giving the desired adduct 8 with complete diastereoselec-
tivity (Scheme 2). Treatment of 8 with potassium hydro-
xide and sodium borohydride in methanol provided a
mixture of lactone 9 and ester 10 without loss of the
enantiomeric purity. The mixture was subjected to amino-
lysis to provide dimethylamide 11. Propargylation of the
hydroxy group, reductive cleavage of the amide moiety,10
followed by mesylation of the resulting alcohol, afforded
12. Subsequent deprotection ofthe catechol was conducted
in a two-step sequence.11 Oxidation of the methylenedioxy
moiety with lead tetraacetate provided an acetoxydioxolan.
The ensuing methanolysis under basic conditions liberated
the catechol, which underwent an intramolecular SN2 reac-
tion to give the desired phenol 5 in good yield.
converged into a single epimer by treatment with CSA in
methanol to give 13. We next pursued the construction of
the other quaternary stereogenic center by utilizing the
steric bias of the bicylclo [2.2.2] system. Homologation of
the ketone moiety in 13 was effected using a HornerÀ
WadsworthÀEmmons reaction to give an unsaturated
ester as a single isomer.12 This was then reduced with
lithium aluminum hydride to provide 14. After alkylation
with iodomethyltributyltin,13 a facile [2,3]-Wittig rear-
rangement14 proceeded diastereoselectively, on treatment
with methyllithium in the presence of HMPA, to give a
homoallyl alcohol,15 which was benzylated to furnish 15.
Scheme 3. Construction of the Quaternary Stereogenic Centers
Scheme 2. Synthesis of Phenol 5
Having successfully constructed the quaternary stereo-
genic center, which corresponds to the spiro carbon, we
turned our attention to cleaving the bicyclo [2.2.2] skeleton
(Scheme 4). When 15 was subjected to careful ozonolysis,
the most electron rich and constrained trisubstituted dou-
ble bond underwent selective cleavage to give, after isom-
erization of the double bond by treatment with potassium
carbonate, ketoaldehyde 16. Thus, the highly substituted
cyclohexane core of anisatin was established.
The ketoaldehyde was reduced tothe corresponding diol
whose primary alcohol was then protected with a TIPS
group. Conversion of 17 to 18 by Chugaev elimination16
set the stage for construction of the cyclopentene ring.
Thus, acidic hydrolysis of the ketal was followed by
conversion of the resulting primary alcohol to iodide 19.
Upon treatment with tert-butyllithium, Barbier-type cycli-
zation took place to give a cyclopentanol, which was
dehydrated with Burgess reagent17 to afford 20.
We next focused on the intramolecular DielsÀAlder
reaction to construct the bicyclo [2.2.2] skeleton (Scheme 3).
Phenol 5 was treated with iodobenzene diacetate in
methanol to give a 1:1 diastereomeric mixture of ortho-
quinone monoketals 4 (P = Me). Upon heating in toluene
to reflux, both diastereomers underwent a DielsÀAlder
reaction6 to furnish tetracyclic adducts as a mixture of the
epimers at the ketal moiety. The mixture could easily be
(6) For reviews, see: (a) Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res.
2002, 35, 856. (b) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev.
2004, 104, 1383. (c) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron
2010, 66, 2235. (d) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed.
2011, 50, 4068.
(12) An X-ray crystallographic study of the R,β-unsaturated ester
revealed that the bicyclo[2.2.2]octadiene skeleton was twisted by the
ether and the ketal linkages, and the carbonyl group leaned to the
opposite side of the methoxy group.
(7) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
ꢀ
4229. (b) Navarro, C.; Moreno, A.; Csaky, A. G. J. Org. Chem. 2009, 74,
466. For reviews of the rhodium-catalyzed 1,4-addition, see: (g) Fagnou,
K.; Lautens, M. Chem. Rev. 2003, 103, 169. (h) Hayashi, T.; Yamasaki, K.
Chem. Rev. 2003, 103, 2829.
(8) Caturla Javaloyes, J. F.; Vidal Gispert, L.; Lumeras Amador, W.
WO2008/017461, 2008.
(9) Moradei, O. M.; Paquette, L. A. Org. Synth. 2003, 80, 66.
(10) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(11) Ikeya, Y.; Taguchi, H.; Yoshioka, I. Chem. Pharm. Bull. 1981,
29, 2893.
(13) Seitz, D. E.; Carroll, J. J.; Cartaya, M. C. P.; Lee, S.; Zapata, A.
Synth. Commun. 1983, 13, 129.
(14) (a) Depuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431. (b)
Nace, H. R. Org. React. 1962, 12, 57.
(15) In addition to the steric bias of the bicyclo [2.2.2] system, the
stereoselectivity of the [2,3]-Wittig rearrangement may be effected by
coordination of both the methoxy group and the ether linkage to the
lithium atom in the lithiated intermediate.
(16) Nakai, T.; Mikami, K. Org. React. 1994, 46, 105.
(17) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744.
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