Asymmetric aldol-Tishchenko reaction catalyzed by Yb-complexes with basic amino acid-derived ligands

Article abstract of DOI:10.1016/j.tetasy.2011.02.026

Simple amino acid-derived esters have been identified as promising chiral sources for the ytterbium-catalyzed aldol-Tishchenko reaction of aromatic aldehydes with aliphatic ketones. The 1,3-anti-diols with three stereogenic centers were isolated in excellent yields, complete anti-diastereocontrol and enantioselectivities of up to 50% ee.

Full text of DOI:10.1016/j.tetasy.2011.02.026

Tetrahedron: Asymmetry 22 (2011) 464–467
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric aldol-Tishchenko reaction catalyzed by Yb-complexes with
basic amino acid-derived ligands
a
a
a,b,
⇑
´
Maciej Stodulski , Agnieszka Maminska , Jacek Mlynarski
a Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
b Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple amino acid-derived esters have been identified as promising chiral sources for the ytterbium-
catalyzed aldol-Tishchenko reaction of aromatic aldehydes with aliphatic ketones. The 1,3-anti-diols with
three stereogenic centers were isolated in excellent yields, complete anti-diastereocontrol and enantiose-
lectivities of up to 50% ee.
Received 23 November 2010
Accepted 15 February 2011
Available online 30 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
R
O
OH
O
R
R
O
OH
R1
The aldol-Tishchenko reaction is a unique, one step methodol-
ogy for the synthesis of 1,3-dioxygenated compounds from car-
bonyl substrates.1 This transformation is a useful methodology
for the construction of defined stereogenic centers and represents
a valuable tool for broadening the scope of classical aldol reaction.2
Despite the enormous synthetic potential of the aldol-Tishchenko
reaction of unmodified ketones with aldehydes leading directly
to the important class of 1,3-diols, its enantioselective variant
requires further exploration. Only a limited number of publications
have described an enantioselective aldol-Tishchenko reaction of
ketones. In principal, there are two general methodologies avail-
able in the field: the direct aldol-Tishchenko the reaction of
ketones3 and reaction of preformed ketone aldols.4
cat.
R1
R
R1
2 RCHO
OH OH
R1
R
Scheme 1. Condensation of ketones with aldehydes by means of a catalytic aldol-
Tishchenko reaction.
In the former direct aldol-type methodology, three stereogenic
centers can be created by aldol-Tishchenko reaction of an aldehyde
with ethyl ketones leading to 1,3-diols even from demanding
aliphatic ketones (Scheme 1).
ligand composed of selectively blocked simple chiral amino acids,
as depicted at Scheme 2.
Previously, we reported attempts to carry out the asymmetric
aldol-Tishchenko reaction using an amino acid-based chiral ligand
along with ytterbium salts, by which the direct asymmetric aldol
reaction of 3-pentanone can be efficiently accomplished.3g We
have presented careful insight into a new class of ytterbium com-
plexes with C2-symmetric chiral bis(ester) and (bis)amide ligands
for the tandem asymmetric aldol reaction. We have shown that
the modular design of the catalyst is possible by varying the start-
ing chiral backbone and amino acid parts of the ligands. These find-
ings motivated us to further tune the catalyst and investigate the
possible catalytic efficiency of a directly available, less complex
L =
O
O
O
N
N
N
Ph
Ph
O
O
Ph
O
2
this study
1
Scheme 2. Examples of ligands used in previous and current studies.
The discovery and development of novel chiral ligands are of
significant importance in asymmetric catalysis, especially when
composed of inexpensive and readily available chiral sources.
⇑
Corresponding author. Tel.: +48 12 663 2035; fax: +48 12 634 0515.
E-mail address: jacek.mlynarski@gmail.com (J. Mlynarski).
