Alcohol cross-coupling for the kinetic resolution of diols via oxidative esterification

Article abstract of DOI:10.1021/jo502670p

We present an organocatalytic C-O-bond cross-coupling strategy to kinetically resolve racemic diols with aromatic and aliphatic alcohols, yielding enantioenriched esters. This one-pot protocol utilizes an oligopeptide multicatalyst, m-CPBA as the oxidant, and N,N-diisopropylcarbodiimide as the activating agent. Racemic acyclic diols as well as trans-cycloalkane-1,2-diols were kinetically resolved, achieving high selectivities and good yields for the products and recovered diols.

Full text of DOI:10.1021/jo502670p

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Note
Alcohol Cross-Coupling for the Kinetic
Resolution of Diols via Oxidative Esterification
Christine Hofmann, Jan M. Schümann, and Peter Richard Schreiner
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502670p • Publication Date (Web): 08 Jan 2015
Downloaded from http://pubs.acs.org on January 18, 2015
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The Journal of Organic Chemistry
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Alcohol Cross Coupling for the Kinetic Resolution of Diols via
Oxidative Esterification
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Christine Hofmann, Jan M. Schümann, and Peter R. Schreiner*
Institute of Organic Chemistry, JustusꢀLiebig University, HeinrichꢀBuffꢀRing 58, 35392 Giessen, Germany.
* prs@uniꢀgiessen.de.
ABSTRACT: We present an organocatalytic C–Oꢀbond crossꢀcoupling strategy to kinetically resolve racemic
diols with aromatic and aliphatic alcohols yielding enantioenriched esters. This oneꢀpot protocol utilizes an oliꢀ
gopeptide multicatalyst, mꢀCPBA as the oxidant, and N,N’ꢀdiisopropylcarbodiimide as the activating agent. Raꢀ
cemic acyclic diols as well as transꢀcycloalkaneꢀ1,2ꢀdiols were kinetically resolved, achieving high selectivities
and
good
yields
for
the
products
and
recovered
diols.
Crossꢀcoupling reactions1 describe C–C or C–heteroatom2 σꢀbond formation of two molecular fragments of
intrinsically competing reactivities; such reactions are often catalyzed by transition metals. Replacing the metal
catalyst by an organocatalyst is highly challenging, but this would enable the realization of novel C–X bondꢀ
forming strategies in organic synthesis.3 A pertinent example is the oxidative crossꢀcoupling of alcohols to
esters,4 which is of high practical relevance due to their synthetic versatility for the preparation of natural
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products, polymers, and pharmaceuticals. There are many procedures for the preparation of mixed esters starting
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4ꢀ5
from different alcohols using transitions metals,2c,
molecular iodine,6 CBr4 as bromine source7 or Nꢀ
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heterocyclic carbenes.8 Scheidt contributed also an enantioselective variant with moderate enantioselectivities.8a
However, there is no report on a highly enantioselective organocatalytic oxidative esterification, combining two
different alcohols. Here we present the kinetic resolution of racemic diols starting from aliphatic or aromatic
alcohols (Scheme 1).
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Recently, we have shown that (±)ꢀtransꢀcycloalkaneꢀ1,2ꢀdiols can be kinetically resolved using peptide catalyst
A,9 which is equipped with a nucleophilic Nꢀπꢀmethylhistidine10 moiety for enantioselective acyl transfer
employing anhydrides as the acyl source (Scheme 1).9d This approach also resulted in the first enantioselective
Steglich esterification11 starting from carboxylic acids as an acyl source.9b Most recently, we showed aldehydes
could be oxidized in situ and used to resolve diols with high enantioselectivities with multicatalyst B12 (Scheme
1).
Scheme 1. Various acyl sources for the kinetic resolution of transꢀcyclohexaneꢀ1,2ꢀdiol 4b using catalyst A or
B
Alcohols would even be better acyl equivalents owing to their high stability and ubiquitous accessibility. We
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thus turned our attention to developing an organocatalytic enantioselective C–O alcohol crossꢀcoupling protocol
of diols using multicatalyst B, equipped with oxidation and acyl transfer active sites.12 Our concept envisaged the
oxidation of a mono alcohol followed by conversion to the corresponding enantioenriched hydroxy ester in the
presence of a diol in a oneꢀpot fashion (Scheme 1).
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Scheme 2. Oneꢀpot kinetic resolution of racꢀdiols using multicatalyst B
Realizing this alcohol coupling strategy, we attempted to oxidize the alcohol to the corresponding aldehyde and
transfer it in situ to a mixed anhydride with multicatalyst B, pyridine, pꢀnitrobenzoic acid (pNBA) and tꢀBuOCl;
mixed anhydrides generated from aldehydes can act as acyl synthons (Scheme 1).12b, 13 However, this procedure
only provides unsatisfactory conversions and enantioselectivities for the product and the recovered diol.
Therefore, we decided to oxidize mono alcohols to the corresponding acids in situ with multicatalyst B and a
terminal oxidant. The resulting acid was activated with dehydrating agent 3 (N,N′ꢀdiisopropylcarbodiimide, DIC)
giving a mixed anhydride, whereby the less steric hindered acyl group (and more stable acyl moiety) of the
anhydride was transferred enantioselectively onto the diol.
