2
would ultimately be derived from the C -symmetrical, chiral
ketone 1. Reduction of the resulting bislactam would lead
to sparteine. Note that the stereochemistry of sparteine
requires that one of the two appendages containing an
ultimately reactive nitrogen moiety be placed onto this ketone
in an endo position and the other in an exo orientation.
Norbornadiene was subjected to chiral (bis)hydrosilation
Scheme 3
(HSiCl3, (-)-S-MOP, allylpalladium chloride dimer; then
H
2
O
2
, KI, KHCO ), which was previously shown to provide
3
6
the diol corresponding to (+)-1 with high enantio- and
regioselectivity (Scheme 2). Swern oxidation gave diketone
Scheme 2
we were not able to effect another intramolecular Schmidt
reaction on this compound (or many closely related ana-
logues!) under a wide range of conditions known to promote
1
0
this process. We hypothesize that the inactivity of these
compounds was due to preferential Lewis or protic acid
coordination to the amine nitrogen or lactam carbonyl instead
of the ketone needed for successful reaction with the weakly
7
(
+)-1, which could be brought to effective enantiomeric
purity by simple recrystallization from ether/hexane ([R]
4.5 (c 2.7, EtOH), mp 141.5-142 °C). Our attempts to
alkylate enolates derived from 1 directly failed due to
apparent decomposition. However, monoketalization fol-
lowed by an aldol reaction with aldehyde 2 gave enone 3
D
-
11
nucleophilic azide. We therefore turned our attention to
nitrogen nucleophiles that should not require promotion by
Lewis acid catalysts, eventually rescuing this route with a
8
following elimination. At this point, treatment with H
2
and
12
novel variant of the photo-Beckmann rearrangment.
Pd/C both removed the benzylic ether and reduced the R,â-
unsaturated olefin. Hydrogenation from the less hindered exo
face established the desired endo orientation of this side
The literature holds only a few examples of the photo-
chemical rearrangement of nitrones embedded into a mul-
ticyclic structure and fewer still that proceed in acceptable
9
chain. A modified Mitsunobu azidation afforded 4, which
1
3
chemical yields. In the present case, displacement of the
iodide with BocNHOBoc followed by deprotection of the
hydroxylamine gave nitrone 8 by intramolecular condensa-
tion. Photolysis in benzene at 254 nm afforded smooth
4
was treated with excess TiCl to smoothly effect an intramo-
lecular Schmidt reaction,10 which was accompanied by
deketalization and resulted in 5.
Although the direct alkylation of keto lactam 5 was
inefficient (10-19%), the corresponding amine reacted
smoothly with base and 1,4-iodochlorobutane to give 6 in
(11) Some circumstantial evidence in support of this view includes the
following two observations: (1) IR spectroscopy of the keto lactam 5 shows
that the lactam carbonyl is readily coordinated by Lewis acids (the νCdO
7
6% overall yield for four steps (Scheme 3). This time,
-
1
shifts by ca. -20 cm in the presence of TiCl4), but there is no evidence
for coordination of the ketone carbonyl in even a very large excess of Lewis
acid (>20 equiv). (2) Even simple acid-promoted reactions such as dimethyl
ketal formation of compounds such as 5 have proven difficult.
simple exo alkylation gave the chloride as a single stereo-
isomer. Obtained from a Finklestein reaction, the iodide could
be converted to the corresponding azide with ease. However,
(12) (a) Suginome, H.; Furukawa, K.; Orito, K. J. Chem. Soc., Perkin
Trans. 1 1991, 917-921. (b) Suginome, H.; Furukawa, K.; Orito, K. J.
Chem. Soc., Chem. Commun. 1987, 1004-1005. (c) Suginome, H.; Kaji,
M.; Yamada, S. J. Chem. Soc., Perkin Trans. 1 1988, 321-326. (d)
Suginome, H. Kagaku No Ryoiki 1976, 30, 578-591.
(13) (a) Johnson, G. P.; Marples, B. A. Tetrahedron Lett. 1985, 26,
4115-4118. (b) Black, D.; Johnstone, L. M. Aust. J. Chem. 1984, 37, 609.
(c) Black, D.; Johnstone, L. M. Aust. J. Chem. 1984, 37, 577-585. (d)
Albini, A.; Fasani, E.; Frattini, V. J. Chem. Soc., Perkin Trans. 2 1988,
235-240. (e) Bourguet, E.; Baneres, J.-L.; Girard, J.-P.; Parello, J.; Vidal,
J.-P.; Lusinchi, X.; Declercq, J.-P. Org. Lett. 2001, 3, 3067-3070.
(
5) Early studies related to this synthesis have appeared: Wendt, J. A.;
Aub e´ , J. Tetrahedron Lett. 1996, 37, 1531-1534.
(
(
(
6) Hayashi, T. Acta Chem. Scand. 1996, 50, 259-266.
7) Weissfloch, A.; Azerad, R. Bioorg. Med. Chem. 1994, 2, 493-500.
8) This aldehyde was prepared from butanediol in 90% overall yield
by monobenzylation followed by TEMPO oxidation.
(
9) Viaud, M. C.; Rollin, P. Synthesis 1990, 130-132.
(10) Milligan, G. L.; Mossman, C. J.; Aub e´ , J. J. Am. Chem. Soc. 1995,
1
17, 10449-10459.
2578
Org. Lett., Vol. 4, No. 15, 2002