Studies toward the AB ring system of the tetrapetalone natural products

Article abstract of DOI:10.1016/j.tet.2015.05.021

Abstract Synthetic efforts toward the rapid assembly of the AB ring system of the tetrapetalones is described. Key to this work was the use of [3+2] cycloaddition/oxidative extrusion methodology to furnish functionalized aryl enones. The Nazarov cyclization of these substrates was examined, and optimized to generate the AB ring carbon skeleton. Then, Pd-catalyzed cross-coupling were conducted, and conditions were identified that enabled installatiion of the requisite C14-N bond.

Full text of DOI:10.1016/j.tet.2015.05.021

Tetrahedron 71 (2015) 5886e5896
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies toward the AB ring system of the tetrapetalone natural
products
*
Peter N. Carlsen, Chao Jiang, Ildiko R. Herrick, Alison J. Frontier
Department of Chemistry, University of Rochester, Rochester, NY 14627, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetic efforts toward the rapid assembly of the AB ring system of the tetrapetalones is described. Key
to this work was the use of [3þ2] cycloaddition/oxidative extrusion methodology to furnish function-
alized aryl enones. The Nazarov cyclization of these substrates was examined, and optimized to generate
the AB ring carbon skeleton. Then, Pd-catalyzed cross-coupling were conducted, and conditions were
identified that enabled installatiion of the requisite C14eN bond.
Received 17 March 2015
Received in revised form 5 May 2015
Accepted 6 May 2015
Available online 14 May 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Cross-coupling
Cyclization
Natural products
Polycycles
1. Introduction
in the conversion of arachidonic acid to the leukotrienes, which are
signaling molecules implicated in several inflammatory diseases.5
In 2003, Hirota and co-workers isolated tetrapetalone A (1,
Fig. 1) from a Streptomyces culture broth, and this natural product
was found to inhibit soybean lipoxygenase (SLO).1,2 Tetrapetalones
B (2), C (3), and D (4) were also isolated from a Streptomyces culture
extract in a separate report, and these natural products were also
found to inhibit SLO.3 Since the catalytic domain of plant and
mammalian lipoxygenases is highly conserved,4 the study of an SLO
inhibitor like tetrapetalone A could lead to the identification of new
human lipoxygenase (HLO) inhibitors. HLOs catalyze the first step
The SLO inhibition of the tetrapetalones was moderate, but
comparable to known SLO inhibitors kojic acid and nordihy-
droguaiaretic acid (NDGA) (Table 1).3,6 However, when tetrapet-
alone A was derivatized to tetrapetalone A-Me (5) via treatment of
1 with diazomethane, all SLO inhibitory activity was eliminated
(entry 5).6 5 was subjected to acidic hydrolysis to furnish tetra-
Table 1
Inhibitory activities of 1e5 against soybean lipoxygenase
Compound
IC50 (mM)
1
2
190e460
320
3
360
4
240
5
>1000
110e280
190e290
Kojic acid (positive control)
NDGA (positive control)
petalone A-Me aglycon (6), and the absolute configuration of this
material was determined by the preparation of Mosher esters.6
Hirota and co-workers also discovered the radical scavenger
ansaetherone (7) present in a Streptomyces culture extract, and
theorized that it could be an intermediate in the biosynthesis of the
tetrapetalones.7
Fig. 1. Structures of tetrapetalones AeD, derivatives, and ansaetherone.
* Corresponding author. Tel.: þ1 585 275 2568; fax: þ1 585 276 0205; e-mail
address: frontier@chem.rochester.edu (A.J. Frontier).
http://dx.doi.org/10.1016/j.tet.2015.05.021
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

P.N. Carlsen et al. / Tetrahedron 71 (2015) 5886e5896
5887
The tetrapetalone natural products possess a
b-D-rhodinose
moiety connected to a tetracyclic core with unprecedented com-
plexity. Key features of this core include a para-quinol A ring, a five-
membered B ring containing four contiguous stereogenic centers,
a 7-membered C ring containing a bridging trisubstituted olefin,
and a tetramic acid D ring. Furthermore, a study whereby Strepto-
myces were fed 13C-enriched building blocks revealed that the
rhodinose moiety is derived from glucose, the A ring is derived
from 3-amino-5-hydroxybenzoic acid, and the remainder of the
molecule is constructed from propanoate and butanoate building
blocks, probably by the action of polyketide synthase.8
To date, a total synthesis of tetrapetalone A has not been re-
ported, though several laboratories have published synthetic ap-
proaches. The first report appeared in 2005 by Porco and co-
workers, who sought to test a biosynthetic hypothesis: the tetra-
cyclic core was formed through an oxidative transannular [4þ3]
cyclization of an ansa-bridged macrocycle.9a While the group ini-
tially reported the success of this strategy, a later disclosure in-
dicated that while oxidation had been successful, the cycloaddition
had not.9b In 2010, Sarpong and co-workers published an approach
that culminated in the first synthesis of the tetracyclic skeleton of
the tetrapetalone system.10 In brief, they constructed the AB ring
system via Nazarov cyclization, ABD ring system via Paal-Knorr
methodology, and the ABCD ring system via an oxidation/Frie-
deleCrafts acylation/oxidation cascade.10 Two other approaches
toward the tetrapetalone core have been published by Hong
(2009)11 and Pettus (2014).12
Scheme 2. Aryl enone synthesis via Knoevenagel condensation.
We solved this problem by employing a different method pre-
viously explored in our group for the mild construction of aryl
enones.14b,17 As shown in Scheme 3, alkynes of type 14 and nitrones
of type 15 undergo [3þ2] cycloaddition followed by oxidative
chelotropic extrusion of nitrosomethane to furnish aryl enones of
type 16. The results are shown in Table 2. For example, the protocol
furnished aryl enone 16a, containing the requisite methyl group on
C6, from alkyne 14a and nitrone 15a (entry 1). This substrate could
not be prepared using the Knoevenagel condensation protocol in
Scheme 2. The olefin geometry of aryl enone 16a was determined to
be predominantly Z (>19:1 ratio), by examining the 3J coupling
constants between the ketone carbon and the ester carbon with the
C7 proton, which were obtained using selective proton-decoupled
carbon NMR techniques.18 In an attempt to prepare the aryl
enone unsubstituted at the alkene terminus, which we thought
would be optimal for subsequent C ring formation, nitrone 15b was
tested in the cycloaddition, but it decomposed under the elevated
thermal conditions. Fortunately, nitrone 15c, featuring a vinyl tri-
methylsilyl group, underwent smooth cycloaddition/extrusion
(entry 3). The trimethyl silyl group stabilizes the nitrone and serves
as a protecting group for the desired 1,1-disubstituted alkene, as it
is readily removed under acidic conditions (vide infra).
In 2014, our group reported the first synthesis of tetrapetalone
A-Me aglycon (6).13 Herein is an account of our early work on the
project, detailing Nazarov cyclization studies targeting the inda-
none precursor to the AB ring system, and the installation of the
C14eN bond of the A ring.
2. Results/discussion
From the outset, we planned to construct the AB ring system
using a polarized Nazarov cyclization on a substrate resembling aryl
enone 8, to form bicycle 9 (Scheme 1).14 This strategy would allow
us to convert the aromatic A ring into a para-quinol in a late-stage
transformation, and the
b-ketoester to a cyclopentane with the
requisite C9 alkoxy group and C8 methyl group. Based on our earlier
work on cyclizations of polarized aromatic systems,15 and Sarpong’s
study of a closely related cyclization,16 we expected the cyclization
to be possible, but perhaps difficult to achieve catalytically, and
certainly difficult to achieve enantioselectively.
Scheme 3. [3þ2] Cycloaddition/oxidative extrusion cascade for preparation of func-
tionalized aryl enones.
Table 2
Synthesis of aryl enones 16aee via [3þ2] cycloaddition/oxidative extrusion cascade
Entry
R1
R2
Yield
dr
1
2
3
4
5
6
OTIPS (14a)
OTIPS (14a)
OTIPS (14a)
Br (14b)
Br (14b)
Br (14b)
Ph (15a)
H (15b)
TMS (15c)
Ph (15a)
TMS (15c)
TBS (15d)
80% (16a)
d
nda (16b)
85% (16c)
79% (16d)
77% (16e)
>19:1 (Z:E)
d
5:1
>20:1
1.7:1
Scheme 1. Outline of the polarized Nazarov cyclization in the context of AB ring
construction.
7.1:1
a
Not determined. See Experimental section.
Over the course of our investigations on the tetrapetalone ring
system, we prepared and cyclized a number of different aryl vinyl
ketones. Aryl vinyl ketone 13 was easily prepared utilizing a Kno-
venagel condensation protocol previously reported in our group
We also prepared aryl bromides 16cee (entries 4e6) using the
[3þ2] cycloaddition/cheletropic extrusion sequence. As in entries 1
and 3, nitrones 15a and 15c underwent the reaction cascade
(Scheme 2).14 However, Knoevenagel condensation of
a-methyl-
trans-cinnamaldehyde with b-ketoester 12 failed.

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P.N. Carlsen et al. / Tetrahedron 71 (2015) 5886e5896
smoothly (entries 4 and 5). The more robust vinyl tert-butyldime-
thylsilane was also prepared, as alternative protection for the 1,1
disubstituted alkene (entry 6).
of 16d to these conditions, or to (TMS)NTf2,20 resulted in de-
composition (entries 5 and 6). However, aryl enone 16d did cyclize
upon treatment with either superstoichiometric AlCl316 (entry 7) or
Sc(OTf)3 (entry 8), furnishing indanone 18d. As in entry 3, proto-
desilylation occurred under the reaction conditions.
We were curious to see whether the protodesilylation was
contributing to the decomposition seen in the experiments in en-
tries 5 and 6. Hence, we examined the Nazarov cyclization of aryl
enone 16e, with the assumption that its vinyl tert-butyldime-
thylsilyl group would not be cleaved as readily as a vinyl trime-
thylsilyl group. Unfortunately, attempts to catalyze the cyclization
of 16e with Sc(OTf)3/Li(ClO4), Cu(OTf)2/Li(ClO4), Al(OTf)3, and (TMS)
NTf2 all resulted in decomposition. As in entry 7, super-
stoichiometric AlCl3 promoted the cyclization, affording indanone
With aryl dienones 13 and 16aee in hand, we could evaluate
conditions for Nazarov cyclization (Table 3). Nazarov cyclization of
13 with catalytic Cu(OTf)2 gave the trans cyclopentanone as the
only detectable product in 81% yield (entry 1). A similar result was
obtained with aryl enone 16a using catalytic Cu(ClO4)2 (entry 2).
