Catalytic Enantioselective Synthesis of (-)-Podophyllotoxin

Article abstract of DOI:10.1021/acs.orglett.7b03236

The first catalytic enantioselective total synthesis of (-)-podophyllotoxin is accomplished by a challenging organocatalytic cross-aldol Heck cyclization and distal stereocontrolled transfer hydrogenation in five steps from three aldehydes. Reversal of se

Full text of DOI:10.1021/acs.orglett.7b03236

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. 2017, 19, 6530−6533
Catalytic Enantioselective Synthesis of (−)-Podophyllotoxin
Saumen Hajra,*,† Sujay Garai,†,‡ and Sunit Hazra‡,§
†Centre of Biomedical Research (CBMR), Sanjay Gandhi Postgraduate Institute of Medical Sciences Campus, Raebareli Road,
Lucknow 226014, UP, India
‡Department of Chemistry, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur 721302, WB, India
S
* Supporting Information
ABSTRACT: The first catalytic enantioselective total synthesis of (−)-podophyllotoxin is accomplished by a challenging
organocatalytic cross-aldol Heck cyclization and distal stereocontrolled transfer hydrogenation in five steps from three aldehydes.
Reversal of selectivity in hydrogenation led to the syntheses of other stereoisomers from the common precursor.
odophyllotoxin 1 and its natural analogues (Figure 1)
isolated from Podophyllum species have been extensively
has produced other potent drugs. Thus, there have been
constant efforts from synthetic chemists for the asymmetric
synthesis of these compounds for the last 60 years.4,5 In 1988,
the first asymmetric total synthesis of 1 was reported by
Meyer’s group in 24 steps.5a Since then, several elegant
strategies have been developed for its asymmetric synthesis
involving either chiral auxiliary, chiral pool, or resolution
strategies.5b−h However, the catalytic and enantioselective
concise total synthesis of 1 has so far remained an unmet
challenge. Herein, we report the first catalytic enantioselective
synthesis of (−)-podophyllotoxin 1, (−)-isopodophyllotoxin 1′,
(−)-picropodophyllin 4, (+)-isopicropodophyllin 3′, (+)-iso-
picropodophyllone 3, and a formal total synthesis of
(+)-podophyllotoxin ent-1 from a common intermediate.
Construction of a general backbone to access different
stereoisomeric compounds is strategically attractive but
synthetically challenging. Our primary goal was to achieve a
common intermediate that will later be diversified to access
different isomeric aryl tetralin lignans. Podophyllotoxin 1 bears
four contiguous stereocenters with the relative stereochemistry
of cis1,2-trans2,3-trans3,4. We proposed the structure of an
enantiopure dihydronaphthalene 5 as a common intermediate
and hypothesized that it might undergo distal stereocontrol
hydrogenation, governed by the C4-OR stereochemistry, and
lead to 1 (Scheme 1), whereas proximal stereocontrol by the
lactone methylene unit during hydrogenation was anticipated
to provide isopicropodophyllin viz. 3. The intermediate 5 could
easily be synthesized from lactone 6, which could be obtained
by the anti-aldol reaction of 6-bromopiperonal 7 and methyl 4-
oxobutanoate 8 followed by the chemoselective reduction−
lactonization.
P
Figure 1. (−)-Podophyllotoxin and its stereoisomeric compounds.
studied over the last two centuries for their significant biological
profile and structural diversity.1 This bioactive molecule is used
for the treatment of genital warts and serves as a synthetic
precursor for the chemotherapeutic drugs etoposide 2a and
teniposide 2b, widely used as type II topoisomerase inhibitors
for the treatment of testicular and lung cancer, leukemia,
lymphoma, and Kaposi’s sarcoma.2 In addition, the natural
isomeric lignans of 1 exhibit important bioactivities. The IGF-
1R inhibitory molecule picropodophyllin 4 exhibits strong
activity toward hepatocellular carcinoma, chemoresistant
ovarian cancer cells, Ewing’s sarcoma cells, and human lung
cancer cell lines.3 SAR studies and structural modification of 1
Received: October 17, 2017
Published: December 6, 2017
© 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b03236
Org. Lett. 2017, 19, 6530−6533

