Biomimetic assembly of leucoridine A

Article abstract of DOI:10.1002/ejoc.201500041

The three-step biomimetic assembly of leucoridine A, a pseudosymmetric bisindole of Leuconotis griffithi (Apocynaceae) is described. The semisynthetic route provides suitable conditions toward the central 3-spiro-1,2,3,4-tetrahydropiperidine ring connecting the two subunits of the highly congested structure. The biomimetic assembly by a Diels-Alder or alternatively an imino-Rauhut-Currier reaction affords the natural (S)-diastereomer of leucoridine A as the sole product. The sequence, repeated in a one-pot cascade, supports a non-enzymatic pathway for the assembly of this bisindole and the known related alkaloids. The biomimetic cascade assembly of leucoridine A, a pseudosymmetric bisindole of Leuconotis griffithi (Apocynaceae) is described. The semisynthetic route provides suitable conditions toward the central 3-spiro-1,2,3,4-tetrahydropiperidine ring connecting the two subunits of the highly congested structure. The biomimetic assembly by an imino-Rauhut-Currier reaction affords the natural (S)-diastereomer of leucoridine A as the sole product.

Full text of DOI:10.1002/ejoc.201500041

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500041
Biomimetic Assembly of Leucoridine A
Sarah Benayad,[a] Mehdi A. Beniddir,[a] Laurent Evanno,*[a] and Erwan Poupon*[a]
Dedicated to Professor Guy Lewin on the occasion of his retirement
Keywords: Alkaloids / Bisindole / Leucoridine / Biomimetic synthesis / Rauhut–Currier
The three-step biomimetic assembly of leucoridine A, a
pseudosymmetric bisindole of Leuconotis griffithi (Apo-
cynaceae) is described. The semisynthetic route provides
suitable conditions toward the central 3-spiro-1,2,3,4-tetra-
hydropiperidine ring connecting the two subunits of the
highly congested structure. The biomimetic assembly by a
Diels–Alder or alternatively an imino-Rauhut–Currier reac-
tion affords the natural (S)-diastereomer of leucoridine A as
the sole product. The sequence, repeated in a one-pot
cascade, supports a non-enzymatic pathway for the assembly
of this bisindole and the known related alkaloids.
indole unit. In a second step, the spiranic C-16/C-17Ј
connection would be formed by an intramolecular addition
of the intermediary enamine onto the second Michael
acceptor. This unique anchorage pathway (and especially
the possible implication of a biosynthetic imino-Rauhut–
Currier reaction) prompted us to chemically investigate
such a cascade of reactions that could eventually support
the biosynthetic scheme.
Introduction
Leucoridine A (1) is a complex bisindole alkaloid iso-
lated in 2010 from Leuconotis griffithii (Apocynaceae) that
shows moderate cytotoxicity towards human KB cells (IC50
1 μm).[1] Two identical strychnan units connected through a
central 3-spiro-1,2,3,4-tetrahydropyridine ring is at the ori-
gin of the pseudosymmetric structure of leucoridine A (1,
Figure 1). Related bisaspidospermatan leucofoline (2)[2] and
bisaspidosperman anhydrohazuntiphyllidine (3)[3] are
among the sole other structures that contain such a tetra-
hydropyridine ring as the linking pattern between two
monoterpene indole units.[4] In terms of biosynthesis, the
assembly of the bisindole structure of leucoridine A (1) and
related alkaloids would originate from two identical mono-
mers (Scheme 1).[5] In fact, when focusing on leucoridine A
(1), monomeric strychnan-type geissoschizoline (4) could be
at the origin of 1. Oxidation of 4 into 1,2-dehydro-
geissoschizoline (5, also known as a naturally occurring
structure)[6] may in turn dehydrate to afford hypothetical 6
(formally corresponding to 19,20-dihydrovalparicine).[7]
From that point, two plausible pathways are then likely to
occur to explain the assembly of 1: an aza-Diels Alder reac-
tion or a stepwise imino-Rauhut–Currier type reaction. In
this latter scenario, the first C-17/N-1Ј connection would be
formed by the addition of the nitrogen N-1Ј of the first
unit onto the Michael acceptor of the second monoterpene
[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
E-mail: laurent.evanno@u-psud.fr
erwan.poupon@u-psud.fr
http://www.biocis.u-psud.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500041.
