Solid phase synthesis of heterocycles by cyclization/cleavage methodologies

Combinatorial Chemistry and High Throughput Screening

Volumn 1, Issue 4, 1998, Pages 185-214

  Van Maarseveen, Jan H ^a  

^a Solvay Pharmaceuticals Inc   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLOPEPTIDE; HETEROCYCLIC COMPOUND; PEPTIDE LIBRARY;

CHEMICAL MODEL; CHEMISTRY; METHODOLOGY; REVIEW; SYNTHESIS;

CHEMISTRY, PHARMACEUTICAL; HETEROCYCLIC COMPOUNDS; MODELS, CHEMICAL; PEPTIDE LIBRARY; PEPTIDES, CYCLIC;

EID: 0032235388     PISSN: 13862073     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (84)

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10. Only publications are included describing approaches in which the bond forming process for ring-closure occurs simultaneously with cleavage of the linking bond to liberate a cyclic molecule. Approaches which describe release of a linear molecule from the resin followed by ring closure in solution thus fall outside the scope of this review.
11. Very recently it has been shown that cyclotetrapeptides can be synthesized in solution in high yields using metal centers as a template for cyclization: Haas, K.; Ponikwar, W.; Nöth, H.; Beck, W. Angew. Chem. Int. Ed. 1998, 37, 1086-1089. For examples of classical high-dilution solution phase approaches see references cited.
12. It is generally assumed that intramolecular reactions are favored with substrates immobilized on (polystyrene) resins. This phenomena is mostly explained by the so called "pseudo infinite dilution" effect due to intraresin site separation. However, extensive research revealed that the matrix of the commonly used resins (1-2% DVB -polystyrenes, 0.1-2 mmol/g) in swollen condition is highly flexible. It was shown that the extent to which intermolecular reactions in the swollen polymer matrix occur depend on the kinetics; fast reactions benefit from pseudo high dilution while slow reactions may suffer from on-resin intermolecular side reactions. In cyclopeptide cyclorelease, which is a relatively slow process, the majority of the formed resin bound oligomers remain attached. Although generally a C/C cyclopeptide strategy gives higher yields than using high dilution solution conditions, the main advantage is due to the general ease of work-up of solid phase reactions and the higher purity of the released cyclopeptides. See: a) Scott, L.T.; Rebek, J.; Ovsyanko, L.; Sims, C.L. J. Am. Chem. Sac. 1977, 99, 625-626. b) Crowley, J.I.; Rapoport, H. Acc. Chem. Res. 1976, 9, 135-144. c) Mazur, S.; Jayalekshmy, P. J. Am. Chem. Soc. 1979, 101, 677-683. d) Rothe, M.; Lohmüller, M.; Breuksch, U.; Schmidtberg, G. Angew. Chem. Int. Ed. Engl. 1994, 33, 1960-1961. e) Yan, B.; Sun, Q. J. Org. Chem. 1998, 63, 55-58.
13. It is generally assumed that intramolecular reactions are favored with substrates immobilized on (polystyrene) resins. This phenomena is mostly explained by the so called "pseudo infinite dilution" effect due to intraresin site separation. However, extensive research revealed that the matrix of the commonly used resins (1-2% DVB -polystyrenes, 0.1-2 mmol/g) in swollen condition is highly flexible. It was shown that the extent to which intermolecular reactions in the swollen polymer matrix occur depend on the kinetics; fast reactions benefit from pseudo high dilution while slow reactions may suffer from on-resin intermolecular side reactions. In cyclopeptide cyclorelease, which is a relatively slow process, the majority of the formed resin bound oligomers remain attached. Although generally a C/C cyclopeptide strategy gives higher yields than using high dilution solution conditions, the main advantage is due to the general ease of work-up of solid phase reactions and the higher purity of the released cyclopeptides. See: a) Scott, L.T.; Rebek, J.; Ovsyanko, L.; Sims, C.L. J. Am. Chem. Sac. 1977, 99, 625-626. b) Crowley, J.I.; Rapoport, H. Acc. Chem. Res. 1976, 9, 135-144. c) Mazur, S.; Jayalekshmy, P. J. Am. Chem. Soc. 1979, 101, 677-683. d) Rothe, M.; Lohmüller, M.; Breuksch, U.; Schmidtberg, G. Angew. Chem. Int. Ed. Engl. 1994, 33, 1960-1961. e) Yan, B.; Sun, Q. J. Org. Chem. 1998, 63, 55-58.
