Enantioselective sequential conjugate addition-allylation reactions: A concise total synthesis of (+)-podophyllotoxin

Article abstract of DOI:10.1021/ol8026208

(Chemical Equation Presented) A highly flexible and concise total synthesis of (+)-podophyllotoxin featured with an enantioselective sequential conjugate addition-allylation reaction was reported. Starting from commercially available 3,4,5-trimethoxycinna

Full text of DOI:10.1021/ol8026208

ORGANIC
LETTERS
2009
Vol. 11, No. 3
597-600
Enantioselective Sequential Conjugate
Addition-Allylation Reactions: A
Concise Total Synthesis of
(+)-Podophyllotoxin
Yingming Wu, Jingfeng Zhao, Jingbo Chen, Chengxue Pan, Liang Li, and
Hongbin Zhang*
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; zhang_hongbin@hotmail.com
Received November 13, 2008
ABSTRACT
A highly flexible and concise total synthesis of (+)-podophyllotoxin featured with an enantioselective sequential conjugate addition-allylation
reaction was reported. Starting from commercially available 3,4,5-trimethoxycinnamic acid, this new route leads to (+)-podophyllotoxin 1 in
only eight steps with 29% overall yield.
The natural aryltetralin lactone (+)-podophyllotoxin (1)
(Figure 1) occupies a unique position among lignans with
an intriguing structure (four contiguous chiral centers, rigid
trans lactone, pseudoaxial ring E, and facile epimerization
at C2 and C4). It has currently been used for the treatment
of venereal warts and also served as an important precursor
for the preparation of clinical antitumor drugs etoposide
and teniposide.1 A growing demand for podophyllotoxin
worldwide has exerted severe pressure on the plant
resource.2 Owing to its significant clinical role, interesting
molecular architecture and the supply issue, development
of efficient synthetic routes leading to enantioselective
synthesis of podophyllotoxin retains a target of pursuit
for decades.
As part of our ongoing program in seeking more efficient
and flexible synthetic strategies toward bioactive natural
products and its analogues, we recently reported a new route
(12 steps) for the synthesis of (()-podophyllotoxin, with the
key reaction being a sequential reaction of aryl lithium
conjugate addition coupled with alkylation of allyl bromide
toward cinnamic derivative 3 (Scheme 1).3 Dealing with the
key reaction in a racemic approach is the major drawback
of our previous synthesis. In this paper, we report a highly
enantioselective version for the key Michael addition-
(1) (a) Liu, Y.-Q.; Yang, L.; Tian, X. Curr. Bioact. Compd. 2007, 3,
37. (b) Cragg, G. M.; Newman, D. J. J. Ethnopharmacol. 2005, 100, 72.
(c) Gordaliza, M.; Garc´ıa, P. A.; Miguel del Corral, J. M.; Castro, M. A.;
Go´mez-Zurita, M. A. Toxicon 2004, 44, 441. (d) Silverberg, L. J.; Dillon,
J. L.; Vemishetti, P.; Sleezer, P. D.; Discordia, R. P.; Hartung, K. B.; Gao,
Q. Org. Proc. Res. DeVelop. 2000, 4, 34.
(2) (a) Eyberger, A. L.; Dondapati, R.; Porter, J. R. J. Nat. Prod. 2006,
69, 1121. (b) Lin, H.-W.; Kwok, K. H.; Doran, P. M. Biotechnol. Prog.
2003, 19, 1417. (c) Canel, C.; Moraes, R. M.; Dayan, F. E.; Ferreira, D.
Phytochemistry 2000, 54, 115.
(3) Wu, Y.; Zhang, H.; Zhao, Y.; Zhao, J.; Chen, J.; Li, L. Org. Lett.
2007, 9, 1199.
10.1021/ol8026208 CCC: $40.75
Published on Web 12/23/2008
2009 American Chemical Society

