One-pot highly enantioselective catalytic Mannich-type reactions between aldehydes and stable α-amido sulfones: asymmetric synthesis of β-amino aldehydes and β-amino acids

Article abstract of DOI:10.1016/j.tetlet.2009.10.130

A highly enantioselective catalytic route to carbamate- and benzoate-protected β-amino aldehydes and β-amino acids is presented. The amino acid-catalyzed one-pot asymmetric reaction between unmodified aldehydes and α-amido sulfones gives the corresponding

Full text of DOI:10.1016/j.tetlet.2009.10.130

Tetrahedron Letters 51 (2010) 234–237
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One-pot highly enantioselective catalytic Mannich-type reactions between
aldehydes and stable a-amido sulfones: asymmetric synthesis of b-amino
aldehydes and b-amino acids
*
*
Luca Deiana, Gui-Ling Zhao , Pawel Dziedzic, Ramon Rios, Jan Vesely, Jesper Ekström, Armando Córdova
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective catalytic route to carbamate- and benzoate-protected b-amino aldehydes and
b-amino acids is presented. The amino acid-catalyzed one-pot asymmetric reaction between unmodified
Received 21 August 2009
Revised 16 October 2009
Accepted 28 October 2009
Available online 1 November 2009
aldehydes and
>99% ee.
a-amido sulfones gives the corresponding b-amino compounds with up to 95:5 dr and 97–
Ó 2009 Elsevier Ltd. All rights reserved.
The Mannich reaction and similar transformations involving
nucleophilic addition to the C@N bond of imine derivatives are of
significant importance in organic synthesis.1 The resulting Man-
nich bases are valuable amine-containing compounds utilized as
building blocks for pharmaceutically valuable compounds and nat-
ural products.2 In the arena of asymmetric catalysis,3 the first suc-
cessful examples of catalytic asymmetric additions of enolates to
imines led to the beginning of the rapidly growing area of catalytic
indirect Mannich-type reactions.4 Direct catalytic asymmetric
Mannich-type reactions have also been developed using heterodi-
metallic complexes and di-nuclear zinc organometallic complexes,
copper(II) bisoxazoline (BOX) complexes and Pd-complexes as cat-
alysts, among others.5–7 In addition, organocatalytic direct enantio-
selective Mannich-type reactions have been developed.3c,3d These
asymmetric transformations are catalyzed by chiral Brønsted
acids,8 cinchona alkaloids,9 proline and its derivatives,10 peptide
derivatives11 and acyclic amino acids.12
example, a-amido sulfones 1 are useful and highly suitable precur-
sors as they are bench-stable solids and can be obtained readily by
condensation of a carbamate and a sodium aryl sulfinate with the
desired aldehyde.16 The
a-amido sulfones 1 furnish the corre-
sponding moisture-sensitive imines when treated with a base. In
this context, they have been used in reactions employing metal-
stabilized enolates,17 and the in situ formation of the imine has
also been used in phase-transfer-catalyzed reactions in combina-
tion with an inorganic base.18 Despite the considerable benefits
of this approach, which combines both operational simplicity and
high selectivity via small molecule catalysis with the convenience
of the employment of a-amido sulfones 1, it has, to the best of our
knowledge, not been applied to Mannich-type reactions employing
natural amino acids as catalysts and to syn-diastereoselective
transformations.19 Based on this and our previous experience,13b,15
we decided to investigate this one-pot strategy for the catalytic
enantioselective Mannich-type addition of aldehydes to N-carbam-
In this context, amino acids and their derivatives have been em-
ployed as catalysts for the addition of aldehydes to N-p-methoxy-
phenyl (PMP) imines10,12 and N-carbamoyl imines such as N-Boc-
imines,13 N-Cbz-imines14 and N-(phenylmethylene)benzamides.15
However, because of their inherent high reactivity, N-carbamoyl
imines are rather sensitive towards moisture and air, and their
preparation is rather troublesome and their storage requires pre-
cautions. A possible and economic route to avoid these drawbacks
is the in situ generation of the imine through the use of precursors
oyl imines derived in situ from a-amido sulfones 1 using natural
amino acids as catalysts. Herein, we present the successful applica-
tion of this approach to the one-pot, highly enantioselective amino
acid-catalyzed synthesis of b-amino aldehydes and b-amino acids
with up to 95:5 dr and 97–>99% ee.
