Efficient and general approach to eremophilanes using siloxyalkyne-alkene metathesis

Article abstract of DOI:10.1021/jo049431g

An efficient skeletal reorganization of a terminal alkene armed with an appropriate siloxy alkyne fragment is a pivotal step in our novel and general strategy for the construction of a bicyclic core of eremophilanes with complete diastereocontrol and high synthetic efficiency. Our approach features three significant strategic elements. First, the enyne metathesis precursor is assembled via a highly endo-selective Diels-Alder reaction. Second, installation of the siloxy group at the alkyne terminus enables the regio-selective assembly of the ensuing enone fragment via intramolecular enyne cyclization. Third, the common enone precursor offers the necessary flexibility of accessing several natural products of the eremophilane family.

Full text of DOI:10.1021/jo049431g

reaction provided a novel access to a range of cyclic silyl
dienol ethers and was amenable to the construction of
highly functionalized enones. Herein, we extend the scope
of this method and demonstrate the utility of the siloxy-
alkyne-alkene metathesis in the arena of target-oriented
synthesis. This communication describes an original and
general strategy to several natural products, including
R- and â-eremophilanes, and fukinone, which originated
from a common synthetic precursor assembled via si-
loxyalkyne alkene metathesis.
Efficien t a n d Gen er a l Ap p r oa ch to
Er em op h ila n es Usin g Siloxya lk yn e-Alk en e
Meta th esis
D. Srinivasa Reddy and Sergey A. Kozmin*
University of Chicago, Department of Chemistry,
5735 South Ellis Avenue, Chicago, Illinois 60637
skozmin@uchicago.edu
Received April 6, 2004
SCHEME 1
Abstr a ct: An efficient skeletal reorganization of a terminal
alkene armed with an appropriate siloxy alkyne fragment
is a pivotal step in our novel and general strategy for the
construction of a bicyclic core of eremophilanes with com-
plete diastereocontrol and high synthetic efficiency. Our
approach features three significant strategic elements. First,
the enyne metathesis precursor is assembled via a highly
endo-selective Diels-Alder reaction. Second, installation of
the siloxy group at the alkyne terminus enables the regio-
selective assembly of the ensuing enone fragment via in-
tramolecular enyne cyclization. Third, the common enone
precursor offers the necessary flexibility of accessing several
natural products of the eremophilane family.
The enyne metathesis is characterized uniquely by the
formation of two new carbon-carbon bonds as a conse-
quence of a metal-catalyzed skeletal reorganization of the
appropriate enyne precursor.1 This transformation rep-
resents a valuable and versatile method for the synthesis
of cyclic and acyclic dienes.2 In contrast to the parent
olefin metathesis,3 however, there are only a few suc-
cessful applications of the enyne metathesis to the area
of complex natural product synthesis.4 In part, this
disparity can be attributed to the difficulty of the
subsequent regioselective functionalization of the diene
products arising from simple, unfunctionalized enyne
precursors. Recently, we described a highly efficient
participation of siloxyalkynes in Ru-catalyzed intramo-
lecular enyne metatheses with terminal alkenes.5 This
Eremophilanes comprise a unique set of plant metabo-
lites with more then 100 individual natural products.6
Isolated primarily from the flowering plants of the
Compositae family, this class of sesquiterpenes is char-
acterized by the cis-fused [4.4.0] decalin architecture. The
diverse biological properties of eremophilanes, combined
with the unique structural and conformational chal-
lenges, have attracted considerable synthetic attention.7
Our unique and general approach was designed to fully
exploit the synthetic versatility of the enone moiety
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15325. Also see ref 13.
10.1021/jo049431g CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/12/2004
4860
J . Org. Chem. 2004, 69, 4860-4862

