Enantioselective synthesis of 4-hydroxy-2-cyclohexenones through a multicomponent cyclization

Article abstract of DOI:10.1002/anie.201004413

Three metal cooperation promotes the one-pot selective coupling of a chromium carbene complex, an imide lithium enolate, and a propargylic organomagnesium reagent giving access to novel and densely functionalized 4-allenyl-2-cyclohexenones (see scheme). These useful synthetic intermediates have been prepared through a cyclization process that involves newly reported reaction steps and an unusually high level of asymmetric induction. Copyright

Full text of DOI:10.1002/anie.201004413

Communications
DOI: 10.1002/anie.201004413
Multicomponent Reactions
Enantioselective Synthesis of 4-Hydroxy-2-cyclohexenones through a
Multicomponent Cyclization**
Josꢀ Barluenga,* Marcos G. Suero, Raquel De la Campa, and Josefa Flꢁrez
Multicomponent reactions (MCRs) that combine three or
more substrates and produce several bonds and stereocenters
in a single operation have recently emerged as a powerful
strategy for the rapid construction of complex molecular
architectures.[1] Fischer carbene complexes (FCCs) containing
Group 6 transition metals have been recognized as very
effective reagents to promote a wide range of multicompo-
nent coupling reactions.[2] In this context, our research group
Scheme 1. Five-component synthesis of novel 4-allenyl-4-hydroxy-2-
cyclohexenones by sequential coupling of three starting materials.
has successfully described the diastereoselective synthesis of
either pentasubstituted cyclopentanols or tetrasubstituted
1,4-cyclohexanediols by a multicomponent sequential reac-
tion of a Fischer alkoxycarbene complex, a ketone or ester
lithium enolate, and allylmagnesium bromide.[3] To explore
new multicomponent synthetic strategies with substrates
containing an alkyne/allene unsaturation and to prepare the
corresponding derivatives as enantiomerically pure com-
pounds, we turned our attention to N-acyloxazolidinones.
The 1,3-oxazolidin-2-one system, which was first employed as
a chiral auxiliary by Evans, has been successfully and widely
applied in asymmetric synthesis.[4] The enolates of chiral
nonracemic N-acyl-1,3-oxazolidin-2-ones have been mainly
used in asymmetric alkylation and aldol addition reactions.[4,5]
Herein, we report a novel diastereoselective multicompo-
nent cyclization that combines an alkoxycarbene complex of
chromium, an imide lithium enolate, and an initially prepared
propargylic organomagnesium reagent. Incorporation of the
Grignard reagent as an allenyl unit occurred with subsequent
insertion of a carbonyl ligand to produce 4-allenyl-4-hydroxy-
2-cyclohexenones with high asymmetric induction
(Scheme 1).
chromium methoxycarbene complex 1 with imide lithium
enolate 2a, and then with a 3-substituted propargylmagne-
sium bromide (3a–d), performed under the reaction condi-
tions summarized in Table 1, led, after hydrolysis and
decoordination of the metal species by exposure to air and
light, to the corresponding 2,3,4,4,6,6-hexasubstituted 2-
cyclohexenone rac-4 as a single diastereoisomer. In these
reactions, mainly aryl (Table 1, entries 1–6 and 10–12) and
heteroaryl carbene complexes (Table 1, entries 7, 8, and 13) in
addition to an alkylcarbene derivative (Table 1, entry 9) were
employed.
