C-H Functionalization of N-Methylated Amino Acids and Peptides as Tool in Natural Product Synthesis: Synthesis of Abyssenine A and Mucronine e

Article abstract of DOI:10.1021/acs.orglett.8b03475

N-Methylated amino acids and peptides with an 8-aminoquinoline (AQ) directing group can be subjected to stereoselective Pd-catalyzed β-functionalizations. The best results are obtained with aryl iodides, but alkyl and alkenyl side chains can also be introduced. The AQ protecting group can easily be removed, providing the free carboxylic acid, which can be used directly in peptide couplings. This protocol was used successfully as a key step in the synthesis of the cyclopeptide alkaloids abyssenine A and mucronine E.

Full text of DOI:10.1021/acs.orglett.8b03475

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
C−H Functionalization of N‑Methylated Amino Acids and Peptides
as Tool in Natural Product Synthesis: Synthesis of Abyssenine A and
Mucronine E
Thorsten Kinsinger and Uli Kazmaier*
Organic Chemistry I, Saarland University, Campus, Building C4.2, D-66123 Saarbrucken, Germany
̈
S
* Supporting Information
ABSTRACT: N-Methylated amino acids and peptides with an 8-aminoquinoline (AQ) directing group can be subjected to
stereoselective Pd-catalyzed β-functionalizations. The best results are obtained with aryl iodides, but alkyl and alkenyl side
chains can also be introduced. The AQ protecting group can easily be removed, providing the free carboxylic acid, which can be
used directly in peptide couplings. This protocol was used successfully as a key step in the synthesis of the cyclopeptide alkaloids
abyssenine A and mucronine E.
Scheme 1. Pd-Catalyzed β C(sp3)-H Functionalizations of
N-Methylated amino acids are widely found in nature,
α-Amino Acids
especially in peptidic natural products with interesting
biological activities,1 such as cyclosporine,2 miuraenamide,3
or lagunamide,4 to name only a few. In many cases, these
amino acids bear unusual side chains and have a strong
influence on the properties of these compounds.5 From a
synthetic as well as pharmaceutical point of view, straightfor-
ward approaches toward these unusual amino acids are highly
interesting and desired. Transition-metal-catalyzed functional-
izations of C−H bonds are very efficient tools allowing this
kind of modifications and therefore are the focus of intense
research.6 In contrast to classical peptide syntheses, generally
beginning with the asymmetric synthesis of the required
unusual amino acids and their subsequent incorporation into a
peptide using classical peptide coupling reagents, the C−H
functionalization approach is a more direct protocol. In this
case, the desired side chain can be introduced into an enantio-
or diastereomerically pure amino acid or peptide at a certain
position. Therefore, this protocol is especially suited for the
synthesis of natural products and derivatives thereof.7 A wide
range of methods has been developed to introduce aryl, alkyl,
alkenyl, or alkynyl substituents into the β-position of N-
phthaloylated non cyclic amino acids (Scheme 1A), but most
protocols proceed nicely only with this protecting group.6,8
Only very few examples with other protecting groups are
reported9 which cannot be used with amino acid derivatives
containing a N−H functionality, probably because NH-amides
themselves can act as a directing group.10 Recently, Qin et al.
have reported the β-arylation of N-benzylated Boc-protected
noncyclic amino acids.11 By far, the best investigated examples
are highly stereoselective β-functionalizations of N-protected
cyclic amino acids such as proline or pipecolic acid.12 Recently,
we have shown that this kind of modification can also be
carried out at the C-terminus of the peptides (Scheme 1B).13
Received: October 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03475
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Letter
Because of our long lasting interest in the total synthesis of
peptide natural products,14 we became interested in seeing if
Pd-catalyzed β-functionalizations can also be applied to N-
methylated amino acids and peptides (Scheme 1C), structural
motifs found very often in natural products such as the
cyclopeptide alkaloids abyssenine A and mucronine E.15
At the beginning, we tried to transfer the standard
conditions used successfully for the modification of proline
(peptides) also to N-protected N-methylated alanine deriva-
tives. 8-Amino quinoline (AQ) was used as a carboxylic acid
linked directing group,6d and the results obtained are
summarized in Table 1. In contrast to unmethylated alanine
Scheme 2. Substrate S: β-Functionalisation of N-Methyl
Amino Acids and Peptides
Table 1. Optimization of Reaction Conditions for
Monoselective β C−H Functionalization
temp
conversion
(%)
ratio
a
entry additive
1
2
solvent
(°C)
2aa/3aa
toluene
toluene
toluene
t-AmylOH
t-AmylOH
100
100
60
60
45
100
47
51
100
100
0:100
35:65
69:31
82:18
88:12
b
3
4
5
DBP
DBP
a
b
DBP = (BnO)2PO2H. 1.0 equiv of Ar-I was used.