When aryl enone 16b was subjected to Cu2þ catalysis, cleavage of
the TMS group occurred, presumably due to trace Bronsted acid
present in the reaction mixure (entry 3).19 This convenient desily-
lation facilitated the ring-closing metathesis studies that led to the
formation of the C ring.13 Indanone 18b was isolated (in crude form)
as a 3:1 mixture of trans:cis isomers (see experimental section).
Table 3
Synthesis of indanones via Nazarov cyclization
#
Starting material
Conditions
Product
Yield; dr (trans:cis)
81%; >20:1
1
5 mol % Cu(OTf)2, DCE, 60 ꢀC
2
3
4
5 mol % Cu(ClO4)2, DCE, 45 ꢀC
75%; >20:1
5 mol % Cu(ClO4)2, DCE, rt
nda; 3:1
cat. Sc(OTf)3/Li(ClO4), DCE, 45 ꢀC
81%; 3:1
5
cat. Sc(OTf)3/Li(ClO4), DCE, 45 ꢀC
db
6
7
8
16d
16d
16d
(TMS)NTf2
1.1 equiv AlCl3, DCE, 0 ꢀC
1.1 equiv Sc(OTf)3, DCE, rt
18d
18d
18d
db
71%; 3.6:1
46%; 3.6:1
9
1.1 equiv AlCl3, DCE, 0 ꢀC
18d
w70e75%; 3.6:1
a
Not determined. See Experimental section.
Decomposition.
b
The inclusion of the electron-withdrawing bromide group on
18d. Thus, appending the bulkier TBS group on the vinyl terminus
in place of the more labile TMS group did not appear to have any
effect on the efficiency of the cyclization.
As shown in Scheme 4, indanone 18a was functionalized (at C8)
and converted to the aryl triflate in preparation for the anticipated
installation of the C17eN bond via Buchwald-Hartwig cross-cou-
pling. Thus,18a was decarbalkoxylated,21 and methylated to furnish
indanone 19 (Scheme 4). This material was then globally
aryl enone substrates predictably reduced the reactivity of these
substrates in the Nazarov cyclization reaction. For example, treat-
ment of 16c with catalytic Sc(OTf) at 45 ꢀC resulted in no reaction. It
was only by using the Sc(OTf)3/Li(ClO4) catalyst combination
(which we had used previously to cyclize other unreactive aryl
enones)15 that an 81% yield of 18c could be obtained from 16c, as
a 3:1 mixture of trans:cis isomers (entry 4). Surprisingly, subjection

P.N. Carlsen et al. / Tetrahedron 71 (2015) 5886e5896
5889
We originally planned to install the requisite C14eN bond using
the powerful and versatile Buchwald-Hartwig cross-coupling
technology (Table 4).22 Initially, we tried the cross-coupling of aryl
triflate 20 with lactam 26 (entry 1),23 with no success. We next
attempted cross-coupling with tertiary amine 27, with a sub-
stitution pattern mapping onto C4 of tetrapetalone A. Our initial
experiment again resulted in no reaction (entry 2), but use of the
stronger base NaOtBu resulted in detectable amounts of cross-
coupled products (entry 3). It was clear that the poor results of
these initial studies were due to the considerable steric hindrance
of both coupling partners: the ortho-substituted aryl triflate and the
tertiary amine.
Scheme 4. Transformation of 18a to aryl triflate 20.
To test this hypothesis, we attempted cross-coupling between
aryl triflate 22 (containing the more robust methyl ether protecting
group on C12) and the less sterically hindered amines 29 and 31
(entries 4 and 5). The result was a dramatic increase in the yield of
the reaction. We also attempted the cross-coupling of the imine
3324 with aryl triflate 21, which delivered the imine derivative 34 in
modest yield (entry 6). Imine 34 could be hydrolyzed to the aniline
(35) in 56% yield using aqueous acid.
deprotected with TBAF, chemoselectively protected at the less
hindered hydroxyl group, and then treated with triflic anhydride
and pyridine to furnish aryl triflate 20.
Aryl triflate 21 was synthesized following the reactions in
Scheme 4, except the C8 methyl group was not installed. This ma-
terial was then deprotected with TBAF and methylated to furnish
aryl triflate 22 (Scheme 5).
In many instances, phenol byproducts arising from hydrolysis of
the triflyl group were detected in the reactions in entries 1e6. To
avoid this, we prepared aryl bromides to test in the cross-coupling
reactions. First, we attempted the cross coupling of sterically hin-
dered amine 27 with aryl bromide 23. Unsurprisingly, no cross-
coupled product was detected. We returned to the cross-coupling
of imine 33, which furnished aniline 35 in 27% yield after hydro-
lysis (entry 7). The next coupling partner we investigated was
ammonia, which has essentially no steric hindrance. Using the
protocol of Stradiotto,25 we were able to cross-couple ammonia to
aryl bromide 25 to furnish aniline 36 in 97% yield (entry 9). In
a previous report, we successfully elaborated aniline 36 into tet-
rapetalone A-Me aglycon (6).13
Scheme 5. Transformation of aryl triflate 21 to aryl triflate 22.
As in Scheme 4, indanone 18c was subjected to decarbalkox-
ylation to furnish aryl bromide 23. Aryl bromide 25 was prepared in
a similar fashion (Scheme 6). Indanone 18d was decarbalkoxylated,
methylated, and reduced to furnish alcohol 24, which was pro-
tected as the triisopropylsilyl ether. Importantly, both the C8
methylation and the reduction in Scheme 6 were found to be dia-
stereoselective, and the relative stereochemistry on the B ring was
confirmed by single-crystal X-ray crystallography (Fig. 2). This
relative stereochemistry also matched the desired stereochemistry
present in the B ring of tetrapetalone A.
3. Conclusions
In summary, we have described our laboratory’s strategies to-
ward the synthesis of the AB ring of the tetrapetalones. We used
three key steps to construct the important architectural features of
the AB ring system. We first used a [3þ2] cycloaddition between
strategically functionalized alkynoates and nitrones, followed by
oxidative extrusion of nitrosomethane to furnish aryl enones. Then,
we used Nazarov cyclization on these aryl enones to form the AB
ring carbon skeleton. Last, we used Pd-catalyzed cross-coupling to
install the requisite C14eN bond. Ongoing work in our laboratory is
focused on the completion of the total synthesis of tetrapetalone A,
as well as synthesis of other tetrapetalone natural products, and
evaluation of their biological activity.
4. Experimental section
4.1. General
Scheme 6. Transformation of indanone 18d to aryl bromide 25.
All reactions were carried out under an argon or N2 atmo-
sphere in flame- or oven-dried glassware with magnetic stirring
unless otherwise noted. Cold baths were prepared by mixing
acetone/dry ice (ꢁ78 ꢀC) or acetonitrile/dry ice (ꢁ40 ꢀC). Re-
agents were used as obtained from commercial suppliers without
further purification unless otherwise noted. Cu(ClO4)2 was dried
in a vacuum oven at 40 ꢀC for 24 h, then ground and stored in
a glovebox prior to use. Tetrahydrofuran, diethyl ether, methy-
lene chloride, 1,2-dichloroethane, and toluene were purchased
from Fisher and dispensed using the Glass Contour solvent pu-
rification system. Celite 545 was purchased from EMD. ACS grade
hexanes and ethyl acetate were used for column chromatogra-
phy. Thin layer chromatography (TLC) was performed on pre-
Fig. 2. ORTEP diagram of alcohol 24.

5890
P.N. Carlsen et al. / Tetrahedron 71 (2015) 5886e5896
Table 4
C14eN bond formation studies
#
Starting material
Conditions
Product
Yield
1
da
da
K3PO4, Pd(PPh3)4, Xantphos, dioxane, 110 ꢀC
2
ea
da
Cs2CO3, Pd(OAc)2, BINAP, PhCH3, 105 ꢀC
3
21
27
db
NaOtBu, 10% Pd(OAc)2, 20% BINAP, PhCH3, 105 ꢀC
4
40%
K3PO4, 5% Pd2(dba)3, 10% DavePhos, PhCH3, 105 ꢀC
5
22
50%
Cs2CO3, 10% Pd(OAc)2, 15% BINAP, PhCH3, 100 ꢀC
6
21
28%
NaOtBu, 3% Pd2(dba)3, 4.5% BINAP, PhCH3, 90 ꢀC
7
8
33
27%
97%
NaOtBu, Pd2(dba)3, BINAP, PhCH3, 110 ꢀC; cat. HCl, THF, rt
NH3
NaOtBu, [Pd(allyl)Cl]2, Mor-DalPhos, Dioxane, PhCH3, 90 ꢀC
a
No reaction.
Trace amount of product detected.
b

P.N. Carlsen et al. / Tetrahedron 71 (2015) 5886e5896
5891
coated silica gel 60 F254 glass-supported plates from EMD, and
visualization was performed with a UV lamp followed by staining
with potassium permanganate, p-anisaldehyde, ninhydrin, or
ceric ammonium molybdate solution followed by heating. Col-
7.57 (d, J¼1.8 Hz, 1H), 7.34e7.28 (m, 5H) 7.20 (d, J¼11.5 Hz, 1H),
6.96 (d, J¼2.3 Hz, 2H), 6.67 (t, J¼2.3 Hz, 1H), 3.84 (s, 6H), 3.77 (s,
3H).
4.2.3. Alkynoate 14a. Prepared according to Ref. 17. 1H NMR
ꢀ
umn chromatography was carried out on EM Science 60 A silica
gel (230e400 mesh). Chloroform-d and Methanol-d4 was pur-
chased from Cambridge Isotope Laboratories.
