Access to Enantiopure Advanced Intermediates en Route to Madangamines

Article abstract of DOI:10.1002/chem.201904045

The synthesis of enantiopure ABCE and ABCD tetracyclic advanced intermediates en route to madangamine alkaloids and studies for the construction of the triunsaturated 15-membered D ring of madangamine B and the saturated 13-membered D ring of madangamine E are reported.

Full text of DOI:10.1002/chem.201904045

A Journal of
Accepted Article
Title: Access to Enantiopure Advanced Intermediates en Route to
Madangamines
Authors: Celeste Are, Maria Pérez, Roberto Ballette, Stefano Proto,
Federica Caso, Nihan Yayik, Joan Bosch, and Mercedes
Amat
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Access to Enantiopure Advanced Intermediates en Route to
Madangamines
Celeste Are,[a] Maria Pérez,[b] Roberto Ballette,[a] Stefano Proto,[a] Federica Caso,[a] Nihan Yayik,[a] Joan
Bosch,[a] and Mercedes Amat*[a]
Although the isolation of madangamines AE was reported in
the 1990s[1a,b] and since then these alkaloids have been the
subject of numerous synthetic studies,[3] the first total
Abstract: The synthesis of enantiopure ABCE and ABCD tetracyclic
(enantioselective) synthesis of a member of this group, (+)-
advanced intermediates en route to madangamine alkaloids and
madangamine D, was not reported until 2014.[4] Our approach
studies for the construction of the triunsaturated 15-membered D
involved the use of a bridged diazatricyclic platform (rings ABC)
ring of madangamine B and the saturated 13-membered D ring of
containing the appropriate functionality, at C-3 and the C-9
madangamine E are reported.
substituent, for the subsequent assembly of the peripheral
macrocyclic
D
and
E
rings. In this context, using
a
Introduction
phenylglycinol-derived oxazolopiperidone lactam as the starting
enantiomeric scaffold, we have developed a flexible route for the
Madangamines are a small group of pentacyclic diamine
alkaloids isolated[1] from marine sponges belonging to the order
Haplosclerida.[2] Six members of this family have been identified
so far. Natural madangamines A and F have exhibited in vitro
cytotoxicity against a variety of human cancer cell lines.
Structurally, madangamines AE share a bridged C5N-C5N-C6
diazatricyclic core (rings ABC) and the eastern 11-membered
ring (ring E), which incorporates two skipped (Z,Z)-configurated
double bonds, one of them trisubstituted. However, they differ in
the macrocyclic western D ring, both in size (13-, 14-, or 15-
membered) and in the number (0, 1, or 3) and position of double
bonds. Madangamine F possesses four double bonds in a 13-
membered E ring and an additional hydroxy substituent at C-4 of
the core ABC nucleus (Figure 1).
generation of
the
aforementioned key diazatricyclic
intermediates.[3g,h,4,5] We have also developed a straightforward
two-step sequence to build the 11-membered E ring, in which
the skipped (Z,Z)-octadienoate chain on C-3 needed for the final
macrolactamization
stereoselectivity by using a C8 nonstabilized ylide.[4-6]
is
incorporated
with
acceptable
The viability of our general strategy was recently demonstrated
by the formal synthesis of (+)-madangamine A, which features a
skipped (Z,Z,Z)-unsaturated 15-membered D ring.[5]
Scheme 1. Our general strategy for the synthesis of madangamine alkaloids.
Also recently, outstanding synthetic work by Sato and Chida
resulted in a unified total synthesis of (+)-madangamines AE.[7]
Their strategy is based on a late-stage construction of the
macrocyclic D ring from a common advanced ABCE tetracyclic
intermediate bearing a C-9 hydroxypropyl chain. Two crucial
steps of the synthesis are the intramolecular N-acyliminium
cyclization of a propargylsilane to assemble the vinylidene-
substituted diazatricyclic ABC ring core and the stereoselective
hydroboration of the 1,1-disubstituted allene to install a C-3 (Z)-
hydroxyethylidene substituent. A subsequent Pd-coupling of the
corresponding methyl carbonate with an appropriate C6 (Z)-
vinylstannane generates the skipped (Z,Z)-octadienoate chain
required for the closure of the E ring (Scheme 2). All synthetic
madangamines AE showed antiproliferative effects against a
variety of human cancer cell lines. These syntheses shed
valuable light on the role of the different D rings in the bioactivity.
