Catalytic enantioselective synthesis of carbocyclic and heterocyclic spiranes: Via a decarboxylative aldol cyclization

Article abstract of DOI:10.1039/d0sc02366c

The synthesis of a variety of enantioenriched 1,3-diketospiranes from the corresponding racemic allyl β-ketoesters via an interrupted asymmetric allylic alkylation is disclosed. Substrates possessing pendant aldehydes undergo decarboxylative enolate forma

Full text of DOI:10.1039/d0sc02366c

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COMMUNICATION
Catalytic Enantioselective Synthesis of Carbocyclic and
Heterocyclic Spiranes via a Decarboxylative Aldol Cyclization
Kazato Inanaga,† Marco Wollenburg, † Shoshana Bachman, Nicholas J. Hafeman, and Brian M.
Stoltz*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
building blocks. Of particular interest are spirocylic compounds
bearing a chiral, quaternary carbon as the spiro atom. Due to the
difficulty associated with the enantioselective preparation of all-
carbon quaternary centers,4 and the added challenge of
spirocyclization, a catalytic asymmetric approach to these ring
systems represents a significant challenge for modern, asymmetric
catalysis.
The synthesis of a variety of enantioenriched 1,3-diketospiranes
from the corresponding racemic allyl
b
-ketoesters via an
interrupted asymmetric allylic alkylation is disclosed.
Substrates possessing pendant aldehydes undergo
decarboxylative enolate formation in the presence of a
chiral Pd catalyst and subsequently participate in an
enantio- and diastereoselective, intramolecular aldol
One particularly interesting and underexplored subclass of
spirocyclic compounds are 1,3-diketospiranes such as those shown
in Figure 1A. While the preparation of racemic 1,3-diketospiranes
such as 1-5 is known and relatively straightforward,5 these scaffolds
are significantly more difficult to prepare as single enantiomers.6
Depending upon the identity of each of the rings within the
spirocyclic framework, these compounds can possess either axial
(e.g. 1 and 3, Fig 1B) or point chirality. Previous enantioselective
routes to these motifs have relied almost exclusively on chiral
resolution technology or chiral auxiliaries to prepare
enantioenriched samples of 1–5, with only 2 examples of asymmetric
catalysis being utilized in the context of the synthesis of these
compounds.6c,6h
reaction to furnish spirocyclic
b
-hydroxy ketones which
may be oxidized to the corresponding enantioenriched
diketospiranes. Additionally, this chemistry has been
extended to -allylcarboxy lactam substrates leading to a
a
formal synthesis of the natural product (–)-isonitramine.
The enantioselective construction of spirocyclic compounds remains
an enduring challenge in organic synthesis, and has been the subject
of intensive investigation in recent years.1 Owing to their prevalence
in bioactive natural products and privileged ligand scaffolds, as well
as their potential in drug discovery, methods for the stereoselective
preparation of these unique motifs represent powerful technologies
in synthetic chemistry.2,3 At present, there are few reliable methods
for the direct catalytic, enantioselective synthesis of these valuable
A
O
O
O
Via:
PdIILX
n
O
Pd(OAc)2
A
O
O
O
O
PPh3, MeCN
OH
n
n
CHO
n
n
CHO
ref. 9
O
O
O
B
1
2
3
(n = 1)
(n = 2)
4
(n = 1)
O
O
5 (n = 2)
O
1. Pd(OAc)2, L*
Brønsted acid
2. Oxidation
This Research:
enantioselective
construction of
all- carbon quaternary
spiro centers
n’
B
O
O
O
No reports of direct
access via asymmetric
catalysis
n
n
O
CHO
n’
O
O
Axial Chirality
Point Chirality
Figure 2. A) Previously reported example of an interrupted allylic
alkylation reaction. B) Development of an enantioselective variant,
and application to the synthesis of 1,3-diketospiranes.
Figure 1. Examples of 1,3-diketospiranes and their stereochemical
properties.