(400 MHz, CDCl3)
d
6.70 (d, J¼2.4 Hz, 2H), 6.52 (t, J¼2.4 Hz,1H), 3.83
(s, 3H), 1.24 (m, 6H), 1.10 (d, J¼9.0 Hz, 36H); 13C NMR (100 MHz,
1H NMR spectra were recorded on a 400 MHz Bruker Avance
spectrometer or a 500 MHz Bruker Avance spectrometer at room
temperature. Chemical shifts are given in parts per million (ppm)
from tetramethylsilane, referenced to solvent residual proton res-
CDCl3): d 157.0, 154.5, 120.3, 117.5, 115.3, 86.6, 79.6, 52.7, 17.4, 12.6;
IR (neat, cmꢁ1): 2943.7, 2891.1, 2866.5, 2218.9, 1715.6, 1577.7,
1462.4, 1427.2, 1241.6.
onance (d¼7.26 for CHCl3,
d¼3.31 for CH3OH). Some NMR spectra
4.2.4. Alkynoate 14b. Prepared according to Ref. 13. 1H NMR
(400 MHz, CDCl3)
7.01e6.97 (m, 1H), 3.83 (s, 3H), 1.31e1.18 (m, 3H), 1.09 (d, J¼7.3 Hz,
18H). 13C NMR (100 MHz, CDCl3)
156.89, 154.26, 128.45, 126.25,
122.83, 122.67, 121.92, 84.63, 80.89, 53.04, 17.94, 12.69; IR (neat,
cmꢁ1): 2947, 2866, 2230, 1717, 1586, 1555, 1462, 1424, 1319, 1292,
1231, 1196, 1157, 976, 883, 853, 810, 733, 675, 648, 621; HRMS (ESI):
contain tetramethylsilane as an internal reference. NMR data are
reported as: chemical shift, multiplicity (s¼singlet, d¼doublet,
t¼triplet, q¼quartet, m¼multiplet, dd¼doublet of doublets,
dq¼doublet of quartets, br¼broad), coupling constants (J) given in
Hz, and integration. 13C NMR spectra were recorded on a 100 MHz
Bruker Avance spectrometer or a 125 MHz Bruker Avance spec-
trometer at room temperature with proton decoupling. Chemical
shifts are given in parts per million (ppm) from tetramethylsilane,
d
7.31e7.29 (m, 1H), 7.12 (t, J¼2.0 Hz, 1H),
d
Calculated for
411.0990.
C
19H28BrO3Si ([MþH]þ): m/z 411.0991, found:
referenced to solvent carbon resonance (
d
¼77.16). Infrared spectra
(IR) were recorded on a Shimadzu FTIR 8400S (ATR Mode) spec-
trometer or an ATI Mattson Genesis FTIR spectrometer. High reso-
lution mass spectra (HRMS) were measured by the Chemistry
Instrumentation Center of the University of Buffalo, Buffalo, NY
14260 or the Mass Spectrometry Lab of the University of Illinois,
Urbana, IL 61801. X-ray crystallography data were collected by the
X-ray Crystallographic Facility of the University of Rochester,
Rochester, NY 14627.
4.2.5. Nitrone 15a. Prepared according to Ref. 17. 1H NMR
(400 MHz, CDCl3): 8.26 (s, 1H), 7.36e7.34 (m, 5H), 6.93 (s, 1H),
3.79 (s, 3H), 2.19 (s, 3H).
d
4.2.6. Nitrone 15b. Prepared according to Ref. 17. 1H NMR
(400 MHz, CDCl3)
1.99 (s, 3H).
d 6.83 (s,1H), 6.57 (s,1H), 5.39 (s,1H), 3.73 (s, 3H),
4.2.7. Nitrone 15c. Prepared according to Ref. 13. 1H NMR
(500 MHz, CDCl3) 6.90 (s, 1H), 6.80 (s, 1H), 3.68 (s, 3H), 2.09 (s,
3H), 0.14 (s, 9H). 13C NMR (125 MHz, CDCl3)
142.15, 138.07, 137.20,
d
4.2. Preparation of intermediates
d
54.46, 20.95, ꢁ0.20. IR (neat, cmꢁ1): 2955, 2897, 1562, 1416, 1385,
1304,1246,1177,1153, 1026, 961, 918, 833, 768, 748, 691, 644; HRMS
(ESI): Calculated for C8H18NOSi ([MþH]þ): m/z 172.1158, found:
172.1155.
4.2.1.
b-Keto ester 12. In a 25 mL round-bottom flask, potassium
hydride (30% in mineral oil, 273.0 mg, 2.0 mmol) and sodium hy-
dride (60% in mineral oil, 324.4 mg, 8.1 mmol) were washed with
dry hexanes, then THF (4 mL) was added, followed by dime-
thylcarbonate (0.7 mL, 8.1 mmol), and a solution of commercially-
available 30,50-dimethoxy-acetophenone (730.7 mg, 4.1 mmol) in
THF (5 mL). The reaction was stirred in a 65 ꢀC oil bath for 2 h,
cooled, then quenched with water (20 mL). The layers were sepa-
rated, and the aqueous layer was extracted with ether (3ꢂ10 mL).
The organic phases were combined and dried over MgSO4, filtered,
and concentrated. The crude material was purified by column
chromatography (8:1 hexanes:ethyl acetate), yielding 619.7 mg
4.2.8. Nitrone 15d. Prepared in analogy to 15c. 1H NMR (400 MHz,
CDCl3)
d 6.87 (s, 1H), 6.86 (s, 1H), 3.71 (s, 3H), 2.14 (s, 3H), 0.91 (s,
9H), 0.13 (s, 6H).
4.2.9. Aryl enone 16a. In a dry 100 mL round-bottom flask was
weighed the nitrone 15a (1.40 g, 8.0 mmol), 14a (3.6 g, 7.1 mmol),
and toluene (35 mL), and the solution was heated at 80 ꢀC for 16 h.
The solution was concentrated, and CH2Cl2 (35 mL) was added,
cooled to ꢁ20 ꢀC, and m-CPBA (2.5 g, 11.6 mmol) was added and
stirred for 30 min. The reaction was quenched with saturated
Na2SO3 (50 mL), the layers were separated and the aqueous phase
was extracted with CH2Cl2 (2ꢂ50 mL), the organic phases were
combined and washed with brine (50 mL). The organic phase was
dried over Na2SO4, filtered, and concentrated. The crude material
was purified by column chromatography (8:1 hexanes:ethyl ace-
(64%) of 12. 1H NMR (400 MHz, CDCl3)
d
7.04 (d, J¼2.1 Hz, 1H), 6.65
(s, 1H), 3.95 (s, 2H), 3.80 (s, 6H), 3.73 (s, 3H). 13C NMR (101 MHz,
CDCl3)
45.85.
d 192.16, 167.95, 161.03, 137.84, 106.34, 106.03, 55.66, 52.55,
4.2.2. Aryl enone 13. In a 50 mL round-bottom flask, a solution of
-ketoester 12 (619.7 mg, 2.6 mmol) in benzene (12 mL) was
combined with piperidine (30 L, 0.3 mmol), acetic acid (90 L,
b
m
m
tate), yielding 3.0 g (65%) of 16a. 1H NMR (400 MHz, CDCl3):
d 7.66
1.6 mmol), and trans-cinnamaldehyde (0.4 mL, 2.9 mmol). The
flask was fitted with a DeaneStark trap, and refluxed for 16 h.
The reaction was cooled, diluted with benzene, and washed with
NH4Cl (50 mL), NaHCO3 (50 mL), and brine (25 mL). The organic
layer was dried over MgSO4, filtered, and concentrated. The crude
material was purified by column chromatography (8:1 hex-
anes:ethyl acetate), yielding 677.3 mg (74%) of 13. Characterized
as a mixture, E:Z¼3:1, following the procedure of Ref. 18; E iso-
(d, J¼0.8 Hz, 1H), 7.36e7.34 (m, 5H), 7.07 (d, J¼2.4 Hz, 2H), 6.98 (s,
1H), 6.65 (t, J¼2.0 Hz, 1H), 3.69 (s, 3H), 1.79 (s, 3H), 1.30e1.16 (m,
6H), 1.12 (d, J¼9.0 Hz, 36H); 13C NMR (100 MHz, CDCl3):
d 195.0,
165.8, 157.3, 147.8, 141.9, 138.9, 136.2, 133.3, 129.7, 129.2, 128.3,
128.0, 117.3, 113.7, 52.3, 17.8, 12.5; IR (neat, cmꢁ1): 3023.7, 2944.7,
2892.3, 1724.2, 1713.6, 1678.6, 1672.0, 1587.8, 1442.8, 1333.8, 1249.2,
1197.6; HRMS (EI) calculated for C38H58O5Si2 650.3817, found
3
650.3817. Z 3JCeH¼4.2 Hz for Cketone-H, JCeH¼7.5 Hz for Cester-H.
mer: 1H NMR (400 MHz, CDCl3)
d 7.73e7.67 (m, 1H), 7.43e7.35
(m, 5H), 7.08 (d, J¼2.3 Hz, 2H), 7.02 (s, 1H), 6.76 (dd, J¼15.4,
4.2.10. Aryl enone 16b. In a dry 100 mL round-bottom flask was
weighed the nitrone 15c (0.33 g, 1.94 mmol), 14a (0.5 g, 1 mmol),
11.8 Hz, 1H), 6.69 (t, J¼2.3 Hz, 1H), 3.84 (s, 6H), 3.74 (s, 3H). Z
isomer: 1H NMR (400 MHz, CDCl3)
d
7.79 (dd, J¼15.5, 11.5 Hz, 1H),

5892
P.N. Carlsen et al. / Tetrahedron 71 (2015) 5886e5896
and toluene (5 mL), and the solution was heated at 80 ꢀC for 16 h.
The solution was concentrated, and CH2Cl2 (35 mL) was added,
cooled to ꢁ20 ꢀC, and m-CPBA (0.38 g, 1.7 mmol) was added and
stirred for 30 min. The reaction was quenched with saturated
Na2SO3 (10 mL), the layers were separated and the aqueous phase
was extracted with CH2Cl2 (2ꢂ10 mL), the organic phases were
combined and washed with brine (10 mL). The organic phase was
dried over Na2SO4, filtered, and concentrated. The crude material
was used for the next step. 16b was characterized as two isomers
17.99, 17.95, 17.59, 12.70, ꢁ0.39, ꢁ0.47; IR (neat, cmꢁ1): 2947, 2893,
2866, 1728, 1593, 1562, 1435, 1385, 1366, 1343, 1281, 1250, 1215,
1169, 1099, 1057, 995, 972, 941, 914, 880, 845, 752, 733, 687, 648;
HRMS (ESI): Calculated for C26H42BrO4Si2 ([MþH]þ): m/z 553.1805,
found: 552.1814.