derivatives, which gave only moderate conversion, the Cbz-
protected derivative 1a showed a clean, complete reaction in
the presence of AgOAc as a base but provided the double
arylated product (3aa) exclusively (entry 1). Reducing the
amount of aryl iodide to only one equivalent did not result in a
selective monosubstitution (2aa) but gave a mixture of 2aa/
3aa, while almost half of the starting material was recovered
(entry 2). Reducing the reaction temperature also resulted in
incomplete conversion and a product mixture, although in
another ratio (entry 3). The conversion could significantly be
increased by switching from toluene to tert-amyl alcohol as a
solvent and on an addition of 0.2 equiv of dibenzyl phosphate
(DBP).16 Here, full conversion was already observed at 60 °C,
and the desired monoarylated product 2aa was formed
preferentially (entry 4). The temperature could be reduced
further to 45 °C and the ratio of 2aa/3aa increased to 88:12
(entry 5) (2aa, 73%; 3aa, 8% isolated yields). It should be
mentioned that only 50% conversion was observed with
toluene as solvent in the absence of DBP (not shown).
Under these optimized conditions, we investigated the
arylation using a wide range of different aryl iodides, bearing
electron-donating as well as electron-withdrawing groups
(Scheme 2A). Good isolated yields (2a series) were obtained
in most cases. Boc-protected alanines (1b) seem to be less
reactive. Here, slightly higher reaction temperatures were
required to get good conversion, but the yield of 2ba was
lower, mainly because of the formation of the double arylated
product. Iodo phenols with an unprotected OH group are also
suitable, but here the yields were significantly lower (2af, 2ag).
In contrast, the direct introduction of a formylated phenyl
group proceeded without problems (2ad), as did the coupling
with p-nitro-iodo benzene (2ae). While substituents in the
meta- and para-position are well suited, the yields drop
significantly with some o-substituted iodo arenes. For example,
o-bromo-iodo benzene gave a yield <10%, even at 100 °C (not
shown).
Next, we enlarged the synthetic potential to the modification
of dipeptides (1c). Peptides are known to form relatively stable
Pd complexes,17 but this side reaction is probably suppressed
by the N-methyl group which prevents chelate complex
formation. Although slightly higher reaction temperatures are
required for good conversions, the yields obtained were only
slightly lower compared to the results obtained with the amino
acid. Interestingly, heterocyclic ring systems could also be
incorporated with similar success.
While aryl iodides are common substrates, the coupling of
alkyl- and alkenyl-halides is by far less documented.18
Therefore, we also investigated the reaction of these substrates
(Scheme 2B). Using methyl iodide as an electrophile gave the
desired α-aminobutyric acid derivative 2ai in moderate yield,
but surprisingly, only small amounts of the disubstituted
product were formed, while most of the starting material was
recovered (83% yield based on recovered starting material).
The major problem here was probably the high volatility of the
B
DOI: 10.1021/acs.orglett.8b03475
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Letter
electrophile (bp 42 °C) under the reaction conditions, even
when the reaction was carried out in a sealed tube. In contrast,
the yield was better in the reaction leading to glutamic acid
derivative 2aj. These reactions could be carried out at a higher
reaction temperature without significant double alkylation. In
this case, α-bromo acetate was used as an electrophile, while
aryl bromides do not react under these conditions. Coupling
with methyl β-iodo acrylate under the same conditions gave
significant amounts of the double substitution product as well
as the α,β,γ,δ-unsaturated amino acid derivative as an
elimination product. To avoid these side reactions, the reaction
temperature was reduced to 40 °C, resulting in a longer
reaction time. Addition of trifluoroacetic acid as reported by
Chen et al.18a did not improve the conversion rate and yield.
Next, we attempted the modification of other amino acids,
using the corresponding leucine and phenylalanine derivatives
(Scheme 2C). In this case, no double substitution was
observed, and therefore the reaction temperature could be
increased to 100 °C. Under these conditions, the substituted
leucine derivatives (4a series) were obtained in 64−73% yields.
Only one set of signals could be observed in the NMR spectra
of the crude reaction mixture, implicating a highly selective
functionalization step. The phenylalanine derivative was more
sluggish, requiring longer reaction times. However, under these
conditions, no epimerization was observed and the substitution
product 5aa was obtained in a highly diastereoselective fashion
(dr 95/5).