14. It is generally assumed that intramolecular reactions are favored with substrates immobilized on (polystyrene) resins. This phenomena is mostly explained by the so called "pseudo infinite dilution" effect due to intraresin site separation. However, extensive research revealed that the matrix of the commonly used resins (1-2% DVB -polystyrenes, 0.1-2 mmol/g) in swollen condition is highly flexible. It was shown that the extent to which intermolecular reactions in the swollen polymer matrix occur depend on the kinetics; fast reactions benefit from pseudo high dilution while slow reactions may suffer from on-resin intermolecular side reactions. In cyclopeptide cyclorelease, which is a relatively slow process, the majority of the formed resin bound oligomers remain attached. Although generally a C/C cyclopeptide strategy gives higher yields than using high dilution solution conditions, the main advantage is due to the general ease of work-up of solid phase reactions and the higher purity of the released cyclopeptides. See: a) Scott, L.T.; Rebek, J.; Ovsyanko, L.; Sims, C.L. J. Am. Chem. Sac. 1977, 99, 625-626. b) Crowley, J.I.; Rapoport, H. Acc. Chem. Res. 1976, 9, 135-144. c) Mazur, S.; Jayalekshmy, P. J. Am. Chem. Soc. 1979, 101, 677-683. d) Rothe, M.; Lohmüller, M.; Breuksch, U.; Schmidtberg, G. Angew. Chem. Int. Ed. Engl. 1994, 33, 1960-1961. e) Yan, B.; Sun, Q. J. Org. Chem. 1998, 63, 55-58.
15. It is generally assumed that intramolecular reactions are favored with substrates immobilized on (polystyrene) resins. This phenomena is mostly explained by the so called "pseudo infinite dilution" effect due to intraresin site separation. However, extensive research revealed that the matrix of the commonly used resins (1-2% DVB -polystyrenes, 0.1-2 mmol/g) in swollen condition is highly flexible. It was shown that the extent to which intermolecular reactions in the swollen polymer matrix occur depend on the kinetics; fast reactions benefit from pseudo high dilution while slow reactions may suffer from on-resin intermolecular side reactions. In cyclopeptide cyclorelease, which is a relatively slow process, the majority of the formed resin bound oligomers remain attached. Although generally a C/C cyclopeptide strategy gives higher yields than using high dilution solution conditions, the main advantage is due to the general ease of work-up of solid phase reactions and the higher purity of the released cyclopeptides. See: a) Scott, L.T.; Rebek, J.; Ovsyanko, L.; Sims, C.L. J. Am. Chem. Sac. 1977, 99, 625-626. b) Crowley, J.I.; Rapoport, H. Acc. Chem. Res. 1976, 9, 135-144. c) Mazur, S.; Jayalekshmy, P. J. Am. Chem. Soc. 1979, 101, 677-683. d) Rothe, M.; Lohmüller, M.; Breuksch, U.; Schmidtberg, G. Angew. Chem. Int. Ed. Engl. 1994, 33, 1960-1961. e) Yan, B.; Sun, Q. J. Org. Chem. 1998, 63, 55-58.
16. It is generally assumed that intramolecular reactions are favored with substrates immobilized on (polystyrene) resins. This phenomena is mostly explained by the so called "pseudo infinite dilution" effect due to intraresin site separation. However, extensive research revealed that the matrix of the commonly used resins (1-2% DVB -polystyrenes, 0.1-2 mmol/g) in swollen condition is highly flexible. It was shown that the extent to which intermolecular reactions in the swollen polymer matrix occur depend on the kinetics; fast reactions benefit from pseudo high dilution while slow reactions may suffer from on-resin intermolecular side reactions. In cyclopeptide cyclorelease, which is a relatively slow process, the majority of the formed resin bound oligomers remain attached. Although generally a C/C cyclopeptide strategy gives higher yields than using high dilution solution conditions, the main advantage is due to the general ease of work-up of solid phase reactions and the higher purity of the released cyclopeptides. See: a) Scott, L.T.; Rebek, J.; Ovsyanko, L.; Sims, C.L. J. Am. Chem. Sac. 1977, 99, 625-626. b) Crowley, J.I.; Rapoport, H. Acc. Chem. Res. 1976, 9, 135-144. c) Mazur, S.; Jayalekshmy, P. J. Am. Chem. Soc. 1979, 101, 677-683. d) Rothe, M.; Lohmüller, M.; Breuksch, U.; Schmidtberg, G. Angew. Chem. Int. Ed. Engl. 1994, 33, 1960-1961. e) Yan, B.; Sun, Q. J. Org. Chem. 1998, 63, 55-58.
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73. All three used building blocks, each containing one stereocentre, were optically pure. Of the five stereocenters present in the C/C precursor sequence, two are present as a 1/1 mixture of both epimers, as a result of the non-stereoselective aldol condensation. Because the final RCM reaction may give both the E and Z double bonds, theoretically eight geometrically or diastereomerically different cyclcolefins can be obtained.
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77. 8 spacer unit (allows Ru alkylidene regeneration via on-resin cross-metathesis). Also, the addition of styrene may be beneficial due to acceleration of the regeneration of Ru alkylidene species (especially at the end of the reaction when only little C/C RCM diene precursors are present). See also the next reference.
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