First enantioselective synthesis of the diazatricyclic core of madangamine alkaloids

Article abstract of DOI:10.1002/chem.201000421

En route to madangamines: A unified strategy has been developed for the enantioselective assembly of functionalized diazatricyclic synthetic precursors of madangamines (see scheme; Bn=benzyl, Boc=tert-butoxycarbonyl, Mbs=paramethoxybenzenesulfonyl).

Full text of DOI:10.1002/chem.201000421

DOI: 10.1002/chem.201000421
First Enantioselective Synthesis of the Diazatricyclic Core
of Madangamine Alkaloids
Mercedes Amat,* Maria Pꢀrez, Stefano Proto, Teresa Gatti, and Joan Bosch*[a]
9438
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9438 – 9441

COMMUNICATION
Madangamines are a small group of complex pentacyclic
alkaloids isolated from marine sponges of the order Haplo-
sclerida, biogenetically derived from partially reduced bis-3-
alkylpyridine macrocycles.[1] Madangamine A, isolated from
Xestospongia ingens by Andersen and co-workers in 1994,[2]
was the first example of this new class of pentacyclic alka-
loids and showed significant in vitro cytotoxicity against a
number of cancer cell lines (Scheme 1). Soon afterwards,
macrocycle of madangamines A–E[6] have been reported to
date, all of them in the racemic series.[7]
We present herein, the enantioselective construction of
the bridged diazatricyclic ABC ring system of madanga-
mines, containing the appropriate substitution and function-
ality for the synthesis of these alkaloids. The synthesis starts
from the known[8] enantiopure oxazolopiperidone lactam 1,
which is easily accessible by a cyclocondensation reaction of
(R)-phenylglycinol[9] with racemic methyl 4-formyl-6-hept-
AHCTUNGTREGeNNNU noate, in a process that involves a dynamic kinetic resolu-
tion[10] (Scheme 2; madangamine numbering). The key steps
Scheme 1. Madangamine alkaloids.
four new members of this group, madangamines B–E, were
isolated from the same sponge,[3] and more recently madan-
gamine F, also showing cytotoxic activity, has been isolated
from the marine sponge Pachychalina alcaloidifera.[4]
Structurally, madangamines possess an unprecedented di-
ACHTUNGTRENNUNGazatricyclic core (ABC rings) and two linear bridges con-
necting N-7 to C-9 (D ring) and N-1 to C-3 (E ring), the
former varying in each madangamine both in carbon length
and in the position and degree of unsaturation, whereas the
latter is identical in madangamines A–E (an 11-membered
E ring), but different in madangamine F (a 13-membered
E ring). In addition, madangamine F incorporates a hydroxy
group at C-4. The absolute configuration of the madanga-
mines remains unknown.
No total syntheses of the madangamine alkaloids have
been reported so far. Only four synthetic approaches to the
diazatricyclic ABC core of madangamines[5] and the synthe-
sis of a tricyclic substructure embodying the 11-membered E
Scheme 2. Synthetic strategy; PG=protecting group.
of the synthesis are: 1) a stereoselective conjugate addition
of an allyl group to an activated unsaturated lactam derived
from 1; 2) the closure of the carbocyclic C ring by a ring-
closing olefin metathesis reaction; 3) the stereoselective gen-
eration of the C-9 quaternary stereocenter, after reductive
removal of the chiral inductor; and 4) the closure of the pi-
peridine A ring by an intramolecular aminohydroxylation
reaction by taking advantage of the carbon–carbon double
bond of the cyclohexene moiety.
Scheme 3 outlines the initial steps of the synthesis. The
starting lactam 1 was converted in excellent yield to the un-
saturated lactam 2 by sequential treatment with (TMS)2NLi
(TMS=trimethylsilyl), di-tert-butyl dicarbonate (Boc2O),
and PhSeCl, followed by oxidation of the resulting mixture
of selenides. We selected the easily removable electron-with-
drawing tert-butoxycarbonyl (Boc) group as the activating
group for the subsequent conjugate addition,[11] since it can
be easily removed under nonreductive conditions, without
affecting the carbon–carbon double bonds. The conjugate
addition of an allyl group to 2 was satisfactorily accom-
plished with allylmagnesium bromide in the presence of
CuI, LiCl, and TMSCl.[12] The reaction was stereoselective
as a consequence of the stereoelectronic control,[13] which
was made evident by the isolation (77% overall yield) of a
cis-diallyl derivative 3 after the removal of the Boc group.
[a] Prof. M. Amat, Dr. M. Pꢁrez, S. Proto, T. Gatti, Prof. J. Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy
and Institute of Biomedicine (IBUB), University of Barcelona
Av. Joan XXIII s/n, 08028 Barcelona (Spain)
Fax : (+34)934024539
E-mail: amat@ub.edu
joanbosch@ub.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000421.
Chem. Eur. J. 2010, 16, 9438 – 9441
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9439