Table 2. Optimization of Reaction Conditions for the C−H
Activation with Aromatic Aldehydes 6
temp
(°C)
yield
(%)
entry
1
PG
6
R
t (d)
7
1
2
3
4
5
6
7
1a
1a
1b
1b
1b
1b
1b
Cbz
Cbz
Boc
Boc
Boc
Boc
Boc
6a
6a
6a
6a
6b
6b
6b
H
H
H
3
4
3
4
6
3
4
50
50
60
55
45
60
80
7aa
7aa
7ba
7ba
7bb
7bb
7bb
54
61
54
60
9
H
OMe
OMe
OMe
22
45
relatively low reactivity with other o-substituted aryl iodides,
which might also be an issue here. If the aldehyde functionality
can be introduced directly, the further synthesis should be
straightforward.
On the basis of our good results obtained so far with the
Cbz-protecting group, we initiated our investigations with our
standard substrate 1a, keeping in mind that the cleavage of the
Cbz later on might be critical in the presence of the aldehyde
or enamide functionality. With the trisubstituted iodo aldehyde
6a, the reaction required 3 days at 50 °C for an acceptable
result (Table 1, entry 1). Prolongation of the reaction time to 4
days (entry 2) increased the isolated yield to 61%, which was
comparable to our previous results shown in Scheme 1.
Unfortunately, we were not able to remove the Cbz-protecting
group neither by catalytic hydrogenation or with HBr/HOAc
from 7aa nor at a later stage of the synthesis. Therefore, we
explored also reactions of the Boc-protected alanine derivative
1b. Interestingly, in this case the results obtained were
comparable to results obtained with 1a, although slightly
higher reaction temperatures were applied (entries 3 and 4).
Even higher temperatures were required for couplings with
the tetrasubstituted arene 6b. Here, the reaction had to be
heated to 80 °C for 4 d to get an acceptable yield of the
coupling product 7bb (entries 5−7). It should be mentioned
that unreacted starting material could be recovered during
workup and the moderate isolated yield resulted from
incomplete conversions and not from the formation of side
products. In these cases, no double substitution was observed.
With aldehydes 7a and 7b in hand, a subsequent Wittig
reaction using Ph3PCH2I2/NaHMDS and HMPA, according
to Evano et al., provided the Z-configured vinyl iodides 8b in
excellent yield (Scheme 3).19b To remove the AQ directing
group, a common two-step process was used via a N-Boc-
protected AQ-intermediate, which was saponified with LiOOH
to 9b.7 For the next steps, we used a slightly modified protocol
from Evano et al.19b beginning with an epimerization-free
peptide coupling to 10b, followed by a Cu-mediated
cyclization, giving rise to 11b. Finally, the two natural products
were obtained in excellent yield after removing the Boc-
protecting group with TMSOTf.
Luckily, we were able to crystallize the substitution product
4ae, and X-ray structure analysis (Figure 1) clearly indicated
that the anti-product was formed preferentially. This is in good
agreement with the results obtained for N-phthaloylated amino
acids.8
Figure 1. X-ray structure of compound 4ae.
On the basis of the good results obtained with p-iodo
benzaldehyde (2ad, 75%), we decided to explore this coupling
further and to apply our protocol for the synthesis of the
cyclopeptide alkaloids abyssenine A and mucronine E. These
compounds are members of a class of natural products
containing 13−15-membered cycles containing a peptide
fragment adjacent to an aromatic ring system and a (Z)-
configured enamide.14 Several different approaches toward
these unusual amino acids are already described in the
literature,19 but common to all of them is a multistep synthesis
required to install the desired substitution pattern on the
aromatic ring and to control the stereochemical outcome of
the synthesis. Here, the C−H functionalization would be a
significant improvement. Therefore, we investigated the
coupling of highly substituted iodo benzaldehydes 6 in more
detail (Table 2) because in our previous work we observed a
In conclusion, we could show that N-protected N-
methylated amino acids are suited to be modified by
palladium-catalyzed β-C−H functionalization. The reaction
proceeds epimerization free and allows the introduction of aryl,
C
DOI: 10.1021/acs.orglett.8b03475
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ORCID
Scheme 3. Total synthesis of Abyssenine A (12ba) and
Mucronine E (12bb)
Uli Kazmaier: 0000-0001-9756-0589
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by Saarland University. We thank Dr.
V. Huch, Saarland University, for X-ray structure analysis.
■
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suitable to modify C-terminal alanines of dipeptides. The AQ
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03475.
Detailed experimental procedures and copies of NMR
spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: u.kazmaier@mx.uni-saarland.de
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