4.2.13. Aryl enone 16e. To a 50 ml round-bottom flask was added
15d (0.533 g, 2.5 mmol), 14b (1.028 g, 2.5 mmol), and toluene
(25 ml). The flask was purged with argon for 10 min. The reaction
mixture was heated at 80 ꢀC overnight. The solution was concen-
trated under reduced pressure. To the crude material (1.4 g) was
added CH2Cl2 (25 ml). The solution was cooled to 0 ꢀC. m-CPBA
(77%, 1.00 g) was added, and the solution stirred for 30 min. The
reaction was quenched with a saturated aqueous solution of
Na2SO3, diluted and extracted with ether, dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The crude residue
was purified by flash column chromatography (19:1 hexanes:ethyl
acetate) to afford 16e (1.147 g, 77%). 1H NMR (400 MHz, CDCl3)
(5:1) 1H NMR (400 MHz, CDCl3)
d
7.46 (d, J¼0.8 Hz,1H, maj. isomer),
7.04 (d, J¼2.0 Hz, 1H, maj. isomer), 6.89 (s, 1H, min isomer), 6.80 (s,
1H, min isomer), 6.61 (s, 1H, min isomer), 6.65 (s, 1H, maj. isomer),
6.10 (s, 1H, maj. isomer), 5.97 (s, 1H, min isomer), 3.83 (s, 3H,
min isomer), 3.67 (s, 3H, maj. isomer), 1.98 (s, 3H, min isomer), 1.69
(s, 3H, maj. isomer), 1.26e1.21 (m, 6H, both isomers), 1.11e1.09 (m,
36H, both isomers), 0.16 (s, 9H, min isomer), 0.09 (s, 9H, maj. iso-
mer); 13C NMR (125 MHz, CDCl3)
d 194.9, 165.8, 157.3, 156.9, 149.6,
148.1, 146.9, 145.8, 145.3, 138.8, 129.0, 117.3, 115.8, 113.7, 52.3, 29.7,
19.7, 17.9, 17.8, 12.6, ꢁ0.5, ꢁ0.6; IR (neat) 2945, 2867, 1726, 1678,
1585, 1461, 1439, 1332, 1237, 1168, 1028, 998 cmꢁ1; HRMS m/z calcd
for C35H63O5Si3 (MþHþ) 647.3978, found 647.3981.
d
7.63 (s, 1H), 7.51 (s, 1H), 7.32e7.28 (m, 1H), 7.23 (t, J¼1.9 Hz, 1H),
6.09 (s, 1H), 3.70 (s, 3H), 1.70 (s, 3H), 1.33e1.17 (m, 3H), 1.08 (d,
J¼7.3 Hz, 18H), 0.83 (s, 9H), 0.03 (s, 6H). 13C NMR (101 MHz, CDCl3)
d
193.74, 165.70, 157.36, 149.29, 147.51, 143.56, 139.41, 128.34,
4.2.11. Aryl enone 16c. To a 10 ml round-bottom flask was added
14b (0.617 g, 1.5 mmol), 15a (0.289 g, 1.65 mmol, 1.1 equiv), and
toluene (5 ml). The flask was purged with argon for 10 min and
heated at 80 ꢀC overnight. The reaction mixture was concentrated
under reduced pressure. To a 10 ml round-bottom flask was added
the crude material (0.75 g, 1.28 mmol) and CH2Cl2 (5 ml). The flask
was cooled to 0 ꢀC. m-CPBA (77%, 0.8625 g, 5 mmol, 3 equiv) was
added and the reaction mixture was stirred for 30 min. The reaction
mixture was quenched with a saturated aqueous solution of
Na2SO3, extracted with ether, dried over MgSO4, filtered, and con-
centrated under reduced pressure. The crude residue was purified
by flash column chromatography (9:1 hexanes:ethyl acetate) to
128.28, 124.66, 123.30, 119.25, 52.66, 26.42, 20.35, 17.94, 17.23,
12.68, ꢁ4.65.
4.2.14. Indanone 17. In a 10 mL round-bottom flask, Cu(OTf)2
(51.5 mg, 0.1 mmol) was weighed, and a solution of 13 (467.3 mg,
1.3 mmol) and DCE (5 mL) was added. The reaction was stirred in an
oil bath at 60 ꢀC for 1.5 h, then filtered through a plug of silica gel
and concentrated, yielding 372.6 mg (81%) of 17. 1H NMR (400 MHz,
CDCl3):
d
7.38e7.25 (m, 5H), 6.78 (d, J¼2.0 Hz,1H), 6.68 (d, J¼2.0 Hz,
1H), 6.50 (d, J¼15.6 Hz, 1H), 6.24 (dd, J¼8.0, 15.6 Hz, 1H), 4.53 (dd,
J¼2.8, 8.0 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 6H), 3.62 (d, J¼3.2 Hz, 1H);
13C NMR (100 MHz, CDCl3):
d 198.4, 168.7, 161.8, 157.9, 137.3, 137.0,
afford 16c (0.67 g, 94%). 1H NMR (400 MHz, CDCl3)
d
7.70 (d,
136.8, 131.1, 128.9, 128.4, 127.4, 126.2, 126.0, 106.6, 96.6, 60.9, 55.6,
52.7, 43.3; IR (neat, cmꢁ1): 3003.4, 2950.9, 2941.2, 1738.2, 1708.8,
1611.4, 1493.8, 1306.2, 1203.0; HRMS (EI) calculated for C21H21O5
353.1384, found 353.1369.
J¼0.6 Hz, 1H), 7.69 (t, J¼1.5 Hz, 1H), 7.52e7.20 (m, 7H), 7.00 (s, 1H),
3.72 (s, 3H), 1.79 (d, J¼0.9 Hz, 3H), 1.35e1.17 (m, 3H), 1.08 (d,
J¼7.3 Hz, 18H).
4.2.12. Aryl enone 16d. To a 25 ml round-bottom flask was added
alkynoate 14b (0.950 g, 2.31 mmol), nitrone 15c (0.435 g,
2.54 mmol, 1.1 equiv), and toluene (10 ml). The flask was heated at
80 ꢀC overnight. The reaction mixture was concentrated under
reduced pressure. To the crude material was added CH2Cl2 (10 ml).
The flask was cooled to 0 ꢀC. m-CPBA (77%, 1.55 g, 6.93 mmol,
3 equiv) was added and the reaction mixture was stirred for one
hour at 0 ꢀC. The reaction mixture was quenched with a saturated
aqueous solution of Na2SO3 and extracted three times with CH2Cl2.
The combined organic extracts were added to a larger solution of
saturated aqueous Na2SO3 and extracted three times with CH2Cl2.
The combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude residue was purified by flash column chromatography (19:1
hexanes:ethyl acetate) to afford aryl dienone 96 (1.12 g, 2.02 mmol,
88% yield) as an inseparable mixture of geometric isomers (1.7:1)
4.2.15. Indanone 18a. In a dry 10 mL round-bottom flask was
weighed Cu(ClO4)2 (7.0 mg, 0.03 mmol), and a solution of 16a
(341 mg, 0.5 mmol) in DCE (5 mL) was added. The solution was
stirred at 45 ꢀC and monitored by NMR (aliquots were periodically
removed from the reaction, filtered through Celite with CH2Cl2, and
concentrated) for 8 h, then the reaction mixture was filtered
through a plug of silica gel and flushed with CH2Cl2 then concen-
trated. The crude material was purified by column chromatography
(10:1 petroleum ether:ether), yielding 272 mg (80%) of 18a. 1H NMR
(400 MHz, CDCl3):
d
7.35e7.15 (m, 5H), 6.88 (d, J¼2.0 Hz, 1H), 6.66
(d, J¼2.0 Hz, 1H), 6.26 (s, 1H), 4.46 (d, J¼3.2 Hz, 1H), 3.78 (s, 3H),
3.49 (d, J¼3.2 Hz, 1H), 1.64 (s, 3H), 1.24 (m, 6H), 1.12 (d, J¼9.0 Hz,
36H); 13C NMR (100 MHz, CDCl3):
d 198.7, 169.2, 157.7, 154.5, 138.3,
138.2, 137.6, 137.4, 128.8, 127.9, 126.2, 117.3, 106.7, 61.0, 52.8, 50.0,
17.8, 12.5; IR (neat, cmꢁ1): 2945.1, 2891.1, 2866.0, 1747.4, 1712.7,
1606.6, 1479.3, 1348.2, 1180.4; HRMS (EI) calculated for C38H58O5Si2
650.3817, found 650.3817.
and vibrant yellow oil. 1H NMR (400 MHz, CDCl3)
d 7.62 (s, 1H, maj.
isomer), 7.49 (s, 1H maj. isomer), 7.39 (s, 1H, min isomer), 7.29 (s,
1H, maj. isomer), 7.24 (t, J¼1.9 Hz,1H, maj. isomer), 7.20 (t, J¼1.9 Hz,
1H, min isomer), 7.08 (s, 1H, min isomer), 6.86 (s, 1H, min isomer),
6.09 (s, 1H, maj. isomer), 6.02 (s, 1H, min isomer), 3.82 (s, 3H,
min isomer), 3.70 (s, 3H, maj. isomer), 1.97 (s, 3H, min isomer), 1.68
(s, 3H, maj. isomer), 1.31e1.19 (m, 3H), 1.15e1.05 (m, 18H), 0.16 (s,
9H, min isomer), 0.08 (s, 9H, maj. isomer); 13C NMR (100 MHz,
4.2.16. Indanone 18b. In a dry 10 mL round-bottom flask was
weighed Cu(ClO4)2 (13.0 mg, 0.05 mmol), and a solution of crude
16b from previous step in DCE (10 mL) was added. The solution was
stirred at room temperature and monitored by NMR (aliquots were
periodically removed from the reaction, filtered through Celite with
CH2Cl2, and concentrated) for 2 h, then the reaction mixture was
filtered through a plug of silica gel and flushed with CH2Cl2 con-
centrated. The crude material was used for the next step. 18b was
CDCl3)
d 193.81, 192.54, 167.28, 165.69, 157.38, 156.93, 150.29,
149.10, 146.88, 146.67, 146.42, 139.92, 139.55, 128.44, 128.31, 127.01,
124.63, 123.31, 122.86, 119.23, 119.12, 52.63, 52.58, 20.01, 18.70,
characterized as two isomers (3:1) 1H NMR (400 MHz, CDCl3)
d 6.84

P.N. Carlsen et al. / Tetrahedron 71 (2015) 5886e5896
5893
(d, 1H, J¼2.0 Hz, maj. isomer), 6.76 (d, 1H, J¼2.0 Hz, min isomer),
6.63 (d, 1H, J¼2.0 Hz, maj. isomer), 6.42 (d, 1H, J¼2.0 Hz, min iso-
mer), 5.15 (s, 1H, min isomer), 4.96 (s, 1H, min isomer), 4.82 (s, 1H,
maj. isomer), 4.70 (s, 1H, maj. isomer), 4.34 (s, 1H, min isomer), 4.30
(d, 1H, J¼2.8 Hz, maj. isomer), 3.81 (s, 1H, maj. isomer), 3.79 (s,
2.25H), 3.69 (s, 0.25H), 3.41 (d, 0.75H, J¼3.2 Hz), 1.63 (s, 3H, maj.
