Synthesis and Computational Studies Demonstrate the Utility of an Intramolecular Styryl Diels-Alder Reaction and Di-t-butylhydroxytoluene Assisted [1,3]-Shift to Construct Anticancer dl-Deoxypodophyllotoxin

Article abstract of DOI:10.1021/acs.joc.7b02957

Deoxypodophyllotoxin is a secondary metabolite lignan possessing potent anticancer activity with potential as a precursor for known anticancer drugs, but its use is limited by scarcity from natural sources. We here report the total synthesis of racemic de

Full text of DOI:10.1021/acs.joc.7b02957

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Article
Synthesis and Computational Studies Demonstrate the Utility of
an Intramolecular Styryl Diels-Alder Reaction and BHT Assisted
[1,3]-shift to Construct Anticancer dl-Deoxypodophyllotoxin
Diana I. Saavedra, Benjamin D. Rencher, Doo-Hyun Kwon,
Stacey J. Smith, Daniel H. Ess, and Merritt B Andrus
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02957 • Publication Date (Web): 17 Jan 2018
Downloaded from http://pubs.acs.org on January 17, 2018
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Synthesis and Computational Studies Demonstrate the Utility of
an Intramolecular Styryl Diels-Alder Reaction and BHT Assisted
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[1,3]-shift to Construct Anticancer dl-Deoxypodophyllotoxin
Diana I. Saavedra, Benjamin D. Rencher, Doo-Hyun Kwon, Stacey J. Smith, Daniel H. Ess,* and
Merritt B. Andrus*
Brigham Young University, Department of Chemistry and Biochemistry, C100 BNSN, Provo, Utah
84604
mbandrus@chem.byu.edu
dhe@chem.byu.edu
ABSTRACT: Deoxypodophyllotoxin is a secondary metabolite lignan possessing potent anticancer ac-
tivity with potential as a precursor for known anticancer drugs, but its use is limited by scarcity from
natural sources. We here report the total synthesis of racemic deoxypodophyllotoxin (DPT) in seven
steps using an intramolecular styryl Diels-Alder reaction (ISDA) strategy uniquely suited to assemble
the deoxypodophyllotoxin core. Computational studies are also reported for this reaction that demon-
strate the ability to overcome the limitations of slow reactivity and electronic mismatch of the diene and
dieneophile. Density functional theory was used to analyze concerted, polar, and singlet-open-shell
diradical reactions pathways, which identified a low-energy concerted [4+2] Diels-Alder pathway fol-
lowed by a faster di-t-butylhydroxytoluene (BHT) assisted [1,3]–formal hydrogen shift.
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Introduction
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The intramolecular styryl Diels-Alder reaction (ISDA) reaction is a [4+2] cycloaddition that utilizes
styryl functionality acting as the diene to react with electron deficient alkyne dienophiles.1 While this
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cycloaddition holds significant promise for the construction of complex structures, there are only limited
examples of successful use. Simple biaryl compounds have been reported, including N-alkyl amides
with favorable conformational effects2 and unsubstituted phenylallyl esters.3 Variations on these reac-
tions include AgF/K2CO3 (DCE, 100 °C ),3 phosphazene base P4-t-Bu (100 °C),4 and microwave irradia-
tion at 180 °C (Scheme 1).5
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Scheme 1. Examples of ISDA reactions.
Detailed mechanistic studies with substituted esters and applications to complex synthetic targets are
lacking. This is in part due to major drawbacks to this reaction, which include slow reactivity due to loss
of aromaticity in the [4+2] reaction step and electronic mismatch with two electron rich aryl functional
groups when applied to lignan type targets (Scheme 2). There is also the need for a potentially problem-
atic thermal [1,3]–hydrogen shift for rearomatization. Despite these major potential drawbacks, here we
report the successful use of the ISDA reaction strategy in a 7-step racemic synthesis of deoxypodophyl-
lotoxin (DPT). To our knowledge this is the first application of the ISDA reaction in the synthesis of a
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complex target. Density functional theory (DFT) calculations reveal that the key ISDA occurs in one
step and then the formal [1,3]–hydrogen shift is mediated by BHT in a two-step radical reaction. DFT
calculations also provide insight into improvement of the reaction for future applications.
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Scheme 2. ISDA reaction strategy in route to DPT.
Synthetic target
DPT (Figure 1) isolated from the plant A. Silvestris in very small quantities,6 has recently received in-
creasing interest due to its demonstrated potential as a less toxic, antitumor and antiviral agent, when
compare to major isolate podophyllotoxin.7 DPT is a non-alkaloid lignan, closely related to podophyllo-
toxin that is a precursor of the FDA approved topoisomerase II drugs Etoposide and Teniposide used
commonly for lung and testicular cancer treatment (Figure 1).8
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Figure 1. Podophyllotoxin based anti-cancer agents.
