Efficient entry to amino sugars and derivatives via asymmetric organocatalytic Mannich reactions

Article abstract of DOI:10.1055/s-2006-942542

An efficient biomimetic C₃+C_n entry to amino sugars and derivatives via a direct asymmetric organocatalytic Mannich methodology employing 2,2-dimethyl-1,3-dioxan-5-one as a dihydroxyacetone phosphate equivalent and N-PMP or N-Boc pro

Full text of DOI:10.1055/s-2006-942542

PAPER
3597
Efficient Entry to Amino Sugars and Derivatives via Asymmetric
Organocatalytic Mannich Reactions
A
mino Sugars via
i
A
sym
m
e
etric
O
rga
t
nocatal
e
ytic Manni
r
h
Reactions Enders,* Christoph Grondal, Marianna Vrettou
Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 19 May 2005
Dedicated to Professor Martin F. Semmelhack on the occasion of his 65th birthday
cle is aimed at enlarging the scope of this methodology.
Thus, the existing methodology has been broadened to in-
corporate an organocatalytic Mannich reaction employing
N-Boc imines, as well as further elaboration of the result-
Abstract: An efficient biomimetic C3+Cn entry to amino sugars and
derivatives via a direct asymmetric organocatalytic Mannich meth-
odology employing 2,2-dimethyl-1,3-dioxan-5-one as a dihydroxy-
acetone phosphate equivalent and N-PMP or N-Boc protected
imines has been developed. The Mannich bases were obtained in ing Mannich bases via diastereoselective reduction and
high diastereo- and enantiomeric excesses (78% to >99% de, 81–
direct reductive amination reactions.
98% ee) and were further elaborated using diastereoselective reduc-
tion protocols, as well as via diastereoselective direct reductive
Initially, the three-component organocatalytic Mannich
reaction between the dihydroxyacetone equivalent 2,2-
dimethyl-1,3-dioxan-5-one (1),15 p-anisidine (2) and vari-
ous aldehydes 3 was investigated (Scheme 1). The ob-
served syn configuration of the products 4 has been
previously confirmed.13a
amination reactions.
Key words: organocatalysis, Mannich reaction, amino sugars,
asymmetric synthesis, reductive amination
A wide range of aldehydes was screened and to our de-
light the corresponding Mannich bases were obtained in
moderate to excellent yields and with good to excellent
diastereo- and enantioselectivities employing proline (S)-
5 and the TBS-protected hydroxy proline 6 as catalysts.
We could show that 6 is often the catalyst of choice re-
garding stereoselectivity and yield (Table 1).
The rapidly developing area of organocatalysis has at-
tracted much attention during the past few years and in
particular the development of asymmetric reactions cata-
lyzed by proline.1 The Mannich reaction represents a
powerful tool of organic synthetic chemistry and has
found broad application in the preparation of synthetic
building blocks, especially aimed towards the synthesis of
natural products and biologically active compounds.2,3
The direct proline-catalyzed asymmetric three-compo-
nent Mannich reaction was first reported by List4 and Bar-
bas.5,6 Although proline has been used as an efficient
organocatalyst,1,7 its derivatives have also been studied
and successfully employed in a number of cases.8 Amino
sugars comprise a class of carbohydrates where one or
more hydroxyl groups have been replaced by amino
groups. They are found as components of glycoproteins,
glycolipids, aminoglycosides, as well as numerous bio-
logically active secondary metabolites.9 They play impor-
tant physiological roles and are of potential interest for the
development of novel drugs.10 As a result, there is a wide
range of approaches for the preparation of amino sugars.
The major part of these use naturally occurring carbohy-
drates and involve several protecting group manipula-
tions, as well as oxidation–reduction steps.11
Alternatively, a linear sequence is employed, which gen-
erally requires numerous reaction steps.12 We recently
reported the development of a diastereo- and enantio-
selective organocatalytic Mannich reaction which paves
the way to selectively protected amino sugars and their
unnatural derivatives in one step13,14 and the current arti-
OCH3
O
O
NHPMP
R
10–30 mol% cat.
solvent, 2 °C
O
+
+
H
R
O
O
O
O
57–98%
3
H3C CH3
H3C CH3
NH2
1
4
2
(de = 78 to >99%,
ee = 69–98%)
TBSO
cat.:
CO2H
CO2H
N
H
N
H
(S)-5
6
Scheme 1 Direct organocatalytic Mannich reactions via N-p-meth-
oxyphenyl imines
In the case of a-substituted aldehydes bearing a stereogen-
ic center (4d-h), (S)-proline was found to be the appropri-
ate catalyst for R-configured substrates, whereas (R)-
proline was employed in the case of S-configured com-
pounds.
In several cases, the organocatalysis was also performed
at different temperatures in an attempt to optimize the se-
lectivities observed. Despite the fact that initially there
seemed to be a trend of decreasing selectivity at lower
SYNTHESIS 2006, No. 21, pp 3597–3604
Advanced online publication: 02.08.2006
DOI: 10.1055/s-2006-942542; Art ID: Z10206SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
6

3598
D. Enders et al.
PAPER
Table 1 Catalytic Asymmetric Three-Component Mannich Reaction of Dioxanone 1 with p-Anisidine (2) and Aldehydes 3 To Give the
Corresponding b-Aminoketones 4a
4
R
Cat. (mol%)
(S)-5 (30)
6 (20)
Yield (%)b
Solvent
DMF
DMF
DMF
DMF
NMP
NMP
NMP
MeCN
Water (equiv)
de (%)c
>99d
>99d
96
ee (%)d
98
ae
ae
b
b
c
CH(OCH3)3
CH(OCH3)3
CO2Et
91
98
91
94
68
70
94
69
4
4
3
–
–
3
3
5
93
(S)-5 (10)
6 (20)
98
CO2Et
96
95
CO2Bn
CO2Et
(S)-5 (30)
6 (20)
96
96
c
96
93
d
d
CH2OBn
CH2OBn
(S)-5 (30)
6 (20)
60d
82
88d
96
80 (≥96)f
98g
96g
96g
O
O
e
f
(S)-5 (30)
(R)-5 (30)
(R)-5 (30)
57
67
63
DMF
DMF
DMF
–
–
–
CH3
H3C
O
96
96
BocN
CH3
H3C
O
g
CbzN
H3C
CH3
Cbz
(S)-5 (30)
6 (20)
83
85
MeCN
MeCN
–
–
86
96
96g
96g
N
h
i
N
(S)-5 (10)
6 (20)
67
70
NMP
NMP
–
3
96
96
51
81
Cl
(S)-5 (30)
6 (20)
75
96
DMF
MeCN
2
5
60
78
67
87
j
k
6 (20)
96
MeCN
5
78d
78
NO2
a General reaction conditions: dioxanone 1 (0.77 mmol), p-anisidine (2; 0.42 mmol), aldehyde 3 (0.38 mmol), catalyst (10-30 mol%), solvent
(1 mL), 2 °C, 25 d.
b Yields of 4 after flash chromatography on silica gel.
c Determined by 1H NMR and 13C NMR spectroscopy.
d Determined by HPLC on chiral stationary phases (Daicel Chiralpak AD, Daicel Chiralcel OD).
e Full characterization of 4a was previously reported.13a,
f After flash chromatography on silica gel.
g Based on the ee value of the corresponding aldehydes 3.
temperatures,13a following further investigation, the vari- carrying out the reaction in two different solvents (DMF
ation of selectivity with temperature seems to be sub- and NMP) and at three different temperatures support the
strate-dependent (Table 2).
opposite.
