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Highly Stereoselective Allylic Alkylations of Peptides.

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Angewandte
Chemie
Allylation
DOI: 10.1002/anie.200600509
Highly Stereoselective Allylic Alkylations of
Peptides**
Uli Kazmaier,* Jan Deska, and Anja Watzke
Dedicated to Professor Barry M. Trost
on the occasion of his 65th birthday
Cell proteins and peptides in eukaryotes are generally
produced by means of ribosomal peptide synthesis. In
contrast, prokaryotes employ a completely different mechanism comparable to polyketide synthesis.[1] This nonribosomal
peptide synthesis enables the lower organisms to generate a
high diversity of peptide structures. Therefore, their metabolites often contain rather exotic amino acids, such as d- and
N-methylated amino acids, which are often incorporated into
cyclic peptides.[2] A typical example is cyclosporin C, an
immunosuppressant used after organ transplants (Figure 1).[3]
In general, these secondary metabolites show interesting
biological properties, and because of that, flexible synthetic
protocols for structure–activity investigations are highly
desirable. Besides the classical peptide syntheses, the modification of peptides is an interesting, alternative approach.
While the modification of a functionalized side chain is not
really that difficult,[4] the direct introduction of a side chain
into a given peptide is far from trivial, especially with respect
to the stereochemical outcome of the reaction. In principle,
peptide-incorporated glycine cations,[5] radicals,[6] and anions
[*] Prof. Dr. U. Kazmaier, Dipl.-Chem. J. Deska, Dr. A. Watzke
Universit)t des Saarlandes
Institut f-r organische Chemie
Im Stadtwald, Geb. 23.2, 66123 Saarbr-cken (Germany)
Fax: (+ 49) 681-302-2409
E-mail: u.kazmaier@mx.uni-saarland.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(Ka880/6) and the Fonds der Chemischen Industrie.
Angew. Chem. Int. Ed. 2006, 45, 4855 –4858
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4855
Communications
Table 1: Stereoselective modifications of dipeptides 3.
Figure 1. Cyclosporin C; Sar = sarcosin subunit.
can be generated as reactive intermediates for further
modifications. Especially the last approach was investigated
intensively by Seebach et al.[7] Probably the most spectacular
success was the regio- and stereoselective alkylation of the
sarcosin (Sar) subunit in cyclosporin.[8] In this case, one face of
the enolate is shielded by the deprotonated peptide ring, and
therefore the attack of the electrophile occurs preferentially
from the opposite face. In comparison, modifications of linear
peptides proceed unselectively, giving rise to diastereomeric
mixtures.
Our group has also been investigating stereoselective
peptide modifications for some time. Our goal is to transfer
the chiral information of a given peptide chain via metal–
peptide complexes to the newly formed stereogenic center.[9]
A first successful example was the Claisen rearrangement of a
peptide enolate which provided allylated peptides in high
yields. Depending on the protecting group (PG) and chelating
metal salt (MXn) used, the diastereoselectivity was good to
excellent and the S,R diastereomer was always formed
preferentially (Scheme 1).[10] . The diastereoselectivity may
be explained by a highly ordered chair-like transition state
and the likely multiple coordination of the chelating metal to
the peptide chain, ,[11] resulting in a one-sided shielding of the
peptide enolate.
Scheme 1. Chelatenolate Claisen rearrangement of peptides. R = alkyl;
R’ = alkyl, aryl. LDA = lithium diisopropylamide, PG = protecting group.
As we were interested to see whether this concept can also
be applied to intermolecular modifications, we investigated
the alkylation of tosyl- and tert-butoxycarbonyl(Boc)-protected leucine peptides 3 with several alkylating agents
(Table 1). To determine the configuration of the new stereogenic center, we introduced preferentially alkyl groups
corresponding to the natural proteinogenic amino acids, or
those which can be interconverted easily into these. We found
that both protecting groups are suitable. In general, the Boc
protecting group gave the best yields, the tosyl group the best
4856
www.angewandte.org
Entry
Substr.
PG
RX
Prod.
