Synthesis of Quaternary Carbon Stereogenic Centers by Diastereoselective Conjugate Addition of Boron-Stabilized Allylic Nucleophiles to Enones

Article abstract of DOI:10.1021/jacs.0c03900

A method for the site-selective and diastereoselective conjugate addition of boron-stabilized allylic nucleophiles to α,β-unsaturated ketones is disclosed. Transformations involve easily prepared γ,γ-disubstituted allyldiboron reagents and proceed in the presence of a fluoride activator at 80 °C. Reactions proceed with a wide variety of enones and allyldiboron reagents efficiently to deliver ketone products that contain otherwise difficult-to-access vicinal β-tertiary and γ-quaternary carbon stereogenic centers and an alkenylboron moiety. The utility of the method is highlighted by several transformations, including cross-coupling and carbocyclizations.

Full text of DOI:10.1021/jacs.0c03900

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Communication
Synthesis of Quaternary Carbon Stereogenic Centers By Diastereoselective
Conjugate Addition of Boron-Stabilized Allylic Nucleophiles to Enones
Michael Z Liang, and Simon J. Meek
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03900 • Publication Date (Web): 14 May 2020
Downloaded from pubs.acs.org on May 14, 2020
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Journal of the American Chemical Society
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Synthesis of Quaternary Carbon Stereogenic Centers By
Diastereoselective Conjugate Addition of Boron-Stabilized Allylic
Nucleophiles to Enones
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Michael Z. Liang and Simon J. Meek*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290.
Supporting Information Placeholder
In the examples noted above, reactions involve the
intermolecular addition of either the parent allyl
fragment, or in a few cases, the stereoselective addition
of -
Scheme 1. Allylic Nucleophile 1,4-Addition and
Boron-Stabilized Carbanion Reactivity.
ABSTRACT:
A
method for the site- and
diastereoselective conjugate addition of boron-stabilized
allylic nucleophiles to α,β-unsaturated ketones is
disclosed. Transformations involve easily prepared -
disubstituted allyldiboron reagents, and proceed in the
presence of a fluoride activator at 80 °C. Reactions
proceed with a wide variety of enones and allyldiboron
reagents efficiently to deliver ketone products that
contain otherwise difficult-to-access vicinal -tertiary
and -quaternary carbon stereogenic centers, and an
alkenylboron moiety. The utility of the method is
highlighted by several transformations, including cross-
coupling and carbocyclizations.
A. Allylic Nucleophile 1,4-Addition:
O
O
cat. (L)-M
R1
G
or
+
Lewis acid
R2
2
R2 R1
3
1
G = Si, Sn, Ta, Ba, Cu, Mg, B
B. Benzyl Trisboronates: Deborylative 1,4-Addition
Me
O
Na
NaOEt;
B(pin)
B(pin)
6
O
(pin)B
Ar
B(pin)
OMe
;
OMe
Me
Ar
(pin)B
(pin)B
Ar
B(pin)
Me
then Me–I
4
5
C. Boron-Stabilized Carbanion Reactivity: [(pin)B]2–R Deborylation
Stereoselective methods for the synthesis of
compounds that contain quaternary carbon centers are
critical to the preparation and discovery of bioactive
molecules.1 1,4-Addition of allylic nucleophiles to
electron-deficient alkenes provides an effective strategy
for the generation of complex molecular structures.
Pioneering studies by Hosomi-Sakurai with allylsilanes2
have led to the development of methods with other
allylmetals (Si,3 Sn,4 Cu,5 Ta,6 Ba,7 In8) that provide
access to -allyl-substituted carbonyls (Scheme 1A).
Related catalytic enantioselective variants have also been
reported that employ copper and ytterbium chiral Lewis
acid catalysts in the presence of allylsilane9 or
stannane.10 Pinacolato allylboronates have also been
successfully employed in catalytic enantioselective 1,4-
addition reactions with dialkylidene ketones with a chiral
nickel catalyst.11 Furthermore, enantioselective Cu-
catalyzed 1,4- and 1,6-conjugate additions of in situ
generated boron-substituted allylcopper species to
dienoates proceed with high selectivity.12,13 Indirect
synthesis of enantioenriched 1,4-allyl conjugate addition
products can also be achieved by an enantioselective 1,2-
allylboration/oxy-Cope rearrangement sequence with
-unsaturated -ketoesters.14
 Previous Work: (R3 = alkyl;
 This Work: (R3 = allyl; w/ enones)
E–X: R–X, C=O, C=N, epoxides)
R5
B(pin)
R3
[M]
[M]
alkyl
CsF
R4