Organic Letters
Letter
a
Scheme 1. Unified Retrosynthesis of (−)-Podophyllotoxin
and Its Isomers
Table 1. Optimization for Intramolecular Heck Reaction
yield (%)
entry
catalyst
ligand
base
TEA
5
5′
nd
1
2
3
4
5
6
Pd(OAc)2
PdCl2PPh3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Ph3P
Ph3P
none
none
Ph3P
Ar3P
Ar3P
Ar3P
15
K2CO3
TEA
22
34
61
67
84
84
21
22
12
7
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
In our previous report, we observed that organocatalytic
cross aldol reaction with electron-rich aldehyde was difficult to
achieve.6 Further, the scarcity of literature reports on the same
made our synthesis tougher.6b,7 Initially we found the aldol
reaction of piperonal gave only a trace amount of the aldol
product; however, the use of 6-bromopiperonal gave the
desired lactone with low yield (20%) but with excellent
selectivity (dr 24:1, ee 95%).6c The self-aldol reaction of 8 was
found to be the major factor behind this low yield of the
attempted cross-aldol reaction. Any attempt to match the
reactivity between 7 and 8 was not successful. Finally, the use of
excess (5 equiv) donor aldehyde 8 (which is in contrary to
traditional organocatalytic aldol procedure) and its portionwise
addition helped to achieve lactone 6 in 1 g scale with high yield
(75%) and excellent selectivity (dr 33:1, ee 99%; Scheme 2).
b
7
5
c
8
5
a
Conditions: 0.05 g of substrate 10 in 0.5 mL of DMF, 20 mol % of
b
catalyst, 2 equiv of base, ligand (2 × catalyst mol %). 10 mol % of
catalyst used. 5 mol % of catalyst used. Ar3P = tri(o-tolyl)phosphine.
c
Pd2dba3 was found to be the most effective one. Reaction
without any ligand produced the desired product 5 in low yield
along with the C1 dearylated Heck product 5′ (Table 1, entries
3−4). Gratifyingly, the use of a suitable ligand and base
produced 5 as the major product and the suppression of
catalyst loading gave better yield by inhibiting the side products
formation (entries 6−8).
The final crucial step of our synthetic strategy was the
stereocontrolled reduction of 5. To achieve this, we attempted
a Pd/C catalyzed hydrogenation. Reaction in MeOH showed
the high proximal selectivity providing 12 (entry 1, Table 2).
Variation in the solvent, catalyst, and temperature had little
effect on the proximal selectivity. Bulky catalysts such as
RhCl(PPh3)3 and [Ir(cod)(PCy3)(py)]PF6 produced no
reaction (See SI for details). Thus, it was quite challenging to
get the distal stereocontrol product 11. However, catalytic
transfer hydrogenation (CTH)9 with HCO2NH4 in MeOH was
quite interesting and provided better distal selectivity (entry 5
vs entry 1, Table 2). This led us to study the effect of solvent in
CTH. Delightfully, we observed a linear correlation of distal
selectivity with the increase in linear chain length of primary
alcohols (entries 5−10 and Figure 2). Ultimately, we achieved
higher distal stereocontrol effect over proximal effect with
HCO2Na in 1-pentanol (entry 14). This is the first report of
selectivity switching by using solvent dependent substrate
stereocontrolled CTH (entry 14 vs entry 5). A controlled
amount of added water in HCO2Na-mediated CTH was found
to be very crucial for the reaction and the distal selectivity, as
there was no reaction without water and excess water lowered
the selectivity (entry 15).
The above observations indicated a probable coordination of
solvent with Pd catalyst (Scheme 3). This coordination, in turn,
generated a bulky solvent coordinated active catalytic species C,
which is responsible for the increase in distal selectivity. This
mechanism is in line with the CTH mechanism proposed by
the Elsevier and Cazin groups.9c−e When the CTH was
performed in CD3OD a substantial amount of deuterium
incorporation was observed in 11/12 (see the SI for details).
The abundance ratios of D-H and H−H insertion in 11/12
were 1.01 and 1.52, respectively (Scheme 3).
Scheme 2. Synthesis of Z-Benzylidene Lactone 10
The choice of protecting group was crucial for our synthesis
as it would later direct the distal stereoselectivity. Among
different protecting groups, we found TBSOTf in THF was the
most effective one. The Li-HMDS-mediated second aldol
reaction of 9 with 3,4,5-trimethoxybenzaldehyde and sub-
sequent treatment of the crude aldol adduct with MsCl and
base produced the corresponding Z-benzylidene lactone 10 as a
major diastereoisomer. Next, we examined the conditions for
intramolecular Heck reaction (Table 1).8 The presence of a
substantially bulky ortho-substitution of bromoarene and the
conformationally congested tethered trisubstituted Z-alkene
made the attempted Heck reaction quite challenging.
Desilylated 10 during the Heck coupling provided either a
naphthalene derivative as a major product or a complex
reaction mixture. Among different Pd catalysts employed,
The lower value of D-incorporation or, in other words, the
higher value of dihydrogen insertion in the case of HCO2NH4
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Organic Letters
Letter
distal stereocontrolled hydrogenation of 5 with HCO2Na in 1-
pentanol followed by TBS deprotection of the crude reduced
product with TBAF−AcOH accomplished the total synthesis of
