Biomimetic three-component assembly of the central core of halichonadins K and L

Article abstract of DOI:10.1002/ejoc.201201316

The one-step cascade assembly of the central core of halichonadins K and L, two dimeric sesquiterpenoids of marine origin, is described for a model system providing suitable conditions towards the total synthesis of the two molecules. A biomimetic multicomponent reaction involving a glycine, a C₅ unit presumably derived from lysine, and an isocyanide mimic of the terpene decalins is studied. A one-pot multicomponent reaction involving the reaction of an isocyanide with an in situ generated dihydropyridinium salt permits a straightforward access to a biomimetic model of the recently isolated halichonadins K and L. Copyright

Full text of DOI:10.1002/ejoc.201201316

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201316
Biomimetic Three-Component Assembly of the Central Core of
Halichonadins K and L
François Senejoux,[a] Laurent Evanno,[a] and Erwan Poupon*[a]
Keywords: Natural products / Alkaloids / Biomimetic synthesis / Multicomponent reactions / Amino acids
The one-step cascade assembly of the central core of hali-
chonadins K and L, two dimeric sesquiterpenoids of marine
origin, is described for a model system providing suitable
conditions towards the total synthesis of the two molecules.
A biomimetic multicomponent reaction involving a glycine,
a C5 unit presumably derived from lysine, and an isocyanide
mimic of the terpene decalins is studied.
Knowing the existence of halichonadin C[2] (3, Figure 1),
which strictly corresponds to the decalin part of 1 and 2
but flanked by an isocyanide functional group,[3,4] the as-
sembly may, in principle, be explained by a Strecker-type
reaction followed by hydrolysis into the amide (vide infra).
It is then plausible to trace back (Figure 2), besides the two
halichonadin C units, a hydroxylated C5 unit, which could
presumably be derived from l-lysine (4), and a C2 or C2/
C2-C6N-substituents (in the case of 1 or 2, respectively),
which could find their origin in glyoxylic acid (5) and l-
phenylalanine (6).
Introduction
Halichonadins K and L (1 and 2, Figure 1), recently iso-
lated from a marine sponge Halichondria sp., are striking
new dimeric terpenoids.[1] In fact, two sesquiterpenic decal-
ins are linked through an unusual piperidine ring in the way
that this latter is (1) N-substituted by an amino acid chain,
(2) hydroxylated at the 4-position, and finally and most im-
portantly (3) substituted by two amide functions that bear
the decalins at the 2,6-positions in a cis configuration.
Figure 1. Structures of halichonadins K, L, and C (1–3).
Figure 2. Plausible biosynthetic building blocks of halichonad-
In terms of biosynthesis, whereas the terpenic decalin
substructures are of the classical eudesmane type, the
puzzling origin of the central core caught our attention.
ins K, L, and C (1–3).
In agreement with Kobayashi’s proposal,[1] we herein give
a full mechanistic hypothesis towards 1 and 2 as represented
in Scheme 1. A central dihydropyridinium salt such as 7
(that may arise from classical biochemical transformations
from l-lysine and glyoxylic acid) could be considered as a
central electrophilic intermediate permitting the assembly
of the different parts of 1 and 2. The mechanism involved
in the particular formation of the amidic lateral substituents
is highlighted in Scheme 1 and is reminiscent of that of
[a] Université Paris-Sud, Laboratoire de Pharmacognosie associé
au CNRS, UMR 8076 BioCIS, LabEx LERMIT, Faculté de
Pharmacie, 5,
rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France
Fax: +33-1-46835399
E-mail: erwan.poupon@u-psud.fr
Homepage: http://www.biocis.u-psud.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201316.
Eur. J. Org. Chem. 2013, 453–455
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
453

F. Senejoux, L. Evanno, E. Poupon
SHORT COMMUNICATION
known multicomponent reactions of the Ugi type.[5] The investigate the assembly of the central core of these intri-
nucleophilic attack of the isocyanide onto the iminium salt guing new natural substances.