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Table 1. Substrate scope using ethanol 1a as acyl source.
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yieldb (eec) /%
entry
product
t /ha
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4
n.d.e (46)
n.d.e (44)
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37 (97)
40 (92)
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42 (84)
43 (84d)
39 (81)
O
O
OH
5da
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n.d.e (75d)
37 (73)
n.d.e (38d)
43 (73)
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40 (64)
23 (76)
b
c
aReaction time for esterification, Yield of isolated product and recovered diol, Determined by chiral GC,
dDetermined by chiral HPLC, en.d. = no data.
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We optimized the reaction conditions for the oxidation of propanol (1b) to propionic acid with various oxidants.
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Toluene has proven to be the best solvent for the kinetic resolution of 1,2ꢀdiols with A, and therefore we also used
it for the oxidation step.9a, b, d, 13 Using stoichiometric amounts of trichloroisocyanuric acid (TCCA) and B resulꢀ
ted in full conversion to the acid but in the subsequent esterification no product formed, likely due to catalyst
inhibiꢀtion due to the hydrochloric acid generated in the oxidation step (addition of base did not improve this
situation). tꢀBuOCl is not a suitable oxidation agent in this context because of its exothermic reaction with water.
Use of 2.0 equiv of mꢀCPBA 2 as a stoichiometric oxidant gave nearly full conversion (90%, determined by GC)
to propionic acid after 6 h at room temperature. We stirred the reaction for 15 h until the decomposition of the
peracid was complete to avoid oxidation of the diol. The generated “waste” 3ꢀchlorobenzoic acid (mꢀCBA) was
used in the next step generating a mixed anhydride with propionic acid using N,N’ꢀdiisopropylcarbodiimide 3 to
remove water. We identified the ratio of the mixed and symmetric anhydrides of propionic acid and 3ꢀ
chlorobenzoic acid formed during the reaction with NMR as described before.12b, 14 The anhydrides formed in a
ratio of approximately 3:1 of mixed anhydride (3ꢀchlorobenzoic propionic anhydride) relative to the symmetric
anhydride of propionic acid (see Supporting Information).
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We recently showed that benzoic anhydrides generally react quite sluggishly with alcohols, owing to the
increased stability of the intermediate acylium imidazolium ion.9a, b This is consistent with this “wasteꢀreꢀuse”ꢀ
protocol. Despite use of an excess of mꢀCBA we observed only 5% of aromatic byꢀproduct (2ꢀ
hydroxycyclohexyl 3ꢀchlorobenzoate) under our optimized reaction conditions.
In an attempt to minimize the amount of the aromatic byꢀproduct through use of sterically hindered peracids
that would form Yamaguchiꢀtype anhydrides,15 we generated the peracids by treating the corresponding acyl
chloride with 30% H2O2 in basic media.16 Iodometric titration showed that smaller amounts of more sterically
hindered peracids (compared to mꢀCPBA) formed, which are useless for our protocol. The aromatic byꢀproduct
was minimized by using 2.0 equiv of dehydrating agent 3 (with lower amounts no product was obtained) with a
reaction time of 2 h at room temperature and 0.5 equiv of 4b. Relatively high dilution was required to achieve
high enantioselectivities in the kinetic resolution for 4b, but this is common for these types of reactions.9d, 17
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Scheme 3. Kinetic resolution of racꢀ4b using various alcohols as acyl synthons (yields of isolated products are
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shown)
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With these optimized reaction conditions we generally obtained good yields and enantioselectivities for
recovered diol 4b and product 5bb (4b: 37%, 91% ee; 5bb: 45%, 82% ee, Scheme 3); as this is not a pseudoꢀfirst
order reaction no Sꢀvalues can be given. We expanded the substrate scope and tested transꢀcycloalkaneꢀ1,2ꢀdiols
and racemic acyclic diols using ethanol 1a as acyl source (Table 1). The best results were achieved for the kinetic
resolution of racꢀ4b starting from ethanol 1a (4b: 37%, 97% ee; 5ba: 42%, 84% ee, Table 1). Diols 4c and 4d
with larger ring sizes showed comparable results. Cyclic diol 4a and acyclic aromatic diol 4e react faster in the
acylation sequence but selectivities for the products (5aa, 5ea) were only up to 44% ee. The successful
conversion of aliphatic acyclic diols 4f and 4g demonstrates that this coupling protocol is not limited to cyclic
diols (e.g., 73% ee, for both 4f and 5fa, respectively, Table 1). In all tested reactions 3ꢀchlorobenzoic byꢀproduct
formation is low (≤ 6%).
Various alcohols were employed to probe the generality and utility of this coupling protocol using racꢀ4b. Full
conversion of the alcohol was determined by GC. Aliphatic alcohols 1bꢀ1e showed high enantioselectivities and
high yields for the reisolated diol 4b and products 5bbꢀ5bd and 5bg. Using sterically more hindered alcohols
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resulted in increased formation of aromatic byꢀproduct (4–7%, for details see Experimental Section). Alcohols 1e
and 1h showed insufficient selectivities under these conditions. This procedure works well also with aromatic
alcohols 1i and 1k, achieving a maximum ee of 91% for recovered diol 4b (Scheme 3).
