A multicatalyst system for the one-pot desymmetrization/oxidation of meso-1,2-alkane diols

Article abstract of DOI:10.1002/chem.201100498

Two is better than one: We demonstrate the viability of an organocatalytic reaction sequence along a short peptide backbone that carries two independent catalytic functionalities, which allow the rapid, one-pot acylative desymmetrization and oxidation of meso-alkane-1,2-diols to the corresponding acetylated acetoins with good yields and enantioselectivities (see scheme). Copyright

Full text of DOI:10.1002/chem.201100498

COMMUNICATION
DOI: 10.1002/chem.201100498
A Multicatalyst System for the One-Pot Desymmetrization/Oxidation of
meso-1,2-Alkane Diols
Christian E. Mꢀller, Radim Hrdina, Raffael C. Wende, and Peter R. Schreiner*[a]
Stereoselective, homogeneously catalyzed cascade reac-
tions are a key step toward resource-efficient transforma-
tions at the forefront of synthetic chemistry;[1–4] these types
of reactions are well known and are labeled as domino,
tandem, cascade, or zipper transformations.[2–4] Arguably, all
catalyzed reactions to date can be classified with the princi-
ples 1–4 (Figure 1), but we are unaware of a concept that
There are several (organo)catalytic approaches following
principle 2 (Figure 1) by using a single catalyst and the same
activation mode for each catalytic cycle.[1–4] Organocatalyt-
ic[3–6] as well as combined metal and organocatalytic (3,
Figure 1)[4–7] cascade reactions are of contemporary interest.
To the best of our knowledge there is only one example for
a homogeneous (5, Figure 1) reaction using an achiral heter-
odimetallic catalyst.[8]
Here we present the first approach of an organocatalytic
enantioselective concurrent tandem[1] (“assembly line”) re-
action by utilizing a multicatalyst with orthogonal (i.e., inde-
pendent) catalytic moieties (CMs). Some of the obvious
challenges with this concept are a) the selection of a proper
backbone that is modular and compatible with all reaction
conditions; b) compartmentalization of the catalytic moiet-
ies so that they do not interfere with each other (i.e., design
of a spacer (Figure 1); c) the activities of the individual cata-
lytic moieties (CMs) must be retained; d) the solubility of
the multicatalyst in all the solvents required for the entire
sequence; and e) the ease of preparation of the multicata-
lysts, ideally by automated synthesis. A far-fetched but not
unreasonable goal would be the use of a library of CMs that
can be assembled to serve the purpose of synthesizing a
complex organic molecule in one pot by a programmed
series of catalyzed reactions utilizing a retrosynthetic algo-
rithm.
It is clear that our one-pot multicatalyst approach has
some operational advantages (e.g., decreases solvent use,
time, and enables a simpler workup) that become apparent
as the number of catalyzed steps increases. The present
work provides proof-of-principle studies of a new concept in
catalysis.
The challenges in a) and e) can be addressed by selecting,
for example, an oligopeptide backbone that can be assem-
bled readily. Oligopeptides with a secondary structure have
shown to be highly versatile for the transfer of electrophiles
to alcohols.[9] For the compartmentalization of the catalytic
sites we chose a lipophilic admantane g-amino acid (AGly in
our shorthand notation),[10] which also enables the catalyst
solubility in a broad variety of solvents. Such oligopeptides
without apparent secondary structures[11] have proven to be
particularly effective in stereoselective acyl-transfer reac-
tions,[5,12] thus we have selected this type of catalyst for the
present study.
Figure 1. Prevalent catalytic principle reactions 1–4. Simplified depiction of
the multicatalysis concept (reaction 5).
utilizes a multicatalyst system (principle 5), in which a varie-
ty of organocatalytic moieties is strung together on an arbi-
trary backbone. This concept is reminiscent of an assembly
line, in which each interconnected station performs a partic-
ular function and only their proper sequence gives the de-
sired product. It is also akin to many biological processes
such as the protein biosynthesis.
[a] Dr. C. E. Mꢀller, Dr. R. Hrdina, M. Sc. R. C. Wende,
Prof. Dr. P. R. Schreiner
Institute of Organic Chemistry
Justus-Liebig University
Heinrich-Buff-Ring 58
35392 Giessen (Germany)
Fax : (+49)641-9934309
E-mail: prs@org.chemie.uni-giessen.de
We chose the enantioselective, catalytic acetylation and
subsequent catalytic oxidation of meso-1,2-cycloalkane diol
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100498.
