Passerini reaction-amine deprotection-acyl migration peptide assembly: Efficient formal synthesis of cyclotheonamide c

Article abstract of DOI:10.1021/ol900048r

A short, convergent, formal total synthesis of cyclotheonamide C is described. The key linear pentapeptide intermediate is assembled at the same time as the elaboration of the α-hydroxyhomoarginine (H-hArg) residue via a three-component Passerini reaction

Full text of DOI:10.1021/ol900048r

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1167-1170
Passerini Reaction-Amine
Deprotection-Acyl Migration Peptide
Assembly: Efficient Formal Synthesis of
Cyclotheonamide C
Sophie Faure,*,† Thomas Hjelmgaard,† Stéphane P. Roche,† and David J. Aitken*,‡
Laboratoire de Synthe`se et Etude de Syste`mes d’Inte´reˆt Biologique, SEESIB (UMR
6504-CNRS), UniVersite´ Blaise Pascal-Clermont-Ferrand 2, 24 aVenue des Landais,
63177 Aubie`re Cedex, France, and Laboratoire de Synthe`se Organique et
Me´thodologie, ICMMO (UMR 8182-CNRS), UniVersite´ Paris-Sud 11, Baˆt. 420, 15 rue
Georges Clemenceau, 91405 Orsay Cedex, France
sophie.faure@uniV-bpclermont.fr; daVid.aitken@u-psud.fr
Received January 11, 2009
ABSTRACT
A short, convergent, formal total synthesis of cyclotheonamide C is described. The key linear pentapeptide intermediate is assembled at the
same time as the elaboration of the r-hydroxyhomoarginine (H-hArg) residue via a three-component Passerini reaction-amine deprotection-O,N-
acyl migration strategy.
R-Hydroxyhomoamino acids (H-hXaa) and their oxidized
counterparts R-ketohomoamino acids (K-hXaa) are present
in natural products1 and in synthetic, biologically active
compounds, notably taxane anticancer agents2 and protease
inhibitors.3 The R-ketohomoarginine (K-hArg) residue is a
structural feature of each of the cyclotheonamides (Cts), a
family of cyclic pentapeptides isolated from the marine
sponges Theonella swinhoei and Theonella ircinia.4 The Cts
are potent inhibitors of serine proteases such as thrombin
(IC50 ) 2.9-200 nM),4 and the highly electrophilic K-hArg
plays a key role in the covalent attachment of Cts to the
(3) Recent leading articles: (a) Qian, J.; Cuerrier, D.; Davies, P. L.; Li,
Z.; Powers, J. C.; Campbell, R. L. J. Med. Chem. 2008, 51, 5264. (b)
Njoroge, F. G.; Chen, K. X.; Shih, N-Y.; Piwinski, J. J. Acc. Chem. Res.
2008, 41, 50. (c) Mimoto, T.; Nojima, S.; Terashima, K.; Takaku, H.;
Shintani, M.; Hayashi, H. Bioorg. Med. Chem. 2008, 16, 1299. (d) Hamada,
Y.; Abdel-Rahman, H.; Yamani, A.; Nguyen, J.-T.; Stochaj, M.; Hidaka,
K.; Kimura, T.; Hayashi, Y.; Saito, K.; Ishiura, S.; Kiso, Y. Bioorg. Med.
Chem. Lett. 2008, 18, 1649. (e) Maryanoff, B. E. J. Med. Chem. 2004, 47,
769.
† Universite´ Blaise Pascal-Clermont-Ferrand 2.
‡ Universite´ Paris-Sud 11.
(1) Spiteller, P.; von Nussbaum, F. In EnantioselectiVe Synthesis of
ꢀ-Amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A., Eds.; Wiley-VCH:
Hoboken, 2005; Chapter 2.
(2) Chen, J.; Kuznetzova, L. V.; Ungreanu, I. M.; Ojima, I. In
EnantioselectiVe Synthesis of ꢀ-Amino Acids, 2nd ed.; Juaristi, E., Solos-
honok, V. A., Eds.; Wiley-VCH: Hoboken, 2005; Chapter 19.
(4) (a) Fusetani, N.; Matsunaga, S. J. Am. Chem. Soc. 1990, 112, 7053.
(b) Nakao, Y.; Matsunaga, S.; Fusetani, N. Bioorg. Med. Chem. 1995, 3,
1115. (c) Nakao, Y.; Oku, N.; Matsunaga, S.; Fusetani, N. J. Nat. Prod.
1998, 61, 667. (d) Murakami, Y.; Takei, M.; Shindo, K.; Kitazume, C.;
Tanaka, J.; Higa, T.; Fukamachi, H. J. Nat. Prod. 2002, 65, 259.
