Mechanism-based enhancement of scope and enantioselectivity for reactions involving a copper-substituted stereogenic carbon centre

Article abstract of DOI:10.1038/NCHEM.2861

A rapidly emerging set of catalytic reactions involves intermediates that contain a copper-substituted stereogenic carbon centre. Here, we demonstrate that an intimate understanding of this distinction provides ways for addressing limitations in reaction scope and explaining why unexpected variations in enantioselectivity often occur. By using catalytic enantioselective Cu-boryl addition to alkenes as the model process, we elucidate several key mechanistic principles. We show that higher electrophile concentration can lead to elevated enantioselectivity. This is because diastereoselective Cu-H elimination may be avoided and/or achiral Cu-boryl intermediates can be converted to allyl-B(pin) rather than add to an alkene. We illustrate that lower alkene amounts and/or higher chiral ligand concentration can minimize the deleterious influence of achiral Cu-alkyl species, resulting in improved enantiomeric ratios. Moreover, and surprisingly, we find that enantioselectivities are higher with the less reactive allylphenyl carbonates as chemoselective copper-hydride elimination is faster with an achiral Cu-alkyl species.

Full text of DOI:10.1038/NCHEM.2861

ARTICLES
PUBLISHED ONLINE: 2 OCTOBER 2017 | DOI: 10.1038/NCHEM.2861
Mechanism-based enhancement of scope and
enantioselectivity for reactions involving a
copper-substituted stereogenic carbon centre
Jaehee Lee†, Suttipol Radomkit†, Sebastian Torker, Juan del Pozo and Amir H. Hoveyda
*
A rapidly emerging set of catalytic reactions involves intermediates that contain a copper-substituted stereogenic carbon
centre. Here, we demonstrate that an intimate understanding of this distinction provides ways for addressing limitations in
reaction scope and explaining why unexpected variations in enantioselectivity often occur. By using catalytic
enantioselective Cu–boryl addition to alkenes as the model process, we elucidate several key mechanistic principles.
We show that higher electrophile concentration can lead to elevated enantioselectivity. This is because diastereoselective
Cu–H elimination may be avoided and/or achiral Cu–boryl intermediates can be converted to allyl–B(pin) rather than add
to an alkene. We illustrate that lower alkene amounts and/or higher chiral ligand concentration can minimize the
deleterious influence of achiral Cu–alkyl species, resulting in improved enantiomeric ratios. Moreover, and surprisingly, we
find that enantioselectivities are higher with the less reactive allylphenyl carbonates as chemoselective copper–hydride
elimination is faster with an achiral Cu-alkyl species.
n early case of a transformation that proceeds via a com- then, is exactly how does the enantiomeric purity of a Cu-alkyl
pound that bears a Cu-substituted stereogenic centre intermediate erode, and is the dearth of examples with strongly
A
entails addition of a Cu–B(pin) (pin, pinacolato) complex electron-rich and electron-deficient alkenes tied to these issues?
to an (E)-β-alkylstyrene (Fig. 1). The resulting Cu-alkyl species
(i) then reacts with MeOH or MeOD in situ to give products in Results
>98% e.e. (>98:2 e.r.) and d.r., respectively1. In such processes, the We chose an enantioselective allyl–boron addition that would be
final e.e. depends on how stereoselectively an organometallic promoted by a single Cu-based complex (that is, no Pd-based co-
species is formed and by what mechanism the electrophile is catalyst) as the platform for this investigation. The lure of avoiding
trapped. Another example involves a chiral Cu complex along a precious metal notwithstanding, comparison of the one- versus
with an achiral bis-phosphine–Pd co-catalyst and an allyl carbonate two-catalyst approach would be more informative (for example,
(via ii, Fig. 1)2. Generally, additions to aliphatic olefins are less effi- does a co-catalyst help minimize enantioselectivity fluctuation?); the
cient, but aryl and heteroaryl olefins or alkenyl boronates3 and study would offer additional relevant data vis-à-vis Cu–H-catalysed
silanes4 are suitable and Cu–C and/or C–B(pin) bonds can be func- reactions16, which are also facilitated by a single catalyst.
tionalized further. Reactions that begin with enantioselective Cu–H
addition (via iii)5 are a notable subset.
Efficient one-catalyst process. We used the transformation shown in
Despite numerous reports and advances, key shortcomings entry 1, column A, Table 1, to identify an appropriate chiral catalyst.
persist. In the disclosure corresponding to the two-catalyst NHC ligands and most phosphines were ineffective (for example,
protocol2 there is no mention of allyl–boron additions to electron- <10% yield with L1 or L2, Fig. 1; see Supplementary Section 4 for
rich aryl alkenes or those involving more hindered (for example, details). The exceptions were L3a and L3b17, the use of which led to
2-substituted) electrophiles. Furthermore, enantioselective Cu–B the formation of 2a in 90% and 88% e.e., respectively. Although, in
(pin) or Cu–H additions with electron-deficient aryl olefins are this particular instance, the e.e. was slightly lower compared to
either not mentioned6–10 or are found to be less enantioselective11–14 when the Cu/Pd regime2 was adopted (90% compared to 95% e.e.),
(for example, halo-, trifluoromethyl- or ester-substituted). It is this is a useful selectivity level, ligand loading was less (total of
unclear why enantioselectivity is lower with some substrates or at 5.5 mol% as opposed to 17 mol%) and room temperature sufficed
times depends on electrophile identity, despite the fact that the (rather than 0 °C). Still, our main goal was to expand the scope of
Cu–B(pin)/Cu–H addition step is stereochemistry-determining the method through a stronger appreciation of the mechanistic details.
(for example, 94% e.e. compared to 76% e.e., Fig. 1).
Electronic effects are central in these matters. Addition of a Cu–B Electronic properties of alkenes and e.e. Organoboron products
(pin) or Cu–H complex to an electron-deficient alkene is faster1,15
,
were in most instances obtained in ≥55% yield and ≥90% e.e.
but the resulting Cu-alkyl compound is probably less nucleophilic. (Table 1; for additional examples see Supplementary Section 6).
