Application of the peptide Claisen rearrangement toward the synthesis of cyclic peptides

Article abstract of DOI:10.1021/ol9910262

(formula presented) Allylic esters of peptides undergo Claisen rearrangement after deprotonation in the presence of tin chloride, giving rise to allylated peptides. Subsequent N-allylation and ring-closing metathesis provides the corresponding cyclic pept

Full text of DOI:10.1021/ol9910262

ORGANIC
LETTERS
1999
Vol. 1, No. 11
1763-1766
Application of the Peptide Claisen
Rearrangement toward the Synthesis of
Cyclic Peptides
Uli Kazmaier* and Sabine Maier
Organisch-Chemisches Institut der UniVersita¨t, Im Neuenheimer Feld 270,
69120 Heidelberg, Germany
ck1@popix.urz.uni-heidelberg.de
Received September 8, 1999
ABSTRACT
Allylic esters of peptides undergo Claisen rearrangement after deprotonation in the presence of tin chloride, giving rise to allylated peptides.
Subsequent N-allylation and ring-closing metathesis provides the corresponding cyclic peptides. The yields in the last step strongly depend
on the ring size formed.
Cyclic peptides are widely found in marine organisms and
fungi.1 Many of these peptides show significant biological
activities2 and are therefore highly interesting from a
pharmaceutical point of view.3 In higher organisms, cyclic
structures can be formed by oxidation of two cysteine
subunits, a process which is generally used to stabilized
secondary and tertiary structures of peptides. Cystine-
containing peptides are also found preferentially in peptide
hormones and in a number of redox-active proteins (1).4 In
these last examples the disulfide bridge locks a tetrapeptide
fragment of the protein chain into a â-turn type structure.5
Frequently, loops and turn in peptides and proteins are
responsible for their biological activity, and therefore these
structures are highly interesting from a pharmaceutical point
of view, and as targets for peptidomimetics.6 Cyclizations
of peptides, in general, results in an increased stability toward
proteases, also in cystine peptides the disulfide bonds are
sensitive to reduction. The metabolic stability of these
compounds can dramatically be increased by replacing the
critical disulfide bond by a noncleavable C-C bonds.7
Therefore a lot of investigations have been carried out toward
the synthesis of carba analogues of cystine, such as 2,7-
diaminosuberic acid.8 Very recently Williams9 and Grubbs10
described syntheses based on a dimerization of tethered allyl
glycines via ring closing metathesis.11 As shown by Grubbs
(6) Reviews: Tetrahedron Symposia-in-print 50 (Kahn, M. Ed.; 1993.
Giannis, A.; Kolter, T. Angew. Chem. 1993, 105, 1303; Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1244.
(7) Nutt, R. F.; Veber, D. F.; Saperstein, R. J. Am. Chem. Soc. 1980,
102, 6539.
(8) Nutt, R. F.; Strachan, R. G.; Veber, D. F.; Holly, F. W. J. Org. Chem.
1980, 45, 3078. Williams, R. M.; Yan, C. J. Org. Chem. 1992, 57, 6519.
Bold, G.; Allmendinger, T.; Herold, P.; Moesch, L.; Scha¨r, H. P.; Duthaler,
R. O. HelV. Chim. Acta 1992, 75, 865. Lange, M.; Fischer, P. M. HelV.
Chim. Acta 1998, 81, 2053.
(9) Williams, R. M.; Liu, J. J. Org. Chem. 1998, 63, 2130.
(10) O’Leary, D. J.; Miller, S. J.; Grubbs, R. H. Tetrahedron Lett. 1998,
39, 1689.
(1) Amino Acids, Peptides and Proteins; Specialist Periodical Reports;
Chemical Society: London.
(2) Gra¨fe, U. Biochemie der Antibiotika; Spektrum: Heidelberg, 1992.
Antibiotics and AntiViral Compounds; Krohn, K., Kirst, H. A., Maag, H.,
Eds.; VCH: Weinheim, 1993.
(3) Mutschler, E. Arzneimittelwirkungen; Wissenschaftliche Verlagsge-
sellschaft: Stuttgart, 1991. Eberle, A. E. Chimia 1991, 45, 145.
(4) Musiol, H.-J.; Siedler, F.; Quarzago, D.; Moroder, L. Biopolymers
1994, 34, 1553. Siedler, F.; Quarzago, D.; Rudolph-Bohner, S.; Moroder,
L. Biopolymers 1994, 34, 1563.
(11) Reviews: Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 28, 446. Koert, U. Nachr. Chem. Tech. Lab. 1995, 43, 809. Schuster,
M.; Blechert, S. Angew. Chem. 1997, 109, 2124; Angew. Chem., Int. Ed.
Engl. 1997, 36, 2036. Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1
1998, 371. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(5) Rizo, J.; Gierasch, L. M. Annu. ReV. Biochem. 1992, 61, 387.
10.1021/ol9910262 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/21/1999

