Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling

Article abstract of DOI:10.1021/jacs.7b06567

A nickel-catalyzed conjunctive cross-coupling between non-conjugated alkenes, aryl iodides, and alkylzinc reagents is reported. Excellent regiocontrol is achieved utilizing an 8-aminoquinoline directing group that can be readily cleaved to unmask net β,γ-dicarbofunctionalized carboxylic acid products. Under optimized conditions, both terminal and internal alkene substrates provided the corresponding alkyl/aryl difunctionalized products in moderate to excellent yields. The methodology developed herein represents the first three-component 1,2-dicarbofunctionalization of non-conjugated alkenes involving a C(sp³)-C(sp³) reductive elimination step.

Full text of DOI:10.1021/jacs.7b06567

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Communication
Nickel-Catalyzed #,#-Dicarbofunctionalization of Alkenyl
Carbonyl Compounds via Conjunctive Cross-Coupling
Joseph Derosa, Van Tran, Mark N. Boulous, Jason S. Chen, and Keary M. Engle
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06567 • Publication Date (Web): 24 Jul 2017
Downloaded from http://pubs.acs.org on July 24, 2017
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Nickel-Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl
Compounds via Conjunctive Cross-Coupling
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Joseph Derosa‡, Van T. Tran‡, Mark N. Boulous, Jason S. Chen and Keary M. Engle*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United
States
ABSTRACT: A nickel-catalyzed conjunctive cross-coupling between non-conjugated alkenes, aryl iodides, and alkylzinc reagents is
reported. Excellent regiocontrol is achieved utilizing an 8-aminoquinoline directing group that can be readily cleaved to unmask
net β,γ-dicarbofunctionalized carboxylic acid products. Under optimized conditions, both terminal and internal alkene substrates
provided the corresponding alkyl/aryl difunctionalized products in moderate to excellent yields. The methodology developed
herein represents the first 1,2-dicarbofunctionalization of non-conjugated alkenes involving a three-component C(sp3)–C(sp3)
cross-coupling
reaction.
Since their inception transition-metal-catalyzed cross-
above, Sigman has reported 1,2-diarylation of terminal al-
kenes to introduce the same aryl group at both positions.11
Relevant intramolecular two-component alkene 1,2-
dicarbofunctionalization reactions have also been reported, in
which the alkyl halide electrophile12 or carbon nucleophile13
are intramolecularly tethered to the alkene.
coupling reactions have emerged as invaluable tools for forg-
ing C–C bonds in complex molecule synthesis.1 Recent ad-
vances have enabled efficient C(sp3)–C(sp2) bond formation,
often utilizing privileged ligand scaffolds to facilitate oxidative
addition/reductive elimination and prevent otherwise rapid
β-hydride elimination.2 Alkyl–alkyl C(sp3)–C(sp3) cross-
coupling is arguably an even more difficult challenge and has
been actively studied during the past several years.3-5 In this
context, Fu has elegantly utilized alkyl electrophiles contain-
ing chelating groups to promote such transformations.4 While
two-component cross-couplings to achieve alkyl–alkyl bond-
formation have been vigorously pursued, the development of
a practically useful three-component variant remains an un-
met challenge. Specifically, we were attracted to the notion
that a non-conjugated alkene containing a coordinating group
could be used as a conjunctive reagent3d,6 to facilitate the
union of an organometallic nucleophile and an organohalide
electrophile. Such a reaction would provide a powerful meth-
od for vicinal dicarbofunctionalization that would enable rap-
id build-up of molecular complexity and would rely on a key
C(sp3)–C(sp3) bond-forming step.