Conversely, an electron-rich olefin probably generates a more reactive As expected, there were several shortcomings. (1) Reactions with
Cu-alkyl species slowly. It has been surmised11 that some kinetic electron-deficient olefins were much less enantioselective. ortho-
enantioselectivity might be lost if an organocopper intermediate Trifluoromethyl 2d (entry 4, column A) and meta-carboxylic
were to react slowly, whereas rapid trapping, for example with higher ester styrene 2g (entry 7, column A) were formed in 66% and
electrophile concentration, could improve e.e. The central question, 64% e.e., respectively and para-ester- and trifluoromethyl-substituted
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA. †These authors contributed equally to this
work. e-mail: amir.hoveyda@bc.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2861
ARTICLES
2009 (ref. 1)
B(pin)
Me
B(pin)
MeOD or MeOH
(pin)B–Cu(I)Ln
NHC ligand
>98:2 d.r. (with MeOD),
Ph
Ph
Ph
Me
Me
98% e.e. (99:1 e.r., with MeOH)
Cu(I)Ln
D(H)
i
2015 (ref. 2)
5.0 mol% Pd(dppf)Cl2
Limitations in scope:
only one case for an alkene with an EWG
(gave notably lower e.e.);
(pin)B–Cu(I)Ln
R
R
R
B(pin)
B(pin)
Cu(I)Ln
t-Bu
Allyl electrophile
12 mol%
MeO
G
no alkenes with an EDG;
no 2-substituted allyl electrophiles
S
ii
O
90–97% e.e.
P(i-Pr)2
(95:5–98.5:1.5 e.r.)
with electron-neutral alkenes
Oi-Pr
L1
2015 (ref. 5)
(dan)B
n-Hex
n-Hex
94% e.e. (97:3 e.r.)
N
N
H
Why does e.e. vary
as a function of
electrophile?
H–Cu(I)Ln
G2N–OBz
(dan)B
(dan)B
n-Hex
n-Hex
(dan)B
Cu(I)Ln
O
iii
O
O
PAr2
PAr2
10 mol%
76% e.e. (88:12 e.r.)
Ar = 3,5-(t-Bu)2-4-MeOC6H2
L2
O
The case study
Main goals:
R
(pin)B–Cu(I)Ln
Allyl electrophile
No co-catalyst
broader scope and/or higher e.e. through
mechanistic insight for Cu–B(pin) &
Cu–H-catalysed reactions
R
R
B(pin)
G
B(pin)
Cu(I)Ln
Chiral bis-phosphine
ii
Figure 1 | Key problems and goals of this study. Despite significant advances, notable questions remain unanswered. Cu–B(pin) addition to aryl alkenes is
site- and syn-selective, and the Cu-alkyl species can react in situ with an allyl electrophile. However, reactions require high ligand loading and a precious
metal co-catalyst, and scope is limited. Transformations involving Cu–H additions have also been developed, where enantioselectivities can vary widely
depending on electrophile identity, despite organocopper formation being stereochemistry-determining. With the development of catalytic site- and
enantioselective boron–allyl additions as the model study, several key mechanistic issues will be examined that allow for the scope of the reactions to be
expanded considerably. NHC, N-heterocyclic carbene; Ln, ligands; e.r., enantiomeric ratio; pin, pinacolato; dppf, 1,1′-bis(diphenylphosphino)ferrocene; EWG,
electron-withdrawing group; EDG, electron-donating group; dan, 1,8-diaminonaphthalene; Bz, benzoyl; G, functional group.
2k and 2l (entries 11–12, column A) were generated in 2% and selectivity would be less diminished11. Indeed, whereas 2g was formed
16% e.e., respectively. The same was true with the Cu/Pd approach. in 64% e.e. with a 3:1 aryl olefin:1a mixture (entry 7, column A),
For the sole reported example with a clearly electron-deficient when the ratio was reversed, the selectivity improved to 90% e.e.
alkene, 2l was formed in 82% e.e.2 (compared to 95% e.e. for 2a; (entry 7, column B). 2-Naphthyl-substituted 2e (92% e.e. for entry 5,
for more on this see below). No rationale was provided for this column B compared to 78% e.e. for entry 5, column A), meta-B
significant selectivity gap. (2) para-Methoxy-substituted 2h (entry 8, (pin)-substituted 2f (93% e.e. for entry 6, column B compared to
column A; not reported previously2) was obtained in 94% e.e. and 66% e.e. for entry 6, column A) and para-B(pin)-substituted 2j (84%
28% yield. The lower efficiency is probably because reaction of a e.e. for entry 10, column B compared to 64% e.e. for entry 10,
Cu–B(pin) complex to a more electron-rich substrate is slower column A) were also generated with notably higher enantioselectivity.
and its addition to an allylic phosphate (to give allyl–B(pin))18,19 Therefore, the differences in kinetic selectivity in the initial Cu–B(pin)
becomes the major side reaction (see Fig. 5a for optimal conditions). addition step are not the reason for the e.e. variations.
The data for 2d, 2g and 2k were not included in the disclosure on
Nonetheless, we soon discovered that matters are more complex.
On several occasions, increasing the allylphosphate concentration did
not improve e.e. For example, although the yield for 2k was much
the Cu/Pd approach2 (the same for 2f, 2j and 2n–p, Table 1).
Alkene:electrophile ratio and e.e. Enantioselectivity variations higher (72% for entry 11, column B compared to 14% for entry 11,
might arise from a difference in kinetic selectivity in the Cu–B column A), there was little impact on enantioselectivity of its formation
(pin) addition step, or it might be that a slower forming but more or that of para-trifluoromethyl-substituted 2l (entry 12, column A and
nucleophilic Cu-alkyl intermediate (2h, entry 8, column A, B; see ‘Epimerization’ section for rationale). With para-methoxy-
Table 1) reacts faster so that the initial (and high) substituted 2h (entry 8) the Cu-alkyl species is exceedingly nucleophilic
enantioselectivity is better preserved. The less nucleophilic Cu- and reversing the alkene:electrophile ratio does not improve the e.e.
alkyl species derived from electron-deficient alkenes would react
less readily and there could be more extensive e.e. loss before C–C Electrophile size and e.e. With a 2-substituted allylphosphate,
bond formation. In this latter scenario, higher allylphosphate Cu-alkyl trapping should be slower and enantioselectivity would be
concentration should lead to faster alkylation and the kinetic expected to suffer. Indeed, transformations leading to 2n (entry
2
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ARTICLES
Table 1 | Scope of the catalytic process, and the effect of substrate ratio and electrophile identity.
B2(pin)2
Ar
(1.1 equiv.)
