A recyclable and highly stereoselective multi-fluorous proline catalyst for asymmetric aldol reactions

Article abstract of DOI:10.1016/j.tetlet.2020.151657

A recyclable fluorous proline catalyst with high stereoselectivity that functions as a catalyst for asymmetric aldol reactions is described. Its high stereoselectivity and facile recovery are achieved by employing a multi-fluorous tag attachment strategy. Although a gradual decrease was observed with respect to the catalytic activity, the catalyst can be separated from the reaction mixture by adsorption onto FluoroFlash and can be reused in that form for a maximum of five times while maintaining a high stereoselectivity.2019 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2020.151657

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A recyclable and highly stereoselective multi-fluorous proline catalyst for asym-
metric aldol reactions
Kazuki Ishihara, Riho Obayashi, Machiko Gotoh, Yuki Watanabe, Yuki
Kobayashi, Kotaro Ishihara, Takayuki Shioiri, Masato Matsugi
PII:
S0040-4039(20)30076-9
DOI:
https://doi.org/10.1016/j.tetlet.2020.151657
TETL 151657
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 November 2019
6 January 2020
21 January 2020
Please cite this article as: Ishihara, K., Obayashi, R., Gotoh, M., Watanabe, Y., Kobayashi, Y., Ishihara, K., Shioiri,
T., Matsugi, M., A recyclable and highly stereoselective multi-fluorous proline catalyst for asymmetric aldol
reactions, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151657
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Graphical Abstract
A recyclable and highly stereoselective
multi-fluorous proline catalyst
for asymmetric aldol reactions
Leave this area blank for abstract info.
Kazuki Ishihara, Riho Obayashi, Machiko Gotoh, Yuki Watanabe, Yuki Kobayashi, Kotaro Ishihara, Takayuki
Shioiri, and Masato Matsugi
F
F
F
F
A recyclable catalyst
F
F
F
via medium-fluorous strategy
F
F
F
F
multi-fluorous
proline catalyst
F
F
F
O
O
OH
O
F
F
F
F
F
1 mol%, rt
F
H
O
multi-fluorous
proline catalyst
supported on FluoroFlash®
+
in H2O:
O
O2N
O2N
81%, >99%ee; anti : syn = 100 : 0
F
N
F
in toluene:
92%, >99%ee; anti : syn = 97 : 3
H
HN
S
F
high stereoselectivity (97-99%ee)
up to fifth cycle.
O
O