followed by hydrolysis of the nitrilium intermediate could,
in that way, explain the formation of the amides of hal-
Results and Discussion
ichonadins K and L. In view of this plausible and detailed
biosynthetic scenario, our interest in biomimetic syntheses
in the field of natural product synthesis prompted us to
Glutaraldehyde (8), a C5 dialdehyde, is an ideal biomime-
tic equivalent of l-lysine[6] when dihydropyridinium salt in-
termediates are postulated, as is the present case with pos-
tulated intermediate 7. Thus, glutaraldehyde (which pro-
vides the presumably lysine-derived C5 unit), cyclohexane
isocyanide (9, as a convenient surrogate of the terpene moi-
ety), and glycine methyl ester (10) were chosen for the study
of the one-step three-component assembly of the central
core of 1 and 2. The mixture of the units was studied, and
in MeOH/H2O a satisfactory 36% yield of new compound
11 was observed. Indeed, the reaction between 8 and 10
permits access to a reactive dihydropyridinium salt that is
related to postulated 7, which then undergo two stabilizing
nucleophilic attacks from 9.[7] Structure elucidation re-
vealed the awaited formation of the multicomponent reac-
tion adduct corresponding to the central core of 1 obtained
as a single cis-diastereomer, as ascertained by NMR spec-
troscopy. Following Kobayashi’s strategy for the correlation
between 1 and 2, model compound 11 was hydrolyzed into
corresponding acid 12 and finally converted by esterifica-
tion under classical coupling conditions [1-ethyl-3-(3-di-
methylaminopropyl)carbodiimide (EDC) and N-hydroxy-
benzotriazole (HOBt)] into 13, which corresponds to an ad-
vanced biomimetic model for halichonadin L (2). Analysis
of compounds 11 and 13 by NMR spectroscopy was in
agreement with the data available for 1 and 2. Specifically,
identical chemical shifts for the CH protons at the 2,6-posi-
tions of the piperidine ring allowed the relative cis configu-
ration to be ascertained [11: δ(1H) = 4.15 ppm, δ(13C) =
62.3 ppm; 13: δ(1H) = 4.21 ppm, δ(13C) = 61.9 ppm, see the
Experimental Section for details].
Conclusions
We have set the stage and provided optimized experimen-
tal conditions for the biomimetic assembly of the central
core of original halichonadins K and L, which thereby rein-
forces its proposed biosynthetic scheme. The present work
also opens the way to the convergent synthesis of a large
number of analogs for biological evaluation. Finally, this
straightforward access to piperidine heterocycles also con-
tributes to the long-lasting interest in cascade[8] and multi-
component[9] reactions in the field of natural product total
synthesis, especially when inspired by nature biosynthetic
pathways.
Scheme 1. Detailed biosynthetic scenario towards halichonadins K,
L, and C (1–3) and biomimetic multicomponent model reaction.
Reagents and conditions: (a) MeOH/4% citric acid in H2O, 10 + 8
Experimental Section
General: Reactions were monitored by thin-layer chromatography
carried out on silica gel plates (Merck TLC Silica gel 60F254) by
using UV light as a visualizing agent and sulfuric vanillin/heat and
Draggendorff reagent/heat as developing agents. Merck Silica gel
(1.2 equiv.), r.t., 3 min, then
9 (2 equiv.), 48 h, r.t. (36%);
(b) MeOH/KOH in H2O, r.t., 12 h (84%); (c) 2-phenylethylamine
(1 equiv.), EDC (1.2 equiv.), HOBt (1.2 equiv.), CH3CN, 12 h, r.t.
(61%).
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Eur. J. Org. Chem. 2013, 453–455

Biomimetic Assembly of the Central Core of Halichonadins K and L
Geduran® Si 60 (particle size 40–63 mm) and Sephadex LH-20®
(Pharmacia) gels were used for column chromatography. NMR
spectra were recorded in [D5]pyridine with an AM-300 (300 MHz)
or AM-400 (400 MHz) Bruker spectrometer and calibrated by
using undeuterated pyridine as an internal reference. IR spectra
were recorded with a Vector 22 Bruker spectrometer. Mass spectra
were recorded at the “Service d’Analyse des Médicaments et des
Métabolites” (Université Paris-Sud).
