Concise stereoselective synthesis of (-)-podophyllotoxin by an intermolecular iron(III)-catalyzed Friedel-Crafts alkylation

Article abstract of DOI:10.1002/anie.200802611

(Chemical Equation Presented) Without further ado, the building blocks 1-3 were combined in three C-C bond-forming reactions to provide the enantiomerically pure natural product (-)-podophyllotoxin (4). The stereogenic center at C1 was generated in the key reaction, a diastereoselective iron(III)-catalyzed intermolecular Friedel-Crafts alkylation.

Full text of DOI:10.1002/anie.200802611

Angewandte
Chemie
DOI: 10.1002/anie.200802611
Natural Product Synthesis
Concise Stereoselective Synthesis of (ꢀ)-Podophyllotoxin by an
Intermolecular Iron(III)-Catalyzed Friedel–Crafts Alkylation**
Daniel Stadler and Thorsten Bach*
Owing to their diverse biological activities, in particular their
cytotoxicity and antiviral properties, podophyllotoxin (1) and
its derivatives are important members of the lignane class of
natural products.[1] The biological profile of these compounds,
which has inspired the design of new drugs, has been
investigated intensively. The biological activity of podophyl-
lotoxin has generated strong interest in the development of
synthetic routes to this natural product.[2] Since the first
synthesis of enantiomerically pure (ꢀ)-podophyllotoxin (1)
by Meyers and co-workers[3] in a 24-step sequence, another
five syntheses of the enantiomerically pure natural product
have been reported.[4,5] Many additional studies have been
concerned with the development of formal total syntheses
and syntheses of racemic podophyllotoxin.[2] In all synthetic
approaches to podophyllotoxin, the modular generation of
the tetracyclic backbone and the brevity of the sequence are
of central importance. We report herein a six-step total
synthesis of enantiomerically pure (ꢀ)-podophyllotoxin with
an iron(III)-catalyzed Friedel–Crafts alkylation as a key step.
Apart from the use of a terminal alkene as an aldehyde
equivalent, no protecting-group manipulations were required
in the entire synthetic sequence.
methods included a Heck reaction, a Nozaki–Hiyama cou-
pling, and a classical Lewis acid mediated hydroxyalkylation.
A diastereoselective intermolecular Friedel–Crafts alkylation
was designed as the pivotal step, which should establish the
stereogenic center at C1.
In accordance with the outlined plan, the synthesis
commenced with the Taniguchi lactone (3), which is acces-
sible in enantiomerically pure form from 2-butyne-1,4-diol in
two steps with a subsequent conventional resolution[7] or in six
steps through an enantioselective iridium-catalyzed allyla-
tion.[8] An aldol reaction with aldehyde 4 afforded 5 with
excellent stereoselectivity with respect to the stereogenic
center at the a position of the lactone (Scheme 2). The fact
Our retrosynthesis involved the disconnection of the
target molecule into the three similarly sized fragments 2, 3,
and 4 (Scheme 1).[6] We planned to use an intramolecular
arylation to complete the tetracyclic core. Possible cyclization
Scheme 2. Aldol reaction und subsequent intermolecular Friedel–Crafts
alkylation: a) LDA (1.1 equiv), THF, ꢀ788C, 30 min, then 4 (1.1 equiv),
ꢀ788C, 3 h, 94% (d.r. 52:48); b) see Table 1. LDA=lithium diisopro-
pylamide.
that the simple diastereoselectivity was low, as expected, was
of no relevance, as the hydroxy group was substituted with an
aryl group in the next step in a SN1-type alkylation. To this
end, 5 was treated with 1,3-benzodioxole (2a, X = H) and
other derivatives 2 under acid catalysis. On the basis of our
previous studies on diastereoselective Friedel–Crafts alkyla-
tion reactions with chiral benzylic carbenium ions,[9] we
expected the stereoisomer 6 to be the predominant product.
