Eight-step total synthesis of the cyclopeptide alkaloid mucronine E

Article abstract of DOI:10.1055/s-2007-1000833

An eight-step total synthesis of the 15-membered ring cyclopeptide alkaloid mucronine E is reported. Key steps include the formation of the highly substituted aromatic core using an asymmetric hydrogenation-Vilsmeier formylation sequence. Central to our approach was a macroamidation protocol using a copper-catalyzed coupling reaction to install the enamide with a concomitant straightforward macrocyclization. This synthesis also allowed for the assignment of both relative and absolute configurations of mucronine E. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000833

LETTER
29
Eight-Step Total Synthesis of the Cyclopeptide Alkaloid Mucronine E
Synthesis of the
Cyclo
a
A
lk
t
aloid M
h
ucronine
E
ieu Toumi, François Couty, Gwilherm Evano*
Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles Saint Quentin en Yvelines,
45 Avenue des Etats-Unis, 78035 Versailles Cedex, France
Fax +33(1)39254452; E-mail: evano@chimie.uvsq.fr
Received 24 July 2007
Cyclopeptide alkaloids are usually present as complex
mixtures isolated from various parts of the plant. Yields
from dried plants vary from 0.0002–1% depending on the
plant source, location, method of isolation, and the plant
Abstract: An eight-step total synthesis of the 15-membered ring
cyclopeptide alkaloid mucronine E is reported. Key steps include
the formation of the highly substituted aromatic core using an asym-
metric hydrogenation–Vilsmeier formylation sequence. Central to
our approach was a macroamidation protocol using a copper-cata- maturity. Therefore, the biological profile of this class of
lyzed coupling reaction to install the enamide with a concomitant
natural products is not well defined. Some cyclopeptides
straightforward macrocyclization. This synthesis also allowed for
have been reported to show activity against Gram-positive
the assignment of both relative and absolute configurations of mu-
bacteria and some fungi,3 others have been found to inhib-
cronine E.
it energy transfer in plants by interrupting photophospho-
rylation.4 Frangulanine, a 14-membered cyclopeptide, has
Key words: alkaloids, copper-catalysis, macrocycles, peptides, to-
tal synthesis
exhibited selective ionophoric properties5 and sanjoinine,
a cyclopeptide isolated from the seeds of a plant used in
Chinese medicine for the treatment of insomnia,6 as well
as paliurines7 have been recently reported to display sed-
ative or hypnotic properties. Recent studies report anti-
plasmodial properties for ziziphines.8 However, the
limited supplies of cyclopeptide alkaloids have not been
sufficient for extensive pharmacological investigations of
this class of compounds, and the lack of an efficient syn-
thetic strategy has limited structure–activity relationship
studies.
Cyclopeptide alkaloids are a group of closely related
polyamide bases of plant origin. Although they were men-
tioned in the literature as early as 1884,1 the isolation and
structural elucidation of pandamine in 19662 marks the
beginning of a growing interest in these natural products
which nowadays encompass over 200 compounds. Struc-
turally speaking, they possess a 13-, 14-, or 15-membered
cycle containing a peptide unit connected to an aromatic
ring in either a 1,4- or a 1,3-orientation by enamide and
alkyl-aryl ether (or methylene) linkages (Figure 1).3
Their biological properties together with their intriguing
structures have caused a steady stream of studies directed
toward synthesis of these natural products during the past
decades. These studies have revealed that the synthetic
challenges for these targets include formation of the
strained macrocycles and introduction of their enamide
unit. The initial report by Schmidt utilized the macrolac-
tamization of a pentafluorophenyl ester,9 which was later
on used in the total syntheses of Joullié10 and Han,11 while
Zhu’s synthesis incorporated an intramolecular SNAr re-
action as macrocyclization protocol.12 However, all these
protocols chose elaboration of the enamide moiety via dif-
ferent stepwise elimination methods after macrocycliza-
tion, which somehow decreased the overall synthetic
efficiency. Recently, we have developed an alternative
cyclization strategy based on an intramolecular amidation
reaction and have successfully implemented it in efficient
asymmetric syntheses of paliurine F13 and abyssenine
A.14,15 We now report on the extension of this synthetic
route to a straightforward total synthesis of mucronine E
(3), a 15-membered cyclopeptide alkaloid whose stereo-
chemistry is still unknown, even though this macrocycle
was isolated 30 years ago from Zizyphus mucronata
Willd.16 We assumed that the configuration of its four ste-
reocenters was S,S,S,S as depicted in Figure 1, since the
same stereochemistry was assigned for mucronine B, a
O
O
O
NH
HN
HN
O
OMe
NH
O
O
O
N
N
HN
frangulanine (2)
(14-membered ring)
O
O
HN
MeO
OMe
N
HN
O
NH
O
NH
paliurine F (1)
(13-membered ring)
O
NH
mucronine E (3)
(15-membered ring)
Figure 1 Representative cyclopeptide alkaloids
SYNLETT 2008, No. 1, pp 0029–0032
x
x.
x
x.
2
0
0
7
Advanced online publication: 11.12.2007
DOI: 10.1055/s-2007-1000833; Art ID: D22807ST
© Georg Thieme Verlag Stuttgart · New York

