9 readily and in high yield. The stabilized anion from 9 was
then condensed with acetaldehyde. In the same pot, deacy-
lation, cyclization, and then sulfinic acid elimination from
intermediate 10 proceeded to supply the requisite pyrone.
Subsequent MOM group cleavage provided flavasperone 4.
Our attention then turned to formation of the chiral biaryl.
From the standpoint of an asymmetric coupling with the 1,5-
diaza-cis-decalin copper catalyst, substrate 4 appears ideal.
The heterocyclic ring constrains the C3 carbonyl to align
with the C2 hydroxyl for optimal chelation to copper.7e In
addition, the C4 group is withdrawing via conjugation to
the C3 carbonyl; electron-withdrawing groups at C4 suppress
racemization of the binaphthyl during the oxidative coupling.7d
Thus, we were quite surprised to discover that the reaction
of 4 with the chiral copper catalyst was sluggish. After one
week at 40-45 °C with 10 mol % of catalyst, only 36% of
the product (3) was isolated but the selectivity was good
(∼80% ee). Reasoning that the optimized chelation with 4
inhibits turnover, greater amounts of the diaza-cis-decalin
copper oxidant were employed. The yield of 3 could be
improved to 60% with stoichiometric catalyst while main-
taining the selectivity (80% ee, Scheme 3).
Scheme 1. Synthesis Analysis of Nigerone
of flavasperone 46 to form the C1,C1′-bond using our 1,5-
diaza-cis-decalin copper catalysts.7
The required substrate 4 was efficiently prepared via the
process outlined in Scheme 2. Naphthol 7 was constructed
Scheme 2. Synthesis of the Biaryl Coupling Precursor
Scheme 3. Formation of Bisisonigerone
With (R)-3 in hand, the intriguing isomerization directly
to 1 was investigated (Scheme 4) upon the basis of precedent
from much simpler systems.8 The key question was whether
such an isomerization would be thermodynamically favorable
and whether side reactions would interfere. In particular,
elimination of acetone enolate from the 1,3-dicarbonyl
tautomer 12 of 11 to form 14 was a concern (Scheme 5).
An analysis of the structures of of 3, 2, and 1 was promising.
Nigerone (1) appears to be the most stable of the three as
the C2 position of the binaphthyl is less hindered compared
to C4 (the C5 group is coplanar to C4, and the C1 biaryl is
70° out-of-plane) and should better accommodate the het-
erocyclic portion (hydrogen bonding is equivalent in the two
via an approach that we found to be highly efficient for the
structural type.7d Preparation of the pyrone ring in 4 was
the most difficult aspect of the synthesis. The obvious
disconnection involving addition of acetone to the methyl
ester of 8 to introduce the carbons of the pyrone ring failed.
On the other hand, addition of the dimsyl anion to 8 provided
(7) (a) Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3, 1137-
1140. (b) Kozlowski, M. C.; Li, X.; Carroll, P. J.; Xu, Z. Organometallics
2002, 21, 4513-4522. (c) Xie, X.; Phuan, P.-W.; Kozlowski, M. C. Angew.
Chem., Int. Ed. 2003, 42, 2168-2170. (d) Mulrooney, C. A.; Li, X.;
DiVirgilio, E. S.; Kozlowski, M. C. J. Am. Chem. Soc. 2003, 125, 6856-
6857. (e) Li, X.; Hewgley, J. B.; Mulrooney, C. A.; Yang, J.; Kozlowski,
M. C. J. Org. Chem. 2003, 68, 5500-5511.
(8) For a precedent for this type of isomerization in a nonbiaryl system,
see: Kanai, Y.; Ishiyama, D.; Senda, H.; Iwatani, W.; Takahashi, H.; Konno,
H.; Tokumasu, S.; Kanazawa, S. J. Antibiot. 2000, 53, 863-872.
(5) (a) Boutibonnes, P.; Malherbe, C.; Kogbo, W.; Marais, C. Microbiol.,
Aliments, Nutr. 1983, 1, 259-264. (b) Boutibonnes, P.; Malherbe, C.;
Auffray, Y.; Kogbo, W.; Marais, C. IRCS Med. Sci.: Libr. Compend. 1983,
11, 430-431. (c) Boutibonnes, P.; Auffray, Y.; Malherbe, C.; Kogbo, W.;
Marais, C. Mycopathologia 1984, 87, 43-49. (d) Auffray, Y.; Boutibonnes,
P. Mutat. Res. 1986, 171, 79-82.
(6) Flavasperone (13) has been synthesized previously by a different route
entailing 10 steps: Bycroft, B. W.; Roberts, J. C. J. Chem. Soc. 1963, 4868-
4872.
386
Org. Lett., Vol. 9, No. 3, 2007