Given our laboratory’s longstanding focus on the development of
catalytic methods for the asymmetric a-functionalization of carbonyl
compounds for the synthesis of quaternary centers, in addition to the
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lack of currently available stereoselective methods for the synthesis
Journal Name
After surveying a variety of Brønsted acids, we found that
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DOI: 10.1039/D0SC02366C
of 1,3-diketospiranes, we became interested in targeting this class of phenols performed best, with 3,5-dimethylphenol providing the
molecules.7,8 As an inspiration, we turned to a seminal report by Tsuji highest combination of yield and enantioselectivity. Thus, the use of
and coworkers (Figure 2A) detailing a palladium-catalyzed aldol Pd(OAc)2 (10 mol %) with (S)-t-Bu-PHOX and 3,5-dimethylphenol as
reaction via decarboxylative enolate formation and subsequent the Brønsted acid in 1,4-dioxane (0.1 M) at 40 °C proved optimal
intramolecular trapping with a pendant aldehyde. Given our
mechanistic understanding of related asymmetric processes wherein
chiral Pd-enolates have been implicated, we hypothesized that a
chiral Pd-enolate might be able to trap the electrophile in a
stereocontrolled fashion. We envisioned that oxidation of the
resultant b-hydroxyketone would then furnish the desired
enantioenriched 1,3-diketospiranes.
Our study commenced with the development of an
enantioselective variant of Tsuji’s intramolecular aldol reaction.9
After examining a wide variety of Pd precatalysts, chiral ligands, and
solvents (see SI for details), we were delighted to find that exposure
of substrate 2a to Pd(OAc)2 and (S)-t-Bu-PHOX in THF delivered
diastereomeric spirocycles 2b and 2c, albeit in low yield and
moderate diastereo- and enantioselectivity (Table 1, entry 1). Upon
further investigation, we found that the addition of a Brønsted acid
to the reaction is crucial for good yields of the desired spirocyclic
products (Table 1, entries 2,3), and thus reasoned that it must play a
critical role in the reaction mechanism.
(entry 12), furnishing spirocyclic b-hydroxy ketones 2b and 2c in 90%
isolated yield, 85% ee (major diastereomer 2b) in an 85:15 d.r.10
We envision that the catalytic cycle (Figure 3) commences with
oxidative deallylation of b-ketoester 2a by a Pd(0) (M-1) species to
furnish Pd(II) carboxylate M-2. A transmetalation onto Pd(II) species
M-7 generates a new Pd(II) carboxylate (M-4) that can then undergo
rate-limiting decarboxylative enolate formation.11 Enolate M-5 then
undergoes an intramolecular aldol cyclization to Pd(II) alkoxide M-6,
which enantioselectively sets the stereochemistry at the quaternary
spiro atom. At this point, the Brønsted acid (i.e., H+) serves to
protonate the resulting alkoxide, releasing the product (2b), and
regenerating Pd(II) species M-7 while the conjugate base (i.e., A–)
acts as a nucleophile by reductive deallylation of M-3 to regenerate
Pd(0) species M-1.12 This proposed cycle accounts for the critical role
of the Brønsted acid observed in this reaction, as well as the fact that
a Pd(II) precatalyst may be employed. We envision that only a small
excess of phosphine ligand is required to produce a limited amount
of Pd(0) species M-1, to enter the b-ketoester activation cycle.
O
O
O
O
O
O
O
(S)-t-Bu-PHOX (12.5 mol %)
+
O
CHO
*
Pd(OAc)2 (10 mol %)
acid (1.0 equiv)
solvent (0.1 M)
A
OH
OH
N
P
CHO
2a
Pd0
30–32 °C, 13–23 h
A–
2a
2b
2c
M-1
Reductive
deallylation
Oxidative
addition
*
N
O
P
O
Table 1. Optimization of the asymmetric spirocyclization.
+
PdII
*
N
P
O
%
d.r.
%
β-Ketoester
Activation
PdII
entry
acid
solvent
conv.a,b
(b:c)a
eec
CHO
*
1
2
72
(53)
58
(23)
9 (13)
74
(45)
81
(30)
81
(31)
82
(29)
84
(44)
83
(24)
81
(42)
83
(47)
85
none
THF
48
42:58
M-2
M-3
Transmetallation
aniline
THF
THF
THF
>99
>99
–e(77)
69:31
72:28
60:40
N
P
+
O
O
PdII
*
3
Meldrum’s acid
acetic acid
N
P
4d
OAc
O
O
PdII
OAc
5
CHO
phenol
thymol
THF
THF
THF
THF
THF
THF
THF
71
>99
>99
>99
76
74:26
76:24
67:33
41:59
63:37
74:26
75:25h
85:15h
M-7
OH
M-4
6
Decarboxylative
enolate formation
2b
Protonation
7
CO2
2-methoxyphenol
H+
8
2,6-
Aldol Cyclization
dimethoxyphenol
3,5-
dimethoxyphenol
9
*
*
N
O
P
N
P
O
PdII
10
11f
12f,g
PdII
3,5-dimethylphenol
3,5-dimethylphenol
3,5-dimethylphenol
68
OAc
O
OAc
–e(91)
CHO
M-6
1,4-
dioxane
–e(90)
Intramolecular
aldol
(73)
M-5
aDetermined by GC unless otherwise noted. Parenthetical value is
yield of isolated product. cDetermined by SFC after transformation to
benzoyl ester; parenthetical value is ee of minor diastereomer.