Figure 1. Structure of leucoridine A (1) and related alkaloids.
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S. Benayad, M. A. Beniddir, L. Evanno, E. Poupon
SHORT COMMUNICATION
lytic amount of trifluoroacetic acid (TFA) afforded 19,20-
dihydrovalparicine (6)[10] alongside
of 1.
a minute amount
Scheme 1. Plausible biosynthetic scenarios towards leucoridine A
(1) from known natural substances.
Scheme 2. Biomimetic assembly of leucoridine A (1). Reaction con-
ditions: (a) HCl (aq. 2 m), room temp., 30 min, (4: 74%, 8: 77%);
(b) MnO2 (20 equiv.), CHCl3, room temp., 18 h (5: 60%, 9: 15%);
(c) TFA (0.05 equiv.), CH2Cl2, 0 °C, 30 min (65%); (d) toluene, re-
flux, 3 d; (e) TFA (0.08 equiv.), CH2Cl2, 0 °C, 2 h (32%); (f) MnO2
(20 equiv.), TFA (0.08 equiv.), CH2Cl2, 12 h (Ͼ90% conv. see also
Figure 3).
Results and Discussion
Isolated from Geissospermum laeve, the bisindole
Besides the ionic pathway, an alternative aza-Diels–Alder
geissolosimine (7) was selected as a convenient starting ma- cycloaddition[12,13] could also be considered to explain the
terial for a semisynthetic route, since its geissoschizoline (4) formation of the bisindole framework. This scenario was
subunit corresponds to the constitutive strychnan monomer partially set aside by a control experiment.[14] When com-
of 1 (Scheme 2).[8,9] In the laboratory’s collections of natural pound 6 was refluxed in toluene for three days, no forma-
products, we were in possession of a sample of geissolosim- tion of 1 was detected by HPLC analysis and starting mate-
ine from the late 1950s original work of Maurice–Marie rial 6 was recovered unchanged. In accordance with the
Janot, and the complete structural analysis confirmed the stated hypothesis of biosynthesis, the central 3-spiro-
identity of the sample. Hydrolysis of the hemi-aminal func- 1,2,3,4-tetrahydropyridine ring of 1 was readily formed in
tion of the bisindole 7 in an aqueous 2 m HCl solution pro- the presence of a catalytic amount of TFA in dichlorometh-
vided vellosimine (8) in addition to desired geissoschizoline ane. After two hours of stirring, the reaction went to com-
(4). Starting from geissoschizoline (4), a two-step sequence pletion and 1 was assembled as a single diastereomer by a
installed the Michael acceptor 6 necessary for the assembly plausible imino-Rauhut–Currier reaction (Scheme 2). Un-
of 1. The indoline 4 was first oxidized by manganese(IV) fortunately, the bisindole framework partially decomposed
oxide giving idolenine 5[10] together with the C-10-oxidative during flash chromatography attempts on silica gel. A fast
adduct 9 as a minor product.[11] Then, treatment by a cata- preparative-HPLC purification of the crude reaction mix-
2
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Biomimetic Assembly of Leucoridine A
ture was needed to afford 1 with a 32% isolated yield.[15]
The absolute configuration of the central linkage of the
molecule was assigned by 2D NOESY NMR analysis as
shown in Figure 2. In the central 3-spiro-1,2,3,4-tetra-
hydropyridine ring, correlations between H-17a/H-12Ј and
H-19 and H-17b/H-6Јa indicated that they were all cofa-
cial.[16] Furthermore, the H-17Јa/H-14b correlation reflects
the spatial organization of the other face of the molecule.
