Asymmetric α -Amination of chiral protected -hydroxyaldehydes catalyzed by proline

Article abstract of DOI:10.1055/s-0029-1218001

Proline-catalyzed -amination of a variety of chiral -hydroxyaldehydes followed by reduction step afforded the corresponding chiral 2-hydrazino-1,3-diols in good yields, enantioselectivities and diastereoselectivities. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218001

LETTER
3007
Asymmetric a-Amination of Chiral Protected b-Hydroxyaldehydes Catalyzed
by Proline
Asymmetric
a
-A
m
a
ination of
m
Chiral Protected
b
-
z
H
ydroxyal
i
Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles St-Quentin-en-Yvelines,
45, Avenue des Etats-Unis, 78035 Versailles Cedex, France
Fax +33(1)39254452; E-mail: greck@chimie.uvsq.fr
Received 16 July 2009
OTBS
CbzN
OTBS
CbzN
OTBS
Abstract: Proline-catalyzed a-amination of a variety of chiral b-
hydroxyaldehydes followed by reduction step afforded the corre-
+
OH
OH
O
sponding chiral 2-hydrazino-1,3-diols in good yields, enantioselec-
tivities and diastereoselectivities.
(R)-1
NHCbz
NHCbz
1) Cat.*, DBAD, MeCN, r.t.
2) NaBH4, EtOH, 0 °C
Key words: amination, organocatalysis, diastereoselectivity, b-
hydroxyaldehyde, 2-hydrazino-1,3-diol, azodicarboxylate
(S,R)-2
(R,R)-3
OTBS
CbzN
OTBS
OTBS
+
OH
OH
O
a-Functionalization of carbonyl compounds catalyzed by
chiral primary or secondary amines has emerged as a
powerful method to create carbon–carbon or carbon–het-
eroatom bonds.1,2 In this field, electrophilic a-amination3
which was first reported by Jørgensen4 and List5 indepen-
dently in 2002 is an efficient transformation to form C–N
bond stereoselectively. Either aliphatic4,5 or a-branched6
aldehydes or ketones7 undergo this reaction with azodi-
carboxylate and various organocatalysts such as cyclic
amino acids derivatives.8 a-Amino carbonyl derivatives
are obtained in good yields and excellent enantioselectiv-
ities. As a result, this reaction has been employed in sev-
eral natural product syntheses.9 However a-amination of
chiral b-functionalized aldehydes has not been investigat-
ed to date. Herein, we report the asymmetric a-amination
of protected b-hydroxyaldehydes catalyzed by proline and
its derivatives which provide diastereoselectively enan-
tioenriched vicinal amino alcohol in good yields.
CbzN
NHCbz
(S)-1
NHCbz
(R,S)-2
(S,S)-3
Scheme 1
in shorter reaction time with 88% yield and an excellent
diastereomeric ratio of 94:6 (entry 2).12
The same reaction was performed using an achiral orga-
nocatalyst such as pyrrolidine (20 mol%); under these
conditions, the diastereomeric excess did not exceed 8%
(anti/syn, 54:46).
Then, D-proline was tested as chiral organocatalyst, and
the syn-(R,R)-3 compound was obtained as the major
diastereomer in a diastereomeric ratio (anti/syn) of 8:92
(entry 3). This observation suggests a matched-mis-
matched effect.
When substrate (S)-1 was used, similar results were ob-
served. syn-2-Hydrazino-1,3-diol (S,S)-3 or anti-2-
hydrazino-1,3-diol (R,S)-2 were obtained as the major dia-
stereomers with L-proline or D-proline as catalyst, respec-
tively (entries 4 and 5).
The amination reaction of the two antipodes of 3-tert-
butyldimethylsilyloxybutanal10 (1) with dibenzyl azodi-
carboxylate (DBAD) in the presence of proline-type cata-
lysts was selected as a model. The anti- or syn-2-
hydrazino-1,3-diols, 2 or 3, respectively, were isolated af-
ter reduction of the aldehyde using NaBH4 in ethanol Finally, when the reaction was conducted at 0 °C, no im-
(Scheme 1).
provement in terms of yield or selectivity was observed
(entry 6).
Starting from enantiopure (R)-1, the electrophilic amina-
tion organocatalyzed by L-proline afforded the anti-(S,R)- Then, different catalysts were tested for this reaction such
2 compound as the major diastereomer (Table 1).11
as the tert-butoxyprolines I and II13 and the a,a-diarylpro-
linol silyl ether III14 (Figure 1).
First, the reaction was run using 10 mol% catalytic load-
ing and anti-(S,R)-2 was isolated in 62% yield and a dias-
tereomeric ratio of 90:10 (Table 1, entry 1). Increasing the
catalyst loading to 20 mol% gave a better result and the
expected anti-2-hydrazino-1,3-diol (S,R)-2 was obtained
Ot-Bu
Ot-Bu
Ar
Ar
OTMS
CO2H
CO2H
Cat.* =
N
N
H
N
H
H
Ar = 3,5-(CF3)Ph
SYNLETT 2009, No. 18, pp 3007–3010
Advanced online publication: 08.10.2009
x
x
.x
x
.2
0
0
9
I
II
III
DOI: 10.1055/s-0029-1218001; Art ID: G23609ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1