Whereas the reaction of 2a with 5 proceeded smoothly
under the usual reaction conditions (HBF4·OEt2 in CH2Cl2)
with good diastereoselectivity to give product 6a (d.r. 85:15;
Table 1, entry 1), the analogous reactions of the substituted
derivatives 2b (X = Br), 2c (X = OTf), and sesamol (2d, X =
OH) failed (Table 1, entries 2–4). Only O-allyl-protected
Scheme 1. Retrosynthetic disconnection of (ꢀ)-podophyllotoxin (1)
into fragments 2, 3, and 4.
[*] M.Sc. D. Stadler, Prof. Dr. T. Bach
Lehrstuhl für Organische Chemie I
Technische Universität München
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax: (+49)89-289-13315
E-mail: thorsten.bach@ch.tum.de
[**] This project was supported by the Deutsche Forschungsgemein-
schaft (Ba 1372-12).
Supportinginformation for this article is available on the WWW
http://dx.doi.org/10.1002/anie.200802611.
Angew. Chem. Int. Ed. 2008, 47, 7557 –7559
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7557

Communications
sesamol 2e underwent the desired reaction to afford products
6e and 7e (d.r. = 84:16; Table 1, entry 5). The discovery that
this last reaction was also promoted by a catalytic amount of
Bi(OTf)3 (Table 1, entry 6)[10] prompted us to evaluate Bi
catalysis with substrates 2b–2d. Under these conditions,
sesamol (2d) was transformed diastereoselectively into the
desired product 6d (d.r. 90:10; Table 1, entry 9); no con-
version was observed with 2b and 2c (entries 7 and 8).
Further optimization studies led to the identification of
FeCl3,[11] which outperformed even AuCl3 (Table 1, entry 10),
as the optimum catalyst for the transformation of 5 into 6d
(entry 11).[12] The product 6d was formed with high diaste-
reoselectivity in nearly quantitative yield (d.r. 94:6; Table 1,
entry 11).
Scheme 3. Undesired regioselectivity in the BF3-catalyzed cyclization of
6a: a) OsO4 (5 mol%), NMO (3 equiv), CH2Cl2, 208C, 4 h, then NaIO4
(2 equiv), 30 min, 92%; b) BF3·OEt2 (10 equiv), CH2Cl2, ꢀ788C, 3 h,
41%. NMO=N-methylmorpholine N-oxide.
For the completion of the synthesis, different cyclization
methods were evaluated. Unfortunately, an attempted Lewis
acid catalyzed ring closure, which would have given rise to the
shortest possible sequence, did not afford the desired product.
Although oxidative cleavage of the terminal alkene to
provide the aldehyde proceeded smoothly, electronic and
conformational factors[13] prohibited the envisaged cyclization
onto the 1,3-benzodioxole substituent. Instead, under a
variety of conditions (one example is shown in Scheme 3),
cyclization always occurred by electrophilic attack at the
trimethoxyphenyl substituent to generate the podophyllo-
toxin isomer 8.
Reactions of triflate 6c, which can be prepared readily
from alcohol 6d (Scheme 4), were more successful. A Heck
reaction[14] led to the desired cyclized product 9.[15] An
attempted Nozaki–Hiyama coupling reaction[16] investigated
as an alternative cyclization procedure (after oxidative
cleavage of the terminal alkene to give the corresponding
aldehyde) did not lead to podophyllotoxin. Olefin 9 was
converted smoothly by dihydroxylation and periodate cleav-
age into podophyllotoxon,[17] which was reduced diastereose-
lectively to 1 by a previously reported procedure.[18]
Scheme 4. Completion of the total synthesis of (ꢀ)-podophyllotoxin
(1): a) Tf2O (1.5 equiv), NEt3 (2 equiv), CH2Cl2, 08C, 1 h, 89%; b) Pd-
(OAc)2 (10 mol%), PPh3 (0.3 equiv), K2CO3 (3 equiv), MeCN, 808C,
20 h, 58%; c) OsO4 (5 mol%), NMO (3 equiv), CH2Cl2, 208C, 4 h, then
NaIO4 (2 equiv), 30 min, 95%; d) LiAlH(OtBu)3 (10 equiv), Et2O,
ꢀ78!208C, 18 h, 79% (d.r. 98:2). Tf=trifluoromethanesulfonyl.
