Stereospecific Cross Couplings to Set Benzylic, All-Carbon Quaternary Stereocenters in High Enantiopurity

Article abstract of DOI:10.1021/jacs.6b08075

Asymmetric preparation of all-carbon quaternary stereocenters is an important goal. Despite advances in formation of highly enantioenriched products with quaternary stereocenters proximal to a functional group, methods to install quaternary stereocenters isolated from functional groups are limited. Transition metal catalysis offers a potential solution, but prior cross couplings are limited to allylic substrates or deliver little to no enantiomeric enrichment. We report a stereospecific, nickel-catalyzed Suzuki-Miyaura arylation of tertiary benzylic acetates to deliver products with diaryl and triaryl quaternary stereocenters in high yields and ee's. This reaction employs an inexpensive, air-stable Ni(II) salt and commercially available phosphine ligand to transform tertiary alcohol derivatives, which are easily available in exceptional ee, into valuable products with stereoretention.

Full text of DOI:10.1021/jacs.6b08075

Communication
pubs.acs.org/JACS
Stereospecific Cross Couplings To Set Benzylic, All-Carbon
Quaternary Stereocenters in High Enantiopurity
Qi Zhou,† Kelsey M. Cobb, Tianyu Tan, and Mary P. Watson*
Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
Scheme 1. Benzylic Stereocenters via Cross Couplings
ABSTRACT: Asymmetric preparation of all-carbon qua-
ternary stereocenters is an important goal. Despite
advances in formation of highly enantioenriched products
with quaternary stereocenters proximal to a functional
group, methods to install quaternary stereocenters isolated
from functional groups are limited. Transition metal
catalysis offers a potential solution, but prior cross
couplings are limited to allylic substrates or deliver little
to no enantiomeric enrichment. We report a stereospecific,
nickel-catalyzed Suzuki−Miyaura arylation of tertiary
benzylic acetates to deliver products with diaryl and triaryl
quaternary stereocenters in high yields and ee’s. This
reaction employs an inexpensive, air-stable Ni(II) salt and
commercially available phosphine ligand to transform
tertiary alcohol derivatives, which are easily available in
exceptional ee, into valuable products with stereoretention.
of an azirdine.11 Given these limitations, one of the best current
methods to prepare quaternary stereocenters isolated from
functional groups is Aggarwal’s enantiospecific, metal-free
coupling of tertiary boronic esters with aryl lithium reagents.12
Unlike the limitations with tertiary electrophiles, extensive
progress has been made in metal-catalyzed cross couplings of
secondary electrophiles.10a In addition to enantioselective cross
couplings pioneered by Fu,13 Jarvo, we, and others have
demonstrated stereospecific cross couplings of secondary
benzylic electrophiles (Scheme 1B).14 Given the high steric
hindrance tolerated, including branched alkyl groups,14i we
envisioned that a stereospecific cross coupling of tertiary
electrophiles may be possible. When coupled with enantiose-
lective ketone alkylation, this method would offer a powerful
asymmetric synthesis of benzylic quaternary stereocenters from
readily available, achiral ketone precursors (Scheme 1C). This
strategy avoids differentiation of similar alkyl groups (R1 and
R2) with a chiral catalyst, a highly challenging task at a saturated
carbon of an acylic substrate. We now report the successful
development of a stereospecific, nickel-catalyzed Suzuki−
Miyaura arylation of tertiary benzylic acetates to deliver diaryl
and triaryl quaternary stereocenters in high yields and ee’s. This
reaction employs an inexpensive, air-stable Ni(II) salt and
commercially available phosphine ligand to transform tertiary
alcohol derivatives, which are easily available in exceptional ee’s,
into valuable products with stereoretention. This reaction
demonstrates that transition metal catalysis can be used with
nonallylic tertiary electrophiles in stereospecific substitutions.