isomer), 1.58 (s, 3H, min isomer), 1.31e1.22 (m, 6H, both isomers),
1.13e1.11 (m, 36H, both isomers); 13C NMR (125 MHz, CDCl3)
The crude product was purified by column chromatography (16:1
hexanes:ethyl acetate) to give 2.4 g (99%) of decarboxylated inda-
none. 1H NMR (400 MHz, CDCl3):
d 7.35e7.15 (m, 5H), 6.87 (d,
J¼1.6 Hz, 1H), 6.63 (d, J¼2.0 Hz, 1H), 6.23 (s, 1H), 4.14 (dd, J¼2.0,
8.0 Hz, 1H), 3.02 (dd, J¼8.0, 19.2 Hz, 1H), 2.47 (dd, J¼2.0, 19.2 Hz,
1H), 1.70 (s, 3H), 1.24 (m, 6H), 1.07 (d, J¼7.4 Hz, 36H); 13C NMR
(100 MHz, CDCl3):
d 206.1, 157.4, 154.6, 140.0, 139.3, 139.1, 138.0,
128.8, 127.9, 126.0, 125.6, 116.5, 105.9, 45.3, 44.6, 17.8, 15.5, 13.0,
12.6; IR (neat, cmꢁ1): 2943.7, 2865.5, 1715.6, 1470.1, 1343.8, 1175.1;
HRMS (EI) calculated for C36H57O3Si2 593.3841, found 593.3829.
In a 10 mL round-bottom flask, a solution of i-Pr2NH (0.2 mL,
1.0 mmol), n-BuLi (2.5 M solution in hexanes, 0.3 mL, 0.7 mmol),
and THF (1 mL) was stirred at 0 ꢀC for 15 min, then cooled to ꢁ40 ꢀC.
A solution of the decarboxylated material (300.0 mg, 0.5 mmol) in
THF (2 mL) was added, and the reaction was stirred at ꢁ40 ꢀC for
5.5 h, then MeI (0.2 mL, 3.2 mmol) was added and the reaction was
stirred for an additional 4 h at ꢁ20 ꢀC. The reaction was quenched
while cold with saturated aqueous NH4Cl and the layers were
separated. The organic phase was diluted with hexanes (10 mL) and
washed with water (3ꢂ10 mL), then brine (10 mL). The organic
layer was dried over MgSO4, filtered, and concentrated in vacuo.
The crude product was purified by column chromatography (16:1
hexanes:ethyl acetate) to give 247.3 mg (81%) of 19.
d
198.7, 169.3, 157.6, 156.9, 154.4, 153.0, 144.2, 141.4, 138.7, 138.5,
138.0, 117.3, 114.8, 112.6, 112.2, 106.6, 105.9, 105.0, 60.8, 52.7, 51.1,
50.3, 47.9, 29.7, 20.1, 17.9, 17.8, 13.3, 13.1, 12.6; IR (neat) 2945, 2892,
2867, 1720, 1605, 1478, 1348, 1310, 1248, 1176, 882, 766 cmꢁ1; HRMS
m/z calcd for C32H54O5NaSi2 (MþNaþ) 597.3402, found 597.3402.
4.2.17. Indanone 18c. To a flame-dried 25 ml round-bottom flask in
a glove box was added Sc(OTf)3 (0.03 g, 0.06 mmol, 0.05 equiv) and
Li(ClO4) (0.03 g, 0.18 mmol, 0.15 equiv). The flask was removed from
the glove box and dry DCE (12 ml) was added. 16c (0.67 g,1.2 mmol)
was added, and the reaction mixture was heated at 45 ꢀC overnight.
The reaction mixture was quenched with water, extracted with
ether, dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude residue was purified by flash column chro-
matography (9:1 hexane:ethyl acetate) to afford 18c as a 3:1 mix-
ture of anti:syn isomers (0.546 g, 81%). For major (presumably anti)
1H NMR (400 MHz, CDCl3):
d 7.35e7.15 (m, 5H), 6.87 (d,
isomer: 1H NMR (400 MHz, CDCl3)
d
7.39 (d, J¼2.2 Hz, 1H),
J¼2.0 Hz, 1H), 6.62 (d, J¼2.0 Hz, 1H), 6.30 (s, 1H), 3.60 (d, J¼3.2 Hz,
1H), 2.43 (dt, J¼7.4, 3.2 Hz, 1H), 1.72 (s, 3H), 1.36 (d, J¼7.4 Hz, 3H),
1.24 (m, 6H), 1.07 (d, J¼7.4 Hz, 36H); 13C NMR (100 MHz, CDCl3):
7.37e7.20 (m, 5H), 7.18 (d, J¼2.2 Hz, 1H), 6.38 (s, 1H), 4.47 (d,
J¼3.0 Hz, 1H), 3.81 (s, 3H), 3.61 (d, J¼3.0 Hz, 1H), 1.70 (d, J¼1.1 Hz,
3H), 1.35e1.23 (m, 3H), 1.11 (d, J¼7.2 Hz, 18H).
d
208.6, 157.4, 154.7, 139.1, 138.7, 138.0, 137.6, 128.9, 127.9, 126.0,
125.7, 116.6, 106.2, 55.1, 49.9, 17.8, 15.9, 15.2, 13.1, 12.6; IR (neat,
cmꢁ1): 2943.2, 2866.0, 1715.6, 1604.7, 1470.6, 1341.9, 1174.6; HRMS
(EI) calculated for C37H59O3Si2 607.3997, found 607.3998.
4.2.18. Indanone 18d. To a 25 ml round-bottom flask in a glove box
was added AlCl3 (0.231 g, 1.73 mmol, 1.1 equiv). The flask was re-
moved from the glove box and DCE (15 ml) was added. The flask
was cooled to 0 ꢀC. Aryl enone 16d (0.869 g, 1.57 mmol) was added,
and the reaction mixture turned deep red. The reaction mixture
was stirred for 30 min. The reaction mixture was quenched with
saturated aqueous potassium sodium tartrate, which turned the
reaction mixture green, then yellow. The reaction mixture was
extracted three times with Et2O. The combined organic extracts
were washed with brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude residue was purified by
flash column chromatography (19:1 hexanes:ethyl acetate) to af-
ford 110 as a 3.6:1 mixture of anti:syn isomers (0.597 g, 1.24 mmol,
4.2.20. Indanone S1. In a 200 mL round-bottom flask, crude 18b
(207 mg, 0.36 mmol) from previous steps was dissolved in toluene
(4.1 mL), then water (0.41 mL) and DABCO (21 mg, 0.18 mmol) were
added. The solution was refluxed for 12 h, and quenched with
saturated aqueous NH4Cl (100 mL). The layers were separated and
the organic phase was washed with water (2ꢂ100 mL) then brine
(100 mL). The organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. The crude material was used for the next
step.
79% yield). 1H NMR (400 MHz, CDCl3)
d
7.37 (d, J¼2.2 Hz, 1H, maj.
isomer), 7.15 (d, J¼2.2 Hz, 1H, maj. isomer), 7.09 (d, J¼2.2 Hz, 1H,
min isomer), 7.06 (d, J¼2.2 Hz, 1H, min isomer), 5.19 (s, 1H, min
isomer), 5.09 (s, 1H, min isomer), 4.92 (s, 1H, maj. isomer), 4.69 (s,
1H, maj. isomer), 4.30 (s, 1H, min isomer), 4.28 (d, J¼2.7 Hz,1H, maj.
isomer), 3.82 (s, 3H, min isomer), 3.78 (s, 3H, maj. isomer), 3.50 (d,
J¼2.7 Hz, 1H, maj. isomer), 2.34 (d, J¼4.5 Hz, 1H, min isomer), 1.64
(s, 3H), 1.35e1.20 (m, 3H), 1.15e1.05 (m, 18H); 13C NMR (100 MHz,
In a 25 mL round-bottom flask, the crude material from previous
step was dissolved in THF (3.1 mL) and the solution was cooled to
0 ꢀC, then TBAF (1.0 M solution in THF, 0.6 mL, 0.6 mmol) was added
and the reaction was stirred for 1 h. The solution was quenched
with saturated aqueous NH4Cl and the layers were separated. The
organic phase was diluted with diethyl ether (20 mL) and washed
with water (3ꢂ10 mL), then brine (10 mL). The organic layer was
dried over MgSO4, filtered, and concentrated in vacuo. The crude
product was purified by column chromatography (1:1 hex-
anes:ethyl acetate) to give 66 mg (33%, yield over 4 steps from 14a)
CDCl3)
d 197.82, 168.72, 157.41, 157.30, 156.72, 146.72, 143.52,
139.76, 139.38, 138.48, 131.91, 125.57, 123.67, 122.40, 119.91, 117.07,
114.25, 113.05, 111.15, 107.44, 107.15, 61.23, 53.09, 52.98, 51.46,
50.48, 48.17, 20.53, 18.63, 17.96, 17.59, 17.39, 16.94, 13.00, 12.69. IR
(neat, cmꢁ1): 2947, 2866, 1721, 1651, 1586, 1555, 1458, 1377, 1292,
1219, 1157, 1134, 1069, 961, 883, 799, 729, 687, 648; HRMS (ESI):
Calculated for
481.1402.
