Asymmetric Chemoenzymatic Synthesis of (?)-Podophyllotoxin and Related Aryltetralin Lignans

Article abstract of DOI:10.1002/anie.201904102

(?)-Podophyllotoxin is one of the most potent microtubule depolymerizing agents and has served as an important lead compound in antineoplastic drug discovery. Reported here is a short chemoenzymatic total synthesis of (?)-podophyllotoxin and related aryltetralin lignans. Vital to this approach is the use of an enzymatic oxidative C?C coupling reaction to construct the tetracyclic core of the natural product in a diastereoselective fashion. This strategy allows gram-scale access to (?)-deoxypodophyllotoxin and is readily adaptable to the preparation of related aryltetralin lignans.

Full text of DOI:10.1002/anie.201904102

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Asymmetric Chemoenzymatic Synthesis of (–)-Podophyllotoxin
and Related Aryltetralin Lignans
Authors: Jian Li, Xiao Zhang, and Hans Renata
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904102
Angew. Chem. 10.1002/ange.201904102
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10.1002/anie.201904102
Angewandte Chemie International Edition
COMMUNICATION
Asymmetric Chemoenzymatic Synthesis of (–)-Podophyllotoxin
and Related Aryltetralin Lignans
Jian Li,+ Xiao Zhang,+ and Hans Renata*[a]
Abstract: (–)-Podophyllotoxin is one of the most potent microtubule
depolymerizing agents and has served as an important lead
compound in antineoplastic drug discovery. Here, we report a short
chemoenzymatic total synthesis of (–)-podophyllotoxin and related
aryltetralin lignans. Vital to this approach is the use of an enzymatic
oxidative C–C coupling reaction to construct the tetracyclic core of
the natural product in a diastereoselective fashion. This strategy
allows gram scale access to (–)-deoxypodophyllotoxin and is readily
adaptable to the preparation of related aryltetralin lignans.
chemoenzymatic synthesis of (–)-deoxypodophyllotoxin, (–)-epi-
podophyllotoxin and (–)-podophyllotoxin via biocatalytic kinetic
resolution of racemic dibenzylbutyrolactone precursors.7 In
contrast, our approach establishes the absolute stereochemistry
of the dibenzylbutyrolactone precursor at an early stage and
does not require a kinetic resolution process to provide the
enantioenriched tetracyclic product in the key enzymatic
cyclization step.
OH
A
HO
O
O
Me
O
OH
O
The aryltetralin lignans are an important family of secondary
metabolites possessing a wealth of antiviral, antibacterial, and
antineoplastic activities.1 The most prominent member of the
O
O
O
O
O
O
Ar1
Ar2
Ar3
=
=
=
O
O
O
family, (–)-podophyllotoxin (1, Figure 1A), is
a
potent
O
microtubule depolymerizer that binds to the colchicine site of the
tubulin subunit.2 The use of 1 as a lead compound in anticancer
drug development has led to the identification of several
synthetic derivatives, including etoposide (2) and teniposide,
which are currently used to treat several types of cancer.3 In
contrast to 1, the antineoplastic properties of these synthetic
derivatives arise from inhibition of topoisomerase II during the
late S and early G2 stage of the cell cycle. Several other
aryltetralin lignans with alternative substitution patterns on the
aryl rings have also been identified in nature (e.g., 3–6).4
Interestingly, investigations into the bioactivities of these lignans
have suggested that subtle changes in the substitution patterns
of the aromatic rings could significantly affect the microtubule
depolymerizing activity and therapeutic window of the
scaffold.4b,d,e The medicinal importance of this natural product
family has spurred numerous chemical approaches,5,6 including
a recent Pd-catalyzed C–H arylation strategy to 1 by Maimone.6c
Despite this progress, an efficient enantioselective approach to
