Highly enantioselective organocatalytic addition of unmodified aldehydes to N-Boc protected imines: one-pot asymmetric synthesis of β-amino acids

Article abstract of DOI:10.1016/j.tetlet.2006.11.076

Highly enantioselective catalytic routes to Boc protected β-amino aldehydes, β-amino acids and γ-amino alcohols are presented. The organocatalytic asymmetric reactions between unmodified aldehydes and N-Boc protected aryl imines proceed with excellent che

Full text of DOI:10.1016/j.tetlet.2006.11.076

Tetrahedron Letters 48 (2007) 421–425
Highly enantioselective organocatalytic addition of
unmodified aldehydes to N-Boc protected imines:
one-pot asymmetric synthesis of b-amino acids
*
´
Jan Vesely, Ramon Rios, Ismail Ibrahem and Armando Cordova
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Received 7 October 2006; revised 29 October 2006; accepted 10 November 2006
Abstract—Highly enantioselective catalytic routes to Boc protected b-amino aldehydes, b-amino acids and c-amino alcohols are pre-
sented. The organocatalytic asymmetric reactions between unmodified aldehydes and N-Boc protected aryl imines proceed with
excellent chemo- and enantioselectivities to give the corresponding compounds in high yields with up to >19:1 dr and 93% to
>99% ee.
Ó 2006 Published by Elsevier Ltd.
The Mannich reaction has found a multitude of applica-
tions in organic chemistry. The resulting Mannich bases
are of particular interest due to their utilization as syn-
thetic building blocks and precursors of pharmaceuti-
cally valuable compounds.1,2 Chemists have developed
several stoichiometric indirect stereoselective Mannich
Mannich reactions are catalyzed by chiral Brønsted
acids,10 cinchona alkaloids,11 proline and its deriva-
tives,12 peptide derivatives13 and amino acids.14 In this
context, we and Hayashi have reported the amino acid
catalyzed addition of unmodified aldehydes to aryl
N-p-methoxyphenyl (PMP) imines Eq. 1.15,16
MeO
OMe
+
MeO
COOH
N
H
O
NH
O
N
NH
ð1Þ
NaBH4
(20-30 mol%)
H
Ar
H
Ar
H
Ar
OH
R
R
transformations that utilize preformed enol equivalents
or imines.3,4 The first successful examples of catalytic
asymmetric additions of enolates to imines led to an
intense study of catalytic indirect Mannich reactions.5
Recently, heterodimetallic complexes and di-nuclear
zinc organo-metallic complexes were reported as cata-
lysts for highly enantioselective direct Mannich-type
reactions.6,7 Moreover, chiral copper(II) bisoxazoline
(BOX) complexes are also catalysts for direct asymmet-
ric Mannich-type reactions.8 Recently, organocatalysis
has been added to the synthetic repertoire for this
important transformation.9 These direct asymmetric
The corresponding PMP-protected b-amino aldehydes
are not very stable and are therefore reduced in situ to
the corresponding c-alcohols. In addition, removal of
the PMP group requires oxidative conditions and can
be low yielding. Enders recently reported two elegant
examples of addition of ketones to Boc imines.17 Based
on this and our previous experience in organocatalysis,18
we envisioned an organocatalytic reaction between Boc
protected imines and unmodified aldehydes.19 This pos-
sible reaction would be of high synthetic importance
since it would be a direct route to Boc protected b-
amino acids,2f,20 which can be used directly in peptide
and c-amino alcohols synthesis (Eq. 2). Moreover, the
side chain of Docetaxel (Taxotere), one of the most
important cancer chemotherapeutic substances, is a
Boc protected a-hydroxy-b-amino acid.21
*
Corresponding author. Tel.: +46 8 162479; fax: +46 8 154908; e-mail
addresses: acordova@organ.su.se; acordova1a@netscape.net
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.11.076