Yield [%]
d.r.[a]
1
2
3
4
5
3a
3b
3a
3b
3a
Boc
Ts
Boc
Ts
Boc
MeI
MeI
BnBr
BnBr
4a
4b
5a
5b
6a
92
70
50
53
73
50:50
85:15
60:40
85:15
50:50
6
3b
Ts
6b
63
90:10
7
3b
Ts
7b
60
88:12
8
3a
Boc
8a
61
85:15
9
3b
Ts
8b
75
76:24
10
3c
TFA
8c
82
73:27
[a] S,R/S,S. [b] The catalyst was 1 mol % [{(allyl)PdCl}2]; E = COOEt, Ts =
tosyl, TFA = trifluoroacetate.
selectivities. With respect to the chelating metal salt, many
different salts (MgCl2, CoCl2, NiCl2, MnCl2) can be used, but
ZnCl2 gave the most reproducible results. Like to the Claisen
rearrangement, the S,R products were formed preferentially.
Besides alkyl and allyl halides also carbonyl compounds could
be used with comparable results (Table 1, entry 7). In this case
diastereomeric ratios (d.r.) up to 9:1 could be obtained.
Since some time we have also been investigating palladium-catalyzed allylic alkylations of chelated enolates,[12] and
therefore it was obvious to investigate this reaction also with
deprotonated peptides of type 3 as nucleophiles. This is not a
trivial issue, because peptides are known to form relatively
stable complexes with palladium,[11] which might result in
complexation and deactivation of the catalyst. But we hoped
that in the case of the metal peptide complexes this might not
be a major problem. Therefore, we also investigated the
reaction of our model peptides 3 a/b with methallyl carbonate
9 in the presence of Pd0 and found that in this case the Boc
derivative 3 a gave the best selectivity (Table 1, entry 8) and
the tosyl derivative 3 b the best yield (Table 1, entry 9).
After our good experience with N-trifluoroacetylated
amino acid esters, we also used this protecting group on our
model peptide. Indeed, the best yield was achieved with 3 c
(Table 1, entry 10). In principle, the yields obtained in the
allylic alkylation were comparable to those using allyl
bromide (Table 1, entries 5 and 6), although in the Pdcatalyzed version a side product formed: the corresponding
ethyl ester resulting from a nucleophilic attack of the
liberated EtOH (from the allylic carbonate) onto the terminal
ester functionality.
To suppress this side reaction and to increase the yield we
switched to the more stable tert-butyl ester 10 a (Table 2). For
complete conversion of the peptide we used an excess of 9. At
least 3 equiv of base were required for peptide enolate
formation (two for the acidic NH groups, one for the enolate).
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 4855 –4858
Angewandte
Chemie
Table 2: Palladium-catalyzed allylic alkylation of dipeptides 10.
Entry
Substr.
AA
Equiv 9
Prod.
Yield [%][a]
d.r.[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
10 a
10 b
10 c
10 a
10 a
10 a
10 b
10 c
10 d
10 e
10 f
10 g
10 h
Leu
Phe
Tle
Leu
Leu
Leu
Phe
Tle
Tyr-OMe
Ala
Met
Ser-OBOM[c]
Ser-OTBDPS[c]
2
2
2
0.85
0.7
0.5
0.7
0.7
0.7
0.7
0.7
0.7
0.7
11 a
11 b
11 c
11 a
11 a
11 a
11 b
11 c
11 d
11 e
11 f
11 g
11 h
76
82
59
77
89
91
92
73
93
85
60
71
98
84:16
90:10
92:8
90:10
90:10
90:10
93:7
93:7
92:8
83:17
90:10
81:19
92:8
83 % (Table 2, entry 11). Other amino acids with linear side
chains, such as methionine, gave better results (Table 2,
entry 12). The lowest selectivity so far was obtained with the
serine derivative 10 g, but in this case both the yield and the
selectivity could be increased without any problem by using a
sterically more demanding protecting group (Table 2,
entry 13).
In reactions of peptides with functionalized side chains,
such as 10 f and 10 g, coordination of the catalyst to the side
chain might be an option theoretically and would result in the
opposite S,S diastereomer as the favored product. In all
examples investigated so far, however, the S,R diastereomer
was the major isomer, as determined by HPLC of the
hydrogenated allylation products.[13] To illustrate that this
concept is suitable for the introduction of several types of side
chains, we also varied the allylic carbonates used (Scheme 2).