3008
R. Ait-Youcef et al.
LETTER
Table 1 a-Amination of (R)- and (S)-3-tert-Butyldimethylsilyloxybutanal (R)-1 and (S)-1 Organocatalyzed by L- and D-Proline
Entry
Substrate
(R)-1
(R)-1
(R)-1
(S)-1
Catalyst
Time
Yield
62%
88%
69%
72%
84%
53%
anti/syna
90:10
94:6
Major product
(S,R)-2
1
2
3
4
5
6
L-Pro (10 mol%)
L-Pro (20 mol%)
D-Pro (20 mol%)
L-Pro (20 mol%)
D-Pro (20 mol%)
L-Pro (20 mol%)
3.5 h
2.5 h
(S,R)-2
2.5 h
8:92
(R,R)-3
(S,S)-3
2.5 h
8:92
(S)-1
2.5 h
94:6
(R,S)-2
(S)-1
8 h at 0 °C
18:82
(S,S)-3
a Determined by 1H NMR analysis of the crude product.
The use of catalyst I for the amination of (R)-1 did not im- 4-acetate after reduction of the ester group to aldehyde,
prove the diastereoselectivity (anti/syn, 94:6) but a lower was submitted to the a-amination reaction. The anti-a-
yield of 66% was noticed (Table 2, entry 1). A moderate hydrazino alcohol 5 was obtained with a moderate yield of
yield was also obtained with the catalyst II and the diaste- 65% and excellent diastereoselectivity (anti/syn, 95:5; en-
reoselectivity in favor of the aminated product (S,R)-2 de- try 1). In contrast, the formation of the compound 6 was
creased (anti/syn, 78:28; entry 2). Finally, as expected the observed without syn selectivity showing a great enhance-
catalyst III induced the opposite configuration for the cre- ment of the mismatched effect (entry 2). To compare the
ated aminated center giving the syn diastereomer (R,R)-3 influence of protecting groups on the starting material, we
in a ratio of 9:91 and a yield of 75% (entry 5). This last ex- synthesized the functionalized butanal 7 derived from the
periment was run with a longer reaction time (i.e. 24 h).
corresponding b-hydroxyester16 after TBS protection of
the secondary alcohol and reduction of the ester group.
When the reaction was conducted with L-proline, the
product 8 was obtained in 82% yield and a diastereomeric
ratio (anti/syn) of 88:12 (entry 3). If D-proline was used,
the syn diastereomer 9 was the major compound and iso-
lated in 74% yield with a diastereomeric ratio (anti/syn) of
18:82 (entry 4). The enamine intermediate formed with
the aldehyde 7 and D-proline might be less conformation-
ally constrained compared to that obtained with the alde-
hyde 4 as shown by the lower mismatched effect. Finally,
the functionalized pentanal 10 prepared from the corre-
sponding b-hydroxyester17 after TBS protection of the
secondary alcohol and reduction of the ester group was
tested. The use of D-proline gave product 11 in 61% yield
and a anti/syn ratio of 85:15 and the use of L-proline fur-
nished the syn diastereomer 12 with a comparable yield of
63% and a diastereomeric ratio (anti/syn) of 17:83.
The matched-mismatched effect was observed as prece-
dently starting from (S)-1. The catalysts I and II favored
the syn diastereomer (S,S)-3 with the ratios of 11:89 and
33:67, respectively (entries 4 and 5). The anti diastereo-
mer (R,S)-2 was isolated after 24 hours with a very good
yield of 93% and a diastereomeric ratio of 93:7 (entry 6).
This methodology affords a straightforward access to the
four possible stereomers of protected threoninol deriva-
tives 2 and 3 in good yields up to 88% and high diastere-
oselectivities (anti/syn) of 94:6 and 8:92, respectively.15
The anti/syn mixture could be easily separated by medi-
um-pressure liquid chromatography to afford each diaste-
reomer as an enantiopure compound. We examined this
transformation with a variety of functionalized chiral b-
hydroxyaldehydes.
The results are summarized in Table 3. A hindered alde-
hyde containing cyclic acetal (4) obtained from commer-
cially available methyl (4S)-2,2-dimethyl-1,3-dioxolane-
In conclusion, the a-amination of chiral b-hydroxyalde-
hydes organocatalyzed by L- or D-proline followed by a
reduction of the aldehyde functionality was proved to be
an efficient access to the four possible stereomers of the
corresponding 2-hydrazino-1,3-diols with an excellent
control of the stereoselectivity. This transformation could
be easily performed at room temperature using 20 mol%
of catalyst loading.
Table 2 Catalyst Screening for the a-Amination of (R)- and (S)-3-
tert-Butyldimethylsilyloxybutanal (R)-1 and (S)-1
Entry Substrate Catalyst
Time
Yield anti/syna Major
product
1
2
3
4
5
6
(R)-1
(R)-1
(R)-1
(S)-1
(S)-1
(S)-1
I (20 mol%)
II (20 mol%)
1.5 h 66% 94:16 (S,R)-2
0.75 h 64% 72:28 (S,R)-2
Acknowledgment
III (20 mol%) 24 h
75%
9:91 (R,R)-3
We thank the ANR CP2D for financial support.
I (20 mol%)
II (20 mol%)
1.5 h 62% 11:89 (S,S)-3
0.75 h 82% 33:67 (S,S)-3
References and Notes
(1) Xu, L. W.; Luo, J.; Lu, X. Chem. Commun. 2009, 1807.
(2) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
Rev. 2007, 107, 5471.
III (20 mol%) 24 h
93% 93:7
(R,S)-2
a Determined by 1H NMR analysis of the crude product.
Synlett 2009, No. 18, 3007–3010 © Thieme Stuttgart · New York

