Chiral Br?nsted Acid-Catalyzed Stereoselective Mannich-Type Reaction of Azlactones with Aldimines

Article abstract of DOI:10.1021/jo5024975

A highly diastereo- and enantioselective Mannich-type reaction of azlactones with aldimines catalyzed by a chiral phosphoric acid is described. Only 3 mol % catalyst was required to prepare the Mannich adducts in good yields with high stereochemical contr

Full text of DOI:10.1021/jo5024975

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Note
Chiral Bronsted Acid-Catalyzed Stereoselective
Mannich-type Reaction of Azlactones with Aldimines
Eloah P Ávila, Rodrigo M. S. Justo, Vanessa P Gonçalves,
Adriane A. Pereira, Renata Diniz, and Giovanni W Amarante
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5024975 • Publication Date (Web): 03 Dec 2014
Downloaded from http://pubs.acs.org on December 11, 2014
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Chiral Brønsted AcidꢀCatalyzed Stereoselective
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Mannichꢀtype Reaction of Azlactones with Aldimines‡
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Eloah P. Ávila, Rodrigo M. S. Justo, Vanessa P. Gonçalves, Adriane A. Pereira,
Renata Diniz and Giovanni W. Amarante*
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Chemistry Department, Federal University of Juiz de Fora, Cidade Universitária
Martelos, Martelos, Juiz de Fora / MG / Brazil / CEP: 36036-900
corresponding author: giovanni.amarante@ufjf.edu.br
‡Dedicated to Professor Fernando Coelho in recognition of his outstanding contributions to
Brazilian chemistry.
TOC graphic
iPr
Pri
Pri
O
O
O
P
OH
Pri
O
N
NHSO2CH3
R1
Pri
3 mol%
H3CO2S
H
N
R
iPr
Ph
N
O
+
O
R
R1
O
Ph
up to 74%
> 19:1 dr
> 99:1 er
Abstract
A highly diastereoꢀ and enantioselective Mannichꢀtype reaction of azlactones
with aldimines catalyzed by a chiral phosphoric acid is described. Only 3 mol%
of the catalyst was required to prepare the Mannich adducts in good yields with
high stereochemical control (up to > 19:1 dr, > 99:1 er). Moreover, the final
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product contains two consecutive stereogenic centers, one of which is
quaternary.
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Keywords: azlactones; aldimines; Mannichꢀtype reaction; asymmetric
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organocatalysis; chiral phosphoric acid.
Chiral α,βꢀdiaminoacid derivatives are very important building blocks in organic
chemistry as they possess remarkable pharmacological properties. Viso and coꢀ
workers have showed the importance of these motifs in treatment of
neurodegenerative diseases and various cancers. [1] A variety of methods for
the synthesis chiral α,βꢀdiaminoacid derivatives have been reported. [1] One
attractive route utilizes azlactones; as these rings are essentially protected
aminoacids that are readily unmasked under acidic conditions. Additionally,
azlactones can be easily prepared on preparative scale following literature
protocols and derivatized through [2] Mannichꢀtype reaction [3] mediated by
transition metals or organocatalysts [4], [5].
In particular, chiral gold(I) complexes have been used to catalyze the
enantioselective Mannich reaction of azlactones. Reaction of aliphatic
mesitylsulfonimines with azlactones in the presence of a spirocyclic
bisphosphine gold(I) benzoate complex (xylylꢀSDP(AuOBz)2), provided the
desired 1,2ꢀantiꢀMannich adducts in high yields and selectivities. [4] In contrast,
organocatalytic approaches tolerate both aromatic and aliphatic imines for
synthesis of chiral α,βꢀdiaminoacid derivatives in high yields and selectivities.
[5a], [5b]. Interestingly, the major product observed in these reactions were the
1,2ꢀsyn diastereomers.
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Since the pioneering work of Terada [6] and Akiyama [7] which demonstrated
the potential of chiral phosphoric acids as organocatalysts, new applications
exploiting the Hꢀdonor capacity of these catalysts have appeared in the
literature. [8] In our research program [9], we envisioned that chiral phosphoric
acids could be an alternative, metalꢀfree catalyst for the reaction between
azlactones and aldimines. Moreover, we envisioned that this approach may be
complementary to existing organocatalytic methods and provide access to the
1,2ꢀantiꢀdiaminoacid derivatives from aromatic imines.