good enantioselectivities in the literature (ref 4e, f), our
substrate failed (Scheme 1), however, with a diastereomeric
mixture of compound 5 being obtained. We reckoned that
the steric hindrance as well as chelation effects enhanced
by the oxazolidine moiety might be the cause of low
stereoselectivity.
Scheme 1
.
Initial Attempts toward Enantioselective Sequential
Michael Addition-Alkylation
Having failed to effect the desired conversion, alternative
way was thus sought. Carefully analysis of the model of
natural pseudoephedrine derived oxazolidine; it was postu-
lated that a chelated chiral aryllithium reagent would favor
the formation of diastereoisomer with desired stereochemistry
(Scheme 2).
Scheme 2. New Retrosynthetic Analysis of Podophyllotoxin
alkylation process and a concise (eight steps) total synthesis
of (+)-podophyllotoxin.
Figure 1. Natural podophyllotoxin and podophyllotoxone.
Based on model analysis, unnatural (+)-pseudoephe-
drine might provided the desired absolute configuration
for the synthesis of natural podophyllotoxin. Because we
were only able to access natural (+)-pseudoephedrine, we
decided to use (+)-pseudoephedrine to confirm the model
postulate. 6-Bromopiperonal was therefore treated with
(+)-pseudoephedrine and directly converted to oxazolidine
8 as a single diastereomer (Scheme 3).6
Our initial plan to address the key Michael addition-
alkylation was to utilize protocols developed by Alexakis4e
and Frey4f (in both cases, enantiopure pseudoephedrine was
used in Michael acceptor both as a protecting group and a
chiral auxiliary on the aldehyde motif of cinnamic deriva-
tives, only Michael addition, without the subsequent alky-
lation, being reported).4
When oxazolidine-derived aryllithium was used as
reagent, conjugate addition-alkylation occurred as ex-
pected, and after deprotection with aqueous acetic acid, a
diastereomeric mixture (syn/anti ) 1/11) was obtained in
64% yield with an enantiomeric excess of 84.8% being
observed (Chiral HPLC analysis on AD-H column). In
order to optimize the stereoselectivity, we decided to add
N,N,N′,N′-tetramethylethylenediamine (TMEDA), a fre-
quently used solvating agent in organolithium chemistry7
with observed beneficial effects on stereoselectivity.7a To
our delight, addition of TMEDA not only provided
excellent diastereoselectivity (with no syn-diastereoisomer
being detected by NMR, dr ) 96.8% by Chiral HPLC,
Since natural (S,S)-(+)-pseudoephedrine was the only
available material in hand,5 it was then employed to prepare
oxazolidine 4. Although substrates similar to 4 resulted in
(4) For recent application of ephedrine derivatives in Michael addition,
see:(a) Kummer, D. A.; Chain, W. J.; Morales, M. R.; Quiroga, O.; Myers,
A. G. J. Am. Chem. Soc. 2008, 130, 13231. (b) Reyes, E.; Vicario, J. L.;
Carrillo, L.; Badia, D.; Uria, U.; Iza, A. J. Org. Chem. 2006, 71, 7763. (c)
Reyes, E.; Vicario, J. L.; Carrillo, L.; Badia, D.; Iza, A.; Uria, U. Org.
Lett. 2006, 8, 2535. (d) Smitrovich, J. H.; DiMichele, L.; Qu, C.; Boice,
G. N.; Nelson, T. D.; Huffman, M. A.; Murry, J. J. Org. Chem. 2004, 69,
1903. (e) Alexakis, A.; Sedrani, R.; Mangeney, P.; Normant, J. F.
Tetrahedron Lett. 1988, 29, 4411. (f) Frey, L. F.; Tillyer, R. D.; Caille,
A.-S.; Tschaen, D. M.; Dolling, U.-H.; Grabowski, E. J. J.; Reider, P. J. J.
Org. Chem. 1998, 63, 3120.
(5) Due to the regulation governing the sale and production of ephedrine
and pseudoephedrine in China, we are only able to access natural (+)-
ephedrine and natural (+)-pseudoephedrine; we are unable to get unnatural
ephedrine and pseudoephedrine, although those two isomers are listed in
the Aldrich catalogue.
(6) Neelakantan, L. J. Org. Chem. 1971, 36, 2256.
(7) (a) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org. Chem. 2002,
67, 1496. (b) Collum, D. B. Acc. Chem. Res. 1992, 25, 448.
598
Org. Lett., Vol. 11, No. 3, 2009

