Journal of the American Chemical Society
Article
a series of novel chiral ligands, (R,R)-5,8-Si-QuinoxP* [Si =
TMS, TES, or TIPS], which bear various sterically demanding
silyl groups (Figures S1−S5). A single-crystal X-ray diffraction
analysis revealed that (R,R)-5,8-TMS-QuinoxP* is entirely
twisted with interlocking structures between the phosphine
and silyl moieties on the ligand backbone (Figure 2B). To
investigate the coordination behavior of this ligand toward
transition metals, we then prepared a palladium(II) dichloride
complex (Figure 2C). The solid-state structure of this
palladium(II) complex also indicated the presence of a twisted
molecular plane and interlocking structures between the silyl
groups on the ligand and the phosphine substituents.
We then applied these modified ligands to the copper(I)-
catalyzed direct enantioconvergent allylic borylation of racemic
six-membered cyclic allyl electrophiles (1) in order to
determine their effect on the catalytic performance (Table
1).24,39−42 We have previously reported that the copper(I)-
TMS, TES, or TIPS], in the direct enantioconvergent
borylation of rac-1a (entries 2−5). In the presence of (R,R)-
5,8-TMS-QuinoxP*, the reactivity and enantioselectivity were
improved, even when [Cu(MeCN)4]BF4 was used (entry 2:
92%, 93% ee). When (R,R)-5,8-TMS-QuinoxP* was tested
under the conditions used for Cu(O-t-Bu), the enantioselec-
tivity was higher than that using silyl-free (R,R)-QuinoxP*
(entry 3: 77%, 94% ee).24 The reaction using (R,R)-5,8-TES-
QuinoxP* exhibited lower enantioselectivity, although the
reactivity was still high (entry 4: 94%, 85% ee). Conversely, the
reaction using (R,R)-5,8-TIPS-QuinoxP* showed high reac-
tivity and enantioselectivity (entry 5: 95%, 93% ee). We also
examined several chiral bisphosphine ligands, i.e., (R)-
SEGPHOS and (R,R)-Me-Duphos (entries 6 and 7). Both
chiral bisphosphine ligands resulted in low enantioselectivity
(entry 6: 57%, 25% ee; entry 7:89%, 45% ee). Therefore, it is
feasible to conclude that the presence of the silyl groups on the
backbone of QuinoxP*-type ligands enhances the reactivity
and enantioselectivity of the direct enantioconvergent
borylation of the six-membered-ring substrate.
Table 1. Ligand Screening for the Direct Enantioconvergent
a
Borylation of Racemic 1a
Subsequently, we investigated the substrate scope of this
direct enantioconvergent borylation with respect to racemic
five-, six-, and seven-membered-ring substrates rac-1, including
heterocycles, using (R,R)-5,8-TMS-QuinoxP* (Table 2). The
effect of the silyl groups was also examined for each substrate
rac-1. Allylboronate (S)-3a was obtained in high yield and
enantioselectivity when (R,R)-5,8-TMS-QuinoxP* was used
[(R,R)-5,8-TMS-QuinoxP*: 92%, 93% ee, (R,R)-QuinoxP*:
12%, 79% ee]. Furthermore, the reaction using (R,R)-5,8-
TMS-QuinoxP* was applicable to heterocyclic substrates rac-
1b−e. Products including a piperidine structure with various
protecting groups were also furnished in higher yield and
excellent enantioselectivity compared to those using (R,R)-
QuinoxP* [(R)-3b, (R,R)-5,8-TMS-QuinoxP*: 85%, 95% ee;
(R,R)-QuinoxP*: 50%, 76% ee; (R)-3c, (R,R)-5,8-TMS-
QuinoxP*: 84%, 90% ee; (R,R)-QuinoxP*: 67%, 83% ee;
(R)-3d, (R,R)-5,8-TMS-QuinoxP*: 84%, 90% ee, (R,R)-
QuinoxP*: 38%, 82% ee]. Moreover, the reaction of the
dihydropyran-type substrate rac-1e afforded (R)-3e with high
reactivity and excellent enantioselectivity, although (R)-3e was
slightly unstable toward purification on silica gel [(R,R)-5,8-
TMS-QuinoxP*: 92%, 96% ee; (R,R)-QuinoxP*: 84%, 80%
ee]. The reactivities of the products were slightly lower for
dimethyl-moiety-bearing substrate rac-1f, whereas the use of
(R,R)-QuinoxP* afforded only trace amounts of (S)-3f [(R,R)-
5,8-TMS-QuinoxP*: 73%, 84% ee; (R,R)-QuinoxP*: <5%].