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The azlactone and imine skeletons are both readily accessed following literature
protocols. [4] To our delight, the reaction between azlactone 1a and aldimine 2a
catalyzed by only 3 mol% of the comercial available (S)ꢀ3,3′ꢀBis(2,4,6ꢀ
triisopropylphenyl)ꢀ1,1′ꢀbinaphthylꢀ2,2′ꢀdiyl hydrogenphosphate, (S)ꢀTRIP [10],
in toluene gave the desired Mannich adduct 3a in good yield (70 %; isolated
yield) and excellent enantioꢀ and diastereoselectivity (Table 1, entry 3).
However, increasing the size of the sulfonamide led to a decrease in yield.
Only traces of product was detected when dichloromethane (Table 1, entry 2)
was used as solvent. While performing the reaction in THF provided the desired
product in moderate yield, the diastereoselectivity of the transformation was
low. Significant background of reaction was observed when either acetone or
chloroform was used. The catalyst loading could be drop to 2 mol% without any
loss of stereoselectivity, albeit at a lower isolated yield (50 %). Having optimized
reaction conditions, experiments to evaluate the substrate scope of this
transformation were conducted (Table 2).
Table 1. Optimization of reaction conditions for the stereoselective Mannichꢀtype reaction [a]
.
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iPr
Pri
5
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Pri
O
O
O
P
OH
Pri
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Pri
iPr
O
N
NHR
(S)ꢀTRIP, 3 mol%
R
N
Me
Ph
N
O
+
Solvent,
rt; 24 h
Ph
H
O
Me
O
Ph
Ph
1a
2a
3a
e.r.c
yieldd
d.r.b
(anti/syn)
entry
R
solvent
1
2
1:1
1:1
99:1/99:1
Nde
40
traces
70
mesyl
mesyl
THF
CH2Cl2
PhMe
PhMe
PhMe
PhMe
PhMe
mesyl
tosyl
3
> 19:1
5:1
> 99:1
Nde
Nde
4
20
mesityl
mesyl
mesyl
5
2:1
15
6f
7g
> 19:1
ꢀ
> 99:1
ꢀ
55
ꢀ
[a] Reactions were carried out using 0.2 mmol of 1, 0.006 mmol of (S)ꢀTRIP (3 mol%), and 0.21
1
mmol of 2 in PhMe (0.2 M in azlactone). [b] Determined by H NMR analysis of the crude
reaction mixture. [c] Determined by enantiodiscriminating HPLC. [d] Isolated yield. [e] Not
determined. [f] Without molecular sieves. [g] No catalyst, 48 h.
Various aromatic imines, containing either electronꢀwithdrawing or electron
donating groups, could be used in the reaction. For example, a benzaldehyde
derivative containing fluorine at pꢀposition works quite well, providing the
Mannich adduct 3g in good yield with both diastereoꢀ and enantioselectivity (>
19:1 dr and 98:2 er). Phenylalanine derivative azlactone could also be used
under optimized reaction conditions, yielding product 3i in >98% ee. The
relative and absolute stereochemistry (1,2ꢀanti) of the Mannich adduct 3b was
determined by Xꢀray crystallographic structure (Figure 1). The other products
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were assigned on the analogy. To the best of our knowledge this work
comprises the first highly enantioꢀ and diastereoselective Mannichꢀtype reaction
between azlactone and aldimines catalyzed by a chiral phosphoric acid. A
variety of aliphatic imines were evaluated; however, all led to complex product
mixtures which could not be deciphered [12].
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Table 2. Diastereoꢀ and Enantioselective Mannichꢀtype addition of azlactones to aldimines [a]
.