Formation of compounds rac-4 reveals the successful
addition of imide enolate 2a to the carbene complex 1, which
Table 1: Diastereoselective synthesis of 4-hydroxy-2-cyclohexenones rac-
4.[a]
The feasibility of the envisaged coupling reaction was
initially explored using the lithium enolate of 3-acetyloxazo-
lidin-2-one 2a (prepared with lithium diisopropylamide
(LDA) in THF at ꢀ788C) and propargylic organomagnesium
reagents 3a–d (R2 = Me, Et, Bu, Ph) generated from the
corresponding propargylic bromide and Mg (0.3 mol%
HgCl2, Et2O, 0 8C). Thus, the successive reaction of a
Entry
1
R1
3
R2
rac-4
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1a
1j
1c
1g
Ph
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3c
3d
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
rac-4a
rac-4b
rac-4c
rac-4d
rac-4e
rac-4 f
rac-4g
rac-4h
rac-4i
rac-4j
rac-4k
rac-4l
rac-4m
80
54
69
71
75
52
70
61
65
71
57
63
55
2-naphthyl
p-MeOC6H4
p-TBSOC6H4
p-ClC6H4
[*] Prof. Dr. J. Barluenga, Dr. M. G. Suero, R. De la Campa, Dr. J. Flꢀrez
Instituto Universitario de Quꢁmica Organometꢂlica
“Enrique Moles”, Unidad Asociada al CSIC
Universidad de Oviedo, Juliꢂn Claverꢁa 8, 33006 Oviedo (Spain)
Fax: (+34)98-510-3450
p-BrC6H4
5-TMS-2-furyl
5-TMS-2-thienyl
cyclopentyl
Ph
p-CF3C6H4
p-MeOC6H4
5-TMS-2-furyl
9
10
11
12
13
E-mail: barluenga@uniovi.es
Et
Bu
Ph
[**] Financial support of this work by the MEC of Spain (grant
no. CTQ2007-61048/BQU) and the Principado de Asturias (project
no. IB08-088) is gratefully acknowledged. M.G.S. and R.D.C. thank
the MEC of Spain for a FPU predoctoral fellowship.
[a] Reaction conditions: 1) 2a (1.2 equiv), ꢀ788C, 15 min; 2) 3
(2.6 equiv), ꢀ788C, 30 min; then ꢀ558C, 12 h; then ꢀ55!208C, 8 h.
[b] Yield of isolated product based on carbene complex 1. TBS=tert-
butyldimethylsilyl, THF=tetrahydrofuran, TMS=trimethylsilyl.
Supporting information for this article, including experimental
details, is available on the WWW under http://dx.doi.org/10.1002/
anie.201004413.
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Chemie
occurs at low temperature and is an almost instantaneous
reaction. The formation of these compounds also indicates
the selective incorporation of the organomagnesium reagent
as an allenyl unit.[6,7] The structure of these novel derivatives
rac-4 combines five reacting components in a sequential
diastereoselective coupling process where the carbene ligand,
the enolate framework, one of the two allenyl groups, and a
carbonyl ligand have come together to form the highly
substituted cyclohexene core (formal [2E + 2A + 1C +
performed under the experimental conditions indicated in
Table 2 with carbene complexes 1a,d, lithium enolate 2c
derived from (R)-3-acetyl-4-benzyl-2-oxazolidinone, and 2-
butynylmagnesium bromide (3a) gave access to the enantio-
mers of compounds 4a,d (ent-4a,d; see structures following
Table 2) which were also formed with excellent enantioselec-
tivities.
The structure and relative stereochemistry of products 4
were ascertained by 1D and 2D NMR spectroscopic experi-
ments[12] (the latter studies were carried out with compounds
4c,f,h) and further confirmed by single-crystal X-ray analysis
of ent-5d, which allowed us to establish the absolute config-
uration of the stereogenic carbon atoms (see the Supporting
Information).[13] Compound ent-5d was obtained after
removal of the tert-butyldimethylsilyl (TBS) protective
group of ent-4d by treatment with potassium fluoride
(saturated aqueous solution) in THF/DMF (3:1) at room
temperature (Scheme 2). The reaction occurred without
1
CO] cyclization).[8,9]
Subsequently, analogous experiments were conducted
with lithium enolate 2b, prepared from (S)-3-acetyl-4-
benzyl-2-oxazolidinone and LDA (THF, ꢀ788C), and the
results are summarized in Table 2. The reactions with differ-
ent aryl/heteroarylcarbene complexes 1 and different prop-
argylic organomagnesium bromides 3a–d afforded the corre-
sponding 2-cyclohexenones 4, which contain two quaternary
stereocenters at the a and g positions and that were uniformly
generated either as highly enantioenriched or enantiomeri-
cally pure compounds.[10] The chemical yield of compound 4l
could be slightly improved using the corresponding organo-
cerium reagent prepared by treatment of Grignard reagent 3c
with CeCl3 (Table 2, entry 11).[11] Furthermore, the reactions
Table 2: Enantioselective synthesis of 4-hydroxy-2-cyclohexenones 4.[a]
Scheme 2. Removal of the TBS group. DMF=N,N-dimethylformamide.
diminishing the ee value. A similar procedure allowed the
conversion of 4d into phenol derivative 5d (80%, 99% ee).
The enantiomeric purity of compounds 5d and ent-5d was
checked by HPLC analysis on a chiral stationary phase using a
Chiralcel OD-H column.