DPT inhibits microtubule formation during mitosis with enhanced binding and inhibition activity
compared with podophyllotoxin (ID50 0.5 nM tubulin-β vs 0.6 nM podophyllotoxin).9 DPT is also less
cytotoxic to normal, untransformed cells (WI-38, lung, 79 ꢀM).10 The molecular targets of DPT include
tubulin (0.5 nM) preventing microtubule assembly halting cell division (G2/M).9 Cell cycle arrest at this
point leads to protein expression (cyclin A, B1, caspase 3,7) promoting apoptosis.11 DPT also shows
promising anti-inflammatory (COX-1,2: IC50 10nM, 12ꢀM),12 anti-viral (HSV-1,2:ED50 4.0, 11 ng/mL
vs. acyclovir 50ng/mL),13 anti-allergy,14 antibacterial,15 and platelet aggregation inhibition activity.16
DPT development remains hampered by its scarcity of isolation from the mayapple plant A. silvestris
and related species (232mg/kg).6 These plants have recently been listed as endangered in India and Chi-
na.7 Endophytic fungi (A. fumigatus) have also been shown to produce DPT but only in very small
amounts.17
Previous DPT synthesis and comparison to ISDA synthesis
The total synthesis of DPT has been previously reported ranging from 10 to 20 steps (Scheme 3).18
Rodrigo reported in 198018a a stereo and region-controlled synthesis using a series of reductions and
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isomerizations. The core of DPT was made in moderate yield using a classic normal demand Diels-
Alder reaction of isobenzofuran with dimethyl acetylenedicarboxylate. Jones18c made the core in a simi-
lar fashion by performing a Diels-Alder reaction between a pyrone and dimethyl maleate followed by
decarboxylation and a series of reductions. Other methodologies involving classic normal demand
Diels-Alder reactions have been used. Takano18b and Charlton18d utilized in situ formed o-
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quinodimethane dienes reacted with maleic acid type dienophiles. Takano employed a Peterson like re-
action to make the diene while Charlton used the decomposition of a cyclobutene for its formation and
reaction. These approaches presented difficulties concerning converting the dicarbonyl products to the
needed lactone moiety. Alternatively, a promising enantioselective 14 step route by Achiwa employed
asymmetric reduction to install the stereochemistry early in the synthesis followed by Friedel-Crafts cy-
clization.19 Unfortunately, catalytic hydrogenation and lactonization at the end of the synthesis gave a
mixture of lactones decreasing the yield. Peng more recently reported a racemic 10-step radical cascade
based route to an analog of DPT using mild conditions and air stable materials (Scheme 3).20
Normal demand Diels-Alder
Ar
CO2Me
O
O
+
Normal demand Diels-Alder
CO2Me
Ar
Normal demand Diels-Alder
Takano
MeO2C
O
Ar
CO2Me
O
10 steps
+
O
CO2Me
O
O
O
+
OMe
O
Jones
CO2Me
12 steps
11 steps
MeO
OMe
Rodrigo
Normal demand Diels-Alder
OH
O
O
RO2C
H
H
O
O
Ar
O
O
+
CO2R
16 steps
Charlton
DPT
14 steps
Ar
Ar
I
O
H
O
O
OEt
Br
CO2H
O
O
O
O
O
iso-DPT
O
O
CO2Me
Peng
Asymmetric reduction
Friedel-Crafts cyclization
Achiwa
10 steps
Scheme 3. Comparison of synthesis strategies of DPT.
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Our new approach now reports a short 7-step synthesis that involves simultaneous formation of the
cyclohexyl core and lactone functionality together with a stereocenter in a single step using the ISDA
strategy, a reaction uniquely suited to assemble lignans of this type (Scheme 4).
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8
OMe
9
MeO
MeO
MeO
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OMe
H
MeO
O
O
O
O
O
O
O
3,4,5-trimethoxy
benzaldehyde
OMe
OMe
O
O
O
Steglich
esterification
OMe
H
O
DPT
OH
ISDA
O
3,4-(methylenedioxy)
cinnamic acid
Scheme 4. Key retrosynthetic steps.
Our synthesis began with inexpensive 3,4-methylenedioxy cinnamic acid 1 and 3,4,5-
trimethoxybenzaldehyde 2 (Scheme 5). These two compounds contain the aryl substituents needed to
directly assemble DPT. Transformation of cinnamic acid 1 via Fisher esterification 3 and subsequent
DIBAL reduction gave the corresponding alcohol 4 in 73% yield. 3,4,5-Trimethoxybenzaldehyde 2 was
converted into the corresponding dibromoalkene 5. Treatment under Corey-Fuchs conditions and trap-
ping with carbon dioxide gave the corresponding alkyne acid 6 in 88% yield (Scheme 5). Compounds 4
and 6 are precursors for the key ester intermediate needed for the ISDA reaction.
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Scheme 5. Synthesis of precursors compounds 4 and 6.
For the coupling of precursors 4 and 6, esterification with DCC and DMAP was explored giving the
electron rich ester 7 in modest yield, 61%. Purification of this ester was made difficult due to product
co-elution with dicyclohexyl urea by-product upon purification. Use of water soluble EDCI for this step
gave product in lower yield. Mitsunobu coupling conditions with alcohol 4 and alkyne acid 6 proved
superior in this case giving a 63% yield with improved product purification (Scheme 5).
With the successful coupling of pieces 4 and 6, the original Klemm thermal conditions1 (DMF, reflux
190 °C ) were initially examined for the key ISDA reaction of the electron rich diaryl allyl propiolate
ester 7 (Table 1). Unfortunately, these conditions resulted in low yields (<10%) with extensive decom-
position. We also explored the recent conditions reported by Jinheng using silver(I) hexafluoroantimo-
nate,3 again finding decomposition of the starting material and no desired ISDA product formation.
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Scheme 6. Synthesis of DPT by ISDA reaction followed by reduction.
We hypothesized that decomposition may be due to side radical reactions involving polymerization of
the sensitive alkyne allyl ester. To minimize radical side reactions di-t-butylhydroxytoluene (BHT) was
used as an additive (Table 1).21 Diverse solvents (acetonitrile, DMF, toluene, benzonitrile) and condi-
tions were explored. Polar solvents improved the reaction and benzonitrile proved to be optimal in this
case. Concentrated solvent (0.1 M) was used to increase reaction yields. Effective conditions were
found with the addition of BHT (1.5 equiv.) in benzonitrile within 2 hours. Two isomeric products were
obtained in 56% overall yield with 1.6:1 selectivity of isomeric products. X-ray crystal structures were
obtained for purified isomers confirming the structure of the major 8 and the minor 9 Diels-Alder prod-
ucts (See supporting information, figures S1 and S2).
Table 1. ISDA reaction conditions.
