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OTBDMS-11-epi-ascomycin 10. Finally, conventional
removal of the TBDMS-protecting groups (5% aq HF–
acetonitrile) completed the conversion of ascomycin into
11-epi-ascomycin 3 via ASD 732 4.
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In contrast to ascomycin, which exists in CDCl3 solution
as a mixture of six- and seven-membered hemiketal
forms (ratio ꢀ 15:1), 11-epi-ascomycin adopts exclu-
sively two diastereoisomeric [10(S) and 10(R)] six-
membered hemiketal forms in the ratio 4:1. Whether the
10(R) or the 10(S) isomer represents the major constit-
uent could not be determined as no diagnostically
relevant NOEs could be observed. As deduced from
two-dimensional NMR experiments, the major isomer
exists as a mixture of rotamers with respect to the
geometry (E vs Z ¼ 1:1) at the amide bond, whereas for
the minor isomer >90% of the trans-amide configuration
is observed.9;10 Notably, 11-epi-ascomycin is stable to-
wards acidic reaction conditions (e.g., the conditions
used for its deprotection, 10 fi 3 in Scheme 1), whereas
under weakly basic conditions (triethylamine in aceto-
nitrile solution at rt) a rapid and complete conversion
into ascomycin is observed. In contrast, applying the
same reaction conditions to ascomycin, no formation of
11-epi-ascomycin is detectable. Upon storage of asco-
mycin in protic or aprotic organic solutions or aqueous-
organic solutions, no formation of 11-epi-ascomycin
could be detected as well. Surprisingly, upon treatment
of 11-epi-ascomycin with the strong base DBU in ace-
tonitrile solution at room temperature, ASD 732 4 is
rapidly formed as the sole product together with only
minor amounts of ascomycin. As the mechanism of the
conversion of ascomycin itself into ASD 732, which
requires epimerisation, rearrangement and ring forma-
tion, is not yet fully understood, the smooth conversion
of 11-epi-ascomycin into ASD 732 4 gives a first hint
that this peculiar transformation might proceed via a
C11-epimerisation as the first step. More detailed
mechanistic investigations of this reaction are ongoing
and will be reported in due course.
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9. For a simple determination of the E/Z-ratio via NMR, see:
€
Baumann, K.; Hogenauer, K.; Schulz, G.; Steck, A. Magn.
Reson. Chem. 2002, 40, 443–448.
10. 13C NMR (CDCl3): d (cis/trans-major isomer/trans-minor
isomer, ppm): 169.99/170.26/168.65 (C1); +/52.44/52.66
(C2); 26.79/27.53/26.72 (C3); 20.83/22.01/21.06 (C4);
23.92/24.67/24.85 (C5); 40.31/44.70/44.09 (C6); 167.10*/
167.13*/164.44 (C8); 199.01/193.65/200.36 (C9); 99.10/
98.93/99.80 (C10); 29.28/34.88/32.39 (C11); 28.99/++/++
(C12); 71.10/70.96/n.d. (C13); 72.91/72.91/75.10 (C14);
80.61/76.32/76.95 (C15); 36.51/32.61/32.33 (C16); 27.32*/
26.81*/26.47 (C17); 50.00/49.01/48.64 (C18); 138.85/
139.26/140.39 (C19); 124.45/123.59/123.38 (C20); 55.18/
54.38/55.42 (C21); 214.10/213.32/214.67 (C22); 44.59/
44.59/43.51 (C23); 69.96/70.18/69.63 (C24); 40.16*/
39.98*/40.77 (C25); 78.10/77.77/78.70 (C26); 131.98/
132.33/131.96 (C27); 14.78/14.49/14.78 (C28); 129.31/
130.95/128.83 (C29); 35.32/35.46/35.32 (C30); 35.25/
35.02/34.62 (C31); 84.74*/84.57*/84.61 (C32); 73.95/
73.95/73.98 (C33); 31.60/31.60/31.72 (C34); ++/++/++
(C35); 25.33/25.08/25.33 (C36); 11.97*/11.89*/12.09
(C37); +/+/+ (13-OMe); 57.50/57.81/57.57 (15-OMe); +/
+/+ (32-OMe); +++/15.61/15.76 (11-Me); 21.22/20.46/
19.56 (17-Me); +++/16.44/+++ (19-Me); 10.31*/10.22*/
10.38 (25-Me). (*) Opposite E/Z-assignment possible; (+)
one of seven signals between 56.58 and 56.96; (++) one of
the five signals at 31.14, 31.09, 30.95, 30.79 and 30.73;
(+++) one of three signals at 16.17, 16.14 and 16.08.
References and Notes
1. For reviews, see: (a) Grassberger, M. A.; Baumann, K.
Curr. Opin. Ther. Patents 1993, 931–937; (b) Stuetz, A.;
Grassberger, M. A.; Baumann, K.; Edmunds, A. J. F.;
Hiestand, P.; Meingassner, J. G.; Nussbaumer, P.;
Schuler, W.; Zenke, G. Perspect. Med. Chem. 1993, 427–
443.
2. (a) Graham-Brown, R.; Grassberger, M. Int. J. Clin.
Pract. 2003, 57, 319–327; (b) Eichenfield, L. F.; Beck, L. J.