Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008;47(45):8605-10.
doi: 10.1002/anie.200804228.

Total synthesis of the originally assigned structure of vannusal B

K C Nicolaou  1 , Hongjun Zhang, Adrian Ortiz, Philippe Dagneau
Affiliations

Total synthesis of the originally assigned structure of vannusal B

K C Nicolaou et al. Angew Chem Int Ed Engl. 2008.
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
Originally assigned structures of vannusals A (1a) and B (1b).
Figure 2
Figure 2
Retrosynthetic analysis vannusal B (1b).
Figure 3
Figure 3
X-Ray derived ORTEP drawing of 14.
Figure 4
Figure 4
X-Ray derived ORTEP drawing of 19.
Figure 5
Figure 5
X-Ray derived ORTEP drawing of 34.
Scheme 1
Scheme 1
Enantioselective construction of vinyl iodide 2. Reagents and conditions: (a) POCl3 (2.2 equiv), py, 90 °C, 2 h, 97 %; (b) BH3•THF (2.5 equiv), cylcohexene (2.5 equiv), −40 → 0 °C, 2 h; then 4, −40 → 25 °C, 12 h; then 50 °C, 30 min; then 30 % H2O2 / 3 N NaOH (2:1 v/v), 25 → 50 °C, 12 h, 51 %; (c) Ac2O (3.0 equiv), 4-DMAP (0.02 equiv), py, 25 °C, 3 h, 100 %; (d) Lipase Amano PS (100 wt %), acetone:phosphate buffer (pH = 7) (2:1), 25 °C, 48 h, 100 %, 99 % ee; (e) TBDPSCl (1.2 equiv), imid (3.0 equiv), CH2Cl2, 25 °C, 12 h, 99 %; (f) DIBAL-H (1.0 M in hexanes, 2.5 equiv), CH2Cl2, −78 °C, 30 min, 98 %; (g) Martin’s sulfurane (1.3 equiv), Et3N (3.0 equiv), CH2Cl2, 25 °C, 12 h, 99 %; (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 (8.5 equiv), tBuLi (1.7 M in pentane, 8.0 equiv), THF, −78 °C, 5 min; then BF3•Et2O, 2 min; 9, −78 → −20 °C, 30 min, 83 %; (j) pNO2C6H4CO2H (1.5 equiv), DEAD (1.5 equiv), Ph3P (1.8 equiv), benzene, 0 → 25 °C, 18 h, 94 %; (k) DIBAL-H (1.0 M in hexanes, 2.5 equiv), CH2Cl2, −78 °C, 30 min, 96 %; (l) BOMCl (3.0 equiv), iPr2NEt (10 equiv), PhMe, 90 °C 12 h; (m) TBAF (1.0 M in THF, 15 equiv), 70 °C, 97 % over two steps; (n) NMO (1.5 equiv), TPAP (0.03 equiv), CH2Cl2:CH3CN (9:1), 12 h, 96 %; (o) TrisNHNH2 (1.8 equiv), THF, 5 h, 80 %; (p) nBuLi (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 %; (q) pBrC6H4NCO (4.0 equiv), Et3N (6.0 equiv), 25 °C; (r) TBAF, THF, 25 °C, 91 % for two steps. 4-DMAP = 4-dimethylaminopyridine, py = pyridine, TBDPS = tert-butyldiphenylsilyl, imid = imidazole, DIBAL-H = diisobutylaluminum hydride NIS = N-iodosuccinimide, DEAD = diethylazodicarboxylate, BOM = benzyloxymethyl, TBAF = tetra-n-butylammonium fluoride, NMO = N-methylmorpholine-N-oxide, TPAP = tetra-n-propylammoniumperuthenate, Tris = triisopropylsulfonyl.
Scheme 2
Scheme 2
Construction of aldehyde 3. Reagents and conditions: (a) B-Br-catecholborane (3.5 equiv), CH2Cl2, 25 → 50 °C, 3 h; (b) TIPSCl (1.5 equiv), imid (6.0 equiv), DMF, 24 h, 70 % for two steps; (c) IBX (4.0 equiv), DMSO, 50 °C, 4 h, 90 %; (d) TiCl4 (1.0 M in CH2Cl2, 1.2 equiv), Et3N (3.0 equiv), CH2Cl2, −78 → −30 °C, 30 min; then acetone, −92 °C, 12 h (9:1 dr); (e) TESOTf (3.0 equiv), 2,6-lut. (5.0 equiv), −78 → −40 °C, 1 h, 81 % for the two steps; (f) NaBH4 (20 equiv), THF:MeOH (1:1), −10 → 25 °C, 5 h; (g) PPTS (0.2 equiv), EtOH, 25 °C, 2 h, 85 % for two steps; (h) Ac2O (30 equiv), 4-DMAP (0.1 equiv), Et3N (40 equiv), CH2Cl2, 25 °C, 18 h, 79 %; (i) 2-methoxypropene (20 equiv), CSA (1.0 equiv), CH2Cl2, −78 → −30 °C, 3 h, 82 %; (j) CH3MgBr (50 equiv), PhMe, 50 °C, 8 h, 94 %; (k) SEMCl (10 equiv), iPr2NEt (30 equiv), TBAI (1.0 equiv), CH2Cl2, 50 °C, 48 