Total synthesis of the cyclopeptide alkaloid paliurine E. insights into macrocyclization by ene-enamide RCM

Article abstract of DOI:10.1021/jo702092x

(Chemical Equation Presented) The total synthesis of (-)-paliurine E is described in 14 steps and 11% overall yield. The first successful application of ene-enamide ring-closing metathesis for macrocyclization serves as the foundation for this synthesis a

Full text of DOI:10.1021/jo702092x

Total Synthesis of the Cyclopeptide Alkaloid Paliurine E. Insights
into Macrocyclization by Ene-Enamide RCM
Mathieu Toumi, Franc¸ois Couty, and Gwilherm Evano*
Institut LaVoisier de Versailles, UMR CNRS 8180, UniVersite´ de Versailles Saint Quentin en YVelines,
45 aVenue des Etats-Unis, 78035 Versailles Cedex, France
eVano@chimie.uVsq.fr
ReceiVed September 25, 2007
The total synthesis of (-)-paliurine E is described in 14 steps and 11% overall yield. The first successful
application of ene-enamide ring-closing metathesis for macrocyclization serves as the foundation for
this synthesis and allowed for a straightforward installation of the challenging cyclic enamide together
with the macrocycle. In the course of these synthetic studies, we also found that very subtle and minor
structural modification of the enamide resulted in dramatic and unexpected changes of their reactivity
since a primary amide or an aromatic aldehyde can be obtained after reaction with Grubbs’ second-
generation catalyst. Further insights on the macrocyclization by ene-enamide RCM are also discussed.
Introduction
has functional group tolerance. If especially efficient for the
synthesis of medium-sized rings, RCM is now also recognized
as one of the most straightforward and reliable methods for the
formation of large ring systems. It compares favorably to all
current synthetic alternatives and has been used as key step in
the synthesis of an impressive number of macrocyclic natural
products.2,3
Alkenes, alkynes, dienes, and enynes have been used as
substrates for RCM, and the selective formation of one or more
rings has been reported in numerous publications.1 In contrast,
Over the last 10 years, ring-closing metathesis (RCM) has
emerged as a major tool for the synthesis of complex molecules
due to the development of well-defined metathesis catalysts
which are tolerant to many functional groups and reactive toward
a wide range of substrates.1 With the advent of these catalysts,
the reproducibility and yields have markedly improved and so
(1) For recent reviews on metathesis reactions, see: (a) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (b) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18-29. (c) Connon, S. J.; Blechert, S.
Angew. Chem., Int. Ed. 2003, 42, 1900-1923. (d) Schrock, R. E.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2003, 42, 4592-4633. (e) Grubbs, R. H.
Tetrahedron 2004, 60, 7117-7140. (f) Schrodi, Y.; Pederson, R. L.
Aldrichim. Acta 2007, 40, 45-52.
(2) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4490-4527.
(3) Gradillas, A.; Pe´rez-Castells, J. Angew. Chem., Int. Ed. 2006, 45,
6086-6101.
10.1021/jo702092x CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/19/2008
1270
J. Org. Chem. 2008, 73, 1270-1281

Total Synthesis of the Cyclopeptide Alkaloid Paliurine E
the metathesis of heteroatom-substituted olefins, which offers
vast functionalization possibilities and clearly increases further
the versatility of this reaction, has been studied only recently.4
While vinylsilanes,5 ethers,6 boronates,7 phosphonates,8 chlo-
rides,9 fluorides,10 vinylazinium salts,11 as well as enamides12
have been shown to participate in RCM to form small- to
medium-sized ring systems, although with generally decreased
reactivity, there are still no reports on their use for the formation
of macrocyclic systems. In this contribution, we report on the
first successful use of a macrocyclization by ene-enamide
RCM, culminating in the first total synthesis of the 13-membered
ring cyclopeptide alkaloid paliurine E. In the course of these
studies, we also found that small changes in the metathesis
substrates can have a dramatic impact on the course of the
metathesis reaction. Investigation of the scope of the macrocyclic
enamide-forming reaction also provided some insights into
macrocyclization by ene-enamide RCM.
Strategic Considerations. 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- (e.g., ziziphine Q), 14- (e.g., frangufoline),
or 15-membered (e.g., abyssenine A) cycle containing an
aromatic ring. The remainder of the macrocycle consists of a
peptide unit connected to the aromatic ring in either a 1,4- or a
FIGURE 1. Cyclopeptide alkaloids family of natural products.
1,3-orientation by enamide and alkyl aryl ether (or methylene)
linkages (Figure 1). To date, over 200 structures have been
described and these natural products, which have been used
historically for the treatment of a variety of ailments, have also
been shown to display numerous biological activities including
sedative, antibacterial, antifungal, and antiplasmodic.13
The interesting topology of these natural products coupled
with their restricted natural availability (0.0002-1% of dried
plants) and interesting bioactivities have drawn significant
interest from the synthetic community. Several strategies have
been used for the key macrocyclization step. The first synthesis
of these compounds by Schmidt14 utilized the macrolactamiza-
tion of a pentafluorophenyl ester, a strategy which was later on
used in the total syntheses of cyclopeptide alkaloids by Joullie´15
and Han.16 The synthesis of sanjoinine G1 and mauritines by
Zhu incorporated an intramolecular SNAr reaction for macro-
cyclization.17 A common feature of the previous synthetic efforts
was the use of a four-step sequence to install the enamide
(starting from the corresponding amino alcohol via thermal
elimination of an intermediate selenoxide) after the crucial
macrocyclization step, which somehow reduced the overall
efficiency of the syntheses. More recently, we reported the use
of a copper-mediated intramolecular amidation reaction to form
this enamide with concomitant macrocyclization.18,19 In the
course of these synthetic studies, we considered forming the
macrocyclic enamide in the recently isolated cyclopeptide
alkaloid paliurine E 1,20 after installation of the side chain from
precursor 2, via a challenging macrocyclization by RCM starting
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F.; Ho¨genauer, K.; Simic, O.; Antonello, A.; Smith, M. D.; Ley, S. V.
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Chem. 1983, 48, 2680-2685. (b) Schmidt, U.; Schanbacher, U. Angew.
Chem., Int. Ed. Engl. 1983, 22, 152-153. (c) Schmidt, U.; Za¨h, M.;
Lieberknecht, A. J. Chem. Soc., Chem. Commun. 1991, 1002-1004.
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114, 10181-10189. (b) Xiao, D.; East, S. P.; Joullie´, M. M. Tetrahedron
Lett. 1998, 39, 9631-9632. (c) East, S. P.; Shao, F.; Williams, L.; Joullie´,
M. M. Tetrahedron 1998, 54, 13371-13390.
(16) 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, 1909-1914.
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J. Org. Chem, Vol. 73, No. 4, 2008 1271

Toumi et al.
SCHEME 1. Ene-Enamide RCM-Based Retrosynthetic
Analysis of Paliurine E (1)
SCHEME 2. Synthesis of the Hydroxyproline-Styrene
Fragment 4a
a Reagents and conditions: (a) CuI (10%), 1,10-phenanthroline (20%),
Cs2CO3, toluene, 110 °C, 79%; (b) TBAF, THF, -20 °C to rt, 89%; (c)
DMSO, (COCl)2, Et3N, CH2Cl2, -78 to 0 °C; (d) NaClO2, NaH2PO4,
2-methylbut-2-ene, t-BuOH/THF/H2O, rt, 86% (two steps).
from ene-enamide 3 (Scheme 1). Despite many examples of
macrocyclization using this transformation starting from dienes
as substrates,2 this strategic decision bore considerable risk and
might even seem somewhat counterintuitive due to the low
reactivity of enamides in RCM reactions and the presence of
polar substituents in the substrate at positions where they can
chelate the incipient metal carbene intermediates, which usually
strongly impacts the effectiveness of the reaction.21 However,
we felt that if successful, this macrocyclization strategy would
afford a straightforward entry to cyclopeptide alkaloids and
could further increase the usefulness of RCM-based macrocy-
clizations.
For the sake of flexibility and to easily evaluate the reactivity
and influence of the enamide group toward RCM, it was decided
to incorporate this enamide residue at the very end of the
synthesis by coupling of fragments 4 and 5, after formation of
the aryl alkyl ether in 4 (Scheme 1).
Synthesis of Enamide Fragments. To evaluate in detail the
reactivity of ene-enamides toward RCM, several substituted
enamides were prepared from N-Boc-isoleucine 11. To this end,
11 was first cleanly converted to its amide derivative 12 by
activation of the carboxylic acid in 11 as a mixed anhydride
followed by reaction with ammonia (Scheme 3). Monosubsti-
tuted enamide derivative 5a could then be obtained in excellent
yield using a palladium-catalyzed vinyl transfer from butyl vinyl
ether,24,25 while ene-enamide 5b was more conveniently
synthesized by reacting 12 with (E)-1-iodohepta-1,6-diene in
the presence of catalytic amounts of copper iodide and N,N′-
dimethylethylene-1,2-diamine.26 To access propenylamide 5c
as well as its benzyl-protected derivative 5d, we found that they
were best obtained using an isomerization of the corresponding
allylamides 13 and 14: amidation of 11 respectively with
allylamine or allylbenzylamine followed by isomerization with
27
RuClH(CO)(PPh3)3 efficiently gave the desired enamides 5c
Results and Discussion
and 5d in excellent overall yields (Scheme 3).
Synthesis of the Hydroxyproline-Styrene Fragment. The
synthesis of the hydroxyproline-styrene fragment 4 closely
followed the one we reported for the synthesis of paliurine F18a
and commenced with an Ullmann-type copper-mediated aryla-
tion22 between the highly functionalized hydroxyprolinol deriva-
tive 618a and iodostyrene 723 using catalytic CuI and 1,10-
phenanthroline, with cesium carbonate as base and a modest
excess (1.6 equiv) of iodide 7 in toluene at 110 °C (Scheme 2).
Under these conditions, pyrrolidinyl aryl ether 8 was obtained
in 79% yield and was transformed into the corresponding
carboxylic acid 4 after TBS deprotection and two-step oxidation
(Swern/buffered NaClO2) of the resulting primary alcohol 9.
Preparation of Acyclic Ene-Enamides. At this stage, the
preparation of the acyclic substrates for the ene-enamide RCM
was completed by coupling of phenoxyproline 4 with enamide
fragments 5. To this end, the Boc group of enamides 5a-d
was first carefully deprotected with anhydrous zinc bromide in
dichloromethane and the resulting unstable free amines 15a-d
were coupled with carboxylic acid 4 using EDC and HOBt.
Using this sequence, ene-enamides 16a-d were obtained in
good overall yields (Scheme 4).
Macrocyclization by Ene-Enamide Ring-Closing Metath-
esis. Completion of the preparation of acyclic ene-enamides
finally set the stage for the crucial ene-enamide ring closing
metathesis reaction.12a Acyclic substrates 16a-d were reacted
with 10 mol % of Grubbs’ second-generation catalyst GII in
refluxing 1,2-dichloroethane for 24 h, followed by addition of
(20) (a) Lin, H. Y.; Chen, C. H.; You, B. J.; Liu, K. C. S. C.; Lee, S. S.
J. Nat. Prod. 2000, 63, 1338-1343. (b) Lee, S. S.; Su, W. C.; Liu, K. C.
S. C. Phytochemistry 2001, 58, 1271-1276.
(21) For examples, see: (a) Fu¨rstner, A.; Langemann, K. J. Org. Chem.
1996, 61, 3942-3943. (b) Fu¨rstner, A.; Kindler, N. Tetrahedron Lett. 1996,
37, 7005-7008. (c) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792-
803. (d) Fu¨rstner, A.; Thiel, O. R.; Lehmann, C. W. Organometallics 2002,
21, 331-335.
(24) Brice, J. L.; Meerdink, J. E.; Stahl, S. S. Org. Lett. 2004, 6, 1845-
1849.
(25) In contrast, all attempts at copper-mediated amidation of 12 with
vinyl bromide using various catalytic systems failed to give the desired
unsubstituted enamide in good and reproducible yields.
(26) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003,
5, 3667-3669.
(27) Krompiec, S.; Pigulla, M.; Krompiec, M.; Baj, S.; Mrowiec-Białon´,
J.; Kasperzyk, J. Tetrahedron Lett. 2004, 45, 5257-5261.
(22) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973-976.
(23) Obtained in three steps and 77% overall yield from salicyladehyde
using an iodination (ICl, AcOH)-methylation (Me2SO4, K2CO3, acetone)-
Wittig sequence. See the Experimental Section for more details.
1272 J. Org. Chem., Vol. 73, No. 4, 2008

