Enantiomerically enriched trans-diols from alkenes in one pot: A multicatalyst approach

Article abstract of DOI:10.1039/c2cc17435a

Multicatalysts consisting of non-natural oligopeptides with distinctly different catalytic moieties create molecular complexity in a multistep one-pot sequence starting from simple alkenes yielding highly enantiomerically enriched trans-diols. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17435a

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COMMUNICATION
Enantiomerically enriched trans-diols from alkenes in one pot: a
multicatalyst approachwz
Radim Hrdina, Christian E. Muller, Raffael C. Wende, Lukas Wanka and Peter R. Schreiner*
¨
Received 28th November 2011, Accepted 10th January 2012
DOI: 10.1039/c2cc17435a
Multicatalysts consisting of non-natural oligopeptides with
distinctly different catalytic moieties create molecular complexity
in a multistep one-pot sequence starting from simple alkenes
yielding highly enantiomerically enriched trans-diols.
Organocatalysis has become a powerful tool for the synthesis
of enantiomerically pure compounds,1 and multiple reaction
one-pot approaches are particularly attractive by way of their
resource and energy efficiency.2–4 Examples include one
catalyst performing several reaction steps or several individual
catalysts that catalyze a single reaction step of a longer
sequence.5 Multicatalyst approaches, where different catalytic
moieties are connected to one common catalyst backbone, are,
however, rare.6,7 These approaches may share the operational
advantages of one-pot reaction sequences and additionally
improve the material balance, operational efficiency, and
individual reaction steps by providing higher local concentrations
at the common catalyst backbone for the individual steps.
Here we show a multicatalyst approach for the preparation
of enantiomerically enriched trans-1,2-diols (3) starting from
simple symmetrical alkenes (1). We envisioned that epoxidation
of 1 by an in situ generated peracid (cat 1) should give the
corresponding epoxides 2. Opening of 2 with water would lead
to the diols (ꢀ)-3 that can be kinetically resolved via catalytic
enantioselective acylation using a nucleophilic N-p-methyl histi-
dine moiety as the active center (cat 2) (Scheme 1).8–10 As multi-
catalysts we focused on short oligopeptides A–F (Schemes 2 and 3)
that allow ready and automated variation of all components.11
Scheme 2 Peptide
F multicatalyst leading to enantioenriched
trans-diols 3 and monoacylated diols 4 from simple alkene 1.
Our previous studies12 showed that the incorporation of a rigid
non-natural g-amino adamantane carboxylic acid13 leads to a
lipophilic (for use in organic solvents) and structurally defined
oligopeptide that effectively separates the catalytic centers.12
We present the key results first, followed by an analysis of
the development and optimization of the sequence; peptide F
turned out to be the most efficient multicatalyst.y The b-aspartate
moiety catalyzes the epoxidation of 1 to 2, followed by opening
of 2 with hydrazine bisulfate14 and water in toluene leading to
the corresponding diol (ꢀ)-3, which was kinetically resolved to
the enantiomerically enriched monoacetylated 4 in the last step.
Overall yields of up to 34% (the maximum would be 50%) and
enantioselectivities up to 99% for the recovered diol (s-values15
up to 26 at the preparative scale) could be obtained with this
three step one-pot reaction sequence (Scheme 2).
The catalysts A–F were optimized with regard to the
terminal kinetic resolution. The role of the spacer is crucial
and we found that the optimal distance between the catalytic
moieties should be three amino acids. The solvent of choice for
these types of reactions is known to be toluene, which pro-
motes secondary interactions between the acylium ion and the
1,2-diol responsible for the enantioselectivity (Scheme 3).8,10
We focused next on the epoxidation, the first step of the
desired reaction sequence. The challenge is to avoid oxidation
of the catalyst during the epoxidation and interference of the
Scheme 1 One-pot sequence from alkenes 1 to enantioenriched diols
3 and monoprotected diols 4 with a multicatalyst.
Institute of Organic Chemistry, Justus-Liebig University,
Heinrich-Buff-RIng 58, D-35392 Giessen, Germany.
E-mail: prs@org.chemie.uni-giessen.de; Fax: +49 641 9934309;
Tel: +49 641 9934300
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and analytical data. See DOI: 10.1039/c2cc17435a
c
2498 Chem. Commun., 2012, 48, 2498–2500
This journal is The Royal Society of Chemistry 2012