In the case of 4d, for instance, the results collected from Due to their reactivity and pure E geometry, PMP imines
performing the reaction in NMP at three different temper- have so far dominated this area of research. The use of dif-
atures support a downward trend with decreasing temper- ferently protected imines, however, would also be of in-
ature, whereas in the case of 4k, the data obtained from terest and we are pleased to report that equally satisfactory
Synthesis 2006, No. 21, 3597–3604 © Thieme Stuttgart · New York

PAPER
Amino Sugars via Asymmetric Organocatalytic Mannich Reactions
3599
Table 2 Variation of Diastereomeric and Enantiomeric Excess Val-
ues with Increasing Temperature
4a
Me4NHB(OAc)3,
AcOH, MeCN,
L-Selectride,
THF, –78 °C
–30 °C to –24 °C
4a
Solvent
–10 °C
2 °C
25 °C
98%
77%
de, ee (%)
de, ee (%)
de, ee (%)
OH NHPMP
OH NHPMP
d
k
k
NMP
DMF
NMP
46, 49
66, 29
71, 60
76, 80
60, 15
72, 60
55, 81
70, 12
76, 45
OCH3
OCH3
O
O
OCH3
O
O
OCH3
H3C CH3
H3C CH3
12, de ≥96%
a Compound (S)-5 was used as organocatalyst.
11, de ≥96%
Scheme 3 Diastereoselective syn- and anti-reduction of 4a
results were obtained in the case of (E)-Boc imines 7 and
816 (Scheme 2). To the best of our knowledge this is the
first example of an organocatalytic Mannich reaction em-
ploying Boc imines. We recently reported a concise syn-
thesis of (+)-polyoxamic acid starting from the Mannich
base 10.13b The use of Boc imines complements that of
PMP imines since the Boc group can be easily removed
under acidic instead of oxidative conditions. To our de-
light the stereoselectivities are nearly perfect and we ob-
tained only the syn-Mannich product. We therefore
propose the transition state which is depicted in Scheme 2
and is based on List’s model.4
OH NHPMP
(CH3)4NBH(OAc)3, AcOH,
MeCN, –30 °C to –24 °C
CO2Et
4b
O
O
90%
H3C CH3
13, de ≥96%
Scheme 4 Diastereoselective anti-reduction of 4b
OH NHBoc
L-Selectride,
THF, –78 °C
Ph
9
O
NHBoc
R
Boc
80%
O
O
(S)-5 (30 mol%)
CF3CH2OH, r.t.
N
1
+
H3C CH3
H
R
O
O
7, R = Ph
8, R = 2-furyl
14, de ≥96%
H3C CH3
9, R = Ph, 85%, de ≥99, ee = 96%
10, R = 2-furyl, 85% de >96%, ee = 92%
Scheme 5 Diastereoselective syn-reduction of 9
9 using Me4NHB(OAc3) failed and resulted in quantita-
tive recovery of the starting material.
O
H
O
N
H
Alternatively, the derivatization of the Mannich products
is possible, e.g. via diastereoselective direct reductive am-
ination, as illustrated for 4a and 4c (Schemes 6 and 7).
The direct reductive amination was carried out using
NaHB(OAc)3, BnNH2 and acetic acid. This protocol in-
cludes an in situ imine formation, followed by a highly
chemo- and diastereoselective reduction of the imine.18
The diamine 15 also represents a protected aminosugar, in
this case the protected 2,4-diamino-2,4-dideoxy-L-xylose.
t-BuO
N
O
R2
R3
R1
Scheme 2 Organocatalytic Mannich reaction using Boc imines
Further elaboration of the Mannich products into the cor-
responding b-amino alcohols is also possible as exempli-
fied for 4a, 4b and 9. In the case of 4a (Scheme 3) it was
possible to access both diastereoisomers (syn17 and anti)
with high selectivities, whereas with 4b only the anti iso-
mer could be selectively obtained (Scheme 4). These b-
aminoalcohols 11 and 12 represent the selectively and or-
thogonal protected 2-amino-2-deoxyaldopentoses 2-ami-
no-2-deoxy-D-arabinose (11) and 2-amino-2-deoxy-L-
xylose (12), whereas 13 constitutes a protected 4-epi-(+)-
polyoxamic acid.
Bn
NH NHPMP
NaHB(OAc)3, BnNH2,
CH2Cl2, 2 °C
OCH3
4a
73%
O
O
OCH3
H3C CH3
15, de ≥96%
Scheme 6 syn-Selective direct reductive amination of 4a
In addition, we have also carried out the diastereoselective
reduction of the Mannich base 9. The syn b-aminoalcohol
14 was also obtained with high diastereoselectivity
(Scheme 5). All attempts for an anti selective reduction of
Interestingly, the direct reductive amination of the 4c was
followed by in situ cyclization to afford a 10:1 mixture of
16 and 17, which can be easily separated by column chro-
matography.
Synthesis 2006, No. 21, 3597–3604 © Thieme Stuttgart · New York

3600
D. Enders et al.
PAPER
stored for 5 d at 2 °C before quenching with a pH 7 phosphate buffer
(200 mL). The resulting biphasic mixture was stirred for an addi-
tional 15 min at r.t. before addition of Et2O (200 mL) and separation
of the phases. The aqueous layer was extracted with Et2O (3 × 100
mL) and the combined extracts were dried over Na2SO4. Evapora-
tion of the solvent under reduced pressure, followed by flash chro-
matography (silica gel, n-pentane-Et2O, 2:1), afforded the desired
product 4b as a slightly yellow oil (4.14 g, 91%); ee = 98% [HPLC
analysis: Daicel OD at r.t., n-heptane-i-PrOH = 80:20 (0.5 mL/
O
BnN
NHPMP
O
O
H3C CH3
NaHB(OAc)3,
AcOH, BnNH2,
CH2Cl2, 2 °C
16
4c
+
O
24
min), t1 = 10.5 min (minor), t2 = 13.3 min (major)]; [a]D –88.0
99%
(c = 1.00, CHCl3).
BnN
IR (CHCl3): 3395, 2990, 2940, 2838, 1845, 1798, 1744, 1714, 1652,
1620, 1575, 1513, 1463, 1367, 1280, 1231, 1158, 1096, 1032, 968,
906, 828, 667, 613, 530 cm–1.
1H NMR (400 MHz, C6D6): d = 0.84 (t, J = 7.1 Hz, 3 H), 1.16 (s, 3
H), 1.22 (s, 3 H), 3.31 (s, 3 H), 3.71-3.83 (m, 2 H), 3.92-4.00 (m,
2 H), 4.67 (app t, J = 1.8 Hz, 1 H), 4.80 (d, J = 2.5 Hz, 1 H), 6.70-
6.74 (m, 2 H), 6.76-6.80 (m, 2 H).
13C NMR (100 MHz, C6D6): d = 14.1 (CH3), 23.1 (CH3), 24.3
(CH3), 55.0 (CH3), 59.7 (CH), 61.1 (CH2), 67.1 (CH2), 77.0 (CH),
100.5 (C), 114.9 (CH), 117.3 (CH), 141.4 (C), 154.1 (C), 171.0 (C),
205.3 (C).
NHPMP
O
O
H3C CH3
17
Scheme 7 Diastereoselective direct reductive amination of 4c, fol-
lowed by in situ lactamization
In conclusion, the scope of a direct asymmetric organocat-
alytic Mannich reaction using 2,2-dimethyl-1,3-dioxan-5-
one as a dihydroxyacetone equivalent and PMP-imines
derived from structurally diverse aldehydes has been suc-
cessfully enlarged via diastereoselective reduction and di-
rect reductive amination reactions. Furthermore, initial
examples of this methodology adapted to Boc imines have
also given excellent results. Overall, this biomimetic
C3+Cn methodology represents a concise and efficient
way to access amino sugars and derivatives of this impor-
tant class of biomolecules.
