Total Synthesis of (±)-Brazilin Using [4 + 1] Palladium-Catalyzed Carbenylative Annulation

Article abstract of DOI:10.1021/acs.joc.9b02343

Palladium-catalyzed carbene insertion was utilized in a formal synthesis of (±)-picropodophyllone and a total synthesis of (±)-brazilin. All prior syntheses of brazilin have involved a Friedel-Crafts alkylation in the key carbon-carbon bond forming events. The palladium-catalyzed [4 + 1] reaction generates a 1-arylindane with all of the functionalities needed for formation of the indano[2,1-c]chroman ring system of brazilin. The synthesis of (±)-brazilin was achieved in 11 steps (longest linear sequence) with an overall 11% yield.

Full text of DOI:10.1021/acs.joc.9b02343

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Article
Total Synthesis of (±)-Brazilin using a [4+1]
Palladium-Catalyzed Carbenylative Annulation
Vanessa Arredondo, Daniel E. Roa, Eugene S. Gutman, Nancy O. Huynh, and David L Van Vranken
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02343 • Publication Date (Web): 22 Oct 2019
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Total Synthesis of ()-Brazilin
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using a [4+1] Palladium-Catalyzed Carbenylative Annulation
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Vanessa Arredondo, Daniel E. Roa, Eugene S. Gutman, Nancy O. Huynh, David L. Van Vranken*
Department of Chemistry, University of California, Irvine, 1102 Natural Sciences II, Irvine,
California 92697, United States
[4+1]
carbenylative
CO2Me
CO2Me
annulation
MeO
MeO
MeO
MeO
HO
HO
CO2Me
OH
-
10 mol%
CO2Me
OBn
Na+
PdCl2(CH3CN)2
(4-FC6H4)3P
I
O
H
N
TsN
Na
THF, 60 ºC
90%
OBn
OH
OMe
(±)-brazilin
OMe
Abstract
Palladium-catalyzed carbene insertion was utilized in a formal synthesis of (±)-picropodophyllone
and a total synthesis of ()-brazilin. All prior syntheses of brazilin have involved a Friedel–Crafts
alkylation in the key carbon-carbon bond forming events. The palladium-catalyzed [4+1] reaction
generates a 1-arylindane with all of the functionality needed for formation of the indano[2,1-
c]chroman ring system of brazilin. The synthesis of ()-brazilin was achieved in 11 steps (longest
linear sequence) with an overall 11% yield.
Introduction
Extracts from the heartwood of Caesalpinia sappan have been used as natural dyes for
over two millennia.1,2 The correct indano[2,1-c]chroman structure of brazilin, a major constituent
of sappanwood extracts, was not determined until 1908 (Figure 1).3 Under ambient conditions,
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brazilin undergoes facile oxidation to the chromophore brazilein A. The related indano[2,1-
c]chroman haematoxylin, is still used as a principal tissue stain, and undergoes a similar oxidation
to hematein. Sappanwood extracts are used in traditional Asian medicine and have been the subject
of continuous and extensive biological studies.4 Brazilin has been studied for the treatment of
diabetes,5 arthritis,6 and various cancer types.7
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(+)-haematoxylin
tissue stain
(-)-brazilein A
immunosuppressive
(+)-brazilin
antitumor
HO
HO
HO
O
OH
OH
OH
O
HO
HO
O
O
H
H
OH
OH
OH
OH
Figure 1. Brazilin and related bioactive indano[2,1-c]chromans.
Perkin and Robinson first reported the synthesis of the brazilin indano[2,1-c]chroman ring
system using a biomimetic4b,8 Friedel–Crafts cyclization9,10,11 to form the five-membered
indane12,13,14 or the six-membered pyran ring.15,16,17 18 Yadav and co-workers add the aryl ring to
an indane core using an intermolecular Friedel–Crafts followed by cyclization to form the six-
membered pyran.19 Alternative synthetic strategies could broaden access to derivatives with
improved activity so we were prompted to investigate an alternative synthesis of brazilin through
a non-obvious disconnection. In 2014, we developed palladium-catalyzed [5+1] and [4+1] carbene
insertions of aryl iodides and N-tosylhydrazones which gave access to the 1-aryltetralin and 1-
arylindane cores present in natural products such as podophyllotoxin and brazilin, respectively.20
When the [5+1] palladium-catalyzed carbene insertion was applied to aryl iodide 1 and N-
tosylhydrazone 2, it generated 1-aryltetralin derivative 3 which is a key intermediate in the Kende
syntheses of (±)-picropodophyllone and (±)-podophyllotoxin (Scheme 1).21 Given the modest
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yield for the [5+1] annulation reaction and the difficulty of removing azine side product, we set
out to explore the applicability of the [4+1] palladium-catalyzed carbene insertion to a total
synthesis of (±)-brazilin.
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Scheme 1. Formal synthesis of (±)-picropodophyllone using a [5+1] palladium-catalyzed carbene
insertion.
O
O
O
O
O
O
1. NaH, THF
CO2Et
OEt
CO2Et
CO2Et
1
2. 10 mol %
PdCl2(CH3CN)2
(4-FC6H4)3P
THF, 60 ºC
I
N
O
TsHN
3
50%
2
MeO
OMe
MeO
OMe
OMe
O
OMe
O
O
O
O
(±)-picropodophyllone
MeO
OMe
OMe
During our initial development of the palladium-catalyzed [4+1] carbenylative annulation
we found that ortho-oxygenation on the N-tosylhydrazone was slightly detrimental to the yield,
whereas oxygenation on the aryl iodide was slightly beneficial, as exemplified by previously
published yields for arylindanes 6 and 7, respectively (Figure 2).20,22 These substituent effects
appear to counter each other leading to useful yields of highly oxygenated 1-arylindanes 8aa–8ba
(Figure 2). Valdés and coworkers have successfully employed oxygenated N-tosylhydrazones in
[4+1] carbenylative Heck reactions.23 N-Tosylhydrazones with bromine substituents are well-
tolerated in these reactions,20 providing the opportunity for further late stage functionalizations.
Broadened peaks and a minor impurity were particularly apparent in the 1H NMR spectra
of 1-arylindanes 8ba and 8bb in spite of chromatographic homogeneity under all conditions tested.
Counter to the expectations of A1,3 strain, these hindered compounds, and some of the 1-
arylindanes described later, appear to exist as two conformers based on the presence of two sets of
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broadened peaks in the 1H NMR spectra in a ca 5:1 ratio. For 1-arylindane 8bb, the peaks converge
at 110–120 °C and sharpen into well-resolved signals at 0 °C in DMF-d7 (see supporting
information). Two low energy conformers of 8bb were identified with MMFF94 and shown to be
different in energy by 0.78 kcal/mol at the b3lyp/6-31G(d) level of theory (supporting
information). In the lowest energy conformer, A1,3 strain is minimized by the syn orientation of
the BnO group with the methine C–H,24 but the aryl substituent ends up in a hindered pseudoaxial
position. In the higher energy conformer, the aryl substituent is pseudoequatorial, but is not
oriented to minimize A1,3 strain. The requirement for a half-chair flip and rotation about the highly
congested aryl-indanyl bond could result in an energy barrier significant enough to explain the
broadening of peaks between 60 °C and 100 °C. In a 1-D gradient NOE experiment, irradiation of
the O-benzyl methylene protons at 5.12 ppm in the major conformer of 1-arylindane 8bb at 0 °C
in CDCl3, led to a reduction in signal of the O-benzyl methylene protons at 4.64 ppm in the minor
conformer, consistent with conformational interconversion (see supporting information for
spectra).25
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4a, R1, R2 = –OCH2O–
4b, R1, R2 = OMe
R1
R2
R1
R2
CO2Me
CO2Me
CO2Me
CO2Me
1. NaH, THF, -10 °C
2. PdCl2(CH3CN)2
P-(4FC6H4)3
THF, 60 ºC
I
R3
N
R3
TsHN
1-aryl-
indanes
5a, R3, R4 = OBn
5b, R3 = OBn, R4 = OMe
R4
R4
CO2Me
CO2Me
CO2Me
CO2Me
O
O
OMe
6
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60%
98%
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CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
O
O
O
O
OBn
OBn
OBn
8aa
8ba
8bb
84%
80%
90%
OBn
OBn
OMe
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Figure 2. Palladium-catalyzed insertion of oxygenated aryl iodides and N-tosylhydrazones.
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With access to a number of O-protected 1-arylindane intermediates we set out to remove
the vestigial carboxymethyl group and close the dihydropyran ring (Scheme 2). Intramolecular
cyclization under either neutral or basic conditions should favor 6-endo-tet cyclization26 on the
less substituted position of a 1,1-disubstituted epoxide. Krapcho decarboxylation of geminal
diester 8aa generated a 1:1 mixture of carboxymethyl epimers (9) that were reduced to primary
alcohol 10 as a mixture of isomers. Initial attempts to eliminate the alcohol via the mesylate failed,
but exocyclic alkene 11 was obtained through a selenoxide elimination. Treatment of alkene 11
with m-CPBA gave epoxide 12 as an inseparable 6.5:1 mixture of diastereomers, presumably from
the face opposite the allylic arene substituent. Debenzylation was accompanied by spontaneous 5-
exo-tet cyclization to produce the indano[2,1-b]benzofuran 13 containing the core of the
kaempferiaosides A and B,27,28 but not the desired indano[2,1-c]chroman ring system of brazilin.
