Tetramethyleneethane Equivalents: Recursive Reagents for Serialized Cycloadditions

Article abstract of DOI:10.1021/jacs.5b04091

New reactions and reagents that allow for multiple bond-forming events per synthetic operation are required to achieve structural complexity and thus value with step-, time-, cost-, and waste-economy. Here we report a new class of reagents that function like tetramethyleneethane (TME), allowing for back-to-back [4 + 2] cycloadditions, thereby amplifying the complexity-increasing benefits of Diels-Alder and metal-catalyzed cycloadditions. The parent recursive reagent, 2,3-dimethylene-4-trimethylsilylbutan-1-ol (DMTB), is readily available from the metathesis of ethylene and THP-protected 4-trimethylsilylbutyn-1-ol. DMTB and related reagents engage diverse dienophiles in an initial Diels-Alder or metal-catalyzed [4 + 2] cycloaddition, triggering a subsequent vinylogous Peterson elimination that recursively generates a new diene for a second cycloaddition. Overall, this multicomponent catalytic cascade produces in one operation carbo- and heterobicyclic building blocks for the synthesis of a variety of natural products, therapeutic leads, imaging agents, and materials. Its application to the three step synthesis of a new solvatochromic fluorophore, N-ethyl(6-N,N-dimethylaminoanthracene-2,3-dicarboximide) (6-DMA), and the photophysical characterization of this fluorophore are described. (Chemical Equation Presented).

Full text of DOI:10.1021/jacs.5b04091

Subscriber access provided by UB + Fachbibliothek Chemie | (FU-Bibliothekssystem)
Article
Tetramethyleneethane Equivalents: Recursive
Reagents for Serialized Cycloadditions
Paul A Wender, Matthew S. Jeffreys, and Andrew G Raub
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 11 May 2015
Downloaded from http://pubs.acs.org on May 11, 2015
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 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
Paul A. Wender*, Matthew S. Jeffreys‡, Andrew G. Raub‡
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, Department of Chemical and Systems Biology, Stanford University, Stanford, California,
94305-5080
ABSTRACT: New reactions and reagents that allow for multiple bond-forming events per synthetic operation are required
to achieve structural complexity and thus value with step-, time-, cost- and waste-economy. Here we report a new class of
reagents that function like tetramethyleneethane (TME), allowing for back-to-back [4+2] cycloadditions, thereby amplify-
ing the complexity-increasing benefits of Diels-Alder and metal-catalyzed cycloadditions. The parent recursive reagent,
DMTB (2,3-dimethylene-4-trimethylsilylbutan-1-ol), is readily available from the metathesis of ethylene and THP-
protected 4-trimethylsilylbutyn-1-ol. DMTB and related reagents engage diverse dienophiles in an initial Diels-Alder or
metal-catalyzed [4+2] cycloaddition, triggering a subsequent vinylogous Peterson elimination that recursively generates a
new diene for a second cycloaddition. Overall, this multi-component catalytic cascade produces in one operation carbo-
and hetero-bicyclic building blocks for the synthesis of a variety of natural products, therapeutic leads, imaging agents,
and materials. Its application to the three step synthesis of a new solvatochromic fluorophore, 6-DMA (N-ethyl(6-N,N-
dimethylaminoanthracene-2,3-dicarboximide)), and the photophysical characterization of this fluorophore, are described.
connecting back-to-back cycloadditions (Figure 1).
Introduction
The success of a synthesis is generally measured in terms
of cost, time, yield, waste, and length; metrics influenced
to varying degrees, but mainly, by step economy.1 In gen-
eral, synthetic strategies with the greatest number of tar-
get relevant bond forming events per synthetic operation
are the most step economical.2 However, most reactions,
including the venerable Diels-Alder cycloaddition, form
at most only two new bonds per operation. To achieve
greater step economy in accessing targets of value, new
reactions, reagents, and strategies that would increase
this bonds-per-operation count are required. Nature’s
solution to this problem is instructive, often taking the
form of recursive reactions in which a single bond form-
ing event is serially repeated. Biosynthetic cation-alkene
cyclizations3,4 are quintessential examples of how com-
plexity is amplified through such recursive processes.
