Highly diastereoselective and enantioselective direct organocatalytic anti-selective Mannich reactions employing N-tosylimines

Article abstract of DOI:10.1039/b706793c

Organocatalytic direct anti-selective Mannich reactions of O-TBS-hydroxyacetone with various N-tosylimines derived from aromatic aldehydes in the presence of L-threonine-derived catalyst afforded 1,2-amino alcohols in good yields and with enantioselectivi

Full text of DOI:10.1039/b706793c

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Highly diastereoselective and enantioselective direct organocatalytic
anti-selective Mannich reactions employing N-tosylimines{
Lili Cheng,a Xiao Han,a Huiming Huang,a Ming Wah Wonga and Yixin Lu*ab
Received (in Cambridge, UK) 8th May 2007, Accepted 9th July 2007
First published as an Advance Article on the web 3rd August 2007
DOI: 10.1039/b706793c
sulfone functionality are expected to form hydrogen bonds with
hydrogen bond donors in the threonine-derived catalysts. If the
above interactions are optimized to yield a well-defined transition
state, high enantioselectivity could be achieved.
Organocatalytic direct anti-selective Mannich reactions of
O-TBS-hydroxyacetone with various N-tosylimines derived
from aromatic aldehydes in the presence of L-threonine-derived
catalyst afforded 1,2-amino alcohols in good yields and with
enantioselectivities of 99% in almost all cases.
We performed our initial screenings with O-TBS-hydroxyace-
tone and N-tosylimine, in the presence of various siloxy containing
organocatalysts (Table 1). To our delight, anti-Mannich products
with excellent enantiomeric excess were obtained when the
reactions were carried out in the presence of water (entries 1–3).
A solvent screening (entries 4–11) was then performed to identify
the best reaction conditions. Among the various organic solvents
tested, toluene was found to be the best solvent. When the reaction
was carried out in toluene in the presence of catalyst 1a, the desired
product was obtained in good yield with 27 : 1 anti to syn
selectivity and with 99% ee (entry 6).
The asymmetric Mannich reaction1 is one of the most powerful
carbon–carbon bond-forming reactions for the construction of
nitrogen-containing compounds. The utilization of this reaction
allows for the preparation of optically enriched b-amino carbonyl
compounds and their derivatives.2 The direct Mannich reactions
employing ketones and preformed imines were recently reported
by Trost,3 Shibasaki4 and Jorgensen.5 Because of the synthetic
versatility of amino carbonyl compounds, it is of great interest to
generate Mannich products with either syn- or anti-selectivity. The
syn-Mannich reactions are quite well-established, and have been
accomplished by using Cu-,5a,6 In-,4b La-,7 Zr-8 or Zn-derived3a,9
organometallic catalysts. With the recent exciting development of
organocatalysis,10 a number of organocatalysts have also been
found to catalyze syn-selective Mannich reactions. These catalysts
include Brønsted acids,11 cinchona alkaloids,12 phase-transfer
catalysts,13 and proline and its derivatives.14 On the other hand,
anti-selective Mannich reactions are more challenging.3b4a,15 We
recently disclosed primary amino acid-promoted direct asymmetric
aldol reactions and Mannich reactions in the presence of water.16
Herein, we wish to report highly enantioselective and anti-selective
Mannich reactions between an unmodified hydroxy ketone and
N-tosylimines that can be promoted by a threonine-derived
organocatalyst.
Organocatalyst 1a proved to be remarkably effective (Table 2).
The reactions between O-TBS-hydroxyacetone and various
N-tosylimines afforded the anti-selective Mannich products in
Table 1 Screening of the asymmetric Mannich reactions between
O-TBS-hydroxyacetone and N-tosyliminea
Hydroxyacetone is a very useful donor, and its Mannich
reaction could yield synthetically versatile 1,2-amino alcohols. In
our earlier report,16c we described the successful development of
direct asymmetric three-component anti-Mannich reactions
employing an aldehyde, 4-methoxyaniline (p-anisidine), and
O-benzyl hydroxyacetone with threonine-derived 1b as the
organocatalyst. To further develop more efficient anti-Mannich
reactions, we reasoned that the combination of properly designed
preformed imine and threonine-based catalyst might be a feasible
approach. N-Tosylimines5a,17 have been widely used, and might be
good substrates in our reactions. The two oxygen atoms from
Entry Catalyst Solvent Time/h Yieldb (%) anti : sync eed (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
H2O
H2O
H2O
DMSO 42
toluene 42
toluene 37
THF
CH2Cl2 37
DMF 37
dioxane 37
CHCl3 37
36
42
42
51
38
45
—
67
76
43
54
10 : 1
6 : 1
11 : 1
—
21 : 1
27 : 1
4 : 1
13 : 1
—
99
98
99
—
99
99
91
98
—
92
99
e
37
,5
20
54
10
11
a
4 : 1
14 : 1
aDepartment of Chemistry, National University of Singapore, 3 Science
Drive 3, Singapore, 117543, Republic of Singapore.
E-mail: chmlyx@nus.edu.sg; Fax: +65-6779-1691; Tel: +65-6516-1569
bThe Medicinal Chemistry Program, Office of Life Sciences, National
University of Singapore, Singapore
{ Electronic supplementary information (ESI) available: Experimental,
characterisation of products and Cartesian coordinates of the optimized
(HF/3-21G) anti-transition state. See DOI: 10.1039/b706793c
The reactions were performed with O-TBS-hydroxyacetone (either
at 0.5 mmol (entries 1–5) or 0.11 mmol (entries 6–11)), N-tosylimine
(0.1 mmol) and catalyst (0.01 mmol) in solvent (0.2 ml) at room
b
c
temperature; Isolated yield. The anti to syn ratio was determined
by 1H NMR analysis of the crude product. The ee value of the
d
e
anti-isomer was determined by chiral HPLC analysis.
determined.
Not
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Chem. Commun., 2007, 4143–4145 | 4143