dReaction performed for 37 h. eConsumption of 6a was monitered by
TLC. fReaction performed at 40 °C. g15 mol % ligand. hDetermined by
1H NMR.
b
Figure 3. Mechanistic proposal including Brønsted acid-mediated
catalyst turnover (A- represents conjugate base of the Brønsted acid
additive).
2 | J. Name., 2012, 00, 1-3
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With optimal conditions for the spirocyclization in hand, we next
turned our attention to the application of this reaction toward the
synthesis of various 1,3-diketospiranes. Cyclic allyl b-ketoesters of
varying core ring sizes possessing aldehydes with different tether
lengths were synthesized and subjected to the optimized
spirocyclization conditions. We found that the conditions developed
performed generally well across various ring sizes and tether lengths
providing spirocyclic b-hydroxyketones in high yields and with high
enantioselectivity, albeit with moderate diastereoselectivity. The
diastereomeric mixtures obtained were generally difficult to
enantioenriched 1,3-diketospiranes. Importantly, following
oxidation, the modest diastereomeric mixtures converged to
enantioenriched diketones, demonstrating that the primary
enantiocontrol is occurring at the quaternary center by
differentiation of the enantiotopic faces of the enolate.
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DOI: 10.1039/D0SC02366C
Additionally, recrystallization of spiro[4.4]nonanedione
1 and
spiro[5.5]undecanedione in hexanes provided these products
3
in excellent levels of enantioenrichment (94% and 95% ee,
respectively). The relative configurations of the spiro
b
-hydroxyketone diastereomers 1b/c, 2e/f, and 3b/c (Table 2,
entries 1,2 and 4) were determined by comparing chemical
shifts to literature values,6f while absolute configuration of the
O
1. (S)-t-Bu-PHOX, Pd(OAc)2
3,5-Me2C6H3OH
O
O
m
quaternary carbon atom in
1 and 2 (entries 1 and 2) was
1,4-dioxane, 35–40 °C
O
determined by comparing optical rotations with reported
2. DMP, CH2Cl2, 23 °C
n
m
literature values.6a,6f
n
O
CHO
1–4a, 2d
1–4
O
O
O
O
Pd(OAc)2
(S)-t-Bu-PHOX
Table 2. Enantioselective synthesis of 1,3-diketospiranes.
m
m
+
BzN
BzN
BzN
O
3,5-Me2C6H3OH
1,4-dioxane
35–40 °C
n
n
aldol
product
%
yield
oxidized
productb
%
yield
m
n
HO
7–10b
HO
7–10c
entry
d.r.a
% eec
83 (95)d
73
CHO
7–10a
Table 3. Enantioselective synthesis of spirocyclic β-hydroxy lactams.
O
O
%
yield
% eea
of b,c
entry
products
d.r. (b:c)
50:50
1
2
3
4
5
6
7
77
84
90
82
92
76
94
72:28
67:33
85:15
76:24
66:34
67:33
62:38
88
88
93
82
O
HO
1
1b
O
O
O
O
BzN
BzN
1
2
94
55, 31
77, 32
HO
HO
O
HO
7b
O
7c
O
2
2e
O
O
BzN
BzN
87
67:33
84
O
HO
8b
HO
8c
OH
2
2b
3b
4b
5b
O
O
O
O
3b
91
78:22
89, 79
93, 69
84 (94)d
BzN
BzN
OH
OH
O
OH
3
9b
9c
O
O
O
O
BzN
BzN
4
93
58:42
93
81
OH
O
OH
OH
10b
10c
4
O
aDetermined by SFC. bThymol used as Brønsted acid.
