Enantioselective counter-anions in photoredox catalysis: The asymmetric cation radical Diels-Alder reaction

Article abstract of DOI:10.1016/j.tet.2018.03.052

Control of absolute stereochemistry in radical and ion radical transformations is a major challenge in synthetic chemistry. Herein, we report the design of a photoredox catalyst system comprised of an oxidizing pyrilium salt bearing a chiral N-triflyl pho

Full text of DOI:10.1016/j.tet.2018.03.052

Accepted Manuscript
Enantioselective counter-anions in photoredox catalysis: The asymmetric cation
radical Diels-Alder reaction
Peter D. Morse, Tien M. Nguyen, Cole L. Cruz, David A. Nicewicz
PII:
S0040-4020(18)30325-9
10.1016/j.tet.2018.03.052
TET 29392
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 January 2018
Revised Date: 22 March 2018
Accepted Date: 23 March 2018
Please cite this article as: Morse PD, Nguyen TM, Cruz CL, Nicewicz DA, Enantioselective counter-
anions in photoredox catalysis: The asymmetric cation radical Diels-Alder reaction, Tetrahedron (2018),
doi: 10.1016/j.tet.2018.03.052.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Enantioselective counter-anions in
photoredox catalysis: the asymmetric cation
radical Diels-Alder reaction
Leave this area blank for abstract info.
Peter D. Morse, Tien, M. Nguyen, Cole L. Cruz and David A. Nicewicz
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Enantioselective counter-anions in photoredox catalysis: the asymmetric cation
radical Diels-Alder reaction
Peter D. Morse a, Tien M. Nguyen a, Cole L. Cruz a and David A. Nicewicz a,*
aDepartment of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Control of absolute stereochemistry in radical and ion radical transformations is a major
challenge in synthetic chemistry. Herein, we report the design of a photoredox catalyst system
comprised of an oxidizing pyrilium salt bearing a chiral N-triflyl phosphoramide anion. This
class of chiral organic photoredox catalysts is able to catalyze the formation of cation radical-
mediated Diels-Alder transformations in up to 75:25 e.r. in both intramolecular and
intermolecular examples.
Available online
Keywords:
photoredox
catalysis
2009 Elsevier Ltd. All rights reserved
.
enantioselective
cycloaddition
chiral anion
for similar conjugate addition reactions.4 The Knowles group has
demonstrated absolute stereocontrol in ketyl radical chemistry,
enabled by a key proton-coupled electron transfer event to
generate the reactive species that is coordinated to a chiral
Brønsted acid catalyst.5 Additionally, enzymatic processes have
recently been shown to be compatible with photoredox catalysis
and allow for enantioinduction.6 These methods have proven to
be very powerful, and share many common features. In each
case, the reactions proceed by a mechanism in which the starting
material is reduced by the photoredox catalyst in order to arrive
at the desired reactive intermediate. The substrates for these
reactions also all contain functional groups, specifically
carbonyls, which serve as sites for association with the chiral co-
catalyst, via either covalent or non-covalent interactions.
1. Introduction
In recent years, research in the field of photoredox catalysis
has resulted in the development of numerous, powerful new
transformations for organic synthesis that are complementary to
reactions proceeding by two electron processes.1 A central
challenge in the field is the development of methods to conduct
these reactions in an asymmetric manner, as access to
enantiopure products is critical for the development of new
bioactive compounds. However, photoredox catalysis is distinct
from other common modes of catalysis in a way which makes
developing enantioselective reactions especially challenging.
Namely, after the key electron (or energy) transfer event occurs
between substrate and catalyst, the two are no longer necessarily
associated in solution. Subsequent bond-forming steps can
therefore take place off-catalyst, which poses a challenge to
traditional methods for asymmetric induction, such as
introducing chiral ligands to the catalyst. Success in this field
therefore requires engineering systems in which the activated
substrate is necessarily associated with an element of chirality
during the enantiodetermining step of the reaction. Several key
advances have recently been made in this area, though reports
remain sparse (Scheme 1).
Yoon: Lewis Acid/
Photoredox Catalysis
MacMillan: Enamine Catalysis
Me
O
N
[Eu]*
O
R
R'
N
EWG
R
R'
R''
Meggers: Lewis Acid/
Photoredox Dual Catalysis
Knowles: Proton Coupled Electron
Transfer
O
R*
R*
The state of the art in this field includes MacMillan’s use of
chiral enamine catalysis, which affords excellent stereocontrol in
reactions with electron-deficient radical partners.2 The Yoon
group has developed a dual photoredox/Lewis acid catalyst
system that enables enantioselective [2+2] cycloaddition
reactions, as well as radical conjugate addition reactions.3 The
Meggers group has developed a chiral-at-Iridium complex
capable of acting both as a Lewis acid and photoredox catalyst
[Ir]*
O
O
O
N
P
H
R
EWG
OH
O
N
R
R'
Me
Scheme 1. Asymmetric photoredox catalysis – prior art

2
Tetrahedron
ACCEPTED MANUSCRIPT
An archetypal example of a reaction that operates via this
control the absolute stereochemistry of these types of reactions
manifold is the cation-radical Diels-Alder reaction (Scheme 2).
(Scheme 2). In a single example reported by Schuster, low levels
of enantioinduction (15% ee, yield not given) were observed in a
cation-radical Diels-Alder reaction promoted by a neutral,
axially-chiral cyanoarene photosensitizer, lending support to this
hypothesis.11 Moreover, a recent report utilizing an acridinium
This transformation was initially reported by Bauld7 using
ground-state one-electron oxidants, and has been greatly
expanded upon through photoredox manifolds in recent years by
the Yoon group and others.8 The reaction is powerful due to its
ability to enable Diels-Alder reactions between pairs of electron-
rich dienes and dienophiles. The transformation begins with the
one-electron oxidation of the electron-rich dienophile i (Scheme
2). The dienophile is now rendered electrophilic (ii), and readily
undergoes cyclization with diene iii, giving intermediate iv. One-
electron reduction of this intermediate furnishes the final product
v, and also serves to either turn over the catalyst, or propagate the
reaction via a chain mechanism.9
photooxidant
showed
enantioinduction
in
a
hydrofunctionalization reaction using a chiral anion.12
We therefore set out to develop a new class of organic
photoredox catalysts, in which a pyrylium-based photooxidant is
paired with a chiral anion, and ascertain whether these
compounds could be used to control the absolute stereochemistry
of the cation radical Diels-Alder reaction. The design of this
catalyst system is especially appealing to us, as the goal of ion
pairing directly with the radical-cation intermediates circumvents
the need for chelating functional groups, such as carbonyls, to be
present in the substrates.