All physical properties of synthetic (ꢀ)-podophyllotoxin
(1), which was obtained from the Taniguchi lactone (3) in
35% overall yield, were identical to those of the natural
product. The synthesis illustrates that a stereogenic center in
the b position to an ester or lactone moiety can be constructed
highly diastereoselectively through a Lewis acid catalyzed SN1
reaction if a stereogenic center is already present in the
a position.
Received: June 4, 2008
Published online: August 29, 2008
Table 1: Optimization of the reaction conditions for the diastereoselective Friedel–Crafts alkylation.
Entry
X
2
Acid (mol%)
Solvent
T [8C]
t [min]
Yield [%][c]
d.r.[d]
6/7
Keywords: antitumor agents ·
catalysis · diastereoselectivity ·
natural products · total synthesis
.
1[a]
2[a]
H
Br
2a
2b
2c
2d
2e
2e
2b
2c
2d
2d
2d
HBF4 (400)
HBF4 (400)
HBF4 (400)
HBF4 (400)
HBF4 (125)
Bi(OTf)3 (10)
Bi(OTf)3 (10)
Bi(OTf)3 (10)
Bi(OTf)3 (10)
AuCl3 (10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
CH2Cl2
20
20
20
45
45
45
45
15
80
80
120
80
60
60
76
–
–
85:15
–
–
3[a]
OTf
OH
OAllyl
OAllyl
Br
OTf
OH
OH
OH
4[a]
20
–
–
5[b]
ꢀ78!20
97
94
–
84:16
77:23
–
[1] M. Gordaliza, P. A. García, J. M.
Miguel del Corral, M. A. Castro,
M. A. Gómez-Zurita, Toxicon
2004, 44, 441 – 459.
[2] For reviews, see: a) R. S. Ward,
Phytochem. Rev. 2003, 2, 391 –
400; b) R. S. Ward, Nat. Prod.
Rep. 1999, 16, 75 – 96; c) R. S.
Ward, Synthesis 1992, 719 – 730;
d) R. S. Ward, Tetrahedron 1990,
46, 5029 – 5041.
6[b]
20
7[b]
20
20
20
20
8[b]
–
–
9[b]
95
98
99
90:10
90:10
94:6
10[b]
11[b]
FeCl3 (5)
20
[a] HBF4 (4 equiv) and the correspondingnucleophile 2 (10 equiv) were dissolved in CH2Cl2, and alcohol
5 (50 mm in CH2Cl2) was added dropwise over a period of 30 min with a syringe pump. [b] Compound 2
(4 equiv) was used in the solvent indicated. [c] Yield of the isolated product. [d] The diastereomeric ratio
was determined by 1H NMR spectroscopy of the crude product. Tf=trifluoromethanesulfonyl.
7558
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 7557 –7559

Angewandte
Chemie
[3] R. C. Andrews, S. J. Teague, A. I. Meyers, J. Am. Chem. Soc.
1988, 110, 7854 – 7858.
[11] For recent reviews on iron catalysis, see: a) C. Bolm, J. Legros, J.
Le Paih, L. Zani, Chem. Rev. 2004, 104, 6217 – 6254; b) S.
Enthaler, K. Junge, M. Beller, Angew. Chem. 2008, 120, 3363 –
3367; Angew. Chem. Int. Ed. 2008, 47, 3317 – 3321.
[4] For the synthesis of enantiomerically pure (+)-or ( ꢀ)-podo-
phyllotoxin, see: a) R. Van Speybroeck, H. Guo, J. van der
Eycken, M. Vandewalle, Tetrahedron 1991, 47, 4675 – 4682;
b) E. J. Bush, D. W. Jones, J. Chem. Soc. Chem. Commun. 1993,
1200 – 1201; E. J. Bush, D. W. Jones, J. Chem. Soc. Perkin Trans. 1
1996, 151 – 155; c) S. B. Hadimani, R. P. Tanpure, S. V. Bhat,
Tetrahedron Lett. 1996, 37, 4791 – 4794; d) D. B. Berkowitz, S.