5-Exo-tet cyclization on the more substituted position of the epoxide was favored even when the
debenzylation was carried out in the presence of base.
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Scheme 2. Initial synthetic strategy to brazilin involving late-stage formation of the
dihydropyran.a
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R
H
OH
O
O
O
O
CO2Me
OBn
b
c
OBn
6
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9
8aa
(R = CO2Me)
10
a
OBn
1:1 dr
OBn
9 R = H
(1:1 dr)
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O
O
O
d
e
O
O
OBn
OBn
11
12
6.5:1 dr
OBn
OH
OBn
HO
O
O
O
O
O
O
H
H
not
13
observed
OH
OH
aReagents and conditions: (a) NaI, NaHCO3, DMF, 155 °C, 86%;
(b) LiAlH4, THF, 65 °C, 94%; (c) o-O2NC6H4SeCN, PPh3, THF, 23
°C, then 30% (w/w) H2O2, THF, 23 °C, 38%; (d) m-CPBA,
NaHCO3, DCM, 23 °C, 40%; (e) 49 mol % Pd(OH)2/C, H2,
MeOH:THF (1:1), 23 °C, 49%.
We recognized the possibility of intercepting an exocyclic alkene 16 previously reported
by both Zhang28 and Yadav19 and used by Yadav in a synthesis of brazilin. Bis-methoxy alkene 16
was prepared using the same sequence employed for synthesis of methylenedioxy alkene 11 in an
overall yield of 48% (Scheme 3). Epoxidation of alkene 16 also generated a ca 7:1 mixture of
diastereomeric epoxides corresponding to 12, but the major isomer could be crystallized by vapor
diffusion (CH2Cl2/hexane) and the epoxide oxygen was confirmed to be anti to the axial aryl
substituent on the five-membered ring (see supporting information for S12ba). Following the
dihydroxylation procedure of Zhang and co-workers, we obtained an 11:1 ratio of diastereomers
17 and 18 (Scheme 3). Surprisingly, the minor diastereomer 18 from dihydroxylation, and not the
major diastereomer 17, was found to match the diol prepared by Yadav through a different route,
suggesting that the dihydroxylation proceeds from the same face as the hindered aryl substituent
and that the dihydroxylation product had been previously mis-assigned. That structural mis-
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assignment would explain the fact that the Yadav diol 18 was convertible to brazilin, whereas the
Zhang diol 17 was not.
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Scheme 3. Dihydroxylation gives the wrong diastereomer a
MeO
MeO
MeO
MeO
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CO2Me
CO2Me
a-c
d
OBn
OBn
8ba
16
OBn
OBn
MeO
MeO
MeO
MeO
OH
OH
OH
OH
+
OBn
OBn
17
syn
major
18
anti
minor
11:1 dr
OBn
OBn
aReagents and conditions:(a) NaI, NaHCO3, DMF, 155 °C, 94%;
(b) LiAlH4, THF, 65 °C, 94%; (c) o-O2NC6H4SeCN, PPh3, THF,
23 °C, then 30% (w/w) H2O2, THF, 23 °C, 54%; (d) NMO/OsO4,
acetone:H2O (9:1), 0 °C, 89%.
Given the challenges associated with stereoselective functionalization of the exocyclic
alkene 16 and subsequent 5-exo-tet cyclization, we returned to the cyclic malonate 8ba generated
from the palladium-catalyzed [4+1] (Scheme 4), hoping to form the lactone with one of the ester
groups. Hydrogenolysis of dibenzyl ether 8ba gave the free resorcinol 19 and the desired lactone
product 20 containing the tetracyclic ring system of brazilin. The remaining resorcinol 19 was
driven to chromanone 20 by heating with p-toluenesulfonic acid. Krapcho decarboxylation of the
methyl ester of 20 was accompanied by a competing methylation of the free phenolic group by the
chloromethane byproduct to afford O-methyl ether 22 as the major product. Attempts to prevent
the unwanted methylation were unsuccessful so the remaining phenol 21 was alkylated with
dimethyl sulfate to afford the O-methyl ether 22 in 90%, for an overall yield of 67% for the
decarboxylation/methylation process.
With chromanone 22 in hand, we proceeded to investigate the reduction,29 dehydration,30
and hydroboration-oxidation31 sequence to access O-trimethylbrazilin. The lactone 22 was
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reduced to lactol 23 in 48% yield (5.8:1 mixture of lactol isomers). Attempts to dehydrate the lactol
were unsuccessful under E1, E2 and syn-elimination conditions possibly attributable to the
incompatibility between oxocarbenium intermediates and electron-rich arenes or the sensitivity of
the enol ether.
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Scheme 4. Early-stage access to indano[2,1-c]chroman core through lactonization.a
The great facility of lactonizing one of the geminal carboxymethyl groups of malonate 8ba,
inspired a similar approach involving cyclization onto one of two geminal mesylates by one of the
four phenolic groups protected as an O-benzyl ether (Scheme 5). This was easily accomplished by
reducing the carboxymethyl groups of geminal ester 8bb to afford the corresponding geminal
alcohol 24 in 71% yield. Mesylation of the hydroxyl groups and hydrogenolysis of the benzylic
protecting group generated the phenolic mesylate 26 in high yield. As described for 1-arylindane
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8bb, geminal alcohol 24, bis-mesylate 25, and even bis-mesylate 26 (lacking an O-benzyl group)
5
6
1
exhibited a second minor conformer evident in the H NMR spectrum. Deprotonation of the
7
8
9
phenolic group was followed by facile cyclization onto the syn mesylate to form the desired
dihydropyran ring of indanochroman 27 in 81% yield. The extraneous mesylate was removed with
lithium aluminum hydride to afford the neopentyl alcohol 28 which was oxidized to aldehyde 29
in 88% yield using Dess-Martin periodinane.
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Scheme 5. Total synthesis of (±)-brazilin from bis-mesylate 26.
HO
MeO
MeO
CO2Me
CO2Me
OH
OR
a
b
MeO
MeO
OBn
H
8bb
24 (R = Bn)
25 (R = H)
c
OMe
OMe
MsO
MsO
H
MeO
MeO
MeO
OMs
OH
e
d
MeO
O
H
26
27
OMe
O
OMe
HO
MeO
MeO
MeO
MeO
OH
f
g
O
H
H
28
30
29
OMe
OH
OMe
OH
MeO
MeO
HO
HO
h
O
O
H
H
(±)-brazilin
OMe
OH
aReagents and conditions: (a) LiAlH4, THF, 0 °C, 71%; (b) MsCl, NEt3,
0 to 5 °C, 95%; (c) 24 mol % Pd(OH)2/C, H2, MeOH:THF (1:1), 23 °C,
99%; (d) NaH, THF, 0 °C, 81%; (e) LiAlH4, THF, 65 °C, 90% (f) DMP,
DCM, 0 to 5 °C, 86%; (g) NaOH, 30% (w/w) H2O2, MeOH, 65 °C, 42%;
(h) BBr3, DCM, 0 to 23 °C, 68%.
The aldehyde was subjected to Bayer-Villiger oxidation under nucleophilic conditions in
order to minimize collateral oxidation of the electron-rich aromatic ring to afford O-
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trimethylbrazilin, 30, in 42% (>95% purity) yield upon treating aldehyde 29 with NaOH and 30%
(w/w) H2O2. The methyl groups were removed with BBr3, as previously reported, to afford ()-
brazilin in 68% (>95% purity); as noted by others,32 the catechol brazilin is highly sensitive to
oxidation.
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Palladium-catalyzed [5+1] and [4+1] carbenylative annulation reactions with electron-rich
aromatic rings have led to a formal synthesis of (±)-picropodophyllone and a total synthesis of (±)-
brazilin. The [4+1] annulation reaction approach to ()-brazilin varies dramatically from the
Perkin-Robinson strategy first proposed over a century ago. The powerful palladium reaction
brings in nearly all of the necessary functionality, but strategies to access the dihydropyran ring
via epoxide ring opening or lactonization proved unworkable. Ultimately, a strategy involving
construction of the dihydropyran ring through diastereotopic displacement of a mesylate paved the
way for the synthesis of ()-brazilin in 8 steps from the corresponding aryl iodide and in 12%, 11
steps in the longest linear sequence from commercial 3,4-dimethoxybenzyl alcohol (11% overall
yield).
EXPERIMENTAL SECTION
GENERAL INFORMATION AND REAGENTS
All reactions were performed under an atmosphere of dry N2 gas. Anhydrous solvents and
reagents, where applicable, were transferred using Schlenk technique. Toluene, tetrahydrofuran
(THF), diethyl ether (Et2O), and dichloromethane (CH2Cl2) were dried by passage through alumina
according to the procedure of Grubbs and co-workers.33 All other solvents were purified according
to reported procedures.34 Unless otherwise noted, all reagents were commercially obtained and
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used without prior purification. Where applicable, acetone Optima™ (Fisher), and 30% (w/w)
H2O2 (Fisher) was used.
