Scheme 6. Synthesis of Mimosifoliol and O-Me-Detrola
Scheme 7. Formal Synthesis of (()-Podophyllotoxina
a Reagents and conditions: (a) 2,5-dimethoxyphenol, 5 mol %
(dppm)Re(O)Cl3, 5 mol % KPF6, MeNO2, 65 °C, 69%. (b) TBAF,
THF, 0 °C, 92%. (c) H2, Pd/BaSO4, quinoline, EtOAc, rt, 91%. (d)
4-methylanisole, 5 mol % (dppm)Re(O)Cl3, 5 mol % KPF6, MeNO2,
65 °C, 90%. (e) Cy2BH, THF, 0 °C, then NaOH, H2O2, 90%.
Similarly, detrol (tolterodine) is available from Re(V)-
catalyzed functionalization of 4-methylanisole with propargyl
alcohol 11. The TMS-protected acetylene (13) smoothly
underwent hydroboration to carboxylic acid 14, which can
be converted into O-Me-detrol.11
a Reagents and conditions: (a) safrole, 5 mol % (dppm)Re(O)Cl3,
5 mol % AgPF6, MeNO2, 50 °C, 66%. (b) (i) NaI, AcOH, 115 °C,
76-92%; (ii) DIBAL-H, CH2Cl2, 0 °C, 77%. (c) Pd(OAc)2, PPh3,
Ag2CO3, PhH, 50 °C, 91%. (d) TBSCl, TEA, DMAP, CH2Cl2, rt,
89%. (e) (i) O2, hν, TPP, CCl4, 0 °C, 80%; (ii) Al(Hg), THF, H2O,
rt, 96%. (f) TBAF, THF, 0 °C, 96%. (g) Pb(OAc)4, NaHCO3,
CH2Cl2, 0 °C, 15 min, then PDC, 39%.
We also envisioned that the rhenium-catalyzed propargy-
lation reaction could provide rapid entry into cytotoxic
aryltertralin lactones such as podophyllotoxin.12 To this end,
rhenium-catalyzed coupling of ethyl propiolate 15 with
safrole yielded 16 in 66% as a ∼6:1 mixture of separable
regioisomers.13 Iodination followed by DIBAL-H reduction
provided a vinyl iodide14 that was employed in an intramo-
lecular Heck reaction15 to afford diene 17. After silyl
protection of the alcohol, the diene was photooxygenated
and reduced with Al(Hg)16 to give diol 18. Deprotection of
the silyl ether, followed by one-pot Pb(OAc)4 diol cleavage
and PDC oxidation, gave â-apopicropodophyllin. The con-
version of â-apopicropodophyllin to podophyllotoxin has
been previously described.12c
and gives water as the only byproduct. This reaction provides
a powerful and practical alternative for the construction of
aryl C-C bonds as exemplified by its application to synthesis
of benzhydryl-containing compounds such as podophyllo-
toxin. The regioselectivity of the propargylation is consistent
with that of electrophilic aromatic substitution; however, the
exact nature of the electrophile derived from the propargyl
alcohol remains unclear.17 Studies on the mechanism of the
propargylation reaction and development of this class of
reactions are ongoing in our laboratories.
Acknowledgment. We gratefully acknowledge the UC
Cancer Research Coordinating Committee, Merck Research
Laboratories, Amgen, Inc., and Eli Lilly & Co. for financial
support. J.J.K.S. thanks Eli Lilly & Co. for a graduate
fellowship. The Center for New Directions for Organic
Synthesis is supported by Bristol-Myers Squibb as a Spon-
soring Member and Novartis Pharma as a Supporting
Member.
In summary, we have developed a mild rhenium-catalyzed
reaction of aromatic compounds with propargyl alcohols for
the conversion of aryl and heteroaryl C-H bonds into C-C
bonds. The reaction is tolerant of air and moisture, and in
many cases requires only a slight excess of the nucleophile
(11) (a) Andersson, P. G.; Schink, H. E.; Osterlund, K. J. Org. Chem.
1998, 63, 8067. (b) Botteghi, C.; Corrias, T.; Marchetti, M.; Paganelli, S.;
Piccolo, O. Org. Process Res. DeV. 2002, 6, 379.
(12) (a) Lee, K.-S. Med. Res. ReV. 1999, 19, 569. (b) Gordaliza, M.;
Castro, M. A.; Miguel del Corral, J. M.; Lopez-Vazquez, M. L.; San
Feliciano, A.; Faircloth, G. T. Bioorg. Med. Chem. Lett. 1997, 7, 2781. (c)
Andrews, R. C.; Teague, S. J.; Meyers, A. I. J. Am. Chem. Soc. 1988, 110,
7854.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
(13) Small amount of a dimer of 15 was also isolated (see Supporting
Information)
OL049649P
(14) Piers, E.; Harrison, C. L.; Zetina-Rocha, C. Org. Lett. 2001, 3, 3245.
(15) (a) Achmatowicz, B.; Jankowski, P.; Wicha, J. Tetrahedron Lett.
1996, 37, 5589. (b) Mascarenas, J. L.; Garcia, A. M.; Castedo, L.; Mourino,
A. Tetrahedron Lett. 1992, 33, 4365.
(16) Nicolaou, K. C.; Gunzer, J. L.; Shi, G.-Q.; Agrios, K. A.; Gartner,
P.; Yang, Z. Chem. Eur. J. 1999, 5, 646.
(17) Reaction of 4b and 2-naphthol catalyzed by cationic ruthenium6b
complexes affords pyran 8, while our rhenium-catalyzed reaction exclusively
produces propargyl adduct 7b (Scheme 3). This suggests that the reactions
are proceeding through different mechanisms or nucleophilic attack on
different electrophilic intermediates.
Org. Lett., Vol. 6, No. 8, 2004
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