Total Synthesis of the Cyclopeptide Alkaloid Paliurine E
SCHEME 3. Synthesis of Enamide Fragments 5a
a Reagents and conditions: (a) isobutyl chloroformate, N-methylmorpholine, DME, 0 °C, then ammonia, quant; (b) butyl vinyl ether, (1,10-
phenanthroline)Pd(OCOCF3)2 (10%), 75 °C, 81%; (c) (E)-1-iodohepta-1,6-diene, CuI (10%), N,N′-dimethylethylene-1,2-diamine (20%), K2CO3, THF, 70
°C, 69%; (d) isobutyl chloroformate, N-methylmorpholine, DME, 0 °C, then allylamine, quant; (e) RuClH(CO)(PPh3)3 (2.5%), THF, reflux, 92%, dr: 6:4;
(f) allylbenzylamine, EDC, HOBt, N-methylmorpholine, DMF, 0 °C to rt, 90%; (g) RuClH(CO)(PPh3)3 (2.5%), THF, reflux, 86%, dr >95:5.
another 10 mol % of the catalyst and further reaction for 24 h
under high dilution conditions (0.005 M).28 As can be seen from
the results collected in Scheme 5, a dramatic difference in the
reactivity of acyclic ene-enamides was observed. When reacted
with GII in refluxing 1,2-dichloroethane, monosubstituted
enamide 16a furnished only 8% of the desired cyclopeptide core
2, and amide 17 was obtained as the major product. Formation
of 17 could be attributed to the thermal instability of 16a since
a similar transformation was noticed without the catalyst.29
Encouraged by the formation of the desired macrocyclic
compound, though in trace amounts, we decided to use ene-
enamide 16b bearing an additional methyl group, hoping for
some stabilization of the enamide moiety. We were therefore
delighted to see that when submitted to the crucial macro-
cyclization step, this enamide gave 49% isolated yield of the
desired cyclopeptide 2 and the amount of amide 17 was
considerably reduced (only 13%).28,29 This result brings this first
successful example of macrocyclization by ene-enamide RCM
at a useful synthetic level (Scheme 5). In an attempt to further
increase the yield of the desired cyclopeptide core 2, the
influence of various additives,30 which would either prevent
chelation of the substrate with the catalyst or degradation of
the latter, was studied. However, all of the additives evaluated
failed to bring any noticeable improvement (2,6-dichloro-1,4-
benzoquinone, copper chloride, triphenylarsine, triphenylphos-
phine oxide) or were not compatible with the presence of the
enamide group in 16b (chlorocatecholborane, titanium isopro-
poxide).
In an attempt to improve the formation of the macrocyclic
enamide, two additional strategies were evaluated. Since the
problem in this macrocyclization clearly is the low reactivity
of the enamide, we first considered forcing the formation of an
alkylidene complex at this position using Hoye’s relay RCM
strategy starting from diene-enamide 16c.31 This relay approach
involves temporary incorporation of a tether containing a
sterically unencumbered terminal olefin for initiation of the
catalytic cycle. The olefin is positioned such that a kinetically
favorable formation of a five-membered ring is used to deliver
the ruthenium onto the sterically hindered or less reactive
position with concomitant extrusion of the ring. While this
strategy has proven to be successful for macrocyclization in a
(28) Grubbs’ first-generation catalyst was also evaluated but failed to
give even traces of the desired cyclic compound.
(29) A [3,3]-sigmatropic rearrangement might account for the thermal
instability of enamide 16a. The presence of the additional methyl group in
propenyl amide 16b (mixture of E and Z isomers) would therefore block
the rearrangement of Z-16b, which could explain the greater thermal stability
of 16b. The presence of this additional methyl group might also change
the electronic properties of the enamide and account for its reactivity.
(30) (a) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1997, 119, 3887-3897. (b) Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc.
1997, 119, 9130-9136. (c) Bourgeois, D.; Pancrazi, A.; Nolan, S. P.; Prunet,
J. J. Organomet. Chem. 2002, 643, 247-252. (d) Hong, S. H.; Sanders, D.
P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160-17161.
(e) Vedrenne, E.; Dupont, H.; Oualef, S.; Elka¨ım, L.; Grimaud, L. Synlett
2005, 670-672. (e) Mo¨ıse, J.; Arseniyadis, S.; Cossy, J. Org. Lett. 2007,
9, 1695-1698.
(31) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H.
J. Am. Chem. Soc. 2004, 126, 10210-10211.
J. Org. Chem, Vol. 73, No. 4, 2008 1273

Toumi et al.
SCHEME 4. Fragment Assembly: Preparation of Acyclic Ene-Enamidesa
a Reagents and conditions: (a) ZnBr2 (4.5 equiv), CH2Cl2, 0 °C to rt; (b) EDC, HOBt, N-methylmorpholine, DMF, 0 °C to rt.
couple of cases,32,33 it failed using 16c and a complex mixture
of unidentified and inseparable compounds was obtained.34,35
Alternatively, the ring-closing metathesis of benzyl-protected
ene-enamide 16d was envisioned: the presence of an additional
benzyl group was expected to stabilize the enamide which could
then react with the catalyst before decomposition. The tertiary
enamide in 16d was, indeed, considerably more stable since no
trace of amide could be observed in the crude reaction mixture
and starting material was mainly recovered along with trace
amounts of aldehyde 18. Surprised by the formation of this most
unexpected byproduct, we tried to force this reaction by using
a stoichiometric amount of the catalyst. Using these conditions,
a 1:1 mixture of starting material and aldehyde 18 was now
isolated. A rationale for the formation of 18 is the formation of
a relatively stable Hoveyda-Grubbs-like alkylidene complex36
19 by reaction of the ruthenium catalyst with the methoxystyrene
group (Scheme 6). Steric hindrance or a change in the
conformation of the enamide37 due to the presence of the benzyl
group on the enamide probably prevents the second [2 + 2]
cycloaddition to occur. Alkylidene complex 19 being unable to
react with the enamide olefin, it finally reacts with water from
the air to give aldehyde 18.38,39
This study not only demonstrated the feasibility of ene-
enamide RCM-based macrocyclization but also showed that
small changes in the substitution pattern of the ene-enamide
can have a dramatic impact on the outcome of this reaction
(Scheme 5). Pleased to observe that the ene-enamide RCM
proceeded starting from substrate 16b, affording macrocyclic
enamide 2, we next decided to investigate the possibility to
obtain this macrocyclic compound using a one-pot isomeriza-
tion/ene-enamide RCM sequence starting from an allylic amide
in place of the enamide.
Macrocyclization by Isomerization/Ene-Enamide Ring-
Closing Metathesis Sequence. Considering that the enamide
moiety in the N-Boc-isoleucine-propenylamide fragment 5c was
installed by isomerization of the corresponding allylamide 13
(Scheme 3) and since ruthenium carbenes have been recently
(32) For a review, see: Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44,
1912-1915.
(33) For examples of macrocyclization using relay ring-closing metath-
esis, see: (a) Wang, X.; Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr.
Angew. Chem., Int. Ed. 2004, 43, 3601-3605. (b) Roethle, P. A.; Chen, I.
T.; Trauner, D. J. Am. Chem. Soc. 2007, 129, 8960-8961.
(34) Not a trace of the macrocyclic enamide could be detected in the
crude reaction mixture.
(37) As pointed out by one of the reviewers, the bulk of the benzyl group
can cause the alkene moiety to adopt a conformation where it is parallel to
the carbonyl. In this conformation, it appears the alkene will not be able to
approach the Ru-alkylidene with a favorable geometry for orbital overlap.
(38) Kim, M.; Eum, M.-S.; Jin, M. Y.; Jun, K.-W.; Lee, C. W.; Kuen,
K. A.; Kim, C. H.; Chin, C. S. J. Organomet. Chem. 2004, 689, 3535-
3540.
(39) All attempts at characterization of an intermediate alkylidene
ruthenium complex in the crude reaction mixture, or at its isolation, even
in the presence of copper chloride to trap the tricyclohexylphosphine, failed.
(35) For examples of substrates failing to undergo relay ring-closing
metathesis, see: (a) Hoye, T. R.; Wang, J. J. Am. Chem. Soc. 2005, 127,
6950-6951. (b) Helmboldt, H.; Kohler, D.; Hiersemann, M. Org. Lett. 2006,
8, 1573-1576. (c) Trost, B. M.; Yang, H.; Thiel, O. R.; Frontier, A. J.;
Brindle, C. S. J. Am. Chem. Soc. 2007, 129, 2206-2207. (d) Fu¨rstner, A.;
Fasching, B.; O’Neil, G. W.; Fenster, M. D. B.; Godbout, C.; Ceccon, J.
Chem. Commun. 2007, 3045-3047.
(36) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168-8179.
1274 J. Org. Chem., Vol. 73, No. 4, 2008