The Cation-Radical Diels-Alder Reaction:
EDG
EDG
Photoredox
Catalyst
EDG
EDG
+
2. Results and Discussion
hυ
racemic
At the outset of the project, we hypothesized that the chiral
anion would need to be sufficiently non-nucleophilic in nature in
order to avoid directly reacting with either the photo-oxidant or
charged intermediates. We focused our attention on anions
derived from chiral Bronsted acids, due to their tunable steric and
Proposed Mechanism:
EDG
EDG
EDG
v
i
*
[Cat]
A
[Cat]
hv
A
electronic properties 13
They have also been successfully
.
employed as chiral anions in a number of previously reported
transformations.14 Triaryl pyryliums were chosen as the
photooxidant due to their easily tunable high excited state
reduction potentials, mono-cationic nature, and prior use as
catalysts in Diels-Alder reactions.10
[Cat]
A
SET
SET
Proposed Key Ion-
Pairing Interaction
[Cat]
EDG
[Cat]
EDG
EDG
A
ii
We found that the preparation of the desired oxopyrylium salts
could be accomplished in a very straightforward manner. A
precursor ene-dione molecule was found to undergo an acid
promoted cyclization to the oxopyrylium when heated in the
presence of an appropriate chiral Bronsted acid. This strategy
proved general and allowed us to construct our library of chiral
catalysts. Furthermore, the salts have proven to be highly stable
and can be stored on the bench top for extended periods of time.
A
iv
EDG
iii
= Single Electron Transfer
This work:
SET
Oxopyrylium
Photoredox Catalyst:
R
Ar
Ar
BF4
A series of catalysts were evaluated bearing different
couteranion structures with triene 2a as the substrate (Table
O
O
P
O
X
1). In general, anions derived from
N-trifylphosphoramides
Ar
O
Ar
Ar
O
Ar
afforded the desired Diels-Alder adduct whereas chiral
phosphate anions did not, possibly due to the higher
nucleophilicity of the latter species. We also found that
sterically demanding groups were necessary at the 3,3’-
positions of the BINOL-derived anions, with triphenylsilyl
groups ultimately proving most effective. We attribute this
success to two factors: in addition to creating a highly
demanding chiral environment, the bulky nature of the
triphenylsilyl groups may also further decrease the effective
nucleophilicity of the anion, thereby enhancing reactivity.
Toluene proved uniquely effective as a solvent during an
initial screen. Conversion was observed in dichloromethane,
but no enantioselectivity. Nonpolar, non-aromatic solvents
were not successful, likely due in part to poor catalyst
solubility. 1e was explored as well, the conjugate acid of
which has recently been reported as a highly effective
Brønsted acid catalyst15, gave conversion to the desired
product in dichloromethane, but did not give appreciable
levels of enantioselectivity under several conditions.
Catalyst 1c proved uniquely effective and so was carried
forward for further study.
[Cat]
A
1
R
Enantioinduction via:
EDG
EDG
O
O
O
P
X
R
close ion pairing in non-polar media
Scheme 2. The cation radical Diels-Alder reaction and current work
Pyrylium salts are a class of organic photoredox catalysts that
are strong one-electron photooxidants and are known catalysts
for this transformation.10 Being cationic in nature, they also bear
a non-coordinating anion, such as a tetrafluoroborate (BF4) anion.
Based on the proposed mechanism for the reaction, if it were to
be run in a relatively non-polar solvent, then presumably the BF4
anion would become paired with the cation radical intermediates
of the reaction (ii and iv) after electron transfer occurs. This led
us to consider whether an ion pairing interaction between a
radical cation intermediate and chiral counterion could be used to

3
favourable π-stacking interactions helping to organize the
ACCEPTED MANUSCRIPT
Table 1. Optimization of enantioselective Diels-Alder
transition state of the desired pathway, though further study is
required to elucidate the exact nature of the interactions involved.
reactiona
H
i-Pr
i-Pr
O
3.5 mol % catalyst
Table 2. Solvent effect on enantioselectivity of Diels-Alder
O
reactiona
470 nm LEDs
H
PMP
PMP
PhMe, –20
C
Entry
Solvent Dielectric
Yield[%]
d.r.
e.r.
2a
3a
72 h
constant (ɛr)b
PMP = -C6H4(4-OMe)
1
2
3
4
PhCF3
PhBr
9.22
5.45
2.38
2.36
23
10:1
3:1
6:1
--
61:39
66:34
75:25
72:28
27
PhMe
Xylenes
75
<10
b
aSame reaction conditions as Table 1, Entry 3. Values
taken from ref 17.
We then investigated the scope of the intramolecular
cycloaddition reaction with a series of triene substrates under
the optimized reaction conditions (Figure 1). Substitution at
the 2-position of the diene proved to be critical for obtaining
both moderate yields and levels of enantioinduction –
replacement with less bulky substituents (i.e. Me, 3d) resulted
in complete loss of enantiocontrol. Furthermore, the use of
other linkers other than an ether (i.e. NTs, 3e) also resulted in
an inexplicable loss of enantioselectivity for the cycloaddition
reaction.
Entry
Catalyst
Solvent
Yield[%]b d.r.b
e.r.c
1
1a
1b
1c
1c
1c
1c
1d
1e
1e
1e
1e
PhMe
PhMe
PhMe
DCM
THF
<5
<5
72
44
<5
<5
<5
<5
53
25
25
--
--
2
--
--
3
6:1
10:1
--
75:25
50:50
--
4
5
6
Et2O
--
--
7
PhMe
PhMe
DCM
PhCF3
DCM:PhMe
(9:1)
--
--
8d
9d,e
10d
11d
--
--
6:1
6:1
6:1
51:49
50:50
53:47
a
Reactions were carried out in dry PhMe [0.2 M] in a
cooling bath, with strips of blue LEDs (λmax = 470 nm) coiled
around the reactions (see supporting information for details).
1
bDetermined by H NMR spectroscopic analysis of the crude
reaction mixture relative to the internal standard (Me3Si)2O.
cDetermined by HPLC analysis of purified material using a
chiral stationary phase. dReaction performed using a 2.5 mol %
catalyst loading. eReaction performed at -30 °C.