30
M. Toumi et al.
LETTER
O
structurally related cyclopeptide alkaloid isolated from
the same plant, through total synthesis.9c
(MeO)2P
MeO
O
OMe
MeO
OMe
MeO2C NHBoc
Our strategy for the synthesis of mucronine E (3) is out-
lined in Scheme 1. Facile generation of the fully elaborat-
ed macrocyclic core relies on a challenging copper-
mediated intramolecular amidation reaction using amido-
vinyl iodide 4 as the enamide precursor. The synthesis of
this acyclic intermediate 4 would then just require an effi-
cient preparation of the highly functionalized, suitably
protected, amino acid 5. The presence of an aldehyde moi-
ety in 5 would finally allow for the installation of the Z-
vinyl iodide after coupling of fragments 5 and 6.
8
N,N,N',N'-tetramethyl-
guanidine, CH2Cl2
r.t., 89%
MeO2C
NHBoc
9
7
{Ph(cod)[(S,S)-Et-DuPHOS]}+TfO–
H2 (5 atm)
MeOH, 25 °C
95%, >95% ee
MeO
OMe
MeO
OMe
NaH, MeI, DMF
r.t., quant.
MeO
OMe
MeO
OMe
I
Boc
Boc
N
CO2Me
11
BocHN
CO2Me
10
HN
N
O
O
NH
O
NH
NH
NH2
O
O
POCl3, DMF
60 °C, then
3 M NaOH
r.t., 68%
NH
NH
O
4
mucronine E (3)
MeO
OMe
O
O
MeO
N
OMe
O
O
H2N
Boc
NH
N
CO2H
NH2
+
5
Boc
CO2H
Scheme 2 Asymmetric synthesis of the aminoacid fragment 5
6
5
the amide group required for the macrocyclization step af-
ter introduction of the other two constitutive amino acids
of the macrocycle, a direct peptide bond formation be-
tween 5 and isoleucine-leucinamide 614 was envisioned.
Therefore, condensation of the acid 5 with dipeptide 6 was
conducted under the action of BOP to provide tripeptide
12 without any noticeable epimerization (Scheme 3). Fi-
nally, and to install the Z-vinyl iodide required for the fi-
nal macroamidation step, aldehyde 12 was treated with
Stork–Zhao reagent20 and gave the fully elaborated acy-
clic skeleton 4 in moderate yield but with complete dia-
stereoselectivity.
Scheme 1 Retrosynthetic analysis of mucronine E
Compared to our synthesis of abyssenine A,14 the pres-
ence of two methoxy groups on the aromatic core of mu-
cronine E allowed for the design of an especially
straightforward preparation of its aminoacid fragment 5
(Scheme 2).
This synthesis started from commercially available 2,4-
dimethoxybenzaldehyde (7). In order to install the amino
acid group of the target fragment, 7 was first reacted with
phosphonate 817 and gave the (Z)-dimethoxydehydrophe-
nylalanine derivative 9. Catalytic asymmetric hydrogena-
tion of 9 then proceeded smoothly in the presence of
{Rh(cod)[(S,S)-Et-DuPHOS]}+TfO–18 to afford the corre-
sponding amino ester 10 with excellent yield and enanti-
oselectivity (95%, >95% ee) and the exocyclic N-methyl
group of mucronine E was next installed by methylation
of 10 using Benoiton’s racemization-free conditions.19
Vilsmeier formylation of 11 was then carried out using
POCl3 and DMF at 60 °C followed by in situ hydrolysis of
the intermediate chloroamine with sodium hydroxide
which proceeded with concomitant cleavage of the methyl
ester to give 5, therefore saving us an additional saponifi-
cation step (Scheme 2).
This set the stage for the crucial macrocyclization
step:13,14 Subjection of iodoamide 4 to catalytic copper(I)
iodide and N,N¢-dimethylethylenediamine21 in THF under
high dilution conditions at 63 °C smoothly provided the
15-membered ring 13 in 84% yield (Scheme 4). The most
striking feature of this approach is that this mild intramo-
lecular amidation protocol proceeds with complete regi-
oselectivity for the terminal amide, without any
epimerization at the three amino acid stereocenters or
isomerization of the Z-vinyl iodide and without dimeriza-
tion or formation of higher oligomers. Finally, careful re-
moval of the Boc group using TMSOTf and 2,6-lutidine
provided synthetic mucronine E (3) which was identical in
all respects {Mp, NMR [a]D20, IR, UV, and MS} to the
natural product,16,22 therefore establishing both its relative
and absolute configurations.23
Having in hand useful quantities of the amino acid frag-
ment 5, the assembly of the acyclic skeleton of mucronine
E was next undertaken. To avoid a stepwise installation of
Synlett 2008, No. 1, 29–32 © Thieme Stuttgart · New York