Scheme 1. Background and Synopsis of Current Work
A. Transition-metal-catalyzed 1,2-difunctionalization of alkynes
X
MII
E
X
MII
R1
E
R
BX2
R
E
R1
R2
carbometalation
R2
transmetalation /
reductive elimination
R1
R2
B. Palladium-catalyzed 1,2-dicarbofunctionalization via nucleopalladation (Previous Work)
DG
PdII
PdII
DG
DG
E
E
X
R
R
R
O
O
O
nucleo-
oxidative addition /
reductive elimination
Nu
Nu
(anti)
palladation
Nu
• limited nucleophile scope • isomerization leads to low d.r. • harsh reaction conditions
C. Nickel-catalyzed 1,2-dicarbofunctionalization via conjuctive cross-coupling (This Work)
X
[R–M]
NiII
DG
R
DG
NiII Ar
DG
R = alkyl, aryl
R
R
O
R
O
O
carbonickelation
transmetalation /
reductive elimination
(syn) Ar
Ar
• broad scope of aryl electrophiles • aryl and alkyl nucleophiles tolerated
• high d.r. with non-conjugated internal alkenes • high yields • mild reaction conditions
Previous research on three-component cross-coupling
reactions with C–C π bonds have generally employed conju-
gated alkenes (e.g., styrenes and acrylates),3d,7 allenes,8 1,3-
dienes,9 or alkynes.10 In these catalytic processes, regioselec-
tivity is controlled by the innate polarization of the π-system
and/or the resulting stability of the organometallic interme-
diate. Such systems either lack β-hydrogen atoms or proceed
via formation of a π-allyl/benzyl intermediate. In the context
of alkyne 1,2-difunctionalization, Larock and coworkers re-
ported a pioneering example of 1,2-diarylation of internal
alkynes with aryl boronic acids and aryl halides using catalytic
palladium (Scheme 1A).10a In addition to the examples cited
Our group has previously found that when intramolecu-
larly tethered to non-conjugated alkenes, removable biden-
tate directing groups can effectively control regiochemical
outcomes and prevent β-hydride elimination in alkene hydro-
functionalization and 1,2-dicarbofunctionalization reactions
using palladium(II) as catalyst.14,15 Specifically, in this latter
category, we recently developed an anti-β,γ-vicinal-
dicarbofunctionalization reaction via Pd(II)/Pd(IV) catalysis
that facilitates addition of indole, 2-naphthol, and 1,3-
dicarbonyl nucleophiles to the γ-position and C(sp2)/C(sp)
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carbon electrophiles at the β position.15 In addition to the
limited nucleophile scope of this reaction, isomerization of
acyclic internal alkenes was observed, leading to mixtures of
diasteroisomers, greatly limiting the overall utility of this re-
action.
three-component reaction, but in practice this could be
avoided through choice of appropriate reaction conditions.
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8
In a series of initial experiments, we were pleased to ob-
serve that the desired product was formed in 49% yield with
only 10 mol% Ni(cod)2 at room temperature using Daugulis’s
8-aminoquinoline (AQ) directing group (entry 1). Interesting-
ly, the reaction also resulted in the formation of a 1,2-
We thus questioned whether it would be possible to de-
velop a conjunctive cross-coupling that would proceed with
opposite polarity. We envisioned that such a reaction would
enable access to syn-difunctionalized products and would
potentially allow for C(sp3)–C(sp3) coupling between an in-
termediate organometallic species and an alkyl organometal-
lic nucleophile. Though such a reaction could potentially be
achieved via a Pd(0)/Pd(II) cycle, we were attracted to the use
of nickel as the catalyst given its efficacy in promoting C(sp3)–
C(sp3) coupling.
1
diarylation product in modest yield (30% by H NMR), sug-
gesting a potential competitive pathway from the putative
nickelacycle intermediate (see Supporting Information). This
byproduct was effectively suppressed by using dioxane as
solvent and increasing the temperature to 50 °C, yielding the
desired product in 88% isolated yield (entry 7). We were also
pleased to find that NiCl2•glyme provided moderate yield in
DMF, even when all operations were performed outside of
the glovebox (entry 4), providing an alternative procedure
that may be more appealing for some end-users. Yields were
generally superior with Ni(cod)2, however, so we elected to
focus on this precatalyst for the remainder of the investiga-
tion (entry 9). As expected, a control experiment showed that
the reaction did not occur in the absence of nickel catalyst
(entry 10). Though many of the directing groups that were
tested proved ineffective throughout the optimization pro-
cess, both the oxazoline and thioether directing groups
showed promising reactivity (entries 16 and 17). Interestingly,
using 1 equivalent of the dialkyl zinc reagent resulted in only
8% yield, suggesting that the N–H bond consumes the first of
the two equivalents needed for the optimized reaction condi-
tions.
