Highly diastereo- and enantioselective synthesis of α-alkyl norstatine derivatives: Catalytic asymmetric mannich reactions of 5H-Oxazol-4-ones

Article abstract of DOI:10.1002/anie.201201804

Going Mannich: The title reaction results in the first catalytic asymmetric synthesis of syn-α-alkyl norstatine derivatives. Excellent enantioselectivities and diastereoselectivities were achieved with a series of N-diphenylphosphinoyl-protected imines and 5H-oxazol-4-ones by using the catalyst 1/Zn. Importantly, the involvement of the diethyl phosphoramidate 2 was critical to achieve good enantioselectivities in the present Mannich reaction. Copyright

Full text of DOI:10.1002/anie.201201804

Angewandte
Chemie
DOI: 10.1002/anie.201201804
Asymmetric Catalysis
Highly Diastereo- and Enantioselective Synthesis of a-Alkyl Norstatine
Derivatives: Catalytic Asymmetric Mannich Reactions of 5H-Oxazol-
4-ones**
Depeng Zhao, Linqing Wang, Dongxu Yang, Yixin Zhang, and Rui Wang*
The catalytic asymmetric synthesis of b-amino acids[1] has
been an intense area of research in recent years as these
unnatural amino acids are basic elements of peptides and
peptidomimetic precursors of many physiologically active
compounds.[2] In particular, many efforts have focused on
synthetic methods towards a-hydroxy b-amino acid (norsta-
tine) derivatives,[3] which have been used as a side chain in
taxol analogues,[4] and are observed in natural products such
as leuhistin.[5] Despite previous success, the stereoselective
synthesis of a-alkyl a-hydroxy b-amino acids bearing a qua-
ternary stereogenic center is still challenging.
In 2010, Wolfe and co-workers described an asymmetric
tandem Wittig rearrangement/Mannich reaction to prepare
such compounds using 2-phenylcyclohexanol as a chiral
auxiliary (Scheme 1a).[6] With this protocol, both syn- and
anti-selective products were accessed with high enantioselec-
Scheme 1. Protocols for asymmetric synthesis of a-alkyl a-hydroxy b-
amino acids.
tivities and diastereoselectivities using specific protective
groups. To date, only a few catalytic methods have been
developed for a-alkyl norstatine derivatives.[7] Hu, Gong, and
co-workers reported a three-component reaction of diazo
compounds with alcohols and imines catalyzed by [Rh2-
(OAc)4] and a chiral Brønsted acid (Scheme 1b). In this
process, anti-a-aryl norstatine derivatives were synthesized in
high yields with excellent enantioselectivities.[7] In view of
previous failures of the direct Mannich reaction of a-alkyl a-
hydroxy acids derivatives,[8] we envisioned that the 5H-
oxazol-4-ones[9] 2 might serve as highly reactive equivalents
of a-alkyl a-hydroxy acids and undergo an asymmetric
Mannich reaction,[10] an efficient approach to these com-
pounds (Scheme 1c). The high reactivity of 5H-oxazol-4-one
compared to other equivalents of a-alkyl a-hydroxy acids is
attributed to the aromatization resulting from the enolization
of 5H-oxazol-4-one, thus enabling the intermediates to be
more stable and thereby increasing the reactivity. Herein we
describe our efforts on this subject, and the resulting access to
a series of syn-a-alkyl norstatine derivatives with high
enantioselectivities and diastereoselectivities.
Given our continued interest in the asymmetric synthesis
of unnatural amino acids,[11] especially oxazolones,[12,13] we
decided to investigate the asymmetric Mannich reaction of
the 5H-oxazol-4-ones 2. Fortunately, we found that the
reaction between the N-Dpp (Dpp = diphenylphosphinoyl)
imine 1a and 5H-oxazol-4-one 2a could be efficiently
catalyzed by a zinc catalyst[14] such as the salen 4/Zn complex
(Scheme 2). The Mannich adducts can be obtained with good
yield and excellent diastereoselectivity, though with low
enantioselectivity in the presence of salen 4/Zn (78%,
7% ee, 20:1 d.r.) at room temperature. Encouraged by these
results, a series of salen-type ligands, 5–7, were synthesized
including the dinuclear zinc ligand 7. These salen/Zn catalysts
were also found to be ineffective for the current Mannich
reaction. In addition, the substituted binol 8 was tested and
resulted in low conversion. Interestingly, when the thienyl-
ProPhenol ligand L1[15] was employed for the reaction, an
encouraging ee value was obtained along with excellent
diastereoselectivity. In contrast, the phenyl ligand L2 gave
low diastereoselectivity under the same reaction conditions.
