Highly convergent route to cyclopeptide alkaloids. Total synthesis of ziziphine N

Article abstract of DOI:10.1021/ol070271f

Figure presented A highly convergent protocol to cyclopeptide alkaloids, as demonstrated by the first total synthesis of antiplasmodial agent ziziphine N, is developed. The key elements include construction of its aryl ether unit via Mitsunobu reaction, i

Full text of DOI:10.1021/ol070271f

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1367-1369
Highly Convergent Route to
Cyclopeptide Alkaloids. Total Synthesis
of Ziziphine N
Gang He, Jing Wang, and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
madw@mail.sioc.ac.cn
Received February 2, 2007
ABSTRACT
A highly convergent protocol to cyclopeptide alkaloids, as demonstrated by the first total synthesis of antiplasmodial agent ziziphine N, is
developed. The key elements include construction of its aryl ether unit via Mitsunobu reaction, installation of its enamide part via CuI/N,N-
dimethylglycine-catalyzed coupling reaction, and ring closure with coupling agents such as FDDP and DPPA.
Cyclopeptide alkaloids are a growing family that contains
over 200 members discovered from a wide range of plant
species.1 Since historically many of these species have been
used for medicinal purposes in the treatment of a variety of
ailments, it is not surprising that cyclopeptide alkaloids are
found to possess significant biological properties (such as
sedative, antibacterial, antiplasmodial, and antifungal activi-
ties)1a and thus may serve as leads for drug discovery.
However, restricted natural availability of these compounds
and lack of practical synthetic methods do not allow
systematic studies on the biological properties.1a This fact,
together with their intriguing structures, has caused a steady
stream of studies directed toward synthesis of these natural
products during the past decades.2-7
Structurally, cyclopeptide alkaloids contain a 13-, 14-, or
15-membered macrocycle bearing a peptide unit, which is
connected to a benzene ring with either a 1,4- or a
(2) For a comprehensive review, see: Joullie´, M. M.; Richard, D. J.
Chem. Commun. 2004, 2011-2015.
(3) For macrocyclization studies, see: (a) Lagarias, J. C.; Houghten, R.
A.; Rapoport, H. J. Am. Chem. Soc. 1978, 100, 8202-8212 and references
cited therein. (b) Schmidt, U.; Griesser, H.; Lieberknecht, A.; Talbiersky,
J. Angew. Chem., Int. Ed. Engl. 1981, 20, 280-281. (c) Nutt, R. F.; Chen,
K.-M.; Joullie´, M. M. J. Org. Chem. 1984, 49, 1013-1021.
(1) For a recent review, see: (a) Gournelis, D. C.; Laskaris, G. G.;
Verpoorte, R. Nat. Prod. Rep. 1997, 75-82. For recent reports on isolation,
see: (b) Lin, H.; Chen, C.-H.; You, B.-J.; Liu, K. C. S. C.; Lee, S.-S. J.
Nat. Prod. 2000, 63, 1338-1343. (c) Morel, A. F.; Araujo, C. A.; Silva,
U. F.; Hoelzel, S. C. S. M.; Za´chia, R.; Bastos, N. R. Phytochemistry 2002,
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Chim. Acta 2003, 86, 127-138. (e) Suksamrarn, S.; Suwannapoch, N.;
Aunchai, N.; Kuno, M.; Ratananukul, P.; Haritakun, R.; Jansakul, C.;
Ruchirawat, S. Tetrahedron 2005, 61, 1175-1180. (f) Morel, A. F.;
Maldaner, G.; Ilha, V.; Missau, F.; Silva, U. F.; Dalcol, I. I. Phytochemistry
2005, 66, 2571-2576.
(4) (a) Schmidt, U.; Lieberknecht, A.; Griesser, H.; Ha¨usler, J. Angew.
Chem., Int. Ed. Engl. 1981, 20, 281-282. (b) Schmidt, U.; Lieberknecht,
A.; Griesser, H. Angew. Chem., Int. Ed. Engl. 1981, 20, 1026-1027. (c)
Schmidt, U.; Schanbacher, U. Angew. Chem., Int. Ed. Engl. 1983, 22, 152-
153. (d) Schmidt, U.; Za¨h, M.; Lieberknecht, A. J. Chem. Soc., Chem.
Commun. 1991, 1002-1004. (e) Heffner, R. J.; Jiang, J.; Joullie´, M. M. J.
Am. Chem. Soc. 1992, 114, 10181-10189. (f) East, S. P.; Joullie´, M. M.
Tetrahedron Lett. 1998, 39, 7211-7214. (g) East, S. P.; Shao, F.; Williams,
L.; Joullie´, M. M. Tetrahedron 1998, 54, 13371-13390.
(5) Kim, Y.-A.; Shin, H.-N.; Park, M.-S.; Cho, S.-H.; Han, S.-Y.
Tetrahedron Lett. 2003, 44, 2557-2560.
10.1021/ol070271f CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/09/2007