URL: http://www.jacekmlynarski.pl (Jacek Mlynarski).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.026

M. Stodulski et al. / Tetrahedron: Asymmetry 22 (2011) 464–467
465
Herein, we report the synthesis and application of new ytterbium-
based catalysts armed with chiral amino acids to the valuable di-
rect asymmetric aldol reaction leading directly to 1,3-diols.
similar yield and stereoselectivity were obtained (Table 1, entry
7). In all cases tested, THF was the best solvent.
To improve the enantioselectivity further, we changed the li-
gand structure to tune the electronic nature and steric hindrance
around catalytic center. Thus, we prepared a series of ligands based
on alanine 4–12, valine 13 and proline 14; all collected data are
shown in Table 2.
2. Results and discussion
Based on our previous findings, we determined a few structural
elements to be necessary for catalyst activity. First, we know that
ligands without a tertiary amine group were inferior in this appli-
cation. Second, the aromatic substituents in the catalyst backbone
were indispensable for the reactivity. The most promising levels of
enantioselectivity (40%) and yield (95%) were obtained with a
catalyst composed of ytterbium triflate and ester type ligands
derived from dimethylalanine 1 in a 1:1 ratio.3d,f Giving up on
C2-symmetry, we started from a similar amino acid structure 2
Table 2
The aldol-Tishchenko reaction of 3-pentanone with benzaldehyde catalyzed by Yb
complex with various ligands
O
O
O
O
N
N
N
N
O
O
O
O
containing an ordinary benzyl ester function. Ligand
2 was
efficiently prepared by the DCC-promoted esterification of an
N-blocked chiral amino acid with benzyl alcohol (Scheme 3).
4
5
6
7
F
OMe
O
O
(i)
N
(ii)
N
L-Ala
O
O
Ph
O
O
N
OH
N
N
2
O
O
O
Scheme 3. Synthesis of a model ligand. Reagents and conditions: (i) CH2O, H2, Pd-C
(10%), EtOH, 20 h, rt, 100%; (ii) BnOH, DCC, DMAP, DCM, 20 h, rt, 71%.
9
10
8
As a model reaction we selected the addition of benzaldehyde
to 3-pentanone in THF at rt since this transformation has already
been extensively investigated. The ketone (0.95 mmol, two-fold
excess) and aldehyde substrates (1.00 mmol) were added to
the catalyst preformed from the chiral ligand and Yb(OTf)3
(20 mol %). As can be seen from Table 1, the conditions applied fur-
nished the diol 3 with varying yields and enantioselectivities.
O
O
N
N
O
O
O
O
O
N
N
O
13
14
12
11
Table 1
The aldol-Tishchenko reaction of 3-pentanone with benzaldehyde catalyzed by Yb-2
complex
OH OH
O
1) Yb(OTf)3 / L (1:4), THF, rt, 4h
OH OH
O
1) Yb(OTf)3 / 2, rt, 4h
2) MeOH, MeONa
2) MeOH, MeONa
Ph
Ph
2 PhCHO +
2 PhCHO +
3
3
Yielda (%)
eeb (%)
Entry
Yb(OTf)3:2
Solvent
Yielda (%)
eeb (%)
Entry
Ligand
Cat. loading (mol %)
1
2
3
4
5
6
7
8
1:1 (20 mol %)
1:2 (20 mol %)
1:3 (20 mol %)
1:4 (20 mol %)
1:4 (20 mol %)
1:4 (20 mol %)
1:4 (15 mol %)
1:4 (10 mol %)
THF
THF
THF
THF
MeCN
Dioxane
THF
85
93
93
98
70
75
92
50
16
36
42
45
6
26
45
45
1
2
3
4
5
6
7
8
4
5
6
7
8
9
10
11
12
13
14
20
20
20
15
15
15
20
15
15
15
15
98
44
—
—
50
32
44
46
28
22
8
Trace
Trace
92
50
93
93
96
77
95
THF
9
10
11
a
Yield of isolated diol 3.