In an initial experiment, we found that (S)-proline catalyzed
the reaction between
a-amido sulfone 1a (0.25 mmol) and prop-
anal 2a (0.75 mmol) via the intermediacy of imine 4a with high
chemoselectivity to give the corresponding b-amino aldehydes 3a
and 3a0 in high yields in a 50:50 ratio (Eq. 1). To our delight, the
enantioselectivity was high (96% ee, syn-diastereoisomer; 94% ee,
anti-isomer).
with a good leaving group at the carbon
a to the nitrogen atom. For
In order to improve the diastereoisomeric ratio of 3a, we
screened several inorganic bases in combination with proline as
the catalyst (Table 1).20
* Corresponding authors. Tel.: +46 8 162479; fax: +46 8 154908 (A.C.).
E-mail addresses: zhaogl@organ.su.se (G.-L. Zhao), acordova@organ.su.se,
acordova1a@netscape.net (A. Córdova).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.130

L. Deiana et al. / Tetrahedron Letters 51 (2010) 234–237
235
(S)-proline
(20 mol%)
Boc
Boc
Boc
O
NH
O
NH
O
HN
K2CO3 (5 equiv)
+
+
SO2Ar1
H
H
H
CHCl3, 16 h, rt
3a': 94% ee
1a
2a (3 equiv)
3a: 96% ee
ð1Þ
71% yield, 50:50 dr
O
Boc
H
N
4a
Several of the inorganic bases investigated in combination with
(S)-proline enabled the formation of 3a with high enantioselectiv-
ity (entries 1, 2, 4 and 5). The use of NaF and KF enabled the asym-
metric assembly of 3a from 1a with moderate to high
diastereoselectivity (entries 4 and 5).21 The choice of CHCl3 as a
solvent gave the highest stereoselectivity. For example, the combi-
nation of KF and proline in CHCl3 gave an 84% combined yield of
the two diastereoisomers with 91:9 dr (syn/anti) and >99% ee (en-
try 5). Encouraged by these results, we decided to investigate the
nantly as the syn-diastereomer with >99% ee (entry 3). The
opposite enantiomers ent-3a and ent-3b with >99 and 99% ee,
respectively, were prepared by using (R)-proline as the catalyst.
Moreover, the reaction is operationally simple and readily scaled
up. For example, to a mixture of 1b (4 mmol, 1.44 g) in CHCl3
(20 mL) were added KF (7.2 mmol, 1.8 equiv), aldehyde 2a
(12 mmol, 3 equiv) and (S)-proline (0.8 mmol, 20 mol %) at room
temperature. After stirring for 16 h the reaction was quenched
by the addition of water (20 mL). The aqueous layer was ex-
tracted with CHCl3 (40 mL), the organic layer was dried over
Na2SO4 and the solvent was removed under reduced pressure. Sil-
ica gel column chromatography (pentane–EtOAc mixtures) fur-
nished the corresponding aldehyde 3b in 70% yield with 10:1 dr
and 99% ee. The b-amino aldehydes 3 were also converted into
catalytic one-pot asymmetric reaction between various
a-amido
sulfones 1 and different aldehydes 2 with KF as the base and (S)-
proline as the organocatalyst (Table 2).22
The one-pot enantioselective reactions proceeded with excel-
lent chemo- and enantioselectivity and the corresponding N-
Boc-, Cbz- and benzoyl-protected b-aminoaldehydes 3a–3j were
obtained in moderate to high yields with 97–99% ee. For example,
the corresponding b-amino acid 5b23 in high yield or
c-amino
alcohol 6 by oxidation and reduction, respectively (Scheme 1).
(S)-proline catalyzed the asymmetric reaction between
sulfone 1c and propanal with high chemoselectivity and Boc-pro-
tected b-amino aldehyde 3c was isolated in 92% yield predomi-
a-amido
Comparison with the literature established that the absolute ste-
reochemistry of 5b {½a D25
ꢀ
ꢁ15.2 (c 1.0), lit. ½a D25
ꢀ
ꢁ15.2 (c 1.0)13b
}
was (2S,3R).