Given the exceptional synthetic utility of the Diels-Alder
and related metal-catalyzed [4+2] cycloadditions, we
wondered whether they could be deployed recursively in
a diene-based cycloaddition that regenerates another
diene.5,6 This intriguing 4-bond disconnection strategy to
bicyclo[4.4.0]ring systems – a common feature in natural
products,7 materials,8 imaging agents9,10, and potentially
oligomeric acenes – leads conceptually to the tetrameth-
yleneethane diradical (TME) as a key species capable of
Figure 1. Retrosynthetic analysis of [4.4.0]bicycles into two
dienophiles and the tetramethyleneethane (TME) diradical
However, as shown in a brilliant series of studies
by Dowd, TME itself has a half-life of only 20 minutes at
-196 °C and preparations of its precursors can be lengthy.11
Predating these studies, Alder and Ackermann serendipi-
tously uncovered a TME equivalent, reporting that allene
and maleic anhydride when heated in a “Bombenrohr” for
3 days at 175 °C produce an octahydronaphthalene prod-
uct in 16% yield, putatively through the formation and
reaction of 1,2-bis-methylenecyclobutane (BMCB).12 Un-
fortunately, the volatility and reactivity of BMCB limits its
use in recursive processes. Other creative concepts for
diene-generating diene cycloadditions have since been
reported; however, these involve multistep sequences,
harsh conditions, or volatile or difficult to access reac-
tants that limit utility.12–23 Here we report the design and
development of a versatile TME equivalent, DMTB (2,3-
dimethylene-4-trimethylsilylbutan-1-ol: 1), that is readily
prepared and safely handled on scale. This TME
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
1
2
3
4
5
6
Figure 2. DMTB and THP-DMTB: tetramethyleneethane equivalents for recursive cycloadditions.
7
8
9
equivalent efficiently engages dienophiles in an initial
Diels-Alder or metal-catalyzed [4+2] cycloaddition, which
then allows for a catalyzed vinylogous Peterson elimina-
tion24 to produce a second diene captured in a subsequent
[4+2] cycloaddition (Figure 2). A single dienophile can be
used in both cycloadditions to produce 2:1 products or
different dienophiles can be deployed to produce 1:1:1 bi-
cyclic products. Thus, in one synthetic operation, this
three component process involving as many as three cata-
lytic cycles efficiently produces four new bonds and a car-
bo- or hetero[4.4.0]bicyclic product, a core subunit found
in many synthetic targets, and here applied to the synthe-
sis of a new solvatochromic imaging agent with excellent
photophysical properties for biological applications.9,10
To investigate whether DMTB would serve as a
TME equivalent capable of connecting back-to-back cy-
cloadditions, we combined it with an excess of N-
phenylmaleimide in 1,2-dichloroethane (Figure 3). After 4
hours, cycloadduct 5 formed cleanly, and was transformed
to diene 6 upon addition of [(naph)Rh(COD)]SbF6.29 Over
the course of 2 days at room temperature, diene 6 was
converted to the 2:1 cycloadduct 7 in 96% overall yield (dr
8:1 favoring the cis-anti-cis isomer, See Supplementary
Information). To determine whether other conditions
would effect the intervening Peterson 1,4-elimination,30,31
cycloadduct 5, obtained in 98% yield from the reaction of
DMTB with N-phenylmaleimide, was used as a test sub-
strate (Table 1). Both protic and Lewis acid catalysts were
found to work well, leading, in the preferred cases, to rap-
id (<3 hours) and efficient (>90%) conversion to diene 6
even at room temperature.
