Intramolecular alkylative arylation of oxabicylic alkene: A potential diene approach for the synthesis of estrone and analogous steroid structures

Article abstract of DOI:10.1021/ol049618u

Regioselective and stereospecific intramolecular alkylative arylation of unsaturated oxabicyclic diol 6, mediated by Lewis acid or strong protic acid to give the tetracyclic products 7a and 7b, as shown above, represents the first example of an electrophilic (cationic in character) ring-opening-cyclization of oxabicyclic alkene. This constitutes the key cyclization step for a long-standing and potentially useful diene approach for the synthesis of estrone and analogous steroid structures.

Full text of DOI:10.1021/ol049618u

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1333-1335
Intramolecular Alkylative Arylation of
Oxabicylic Alkene: A Potential Diene
Approach for the Synthesis of Estrone
and Analogous Steroid Structures†
,‡
Wei-Dong Z. Li* and Kun Wei
National Laboratory of Applied Organic Chemistry, Lanzhou UniVersity,
Lanzhou 730000, China
wdli@fas.harVard.edu
Received March 1, 2004
ABSTRACT
Regioselective and stereospecific intramolecular alkylative arylation of unsaturated oxabicyclic diol 6, mediated by Lewis acid or strong protic
acid to give the tetracyclic products 7a and 7b, as shown above, represents the first example of an electrophilic (cationic in character)
ring-opening−cyclization of oxabicyclic alkene. This constitutes the key cyclization step for a long-standing and potentially useful diene approach
for the synthesis of estrone and analogous steroid structures.
Estrone (1) and analogous steroids are physiologically highly
active compounds, and thus a variety of synthetic strategies
Figure 1.
An interesting early synthetic approach explored by
Cohen3 in 1935 is shown in eq 1, in which the attempted
and methods have been developed for this important class
(2) For recent examples, see: (a) Tsogoeva, S. B.; Du¨rner, G.; Bolte,
M.; Go¨bel, M. W. Eur. J. Org. Chem. 2003, 1661. (b) Schuster, T.; Kurz,
M.; Go¨bel, M. W. J. Org. Chem. 2000, 65, 1697. (c) Quinkert, G.; Grosso,
M. D.; Do¨ring, A.; Do¨ring, W.; Schenkel, R. I.; Bauch, M.; Dambacher,
of substances,1 among which the diene cycloaddition ap-
proaches are the most extensively studied.2
G. T.; Bats, J. W.; Zimmermann, G.; Du¨rner, G. HelV. Chim. Acta. 1995,
† In memory of the late R. B. Woodward.
78, 1345. (d) Quinkert, G.; del Grosso, M.; Bucher, A.; Bauch, M.; Do¨ring,
W.; Bats, J. W.; Du¨rner, G. Tetrahedron Lett. 1992, 33, 3617. (e) Tanaka,
K.; Nakashima, H.; Taniguchi, T.; Ogasawara, K. Org. Lett. 2000, 2, 1915.
(f) Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 1996, 37, 7403. (g) Rigby,
J. H.; Warshakoon, N. C.; Payen, A. J. J. Am. Chem. Soc. 1999, 121, 8237.
‡ Current address: Department of Chemistry and Chemical Biology,
Harvard University, 12 Oxford Street, Cambridge, MA 02138.
(1) For reviews, see: (a) Groen, M. B.; Zeelen, F. J. Recl. TraV. Chim.
Pays-Bas 1986, 105, 465. (b) Zeelen, F. J. Nat. Prod. Rep. 1994, 11, 607.
10.1021/ol049618u CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/19/2004

intramolecular cyclization of a diene-maleic anhydride (MA)
adduct 3 to an analogous structure 2 was unsuccessful.
Woodward had investigated4 this approach in 1940 at MIT,
in which furan derivatives 4a and 4b were employed as the
dienes5 for the Diels-Alder cycloaddition with MA (eq 2).
However, due to some difficulties in the catalytic hydrogena-
tion of cycloadducts 5a and 5b,6 the subsequent assumed
acid-mediated isomerization-cyclization7 of the postulated
dihydro derivatives of 5a and 5b to establish estrone analogue
2 or related structures was left unverified, due presumably
to the ready dissociation of cycloadducts 5a and 5b via retro-
Diels-Alder process.4,8
In connection with our general program on the develop-
ment of novel strategy for stereocontrolled terpenoid syn-
thesis based on the cationic ring-opening-cyclization of
oxabicyclic alkenes,9 we report here a successful realization
of the aforementioned strategic approach to estrone-like
steroid structures attempted by Cohen and Woodward many
decades ago, via a novel electrophilic cyclization of the
unsaturated oxabicyclic intermediate.10 To prevent the ready
dissociation of the Diels-Alder cycloadduct 5, the labile
adduct 5b11 was directly reduced by LiAlH4 in THF to give
the corresponding oxabicyclic diol 6 (Scheme 1). The
(i.e., MeSO3H or CF3SO3H) were found to be effective to
promote the intramolecular alkylative arylation of unsaturated
oxabicycle 6 to give dehydrated tetracyclic products 7a (more
polar) and 7b in a ratio of ca. 3:1 (para vs ortho cyclization)12
and in an overall yield of 70%, while relatively weaker Lewis
acids such as EtAlCl2, MgI2, or ZnI2, as well as weaker protic
acids (i.e., CH3CO2H, HCO2H, or CF3CO2H), resulted in no
apparent reaction (starting material was recovered). The
reactions are generally carried out in a dilute (<0.1 M)
solution of CH2Cl2 at 0 °C to ambient temperature with 30
mol % acid catalyst.13 In contrast, the saturated oxabicycles
8a and 8b14 did not yield any intramolecular arylation product
under a variety of acidic conditions, and underwent instead
epoxy ring-opening to give cyclohexene derivatives 9a and
9b, respectively, on treatment with strong protic acids (i.e.,
CF3SO3H or MeSO3H) in moderate yields (eqs 3 and 4).
These results indicated that the previously assumed4a,7 acid-
mediated isomerization-cyclization of analogous precursors
(vide supra) leading to a steroid skeleton would not take place
readily even under strongly acidic conditions.
Scheme 1a
It is apparent that the presence of the olefinic function in
the unsaturated oxabicyclic ring system is crucial for the
observed cyclization reaction. It is important to note that the
trans-fused BC ring system was formed exclusively in this
intramolecular cationic cyclization, presumably via a con-
certed pathway of exo-SN2′ type as illustrated in eq 5, which
involves consecutive epoxy ring-opening, olefinic double-
bond transposition, and para-selective alkylative arylation,15
a Conditions: (a) LiAlH4, THF, 0 °C to rt, 40% from 4b. (b)
Lewis acid or protic acid (see text).
designated acid-mediated cyclization reaction of 6 was
examined next.
To our delight, common strong Lewis acids such as
TMSOTf, BF3‚(OEt2), TiCl4, or SnCl4 and strong protic acids
(10) For a recent account on the transition metal-catalyzed nucleophilic
alkylative ring-opening of oxabicyclic alkenes and synthetic applications,
see: Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48.
For an excellent review on Using Ring-Opening Reactions of Oxabicyclic
Compounds as a Strategy in Organic Synthesis, see: Chiu, P.; Lautens, M.
Top. Curr. Chem. 1997, 190, 1-85. For some recent examples, see also:
(a) Nakamura, M.; Matsuo, K.; Inoue, T.; Nakamura, E. Org. Lett. 2003,
5, 1373. (b) Arrayas, R. G.; Cabrera, S.; Carretero, J. C. Org. Lett. 2003,
5, 1333. (c) Lautens, M.; Hiebert, S. J. Am. Chem. Soc. 2004, 126, 1437.
(11) Obtained as a crude exo-isomeric (>50:1) adduct; see also ref 8.
(12) For an earlier similar regioselective cationic intramolecular arylation,
see: (a) Bartlett, P. A.; Johnson, W. S. J. Am. Chem. Soc. 1973, 95, 7501.
(b) Bartlett, P. A.; Brauman, J. I.; Johnson, W. S.; Volkmann, R. A. J. Am.
Chem. Soc. 1973, 95, 7502. (c) Groen, M. B.; Zeelen, F. J. Recl. TraV.
Chim. Pays-Bas 1979, 98, 239 and earlier papers in this series.
(13) No apparent reaction occurred at lower temperature; see Supporting
Information for a typical experimental procedure.
(14) Prepared from the corresponding unsaturated precursors (i.e., 6) by
catalytic hydrogenation in MeOH over 10% Pd-C at ambient temperature.
(15) For a recent example of acid-catalyzed intramolecular arylation,
see: Harrowven, D. C.; Tyte, M. J. Tetrahedron Lett. 2004, 45, 2089.
(3) (a) Cohen, A. J. Chem. Soc. 1935, 429. (b) Cohen, A. Nature 1935,
869. (c) Cohen, A.; Warren, F. L. J. Chem. Soc. 1937, 1315.
(4) (a) Woodward, R. B. J. Am. Chem. Soc. 1940, 62, 1478. (b)
Woodward, R. B. A Synthetic Attack on the Oestrone Problem. Ph.D.
Thesis, Massachusetts Institute of Technology, Cambridge, MA, 1937. (c)
Woodward, R. B. Preliminary Studies in the Synthesis of the Polynuclear
Hydroaromatic Ring Systems. B.S. Thesis, Massachusetts Institute of
Technology, Cambridge, MA, 1936.
(5) Diels, O.; Alder, K. Liebigs Ann. Chem. 1931, 490, 243.
(6) Catalytic hydrogenation (over Pd-C) of analogous intermediates can
be carried out smoothly in alcoholic solvent (vide infra); see also footnote
12 in ref 4.
(7) Cf.: (a) Cook, J. W.; Hewett, C. L. J. Chem. Soc. 1933, 1098. (b)
Cook, J. W.; Hewett, C. L. J. Chem. Soc. 1934, 365. (c) Cook, J. W.; Hewett,
C. L.; Girard, A. J. Chem. Soc. 1934, 653.
(8) Woodward, R. B.; Baer, H. J. Am. Chem. Soc. 1948, 70, 1161.
(9) Zhang, Z.; Li, W.-D. Z.; Li, Y. Org. Lett. 2001, 3, 2555.
1334
Org. Lett., Vol. 6, No. 8, 2004

along with the facile dehydrative tetrahydrofuran ring forma-
tion. The structures of the tetracycles 7a and 7b were fully
characterized by extensive spectroscopic analysis (including
NOE and two-dimensional NMR) and confirmed furthermore
by the following chemical transformations (Scheme 2): (1)
that it is more convenient to reduce the olefination product
13 by magnesium in absolute methanol to give 4b in nearly
18
quantitative yield (Scheme 3).
Scheme 3a
Scheme 2a
t
a Conditions: (a) (i) Ph3P, benzene; (ii) BuOK, THF, then
furfural, 0 °C to rt, 82%. (b) Mg, MeOH, reflux, 98%.
In summary, the key cyclization step of a long-standing
strategic diene approach19 directed toward the synthesis of
estrone and analogous steroid structures was realized via a
novel acid-catalyzed regioselective and stereospecific in-
tramolecular alkylative arylation of oxabicyclic alkene
intermediates. The success of the electrophilic (cationic)
cyclization of unsaturated oxabicyclics initiated by acid-
mediated 1,4-epoxy ring-opening20 should provoke the
investigation of cyclization of substrates bearing other
π-nucleophiles (i.e., olefinic or electron-rich systems) and
implies further application of oxabicyclic alkene as a
stereocontrolling template21 for natural product synthesis.
Studies along these lines are under way in our laboratory.
a Conditions: (a) H2, 10% Pd-C, MeOH, 96%. (b) Cat.
p-TsOH‚H2O, benzene, reflux, 80%.
catalytic hydrogenation of 7a gave the corresponding dihydro
derivative 10 (mp 144-145 °C), and (2) ready dehydration
on treatment with p-TsOH in refluxing benzene produced
the sole elimination product 11 in 80% yield. The chemical
structures of both 10 and 11 were verified by spectroscopic
methods.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (Distinguished Youth Fund
29925204; Funds 20021001 and 20172022) and Ministry of
National Education of China (Funds 99114 and 2000-66)
for financial support. The Cheung Kong Scholars program
is gratefully acknowledged.
To the best of our knowledge, this is the first example of
an acid-mediated cationic intramolecular alkylative cycliza-
tion16 of an oxabicyclic alkene initiated by the epoxy ring-
opening, although various catalytic nucleophilic ring-opening
reactions of oxabicyclic alkenes have been studied exten-
sively.10 Since the tetracyclic product 7a is of great potential
for further elaboration to the analogous steroid structures,17
the synthetic method demonstrated herein represents a novel
diene cycloaddition approach for steroids.
Supporting Information Available: Experimental pro-
cedures and spectral data of compounds 4b, 6, 7a, 7b, 9a,
9b, 10, 11, and 13. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL049618U
(18) Cabares, J.; Mavoungou-Gomes, L. Bull. Soc. Chim. Fr. 1986, 401.
(19) Introduction of the angular methyl on the steroid framework by this
approach would be possible by employing citraconic anhydride as a
dienophile in the furano Diels-Alder cycloaddition stage; cf. ref 4c and
see also: Corey, E. J. The Condensation of Citraconic and Maleic
Anhydrides with Chloroprene and Ethoxyprene. B.S. Thesis, Massachusetts
Institute of Technology, Cambridge, MA, 1948.
Although Woodward had described the synthesis of furano
diene precursors 4a and 4b in some detail in 1940,4 we found
(20) This mode of initiation could be regarded as a novel type of initiating
method for cationic π-cyclization, compared with other well-known methods
based on other oxy-functional units (i.e., epoxide, allylic alcohol, acetal).
Cf.: ref 9 for an earlier example.
(21) An asymmetric furano Diels-Alder cycloaddition to optically pure
oxabicycle 6 or analogue would ensure an enantiocontrolled synthesis based
on this strategy.
(16) For the only example of intramolecular anionic alkylative ring-
opening-cyclization of oxabicyclic alkenes, see: Lautens, M.; Kumanovic,
S. J. Am. Chem. Soc. 1995, 117, 1954.
(17) Cf., synthesis of equilin and equilenin: (a) Zderic, J. A.; Carpio,
H.; Bowers, A.; Djerassi, C. Steroids 1963, 1, 233. (b) Stein, R. P.; Buzby,
G. C., Jr.; Smith, H. Tetrahedron Lett. 1966, 7, 5015.
Org. Lett., Vol. 6, No. 8, 2004
1335