O
NHSO2CH3
R1
(S)ꢀTRIP, 3 mol%
H3CO2S
N
R
Ph
N
O
+
Toluene,
H
O
R
N
MS 4A; rt; 24 h
R1
O
Ph
O
1
2
3
O
O
O
NHSO2Me
NHSO2Me
Ph
Me
O
NHSO2Me
O
N
Me
Ph
Ph
Ph
N
N
Me
Ph
3b [d,e]: 72%
> 19:1 dr
> 99:1 er
3c: 73%
> 19:1 dr
99:1 er
Cl
3a: 70%
> 19:1 dr [b]
> 99:1 er [c]
O
O
O
NHSO2Me
NHSO2Me
NHSO2Me
O
O
O
N
N
Me
Me
N
Me
Cl
3e: 51%
Ph
Ph
Ph
3d [f]: 72%
10:1 dr
96:4 er
Br
3f: 74%
> 19:1 dr
98:2 er
Cl
> 19:1 dr
91:9 er
O
O
O
O
NHSO2Me
NHSO2Me
NHSO2Me
NHSO2Me
O
O
O
O
N
N
Me
Me
N
Ph
Ph
Me
N
Bn
Ph
Ph
3j [d,g]: 54%
> 19:1 dr
> 99:1 er
CF3
3i [f]: 66%
11:1 dr
>99:1 er
F
3g: 74%
> 19:1 dr
98:2 er
3h: 65%
> 19:1 dr
88:12 er
CH3
[a] Reactions were carried out using 0.2 mmol of 1, 0.006 mmol of (S)ꢀTRIP (3 mol%), and 0.21
1
mmol of 2 in PhMe (0.2 M in azlactone). [b] Determined by H NMR analysis of the crude
reaction mixture. [c] Determined by chiral HPLC. [d] (R)ꢀTRIP used as catalyst. [e] Relative and
absolute stereochemistry of 3b was determined by Xꢀray crystallography and the other products
were assigned in analogy. [f] Only the major diastereomer was isolated. [g] 5 mol% of catalyst.
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Figure 1. Xꢀray crystallographic structure of 3b.
Yamanaka and Akiyama have proposed that the Mannichꢀtype reaction of a
special hydroxyaldimine catalyzed by a chiral phosphoric acid proceeds through
coordination of both oxygen atoms of the chiral phosphoric acid to the aldimine.
[13] Terada and coꢀworkers have showed a chiral phosphoric acid catalyzed
enantioselective addition of azlactones to 3ꢀvinylindoles; in this case, the chiral
phosphoric acid activates both the enol intermediate of azlactone and the vinyl
double bond system. [14] Thus, a plausible transition state for the reaction of
imine and azlactone in the presence of TRIP is proposed. [15] We hypothesize
that the phosphoric acid could stabilize the enol intermediate of azlactone and
also activated the imine through protonation of the nitrogen lone pair, providing
the Mannich adducts in high selectivities (Figure 2).
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iPr
Pri
O
O
Pri
P
iPr
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O
O
H
O
O
H
iPr
S
Pri
N
O
Me
R
O
Ar
N
Ph
Figure 2. Plausible activation mode for the stereoselective reaction between azlactones and
aldimines catalyzed by a phosphoric acid.
To probe the reversibility of the reaction the enantioenriched Mannich addition
product 3b was resubjected to catalytic reaction condition in the presence of a
racemic acid, (+/ꢀ)ꢀCSA (camphorsulfonic acid), following the general procedure
for Mannich reaction. After 24 h at room temperature, the product was reꢀ
isolated in > 99% ee, suggesting that the σ CꢀC bond step formation is
irreversible (eq 1).
O
NHSO2CH3
O
NHSO2CH3
(+/-)ꢀCSA, 5 mol%
O
O
Ph
CH3
Ph
(1)
Toluene,
N
CH3
N
Ph
MS 4A; rt; 24 h
Ph
3b
> 99% ee
3b
> 99% ee
The ring opening, followed by amide deprotection of the enantioenriched
Mannich addition product 3b under the presence of a mineral acid provided the
amino acid 5 in two steps and with 75 % overall yield (Scheme 1).
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O
O
O
N
NHSO2CH3
NHSO2CH3
HO
HCl
OH
Ph
HCl
H3C
H2N
O
Ph
CH3
Ph
CH3
100 oC; 10 h
75 %
. HCl
HN
Ph
CH3CN,
rt; 1 h
Ph
NHSO2CH3
3b
O
quantitative yield
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Scheme 1. Preparation of amino acid 5.
Conclusion
In summary, a Brønsted acid catalyzed highly diastereoꢀ and enatioselective
Mannichꢀtype addition of azlactones with aldimines is presented. Only 3 mol%
of the commercial available phosphoric acid (TRIP) was used to provide
protected 1,2ꢀanti diamino acid derivatives in moderate to good yields and with
near perfect control of both diastereoꢀ and enantioselectivity (up to > 19:1 dr
and > 99:1 er). Besides the new σ CꢀC bond formation, two stereogenic centers
are created, one of them a quaternary.
