Rational design of asymmetric organocatalysts - Increased reactivity and solvent scope with a tetrazolic acid

Article abstract of DOI:10.1016/j.tetasy.2004.04.029

Replacement of the carboxylic acid functionality in the widely used organocatalyst proline with a tetrazolic acid leads to a catalyst with increased reactivity and solvent scope, as demonstrated in the direct catalytic asymmetric aldol reaction.

Full text of DOI:10.1016/j.tetasy.2004.04.029

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1831–1834
Rational design of asymmetric organocatalysts––increased
reactivity and solvent scope with a tetrazolic acid
Antti Hartikka and Per I. Arvidsson*
Organic Chemistry, Department of Chemistry, Box 599, SE-751 24 Uppsala, Sweden
Received 16 April 2004; accepted 26 April 2004
Available online 28 May 2004
Abstract—Replacement of the carboxylic acid functionality in the widely used organocatalyst proline with a tetrazolic acid leads to a
catalyst with increased reactivity and solvent scope, as demonstrated in the direct catalytic asymmetric aldol reaction.
Ó 2004 Elsevier Ltd. All rights reserved.
Catalysis of asymmetric reactions by simple metal-free
organic molecules is currently receiving immense inter-
for several of these transformations are slow, a fre-
quently encountered disadvantage of organocatalyzed
reactions.
1
est. The seminal work by List, Lerner, Barbas and
2
others on the intermolecular adaptation of the proline
catalyzed direct asymmetric aldol reactions (Hajos–
With this in mind, we set out to design a more reactive
catalyst for the direct asymmetric aldol reaction. Both
experimental and theoretical studies support that the
rate-determining step of this reaction in solution is the
reaction between enamine intermediate I, initially
formed after condensation of proline with the ketone
component, with the aldehyde component II proceeding
through transition state A TS-A and leading to product
3
Parrish–Eder–Saur–Wiechert reaction) nicely illustrates
the advantages of this methodology, which is charac-
terized by operational simplicity, high efficiency, and a
biomimetic ‘green’ approach. Further studies, primarily
by the groups of List and Barbas, have demonstrated
the use of enamine intermediates also in other important
4
5
reactions, for example, Mannich, Michael, and elec-
6
8
trophilic a-amination. Surprisingly, the parent amino
III, Scheme 1.
acid proline is often found to be the most efficient cat-
alyst for these enamine mediated processes, yielding
high stereoselectivity and yield for various substrates in
Several theoretical studies have highlighted the impor-
tance of the carboxylic acid functionality of proline
in this reaction. The role of the carboxylic acid is
7
several different reaction types. Still, the reaction rates
O
O
O
O
O
O
O
OH
-
H2O
N
N
OH
N
R
H
OH
N
H
OH
II
I
H
R
R
OH
O
N
+ H2O
N
N
R
O
H
OH HO
OH
O
R
O
O
O
O
O
H
III
TS-A
Scheme 1. Proposed mechanism for the proline catalyzed asymmetric aldol reaction.
*
0
Corresponding author. Tel.: +46-18-471-3787; fax: +46-18-471-3818; e-mail: per.arvidsson@kemi.uu.se
957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.029