Total Synthesis of the Cyclopeptide Alkaloid Paliurine E
SCHEME 5. Ene-Enamide Ring-Closing Metathesisa
a Reagents and conditions: (a) Grubbs’ second-generation catalyst GII (2 × 10%), 1,2-dichloroethane (0.005 M), reflux; (b) GII (1 equiv), 1,2-dichloroethane
b
(0.005 M), reflux Isolated yield with 1 equiv of GII (conditions b); traces only with 20% of GII.
SCHEME 6. Possible Intermediate for the Formation of Aldehyde 18 from Ene-Enamide 16d
J. Org. Chem, Vol. 73, No. 4, 2008 1275

Toumi et al.
SCHEME 7. Macrocyclization by Isomerization/Ene-Enamide Ring-Closing Metathesis Sequencea
a Reagents and conditions: (a) ZnBr2 (4.5 equiv), CH2Cl2, 0 °C to rt, then 4, EDC, HOBt, N-methylmorpholine, DMF, 0 °C to rt, 92%; (b) Grubbs’
second-generation catalyst GII (2 × 10%), 1,2-dichloroethane (0.005M), reflux, 36%.
SCHEME 8. Completion of the Synthesisa
a Reagents and conditions: (a) TMSOTf, 2,6-lutidine, CH2Cl2, -10 to 0 °C; (b) N,N-dimethyl-L-phenylalanine, HATU, HOAt, DIPEA, DMF, 0 °C to rt,
78% (two steps).
shown to be excellent catalysts for this kind of isomerization
reactions,40,41 it was reasoned that the macrocyclic enamide 2,
required for the preparation of paliurine E, might be obtained
starting from acyclic allylic amide 20 using an isomerization/
ene-enamide ring-closing metathesis sequence. This alternative
to the ene-enamide RCM would shorten the synthesis and
provide additional insights into the preparation of macrocyclic
enamides using RCM-based strategies.
To test this opportunity, allylamide 20 was prepared by
deprotection of 13 as before and condensed with acid 4. When
reacted with Grubbs’ second-generation catalyst under high
dilution, allylamide 20 was first smoothly isomerized to the
corresponding enamide which then underwent the ene-enamide
RCM to macrocycle 2 in 36% yield (Scheme 7).42
Completion of the Synthesis of Paliurine E. With useful
quantities of the macrocyclic core 2 in hand, the synthesis of
paliurine E was finally achieved in two steps. First, deprotection
of the Boc group was achieved using TMSOTf and 2,6-lutidine.
Finally, HATU/HOAt-mediated coupling of 21 with N,N-
dimethyl-L-phenylalanine gave the desired paliurine E (1) in
78% over the two final steps (Scheme 8). The synthetic (-)-
paliurine E exhibited physical, spectroscopic, and spectrometric
characteristics (1H NMR, 13C NMR, IR, [R]D, UV, and MS)
identical to those reported for the natural product.20
Conclusion
With their especially appealing molecular architectures and
potent biological activities, the cyclopeptide alkaloids present
an interesting challenge to the synthetic chemist and also an
opportunity to test the scope and applicability of an important
carbon-carbon bond-forming reaction in complex situations.
Our flexible approach to these structures allowed us, with slight
modifications, to test synthetic strategies based on ene-enamide
ring-closing metathesis as a potential tool for their construction.
Results of these investigations were somewhat surprising since
very subtle changes on the enamides resulted in dramatic
changes on their reactivity. This provided interesting insights
on the macrocyclization by ene-enamide RCM and allowed
for the completion of the first total synthesis of paliurine E in
a limited number of steps featuring an installation of the
challenging enamide concomitant with the macrocyclization. The
exercise unearthed interesting chemistry and may also serve as
a guide in future endeavors directed toward the construction of
similar structures to the ones described here.
(40) (a) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan,
S. P. J. Org. Chem. 2000, 65, 2204-2207. (b) Alcaide, B.; Almendros, P.;
Alonso, J. M.; Aly, M. F. Org. Lett. 2001, 3, 3781-3784. (c) Alcaide, B.;
Almendros, P.; Alonso, J. M. Chem. Eur. J. 2003, 9, 5793-5799. (c)
Alcaide, B.; Almendros, P.; Alonso, J. M.; Luna, A. Synthesis 2005, 668-
672. (d) Alcaide, B.; Almendros, P.; Alonso, J. M. Tetrahedron Lett. 2003,
44, 8693-8695. (e) Schmidt, B. Eur. J. Org. Chem. 2004, 1865-1880. (f)
McNaughton, B. R.; Bucholtz, K. M.; Camaano-Moure, A.; Miller, B. L.
Org. Lett. 2005, 7, 733-736. (g) Alcaide, B.; Almendros, P.; Alonso, J.
M. Chem. Eur. J. 2006, 12, 2874-2879.
(41) Allylamide 13 could easily be isomerized to the corresponding
enamide 5c using catalytic amounts of Grubbs’ second-generation catalyst.
See the Experimental Section for details.
(42) For a reverse ene-allylamide RCM/isomerization sequence which
does not involve the loss of one carbon atom, see: Fustero, S.; Sa´nchez-
Rosello´, M.; Jime´nez, D.; Sanz-Cervera, J. F.; del Pozo, C.; Acena, J. L. J.
Org. Chem. 2006, 71, 2706-2714.
Experimental Section
General Information. All reactions were carried out in oven-
or flame-dried glassware under an argon atmosphere employing
standard techniques in handling air-sensitive materials.
All solvents were reagent grade. Tetrahydrofuran (THF) and
toluene were freshly distilled from sodium/benzophenone under
argon immediately prior to use. Dichloromethane, DMSO, and DMF
were freshly distilled from calcium hydride. 1,2-Dichloroethane was
successively distilled over phosphorus pentoxide and calcium
hydride under argon and degassed before use. Methanol was
distilled from magnesium turnings and iodine.
1276 J. Org. Chem., Vol. 73, No. 4, 2008