Figure 1. Scope of the intramolecular enantioselective cation radical
Diels-Alder reaction
Given the promising results with toluene, we probed the effect
of the aromatic solvent identity further using catalyst 1c and
substrate 2a (Table 2). Overall, we observed a general trend that
enantioselectivity is inversely correlated with solvent dielectric
constant ɛr. This observation supports our hypothesis that close
ion pairing is necessary for the relay of chiral information from
anion to substrate.16 The requirement for aromatic solvents to be
used is intriguing as well, especially since a modest 61:39 e.r.
was observed in trifluorotoluene, despite it being more polar (ɛr =
9.22) than dichloromethane (ɛr = 8.93).16 We attribute this to
We also tested a number of intermolecular reactions, and the
results are summarized in Figure 2. Using the highly reactive
cyclopentadiene with PMP-styrene derivatives resulted in the
formation of [2.2.1]-bicycloheptenes in good levels of
diastereocontrol, with similar levels of enantiocontrol observed in
the intramolecular reactions (4a and 4b, eq 1). In the absence of
the single electron oxidation catalyst, no product formation was
observed. Cryogenic temperatures (–60 °C) were required to
observe any enantioselectivity in the [4+2] reaction. Less reactive

4
Tetrahedron
ACCEPTED MANUSCRIPT
dienes such as 2,3-dimethyl-1,3-butadiene gave only trace
spec detector (MSD). Thin layer chromatography (TLC) was
amounts of the desired cyclohexene adduct 4c, but again with
similar levels of stereocontrol (75:25 e.r., eq 2).
performed on SiliaPlate 250 ꢀm thick silica gel plates purchased
from Silicycle. Visualization was accomplished using
fluorescence quenching, KMnO4 stain, or ceric ammonium
molybdate (CAM) stain followed by heating. Organic solutions
were concentrated under reduced pressure using a Büchi rotary
evaporator. Purification of the reaction products was carried out
by chromatography using Siliaflash-P60 (40-63 ꢀm) or
Siliaflash-T60 (5-20 ꢀm) silica gel purchased from Silicycle.
All reactions were carried out under an inert atmosphere of
nitrogen in flame-dried glassware with magnetic stirring unless
otherwise noted. Irradiation of photochemical reactions was
carried out using a Par38 Royal Blue Aquarium LED lamp
(Model # 6851) fabricated with high-power Cree LEDs as
purchased from Ecoxotic (www.ecoxotic.com), with standard
borosilicate glass vials purchased from Fisher Scientific. Yield
refers to isolated yield of analytically pure material unless
otherwise noted. NMR yields were determined using
hexamethyldisiloxane as an internal standard.
Figure 2. Scope of the intermolecular enantioselective cation radical
All materials were used as received unless otherwise stated.
Starting materials for the synthesis of substrates 2a-e were
synthesized according to known procedures and spectral data
matched those already reported (see supporting information).
Diels-Alder reaction
3. Conclusions
In summary, we have developed a novel class of chiral
photoredox catalysts consisting of a cationic oxopyrylium
photooxidant bearing a chiral anion. In this report, we have
demonstrated that this catalyst system is capable of modest levels
of control of the absolute stereochemistry of cation radical Diels-
Alder reactions. These results serve as an important proof-of-
concept that ion pairing between cation radical intermediates and
chiral anions is a viable and potentially general mode of
asymmetric induction for these transformations. It is noteworthy
that the substrates used in this reaction do not posses any
additional functional handles, such as carbonyls, for coordination
with the catalyst, which are typically required in other reported
enantioselective Diels-Alder reactions, as well as enantioselective
photoredox reactions. We are currently interested in using the
knowledge gained from this study to further improve the design
of our catalysts, as well as apply them to new reaction manifolds.
4.2. Procedure for Asymmetric Cation-Radical Diels-Alder
Reactions (Figure 1 and 2)
Substrate (0.2 mmol) and 1c (3.5 mol-%) were added to a
flame dried vial with stir bar added, covered in aluminum foil to
block light, and transferred to a glove box. The material was
dissolved in PhMe (1.0 mL) and the vial was sealed. The vial was
then removed from the glove box and placed in a cryobath set to
the appropriate tempterature after removing the foil cover. The
cryobath contained an irradiation setup consisting of blue LED
strips wrapped around a small section of a test tube rack (pictured
below). After stirring and cooling for 10 minutes in darkness, the
sample was irradiated by the LEDs for 72h. The reaction mixture
was passed through a plug of silica and eluted with DCM to
remove the catalyst. The crude mixture was then concentrated
and purified by column chromatography.
4.2.1. 6-isopropyl-4-(4-methoxyphenyl)-1,3,3a,4,5,7a-
hexahydroisobenzofuran (3a)
4. Experimental Data
4.1. General Methods
Compound 3a was prepared according to the general procedure
and obtained in a 57% yield as a colorless solid after purification
by column chromatography with silica gel and DCM; 1H NMR:
(400 MHz, CDCl3) δ 7.18 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.6
Hz, 2H), 5.61 (s, 1H), 4.12 (t, J = 7.2 Hz, 1H), 3.82 (s, 4H), 3.44
(dd, J = 11.6, 7.0 Hz, 1H), 3.34 (dd, J = 11.2, 7.7 Hz, 1H), 2.86
(td, J = 11.2, 6.2 Hz, 1H), 2.67 – 2.54 (m, 1H), 2.54 – 2.42 (m,
Infrared (IR) spectra were obtained using a Jasco 260 Plus
Fourier transform infrared spectrometer. Proton, carbon, and
fluorine magnetic resonance spectra (1H NMR and 13C NMR)
were recorded on a Bruker model DRX 400 or 600 (1H NMR at
400 MHz or 600 MHz and 13C NMR at 100 MHz or 150 MHz
spectrometer. Chemical shifts for protons are reported in parts
per million downfield from tetramethylsilane and are referenced
to residual protium in solvent (1H NMR: CHCl3 at 7.26 ppm).