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
Results and Discussion
The synthesis of our parent TME reagent (Scheme 1:
DMTB, 1) uses a strategy that would be generally applica-
ble to the synthesis of many related reagents. Commer-
cially available alkyne 3 is first alkylated using a previous-
ly published procedure25 and the resulting alkyne 4 is
converted to THP-DMTB (2) through an enyne metathe-
sis conducted under one atmosphere of ethylene gas us-
ing Grubbs’ Second Generation catalyst. While previous
studies have used higher catalyst loadings and elevated
temperatures for similar substrates,26,27 the conditions
employed here for the synthesis of THP-DMTB (2) are
unexpectedly efficient and can be conducted on a multi-
gram scale. The hydrolysis of THP-DMTB (2) to the de-
sired alcohol 1 was accomplished with boric acid in reflux-
ing ethanol which gave DMTB in 70% yield with a minor
amount (6 %) of the protodesilylated alcohol product.28
DMTB can be prepared on gram-scale and is readily puri-
fied by column chromatography. It is an air-stable liquid
and can be stored at -20 °C for months. In practice, the
THP-DMTB is an effective storage point and can be used
as a TME equivalent on its own or converted as needed to
DMTB.
Scheme 2. DMTB (1) functions as a TME equivalent in
single-flask operations under a variety of conditions.
Table 1. Conditions for the elimination of 5 to 6
Scheme 1. A simple, scalable synthesis of tetrameth-
yleneethane equivalents, DMTB and THP-DMTBa
a(a)i. n-BuLi, ii. TMSCH2I, THF, 90%; (b) Grubbs II, 1 atm
ethylene, DCM, RT, 16 h, 95%; (c) B(OH)3, EtOH, reflux, 1
h, 70%
2
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
1
2
3
Table 2. Summary of one-flask [4+2]/elimination/[4+2] reactions using tetramethyleneethane equivalents DMTB
and THP-DMTB.
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
Activated acetylenes (e.g. dimethyl acetylenedicarbox-
The diverse and effective conditions for the vinylogous
Peterson elimination make possible a range of one-
operation cycloaddition/elimination/cycloaddition op-
tions, including consecutive Diels-Alder or metal-
catalyzed processes or a mixture of the two with the same
or different dienophiles. Initial work focused on using
DMTB to connect two Diels-Alder cycloadditions; either
with two equivalents of a single dienophile or with two
different dienophiles added in a serialized fashion. Thus,
with AlCl3 as the Lewis acid instead of Rh(I), DMTB and
N-phenylmaleimide provide compound 7 (Table 2) in one
operation in greatly reduced reaction times (1.5 h) and in
high yield (97%). Similarly, the use of 1,4-naphthoquinone
as a dienophile and ZnCl2 as the Lewis acid leads, in one
operation, to the hexacene precursor 8,32–34 in 95% yield.
Complementing this route to 2:1 adducts, the 1:1:1 adduct
9 is obtained in 78% yield by using 1 equivalent of N-
phenylmaleimide first and then dimethyl fumarate as a
second component. Interestingly, switching the order of
ylate : DMAD) were also shown to be effective Diels-Alder
partners in our system (10). As exemplified by 11 and 12
(Table 2), heteroatomic dienophiles such as 4-phenyl-
1,2,4-triazoline-3,5-dione and diethyl oxomalonate both
function effectively in this reaction, providing facile ac-
cess to a diverse array of heterocyclic compounds of the
isochromane and pyridazine families.
We and others have previously shown that cer-
tain transition metals can effectively catalyze multi-step
diene-dienophile cycloadditions that are otherwise elec-
tronically disfavored under Diels-Alder conditions due to
a poor highest occupied molecular orbital (HOMO) -
lowest unoccupied molecular orbital (LUMO) gap.24,35–38
Phenylacetylene, for example, is an ineffective dienophile
under conventional thermal Diels-Alder conditions in-
volving 1. When it is combined with an activated dieno-
phile (DMAD) and 1, cycloaddition occurs only with
DMAD. However, addition of [(naph)Rh(COD)]SbF6 to
this mixture results in elimination and subsequent Rh(I)
catalyzed cycloaddition to afford cycloadduct 13a in high
yield. With Rh(I) catalysis, a large variety of commercially
the
addition
(dimethyl
fumarate
then
N-
phenylmaleimide) results in a similar outcome (73%).
