Asymmetric hydroalkylation of alkynes and allenes with imidazolidinone derivatives: α-alkenylation of α-amino acids

Article abstract of DOI:10.1039/d1sc00240f

This work reports a new method for the synthesis of quaternary α-alkenyl substituted amino acids by the enantio- and diastereoselective addition of imidazolidinone derivatives to alkynes and allenes. Further hydrolysis of the imidazolidinone products under acidic conditions afforded biologically relevant amino acid derivatives. This method is geometry-selective (E-isomer), enantio- and diastereoselective, and products were obtained in good to excellent yields. The utility of this new methodology is proved by its operational simplicity and the successful accomplishment of gram-scale reactions. Experimental and computational studies suggest the key role of Li in terms of selectivity and support the proposed reaction mechanism.

Full text of DOI:10.1039/d1sc00240f

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Asymmetric hydroalkylation of alkynes and allenes
with imidazolidinone derivatives: a-alkenylation of
a-amino acids†
Cite this: DOI: 10.1039/d1sc00240f
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
Farhad Panahi, Hormoz Khosravi,
Felix Bauer and Bernhard Breit
This work reports a new method for the synthesis of quaternary a-alkenyl substituted amino acids by the
enantio- and diastereoselective addition of imidazolidinone derivatives to alkynes and allenes. Further
hydrolysis of the imidazolidinone products under acidic conditions afforded biologically relevant amino
acid derivatives. This method is geometry-selective (E-isomer), enantio- and diastereoselective, and
products were obtained in good to excellent yields. The utility of this new methodology is proved by its
operational simplicity and the successful accomplishment of gram-scale reactions. Experimental and
computational studies suggest the key role of Li in terms of selectivity and support the proposed
reaction mechanism.
Received 13th January 2021
Accepted 21st April 2021
DOI: 10.1039/d1sc00240f
rsc.li/chemical-science
to allenes and alkynes,11 we envisioned that the direct inter-
molecular hydroalkylation of alkynes and allenes with imida-
Introduction
zolidinone derivatives may provide a new way to obtain
quaternary a-alkenyl substituted amino acids (Scheme 1b). This
new transformation is highlighted by an increase in the struc-
tural complexity of amino acids through the formation of a new
C–C bond which generates a new quaternary stereocenter in
Alpha quaternary amino acids (a-AAs) not only have a key role in
the modication of peptide conformations but also are
employed as building blocks for the preparation of biologically
and medicinally compounds.1 The introduction of a fourth
substituent to the a-carbon (carbon bears the amino and
carboxyl groups) of amino acids is a common approach in the
asymmetric synthesis of quaternary a-AAs.2 While enantiose-
lective alkylation at a-carbon is well developed, the introduction
of unsaturated substituents (aryl and alkenyl) at this carbon has
proved more challenging.3
Alkenyl a-AAs are important structure motifs to serve as
building blocks in synthetic chemistry and drug discovery.
These structures have shown interesting biological activities
such as antibiotic and anticancer properties.4 Despite of its
relevance, the methodologies for the synthesis of enantiopure
alkenyl amino acids are limited,5 among them [2,3]-sigmatropic
rearrangement of selenimides,6 a-2-tosylethenylation of (S)-2-
(pyrrolidin-1-yl)propanoic acid esters,7 and use of alkenylbor-
onic acids are the most used.8 Recently, an intramolecular
method for the a-alkenylation of a-AA was reported using dia-
stereoselective rearrangement of an N0-alkenyl urea substrate9
according to the Seebach's “self-regeneration of stereocenters”
method (Scheme 1a).10 Thus, considering our extended knowl-
edge on the regioselective addition of different pronucleophiles
high diastereoselectivity. Simultaneously,
a tri-substituted
alkene function is generated with high E-selectivity, itself an
important challenge in modern organic synthesis.12 To the best
of our knowledge, hydroalkylation of alkynes and allenes with
imidazolidinone derivatives toward synthesis of a-alkenylated
a-amino acids has not been reported.
Results and discussion
To evaluate the feasibility of this hypothesis, the a-alkenylation
of a-AAs via hydroalkylation of alkynes was started using imi-
dazolidinone 1a and alkyne 2a as model substrates (Table 1). An
initial
experiment
with
KHMDS
(HMDS
¼
¨
¨
Institut fur Organische Chemie, Albert-Ludwigs-Universitat Freiburg, Albertstraße 21,
79104 Freiburg im Breisgau, Germany. E-mail: bernhard.breit@chemie.uni-freiburg.
de
† Electronic supplementary information (ESI) available. CCDC 1950247. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1sc00240f
Scheme 1 Alkenylation of amino acid derivatives by N0 / C migration
(a) and using intermolecular hydroalkylation of alkynes or allenes (b).