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For the reduction of compound 8 to give DPT, Mg/CH3OH conditions were found to be most effec-
tive. This reduction provided the needed cis-stereochemistry for DPT (Scheme 6) as confirmed by NOE
studies (see supporting information) and NMR comparison. In this case there was no evidence of de-
composition or reduction of other functionality observed. Hydrogenations using various Pd-based cata-
lyst including elevated pressure proved to be ineffective. Use of dissolving Na or Li metal conditions
was failed generating numerous side products.
Reaction pathways examined with DFT calculations
Because no cycloaddition intermediates could be observed, we turned to DFT calculations to examine
possible pathways to understand the mechanism and reactivity of the novel ISDA reaction and [1,3]-
hydrogen shift reactions to explain the mixture of isomers obtained. M06-2X/6-31G(d,p) calculations
were performed in Gaussian 0922 with an ultrafine integration grid.23 Frequency and intrinsic reaction
coordinate (IRC) calculations were used to verify connections on the potential energy surfaces. Report-
ed free energies corresponded to (U)M06-2X/def2-TZVP//(U)M06-2X/6-31G(d,p) with the benzonitrile
SMD solvation model.24 Because of the aryl radical stabilizing groups, several stepwise Diels-Alder
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pathways were explored that involved open-shell singlet diradical intermediates. Our previous work
showed that either the M06-2X or our DR-1 functional combined with spin projection to remove triplet
wave function contamination giving accurate open-shell singlet energies.25
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The major Diels-Alder routes examined on the singlet energy surface are shown in Scheme 7. Path-
ways A-C involve the styrene functioning as the diene and the alkynyl moiety as the dienophile. Path-
way A involves construction of the lactone ring with one C-C bond formed generating a polar or diradi-
cal intermediate stabilized by multiple aryl group delocalization. This polar/diradical intermediate can
then undergo ring closure at two different catechol arene positions to form either of the cycloaddition
regioisomers. Alternatively, one-step concerted pathways B and C, can lead to these cycloadducts.
Pathway D involves reversal of the diene and dieneophile units where the alkynyl aryl unit acts as the
diene and the styryl alkene acts as the dieneophile.
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A) Polar or
Diradical Pathways
O
O
O
O
Radical
Closure
Ar
O
O
OMe
OMe
B) Concerted path 1
O
O
O
O
O
Ar =
Ar
O
Bond Rotation
&
OMe
Ar
Radical
Closure
C) Concerted path 2
O
O
O
O
Ar
OMe
Ar’
D) Alternative
Diene/Dienophile Pair
OMe
OMe
Ar’ =
O
O
O
O
Scheme 7. Outline of stepwise and concerted cycloaddition pathways.
The mixture of diastereomers 8 and 9 could result from pathway A with competitive cyclization and
bond rotation. Therefore, we first examined stepwise polar and diradical pathways. The lowest-energy
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stepwise transition state, TS1, was first located with a zwitterionic electronic configuration. However,
re-optimization of the wavefunction showed a lower energy open-shell singlet unrestricted solution with
an <S2> value of ~0.35. To provide an accurate estimate of the electronic energy, spin-projection was
used to remove the triplet spin contamination. The spin-projected activation free energy ꢁG‡ for TS1 is
34.2 kcal/mol relative to the lowest energy conformation of 7.
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The IRC shows smooth connection of TS1 to diradical intermediate 10 with complete singlet open-
shell character (<S2> ~1.0). From diradical 10, open-shell transition states TS2 and TS3 form the second
C-C bond and lead to cycloadducts 11 and 12. We initially assumed that these transition states control
cycloadduct selectivity because the ꢁG‡ values are 24.4 and 25.4 kcal/mol, respectively, which roughly
matches the experimentally observed 1.6:1 selectivity.
However, we also located concerted transitions TS4 and TS5 that lead in one step to 11 and 12. These
concerted transition states are very asynchronous with a difference of ~0.8 Å in the partial C-C bond
forming distances. More importantly, the stabilizing effect of the second C-C partial bond in these con-
certed transition states is large enough to overcome the greater entropic penalty and decrease in aryl
group radical delocalization compared with TS1 to provide a lower energy transition state. The ꢁG‡
values for TS4 and TS5 are 28.8 and 31.6 kcal/mol, respectively, which are 5.4 kcal/mol and 2.6
kcal/mol lower than TS1. While the ꢁꢁG‡ between TS4 and TS5 is 2.8 kcal/mol, and overestimates the
ratio of 11 to 12, the ꢁꢁH‡ between these transition states is 1.8 kcal/mol and more in accord with the
experimental ratio. Recalculation of thermochemical corrections at 433 K gave a ꢁꢁG‡ between TS4
and TS5 of 1.9 kcal/mol, which is a value that is closer to the experimental product ratio. We believe
that the cycloadduct ratio, and therefore, the product ratio after [1,3]-hydrogen shift is controlled by TS4
and TS5 because cycloaddition is >15 kcal/mol exergonic and likely irreversible.
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1
2
3
4
Bond
rotation
O
O
O
O
Ar
TS2
5
6
7
8
A) Diradical
stepwise path
O
O
O
ꢁG 25.4
O
O
O
(ꢁH 18.8)
O
O
Ar
O
O
TS1
ꢁG 34.2
10
O
O
Ar
ꢁG 22.9
(ꢁH 20.2)
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(ꢁH 29.3)
Ar
TS3
B) concerted
ꢁG 24.4
(ꢁH 18.7)
O
O
O
path 1
O
O
O
O
O
O
O
O
H
O
Ring closure
Ring closure
Ar
Ar
7
11
Ar
TS4
ꢁG -17.3
(ꢁH -23.1)
ꢁG 28.8
(ꢁH 23.3)
0.0
(0.0)
C) concerted path
2
O
O
12
O
O
H
O
O
O
O
Ar
Ar
TS5
ꢁG 31.6
OMe
OMe
ꢁG -9.7
(ꢁH -15.0)
Ar =
(ꢁH 25.1)
OMe
O
O
TS7
ꢁG 31.1
(ꢁH 27.7)
O
O
O
O
O
O
O
O
TS6
ꢁG 29.9
(ꢁH 26.3)
13
0.0
O
(0.0)
O
Scheme 8. Concerted and stepwise Diels-Alder pathways examined by DFT calculations. (kcal/mol)
The diastereoselectivity is due to a small intrinsic diene-dienophile interaction preference and steric
interactions between the methoxy-subsituted arene group and the catechol group in the concerted transi-
tion states.26 This was examined by removing the 3,4,5-methoxy substitution of the arene followed by
re-calculation of the concerted transition states, which decreases the ꢁꢁG‡ to 1.2 kcal/mol and ꢁꢁH‡ to
1.4 kcal/mol TS6 and TS7 (see insert in Scheme 8).
