C O M M U N I C A T I O N S
Scheme 3. Alkoxysilanol-Facilitated Synthesis of 3
may be favored to afford [4 + 4] dimer 13. In contrast, dimerization
of unprotected monomer 4 to afford 2 may be facilitated by
hydrogen bonding through 17a (R ) H).1g
In summary, we have developed a strategy for the synthesis of
the epoxyquinol dimer RKB-3564 D employing an alkoxysilanol
protecting group to redirect the inherently favored [4 + 2]
dimerization of 2H-pyran monomers to a [4 + 4] manifold.
Preliminary mechanistic studies suggest that the [4 + 4] dimer-
ization may occur through a stepwise, ionic process. Further studies
to examine the scope of the dimerization process and further
applications are currently under investigation.
Scheme 4
Acknowledgment. Financial support from the American Cancer
Society (RSG-01-135-01) is gratefully acknowledged. We thank
Bristol-Myers Squibb for an Unrestricted Grant in Synthetic Organic
Chemistry (J.A.P, Jr.), Dr. Emil Lobkovsky (Cornell University)
for X-ray crystal structure analysis, and Prof. Daniel J. O’Leary
(Pomona College) for helpful discussions.
Scheme 5. RKB-3564 D Derivatives
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF), including X-ray
crystal structure coordinates for 3 and 6. X-ray crystallographic files
in CIF format. This material is available free of charge via the Internet
Scheme 6
References
(1) Isolation of epoxyquinol A: (a) Kakeya, H.; Onose, R.; Koshino, H.;
Yoshida, A.; Kobayashi, K.; Kageyama, S.-I.; Osada, H. J. Am. Chem.
Soc. 2002, 124, 3496. Epoxyquinol B: (b) Kakeya, H.; Onose, R.;
Yoshida, A.; Koshino, H.; Osada, H. J. Antibiot. 2002, 55, 829. Synthetic
studies: (c) Li, C.; Bardhan, S.; Pace, E. A.; Liang, M.-C.; Gilmore, T.
D.; Porco, J. A., Jr. Org. Lett. 2002, 4, 3267. (d) Shoji, M.; Yamaguchi,
J.; Kakeya, H.; Osada, H.; Hayashi, Y. Angew. Chem., Int. Ed. 2002, 41,
3192. (e) Shoji, M.; Kishida, S.; Takeda, M.; Kakeya, H.; Osada, H.;
Hayashi, Y. Tetrahedron Lett. 2002, 43, 9155. (f) Mehta, G.; Islam, K.
Tetrahedron Lett. 2003, 44, 3569. (g) Shoji, M.; Kishida, S.; Kodera, Y.;
Shiina, I.; Kakeya, H.; Osada, H.; Hayashi, Y. Tetrahedron Lett. 2003,
44, 7205.
(2) Osada, H.; Kakeya, H.; Konno, H.; Kanazawa, S. PCT Int. Appl. 2002,
WO 0288137.
(3) (a) Sieburth, S. McN.; Cunard, N. Tetrahedron 1996, 52, 6251. (b) Simig,
G.; Schlosser, M. Tetrahedron Lett. 1994, 35, 3081. (c) Sugiura, M.; Asai,
K.; Hamada, Y.; Hatano, K.; Kurono, Y.; Suezawa, H.; Hirota, M. Chem.
Pharm. Bull. 1998, 46, 1862.
We have found that dimer 3 is not stable and is converted to 2
at room temperature in the dark. This rearrangement is faster in
polar solvents,7 suggesting an ionic mechanism (Scheme 4).
Zwitterionic intermediate 14 may be generated by cleavage of the
C1-C1′ bond facilitated by the electron rich pyran oxygen.13 On
the other hand, dimer 3 may be stabilized by two secondary alcohols
through lowered electron density of the pyran oxygens by hydrogen
bonding.14 This may explain the relative instability of 3 in polar
solvents. To further support these assumptions, we prepared two
derivatives from 3 (Scheme 5). It was found that bis-bromobenzoate
derivative 15 rearranged to the corresponding epoxyquinol B
structure faster than 3 to 27 presumably due to the lack of secondary
alcohols to reduce the electron density of the pyran oxygens. In
contrast, tetraol 16 (prepared by diastereoselective reduction of 3)
was a stable compound likely due to the absence of a carbonyl as
an electron acceptor.
The previous discussion suggests that [4 + 4] dimerization of
12 may involve a related stepwise, ionic process.15 Initial C-C
bond formation to form zwitterionic intermediate 17 (Scheme 6)
may be facilitated by two intermolecular hydrogen bonds.12a By
rotation of the newly formed C-C bond, two possible products
may be produced. Formation of 17a and the resultant attack of the
oxonium ion by the R-carbon of the dienolate may be prohibited
by steric interactions between bulky alkoxysilanol substituents. To
alleviate steric congestion, formation of 17b and δ-carbon attack
(4) 1H NMR analysis (ref 2) shows seven proton signals and thus a symmetric
structure for RKB-3564 D.
(5) Ni(0): (a) Wender, P. A.; Tebbe, M. J. Synthesis 1991, 1089. Pd(0): (b)
Murakami, M.; Itami, K.; Ito, Y. Synlett 1999, 951.
(6) It was not possible to separate 4 and 4′ as both diastereomers (ap-
proximately 1:1) exist in equilibrium with small amount of the corre-
sponding aldehyde and dimerize quickly upon concentration.
(7) Synthetic (+)-3 was identical to natural (+)-3 (ref 2) by 1H and 13C NMR,
mass spectrum, and [R]D. See Supporting Information for details.
(8) For [2 + 2] cycloaddition of an enone and vinyl ether, see: Corey, E. J.;
Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem. Soc. 1964, 86,
5570.
(9) Shotwell, J. B.; Hu, S. J.; Medina, E.; Abe, M.; Cole, R.; Crews, C. M.;
Wood, J. L. Tetrahedron Lett. 2000, 41, 9639.
(10) In contrast to the results reported in ref 1g, we found that [4 + 2] dimers
were formed from 2H-pyrans 10 and 11 (neat, 40 h).
(11) For preparation of diisopropylalkoxysilanols, see: (a) Ushioda, M.;
Kadokura, M.; Moriguchi, T.; Kobori, A.; Aoyagi, M.; Seio, K.; Sekine,
M. HelV. Chim. Acta 2002, 85, 2930. (b) Quan, L. G.; Cha, J. K. J. Am.
Chem. Soc. 2002, 124, 12424.
(12) For an excellent review on organosilanols, including hydrogen bonding,
see: (a) Lickiss, P. D. AdV. Inorg. Chem. 1995, 42, 147. For an
aryldialkylsilanol-directed metalation, see: (b) Sieburth, S. McN.; Fen-
sterbank, L. J. Org. Chem. 1993, 58, 6314.
(13) The X-ray structure of 3 also shows a C1-C1′ distance of 1.567 Å (typical
Csp3-Csp3 distance is 1.49 Å - 1.54 Å).
(14) In the X-ray structure of 3, the distance between the secondary alcohol
and pyran oxygen is 3.1-3.3 Å which may be suitable for weak to
moderate intramolecular H-bonding, see Jeffrey, G. A. An Introduction
to Hydrogen Bonding; Oxford University Press: New York, 1997.
(15) In preliminary studies, we have been unable to trap any radical intermedi-
ates in the [4 + 4] process using agents including TEMPO and Bu3SnH.
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