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Table 1 Optimization of the reaction conditiona
Temp.
Entry
Base (eq.)
(ꢀC)
Yieldb (%)
drd
ere
1
2
3
4
5
6
7
8
KHMDS (2.0)
NaHMDS (2.0)
LiHMDS (2.0)
LiHMDS (2.0)
LiHMDS (2.0)
LiHMDS (2.0)
LiHMDS (1.0)
LiHMDS (0.5)
80
80
80
80
50
r.t.
80
80
73 (79)c
75 (82)c
83 (91)c
78f
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
68 : 32
56 : 44
>99 : 1
94 : 6
>99 : 1
>99 : 1
>99 : 1
ND
48
25g
23
<5
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), M(Li,Na,K) HMDS
b
(0.4 mL, 1.0 M in THF), THF (2.0 mL, 0.08 M). Yields reported for
c
isolated products. NMR yield with 1,3,5-trimethoxybenzene (TMB) as
reference. dr was determined using 1H-NMR. er was determined by
d
e
f
g
chiral HPLC. Toluene was used as the solvent. Reaction time was
48 h.
hexamethyldisilazane) afforded 73% of desired product 3a with
complete diastereoselectivity albeit with a low enantiomeric
ratio (er) of 68 : 32 (Table 1, entry 1). Using NaHMDS the yield
was slightly improved, but the er decreased to 56 : 44, while the
dr maintained >99 : 1 (Table 1, entry 2). Remarkably, switching
to LiHMDS, 3a was produced in 83% isolated yield in perfect dr
and er (Table 1, entry 3).13
No improvement was observed using other bases proving
that LiHMDS is the most efficient base for this protocol (Table
1S†). The solvent screening revealed that THF is the best solvent
for this transformation (Table 2S†). In the case of toluene, 78%
yield was achieved, however, a slight decrease of the er was
observed (Table 1, entry 4). Then, different temperatures were
tested nding 80 ꢀC as the optimal (Tables 3S† and 1, entries 5 &
6). It should be noted that the yield dramatically decreased
when one equivalent of base was used. Unexpectedly with half
equivalent of the base the process did not occur (Table 1, entries
7 & 8). Moreover, the ratio between the starting materials and
the base is critical in this process, getting the best results with
a 1 : 1 : 2 ratio for 1a : 2a : base (Table 4S†). With the optimal
conditions in hand, we turned our attention to the scope of both
amino acids and alkynes (Scheme 2). The scope of imidazoli-
dinone derived amino acids as nucleophile partners were eval-
Scheme 2 The substrate scope of alkynes and amino acids. Reaction
conditions: 1a (0.2 mmol), 2 (0.2 mmol), LiHMDS (0.4 mL, 1.0 M in THF),
THF (2.0 mL, 0.08 M), 80 ꢀC, 20 h. Yields reported for isolated prod-
ucts. dr were determined using 1HNMR. aer not determined.
of the phenyl ring delivered the corresponding products in high
yields and dr.
Alkynes containing naphthyl (3h,i,ab,ae,af), thiophenyl (3j,k)
and 1,3-benzodioxole (3ai) worked well under these conditions.
Sterically hindered substrates such as ortho-substituted (3m,ah)
and 1-naphthyl alkynes (3i,ab,af) gave also products in good
yields. Halogen atoms (F, Cl, Br) in different positions (ortho,
meta, and para) were tolerated, resulting in the halogenated
products in good to excellent yields and high dr, allowing for
further functionalizations. No evidence of dehalogenation or
benzyne formation was observed for this type of substrates.
Only a slight loss of dr was observed for bromo-substituted
substrates.
In order to show the versatility and the selectivity of this
method, some alkynes with particular functionalities were used.
In this sense, the reaction of a polyouro-substituted alkyne
gave 3m and 3ah in high yields and dr. Moreover, a conjugated
alkyne ((E)-pent-1-en-3-yn-1-ylbenzene) resulted in product 3n
in high yields preserving the conguration of the initial double
uated.
Imidazolidinone
derivatives
from
proline,
phenylalanine, methionine, leucine, tyrosine, and phenyl-
glycine (as non-natural a-AAs) reacted with different alkynes,
affording the products (3a-ai) in good to excellent yields.
