Communication
doi.org/10.1002/chem.202005081
Chemistry—A European Journal
Scheme 3. Substrate scope of the asymmetric diorganozinc additions to pyr-
azole-4,5-dione 1. Reaction conditions: 0.2 mmol of 1, 1.5 equiv of 2,
20 mol% of L7, EA, 08C, 12–24 h.
Scheme 4. Substrate scope of the asymmetric dimethylzinc additions to N-
substituted isatin 4. Reaction conditions: 0.2 mmol of 4, 2.0 equiv of 2,
20 mol% of ent-L7, DCM, À408C, 20–36 h.
ucts 3o–3q in high yields (89–95%) and enantioselectivities
(80–88%). Furthermore, alkyl analogues at C1-position were
also tolerated in this reaction, although a relatively low ee
were obtained (3r-3u, 82–90%, 83–86% ee). Finally, we tested
the Et2Zn addition to prochiral ketone 1. To our delight, the
desired tertiary alcohols 3v–3x bearing ethyl group could be
obtained in moderated yield and enantioselectivity. Our re-
peated attempts to use other diorganozinc reagents were un-
successful, only very low enantioselectivity could be generated
(see details in Supporting Information). The chiral tertiary alco-
hols were assigned to the S-configuration, based on the X-ray
analysis of the single crystal of product 3a.
To further demonstrate the synthetic utility of this methodol-
ogy, we extended the substrate scope to the synthesis of 3-
substituted-3-hydroxy-2-oxindoles, which is present in various
natural products and biological compounds.[15] Arundaphine,
convolutamydine C, maremycin B and paratunamide D are rep-
resentative examples of a growing list of bioactive natural pro-
ducts.[15d] Especially, there are few methods for the catalytic
asymmetric synthesis of chiral 3-hydroxy-3-methyl-2-oxindoles
in previous report.[16] Shibashaki[16d] and Pedro’s group[16e] re-
ported the enantioselective addition of Me2Zn to isatins cata-
lyzed by proline-derived aminodiol and a-hydroxyamides
ligand, respectively, and only moderate ee values were ob-
tained. We performed the reaction between N-substituted isa-
tins 4 and Me2Zn in the presence of DCM at À408C. Most of
the isatin derivatives reacted smoothly with Me2Zn to afford
the corresponding 3-hydroxy-3-methyl-2-oxindoles 5 in excel-
lent yields with excellent enantioselectivities (Scheme 4). For
example, either electron-donating or withdrawing group of the
phenyl ring at N-aryl position were compatible under the opti-
nating groups, such as 1-naphthyl, benzyl, ethyl, et al were
also tolerated in this reaction, providing diverse 3-hydroxy-3-
methyl-2-oxindoles 5g–5l in excellent yield and high enantio-
selectivities. However, when the protecting group was elec-
tron-withdrawing group such as acetyl, the product 5m was
obtained in moderate yield, albeit with high ee. The absolute
configuration of 5 was determined by comparison to reported
literature.[16e]
Next, the effect of substitution on the benzene ring of N-
phenyl protected isatins 4 was evaluated (Table 2). In general,
electron-donating group at different position on the benzene
ring afforded the desired products in higher enantioselectivi-
ties in comparison with the electron-withdrawing group (en-
tries 1–6). Very importantly, we observed that other diorgano-
zinc reagents such as Et2Zn and nBu2Zn were also tolerated in
this reaction, although a slightly lower yields and enantioselec-
tivities were obtained (entries 7–10).
In order to understand the mechanism of this reaction, a
non-linear effect (NLE) study was conducted. The enantiopuri-
ties of the products were evaluated using various chiral amino
ligands L7 with 20%, 40%, 60% and 80% ee, respectively, and
a (+)-NLE was observed in this study (see detailed results in
Supporting Information). Based on the previous report[6f,17] and
the NLE studies, we proposed a plausible catalytic mechanism
of this reaction. As shown in Scheme 5, amino alcohoLL7 is de-
protonated to form a zinc aminoalkoxide species which could
further coordinates to pyrazole-4,5-diones 1. In addition, an-
other molecular of Me2Zn might coordinate with oxygen atom,
mized conditions to give the desired product 5a–5 f in 90– resulting in a si-face attack of Me2Zn through a six-membered
97% yields and 91–94% ee. Other N-substituted electron-do- transition-state. The outcome of the diorganozinc addition of
Chem. Eur. J. 2021, 27, 4302 –4306
4304
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