Experimental Section
Representative experimental for the enantioꢀ and diastereoselective Mannichꢀ
type addition of azlactones to aldimines: In a flammed screw cap vial and under
nitrogen atmosphere and with molecular sieves (50 mg), 0.2 mmol of azlactone
was added. After, toluene was canulated at the concentration of 0.2 mol.Lꢀ1 in
azlactone. To this solution, 0.006 mmol (3 mol%) of phosphoric acid was added
followed by 0.21 mmol of imine. The reaction was kept at room temperature and
under nitrogen atmosphere for 24 h. The reaction was then diluted in CH2Cl2
(10 mL) and washed with saturated solution of sodium bicarbonate (5 mL). The
organic phase was dried over anidrous Na2SO4 and concentrated under
reduced pression. An aliquot was taken to the NMR and the diastereoisomeric
ratio was measured by 1H NMR analysis. After, the crude reaction mixture was
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purified through silica gel chromatography by using ethyl acetate: hexanes as
solvents (up to 2:1 ethyl acetate/hexanes). The major diastereomers were
submitted to chiral HPLC analysis and then fully characterized by the
conventional elemental analysis.
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Characterization data for the Mannich adducts 3aꢀj
1
(3a): Diastereoisomeric ratio (dr) from H NMR analysis of crude reaction mixture (> 19:1)
(anti/syn). The product was purified by column chromatography on silica gel (Hexanes/AcOEt
1
3:1 to 2:1) to afford product 3a (50.1 mg, 70%); H NMR (250 MHz, CDCl3) δ: 7.86 (d, 2H, J =
7.1 Hz), 7.58ꢀ7.55 (m, 1H), 7.49ꢀ7.43 (m, 2H), 7.22ꢀ7.19 (m, 5H), 5.71 (d, 1H, J = 10 Hz), 4.87
(d, 1H, J = 10 Hz), 2.56 (s, 3H), 1.82 (s, 3H); 13C NMR (63 MHz) δ: 177.5, 161.5, 135.5, 133.1,
129.1, 128.8, 128.7, 128.0, 127.6, 125.1, 73.7, 61.9, 41.9, 22.1; HRMS: calcd for
[C18H18N2O4S]+ ([M+H]+): m/z 359.1066, found 359.1079; HPLC Chiralpak IA column
(Hex/iPrOH 95/05, 0.7 mL/min) tR 26.6 min (major), 28.7 min (minor): > 99:1 er. See reference
4.
1
(3b): Diastereoisomeric ratio (dr) from H NMR analysis of crude reaction mixture (> 19:1)
(anti/syn). The product was purified by column chromatography on silica gel (Hexanes/AcOEt
1
3:1 to 2:1) to afford product 3b (51.6 mg, 72%); H NMR (250 MHz, CDCl3) and 13C NMR (63
MHz): identical 3a; HPLC Chiralpak IA column (Hex/iPrOH 95/05, 0.7 mL/min) tR 26.8 min
(minor), 29.3 min (major): > 99:1 er. See reference 4.
1
(3c): Diastereoisomeric ratio (dr) from H NMR analysis of crude reaction mixture (> 19:1)
(anti/syn). The product was purified by column chromatography on silica gel (Hexanes/AcOEt
3:1 to 2:1) to afford product 3c (57.2 mg, 73%); 1H NMR (250 MHz, CDCl3) δ: 7.88ꢀ7.85 (m, 2H),
7.60ꢀ7.45 (m, 3H), 7.26ꢀ7.14 (m, 4H), 5.75 (d, 1H J = 9.8 Hz), 4.86 (d, 1H, J = 9.8 Hz), 2.61 (s,
3H), 1.63 (s, 3H). 13C NMR (75 MHz) δ: 177.5, 162.0, 135.4, 134.6, 133.6, 129.4, 129.3, 128.3,
125.1, 78.8, 61.5, 42.4, 22.4.; HRMS: calcd for [C18H17N2O4SCl]+ ([M+H]+): m/z 393.0676,
found 393.0707; HPLC Chiralpak IA column (Hex/iPrOH 90/10, 0.5 mL/min) tR 26.0 min (major),
30.4 min (minor): 99:1 er.