10.1021/ol900048r CCC: $40.75
Published on Web 02/09/2009
2009 American Chemical Society

enzyme active site.5 Due to their biological activity and their
challenging molecular structure, the Ct family has attracted
the attention of a number of research groups, and several
total syntheses of CtA and/or CtB have been described.6 In
each case, the K-hArg feature was revealed in a late-stage
oxidation of an R-hydroxyhomoarginine (H-hArg) residue
which had been incorporated into a cyclic pentapeptide. As
a result, the several-step preparation of an appropriately
protected H-hArg residue was required upstream. A different
approach was adopted by Wasserman in his total synthesis
of CtE2 and CtE3 whereby the K-hArg feature was generated
sooner in the synthetic sequence through use of R-ketocy-
anophosphorane amino acid intermediates.7 We recently
adapted this elegant approach for a total synthesis of CtC
(1; Figure 1), revealing some limitations on the way.8 Taking
A potentially useful synthetic extension is the Passerini
reaction-amine deprotection-acyl migration (PADAM)
sequence, first conceived as a tool for combinatorial synthesis
of peptidomimetics12,13 (Scheme 1). This process involves
Scheme 1.
PADAM Sequencea
a Key: (a) P-3CR; (b) amine deprotection, followed by O,N-acyl
migration. Optionally, this sequence can be followed by an oxidation (c).
reaction of an aldehyde 2, an isonitrile 3, and a carboxylic
acid 4 to give the P-3CR R-acyloxyamide product 5, whose
N-terminal is then deprotected to induce O,N-migration of
the acyl fragment to provide a H-hXaa-containing peptide
6. Optional subsequent oxidation leads to the corresponding
K-hXaa-peptide 7. To date, only one application has been
described in natural product synthesis, that of eurystatin
A.14,15 The use of this approach for the synthesis of
cyclotheonamide-type fragments was at one stage considered,
although no cyclic peptide assembly was ventured.16
We reasoned that, with judicious choice of appropriately
protected amino acid and peptide fragments, a PADAM
strategy could be applied to the construction of complex
linear pentapeptides and provide a concise access to CtC.
The two dipeptide isonitriles 10a and 10b were obtained by
formylation of the known9,17 parent amines 8 followed by
dehydration of the resulting formamides 9 (Scheme 2).
Figure 1. Molecular structure of cyclotheonamide C (CtC).
CtC as a representative target within the family, we have
sought to develop convergent synthetic strategies which
feature simultaneous peptide assembly and creation of the
H-hArg (or K-hArg) residue; adopting this concept, we
recently described the first total synthesis of CtC.9
Scheme 2. Synthesis of Isonitriles 10a and 10b
The Passerini three-component reaction (P-3CR)10 has
emerged as a powerful tool for establishing molecular
complexity in a single step with optimal atom economy.11
(5) (a) Maryanoff, B. E.; Qiu, X.; Padmanabhan, K. P.; Tulinsky, A.;
Almond, H. R.; Andrade-Gordon, P.; Greco, M. N.; Kauffman, J. A.;
Nicolaou, K. C.; Liu, A.; Brungs, P. H.; Fusetani, N. Proc. Natl. Acad. Sci.
USA 1993, 90, 8048. (b) Lewis, S. D.; Ng, A. S.; Baldwin, J. J.; Fusetani,
N.; Naylor, A. M.; Shafer, J. A. Thrombosis Res. 1993, 70, 173. (c) Lee,
A. Y.; Hagihara, M.; Karmacharya, R.; Albers, M. W.; Schreiber, S. L.;
Clardy, J. J. Am. Chem. Soc. 1993, 115, 12619. (d) Ganesh, V.; Lee, A. Y.;
Clardy, J.; Tulinsky, A. Protein Sci. 1996, 5, 825.
(6) (a) Hagihara, M.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114,
6570. (b) Wipf, P.; Kim, H. J. Org. Chem. 1993, 58, 5592. (c) Deng, J.;
Hamada, Y.; Shioiri, T.; Matsunaga, S.; Fusetani, N. Angew. Chem., Int.
Ed. 1994, 33, 1729. (d) Maryanoff, B. E.; Greco, M. N.; Zhang, H.-C.;
Andrade-Gordon, P.; Kauffman, J. A.; Nicolaou, K. C.; Liu, A.; Brungs,
P. H. J. Am. Chem. Soc. 1995, 117, 1225. (e) Bastiaans, H. M.; van der
Baan, J. L.; Ottenheijm, C. J. J. Org. Chem. 1997, 62, 3880.
(7) (a) Wasserman, H. H.; Zhang, R. Tetrahedron Lett. 2002, 43, 3743.
(b) Wasserman, H. H.; Zhang, R. Tetrahedron 2002, 58, 6277.