Scheme 4 Opening of epoxides using hydrazine bisulfate as
organocatalyst.
choice because it is able to dissolve all components of the
reaction.
We screened a large variety of small organocatalysts using
cyclohexene oxide (2a) as the model compound for the epoxide
opening step (for details see ESIz). Hydrazine bisulfate14
was found to be the catalyst of choice as its solubility in water
and insolubility in nonpolar organic solvents lead to Brønsted
acid catalyzed biphasic epoxide opening (Scheme 4). In polar
solvents such as DCM or acetonitrile the opening proceeds
more slowly because of the addition of the bisulfate to the
epoxide. In the case of the 2e, 2f, and 2g this protocol failed
and 1 eq. of TFA (see ESIz for details) was required to form the
corresponding TFA esters, which were subsequently hydrolyzed
by Hunig base and water to the diols 3. The same was observed
for 2e and 2g in the chromium–salen complex catalyzed opening
with azide.17
Scheme 3 Kinetic resolution of trans-cyclohexane-1,2-diol (ꢀ3a) by
bifunctional catalysts A–F containing an a- or b-aspartate moiety
(cat 1) and a N-p-methyl histidine moiety (cat 2); the performance of
the monofunctional catalyst G is additionally given for comparison.
epoxidation side products with the subsequent transformations.
The epoxidation of alkenes was studied with carboxylic acids as
catalysts, hydrogen peroxide as the oxidant and carbodiimide as
the dehydrating agent; phthalic acid was found to be a powerful
organocatalyst in this reaction.
Focusing on the last two steps of the sequence, we
observed that the one-pot epoxide opening catalyzed by
hydrazine bisulfate and subsequent acetylation led to highly
Comparing its reactivity with terephthalic acid, we conclude
that the epoxidation proceeds through internal anhydride
formation followed by opening with hydrogen peroxide and
epoxidation of the alkene through the phthalic monoperacid
intermediate (Table 1).16 The epoxidation proceeds in DCM as
well as in toluene. A diacid moiety containing multicatalysts
D, E, and F proved to be active; catalysts E and F with
C-terminal b-aspartate led to good conversions (Table 1). In
the case of the peptide multicatalysts DCM was the solvent of
Table 1 Comparison of the catalytic activity of phthalic acid, terephthalic
acid, and multicatalysts D–E in the epoxidation of cyclohexene
Conversion (%)
4 h
18 h
24 h
48 h
Catalyst
mol%
2
5
50a
—
54a
90a
60a
92a
—
—
10
—
92a
93a
—
2
o10a
—
—
—
—
20a
—
D
E
F
5
5
5
—
—
—
—
—
—
10b
87b
88b
a
b
1.2 eq. H2O2, 1.2 eq. DIC. Additional 1.2 eq. H2O2 and 1.2 eq.
DIC were added after 24 h.
Scheme 5 Catalytic opening of epoxides (2) to trans-alkane-1,2-diols
(3) and subsequent kinetic resolution catalyzed by the peptide salt GS.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2498–2500 2499