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Table 1. Optimization of β,γ-dicarbofunctionalizationa
10 mol% Ni
ZnEt2
I
O
O
Et
+
DG
DG
solvent, 12 h
entry
DG
Ni source
solvent
temperature (ºC)
% yieldb
1
2
3
A
A
A
Ni(cod)2
Ni(cod)2
Ni(cod)2
DMF (0.3 M)
toluene (0.3 M)
THF (0.3 M)
rt
rt
rt
49
14
52
51c
60
4
5
6
A
A
A
NiCl2•glyme
Ni(cod)2
DMF (0.3 M)
rt
rt
rt
dioxane (0.3 M)
dioxane (0.1 M)
Ni(cod)2
71
88c
40
7
8
A
A
A
A
B
C
Ni(cod)2
Ni(cod)2
NiCl2•glyme
none
dioxane (0.1 M)
dioxane (0.1 M)
dioxane (0.1 M)
dioxane (0.1 M)
dioxane (0.1 M)
dioxane (0.1 M)
50
100
50
9
16
10
11
12
50
n.d
n.d.
n.d.
Ni(cod)2
Ni(cod)2
100
50
13
14
15
16
17
18d
D
E
F
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
dioxane (0.1 M)
dioxane (0.1 M)
dioxane (0.1 M)
dioxane (0.1 M)
dioxane (0.1 M)
dioxane (0.1 M)
50
50
50
50
50
50
n.d.
n.d.
n.d.
77
Table 2. Aryl/Vinyl Electrophile and Alkyl/Aryl Nucleophile
Scopea
G
H
A
O
10 mol% Ni(cod)2
2 equiv ZnR2
23
I
O
R
+
N
8
H
N
(AQ)
AQ
dioxane, 50 ºC, 12 h
H
1a
N
2a–o
H
N
N
H
N
H
N
CHO
N
PPh2
Br
OMe
A
B
C
D
DG =
CO2Et
O
Et
O
Et
O
Et
AQ
AQ
AQ
AQ
AQ
2b, 80%
2a, 82%
Et
2c, 75%
N
O
N
H
N
CF3
H
H
N
S
O
N
O
Et
Me
H
O
Et
O
F
G
E
Me
AQ
AQ
Me
F
2f, 81%
2d, 69%
Et
OMe
Cl
2e, 70%
aReaction conditions: alkene (0.1 mmol), iodobenzene (0.2
O
Me
b
O
Et
N
O
O
S
mmol), diethyl zinc (1.0 M in hexanes, 2 equiv). Yields de-
AQ
Cl
AQ
AQ
1
2i, 61%
termined by H NMR analysis using CH2Br2 as internal stand-
2h, 33%
2g, 43%
c
ard unless noted otherwise; n.d. = not detected. Isolated
Me
n-
Pr
O
Et
O
yield. 1equiv ZnEt2 (1.0 M in hexanes).
AQ
2k, 88% (ZnEt2)
AQ
2j, 81%
2l, 79% (n-PrZnBr)b
85% (EtZnBr)b
82% (EtZnCl)b
We set out to reduce our hypothesis to practice by opti-
mizing reaction conditions and the directing group structure
in parallel. To begin, we selected a collection of representa-
tive mono- and bidentate directing groups. Notably, Chatani
has previously found that N,N-bidentate directing groups
enable C(sp2)–H and C(sp3)–H activation under nickel cataly-
sis.16,17 In order to achieve the desired carbon-
ickelation/C(sp3)–C(sp3) cross-coupling sequence, we elected
to screen using diethyl zinc as the nucleophile and iodoben-
zene as the electrophile (Table 1). At the outset, we antici-
pated that Negishi coupling between diethylzinc and iodo-
benzene could potentially be competitive with the desired
O
OEt
OMe
O
O
O
AQ
AQ
2n, 62% (c-PrZnBr)b
AQ
2o, 57% (RZnBr)b
2m, 71%
aReaction conditions: 1a (0.25 mmol), iodoarene/vinyl iodide
(0.5 mmol), organozinc reagent (2 equiv). Percentages repre-
sent isolated yields. bAlkylzinc halide (3 equiv).
We first examined the scope of aryl electrophiles and or-
ganozinc nucleophiles for this regioselective β,γ-
dicarbofunctionalization reaction (Table 2). We were satisfied
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to find that both electron-rich and electron-deficient arenes
analogy to 3c and 3i, which were deteremined by X-ray crys-
tallography.
