Palladium-Catalyzed Enantioselective Redox-Relay Heck Arylation of 1,1-Disubstituted Homoallylic Alcohols

Article abstract of DOI:10.1021/jacs.6b06994

An enantioselective redox-relay oxidative Heck arylation of 1,1-disubstituted alkenes to construct β-stereocenters was developed using a new pyridyl-oxazoline ligand. Various 1,2-diaryl carbonyl compounds were readily obtained in moderate yield and good to excellent enantioselectivity. Additionally, analysis of the reaction outcomes using multidimensional correlations revealed that enantioselectivity is tied to specific electronic features of the 1,1-disubstituted alkenol and the extent of polarizability of the ligand.

Full text of DOI:10.1021/jacs.6b06994

Subscriber access provided by Northern Illinois University
Communication
Palladium-Catalyzed Enantioselective Redox-Relay Heck
Arylation of 1,1-Disubstituted Homoallylic Alcohols
Zhi-Min Chen, Margaret J Hilton, and Matthew S Sigman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b06994 • Publication Date (Web): 29 Aug 2016
Downloaded from http://pubs.acs.org on August 29, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Zhi-Min Chen, Margaret J. Hilton, and Matthew S. Sigman*
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
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
E-mail: sigman@chem.utah.edu
elimination. Specifically, β-hydride elimination of HS (Hstyrenyl
)
would yield the traditional Heck product, trisubstituted styrene
B, or β-hydride elimination of HR (Hrelay) would ultimately lead
to the desired aldehyde compound. The styrenyl product is not
only thermodynamically more stable but is also historically
formed using terminal alkenes under similar conditions.10 Here-
in, we present the development of a successful enantioselective
redox-relay Heck reaction of 1,1-homoallylic alcohols forming
the desired 1,2-diaryl structures. This outcome required the use
of a new pyridyl-oxazoline (PyrOx) ligand to overcome the
propensity of trisubstituted-styrene formation and achieve high
enantioselectivity with this new alkene class.
ABSTRACT: An enantioselective redox-relay oxidative Heck
arylation of 1,1-disubstituted alkenes to construct β-
stereocenters was developed using a new pyridyl-oxazoline
ligand. Various 1,2-diaryl carbonyl compounds were readily
obtained in moderate yield and good to excellent enantioselec-
tivity. Additionally, analysis of the reaction outcomes using
multidimensional correlations revealed that enantioselectivity
is tied to specific electronic features of the 1,1-disubstituted
alkenol and the extent of polarizability of the ligand.
Molecules containing a 1,2-diaryl motif are a common scaffold
in various medicinally relevant molecules. For example, several
1,2-diaryl compounds target vitronectin receptor antagonists,
implicated in the treatment of osterporosis and breast cancer, and
the urokinase receptor, an important cell surface GPI-anchored
protein suggested to promote tumor metastasis (Figures 1a).1
Accordingly, various synthetic methods have been developed,
including benzylation of cinnamyl compounds,2 diarylation of
alkenes,3 isomerization of trisubstituted styrene alcohols,4 and
arylation of tert-cyclobutanols via C‒C bond cleavage.5 Despite
these advances, catalytic enantioselective variants to access 1,2-
diaryl carbonyl compounds are rare and suffer from limited
substrate scope.6 We saw this dearth of examples as an
opportunity to explore our recently developed enantioselective
redox-relay Heck reaction of multi-substituted alkenols on 1,1-
disubstituted alkenes (Figure 1b).7,8 Successful development of
such a protocol would provide direct and modular access to
enantiomerically enriched 1,2-diaryl carbonyl structures.
Table 1. Optimization.a
Figure 1. Effective drug candidates containing 1,2-diaryl motifs
and proposed strategy.
aEach entry represents the isolated yield on 0.3 mmol scale at rt and
used 3.0 equivs of p-chlorophenylboronic acid unless otherwise noted.