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oligopeptide and 2,2,6,6-tetramethylpiperidine N-oxide
(TEMPO) as the oxidizer) are still active and perform their
independent functions when placed into one catalyst struc-
ture, but also that the oxidation step occurs under milder
conditions than in the separate protocols. Whereas the op-
erational advantages for the present reaction sequence are
minor, our emphasis here is on the viability of this ap-
proach.
There are only a few enzymatic and chemical approaches
using stereoselective acetyl transfer for the desymmetriza-
tion of, for example, 1a.[13,14] The desymmetrization of meso-
1,2-diols utilizing acetyl transfer is generally difficult, owing
to facile intramolecular acetyl group migration of the mo-
noprotected product 2,[5,14,15] therefore immediate oxidation
of the second OH group is an effective way to suppress rac-
emization.[5] The obtained acylated a-acetoxy ketones (3,
acetoins) are valuable chiral building blocks for which there
are only a few selective syntheses (especially for cyclic
ones).[5,16,17]
Scheme 1. Modular approach to build a multicatalyst in the organocata-
lytic sequence of 1a to 3a.
1a as the test reaction (Scheme 1) because these two pro-
cesses can be conducted in a one-pot approach by using two
separate catalysts with good ee values and good overall
yields (Scheme 1).[5] Here we will demonstrate not only that
the two active catalysts (a p-Me-histidine residue on the
As we already had a very active acylation platform at
hand (A, Scheme 2),[5,12] we first focused our attention to at-
taching a terminal TEMPO moiety to the oligopeptide back-
Scheme 2. Peptide-based multicatalysts and the schematic overlay of catalysts A and B.
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Chem. Eur. J. 2011, 17, 6309 – 6314

One-Pot Multicatalyst System
COMMUNICATION
Table 2. Optimization of the oxidation of 2a with peptide catalyst C.
bone (catalyst B, Scheme 2). This represents a logical exten-
sion of acylation catalyst A and is a test of the degree of the
required orthogonality of the reactivity of the individual
CMs.[5,12] Our initial proposal for B was to replace only the
methyl ester group of catalyst A with the TEMPO-amide
functionality, which would retain the selectivity of A in the
acylative desymmetrization of 1a, then to use the TEMPO
moiety for the subsequent oxidation of intermediate 2a
(Scheme 1). A molecular force-field analysis of the acylated
catalysts A and B reveals that the overall catalyst structures
are very similar (see the overlay of the two structures in
Scheme 2, top right) so that the acylation should not be af-
fected negatively by the addition of the TEMPO moiety;
both CMs are spatially well-separated.
Additionally, we varied the acylation–oxidation multica-
talysis platform with respect to lipophilicity and the position
of the TEMPO moiety (catalysts C–F). To check whether
B–F indeed display the desired activity, we first examined
their efficacy in the acylative desymmetrization of 1a to 2a
(Table 1).
Entry
C [mol%]
mCPBA
[equiv]
Bu4NBr
[mol%]
T
[8C]
t[h]
Yield
[%][a]
G
N
1
2
3
4
5
6
7
8
10
10
0
5
5
5
5
5
5
5
5
5
5
0
5
5
3.5
3.5
2
2
1
1
5
5
5
3
3
3
3
10
10
10
5
5
5
5
5
5
5
5
5
0
5
5
5
3.5
3.5
2
RT
1
3
4
1
3
1
3
1
3
1
3
1
1
1
1
3
1
3
1
3
1
3
1
3
1
3
73.8
70.8
0
RT
RT
RT
RT
RT
RT
RT
RT
48.7
21.2
65.5
65.0
55.1
58.9
52.9
88.7
>99
25.4
0
3
1.5
1.5
1
1
3
3
3
3
3
1.5
1.5
3
3
3
3
3
3
3
9
10
11
12
13
15
16
17
18
19
20
21
22
23
24[b]
25[b]
26[c]
27[c]
À20
À20
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
86.8
94.2
89.3
95.8
40.3
55.9
9.7
Table 1. Desymmetrization of meso-diol 1a with catalysts B–F.
2
1
1
5
5
5
5
10.1
63.1
>99
7.8
Entry
cat.
Yield 2a [%][a,b]
e.r.[b] 2a
3
3
3
1
2
3
4
5
B
C
D
E
F
76.5
54.6
20.3
49.6
50.5
88:12
74:26
49:51
67:33
69:31
5
20.4
[a] All reactions were performed with 0.03 mmol of substrate. Yields
were determined by GC analysis. [b] TEMPO was used as the catalyst.
[c] TEMPO amine was used as the catalyst; see the Supporting Informa-
tion for details.