[a] Yield determined relative to the minor component. [b] S,R/S,S.
[c] Tle = tert-leucine, BOM = benzyloxymethyl, TBDPS = tert-butyldiphenylsilyl.
Variation of the amount of base used indicated that a slight
excess of base increases the yield, while a large excess is
counterproductive. Therefore, we carried out all reactions in
the presence of 3.5 equiv of base. Interestingly, with the tertbutyl ester 10 a the selectivity was superior to that of the
corresponding methyl ester 3 c (Table 1, entry 1). For example, with the phenylalanine derivative 10 b a diastereomeric
ratio of 9:1 could be obtained, and this in a very high yield
(Table 2, entry 2). Owing to the high reactivity of the chelated
enolates, the reactions started at temperatures as low as
78 8C and were complete after warming up to 50 8C. One
might expect that the selectivity should increase with growing
steric bulk of the inducing amino acid. Therefore, we also
investigated the tert-leucine (Tle) derivative 10 c, and indeed,
the highest selectivity was obtained in this case, although the
yield was a little lower (Table 2, entry 3).
The last parameter of optimization that we varied was the
ratio of peptide enolates to allylic carbonate 9. When the
peptide enolate was used in excess, not only the yield but also
the selectivity increased significantly (Table 2, entries 1 and
4–6). The optimal peptide enolate/allyl carbonate ratio was
found to be 1.5:1. Under these optimized conditions both
yields and the selectivities were about 90 % (Table 2, entry 5).
To illustrate the broad applicability of this protocol we
allylated a wide range of other dipeptides. And indeed, under
the new, optimized conditions excellent yields were achieved
with the phenylalanine peptide 10 b (Table 2, entry 7), and
even the tert-leucine derivative 11 c was obtained in good
yield (Table 2, entry 8). The results with the protected
tyrosine derivative 10 d were similar (Table 2, entry 9).
While the diastereoselectivity obviously depends on the
steric bulk of the inducing amino acid, it was interesting to
see how much the selectivity drops when only “small” amino
acids were incorporated into the peptide. But even with the
alanine derivative 10 c the diastereoselectivity still reached
Angew. Chem. Int. Ed. 2006, 45, 4855 –4858
Scheme 2. Stereoselective allylations of peptides. LHMDS = lithium
hexamethyldisilazanide.
In all examples investigated the yields and the selectivities
were excellent. For example, with the cinnamyl carbonate 12
the linear substitution product 13 was formed exclusively. In
contrast, the reaction of the alkyl-substituted carbonate 14
can be expected to give the regioisomeric products 15 a and
15 b, but also in this case the linear product was 15 a formed
preferentially.
In conclusion, we could show that palladium-catalyzed
allylic alkylation is an excellent tool for the stereoselective
modification of peptides. The selectivities obtained are in the
range of 80–90 %. Reactions using chiral p-allyl palladium
complexes and those in the presence of chiral ligands as well
as applications to natural product synthesis are currently
under investigation.