Table 1
Screening of inorganic bases for the enantioselective reactions between 1a and 2aa
(S)-proline
(20 mol%)
Boc
Ar
Boc
O
NH
O
HN
Base (2-5 equiv)
+
3a'
+
H
H
Ar
SO2Ar1
Solvent, 16 h, rt
1a: Ar = Naphth, Ar1 = p-Tol 2a (3 equiv)
3a
Entry
Base
Solvent
Yieldb (%)
drc
eed (%)
e
1
2
3
4
5
6
7
8
K2CO3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DMF
71
76
Trace
14
84
45
72
67
50:50
50:50
—
67:33
91:9
93:7
50:50
83:17
96 (94)g
87 (85)g
—
e
K3PO4
Cs2CO3
NaFe
KFe
e
99 (99)g
>99 (n.d.)g
97 (n.d.)g
36 (36)g
99 (99)g
KFf
KFe
KFe
CH2Cl2
a
Experimental conditions: a mixture of 1a (0.25 mmol), propanal 2a (0.75 mmol), base and catalyst (20 mol %) in solvent (1.25 mL) was stirred under the conditions
displayed in the Table.
b
Combined isolated yield of pure compounds 3a and 3a0.
c
Determined by 1H NMR analyses of the crude reaction mixture.
d
Determined by chiral-phase HPLC analysis of alcohol 6a obtained by reduction of isolated 3a.
5 equiv of base was used.
2.5 equiv of base was used.
ee of the anti-isomer.
e
f
g

236
L. Deiana et al. / Tetrahedron Letters 51 (2010) 234–237
Table 2
References and notes
Direct organocatalytic asymmetric Mannich reactions between
a-amido sulfones 1
and aldehydes 2a
1. Mannich, C.; Krösche, W. Arch. Pharm. 1912, 250, 647.
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(S)-proline
O
O
(20 mol%)
R1 NH
O
O
HN
R1
SO2Ar1
KF (5 equiv)
+
3'
+
H
Ar
H
Ar
Hellmann, H.; Optiz, G. a-Aminoalkylierung; Verlag Chemie: Weinheim, 1960. p
CHCl3, 16 h, rt
R
1; (f)For examples, see: Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
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R
3
1: Ar1 = p-tol
2 (3 equiv)
R1
Entry Ar
R
Product Yieldb (%) drc
eed (%)
1
2
3
4
5
6
7
8
9
Naphth
Ph
4-ClC6H4
Me t-BuO 3a
Me t-BuO 3b
Me t-BuO 3c
84
67
92
90
72
83
53
50
76
47
91:9
91:9
90:10 >99
89:11 99
>99e
99
4-MeOC6H4 Me t-BuO 3d
4-MeC6H4
Me t-BuO 3e
95:5
99
Ph
Ph
Naphth
Ph
Ph
Me BnO
Me Ph
Me BnO
Et
iPr
3f
3g
3h
80:20 99e
67:33 97
75:25 98
t-BuO 3i
t-BuO 3j
91:9
95:5
99
99
10
a
Experimental conditions: a mixture of 1 (0.25 mmol), aldehyde 2 (0.75 mmol),
KF (1.25 mmol) and (S)-proline (20 mol %) in CHCl3 (1.25 mL) was stirred at rt for
16 h.
b
Isolated combined yield of pure compound 3 and 30.
Syn/anti ratio determined by 1H NMR analysis.
c
d
Determined by chiral-phase HPLC analysis of pure aldehyde 3.
Determined by chiral-phase HPLC analysis of alcohol 6 obtained by reduction of
e
isolated 3. The ee of the minor diastereoisomer is not shown.
8. (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43,
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Fini, F.; Fochi, M. F.; Pettersen, D.; Sgarzani, V.; Ricci, A. Chem Eur. J. 2007, 13,
8338.
O
O
R1 NH
O
R1 NH
Ar
O
(a)
Ar
H
OH
R
3
5b: Ar = Ph, R1 = t-BuO
10. For selected examples, see: (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336; (b)
Córdova, A.; Watanabe, S.-i.; Tanaka, F.; Notz, W.; Barbas, C. F., III J. Am. Chem.
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Córdova, A. Chem. Commun. 2006, 1760; (j) Ibrahem, I.; Casas, J.; Córdova, A.
Angew. Chem., Int. Ed. 2004, 43, 6528; (k) Ibrahem, I.; Zou, W.; Casas, J.; Sundén,
H.; Córdova, A. Tetrahedron 2006, 62, 357; (l) Chi, Y.; Gellman, S. J. Am. Chem.
Soc. 2006, 128, 6804; (m) Ibrahem, I.; Sundén, H.; Dziedzic, P.; Rios, R.; Córdova,
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Córdova, A. Chem. Eur. J. 2004, 10, 1987; (p) Ibrahem, I.; Córdova, A. Tetrahedron
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11. Wenzel, E. N.; Jacobsen, E. N. J. Am Chem. Soc. 2002, 124, 12964.
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Eur. J. 2005, 11, 7024; (b) Dziedzic, P.; Córdova, A. Tetrahedron: Asymmetry
2007, 18, 1033; (c) Cheng, L.; Han, X.; Huang, H.; Wah Wong, M.; Lu, Y. Chem.