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We also probed the “identity reaction” whereby the mono alcohol 1 serves as acyl and alcohol component at
the same time. Indeed, an excess of alcohol 1 resulted in dimer 6 (Scheme 4). Such symmetric esters find multiꢀ
ple applications in the food and fragrance industries.18 We oxidized alcohol 1 with 1.0 equiv mꢀCPBA (for maxꢀ
imum conversion 2.0 equiv mꢀCPBA are necessary) and 2.5 mol % TEMPO as catalyst to the corresponding acid.
With DIC a mixed anhydride formed and catalytic amounts of 4ꢀdimethylaminopyridine (DMAP) transferred the
acyl group of the anhydride onto the remaining alcohol 1. Yields for 6g and 6k over three steps in one pot were
good, and this protocol offers novel access to symmetric esters.
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Scheme 4. Oneꢀpot dimerization of alcohols 1g and 1k
We have shown that aliphatic and aromatic alcohols can be coupled enantioselectively with racemic transꢀ
cycloalkaneꢀ1,2ꢀdiols and racemic acyclic diols under oxidative conditions achieving good yields and high
enantioselectivities with multicatalyst B. Using the synthetically readily accessible alcohols as acyl sources, this
coupling protocol extends the existing range of substrates that can serve as acyl synthons (anhydrides,9d acids,9b
and aldehydes12b) to resolve racemic diols kinetically. Future challenges include an expansion of this protocol to
racemic mono alcohols and recovery and immobilization of multicatalyst B.
EXPERIMENTAL SECTION
General remarks. Unless otherwise noted chemicals were purchased at the highest purity grade available and
were used without further purifications. All solvents were distilled prior to use. Toluene was distilled from
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appropriate drying agents prior to use and stored under argon atmosphere. Column chromatography and filtration
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was conducted using silica gel (0.040 – 0.063 mm). TLC Rf values are reported. H and 13C NMR spectra were
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recorded on 600, 400, or 200 MHz spectrometers, respectively, using TMS as the internal standard with chemical
shifts given in ppm relative to TMS or the respective solvent residual peaks. ESI mass spectra were recorded
using methanol solutions of the respective compounds. High resolution ESI mass spectrometry was performed on
a ESIꢀTOF mass spectrometer using methanol solutions of the respective compounds.
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Synthesis of multicatalyst B. Multicatalyst B was synthesized in solution using Bocꢀstrategy and EDC/HOBt
mediated couplings as described in the literature. Analytical data of the peptide was identical with those reported
in the literature.12
Availability of the alcohols and racemic starting materials. The achiral alcohols were purchased at the
highest purity grade available. Racemic transꢀcyclopentaneꢀ1,2ꢀdiol (rac-4a), transꢀcyclohexaneꢀ1,2ꢀdiol (rac-
4b), and racꢀhydrobenzoin (rac-4e) was purchased and used without further purification. Transꢀcycloheptaneꢀ
1,2ꢀdiol (rac-4c), transꢀhexaneꢀ1,2ꢀdiol (racꢀ4f) and transꢀoctaneꢀ1,2ꢀdiol (racꢀ4g), was synthesized according to
the method of the Organikum19 using the freshly distilled (cycloꢀ) alkene, formic acid, H2O2 followed by a
saponification with aq. NaOH. Transꢀcyclooctaneꢀ1,2ꢀdiol (rac-4d) was synthesized via epoxide opening of
cyclooctaneoxide, in water with pꢀtoluenesulfonic acid.9d
Description of standard conditions for catalytic runs with diols 4a-g (Table 1). The conditions for the
kinetic resolutions of transꢀcyclopentaneꢀ1,2ꢀdiol (rac-4a), transꢀcyclohexaneꢀ1,2ꢀdiol (rac-4b), transꢀ
cycloheptaneꢀ1,2ꢀdiol (rac-4c), transꢀcyclooctaneꢀ1,2ꢀdiol (rac-4d), racꢀhydrobenzoin (4e), transꢀhexaneꢀ3,4ꢀ
diol (rac-4f), transꢀoctaneꢀ4,5ꢀdiol (rac-4g) with ethanol 1a are given exemplarily by the following experimental
protocol. Ethanol (59 ꢁL, 1.0 mmol) and multicatalyst B (23 mg, 25 ꢁmol, 2.5 mol%) were dissolved in 5 mL
toluene. Oxidizing agent, mꢀCPBA (430 mg, 2.0 mmol), was added at room temperature and the reaction mixture
was stirred 15 h. After oxidation the reaction was diluted with 200 mL toluene and N,N′ꢀdiisopropylcarbodiimide
(DIC, 310 ꢁL, 2.0 mmol) was added to generate the mixed anhydride. After 2 h reaction time the reaction
mixture was cooled to 0 °C and the diol (0.5 mmol) was added. The reaction mixture was quenched with 10 mL
methanol and then filtered through 60 g silica gel washed with EtOAc to remove the catalyst. Purification
methods were different for each synthesis and can be found in the corresponding paragraph (see below).