MS (CI, methane): m/z = 338 [M + H]+.
Anal. Calcd for C17H23NO6: C, 60.52; H, 6.87; N, 4.15. Found: C,
60.37; H, 6.75; N, 4.24.
4d
According to GP 1, dioxanone 1 (200 mg, 1.54 mmol), benzoyloxy-
acetaldehyde (3d; 114 mg, 0.77 mmol), p-anisidine (2; 102 mg, 0.84
mmol) and (S)-6 (36 mg, 0.16 mmol) were reacted in MeCN con-
taining H2O (8 mL, 5 equiv) for 40 h. After purification by column
chromatography (silica gel, n-pentane-Et2O = 2:1), 4d was ob-
tained as a colorless solid (226 mg, 77%); mp 51-52 °C; ee = 96%
[HPLC analysis: Daicel OD at r.t., n-heptane-i-PrOH = 80:20 (0.8
mL/min); t1 = 10.6 min (major), t2 = 13.5 min (minor)]; [a]D22 –94.3
(c = 0.95, CHCl3).
All solvents were dried by conventional methods. Starting materials
and reagents were purchased from commercial suppliers and were
used without further purification unless otherwise stated. THF was
freshly distilled from Na-Pb alloy under Ar. CH2Cl2 and MeCN
were freshly distilled from CaH2 under Ar. AcOH was distilled
from CrO3 under Ar. Preparative column chromatography was per-
formed using silica gel 60, particle size 0.040-0.063 mm (230-240
mesh, flash). Analytical TLC was carried out employing silica gel
60 F254 plates. Visualization of the developed chromatograms was
performed by ultraviolet irradiation (254 nm) or staining using acid-
ic ammonium molybdate. Optical rotation values were measured on
a Perkin-Elmer P241 polarimeter. Microanalyses were obtained
with a Vario EL element analyzer. Mass spectra were recorded on a
Finnigan SSQ7000 spectrometer. High-resolution mass spectra
were recorded on a Finnigan MAT95 spectrometer. IR spectra were
IR (CHCl3): 3380, 3030, 2989, 2937, 2897, 2864, 1514, 1455, 1377,
1234, 1097, 1035, 860, 823, 749, 699 cm–1.
1H NMR (300 MHz, C6D6): d = 1.45 (s, 3 H), 1.50 (s, 3 H), 3.50 (t,
J = 9.0 Hz, 1 H), 3.61 (dd, J = 4.3, 9.0 Hz, 1 H), 3.74 (s, 3 H), 3.97
(d, J = 16.8 Hz, 1 H), 4.21 (dd, J = 1.5, 16.8 Hz, 1 H), 4.46 (d, J =
11.9 Hz, 1 H), 4.56 (d, J = 11.9 Hz, 1 H), 4.62 (app s, 1 H), 6,63 (d,
J = 8.9 Hz, 2 H), 6.74 (d, J = 8.9 Hz, 2 H), 7.25-7.35 (m, 5 H).
13C NMR (75 MHz, C6D6): d = 23.2, 24.8 (CH3), 53.9 (CH), 55.7
(CH3), 67.3, 67.8, 73.2 (CH2), 74.2 (CH), 100.4 (C), 114.9 (CH),
115.8 (CH), 127.6 (CH), 127.7 (CH), 128.4 (CH), 137.9 (C), 140.6
(C), 152.7 (C), 208.2 (C).
MS (EI): m/z = 385 [M + H]+.
1
measured on a Perkin-Elmer FT-IR 1760 spectrophotometer. H
NMR and 13C NMR spectra were recorded on Varian Mercury 300,
Inova 400 or Unity 500 spectrometers with tetramethylsilane as the
internal standard and at ambient temperature unless otherwise stat-
ed. Analytical HPLC and GC analyses were performed on Hewlett-
Packard 1100 Series and Varian CP 3800 Series chromatographs,
respectively. All racemic samples were obtained according to GP 1
using equal amounts of (S)- and (R)-proline. Compounds 4e,19 4f,20
4g,21 4h22 and 623 were synthesized by standard procedures.
Anal. Calcd for C22H27NO5: C, 68.55; H, 7.06; N, 3.63. Found: C,
68.48; H, 6.97; N, 3.79.
4e
According to GP 1, dioxanone 1 (400 mg, 3.08 mmol), (R)-2,3-O-
(isopropylidene)-D-glyceraldehyde (3e; 300 mg, 2.31 mmol), p-ani-
sidine (2; 314 mg, 2.54 mmol) and (S)-5 (81 mg, 0.70 mmol) were
reacted in DMF (23 mL) for 5 d. After purification by column chro-
matography (silica gel, n-pentane-Et2O = 2:1), 4e was obtained as
a pale yellow oil (274 mg, 96%); ee = 98% (based on the ee of the
starting aldehyde); [a]D21 +3.1 (c = 0.79, C6H6).
Organocatalytic Mannich Reaction (4b); General Procedure
(GP 1)
To a mixture of ethyl glyoxylate (3b; 2.00 mL, 13.50 mmol, 50%
solution in toluene) and p-anisidine (2; 1.66 g, 13.5 mmol) in DMF
(135 mL) at 0 °C was added (S)-5 (155 mg, 1.35 mmol), followed
by dioxanone 1 (1.76 g, 13.50 mmol). The reaction mixture was
IR (CHCl3): 3380, 2989, 2938, 2894, 2835, 1747, 1514, 1461, 1378,
1229, 1154, 1070, 1041, 896, 826, 758 cm–1.
1H NMR (400 MHz, C6D6): d = 1.23 (s, 3 H), 1.27 (6 H), 1.43 (3 H),
3.34 (s, 3 H), 3.51 (d, J = 10.2 Hz, 1 H), 3.68 (d, J = 16.7 Hz, 1 H),
Synthesis 2006, No. 21, 3597–3604 © Thieme Stuttgart · New York

PAPER
Amino Sugars via Asymmetric Organocatalytic Mannich Reactions
3601
3.82 (dd, J = 1.7, 16.7 Hz, 1 H), 3.85 (dd, J = 4.9, 8.9 Hz, 1 H), 3.90
(dd, J = 4.9, 8.9 Hz, 1 H), 4.00 (m, 1 H), 4.28 (t, J = 10.2 Hz, 1 H),
4.75 (s, 1 H), 6.60 (d, J = 9.1 Hz, 2 H), 6.69 (d, J = 9.1 Hz, 2 H).
13C NMR (100 MHz, C6D6): d = 23.0 (CH3), 24.9 (CH3), 26.1
(CH3), 27.3 (CH3), 55.0 (CH3), 57.9 (CH), 67.2 (CH2), 67.3 (CH2),
75.7 (CH), 75.9 (CH), 100.1 (C), 109.3 (C), 115.0 (CH), 116.2
(CH), 141.0 (C), 153.4 (C), 207.1 (C).
mmol) and p-anisidine (2; 528 mg, 4.29 mmol) were reacted in
MeCN (43 mL) in the presence of (S)-6 (210 mg, 0.86 mmol) for 5
d. Purification by flash chromatography (silica gel, n-pentane-
EtOAc = 85:15) afforded 4h as a pale yellow oil (1.67 g, 83%); ee
≥96% (based on the ee of the starting aldehyde); [a]D22 +33.5 (c =
1.64, CHCl3).