[a] All reactions were performed with 0.03 mmol of substrate and were
quenched with MeOH after the reaction. Without a catalyst, no conver-
sion was observed. [b] Yields and enantiomer ratios were determined by
GC analysis. See the Supporting Information for details.
could be obtained with C (5 mol%), mCPBA (3 equiv), and
Bu4NBr (5 mol%) at 08C (Table 2, entry 12) in a fast reac-
tion (1 h), a condition necessary to avoid racemization of
2a. Decreasing the amount of mCPBA also suppressed the
undesired Baeyer–Villiger oxidation of 3a; without C no re-
action takes place (Table 2, entries 3 and 15). The enanatio-
meric ratio (e.r.) values of the product were determined for
all peptide-C-catalyzed oxidations of Table 2; only marginal
selectivities were observed (the same is true for catalyst B).
More importantly, B and C are more active than TEMPO
(Table 2, entry 24), whose yield was only 63.1% after 1 h
using the same conditions as for entry 12. TEMPO amine
(the precursor for the synthesis of the TEMPO peptides)
only gave the product in 7.8% yield after 1 h (Table 2,
entry 26). That is, although the short peptide is not capable
of an enantioselective oxidation, it does aid in the oxidation
step, most likely through a binding event and a resulting
proximity effect as suggested for the preceding acylation
step.[11]
We were pleased to observe that the (p-Me)-His moiety
was active in the presence of the TEMPO moiety in all
cases. Indeed, the best results were obtained for peptide B
(88:12 e.r.) whose acylation CM in form of catalyst A was
optimized earlier.[5,12] While C provided similar enantiose-
lectivities, peptides D–F proved to be less effective. This im-
portant finding emphasizes that active CMs for one catalytic
reaction can be transferred into a multicatalyst by combin-
ing them with other CMs without significant change, if any,
in the individual CM selectivities.
With the good yields and selectivities for B in hand we in-
vestigated the TEMPO-moiety-catalyzed oxidation. We
chose the oxidation of racemic 2a in toluene (often the sol-
vent of choice for peptide catalyzed selective acylations)[9]
as the test reaction utilizing a variety of known TEMPO-cat-
alyzed oxidation protocols.[18,19] Only the TEMPO/tetrabutyl
ammonium bromide/mCPBA protocol led to significant con-
versions at room temperature. Our results and optimization
studies with catalyst C (to demonstrate generality) in place
of TEMPO are summarized in Table 2. Full conversions
Multicatalysts B and C were then employed for a one-pot
acylation/oxidation reaction sequence employing acetic an-
hydride in toluene, followed by addition of meta-chloroper-
benzoic acid (mCPBA) and Bu4NBr (results shown for B in
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P. R. Schreiner et al.
Table 3. Desymmetrization of meso-diol 1a and subsequent oxidation of
2a to 3a with catalyst B at various temperatures.
Our multicatalyst acylation/oxidation protocol is also ap-
plicable to other vicinal meso-diols (Table 5). The yields and
selectivities are generally good; the best result could be ob-
tained for cis-cyclooctane-1,2-diol 1c (e.r. 91:9, 83% isolated
product yield). The slightly lower yields for 3b and 3d are
due to a fast Baeyer–Villiger oxidation of the products
(Table 5).
Table 5. Concurrent tandem desymmetrization/oxidation of meso-diols 1
under optimized conditions with multicatalyst B.
Acylation
Oxidation
T [8C] t [h] Conversion Yield
e.r.[b] 2a Conversion to e.r.[b]
[%][a,c]
2a [%][a,c]
3a [%][a,c]
3a
Product[c]
t [h]
desym.
t [h]
ox.
Yield 3
e.r.[b]
3
[%][a]
RT
10
0
6
6
7
22
20
20
89.1
80.6
87.1
87.5
77.2
79.5[d]
70.6
72.1
76.5
67.7
67.1
69.0[d]
85:15
87:13
88:12
83:17
80:20
80:20[d]
51.6
91.0
84:16
87:13
88:12
84:16
82:18
79:21[d]
3b
3a
3c
3d
2
6
3
5
0.5
1
60
70
83
49
87:13
88:12
91:9
>99
>99
57.2
À10
À20
À20
77.1[d]
[a] All reactions were performed with 0.03 mmol of substrate. [b] Enan-
tiomeric ratios were determined by chiral GC analysis. [c] Conversions
and yields were determined by GC analysis. [d] 10 mol% of catalyst B
was used; see Supporting Information for details.
1
0.5
83:17
[a] All reactions were performed in toluene with 0.5 mmol of 1; there is
no conversion without catalyst. The yields are the isolated product yields
of the purified products. [b] Enantiomeric ratios were determined by
chiral GC analysis; see the Supporting Information for details. [c] The ab-
solute configurations of enantiomerically pure (+)-3a and (À)-3b ob-
tained with B is R in both cases, as determined by comparison with litera-
ture data;[17] this gives 1-acetoxy-2-hydroxycyclohexane 2a and 1-ace-
toxy-2-hydroxycyclopentane 2b as (1R,2S).