h, 96 %; (l) O3, py (1.0 equiv), CH2Cl2:MeOH (1:1), −78 °C; then Ph3P (5.0 equiv), −78 → 25 °C, 1 h, 96 %; (m) KH (10 equiv), allyl chloride (20 equiv), HMPA (5.0 equiv), DME, −10 → 25 °C, 3 h, 92 %; (n) iPr2NEt (1.0 equiv), 1,2-dichlorobenzene, 200 °C (µ-wave), 20 min; then NaBH4 (20 equiv), MeOH, 1 h, 25 °C, 88 % for two steps; (o) BOMCl (6.0 equiv), iPr2NEt (15 equiv), CH2Cl2, 50 °C 12 h; (p) O3, py (1.0 equiv), CH2Cl2:MeOH (1:1), −78 °C; then Ph3P (5.0 equiv), −78 → 25 °C, 1 h, 85 % for two steps; (q) TBSCl (10 equiv), DBU (20 equiv), CH2Cl2, 25 °C, 36 h; (r) O3, py (1.0 equiv), CH2Cl2:MeOH (1:1), −78 °C; then Ph3P (5.0 equiv), −78 → 25 °C, 1 h, 97 % for two steps. TIPS = triisopropylsilyl, TES = triethylsilyl, 2,6-lut. = 2,6-dimethylpyridine, PPTS = pyrdinium p-toluene-sulfonate, CSA = camphorsufonic acid, HMPA = hexamethylphosphoramide, DBU = 1,8-diazoicyclo[5.4.0]undec-7-ene.
Scheme 3
Scheme 3
Completion of the synthesis of structure 1b. Reagents and conditions: (a) 2 (1.3 equiv), tBuLi (2.6 equiv), THF, −78 → −40 °C, 30 min; then 3 (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), imid (5.0 equiv), CH2Cl2, 25 °C, 1 h, 99 %; (d) KHMDS (0.5 M in PhMe, 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, 92 % for two steps; (f) TEMPO (1.0 equiv), PhI(OAc)2 (3.0 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 % (26: 28 %, 27: 52 %); (h) POCl3 (60.0 equiv), py, 60 °C, 3 h, 85 %; (i) CS2 (8.0 equiv), NaH (6.0 equiv), THF, 0 → 25 °C, 30 min; then CH3I (12 equiv), 0 → 25 °C, 3 h; then 185 °C (µ-wave), 1,2-dichlorobenzene, 15 min, 92 %; (j) 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 NaOH (1:1), 25 → 40 °C, 1 h; 65 % (1:1.3 mix); (k) oNO2C6H4SeCN (2.0 equiv), nBu3P (6.0 equiv), py (12 equiv), THF, 25 °C; then 30 % H2O2, 0 → 25 °C, 67 %; (l) KHMDS (0.5 M in PhMe, 5.0 equiv), TESCl (5.0 equiv), Et3N (8.0 equiv), THF, −78 → 25 °C, 30 min, 94 %; (m) LiDBB (excess), THF, −78 → −50°C, 30 min, 84 %; (n) TEMPO (1.0 equiv), PhI(OAc)2 (3.0 equiv), CH2Cl2, 25 °C, 24 h, 88 %; (o) Ac2O (30 equiv), Et3N (30 equiv), 4-DMAP (1.0 equiv), CH2Cl2, 25 °C, 12 h, 100 %; (p) HF•py/THF (1:4), 25 °C, 3 h; then 3 N aq. HCl/THF (1:3), 25 °C, 6 h, 80 %. KHMDS = potassium hexamethyldisilyazide, TEMPO = 2,2,6,6-teramethyl-1-piperidinyloxy free radical, LiDBB = Lithium ditert- butylbiphenyl.
Scheme 4
Scheme 4
Synthesis of crystalline derivative 34. Reagents and conditions: (a) DEAD (10 equiv), Ph3P (10 equiv), pNO2C6H4CO2H (10 equiv), benzene, 60 °C, 2 h, 88 % based on 58 % conversion; (b) LiDBB, THF, −78 → −50 °C; (c) HF•py/THF, 25 °C, 4 h; (d) pBrC6H4NCO (10 equiv), py, 40 °C, 70 % for the three steps.
See this image and copyright information in PMC

References

    1. Guella G, Dini F, Pietra F. Angew. Chem. 1999;111:1217–1220. - PubMed
    2. Angew. Chem. Int. Ed. 1999;38:1134–1136. - PubMed
    1. Guella G, Callone E, Di Giuseppe G, Frassanito R, Frontini FP, Mancini I, Dini F. Eur. J. Org. Chem. 2007:5226–5234.
    1. Griedinger DS, Ginsburg D. J. Org. Chem. 1957;22:1406–1410.

    1. For reviews on enzymatic desymmetrization in organic synthesis, see Garcia-Urdiales E, Alfoso I, Gotor V. Chem. Rev. 2005;105:313–354. Hartung IV, Hoffmann HMR. Angew. Chem. 2004;116:1968–1984. Angew. Chem. Int. Ed. 2004;43:1934–1949.

    1. Martin SF, Dodge JF. Tetrahedron Lett. 1991;32:3017–3020.

Publication types

Substances

LinkOut - more resources