84e
– –
– –
OH
Given the success of our protocol for the synthesis of 1,3-
diketospiranes, we next became interested in expanding the scope
of this procedure for the preparation of other spirocyclic 1,3-
dicarbonyl systems. As N-protected lactams have previously been
shown to perform exceptionally well in our Pd-catalyzed asymmetric
allylic alkylation reactions,8c and owing to the prevalence of N-
heterocyclic spirocycles in natural products and bioactive molecules,
we turned our attention to this class of substrates.
O
72f
– –
– –
OH
6b
aDetermined by 1H NMR. bOxidized with DMP. cDetermined by chiral
d
e
GC. After recrystallization from hexane. Determined by SFC after
transformation to benzoyl ester. fDetermined by SFC.
Gratifyingly, we found that, after switching to acetic acid as the
Brønsted acid, aldehyde-containing N-benzoyl lactams 7a-10a (Table
separate by flash chromatography, and thus, these mixtures
were treated directly with DMP to furnish the desired 3) proved competent substrates for our spirocyclization protocol.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Lactam substrates generally furnish outstanding yields of
diastereomeric mixtures of spirocyclic β-hydroxy lactams in up to
78:22 dr. Importantly, the diastereomers of this substrate class are
readily separable by flash column chromatography on silica. While
the pyrrolidinone substrates provide the corresponding
azaspirocycles 7b/c and 8b/c in high yield, the dr’s and ee’s are
diminished (entries 1 and 2). By contrast, the major diastereomers of
the 6,5-azaspirocycle 9b (entry 3) and the 6,6-azaspirocycle 10b
(entry 4) could be prepared with excellent ee, while the minor
diastereomers 9 and 10c were obtained in only moderate ee.
Conflicts of interest
The authors declare no conflicts of interest.
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DOI: 10.1039/D0SC02366C
Acknowledgements
The authors wish to thank NIH-NIGMS (R01GM080269), Astellas
Pharma, Inc. (postdoctoral fellowship to K.I.), the Alfried Krupp von
Bohlen and Halbach Foundation (fellowship to M.W.) and Amgen,
Inc. (graduate fellowship to S.B.). We also thank Dr. Scott C. Virgil for
his support with chromatographic analysis, high-resolution mass
analysis, and assistance during the crystallization process.
Debenzoylation of 6,6-azaspirocycle 10b furnishes lactam 13, a
synthetic intermediate previously employed in the synthesis of the
alkaloid (–)-isonitramine8f,13 thus completing
a
7-step
1
For reviews of enantioselective synthesis of spirocyclic compounds, see: a) R.
Rios, Chem. Soc. Rev., 2012, 41, 1060; b) A. K. Franz, N. V. Hanhan, N. R. Ball-
Jones, ACS Catal., 2013, 3, 540; c) N. R. Ball-Jones, J. J. Badillo, A. K. Franz, Org.
Biomol. Chem., 2012, 10, 5165; d) B. M. Trost, M. Brennan, Synthesis, 2009, 18,
3003; e) D. Cheng, Y. Ishihara, B. Tan, C. F. Barbas, III; ACS Catal., 2014, 4, 743.
For general reviews of synthetic strategies toward spirocycles, see: a) L. K.
Smith, I. R. Baxendale, Org. Biomol. Chem., 2015, 13, 9907; b) A. P. Krapcho,
Synthesis, 1974, 6, 383; c) M. Sannigrahi, Tetrahedron, 1999, 55, 9007; d) R.
Pradhan, M. Patra, A. K. Behera, B. K. Mishra, R. K. Behera, Tetrahedron, 2006,
62, 779; e) C. V. Galliford, K. A. Scheidt, Angew. Chem. Int. Ed., 2007, 46, 8748;
f) S. Kotha, A. C. Deb, K. Lahiri, E. Manivannan, Synthesis, 2009, 2, 165; g) C.-X.
Zhuo, C. Zheng, S.-L. You, Acc. Chem. Res., 2014, 47, 2558; h) V. A. D’yakonov,
O. A. Trapeznikova, A. de Meijere, U. M. Dzhemilev, Chem. Rev., 2014, 114,
5775.
enantioselective synthesis of this natural product (Scheme 1).
