Kinetic resolution of trans-cycloalkane-1,2-diols via Steglich esterification

Article abstract of DOI:10.1039/c001075h

We describe the efficient and highly enantioselective kinetic resolution of trans-cycloalkane-1,2-diols utilizing an enantioselective Steglich reaction with a variety of carboxylic acids that form the corresponding anhydrides in situ.

Full text of DOI:10.1039/c001075h

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Kinetic resolution of trans-cycloalkane-1,2-diols via Steglich
esterificationw
Radim Hrdina,z Christian E. Mullerz and Peter R. Schreiner*
¨
Received (in Cambridge, UK) 18th January 2010, Accepted 1st February 2010
First published as an Advance Article on the web 25th February 2010
DOI: 10.1039/c001075h
We describe the efficient and highly enantioselective kinetic
resolution of trans-cycloalkane-1,2-diols utilizing an enantio-
selective Steglich reaction with a variety of carboxylic acids that
form the corresponding anhydrides in situ.
resolution of 26 and the desymmetrization of cis-1,2-diols10
by enantioselective acylation using various anhydrides. The
origin of the observed high enantioselectivities was proposed
to arise from the preferential binding of one trans-1,2-diol
enantiomer to the peptide catalyst in the rate-limiting
stereodifferentiating step;6 independent computations provided
convincing evidence for this proposal.11 These findings led us
to re-examine the Steglich esterification protocol and its
adaptation to an enantioselective version.
Esterification is one of the key reactions that ubiquitously
appear both in nature and in organic synthesis.1 While
biosynthetic ester formation generally proceeds through a
mixed anhydride consisting of the transferred acyl function
and ATP,2 the chemist’s often employed variant is the Steglich
esterification using acids and carbodiimides in the presence of
4-dimethylaminopyridine (DMAP) as a nucleophilic catalyst.3
This reaction is viewed as proceeding through an O-acyl
isourea intermediate4 that is converted into a symmetrical
anhydride of the corresponding acid.5 As we recently showed
that trans-cycloalkane-1,2-diols (2)6 can be kinetically resolved
utilizing anhydrides and an oligopeptide catalyst (such as 1,
Scheme 1), we envisaged a Steglich-type protocol by using a
variety of achiral carboxylic acids (3) for the resolution of
rac-2. Using the acids instead of the anhydrides is a clear
advantage when a particular anhydride cannot be prepared (as
for, e.g., formic acid, 3a) or is generally not readily available
(as for, e.g., phenylacetic acid, 3g).
To probe this idea we first applied a modified Steglich
protocol to the enantioselective kinetic resolution of (ꢀ)-2
using nucleophilic oligopeptide 1 in place of DMAP of the
original reaction. Indeed, the same high enantioselectivity
levels of the present protocol as compared to reactions utilizing
the pre-formed anhydrides6 underscores the in situ anhydride
formation and the high utility of this transformation.
We first optimized the conditions for the kinetic resolution
of (ꢀ)-2 using acetic acid and dialkylcarbodiimides in toluene
with 2 mol% of 1 at 0 1C (Table 1). Nonpolar toluene has
proven to be the best solvent for this transformation probably
because of intermediate salt formation and tight ion pair
association at the acylium ion stage required for stereoinduction;
DCM can also be employed but gives a lower S-value for 4b.
The choice of carbodiimide is not critical but the highest
enantioselectivity for the resolved diol was obtained with
diisopropylcarbodiimide (DIC). Remarkably, a comparison
of the acetylation of 2 with DMAP vs. 1 shows that our
catalyst not only is much more active but also that diacylation,
There are many highly selective acylation protocols for
alcohols,7 yet, to the best of our knowledge, none that use
carboxylic acids with carbodiimides, i.e., an enantioselective
Steglich esterification. On the other hand, there are only a few
reports on the generation of anhydrides for the resolution of
alcohols or acids8 and the generalization of these protocols
would expand the versatility of this important reaction.
Of a variety of simple, chiral, and highly lipophilic oligo-
peptides9 bearing an N-p-methyl histidine catalytic moiety 1
has been shown to be very effective in catalyzing the kinetic
Table 1 Kinetic resolution of trans-cyclohexane-1,2-diol (ꢀ)-2 under
various conditions; optimization studies
Molar ratio
ee (%)
(ꢀ)-2 3b DIa
(R,R)-4b (S,S)-2
t/h C (%)b
Se
1
1
1
1
1
1
1
1
1
1
2
2
2
2
DCC, 1.0 14
DIC, 1.0 14
EDC, 1.0 14
51
54
46
55
56
56
9
87
83
89
81
80
76
77
91
97
76
>99
>99
98
45
44
39
>50
>50
33
Scheme 1 The Steglich reaction catalyzed by nucleophilic catalyst 1.
DIC, 1.2
DIC, 2.0
DIC, 1.2
DIC, 1.2
10
7
Institute of Organic Chemistry, Justus-Liebig University,
Heinrich-Buff-Ring 58, 35392 Giessen, Germany.
E-mail: prs@org.chemie.uni-giessen.de; Fax: 0641/99 34309;
Tel: 0641/99 34300
w Electronic supplementary information (ESI) available: Experimental
procedures and spectra. See DOI: 10.1039/c001075h
z RH and CEM are considered equal first authors.
8c
24d
8
8
a
b
DI = Diimide, equiv. given. Conversion. At r.t. In DCM.
c
d
e
S-values (selectivity factors) determined by the method of Kagan
and Fiaud.12
ꢁc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 2689–2690 | 2689

