A Family of Chiral Ferrocenyl Diols: Modular Synthesis, Solid-State Characterization, and Application in Asymmetric Organocatalysis

Article abstract of DOI:10.1002/anie.201604840

Readily available chiral diol scaffolds are useful as sources of chirality for asymmetric synthesis, however, few such scaffolds are readily available in enantiopure form. Reported herein is a cheap and modular synthesis of a novel family of chiral ferroc

Full text of DOI:10.1002/anie.201604840

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Communications
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International Edition: DOI: 10.1002/anie.201604840
German Edition: DOI: 10.1002/ange.201604840
Planar Chirality
A Family of Chiral Ferrocenyl Diols: Modular Synthesis, Solid-State
Characterization, and Application in Asymmetric Organocatalysis
Chris Nottingham, Helge Mꢀller-Bunz, and Patrick J. Guiry*
Dedicated to Dr. James B. Thomson[1]
Abstract: Readily available chiral diol scaffolds are useful as
sources of chirality for asymmetric synthesis, however, few such
scaffolds are readily available in enantiopure form. Reported
herein is a cheap and modular synthesis of a novel family of
chiral ferrocenyl diols in excellent yields with excellent enantio-
and diastereoselectivity (> 99% ee and 99% de). These diols
possess not only planar and central chirality, but also axial
Scheme 1. Planar-chiral ferrocenyl ligands and catalysts.
chirality around the central iron atom. Characterization of
these diols by X-ray crystallography revealed intra- and
intermolecular hydrogen-bond networks depending on sub-
stitution at the carbinol positions. The potential of these diols as
catalysts was subsequently demonstrated in an asymmetric
hetero-Diels–Alder reaction which provided cycloadducts in
up to 84% yield with ee values ranging from À92 to + 72%.
W
ith applications as chiral auxiliaries, ligands, and catalysts,
C2-symmetrical diols represent one of the most important
structural motifs in asymmetric synthesis.[2] Such diols often
serve as valuable synthons for chiral diamine ligands,
diphosphine ligands, phosphoramidites, and phosphoric
acids, further highlighting their potential and making them
among the most sought after motifs in asymmetric catalysis.[3]
Indeed, out of the eight privileged chiral ligands and catalysts
originally identified by Yoon and Jacobsen,[4] three were
either derived from, or were chiral diols (TADDOL, BINOL,
and BINAP). In line with this finding, 1,2-disubstituted
ferrocenes which possess planar chirality have proven to be
excellent ligand/catalyst backbones for asymmetric catalysis
(Scheme 1).[5]
Figure 1. Novel ferrocenyl-based diol scaffold. Cp=cyclopentadienyl.
Encouraged by the potential offered by a new diol
scaffold and the success of ferrocenyl planar chirality as
a control element in asymmetric transformations, we set out
to design a novel family of planar-chiral ferrocenyl diols
which could take advantage of the flexible nature of the
ferrocenyl backbone (Figure 1). These diols would possess
planar chirality on both ferrocenyl Cp rings, central chirality
at both carbinol carbon atoms, and axially chirality around the
iron center. Such enantiopure, C2-symmetrical diols would
have potential not only in asymmetric synthesis, but also in
materials chemistry.[2c,6]
Key to our synthetic strategy was the elegant catalytic
À
asymmetric C H activation/cyclization methodology
reported independently by the groups of You and Gu.[7]
Indeed, the synthesis of the key intermediate diketone
(Rp)-1 was reported by both You and Gu as part of their
substrate scope, although the preparation of the required
starting materials 2 and 3 was unfortunately not described in
detail and the ligand and precatalyst loadings reported for the
asymmetric cyclization step were quite high (for structures
see Table 1). Furthermore, (Rp)-1 was reported to decompose
at room temperature.[7b] However, we found this to be
a robust, bench-stable compound over the course of our
studies (18 months). Aware that a simple and cost-effective
synthesis enhances the application opportunities of any new
chiral scaffold we began to optimize a synthetic route towards
[*] C. Nottingham, H. Mꢀller-Bunz, P. J. Guiry
Centre for Synthesis and Chemical Biology
School of Chemistry, University College Dublin
Belfield, Dublin 4 (Ireland)
E-mail: p.guiry@ucd.ie
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604840.