MOR

(pin)B
(pin)B
(pin)B
10
8
(pin)B–F
7a; R3= alkyl, aryl
(pin)B-OR
Boron- and
Allyl-stabilized
O
Boron-stabilized
7b; R3= allyl
O
E
X
 Stereoselective 1,4-Addition
H
R
• Up to >98:2 dr, >98:2 ,
>98:2 1,4:1,2
• Vicinal -quaternary and -
tertiary carbon stereogenic
centers
O
OH
H
alkyl

B(pin)
R

R5 R4
B(pin)
• E & Z stereospecific allyl
additions
• Versatile E-alkenyl boron
11
9
-selective 1,4-addition
1,2-addition
monosubstituted allylic nucleophiles.12b–c In contrast,
protocols for the diastereoselective synthesis of γ-
quaternary carbon stereocenters through intermolecular
1,4-allyl additions are non-existent.15 Transformations
are limited to a small number of reports on intramolecular
Lewis acid promoted Hosomi-Sakurai annulations.16
At the center of the present studies is the generation and
reactivity of -boryl carbanions (e.g., 8) that begin with
the deborylation of geminal bis(boronates) (Scheme
1C).17 Recently, efforts in our laboratory and others have
focused on the formation of boron-stabilized carbanions
generated by deborylation of 1,1-bis(boronates) and their
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Journal of the American Chemical Society
utility in C–C bond forming methods.18 In this context,
Page 2 of 7
slight improvement, delivering 13a in 33% yield, 96:4 dr
and 96:4 : (entry 4). Further increasing the amount of
CsF to 500 mol % delivers 13a in 65% yield (95:5 dr),
however, significant decomposition of 12 (35%) is
observed.23 Increasing the reaction temperature to 60 °C
led to a marked improvement in reaction efficiency,
affording 13a in 54% yield, >98:2 dr (entry 5); however,
increasing CsF to 200 mol % proved deleterious (entry 6).
At this juncture, a brief survey of solvents (entries 7–9)
and further temperature optimization identified 50 mol %
CsF in DME at 80 °C as optimal reaction conditions for
the formation of 13a (90% yield, 96:4 dr, and 90:10 rr,
entry 10). Notably, 20 mol % CsF at 80 °C delivers 13a
in 56% yield and >98:2 dr (entry 11), while use of 50 mol
% KF instead of CsF results in <2% conversion to 13a
(entry 12).
1
2
3
4
5
6
7
8
reactions generally utilized alkyl or benzyl 1,1-
bis(boronates) reagents with a variety of carbon
electrophiles. Of particular significance is a recent study
by Chirik on the deborylative 1,4-addition of 1,1,1-tris-
boronates (4) (Scheme 1B).19 Recently, we have
introduced Cu-catalyzed allylic nucleophile additions to
ketones and imines with -disubstituted allyldiborons
(e.g., 7b).20,21 In this study, we report the first general
method for the diastereoselective synthesis of γ-
quaternary carbon stereogenic centers via site-selective
intermolecular allylic nucleophile 1,4-addition to α,β-
unsaturated ketones. Reactions employ -disubstituted
allyldiboron reagents (e.g., 7b) in the presence of CsF as
an activator, and furnish products in up to 96% yield and
>98:2 dr. The proposed reaction proceeds via a boron-
stabilized allyl carbanion (10) and C–C bond formation
occurs with high -selectivity at the more congested
carbon. Of note, in a recent report of alkoxide promoted
deborylative alkylation of 1,1-allyldiborons (e.g., via 10),
C–C bond formation was found to proceed with high -
selectivity.22
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27
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Scheme 2. -Unsaturated Ketone Scopea–c
O
O
Me B(pin)
50 mol % CsF
+
H
n-Bu
B(pin)