The absolute configuration of the C-16 spiranic carbon was
consequently assigned 16S and identical to that of the natu-
ral product.[1]
Figure 3. Assembly of leucoridine (1) from 4; LC/MS chromato-
grams after 2 h (A) and 12 h (B).
Conclusions
In this work, we provide optimized experimental condi-
tions for the assembly of the central 3-spiro-1,2,3,4-tetra-
hydropyridine linking pattern of leucoridine A (1), support-
ing, thereby, an imino-Rauhut–Currier scenario instead of
an aza-Diels–Alder process. The step-by-step procedure
gave evidence for the biosynthetic route from geissoschiz-
oline (4) and the unprecedented one-pot procedure reflects
the high degree of spontaneity of its biosynthesis. The for-
mation of the bisindole as the sole diastereomer shows that
chiral induction is under full substrate control and sup-
ports, thereby, a non-enzymatic pathway.
Figure 2. Key NOESY correlations of synthetic leucoridine A (1).
Formation of a single diastereomer indicates that chiral
induction is under full substrate control revealing a non-
compulsory enzymatic pathway for the biosynthesis of the
highly congested structure of 1. Given the efficiency of the
assembly step, we investigated the process by repeating the
sequence in a two-step and then a one-pot protocol to fully
exploit the high degree of spontaneity of the reaction. As
Experimental Section
Oxidation of Geissoschizoline (4): Manganese(IV) oxide (210 mg,
the dehydration of dehydrogeissoschizoline (5) and the bio- 2.41 mmol) was added to a solution of geissoschizoline (4; 70 mg,
0.24 mmol) in chloroform (10 mL). After 18 h of stirring, the reac-
tion mixture was filtered and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (dichlorometh-
ane/methanol: 94:6) afforded 1,2-dehydrogeissoschizoline (5;
43 mg; 60%) and compound 9 (11 mg; 15%).
mimetic assembly were performed in the same acidic condi-
tions, compound 5 was stirred for 10 h in the presence of
TFA in dichloromethane. Under these conditions we ob-
served the formation of 1, again the adduct partially de-
composed during purification. To explore the spontaneous
assembly of the two strychnan units, geissoschizoline (4)
was engaged in a one-pot procedure in the presence of man-
ganese(IV) oxide and TFA. After 2 h, as shown in Figure 3-
A, geissoschizoline (4) was completely oxidized into de-
hydrogeissoschizoline (5), and 1 was formed as the main
product with 19,20-dihydrovalparicine (6) present only as
a minor product. After 12 supplementary hours, LC/MS
analysis showed that the one-pot procedure went to com-
pletion (Figure 3-B).
1,2-Dehydro-curan-17-ol
–
1,2-Dehydrogeissoschizoline (5): 1H
NMR (300 MHz, [D]chloroform): δ = 7.56 (dd, J = 7.5, 0.9 Hz, 1
H), 7.33 (dd, J = 7.5, 0.9 Hz, 1 H), 7.31 (td, J = 7.5, 0.9 Hz, 1 H),