To our delight, a wide range of aryl-methyl alkynes were
tolerated affording the corresponding a-alkenylated amino acid
derivatives in high yields and perfect dr (Scheme 2). It was
observed that alkynes bearing substituents at ortho- (3m,ah),
meta- (3b–d,g,o,r,x,z), and para- (3e,f,l,p,s,w,aa,ad,ag) positions
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bond. Product 3ag proved that only aryl-methyl alkyne groups
Considering that the base-promoted isomerization of
are active substrates in this transformation. Interestingly, when alkynes to allenes is well-known,16 we assume that the reaction
using bis-alkyne (1,4-di-(prop-1-yn-1-yl)benzene) only one could proceed by the attack of the imidazolidinone enolate to
functional group reacted, which provide opportunities for new the central carbon of the generated allene.17 This assumption
structural diversities (3l,aa). As shown in Scheme 2, the er for all was supported by the requirement of two equivalents of base:
type of amino acids are excellent and only in the case of phenyl one equivalent for the enolate formation and another one for
glycine due to some racemization because of its acidifying side the alkyne to the allene isomerization. Indeed, using 1-phenyl-
chain, starting material could not be obtained in high er.3b allene (4) as the substrate in the presence of one equivalent of
However, the hydroalkylation process was accomplished in high base compound 3a was obtained in 85% isolated yield at 80 ꢀC
stereoselectivities.
in THF. This shows that allenes can also be used as substrates.
Stereodivergency can be achieved using either trans- or cis- Using this modied methodology several imidazolidinone
imidazolidinones which can be easily synthesized from L-amino derivatives were converted to the corresponding products
acids (Scheme 3a).14 In this way, it is possible to access both (Scheme 4). Similar high yields and stereoselectivities were
optical antipodes of the desired functionalized amino acid in observed as for the alkyne substrates. Internal allenes also
high er. In order to highlight the utility of this methodology, worked with this method (3aj,k). An X-ray crystal structure
a large-scale synthesis (5.5 mmol) of compound 3a was per- analysis of a suitable single crystal of 3ac conrmed its relative
formed with 74% isolated yield in high dr (>99 : 1) and er (>99 : and absolute conguration (Scheme 4).
1) (Scheme 3b). Hydrolysis of the imidazolidinone products
We propose a plausible reaction pathway for the hydro-
resulted in the release of amino acid derivatives preserving the alkylation of alkynes and allenes with imidazolidinones in
enantiomeric purity and the alkene geometry (Scheme 3c).15
Fig. 1a. The rst equivalent of the base might initiate the
alkyne–allene isomerization process and form monolithiated
allene (I). Then, in the presence of a second equivalent of the
base I could give a dilithiated allenyl species (II). Based on
control experiments this species seems to be the more stable
allenyl intermediate.18 Formation of free allene as an electro-
phile coupling partner in this reaction is possible by proton-
ation of the lithiated allenyl species.19 Also, the deprotonation
of the imidazolidinone would afford the corresponding lithium
enolate (III). Then, the nucleophilic attack of III to the central
allene carbon dictates the alkene geometry anti relative to the
aryl group. Finally, protonation of the related carbanion (IV)
with HMDS delivers the product.
Scheme
3 (a) Stereodivergent synthesis of quaternary a-alkenyl
substituted imidazolidinone derivatives and their hydrolysis towards a- Scheme 4 Hydroalkylation of allenes with imidazolidinone derivatives.
AAs. (b) Large scale synthesis of a-alkenylated amino acid derivatives. Reaction conditions: 1a (0.2 mmol), 4a (0.2 mmol), LiHMDS (0.2 mL,
(c) The chemical structure of some a-alkenyl substituted amino acids 1.0 M in THF), THF (2.0 mL, 0.09 M), 80 ꢀC, 20 h. Yields reported for
after hydrolysis of imidazolidinone derivatives.
isolated products.
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IR reaction mixture aer quenching with CD3OD showed the
regeneration of alkyne 2a with 65% of deuterium labeling in the
methyl group (Fig. 1a). These experiments conrm the presence
of dilithiated allenyl species II which is in equilibrium with the
alkyne, allene, and monolithiated allene moieties.19,20
The C]O stretching absorption corresponding to the amide
carbonyl group in 1a (ꢁ1709 cmꢂ1) was decayed upon addition
of one equivalent of LiHMDS and a new peak at ꢁ1666 cmꢂ1
was formed which corresponds to the enolate of 1a. Progress of
the reaction showed the appearance of a new C]O stretching
absorption bond which is attributed to the product
(ꢁ1712 cmꢂ1).