Chemical shifts for carbons are reported in parts per million
downfield from tetramethylsilane and are referenced to the
carbon resonances of the residual solvent peak (13C NMR: CDCl3
at 77.0 ppm). NMR data are represented as follows: chemical
shift, multiplicity (s = singlet, d = doublet, dd = doublet of
doublet, ddd = doublet of doublet of doublet, dddd = doublet of
doublet of doublet of doublet, dtd = doublet of triplet of doublet, t
= triplet, q = quartet, qd = quartet of doublet, sept = septuplet, m
= multiplet), coupling constants (Hz), and integration. Mass
spectra were obtained using either a Micromass Quattro II (triple
quad) instrument with nanoelectrospray ionization or an Agilent
6850 series gas chromatograph instrument equipped with a split-
mode capillary injection system and Agilent 5973 network mass
1H), 2.34 – 2.08 (m, 3H), 1.05 (dd, J = 6.8, 1.7 Hz, 6H); 13
C
NMR: (100 MHz, CDCl3) δ 158.0, 146.4, 137.1, 127.6, 115.8,
113.9, 71.4, 71.4, 70.6, 55.2, 55.2, 48.5, 45.3, 42.70, 38.1, 34.4,
21.6, 21.5, 21.4; MS (GC-MS) Calculated m/z = 272.17, Found
m/z = 272.20; IR (thin film): 3902, 3870, 3819, 3801, 3749,
3710, 3031, 2959, 2929, 2869, 2003, 1792, 1732, 1584, 1463
4.2.2. 6-cyclohexyl-4-(4-methoxyphenyl)-1,3,3a,4,5,7a-
hexahydroisobenzofuran (3b)
Compound 3b was prepared according to the general procedure
and obtained in a 63% yield as a colorless solid after purification
by column chromatography with silica gel and DCM; 1H NMR:
(400 MHz, CDCl3) δ 7.14 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.7
Hz, 2H), 5.56 (s, 1H), 4.08 (t, J = 7.2 Hz, 1H), 3.79 (s, 3H), 3.76
(t, J = 7.3 Hz, 1H), 3.40 (dd, J = 11.6, 7.0 Hz, 1H), 3.30 (dd, J =
11.2, 7.7 Hz, 1H), 2.83 (td, J = 11.2, 6.2 Hz, 1H), 2.63 – 2.51 (m,
1H), 2.51 – 2.40 (m, 1H), 2.25 – 2.06 (m, 2H), 1.89 – 1.61 (m,

5
6H), 1.33 – 1.06 (m, 5H); 13C NMR: (101 MHz, CDCl3) δ 158.1,
2.61 (q, J = 10.4 Hz, 1H), 2.40 (dd, J = 18.2, 6.4 Hz, 1H), 2.22
ACCEPTED MANUSCRIPT
145.9, 137.2, 127.6, 116.2, 114.0, 71.5, 70.6, 55.2, 48.6, 45.3,
45.0, 42.8, 38.90, 32.2, 32.1, 26.7, 26.3.; MS (GC-MS)
Calculated m/z for [M] = 312.21, Found m/z for [M] = 312.22; IR
(thin film): 2924, 2851, 1611, 512, 1448, 1302, 1249, 1178,
1110, 1035
(qd, J = 11.2, 6.9 Hz, 1H), 2.12 (ddt, J = 14.5, 10.7, 5.5 Hz, 1H).
13C NMR: (151 MHz, CDCl3) δ 158.1, 140.1, 139.4, 136.7,
128.8, 128.3, 127.6, 126.1, 120.3, 113.9, 77.2, 76.7, 71.28, 70.62,
55.2, 48.6, 45.4, 43.6, 42.6, 39.9.
MS (GC-MS) Calculated m/z = 320.43, Found m/z = 320.20
IR (thin film): 3082, 3060, 3027, 3000, 2932, 2908, 2836, 1652,
1607, 1577, 1511, 1495, 1453, 1441, 1420
4.2.3. 6-benzyl-4-(4-methoxyphenyl)-1,3,3a,4,5,7a-
hexahydroisobenzofuran (3c)
Compound 3c was prepared according to the general procedure
and obtained in a 43% yield as a colorless solid after purification
by column chromatography with silica gel and DCM; 1H NMR:
(600 MHz, CDCl3) δ 7.28 (dd, J = 15.8, 8.4 Hz, 2H), 7.21 (t, J =
7.4 Hz, 1H), 7.17 (d, J = 7.5 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H),
6.82 (d, J = 8.2 Hz, 2H), 5.64 (s, 1H), 4.10 (t, J = 7.3 Hz, 1H),
3.78 (s, 3H), 3.76 (t, J = 7.4 Hz, 1H), 3.44 (dd, J = 11.6, 7.1 Hz,
1H), 3.40 – 3.20 (m, 3H), 2.82 (td, J = 11.2, 6.3 Hz, 1H), 2.61 (q,
J = 10.4 Hz, 1H), 2.40 (dd, J = 18.2, 6.4 Hz, 1H), 2.22 (qd, J =
4.3. Procedure for Formation of Chiral Anion Pyrylium Salts
(Table 1)
The Brønsted acid (1 equiv.) and 1f (1 equiv.) were added to
a vial and suspended in EtOH. Upon heating to approx. 60 °C
using a heat gun for 5 minutes, all material dissolved and the
solution took on a bright orange color. The crude reaction
mixture was allowed to cool and concentrated upon complete
consumption of the starting material. The crude product was
dissolved in MeOH and shaken with hexanes. After separation,
concentration of the MeOH layer and drying under high vacuum
overnight afforded pure oxopyrilium salts. These compounds are
benchtop stable for several days but should be stored at low
temperatures for extended periods.
