Conversion of ascomycin into its furano-isomers

Article abstract of DOI:10.1055/s-1999-3096

The high reactivity of the unmasked tricarbonyl segment of ascomycin potentially allows the formation of numerous isomers in the binding domain. In this paper, the synthesis of a novel class of hypothetical equilibrium products of ascomycin is described.

Full text of DOI:10.1055/s-1999-3096

LETTER
877
Conversion of Ascomycin into its Furano-Isomers
Karl Baumann,* Berndt Oberhauser, Gertrude Strnadt, Hermann Knapp, Gerhard Schulz and Maximilian A.
Grassberger
Department of Chemistry and Pharmacology, Novartis Forschungsinstitut, Brunner Strasse 59, A-1235 Vienna, Austria
Fax +43(1)86634 354; E-mail: karl.baumann@pharma.novartis.com
Received 28 January 1999
Dedicated with best wishes to our inspiring teacher Professor A. Eschenmoser, in recognition of his brilliant contributions on the art and
science of organic chemistry
and in man.5 SDZ ASM 981 (33-epi-chloro-ascomycin, 2)
Abstract: The high reactivity of the unmasked tricarbonyl segment
is the first representative in clinical development for the
of ascomycin potentially allows the formation of numerous isomers
treatment of inflammatory skin diseases.6-10 Ascomycin
in the binding domain. In this paper, the synthesis of a novel class
and related macrolactams feature in the ”binding domain”
(Fig.1)11-14 the unusual pattern of three adjacent carbonyl
groups (C8-C10), whereby one carbonyl group is in-
volved in hemiketal formation with the secondary hydrox-
yl group at C-14. The structure shown in Fig.1 is the main
isomeric form adopted in organic solution as determined
by NMR analysis.15
of hypothetical equilibrium products of ascomycin is described.
Key words: ascomycin, isomers, binding domain, tricarbonyl
Ascomycin (1) is a macrolactam isolated from the fermen-
tation broth of Streptomyces hygroscopicus var. asco-
myceticus.1-3 Derivatives of ascomycin have shown
interesting anti-inflammatory activities in animal models4
Hypothetically, however, the close proximity of the tricar-
bonyl portion to the hydroxyl group at C-14 allows the po-
tential formation of numerous alternative isomers (Fig. 2).
Thus, in solution, the six- and seven membered
hemiketals (A, B) might be generated via the free tricar-
bonylform (T), followed by unspecific hemiketalization.
Considering a preceding enolization at the tricarbonyl unit
(T-E), the formation of the corresponding 11-epi-isomers
of A, B has to be taken into account as well. Furthermore,
1,4-addition of the 14-hydroxyl at the hypothetical enol E
would result in the formation of the furano-enediol ED,
which might exist as such or as a set of tautomeric ”fura-
no-ascomycins” after tautomerization (F1, F2, Fig.2).
Despite the numerous formal equilibrium products that
could potentially be formed, only two isomeric
hemiketals16-18 have so far been identified and character-
ized in solutions of ascomycin or related macrolactams.
Figure 1
Figure 2 Hypothetical flexibility of the binding domain of ascomycin (only partial structures shown)