1832
A. Hartikka, P. I. Arvidsson / Tetrahedron: Asymmetry 15 (2004) 1831–1834
dual: First, it orients the incoming aldehyde through
a hydrogen bond, which ensures that the reaction
proceeds on only one face of the pyrrolidine ring.
The second, and most important, role of the carboxylic
acid function is to lower the activation barrier of the
reaction by charge stabilization along the C–C bond-
formation by means of the intramolecular hydro-
gen bond shown in TS-A. Theoretical studies have
suggested that this stabilization could lower the activa-
tion barrier for the aldol reaction with up to 18 kcal/
Direct catalytic aldol reactions between acetone and the
‘benchmark’ substrate p-nitrobenzaldehyde 2, to yield
(R)-4-hydroxy-4-(p-nitrophenyl)-butan-2-one 3, were set
up to assess the effect on rate and selectivity upon sub-
1
stitution of the carboxylic acid to tetrazolic acid. H
NMR spectroscopy was used to monitor the progress of
14
the reaction. As seen in Figure 1a, the reactivity dif-
ference between 1 and proline is small for this highly
reactive aldehyde. However, it should be noted that 1
repeatable gives full conversion of the substrate, while
the reaction with proline at 20% catalyst loading often
slows down considerably after about 70% conversion.
The short reaction times needed to get >90% conver-
sions with this substrate are notable. Previous studies
with proline as catalyst typically report reaction times of
24–48 h. Thus, also the proline catalyzed process ap-
pears faster than previously noted.
8b
mol; this is also supported by experiment showing that
2c
the carboxamide of proline is unreactive. Based on the
suggested mechanism, we reasoned that a stronger
hydrogen bond donor should lower the energy of the
transition state further, and thus lead to increased
reactivity.
We figured, that a suitable catalyst could be obtained
by replacing the carboxylic acid functionality in
proline with a tetrazolic acid, that is yielding 5-pyrrol-
The practical significance of the increased reactivity of
the tetrazole derivative over proline gets more apparent
when less reactive aldehydes are employed as aldol
acceptors. A large difference in reaction rate is seen for
the reaction of p-methoxybenzaldehyde 4 to yield (R)-4-
hydroxy-4-(p-methoxyphenyl)-butan-2-one 5 (Fig. 1b),
and for the transformation of the aliphatic aldehyde
9
idine-2-yltetrazole 1. Compound 1 was readily prepared
by catalytic hydrogenation of the CBz-protected
analogue, which in turn was synthesized through
Sharpless’ recently developed ‘click’-methodology,
10
Scheme 2.
trimethylacetaldehyde
methyl-hexan-2-one 7 (Fig. 1c).
6
into (R)-4-hydroxy-5,5-di-
Tetrazoles and carboxylic acids have similar structural
requirements and aqueous pK values; however, the
tetrazole group has increased lipophilicity and metabolic
a
Regarding the enantioselectivity, no large differences
were seen between the two catalysts, as might be
expected by the similar three-dimensional (flat) structure
of the carboxylic- and tetrazolic acid function.
11
stability. These properties have led to a widespread use
of tetrazoles as carboxylic acid replacements in medici-
nal chemistry, but catalysts containing a tetrazole
12
functionality have only been reported very recently.
Although the pK of a tetrazole and its corresponding
carboxylic acid is very similar in aqueous solution, the
a
Another rationale for the tetrazolic acid replacement
was the increased lipophilicity of this group as compared
to the carboxylic acid. Catalyst 1 would be expected to
have a larger solvent scope than proline. To investigate
this proposal, we performed the aldol reaction between
acetone and 2 in various solvents (Table 1, entries 1–12).
The tetrazole catalyst 1 was shown to be more reactive
than proline in all solvents investigated. In addition, it
was found that the reaction could be performed in less
polar solvents than those normally employed for the
reaction. The reactivity and selectivity of 1 in DMF was
comparable to that obtained in DMSO, suggesting that
DMF is the solvent of choice for the direct asymmetric
aldol reaction with this catalyst. In contrast to what was
observed in DMSO, addition of up to 10% water to the
DMF leads to a small increase in enantioselectivity
(cf. entries 3, 4, and 13). The use of DMF, instead of
pK difference in organic solvents can be markedly dif-
a
ferent as evidenced for acetic acid (pK
pK
a
(H
(H
2
O) ¼ 4.75,
a
(DMSO) ¼ 12.3) and tetrazole (pK
a
2
O) ¼ 4.86,
13
pK (DMSO) ¼ 8.2). Since DMSO is the most com-
a
monly employed solvent for the proline catalyzed aldol
condensation we thought that proline tetrazole might
show increased reactivity as compared to proline. Fur-
ther, the use of DMSO is expected to promote the for-
mation of a Zimmerman–Traxler type of TS, as the
required 1H-tautomer of the tetrazole functionality is
known to be predominant in polar aprotic media like
DMSO. Catalyst 1 is also expected to stabilize the
developing negative charge in TS-A better than proline,
due to charge delocalization over the whole tetrazole
ring.
O
COOH
COOH
Boc2O
CBz-Cl
90%
Cyanuric chloride
96%
CN
NH2
N
H
N
CBz
NH HCO
N
CBz
4
3
N
CBz
96%
N N
N N
N N
NH
NaN3, ZnBr2
8%
2
H , Pd/C
95%
N
N
9
N
N
H
N
N
CBz
N
N
H
H
H
1-1H
1-2H
Scheme 2. Synthesis of 5-pyrrolidine-2-yltetrazole 1. Compound 1 exists as a mixture of tautomers 1-1H and 1-2H.

