Efficient robotic synthesis. Multi-component preparation of a tricyclic template by solid phase Tsuge reaction

Tetrahedron Letters

Volumn 39, Issue 32, 1998, Pages 5869-5872

  Bicknell, Andrew J ^a   Hird, Nicholas W ^a   Readshaw, Simon A ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CARBOXYLIC ACID DERIVATIVE; INDOLIZINE DERIVATIVE; MALEIMIDE; NITRILE; PYRIDINIUM DERIVATIVE; RESIN;

ARTICLE; DRUG SYNTHESIS; REACTION ANALYSIS; ROBOTICS;

EID: 0032490890     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(98)01185-X     Document Type: Article

References (22)

1. 1. a) Dewitt, S.H.; Czarnik, A.W. Current Opinion in Biotechnology, 1995, 6, 640-645.
2. b) Hardin, J.H.; Smietana, F.R. Molecular Diversity 1996, 1, 270-274.
3. c) Mjali, A.M.M.; Toyonaga, B.E. High throughput Screening, 1997, 209-221 Ed. Devlin, J.P.
4. 2. a) Cassells, J. IBC Combinatorial Technologies Conference, Coronada, October 1997.
5. b) Main, B. G.; Rudge, D.A. ISLAR Proceedings, 1994, 11, 425-434
6. c) Ahrweiler, P.M.; Harness, J.R.; Baker, W.; Towell, J.A.; Holub, D. American Laboratory 1997 12-14.
7. 3. For the use of the "mix-and-split" approach to generate arrays see: Czarnik A.W.; Nova, M.P. Chemistry in Britain, 1996, (Oct) 39-41.
8. 4. a) Armstrong, R.W.; Combs, A.P.; Tempest, P.A.; Brown, S.D.; Keating, T.A. Acconts Chem. Res. 1996, 29, 123-131.
9. b) Keating, T.A; Armstrong, R.W. J. Am. Chem. Soc. 1996, 118, 2574-2583.
10. 5. a) Hamper, B.C.; Dukesherer, D.R.; South, M.S. Tet. Letts., 1996, 37, 3671.
11. b) Tietze, L.; Synlett 1996, 1043.
12. c) Kiselyov, A. Tet. Letts., 1997, 38, 6163.
13. 6. Advanced ChemTech 496 Multiple Organic Synthesiser.
14. 7. Tsuge, O.; Kanemasa, S., Takenaka, S. Bull. Chem. Soc. Jpn. 1986, 59, 3631-3635.
15. 8. Recently a similar multicyclic template has been prepared by solid-phase intramolecular azomethine ylide cycloaddition: Gong, Y-D.; Najdi, S.; Olmstead, M.M.; Kurth, M.J. J. Org. Chem. 1998, 63, 3081-3086.
16. 9. To a suspension of Wang resin (7 mmol) in dry DCM (100 mL) in a round bottom flask under argon and cooled to 0°C was added dropwise chloroacetyl chloride (14 mmol) and the mixture stirred for 2 h. The resin was removed by filtration and washed with 3×10 mL DCM, THF and dioxane followed by 1×10 mL diethyl ether. The resin was suspended in dry DCM and pyridine (30mmol) was added and the mixture shaken for 24h at RT and the product was worked up as above.
17. 10. Vo, N.H.; Eyermann, C.J.; Hodge, C.N. Tet. Letts., 1997, 38, 7951-7954. (equation presented)
18. 2H), 171.8 (1-C), 175.5 (3-C), 188.3 (1′-C).
19. 7.
20. 13. Typical Procedure: To a suspension of 1 (0.032mmol) in dry THF was added maleimide (0.16 mmol) followed by triethylamine (0.16 mmol) dropwise over 1 min. After 1 h shaking at RT the resin was filtered, and resuspended in dry THF and imidoyl chloride nitrile oxide precursor (0.16 mmol) was added followed by triethylamine (0.16 mmol) dropwise over 5 min while shaking. After 2 h the resin was filtered and washed with 3×10 mL DCM, THF and dioxane followed by 1×10 mL diethyl ether.
21. 14. ACT MOS Protocol: Resin 1 (0.032 mmol) was added to each well and washed with 3×1 ml THF. Maleimide solution in dry THF (0.75 ml 0.21M soln, 0.16 mmol) was added and the block shaken for 1 min. Triethylamine in dry THF (0.25 ml 0.32M, 0.08 mmol) was added, followed by mixing for 5 min. A second 0.25ml aliquot of triethylamine solution was added and the block shaken for a further 1h, after which it was drained and washed with 1ml THF. Next imidoyl chloride solution in dry THF (0.75 ml, 0.21M, 0.16 mmol) was dispensed, and the triethylamine solution was dispensed in 2 aliquots as above. The block was shaken for a further 1 h, drained and worked up by 3×1ml successive washes of THF DCM, MeOH and DCM prior to cleavage with 1 ml TFA/DCM (1:1).
22. 15. HPLC was carried out using Beckmann System Gold, 100mm, gradient 0% to 100% MeCN in 0.1% aqueous TFA over 40min, flow rate 0.5ml/min, and detection at 220nm.