B(pin)
B(pin)
DME (0.5M)
80 °C, 18 h

n-Bu Me
13a–k
14
(1.0 equiv)
12
(1.0 equiv)
Table 1. Reaction Optimizationa
O
O
O
O
O
O
H
H
H
B(pin)
B(pin)
X mol %
Activator
Me B(pin)
B(pin)
H
+
n-Bu Me
n-Bu Me
n-Bu Me


B(pin)

+
n-Bu
n-Bu

Solvent (0.5 M)
Temp °C, 18 h
n-Bu Me
13a
13b
72% yield, 98:2 dr
13c
91% yield, 98:2 dr
85:15 : rr
(pin)B
Me
1
12
(1.0 equiv)
93% yield, >98:2 dr
(1.0 equiv)
-13a
-13a
90:10 : rr (1.5 mmol)
>98:2 : rr
rr (:)c,d
Solvent
Entry Activator; mol %
Temp (°C) Yield (%);b drc
O
O
O
Me
Me
B(pin)
1
2
3
4
5
6
7
8
22
22
22
22
60
60
60
60
60
80
80
80
8; 92:8
>98:2
79:21
>98:2
96:4
93:7
94:6
90:10
93:7
88:12
90:10
89:11
n.d.
KOtBu; 100
NaOtBu; 100
NaOMe; 100
CsF; 100
CsF; 100
CsF; 200
CsF; 100
CsF; 100
CsF; 100
CsF; 50
THF
THF
THF
THF
THF
THF
DME
Dioxane
C6H6
DME
DME
DME
20; 96:4
31; 92:8
33; 96:4
54; >98:2
29; 98:2
59; 96:4
34; >98:2
33; >98:2
90; 96:4
56; >98:2
<2
H
H
H
Me
Me
B(pin)
B(pin)
n-Bu Me
13e
n-Bu Me
n-Bu Me
13d
13f
96% yield, 96:4 dr
87:13 : rr
70% yield, >98:2 dr
92:8 : rr
91% yield, 87:13 dr
>98:2 : rr
O
9
O
O
Me
1
H
3
10
11
12
Me
CsF; 20
KF; 50
H
H
n-Bu Me
B(pin)
B(pin)
B(pin)
2
aReactions performed under N2 atmosphere. bYield determined by
analysis of 1H NMR spectra of unpurified reactions with DMF as
internal standard. cDiastereomeric ratios (dr) determined by analysis of
1H NMR spectra of purified products (diastereoisomers cannot be
separated by SiO2 chromatography). d>98:2 1,4:1,2 addition all cases.
Experiments were run in duplicate. See the SI for details.
Me n-Bu
Me
n-Bu Me
13gd
92% yield, >98:2 dr 2:3
>98:2 : rr (74:26 dr 1:2)
O
13i (from rac enone)
96% yield, 96:4 dre
>98:2 : rr
13h (from rac enone)
94% yield, 95:5 dre
>98:2 : rr
O
O
Me
H
Me
Me
Me
B(pin)
B(pin)
B(pin)
Me
To investigate the reactivity of boron-stabilized allylic
carbanions, we began by evaluating the reaction of
cyclohexenone 1 with the 1,1-diborylallylic reagent 12 to
afford 13a (Table 1). From the outset, a key objective of
our studies was to develop a robust process that is not
only efficient but also highly diastereo- and site-selective.
Initial control reactions, either in the absence of a Lewis
base activator or in the presence of typical Hosomi-
Sakurai Lewis acids (e.g., TiCl4), established that there is
no background reaction to either 1,4- or 1,2-addition
products (see SI for details). In contrast, treatment of 1
and 12 with 100 mol % of KOtBu, NaOtBu, or NaOMe
(entries 1–3) in THF at 22 °C for 18 h, affords 13a in up
to 31% yield and 96:4 dr. Switching to CsF as a less basic
activator to avoid competitive deprotonation resulted in a
n-Bu Me
n-Bu Me
n-Bu Me
13j
13k
<5% conv
13l
72% yield, 94:6 dr
80:20 : rr
<5% conv
aReactions performed under N2 atmosphere. bYields of purified
products after SiO2 chromatography. cDiastereomeric ratios (dr)
determined by analysis of 1H NMR spectra of purified products.
Experiments were run in duplicate. See the SI for details. dTreatment
of 13g with 1 equiv DBU in THF at 22 °C increases dr from 74:26 to
93:7. eDr with respect to all stereocenters.
With an effective protocol developed, an analysis of
the α,β-unsaturated ketone component in the site- and
stereoselective allylic nucleophile 1,4-addition was
undertaken. As illustrated in Scheme 2, the reaction is