Data for the preparative kinetic resolution of rac-4b with 1a. After the filtration the solvents were removed
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under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with EtOAc:Et3N 99.9:0.1 afforded 22 mg (0.19 mmol, 37%, Rf = 0.20) of diol 4b, 33
mg (0.21 mmol, 42%, Rf = 0.64) of monoacetate 5ba and 5 mg (0.02 mmol, 4%, Rf = 0.84) of aromatic byꢀ
product (2ꢀhydroxycyclohexyl 3ꢀchlorobezoate, 7b). The isolated compounds were then directly characterized by
NMR and the enantiomeric excess for 4b (97% ee) and 5ba (84% ee) was determined by chiral GC analysis.
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Enantiomers of diol 4b were separated by chiral GC employing a 30 m FSꢀHydrodex γꢀDiMOM column
(MacheryꢀNagel). T (Injector + Detector) = 250 °C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar.
Conditions: 100 °C – 240 °C, 10 °C/min. Retention Times: R1 (S,S) = 29.2 min; R2 (R,R) = 29.6 min. Racemic
5ba was synthesized as described in literature to proof GC retention times.9d Enantiomers of monoacetate 5ba
were separated by chiral GC employing a 30 m FSꢀHydrodex γꢀDiMOM column (MacheryꢀNagel). T (Injector +
Detector) = 250 °C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar. Conditions: 100 °C – 240 °C, 10
°C/min. Retention Times: R1 (S,S) = 40.0 min; R2 (R,R) = 40.8 min. Analytical data of the product (rac-5ba)
were identical with those reported in the literature.20 Analytical data for 7b: 1H NMR (200 MHz, CDCl3): δ/ppm
= 8.04 – 8.00 (s, 1 H); 7.97 – 7.88 (d, J = 7.8 Hz; 1 H); 7.57 – 7.46 (d, J = 7.8 Hz; 1 H); 7.44 – 7.32 (t, J = 7.8 Hz;
1 H); 4.93 – 4.76 (m, 1 H); 3.82 – 3.60 (m, 1 H); 2.17 –1.92 (m, 3 H); 1.83 – 1.68 (m, 2 H); 1.49 – 1.29 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ/ppm = 165.5; 134.5; 133.1; 132.1; 129.7; 127.8; 79.2; 72.8; 33.1; 30.0; 23.9; 23.8.
IR (KBr): ~ν /cmꢀ1 = 3448; 2931; 2862; 1717; 1573; 1287; 1256; 1124; 1072; 1014; 744. HRꢀMS (ESI): m/z =
277.0608 [M+Na]+ (calc. m/z = 277.0607). Anal. calcd for C13H15ClO3: C 61.30, H 5.94; found: C 61.22, H 5.91.
Data for the preparative kinetic resolution of rac-4a with 1a. Enantiomeric excess for 5aa (44% ee) and 4a
(46% ee) were determined without further purification step. Enantiomers of diol 4a were separated by chiral GC
employing a 30 m FSꢀHydrodex βꢀ6TBDAc column (MacheryꢀNagel). T (Injector + Detector) = 250 °C.
Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar. Conditions: 100 °C – 180 °C, 2 °C/min. Retention
Times: R1 (S,S) = 26.7 min; R2 (R,R) = 27.2 min. Racemic 5aa was synthesized as described in literature to proof
retention times.9d Enantiomers of monoacetate 5aa were separated by chiral GC employing a 30 m FSꢀHydrodex
βꢀ6TBDAc column (MacheryꢀNagel). T (Injector + Detector) = 250 °C. Splitflow = 80 mL/min. Precolumn
pressure = 0.8 bar. Conditions: 100 °C – 180 °C, 2 °C/min. Retention Times: R1 (S,S) = 19.0 min; R2 (R,R) =
18.6 min. Analytical data of the product (rac-5aa) were identical with those reported in the literature.20
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Data for the preparative kinetic resolution of rac-4c with 1a. After the filtration the solvents were removed
under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with Hexane:EtOAc:Et3N (3:7:0.01) afforded 26 mg (0.20 mmol, 40%, Rf = 0.21) of
diol 4c. Monoacetate 5ca and byꢀproduct 7c were separated by a further column chromatography (7:3
Hexane:EtOAc) resulting in 37 mg (0.22 mmol, 43%, Rf = 0.19) of monoacetate 5ca and 6 mg (0.02 mmol, 5%,
Rf = 0.21) aromatic byꢀproduct 7c. The isolated compounds were then directly characterized by NMR and the
enantiomeric excess for 4c (92% ee) and 5ca (84% ee) was determined by chiral GC analysis.
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Enantiomers of diol 4c were separated by chiral GC employing a 30 m FSꢀHydrodex βꢀ6TBDM column
(MacheryꢀNagel). T (Injector + Detector) = 250 °C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar.
Conditions: 140 °C isotherm. Retention Times: R1 (S,S) = 9.5 min; R2 (R,R) = 9.8 min. Racemic 5ca was
synthesized as described in literature to proof retention times.9d Enantiomers of monoacetate 5ca were separated
by chiral HPLC employing a Chiralpak IA column (Daciel). Eluent: Hexane/2ꢀPropanol 90:10. Flow: 1.00
ml/min. UVꢀdetector λ = 220 nm and refractometer. Retention Times: R1 (S,S) = 7.6 min; R2 (R,R) = 8.6 min.