IR (CHCl3): 3389, 2989, 2953, 2885, 2834, 1747, 1695, 1617, 1588,
1513, 1452, 1416, 1377, 1355, 1231, 1098, 1039, 974, 902, 824,
757, 700, 667, 610, 582, 520 cm–1.
1H NMR (300 MHz, C6D6, 70 °C): d = 1.28 (s, 7 H), 1.43-1.60 (m,
2 H), 1.81-1.87 (m, 2 H), 3.00-3.06 (m, 1 H), 3.36-3.38 (m, 2 H),
3.39 (s, 3 H), 3.71 (d, J = 16.5 Hz, 1 H), 3.91 (d, J = 16.5 Hz, 1 H),
4.13 (br, 1 H), 4.34 (br, 1 H), 4.64 (app d, J = 4.1 Hz, 1 H), 5.16 (br,
1 H), 6.65 (d, J = 8.5 Hz, 2 H), 6.69 (d, J = 8.5 Hz, 2 H), 7.09 (d,
J = 7.0 Hz, 1 H), 7.16 (br, 2 H), 7.32 (d, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, C6D6, 70 °C): d = 23.4 (CH3), 24.4 (CH2), 25.0
(CH3), 27.8 (CH2), 46.8 (CH2), 55.4 (CH3), 56.4 (CH), 60.9 (CH),
67.0 (CH2), 67.3 (CH2), 100.3 (C), 115.3 (CH), 115.8 (CH), 128.3
(CH), 128.5 (CH), 137.6 (C), 142.1 (C), 153.2 (C), 155.2 (C), 206.5
(C).
MS (EI, 70 eV): m/z = 365 [M]+.
Anal. Calcd for C19H27NO6: C, 62.45; H, 7.45; N, 3.83. Found: C,
62.82; H, 7.41; N, 3.84.
4f
According to GP 1, dioxanone 1 (600 mg, 4.62 mmol), N-Boc-pro-
tected (S)-Garner aldehyde 3f (530 mg, 2.31 mmol), p-anisidine (2;
310 mg, 2.50 mmol) and (R)-5 (81 mg, 0.70 mmol) were reacted in
DMF (23 mL) for 5 d. After purification by column chromatogra-
phy (silica gel, n-pentane-Et2O = 2:1), 4f was obtained as a pale
yellow oil (718 mg, 67%); ee >96% (based on the ee of the starting
aldehyde); [a]D24 –4.7 (c = 1.35, CHCl3).
IR (CHCl3): 3397, 2980, 2937, 2835, 1748, 1692, 1515, 1463, 1375,
1241, 1172, 1097, 1045, 849, 822, 758 cm–1.
MS (EI, 70 eV): m/z = 468 [M]+, 469 [M + H]+.
1H NMR (400 MHz, C6D6, 70 °C): d = 1.29 (s, 6 H), 1.45 (s, 9 H),
1.48 (s, 3 H), 1.58 (s, 3 H), 3.39 (s, 3 H), 3.70 (dd, J = 1.3, 16.8 Hz,
1 H), 3.74 (m, 1 H), 3.87 (d, J = 16.8 Hz, 1 H), 4.05 (br, 2 H), 4.26
(d, J = 9.3 Hz, 1 H), 4.36 (br, 1 H), 4.83 (d, J = 5.2 Hz, 1 H), 6.73
(m, 4 H).
13C NMR (100 MHz, C6D6, 70 °C): d = 23.4 (CH3), 24.6 (CH3), 25.2
(CH3), 27.2 (CH3), 28.5 (CH3), 55.3 (CH3), 55.4 (CH), 60.6 (CH),
64.8 (CH2), 67.3 (CH2), 77.2 (CH), 79.9 (C), 94.1 (C), 100.3 (C),
115.3 (CH), 115.5 (CH), 142.2 (C), 152.6 (C), 153.2 (C), 206.1 (C).
HRMS: m/z [M]+ calcd for C26H32N2O6: 468.2260; found:
468.2260.
4i
According to GP 1, dioxanone 1 (1.21 g, 9.34 mmol), freshly dis-
tilled pyridine-2-carbaldehyde (3i; 1.00 g, 9.34 mmol) and p-anisi-
dine (2; 1.15 mmol, 9.34 mmol) were reacted in NMP containing
H2O (3 equiv, 93 mL) in the presence of (S)-6 (458 mg, 1.87 mmol)
for 5 d. Purification by flash chromatography (silica gel, n-pen-
tane-EtOAc = 80:20) afforded 4i as a pale yellow solid (2.14 g,
67%); ee = 81% [HPLC analysis: Daicel AD, r.t., n-heptane-i-
PrOH = 90:10 (1 mL/min), t1 = 16.9 min (minor), t2 = 25.6 min (ma-
jor)]; mp 95-98 °C; [a]D22 = –102.4 (c = 1.64, CHCl3).
MS (EI, 70 eV): m/z = 464 [M + H]+.
Anal. Calcd for C24H36N2O7: C, 62.05; H, 7.81; N, 6.03. Found: C,
62.07; H, 7.80; N, 5.84.
IR (KBr): 3424, 3367, 3057, 2991, 2937, 2866, 2834, 2367, 2344,
1747, 1593, 1513, 1438, 1378, 1328, 1241, 1177, 1098, 1039, 981,
894, 828, 763, 707, 665, 621, 582, 526, 490 cm–1.
1H NMR (300 MHz, C6D6): d = 1.03 (s, 3 H), 1.20 (s, 3 H), 3.30 (s,
3 H), 3.82 (d, J = 16.8 Hz, 1 H), 4.05 (dd, J = 1.5, 16.8 Hz, 1 H),
4.76 (br, 1 H), 5.16 (app t, J = 1.7 Hz, 1 H), 5.53 (d, J = 1.9 Hz, 1
H), 6.53-6.56 (m, 2 H) 6.57 (d, J = 9.1 Hz, 2 H), 6.67 (d, J = 9.1
Hz, 2 H), 6.98 (dt, J = 1.9, 7.5 Hz, 1 H), 8.42-8.45 (m, 1 H).
13C NMR (75 MHz, C6D6): d = 22.4 (CH3), 24.4 (CH3), 54.8 (CH3),
59.1 (CH), 67.2 (CH2), 78.5 (CH), 100.1 (C), 114.9 (CH), 115.2
(CH), 121.6 (CH), 121.7 (CH), 135.7 (CH), 140.9 (C), 148.9 (CH),
152.9 (C), 159.9 (C), 206.0 (C).
4g
According to GP 1, dioxanone 1 (600 mg, 4.62 mmol), (S)-Cbz-pro-
tected Garner aldehyde 3g (607 mg, 2.31 mmol), p-anisidine (2; 314
mg, 2.54 mmol) and (R)-5 (81 mg, 0.70 mmol) were reacted in DMF
(23 mL) for 5 d. After purification by column chromatography (sil-
ica gel, n-pentane-Et2O = 1:1), 4g was obtained as a pale yellow oil
(725 mg, 63%); ee ≥96% (based on the ee of starting aldehyde);
[a]D24 = +31.8 (c = 0.79, C6H6).
IR (CHCl3): 3396, 2988, 2940, 2882, 2832, 2362, 2335, 1747, 1701,
1515, 1460, 1408, 1378, 1350, 1241, 1158, 1094, 1049, 904, 825,
757, 700 cm–1.