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878
K. Baumann et al.
LETTER
Therefore, we aimed not only at the detection, isolation, The formation of 4a,b and 5a,b can be explained by as-
and characterization of such equilibrium products but also suming (a) an equilibrium between 24,33-bis-OTBDMS-
at the synthetic accessibility of further, yet unknown, iso- ascomycin 3 and its furano-derivatives (i.e. the enediol
mers. In a previous communication, we presented the ED), (b) tautomerization and replacement of either the 9-
multigram conversion of ascomycin into its major equilib- OH or the 10-OH group by iodine followed by (c) iodide
rium product, the seven-membered hemiketal isomer B ion mediated dehalogenation (Fig.3).21
(compare Fig. 2).16 Here, we report on the synthesis of
Transformation of the main products 5a and 5b back into
four diastereoisomeric furano-ascomycins 8a-d corre-
the target products (F1, F2, Fig.2) required only a few
sponding to the general structures F1, F2. For the forma-
straightforward functional group manipulations (Schemes
tion of the furan ring, an unexpected reaction, occurring at
2,3). Applying a recently reported methodology,22 oxida-
the binding domain of ascomycin, turned out to be help-
tion of the activated methylene group in 5a,b with Dess-
Martin periodinane in the presence of pyridine yielded the
yellow tricarbonyl derivatives 6a and 6b respectively,
which after fluoride-mediated removal of the TBDMS-
ful: action of diiodo-triphenyl-phosphorane in the pres-
ence of imidazole, in refluxing acetonitrile, converted
24,33-bis-OTBDMS-ascomycin19 3 into a mixture of the
9- and 10-deoxo-furano-ascomycins 4a,b and 5a,b, re-
groups (24,33-OHs), provided the unprotected derivatives
spectively (Scheme 1).20
7a and 7b in high yields (Scheme 2).23
Scheme 1 (only partial structures shown)
Scheme 2 (only partial structures shown)
Selective reduction of the highly activated 9-carbonyl
group of 7a by treatment with zinc/glacial acetic acid in
acetonitrile solution at r.t. provided, after chromatograph-
ic separation, the furano-ascomycins 8a and 8b in high
yield. Starting from 7b, the 11-epi-furano-ascomycins 8c
and 8d were obtained in an analogous manner (Scheme
3).24
Structural assignment, especially of the furano-ascomy-
cins 4a,b and 5a,b, was laborious. These compounds exist
in CDCl3-solution as a mixture of conformers (cis vs.
trans-geometry at the amide bond). In addition, an equi-
librium between the ketone- and an enol-form is observed
in 5a,b, causing the overlap of four complex sets of sig-
nals. However, the carbon-skeleton, as well as the stere-
ochemical configuration at C-11, of both 4a and 4b could
be elucidated unambiguously from their NMR-data. Al-
though the structures of 5a,b could be solved, attempts to
determine their absolute configuration at C-11 via NMR
Figure 3 (only partial structures shown)
spectroscopy failed. In this case, the absolute configura-
Synlett 1999, S1, 877–880 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Isomers of the Macrolactam Ascomycin
879
Medicinal Chemistry, Testa, B.; Kyburz, E,; Fuhrer, W.;
Giger, R. (Eds.), Verlag Helv. Chim. Acta, Basle and VCH,
Weinheim, 1993, Chapt. 27, 427-44.
tion at C-11 could only be assigned indirectly, using the
less complex NMR-data sets of the corresponding oxi-
dized derivatives 6a and 6b. The absolute configurations
at C-9 of 8a-d are not yet known. However, the 11-S-fura-
no-ascomycins25 8a and 8b differ only with respect to the
stereochemical configuration at C-9. The same applies for
the 11-R-derivatives26 8c and 8d, as could be shown by
equilibration experiments under basic conditions. Thus,
treatment of either isolated pure 8a or 8b with triethy-
lamine in acetonitrile solution led to a fast epimerization
at C-9 generating a mixture of the isomers 8a,b. Analo-
gous results were obtained starting from the 11-epi-iso-
mers 8c,d. With exception of this equilibration reaction,
(5) Rappersberger, K.; Meingassner, J. G.; Fialla, R.; Fodinger,
D.; Sterniczky, B.; Rauch, S.; Putz, E.; Stuetz, A.; Wolff, K..
J. Invest. Dermatol. 1996, 106, 701.
(6) Grassberger, M.A.; Baumruker, T.; Enz, A.; Hiestand, P.;
Kalthoff, F.; Schuler, W.; Schulz, M.; Werner, F.-J.: Winiski,
A.; Wolff, B.; Zenke, G. Br. J. Dermatol. in press.
(7) Van Leent, E. J. M.; Graber, M.; Thurston, M.; Wagenaar, A.;
Spuls, P. I.; Bos, J. D. Arch. Dermatol. 1998, 134, 805.
(8) Graul, A.; Castaner, J. Drugs Future 1998, 23, 508.