M. Amat, J. Bosch et al.
tion reaction by using mercuric trifluoroacetate, with subse-
quent treatment of the organomercury intermediate with
oxygen and NaBH4. The resulting enantiopure diazatricyclic
alcohol 14 possesses suitable functionality both at C-3 and
the C-9 chain to allow the building of the macrocyclic D and
E rings of madangamines. The synthesis of 14 constitutes
the first enantioselective construction of the diazatricyclic
core of these alkaloids.
With minor modifications, the above strategy was adapted
for the synthesis of other enantiopure ABC substructures of
madangamine alkaloids en route to these natural products.
Thus, Scheme 5 outlines the synthesis of the diazatricyclic
derivative 23, which has an 11-carbon chain at C-9 function-
alized at the terminal position as required for the construc-
tion of the 14-membered D ring of madangamine D. This
chain was incorporated in a straightforward manner, either
from the N-Boc-protected hexahydroisoquinolone 7 or, in
higher overall yield, from the N-tosyl derivative 8, by using
11-(benzyloxy)undecyl iodide in the alkylation step. The
synthetic sequence parallels that previously developed, al-
though in this series a Boc group was used as the protecting
group of the hydroisoquinoline nitrogen, and the Staudinger
procedure (Ph3P/H2O) was employed for the reduction of
the intermediate azide 19.
The closure of the piperidine A ring was initially accom-
plished by the aminomercuriation procedure, which led to
the tricyclic amino alcohol 21 in only moderate overall
yield. A subsequent protection of the piperidine nitrogen
with p-methoxybenzenesulfonyl chloride led to the orthogo-
nally protected diazatricyclic derivative 22 (72% yield),
which was then oxidized to ketone 23 (78% yield).
The intramolecular aminohydroxylation step was substan-
tially improved by using a different methodology involving
the meta-chloroperbenzoic acid (mCPBA) oxidation of the
cyclohexene double bond of the intermediate azide 19 and
reduction of the resulting azido epoxide 24 with Me3P/H2O.
Under these conditions, the initially formed amino epoxide
undergoes a smooth in situ cyclization, leading directly to
the tricyclic amino alcohol 21, which was immediately con-
verted to sulfonamide 22. The overall yield of these four
transformations from azide 19 was 45%.
Scheme 3. Enantioselective construction of the cis-hexahydroisoquino-
lone moiety; TFA=trifluoroacetic acid, Ts=tosyl.
Ring-closing metathesis[14] of 3, followed by reductive re-
moval of the phenylethanol moiety from the resulting tricy-
clic lactam 4 by treatment with Et3SiH/TiCl4 and then Na/
liq. NH3, led to cis-hexahydroisoquinolone (6), which was
then protected as either an N-Boc 7 or N-tosyl 8 derivative.
The crucial quaternary stereocenter at C-9 was installed
by taking advantage of the acidity of the methylene protons
a to the lactam carbonyl. Thus, introduction of a methoxy-
carbonyl group from 7, followed by stereoselective alkyla-
tion of the resulting 1,3-dicarbonyl derivative with a func-
tionalized alkyl iodide, afforded 9 (Scheme 4). The methoxy-
carbonyl group not only acts as an element of stereocontrol,
allowing the subsequent alkylation to occur at the most ac-
cessible face, but is also the precursor of the aminomethyl
chain required for the closure of the A ring. Indeed, after
removal of the N-Boc protecting group, LiAlH4 treatment
of 10 brought about the reduction of the lactam and ester
carbonyl groups leading to alcohol 11, which was protected
as an N-sulfonyl derivative 12 and then converted into the
amino derivative 13 via an azide.
In summary, the diazatricyclic core common to all ma-
dangamines has been enantioselectively assembled for the
first time, which represents a significant breakthrough in the
total synthesis of these complex natural products. Further
Finally, closure of the piperidine A ring was accomplished
following the Weinreb procedure,[5a] by an aminomercuria-
Scheme 4. First enantioselective assembling of the diazatricyclic core of madangamines; Ms=methanesulfonyl, Mbs=para-methoxybenzenesulfonyl.
9440
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9438 – 9441