1H NMR (400 MHz, C6D6, 70 °C): d = 1.22 (s, 3 H), 1.28 (s, 3 H),
1.46 (s, 3 H), 1.60 (s, 3 H), 3.39 (s, 3 H), 3.67-3.74 (m, 2 H), 3.89
(d, J = 16.5 Hz, 1 H), 4.10 (br, 2 H), 4.18 (dd, J = 1.7, 9.3 Hz, 1 H),
4.33 (br, 1 H), 4.72 (d, J = 5.0 Hz, 1 H), 5.14 (s, 2 H), 6.58-6.69 (m,
4 H), 7.05-7.35 (m, 5 H).
13C NMR (100 MHz, C6D6, 70 °C): d = 22.8 (CH3), 24.1 (CH3), 24.8
(CH3), 26.2 (CH3), 55.1 (CH3), 55.2 (CH), 60.3 (CH), 64.7 (CH2),
66.8 (CH2), 67.0 (CH2), 76.5 (CH), 94.2 (C), 99.9 (C), 115.0 (CH),
115.1 (CH), 127.5 (C), 127.8 (CH), 128.1 (CH), 128.3 (CH), 136.6
(C), 141.5 (C), 152.9 (C), 205.8 (C).
MS (CI, methane): m/z = 343 [M + H]+.
Anal. Calcd for C19H22N2O4: C, 66.65; H, 6.48; N, 8.18. Found: C,
66.33; H, 6.38; N, 8.20.
4j
According to GP 1, dioxanone 1 (200 mg, 1.54 mmol), o-chloroben-
zaldehyde (3j; 108 mg, 0.77 mmol), p-anisidine (2; 102 mg, 0.84
mmol) and (S)-5 (36 mg, 0.16 mmol) were reacted in DMF contain-
ing H2O (8 mL, 2 equiv) for 40 h. After purification by column
chromatography (silica gel, n-pentane-Et2O = 2:1) 4j was obtained
as a pale yellow oil (274 mg, 96%); ee = 87% [HPLC analysis: Da-
icel OD at r.t., n-heptane-i-PrOH = 95:5 (0.8 mL/min); t1 = 9.9 min
(major), t2 = 8.3 min (minor)]; [a]D21 –3.1 (c = 0.99, CHCl3).
MS (EI, 70 eV): m/z = 498 [M + H]+.
Anal. Calcd for C27H34N2O7: C, 65.04; H, 6.87; N, 5.62. Found: C,
65.33; H, 7.17; N, 5.94.
IR (CHCl3): 3399, 2992, 2937, 2834, 1751, 1514, 1468, 1443, 1379,
1238, 1092, 1039, 823, 757 cm–1.
1H NMR (400 MHz, C6D6): d = 0.89 (s, 3 H), 1.28 (s, 3 H), 3.25 (s,
3 H), 3.81 (d, J = 17.1 Hz, 1 H), 4.02 (dd, J = 1.4, 17.1 Hz, 1 H),
4h
According to GP 1, dioxanone 1 (558 mg, 4.29 mmol), (S)-2-
formylpyrrolidine-1-carboxylic acid benzyl ester (3h; 1.00 g, 4.29
Synthesis 2006, No. 21, 3597–3604 © Thieme Stuttgart · New York

3602
D. Enders et al.
PAPER
4.64 (s, 1 H), 4.75 (s, 1 H), 6.01 (s, 1 H), 5.51-6.62 (m, 4 H), 6.72
(dt, J = 1.4, 8.0 Hz, 1 H), 6.85 (dt, J = 1.1, 8.0 Hz, 1 H), 7.15 (dd,
J = 1.1, 8.0 Hz, 1 H), 7.39 (dd, J = 1.4, 7.7 Hz, 1 H).
Anal. Calcd for C18H25NO5: C, 64.46; H, 7.51; N, 4.18. Found: C,
64.24; H, 7.73; N, 4.14.
Diastereoselective Reduction with Me4NHB(OAc)3 (Amino Al-
cohol 11); General Procedure (GP 2)
13C NMR (100 MHz, C6D6): d = 22.3 (CH3), 24.9 (CH3), 54.1
(CH3), 55.0 (CH), 67.4 (CH2), 78.0 (CH), 100.3 (C), 115.1 (CH),
115.5 (CH), 126.7 (CH), 128.6 (CH), 129.0 (CH), 129.6 (CH),
133.2 (C), 137.3 (C), 139.0 (C), 153.1 (C), 204.7 (C).
(CH3)4NBH(OAc)3 (1.16 g, 4.40 mmol) was dissolved in MeCN (9
mL) and AcOH (0.51 mL, 8.80 mmol) and cooled to –30 °C. Then
ketone 4a (300 mg, 0.88 mmol, dissolved in 0.5 mL MeCN) was
added and stored for 2 d at –24 °C in a freezer. The reaction was
quenched with 0.5 N sodium tatrate solution (4 mL) and extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were dried
over Na2SO4, filtered and purified by flash chromatography (silica
gel, n-pentane-Et2O, 1:2) to afford the product 11 as a yellow oil
(230 mg, 77%); [a]D21 –15.4 (c = 0.99, CHCl3).
MS (EI, 70 eV): m/z = 375 [M + H]+.
Anal. Calcd for C20H22ClNO4: C, 63.91; H, 5.90; N, 3.73. Found: C,
64.20; H, 6.00; N, 3.89.
4k
According to GP 1, dioxanone 1 (861 mg, 6.62 mmol), p-nitro-
benzaldehyde (3k; 1.00 g, 6.62 mmol) and p-anisidine (2; 815 mg,
6.62 mmol) were reacted in MeCN containing H2O (5 equiv, 66
mL) in the presence of (S)-6 (325 mg, 1.32 mmol) for 5 d. Purifica-
tion by flash chromatography (silica gel, n-pentane-EtOAc =
85:15) afforded 4k as a bright orange solid (2.45 g, 96%); mp 55-
58 °C; ee = 87% [HPLC analysis: Daicel AD at r.t., n-heptane-
i-PrOH = 90:10 (0.7 mL/min); t1 = 26.8 min (minor), t2 = 32.0 min
(major)]; [a]D23 +5.7 (c = 5.27, CHCl3).
IR (CHCl3): 3404, 2992, 2939, 2834, 1516, 1461, 1379, 1236, 1201,
1124, 1073, 980, 888, 823, 756 cm–1.
1H NMR (500 MHz, C6D6): d = 1.34 (s, 3 H), 1.46 (3 H), 3.17 (s, 3
H), 3.24 (s, 3 H), 3.39 (s, 3 H), 3.52 (m, 1 H), 3.70 (m, 2 H), 4.01
(dd, J = 1.5, 7.3 Hz, 1 H), 4.16 (dd, J = 1.5, 9.1 Hz, 1 H), 4.48 (d,
J = 7.3 Hz, 1 H), 6.68 (dt, J = 2.6, 8.9 Hz, 2 H), 6.79 (dt, J = 2.6, 8.9
Hz, 2 H).
13C NMR (100 MHz, C6D6): d = 19.5 (CH3), 28.9 (CH3), 54.2
(CH3), 54.9 (CH3), 55.4 (CH3), 56.0 (CH), 62.9 (CH), 65.2 (CH2),
74.0 (CH), 98.8 (C), 105.5 (CH), 114.9 (CH), 115.3 (CH), 143.5
(C), 152.6 (C).
IR (KBr): 3389, 2993, 2939, 2835, 2453, 2279, 1929, 1750, 1673,
1603, 1517, 1464, 1380, 1346, 1237, 1177, 1107, 1040, 982, 907,
852, 824, 757, 695, 668, 624, 525 cm–1.
