Direct catalytic enantioselective α-aminomethylation of aldehydes

Article abstract of DOI:10.1002/chem.200600725

The direct catalytic asymmetric α-aminomethylation of aldehydes is presented. The chiral amine and amino acid catalyzed reactions between unmodified aldehydes and a formaldehyde-derived imine precursor were fast and proceeded with high chemo- and enantios

Full text of DOI:10.1002/chem.200600725

FULL PAPER
DOI: 10.1002/chem.200600725
Direct Catalytic Enantioselective a-Aminomethylation of Aldehydes
Ismail Ibrahem, Gui-Ling Zhao, and Armando Córdova*[a]
Abstract: The direct catalytic asymmetric a-aminomethylation of aldehydes is pre-
sented. The chiral amine and amino acid catalyzed reactions between unmodified
aldehydes and a formaldehyde-derived imine precursor were fast and proceeded
with high chemo- and enantioselectivities. The corresponding dibenzyl-protected
g-amino alcohols were isolated in high yields with up to 98% ee after in situ reduc-
tion. The reaction is a novel entry to valuable b2-amino acid derivatives.
Keywords: alpha-aminomethyla-
tion · aldehydes · amino acids ·
asymmetric catalysis · diarylprolinol
Introduction
chincona alkaloids,[9] and amino acids and their deriva-
tives.[10] Recently, the direct catalytic asymmetric a-amino-
methyaltion of ketones was reported.[11] However, develop-
ing a direct catalytic enantioselective a-aminomethylation of
aldehydes is more challenging.[12] This reaction is highly in-
teresting, as it is a direct entry to b-amino aldehydes, which
can be converted to important b2-amino acid derivatives and
g-amino alcohols [Eq. (1)].
The classical Mannich reaction,[1] in which an aminomethyl
group is introduced in the a-position to a carbonyl com-
pound, is an important reaction in organic chemistry.[2] The
resulting Mannich bases are of particular interest due to
their biological activity, use as synthetic building blocks, and
precursors of valuable pharmaceutical g-amino alcohols.[2] In
this context, a few elegant dia-
steroselective a-aminomethyla-
tion reactions have been devel-
oped.[3,4]
The development of catalytic
asymmetric Mannich-type reac-
tions has received increased at-
tention in recent years.[5] These
reactions are used for the syn-
thesis of valuable chiral nitro-
gen-containing
compounds,
such as amino acid derivatives,
b-lactams, and amino alco-
hols.[5–11] Direct catalytic Mannich-type reactions between
ketones and preformed imines are catalyzed by organome-
tallic complexes[7] with high enantioselectivity. Moreover, or-
ganocatalytic direct asymmetric Mannich-type reactions
have been developed that are catalyzed by Brønsted acids,[8]
However, proline does not catalyze the direct one-pot
three-component a-aminomethylation of aldehydes and the
desired products are not formed.[11b] Enders and Shibasaki
have utilized aminomethyl ethers,[4,7a] which are useful
equivalents of iminium ions, in stereoselective asymmetric
a-aminomethylation reactions with ketones. Inspired by
these reports and our experience in organocatalysis,[13] we
envisioned a plausible novel chiral amine-catalyzed direct
catalytic asymmetric a-aminomethylation reaction between
aldehydes and aminomethyl ethers [Eq. (2)].
[a] I. Ibrahem, Dr. G.-L. Zhao, Prof. Dr. A. Córdova
Department of Organic Chemistry
The Arrhenius Laboratory, Stockholm University
10691 Stockholm (Sweden)
Herein, we report the direct catalytic enantioselective a-
aminomethylation reactions between aldehydes and a diben-
zylamine-derived aminomethyl ether, which furnished the
Fax : (+46)8-154-908
E-mail: acordova@organ.su.se
acordova1a@netscape.net
Chem. Eur. J. 2007, 13, 683 – 688
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
683

lation reaction with the highest enantioselectivity. For in-
stance, (S)-proline and chiral pyrrolidine 8 catalyzed the for-
mation of ent-4a with 65% ee and 4a with 78% ee, respec-
tively (entries 1 and 7). Moreover, catalysts 5–7 furnished
the opposite enantiomer, ent-3a, as opposed to protected
chiral prolinols 8 and 9. The efficiency and enantioselectivity
of the protected diarylprolinol-catalyzed enantioselective re-
actions were significantly improved by the addition of an or-
ganic acid (20 mol%). We found that acetic acid gave the
best results with respect to conversion and enantioselectivity
of the reaction. The addition of achiral alkali cations has
been shown by Adolfsson and co-workers to increase the
enantioselectivity of small peptide catalyzed asymmetric
transformations.[18] Thus, we decided to investigate the possi-
bility of using this positive additive effect on the chiral pyr-
rolidine 8-catalyzed asymmetric a-aminomethyaltion reac-
tion (Table 2).