Next, we examined the scope of non-conjugated α-
1
2
3
4
5
6
7
8
gave the desired product in good to excellent yield (2a–2f).
Additionally, we were pleased to observe that the reaction
appeared to be chemoselective for C(sp2)–I bond cleavage
over C(sp2)–Br bond cleavage, allowing for potential down-
stream diversification (2b). Heterocycles such as thiophene
and pyridine were tolerated, though the latter required steric
blocking of the coordinating nitrogen atom, providing the
corresponding heteroarylation products in modest yields (2g
and 2h). Both ortho-fluoro and -methoxy substituted arenes
were also found to be competent electrophiles under the
optimized reaction conditions (2e and 2f). Although in general
alkenyl iodides are not suitable reaction partners (potentially
due to secondary reactions that can take place with the cor-
responding products), we found that cyclohexenyl iodide was
a competent electrophile, delivering 2i in 61% yield. Lastly,
we set out to test the nucleophile scope by substituting di-
ethyl zinc with other alkyl zinc nucleophiles (2j–2o). Gratify-
ingly, we observed the formation of the desired products in
high yields using dimethyl zinc (2j) and diphenyl zinc (2m).
Additionally, the reaction is also compatible with monoalkyl
zinc halides (2k, 2l, and 2o), which are milder, more stable,
and easier to access. We were delighted to obtain cyclopropy-
lated product 2n, establishing the viability of secondary–
secondary C(sp3)–C(sp3) coupling; however, more hindered
secondary alkyl nucleophiles were not tolerated in the reac-
tion. For example, when diisopropyl zinc is subjected to the
reaction conditions, we observed only a mixture of mono-
and diarylation byproducts. This could be due to the in-
creased number of accessible β-hydrogen atoms on the
transmetalating agent, promoting undesired β-hydride elimi-
nation. Alternatively, the increased steric demands could
suppress the rate of transmetallation onto the relatively hin-
dered nickelacycle (vide infra). Another limitation of this
method at present is incompatibility with coordinating het-
eroatoms, such as free alcohols or amines, which we hypoth-
esize can chelate the nickel species, preventing successive
turnovers.
substituted terminal alkenes and internal alkenes (1b–1k)
(Table 3). To probe the effect of alkene structure on reactivi-
ty, we used iodobenzene as the electrophile and either dime-
thyl or diethylzinc as the nucleophile. To our delight, α-
substituted substrates were reactive, providing the desired
products in moderate yields (3a–3d). Notably, with mono-α-
substituted substrates, increasing the steric bulk of the α-
substituent led to significantly increased diastereomeric rati-
os, though this came at the expense of yield.18 The relative
stereo chemistry of the major diastereomer of 3c was estab-
lished by X-ray crystallography. The trans orientation of the α
and β substituents presumably arises from formation of the
more stable trans-nickelacycle upon carbonickelation.15 As for
internal substrates, we were pleased to observe high yields of
only the syn-diastereomer under the optimal reaction condi-
tions (3e–3j). The syn selectivity of the reaction was estab-
lished by analysis of the X-ray crystal structure of 3i. Notably,
both diastereomers could be accessed based on the stereo-
chemistry of the alkene substrate (i.e., E to 1e, Z to 1f), sug-
gesting that this nickel-catalyzed process does not isomerize
the starting material. A pendant phthalimide-protected amine
was also tolerated in the reaction (3i). Interestingly, a cyclo-
pentenyl substrate was viable in the reaction (3j), providing
access to a cyclopentane stereotriad that would otherwise be
difficult to prepare. Given our success with β,γ-
dicarbofunctionalization, we then sought to access γ,δ-
dicarbofunctionalized products by subjecting a pentenoic acid
derived substrate, which contains one additional methylene
spacer, to the reaction conditions; however, in this case we
were only able to detect isomerization and a mixture of dia-
rylation products. This result speaks to the importance of the
5-membered nickelacycle intermediate in productive cataly-
sis.