b
The ee of diols was determined by HPLC using a chiral stationary phase AD-H
90
24
column.3f
a
Yield of isolated diol 3.
b
The most promising level of enantioselectivity was obtained for
The ee of diols was determined by HPLC using a chiral stationary phase AD-H
column.3f
the (1:4) ratio of Yb-salt to ligand using 20 mol % of catalyst load-
ing (Table 1, entry 4). The desired 1,3-diol was isolated in 98% yield
and with full 1,2-anti-1,3-anti diastereoselectivity. By using HPLC
and high resolution NMR’s, we did not observe formation of other
diastereoisomeric esters, which is in agreement with the previ-
While the application of a backbone with a para-methyl-
substituted ring was not progressive, the most promising level of
enantioselectivity was obtained with the sterically hindered
mesityl-derived ester 7 (Table 2, entry 4). Application of tri-O-
isopropyl-substituted ring in ligand 8 led to a decrease in yield
and enantioselectivity. When the para-methyl group in the ring
was changed to para-methoxy or para-fluoro groups, the reactivity
dropped sharply, and the formation of only trace amounts of
ously published findings.3 For the
L-alanine-based ligand, the
(1S,2S,3R)-configured product was predominant in the enantiomer
mixture. The absolute configurations of the esters and related diols
have previously been established in our laboratory using CD tech-
nique.3f When the catalyst amount was reduced to 15 mol %, a

466
M. Stodulski et al. / Tetrahedron: Asymmetry 22 (2011) 464–467
condensation products was observed. Alkyl esters 11 and 12
showed high activity but the observed levels of selectivity were
unsatisfactory. The application of valine and proline based ligand
was also not promising.
aldol-Tischenko methodology to the synthesis of more complex
molecules.
4. Experimental
4.1. General
With the optimal reaction conditions identified and by using a
ligand 7 combined with ytterbium triflate, the scope of the tandem
aldol-Tishchenko procedure was investigated by employing vari-
ous ketone substrates as well as differently substituted aldehydes.
As demonstrated in Table 3, the elaborated catalyst was found ac-
tive or very active for a wide range of ketones.
All reactions involving organometallic or other moisture sensi-
tive reagents were carried out under argon with standard vacuum
line techniques and glassware that was flame dried and cooled un-
der Ar before use. Solvents were dried according to standard proce-
dures. All organic solutions were dried over Na2SO4. Thin layer
chromatography was performed with aluminum plates coated
with 60 F254 silica (Merck). Plates were visualized with UV light
(254 nm) and ethanolic phosphomolybdic acid solution or etha-
nolic ninhydrin solution followed by heating. Reaction products
were purified by flash chromatography with silica gel 60 (240–
400 mesh, Merck). Optical rotations were measured with a JASCO
Dip-360 Digital Polarimeter at room temperature. Specific rota-
tions are reported in 10ꢀ1 deg cm2 gꢀ1 and in concentrations of
grams per 100 mL. 1H NMR spectra were recorded with a Varian-
200, Varian-400, or Bruker-500 spectrometer in or CDCl3 with
Me4Si as an internal standard. High-resolution mass spectra were
recorded with a Mariner PerSeptive Biosystems mass spectrometer
with a time-of-flight (TOF) detector. IR spectra were recorded with
a Perkin–Elmer FT-IR-1600 spectrophotometer as either a thin film
on NaCl plates (film), as a KBr disk (KBr), or as chloroform solutions
in 0.1 mm cells (CHCl3), as stated.
In addition to benzaldehyde, other aromatic aldehydes reacted
effectively to give diols in good yields with high stereoselectivity
(Table 3, entries 1 and 2). A number of ketones can be used as do-
nors without a loss of efficiency or enantiocontrol (entries 5–9).
Only the less hindered diisobutyl aldehyde was unreactive under
reaction conditions.
