98
T. Fujimura et al. / Tetrahedron Letters 43 (2002) 97–99
ation of 5 followed by treatment of the resulting ter-
tiary acetate 6, mp 124–125°C, [h]2D8 −163.5 (c 1.1,
CHCl3), with sodium acetate in the presence of
dichlorobis(acetonitrile)palladium(II) in THF induced
facile isomerization to furnish the primary acetate 7 as
an inseparable E/Z mixture, from which the primary
alcohol mixture 8 was obtained after alkaline methanoly-
sis. Upon treatment with N,N-dimethylacetaminde
dimethyl acetal9 at 280°C in diphenyl ether, the primary
alcohol mixture 8 furnished diastereoselectively the
acetamide 9, [h]2D8 −83.2 (c 0.7, CHCl3), having a qua-
ternary stereogenic center as the only product.
Although the stereochemistry of the quaternary stereo-
genic center was not determined at this stage, it was
assumed, on the basis of accumulated precedents,4 that
the Eschenmoser reaction of 8 should occur diastereose-
lectively to install the newly introduced functionality
from the convex-face giving rise to the quaternary
product 9 with an endo-vinyl functionality. This
assumption was confirmed at a later stage (Scheme 2).
smoothly to give the expected cyclohexene 13, [h]D26
+81.4 (c 1.0, CHCl3), in 93% yield. Although the effect
of the sodium hydrogen carbonate is uncertain, when it
is not used the reaction proceeds with considerable
decomposition. This is particularly true when
a
hydroxyl functionality is present in the substrate
(Scheme 3).
In order to obtain (+)-quebrachamine 23, the amide 13
was first reduced with lithium triethylborohydride11 to
give the primary alcohol 14, [h]2D7 +60.0 (c 0.9, CHCl3),
from which the silyl protective group was removed to
give the diol 15, [h]2D7 +69.9 (c 0.4, CHCl3). Upon
sequential ozonolysis, reduction with sodium borohy-
dride, and glycol-cleavage with sodium periodate in the
same flask, the diol 15 furnished the lactol 16 in 67%
overall yield from the amide 13. Oxidation of the lactol
16 with tetrapropylammonium perruthenate12 (TPAP)
afforded the formyl-lactone 18, in one step as an
unstable oil, which could also be obtained in compara-
ble overall yield via the hydroxy–lactone 17, [h]2D7 +2.7
(c 0.7, CHCl3), by sequential Fetizon oxidation13 and
Swern oxidation.14
To unambiguously confirm its stereochemical pathway,
as well as to demonstrate its synthetic utility, com-
pound 9 was converted via the hydrogenated product
10 into (+)-quebrachamine 23, an Aspidosperma indole
alkaloid having a quaternary (R)-stereogenic center.5
Thus, the vinyl-amide 9 was first hydrogenated on
palladized charcoal to give the ethyl–amide 10, mp
95–96°C, [h]2D9 −69.5 (c 1.6, CHCl3). Upon exposure to
zinc in methanol containing acetic acid,4 compound 10
afforded the hydroxy–olefin 11, mp 136–137°C, [h]D31
−20.1 (c 1.0, CHCl3), by reductive cleavage of its
bromo–ether linkage with regeneration of the olefin and
the secondary hydroxyl functionalities. Direct thermol-
ysis of the secondary alcohol 11 in diphenyl ether at
280°C afforded the expected retro-Diels–Alder product
in low yield accompanied by a complex mixture of
by-products. However, thermolysis of its TBS ether 12,
[h]2D9 +9.6 (c 0.4, CHCl3), in diphenyl ether at 280°C in
the presence of sodium hydrogen carbonate10 proceeded
Condensation of the lactone 18 with tryptamine in
benzene containing trifluoroacetic acid at reflux fur-
nished the tetracyclic lactam 19 in one step as a mixture
of two epimers by consective imine formation,
intramolecular Pictet–Spengler reaction, and lactamiza-
tion under the reaction conditions. The mixture was
reduced with lithium aluminum hydride to give the
tertiary amine mixture 20 the racemic mixture of which
had been obtained15 and ultimately transformed15 into
racemic quebrachamine ( )-23. Using the same proce-
dure for the racemic synthesis, the mixture 20 was
converted to the mesylate 21 which was immediately
refluxed in chloroform to give the quaternary ammo-
nium mesylate mixture 22. Upon subjection to Birch
reduction,16 the mesylate mixture 22 furnished (+)-que-
Br
Br
Br
Br
i
ii
iv
vi
(–)-2
O
O
O
O
O
O
OR
RO
NMe2
5:R = H
6:R = Ac
7:R = Ac
8:R = H
4
iii
v
9
Scheme 2. Reagents and conditions: (i) NBS, CH2Cl2, rt (99%); (ii) vinyl-Mg-Br, CeCl3, THF, −78°C (87%); (iii) Ac2O, pyridine,
DMAP (cat.), rt (95%); (iv) PdCl2(MeCN)2 (cat.), THF, rt (100%); (v) K2CO3, MeOH, rt (98%); (vi) MeC(NMe2)(OMe)2, Ph2O,
reflux (96%).
OTBS
OR
Br
i
ii
iv
9
O
O
O
O
NMe2
NMe2
NMe2
13
11:R = H
12:R = TBS
10
iii
Scheme 3. Reagents and conditions: (i) H2, 10% Pd-C, AcOEt (92%); (ii) Zn, AcOH–MeOH (1:10), reflux (93%); (iii) TBS-Cl,
imidazole, DMF, rt (94%); (iv) Ph2O, NaHCO3, reflux (93%).