Enantioselective addition of oxazolones to N-protected imines catalysed by chiral thioureas

Article abstract of DOI:10.1039/c5ra00092k

Hydrogen bond-catalysed aza-Mannich addition of oxazolones to various protected aldimines has been developed. The resulting, highly functionalized, oxazolones contain a quaternary stereogenic centre and can serve as precursors for chiral α,β-diamino acids with different protecting groups on each amino group. The process benefits from the versatile bifunctional thiourea catalysts, which effect the formation of these products in high yields and stereoselectivities.

Full text of DOI:10.1039/c5ra00092k

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Enantioselective addition of oxazolones to
N-protected imines catalysed by chiral thioureas†
Cite this: RSC Adv., 2015, 5, 12890
Matej Zˇ abka, Andrea Malastova and Radovan Sˇ ebesta*
´
Received 3rd January 2015
Accepted 16th January 2015
DOI: 10.1039/c5ra00092k
www.rsc.org/advances
Hydrogen bond-catalysed aza-Mannich addition of oxazolones to
In this context, we present chiral thiourea catalyzed Mannich
various protected aldimines has been developed. The resulting, highly type reaction of oxazolones with N-protected aldimines. Such
functionalized, oxazolones contain a quaternary stereogenic centre additions have not been described with hydrogen-bonding
and can serve as precursors for chiral a,b-diamino acids with different catalysts so far.
29–32
33
protecting groups on each amino group. The process benefits from
Fig. 1 depicts nine thioureas 1–3,
and 4–5, which have
the versatile bifunctional thiourea catalysts, which effect the formation been used in this study.
34,35
of these products in high yields and stereoselectivities.
Fig. 2 depicts two squaramide catalysts 6 and 7.
We rst screened the reaction between imine 8a and oxa-
zolone 9a and planned to utilize several bifunctional thiourea
catalysts, with different amine functionalities (Fig. 1). We tested
Jacobsen-type catalysts 1a–c in toluene, which afforded product
Enantiomerically pure a-substituted a,b-diamino acids consti-
tute a group of useful building blocks for chiral auxiliaries and
biologically active compounds, including peptides with antibi-
10a with poor enantioselectivity (Scheme 1 and Table 1, entries
1
otic activity. A number of reports have recently appeared
2–4). Excellent yield and a moderate enantioselectivity were
dealing with the preparation of enantiopure a,b-diamino acids
achieved by using Takemoto catalyst (entry 6). Catalyst 3 with no
amine functionality did not perform well. These results suggest
that both tertiary or secondary amine functional group and an
activating, electron-withdrawing substituent on the thiourea
resulting in higher acidity are necessary for the good
2,3
by the Mannich reaction starting from oxazolones. Oxazol-
4
,5
5
(4H)-ones are masked amino acid fragments, widely used in
6
–15
the construction of quaternary a-amino acids.
These proce-
16
dures, utilizing e.g. TMS-quinine, chiral ion-pair catalysts
17,18
19
including phosphonium salts,
binaphthyl betaines, phos-
20
21
phoric acid derivatives, and gold complexes give products in
excellent yields and stereoselectivities. However, quite complex
catalysts or high catalyst loadings are, usually, required. Catal-
ysis using chiral hydrogen-bond donors, particularly thioureas
and squaramides, has recently emerged as a frontier of research
22–25
in asymmetric organocatalysis.
Chiral, bifunctional thio-
urea catalysts are capable of activating both the electrophile and
26–28
the nucleophile, leading to an enantioenriched product.
Moreover, they offer superior advantages with respect to their
stability and cost. Therefore, we decided to evaluate a series of
easily prepared bifunctional thioureas to address the issue of
stereoselective formation of a,b-diamino acids by the Mannich
reaction between oxazolones and imines.
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University,
Mlynsk a´ Dolina CH-2, SK-842 15 Bratislava, Slovakia. E-mail: radovan.sebesta@
fns.uniba.sk
†
Electronic supplementary information (ESI) available: Experimental procedures,
characterisation data, and computational details. See DOI: 10.1039/c5ra00092k
Fig. 1 Thiourea catalysts used in this study.
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Table 2 Screening of solvents in the addition of oxazolone 9a to imine
a
8a
b
c
Entry
Solvent
Yield (%)
dr
er
d
1
2
3
4
5
6
7
PhMee
55
43
53
63
72
64
64
2.3 : 1
2.6 : 1
2.3 : 1
3 : 1
3.5 : 1
2.6 : 1
3 : 1
89 : 11
89 : 11
87 : 13
88 : 12
90 : 10
84 : 16
70 : 30
PhMe
CH
Xylenes
Et
CHCl
MeCN
2
Cl
2
2
O
Fig. 2 Squaramide catalysts used in this study.
