Angewandte
Chemie
DOI: 10.1002/anie.201105362
Synthetic Methods
Regio- and Stereoselective Synthesis of Cyclopentenones:
Intermolecular Pseudo-Pauson–Khand Cyclization**
Josꢀ Barluenga,* Ana ꢁlvarez-Fernꢂndez, ꢁngel L. Suꢂrez-Sobrino, and Miguel Tomꢂs
Apart from being a common structural unit in natural
products and pharmaceuticals,[1] the cyclopentenone ring
does represent a fundamental and versatile building block
for the construction of complex molecules.[2] Apart from a
number of reports,[3] the Pauson–Khand[4] and, to a lesser
extent, the Nazarov cyclization[5] are recognized by far as the
Scheme 1. New cyclopentenone approach.
most efficient ways to access the cyclopentenone system.
However, some drawbacks occasionally limit the generality of
these procedures. The Nazarov cyclization suffers from the
availability of the divinylketone structures as well as the
occurrence of side reactions derived from the oxyallyl cation
intermediate. Regarding the popular Pauson–Khand reaction,
even though the intramolecular process is recognized as the
most efficient access to fused cyclopentenones, there are
significant drawbacks in the case of the intermolecular
reaction, the major one being the necessity of using highly
reactive or strained alkenes.[6,7] In contrast, advances have
been made to replace the highly toxic carbon monoxide with
more friendly CO sources like aldehydes.[8]
Importantly, the asymmetric version of these processes
still requires additional development. The asymmetric Naz-
arov cyclization of a- and a’-functionalized divinylketones
(donor or acceptor groups) has been successfully performed
using metal- and organocatalysts.[9] Alternatively, while the
intramolecular asymmetric Pauson–Khand reaction has been
accomplished with different metal catalysts, the intermolec-
ular version still does represent a challenging goal.[4a] In this
context, only Riera, Verdager, and co-workers have reported
outstanding achievements using alkyne/[Co2(CO)4L*] com-
plexes and norbornadiene.[10,11]
corresponding alkenyl lithium 2 and alkynylcarbene complex
1 derivatives.[13]
A THF solution of the chromium alkynylcarbene 1,
readily made from terminal alkynes and [Cr(CO)6], was
added dropwise at ꢀ788C to a solution of the alkenyl
organollithium 2, which was generated by metalation of
bromoalkenes with tert-butyllithium. The reaction was kept at
ꢀ788C for one hour, warmed to room temperature, and then
stirred for two hours. The mixture was quenched with
aqueous ammonium chloride and demetalated (sunlight).
The aqueous layer was extracted (diethyl ether), and the
solvents were removed from the collected organic layers. The
resulting crude material was treated with concentrated HCl in
methylene chloride to hydrolyze the intermediate enol, thus
affording exclusively the cyclopentenones 3 in good yields
(50–85%) after chromatographic purification (Scheme 2).
The structure of compound 3b was confirmed by X-ray
analysis.[14]
Scheme 2 shows the scope of this [3+2] cyclization. A
number of bromoalkenes were first tested with the alkynyl
carbenes 1 having aryl substituents with different electronic
structures (R1 = Ar; products 3a–o). It was found that a- and
b-monosubstituted bromoalkenes work satisfactorily (3a–c);
moreover, both regioisomers are available by simply starting
with the appropriate bromoalkene (3a versus 3b). Interest-
ingly, the reaction with b,b-disubstituted and a,b,b-trisubsti-
tuted bromoalkenes takes place in higher yields, thus furnish-
ing the cyclopentenones 3d–g and spirocyclopentenone 3h
having an all-carbon-substituted quaternary center. This
protocol also enables access to the cyclopentane- and
cyclohexane-fused cyclopentenones 3i–o in synthetically
useful yields. Finally, the reaction works fairly with hetero-
aryl-, cycloalkyl-, and trimethylsilyl-substituted metal car-
benes 1 (3p, 3q, and 3r, respectively).
These facts inspired us to develop a complementary
Pauson–Khand cyclopentenone approach (Scheme 1) that is
based on 1) simplicity (short experimental protocol and
readily available substrates and reagents), and 2) the use of
recyclable [M(CO)6][12] as the source of CO. Overall, the
strategy requires a bromoalkene, [M(CO)6], and an alkyne to
generate the cyclopentene ring 3 by cyclization of the
[*] Prof. J. Barluenga, A. ꢀlvarez-Fernꢁndez, Dr. ꢀ. L. Suꢁrez-Sobrino,
Prof. M. Tomꢁs
Instituto Universitario de Quꢂmica Organometꢁlica “Enrique
Moles”, Unidad Asociada al CSIC, Universidad de Oviedo
Julian Claverꢂa 8, Oviedo (Spain)
A simple approach to understanding this stepwise cycli-
zation is shown in Scheme 3. First, the Michael-type addition
of 2 to 1 would form the metallated intermediate A.
Quenching with aqueous ammonium chloride would provide
the cis-metallatriene intermediate B (best represented as the
charged species), which spontaneously undergoes ring clo-
sure/metal elimination to the cyclopentadienylether 4.[15] In
E-mail: barluenga@uniovi.es
[**] This research was partially supported by the Goverments of Spain
(CTQ2010-20517-C02-01) and Principado de Asturias (IB08-088;
Severo Ochoa-PCTI predoctoral fellowship to A.A.-F.)
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 183 –186
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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