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We also verified that the concerted and stepwise transition states for pathway D are higher in energy
1
2
3
4
5
than the concerted transition states TS4 and TS5 (Scheme 9). In this pathway, the diene and dieneophile
are reversed. The concerted transition state, TS8, has a ꢁG‡ of 38.6 kcal/mol due to the highly strained
6
7
8
9
allenyl type structure. Therefore, the stepwise transition state, TS1, is lower in energy with ꢁG‡ of 34.1
kcal/mol. While this free energy barrier is the same to the other stepwise transition state, it is higher than
TS4 and TS5.. More importantly, the strain in the allenyl-type group results in a cycloadduct 14 that is
16.4 kcal/mol endergonic.
10
11
12
13
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a)
Ar
Ar
OMe
Ar
O
H
OMe
OMe
OMe
OMe
OMe
Concerted
O
O
O
O
OMe
OMe
0.0
(0.0)
7
TS8
ꢁG 38.6
(ꢁH 33.7)
O
14
OMe
ꢁG 16.4
(ꢁH 9.1)
O
O
Ar =
b)
O
O
O
O
O
O
O
O
O
Concerted
O
O
O
H
Ar
Ar
0.0
16
Ar
15
(0.0)
TS9
ꢁG -12.1
(ꢁH -17.1)
ꢁG 35.6
(ꢁH 31.0)
OMe
Ar =
OMe
OMe
Scheme 9. a) Alkyne diene pathway. b) Carbonyl role in defining diene of ISDA reaction. (kcal/mol)
The carbonyl position plays a significant role in defining the reactivity of the diene and the dienophile.
To explore this relationship, we calculated concerted and stepwise singlet and triplet pathways (see sup-
porting information, scheme S3) with substrate 15 in which the carbonyl has been moved into conjuga-
tion with the styryl group withdrawing electrons from the diene (Scheme 9b). In this case, the concerted
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TS9 has a ꢁG‡ of 35.6 k/mol. The withdrawing effect of the carbonyl closer to the diene raises the ener-
gy barrier 6.8 kcal/mol when compared to the concerted mechanism pathway B. This suggested that the
position of the carbonyl close to the dienophile plays a more important role than the electron donation of
the substituents and that the electronic mismatch caused by the electron rich aryl substituents can be
overcome.
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Because a unimolecular thermal concerted [1,3]-shift is unlikely,27,28 we explored several pathways
showing BHT assisted hydrogen migration. These pathways included concerted and step-wise BHT as-
sisted and stepwise BHT radical pathways.
We examined BHT-mediated formal [1,3]-shift pathways for both intermediates 11 and 12. Scheme 10
shows several possible pathways for intermediate 11 (see supporting information for intermediate 12).
While there is the potential that the hydroxyl version of BHT mediates either a one-step or two-step 1,3-
tautomerization pathway, based on the activation barriers this seems unlikely. For example, the transi-
tion state for a one-step concerted proton shuttling mechanism has a barrier of ꢁG‡ 50.7 kcal/mol rela-
tive to intermediate 11 and free BHT. The large size of BHT probably precludes a highly organized tran-
sition state with multiple BHTs shuttling the proton in one step. Also, as suspected, BHT is a poor medi-
ator of stepwise proton transfer. Proton transfer from 11 to BHT requires approximately 50 kcal/mol.
Addition of explicit benzonitrile solvent to the calculation to stabilize the resulting anion of 11 did not
significantly stabilize this intermediate.
BHT was added into the reaction to prevent radical side reactions, likely radical polymerization of the
alkyne ester. Therefore, it is reasonable that at least small quantities of BHT hydroxyl radicals are
formed under reaction conditions and potentially provide a route for the hydrogen [1,3]-shift. It is
known that BHT reacts with trace oxygen to generate radicals.29 The reactivity of BHT hydroxyl radical
as well as the parameters of its formation and stability have been previously examined.30
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The lowest energy pathway we identified for the [1,3]-shift involves hydrogen atom transfer to the
1
2
BHT hydroxy radical to generate a transient, but relatively stabilized, delocalized carbon radical
(Scheme 10). TS12 has a barrier of 26.9 kcal/mol. The barrier for hydrogen atom transfer back to the
radical intermediate to complete the [1,3]-shift via TS13 is 20.3 kcal/mol. Both of these hydrogen-atom
transfer barriers are lower in energy than the Diels-Alder pathways. Other step-wise radical based paths
may also be operative in this case for the formal [1,3]-hydrogen shift involving more complex species,
that where not addressed at this time. While there remains less certainty on this final process, it is clear
that the Diels-Alder step is higher in energy being rate and selectivity determining.