Total Synthesis of the Cyclopeptide Alkaloid Paliurine E
Allylamine, diisopropylethylamine, N-methylmorpholine, tri-
ethylamine, 2,6-lutidine, and N,N′-dimethylethylenediamine were
distilled over calcium hydride. 1,2-Dimethoxyethane was synthesis
grade and used as supplied. Copper(I) iodide (99,999% purity) and
Grubbs’ second-generation catalyst were purchased from a com-
mercial supplier and used as supplied. Finely powdered potassium
carbonate (325 mesh) and cesium carbonate were used for copper-
mediated coupling reactions. All other reagents were used as
supplied.
Unless otherwise noted, reactions were magnetically stirred and
monitored by thin layer chromatography using 60F254 plates.
Chromatography was performed with silica gel 60 (particle size
35-70 µm) supplied by SDS. Yields refer to chromatographically
and spectroscopically pure compounds, unless otherwise noted.
Proton NMR spectra were recorded using an internal deuterium
lock at ambient temperature on a Bruker 300 MHz spectrometer.
Internal references of δH 7.26 and δH 2.50 were used for CDCl3
and DMSO-d6, respectively. Data are presented as follows: chemi-
cal shift (in ppm on the δ scale relative to δTMS ) 0), multiplicity
(s ) singlet, d ) doublet, t ) triplet, q ) quartet, quint ) quintuplet,
m ) multiplet, br ) broad, app ) apparent), coupling constant
(J/Hz) and integration. Resonances that are either partially or fully
obscured are denoted obscured (obs). Carbon-13 NMR spectra were
recorded at 75 MHz. Internal references of δC 77.16 and δC 39.52
were used for CDCl3 and DMSO-d6, respectively.
Hz, d, J ) 11.1 Hz, 1H), 4.84 and 4.80 (rotamers, d, J ) 3.0 Hz,
d, J ) 4.1 Hz, 1H), 3.80-4.07 (m, 2H), 3.81 (s, 3H), 3.46-3.73
(m, 3H), 2.05-2.29 (m, 2H), 1.49 (s, 9H), 0.92 (s, 9H), 0.08 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 154.7, 151.6 and 151.3
(rotamers), 151.4, 131.5 and 131.4 (rotamers), 128.0, 115.5, 115.1
and 114.6 (rotamers), 115.0, 112.2 and 112.1 (rotamers), 80.0 and
79.8 (rotamers), 79.6 and 79.4 (rotamers), 64.2, 63.1 and 62.5
(rotamers), 56.3 and 56.2 (rotamers), 45.4 and 45.1 (rotamers), 30.1
and 28.9 (rotamers), 28.7, 26.0, 18.4, -5.3, -5.4; IR (neat) νmax
1694, 1682, 1494, 1393, 1180 cm-1; CIMS (NH3 gas) 464 (37),
408 (31), 364 (26), 350 (100), 306 (12); ESIHRMS m/z calcd for
C25H41NO5SiNa [M + Na]+ 486.2652, found 486.2638.
(2R,3S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-3-(4-methoxy-
3-vinylphenoxy)pyrrolidine 9. A solution of 8 (1.5 g, 3.2 mmol)
in THF (30 mL) was treated with a solution of TBAF (1 M solution
in THF, 4.9 mL, 4.9 mmol) at -20 °C. The resulting light yellow
mixture was warmed to rt over 2 h and quenched with water. The
aqueous layer was extracted with Et2O, and the combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated. The crude residue was purified by flash chromatog-
raphy over silica gel (AcOEt/petroleum ether: 1/1) to give the
unprotected alcohol 9 (1.0 g, 2.9 mmol, 89%) as a white solid:
mp 82 °C; [R]2D0 -12 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.05 (br s, 1H), 7.00 (dd, J ) 17.3, 11.1 Hz, 1H), 6.78 (br s,
2H), 5.70 (d, J ) 17.3 Hz, 1H), 5.26 (d, J ) 11.1 Hz, 1H), 4.81
and 4.59 (rotamers, br s, br s, 1H), 4.11 and 3.94 (rotamers, br m,
br m, 1H), 3.79 (s, 3H), 3.70-3.86 (m, 2H), 3.44-3.61 (m, 2H),
2.05-2.16 (m, 2H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
157.0, 151.7, 151.0, 131.4, 127.9, 115.9, 115.0, 114.2, 112.3, 80.5,
79.2, 65.2, 64.8, 56.3, 45.8, 30.0, 28.6; IR (KBr) νmax 3410, 2952,
1675, 1484, 1214, 1042, 872 cm-1; ESIMS (positive mode) 721.4;
ESIHRMS m/z calcd for C19H27NO5Na [M + Na]+ 372.1787, found
372.1803.
Due to the presence of complex rotameric mixtures, it was
necessary to record 1H and 13C NMR spectra of dipeptides as well
as acyclic ene-enamides in DMSO-d6 at 345 K. Even at those
temperatures, some 13C peaks were poorly resolved and are denoted
“broad” (br).
4-Iodo-1-methoxy-2-vinylbenzene 7. To a suspension of
methyltriphenylphosphonium bromide (20.5 g, 57.3 mmol) in THF
(200 mL) at -78 °C was added n-butyllithium (1.6 M in hexanes,
32.0 mL, 51.2 mmol). The resulting orange solution was stirred at
-78 °C for 1 h and a solution of 5-iodo-2-methoxybenzaldehyde18a
(5.0 g, 19.1 mmol) in THF (50 mL) was added via cannula. The
reaction mixture was warmed to 0 °C over 2 h and quenched with
100 mL of saturated NH4Cl aqueous solution. The organic layer
was separated, and the aqueous layer was extracted with AcOEt.
Combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated. The crude residue was purified
by flash chromatography over silica gel (Et2O/petroleum ether: 2/8)
to give the desired substituted styrene 7 (4.1 g, 15.8 mmol, 83%)
(2S,3S)-1-tert-Butoxycarbonyl-2-formyl-3-(4-methoxy-3-vinyl-
phenoxy)pyrrolidine 10. DMSO (430 µL, 6.1 mmol) was added
to a solution of oxalyl chloride (450 µL, 5.1 mmol) in dichloro-
methane (15 mL) at -78 °C. The resulting solution was stirred at
-78 °C for 30 min, and a solution of 9 (850 mg, 2.43 mmol) in
dichloromethane (20 mL) was added dropwise via cannula. The
reaction mixture was stirred for 30 min at -78 °C before adding
triethylamine dropwise (1.5 mL, 10.7 mmol), and the mixture was
warmed to 0 °C over 4 h. The reaction was next quenched at 0 °C
with water and diluted with CH2Cl2. The aqueous layer was
extracted with CH2Cl2, and the combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated
to give the desired aldehyde 10 as an orange oil (850 mg, 2.43
mmol, quant) which was used without purification in the next
1
as a pale yellow liquid. H NMR (300 MHz, CDCl3) δ 7.65 (d, J
) 2.2 Hz, 1H), 7.42 (dd, J ) 8.6, 2.2 Hz, 1H), 6.84 (dd, J ) 17.7,
11.1 Hz, 1H), 6.54 (d, J ) 8.6 Hz, 1H), 5.63 (d, J ) 17.7 Hz, 1H),
5.21 (d, J ) 11.1 Hz, 1H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 156.6, 137.4, 135.2, 130.4, 129.4, 115.8, 113.2, 83.2, 55.7; IR
(neat) νmax 2991, 1480, 1240, 1122, 1025 cm-1. ESIMS (positive
mode) 283.1; ESIHRMS m/z calcd for C9H9IONa [M + Na]+
282.9596, found 282.9603.
step: [R]2D0 -31 (c 2.4, CHCl3); H NMR (300 MHz, CDCl3) δ
1
9.68 and 9.62 (rotamers, s, s, 1H), 7.10 and 7.09 (rotamers, s, s,
1H), 7.01 and 6.99 (rotamers, dd, J ) 17.7, 11.1, dd, J ) 17.7,
11.1 Hz, 1H), 6.81-6.83 (m, 2H), 5.75 and 5.73 (rotamers, d, J )
17.7 Hz, d, J ) 17.7 Hz, 1H), 5.29 and 5.25 (rotamers, d, J ) 11.1
Hz, d, J ) 11.1 Hz, 1H), 4.86 (br s, 1H), 4.49 and 4.30 (rotamers,
s, s, 1H), 3.61-3.85 (m, 2H), 3.80 (s, 3H), 2.18-2.26 (m, 1H),
1.90-2.04 (m, 1H), 1.49 and 1.42 (rotamers, s, s, 9H); 13C NMR
(75 MHz, CDCl3) δ 200.3 and 200.1 (rotamers), 155.1 and 154.0
(rotamers), 152.0, 150.5, 131.2, 128.0, 115.8, 115.2, 114.1, 112.3,
81.0 and 80.7 (rotamers), 79.1 and 77.8 (rotamers), 70.9 and 70.6
(rotamers), 56.2, 45.9 and 45.0 (rotamers), 31.1 and 30.5 (rotamers),
28.5; IR (neat) νmax 2949, 1738, 1712, 1693, 1494, 1393, 1217,
911 cm-1; CIMS (NH3 gas) 370.0 (22), 242.3 (67), 186.3 (100);
ESIHRMS m/z calcd for C19H25NO5Na [M + Na]+ 370.1630, found
370.1637.
(2R,3S)-1-tert-Butoxycarbonyl-2-tert-butyldimethylsilyloxy-
methyl-3-(4-methoxy-3-vinylphenoxy)pyrrolidine 8. A 15 mL
pressure tube was charged with 4-iodo-1-methoxy-2-vinylbenzene
7 (830 mg, 3.2 mmol), alcohol 618a (1.0 g, 3.0 mmol), cesium
carbonate (1.95 g, 6.0 mmol), 1,10-phenanthroline (108 mg, 0.6
mmol), and copper(I) iodide (57 mg, 0.3 mmol). Toluene (2 mL)
was added, the pressure tube was closed, and the brownish
suspension was heated to 110 °C for 24 h. Another portion of
4-iodo-1-methoxy-2-vinylbenzene 7 (415 mg, 1.6 mmol) was then
added, and the reaction mixture was heated for an additional 24 h
and cooled to rt. Crude reaction mixture was finally filtered over
a plug of silica gel (washed with AcOEt), concentrated, and purified
by flash chromatography over silica gel (AcOEt/petroleum ether
15/85) to yield aryl ether 8 as a colorless oil (1.1 g, 2.4 mmol,
(2S,3S)-1-tert-Butoxycarbonyl-3-(4-methoxy-3-vinylphenoxy)-
proline 4. To a solution of 10 (850 mg, 2.43 mmol) in a mixture
of THF (7 mL) and tert-butanol (24 mL) was added 2-methylprop-
2-ene (2.6 mL), followed by a solution of sodium chlorite (80%,
660 mg, 5.8 mmol) and sodium dihydrogen phosphate dihydrate
79%): [R]2D0 -2 (c 1.5, CHCl3); H NMR (300 MHz, CDCl3) δ
1
6.96-7.06 (m, 2H), 6.85-6.91 (m, 1H), 6.78 and 6.77 (rotamers,
d, J ) 8.8 Hz, d, J ) 8.8 Hz, 1H), 5.72 and 5.71 (rotamers, d, J )
17.7 Hz, d, J ) 17.7 Hz, 1H), 5.28 and 5.27 (rotamers, d, J ) 11.1
J. Org. Chem, Vol. 73, No. 4, 2008 1277

