Total synthesis of podophyllotoxin and select analog designs via C–H activation

Article abstract of DOI:10.1016/j.tet.2019.04.052

An account of our previously disclosed total synthesis of the aryltetralin lignan natural product podophyllotoxin, a building block used in the synthesis of the FDA-approved anticancer drug etoposide, is disclosed. A C–H activation disconnection was viewed as being amenable to the preparation of E-ring modified analogs but proved challenging to execute. Various insights into palladium-catalyzed C–H arylation reactions on complex scaffolds are reported ultimately leading to the implementation of this strategy and the synthesis of compounds inaccessible by semisynthetic means.

Full text of DOI:10.1016/j.tet.2019.04.052

Accepted Manuscript
Total synthesis of podophyllotoxin and select analog designs via C–H activation
Chi P. Ting, Esther Tschanen, Esther Jang, Thomas J. Maimone
PII:
S0040-4020(19)30464-8
https://doi.org/10.1016/j.tet.2019.04.052
TET 30297
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 February 2019
Revised Date: 19 April 2019
Accepted Date: 22 April 2019
Please cite this article as: Ting CP, Tschanen E, Jang E, Maimone TJ, Total synthesis of
podophyllotoxin and select analog designs via C–H activation, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.04.052.
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Graphical Abstract
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Total Synthesis of Podophyllotoxin and
Select Analog Designs by C-H Activation
Chi P. Ting, Esther Tschanen, Esther Jang, and Thomas J. Maimone*

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Total Synthesis of Podophyllotoxin and Select Analog Designs via C–H Activation
Chi P. Ting, Esther Tschanen, Esther Jang, and Thomas J. Maimonea*
aDepartment of Chemistry, University of California–Berkeley, Berkeley, CA 94720 (USA)
ABSTRACT
ARTICLE INFO
Article history:
Received
Received in revised form
Accepted
An account of our previously disclosed total synthesis of the aryltetralin lignan natural product
podophyllotoxin, a building block used in the synthesis of the FDA-approved anticancer drug
etoposide, is disclosed. A C–H activation disconnection was viewed as being amenable to the
preparation of E-ring modified analogs but proved challenging to execute. Various insights into
palladium-catalyzed C-H arylation reactions on complex scaffolds are reported ultimately
leading to the implementation of this strategy and the synthesis of compounds inaccessible by
semisynthetic means.
Available online
Keywords:
Chemotherapy
C–H activation
total synthesis
natural products
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
nucleus, but most has been limited to semisynthetic modification
of 1 and its derivatives.6 In 2011, Chan and co-workers disclosed
the first X-ray crystal structure of 2 bound to its biological target
at 2.16 Å resolution (Figure 2).7 This molecular snapshot
revealed two molecules of 2, separated by four base pair units,
stabilizing the DNA/TOPIIβ cleavage complex. This
crystallographic study also confirmed, and expanded on,
previously suspected molecular interactions, such as the binding
of the flat, aromatic B-ring of 2 with the DNA bases and the
importance of the free phenol on the E ring (C-4’).6,8 The E-ring
phenol was found to engage in hydrogen bonding with an
Natural products and their derivatives are instrumental and
proven weapons in the fight against human disease and their
study continues to turn up unexpected biological findings even
today.1 Perhaps nowhere have such molecules proven more
influential than in the area of cancer chemotherapy wherein their
structures have influenced an estimated 60% of oncology drugs.2
The conversion of the aryltetralin lignan natural product
podophyllotoxin (1) into the anticancer drugs etoposide (2) and
teniposide (3) represents one such success story.3 These
chemotherapeutics remain in use today for the treatment of a
variety of cancers including small cell lung and testicular cancer,
lymphoma, Kaposi’s sarcoma, and various forms of leukemia.4
Over a period of 20 years spanning more than 600 prepared
derivatives, von Wartburg, Stähelin, and co-workers found that
podophyllotoxin derivatives possessing a free phenol at C-4’ and
a glycosylated, epimerized C-4 secondary hydroxyl group (see 2
and 3) represented a superior class of cytotoxins relative to 1.
Importantly, this work did not simply improve on the potency of
1, but rather fundamentally changed its mechanism of action
entirely. Whereas 1 is known to bind tubulin, 2 and 3 accessed a
novel mode of action wherein they function as “poisons” of
human topoisomerase II (TOPII).3,4,5 These compounds act not by
inhibiting the free TOPII enzyme, but rather by stabilizing the
cleavage complex formed between DNA and TOPII as part of the
enzyme’s mechanism for regulating DNA supercoiling.5 In this
scenario, the double strand DNA break induced by TOPII cannot
be re-ligated thus ultimately triggering apoptotic cell death
pathways.
aspartic acid residue (D479) of topoisomerase II (Figure 3A).
Figure 1. Cytotoxic aryltetralin lignan natural products and their
derivatives.
In addition to the foundational medicinal chemistry work that
initially led to 2 and 3, significant structure activity relationship
(SAR) studies have been constructed around the etoposide

2
Tetrahedron
ACCEPTED MANUSCRIPT
Figure 2. X-ray crystal structure of an etoposide/DNA/human
TOPIIβ cleavage complex as determined by Chan et al.7
Etoposide molecules are shown in yellow, DNA in brown, and
enzyme in purple (RSCB PDB: 3QX3)
This finding is important as it clarifies the molecular interactions
responsible for stabilizing the DNA/protein interface. The E-ring
of etoposide, however, is also a metabolic liability as it readily
forms both catechol and quinone intermediates upon cytochrome
P450-mediated metabolic oxidation.9 Etoposide quinone in
particular is thought to have additional targets and mechanisms
of action and may contribute to deleterious chromosomal
translocations (11q23 chromosome translocations) seen in a
small percentage of the patient population.10 Such translocations
are associated with the formation of secondary cancers
(leukemias).11 Thus the formation of more metabolically robust
E-rings which can still engage D479 and stabilize the
DNA/protein interface could be of therapeutic value.12
synthetic strategy to access podophyllotoxin derivatives
employing C-H activation. (G = guanine, DG = directing group)
derivative 9, these researchers obtained adducts 10 and 11 as a
3:1 mixture of diastereomers in over 80% combined yield. By
merging these findings with a late stage C–H arylation reaction
of a common intermediate, we envisioned reducing the number
of steps needed to make multiple analogs. Moroever,
cyclobutanols lacking the aryl group present in 9 are easily
prepared.
We envisioned that aromatic compounds of similar size, but
without the propensity for oxidation (i.e. non-phenolic
derivatives) could represent interesting lead scaffolds; moreover,
such structures are not easily accessible from semisynthetic
alteration of podophyllotoxin (Figure 3B). Carboxylic acid 4 is
envisaged to present an altered motif capable of hydrogen-
bonding to TOPII, but from a not easily oxidized thiophene core.
Pyridine N-oxide 5 possesses similar shape to the natural
phenolic substrate, but can only act as a hydrogen-bond acceptor
and features an aromatic ring already in a highly oxidized form.
Figure 4. Durst’s benzocyclobutane ring opening/intramolecular
cycloaddition strategy to access the aryltetralin lignan
scaffold.14f,14j
Finally, difluoromethyl-containing
6
could probe the
effectiveness of an acidic C-H bond as a hydrogen bond donor.
An ideal strategy to prepare these, and other, aromatic groups
would be to append them late-stage to a common building block
containing the A, B, and C-rings (Figure 3C). Direct C–H bond
arylation, which has become a powerful tool in synthesis,13 was
imagined as being an ideal platform for this endeavor (see 8 to 7).
Herein we detail the evolution of this synthetic platform toward
novel podophyllotoxins.14cc
2. Results and Discussion
2.1 Construction and Reactivity of C-H Arylation Precursors
Initial forays into the construction of a suitable C–H activation
precursor substrate focused on the examination of intermolecular
o-quinodimethane cycloadditions between
a
range of
benzocyclobutanols (see 12-14) and dienophiles containing
commonly employed amide directing groups (see 15-18) (Figure
5).17 Reacting TIPS (see 13) and TBS-protected (see 14)
benzocyclobutanols with these dienophiles under thermal
conditions (PhH, 80°C) led to tricyclic Diels-Alder adducts 19-24
in moderate yields (23-59%). Notably these yields refer to
isomerically pure material obtained after recrystallization. The
relative stereochemistry of adduct 19 was also secured via X-ray
crystallographic analysis. We were unable to promote the
cycloaddition using free alcohol 12 as a more rapid proton
transfer/aromatization event ensued leading to aldehyde 25.