3
4
5
6
7
8
9
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12
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O
Ar
H
O
O
O
O
O
O
BHT radical
Stepwise
O
O
O
OH
Ar
O
H
O
O
Ar'
Ar'
TS11
ꢁG -13.5
(ꢁH -33.6)
O
17
Ar
Ar'
TS10
ꢁG 9.6
(ꢁH -12.1)
ꢁG -33.8
(ꢁH -54.7)
Ar
O
H
O
O
O
O
O
O
O
O
O
concerted
O
H
O
H
O
Ar'
8
ꢁG -17.3
(ꢁH -23.1)
Ar
Ar'
TS12
ꢁG 33.4
(ꢁH 9.9)
11
ꢁG -40.0
(ꢁH -57.1)
O
O
O
OH2
Proton transfer
O
18
ꢁG 38.6
ꢁH 14.7
Ar
Ar'
OMe
OMe
OMe
HO
O
t-Bu
t-Bu
BHT
t-Bu
t-Bu
Ar' =
BHT
radical
Scheme 10. [1,3]-hydrogen shift pathways leading to isolated product 8.
.
Conclusions
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The total synthesis of dl-deoxypodophyllotoxin has been achieved in a seven-step synthesis using a
key intramolecular styryl Diels-Alder reaction (ISDA). Density functional theory was used to analyze
this unique reaction finding two components of the process. The first one is the intramolecular Diels-
Alder reaction of an electron rich ester with arene dearomatization. The concerted, asynchronous path-
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2
3
4
5
6
7
8
9
way is favored over the singlet diradical mechanism. The small energy difference between TS4 and TS5
is due to steric interactions and correlates with the mixture of isomers obtained experimentally. The se-
cond component of the ISDA reaction is a BHT assisted [1,3]-formal hydrogen transfer that leads to re-
aromatization. The concerted Diels-Alder step is the rate determine step of the (ISDA) process and rota-
tion of the sigma bond of the styryl group gives the minor and major products isolated.
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With this work, we demonstrate a short, practical route to a versatile lignan natural product with po-
tential to generate new approaches to anticancer lead development. This work also showcases the devel-
opment of new synthetic and theoretical tools providing a sound platform for future development of the
key ISDA reaction and applications to related lignan targets.
Experimental Section
General Experimental Methods. All reactions were performed in flame or oven dried glassware under
Argon. Air and moisture-sensitive reagents were introduced via dry syringe. Solvents used in the reac-
tions (THF, DCM, and toluene) were drawn from a pressurized dry solvent system. In this system,
HPLC or similar grade solvent is flushed through activated alumina casks and stored under argon, thus
keeping the solvent dry. Purification through flash chromatography was performed using 230 x 400
mesh silica gel. All 1H and 13C NMR were obtained with 500 MHz and 125 MHz using deuterium chlo-
1
13
roform (7.27 ppm H NMR, 77.4 ppm C NMR) as reference. Multi-mode source mass spectrometer
(ESI) was used for all the mass spectral data.
Methyl (E)-3-(benzo[d][1,3]dioxol-5-yl) acrylate 3. To a solution of 3,4- (methylenedioxy)cinnamic
acid (5.0 g, 25.9 mmol) in methanol (0.4 M, 65 mL) was added carefully and slowly concentrated
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The Journal of Organic Chemistry
H2SO4 (3.1 mL). The mixture was heated at reflux (65 °C) overnight. The reaction mixture was cooled
to room temperature and the white precipitate was filtrated (product). Solid NaHCO3 (6.1g) was slowly
added to the solution. The solution was added to a funnel extraction containing methylene chloride and
washed with water (3 x 50 mL) and brine. The organic layer was dried (MgSO4) and concentrated. The
resulting solid was crystallized with ethyl acetate and hexane (5.27 g, 99%) generating 3 as a white sol-
id. Characterization data: TLC Rf 0.6 (35% EtOAc/hexanes); mp = 132-136 °C; 1H NMR (CDCl3, 500
MHz) 3.78 (s, 3H), 5.99 (s, 2H), 6.26 (d, J= 15.9 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.99 (d, J= 8.0 Hz,
1H), 7.02 (s, 1H), 7.59 (d, J= 15.8, 1H); 13C NMR (CDCl3, 125 MHz) 51.6, 101.6, 106.5, 108.5, 115.7,
124.5, 128.8, 144.6, 148.3, 149.6, 167.6; IR 1703, 1625 cm-1; HRMS (ESI-TOF) m/z: [M]+• Calcd for
C11H10O4 206.0579; Found 206.0566.
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(E)-3-(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-ol 4. To a stirred solution of methyl (E)-3-
(benzo[d][1,3]dioxol-5-yl) acrylate 3 (1.3 g, 6.31 mmol) in dry methylene chloride (0.1 M, 63 mL)
cooled to 0 °C (ice water bath) under Argon gas was slowly added DIBAL (diisobutylaluminum hy-
dride, 16 mL, 1.0 M in heptanes, 2.5 equiv.) via syringe. The mixture was allowed to warm to room
temperature for 2h. To the mixture was slowly added methanol (7 mL) followed by aqueous HCl (1 M,
61 mL). The mixture was added to a separatory funnel containing water (10 mL). The aqueous layer
was extracted with methylene chloride (2 x 30 mL) and the combined organic layers were dried
(MgSO4). The dry organic layers were submitted to silica gel chromatography (50% EtOAc/hexanes) to
obtain the desired alcohol 4 (73%, 800 mg) as a white solid. Characterization data: TLC Rf 0.4 (35%
EtOAc/hexanes); mp = 75.8-78.1 °C; 1H NMR (CDCl3, 500MHz) 4.29 (d, J= 4.1 Hz, 2H), 5.96 (s, 2H),
6.17-6.23 (obs m, 1H), 6.53 (d, J= 15.9, 1H), 6.76 (d, J= 7.9, 1H), 6.81 (d, J= 7.9, 1H), 6.93 (s, 1H); 13C
NMR (CDCl3, 125 MHz) 63.8, 101.1, 105.7, 108.3, 121.2, 126.7, 131.0, 131.1, 147.3, 148.0; IR 3264,
2888, 1445 cm-1; HRMS (ESI-TOF) m/z: [M]+• Calcd for C10H10O3 178.0630; Found 178.0629.