A. Hartikka, P. I. Arvidsson / Tetrahedron: Asymmetry 15 (2004) 1831–1834
1833
Table 1. Direct catalytic asymmetric aldol reaction between acetone
and p-nitrobenzaldehyde 2 in various solvents
O
OH O
Cat. 20%
H
Acetone : DMSO
a
b
1
:
4
Entry
Solvent
Catalyst
Temp
(°C)
Yield
(%)
Ee
(%)
O N
O N
2
2
2
3
1
2
3
4
5
6
7
8
9
DMSO
DMSO
1
Proline
25
25
25
25
25
25
25
25
25
25
25
25
25
5
93
75
76
36
88
55
70
45
85
83
93
50
89
80
77
76
73
71
63
66
44
61
54
0
100
Proline 73 % ee
1
c
c
DMSO/H
DMSO/H
Dioxane
Dioxane
Toluene
Toluene
2
O
O
1
Proline
80
76 % ee
2
1
Proline
6
4
0
0
1
Proline
d
PBS
PBS
1
Proline
d
10
11
12
13
14
15
0
20
Proline
DMF
DMF
1
Proline
70
70
76
81
86
1
0
c
DMF/H
DMF
2
O
1
1
1
0
500
1000
1500
Time (s)
2000
2500
3000
DMF
)50
O
OH O
Cat. 20%
Acetone : DMSO
14
All reactions were performed with 20 mol % catalyst. The reaction
time was 4 h.
H
1
: 4
a
MeO
MeO
Isolated yield after chromatography.
Enantiomeric excess of (R)-4.
b
4
5
c
10% water added.
PBS buffer at pH 7.4.
100
d
Proline 65 % ee
80
1
67 % ee
To summarize, we have presented an efficient synthetic
route to the tetrazolic acid analogue of proline, and
shown that this catalyst has markedly increased reac-
tivity, as compared to proline, in the direct asymmetric
aldol reaction. In addition to increased reactivity, this
new catalyst also shows expanded solvent scope. The
wide use of proline in organocatalyzed processes, and
the fact that organocatalyzed reactions often depend on
essential hydrogen bond stabilization of the transition
state, suggest that 1 and other tetrazole derivatives will
be useful new entities for organocatalyst design.
6
0
Proline
4
0
0
0
2
1
0
50
100
150
200
250
Time (min)
O
OH O
Cat. 20%
H
Acetone : DMSO
1
: 4
6
7
100
Proline
Acknowledgements
80
Proline 99 % ee
Financial support from The Swedish Research Council
(VR) is gratefully acknowledged. Jenny Jansson con-
tributed to the synthesis of 1 during an undergraduate
training period.
6
0
0
1
99 % ee
4
1
20
0
0
100
200
300
400
Time (min)
500
600
700
800
References and notes
1
2
. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001,
Figure 1. Graphs showing the conversion of starting aldehyde as a
function of time during catalyzed direct asymmetric aldol reaction with
acetone at 25 °C. As seen, the reaction with the tetrazole catalyst 1 is
considerably faster with proline, especially for more unreactive sub-
4
5
0, 3726; (b) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002,
8, 2481.
. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem.
Soc. 2000, 122, 2395; (b) List, B.; Pojarliev, P.; Castello, C.
Org. Lett. 2001, 3, 573; (c) Sakthivel, K.; Notz, W.; Bui,
T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260;
14
strates. Typical experimental procedures are described.
DMSO, also allows the reaction temperature to be
lowered. As expected, a lower reaction temperature
leads to an increase in enantioselectivity, while the
reactivity in this case is surprisingly well maintained
(
d) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.;
Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc.
003, 125, 5262; For a review on asymmetric aldol
2
reactions, see: (e) Palomo, C.; Oiarbide, M.; Garcia, J.
M. Chem. Soc. Rev. 2004, 33, 65.
(
entries 11, 14, and 15).

1834
A. Hartikka, P. I. Arvidsson / Tetrahedron: Asymmetry 15 (2004) 1831–1834
3
4
5
6
. (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
615; (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem.,
Int. Ed. 1971, 10, 496; (c) Cohen, N. Acc. Chem. Res. 1976,
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Porjalev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc.
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1
clic Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E.
F. V., Eds.; Pergamon: Oxford, UK, 1996; Vol. 4; (b)
Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379.
9
12. Some of the results presented herein first appeared on a
poster at the ‘Uppsala University Section of Chemistry
Conference’ in October 2003: (a) Artikka, A.; Arvidsson,
P. I. ‘Core Ligand Structures from Nature––Development
and Application of Asymmetric Catalysts’. Two other
papers describing the use of 1 in organocatalytic reactions
have appeared during preparation of this manuscript:
Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 3,
558; (b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
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790; (c) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.;
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24, 6254.
14. General procedure: L-proline or 1 (0.02 mmol) was stirred
in a mixture of the solvent and acetone (4:1, 1 mL) for
15 min. Thereafter, the aldehyde acceptor (0.1 mmol) was
added and the homogenous mixture stirred for the
reported time. The mixture was quenched with 1 mL of
1
7
. (a) List, B. Synlett 2001, 11, 11675; (b) List, B. Tetrahe-
dron 2002, 58, 5573.
8
. (a) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J.
Am. Chem. Soc. 2003, 125, 16; (b) Bahmanyar, S.; Houk,
K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125,
satd aq NH
organic layer was dried (Na
trated to give the aldol products after column chromato-
graphy. Conversions were determined directly by
performing the reaction in an NMR tube using DMSO-
4
Cl solution and extracted with EtOAc. The
SO ), filtered, and concen-
2
4
2475; (c) Arno, M.; Domingo, L. R. Theor. Chem. Acc.
2002, 108, 232; (d) Rankin, K. N.; Gauld, J. W.; Boyd, R.
J. J. Phys. Chem. 2002, 106, 5155.
. Almquist, R. G.; Chao, W.-R.; Jennings-White, C. J. Med.
Chem. 1985, 28, 1067.
6
d and solvent suppression of the acetone signal. The
9
enantioselectivity was determined after chromatography
using Daicel Chiralpak AS (3 and 5) or Chiralpak AD (7)
as reported in Ref. 2d.
1
0. Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4, 2525.