enzylic, all-carbon quaternary stereocenters are present in
Ba variety of bioactive molecules, including natural products
and those developed in pharmaceutical and medicinal
chemistry.1 Given their biomedical application, asymmetric
synthesis of molecules with quaternary stereocenters is crucial,
and great advances have been made to prepare several classes of
quaternary stereocenters.2 Tremendous progress has been
made in intramolecular reactions to deliver quaternary
stereocenters.3 For intermolecular reactions, successful ap-
proaches focus largely on reactions at sp2-carbons, such as
enolate allylations1b,4 or arylations,1c conjugate additions,1d,5
redox-relay Heck reactions,6 and hydrovinylations of styrenes.7
In contrast to these notable advances to deliver important
carbonyl and vinyl products, synthesis of highly enantioen-
riched products with benzylic quaternary stereocenters isolated
from functional groups remains a challenge. Stereospecific
substitution (SN2) of tertiary electrophiles is outcompeted by
elimination (E2).8 A transition metal-catalyzed cross coupling
has the potential to overcome this limitation. However, the
steric bulk of a tertiary alkyl group results in hindered oxidative
addition (alkyl electrophiles) or transmetalation (alkyl
nucleophiles). The presence of β-hydrogens leads to β-hydride
elimination and isomerization. Thus, cross couplings to deliver
quaternary stereocenters in high enantiomeric excess (ee) are
limited to allylic electrophiles.9 Cross couplings of nonallylic
tertiary alkyl substrates typically result in achiral or racemic
products (Scheme 1A).10 In the single example of a cross
coupling to form an enantioenriched quaternary stereocenter,
Doyle showed a promising 27% ee in a Negishi cross coupling
Received: August 3, 2016
© XXXX American Chemical Society
A
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Communication
a
Table 1. Optimization of Benzylic Arylation
b
yield (%)
c
d
entry
ligand (mol %)
temp (° C)
solvent
PhMe
4 (ee, %)
5
es (%)
1
2
3
4
5
6
7
8
none
80
80
60
60
40
40
40
40
40
40
40
93 (20)
74 (87)
72 (90)
63 (93)
57 (96)
81 (96)
97 (97)
92 (96)
90 (95)
99 (97)
0
2
21
PhPCy2 (11)
PhMe
22
25
24
9
90
PhPCy2 (11)
PhMe
93
PhPCy2 (11)
THF
96
CyJohnPhos (11)
CyJohnPhos (5)
CyJohnPhos (5)
CyJohnPhos (5)
CyJohnPhos (5)
CyJohnPhos (5)
SIMes·HBF4 (5)
THF
99
THF
6
99
1,4-dioxane
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
5
>99
99
8
e
9
6
98
e
e
,
,
f
f
10
11
≤3
0
>99
a
b
c
Conditions: 1a (0.10 mmol), 2a (1.0 equiv), Ni(cod)2 (5 mol %), ligand, NaOMe (2.0 equiv), solvent (0.4 M), unless otherwise noted.
1
1
Determined by H NMR using an internal standard. Total yields over 100% reflect the error of H NMR yields, particularly for minor products.
d
e
Determined by HPLC using a chiral stationary phase. es = enantiospecificity = (eeproduct)/(eestarting material). NiCl2·DME in place of Ni(cod)2.
f
Boronate ester 3a (2.0 equiv) in place of boroxine 2a.
We selected carboxylates of 2-(naphthalen-2-yl)butan-2-ol
However, cross coupling with the aryl potassium trifluoroborate
resulted predominantly in hydrolysis of acetate 1a; no desired
product 4 was observed.21 Although N-heterocyclic carbene
ligands have been used in cross couplings of secondary benzylic
carbamates,14h the use of 1,3-bis(2,4,6-trimethylphenyl)-4,5-
dihydroimidazolium tetrafluoroborate (SIMes·HBF4) as the
ligand precursor resulted in no desired product 4 or alkene 5;
90% recovered acetate was observed (entry 11). Given the
potential for hydrolysis of acetate 1a in the presence of
NaOMe, we also investigated the use of 2-(naphthalen-2-
yl)butan-2-ol itself as substrate. However, neither 4 nor 5 were
observed, and 75% of the alcohol was recovered.