Entry
1
R1
3
R2
4
Yield [%][b] ee [%][c]
The chemical characterization of a reaction intermediate
was achieved by using a deuterium source. To this effect, the
reaction of carbene complex 1a with enolate 2b and organo-
magnesium 3a was quenched at ꢀ308C with an excess
amount of deuterated hydrochloric acid (1m DCl in Et2O),
thereby affording compound 4n that contains a deuterium
atom bonded to the a-Me group but with only 44%
deuterium incorporation (see structure following Table 2).[14]
A plausible mechanistic pathway to explain the formation
of compounds 4 is outlined in Scheme 3 and consecutively
involves: 1) initial addition of the imide lithium enolate 2 (2b
in the Scheme) to the carbene carbon atom of complex 1 leads
to lithium alkylpentacarbonylchromate intermediate A;
2) subsequent double addition of the organomagnesium
derivative 3a–d to the exocyclic carbonyl group of the N-
acyl-2-oxazolidinone moiety which entails an unprecedented
removal of this chiral auxiliary group,[15] proceeds regioselec-
1
2
3
4
5
6
7
8
1a Ph
3a Me 4a
3a Me 4b
3a Me 4c
3a Me 4d
3a Me 4e
3a Me 4 f
3a Me 4g
84
51
70
79
69
53
72
53
99
99
98
99
97
99
99
98
99
99
99
99
1b 2-naphthyl
1c p-MeOC6H4
1d p-TBSOC6H4
1e p-ClC6H4
1 f p-BrC6H4
1g 5-TMS-2-furyl
1h 5-TMS-2-thienyl 3a Me 4h
1a Ph
9
3b Et
3b Et
4j
4k
80
10
11
12
1j
p-CF3C6H4
61
1c p-MeOC6H4
1g 5-TMS-2-furyl
3c Bu 4l
3d Ph
56 (70)[d]
4m 50
[a] Reaction conditions: 1) 2b (1.2 equiv), ꢀ788C, 15 min; 2) 3
(2.6 equiv), ꢀ788C, 30 min; then ꢀ558C, 12 h; then ꢀ55!208C, 8 h.
[b] Yield of isolated product based on carbene complex 1. [c] Enantio-
meric excess was determined by HPLC analysis on a chiral stationary
phase using a Chiralcel OD-H column, and was compared with the
corresponding racemic mixture rac-4. [d] Yield when the reaction was
carried out with the corresponding organocerium compound prepared
from 3c and CeCl3 (1.2 equiv) in THF.
tively incorporating two allenyl units and provides adduct B;
3
ꢀ
3) insertion of CO into the C(sp ) Cr s bond of adduct B
affords allenyl substituted lithium acyltetracarbonylchromate
complex C; 4) a final intramolecular carbometalation reac-
=
tion of the terminal C C bond of one of the allene groups
produces allylchromate intermediate D. The origin of this
ꢀ
regioselective insertion of the allene fragment into the C(O)
ꢀ
Cr s bond with selective formation of the C(O) C bond at the
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Communications
steric interaction would be much lower with an oxygen atom
at that position.[19]
The regioselective and diastereoselective reduction of the
carbonyl group of compounds 4a,f was readily accomplished
under Luche conditions[20] (NaBH4, anhydrous CeCl3), thus
affording cis-2-cyclohexene-1,4-diols 6a,f as enantiomerically
pure compounds (Scheme 4; the enantiomeric purity of 6a
Scheme 4. Diastereoselective synthesis of cis-2-cyclohexene-1,4-diols 6.
was checked by HPLC analysis on a chiral stationary phase
using a Chiralcel OD-H column). The configuration of
compounds 6 was established from the 2D NOESY experi-
ment on 6 f,[12] which revealed a cis relative disposition of the
three oxygenated substituents (MeO and two OH groups).
The relative configuration of the newly formed stereogenic
center can be rationalized by assuming the formation of
chelated intermediate IV[20] by coordinating the cerium ion to
the oxygen atoms (the intramolecular hydrogen bond would
favor the 1,3-diaxial orientation of the OH and MeO groups).