corresponding g-amino alcohols in high yields with up to
98% ee after in situ reduction. The enantioselectivity of the
protected diaryprolinol-catalyzed reactions was significantly
improved by the addition of lithium halide salts.
Results andDiscussion
In initial experiments, we screened proline 5, proline deriva-
tives 6[14]–7[10o,15], and chiral pyrrolidines 8–9[16] for their abil-
ity to catalyze the reaction between dibenzyl amine-derived
aminomethyl ether 1[4a] and isovaleraldehyde 2a under dif-
ferent reaction conditions. A few of them are shown in
Table 1.
Table 2. Screen of different additives.[a]
Table 1. Catalysts screened.[a]
Entry
Additive
Solvent
Conv. [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
none
NaCl
LiCl
DMF
DMF
DMF
DMF
80
>95
>95
>95
>95
96
>95
90
>95
96
78
72
90
96
88
74
75
66
75
58
58
37
LiBr
LiIDMF
LiClO4
LiOAc
NH4Cl
LiBr
LiBr
LiBr
LiBr
DMF
DMF
DMF
CH3CN
NMP
Entry
Catalyst
Solvent
T [8C]
t [h]
Conv. [%][b]
ee [%][c]
9
10
11
12
1
2
3
4
5
6
7
8
5
5
6
7
8
8
8
9
DMF
DMF
DMF
DMSO
CHCl3
CH3CN
DMF
À20
4
À20
23
4
16
2
16
2
4
4
>95
>95
>95
>95
46
65[d]
51[d]
55[d]
18[d]
68
iPrOH
CHCl3
68
86
[a] The additive (1 mmol) was added to a vial containing the solvent
(1 mL) and the mixture was stirred for 5 min. Next, the catalyst and the
aldehyde 2a (1 mmol) were added and the reaction temperature de-
creased to À258C. The aminomethyl ether 1 (0.5 mmol) was added and
the reaction was vigorously stirred for 2 h followed by addition of MeOH
(2 mL). The b-amino aldehyde 3a was reduced in situ to amino alcohol
4a, which was isolated by silica-gel column chromatography. [b] Con-
version was determined by NMR spectroscopic analyses. [c] Determined
by chiral-phase HPLC analysis of 4a.
4
>95[e]
80[e]
66[e]
78[e]
50[e]
À25
2
3
CHCl3
4
>95[e]
[a] Aldehyde 2a (1 mmol) was added at the temperature shown in the
table to a vial charged with the catalyst (20 mol%) in solvent (1 mL).
Next, the aminomethyl ether 1 (0.5 mmol) was added. After stirring for
the time shown in the table, MeOH (2 mL) was added, the temperature
was set to À258C, and then the b-amino aldehyde 3a was reduced in situ
to amino alcohol 4a, which was isolated by silica-gel column chromatog-
raphy. [b] Conversion was determined by NMR spectroscopic analyses.
[c] Determined by chiral-phase HPLC analysis of 4a. [d] Enantiomeric
excess of ent-4a. [e] Acetic acid added (20 mol%).
We found that the addition of salts increased the rate of
the reactions. Notably, lithium halide salts significantly in-
creased the enantioselectivity in the following order: LiBr>
LiCl>LiI. For instance, complete conversion was achieved
within 2 h by the addition of LiBr (2 equiv) and the optical
purity of 4a produced increased from 78 to 96% ee. This
positive effect is plausibly due to the higher Lewis acidity of
the lithium halide salts as compared to LiClO4 and LiOAc,
which did not increase the enantioselectivity of the reaction.