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
available alkynes can be employed in the same fashion as a 1 M solution of DMTB and the chloroaryne precursor 18
1
2
3
4
5
6
7
8
post-Peterson elimination dienophiles providing the cor-
responding cycloadducts in one operation in good to ex-
cellent yields (13a-h, 14, 15, Table 2). Internal and termi-
nal alkynes worked equally well. Of further synthetic
note, the resultant tetrahydronaphthalenes can be readily
transformed to the fully aromatic naphthalene core using
DDQ, as exemplified by the transformation of 13a to its
naphthalene derivative in 80% yield (See Supplementary
Information).
were added to a solution of N-ethylmaleimide. Under
these conditions (See Supplementary Information), 1.2 g
of the desired hexahydroanthracene 19 was obtained in
86% yield. Oxidation of 19 utilizing a modified Wohl-
Ziegler procedure furnished the desired anthracene core
2049 (96% yield) and modified C-N coupling chemistry
readily produced the desired 6-DMA (21) in 80% yield.50
This new fluorophore is thus formed in only three syn-
thetic operations in 72% overall yield from chloroaryne
precursor 18 and DMTB.
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
Initial attempts to perform sequential metal-
catalyzed [4+2] cycloadditions between DMTB and al-
kynes, i.e. involving catalysis of each step of the cycload-
dition/elimination/cycloaddition sequence, led to low
yields due to decomposition of DMTB under the reaction
conditions. The use of THP-DMTB circumvented this
problem and allowed for successful conversion to 2:1 ad-
ducts of an alkyne and TME equivalent (17, Table 2). Due
to the facility of the elimination at room temperature, the
conditions used for the synthesis of 17 were not amenable
to accessing 1:1:1 adducts resulting from the use of differ-
ent alkynes. However, a change in solvent and reduction
in temperature (0 °C) for the initial cycloaddition mark-
edly reduces the rate of elimination while allowing the
initial rhodium-catalyzed [4+2] cycloaddition to proceed.
Allowing the reaction to warm to room temperature and
addition of a second alkyne leads efficiently to 1:1:1 cy-
cloadducts (16a-e, Table 2). Utilizing this optimized pro-
cedure in which a single catalyst under different condi-
tions is capable of effecting multiple reactions, a topic of
understandably great current interest,39 the synthesis of a
number of tetrahydronaphthalene structures resulting
from unactivated alkynes was achieved in high yield.
This recursive process provides highly step-
economical access to numerous targets of interest. Perti-
nent to our studies on drug delivery,40 this process can be
used to access solvatochromic dyes (e.g., 6-DMN41 and
ANTHRADAN42). Such agents report on their local mo-
lecular environments through changes in their observable
fluorescent properties and have found considerable use in
studies on DNA binding to proteins,43 protein-protein
interactions,9,44 membrane viscosity, dynamics, and per-
meation,45,46 and protein structure.47 Using our recursive
strategy, we set out to make 6-DMA (21), a new and po-
tentially broadly useful solvatochromic dye, as it would be
expected to exhibit enhanced photophysical properties in
biological applications relative to 6-DMN (Scheme 3).
The synthesis of the 6-DMA fluorophore also
Scheme 3. The synthesis of novel fluorophore 6-
DMAa
a(a)i. DCE, reflux, ii. 1-5% ZnCl2, 60 °C, iii. TBAF, 0 °C;
(b)i. NBS, (PhCOO)2, CCl4, reflux, 17 h, ii. NEt3, RT, 20
min; (c) HNMe2, 5% RuPhos Pd G2, 5:1 Toluene/t-BuOH,
Cs2CO3, 100 °C, 8.5 h
The photophysical properties of the novel dye 21
are summarized in Figure 3a and 3b. 6-DMA exhibits an
acute sensitivity to its environment. The maximum emis-
sion occurs at 527 nm in toluene and 691 nm in methanol.
