Scheme 1. Synthesis of Saframycin A (1)
The pathway to saframycin A from the Et 743 intermediate
in methylene chloride in the presence of a catalytic amount
of PdCl2(PPh3)2. A novel oxidation was used to convert the
phenol 4 to the corresponding 1,4-benzoquinone. Although
1-fluoro-3,5-dichloropyridinium triflate is generally used as
a reagent for electrophilic fluorination,7 it can serve also as
an electron acceptor and as such effects the oxidation of
phenol 4 to 1,4-benzoquinone and the concomitant cleavage
of the methoxymethyl (MOM) protecting group to form 6
in a single step under mild conditions (CH2Cl2 solution at 0
°C for 2 h). One possible explanation of the facile MOM
protecting group cleavage which is consistent with the
isolation of phenol 5 rather than its further oxidation product-
(s) is the occurrence of the sequence:
2 is outlined in Scheme 1. The phenolic function of 2 was
protected as the allyl ether, and the tert-butyldiphenylsilyl
group was cleaved with tetra-n-butylammonium fluoride to
generate a primary alcohol which was converted via the
corresponding tosylate (toluenesulfonic anhydride, diisopro-
pylethylamine, and 4-(dimethylamino)pyridine) to the azide
3 by displacement using LiN3 as nucleophile in dimethyl-
formamide at 70 °C. The azide 3 was transformed into the
phenolic pyruvamide 4 by the sequence (1) reduction of azide
to primary amine with dithiothreitol and triethylamine in
methanol at 23 °C,5,6 (2) N-acylation with pyruvyl chloride
and 4-(dimethylamino)pyridine in CH2Cl2, and (3) deallyla-
tion by treatment with tri-n-butyltin hydride and acetic acid
(a) ROCH2OCH3 f ROCHFOCH3
(3) (a) Arai, T.; Takahashi, K.; Kubo, A. J. Antibiot. 1977, 30, 1015.
(b) Arai, T.; Takahashi, K.; Nakahara, S.; Kubo, A. Experientia 1980, 36,
1025. For reviews on the saframycins, see: (a) Arai, T.; Kubo, A. In The
Alkaloids Chemistry and Pharmacology; Brossi, A., Ed.; Academic Press:
New York, 1983; Vol. 21, Chapter 3. (b) Remers, W. A. In The Chemistry
of Antitumor Antibiotics; Wiley: New York, 1988; Vol. 2, Chapter 3.
(4) (a) Fukuyama, T.; Yang, L.; Ajeck, K. L.; Sachleben, R. A. J. Am.
Chem. Soc. 1990, 112, 3712. (b) Myers, A. G.; Kung, D. Book of Abstracts,
216th National Meeting of the American Chemical Society, Boston, MA;
American Chemical Society, Washington, DC, 1998; Abstract ORGN0501.
(5) (a) Staros, J. V.; Bayley, H.; Standring, D. N.; Knowles, J. R.
Biochem. Biophysic. Res. Commun. 1978, 80, 568. (b) Bayley, H.; Standring,
D. N.; Knowles, J. R. Tetrahedron Lett. 1978, 39, 3633.
(b) ROCHFOCH3 + H2O f ROH + HCOOCH3
Such a pathway implies that 1-fluoro-3,5-dichloropyridinium
triflate might be a generally useful reagent for the selective
cleavage of MOM ethers. This point is under investigation
and will be reported separately.
(7) (a) Umemoto, T.; Kawada, K.; Tomita, K. Tetrahedron Lett. 1986,
27, 4465. (b) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.;
Kawada, K.; Tomita, K. J. Am. Chem. Soc. 1990, 112, 8563. (c) Lal, G. S.;
Pez, G. P.; Syvret, R. G. Chem. ReV. 1996, 96, 1737.
(6) Hydrogen sulfide in pyridine was less effective for the azide f amine
reduction, see: Adachi, T.; Yamada, Y.; Inoue, I. Synthesis 1977, 45.
76
Org. Lett., Vol. 1, No. 1, 1999