Asymmetric Mannich synthesis of α-amino esters by anion-binding catalysis

Article abstract of DOI:10.1021/ja5075163

We report a scalable, one-pot Mannich route to enantioenriched α-amino esters by direct reaction of α-chloroglycine ester as a practical imino ester surrogate. The reaction is promoted by a chiral aminothiourea, which is proposed to operate cooperatively

Full text of DOI:10.1021/ja5075163

Communication
pubs.acs.org/JACS
Open Access on 09/01/2015
Asymmetric Mannich Synthesis of α‑Amino Esters by Anion-Binding
Catalysis
Masayuki Wasa,† Richard Y. Liu,† Stephane P. Roche,*,‡ and Eric N. Jacobsen*,†
́
†Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
‡Department of Chemistry & Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431, United States
S
* Supporting Information
generation of imine.8 To overcome these limitations, we
envisioned the application of chiral bifunctional catalysts
capable of both generating imine from its surrogate and
inducing asymmetric addition of the enolate.
ABSTRACT: We report a scalable, one-pot Mannich
route to enantioenriched α-amino esters by direct reaction
of α-chloroglycine ester as a practical imino ester
surrogate. The reaction is promoted by a chiral amino-
thiourea, which is proposed to operate cooperatively by
generating an iminium ion by chloride abstraction and an
enolate by deprotonation, followed by highly stereo-
selective C−C bond formation between both reactive
intermediates associated non-covalently within the catalyst
framework.
The use of chiral thioureas to promote anion abstraction
from neutral organic electrophiles to generate highly reactive
cationic intermediates has emerged as a powerful platform in
asymmetric catalysis.9,10 Recently, the Roche group reported a
practical route to α-chloroglycine esters by reaction of
carbamates or amides with ethyl glyoxylate, acetyl chloride,
and acetic acid in the context of a new route to racemic α-
arylglycine esters.11 We considered whether α-chloroglycine
esters prepared in this manner could be engaged directly in
thiourea-catalyzed enantioselective Mannich reactions (Scheme
1).3 Specifically, thiourea-induced chloride abstraction could
serve to generate a reactive N-acyliminium ion, while the basic
amine functionality could generate and position an enolate for
nucleophilic addition to give the desired enantioenriched α-
amino esters. We describe here the application of such an
anion-binding strategy in a practical Mannich synthesis of
aspartic acid derivatives. This methodology circumvents the
multi-pot, base-mediated preparation of N-carbamoyl imino
esters from imine surrogates developed previously.3f,g,i,5,7
We examined the Mannich reactions using N-Cbz α-
chloroglycine ethyl ester (1-Cbz) as the model substrate and
bifunctional thioureas as potential catalysts. We discovered that
Takemoto’s tertiary aminothiourea catalyst 23e,12 promoted the
reaction between 1-Cbz and dibenzoylmethane in DCM at −30
°C in the presence of 4 Å molecular sieves (MS), affording the
Mannich product in 90% yield and 93% ee (Table 1, entry
1).13−15 Thiourea catalysts lacking the tertiary amino group
gave no desired product. Substrates bearing other carbamate or
acyl N-protecting groups afforded significantly inferior results in
comparison to Cbz with respect to reaction enantioselectivity
(entries 2−8).16 Reaction temperature and solvent were also
found to exert profound effects on enantioselectivity (entries 1,
9−16). Optimal results were obtained at −30 °C in DCM, with
lower temperatures affording no advantage.
he Mannich reaction involves the enantioselective
Taddition of enolate equivalents to aldimines or ketimines
to produce β-amino esters.1 Practical, asymmetric methods
have been enabled by the identification of various chiral metal
and organic catalysts.1−3 Mannich reactions involving N-
carbamoyl imino esters as electrophilic partners afford chiral
carbamate-protected α-amino esters directly, and this repre-
sents a most attractive route to this important class of
products.4 However, the instability of imino esters, which
require cumbersome preparation and strictly controlled
conditions in catalytic reactions, is an inherent limitation. To
counter this obstacle, α-haloglycine esters5,6 and α-amido
sulfones3f,g,i,7 have been exploited as imine surrogates in
Mannich-type reactions (Scheme 1). These systems, however,
require multi-pot operations and use of excess base for the
Scheme 1. Asymmetric Mannich Synthesis of α-Amino
Esters
We considered whether the stoichiometric HCl byproduct of
the Mannich reaction might have a deleterious effect on catalyst
performance by forming a salt with its tertiary amine moiety.
Indeed, the HCl salt of 2 catalyzes formation of 3a in only 21%
yield and 18% ee under the conditions of the model reaction
(Table 2, entries 1 and 2). We explored whether added bases
Received: July 29, 2014
Published: September 1, 2014
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
a b
,
Table 1. Evaluation of Reaction Parameters
entry
PG
Cbz
solvent
temp (°C)
yield (%)
ee (%)
entry
PG
solvent
temp (°C)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
−30
−30
−30
−30
−30
−30
−30
−30
90
71
83
82
50
84
78
40
93
66
58
82
44
76
43
25
9
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
DCM
DCM
DCM
CHCl3
toluene
Et2O
rt
0
65
70
80
42
61
66
66
71
44
88
90
44
80
90
80
81
Fmoc
Troc
10
11
12
13
14
15
16
−78
−30
−30
−30
−30
−30
MeO2C−
PhO2C−
Ac
Bz
TBME
THF
TFA
a
Conditions: substrate (0.05 mmol), catalyst (10 mol%), diketone (0.1 mmol), 4 Å MS (20 mg), DCM (1 mL), under N2, initially cooled to −78 °C
b
1
and stirred at the temperature denoted in the table for 36 h. The yield was determined by H NMR analysis of the crude reaction mixture using
CH2Br2 as the internal standard.
ab
,
Table 2. Effect of Et3N
Table 3. Asymmetric Mannich Reaction with 1,3-
a d
−
Diketones
entry
catalyst (mol%)
additive (mol%)
yield (%)
ee (%)
1
2
3
4
5
6
2 (10)
none
70
21
76
95
96
83
70
88
18
84
99
99
94
93
2·HCl (10)
2·HCl (10)
2 (10)
none
Et3N (50)
Et3N (50)
Et3N (25)
Et3N (25)
Et3N (50)
2 (10)
2 (5)
c
7
2 (10)
a
Conditions: substrate (0.05 mmol), catalyst (10 mol%), diketone (0.1
mmol), DCM (1 mL), under N2, initially cooled to −78 °C and stirred
b
at −0 °C, 36 h. The yield was determined by the 1H NMR analysis of
c
the crude product using CH2Br2 as the internal standard. Reaction
carried out in the absence of added 4 Å MS.
a
Conditions: substrate (0.25 mmol), catalyst (10 mol%), diketone (0.5
mmol), 4 Å MS (40 mg), Et3N (25 mol%), DCM (5 mL), under N2,
b
could serve to regenerate active catalyst 2 from the HCl salt.
While inorganic bases conferred no improvement on reaction
performance, introduction of Et3N (0.5 equiv) to the reaction
with 2·HCl resulted in formation of 3a in 76% yield and 84% ee
(entry 3). Addition of Et3N to the reaction with the free base
had a striking, positive effect, with formation of 3a in 95% yield
and 99% ee (entries 1 vs 4). Ultimately, it was found that
addition of 25 mol% of Et3N was sufficient to obtain optimal
results (entry 5). Reduction of the catalyst loading or omission
of 4 Å MS13 had a deleterious effect on both yield and ee
(entries 6 and 7).
A variety of 1,3-diketones were found to participate
effectively in enantioselective Mannich reactions with 1-Cbz
catalyzed by 2 (Table 3). Whereas some variability was
observed in reactions carried out at 0.25 mmol scale on 0 °C,
consistent and optimal results were obtained at −30 °C. Both
symmetrical and unsymmetrical 1,3-diaryl-diketones afforded
products in high ee (3a, 3e, 3f). α-Fluorinated β-diketones also
underwent highly enantioselective reactions (3d, 3g). A nearly
statistical mixture of diastereomers was obtained in the case of
3g, which bears a non-epimerizable β-dicarbonyl stereocenter.
Unsymmetrical alkyl-aryl diketones were also found to be
compatible substrates for the enantioselective reaction (3b);
however, aliphatic 1,3-diketone underwent reaction with 1-Cbz
with lower ee (3c).
initially cooled to −78 °C and stirred at −30 °C, 36 h. Isolated yield.
c
1
dr was determined by H NMR and HPLC analyses of the crude
d
product. Absolute configuration assigned by analogy to product 4h
(Table 4).
Reactions of 1-Cbz with β-ketoesters proceeded to afford
Mannich products with moderate-to-high enantioselectivity
(Table 4).17,18 The resulting ketodiesters may be subjected to
decarboxylation to reveal valuable β-keto α-amino acid
derivatives.19 In particular, products bearing electron-neutral
or -deficient aryl ketone groups (4a, 4c−k) were obtained with
generally good yields and ≥89% ee. Whereas variation of the
size of the ester substituent had little impact on the reaction
outcome (e.g., 4a vs 4g, 4i vs 4j), the use of benzhydryl esters
had a significant positive effect on reaction enantioselectivity
(e.g., 4a vs 4h). This latter effect made it possible to obtain
alkyl ketone products in high ee and good yield (4k).