This corresponds to a large spectral red-shift of 164 nm in
contrast to the lower benzolog 6-DMN, which displays a
spectral red-shift of only 100 nm in the same solvents.40
Despite the large difference in emission, the solvato-
chromic shift in absorption is minimal: changing only 7
nm between the two solvents. In addition, the extension
of the chromophore from a naphthalene to an anthracene
core results in approximately a 40 nm increase in the
wavelength of maximum absorption. This is a useful
property in that lower energy light minimizes stimulating
cellular autofluorescence.51 Another important quality of
solvatochromic dyes is their ability to exhibit on/off fluo-
rescence between aprotic and protic environments re-
spectively. To investigate the potential of 6-DMA as an
on/off fluorophore the quantum yields were determined
in a number of common solvents. The highest quantum
yield (QY, ) observed for 6-DMA was in 1,4-dioxane ( =
0.48) and the lowest was in methanol ( = 0.0027). The
difference in quantum yields corresponds to a 180-fold
decrease in fluorescence intensity, which is an order of
magnitude more than 6-DMN (18-fold decrease in QY).
Research is currently underway for the derivatization of
presented a new direction for our TME studies as it re-
quired compatibility between our reagent and conditions
required for aryne generation and cycloaddition. Signifi-
cantly, in one synthetic operation, initiated by N-
ethylmaleimide cycloaddition with DMTB, followed by
zinc catalyzed elimination and TBAF triggered aryne for-
mation using an easily synthesized chloroaryne equiva-
lent, 1848, afforded the desired dye precursor 19 in 94%
yield. To avoid an undesirable exotherm on larger scales,
4
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
this new class of solvatochromic dyes to allow for incor- gents allow facile access to commonly encountered ring
1
2
3
4
5
6
poration into biological systems and will be reported on
in due course.
systems, herein illustrated in a three-step synthesis of a
promising new solvatochromic fluorophore (21). Further
studies on these fluorophores and other applications of
this methodology are ongoing in our laboratory and will
be reported in due course.
7
8
9
Detailed experimental procedures and characterization of
new compounds. Experimental procedures for 6-DMA fluo-
rescence measurements and photophysical data. This mate-
rial is available free of charge via the Internet at
http://pubs.acs.org.
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
* Email: wenderp@stanford.edu
‡These authors contributed equally.
The authors declare no competing financial interest.
This research was supported by the National Science Foun-
dation (NSF, CHE1265956) and the National Institutes of
Health (CA031845). M.S.J. gratefully acknowledges an Abbott
Laboratories Stanford Graduate Fellowship.
(1) Wender, P. A. Nat. Prod. Rep. 2014, 31 (4), 433–440.
(2) (a) Wender, P. A.; Miller, B. L. In Organic Synthesis: Theo-
ry and Applications; Hudlicky, T., Eds.; JAI Press: Greenwich, CT,
1993; Vol. 2, pp 27–66. (b) Wender, P. A.; Miller, B. L. Nature
2009, 460, 197–201.
(3) Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105 (12),
4730–4756.
(4) Pronin, S. V.; Shenvi, R. A. Nat. Chem. 2012, 4 (11), 915–920.
(5) Newton, C. G.; Drew, S. L.; Lawrence, A. L.; Willis, A. C.;
Paddon-Row, M. N.; Sherburn, M. S. Nat. Chem. 2015, 7 (1), 82–
86.
(6) Souweha, M. S.; Enright, G. D.; Fallis, A. G. Org. Lett. 2007,
9 (25), 5163–5166.
(7) Sun, C.; Wang, Q.; Brubaker, J. D.; Wright, P. M.; Lerner,
C. D.; Noson, K.; Charest, M.; Siegel, D. R.; Wang, Y.-M.; Myers,
A. G. J. Am. Chem. Soc. 2008, 130 (52), 17913–17927.
(8) Payne, M. M.; Parkin, S. R.; Anthony, J. E. J. Am. Chem.
