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Volumn 6, Issue 2, 2004, Pages 286-292

Macrolactones in diversity-oriented synthesis: Preparation of a pilot library and exploration of factors controlling macrocyclization

Author keywords

[No Author keywords available]

Indexed keywords

LACTONE DERIVATIVE; MACROLIDE;

EID: 1842454311     PISSN: 15204766     EISSN: None     Source Type: Journal    
DOI: 10.1021/cc020076m     Document Type: Article
Times cited : (38)

References (55)
  • 3
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    • Small molecule inhibitors of a protein can make analysis of protein function using DNA microarray richer in information. By assaying mRNA at multiple time points following the addition of small molecule inhibitor to cells, early effects can be differentiated from late effects. See: Bernstein, B. E.; Tong, J. K.; Schreiber, S. L. Proc. Natl. Acad Sci. U.S.A. 2000, 97 (25), 13708-13713.
    • (2000) Proc. Natl. Acad Sci. U.S.A. , vol.97 , Issue.25 , pp. 13708-13713
    • Bernstein, B.E.1    Tong, J.K.2    Schreiber, S.L.3
  • 10
    • 0033380609 scopus 로고    scopus 로고
    • (e) Zhao, A.; et al. J. Antibiot. 1999, 52, 1086-1094.
    • (1999) J. Antibiot. , vol.52 , pp. 1086-1094
    • Zhao, A.1
  • 15
    • 1842437476 scopus 로고    scopus 로고
    • note
    • Even if two compounds have a similar preferred conformation, they may vary in the energetic costs of occupying an alternative conformation. Thus, the free energy penalty for distortion of one of the small molecules upon binding to a protein target will differ from that of the other. Therefore, macrolide libraries may achieve a high level of structural diversity by containing molecules that can achieve different macrocycle conformations.
  • 36
    • 1842541804 scopus 로고    scopus 로고
    • note
    • For acid protection, methyl esters could not be selectively removed without cleavage of the ester linkage between monomers. A MOM ester was compatible with monomer and macrolide synthesis and had the advantage that it did not preclude the use of allylic alcohols in the library synthesis. However, on solid phase, alcohols with MOM esters did not couple to acids cleanly. For alcohol protection, a 4-methoxyphenyl ether was also investigated, but conditions for its removal on solid-phase cleaved the silyl ether linkage to the bead.
  • 37
    • 1842541806 scopus 로고    scopus 로고
    • note
    • The PMP group was not meant to be removed and was used as a diversity element.
  • 40
    • 0001595852 scopus 로고
    • Otera, J. Chem. Rev. 1993, 93, 1449-1470.
    • (1993) Chem. Rev. , vol.93 , pp. 1449-1470
    • Otera, J.1
  • 41
    • 1842541805 scopus 로고    scopus 로고
    • note
    • For more details, see Supporting Information.
  • 43
    • 1842437478 scopus 로고    scopus 로고
    • note
    • Alcohols 12, 9a, and 9b can form lactones, but this reaction was slow if acid was rigorously removed and the compounds were stored at -20°C.
  • 44
    • 1842489771 scopus 로고    scopus 로고
    • note
    • Estimates based on bead swelling properties in various solvents indicate that hydroxyacid would be present at 0.1-0.2 M on the solid phase.
  • 45
    • 1842437479 scopus 로고    scopus 로고
    • note
    • Interestingly, the nuclear magnetic resonance (NMR) of B2 was unsymmetrical (Figure 3), giving different signals for protons that are chemically equivalent. Nuclear Overhauser effect spectroscopy (NOESY) data indicates that while one alkene proton interacts with the methylene proton, the symmetrical alkene proton interacts with the allylic proton and not with the methylene protons. This indicates that the 14-member macrocycle has an unsymmetrical conformation.
  • 48
    • 1842594263 scopus 로고    scopus 로고
    • note
    • Cyclization was initially effected by activation with 2,4,6-trichlorobenzoyl chloride in the presence of Hunig's base. After 20 h, additional benzoyl chloride and base were added, followed by DMAP. It had previously been shown that, for the model macrolide, cyclization could occur without DMAP and that DMAP increased the side reaction of coupling between hydroxyacids. Therefore, it was decided that cyclization would first be performed without DMAP to cyclize those rings that could close efficiently without DMAP. Next, a cyclization reaction accelerated by DMAP to close rings that were less efficiently cyclized would be conducted.


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.