5.5 mol%
L3a Ar', Ar = Ph
PAr2
PAr'2
or
S
Ar
L3b Ar = 3,5-(Me)2C6H3, Ar' = Ph
B(pin)
1a R, H; LG, OPO(OEt)2
1b R, Ph; LG, OPO(OEt)2
1c R, Me; LG, OPO(OEt)2
1d R, SiMe3; LG, OPO(OEt)2
1e R, H; LG, OCO2Ph
LG
5.0 mol% CuCl,
R
R
1.5 equiv. NaOt-Bu, THF, 22 °C, 14 h
2
with 1a, 1b, 1c, or 1d
with 1e
A: 3:1,
Alkene: Electrophile
B: 1:3,
Alkene: Electrophile
C: 3:1 (i) or 1:3 (ii),
Alkene: Electrophile
Entry
Ar; Electrophile
Product
Conv. (%)*;
Yield (%)†
e.e.§
Conv. (%)*;
Yield (%)†
e.e.§
Conv. (%)*;
Yield (%)†
e.e.§
90
90
78
66
78
66
64
94
84
64
2
1
Ph; 1a
2a
2b
2c
2d
2e
2f
>98; 67
>98; 59
98; 54
2
o-MeOC6H4; 1a
o-FC6H4; 1a
3
79; 64 (i)
68; 50 (ii)
92
92
4
o-F3CC6H4; 1a
2-naphthyl; 1a
m-(pin)BC6H4; 1a
m-tert-BuO2CC6H4; 1a
p-MeOC6H4; 1a
p-FC6H4; 1a
>98; 46
>98; 65
>98; 44
>98; 69
>98; 28
>98; 66
>98; 48
22; 14
5
80; 50
71; 52
83; 62
92
93
90
6
7
2g
2h
2i
8
9
98; 65 (i)
96
92
66; 56
84
4
10
11
12
13
14
15
16
p-(pin)BC6H4; 1a
p-tert-BuO2CC6H4; 1a
p-F3CC6H4; 1a
3-Boc-indolyl; 1a
Ph; 1b
2j
>98; 72
>98; 79
2k
2l
16
96
80
80
90
34
>98; 68 (ii)
>98; 70
>98; 58
>98; 60
45; 29
2m
2n
2o
2p
>98; 51
>98; 84
>98; 84
92
90
92
Ph; 1c
Ph; 1d
>98; 63
Reactions were carried out under a N2 atmosphere with L3a as the chiral ligand, except for L3b in the case of 2l when 1a serves as the electrophile and also with 2n and 2o). *Conv. determined by analysis of the
1H NMR spectra of the unpurified mixtures ( 2%). †Yields are of isolated and purified product ( 5%); differences between conv. and yield are due to allyl–B(pin) formation (excess alkene) or of proto-boryl
addition products (excess allyl electrophile). §e.e. determined by high-performance liquid chromatography analysis ( 1%). Experiments were performed at least in triplicate. See Supplementary Section 5 for
experimental and analytical details. pin, pinacolato; Boc, tert-butoxycarbonyl.
14, column A and B) and 2o (entry 15, column A and B), which generally led to higher e.e. (compared to 1a; enties 3, 4, 9 and 12,
contain 2-substituted alkenes, were more enantioselective when column C, Table 1). To counter the lower reactivity of 1e, larger
additional amounts of electrophile was present (92% e.e. amounts of this electrophile were used with the more electron-
compared to 80% e.e. and 90% e.e. compared to 80% e.e.). With withdrawing aryl olefins 2d and 2l (less nucleophilic copper–alkyl
alkenylsilane 2p (entry 16, column A and B), the same alteration intermediates). Thus, 2c, 2d, 2i and 2l were obtained in 92–96% e.e.
was less consequential (see Supplementary Section 5 for analysis).
(entries 3, 4, 9 and 12, column C, compared to 16–84% e.e. for entries
3, 4, 9 and 12, column A). With electron-neutral or electron-rich
Advantage of the one-catalyst method. Under the Cu/Pd conditions, olefins, the use of allylphosphate was often preferred due to better yields
where higher electrophile concentration means increasing the amount asopposedtohighere.e.(seeSupplementarySections5and11fordetails).
of allyl carbonate as well as the co-catalyst, e.e. could not be improved
by adjusting the electrophile and co-catalyst concentration (see Mechanism. Labelling, spectroscopic and computational experiments
Supplementary Section 13 for details). This might be because the were carried out to elucidate the basis of the reactivity and
presence of achiral bis-phosphine Pd species causes an achiral enantioselectivity trends. These studies revealed that while
Cu–B(pin) complex to be generated by ligand exchange20, and the epimerization at the Cu-substituted stereogenic centre has limited
resulting non-enantioselective pathways offset any advantage that relevance, alkene concentration and Cu–H elimination have
might result from a change in conditions.
considerably broader influence.
Higher e.e. with a less reactive electrophile. Faster Cu-alkyl trapping Epimerization. Reactions with (E)- and (Z)-β-deuterio-para-tert-
is not the only way to obtain high enantioselectivity. Regardless of butyl ester substituted styrene afforded 2k-d in low d.r. (Fig. 2a),
the alkene:electrophile ratio, use of allylphenyl carbonate 1e, shown to indicating that epimerization is fast23. The same was observed with
be less reactive than allylphosphate (Supplementary Section 11)21,22
,
the Cu/Pd system2 (see Supplementary Section 13 for details). For
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ARTICLES
a
t-BuO2C
b
B(pin)
B(pin)
D
Ar
D
(3.0 equiv.)
t-BuO2C
D
Ar
D
(EtO)2OPO
(EtO)2OPO
anti-2g-d
2k-d
90% conv., 60:40 d.r.
1a
1a
>98% d.s.,
87:13 vs 86:14 e.r. for unlabelled alkene
(3.0 equiv.)
With L3b
With L3b
B2(pin)2
(data in
Fig. 2c
are with
L3a)
B2(pin)2
(1.1 equiv.)
(1.1 equiv.)
D
t-BuO2C
D
t-BuO2C
B(pin)
OM
M = CuLn, or Na
D
D
B(pin)
Ar
syn-2g-d
>98% d.s.,
87:13 vs 86:14 e.r. for unlabelled alkene
t-BuO
B(pin)
D
Ar
2k-d
(3.0 equiv.)
3
81% conv., 35:65 d.r.
c
P2
P2
R
O
R
O
t-BuO Cu Ot-Bu
P
P
P
Cu
Cu
Cu
Cu
P
P Cu Cu
Ar
B(pin)
O
R
O
α
P
t-BuO Cu Ot-Bu
Ot-Bu
P2
R
γ
P2
x
x
1 = R, Ot-Bu (formed less readily)
2 = R, OMe (formed more readily)
xi
Cu
P
ix
P
B2(pin)2
High SN2' &
e.e.
(pin)B–Ot-Bu
iv
B2(pin)2
(pin)B–Ot-Bu
Excess allyl electrophile
–
can reduce [xii]
OR
B(pin)
NaOt-Bu
NaOt-Bu
P2
P2
Less
reactive
(increases e.e.)
Ar
B(pin)
B(pin)
γ
–
OR
Cu
+
Cu
P
Cu
+
P
B(pin)
P
Ot-Bu
Na
α
xii
P
More reactive v
viii
Electron-deficient Ar:
competitive with
Ar
Ar
Ar
Electron-neutral
or electron-rich Ar:
faster than
formation of rac-xiii
(increases e.e.)
re-formation of v
(decreases e.e.)