1,3-orientation. The previous studies have revealed that the
synthetic challenges for these targets include formation of
the strained macrocycles and introduction of their enamide
unit.2-6 For macrocyclization, Schmidt and co-workers
developed an activated ester method,3b which greatly facili-
tated the total synthesis of the macrolactams,4 while Zhu’s
SNAr cyclization6 and Lipshutz’s oxazolophane approach7
also showed ideal capability for assembling a number of
cyclopeptide alkaloids. However, all these protocols chose
elaboration of the enamide moiety via different elimination
methods after macrocyclization.2-6 Such tedious and low-
yielding manipulations remarkably decreased the synthetic
efficiency. Herein, we wish to report a new strategy for
assembling cyclopeptide alkaloids in a highly convergent
manner, as demonstrated by the first total synthesis of
antiplasmodial agent ziziphine N (1, Figure 1).1e In this
Scheme 1
As outlined in Scheme 1, our synthesis of ziziphine N started
from the preparation of pyrrolidine 39a and vinyl iodide 4.
By using our modified procedure (replacement of isopropenyl
chloroformate with inexpensive DCC),9b we converted
protected D-serine 6 into pyrrolidinone 7 in 40∼50% yields.
Reduction of 7 with borane-dimethyl sulfide provided the
desired alcohol 3. In a parallel procedure, Reimer-Tiemann
reaction of monoprotected hydroquinone 8 and subsequent
methylation of phenol afforded aldehyde 9.10 Subjecting the
aldehyde 9 to a Wittig olefination reaction with Ph3P+(CH2I)I-
gave rise to a vinyl iodide as a mixture of the Z- and
E-isomers.11 The stereoselectivity was not satisfactory in this
1
case, as a ratio of about 3:1 was determined by H NMR.
Fortunately, pure isomer 4 (56% yield from 9) could be
isolated via chromatography after treatment of the above
mixture with PPTS in methanol.
Figure 1. Structure and retrosynthetic analysis of ziziphine N.
Connection of 3 and 4 via a Mitsunobu reaction12 was
our next planned step. This reaction was found to be rather
sluggish at room temperature mainly because 4 was an
electron-rich phenol. However, a reasonable yield for the
desired product 10 was obtained by raising the reaction
temperature to 80 °C (Scheme 2). Coupling of 10 and
N-alloxycarbonyl-L-proline amide 5 under our standard
conditions (CuI/N,N-dimethylglycine, Cs2CO3, dioxane, 80
°C) produced enamide 11.8a Cleavage of the silyl ether in
11 followed by stepwise oxidation of the liberated alcohol
gave an acid, which was exposed to Pd(PPh3)4/Et2NH13 to
provide the desired amino acid 12 in 56% overall yield.
The stage was now set for the crucial macrocyclization.
We assumed that Schmidt’s protocol3b,4 would not be suitable
because the enamide moiety may not survive the Pd/C-
protocol, the formation of the enamide unit in the key
intermediate 2 was set up at an early stage via a CuI/N,N-
dimethylglycine-catalyzed coupling reaction of the amide 5
with a Mitsunobu reaction product of vinyl iodide 4 and
alcohol 3.8a
Ziziphine N is a new member of the ziziphine family that
displayed potent antiplasmodial activity with an IC50 value
of 3.92 µg/mL. Its structure was tentatively inferred to 1 by
comparing the spectroscopic data with those of ziziphine A.
(6) (a) Zhu, J.; La¨ıb, T.; Chastanet, J.; Beugelmans, R. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2517-2519. (b) La¨ıb, T.; Bois-Choussy, M.; Zhu,
J. Tetrahedron Lett. 2000, 41, 7645-7649. (c) Temal-La´ıb, T.; Chastanet,
J.; Zhu, J. J. Am. Chem. Soc. 2002, 124, 583-590. (d) Cristau, P.; Temal-
La´ıb, T.; Bois-Choussy, M.; Martin, M.-T.; Vors, J.-P.; Zhu, J. Chem.-
Eur. J. 2005, 11, 2668-2679.
(7) Lipshutz, B. H.; Huff, B. E.; McCarthy, K. E.; Miller, T. A.;
Mukarram, S. M. J.; Siahaan, T. J.; Vaccaro, W. D.; Webb, H.; Falick, A.
M. J. Am. Chem. Soc. 1990, 112, 7032-7041.
(8) (a) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809-1812. For
related studies, see: (b) Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman, B.
J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 7889-7901. (c) Jiang,
L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667-
3669. (d) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr. Org. Lett. 2004, 6,
27-30. (e) Coleman, R. S.; Liu, P.-H. Org. Lett. 2004, 6, 577-580. (f)
Hu, T.; Li, C. Org. Lett. 2005, 7, 2035-2038.
(9) (a) Jiang, J. J.; Li, W.-R.; Przeslawski, R. M.; Joullie´, M. M.
Tetrahedron Lett. 1993, 34, 6705. (b) Ma, D.; Ma, J.; Ding, W.; Dai, L.
Tetrahedron:Asymmetry 1996, 7, 2365-2370.
(10) Satoh, Y.; Stanton, J. L.; Hutchison, A. J.; Libby, A. H.; Kowalski,
T. J.; Lee, W. H.; White, D. H.; Kimble, E. F. J. Med. Chem. 1993, 36,
3850-3594.
(11) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
(12) Mitsunobu, O. Synthesis 1981, 1-28.
(13) Ciommer, M.; Kunz, H. Synlett 1991, 593-596.
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Org. Lett., Vol. 9, No. 7, 2007

