Communications
doi.org/10.1002/ejoc.202100259
such as (R,R)-L1* (Figure 2), allowed the direct asymmetric N-
corresponding L2*-derived catalysts, allowing to reduce the
catalyst loading.[14]
allylation of N-unprotected amino acid esters with outstanding
levels of stereocontrol. Despite their architectural relationship
with the broadly established Trost ligand L2*,[16] our ligands
proved to be clearly superior not only in terms of stereo-
induction but also by exhibiting a strong ligand acceleration. In
fact, the catalysts generated in-situ from L1* using [Pd(allyl)Cl]2
as a metal source were found to be much more active than the
Against this background we reasoned that our method for
the asymmetric N-allylation of amino acid esters should open a
general and stereo-divergent entry towards opines (5) as
outlined in Scheme 1, provided that the oxidative cleavage of
the allylation products (6) can be efficiently performed. While
we had previously used only the carbonate rac-8 (with R=Et) to
demonstrate the N-allylation protocol, we were interested in
adapting the methodology also to other carbonates, especially
employing rac-8a (R=Me) formally as a pyruvate equivalent (see
above) to access N2-(1-carboxyethyl) amino acids (5, R=Me) in
both diastereomeric series. Noteworthy, while this work was in
progress, Lei and coworkers reported a synthesis of pseudopa-
line (4) via Pd-catalyzed allylation of an N-nosylated amino acid
ester employing methyl cyclopentenyl carbonate in the pres-
ence of a chiral ligand of type L2*.[6]
We started our investigation with the Pd-catalyzed asym-
metric allylation of simple (N-unprotected) glycine esters
employing the carbonate rac-8a and (R,R)-L1* as a most
promising chiral ligand.[14] The results, summarized in Table 1,
indicate that the desired allylic amines of type 9 were formed
with good to excellent enantioselectivity in all cases, depending
on the reaction conditions. Using glycine tert-butyl ester (7a) at
a concentration of 2.00 M full consumption of rac-8a was
Figure 2. Structure of the C2-symmetric iPr-MediPhos ligand L1* in compar-
ison to the Trost ligand L2*.
°
already observed after one hour at 25 C (entry 1), however, the
enantioselectivity (72% ee) was somewhat disappointing.
Dilution of the catalytic system led to longer reaction times but
also to an increase of the enantiomeric excess (entries 2 and 3).
We then asked ourselves whether the commercially available
hydrochloride salts 7b or 7c, respectively, could be employed
as a more practical alternative to the volatile glycine ester 7a.
This could indeed be achieved by simply adding equimolar
amounts of NEt3 to the reaction system (entries 4 to 10). Under
optimized conditions (entry 11) the methyl ester 9c was
obtained with an enantioselectivity of 97% ee after 15 h in the
presence of 2 mol% of the in-situ formed Pd catalyst. The
expected (R)-configuration of the product 9c[14] was confirmed
after conversion to the diester 12 by comparison of the
molecular rotation with an L-alanine-derived reference sample.
Noteworthy, the enantioselectivity proved to be time-independ-
ent, and the reactions were usually run overnight to ensure full
conversion (15–22 h).
Scheme 1. A strategy for the stereo-divergent synthesis of opines based on
Pd-catalyzed asymmetric N-allylation.
Table 1. Optimization of the asymmetric N-allylation of glycine esters
employing the chiral ligand (R,R)-L1*.[a]
Entry
Amine
Conc[b]
[mol/l]
Conversion[c]
[%]
ee[d]
[%]
The transformation of the N-allylation product 9c into
strombine (13) as a most simple opine was achieved as shown
in Scheme 2. For the crucial oxidative cleavage of the C=C
double bond we applied the ozonolysis protocol of Marshall,[17]
which leads directly to the methyl ester. However, the amine
function had to be protected as a Boc derivative (10) to avoid
complete decomposition of the material during the oxidation
step. The diester 11 was finally deprotected to afford strombine
(13, isolated as the hydrochloride salt) in 60% overall yield from
9c.
1
2
3
4
5
6
7
8
7a
7a
7a
7b
7b
7b
7c
7c
7c
7c
7c
2.00
1.00
0.50
2.00
1.00
0.50
2.00
1.00
0.50
0.25
0.25
100
100
100
100
100
100
100
100
100
45[e]
100
72
78
85
75
82
84
90
91
94
97
97
9
10
11[f]
[a] Reactions were performed on a 0.7 mmol scale using either 7a (1.3 eq)
or 7b/c in the presence of Et3N (1.3 eq). [b] Concentration of rac-8a. [c]
Conversion of rac-8a (GC-MS). [d] Enantiomeric excess of 9 determined by
GC on a chiral stationary phase; configurational assignments are based on
rotary values given in the literature for compound 12. [e] Conversion after
22 h. [f] 1 mol% of [Pd(allyl)Cl]2 and 2.6 mol% of L1* were used.
Having elaborated reliable conditions both for the asym-
metric N-allylation of glycine esters (Table 1) and the oxidative
cleavage of the olefin (Scheme 2), we next investigated the
application of the protocols to the diastereoselective synthesis
Eur. J. Org. Chem. 2021, 2099–2102
2100
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