Er values were determined by SFC. b The reaction was performed at
10 C.
On the basis of our previous success, chiral PyrOx ligand L1
was first examined with Pd(CH3CN)4(OTf)2 as a precatalyst under
standard redox-relay oxidative Heck conditions7c using 1,1-
disubstituted alkene 1a and p-chlorophenylboronic acid as model
coupling partners. When DMF was used as solvent, the desired
relay product (2e) was only produced in 24% yield and a disap-
pointing 69.5:30.5 er (entry 1). The mass balance was a combina-
tion of unreacted starting material and the traditional Heck
product. To improve the reaction outcome, we evaluated several
PyrOx ligands with modifications (entries 2-4) to the oxazoline
portion. By incorporating aryl groups into the ligand structure,
potential involvement of noncovalent π interactions between the
ligand substituent and the substrate became evident. A considera-
ble enhancement was observed using ligand L4 (89:11 er) in com-
parison to L1 (69.5:30.5 er), which lacks an aryl group (a putative
explanation is discussed below). In further optimization of the
In contrast to our previous reports, initial migratory insertion
of the Pd-Ar species into 1,1-disubstituted alkenols forms a new
C‒C bond at the terminal position of the alkene, and the chiral
center is established β-to this site (A, Figure 1b).9 A central
concern for this substrate class involves selective β-hydride
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
1
2
3
4
5
6
reaction conditions, solvent proved the most important variable as
taining a secondary alcohol gave 95.5:4.5 er, although in lower
yield than observed with a primary alcohol (2aa compared to 2e).
illustrated with initial identification of MeOH as the reaction sol-
vent (entries 7-8). Ultimately, a combination of MeOH and MTBE
provided the best results in terms of both yield and enantioselec-
tivity, yielding product 2e in 63% and 95.5:4.5 er (entry 9).
Table 3. Scope of the Homoallylic Alcoholsa
Using these optimal conditions, the reaction scope was explored
with a number of arylboronic acids (Table 2). In general, the de-
sired 1,2-diaryl carbonyl compounds were obtained with moderate
yields and good to excellent enantiomeric ratios. Again, the mass
balance was mainly composed of the traditional Heck product.
Compared with p-chlorophenylboronic acid (2e), the use of elec-
tron-rich arylboronic acids decreased the yield and the enantiose-
lectivity (2a, 2b), while electron-withdrawing groups in the meta-
or para-position did not have a significant effect (2c-h). This is
consistent with a greater propensity for β-hydride elimination at
HS with adjacent electron-rich arenes observed previously in our
lab.4c,10 Substituents at the ortho-position led to a modest reduc-
tion in enantioselectivity (2i, 2j). Finally, multi-substituted aryl-
boronic acids were tested in this reaction (2j-o). In particular, the
use of 3,5-dichlorophenylboronic acid afforded the desired prod-
uct 2m in 98:2 er. It should also be noted that a simple heteroaro-
matic boronic acid, 2-dibenzofuranyl, was successfully incorpo-
rated, providing the corresponding product 2o in 52% yield and
93:7 er. However, other Lewis basic boronic acids were incompat-
ible under these reaction conditions.11
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
Table 2. Arylboronic Acid Scopea
a
Ar = p-chlorophenyl. Each entry represents the isolated yield on 0.3
mmol scale and used 3.0 equivs of arylboronic acid. Er values were
determined by SFC. bOn 3 mmol scale, 2q was isolated in 55% yield
and 95.5:4.5 er. cPhenylboronic acid was used. dThe absolute
configuration was determined to be (R) and thus the rest of the prod-
ucts, except 2ac and 2ad, were assigned as (R) by analogy. The abso-
lute configuration of 2ad was determined to be (S) and thus 2ac was
assigned as (S) by analogy.12
Table 4. Chain-Length Effecta
a
Ar = p-chlorophenyl. Each entry represents the isolated yield on 0.3
mmol scale and used 3.0 equivs of p-chlorophenylboronic acid. Er
values were determined by SFC.
a
Ar2 = p-tolyl. Each entry represents the isolated yield on 0.3 mmol
scale and used 3.0 equivs of arylboronic acid. Er values were
determined by SFC.
As the enantiodetermining step is likely migratory insertion of
the alkene (C to D, Figure 1b),9a we hypothesized that the reaction
of an 1,1-disubstituted alkene with two similar alkyl substituents
would lead to low enantioselectivity due to a difficult differentia-
tion of the substituents by the catalyst. Indeed, when alkyl-
substituted alkenols were explored, the corresponding products
were obtained with poor er and opposite face selection (2ad-ae).
