₂:MeOH (1:1), −78 °C; then Ph₃P (5.0 equiv), −78 → 25 °C, 1 h, 78% for the two steps; (j) TBSCl (7.0 equiv), DBU (14 equiv), CH₂Cl₂, 25 °C, 12 h; (k) O₃, py (1.0 equiv), CH₂Cl₂:MeOH (1:1), −78 °C; then Ph₃P (5.0 equiv), −78 → 25 °C, 1 h, 95% for the two steps.

Scheme 9

Construction of Enantiopure Hydroxy Acetate (−)-50a ^aReagents and conditions: (a) POCl₃ (2.2 equiv), py, 90 °C, 2 h, 97%; (b) BH₃•THF (2.5 equiv), cyclohexene (2.5 equiv), −40 → 0 °C, 2 h; then 29, −40 → 25 °C, 12 h; then 50 °C, 30 min; then 30% H₂O₂/aq. 3 N NaOH (1:1 v/v), 25 → 50 °C, 12 h, 51%; (c) Ac₂O (3.0 equiv), 4-DMAP (0.02 equiv), py, 25 °C, 3 h, quant.; (d) Lipase Amano PS (100 wt%), acetone:phosphate buffer pH = 7 (2:1), 25 °C, 48 h, quant., 99% ee; (e) (S)-MPT-Cl (1.2 equiv), py, 25 °C, 18 h, 91%.

Scheme 10

Construction of Hydroxy Olefin (+)-56 and X-ray Derived ORTEP of Carbamate (−)-57a ^aReagents and conditions: (a) TBDPSCl (1.2 equiv), imidazole (3.0 equiv), CH₂Cl₂, 25 °C, 12 h, 93%; (b) DIBAL-H (1.0 M in hexanes, 2.5 equiv), CH₂Cl₂, −78 °C, 30 min, 98%; (c) (S)-MTP-Cl (1.5 equiv), py, 25 °C, 18 h, 83%; (d) Martin’s sulfurane (1.3 equiv), Et₃N (3.0 equiv), CH₂Cl₂, 25 °C, 12 h, 91%; (e) NMO (1.5 equiv), TPAP (0.03 equiv), CH₂Cl₂:MeCN (9:1), 25 °C, 12 h, 96%; (f) KHMDS (0.5 M in toluene, 1.5 equiv), PhNTf₂ (1.25 equiv), THF, −78 → −40 °C, 30 min; (g) Et₃SiH (2.5 equiv), Pd(Ph₃P)₄ (0.02 equiv), DMF, 50 °C, 3 h, 95% for the two steps; (h) NIS (1.5 equiv), THF:H₂O (4:1), 0 → 25 °C, 1.5 h; then K₂CO₃ (2.5 equiv), MeOH, 25 °C, 18 h, 91%; (i) 2-bromopropene (4.5 equiv), t-BuLi (1.7 M in pentane, 8.0 equiv), THF, −78 °C, 5 min; then BF₃•Et₂O (2.0 equiv), 2 min; (+)-55, −78 → −20 °C, 30 min, 83%; (j) p-BrC₆H₄NCO (4.0 equiv), Et₃N (6.0 equiv), 25 °C; (k) TBAF (8.0 equiv), THF, 25 °C, 12 h, 74% for the two steps.

Scheme 11

Mechanistic Rationale for the Stereoselective Epoxidation of Olefin (−)-54 Through Iodohydrin Formation

Scheme 12

Construction of Vinyl Iodide (−)-26a ^aReagents and conditions: (a) p-NO₂C₆H₄CO₂H (1.5 equiv), DEAD (1.5 equiv), Ph₃P (1.8 equiv), benzene, 0 → 25 °C, 18 h, 94%; (b) DIBAL-H (1.0 M in hexanes, 2.5 equiv), CH₂Cl₂, −78 °C, 30 min, 96%; (c) BOMCl (3.0 equiv), i-Pr₂NEt (10 equiv), toluene, 90 °C, 12 h; (d) TBAF (1.0 M in THF, 10 equiv), 70 °C, 8 h, 97% over the two steps; (e) NMO (1.5 equiv), TPAP (0.03 equiv), CH₂Cl₂:MeCN (9:1), 12 h, 96%; (f) TrisNHNH₂ (1.5 equiv), Na₂SO₄ (100 wt%), THF, 4 h, 90%; (g) n-BuLi (2.5 M in hexanes, 2.1 equiv), THF, −78 → −25 °C, 20 min; then I₂ (2.0 equiv), −78 → −25 °C, 20 min, 90%; (h) KHMDS (0.5 M in toluene, 1.5 equiv), PhNTf₂ (1.5 equiv), THF, −78 → − 40 °C, 30 min, 94%; (i) Me₃SnSnMe₃ (2.0 equiv), LiCl (10 equiv), PdCl₂(dppf)₂ (0.1 equiv), dioxane, 60 °C, 12 h; (j) NIS (1.5 equiv), THF, −50 °C, 50% for the two steps.