Enantioselective Synthesis of the Core of Madangamine Alkaloids
COMMUNICATION
Scheme 5. Towards the enantioselective synthesis of madangamine D; Bn=benzyl.
elaboration of the advanced synthetic intermediate 23 into
madangamine D is currently in progress in our laboratory.
[8] a) M. Amat, M. Pꢁrez, A. T. Minaglia, N. Casamitjana, J. Bosch,
Org. Lett. 2005, 7, 3653–3656; b) M. Amat, M. Pꢁrez, A. T. Mina-
glia, B. Peretto, J. Bosch, Tetrahedron 2007, 63, 5839–5848.
[9] For reviews on the use of aminoalcohol-derived oxazolopiperidone
lactams as chiral building blocks for the enantioselective synthesis
of complex piperidine-containing alkaloids, see: a) M. D. Groaning,
A. I. Meyers, Tetrahedron 2000, 56, 9843–9873; b) C. Escolano, M.
Amat, J. Bosch, Chem. Eur. J. 2006, 12, 8198–8207; for more recent
work, see: c) M. Amat, O. Lozano, C. Escolano, E. Molins, J. Bosch,
J. Org. Chem. 2007, 72, 4431–4439; d) M. Amat, M. M. M. Santos,
O. Bassas, N. Llor, C. Escolano, A. Gꢂmez-Esquꢁ, E. Molins, S. M.
Allin, V. McKee, J. Bosch, J. Org. Chem. 2007, 72, 5193–5201; e) M.
Amat, R. Griera, R. Fabregat, J. Bosch, Angew. Chem. 2008, 120,
3396–3399; Angew. Chem. Int. Ed. 2008, 47, 3348–3351; f) M.
Amat, A. Gꢂmez-Esquꢁ, C. Escolano, M. M. M. Santos, E. Molins,
J. Bosch, J. Org. Chem. 2009, 74, 1205–1211; g) M. Amat, N. Llor,
B. Checa, E. Molins, J. Bosch, J. Org. Chem. 2010, 75, 178–189.
[10] For reviews, see: a) R. Noyori, M. Tokunaga, M. Kitamura, Bull.
Chem. Soc. Jpn. 1995, 68, 36–56; b) R. S. Ward, Tetrahedron: Asym-
metry 1995, 6, 1475–1490; c) S. Caddick, K. Jenkins, Chem. Soc.
Rev. 1996, 25, 447–456; d) F. F. Huerta, A. B. E. Minidis, J.-E. Bꢃck-
vall, Chem. Soc. Rev. 2001, 30, 321–331; e) H. Pellissier, Tetrahedron
2003, 59, 8291–8327; f) C. Wolf, Dynamic Stereochemistry of Chiral
Compounds, RSC, Cambridge, 2008, Chapter 7.
[11] a) L. E. Overman, A. J. Robichaud, J. Am. Chem. Soc. 1989, 111,
300–308; b) J. Cossy, O. Mirguet, D. Gomez Pardo, J.-R. Desmurs,
New J. Chem. 2003, 27, 475–482; c) A. Deiters, M. Pettersson, S. F.
Martin, J. Org. Chem. 2006, 71, 6547–6561, and references therein.
[12] a) E. J. Corey, N. W. Boaz, Tetrahedron Lett. 1985, 26, 6019–6022;
b) A. Alexakis, J. Berlan, Y. Besace, Tetrahedron Lett. 1986, 27,
1047–1050; c) E. Nakamura, S. Matsuzawa, Y. Horiguchi, I. Kuwaji-
ma, Tetrahedron Lett. 1986, 27, 4029–4032.
