Lewis acid-catalyzed annulative partial dimerization of 3-aryloxyacrylates to 4-arylchroman-2-ones: Synthesis of analogues of tolterodine, RORγ inhibitors and a GPR40 agonist

Article abstract of DOI:10.1039/c8cc09785b

A beguiling annulative partial dimerization of 3-aryloxyacrylates to 4-arylchroman-2-ones catalyzed by Lewis acid (BF₃·OEt₂) has been developed. The reaction involves two molecules of 3-aryloxyacrylate, resulting in the loss of one propiolate molecule to furnish 4-arylchroman-2-one, an important structural motif found in many natural products. This methodology has been elaborated to synthesize analogues of tolterodine, RORγ inhibitors and a GPR40 agonist.

Full text of DOI:10.1039/c8cc09785b

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
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DOI: 10.1039/C8CC09785B
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COMMUNICATION
Lewis Acid-Catalyzed Annulative Partial Dimerization of 3-
Aryloxyacrylates to 4-Arylchroman-2-ones: Synthesis of Analogues
of Tolterodine, ROR Inhibitor and a GPR40 Agonist
Received 00th January 20xx,
Accepted 00th January 20xx
Rupesh A. Kunkalkara and Rodney A. Fernandes*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A beguiling annulative partial dimerization of 3-aryloxyacrylates to pendant aryloxyacrylate in compound 3a, followed by in-situ
4-arylchroman-2-ones catalyzed by Lewis acid (BF3·OEt2) has been enolate cyclization to give benzopyran 4 (Scheme 1B). However,
developed. The reaction involves two molecules of 3- to our delight, it delivered an annulative partially dimerized/
aryloxyacrylate, resulting in the loss of one propiolate molecule to rearranged product 4-arylchroman-2-one 5a with two
furnish 4-arylchroman-2-one, an important structural motif found molecules of 3a being involved with a concomitant loss of one
in many natural products. This methodology has been elaborated propiolate molecule (Scheme 1C). Such an annulative partial
to synthesize analogues of tolterodine, RORγ inhibitors and a dimerization is hitherto unknown to the best of our knowledge
GPR40 agonist.
and much to our astonishment that several substrates
underwent the HT-cyclization in the seminal work of Sames et
al.4 Product 5a was characterized by 1H and 13C NMR and HRMS
data. Further the structure was confirmed unambiguously by
single crystal XRD (Scheme 1).5
The molecular rearrangements occupy an important niche in
synthetic organic chemistry1 and are important for building
unusual complexities in the products from rather simple
substrates or easy-to-make starting materials. Many natural
products and valuable compounds have been synthesized by
molecular rearrangements.1,2 Acid-catalyzed rearrangements
offer a unique opportunity in cascade reactions, leading to
several bonds being formed in a single operation. Such
reactions are sought after for being atom economic and highly
resource conservative. Atkinson and co-workers had shown a
remarkable 1,5-hydride shift in acyclic systems containing ,-
unsaturated ketones, creating an intermediate enolate that
cyclized with the benzylic cation to give a cyclic product.3a
Latter, Reinhoudt et al.3b described a similar 1,5-hydride shift,
to produce fused heterocycles. Noguchi et al.3c also reported
similar chemistry for preparing fused pyridine compounds.
Extensive work by Dalibor Sames and co-workers4 on such
hydride transfer cyclization (called HT-cyclization) has opened a
new avenue for several types of substrates to be employed for
1,5-hydride shift and subsequent cyclization. In their work, the
aryl-alkyl ether 1 failed to rearrange initially when BF3·OEt2 was
used, but the desired HT-cyclized product 2 was obtained with
Sc(OTf)3 in a sealed tube (Scheme 1A).4c We believed that, an
aryl methyl group would also provide an active hydride to the
H
MeO2C
CO2Me
CO2Me
CO2Me
Sc(OTf)3 (0.1 equiv)
A
B
H
80 oC sealed vial
CH2Cl2, 24 h, 91%
O
O
2
1
H
O
BF3.OEt2 (0.5 equiv)
DCE, 80 o
O
CO2Et
CO2Et
H
C
CO2Et
3a
4
O
O
O
C
BF3.OEt2 (0.5 equiv)
DCE, 80 oC, 94%
OH
3a
5a
annulative partial
dimerization
5a
Scheme 1 Hydride transfer cyclization and a new partial annulative dimerization.