7.24 (td, J = 7.5, 0.9 Hz, 1 H), 3.94 (dd, J = 11.2, 4.2 Hz, 1 H),
3.88 (dd, J = 11.2, 7.3 Hz, 1 H), 3.80 (m, 1 H), 3.29 (td, J = 12.0,
5.8 Hz, 1 H), 3.26–3.17 (m, 2 H), 2.91 (m, 1 H), 2.80 (ddd, J =
13.7, 11.8, 6.9 Hz, 1 H), 2.51 (t, J = 12.1 Hz, 1 H), 1.98 (br. s, 1
H), 1.95 (dd, J = 13.7, 6.0 Hz, 1 H), 1.79 (m, 1 H), 1.68 (ddd, J =
13.8, 3.6, 2.3 Hz, 1 H), 1.39 (m, 2 H), 1.11 (ddd, J = 13.8, 4.4,
2.3 Hz, 1 H), 1.01 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz,
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S. Benayad, M. A. Beniddir, L. Evanno, E. Poupon
SHORT COMMUNICATION
[D]chloroform): δ = 193.0, 153.4, 144.36, 127.8, 125.7, 120.9, 120.0,
1.56 (m, 2 H), 1.37 (dt, J = 14.4, 3.1 Hz, 1 H), 1.03 (q, J = 7.4 Hz,
6 H) ppm. 13C NMR (75 MHz, [D]chloroform): δ = 187.0, 153.2,
149.5, 147.2, 145.7, 133.9, 128.4, 128.4, 126.8, 121.7, 120.9, 120.4,
120.3, 110.6, 109.7, 68.1, 64.3, 60.8, 57.0, 52.6, 51.9, 50.5, 49.8,
49.3, 47.8, 46.1, 44.0, 41.7, 38.2, 37.5, 34.2, 32.5, 30.0, 29.7, 27.4,
69.9, 66.0, 64.5, 57.4, 51.4, 41.6, 38.2, 35.9, 33.4, 28.6, 24.6, 11.5
ppm. IR (neat): ν = 3384, 1741, 1609, 1556, 1454 cm–1. HRMS
˜
(ESI): calcd for C19H25N2O+ [M + H]+ 297.1967; found 297.1965.
[α]D = –44 (c = 0.6, CHCl3).
24.8, 12.9, 11.6 ppm. IR (neat): ν = 3384, 1741, 1609, 1556,
˜
10-(Curan-17-yloxy)-1,2-dehydrocuran-ol (9): 1H NMR (400 MHz,
[D]chloroform): δ = 7.46 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 2.3 Hz,
1 H), 7.18 (td, J = 7.5, 1.4 Hz, 1 H), 7.14–7.07 (m, 2 H), 6.99 (d,
J = 7.9 Hz, 1 H), 6.90 (td, J = 7.5, 1.0 Hz, 1 H), 4.05 (d, J = 8.1 Hz,
1 H), 4.00–3.82 (m, 3 H), 3.70 (d, J = 3.3 Hz, 1 H), 3.65 (dd, J =
11.2, 5.7 Hz, 1 H), 3.58–3.50 (m, 2 H), 3.24–3.10 (m, 4 H), 3.00
(ddd, J = 12.6, 9.0, 3.4 Hz, 1 H), 2.86 (m, 1 H), 2.80 (m, 1 H), 2.61
(q, J = 7.8 Hz, 1 H), 2.48–2.32 (m, 3 H), 2.24 (s, 1 H), 2.15–2.00
(m, 2 H), 2.00–1.90 (m, 3 H), 1.73 (m, 1 H), 1.63 (d, J = 14.2 Hz,
1 H), 1.46–1.29 (m, 4 H), 1.06 (d, J = 14.2 Hz, 2 H), 1.1–1.0 (m, 6
H) ppm. 13C NMR (101 MHz, [D]chloroform): δ = 191.0, 148.5,
146.1, 145.8, 143.0, 134.4, 129.1, 121.9, 121.6, 121.0, 116.5, 111.3,
109.8, 74.9, 70.0, 66.2, 64.6, 61.5, 61.3, 57.4, 54.6, 53.2, 52.0, 51.5,
41.5, 41.1, 40.9, 39.6, 38.2, 36.0, 34.0, 28.7, 27.3, 24.9, 24.7, 22.1,
1454 cm–1. HRMS (ESI): calcd for C38H45N4+ [M + H]+ 557.3644;
found 557.3647. [α]D = –47 (c = 0.4, CHCl3).
Acknowledgments
Karine Leblanc is gratefully acknowledged for HPLC analysis.
Claire Troufflard and Jean-Christophe Julian are gratefully ac-
knowledged for NMR spectroscopy assistance.
[1] a) C. Y. Gan, T. Etoh, M. Hayashi, K. Komiyama, T. S. Kam,
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11.5, 11.2 ppm. IR (neat): ν = 2961–2874, 1617, 1484, 1460 cm–1.
