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1
Tetrahedron Letters
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
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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