In addition, lithium with its higher Lewis acidity was the
cation of choice, as NaCl did not improve the enantioselec-
tivity of the reaction. Moreover, the highest enantioselectivi-
To our delight, all the chiral amines catalyzed the forma-
tion of the corresponding a-aminomethylated aldehyde 3a
in high conversion (>95%), which was reduced in situ to
the more stable alcohol 4a.[17] All reactions were highly che-
moselective and traces of elimination products were only
detected after full conversion had occurred. Proline 5 and
diphenylprolinol 8 catalyzed the asymmetric a-aminomethy-
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Chem. Eur. J. 2007, 13, 683 – 688

a-Aminomethylation of Aldehydes
FULL PAPER
ty for the solvents tested was achieved in DMF, which sug-
gests that the solubility of the lithium halide salts may be
important. With these results in hand, we decided to investi-
gate the chiral pyrrolidine 8-catalyzed reaction between di-
benzylaminomethyl ether 1 and different aldehydes 2 in the
presence of LiBr (Table 3).
catalytic asymmetric a-aminomethylation of aldehydes is an
efficient direct entry for the synthesis of b2-amino acids,
which are present in natural products and used as building
blocks in important b-peptide foldamers.[19–20]
Moreover, the b2-amino acid synthesis established that
protected (S)-diarylprolinols 8 and 9 furnished (R)-aminoal-
dehydes 3 and that (S)-proline and its derivatives 6 and 7
furnished the opposite (S)-enantiomers ent-3. Based on
these results we propose transition-state I to account for the
stereochemical outcome for the protected diarylprolinol-cat-
alyzed, highly enantioselective reactions (Figure 1). In ac-
Table 3. Chiral diphenyl prolinol 8-catalyzed direct asymmetric a-amino-
methylation of aldehydes 2.[a]
Entry
R
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
iPr
Me
PhCH2
n-pent
4a
4b
4c
4d
4e
4 f
80
82
79
81
78
75
96
98
98
91
92
95
TBSOCH2
[a] LiBr (1 mmol) was added to a vial containing DMF (1 mL) and the
mixture was stirred until it became homogeneous. Next, the catalyst and
the aldehyde 2 (1 mmol) were added and the reaction temperature de-
creased to À258C. The aminomethyl ether 1 (0.5 mmol) was added and
the reaction was vigorously stirred for 2 h followed by addition of MeOH
(2 mL). The b-amino aldehyde 3 was reduced in situ to amino alcohol 4,
which was isolated by silica-gel column chromatography. [b] Isolated
yield of pure amino alcohol 4. [c] Determined by chiral-phase HPLC
analysis. TBS=tert-butyldimethyl silyl.
Figure 1. Proposed transition-state models evoked to account for the
enantioselectivity of the (S)-diarylprolinol 8 and 9, (S)-proline, and 6-cat-
alyzed reactions.
cordance, the Re-face of the chiral enamine is approached
by the aminomethyl ether 1 via a plausible six-membered
transition state. The proton from the acetic acid or lithium
cation possibly stabilizes the proposed transition-state I by
activation of the methoxy leaving group of 1. Transition-
state II is plausibly less-favored due to repulsion between
the lithium cation and the iminium ion.
In the case of the (S)-proline- and 6-catalyzed a-amino-
methylation reaction, the plausible ionic transition state III
is proposed to account for the stereochemical outcome of
the reaction (Figure 1). Thus, the Si-face of the chiral enam-
ine is approached by the in situ generated iminium ion
which forms an ionic intermediate with the carboxylate
The direct catalytic asymmetric a-aminomethylation reac-
tions were fast, highly chemo- and enantioselective, and the
corresponding amino alcohol products 4 were isolated in
high yields with up to 98% ee. In most cases, the amino al-
cohols were furnished with >90% ee. For instance, the cata-
lytic asymmetric a-aminomethylations of aldehydes 2b and
2c with 1 gave the corresponding amino alcohols 4b and 4c
after one-pot reduction with NaBH4 in 82 and 79% yields
with 98% ee, respectively.
To establish the absolute configuration of the amino alco-
hols 4 and demonstrate the synthetic utility of the novel re-
action, amino alcohol 4b was
deprotected to amino alcohol
10, which was directly convert-
ed to Boc-protected amino al-
cohol 11 in 95% yield
(Scheme 1). Subsequent oxida-
tion gave the corresponding
naturally-occurring
Boc-pro-
tected (R)-3-amino-2-methyl-
propanoic acid 12 in high yield
as established by optical rota-
tion and comparison to the lit-
erature ([a]D =À17.5 (c=1.0 in
MeOH), lit.[19] [a]D =À18.4 (c=
2.0 in MeOH)). Thus, the direct Scheme 1. Asymmetric synthesis of Boc-protected (R)-3-amino-2-methyl-propanoic acid 12.