To evaluate a C–H arylation strategy toward derivatives of 2
and 3, a suitable stereodefined tricyclic precursor was needed
(see 8, Figure 3C). While many elegant strategies have been
developed to synthesize 1,14,15 we were particularly inspired by
the work of Durst et al. which utilized an intramolecular
cycloaddition of an in-situ generated o-quinodimethane to
assemble the aryltetralin lignan framework (Figure 4).14f,14j,16
Upon heating urethane
Figure 3. A) Etoposide E-ring binding as determined by Chan’s
X-ray crystallographic studies.7 B) Nonnatural E-ring designs. C)

3
O
OR
OR
O
O
ACCEPTED MANUSCRIPT
CO2Me
O
ArHN
CO2Me
PhH
80°C
O
O
15 (Ar = C6F5)
12 (R = H)
16 (Ar = (4-CF3)C6F4)
17 (Ar = (2-SMe)C6H4)
18 (Ar = 8-quinolinyl)
NHAr
13 (R = TIPS)
14 (R = TBS)
19-24
OR
OR
CO2Me
CO2Me
O
O
O
CHO
O
O
O
O
O
F
F
Me
HN
F
F
HN
F
F
25
sole product
when
employing 12
CF3
F
F
F
59%, 19 (R = TBS)
45%, 20 (R = TIPS)
33%, 21 (R = TIPS)
was arylated product 33 (Figure 8B). Solid state structural
inspection of the two
Figure 6. Initial attempts to elicit Pd-catalyzed C–H bond
arylation instead led to β-lactam 26.
OR
OR
CO2Me
O
CO2Me
O
O
O
O
O
obtained palladacycles (27 and 32) revealed significant
differences with respect to the conformation of the cyclohexene
ring to which the palladium is attached (podophyllotoxin C-ring).
In 27, the ring adopts a distorted twist boat-like structure while in
32 a more chair-like ring is observed (Figure 8C). It appears
plausible that these differences affect the reductive elimination
process, which presumably occurs from a high-valent PdIV
intermediate.22 The desired C–C reductive elimination of an aryl
group requires the palladium complex to rotate underneath the C-
ring in the transition state as the metal center becomes amide-
ligated PdII. For 32 this is presumably possible, but for 27,
significant steric encumbrance would be encountered and thus
the reductive elimination of a
HN
HN
N
MeS
23%, 22 (R = TBS)
30%, 23 (R = TBS)
27%, 24 (R = TIPS)
19 [X-ray]
Figure 5. Synthesis of substrates for downstream C–H activation
studies via a thermal o-quinodimethane cycloaddition. Yields
shown are for single isomers obtained after re-crystallization.
With access to sufficient quantities of
a range of
cycloadducts, we proceeded to examine the key C-H arylation
reaction (Figure 6). Subjecting tricycle 23, which contains the
strongly coordinating aminoquinoline directing group, to Pd-
catalyzed arylation conditions with trimethoxyiodobenzene did
not form the desired product, but rather β-lactam 26 whose
structure was confirmed by X-ray analysis.18 This unexpected
result was both encouraging and troubling; it suggested that C–H
activation was indeed possible in this rigid polycyclic system, but
that reductive elimination, or a formal equivalent, of a C–N bond
outcompeted that of a C–C one. These studies also led us to
question if the ester functional group was ideal for this work as
the yields of 26 were modest and products which appeared to
stem from E1cB elimination of the OTBS group and subsequent
aromatization (i.e naphthalenes) were detected in various crude
reaction mixtures.19
In an effort to better understand the origins of 26, and the
reductive elimination process in general, we prepared
cyclometallated, acetonitrile-bound palladium complex 27 in one
step from 24 (Figure 7). An X-ray crystal structure of 27 was
obtained and was in accordance with previously characterized
palladacycles with respect to bond lengths and geometry.20
Unlike previous complexes, however, this material gave high
yields of β-lactam product (see 28) when heated with an excess
of trimethoxyiodobenzene in t-BuOH solvent. Notably, if this
stoichiometric reaction was conducted in MeOH, ether 29 was
formed as the major product as a mixture of diastereomers.
Complex 27 was also reacted with a variety of aryl nucleophiles
based on boron, tin, zinc, and copper, but C–C coupled product
30 was not produced in any case.21
Based on these results, we prepared acetonide 31 in 3 steps
from 24 via a reduction/deprotection/ketalization sequence
(Figure 8A). In analogy to 27, reacting 31 with palladium acetate
yielded palladacycle 32 which was also crystallographically
characterized. To our delight, when 32 was heated in the
presence of trimethoxyiodobenzene, the major product formed
Figure 7. Synthesis and reactivity of palladacycle 27.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Figure 8. A) Synthesis of cyclic acetonide-containing palladacycle 32. B) Successful C–C reductive elimination. C) Conformational
difference between palladacycles 27 and 32.
typically less-favored ligand may be preferred.23
evaluation of additives revealed that dibenylphosphate could
improve the yield further (entry 11).27 We suspect this agent
helps promote catalyst turnover by facilitating transfer of the
palladium from the metal-ligated product back to 36. Extending
the reaction time to fifty hours led to a synthetically useful 58%
yield of arylated product 37 (entry 12). We then extended these
conditions to the C–H arylation of other aryl iodides (Figure 9B).
Simple arenes containing a dioxolane group and bromine atom
underwent coupling (see 38 and 39) as did a naphthalene and N-
protected indole substrate (see 40 and 41). Compounds required
for our ongoing etoposide medicinal chemistry efforts also could
be synthesized, albeit in lower yields. A dimethoxy pyridine ring
(see 42) could be coupled as well as a thiophene ester unit (44).
For these substrates, simple potassium carbonate/silver carbonate
The successful formation of 33 led us to investigate a
catalytic arylation process, a task which proved challenging
(Figure 9). A variety of acetonide substrates with different
directing groups (see 34-36) were prepared in analogy to 31 and
their reactivity probed (Figure 9A). We observed very little
product when employing weakly-coordinating fluoroamide
directing groups and a designer quinoline ligand (See entries 1
and 2).24 Substantial quantities of product were observed,
however, when using superstoichiometric 2,6-lutidine as additive
(entry 4). Similarly, substrate 31, which possesses the strongly
coordinating aminoquinoline directing group, did not perform
well under catalytic conditions (entries 5 and 6). The thiomethyl
aniline-based directing group (see 36) proved superior and was
selected for further optimization (entry 7).25,26 An extensive
additives
proved
optimal.
Figure 9. Catalytic C–H arylation studies A) Selected optimization results. B) Successful couplings. C) Aryliodide substrates which
did not undergo C–H bond arylation. ayields determined by 1H NMR. b isolated yield.c reaction run for 50 h. dK2CO3/(BnO)2PO2H used.
eAg2CO3/K2CO3 used.

5
ACCEPTED MANUSCRIPT
Scheme 1. A) Short total synthesis of 1. B) Novel podophyllotoxins prepared.
Additionally, a difluoromethyl-containing arene (see 43) could
also be incorporated, albeit it in low yield (24%). Despite these
successes though, many substrates gave trace or no product at all
under these optimized sets of reaction conditions (Figure 9C).
Aryl iodides containing a coordinating group ortho to the iodide,
including a pyridine nitrogen, aniline amino group, or oxygen
atom all proved problematic as did unprotected heteroatoms such
as a free indole N-H and free phenol O-H.
ketalization of the crude reaction mixture, C–H activation
precursor 36 was easily accessed. Notably 36 can be made using
only one chromatographic event from commercial materials.
Following C–H arylation, we discovered that 1 and 4-epi 1 were
accessible in a single operation, which was fortuitous since
directing group removal can be problematic and often requires
forcing conditions. By simply stirring the arylated products in a
mixture of TFA/THF/H2O, a cascade of events ensued wherein
the ketal was hydrolyzed and the lactone D-ring assembled with
concomitant expulsion of the directing group. The strong acidity
of the reaction mixture, combined with the electron-rich nature of
the B-ring also served to also promote epimerization of the C-4
hydroxyl group-presumably by a SN1 process. Thus 1 was formed
with a substantial amount of epi-1, a compound which can also
be used in the synthesis of etoposides.29 Using these conditions,
previously described arylation adducts 38-44 could be
transformed into fully synthetic podophyllotoxin analogs (46-52)
as a mixture of hydroxyl diastereomers (~1.5:1 dr at C-4). Efforts
to convert these compounds into derivatives of 2 and 3 are
underway.
