Communication
A significantly more enantiocontrolled alkylation of oxindole
10 (Figure 2B) was carried out by Ooi et al. in 2011,[12] using a
chiral 1,2,3-triazolium ion-based phase-transfer catalyst 11.
Jiang et al. in 2013,[13] employed a bicyclic guanidinium ion 15
(Figure 2C) as a catalyst–in conjunction with a Lewis acid co-
catalyst–to promote the alkylation of 3-substituted-2-oxindoles
13a–c with activated alkyl bromides such as 14. In the main,
highly selective examples of these PTC-catalyzed alkylations re-
actions often involve oxindoles incorporating a simple methyl-,
benzyl or aryl-substituent at position 3, which leaves the prod-
uct less than ideally placed for further structural modification.
Herein we describe the highly enantioselective alkylation of
ester-substituted 2-oxindole 17[14] using a newly developed
bulky, cinchona alkaloid-derived bifunctional phase-transfer
catalyst 18 and the application of the methodology in the
total synthesis of (À)-debromoflustramine B (Figure 2D).
Table 1. Catalyst evaluation.
Initial efforts were focused on the development of new cin-
chona alkaloid-based phase transfer catalysts capable of hydro-
gen bonding as a control element.[15] We began by investigat-
ing the alkylation of the potentially malleable oxindole 17 with
benzyl bromide in the presence of an aqueous solution of po-
tassium carbonate and dichloromethane, to yield 20 with the
formation of a quaternary carbonaceous stereocenter (Table 1).
In the absence of the phase transfer catalyst no reaction is ob-
served under these conditions.[16] Catalysis by the urea-substi-
tuted ammonium salt 21 (first prepared by Dixon et al.[15b]) pro-
ceeded smoothly and with moderate enantiocontrol. The intro-
duction of electron-withdrawing substituents on the benzyl
unit in the 3,5- or 2,6-positions led to marginal increases in
enantiocontrol (i.e., catalysts 22–24). Exchange of the phenyl
unit of the benzyl substituent with an anthracenyl group (i.e.,
25) diminished product ee, although this could be ameliorated
somewhat through the introduction of a phenyl group at C-2
of the catalyst’s quinoline moiety (i.e., catalyst 26). Interesting-
ly, returning to the N-benzyl motif and installing two bulky
tert-butyl substituents allowed the formation of 20 with im-
proved selectivity, and again incorporation of a C-2 phenyl unit
proved advantageous (i.e., catalysts 27–28). The role that the
C-2 aryl unit plays in improving the enantioselectivity of the
process is unclear at present. Recently, we reported the results
of calculations which demonstrated that this unit can partici-
pate (via the o-hydrogen atom on phenyl substituent) in at-
tractive O-H-C interactions with a squaramide-bound enolate
in a bifunctional cinchona-alkaloid derived catalyst system;
however a precise explanation of the role of the phenyl unit in
this process awaits further study.[16]
[a] Conversion determined by 1H NMR spectroscopy using para-iodoani-
sole as an internal standard. [b] ee determined by chiral HPLC analysis
after isolation by column chromatography. [c] CH2Cl2 (1.0m), K2CO3 (s)
(2.0 equiv), À308C.
The importance of the N-3,5-bis-trifluromethylphenyl moiety
is illustrated by the poor performance of catalyst 29, in which
this group has been exchanged with a tert-butyl substituent.
Next we examined the use of squaramide derivatives. Initial re-
sults were promising: the squaramide analogue of 25 (i.e., 30)
promoted the reaction with superior ee (54 vs. 26%) albeit
with a slow reaction rate. Similar catalyst modifications to
those carried out in the urea series were then made (i.e., cata-
lysts 31–33)–and while levels of enantiomeric excess rivalled
the best urea based catalysts, the reactions were prohibitively
slow. The contribution from the urea N-3,5-bis-trifluromethyl-
phenyl moiety, the marked difference in rate between the
urea- and squaramide-catalyzed reactions and the lack of enan-
tiocontrol when neither are present[17] strongly implicates the
hydrogen-bond donating unit as being a key driver of the cat-
alysis.
Given the inferiority of squaramides in this process, focus re-
turned to the urea based systems. Catalyst 18, which compris-
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Chem. Eur. J. 2018, 24, 1 – 5
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