LETTER
Synthesis of the Cyclopeptide Alkaloid Mucronine E
31
MeO
OMe
O
This new strategy clearly renders the elaboration of this
class of natural products much easier than previously and
should therefore facilitate the synthesis of analogues for
their further pharmacological evaluation and structure–
activity studies.
BOP, DIPEA, DMF
then Ile-Leu-NH2 (6)
0 °C to r.t., 47%
Boc
N
CO2H
5
MeO
OMe
O
Acknowledgment
Boc
N
The authors thank the CNRS for financial support. M.T. acknow-
ledges the Ministère de la Recherche for a graduate fellowship.
(Ph3P+CH2I)I–
O
NaHMDS
THF, HMPA
NH
NH2
O
–78 °C, 50%, >95% de
NH
References and Notes
O
(1) Clinch, J. H. M. Am. J. Pharm. 1884, 56, 131.
(2) Pais, M.; Jarreau, F. X.; Lusinchi, X.; Goutarel, R. Ann.
Chim. (Paris) 1966, 14, 83.
12
MeO
OMe
I
(3) For reviews, see: (a) Gournelif, D. C.; Laskaris, G. G.;
Verpoorte, R. Nat. Prod. Rep. 1997, 14, 75. (b) Joullié, M.
M.; Richard, D. J. Chem. Commun. 2004, 2011. (c) Tan, N.
H.; Zhou, J. Chem. Rev. 2006, 106, 840. (d) El-Seedi, H. R.;
Zahra, M. H.; Goransson, U.; Verpoorte, R. Phytochem. Rev.
2007, 6, 143.
Boc
N
O
NH
NH2
O
NH
O
(4) Ravizzini, R. A.; Andreo, C. S.; Vallejos, R. H. Plant Cell
Physiol. 1977, 18, 701.
4
(5) Kawai, K.; Nozawa, Y.; Ogihara, Y. Experientia 1977, 33,
1454.
Scheme 3 Synthesis of the acyclic skeleton
(6) Han, B. H.; Park, M. H.; Park, J. H. Pure Appl. Chem. 1989,
61, 443.
(7) Lee, S. S.; Su, W. C.; Liu, K. C. S. C. Phytochemistry 2001,
58, 1271.
(8) Suksamrarn, S.; Suwannapoch, N.; Aunchai, N.; Kuno, M.;
Ratananukul, P.; Haritakun, R.; Jansakul, C.; Ruchirawat, S.
Tetrahedron 2005, 61, 1175.
MeO
OMe
I
H
N
CuI,
Boc
N
H
N
O
Cs2CO3, THF
63 °C, 84%
NH
NH2
O
NH
(9) (a) Schmidt, U.; Lieberknecht, A.; Bökens, H.; Griesser, H.
J. Org. Chem. 1983, 48, 2680. (b) Schmidt, U.;
Schanbacher, U. Angew. Chem., Int. Ed. Engl. 1983, 22,
152. (c) Schmidt, U.; Schanbacher, U. Liebigs Ann. Chem.
1984, 1205. (d) Schmidt, U.; Zäh, M.; Lieberknecht, A.
J. Chem. Soc., Chem. Commun. 1991, 1002.
(10) (a) Heffner, R. J.; Jiang, J.; Joullié, M. M. J. Am. Chem. Soc.
1992, 114, 10181. (b) Xiao, D.; East, S. P.; Joullié, M. M.
Tetrahedron Lett. 1998, 39, 9631. (c) East, S. P.; Shao, F.;
Williams, L.; Joullié, M. M. Tetrahedron 1998, 54, 13371.
(11) Han, B. H.; Kim, Y. C.; Park, M. K.; Park, J. H.; Go, H. J.;
Yang, H. O.; Suh, D. Y.; Kang, Y. H. Heterocycles 1995, 41,
1909.
O
4
MeO
OMe
NH
TMSOTf
2,6-lutidine
Boc
N
O
NH
O
CH2Cl2
O
–20 °C to 0 °C, 92%
NH
13
MeO
OMe
(12) (a) Laïb, T.; Zhu, J. Tetrahedron Lett. 1999, 40, 83.
(b) Laïb, T.; Bois-Choussy, M.; Zhu, J. Tetrahedron Lett.
2000, 41, 7645. (c) Temal-Laïb, T.; Chastanet, J.; Zhu, J.
J. Am. Chem. Soc. 2002, 124, 583. (d) Cristau, P.; Temal-
Laïb, T.; Bois-Choussy, M.; Martin, M. T.; Vors, J. P.; Zhu,
J. Chem. Eur. J. 2005, 11, 2668.
HN
O
NH
NH
O
NH
O
(13) Toumi, M.; Couty, F.; Evano, G. Angew. Chem. Int. Ed.
mucronine E (3)
2007, 46, 572.
(14) Toumi, M.; Couty, F.; Evano, G. J. Org. Chem. 2007, 72,
9003.
Scheme 4 Completion of the synthesis of mucronine E
(15) An intermolecular copper-mediated amidation reaction–
macrolactamization strategy was reported by Ma for the
synthesis of ziziphine N: He, G.; Wang, J.; Ma, D. Org. Lett.
2007, 9, 1367.
(16) Tschesche, R.; David, S. T.; Zerbes, R.; von Radloff, M.;
Kaußmann, E. U.; Eckhardt, G. Justus Liebigs Ann. Chem.
1974, 1915.
In summary, we have developed an efficient and straight-
forward total synthesis of mucronine E, which imple-
ments the general and unified route to cyclopeptide we
designed. Mucronine E could be obtained in only eight
steps and 10% overall yield from commercially available
starting materials. The key step of our synthesis relies on
installation of enamide concomitant with macrocycliza-
tion using a copper-mediated macroamidation reaction.
(17) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53.
(18) Burk, M. J. Acc. Chem. Res. 2000, 33, 363.
Synlett 2008, No. 1, 29–32 © Thieme Stuttgart · New York