422
J. Vesely et al. / Tetrahedron Letters 48 (2007) 421–425
Boc
Ar
NH
O
OH
NaClO2
R
Boc
Boc
H
O
NH
O
N
X
N
H
+
H
Ar
H
Ar
R
ð2Þ
R
Boc
NH
NaBH4
Ar
OH
Boc
NH
O
R
C6H5
OH
OH
Taxotere side-chain
Herein, we present a simple highly enantioselective
organocatalytic addition of unmodified aldehydes to
N-Boc protected imines that gives the corresponding
b-amino aldehydes in high yields with >19:1 dr and
93% to >99% ee.
the optically active aldehyde 3a was quite stable and pre-
cipitated in CH3CN and CHCl3 at 4 °C as a white solid.
The highest yield and enantioselectivity were obtained
when DMF was used as the solvent. Encouraged by
these excellent results, we decided to investigate the
catalytic asymmetric Mannich reaction between various
N-Boc protected imines 1 and different aldehydes 2
with (S)-proline as the organocatalyst (Table 2).22
In an initial catalyst and solvent screen, we found that
(S)-proline 4 and 4-hydroxyproline 5 catalyzed the reac-
tion between phenyl N-Boc imine 1a (0.25 mmol) and
propionaldehyde 2a (0.75 mmol) with high chemoselec-
tivity to give the corresponding b-amino aldehyde 3a
in high yields with excellent diastereomeric ratios and
ee’s (Table 1).22
The catalytic Mannich reactions proceeded with excel-
lent chemo- and enantioselectivities and the correspond-
ing b-amino aldehydes 3a–e were obtained in high yields
with 93% to >99% ee. For instance, (S)-proline cata-
lyzed the asymmetric reaction between imine 1d and
propanal with high chemoselectivity, and Boc protected
b-amino aldehyde 3d was isolated in 73% yield as the
predominant diastereomer and >99% ee (entry 4).
Moreover, the reactions were operationally simple and
readily scaled-up. The b-amino aldehydes were also con-
(S)-Proline catalyzed the formation of b-amino aldehyde
3a in good to high yields with >19:1 dr (syn:anti) and
96% to >99% ee in all the solvents tested. Moreover,
hydroxyproline 5 catalyzed the formation of 3a in 62%
yield with >19:1 dr and >99% ee (entry 7). In addition,
Table 1. Catalyst screen for the enantioselective reactions between 1a and 2aa
Catalyst
Boc
Ar
Boc
H
O
NH
O
N
(20 mol%)
+
H
H
Ar
Solvent, 16 h
1a: Ar = C6H5
2a (3 equiv)
3a
HO
O
O
N
N
H
OH
H
OH
4
5
Entry
Catalyst
Solvent
Temp (°C)
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
4
4
4
4
4
4
5
CH3CN
CH3CN
CHCl3
DMSO
DMF
rt
4
4
4
4
4
4
62
70
82
67
85
80
62e
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
99
>99
96
97
>99
99
NMP
DMF
>99
a Experimental conditions: A mixture of 1a (0.25 mmol), propionaldehyde 2a (0.75 mmol) and catalyst (20 mol %) in 1.0 mL solvent was stirred
under the conditions displayed in the Table.
b Isolated yield of pure compound 3a.
c Determined by 1H NMR.
d Determined by chiral-phase HPLC analysis.
e Reaction stopped after 6 h, 30 mol % catalyst.

J. Vesely et al. / Tetrahedron Letters 48 (2007) 421–425
423
Table 2. Direct organocatalytic asymmetric Mannich reactions between N-Boc protected imines 1 and aldehydes 2a
(S)-proline
(20 mol%)
Boc
Ar
Boc
H
O
NH
O
N
+
H
H
Ar
DMF, 4 °C
R
R
1
2
3
Entry
Ar
R
Product
Time (h)
Yieldb (%)
drc
eed (%)
1
2
Ph
Ph
Me
i-Pr
3a
3b
16
16
85
77
>19:1
>19:1
>99
93
3
Ph
3c
16
75
>19:1
98
4
5
4-ClC6H4
4-MeOC6H4
Me
Me
3d
3e
15
16
73
78
>19:1
>19:1
99
99
a Experimental conditions: A mixture of 1a (0.25 mmol), propionaldehyde 2a (0.50 mmol) and (S)-proline (20 mol %) in 1.0 mL DMF was stirred at
4 °C.
b Isolated yield of pure compound 3.
c syn/anti Ratio determined by 1H NMR analysis.
d Determined by chiral-phase HPLC analyses.
Boc
Ar
Boc
Ar
NH
O
NH
O
(a)
(b)
1a
+
2a
H
OH
3a: Ar = Ph
6a
(c)
O
(d)
Boc
Ar
NH2
NH
HCl
OH
Ar
OH
7a
8a
Scheme 1. Reagents and conditions: (a) (S)-proline (20 mol %), DMF, 4 °C, 18 h, 85%; (b) NaClO2, iso-butene, KH2PO4, t-BuOH/H2O 2:1, 68%; (c)
HCl (8 M), dioxane, rt, 99%; (d) NaBH4, MeOH, 0 °C, 79%.
verted to the corresponding b-amino acids 6 or c-amino
alcohols 8 by oxidation and reduction, respectively
(Scheme 1).
For example, aldehyde 3a was oxidized to b-amino acid
6a in high yield.23 Subsequent deprotection gave the
corresponding b-amino acid 7a as the hydrochloride
salt. Comparison with the literature established that
25
the absolute stereochemistry of 7a ð½aꢀD +1.8 (c 1.0)),
25
lit. ð½aꢀD +1.7 (c 1.06)24) was (2S,3S). On the basis of
R1
the absolute configuration, we propose transition-state
model I to account for the diastereo- and enantioselec-
tivity of the amino acid catalyzed formation of b-amino
aldehydes 3 (Fig. 1). Hence, the (S)-proline derivative
forms an enamine with the aldehyde which is attacked
by the N-Boc protected imine from its Si-face providing
(3S)-syn-b-amino acid derivatives. This is in accordance
with the transition states of previously reported proline-
catalyzed Mannich reactions, in which Si-facial attack
occurs.12,15,16
H
O
N
Boc
O
H
N
H
H
Ar
R
R1 = H, OH
I
In summary, we have reported a simple, highly enantio-
selective, organocatalytic asymmetric Mannich reaction.
The chiral pyrrolidine catalyzed reactions between aryl
Boc imines and unmodified aldehydes proceeded with
high chemo- and enantioselectivities to furnish b-amino
aldehydes in high yields with 93% to >99% ee. Further
elaboration of this novel transformation, its synthetic
Boc
Ar
NH
O
H
R
Figure 1. Transition-state models evoked to account for the enantio-
selectivity of the (S)-proline and hydroxyproline catalyzed reactions.