B(pin)
B(pin)
B(pin)
–
+
Ar
Ar
Cu
Ar
Ar
B(pin)
rac-ix
Na
γ
Ar
γ
Ot-Bu
xiii
B(pin)
Cu
t-BuO
Na
Cu
Ar
or
B(pin)
Cu
α
α
O
P
P
γ
α
Ot-Bu
γ
B(pin)
rac-ix
Cu
Na
γ
α
O
P
P
OR
α
P
OEt
O
OR
P
OEt
O
xv
vi
OEt
OR
vii
Lower SN2':SN2
& racemic
xiv
OEt
d
I
31P NMR (–20 °C), CuOt-Bu + L3c
II 31P NMR (–20 °C)
III 31P NMR (22 °C)
PAr2
v
S
iv
vimajor diast.
PAr'2
JPP = 113 Hz
L3c
JPP = 163 Hz
iv
x1
L3c
Ar = Ph,
Ar’ = 3,5-(Me)2C6H3
JPP = 193 Hz
viminor diast.
L3c
J
PP = 161 Hz
B2(pin)2
L3c
p-CF3C6H4
–12 –14 –16 –18 –20 –22 –24 –26 –28
ppm
0
–12 –14 –16 –18 –20 –22 –24 –26 –28
ppm
–12 –14 –16 –18 –20 –22 –24 –26 –28 –30
ppm
Figure 2 | Labelling studies, the catalytic cycle and temporary loss of the chiral ligand. a, Labelling experiments shed critical light, and it appears that at
one point in the catalytic cycle the chiral ligand might dissociate from the Cu centre to cause a lowering of e.e. b, Labelling experiments reveal that e.e.
variations have different origins, depending on the nature of the aryl olefin involved. c, The most efficient catalytic cycle involves transition structure vii
leading to ix with high enantioselectivity. However, a competitive pathway consistent with the experimental data involves dislodging the bis-phosphine ligand
(iv → x → xi) and formation of an achiral complex (xii), resulting in lower SN2′ selectivity and formation of rac-ix (via xiv or xv). d, Spectroscopic analysis
(A–C, with L3c) reveals that there is a considerable amount of free chiral ligand except at the Cu–alkyl stage of the catalytic cycle and at certain points
competitive addition by an achiral Cu–B(pin) species can lead to lower SN2′ and enantioselectivity. Reducing the concentration of the alkene thus leads to
higher e.e. See Supplementary Section 14 for details. pin, pinacolato; P, diaryl-phosphine ligand; P2, bis-phosphine ligand; R, PO(OEt)2 or CO2Ph; bis-phos.,
unbound bis-phosphine.
supporting ‘radical clock’ experiments, see Supplementary Section 10. Section 9 for details). Again, similar results were obtained under
Changes in catalyst concentration did not impact e.e., showing that Cu/Pd conditions2. Thus, in most instances, diminution in e.r.
epimerization does not proceed via a bimetallic transition state24. does not arise from Cu–alkyl trapping with inversion of
The electron-deficient aryl unit probably stabilizes electron density at stereochemistry25 or Cu–C bond rupture26, as, otherwise, d.r.
the benzylic site, facilitating heterolytic cleavage/re-formation of the would be lower when labelled alkenes were used.
Cu–C bond through epimerization via metal-enolate 3 (Fig. 2a). A
What might be behind the loss of enantioselectivity? Why does
para-ester-substituted aryl olefin was the only case where increasing increasing electrophile concentration not lead to higher e.e. with
the electrophile concentration (Table 1, entry 11, column A and B) the more strongly electron-deficient olefins (for example, para-
or the use of allylphenyl carbonate did not enhance e.e. Loss of ester-substituted 2k (entry 11, column A and B, Table 1) in contrast
enantioselectivity is too facile in this particular case.
to para-trifluoromethylphenyl-substituted 2l (entry 12))? Could it
be that in some cases, e.e. improves (for example, 2g, entry 7,
Temporary ligand loss at the Cu–alkoxide stage. Reactions with Table 1) by reversal of the alkene:electrophile ratio because the
other mono-deuterated alkenes, such as those shown in Fig. 2b, alkene concentration is reduced and not simply as a result of
were completely diastereospecific (>98% d.s.; see Supplementary higher electrophile concentration?
4
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ARTICLES
a
F3C
Chiral Cu
OPO(OEt)2
Chiral Cu
complex
F3C
OPO(OEt)2
complex
+
+
B(pin)
B(pin)
B2(pin)2
B2(pin)2
2a
2l
styr.:allylphos.
100
100
95
90
85
80
75
70
65
60
55
50
92% e.e.
88% e.e.
1:3
3:1
0.11:1
0.33:1
1:0.33
95
90
85
80
75
70
65
60
55
50
76% e.e.
90% e.e.
1:1
Increase in [alkene]: large decrease in e.e.
Increase in [electrophile]: small increase in e.e.
styr.:allylphos.
0.11:1
styr.:allylphos.
1:0.11
78% e.e.
0.33:1
34% e.e.
1:3
3:1
styr.:allylphos.
1:1
1:0.33
1:0.11
Increase in [alkene]: small decrease in e.e.
Increase in [electrophile]: large increase in e.e.
16% e.e.
12% e.e.
Styrene : allylphosphate
p-F3C-styrene : allylphosphate
b
c
5.5–20 mol% L3b,
5.0 mol% CuCl
Ar
OPO(OEt)2
1a
B(pin)
5.5 mol% L3b: 72% e.e. (86:14 e.r.)
10 mol% L3b: 85% e.e. (90.5:9.5 e.r.)
20 mol% L3b: 90% e.e. (95:5 e.r.)
+
t-BuO2C
1.1 equiv. B2(pin)2,
1.5 equiv. NaOt-Bu, THF, 22 °C, 14 h
3:1 (non-optimal ratio)
2g
3:1 styrene:allylphosphate:
no ligand: 85% SN2'
with 5.5 mol% L3b: 91% SN2'
Ar
Ar
B(pin)
D
0–5.5 mol% ligand, 5.0 mol% CuCl
B(pin)
t-BuO2C
D
+
1.1 equiv. B2(pin)2,
D
1:3 styrene:allylphosphate:
with 5.5 mol% L3b: >98% SN2'
with 5.5 mol% PPh3: >98% SN2'
D
D
1.5 equiv. NaOt-Bu, THF, 22 °C, 14 h
D
OPO(OEt)2
1a-d2
2g-d2 (SN2')
2g-d2 (SN2)
Figure 3 | Effect of olefin concentration on e.e. and SN2′ selectivity. Lower alkene concentration and higher electrophile concentration can improve e.e.
a, Changing the concentration of aryl olefin and/or allylic phosphate can impact e.e. With electron-neutral olefins the concentration of the allylic electrophile
is mildly influential. However, with electron-deficient alkenes it is the olefin concentration that plays a major role. b, Higher chiral bis-phosphine loading leads
to a significant increase in e.e. See Supplementary Section 5 for experimental and analytical details. pin, pinacolato. c, Studies with D-labelled allylphosphate
show that a phosphine ligand is needed for high SN2′selectivity and that selectivity is reduced when there is excess aryl olefin, implying competitive reaction
by an achiral Cu–B(pin) species.