With these results in hand, we then tried to optimize the
Mannich reaction with L1/Et2Zn by changing variables such
as reaction temperature and solvent. In running the reaction
at lower temperatures, we were satisfied to find that the
ee value increased to 50% at 08C and 67% at À208C with
[*] Dr. D. Zhao,[+] L. Wang,[+] D. Yang, Y. Zhang, Prof. Dr. R. Wang
Key Laboratory of Preclinical Study for New Drugs of Gansu
Province, School of Basic Medical Sciences, and Institute of
Biochemistry and Molecular Biology, School of Life Sciences
Lanzhou University, Lanzhou, 730000 (P.R. China)
E-mail: wangrui@lzu.edu.cn
[+] These authors contributed equally to this work.
[**] We are grateful for grants from the National Natural Science
Foundation of China (nos. 90813012 and 20932003), the Key
National S&T Program “Major New Drug Development” of the
Ministry of Science and Technology (2012ZX09504001-003), and the
Scholarship Award for Distinguished Doctoral Candidates of
Lanzhou University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201804.
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Table 1: Optimization of the Mannich reaction.
Entry[a] Additive (mol%) Solvent Yield [%][b]
d.r.[c] ee [%][d]
1
2
3
4
5
6
7
8
–
–
–
–
THF
THF
toluene
CPME
DME
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
89
65
83
73
75
85
79
85
80
91
92
92
70
56
trace
85
97:3
96:4
98:2
50
67[e]
34
90:10 48
–
97:3
99:1
99:1
99:1
98:2
99:1
>99:1
>99:1
98:2
94:6
–
37
86
83
86
89
89
92
95
76
23
–
9a (10)
9b (10)
9c (10)
9d (10)
9e (10)
9e (20)
9e (30)
(S)-9 f (30)
(R)-9 f (30)
10(30)
11, POPh3 (30)
9
10
11
12
13
14
15
16
95:5
69
[a] Unless otherwise noted, reactions were carried out with 1a
(0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), and L1/Et2Zn (10
mol%) in 2.0 mL solvent at 08C for 24 h. [b] Yield of isolated product.
1
[c] Determined by H and 31P NMR spectroscopic analysis. [d] The
enantiomeric excess was determined by HPLC analysis. [e] The reaction
was carried out at À208C. CPME = cyclopentylmethyl ether, THF =
tetrahydrofuran.
the metal center either permanently or temporarily, and
thereby prevent the unfavorable cross-binding pathway.
Fortunately, after screening a large number of potential
candidates, we successfully identified the diphenylphosphin-
amide 9a as an effective ligand (Table 1, entry 6). The
enantioselectivity increased remarkably to 85% together
with the diastereoselectivity (99:1) by using 10 mol% of 9a.
Inspired by this result, a series of analogues, dialkyl phos-
phoramidates 9b–e, were prepared and tested in the current
Mannich reaction (Table 1, entries 7–10). The results sug-
gested the diethyl phosphoramidate 9e was the most effective
of the series with respect to both ee and d.r. values (Table 1,
entry 10). Then the amount of the diethyl phosphoramidate
9e was investigated and we were pleased to find that the best
result was obtained with 30 mol% of 9e (Table 1, entry 12).
Two chiral phosphoramidates, (R)-9 f and (S)-9 f, derived
from binol were also tested and proved not to be as effective
as the achiral ones (Table 1, entries 13 and 14). In addition,
low conversion was observed when the diphenylphosphinic
acid 10 was subjected to the system, possibly because the
catalyst decomposed under the acidic conditions. The unsat-
isfactory results obtained with triphenylphosphine oxide 11
also emphasized the essential role of the amide group of the
phosphoramidate.