Figure 1. Madangamine alkaloids.
[a]
Dr. C. Are, Dr. R. Ballette, Dr. S. Proto, Dr. F. Caso, N. Yayik, Prof.
J. Bosch, Prof. M. Amat
Laboratory of Organic Chemistry
Faculty of Pharmacy and Food Sciences, and Institute of
Biomedicine (IBUB)
University of Barcelona, 08028 Barcelona (Spain)
E-mail: amat@ub.edu
[b]
Dr. M. Pérez
Department of Nutrition, Food Sciences and Gastronomy
Faculty of Pharmacy and Food Sciences, and Institute of Nutrition
and Food Safety (INSA-UB)
University of Barcelona, 08921 Santa Coloma de Gramanet (Spain)
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diene 4 in 45% yield as a 7:1 mixture of Z/E isomers.
Remarkably, the stereoselectivity of this reaction was higher
than that observed (2.2:1) in a similar Wittig reaction from an
ABCD tetracyclic ketone during our synthesis of (+)-
madangamine D.[4] Removal of the N-tosyl protecting group,
followed by alkaline hydrolysis of the ester function and EDCI-
promoted macrolactamization of the resulting crude amino acid,
provided tetracyclic lactam 5, an immediate synthetic precursor
of (+)-madangamine D[8] (Scheme 3).
The above satisfactory results spurred us to apply the same
methodology for the construction of the E ring from tricyclic
ketone 7, an intermediate in our synthesis of (+)-madangamine
A.[5] After Wittig reaction of 7 with the ylide derived from 3 (65%;
Z/E, 4:1 ratio), the closure of the E ring was accomplished in
48% overall yield from 8, providing the C-9 3,3-
(ethylenedioxy)propyl substituted tetracycle 9, a potential ABCE
tetracyclic intermediate for the synthesis of (+)-madangamines
AE. The corresponding N-Teoc alcohol and (in some cases)
aldehyde are common intermediates in the SatoChida unified
total synthesis of madangamine alkaloids.[7]
Scheme 2. The common ABCE tetracyclic intermediate in the SatoChida
unified total synthesis of madangamines.
The comprehensive work of Sato and Chida prompted us to
disclose our recent studies in the field of madangamines. They
include the assembly of the triunsaturated 15-membered D ring
of madangamine B and the saturated 13-membered D ring of
madangamine E, as well as the synthesis of enantiopure ABCE
and ABCD tetracyclic advanced intermediates en route to the
alkaloids of this group.
In an attempt to develop alternative procedures for the closure of
the E ring common to madangamines AE, we focused our
attention on macroannulations from model azabicyclic ketones
10, based on olefin ring-closing metathesis (RCM),[10]
carbonylolefin metathesis,[11] or McMurry[12] reactions.
Results and Discussion
Synthesis of ABCE tetracyclic precursors of madangamines
Scheme 4 outlines the preparation of the required substrates, by
N-deprotection of 10 followed by acylation with the appropriate
unsaturated acid. Unfortunately, all attempts to induce RCM,
using a variety of catalysts (Grubbs I and II, Hoveyda-Grubbs,
Schrock), either from amide 11 or amine 12 were ineffective. In
some runs, products arising from a cross-metathesis were
detected. Similar disappointing results were obtained in the
cyclization of 13 using the Schrock catalyst, although in this
case trace amounts of the tricyclic lactam 14 were detected. Nor
did the desired cyclization occur when the unstable aldehyde
resulting from deprotection/oxidation of the silyl derivative 15
was subjected to McMurry reaction conditions.
AE
Our synthesis of (+)-madangamine D[4] involved the closure of
ring E from an ABCD tetracyclic intermediate. Taking advantage
of the previously reported[3g] tricyclic intermediate 1, we
envisaged a complementary approach to (+)-madangamine D,
via the ABCE tetracyclic precursor 5, which bears the C-9
benzyloxyundecyl substituent required for the final closure of the
D ring.[8]
The assembly of the (Z,Z)-skipped E-ring was accomplished
with excellent stereoselectivity following our previously
developed Wittig/macrolactamization sequence using the eight-
carbon ylide derived from phosphonium salt 3.[9] Thus, after N-
tosylation of 1 and Dess-Martin periodinane oxidation of the
resulting tricyclic alcohol, Wittig reaction of ketone 2 with the
ylide generated from 3 satisfactorily gave the expected (Z,Z)-
Scheme 3. Access to ABCE tetracyclic precursors of (+)-madangamines AE.