Experimental Section
11 b: In a Schlenk tube hexamethyldisilazane (233 mg, 1.44 mmol)
was dissolved in abs. THF (2.0 mL) under argon. After the solution
had been cooled to 78 8C, a 1.6 m solution of nBuLi (0.82 mL,
1.31 mmol) was added slowly. The solution was stirred for 10 min
before the cooling bath was removed and the solution was stirred for a
further 10 min. In a second Schlenk flask ZnCl2 (57 mg, 0.42 mmol)
was dried with a heat gun under vacuum. After the solution had been
cooled to room temperature, a solution of (S)-Tfa-Phe-Gly-OtBu
(140 mg, 0.375 mmol) in THF (2 mL) was added. The freshly
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4857
Communications
prepared LHMDS solution was cooled again to 78 8C before the
peptide/ZnCl2 solution was slowly added. A solution of
[{(allyl)PdCl}2] (1.8 mg, 5.0 mmol), PPh3 (5.9 mg, 22.5 mmol), and
methallyl ethylcarbonate (36 mg, 0.25 mmol) was prepared in THF
(0.5 mL). This solution was added to the enolate at 78 8C. The dry
ice was removed from the cooling bath, and the reaction mixture was
allowed to warm to 50 8C over 2 h before it was diluted with ether
and hydrolyzed with 1m HCl. After the reaction mixture was allowed
to warm to room temperature, the layers were separated and the
aqueous layer was extracted twice with ether. The combined organic
layers were dried (Na2SO4), the solvent was evaporated in vacuo, and
the crude product was purified by flash chromatography (silica gel,
hexanes/EtOAc 92:8). Yield: 99 mg (0.231 mmol, 92 %) 11 b as a
white solid, m.p. 113–114 8C. 1H NMR (500 MHz, CDCl3): d = 1.35 (s,
9 H) 1.63 (s, 3 H), 2.20 (dd, J = 7.9, 6.3 Hz, 2 H), 2.27 (dd, J = 7.6,
6.3 Hz, 2 H), 3.03 (d, J = 6.9 Hz, 2 H), 4.41 (dt, J = 7.9, 6.3 Hz, 1 H),
4.56 (s, 1 H), 4.64 (dt, J = 7.6, 6.7 Hz, 1 H), 4.71 (s, 1 H), 6.33 (d, J =
7.9 Hz, 1 H), 7.22–7.11 (m, 5 H), 7.56 ppm (d, J = 7.6 Hz, 1 H).
13
C NMR (125 MHz, CDCl3): d = 21.71, 27.88, 38.56, 40.61, 51.13,
54.69, 82.62, 114.63, 116.33 (q, 106 Hz), 127.42, 128.77, 129.25, 135.30,
140.29, 156.62 (q, 37.2 Hz), 168.78, 170.46 ppm. HRMS (CI): calcd for
C23H30N2F3O4 [M+H]+: 429.1992; found: 429.2041; HPLC (Reprosil
100 Chiral-NR 8 mm, hexane/iPrOH 99.5:0.5, 1.5 mL min 1, l =
209 nm): t(S,S) = 16.65 min, t(S,R) = 22.07 min; d.r. 93:7.
[10]
[11]
[12]
[13]
Kazmaier, S. Maier, F. L. Zumpe, Synlett 2000, 1523 – 1535;
e) S. Maier, U. Kazmaier, Eur. J. Org. Chem. 2000, 1241 – 1251.
U. Kazmaier, S. Maier, J. Org. Chem. 1999, 64, 4574 – 4575.
Review on peptide–metal complexes: K. Severin, R. Bergs, W.
Beck, Angew. Chem. 1998, 110, 1722 – 1743; Angew. Chem. Int.
Ed. 1998, 37, 1634 – 1654.
a) U. Kazmaier, F. L. Zumpe, Angew. Chem. 1999, 111, 1572 –
1574; Angew. Chem. Int. Ed. 1999, 38, 1468 – 1470; b) U.
Kazmaier, F. L. Zumpe, Angew. Chem. 2000, 112, 805 – 807;
Angew. Chem. Int. Ed. 2000, 39, 802 – 804; c) T. D. Weiß, G.
Helmchen, U. Kazmaier, Chem. Commun. 2002, 1270 – 1271;
d) U. Kazmaier, Curr. Org. Chem. 2003, 317 – 328; e) U. Kazmaier, M. Pohlman, Synlett 2004, 623 – 626; f) U. Kazmaier, T.
Lindner, Angew. Chem. 2005, 117, 3368 – 3371; Angew. Chem.
Int. Ed. 2005, 44, 3303 – 3306.
Determination of the configuration for dipeptide 11 b: An
analytical sample of allylated dipeptide 11 b was dissolved in
MeOH und subjected to hydrogenation (10 % Pd/C) under
normal pressure. The resulting dipeptide, TFA-Phe-Leu-OtBu,
was compared with a S,S reference sample: HPLC (Reprosil 100
Chiral-NR 8 mm, hexane/iPrOH 99.5;0.5, 1.5 mL min 1, l =
209 nm): S,S Reference: tR = 13.94 min; H2-11 b: tminor =
13.97 min, tmajor = 19.62 min.
Received: February 7, 2006
.
Keywords: allylation · asymmetric synthesis · chelates ·
palladium · peptides
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