Toumi et al.
(796 mg, 5.1 mmol) in water (7 mL). The yellow reaction mixture
was then stirred for 1 h, carefully quenched with a 1 M HCl
solution, and diluted with ether. The aqueous layer was extracted
with ether, and the combined organic layers were dried over MgSO4,
filtered, and concentrated. The crude residue was purified by flash
chromatography over silica gel (CH2Cl2/EtOH: 98/2) to give the
acid 4 as a yellow oily solid (762 mg, 2.10 mmol, 86% over two
4.0 mmol), (E)-1-iodo-hepta-1,6-diene44 (890 mg, 4.0 mmol),
copper(I) iodide (76 mg, 0.4 mmol), and potassium carbonate (830
mg, 6.0 mmol). The tube was evacuated under high vacuum,
backfilled with argon, and closed with a rubber septa. Dry and
degassed THF (4 mL) and N,N′-dimethylethylene-1,2-diamine (85
µL, 0.8 mmol) were next added, the rubber septa was replaced by
a Teflon stopper, and the light blue suspension was sonicated for
2 min before being heated to 70 °C for 15 h. The reaction mixture
was cooled to rt, filtered over a plug of silica gel (washed with
AcOEt), and concentrated. The crude residue was purified by flash
chromatography over silica gel (AcOEt/petroleum ether: 1/9) to
give the desired enamide 5b (899 mg, 3.1 mmol, 69%) as a white
steps): [R]2D0 -30 (c 0.5, CHCl3); H NMR (300 MHz, CDCl3) δ
1
8.51 (br s, 1H), 7.06 and 7.04 (rotamers, s, s, 1H), 6.95 and 6.93
(rotamers, dd, J ) 17.2, 11.1 Hz, dd, J ) 17.2, 11.1 Hz, 1H), 6.71-
6.77 (m, 2H), 5.68 and 5.66 (rotamers, d, J ) 17.2 Hz, d, J ) 17.2
Hz, 1H), 5.21 and 5.19 (rotamers, d, J ) 11.1 Hz, d, J ) 11. Hz,
1H), 4.96 and 4.82 (rotamers, s, s, 1H), 4.50 and 4.38 (rotamers, s,
s, 1H), 3.55-3.68 (m, 1H), 3.73 (s, 3H), 3.54-3.60 (m, 1H), 2.10-
2.14 (m, 2H), 1.42 and 1.33 (rotamers, s, s, 9H); 13C NMR (75
MHz, CDCl3) δ 175.0 and 173.1 (rotamers), 156.1 and 154.1
(rotamers), 151.8, 150.4, 131.1, 127.9, 115.6 and 115.4 (rotamers),
115.1, 113.8 and 113.7 (rotamers), 112.4, 81.6, 80.8, 80.3 and 78.9
(rotamers), 64.8, 56.2, 45.3 and 44.7 (rotamers), 30.4 and 29.8
(rotamers), 28.4 and 28.3 (rotamers); IR (neat) νmax 3437, 3211,
2981, 1696, 1414, 1209 cm-1; CIMS (NH3 gas) 381 (9), 363 (100),
325 (94), 308 (56), 264 (60), 150 (49); ESIHRMS m/z calcd for
C19H25NO6Na [M + Na]+ 386.1580, found 386.1562.
solid: mp 115 °C; [R]2D0 +5 (c 1.3, CHCl3); H NMR (300 MHz,
1
CDCl3) δ 7.77-7.96 (m, 1H), 6.68 (dd, J ) 13.8, 10.8 Hz, 1H),
5.71-5.85 (m, 1H), 5.11-5.20 (m, 2H), 4.92-5.01 (m, 2H), 3.95
(app t, J ) 8.3 Hz, 1H), 1.98-2.07 (m, 4H), 1.84-1.92 (m, 1H),
1.38-1.57 (m, 3H), 1.43 (s, 9H), 1.03-1.16 (m, 1H), 0.93 (d, J )
6.6 Hz, 3H), 0.89 (t, J ) 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 169.0, 156.1, 138.6, 122.2, 114.7, 114.0, 80.1, 59.4, 37.0, 33.2,
29.2, 29.0, 28.3, 24.8, 15.6, 11.3; IR (KBr) νmax 3319, 2955, 1680,
1649, 1521, 1168, 953, 646 cm-1; CIMS (NH3 gas) 327 (9), 325
(100), 269 (13), 225 (9); ESIHRMS m/z calcd for C18H32N2O3Na
[M + Na]+ 347.2311, found 347.2323.
N-Boc-isoleucine-allylamide 13. To a solution of N-Boc-
isoleucine 11 (1.75 g, 7.6 mmol) and N-methylmorpholine (1.0 mL,
9.1 mmol) in DME (100 mL) was added isobutyl chloroformate
(1.2 mL, 9.1 mmol) dropwise at 0 °C. The resulting mixture was
stirred at 0 °C for 2 min, and allylamine (11.3 mL) was then added.
The resulting white slurry was vigorously stirred at rt for 1 h and
quenched with water. Dichloromethane was added, the organic layer
was separated, and the aqueous layer was extracted with dichlo-
romethane. Combined organic layers were successively washed with
a 1 M HCl aqueous solution and brine, dried over MgSO4, filtered,
and concentrated under vacuum to yield the desired allylamide 13
as a white solid (2.1 g, 7.6 mmol, quant): mp 106 °C; [R]2D0 -13
(c 2.2, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.64 (s, 1H), 5.71-
5.86 (m, 1H), 5.27 (d, J ) 8.7 Hz, 1H), 5.14 (dd, J ) 17.2, 1.4 Hz,
1H), 5.07 (d, J ) 10.2 Hz, 1H), 3.96 (app t, J ) 7.9 Hz, 1H), 3.84
(app q, J ) 5.9 Hz, 2H), 1.77-1.85 (m, 1H), 1.45-1.55 (m, 1H),
1.39 (s, 9H), 1.01-1.15 (m, 1H), 0.89 (d, J ) 6.2 Hz, 3H), 0.86 (t,
J ) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.9, 156.0, 134.1,
116.4, 79.8, 59.4, 41.8, 37.2, 28.4, 24.8, 15.6, 11.4; IR (KBr) νmax
3319, 2966, 2645, 1675, 1557, 1168, 922, 651 cm-1; CIMS (NH3
gas) 271 (100), 215 (52), 186 (13), 171 (17), 130 (8), 86 (24);
ESIHRMS m/z calcd for C14H26N2O3Na [M + Na]+ 293.1841,
found 293.1837.
N-Boc-isoleucinamide 12. To a solution of N-Boc-isoleucine
11 (5.0 g, 21.6 mmol) and N-methylmorpholine (2.85 mL, 25.9
mmol) in DME (100 mL) was added isobutyl chloroformate (3.35
mL, 25.9 mmol) dropwise at 0 °C. The resulting mixture was stirred
at 0 °C for 2 min, and a solution of ammonia (30 wt % aqueous
solution, 8 mL) was then added. The resulting white slurry was
vigorously stirred at rt for 1 h and quenched with water. Dichloro-
methane was added, the organic layer was separated, and the
aqueous layer was extracted with dichloromethane. Combined
organic layers were successively washed with a 1 M HCl aqueous
solution and brine, dried over MgSO4, filtered, and concentrated
under vacuum to yield the desired amide 12 as a white solid (5.0
g, 21.6 mmol, quant): mp 153 °C; [R]2D0 -7 (c 2.3, CHCl3); H
1
NMR (300 MHz, DMSO-d6) δ 7.26 (s, 1H), 6.99 (s, 1H), 6.55 (d,
J ) 9.0 Hz, 1H), 3.75 (app t, J ) 9.0 Hz, 1H), 1.60-1.70 (m, 1H),
1.32-1.42 (m, 1H), 1.38 (s, 9H), 1.00-1.13 (m, 1H), 0.82 (d, J )
6.7 Hz, 3H), 0.81 (t, J ) 6.7 Hz, 3H); 13C NMR (75 MHz, DMSO-
d6) δ 173.4, 155.3, 77.8, 58.6, 36.4, 28.1, 24.3, 15.5, 11.0; IR (KBr)
ν
max 3380, 3350, 3201, 2955, 1680, 1639, 1516, 1311, 1250, 1157,
661 cm-1; CIMS (NH3 gas) 361 (37), 316 (42), 248 (11), 186 (100),
175 (51), 131 (67), 86 (27); ESIHRMS m/z calcd for C11H22N2O3-
Na [M + Na]+ 253.1528, found 253.1519.
N-Boc-isoleucine-vinylamide 5a. A slurry of N-Boc-isoleucin-
amide 12 (920 mg, 4.0 mmol) in butyl vinyl ether (10 mL) was
N-Boc-isoleucine-prop-1-enylamide 5c. To a solution of N-Boc-
isoleucine-allylamide 13 (1.0 g, 3.7 mmol) in THF (5 mL) was
added RuClH(CO)(PPh3)3 (88 mg, 0.09 mmol). The resulting
solution was refluxed for 2 h and concentrated. The crude residue
was directly purified by flash chromatography over silica gel
(petroleum ether/AcOEt: 8/2) to yield the desired prop-1-enylamide
5c (mixture of E and Z isomer in a 6:4 ratio) as a white solid (925
43
treated with (1,10-phenanthroline)Pd(OCOCF3)2 (205 mg, 0.4
mmol) at 75 °C. The resulting brownish slurry was left open to air
and stirred at 75 °C for 4 h, concentrated, and directly purified by
flash chromatography over silica gel (petroleum ether/AcOEt: 7/3)
to yield the desired vinylamide 5a as a white solid (830 mg, 3.2
mmol, 81%): mp 137 °C; [R]2D0 +5 (c 0.5, CHCl3); 1H NMR (300
MHz, CDCl3) δ 8.83 (d, J ) 9.4 Hz, 1H), 6.89 (app dt, J ) 15.7,
9.4 Hz, 1H), 5.53 (d, J ) 8.3 Hz, 1H), 4.59 (d, J ) 15.7 Hz, 1H),
4.36 (d, J ) 9.4 Hz, 1H), 4.03 (app t, J ) 8.3 Hz, 1H), 1.76-1.83
(m, 1H), 1.46-1.60 (m, 1H), 1.41 (s, 9H), 1.08-1.18 (m, 1H),
0.92 (d, J ) 6.7 Hz, 3H), 0.86 (t, J ) 7.4 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 170.3, 156.4, 128.5, 96.6, 80.1, 59.3, 37.2, 28.4,
25.0, 15.5, 11.1; IR (KBr) νmax 3293, 1675, 1634, 1527, 1245, 1168,
856, 840 cm-1; CIMS (NH3 gas) 257(100), 201 (57), 186 (22),
157 (49), 130 (12), 86 (17); ESIHRMS m/z calcd for C13H24N2O3-
Na [M + Na]+ 279.1685, found 279.1694.
mg, 3.4 mmol, 92%): mp 92 °C; [R]2D0 -12 (c 0.5, CHCl3); H
1
NMR (300 MHz, DMSO-d6) δ 9.70 (d, J ) 9.9 Hz, 0.6H), 9.25
(d, J ) 10.2 Hz, 0.4H), 6.86 (d, J ) 8.6 Hz, 0.4H), 6.78 (d, J )
8.6 Hz, 0.6H), 6.48-6.61 (m, 1H), 5.18 (dq, J ) 6.8, 6.8 Hz, 0.6H),
4.69 (dq, J ) 8.6, 7.1 Hz, 0.4H), 3.99 (app t, J ) 8.6 Hz, 0.4H),
3.76 (app t, J ) 8.6 Hz, 0.6H), 1.57-1.70 (m, 1H), 1.63 (dd, J )
7.4, 1.7 Hz, 1.8H), 1.61 (dd, J ) 8.0, 1.4 Hz, 1.2H), 1.33-1.47
(m, 1H), 1.37 (s, 9H), 1.03-1.15 (m, 1H), 0.76-0.83 (m, 6H);
13C NMR (75 MHz, DMSO-d6) δ 170.0 and 169.0 (isomers), 155.4
and 155.3 (isomers), 123.7 and 122.0 (isomers), 106.7 and 105.3
(isomers), 77.9, 58.7 and 58.3 (isomers), 36.2, 28.1, 24.5 and 24.4
(isomers), 15.3, 14.8 and 11.3 (isomers), 10.7; IR (KBr) νmax 3309,
3053, 2971, 1685, 1542, 1240, 1173, 651 cm-1; ESIMS (positive
(E)-N-Boc-isoleucine-hepta-1,6-dienylamide 5b. A 15 mL
pressure tube was charged with N-Boc-isoleucinamide 12 (920 mg,
(43) Prepared according to McKeon, J. E.; Fitton, P. Tetrahedron 1972,
28, 233-238.
(44) Iyer, R. S.; Kuo, G.-H.; Helquist, P. J. Org. Chem. 1985, 50, 5898-
5900.
1278 J. Org. Chem., Vol. 73, No. 4, 2008