In this conformation the delivery of the hydride occurred
from the less hindered face of the ketone carbonyl group, thus
producing the equatorial allylic alcohol (axial attack of
hydride under Luche conditions is mainly observed in the
reduction of substituted cyclohexenones).[20]
Scheme 3. Mechanistic pathway for the formation of 4-hydroxy-2-cyclo-
hexenones 4.
central allene carbon would be the generation of the most
stable s-allylic/p-allylic chromate complex D.[16] This inter-
mediate, which has a concurrent homoenolate nature, is
susceptible to further elaboration. Thus, at ꢀ308C intermedi-
ate D (R1 = Ph, R2 = Me) is trapped with DCl as described
above. Chelation of the lithium atom to both sp3-hybridized
oxygen atoms of the chain as shown in intermediate C may
ꢀ
control the selective new insertion into the C(O) Cr bond of
In summary, we have developed a novel cyclization
reaction from three simple, readily available reacting materi-
als: carbene complex, imide enolate, and propargylic!
allenylic organomagnesium reagents. This process provides
an efficient and diastereoselective access to densely function-
alized 4-hydroxy-2-cyclohexenones that display unprece-
dented substitution patterns not readily accessible through
other approaches. Both enantiomers of these products were
prepared in a highly enantioenriched form using chiral N-
acetyl-2-oxazolidinones in a strategy that involves the enan-
tioselective generation of quaternary stereocenters. Further
diastereoselective reduction of the carbonyl group of 4-
hydroxy-2-cyclohexenones enlightens the potential synthetic
application of these useful chiral building blocks.[21] This
transition-metal-assisted multicomponent cyclization method
proceeds through a pathway that entails new transformations:
the addition of imide lithium enolates to Fischer carbene
complexes is reported for the first time, the double organo-
magnesium addition to the exocyclic carbonyl group of N-
acyl-2-oxazolidinones derivatives represents a new procedure
for removal of this chiral auxiliary group, and the proposed
intramolecular carbometalation of an allene with acyltetra-
carbonylchromate complexes is also an unprecedented pro-
cess.
the adequately positioned allenyl unit.[3c] The final protona-
tion of complex D leads to 4-hydroxy-2-cyclohexenone 4.
The absolute sense of stereoinduction observed for this
reaction is consistent with a chelated enolate approaching the
carbene complex from the less hindered face as shown in six-
membered chair-like transition state model E or in the
Newman projection model E’ (Scheme 3), which assumes an
approximation of the reagents with an anti orientation of the
donor and acceptor p systems and places the bulky substitu-
ent of the enolate away from the (CO)5Cr group to avoid
steric interactions.[17] Notably, there is a high level of
asymmetric induction observed in the addition of N-acety-
loxazolidinone lithium enolates 2b,c to the carbene carbon
atom of FCCs 1 in comparison to the poor levels of
enantioselection that these unsubstituted metal enolates
(such as 2b,c) exhibit in aldol condensation additions.[5a,18]
This observed difference in diastereofacial selection may be a
consequence of the larger size of the (CO)5Cr group
compared with the oxygen atom of a carbonyl group. The
bulkiest (CO)5Cr fragment would impose severe steric
interactions with the oxazolidinone group as indicated in
the approach topology F for addition to the opposite prochiral
face of the carbene complex 1 (Scheme 3). This unfavorable
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Received: July 19, 2010
[11] a) T. Imamoto, N. Takiyama, K. Nakamura, T. Hatajima, Y.
Revised: September 17, 2010
Published online: November 10, 2010
Kamiya, J. Am. Chem. Soc. 1989, 111, 4392 – 4398; b) U. Groth,
C. Kesenheimer, J. Neidhꢁfer, Synlett 2006, 1859 – 1862; see also:
c) T. Imamoto in Comprehensive Organic Synthesis Vol. 1 (Eds.:
B. M. Trost, I. Fleming, S. L. Schreiber), Pergamon, Oxford,
1991, pp. 231 – 250.
Keywords: asymmetric synthesis · carbene ligands ·
.
carbocyclization · 2-cyclohexenones · multicomponent reactions
[12] 1H, 13C, DEPT, HSQC, HMBC, COSY, and NOESY NMR
spectra were measured.
[13] CCDC 783451 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[14] When quenching of the reaction with DCl (1m in Et2O) was
effected at 208C, incorporation of deuterium was not observed
and 4a (71%) was isolated, presumably as a result of the
presence of diisopropylamine (see Ref. [3]).
[15] Recovery of the chiral auxiliary group can be achieved by flash
column chromatography. For example, in the experiment of
Table 2, entry 4, 76% of the chiral auxiliary group was recovered
with this technique.