aryltetralin lignans has proven elusive thus far. Herein, we
describe an asymmetric, chemoenzymatic approach to 1 that
MeO
MeO
OMe
MeO
OMe
OMe
OH
etoposide (2)
MeO
MeO
(–)-podophyllotoxin (1)
Related aryltetralin lignans
(–)-austrobailignan 1 (3)
Arx = Ar1; Ary = Ar4; R = H
(–)-sikkimotoxin (4)
MeO
OMe
OMe
Arx
O
Ar4
=
Arx = Ar2; Ary = Ar3; R = OH
O
O
O
(–)-polygamain (5)
Arx = Ar1; Ary = Ar1; R = H
(–)-morelensin (6)
Ary
Arx = Ar1; Ary = Ar2; R = H
B
OMe
OH
OH
MeO
HO
OH
O
DIR
PLR
H
H
OH
O
OMe
HO
OMe
OH
OH
MeO
(+)-pinoresinol (8)
9
coniferyl
alcohol (7)
4 steps
O
O
O
O
O
O
O2, αKG,
2-ODD-PH
features
dibenzylbutyrolactone precursor and harnesses the biocatalytic
utility of non-heme dioxygenase from podophyllotoxin
enantioselective
construction
of
the
key
Biosynthetic logic:
• indirect strategy
• inefficient ring tailoring
• > 8 steps to 1
O
O
a
MeO
OMe
MeO
OMe
biosynthesis to forge the key C ring of the natural product. We
showcase the scalability and practicality of this approach by
conducting the biocatalytic transformation on gram scale in
excellent yield. Finally, we demonstrate the general utility of this
synthetic strategy in the concise synthesis of related aryltetralin
lignin natural products. During the preparation of this manuscript,
OMe
(–)-deoxypodophyllotoxin (11)
OMe
(–)-yatein (10)
Figure 1. A. Chemical structures of (–)-podophyllotoxin (1), etoposide (2), and
related aryltetralin lignans. B. Biosynthetic pathway for the production of (–)-
deoxypodophyllotoxin (11) from coniferyl alcohol (7) in Podophyllum
hexandrum.
Kroutil, Fuchs and coworkers reported
a complementary
Biosynthetically, podophyllotoxin arises from oxidative
dimerization of coniferyl alcohol (7, Figure 1B).8 A proton-
coupled electron transfer event in the presence of dirigent
protein (DIR) converts 7 to enantioenriched (+)-pinoresinol (8),
which is subsequently reduced by pinocresol lariciresinol
reductase (PLR) to the corresponding diol (9). Oxidation to the
butyrolactone and several ring tailoring events by two P450s
and a SAM-dependent methyltransferase affords (–)-yatein (10).
A non-heme dioxygenase, referred to as 2-ODD-PH, effects an
[a]
[+]
Dr. Jian Li, Dr. Xiao Zhang, Prof. Dr. Hans Renata
Department of Chemistry
The Scripps Research Institute
130 Scripps Way, Jupiter, FL 33458
E-mail: hrenata@scripps.edu
These authors contributed equally to this work
Supporting information for this article is given via a link at the end of
the document.
oxidative
C–C
coupling
to
convert
10
to
(–)-
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10.1002/anie.201904102
Angewandte Chemie International Edition
COMMUNICATION
deoxypodophyllotoxin (11). While the enzymes that are
responsible for the conversion of 11 to 1 have not been
identified to date, the accumulation of (–)-epi-podophyllotoxin in
tobacco leaves has been observed to be dependent on
CYP82D61 expression, implicating the potential role of this
enzyme in late-stage tailoring. More recently, in vitro studies by
Chang, Chien and coworkers provided biochemical confirmation
for the role of 2-ODD-PH in the oxidative benzylic coupling step
and shed some light on the mechanistic nature of this
transformation.9
30) and ca. 1.6 g of 10 could be oxidized in a single pass,
translating to a titer yield of more than 3 g/L. With 11 in hand, an
efficient strategy to introduce the secondary alcohol at C7 was
sought. Prior synthesis of related aryltetralin lignans suggest that
a two-step process with NBS and PCC could be employed to
introduce ketone functionality at C7.6g,13 We found that the use
14
of CrO3 as oxidant allowed for direct access to the C7 ketone
product, which in turn could be reduced with L-Selectride6g to
complete our chemoenzymatic synthesis of (–)-podophyllotoxin.