Additional X-ray crystal structures for 5, 11, 12, and 17 are included in
the Supporting Information. CCDC 1480208–1480215 contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
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(Sp)-1. This culminated in a high-yielding, chromatography-
free synthesis of the requisite starting materials 2 and 3 and an
optimized, chromatography-free synthesis of (Sp)-1 utilizing
low palladium and ligand loadings to provide the desired
products in excellent yields with complete enantiocontrol
(Table 1). These optimized reaction conditions facilitated the
preparation of multigram quantities of our key intermediate,
(Sp)-1, in just two steps from cheap and readily available
starting materials.[8]
Table 1: Optimized synthesis of (Sp)-1.
Scheme 2. Synthesis of substituted diols. [a] NaBH4. [b] Organolithium
reagent. [c] TMSCF3/TBAF. [d] Grignard reagent; see the Supporting
Information for details. Cy=cyclohexyl, Fc=ferrocenyl, TBAF=tetra-n-
butylammonium fluoride, TMS=trimethylsilyl.
Entry
X
BINAP
(mol%) (mol%)
Pd(OAc)2
t [h] Yield [%]
ee [%] de [%]
Gu[7a]
1
I
I
13.0
3.5
5.0
10.0
2.5
2.5
5
20
53
1
61
99
97
96
98[a]
>99
99[b]
>99
92
99
–
You[7b] Br
2
Br
3.5
2.5
98
[a] (R)-BINAP was used to provide (Rp)-1 without pivalic acid. [b] (R)-
BINAP was used to provide (Rp)-1 in p-xylene at 808C with 1.5 equiv of
Cs2CO3. See the Supporting Information for additional screening results.
BINAP=2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl.
With access to large quantities of (Sp)-1, we prepared
a range of 15 diols, with varying electronics and sterics at the
carbinol position, in generally good to excellent yields and all
with complete enantiocontrol provided by stereoselective
Re attack on the diketone (Scheme 2). An X-ray crystal
structure of 4 confirmed the absolute configuration at the
carbinol position and revealed an intricate hydrogen-bonding
network between five individual molecules in the unit cell
(Figure 2; left). This type of hydrogen bonding is similar to
that observed with the privileged ligand TADDOL.[2c] Fur-
thermore, because of axial rotation around the metal center of
ferrocene, the diol can adopt a number of orientations, thus
showcasing the flexible nature of the scaffold (Figure 2;
right). Conversely, the tertiary diols generally crystallized
with a “folded” conformation as illustrated with the CF3-
substituted diol 6 (Figure 3). In this case the two Cp rings of
ferrocene have rotated to direct the two hydroxy groups away
from each other, thus eliminating the possibility of intra-
molecular hydrogen bonding. As the aryl–aryl distance
between the two benzene rings is roughly 3.7 ꢀ in each
case, it is possible that p–p stacking interactions are stabiliz-
ing the diols in this folded conformation.
Figure 2. Left: Unit cell of secondary diol 4 showing an intra- and
intermolecular hydrogen-bonding network. Right: Individual molecules
of 4 taken from two separate crystal structures illustrate the flexibility
of the diol scaffold. O red, Fe orange, Cl green.
Figure 3. Front view (left) and top view (right) of the CF3-substituted
diol 6 in the solid state showing possible p–p stacking. O red,
Fe orange, F yellow.
An exception to this general trend with tertiary diols was
the C6F5-substituted diol 13, which crystallized with the same
“open” conformation as the secondary diol 4, thus resulting in
the formation of both inter- and intramolecular hydrogen
bonds to provide the dimer shown (Figure 4).
With members of our novel diol family demonstrating
their propensity to form hydrogen bonds in the solid state we
sought to apply these diols in asymmetric catalysis as a proof
of concept.[2d] To this end we drew inspiration from the
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Table 3: Substrate scope for hetero-Diels–Alder.
Figure 4. Dimer (left) and cross-section (right) of the C6F5-substituted
diol 13 in the solid state. O red, Fe orange, F yellow.
elegant work of Rawal and co-workers, who demonstrated
that diols such as TADDOL and BAMOL catalyze the
hetero-Diels–Alder reaction between activated amino siloxy
dienes and aldehydes.[9] As an initial test we employed the
privileged catalyst TADDOL 19 as a control in the reaction of
Rawalꢁs diene with benzaldehyde before screening our range
of novel diols, which allowed us to identify two of our diols as
suitable chiral catalysts (Table 2). Interestingly, while all
Yield is that of the isolated product. The ee value was determined by
chiral SFC, see the Supporting Information for details.