5-(2,2-dibromovinyl)-1,2,3-trimethoxybenzene 5. To a solution of triphenylphosphine (3 equiv, 45.8
mmol, 12.03 g) in dry methylene chloride (0.3 M, 153 mL) cooled to 0 °C under Argon gas, was added
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carbon tetrabromide (1.5 equiv, 22.94 mmol, 7.60 g) and stir at 0 °C for 15 min. To the solution was
added 3,4,5-trimethoxybenzaldehyde (3.0 g, 15.29 mmol) in dry methylene chloride (2 M, 8 mL). The
resulting mixture was stir at rt overnight. The mixture was triturated with cold hexanes (45 mL) and fil-
ter (paper cone) to remove excess triphenylphosphine. The filtrate was concentrated and subjected to
silica gel chromatography (10% EtOAc/hexanes) to obtain dibromoolefin product 5 (82%, 4.39 g) as a
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yellow solid. Characterization data: TLC Rf 0.6 (35% EtOAc/hexanes); mp = 57–60 °C; H NMR
13
(CDCl3, 500MHz) 3.85 (s, 6H), 3.86 (s, 3H), 6.78 (s, 2H), 7.39 (s, 1H); C NMR (CDCl3, 125 MHz)
56.1, 56.2, 60.8, 60.9, 88.8, 105.7, 130.5, 136.6, 138.3, 153.0; IR 3004, 2835, 1577 cm-1; HRMS (ESI-
TOF) m/z: [M]+• Calcd for C11H12Br2O3 349.9153; Found 349.9147.
3-(3,4,5-trimethoxyphenyl)propiolic acid 6. To a solution of 5-(2,2-dibromovinyl)-1,2,3-
trimethoxybenzene (3.30 g, 9.43 mmol) in dry THF (0.6 M, 16.00 mL) under Argon gas cooled to –78
°C (dry ice / acetone bath) was added a solution of n-butyllithium (2.5 M, 1.9 equiv, 17.92 mmol, 7.16
mL) the dark brown solution was stirred for 20 min at –78 °C and solid carbon dioxide (crushed, 10
equiv., 120 mmol, 5.00 g – excess) was added at once. The mixture is gradually allowed to warm to rt
stirring continuously. The mixture was poured into water in a separatory funnel and a 1:1 mixture of
EtOAc/ hexanes (50 mL) was added. The aqueous part was acidified (pH 2 approximately) with HCl
(6.0 N) and extracted with ethylacetate (3 x 50 mL). The organic layers were combined, dried (MgSO4)
and concentrated to access the desired propiolic acid 6 (88%, 1.95 g) as an orange solid. Characteriza-
1
tion data: TLC Rf 0.10 (35% EtOAc/hexanes); mp= 137–142 °C, H NMR (CDCl3, 500MHz) 3.86 (s,
13
6H), 3.89 (s, 3H), 6.85 (s, 2H); C NMR (CDCl3, 125 MHz) 56.3, 56.3, 61.1, 61.1, 79.4, 89.4, 110.6,
113.7, 113.7, 153.2, 158.4; IR 3472, 2951, 2213, 1704 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C12H13O5 237.0762; Found 237.0741.
(E)-3-(benzo[d][1,3]dioxol-5-yl)allyl 3-(3,4,5-trimethoxyphenyl)propiolate 7. To a THF solution (0.2
M, 7 mL) of (E)-3-(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-ol 4 (1 equiv. 1.4 mmol, 0.25 g) and 3-(3,4,5-
trimethoxyphenyl)propiolic acid 6 (1.2 equiv, 1.68 mmol, 0.4 g) was added diisopropyl azodicarbox-
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The Journal of Organic Chemistry
ylate (1.2 equiv, 1.68 mmol, 0.35 mL) at once. The solution was cooled to 0 °C and solid tri-
phenylphosphine (1.2 equiv, 1.68 mmol, 0.44 g) was added along with additional 2 mL of THF. The
solution was then warmed to rt and stirred for 48 hr. The solution was concentrated and subjected to sil-
ica gel chromatography (30% ethyl acetate/hexanes) to yield the desired ester as a white solid 7 (63%,
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9
1
357 mg). Characterization data: TLC Rf 0.46 (35% EtOAc/hexanes); mp = 128.0–129.6 °C; H NMR
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(CDCl3, 500MHz) 3.86 (s, 6H), 3.89 (s, 3H) 4.86 (d, J= 6.4 Hz, 2H), 6.14-6.20 (obs m, 1H), 6.64 (d, J=
13
15.9, 1H), 6.77 (d, J= 9.0, 1H), 6.85 (s, 2H), 6.86 (d, J= 1.1, 1H), 6.95 (s, 1H); C NMR (CDCl3, 125
MHz) 56.2, 61.0, 66.7, 87.0, 101.2, 105.9, 108.3, 110.4, 114.1, 120.1, 121.8, 130.4, 135.4, 143.1, 153.9;
IR 2853, 2217, 1708, 1700 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H21O7 397.1287; Found
([M+H]) 397.1278.