tolerant of a broad range of enones generally exhibiting
high levels of efficiency and selectivity. For example,
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of allyldiboron containing Et/Me substituents proceed
reactions with cyclic enones of various ring sizes (58;
13a–d), as well as enones bearing gem-dimethyl
functionality on the ring (13e–f) proceed efficiently.
Enones bearing 2-methyl substitution enable the
formation of three contiguous stereocenters; for example,
13g is generated in 92% yield, and >98:2 dr 2:3 but 74:26
dr 1:2 due to modest selectivity of enolate protonation.
Reaction of racemic enones bearing monomethyl
substitution at the 4- and 6-positions also permits the
generation of three stereogenic centers in high
stereoselectivity; the formation of 13h and 13i in 94% and
96% yield in 95:5 dr and 96:4 dr, respectively are
illustrative. Equally efficient C–C bond formation
proceeds with apoverbenone (13j) a naturally occurring
terpene with a [3.1.1] scaffold. Unfortunately, it was
found 3-substituted and acyclic enones do not react under
the current reaction conditions (e.g., 13k–l).
1
2
3
4
5
6
7
8
stereospecifically to afford 16a (82% yield, 98:2 dr) and
16b (87% yield, >98:2 dr). These results demonstrate that
at 80 °C, the stereochemical integrity of the B-stabilized
carbanion is maintained, and enables selective access to
both stereoisomers.
substituents, for example, pendant aryl, silylether,
isopropyl, and cyclopropyl groups undergo
Allyldiborons bearing various
stereoselective C–C bond formation to afford 16c–f in
high yield. Furthermore, cyclic allyldiboron reagents can
be employed to incorporate cyclobutane (16g) and
cyclohexene (16h) ring systems, albeit with diminution in
dr. Notably, 16h is formed exclusively as the B-
substituted quaternary center in >98:2 : site-selectivity.
Relatedly, it was found increasing sterics in acyclic allylic
nucleophiles results in lower : site-selectivity; for
example, reaction of an isopropyl-substituted reagent
with 1 under standard reaction conditions furnishes 16i in
76% yield, and 93:7 dr ( isomer) but 76:24 :.
Symmetrical substituted allyl nucleophiles also react
equally effectively under standard conditions to afford
alkenyl borons 16j–k in high yield. Lastly, aryl
substituted quaternary carbon stereocenters (e.g., 16l)
could not be formed through the current protocol.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. -Disubstituted Allyldiboron Scopea–c
O
O
R2
B(pin)
B(pin)
50 mol % CsF
H
R1
+
B(pin)
DME (0.5M)
80 °C, 18 h
R1
R2
16a–l
1
15
(1.0 equiv)
(1.0 equiv)
O
O
O
Scheme 4. Stereoselective 1,4-Addition with -
H
H
H
Monosubstituted Allylic Nucleophilesa–c
B(pin)
B(pin)
B(pin)
Ph
Me
Me
Me
Me
Me
O
B(pin)
16a
16b
16c
Me B(pin)
50 mol % CsF
50 mol % CsF
82% yield, 98:2 dr
87% yield, >98:2 dr
76% yield, >98:2 dr
Me
O
B(pin)
B(pin)
Z-17
>98:2 : rr
96:4 : rr
86:14 : rr
O
DME (0.5M)
80 °C, 18 h
DME (0.5M)
80 °C, 18 h
O
O
E-17
1
O
H
H
H
B(pin)
B(pin)
OTBS
B(pin)
H
H
B(pin)
B(pin)
(pin)B
Z-23
Me
Me
Me
Me
(pin)B
B(pin)
Me
Me
Me
16d
16e
16f
18a
18b
93% yield, 94:6 dr
88:12 : rr
81% yield, 98:2 dr
93% yield, 95:5 dr
83% yield, 81:19 dr
97% yield, 85:15 dr
92:8 : rr
94:6 : rr
O
O
O
>98:2 : rr
95:5 : rr
B(pin)
• From Allyldiborons Z-17 or Z-23:
• From Allyldiboron E-17:
O
H
H
O