424
J. Vesely et al. / Tetrahedron Letters 48 (2007) 421–425
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application and mechanistic studies are ongoing in our
laboratory.25
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Acknowledgements
We gratefully acknowledge the Swedish National
Research Council and Carl-Trygger Foundation for
the financial support.
´
9. Cordova, A. Acc. Chem. Res. 2004, 37, 102.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.11.076.
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List at IASOC at Ischia in Italy on 17th of September
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J. Vesely et al. / Tetrahedron Letters 48 (2007) 421–425
425
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23. Preparation of acid 6a: To a solution of 3a (26 mg,
0.1 mmol) in chloroform (1 mL), isobutene (0.1 mL), tert-
butanol (0.4 mL), H2O (0.2 mL), KH2PO4 (54.4 mg,
4.0 mmol) and NaClO2 (36 mg, 4.0 mmol) were added
sequentially at room temperature. After 16 h, the crude
product was purified by column chromatography
(pentane/EtOAc mixtures) to afford 19 mg (68%) of the
22. Typical experimental procedure: To a stirred solution of
(S)-proline (20 mol %) and imine 1a (1.0 equiv,
0.25 mmol) in DMF (1.0 mL) at 4 °C was added aldehyde
2 (2 equiv, 0.5 mmol). The reaction was vigorously stirred
for the reported time. Next, the reaction was directly
loaded on a silica gel column and immediate chromato-
graphy (pentane/EtOAc-mixtures or toluene/EtOAc-mix-
tures) furnished the corresponding aldehyde. Compound
3a: 1H NMR (400 MHz, CDCl3): d = 9.71 (br s, 1H),
7.39–7.23 (m, 5H), 5.22–5.08 (m, 2H), 2.86 (br s, 1H), 1.41
(s, 9H), 1.06 (d, J = 6.8 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d = 203.2, 155.5, 134.6, 128.9, 127.8, 126.8, 79.5,
25
desired acid 6a; ½aꢀD ꢁ15.2 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 7.34–7.24 (m, 5H), 5.43 (br s, 1H),
4.99 (br s, 1H), 2.94 (br s, 1H), 1.41 (s, 9H), 1.16 (d,
J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): d = 178.6,
155.3, 133.8, 128.6, 127.7, 126.9, 79.9, 56.4, 45.0, 28.4,
13.2. HRMS (ESI): calcd for [M+Na]+ (C15H21NO4)
requires m/z 302.1363, found 302.1349.
24. Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc.,
Perkin. Trans. 1 1994, 1141.
25
54.8, 51.7, 28.4, 9.4; ½aꢀD +2.4 (c 1.0, CHCl3). The
25. The reaction also works for Cbz protected alimines. For
instance, the reaction between benzaldehyde derived Cbz
protected imine (0.25 mmol) and propionaldehyde
(0.5 mmol) in DMF at 4 °C gave the corresponding Cbz
protected b-aminoaldehyde after 17 h in 80% yield with
4:1 dr and 72% ee.
enantiomeric excess was determined by HPLC on Daicel
Chiralpak AD with hexane/i-PrOH (90:10) as the eluent.
Flow: 0.5 mL/min; minor isomer: tR = 18.1 min; major
isomer: tR = 23.5 min; HRMS (ESI): calcd for [M+Na]+
(C15H21NO3) requires m/z 286.1414, found 286.1400.