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10
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Scheme 2. Multi-Gram-Scale Reaction and AQ Removal
Table 3. Alkene Substrate Scope
10 mol% Ni(cod)2
I
2 equiv ZnEt2
O
R3
O
O
O
Et
10 mol% Ni(cod)2
2 equiv Zn(R3)2
O
+
R2
I
Ph
N
AQ
AQ
HO
+
AQ
dioxane, 50 ºC, 12 h
[multi-gram-scale]
H
R1
2h, 2.1 g
82%
R1
R2
N
1a
dioxane, 50 ºC, 12 h
(AQ)
1b–k
3a–k
O
Et
NaOH
Et
AQ
EtOH, reflux
O
Et
O
Et
4, 1.2 g
98%
O
Et
2h
O
Et
AQ
AQ
AQ
AQ
AQ
Ph
Me Me
3a, 68%
Me
[X-ray]
To highlight the practicality of this nickel-catalyzed β,γ-
Br
(±)-3b, 73%
(2:1 d.r.)
(±)-3c, 60%
(5:1 d.r.)
(±)-3d, 56%
(4:1 d.r.)
dicarbofunctionalization reaction, the procedure was carried
out on multi-gram scale to yield 2.1 g of 2h (82%), which was
readily deprotected in nearly quantitative yield to provide 1.2
g of 4 (98%) (Scheme 2).19
O
Et
O
Me
O
Me
O
Me
AQ
AQ
AQ
Me
Et
Me
Me
Et
(±)-3e, 50%
(>20:1 d.r.)
(±)-3f, 71%
(from E)
(>20:1 d.r.)
(±)-3g, 73%
(from Z)
(>20:1 d.r.)
(±)-3h, 72%
(from E)
(>20:1 d.r.)
A plausible mechanism for this nickel-catalyzed β,γ-
dicarbofunctionalization reaction is proposed below (Scheme
3). Initially, the active nickel(0)-species, which could poten-
tially already be bound to the directing group, performs oxi-
dative addition on the aryl iodide. The resulting nickel(II)-
oxidative addition complex coordinates the alkene moiety
and undergoes a regioselective 1,2-insertion to yield 5-
membered, AQ-chelated intermediate A. At this stage, an
organozinc reagent can intercept A in a transmetalation event
O
Me
O
Me
O
Me
AQ
AQ
AQ
NPhth
n-Bu
(±)-3i, 70%
(from E)
(±)-3j, 31%
(from E)
(±)-3k, 45%
(>20:1 d.r.)
[X-ray]
(>20:1 d.r.)
(>20:1 d.r.)
aReaction conditions: 1b–k (0.25 mmol), iodobenzene (0.5
mmol), dialkyl zinc solution (2 equiv). Percentages represent
isolated yields. Stereochemical outcomes were assigned by
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to yield intermediate B, which can then undergo C(sp3)–C(sp3)
* keary@scripps.edu
1
2
3
4
5
6
7
8
reductive elimination to provide the desired product and re-
generate nickel(0) to close the cycle. To gain a better under-
standing of relative rates of the desired three-component
coupling and the potential alternative Negishi coupling reac-
tion, we performed the reaction of 4-iodoanisole and diethyl
zinc in the absence of alkene (see Supporting Information).
The reaction yielded 10% of the Negishi coupling product,
70% iodoarene starting material, and 20% reduced arene.
When a surrogate AQ-based ligand was added, formation of
the reduction byproduct was suppressed, but the Negishi
byproduct was still only formed in 30% yield. These data sug-
gest that under the optimized conditions, Negishi cross-
coupling is substantially slower than the three-component
reaction. The origins of this phenomenon are currently being
probed in more detail.
Author Contributions
‡ J.D and V.T.T. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
9
This work was financially supported by TSRI, Pfizer, Inc., and the
Donald E. and Delia B. Baxter Foundation (Young Faculty Award
to K.M.E.). We thank Prof. Arnold L. Rheingold and Dr. Milan
Gembicky (UCSD) for X-ray crystallographic analysis and Dr. Dee-
Hua Huang and Dr. Laura Pasternack for assistance with NMR
spectroscopy. We further thank Dr. Josep Cornella (Max-Planck-
Institut für Kohlenforschung), Jacob T. Edwards (Baran Lab, TSRI),
and Tyler G. Saint-Denis (Yu lab, TSRI) for support and encour-
agement.
