5836
M. A. R. C. Bulusu et al. / Tetrahedron Letters 45 (2004) 5833–5836
hydride affording the required allyl alcohol 14 in a 50%
yield over two steps ((i) 1.06 equiv Pd(OAc)2, 5% aq
NaHCO3, CH3CN/THF: 2/1, 0 °C, 20 h, workup; (ii)
described above, indicate the viability of 5 as a useful
intermediate for synthesis of other novel analogues.
i
2.8 equiv Bu2AlH, toluene, )70 °C, 2.3 h). Oxidation of
the C(9)–OH of 14 with Cu(II) acetate, followed by
selective activation of the allylic alcohol as methyl
carbonate derivative afforded 15 in a 67% overall yield
Acknowledgements
ꢀ
((i) 4 equiv Cu(OAc)2, 0.3 equiv pyridine, 4 A MS, O2,
T.T. and C.R. thank the Leonardo da Vinci European
Program for fellowships.
CH2Cl2, rt, 5 d; workup; (ii) 4 equiv MeOCOCl in
portions, 10 equiv pyridine, cat. DMAP, 0–25 °C, 6 h).
Pd-catalysed cyclisation of the allyl carbonate 15,
followed by chromatographic separation of the epimers,
led to the protected (5S)-vinylproline analogue 16a
(27%) and the (5R)-proline analogue 17a (30%)
(10 mol % (PPh3)4Pd, CH3CN, 4 d at 50 °C and 16 h at
70 °C). Noteworthy here are the longer reaction time
and the higher temperature required for the cyclisation
of 15, compared to those for 7 and 10. Desilylation of
16a gave 16b (4% HF, CH2Cl2/CH3CN, 25 °C, 18 h) in a
76% yield, which after Dess Martin’s oxidation afforded
19 in a 48% yield (1.3 equiv periodinane, CH2Cl2, rt,
4 h,). Similarly 17a after desilylation gave 17b (56%),
which after oxidation as above afforded 18 in a 62%
yield.
References and notes
1. (a) Arai, T.; Koyoma, Y.; Suenaga, T.; Honda, H. J.
Antibiot. Ser. A 1962, 15, 231–232; (b) Hatanaka, H.;
Iwami, M.; Kino, T.; Goto, T.; Okuhara, M. J. Antibiot.
1988, 41, 1586–1591; (c) Hatanaka, H.; Kino, T.; Miyata,
S.; Inamura, N.; Kuroda, A.; Goto, T.; Tanaka, H.;
Okuhara, M. J. Antibiot. 1988, 41, 1592–1601; (d) Mori-
saki, M.; Arai, T. J. Antibiot. 1992, 45, 126–128.
2. (a) Grassberger, M.; Baumruker, T.; Enz, A.; Hiestand, P.;
Hultsch, T.; Kalthoff, F.; Schuler, W.; Schulz, M.; Werner,
F.-J.; Winiski, A.; Wolff, B.; Zenke, G. Br. J. Dermatol.
1999, 141, 264–273; (b) Eichenfield, L. F.; Beck, L.
J. Allergy Clin. Immunol. 2003, 111, 1154–1168; (c)
Graham-Brown, R. A. C.; Grassberger, M. Int J. Clin.
The 1H NMR spectra of the proline derivatives 16a, 16b
and 19 showed signals at d 4.51 (dd, J ¼ 8:5, 2.1 Hz),
4.70 (dd, J ¼ 8:5, 2.3 Hz) and 4.46 (dd, J ¼ 8:6, 2.1 Hz),
respectively, which are assigned to H–C(2) based on
C–H correlation spectra. These splittings are similar to
those in (5R)-methoxy proline analogue of ascomycin
reported earlier,5 and indicate (5S)-configuration for
16a, 16b and 19, with the C(1) placed pseudoaxially as
€
Pract. 2003, 57, 319–327; (d) Wolff, K.; Stutz, A. Expert
Opin. Pharmacother. 2004, 5(3), 643–655.
3. VanDuyne, G. D.; Standaert, R. F.; Karplus, P. A.;
Schreiber, S. L.; Clardy, J. Science 1991, 252, 839–842.
4. (a) Askin, D.; Reamer, R. A.; Joe, D.; Volante, R. P.;
Shinkai, I. J. Org. Chem. 1990, 55, 5448–5450; (b) Askin,
D.; Joe, D.; Reamer, R. A.; Volante, R. P.; Shinkai, I. J.
Org. Chem. 1990, 55, 5451–5454; (c) Horvath, A. Ph.D.
Thesis, University of Vienna, 1993.
1
drawn for 19 in Scheme 2. On the other hand, the H
5. (a) Bulusu, A. R. C. M.; Haidl, E. H.; Schulz, G.;
Waldstaetten, P.; Grassberger, M. Ind. J. Chem. 1999,
38B, 1159–1164; (b) Bulusu, A. EP 0626385A, Sandoz
Ltd, 1994; (c) Bulusu, A. R. C. M.; Waldstaetten, P.;
Schulz, G.; Grassberger, M. Tetrahedron Lett. 2004, 45,
2523–2526; (d) Bulusu, A. R. C. M.; Waldstaetten, P.;
Tricotet, T.; Schulz, G. Tetrahedron Lett. 2004, 45, 2527–
2530.
NMR spectra of 17a, 17b and 18 showed signals at d
4.49 (t, J ¼ 8:6 Hz), 4.55 (t, J ¼ 8:3 Hz) and 4.41
(t, J ¼ 8:4 Hz), respectively, which are assigned to
H–C(2). Again, these splittings are analogous to those in
(5S)-methoxyproline analogue of ascomycin,5 indicating
(5R)-configuration for 17a, 17b and 18, with C(1) placed
pseudoequatorially as drawn in Scheme 2 for 18.
6. All compounds were fully characterised using 1H NMR
(400, or 500 MHz), 13C NMR (100 or 125 MHz) and mass
spectral data and elementary analysis. The 1H and 13C-
signal assignments for representative compounds were
In summary, we could synthesise the 6-vinyl analogue 12
and the 5-vinylproline analogues 18 and 19 of ascomycin
starting from the aldehyde 5 in fewer steps than would
have required using reported strategies. The conforma-
tional differences in the amino acid moiety arising from
the substitution are interesting. The presence of new
reactive terminal double bonds in these vinyl analogues
opens scope for further modifications. The easy avail-
ability of 5 in multigram quantities from ascomycin via
the photo product 4, and the exemplary syntheses
1
made through C–H correlation spectra and H-decoupling
experiments. IUPAC numbering of ascomycin is retained
for all analogues.
7. Zumpe, F. L.; Kazmeier, U. Synth. 1999, 10, 1785–1791.
8. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–
4156.
9. Takayama, H.; Koike, T.; Aimi, N.; Sakai, S. I. J. Org.
Chem. 1992, 57, 2173–2176.