This method is simple, and 4-arylchroman-2-ones (4-
aryldihydrocoumarin),6 an important structural motif found in
many natural products7,8 (Figure 1, for e.g. the calomelanols 6a-
h,7a-c poinsettifolactone 6i7d and gnetumontanin C 6j7f), could be
obtained in one step from the substrates of type 3. Further, the
4-arylchroman-2-ones could serve as intermediates for drugs
and bioactive compounds like tolterodine 7,9 the GPR40
agonists 810 and the ROR inhibitor ()-ML209 98e (Figure 1).
a. Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai
400 076, India . E-mail: rfernand@chem.iitb.ac.in
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Journal Name
R2
R2
View Article Online
O
DOI: 10
O
.1039/C8CC09785B
R
O
OEt
BF3.OEt3 (0.5 equiv)
OH
O
O
OH
R
DCE, 80 oC, time (h)
O
OH
R
3
(2 equiv)
5
24 examples
HO
O
O
R
O
O
O
O
O
O
O
R'
O
R1
6d
6e
R
O
1 = R2 = OH
,
R
calomelanol E
calomelanol G
R1
1 = OMe, R2 = OH
OH
,
R
OH
R'
1 = OMe, R2 = H
6a
6b
6c
,
,
6f calomelanol H, R1 = OH, R2 = H
6g calomelanol I, R1 = H, R2 = OH
6h calomelanol J, R1 = R2 = H
calomelanol A
calomelanol B
R
1 = OH, R2 = H
R
R'
R'
Calomelanol C, R1 = H, R2 = OH
OH
OH
R
R
OH
54%
MeO
HO
O
5q
5r
5s
5t
5u
5v
71%
64%
63%
, R = F, R' = H,
, R = Cl, R' = H,
, R = Br, R' = H,
, R = I, R' = H,
, R = Br, R' = Me,
(12 h)
(12 h)
(12 h)
OH
5a, 94%
3a
3a
3a
)
(4 h, from E-
(4 h, from Z-
(4 h, 4:1 E/Z-
O
)
)
5k
5l
5m
5n
, R = R' = H,
(10 h)
60%
(10 h)
(12 h)
N
5a 93%
,
OMe
, R = Me, R' = H,
(5 h)
5a 94%
,
48%
55%
, R = R' = Me,
, R =Cl, R' = H,
OMe
O
52%
(12 h)
66%
NR
NR
(12 h)
(12 h)
(12 h)
O
O
O
, R = CHO, R' = H,
, R = NO2, R' = H,
O
O
O
O
O
5w
MeO
OH
OH
HO
6j
O
O
O
9
(-)-ML209
R
R' EtO
ROR assay: IC50 = 0.5 M
gnetumontanin C
O
6i
poinsettifolactone
N
5o 57%
,
(5 h)
O
R
HO
OH
5b,
5c,
93%
88%
OH
R = Me,
R = Bu,
(4 h)
(5 h)
(4 h)
(5 h)
72%
73%
(10 h)
(10 h)
44%
OH
OH
t
R
R'
O
O
5d
5e
5f,
5g
5h
87%
78%
O
O
, R = Et,
, R = Bu,
R = -CH2CH2 Pr,
, R = -CH2CH2-Ph,
, R = Ph,
HO
O
i
R
OH
OC4H9
ED50 = 4.8 M
(5 h)
5 h)
8a
8b
ED50 = 0.3 M
5x
5y
5z
82%
73%
, R = R' = Me,
, R = R' = Pr,
, R = Et, R' = OEt,
(3 h)
(3 h)
5p 72%
,
(12 h)
84%
74%
i
7
tolterodine (Detrol)
5i
5j
, R = OMe,
, R = -CH2CO2Me,
GPR40 agonist at Human GPR40 receptor
85%
(12 h)
(rt, 3 d)
Fig. 1 4-Aryldihydrocoumarin natural products and related drug molecules.
Scheme 2 Annulative partial dimerization/rearrangement of various ethyl 3-
aryloxyacrylates 3. NR = No reaction.