Under the optimized conditions, a range of aryl boronate
esters underwent cross coupling (Scheme 2). Electron-rich (7,
8, 14, 15) and electron-poor (4, 9−13) aryl groups can be
incorporated. A range of functional groups is well tolerated,
including ether (4, 8), aniline (7), aryl chloride and fluoride (9,
13), amide (10), ester (11), trifluoromethyl (12), and
dioxolane (14) groups. Aryl groups with increased steric
hindrance can also be used successfully (15). In every case, near
perfect levels of stereochemical fidelity were observed.
Unfortunately, the use of heteroaryl boronic esters (pyridyl,
furyl, indolyl) was not successful, and the use of vinyl boronate
esters resulted in low yields. The absolute configuration of 10
was determined to be R via X-ray crystallography using Cu Kα
radiation.22 The expected S configuration of acetate 1a, as well
as the alcohol precursor to 18, was also confirmed via X-ray
crystallography. The conversion of (S)-1a to (R)-10 demon-
strates that this reaction proceeds with overall retention of
absolute configuration.23 Absolute configurations of other
products were assigned by analogy.
(1) for initial investigation. Tertiary alcohols are easily prepared
in 89−99% ee via Walsh’s enantioselective additions of alkyl,15
vinyl,16 and arylzinc reagents,17 as well as allyl stannanes,18 to
acetophenones.19 Acylation then delivers acetate 1a, which is
stable for >4 months when stored at −35 °C under N2.
Notably, pivalate 1a′ or carbamate 1a″ did not form under
standard acylation conditions, indicating how sterically
congested the tertiary alcohol is.
Using 3-(methoxy)phenyl boroxine as the model nucleo-
phile, under conditions similar to those for the cross coupling
of secondary benzylic pivalates with aryl boroxines, high yield of
desired product 4 was observed (Table 1, entry 1).14a However,
the stereochemical fidelity was poor (21% es). Because the use
of monodentate phosphines had proven helpful in other
stereospecific cross couplings, we investigated the use of
PhPCy2. High levels of stereochemical fidelity were achieved,
particularly at lower reaction temperature and with THF as
solvent (entries 2−4). However, alkenes 5 formed compet-
itively. Although these alkenes may form via E2 elimination,
they are more likely due to β-hydride elimination. Their
formation depends on catalyst, and acetate 1a largely
decomposes by hydrolysis (not E2) in the presence of only
NaOMe. We thus examined Buchwald ligands, hoping that the
hemilabile arene would block the open coordination site
necessary for β-hydride elimination.20 Indeed, the use of 2-
(dicylohexylphosphino)biphenyl, CyJohnPhos, resulted in less
alkenes and even higher levels of stereochemical fidelity (entry
5). By using a 1:1 ratio of Ni(cod)2:CyJohnPhos, high yield of
4 (81%) was observed (entry 6). To maximize the method’s
attractiveness, we prioritized the use of 2-methyl THF as a
“greener” solvent (entries 6−8) and an air-stable nickel(II)
precatalyst (NiCl2·DME, entry 9). Under these conditions, the
use of boronate ester 3a in place of boroxine 2a resulted in a
near perfect yield and stereochemical fidelity (entry 10). Use of
the analogous aryl boronic acid and pinacol ester resulted in
86% yield with 98% es, and 80% yield with 98% es, respectively.
A variety of tertiary acetates also successfully underwent
arylation (Scheme 3). For the aryl substituent (Ar1), electron-
rich naphthyl groups (16) and increased steric hindrance (17)
are well tolerated. Heteroaryl groups can also be used (18).