LETTER
Asymmetric a-Amination of Chiral Protected b-Hydroxyaldehydes
3009
Table 3 a-Amination of Functionalized Chiral b-Hydroxyaldehydes
Entry
1
Substrate
Catalyst
L-Pro
Yield
65%
anti/syna
Major product
O
O
O
O
95:5
OH
OH
O
NCbz
CbzHN
4
5
O
O
O
O
2
D-Pro
70%
50:50
O
NCbz
CbzHN
4
6
OTBS
OTBS
TIPSO
OH
3
4
5
6
L-Pro
D-Pro
D-Pro
L-Pro
82%
74%
61%
63%
88:12
18:82
85:15
17:83
TIPSO
O
O
NCbz
CbzHN
7
8
OTBS
OTBS
TIPSO
OH
TIPSO
NCbz
CbzHN
7
9
OMe OTBS
OMe OTBS
OMe OTBS
MeO
11
OH
MeO
O
NCbz
CbzHN
10
OMe OTBS
MeO
12
OH
MeO
O
NCbz
CbzHN
10
a Determined by 1H NMR analysis of the crude product.
(3) For either diastereoselective or organocatalytic electrophilic
a-amination, see: Greck, C.; Drouillat, B.; Thomassigny, C.
Eur. J. Org. Chem. 2004, 1377.
(4) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.;
Jørgensen, K. A. Angew. Chem. Int. Ed. 2002, 41, 1790.
(5) List, B. J. Am. Chem. Soc. 2002, 124, 5656.
Tetrahedron Lett. 2009, 50, 492. (e) Nishikawa, Y.;
Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron 2009,
65, 1608.
(10) 3-tert-Butyldimethylsilyloxybutanal (1) was synthesized in
two steps (TBS protection and DIBAL-H reduction of the
ester moiety) from ethyl 3-hydroxybutyrate commercially
available in both enantiomeric forms.
(6) (a) Vogt, H.; Vanderheiden, S.; Bräse, S. Chem. Commun.
2003, 2448. (b) Baumann, T.; Vogt, H.; Bräse, S. Eur. J.
Org. Chem. 2007, 266. (c) Baumann, T.; Bächle, M.;
Hartmann, C.; Bräse, S. Eur. J. Org. Chem. 2008, 2207.
(7) (a) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bogevig,
A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254.
(b) Liu, T.; Cui, H.; Zhang, Y.; Jiang, K.; Du, W.; He, Z.;
Chen, Y. Org. Lett. 2007, 9, 3671.
(8) (a) Dahlin, N.; Bøgevig, A.; Adolfsson, H. Adv. Synth.
Catal. 2004, 346, 1101. (b) Thomassigny, C.; Prim, D.;
Greck, C. Tetrahedron Lett. 2006, 47, 1117. (c) Hayashi,
Y.; Arakate, S.; Imai, Y.; Hibino, K.; Chen, Q. Y.;
Yamaguchi, J.; Uchimaru, T. Chem. Asian. J. 2008, 3, 225.
(9) (a) de Figueiredo, R. M.; Christmann, M. Eur. J. Org. Chem.
2007, 2575; and references cited therein. (b) Sudalai, A.
Tetrahedron 2007, 63, 9758. (c) George, S.; Suryavanshi,
G. S.; Sudalai, A. Tetrahedron Lett. 2008, 49, 6791.
(d) Kalch, D.; De Rycke, N.; Moreau, X.; Greck, C.
(11) To determine the relative configuration of anti-2, we
synthesized this compound via diastereoselective electro-
philic amination method from ethyl (R)-3-hydroxybutyrate
using LDA, ZnBr2 and DBAD. For this reaction, see: Genêt,
J. P.; Jugé, S.; Mallart, S. Tetrahedron Lett. 1998, 29, 6765.
(12) General Procedure for the Organocatalytic a-
Amination: Dibenzylazodicarboxylate (1 mmol) and D- or
L-proline (0.2 mmol, 20 mol%) in MeCN (10 mL) were
treated with an aldehyde (1.5 mmol) at r.t. The reaction
mixture was stirred at this temperature until the yellow color
of the azodicarboxylate had disappeared. The mixture was
treated with EtOH (10 mL) and NaBH4 (40 mg) and was
stirred for 5 min at 0 °C. The reaction was worked up with
aq NH4Cl solution and EtOAc. The organic layers were
dried (MgSO4), filtered, and concentrated. Medium-pressure
column chromatography on silica gel with EtOAc–pentane
Synlett 2009, No. 18, 3007–3010 © Thieme Stuttgart · New York