Choi, J.-H. Maeng, J. Org. Chem. 2000, 65, 847 – 860; e) A. J.
Reynolds, A. J. Scott, C. I. Turner, M. S. Sherburn, J. Am. Chem.
Soc. 2003, 125, 12108 – 12109.
[5] For the synthesis of (ꢀ)-epipodophyllotoxin, see: U. Engelhardt,
A. Sarkar, T. Linker, Angew. Chem. 2003, 115, 2591 – 2593;
Angew. Chem. Int. Ed. 2003, 42, 2487 – 2489, and references
therein.
[6] During our study, a formal total synthesis of (ꢁ )-podophyllo-
toxin was reported in which a Heck reaction was used for an
intramolecular arylation: F. Mingoia, M. Vitale, D. Madec, G.
Prestat, G. Poli, Tetrahedron Lett. 2008, 49, 760 – 763.
[7] a) K. Kondo, F. Mori, Chem. Lett. 1974, 741 – 742; b) F. Ishibashi,
E. Taniguchi, Bull. Chem. Soc. Jpn. 1988, 61, 4361 – 4366.
[8] C. Gnamm, S. Förster, N. Miller, K. Brödner, G. Helmchen,
Synlett 2007, 790 – 794.
[12] P. Rubenbauer, T. Bach, Adv. Synth. Catal. 2008, 350, 1125 –
1130.
[13] Besides the thermodynamic preference for the formation of
isomer 8 with a pseudoequatorial aryl group at C1, the higher
nucleophilicity of the trimethoxyphenyl group may favor attack
at the activated aldehyde carbon atom.
[14] a) H. A. Dieck, R. F. Heck, J. Am. Chem. Soc. 1974, 96, 1133 –
1136; b) R. F. Heck, Org. React. 1982, 27, 345 – 390; c) I. P.
Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009 – 3066;
d) K. Olofsson, H. Sahlin, M. Larhed, A. Hallberg, J. Org. Chem.
2001, 66, 544 – 549.
[15] For the synthesis of (ꢀ)-4-deoxy-4-methylenepodophyllotoxin
(9) from (ꢀ)-podophyllotoxin, see: E. Roulland, P. Magiatis, P.
Arimondo, E. Bertounesque, C. Monneret, Bioorg. Med. Chem.
2002, 10, 3463 – 3471.
[16] a) Y. Okude, S. Hirano, T. Hiyama, H. Nozaki, J. Am. Chem. Soc.
1977, 99, 3179 – 3181; b) T. Hiyama, K. Kimura, H. Nozaki,
Tetrahedron Lett. 1981, 22, 1037 – 1040; c) G. C. Hargaden, P. J.
Guiry, Adv. Synth. Catal. 2007, 349, 2407 – 2424; d) R. L. Halter-
man, C. Zhu, Tetrahedron Lett. 1999, 40, 7445 – 7448.
[17] For the synthesis of (ꢀ)-podophyllotoxon from (ꢀ)-podophyl-
lotoxin, see: P. H. Höfert, R. Matusch, Helv. Chim. Acta 1994, 77,
771 – 777.
[9] a) D. Stadler, T. Bach, Chem. Asian J. 2008, 3, 272 – 284; b) D.
Stadler, F. Mühlthau, P. Rubenbauer, E. Herdtweck, T. Bach,
Synlett 2006, 2573 – 2576; c) F. Mühlthau, D. Stadler, A. Goep-
pert, G. A. Olah, G. K. S. Prakash, T. Bach, J. Am. Chem. Soc.
2006, 128, 9668 – 9675.
[18] H. Yamaguchi, M. Arimoto, S. Nakajima, M. Tanoguchi, Y.
Funaka, Chem. Pharm. Bull. 1986, 34, 2056 – 2060.
[10] P. Rubenbauer, T. Bach, Tetrahedron Lett. 2008, 49, 1305 – 1309.
Angew. Chem. Int. Ed. 2008, 47, 7557 –7559
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7559