2.2 Total Synthesis of Podophyllotoxin and Derivatives
With a successful C–H arylation reaction established, we then
developed a synthesis of 1 and derivatives (Scheme 1). Owing to
the low diastereoselectivity observed in the thermal cycloaddition
reactions of benzocyclobutanols (typically ~2:1-4:1 dr) (Figure
5), we sought to improve on this process with optimal dienophile
17 (Scheme 1A). Inspired by the work of Choy,28 we found that
low temperature anionic ring opening of 12 followed by
cycloaddition
with
17
proceeded
smoothly
and
diastereoselectively. Further experimentation also revealed that
the intermediate potassium alkoxide formed (see 45) could be
directly reduced with lithium triethylborohydride, and upon
3. Conclusion
In conclusion, a short total synthesis of the therapeutically vital
plant natural product podophyllotoxin (1) has been developed
using a C–H bond arylation strategy. During these investigations
we uncovered some previously underappreciated aspects of the
reductive elimination process from high valent palladium centers.
These organometallic studies proved to be crucial in developing a
workable synthesis of 1 as well as derivatives not accessible via
semi-synthetic modification of the natural product. From a
strategic perspective, the incorporation of a C–H activation
disconnection late-stage enabled the synthesis of multiple
derivatives from a common building block. While late-stage
compound diversification involving C–C bond formation is
commonplace in medicinal chemistry settings, its power has not
been fully realized in the natural product arena, particularly in
dense, stereochemically-rich compound space. Approaching total
synthesis from the vantage point of medicinal chemistry brings
significant challenges, but can also offer great opportunity for
innovation and the exploration of cutting-edge methodologies in
complex
settings.

6
Tetrahedron
4. Experimental section
concentrated in vacuo. The crude mixture was purified by
ACCEPTED MANUSCRIPT
column chromatography (gradient 5% → 20% EtOAc in
hexanes) to afford the product as 4.0:1 mixture of
4.1 General
a
diastereomers. The mixture was recrystallized using 30% ether in
Unless stated otherwise, all reactions were performed in oven-
dried or flame-dried glassware sealed with rubber septa under a
nitrogen atmosphere. Dry tetrahydrofuran (THF), and toluene
were obtained by passing these previously degassed solvents
through activated alumina columns. Anhydrous methanol and
benzene were used directly from SureSeal® bottles from Aldrich.
Volatile amines, and ethanol were distilled over calcium hydride
hexanes to afford 20 (1.4 g, 45% yield) as a white solid: mp 183-
o
1
184 C; H NMR (600 MHz, CDCl3) δ 7.38 (bs, 1 H), 6.74 (s, 1
H), 6.66 (s, 1 H), 5.93 (d, J = 13.8 Hz, 2H), 5.31 (s, 1H), 3.77 (s,
3 H), 3.69 (td, J = 10.8, 7.8, 7.8 Hz, 1 H), 3.26 (dd, J = 16.2, 7.8
Hz, 1 H), 3.03 (dd, J = 16.2, 7.8 Hz, 1H), 2.98 (d, J = 10.8, 1H),
1.01-0.98 (m, 12 H), 0.86 (s, 9 H); 13C NMR (150 MHz, CDCl3)
δ 174.6, 173.2, 148.2, 146.9, 130.6, 128.7, 109.1, 108.5, 101.2,
71.5, 52.3, 50.5, 37.9, 30.9, 18.3, 18.0, 13.1; 19F NMR (376.5
MHz , CDCl3) δ -144.1 (d, J = 26.4 Hz), -156.0 (t, J = 22.6 Hz), -
161.7 (t, J = 22.6 Hz); IR (thin film) 3261, 2946, 2867, 1742,
1681 cm-1; HRMS (ESI) calcd for [C29H34O6N1F5NaSi]+ (M+H)+:
m/z 638.1968, found 638.1976. Carbons that are heavily split by
fluorine were not observed in the 13C NMR.
before use.
Reactions were monitored by thin layer
chromatography (TLC) on SilicycleSiliaplateTM glass backed
TLC plates (250 ꢀm thickness, 60 Å porosity, F-254 indicator)
and visualized by UV irradiation and potassium permanganate
stain. Volatile solvents were removed under reduced pressure
with a rotary evaporator. Flash column chromatography was
performed using Silicycle F60 Å, 230x400 mesh silica gel (40-63
ꢀm). 1H NMR and 13C NMR spectra were obtained with Bruker
4.2.3. Cycloadduct 21: A flame-dried 500 mL round-bottom
flask was charged with 13 (7.5 g, 23 mmol, 4.0 equiv), 16 (2.0 g,
5.8 mmol, 1.0 equiv) and anhydrous benzene (150 mL). The
reaction mixture was heated to 80 °C and held at this temperature
for 24 h. Upon cooling to room temperature, the reaction mixture
was concentrated in vacuo. The crude mixture was purified by
column chromatography (gradient 20% → 30% EtOAc in
hexanes) to afford the product as 2.0:1 mixture of diastereomers.
The mixture was recrystallized using 20% ether in hexanes to
afford 21 (1.2 g, 33% yield) as a white solid: mp 167-168 oC; 1H
NMR (600 MHz, CDCl3) δ 7.79 (bs, 1 H), 6.74 (s, 1 H), 6.65 (s,
1 H), 5.94 (d, J = 7.2 Hz, 2 H), 5.31 (d, J = 2.0 Hz, 1 H), 3.77 (s,
3 H), 3.72 (td, J = 10.8, 8.0, 8.0 Hz, 1 H), 3.26 (dd, J = 16.4, 8.0
Hz, 1 H), 3.03 (dd, J = 16.4, 8.0 Hz, 1 H), 2.96 (d, J = 2.0 Hz, 1
H), 1.01 - 0.97 (m, 12 H), 0.85 (s, 9 H); 13C NMR (150 MHz,
CDCl3) δ 174.1, 173.3, 148.1, 145.9, 130.4, 128.5, 108.9, 108.6,
101.2, 71.3, 52.4, 50.5, 38.0, 30.8, 18.3, 18.0, 13.1; 19F NMR
(376.5 MHz, CDCl3) δ -55.2 (t, J = 22.6 Hz, CF3), -140.1, -142.4
(d, J = 15.1 Hz); IR (thin film) 3256, 2947, 2868, 1743, 1687,
1655, 1508 cm-1; HRMS (ESI) calcd for [C30H34O6N1F7NaSi]+
(M+H)+: m/z 688.1936, found 688.1947. Carbons that are heavily
split by fluorine were not observed in the 13C NMR.
1
spectrometers operating at 400, 500, or 600 MHz for H, 150
MHz for 13C or 365 MHz for 19F. Chemical shifts are reported
relative to the residual solvent signal (1H NMR: δ = 7.26; 13C
NMR: δ = 77.16). NMR data are reported as follows: chemical
shift (multiplicity, coupling constants where applicable, number
of hydrogens). Splitting is reported with the following symbols:
s = singlet, bs = broad singlet, d = doublet, t = triplet, dd =
doublet of doublets, td = triplet of doublets, m = multiplet. IR
spectra were taken on a Nicolet 380 spectrometer as thin films on
NaCl plates and are reported in frequency of absorption (cm-1).
High-resolution mass spectra (HRMS) were obtained by the mass
spectral facility at the University of California, Berkeley using a
Finnigan LTQFT mass spectrometer (Thermo electron
corporation). X-ray crystal structures were obtained by the X-ray
crystallography facility at the University of California, Berkeley.