The most likely enantioselective route is shown in Fig. 2c— bis-phosphine–Cu–Ot-Bu iv is regenerated, ligand loss becomes
conversion of chiral Cu-alkoxide iv to Cu–alkyl vi would deliver problematic. Spectroscopic studies confirm that with excess chiral
ix via transition structure vii, which in turn affords Cu-alkyl viii ligand the equilibrium shifts towards the bis-phosphine–Cu
(more on this later), and reductive elimination would then generate complex (see Supplementary Section 14 for details). An achiral
the final product ix. Spectroscopic studies show that the chiral Cu–B(pin) species (xii) lacks the Lewis basic phosphine ligand, is
ligand dissociates from the metal centre at the Cu–Ot-Bu stage. less nucleophilic, and cannot readily react with an electron-rich
Subjection of Cu–Ot-Bu to 1.1 equiv. of L3c (spectrum I, Fig. 2d) alkene (xii → xiii). Density functional theory (DFT) calculations
generated an equal mixture of iv, the derived aggregates (for confirm that addition of an achiral Cu–B(pin) to an electron-poor
example, x1), 30 mol% of unbound ligand and thus in all likelihood olefin is more favourable and can be problematic (Fig. 4a; for full-
the well-characterized copper-alkoxide, xi27 (Fig. 5a). Addition of system calculations see Supplementary Section 18). Faster reaction
B2(pin)2 yielded L3c–Cu complex v, which is stable enough for between an achiral Cu–B(pin) complex and an electron-poor alkene
analysis at –20 °C (spectrum II). There was also ∼30% unbound suggests that olefin concentration must be kept low for higher e.e.,
bis-phosphine ligand, the same amount present at the Cu–Ot-Bu allowing ligand association to convert xii to v before Cu–B(pin)
stage; this indicates that there is no chiral ligand reassociation reacts with an alkene (Curtin–Hammett kinetics). This is unlike
upon Cu–B bond formation and that at this point achiral Cu– when an electron-neutral or electron-rich olefin is used, where alter-
(pin) complex is available (see Supplementary Section 14 for a spec- ing the alkene concentration is largely inconsequential and only
troscopic analysis). Addition of para-CF3-styrene at –20 °C afforded increasing the electrophile amount positively impacts e.e. The invol-
vi in 99:1 d.r. (∼75% conv.). When the mixture was allowed to warm vement of achiral Cu–B(pin) species (xii) explains why higher electro-
to 22 °C (spectrum III, Fig. 2d) there was complete conversion and phile concentration elevates e.e. Increasing the amount of allylic
stereoselectivity was reduced to 72:28 d.r. with ∼10% of unbound phosphate facilitates conversion of chiral as well as achiral Cu–B
L3c remaining, which is equal to the excess 0.1 equiv. used initially. (pin) complexes (v and xii) to allyl–B(pin) by-product (Fig. 2c)18,19
.
A Cu–alkoxide oxygen atom can form a bridge between tran- However, the net effect would be more diminution in the concen-
sition metals and facilitate aggregation28–30, ligand dissociation tration of achiral xii, which probably alkylates faster than bis-phos-
and generation of achiral Cu–B(pin) species. Accordingly, when phine-containing v because, as supported by DFT calculations, in
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2861
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a
PMe3
Cu
PMe3
Cu
−
OPO(OEt)2
H
tsCuB-add
21.6
(pin)B
(pin)B
H
X
X
H
20
10
H
Me3P
+
Cu
Me3P
+
Cu
tsCuHE
13.9
tsas
12.6
tsCuB-add
11.1
pc1
10.2
(pin)B
(pin)B
Ar
OPO(OEt)2
Ar
–
π−allyl
pc3
0.2
tsas
7.7
pc1
6.2
1.0
tsCuHE
5.6
PMe3
0
Cu−alkyl
−10.5
(pin)B
Cu
pc2
−8.3
π−allyl
−0.5
Cu−B(pin)
pc3
−7.9
0.0
H
X
OPO(OEt)2
H
–10
–20
PMe3
Cu
pc2
−9.8
Me3P
PMe3
Cu
Cu(PMe3)
H
X = NMe2
X = CO2Me
H
B(pin)
Cu
(pin)B
(pin)B
H
Ar
Cu−alkyl
−17.9
(pin)B
X
H
H
X
b
B(pin)
B(pin)
Ph
(EtO)2OPO
1b
D
D
With L3b
With L3b
Ar
D
Ph
anti-2n-d
Ph
syn-2n-d
6:1 alkene: allylphosphate:
D
B2(pin)2
(1.1 equiv.)
Ar
6:1 alkene: allylphosphate:
78% vs. 76% e.e. for un-labeled alkene
1:3 alkene: allylphosphate:
92% vs. 76% e.e. for un-labeled alkene
1:3 alkene: allylphosphate:
>98% ds
94% vs. 92% e.e. for un-labeled alkene
in all cases
88% vs. 92% e.e. for un-labeled alkene
With (Z)-β-deuterio-aryl olefins:
With (E)-β-deuterio-aryl olefins:
D
H
H
D
H
D
Ar
Ar
Ar
P
D
Ar
P
B(pin)
Ar
P
B(pin)
Ar
P
H
B(pin)
B(pin)
P
Cu–H elim.
Cu–D elim.
B(pin)
H
D
B(pin)
H
Cu
D
Cu
Cu
Cu
Cu
Cu
Slower
Faster
P
P
P
P
P
P
P
(higher e.e.)
(lower e.e.)
c
p-F3CC6H4
α
Ph
P
B(pin)
P
P
P
P
B(pin)
Cu
5
Cu
Cu
Ph
(2.1 equiv.)
Ph
p-F3CC6H4
P
B(pin)
+
B(pin)
+
4
B(pin)
β
(~80%)
thf-d8, 22 °C, 2 h
6
7
8
4
(~20%)
(~20%)
(<2%)
d
Enantioselective pathway
Corrective pathway
Ar
Faster
B(pin)
Ar
Ar
P
B(pin)
Ar
B(pin)
Would not reduce e.e.
