Total synthesis of paliurine F

Article abstract of DOI:10.1002/anie.200602865

A couple of coppers: An efficient, asymmetric synthesis of the sedative cyclopeptide alkaloid paliurine F has been achieved. The strategy employs two copper(I)-mediated coupling reactions as key steps to install the aryl ether linkage as well as to form t

Full text of DOI:10.1002/anie.200602865

Communications
DOI: 10.1002/anie.200602865
Natural Products Synthesis
Total Synthesis of Paliurine F**
Mathieu Toumi, François Couty, and Gwilherm Evano*
Dedicated to Professor James S.Panek on the occasion of his 50th birthday
Cyclopeptide alkaloids are natural products that have been
isolated from the leaves, stem bark, root bark, and seeds of a
wide variety of plant species throughout the world. They are
distinguished by their structural similarity and possess a 13-
(1), 14- (2), or 15-membered (3) cycle containing an aromatic
ring. The remainder of the macrocycle consists of a peptide
unit that is connected to the aromatic ring in either a 1,4or
1,3 orientation with enamide and alkyl aryl ether (or meth-
ylene) linkages (Scheme 1). To date, over two hundred
of dried plants), prompted immediate interest from the
synthetic community. Thus, several strategies have been
used for the key macrocyclization step. The initial report by
Schmidt et al.[2] utilized the macrolactamization of a penta-
fluorophenyl ester, which was later used in total syntheses by
the research groups of JoulliØ[3] and Han.[4] The synthesis of
sanjoinine G1 and the mauritines by Zhu and co-workers
incorporated an intramolecular SNAr reaction as the macro-
cyclization protocol.[5] Examination of these syntheses, along
with the synthetic approaches to these alkaloids,[6–8] reveals
that the moderately complex chemical structure of these
natural products is a challenging target. Primary synthetic
challenges that must be overcome are: a) the formation of the
alkyl aryl ether, b) the enamide formation, and c) the macro-
cyclization. Herein, we report our efforts in this field, which
led not only to the first total synthesis of the sedative
cyclopeptide alkaloid paliurine F (4),[9,10] but also to the use of
the recently developed copper(I)-mediated coupling reac-
tions for the installation of the key structural elements of
paliurine F and for the macrocyclization step.
From a retrosynthetic perspective, we envisioned instal-
lation of the peptidic side chain late in the synthesis, thereby
permitting construction of paliurine F from the advanced
precursor 5 as depicted in Scheme 2. To install the cyclic
enamide and simultaneously effect macrocyclization, we
decided to employ a challenging intramolecular copper(I)-
mediated amidation reaction[11–13] using the amido vinyl
iodide 6 as the enamide precursor. Further analysis of 6
suggested a disconnection at the aryl ether bond to give the
hydroxypyrrolidine 7 and the aromatic fragment 8, which
Scheme 1. Cyclopeptide alkaloids: 3 subclasses, over200 members.
structures have been described and these natural products,
which have been used historically for the treatment of a
variety of ailments, have been shown to have numerous
biological activities which include sedative, antibacterial,
antifungal, and antiplasmodial effects.[1]
The interesting topology of these natural products,
coupled with their restricted natural availability (0.0002–1%
[*] M. Toumi, Prof. F. Couty, Dr. G. Evano
Institut Lavoisierde Versailles, UMR CNRS 8180
UniversitØ de Versailles Saint-Quentin en Yvelines
45, avenue des Etats-Unis, 78035 Versailles Cedex (France)
Fax: (+33)1-3925-4452
E-mail: evano@chimie.uvsq.fr
[**] This research was supported by the French CNRS. The authors
thank Dr. K. Wright, Dr. B. Drouillat, and Dr. J.-P. Mazaleyrat for
helpful and stimulating discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Retrosynthetic analysis of paliurine F (4). Boc=tert-butyl-
oxycarbonyl, TBS=tert-butyldimethylsilyl.
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could be coupled together using a copper-mediated arylation
reaction.[14]
(20 mol%), and cesium carbonate as a base in toluene at
1258C and using a slight excess (1.4equiv) of the iodide 8
(Scheme 4). Under these conditions, pyrrolidinyl aryl ether 12
was obtained in 75% yield. After coupling fragments 7 and 8,
several chemical manipulations were necessary before the
macrocyclization procedure. To that end, the (Z)-vinyl iodide
required for the final macroamidation step was installed
stereoselectively using the Stork–Zhao olefination reagent
(97%, > 95% de),[20] the TBS ether was deprotected using
TBAF in THF, and the resulting primary alcohol was
converted into the acid by using a two-step sequence
(Swern/buffered NaClO2 oxidations) in good overall yield.
Finally, the second constitutive amino acid of the macrocycle
was introduced using an EDC/HOBt-mediated coupling with
isoleucinamide. This latter step, which proceeded in 75%
yield, allowed us to introduce the amide group necessary for
the intramolecular amidation reaction (Scheme 4).
Our synthesis began with the asymmetric preparation of
the hydroxyprolinol 7.[15] Our goal was to design a substrate-
controlled asymmetric route with a limited number of steps
and protecting groups to enable synthesis of multigram
quantities of this fragment. Therefore, the commercially
available N-Boc-d-serine 9 was chosen as the starting point of
the synthesis (Scheme 3). The treatment of 9 with excess
TBSCl in DMF followed by acidic workup allowed for smooth
protection of the alcohol. The resulting free carboxylic acid
was subjected to a modification of the Tegner reaction
reported by Knudsen and Rapoport,[16] which involved depro-
tonation of the acid with one equivalent of butyllithium
followed by addition of two equivalents of allylmagnesium
bromide. This route afforded the unconjugated ketone 10 in