4.2 Experimental procedures and data for synthetic
compounds
4.2.1. Cycloadduct 19: A flame-dried 500 mL round-bottom
flask was charged with 14 (3.07 g, 10.8 mmol, 3.0 equiv), 15
(1.06 g, 3.59 mmol, 1.0 equiv) and benzene (100 mL). The
reaction mixture was heated to 80 °C and held at this temperature
for 12 h. Upon cooling to room temperature, the reaction mixture
was concentrated in vacuo. The crude mixture was purified by
column chromatography (gradient 5% → 10% EtOAc in
hexanes) to afford the product as a mixture of diastereomers
(~2.5:1). The mixture was recrystallized from ether and hexanes
4.2.4. Cycloadduct 22: A flame-dried 250 mL round-bottom
flask was charged with 14 (2.52 g, 9.08 mmol, 3.0 equiv), 17
(760 mg, 3.03 mmol, 1.0 equiv), and benzene (50 mL). The
reaction mixture was heated to 80 °C and held at this temperature
for 12 h. Upon cooling to room temperature, the reaction mixture
was concentrated in vacuo. The crude mixture was purified by
column chromatography (gradient 10% → 20% EtOAc in
o
to afford 19 (1.2 g, 59%) as a white solid: mp 174-175 C; 1H
NMR (600 MHz, CDCl3) δ 7.34 (bs, 1 H), 6.66 (s, 1 H), 6.63 (s,
1 H), 5.94 (d, J = 15.6 Hz, 2 H), 5.13 (s, 1 H), 3.77 (s, 3 H), 3.58
(td, J = 15.0, 13.8, 13.8 Hz, 1 H), 3.19 (dd, J = 16.2, 7.2 Hz, 1
hexanes) to afford the product as
a 2.0:1 mixture of
diastereomers. The mixture was recrystallized from EtOAc to
1
H), 3.01 (m, 2 H), 0.79 (s, 9 H), 0.09 (s, 3 H), -0.13 (s, 3 H); 13
C
afford 22 (370 mg, 23% yield): H NMR (600 MHz, CDCl3) δ
8.65 (bs, 1 H), 8.29 (d, J = 7.8 Hz, 1 H), 7.50 (d, J = 7.8, 1 H),
7.28 (m, 1 H), 7.05 (m, 1 H), 6.68 (s, 1 H), 6.62 (s, 1 H), 5.94 (d,
J = 17.4 Hz, 2 H), 5.14 (d, J = 2.4 Hz, 1 H), 3.71 (s, 3 H), 3.48
(td, J = 10.8, 9.6, 7.2 Hz, 1 H), 3.18 (dd, J = 16.8, 7.2 Hz, 1 H),
3.10 (dd, J = 10.8, 2.4 Hz, 1 H), 2.99 (dd, J = 16.8, 9.6 Hz, 1 H),
2.48 (s, 3H), 0.81 (s, 9 H), 0.10 (s, 3 H), -0.13 (s, 3 H); 13C NMR
(150 MHz, CDCl3) δ 173.9, 172.6, 147.9, 145.9, 138.9, 133.5,
130.0, 129.2, 128.6, 125.5, 124.4, 120.9, 109.0, 108.7, 101.2,
70.8, 52.2, 49.7, 39.3, 32.4, 25.9, 19.1, 18.3, -3.69, -4.71.
NMR (150 MHz, CDCl3) δ 174.6, 173.0, 148.1, 146.0, 129.8,
128.3, 108.8, 101.2, 70.9, 52.4, 50.0, 38.1, 31.6, 25.9, 18.2, -3.84,
-4.65; 19F NMR (376 MHz, CDCl3) δ -144.0 (d, J = 18.8 Hz), -
156.0 (t, J = 22.6 Hz), -161.7 (t, J = 22.6 Hz); IR (thin film)
3263, 2954, 2931, 2896, 2858, 1743, 1682, 1654 cm-1; HRMS
(ESI) calcd for [C26H28O6N1F5NaSi]+ (M+Na)+: m/z 596.1498,
found 596.1498; Carbons that are heavily split by fluorine were
not observed in 13C NMR. Crystals suitable for X-ray diffraction
were obtained by slow vapor diffusion of heptane into a
diisopropyl ether solution of 19.
4.2.5. β-lactam 26: A flame-dried reaction tube was charged with
23 (50 mg, 0.094 mmol, 1.0 equiv), 5-iodo-1,2,3-
trimethoxybenzene (110 mg, 0.375 mmol, 4.0 equiv), Pd(OAc)2
(4.0 mg, 0.019 mmol, 0.2 equiv), and Ag2CO3 (78 mg, 0.282
mmol, 3.0 equiv). Under a nitrogen atmosphere, t-BuOH (2 mL)
was added into the reaction vessel. The reaction mixture was
4.2.2. Cycloadduct 20: A flame-dried 100 mL round-bottom
flask was charged with 13 (3.33 g, 10.3 mmol, 2.0 equiv), 15 (1.5
g, 5.1 mmol, 1.0 equiv) and benzene (30 mL). The reaction
mixture was heated to 80 °C and held at this temperature for 24
h. Upon cooling to room temperature, the reaction mixture was

7
stirred for 24 hours at 110 °C. After cooling to room temperature,
the reaction was quenched with 1 M HCl and the mixture
extracted with EtOAc (3 x 20 mL). The combined organic layers
were washed with brine, dried over MgSO4 and concentrated in
vacuo. The crude mixture was purified by column
chromatography using (gradient 10% → 25% EtOAc in hexanes)
2.0 mmol, 2.0 eq) added dropwise. After 15 minutes of stirring
ACCEPTED MANUSCRIPT
at -78 °C, the reaction mixture was warmed to room temperature
and stirred for an additional 4 hours. The reaction mixture was
diluted with saturated aqueous NH4Cl (20 mL) and thoroughly
extracted with EtOAc (3 x 50 mL). The combined organic layers
were washed with brine, dried over MgSO4 and concentrated in
vacuo to afford a diol intermediate (528 mg) as a white solid that
was used without further purification. iii. To a round-bottom
flask containing the aforementioned crude diol was added p-
toluenesulfonic acid monohydrate (16.0 mg, 0.08 mmol, 0.1
equiv), 2,2-dimethoxypropane (12.0 mL), and anhydrous THF
(20 mL). The reaction mixture was stirred for 12 hours before it
was quenched with saturated aq. NaHCO3 (50 mL) and extracted
with dichloromethane (3 x 100 mL). The combined organic
layers were washed with brine, dried over MgSO4 and
concentrated in vacuo. The crude mixture was purified by
column chromatography (gradient 20% → 50% EtOAc in hexanes)
to afford 31 (432 mg, 31% overall yield from 24). Using this
general procedure, acetonide 34 was obtained in 57% overall
yield from 20 and acetonide 35 was obtained in 39% overall
yield from 21. Data for 34: IR (thin film) 3270, 3004, 2903,
1696, 1523 cm-1;1H NMR (600 MHz, CDCl3) δ 7.38 (s, 1H), 6.60
(d, J = 16.7 Hz, 2H), 6.02 – 5.86 (m, 2H), 4.89 (d, J = 2.7 Hz,
1H), 4.24 (dd, J = 13.4, 2.9 Hz, 1H), 3.95 (d, J = 12.9 Hz, 1H),
3.41 (td, J = 12.0, 4.7 Hz, 1H), 3.05 (dd, J = 16.5, 12.3 Hz, 1H),
2.86 (dd, J = 16.7, 4.8 Hz, 1H), 1.94 (d, J = 11.4 Hz, 1H), 1.64 (s,
3H), 1.51 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 173.3, 148.4,
146.7, 129.2, 127.3, 109.5, 108.3, 101.3, 100.0, 68.6, 61.7, 39.2,
36.7, 32.9, 29.9, 19.4; 19F NMR (565 MHz, CDCl3) δ -145.3 (d, J
= 17.7 Hz), -157.0 (t, J = 21.5 Hz), -163.3 (dd, J = 22.2, 6.2 Hz).
Data for 35: IR (thin film) 3267, 3226, 3005, 2252, 1708 cm-1;1H
NMR (600 MHz, CDCl3) δ 7.93 (s, 1H), 6.61 (s, 1H), 6.47 (s,
1H), 5.92 (d, J = 5.2 Hz, 2H), 4.89 (s, 1H), 4.22 (d, J = 12.9 Hz,
1H), 3.86 (d, J = 12.8 Hz, 1H), 3.36 (td, J = 12.0, 4.5 Hz, 1H),
2.95 (dd, J = 16.3, 12.4 Hz, 1H), 2.73 (dd, J = 16.6, 4.5 Hz, 1H),
1.94 (d, J = 11.7 Hz, 1H), 1.64 (s, 3H), 1.57 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 172.7, 148.3, 146.5, 128.9, 126.9, 109.1,
107.9, 101.3, 100.1, 68.4, 61.4, 39.3, 36.1, 33.3, 29.4, 19.2; 19F
NMR (565 MHz, CDCl3) δ -57.0 (t, J = 21.7 Hz), -140.7 – -142.3
(m), -143.5 (d, J = 18.0 Hz). Data for 31: IR (thin film) 3324,
2985, 1674, 1525, 1483, 1275 cm-1; 1H NMR (400 MHz, CDCl3)
δ 10.20 (bs, 1H), 8.81 (d, J = 3.2 Hz, 2H), 8.16 (d, J = 8.3 Hz,
1H), 7.54 (d, J = 7.0 Hz, 2H), 7.45 (dd, J = 8.4, 4.2 Hz, 1H), 6.73
(s, 1H), 6.61 (s, 1H), 5.92 (d, J = 11.3 Hz, 2H), 4.92 (d, J = 3.0
Hz, 1H), 4.22 (dd, J = 12.5, 3.3 Hz, 1H), 3.96 (d, J = 11.9 Hz,
1H), 3.57 (dt, J = 11.4, 5.7 Hz, 1H), 3.35 – 3.01 (m, 2H), 2.11 (d,
J = 13.1 Hz, 1H), 1.62 (s, 3H), 1.51 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 173.3, 148.6, 148.1, 146.5, 138.6, 136.4, 134.5, 129.7,
128.1, 127.8, 127.5, 121.9, 121.8, 116.6, 109.8, 108.5, 101.2,
99.5, 68.5, 62.0, 41.0, 36.9, 33.5, 29.8, 19.6; HRMS (ESI) calcd
for [C25H25O5N2]+ (M+H)+: m/z 433.1758, found 433.1751.