11.2, 6.9 Hz, 1H), 2.12 (ddt, J = 14.5, 10.7, 5.5 Hz, 1H); 13
C
NMR: (151 MHz, CDCl3) δ 158.1, 140.1, 139.4, 136.7, 128.8,
128.3, 127.6, 126.1, 120.3, 113.9, 77.2, 76.7, 71.28, 70.62, 55.2,
48.6, 45.4, 43.6, 42.6, 39.9; MS (GC-MS) Calculated m/z =
320.43, Found m/z = 320.20; IR (thin film): 3082, 3060, 3027,
3000, 2932, 2908, 2836, 1652, 1607, 1577, 1511, 1495, 1453,
1441, 1420
4.2.4. 6-methyl-4-(4-methoxyphenyl)-1,3,3a,4,5,7a-
hexahydroisobenzofuran (3d)
4.3.1. 2,4,6-tris(4-methoxyphenyl)pyrylium ((11bR)-4-oxido-
2,6-diphenyldinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-
yl)((trifluoromethyl)sulfonyl)amide (1a)
Compound 3d was prepared according to the general procedure
and obtained in a 10% yield as a colorless solid after purification
by column chromatography with silica gel and DCM; 1H NMR:
(600 MHz, CDCl3) δ 7.16 – 7.11 (m, 2H), 6.85 (d, J = 8.6 Hz,
2H), 5.56 (s, 1H), 4.08 (t, J = 7.2 Hz, 1H), 3.79 (s, 3H), 3.76 (t, J
= 7.4 Hz, 1H), 3.41 (dd, J = 11.6, 7.0 Hz, 1H), 3.31 (dd, J = 11.2,
7.7 Hz, 1H), 2.85 (td, J = 11.2, 6.3 Hz, 1H), 2.56 (d, J = 9.9 Hz,
1H), 2.40 (dd, J = 18.1, 6.5 Hz, 1H), 2.19 (m, 2H), 1.70 (s,
3H);13C NMR: (151 MHz, CDCl3) δ 158.1, 137.0, 136.8, 127.7,
118.8, 114.0, 71.4, 70.7, 55.2, 48.6, 45.5, 42.7, 41.9, 22.9; MS
(GC-MS) Calculated m/z = 244.15, Found m/z = 244.20; IR (thin
film): 3082, 3060, 3027, 3000, 2932, 2908, 2836, 1652, 1607,
1577, 1511, 1495, 1453, 1441, 1420
Compound 1a was prepared according to the general procedure
and obtained in a 74% yield as an orange solid after extraction.;
1H NMR: (600 MHz, CDCl3) δ 8.03 – 7.72 (m, 14H), 7.49 – 7.38
(m, 2H), 7.32 (dd, J = 28.8, 8.5 Hz, 2H), 7.24 (t, J = 7.7 Hz, 4H),
7.09 (d, J = 3.7 Hz, 4H), 6.77 (d, J = 8.5 Hz, 4H), 6.33 (d, J = 8.4
Hz, 2H); 13C NMR: (151 MHz, CDCl3) δ 166.8, 165.4, 164.6,
161.4, 138.0, 137.0, 134.7, 134.1, 132.4, 132.2, 131.2, 131.1,
131.0, 130.4, 130.3, 130.0, 130.0, 128.3, 128.2, 127.7, 127.1,
127.0, 127.0, 126.9, 126.2, 125.9, 125.2, 125.2, 123.4, 120.3,
115.3, 115.2, 109.8, 55.6, 55.2; MS (ESI) Calculated m/z for [M-
H] = 862.21, Found m/z for [M-H] = 863.21778, Calculated m/z
for [M+] = 399.16, Found m/z for [M+] = 399.15859; IR (thin
film): 3432, 2077, 1631, 1606, 1589, 1512, 1484, 1438, 1306,
1261, 1243, 1178, 1096
4.2.5. 6-isopropyl-4-(4-methoxyphenyl)-2-tosyl-
2,3,3a,4,5,7a-hexahydro-1H-isoindole (3e)
Compound 3e was prepared according to the general procedure
and obtained in a 42% yield as a colorless solid after purification
by column chromatography with silica gel and DCM; 1H NMR:
(600 MHz, CDCl3) δ 7.72 – 7.68 (m, 2H), 7.33 (d, J = 7.9 Hz,
2H), 7.09 – 7.05 (m, 2H), 6.90 – 6.85 (m, 2H), 5.47 (s, 1H), 3.83
(s, 3H), 3.70 (dd, J = 9.1, 7.3 Hz, 1H), 3.33 (dd, J = 9.5, 6.8 Hz,
1H), 2.94 (dd, J = 11.8, 9.1 Hz, 1H), 2.75 (dd, J = 11.3, 9.5 Hz,
1H), 2.68 (td, J = 11.2, 6.2 Hz, 1H), 2.46 (s, 1H), 2.37 (ddt, J =
17.9, 6.2, 1.8 Hz, 1H), 2.30 – 2.22 (m, 1H), 2.17 (p, J = 6.9 Hz,
1H), 2.13 – 2.05 (m, 1H), 1.92 (qd, J = 11.3, 6.8 Hz, 1H), 0.99
(dd, J = 6.9, 3.8 Hz, 6H); 13C NMR: (151 MHz, CDCl3) δ 158.3,
146.7, 143.1, 136.0, 129.6, 127.6, 127.2, 116.1, 114.1, 55.2, 52.3,
51.3, 47.3, 43.8, 43.1, 37.3, 34.4, 21.5, 21.5, 21.3; MS (ESI)
Calculated m/z for [M+H] = 426.2103, Found m/z for [M+H] =
426.2082
4.3.2. 2,4,6-tris(4-methoxyphenyl)pyrylium ((11bR)-4-oxido-
2,6-bis(triphenylsilyl)dinaphtho[2,1-d:1',2'
f][1,3,2]dioxaphosphepin-4-yl)((trifluoromethyl)sulfonyl)amide
(1b)
Compound 1b was prepared according to the general procedure
and obtained in a 83% yield as an orange solid after extraction.;
1H NMR: (600 MHz, CDCl3) δ 8.27 (d, J = 9.0 Hz, 4H), 8.16 (s,
2H), 8.13 (d, J = 8.6 Hz, 2H), 7.97 (s, 2H), 7.69 (d, J = 8.3 Hz,
2H), 7.64 – 7.52 (m, 12H), 7.33 (d, J = 8.5 Hz, 2H), 7.29 (t, J =
7.5 Hz, 2H), 7.22 (t, J = 7.7 Hz, 2H), 7.01 (d, J = 7.8 Hz, 18H),
6.91 (d, J = 8.7 Hz, 4H), 6.48 (d, J = 8.4 Hz, 2H), 3.67 (s, 6H),
3.33 (s, 3H); 13C NMR: (151 MHz, CDCl3) δ 167.0, 165.3, 164.5,
161.9, 141.0, 136.9, 135.4, 134.4, 133.6, 130.7, 129.8, 128.5,
128.5, 127.1, 126.9, 126.3, 124.1, 123.9, 122.4, 121.5, 115.3,
115.1, 111.4, 77.2, 77.0, 76.7, 55.7, 55.5; MS (LTQ FT-ICR MS)
Calculated m/z for [M-] = 862.21, Found m/z for [M-] =
863.21778, Calculated m/z for [M+] = 399.16, Found m/z for
[M+] = 399.15862; IR (thin film): 3428, 3069, 3049, 2937, 2041,
1628, 1604, 1512, 1486, 1438, 1408, 1262, 1244, 1178, 1104
4.3.3. 2,4,6-tris(4-methoxyphenyl)pyrylium ((11bR)-4-oxido-
2,6-bis(triphenylsilyl)-8,9,10,11,12,13,14,15-
4.2.2. 5-ethyl-6-(4-methoxyphenyl)bicyclo[2.2.1]hept-2-ene (4b)
Compound 4b was prepared according to the general procedure
and obtained in a 43% yield as a colorless solid after purification
by column chromatography with silica gel and DCM.