assembled via siloxyalkyne-alkene metathesis5 for the
subsequent elaboration into a range of structural motifs
found in eremophilanes. To this end, we envisioned a
bicyclic enone 4 (Scheme 1) to serve as a common
intermediate for the assembly of several representative
eremophilanes. Enone 4, in turn, would derive from an
intramolecular enyne metathesis of the appropriately
functionalized siloxy alkyne 5. Diastereoselective con-
struction of 5 would entail an endo-selective Diels-Alder
reaction of diene 7 with aldehyde 6.
products. To our delight, subjection of siloxy alkyne 5 to
Ru catalyst A10 under our standard conditions [A (5 mol
%), 50 °C, 30 min]5 resulted in facile and quantitative
ring closure, which was evident from monitoring this pro-
1
cess by H NMR spectroscopy. Subsequent in situ expo-
sure of the resulting siloxy diene to a solution of hydrogen
fluoride in MeCN furnished bicyclic enone 4 in 85% yield
after chromatographic purification (Scheme 3).
SCHEME 3
The synthesis began with a systematic evaluation of
Lewis acid catalysis of the Diels-Alder reaction between
diene 7 and dienophile 6. As a result of this search, we
found that this reaction can be successfully performed
in the presence of MeAlCl2 (Scheme 2). Gratifyingly, an
excellent level of endo-selectivity was observed (dr 92:8,
86% yield). Indeed, this highly diastereoselective [4 + 2]
cycloaddition provides a simple solution for fully stereo-
controlled installation of the three stereogenic centers
present in eremophilanes, setting the stage for efficient
elaboration to the bicyclic scaffold. Conversion of alde-
hyde 8 to the one-carbon homologated ester 9 was
efficiently accomplished via Wittig methoxymethylena-
tion, followed by hydrolysis/oxidation of the resulting enol
ether with CrO3 and subjection of the resulting acid to
ethereal diazomethane (74%, two steps). Alkene hydro-
genation with concomitant removal of the benzyl ether,
followed by Swern oxidation and Wittig methylenation,
afforded ester 11, setting the stage for the introduction
of siloxyalkyne moiety. In the event, dibromomethyl-
lithium addition to ester 11 and subjection of the result-
ing dibromomethyl ketone to LHMDS and n-BuLi fol-
lowed by silylation of the ynolate anion furnished the
requisite siloxy alkyne 5 in 73% yield.8,9
Our subsequent efforts centered on further elaboration
of enone 4 to R- and â-eremophilanes (Scheme 4). To this
end, convex-face hydrogenation of 4 furnished axially
disposed ketone 12 (dr 80:20). Wittig methylenation and
hydrogenation completed the assembly of R-eremophilane
1 (11 steps). Alternatively, base-promoted epimerization
of ketone 12 furnished a thermodynamically favorable
equatorial isomer 13 (dr > 95:5). Wittig methylenation
of ketone 13 followed by hydrogenation afforded â-er-
emophilane 1 (12 steps). The 500 MHz 1H NMR and 125
MHz 13C NMR spectra of synthetic eremophilanes 1 and
14 were in excellent agreement with those reported in
the literature.11
SCHEME 4
SCHEME 2
Having secured access to R- and â-eremophilanes, we
focused our next effort on the synthesis of fukinone,
(8) Kowalski, C. J .; Haque, M. S.; Fields, K. W. J . Am. Chem. Soc.
1985, 107, 1429-1430.
(9) For a preparative modification of the original Kowalski protocol,
see: Smith, A. B., III; Kozmin, S. A.; Paone, D. V. J . Am. Chem. Soc.
2000, 122, 4984-4985.
(10) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956.
Siloxyalkyne alkene metathesis of enyne 5 represented
a pivotal point in the synthesis, as the product of this
transformation was envisioned to lead to several natural
J . Org. Chem, Vol. 69, No. 14, 2004 4861

another notable member of this class of natural prod-
ucts.12 Importantly, our strategy would represent a
conceptually novel entry into this target and would rival
the efficiency of the previously reported approaches.13
Fukinone was envisioned to arise from the PCC-mediated
transposition of enone 4 following the initial 1,2-addition
(Scheme 5). Indeed, treatment of enone 4 with methyl-
desired transposition of 15 using PCC proceeded without
success. To circumvent this issue, we developed a three-
step protocol carried out without any purification of the
intermediates. This sequence entailed hydroboration,
J ones oxidation and dehydration of the resulting â-hy-
droxy ketone to afford fukinone 2. Comparison of the 500
MHz 1H NMR and 125 MHz 13C NMR data of 2 revealed
that this material was identical to the previously reported
natural product.12,13 Importantly, fukinone represents a
well-established precursor to several additional members
of the eremophilane family. For instance, exposure of
fukinone to Ac2O in H2SO4 affords furanoeremophilane
(16) in a single operation.14 In addition, base-promoted
fragmentation followed by lactonization provides a simple
two-step route to bakkenolide A (17).15
SCHEME 5
In conclusion, we have developed an efficient and
highly stereocontrolled strategy to the eremophilane
family of natural products. Our approach features three
significant strategic elements. First, the enyne metath-
esis precursor is assembled via a highly endo-selective
Diels-Alder reaction. Second, installation of the siloxy
alkyne moiety enables a highly efficient and regioselec-
tive assembly of the ensuing enone fragment via in-
tramolecular Ru-catalyzed enyne cyclization. Third, the
resulting enone segment offers the necessary synthetic
flexibility of accessing several natural products of the
eremophilane family with high efficiency and diastereo-
selectivity. Most importantly, this work provides a clear
demonstration of the general synthetic utility of the
siloxyalkyne-alkene metathesis in the area of target-
oriented synthesis.
lithium (ether, -78 °C) furnished tertiary alcohol 15 in
95% yield. However, multiple attempts to induce the
Ack n ow led gm en t. Financial support for this work
was provided by the University of Chicago and Ameri-
can Cancer Society Institutional Research Grant. S.A.K.
is a fellow of the Alfred P. Sloan Foundation.
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J O049431G
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4862 J . Org. Chem., Vol. 69, No. 14, 2004