1
to afford 26 (20 mg, 40% yield) as a white solid: H NMR (600
MHz, CDCl3) δ 9.00 (d, J = 3.0 Hz, 1 H), 8.13 (d, J = 7.8 Hz, 1
H), 7.89 (d, J = 7.2 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.47 -
7.42 (m, 2 H), 6.96 (bs, 1 H), 6.88 (bs, 1 H), 6.36 (d, J = 4.8 Hz,
1 H), 5.80 (d, J = 39.6 Hz, 2 H), 5.22 (bs, 1 H), 4.14 (bs, 1 H),
3.77 (bs, 1 H), 3.60 (bs, 3 H), 0.90 (bs, 9 H), 0.260 (bs, 3 H),
0.158 (bs, 3 H); 13C NMR (150 MHz, CDCl3) δ 171.4, 149.3,
141.8, 136.1, 132.6, 129.1, 126.4, 125.4, 121.6, 100.8, 60.9, 56.2,
51.7, 46.7, 29.6, 25.7, 18.2, -4.82, -5.02. Crystals suitable for X-
ray diffraction were obtained by slow diffusion of pentane into an
ether solution of 26
4.2.6. Methyl ether 29: A flame-dried reaction tube was charged
with 27 (30 mg, 0.042 mmol, 1.0 equiv) and 5-iodo-1,2,3-
trimethoxybenzene (48 mg, 0.16 mmol, 3.9 equiv). The reaction
vessel was evacuated and backfilled with nitrogen three times
before the addition of anhydrous methanol (1 mL). The reaction
mixture was heated to 70 °C and held at this temperature for 24
h. After cooling to room temperature, the reaction mixture was
concentrated in vacuo. The crude mixture was purified by
column chromatography using 20% EtOAc in hexanes as the
eluting solvent to afford 29 and epi-29 (13 mg, 51% yield) as a
1.2:1 mixture of diastereomers: Major diastereomer 1H NMR
(400 MHz, CDCl3) δ 10.44 (bs, 1 H), 8.86 (d, J = 1.6 Hz, 1 H),
8.78 (d, J = 1.6 Hz, 1 H), 8.16 (d, J = 1.6 Hz, 1 H), 7.53 – 7.45
(m, 3 H), 6.96 (s, 1 H), 6.82 (s, 1 H), 5.99 (d, J = 3.6 Hz, 2 H),
5.22 (d, J = 2.8 Hz, 1 H), 4.83 (d, J = 9.6 Hz, 1 H), 3.94 – 3.85
(m, 1 H), 3.67 (s, 3 H), 3.49 (s, 3 H), 3.33 (dd, J = 10.9, 2.0 Hz, 1
H), 1.08 - 0.96 (m, 12 H), 0.97 – 0.93 (m, 9 H); Minor
diastereomer 1H NMR (400 MHz, CDCl3) δ 10.55 (bs, 1 H), 8.86
(d, J = 1.6 Hz, 1 H), 8.77 (d, J = 1.6 Hz, 1 H), 8.15 (d, J = 1.6
Hz, 1 H), 7.53 – 7.45 (m, 3 H), 6.96 (s, 1 H), 6.92 (s, 1 H), 5.96
(d, J = 4.0 Hz, 2 H), 5.52 (d, J = 4.8 Hz, 1 H), 5.05 (d, J = 5.6
Hz, 1 H), 3.81 – 3.78 (m, 2 H), 3.72 (s, 3 H), 3.54 (s, 3 H), 1.08 -
0.96 (m, 12 H), 0.97 – 0.93 (m, 9 H); 13C NMR (150 MHz,
CDCl3) δ 172.9, 172.6, 172.0, 170.5, 148.5, 148.3, 148.3, 147.3,
147.1, 147.0, 138.8, 138.8, 136.3, 136.3, 134.9, 134.9, 132.0,
131.9, 130.0, 129.3, 128.1, 128.1, 127.5, 127.4, 121.7, 121.6,
121.6, 121.5, 116.9, 116.7, 108.2, 107.5, 107.4, 107.1, 101.3,
101.2, 79.0, 77.8, 70.6, 70.2, 58.1, 55.2, 52.0, 51.9, 49.2, 48.5,
47.3, 44.6, 29.8, 18.4, 18.2, 18.2, 18.1, 13.2, 12.8.
4.2.7. Acetonides 31, 34, 35: i. A flame-dried round-bottom flask
was charged with ester 24 (1.30 g, 2.25 mmol, 1.0 equiv) and
anhydrous THF (60 mL). The reaction vessel was evacuated and
backfilled with nitrogen, cooled to -78 °C, and LiAlH4 solution
(1.0 M in THF, 4.5 mL, 4.5 mmol, 2.0 equiv) added dropwise.
After 15 minutes at -78 °C, the reaction mixture was warmed to
0 °C, stirred for 10 minutes at this temperature, and slowly
quenched by the addition of EtOAc (1 mL) followed by saturated
aqueous ammonium chloride (1 ml). The reaction mixture was
diluted with 10% Rochelle’s salt solution (100 ml) and
thoroughly extracted with EtOAc (3 x 150 mL). The combined
organic layers were washed with brine, dried over MgSO4 and
concentrated in vacuo. The crude mixture was purified by
column chromatography (gradient 10% → 20% EtOAc in hexanes)
to afford the intermediate primary alcohol (470 mg, 38%) as a
white solid. ii. A flask was charged with the aforementioned
primary alcohol (547 mg, 1.00 mmol, 1.0 equiv) and anhydrous
THF (10 mL). The reaction vessel was evacuated and backfilled
with nitrogen, cooled to -78 °C, and TBAF (1 M in THF, 2.0 mL,
4.2.9. C-H Arylation Products 37-41: [General Procedure using
(BnO)2PO2H and K2CO3 as additives]: An oven-dried reaction
tube was charged with acetonide 32 (0.1 mmol, 1 equiv),
aryliodide (0.2 mmol, 2 equiv), Pd(OAc)2 (0.015 mmol, 0.15
equiv), K2CO3 (0.15 mmol, 1.5 equiv), and dibenyl phosphate
(0.04 mmol, 0.4 equiv). The vessel was evacuated and backfilled
with argon and this cycle repeated twice. t-AmylOH (1 mL) was
added and the sealed reaction vessel was heated to 110 °C for 50
hours. After cooling to room temperature, the mixture was
diluted with EtOAc (5 mL) and quenched with saturated aq. NaI
solution (5 mL). The aqueous layer was extracted with EtOAc (3
x 15 mL) and the combined organic layers were washed with
brine, dried over MgSO4 and concentrated in vacuo. Silica gel

8
Tetrahedron
column chromatography of the crude material afforded the
1H), 7.76 (d, J = 8.7, 1H), 7.72 (d, J = 8.4, 2H), 7.48 (d, J = 7.8,
ACCEPTED MANUSCRIPT
arylated product.
1H), 7.45 (d, J = 3.7, 1H), 7.24 (t, J = 7.6, 1H), 7.21 (d, J = 8.0,
2H), 7.07 (t, J = 7.6, 1H), 6.95 (s, 1H), 6.87 (d, J = 8.6, 1H), 6.81
(s, 1H), 6.43 (d, J = 3.7, 1H), 6.37 (s, 1H), 5.89 (d, J = 12.9, 2H),
5.04 (d, J = 3.6, 1H), 4.62 (d, J = 5.6, 1H), 4.15 (dd, J = 12.7,
4.6, 1H), 3.84 (dd, J = 12.6, 3.3, 1H), 3.73 (dd, J = 12.1, 5.7, 1H),
2.45 – 2.36 (m, 1H), 2.35 (s, 3H), 2.27 (s, 3H), 1.62 (s, 3H), 1.42
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 170.1, 148.4, 147.2,
145.0, 138.4, 136.3, 135.7, 134.0, 133.4, 132.5, 130.8, 130.1,
130.0, 129.2, 128.4, 127.0, 127.0, 126.6, 126.4, 125.0, 124.4,
122.3, 120.4, 113.0, 109.6, 109.2, 109.0, 101.3, 100.2, 99.8, 67.8,
61.8, 48.5, 46.1, 31.1, 28.4, 21.8, 20.6, 19.0; HRMS (ESI) calcd.
for [C38H36O7N2NaS2]+ (M+Na)+: m/z 719.1856, found 719.1884.