Analytical data of the product (rac-5ca) were identical with those reported in the literature.20b Analytical data for
7c: 1H NMR (200 MHz, CDCl3): δ/ppm = 8.04 – 7.98 (s, 1 H); 7.97 – 7.90 (d, J = 7.8 Hz; 1 H); 7.57 – 7.50 (d, J
= 7.8 Hz; 1 H); 7.43 – 7.35 (t, J = 7.8 Hz; 1 H); 5.03 – 4.93 (m, 1 H); 3.96 – 3.86 (m, 1 H); 2.58 – 2.39 (s, 1 H);
1.96 –1.85 (m, 2 H); 1.83 – 1.70 (m, 4 H); 1.66 – 1.51 (m, 4 H). 13C NMR (50 MHz, CDCl3): δ/ppm = 165.7;
134.6; 133.1; 132.1; 129.7; 129.7; 127.8; 83.1; 75.9; 32.8; 30.4; 28.2; 23.0; 22.9. IR (KBr): ~ν /cmꢀ1 = 3494;
2934; 2854; 1701; 1572; 1340; 1324; 1290; 1258; 1140; 1036; 754; 741. HRꢀMS (ESI): m/z = 291.0760
[M+Na]+ (calc. m/z = 291.0758). Anal. calcd for C14H17ClO3: C 62.52, H 6.38; found: C 62.57, H 6.38.
Data for the preparative kinetic resolution of rac-4d with 1a. After the filtration the solvents were removed
under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with Hexane:EtOAc:Et3N (3:7:0.01) afforded 30 mg (0.21 mmol, 41%, Rf = 0.26) of
diol 4d. Monoacetate 5da and byꢀproduct 7d were separated by a further column chromatography (7:3
Hexane:EtOAc) resulting in 36 mg (0.20 mmol, 39%, Rf = 0.24) of monoacetate 5da and byꢀproduct 7d 8 mg
(0.02 mmol, 5%, Rf = 0.25). The isolated compounds were then directly characterized by NMR and the
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enantiomeric excess for 4d (92% ee) and 5da (81% ee) was determined by chiral GC analysis.
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Enantiomers of diol 4d were separated by chiral GC employing a 30 m FSꢀHydrodex βꢀ6TBDM column
(Machery Nagel). T (Injector + Detector) = 250 °C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar.
Conditions: 80 °C – 130 °C, 0.4 °C/min. Retention Times: R1 (S,S) = 100.8 min; R2 (R,R) = 102.9 min. Racemic
5da was synthesized as described in literature to proof retention times.9d Enantiomers of monoacetate 5da were
separated by chiral GC employing a 30 m FSꢀHydrodex βꢀ6TBDM column (Machery Nagel). T (Injector +
Detector) = 250 °C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar. Conditions: 80 °C – 130 °C, 0.4
°C/min. Retention Times: R1 (S,S) = 93.8 min; R2 (R,R) = 94.7 min. Analytical data of the product (rac-5ca)
were identical with those reported in the literature.20b, 21 Analytical data for 7d were identical with those reported
in the literature.22
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Data for the preparative kinetic resolution of rac-4e with 1a. Enantiomeric excess for 5ea (38% ee) and 4e
(75% ee) were determined without further purification step. Enantiomers of diol 4e were separated by chiral
HPLC employing a Chiralpack IA column (Daciel) Eluent: Hexane/2ꢀPropanol 95:5. Flow: 1 mL/min. UVꢀ
detector λ = 220 nm and refractometer. Retention Times: R1 (S,S) = 23.1 min; R2 (R,R) = 26.7 min. Racemic 5ea
was synthesized as described in literature to proof retention times.23 Enantiomers of diol 5ea were separated by
chiral HPLC employing a Chiralpack IA column (Daciel). Eluent: Hexane/2ꢀPropanol 90:10. Flow: 1 mL/min.
UVꢀdetector λ = 220 nm and refractometer. Retention Times: R1 (S,S) = 12.9 min; R2 (R,R) = 9.5 min. Analytical
data of the product (rac-5ea) were identical with those reported in the literature.23
Data for the preparative kinetic resolution of rac-4f with 1a. After the filtration the solvents were removed
under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with Hexane:EtOAc:Et3N (3:7:0.01) afforded 22 mg (0.19 mmol, 37%, Rf = 0.38) of
diol 4f, 34 mg (0.21 mmol, 43%, Rf = 0.64) of monoacetate 5fa. The isolated compounds were then directly
characterized by NMR and the enantiomeric excess for 4f (73% ee) and 5fa (73% ee) was determined by chiral
GC analysis.
Enantiomers of diol 4f were separated by chiral GC employing a 30 m FSꢀHydrodex βꢀ6ꢀTBDM column
(MachereyꢀNagel). T (Injector + Detector) = 250 °C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar.