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(3d): Diastereoisomeric ratio (dr) from 1H NMR analysis of crude reaction mixture (10:1)
(anti/syn). The product was purified by column chromatography on silica gel (Hexanes/AcOEt
3:1 to 2:1) to afford product 3d (56.5 mg, 72%); 1H NMR (250 MHz, CDCl3) δ: 7.85ꢀ7.57 (m, 2H),
7.56ꢀ7.26 (m, 3H), 7.22ꢀ7.12 (m, 5H), 5.70 (d, 1H, J = 9.8 Hz), 4,85 (d, 1H, J = 9.9 Hz), 2.64 (s,
3H), 1.81 (s, 3H); 13C NMR (75 MHz) δ: 177.4, 162.0, 138.0, 135.0, 133.6, 130.3, 129.6, 129.2,
128.2, 128.1, 126.0, 125.1, 73.7, 61.6, 42.4, 22.3; HRMS: calcd for [C18H17N2O4SCl]+ ([M+H]+):
m/z 393.0676, found 393.0677; HPLC Chiralpak IA column (Hex/iPrOH 90/10, 0.5 mL/min) tR
19.6 min (major), 22.4 min (minor): 96:4 er.
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1
(3e): Diastereoisomeric ratio (dr) from H NMR analysis of crude reaction mixture (> 19:1)
(anti/syn). The product was purified by column chromatography on silica gel (Hexanes/AcOEt
1
3:1 to 2:1) to afford product 3e (39.9 mg, 51%); H NMR (300 MHz, CDCl3) δ: 8.05 (d, 1H, J =
7.8 Hz), 7.67ꢀ7.62 (m, 2H), 7.56ꢀ7.32 (m, 5H), 5.60 (d, 1H, J = 11.1 Hz), 5.27 (d, 1H, J = 11.1
Hz), 2.66 (s, 3H), 1.40 (s, 3H); 13C NMR (75 MHz) δ: 179.4, 162.4, 135.1, 134.5, 133.7, 130.3,
130.1, 129.2, 129.0,
128.5, 128.0, 125.5, 73.7, 57.3, 41.5, 21.0; HRMS: calcd for
[C18H17N2O4SCl]+ ([M+H]+): m/z 393.0676, found 393.0681; HPLC Chiralpak IA column
(Hex/iPrOH 96/04, 0.45 mL/min) tR 59.4 min (major), 67.9 min (minor): 91:9 er.
(3f): Diastereoisomeric ratio (dr) from 1H NMR analysis of crude reaction mixture (> 19:1)
(anti/syn). The product was purified by column chromatography on silica gel (Hexanes/AcOEt
3:1 to 2:1) to afford product 3f (64.5 mg, 74%); 1H NMR (300 MHz, CDCl3) δ: 7.90ꢀ7.87 (m, 2H) ,
7.66ꢀ7.60 (m, 1H), 7.53ꢀ7.48 (m, 2H), 7.41ꢀ7.37 (m, 2H), 7.12ꢀ7.10 (m, 2H), 5.67 (d, 1H, J =
9.9 Hz), 4.86 (d, 1H, J = 9.9 Hz), 2.63 (s, 3H), 1.82 (s, 3H); 13C NMR (75 MHz) δ: 177.5, 162.0,
135.1, 133.6, 132.2, 129.5, 129.2, 128.3, 125.1, 123.7, 73.7, 61.5, 42.5, 22.5; HRMS: calcd
for [C18H17N2O4SBr]+ ([M+H]+): m/z 437.0171, found 437.0181; HPLC Chiralpak IB column
(Hex/iPrOH 97/03, 0.8 mL/min) tR 44.9 min (major), 54.3 min (minor): 98:2 er.
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(3g): Diastereoisomeric ratio (dr) from H NMR analysis of crude reaction mixture (> 19:1)
(anti/syn). The product was purified by column chromatography on silica gel (Hexanes/AcOEt
3:1 to 2:1) to afford product 3g (55.6 mg, 74%); 1H NMR (300 MHz, CDCl3) δ: 7.90ꢀ7.88 (m, 2H),
7.65ꢀ7.60 (m, 1H), 7.52ꢀ7.47 (m, 2H), 7.28ꢀ7.22 (m, 2H), 6.98ꢀ6.92 (m, 2H), 5.93 (d, 1H, J =
9.9 Hz), 4.90 (d, 1H, J = 9.9 Hz), 2.63 (s, 3H), 1.83 (s, 3H); 13C NMR (75 MHz) δ: 177.6, 163.4
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(d, J = 207 Hz), 162.0, 161.5, 133.6, 131.9, 131.8, 129.8, 129.7, 129.2, 128.3, 125.1, 116.1 (d,
J = 22 Hz), 74.0, 61.5, 42.3, 22.3; HRMS: calcd for [C18H17N2O4SF]+ ([M+H]+): m/z 377.0971,
found 377.0991; HPLC Chiralpak IB column (Hex/iPrOH 97/03, 0.8 mL/min) tR 38.4 min (major),
47.4 min (minor): 98:2 er.