et al. this ring-closing approach can directly be used for the
synthesis of cyclic peptides, such as 2, a carba analogue of
the glutaredoxin active site 1.12 This is an extremely
straightforward approach toward these â-turn mimetics, but
also smaller and larger ring systems can be obtained by this
protocol.13
manganese enolates, and therefore this approach is only
suitable for the stereoselective introduction of allylic side
chains onto peptides if esters of chiral allylic alcohols are
used. On the other hand, if allylic esters of tosylated peptides
were subjected to Claisen rearrangement, the rearrangement
products are obtained in a highly diastereoselective fashion.19
Tosyl-protected amino acids are also suitable substrates for
palladium-catalyzed allylic alkylations, giving rise to N-
allylated derivatives under very mild conditions.20
Herein we describe applications of these protocols to the
synthesis of cyclic peptides. We started our investigations
with the rearrangement of peptide ester 6 (Scheme 2).21 In
Scheme 2a
For quite some time we have been investigating syntheses
of γ,δ-unsaturated amino acids.14 One approach toward these
structures is based on a variation of the Claisen rearrange-
ment, proceeding via chelated amino acid ester enolates 4
(Scheme 1).15 If esters of chiral allylic alcohols 3 are used,
Scheme 1
the corresponding enantiomerically pure amino acids 5 are
obtained.16
a Conditions: (a) 5.0 equiv of LHMDS, 2.0 equiv of SnCl2, THF,
-78 °C f room temperature, 16 h; (b) CH2N2, ether, 10 min; (c)
1 mol % (allylPdCl)2, 4.5 mol % PPh3, allyl carbonate, THF, room
temperature, 16 h; (d) 10-15 mol % RuCl2(PCy3)2(dCHPh),
toluene, room temperature f 90 °C, 8 h.
This protocol is not limited to the rearrangement of amino
acid esters, but can also be applied to peptides. Therefore,
we thought to use the chiral information of the peptide chain
as a stereocontrolling element. In our first attempts, we
investigated the rearrangement of various peptide methyl
allylic esters, with only moderate success.17 To improve the
yield and also the selectivity of the rearrangement, we carried
out an extensive screening with regard to the NR-protecting
group, the substitution pattern in the allylic ester moiety, and
also the metal salt used for chelation. MnCl2 was found to
give excellent yields in the rearrangement of various types
of peptide esters, but without any selectivity.18 The peptide
chain has no influence on the rearrangement of these
the presence of tin chloride, used for chelation, the rearranged
product 7 was obtained in excellent yield and highly
stereoselective. An induced diastereoselectivity of 84% was
remarkable, especially with respect that the only chiral center
in the peptide 6 was seven atoms away from the newly
formed chiral center.19 The (R)-configured amino acid was
formed preferentially with high syn selectivity (>95%).22 The
subsequent N-allylation gave rise to the N-allylated product
(12) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc.
1996, 118, 9606.
(19) Kazmaier, U.; Maier, S. J. Org. Chem. 1999, 64, 4574.
(20) Zumpe, F. L.; Kazmaier, U. Synlett 1998, 1199. Zumpe, F. L.;
Kazmaier, U. Synthesis, in press.
(13) Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 5855.
Clark, T. D.; Ghadiri, M. R. J. Am. Chem. Soc. 1995, 117, 12364.
Pernerstorfer, J.; Schuster, M.; Blechert, S. J. Chem. Soc., Chem. Commun.
1997, 1949. Ripka, A. S.; Bohacek, R. S.; Rich, D. H. Bioorg. Med. Chem.
Lett. 1998, 8, 357. Cabrejas, L. M. M.; Rohrbach, S.; Wagner, D.; Kallen,
J.; Zenke, G.; Wagner, J. Angew. Chem. 1999, 111, 2595; Angew. Chem.,
Int. Ed. Engl. 1999, 38, 2443.
(14) Review: Kazmaier, U. Liebigs Ann./Recl. 1997, 285 and references
therein.
(15) Kazmaier, U. Angew. Chem. 1994, 106, 1046; Angew. Chem., Int.
Ed. Engl. 1994, 33, 998.
(21) General Procedure for Peptide Claisen Rearrangements: A total
of 0.2 mmol of the corresponding peptide ester were dissolved in 4 mL of
THF, before 0.4 mmol (380 mg) of tin chloride were added. The mixture
was cooled to -70 °C. A freshly prepared solution of 1 mmol LHMDS in
2.5 mL of THF was added slowly, and the reaction mixture was allowed to
warm to room temperature overnight. The resulting solution was hydrolyzed
by vigorous stirring for 1 h with 5 mL of 1 N HCl solution. After separation
of the aqueous layer the rearrangement product was extracted three times
with 10 mL of 1 N NaOH solution. The combined basic aqueous layers
were acidified with 1 N HCl solution (pH 1), and the peptide was extracted
twice with methylene chloride (15 mL each). After evaporation of the
solvent, the crude product was converted into the corresponding methyl
esters with diazomethane and purified by flash chromatography.
(16) Kazmaier, U.; Schneider, C. Synlett, 1996, 975. Kazmaier, U.;
Schneider, C. Synthesis 1998, 1321.
(17) Kazmaier, U. J. Org. Chem. 1994, 59, 6667.
(18) Kazmaier, U.; Maier, S. J. Chem. Soc., Chem. Commun. 1998, 2535.
1764
Org. Lett., Vol. 1, No. 11, 1999

