En route to multicatalysis: Kinetic resolution of trans-cycloalkane-1,2- diols via oxidative esterification

Article abstract of DOI:10.1039/c3cc48584f

We demonstrate the application of a multicatalyst to the oxidation of a broad variety of aldehydes and subsequent enantioselective esterification of the incipient acids with (±)-trans-cycloalkane-1,2-diols. This reaction operates well with a multicatalyst bearing two independent catalytic moieties that provide monoprotected 1,2-diols in one pot.

Full text of DOI:10.1039/c3cc48584f

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En route to multicatalysis: kinetic resolution of
trans-cycloalkane-1,2-diols via oxidative
esterification†
Cite this: Chem. Commun., 2014,
50, 1221
Received 10th November 2013,
Accepted 26th November 2013
Christine Hofmann, Soren M. M. Schuler, Raffael C. Wende and Peter R. Schreiner*
¨
DOI: 10.1039/c3cc48584f
www.rsc.org/chemcomm
We demonstrate the application of a multicatalyst to the oxidation
of a broad variety of aldehydes and subsequent enantioselective
esterification of the incipient acids with (Æ)-trans-cycloalkane-
1,2-diols. This reaction operates well with a multicatalyst bearing
two independent catalytic moieties that provide monoprotected
1,2-diols in one pot.
Multicatalysts carry distinct catalytic moieties on a backbone
that allows modular synthesis, for instance, an oligopeptide.
The combination of several catalytic moieties provides reactivity
and operational simplicity not attainable with multiple single
catalysts, and complex molecules can be prepared from simple
starting materials with high efficiency.1 The obvious challenges
with this concept are the mutual compatibility of the catalytic
moieties and the versatility as well as generality of a multicatalyst,
for instance, in changing a particular reaction order. Based on
the concept of retrocatalysis1 we designed peptide catalyst A
(Scheme 1) as a multicatalyst, and it has previously been applied
as an efficient multicatalyst for the one-pot desymmetrization of
cis-cycloalkane-1,2-diols (e.g., meso-1b) and oxidation of the con-
figurationally unstable monoacetate (R,S)-2.2 Therefore, we envi-
sioned A also to be a promising catalyst for a reverse reaction
sequence, for instance, the oxidation of aldehydes followed by an
enantioselective esterification (Scheme 1).
Scheme 1 Versatility of multicatalyst A.
One-pot oxidative esterifications of aldehydes have become a
conceptually and economically attractive alternative to tradi-
tional ester synthesis.3 Thus, there are several examples for mixed anhydrides that can be converted to esters in situ.7 We
oxidative esterifications of aldehydes activated by transition- envisaged redesigning this oxidative esterification protocol as an
metal catalysts4 or N-heterocyclic carbenes.5 Recently, Szpilman application for multicatalyst A. Before using A we first elaborated
et al. reported an efficient TEMPO6 (B) catalyzed oxidation of the single-step reactions with B and oligopeptide C8 to determine
aldehydes activated with carboxylic acid 7e (Table 1) to yield the feasibility of the individual reactions and for optimization as
well as comparison with existing procedures.
Recently, we have shown that oligopeptide catalysts9 bearing
an N-p-methyl histidine moiety (e.g., C) very efficiently transfer
Institute of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 58,
35392 Giessen, Germany. E-mail: prs@uni-giessen.de; Fax: +49 0641-99 34309;
acyl groups enantioselectively onto trans- and cis-cycloalkane-
Tel: +49 0641-99 34300
1,2-diols.10 Peptide catalyst C also led to the first realization of
† Electronic supplementary information (ESI) available: Experimental procedures
and spectra. See DOI: 10.1039/c3cc48584f
an enantioselective Steglich esterification.11 Using an aldehyde
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Table 1 Screening of various acids (7a–f) under optimized reaction
Table 2 Kinetic resolution of trans-cycloalkane-1,2-diols 1a–1d
conditions
ee/%
Diol
n
Ca (yield 1, 6)/%
1
6
Sb
1a
1b
1c
1d
1
2
3
4
70 (n.d., n.d.)
47 (46, 43)
49 (48, 43)
50 (39, 47)
76
81
86
94
31
88
88
93
4
39
43
>50
a
Conversion determined by chiral GC and HPLC, 1.0 mmol 4a.
S = selectivity factors,15 n.d. = not determined.
b
ee/%
R
Ca/%
1
6
Sb
Further investigations are necessary to determine which of the
formed anhydrides is transferred faster onto the acylation
moiety.
To expand the substrate scope we tested various trans-
cycloalkane-1,2-diols 1 in the kinetic resolution with 1 equiv.
of acyl source affording the corresponding hydroxy ester with
high enantioselectivities and good yields (Table 2). The selectivities
depend on the ring size of the substrate, with trans-cyclooctane-1,