combined organic layers were then dried with MgSO4, filtered, and
concentrated under reduced pressure. The crude residue was puri-
fied by flash chromatography on silica gel (CH2Cl2/MeOH, 98:2)
to provide 13 (50 mg, 61%) as an amorphous colorless solid. 1H
NMR (400 MHz, [D5]pyridine): δ = 1.06 (m, 2 H), 1.17–1.37 (8 H),
1.45 (m, 2 H), 1.55–1.70 (4 H), 1.75 (m, 2 H), 1.85–2.00 (8 H), 2.88
(t, J = 7.2 Hz, 2 H), 3.67 (m, 2 H), 3.70 (m, 2 H), 4.00 (m, 2 H),
4.21 (t, J = 6 Hz, 2 H), 7.23–7.32 (5 H), 8.37 (d, J = 7.6 Hz, 2 H),
8.76 (t, J = 5.6 Hz, 1 H) ppm. 13C NMR (75 MHz, [D5]pyridine):
δ = 20.2, 25.7, 26.2, 29.0, 33.6, 33.8, 36.7, 41.4, 48.6, 57.5, 61.9,
(R,S)-Methyl
2,6-Bis(cyclohexylcarbamoyl)piperidin-1-yl-acetate
(11): To a solution of glycine methyl ester hydrochloride (500 mg,
4.0 mmol) in MeOH (5 mL) was added a 4% aqueous solution of
citric acid followed by the addition of glutaraldehyde (480 mg,
4.8 mmol, 1.2 equiv., 870 μL of a 50% aqueous solution). The mix-
ture was stirred for 3 min at room temperature and then cyclohex-
ylisocyanide (890 μL, 8.0 mmol, 2 equiv.) was slowly added. The
resulting reaction mixture was then stirred for 48 h at room tem-
perature, diluted with H2O (40 mL), and extracted with CH2Cl2
(4ϫ 20 mL). The combined organic extracts were dried with anhy-
drous MgSO4, filtered, and evaporated under reduced pressure. The
residue was purified by flash chromatography on silica gel (cyclo-
hexane/ethyl acetate, 1:1 then 3:7) and by Sephadex® LH-20 col-
umn chromatography (MeOH/CH2Cl2, 1:1) to provide 11 as a col-
127.0, 129.2, 129.6, 140.4, 172.1, 173.6 ppm. IR (film): ν = 3200,
˜
2950–2900, 2854, 1640, 1527, 1451, 1250 cm–1. HRMS (TOF MS
ES+): calcd. for C29H45N4O3 [M + H]+ 497.3486; found 497.3491.
Supporting Information (see footnote on the first page of this arti-
1
cle): H NMR and 13C NMR spectra of compounds 11–13.
Acknowledgments
We thank Jean-Christophe Jullian for NMR assistance.
[1] Isolation of halichonadins K and L: N. Tanaka, S. Suto, H.
Ishiyama, T. Kubota, A. Yamano, M. Shiro, J. Fromont, J. Ko-
bayashi, Org. Lett. 2012, 14, 3498–3501.
[2] Isolation of halichonadin C: H. Ishiyama, A. Hashimoto, J.
Fromont, Y. Hoshino, Y. Mikami, J. Kobayashi, Tetrahedron
2005, 61, 1101–1105
[3] Isocyanide marine natural products, review article: M. J. Gar-
son, J. S. Simpson, Nat. Prod. Rep. 2004, 21, 164–179.
[4] Isocyanide biosynthetic studies, see for example: a) M. J. Gar-
son, J. S. Simpson, Org. Biomol. Chem. 2004, 2, 939–948; b)
S. F. Brady, J. Clardy, Angew. Chem. 2005, 117, 7225; Angew.
Chem. Int. Ed. 2005, 44, 7063–7065.
1
orless oil (588 mg, 36%). H NMR (400 MHz, [D5]pyridine): δ =
1.07 (m, 2 H), 1.18–1.30 (8 H), 1.43 (m, 2 H), 1.53–1.68 (4 H), 1.73
(m, 2 H), 1.82–2.04 (8 H), 3.64 (s, 3 H), 3.68 (d, J = 17.2 Hz, 1 H),
3.85 (d, J = 17.2 Hz, 1 H), 3.99 (m, 2 H), 4.15 (m, 2 H), 7.86 (d, J
= 8.4 Hz, 2 H) ppm. 13C NMR (75 MHz, [D5]): δ = 20.1, 25.5,
26.2, 28.2, 33.5, 33.6, 48.3, 52.2, 54.8, 62.3, 173.0, 173.4 ppm. IR
(film): ν = 2950–2900, 2858, 1741, 1658, 1642, 1529, 1200 cm–1.
˜
HRMS (TOF MS ES+): calcd. for C22H38N3O4 [M + H]+
408.2856; found 408.2863.