The reaction of 3a as model compound with various Lewis
and Brønsted acids was first optimized to reveal that BF3·OEt2
(0.5 equiv) in 1,2-dichloroethane (DCE) at 0.02 M concentration
and 80 C were optimum requirement giving the product 5a in
94% yield in 4 h (see Table 1 in SI for details). The minor Z-
acrylates (Z-3) obtained during the preparation of 3 were found
to provide the same product 5. Thus, the reaction does not
necessitate the separation of the two geometric isomers of the
3-aryloxyacrylates. With the optimized conditions, the scope
and limitations of the annulative partial dimerization was
investigated as shown in Scheme 2, to furnish the 4-
arylchroman-2-ones 5 in good to excellent yields. The reaction
worked well with alkyl, aryl, methoxy or methylacetate
substituents on the aryloxy part of the substrate 3a-j to give 4-
arylchroman-2-ones 5a-j in 44-94% yields. The product 5j
required 3 days for the complete consumption of 3j and was
obtained in moderate yield (44%, a reaction at 80 C gave poor
yields). It can be noted that since the para-position in 3a-j was
blocked, the electrophilic substitution occurred at the ortho-
position. When the para- and/or ortho-position was free e.g., in
3k-n, the reaction resulted in substitution exclusively at the
para-position to give 5k-n respectively. The trend in yields could
be a result of increased nucleophilicity of phenol because of the
alkyl groups or due to steric crowding. This was more evident
for 3o and 3p, which gave coumarins 5o and 5p, respectively,
through oxonium-arylation and 4-aryloxy elimination rather
than O-C migration. Halide substituted substrates also reacted
well to give 4-arylchroman-2-ones 5n and 5q-u in good yields of
52-71%. The halide group can be used as handle for various
coupling reactions for molecular diversity. The aryl ring needs
to be nucleophilic enough for the electrophilic substitution.
Hence, substrates with electron-withdrawing groups, 3v and
3w, did not undergo this reaction. When the ortho positions
were blocked, the substrates 3x-z gave un-cyclized ,-bis-
arylacetates 5x-z in good yields, because of no ortho-hydroxy
group for lactonization.
We further considered synthetic modifications of the 4-
aryldihydrocoumarins. The 4-arylchroman-2-one 5k was
elaborated efficiently to 8a, a GPR40 agonist by first phenolic
OH alkylation to 10 and then lactone hydrolysis (Scheme 3).9,10
GPR40 is a G-protein-coupled receptor primarily expressed in
pancreatic β-cells. It is an attractive therapeutic target to
control type 2 diabetes. GPR40 agonists are known to stimulate
insulin secretion and reduce circulating glucose levels in a
glucose dependent manner.11 Compound 8a showed ED50 = 4.8
M at the Human GPR40 receptor.10 The DiBAL-H reduction of
5a and 5q to the lactols and further one-pot reductive
amination gave tolterodine analogues 7a and 7q in good yields
(Scheme 3).9,12 Tolterodine, traded as detrol is an
antimuscarinic drug13a that is used for the treatment of urinary
incontinence and acts on M2 and M3 subtypes of muscarinic
receptors.13b The 4-aryldihydrocoumarins 5a and 5q were
converted to 9a and 9q by reacting with piperidine (Scheme 3).
RORt, a retinoic acid-related orphan receptor plays a key role
in the differentiation of TH17 cells. Antagonizing the activity of
RORγt transcription is a potential means to treat TH17-related
autoimmune diseases.14 Littman et al.8e prepared several
diphenylpropanamides and found ()-ML209 9 (Figure 1) as a
significant ROR inhibitor (ROR essay: IC50 = 0.5 M).
We further considered mechanistic studies for ascertaining
the series of intermediary steps. A reaction on two different,
mixed substrates was carefully examined (Scheme 4), with one
chosen to have both ortho-positions substituted to avoid
cyclization, thus expecting to give three products instead of four
if there was cross-over of aryl groups. Indeed the reaction
delivered three products as expected. For example, the reaction
2 | J. Name., 2012, 00, 1-3
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of equimolar amounts of 3x and 3b (Scheme 4, entry 1) aromatization gives 23 via the enol 22. The lossVioewf ADrt2iclienOntlhinee
provided
deuterium experiment could be duDeOI:to10.1t0h3e9/C8reCvCe0r9s7i8b5lBe
enolization (22 to 23). The lactonization of 23 gives 5. The O-C
O
O
O
OH
OH
LiOH
R1
O
OEt
THF/MeOH/H2O
rt, 12 h, 61%
O
OEt
O
OC4H9
R4
OR
R3
8a
O
.