Table 3
Yb(OTf)3-promoted asymmetric aldol-Tishchenko reaction
1) Yb(OTf)3 / 7, (1:4, 15 mol%)
THF, rt,16 h
OH OH
R"
O
2) MeOH, MeONa
R
R"
2RCHO +
R'
R'
O
O
O
K2
K1
K3
O
O
4.2. General procedure for the synthesis of ligands
Benzyl alcohol (1.00 mmol), N,N-dimethylamino acid (1.20
mmol), 1,3-dicyclohexylocarbodiimide (1.20) mmol and DMAP
(0.10 mmol) were stirred in dry DCM (5 mL) under an argon atmo-
sphere for 24 h. The precipitate was removed by filtration, and the
residue was washed with DCM (5 mL). The solvent was evaporated,
and the residue was purified by flash column chromatography.
Cl
K5
Yielda (%)
K4
Entry
Ketone
Aldehyde
eeb (%)
1
2
3
4
5
6
7
8
9
K1
K1
K1
R = Ph
R = pMeOC6H4
R = pClC6H4
92
75
92
50
52
40
98
40
36
44
—
After one recrystallisation
60–65%
93
4.2.1. Benzyl (2S)-2-(dimethylamino)propanoate 2
K2
K2
K3
K4
K6
R = Ph
R = pClC6H4
R = Ph
R = Ph
R = Ph
Colorless oil; yield 71%, ½a D25:1
¼ ꢀ16:5 (c 0.62, CHCl3); Rf = 0.25
ꢁ
75
35
0
95
(Hex/AcOEt, 3:2); 1H NMR (CDCl3, 200 MHz) d: 1.30 (d, 3H,
J = 7.0 Hz), 2.33 (s, 6H), 3.29 (q, 1H, J = 7.0 Hz), 5.16 (s, 2H), 7.27–
7.40 (m, 5H); 13C NMR (CDCl3, 50 MHz) d: 14.9, 41.6, 62.7, 66.0,
128.1, 128.2, 128.4, 135.9, 172.9; IR (CHCl3): 2980, 2940, 2782,
1732, 1455, 1165, 731, 698 cmꢀ1; HRMS (ESI) calculated for
40
a
Yield of isolated diol 3.
b
The ee of diols was determined by HPLC using a chiral stationary phase AD-H
column.3f
C
12H17NO2Na [M+Na]+ 230.1152, found 230.1155.
It is noteworthy that one recrystallization (hexane with 2-
4.2.2. 4-Methylbenzyl (2S)-2-(dimethylamino)propanoate 4
Colorless oil; yield 86%, ½a D25:9
¼ ꢀ21:8 (c 0.40, CHCl3); Rf = 0.30
ꢁ
propanol) of the 1,3-diol derived from 4-chlorbenzaldehyde and
3-pentanone gave the diol with high enantiomeric purity (98%
ee) in good yield of ca. 60% (entry 4, calculated from the starting
carbonyl reactants). In this case, the chiral diol crystallizes easily
as racemic crystals leaving in the solution enantiomerically
enriched products. This observation is very important for the syn-
thetic application of the presented asymmetric methodology.
(Hex/AcOEt, 2:3); 1H NMR (CDCl3, 200 MHz) d: 1.22 (d, 3H,
J = 7.0 Hz), 2.24 (s, 6H), 2.30 (s, 3H), 3.19 (q, 1H, J = 7.0 Hz), 5.03
(s, 2H), 7.05 (ABq, 4H); 13C NMR (CDCl3, 50 MHz) d: 14.6, 20.8,
41.2, 62.4, 65.9, 128.1, 128.9, 132.4, 137.8, 172.5; IR (CHCl3):
2980, 2938, 2868, 1732, 1452, 1165, 1107, 806 cmꢀ1; HRMS (ESI)
calculated for C13H20NO2 [M+H]+ 222.1489, found 222.1499.