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Table 2 Organocatalyst 1a-promoted direct Mannich reactions with
various N-tosylimines derived from aromatic aldehydesa
Entry Product
Time/h Yieldb (%) anti : sync eed (%)
1
2
3
4
5
6
7
8
9
4 (R = p-Br)
5 (R = p-Cl)
6 (R = p-F)
7 (R = o-CF3)
8 (R = p-CH3)
9 (R = o-CH3)
10 (R = p-OCH3)
11 (R = 1-naphthyl) 44
12 (R = 2-naphthyl) 44
13 (R = p-CN)
14 (R = p-NO2)
40
28
40
24
44
45
44
70
76
79
76
87
75
67
61
75
74
87
23 : 1
23 : 1
12 : 1
34 : 1
20 : 1
102 : 1
18 : 1
70 : 1
40 : 1
40 : 1
17 : 1
99
99
99
99
99
99
99
99
99
99
97
10
11
a
63
72
Fig. 1 Calculated transition state for the anti- Mannich product
formation: the important role of the sulfone group in stabilizing the
transition state is reflected in the hydrogen bonds (dotted lines).
The reactions were performed with O-TBS-hydroxyacetone
(0.11 mmol), N-tosylimine (0.1 mmol) and catalyst (0.01 mmol) in
b
c
toluene (0.2 ml) at room temperature. Isolated yield. The anti to
syn ratio was determined by 1H NMR analysis of the crude product.
The ee value of the anti-isomer was determined by chiral HPLC
d
also gave excellent results (entry 7). However, reactions employing
preformed PMP-, Bn- or Boc-18 imines only afforded low
enantioselectivities (entries 3–5). While natural tryptophan or
threonine was completely ineffective (entries 1 and 2), threonine
derivative with sterically hindered group at the hydroxy position
was effective (entry 9). Preliminary calculations{ have supported
the key experimental findings, and the calculated transition state
for the major anti- product is depicted in Fig. 1. Both sulfone
oxygen atoms are involved in hydrogen bondings in the calculated
transition state for the major stereoisomer, and the formation of
Z-enamine is facilitated by hydrogen bonding. Furthermore, our
calculations suggest that the enantioselectivity is independent of
the electronic nature of the tosyl aromatic group. The predominant
isomer can be formed via the attack of N-tosylimine by the
enamine from the Si face.
analysis.
good yields with excellent diastereoselectivity and enantio-
selectivity. The method is applicable to virtually any aromatic
aldehydes, regardless the electronic nature of the aryl aldehyde. An
extension to Mannich reactions involving aliphatic aldehydes was
unsuccessful. The Mannich reactions employing N-tosylimines
derived from aliphatic aldehydes lead to complex product
mixtures.
The absolute configuration of the Mannich product was
determined to be (3R, 4R)-3. The reaction mechanism is unclear
at the moment. We have carried out some preliminary experiments
to explore the importance of various groups in this highly
enantioselective anti-Mannich reaction (Table 3). Sulfonamide
functionality appears to be important, and methanesulfonamide
In summary, we discovered that employment of N-tosylimines
can result in remarkably efficient enantioselective anti-Mannich
reactions. The involvement of both oxygen atoms of sulfone in
hydrogen bonding network to stablize the transition state is
unprecedented, and may have implications for the design of novel
organocatalytic systems. Computational studies to fully under-
stand the observed high stereoselectivities and mechanistic
investigations are in progress in our laboratory, and will be
reported in due course.
Table 3 Sulfonamide functionality is important in promoting reac-
tions with high stereoselectivitiesa
Entry R1 R2
Cat
Time/h Yieldb (%) anti : sync eed (%)
We wish to thank the National University of Singapore for
generous financial support and Professor Peter W. Schiller for
proof-reading.
e
—
1
2
TBS Ts
TBS Ts
44
72
,10
—
—
L-Trp
L-Thr
—
—
3
4
5
6
7
8
9
a
TBS PMP 1a
25
20
48
40
48
40
80
93
,20
,20
75
1 : 3
1 : 1
—
51
17
—
—
98
98
99
Notes and references
TBS Bn
TBS Boc
1a
1a
1a
1 C. Mannich and W. Krosche, Arch. Pharm. (Weinheim, Ger.), 1912,
250, 647.
H
Ts
—
TBS SO2Me 1a
Bn Ts
TBS Ts
14 : 1
20 : 1
50 : 1
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1a
47
,30
O-tBu-Thr 44
The reactions were performed with hydroxyacetone (0.11 mmol),
imine (0.1 mmol) and catalyst (0.01 mmol) in toluene (0.2 ml) at
room temperature. Isolated yield. The anti to syn ratio was
b
c
determined by 1H NMR analysis of the crude product. The ee
d
value of the anti-isomer was determined by chiral HPLC analysis.
Not determined.
e
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Chem. Commun., 2007, 4143–4145 | 4145