Scheme 2. Preliminary ligand screening. [a] All reactions were carried
out with 1a (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), and
L/Et2Zn (10 mol%) in 2.0 mL solvent at RT. For 4, 5, 6, and 8,
L/Et2Zn=1:1; for 7, L1, and L2, L/Et2Zn=1:2.
excellent diastereoselectivities (Table 1, entries 1 and 2). The
ee value increased at lower temperature at the expense of
conversion. A screening of solvents (Table 1, entries 3–5)
showed that THF was the best solvent with respect to
enantioselectivity. After careful examination of the structure
of the 5H-oxazol-4-ones, we found that they could viewed as
cyclic N-acyl imines, which might have a dual binding mode to
the metal. So we assume 5H-oxazol-4-one can adopt two
different dual binding modes with regard to the L1/Et2Zn
complex, that is, an independent binding: 5H-oxazol-4-one
binds to only one zinc center of the catalyst, and cross-
binding: 5H-oxazol-4-one binds to the two zinc centers (E;
see Scheme 4). We believe the cross-binding is not conducive
to the final enantioselectivity. Therefore, we considered using
Lewis-basic additives, which might be able to coordinate to
With the established optimized reaction conditions as
indicated in entry 12 of Table 1, the substrate scope of the
2
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Mannich reaction using various 5H-oxazol-4-ones 2 and Dpp-
imines 1 was examined. Initially, a series of 5H-oxazol-4-one
derivatives bearing alkyl groups at the C5-position were
investigated with 1a (Table 2). The results showed that 5H-
oxazol-4-ones 2a–f were amenable to the catalysis and the
alkyl group had no obvious effect on the yield and stereose-
lectivities (Table 2, entries 1–5). We also tested the Mannich
reaction with (S,S)-L1, and as expected, the product enantio-
mers were obtained with similar results (Table 2, entries 1–5).
Subsequently, the aromatic Dpp-imines 1 bearing various
substituents and imines with condensed rings or heteroaryl
units were examined with 2a (Table 2, entries 7–17). In
general excellent results were achieved, except for 1 f and
1l, which resulted in lower enantioselectivities (Table 2,
entries 11 and 17). In view of the synthetic utility of the
product, the reaction was also conducted with the aliphatic
imine 1l and reasonable results were observed (Table 2,
entry 18). Importantly, a preformed complex of L1/9e/Et2Zn
was also investigated in the Mannich reaction of 1a and 2a
(Table 2, entry 19). With the preformed air-stable complex of
L1/9e/Et2Zn, the reaction could be performed without the
protection of argon atmosphere and gave identical results.
This improvement greatly facilitates the operation of the
experiment.
Furthermore, when the Mannich reaction of the 5H-
oxazol-4-one 2g was performed on a gram scale, 3ag was
obtained with 89% yield (1.92 g), greater than 99:1 d.r., and
92% ee (Table 2, entry 20). The additional transformation of
the product into a-alkyl a-hydroxy b-amino acid derivatives
was exemplified by conversion of 3ag. As shown in Scheme 3,
Table 2: Scope of the Mannich reaction.
Entry[a] R1
2
3
Yield [%][b]
92(93)
d.r.[c,e] ee [%][d,e]
1
2
3
4
5
6
4-MeC6H4
2a 3a
>99:1
95(96)[f]
92(94)
90(91)
94(91)
94(92)
91(93)
Scheme 3. Transformation of the Mannich adducts.
(>99:1)
>99:1
(>99:1)
>99:1
(>99:1)
98:2
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
2b 3ab
2c 3ac
2d 3ad
2e 3ae
2 f 3af
91(89)
91(93)
90(87)
88(89)
92(87)
the product 3ag can be readily hydrolyzed to the a-alkyl a-
hydroxy b-amino acid derivative 12 under acidic conditions.
A plausible mechanism is on the basis of the absolute
configuration of 3a that was obtained from using (S,S)-L1.
The first step may involve the formation of complex A
(Scheme 4) with participation of L1, 9e, and Et2Zn. In this
process, the bifunctional diethyl phosphoramidate 9e might
function as a Brønsted acid and a Lewis base, which is possibly
involved in deprotonation and coordination with the metal
center. This aspect can be ascertained by previous reports
from Hoveyda and co-workers,[17] who found that diethyl
phosphoramidate reacted with Et2Zn and greatly improved
enantioselectivities of the products. The covalent bond
enables its tight binding to the two zinc atoms. The two
substrates then bind to the two zinc atoms independently
through dual-mode binding (Scheme 4, complex C). After-
wards, the 5H-oxazol-4-ones 2a is enolized and undergoes the
stereospecific addition. High diastereoselectivities were sup-
posed to be attributed to the repulsion between the Dpp
group and the phenyl group of the 5H-oxazol-4-one. In the
absence of phosphoramidates, a competitive pathway, in
which the 5H-oxazol-4-one binds to both of the zinc centers of
the catalyst, may occur (E; Scheme 4). This cross-binding of
2a to the catalyst is disadvantageous as this mode impedes the
coordination of the Dpp imine and both the Re and Si faces of
the 5H-oxazol-4-one are open.