3010
R. Ait-Youcef et al.
LETTER
mixture (1:4) gave the desired anti- or syn-2-hydrazino-1,3-
diol as a single diastereomer.
[a]D25 –25 (c = 1, CH2Cl2) for (S,R)-2; [a]D25 +24 (c = 1,
CH2Cl2) for (R,S)-2.
(13) Ait-Youcef, R.; Kalch, D.; Moreau, X.; Thomassigny, C.;
Greck, C. Lett. Org. Chem. 2009, 6, 377.
(14) Franzén, J.; Marigo, M.; Fielenbach, D.; Kjrsgaard, A.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296.
(15) Characterization of Selected Compounds:
Compound 3: 1H NMR (300 MHz, CDCl3): d = (–0.01)–0.05
(m, 6 H), 0.81–0.82 (m, 9 H), 1.08–1.18 (m, 3 H), 3.48–4.04
(m, 4 H), 4.20–4.38 (m, 1 H), 5.14–5.30 (m, 4 H), 6.69–6.74
(m, 1 H), 7.32–7.37 (m, 10 H). 13C NMR (75 MHz, CDCl3):
d = –5.3, –5.2, –4.3, –4.2, 17.6, 21.2, 21.3, 25.5, 25.6, 59.7,
59.8, 64.1, 65.8, 68.1, 68.2, 68.5, 68.7, 127.6, 128.0, 128.1,
128.2, 128.4, 128.5, 135.2, 135.5, 135.8, 156.3, 156.9,
157.6, 158.2. MS (ESI): m/z = 525.4 [M + Na+]. IR: 3401,
3270, 2953, 2855, 1721, 1256, 1072, 836, 776, 696 cm–1.
Anal. Calcd for C26H38N2O6Si: C, 62.12; H, 7.62; N, 5.57.
Found: C, 62.02; H, 7.35; N, 5.55. [a]D25 –3 (c = 1, CH2Cl2)
for (R,R)-3; [a]D25 +3 (c = 1, CH2Cl2) for (S,S)-3.
Compound 2: 1H NMR (300 MHz, CDCl3): d = 0.01–0.05
(m, 6 H), 0.86 (s, 9 H), 1.08–1.16 (m, 3 H), 3.51–3.99 (m, 4
H), 4.15–4.33 (m, 1 H), 5.16–5.29 (m, 4 H), 6.54 (s, 1 H),
7.28–7.37 (m, 10 H). 13C NMR (75 MHz, CDCl3): d = –5.1,
–4.3, 17.7, 21.1, 25.6, 59.1, 59.6, 66.3, 67.0, 67.4, 68.1, 68.3,
68.5, 127.5, 127.7, 128.0, 128.1, 128.3, 128.4, 128.5, 135.0,
135.4, 135.6, 156.0, 157.0, 158.2, 158.9. MS (ESI): m/z =
525.4 [M + Na+]. IR: 3409, 3272, 2955, 2856, 1722, 1268,
1097, 833, 777, 696 cm–1. Anal. Calcd for C26H38N2O6Si: C,
62.12; H, 7.62; N, 5.57. Found: C, 62.06; H, 7.55; N, 5.48.
(16) Bourdreux, Y.; Drouillat, B.; Greck, C. Synlett 2005, 2086.
(17) Poupardin, O.; Greck, C.; Genêt, J. P. Synlett 1998, 1279.
Synlett 2009, No. 18, 3007–3010 © Thieme Stuttgart · New York

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