In previous work4 we have reported a synthetic sequence
for the enantioselective assembly of the advanced diaza-
tricyclic intermediates A and B en route to madangamines,
bearing rings ABC with the appropriate substitution and
functionality to construct the macrocyclic D and E rings of
these alkaloids (Figure 2).
Scheme 1. Model Annulation Studies: The Macrocyclic D Ring
of Madangamine D
Figure 2. Advanced enantiopure diazatricyclic intermediates en
route to madangamines.
In this letter we report the construction of saturated and
(poly)unsaturated 13-, 14-, and 15-membered rings (the
western D ring of madangamines) as well as the (Z,Z)-
unsaturated 11-membered E ring common to madanga-
mines AÀE.
As model systems for the closure of the D ring we used
substituted piperidines 1À3 (Figure 3), which would allow
us to perform macrocyclization reactions by reductive
amination or lactamization (from 1 and 3), or by ring-
closing olefin metathesis (from 2).
We then focused our attention on macroannulations
involving ring-closing metathesis reactions.5 The required
dienes 2, bearing unsaturated chains of different lengths,
were prepared from 3-methoxycarbonyl-2-piperidone by
successive C-alkylation and N-acylation reactions, as out-
lined in Scheme 2. Gratifyingly, diene 2a underwent a ring-
closing metathesis reaction on treatment with the second-
generation Grubbs catalyst, leading to the 14-membered
(E)-unsaturated lactam 9a in excellent yield.6 Cyclization
of dienes 2b and 2c to the corresponding 13-membered ring
alkenes 9b and 9c were also satisfactory, although the
yields were lower.7
Having achieved model macrocyclizations to construct
13- and 14-membered rings, like those present in madan-
gamines CÀE, we then explored the construction of the
skipped (Z,Z,Z)-unsaturated 15-membered ring charac-
teristic of madangamine A. The required 12-carbon chain
was installed sequentially, by C-alkylation of δ-valerolac-
tam with 4-iodo-1-(trimethylsilyl)but-1-yne8 followed by
cuprous iodide catalyzed coupling of the terminal alkyne
10 with 8-bromo-1-(triisopropylsilyloxy)octa-3,6-diyne.9
Reduction of the resulting triyne 11 with dicyclohexyl-
borane10 stereoselectively provided the unstable all-cis
Figure 3. Model systems.
Alcohols 1, bearing the 11-carbon chain required to
build up the 14-membered D ring of madangamine D,
were prepared from N-Boc valerolactam, as outlined in
Scheme 1. Initial attempts to perform the macrocyclization
by lactamization of carboxylic acid 4, generated by PDC
oxidation of 1, were not satisfactory as dimer 6 was the
only isolable product. When the reaction was conducted
under high dilution conditions, the desired bicyclic lactam
5 was formed in acceptable yield. Alternatively, DessÀ
Martin oxidation of 1a, followed by N-deprotection of the
resulting aldehyde7 and reductiveaminationunder diluted
conditions, satisfactorily led to the azabicyclic derivative 8
in acceptable overall yield.
(7) E/Z mixtures of isomers (2:1 ratio) were formed in these reactions.
In the cyclization of 2b, the corresponding dimer was isolated in 12%
yield.
(8) Dutheuil, G.; Webster, M. P.; Worthington, P. A.; Aggarwal,
V. K. Angew. Chem., Int. Ed. 2009, 48, 6317–6319.
(9) Gueugnot, S.; Aiami, M.; Linstrumeile, G.; Mambu, L.; Petit, Y.;
(5) For reviews on the construction of macrocyclic rings by RCM
reactions, see: (a) Meng, Q.; Hesse, M. Top. Curr. Chem. 1991, 161, 109–
176. (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238. (c)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
ꢀ
^
44, 4490–4527. (d) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int.
Larcheveque, M. Tetrahedron 1996, 52, 6635–6646.
Ed. 2006, 45, 6068–6101.
(6) Only trace amounts of the Z-isomer in compound 9a were
(10) For a review on the construction of (Z,Z) skipped 1,4-dienes,
see: Durand, S.; Parrain, J.-L.; Santelli, M. J. Chem. Soc., Perkin Trans.
1 2000, 253–273.
detected by 1H NMR.
Org. Lett., Vol. 14, No. 15, 2012
3917
Proto, Stefano