+
5k
n-C4H9I, CsF
DMF, rt
, R = H
R2
or
GPR40 agonist (ED50 = 4.8 M
at Human GPR40 receptor)
3a 3b 3c
,
or
3x 3y 3z
,
10
, R = Bu
12 h, 81%
R
BF3 OEt2
(0.5 equiv)
DCE, 80 o
4 h
C
OH
R1
O
i. DiBAL-H, CH2Cl2
OEt
N
R4
-20 oC, 6 h
O
R'
OH
O
HO
ii. Pd/C, EtOH
diisopropylamine
H2 (20 atm)
OH
R4
+
O
R1
R
R2
O
R'
R
R3
60 oC, 12 h
7'a
7'q
, R = R' = Me, 83%
, R = H, R' = F 74%
R2
OH
OH
B
R3
A
R
R'
O
R
OH
R4
O
R'
N
R'
5a
5q
, R = R' = Me
, R = H, R' = F
piperidine
HO
R
O
+
R1
OH
R3
DMA, 80 oC, 8 h
R'
C
R2
9'a
9'q
R = R' = Me, 71%
R = H, R' = F, 76%
5bx
probable ROR inhibitors
entry R1, R2, R3, R4 (3)
yield A yield B yield C
5b, 27% 5x, 25% 5bx, 37%
Scheme 3 Synthesis of GPR40 agonist 8a, tolterodine analogues (7a & 7q) and probable
ROR inhibitors (9a & 9q).
1
2
3
4
5
R1 = R2 = R3 = Me, R4 = H
R1 = R2 = i-Pr, R3 = Me, R4 = H 5b, 30% 5y, 25% 5by, 35%
R1 = R2 = i-Pr, R3 = R4 = Me
5a, 32% 5y, 21% 5ay, 32
5b (27%), 5x (25%) and the aryl group cross-over product 5bx
(37%, structure confirmed by single crystal XRD).5 Similarly,
compounds 5by, 5ay, 5cy and 5az (entries 2-5) were obtained
as cross-over products and is an extension of this method to
obtain compounds with two different aryl moieties. It also
indicated the cleavage of C3-O aryloxy-acrylate bond.
R1 = R2 = i-Pr, R3 = t-Bu, R4 = H 5c, 28% 5y, 23% 5cy, 34%
R1 = Et, R2 = OEt, R3 = R4 = Me 5a, 27% 5z, 24% 5az, 32%
Scheme 4 Cross-over experiments of mixed 3-aryloxyacrylates.
O
The cleavage of C3-O bond was further supported by the
reaction of compound 11 (Scheme 5), to give the usual product
5b (68%) and the fused naphthyl coumarin 12 (33%), which
arises from the naphthyl propiolate that is formed by the
cleavage of C3-O bond. 2-Naphthol (58%) was also isolated from
this reaction. This was similar to compounds 5o and 5p (Scheme
2). To substantiate this claim we prepared separately 2-
naphthyl propiolate 13, and reacted it with BF3·OEt2 to give 12
in 45% yield. Further, the reaction of n-decyl 3-aryloxyacrylate
14 with BF3·OEt2 gave the phenol 15 (quant), n-decylpropiolate
16 (35%) and n-decanol (46%). This clearly indicated the
cleavage of the C3-O bond. A deuterium labelling study was also
conducted (Scheme 5). The di-deuterated 3-aryloxyacrylate 3b,
obtained in good yield with deuterium incorporation as D1
(84%) and D2 (78%) was treated with BF3·OEt2 (0.5 equiv) to
provide compound 5b. This had D1 (80%), while there was loss
at D2 (18%). The loss at D2 could be attributed to the reversible
enolization (see reaction mechanism, Scheme 6). It also
indicated that the -hydrogen of the acrylate that corresponds
to D1 is not involved.
O
O
.
BF3 OEt2
O
(0.5 equiv)
O
OH
DCE, 80 o
12 h
C
11 (2 equiv)
5b (68%)
+
O
+
2-naphthol (58%)
O
.
BF3 OEt2
O
(0.5 equiv)
12
12 (33%))
O
DCE, 80 o
12 h, 45%
C
13
.
BF3 OEt2
O
OC10H21
OH
O
(0.5 equiv)
+
O
DCE, 80 o
12 h
C
OC10H21
16 (35%)
14
15 (quant.)