Furthermore, the stereochemistry of 13 (and thus of 10b) could be
confirmed by chemical correlation with this known intermediate
(Scheme 1). The absolute and relative stereochemistry of all other
azaspirocycles has been determined in analogy to compound 8b
(Table 3, entry 2), which was determined by X-ray diffraction.
2
Scheme 1. Formal synthesis of (–)-isonitramine.
1.
OEt
1. n-BuLi, THF
–78 °C, then
BzCl
O
O
O
Br
OEt
3
4
For synthesis of selected spirocyclic natural products, see: a) A. Lerchner, E. M.
Carreira, J. Am. Chem. Soc., 2002, 124, 14826; b) B. M. Trost, M. K. Brennan Org.
Lett., 2006, 8, 2027; c) T. Doi, Y. Iijima, M. Takasaki, T. Takahashi J. Org. Chem.,
2007, 72, 3667.
t-BuOK, PhMe, 80 °C
HN
BzN
O
2. LDA, THF
–78 °C, then
O
2. HCl, acetone/H2O
0 – 23 °C
69% yield over
2 steps
11
12
N
O
For reviews of enantioselective synthesis of quaternary all-carbon
stereocenters, see: a) K. Fuji, Chem. Rev., 1993, 93, 2037; b) E. J. Corey, A.
Guzman-Perez, Angew. Chem. Int. Ed., 1998, 37, 388–401; c) J. Christoffers, A.
Mann, Angew. Chem. Int. Ed., 2001, 40, 4591; d) I. Denissova, L. Barriault,
Tetrahedron, 2003, 59, 10105; e) C. J. Douglas, L. E. Overman, Proc. Natl. Acad.
Sci. U. S. A., 2004, 101, 5363; f) J. Christoffers, A. Baro, Adv. Synth. Catal., 2005,
347, 1473; g) B. M. Trost, C. Jiang, Synthesis, 2006, 3, 369; h) P. G. Cozzi, R.
Hilgraf, N. Zimmermann, Eur. J. Org. Chem., 2007, 2007, 5969; i) J. Prakash, I.
Marek, Chem. Commun., 2011, 47, 4593; j) K. W. Quasdorf, L. E. Overman,
Nature, 2014, 516, 181; k) Y. Liu, S.-H. Han, W.-B. Liu, B. M. Stoltz, Acc. Chem.
Res., 2015, 48, 740; l) J. Feng, M. Holmes, M. J. Krische, Chem. Rev., 2017, 117,
12564; m) D. Pierrot, I. Marek, Angew. Chem. Int. Ed., 2019, 59, 36.
For examples of racemic syntheses of 1,3-diketospiranes, see: a) H. Gerlach, W.
Muller, Angew. Chem. Int. Ed., 1972, 11, 1030; b) T. N. Wheeler, C. A. Jackson,
K. H. Young, J. Org. Chem., 1973, 39, 1318; c) W. Carruthers, A. Orridge, J. Chem.
Soc. Perkin Trans. 1, 1977, 21, 2411.
For preparations of enantioenriched 1,3-diketospiranes, see: a) H. Gerlach,
Helv. Chim. Acta, 1968, 51, 1587; b) E. G. E. Hawkins, R. Large, J. Chem. Soc.
Perkins Trans. 1, 1973, 2169; c) T. Hayashi, K. Kanehira, T. Hagihara, M. Kumada,
J. Org. Chem., 1988, 53, 113; d) R. Brunner, H. Gerlach, Tetrahedron:
Asymmetry, 1994, 5, 1613; e) J. A. Nieman, M. Parvez, B. A. Keay, Tetrahedron:
Asymmetry, 1993, 4, 1973; f) H. Suemune, K. Maeda, K. Kato, K. Sakai, J. Chem.
Soc. Perkin. Trans. 1, 1994, 3441; g) Z. Han, Z. Wang, K. Ding, Adv. Synth. Catal.,
2011, 353, 1584; h) H. Tsukamoto, A. Kawase, T. Doi, Chem. Commun., 2015, 51,
8027.
N
ref. 12
O
O
O
Pd(OAc)2 (10 mol %)
(S)-t-Bu-PHOX (15 mol %)
BzN
O
BzN
thymol, 1,4–dioxane, 40 °C
CHO
OH
54% yield, 93% ee
10a
10b
O
NH3 (aq.)