(−)-podophyllotoxin 1 in 27% overall yield over five steps
(Scheme 4). The spectral and analytical data of the synthesized
Table 2. Catalytic Hydrogenation of Compound 5 (Selected
Optimization Conditions)
a
Scheme 4. Total Synthesis of (−)-Podophyllotoxin,
(−)-Picropodophyllin, (+)-Isopicropodophyllin, and
(+)-Isopicropodophyllone
b
entry
solvent
MeOH
H source
temp (° C) time (h) 11/12
1
H2/1 atm
H2/1 atm
H2/1 atm
H2/1 atm
HCO2NH4
HCO2NH4
HCO2NH4
HCO2NH4
HCO2NH4
HCO2NH4
HCO2NH4
HCO2NH4
HCO2Na
27
27
27
27
40
40
40
40
40
40
40
40
40
40
40
12
12
12
12
6
1:10
1:1.7
1:10
1:2.5
1:3
2
EtOH
3
n-propanol
toluene/EtOH
MeOH
4
5
6
EtOH
6
1:1.5
1:1.5
1:1.4
1:1
7
1-propanol
1-butanol
1-pentanol
1-hexanol
2-propanol
1-pentanol
1-pentanol
1-pentanol
1-pentanol
6
8
6
9
6
10
11
6
1:1
6
1:2.5
c
12
6
1.2:1
d
13
12
12
12
1.5:1
1.5:1
e
14
HCO2Na
HCO2Na
f
15
1.15:1
a
Conditions: 0.02 g of substrate 5 in 1 mL solvent, 20% catalyst (by
b
1
wt.), 30 equiv formate. Determined by the H NMR analysis of the
crude reaction mixture. 1-pentanol/H2O (5:1) used. 10 equiv H2O
used. 20 equiv H2O used. 30 equiv H2O used.
c
d
e
f
compound 1 was in good agreement with that of the natural
product.5d,h Desilylation of the crude hydrogenated product
obtained from 5 with TBAF instead of TBAF-AcOH at room
temperature gave directly (−)-picropodophyllin 4 in good yield
via in situ isomerization at C2. Pd/C-catalyzed proximal
stereocontrolled hydrogenation with hydrogen (H2 balloon) in
MeOH followed by sequential TBAF mediated desilylation of 5
afforded the (+)-isopicropodophyllin 3′. PDC oxidation of 3′
completed the total synthesis of another natural product,
(+)-isopicropodophyllone 3. The synthesized 3 can easily be
transformed to ent-1 following the steps reported in the
literature5f completing a formal total synthesis of (+)-podo-
phyllotoxin (Scheme 4). Hence, changing our chiral catalyst to
D-proline would lead to (−)-podophyllotoxin 1 with high
diastereoselectivity via the isopicropodophyllone intermediate.
As an appended application, we also investigated the
reductive Heck reaction of 10 instead of the two-step Heck
reaction and hydrogenation sequence. Surprisingly, compound
10 did not respond to the reductive Heck reaction, but after
desilylation, it responded to the Pd2dba3 catalyzed reductive
Heck reaction with sodium formate and afforded (−)-iso-
podophyllotoxin 1′ in good yield (64%; Scheme 5).
Figure 2. Graphical presentation for the comparison of distal
selectivity between CTH and hydrogenation.
Scheme 3. Plausible Mechanism for the Effect of ROH in
CTH
+
indicates the possibility of a competing H-transfer from NH4
vs CD3OD. This deuterium incorporation further confirmed
that one of the H-transfers takes place from the ROH which
probably coordinates with the catalyst. Thus, Pd/C-catalyzed
In conclusion, the first catalytic enantioselective total
synthesis of (−)-podophyllotoxin has been accomplished in
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Organic Letters
Letter
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2, 341.
Scheme 5. Total Synthesis of (−)-Isopodophyllotoxin
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Speybroeck, R.; Guo, H.; Van der Eycken, J.; Vandewalle, M.
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́
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only five steps starting from commercially available 6-
bromopiperonal with an overall yield of 27% and 99% of ee,
along with the total synthesis of (−)-picropodophyllin,
(−)-isopodophyllotoxin, (+)-isopicropodophyllin, and (+)-iso-
picropodophyllone and a formal total synthesis of (+)-podo-
phyllotoxin. The hydrogenation studies reported herein imply
that even with the same catalyst, distal and proximal
stereoselectivity can be achieved by altering the hydrogen
source and solvent. The advantage of our strategy lies in the
utilization of three catalytic steps out of five steps employed as
well as in use of the common intermediate to synthesize other
stereoisomers.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03236.
Experimental details for all reactions and analytic details
for all products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: saumen.hajra@cbmr.res.in. Fax: (+91)-522-2668995.
Tel: (+91)-522-2668861.
ORCID
Saumen Hajra: 0000-0003-0303-4647
Present Address
§(S.H.) Department of Applied Chemistry, Faculty of
Engineering, Osaka University, Suita, Osaka 5650871, Japan
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by CSIR, New Delhi (02(0184)/
14/EMR-II). S.G. thanks UGC, New Delhi, for a research
fellowship. We thank the Director, CBMR, for research
facilities.
DEDICATION
■
This work is dedicated to Professor Tarun K. Sarkar (former
Professor of Chemistry, IIT Kharagpur) on the occasion of his
70th birthday.
REFERENCES
■
(1) For reviews, see: (a) Imbert, T. Biochimie 1998, 80, 207. (b) Yu,
X.; Che, Z.; Xu, H. Chem. - Eur. J. 2017, 23, 1. (c) Ward, R. S. Nat.
Prod. Rep. 1997, 14, 43. (d) Ayres, D. C.; Loike, J. D. Lignans:
Chemical, Biological and Clinical Properties; Cambridge University
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DOI: 10.1021/acs.orglett.7b03236
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