+
C9H19CH2OH
n-decanol (46%)
K2CO3
CH3CN
O
O
CH2Cl2, p-cresol
O
O
NMM, 6 h, rt
69% over 2 steps
D2O, rt
1.5 h
D1
17a
17b
O
O
D2
BF3.OEt2
(0.5 equiv)
D2
OH
O
OEt
D1
D1
O
DCE, 80 o
6 h, 86%
C
Considering the various experiments and results, the
mechanism as shown in Scheme 6 is proposed. Co-ordination of
BF3·OEt2 with the carbonyl group of 3 gives the oxo-carbenium
ion 18. The C3-O bond cleavage of another molecule of 3 gives
the +BF3-phenoxide 19 that undergoes electrophilic substitution
with 18 to produce 21. Next, the O- to C-aryl migration and
D1 = 80%
D2 = 18%
3b' (2 equiv)
D1 = 84%, D2 = 78%
5b'
Scheme 5 Experiments to ascertain C3-O bond cleavage in 3-aryloxyacrylates and
deuterium labelling study.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
(4) (a) S. J. Pastine, D. Sames, Org. Lett., 2005, 24, 5429; (b) K. M.
aryl-migration was proved by the reaction of 24 (prepared
separately) to give the product 5aa in 92% yield (Scheme 6). The
presence of ortho-substituents directs the electrophilic
substitution at para position. This prevents cyclization, giving
the 3,3-bis-arylacetates 5x-z as there is no ortho-hydroxyl group
for lactonization.
McQuaid, D. Sames, J. Am. Chem. Soc., 2009, 131, V4ie0w2.Ar(ticc)leKO.nMline.
DOI: 10.1039/C8CC09785B
McQuaid, J. Z. Long, D. Sames, Org. Lett., 2009, 14, 2972; (d) P. A.
Vadola, I. Carrera, D. Sames, J. Org. Chem., 2012, 77, 6689.
(5) CCDC 1873459 (5a) and 1873458 (5bx) contains the
supplementary crystallographic data.
(6) For recent synthesis of 4-aryldihydrocoumarins see: (a) J.
Oyamada, Kitamura, T. Tetrahedron 2006, 62, 6918; (b) J. C. Allen,
G. Kociok-Köhn, C. G. Frost, Org. Biomol. Chem., 2012, 10, 32; (c)
I. Ibrahem, G. Ma, S. Afewerki, A. Córdova, Angew. Chem., Int. Ed.,
2013, 52, 878; (d) L. Caruana, M. Mondatori, V. Corti, S. Morales,
A. Mazzanti, M. Fochi, L. Bernardi, Chem. Eur. J., 2015, 21, 6037;
(e) G. Yue, K. Lei, H. Hirao, J. S. Zhou, Angew. Chem., Int. Ed., 2015,
54, 6531; (f) G. -T. Li, Z. -K. Li, Q. Gu, S.-L. You, Org. Lett., 2017, 19,
1318.
+
BF3.OEt2
O
OEt
O
OEt
OBF3
R
R
O
3
18
+ O
F3B
R
BF3
O
H
O
+
OEt
OEt
+
R
-H+
O
20
19
3'
(7) For 4-aryldihydrocoumarin natural products see: (a) F. Asai, M.
Iinuma, T. Tanaka, M. Mizuno, Phytochemistry, 1991, 30, 3091;
(b) F. Asai, M. Iinuma, T. Tanaka, M. Mizuno, Heterocycles, 1992,
33, 229; (c) M. Iinuma, T. Tanaka, M. Takenaka, M. Mizuno, F.
Asai, Phytochemistry, 1992, 31, 2487; (d) B. T. Ngadjui, G. W. F.
Kapche, H. Tamboue, B. M. Abegaz, J. D. Connolly,
Phytochemistry, 1999, 51, 119; (e) X. Sun, A. T. Sneden, Planta
Med., 1999, 65, 671; (f) X. M. Li, M. Lin, Y. H. Wang, X. Liu, Planta
Med., 2004, 70, 160.
(8) For bioactivities of 4-aryldihydrocoumarins see: (a) Q. Xiong,
W. Fan, Y. Tezuka, I. K. Adnyana, P. Stampoulis, M. Hattori, T.
Namba, S. Kadota, Planta Med., 2000, 66, 127; (b) N. Tabanca, R.
S. Pawar, D. Ferreira, J. P. Marais, S. I. Khan, V. Joshi, I. A. Khan,
Planta Med., 2007, 73, 1107; (c) K. V. Sashidhara, S. P. Singh, S. V.
Singh, R. K. Srivastava, K. Srivastava, J. K. Saxena, S. K. Puri, Eur. J.
Med. Chem., 2013, 60, 497; (d) S. Xu, M. Y. Shang, G. X. Liu, F. Xu,
X. Wang, C. C. Shou, S. Q. Cai, Molecules, 2013, 18, 5265; (e) J. R.
Huh, E. E. Englund, H. Wang, R. Huang, P. Huang, F. Rastinejad, J.