3
a
Experimental conditions: imine 8a (0.1 mmol), oxazolone 9a (1.2 eq.),
b
1
catalyst 4b (10 mol%), solvent (0.5 mL), rt, 18 h. Determined by H
NMR analysis of the crude reaction mixture. er of the major
c
d
diastereomer determined by HPLC analysis.
0.1 M solution.
e
ꢀ
À35 C to rt.
inferior enantioselectivity, as this solvent can partially disrupt
hydrogen bonds (Table 2, entry 7).
Scheme 1
We then proceed to evaluate the reaction with more sterically
demanding oxazolone 9b. This substrate provided product 10b
with excellent diastereo- and enantioselectivity with catalyst 4a
Table 1 Screening of catalysts in the addition of oxazolone 9a to imine at À5 ꢀC (Table 3, entry 2). Increasing the concentration or
a
8
a
adding molecular sieves (4A) did not have any effect on the
selectivity (Table 3, entries 3 and 4). Lower catalyst loading (1
and 5 mol%) decreased the yield of product 10b but its diaste-
reomeric and enantiomeric purity remained high (Table 3,
entries 5–6). Catalyst 4b afforded slightly inferior result in
comparison to catalyst 4a (Table 3, entry 7). The catalyst 5,
which is the pseudo-enantiomer of catalyst 4a, provided the
product with the opposite stereochemistry in equally high
b
c
d
Entry
Catalyst
Yield (%)
dr
er
1
2
3
4
5
6
7
8
9
DABCO
76
71
49
18
20
4.1 : 1
2.1 : 1
5.2 : 1
1.5 : 1
1.4 : 1
3.7 : 1
0.9 : 1
1.6 : 1
3 : 1
0
1a
1b
1c
2a
2b
3
51 : 49
63 : 37
54 : 46
53 : 47
17 : 83
g
g
99
25
g
59 : 41 enantiomeric ratio (Table 3, entry 8). Use of the squaramide-
e
4a
65
82
80
78
64
77 : 23
90 : 10
79 : 21
90 : 10
37 : 63
derived catalyst 6, analogous to the Takemoto catalyst 2b, led
to inferior results (Table 3, entry 9). Squaramide catalyst 7,
4a
4a
f
10
11
12
3.3 : 1
3 : 1
1.5 : 1
4b
5
a
a
Table 3 Catalyst screening in the reaction with oxazolone 9b
Experimental conditions: imine 8a (0.1 mmol), oxazolone 9a (1.2 eq.),
catalyst (10 mol%), toluene (0.5 mL), rt, 18 h. Combined isolated yield
of both diastereomers. Determined by H NMR analysis of the crude
reaction mixture. er of the major diastereomer determined by HPLC
analysis. 1 eq. oxazolone was used. 1.5 eq. oxazolone was used.
Conversion determined by H NMR.
b
c
1
d
e
f
g
1
36
performance of the catalyst. Thus cinchona-alkaloid catalyst
a gave the product in excellent yield and good enantiose-
b
c
Entry
Catalyst
Yield (%)
dr
er
4
lectivity (Table 1, entry 9). We have also found that a small
excess of the oxazolone (1.2 eq.) was benecial for the reaction
1
2
3
4
5
6
7
8
9
4a
58
67
78
78
58
48
50
82
67
44
8 : 1
12 : 1
12 : 1
8 : 1
8 : 1
8 : 1
8 : 1
8 : 1
3 : 1
4 : 1
88 : 12
96 : 4
93 : 7
93 : 7
94 : 6
97 : 3
92 : 8
10 : 90
33 : 67
86 : 14
d
4a
e
(Table 1, cf. entries 8–10). Structurally similar catalyst 4b with an
4a
f
ethyl group instead of a vinyl group performed equally well as
catalyst 4a.
Our next goal was to screen solvents and evaluate concen-
tration effects to achieve higher stereoselectivity. Experiments
were typically conducted at 0.2 M concentration. Running the
4a
4a
g
h
4a
4b
5
6
reaction at lower concentration (0.1 M) resulted in lower yield, 10
7
but the selectivity did not improve (Table 2, entry 1). By using
a
Experimental conditions: imine 8a (0.1 mmol), oxazolone 9b (1.2 eq.),
b
1
different, non-polar solvents, however, only small change was catalyst 4a (10 mol%), toluene (0.5 mL), rt, 18 h. Determined by H
c
NMR analysis of the crude reaction mixture. er of the major
observed in terms of diastereo- and enantioselectivity (Table 2,
entries 3–6). Use of acetonitrile as a more polar solvent led to
d
ꢀ
e
diastereomer determined by HPLC analysis. À5 C, 3 days. 0.4 M
f
g
h
solution. MS 4A (50 mg) added. 1 mol%. 5 mol%.
