doi: 10.1002/anie.200902028.
The true structures of the vannusals, part 1: Initial forays into suspected structures and intelligence gathering
Affiliations
- PMID: 19562816
- PMCID: PMC2777636
- DOI: 10.1002/anie.200902028
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The true structures of the vannusals, part 1: Initial forays into suspected structures and intelligence gathering
Angew Chem Int Ed Engl.
2009.
No abstract available
Figures
Originally assigned structures of vannusals A (1) and B (2) and initially targeted stereoisomers 3 [C21-epi-2] and 4 [C21-epi, C25-epi-2].
Key 1H NMR coupling constant (w-JH26, 15left = 1.6 Hz) and NOE exhibited by both the originally assigned structure (synthetic, 2) and natural vannusal B.
Retrosynthetic analysis of vannusal B stereoisomer 3 [C21-epi-2]. BOM = benzyloxymethyl; SEM = trimethylsilylethoxymethyl; TIPS = triisopropylsilyl.
Key 1H NMR coupling constants of vannusal B structure 3 (JH25,21 = 8.5 Hz, w-JH26,15left = 2.0 Hz)
Key 1H NMR coupling constants (w-JH26, 15left = 1.5 Hz, JH25, 21 = 3.5 Hz) and selected chemical shifts for vannusal B structure 4 and comparisons with those of natural vannusal B and its originally assigned structure (2).
Relevant NOE’s and coupling constants (J) of AB ring model compounds 31a–31e. R =TBDPS = tert-butyldiphenylsilyl.
Construction of nitrile 12 (top) and X-ray derived ORTEP drawing of 13 (bottom). Reagents and conditions: (a) Martin’s sulfurane (1.1 equiv), Et3N (10 equiv), CH2Cl2, 25 °C, 5 h, 87 %; (b) tBuOOH (3.0 equiv), VO(acac)2 (0.2 equiv), PhH, 25 °C, 6 h, 90 %; (c) Ac2O (10 equiv), Et3N (30 equiv), 4-DMAP (1.0 equiv), CH2Cl2, 4 h, 25 °C, 90 %; (d) Et2AlCN (10 equiv), PhMe, −78→−20 °C, 19 h, 81 %; (e) K2CO3 (1.0 equiv), MeOH, 25 °C, 2 h, 100 %; (f) DMF/2,2-dimethoxypropane (1:1), PPTS (1.0 equiv), 24 h, 89 %.
Construction of aldehyde (±)-6. Reagents and conditions: (a) SEMCl (10 equiv), iPr2NEt (30 equiv), CH2Cl2, 50 °C, 48 h, 90 %; (b) DIBAL-H (1.1 equiv), PhMe, −78→30 °C, 1 h; then 0.1 M HCl, 25 °C, 20 min; (c) MeMgBr (10 equiv), THF, 0 °C, 30 min; (d) NMO (2.0 equiv), TPAP (0.05 equiv), CH2Cl2/CH3CN (7:1), 25 °C, 3 h; (e) MeMgBr (10 equiv), THF, −10 °C, 20 min, 72 % for four steps; (f) KHMDS (2.0 equiv), SEMCl (5.0 equiv), Et3N (10 equiv), 1 h, 92 %; (g) O3, py (1.0 equiv), CH2Cl2:MeOH (1:1), −78 °C; then Ph3P (5.0 equiv), −78→25 °C, 1 h, 89 %; (h) KH (10 equiv), allyl chloride (30 equiv), HMPA (10 equiv), DME, 25 °C, 12 h, 91 %; (i) iPr2NEt (1.0 equiv), o-dichlorobenzene, 200 °C (μ-waves), 20 min; then NaBH4 (10 equiv), MeOH, 1 h, 25 °C, 91 % for two steps; (j) BOMCl (10 equiv), iPr2NEt (30 equiv), nBu4NI (1.0 equiv), CH2Cl2, 50 °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, 92 % for two steps; (l) TBSCl (10 equiv), DBU (20 equiv), CH2Cl2, 25 °C, 48 h; (m) O3, py (1.0 equiv), CH2Cl2:MeOH (1:1), −78 °C; then Ph3P (5.0 equiv), −78→25 °C, 1 h, 92 % for two steps. HMPA = hexamethylphosphoramide, DBU = 1,8-diazoicyclo[5.4.0]undec-7-ene.