Chem. Eur. J. 2007, 13, 683 – 688
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685

A. Córdova et al.
Typical experimental procedure for the additive screen: The additive
(1 mmol) was added to a vial containing DMF (1 mL) and the mixture
was stirred at room temperature for 5 min. Next, the catalyst 8 was
added followed by the addition of aldehyde 2a (1 mmol) at room temper-
ature. The reaction temperature was decreased to À258C and the amino-
methyl ether 1 (0.5 mmol) was added. After 2 h of vigorously stirring,
MeOH (2 mL) was added and the b-amino aldehyde 3a was reduced in
situ with excess NaBH4 (10 mmol) to amino alcohol 4a at À258C. The re-
action temperature was then increased to 08C. After 5 min of stirring,
the solution was poured into a mixture of aqueous NH4Cl (4 mL) and
Et2O (20 mL) at 08C. Excess Na2SO4 was added to the stirred aqueous
mixture and after the solution had become clear, the drying agent was re-
moved by filtration. Next, the solvent was removed under reduced pres-
sure followed by purification of the crude product mixture by silica-gel
column chromatography (toluene/EtOAc 2:1) to afford g-amino alcohol
4a as a clear oil. The ee of 4a was determined by chiral-phase HPLC
analysis.
group of the amino acid catalyst. Hence, the chiral pyrroli-
dine and proline-catalyzed a-aminomethylation reaction
plausibly occurs via completely different transition states.
Conclusion
We report the direct catalytic asymmetric a-aminomethyla-
tion of aldehydes. The simple amino acid and chiral pyrroli-
dine-catalyzed reactions are highly chemo- and enantioselec-
tive. The diarylprolinol-catalyzed reactions furnished the
corresponding dibenzyl protected g-amino alcohols in high
yields with up to 98% ee after in situ reduction. In this case,
the enantioselectivity was increased by the presence of achi-
ral lithium halide salts. Notably, the a-aminomethylation re-
action is a novel entry for the asymmetric synthesis of b2-
amino acids. Moreover, the a-aminomethylation reaction
shows that imine equivalents with a readily removable pro-
tective group can be used in organocatalytic Mannich-type
reactions. Further elaboration of this transformation, density
functional studies, and its synthetic applications to natural
product synthesis are ongoing.
Typical experimental procedure: (see Table 3, entry 1) To a vial contain-
ing DMF (1 mL) was added LiBr (1 mmol) and the mixture was stirred
at room temperature until it had become homogeneous. Next, the cata-
lyst 8 (20 mol%) and acetic acid (20 mol%) were added followed by the
addition of aldehyde 2a (1 mmol) at room temperature. The reaction
temperature was decreased to À258C and the aminomethyl ether 1
(0.5 mmol) was added. After 2 h of vigorously stirring, MeOH (2 mL)
was added and the b-amino aldehyde 3a was reduced in situ with excess
NaBH4 (10 mmol) to amino alcohol 4a at À258C. The reaction tempera-
ture was then increased to 08C. After 5 min of stirring, the solution was
poured into a mixture of aqueous NH4Cl (4 mL) and Et2O (20 mL) at
08C. Excess Na2SO4 was added to the stirred aqueous mixture, and after
the solution had become clear, the drying agent was removed by filtra-
tion. Next, the solvent was removed under reduced pressure followed by
purification of the crude product mixture by silica-gel column chromatog-
raphy (toluene/EtOAc 2:1) to afford g-amino alcohol 4a in 80% yield as
a clear oil. The ee of 4a was 96% as determined by chiral-phase HPLC
analysis.
Compound (2R)-4a: 1H NMR (CDCl3, 400 MHz): d=0.80 (d, J=6.8 Hz,
3H), 0.85 (d, J=6.8 Hz, 3H), 1.48 (m, 1H), 1.90 (m, 1H), 2.48 (m, 1H),
2.69 (m, 1H), 3.15 (d, J=13.1 Hz, 2H), 3.34 (m, 1H), 3.72 (m, 1H), 4.02
(d, J=13.1 Hz, 2H), 5.38 (brs, 1H), 7.28–7.37 ppm (m, 10H); 13C NMR
(100 MHz): d=20.0, 20.4, 28.8, 42.0, 57.9, 59.3 (2C), 67.2, 127.6, 128.7,
129.6, 138.0 ppm; HPLC (Daicel Chiralpak OD-H, isohexanes/iPrOH
97:3, flow rate: 0.5 mLminÀ1, l=257 nm): major isomer: tR =19.31 min,
minor isomer: tR =23.52 min; [a]D =À58.5 (c=1.0 in CHCl3); MALDI-
TOF MS: calcd for C20H27NO: 320.1990 [M+Na]+; found: 320.1991.