Scheme 13

Coupling of Vinyl Iodide (−)-26 with Aldehydes (+)-27 and (±)-27 and Preparation of γ-Lactones (−)-71 and (+)-72a ^aReagents and conditions: (a) (−)-26 (1.3 equiv), t-BuLi (2.6 equiv), THF, −78 → −40 °C, 30 min; then (+)-27 or (±)-27 (1.0 equiv), −40 → 0 °C, 20 min, (−)-69: 80% or (−)-69: 40%; (+)-70: 40%; (b) TBAF (1.0 M in THF, 4.0 equiv), THF, 25 °C, 5 h, (−)-24: 86%; (+)-25: 97%; (c) PhI(OAc)₂ (5.0 equiv), TEMPO (0.5 equiv), CH₂Cl₂, 25 °C, 48 h, (−)-71: 80%; (+)-72: 80%.

Scheme 14

Synthesis of Aldehyde Carbonate (−)-73 and Initial SmI₂-Mediated Cyclization Resultsa ^aReagents and conditions: (a) TESC1 (2.0 equiv), imidazole (5.0 equiv), CH₂C1₂, 25 °C, 0.5 h, 97%; (b) KHMDS (0.5 M in toluene, 2.5 equiv), ClCO₂Me (4.0 equiv), Et₃N (4.0 equiv), THF, −78 → 25 °C, 1 h; (c) HF•py:py (1:4), 0 → 25 °C, 12 h, 78% for the two steps; (d) PhI(OAc)₂ (5.0 equiv), TEMPO (1.0 equiv), CH₂C1₂, 25 °C, 24 h, 98%; (e) Sml₂ (0.1 M in THF, 5.0 equiv), HMPA (15 equiv), THF, −10 → 25 °C, 30 min, ca. 20%.

Scheme 15

Preparation of Crystalline p-Bromophenyl Carbamate (−)-81 and Its X-ray Derived ORTEPa ^aReagents and conditions: (a) DEAD (10 equiv), Ph₃P (10 equiv), p-NO₂C₆H₄CO₂H (10 equiv), benzene, 70 °C, 2 h, 88% based on recovered starting material (40%); (b) LiDBB, THF, −78 → −50 °C; 0.5 h, 90%; (c) HF•py:THF, 25 °C, 4 h, 93%; (d) p-BrC₆H₄NCO (10 equiv), py, 40 °C, 12 h, 84%.

Scheme 16

Synthesis of Aldehyde (±)-86a ^aReagents and conditions: (a) Ac₂O (30 equiv), 4-DMAP (0.1 equiv), Et₃N (40 equiv), CH₂Cl₂, 25 °C, 18 h, 79%; (b) 2-methoxypropene (20 equiv), CSA (1.0 equiv), CH₂Cl₂, −78 → −30 °C, 3 h, 82%; (c) MeMgBr (50 equiv), toluene, 50 °C, 8 h, 94%; (d) SEMCl (10 equiv), i-Pr₂NEt (30 equiv), n-Bu₄NI (1.0 equiv), CH₂Cl₂, 50 °C, 48 h, 96%; (e) O₃, py (1.0 equiv), CH₂Cl₂:MeOH (1:1), −78 °C; then Ph₃P (5.0 equiv), −78 → 25 °C, 1 h, 96%; (f) KH (10 equiv), allyl chloride (20 equiv), HMPA (5.0 equiv), DME, −10 → 25 °C, 3 h, 92%; (g) i-Pr₂NEt (1.0 equiv), 1,2-dichlorobenzene, 200 °C (µ-waves), 20 min; then NaBH₄ (20 equiv), MeOH, 1 h, 25 °C, 88% for the two steps; (h) BOMCl (6.0 equiv), i-Pr₂NEt (15 equiv), CH₂Cl₂, 50 °C, 12 h; (i) O₃, py (1.0 equiv), CH₂Cl₂:MeOH (1:1), −78 °C; then Ph₃P (5.0 equiv), −78 → 25 °C, 1 h, 85% for the two steps; (j) TBSCl (10 equiv), DBU (20 equiv), CH₂Cl₂, 25 °C, 36 h; (k) O₃, py (1.0 equiv), CH₂Cl₂:MeOH (1:1), −78 °C; then Ph₃P (5.0 equiv), −78 → 25 °C, 1 h, 97% for the two steps.