3. Conclusion
4.2.3. 4-Methoxybenzyl (2S)-2-(dimethylamino)propanoate 5
Colorless oil; yield, 80%, ½a D25:7
¼ ꢀ15:5 (c 0.27, CHCl3); Rf = 0.30
ꢁ
(Hex/AcOEt, 2:3); 1H NMR (CDCl3, 200 MHz) d: 1.26 (d, 3H,
J = 7.0 Hz), 2.29 (s, 6H), 3.22 (q, 1H, J = 7.0 Hz), 3.78 (s, 3H), 5.07
(s, 2H), 6.85 (d, 2H, J = 8.5 Hz), 7.30 (d, 2H, J = 8.5 Hz); 13C NMR
(CDCl3, 50 MHz) d: 15.1, 41.8, 55.4, 63.0, 66.3, 114.1, 128.2,
130.4, 159.8, 173.2; IR (CHCl3): 2967, 2938, 2834, 1728, 1614,
1516, 1248, 1166 cmꢀ1; HRMS (ESI) calculated for C13H20NO3
[M+H]+ 238.1438, found 238.1444.
In conclusion, we have devised a novel amino acid-based chiral
catalyst for the enantioselective aldol-Tishchenko reaction be-
tween ketones and aromatic aldehydes. The most reactive ligand
for this tandem process was readily prepared (in two steps) from
commercially available starting materials. Current studies are
being directed at further improving the enantioselectivity of
the reactions and the practical application of the asymmetric

M. Stodulski et al. / Tetrahedron: Asymmetry 22 (2011) 464–467
467
4.2.4. 4-Fluorobenzyl (2S)-2-(dimethylamino)propanoate 6
128.5, 136.0, 171.6; IR (CHCl3): 2962, 2938, 2872, 1729, 1455,
1151, 1122, 697 cmꢀ1; HRMS (ESI) calculated for C14H22NO2
[M+H]+ 236.1645, found 236.1647.
Colorless oil; yield 62%, ½a D25:9
¼ ꢀ24:4 (c 0.06, CHCl3); Rf = 0.30
ꢁ
(Hex/AcOEt, 2:3); 1H NMR (CDCl3, 200 MHz) d: 1.29 (d, 3H,
J = 6.8 Hz), 2.28 (s, 6H), 3.30 (q, 1H, J = 6.8 Hz), 5.13 (s, 2H), 7.00–
7.18 (m, 2H), 7.38–7.40 (m, 2H); 13C NMR (CDCl3, 50 MHz) d:
15.1, 41.9, 63.0, 65.7, 115.7 (d, J = 85.8 Hz), 130.6 (d, J = 33.4 Hz),
132.5, 162.9 (d, J = 981.6 Hz), 173.1; IR (CHCl3): 2968, 2931,
2874, 1615, 1572, 1220, 772, 635 cmꢀ1; HRMS (ESI) calculated
for C12H17NO3 [M+H]+ 226.1238, found 238.1241.
4.2.12. Benzyl (2S)-1-methyltetrahydro-1H-pyrrole-2-
carboxylate 14
Colorless oil; yield 80%, ½a D24:5
¼ ꢀ71:1 (c 0.28, CHCl3); Rf = 0.20
ꢁ
(Hex/AcOEt, 2:3); 1H NMR (CDCl3, 200 MHz) d: 1.75–2.38 (m, 5H),
2.40 (s, 3H), 2.96–3.20 (m, 2H), 5.18 (s, 2H), 7.35–7.45 (m, 5H);
13C NMR (CDCl3, 50 MHz) d: 23.1, 29.6, 40.8, 56.3, 66.2, 67.4,
126.8, 128.1, 128.4, 135.9, 173.5; IR (CHCl3): 2947, 2782, 1744,
1455, 1167, 1054, 749, 697 cmꢀ1; HRMS (ESI) calculated for
4.2.5. 2,4,6-Trimethylbenzyl (2S)-2-(dimethylamino)-
propanoate 7
Colorless oil; yield 90%, ½a D25:6
ꢁ
¼ ꢀ14:9 (c 1.08, CHCl3); Rf = 0.40
C
13H18NO2 [M+H]+ 220.1332, found 220.1336.