Me
B(pin)
O
R
(pin)B
Me
Me
Me
Me
B(pin)
H
H
Me
B(pin)
B(pin)
Me
16g
16h
16i
Me
20; R=Me
37% yield, 85:15 dr
>98:2 : rr
21; R=C5H11
44% yield, 75:25 dr
>98:2 : rr
88% yield, 80:20 dr
38% yield, 78:22 dr
76% yield, 93:7 dr
(pin)B
>98:2 : rr
>98:2 : rr
76:24 : rr
22e
19d (with Z-23)
82% yield, >98:2 dr
>98:2 : rr
O
O
O
42% yield, 84:16 dr
>98:2 : rr
H
H
H
B(pin)
B(pin)
B(pin)
Me Me
Me Ph
aReactions performed under N2 atmosphere. bYields of purified
products after SiO2 chromatography. Experiments were run in
16j
94% yield
98:2 : rr
16k
72% yield
95:5 : rr
16l
<5% conv
c
duplicate. Diastereomeric ratios (dr) determined by analysis of 1H
d
NMR spectra of purified products. See the SI for details. With 2.0
equiv of 1. eFrom rac 4-((tert-butyldimethylsilyl)oxy)cyclopent-2-en-
aReactions performed under N2 atmosphere. bYields of purified
products after SiO2 chromatography. cDiastereomeric ratios (dr)
determined by analysis of 1H NMR spectra of purified products.
Experiments were run in duplicate. See the SI for details.
1-one.
Having established a protocol for the site- and
diastereoselective 1,4-addition of -disubstituted
Next, we set out to determine the ability of the reaction
to tolerate structural variations relating to the allyldiboron
component (Scheme 3). A series of trisubstituted
allyldiborons bearing pendant functionality were
prepared and subjected to the reaction conditions with
enone 1. Reaction of both E and Z geometrical isomers
allylboron
carbanions,
mono--substituted
allyldiborons21 were investigated to allow for the
stereoselective preparation of vicinal tertiary carbon
stereogenic centers (Scheme 4). Under the optimal
reaction conditions (50 mol % CsF, 80 °C), both Z-17 and
E-17 crotyl isomers react with cyclohexenone with to
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Journal of the American Chemical Society
diastereomeric purity.26 Lastly, sodium perborate
Page 4 of 7
deliver 18a and 18b in 83% and 97% yield (>98:2 :),
albeit with diminished diastereoselectivity (18a: 81:19 dr;
18b: 85:15 dr). A rationale for the lower dr is likely the
result of a smaller substituted allyl nucleophile or minor
E/Z isomerization prior to C–C bond formation. An
additional noteworthy point, is that in both cases the
sterically less hindered crotyl nucleophiles react with
1
2
3
4
5
6
7
8
oxidation furnishes aldehyde 28 (Scheme 5B), which can
be cyclized with (1) HCl(aq) to bicyclic enone 29, and (2)
by
a
two-step
Horner-Wadsworth-Emmons
olefination/NaOH cyclization to hydrindane 30
containing 4 contiguous stereocenters (>98:2 dr).
To gain mechanistic understanding of the 1,4-allyl
addition reaction, a deuterium quench was used to probe
whether an enolate was formed at the end of the reaction
(Scheme 6A). It was found that 32 is generated in 66%
yield with 83% D incorporation at the -position
corresponding to a boron-enolate protonation.27,28 Next,
a comparison to the reactivity of monoboronallyl reagents
was probed. Under standard conditions, treatment of 33
with 50 mol % CsF at 80 °C results in <2% conversion to
either
high 1,4:1,2 (>98:2) selectivity.
In comparison,
synthetically versatile diboronate 19, formed by the
reaction of trisboronate Z-2324 and 1, is afforded in 82%
yield as a single diastereo- (>98:2 dr) and site-isomer
(>98:2 rr). Three additional examples, 20–22, serve to
illustrate that mono--substituted allylic nucleophiles
display increased reactivity but slightly lower
