A new and efficient strategy for the synthesis of podophyllotoxin and its analogues

Article abstract of DOI:10.1021/ol0630954

Figure presented An efficient and stereoselective strategy for the total synthesis of podophyllotoxin was developed. This route leads to podophyllotoxin 1 in only 12 steps with 29% overall yield. A notable feature of this synthetic strategy is the use of

Full text of DOI:10.1021/ol0630954

ORGANIC
LETTERS
2
007
Vol. 9, No. 7
199-1202
A New and Efficient Strategy for the
Synthesis of Podophyllotoxin and Its
Analogues
1
Yingming Wu, Hongbin Zhang,* Yuanhong Zhao, Jingfeng Zhao,
Jingbo Chen, and Liang Li
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan UniVersity),
Ministry of Education, School of Chemical Science and Technology, Yunnan
UniVersity, Kunming, Yunnan 650091, P. R. China
zhanghb@ynu.edu.cn
Received December 21, 2006
ABSTRACT
An efficient and stereoselective strategy for the total synthesis of podophyllotoxin was developed. This route leads to podophyllotoxin 1 in
only 12 steps with 29% overall yield. A notable feature of this synthetic strategy is the use of the cascade addition alkylation to ensure the
key C1 C2 stereochemistry that is pivotal for the synthesis of podophyllotoxin.
−
−
The natural product podophyllotoxin (1), a potent inhibitor
The important biological activities as well as the intriguing
structure (four contiguous chiral centers, rigid trans lactone,
pseudoaxial ring E, and facile epimerization at C2 and C4)
of podophyllotoxin have long attracted the attention of
numerous research groups. Synthetic efforts directed toward
those aryl tetrahydronaphthalene lignan lactones have gener-
of microtubule assembly, is the major constituent of the
1
podophyllum family. Podophyllotoxin is currently used for
the treatment of venereal warts and also has served as an
important precursor for the preparation of clinical anti-tumor
2
drugs etoposide and teniposide. A recent report also raised
5
ated a great deal of creative methodologies. Although there
are numerous documented strategies for the syntheses of
the possibility of using podophyllotoxin derivatives as anti-
3
HIV agents. Owing to its significant clinical role, the
synthesis and biological studies of podophyllotoxin and its
analogues have been an important topic in medicinal
4
chemistry. The structure of podophyllotoxin is shown in
Figure 1.
(
1) (a) MacRae, W. D.; Hudson, J. B.; Towers, B. H. N. Planta Med.
1
993, 55, 531. (b) Gordaliza, M.; Garc ´ı a, P. A.; Miguel del Corral, J. M.;
Castro, M. A.; G o´ mez-Zurita, M. A. Toxicon 2004, 44, 441 and references
therein.
(2) (a) Hande, K. R. Eur. J. Cancer 1998, 34, 1514. (b) Damayanthi,
Y.; Lown, J. W. Curr. Med. Chem. 1998, 5, 205. (c) Silverberg, L. J.; Dillon,
J. L.; Vemishetti, P.; Sleezer, P. D.; Discordia, R. P.; Hartung, K. B.; Gao,
Q. Org. Process Res. DeV. 2000, 4, 34 and references therein.
(
3) Zhu, X.-K.; Guan, J.; Xiao, Z.; Cosentino, L. M.; Lee, K.-H. Bioorg.
Figure 1. Podophyllotoxin and picropodophyllin.
Med. Chem. 2004, 12, 4267.
1
0.1021/ol0630954 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/28/2007