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(3h): Diastereoisomeric ratio (dr) from H NMR analysis of crude reaction mixture (> 19:1)
(anti/syn). The product was purified by column chromatography on silica gel (Hexanes/AcOEt
3:1 to 2:1) to afford product 3h (55.4 mg, 65%): 1H NMR (500 MHz, CDCl3): δ 7.89ꢀ7.87 (m,
2H), 7.64ꢀ7.61 (m, 1H), 7.54ꢀ7.49 (m, 4H), 7.39ꢀ7.37 (m, 2H), 5.86 (d, 1H, J = 9.8 Hz), 4.98 (d,
1H, J = 9.8 Hz), 2.67 (s, 3H), 1.85 (s, 3H).
13C NMR (125 MHz): 177.2, 161.8, 133.5, 131.3 (q, J
= 32.7 Hz), 129.0, 128.1, 128.0 125.7 (q, J = 3.8 Hz), 123.6 (q, J = 270.6 Hz), 73.5, 61.4, 42.3,
22.3. HRMS: calcd for [C19H17N2O4SF3]+ ([M+H]+): m/z 427.0939, found 427.0951; HPLC
Chiralpak IB column (Hex/iPrOH 97/03, 0.8 mL/min) tR 41.8 min (major), 52.2 min (minor):
88:12 er.
(3i): Diastereoisomeric ratio (dr) from 1H NMR analysis of crude reaction mixture (11:1)
(anti/syn). The product was purified by column chromatography on silica gel (Hexanes/AcOEt
1
3:1) to afford product 3i (57.3 mg, 66 %); H NMR (500 MHz, CDCl3): δ 7.70ꢀ7.68 (m, 2H),
7.56ꢀ7.53 (m, 1H), 7.44ꢀ7.40 (m, 2H), 7.29ꢀ7.26 (m, 5H), 7.17ꢀ7.12 (m, 5H), 5.82 (d, 1H, J =
10.0 Hz), 5.06 (d, 1H, J = 10.0 Hz), 3.85 (d, 1H, J = 13.2 Hz), 3.43 (d, 1H, J = 13.2 Hz), 2.58 (s,
3H). 13C NMR (125 MHz) δ: 176.1, 161.7, 133.5, 133.0, 130.3, 129.2, 128.9, 128.7, 128.2,
127.80, 127.75, 127.3, 124.9, 78.8, 61.7, 42.0, 41.7.; HRMS: calcd for [C24H22N2O4S]+
([M+H]+): m/z 435.1379, found 435.1385; HPLC Chiralpak IA column (Hex/iPrOH 95/05, 0.5
mL/min) tR 38.8 min (major), 45.8 min (minor): > 99:1 er.
(3j): Diastereoisomeric ratio (dr) from 1H NMR analysis of crude reaction mixture (> 19:1)
(anti/syn). The product was purified by column chromatography on silica gel (Hexanes/AcOEt
1
3:1) to afford product 3i (47.5 mg, 54 %); H NMR (300 MHz, CDCl3): δ 7.91ꢀ7.87 (m, 2H),
7.64ꢀ7.58 (m, 1H), 7.51ꢀ7.46 (m, 2H), 7.11ꢀ7.02 (m, 4H), 5.74 (d, 1H, J = 10.0 Hz), 4.84 (d, 1H,
J = 10.0 Hz), 2.56 (s, 3H), 2,25 (s, 3H), 1.83 (s, 3H). 13C NMR (75 MHz) δ: 177.8, 161.7, 139.2,
133.3, 132.8, 129.7, 129.1, 128.2, 127.7, 125.4, 74.0, 61.9, 42.2, 22.4, 21.3.; HRMS: calcd for
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[C19H20N2O4S]+ ([M+H]+): m/z 373.1222, found 373.1240; HPLC Chiralpak IA column
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5
(Hex/iPrOH 95/05, 0.5 mL/min) tR 41.1 min (minor), 53.4 min (major): > 99:1 er.
