Scaffolding catalysis: Expanding the repertoire of bifunctional catalysts

Article abstract of DOI:10.1055/s-0031-1290321

Inducing an intramolecular reaction is a powerful means of accelerating reactions. Though this mechanism of catalysis is common in enzymes, it is underutilized in synthetic catalysts. This article outlines our groups recent efforts to use reversible coval

Full text of DOI:10.1055/s-0031-1290321

SYNPACTS
321
Scaffolding Catalysis: Expanding the Repertoire of Bifunctional Catalysts
Bifunctional
C
ata
l
i
ysts an L. Tan,* Xixi Sun, Amanda D. Worthy
Department of Chemistry, Boston College, 2609 Beacon St., Chestnut Hill, MA 02467, USA
Fax +1(617)5526351; E-mail: kian.tan.1@bc.edu
Received 21 November 2011
Abstract: Inducing an intramolecular reaction is a powerful means
of accelerating reactions. Though this mechanism of catalysis is
common in enzymes, it is underutilized in synthetic catalysts. This
article outlines our group’s recent efforts to use reversible covalent
bonding to induce an intramolecular reaction, allowing for rate ac-
celeration as well as control of the selectivity in the desymmetriza-
tion of 1,2-diols.
Key words: asymmetric catalysis, desymmetrization, organocatal-
ysis, diols, enantioselectivity
The development of new catalysts is a constantly evolving
process. To design a new catalytic system requires an un-
derstanding of how reactions are accelerated. In general
terms, there are two fundamental means for catalysts to
accelerate reactions: 1) activation of the substrate(s) 2)
preorganization of the substrate(s). For synthetic catalysts
a significant amount of attention has been placed on the
activation of substrates through the generation of reactive
intermediates (e.g., Lewis acid or base activation, enam-
ine formation, metal complexation).1 In contrast, nature
has focused on accelerating reactions in large part through
preorganization of substrates.2 Using substrate-binding
forces, enzymes can position substrates near catalytic res-
idues effectively turning multimolecular steps into pseu-
do-intramolecular transformations. Through substrate-
binding forces, enzymes make a down payment in entropy
that can be used to accelerate a subsequent step. Generi-
cally, bimolecular elementary steps require 15–35 eu in
activation entropy; therefore, turning a biomolecular step
into a unimolecular step has the potential to provide a rate
enhancement of 104–108 for 1 M reactants at room tem-
perature.3
Kian Tan (left) was born in Virginia Beach, VA, USA. In 1999 he re-
ceived his BSc degree in chemistry from the University of Virginia,
and in 2004, he earned his PhD in chemistry from the University of
California, Berkeley. After a two-year post-doctoral fellowship in the
laboratories of Eric Jacobsen at Harvard University, he began his in-
dependent career as an assistant professor at Boston College.
Amanda Worthy (center) was born in Petersburg, WV, USA. She re-
ceived her BA at Goucher College, and is currently a 5th year PhD stu-
dent in the chemistry department at Boston College.
Xixi Sun (right) was born in Chongqing, China. He received his BSc
at the University of Science and Technology of China, and is current-
ly a 4th year PhD student in the chemistry department at Boston Col-
lege.
functional catalysis in the asymmetric additions to carbo-
nyls are shown in Figure 1 from the Corey,5 Noyori,6 and
Shibasaki laboratories.4f Subsequent to this work bifunc-
tional catalysts have been designed for both metal and
Ph
Me
Me
R1
R1
O
N
Zn
B
N
R2
H
O
Ph
This SynPact article will outline our inspirations and re-
cent efforts to develop catalysts that tap into this mode of
rate acceleration.
O
O
R3Zn
R3
R2
H2B
H
R3
Corey oxazaborolidine
Noyori aldehyde
alkylation
reduction
The design and application of bifunctional catalysts is one
approach that chemists have employed to capture the rate
acceleration provided by induced intramolecularity. In
many cases the catalysts are designed to have a Lewis
acidic and basic site allowing for dual activation of an
electrophile and nucleophile.4 Some early examples of bi-
Ph
P
Me2
Si
Ph
O
C
R1
N
O
H
O
Al Cl
O
O
PR2
3
Shibasaki Strecker
reaction
SYNLETT 2012, 23, 321–325
x
x
.
x
x
.
2
0
1
2
Advanced online publication: 25.01.2012
DOI: 10.1055/s-0031-1290321; Art ID: P69211ST
Figure 1 Proposed intermediates with bifunctional catalysts
© Georg Thieme Verlag Stuttgart · New York

