Stereoselective Modification of N-(α-Hydroxyacyl)-glycinesters via Palladium-Catalyzed Allylic Alkylation

Article abstract of DOI:10.1021/acs.orglett.9b01497

N-(α-Hydroxyacyl)-glycinesters can be used as excellent nucleophiles in Pd-catalyzed allylic alkylation. The method allows for the stereoselective introduction of a wide range of side chains, including highly functionalized ones. Both diastereomers can be accessed through variation of the reaction conditions. Furthermore, the use of stannylated carbonates introduces vinylstannane motifs, which are eligible for subsequent C-C coupling reactions.

Full text of DOI:10.1021/acs.orglett.9b01497

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoselective Modification of N‑(α-Hydroxyacyl)-glycinesters via
Palladium-Catalyzed Allylic Alkylation
Alexander Horn and Uli Kazmaier*
Organic Chemistry I, Saarland University, Campus, Building C4.2, D-66123 Saarbrucken, Germany
̈
S
* Supporting Information
ABSTRACT: N-(α-Hydroxyacyl)-glycinesters can be used as excellent nucleophiles in Pd-catalyzed allylic alkylation. The
method allows for the stereoselective introduction of a wide range of side chains, including highly functionalized ones. Both
diastereomers can be accessed through variation of the reaction conditions. Furthermore, the use of stannylated carbonates
introduces vinylstannane motifs, which are eligible for subsequent C−C coupling reactions.
ransition metal-catalyzed allylic alkylations serve as
powerful tools for stereoselective C−C bond formation
preferentially stereoselective incorporation of a side chain onto
a given (depsi)-peptide, an approach that is synthetically
challenging. Problems typically arise from the occasionally
harsh reaction conditions, the influence of side chains of
(depsi)-peptides on reactivity and selectivity, and the presence
of functional groups that can undergo side reactions. The first
promising results were obtained by Seebach et al.,10 who
reported stereo- and regioselective alkylations of a deproto-
nated sarcosine subunit in cyclosporin and other cyclic
peptides.11 While such modifications via glycine enolates are
quite popular, glycine cations12 and radicals13 can also be used
as reactive intermediates for functionalization. In addition,
direct C−H functionalizations of glycine derivatives have been
described by various groups recently.14
Our group has been involved in allylic alkylation chemistry
for several years, principally investigating Pd-catalyzed allylic
alkylation of chelated glycine esters.15 This protocol could later
be expanded to aminoketones,16 α-hydroxyesters,17 or even
peptides (Scheme 1A, top row).18 Besides Pd catalysts, Ru19
and Rh complexes20 have been applied, showing different
characteristics with regard to regio- and stereoselectivity.
Recently, the group of Zhang described comparable
modifications of peptide aldimines via allylic alkylation using
Cu and Pd complexes (Scheme 1A, bottom row).21 Because of
our long-lasting interest in the total synthesis of peptide and
depsipeptide natural products,22 we also became interested in
Pd-catalyzed allylic alkylation of small peptides containing C-
terminal α-hydroxy acids (Scheme 1B).
T
and are widely applied in the synthesis of biologically active
molecules.1 Among the many transition metals used in allylic
alkylations, palladium is generally recognized as the most
versatile metal due to its ability to catalyze a variety of different
reactions. In early reports, stabilized carbanions such as
malonates were generally used as nucleophiles, but more
recently, nonstabilized enolates of esters,2 amides,3 and
ketones have received more attention.4 The decarboxylative
allylic alkylation of ketones has found widespread applications.
Major contributions in this field include the work of Tsuji,5
Trost,6 and Stoltz.7
Nonproteinogenic amino acids not only are versatile
building blocks for synthetic chemists8 but also are found in
numerous natural products isolated from sponges, bacteria, or
fungi. In general, these secondary metabolites are produced by
nonribosomal peptide synthesis.9 This allows for the
incorporation of components other than amino acids, e.g.,
hydroxy acids in depsipeptides (Figure 1).
To enable the synthesis of such natural products and
