Regio- and stereoselective synthesis of cyclopentenones: Intermolecular Pseudo-Pauson-Khand cyclization

Article abstract of DOI:10.1002/anie.201105362

Doing the two step: A very simple two-step access to polysubstituted cyclopentenones from terminal alkynes, [M(CO)₆], and bromoalkenes is described. This protocol is an alternative to the intermolecular Pauson-Khand reaction, and can be used wi

Full text of DOI:10.1002/anie.201105362

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
under http://dx.doi.org/10.1002/anie.201105362.
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183

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Communications
(Scheme 4). When a mixture of the carbene 1 and alkenyl
lithium 2 was stirred at low temperature, treated with CuBr
(1 equiv) at room temperature, and then with reactive
Scheme 4. Functionalization of the cyclopentenones at C2 to give the
products 5. NBS=N-bromosuccinimide.
electrophiles (allyl iodide, NBS, bis(pyridine)iodonium tetra-
fluoroborate), the synthetically valuable cycloadducts 5a–c
and 4b were isolated in moderate to good yields (51–83%).
The present methodology seems amenable for the asym-
metric cyclization by starting from the chiral nonracemic
tungsten carbenes 6 derived from (ꢀ)-8-phenylmenthol
(Scheme 5).[17] Our goal was to apply this protocol to the
enantioselective synthesis of cyclopentenones featuring an
all-carbon-substituted quaternary stereogenic center (R3,
R4 ¼ H).[18] First, treatment of 6 with methyl- and ethyl-
substituted cycloalkenyllithium 2, under the experimental
protocol given for the carbenes 1, resulted in the formation of
cyclohexane- and cyclopentane-fused cyclopentenones
(4R,5R)-3j–o in 45–70% yield and greater than 94% ee in
Scheme 2. Cyclopentenones 3 obtained from alkynyl carbenes 1 and
vinyllithium compounds 2. PCP=p-chlorophenyl, PMP=p-methoxy-
phenyl, PTFP=p-trifluoromethylphenyl, THF=tetrahydrofuran.
Scheme 3. Proposed mechanism for the formation of 3.
this way, protonated (4a) and deuteriated ([D]-4a) adducts
were isolated with H2O and D2O, respectively.[16]
If one assumes the presence of A, additional functional-
ization at C2 might be feasible with other electrophiles
Scheme 5. Chiral nonracemic cyclopentenones obtained from a tung-
sten carbene derived from (ꢀ)-8-phenylmenthol 6.
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Angewandte
Chemie
most cases.[19] When the metal carbene 6 bears an electron-
rich aryl substituent (R1 = PMP) lower selectivity was
attained [(ꢀ)-3n]. In contrast, we found that either (Z)- or
(E)-2-phenylpropenyl lithium (or Z/E mixtures) underwent
cycloaddition with the enantiopure carbenes 6 (R1 = Ph,
PCP), thus leading to cyclopentenones (+)-(S)-3e,f in mod-
erate yield (48–55%) and high enantioselectivity (87–
92%).[19] Crystallization of (+)-3 f afforded a single crystal-
line isomer (> 99% ee) whose structure was established by X-
ray analysis.[14]
Received: July 29, 2011
Published online: November 17, 2011
Keywords: carbenes · chromium · cyclization ·
.
enantioselectivity · tungsten
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phenylmenthyloxy group would block the bottom face of the
ꢀ
C3 C4 bond of the 1-metalla-1,3,5-hexatriene (intermediate
ꢀ
B’) thus forcing the C6 C2 bond formation to occur through
ꢀ
from the top face of the W C2 carbene moiety. This approach
leads to the (4R,5R)-cycloalkane-fused cyclopentenones 3j–o.
The convergent formation of (+)-(S)-3e,f could be under-
stood by previous cis-B’/trans-B’ equilibration with subse-
quent cyclization of the more stable trans species.[21]
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[11] For the first intermolecular asymmetric cobalt-catalyzed
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2128.
In conclusion, a very simple two-step access to polysub-
stituted cyclopentenones from terminal alkynes, [M(CO)6],