Experimental Section
General: Chemicals and solvents were either purchased puriss p.A. from
commercial suppliers or purified by standard techniques. Amino methyl
ether 1 was synthesized according to literature procedures.[21] For TLC,
silica gel plates Merck 60 F254 were used and compounds were visualized
by irradiation with UV light and/or by treatment with a solution of phos-
phomolybdic acid (25 g), CeACHTREU(NG SO4)2·H2O (10 g), conc. H2SO4 (60 mL), and
H2O (940 mL) followed by heating or by treatment with a solution of p-
anisaldehyde (23 mL), conc. H2SO4 (35 mL), acetic acid (10 mL), and
ethanol (900 mL) followed by heating. Flash chromatography was per-
formed by using silica gel Merck 60 (particle size 0.040–0.063 mm), 1H
and 13C NMR spectra were recorded on Varian AS 400. Chemical shifts
are given in d relative to TMS, and the coupling constants J are given in
Hz. The spectra were recorded in CDCl3 at room temperature, and TMS
served as internal standard (d=0 ppm) for 1H NMR. CDCl3 was used as
internal standard (d=77.0 ppm) for 13C NMR. HPLC was carried out by
using a Waters 2690 Millennium with photodiode array detector. Optical
Typical experimental procedure for chiral pyrrolidine 8-catalyzed direct
a-aminomethylation of aldehydes: LiBr (1 mmol) was added to a vial
containing DMF (1 mL) and the mixture was stirred at room temperature
until it became homogeneous. Next, the catalyst 8 (20 mol%) and acetic
acid (20 mol%) were added followed by the addition of aldehyde 2
(1 mmol) at room temperature. The reaction temperature was decreased
to À258C and the aminomethyl ether 1 (0.5 mmol) was added. After 2 h
of vigorously stirring, MeOH (2 mL) was added and the b-amino alde-
hyde 3 reduced in situ with excess NaBH4 (10 mmol) to amino alcohol 4
at À258C. The reaction temperature was then increased to 08C. After
5 min of stirring, the solution was poured into a mixture of aqueous
NH4Cl (4 mL) and Et2O (20 mL) at 08C. Excess Na2SO4 was added to
the stirred aqueous mixture, and after the solution had become clear, the
drying agent was removed by filtration. Next, the solvent was removed
under reduced pressure followed by purification of the crude product
mixture by silica-gel column chromatography (toluene/EtOAc mixtures)
to afford g-amino alcohol 4 as a clear oil. The ee of 4 was determined by
chiral-phase HPLC analysis.
rotations were recorded on
a Perkin–Elemer 241 Polarimeter (l=
589 nm, 1 dm cell). High-resolution mass spectra were recorded on an
IonSpec FTMS mass spectrometer with a DHB-matrix and a Bruker Mi-
crOTOF spectrometer.
Typical experimental procedure for the catalyst screen: The catalyst
(20 mol%), followed by aldehyde 2a (1 mmol) was added to a vial con-
taining the solvent (1 mL) at room temperature. Next, the reaction tem-
perature was set to the value shown in Table 1 and the aminomethyl
ether 1 (0.5 mmol) was added. After vigorously stirring for the time
shown in the table, MeOH (2 mL) was added and the b-amino aldehyde
3a was reduced in situ with excess NaBH4 (10 mmol) to amino alcohol
4a at À258C. Next, the reaction temperature was increased to 08C. After
5 min of stirring, the solution was poured into a mixture of aqueous
NH4Cl (4 mL) and Et2O (20 mL) at 08C. Excess Na2SO4 was added to
the stirred aqueous mixture and after the solution had become clear, the
drying agent was removed by filtration. The solvent was then removed
under reduced pressure followed by purification of the crude product
mixture by silica-gel column chromatography (toluene/EtOAc 2:1) to
afford g-amino alcohol 4a as a clear oil. The ee of 4a was determined by
chiral-phase HPLC analysis.