podophyllotoxin, many unfortunately fail to meet adequate
measures of efficiency, stereoselectivity, and/or flexibility.
Furthermore, only a few proceed through tactics that do not
involve epimerization of thermodynamically more stable
picropodophyllin 2 to 1, via kinetic protonation of ester
product 6. Although the relative stereochemistry might be
predicted by the model shown in Scheme 1, it was not
confirmed at this stage. No attempt was made to determine
the stereochemistry, because this issue could be addressed
in a later stage of our synthesis. It was worthwhile to note
that when the reaction was conducted with the methyl ester
of unsaturated carbonyl compound 4b, the same operation
resulted in mainly 1,2-addition with no desired 1,4-addition
product being obtained. A bulky tert-butyl ester group is
necessary for the initial Michael addition (Scheme 2).
6
enolates of 2 at a later stage in the synthetic routes.
In seeking a more efficient and flexible synthetic strategy
toward aryltetralin lactone podophyllotoxin 1 and its ana-
logues, we have designed a new route outlined in Scheme 1
Scheme 1. Retrosynthetic Analysis of Podophyllotoxin
Scheme 2. Key Conjugate Addition-Alkylation
that should require fewer steps and result in high stereo-
selectivities. Key to the success of our new approach was a
tandem process that was initiated by aryl lithium and
quenched with allyl bromide, a conjugate addition followed
by enolate alkylation. We anticipated that a desired anti
stereochemistry would be ensured at this step.
We started our research with the protection of the carbonyl
group in 6-bromopiperonal, a commercially available mate-
rial. After a successful Heck reaction, we obtained R,â-
unsaturated ester 4 (4a and 4b). The next conjugate addition/
enolate alkylation toward 4a was carried out initially with
organocupurate. Unfortunately, we did not obtain the desired
tandem process, with mainly starting material being obtained.
Utilization of aryl lithium generated in situ finally promoted
the cascade reaction. As expected, only one diastereoisomer
was obtained in 75% yield together with minor 1,2-addition
After deprotection of the ketal moiety, the resulting
aldehyde 7 was submitted to an oxidative cleavage process.
Dihydroxylation of aldehyde 7 with osmium tetroxide
4
followed by treatment with NaIO afforded dialdehyde 8 in
9
4% yield over two steps (Scheme 3). Although chroma-
tography could be conducted, the liable dialdehyde 8 was
better used in the next aldol reaction without further
purification. In the presence of potassium carbonate in
methanol, the aldol condensation afforded high yield (99%)
of unsaturated aldehyde 9. The relative stereochemistry for
C2 and C3 was established by a ROESY spectrum and could
also be deduced by the coupling constant (4.8 Hz) between
the proton in C2 and the proton in C3. Although compound
(4) (a) Canel, C.; Moraes, R. M.; Dayan, F. E.; Ferreira, D. Phytochem-
istry 2000, 54, 115. (b) Castro, M. A.; M ´ı guel del Corral, J. M.; Gordaliza,
M.; Garc ´ı a, P. A.; G o´ mez-Zurita, M. A.; Garc ´ı a-Gr a´ valos, M. D.; de la
Iglesia-Vicente, J.; Gajate, C.; An, F.; Mollinedo, F.; Feliciano, A. S. J.
Med. Chem. 2004, 47, 1214. (c) Srivastava, V.; Negi, A. S.; Kumar, J. K.;
Gupta, M. M.; Khanuja, S. P. S. Bioorg. Med. Chem. 2005, 13, 5892.
(
5) For reviews of synthetic approaches to pododphyllotoxin, see: (a)
Ward, R. S. Synthesis 1992, 719. (b)Ward, R. S. Nat. Prod. Rep. 1999, 16,
5. (c) Ward, R. S. Phytochem. ReV. 2003, 2, 391. For recent synthesis of
9
could be utilized for the synthesis of podophyllotoxin and
7
podophyllotoxin and its derivatives, see: (d) Berkowitz, D. B.; Choi, S.;
Maeng, J.-H. J. Org. Chem. 2000, 65, 847. (e) Poli, G.; Giambastiani, G.
J. Org. Chem. 2002, 67, 9456. (f) Engelhardt, U.; Sarkar, A.; Linker, T.
Angew. Chem., Int. Ed. 2003, 42, 2487. (g) Reynolds, A. J.; Scott, A. J.;
Turner, C. I.; Sherburn, M. S. J. Am. Chem. Soc. 2003, 125, 12108. (h)
Casey, M.; Keaveney, C. M. Chem. Commun. 2004, 184.
its analogues, a better intermediate was sought. To our
delight, treatment of dialdehyde 8 with L-proline resulted in
only one pair of diastereisomers at the C4 position.7
Chromatography of the aldol product was problematic and
led to conjugate aldehyde 9; a silica gel mediated dehydration
process might occur in column chromatography. This issue
was finally solved by direct reduction of the aldol product
with sodium borohydride to 1,3-diol 10 (see Scheme 4). An
(6) (a) Forsey, S. P.; Rajapaksa, D.; Taylor, N. J.; Rodrigo, R. J. Org.
Chem. 1989, 54, 4280 and epimerization of C3 required. (b) Kraus, G. A.;
Wu, Y. J. Org. Chem. 1992, 57, 2922. (c) Charlton, J. L.; Koh, K. J. Org.
Chem. 1992, 57, 1514. (d) Bush, E. J.; Jones, D. W. J. Chem. Soc., Perkin
Trans. 1 1996, 151.
1200
Org. Lett., Vol. 9, No. 7, 2007