(9) Meingassner, J. G.; Grassberger, M.; Fahrngruber, H.; Moore,
H. D.; Schuurman, H.; Stuetz, A. Br. J. Dermatol. 1997, 137,
568.
the isolated pure furano-ascomycins 8a-d turned out to be (10) Paul C., Ho V.C. Seminars in Cutaneous Medicine and
Surgery 1998, 17, 1-5.
remarkably stable towards several conditions. No decom-
(11) Van Duyne, Gregory D.; Standaert, Robert F.; Karplus, P.
position at r.t., even after storage for several months could
Andrew; Schreiber, Stuart L.; Clardy, Jon. Science 1991, 252,
be seen. More importantly, no back-conversion into the
parent compound ascomycin in protic or aprotic solutions,
839, and references cited therein.
(12) For a review, see: Grassberger, M. A.; Baumann, K. Current
under neutral, basic or acidic conditions could be detect-
ed. Likewise no formation of 8a-d was observed in solu-
tions of ascomycin. As a result, no evidence for an
equilibration between the furano-ascomycins 8a-d and
the parent compound ascomycin (1) could be demonstrat-
ed.
Opinion in Therapeutic Patents, 1993, 931.
(13) Griffith, J. P.; Kim, J. L.; Kim, E. E.; Sintchak, M. D.;
Thomson, J. A.; Fitzgibbon, M. J.; Fleming, M. A.; Caron, P.
R.; Hsiao, K.; Navia, M. A. Cell 1995, 82, 507.
(14) Kissinger, C. R.; Parge, H. E.; Knighton, D. R.; Lewis, C. T.;
Pelletier, L. A.; Tempczyk, A.; Kalish, V. J.; Tucker, K. D.;
Showalter, R. E.; Moomaw, E. W.; Gastinel, L. N.; Habuka,
N.; Chen, X.; Maldonado, F.; Barker, J. E.; Bacquet, R.;
Villafranca, E. J. Nature 1995, 378, 641.
(15) Mierke, D. F.; Schmieder, P.; Karuso, P.; Kessler, H. Helv.
Chim. Acta 1991, 74, 1027.
(16) Baumann, K.; Oberhauser, B.; Grassberger, M. A.; Haidl, G.;
Schulz, G. Tetrahedron Lett. 1995, 36, 2231.
(17) Gailliot, F. P.; Natishan, T. K.; Ballard, J. M.; Reamer, R. A.;
Kuczynski, D.; McManemin, G. J.; Egan, R. S.; Buckland, B.
C. J. Antibiot. 1994, 47, 806.
(18) Namiki, Y.; Kihara, N.; Koda, S.; Hane, K.; Yasuda, T. J.
Antibiot. 1993, 46, 1149.
(19) Zimmer, R.; Grassberger, M. A.; Baumann, K.; Schulz, G.;
Haidl, E.. Tetrahedron 1994, 50, 13655.
(20) Preparation of 4a,b and 5a,b: Iodine (2.49g, 9.8mmol) was
added to a solution of triphenylphosphine (2.49g, 9.8mmol)
and imidazole (1.67g, 24.5mmol) in 250ml CH3CN. After
10min at r.t. 24,33-bis-OTBDMS-ascomycin 3 (5.0g,
4.9mmol) was added in one portion and the mixture was
allowed to reflux for 15h. After cooling to r.t., the mixture was
partitioned between 1N HCl and AcOEt. The organic layer
was separated, washed twice with brine, dried over Na2SO4
and concentrated under reduced pressure. Column chromato-
graphy over silica gel (gradient: toluene : AcOEt = 9-4 : 1)
gave 650mg of a mixture of 3 and 4a,b, 1.82g (37%, 5a) and
984mg (20%, 5b) respectively. Flash chromatography of the
mixture of 3 and 4a,b over silica gel (gradient: CH2Cl2 : ace-
tone = 30-15 : 1) provided 70mg (1,4%, starting material 3),
345mg (7%, 4a) and 150mg (3%, 4b), respectively.
(21) Iodide ion catalyzed dehalogenations of 2-halo ketones have
been reported, see: Mandal, A. K.; Nijasure, A. M. Synlett
1990, 554.