(8) Roche, S. P.; Faure, S.; El Blidi, L.; Aitken, D. J. Eur. J. Org. Chem.
2008, 5067.
The sensitive dehydration step was examined using several
systems (Burgess’ salt; triphosgene-NEt3; POCl3-NEt3)18
(12) (a) Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985. (b)
Banfi, L.; Guanti, G.; Riva, R.; Basso, A.; Calcagno, E. Tetrahedron Lett.
2002, 43, 4067. (c) Basso, A.; Banfi, L.; Riva, R.; Piaggio, P.; Guanti, G.
Tetrahedron Lett. 2003, 44, 2367. (d) Banfi, L.; Basso, A.; Guanti, G.; Riva,
(9) Roche, S. P.; Faure, S.; Aitken, D. J. Angew. Chem., Int. Ed. 2008,
47, 6840.
R. Mol. DiVersity 2003, 6, 227.
(13) An interesting related process involving acylcyanides in place of
(10) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126.
aldehydes has been described: Oaksmith, J. M.; Peters, U.; Ganem, B. J. Am.
(11) Recent reviews: (a) Banfi, L.; Riva, R. Org. React. 2005, 65, 1.
(b) Zhu, J.; Bienayme´, H. Multicomponent Reactions; Wiley-VCH: New
York, 2005. (c) Do¨mling, A. Chem. ReV. 2006, 106, 17.
Chem. Soc. 2004, 126, 13606
(14) Owens, T. D.; Araldi, G.-L.; Nutt, R. F.; Semple, J. E. Tetrahedron
Lett. 2001, 42, 6271
.
.
1168
Org. Lett., Vol. 11, No. 5, 2009

Scheme 3. Optimization of the P-3CR and Elaboration of Pentapeptide 14 Using the PADAM Sequence
to minimize degradation and racemization. The latter set of
conditions gave the best results, allowing the isolation of
the pure isonitriles in 52% and 38% yields for the two steps,
respectively, without racemization.19 The two amino alde-
hyde components 11a and 11b9,20 and the two dipeptide acids
12a and 12b8,21 (shown in Scheme 3) were obtained using
previously reported methods.
With the appropriate reagents in hand, we focused our
attention on the PADAM sequence, beginning with the study
of the P-3CR construction of R-acyloxyamides 13 (Table
1). Bearing in mind that subsequent selective deprotection
that the excess of aldehyde and/or acid partner did not
improve the reaction (entry 3). While the isolation of 13b
was a significant achievement, in that it demonstrated that
P-3CR assembly of pentadepsipeptides was possible, we
desired a protecting group suite which would allow a
subsequent one-step N/C-termini deprotection protocol for
macrocyclization. This objective was achieved by preparing
the pentadepsipeptide 13c from isonitrile 10b, Fmoc-amino
aldehyde 11b, and Boc-dipeptide acid 12a in an acceptable
44% yield (entry 4).22 Use of a purified isonitrile 10b sample
proved to be vital, since the employment of crude dipeptide
drastically decreased the yield of 13c (entry 5).
Selective Fmoc deprotection of the pentadepsipeptide 13c
using diethylamine at 0 °C followed by O,N-dipeptide
migration induced by treatment with triethylamine at room
temperature provided the key linear pentapeptide 14 in 88%
yield (Scheme 3). The transacylation step might conceivably
have taken place during the Fmoc deprotection step, but to
ensure its completion, the crude deprotected material was
subjected to the reported transacylation conditions.12,16,23 In
this way, we successfully created the H-hArg feature within
a complex linear pentapeptide, which represents the most
elaborate use of the PADAM strategy to date.
Table 1. P-3CR Preparation of Depsipeptides 13 in Scheme 3a
entry
10b
11 (equiv)
12 (equiv)
product
yield (%)
1
2
3
4
5
10a
10a
10a
10b
10bc
11a (1.2)
11b (1.2)
11b (2.3)
11b (1.2)
11b (1.2)
12b (1.2)
12a (1.2)
12a (2.3)
12a (1.2)
12a (1.2)
13a
13b
13b
13c
13c
0
57
53
44
13
a Standard conditions: 0.02 M solution of 10, CH2Cl2 + trace of DMF,
rt, 3-6 days. b 1 equiv of isonitrile was used in each case. c Crude material
was used.