B(pin)
Fast
–
+
Na
Cu
Cu
+
+
OCO2Ph
OCO2Ph
Less reactive
P
Ar
B(pin)
Less reactive
Ot-Bu
Slower
ix
vi
More nucleophilic
xiii
rac-ix
Would reduce e.e.
high e.r.
Less nucleophilic
Figure 4 | Different roles of Cu–H elimination. Cu–H elimination can have a negative or a positive impact on e.e. a, DFT calculations (PMe3 as model ligand
as monodentate complex alkylates) suggest that Cu–H elimination can be competitive with allylic substitution (Cu–alkyl → tsCuHE → pc2 versus Cu-alkyl →
pc3 → tsas → π-allyl). Cu–H elimination can thus impact e.e. when C–C bond formation is slower. These studies also show that Cu–B(pin) addition to an
electron-deficient alkene is favoured, leading to a decrease in e.e. due to temporary chiral ligand dissociation (Fig. 2). DFT calculations were performed at the
MN12SX/Def2TZVPP//ωB97XD/Def2SVP level in THF (SMD: solvation model based on density). b, Indeed, with a slower reacting 2-substituted allylic
phosphate (with lower electrophile concentration), reaction with (Z)-β-deuterioalkene is more enantioselective, indicating that inhibiting Cu–H elimination can
lead to higher e.e. In one D-labelled aryl olefin Cu–D elimination/re-addition is slower for (Z)-β-deuterioalkenes and less prone to loss of enantioselectivity.
c, A crossover experiment (with L3c) support the involvement of Cu–H elimination, also demonstrating that re-addition does not cause a diminution in e.e.
(that is, a β-Cu–C bond is formed). d, Because an achiral Cu–alkyl intermediate is less nucleophilic (xiii versus vi) but might undergo Cu–H elimination
readily, use of a less reactive electrophile can lead to higher e.r. See Supplementary Information for details (for Fig. 4a, Supplementary Section 18; for Fig. 4b,
c, Supplementary Sections 9 and 14). pin, pinacolato; pc, π complex; ts, transition state; B-add, boryl addition; CuHE, Cu–H elimination; as, allylic substitution.
6
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ARTICLES
O
a
B(pin)
Me
O
F3C
MeO
NMe
B
B(pin)
O
O
B(pin)
B(pin)
(pin)B
B(pin)
2h
2l
One-catalyst
(1:3 alkene:allylcarbonate):
2o
2f
One-catalyst
(1:3 alkene:allylphosphate):
52% yield, 93% e.e. (96.5:3.5 e.r.)
Two-catalyst (Cu/Pd):
2q
One-catalyst
(6:1 alkene:allylphosphate):
40% yield, 92% e.e. (96:4 e.r.) 68% yield, 92% e.e. (96:4 e.r.) 84% yield, 90% e.e. (95:5 e.r.)
One-catalyst
(1:6 alkene:allylic phosphate):
One-catalyst
(3:1 alkene:allylphosphate):
59% yield, 90% e.e. (95:5 e.r.)
Two-catalyst (Cu/Pd):
<2% conv.
Two-catalyst (Cu/Pd):
<5% conv.
Two-catalyst (Cu/Pd):
51% yield, –82% e.e. (91:9 e.r.) 19% yield, –78% e.e. (11:89 e.r.)
Two-catalyst (Cu/Pd):
24% yield, –96% e.e. (2:98 e.r.)
Me
OMe
O
O
O
Me
OMe
Me
OMe
Me
Me
OH
OH
MeO
MeO
MeO
B(pin)
9
Refs 37,38
4 steps
O
O
(3.0 equiv.)
O
B2(pin)2
(1.1 equiv.)
Me
OH
Me
OH
2r
Me
10
Me
OH
Me
Me
One-catalyst, gram scale:
64% yield, 94% e.e. (97:3 e.r.)
(91% recovered 9)
Two-catalyst (Cu/Pd):
62% yield, –82% e.e. (9:91 e.r.)
(–)-Heliespirone C (+)-Heliespirone A
OPO(OEt)2
42% overall yield,
89:11 d.r.
1a
(1.0 equiv.)
b
With 2.2 mol% L2:
1:0.3 alkene:O-benzoylhydroxylamine
O
98% yield, 80% e.e. (90:10 e.r.)
O
O
PAr2
PAr2
2.2–8.8 mol%
1:1.2 alkene:O-benzoylhydroxylamine
87% yield, 86% e.e. (93:7 e.r.; ref. 45)
L2
O
1:3 alkene:O-benzoylhydroxylamine
75% yield, 92% e.e. (96:4 e.r.)
––––––––––––––––––––––––
With 8.8 mol% L2:
Ar = 3,5-(t-Bu)2,4-MeOC6H2
2.0 mol% Cu(OAc)2, 2.0 equiv. (EtO)2MeSiH,
THF, 40 °C, 36 h
OBz
NBn2
NBn2
11
1:1.2 alkene:amine–oxide
85% yield, 86% e.e. (93:7 e.r.)
With 10 mol% L2:
1.2:1 alkene:O-benzoylhydroxylamine
57% yield, 76% e.e. (88:12 e.r.; ref. 5)
(dan)B
(dan)B
n-hex
n-hex
10–40 mol% L2
N
OBz
N
1:3 alkene:O-benzoylhydroxylamine
43% yield, 92% e.e. (96:4 e.r.)
––––––––––––––––––––––––
With 40 mol% L2:
1.2:1 alkene:O-benzoylhydroxylamine
54% yield, 94% e.e. (97:3 e.r.)
10 mol% Cu(OAc)2, 3.0 equiv. PMHS,
4.0 equiv. LiOt-Bu, THF, 22 °C, 4 h
12
Figure 5 | Broader scope and generality. The new mechanistic knowledge allows for a broader scope. a, Without a Pd-based co-catalyst and by adjusting
the alkene:electrophile ratio based on the structural attributes of the substrates, the scope of a catalytic process may be significantly broadened. This is
illustrated by the representative examples shown here. Experiments were performed at least in triplicate. b, The impact of the findings resulting from the
present study extend to transformations involving enantioselective Cu–H addition as the initial step. Thus, higher enantioselectivity, at times significant
(for example, 16 obtained in 92% versus 76% e.e.), can be achieved by modifying the reaction conditions. Moreover, it is now easier to understand why
higher catalyst loading makes little impact in reactions involving an electron-rich alkene by have a more substantial effect when an electron-deficient olefin
is involved. See Supplementary Sections 7 and 12 for the complete synthesis route and all experimental and analytical details. pin, pinacolato;
PMHS, polymethylhydrosiloxane.