Product 37: Obtained in 58% using 26 mg of 36: IR (thin film)
1
3002, 2933, 2836, 1702, 1587, 1504 cm-1; H NMR (400 MHz,
CDCl3) δ 8.41 (bs, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4
Hz, 1H), 7.32 – 7.20 (m, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.79 (s,
1H), 6.46 (s, 1H), 6.03 (s, 2H), 5.95 (d, J = 1.4 Hz, 1H), 5.91 (d,
J = 1.4 Hz, 1H), 5.03 (d, J = 3.6 Hz, 1H), 4.50 (d, J = 5.8 Hz,
1H), 4.22 (dd, J = 12.4, 4.7 Hz, 1H), 3.92 (dd, J = 12.4, 3.6 Hz,
1H), 3.73 (s, 3H), 3.70 (dd, J = 12.1, 5.7 Hz, 1H), 3.50 (s, 6H),
2.45 – 2.38 (m, 1H), 2.36 (s, 3H), 1.63 (s, 3H), 1.42 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 170.1, 152.9, 148.5, 147.3, 138.4,
137.3, 136.7, 133.2, 132.0, 129.2, 128.2, 124.8, 124.5, 120.2,
109.6, 109.2, 107.0, 101.4, 99.9, 67.7, 62.0, 60.9, 56.0, 48.8,
46.3, 31.4, 29.9, 28.2, 20.7, 19.3; HRMS (ESI) calcd for
[C32H35O8NNaS]+ (M+Na)+: m/z 616.1976, found 616.1972.
4.2.10. C-H Arylation Products 42-44: [General Procedure using
Ag2CO3 and K2CO3 as additives]: An oven-dried reaction tube
was charged with acetonide 36 (0.1 mmol, 1 equiv.), Pd(OAc)2
(0.02 mmol, 0.20 equiv), K2CO3 (0.3 mmol, 3 equiv), Ag2CO3
(0.4 mmol, 0.4 equiv), and aryliodide (0.4 mmol, 4 equiv). The
tube was evacuated and back-filled with nitrogen and then
toluene (1 mL) added. The reaction tube was placed into a pre-
heated 115 °C oil bath and heated for 38-44 hours. The reaction
mixture was cooled to room temperature, diluted with EtOAc (10
mL), and quenched with saturated aq. NaHCO3 (10 mL). The
aqueous layer was extracted with EtOAc three times and the
combined organic layers washed with brine, dried over MgSO4,
and concentrated in vacuo. Silica gel column chromatography
afforded the arylated product.
Product 38: Obtained in 78% yield using 50 mg of 36: IR (thin
film) 2959, 2925, 2854, 2360, 1699, 1505, 1486, 1436, 1275,
1
1260, 1231, 1039, 749 cm-1; H NMR (600 MHz, CDCl3) δ 8.47
(s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.27 (t,
J = 7.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.78 (s, 1H), 6.59 (d, J
= 7.9 Hz, 1H), 6.43 (s, 1H), 6.40 (d, J = 7.6 Hz, 1H), 6.28 (s,
1H), 5.91 (d, J = 10.7 Hz, 2H), 5.86 (d, J = 4.2 Hz, 2H), 5.01 (d,
J = 3.5 Hz, 1H), 4.46 (d, J = 5.7 Hz, 1H), 4.18 (dd, J = 12.5, 4.4
Hz, 1H), 3.88 (dd, J = 12.7, 3.1 Hz, 1H), 3.69 (dd, J = 12.1, 5.7
Hz, 1H), 2.45 – 2.34 (m, 4H), 1.62 (s, 3H), 1.41 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 170.2, 148.5, 147.6, 147.3, 146.7,
138.4, 135.0, 133.3, 132.3, 129.3, 128.3, 125.0, 124.4, 122.9,
120.6, 109.9, 109.5, 109.3, 108.0, 101.3, 101.1, 99.7, 67.9, 61.8,
48.4, 46.0, 31.0, 28.6, 20.5, 19.2; HRMS (ESI) calcd for
[C30H29O7NNaS]+ (M+Na)+: m/z 570.1557, found 570.1576.
Product 39: Obtained in 43% (1H NMR yield) from 50 mg of 36:
IR (thin film) 3304, 2925, 1506, 1275, 1260, 1232, 1077, 764,
749 cm-1; 1H NMR (600 MHz, CDCl3) δ 8.51 (s, 1H), 8.14 (d, J =
8.1, 1H), 7.51 (d, J = 7.8, 1H), 7.31 – 7.26 (m, 3H), 7.08 (t, J =
7.8, 1H), 6.79 (s, 1H), 6.73 (d, J = 8.5, 2H), 6.38 (s, 1H), 5.92 (d,
J = 11.9, 2H), 5.02 (d, J = 3.4, 1H), 4.49 (d, J = 5.7, 1H), 4.17
(dd, J = 12.6, 4.3, 1H), 3.86 (dd, J = 12.6, 3.0, 1H), 3.74 (dd, J =
12.1, 5.8, 1H), 2.39 (s, 3H), 2.33 – 2.28 (m, 1H), 1.62 (s, 3H),
1.42 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 169.9, 148.6, 147.4,
140.3, 138.3, 133.4, 131.7, 131.4, 131.3, 129.3, 128.5, 125.1,
124.6, 121.4, 120.5, 109.4, 109.4, 101.4, 99.7, 67.9, 61.8, 48.2,
45.7, 31.0, 28.7, 20.4, 19.2; HRMS (ESI) calcd for
[C29H28O5NBrNaS]+ (M+Na)+: m/z 604.0764, found 604.0786.
Product 42: Obtained in 30% yield using 260 mg of 36 (in 10 mL
of toluene): 1H NMR (300 MHz, CDCl3): δ 8.49 (s, 1H), 8.18 (d,
J = 8.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.29 (m, 1H), 7.08 (t, J
= 7.6 Hz, 1H), 6.77 (s, 1H), 6.39 (s, 1H), 5.92 (d, J = 4.7 Hz,
2H), 5.83 (s, 2H), 5.00 (d, J = 3.5 Hz, 1H), 4.41 (d, J = 5.9 Hz,
1H), 4.18 (dd, J = 12.8, 4.5 Hz, 1H), 3.88 (dd, J = 12.5, 2.6 Hz,
1H), 3.77 (s, 6H), 3.72 (m, 1H), 2.39 (s, 3H), 2.38 (d, J = 3.0 Hz,
1H), 1.62 (s, 3H), 1.42 (s, 3H). HRMS (ESI) calcd for
[C30H32O7N2S]+ [M+H]+: m/z 565.2003, found 565.2006.
1
Product 43: Obtained in 24% yield using 51 mg of 36: H NMR
(600 MHz, CDCl3): δ = 8.50 (br s, 1H), 8.19 (dd, J = 8.2, 1.4 Hz,
1H), 7.49 (dd, J = 7.8, 1.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.27
(t, J = 7.5 Hz, 1H), 7.07 (td, J = 7.6, 1.4 Hz, 1H), 6.80 (s, 1H),
6.80 (t, J = 56.5 Hz, 1H), 6.51 (s, 1H), 6.41 (s, 1H), 6.39 (dd, J =
8.0, 1.5 Hz, 1H), 5.92 (dd, J = 13.4, 1.4 Hz, 2H), 5.03 (d, J = 3.5
Hz, 1H), 4.55 (d, J = 5.8 Hz, 1H), 4.19 (dd, J = 12.6, 4.4 Hz, 1H),
3.90 (dd, J = 12.8, 3.1 Hz, 1H), 3.77 (dd, J = 12.1, 5.9 Hz, 1H),
3.45 (s, 3H), 2.38 (s, 3H), 2.35 (dd, J = 12.0, 3.7 Hz, 1H), 1.63 (s,
3H), 1.43 (s, 3H). 13C NMR (150 MHz, CDCl3): δ = 169.9, 157.0,
148.6, 147.4, 145.6, 138.1, 133.1, 131.4, 129.2, 128.4, 126.0,
126.0, 125.9, 125.0, 124.6, 121.8, 121.3, 120.4, 119.0, 113.2,
112.5, 111.7, 110.1, 109.4, 109.3, 108.8, 101.4, 99.7, 67.8, 61.8,
55.7, 55.3, 48.8, 45.9, 31.1, 30.1, 29.9, 28.5, 20.4, 19.1. HRMS
(ESI–) calcd for [C31H30O6SNF2]- [M-H]-: m/z 582.1762, found
582.1761.