Compound (2R)-4b: 1H NMR (CDCl3, 400 MHz): d=0.71 (d, J=6.7 Hz,
3H), 2.27 (m, 1H), 2.40 (m, 1H), 2.55 (m, 1H), 3.16 (d, J=13.2 Hz, 2H),
3.26 (m, 1H), 3.61 (m, 1H), 4.02 (d, J=13.2 Hz, 2H), 5.49 (brs, 1H),
7.30–7.40 ppm (m, 10H); 13C NMR (100 MHz): d=15.2, 31.7, 59.2 (2C),
61.6, 70.7, 127.5, 128.7, 129.4, 138.2 ppm; HPLC (Daicel Chiralpak OD-
H, isohexanes/iPrOH 99:1, flow rate: 0.5 mLminÀ1, l=257 nm): major
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Chem. Eur. J. 2007, 13, 683 – 688

a-Aminomethylation of Aldehydes
FULL PAPER
isomer: tR =36.70 min, minor isomer: tR =43.30 min; [a]D =À46.4 (c=1.0
in CHCl3); HRMS (ESI): m/z: calcd for C18H24NO: 270.1852 [M+H]+;
found: 270.1846.
removed under reduced pressure followed by purification of the crude
product 12 by silica-gel column chromatography (pentane/EtOAc 1:5) to
afford b2-amino acid 12 as
a
solid (73% yield). 1H NMR (CDCl3,
1
400 MHz): d=1.20 (d, J=7.0 Hz, 3H), 1.42 (s, 9H), 1.81 (m, H), 3.01 (m,
1H), 3.20 (m, 1H), 3.31 (m, 1H), 5.05 ppm (brs, 1H); 13C NMR
(100 MHz): d=14.8, 28.6, 40.2, 42.9, 79.8, 156.3, 181.0 ppm; [a]D =À17.5
(c=1.0 in MeOH), lit.[19] [a]D =À18.4 (c=2.0 in MeOH).
(S)-Proline-catalyzedsynthesis of ent-3a: (S)-Proline (20 mol%) fol-
lowed by aldehyde 2a (1 mmol) was added to a vial containing the sol-
vent (1 mL) at À208C. Next, the aminomethyl ether 1 (0.5 mmol) was
added. After vigorously stirring for 5 h, the reaction was quenched by ex-
traction with aqueous NH4Cl solution (4 mL) and Et2O (3”20 mL). The
organic phase was then dried with Na2SO4. The drying agent was re-
moved by filtration and the solvent was removed under reduced pressure
followed by purification of the crude product ent-3a by silica-gel column
chromatography (pentane/EtOAc 10:1) to afford b-amino aldehyde 3a as
a clear oil (66% yield, 54% ee).
Compound ent-3a: 1H NMR (400 MHz, CDCl3): d=0.84 (d, J=6.8 Hz,
3H), 0.92 (d, J=6.8 Hz, 3H), 1.81–1.86 (m, 1H), 2.33–2.38 (m, 1H), 2.52
(dd, J=12.8, 4.4 Hz, 1H), 2.90 (dd, J=12.8, 11.2 Hz, 1H), 3.25 (d, J=
13.6 Hz, 2H), 3.80 (d, J=13.6 Hz, 2H), 7.22–7.34 (m, 10H), 9.32 ppm (d,
J=4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=20.3, 20.5, 27.6, 51.6,
56.4, 58.6, 127.2, 128.4, 129.2, 139.1, 205.4 ppm; [a]2D5 =+25.0 (c=1.0 in
CHCl3); the ee was determined by HPLC on Daicel Chiralpak ODH
with isohexanes/iPrOH (99:1) as the eluent: major isomer: tR =12.94 min,
minor isomer: tR =14.66 min; HRMS (ESI): m/z: calcd for C20H26NO:
296.2009 [M+H]+; found: 296.2006.
Compound (2R)-4c: H NMR (CDCl3, 400 MHz): d=2.29–2.39 (m, 3H),
2.46 (m, 1H), 2.58 (m, 1H), 3.15 (d, J=13.1 Hz, 2H), 3.31 (m, 1H), 3.68
(m, 1H), 3.94 (d, J=13.1 Hz, 2H), 5.38 (brs, 1H), 7.18–7.34 ppm (m,
15H); 13C NMR (100 MHz): d=36.7, 38.7, 59.1, 59.2, 68.6, 59.2 (2C),
68.6, 127.6, 128.6, 128.7, 129.1, 129.5, 138.0, 140.1 ppm; HPLC (Daicel
Chiralpak OD-H, isohexanes/iPrOH 97:3, flow rate: 0.5 mLminÀ1, l=
257 nm): major isomer: tR =38.21 min, minor isomer: tR =58.42 min;
[a]D =À51.2 (c=1.0 in CHCl3). HRMS (ESI): m/z: calcd for C24H28 NO:
346.2165 [M+H]+; found: 346.2169.