stereospecificity compared with trisubstituted variants.
Moreover, the reduced steric congestion renders mono--
substituted nucleophiles more broadly reactive; for
example, the formation of 20–22 arise from reactions
with enones that do not currently engage with the -
disubstituted variants (e.g., see 13l Scheme 2).25
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Mechanism Experiments and
Stereochemical Analysisa-b
83% D
incorporation
A. Deuterium Incorporation: quench with CD3OD
O
B(pin)
Me
O
D
H
Scheme 5. Synthetic Utility of the 1,6-
Ketoalkenylboronatesa
Me
Me
Me
standard
conditions
14f
12
CD3OD;
+
H
B(pin)
AgNO3
SiO2
1.0
1.0
Me n-Bu
equiv
equiv
A. Alkenylboron Transformations:
Me n-Bu
32
31
66% yield, 95:5 dr
O
O
Cu(OAc)2 (2 equiv)
NEt3 (2 equiv)
O
B. Monoboryl Reagent: with (pin)B–prenyl
5 mol% Pd/C, H2
MeOH, 23 °C
O
H
H
Me
B(pin)
O
60 °C, 12 h
50 mol % CsF
4 h
+
Me n-Bu
Me n-Bu
Me
B(pin)
O
DME, 80 °C
18 h
Me Me
34
24
98% yield
27
87% yield
1
33
(1.0 equiv)
H
(1.0 equiv)
<2% conv 1,2- or 1,4-addition
B(pin)
13a
C. Stereochemical Determination and Proposed Stereochemical Model:
(>98:2 dr; 90:10 :
Me n-Bu
Me
O
O
LA
LA
H
O
B
O
O
O
O
5 mol% Pd(PPh3)4
C(sp2)–Br
H
H
O
O
B
H
H
H
Me
RE
RZ
Na2CO3 (3 equiv)
MeOH/H2O/C6H6
80 °C, 16 h
O
Me
H
Me n-Bu
Me n-Bu
Me
H
H
vs
Me
H
RZ
RE
nOE
25
26
35
C(sp2)–Br: 2-bromonaphthalene
79% yield
C(sp2)–Br: isocrotyl bromide
84% yield
48% yield, 85:15 dr
A – Favored
B – Disfavored
29
LA = Cs+ or (pin)B–F
from 18b
D. Working Mechanism of CsF Inititated Conjugate Allyl Addition:
B(pin)
H
B. Synthesis of Carbocylic Scaffolds: oxidation/cyclization
O
Me
H
Me
H
Cs
O
O
Cs–F
(pin)B
or
F
B(pin)
B(pin)
B(pin)
R
R
B(pin)
B(pin)
X
NaBO3•4H2O
H
H
2.5% HCl(aq)
THF, 60 °C, 1 h
37
O
36
B(pin)
Me
R
polarized C–B bond
THF/H2O
23 °C, 1 h
Me n-Bu
Me n-Bu
40
28
13a
Cs
(>98:2 dr; 90:10 :)
Cs
H
H
Me
Me
O
Me B(pin)
B(pin)
(2 equiv)
(EtO)2OP
K2CO3 (2 equiv)
O
B(pin)
B(pin)
R
Me
R
C
38
R
O
H
Me
LA
 unfavorable  bond
O
LA
O
36
O
rotation
30
THF/H2O, 23 °C, 18 h;
LA = Cs+
or (pin)B–F
H
Me
n-Bu
68% yield
NaOH (2 equiv)
MeOH/H2O, 23 °C
18 h
H
>98:2 dr
Me
n-Bu
B(pin)
29
H
79% yield
39
Me
R
aSee SI for details.
aSee SI for details. bAttempted reaction of 30 with PhCHO or MeI
afforded <5% conv.
To highlight the synthetic utility of the 1,6-keto-
alkenylboronate products prepared by this method, the
experiments in Scheme 5 were conducted. In Scheme 5A,
it was shown that hydrogenation of the alkenylboron
proceeds without issue and affords the boronate ester 24
in excellent yield. Next, it was shown that C–C and C–O
cross coupling of the alkenylboron can be achieved under
Pd and Cu catalysis to afford the derived alkenylarene 25,
diene 26, and enol ether 27 with complete preservation of
1,2- or 1,4-allyl addition products, clearly highlighting
that the second boron group is critical for reactivity. The
relative stereochemistry of the major diastereomer was
determined by NOE experiments with 29 (Scheme 6C),
establishing the E-substituent of the nucleophile as anti to
the methine of the cyclohexane ring. This was further
confirmed since the stereochemistry of 18b, formed by
reaction of Z-17 was established by protodeboration to
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known compound 35.29 A proposed stereochemical
1
Centers in Acyclic Systems. Chem. Commun. 2011, 47, 4593–4623. (b)
Minko, Y.; Marek, I. Stereodefined Acyclic Trisubstituted Metal
Enolates Towards the Asymmetric Formation of Quaternary Carbon