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In view of the above results, we decided to apply the
methodology to the tetracyclic alkynyl derivative 21, which was
prepared in 50% overall yield from the advanced intermediate 9
in two steps: acid hydrolysis of the acetal function and
subsequent reaction of the resulting somewhat unstable
aldehyde with
a phosphozene base in the presence of
nonafluorobutane-1-sulfonyl fluoride (NfF)[17]. Unfortunately, the
n-BuLi-promoted coupling of 21 with the unactivated iodide 17
under the previously established conditions occurred with
abundant decomposition, affording the desired dienyne 22 in
negligible yield (Scheme 6). Extensive decomposition, or
recovery of the starting material, was also observed in the
attempts to induce the coupling from tricyclic alkyne 23, which
was prepared from 8 by the procedure previously used for 21.
The strong nucleophilic character of n-BuLi combined with the
presence of a lactam or ester carbonyl group could account for
the failure of the above coupling reactions.
Scheme 4. Model studies on the closure of the E ring.
Studies on the construction of the D ring of madangamine B
Madangamine B features a 15-membered D ring embodying a
skipped (Z,Z)-diene and an isolated double bond. It differs from
madangamine A only in the position and stereochemistry of one
double bond (Z C29C30 in madangamine A but E C30C31 in
madangamine B). To date, there is only one report on the
construction of the D ring of madangamine B. In the SatoChida
synthesis of this alkaloid[7b] the (Z,Z,E)-dodecatriene chain
needed for the ring closure was assembled stepwise from a C-9
3-oxopropyl substituent by a sequence involving a one-carbon
dehomologation, a Takai olefination, and a Wittig reaction (3C 
1C + 4C + 6C strategy).
Scheme 6. Attempted construction of the D ring of madangamine B from
tricyclic or tetracyclic precursors.
Construction of the D ring of madangamine E
Using a model 3-(2-propynyl)piperidine derivative, we devised a
straightforward procedure based on the coupling reaction of an
alkyne with an unactivated nonadienyl halide (3C + 9C strategy).
Although the Pd- or Ni-catalyzed Sonogashira coupling[13] of
alkyne 16[14] with the unactivated halide 17[15] took place in only
moderate yield (<25%),[16] alkylation under basic conditions (n-
BuLi, THF, reflux, 24h) afforded the desired dienyne 18 in 40%
yield. After stereoselective Na/liq. NH3 reduction of the alkyne to
an (E)-alkene and exchange of the TIPS protecting group for a
tosylate, removal of the Boc group in the resulting (Z,Z,E)-triene
19 followed by intramolecular alkylation provided compound 20,
the AD ring moiety of madangamine B (Scheme 5).
In the reported synthesis of (+)-madangamine E, the saturated
13-membered D ring was constructed by copper-mediated
alkylation of a C-9 bromopropyl-substituted ABCE tetracyclic
derivative with a C7-Grignard reagent and a final macrocyclic
alkylation.[7]
Illustrating the versatility of the tricyclic scaffolds 24 and 25, key
intermediates in our syntheses of madangamines A[5] and D,[4]
respectively, we have developed an alternative procedure for the
closure of the D ring of madangamine E, via the 3-butenyl
derivative 26, using
a
ring-closing metathesis reaction[18]
(Scheme 7). After acid hydrolysis of the acetal function, the
terminal double bond of 26 was introduced by a Wittig reaction
from 24 or following the Grieco dehydration protocol via a C-9 4-
hydroxybutyl derivative starting from 25. Removal of the N-Boc
protecting group followed by acylation with 7-octenoic acid
provided diene 27, which underwent RCM with excellent yield
using the Grubbs 1st generation catalyst. Hydrogenation of the
resulting Z/E mixture of alkenes (2:1 ratio) followed by
deprotection of the hydroxy substituent led to alcohol 28, an
advanced ABCD tetracyclic intermediate towards (+)-
madangamine E.
Scheme 5. Model studies for the construction of the D ring of madangamine B.
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Scheme 7. Access to an ABCD tetracyclic intermediate for the synthesis of (+)-madangamine E.
Conclusions
acknowledged. We also acknowledge the networking
contribution from the COST Action CM1407.