1H NMR (300 MHz, C6D6): d = 0.93 (d, J = 1.4 Hz, 3 H), 1.76 (d,
J = 1.4 Hz, 3 H), 3.29 (d, J = 0.8 Hz, 3 H), 3.73 (dd, J = 2.1, 16.9
Hz, 1 H), 3.85 (dt, J = 1.4, 16.9 Hz, 1 H), 4.13 (br, 1 H), 5.03 (br, 1
H), 6.41 (dd, J = 1.6, 8.8 Hz, 2 H), 6.69 (d, J = 8.8 Hz, 2 H), 6.97
(dd, J = 3.0, 8.7 Hz, 2 H), 7.78 (dd, J = 1.4, 8.7 Hz, 2 H).
MS (EI, 70 eV): m/z = 341 [M + H]+.
Anal. Calcd for C17H27NO6: C, 59.81; H, 7.97; N, 4.10. Found: C,
60.31; H, 8.01; N, 3.89.
Diastereoselective Reduction with L-Selectride (Amino Alcohol
12); General Procedure (GP 3)
13C NMR (75 MHz, C6D6): d = 22.7 (CH3), 24.4 (CH3), 55.2 (CH3),
57.3 (CH), 67.2 (CH2), 100.7 (C), 115.2 (CH), 116.0 (CH), 123.5
(CH), 128.1 (CH), 140.0 (C), 147.5 (C), 147.6 (C), 153.7 (C), 205.4
(C).
To a solution of 4a (180 mg, 0.53 mmol) in THF (4 mL) was added
dropwise a 1 M solution of L-Selectride in THF (0.69 mL, 0.69
mmol) at –78 °C. After 2 h the reaction mixture was warmed to r.t.,
then Et2O (8 mL) and sat. NH4Cl solution (4 mL) were added and
stirring was continued for an additional 10 min. The phases were
separated and the aqueous layer was extracted with EtOAc (3 × 10
mL). The combined organic extracts were washed with brine (5
mL), dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified by flash chromatography (silica gel,
n-pentane-Et2O, 1:4) to afford the product 12 as a colorless solid
(178 mg, >98%); mp 51-52 °C; [a]D22 –14.9 (c = 0.90, CHCl3).
MS (CI, methane): m/z = 387 [M + H]+.
Anal. Calcd for C20H22N2O6: C, 62.17; H, 5.74; N, 7.25. Found: C,
62.04; H, 5.80; N, 7.01.
9
To a solution of 7 (1.00 g, 4.87 mmol) in CF3CH2OH (49 mL) at am-
bient temperature was added (S)-5 (168 mg, 1.46 mmol), followed
by dioxanone 1 (634 mg, 4.87 mmol) and the mixture was stirred for
an additional 5 d. Upon reaction completion a pH 7 phosphate buff-
er (50 mL) was added and the mixture was stirred for 15 min. The
layers were separated and the aqueous phase was extracted with
CH2Cl2 (3 × 50 mL). The combined organic layers were dried over
Na2SO4 and the solvent was removed under reduced pressure. Puri-
fication by flash chromatography (silica gel, n-pentane-Et2O = 2:1)
afforded the desired product 9 as a colorless solid (1.39 g, 85%); mp
60-63 °C; ee = 96% [chiral GC analysis: CP Chirasil-DEX CB,
140-10iso-1-160-3-180-50iso; t1 = 42.7 min (minor), t2 = 43.3 min
(major)]; [a]D23 –137.0 (c = 1.73, CHCl3).
IR (CHCl3): 3370, 2998, 2940, 2834, 1513, 1462, 1380, 1240, 1199,
1121, 1082, 1043, 978, 857, 827, 757 cm–1.
1H NMR (500 MHz, C6D6): d = 1.26 (s, 3 H), 1.48 (s, 3 H), 3.03 (s,
3 H), 3.14 (s, 3 H), 3.38 (s, 3 H), 3.50 (q, J = 1.8 Hz, 1 H), 3.67 (dd,
J = 1.9, 12.2 Hz, 1 H), 3.75 (app t, J = 4.6 Hz, 1 H), 3.82 (dd, J =
2.5, 12.2 Hz, 1 H), 4.12 (dd, J = 2.5, 4.6 Hz, 1 H), 4.43 (d, J = 4.9
Hz, 1 H), 6.68 (dt, J = 2.4, 9.1 Hz, 2 H), 6.77 (dt, J = 2.4, 9.1 Hz, 2
H).
13C NMR (100 MHz, C6D6): d = 18.9 (CH3), 29.6 (CH3), 54.8
(CH3), 55.2(CH3), 55.6 (CH3), 59.8 (CH), 66.0 (CH2), 66.3 (CH),
70.7 (CH), 99.1 (C), 105.5 (CH), 115.0 (CH), 116.9 (CH), 142.6
(C), 153.6 (C).
IR (KBr): 3425, 3066, 3031, 2981, 2936, 2866, 2381, 1755, 1719,
1499, 1375, 1328, 1228, 1172, 1099, 1053, 979, 889, 849, 800, 754,
702, 567, 528 cm–1.
1H NMR (400 MHz, C6D6, 70 °C): d = 1.01 (s, 3 H), 1.11 (s, 3 H),
1.39 (s, 9 H), 3.69 (d, J = 16.9 Hz, 1 H), 3.83 (d, J = 16.9 Hz, 1 H),
4.28 (br, 1 H), 5.56 (br, 2 H), 7.03-7.18 (m, 3 H), 7.31 (d, J = 7.1
Hz, 2 H).
MS (EI): m/z = 341 [M + H]+.
Anal. Calcd for C17H27NO6: C, 59.81; H, 7.97; N, 4.10. Found: C,
60.31; H, 8.01; N, 3.89.
Amino Alcohol 13
13C NMR (100 MHz, C6D6, 70 °C): d = 22.8 (CH3), 23.8 (CH3), 28.1
(CH3), 53.5 (CH), 66.8 (CH2), 77.8 (CH), 79.1 (C), 100.4 (C), 126.9
(CH), 127.0 (CH), 127.9 (CH), 140.3 (C), 154.5 (C), 205.1 (C). MS
(CI, methane): m/z = 336 [M + H]+.
According to GP 2, 4b (337 mg, 1.00 mmol) was treated with
Me4NHB(OAc)3 (1.32 g, 5.00 mmol) in MeCN (10 mL) in the pres-
ence of AcOH (0.58 mL, 10.00 mmol) overnight. Following flash
chromatography (silica gel, n-pentane-EtOAc = 7:3) 13 was col-
Synthesis 2006, No. 21, 3597–3604 © Thieme Stuttgart · New York

PAPER
Amino Sugars via Asymmetric Organocatalytic Mannich Reactions
3603
23
lected as a colorless oil (305 mg, 90%); [a]D –27.4 (c = 3.12,
(CH), 99.2 (C), 105.4 (CH), 115.0 (CH), 115.7 (CH), 127.2 (CH),
128.5 (CH), 129.1 (CH), 140.9 (C), 144.9 (C), 152.8 (C).
CHCl3).
IR (CHCl3): 3715, 3421, 2990, 2944, 2392, 2295, 1736, 1608, 1516,
1465, 2295, 1736, 1608, 1516, 1465, 1377, 1238, 1162, 1074, 960,
917, 827, 756, 671, 517 cm–1.
1H NMR (400 MHz, C6D6): d = 0.89 (t, J = 7.0 Hz, 3 H), 1.25 (s, 3
H), 1.43 (s, 3 H), 3.34 (s, 3 H), 3.48 (dd, J = 9.5, 11.1 Hz, 1 H), 3.68
(dd, J = 5.6, 11.1 Hz, 1 H), 3.83-3.94 (m, 2 H), 4.03 (dq, J = 3.8,
7.0 Hz, 1 H), 4.29 (dd, J = 1.6, 9.3 Hz, 1 H), 4.46 (br, 1 H), 4.57 (br,
1 H), 6.58 (d, J = 8.9 Hz, 2 H), 6.75 (d, J = 8.9 Hz, 2 H).
13C NMR (75 MHz, C6D6): d = 14.3 (CH3), 19.2, (CH3), 28.7 (CH3),
55.2 (CH3), 58.0 (CH), 60.9 (CH2), 62.9 (CH), 65.0 (CH2), 75.8
(CH), 99.1 (C), 115.2 (CH), 115.8 (CH), 142.4 (C), 153.5 (C), 172.3
(C).