Stereocentres. Chem. Commun. 2014, 50, 12597–12611. (c) Marek, I.;
Minko, Y.; Pasco, M.; Mejuch, T.; Gilboa, N.; Chechik, H.; Das, J. P.
All-Carbon Quaternary Stereogenic Centers in Acyclic Systems
through the Creation of Several C-C Bonds per Chemical Step. J. Am.
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Quaternary Stereocenters: Assembly of Key Building Blocks for the
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Chem. 2016, 81, 10376–10382.
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Reactions By Using Allylstannanes in the Presence of a Lewis Acid.
Chem. Lett. 1979, 8, 977–980. (b) Williams, D. R.; Mullins, R. J.;
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model for the reaction is shown by structure A. Allyl
carbanion addition to an enone, activated by either
(pin)B–F or via cesium bridge between a pinacol
oxygen,30 allows for stereoselective C–C bond formation
where the nucleophile stereochemistry (RE and RZ) is
relayed to the product with high fidelity. Addition via the
opposite face of the nucleophile (B) appears disfavored
due to sterics. Based on the data above, a proposed
mechanism is depicted in Scheme 6D. Cesium fluoride
initiates the reaction to generate 37, which can then be
reformed by reaction of the resulting enolate with another
equivalent of 36. The need for 50 mol % CsF versus 10
mol % likely arises due to reaction of the enolate (39) with
(pin)B–F, which inhibits the process. The lack of E/Z
isomerization of the allylic carbanion can also be
rationalized by an unfavorable -bond rotation that
localizes the carbanion on carbon (e.g., B).
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In summary, the investigations described above detail
a
practical and efficient method for the first
diastereoselective synthesis of γ-quaternary carbon
stereogenic centers through intermolecular 1,4-allyl
additions. Boron-stabilized allylic nucleophiles, formed
by Lewis base boron activation, react site-selectively and
stereospecifically
to
deliver
versatile
1,6-
ketoalkenylboronate products. Development of other
stereoselective C–C bond forming reactions of B-
stabilized allylic nucleophiles are in progress.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and spectral
and analytical data for all products. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sjmeek@unc.edu
ORCID
Simon J. Meek: 0000-0001-7537-9420
Notes
Authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support was provided by the United States National
Institutes of Health, Institute of General Medical Sciences
(R01GM116987). Mass spectrometry facilities in the Department
of Chemistry at University of North Carolina are supported by the
National Science Foundation (CHE1726291).
(7) Yanagisawa, A.; Habaue, S.; Yasue, K.; Yamamoto, H.
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Organogallium and Organoindium Reagents. Tetrahedron Lett. 1999,
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Diborylmethane. J. Am. Chem. Soc 2017, 139, 14061–14064. (n) Jang,
W. J.; Yun, J. Catalytic Asymmetric Conjugate Addition of a
Borylalkyl Copper Complex for Chiral Organoboronate Synthesis.
Angew. Chem. Int. Ed. 2019, 58, 18131–18135.
(19) Palmer, W. N.; Zarate, C.; Chirik, P. J. Benzyltriboronates:
Building Blocks for Diastereoselective Carbon–Carbon Bond
Formation. J. Am. Chem. Soc. 2017, 139, 2589–2592.
10
11
12
13
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15