good yield and without any epimerization. Ketone 10 was
then used to introduce the second stereo-
center of the target molecule. We were
delighted to find that simple treatment of
10 with sodium borohydride provided the
desired protected amino diol 11 as a single
diastereoisomer (through NHBoc-chela-
tion control),[17] even though reduction of
related substrates is known to mainly
proceed with poor to moderate selectiv-
ity.[18] Formation of the pyrrolidine ring
was initiated by oxidative cleavage of the
double bond; spontaneous cyclization of
the intermediate aminoaldehyde followed
by reduction of the resulting protected
aminal using boron trifluoride and trie-
thylsilane ultimately gave the desired
hydroxypyrrolidine
7 in 54% overall
yield from N-Boc-d-serine 9 (in five
steps with one purification).
Scheme 4. Fragment coupling and assembly of the acyclic skeleton 6. EDC=3-(3-dimethyl-
aminopropyl)-1-ethylcarbodiimide, HMDS=1,1,1,3,3,3-hexamethyldisilazane, HMPA=hexa-
methyl phosphoramide, HOBt=1-hydroxy-1H-benzotriazole, NMM=N-methylmorpholine,
TBAF=tetra-n-butylammonium fluoride.
We next investigated the Ullmann-
type
copper-mediated
arylation[14]
between the highly functionalized cyclic
alcohol 7 and aryl iodide 8[19] for the
assembly of the acyclic fragment 6. After
screening several reaction conditions, it was determined that
this coupling was best effected by using a slight modification
of the procedure reported by Buchwald and co-workers.[14a]
This involved using CuI (10 mol%), 1,10-phenanthroline
Having the iodoamide 6 in hand, we next explored the
crucial macrocyclization step. A brief survey of various
catalytic systems reported by the research groups of
Porco,[11] Buchwald,[12] and Ma[13] for the amidation of vinyl
iodides revealed dramatic differences in reactivity. While
initial investigations of the intramolecular amidation using
combinations of copper iodide and triphenylphosphine[11a,21]
or N,N-dimethylglycine[13] failed to give any cyclization
product, [Cu(CH3CN)4]PF6, which was also examined as a
copper(I) source, with 3,4,7,8-tetramethyl-1,10-phenanthro-
line as ligand, afforded the desired product, but only in trace
amounts.[11b] To our delight, we eventually found that
subjecting the acyclic skeleton 6 to copper(I) thiophene-2-
carboxylate in N-methylpyrrolidine at 908C[11a] smoothly
provided the desired macrocyclic enamide 5 in 60% yield.
Switching to the CuI/N,N’-dimethylethylenediamine catalytic
system[12] improved the yield slightly, thus providing 5 in 70%
yield, along with 20% of recovered starting material. This
Scheme 3. Asymmetric synthesis of the hydroxypyrrolidine fragment 7.
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Communications
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Scheme 5. Macrocyclization and completion of the synthesis. Fmoc=9-fluorenyl-
methyloxycarbonyl, HATU=N-[(dimethylamino)-1H-1,2,3-triazole[4,5-b]-pyridin-1-
ylmethylene]-N-methylmethanaminium hexafluorophosphate, HOAt=7-aza-l-hydroxy-
1H-benzotriazole, TMS=trimethylsilyl. Yield in square brackets is based on recovered
starting material.
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enamide group of the target molecule (Scheme 5).[22,23]
Removal of the Boc group was then achieved in good
yield using TMSOTf and 2,6-lutidine.[3b] Finally, coupling of
14 with N-Fmoc-l-isoleucine, followed by removal of the
Fmoc group by treatment with diethylamine in acetonitrile,
and subsequent coupling with N,N-dimethyl-l-leucine gave
the desired paliurine F (4) in 57% yield over the three final
steps (Scheme 5). The physical, spectroscopic, and spectro-
metric characteristics (1H NMR, 13C NMR, IR, [a]D, UV, and
MS) of synthetic (À)-paliurine F corresponded well to those
reported for the natural product.[9,24]
In summary, the first total synthesis of paliurine F has
been achieved in 16 steps (longest linear sequence) and 6.5%
overall yield. Notable features of our synthetic approach
include an efficient copper(I)-mediated arylation of a highly
substituted alcohol to build the aryl ether bond. Herein we
have documented the first example of an intramolecular
copper(I)-mediated vinylation to install the 13-membered
macrocyclic enamide, thereby further expanding the scope of
these underdeveloped useful reactions which allow new bond
disconnections in total synthesis. This convergent approach
should be easily applicable to the synthesis of 14-membered
ring cyclopeptide alkaloids, as well as to the construction of
analogues for further biological testing, which will be
reported later.
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[17] The relative stereochemistry of 11 was confirmed by NOE
experiments on the oxazolidinone obtained after reaction of 11
with sodium hydride; see the Supporting Information for more
details.
Received: July 18, 2006
Published online: October 11, 2006
Keywords: alkaloids · copper· enamides · macrocyclization ·
.
total synthesis
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[19] Obtained in two steps and 93% from salicylaldehyde using an
iodination (ICl, AcOH)/methylation (Me2SO4, K2CO3, acetone)
sequence; see the Supporting Information for more details.
[20] G. Stork, K. Zhao, Tetrahedron Lett. 1989, 30, 2173 – 2174.
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[24] The synthetic material displayed spectroscopic properties
(1H NMR, 13C NMR, IR, UV, MS) that corresponded with
those reported for the natural product. However, the observed
optical rotation of synthetic 4 ([a]2D0 = À468, c = 1.1 in CH3CN)
was found to be higher than the reported value ([a]2D0 = À323, c =
1.0 in CH3CN).[9] The reason for this discrepancy is unclear at
present, although it might be attributed to contamination by a
small amount of impurity in the natural sample.
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