the chiral complex one arm of the bidentate ligand must dissociate there is a further decrease in e.e.; above a certain point in olefin con-
before allylic substitution can occur (see vi → vii → viii, Fig. 2c). centration (that is, 1:1–3:1 alkene:allylphosphate, sequence shown in
Less Cu–alkyl intermediate xiii is thus formed and enantioselectivity red) the adventitious pathway becomes sufficiently competitive that
improves. The following observations offer more clarification.
there is no longer a major change in enantioselectivity (non-Curtin–
Systematic study of the effect of concentration (changing only Hammett regime). The following data support the proposed scen-
one substrate concentration at a time; Fig. 3a) indicated that ario. (1) With 20 mol% L3b (Fig. 3b), 2g was obtained in 90% e.e.
although increasing the amount of electrophile can lead to higher (compared to 72% e.e. at 5.5 mol% ligand and 3:1 alkene:allylpho-
e.e. with an electron-neutral styrene, variations in olefin concen- sphate). (2) With the smaller NaOMe (versus NaOt-Bu), expected
tration have a stronger influence on reactions with a more electron- to bridge Cu centres and cause ligand dissociation more efficiently
deficient olefin (90% to 88% e.e. for 2a compared to 76% to 16% (x2 versus x1, Fig. 2c), e.e. was lower (2g in 44% e.e. with NaOMe
e.e. for 2l; pathways shown in red). With excess alkene, addition of compared to 72% e.e. with NaOt-Bu and 5.5 mol% L3b).
achiral Cu–B(pin) to the more reactive electron-deficient π bond is
faster than its association with the chiral ligand (xii → v) and bis-phosphine–Cu complex would deliver high SN2′ selectivity
Fluctuations in SN2′ selectivity elucidate matters further. A
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2861
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due to the maximum overlap between the largest highest occupied compete better with diastereoselective Cu–H elimination and e.e.
molecular orbital (HOMO) and lowest unoccupied molecular improves. It would be difficult to anticipate to what extent and
orbital (LUMO) coefficients in transition structure vii (Fig. 2c, dxy how much faster one isomer might undergo Cu–H elimination.
orbital and at Cγ, respectively)31. The Cu–alkyl bond in square What is key is the feasibility of Cu–H elimination, which, as will
planar viii is thus formed syn to Cγ, favouring the SN2′ mode of be shown in the following, has a more general influence on
addition (ix). With an achiral alkyl–Cu complex (xiv–xv, Fig. 2c), product enantiopurity.
SN2′ selectivity is lower because sodium ion chelation with the alk-
oxide oxygen32 and phosphate moiety directs the reaction. These High e.e. due to Cu–H elimination. Although counterintuitive, use
scenarios are supported by DFT calculations (Supplementary of the less reactive allylphenyl carbonate Cu–H elimination gives
Section 18). In the reaction with meta-tert-butylester-substituted rise to higher e.e. One clue to the reason for this effect was the
styrene and 1a-d2 (non-optimal conditions, 3:1 alkene:electrophile) larger amounts of alkenyl–B(pin) formed in reactions with
without a ligand and with L3b present, the SN2′:SN2 ratios were allylphenyl carbonate (∼40% compared to <5% with
85:15 and 91:9, respectively (Fig. 3c). In contrast, with an optimal allylphosphate without a chiral bis-phosphine and ∼10% versus
alkene:electrophile ratio (1:3) and a chiral bis-phosphine present, ∼2% with allylphosphate under catalytic enantioselective
the SN2′:SN2 ratio was >98:2. As long as the alkene concentration conditions). Unlike when an allylic phosphate is involved (see
was kept low, regardless of the ligand identity (L3b or PPh3), the above), there is minimal trapping of the achiral Cu–B(pin) species
SN2 product could not be detected.
(xiii, Fig. 4d, namely insignificant formation of the allyl–B(pin)
The above findings show that, for higher e.e., particularly with by-product).
electron-deficient alkenes, it is more crucial to counter the deleter-
The racemic pathway may be circumvented by chemoselective
ious effect of achiral Cu–B(pin) complex formation by lowering the Cu–H elimination of an achiral Cu-alkyl intermediate (versus the
alkene concentration and/or increasing ligand loading. There was derived bis-phosphine complex). This is for two reasons: (1) a
less increase in e.e. at higher electrophile concentration for products bis-phosphine–Cu-alkyl species is less prone to undergo Cu–H
such as 2l because alkene concentration was still too high (unlike elimination than its unbound, achiral variant34; and (2) with the
electron-neutral alkenes, Table 1).
less reactive carbonate and under the more dilute catalytic con-
ditions, intramolecular Cu–H elimination in xiii (Fig. 4d) is prob-
Cu–H elimination. Cu–H elimination is well documented15,33–35 ably faster compared to intermolecular events, such as allylic
and has been used in reaction development36. Through substitution (to give rac-ix), or reassociation with the chiral ligand
computational studies (Fig. 4a) we find that, especially with an (xiii → rac-vi). Therefore, especially for 2d and 2l, the e.e. is high
electron-deficient alkene substrate (red versus blue pathway), only when carbonate 1e is used (Table 1, entries 4 and 12,
Cu–H elimination is able to compete with allylic substitution column C). The adverse effect of Cu–H elimination when Cu-
(Cu–alkyl → tsCuHE → pc2 versus Cu–alkyl → pc3 → tsas → π-allyl). alkyl trapping is slow is applicable here (Fig. 4c), but the ability of
In the following, we illustrate that such processes can adversely or the same process to block an achiral Cu-alkyl complex to generate
favourably impact enantioselectivity, depending on the alkene and/or racemic products appears to be the dominant factor.
the electrophile involved.