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All reactions were monitored by thin-layer chromatography (TLC) and visualized by UV
(254 nm) illumination and by KMnO4 and p-anisaldehyde (p-anis) dip stains. The p-anis stain was
prepared by adding 25 mL of concentrated sulfuric acid to a chilled solution of 95% ethanol (676
mL, made from 200 proof ethanol and de-ionized water). Glacial acetic acid (7.5 mL) and p-
anisaldehyde (99%, 18.4 mL) were then added to afford a colorless solution. The stain was stored
at 0 °C. Analytical TLC was performed using EMD Millipore 0.25 mm Silica gel 60 F254 20 × 20
cm plates (EM1.05715.0001). “Flash” chromatography on silica gel was performed using Agela
Technologies Flash Silica sorbent (40-63 µm) silica gel of 230-400 mesh (CS605025-P). Unless
otherwise indicated, all reactions were heated using a silicon oil bath on a temperature-controlled
heating-stirring plate.
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1H and 13C NMR spectral data were recorded at 23 °C using a Bruker Avance 500 or 600
MHz spectrometer equipped with a cryoprobe. All spectra were calibrated to tetramethylsilane
(0.00 ppm) unless otherwise specified, in which case the reference peak will be reported as Shift
(reference). In general, NMR spectra taken in CDCl3 were calibrated to tetramethylsilane (0.00
1
13
ppm). H and C NMR spectra taken in CD3OD were calibrated to 3.31 ppm and 49.15 ppm,
1
13
respectively. H and C NMR spectra taken in DCON(CD3)2 were calibrated to 2.75 ppm, and
163.15 ppm, respectively. Variable temperature 1H NMR stacked spectra taken in DCON(CD3)2
were calibrated to 8.03 ppm. 1H and 13C NMR spectra taken in C6D5CD3 were calibrated to 2.09
ppm and 20.4 ppm, respectively.
The NMR data are reported as follows: chemical shift in ppm (δ), multiplicity (br = broad,
app = apparent, s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet), coupling
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constants (Hz), and integration. NMR data was processed using Mestrelab Research MestReNova
11.0.2 software, using automatic baseline correction, automatic phasing, and the multiplet analysis
function. Infrared spectroscopy data was acquired using a PerkinElmer Spectrum Two IR
Spectrometer or a Thermo Scientific iD5 ATR (Nicolet iS5) Spectrometer. Mass spectra were
obtained using a Waters (Micromass) LCT premier with a TOF analyzer using the ionization
method indicated. Melting points were taken on a Thermo Scientific Electrothermal Mel-Temp®
apparatus (Model No. 1001D) using a mercury thermometer. The reported melting point values
are uncorrected. Chemical names found in the supporting information were generated using
PerkinElmer ChemBioDraw Ultra 13.0 software.
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SYNTHETIC PROCEDURES
Diethyl 2-(2-(6-iodobenzo[d][1,3]dioxol-5-yl)-2- oxoethyl)malonate, 1.
O
Malonate 1 was synthesized following a modified procedure from Ziegler and
O
CO2Et
CO2Et
co-workers.35 Briefly, a 25 mL 2-neck round-bottom flask was equipped with
O
I
1
a stir bar, flame-dried, and charged with aryl iodide 1-(6- iodobenzo[d][1,3]dioxol-5-yl)ethan-1-
one (0.300 g, 1.03 mmol). The round-bottom flask was evacuated and backfilled with N2 ( 3)
before being charged with DCM (6.1 mL) and TFA (0.04 mL, 0.52 mmol). To the yellow solution
was added pyridinium tribromide (0.363 g, 1.14 mmol) in four portions over four hours. The flask
was wrapped in aluminum foil during the reaction to exclude light. After 10 h, starting material
was no longer detectable by TLC (100% toluene). The crude reaction mixture was quenched with
saturated aqueous NaHCO3 (6.0 mL) and stirred until gas ceased evolving. The crude reaction
mixture was transferred to a separatory funnel and washed once with 6 mL of aqueous 1 N HCl.
The aqueous layer was extracted with DCM (1  12 mL) and the combined organic phases were
washed with brine (1  20 mL), dried (Na2SO4), and concentrated in vacuo. The resulting yellow
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oil was immediately subjected to flash chromatography (10:90 hexanes:toluene) to afford the crude
5
6
α-bromoketone as a clear oil (0.203 g) which was taken on to the alkylation step. Rf = 0.55 (100%
7
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1
toluene). H NMR (500 MHz, CDCl3) δ 7.36 (s, 1H), 7.02 (s, 1H), 6.07 (s, 2H), 4.40 (s, 2H).
13C{1H} NMR (126 MHz, CDCl3) δ 193.5, 150.9, 148.3, 134.1, 120.5, 109.5, 102.6, 82.4, 32.7.
A flame-dried 25 mL, 2-necked round-bottom flask equipped with a short-stem vacuum
adapter and rubber septum was charged with un-rinsed 60% NaH/mineral oil (0.066 g, 1.65 mmol),
and a stir bar. The flask cooled was to –10 °C in a brine-ice bath, and charged with THF (4.5 mL).
Diethyl malonate (0.272 g, 1.65 mmol) was added dropwise via syringe over 5 min resulting in a
white slurry. After 25 min, a solution of α-bromoketone from the previous step (0.203 g, 0.55
mmol) in THF (1.0 mL) was added dropwise via syringe over 1 min. The reaction was removed
from the brine-ice bath and warmed to 23 °C while stirring. After 4.5 h, α-bromoketone was no
longer detectable by TLC (25:75 EtOAc:hexanes). The reaction mixture was quenched with 15
mL of saturated aqueous NH4Cl and transferred to a separatory funnel. The mixture was extracted
with Et2O (3  20 mL) and the combined organic phases were dried (Na2SO4) and concentrated in
vacuo to afford a clear oil. The oil was purified by flash chromatography (10:90 EtOAc:hexanes)
to yield diethyl 2-(2-(6-iodobenzo[d][1,3]dioxol-5-yl)-2-oxoethyl)malonate 1 as a clear oil (0.153
g, 62%). Rf = 0.51 (20:80 EtOAc:hexanes). 1H NMR (500 MHz, CDCl3) δ 7.36 (s, 1H), 7.15 (s,
1H), 6.05 (s, 2H), 4.23 (qd, J = 7.1, 3.2 Hz, 4H), 4.06 (t, J = 7.2 Hz, 1H), 3.45 (d, J = 7.2 Hz, 2H),
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1.29 (t, J = 7.1 Hz, 6H); C{1H} NMR (126 MHz, CDCl3) δ 198.5, 168.8, 150.6, 148.3, 135.6,
120.7, 109.2, 102.4, 81.5, 61.9, 47.5, 40.2, 14.1; HRMS (ESI): m / z calcd for C16H17O7INa [M +
Na]+ 470.9917, found 470.9906.
N'-(2,4-Bis(benzyloxy)benzylidene)-4-methylbenzenesulfonohydrazide, 5a.
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NHTs
3,5-Dibenzyloxy-N-tosylhydrazone 5a was synthesized as published by
Aggarwal and co-workers with slight modification.36 To a solution of p-
toluenesulfonyl hydrazide (1.8 g, 9.5 mmol) in 5 mL of MeOH was added 2,4-
N
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8
BnO
OBn
5a
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dibenzyloxybenzaldehyde (3.0 g, 9.4 mmol) in three portions over 15 min. A thick yellow
precipitate formed during the course of the reaction. Additional MeOH (25 mL) was added to
ensure proper stirring. Upon complete consumption of the starting benzaldehyde (30 min), the
reaction was cooled (0 °C) for 15 min. The yellow precipitate was filtered, washed with cold
MeOH, and then purified by flash chromatography (0:100 – 20:80 EtOAc:hexanes) to yield N-
tosylhydrazone 5a as a pale yellow solid (3.8 g, 83%). Rf = 0.37 (30:70 EtOAc:hexanes). mp =
154155 °C; 1H NMR (500 MHz, CDCl3) δ 8.07 (s, 1H), 7.84 (dd, J = 8.4, 2.2 Hz, 2H), 7.78 (d, J
= 8.8 Hz, 1H), 7.61 (s, 1H), 7.45 – 7.30 (m, 10H), 7.26 (d, J = 8.4 Hz, 2H), 6.57 (dd, J = 8.7, 2.3
13
Hz, 1H), 6.52 (d, J = 2.3 Hz, 1H), 5.04 (s, 2H), 4.97 (s, 2H), 2.38 (s, 3H); C{1H} (125 MHz,
CDCl3)  161.9, 158.3, 144.06, 144.04, 136.3, 136.1, 135.4, 129.6, 128.77, 128.75, 128.3, 128.2,
127.9, 127.8, 127.5, 115.2, 106.9, 100.1, 70.4, 70.2, 21.6; IR (ATR) 3201, 1601, 1164 cm-1. HRMS
(ESI): m / z calcd for C28H26N2O4SNa [M + Na]+ 509.1511, found 509.1499.
N'-(2-(Benzyloxy)-4-methoxybenzylidene)-4-methylbenzenesulfono-hydrazide, 5b.
