Divergent Asymmetric Syntheses of Podophyllotoxin and Related Family Members via Stereoselective Reductive Ni-Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b00408

A nickel-catalyzed reductive cascade approach to the efficient construction of diastereodivergent cores embedded in podophyllum lignans is developed for the first time. Their gram-scale access paved the way for unified syntheses of naturally occurring podophyllotoxin and other members.

Full text of DOI:10.1021/acs.orglett.8b00408

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Divergent Asymmetric Syntheses of Podophyllotoxin and Related
Family Members via Stereoselective Reductive Ni-Catalysis
Jian Xiao,† Xiao-Wei Cong,† Gui-Zhen Yang,† Ya-Wen Wang,†,‡ and Yu Peng*,†,‡
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China
‡School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
S
* Supporting Information
ABSTRACT: A nickel-catalyzed reductive cascade approach to the efficient construction of diastereodivergent cores embedded
in podophyllum lignans is developed for the first time. Their gram-scale access paved the way for unified syntheses of naturally
occurring podophyllotoxin and other members.
Scheme 1. Reductive Cyclization Logic to Podophyllotoxin
hile recent years have witnessed impressive developments
1
Win the area of nickel-catalyzed reductive coupling, this
carbon−carbon formation method has not yet successfully been
applied within the context of natural product synthesis.
Moreover, the state-of-the art in this field has mainly concerned
intermolecular couplings,2 while less attention was paid to fully
intramolecular reactions3 and stereocontrolled tandem cycliza-
tions, which our group focused on.4 Further demonstration of
the total synthesis of bioactive natural products and
pharmaceuticals still remains elusive and, thus, is in high
demand.5
Podophyllotoxin [PT (1), Scheme 1], as a representative
aryltetralin lignan6 of the podophyllum family, has received
widespread attention from the research community. This
molecule can be used for the treatment of angogenital warts,
and its derivatives have also been used as chemotherapy drugs,
such as etoposide and teniposide for leukemia, lung, and
testicular cancer.7 Historically, PT molecules featuring strained
trans-ring fusion, four contiguous chiral centers, and an axially
locked C9-aryl substituent had been a challenging target. Some
total syntheses of PT have been reported so far,8,9 continuously
inspiring innovative tactics developments. Herein, we devised a
new and concise route to 1. First, a Ni-catalyzed reductive
cascade of dibromide 2 would lead to the generation of
tetrahydronaphtho[2,3-c]furan (tetrahydronaphtho = THN)
core 3 embedded in this kind of lignans. Formation of
diastereodivergent products in such a single operation for the
construction of two C−C bonds is a desired goal,10 therefore
enabling access to any members of the podophyllum family in
principle. Followed by the subsequent regioselective C−H bond
oxidation, this class of tetralin lactone lignans, including 1 with
four contiguous chiral centers, would be synthesized efficiently.
Our synthesis commenced with commercially available 6-
bromopiperonal (Scheme 2). The elongation of its carbon chain
was carried out through Horner−Wadsworth−Emmons (HWE)
olefination with triethyl phosphonoacetate, and the generated
ester could be converted into the corresponding acyl chloride by
saponification and the next reaction with pivaloyl chloride. The
next stage was the introduction of a chiral auxiliary, which was
completed by a condensation between the resulting acyl chloride
and (S)-4-phenyl-2-oxazolidinone in 10 g scale and a good
Received: February 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00408
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Gram-Scale Syntheses of Stereodivergent Cores in Podophyllum Lignans
overall yield. The crucial asymmetric conjugate addition
reaction11 was achieved by subjection of an arylcopper(I)
reagent in situ generated from (3,4,5-trimethoxyphenyl)-
magnesium bromide to the above α,β-unsaturated acyl
oxazolidinone 4, with excellent diastereocontrol (5, dr = 97:3)
and 80% yield. This remote chirality-controlled transformation
could be scaled up to 8 g without significant loss of the efficiency.
More importantly, ent-5 could also be easily obtained, in
principle, from similar reactions with (R)-4-phenyl-2-oxazolidi-
none, therefore demonstrating a potentially enantiodivergent
feature of this approach for the construction of a diaryl methine
center.12 The chiral auxiliary in 5 was then removed through
reduction mediated by NaBH4, and the optical purity of the
resulting alcohol S1 (Supporting Information) was determined
as 93% ee. The subsequent oxidation and acetalization gave 6 in
nearly quantitative yield. Upon exposure of this acetal to a
mixture of TMSOTf and DIPEA,13 β-elimination occurred to
provide the enol ether 7 as a Z/E mixture in 67% (85% brsm)
yield. The site-selective bromination at the double bond proved
quite challenging. The initial screening experiments with various
bromonium reagents (NBS, Br2, et al.), including BDSB adapted
