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achievements of constitutional and stereochemical control
Enantioselective Synthesis of (þ)-Estrone Exploiting
a Hydrogen Bond-Promoted Diels-Alder Reaction
are closely associated with synthetic approaches toward
estrone and related estrogens. Beginning with Dane’s un-
successful attempt to synthesize rac-3 from diene 1 and
diketone 2,4 Valenta’s variant5 of Johnson’s synthesis6;
both starting from diene 17;is among the early applications
of Lewis acid catalyzed Diels-Alder reactions8 in natural
product synthesis. With the advent of effective chiral Lewis
acids, Dane’s concept regained attention. A TADDOL (R,R,
R0,R0-tetraaryl-1,3-dioxolane-4,5-dimethanol) based titanium
Lewis acid9 allowed Quinkert for the first time to implement
Dane’s original concept with high levels of constitutional
control and enantioselection.10 More recently Corey has
demonstrated the utility of his oxazaborolidinium catalysts
by synthesizing (þ)-estrone from diene 1.7b,c
€
Marko Weimar, Gerd Durner, Jan W. Bats, and
€
Michael W. Gobel*
Institut fu€r Organische Chemie und Chemische Biologie,
€
Goethe-Universitat Frankfurt, Max-von-Laue-Strasse 7,
D-60438 Frankfurt am Main, Germany
Received January 13, 2010
Although the field of enantioselective catalysis was domi-
nated in the past by metal containing catalysts, the past decade
has seen an important number of highly selective reactions
catalyzed by hydrogen bond donors such as chiral ureas and
thioureas.11 The acceleration of Diels-Alder reactions by
hydrogen bonds was reported even prior to Lewis acid
catalysis.12 However, when compared to traditional strong
Lewis acids, hydrogen bond donors are mostly considered to
be rather weak electrophiles that are inferior at least in terms
of rates. In contrast to this view, we will show below that a
metal free catalyst forming up to three hydrogen bonds with
diketone 2 promotes the Diels-Alder reaction with diene 1 as
efficiently as the best titanium TADDOLates used earlier in
this step, thus leading to a new organocatalytic variant of the
Quinkert-Dane synthesis of (þ)-estrone (Scheme 1).
Starting from Dane’s diene and methylcyclopentenedione,
(þ)-estrone is synthesized along the Quinkert-Dane route
in 24% total yield. The key step is an enantioselective Diels-
Alder reaction promoted by an amidinium catalyst as
efficiently as by a traditional Ti-TADDOLate Lewis acid.
In previous studies we demonstrated the hydrogen bond-
mediated complexation of diketone 2 and lipophilic amidinium
ions, resulting in a significant acceleration of the cycloaddition
with Dane’s diene 1.13 Axially chiral amidine 8a14 was intended
to form three hydrogen bonds with dienophile 2.15 However,
Estrone 7, due to its relatively simple structure and its
considerable pharmaceutical importance, has become;and
still is;a most popular target compound for the develop-
ment of novel synthetic methodologies.1,2 This applies in
particular to the Diels-Alder reaction:3 numerous milestone
(1) Selected classical syntheses: (a) Anner, G.; Miescher, K. Helv. Chim.
Acta 1948, 31, 2173–2183. (b) Ananchenko, S. N.; Torgov, I. V. Tetrahedron
€
Lett. 1963, 4, 1553–1558. (c) Rufer, C.; Schroder, E.; Gibian, H. Justus
Liebigs Ann. Chem. 1967, 701, 206–216. (d) Cohen, N.; Banner, B. L.; Eichel,
(4) (a) Dane, E.; Schmitt, J. Liebigs Ann. Chem. 1938, 536, 196–203. (b)
Dane, E.; Schmitt, J. Liebigs Ann. Chem. 1939, 537, 246–249. (c) Singh, G. J.
Am. Chem. Soc. 1956, 78, 6109–6115.
(5) Das, J.; Kubela, R.; MacAlpine, G. A.; Stojanac, Z.; Valenta, Z. Can.
J. Chem. 1979, 57, 3308–3319.
€
W. F.; Parrish, D. R.; Saucy, G.; Cassal, J.-M.; Meier, W.; Furst, A. J. Org.
Chem. 1975, 40, 681–685. (e) Eder, U.; Gibian, H.; Haffer, G.; Neef, G.;
Sauer, G.; Wiechert, R. Chem. Ber. 1976, 109, 2948–2953. (f) Bartlett, P. A.;
Johnson, W. S. J. Am. Chem. Soc. 1973, 95, 7501–7502.
(6) Cole, J. E., Jr.; Johnson, W. S.; Robins, P. A.; Walker, J. J. Chem. Soc.
