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. 2014 Oct 6;53(41):10970-4.
doi: 10.1002/anie.201406815. Epub 2014 Aug 27.

Total synthesis of myceliothermophins C, D, and E

K C Nicolaou  1 , Lei Shi, Min Lu, Manas R Pattanayak, Akshay A Shah, Heraklidia A Ioannidou, Manjunath Lamani
Affiliations

Total synthesis of myceliothermophins C, D, and E

K C Nicolaou et al. Angew Chem Int Ed Engl. .

Abstract

The total synthesis of cytotoxic polyketides myceliothermophins E (1), C (2), and D (3) through a cascade-based cyclization to form the trans-fused decalin system is described. The convergent synthesis delivered all three natural products through late-stage divergence and facilitated unambiguous C21 structural assignments for 2 and 3 through X-ray crystallographic analysis, which revealed an interesting dimeric structure between its enantiomeric forms.

Keywords: cascade reactions; decalin; natural products; polyketides; total synthesis.

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Figures

Figure 1
Figure 1
Structures of myceliothermophins E (1), C (2), D (3) and retrosynthetic analysis.
Figure 2
Figure 2
X-Ray derived ORTEP representation of A) 3,5-dinitrobenzoate (±)-13 and B) synthetic myceliothermophin C [(±)-2]. Thermal ellipsoids at 30% probability. gray = C, red = O, blue = N, green = H for both ORTEPS.
Scheme 1
Scheme 1
Preparation of decalin system 6 and 3,5–dinitrobenzoate 13. A) Reagents and conditions: a) NaH (1.3 equiv), (CH3)3SO+ l− (1.3 equiv), DMSO, 0 °C, 3 h, 96% (ca 1:1 dr); b) O3; then Me2S (3.0 equiv), CH2Cl2, −78 °C, 1 h; then Ba(OH)2 (1.1 equiv), 11 (1.1 equiv), THF:H2O (10:1), 0 °C, 2 h, 84% (ca 1:1 dr); c) InCl3 (0.5 equiv), CH2Cl2, 25 °C, 0.5 h, 85% (ca 1:1 dr); d) PTSA (0.1 equiv), benzene, reflux, 3 h, 92% (ca 3:1 dr); e) see Table 1, entry 5: TiCl4, MS 4Å, CH2Cl2, 25 °C, 72 h, 23% (ca 10:1 dr); entry 6: InCl2, C6H6, 45 °C, 5 h, 30% (ca 4.5:1); f) PTSA (0.1 equiv), benzene, reflux, 3 h, 65% (ca 3:1 dr); B) Reagents and conditions: g) NaBH4 (1.2 equiv), MeOH, 0 °C, 1 h, 61% (≥ 20:1 dr); h) 3,5- C6H3(NO2)2COCl (1.2 equiv), DMAP (2.0 equiv), CH2Cl2, 25 °C, 2 h, 95% (≥ 20:1 dr); PTSA = p-toluenesulfonic acid.
Scheme 2
Scheme 2
Synthesis of the aldehyde 4. Reagents and conditions: a) 6 (ca 3:1 dr), LDA (3.0 equiv); then 14 (2.0 equiv), THF, −78 °C, 0.5 h; b) TBSCl (1.2 equiv), DMAP (0.1 equiv), imidazole (2.0 equiv), CH2Cl2, 0 °C, 2 h, 81% for the two steps (ca 3:1 dr); c) NaBH4 (1.0 equiv), MeOH, −10 °C, 1 h; then flash column chromatography, 65% for pure alcohol 17; d) mCPBA (1.5 equiv), NaHCO3 (2.0 equiv), CH2Cl2, 0 °C, 10 h, 92% (ca 2:1 dr); e) MsCl (1.5 equiv), Et3N (2.0 equiv), CH2Cl2, 0 °C,1 h, 97% (ca 2:1 dr); f) Lithium naphthalide (2.0 equiv), THF, −30 °C, 3 h, 83% (ca 2:1 dr); g) DMP (1.1 equiv), NaHCO3 (2.0 equiv), CH2Cl2, 25 °C, 1 h, 95%; h) allyltrimethylsilane (1.1 equiv), TiCl4 (1.2 equiv), CH2Cl2, −78 °C, 2 h, 98%; i) KHMDS (2.0 equiv), MeI (2.0 equiv), THF, −78 °C, 4 h, 87% (≥ 20:1 dr); j) O3; then Me2S, CH2Cl2, −78 °C, 1 h; then NfF (1.2 equiv), P1-base (3.0 equiv), DMF, 0 °C, 3 h, 82%; k) DIBAL (1.0 equiv), CH2Cl2, −78 °C, 0.5 h, 98%; then POCl3 (5.0 equiv), pyridine, MeCN, 70 °C, 12 h, 81%; l) ZrCp2Cl2 (2.0 equiv), Me3Al (5.0 equiv), CH2Cl2, −20→25 °C, 24 h; then l2 (1.1 equiv), 25 °C, 24 h, 81%; m) Me2Zn (2.0 equiv), (Ph3P)2PdCl2 (5 mol%), THF, 0 °C, 3 h, 94%; n) TBAF (1.1 equiv), THF, 70 °C, 5 h, 91%; o) DMP (1.0 equiv), NaHCO3 (2.0 equiv), CH2Cl2, 25 °C, 0.5 h, 95%. NfF = nonafluorobutanesulfonyl fluoride, P1-base = phosphazene base P1-tBu-tris(tetramethylene), LDA = lithium diisopropylamide, DMAP = 4-dimethylaminopyridine, DMP = Dess–Martin periodinane.
Scheme 3
Scheme 3
Synthesis of pyrrolidinone building block 5. Reagents and conditions: a) 27 (3.0 equiv), THF, 25 °C, 24 h; then MeOH:H2SO4 (10:1), 62%; b) nBuLi (1.2 equiv), TeocONP (1.2 equiv), HMPA (1.0 equiv), THF, −78 °C, 10 h, 82%. TeocONP = 4-nitrophenyl 2-(trimethylsilyl)ethyl carbonate, HMPA = hexamethylphosphoramide.
Scheme 4
Scheme 4
Completion of the total synthesis of myceliothermophins E (1), C (2) and D (3). Reagents and conditions: a) LDA (1.0 equiv); then 4, THF, −78 °C, 0.5 h, 85%; b) DMP (5.0 equiv), CH2Cl2, 25 °C, 6 h, 90% combined for 31a and 31b (ca 1:1 dr); c) NaH (1.1 equiv), THF, 25 °C, 0.5 h; then PhSeCl (1.0 equiv), −78 °C, 0.5 h; d) NaIO4 (2.0 equiv), MeCN, 25 °C, 2 h, 78% for the two steps; e) TBAF:AcOH (1:1) (2.0 equiv), THF, 0 → 25 °C, 5 h, 92%; (f) 47% aq. HF, MeCN, 0 → 25 °C, 2 h, 81%; DMP = Dess–Martin periodinane.
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