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some phenones 5, TEMPO 8, and cyclization products 9, respec-
tively.
Conclusion
We report here an unprecedented tandem process consisting
of main-group organometallic, transition-metal-catalyzed, and
radical reaction steps. The controlled use of two- and single-
electron-transfer steps enables the selective manipulation of
a wide variety of reactive intermediates in the sequence, which
provides easy access to complex cyclopentanes from inexpen-
sive commodity chemicals. Overall, nine to ten elementary
steps were lined up in sequence, during which one CꢀO and
three CꢀC bonds were formed, and a CꢀH bond was translo-
cated. The average efficiency for each of these elementary
steps amounts to 92% for product 9h, which was isolated
with the lowest yield of 49%, but reaches or exceeds 95% for
most other products 9. Reactivity incompatibilities, such as the
non-proceeding cyclization of the organometallic enolate,
were overcome by switching to the constitutionally identical,
but considerably more reactive, radical intermediate. Similarly,
the facile SET oxidation of cyclic radicals to the corresponding
carbocations during the formation of vinylcyclopentane 11 is
a promising extension. Several individual parts of the sequen-
ces, such as the optimized catalytic conditions for isomeriza-
tion, are useful for other applications. The reported redox and
intermediate diversity promises to significantly increase the
flexibility of synthetic planning toward more efficient target-
oriented syntheses of natural products, drug leads, and materi-
als. An antiviral screen revealed the promising activity of some
derivatives against the hepatitis C genotype 1 and dengue vi-
ruses, with no significant toxicity, thus providing a new and
easily accessible lead for further investigation.
Vinylcyclopentanedicarboxylate (11)
Phenyllithium 1a (0.72 mL, 1.3 mmol, 1.8m in dibutyl ether) was
added dropwise to a,b-unsaturated aldehyde 2a (1.3 mmol) in
DME (8 mL) at ꢀ58C under an argon atmosphere. After stirring for
15 min, (p-cymene)ruthenium dichloride dimer (39.7 mg,
0.065 mmol, 5 mol%) was added. The flask was removed from the
cooling bath, P(OMe)3 (0.016 mL, 0.13 mmol, 10 mol%) was added
dropwise, and the mixture was stirred at room temperature for 5–
10 min. The homogeneous solution was heated at a temperature
of 868C in an oil bath until conversion of the allylic alkoxide 3a to
ketone enolate 4a was complete based on TLC or GC analysis, typ-
ically 30–45 min. The reaction mixture was cooled to ꢀ458C and
the diene 10 (312.5 mg, 1 mmol) in dry DME (2 mL) was added.
The reaction mixture was stirred at the same temperature until
completion (3–4 h). Ferrocenium hexafluorophosphate 7 (662 mg,
2 mmol) was added in one portion. Additional ferrocenium hexa-
fluorophosphate (ca. 165 mg, 0.5 mmol) was added until the reac-
tion mixture became blue-green. Stirring was continued for
20 min. The reaction was quenched by a few drops of water and
then filtered through a pad of silica gel, which was washed thor-
oughly with diethyl ether. The filtrate was evaporated under
vacuum, the crude product was preadsorbed on silica gel, and
then purified by flash column chromatography (gradient of hex-
anes/EtOAc, 100:1 to 2:1). Ferrocene eluted first followed by some
phenone 5, and the cyclized product 11, respectively.
Typical procedure for deprotection of compounds 9a, 9g,
and 9j
A 3:1 diastereomeric mixture of 9a (100 mg, 0.188 mmol) was dis-
persed in a mixture of acetic acid (1.1 mL) and water (0.4 mL). THF
was added dropwise until a homogeneous solution was formed
(1 mL). Zinc dust (555 mg, 8.46 mmol) was added with vigorous
stirring and the reaction mixture was heated at 808C for 1 h. The
mixture was cooled to room temperature, diluted with CH2Cl2
(15 mL) and filtered. The filtrate was neutralized with saturated
K2CO3 solution to a pH of about nine. The organic layer was sepa-
rated, washed twice with water, dried over Na2SO4, and evaporated
to give the crude product, which was purified by flash chromatog-
raphy (gradient of hexanes/EtOAc, 100:1 to 2:1).
Experimental Section
General procedure using lithium–halogen exchange
tBuLi (1.53 mL, 2.6 mmol, 1.7m in pentane) was added to a stirred
solution of the aryl halide (1.3 mmol) in DME (8 mL) at ꢀ788C
under an argon atmosphere. After 35 min, the a,b-unsaturated al-
dehyde 2 (1.3 mmol) was added at once. After stirring at the same
temperature for 15 min, (p-cymene)ruthenium dichloride dimer
(39.7 mg, 0.065 mmol, 5 mol%) was added. The flask was removed
from the cooling bath, P(OMe)3 (0.016 mL, 0.13 mmol, 10 mol%)
was added dropwise and the mixture was stirred at room tempera-
ture for 5 min. The homogeneous solution was heated at a temper-
ature of 868C in an oil bath until conversion of the allylic alkoxide
3 to ketone enolate 4 was complete based on TLC or GC analysis,
typically 30–45 min. The reaction mixture was cooled to ꢀ458C
and the diene 6 (1 mmol) in dry DME (2 mL) was added. The reac-
tion mixture was stirred at the same temperature until complete
(3–4 h). TEMPO 8 (47 mg, 0.3 mmol) was added followed by a thor-
oughly homogenized mixture of TEMPO 8 (110 mg, 0.7 mmol) and
ferrocenium hexafluorophosphate 7 (331 mg, 1 mmol) in small por-
tions with vigorous stirring. Additional 7 (ca. 165 mg, 0.5 mmol)
was added until the reaction mixture became blue-green. Stirring
was continued for 20 min. The reaction was quenched by a few
drops of water and then filtered through a pad of silica gel, which
was washed thoroughly with diethyl ether. The filtrate was evapo-
rated under vacuum, the crude product was preadsorbed on silica
gel, and then purified by flash column chromatography (gradient
of hexanes/EtOAc, 100:1 to 1:1). Ferrocene eluted first, followed by
Acknowledgements
We acknowledge generous financial support by the Grant
Agency of the Czech Republic (P203/09/1936), the Institute of
Organic Chemistry and Biochemistry of the Academy of Scien-
ces of the Czech Republic (RVO: 61388963), and the Gilead
Sciences & IOCB Research Center. P.J. and U.J. acknowledge fi-
nancial support by the COST action CM1201 “Biomimetic Radi-
cal Chemistry”. I.C. thanks the Ministry of Education, Youth and
Sports of the Czech Republic (MSM0021620857) for financial
support.
Keywords: antiviral activity · cyclopentanes · isomerization ·
organic synthesis · radicals
Chem. Eur. J. 2014, 20, 10298 – 10304
10303
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim