Stereodivergent Mannich reaction of bis(trimethylsilyl)ketene acetals with N-tert -butanesulfinyl imines by Lewis acid or Lewis base activation, a one-pot protocol to obtain chiral β-amino acids

Article abstract of DOI:10.1039/c7ob01853c

We report a one-pot synthesis of chiral β^2,2,3-amino acids by the Mannich addition of bistrimethylsilyl ketene acetals to N-tert-butanesulfinyl imines followed by the removal of the chiral auxiliary. The synthesis and isolation of pure β-amino acid hydrochlorides were conducted under mild conditions, without strong bases and this method is operationally simple. The stereoselective reaction was promoted by two different activation methods that lead to different stereoisomers: (1) Lewis Acid (LA) catalysis with boron trifluoride diethyl etherate and (2) Lewis Base (LB) catalysis with tetrabutylammonium difluorotriphenylsilicate. The reaction presented good diastereoselectivity with LB activation and moderate to good dr with LA catalysis. The exceptions in both protocols were imines with electron donating groups in the aromatic ring.

Full text of DOI:10.1039/c7ob01853c

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Chem., 2017, DOI: 10.1039/C7OB01853C.
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Stereodivergent Mannich reaction of bis(trimethylsilyl)ketenes with
N-tert-butanesulfinyl imines by Lewis acid or Lewis base activation,
a one-pot protocol to obtain chiral β-amino acids.
Margarita Cantú-Reyes, Isabel Alvarado-Beltrán, Ricardo Ballinas-Indilí, Cecilio
Álvarez-Toledano, Marcos Hernández-Rodríguez*
Instituto de Química, Universidad Nacional Autónoma de México
Circuito Exterior, Ciudad Universitaria, Del. Coyoacán, 04510, Cd. Mx., México
e-mail: marcoshr@unam.mx
Abstract
We report a one-pot synthesis of chiral β2,2,3-amino acids by the Mannich addition of
bistrimethylsilyl ketenes to N-tert-butanesulfininyl imines followed by the removal of
the chiral auxiliary. The synthesis and isolation of pure β-amino acids hydrochlorides
was under mild conditions, without strong bases and operationally simple. The
stereoselective reaction was promoted by two different activation methods that lead
to different stereoisomers: (1) Lewis Acid (LA) catalysis with boron trifluoride diethyl
etherate and (2) Lewis Base (LB) catalysis with tetrabutylammonium
difluorotriphenylsilicate. The reaction presented good diastereoselectivity with LB
activation and moderate to good d.r. with LA catalysis. The exceptions on both
protocols were imines with electron donating groups in the aromatic ring.
Introduction
β-Amino acids have important applications on peptides and structures with biological
properties.1 Chiral β-amino acids can be synthetized by chiral pool approximation by
homologation of α-amino acids,2 conjugated addition to α,β-unsaturated esters,3
alkylation of enolates,4 double bond hydrogenation5 and Mannich reactions trough
enantioselective6 or diastereoselective methods.7 Among the reported auxiliaries for
diastereoselective Mannich reactions N-tert-butanesulfinyl imines8 are the most used
in combination with titanium enolates,9 Reformatsky reagents,10 and other
nucleophilic enolates.11 Due to the good selectivity in this addition, this methodology
has been successfully used in the total synthesis of compounds.12
It would be very useful to find alternatives to this Mannich reaction that do not use
extremely moisture sensitive enolates. In this regard, methyl trimethylsilyl
dimethylketene acetal has been used as nucleophile along with the addition of a Lewis
1

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acid to activate the imine.13 Nevertheless, the scope of the reaction is limited to
activated imines. Bis(trimethylsilyl)ketenes14 are more nucleophilic according to Mayr
scale15 and an interesting feature is that the product of the reaction is an acid instead
of an ester, which eliminates the subsequent deprotection of the acid that sometimes
could be problematic.9 Due to the easy removal of the sulfinyl group we envisioned
that a one-pot protocol could be implemented with this nucleophile. Hence, in this
work we explored the Mannich addition of bis(trimethylsilyl)ketenes to N-
sulfinylimines catalyzed by Lewis acid and Lewis base16 (Figure 1).
O
S
OM
OR
O
S
Previous
work
t-Bu
NH
*
O
t-Bu
t-Bu
N
N
M = Li, Mg, Ti, TMS
OTMS
R
OR
R
R
O
S
1)
NH2
O
OTMS
This
work
R
OH
*
LA or LB
2) HCl
one-pot
Figure 1. Mannich reaction with t-butanesulfinyl Imines
Results and discussion
We began these experiments by studying the effect of Lewis acid (LA) activation.
Metallic salts as LA17 did not promote the reaction (Table 1, exp. 1-4). The use of
TMSOTf afforded good yield of the product with little selectivity (Table 1, exp. 5).
When we employed boron trifluoride diethyl etherate higher selectivity with little
conversion was the result (Table 1, exp. 6), the use of the BF3 dimethyl sulfide
complex did not improve the outcome (Table 1, exp 7). Therefore, we studied the
simultaneous
activation
of
the
nucleophile
by
tetrabutylammonium
triphenyldifluorosilicate (TBAT)18 and found out that the selectivity is almost the
same with a significant improvement in yield (Table 1, exp. 8). Further studies with
different solvents did not raise the selectivity (Table 1, exp. 9-15) nor the use of a
metallic salt and TBAT (Table 1, exp. 16).
2

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Table 1. Optimization of Mannich reaction catalyzed by Lewis acid.
O
S
OTMS
OTMS
t-Bu
NH
3a
O
S
CO2H
Ph
t-Bu
N
2
Ph
3 equiv. LA
24 h, 20 °C
O
S
1a
t-Bu
NH
CO2H
Ph
4a
Exp.
1
2
3
4
5
6
7
LA
Solvent Conversiona d.r. 3a:4aa
Sc(OTf)3
Zn(OTf)2
AgOTf
Cu(OTf)2
TMSOTf
BF3·OEt2
DCM
DCM
DCM
DCM
DCM
DCM
NR
8
7
12
81
33
12
99
65
ND
56:44
43:57
46:54
33:67
74:26
62:30
75:25
75:25
69:31
ND
BF3·SMe2 DCM
8 b BF3·OEt2
9 b BF3·OEt2
10 b BF3·OEt2 CHCl3
11 b BF3·OEt2 MePh
12 b BF3·OEt2
13b BF3·OEt2
14b BF3·OEt2 CH3CN
DCM
DCE
45
NR
60
Et2O
THF
80:20
81:19
ND
26
Traces
Traces
33
15b BF3·OEt2
16b
AgOTf
DMF
ND
DCM
30:70
a Determined by 1H NMR. b It was added 0.1 equiv of TBAT.
Recrystallization of the major diastereomer 3a afforded suitable crystals that allow us
to assign the new stereocenter as R (Figure 2).
3

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Figure 2. X-ray structure of 3a (CCDC 1523513).
Whereas a LA activates the electrophile, a Lewis base (LB) can activate the
nucleophile. The results in Table 1 indicate an effect of the fluoride ion on activating
the silicon of the enol, hence, we explored the activation of the reaction by only a LB.
We repeated the experiment with only substoichiometric amounts of TBAT in the
same conditions and find out that the Mannich adduct was produced with low
selectivity and the opposite diastereomer was obtained (Table 2, exp. 1). When we
explored the reaction in other solvents good selectivity was attained in ethereal media
in THF obtaining a quantitative conversion and high selectivity (Table 2, exp. 6). This
pronounced effect of the solvent with LB catalysis indicates an optimal polarity with
ethereal solvents, particularly with THF. This observation is in line with others ionic
LB catalysts that are soluble in this media.19-20
When we tried other neutral LB or typical fluoride sources as cesium fluoride or
tetrabutylammonium fluoride no activation was found. We think that the efficiency of
TBAT over other fluoride sources to activate organosilicon compounds could be
attributed to the fact that is a non-hygroscopic solid that provides anhydrous fluoride
ion soluble in organic media.20
Table 2. Effect of different solvents on Mannich reaction catalyzed by Lewis base.
O
S
OTMS
OTMS
t-Bu
NH
3a
O
S
CO2H
CO2H
Ph
t-Bu
N
2
Ph
O
S
0.1 eq. TBAT
24 h, 20 °C
1a
t-Bu
NH
Ph
4a
Exp.
1
2
Solvent
DCM
Toluene
Conversiona d.r. 3a : 4aa
77
99
32:68
13:83
4

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3
4
5
6
7
8
9
DCE
Et2O
MTBE
THF
EtOAc
CH3CN
DMF
70
52
92
98
67
73
70
24:76
9:91
9:91
3:97
10:90
38:62
25:75
a Determined by 1H NMR.
1
Figure 3 shows the crude H NMR spectrum of both reactions showing that the major
diastereomer obtained with TBAT catalysis only is the minor diastereomer in the BF3
activation.
a)
b)
1
Figure 3. Crude H NMR spectra of the stereodivergent Mannich reaction. (a) Lewis
acid activation (3 equiv. of BF3·OEt2 and 0.1 equiv. of TBAT, exp. 8 in Table 1). (b)
Lewis base activation (0.1 equiv. TBAT, exp. 6 in Table 2).
We wanted to know if this stereodivergent result was consistent with different
sulfinylimines and also implement the proposed one-pot protocol to obtain chiral β-
amino acids. Table 3 and 4 summarizes the results obtained with these two ways to
promote the reaction. As planned, the pure β-amino acid hydrochlorides can be
obtained by a one-pot protocol: Mannich reaction and after 1 day (measure the d.r. of
the product that would translate to e.r of amino acid 5) then add HCl (6M in dioxane)
and methanol to remove the sulfinyl group. The formed amino acid hydrochloride not
soluble in organic media precipitates facilitating its isolation. It was observed that: (1)
in all cases LB and LA catalyzed reaction promote different diastereomer, (2) most of
the times the d.r obtained by LB only is higher than the combination BF3-TBAT, (3)
both activations presented good selectivities with electron withdrawing groups and
modest to low selectivity with electron donating substituents as can be seen by
comparing amino acids 5b (p-NO2) vs 5g (p-OMe), besides the yield is in average
5

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lower with electrondonating groups, which denotes a dependence on the electrophilic
character on the imine and (4) it must be highlighted the mildness of the reaction
conditions that it did not cleave the ester group in 5c.
Table 3. One-pot Mannich reaction between bis(trimethylsilyl)ketene 2 and N-tert-
butanesulfinyl imines promoted by Lewis acid.
O
S
1) 2, 3 equiv. BF3•OEt2,
0.1 equiv. TBAT, DCM
NH
2 •HCl
CO2H
t-Bu
N
Ar
2) HCl, MeOH
Ar
1
5
Compounda
Ar
d. r. b Yield of 5
(R)-5
5a
5b
5c
5d
5e
5f
5g
5h
5i
3 : 4
(%)c
66
85
94
79
83
43
81
40
51
Ph
79:21
84:16
4-NO2C6H4
4-CO2MeC6H4 92:8
4-CF3C6H4 86:14
3,5-(CF3)2C6H3 84:16
4-MeC6H4
4-OMeC6H4
68:32
54:46
2-Thiophenyl 68:32
1-Naphth 95:5
b
1
aAll amino acids are (R) except for 5h which is (S) by CIP rules. Determined by H
NMR of an aliquot of the reaction, see Figures S28 to S45 in Supporting information.
cIsolated yield.
Table 4. One-pot Mannich reaction between bis(trimethylsilyl)ketene 2 and N-tert-
butanesulfinyl imines promoted by Lewis base.
O
S
NH
2 •HCl
CO2H
1) 2, 0.1 equiv. TBAT, THF
t-Bu
N
Ar
2) HCl, MeOH
Ar
1
5
Compounda
Ar
d. r. b Yield of 5
(S)-5
5a
5b
5c
5d
5e
3 : 4
3:97
9:91
(%)c
99
86
87
72
82
71
42
Ph
4-NO2C6H4
4-CO2MeC6H4 8:92
4-CF3C6H4 7:93
3,5-(CF3)2C6H3 12:88
4-MeC6H4
4-OMeC6H4
5f
5g
33:67
35:65
6

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5h
5i
2-Thiophenyl 32:68
79
50
1-Naphth
26:74
aAll amino acids are (S) except for 5h which is (R) by CIP rules. Determined by H
NMR of an aliquot of the reaction, see Figures S28 to S45 in Supporting information.
cIsolated yield.
b
1
With others cyclic nucleophiles good diastereoselectivity was found with both
methods to promote the Mannich reaction (Figure 4).
Method A: (1) cyclic bis(trimethylsilyl)ketene 2, 3 equiv
BF3•OEt2, 0.1 equiv. TBAT, DCM.
(2) HCl, MeOH
. HCl
CO2H
NH2
. HCl
CO2H
NH2
NH2
. HCl
CO2H
Ph
Ph
Ph
(R)-6a
37%
(R)-6b
70%
(R)-6c
70%
(92:8)
(93:7)
(66:33)
Method B: (1) cyclic bis(trimethylsilyl)ketene 2,
0.1 equiv. TBAT, THF.
(2) HCl, MeOH
. HCl
CO2H
NH2
. HCl
CO2H
NH2
NH2
. HCl
CO2H
Ph
Ph
Ph
(S)-6a
49%
(S)-6b
55%
(S)-6c
99%
(91:9)
(94:6)
(90:10)
Figure 4. One- pot Mannich reaction between cyclic bis(trimethylsilyl)ketenes and N-
tert-butanesulfinyl imine 1 promoted by the two methods described herein. Isolated
yield of the aminoacid and d.r. of the stereoselective reaction shown in parenthesis
(see Figures S46-S51 in ESI).
To show the usefulness on the synthesis of pure β-amino acids by the developed
procedures a scale up reaction was carried out and no significant decrement of the
stereoselectivity, yield or purity of the isolated amino acid was found (Figure 5).
7

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NH2 •HCl
CO2H
1) 2, 3 equiv. BF3•OEt2,
0.1 equiv. TBAT, DCM
Ph
(R)-5
95 %, (78:22)
O
S
2) HCl, MeOH
t-Bu
N
•HCl
NH2
Ph
1
0.5 g
1) 2, 0.1 equiv. TBAT, THF
CO2H
Ph
(S)-5
87 %, (98:2)
2) HCl, MeOH
Figure 5. Scale up of the one- pot Mannich reaction between cyclic
bis(trimethylsilyl)ketenes 6 and N-tert-butanesulfinyimine 1.
The sterodivergency found in the Lewis acid/Lewis base catalysis could be explained
by two different transition states shown in Figure 4. The LB catalyzed reaction with
only TBAT, the activated enolate A was obtained by the addition of fluoride. This
nucleophile is added to the exposed Re face of the imine by the typical acyclic control
reported for Ellman’s sulfinylimines3 and the S configuration of the product 4 is
obtained. On the other hand, when boron trifluoride was added, the LA trapped the
enolate forming a tetracoordinated boron that slowly returned to tricoordinated
boron C by liberating another fluoride ion. The acidic nature of the boron coordinate
to the sulfinylimines by a cyclic transition state via a 6 membered ring or 8 membered
ring that allocate the tert-butyl in a pseudoecuatorial disposition (D and E) and the
addition takes place to the Si face of the imine D producing compound 3.
O
S
TBAT
t-Bu
N
S
O
S
TBA+
O
N
TBA+ F-
O
OTMS
OTMS
H
R
Me
Me
R
t-Bu
NH O
OTMS
H
TMSO
TBAT only
R
OH
O-
TBA+
A
B
4
BF3•OEt2
OTMS
F
B
Me
H
O
F
S
R
O
S
N
O
Me
imine
t-Bu
NH O
OBF2 + F-
OTMS
D
R
OH
R
F
B
OTMS
N
3
C
F
H
Me
O
t-Bu
S
O
Me
E
Figure 6. Mechanism of stereodivergence Mannich reaction found with LA and LB
activation.
8

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In conclusion, we developed a one pot protocol to obtain new chiral β2,2,3-amino acids
under mild conditions without strong bases and easy isolation of the product by the
Mannich addition of bis(trimethylsilyl)ketenes to N-sulfinylimines catalyzed by LA or
LB followed by the removal of the chiral auxiliary. Each promoter of the reaction
conducts to the opposite diastereomer thus with the same auxiliary both
enantioenriched enantiomers can be obtained.
Acknowledgements
We thank DGAPA-UNAM (grant IN209915) and CONACyT (grant 254014) for financial
support. M. C.-R., I. A.-B., and R. B-I. gratefully acknowledge CONACyT-México for Ph.D.
scholarships. We also thank S. Hernández for the X-ray diffraction analysis, J. Pérez, L.
Velasco, M. C. García for mass analyses and M. A. Peña, M. I. Chávez, E. Huerta, B.
Quiroz, M. Aguilar, G. Cortés and D. Vázquez for technical support.
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DOI: 10.1039/C7OB01853C
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