(dl)-5-(3,4,5-trimethoxyphenyl)-8a,9-dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(8H)-one
(major) 8. To a solution of (E)-3-(benzo[d][1,3]dioxol-5-yl)allyl 3-(3,4,5-trimethoxyphenyl)propiolate
7 (1 equiv, 0.1 g, 0.25 mmol) in benzonitrile (0.1 M, 2.5 mL) was added 2,6 di-t-butylhydroxytoluene
(BHT, 1.5 equiv., 0,37 mmol, 0.08 g). The mixture was heated at reflux (160 °C) for 2h. The mixture
was cooled to rt, diluted with hexane (5 mL) and subjected to radial chromatography (25% EtOAc
/hexanes) to yield two Diels-Alder products (overall 56%, 55.1 mg) the major product 8 as white solid
(34.4% yield, 34.1 mg) and the minor product 9 as a green solid (21.2% yield, 21mg). Characterization
1
data for Major Diels-Alder product 8: TLC Rf 0.12 (35% EtOAc/hexanes); mp = 240–242 °C; H
NMR (CDCl3, 500 MHz) 2.81 (obs t , J= 15.8 Hz, 1H), 2.95 (dd, J= 6.6, 8.3 Hz, 1H), 3.44-3.36 (m,
1H), 3.85 (s, 6H), 3.93 (s, 3H), 4.02 (obs t, J= 8.8 Hz, 1H), 4.71 (obs t, J= 8.8, 1H), 5.98 (s, 2H), 6.10
13
(s, 1H), 6.52 (s, 1H), 6.56 (s, 1H), 6.78 (s, 1H) C NMR (CDCl3, 125 MHz) 33.3, 35.8, 56.2, 61.0,
68.0, 70.9, 101.8, 103.6, 107.2, 108.6, 109.5, 119.1, 119.9, 129.6, 130.7, 146.8, 147.3, 148.7, 153.0; IR
cm-1 2917, 1744; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H21O7 397.1287; Found 397.1288.
1
Minor Diels-Alder product 9: TLC Rf 0.14 (35% EtOAc/hexanes); mp = 194–197 °C; H NMR
(CDCl3, 500 MHz) 2.75 (obs t J= 15.0 Hz, 1H), 2.97 (dd, J=6.0, 8.6, 1H) 3.34-3.41 (m, 1H), 3.84 (s,
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6H), 3.92 (s, 3H), 4.02 (obs t, J= 8.7, 1H), 4.69 (obs t, J= 8.9, 1H), 5.63 (s, 1H), 5.72 (s,1H), 6.62 (s,
2H), 6.75 (s, 1H), 6.76 (s, 1H); 13C NMR (CDCl3, 125 MHz) 33.5, 36.6, 56.2, 61.0, 70.6, 101.1, 109.1,
118.5, 120.4, 123.0, 129.0, 129.6, 144.4, 146.9, 147.8, 152.4, 167.9; IR cm-1 1747; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C22H21O7 397.1287; Found 397.1199.
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Deoxypodophyllotoxin
(DPT)
(5S,5aS,8aR)-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-
tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one. To a solution of (R)-5-(3,4,5-
trimethoxyphenyl)-8a,9-dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(8H)-one 8 (1 equiv, 0.02g,
0.038 mmol) in 1:1 MeOH (0.1M, 0.42 mL) and THF (0.1 M, 0.42 mL) at –15 °C (ethyleneglycol-dry
ice bath) was added freshly crushed Mg (30 equiv, 1.13 mmol, 0.03 g) and ammonium chloride (2
equiv., 0.07 mmol, 0.004 g). The mixture was gradually allowed to warm to rt stirring vigorously for 3
h. Saturated solution of NH4Cl (7 mL) was added at –15 °C and allowed to warm to rt. The mixture was
placed in a funnel extraction and washed with dichloromethane and water (3 x 20 mL). The combined
organic phases were dried in MgSO4, concentrated and crystalized in hot methanol obtaining white
small precipitate of final product DPT (51.2% yield 7.7 mg). Characterization data: TLC Rf 0.10 (35%
EtOAc/hexanes); mp = 199.0-200.5 °C; 1H NMR (CDCl3, 500 MHz) 2.52 (dd, J= 9.9 ,5.4 Hz, 1H),
2.88 (dd, J= 9.1, 6.2 Hz, 1H), 3.0-3.09 (obs m, 1H), 3.35 (dd, J = 2.4, 7.1 Hz, 1H), 3.79 (s, 6H), 3.84 (s,
3H), 3.99 (dd, J= 2.6, 6.6 Hz 1H), 4.38 (d, J= 2.1 Hz, 1H), 4.46 (obs t, J= 8.3, 1H), 5.93 (s, 1H), 5.96 (s,
13
1H), 6.34 (s, 2H), 6.59 (s, 1H), 6.68 (s, 1H); C NMR (CDCl3, 125 MHz) 32.0, 33.0, 45.3, 46.4, 56.2,
60.4, 60.9, 72.7, 101.0, 104.9, 108.8, 109.9, 128.3, 130.4, 138.2, 146.8, 146.9, 153.4, 178.4; IR 1757
cm-1; HRMS (ESI-TOF) m/z: [M+NH4]+ Calcd for C22H26NO7 416.1709; Found 416.1705. To further
prove the stereochemistry of hydrogens 4 and 5, 1D NOESY experiments were performed. When H2
was irradiated, increments on H3,4,1 were enhanced. On the other hand when H4 was also irradiated
increments on H5, 2 and 3 were enhanced. The fact that enhancement on H5 only occurs when H4 is
irradiated demonstrates the cis-configuration of the final product.
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ASSOCIATED CONTENT
Supporting Information.
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NMR, X-ray characterization, and Computational assessments of all the pathways presented. This mate-
rial is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
* mbandrus@chemdept.byu.edu
* dhe@chem.byu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support was provided by the Simmons Cancer Center at Brigham Young University as a fel-
lowship to D.I.S.
REFERENCES
(1) Klemm, L. H.; Lee, D. H.; Gopinath, K. W.; Kloppenstein, C. E. J. Org. Chem. 1966, 31, 2376–
2380.
(2) Klemm, L.; McGuire, T.; Gopinath, K. J. Org. Chem. 1976, 41, 2571–2579.
(3) Jiansheng, T.; Yexian, X.; Zhiqiang, W; Jinheng, L. Chin. J. Org. Chem. 2011, 31, 653–658.
