Letter
Enantioselective Addition of Azlactones to Ethylene Sulfonyl
Fluoride via Dual Catalysis
sı
*
ACCESS
ABSTRACT: Enantioselective conjugate addition of azlactones to ethylene sulfonyl fluoride has been achieved via the cooperative
catalysis with (DHQD)2PHAL and a hydrogen-bond donor (HBD). This approach furnishes a facile access to a range of structurally
diverse azlactone sulfonyl fluoride derivatives with good to excellent yields and enantioselectivities. The combination of azlactone
and sulfonyl fluoride group produces valuable unnatural α-quaternary amino acid derivatives for the drug discovery.
group. These products are valuable for drug discovery, because
of their conformationally constrained nature of α-quaternary
amino acid and covalent warhead of sulfonyl fluoride. Here, we
report an enantioselective conjugate addition of azlactones to
ESF via the cooperative catalysis with (DHQD)2PHAL and a
hydrogen-bond donor (HBD). A series of azlactone sulfonyl
fluoride derivatives were obtained with good to excellent yields
and enantioselectivities.
The conjugate addition of azlactone 1a to ESF was used as
the model reaction. A variety of chiral organocatalysts were
examined, and the results are listed in Table 1. In our previous
works, the bifunctional organocatalyst 2a was found to be the
best catalyst for the conjugate reaction of ESF.9,10 However, in
the present reaction, catalyst 2a gave almost racemic product
4a with poor yield (Table 1, entry 1). The thiourea analog 2b
also provided low yield and enantioselectivity (Table 1, entry
2). The quinine 2c and cinchonine 2d were found to give
improved yields; however, the enantioselectivities were
unsatisfactory (Table 1, entries 3 and 4). A number of other
organocatalysts were also tried, but only low to moderate
yields and poor enantioselectivities were obtained (see details
ulfonyl fluoride is a valuable synthetic motif that has great
Sprospects in the area of pharmaceuticals, agrochemicals,
and materials.1 Sulfonyl fluoride is also known to be a potential
irreversible inhibitor or protein probe, because of its high
thermodynamic stability, controllable reactivity, and biocom-
patibility.2 However, the availability of sulfonyl fluoride
derivatives is still challenging.3 Mostly, ethenesulfonyl fluoride
(ESF), which is a strong Michael acceptor as well as Diels−
Alder dienophile, is a useful reagent for the introduction of a
sulfonyl fluoride group.4 In 2014, Sharpless and co-workers
reviewed the reactions of ESF with amines, N-containing
heterocyclic compounds, and amino acids.5 Sharpless, Qin, and
other groups then developed more transformations of ESF.6
Despite the progresses, asymmetric transformation of ESF had
rarely been explored before. In 2019, Leung group reported
phosphapalladacycle catalyzed enantioselective hydrophosphi-
nation reaction of β-arylethenesulfonyl fluorides.7 In the same
year, Rh-diene catalyzed enantioselective conjugate addition of
arylboronic acid to β-arylethenesulfonyl fluorides8 was
reported by the Qin group. Recently, our group developed
enantioselective conjugate additions of 3-amido-2-oxindoles to
ESF9 catalyzed by quinine-derived squaramides. In addition,
the enantioselective conjugate addition of N-2,2,2-trifluoroe-
thylisatin ketimines to ESF was also achieved.10
Received: April 7, 2021
Published: May 24, 2021
Given the unique value of azlactones11 and sulfonyl fluoride,
we are interested in an asymmetric reaction of azlactones and
ESF. The transformation can offer an appealing way to access
α-quaternary amino acid derivatives with sulfonyl fluoride
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4228−4232
4228