Taken together, this route proceeded in five steps in asymmetric
fashion with 28% overall yield. It is worth noting that an
alternative route to 1 starting from alcohol 14 was also explored
as it would hypothetically enable a three-step asymmetric
synthesis of 1 from commercial materials (Scheme 1C).15
However, the use of 2-ODD-PH on 14 failed to elicit the desired
C–C coupling to forge the C ring of 1 and led only to recovery of
unreacted 14 in our hands.
benzylic
oxidation;
enzymatic
oxidative
coupling
OH
O
O
O
O
O
oxidative
enolate
O
O
O
O
OH
OH
coupling
O
O
O
ref. 11
MeO
OMe
MeO
OMe
MeO
OMe
OMe
1
OMe
10
• five step asymmetric chemoenzymatic strategy to 1
OMe
A
O
LDA, CuII;
LiBH4;
DBU, Δ
Figure 2. Retrosynthetic analysis of (–)-podophyllotoxin (1) employing
CO2tBu
O
O
O
O
chemoenzymatic disconnections.
OMe
OMe
O
N
O
+
O
O
From synthetic economy perspective,10 the biosynthetic logic
involved in podophyllotoxin production suffers from several non-
strategic bond-forming steps. Several steps are expended on
the oxidation state adjustments of the butyrolactone moiety as
well as on the alteration of the substitution pattern on the aryl
rings. We hypothesized that a chemoenzymatic approach that
involves rapid asymmetric construction of 10 and harnesses the
synthetic utility of 2-ODD-PH in the key C ring formation would
enable a more efficient approach towards 11 (Figure 2). A late-
stage chemical oxidation on 11 would introduce the requisite
secondary alcohol and complete the synthesis of 1. To this end,
we conducted an asymmetric synthesis of 10 through the use of
oxidative enolate coupling methodology developed by Baran and
coworkers (Scheme 1A).11 Coupling of oxazolidinone 12 and
ester 13 in the presence of LDA and CuII salt effected the
formation of the dicarbonyl product as an inconsequential
mixture of diastereomers. Subjection of this intermediate to
chemoselective reduction with LiBH4 and thermal equilibration
with DBU afforded 10, the native substrate of 2-ODD-PH, as a
single diastereomer in moderate overall yield and set the stage
for the key enzymatic coupling step.
iPr
51%
single
diastereomer
MeO
OMe
OMe
13
OMe
10
12
O2, Fe2+
,
(see Scheme
1B)
αKG, 2-ODD-PH
OH
O
O
O
1. CrO3, 3,5-DMP
2. L-Selectride
O
O
O
O
58%
O
MeO
OMe
MeO
OMe
OMe
OMe
(–)-podophyllotoxin (1)
11
95% isolated yield
gram scale
11
B
pET-28a-
2-ODD-PH
pET-28a-2-ODD-PH +
pGro7
conditions [10]
(in lysate) (mM) conversion (%)
NMR
I
II
III
IV
V
VI
VII kDa
ODD^
100
80
10
10
20
58
46
>99
ODD +
GroES/
GroEL^
32
10
95
ODD +
GroES/
GroEL#
25
22
17
C
OH
OH
For practical reasons, we elected to conduct the enzymatic
transformation using clarified lysate of E. coli expressing 2-ODD-
PH. When expressed as N-His6-tagged protein, 2-ODD-PH was
observed to exist predominantly in insoluble form (Scheme 1B).
Despite the suboptimal enzyme expression, clarified lysate of E.
coli expressing N-His6-tagged 2-ODD-PH could be used to
catalyze the conversion of 10 to 11 in moderate conversion (ca.
20% conversion on 10 mg scale). To ensure adequate material
throughput in our synthesis, we embarked on further enzyme
expression optimization. Co-expression of chaperones GroEL
and GroES12 was found to boost the soluble expression level of
N-His6-tagged 2-ODD-PH and in turn enabled full conversion of
10 to 11 using clarified lysate. Gratifyingly, the biotransformation
could be conducted on gram scale without any appreciable loss
in conversion to afford 95% isolated yield of 11. Under these
conditions, 400 mL of clarified lysate could be produced
O2, Fe2+
αKG,
,
7
8
O
O
O
O
O
O
2-ODD-PH
7'
O
O
no reaction
MeO
OMe
MeO
OMe
OMe
14
OMe
1
Scheme 1. A. Chemoenzymatic total synthesis of (–)-podophyllotoxin (1)
starting from 12 and 13. B. Improvement in soluble expression of 2-ODD-PH
in the presence of chaperones GroES/GroEL and corresponding improvement
in the conversion of 10 to 11 using clarified lysate. (I) Induction at OD600 = 0.8
with 25 µM IPTG; (II) Insoluble fraction; (III) Induction at OD600 = 0.8 with 25
µM IPTG; (IV) Insoluble fraction; (V) Induction at OD600 = 1.4 with 25 µM IPTG;
(VI) Insoluble fraction; (VII) Protein ladder. ^Reaction conducted at 10 mg
scale. #Reaction conducted at 1.5
g scale. C. Attempted conversion of
advanced intermediate 14 to 1 using 2-ODD-PH as oxidation biocatalyst. See
consistently from 500 mL of expression culture (pre-lysis OD600
=
Supporting Information for full experimental details.