Product 40: Obtained in 88% yield from 50 mg of 36: IR (thin
film) 3334, 2988, 1539, 1577, 1435, 1230, 1163, 1038, 749 cm-1;
1H NMR (600 MHz, CDCl3) δ 8.51 (s, 1H), 8.07 (d, J = 8.2, 1H),
7.75 – 7.70 (m, 1H), 7.64 (d, J = 8.5, 1H), 7.59 – 7.54 (m, 1H),
7.49 (dd, J = 7.9, 1.6, 1H), 7.41 – 7.34 (m, 2H), 7.28 (d, J = 1.7,
1H), 7.22 (t, J = 8.4, 7.9, 1H), 7.05 (t, J = 7.7, 1H), 7.02 (d, J =
8.5, 1H), 6.85 (s, 1H), 6.44 (s, 1H), 5.92 (s, 1H), 5.90 (s, 1H),
5.10 (d, J = 3.5, 1H), 4.72 (d, J = 5.8, 1H), 4.18 (dd, J = 12.6,
4.5, 1H), 3.87 (dd, J = 12.7, 3.2, 1H), 3.81 (dd, J = 12.1, 5.8, 1H),
2.50 – 2.44 (m, 1H), 2.30 (s, 3H), 1.64 (s, 3H), 1.44 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 170.1, 148.6, 147.3, 138.8, 138.5,
133.3, 133.3, 132.7, 132.2, 129.2, 128.6, 128.5, 127.9, 127.8,
127.8, 127.7, 126.1, 125.9, 125.0, 124.4, 120.5, 109.7, 109.3,
101.3, 99.7, 68.0, 61.8, 48.8, 46.1, 31.2, 28.6, 20.5, 19.1; HRMS
(ESI) calcd for [C33H31O5NNaS]+ (M+Na)+: m/z 576.1815, found
576.1833.
1
Product 44: Obtained in 35% yield using 50 mg of 36: H NMR
(600 MHz, CDCl3): δ = 8.15 (br s, 1H), 7.54 (d, J = 3.8 Hz, 1H),
7.49 (d, J = 7.7 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.07 (t, J = 7.6
Hz, 1H), 6.77 (s, 1H), 6.69 (d, J = 3.8 Hz, 1H), 6.50 (s, 1H), 5.91
(d, J = 6.4 Hz, 2H), 5.00 (d, J = 3.4 Hz, 1H), 4.79 (d, J = 5.6 Hz,
1H), 4.23 (dd, J = 12.7, 4.2 Hz, 1H), 3.94 (dd, J = 12.7, 2.8 Hz,
1H), 3.77 (s, 3H), 2.53 (dd, J = 12.2, 3.5 Hz, 1H), 2.39 (s, 3H),
1.62 (s, 3H), 1.41 (s, 3H). 13C NMR (150 MHz, CDCl3): δ =
169.3, 162.4, 152.8, 148.4, 147.6, 137.9, 133.1, 132.9, 132.8,
131.2, 128.9, 127.7, 127.2, 125.3, 124.6, 120.8, 109.4, 109.2,
101.3, 99.5, 67.5, 61.6, 52.0, 45.2, 44.3, 31.3, 28.6, 20.0, 18.9.
Product 41: Obtained in 45% yield from 50 mg of 36: IR (thin
film) 3337, 3054, 2988, 2885, 1733, 1649, 1578, 1371, 1091, 754
cm-1; 1H NMR (600 MHz, CDCl3) δ 8.42 (s, 1H), 8.06 (d, J = 8.2,

9
HRMS (ESI) calcd for [C29H29O7NS2Na]+ [M+Na]+: m/z
590.1283, found 590.1272.
5.0, 1H), 2.85 (dtd, J = 14.2, 10.0, 7.2, 1H), 2.05 (bs, 1H); 13C
ACCEPTED MANUSCRIPT
NMR (150 MHz, CDCl3) δ 174.2, 148.2, 148.0, 137.7, 133.4,
133.1, 132.7, 131.7, 130.0, 129.0, 128.2, 127.7, 127.7, 126.2,
110.1, 106.4, 101.7, 73.2, 71.5, 45.4, 44.3, 41.0; HRMS (ESI)
calcd for [C23H18O5Na]+ (M+Na)+: m/z 397.1046, found
397.1058.
4.2.10. Podophyllotoxin (1) and Analogs 46-52: [General
procedure]: A 10 mL round bottom flask was charged with the
arylated product (0.1 mmol, 1 equiv), THF (1 mL), and H2O (1
mL). The mixture was cooled to 0°C and TFA (1 mL) was added
dropwise. The reaction mixture was slowly warmed to room
temperature over the course of 24 hours at which point it was
diluted with EtOAc (5 mL), quenched with NaHCO3 (15 mL),
and extracted with EtOAc (3 x 10 mL). The organic phase was
washed with brine, dried over MgSO4 concentrated in vacuo, and
purified by column chromatography to give the podophyllotoxin
derivative as a mixture of C-4 diastereomers (typically ~ 1.5:1 dr)
Analog 49: obtained in 72% on 22 mg scale (1.6:1 mixture): IR
(thin film) 3456, 3004, 2970, 1738, 1365, 1229, 1217, 757 cm-1;
1H NMR (600 MHz, (CD3)2CO) δ 7.41 (d, J = 8.5, 2H), 7.20 (s,
1H), 7.10 (d, J = 8.4, 2H), 6.47 (s, 1H), 5.98 (d, J = 4.4, 2H),
4.96 (bs, 1H), 4.82 (d, J = 9.7, 1H), 4.62 (d, J = 5.2, 1H), 4.51
(dd, J = 8.7, 7.1, 1H), 4.16 (dd, J = 10.5, 8.6, 1H), 3.13 (dd, J =
14.4, 5.3, 1H), 2.77 – 2.65 (m, 1H); 13C NMR (150 MHz,
(CD3)2CO) δ 175.1, 148.6, 148.6, 141.5, 136.2, 134.1, 132.0,
131.7, 121.6, 110.2, 107.7, 102.5, 72.7, 72.2, 45.4, 44.5, 41.7.
Analog 50: obtained in 57% on 42.4 mg scale (1.8:1 mixture): 1H
NMR (600 MHz, CDCl3): major isomer: δ = 7.64 (d, J = 3.9 Hz,
1H), 7.14 (s, 1H), 7.06 (dd, J = 3.9, 0.8 Hz, 1H), 6.58 (s, 1H),
5.99 (s, 2H), 4.82 (d, J = 4.2 Hz, 1H), 4.75 (d, J = 8.7 Hz, 1H),
4.66 (dd, J = 8.9, 6.4 Hz, 1H), 4.15 (t, J = 9.6 Hz, 1H), 3.83 (m, J
= 5.6 Hz, 1H), 3.82 (s, 3H), 2.86 (m, 1H). minor isomer: δ = 7.62
(d, J = 3.9 Hz, 1H), 7.03 (d, J = 4.0 Hz, 1H), 6.85 (s, 1H), 6.62
(s, 1H), 6.00 (m, 2H), 4.87 (d, J = 3.3 Hz, 1H), 4.84 (d, J = 5.2
Hz, 1H), 4.42 (d, J = 2.1 Hz, 1H), 4.13 (m, 1H), 3.81 (s, 3H),
3.33 (dd, J = 14.2, 5.1 Hz, 1H), 2.83 (m, 1H). 13C NMR (150
MHz, CDCl3) (combined minor and major isomers): δ = 175.0,
174.2, 162.7, 162.7, 151.8, 151.3, 148.6, 148.4, 148.1, 147.9,
133.6, 133.2, 133.0, 132.8, 131.6, 131.1, 130.3, 129.0, 129.0,
110.5, 109.8, 109.5, 106.8, 101.9, 101.7, 72.5, 71.7, 68.1, 66.6,
52.3, 52.3, 45.2, 41.5, 40.4, 39.8, 39.6, 38.9, 29.8.
