influence the facial selectivity of the Wolff-Kishner reduc-
tion of the C(1) carbonyl, thereby allowing us to stereospe-
cifically prepare dienes 13-r and 13-ꢀ. Intramolecular
addition of the C(19) hydroxyl group to the C(1),C(10)-
double bond would generate a tetrahydrofuran ring and
introduce the C(10)-stereocenter (i.e., 13-r f 14-r) and
oxidation of the aromatic C-ring of 14-r to a p-benzoquinone
would complete the synthesis of 1. Removal of the protecting
group from ether 13-ꢀ would afford an alcohol that would
be oxidized to a carboxylic acid. Subsequent lactone forma-
tion (cf. 15-ꢀ) and oxidation of the C-ring would culminate
in the synthesis of 5-epi-icetexone (3). Similarly, oxidation
of alcohol 13-r to a carboxylic acid, followed by lacton-
ization (cf. 15-r) and oxidation of the C-ring, would furnish
icetexone (2).
Scheme 1. Failed Strategy
Our synthetic strategy required us to prepare a chiral
3-alkoxycyclohexenone derivative (Scheme 3). In 1999,
Yamada and co-workers prepared (-)-3-ethoxy-6-hydroxy-
methyl-6-methylcyclohex-2-en-1-one (-)-16 in high e.e. via
an enzymatic resolution of racemic 16;13 hence, this optically
active starting material was easy to prepare. The next step
was to couple the A- and C-rings using an alkylation.
However, we were concerned that (-)-16 could undergo a
retro-Aldol fragmentation faster than alkylation, so a suitable
protecting group was needed to preclude this. The ideal
protecting group had to be stable to both protic and Lewis
acids, and the conditions for its removal had to be tolerant
of olefins, ketones, and aryl methyl ethers. After careful
consideration, enantiomerically enriched alcohol (-)-16
(99% e.e.) was converted to benzyl ether 17. In 1994 we
synthesized bromide 18 from vanillin via an eight-step
sequence but in only 25% overall yield.14 Here we report
that 18 can be prepared in large quantities and in >45%
overall yield from carvacrol (19)15 via a six-step sequence.
In the first step, carvacrol was brominated in acetic acid to
give a dibromide-phenol, which was then methylated to give
ether 20. Arene 20 was treated with NBS to form a benzyl
bromide, which was immediately treated with sodium actetate
to give acetate 21 in 70% overall yield. Treatment of
dibromide 21 with excess copper(I) methoxide16 substituted
methoxy groups for the two bromines and liberated alcohol
22 via transesterification. Alcohol 22 was then converted to
bromide 18 using PBr3.
route. Second, in our synthesis of (-)-salviasperanol,3c
treatment of enynone 8 with excess BF3-etherate and a
catalytic quantity of ethanethiol gave dienone 9 in 94% yield
(Scheme 2). Incorporating this observation into our icetexone
Scheme 2. Prior Results and Retrosynthetic Analysis
In 1981, Smith and co-workers alkylated 3-isobutoxy-6,6-
dimethylcyclohexen-2-en-1-one with iodomethane at the
R-position in 61% yield using LDA and HMPA.17 In our
hands, treatment of the enolate derived from 17 with bromide
18 using the reported conditions gave predominantly bis-
alkylation. Fortunately, replacing HMPA with DMPU pro-
strategy would allow us to efficiently introduce the C(6),C(7)-
doublebond.Afinalobservation4b wasthattheWolff-Kishner
reduction of dienone 9 produces diene (()-10 having a
double bond at C(6),C(7)11 and a trisubstituted double bond
at C(1),C(10), which would enable us to functionalize the
C(10) position.12 These observations led us to prepare
enynone 11, an analogue of 8, with the requisite stereo-
chemistry at C(4) and an additional methoxy substituent at
C(14). Cyclization of 11 would produce dienone 12 with a
C(6),C(7)-double bond and a fully substituted C-ring. We
were hopeful that the asymmetric center at C(4) would
(13) Miyaoka, H.; Kajiwara, Y.; Hara, M.; Suma, A.; Yamada, Y.
Tetrahedron: Asymmetry 1999, 10, 3189–3196.
(14) Majetich, G.; Zhang, Y. J. Am. Chem. Soc. 1994, 11, 4979–4980.
(15) Kjonaas, R. A.; Mattingly, S. P. J. Chem. Educ. 2005, 82, 1813–
1814.
(16) (a) Manchand, P. S.; Townsend, J. M.; Belica, P. S.; Wong, H. S.
Synthesis 1980, 409–410. (b) So¨derberg, B. C.; Fields, S. L. Org. Prep.
Proceed. Int. 1996, 2, 221–225.
(17) Smith, A. B.; Levenberg, P. A.; Jerris, P. J.; Scarborough, R. M.;
Wovkulich, P. M. K. J. Am. Chem. Soc. 1981, 103, 1501–1513.
(18) Suzuki, A.; Hara, S.; Satoh, Y.; Miyaura, N. Bull. Chem. Soc. Jpn.
1986, 59, 2029–2031.
(11) Li, Y. Ph.D. Dissertation, University of Georgia, Athens, GA 2006.
(12) Gonzalo Blay, G.; Garcia, B.; Molina, E.; Pedro, J. R. J. Org. Chem.
2006, 71, 7866–7869.
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