The synthesis of the ABCE tetracyclic derivatives 5 and 9 from
ABC tricyclic precursors further illustrates the usefulness of the
straightforward Wittig/macrolactamization sequence we had
developed for the assembly of the Z,Z-unsaturated 11-
membered E ring shared by madangamines AE. Alternative
strategies for the closure of the E ring, involving RCM, carbonyl-
olefin metathesis, or McMurry reactions met with no success.
Tetracyclic intermediate 5 can be envisaged as an immediate
synthetic precursor of madangamine D, whereas tetracyclic
derivatives closely related to acetal 9 have been used as
common intermediates in the SatoChida unified synthesis of
madangamines AE.
On the other hand, although a procedure for the construction of
the (Z,Z,E)-unsaturated D ring characteristic of madangamine B
has been established operating from a model piperidine system,
its application to carbonyl-bearing ABC tricyclic or ABCE
tetracyclic derivatives was unsuccessful.
Finally, the ABC tricyclic intermediates 24 and 25, each one
bearing a different functionalized chain at C-9, have served as
platforms for the construction of the saturated D ring of
madangamine E using a ring-closing metathesis reaction.
Taking advantage of the functionalization at C-3 in the advanced
tetracyclic intermediate 28, the E ring could be assembled using
the methodology applied in the above preparation of ABCE
tetracycles 5 and 9 as well as previously in our synthesis of
madangamines A and D.
All the above results confirm the viability and versatility of our
general strategy for the synthesis of madangamine alkaloids.
We now have in hand efficient procedures for the construction of
the functionalized ABC core of madangamines with appropriate
substituents at C-9 for the subsequent assembly of the
peripheral D and E rings.
Keywords: alkaloids • macrocycles • madangamines • total
synthesis • skipped dienes
[1]
a) F. Kong, R. J. Andersen, T. M. Allen, J. Am. Chem. Soc. 1994, 116,
6007–6008; b) F. Kong, E. I. Graziani, R. J. Andersen, J. Nat. Prod.
1998, 61, 267–271; c) 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. Ferreira, E. Hajdu, U. S. Pinheiro, R. G. S. Berlinck, J. Nat. Prod.
2007, 70, 538–543.
[2]
For a review on the isolation, characterization, biosynthesis, biological
activity, and synthesis of madangamine alkaloids, see: a) M. Amat, M.
Pérez, R. Ballette, S. Proto, J. Bosch, In The Alkaloids, Vol. 74 (Ed.: H.-
J. Knölker), Elsevier, Oxford, 2015, pp. 159–199. For reviews on
polycyclic marine alkaloids isolated from sponges of the order
Haplosclerida, see: b) R. J. Andersen, R. W. M. Van Soest, F. Kong, In
Alkaloids: Chemical and Biological Perspectives, Vol. 10 (Ed.: S. W.
Pelletier), Pergamon Press, New York, 1996, pp. 301355; c) J.
Rodríguez, In Studies in Natural Products Chemistry, Vol. 24 (Ed.: A.-
U. Rahman), Elsevier, Oxford, UK, 2000, pp. 573681; d) B. Cheng, J.
Reyest, Nat. Prod. Rep. 2019, Doi: 10.1039/c9np00031c.
[3]
a) N. Matzanke, R. J. Gregg, R. J. Weinreb, M. Parvez, J. Org. Chem.
1997, 62, 1920–1921; b) N. Yamazaki, T. Kusanagi, C. Kibayashi,
Tetrahedron Lett. 2004, 45, 6509–6512; c) H. M. Tong, M.-T. Martin, A.
Chiaroni, M. Benechie, C. Marazano, Org. Lett. 2005, 7, 2437–2440; d)
Y. Yoshimura, J. Inoue, N. Yamazaki, S. Aoyagi, C. Kibayashi,
Tetrahedron Lett. 2006, 47, 3489–3492; e) Y. Yoshimura, T. Kusanagi,
C. Kibayashi, N. Yamazaki, S. Aoyagi, Heterocycles 2008, 75,
13291354; f) J. Quirante, L. Paloma, F. Diaba, X. Vila, J. Bonjoch, J.
Org. Chem. 2008, 73, 768–771; g) M. Amat, M. Pérez, S. Proto, T.
Gatti, J. Bosch, Chem. Eur. J. 2010, 16, 9438–9441; h) M. Amat, R.
Ballette, S. Proto, M. Pérez, J. Bosch, Chem. Commun. 2013, 49,
3149–3151; i) Y. Yanagita, T. Suto, N. Matsuo, Y. Kurosu, T. Sato, N.