Compound (2R)-4d: 1H NMR (CDCl3, 400 MHz): d=0.89 (t, J=7.2 Hz,
3H), 1.02 (m, 2H), 1.22–1.32 (m, 6H), 2.05 (m, 1H), 2.45 (m, 1H), 2.55
(m, 1H), 3.15 (d, J=13.1 Hz, 2H), 3.25 (m, 1H), 3.70 (m, 1H), 4.04 (d,
J=13.1 Hz, 2H), 5.66 (brs, 1H), 7.26–7.40 ppm (m, 10H); 13C NMR
(100 MHz): d=14.2, 22.7, 27.1, 30.1, 32.2, 36.6, 59.2 (2C), 60.4, 69.2,
127.6, 128.7, 129.5, 138.1 ppm; HPLC (Daicel Chiralpak OD-H, isohex-
anes/iPrOH 97:3, flow rate: 0.5 mLminÀ1, l=257 nm): major isomer: tR =
18.14 min, minor isomer: tR =20.10 min; [a]D =À56.4 (c=1.0 in CHCl3).
HRMS (ESI): m/z: calcd for C22H32NO: 326.2478 [M+H]+; found:
326.2484.
Compound (2R)-4e: 1H NMR (CDCl3, 400 MHz): d=1.83 (m, 2H), 2.17
(m, 1H), 2.49 (m, 1H), 2.57 (m, 1H), 3.18 (d, J=13.1 Hz, 2H), 3.28 (m,
1H), 3.70 (m, 1H), 4.02 (d, J=13.1 Hz, 2H), 5.00 (m, 2H), 5.36 (brs,
1H), 5.74 (m, 1H), 7.28–7.40 ppm (m, 10H); 13C NMR (100 MHz): d=
34.6, 36.5, 59.3 (2C), 59.5, 68.6, 116.6, 127.6, 128.8, 129.5, 136.3,
138.1 ppm; HPLC (Daicel Chiralpak OD-H, isohexanes/iPrOH 97:3, flow
(2S)-N,N-Dibenzyl-2-aminomethyl-3-methylbutanoic
acid:
KH2PO4
rate: 0.5 mLminÀ1
, l=257 nm): major isomer: tR =22.43 min, minor
(0.48 mmol), 2-methyl-2-butene (1.9 mmol), and NaClO2 (0.95 mmol)
were added to a stirred solution of amino aldehyde ent-3a (0.24 mmol),
synthesized by (S)-proline catalysis, in tBuOH/H2O (5:1, 3.0 mL). The
mixture was stirred for 17 h and turned from yellow to colorless. The re-
action mixture was then concentrated under reduced pressure, extracted
with EtOAc, and washed with H2O and brine. The organic extracts were
dried with Na2SO4. The drying agent was removed by filtration and the
solvent was removed under reduced pressure followed by purification of
the crude product by silica-gel column chromatography (toluene/EtOAc
2:1) to afford the corresponding 2-aminomethyl-3-methylbutanoic acid as
a clear oil (72% yield). 1H NMR (300 MHz, CDCl3): d=0.86 (d, J=
6.9 Hz, 3H), 0.94 (d, J=6.9 Hz, 3H), 2.34–2.37 (m, 1H), 2.48 (m, 1H),
2.61 (dd, J=12.3, 4.5 Hz, 1H), 2.92 (t, J=12.3 Hz, 1H), 3.50 (d, J=
13.5 Hz, 2H), 3.95 (d, J=13.5 Hz, 2H), 7.19–7.37 (m, 10H), 11.62 ppm
(brs, 1H); 13C NMR (75 MHz, CDCl3): d=18.6, 20.2, 27.4, 45.8. 50.9,
57.8, 128.3, 128.9, 129.7, 135.3, 175.8 ;
isomer: tR =31.71 min; [a]D =À52.0 (c=1.0 in CHCl3). HRMS (ESI):
calcd for C20H26 NO: 296.2009 [M+H]+; found: m/z: 296.2019.