8 without any racemization.23 This can be explained by the
extremely mild reaction conditions. The base required for
the deprotonation of the tosylamide is generated in situ
(EtO-) from the allylic carbonate, and therefore this approach
is suitable even for the allylation of sensitive amino acids
and peptides. Unfortunately all attempts to cyclize the
diallylated substrate 8 under different reaction conditions and
various amounts of Grubbs’s catalyst were unsuccessful.24
tion of the linear peptide chain. Probably trans amide bonds
avoid the approximation of the allyl termini. Therefore we
decided to enlarge the ring size and to introduce one proline,
which is suitable to form cis amide bonds and turn structures.
Scheme 4a
Scheme 3a
a Conditions: (a) 5.0 equiv of LHMDS, 2.0 equiv of SnCl2, THF,
-78 °C f room temperature, 16 h; (b) CH2N2, ether, 10 min; (c)
1 mol % (allylPdCl)2, 4.5 mol % PPh3, allyl carbonate, THF, room
temperature, 16 h; (d) 10 mol % RuCl2(PCy3)2(dCHPh), CH2Cl2,
reflux, 14 h.
a Conditions: (a) 5.0 equiv of LHMDS, 2.0 equiv of SnCl2, THF,
-78 °C f room temperature, 16 h; (b) CH2N2, ether, 10 min; (c)
HCl, dioxane, 0 °C, 30 min; (d) 1 equiv N-tosyl-N-allyl-â-Ala, 1.1
equiv TBTU,30 5 equiv, NEt3, CH2Cl2, 10h; (e) 1 equiv of Boc-
Ser(Oall), 1.1 equiv of TBTU, 5 equiv of NEt3, CH2Cl2, 8 h; (f) 10
mol % RuCl2(PCy3)2(dCHPh), CH2Cl2, reflux, 15 h.
What are the reasons? We focused on three parameters:
(a) the unsaturated amino acid, (b) the ring size; and (c) the
amino acid sequence. In all ring closing metatheses described
in the literature so far, only unbranched allylglycines, or
related amino acids, were used as substrates. Probably the
methyl group of the C terminal amino acid caused the
troubles. Unfortunately exchanging this amino acid by
allylglycine was just as fruitless as reducing the ring size by
replacing the â-amino acid by an R-amino acid such as
leucine. Obviously 12- and 13-membered peptide rings are
not the best targets for this strategy. The problems with these
medium-sized rings may result from an unsuitable conforma-
Rearrangement of the tetrapeptide ester 9 gave the desired
allylated tetrapeptide 10 in excellent yield (Scheme 3).25
N-Allylation provided the substrate 11 for the subsequent
ring-closing metathesis,26 which now resulted in the forma-
tion of the desired cyclic peptide 12 (15-membered ring) in
high yield.27 This is in good agreement with the results
described by Grubbs et al. for comparable peptides such as
2 (14-membered ring).
(22) The stereochemical outcome of this reaction probably can be
explained by a 4-fold coordination of the deprotonated peptide chain toward
the chelating metal ion. In such a complex, one face of the enolate is shielded
by the isopropyl side chain of the (S)-valine. Claisen rearrangement
obviously occurs from the “opposite” face giving rise to an (R)-amino acid.
See also ref 19.