THF
LAH
HN
HN
THF
OH
OH
(–)-isonitramine
ref. 13a
95% yield
5
6
13
In conclusion, we have reported a catalytic, enantioselective
method for the construction of spirocyclic compounds containing all-
carbon quaternary centers. This transformation provides
unprecedented access to enantioenriched 1,3-diketospiranes of
several sizes as well as spirocyclic b-hydroxy lactams which are useful
for natural product synthesis, as evidenced by our application of this
chemistry to the synthesis of (–)-isonitramine in 7 steps from
commercially available starting materials. We envision that this
method will be applicable to a wide range of potential target
molecules, as well as provide access to a variety of valuable chiral
building blocks.
7
For accounts and reviews of palladium-catalyzed allylic alkylation chemistry,
see: a) B. M. Trost, D. L. Van Vranken, Chem. Rev., 1996, 96, 395; b) B. M. Trost,
Acc. Chem. Res., 1996, 29, 355; c) G. Helmchen, J. Organomet. Chem., 1999, 576,
203; d) B. M. Trost, Chem. Pharm. Bull., 2002, 50, 1; e) T. Gräning, H.-G. Schmalz,
Angew. Chem. Int. Ed., 2003, 42, 2580; f) B. M. Trost, J. Org. Chem., 2004, 69,
5813; g) S.-L. You, L.-X. Dai, Angew. Chem. Int. Ed., 2006, 45, 5246; h) J. T. Mohr,
B. M. Stoltz, Chem. Asian J., 2007, 2, 1476; i) Z. Lu, S. Ma, Angew. Chem. Int. Ed.,
2008, 47, 258; j) D. C. Behenna, J. T. Mohr, N. H. Sherden, S. C. Marinescu, A. W.
Harned, K. Tani, M. Seto, S. Ma, Z. Novák, M. R. Krout, R. M. McFadden, J. L.
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Roizen, J. A. Enquist, Jr., D. E. White, S. R. Levine, K. V. Petrova, A. Iwashita, S. C.
Virgil, B. M. Stoltz, Chem. Eur. J., 2011, 17, 14199; k) J. D. Weaver, A. Recio, III,
A. J. Grenning, J. A. Tunge, Chem. Rev., 2011, 111, 1846; l) A. Y. Hong, B. M.
Stoltz, Eur. J. Org. Chem., 2013, 2013, 2745; m) Y. Liu, S.-J. Han, W.-B. Liu, B. M.
Stoltz, Acc. Chem. Res., 2015, 48, 740.
View Article Online
DOI: 10.1039/D0SC02366C
8
a) D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc., 2004, 126, 15044; b) B. M.
Trost, J. Xu, T. Schmidt, J. Am. Chem. Soc., 2009, 131, 18343; c) D. C. Behenna,
Y. Liu, T. Yurino, J. Kim, D. E. White, S. C. Virgil, B. M. Stoltz, Nat. Chem., 2012,
4, 130; d) C. M. Reeves, C. Eidamshaus, J. Kim, B. M. Stoltz, Angew. Chem. Int.
Ed., 2013, 52, 6718; e) K. M. Korch, C. Eidamshaus, D. C. Behenna, S. Nam, D.
Horne, B. M. Stoltz, Angew. Chem. Int. Ed., 2015, 54, 179; f) Y. Numajiri, B. P.
Pritchett, K. Chiyoda, B. M. Stoltz, J. Am. Chem. Soc., 2015, 137, 1040; g) R. A.
Craig, II, S. A. Loskot, J. T. Mohr, D. C. Behenna, A. M. Harned, B. M. Stoltz, Org.
Lett., 2015, 17, 5160.
9
J. Nokami, T. Mandai, H. Watanabe, H. Ohyama, J. Tsuji, J. Am. Chem. Soc., 1989,
111, 4126.
10 See Supporting Information for experimental details, full optimization of the
reaction conditions, and the synthesis of substrates.
11 N. H, Sherden, D. C. Behenna, S. C. Virgil, B. M. Stoltz, Angew. Chem. Int. Ed.,
2009, 48, 6840.
12 Varying amounts of the corresponding allyl phenyl ether have been observed
and isolated suggesting that allylic alkylation of the phenol is the terminal fate
of the allyl unit in these catalytic reactions.
13 M. Keppens, N. De Kimpe, J. Org. Chem., 1995, 60, 3916.
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