Broader scope. At this point, a rational platform for achieving
Cu–H elimination can reduce e.e. The data in Fig. 4b show that broader applicability is available. The cases in Fig. 5a are illustrative;
adventitious Cu–H elimination is one reason why except for 2l, none were previously reported under the two-catalyst
enantioselectivity is lower if Cu–alkyl trapping is slow (that is, conditions2. With relatively electron-rich substrates (for example,
when excess alkene is used). With the unlabelled alkene or E-β- 2h or 2r), where Cu–alkyl formation is more sluggish, higher
deuteriostyrene there was only a small change in e.e., especially alkene concentration led to high yield and e.e. The positive effect
considering experimental error, irrespective of the relative of a less reactive electrophile in reactions with a strongly electron-
amounts of styrene or its 2-phenyl-substituted variant, 1b. With deficient alkene is underscored by the improved yield and e.e.
excess Z-β-deuteriostyrene, on the other hand, syn-2n-d was for 2l. When electron-neutral styrene is used (for example, 2o),
generated in notably higher e.e. compared to when unlabelled larger amounts of allylic phosphate reduce the possibility of
styrene was used (92% versus 76%). Thus, while reaction for the Z diastereoselective Cu–H elimination and lower the concentration
isomer would either involve a slower Cu–D elimination (primary of achiral Cu–B(pin), resulting in higher e.e. Gram-scale synthesis
isotope effect) or Cu–H elimination via a sterically hindered of 2r proceeded in higher enantioselectivity (94% e.e. compared
intermediate (eclipsing Ar and B(pin)), β-hydride elimination can to 82% e.e. with the two-catalyst method). Diol 10, applicable to
proceed readily with the E isomer (Fig. 4b).
synthesis of heliespirones A and C37,38, was prepared from 2r in
Additional insight was gained by spectroscopic studies (Fig. 4c). four steps and 42% overall yield (89:11 d.r.; see Supplementary
Treatment of a sample of Cu-alkyl complex 4 (82:18 d.r.) with para- Section 7 for details). Unreacted 9 was recovered easily (91% yield).
trifluoromethyl alkenyl–B(pin) (5) afforded ∼20% alkenyl–B(pin) 6 Compounds 2r or 10 cannot be accessed by enantioselective
and isomeric species 7 (22 °C, 2 h; Supplementary Section 14). hydroboration39–43 or conjugate addition of an aryl or a prenyl
Hence, Cu–H elimination converts 4 to 6 and the metal–hydride group to an enoate44.
complex generated adds preferentially to the more electrophilic
alkene (5 versus styrene; <2% 8).
Relevance to Cu–H-catalysed processes. Reactions with electronic-
Because of the polarity reversal in the olefin in alkenyl–B(pin) 5 neutral dihydronaphthalene and electron-deficient alkenyl–B(dan)
(versus an aryl olefin or phenyl alkenyl–B(pin)) Cu–H re-addition were investigated to see if the abovementioned principles apply to
yields a homobenzylic Cu–C bond15. This indicates that, under Cu–H additions as well (Fig. 5b). With dihydronaphthalene8,
unoptimal conditions (excess alkene versus allyl electrophile), low- increasing the hydroxyamine concentration led to improvement in
ering of e.e. does not originate from Cu–H re-addition with the enantioselectivity (11 from 80% to 92% e.e.); similarly, in the
same regioselectivity but on the opposite enantiotopic face of the reaction with alkenyl–B(dan)5 there was a significant increase in
alkenyl–B(pin) (see Supplementary Section 18 for DFT studies). e.e. when larger electrophile amounts were present (from 76% to
Instead, diminished enantioselectivity might be attributed to the 92% e.e.). However, based on the above studies, with the more
major Cu-alkyl diastereomer undergoing faster Cu–H elimination. electron-deficient alkenyl–B(dan), e.e. variations are probably
At higher electrophile concentration, Cu-alkyl trapping can caused by a lesser contribution by adventitious addition of an
8
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2861
ARTICLES
11. Gribble, M. W., Pirnot, M. T., Bandar, J. S., Liu, R. Y. & Buchwald, S. L.
achiral Cu–H complex. This is supported by the distinct way by
which increased ligand loading impacts these reactions: with
dihydronaphthalene there was no change in e.e. when 2.0 or 8.0
mol% L2 was used, but 12 was generated in 94% e.e. compared to
76% e.e. with fourfold lower ligand loading. Only in the latter
instance is competitive addition by an achiral Cu–B(pin) complex an
issue and a shift in equilibrium away from the achiral Cu–H
complex becomes consequential.
Asymmetric copper hydride-catalyzed Markovnikov hydrosilylation of
vinylarenes and vinyl heterocycles. J. Am. Chem. Soc. 139, 2192–2195 (2017).
12. Bandar, J. S., Pirnot, M. T. & Buchwald, S. L. Mechanistic studies lead to
dramatically improved reaction conditions for the Cu-catalyzed asymmetric
hydroamination of olefins. J. Am. Chem. Soc. 137, 14812–14818 (2015).
13. Friis, S. D., Pirnot, M. T. & Buchwald, S. L. Asymmetric hydroarylation of
vinylarenes using a synergistic combination of CuH and Pd catalysis. J. Am.
Chem. Soc. 138, 8372–8375 (2016).
14. Bandar, J. S., Ascic, E. & Buchwald, S. L. Enantioselective CuH-catalyzed
reductive coupling of aryl alkenes and activated carboxylic acids. J. Am. Chem.
Soc. 138, 5821–5824 (2016).
Conclusions
15. Laitar, D. S., Tsui, E. Y. & Sadighi, J. P. Copper(I) β-boroalkyls from alkene
insertion: isolation and rearrangement. Organometallics 25, 2405–2408 (2006).
16. Wang, Y. -M. & Buchwald, S. L. Enantioselective CuH-catalyzed hydroallylation
of vinylarenes. J. Am. Chem. Soc. 138, 5024–5027 (2016).
17. Kadyrov, R., Iladinov, I. Z., Almena, J., Monsees, A. & Riermeier, T. H. Chiral
diphosphine ligands based on camphor: synthesis and applications in
asymmetric hydrogenations. Tetrahedron Lett. 46, 7397–7400 (2005).
18. Guzman-Martinez, A. & Hoveyda, A. H. Enantioselective synthesis of
allylboronates bearing a tertiary or quaternary B-substituted stereogenic carbon
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These investigations shed light on several factors that directly impact
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employed—a surprising twist considering that in certain cases e.e.
is boosted by faster Cu-alkyl trapping (Table 1). As highlighted by
the representative applications in Cu–H-catalysed processes
(Fig. 5b), the newly acquired understanding and its strategic impli-
cations are likely to be instrumental in the success of future endea-
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Received 12 January 2017; accepted 1 August 2017;
published online 2 October 2017
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2861
ARTICLES
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Author contributions
J.L. and S.R. identified the optimal catalyst and conditions, developed the catalytic
enantioselective transformations and performed the labelling and related experiments. S.T.
and J.d.P. designed and performed the computational and spectroscopic studies,
respectively, and developed the related mechanistic hypotheses. A.H.H. directed the
investigations and composed the manuscript with revisions provided by the other authors.
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enantioselective hydroboration of acyclic and exocyclic 1,1-disubstituted aryl
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Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations. Correspondence and
requests for materials should be addressed to A.H.H.
Acknowledgements
This research was supported by a grant from the National Institutes of Health (GM-47480) Competing financial interests
and the National Science Foundation (CHE-1362763). J.d.P. is an Alfonso Martin Escudero
The authors declare no competing financial interests.
10
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