MS (EI): m/z = 430 [M + H]+.
Anal. Calcd for C24H34N2O5: C, 66.95; H, 7.96; N, 6.51. Found: C,
66.94; H, 7.46; N, 6.30.
Diamines 16 and 17
According to GP 4, b-aminoketone 4c (250 mg, 0.63 mmol) and
BnNH2 (0.28 mL, 2.60 mmol) in CH2Cl2 (4 mL) were treated with
NMe4HB(OAc)3 (533 mg, 2.50 mmol) and AcOH (0.145 ml, 2.50
mmol) for 4 d. The crude mixture was purified by flash chromatog-
raphy (silica gel, n-pentane-Et2O = 1:2) to afford the major diaste-
reoisomer 16 as a cream-colored foam (213 mg, 89%) and the minor
diastereoisomer 17 as a yellow oil (25 mg, 10%).
MS (CI, methane): m/z = 340 [M + H]+.
16
Mp 47-48 °C; [a]D21 –27.1 (c = 1.04, CHCl3).
Anal. Calcd for C17H25NO6: C, 60.16; H, 7.42; N, 4.13. Found: C,
59.76; H, 7.69; N, 4.35.
IR (CHCl3): 3346, 2991, 2932, 1693, 1514, 1439, 1242, 1106, 1037,
824, 756 cm–1.
Amino Alcohol 14
1H NMR (500 MHz, CDCl3): d = 1.38 (s, 6 H), 3.66 (m, 3 H), 3.75
(s, 3 H), 3.78 (dd, J = 1.8, 6.1 Hz, 1 H), 3.95 (s, 1 H), 4.16 (d, J =
15.0 Hz, 1 H), 4.28 (d, J = 4.5 Hz, 1 H), 4.86 (d, J = 15.0 Hz, 1 H),
6.82 (dd, J = 2.1, 9.1 Hz, 2 H), 7.25 (dd, J = 2.1, 9.1 Hz, 2 H), 7.28-
7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 22.0 (CH3), 26.4 (CH3), 45.0
(CH2), 54.5 (CH), 55.7 (CH3), 59.0 (CH2), 62.6 (CH), 68.9 (CH),
99.7 (CH3), 114.9 (CH), 115.2 (CH), 127.9 (CH), 128.0 (CH), 128.9
(CH), 135.4 (C), 140.9 (C), 153.2 (C), 173.9 (C).
According to GP 3, 9 (1.00 g, 2.98 mmol) was treated with L-Selec-
tride (3.58 mL, 3.58 mmol) in THF (26 mL) for 5 h. Purification by
flash chromatography (silica gel, n-pentane-EtOAc = 7:3) afforded
14 as a colorless solid (804 mg, 80%); mp 185-187 °C; [a]23D +0.5
(c = 2.96, CHCl3).
IR (KBr): 3481, 3410, 2977, 2922, 2364, 2344, 1690, 1520, 1458,
1376, 1288, 1252, 1169, 1117, 1073, 1020, 980, 954, 912, 859, 828,
747, 700, 620, 577, 535, 474 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.32 (br, 9 H), 1.46 (s, 3 H), 1.49
(s, 3 H), 2.79 (app d, J = 11.3 Hz, 1 H), 3.05 (app d, J = 10.7 Hz, 1
H), 3.73 (dd, J = 1.9, 12.4 Hz, 1 H), 3.77 (app d, J = 8.8 Hz, 1 H),
3.87 (dd, J = 1.4, 12.4 Hz, 1 H), 4.70 (br, 1 H), 5.12 (d, J = 4.1 Hz,
1 H), 7.23-7.28 (m, 1 H), 7.30-7.35 (m, 2 H), 7.37-7.40 (m, 2 H).
MS (EI): m/z = 382 [M + H]+.
Anal. Calcd for C22H26N2O4: C, 69.09; H, 6.85; N, 7.32. Found: C,
68.62; H, 6.96; N, 7.09.
17
13C NMR (75 MHz, CDCl3): d = 18.4 (CH3), 28.2 (CH3), 29.6
(CH3), 56.4 (CH), 62.5 (CH), 65.9 (CH2), 74.8 (CH), 79.5 (C), 99.7
(C), 127.4 (CH), 127.5 (CH), 128.4 (CH), 139.4 (C), 155.9 (C).
[a]D21 = +32.8 (c = 0.95, CHCl3).
IR (CHCl3): 3346, 2991, 2932, 1693, 1514, 1439, 1242, 1106, 1037,
824, 756 cm–1.
MS (CI, methane): m/z = 338 [M + H]+.
1H NMR (400 MHz, CDCl3): d = 1.28 (s, 3 H), 1.33 (s, 3 H), 3.64
(dd, J = 9.3, 11.3 Hz, 1 H), 3.79 (s, 3 H), 3.87 (dd, J = 5.5, 11.3 Hz,
1 H), 3.98 (m, 1 H), 4.15 (dd, J = 2.2, 9.1 Hz, 1 H), 4.43 (d, J = 2.2
Hz, 1 H), 5.06 (d, J = 12.1 Hz, 1 H), 5.26 (d, J = 12.1 Hz, 1 H), 6.68
(m, 2 H), 6.79 (m, 2 H), 7.26-7.34 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 19.0 (CH3), 28.2 (CH3), 55.6
(CH3), 57.5 (CH), 62.9 (CH), 64.5 (CH2), 66.8 (CH2), 74.9 (CH),
99.0 (C), 114.7 (CH), 115.2 (CH), 128.1 (CH), 128.2 (CH), 128.3
(CH), 135.5 (C), 140.8 (C), 153.4 (C), 173.5 (C).
Anal. Calcd for C18H27NO5: C, 64.07; H, 8.07; N, 4.15. Found: C,
63.82; H, 8.01; N, 3.94.
Diastereoselective Reductive Amination with Me4NHB(OAc)3
(Diamine 15); General Procedure (GP 4)
To a solution of the b-aminoketone 4a (103 mg, 0.30 mmol) and
BnNH2 (0.076 mL, 0.70 mmol) in CH2Cl2 (2 mL) at 2 °C were add-
ed Me4NHB(OAc)3 (184 mg, 0.43 mmol) and AcOH (0.017 mL,
0.30 mmol) and the reaction mixture was stored at this temperature
for 2 d. The reaction was quenched with 0.5 N sodium tartrate solu-
tion (4 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined
organic extracts were dried over Na2SO4, filtered and purified by
flash chromatography (silica gel, n-pentane-Et2O = 1:2) to afford
MS (EI, 70 eV): m/z = 382 [M + H]+.
Anal. Calcd for C22H26N2O4: C, 69.09; H, 6.85; N, 7.32. Found: C,
68.75; H, 6.71; N, 7.05.
21
product 15 as a yellow oil (97 mg, 73%); [a]D +14.4 (c = 0.99,
CHCl3).
Acknowledgment
IR (CHCl3): 3398, 2998, 2934, 2834, 1616, 1514, 1454, 1379, 1237,
1147, 1078, 1043, 977, 822, 757, 702, 668 cm–1.