C
23H34BrO4Si ([MþH]þ): m/z 481.1410, found:
of S1. 1H NMR (400 MHz, CD3OD)
1H, J¼2.4 Hz), 4.76 (s, 1H), 4.69 (s, 1H), 4.02 (dd, 1H, J¼2.0, 7.6 Hz),
2.94 (dd, 1H, J¼8.0, 19.2 Hz), 2.34 (dd, 1H, J¼2.0, 19.2 Hz), 1.60 (s,
3H).
d
6.59 (d, 1H, J¼2.0 Hz), 5.56 (d,
4.2.19. Indanone 19. In a 200 mL round-bottom flask, indanone 18a
(2.6 g, 4.0 mmol) was dissolved in toluene (45 mL), then water
(1 mL) and DABCO (224.8 mg, 2.0 mmol) were added. The solution
was refluxed for 12 h, and quenched with saturated aqueous NH4Cl
(100 mL). The layers were separated and the organic phase was
washed with water (2ꢂ100 mL) then brine (100 mL). The organic
layer was dried over MgSO4, filtered, and concentrated in vacuo.
4.2.21. Aryl triflate 20. In a 25 mL round-bottom flask, diprotected
19 (402.0 mg, 0.7 mmol) was dissolved in THF (6 mL) and the so-
lution was cooled to 0 ꢀC, then TBAF (1.0 M solution in THF, 1.2 mL,

5894
P.N. Carlsen et al. / Tetrahedron 71 (2015) 5886e5896
1.2 mmol) was added and the reaction was stirred for 1 h. The so-
lution was quenched with saturated aqueous NH4Cl and the layers
were separated. The organic phase was diluted with diethyl ether
(20 mL) and washed with water (3ꢂ10 mL), then brine (10 mL). The
organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The crude product was purified by column chromatography
(2:1 hexanes:ethyl acetate) to give 147.4 mg (76%) of diphenol. 1H
The organic layer was dried over MgSO4, filtered, and concentrated
in vacuo. The crude product was purified by column chromatog-
raphy (3:1 hexanes:ethyl acetate) to give 408 mg (99%) of phenol.
1H NMR (400 MHz, CDCl3)
d 7.36e7.32 (m, 3H), 7.27e7.22 (m, 3H),
7.12 (m, 1H), 6.53 (s, 1H), 6.34 (b, 1H), 4.40 (dd, 1H, J¼2.8, 8.0 Hz),
3.13 (dd, 1H, J¼8.0, 19.6 Hz), 2.66 (dd, 1H, J¼2.8, 19.6 Hz), 1.63 (s,
3H); 13C NMR (400 MHz, CDCl3)
d 204.4, 157.5, 147.6, 141.1, 139.6,
NMR (400 MHz, CDCl3):
6.72 (d, J¼2.0 Hz, 1H), 6.71 (s, 1H), 3.67 (d, J¼4.0 Hz, 1H), 2.60 (dt,
J¼7.2, 4.0 Hz, 1H), 1.76 (s, 3H), 1.37 (d, J¼7.2 Hz, 3H).
d
7.38e7.30 (m, 5H), 6.93 (d, J¼2.0 Hz, 1H),
137.2, 135.4, 128.8, 128.6, 128.1, 126.6, 116.3, 109.4, 77.2, 45.5, 43.5,
14.2.
TMSCHN2 (2.0 M in Et2O, 0.275 mL, 0.55 mmol) was added to
a stirred solution of phenol from the previous step (206 mg,
0.5 mmol) and N, N-diisopropylethylamine (91 mg, 0.7 mmol) in
methanoleacetonitrile (1:9, 2 mL) at room temperature. The mix-
ture was stirred for 15 h at room temperature, and concentrated in
vacuo. The crude was dissolved in Et2O (15 mL), washed with sat-
urated aqueous NH4Cl (3ꢂ10 mL) and water (3ꢂ10 mL), then brine
(10 mL). The organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by column
chromatography (3:1 hexanes:ethyl acetate) to give 186 mg (82%)
In a 25 mL round-bottom flask, diol from the previous step
(240.0 mg, 0.8 mmol) was dissolved in CH2Cl2 (11 mL), and TEA
(0.1 mL, 0.7 mmol) and TIPS-Cl (0.2 mL, 0.8 mmol) were added. The
reaction was stirred for 16 h, then quenched with saturated aque-
ous NH4Cl and the layers were separated. The organic phase was
diluted with CH2Cl2 (10 mL) and washed with water (10 mL), then
brine (10 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by column
chromatography (15:1 hexanes:ethyl acetate) to give 155.6 mg
(42%) of monophenol. 1H NMR (400 MHz, CDCl3):
d
7.38e7.30 (m,
of 22. 1H NMR (400 MHz, CDCl3)
d 7.36e7.21 (m, 5H), 7.11 (s, 1H),
5H), 6.86 (d, J¼2.0 Hz, 1H), 6.75 (s, 1H), 6.68 (d, J¼2.0 Hz, 1H), 5.68
(s,1H), 3.68 (d, J¼4.4 Hz,1H), 2.57 (dt, J¼7.2, 4.4 Hz,1H),1.78 (s, 3H),
1.37 (d, J¼7.2 Hz, 3H), 1.28 (m, 3H), 1.09 (d, J¼7.4 Hz, 18H); 13C NMR
6.53 (s, 1H), 4.40 (dd, J¼2.8, 8.0 Hz, 1H), 3.91 (s, 3H), 3.12 (dd, J¼8.0,
19.6 Hz, 1H), 2.65 (dd, J¼2.8, 19.6 Hz, 1H), 1.63 (s, 3H); 13C NMR
(400 MHz, CDCl3)
d 203.7, 161.2, 147.5, 141.3, 139.7, 137.3, 135.7,
(100 MHz, CDCl3):
d
207.4, 158.1, 154.8, 138.6, 138.1, 136.7, 131.8,
128.9, 128.6, 128.1, 126.6, 116.4, 105.8, 77.2, 56.3, 45.5, 43.5, 14.2; IR
(neat) 2917, 1720, 1486, 1425, 1296, 1244, 1212, 1140, 1071, 1036,
964, 861 cmꢁ1; HRMS m/z calcd for C20H17O5F3S (Mþ) 426.0743,
found 426.0743.
128.9, 128.3, 128.2, 127.1, 114.0, 106.3, 55.0, 48.6, 17.7, 14.7, 14.2, 12.6;
IR (neat, cmꢁ1): 3204.8, 2943.2, 2865.5, 1680.9, 1470.1, 1345.7,
1177.5; HRMS (EI) calculated for C28H39O3Si 451.2663, found
451.2648.
In a 25 mL round-bottom flask, monophenol from the previous
step (155.6 mg, 0.4 mmol) was dissolved in CH2Cl2 (2 mL) and
cooled to 0 ꢀC, then pyridine (0.08 mL, 1.0 mmol) and Tf2O (0.1 mL,
0.6 mmol) were added and the reaction was stirred in an ice bath
for 2 h. The reaction was quenched with saturated aqueous NH4Cl
and the layers were separated. The organic phase was diluted with
hexanes (15 mL) and washed with brine (10 mL). The organic layer
was dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by column chromatography (8:1 hex-
anes:ethyl acetate) to give 190.2 mg (93%) of aryl triflate 20. 1H
4.2.24. Aryl bromide 23. To a 25 ml round-bottom flask was added
DABCO (0.142 g,1.26 mmol,1.43 equiv), toluene (8 ml), H2O (0.8 ml),
and 18c (0.491 g, 0.882 mmol). The flask was purged with argon for
10 min. The reaction mixture was refluxed overnight. The reaction
mixture was diluted with water and ether, extracted with ether,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude residue was purified by flash column chromatog-
raphy (19:1 ether:hexane) to afford aryl bromide 23 (0.371 g, 84%).
1H NMR (400 MHz, CDCl3)
d
7.37 (d, J¼2.2 Hz,1H), 7.34e7.20 (m, 5H),
7.19 (d, J¼2.2 Hz, 1H), 6.39 (s, 1H), 4.15 (dd, J¼8.0, 2.0 Hz, 1H), 3.08
(dd, J¼19.3, 8.0 Hz, 1H), 2.61 (dd, J¼19.3, 2.0 Hz, 1H), 1.63 (s, 3H),
1.40e1.20 (m, 3H),1.11 (d, J¼7.3 Hz,18H). 13C NMR (100 MHz, CDCl3)
NMR (400 MHz, CDCl3):
d
7.38e7.30 (m, 6H), 7.05 (d, J¼2.4 Hz, 1H),
6.56 (s,1H), 3.83 (d, J¼4.0 Hz,1H), 2.58 (dt, J¼7.2, 4.0 Hz,1H),1.67 (s,
3H), 1.40 (d, J¼7.2 Hz, 3H), 1.27 (m, 3H), 1.12 (d, J¼7.2 Hz, 18H); 13
C
d 204.98,157.16,147.42,140.36,137.89,137.30,131.25,128.86,128.23,
NMR (100 MHz, CDCl3):
d
205.8, 157.7, 147.3, 140.3, 138.0, 137.4,
126.52, 122.57, 112.37, 44.44, 18.02, 17.89, 12.72.
134.9, 129.1, 128.9, 128.8, 128.0, 126.5, 119.9, 113.9, 55.0, 50.9, 49.1,
17.7, 14.8, 14.2, 12.5; IR (neat, cmꢁ1): 2944.6, 2868.0, 1723.8, 1615.3,
1470.6, 1424.3, 1313.4, 1245.0, 1207.8, 1139.0, 992.3; HRMS (EI)
calculated for C29H37O5SiSF3 582.2078, found 582.2077.
4.2.25. Alcohol 24. To a 25 ml round-bottom flask was added 18d
(0.475 g, 0.987 mmol), DABCO (0.055 g, 0.493 mmol, 0.5 equiv),
toluene (10 ml), and H2O (1 ml). The solution was heated at 80 ꢀC
overnight. The solution was quenched with saturated aqueous
NH4Cl and extracted three times with Et2O. The combined organic
extracts were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude residue was puri-
fied by flash column chromatography (19:1 hexanes:ethyl acetate)
to afford decarboxylated indanone (0.382 g, 0.902 mmol 91% yield).
LDA was prepared according to the following: to a 50 ml round-
bottom flask was added THF (15 ml) and diisopropylamine (1.37 ml,
9.74 mmol, 1.21 equiv). The solution was cooled to ꢁ40 ꢀC, and n-
BuLi (3.66 ml, 2.42M in hexanes, 1.1 equiv) was added. The solution
was stirred at ꢁ40 ꢀC for 40 min. Then, decarboxylated indanone
from the previous step (3.41 g, 8.05 mmol), in THF (38 ml) was
added dropwise. The solution was stirred and maintained at ꢁ40 ꢀC
for three hours. Then, MeI (24.9 ml, 400 mmol, 50 equiv) was added
to the solution, which was slowly raised to room temperature
overnight. The reaction was quenched the next day with 1M
aqueous HCl and extracted three times with Et2O. The combined
organic fractions were washed with saturated NaHCO3, concen-
trated under reduced pressure, and taken to the next step without
further purification.