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derived from quinine, also gave the product with slightly lower
enantioselectivity (Table 3, entry 10).
We noticed that the product from oxazolone 9b was formed
with good enantioselectivity only if it was contaminated by
benzoic anhydride impurity. Benzoic anhydride may remain in
the oxazolone from its synthesis and it probably forms benzoic
acid under the reaction conditions. It is difficult to completely
remove it from the oxazolones. When particular care was taken
to remove it, the reaction surprisingly proceeded without any
stereoselectivity (Table 4, entry 1). The acid may facilitate
nucleophile formation from oxazolone as well as activate the
imine. In terms of stereoselectivity, the acid helps in better
organization of the transition state. Therefore, we screened
several acid co-catalysts. Indeed, we found that acid additive is
necessary for the good performance of the catalyst, otherwise
only racemic mixture was obtained. Benzoic acid afforded the
best results in terms of diastereomeric and enantiomeric purity
of the product 10b (Table 4, entry 2). Interestingly, use of
sodium benzoate also improved the reaction to certain degree
(Table 4, entry 3). This indicates involvement of the benzoate
anion in the enantio-determining step of the reaction. No
improvement was achieved using different acids with varying
acidities (entries 4–9). Interestingly, chiral mandelic acid gave
the same result when used as racemate or enantiomerically
pure. This suggests that the inuence of the anion of acid is in
overall steric volume rather than any specic interactions in the
transition state. A similar, but less pronounced effect of the acid
37
co-catalyst was observed in an aldol addition.
Next, we varied the sulfonyl protecting group at the imine.
Mesyl-protected imine 8b provided product 10c in high yield
with excellent enantioselectivity. Differently substituted oxazo-
lones 9b (i-Pr) and 9c (Bn) gave inferior results with mesyl imine
8
8
b. High diastereoselectivity was achieved with naphthyl imine
c while the enantioselectivity remained high. More sterically
Fig. 3 Oxazolones 10a–k obtained by the reactions of imine 8 (0.1
demanding imines 8d–e (2,4,6-trimethylphenyl and 2,4,6-tri(i-
sopropyl)phenyl) gave products with high enantiomeric ratios
only with oxazolone 9b, rather than with 9a. Fig. 3 depicts
structures of all products 10.
mmol), oxazolone 9 (1.2 eq.), catalyst 4a (10 mol%), PhCO
2
H (10 mol%),
ꢀ
toluene (0.5 mL), rt, 18 h; 10b was obtained at À5 C.
These results show that in order to achieve high selectivity,
steric demands of substrates must match. It seems that oxazo-
lones with less sterically demanding substituents (e.g. 9a)
should be combined with imines containing smaller protecting
group, such as mesyl (8b). On the other hand, more sterically
demanding oxazolones need imines with bigger protecting
groups.
We have conrmed absolute conguration of compounds
10a and 10b to be (S,R) by comparison of its electronic CD
spectra with theoretically calculated ones. Fig. 4 shows spectra
for compound 10b; for more details see ESI.†
Table 4 Screening of acid additives in the reaction of oxazolone 9b
with imine 8a
a
b
c
Entry
Additive
Yield (%)
dr
er
1
2
3
4
5
6
7
8
9
—
52
54
62
36
48
65
43
35
35
68
1.2 : 1
13 : 1
4 : 1
6.3 : 1
5.5 : 1
3 : 1
5.5 : 1
9 : 1
9 : 1
49 : 51
95 : 5
73 : 27
91 : 9
85 : 15
77 : 23
85 : 15
93 : 7
PhCO
PhCO
AcOH
TFA
2-IC
4-BrC
(RS)-Mandelic acid
(R)-Mandelic acid
PhCH
2
H
2
Na
d
6
H
4
CO
2
H
6
H
4
CO
2
H
With the help of quantum-chemical calculations (HF, 3-
21G), we also proposed a possible model of transition state for
93 : 7
1
0
2
CO
2
H
6.5 : 1
86 : 14 the addition, which explains observed stereochemistry of
a
products (see ESI†).
Experimental conditions: imine 8a (0.1 mmol), oxazolone 9b (1.2 eq.),
catalyst 4a (10 mol%), additive (10 mol%), toluene (0.5 mL), rt, 18 h.
Azlactones 10 can be cleaved in acidic medium to a,b-dia-
mino acids. The compound 10b afforded acid 11 in quantitative
yield (Scheme 2). By comparison of the sign of its optical
b
1
c
Determined by H NMR analysis of the crude reaction mixture. er
d
of the major diastereomer determined by HPLC analysis. 100 mol%
used.
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