1H NMR: (600 MHz, CDCl3) δ 7.28 (dd, J = 15.8, 8.4 Hz, 2H),
7.21 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 7.5 Hz, 2H), 7.09 (d, J = 8.6
Hz, 2H), 6.82 (d, J = 8.2 Hz, 2H), 5.64 (s, 1H), 4.10 (t, J = 7.3
Hz, 1H), 3.78 (s, 3H), 3.76 (t, J = 7.4 Hz, 1H), 3.44 (dd, J = 11.6,
7.1 Hz, 1H), 3.40 – 3.20 (m, 3H), 2.82 (td, J = 11.2, 6.3 Hz, 1H),
octahydrodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-
yl)((trifluoromethyl)sulfonyl)amide (1c)

6
Tetrahedron
Compound 1c was prepared according to the general procedure
417.17, Found m/z for [M+H] = 417.20; IR (thin film): 3056,
ACCEPTED MANUSCRIPT
and obtained in a 74% yield as an orange solid after extraction.;
1H NMR: (600 MHz, CDCl3) δ 8.27 (s, 2H), 8.25 – 8.14 (m, 6H),
7.64 – 7.45 (m, 14H), 7.13 – 6.96(m, J = 8.7 Hz, 24H), 6.94 (d, J
= 8.4 Hz, 2H), 3.91 (s, 6H), 3.82 (s, 3H), 2.79 – 2.54 (m, 6H),
2.40 (d, J = 16.7 Hz, 1H), 2.30 (d, J = 17.9 Hz, 1H), 1.90 – 1.55
(m, 8H); 13C NMR: (151 MHz, CDCl3) δ 167.6, 166.2, 165.0,
162.2, 136.9, 136.9, 135.5, 134.9, 133.2, 130.5, 128.4, 128.4,
127.0, 126.9, 124.3, 121.3, 116.0, 115.7, 111.0, 56.2, 55.9, 29.2,
29.0, 27.9, 27.8, 22.9, 22.8, 22.7; MS (LTQ FT-ICR MS)
Calculated m/z for [M-H] = 1002.25, Found m/z for [M-H] =
1002.26177, Calculated m/z for [M+] = 399.16, Found m/z for
[M+] = 399.15867; IR (thin film): 3734. 3648. 3586, 1716, 1588,
1508, 1487, 1243, 1177, 1105
3008, 2961, 2935, 2838, 2571, 2048, 1810, 1677, 1645, 1600,
1509, 1461, 1440, 1423, 1363, 1316
4.4. Procedure for Formation of Diels-Alder Substrates
(Figure 1)
Diene alcohol was dissolved in THF (0.2 M) in a flame-dried
round bottom flask and kept under positive pressure of N2. The
solution was cooled to -78 °C in a dry ice/acetone batch. n-BuLi
(2.5 M in hexane, 1.1 equiv.) added dropwise via syringe. After
stirring for ~5 minutes, MsCl (1.2 equiv.) was added dropwise
via syringe, and solution then stirred for an additional 30
minutes. At the same time, a separate round bottom flask was
charged with LiBr (4.5 equiv.), 4 Å molecular sieves, and THF.
The solution was stirred for 15 minutes and transferred slowly
via cannula into the reaction mixture. Reaction continued stirring
at -78 °C for 30 minutes, then the dry ice/acetone bath was
removed and the reaction continued to stir at room temperature
for 1.5 hours. The mixture was quenched by the addition of
saturated aqueous ammonium chloride extracted 3x with Et2O,
dried over Na2SO4, and concentrated under reduced pressure. The
crude product was dissolved in dry THF (0.2 M) and stirred for 1
hour over 4 Å molecular sieves. Meanwhile, 4-methoxycinnamyl
alcohol (1.5 equiv) was added in small portions to a stirred
solution of NaH (1.6 equiv, 60% dispersion in mineral oil) in dry
THF (0.2 M) at 0 °C. The mixture was stirred for 15 minutes,
then the solution containing the alkyl bromide was transferred via
cannula over several minutes. The reaction was allowed to warm
to room temperature and stirred for 4 hours. The reaction was
quenched by the slow addition of saturated aqueous ammonium
chloride and extracted 3x with Et2O. Combined organic layers
were dried over Na2SO4 and concentrated. Products were purified
by column chromatography using EtOAc/Hexanes.
4.3.4. 2,4,6-tris(4-methoxyphenyl)pyrylium ((11bR)-2,6-bis(1-
mesityl-1H-1,2,3-triazol-4-yl)-4-oxido-8,9,10,11,12,13,14,15-
octahydrodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-
yl)((trifluoromethyl)sulfonyl)amide (1d)
Compound 1d was prepared according to the general procedure
and obtained in a 56% yield as an orange solid after extraction.;
1H NMR: (600 MHz, CDCl3) δ 8.57 (s, 2H), 8.29 (s, 3H), 8.17 (d,
J = 8.4 Hz, 6H), 7.92 (s, 2H), 7.03 (d, J = 8.2 Hz, 4H), 6.89 (s,
2H), 6.82 (s, 4H), 3.86 (s, 6H), 3.74 (s, 3H), 2.88 (dd, J = 15.0,
7.7 Hz, 2H), 2.85 – 2.67 (m, 2H), 2.69 – 2.54 (m, 2H), 2.26 (s,
6H), 2.21 (d, J = 16.5 Hz, 2H), 1.88 (s, 12H), 1.82 – 1.64 (m,
6H), 1.52 (dt, J = 10.3, 4.8 Hz, 2H); 13C NMR: (151 MHz,
CDCl3) δ 167.9, 165.9, 165.1, 162.3, 142.7, 139.4, 134.9, 133.4,
132.1, 130.2, 128.8, 128.2, 127.9, 125.9, 124.1, 120.9, 115.7,
115.6, 110.4, 77.2, 77.0, 76.7, 55.8, 29.1, 27.8, 22.7, 22.5, 21.0,
17.4; MS (LTQ FT-ICR MS) Calculated m/z for [M-] = 727.31,
Found m/z for [M-] = 727.31472, Calculated m/z for [M+] =
399.16, Found m/z for [M+] = 399.15862; IR (thin film): 2938,
2844, 2044, 1630, 1604, 1512, 1485, 1463, 1439, 1307, 1261,