322
K. L. Tan et al.
SYNPACTS
nonmetal catalysts.7 The majority of the examples focus catalytically, a reversible interaction is needed between
on the activation of two reactants in close proximity to one substrate and scaffold (Scheme 1); we chose to use revers-
another; however, in terms of induced intramolecularity, ible covalent bonding in order to make a rigid interaction
activation of the substrate is not required to gain rate ac- with the aim of improving selectivity in the desired reac-
celeration, only proximity. A paragon of this mode of ca- tions.9
talysis was reported by the Kelly group, in which they
Inspired by the works of catalytic directing groups in tran-
demonstrated that an SN2 reaction can be accelerated
sition-metal catalysis,10 we initially applied this idea to
through a templating catalyst (Equation 1).8
regio-,11 diastereo-,12 and enantioselective hydroformyla-
tion reactions.13 In these cases a phosphorous-based
H
H
ligand (2, Scheme 2) was used as the scaffold, where the
phosphorous atom serves to coordinate to the metal cata-
lyst, and the carbon in the orthoformate oxidation state
binds to an array of organic functional groups. Having the
substrate bound to the catalyst generates a chelating
ligand for the metal allowing for both rate enhancement as
well as control of the selectivity. For example, we em-
ployed 2 in the regioselective hydroformylation of 1,1-
disubstituted olefins towards the formation of quaternary
carbon centers.14
N
N
N
N
N
O
NH2
Br
+
O
catalyst
H
H
N
N
N
N
N
O
N
H
O
12-fold rate enhancement
Ph
1) Rh(acac)(CO)2 (4 mol%)
ligand, p-TsOH (0.2 mol%)
OH
O
OH
O
OH
Bn
45 °C, 400 psi CO/H2, benzene
2) NaClO2, H2O–t-BuOH
Ph
Ph
1
NaH2PO4, 2-methyl-2-butene
O
N
NH
H
HN
H
N
N
H
Ph
H
H
N
H
N
Ph3P (8 mol%): no conversion
Me
N
O
N
N
Br
NH2
Me
N
N
b/l = 97:3
72% yield
O
O
Ph
Oi-Pr
P
Ph
2
P
Equation 1 Kelly template accelerated SN2 reaction
Ph
(20 mol%)
Recently our group has capitalized on using proximity as
a means of accelerating reactions by developing organic
scaffolds that colocate a catalyst and starting material.
The generic structure of a scaffolding catalyst has a cata-
lyst-binding site (or bound catalytic residue) and a sub-
strate-binding site (Scheme 1). The key insight for this
concept is that substrate binding does not require simulta-
neous activation of a functional group; therefore, the scaf-
folds can be applied potentially to a wide range of
transformations. In order for these scaffolds to be used
Scheme 2 Branch-selective hydroformylation to form quaternary
carbon centers
Formation of quaternary carbon centers has traditionally
been challenging in hydroformylation due to the strong
preference to place the aldehyde on the least hindered car-
bon.15 Using the scaffolding catalyst, we form the desired
product in high regioselectivity and good yield
(Scheme 2). Notably, a control reaction with Ph3P shows
no conversion to hydroformylation products; furthermore,
employing the methyl ether substrate (which can not bind
to 2) also shows no conversion to product (Equation 2).
These results demonstrate that substrate binding to the
scaffold both accelerates the reaction and controls the se-
lectivity.
starting
=
A
B
cat
material
scaffold
B
A
= product
substrate
binding
product
release
1) Rh(acac)(CO)2 (4 mol%)
2 (20 mol%), p-TsOH (0.2 mol%)
OMe
no conversion
>99% 3
cat
45 °C, 400 psi CO/H2, benzene
2) NaClO2, H2O–t-BuOH
cat
A
Ph
scaffold
NaHPO4, 2-methyl-2-butene
scaffold
3
B
Equation 2 Control reaction with methyl ether 3
transformation
Having successfully applied the scaffolding strategy to
hydroformylation, we looked to expand the concept to
Scheme 1 Catalytic cycle for a scaffolding catalyst
Synlett 2012, 23, 321–325
© Thieme Stuttgart · New York