Scheme 3
.
Enantioselective Sequential Michael
Addition-Alkylation
see model in Scheme 3) but also improved the enantiose-
lectivity dramatically (the ee value was increased to
98.6%). A 65% yield was obtained in the presence of
TMEDA.
In order to get further insight toward the generality of
this process, a number of cinnamic derivatives were
evaluated under optimized conditions, and good yields and
excellent ee were ensured for substrates utilized in this
research. The results are summarized in Figure 2. It was
worthwhile to note that the (S,S)-(+)-pseudoephedrine
could be recycled after deprotection of the oxazolidine
motif, while this new protocol also provided a good access
of pharmacentically important intermediates such as ꢀ,ꢀ-
diaryl R-alkyl-substituted propionic acid derivatives (see
ref 4).
Figure 2. Results of asymmetric sequential conjugate addition-
alkylation. Yields represent isolated yield based on cinnamic
acid derivatives. The absolute configurations (as depicted) were
established by comparison of optical rotation of the synthetic
podophyllotoxin with that of natural podophyllotoxin. Diaste-
1
reoselectivities (dr) were determined by H NMR and enanti-
Havingestablishedtheenantioselectiveaddition-allylation
procedure, we turned our attention to the total synthesis
of podophyllotoxin. Following our previously established
procedure, aldehyde 5 was submitted to an oxidative
cleavage followed by an L-proline-mediated adol cycliza-
tion and a selective oxidation with MnO2 to afford
intermediate 16. In our previous synthesis, ketone 16 was
transformed to podophyllotoxin via a four-step sequence,
a relatively lengthy procedure. We decided to explore a
new approach. After the tert-butyl ester group being
hydrolyzed by treatment with hydrochloric acid in aceto-
nitrile, an esterification with DCC provided (+)-podo-
oselectivities (ee) were determined by chiral HPLC on AD-H
column. Racemic samples were prepared by utilization of
2-(1,3-dioxolan-2yl)aryllithium. (a) Reaction was carried out at
-100 °C.
ent-podophyllotoxin in 98% yield as a single isomer and
thus finalized the enantioselective synthesis ([R]27
)
D
+91.8, c 0.708, CHCl3, 99% ee by HPLC on an AD-H
column).
In summary, we have developed an enantioselective
strategy toward the total synthesis of (+)-podophyllotoxin.
Starting from commercially available 3,4,5-trimethoxy-
cinnamic acid, this new route leads to (+)-podophyllotoxin
1 in only eight steps with 29% overall yield. In comparison
with previous synthetic routes,3,10 our new approach
represents one of the most flexible, efficient, and concise
routes. Although pseudoephedrine has been used as an
phyllotoxone in 90% yield ([R]27 ) +92.9, c 0.113,
D
CHCl3).8 Selective reduction with L-Selectride9 provided
(8) Dewick, P. M.; Jackson, D. E. Phytochemistry 1981, 20, 2277.
(9) In comparison with LiAlH(O-t-Bu)3 used in the literature for the
reduction of the ketone moiety in podophyllotoxone, L-Selectride provided
better yields and selectivity.
Org. Lett., Vol. 11, No. 3, 2009
599

has never been reported. The enantioselective version of the
sequential addition-allylation should be of synthetic value
for the synthesis of pharmaceuticals as well as natural
products. This strategy, coupled with our previous synthetic
route, lays a solid foundation for the synthesis of representa-
tive podophyllotoxin family as well as analogues that are of
interests for medicinal chemistry.
Scheme 4
.
Enantioselective Total Synthesis of
(+)-Podophyllotoxin
Acknowledgment. This work was supported by a grant
from the foundation of the Chinese Ministry of Education
for fostering important scientific research program (706052)
and a grant (20702045) from the National Natural Science
Foundation of China. We thank the Yunnan Provincial
Science & Technology Department for partial financial
support (2007B0006Z).
Supporting Information Available: 1H and 13C NMR and
HPLC spectra of all key intermediates and experimental
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL8026208
(10) For recent synthesis of podophyllotoxin and related analogues, see:
(a) Stadler, D.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 7557. (b) Pullin,
R. D. C.; Sellars, J. D.; Steel, P. G. Org. Biomol. Chem. 2007, 5, 3201. (c)
Kolly-Kovac, T.; Renaud, P. Synthesis 2005, 1459. (d) Casey, M.; Keaveney,
C. M. Chem. Commun. 2004, 184. (e) Reynolds, A. J.; Scott, A. J.; Turner,
C. I.; Sherburn, M. S. J. Am. Chem. Soc. 2003, 125, 12108. (f) Engelhardt,
U.; Sarkar, A.; Linker, T. Angew. Chem., Int. Ed. 2003, 42, 2487. For recent
review on total synthesis of podophyllotoxin, see:Sellars, J. D.; Steel, P. G.
Eur. J. Org. Chem. 2007, 3815.
auxiliary in asymmetric synthesis for many years, to the best
of our knowledge, utilization of pseudoephedrine oxazolidine
in an aryllithium Michael donor as demonstrated in this paper
600
Org. Lett., Vol. 11, No. 3, 2009