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10.1002/anie.201904102
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COMMUNICATION
Despite bearing high structural similarity to yatein, 21 was
unexpectedly converted by 2-ODD-PH to a product (23) that is
regioisomeric to deoxypodophyllotoxin and deoxysikkimotoxin.
While 18 and 19 could be converted to (–)-polygamain (5) and (–
)-morelensin (6) by 2-ODD-PH, the reactions had to be
performed at lower substrate:enzyme ratio to provide
synthetically useful yields of the desired products. A similar trend
was also observed when lactones 20 and 22 were employed in
the enzymatic reaction to produce (–)-austrobailignan 1 (3) and
(–)-hernandin (24), respectively. To properly benchmark the
oxidative coupling efficiency, we also measured total turnover
numbers (TTNs) and specific activities of 2-ODD-PH on
substrates 18–22 and these data were found to be in good
agreement with the yields obtained in the preparative scale
reactions (See Table S4 for TTN and specific activity
measurements). Comparing the relative reactivity of 18 versus
19 and 10 versus 20, we noted that a simple switch of 1,2-
dimethoxy motif to 1,2-methylenedioxy bridge in the southern
fragment led to several fold reduction in reaction conversion.
Furthermore, introduction of an additional methoxy group at C2
(substrates S5–S8) completely abolished enzymatic activity
while an additional methoxy group at C5 (substrate 22) was
tolerated in the reaction. These results indicate that the active
site of 2-ODD-PH is highly sensitive to changes in the
substitution patterns of the aryl rings. Additionally, Kroutil and
Fuchs showed that the trimethoxybenzene moiety in the
southern fragment of the scaffold is essential for successful C–C
coupling when substrates containing C7-OH were used. In
contrast, our results suggest that substrates containing less
electron-rich aromatic rings could still be employed in the
reaction when C7-OH is absent. Taken together, these
observations point to subtle changes in substrate positioning in
the active site when C7-OH is present, which in turn affects the
outcome of the oxidative process. Future structural studies on 2-
ODD-PH are expected to provide some insight on the key
interactions that govern the substrate specificity of the enzyme
and inform subsequent engineering work to expand its substrate
scope.
To further explore the synthetic utility of this approach, we chose
to target the chemoenzymatic preparation of several related
aryltetralin lignans. For optimal divergency, α-alkylation16 of
enantiopure butyrolactones 15–17 and S4 was employed to
prepare the enzymatic cyclization precursors (Figure 3A).
Among the eleven additional dibenzylbutyrolactones tested (18–
22, S2, S3, S5–S8, see Table S3 in the Supporting Information
for a full list of substrates tested), five (18–22) were found to
produce the desired oxidative coupling products when submitted
to the enzymatic reaction without any formation. For these five
substrates, no undesired diastereomers or side products arising
from benzylic hydroxylation were observed.