Deuterium labeling experiments using substrates 1d and 2a
indicated that the deuterium atoms are distributed between two
positions of vinylic hydrogen and methyl group (Fig. 1c).20 This
deuterium distribution is in agreement with a prior alkyne–
allene isomerization and protonation of the carbanion (IV)
(Fig. 1a). It should be noted that quenching the reaction with
D2O did not change the deuterium incorporation, suggesting
that there was no organolithium intermediate present before
(Fig. 1c, entry 4). Additionally, the quenching with methyl
iodide did not result in the alkylated product.
In order to gain further insight into the reaction mechanism,
DFT calculations were carried out.20 Nucleophilic addition of
imidazolidinone to alkyne (or its allene counterpart) was
considered as the key step in the presence of different aggre-
gations of Li (monomer, dimer, and trimer).21 The optimized
structures and relative barrier energies are shown in Fig. 1d,
Scheme S1,† using DME (dimethylether) as a model for THF,
LiHMDS.3DME for solvated LiHMDS and imidazolidinone 1a
and alkyne 2a as substrate. A comparison of the calculated free
energies showed that the stability of transition states depends
on both the degree of aggregation and solvation. We found in
our calculations that in the medium degree of lithium aggre-
gation (dimer), the coordination of solvent to Li (TS-Di-All.DME)
is more benecial than in an unsolvated transition state (Ts-Di-
All, Scheme S1†). In addition, for the transition states with less
aggregated Li (dimer and monomer) coordination of the solvent
seems to be more preferred in comparison to trimer. These
results are in agreement with a previous report.22 Computa-
Fig. 1 (a) The proposed reaction mechanism. (b) The in situ IR ob-
tained of the reaction between substrates 1a and 2a. (c) Deuterium tional details show that the medium degree of lithium aggre-
labeling experiments. (d) Optimized geometry of transition states and
gation (dimer) leads to the most stable transition state.
relative free energies (in kcal molꢂ1 are compared with TS-Tr-All. A). All
Furthermore, the high difference between the energy of TS-Di-
C–H bonds are hidden for simplicity.
All.DME and TS-Di-All.C.DME (9.6 kcal molꢂ1) well demon-
strates the key role of the tert-butyl group in controlling
stereochemistry. More importantly, the geometry of 2a in TS-Di-
Alk.DME shows that carbolithiation of alkyne led to the Z
product while the E-conguration is the only experimentally
observed geometry. The found relative energies of TS-Di-
Alk.DME and TS-Tr-Di-All.DME supports the assumption that
the reaction is exclusively happening between allene and the
enolate.
Detailed mechanistic investigations were performed in order
to support the proposed mechanism. First, the hydroalkylation
reaction was evaluated by in situ IR using 1a and 2a as starting
materials (Fig. 1b).20 Upon addition of LiHMDS (2 eq.) to
a mixture of alkyne in THF at 80 ꢀC, a new absorption band
appeared at ꢁ1926 cmꢂ1. According to literature, this band
could be assigned to a dilithiated allenyl species.18a Based on
a previous report, n-BuLi (2 eq.) was added to 2a and again the
peak at ꢁ1926 cmꢂ1 was observed proving our hypothesis. This
peak disappeared aer quenching with CD3OD and no peak was
detected in the allene area. The NMR and mass analysis of the
Conclusions
In conclusion, we have developed a new method for the enan-
tioselective introduction of an alkenyl substituent to the alpha
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position of amino acids using the diastereoselective hydro-
alkylation of alkynes and allenes with imidazolidinone deriva-
tives obtained from enantiopure amino acids. This reaction
proceeds with complete control of both regio- and diaster-
eoselectivity and allows efficient access to (E)-alkene function-
alized quaternary amino acids. The feasibility of this protocol is
highlighted by its operational simplicity as well as gram scale
application. Further studies in this research eld are currently
ongoing in our group.
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The work was conceptualized by FP and BB. FP initiated the
project and performed the experiments. HK performed the
computational analysis and synthesized some starting mate-
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the manuscript was prepared by FP and the nal dra was
edited by all the authors.
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HMPA (hexamethylphosphoramid) and [12]crown-4 were
used as additive to capture the Li and prevent its action in
the reaction and interestingly ee was decreased to 73%
and 51%, respectively. These experiments suggest the
chelation-control role of Li metal via lithium enolate
formation in this reaction.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank the Alexander von Humboldt Foundation (F.P.) for
´
´
a postdoctoral fellow-ship. We are grateful to Dr Marıa Gonzalez
Rodriguez for reading the manuscript. We thank Dr Manfred
Keller for extensive NMR experimentations and Joshua
Emmerich for challenging HPLC separations.
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