Conditions: 100 °C – 150 °C, 2 °C/min. Retention Times: R1 (S,S) = 25.1 min; R2 (R,R) = 24.7 min. Racemic 5fa
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was synthesized as described in literature to proof retention times.13 Enantiomers of diol 5fa were separated by
chiral GC employing a 30 m FSꢀHydrodex βꢀ6ꢀTBDM column (MachereyꢀNagel). T (Injector + Detector) = 250
°C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar. Conditions: 100 °C – 150 °C, 2 °C/min. Retention
Times: R1 (S,S) = 19.2 min; R2 (R,R) = 22.5 min. Analytical data of the product (rac-5fa) were identical with
those reported in the literature.13
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Data for the preparative kinetic resolution of rac-4g with 1a. After the filtration the solvents were removed
under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with hexane:EtOAc:Et3N (2:1:0.01) afforded 29 mg (0.20 mmol, 40%, Rf = 0.34) of
diol 4g, 22 mg (0.12 mmol, 23%, Rf = 0.53) of monoacetate 5ga. The isolated compounds were then directly
characterized by NMR and the enantiomeric excess for 4g (64% ee) and 5ga (76% ee) was determined by chiral
GC analysis.
Enantiomers of diol 4g were separated by chiral GC employing a 30 m FSꢀHydrodex γꢀDIMOM column
(MachereyꢀNagel). T (Injector + Detector) = 250 °C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar.
Conditions: 100 °C – 150 °C, 2 °C/min. Retention Times: R1 (S,S) = 15.6 min; R2 (R,R) = 15.8 min. Racemic
5ga was synthesized as described in literature to proof retention times.13 Enantiomers of diol 5ga were separated
by chiral GC employing a 30 m FSꢀHydrodex γꢀDIMOM column (MachereyꢀNagel). T (Injector + Detector) =
250 °C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar. Conditions: 100 °C – 150 °C, 2 °C/min.
Retention Times: R1 (S,S) = 17.0 min; R2 (R,R) = 17.2 min. Analytical data of the product (rac-5ga) were
identical with those reported in the literature.13
Description of the preparative experiments with trans-cyclohexane-1,2-diol using the alcohols 1b–k
(Scheme 3). The conditions for the kinetic resolutions of transꢀcyclohexaneꢀ1,2ꢀdiol (rac-4b) with the alcohols
1bꢀ1k as acyl source are given exemplarily by the following experimental protocol. 1.0 mmol alcohol and
multicatalyst B (23 mg, 25 ꢁmol, 2.5 mol%) were dissolved in 5 mL toluene. Oxidizing agent, mꢀCPBA (430
mg, 2.0 mmol), was added at room temperature and the reaction mixture was stirred 15 h. After oxidation the
reaction was diluted with 200 mL toluene and N,N′ꢀdiisopropylcarbodiimide (DIC, 310 ꢁL, 2 mmol) was added to
generate the mixed anhydride. After 2 h reaction time the reaction mixture was cooled to 0 °C and racꢀ4b (58
mg, 0.5 mmol) was added. The reaction mixture was quenched with 10 mL methanol and then filtered through 60
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g silica gel washed with EtOAc to remove the catalyst. Purification methods were different for each synthesis
and can be found in the corresponding paragraph (see below).
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Data for the preparative kinetic resolution of rac-4b with 1b. After the filtration the solvents were removed
under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with EtOAc and 0.1% Et3N afforded 22 mg (0.19 mmol, 37%, Rf = 0.20) of diol 4b.
Monopropionate 5bb and byꢀproduct 7b were separated by a further column chromatography (1:1 hexane:EtOAc)
resulting in 26 mg (0.23 mmol, 45%, Rf = 0.25) of 5bb and 6 mg (0.03 mmol, 5%, Rf = 0.36) of byꢀproduct 7b.
The isolated compounds were then directly characterized by NMR and the enantiomeric excess for 4b (91% ee)
and 5bb (82% ee) was determined by chiral GC analysis.
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Racemic 5bb was synthesized as described in literature to proof retention times.12b Enantiomers of
monopropionate 5bb were separated by chiral GC employing a 30 m FSꢀHydrodex γꢀDiMOM column
(MachereyꢀNagel). T (Injector + Detector) = 250 °C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar.
Conditions: 100 °C – 240 °C, 10 °C/min. Retention Times: R1 (S,S) = 36.7 min; R2 (R,R) = 36.9 min. Analytical
data of the product (rac-5bb) were identical with those reported in the literature.24
Data for the preparative kinetic resolution of rac-4b with 1c. After the filtration the solvents were removed
under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with EtOAc and 0.1% Et3N afforded 23 mg (0.19 mmol, 38%, Rf = 0.20) of diol 4b.
Monoisobutyrate 5bc and byꢀproduct 7b were separated by a further column chromatography (7:3
hexane:EtOAc) resulting in 33 mg (0.18 mmol, 35%, Rf = 0.28) of monoisobutyrate 5bc and 9 mg (0.03 mmol,
7%, Rf = 0.36) byꢀproduct 7b. The isolated compounds were then directly characterized by NMR and the
enantiomeric excess for 4b (87% ee) and 5bc (74% ee) was determined by chiral GC analysis.
Racemic 5bc was synthesized as described in literature to proof retention times.12b Enantiomers of diol 5bc
were separated by chiral GC employing a 30 m FSꢀHydrodex γꢀDiMOM column (MachereyꢀNagel). T (Injector
+ Detector) = 250 °C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar. Conditions: 100 °C – 240 °C, 10
°C/min. Retention Times: R1 (S,S) = 37.1 min; R2 (R,R) = 37.2 min. Analytical data of the monoacylated product
(rac-5bc) were identical with those reported in the literature. 25
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Data for the preparative kinetic resolution of rac-4b with 1d. After the filtration the solvents were removed
under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with EtOAc and 0.1% Et3N afforded 23 mg (0.19 mmol, 38%, Rf = 0.20) of diol 4b.