4.2.22. Aryl triflate 21. 21 was prepared following the synthetic
procedure for 20, except methylation was not carried out. 1H NMR
(400 MHz, CDCl3)
d
7.36e7.32 (t, J¼7.2 Hz, 2H), 7.28e7.23 (m, 3H),
7.07 (d, J¼2.4 Hz, 1H), 6.53 (s, 1H), 4.39 (dd, J¼2.8, 8.0 Hz, 1H), 3.10
(dd, J¼8.4, 19.6 Hz, 1H), 2.63 (dd, J¼3.2, 19.6 Hz, 1H), 1.62 (s, 3H),
1.32e1.27 (m, 3H), 1.13e1.11 (m, 18H); 13C NMR (400 MHz, CDCl3)
d
203.7, 157.8, 147.3, 141.1, 139.7, 137.3, 135.7, 128.9, 128.5, 128.1,
126.6, 120.0, 113.7, 53.4, 45.5, 43.5, 17.7, 14.1, 12.5; IR (neat) 2946,
2868, 1725, 1617, 1476, 1426, 1315, 1245, 1217, 1141, 1064, 999, 942,
882 cmꢁ1; HRMS m/z calcd for C28H35O5F3NaSSi (MþNaþ) 591.1819,
found 591.1824.
4.2.23. Aryl triflate 22. In a 25 mL round-bottom flask, 21 (569 mg,
1 mmol) was dissolved in THF (8.6 mL) and the solution was
cooled to 0 ꢀC, then TBAF (1.0 M solution in THF, 1.7 mL, 1.7 mmol)
was added and the reaction was stirred for 1 h. The solution was
quenched with saturated aqueous NH4Cl and the layers were
separated. The organic phase was diluted with diethyl ether
(20 mL) and washed with water (3ꢂ10 mL), then brine (10 mL).

P.N. Carlsen et al. / Tetrahedron 71 (2015) 5886e5896
5895
The crude material from the previous step was dissolved in
MeOH (80 ml) and cooled to 0 ꢀC. NaBH4 (0.610 g,16.1 mmol, 2 equiv)
was added. The reaction was stirred at 0 ꢀC for 2 h, then quenched
with water. The solution was extracted three times with Et2O, and
the combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude residue was purified by flash column chromatography (19:1
hexanes:ethyl acetate) to afford alcohol 24 (2.37 g, 5.39 mmol, 67%
over two steps) as a crystalline solid. 1H NMR (400 MHz, CDCl3)
screwcap, the flask was sealed, and the mixture was heated to
105 ꢀC with stirring. The mixture was cooled to room temperature,
diluted with ether, filtered through Celite, and concentrated in
vacuo. The crude product was purified by flash chromatography on
silica gel to furnish amine 30 as a 3:1 mixture of isomers (6 mg,
40%). 1H NMR (400 MHz, CDCl3)
d 7.36e7.24 (m, 5H, both isomers),
6.76 (s, 1H, both isomers), 6.66 (d, J¼2.4 Hz, 1H, both isomers), 6.26
(d, J¼2.0 Hz, 1H, both isomers), 4.93 (d, J¼8.8 Hz, 1H, maj. isomer),
4.77 (d, J¼8.0 Hz, 1H, min isomer), 4.15e4.08 (m, 2H, both isomers),
3.82 (s, 3H, both isomers), 3.75 (s, 3H, min isomer), 3.66 (s, 3H, maj.
isomer), 3.03 (dd, J¼8.0, 19.2 Hz, 1H, both isomers), 2.57 (dd, J¼2.8,
19.2 Hz, 1H, both isomers), 1.67 (s, 3H, maj. isomer) 1.63 (s, 3H,
min isomer) 1.43 (d, J¼6.8 Hz, 3H, maj. isomer) 1.41 (d, J¼7.2 Hz, 3H,
d
6.99 (s, 1H), 6.88 (s, 1H), 4.86 (s, 1H), 4.62 (s, 1H), 4.55 (dd, J¼8.5,
4.9 Hz, 1H), 3.19 (d, J¼5.4 Hz, 1H), 2.18 (d, J¼8.5 Hz, 1H), 2.14e2.07
(m, 1H), 1.74 (s, 3H), 1.30e1.21 (m, 3H), 1.16 (d, J¼6.9 Hz, 3H), 1.10 (d,
J¼7.4 Hz, 18H); 13C NMR (100 MHz, CDCl3)
d 156.59, 147.61, 147.12,
134.96, 124.24, 120.96, 115.16, 112.45, 82.41, 58.76, 49.23, 20.49,
17.99, 17.89, 12.70. IR (neat, cmꢁ1): 3287 (br), 3075 (w), 2943 (s),
2866 (s),1605 (s),1555 (s),1458 (s),1412 (w),1377 (w),1285 (s),1211
(m),1177 (m),1142 (s),1057 (s), 999 (s), 880 (s), 845 (s), 814 (w), 760
(s), 733 (m), 683 (s), 644 (w); HRMS (ESI): Calculated for
min. isomer); 13C NMR (400 MHz, CDCl3)
d 205.9, 174.2, 161.7, 145.9,
139.5, 138.9, 137.3, 135.2, 128.8, 128.7, 128.4, 128.2, 128.1, 126.7,
103.9, 103.8, 93.7, 93.6, 55.5, 52.4, 52.2, 51.5, 51.2, 46.2, 43.1, 29.7,
18.7, 18.6, 13.5, 13.4; IR (neat) 2923, 1743, 1707, 1612, 1514, 1449,
1363, 1204, 1170, 1087, 1049 cmꢁ1
C
; HRMS m/z calcd for
C
22H35BrO2SiNa ([MþHþNa]þ): m/z 461.1487, found: 461.1492.
23H25O4NNa (MþNaþ) 402.1676, found 402.1668.
4.2.26. Aryl bromide 25. To a 100 ml round-bottom flask was added
alcohol 24 (2.54 g, 5.78 mmol), TBSCl (3.48 g, 23.1 mmol, 4 equiv),
imidazole (3.15 g, 46.2 mmol, 8 equiv), and THF (57 ml). The solution
was stirred at room temperature overnight. The reaction was
quenched with saturated aqueous NH4Cl and extracted three times
with Et2O. The combined organic fractions were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude residue was purified by flash column chromatog-
raphy (19:1 hexanes:ethyl acetate) to afford aryl bromide 25 (2.90 g,
5.24 mmol, 91% yield) as a translucent oil. 1H NMR (400 MHz, CDCl3)
4.2.29. Amine 32. An oven-dried resealable Schlenk flask was
evacuated and backfilled with argon. The flask was charged with
Pd(OAc)2 (10 mol %), BINAP (15 mol %), and Cs2CO3 (1.4 equiv) and
evacuated and backfilled with argon. The flask was capped with
a rubber septum, and toluene (2 mL/mmol triflate), the aryl triflate
22 (18 mg, 0.04 mmol, 1.0 equiv), and the amine 31 (1.2 equiv) were
added through the septum. The septum was replaced with a Teflon
screwcap, the flask was sealed, and the mixture was heated to 100 ꢀC
with stirring. The mixture was cooled to room temperature, diluted
with ether, filtered through Celite, and concentrated in vacuo. The
crude product was purified by flash chromatography on silica gel to
d
6.94 (d, J¼2.2 Hz,1H), 6.74 (d, J¼2.2 Hz,1H), 4.88 (s,1H), 4.86 (s,1H),
4.58 (d, J¼6.3 Hz, 1H), 3.20 (d, J¼7.2 Hz, 1H), 2.08e1.97 (m, 1H), 1.62
(s, 3H), 1.31e1.19 (m, 3H), 1.15 (d, J¼6.9 Hz, 3H), 1.09 (d, J¼7.2 Hz,
18H), 0.93 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H); 13C NMR (100 MHz, CDCl3)
furnish amine 32 (8 mg, 50%). 1H NMR (400 MHz, CDCl3)
d 7.32e7.23
(m, 8H), 7.10 (m, 2H), 6.64 (d, J¼1.5 Hz, 1H), 6.61 (s, 1H), 6.39 (d,
J¼1.5 Hz, 1H), 4.67 (s, 1H), 4.32 (d, J¼5.0 Hz, 2H), 4.08 (dd, J¼2.0,
7.5 Hz, 1H), 3.82 (s, 3H), 3.03 (dd, J¼7.5, 19.0 Hz, 1H), 2.57 (dd, J¼2.5,
d
156.27, 148.76, 145.74, 134.25, 123.99, 120.63, 114.67, 113.31, 82.12,
58.89, 49.43, 25.92, 19.39, 18.13, 18.03, 17.25, 12.78, ꢁ3.95, ꢁ4.12. IR
(neat, cmꢁ1): 2951, 2931, 2893, 2866, 1605, 1559, 1458, 1362, 1296,
1254, 1180, 1146, 1115, 1067, 999, 868, 833, 772, 733, 683, 671.
19.0 Hz, 1H), 1.64 (s, 3H); 13C NMR (400 MHz, CDCl3)
d 206.0, 161.8,
147.0,139.3,138.8,138.3,137.0,134.7,128.8,128.7,128.2,128.0,127.5,
127.4, 126.7, 103.6, 93.0, 55.5, 47.9, 46.4, 43.2, 13.6; IR (neat) 2921,
2851,1703,1610,1511,1451,1365,1237,1202,1166,1061 cmꢁ1; HRMS
m/z calcd for C26H25O2N (Mþ) 383.1880, found 383.1885.