Synthesis of vannusal B structure 3 [C21-epi-2]. Reagents and conditions: (a) (−)-5 (1.3 equiv), tBuLi (2.5 equiv), THF, −78→−40 °C, 50 min; then (±)-6 (1.0 equiv), −40→0 °C, 20 min; (b) TBAF (2.0 equiv), THF, 25 °C, 6 h, 20, 41% for two steps, d-20, 42 % for two steps; (c) TESCl (2.0 equiv), imid (10 equiv), CH2Cl2, 25 °C, 5 h; (d) KHMDS (5.0 equiv), ClCO2Me (10.0 equiv), Et3N (10 equiv), THF, −78→25 °C, 1 h; (e) HF•py/py (1:4), 0→25 °C, 12 h, 79 % for three steps; (f) PhI(OAc)2 (2.0 equiv), AZADO (0.1 equiv), CH2Cl2, 25 °C, 24 h, 95 %; (g) SmI2 (0.1 M in THF, 4.0 equiv), HMPA (12 equiv), THF, −20→25 °C, 3.5 h, 22β, 33 % yield, 22α, 21 %; (h) NaH (15 equiv), CS2 (30 equiv), THF, 0→25 °C, 30 min; then MeI (45 equiv), 25 °C, 24 h; then 185 °C, μ-waves), o-dichlorobenzene, 15 min, 86 % for two steps; (i) POCl3, pyridine, 72 % (j) ThexBH2 (5.0 equiv), THF, − 10→25 °C, 0.5 h; then BH3•THF (15 equiv), 25 °C, 1 h; then 30 % H2O2/3 N NaOH (1:1 dr), 0→45 °C, 1 h; 70 %; (k) oNO2C6H4SeCN (3.0 equiv), nBu3P (6.0 equiv), py (9.0 equiv), THF, 25 °C; then 30 % H2O2, 0→45 °C, 68 %; (l) KHMDS (6.0 equiv), TESCl (4.0 equiv), Et3N (8.0 equiv), THF, −50→25 °C, 30 min, 89 %; (m) LiDBB (excess), THF, −78→−50 °C, 1 h, 83 %; (n) PhI(OAc)2 (2.0 equiv), 1-Me-AZADO (0.2 equiv), CH2Cl2, 25 °C, 22 h; (o) Ac2O (30 equiv), Et3N (90 equiv), 4-DMAP (2.0 equiv), CH2Cl2, 25 °C, 36 h, 87 % for two steps; (p) 48 % aq. HF:THF (1:3), 25 °C, 7 h, 77 %. KHMDS = potassium hexamethyldisilyazide, Thexyl = thexylborane, LiDBB = Lithium di-tert-butylbiphenyl.
Synthesis of aldehyde (±)-30 and vannusal B structure 4. Reagents and conditions: (a) LDA [generated from iPr2NH (5.0 equiv), nBuLi (2.5 M in haxanes, 5.0 equiv)], THF, −78→−40 °C; then acetone (20 equiv), −40→25 °C, 1 h, (3:1 dr); (b) TESOTf (2.0 equiv), 2,6-lut. (5.0 equiv), −78→−40 °C, 1 h, 66 % for two steps; (c) NaBH4 (20 equiv), THF:MeOH (1:1), −10→25 °C, 4 h; (d) EtOH, PPTS (0.10 equiv), 25 °C, 2 h, 91 % for two steps; (e) (MeO)2C(Me)2:DMF (1:1), PPTS (1.0 equiv), 25 °C, 48 h, 100 %; (f) SEMCl (5.0 equiv), iPr2NEt (15 equiv), nBu4NI (1.0 equiv), CH2Cl2, 50 °C, 24 h, 97 %;
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