Angewandte
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employed under this optimal condition, the product (R)-3aa
99% ee (s = 525) by catalyst P8. The diaryl phosphine oxide
was obtained in 98% ee with recovery of the unreacted (S)-1a
in 99% ee (s = 525, entry 15). From this view, both of the two
enantioisomers of BINOL and its analogues can be easily
obtained just by switching the bifunctional catalysts between
phosphonium iodide P8 and phosphonium bromide P12,
which offers great potential for synthetic applications.
Encouraged by above exciting results, we proceeded to
establish the substrate scope for this novel enantiodivergent
kinetic resolution by A-T reaction. Firstly, the substrate
generality of the kinetic resolution of the 1,1’-biaryl-2,2’-diols
and amino alcohols by bifunctional chiral phosphonium
bromide (P12) catalyzed O-phosphorylation (Table 2). De-
lightfully, an array of phosphine oxides (2a–i) with electron-
donating or electron-withdrawing substituents at the ortho- or
para-position of the phenyl ring were founded to be suitable
reaction partners, giving the corresponding products (S)-3aa
in good to excellent selectivities (s = 22–340), together with
recovery of the unreacted (R)-1a in high yields and ee values
2F bearing methoxy groups at the para-positions of the phenyl
rings gave a relatively low selectivity of 23. For biphenyl diols,
the substituents at the 6,6’-positions showed slight influence
on the selectivity. Whereas 1d having 6,6’-phenyl groups that
contain methoxy groups at the 4-positions of the Ph-
substituents showed a relatively low selectivity of 15. Pleas-
ingly, the non-C2 symmetrical diol 1Q could be resolved
efficiently as well, for which only single ester product was
obtained, leading to the recovery of unreacted substrate in
96% ee. The absolute stereochemistry of the product 3aa
obtained in Table 3 was assigned to be R by X-ray crystallo-
[17]
graphic analysis.
Synthetic applications. As the obtained atropisomeric
biaryls are very useful intermediates to synthesize valuable
molecules, the appealing synthetic scalability and practicality
of this chemistry were demonstrated (Figure 2). Scaled-up
resolutions of the biaryl diols 1a and 1q by catalyst P8 and
P12 were performed, leading to the corresponding com-
pounds with very high selectivities of 458 and 174, respec-
tively. Additionally, the derivatizations of the chiral products
were also investigated to prove the applicability of these
reactions; and exemplarily the O-phosphorylated product
(R)-3aa was readily transformed into different classes of
(
up to 99% ee). Alternatively, the phosphine oxides bearing
benzothiophenyl or naphthyl groups were also proven to be
tolerated for this KR system, providing the corresponding
products (3aj and 3ak) with outstanding selectivities. It is
worth mentioning that unsymmetrical phosphine oxide 2l was
also good partner for this KR reaction and afforded the
desired products (3l and 3l’) in 1:1 dr with high ee values and
the (R)-1a was recovered in 48% yield with 94% ee.
Subsequently, the scope of BINOL compounds was studied
[
18]
important axially chiral ligands/catalysts via simple-steps of
organic operation (Figure 2b).
Mechanistic investigations. In order to gain a better
understanding of this enantiodivergent kinetic resolution
system involving Atherton–Todd reaction, we next investi-
gated the mechanistic differences in the reactions for giving
R-selective and S-selective products, both from (L, D)-
dipeptide derived phosphonium salt catalysts. Importantly,
when the substrate of diphenylphosphine oxide 2a was
subjected to the standard reaction conditions at room
temperature but without catalyst, both of the active P-species,
including diphenylphosphinic chloride A and diphenylphos-
phinic anhydride B, were simultaneously observed in the
(
Table 2b). A range of BINOL analogues (1b–h) with bromo
or different aryl groups at the 6,6’-position, regardless of the
electronic properties of the substituents on the aromatic or
hetereoaromatic rings, were found good substrates under the
above optimized KR conditions, affording the corresponding
products in moderate to good selectivities (s = 19–46) with
recovery of the unreacted (R)-1 in excellent ee (90–99%).
Moreover, when the BINOL derivatives bearing alkly-, aryl-
or heterocyclic groups at 7,7’-positions (1i–p) were employed,
the KR reaction proceed well, leading to the A-T products
3
1
reaction system through the analysis of its real-time P NMR,
but having very low conversions (Figure 3a). When the
catalyst P8 was involved, both of the P-species (A and B)
were generated with much rapid rates; and further the
diphenylphosphinic chloride A was gradually converted into
diphenylphosphinic anhydride B in the same system (Fig-
ure 3b). In contrast, when the catalyst P12 was employed,
only the intermediate B was detected in the reaction mixture,
which indicated that the phosphonium salts differentiated the
conversion rates of in-situ-generated diphenylphosphinic
anhydride B from diphenylphosphinic chloride A (Figure 3c).
Additionally, the transformation of diphenylphosphinic chlo-
ride A into diphenylphosphinic anhydride B had different
reaction rates in the presence of different phosphonium salts
(Figure 3d). These results solidly suggested that the catalysts
truly influenced on the existence of the major P-specie under
the A-T system, thus leading to the different phosphoryla-
tions.
(4ai–p) and the recovered substrates in high s factors (up to
1
057). This KR process could also be applicable to biphenol
1
q (s = 351) and biphenanthrol 1r (s = 16). The widely used
VANOL molecule (1s) was recovered via this KR mode with
S-configuration in 95% ee; and further the NOBIN (1t) was
also subjected to the kinetic resolution system, albeit with
moderate enantioselectivity. Unfortunately, when the spiro-
cyclic diol 1u was used, low selectivity (s = 2) was observed
under the current catalytic system, probably due to the
extremely rigid structure. The absolute stereochemistry of the
product 3aa obtained in Table 2 was determined by X-ray
[
17]
crystallographic analysis.
Subsequently, we further evaluated the scope of the KR
process via the A-T reaction by phosphonium salt P8
(
Table 3). Generally, various biaryl diols 1 and phosphine
oxides 2 with different substitution patterns were effectively
resolved with similarly high selectivity; all substrates tested
were recovered in good to excellent ee (up to 99% ee) with
Subsequently, the control experiments were performed
for getting further mechanistic insights. Under the P8-
catalyzed KR reaction system, 2a was replaced by diphenyl-
phosphinic chloride A and diphenylphosphinic anhydride B,
4
4–61% isolated yield. Representatively, the typical reaction
system could afford the A-T product (R)-3aa in 46% yield
with 98% ee and the recovered substrate 1a in 51% yield with
Angew. Chem. Int. Ed. 2021, 60, 2 – 12
ꢀ 2021 Wiley-VCH GmbH
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