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. 2009;48(37):6870-4.
doi: 10.1002/anie.200903382.

Total synthesis of hirsutellone B

K C Nicolaou  1 , David Sarlah, T Robert Wu, Weiqiang Zhan
Affiliations

Total synthesis of hirsutellone B

K C Nicolaou et al. Angew Chem Int Ed Engl. 2009.
No abstract available

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Figures

Figure 1
Figure 1
Molecular structures of hirsutellones A (1a) and B (1b).
Figure 2
Figure 2
Retrosynthetic analysis of hirsutellone B (1b).
Figure 3
Figure 3
Postulated preferred transition state conformations of I and II leading to tricyclic core product 5.
Figure 4
Figure 4
X-ray derived ORTEP drawing of carbamate 12 (thermal ellipsoids at 30 % probability); gray C, green H, blue N, red O.
Figure 5
Figure 5
X-ray derived ORTEP drawing of diol 16 (thermal ellipsoids at 30 % probability); gray C, green H, blue N, red O.
Scheme 1
Scheme 1
Enantioselective construction of hirsutellone core 5 and carbamate 12. Reagents and conditions: a) Ph3PCH2I2 (1.1 equiv), KHMDS (1.1 equiv), THF, –78→25 °C, 1 h; b) O3, CH2Cl2; then Me2S (10.0 equiv), –78→25 °C, 10 h, 80 % for two steps; c) Ph3P=CHCHO (1.1 equiv), CHCl3, 70 °C, 24 h; d) cat. 9 (10 mol %), H2O2 (aq., 35 % w/w, 1.3 equiv), 0→25 °C, 8 h, CH2Cl2; then Ph3P=CHCO2Me (1.2 equiv), 25 °C, 1 h, 58 % overall yield from 8; d) 11 (2.0 equiv), CuTC (3.0 equiv), NMP, 25 °C, 6 h, 70 %; e) Et2AlCl (5.0 equiv), CH2Cl2, – 78→25 °C, 12 h, 50 %; f) pBrC6H4NCO (3.0 equiv), 4-DMAP (3.1 equiv), CH2Cl2, 0→25 °C, 10 h, quant. KHMDS = potassium hexamethyldisilazide, CuTC = copper(I) thiophene-2-carboxylate, NMP = N-methyl-2-pyrrolidinone.
Scheme 2
Scheme 2
Construction of sulfone 3. Reagents and conditions: a) pTol4BiF (2.5 equiv), Cy2NMe (2.5 equiv), Cu(OAc)2 (20 mol %), PhMe, 25 °C, 12 h; b) LiAlH4 (3.0 equiv), Et2O, 0→25 °C, 2.5 h; c) TEMPO (0.2 equiv), PhI(OAc)2 (1.5 equiv), CH2Cl2, 25 °C, 12 h, 78 % for three steps; d) BrMg(CH2)3OTBS (3.0 equiv), THF, 0→25 °C, 5 h; e) DMP (1.3 equiv), CH2Cl2, 0→25 °C, 2 h, 91 % for two steps; f) CAN (5.0 equiv), MeCN:H2O (20:1), 25 °C, 2.5 h; g) NaBH(OAc)3 (5.0 equiv), PhH, 25 °C, 12 h, 81 % for two steps; h) ZnI2 (5.0 equiv), AcSH (2.0 equiv), CH2Cl2, 25 °C, 6 h, 68 %; i) NaOMe (1.4 equiv), MeOH:THF (1:1, 1.0 mM), 25 °C, 36 h; j) H2O2 (aq., 35 % w/w, 15 equiv), Na2WO4 (1.0 equiv), THF:MeOH (1:1), 0→25 °C, 2 h, 79 % for two steps. Ac = acetyl, TEMPO = 2,2,6,6-tetramethylpiperidine-1-oxyl, TBS = tert-butyldimethylsilyl, DMP = Dess–Martin periodinane, CAN = cerium(IV) ammonium nitrate, THF = tetrahydrofuran.
Scheme 3
Scheme 3
Completion of the total synthesis of hirsutellone B (1b). Reagents and conditions: a) CF2Br2 (5.0 equiv), KOH/Al2O3 (15 % w/w, 2 g per mmol), CH2Cl2/tBuOH (1:1), 0→25 °C, 2 h; b) LHMDS (3.3 equiv), NCCO2Me (8.3 equiv), THF, –78→–50 °C, 0.5 h, 61 % for two steps; c) AD-mix-β (1.0 equiv), MeSO2NH2 (1.7 equiv), tBuOH/H2O (1:1), 25 °C, 18 h, 90 %; d) S=CCl2 (1.5 equiv), 4-DMAP (3.0 equiv), CH2Cl2, 0→25 °C, 1 h; e) AIBN (2.0 equiv), nBu3SnH (10 equiv), PhMe, 100 °C, 2 h, 65 % for two steps; f) DMP (2.0 equiv), CH2Cl2, 25 °C, 2 h, 92 %; g) NH3, MeOH/H2O (4:1), 120 °C, 1 h, 50 %. LHMDS = lithium hexamethyldisilazide, 4-DMAP = 4-dimethylaminopyridine.
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References

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