derivatives for structure−activity relationship (SAR) studies,
the development of flexible synthetic protocols is highly
desirable. One of the most straightforward routes is the direct
Herein, we report the highly stereoselective Pd-catalyzed
allylic alkylation of chelated N-(α-hydroxyacyl)-glycinesters 1.
These can easily be prepared from the corresponding amino
Received: April 29, 2019
Figure 1. Structures of biologically active depsipeptides.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01497
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 1. Pd-Catalyzed Allylic Alkylations of Peptides
Scheme 2. Substrate Scope for Allylic Alkylation of N-(α-
Hydroxyacyl)-glycinesters
f
acids via diazotation/hydrolysis23 and subsequent amide
coupling with glycine tert-butyl ester.
In the beginning, we attempted to transfer the typical
reaction conditions used for peptide enolates (LHMDS as a
base, ZnCl2 for chelation) to the corresponding “hydroxy
peptides” 1.18 However, under these conditions, product 2 was
formed only in a moderate yield with modest diastereose-
lectivity (Table 1, entry 1). The configurations of diaster-
Table 1. Optimization of Reaction Conditions
dr
a
b
entry
base (equiv)
MXn (equiv)
ZnCl2 (1.1)
Al(O-i-Pr)3 (1.1)
ClTi(O-i-Pr)3 (1.1)
ClTi(O-i-Pr)3 (1.5)
ClTi(O-i-Pr)3 (1.5)
ClTi(O-i-Pr)3 (1.5)
ClTi(O-i-Pr)3 (1.5)
(2aa:2aa′)
yield (%)
1
2
3
4
5
6
7
LHMDS (3.5)
LHMDS (3.5)
LHMDS (3.5)
LHMDS (3.5)
LDA (3.5)
62:38
64:36
72:28
73:27
90:10
98:2
53
54
76
84
53
71
82
LDA (3.1)
LHMDS (5.5)
12:88
a
Diastereomeric ratios (dr) were determined by NMR and/or HPLC
b
of the crude reaction mixture. Isolated yield.
eomers 2aa and 2aa′ were assigned after hydrogenation of the
double bond via HPLC comparison with an (S,S)-reference
sample. The use of other metal salts such as Al(O-i-Pr)3 had no
beneficial effect (entry 2; see the Supporting Information for
further details). The yield increased significantly if more
oxophilic titanium Lewis acid ClTi(O-i-Pr)3 was used,
although the selectivity remained reasonable (entry 3). In
the next step, the amount of ClTi(O-i-Pr)3 employed was
increased and the stronger base LDA was used instead of
LHMDS (entries 4 and 5). Despite the the fact that the yield
decreased, the diastereoselectivity increased to 9:1. Variations
in the amount of LDA indicated that a slight excess of base
further increased the selectivity significantly (entry 6).
a
b
Yield of the diastereomeric mixture. Linear (l) and branched (b)
products were formed.27 Using 4 mol % Pd catalyst and 18 mol %
PPh3. The reaction was quenched at −50 °C. Using 1.05 equiv of
ClTi(O-i-Pr)3. Diastereomeric ratios (dr) were determined from the
crude reaction mixture via HPLC and/or NMR, and yields
correspond to the isolated yield of the pure main diastereomer
unless otherwise noted.
c
d
e
f
2fa could all be obtained with (nearly) perfect selectivity
(crude mixture, dr of 96:4−99:1) and good yields.
We also investigated the scope of the allylic alkylation by
varying the allylic carbonates employed (Scheme 2B). At first,
simple allyl ethyl carbonate was used, which afforded 2eb in
high yield with high diastereoselectivity. Pyridyl derivative 2ec
With these optimized conditions, the scope of the reaction
was examined. N-(α-Hydroxyacyl)-glycinesters bearing differ-
ent substituents on the hydroxy acid were reacted with
cinnamyl ethyl carbonate (Scheme 2A). Independent of the
steric demand of the α-hydroxy acid, allylation products 2aa−
B
DOI: 10.1021/acs.orglett.9b01497
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Letter
gave excellent results, while in the case of the electron-rich
furyl derivative 2ed, a significant amount of the branched
product was formed.24 The branched product presumably
results from an SN1-type mechanism instead of an SN2-type
nucleophilic attack on the π-allyl complex (at the sterically less
demanding position). 2-Substituted allyl ethyl carbonates also
worked well (2ee−2eh), providing the desired products as
single diastereomers. Vinyl bromide 2ei showed the lowest
selectivity so far (dr of 90:10), which resulted from
epimerization of the more acidic α-center due to the
electron-withdrawing bromide.25 In this case, the reaction