(Hex/AcOEt, 3:2); 1H NMR (CDCl3, 200 MHz) d: 1.28 (d, 3H,
J = 7.0 Hz), 2.27 (s, 3H), 2.33 (d, 6H, J = 3.8 Hz), 3.25 (q, 1H,
J = 7.0 Hz), 5.20 (s, 2H), 6.85 (s, 2H); 13C NMR (CDCl3, 50 MHz) d:
15.3, 19.4, 20.9, 41.6, 60.8, 62.6, 129.0, 138.0, 138.3, 173.3; IR
4.3. General procedure to obtain the aldol-Tishchenko
At first, Yb(III) triflate (0.15 mmol, 15 mol %) was placed in an
oven-dried flask with a magnetic stirring bar, and the flask was
heated at 200 °C for 10 min in vacuo and then flushed with argon.
After the flask was cooled to room temperature, a solution of ligand
7 (0.15 mmol, 15 mol %) in THF (2 mL) was added. The resulting
solution was stirred for 30 min at room temp under argon. To a
(CHCl3): 2977, 2939, 2866, 1728, 1451, 1215, 1164, 850 cmꢀ1
;
HRMS (ESI) calculated for C15H24NO2 [M+H]+ 250.1802, found
250.1803.
4.2.6. 2,4,6-Triisopropylbenzyl (2S)-2-(dimethylamino)-
propanoate 8
solution of the catalyst, 3-pentanone (100
lL, 0.95 mmol) and
Colorless oil; yield 80%, ½a D25:5
ꢁ
¼ ꢀ11:3 (c 0.32, CHCl3); Rf = 0.30
benzaldehyde (101 L, 1.00 mmol) were added successively. The
l
(Hex/AcOEt, 7:3); 1H NMR (CDCl3, 200 MHz) d: 1.24–1.35 (m, 21H),
2.35 (s, 6H), 2.83–2.96 (m, 1H), 3.13–3.29 (m, 3H), 5.26 (s, 2H), 7.05
(s, 2H); 13C NMR (CDCl3, 50 MHz) d: 15.4, 23.9, 24.3, 29.4, 34.3,
41.7, 59.1, 62.8, 121.1, 126.3, 148.7, 149.6, 173.4; IR (CHCl3):
2963, 2935, 2870, 2830, 2780, 1730, 1458, 1164 cmꢀ1; HRMS
(ESI) calculated for C21H36NO2 [M+H]+ 334.2741, found 334.2740.
resulting solution was stirred for 4–16 h at room temperature
and then dissolved with MTBE and washed with water and brine.
The organic layer was dried with Na2SO4, concentrated, and sub-
mitted to short column chromatography (Hex/AcOEt, 9:1) to afford
a mixture of esters as an oil. The esters obtained were dissolved in
MeOH (2 mL) and treated with NaOMe (5–10 mol %) overnight. The
resulting mixture was purified by column chromatography on sil-
ica gel (Hex/AcOEt, 3:2) to afford diol 3 and, with an analogous pro-
cedure all other diols.
4.2.7. 1-Naphthylmethyl (2S)-2-(dimethylamino)propanoate 9
Colorless oil; yield 81%, ½a D25:7
¼ ꢀ12:8 (c 1.06, CHCl3); Rf = 0.30
ꢁ
(Hex/AcOEt, 2:3); 1H NMR (CDCl3, 200 MHz) d: 1.29 (d, 3H,
J = 7.12 Hz), 2.28 (s, 6H), 3.30 (q, 1H, J = 7.12 Hz), 5.13 (s, 2H),
7.40–7.60 (m, 4H), 7.80–7.88 (m, 2H), 7.95–8.05 (m, 1H); 13C NMR
(CDCl3, 50 MHz) d: 15.0, 41.5, 62.6, 64.1, 123.3, 125.0, 125.7, 126.3,
127.4, 128.5, 129.1, 131.3, 131.4, 133.5, 172.9; IR (CHCl3): 2979,
2937, 2829, 2781, 1730, 1169, 1151, 776 cmꢀ1; HRMS (ESI) calcu-
lated for C16H20NO2 [M+H]+ 258.1489, found 258.1490.