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Procedure for azlactone opening/amide deprotection of Mannich adduct 3b
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To a solution of 3b (35.0 mg, 0.098 mmol) in 2 mL of CH3CN was added HCl (12 mol Lꢀ1, 0.04
mL, 0.56 mmol). The mixture was stirred for 1h at rt, then the volatile materials were removed
under reduced pressure to give the intermediate 4. To the crude, 2 mL of conc. HCl was added
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and the reaction was stirred at 100 C for 10 h. The resulting mixture was concentrated under
reduced pressure, diluted with water (5 mL) and washed three times with ethyl acetate (3 mL
each one). The amino acid 5 (22.5 mg, 0.072 mmol) was obtained by purification through
Amberlite IR 120 resin (HCl) in 75 % yield.
1
(4): H NMR (500 MHz, CD3OD): δ 8.06 (d, 1H, J = 10.0 Hz), 7.94 (br, 1H), 7.68ꢀ7.66 (m, 2H),
7.56ꢀ7.53 (m, 1H), 7.49ꢀ7.45 (m, 4H), 7.35ꢀ7.32 (m, 2H), 7.30ꢀ7.27 (m, 1H), 5.06 (d, 1H, J = 9.5
Hz), 2.60 (s, 3H), 1.53 (s, 3H). 13C NMR (125 MHz, CD3OD): 172.8, 166.6, 138.0, 134.1, 131.6,
128.4, 128.2, 128.0, 127.8, 127.1, 62.5, 61.2, 41.3, 19.5. HRMS: calcd for [C18H20N2O5S]+
([M+Na]+): m/z 399.0991, found 399.0982.
1
(5): H NMR (500 MHz, D2O): δ 7.50ꢀ7.46 (m, 5H), 2.68 (s, 3H), 1.53 (s, 3H). 13C NMR (125
MHz, D2O + Dioxane): 173.4, 135.7, 131.8, 131.3, 130.4, 74.2, 64.1, 42.6, 20.8. HRMS: calcd
for [C11H17ClN2O4S]+ ([MꢀCl]+): m/z 273.0909, found 273.0897.
Acknowledgments
We are grateful to FAPEMIG, CAPES, CNPq (305489/2012ꢀ7), UFJF and Rede
Mineira de Química for the financial support and LabCri (Departamento de
Física – Universidade Federal de Minas Gerais) for use of their Xꢀray facilities.
We thank Prof. F. Dean Toste (UCꢀBerkeleyꢀUSA), Prof. Fernando Coelho (IQꢀ
UNICAMP), Prof. Luiz C. Dias (IQꢀUNICAMP), Prof. Ronaldo A. Pilli (IQꢀ
UNICAMP), Prof. Adão A. Sabino (DQꢀUFMG) and Prof. Mauro V. de Almeida
(DQꢀUFJF) for all their helps with chemicals and elemental analysis. Prof.
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Marco Antônio Barbosa Ferreira (DQꢀUFSCar) is also acknowledge for the
discussion around the manuscript. G.W.A. thanks Dr. Z. Jane Wang for the
comments and English grammar revision.
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Supporting Information Copies of NMR spectra, HPLCs as well as Xꢀray
crystallographic details (CCDC 1005467 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.) This material is available free of charge
via the Internet at http://pubs.acs.org.
References and Notes
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Wang, Q. G.; Leutzsch, M.; van Gemmeren, M.; List, B. J. Am. Chem. Soc. 2013, 135, 15334.
(h) Zhang, H.; Wen, X. J.; Gan, L. H.; Peng, Y. G. Org. Lett. 2012, 14, 2126. (i) Peng, F.ꢀZ.;
Shao, Z.ꢀH.; Curr. Org. Chem. 2011, 15, 4144. (j) Terada, M. Curr. Org. Chem. 2011, 15, 2227.
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Uraguchi, D.; Ueki, Y.; Ooi, T. J. Am. Chem. Soc. 2008, 130, 14088. For a similar example, see:
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Cheng, L.ꢀF.; Yu, J.; Gong, L.ꢀZ. Angew. Chem., Int. Ed. 2012, 51, 4085.
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2012, 4, 603. (f) Wang, Q.; Leutzsch, M.; Gemmeren, M. V.; List, B. J. Am. Chem. Soc. 2013,
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observed azlactone ring opening as a by product, see reference 9d.
[12] Different aliphatic tosyl aldimines were synthesized and the desired product was not
observed under our optimized reaction condition. Several reaction conditions were tested in
order to prepare mesyl aliphatic aldimines, however, all failed.
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