A
Ar1
Ar2
Ar3
=
=
=
O
LHMDS,
AryCH2Br
O
Arx
O
MeO
Arx
O
O
Ary
MeO
MeO
O
Substrate AryCH2Br Product Yield (%)
MeO
15; Arx = Ar1 Ar1CH2Br
15; Arx = Ar1 Ar2CH2Br
15; Arx = Ar1 Ar4CH2Br
16; Arx = Ar2 Ar3CH2Br
17; Arx = Ar4 Ar3CH2Br
18
19
20
21
22
87
82
85
78
53
OMe
OMe
Ar4
=
O
O
B
O2, Fe2+
αKG,
2-ODD-PH
,
Arx
Arx
O
O
O
O
Ary
Ary
O
O
O
O
O
O
O
O
MeO
O
O
MeO
MeO
OMe
OMe
O
OMe
O
OMe
In summary, we have developed a concise chemoenzymatic
synthesis of (–)-podophyllotoxin and related aryltetralin lignans
through the use of three oxidative transformations. A key
oxidative enolate coupling between oxazolidinone 12 and ester
13 efficiently furnished (–)-yatein (10) while establishing the
absolute stereoconfiguration at C8 of the butyrolactone motif. In
the subsequent key step, biocatalytic C–C coupling catalyzed by
2-ODD-PH constructed the tetracyclic core of podophyllotoxin
with complete diastereoselectivity and excellent isolated yield on
gram scale. Finally, a late-stage chemoselective oxidation
enabled rapid introduction of the final secondary alcohol at C7.
Overall, our chemoenzymatic approach towards (–)-
podophyllotoxin constitutes one of the shortest and highest
yielding synthetic route towards this venerable target (five steps,
28% overall yield, see Table S5 for summary of recent
approaches towards 1). The modularity and the scalability of the
route, coupled with the complete avoidance of precious metal
catalysts, should render it attractive for both scale-up production
of 1 and future medicinal chemistry exploration. Similar to our
previous work in the use of non-heme dioxygenases in the
synthesis of complex alkaloids and morphed peptides,12b,17 this
(–)-polygamain (5)
36%^
(–)-morelensin (6)
80%#
23
80%*
2
O
O
O
O
O
O
O
5
O
MeO
MeO
OMe
OMe
O
O
OMe
(–)-hernandin (24)
48%#
(–)-austrobailignan 1 (3)
40%*
Figure 3. A. Diversity-oriented synthesis of dibenzylbutyrolactones 18–22 via
α-alkylation. B. Chemoenzymatic synthesis of 23, (–)-polygamain (5), (–)-
morelensin (6), (–)-austrobailignan I (3), and (–)-hernandin (24) via late-stage
C–C coupling with 2-ODD-PH. *^Reaction conducted at
5 mM substrate
concentration with pre-lysis OD600 = 30. ^Reaction conducted at 1.5 mM
substrate concentration with pre-lysis OD600 = 30. #Reaction conducted at 4
mM substrate concentration with pre-lysis OD600 = 30.
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10.1002/anie.201904102
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COMMUNICATION
431–439; (e) O. A. Pena-Moran, M. K. Villarreal, L. Alvarez-Berber, A.
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Xu, Chem. Eur. J. 2017, 23, 4467–4526.
works provides further evidence for the biocatalytic utility of non-
heme dioxygenases in streamlining the synthesis of medicinally
relevant natural product scaffolds.
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[6]
Experimental Section
For recent total syntheses of 1, see: (a) D. Stadler, T. Bach, Angew.
Chem. Int. Ed. 2008, 47, 7557–7559; (b) Y. Wu, J. Zhao, J. Chen, C.
Pan, H. Zhang, Org. Lett. 2009, 11, 597–600; (c) C. P. Ting, T. J.
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2017, 19, 6530– 6533; (f) J. Xiao, X.-W. Cong, G.-Z. Yang, Y.-W. Wang,
Y. Peng, Org. Lett. 2018, 20, 1651–1654.
See Supporting Information for Experimental Details.
Acknowledgements
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Financial support for this work was generously provided by The
Scripps Research Institute and the National Institutes of Health
(grant GM128895). We acknowledge the Shen lab and the
Roush lab for generous access to their instrumentation.
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Keywords: biocatalysis • total synthesis • podophyllotoxin •
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Jian Li,+ Xiao Zhang,+ Hans Renata*
Page No. – Page No.
Asymmetric Chemoenzymatic
Synthesis of Podophyllotoxin and
Related Aryltetralin Lignans
Text for Table of Contents
Biocatalytic C–C coupling: Podophyllotoxin, a potent microtubule depolymerizing agent, was synthesized in a concise manner
through a strategic use of three oxidative processes. Highlights of the route include a gram-scale biocatalytic C–C coupling to
construct the tetracyclic core of the natural product and a chemoselective late-stage installation of the secondary alcohol at C7.
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