NHTs
To a cooled (0 °C) solution of p-toluenesulfonyl hydrazide (11.7 g, 62.7 mmol)
N
in THF (105 mL) was added 2-benzyloxy-4-methoxybenzaldehyde (11.9 g, 52.3
MeO
OBn
5b
mmol).37 After stirring for 30 min, the reaction mixture was warmed to 23 °C.
A thick yellow precipitate formed during the course of the reaction. Upon consumption of the
aldehyde (1 h 45 min), the reaction was concentrated in vacuo and recrystallized from MeOH to
afford product 5b as an off-white solid (15.6 g, 73%). The filtrate was further recrystallized to
afford additional N-tosylhydrazone 5b as an off-white solid (2.78 g, 13%). The identical samples
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were combined to afford N-tosylhydrazone 5b in 86% yield. Rf = 0.44 (40:60 EtOAc:hexanes,
stains orange by p-anis dip stain). mp = 162–163 °C. 1H NMR (600 MHz, CDCl3) δ 8.09 (s, 1H),
7.84 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.6 Hz, 1H), 7.40 – 7.31 (m, 5H), 7.28 – 7.26 (m, 2H), 6.50
(dd, J = 8.7, 2.3 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 5.00 (s, 2H), 3.79 (s, 3H), 2.38 (s, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 162.8, 158.4, 144.1, 144.0, 136.2, 135.5, 129.6, 128.7, 128.3, 128.0,
127.9, 127.5, 115.1, 106.1, 99.2, 70.5, 55.5, 21.6; IR (ATR) 3193, 3066, 3035, 2862, 2840, 1606,
1506, 1442, 1279, 1155, 1022, 822 cm-1. HRMS (ESI) m / z calcd for C22H22N2O4SH [M + H]+
411.1378, found 411.1378.
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Diethyl 8-oxo-5-(3,4,5-trimethoxyphenyl)-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6,6(5H)-
dicarboxylate, 3.
O
A flame-dried 5 mL, pear-shaped flask was charged with PdCl2(MeCN)2 (2.6
O
CO2Et
O
mg, 0.01 mmol), tris(4-fluorophenyl)phosphine (12.6 mg, 0.04 mmol), and a
CO2Et
3
stir bar. The flask was purged and backfilled with nitrogen three times and then
MeO
OMe
OMe
fitted with a rubber septum. THF (0.3 mL) was then added and the mixture
was stirred for 10 min, resulting in a clear yellow solution.
A separate flame-dried 5 mL, pear-shaped flask containing malonate 1 (44.5 mg, 0.10
mmol), N-tosylhydrazone 2 (72.9 mg, 0.20 mmol), and a stir bar was purged and backfilled with
nitrogen three times and fitted with a rubber septum. THF (0.3 mL) was added and the mixture
was stirred for 10 min resulting in a clear solution.
A separate flame-dried 15 mL, round-bottom flask was equipped with a short-stem vacuum
adapter and charged with un-rinsed 60% NaH/mineral oil (14.4 mg, 0.36 mmol) and a stir bar. The
flask was purged and backfilled with nitrogen three times and fitted with a rubber septum. THF
(0.8 mL) was added and the suspension was cooled to –10 °C in a brine-ice bath. The solution of
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aryl iodide 1 and N-tosylhydrazone 2 in THF was then added dropwise via syringe over 5 min to
the 15 mL flask containing a stirring NaH suspension. During the course of addition, a white solid
precipitated out of solution. The flask containing aryl iodide 1 and N-tosylhydrazone 2 was washed
with THF (2  0.3 mL) and the washes were added to the 15 mL flask.
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The flask was then warmed to 23 °C and stirred for 20 min. Under a stream of nitrogen,
the yellow catalyst solution was added to the reaction. The flask containing catalyst solution was
washed with THF (2  0.3 mL) and the washes were added to the reaction. The reaction mixture
was heated at 60 °C. After 1.5 h, aryl iodide 1 was no longer detectable by TLC.
The reaction mixture was cooled to 23 °C, diluted with 15 mL of Et2O, and passed through
a plug of silica. The plug of silica was washed with Et2O (3  100 mL) and the filtrate was
concentrated in vacuo. The product was purified by flash chromatography on silica gel (25:75
EtOAc:hexanes) to afford a mixture of tetralone 3 and azine (9:1 tetralone 3:azine) as a yellow
solid. (24.5 mg, 50%). Rf = 0.20 (10:90 EtOAc:toluene). 1H NMR (500 MHz, CDCl3) δ 7.47 (s,
1H), 6.64 (s, 1H), 6.23 (s, 2H), 6.02 (s, 2H), 5.05 (s, 1H), 4.19 – 3.98 (m, 4H), 3.80 (s, 3H), 3.73
(s, 6H), 3.28 (d, J = 18.1 Hz, 1H), 3.21 (d, J = 18.0 Hz, 1H), 1.18 (t, J = 7.2 Hz, 3H), 1.14 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 193.1, 169.4, 168.0, 153.4, 153.1, 147.9, 140.5,
137.6, 132.9, 129.5, 128.8, 126.3, 108.8, 107.9, 106.7, 105.4, 103.4, 102.0, 62.4, 62.0, 60.8, 59.9,
56.1, 49.8, 38.4, 13.9, 13.8. HRMS (ESI) m / z calcd for C26H28O10Na [M + Na]+ 523.1580, found
523.1570.
Dimethyl
5-(2,4-bis(benzyloxy)phenyl)-5,7-dihydro-6H-indeno[5,6-d][1,3]dioxole-6,6-
dicarboxylate, 8aa.
CO2Me
CO2Me
O
O
Arylindane 8aa was synthesized using the same carbenylative annulation
procedure for tetralone 3 above. To a stirring, chilled (–10 °C) solution of un-
OBn
8aa
OBn
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rinsed 60% NaH/mineral oil (184 mg, 4.59 mmol) in THF (21.3 mL) was added a pre-stirred
solution of malonate 4a (0.500 g, 1.28 mmol) and N-tosylhydrazone 5a (1.24 g, 2.55 mmol), in
THF (7.1 mL). Additional THF (2  7.1 mL) was used to transfer any remaining reagent solution.
After 15 min, the stirring, cooled, heterogeneous solution was warmed to 23 °C, and stirred an
additional 20 min. A pre-stirred solution of PdCl2(CH3CN)2 (33.1 mg, 0.128 mmol) and P(4-
FC6H5)3 (161 mg, 0.510 mmol) in THF (7.1 mL) was then added. Additional THF (2  7.1 mL)
was used to transfer any remaining catalyst solution. The reaction was heated (60 °C) and
monitored for the consumption of malonate 4a and N-tosylhydrazone 5a starting material. After 2
h, neither was detectable by TLC. The mixture was cooled to 23 °C, diluted with Et2O (25 mL),
and then passed through a pad of silica gel. The pad was rinsed with Et2O (3  15 mL) and the
filtrate concentrated in vacuo to afford a crude red-brown oil. The oil was purified by two rounds
of flash chromatography (0:100 – 10:90 EtOAc:hexanes; then 1:99 EtOAc:toluene) to yield
arylindane 8aa as a yellow solid (574 mg, 80%).Rf = 0.30 (20:80 EtOAc:hexanes, stains mahogany
by p-anis dip stain). mp = 48–58 °C. 1H NMR (500 MHz, CDCl3, 298.0 K) δ 7.54 (s, 2H), 7.43 –
7.29 (m, 6H), 6.68 (s, 0.7H), 6.57 (s, 0.6H), 6.50 (s, 0.3H), 6.41 (s, 1H), 5.89 (s, 4H), 5.08 (s, 2H),
5.03 – 4.92 (m, 2H), 3.97 (d, J = 16.7 Hz, 0.6H), 3.71 (s, 3H), 3.30 (d, J = 16.1 Hz, 0.4H), 3.20 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3, 298.0 K) δ 172.3, 170.0, 158.8, 157.0, 147.4, 137.2, 136.8,
132.5, 130.4, 128.6, 128.5, 128.0, 127.7, 127.6, 127.0, 122.1, 105.5, 104.3, 101.0, 100.3, 70.2,
70.0, 66.3, 52.9, 52.0, 47.9, 39.9; IR (ATR) 2950, 1732, 1233, 1166, 1036 cm-1; HRMS (ESI) m /
z calcd for C34H30O8Na [M + Na]+ 589.1838, found 589.1836.