4.2.27. Amine 28. An oven-dried resealable Schlenk flask was
evacuated and backfilled with argon. The flask was charged with
Pd(OAc)2 (10 mol %), BINAP (20 mol %), and NaOtBu (1.4 equiv) and
evacuated and backfilled with argon. The flask was capped with
a rubber septum, and toluene (2 mL/mmol triflate), the aryl triflate
21 (57 mg, 0.1 mmol, 1.0 equiv), and the amine 27 (1.2 equiv) were
added through the septum. The septum was replaced with a Teflon
screwcap, the flask was sealed, and the mixture was heated to 105 ꢀC
with stirring. The mixture was cooled to room temperature, diluted
with ether, filtered through Celite, and concentrated in vacuo. The
crude product was purified by flash chromatography on silica gel to
4.2.30. Amine 34. An oven-dried resealable Schlenk flask was
evacuated and backfilled with argon. The flask was charged with
Pd2(dba)2 (3 mol %), BINAP (4.5 mol %), and NaOtBu (1.4 equiv) and
evacuated and backfilled with argon. The flask was capped with
a rubber septum, and toluene (2 mL/mmol triflate), the aryl triflate
21 (69 mg, 0.121 mmol, 1.0 equiv), and the amine 33 (1.2 equiv)
were added through the septum. The septum was replaced with
a Teflon screwcap, the flask was sealed, and the mixture was heated
to 90 ꢀC with stirring. The mixture was cooled to room tempera-
ture, diluted with ether, filtered through Celite, and concentrated in
vacuo. The crude product was purified by flash chromatography on
silica gel to furnish amine 34 (20 mg, 28%). 1H NMR (400 MHz,
furnish amine 28 (3 mg, 6%). 1H NMR (500 MHz, CDCl3)
d 7.36e7.20
(m, 5H), 6.83 (s, 1H), 6.65 (s, 1H), 6.36 (s, 1H), 4.16 (dd, J¼2.0, 8.0 Hz,
1H), 3.82 (s, 3H), 3.00 (dd, J¼8.0,19.0 Hz,1H), 2.53 (dd, J¼2.0,19.0 Hz,
1H), 1.64 (s, 3H), 1.32e1.28 (m, 3H), 1.26 (s, 6H), 1.13e1.11 (m, 18H);
CDCl3)
d
7.70 (d, J¼7.2 Hz, 2H), 7.50e7.45 (m,1H), 7.32e7.21 (m, 7H),
13C NMR (400 MHz, CDCl3)
d
206.1, 158.2, 157.8, 139.7, 138.6, 138.2,
7.19e7.16 (m, 1H), 7.12e7.05 (m, 2H), 7.08e7.01 (m, 2H), 6.89 (s, 1H),
6.43e6.48 (m, 1H), 6.36 (s,1H), 3.89 (dd, J¼2.8, 8.0 Hz,1H), 2.87 (dd,
J¼8.0, 19.2 Hz, 1H), 2.52 (dd, J¼2.8, 19.2 Hz, 1H), 1.64 (s, 3H),
1.14e1.07 (m, 3H), 1.03e1.01 (m, 18H); 13C NMR (400 MHz, CDCl3)
137.9,128.8,128.2,128.0,126.12,126.09,109.5,104.4, 55.6, 45.2, 43.9,
29.7, 22.7, 17.9, 14.8, 12.7; IR (neat, cmꢁ1) 2925, 2866, 1718, 1608,
1480, 1445, 1344, 1308, 1220, 1196, 1167, 992, 883.
d
206.1, 167.7, 156.5, 149.8, 139.5, 139.2, 138.8, 137.7, 135.8, 130.9,
4.2.28. Amine 30. An oven-dried resealable Schlenk flask was
evacuated and backfilled with argon. The flask was charged with
Pd2(dba)3 (5 mol %), DavePhos (10 mol %), and K3PO4 (1.4 equiv) and
evacuated and backfilled with argon. The flask was capped with
a rubber septum, and toluene (2 mL/mmol triflate), the aryl triflate
22 (18 mg, 0.04 mmol, 1.0 equiv), and the amine 29 (1.2 equiv) were
added through the septum. The septum was replaced with a Teflon
129.6, 129.0, 128.9, 128.8, 128.1, 127.8, 127.4, 126.0, 118.5, 108.3, 77.2,
46.6, 43.6, 17.8, 13.9, 12.4; IR (neat) 2942, 2865, 1713, 1661, 1598,
1465, 1447, 1317, 1278, 1178, 1072, 1000, 941, 919, 883 cmꢁ1; HRMS
m/z calcd for C40H46O2NSi (MþHþ) 600.3292, found 600.3306.
4.2.31. Amine 35. To a flame-dried 3 ml vial in a glove box was
added Pd2(dba)3 (0.0046 g, 0.005 mmol, 0.05 equiv), BINAP

5896
P.N. Carlsen et al. / Tetrahedron 71 (2015) 5886e5896
(0.011 g, 0.015 mmol, 0.15 equiv), and NaOtBu (0.0115 g, 0.12 mmol,
1.2 equiv). The vial was capped with a pierceable PFTE seal. The vial
was removed from the glove box and dry toluene (0.6 ml) was
added. The mixture was stirred for five minutes. 33 (0.025 ml,
0.15 mmol, 1.5 equiv) and 23 (0.050 g, 0.1 mmol) were added by
syringe, and the vial was heated at 110 ꢀC behind a blast shield
overnight. The reaction mixture was concentrated under reduced
pressure. The crude residue was dissolved in THF (0.33 ml) in a 5 ml
round-bottom flask. 1M aqueous HCl was added (0.033 ml) and the
reaction was stirred for 15 min. The reaction was quenched with
aqueous saturated NaHCO3, diluted and extracted with ether, dried
over MgSO4, filtered, and concentrated under reduced pressure.
The crude material was purified by flash column chromatography
(9:1 hexane:ethyl acetate) to afford aniline 35 (11.6 mg, 27%). 1H
Alice Bergmann (University of Buffalo) for performing high-
resolution mass spectrometry.
Supplementary data
Supplementary data (1H and 13C NMR spectra for compounds.)
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2015.05.021.
References and notes
1. Komoda, T.; Sugiyama, Y.; Abe, N.; Imachi, M.; Hirota, H.; Hirota, A. Tetrahedron
Lett. 2003, 44, 1659e1661.
2. Komoda, T.; Sugiyama, Y.; Abe, N.; Imachi, M.; Hirota, H.; Koshino, H.; Hirota, A.
Tetrahedron Lett. 2003, 44, 7417e7419.
3. Komoda, T.; Kishi, M.; Abe, N.; Sugiyama, Y.; Hirota, A. Biosci. Biotechnol. Bio-
chem. 2004, 68, 903e908.
NMR (400 MHz, CDCl3)
d
7.41e7.13 (m, 5H), 6.69 (d, J¼2.0 Hz, 1H),
6.64 (s, 1H), 6.45 (d, J¼2.0 Hz, 1H), 4.07 (dd, J¼7.8, 2.6 Hz, 1H), 3.99
(s, 2H), 3.01 (dd, J¼19.3, 7.8 Hz, 1H), 2.53 (dd, J¼19.3, 2.6 Hz, 1H),
1.67 (d, J¼0.9 Hz, 3H), 1.36e1.18 (m, 3H), 1.10 (d, J¼7.2 Hz, 18H). 13
C
4. Prigge, S. T.; Boyington, J. C.; Gaffney, B. J.; Amzel, L. M. Proteins: Struct., Funct.,
Genet. 1996, 24, 275e291.
NMR (101 MHz, CDCl3)
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137.29, 133.96, 128.90, 128.39, 127.69, 127.49, 126.84, 103.48, 103.28,
43.46, 18.09, 17.96, 12.75. IR (neat, cmꢁ1) 2943, 2865, 1701, 1619,
1482, 1351, 1236, 1184, 1068, 1013, 946, 883; HRMS m/z calcd for
C
27H38NO2Si (MþHþ) 436.2666, found 436.2658.
4.2.32. Amine 36. To a 100 ml Schlenk bomb was added [Pd(allyl)
Cl]2 (0.0192 g, 0.0524 mmol, 0.01 equiv), Mor-DalPhos (0.0974 g,
0.210 mmol, 0.04 equiv), NaOtBu (1.01 g, 10.5 mmol, 2 equiv), and
toluene (52 ml). The solution was stirred for 10 min. Then, 25 (2.9 g,
5.24 mmol) was added, followed by NH3 (0.5 M solution in 1,4-
dioxane, 31.4 ml, 3 equiv). The Schlenk bomb was sealed and heated
at 110 ꢀC for 1 h. The reaction vessel was cooled, quenched with
saturated aqueous NH4Cl, and extracted three times with Et2O. The
combined extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude res-
idue was purified by flash column chromatography (19:1 hex-
anes:ethyl acetate) to afford aniline 36 (2.48 g, 5.06 mmol, 97%
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yield). 1H NMR (400 MHz, CDCl3)
d
6.24 (d, J¼2.0 Hz, 1H), 6.05 (d,
J¼2.0 Hz, 1H), 5.05 (d, J¼2.0 Hz, 1H), 4.94 (s, 1H), 4.56 (d, J¼7.4 Hz,
1H), 3.75 (s, 2H), 3.15 (d, J¼8.4 Hz, 1H), 2.10e1.98 (m, 1H), 1.64 (s,
3H), 1.32e1.16 (m, 3H), 1.14 (d, J¼6.8 Hz, 3H), 1.09 (d, J¼7.0 Hz, 18H),
0.95 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H); 13C NMR (100 MHz, CDCl3)
19. Vaidya, T.; Cheng, R.; Carlsen, P. N.; Frontier, A. J.; Eisenberg, R. Org. Lett. 2014,
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22. For selected reviews, see: (a) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem.
1999, 576, 125e146; (b) Hartwig, J. F. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-I., Ed.; Wiley-Interscience: New York, NY,
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Acc. Chem. Res. 1998, 31, 805e818; (d) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046e2067; (e) Kienle, M.; Dubbaka, S. R.; Brade, K.; Knochel, P. Eur. J. Org.
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d
156.72, 147.94, 147.28, 144.22, 118.61, 113.66, 106.24, 105.50, 82.18,
56.32, 49.05, 26.01, 18.26, 18.20, 18.12, 16.32, 12.86, ꢁ3.91, ꢁ4.00; IR
(neat, cmꢁ1): 2951, 2928, 2893, 2866, 1613, 1470, 1362, 1254, 1204,
1157, 1096, 1009, 837, 683; HRMS (ESI): Calculated for C28H52NO2Si2
([MþH]þ): m/z 490.3537, found: 490.3531.
Acknowledgements
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We thank the National Institutes of Health (NIGMS R01 GM-
079364) for funding this project, Dr. William W. Brennessel (Uni-
versity of Rochester) for performing X-ray crystallography, and Dr.
Furong Sun (University of Illinois, UrbanaeChampaign) and Dr.