(R,S)-2,6-Bis(cyclohexylcarbamoyl)piperidin-1-yl-acetic Acid (12):
To a solution of 11 (98 mg, 0.24 mmol) in MeOH (3 mL) was added
a solution of KOH (4 m in H2O, 3 mL), and the reaction mixture
was stirred for 12 h at room temperature. The solution was then
diluted with H2O (10 mL), neutralized with 1 m aqueous HCl solu-
tion, and extracted with CH2Cl2 (4ϫ 4 mL). The combined organic
extracts were then dried with MgSO4, filtered, and concentrated
under reduced pressure to afford compound 12 (79 mg, 84%) as a
white amorphous solid. 1H NMR (300 MHz, [D5]pyridine): δ =
1.05 (m, 2 H), 1.18–1.45 (10 H), 1.52–1.70 (4 H), 1.78 (m, 2 H),
1.84–2.04 (8 H), 3.80 (d, J = 17.4 Hz, 1 H), 3.92 (d, J = 17.4 Hz,
1 H), 4.04 (m, 2 H), 4.20 (m, 2 H), 7.14 (br. s, 1 H), 8.09 (d, J =
7.2 Hz, 2 H) ppm. 13C NMR (75 MHz, [D5]pyridine): δ = 20.5,
25.4, 26.2, 27.6, 33.5, 33.6, 48.3, 55.3, 62.4, 173.2, 175.5 ppm. IR
[5] For a recent review on the reactions of isocyanides with imin-
ium ions beyond the Ugi reaction, see: L. El Kaim, L. Gri-
maud, Tetrahedron 2009, 65, 2153–2171.
[6] Glutaraldehyde was recently used as a lysine surrogate in bio-
mimetic synthesis (in theory it could arise from oxidative deam-
ination of aminopentanal). See for example: a) L.-H. Yan, F.
Dagorn, E. Gravel, B. Séon-Méniel, E. Poupon, Tetrahedron
2012, 68, 6276–6283; b) R. Salame, E. Gravel, P. Retailleau, E.
Poupon, Org. Bioorg. Chem. 2010, 8, 2522–2528 and references
cited therein.
[7] For examples of isocyanide additions to pyridinium salts and
dihydropyridines, see: a) N. A. O. Williams, C. Masdeu, J. L.
Díaz, R. Lavilla, Org. Lett. 2006, 8, 5789–5792; b) C. Masdeu,
E. Gómez, N. A. Williams, R. Lavilla, QSAR Comb. Sci. 2006,
25, 465–473; c) C. Masdeu, E. Gómez, N. A. O. Williams, R.
Lavilla, Angew. Chem. 2007, 119, 3103; Angew. Chem. Int. Ed.
2007, 46, 3043–3046.
[8] Cascade reactions in total synthesis, selected review articles: a)
E. A. Anderson, Org. Biomol. Chem. 2011, 9, 3997–4006; b)
K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38, 2993–
3009; c) E. Poupon, E. Gravel, Eur. J. Org. Chem. 2008, 27–42;
d) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem.
2006, 118, 7292; Angew. Chem. Int. Ed. 2006, 45, 7134–7186.
[9] Multicomponent reactions in total synthesis, review article:
B. B. Touré, D. G. Hall, Chem. Rev. 2009, 109, 4439–4486.
Received: October 5, 2012
(film): ν = 2950–2900, 2857, 1643, 1642, 1527, 1451 cm–1. HRMS
˜
(TOF MS ES+): calcd. for C21H36N3O4 [M + H]+ 394.2700; found
394.2704.
(R,S)-[2,6-Bis(cyclohexylcarbamoyl)piperidin-1-yl-acetyl]-(2-phenyl-
ethyl)amine (13): To a solution of 12 (65 mg, 0.17 mmol) and 2-
phenylethylamine (20 mg, 0.17 mmol, 1 equiv.) in CH3CN (4 mL)
was added EDC hydrochloride (38 mg, 0.2 mmol, 1.2 equiv.),
HOBt (27 mg, 0.2 mmol, 1.2 equiv.), and triethylamine (89 μL,
0.66 mmol, 3.8 equiv.). After stirring for 12 h at room temperature,
the reaction mixture was extracted with CH2Cl2 (3ϫ 5 mL). The
Published Online: December 10, 2012
Eur. J. Org. Chem. 2013, 453–455
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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