1243, 1178
4.3.5. 2,4,6-tris(4-methoxyphenyl)pyrylium 1,2,3,4,5-
pentakis((((1S,2R,5S)-2-isopropyl-5-
4.4.1. 1-((E)-3-(((E)-4-isopropylpenta-2,4-dien-1-
yl)oxy)prop-1-en-1-yl)-4-methoxybenzene n (2a)
methylcyclohexyl)oxy)carbonyl)cyclopenta-2,4-dien-1-ide (1e)
Compound 1e was prepared according to the general procedure
and obtained in a 86% yield as an orange solid after extraction.;
1H NMR: (600 MHz, CDCl3) δ 8.44 (s, 2H), 8.38 (d, J = 8.5 Hz,
2H), 8.25 (d, J = 8.4 Hz, 4H), 7.05 (d, J = 8.4 Hz, 4H), 6.95 (d, J
= 8.5 Hz, 2H), 6.89 (s, 2H), 6.82 (s, 4H), 4.74 (m, 5H) 3.90 (s,
6H), 3.88 (s, 3H), 2.15 – 0.68 (m, 95H); 13C NMR: (151 MHz,
CDCl3) δ 169.0, 168.0, 167.1, 166.3, 163.4, 132.9, 131.4, 125.6,
122.0, 117.1, 116.8, 116.6, 111.9, 73.3, 57.3 47.2, 40.0, 34.3,
32.2, 24.5, 23.1, 22.6, 21.8, 16.8; MS (LTQ FT-ICR MS)
Calculated m/z for [M-] = 975.6916, Found m/z for [M-] =
975.6930, Calculated m/z for [M+] = 399.1590, Found m/z for
[M+] = 399.1590;
Compound 2a was prepared according to the general procedure
and obtained in a 57% yield as a colorless solid after purification
by column chromatography with silica gel and DCM; 1H NMR:
(400 MHz, CDCl3) δ 7.18 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.6
Hz, 2H), 5.61 (s, 1H), 4.12 (t, J = 7.2 Hz, 1H), 3.82 (s, 4H), 3.44
(dd, J = 11.6, 7.0 Hz, 1H), 3.34 (dd, J = 11.2, 7.7 Hz, 1H), 2.86
(td, J = 11.2, 6.2 Hz, 1H), 2.67 – 2.54 (m, 1H), 2.54 – 2.42 (m,
1H), 2.34 – 2.08 (m, 3H), 1.05 (dd, J = 6.8, 1.7 Hz, 6H); 13
C
NMR: (100 MHz, CDCl3) δ 158.0, 146.4, 137.1, 127.6, 115.8,
113.9, 71.4, 71.4, 70.6, 55.2, 55.2, 48.5, 45.3, 42.70, 38.1, 34.4,
21.6, 21.5, 21.4; MS (GC-MS) Calculated m/z = 272.17, Found
m/z = 272.20; IR (thin film): 3902, 3870, 3819, 3801, 3749,
3710, 3031, 2959, 2929, 2869, 2003, 1792, 1732, 1584, 1463
4.4.2. 1-((E)-3-(((E)-4-cyclohexylpenta-2,4-dien-1-
4.3.6. (Z)-1,3,5-tris(4-methoxyphenyl)pent-2-ene-1,5-dione
(1f)
To a clean dry RBF was added triaryloxopyrylium
yl)oxy)prop-1-en-1-yl)-4-methoxybenzene (2b)
tetrafluoroborate and sodium acetate. Then the solids were
dissolved in a 1:1 mixture of DCM/H2O. Equipped with reflux
condenser and heated to 50 °C overnight. Cooled to room
temperature then the organic and aqueous layers separated, then
the aqueous layer was extracted with DCM 3x, organic layers
combined and washed with brine, dried over Na2SO4 and
concentrated in vacuo. Chromatographed in 25% EtOAc/Hexanes
to give the desired product (40%).
Compound 2b was prepared according to the general procedure
and obtained in a 63% yield as a colorless solid after purification
by column chromatography with silica gel and DCM; 1H NMR:
(400 MHz, CDCl3) δ 7.14 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.7
Hz, 2H), 5.56 (s, 1H), 4.08 (t, J = 7.2 Hz, 1H), 3.79 (s, 3H), 3.76
(t, J = 7.3 Hz, 1H), 3.40 (dd, J = 11.6, 7.0 Hz, 1H), 3.30 (dd, J =
11.2, 7.7 Hz, 1H), 2.83 (td, J = 11.2, 6.2 Hz, 1H), 2.63 – 2.51 (m,
1H), 2.51 – 2.40 (m, 1H), 2.25 – 2.06 (m, 2H), 1.89 – 1.61 (m,
6H), 1.33 – 1.06 (m, 5H); 13C NMR: (101 MHz, CDCl3) δ 158.1,
145.9, 137.2, 127.6, 116.2, 114.0, 71.5, 70.6, 55.2, 48.6, 45.3,
45.0, 42.8, 38.90, 32.2, 32.1, 26.7, 26.3.; MS (GC-MS)
Calculated m/z for [M] = 312.21, Found m/z for [M] = 312.22; IR
(thin film): 2924, 2851, 1611, 512, 1448, 1302, 1249, 1178,
1110, 1035
1H NMR: (400 MHz, CDCl3) δ = 8.08 (d, J = 8.8 Hz, 2 H), 8.01
(d, J = 8.8 Hz, 6 H), 7.53 (d, J = 8.8 Hz, 2 H), 7.42 (s, 1 H), 7.01
- 6.90 (m, 6 H), 4.86 (s, 2 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.85 (s,
3 H); 13C NMR: (101 MHz, CDCl3) δ = 195.1, 189.4, 163.5,
163.2, 160.6, 151.7, 134.3, 132.3, 130.6, 128.3, 121.8, 114.1,
113.7, 55.5, 42.3; MS (GC-MS) Calculated m/z for [M+H] =

7
4.4.3. 1-((E)-3-(((E)-4-benzylpenta-2,4-dien-1-yl)oxy)prop-
1-en-1-yl)-4-methoxybenzene (2c)
2H), 7.09 – 7.05 (m, 2H), 6.90 – 6.85 (m, 2H), 5.47 (s, 1H),
ACCEPTED MANUSCRIPT
3.83 (s, 3H), 3.70 (dd, J = 9.1, 7.3 Hz, 1H), 3.33 (dd, J = 9.5, 6.8
Hz, 1H), 2.94 (dd, J = 11.8, 9.1 Hz, 1H), 2.75 (dd, J = 11.3, 9.5
Hz, 1H), 2.68 (td, J = 11.2, 6.2 Hz, 1H), 2.46 (s, 1H), 2.37 (ddt, J
= 17.9, 6.2, 1.8 Hz, 1H), 2.30 – 2.22 (m, 1H), 2.17 (p, J = 6.9 Hz,
1H), 2.13 – 2.05 (m, 1H), 1.92 (qd, J = 11.3, 6.8 Hz, 1H), 0.99
(dd, J = 6.9, 3.8 Hz, 6H); 13C NMR: (151 MHz, CDCl3) δ 158.3,
146.7, 143.1, 136.0, 129.6, 127.6, 127.2, 116.1, 114.1, 55.2, 52.3,
51.3, 47.3, 43.8, 43.1, 37.3, 34.4, 21.5, 21.5, 21.3; MS (ESI)