Total Synthesis of the Cyclopeptide Alkaloid Paliurine E
mode) 293.3 (100), 234.4 (33), 193.3 (57); ESIHRMS m/z calcd
for C14H26N2O3Na [M + Na]+ 293.1841, found 293.1839.
warmed to rt. The yellow reaction mixture was quenched with water
and diluted with ether. The aqueous layer was extracted with ether,
and the combined organic layers were successively washed with a
1 M HCl aqueous solution, a saturated aqueous solution of NaHCO3,
and brine, dried over MgSO4, filtered, and concentrated. The crude
residue was finally purified by flash chromatography over silica
gel to give the desired substrates for RCM 16a-d.
Alternate Procedure for Isomerization of 13 to 5c Using
Grubbs’ Second-Generation Catalyst. A solution of N-Boc-
isoleucine-allylamide 13 (405 mg, 1.5 mmol) in toluene (40 mL)
was treated with benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-
imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium
(Grubbs’ second-generation catalyst, 10 mg, 0.01 mmol) at 95 °C
for 3 days. The resulting greenish solution was then concentrated
and directly purified by flash chromatography over silica gel (CH2-
Cl2/MeOH: 95/5) to yield the desired prop-1-enylamide 5c (mixture
of E and Z isomer in a 6:4 ratio) as a white solid (351 mg, 1.3
mmol, 87%).
(2S,3S)-[1-tert-Butoxycarbonyl-3-(4-methoxy-3-vinylphen-
oxy)prolyl]isoleucine-vinylamide 16a. Solvent system for purifica-
tion by flash chromatography over silica gel: AcOEt/petroleum
ether 3/7; white solid (scale 253 mg of compound obtained; yield
86%): mp 75 °C; [R]2D0 -36 (c 0.1, CHCl3); 1H NMR (300 MHz,
DMSO-d6, 345 K) δ 9.77 (d, J ) 9.8 Hz, 1H), 7.78 (d, J ) 8.6 Hz,
1H), 7.14 (d, J ) 2.7 Hz, 1H), 6.87-6.97 (m, 3H), 6.79 (ddd, J )
15.9, 9.8, 8.8 Hz, 1H), 5.81 (dd, J ) 17.7, 1.5 Hz, 1H), 5.26 (dd,
J ) 11.2, 1.5 Hz, 1H), 4.80 (br s, 1H), 4.72 (d, J ) 15.9 Hz, 1H),
4.38 (s, 1H), 4.35 (d, J ) 8.8 Hz, 1H), 4.25 (app t, J ) 8.3 Hz,
1H), 3.77 (s, 3H), 3.37-3.61 (m, 2H), 2.00-2.13 (m, 2H), 1.78-
1.86 (m, 1H), 1.38-1.51 (m, 1H), 1.40 (s, 9H), 1.08-1.26 (m,
1H), 0.84-0.90 (m, 6H); 13C NMR (75 MHz, DMSO-d6, 345 K)
δ 169.3, 168.9, 153.9, 151.6, 150.6, 131.1, 129.0, 127.1, 116.5,
115.1, 114.0, 113.2, 95.5, 80.5 (br), 79.3, 69.5, 66.2, 57.2, 44.8,
36.5, 28.0, 24.4, 18.8, 15.3, 10.7; IR (KBr) νmax 3293, 2966, 2648,
1644, 1701, 1393, 1209, 1163 cm-1; CIMS (NH3 gas) 502 (100),
458 (72), 402 (52), 401 (43), 375 (8), 352 (9), 331 (8); ESIHRMS
m/z calcd for C27H39N3O6Na [M + Na]+ 524.2737, found 524.2717.
(2S,3S)-[1-tert-Butoxycarbonyl-3-(4-methoxy-3-vinylphen-
oxy)prolyl]isoleucine-prop-1-enylamide 16b. Solvent system for
purification by flash chromatography over silica gel: AcOEt/
petroleum ether 35/65; white solid, obtained as a mixture of E and
Z isomer in a 1:1 ratio (scale 146 mg of compound obtained; yield
79%): mp 62 °C; [R]2D0 -42 (c 0.5, CHCl3); 1H NMR (300 MHz,
DMSO-d6, 345 K) δ 9.55 (d, J ) 9.5 Hz, 0.5H), 9.17 (d, J ) 9.7
Hz, 0.5H), 7.80 (d, J ) 8.7 Hz, 0.5H), 7.75 (d, J ) 8.6 Hz, 0.5H),
7.15 (br s, 1H), 6.88-6.97 (m, 3H), 6.50-6.62 (m, 1H), 5.81 (dd,
J ) 17.8, 1.0 Hz, 1H), 5.20-5.30 (m, 1.5H), 4.80 (br s, 1H), 4.69-
4.79 (m, 0.5H), 4.43 (app t, J ) 7.8 Hz, 0.5H), 4.39 (br s, 1H),
4.22 (app t, J ) 8.0 Hz, 0.5H), 3.77 (s, 3H), 3.42-3.61 (m, 2H),
2.00-2.13 (m, 2H), 1.76-1.89 (m, 1H), 1.61-1.65 (m, 3H), 1.43-
1.54 (m, 1H), 1.40 (s, 9H), 1.06-1.22 (m, 1H), 0.82-0.89 (m,
6H); 13C NMR (75 MHz, DMSO-d6, 345 K) δ 169.0 and 168.9
(stereoisomers), 168.6 and 167.7 (stereoisomers), 154.4 (br), 151.2,
150.3, 130.7, 126.8, 123.4 and 121.7 (stereoisomers), 116.1, 114.7,
113.7, 112.9, 106.9 and 105.5 (stereoisomers), 80.4 (br), 78.9, 65.8,
56.7 and 56.3 (stereoisomers), 55.9 and 55.8 (stereoisomers), 44.4,
36.3, 29.0 (br), 27.6, 24.0 and 23.9 (stereoisomers), 14.9, 14.1 and
10.7 (stereoisomers), 10.4; IR (KBr) νmax 3303, 2960, 1685, 1650,
1531, 1486, 1404, 1214, 1168 cm-1; ESIMS (positive mode) 538.4;
ESIHRMS m/z calcd for C28H41N3O6Na [M + Na]+ 538.2893,
found 538.2890.
N-Boc-isoleucine-allylbenzylamide 14. To a solution of N-Boc-
isoleucine 11 (2.0 g, 8.3 mmol) and allylbenzylamine (1.35 g, 9.2
mmol) in DMF (50 mL) was added 1-hydroxybenzotriazole (HOBt,
1.3 g, 9.6 mmol). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC, 1.8 g, 9.4 mmol) and N-methylmorpholine
(1.8 mL, 16.6 mmol) were next added at 0 °C, and the solution
was stirred for 16 h while being progressively warmed to rt. The
yellow reaction mixture was quenched with water and diluted with
ether. The aqueous layer was extracted with ether, and the combined
organic layers were successively washed with a 1 M HCl aqueous
solution, a saturated aqueous solution of NaHCO3, and brine, dried
over MgSO4, filtered, and concentrated. The crude residue was
purified by flash chromatography over silica gel (AcOEt/petroleum
ether: 2/8) to give the desired benzylallylamide 14 (2.8 g, 7.8 mmol,
90%) as a white solid: mp 48 °C; [R]2D0 -30 (c 2.9, CHCl3); H
1
NMR (300 MHz, DMSO-d6, 365 K) δ 7.24-7.34 (m, 5H), 6.26
(d, J ) 8.3 Hz, 1H), 5.74-5.84 (m, 1H), 5.13-5.17 (m, 2H), 4.58
(br s, 2H), 4.29 (app t, J ) 8.3 Hz, 1H), 3.91-4.03 (m, 2H), 1.75-
1.86 (m, 1H), 1.46-1.58 (m, 1H), 1.40 (s, 9H), 1.05-1.19 (m,
1H), 0.85 (d, J ) 7.4 Hz, 3H), 0.84 (t, J ) 7.3 Hz, 3H); 13C NMR
(75 MHz, DMSO-d6, 365 K) δ 172.5, 155.7, 138.1, 134.2, 128.7,
127.9, 127.5, 117.4, 78.8, 55.1, 55.0, 37.1, 28.6, 24.4, 16.1, 11.1;
IR (KBr) νmax 3278, 2991, 1696, 1629, 1168 cm-1; CIMS (NH3
gas) 361 (100), 305 (12); ESIHRMS m/z calcd for C21H32N2O3Na
[M + Na]+ 383.2311, found 383.2296.
(E)-N-Boc-isoleucine-benzylprop-1-enylamide 5d. To a solu-
tion of N-Boc-isoleucine-allylbenzylamide 14 (1.0 g, 2.8 mmol) in
THF (7 mL) was added RuClH(CO)(PPh3)3 (67 mg, 0.07 mmol).
The resulting solution was refluxed for 2 h and concentrated. The
crude residue was purified by flash chromatography over silica gel
(petroleum ether/AcOEt: 9/1) to yield the desired enamide 5d (E
isomer) as a white solid (860 mg, 2.4 mmol, 86%): mp 77 °C;
[R]2D0 +80 (c 1.7 CHCl3); 1H NMR (300 MHz, DMSO-d6) δ
7.13-7.33 (m, 6H), 6.97 (d, J ) 13.5 Hz, 1H), 5.01 (dq, J ) 13.5,
6.2 Hz, 1H), 4.88 (A of AB syst., J ) 15.8 Hz, 1H), 4.75 (B of
AB syst., J ) 15.8 Hz, 1H), 4.49 (app t, J ) 8.4 Hz, 1H), 1.78-
1.85 (m, 1H), 1.60 (d, J ) 6.2 Hz, 3H), 1.39-1.55 (m, 1H), 1.40
(s, 9H), 1.12-1.24 (m, 1H), 0.85 (d, J ) 5.4 Hz, 3H), 0.84 (t, J )
6.9 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 171.1, 155.7, 137.4,
128.2, 126.6, 126.5, 108.3, 78.1, 55.1, 46.3, 35.9, 28.1, 24.1, 15.4,
15.1, 11.0; IR (KBr) νmax 3350, 2955, 1649, 1527, 1163, 968, 738
cm-1; CIMS (NH3 gas) 361 (100), 305 (9); ESIHRMS m/z calcd
for C21H32N2O3Na [M + Na]+ 383.2311, found 383.2323.
Typical Procedure for Fragment Coupling. To a solution of
Boc-protected isoleucinamide enamide derivative 5a-d (0.44
mmol) in CH2Cl2 (10 mL) was added anhydrous zinc(II) bromide
(446 mg, 1.98 mmol) at 0 °C. The resulting white slurry was
vigorously stirred at 0 °C for 1 h, slowly warmed to rt, stirred for
another 1 h, and concentrated. Carboxylic acid 4 (150 mg, 0.41
mmol), 1-hydroxybenzotriazole (HOBt, 54 mg, 0.40 mmol), and
DMF (8 mL) were next added to the resulting white solid. After
complete dissolution of all solids, 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDC, 87 mg, 0.45 mmol) and
N-methylmorpholine (115 µL, 1.04 mmol) were next added at 0
°C, and the solution was stirred for 16 h while being progressively
(E,2S,3S)-[1-tert-Butoxycarbonyl-3-(4-methoxy-3-vinylphenoxy)-
prolyl]isoleucine-hepta-1,6-dienylamide 16c. Solvent system for
purification by flash chromatography over silica gel: AcOEt/
petroleum ether 3/7; white foamy solid, obtained as E enamide
isomer (scale 194 mg of compound obtained; yield 85%): [R]D20
1
-37 (c 0.3, CHCl3); H NMR (300 MHz, DMSO-d6, 345 K) δ
9.54 (d, J ) 9.6 Hz, 1H), 7.75 (d, J ) 8.7 Hz, 1H), 7.15 (d, J )
2.6 Hz, 1H), 6.87-6.97 (m, 3H), 6.57 (ddt, J ) 14.3, 9.6, 1.3 Hz,
1H), 5.82-5.88 (m, 1H), 5.74-5.80 (m, 1H), 5.21-5.31 (m, 2H),
4.93-5.04 (m, 2H), 4.81 (br m, 1H), 4.38 (app s, 1H), 4.23 (t, J )
8.0 Hz, 1H), 3.77 (s, 3H), 3.53-3.62 (m, 1H), 3.42-3.52 (m, 1H),
1.96-2.08 (m, 6H), 1.77-1.86 (m, 1H), 1.38-1.52 (m, 2H), 1.40
(s, 9H), 1.08-1.21 (m, 2H), 0.86 (d, J ) 6.8 Hz, 3H), 0.85 (app t,
J ) 7.4 Hz, 3H); 13C NMR (75 MHz, DMSO-d6, 345 K) δ 169.3,
168.2, 153.9, 151.6, 150.6, 138.4, 131.1, 127.1, 123.1, 116.5, 115.1,
114.5, 114.0, 113.2, 112.4, 80.9, 79.3, 66.2, 57.2, 56.2, 44.8, 36.6,
32.4, 28.7, 28.6, 28.0, 24.4, 15.3, 10.7; IR (KBr) νmax 3305, 1692,
J. Org. Chem, Vol. 73, No. 4, 2008 1279