Notes and references
y Typical procedure for the one-pot epoxidation, epoxide opening and
acetylation sequence catalyzed by peptide F: Catalyst F (0.05 mmol,
21.9 mg, 5%), cyclohexene (1 mmol, 101 mL, 1 eq.) and DIC (1.2 mmol,
185 mL, 1.2 eq.) were dissolved in 2 mL DCM. To this mixture 30%
H2O2 (130 mL, 1.2 eq.) was added and the resulting mixture was
allowed to stir at rt for 24 h. After this time the addition of DIC
(1.2 mmol, 185 mL, 1.2 eq.) and 30% H2O2 (130 mL, 1.2 eq.) was repeated
and the reaction was stirred under the same conditions for 24 h. Then
toluene (6 mL) was added, followed by the addition of H2O (10 mmol,
180 mL, 10 eq.) and hydrazine sulfate (0.1 mmol, 13 mg, 0.1 eq.) and the
reaction was stirred at rt for 18 h. In the next step toluene (180 mL) and
iPr2EtN (5.3 mmol, 876 mL, 5.3 eq.) were added and the reaction was
cooled to 0 1C. Ac2O (5.3 mmol, 540.6 mL, 5.3 eq.) was added and the
kinetic resolution was monitored by chiral GC. After 17 h the reaction
was quenched with MeOH (10 mL), the solvents were evaporated under
reduced pressure and column chromatography on silica gel in hexane/
EtOAc 1:1 provided 56 mg (35%) of 1-acetoxy-cyclohexan-2-ol (60% ee)
4a and 40 mg (34%) of cyclohexane-1,2-diol 3a (92% ee).
Typical procedure for the sequence catalyzed by salt GS: Cat. GS
(0.05 mmol, 40.0 mg, 5 mol%) and cyclohexene oxide (1.0 mmol, 98.1 mg,
101 mL) were dissolved in toluene (1 mL) and water (20 mmol, 360 mL,
20 eq.) was added. The mixture was stirred at rt for 18 h. In the next step
toluene (180 mL) and iPr2EtN (5.3 mmol, 901 mL, 5.3 eq.) were added and
the reaction was cooled to 0 1C. Ac2O (5.3 mmol, 501 mL, 5.3 eq.) was
then added to start the acylation and the kinetic resolution was monitored
by chiral GC. The reaction mixture was then quenched with 10 mL of
methanol, filtered through silica gel (30 g), suspended with ethyl acetate,
and washed with ethyl acetate to remove the catalyst. After evaporation
of the solvent in vacuo the products were purified by column chromato-
graphy. Eluting with ethyl acetate afforded 85.5 mg (0.54 mmol;
54%; 65% ee) of the acetylated diol (Rf = 0.46) and 28.3 mg (0.24 mmol;
24%; 499% ee) of the diol (Rf = 0.22).
Scheme 6 One-pot epoxidation of 1a catalyzed by phthalic acid,
subsequent opening with water catalyzed by the bisulfate moiety on
the peptide and N-p-methyl histidine catalyzed enantioselective
acetylation.
enantioenriched trans-diol 3a (Scheme S1, ESIz). Remarkably,
the acylation was not affected by the 10 eq. of water present in
the reaction mixture, neither through the hydrolysis of the
acetic anhydride nor through the H-bonding capability of
water destroying the crucial catalyst–substrate interactions.
As the epoxide opening is acid catalyzed, we thought of
combining this with the acylation step by preparing the
bisulfate salt of the nucleophilic peptide G, simply by mixing
G (G is the N-acylated analogue of our highly effective
acylation catalyst and shows nearly the same efficiency;12 the
N-Boc group is thereby exchanged with the acetyl group). The
resulting salt GS indeed catalyzes the epoxide opening step
and the neutral catalyst G is subsequently regenerated by
addition of Hunig base. This protocol proved to be highly
efficient for a variety of meso epoxides with s-values up to 48 at
the preparative scale (Scheme 5).
For completeness sake we decided to perform the entire one-
pot sequence starting from cyclohexene with two separate
catalysts, phthalic acid (5 mol%) for the epoxidation of 1a
and GS (5 mol%) for opening of 2a to 3. After the addition of
Hunig base peptide G was deprotonated and catalyzed the
enantioselective acetylation of the diol with an impressive
s-value of 45 at the preparative scale (Scheme 6).
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moieties. This study shows that in a simplified way it is
possible to mimic the work of nature, where reactions occur
in the active sites of enzymes and the products are transferred
to another active site for a subsequent chemical transforma-
tion. The next step is to expand on the number of catalytic
steps with more catalytic sites on a single backbone and to
establish this as a strategy toward reverse catalyst design in the
sense of retrocatalysis analogous to retrosynthesis.
c
2500 Chem. Commun., 2012, 48, 2498–2500
This journal is The Royal Society of Chemistry 2012