(98:2)
>99:1
(>99:1)
99:1
(99:1)
>99:1
99:1
>99:1
98:2
98:2
99:1
99:1
>99:1
7
8
9
10
11
12
13
14
Ph
2a 3b
2a 3c
2a 3d
2a 3e
2a 3 f
2a 3g
87
89
85
87
88
91
90
88
94
93
90
93
85
92
96
92
4-FC6H4
4-ClC6H4
4-BrC6H4
3-ClC6H4
3-MeC6H4
4-MeOC6H4 2a 3h
3-MeOC6H4 2a 3i
15
2a 3j
92
98:2
94
16
17
18
19
20
2-naphthyl
3-furyl
cyclopropyl
4-MeC6H4
4-MeC6H4
2a 3k
2a 3l
2 f 3m
2 f 3af
2g 3ag
93
92
91
93
89
99:1
>99:1
81:19
99:1
90
86
80
91[g]
92[h]
>99:1
[a] Unless otherwise noted, reactions were carried out with 1 (0.2 mmol,
1.0 equiv), 2 (0.3 mmol, 1.5 equiv), and L1/Et2Zn (10 mol%) in 2.0 mL
THF at 08C for 24 h. [b] Yield of isolated product. [c] Determined by H
1
and 31P NMR spectroscopic analysis. [d] The enantiomeric excess was
determined by HPLC analysis. [e] In parentheses are results obtained
from (S,S)-L1. [f] The absolute configuration of 3a from (S,S)-L1 was
determined by X-ray analysis[16] and the other products were assigned by
analogy. [g] The reaction was conducted with a preformed complex of L1/
9e/Et2Zn. For details, see the Supporting Information. [h] The reaction
was performed on 4.0 mmol scale.
In conclusion, we have developed a highly diastereo- and
enantioselective zinc-catalyzed Mannich reaction of 5H-
oxazol-4-ones, which leads to the first catalytic asymmetric
synthesis of syn-a-alkyl norstatine derivatives. Excellent
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Scheme 4. Proposed mechanism of the Mannich reaction.
c) J. Kant, W. S. Schwartz, C. Fairchild, Q. Gao, S. Huang, B. H.
Long, J. F. Kadow, D. R. Langley, V. Farina, D. Vyas, Tetrahe-
dron Lett. 1996, 37, 6495.
enantioselectivities and diastereoselectivities were achieved
with a series of N-Dpp imines and 5H-oxazol-4-ones.
Importantly, the combination of the ProPhenol ligand L1,
dialkyl phosphoramidate, and Et2Zn was found to be a unique
catalyst. Additional studies on the application of the catalyst
system to other reactions and the synthetic utilities of the
Mannich adducts are underway.
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[10] For recent reviews on the asymmetric Mannich Reaction, see:
a) R. G. Arrayꢁs, J. C. Carretero, Chem. Soc. Rev. 2009, 38, 1940;
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Received: March 6, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · heterocycles · phosphorus ·
.
synthetic methods · zinc
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Communications
Asymmetric Catalysis
D. Zhao, L. Wang, D. Yang, Y. Zhang,
R. Wang*
&&&& — &&&&
Highly Diastereo- and Enantioselective
Synthesis of a-Alkyl Norstatine
Derivatives: Catalytic Asymmetric
Mannich Reactions of 5H-Oxazol-4-ones
Going Mannich: The title reaction results
in the first catalytic asymmetric synthesis
of syn-a-alkyl norstatine derivatives.
Excellent enantioselectivities and diaste-
reoselectivities were achieved with
tected imines and 5H-oxazol-4-ones by
using the catalyst 1/Zn. Importantly, the
involvement of the diethyl phosphorami-
date 2 was critical to achieve good
enantioselectivities in the present Man-
nich reaction.
a series of N-diphenylphosphinoyl-pro-
6
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