Additionally, if the aryl group is not in conjugation with the al-
kene, low enantioselectivity was observed (2ac).
Next, substituent effects on the alkenol (1) were evaluated un-
der the standard reaction conditions (Table 3). The electronic na-
ture of para-substituents on the styrenyl moiety had a greater in-
fluence on the enantioselectivity than was observed with substitut-
ed arylboronic acids. In this case, electron-donating groups led to
higher enantioselectivity (2q-t). Unfortunately, an ortho-fluorine
was not well-tolerated, resulting in a significant decrease in yield
and enantioselectivity (2v). It is noteworthy that a substrate con-
2
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
In our previous redox-relay Heck reports, the chain length
enantioselectivity, through linear regression modeling techniques.
When analyzing the effect of substrate identity on the
enantioselectivity in this reaction, a correlation was identified with
three terms: the alkene C=C vibration (νC=C), the O‒H stretching
frequency (νO-H), and the NBO charge of the allylic carbon
(NBOallyl-C, Figure 2a). The electronic nature of the alkene,
modulated by the variable substituent, is likely described using the
alkene stretching frequency, νC=C, and thus plays a crucial role in
the alkene face selection and enantiodetermining step. The chain
length effect can be expressed using νO-H, as demonstrated by the
univariate correlation of this parameter to the enantioselectivities
of products 2p and 2ag-ai (R2 = 0.91, Figure 2b). As this
stretching frequency decreases based on the distance between the
alcohol and the alkene, the observed enantioselectivities also
decrease. A similar trend between the enantioselectivities of these
products with varying chain lengths and NBOallyl-C was also iden-
tified with increasingly negative charge of the allylic carbon corre-
lating with higher enantioselectivity (R2 = 0.92, Figure S6). Both
of these trends suggest that the polarization of the alkyl chain due
to the distance between the alcohol and the alkene is partially
responsible for face discrimination of the substrate that is required
for an enantioselective migratory insertion. We proposed a similar
hypothesis in rationalizing site selectivity trends in the redox-relay
Heck reaction of 1,2-disubstituted alkenols.7b,9a Further, these
trends could also indicate that the electronic and geometric nature
of the alcohol itself is an important element for catalyst recogni-
tion. Overall, identifying these trends revealed several inherent
properties of the alkenol, including the electronic character of the
alkene and the alcohol, that are required for high er.
between the alcohol and the alkene minimally influenced the
enantioselectivity, albeit none of these examples were styrenyl in
nature and used ligand 1 exclusively. Therefore, the profound
effect of chain length on enantioselectivity in this system was
surprising (Table 4). The bis-homoallylic alcohol substrate 1af
delivered desired product 2af in 51% yield and 88.5:11.5 er, a
significantly diminished result as compared to the model
homoallylic substrate (1p). The yields and enantioselectivities
continued to decrease as a function of increasing chain length
(2ag, 2ah).
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
As the primary goal was to synthesize 1,2-diaryl compounds as
described in Figure 1, we focused on the functionalization of
homoallylic alcohols. Nonetheless, the observed product enanti-
oselectivities with longer chain lengths are disappointing from the
perspective of broadening the scope of the reaction. In order to
facilitate a deeper understanding of the limitations of this system
and potentially lend insight to future solutions, analysis of the data
sets in terms of both the substrate and ligand effects on
enantioselectivity was performed.
Figure 2. a) Multidimensional correlation of substrate properties
and enantioselectivities (Leave-K-Out (LKO), K=6). b) Univariate
trend between the chain length and the alcohol stretching fre-
quency. c) Multidimensional correlation of ligand effects and en-
antioselectivies (Leave-One-Out (LOO)).