Toumi et al.
1487, 1220; 1165 cm-1; ESIMS (positive mode) 593.3; ESIHRMS
cm-1; CIMS (NH3 gas) 491.0 (100), 473.0 (57), 418.0 (42); HRMS
(CI, NH3) m/z calcd for C25H36N3O6 [M + H]+ 474.2604, found
474.2607.
m/z calcd for C32H47N3O6Na [M + Na]+ 592.3363, found 592.3379.
(E,2S,3S)-[1-tert-Butoxycarbonyl-3-(4-methoxy-3-vinylphenoxy)-
prolyl]isoleucine-benzylprop-1-enylamide 16d. Solvent system for
purification by flash chromatography over silica gel: AcOEt/
petroleum ether 1/9; white oily solid, obtained as E enamide isomer
(scale 284 mg of compound obtained; yield 91%): [R]2D0 +18 (c
(E,2S,3S)-[1-tert-Butoxycarbonyl-3-(3-formyl-4-methoxyphen-
oxy)prolyl]isoleucine-benzylprop-1-enylamide 18. Solvent system
for purification by flash chromatography over silica gel: AcOEt/
petroleum ether 3/7; oily solid, obtained as E enamide isomer
(scale: 18 mg of compound obtained; yield obtained using 1 equiv
1
0.3, CHCl3); H NMR (300 MHz, DMSO-d6, 345 K) δ 8.12 (d, J
of GII: 39%): [R]2D0 +18 (c 0.3, CHCl3); H NMR (300 MHz,
1
) 8.0 Hz, 1H), 7.10-7.28 (m, 6H), 6.84-6.97 (m, 4H), 5.78 (d, J
) 17.8 Hz, 1H), 5.25 (dd, J ) 11.2, 1.4 Hz, 1H), 5.15 (dq, J )
13.8, 6.5 Hz, 1H), 4.75-4.83 (m, 3H), 4.71 (br s, 1H), 4.43 (s,
1H), 3.77 (s, 3H), 3.57-3.64 (m, 1H), 3.40-3.53 (m, 1H), 2.04-
2.11 (m, 2H), 1.87-1.98 (m, 1H), 1.63 (dd, J ) 6.5, 1.4 Hz, 3H),
1.47-1.51 (m, 1H), 1.40 (s, 9H), 1.07-1.21 (m, 1H), 0.86 (br m,
6H); 13C NMR (75 MHz, DMSO-d6, 345 K) δ 170.2, 169.4, 153.7,
151.6, 150.6, 137.4, 131.2, 131.1, 128.2, 127.1, 126.7, 116.5, 115.1,
114.1, 113.2, 110.5 (br), 81.0 (br), 79.2, 56.2, 53.7, 47.2, 44.8, 39.0,
29.2, 28.0, 23.9, 15.5, 14.9, 10.7; IR (KBr) νmax 3297, 1668, 1642,
1173 cm-1; CIMS (NH3 gas) 606 (100), 532 (42), 458 (23), 376
(22), 287 (31), 170 (29), 148 (41); ESIHRMS m/z calcd for
C35H47N3O6Na [M + Na]+ 628.3363, found 628.3347.
DMSO-d6, 345 K) δ 10.32 (s, 1H), 8.15 (br s, 1H), 7.16-7.31 (m,
9H), 5.14 (dq, J ) 13.3, 6.6 Hz, 1H), 4.80-4.82 (m, 3H), 4.71 (br
s, 1H), 4.43 (s, 1H), 3.90 (s, 3H), 3.54-3.61 (m, 1H), 3.40-3.49
(m, 1H), 2.00-2.07 (m, 2H), 1.87-1.96 (m, 1H), 1.63 (dd, J )
6.6, 1.5 Hz, 3H), 1.47-1.51 (m, 1H), 1.40 (s, 9H), 1.08-1.21 (m,
1H), 0.78-9.88 (br m, 6H); 13C NMR (75 MHz, DMSO-d6, 345
K) δ 188.6, 170.1, 169.2, 156.7, 150.5, 137.4, 128.2, 126.6, 125.1,
124.7, 114.8, 114.2, 80.1 (br), 79.2, 56.6, 53.7, 47.2, 44.6, 36.2,
30.1 (br), 28.0, 23.9, 15.5, 14.9, 10.7; IR (KBr) νmax 3281, 17235,
1278, 1145, 840 cm-1; CIMS (CH4 gas) 608 (100), 552 (53), 461
(13), 405 (12); ESIHRMS m/z calcd for C34H45N3O7Na [M + Na]+
630.3155, found 630.3148.
(2S,3S)-[1-tert-Butoxycarbonyl-3-(4-methoxy-3-vinylphen-
oxy)prolyl]isoleucine-allylamide 20. To a solution of N-Boc-
isoleucine-allylamide 13 (80 mg, 0.30 mmol) in CH2Cl2 (6 mL)
was added anhydrous zinc(II) bromide (304 mg, 1.35 mmol) at 0
°C. The resulting white slurry was vigorously stirred at 0 °C for 1
h, slowly warmed to rt, stirred for another 1 h, and concentrated.
Carboxylic acid 4 (100 mg, 0.275 mmol), 1-hydroxybenzotriazole
(HOBt, 36 mg, 0.0.31 mmol), and DMF (5 mL) were next added
to the resulting white solid. After complete dissolution of all solids,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC,
60 mg, 0.31 mmol) and N-methylmorpholine (76 µL, 0.69 mmol)
were next added at 0 °C, and the solution was stirred for 16 h while
being progressively warmed to rt. The yellow reaction mixture was
quenched with water and diluted with ether. The aqueous layer was
extracted with ether, and the combined organic layers were
successively washed with a 1 M HCl aqueous solution, a saturated
aqueous solution of NaHCO3, and brine, dried over MgSO4, filtered,
and concentrated. The crude residue was finally purified by flash
chromatography over silica gel (petroleum ether/AcOEt: 3/7) to
yield the desired acyclic allylamide 20 as a white glassy solid (130
mg, 0.252 mmol, 92%): [R]2D0 -31 (c 0.2, CHCl3); 1H NMR (300
MHz, DMSO-d6, 345 K) δ 8.00 (br s, 1H), 7.67 (d, J ) 8.5 Hz,
1H), 7.14 (d, J ) 2.8 Hz, 1H), 6.87-7.00 (m, 3H), 5.73-5.87 (m,
2H), 5.26 (dd, J ) 11.2, 1.6 Hz, 1H), 5.13 (app dq, J ) 17.2, 1.6
Hz, 1H), 5.04 (app dq, J ) 10.2, 1.6 Hz, 1H), 4.81 (br m, 1H),
4.38 (app s, 1H), 4.22 (dd, J ) 8.7, 7.3 Hz, 1H), 3.77 (s, 3H),
3.70-3.83 (m, 2H), 3.62 (app tt, J ) 11.0, 3.2 Hz, 1H), 3.45-
3.57 (m, 1H), 2.08 (br m, 1H), 1.76-1.90 (m, 1H), 1.38-1.51 (m,
1H), 1.40 (s, 9H), 1.04-1.18 (m, 2H), 0.82-0.90 (m, 6H); 13C
NMR (75 MHz, DMSO-d6, 345 K) δ 170.3, 169.1, 153.9, 151.6,
150.6, 135.0, 131.1, 127.1, 116.5, 115.2, 114.7, 114.0, 113.2, 79.3,
69.8, 66.2, 57.2, 56.3, 44.8, 40.9, 36.8, 28.0, 24.4, 18.8, 15.4, 10.8;
IR (KBr) νmax 3301, 2984, 1686, 1532, 1170 cm-1; ESIMS (positive
mode) 539.3, 538.3; ESIHRMS m/z calcd for C28H41N3O6Na [M
+ Na]+ 538.2893, found 538.2880.
Typical Procedure for Ene-Enamide RCM Reaction. A 25
mL round-bottom flask was charged with vinyl enamide derivative
16a-d (0.07 mmol). The flask was fitted with a condenser,
evacuated under high vacuum, and backfilled with argon. Dry and
degassed 1,2-dichloroethane (15 mL) and benzylidene[1,3-
bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(t-
ricyclohexylphosphine)ruthenium (Grubbs’ second-generation cata-
lyst, 6 mg, 0.007 mmol) were successively added, and the resulting
purple reaction mixture was refluxed for 24 h. Another portion of
Grubbs’ second-generation catalyst (6 mg, 0.007 mmol) was then
added, and the reaction mixture was refluxed for 24 h, cooled to
rt, left open to air for 1 h, concentrated, and directly purified by
flash chromatography over silica gel.
(2S,3S)-[1-tert-Butoxycarbonyl-3-(4-methoxy-3-vinylphen-
oxy)prolyl]soleucinamide 17. Solvent system for purification by
flash chromatography over silica gel: AcOEt/petroleum ether 8/2;
white glassy solid (scale 72 mg of compound obtained from 16a):
mp 85 °C; [R]2D0 -25 (c 0.7, CHCl3); 1H NMR (300 MHz, DMSO-
d6, 345 K) δ 7.61 (d, J ) 8.7 Hz, 1H), 7.16 (d, J ) 2.7 Hz, 1H),
6.88-7.12 (m, 4H), 5.82 and 5.26 (rotamers, dd, J ) 17.7, 1.5 Hz,
dd, J ) 11.2, 1.5 Hz, 1H), 4.84 (br s, 1H), 4.39 (app s, 1H), 4.21
(dd, J ) 8.5, 6.6 Hz, 1H), 3.78 (s, 3H), 3.57 (app tt, J ) 10.6, 2.9
Hz, 1H), 3.42-3.51 (m, 1H), 2.07-2.10 (br m, 2H), 1.76-1.85
(m, 1H), 1.40-1.54 (m, 1H), 1.41 (s, 9H), 1.04-1.18 (m, 1H),
0.89 (d, J ) 6.8 Hz, 3H), 0.86 (d, J ) 7.4 Hz, 3H); 13C NMR (75
MHz, DMSO-d6, 345 K) δ 172.1, 168.7, 153.5, 151.2, 150.3, 130.8,
127.5, 116.1, 114.8, 113.7, 112.9, 80.4 (br), 79.0, 65.9, 56.6, 55.9,
44.4, 36.4, 29.0 (br), 27.7, 24.0, 15.1, 10.6; IR (KBr) νmax 3319,
2966, 1690, 1486, 1388, 1219, 1173 cm-1; ESIMS (positive mode)
499.3, 498.3; ESIHRMS m/z calcd for C25H37N3O6Na [M + Na]+
498.2580, found 498.2589.
Cyclopeptide Core 2. Solvent system for purification by flash
chromatography over silica gel: Et2O/EtOH 99/1; white solid (scale
67 mg of compound obtained from 16b): mp 188 °C; [R]2D0 -436
(c 0.54, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.43 (d, J ) 11.2
Hz, 1H), 7.22 (d, J ) 5.0 Hz, 1H), 6.87 (dd, J ) 6.9, 11.2 Hz,
1H), 6.83 (d, J ) 9.2 Hz, 1H), 6.74 (dd, J ) 2.9, 8.9 Hz, 1H), 6.65
(d, J ) 2.9 Hz, 1H), 5.85 (d, J ) 9.1 Hz, 1H), 5.43 (dt, J ) 2.7,
8.1 Hz, 1H), 4.25 (app t, J ) 4.6 Hz, 1H), 4.15 (d, J ) 2.6 Hz,
1H), 3.70-3.78 (m, 1H), 3.73 (s, 3H), 3.30-3.39 (m, 1H), 2.39-
2.50 (m, 1H), 2.14-2.24 (m, 1H), 2.00-2.10 (m, 1H), 1.38 (s,
9H), 1.05-1.32 (m, 2H), 0.93 (d, J ) 7.0 Hz, 3H), 0.81 (t, J ) 9.8
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.4, 167.6, 155.3, 151.6,
151.4, 124.5, 121.7, 117.8, 113.9, 111.5, 106.7, 81.2, 78.0, 64.9,
60.4, 56.2, 46.0, 35.3, 32.2, 28.4, 24.6, 16.2, 11.9; IR (KBr) νmax
3319, 2919, 1706, 1650, 1506, 1404, 1214, 1163, 1122, 1030, 764
Cyclopeptide Core 2 via Isomerization/Ene-Enamide RCM
Tandem Reaction. A 25 mL round-bottom flask was charged with
allylamide derivative 20 (35 mg, 0.07 mmol). The flask was fitted
with a condenser, evacuated under high vacuum, and backfilled
with argon. Dry and degassed 1,2-dichloroethane (15 mL) and
benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-
dichloro(tricyclohexylphosphine)ruthenium (Grubbs’ second-gen-
eration catalyst, 6 mg, 0.007 mmol) were successively added, and
the resulting purple reaction mixture was refluxed for 24 h. Another
portion of Grubbs’ second-generation catalyst (6 mg, 0.007 mmol)
was then added, and the reaction mixture was refluxed for 24 h,
cooled to rt, left open to air for 1 h, concentrated, and directly
1280 J. Org. Chem., Vol. 73, No. 4, 2008