Analog 51: obtained in 75% on 41.4 mg scale (1.8:1 mixture): 1H
NMR (600 MHz, CDCl3): major isomer: δ = 7.12 (s, 1H), 6.41 (s,
1H), 6.11 (s, 2H), 5.96 (d, J = 1.4 Hz, 2H), 4.72 (d, J = 9.7 Hz,
1H), 4.58 (dd, J = 8.9, 7.2 Hz, 1H), 4.49 (d, J = 5.1 Hz, 1H), 4.08
(dd, J = 10.4, 8.9 Hz, 1H), 3.85 (s, 6H), 2.85 (dd, J = 14.3, 5.1
Hz, 1H), 2.72 (m, 1H). minor isomer: δ = 6.84 (s, 1H), 6.46 (s,
1H), 6.02 (s, 2H), 5.95 (d, J = 1.4 Hz, 2H), 4.84 (d, J = 3.3 Hz,
1H), 4.51 (d, J = 5.5 Hz, 1H), 4.35 (m, 2H), 3.85 (s, 6H), 3.31
(dd, J = 14.2, 5.5 Hz, 1H), 2.81 (m, 1H). 13C NMR (150 MHz,
CDCl3) (combined minor and major isomers): δ = 174.7, 174.0,
163.1, 163.1, 154.3, 154.0, 148.8, 148.1, 148.1, 147.9, 133.5,
132.0, 131.0, 130.1, 110.3, 109.6, 109.3, 106.5, 103.5, 103.4,
101.8, 101.6, 72.9, 71.5, 67.8, 66.8, 53.6, 44.8, 43.5, 43.4, 41.3,
40.0, 38.6, 29.8.
Podophyllotoxin (1): obtained in 76% on 43 mg scale (1.3:1
mixture): IR (thin film) 3465, 2893, 2837, 1773, 1587, 1482 cm-
1
;
1H NMR (600 MHz, CDCl3) δ 7.11 (s, 1H), 6.51 (s, 1H), 6.37
(s, 2H), 5.98 (d, J = 12.2 Hz, 2H), 4.77 (d, J = 9.5 Hz, 1H), 4.70
– 4.54 (m, 2H), 4.09 (t, J = 9.5 Hz, 1H), 3.81 (s, 3H), 3.76 (s,
6H), 2.84 (dd, J = 14.4, 4.7 Hz, 1H), 2.82 – 2.71 (m, 1H), 2.03
(bs, 1H); 13C NMR (150 MHz, CDCl3) δ 174.5, 152.8, 148.0,
147.9, 137.5, 135.6, 133.3, 131.4, 110.0, 108.6, 106.5, 101.7,
73.1, 71.5, 61.0, 56.5, 45.5, 44.3, 41.0; HRMS (ESI) calcd for
[C22H22O8Na]+ (M+Na)+: m/z 437.1207, found 437.1206
Analog 46: obtained in 67% on 18 mg scale (1.4:1 mixture): IR
(thin film) 3411, 3005, 2359, 2340, 1767, 1502, 1482, 1257,
1
1260, 1037, 764 cm-1; H NMR (600 MHz, CDCl3) δ 7.12 (s,
1H), 6.69 (d, J = 8.0, 1H), 6.64 – 6.59 (m, 2H), 6.46 (s, 1H), 5.96
(s, 2H), 5.90 (dd, J = 7.5, 1.4, 2H), 4.75 (d, J = 9.4, 1H), 4.60
(dd, J = 8.8, 7.0, 1H), 4.56 (d, J = 4.7, 1H), 4.09 (d, J = 9.0, 1H),
2.82 (dd, J = 14.2, 4.8, 1H), 2.80 – 2.72 (m, 1H), 1.96 (bs, 1H);
13C NMR (150 MHz, CDCl3) δ 174.3, 148.1, 147.9, 147.6, 146.9,
133.8, 133.2, 131.8, 124.4, 111.3, 109.9, 107.9, 106.3, 101.6,
101.2, 73.1, 71.5, 45.3, 43.8, 40.9; HRMS (ESI) calcd for
[C20H16O7Na]+ (M+Na)+: m/z 391.0788, found 391.0799.
Analog 47: obtained in 61% on 20 mg scale (1.3:1 mixture):
1
(major isomer): H NMR (600 MHz, CDCl3) δ 7.82 (d, J = 8.7,
1H), 7.76 (d, J = 8.4, 2H), 7.52 (d, J = 3.6, 1H), 7.26 (s, 1H),
7.24 (d, J = 8.3, 2H), 7.16 – 7.10 (m, 2H), 6.56 (d, J = 3.6, 1H),
6.41 (s, 1H), 5.95 (d, J = 1.7, 1H), 4.78 (d, J = 9.4, 1H), 4.71 (d, J
= 4.9, 1H), 4.54 (dd, J = 8.8, 7.2, 1H), 4.08 (dd, J = 10.3, 8.8,
1H), 2.87 (dd, J = 14.2, 5.1, 1H), 2.82 – 2.72 (m, 1H), 2.36 (s,
1
3H), 2.02 (bs, 1H). (minor isomer): H NMR (600 MHz, CDCl3)
δ 7.80 (d, J = 8.6, 1H), 7.76 (d, J = 8.0, 2H), 7.51 (d, J = 3.8,
1H), 7.24 (d, J = 8.1, 2H), 7.17 (s, 1H), 7.03 (d, J = 8.7, 1H),
6.89 (s, 1H), 6.54 (d, J = 3.7, 1H), 6.46 (s, 1H), 5.96 (d, J = 7.2,
2H), 4.89 (d, J = 3.5, 1H), 4.72 (d, J = 5.3, 1H), 4.36 (dd, J =
10.8, 8.2, 1H), 4.29 (t, J = 8.1, 1H), 3.32 (dd, J = 14.2, 5.2, 1H),
2.91 – 2.80 (m, 1H), 2.36 (s, 3H), 1.82 (d, J = 4.2 1H). 13C NMR
(150 MHz, CDCl3) (combined minor and major isomers) δ =
175.0, 174.3, 148.9, 148.1, 147.9, 147.7, 145.2, 145.1, 135.6,
135.6, 135.1, 134.7, 134.0, 134.0, 133.3, 132.8, 132.0, 131.9,
130.7, 130.6, 130.2, 130.2, 127.5, 127.4, 127.1, 126.7, 126.7,
123.8, 123.6, 112.9, 112.9, 110.7, 110.0, 109.1, 109.0, 108.9,
106.4, 101.7, 101.6, 73.1, 71.5, 67.8, 67.0, 45.4, 44.0, 43.8, 40.7,
40.6, 38.2, 21.8; IR (thin film) 3458, 3056, 2913, 17773, 1596,
1483 cm-1; HRMS (ESI) calcd for [C28H23O7NNaS]+ (M+Na)+:
m/z 540.1087, found 540.1095.
4.4 X-ray crystallographic data
Crystallographic data for structures 19 and 26 have been
deposited with the Cambridge Crystallographic Data Centre.
Copies of the data can be obtained free of charge from
http://www.ccdc.cam.ac.uk/products/csd/request/
(CDCC
#
1899263 for 19, #1899264 for 26, #1502051 for 27, and #
1502052 for 32).
Acknowledgments
Financial support was provided by UC-Berkeley, The
American Cancer Society (RSG-15-146-01 to T. J. M.), and the
Research Corporation for the Advancement of Science (Cottrell
Scholar Award to T.J.M). T.J.M. also acknowledges unrestricted
support from Novartis, Bristol-Myers Squibb, Amgen, and Eli
Lilly. C.P.T thanks the NSF (DGE-1106400) and Bristol-Myers
Squibb for predoctoral graduate fellowships. E. J. thanks the UC-
Berkeley College of Chemistry for a summer undergraduate
research award. We are grateful to Dr. Hasan Celik for NMR
Analog 48: obtained in 79% on 18 mg scale (1.4:1 mixture): IR
(thin film) 3411, 3005, 2359, 2340, 1767, 1502, 1482, 1257,
1260, 1037, 764 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.81 – 7.76
(m, 1H), 7.76 – 7.71 (m, 2H), 7.48 – 7.40 (m, 4H), 7.19 (s, 1H),
6.48 (s, 1H), 6.03 – 5.90 (m, 2H), 4.85 – 4.79 (m, 2H), 4.56 (dd,
J = 8.9, 7.2, 1H), 4.10 (dd, J = 10.3, 8.9, 1H), 2.94 (dd, J = 14.3,

10
Tetrahedron
ACCEPTED MANUSCRIPT
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11
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