To gain further insight into this process, the focus shifted to
identifying the subtle structural effects of the ligand on the
enantiodetermining step in this reaction. Using the same modeling
strategy, properties of seven ligands with changes to the oxazoline
were related to the measured enantioselectivities. An excellent
correlation was identified with two terms: an IR intensity of a
specific ring vibration on the pyridine (Iring 3) and the ligand’s
computed polarizability (polar, Figure 2c). Upon closer
examination of the corresponding ring stretch, it was observed that
the C–C bond between heterocycles and the hydrogens or substit-
uents at C3 are also affected by this stretch. Consequently, the
intensity of this frequency is likely accounting for steric effects as
well as the electronic contributions from the substituents on the
oxazoline. Additionally, the polarizability, or the extent of
electron cloud distortion in the presence of an external electric
field, could represent the ability of the ligand’s substituents to
interact in an attractive manner with the substrate.14 As the
electronic natures of the alkene and the alcohol were identified as
significant influences in enabling a highly enantioselective
method, a positive interaction between the aryl substituent or al-
cohol of the substrate and the ligand, such as a π-stacking or lone
pair-π interaction, is plausible.15 Certain geometric constraints are
also observed within these data, including the requirement of a
styrenyl substrate, homoallylic alcohol and a Ph-substituted
oxazoline for high er values. Since attractive interactions are more
sensitive to the distance between the two interacting species,16
these geometric requisites support the presence of an attractive
noncovalent interaction between the ligand and the substrate. By
combining the insight gained from the substrate and ligand effects
as well as our previous computational report, 9a a working hypoth-
esis on the origin of enantioselectivity is proposed (Figure 3). The
proposed transition state, which would lead to the observed prod-
uct enantiomer, features a lone pair-π interaction between the
A multidimensional modeling strategy developed within our
group was executed.13 Through this iterative process, relevant
molecular descriptors are related to the reaction output,
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
1
2
3
4
5
6
7
8
alcohol and the phenyl group on the ligand.15c This interaction is
consistent with the requirements described above.
gew. Chem., Int. Ed. 2009, 48, 154. (c) Urkalan, B. K.; Sigman, M. S.
Angew. Chem., Int. Ed. 2009, 48, 3146. (d) Rene, O.; Lapointe, D.;
́
Fagnou, K. Org. Lett. 2009, 11, 4560. (e) Stokes, B. J.; Liao, L.; de
Andrade, A. M.; Wang, Q.; Sigman, M. S. Org. Lett. 2014, 16, 4666.
(f) You, W.; Brown, M. K. J. Am. Chem. Soc. 2014, 136, 14730. (g)
Tang, C.; Xie, Z. Angew. Chem., Int. Ed. 2015, 54, 7662. (h) You, W.;
Brown, M. K. J. Am. Chem. Soc. 2015, 137, 14578.
Figure 3. Proposed lone pair-π interaction as a controlling ele-
ment in the transition state.
(4) (a) Li, H.; Mazet, C. Org. Lett. 2013, 15, 6170. (b) Larionov, E.;
Lin, L.; Guenee, L.; Mazet, C. J. Am. Chem. Soc. 2014, 136, 16882.
́
́
9
(5) Ziadi, A.; Martin, R. Org. Lett. 2012, 14, 1266.
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
(6) (a) Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc., 1996, 118,
12218. (b) Bull, S. D.; Davies, S. G.; Nicholson, R. L.; Sanganee, H.
J.; Smith, A. D. Org. Biomol. Chem. 2003, 1, 2886. (c) Li, T.; Zhu, J.;
Wu, D.; Li, X.; Wang, S.; Li, H.; Li, J.; Wang, W. Chem.–Eur. J.
2013, 19, 9147. (d) Dell'Amico, L.; Companyó, X.; Naicker, T.;
Bräuer, T. M.; Jørgensen, K. A. Eur. J. Org. Chem. 2013, 5262. (e)
Alonso, D. A.; Kitagaki, S.; Utsumi, N.; Barbas, C. F. Angew. Chem.,
Int. Ed. 2008, 47, 4588. (f) Seo, W. S.; Kim, S. Tetrahedron Lett.
2012, 53, 2809. (g) Izquierdo, J.; Orue, A.; Scheidt, A. K. J. Am.
Chem. Soc. 2013, 135, 10634. (h) Lu, P.; Jackson, J. J.; Eickhoff, J. A.;
Zakarian, A. J. Am. Chem. Soc. 2015, 137, 656. (i) Nishimura, T.;
Matsumura, S.; Maeda, Y.; Uemura, S. Chem. Commun. 2002, 50. (j)
Matsumura, S.; Maeda, Y.; Nishimura, T.; Uemura, S. J. Am. Chem.