Soc. 2005, 127 (22), 8028–8029.
(9) Loving, G. S.; Sainlos, M.; Imperiali, B. Trends Biotechnol.
2010, 28 (2), 73–83.
(10) Benedetti, E.; Kocsis, L. S.; Brummond, K. M. J. Am. Chem.
Soc. 2012, 134 (30), 12418–12421.
(11) Dowd, P. J. Am. Chem. Soc. 1970, 92 (4), 1066–1068.
(12) Alder, K.; Ackermann, O. Chem. Ber. 1954, 87 (10), 1567–
1571.
Figure 3. Photophysical data for fluorophore 6-DMA. a. Se-
lected emission spectra of 6-DMA in various solvents. Emis-
sion maxima are scaled relative to quantum yield. b. Com-
parative analysis of 6-DMA and related fluorophores
Here, we have introduced recursive reagents that
function like tetramethylethane equivalents, bringing
together, through back-to-back cycloadditions, common
building blocks in the form of alkynes, alkenes, arynes,
and heteroatomic dienophiles and efficiently producing in
one operation polycyclic ring systems of potential use in
the synthesis of natural and designed molecules. The rea-
gents allow for the coupling of two Diels-Alder cycloaddi-
tions, a Diels-Alder cycloaddition and a metal-catalyzed
cycloaddition, or two metal-catalyzed cycloadditions with
the same or different dienophiles. A range of conditions
for the crucial Peterson 1,4-elimination enables these re-
cursive cycloadditions to be achieved in one operation.
The use of [(naph)Rh(COD)]SbF6 provides a highly effec-
tive example of a catalytic cascade in which three opera-
tions are controlled by the same catalyst. These new rea-
(13) Hosomi, A.; Otaka, K.; Sakurai, H. Tetrahedron Lett. 1986,
27 (25), 2881–2884.
(14) Bauld, N. L.; Chang, C.-S. J. Am. Chem. Soc. 1972, 94 (21),
7594–7595.
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
(15) Trost, B. M.; Shimizu, M. J. Am. Chem. Soc. 1982, 104 (15),
4299–4301.
(16) Beetz, T.; Kellog, R. M. J. Am. Chem. Soc. 1973, 95 (23),
7925–7926.
(17) Gaoni, Y.; Sadeh, S. J. Org. Chem. 1980, 45 (5), 870–881.
(18) Markoulides, M. S.; Ioannou, G. I.; Manos, M. J.; Chro-
nakis, N. RSC Adv. 2013, 3 (14), 4750–4756.
(19) Hirata, G.; Yamada, N.; Sanada, S.; Onodera, G.; Kimura,
M. Org. Lett. 2015, 17 (3), 600–603.
(20) Takasu, K.; Tanaka, T.; Azuma, T.; Takemoto, Y. Chem.
Commun. 2009, 46 (43), 8246–8248.
(34) Webster, O. W.; Sharkey, W. H. J. Org. Chem. 1962, 27
(9), 3354–3355.
(35) Lee, S. I.; Park, S. Y.; Park, J. H.; Jung, I. G.; Choi, S. Y.;
Chung, Y. K.; Lee, B. Y. J. Org. Chem. 2006, 71 (1), 91–96.
(36) Liao, W.; Yu, Z.-X. J. Org. Chem. 2014, 79 (24), 11949-
11960.
(37) Hilt, G.; Danz, M. Synthesis 2008, (14), 2257–2263.
(38) Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989, 111
(16), 6432–6434.
(39) Abou-Shehada, S.; Williams, J. M. J. Nat. Chem. 2014, 6
(1), 12–13.
1
2
3
4
5
6
7
8
9
(21) Alder, R. W.; Allen, P. R.; Edwards, L. S.; Fray, G. I.; Fuller,
K. E.; Gore, P. M.; Hext, N. M.; Perry, M. H.; Thomas, A. R.;
Turner, K. S. J. Chem. Soc. [Perkin 1] 1994, No. 21, 3071–3077.