Commun. 2007, 4143; (d) Cheng, L.; Wu, X.; Lu, X. Org. Biomol. Chem. 2007, 5,
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13. (a) Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007, 46, 609; (b)
Vesely, J.; Rios, R.; Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2007, 48, 421; (c)
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(d) Dziedzic, P.; Vesely, J.; Córdova, A. Tetrahedron Lett. 2008, 49, 6631; (e)
Vesely, J.; Dziedzic, P.; Córdova, A. Tetrahedron Lett. 2007, 48, 6900; (f) Gianelli,
C.; Sambri, L.; Carlone, A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2008,
47, 8700; (g) Kano, T.; Yamaguchi, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2009,
48, 1838; For the first use of ketones as donors, see: (h) Enders, D.; Grondal, C.;
Vrettou, M. Synthesis 2006, 3597.
(b)
O
R1 NH
Ar
OH
6a: Ar = Ph, R1 = t-BuO
R
Scheme 1. Reagents: ClO2, iso-butene, KH2PO4, t-BuOH/H2O (5:1), 72%. (b) NaBH4,
MeOH, 0 °C, 90%.
In summary, we have reported a highly enantioselective cat-
alytic route to carbamate- and benzoate-protected b-amino alde-
hydes and b-amino acids. The one-pot organocatalytic reactions
between
a-amido sulfones and unmodified aldehydes proceeded
with high chemo- and enantioselectivity to furnish b-amino
aldehydes in high yields with 97–>99% ee. Further elaboration
of this one-pot transformation and its synthetic application are
ongoing in our laboratory. For example, this protocol should also
be applicable to other C–C bond-forming reactions such as the
Aza–Morita–Baylis–Hillman-type reaction.13e
Acknowledgements
14. For the use of the Cbz protecting group, see Refs. 13b,13f and Hayashi, Y.;
Okano, T.; Itoh, T.; Urushima, T.; Ishikawa, H.; Uchimaru, T. Angew. Chem., Int.
Ed. 2008, 47, 9053.
We gratefully acknowledge the Swedish National Research
Council and Carl-Trygger Foundation for financial support.
15. Dziedzic, P.; Schyman, P.; Kullberg, M.; Córdova, A. Chem. Eur. J. 2009, 15, 4044.

L. Deiana et al. / Tetrahedron Letters 51 (2010) 234–237
237
16. For a review see: (a) Petrini, M. Chem. Rev. 2005, 105, 3949; (b) Kanazawa, A.
M.; Denis, J. -N.; Greene, A. E. J. Org. Chem. 1994, 59, 1238; (c) Pearson, W. H.;
Lindbeck, A. C.; Kampf, J. W. J. Am. Chem. Soc. 1993, 115, 2622; (d) Song, J.;
Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
17. (a) Palomo, C.; Oiarbide, M.; Landa, A.; Gonzales-Rego, M. C.; Garcia, J. M.;
Gonzales, A.; Odriozola, J. M.; Martin-Pastor, M.; Linden, A. J. Am. Chem. Soc.
2002, 124, 8637. and references therein; (b) Palomo, C.; Oiarbide, M.; Laso, A.;
Lopez, R. J. Am. Chem. Soc. 2005, 127, 17622.
400 MHz) d 7.84–7.81 (m, 3H), 7.68 (s, 1H), 7.51–7.39 (m, 3H), 5.41 (d,
J = 9.6 Hz, 1H), 5.24 (d, J = 7.2 Hz, 1H), 3.54 (br s, 1H), 3.42 (t, J = 10.4 Hz, 1H),
3.33 (br s, 1H), 2.32–2.25 (m, 1H), 1.48 (s, 9H), 0.72 (d, J = 6.4 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) d 156.8, 138.1, 133.4, 132.6, 128.3, 127.9, 127.7, 126.4, 126.0,
125.1, 123.7, 80.3, 65.2, 54.4, 41.2, 28.5, 10.8; The ee of the product was
determined by chiral HPLC analysis (Chiralpak ODH column, n-hexane-2-
propanol = 95/5,
1.0 mL/min,
210 nm,
tR
(minor) = 13.9 min,
tR
(major) = 17.1 min; HRMS (ESI) (C19H25NO3Na) [M+Na]+ requires m/z
338.1727, found m/z 338.1713.
18. (a) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci, A.
Angew. Chem., Int. Ed. 2005, 44, 7975; (b) Song, J.; Shih, H.-W.; Deng, L. Org. Lett.