Soc. 2003, 125, 8862. (k) Zhang, C.; Yun, J. Org. Lett. 2013, 15, 3416.
(7) For selected our group works, see: (a) Werner, E. W.; Mei, T.-
S.; Burckle, A. J.; Sigman, M. S. Science 2012, 338, 1455. (b) Mei,
T.-S.; Werner, E. W.; Burckle, A. J.; Sigman, M. S. J. Am. Chem. Soc.
2013, 135, 6830. (c) Mei, T.-S.; Patel, H. H.; Sigman, M. S. Nature
2014, 508, 340.
(8) For selected other group works, see: (a) Larock, R. C.; Leung,
W.-Y.; Stolz-Dunn, S. Tetrahedron Lett. 1989, 30, 6629. (b) Bouquil-
lon, S.; Ganchegui, B.; Estrine, B.; Hénin, F.; Muzart, J. J. Organomet.
Chem. 2001, 634, 153. (c) Berthiol, F.; Doucet, H.; Santelli, M. Tetra-
hedron 2006, 62, 4372. (d) Correia, C. R. D.; Oliveira, C. C.; Salles Jr,
A. G.; Santos, E. A. F. Tetrahedron Lett. 2012, 53, 3325. (e) Oliveira,
C. C.; R. Angnes, A.; Correia, C. R. D. J. Org. Chem. 2013, 78, 4373.
(f) Angnes, R. A.; Oliveira, J. M.; Oliveira, C. C.; Martins, N. C.;
Correia, C. R. D. Chem.–Eur. J. 2014, 20, 13117. (g) Oliveira, C. C.;
Pfaltz, A.; Correia, C. R. D. Angew. Chem., Int. Ed. 2015, 54, 14036.
(9) (a) Xu, L.-P.; Hilton, M. J.; Zhang, X.; Norrby, P. O.; Wu, Y.-
D.; Sigman, M. S.; Wiest, O. J. Am. Chem. Soc. 2014, 136, 1960. (b)
Hilton, M. J.; Xu, L.-P.; Norrby, P. O.; Wu, Y.-D.; Wiest, O.; Sigman,
M. S. J. Org. Chem. 2014, 79, 11841.
(10) For selected recent works, see: (a) Parrish, J. P.; Jung, Y. C.;
Shin, S.; Jung, K. W. J. Org. Chem., 2002, 6, 7127. (b) Werner, E. W.;
Sigman, M. S. J. Am. Chem. Soc., 2010, 132, 13981. (c) Werner, E.
W.; Sigman, M. S. J. Am. Chem. Soc., 2011, 133, 9692.
(11) No product was observed using 3-pyridinylboronic acid, 3-
furanylboronic acid and 3-thienylboronic acid.
(12) For details on the assignment of absolute configuration, please
see the supporting information.
(13) Sigman, M. S.; Harper, K. C.; Bess, E. N.; Milo, A. Acc. Chem.
Res., 2016, 49, 1292.
(14) (a) Guckian, K. M.; B. A.; Ren, R. X.; Sheils, C. J.; Tah-
massebi, D. C.; Kool, E. T. J. J. Am. Chem. Soc. 2000, 122, 2213. (b)
Watt, M.; Hardebeck, L. K. E.; Kirkpatrick, C. C.; Lewis, M. J. Am.
Chem. Soc. 2011, 133, 3854.
(15) (a) Raju, R. K.; Bloom, J. W. G.; An, Y.; Wheeler, S. E. Chem-
PhysChem 2011, 12, 3116. (b) Sherrill, C. D. Acc. Chem. Res. 2013,
46, 1020. (c) Singh, S. K.; Das, A. Phys. Chem. Chem. Phys. 2015,
17, 9596.
In summary, we have successfully developed a method to
synthesize enantiomerically enriched 1,2-diaryl carbonyl
compounds,
a common pharmacophore, in good to high
enantioselectivity. The insight gained through uni- and
multivariate correlations has revealed key properties in both the
substrate and ligand, leading to a proposed attractive interaction
responsible for achieving a highly selective process. Detailed
mechanistic studies are in progress to investigate the unexpected
effect of chain length on enantioselectivity and the potential role
of noncovalent π interactions as controlling elements in the enan-
tiodetermining step.