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Broadened peaks are apparent in the 1H NMR, suggesting rotamers. Additional 1H NMR
1
data is reported below. The corresponding H NMR spectra can be found in the supporting
1
information. H NMR (500 MHz, CDCl3, 253.0 K) δ 7.60 – 7.52 (m, 2H), 7.49 – 7.33 (m, 8H),
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6.73 (s, 1H), 6.60 (d, J = 2.3 Hz, 1H), 6.52 – 6.49 (m, 1H), 6.46 (s, 1H), 6.43 (dd, J = 8.5, 2.3 Hz,
1H), 5.95 – 5.93 (m, 2H), 5.91 (s, 1H), 5.17 – 5.04 (m, 2H), 5.05 – 4.90 (m, 2H), 4.00 (d, J = 16.8
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Hz, 1H), 3.76 (d, J = 1.1 Hz, 3H), 3.34 (d, J = 16.8 Hz, 1H), 3.25 (s, 3H); H NMR (600 MHz,
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CDCl3, 328.0 K) δ 7.75 – 7.25 (m, 9H), 6.88 – 6.20 (m, 4H), 5.98 – 5.74 (m, 2H), 5.19 – 4.87 (m,
4H), 3.94 (d, J = 16.6 Hz, 1H), 3.69 (s, 3H), 3.39 – 3.02 (m, 5H); 1H NMR (600 MHz, C6D5CD3,
372.5 K) δ 7.33 (s, 2H), 7.26 – 7.13 (m, 4H), 7.11 – 7.02 (m, 4H), 6.99 – 6.96 (m, 1H), 6.78 (s,
1H), 6.55 (d, J = 2.4 Hz, 1H), 6.44 (s, 1H), 6.38 (d, J = 5.1 Hz, 1H), 6.33 (dd, J = 8.4, 2.4 Hz, 1H),
6.02 (s, 1H), 5.38 (d, J = 7.4 Hz, 1H), 4.78 (s, 2H), 4.75 (s, 2H), 4.10 (d, J = 16.5 Hz, 1H), 3.39
(d, J = 1.3 Hz, 3H), 3.27 (d, J = 16.5 Hz, 1H), 3.03 (d, J = 1.3 Hz, 3H).
Dimethyl
1-(2,4-bis(benzyloxy)phenyl)-5,6-dimethoxy-1,3-dihydro-2H-indene-2,2-
dicarboxylate, 8ba.
MeO
MeO
CO2Me
CO2Me
Arylindane 8ba was synthesized using the same carbenylative annulation
procedure for tetralone 3. Reaction of malonate 4b (2.00 g, 4.89 mmol), N-
tosylhydrazone 5a (3.75 g, 7.34 mmol), un-rinsed 60% NaH/mineral oil (607
OBn
8ba
OBn
mg, 15.2 mmol), PdCl2(CH3CN)2 (127 mg, 0.489 mmol), and P(4-FC6H5)3 (620 mg, 1.95 mmol)
in THF (245 mL) for 2 hr at 60 °C afforded a crude golden-brown solid that was subjected to three
rounds of flash chromatography (25:75 – 30:70 EtOAc:hexanes ( 2); then 1:99 EtOAc:toluene)
to afford a solid mixture of arylindane 8ba and N-tosylhydrazone 5a. Upon diluting the mixture
with Et2O, a white solid remained insoluble. The mixture was cooled (–78 °C) for 20 min and then
filtered. The white solid was washed with cold Et2O to yield arylindane 8ba (2.38 g, 84%). Rf =
0.28 (30:70 EtOAc:hexanes, stains red by p-anis dip stain). mp = 124–126 °C. 1H NMR (500 MHz,
CDCl3) δ 7.57 (d, J = 7.5 Hz, 2H), 7.45 – 7.28 (m, 8H), 6.75 (s, 1H), 6.60 (s, 1H), 6.49 (s, 1H),
6.48 – 6.37 (m, 2H), 5.96 (s, 1H), 5.09 (s, 2H), 5.04 – 4.93 (m, 2H), 4.03 (d, J = 16.6 Hz, 1H),
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3.87 (s, 3H), 3.73 (s, 3H), 3.71 (s, 3H), 3.35 (d, J = 16.6 Hz, 1H), 3.20 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 172.4, 170.1, 158.8, 157.1, 148.9, 148.8, 137.1, 136.8, 135.9, 131.5, 130.5, 128.6,
128.5, 128.0, 127.7, 127.6, 127.1, 122.2, 107.7, 106.7, 105.5, 100.2, 70.2, 70.0, 66.4, 55.9, 52.9,
52.0, 48.3, 40.1; IR (ATR) 2948, 1731, 1502, 1215, 1170, 1151, 1097 cm-1; HRMS (ESI) m / z
calcd for C35H34O8Na [M + Na]+ 605.2151, found 605.2137.
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Dimethyl
1-(2-(benzyloxy)-4-methoxyphenyl)-5,6-dimethoxy-1,3-dihydro-2H-indene-2,2-
dicarboxylate, 8bb.
MeO
MeO
CO2Me
CO2Me
Arylindane 8bb was synthesized using the same carbenylative annulation
procedure for tetralone 3. To a stirring solution of 60% NaH/mineral oil (705
mg, 17.6 mmol) in THF (27.0 mL) at –10 °C was added a pre-stirred solution
OBn
8bb
OMe
of malonate 4b (2.0 g, 4.89 mmol) and N-tosylhydrazone 5b (4.00 g, 9.79 mmol) in THF (27.0
mL). Additional THF (2  27.0 mL) was used to transfer the remaining reagent solution. After 15
min, the stirring, cooled, heterogeneous solution was warmed to 23 °C, and stirred an additional
20 min. A pre-stirred solution of PdCl2(CH3CN)2 (127 mg, 0.489 mmol) and (4-FC6H4)3P (620
mg, 1.95 mmol) in THF (27.0 mL) was then added. Additional THF (2  27.0 mL) was used to
transfer any remaining catalyst solution. The reaction was then heated (60 °C) and monitored by
TLC for the consumption of malonate 4b and N-tosylhydrazone 5b. After 1.5 h, neither was
detectable by TLC. The mixture was cooled to 23 °C, diluted with Et2O (25 mL), and then passed
through a pad of silica gel. The pad was rinsed with Et2O (3  60 mL), and the filtrate concentrated
in vacuo to afford a crude green fluff. The solid was purified by flash chromatography to afford
mixed fractions of product and co-eluting impurities. Successive purifications yielded product 8bb
as a yellow fluff that was crushed into a solid (2.23 g, 90%). Column eluent conditions: four
column volumes of 15:85 EtOAc:hexanes, followed by two column volumes of 20:80
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DCM:toluene, followed by 25:85 – 30:70 EtOAc:hexanes. Mixed fractions were then subjected to
5:95 – 8:92 EtOAc:toluene, followed by 5:95 – 15:85 EtOAc hexanes. Rf = 0.08 (25:75
EtOAc:hexanes, stains pink by p-anis dip stain). Rf = 0.08 (20:80 acetone:hexanes). mp = 144–
146 °C. 1H NMR (600 MHz, CDCl3, 298.0 K) δ 7.64 – 7.51 (broad m, 2H), 7.46 – 7.36 (broad m,
2H), 7.36 – 7.26 (broad m, 1H), 6.93 (s, 0.4H), 6.75 (broad s, 1H), 6.52 (broad s, 1H), 6.48 (s, 1H),
6.32 (broad d, J = 8.6 Hz, 1H), 5.96 (broad s, 1H), 5.33 – 4.90 (broad m, 2H), 4.69 (s, 0.2H), 4.59
(s, 0.2H), 4.03 (broad d, J = 16.6 Hz, 1H), 3.87 (broad s, 3H), 3.74 (s, 3H and s, 1H), 3.73 (s, 3H),
3.71 (s, 3H), 3.35 (d, J = 16.7 Hz, 1H), 3.23 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3, 298.0 K)
δ 172.4, 170.1, 159.7, 157.1, 149.0, 148.8, 137.2, 136.0, 131.5, 130.6, 128.5, 127.7, 127.1, 122.0,
107.8, 106.7, 104.4, 99.4, 70.2, 66.4, 55.93, 55.91, 55.2, 52.9, 52.0, 48.3, 40.1; IR (ATR) 1731,
1504, 1218, 1158, 1098 cm-1; HRMS (ESI) m / z calcd for C29H30O8Na [M + Na]+ 529.1838, found
529.1812.