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Tetrahedron Letters
journal homepage: www.elsevier.com
A recyclable and highly stereoselective multi-fluorous proline catalyst for asymmetric
aldol reactions
Kazuki Ishihara, Riho Obayashi, Machiko Gotoh, Yuki Watanabe, Yuki Kobayashi, Kotaro Ishihara,
Takayuki Shioiri, and Masato Matsugi
Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +81-52-832-1151; fax: +81-52-835-7450; e-mail: matsugi@meijo-u.ac.jp
Article history:
Received
Received in revised form
Accepted
A recyclable fluorous proline catalyst with high stereoselectivity that functions as a catalyst for
asymmetric aldol reactions is described. Its high stereoselectivity and facile recovery are
achieved by employing a multi-fluorous tag attachment strategy. Although a gradual decrease
was observed with respect to the catalytic activity, the catalyst can be separated from the
reaction mixture by adsorption onto FluoroFlash® and can be reused in that form for a maximum
of five times while maintaining a high stereoselectivity.
Available online
Keywords:
Organocatalyst
Proline
2019 Elsevier Ltd. All rights reserved.
Fluorous
Activation
Aldol reaction
In 2000, List’s group reported that proline acts as an excellent
catalyst in asymmetric intermolecular aldol reactions.1 Since
then, research related to asymmetric organocatalyst has
developed rapidly.2 Further, a number of pioneering studies on
improving the catalytic properties of proline by altering and
derivatizing its structure have been published.3 An excellent
example is the groundbreaking research presented by the
Hayashi’s group,4 who reported that the introduction of a bulky
substituent at the 4-position of the proline skeleton drastically
improves its enantioselectivity in aqueous conditions.5 It has also
been reported that stereoselectivity can be improved by
controlling the acidity of the carboxy group moiety of the
proline6 and that prolines bearing sulfonamide structures function
as effective catalysts in asymmetric aldol reactions.7 However, it
has also been reported that the transformation of the carboxy
group into a fluorinated sulfonamide catalyst is not very effective
for the aldol reaction of isatin with acetone even though this
developed an effective catalytic reaction system in which the
fluorous catalyst can be recovered by the solid-state adsorption
after the reaction even though the catalyst is present in the
homogeneous state during the first reaction. Further, we
considered that this recovery and reuse strategy would be
applicable to fluorous proline organocatalysts.
Here, we envisioned the usage of this fluorous tagging
strategy as the basis of the recovery protocol as well as the
exploitation of this strategy for activating the catalyst. We
decided to prepare the novel fluorous proline catalyst 1a depicted
in Figure 1, which contained a highly hydrophobic C8F17 tag
linked to the 4-position via a propylene spacer and a 3,5-
bistrifluoromethylsulfonamide moiety on the carboxy group. We
considered that this catalyst would exhibit high stereoselectivity
for aldol reactions because it contained both a bulky fluorous
moiety on the 4-position4 and a highly acidic amide proton in the
sulfonamide structure7 owing to the presence of the electron-
withdrawing trifluoromethyl groups. We also expected that 1a
would be a recyclable catalyst whose fluorous content of 50.4%,
i.e., “medium fluorous,” would be suitable for our recycling
strategy.9 Although the “light fluorous” proline catalyst 1c having
a C8F17 tag on the 4-position has been already reported by
Fache’s group,11 we expected that the novel medium fluorous
catalyst 1a would be a more stereoselective and recyclable
organocatalyst.
transformation into
a
sulfonamide bearing an electron-
withdrawing group modifies the enantioselectivity for the aldol
reactions.8
We have recently reported a reasonable separation strategy9
for the simple post-reaction recovery of a fluorous Grubbs–
Hoveyda second generation catalyst.10 In this paper, we

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Tetrahedron Letters
The synthetic route to obtain 1a is presented in Scheme 1.
The catalyst was prepared from (2S,4R)-trans-4-hydroxyproline
via a radical addition reaction to introduce the perfluorooctyl
group to the molecule. We also prepared the control catalyst 1b
(see Figure 1), which is a non-fluorous analog of 1a, to compare
their reactivities and stereoselectivities during aldol reactions
(Scheme 2). Furthermore, the fluorous proline 1c was also
prepared using a previously reported method11 for performing
comparisons.
Initially, we assessed whether the aldol reactions proceed
when 1a was used as an organocatalyst. As presented in Table 1,
the reaction performed using p-nitrobenzaldehyde and
cyclohexanone12 as model substrates was successfully completed
at room temperature (Table 1, entries 1–3). Surprisingly, despite
the fact that 1a was very hydrophobic and barely soluble in
water, the reaction proceeded to afford the aldol product with
perfect stereoselectivity in water even though an extended
reaction time was required (Table 1, entry 2). Because this
catalyst was insoluble in water, no further investigation was
performed with respect to these conditions. It was also observed
that the catalyst functioned effectively in toluene, which was a
relatively easy-to-handle solvent for scale-up. Although it was
possible to reduce the reaction time by increasing the amount of
catalyst, both the syn/anti-selectivity and the enantiomeric excess
(anti-form) decreased when a catalyst loading of 30 mol% was
used (Table 1, entry 5).
Catalyst 1b, which was the non-fluorous version of 1a,
exhibited drastically reduced catalytic activity and
stereoselectivity when compared to those of 1a (Table 1, entry 6).
Furthermore, when the fluorous catalyst 1c, which contained a
free carboxy group at the proline 2-position, was used under the
same conditions, the reaction barely progressed at all, and both
the yield and selectivity were considerably low (Table 1, entry 7).
One of the causes of this decreased reactivity is the lower
solubility of 1c in toluene when compared to that of 1a.
Further, the substrate scope of the new catalyst was assessed
using a range of benzaldehydes, as presented in Table 2.12,13
Although high overall stereoselectivities in the ee range of 93%–