ACKNOWLEDGMENTS. The synthetic aspects were support-
ed by NIH (R01GM063540) and the modeling was supported by
NSF (CHE-1361296). We gratefully acknowledge the Center for
High Performance Computing (CHPC) at the University of Utah.
Z.-M.C. would like to thank Shanghai Jiao Tong University for a
postdoctoral fellowship.
Supporting Information Available: Experimental details, ana-
lytical data for products, NMR spectra of products, computations
and modeling details can be found in the supporting information.
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org/.
REFERENCES
(1) (a) Manley, P. J.; Miller, W. H.; Uzinskas, I. N. (SmithKline
Beecham Corporation) Patent EP1218005 A2, July 3, 2002. (b) Mil-
lera, W. H.; Manley, P. J.; Cousins, R. D.; Erhard, K. F.; Heerding, D.
A.; Kwon, C.; Ross, S. T.; Samanen, J. M.; Takata, D. T.; Uzinskas, I.
N.; Yuan, C. C. K.; Haltiwanger, R. C.; Gress, C. J.; Lark, M. W.;
Hwang, S.-M.; James, I. E.; Rieman, D. J.; Willette, R. N.; Yue, T.-L.;
Azzarano, L. M.; Salyers, K. L.; Smith, B. R.; Ward, K. W.; Johanson,
K. O.; Huffman, W. F. Bioorg. Med. Chem. Lett. 2003, 13, 1483. (c)
Wang, F.; Li, J.; Sinn, A. L.; Knabe, W. E.; Khanna, M.; Jo, I.; Silver,
J. M.; Oh, K.; Li, L.; Sandusky, G. E.; Sledge, G. W.; Nakshatri, H.;
Jones, D. R.; Pollok, K. E.; Meroueh, S. O. J. Med. Chem. 2011, 54,
7193. (d) Hasui, T.; Matsunaga, N.; Ora, T.; Ohyabu, N.; Nishigaki,
N.; Imura, Y.; Igata, Y.; Matsui, H.; Motoyaji, T.; Tanaka, T.; Habuka,
N.; Sogabe, S.; Ono, M.; Siedem, C. S.; Tang, T. P.; Gauthier, C. G.;
De Meese, L. A.; Boyd, S. A.; Fukumoto, S. J. Med.
Chem. 2011, 54, 8616. (e) Kim, M.; Ryu, J.; Hah, J. Bioorg. Med.
Chem. Lett. 2013, 23, 1639. (f) Irannejad, H.; Unsal Tan, O.; Ozadali,
K.; Dadashpour, S.; Tuylu Kucukkilinc, T.; Ahangar, N.; Ahmadnejad,
M.; Emami, S. Chem. Biol. Drug Des. 2015, 85, 494. (g) Sun, J.; Chen,
L.; Liu, C.; Wang, Z.; Zuo, D.; Pan, J.; Qi, H.; Bao, K.; Wu, Y.;
Zhang, W. Chem. Biol. Drug Des. 2015, 86, 1541. (h) Koo, K. A.;
Lorent, K.; Gong, W.; Windsor, P.; Whittaker, S. J.; Pack, M.; Wells,
R. G.; Porter, J. R. Chem. Res. Toxicol. 2015, 28, 1519.
(2) (a) Lenz, G. R. J. Org. Chem. 1988, 53, 5791. (b) Mandal, S. K.;
Jana, S.; Roy, S. C. Tetrahedron Lett. 2005, 46, 6115. (c) Franzoni, I.;
L.; Guenee, L.; Mazet, C. Org. Biomol. Chem. 2015, 13, 6338.
(16) Biedermann, F.; Schneider, H.-J. Chem. Rev. 2016, 116, 5216.
́
́
(3) (a) Trejos, A.; Fardost, A.; Yahiaoui, S.; Larhed, M. Chem.
Commun. 2009, 7587. (b) Lundin, M. P.; Esquivias, J.; Fu, C. G. An-
4
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
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
5
ACS Paragon Plus Environment