We became interested in daphnilactone B-type and
yuzurimine-type alkaloids as excellent targets to demon-
strate the applicability of the sequence of the intramole-
cular VilsmeierꢀHaack reaction and azomethine ylide
Scheme 1. Retrosynthetic Analysis of Daphnilactone B-Type
and Yuzurimine-Type Alkaloids
8
cycloaddition we developed recently. This strategy would
allow the construction of, in a single step, three of the five
rings common to all alkaloids found in both of these
classes. Our retrosynthetic analysis of target product 1
starts with the formation of the pyrrolidine ring using a
stabilized azomethine ylide (3 þ 2) cycloaddition (Scheme 1).
This ylide intermediate 2 would be generated from the
deprotonation of an iminium ion obtained from a Vils-
meierꢀHaack cyclization initiated by the activation of
formamide 3. A ring closing metathesis would serve to
form the cycloheptene ring of 3, while a StillꢀGennari
olefination would generate the cis unsaturated ester. The
cis isomer would set the right configuration at C in the
8
tetracyclic product 1 for further reduction to the methyl in
the natural products. The R-allylaldehyde moiety in 4
would come from a Claisen rearrangement of an allyl enol
ether, and the amido-nitrile portion would be the product
of functional group manipulation from bromide 5. The
latter would be derived from 6 by alkylation R to the
carbonyl and further transformations of the lactone.
While no completed synthesis of alkaloids in the daph-
nilactone B and yuzurimine classes has been reported so
far, two research groups published their approaches to the
construction of the core of these daphnanes. Denmark’s
group took advantage of their well established cascade of
intramolecular nitroalkene (4 þ 2) cycloaddition and
nitronate (3 þ 2) cycloaddition to synthesize the bridged
indolizidine core of these alkaloids, in an enantioenriched
9
form (Scheme 2). The advanced intermediate 9 was thus
prepared in 27 steps. Their approach even allowed for the
very challenging formation of the two contiguous quatern-
ary centers (cf. 9, C and C ) found in all alkaloids of these
3
4
Scheme 2. Denmark’s Approach
classes, although when compared to the natural alkaloids,
product 9 contains an additional six-membered ring and
the seven-membered ring is missing.
Earlier this year, the group of Coldham reported the
condensation of bromoaldehyde 11 with ethyl glycinate,
followed by intramolecular alkylation and deprotonation
(
6) (a) For daphnilactone B, see: Sasaki, K.; Hirata, Y. Tetrahedron
Lett. 1972, 13, 1891–1894. (b) For daphnezomine H and I, see: Morita,
H.; Yoshida, N.; Kobayashi, J. Tetrahedron 2000, 2641. (c) For cal-
daphnidine C, see: Zhan, Z.-J.; Zhang, C.-R.; Yue, J.-M. Tetrahedron
2005, 11038.
(
7) (a) For deoxyyuzurimine, see: Yamamura, S.; Terada, Y. Chem.
Lett. 1976, 1381. (b) For daphnetidine D, see: Kubota, T.; Matsuno, Y.;
Morita, H.; Shinzato, T.; Sekiguchid, M.; Kobayashi, J. Tetrahedron
to generate a transient azomethine ylide that was trapped
1
in an intramolecular cycloaddition (Scheme 3). The
0
2006, 4743. (c) For daphniglaucines J and K, see: Takatsu, H.; Morita,
H.; Shenb, Y.-C.; Kobayashi, J. Tetrahedron 2004, 6279. (d) For
daphcalycic acid, see: El Bitar, H.; Nguyen, V. H.; Gramain, A.; S ꢀe venet,
T.; Bodo, B. Tetrahedron Lett. 2004, 515. (e) For daphnezomine K, see
ref 6b. (f) For caldaphnidine A, see ref 6c.
approach is very short (11 steps) to get to 12 that however
lacks the seven-membered ring and the C quaternary
11
center.
4
(
8) (a) L ꢀe vesque, F.; B ꢀe langer, G. Org. Lett. 2008, 10, 4939. (b)
B ꢀe langer, G.; Darsigny, V.; Dor ꢀe , M.; L ꢀe vesque, F. Org. Lett. 2010,
2, 1396.
9) (a) Denmark, S. E.; Baiazitov, R. Y. J. Org. Chem. 2006, 71, 593.
b) Denmark, S. E.; Baiazitov, R. Y.; Nguyen, S. T. Tetrahedron 2009,
5, 6535.
10) Coldham, I.; Burrell, A. J. M.; Guerrand, H. D. S.; Oram, N.
As detailed in Scheme 1, the synthetic strategy we put
forward has the ultimate goal of setting for the first time all
four cycles of the core of daphnilactone B and yuzurimine
1
(
(
6
(
4
(11) Our approach lacks the C quaternary center as well. However,
the latter would be easily incorporated from alkylation on compound 6.
Org. Lett. 2011, 13, 1267.
Org. Lett., Vol. 13, No. 23, 2011
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