Various alkyl substituents (R1) can be incorporated, including
alkyl chains capped with silyl ether (19), aryl (20, 22), and
B
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Communication
a
an acetophenone. Triarylethane 23 formed in 73% yield, 94%
ee, and 98% es (Scheme 3). As previously reported in related
reactions of secondary diaryl carbamates,14f−h a naphthyl
substituent is not required for diaryl acetates. By using 10
mol % Ni/CyJohnPhos catalyst and increased temperature and
time, arylation resulted in 62% yield of triarene 24 with near
perfect stereochemical fidelity. These conditions are not general
for other non-naphthyl substrates, but this promising result
suggests that broad scope of tertiary diaryl acetates may be
possible with a future catalyst. Notably, the only other method
that directly delivers triaryl quaternary stereocenters in high ee
is Aggarwal’s metal-free coupling.12
Scheme 2. Scope of Aryl Boronate Esters
With respect to mechanism, a directed SN2′ oxidative
addition, which has been proposed for stereoretentive cross
couplings of secondary benzylic and allylic electrophiles,9d,14h is
consistent with our observed stereoretention, as well as the
requirement for a naphthyl substituent. In a directed oxidative
addition, the acetate binds the nickel catalyst, directing it to add
in an SN2′ fashion (A, Scheme 4). This mechanism also
a
Conditions: 1a (0.40 mmol), 3 (2.0 equiv), NiCl2·DME (5 mol %),
CyJohnPhos (5 mol %), NaOMe (2.0 equiv), 2-Me-THF (0.4 M), 40
°C, 22 h, unless noted. Average isolated yields ( 9%) and ee’s ( 1%,
determined by HPLC or SFC using a chiral stationary phase) of
Scheme 4. Putative Catalytic Cycle
b
c
duplicate reactions, unless otherwise noted. Single experiment. 60
d
°C, 12 h. 3.0 equiv of 3.
a
Scheme 3. Scope of Tertiary Acetates
suggests why the steric hindrance of a tertiary acetate is
tolerated; this increased bulk is remote to the carbon attacked.
Transmetalation and reductive elimination are well precedented
to proceed with steroeoretention, ultimately resulting in net
retention of configuration.24 Studies are underway to
investigate this intriguing mechanism further.
In summary, we developed a high-yielding Suzuki−Miyaura
arylation of tertiary benzylic acetates to deliver products with
diaryl and triaryl quaternary stereocenters in excellent stereo-
chemical fidelity. By combining this stereospecific cross
coupling with known enantioselective additions to acetophe-
nones, this offers a highly efficient strategy for asymmetric
synthesis of diaryl and triaryl quaternary stereocenters. This
reaction overcomes traditional limitations in utilizing tertiary
electrophiles in substitution reactions, and demonstrates that a
transition metal-catalyzed cross coupling for the synthesis of
enantioenriched quaternary stereocenters can go beyond allylic
electrophiles. Efforts to expand the scope and to investigate the
mechanism are ongoing.
a
Conditions: see Scheme 2. Average isolated yields ( 7%) and ee’s
b
c
d
( 1%). Single experiment. 78%, 83% ee, 99% es (84% ee of 1). 0.3
mmol of 1. 2a (0.83 equiv) in place of 3a. 60 °C. 48 h. Opposite
enantiomer of 1 used. 10 mol % NiCl2·DME, 10 mol % CyJohnPhos,
60 °C, 48 h.
e
f
g
h
i
vinyl (21) groups. Notably, this reaction is not limited to
formation of methyl-substituted quaternary stereocenters;
ethyl-substituted product 22 was formed in 70% yield and
99% es. However, an aryl substituent with an extended π-
system is required; the arylation of 2-([1,1′-biphenyl]-4-
yl)butan-2-yl acetate resulted in no product.
We also pursued the cross coupling of diaryl acetates to
deliver triaryl quaternary stereocenters. These acetates are
easily prepared via enantioselective addition of a diarylzinc to
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b08075.
■
S
Experimental details and data (PDF)
Crystal structure for 10 (CIF)
Crystal structure for 1a (CIF)
Crystal structure for S-1d (CIF)
C
DOI: 10.1021/jacs.6b08075
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Journal of the American Chemical Society
Communication
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AUTHOR INFORMATION
■
Corresponding Author
*mpwatson@udel.edu
Present Address
†Adesis, Inc., 27 McCullough Drive, New Castle, DE 19720.
Notes
The authors declare no competing financial interest.
138, 10774. (k) Lop
2009, 11, 5514.
́ ́
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ACKNOWLEDGMENTS
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NIH (R01 GM111820) is gratefully acknowledged. NMR and
other data were acquired at UD on instruments obtained with
assistance of NSF and NIH funding (NSF CHE0421224,
CHE1229234, CHE0840401, and CHE1048367; NIH P20
GM104316, P20 GM103541, and S10 OD016267).
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can be obtained free of charge from The Cambridge Crystallographic
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