˜
+
HRMS (ESI): calcd for C38H49N4O2 [M + H]+ 593.3856; found
593.3853. [α]D = –83 (c = 0.06, CH3OH).
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hazuntiphyllidine is co-isolated with hazuntiphyllidine, which
bears a supplementary oxygenation of the central 3-spiro-
1,2,3,4-tetrahydropyridine ring.
1,2-Dehydro-curan-16-ene – 19,20-Dihydrovalparicine (6): A 0.25 m
solution of TFA in dichloromethane (38 μL, 0.001 mmol) was
added to a solution of 1,2-dehydrogeissoschizoline (5; 36 mg,
0.21 mmol) in dichloromethane (8 mL). After 30 min of stirring at
0 °C, the reaction mixture was quenched by addition of triethyl-
amine (50 μL) and diluted with ethyl acetate (40 mL). The organic
extract was washed with water (30 mL), dried with MgSO4, filtered
and concentrated under reduced pressure. Purification by flash
chromatography on silica gel (dichloromethane/methanol: 96:4) af-
forded 19,20-dihydrovalparicine (6; 23 mg; 65%). 1H NMR
(300 MHz, [D]chloroform): δ = 7.62 (dd, J = 7.5, 0.9 Hz, 1 H), 7.36
(m, 2 H), 7.22 (td, J = 7.5, 0.9 Hz, 1 H), 6.01 (s, 1 H), 5.23 (t, J =
1.4 Hz, 1 H), 3.91 (s, 1 H), 3.65 (m, 1 H), 3.23 (m, 1 H), 3.18 (m,
1 H), 3.02 (ddd, J = 11.6, 4.5 Hz, 1 H), 2.88 (m, 2 H), 2.51 (t, J =
12.1 Hz, 1 H), 1.90 (m, 2 H), 1.57 (m, 1 H), 1.40 (m, 2 H), 1.01 (t,
J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, [D]chloroform): δ =
188.5, 154.1, 145.4, 142.3, 127.8, 125.4, 120.0, 120.0, 117.1, 67.2,
[4] Interestingly, in a very similar manner, vobtusine and related
bisindoles alkaloids also include tetrahydropyridine cycles, but
having undergone supplementary oxygenations. For related
structures see “The Bisindole Alkaloids”, section “Vobtusine
and Related Alkaloids”: G. A. Cordell in Chemistry of Hetero-
cyclic Compounds, Vol. 21, 4 (Eds.: J. E. Saxton), Wiley-VCH,
Weinheim, 1983, pp. 540–727.
66.0, 56.6, 51.3, 42.5, 36.7, 33.1, 28.4, 24.4, 11.4 ppm. IR (neat): ν
˜
= 2361, 1743, 1672 cm–1. HRMS (ESI): calcd for C19H23N2 [M +
+
H]+ 279.1861; found 279.1865. [α]D = –16 (c = 2.2, CH3OH).