Compound (2R)-4 f: 1H NMR (400 MHz, CDCl3): d=0.00 (s, 6H), 0.84
(s, 9H), 2.19–2.24 (m, 1H), 2.43 (dd, J=12.4, 4.4 Hz, 1H), 2.57 (dd, J=
12.4, 10.4 Hz, 1H), 3.26 (d, J=13.2 Hz, 2H), 3.38 (dd, J=10.4, 6.8 Hz,
1H), 3.45–3.55 (m, 2H), 3.69 (dd, J=10.4, 4.4 Hz, 1H), 3.87 (d, J=
13.2 Hz, 2H), 4.68 (brs, 1H), 7.25–7.33 ppm (m, 10H); 13C NMR
(75 MHz, CDCl3): d=À5.4, 18.3, 26.0, 39.8, 55.5, 59.1 (2C), 64.1, 66.5,
127.4, 128.6, 129.3, 138.4 ppm; [a]D =À31.5 (c=1.0 in CHCl3); the alco-
hol 4 f was acetylated and the ee was determined by HPLC (Daicel Chir-
alpak OD-H, isohexanes/iPrOH 99:1, flow rate: 0.5 mLminÀ1
257 nm): major isomer: tR =14.03 min; minor isomer: tR =15.71 min.
HRMS (ESI): m/z: calcd for C22H32NO2Si: 370.2196 [M+H]+; found:
370.2205.
, l=
(R)-3-[(tert-Butoxycarbonyl)amino]-2-methylpropan-1-ol
(11):[19]
b-
[a]2D5 =+26.3 (c=1.0 in CHCl3).
Amino alchol 4b (2 mmol) in MeOH (10.0 mL) was treated with a cata-
lytic amount of Pd/C. After 17 h of hydrogenolysis (90mPa), the catalyst
was filtered off by using Celite and the solvent concentrated to 4 mL.
The g-amino alcohol 10 was Boc-protected by addition of triethylamine
(400 mL) and di-tert-butyldicarbonate (0.54 g, 2.5 mmol). After 1 h of stir-
ring, the solvent was removed under reduced pressure, the residue was
dissolved in CH2Cl2 and the solution was washed twice with KHSO4 (1m)
and once with brine. The organic layer was dried with Na2SO4, filtered,
and concentrated. The crude amino alcohol 11 was purified by silica-gel
column chromatography (toluene/EtOAc 2:1) to give 11 as a clear vis-
HRMS (ESI): m/z: calcd for
C20H26NO2: 312.1958 [M+H]+; found:
312.1956.
Acknowledgements
We gratefully acknowledge the Swed-
1
cous oil (95% yield). H NMR (CDCl3, 400 MHz): d=0.83 (d, J=7.0 Hz,
ish National Research council and Carl-Trygger Foundation for financial
support. We thank Prof. Dr. H. Adolfsson, Prof. J-E. Bäckvall, and Dr.
A. Zaitsev for valuable discussions.
3H), 1.40 (s, 9H), 1.72 (m, 1H), 3.01 (m, 1H), 3.19 (m, 1H), 3.31 (m,
1H), 3.54 (m, 1H), 5.05 ppm (brs, 1H); 13C NMR (100 MHz): d=14.6,
28.5, 36.4, 42.8, 64.6, 79.7, 157.6 ppm; [a]D =À17.1 (c=1.0 in CHCl3).[19]
[19]
(R)-3-[(tert-Butoxycarbonyl)amino]-2-methylpropanoic
acid(12)
:
RuCl3 hydrate (0.03 mmol) was added to a solution of alcohol (R)-11
(1.2 mmol), sodium periodate (3.5 mmol), CCl4 (2.5 mL), CH3CN
(2.5 mL), and H2O (3.8 mL), and the mixture was stirred at room temper-
ature for 1 h. After this time, the mixture was diluted with CH2Cl2
(10 mL) and then filtered through Celite. The filtrated solution was basi-
fied with K2CO3 (2m) solution, and the water layer was washed with
ether. The aqueous layer was acidified with KHSO4 (1m) at 08C and ex-
tracted with CH2Cl2. The combined organic extracts were dried with
Na2SO4. The drying agent was removed by filtration and the solvent was
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Received: May 24, 2006
Published online: October 13, 2006
688
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 683 – 688