had to be quenched at −50 °C to minimize this epimerization.
Because titanium is a highly oxophilic Lewis acid, we were
interested to see if our protocol is also suitable for the
allylation with (highly) oxygenated allylic carbonates. Under
the typical conditions (1.5 equiv of Ti), however, deprotection
and/or chelation of the carbonates occurred and no clean
reaction was observed. This problem could be solved by
reducing the amount of titanium salt used to 1.05 equiv (2ej
and 2ek).
92:8). For 2-substituted allyl ethyl carbonates, the diaster-
eoselectivities were similar, but the yields were a bit lower
(2ag′). While the configuration of these observed products
could unambiguously be assigned, an explanation for the
preferred formation of the (S,S)-diastereomers under these
reaction conditions has yet to be determined. Initial
assumptions of an ongoing epimerization of the product to
the presumably more stable diastereomer could be excluded by
control experiments.
With both methods in hand, we could selectively synthesize
the (S,R)- and (S,S)-diastereomers of vinylstannane 2ah
(Scheme 4) in large amounts that could be subjected to
Scheme 4. Synthesis of (S,R)- and (S,S)-2ah by Allylic
Alkylation and Further Modifications of the Side Chain
For secondary carbonates, the expected double stereo-
differentiation was observed. The (R)-carbonate formed
diastereomer 2al-1 exclusively in 81% yield (matched case),
while the (S)-carbonate afforded 2al-2 as a mixture of two
diastereomers (dr of 82:18) (mismatched case). The relative
and absolute configurations of these diastereomers were
determined by NOESY-NMR analysis (see the Supporting
Information). We should mention that the corresponding Z-
configured carbonates worked equally well. The (R,Z)-
carbonate afforded E-configured product 2al-2 due to
π−σ−π isomerization (76%, dr of 80:20), while the (S,Z)-
carbonate displayed the matched case and afforded 2al-1 with
comparable results (79%, dr of 99:1).
During our initial optimization of the reaction conditions,
we also observed the formation of (S,S)-product 2aa′ as the
major diastereomer in cases in which a great excess of LHMDS
(5.5 equiv) was used (Table 1, entry 7). This forced us to
investigate these unexpected outcomes in more detail to figure
out if the (S,S)-diastereomers can be easily obtained by simply
changing the reaction conditions (Scheme 3). While valine-
derived depsipeptide 2ba′ was obtained with moderate
selectivity (dr of 87:13), tert-leucine derivative 2da′ was
obtained with significantly better diastereoselectivity (dr of
Scheme 3. Synthesis of (S,S)-Diastereomers 2′ by Allylic
a
Alkylation
further side chain modifications.26 Interestingly, Stille
couplings required special reaction conditions, because the
free hydroxyl group caused protodestannylation as a major side
reaction. To avoid this, the conditions developed by Furstner
̈
et al. worked well with several aryl iodides to afford coupling
products 3a and 3b in good yields.27
Stannane 2ah′ was also treated with iodine to form the
corresponding iodide 4, which was then transformed into
methylester 5 by carbonylation in MeOH. Similarly, Pd-
catalyzed treatment of iodide 4 with amino acids and
dipeptides under an atmosphere of CO produced amides 6a
and 6b in high yields. Despite the free hydroxy group, iodide 4
could also be used in cross coupling reactions, namely
a
Diastereomeric ratios (dr) were determined by NMR and/or HPLC
analysis of the crude reaction mixture.
C
DOI: 10.1021/acs.orglett.9b01497
Org. Lett. XXXX, XXX, XXX−XXX

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In conclusion, we have shown that N-(α-hydroxyacyl)-
glycinesters are excellent nucleophiles in Pd-catalyzed allylic
alkylations. The reaction proceeds well with different types of
N-(α-hydroxyacyl)-glycinesters as well as a series of allylic
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
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Detailed experimental procedures and copies of HPLC,
GC, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: u.kazmaier@mx.uni-saarland.de.
ORCID
Uli Kazmaier: 0000-0001-9756-0589
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by Saarland University.
■
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