(16S)-1,17-(1,2-Dehydro-curan-17,16-diyl)-curane-2(16)-ene – Leu-
coridine A (1): A 0.25 m solution of TFA in dichloromethane
(53 μL, 0.013 mmol) was added to a solution of 19,20-dihydroval-
paricine (6; 58 mg, 0.21 mmol) in dichloromethane (10 mL). After
2 h of stirring at 0 °C, the reaction mixture was quenched by ad-
dition of triethylamine (0.8 mL) and diluted with ethyl acetate
(35 mL). The organic extract was washed with water (20 mL), dried
with MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by preparative HPLC [7% to 20% MeCN in
H2O (0.2% HCOOH) over 20 min at 42 mL min–1, r.t. = 18.3 min;
see the general procedures in the Supporting Information] to afford
leucoridine A (1) as a dihydroformate salt (17 mg, 32%). 1H NMR
(400 MHz, [D]chloroform): δ = 7.37 (d, J = 7.3 Hz, 1 H), 7.35–
7.30 (m, 2 H), 7.26–7.21 (m, 2 H), 7.18 (t, J = 7.3 Hz, 2 H), 6.90
(t, J = 7.8 Hz, 1 H), 6.72 (d, J = 7.8 Hz, 1 H), 4.55 (dd, J = 10.3,
2.7 Hz, 1 H), 4.48 (s, 1 H), 4.00 (s, 1 H), 3.65 (dd, J = 11.8, 5.1 Hz,
1 H), 3.60–3.46 (m, 3 H), 3.37 (dd, J = 12.2, 6.4 Hz, 1 H), 3.10 (d,
J = 10.3 Hz, 1 H), 3.08–2.95 (m, 3 H), 2.89 (d, J = 16.0 Hz, 1 H),
2.56–2.46 (m, 2 H), 2.25 (dd, J = 14.3, 6.0 Hz, 1 H), 2.18 (m, 1 H),
2.15–2.04 (m, 4 H), 1.86–1.75 (m, 3 H), 1.74–1.61 (m, 1 H), 1.63–
[5] a) C. E. Aroyan, A. Dermenci, S. J. Miller, Tetrahedron 2009,
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4
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Biomimetic Assembly of Leucoridine A
[7] K. H. Lim, Y. Y. Low, T. S. Kam, Tetrahedron Lett. 2006, 47,
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[8] M. M. Janot, R. Goutarel, A. Le Hir, F. Puisieux, C. R. Hebd.
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[13]
[14]
For a recent example of a “biomimetic” Diels–Alder strategy
in total Synthesis see: J. Deng, S. Zhou, W. Zhang, J. Li, R. Li,
A. Li, J. Am. Chem. Soc. 2014, 136, 8185–8188 and references
cited therein.
The aza-Diels Alder scenario was not further investigated due
to a lack of starting material, it cannot at this stage be totally
ruled out. The lack of stability of 1 during silica gel purification
however provides elements for an alternative cationic pathway.
[11] For a plausible mechanism see the Supporting Information; a)
H. J. Teuber, O. Lahnstein, J. Prakt. Chem. 1995, 337, 456–467;
b) P. Magnus, A. H. Payne, L. Hobson, Tetrahedron Lett. 2000,
41, 2077–2081; c) T. Sunazuka, K. Yoshida, N. Kojima, T. Shir-
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[12] For examples of “biomimetic” aza-Diels Alder reactions in the
field of total Synthesis see: a) M. G. Memeo, P. Quadrelli,
Chem. Eur. J. 2012, 18, 12554–12582; b) R. Girling, T. Kiyoi,
A. Whiting, Org. Biomol. Chem. 2011, 9, 3105–3121; c) D.
Leca, F. Gaggini, J. Cassayre, O. Loiseleur, S. N. Pieniazek,
J. A. R. Luft, K. N. Houk, J. Org. Chem. 2007, 72, 4284–4287;
[15] Leucoridine A was obtained as the dihydroformate salt after
preparative HPLC.
[16] Letters “a” and “b” are arbitrarily given to the protons
pointing towards the front and towards the back of the plane
of leucoridine A (1), respectively, as represented on Figure 2.
Received: January 12, 2015
Published Online: ᭿
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SHORT COMMUNICATION
Biomimetic Synthesis
The biomimetic cascade assembly of leuco-
ridine A, a pseudosymmetric bisindole of
Leuconotis griffithi (Apocynaceae) is de-
scribed. The semisynthetic route provides
suitable conditions toward the central 3-
spiro-1,2,3,4-tetrahydropiperidine ring con-
necting the two subunits of the highly con-
gested structure. The biomimetic assembly
by an imino-Rauhut–Currier reaction af-
fords the natural (S)-diastereomer of leuco-
ridine A as the sole product.
S. Benayad, M. A. Beniddir, L. Evanno,*
E. Poupon* ....................................... 1–6
Biomimetic Assembly of Leucoridine A
Keywords: Alkaloids / Bisindole / Leucorid-
ine
/ Biomimetic synthesis / Rauhut–
Currier
6
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