The first total synthesis of (corrected) ritterazine M

Article abstract of DOI:10.1021/ol016572l

(Equation Presented) Hecogenin acetate was converted to ritterazine M in 16 operations with an average yield per opearation of 87%. The overall linear yield was 12%. This confirmed 1 as the corrected structure for ritterazine M by total synthesis.

Full text of DOI:10.1021/ol016572l

ORGANIC
LETTERS
2002
Vol. 4, No. 3
317-318
The First Total Synthesis of (Corrected)
Ritterazine M
Seongmin Lee and Philip L. Fuchs*
Department of Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
pfuchs@purdue.edu
Received August 14, 2001 (Revised Manuscript Received October 30, 2001)
ABSTRACT
Hecogenin acetate was converted to ritterazine M in 16 operations with an average yield per opearation of 87%. The overall linear yield was
12%. This confirmed 1 as the corrected structure for ritterazine M by total synthesis.
In the previous paper we proposed that the structure assigned
for ritterazine M was incorrect and made a new assignment,
1,1 based upon NMR difference correlation with the values
published by Fusetani.2 We now confirm this assignment by
providing the first total synthesis of this trisdecacyclic
pyrazine, 1 (Scheme 1).
at this stage. In preparation for cyclization to the 5/6
spiroketal (1,6-dioxaspiro[4,5]decane) it was necessary to
selectively protect the 1,2-diol moiety. This was accom-
plished by monosilylation of the primary alcohol to afford
the corresponding mixture of inseparable TBS silyl ethers 5
in essentially quantitative yield. Without purification, 5 was
reacted with benzoic anhydride, magnesium bromide, and
triethylamine to provide 6 in 87% yield, again (presumably)
as a 5.9:1 mixture. Again without purification, this mixture
was desilylated by using BF3‚OEt2 to give a fourth in-
separable mixture, 7, which was subjected to the Suarez
iodine[III] oxidation1,3 to give spiroketals 8a and 8b which
were separated by chromatography, hydrolyzed, and then
oxidized to the A-ring C-3 ketone 10 (Scheme 2).
Scheme 1
Completion of the total synthesis required PTAB bromi-
nation of 10 to give the R-bromoketone 11 in 82% yield
along with small amounts of the 2,2-dibromide. Displacement
of this material using our optimal conditions provided the
labile equatorial R-azidoketone 12, which was immediately
converted to methoxime 13. Staudinger reduction of 13 gave
the “North M” amino-methoxime 14 in 75% yield. Using
Asymmetric dihydroxylation of terminal olefin 31 provided
a 5.9:1 mixture of diols 4, which were not readily separable
(3) Concepcion, J. L.; Francisco, C. G.; Hernandez, R.; Salazar, J. A.;
Suarez, E. Tetrahedron Lett. 1984, 25, 1953-1956. de Armas, P.;
Concepcion, J. I.; Francisco, C. G.; Hernanez, R.; Salazar, J. A.; Suarez,
E. J. Chem. Soc., Perkin Trans. 1 1989, 405-411. Martin, A.; Salazar, J.
A.; Suarez, E. Tetrahedron Lett. 1995, 36, 4489-4492. Furuta, K.; Nagata,
T.; Yamamoto, H. Tetrahedron Lett. 1988, 29, 2215-2218. Betancor, C.;
Dorta, R. L.; Freire, R.; Prange, T.; Suarez, E. J. Org. Chem. 2000, 65,
8822-8825.
(1) Cephalostatin Support Studies. 21. For 20, see: Lee, S. M.; LaCour,
T. G.; Lantrip, D. A.; Fuchs, P. L. Org. Lett. 2001, 3, 313.
(2) Fukuzawa, S.; Matsunaga, S.; Fusetani, N. Tetrahedron 1995, 51,
6707.
10.1021/ol016572l CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/15/2002

Scheme 2a
Scheme 3a
a (a) OsO4 (2 mol %), (DHQ)2PHAL (10 mol %), K3Fe(CN)6,
K2CO3, t-BuOH/H2O, 0 °C, 8 h; (b) TBSCl, imidazole, DMAP,
DMF; (c) Bz2O, MgBr2‚OEt2, TEA, DCM, 25 °C, 18 h; (d)
BF3‚OEt2, DCM, 0 °C, 5 min; (e) PhI(OAc)2, I2, c-hexane/DCM, 0
°C, 8 h; (f) K2CO3, MeOH/H2O, 25 °C 5h (g) TPAP (5 mol %),
NMO, 4A molecular sieves, DCM, 25 °C, 20 min.
the Guo unsymmetrical pyrazine synthesis,4 substrate 14 was
united with a stoichiometric amount of the “South 7”
R-azidoketone 15.5 This provided 16, the protected form of
ritterazine M, which was globally deprotected to deliver
compound 1 which was shown to have proton and carbon
NMR parameters equivalent to those of authentic ritterazine
M (North section r2 ) 0.99996; South section r2 ) 0.99998;
see Supporting Information). Thus, the structural revision
to 1 (Scheme 3) has been firmly secured by synthesis.
a (h) PTAB, THF, 0 °C, 15 min; (i) TMGN3, MeNO2, 25 °C, 6
h; MeONH2‚HCl, DCM/pyridine, 25 °C, 6 h; (j) PPh3, H2O, THF,
25 °C, 2 d; (k) Bu2SnCl2, PVP, benzene, reflux, 3 h; (l) i. TBAF,
THF, 0 °C, 5 h; ii. K2CO3, MeOH/H2O, reflux, 5 h.
Acknowledgment. We thank the National Institutes of
Health (CA 60548) for support of this work. We are most
grateful to professors Matsunaga and Fusetani for helpful
discussions and an authentic sample of ritterazine M.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra. The material is
available free of charge via the Internet at http://pubs.acs.org.
OL016572L
(4) Guo, C.; Bhandaru, S.; Fuchs, P. L.; Boyd, M. R. J. Am. Chem. Soc.
1996, 118, 10672.
(5) Jeong, J.; Guo, C.; Fuchs, P. L. J. Am. Chem. Soc. 1999, 121, 2071.
318
Org. Lett., Vol. 4, No. 3, 2002