32
M. Toumi et al.
LETTER
(19) Coggins, J. R.; Benoiton, N. L. Can. J. Chem. 1971, 49,
1968.
(20) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
(21) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett.
2003, 5, 3667.
3 H), 2.21 (br s, 1 H), 1.92–2.04 (m, 1 H), 1.69–1.80 (m, 2
H), 1.51 (dqd, J = 13.5, 7.5, 3.3 Hz, 1 H), 1.13 (dqd,
J = 13.5, 7.5, 7.5 Hz, 1 H), 1.00 (d, J = 6.3 Hz, 3 H), 0.94 (d,
J = 6.3 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H), 0.84 (t, J = 7.4
Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 172.3, 169.9,
157.4, 157.2, 130.1, 120.2, 117.6, 116.5, 104.7, 95.9, 66.5,
65.7, 55.9, 52.4, 41.2, 36.5, 33.5, 31.1, 25.9, 25.1, 23.5, 21.1,
15.4, 9.7.
(22) Selected Data for (–)-Mucronine E (3)
Mp 230 °C; [a]D20 –87 (c 0.4, MeOH). 1H NMR (300 MHz,
CDCl3): d = 9.39 (d, J = 7.2 Hz, 1 H), 8.42 (d, J = 11.4 Hz,
1 H), 8.14 (d, J = 6.4 Hz, 1 H), 7.03 (s, 1 H), 6.86 (dd,
J = 11.4, 9.7 Hz, 1 H), 6.47 (s, 1 H), 5.78 (d, J = 9.7 Hz, 1
H), 4.48 (ddd, J = 11.2, 8.0, 3.7 Hz, 1 H), 3.88 (s, 3 H), 3.83
(s, 3 H), 3.35 (dd, J = 13.7, 5.8 Hz, 1 H), 3.22–3.30 (m, 2 H),
2.98 (dd, J = 13.7, 2.2 Hz, 1 H), 2.45–2.56 (m, 1 H), 2.47 (s,
(23) After submission of this manuscript, Ma and co-workers
reported the synthesis of mucronine E using an inter-
molecular copper-catalyzed amidation. See: Wang, J.;
Schaeffer, L.; He, G.; Ma, D. Tetrahedron Lett. 2007, 48,
6717.
Synlett 2008, No. 1, 29–32 © Thieme Stuttgart · New York

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