regioselective oxidation. Similar oxidation of 1,3-diol 10 to
the ketone was reported in the literature; unfortunately,
Scheme 3. Synthesis of Dialdehyde 8 and Related Aldol
Reaction
2
oxidation with MnO provided the desired transformation
8
in low yield (40%). We conducted an oxidation with
activated MnO in dichloromethane and found that 40% yield
2
of ketone 12 was formed together with recovery of pure 1,3-
diol cis-isomer 10â (C4-hydroxyl group in â orientation)
(Scheme 5). This observation suggested that an intra-
Scheme 5. Final Stage of the Total Synthesis of
(()-Podophyllotoxin
anti relative stereochemistry was observed between the ester
group at C2 and the methylene-hydroxyl group at C3. The
relative stereochemistry is shown in Scheme 4.
Scheme 4. Proline-Promoted Aldol Reaction
molecular hydrogen bond might be formed in the 1,3-diol
cis-isomer thus rendering it resistant to oxidation and only
(
7) In principle, two new stereogenic centers were formed and four
diastereisomers were expected. Due to steric effect as depicted in Scheme
, only one pair of diasteroisomers were obtained. Spectra date for key
4
1
intermediates follow. Compound 5: H NMR (300 MHz, CDCl3) δ (ppm)
7
1
1
.06 (1H, s), 6.93 (1H, s), 6.67 (2H, s), 6.24 (1H, s), 5.92 (1H, d, J )
.2Hz), 5.86 (1H, d, J ) 1.2 Hz), 5.85-5.68 (1H, m), 5.03 (1H, d, J )
0.1 Hz), 4.98 (1H, d, J ) 3.0 Hz), 4.37 (1H, d, J ) 11.7 Hz), 4.21-4.12
(
)
1H, m), 4.12-4.03 (3H, m), 3.84 (6H, s), 3.79 (3H, s), 3.09 (1H, ddd, J
1
3
7.1, 7.2, 11.7 Hz), 2.28 (2H, t, J ) 7.1 Hz), 1.17 (9H, s); C NMR (75
MHz, CDCl3) δ (ppm) 173.47, 153.58, 148.31, 146.43, 137.61, 137.04,
135.94, 135.58, 129.33, 117.04, 108.21, 106.39, 105.88, 101.45, 101.26,
In our initial synthetic plan, treatment of 1,3-diol 10 with
acid or Lewis acid would lead to podophyllotoxin 1, a depro-
tection and lactonization process. Unfortunately, treatment
81.02, 65.74, 65.31, 61.18, 56.50, 52.09, 47.81, 36.41, 28.10. Compound
1
9
: H NMR (300 MHz, CDCl3) δ (ppm) 9.58 (1H, s), 7.29 (1H, s), 6.87
(
1H, s), 6.62 (1H, s), 6.24 (2H, s), 5.99 (2H, s), 4.51 (1H, d, J ) 4.8 Hz),
13
3.87 (1H, d, J ) 4.8 Hz), 3.78 (3H, s), 3.74 (6H, s), 1.31 (9H, s);
NMR (75 MHz, CDCl3) δ (ppm) 191.31, 171.02, 153.31, 150.39, 147.32,
C
of 10 with trifluoroacetic acid or BF
3 2
‚Et O led to neopodo-
1
8
45.10, 137.37, 134.30, 134.21, 125.33, 109.99, 108.89, 105.29, 101.84,
phyllotoxin in nearly quantitative yield, probably via a carbon
cation (C4) pathway. This transformation provided a further
evidence for the relative stereochemistry of 1,3-diol 10.
1
1.54, 60.90, 56.25, 46.94, 46.08, 27.90. Compound 12: H NMR (300
MHz, CDCl3) δ (ppm) 7.48 (1H, s), 6.57 (1H, s), 6.20 (2H, s), 6.02 (1H,
s), 5.99 (1H, s), 4.49 (1H, d, J ) 5.4 Hz), 4.23-4.12 (1H, m), 3.88-3.70
(
1H, m), 3.77 (3H, s), 3.73 (6H, s), 3.42 (1H, dd, J ) 5.4, 12.8 Hz), 3.13-
13
Although neopodophyllotoxin has been transformed to
3.06 (1H, m), 2.85 (1H, brs), 1.31 (9H, s); C NMR (75 MHz, CDCl3) δ
ppm) 198.44, 170.25, 153.33, 153.16, 147.99, 141.48, 137.54, 134.41,
26.69, 108.55, 106.65, 105.90, 102.14, 81.78, 62.48, 60.92, 56.23, 47.42,
45.81, 28.04.
(
1
6
c
podophyllotoxin and a formal synthesis could be claimed,
we still decided to convert the 1,3-diol to the ketone by a
Org. Lett., Vol. 9, No. 7, 2007
1201

