the starting material and partially alkylated products. How-
ever, reaction of TBS ether derivative 8b with 95% NaH in
refluxing DME followed by diiodide 9b addition afforded a
mixture of starting material and product (16%). Formation
of spiro ketone 7b was significantly improved when alkylated
with mesylate 9c6c to provide a ∼1:2 mixture of starting
material and product (48%). However, the mixture of starting
material and product could be separated by neither column
chromatography nor HPLC. Therefore, it was essential to
drive the reaction to completion. After a few manipulations,
the best results were obtained by refluxing 8b in THF (0.15
M) with 95% NaH (3.5 equiv) for 3 h, followed by addition
of mesylate (1.5 equiv) at 60 °C for 2 h. Further addition of
0.5 equiv of the mesylate 9c (0.5 equiv) over 2 h provided
a respectable yield of the spiro-product 7b (60%, with an
average yield of 78% for each alkylation). Reaction can be
easily carried out on 5 g scale without deterioration of
reaction yields. Furthermore, excess dimesylate 9c (0.5 equiv)
was easily recovered by trituration of the crude reaction
mixture with hexanes. After successful spiro annulation, we
focused on the olefination reaction of highly hindered spiro
ketone 7b. Wittig olefination of spiro ketone 7b using either
Corey’s reagent (Ph3PdCHLi)10a or the Tebbe10b reaction
provided only low conversion. We attempted the mild and
efficient direct methylenation reported by Yan.11 In our first
attempt, alkene 10 was isolated in 40% yield (80% conver-
sion). This highly functionalized substrate 7b seems to be
sensitive to the reaction conditions. After several attempts,
reaction of spiro-ketone 7b with TiCl4 (4 equiv, 1 M THF),
Mg powder (10 equiv) in DCM-THF (1:1.5, 0.2 M) at 0
°C to rt delivered spiro-alkene 10 (47% yield).
Scheme 1. Retrosynthesis
penyl cuprate addition and hydrogenation of both double
bonds. The tricyclic core of cyanthiwigin AC (6) would be
constructed in enantiopure form from (+)-Hajos-Parrish
ketone via a sequence featuring deconjugative spiro-bis-
alkylation 75,6 followed by isomerization of the double bond
in ring A.
Deprotection of the TBS ether 10 with TBAF followed
by oxidation of the resultant secondary alcohol with Dess-
Martin (D-M) periodinane afforded cyclopentanone deriva-
tive 11 (68% yield from TBS ether). Now the stage was set
for the isomerization of the trisubstituted double bond.
Attempts to isomerize the double bond using either KOH in
methanol12 or concd HCl failed. However, stirring of
cyclopentanone derivative 11 with NaOMe in methanol at
rt cleanly delivered cis-hydrindenone derivative 6 (95%
yield) as the sole product. Tentative assignment of the cis-
ring junction for compound 6 is based on literature prece-
dence,12 which secures the natural product stereochemistry.
After obtaining enone 6 in sufficient quantities, introduction
of the isopropyl group via a 1,4 addition to the unsaturated
ketone was examined. In order to avoid complications,
2-propenyl cuprate was used instead of isopropyl cuprate,
as the former can be easily hydrogenated to the latter. The
alkenyl cuprate was preformed in situ from 2-bromopropene,
n-butyllithium (2-propenyl lithium at -68 °C), and copper(I)
cyanide. Cuprate addition13 to enone 6 at -68 °C for 2 h
Even though (+)-Hajos-Parrish ketone is commercially
available, it can be readily prepared in multigram quantities
with high optical purity.4 Both starting materials 8a (R1,R2
) -OCH2CH2O-)7 and 8b (R1 ) OTBS, R2 ) H)8 were
conveniently prepared from (+)-Hajos-Parrish ketone using
literature procedures. To our surprise, only a single report
of spiro annulation of a ketone similar to 8b was known in
the literature.9 Our initial attempt at reaction of compound
8a and diiodide 9b (Scheme 2) using 60% NaH in DME
provided a complex mixture, without any noticeable amount
of desired spiro ketone 7. We undertook systematic optimi-
zation of several reaction parameters on compound 8a
including variation of the base (KOtBu, KH, 95% NaH),
leaving group of 9a-c, solvent (THF, THF-DME), reaction
time, and temperature. All attempts resulted in a mixture of
(5) Sviridov, S. V.; Vasilevskii, D. A.; Kulinkovich, O. G. Zh. Org. Khim.
1991, 27, 1431-1433.
(6) (a) Gleiter, R.; Ramming, M.; Weigl, H.; Wolfart, V.; Irngartinger,
H.; Oeser, T. Liebigs Ann./Recueil 1997, 1545-1550. (b) Davenport, R.
J.; Regan, A. C. Tetrahedron Lett. 2000, 41, 7619-7622. (c) Dimesylate
is unstable at rt but can be stored in the refrigerator for a few days:
Wasylishen, R. E.; Rice, K. C.; Weiss, U. Can. J. Chem. 1975, 53, 414-
417.
(10) (a) Corey, E. J.; Kang, J.; Kyler, K. Tetrahedron Lett. 1985, 26,
555-558. (b) Pine, S. H.; Shen, G. S.; Hoang, H. Synthesis 1991, 165-
167.
(7) Paquette, L. A.; Wang, T.-Z.; Sivik, M. R. J. Am. Chem. Soc. 1994,
116, 11323-11334.
(8) The compound 8b was prepared from the commercially available
(+)-Hajos-Parrish ketone in two steps (70% yield); see: Isaacs, R.; Di
Grandi, M. J.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 3938-3941.
(9) There is only one report on a similar system; see: Niwa, H.; Nisiwaki,
M.; Tsukada, I.; Ishigaki, T.; Ito, S.; Wakamatsu, K.; Mori, T.; Ikagawa,
M.; Yamada, K. J. Am. Chem. Soc. 1990, 112, 9001-9003.
(11) Yan, T.-H.; Tsai, C.-C.; Chien, C.-T.; Cho, C.-C.; Huang, P.-C. Org.
Lett. 2004, 6, 4961-4963.
(12) Brown, R. F. C.; Burge, G. L.; Collins, D. J. Aust. J. Chem. 1983,
36, 117-134.
(13) Molander, G. A.; Quirmbach, M. S.; Silva, L. S.; Spencer, K. C.;
Balsells, J. Org. Lett. 2001, 3, 2257-2260.
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