(22) Stephan, C.; Munz, C.; tom Dieck, H. J. Organomet.
Chem. 1994, 468 (1–2), 273–278.
(23) Suzuki, T.; Kubomura, K.; Takayama, H. Chem. Pharm.
Bull. (Tokyo) 1991, 39 (8), 2164–2166.
(24) Wender, P. A.; Fournogerakis, D. N.; Jeffreys, M. S.; Qui-
roz, R. V.; Inagaki, F.; Pfaffenbach, M. Nat. Chem. 2014, 6 (5),
448–452.
(25) Malkov, A. V.; Kysilka, O.; Edgar, M.; Kadlčíková, A.; Ko-
tora, M.; Kočovský, P. Chem. – Eur. J. 2011, 17 (26), 7162–7166.
(26) Kinoshita, A.; Sakakibara, N.; Mori, M. J. Am. Chem. Soc.
1997, 119 (50), 12388–12389.
(27) Gregg, T. M.; Keister, J. B.; Diver, S. T. J. Am. Chem. Soc.
2013, 135 (45), 16777–16780.
(28) Gigg, J.; Gigg, R. J. Chem. Soc. C Org. 1967, No. 0, 431–434.
(29) Wender, P. A.; Williams, T. J. Angew. Chem. Int. Ed. 2002,
41 (23), 4550–4553.
(30) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97
(6), 2063–2192.
(40) Stanzl, E. G.; Trantow, B. M.; Vargas, J. R.; Wender, P. A.
Acc. Chem. Res. 2013, 46, 2944-2954.
(41) Vázquez, M. E.; Blanco, J. B.; Imperiali, B. J. Am. Chem.
Soc. 2005, 127 (4), 1300–1306.
(42) Lu, Z.; Lord, S. J.; Wang, H.; Moerner, W. E.; Twieg, R. J. J.
Org. Chem. 2006, 71 (26), 9651–9657.
(43) Riedl, J.; Pohl, R.; Ernsting, N. P.; Orság, P.; Fojta, M.; Ho-
cek, M. Chem. Sci. 2012, 3 (9), 2797–2806.
(44) Cohen, B. E.; McAnaney, T. B.; Park, E. S.; Jan, Y. N.; Box-
er, S. G.; Jan, L. Y. Science 2002, 296 (5573), 1700–1703.
(45) Klymchenko, A. S.; Kreder, R. Chem. Biol. 2014, 21 (1), 97–
113.
(46) Kreder, R.; Pyrshev, K. A.; Darwich, Z.; Kucherak, O. A.;
Mély, Y.; Klymchenko, A. S. ACS Chem. Biol.[Online early ac-
cess]. DOI: 10.1021/cb500922m. Published Online: Feb. 24, 2015.
http://pubs.acs.org/doi/abs/10.1021/cb500922m (accessed March
10, 2015).
(47) Macgregor, R. B.; Weber, G. Nature 1986, 319 (6048), 70–
73.
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
(48) Peña, D.; Cobas, A.; Pérez, D.; Guitián, E. Synthesis 2002,
No. 10, 1454–1458.
(49) Wang, Z.; Kim, C.; Facchetti, A.; Marks, T. J. J. Am. Chem.
Soc. 2007, 129 (44), 13362–13363.
(50) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130 (21), 6686–6687.
(31) Fleming, I.; Morgan, I. T.; Sarkar, A. K. J. Chem. Soc. [Per-
kin 1] 1998, No. 17, 2749–2764.
(32) Anthony, J. E.; Eaton, D. L.; Parkin, S. R. Org. Lett. 2002, 4
(1), 15–18.
(33) Zhang, J.; Smith, Z. C.; Thomas, S. W. J. Org. Chem. 2014,
79 (21), 10081–10093.
(51) Berezin, M. Y.; Achilefu, S. Chem. Rev. 2010, 110 (5), 2641–
2684.
6
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
For Table of Contents Only
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
7
ACS Paragon Plus Environment