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19
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21
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23
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25
26
27
28
29
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59
60
(20) (a) Green, J. C.; Zanghi, J. M.; Meek, S. J. Diastereo- and
Enantioselective Synthesis of Homoallylic Amines Bearing Quaternary
Carbon Centers. J. Am. Chem. Soc. 2020, 142, 1704–1709. (b) Zanghi,
J.
M.;
Meek,
S.
J.
Cu-Catalyzed
Diastereo-
and
Enantioselective Reactions of γ,γ-Disubstituted Allyldiborons with
Ketones. Angew. Chem. Int. Ed. 2020, Accepted DOI:
10.1002/anie.202000675
(21) For examples of stereoselective reactions with -
monosubstituted allyldiborons, see: (a) Miura, T.; Nakahashi, J.;
Murakami, M. Enantioselective Synthesis of (E)-δ-Boryl-Substituted
Anti-Homoallylic Alcohols Using Palladium and a Chiral Phosphoric
Acid. Angew. Chem. Int. Ed. 2017, 56, 6989–6993. (b) Miura, T.;
Nakahashi, J.; Zhou, W.; Shiratori, Y.; Stewart, S. G.; Murakami, M.
Enantioselective Synthesis of Anti -1,2-Oxaborinan-3-Enes from
Aldehydes and 1,1-Di(Boryl)Alk-3-Enes Using Ruthenium and Chiral
Phosphoric Acid Catalysts. J. Am. Chem. Soc. 2017, 139, 10903–
10908. (c) Miura, T.; Oku, N.; Murakami, M. Diastereo- and
Enantioselective Synthesis of (E)-δ-Boryl-Substituted Anti
-
Homoallylic Alcohols in Two Steps from Terminal Alkynes. Angew.
Chem. Int. Ed. 2019, 58, 14620–14624. (d) Park, J.; Choi, S.; Lee, Y.;
Cho, S. H. Chemo- and Stereoselective Crotylation of Aldehydes and
Cyclic Aldimines with Allylic Gem-Diboronate Ester. Org. Lett. 2017,
19, 4054–4057.
(22) Shin, M.; Kim, M.; Hwang, C.; Lee, H.; Kwon, H.; Park, J.;
Lee, E.; Cho, S. H. Facile Synthesis of α-Boryl-Substituted
Allylboronate Esters Using Stable Bis[(Pinacolato)Boryl]Methylzinc
Reagents. Org. Lett. 2020, 22, 2476–2480.
(23) Decomposition of 12 by excess CsF could not be prevented.
(24) Wang, M.; Gao, S.; Chen, M. Stereoselective Syntheses of (E)-
′,-Bisboryl-Substituted
Syn-Homoallylic
Alcohols
via
Chemoselective Aldehyde Allylboration. Org. Lett. 2019, 21, 2151–
2155.
(25) For examples of reactions with -disubstituted allyldiboron
reagents that proceed <5% conversion, see SI.
(26) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. Copper-
Promoted Coupling of Vinyl Boronates and Alcohols: A Mild
Synthesis of Allyl Vinyl Ethers. J. Am. Chem. Soc. 2010, 132, 1202–
1203.
(27) Proto-deboration of the product was required to remove a close
eluting impurity formed in the CD3OD quench.
(28) 1H NMR (CD2Cl2) analysis of a crude reaction between 1 and
12 shows an upfield signal characteristic of an enol species. See SI for
details.
(29) Tokoroyama, T.; Pan, L.-R. Efficient Stereoselective Syntheses
of Both (±)-Juvabione and (±)-epi-Juvabione by New Extracyclic
Stereocontrol Methodology. Tetrahedron Lett. 1989, 30, 197-200.
(30) Midland, M. M. Ab Initio Investigation of the Transition State
for Asymmetric Synthesis with Boronic Esters. J. Org. Chem. 1998,
63, 914–915.
O
O
RZ
B(pin)
B(pin)
(1.0 equiv)
RZ
[M]
50 mol % CsF
H
+
RE


B(pin)


(pin)B
RE
n
n
DME (0.5M)
80 °C, 18 h
(1.0 equiv)
RE RZ
Boron- and
Allyl-stabilized
• 27 Examples • Up to 97% yield, >98:2 dr, >98:2  rr • Quaternary and tertiary
stereogenic centers • Stereospecific allyl transfer • Up to three contiguous
stereocenters • 15 Allyldiboron reagents
• Cyclic and acyclic enones
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