SYNPACTS
Bifunctional Catalysts
323
other transformations. In order to demonstrate the broad
utility of the idea, we applied our strategy to the area of or-
ganocatalysis. Previous work by Hoveyda and Snapper
had shown that 1,2- and 1,3-diols can be efficiently de-
symmetrized using an amino acid based catalyst
(Equation 3).16–18 Using the Hoveyda/Snapper catalyst (4)
as a starting point, we synthesized catalyst 5 guided by our
basic design principle of having a catalytic site adjacent to
a covalent substrate-binding site (Scheme 3).
TBSCl (2 equiv), PMP (1.2 equiv)
HO
OH
i-Pr
HO
OTBS
PMP•HCl (3 mol%), THF, r.t.
cat. (20 mol%)
O
O
N
OMe
N
i-Pr
N
N
i-Pr
i-Pr
N
N
Me
Me
5a
5b
92% yield
94% ee
5% yield
4% ee
OH
TBSO
OH
HO
TBSCl , DIPEA, THF, –78 °C
t-Bu
Equation 4 Desymmetrization of cis-cyclopentane-1,2-diol
H
Me
N
82% yield
92% ee
N
Me
N
H
N
O
t-Bu
4
(30 mol%)
Equation 3 Hoveyda–Snapper desymmetrization of 1,3-diol
hydroformylation catalyst
substrate binding
site
Me
N
silylation catalyst
substrate binding
OMe
P
site
O
Ph
catalyst
binding
site
OMe
2
Figure 2 X-ray crystal structure of 5c
N
N
R'
catalyst
Hoveyda–Snapper
silylation catalyst
N
R
With the optimal catalyst in hand, we extended the sub-
strate scope to include both cyclic and acyclic 1,2-diols.
These substrates generally afford practical levels of yield
(79–93%) and enantioselectivity (86–95% ee, Table 1).
Though a range of substrates work in the desymmetriza-
tion reaction, the rate of reaction is highly dependent on
the nature of the substrate. In general, five- and six-mem-
bered rings form product the fastest, with larger rings and
acyclic substrates reacting at significantly slower rates. To
improve on the practicality of the reaction, we found that
use of TESCl in place of TBSCl shortened the reaction
times and also allowed for the lowering of the equivalence
of silyl chloride relative to substrate. In the case of 2,3-bu-
tane diol, the optimal conditions with TBSCl (4 equiv) re-
quire a reaction time of 36 hours at 0 °C, whereas TESCl
(1.2 equiv) can be performed at room temperature in less
than four hours with comparable yield (84%) and ee
(92%, Equation 5).
Me
5
t-Bu
O
Me
HN
NH
N
t-Bu
N
Me
4
Scheme 3 Design of organic catalyst 5
Optimization of core structure 5 led to the identification of
5a as an efficient catalyst for the desymmetrization of cis-
cyclopentane-1,2-diol (94% ee and 92% yield,
Equation 4).19 An interesting feature of 5a is that the ste-
reocenter at the exchange site likely epimerizes under the
reaction conditions, yet only a single diastereomer is ob-
1
served by H NMR. An X-ray crystal structure of 5c,
formed by exchange of 5a with 4-bromobenzyl alcohol,
shows that the alcohol binds syn to the i-Pr group on the
oxazolidine ring (Figure 2). These data suggest that the
external stereocenter is effectively gearing the stereo-
center at the exchange site. As evidence that the reaction
occurs through a reversible covalent bond, we tested cat-
alyst 5b, which does not contain a substrate-binding site.
Catalyst 5b provides both poor yield (5%) and enantiose-
lectivity (4% ee), consistent with the idea that covalent
bonding of the substrate to the catalyst is necessary for
both selectivity and activity (Equation 4).
TESCl (1.2 equiv), PMP (1.2 equiv)
HO
HO
OH
OTES
PMP•HCl (3 mol%), THF, r.t.
5a (20 mol%)
84% yield
92% ee
Equation 5 Silylation using TESCl
As is often the case some of the more interesting results
are the substrates that provide poor yields or selectivities.
For example, (R,S)-pentane-2,4-diol and trans-cyclohex-
ane-1,2-diol affords less than 5% yield of product. Fur-
© Thieme Stuttgart · New York
Synlett 2012, 23, 321–325

324
K. L. Tan et al.
SYNPACTS
catalytic residue, which is enforced through the covalent
bonding between catalyst and scaffold. We envision that
through proper design of a molecular scaffold that binding
selectivity and proximity can be exploited to achieve reac-
tions that would be challenging using noncovalent inter-
actions.
Table 1 Desymmetrization of 1,2-Diols
Entry
1
Product
Yield (%)
79
ee (%)
89
OH
O
OTBS
OH
2
3
4
87
88
86
90
95
92
Acknowledgment
OTBS
We thank the ACS-PRF (DNI-5001400) and NIGMS
(RO1GM087581) for funding this research. A.D.W. was supported
by a LaMattina graduate fellowship. Mass spectrometry instrumen-
tation at Boston College is supported by funding from the NSF
(DBI-0619576). The Boston College X-ray facility is supported by
funding from the NSF (CHE-0923264).
OH
OTBS
OH
OTBS
OH
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7
82
93
78
90
86
90
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Synlett 2012, 23, 321–325