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1
Broadened peaks are apparent in the HNMR. Using the method of Ley and co-workers,
the broadened peaks are determined to be of rotamers.25 The difference spectrum for the 1D
gradient NOE is provided in the supporting information. Peaks sharpen into well-resolved signals
at temperatures below 23 °C. Additional 1H NMR data is reported below. The corresponding 1H
NMR spectra can be found in the supporting information.1H NMR (600 MHz, CDCl3, 274.2 K) δ
7.60 (d, J = 7.5 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 7.1 Hz,
0.4H), 6.77 (s, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.50 (s, 1H), 6.48 (d, J = 8.6 Hz, 1H), 6.37 (s, 0.2H),
6.32 (dd, J = 8.5, 2.4 Hz, 1H), 6.30 (s, 0.2H), 5.96 (s, 1H), 5.19 (s, 0.2H), 5.16 – 5.05 (m, 2H),
4.69 (d, J = 10.9 Hz, 0.2H), 4.59 (d, J = 11.0 Hz, 0.2H), 4.05 (d, J = 16.6 Hz, 1H), 3.89 (s, 3H),
3.81 (s, 0.5H), 3.78 (s, 0.3H), 3.75 (s, 4H), 3.74 (s, 7H), 3.73 (s, 3H), 3.71 (s, 0.6H), 3.36 (d, J =
16.6 Hz, 1H), 3.24 (s, 4H), 3.01 (d, J = 16.2 Hz, 0.2H). 13C{1H} NMR (151 MHz, CDCl3, 274.2
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K) δ 172.4, 170.2, 159.5, 156.8, 148.6, 148.5, 137.0, 135.7, 131.2, 130.5, 128.5, 127.7, 126.9,
5
6
1
121.6, 107.3, 106.3, 104.0, 99.2, 69.9, 66.2, 55.82, 55.76, 55.2, 53.0, 52.1, 48.0, 39.9; H NMR
7
8
9
(600 MHz, DMF-d7, 298 K) δ 7.68 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.8 Hz, 2H), 7.38 (t, J = 7.4
Hz, 1H), 6.98 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 6.42 (s, 2H), 5.95 (s, 1H), 5.30 (d, J = 12.2 Hz,
1H), 5.21 (d, J = 12.2 Hz, 1H), 4.02 (d, J = 16.7 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H),
3.67 (s, 3H), 3.34 (d, J = 16.7 Hz, 1H), 3.26 (s, 3H). 13C{1H} NMR (151 MHz, DMF-d7, 298 K) δ
172.6, 170.0, 160.2, 157.5, 149.8, 149.6, 138.1, 136.7, 131.8, 130.5, 128.7, 128.0, 127.6, 121.9,
108.2, 107.9, 105.3, 99.7, 70.3, 66.5, 55.8, 55.7, 55.2, 52.9, 51.9, 48.2, 40.0; 1H NMR (600 MHz,
DMF-d7, 274.2 K) δ 7.69 (d, J = 7.5 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H),
7.33 – 7.24 (m, 0.1H), 7.00 (s, 1H), 6.93 (s, 0.1H), 6.76 (d, J = 2.1 Hz, 1H), 6.61 (s, 1H), 6.45 –
6.39 (m, 2H), 5.95 (s, 1H), 5.31 (d, J = 12.2 Hz, 1H), 5.21 (d, J = 12.3 Hz, 1H), 4.86 (d, J = 11.8
Hz, 0.1H), 4.79 (d, J = 12.0 Hz, 0.1H), 4.03 (d, J = 16.6 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.77
(s, 3H), 3.68 (s, 3H), 3.35 (d, J = 16.7 Hz, 1H), 3.27 (s, 3H). 13C{1H} NMR (151 MHz, DMF-d7,
274.2 K) δ 172.7, 170.0, 160.2, 157.4, 149.6, 149.5, 138.2, 136.5, 131.6, 130.6, 128.8, 128.1,
127.6, 121.7, 107.8, 107.6, 105.2, 99.5, 70.2, 66.5, 55.6, 55.57, 55.2, 53.0, 52.1, 48.2, 40.0.
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Methyl
5-(2,4-bis(benzyloxy)phenyl)-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxole-6-
carboxylate, 9 (1:1 syn/anti).
H
O
O
A round-bottom flask containing arylindane 8aa (0.559 g, 0.988 mmol),
anhydrous NaI (0.454 g, 3.06 mmol), and NaHCO3 (0.339 g, 4.04 mmol), was
evacuated and backfilled with N2 ( 3). Anhydrous DMF (8.0 mL) was then
CO2Me
OBn
9
OBn
added. The flask was connected to a water jacketed condenser, and then submerged in an oil bath
(160 °C). The reaction was stirred and monitored for the consumption of arylindane (6 h). The
mixture was cooled to 23 °C. Then, H2O (80 mL) was added while stirring, and the resulting
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solution extracted with Et2O (4  50 mL). The combined organic layers were washed with H2O (
5
6
7
8
3) and with brine ( 1). The organic solution was then dried (MgSO4), and concentrated in vacuo.
The resulting crude yellow oil was purified by flash chromatography (10:90 EtOAc:hexanes) to
afford methyl ester 9 as an inseparable 1:1 mixture of diastereomers as a white foam (0.433 g,
86%). Rf = 0.43 (20:80 EtOAc:hexanes). mp = 40–58 °C. 1H NMR (500 MHz, CDCl3) δ 7.50 –
7.27 (m, 16.1H), 7.20 (d, J = 7.3 Hz, 2.1H), 6.94 (d, J = 8.4 Hz, 1.1H), 6.77 – 6.68 (m, 1.7H), 6.66
(s, 1.1H), 6.63 (d, J = 2.4 Hz, 1.2H), 6.59 (d, J = 2.4 Hz, 0.9H), 6.51 (dd, J = 8.4, 2.4 Hz, 1.2H),
6.47 (s, 0.9H), 6.44 (dd, J = 8.5, 2.4 Hz, 1H), 6.38 (s, 1H), 5.92 – 5.89 (m, 2.9H), 5.89 – 5.87 (m,
1.1H), 5.18 (d, J = 10.0 Hz, 0.9H), 5.09 – 4.93 (m, 7.3H), 4.89 (d, J = 7.6 Hz, 1H), 3.75 (td, J =
8.9, 6.4 Hz, 0.9H), 3.54 (s, 3.1H), 3.48 – 3.36 (m, 1.5H), 3.35 (d, J = 6.5 Hz, 0.5H), 3.19 (s, 2.7H),
3.12 (d, J = 8.4 Hz, 2.1H), 2.99 (dd, J = 15.9, 8.6 Hz, 0.9H); 13C{1H} NMR (126 MHz, CDCl3) δ
175.5, 173.9, 159.0, 158.7, 157.4, 157.3, 147.0, 146.9, 146.8, 137.8, 137.1, 136.9, 136.79, 136.77,
135.5, 134.1, 130.0, 129.7, 128.6, 128.57, 128.5, 128.4, 128.04, 127.98, 127.87, 127.7, 127.6,
127.3, 127.1, 124.3, 122.5, 105.44, 105.40, 105.3, 105.1, 104.7, 104.6, 101.0, 100.9, 100.7, 100.2,
70.2, 70.16, 70.0, 69.9, 52.1, 51.7, 51.1, 49.4, 35.5, 34.3; IR (ATR) 2916, 1732, 1609, 1584, 1502,
1474, 1248, 1167, 1036, 735 cm-1; HRMS (ESI) m / z calcd for C32H28O6Na [M + Na]+ 531.1783,
found 531.1788.
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(5-(2,4-Bis(benzyloxy)phenyl)-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-6-yl)methanol, 10
(1:1 syn/anti).
OH
O
To a cooled (0 °C) solution of methyl ester 9 (1:1 syn/anti, 0.420 g, 0.826
O
OBn
mmol) in THF (69.0 mL) was added LiAlH4 (62.7 mg, 1.65 mmol) portion wise
10
OBn
over 5 minutes, with vigorous stirring. The reaction mixture was warmed to 23
°C and then heated at reflux. Upon consumption of the methyl ester (1 h), the mixture was cooled
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to 23 °C. After, aqueous 0.4 M NaOH (25 mL)was added and the mixture stirred for 5 min. H2O
(50 mL) was added to help solubilize the aluminum salts. The resulting mixture was then filtered
through tightly packed Celite, and the pad was rinsed with EtOAc (3  50 mL). The biphasic
mixture was poured into a separatory funnel and the organic layer removed. The aqueous layer
was extracted with EtOAc (3  50 mL). The combined organic layers were dried (MgSO4), and
concentrated in vacuo. The resulting crude peach solid was purified by flash chromatography
(20:80 EtOAc:hexanes) to afford alcohol 10 as an inseparable 1:1 mixture of diastereomers as a
white solid (0.375 g, 94%). Rf = 0.19 (20:80 EtOAc:hexanes, stains purple by p-anis dip stain). mp
= 118–120 °C. 1H NMR (500 MHz, CDCl3) δ 7.49 – 7.29 (m, 17H), 6.85 (d, J = 8.4 Hz, 1H), 6.73
(s, 1H), 6.70 (s, 2H), 6.69 (s, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 8.4, 2.4 Hz, 1H), 6.49 (s,
1H), 6.46 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 6.40 (d, J = 8.4 Hz, 0.5H), 5.93 – 5.90 (m, 3H), 5.89
(d, J = 1.4 Hz, 1H), 5.19 – 5.06 (m, 1H), 5.05 (s, 2H), 5.03 (s, 2H), 5.00 (s, 2H), 4.81 (d, J = 7.9
Hz, 1H), 4.45 (d, J = 7.1 Hz, 1H), 3.69 – 3.56 (m, 1H), 3.37 (s, 1H), 3.23 (t, J = 10.1 Hz, 1H), 3.03
– 2.98 (m, 0.4H), 2.95 (dd, J = 15.6, 8.1 Hz, 2H), 2.79 (dd, J = 15.4, 7.8 Hz, 1H), 2.66 (dd, J =
15.5, 7.3 Hz, 1H), 2.58 (dd, J = 15.4, 9.6 Hz, 1H), 2.51 (h, J = 7.0 Hz, 1H), 2.26 (d, J = 9.1 Hz,
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1H), 1.68 (t, J = 6.2 Hz, 1H); C{1H} NMR (126 MHz, CDCl3) δ 158.5, 157.1, 156.5, 146.8,
146.72, 146.66, 146.55, 138.8, 138.2, 136.9, 136.8, 136.3, 136.13, 136.12, 135.9, 130.3, 129.3,
128.8, 128.7, 128.6, 128.4, 128.3, 128.1, 128.0, 127.78, 127.75, 127.58, 127.57, 125.6, 122.2,
106.4, 106.0, 105.8, 105.6, 104.9, 104.8, 100.93, 100.90, 100.8, 100.5, 71.0, 70.6, 70.20, 70.18,
65.2, 63.9, 52.6, 48.2, 46.1, 44.0, 34.4, 33.7; IR (ATR) 3390, 2922, 1607, 1583, 1500, 1472, 1166,
1035 cm-1; HRMS (ESI) m / z calcd for C31H28O5Na [M + Na]+ 503.1834, found 503.1830.