Scheme 3 (only partial structures shown)
References and Notes
(1) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino,
T.; Goto, T.; Hashimoto, M.; Taga, T.. J. Am. Chem. Soc.
1987, 109, 5031.
(2) Hatanaka, H.; Kino, T.; Miyata, S.; Inamura, N.; Kuroda, A.;
Goto, T.; Tanaka, H.; Okuhara, M.. J. Antibiot. 1988, 41,
1592.
(3) Morisaki, M.; Arai, T. J. Antibiot. 1992, 45, 126.
(4) For a review, see: Stuetz,A.; Grassberger, M.A.; Baumann,
K.; Edmunds, A.J.F.; Hiestand, P.: Meingassner, J.G.;
Nussbaumer, P.; Schuler, W.; Zenke, G. in Perspectives in
(22) Batchelor, M. J.; Gillespie, R. J.; Golec, J. M. C.; Hedgecock,
C. J. R. Tetrahedron Lett. 1993, 34, 167.
(23) Preparation of 7a: Dess-Martin periodinane (2.96g, 7mmol)
was added to a solution of 5a (1.5g , 1mmol) and pyridine
(0.8g, 10mmol) in 50ml CH2Cl2. After stirring 15 h at r.t., the
mixture was concentrated to 15ml. Purification by flash chro-
matography over silica gel (eluent: n-heptane : AcOEt = 3 : 1)
gave 6a (0.72g, 72%) as yellow foam. 1ml 40w/w % aq.
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LETTER
(26) Spectroscopic data of the 11-S-compounds 8c and 8d:
hydrogen fluoride was added to a solution of 6a (0.5g,
4.9mmol) in 25ml CH3CN. After stirring 7 h at r.t., the mixture
was partitioned between AcOEt and saturated aq. NaHCO3.
The organic layer was separated, washed twice with brine,
dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified by flash chromatography over
silica gel (eluent: AcOEt : n-heptane = 3 : 1). The product
containing fractions were concentrated, re-dissolved in tolue-
ne (in order to remove traces of water) and evaporated to
dryness to give 7a (338mg, 87%) as yellow amorphous
powder. Compound 7b was obtained in the same manner.
8c or 8d; (mixture of rotamers: E-amide:Z-amide = 5:4)
13C NMR (CDCl3 / 125.77 MHz, d in ppm of the E / Z-amide):
213.28 / 211.53 (C-22); 210.48 / 208.78 (C-10); 169.73/
169.44 (C-1 or C-8); 166.52 /.169.13 (C-8 or C-1); 137.08 /
138.63 (C-19); 131.98 / 131.38 (C-28 or C-29); 128.82 /
131.17 (C-29 or C-28); 124.25 / 123.60 (C-20); 89.35 / 89.40
(C-11); 85.49 / 86.18 (C-14); 84.17 / 84.15 (C-32); 83.05 /
83.58 (C-13); 79.26 / 80.6 (C-15); 76.90 / 80.60 (C-26); 78.44
/ 73.84 (C-9); 73.52 / 73.51 (C-33); 69.79 / 67.94 (C-24); 57.5,
56.83, 56.32 / 56.58, 46.47, 56.43 (3x-OMe); 53,58 / 54.65
(C-21); 56.41 / 53.54 (C-2); 48.37 / 48.02 (C-18); 45.01 /
45.21 (C-23); 39.56 / 42.88 (C-6); 40.72 / 40.82 (C-12); 39.60
/ 39.38 (C-25); 33.10 / 35.64 (C-16); 34.92 / 34.92 (C-30);
34.82 / 34.53 (C-31); 31.19 / 31.19 (C-34); 30.71 / 30.51
(C-35); 27.37 / 28.49 (C-17); 27.52 / 25.63 (C-3); 24.70 /
25.85 (11-CH3); 21.21 / 20.91 (C-4); 20.21 / 20.91 (17-CH3);
16.59 / 16.98 (19-CH3); 14.37 / 13.03 (28-CH3); 11.48 / 11.61
(C-37); 9.82 / 9.10 (25-CH3).