Chida, Org. Lett. 2015, 17, 1946–1949; j) F. Diaba, C. Pujol-Grau, A.
Martínez-Laporta, I. Fernández, J. Bonjoch, Org. Lett. 2015, 17, 568–
571; k) A. Bhattacharjee, M. V. Gerasimov, S. DeJong, D. J. Wardrop,
Org. Lett. 2017, 19, 6570–6573; e) M. S. Eastwood, C. J. Douglas, Org.
Lett. 2019, 21, 6149–6154.
Acknowledgements
[4]
[5]
R. Ballette, M. Pérez, S. Proto, M. Amat, J. Bosch, Angew. Chem. Int.
Ed. 2014, 53, 6202–6205.
Financial support from the MINECO/FEDER, Spain (Projects
CTQ2015-65384-R and RTI2018-09974-B-I00) is gratefully
C. Are, M. Pérez, J. Bosch, M. Amat, Chem. Commun. 2019, 55,
72077210.
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[6]
[7]
S. Proto, M. Amat, M. Pérez, R. Ballette, F. Romagnoli, A. Mancinelli, J.
Bosch, Org. Lett. 2012, 14, 3916–3919.
[14] Alkyne 16 was prepared in 65% overall yield by alkylation of 2-
piperidone with 3-bromo-1-(trimethylsilyl)-1-propyne, followed by LiAlH4
reduction, reaction with Boc2O, and desilylation.
a) T. Suto, Y. Yanagita, Y. Nagashima, S. Takikawa, Y. Kurosu, N.
Matsuo, T. Sato, N. Chida, J. Am. Chem. Soc. 2017, 139, 29522955;
b) T. Suto, Y. Yanagita, Y. Nagashima, S. Takikawa, Y. Kurosu, N.
Matsuo, K. Miura, S. Simizu, T. Sato, N. Chida, Bull. Chem. Soc. Jpn.
2019, 92, 545571.
[15] Iodide 17 was prepared by treatment of the corresponding mesylate[7]
with NaI.
[16] Reaction conditions: 1,3-bis(1-adamantyl)imidazolium chloride, [(-
allyl)PdCl]2, CuI, Cs2CO3 or [(MeNN2)NiCl], CuI, Cs2CO3, as reported by
a) M. Eckhardt, C. G. Fu, J. Am. Chem. Soc. 2003, 125, 13642–13643;
b) G. Altenhoff, S. Wurtz, F. Glorius, Tetrahedron Lett. 2006, 47, 2925–
2928; c) O. Vechorkin, D. Barmaz, V. Proust, X. Hu, J. Am. Chem. Soc.
2009, 131, 12078–12079; d) X. Hu, Chimia 2010, 64, 231234.
[17] M. Lyapkalo, M. A. K.; Vogel, E. V. Boltukhina, J. Vavřík, Synlett 2009,
558−561.
[8]
[9]
For the closure of the 14-membered
D
ring from
a
C-9
benzyloxyundecyl-substituted ABC tricyclic derivative, see ref. [3h].
J. Sandri, J. Viala, J. Org. Chem. 1995, 60, 6627–6630.
[10] L. Yet in Org. React. Vol. 89, (Ed.: S. E. Denmark), John Wiley & Sons,
2016, pp. 1–1342.
[11] L. Ravindar, R. Lekkala, K. P. Rakesh, A. M. Asiri, H. M. Marwani, H.-L.
Qin, Org. Chem. Front. 2018, 5, 1381–1391.
[18] For model studies on the construction of the D ring of madangamine E
using a ring-closing metathesis reaction, see refs. [3f] and [6].
[12] T. Takeda, A. Tsubouchi in Org. React. Vol. 82, (Ed.: S. E. Denmark),
John Wiley & Sons, 2013, pp. 1–470.
[13] R. Chinchilla, C. Nájera, Chem. Rev. 2007, 107, 874922.
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Celeste Are,[a] Maria Pérez,[b] Roberto
Ballette,[a] Stefano Proto,[a] Federica
Caso,[a] Nihan Yayik,[a] Joan Bosch,[a]
and Mercedes Amat*[a]
Page No. – Page No.
Access to Enantiopure Advanced
Intermediates en Route to
Madangamines
Valuable tetracyclic synthetic precursors of (+)-madangamines AE and model
studies for the construction of the triunsaturated 15-membered D ring of
Madangamine B are reported.
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