Total Synthesis of the Cyclopeptide Alkaloid Paliurine E
purified by flash chromatography over silica gel (Et2O/EtOH: 99/
1) to yield the desired cyclopeptide core 2 (11.5 mg, 0.024 mmol,
36%) as a white solid (see characterization above).
a saturated aqueous solution of NH4Cl and diluted with ether. The
aqueous layer was extracted with ether, and the combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated. The crude residue was purified by flash chromatog-
raphy over silica gel (CH2Cl2/MeOH/30 wt % aqueous NH3 95/3/
2) to give the desired synthetic paliurine E 1 (52 mg, 95 µmol,
78% over two steps) as a white solid: Rf 0.56 (AcOEt/EtOH 95/
5); mp 190 °C (lit. unreported); [R]2D0 -298 (c 0.6, CH3CN) [lit.20
Deprotected Cyclopeptide Core 21. To a solution of 2 (58 mg,
0.122 mmol) in dichloromethane (3 mL) were added at -10 °C
2,6-lutidine (15 µL, 0.122 mmol) and trimethylsilyl trifluo-
romethanesulfonate (1.4 M solution in dichloromethane, 350 µL,
0.49 mmol). The resulting light pink solution was stirred for 1 h
while being progressively warmed to 0 °C. The mixture was next
hydrolyzed at 0 °C by addition of a saturated aqueous solution of
NaHCO3 and diluted with dichloromethane. The aqueous layer was
extracted with dichloromethane, and the combined organic layers
were washed with brine, dried over MgSO4, filtered, and concen-
trated to give the desired N-deprotected macrocycle 21 as a white
solid which was used without further purification for the next step
(quantitative mass recovery): mp 218 °C; [R]2D0 -452 (c 0.49,
natural paliurine E [R]D20 -382 (c 0.9, CH3CN)]; H NMR (300
1
MHz, CDCl3) δ 8.43 (d, J ) 11.4 Hz, 1H), 7.40 (d, J ) 4.5 Hz,
1H), 7.15-7.24 (m, 3H), 7.06 (dd, J ) 7.7, 1.7 Hz, 2H), 6.94 (dd,
J ) 9.2, 11.3 Hz, 1H), 6.88 (d, J ) 9.0 Hz, 1H), 6.79 (dd, J ) 9.0,
2.9 Hz, 1H), 6.68 (d, J ) 2.9 Hz, 1H), 5.91 (d, J ) 9.1 Hz, 1H),
5.41 (dt, J ) 7.2, 3.0 Hz, 1H), 4.44 (d, J ) 3.0 Hz, 1H), 4.24 (app
t, J ) 4.2 Hz, 1H), 4.00 (ddd, J ) 10.9, 8.5, 2.7 Hz, 1H), 3.79 (s,
3H), 3.44 (dd, J ) 10.3, 3.5 Hz, 1H), 3.06 (dd, J ) 13.0, 10.6 Hz,
1H), 2.92 (dd, J ) 13.0, 3.3 Hz, 1H), 2.86 (dt, J ) 4.2, 10.7 Hz,
1H), 2.40 (s, 6H), 2.36-2.39 (m, 1H), 2.03-2.21 (m, 2H), 1.13-
1.48 (m, 2H), 1.01 (d, J ) 7.0 Hz, 3H), 0.92 (t, J ) 7.3 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 171.3, 170.3, 167.4, 151.6, 151.2,
138.3, 129.1, 128.7, 126.7, 124.5, 121.7, 117.6, 113.9, 111.4, 106.7,
76.9, 68.2, 64.6, 60.5, 56.2, 46.0, 42.1, 35.7, 32.5, 32.4, 24.8, 16.4,
12.1; UV λmax (log ꢀ) 219 (4.81), 320 (4.51); IR (KBr) νmax 3391,
3350, 2966, 2933, 2873, 1670, 1644, 1503, 1460, 1420, 1383, 1296,
1260, 1220, 1178, 1050, 810, 794, 748, 701 cm-1; ESIMS (positive
mode) 571.5 (100), 549.5 (83), 359.5 (11), 148.2 (34); ESIHRMS
m/z calcd for C31H41N4O5 [M + H]+ 549.3077, found 549.3069.
1
CHCl3); H NMR (300 MHz, CDCl3) δ 8.50 (br s, 1H), 6.91 (dd,
J ) 9.2, 11.3 Hz, 1H), 6.92 (d, J ) 9.1 Hz, 1H), 6.82 (dd, J ) 2.9,
9.0 Hz, 1H), 6.65 (br s, 1H), 5.95 (d, J ) 8.9 Hz, 1H), 5.09-5.11
(m, 1H), 4.32 (br s, 1H,), 3.79 (s, 3H), 3.43 (br s, 1H), 3.13-3.20
(m, 1H), 2.90-2.95 (m, 1H), 2.16-2.26 (m, 3H), 1.95-2.03 (br
m, 1H), 1.37-1.47 (m, 1H), 1.02-1.14 (m, 1H), 0.94 (d, J ) 6.9
Hz, 3H), 0.87 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
173.0, 167.0 (br), 151.2, 151.1, 124.1, 121.5, 117.5, 113.8, 111.1,
107.2, 80.9, 69.6, 60.1 (br), 56.1, 47.5 (br), 35.6 (br), 32.0, 25.3,
16.0, 11.7; ESIMS (positive mode) 412.3; HRMS (CI, NH3) m/z
calcd for C20H28N3O4 [M + H]+ 374.2080, found 374.2069.
Paliurine E 1. To a cooled solution of N,N-dimethyl-L-
phenylalanine (36 mg, 0.18 mmol) and 1-hydroxyazabenzotriazole
(HOAt, 30 mg, 0.22 mmol) in DMF (3 mL) were added O-(7-
azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-
phosphate (HATU, 65 mg, 0.17 mmol) and diisopropylethylamine
(90 µL, 0.51 mmol) at 0 °C. The resulting yellow solution was
stirred at 0 °C for 20 min and added dropwise via cannula to a
cooled solution of 21 (46 mg, 0.122 mmol) in DMF (2 mL) at 0
°C. The flask containing the activated acid was rinsed with an
additional portion of DMF (1 mL), which was cannulated into the
solution of the amine. The resulting yellow solution was warmed
to rt and stirred overnight. The mixture was quenched at 0 °C with
Acknowledgment. We thank the CNRS for financial sup-
port. M.T. acknowledges the Ministe`re de la Recherche for a
graduate fellowship.
Supporting Information Available: Characterization data and
1
copies of H and 13C NMR spectra for all new compounds and
paliurine E. Paliurine E spectral data compared to reported data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO702092X
J. Org. Chem, Vol. 73, No. 4, 2008 1281