2007, 9, 603; (c) Niess, B.; Jørgensen, K. A. Chem. Commun. 2007, 1620. See also
Refs. 9b,c.
21. It is important to fine-tune the number of equivalents of KF in order to achieve
the optimum diastereoselectivity.
22. Typical experimental procedure: To
a mixture of 1 (0.25 mmol) in CHCl3
19. During our investigations, an elegant one-pot anti-selective synthesis of 3b0
and 3f0 which requires 4 day reactions was reported, see Ref. 13f.
(1.25 mL) were added KF (5 equiv), aldehyde 2 (0.75 mmol) and (S)-proline
(20 mol %) at room temperature. After stirring for 16 h, the reaction was
quenched by the addition of brine (5 mL) and extracted with EtOAc
(3 ꢂ 25 mL). Next, the combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. Silica gel column chromatography
(pentane–EtOAc mixtures or toluene–EtOAc mixtures) furnished the
corresponding aldehydes 3. Data for 3c: 1H NMR (400 MHz, CDCl3): d = 9.67
(s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 5.22–5.04 (m, 2H), 2.86–
2.78 (m, 1H), 1.40 (s, 9H), 1.06 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
20. Typical experimental procedure: To a mixture of 1a (0.25 mmol) in solvent
(1.25 mL) were added base, aldehyde 2a (0.75 mmol) and (S)-proline
(20 mol %) at room temperature. After stirring for 16 h, the reaction was
quenched by the addition of brine (5 mL) and extracted with EtOAc
(3 ꢂ 25 mL). The combined organic layers were dried with Na2SO4, and the
solvent was removed under reduced pressure. Silica gel column
chromatography of the residue (pentane–EtOAc mixtures or toluene–EtOAc
mixtures) furnished the corresponding aldehyde 3a. ½a D25
ꢀ
ꢁ17.8 (c 1.0, CHCl3).
d = 203.0, 155.3, 129.1, 128.3, 79.8, 51.5, 36.7, 28.5, 9.6; ½a D25
ꢀ
ꢁ3.6 (c 1.0,
1H NMR (CDCl3, 400 MHz) d 9.75 (s, 1H), 7.85–7.81 (m, 3H), 7.70 (s, 1H), 7.52–
7.46 (m, 2H), 7.38–7.36 (m, 1H), 5.35 (br s, 1H), 5.24 (br s, 1H), 2.97 (s, 1H),
1.43 (s, 9H), 1.10 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 203.1, 155.3,
132.9, 129.2, 128.8, 128.0, 127.7, 126.5, 126.2, 125.6, 124.7, 122.9, 79.7, 51.6,
28.4, 28.3, 9.4; HRMS (ESI) (C19H23NO3Na) [M+Na]+ requires m/z 336.1570,
found m/z 336.1558. For the ee determination, the aldehyde 3a was reduced
in situ by diluting the reaction mixture with MeOH (1 mL) and adding excess
NaBH4 at 0 °C. After stirring for 10 min, the reaction mixture was transferred to
a stirred mixture of EtOAc (20 mL) and 2 M HCl (3 mL) at 0 °C. Next, Na2SO4
was added, the solution was filtered and concentrated under reduced pressure.
The crude residue was purified by silica gel column chromatography (pentane–
CHCl3). The enantiomeric excess was determined by HPLC on a Daicel
Chiralpak AD column with hexane-i-PrOH (98:2) as the eluent. Flow: 0.5 mL/
min; minor isomer: tR = 18.8 min; major isomer: tR = 28.8 min; HRMS (ESI):
calcd for (C15H20NO3Cl) [M+Na]+ requires m/z 320.1024, found 320.1035.
23. The b-amino aldehyde 3b (2.1 mmol) was added to t-BuOH/water (5:1, 24 mL),
followed by addition of iso-butene (9 mmol), KH2PO4 (3.2 mmol) and NaClO2
(7.2 mmol). After stirring for 24 h, the reaction mixture was quenched with
brine (25 mL) and extracted with EtOAc (3 ꢂ 75 mL). The combined organic
layer was dried over Na2SO4 and the solvent was removed under reduced
pressure. The crude product was purified by column chromatography
(pentane–EtOAc mixtures) to afford pure acid 5b (72%). The spectral data
were in accordance with the literature, see Ref. 13b.
EtOAc, 2:1) to give pure alcohol 6a. ½a D25
ꢀ
ꢁ48.3 (c 1.0, CHCl3). 1H NMR (CDCl3,