Inglese, C. P. Austin, R. L. Johnson, W. Huang, D. R. Littman, ACS
Med. Chem. Lett., 2013, 4, 79.
F3B+
1
O
OEt
OH
F3B
3
O
OEt
R
O
4
2, 5
OH
R
R
O-C migration/
aromatization
OH
R
22
H+
21
O
OEt
OH
R
lactonization
-EtOH
5
OH
R
5x-z
(no cyclization,
3,3-bisaryl acetates)
3
if ortho-substituents on
23
O
O
BF3.OE2
(0.5 equiv)
O
OEt
O
DCE, 80 o
6 h, 92%
C
24
Scheme 6 Plausible mechanism.
5aa
(9) B. D. Gallahher, B. R. Taft, B. H. Lipshutz, Org. Lett., 2009, 11,
5374 and references therein.
(10) F. Song, S. Lu, J. Gunnet, J. Z. Xu, P. Wines, J. Proost, Y. Liang,
C. Baumann, J. Lenhard, W. V. Murray, K. T. Demarest, G. -H. Kuo,
J. Med. Chem. 2007, 50, 2807.
In summary, we have developed a beguiling annulative
partial dimerization/rearrangement of 3-aryloxyacrylates under
Lewis-acid
conditions
to
4-arylchroman-2-ones
(4-
aryldihydrocoumarins), which are important structural motifs in
many natural products. The reaction occurs through C3-O
aryloxy bond cleavage, electrophilic aromatic substitution, O-C
aryl-migration and lactonization. This method is important, as
addition of a phenol to alkyl/aryl propiolate delivers 3 and in
one step would further provide 4-arylchroman-2-ones 5.
We thank SERB New Delhi (EMR/2017/000499) for financial
support. R.A.K. thanks UGC, India for a research fellowship.
(11) C. F. Burant, Diabetes Care, 2013, 36, S175.
(12) For selected synthesis of tolterodine see: (a) G. Chen, N.
Tokunga, T. Hayashi, Org. Lett., 2005, 7, 2285; (b) F. Ulgheri, M.
Marchetti, O. Piccolo, J. Org. Chem., 2007, 72, 6056; (c) S. Soergel,
N. Tokunga, K. Sasaki, K. Okamoto, T. Hayashi, Org. Lett., 2008,
10, 589; (d) K. Yoo, H. Kim, J. Yun, J. Org. Chem., 2009, 74, 4232.
(13) (a) P. V. Kerrebroeck, K. Kreder, U. Jonas, N. Zinner, A. Wein,
Urology, 2001, 57, 414; (b) D. J. Sellers, T. Yamanishi, C.
R. Chapple, C. Couldwell, K. Yasuda, R. Chess-Williams, J. Auton
Pharmacol., 2000, 20, 171.
Conflicts of interest
There are no conflicts of interest to declare.
(14) (a) T. Hirose, R. J. Smith, A. M. Jetten, Biochem. Biophy. Res.
Commun., 1994, 205, 1976; (b) U. Guendisch, J. Weiss, F. Ecoeur, J.
C. Riker, K. Kaupmann, J. Kallen, S. Hintermann, D. Orain, J. Dawson,
A. Billich, C. Guntermann, PLoS One 2017, 12, e0188391.
Notes and references
(1) (a) C. M. Rojas, Molecular Rearrangements in Organic
Synthesis, 2016, 1st Edn., John Wiley and Sons. (b) S. Moulay,
Chem. Edu. Res. Prac., 2002, 3, 33.
(2) (a) A. S. Kende, Pure & Appl. Chem., 1997, 69, 407; (b) J. Marco-
Contelles, E. Soriano, Rearrangements in Natural Product
Synthesis. In Modern Tools for the Synthesis of Complex Bioactive
Molecules. J. Cossy, S. Arseniyadis, Eds.; Wiley: Hoboken, NJ,
2012; pp 243–269.
(3) (a) R. S. Atkinson, R. H. Green, J. Chem. Soc., Perkin Trans. 1,
1974, 394. (b) W. H. N. Nijhuis, W. Verboom, D. N. Reinhoudt, J.
Am. Chem. Soc., 1987, 109, 3136. (c) M. Noguchi, H. Yamada, T.
A. Sunagawa, J. Chem. Soc., Perkin Trans. 1, 1998, 3327.
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