The practicality of this protocol was demonstrated in the
sequential preparation of N-Cbz α-chloroglycine ester (1-Cbz)
and enantioselective Mannich reaction in a one-pot protocol on
a preparative scale (Scheme 2). As reported previously,11 1-Cbz
could be prepared in nearly quantitative yield from commercial
feedstock molecules. Removal of AcOH and AcCl from the
product mixture of 1-Cbz under reduced pressure was found to
be essential for the subsequent Mannich reaction. Reaction of
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Journal of the American Chemical Society
Communication
Table 4. Asymmetric Synthesis of Aspartic Acid
Derivatives
Scheme 3. Possible Mechanistic Pathways
a d
−
(dibenzoylmethane in the scheme) generates the amine-bound
enolate (B), which attacks the nearby iminium ion in an
enantioselective manner to give the Mannich product 3a. The
plausibility of this mechanism would require that the highly
acidic iminium ion intermediate not interfere with the
generation and addition of the enolate. An alternative reaction
pathway involving the formation of a thiourea-bound N-Cbz
iminoester intermediate (C) generated by the reaction between
the catalyst’s tertiary amine moiety and 1-Cbz must therefore
also be considered, although the mechanism of enolate
generation is less evident in this pathway.
a
Conditions: substrate (0.25 mmol), catalyst (10 mol%), β-ketoester
Regardless of the specific mechanism of catalysis, it is clear
that interactions involving aromatic substituents on the
substrates play a critical role in modulating both reactivity
and enantioselectivity. Replacement of aryl groups for alkyl
groups in the 1,3-diketone substrates leads to sizable decreases
in enantioselectivity and product yield (3a → 3b → 3c, Table
3). In a similar manner, significantly improved results were
obtained using benzhydryl esters (4h, 4k) relative to aliphatic
esters (4a, 4g, 4i, 4j) in the addition of β-ketoesters to 1-Cbz.
Finally, the electronic properties of the aryl substituents in aryl-
β-ketoester nucleophiles correlate directly with product yield
and ee (Table 4, 4c−4f), with electron-deficient substrates
affording highest enantioselectivities. Further elucidation of the
specific catalyst−substrate interactions at play in these reactions
is a subject of ongoing interest in our laboratories.21
(0.5 mmol), 4 Å MS (40 mg), Et3N (25 mol%), DCM (5 mL), under
b
N2, initially cooled to −78 °C and stirred at −30 °C, 36 h. Isolated
c
yield. Products were isolated as the thermodynamic mixtures of
d
diastereomers. The structure and absolute configuration of 4h was
established by X-ray crystallography, and the stereochemistry of all
other products was assigned by analogy.
Scheme 2. Large-Scale, One-Pot Synthesis of 3a
In summary, we have developed an efficient thiourea-
catalyzed enantioselective Mannich reaction that provides
access to a variety of N-carbamoyl α-amino esters. The
products can be obtained using a one-pot protocol on a
preparative scale from commercial substrates and catalyst.
Further application of 1-Cbz and related substrates in
asymmetric catalysis with H-bond donor catalysts is currently
underway.
1-Cbz with 1,3-diphenyl-1,3-propanedione in the presence of
10 mol% catalyst afforded 3a in 97% overall yield and 97% ee.20
This two-step, one-pot synthesis of highly enantioenriched
unnatural amino esters is accomplished using commercially
available substrates and catalyst, and generates only AcOH,
HCl, and Et3N·HCl as byproducts.
The potential mechanisms by which this enantioselective
Mannich reaction of α-chloroglycine esters proceeds merit
consideration. No measurable background reaction between 1-
Cbz and dibenzoylmethane is observed in the absence of the
thiourea catalyst, either with or without added Et3N. This
observation suggests an essential role of the H-bond donor
component of the aminothiourea catalyst 2 not only in
enantiocontrol but also in the generation of the reactive
electrophilic intermediate. Two possible mechanistic pathways
involving thiourea activation of the α-chloroglycine are outlined
in Scheme 3. In the anion abstraction pathway, the thiourea
catalyst abstracts chloride from 1-Cbz to form a thiourea-bound
acyliminium/chloride intermediate (A).10 Reaction of the
tertiary amine moiety in A with the β-dicarbonyl compound
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
■
Corresponding Authors
jacobsen@chemistry.harvard.edu
sroche2@fau.edu
Notes
The authors declare no competing financial interest.
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Journal of the American Chemical Society
Communication
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(10) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Institutes of Health
(GM-43214) for financial support. We thank the Japan Society
for the Promotion of Science (postdoctoral fellowship to
M.W.), Herchel Smith-Harvard Research Fellowship (under-
graduate fellowship to R.Y.L.), and Dr. Shao-Liang Zheng for
help with the X-ray data collection and structure determination.
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