(4) Tang, J. -S.; Xie, Y. -X.; Wang, Z. -Q.; Deng, C. -L.; Li, J. -H. Synthesis 2010, 3204–3210.
(5) Kocsis, L. S.; Brummond, K.M. Org. Lett. 2014, 16, 4158–4161.
(6) Quan, G.; Chin, Y.; Lee, H.; Oh, S. Biother. Res. Insti. 2009, 53, 110–113.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 24
(7) Khaled, M.; Jiang, Z.; Zhang, L. J. Ethnopharmacol. 2013, 149, 24–34.
1
2
3
4
5
6
7
8
9
(8) (a) Yu, X.; Che, Z.; Xu, H. Chem. Eur. J. 2017, 23, 4467–4526. (b) Gordaliza, M.; Garcia, P. A.;
Miguel de Corral, J. M.; Castro, M. A.; Gomez-Zurita, M. A. Toxicon, 2004, 44, 441–459.
(9) Loike J.; Brewer C.; Sternlicht, H.; Gensler, W.; Horwitz, S. Can. Res. 1978, 38, 2688–2693.
(10) Guan, X.-W.; Xu, X. -W.; Feng, S. -L.; Tang, Z. -B. Chen, S. W.; Hui, L. Bioorg. Med. Chem. Lett.
2016, 26, 1561–1566.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11) Yong, Y.; Shin, S. Y.; Lee, Y. H.; Lim, Y. Bioorg. Med. Chem. Lett. 2009, 19, 4367–4371.
(12) Lee, S. H.; Son, M. J.; Ju, H. K.; Lin, C. X.; Moon, T. C.; Choi, H. -G.; Son, J. K.; Chang, H. W.
Biol. Pherm. Bull. 2004, 27, 786–788.
(13) Sudo, K.; Konno, K.; Shigeta, S.; Yokota, T. Antivir. Chem. Chemother. 1998, 9, 263–267.
(14) Lin, C.; Son, M. J.; Ju, H. K.; Moon, T. C.; Lee, E.; Kim, S. H.; Kim, M. -J.; Son, J. K.; Lee, S. H.;
Chang, H. W. Planta Med. 2004, 70, 474–476.
(15) Cho, E. J.; Choi, J. M.; Kim, H. M.; Choi, K.: Ku, J.; Park, K. -W; Kim, J.; Lee, S. Hort. Envir.
Biotechnol. 2013, 54, 326–330.
(16) Chen, J. J.; Chang, Y. L.; Teng, C. M.; Chen, I. S. Planta Med. 2000, 66, 251–256.
(17) Kursari, S.; Lamshoft, M.; Spiteller, M. J. Appl. Microbiol. 2009, 107, 1019–1030.
(18) (a) Rodrigo, R.; J. Org. Chem. 1980, 45, 4538–4540. (b) Takano, S. T.; Otaki, S.; Ogasawara, K. J.
Vhem. J. Chem. Soc. Chem. Commun. 1985, 485–487. (c) Jones, D. W.; Thompson, A. M. J.
Chem. Soc. Perkin Trans. 1, 1993, 2541–2548. (d) Bogucki, D. E.; Charlton, J. L. J. Org. Chem.
1995, 60, 588–593.
(19) (a) Morimoto, T.; Chiba, M.; Achiwa, K. Tetrahedron Lett. 1990, 31, 261-264. (b) Morimoto, T.;
Chiba, M.; Achiwa, K. Tetrahedron 1993, 49, 1793–1806.
(20) Peng, Y.; Xiao, J.; Xu, X. -B.; Duan, S. -M.; Ren, L.; Shao, Y. -L.; Wang, Y. -W. Org. Lett. 2016,
18, 5170–5173.
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The Journal of Organic Chemistry
(21) Nishiyama, Y.; Han-ya, Y.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2014, 136, 6598–
6601.
1
2
3
4
5
6
7
8
9
(22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.;
Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Vreven, T.; Montgomery, J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.;
Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Bu-
rant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.;
Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski,
V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas; Foresman,
J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J., Gaussian 09, Revision B.01. Wallingford CT, 2009.
(23) (a) Zhao, Y.; Truhlar, D. G. J. Chem. Phys 2006, 125, 194101. (b) Zhao, Y.; Truhlar, D. G. Acc.
Chem. Res 2008, 41, 157–167. (c) Zhao, Y.; Truhlar, D. Theor. Chem. Acc. 2008, 120, 215–241.
(d) Jacquemin, D.; Perpète, E. A.; Ciofini, I.; Adamo, C.; Valero, R.; Zhao, Y.; Truhlar, D. G. J.
Chem. Theo. Comput. 2010, 6, 2071–2085.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(24) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378–6396.
(25) Ess, D. H.; Cook, T. C. J. Phys. Chem. A 2012, 116, 4922–4929.
(26) a) Chen. J. S; Houk, K. N.; Foote, C. S. J. Am. Chem. Soc. 1998, 120, 12303–12309. b) Goldstein,
E.; Beno, B.; Houk, K.N. J. Am. Chem. Soc. 1996, 118, 6036–6043. c) Orlova, G.; Goddard, J. D.
J. Org. Chem. 2001, 66, 4026–4035.
(27) Hoffmann, R.; Woodward, R., B., Acc. Chem. Res. 1968, 1, 17–22.
(28) Berson, J. A. Acc. Chem. Res. 1972, 5, 406–414.
(29) Lambert, C.; Black, H.; Truscott, G. Free Rad. Biol. Med. 1996, 21, 395-400.
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(30) Yehye, W. A.; Rahman, N. Ariffin, A.; Hamid, S.; Alhadi, A.; Kadir, F. Yaeghoobi, M. European J.
1
2
3
Med. Chem. 2015, 101, 295 – 312.
4
5
6
7
(31) def2-TZVP basis sets were downloaded from https://bse.pnl.gov/bse/portal (accessed January 1,
2016)
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