and bromoalkenes is described. Importantly, this protocol
enhances to a great extent the challenging intermolecular
Pauson–Khand reaction, especially concerning the alkene
partner and the asymmetric cyclization. Significant features
that reflect the complementarity of the process described
herein to the Pauson–Khand reaction are: 1) different types
of bromoalkenes are productive and the regiochemistry is
completely predetermined, 2) whereas 2-substituted cyclo-
pentenones are obtained from terminal alkynes by the
Pauson–Khand reaction, the procedure described herein
yields 3-substituted cyclopentenones, 3) a halogen atom can
be easily installed at the strategic C2 position, thus allowing
additional functionalization, 4) enantiopure cyclopentenones,
particularly bicyclic cyclopentenones with an all-carbon-
substituted quaternary stereocenter at the bridgehead C5
carbon atom,[22] are readily available with high stereochemical
induction (up to 99% ee).
[12] For an appropriate way to recycle [M(CO)6], see, for instance: R.
Aumann, M. Kçßmeier, K. Roths, R. Frçhlich, Synlett 1994,
1041 – 1044.
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[13] a) This hypothesis is supported by the fact that indole derivatives
actually undergo cyclization with metal carbenes 1 through
nucleophilic addition/ring closure. See: J. Barluenga, E. Tudela,
A. Ballesteros, M. Tomꢁs, J. Am. Chem. Soc. 2009, 131, 2096 –
2097; b) The preparation of 1 is readily performed by addition of
the lithium acetylide to [M(CO)6] and quenching with MeOTf
(see the Supporting Information); c) For the reaction of alkynyl
carbene complexes with enamines, see: R. Aumann, A. G.
Meyer, R. Frçhlich, Organometallics 1996, 15, 5018 – 5027, and
references therein.
[14] CCDC 835349 (3b), 835348 [(+)-3 f], and 835350 (7) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[15] This cyclopentannulation of metallahexatrienes is a well-estab-
lished process in Fischer metal carbene chemistry, though the
mechanism remains unclear. See: a) J. Barluenga, F. Aznar, S.
Barluenga, J. Chem. Soc. Chem. Commun. 1995, 1973 – 1974;
b) J. Barluenga, M. A. Fernꢁndez-Rodriguez, E. Aguilar, J.
Organomet. Chem. 2005, 690, 539 – 587.
[17] Comparison of Group 6 metal carbenes led us to conclude that
chromium carbenes are superior in terms of chemical yield,
whereas much higher asymmetric induction was reached with
tungsten carbenes. This event has been previously observed. See:
J. Barluenga, R. Bernardo de La Rffla, D. de Sꢁa, A. Ballesteros,
M. Tomꢁs, Angew. Chem. 2005, 117, 5061 – 5063; Angew. Chem.
Int. Ed. 2005, 44, 4981 – 4983, and reference [13a].
[18] In the case of R3 = Ph; R4 = H, extensive racemization was
observed to occur through a [1,5]-H shift (compound 4) and/or
enolization (compound 3).
[19] The ee values were determined by HPLC analysis using a chiral
stationary phase.
[20] G. B. Jones, B. J. Chapman, Synthesis 1995, 475 – 497.
[21] The trans orientation of the Ph would enable a more efficient
conjugation of the pentadienyl cation moiety. In fact, replacing
Ph with Ph-CH2-CH2 (1:1 E/Z mixture) resulted in less efficient
cis-B’/trans-B’ discrimination and therefore low induction
(64% ee; see the Supporting Information).
[16] The presumed intermediate A could be trapped with benzalde-
hyde as the electrophile. The reaction does not evolve to the
corresponding cyclopentenone, but the lactone 7 was isolated as
a mixture of diastereoisomers (52% yield; for the X-ray analysis
of the major isomer, see Ref. [14]). The formation of 7 results
from a multicomponent cyclization involving intermediate A,
one CO ligand, and two equivalents of PhCHO.
[22] Access to such
a relevant structural moiety represents a
particular challenge in organic synthesis nowadays. See: B. M.
Trost, C. Jiang, Synthesis 2006, 369 – 396.
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