(24) Preparation of 8a,b: zinc powder (1.0g, 15mmol, 40eq.) was
added to a solution of 7a (300mg, 0.38mmol) in 30ml CH3CN
and 6ml glacial AcOH. After stirring for 2 h at r.t. the mixture
was filtered and partitioned between excess aq. NaHCO3 and
ethyl acetate. The organic layer was washed with brine, dried
over Na2SO4 and evaporated to dryness. Column chromato-
graphy over silica gel (gradient: CH2Cl2 : CH3OH = 50-25 : 1)
gave 99mg (32%, 8a or 8b) and 189mg (61%, 8b or 8a) re-
spectively. The compounds 8c,d were prepared analogously.
(25) Spectroscopic data of the 11-R-compounds 8a and 8b:
13C NMR (CDCl3 / 125.77MHz): 211.89 / 211.41 (C-22);
209.82 / 207.56 (C-10); 169.24 / 169.42 (C-1 or C-8); 168.05
/ 168.46 (C-8 or C-1); 140.17 / 139.24 (C-19); 132.18 / 132.03
(C-28 or C-29); 130.88 / 131.51 (C-29 or C-28); 123.75 /
123.95 (C-20); 87.35 / 87.86 (C-11); 85.67 / 84.72 (C-14);
84.11 / 84.24 (C-32); 81.61 / 81.65 (C-13); 79.89 / 78.76
(C-15); 78.76 / 79.01 (C-26); 73.97 / 68.37 (C-9); 73.48 /
73.50 (C-33); 70.18 / 68.65 (C-24); 58.73, 57.32, 56.55 /
58.14, 57.27, 56.45 (3x-OMe); 55.108 / 55.13 (C-21); 52.86 /
53.42 (C-2); 46.71 / 48.06 (C-18); 44.41 / 44.86 (C-23); 44.10
/ 42.84 (C-6); 41.80 / 42.17 (C-12); 40.48 / 38.97 (C-25);
37.12 / 35.47 (C-16); 34.93 / 34.95 (C-30); 34.69 / 34.50
(C-31); 31.17 / 31.25 (C-34); 30.53 / 30.39 (C-35); 26.86 /
26.98 (C-17); 26.44 / 25.78 (C-5 or C-3); 25.44 / 24.05 (C-3
or C-5); 24.98 / 22.96 (11-CH3); 23.57 / 23.58 (C-36); 21.36 /
21.22 (C-4); 20.51 / 20.34 (17-CH3); 16.38 / 15.55 (19-CH3);
14.01 / 12.90 (28-CH3); 11.63 / 11.63 (C-37); 10.31 / 8.98 (25-
CH3).
8d or 8c; 13C NMR (CDCl3 / 125.77MHz): 212.70 / 212.46
(C-22./ C-10); 169.73 / 168.32 (C-1 / C-8); 138.59 (C-19);
131.47 (C-28); 131.05 (C-29); 123.67 (C-20); 89.42 (C-11);
87.50 (C-14); 84.19 (C-32); 83.18 (C-13); 79.54 (C-15); 72.96
(C-26); 79.33 (C-9); 73.51 (C-33); 68.60 (C-24); 58.17, 56.48,
55.16 (3x-Ome); 55.16 (C21); 51.97 (C-2); 46.57 (C-18);
43.87 (C-23); 44.14 (C-6); 43.25 (C-12); 39.33 (C-25); 35.56
(C-16); 34.96 (C-30); 34.64 (C-31); 31.21 (C-34); 30.55
(C-35); 26.86 / 28.36 (C-17); 25.43 (C-5); 25.44 / 26.38 (C-3);
24.43 (11-CH3); 23.80 (C-36); 20.95 (C-4); 21.07 (17-CH3);
17.76 (19-CH3); 13.46 (28-CH3); 11.79 (C-37); 9.75 (25-
CH3).
Article Identifier:
1437-2096,E;1999,0,S1,0877,0880,ftx,en;W03999ST.pdf
Synlett 1999, S1, 877–880 ISSN 0936-5214 © Thieme Stuttgart · New York