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Scheme 3. Proposed Catalytic Cycle
REFERENCES
(1) For reviews on transition-metal-catalyzed cross-coupling reac-
tions, see: (a) Johansson-Seechurn, C. C. C.; Kitching, M. O.; Colacot,
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(3) For representative examples of C(sp3)–C(sp3) cross-coupling, see:
(a) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 21,
691–694. (b) Devasagayaraj, A.; Studemann, T.; Knochel, P. Angew.
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S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. Science 2016, 352,
801–805.
In conclusion, we have developed a highly regioselective,
three-component conjunctive cross-coupling between or-
ganozinc nucleophiles, aryl electrophiles, and non-conjugated
terminal and internal alkenes by employing a removable bi-
dentate AQ directing group. By utilizing the chelation control
imparted by the AQ auxiliary, the putative nickel(II) interme-
diate was stabilized to enable C(sp3)–C(sp3) cross-coupling
without significant β-hydride elimination, providing a power-
ful strategy for β,γ-dicarbofunctionalization. The reaction was
found to proceed with a broad range of aryl electrophiles and
tolerated both alkyl and aryl nucleophiles. After the reaction,
the AQ group could be easily removed via hydrolysis, illustrat-
ing the potential utility of this method for practitioners. Fu-
ture work will seek to elucidate the reaction mechanism and
to expand the nucleophile and electrophile is currently un-
derway and will be reported in due course.
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trophiles, see: (a) Owston, N. A.; Fu, G. C. J. Am Chem. Soc. 2010,
132, 11908–11909. (b) Lu, Z.; Wilsily, A.; Fu, G. C. J. Am. Chem. Soc.
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R.; Fu, G. C. Adv. Synth. Catal. 2004, 346, 1525–1532. (b) Frisch, A. C.;
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Chierchia, M. P.; Morken, J. P. Science 2016, 351, 70–74. During
preparation of this manuscript, an example of reductive 1,2-
dicarbofunctionalization of alkenes was reported: (b) García-
Domínguez, A.; Li, Z.; Nevado, C. J. Am. Chem. Soc. 2017, 139, 6835–
6838
(7) For syn- or anti-selective carboboration of styrenyl alkenes, see:
Logan, K. M.; Smith, K. B.; Brown, M. K. Angew. Chem. Int. Ed. 2015,
54, 5228–5231.
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G.; Ma, S. Angew. Chem. Int. Ed. 2009, 48, 2788–2791.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental details, graphical guide, analytical data for
1
new compounds, copies of H and 13C NMR spectra, etc.
(PDF)
NMR Spectra (MNova format) (ZIP)
X-ray crystallographic data for 3c (CIF)
X-ray crystallographic data for 3i (CIF)
AUTHOR INFORMATION
Corresponding Author
(9) Liao, L.; Jana, R.; Urkalan, K. B.; Sigman, M. S. J. Am. Chem. Soc.
2011, 133, 5784–5787.
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Journal of the American Chemical Society
(10) (a) Zhou, C.; Emrich, D. R.; Larock, R. C. Org. Lett. 2003, 5, 1579–
Chatani, N. J. Org. Chem. 2014, 79, 11922–11932. (c) Aihara, Y.;
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(11) Urkalan, K. B.; Sigman, M. S. Angew. Chem. Int. Ed. 2009, 48,
3146–3149.
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2001, 123, 5374–5375. (b) Powell, D. A.; Maki, T.; Fu, G. C. J. Am.
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(13) (a) Cong, H.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 3788–3791.
(b) You, W.; Brown, M. K. J. Am. Chem. Soc. 2014, 136, 14730–14733.
(c) You, W.; Brown, M. K. J. Am. Chem. Soc. 2015, 137, 14578–14581.
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(18) With an enantiopure sample of 3d, no evidence of epimerization
was found during the reaction (see Supporting Information)
(19) With more hindered substrates, such as 3c, this hydrolysis pro-
cedure led to erosion of d.r. and low conversion to product. An alter-
native protocol using Cp2ZrHCl to reduce the AQ amide to the corre-
sponding aldehyde was found to be effective, though partial epimer-
ization was observed (see Supporting Information). For previous use
of this method, see: Chapman, L. M.; Beck, J. C.; Wu, L.; Reisman, S.
E. J. Am. Chem. Soc. 2016, 138, 9803–9806
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Am. Chem. Soc. 2011, 133, 14952–14955. (b) Yokota, A.; Aihara, Y.;
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