even 1-bromo-3,5-difluorobenzene could be used in this step
with 74% yield.
Scheme 6. Michael Addition with Aryl Lithium
In summary, we have developed a highly practical,
efficient, and stereoselective strategy for the total synthesis
of podophyllotoxin. This route leads to podophyllotoxin 1
in only 12 steps with 29% overall yield. A notable feature
of this synthetic strategy is the use of a cascade addition-
alkylation to ensure the key C1-C2 stereochemistry that is
pivotal for the synthesis of podophyllotoxin. This work also
lays a foundation for the synthesis of representative of the
podophyllotoxin family as well as analogues that are of
interest for medicinal chemistry. Modification of ring systems
presented in podophyllotoxin is possible by our synthetic
procedure. Synthesis of analogues is currently underway in
our laboratory.
the trans-isomer in the mixture of 1,3-diol 10 was oxidized.
In our previous research, we found that acetonitrile was a
good solvent for reactions with substrates that might form
an intramolecular hydrogen bond. By utilization of aceto-
nitrile as solvent, we finally got the desired ketone 12 in
9
8
2% yield. The tert-butyl group was then removed by
Acknowledgment. This work was supported by a grant
20040673006) from the foundation of the Chinese Ministry
of Education for the promotion of Excellent Young Scholar.
We would like to thank the Natural Science Foundation of
Yunnan Provincial Science & Technology Department for
partial financial support (2005B0002Q).
treatment with 4 N HCl in acetonitrile, and the resulting
product was directly converted to the methyl ester. After
reduction of the ketone moiety with super hydride, a
lactonization furnished podophyllotoxin 1 in 93% yield.
The flexibility of our strategy could be demonstrated by
utilization of another aryl lithium as nucleophile in the key
conjugate addition/enolate alkylation process. We found that
(
1
0
8
6
d
Supporting Information Available: General experimen-
1
13
tal details and H NMR, C NMR, MS, and HRMS spectra
of all key intermediates. This material is available free of
charge via the Internet at http://pubs.acs.org.
(8) Jones, D. W.; Thompson, A. M. J. Chem. Soc., Perkin Trans. 1 1993,
2
541.
(9) Wang, C.; Liu, J.; Ji, Y.; Zhao, J.; Li, L.; Zhang, H. Org. Lett. 2006,
8
, 2479.
(
10) Subrahmanyam, D.; Renuka, B.; Rao, C. V. L.; Sagar, P. S.; Deevi,
D. S.; Babu, J. M.; Vyas, K. Bioorg. Med. Chem. Lett. 1998, 8, 1391.
OL0630954
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Org. Lett., Vol. 9, No. 7, 2007