Table 3). The best results were achieved with B, which gave
a one-pot synthesis of 3a from 1a in 76% overall yield and
with an e.r. of 88:12 at 08C. The often employed use of an
amine as a base did not markedly improve the selectivity of
the desymmetrization at 08C[5] but instead hampered the ox-
idation step.
Although catalysts D–F are somewhat less selective in the
desymmetrization of 1a we decided to compare all catalysts
in the concurrent tandem reaction using the optimized con-
ditions of Table 3. The tested multicatalysts not only differ
in their activities and selectivities in the desymmetrization
step, they also behave differently in the oxidation. Whereas
the more lipophilic catalysts B, C, and F were active in the
oxidation of 2a, D and E proved to be much less effective
(Table 4). The peptide sequence and structure clearly affects
the ability of the TEMPO moiety in the oxidation step.
In our proof-of-principle studies, we have identified the
first organocatalytic multicatalyst reaction by utilizing a
short oligopeptide with two orthogonal catalytic moieties
(CMs). This one-pot reaction sequence results in enantioen-
riched products in good overall yields. Remarkably, the in-
corporation of a TEMPO moiety in an oligopeptide se-
quence increases the oxidation activity compared to using
TEMPO itself, either in the same sequence of reactions or
in a separate reaction. Multicatalyst B is the logical ad-
vancement of acylation peptide A,[5,12] which emphasizes the
modular nature of the CMs.
Table 4. Desymmetrization of meso-diol 1a and subsequent oxidation of
2a to 3a with catalysts B–F. Conditions are the same as in Table 3; T=
08C.
The C-terminal exchange of the methyl ester by the
TEMPO amide has only very little effect on the selectivity
of the desymmetrization reaction. This observed orthogonal-
ity in reactivity is probably achieved through the lipophilic,
bulky, and inert AGly spacer, which keeps the CMs apart
and prevents the formation of a secondary structure.[11] The
next step is to expand on the number of catalytic steps in
complex reaction sequences to develop one-pot, multicata-
lyst synthetic protocols that give valuable, enantiomerically
enriched functional organic molecules from simple precur-
sors.
Acylation
Cat. t [h] Conversion Yield
Oxidation
e.r.[b] Conversion of
2a [%][a,c] 2a 2a to 3a [%][a,c]
e.r.[b] 3a
[%][a,c]
B
C
D
E
F
7
87.1
89.4
50.7
87.1
84.9
76.5
63.5
43.7
65.5
59.3
88:12 >99
88:12
74:26
47:53
67:13
66:34
22
25
23
23
74:26
48:52
65:35
66:34
96
31
65
94
[a] All reactions were performed with 0.03 mmol of substrate. [b] Enan-
tiomeric ratios were determined by chiral GC analysis. [c] Conversions
and yields were determined by GC analysis. See the Supporting Informa-
tion for details.
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Chem. Eur. J. 2011, 17, 6309 – 6314

One-Pot Multicatalyst System
COMMUNICATION
OH group, Bu4NBr (8.1 mg, 0.025 mmol, 5 mol%) and mCPBA (70%,
370 mg, 1.5 mmol, 3 equiv) were added and the reaction mixture was
stirred at 08C for 1 h and then filtered using silica gel (25 g) suspended
with EtOAc to remove the catalyst. The organic solution was washed
four times with NaHCO3 (8%, 25 mL). The aqueous phases were extract-
ed twice with ethyl acetate (30 mL) and the combined organic phases
were washed three times with water (30 mL) and twice with brine
(30 mL). After drying over Na2SO4 and filtering off the drying reagent
the solvents were removed in vacuo. The crude product was purified by
silica gel column chromatography. Eluting with EtOAc/hexane (1:1) af-
forded 54.7 mg (0.35 mmol, 70.0%) of colorless a-acetoxy ketone 3a
(Rf =0.31). The product was characterized by NMR and chiral GC analy-
ses.
Experimental Section
General: Catalysts A–F were synthesized in solution using a Boc-protec-
tion strategy and EDC/HOBt couplings. The generalized peptide synthe-
sis for B is given below. For 1H NMR (400 MHz, CDCl3): see the Sup-
porting Information; the NMR signals are broad because of the unpaired
electron on TEMPO.
Procedure for EDC/HOBt coupling in solution: An equimolar ratio of
the N-Boc-protected amino acid and the peptide fragment, EDC
(1.1 equiv) and HOBt (1.1 equiv) were dissolved in dry dichloromethane.