2-diol (1d) showing the highest and trans-cyclopentane-1,2-diol (1a)
the lowest selectivities.8
7a
7b
7c
7d
7e
7f
p-NO2C6H4
49
38
28
27
23
12
81
48
29
28
27
12
86
78
73
78
90
92
33
13
9
11
25
27
2-CH3-6-NO2C6H3
2,4,6-(Cl)3C6H2
2,4,6-(CH3)3C6H2
C(CH3)3
1-Adamantyl
a
Conversion of rac-1b determined by chiral GC after 24 h reaction time
for esterification, 0.1 mmol 4a. S = selectivity factors.15
b
instead of the acid is advantageous because aldehydes are
Various aldehydes were employed to probe the generality
typically more soluble in organic solvents, easier to purify, and utility of this oxidative esterification protocol. To deter-
more reactive and therefore a more practical intermediate in mine the time for full conversion of the aldehyde, we followed
multistep syntheses.
the conversion by NMR (see ESI† for details). Owing to the low
We optimized the reaction conditions for the enantio- solubility of 7a in the reaction mixture, we used 7c for the NMR
selective oxidative esterification with propanal (4a) and tested investigations, assuming that the time for full conversion of 4
various acids (7a–f) as activators for 4a (Table 1). Toluene has with 7c and 7a are similar (Table 1). Sterically hindered
proven to be the best solvent for the kinetic resolution of diols aldehydes require longer reaction times: for 4a the oxidation
with C and therefore we also used it for the oxidation step.8 was completed in 1 h, while isopentanal (4c) required 9 h and
Complete conversion of 4 was achieved using a stoichiometric isobutanal (4d) 18 h. Aromatic aldehydes proved to be more
amount of pyridine, 1.1 equiv. of 4-nitrobenzoic acid 7a, 5 reactive than aliphatic ones. However, benzaldehyde showed
mol% B and 1.05 equiv. of the oxidant, t-BuOCl, at a concen- insufficient conversion under these conditions; this is due to
tration of 1 M in toluene after 1 h. An excess of pyridine or the increased stability of the anhydride intermediate that we
catalytic amounts of the acid accelerated the background reac- had prepared separately and which does not react under our
tion and resulted in lower enantioselectivities. The esterifica- standard conditions.
tion requires relatively high dilution8,12 (0.005 M) to achieve
high enantioselectivities for 1b and 6b.
After having determined the time for full conversion, aro-
matic and aliphatic aldehydes were oxidized to their corre-
Under optimized reaction conditions 7a and 7b provided the sponding mixed anhydrides and tested in the kinetic resolution
highest conversions of rac-1b within 24 h. The best enantio- of rac-1b. Aldehydes 4b–d, g, and h afforded high enantioselec-
selectivities were achieved with acid 7a. Acids 7e and 7f with tivities and good yields. Cyclohexanal 4e gave lower selectivities
higher pKa values13 showed lower conversion. To identify the while pivaldehyde (4f) showed insufficient conversion due to
ratios of the mixed and symmetric anhydrides of 4a and 7a the increased steric hindrance (Table 3).
formed during the reaction, NMR studies were undertaken.14
With these promising results in hand, our attention turned
The anhydrides formed in a ratio of approximately 3 : 1 : 1 of mixed to the multicatalyst approach. We used 5 mol% of multicatalyst
anhydride relative to the symmetric anhydrides of 4a and 7a. A instead of individual catalysts B and C and applied it to the
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Table 3 Enantioselective oxidative esterification of rac-1b using various
aldehydes 4b–i
with catalyst C. The protocol with individual catalysts can be
unified with multicatalyst A2 that was designed utilizing the
retrocatalysis concept,1 with only slightly reduced enantioselec-
tivities. A natural extension of this work would be the use of
alcohols as the starting materials as this would constitute direct
alcohol cross-coupling.
We thank Dr. H. Hausmann for NMR investigations,
¨
Dr. E. Rocker for competent analytical support and Dr. G. Jakab
for helpful discussions.
Notes and references
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ee/%
Aldehyde
ta/h
Cb (yield 1b, 9)/% 1b
8
Sc
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4b
4c
4d
4e
4f
4g
4h
4i
Decanal
1/24
47 (48, 42)
48 (43, 46)
44 (43, 40)
46 (37, 35)
4 (n.d., n.d.)
79 88 38
76 82 24
72 90 40
Isopentanal
Isobutanal
Cyclohexanal
Pivaldehyde
9/24
18/6d
18/18d
24/48d
52 62
7
4
92 25
Ph(CH2)2CHO 0.5/6d,e 50 (44, 44)
85 82 27
50 93 47
PhCH2CHO
PhCHO
0.5/6d,e 35 (58, 27)
18/48d,e 7 (n.d., n.d.)
6
78
9
a
b
Reaction time for oxidation and esterification. Conversion deter-
mined by chiral GC and HPLC, 1.0 mmol 4. S = selectivity factors.15
c
d
e
2 equiv. of generated anhydride. Concentration for oxidation was
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