Table 2: Catalyst screen for hetero-Diels–Alder reaction.
ee values (36–92%). In many cases the two diol catalysts 12
and 16 provided complementary results with similar ee values
being obtained for the R- and S-enantiomers of the same
product (entries 1–5). Although the yields and ee values
obtained are modest in most cases, the fact that both
enantiomers of the same product can be made simply by
varying the aryl hydroxymethyl group on the catalyst is quite
intriguing. This variation allowed us to obtain ee values of
72% for the R-configured product to 92% of the
S-configured product with the same hand of catalyst and
highlights the potential of this ligand/catalyst scaffold.
With regards to the mode of activation, we propose that
the active catalyst contains both one intramolecular and one
intermolecular hydrogen bond.[10] In this case the intra-
molecular hydrogen bond would further activate the remain-
ing hydrogen by charge stabilization. Indeed, when the
monoalcohol analogue of 12 (bottom Cp ring unsubstituted)
was employed as a catalyst, no product was formed, even after
48 hours, thus indicating that the intramolecular hydrogen
bond is essential for activation of the aldehyde. On the basis
of our crystallographic studies and the observed absolute
configuration of the cycloadducts obtained, we propose the
following possible transition states to account for the
observed stereodivergence (Figure 5 and Figure 6). With 12,
Re-cis would be the major source of the R-configured product
with competition with the Si-trans transition state accounting
for the moderate ee values obtained. With 16, Re-cis is
blocked by steric interactions between the aldehyde R group
and the catalystꢁs upper naphthyl group, thus, accounting for
the moderate to high ee values of the S-configured product
obtained.
Entry
Catalyst
R
Yield [%]
ee [%]
Config.
1
2
3
19
12
16
n.a.
3,5-(CF3)2C6H3
1-Naphthyl
46
37
29
47
70
68
S
R
S
Yield is that of the isolated product. The ee value was determined by
chiral SFC, see the Supporting Information for details and additional
screening results. n.a.=not applicable, TBS=tert-butyldimethylsilyl.
aspects of chirality for the two diols 12 and 16 are identical,
they provide cycloadducts of opposite absolute configuration
(entries 2 and 3).
To probe if this sense of asymmetric induction was general
we carried out a substrate scope with both catalysts (Table 3).
A variety of different aldehydes were examined, including
5-aryl aldehydes with varying substitution at the ortho-, meta-,
and para-positions (entries 1, 2, 5, 7, and 8) along with 2-alkyl
aldehydes (entries 3 and 6) and one vinyl aldehyde (entry 4).
With all eight substrates, 12 provided the same sense of
stereoinduction with moderate to high yields (37–84%) and
moderate to good ee values (40–72%). Conversely, the diol 16
consistently provided the other enantiomer in excess, with low
to moderate yields (13–56%) and moderate to excellent
In summary, we have presented an optimized, chroma-
tography-free synthesis of the chiral diketone (Sp)-1. The
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diols in both materials chemistry and asymmetric catalysis,
along with the synthesis of new ligands and catalysts from this
enantiopure scaffold are currently ongoing in our laboratory
and will be reported in due course.
Acknowledgments
We thank the Irish Research Council (IRC) for the award of
a research scholarship (RS/2012/607) to C.N. We also thank
UCD School of Chemistry and the Centre for Synthesis and
Chemical Biology (CSCB) for the use of analytical facilities.
Keywords: chirality · cycloaddition · diols · organocatalysis ·
planar chirality
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Figure 6. Possible transition states for catalyst 16. The terms Si and
Re define the face of aldehyde primed for attack by the diene while cis
and trans define which aldehyde lone-pair coordinates to the hydroxy
proton.
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stacking interactions in the solid state. As a proof of concept,
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lysts in an asymmetric hetero-Diels–Alder reaction, thus
providing cycloadducts in up to 84% yield with ee values
ranging from À92 to + 72%. Further applications of these
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Received: May 17, 2016
Published online: && &&, &&&&
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Communications
Planar Chirality
C. Nottingham, H. Mꢁller-Bunz,
P. J. Guiry*
&&&& — &&&&
A Family of Chiral Ferrocenyl Diols:
Modular Synthesis, Solid-State
Characterization, and Application in
Asymmetric Organocatalysis
Triple crown of chirality: Reported is the
synthesis of a novel family of chiral
ferrocenyl diols possessing planar, cen-
tral, and axial chirality. X-ray crystallogra-
phy reveals dense intra- and intermolec-
ular hydrogen-bond networks. The
potential of these diols as organocata-
lysts was demonstrated in an asymmetric
hetero-Diels–Alder reaction, thus provid-
ing cycloadducts in up to 84% yield with
ee values ranging from À92 to +72%.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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