This work was supported by the Deutsche Forschungsgemeinschaft
(Schwerpunktprogramm 1179 Organokatalyse) and the Fonds der
Chemischen Industrie (Kekulé fellowship for C.G.). We thank De-
gussa AG, BASF AG, Bayer AG and Wacker Chemie for the dona-
tion of chemicals.
1H NMR (300 MHz, C6D6): d = 1.31 (s, 3 H), 1.43 (s, 3 H), 2.24 (d,
J = 1.7 Hz, 1 H), 3.13 (s, 3 H, CH3), 3.17 (s, 3 H, CH3), 3.40 (s, 3 H,
CH3), 3.44 (d, J = 13.1 Hz, 1 H), 3.51 (dd, J = 1.5, 12.1 Hz, 1 H),
3.73 (d, J = 13.1 Hz, 1 H), 3.88 (dd, J = 1.5, 12.1 Hz, 1 H), 3.98 (dd,
J = 3.2, 6.7 Hz, 1 H), 4.17 (dd, J = 2.1, 6.8 Hz, 1 H), 4.30 (d, J = 3.2
Hz, 1 H), 6.82-6.89 (m, 4 H), 7.10-7.25 (m, 5 H).
References
13C NMR (75 MHz, C6D6): d = 18.7 (CH3), 30.0 (CH3), 50.6 (CH2),
52.0 (CH), 55.3 (CH3), 55.9 (CH3), 58.9 (CH), 60.4 (CH2), 73.8
(1) (a) List, B. Tetrahedron 2002, 58, 5573. (b) List, B. Acc.
Chem. Res. 2004, 37, 548. (c) Notz, W.; Tanaka, F.; Barbas,
C. F. III Acc. Chem. Res. 2004, 37, 580.
Synthesis 2006, No. 21, 3597–3604 © Thieme Stuttgart · New York

3604
D. Enders et al.
PAPER
(2) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int.
Ed. 1998, 37, 1044; Angew. Chem. 1998, 110, 1096.
(b) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
(3) (a) For a first asymmetric Mannich reaction, see: Kober, R.;
Papadopoulos, K.; Miltz, W.; Enders, D.; Steglich, W.
Tetrahedron 1985, 41, 1693. (b) For a first practical
asymmetric Mannich reaction, see: Enders, D.; Ward, D.;
Adam, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1996, 35,
981; Angew. Chem. 1996, 108, 1059.
(4) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) List, B.;
Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc.
2002, 124, 827.
(5) (a) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C.
F. III Tetrahedron Lett. 2001, 42, 199. (b) Córdova, A.;
Notz, W.; Zhong, G.; Betancort, J. M.; Barabs, C. F. III J.
Am. Chem. Soc. 2002, 124, 1842. (c) Córdova, A.;
Watanabe, S.-I.; Tanaka, F.; Notz, W.; Barabs, C. F. III J.
Am. Chem. Soc. 2002, 124, 1866.
(6) For reviews, see: (a) Córdova, A. Acc. Chem. Res. 2004, 37,
102. (b) Marques, M. M. B. Angew. Chem. Int. Ed. 2006, 45,
348; Angew. Chem. 2006, 118, 356. (c) List, B. Chem.
Commun. 2006, 819.
(7) For reviews, see: (a) Asymmetric Organocatalysis;
Berkessel, A.; Gröger, H., Eds.; Wiley-VCH: Weinheim,
2005. (b) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
2004, 43, 5138; Angew. Chem. 2004, 116, 5248.
(8) (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.;
Urushima, T.; Shoji, M.; Hashizume, D.; Koshino, H. Adv.
Synth. Catal. 2004, 346, 1435. (b) Cobb, A. J. A.; Shaw, D.
M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol.
Chem. 2005, 3, 84. (c) Franzén, J.; Marigo, M.; Fielenbach,
D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 18296.
(12) (a) Sibi, M. P.; Lu, J.; Edwards, J. J. Org. Chem. 1997, 62,
5864. (b) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Vega,
J. A. Angew. Chem. Int. Ed. 2000, 39, 2525. (c)Ermolenko,
L.; Sasaki, N. A.; Potier, P. J. Chem Soc., Perkin Trans. 1
2000, 2465. (d) Evans, D. A.; Hu, E.; Tedrow, J. S. Org.
Lett. 2001, 3, 3133. (e) Lu, H.; Su, Z.; Song, L.; Mariano, P.
S. J. Org. Chem. 2002, 67, 3525.
(13) (a) Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew.
Chem. Int. Ed. 2005, 44, 4079; Angew. Chem. 2005, 117,
4147. (b) For an application of this methodology in the
synthesis of (+)-polyoxamic acid, see: Enders, D.; Vrettou,
M. Synthesis 2006, 2155. For a related organocatalytic
aldol methodology, see: (c) Enders, D.; Grondal, C. Angew.
Chem. Int. Ed. 2005, 44, 1210; Angew. Chem. 2005, 117,
1235. (d) Grondal, C.; Enders, D. Tetrahedron 2006, 62,
329. (e) For an application of the organocatalytic aldol
methodology to the synthesis of D-arabino- and L-ribo-
phytosphingosines, see: Enders, D.; Palecek, J.; Grondal, C.
Chem. Commun. 2006, 655.
(14) For related work, see: (a) Westermann, B.; Neuhaus, C.
Angew. Chem. Int. Ed. 2005, 40, 4077; Angew. Chem. 2005,
117, 4145. (b) Ibrahem, I.; Zou, W.; Casas, J.; Sundén, H.;
Córdova, A. Tetrahedron 2006, 62, 357.
(15) Review: Enders, D.; Voith, M.; Lenzen, A. Angew. Chem.
Int. Ed. 2005, 44, 1304; Angew. Chem. 2005, 117, 1330.
(16) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
12964.
(17) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(18) Baxter, E. W.; Reitz, A. B. Org. React. (N.Y.) 2002, 59, 1.
(19) Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Phillips, J.
L.; Prather, D. E.; Schrantz, R. D.; Sear, N. L.; Vianco, C. S.
J. Org. Chem. 1991, 56, 4056.
(9) Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99.
(10) (a) Carbohydrate Based Drug Discovery; Wong, C.-H., Ed.;
Wiley VCH: Weinheim, Germany, 2003, Chap. 24.
(b) Carbohydrate Based Drug Discovery; Wong, C.-H., Ed.;
Wiley VCH: Weinheim, Germany, 2003, Chap. 26.3.
(11) (a) Winterfeld, G. A.; Schmidt, R. R. Angew. Chem. Int. Ed.
2001, 40, 2654; Angew. Chem. 2001, 113, 2718. (b) Chang,
C. W. T.; Clark, T.; Ngaara, M. Tetrahedron Lett. 2001, 42,
6797. (c) Wang, L.; Li, D.; Tuttle, D.; Takemoto, J. Y.;
Chang, C.-W. T. Org. Lett. 2002, 4, 3997. (d) Barroca, N.;
Schmidt, R. R. Org. Lett. 2004, 3, 1551.
(20) Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18.
(21) Marshall, J. A.; Beaudoin, S. J. Org. Chem. 1996, 61, 581.
(22) Dei, S.; Bellucci, C.; Buccioni, M.; Ferraroni, M.; Gualtieri,
F.; Guandalini, L.; Manetti, D.; Matucci, R.; Romanelli, M.
N.; Scapecchi, S.; Teodori, E. Bioorg. Med. Chem. 2003, 11,
3153.
(23) Langley, D. R.; Thurston, D. E. J. Org. Chem. 1987, 52, 91.
Synthesis 2006, No. 21, 3597–3604 © Thieme Stuttgart · New York