Furthermore, we tested N,O-acetal and acetal-type electro-
philes rac-1g and rac-1h as substrates. The reaction of N,O-
acetal rac-1g was carried out at low temperature (0 °C) due to
the relatively high reactivity of the substrate. Even then, the
enantioselectivity of enamine-bearing product (S)-3g was
moderate (90%, 79% ee). However, the reactivity and
enantioselectivity obtained for acetal-type substrate rac-1h
were low (40%, 56% ee). (R,R)-QuinoxP* was not applicable
for either rac-1g or rac-1h [(S)-3g: 10%; (S)-3h,: <5%]. These
results clearly demonstrate the advantageous reactivity and
enantioselectivity of 5,8-TMS-QuinoxP* relative to QuinoxP*.
Next, we examined the direct enantioconvergent borylation
of five-membered-ring substrates using (R,R)-5,8-TMS-Qui-
noxP* and (R,R)-QuinoxP*. The reactions of the cyclo-
pentenol derivative rac-1i using (R,R)-5,8-TMS-QuinoxP* or
(R,R)-QuinoxP* resulted in similar yield and enantioselectivity
of (S)-3i [(R,R)-5,8-TMS-QuinoxP*: 80%, 92% ee; (R,R)-
b
b
c
entry
ligand
conv (%)
yield (%)
ee (%)
1
2
3
(R,R)-QuinoxP*
39
94
>95
>95
>95
92
12
92
77
94
95
57
89
79
93
94
85
93
25
45
(R,R)-5,8-TMS-QuinoxP*
(R,R)-5,8-TMS-QuinoxP*
(R,R)-5,8-TES-QuinoxP*
(R,R)-5,8-TIPS-QuinoxP*
(R)-SEGPHOS
d
4
5
6
7
(R,R)-Me-Duphos
94
a
Conditions: [Cu(MeCN)4]BF4 (0.025 mmol), ligand (0.025 mmol),
rac-1a (0.5 mmol), 2 (1.0 mmol), and K(O-t-Bu) (0.25 mmol) in
b
THF (0.5 mL). Yield and conversion values were determined by
quantitative 1H NMR analysis of the crude material using an internal
c
standard. Enantioselectivity values were determined by HPLC
analysis after derivatization by allylboration of benzaldehyde with
(S)-3a. Conditions: Cu(O-t-Bu) (0.05 mmol), ligand (0.05 mmol),
rac-1a (0.5 mmol), and 2 (0.75 mmol) in Et2O (0.5 mL) at 30 °C.
d
catalyzed direct enantioconvergent borylation using (R,R)-
QuinoxP* can provide chiral allylboronates from racemic allyl
electrophiles without an in situ symmetrization. Regardless of
the chirality of the substrate, a single enantiomer was obtained
via the anti-SN2′ pathway and the syn-SN2′ pathway from both
enantiomers. The direct enantioconvergent borylation of five-
membered cyclic racemic allyl electrophiles under the reported
reaction conditions with Cu(O-t-Bu) furnished the corre-
sponding allylboronates in high yield (up to 98% yield with
97% ee). Conversely, the reaction of the six-membered cyclic
allyl electrophile rac-1a showed lower enantioselectivity
compared to that of five-membered allylic electrophiles (91%
ee).24 Moreover, there was only one example of the reaction of
six-membered cyclic substrate rac-1a. In any case, the use of
Cu(O-t-Bu), which is neither commercially available nor easy
to handle, diminishes the utility of this reaction. However, the
use of the commercially available copper(I) precursor
[Cu(MeCN)4]BF4 resulted in low reactivity and enantiose-
lectivity (entry 1: 12%, 79% ee). Therefore, we examined a
series of silyl-modified ligands, (R,R)-5,8-Si-QuinoxP* [Si =
6415
J. Am. Chem. Soc. 2021, 143, 6413−6422