5-(2,4-Bis(benzyloxy)phenyl)-6-methylene-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxole, 11.
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9
O
O
A flame-dried flask was charged with alcohol 10 (0.302 g, 0.625 mmol), 2-
nitrophenyl selenocyanate (0.865 g, 3.12 mmol.) and THF (2.0 mL). The
heterogeneous solution was stirred briefly prior to adding P(n-Bu)3 (0.77 mL,
OBn
11
OBn
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3.12 mmol) dropwise over 30 min via syringe pump. Upon addition, the heterogeneous solution
turned red in color. At 30 min, additional THF (1.0 mL) was added to ensure proper stirring of the
slurry. The mixture was stirred at 23 °C and monitored by TLC. At 1 h 15 min, the mixture was
concentrated in vacuo and subjected to flash chromatography (30:70 – 40:60 ether:hexanes) to
afford a yellow oil that was carried on to the next step without further purification. The yellow oil
was dissolved in THF (2.0 mL) and then cooled (0 °C) and stirred. Then, degassed 30% (w/w)
H2O2 (146 µL, 6.25 mmol) was added dropwise. Upon completion (3.5 h), the cooled mixture was
quenched with saturated aqueous Na2S2O3 (0.15 mL) and stirred vigorously for 5 min. The mixture
was partitioned between H2O (30 mL) and EtOAc (15 mL). The layers were separated and the
aqueous extracted with EtOAc (2  15 mL), ether (1  15 mL), and EtOAc (1  15 mL) in sequence.
The combined organic layers were washed with saturated NaHCO3 (1  50 mL), brine (1  50
mL), dried (Na2SO4), and concentrated in vacuo. The crude oil was purified by flash
chromatography (2.5:0:97.5 – 2.5:8:89.5 NEt3:EtOAc:hexanes) to afford alkene 11 as a yellow oil
(0.109 g, 38%). Rf = 0.65 (20:80 EtOAc:hexanes, stains blue by p-anis dip stain). 1H NMR (500
MHz, CDCl3) δ 7.47 – 7.24 (m, 10H), 6.88 (d, J = 8.3 Hz, 1H), 6.64 (s, 2H), 6.49 (d, J = 8.5 Hz,
1H), 6.45 (s, 1H), 5.86 (s, 2H), 5.24 (s, 1H), 5.12 – 4.90 (m, 4H and s, 1H), 4.87 (s, 1H), 3.62 (s,
2H). 13C{1H} NMR (126 MHz, CDCl3) δ 158.6, 157.2, 154.1, 146.7, 139.0, 137.0, 136.9, 134.3,
130.1, 128.6, 128.4, 128.0, 127.8, 127.6, 127.3, 126.4, 108.3, 105.7, 105.3, 104.6, 100.74, 100.70,
70.19, 70.15, 49.5, 38.8. IR (ATR) 3064, 3032, 1721, 1608, 1036, 939, 735, 696 cm-1; HRMS
(ESI) m / z calcd for C31H26O4Na [M + Na]+ 485.1729, found 485.1752.
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5-(2,4-Bis(benzyloxy)phenyl)-5,7-dihydrospiro[indeno[5,6-d][1,3]dioxole-6,2'-oxirane], 12.
5
6
7
8
O
O
O
To a flame-dried flask was added a solution of alkene 11 (0.205 g, 0.443 mmol)
in DCM (1.1 mL). The solution was stirred briefly before adding NaHCO3 (49.4
mg, 0.589 mmol) and m-CPBA (112 mg, 0.456 mmol, 70%). The reaction was
OBn
12
6.5:1 dr
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monitored by TLC for the consumption of alkene 11. The reaction was forced to completion by
adding m-CPBA (0.443 mmol) and DCM (0.3 mL) within 1 h, and adding m-CPBA (0.310 mmol),
NaHCO3 (0.443 mmol) and DCM (1.0 mL) at 2 h. At 3 h, the reaction was quenched with aqueous
10% (w/w) Na2SO3 (5 mL) and stirred vigorously for 10 min. The layers were separated and the
aqueous layer was extracted with DCM (3  10 mL). The combined organic layers were washed
with aqueous 5% (w/w) NaHCO3 (1  30 mL), dried (MgSO4), and concentrated in vacuo. The
crude oil was purified by flash chromatography (15:85 EtOAc:hexanes) to yield epoxide 12 as an
inseparable 6.5:1 mixture of diastereomers as a yellow oil (87.7 mg) containing a small amount
(18 mol %, 4 wt.% by 1H NMR) of EtOAc (40% yield of 12). The major diastereomer is reported
1
below. Rf = 0.36 (20:80 EtOAc:hexanes, stains purple by p-anis dip stain). H NMR (500 MHz,
CDCl3) δ 7.45 – 7.28 (m, 10H), 7.23 – 7.17 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.63 (s, 1H), 6.60
(d, J = 2.4 Hz, 1H), 6.48 (dd, J = 8.5, 2.5 Hz, 1H), 6.45 (s, 1H), 5.90 (q, J = 1.5 Hz, 2H), 5.01 (s,
2H), 4.92 (d, J = 3.3 Hz, 2H), 4.54 (s, 1H), 3.19 (d, J = 17.2 Hz, 1H), 2.91 (d, J = 17.2 Hz, 1H),
13
2.73 (d, J = 4.7 Hz, 1H), 2.69 (d, J = 4.8 Hz, 1H); C{1H} NMR (126 MHz, CDCl3) δ 159.2,
157.3, 147.04, 146.99, 137.5, 137.0, 136.7, 133.1, 130.6, 128.8, 128.6, 128.2, 128.0, 127.7, 127.5,
122.9, 105.5, 105.3, 104.8, 101.0, 100.9, 70.3, 70.2, 68.6, 52.1, 51.2, 38.9; HRMS (ESI) m / z calcd
for C31H26O5Na [M + Na]+ 501.1678, found 501.1678.
5a-(Hydroxymethyl)-5a,10b-dihydro-5H-[1,3]dioxolo[4',5':5,6]indeno[2,1-b]benzofuran-8-
ol, 13.
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HO
A portion of the above isolated epoxide 12 (28.2 mg, 0.0589 mmol) was
dissolved in 1:1 MeOH/THF (1.0 mL) and stirred at 23 °C prior to adding
Pearlman’s catalyst, 20 wt. % Pd(OH)2/C (20.6 mg, 0.0294 mmol). The
O
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contents of the flask were evacuated and backfilled with H2 ( 3). Upon consumption of epoxide
12 (30 min), the flask was evacuated and backfilled with N2. The mixture was then diluted with
EtOAc (3 mL) and filtered through tightly packed Celite pad. The pad was rinsed with EtOAc (3
 10 mL), and the organic fraction purged with N2, and concentrated in vacuo to afford a pink oil.
The oil was purified by flash chromatography with degassed solvents (40:60 EtOAc:hexanes) to
yield indano[2,1-b]benzofuran 13 as an off-white oil (9.0 mg) containing a small amount (5 mol
%, 1.7 wt. % and 6 mol %, 1.6 wt. % by 1H NMR) of EtOAc and benzene, respectively (49% yield
of 13). Benzofuran 13 was isolated as an inseparable 10:1 mixture with a structurally similar
compound not matching the desired indano[2,1-c]chroman. This sample was stored in benzene at
–20 °C. Rf = 0.47 (50:50 EtOAc:hexanes, stains pink by p-anis dip stain).1H NMR (600 MHz,
CD3OD) δ 7.15 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 6.64 (s, 1H), 6.29 (dd, J = 8.1, 2.2 Hz, 1H), 6.18
(d, J = 2.2 Hz, 1H), 5.88 (d, J = 1.4 Hz, 1H), 5.85 (d, J = 1.5 Hz, 1H), 4.51 (s, 1H), 3.76 (d, J =
11.8 Hz, 1H), 3.70 (d, J = 11.7 Hz, 1H), 3.25 (d, J = 17.2 Hz, 1H), 3.13 (d, J = 17.3 Hz, 1H).
13C{1H} NMR (151 MHz, CD3OD) δ 161.6 (C), 159.2 (C), 148.9 (C), 148.7 (C), 137.7 (C), 133.9
(C), 125.3 (CH), 122.0 (C), 108.5 (CH), 106.0 (CH), 105.3 (CH), 102.3 (CH2), 101.4 (C), 98.4
(CH), 66.3 (CH2), 54.8 (CH), 42.5 (CH2). IR (ATR) 3321, 1620, 1473, 1144, 1035, 963, 734 cm -
1. HRMS (ESI) m / z calcd for C17H14O5Na [M + Na]+ 321.0739, found 321.0739.
Methyl 1-(2,4-bis(benzyloxy)phenyl)-5,6-dimethoxy-2,3-dihydro-1H-indene-2-carboxylate,
14.