With lactam 2 in hand, we completed the synthesis of 1
via cleavage of the Boc group with ZnBr2 and subsequent
coupling of the liberated secondary amine with N,N-
dimethyl-L-isoleucyl-L-leucine 13 under no-racemization
conditions reported by Zhu and co-workers6b (or stepwise
couplings with N-Fmoc-L-leucine and N,N-dimethyl L-
Scheme 2
22
isoleucine). The spectroscopic data of synthetic 115 ([R]D
22
-324.8 (c 0.24 in CHCl3), lit.1e [R]D -326.6 (c 0.18 in
CHCl3)) are identical in all respects to those reported in the
literature, and our results hereby confirm the proposed
structure for ziziphine N.
In conclusion, we have developed a very convergent
strategy to elaborate cyclopeptide alkaloids illustrated through
the first total synthesis of ziziphine N.16 The key elements
include installation of the enamide part via our CuI/N,N-
dimethylglycine-catalyzed coupling reaction and ring closure
with coupling agents such as FDDP. This new strategy makes
the elaboration of this class of natural products much easier
than previous protocols and would therefore benefit their
further pharmacological evaluation and SAR studies.
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, the National Natural Science Founda-
tion of China (grant 20321202 & 20572119), and the Science
and Technology Commission of Shanghai Municipality
(grant 02JC14032 & 03XD14001) for their financial support.
Supporting Information Available: Experimental pro-
cedures and characterizations for compounds 1, 2, 4, and
10-12. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL070271F
catalyzed hydrogenolysis. As a consequence, the use of
coupling reagents was considered, although only one suc-
cessful example had been reported recently.5 To our delight,
the pentafluorophenyl diphenylphosphinate (FDPP) mediated
macrocyclization14 of the amino acid 12 worked well and
furnished the lactam 2 in 66% yield. It is noteworthy that
the conversion of the commonly used intermediate 3 to the
lactam 2 only took six steps with an overall yield of about
15%. Obviously, the present approach is much more efficient
than all previous routes from related amino alcohols to the
similar lactams.2-6
(15) Selected data for 1: 1H NMR (500 MHz, CDCl3) δ 0.86 (d, J )
6.7 Hz, 3H), 0.94 (d, J ) 6.9 Hz, 6H), 0.95 (t, J ) 6.8 Hz, 3H), 1.14 (m,
1H), 1.48 (m, 2H), 1.56 (m, 1H), 1.64 (m, 1H), 1.75 (m, 2H), 1.94 (m,
2H), 2.24 (s, 6H), 2.36 (m, 1H), 2.46 (m, 1H), 2.55 (d, J ) 5.6 Hz, 1H),
3.26 (m, 1H), 3.57 (m, 1H), 3.80 (s, 3H), 4.21 (m, 2H), 4.38 (d, J ) 5.8
Hz, 1H), 4.52 (dd, J ) 9.0, 4.2 Hz, 1H), 4.75 (dd, J ) 7.9, 7.6 Hz, 1H),
5.94 (d, J ) 8.8 Hz, 1H), 6.80 (br s, 1H), 6.82 (d, J ) 7.3 Hz, 1H), 6.86
(d, J ) 11.6 Hz, 1H), 6.92 (dd, J ) 11.5, 8.8 Hz, 1H), 6.94 (d, J ) 8.8 Hz,
1H), 8.34 (d, J ) 11.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 11.7, 14.3,
21.4, 22.9, 24.4, 24.6, 26.7, 28.8, 32.4, 34.0, 40.6, 42.8, 45.1, 47.6 (2C),
55.7, 61.8, 62.5, 74.1, 78.4, 106.4, 110.5, 113.6, 116.7, 121.4, 123.9, 150.7,
151.0, 167.5, 171.0, 171.3, 171.6; MS m/z 634.2 [M + Na]+; HRMS calcd
for C33H49N5O6Na [M + Na]+ 634.3575, found 634.3578.
(16) During the preparation of this manuscript, Evano and co-workers
reported the synthesis of paliurine F, a structurally related alkaloid of
ziziphine N, by using two Cu-catalyzed couplings. See: Toumi, M.; Couty,
F.; Evano, G. Angew. Chem., Int. Ed. 2007, 46, 572-575.
(14) Chen, S.; Xu, J. Tetrahedron Lett. 1991, 32, 6711-6714.
Org. Lett., Vol. 9, No. 7, 2007
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