Calculated m/z for [M+H] = 426.2103, Found m/z for [M+H] =
426.2082
Compound 2c was prepared according to the general procedure
and obtained in a 43% yield as a colorless solid after purification
by column chromatography with silica gel and DCM; 1H NMR:
(600 MHz, CDCl3) δ 7.28 (dd, J = 15.8, 8.4 Hz, 2H), 7.21 (t, J =
7.4 Hz, 1H), 7.17 (d, J = 7.5 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H),
6.82 (d, J = 8.2 Hz, 2H), 5.64 (s, 1H), 4.10 (t, J = 7.3 Hz, 1H),
3.78 (s, 3H), 3.76 (t, J = 7.4 Hz, 1H), 3.44 (dd, J = 11.6, 7.1 Hz,
1H), 3.40 – 3.20 (m, 3H), 2.82 (td, J = 11.2, 6.3 Hz, 1H), 2.61 (q,
J = 10.4 Hz, 1H), 2.40 (dd, J = 18.2, 6.4 Hz, 1H), 2.22 (qd, J =
11.2, 6.9 Hz, 1H), 2.12 (ddt, J = 14.5, 10.7, 5.5 Hz, 1H); 13
C
NMR: (151 MHz, CDCl3) δ 158.1, 140.1, 139.4, 136.7, 128.8,
128.3, 127.6, 126.1, 120.3, 113.9, 77.2, 76.7, 71.28, 70.62, 55.2,
48.6, 45.4, 43.6, 42.6, 39.9; MS (GC-MS) Calculated m/z =
320.43, Found m/z = 320.20; IR (thin film): 3082, 3060, 3027,
3000, 2932, 2908, 2836, 1652, 1607, 1577, 1511, 1495, 1453,
1441, 1420
Acknowledgments
4.4.4. 1-((E)-3-(((E)-4-methylpenta-2,4-dien-1-
yl)oxy)prop-1-en-1-yl)-4-methoxybenzene (2d)
This project was supported by Award No. R01 GM098340
from the National Institute of General Medical Sciences and an
Eli Lilly Grantee Award (DAN). We are grateful to the Lambert
group for providing chiral acid precursor for the synthesis of
catalyst 1e.
Compound 2d was synthesized according to the following
alteration to the general procedure: The 4-OMe cinnamyl alcohol
was dissolved in THF (0.2 M) in a flame-dried round bottom
flask and kept under positive pressure of N2. The solution was
cooled to 0 °C in a dry ice/acetone batch. n-BuLi (2.5 M in
hexane, 1.1 equiv.) added dropwise via syringe. After stirring for
~5 minutes, MsCl (1.2 equiv.) was added dropwise via syringe,
and solution then stirred for an additional 30 minutes. At the
same time, a separate round bottom flask was charged with LiBr
(4.5 equiv.), 4 Å molecular sieves, and THF. The solution was
stirred for 15 minutes and transferred slowly via cannula into the
reaction mixture. Reaction continued stirring at 0 °C for 30
minutes, then the bath was removed and the reaction continued to
stir at room temperature for 1.5 hours. The mixture was quenched
by the addition of saturated aqueous ammonium chloride,
extracted 3x with Et2O, dried over Na2SO4, and concentrated
under reduced pressure. The crude product was dissolved in dry
THF (0.2 M) and stirred for 1 hour over 4 Å molecular sieves.
Meanwhile, s15 (1.5 equiv) was added in small portions to a
stirred solution of NaH (1.6 equiv, 60% dispersion in mineral oil)
in dry THF (0.2 M) at 0 °C. The mixture was stirred for 15
minutes, then the solution containing the alkyl bromide was
transferred via cannula over several minutes. The reaction was
allowed to warm to room temperature and stirred for 16 hours.
The reaction was quenched by the slow addition of saturated
aqueous ammonium chloride and extracted 3x with Et2O.
Combined organic layers were dried over Na2SO4 and
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concentrated. Products were purified by column chromatography
using 10% EtOAc/Hexanes, affording the final product as a
viscous yellow oil (34%).
; 1H NMR: (600 MHz, CDCl3) δ 7.16 – 7.11 (m, 2H), 6.85 (d, J =
8.6 Hz, 2H), 5.56 (s, 1H), 4.08 (t, J = 7.2 Hz, 1H), 3.79 (s, 3H),
3.76 (t, J = 7.4 Hz, 1H), 3.41 (dd, J = 11.6, 7.0 Hz, 1H), 3.31 (dd,
J = 11.2, 7.7 Hz, 1H), 2.85 (td, J = 11.2, 6.3 Hz, 1H), 2.56 (d, J =
9.9 Hz, 1H), 2.40 (dd, J = 18.1, 6.5 Hz, 1H), 2.19 (m, 2H), 1.70
(s, 3H);13C NMR: (151 MHz, CDCl3) δ 158.1, 137.0, 136.8,
127.7, 118.8, 114.0, 71.4, 70.7, 55.2, 48.6, 45.5, 42.7, 41.9, 22.9;
MS (GC-MS) Calculated m/z = 244.15, Found m/z = 244.20; IR
(thin film): 3082, 3060, 3027, 3000, 2932, 2908, 2836, 1652,
1607, 1577, 1511, 1495, 1453, 1441, 1420
4.4.5. N-((E)-3-(4-methoxyphenyl)allyl)-4-methyl-N-((E)-
5-methyl-4-methylenehex-2-en-1-yl)benzenesulfonamide (2e)
Compound 2e was prepared according to the general procedure
and obtained in a 42% yield as a colorless solid after purification
by column chromatography with silica gel and DCM; 1H NMR:
(600 MHz, CDCl3) δ 7.72 – 7.68 (m, 2H), 7.33 (d, J = 7.9 Hz,
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Tetrahedron
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