(23) General Procedure for the N-Allylations of Peptides. To a stirred
solution of the Ts-protected peptide (1 mmol) in 2 mL of dry THF a solution
of π-allylpalladium chloride dimer (0.01 mmol), triphenylphosphine (0.045
mmol), and the allyl carbonate (2 mmol) was added at room temperature.
The solution was stirred overnight. After evaporation of the solvent, the
residue was purified by flash chromatography.
(25) The newly generated amino acid was formed in racemic form,
because proline containing peptides do not undergo stereoselective Claisen
rearrangements (see ref 19).
(26) General Procedure for Ring Closing Metatheses of Peptides. A
solution of 17 mg (0.02 mmol, 10 mol %) of RuCl2(PCy3)2(dCHPh) in 10
mL of CH2Cl2 was added to a solution of 0.2 mmol of the diallylated peptide
in 40 mL of CH2Cl2 under argon. The clear solution was refluxed overnight.
The solvent was removed in vacuo, and the residue was purified by flash
chromatography.
(27) The double bond was obtained as an inseparable (E/Z) mixture, with
a predominant amount of the (Z) isomer, as indicated by a typical 10.5 Hz
(24) No reaction was observed, even at temperatures up to 90 °C. These
conditions only resulted in decomposition of the catalyst.
1
coupling for the vinylic protons in the H NMR spectrum.
Org. Lett., Vol. 1, No. 11, 1999
1765

To prove if the proline plays a significant role for the
cyclization, we came back to our allylated tripeptides such
as 14 (Scheme 4), which could not by cyclized previously
after N-allylation. Cleavage of the N-protecting group and
coupling with allylated amino acids provided the prolonged
peptides 15 and 16. Subsequent ring-closing metathesis
yielded the corresponding 16-membered cyclic peptides 1728
and 1829 in even higher yields in comparison to the smaller
proline peptide. Obviously ring size plays a major role for
the success of this reaction, and the amino acid sequence
and conformational issues are less important, at least for
peptides with more than 14 ring members.
In conclusion we have shown, that the peptide Claisen
rearrangement is a versatile tool for the allylation of peptides.
The combination of this approach with the palladium-
catalyzed N-allylation and the ring-closing metathesis pro-
vides and straightforward access to cyclic peptides.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft (SFB 247) and the Fonds der Chemischen
Industrie for generous financial support.
(28) The (E) isomer was formed preferentially (J ) 15.4 Hz), which
could be purified by crystallization.
(29) Unfortunately, the olefin geometry could not be determined from
the NMR spectra.
(30) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron
Lett. 1989, 30, 1927.
Supporting Information Available: Analytical and
spectroscopic data of all described peptides. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL9910262
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