Monoisovalerate 5bd and byꢀproduct 7b were separated by HPLC (DiolꢀPhase, 0.48 CV/min., 15% TBME, 85%
hexane) resulting in 40 mg (0.20 mmol, 40%) of monoisovalerate 5bd and 6 mg (0.02 mmol, 5%) byꢀproduct 7b.
The isolated compounds were then directly characterized by NMR and the enantiomeric excess for 4b (87% ee)
and 5bd (79% ee) was determined by chiral CG/HPLC analysis.
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Racemic 5bc was synthesized as described in literature to proof retention times.12b Enantiomers of
monoprotected diol 5bd were separated by chiral HPLC employing a Chiralpack IC column (Daicel). Eluent:
Hexane/2ꢀPropanol 90:10. Flow: 1 mL/min. UVꢀdetector λ = 220 nm and refractometer. Retention Times: R1
(S,S) = 7.8 min; R2 (R,R) = 8.4 min. Analytical data of the monoisovalerate (racꢀ5bd) were identical with those
reported in the literature.12b
Data for the preparative kinetic resolution of rac-4b with 1e. Enantiomeric excess for 5be (50% ee) and 4b
(31% ee) were determined without further purification step. Enantiomers of monopivalate 5be were separated by
chiral GC employing a 30 m FSꢀHydrodex γꢀDiMOM column (MachereyꢀNagel). T (Injector + Detector) = 250
°C. Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar. Conditions: 100 °C, 30 min; 100 °C – 240 °C, 5
°C/min. Retention Times: R1 (S,S) = 40.3 min; R2 (R,R) = 40.4 min. Analytical data of the monoacylated product
(racꢀ5be) were identical with those reported in the literature.9b
Data for the preparative kinetic resolution of rac-4b with 1f. After the filtration the solvents were removed
under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with EtOAc and 0.1% Et3N afforded 20 mg (0.18 mmol, 35%, Rf = 0.20) of diol 4b.
Monocyclohexanecarboxylate 5bd and byꢀproduct 7b were separated by HPLC (DiolꢀPhase, 0.48 CV/min., 15%
TBME, 85% hexane) resulting in 46 mg (0.21 mmol, 41%) of monocyclohexanecarboxylate 5bf and 7 mg (0.03
mmol, 5%) byꢀproduct 7b. The isolated compounds were then directly characterized by NMR and the
enantiomeric excess for 4b (87% ee) and 5bf (79% ee) was determined by chiral CG/HPLC analysis.
Racemic 5bf was synthesized as described in literature to proof retention times.12b Enantiomers of
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monoprotected diol 5bf were separated by chiral HPLC employing a Chiralpack IC column (Daicel). Eluent:
Hexane/2ꢀPropanol 90:10. Flow: 1 mL/min. UVꢀdetector λ = 220 nm and refractometer. Retention Times: R1
(S,S) = 9.2 min; R2 (R,R) = 9.8 min. Analytical data of the monoisovalerate (racꢀ5bf) were identical with those
reported in the literature.12b
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Data for the preparative kinetic resolution of rac-4b with 1g. After the filtration the solvents were removed
under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with EtOAc and 0.1% Et3N afforded 23 mg (0.20 mmol, 40%, Rf = 0.20) of diol 4b.
Monodecanoate 5bg and byꢀproduct 7b were separated by a further column chromatography (7:3 hexane:EtOAc)
resulting in 58 mg (0.23 mmol, 46%, Rf = 0.61) of monodecanoate 5bg and 6 mg (0.02 mmol, 5%, Rf = 0.52) byꢀ
product 7b. The isolated compounds were then directly characterized by NMR and the enantiomeric excess for
4b (89% ee) and 5bg (80% ee) was determined by chiral CG/HPLC analysis.
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Racemic 5bg was synthesized as described in literature to proof retention times.12b Enantiomers of
monoprotected diol 5bg were separated by chiral HPLC employing a Chiralpack IC column (Daicel). Eluent:
Hexane/2ꢀPropanol 95:5. Flow: 1 mL/min. UVꢀdetector λ = 220 nm and refractometer. Retention Times: R1
(S,S) = 12.8 min; R2 (R,R) = 13.5 min. Analytical data of the monoisovalerate (racꢀ5bd) were identical with
those reported in the literature.12b
Data for the preparative kinetic resolution of rac-4b with 1h. Enantiomeric excess for 5bh (48% ee) and 4b
(30% ee) were determined without further purification step. Racemic 5bh was synthesized as described in
literature to proof retention times.12b Enantiomers of monoprotected diol 5bh were separated by chiral GC
employing a 30 m FSꢀHydrodex β ꢀ TBDAc column (MachereyꢀNagel). T (Injector + Detector) = 250 °C.