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Table 2 Kinetic resolution of cyclic trans-1,2-diols
Sterically hindered acids (3e) and (3f) react more slowly;
substituted benzoic acids generally react quite sluggishly,
owing to the increased stability of the intermediate acylium
ions. This is apparent from a comparison of the conversion
times for 3h–j. As found for the use of isobutyric anhydride,13
isobutyric acid 3d leads to the highest ee for 4.
n
t/h
C (%)b
ee (%)
Sc
We have shown here that the much utilized Steglich
esterification protocol can be readily adapted to the enantio-
selective acylation of 1,2-trans-cycloalkane diols utilizing a
short peptide catalyst with a catalytically active His-moiety
and a broad variety of carboxylic acids. The mechanistic
details are currently being elucidated and will be recorded
in full in due course. The adaptation of this strategy to
monoalcohols and possibly other nucleophiles will require
the development of other catalysts, for which the current
platform is a highly promising starting point.
1
3
4
10
16
18
76
55
55
8b, 32
9b, 82
10b, 81
5 >99
6 >99
7 >99
11
>50
>50
a
b
= Diimide, here: DIC. Conversion. S-values (selectivity
c
DI
factors) determined by the method of Kagan and Fiaud.12
as observed to some extent in the reaction with DMAP, does
not occur. The optimized conditions were applied to the
kinetic resolution of other cyclic trans-1,2-diols (Table 2).
The selectivities remained high in all cases and compare very
well to the analogous reaction of the diols with the anhydrides,
which can be rationalized on the basis of the uncatalyzed rapid
anhydride formation.
This work was supported by the Deutsche Forschungsge-
meinschaft (SPP 1179) and the Alexander-von-Humboldt
Foundation (Fellowship to RH).
Notes and references
The next step was the variation of the acid to probe the
generality and utility of this esterification protocol (Table 3).
Apart from electron-donor substituted benzoic acids, the
present protocol is of broad utility. Phenylacetic acid (3g)
was the most reactive, and the kinetic resolution was complete
after only two hours, which is about five times faster than the
acetylation.
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Table 3 Kinetic resolution of trans-cyclohexane-1,2-diols (2) using
various acids
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Carboxylic acid
ee (%)
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4
2
t/h
C (%)b
Sf
3a
3b
HCOOH
CH3COOH
7
15
15
67d
55
41
83
82
83
>99
98
6
>50
45
(51, 39)c
3c
3d
15
41
55
(48, 43)c
83
90
>99
98
>50
>50
24
45
48
54
85
90
86
>99
98
>50
>50
14
(55, 41)c
4e
3e
4
3f
48
60e
57
85
9
3g
PhCH2COOH
2
2
48
48
48
57
(54, 41)c
38e
75
82
60
60
>99
>99
36
84
3
>50
>50
6
10
n. d.
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Rev., 2007, 107, 5759.
3h
3i
3j
PhCOOH
p-Cl-PhCOOH
p-CH3O-PhCOOH
58e
n. d.e
n. d.
10 C. E. Muller, D. Zell and P. R. Schreiner, Chem.–Eur. J., 2009, 15,
9647.
¨
a
b
DI = Diimide, here: DIC. Conversion determined by chiral GC.
c
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Preparative reaction at 1 mmol scale with 1 mol% of 1, isolated
d
product yields of 2 and 4 in %. Doubled solvent volume. 2 equiv.
e
f
of DIC used. S-values (selectivity factors) determined by the method
of Kagan and Fiaud.12
ꢁc
This journal is The Royal Society of Chemistry 2010
2690 | Chem. Commun., 2010, 46, 2689–2690