1962, 244–278.
(7) For more recent syntheses of estrone starting from Dane’s diene 1, see:
(a) Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 1996, 37, 7403–7406. (b)
Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 5984–5986.
(c) Canales, E.; Corey, E. J. Org. Lett. 2008, 10, 3271–3273.
(8) Yates, P.; Eaton, P. J. Am. Chem. Soc. 1960, 82, 4436–4437.
(9) Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.; Wonnacott, A.
Helv. Chim. Acta 1987, 70, 954–974.
(2) Selected recent syntheses: (a) Quellet, L.; Langlois, P.; Deslongchamps,
€
P. Synlett 1997, 689–690. (b) Tietze, L. F.; Nobel, T.; Spescha, M. J. Am. Chem.
Soc. 1998, 120, 8971–8977. (c) Pattenden, G.; Gonzales, M. A.; McCulloch, S.;
Walter, A.; Woodhead, S. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12024–
12029. (d) Lim, C.; Evenson, G. N.; Perrault, W. R.; Pearlman, B. A.
Tetrahedron Lett. 2006, 47, 6417–6420. (e) Soorukram, D.; Knochel, P. Org.
Lett. 2007, 9, 1021–1023. (f) Yeung, Y.-Y.; Chein, R. J.; Corey, E. J. J. Am.
€
(10) (a) Quinkert, G.; Del Grosso, M.; Bucher, A.; Bats, J. W.; Durner, G.
Tetrahedron Lett. 1991, 32, 3357–3360. (b) Quinkert, G.; Del Grosso, M.;
ꢀꢁ
Chem. Soc. 2007, 129, 10346–10347. (g) Herrmann, P.; Budesı
ꢂ
nsky, M.;
´
€
€
Kotora, M. J. Org. Chem. 2008, 73, 6202–6206.
Bucher, A.; Bauch, M.; Doring, W.; Bats, J. W.; Durner, G. Tetrahedron
€
Lett. 1992, 33, 3617–3620. (c) Quinkert, G.; Del Grosso, M.; Doring, A.;
(3) Synthesis of estrogens by intramolecular Diels-Alder reactions of o-
quinodimethanes: (a) Kametani, T.; Matsumoto, H.; Nemoto, H.; Fuku-
moto, K. J. Am. Chem. Soc. 1978, 100, 6218–6220. (b) Funk, R. L.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102, 5253–5261. (c) Oppolzer,
W.; Roberts, D. A. Helv. Chim. Acta 1980, 63, 1703–1705. (d) Grieco, P. A.;
Takigawa, T.; Schillinger, W. J. J. Org. Chem. 1980, 45, 2247–2251. (e) Ito,
Y.; Nakatsuka, M.; Saegusa, T. J. Am. Chem. Soc. 1981, 103, 476–477. (f)
Quinkert, G.; Schwartz, U.; Stark, H.; Weber, W.-D.; Adam, F.; Baier, H.;
€
Doring, W.; Schenkel, R. I.; Bauch, M.; Dambacher, G. T.; Bats, J. W.;
Zimmermann, G.; Durner, G. Helv. Chim. Acta 1995, 78, 1345–1391.
€
(11) (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–
1543. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743.
(12) (a) Wassermann, A. J. Chem. Soc. 1942, 618–621. (b) Rubin, W.;
Steiner, H.; Wassermann, A. J. Chem. Soc. 1949, 3057.
€
(13) Schuster, T.;Kurz, M.;Gobel, M. W. J. Org. Chem. 2000, 65, 1697–1701.
€
€
€
(14) (a) Lehr, S.; Schutz, K.; Bauch, M.; Gobel, M. W. Angew. Chem., Int.
Frank, G.; Durner, G. Liebigs Ann. Chem. 1982, 1999–2040. (g) Hakuba, H.;
€
Ed. 1994, 33, 984–986. (b) Schuster, T.; Gobel, M. W. Synlett 1999, 966–968.
Kitagaki, S.; Mukai, C. Tetrahedron 2007, 63, 12639–12645. (h) Djuric, S.;
Sarkar, T.; Magnus, P. J. Am. Chem. Soc. 1980, 102, 6885–6886. (i) Nicolaou,
K. C.; Barnette, W. E.; Ma, P. J. Org. Chem. 1980, 45, 1463–1470.
€
€
(15) Schuster, T.; Bauch, M.; Durner, G.; Gobel, M. W. Org. Lett. 2000,
2, 179–181.
2718 J. Org. Chem. 2010, 75, 2718–2721
Published on Web 03/19/2010
DOI: 10.1021/jo100053j
r
2010 American Chemical Society