November 1998
SYNLETT
1295
stable axial chirality, but rapidly isomerizes at the axis, thus appearing
as a single species within the NMR time scale. The ring cleavage to give
the now configuratively stable atropo-diastereomeric alcohols 6a and
6b, however, can be performed such that optionally the M- or the P-
atropisomeric form is obtained in high diastereoselectivities, the best
atropisomeric ratios being obtained with borane activated by the
oxazaborolidine20,21 R-7 (up to 94:6 dr in favor of the P-isomer, 6a) and
its enantiomer, S-7 (up to 96:4 dr in favor of the M-isomer, 6b),
respectively. For a good preparative practicability, cheap (since achiral)
hydride transfer reagents, such as L-selectride, are entirely sufficient,
giving up to 83:17 dr.
Scheme 2
The atropo-divergent ring cleavage of the biaryl lactone intermediate 5
to give M- or optionally P-configured, stereochemically stable products
and allowing the first atropisomer-selective total synthesis of
korupensamine B (1b) (and, in principle, korupensamine A) underlines
the efficiency and versatility of the lactone methodology. Applications
of this useful procedure to the total synthesis of further biologically
active natural or synthetically useful unnatural biaryl target molecules,
are in progress.
Acknowledgements: This work was supported by the Deutsche
Forschungsgemeinschaft (Normalverfahren, Br699/5-1) and by the
Fonds der Chemischen Industrie. We gratefully acknowledge engaged
experimental assistance by Michael Échard and Manuela Schäffer. We
would also like to thank Dr. M.R. Boyd and Dr. Y.F. Hallock (US
National Cancer Institute) for an authentic sample of korupensamine B
(1b).
With the biaryl axis established in either atropisomeric form, the
remaining steps of the total synthesis of korupensamines were
exemplarily performed on the M-isomer 6b, to give korupensamine B
(1b). For the construction of the second naphthalene ring, we envisaged
the preparation of the corresponding aldehyde, its Stobbe-type side-
chain prolongation, and ring closure by intramolecular Friedel-Crafts
acylation. Given the known configurative instability of such hydroxy
biaryl aldehydes (which can atropisomerize ’chemically’, via the
corresponding hemiacetals22), 6b was first protected by O-
isopropylation, with subsequent oxidation to give the stereochemically
stable M-configured biaryl aldehyde 8. Apparently because of the
sterically demanding heterocyclic isoquinoline part, its reactivity was
found to be drastically reduced compared to that of formally closely
related Stobbe substrates used previously, e.g. the simple 2-bromo-5-
isopropyloxybenzaldehyde, in which the isoquinoline moiety is replaced
by a halogen substituent.23 Thus, treatment of 8 with various succinate-
related C4-building blocks (e.g. with the corresponding Horner-
Emmons reagent) either did not lead to any noticeable reaction, or,
under more drastic reaction conditions, gave decomposition products,
exclusively. Only by reaction of the ester enolate of diethyl succinate
and subsequent ring closure in acetic anhydride, the desired, still atropo-
diastereomerically homogeneous naphthylisoquinoline 9 was obtained.
Reduction with LAH and reductive elimination of the benzylic oxygen
function on the naphthalene part by hydroxy/halogen exchange and
renewed LAH reduction, followed by an O-methylation gave 10, which
showed fully identical spectroscopic and chromatographic properties as
a sample prepared from authentic korupensamine B (1b), by N-
benzylation and stepwise O-isopropylation of its three phenolic OH
functions. With this encouraging information at hand, the remaining
deprotection steps of 10, to give the authentic natural product,
korupensamine B (1b) were best achieved by treatment with BCl3 and
subsequent hydrogenation. Once again, the synthetic material proved to
be fully identical in all respects with natural material previously isolated
from A. korupensis.2
References and Notes
(1) “Acetogenic Isoquinoline Alkaloids”, part 114, for part 113, see
Bringmann, G.; Wohlfarth, M.; Rischer, H.; Rückert, M.;
Schlauer, J. Tetrahedron Lett. 1998, in press. “Novel Concepts in
Directed Biaryl Synthesis”, part 74, for part 73, see Bringmann,
G.; Dauer, U.; Kraus, J. Tetrahedron 1998, in press.
(2) Hallock, Y.F.; Manfredi, K.P.; Blunt, J.W.; Cardellina II, J.H.;
Schäffer, M.; Gulden, K.-P.; Bringmann, G.; Lee, A.Y.; Clardy,
J.; François, G.; Boyd, M.R. J. Org. Chem. 1994, 59, 6349.
(3) Bringmann, G., Pokorny, F. In The Alkaloids, Vol. 46; Cordell,
G.A., Ed.; Academic Press: New York, 1995; p 127.
(4) Boyd, M.R.; Hallock, Y.F.; Cardellina II, J.H.; Manfredi, K.P.;
Blunt, J.W.; McMahon, J.B.; Buckheit, Jr., R.W.; Bringmann, G.;
Schäffer, M.; Cragg, G.M.; Thomas, D.W.; Jato, J.G. J. Med.
Chem. 1994, 1740.
(5) Hallock, Y.F.; Manfredi, K.P.; Dai, J.-R.; Cardellina II, J.H.;
Gulakowski, R.J.; McMahon, J.B.; Schäffer, M.; Stahl, M.;
Gulden, K.-P.; Bringmann, G.; François, G.; Boyd, M.R. J. Nat.
Prod. 1997, 60, 677.
(6) Hallock, Y.F.; Cardellina II, J.H.; Schäffer, M.; Bringmann, G.;
François, G.; Boyd, M.R. Biomed. Chem. Lett. 1998, 8, 1729.
(7) Bringmann, G.; Götz, R.; Keller, P.A.; Walter, R.; Henschel, P.;
Schäffer, M.; Stäblein, M.; Kelly, T.R.; Boyd, M.R. Heterocycles
1994, 39, 503.
Scheme 2