Analytical data (NMR, IR, MS and chiral stationary phase HPLC)
for all aldol-Tishchenko products from Table 3 have already been
published.3g
Acknowledgments
Project operated within the Foundation for Polish Science TEAM
Programme co-financed by the EU European Regional Develop-
ment Fund.
4.2.8. Diphenylmethyl (2S)-2-(dimethylamino)propanoate 10
Colorless oil; yield 71%, ½a D25:2
¼ ꢀ11:0 (c 1.06, CHCl3); Rf = 0.20
ꢁ
(Hex/AcOEt, 3:2); 1H NMR (CDCl3, 200 MHz) d: 1.32 (d, 3H,
J = 7.1 Hz), 2.32 (s, 6H), 2.37 (q, 1H, J = 7.1 Hz), 6.93 (s, 1H), 7.24–
7.38 (m, 10H); 13C NMR (CDCl3, 50 MHz) d: 15.3, 41.6, 62.8, 76.7,
127.1, 127.1, 127.8, 128.4, 128.4, 140.1, 140.2, 172.2; IR (CHCl3):
2980, 2939, 2868, 2830, 2785, 1734, 1453, 1162, 699 cmꢀ1; HRMS
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4. (a) Simpura, I.; Nevalainen, V. Tetrahedron Lett. 2001, 42, 3905–3907; (b)
Simpura, I.; Nevalainen, V. Tetrahedron 2003, 5, 7535–7546; (c) Schneider, C.;
Hansch, M. Chem. Commun. 2001, 1218–1219; (d) Schneider, C.; Hansch, M.;
Weide, T. Chem. Eur. J. 2005, 11, 3010–3021; (e) Schneider, C.; Hansch, M. Synlett
2003, 837–840; (f) Schneider, C.; Hansch, M.; Sreekumar, P. Tetrahedron:
Asymmetry 2006, 17, 2738–2742; For non-catalytic variant see: (g) Rohr, K.;
Herre, R.; Mahrwald, R. Org. Lett. 2005, 7, 4499–4501; (h) Rohr, K.; Herre, R.;
Mahrwald, R. J. Org. Chem. 2009, 74, 3744–3749.
(ESI) calculated for
306.1466.
C
18H21NO2Na [M+Na]+ 306.1465, found
4.2.9. Methyl (2S)-2-(dimethylamino)propanoate 11
Known compound.5
4.2.10. tert-Butyl (2S)-2-(dimethylamino)propanoate 12
Known compound.6
4.2.11. Benzyl (2S)-2-(dimethylamino)-3-methylbutanoate 13
Colorless oil; yield 82%, ½a D23:3
¼ ꢀ7:6 (c 0.96, CHCl3); Rf = 0.40
ꢁ
(Hex/AcOEt, 9:1); 1H NMR (CDCl3, 200 MHz) d: 0.86 (d, 3H,
J = 6.5 Hz), 0.97 (d, 6H, J = 6.5 Hz), 1.93–2.10 (m, 1H), 2.30 (s, 6H),
2.79 (d, 1H, J = 10.3 Hz), 5.18 (s, 2H), 7.38–7.45 (m, 5H); 13C NMR
(CDCl3, 50 MHz) d: 19.4, 19.6, 27.5, 41.5, 65.6, 74.3, 128.2, 128.4,
5. Pracejus, H.; Kohl, G. Liebigs Ann. Chem. 1969, 722, 1–11.
6. Gacek, M. Tetrahedron 1973, 29, 863–866.