[13] a) P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry,
Pergamon Press, Oxford, 1983, p. 221; b) P. Perlmutter, Conjugate
Addition Reactions in Organic Synthesis, Pergamon Press, Oxford,
1992, p. 25.
Acknowledgements
Financial support from the MICINN, Spain (project CTQ2009-07021/
BQU), and the AGAUR, Generalitat de Catalunya (grant 2009-SGR-
111) is gratefully acknowledged. Thanks are also due to the Leonardo da
Vinci programme (Unipharma Graduates-4) for a mobility grant to T.G.
Keywords: alkaloids
· aminohydroxylation · lactams ·
madangamines · natural products
[1] a) R. J. Andersen, R. W. M. van Soest, F. Kong in Alkaloids: Chemi-
cal and Biological Perspectives, Vol. 10 (Ed.: S. W. Pelletier), Perga-
mon, New York, 1996, pp. 301–355; b) N. Matzanke, R. J. Gregg,
S. M. Weinreb, Org. Prep. Proced. 1998, 30, 1–51; c) R. G. S. Ber-
linck, Top. Heterocycl. Chem. 2007, 10, 211–238.
[2] F. Kong, R. J. Andersen, T. M. Allen, J. Am. Chem. Soc. 1994, 116,
6007–6008.
[3] F. Kong, E. I. Graziani, R. J. Andersen, J. Nat. Prod. 1998, 61, 267–
271.
[4] J. H. H. L. De Oliveira, A. M. Nascimento, M. H. Kossuga, B. C.
Cavalcanti, C. O. Pessoa, M. O. Moraes, M. L. Macedo, A. G. Ferre-
ira, E. Hajdu, U. S. Pinheiro, R. G. S. Berlinck, J. Nat. Prod. 2007,
70, 538–543.
[5] a) N. Matzanke, R. J. Gregg, S. M. Weinreb, M. Parvez, J. Org.
Chem. 1997, 62, 1920–1921; b) N. Yamazaki, T. Kusanagi, C. Ki-
bayashi, Tetrahedron Lett. 2004, 45, 6509–6512; c) H. M. Tong, M.-
T. Martin, A. Chiaroni, M. Bꢁnꢁchie, C. Marazano, Org. Lett. 2005,
7, 2437–2440; d) J. Quirante, L. Paloma, F. Diaba, X. Vila, J. Bon-
joch, J. Org. Chem. 2008, 73, 768–771; e) Y. Yoshimura, T. Kusana-
gi, C. Kibayashi, N. Yamazaki, S. Aoyagi, Heterocycles 2008, 75,
1329–1354.
[14] a) Handbook of Metathesis, Vols. 1–3 (Ed.: R. H. Grubbs), Wiley-
VCH, Weinheim, 2003; b) F.-X. Felpin, J. Lebreton, Eur. J. Org.
Chem. 2003, 3693–3712; c) A. Deiters, S. F. Martin, Chem. Rev.
2004, 104, 2199–2238.
[6] Y. Yoshimura, J. Inoue, N. Yamazaki, S. Aoyagi, C. Kibayashi, Tetra-
hedron Lett. 2006, 47, 3489–3492.
[7] For a review, see: A. Nishida, T. Nagata, M. Nakagawa, Top. Hetero-
cycl. Chem. 2006, 5, 255–280.
Received: February 17, 2010
Published online: April 8, 2010
Chem. Eur. J. 2010, 16, 9438 – 9441
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9441