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MeO
MeO
H
A round-bottom flask containing arylindane 8ba (0.357 g, 0.608 mmol),
anhydrous NaI (0.274 g, 1.83 mmol), and NaHCO3 (0.205 g, 2.43 mmol) was
evacuated and backfilled with N2 ( 3). Anhydrous DMF (4.9 mL) was then
CO2Me
OBn
14
OBn
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added. The flask was connected to a water jacketed condenser, and then submerged in an oil bath
(160 °C). The reaction was stirred and monitored for the consumption of arylindane (6 h). The
mixture was cooled to 23 °C. Then, H2O (50 mL) was added and stirred vigorously. The resulting
solution was extracted with Et2O (4  50 mL). The combined organic layers were washed with
H2O ( 3) and with brine ( 1). The organic solution was then dried (MgSO4), and concentrated in
vacuo. The crude peach solid was purified by flash chromatography (15:85 EtOAc:hexanes) to
afford methyl ester 14 as an inseparable 1.1:1 mixture of diastereomers as a white solid (0.299 g,
94%). Rf = 0.25 (20:80 EtOAc:hexanes, stains violet by p-anis dip stain). mp = 39–46 °C. 1H NMR
(600 MHz, CDCl3) δ 7.48 (s, 2H), 7.45 – 7.26 (m, 18H), 7.22 (d, J = 7.4 Hz, 2H), 6.92 (d, J = 8.3
Hz, 1H), 6.79 (s, 1H), 6.74 (s, 1H), 6.73 – 6.69 (m, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.60 (d, J = 2.4
Hz, 1H), 6.54 (s, 1H), 6.51 (dd, J = 8.4, 2.4 Hz, 1H), 6.47 (s, 1H), 6.44 (dd, J = 8.5, 2.4 Hz, 1H),
5.25 (s, 1H), 5.07 (s, 2H), 5.03 (s, 2H), 5.02 – 4.93 (m, 5H), 3.88 (s, 4H), 3.88 (s, 3H), 3.76 (dd, J
= 8.9, 6.5 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.53 (s, 3H), 3.42 (dd, J = 15.8, 6.5 Hz, 1H), 3.35
(q, J = 7.8 Hz, 1H), 3.19 (s, 3H), 3.17 (d, J = 8.1 Hz, 2H), 3.04 (dd, J = 15.8, 8.5 Hz, 1H); 13C{1H}
NMR (151 MHz, CDCl3) δ 175.7, 174.0, 158.9, 158.7, 157.5, 157.4, 148.6, 148.5, 148.46, 148.4,
137.1, 136.9, 136.8, 136.4, 135.6, 134.4, 133.2, 129.9, 129.85, 128.6, 128.57, 128.5, 128.4, 128.05,
127.99, 127.9, 127.7, 127.6, 127.3, 127.1, 124.7, 122.7, 108.0, 107.7, 107.22, 107.17, 105.4, 105.3,
100.6, 100.2, 70.2, 70.17, 70.05, 69.95, 56.1, 56.03, 56.02, 56.0, 52.2, 51.7, 51.1, 49.3, 35.6, 34.4;
IR (ATR) 2946, 1730, 1606, 1583, 1502, 1164, 1092, 1025, 735 cm-1; HRMS (ESI) m / z calcd for
C33H32O6Na [M + Na]+ 547.2097, found 547.2084.
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(1-(2,4-Bis(benzyloxy)phenyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl)methanol, 15.
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8
MeO
MeO
OH
To a cooled (0 °C) solution of methyl ester 14 (1.1:1 mixture of diastereomers
0.277 g, 0.528 mmol) in THF (40.0 mL) was added LiAlH4 (40.0 mg, 1.06
mmol) portion wise over 5 minutes, with vigorous stirring. The reaction
OBn
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OBn
mixture was warmed to 23 °C and then heated at reflux. Upon consumption of the methyl ester (1
h), the mixture was cooled to 23 °C. After, aqueous 0.4 M NaOH (40 mL) was added and the
mixture stirred for 5 min. H2O (80 mL) was added to help solubilize the aluminum salts. The
resulting mixture was then filtered through tightly packed Celite, and the pad was rinsed with
EtOAc (3  50 mL). The biphasic mixture was poured into a separatory funnel, and the aqueous
phase extracted with EtOAc (3 x 50 mL). The combined organic fractions were dried (MgSO4),
and concentrated in vacuo. The resulting crude yellow solid was purified by flash chromatography
(20:80 – 40:60 EtOAc:hexanes) to afford alcohol 15 an inseparable 1:1 mixture of diastereomers
as a white solid (0.246 g, 94%). Rf = 0.28 (40:60 EtOAc:hexanes, stains bluish-purple by p-anis
dip stain). mp = 48–55 °C. 1H NMR (600 MHz, CDCl3) δ 7.52 – 7.30 (m, 19H), 6.82 (d, J = 8.5
Hz, 1H), 6.81 (s, 1H), 6.77 (s, 1H), 6.72 (s, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.57 (s, 1H), 6.52 (dd, J
= 8.6, 2.6 Hz, 1H), 6.51 (s, 1H), 6.48 – 6.42 (m, 1H), 6.37 (d, J = 8.5 Hz, 1H), 5.19 – 5.05 (m,
4H), 5.03 (s, 2H), 5.01 (s, 2H), 4.86 (d, J = 8.0 Hz, 1H), 4.51 (d, J = 6.7 Hz, 1H), 3.89 (s, 3H),
3.88 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 3.63 (q, J = 5.5 Hz, 2H), 3.38 (s, 1H), 3.24 (t, J = 10.0 Hz,
1H), 3.00 (dt, J = 14.8, 7.5 Hz, 2H), 2.84 (dd, J = 15.3, 7.8 Hz, 1H), 2.69 (dd, J = 15.5, 7.0 Hz,
1H), 2.63 (dd, J = 15.3, 9.5 Hz, 1H), 2.49 (h, J = 6.5 Hz, 1H), 2.27 (d, J = 9.5 Hz, 1H), 1.73 (s,
1H); The absence of 1H from the 7.52 – 7.30 region is likely due to differences in relaxation delay
times. With longer relaxation delay (d1 = 15 s), the integration for the 7.52 – 7.30 region is 20H.
13C{1H} NMR (151 MHz, CDCl3) δ 158.56, 158.52, 157.1, 156.6, 148.37, 148.35, 148.29, 148.23,
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137.7, 136.9, 136.85, 136.83, 136.4, 136.2, 135.0, 134.9, 130.4, 129.2, 128.8, 128.7, 128.6, 128.4,
128.3, 128.08, 128.06, 127.8, 127.6, 125.9, 122.5, 108.3, 107.6, 107.3, 106.4, 106.0, 100.9, 100.4,
71.0, 70.6, 70.22, 70.20, 65.4, 64.0, 56.1, 56.01, 56.00, 52.6, 48.2, 46.3, 44.3, 34.5, 33.9; IR (ATR)
3513, 2932, 1605, 1582, 1500, 1292, 1248, 1216, 1165, 1090, 1024, 735 cm-1; HRMS (ESI) m / z
calcd for C32H32O5Na [M + Na]+ 519.2147, found 519.2148.
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1-(2,4-Bis(benzyloxy)phenyl)-5,6-dimethoxy-2-methylene-2,3-dihydro-1H-indene, 16.
MeO
A flame-dried flask was charged with alcohol 15 (0.300 g, 0.604 mmol), 2-
MeO
OBn
nitrophenyl selenocyanate (0.837 g, 3.02 mmol.) and THF (2.0 mL). The
16
heterogeneous solution was stirred briefly prior to adding P(n-Bu)3 (0.75 mL,
OBn
3.02 mmol) dropwise over 30 min via syringe pump. Upon addition, the heterogeneous solution
turned red in color. At 30 min, additional THF (1.0 mL) was added to ensure proper stirring of the
slurry. The mixture was stirred at 23 °C and monitored by TLC. At 3.5 h, the mixture was
concentrated in vacuo and subjected to flash chromatography (15:85 – 40:60 EtOAc:hexanes) to
afford a yellow oil that was carried on to the next step without further purification. The yellow oil
was dissolved in THF (2.0 mL) and then cooled (0 °C) and stirred. Degassed 30% (w/w) H2O2
(142 µL, 6.04 mmol) was then added dropwise. Upon completion (5.5 h), the cooled mixture was
quenched with saturated aqueous Na2S2O3 (0.15 mL) and stirred vigorously for 5 min. The mixture
was partitioned between H2O (20 mL) and EtOAc (20 mL). The layers were separated and the
aqueous extracted with EtOAc (2  15 mL), and ether (1  15 mL). The combined organic layers
were washed with saturated NaHCO3 (1  50 mL), brine (1  50 mL), dried (Na2SO4), and
concentrated in vacuo. The crude oil was purified by flash chromatography (2.5:0:97.5 – 2.5:8:89.5
NEt3:EtOAc:hexanes) to yield alkene 16 as a yellow oil (0.161 g) containing a small amount (4
mol %, 4 wt. %, by 1H NMR) of bis(o-nitrophenyl) diselenide (54% yield of 16). Rf = 0.28 (20:80
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