Then, triethylamine (2.2 equiv) was added and the solution was stirred
overnight. To the reaction mixture was then added ethyl acetate
(200 mL) and then the solution was extracted with citric acid solution
(0.5m, 4ꢂ25 mL), saturated NaHCO3 solution (4ꢂ25 mL), water (3ꢂ
25 mL), and brine (2ꢂ25 mL). The organic phase was dried over Na2SO4
and filtered and the solvent was evaporated to give the product. The
same strategy was used for the esterification of Boc-l-Phe-OH (1.33 g,
5 mmol) with benzyl alcohol to prepare Boc-l-Phe-OBzl. The Boc-l-(p-
Me)-His-OH couplings were performed using an equimolar ratio of Boc-
l-(p-Me)-His-OH and NH3Cl-AGly-l-Cha-l-Phe-OBzl, EDC (2.2 equiv),
HOBt (2.2 equiv), and Et3N (4.4 equiv) in dry dichloromethane over-
night. All peptide fragments were used in the next coupling step without
further purification.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft
(SPP1179) and the Alexander-von-Humboldt Foundation (fellowship to
R.H.).
Keywords: alcohols · desymmetrization · one-pot synthesis ·
organocatalysis · peptides
Cleavage of the Boc-protecting group: The peptide was dissolved in a so-
lution of HCl (4 N) in 1,4-dioxane (10 mL) and stirred for 45 min. Excess
HCl was removed by flushing the reaction mixture with argon for 45 min.
After evaporation of the solvent in vacuo the deprotected peptides were
used for peptide coupling without purification.
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chromatography (eluting with CHCl3/MeOH 9:1) to afford 1.51 g
(1.8 mmol, 36%) of colorless tetrapeptide Boc-l-(p-Me)-His-AGly-l-Cha-
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Reductive benzyl ester-deprotection: The deprotection of the benzyl
ester Boc-l-(p-Me)-His-AGly-l-Cha-l-Phe-OH (0.5 mmol, 418.6 mg) was
performed by using 10% Pd/C (73.6 mg) in MeOH under hydrogen at-
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Coupling of TEMPO amine with Boc-l-(p-Me)-His-AGly-l-Cha-l-Phe-
OH: An equimolar ratio of Boc-l-(p-Me)-His-AGly-l-Cha-l-Phe-OH
(186.7 mg, 0.25 mmol) and TEMPO amine (42.8 mg, 0.25 mmol), EDC
(2.2 equiv), HOBt (2.2 equiv) and N,N-diisopropylethylamine, (DiPEA,
4.4 equiv) in dry dichloromethane was stirred overnight. The reaction
mixture was added to ethyl acetate (200 mL) and extracted with water
(3ꢂ50 mL) and brine (2ꢂ25 mL). The organic phase was dried over
Na2SO4, filtered and the solvent evaporated. The crude product was then
purified by column chromatography (eluting with CH2Cl2/MeOH 8:2) to
afford 156.5 mg (0.17 mmol, 70%) of a slightly orange product (Rf =
0.82). The peptide was characterized by ESI-MS, HR-ESI-MS, NMR, IR,
EPR, EA and by its specific optical rotation. [a]2D8 =À23.48 (c=
0.647 g 100 mLÀ1; CHCl3). For 1H NMR see the Supporting Informa-
tion.13C NMR (100 MHz, CDCl3): d=176.2 (C=O); 170.7 (C=O); 168.8
(C=O); 168.6 (C=O); 154.4 (C=O); 137.4, 135.3, 128.1, 127.5, 127.3,
126.0, 125.9, 79.3, 53.4, 50.9, 41.2, 39.2, 39.1, 37.8, 37.3, 37.0, 36.2, 33.9,
33.1, 32.3, 31.2, 27.7, 27.2, 26.3, 25.1, 25.0, 24.8 ppm. IR (KBr): v˜ =3309,
3063, 2975, 2923, 2853, 1654, 1510, 1454, 1392, 1366, 1280, 1243,
1168 cmÀ1; MS: (ESI): m/z: calcd for: 900.6 [M+H]+; found: 900.7; 922.6
[M+Na]+; found: 922.5; 938.5 [M+K]+; found: 938.5; 1822.1 [2M+Na]+;
found: 1822.3; HR-ESI: m/z: calcd for: 900.5832 [M+H]+; found
900.5833.
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and the mixture was stirred for 6 h. For the oxidation of the non-acylated
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Received: February 14, 2011
Published online: April 27, 2011
6314
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Chem. Eur. J. 2011, 17, 6309 – 6314