by Snyder,14 always led to overbromination products, mainly due
to reaction on the electron-rich benzene ring. After extensive
optimization studies, we were pleased to find that upon
treatment of enol ether 7 with 2,4,4,6-tetrabromo-2,5-cyclo-
hexadienone (TBCD)15 in CH2Cl2 at 0 °C, the desired β-bromo
acetals 8 were produced as an inseparable mixture in 76% isolated
yield under 4 g scale. By slightly modifying the reaction
conditions in our relevant studies,4h the expected tandem
cyclization of 8 proceeded well to give cis-THN[2,3-c]furan 9a
and trans-THN[2,3-c]furan 9b, which could be separated by flash
column chromatography. Excellent stereoselectivities in this Ni-
catalyzed reductive cyclization4h could be attributed to the
respective adoption of the pseudoboat conformation (8a) and
half-chair conformation (8b), as shown in Scheme 3. With gram
amounts of diastereodivergent 9a and 9b in hand, eight natural
products in the podophyllum family could be synthesized after a
series of oxidation events (Scheme 4).
Scheme 3. Rationalization of Stereoselective Cyclization
The conversion of an acetal moiety in 9a or 9b to the
corresponding lactone was done by initial hydrolysis and
subsequent oxidation of the resulting lactol intermediate.16
(+)-Deoxypicropodophyllin (10) and (+)-isodeoxy-
podophyllotoxin (11) were thus obtained, respectively. Both
their optical rotation and spectroscopic data (Tables S1 and S2)
were consistent with previous reports.16,17 Epimerization at C9a
in 10 under the enolization/quench conditions (LDA, THF, −78
°C then glacial acetic acid)18 led to cytotoxic (−)-deoxypodo-
phyllotoxin (12), whose spectral data (Table S4) and optical
rotation were in agreement with the literature as well.16,19
A
single-crystal analysis of 12 further confirmed its structure
(Figure 1, left; selected H atoms have been omitted for clarity).
B
DOI: 10.1021/acs.orglett.8b00408
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Scheme 4. Divergent Syntheses of Natural Podophyllotoxin and Its Congeners
outcome was not clear at present. Eventually, this problem was
solved by the ring opening of γ-lactone and the oxidation
sequence (right side in Scheme 4). In this regard, treatment of all
trans-THN[2,3-c]furanone 11 with H2SO4 (1 N) in reflux
MeOH provided γ-hydroxyl ester 15 (not shown), which could
be converted into silyl ether 16 by the protection of TBSCl in
93% overall yield. The ketone 17 was thus generated through a
regioselective benzyl oxidation22 with a mixture of 3,5-dimethyl-
pyrazole and CrO3.23 Since ketoester 17 was a known compound
(Table S9) in the previous synthesis of (−)-picropodophyllin
(18) and (−)-picropodophyllone (19) by Meyers,9a the
demonstrated route here also constituted a formal synthesis for
these two natural products.
In summary, we have developed a nickel-catalyzed fully
intramolecular reductive coupling method for the sequential
construction of C−C bonds in stereodivergent THN[2,3-c]furan
scaffolds of antineoplastic aryltetralin lactone lignans. In
particular, this tandem cyclization led to expeditious syntheses
of several closely related podophyllum members, including
naturally occurring podophyllotoxin.
Figure 1. X-ray crystal structures of deoxypodophyllotoxin (left, 12) and
podophyllotoxone (right, 14).
The next goal was an introduction of C4 hydroxyl, which was
expected to be regio- and stereoselective. This formal benzyl C−
H oxidation was accomplished in 81% overall yield through
radical bromination20 under visible-light irradiation, followed by
the hydrolysis of the resulting labile bromide during column
1
chromatography on silica gel. As shown in Table S5, H NMR
spectra of the synthetic (−)-epipodophyllotoxin (13) were in
accord with data reported by Linker.21 The oxidation of 13 with
PDC furnished the synthesis of (−)-podophyllotoxone (14),9g,h
whose absolute stereochemistry was determined by the single-
crystal analysis (Figure 1, right; selected H atoms have been
omitted for clarity). Upon subjection of 14 to L-selectride in
THF at −78 °C, stereospecific reduction of the ketone carbonyl
took place to give 87% of natural podophyllotoxin (1), and its 1H
NMR data (Table S8) were consistent with previous reports.9e,g
In order to access the corresponding natural products with a
higher-oxidation level from 11, an attempted reaction by a similar
operation like that of 12 to 13 was pursued, but surprisingly none
of the desired products were observed. The exact reason for this
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00408.
Experimental procedures, characterization data (PDF)
Copies of 1H/13C NMR (PDF)
Accession Codes
CCDC 1811057−1811058 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
C
DOI: 10.1021/acs.orglett.8b00408
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pengyu@lzu.edu.cn.
ORCID
Yu Peng: 0000-0002-3862-632X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NNSFC (Nos. 21472075 and
21772078). We thank Prof. Xuan Tian (Lanzhou University) for
his generous donation of natural podophyllotoxin sample.
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DOI: 10.1021/acs.orglett.8b00408
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