(18) (a) Skorna, G.; Ugi, I. Angew. Chem., Int. Ed. 1977, 16, 259. (b)
Creedon, S. M.; Crowley, H. K.; McCarthy, D. G. J. Chem. Soc., Perkin
Trans. 1 1998, 1015. (c) Zhao, G.; Bughin, C.; Bienayme´, H.; Zhu, J. Synlett
of the amine of the H-hArg residue was required in order to
allow for the O,N-migration step of the PADAM sequence,
the P-3CR involving isonitrile 10a and the orthogonally
protected duo Boc-amino aldehyde 11a and Fmoc-dipeptide
acid 12b was tested first. Unfortunately, the desired penta-
depsipeptide 13a was never formed; only starting materials
were recovered from reactions conducted under typical
P-3CR conditions (Table 1, entry 1). This problem could be
overcome by simple inversion of the protecting group
ensemble. The P-3CR between Fmoc-amino aldehyde 11b
and Boc-dipeptide acid 12a furnished the desired pentadep-
sipeptide 13b in 57% yield (entry 2).22 It was noteworthy
2003, 8, 1153
.
(19) In related work (unpublished), racemization occurred during the
preparation of the ester isonitrile from enantiomerically pure L-N-formyl-
Phe-OMe in our hands; for similar problems, see: Bon, R. S.; Hong, C.;
Bouma, M. J.; Schmitz, R. F.; De Kanter, F. J. J.; Lutz, M.; Spek, A. L.;
Orru, R. V. A. Org. Lett. 2003, 5, 3759. We therefore verified that no such
problems arose for amide isonitriles, such as 10a and 10b, using a known
model amide isonitrile. See the Supporting Information for details
(20) Review: Gryko, D.; Chalko, J.; Jurczak, J. Chirality 2003, 15, 514
(21) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266
.
.
.
(22) The P-3CR is sometimes diastereoselective; however, in our case,
it was difficult to estimate dr values for depsipeptides 13b (no clear
component separation on NMR or HPLC analyses) and 13c, although for
1
the latter an estimated dr of ∼2:1 can be deduced from H NMR spectral
analysis. Subsequent analysis of product 15, derived from 13c, confirmed
that the dr was low (vide infra). For an enantioselective catalytic P-3CR
and leading references on diastereoselective P-3CR, see: Wang, S.-X.; Wang,
(15) The O,N-acyl migration in an O-acyl isopeptide has been exploited
for the synthesis of an amyloid ꢀ-peptide, see: Skwarczynski, M.; Kiso, Y.
Curr. Med. Chem. 2007, 14, 2813, and references cited therein.
(16) Owens, T. D.; Semple, J. E. Org. Lett. 2001, 3, 3301.
M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47, 388
.
(23) This transformation proved to be difficult to monitor by TLC
(identical Rf values) and 1H NMR (presence of diastereoisomers and
rotamers).
(17) Aitken, D. J.; Faure, S.; Roche, S. Tetrahedron Lett. 2003, 44, 8827.
Org. Lett., Vol. 11, No. 5, 2009
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Scheme 4. Formal Synthesis of Cyclotheonamide C from the PADAM Pentapeptide 14
The acquisition of pentapeptide 14 offered an opportunity
to establish the importance of the order of events en route
to the advanced cyclic peptide 17, a known one-step
precursor of CtC.9 Simultaneous N/C termini deprotection
of pentapeptide 14 was achieved using trifluoroacetic acid,
and macrocyclization was achieved using TBTU/HOBt to
provide the cyclic pentapeptide 15 in 52% yield (Scheme
4). Comparison of analytical data of 15 with those previously
obtained by us for this compound9 indicated a 65:35 mixture
of two diastereomers (see the Supporting Information for
details), undoubtedly the result of limited diastereoselectivity
in the P-3CR formation of 13c. This was of no consequence
for the achievement of our objectives, however, since the
stereogenic center in question becomes an sp2 carbon in the
target molecule. Indeed, oxidation of the H-hArg residue of
15 with DMP gave the CtC precursor 17 as a single
stereoisomer with spectral and physical data identical to those
previously described.8,9 Significantly, the alternative trans-
formation of linear H-hArg pentapeptide 14 into 17 failed
(Scheme 3): attempted oxidation of 14 using DMP provided
none of the desired compound 16, a two-step precursor of
17.8 In conditions which had been successful for the
conversion of 15 into 17, starting material 14 was recovered
unreacted while under more drastic conditions (excess
oxidizing agent; longer reaction times) degradation was
observed.
In conclusion, in this original approach to the synthesis
of CtC, we have demonstrated the unprecedented utility of
the PADAM strategy for the successful assembly of a
complex pentapeptide intermediate from simple precursors
and the simultaneous creation of a masked K-hArg moiety
within it. This third (formal) total synthesis of CtC underlines
the value of retaining a masked K-hArg as long as possible
in the synthetic sequence and is the most convergent to date.
Acknowledgment. We thank the French Ministry for
Research for financial support (Grants to S.P.R. and T.H.).
Supporting Information Available: Full experimental
procedures, characterization data, and copies of NMR spectra
for all significant products; details of model compound study
to confirm no racemization. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL900048R
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Org. Lett., Vol. 11, No. 5, 2009