Scheme 17

Coupling of Vinyl Iodide (−)-26 and Aldehyde (±)-86 and Synthesis of Polycyclic Hydroxy Olefins (−)-90 and (+)-91a ^aReagents and conditions: (a) (−)-26 (1.3 equiv), t-BuLi (2.6 equiv), THF, −78 → −40 °C, 30 min; then (±)-86 (1.0 equiv), − 40 → 0 °C, 20 min, 80%; (b) TBAF (1.0 M in THF, 5.0 equiv), THF, 25 °C, 1 h, 98%; (c) TESCl (1.5 equiv), imidazole (5.0 equiv), CH₂Cl₂, 25 °C, 1 h, 99%; (d) KHMDS (0.5 M in toluene, 3.0 equiv), ClCO₂Me (5.0 equiv), Et₃N (5.0 equiv), THF, −78 → 25 °C, 2 h; (e) HF•py:py (1:4), 0 → 25 °C, 12 h, 88% for the two steps; (f) PhI(OAc)₂ (3.0 equiv), TEMPO (1.0 equiv), CH₂Cl₂, 25 °C, 24 h, 98%; (g) SmI₂ (0.1 M in THF, 5.0 equiv), HMPA (15 equiv), THF, −10 → 25 °C, 30 min, 80% [(−)-90: 28%; (+)-91: 52%].

Scheme 18

Total Synthesis of the Originally Assigned Structure of Vannusal B (2) ^aReagents and conditions: (a) POCl₃ (60 equiv), py, 60 °C, 3 h, 81%; (b) CS₂ (8.0 equiv), NaH (6.0 equiv), THF, 0 → 25 °C, 30 min; then MeI (12 equiv), 0 → 25 °C, 3 h; then 185 °C (µ-waves), 1,2-dichlorobenzene, 15 min, 92%; (c) ThexBH₂ (5.0 equiv), THF, −10 → 25 °C, 1 h; then BH₃•THF (15 equiv), 0 → 25 °C, 30 min; then 30% H₂O₂/3 N aq. NaOH (1:1), 25 → 40 °C, 1 h; 65% overall yield (ca. 1:1.3 dr); (d) o-NO₂C₆H₄SeCN (2.0 equiv), n-Bu₃P (6.0 equiv), py (12 equiv), THF, 25 °C, 10 min; then 30% H₂O₂, 0 → 25 °C, 12 h, 67%; (e) Ac₂O (20 equiv), Et₃N (20 equiv), 4-DMAP (1.0 equiv), CH₂Cl₂, 24 h, 96%; (f) KHMDS (0.5 M in toluene, 5.0 equiv), TESCl (5.0 equiv), Et₃N (8.0 equiv), THF, −78 → 25 °C, 30 min, 94%; (g) LiDBB (excess), THF, −78 → −50 °C, 30 min, 84%; (h) PhI(OAc)₂ (3.0 equiv), TEMPO (1.0 equiv), CH₂Cl₂, 25 °C, 24 h, 88%; (i) Ac₂O (30 equiv), Et₃N (30 equiv), 4-DMAP (1.0 equiv), CH₂Cl₂, 25 °C, 12 h, quant.; (j) HF•py:THF (1:4), 25 °C, 3 h; then 3 N aq. HCl:THF (1:3), 25 °C, 6 h, 80%.

Scheme 19

Total Synthesis of Vannusal B Structure (+)-d-2a ^aReagents and conditions: (a) TESCl (2.0 equiv), imidazole (6.0 equiv), CH₂Cl₂, 25 °C, 30 min, quant.; (b) KHMDS (0.5 M in toluene, 2.5 equiv), ClCO₂Me (4.0 equiv), Et₃N (4.0 equiv), THF, −78 → 25 °C, 2 h; (c) HF•py:py (1:4), 0 → 25 °C, 12 h, 77% for the two steps; (d) PhI(OAc)₂ (5.0 equiv), TEMPO (1.0 equiv), CH₂Cl₂, 25 °C, 24 h, 98%; (e) SmI₂ (0.1 M in THF, 5.0 equiv), HMPA (15 equiv), THF, −10 → 25 °C, 30 min, 73%; (f) TESCl (2.0 equiv), imidazole (6.0 equiv), CH₂Cl₂, 5 h; (g) LiDBB (excess), THF, −78 → −50 °C, 30 min, 92% for the two steps; (h) PhI(OAc)₂ (5.0 equiv), TEMPO (2.0 equiv), CH₂Cl₂, 25 °C, 36 h, 89%; (i) Ac₂O (20 equiv), Et₃N (30 equiv), 4-DMAP (2.0 equiv), CH₂Cl₂, 25 °C, 12 h, 99%; (j) HF•py:THF (1:4), 25 °C, 0.5 h, 89%; (k) 3 N aq. HCl:THF (1:3), 25 °C, 12 h, 92%.