Splitflow = 80 mL/min. Precolumn pressure = 0.8 bar. Conditions: 100 °C – 200 °C, 1.4 °C/min. Retention
Times: R1 (S,S) = 70.3 min; R2 (R,R) = 70.5 min. Analytical data of the monoacylated product (rac-5bh) were
identical with those reported in the literature.26
Data for the preparative kinetic resolution of rac-4b with 1i. After the filtration the solvents were removed
under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with EtOAc and 0.1% Et3N afforded 22 mg (0.19 mmol, 38%, Rf = 0.20) of diol 4b.
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Monophenylacetate 5bi and byꢀproduct 7b were separated by HPLC (Chiralpak IB, 0.24 CV/min., 10%
Isopropanol, 90% hexane) resulting in 54 mg (0.20 mmol, 40%) of monophenylacetate 5bi and 5 mg (0.02 mmol,
4%) byꢀproduct 7b. The isolated compounds were then directly characterized by NMR and the enantiomeric
excess for 4b (84% ee) and 5bi (67% ee) was determined by chiral HPLC/GC analysis.
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Racemic 5bi was synthesized as described in literature to proof retention times.12b Enantiomers of
monoprotected diol 5bi were separated by chiral HPLC employing a Chiralpack IB column (Daicel). Eluent:
Hexane/2ꢀPropanol 90:10. Flow: 0.7 mL/min. UVꢀdetector λ = 220 nm and refractometer. Retention Times: R1
(S,S) = 14.0 min; Rf (R,R) = 10.7 min. Analytical data of the monoacylated product (rac-5bi) were identical with
those reported in the literature.12b
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Data for the preparative kinetic resolution of rac-4b with 1k. After the filtration the solvents were removed
under reduced pressure. The residue was with cold CH2Cl2 suspended and filtrated to remove insoluble 3ꢀ
chlorobenzoic acid. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with EtOAc and 0.1% Et3N afforded 22 mg (0.19 mmol, 37%, Rf = 0.20) of diol 4b.
Monophenylpropionate 5bk and byꢀproduct 7b were separated by a further column chromatography (7:3
hexane:EtOAc) resulting in 57 mg (0.23 mmol, 46%, Rf = 0.27) of monophenylpropionate 5bi and 5 mg (0.02
mmol, 5%, Rf = 0.37) byꢀproduct 7b. The isolated compounds were then directly characterized by NMR and the
enantiomeric excess for 4b (91% ee) and 5bk (60% ee) was determined by chiral HPLC/GC analysis.
Racemic 5bk was synthesized as described in literature to proof retention times.12b Enantiomers of
monoprotected diol 5bk were separated by chiral HPLC employing a Chiralpack IB column (Daicel). Eluent:
Hexane/2ꢀPropanol 90:10. Flow: 0.7 mL/min. UVꢀdetector λ = 220 nm and refractometer. Retention Times: R1
(S,S) = 11.1 min; R2 (R,R) = 9.4 min. Analytical data of the monoisovalerate (racꢀ5bk) were identical with those
reported in the literature.12b
Identification of 3-chlorobenzoic propionic anhydride and propionic anhydride by NMR. Propionic acid
(7.4 µL, 0.1 mmol) and 3ꢀchlorobenzoic acid (31.3 mg, 0.2 mmol) was dissolved in 5 mL tolueneꢀd8 and N,N′ꢀ
diisopropylcarbodiimide (DIC, 31.0 ꢁL, 0.2 mmol) was added to generate the mixed anhydride. After 2 h at
room temperature 0.7 mL were filtered into a NMR tube and subjected to 1H and 13C NMR spectroscopy. NMR
data: see Supporting Information.
Description of the experiments synthesizing symmetric esters 6g and 6k. 2.0 mmol alcohol and 2.5 mol%
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TEMPO (7.8 mg, 5 ꢁmol) were dissolved in 5 mL CH2Cl2. Oxidizing agent, mꢀCPBA (430 mg, 2.0 mmol), was
added at room temperature and the reaction mixture was stirred 15 h. After oxidation N,N′ꢀ
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diisopropylcarbodiimide (DIC, 310 ꢁL, 2 mmol) was added to generate the mixed anhydride. After 2 h reaction
time, 4ꢀdimethylaminopyridine (6.1 mg, 2.5 mol%, 5 ꢁmol) was added and the reaction mixture was stirred 18 h
at room temperature. The reaction mixture was washed three times with saturated NaHCO3 solution, with water
and brine and the organic phase was dried over MgSO4.
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Purification of 6g. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with 9:1 cyclohexane:EtOAc afforded 185 mg (0.59 mmol, 59%, Rf = 0.70) of dimer
6g. Analytical data of the product (6g) were identical with those reported in the literature.18
Purification of 6k. CH2Cl2 was removed and the crude product was purified by silica gel column
chromatography. Eluting with 97:3 hexane:EtOAc afforded 180 mg (0.67 mmol, 67%, Rf = 0.38) of dimer 6k.
Analytical data of the product (6k) were identical with those reported in the literature.18
ASSOCIATED CONTENT
Supporting Information
Copies of 1H and 13C NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: prs@uniꢀgiessen.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Dr. Erwin Röcker and Anika Bernhardt for excellent analytical support, the COST – ORCA action
(CM0905) and the LiebigꢀCollege for creating networking and exchange opportunities. Stimulating discussions
with Prof. Michael Harmata (U Missouri at Columbia) are gratefully acknowledged.
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