[1] a) Multicomponent Reactions (Eds.: J. Zhu, H. Bienaymꢀ),
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[2] For multicomponent reactions mediated by FCCs, see: a) “Metal
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[16] By analogy, carbopalladation of allenes occurs highly regiose-
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Woodall, G. Yoganathan, Tetrahedron Lett. 2000, 41, 7125 – 7128;
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[17] A similar model has been proposed to explain the syn-selective
Michael addition of metal enolates to alkenylcarbene com-
plexes: a) E. Nakamura, K. Tanaka, T. Fujimura, S. Aoki, P. G.
Williard, J. Am. Chem. Soc. 1993, 115, 9015 – 9020; b) J.
Ezquerra, C. Pedregal, I. Merino, J. Flꢂrez, J. Barluenga, S.
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[5] a) D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981,
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Am. Chem. Soc. 1982, 104, 1737 – 1739.
[6] Propargylic metal derivatives generally exist as a mixture of
allenic and propargylic organometallic species in equilibrium.
The origins of regioselectivity in the reactions of these delocal-
ized propargyl metals with carbonyl compounds are very subtle
and poorly understood. The regiochemical selectivities observed
in our work are consistent with reported results; a) H. Yama-
moto, in Comprehensive Organic Synthesis, Vol. 2 (Eds.: B. M.
Trost, I. Fleming, C. H. Heathcock), Pergamon, Oxford, 1991,
pp. 81 – 98; b) B. Alcaide, P. Almendros, C. Aragoncillo, R.
Rodrꢄguez-Acebes, J. Org. Chem. 2001, 66, 5208 – 5216; c) H. P.
Acharya, K. Miyoshi, Y. Kobayashi, Org. Lett. 2007, 9, 3535 –
3538, and references therein.
[7] Analogous experiments carried out with propargylmagnesium
bromide (3, R2 = H) provided bicyclic derivatives through a
different multicomponent cyclization as a consequence of the
selective incorporation of this organomagnesium reagent as a
propargyl fragment. These results will be reported separately.
[8] Topological identification of the cyclization reaction used in a
formal sense to describe the number of atoms provided by each
fragment to the final cycloadduct (E = enolate anion, A = allenyl
group, C = carbene ligand, CO = carbonyl ligand).
[18] The critical role of enolate substitution in aldol asymmetric
induction is well-documented (unsubstituted metal enolates
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E. R. Thornton, Tetrahedron Lett. 1986, 27, 897 – 900; b) B.
Loubinoux, J.-L. Sinnes, A. C. OꢇSullivan, T. Winkler, Tetrahe-
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Muꢈoz, N. Saunders, T. J. Simpson, D. I. Smith, F. Soulas, P.
Watts, C. L. Willis, Org. Biomol. Chem. 2005, 3, 1719—1728.
Highly diastereoselective acetate aldol additions had been
reported using chlorotitanium enolates of N-acetyloxazolidine-
thiones and N-acetylthiazolidinethiones: e) M. T. Crimmins, M.
Shamszad, Org. Lett. 2007, 9, 149 – 152; f) A. Osorio-Lozada,
H. F. Olivo, Org. Lett. 2008, 10, 617—620, and references
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[19] Alternatively to this open transition state, a closed transition
state as depicted in stereochemical models II and III has been
more often proposed for aldol reactions with imide enolates
(these two transition structures II and III will be of more similar
energy); a) D. A. Evans, J. M Takacs, L. R. McGee, M. D. Ennis,
D. J. Mathre, J. Bartroli, Pure Appl. Chem. 1981, 53, 1109 – 1127;
b) D. A. Evans, C. W. Downey, J. T. Shaw, J. S. Tedrow, Org. Lett.
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Sammakia, Org. Lett. 2004, 6, 23 – 25; d) S. Shirokawa, M.
[9] Efforts to promote similar multicomponent cyclizations using b-
substituted imide enolates proved to be unsuccessful. The
experiments conducted with carbene
complex 1a, lithium enolate I, and 2-
butynylmagnesium
bromide
(3a)
afforded an open-chain coupling prod-
uct. These results will be reported
separately.
[10] The reaction of cyclopentylcarbene complex 1i with enolate 2b
and then with Grignard reagent 3a previously treated with CeCl3
(1.2 equiv) in THF, furnished product 4i with very low chemical
yield (10%) and low asymmetric induction (68% ee). In the
absence of CeCl3, formation of 4i was not observed.
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[20] a) J. L. Luche, J. Am. Chem. Soc. 1978, 100, 2226 – 2227; b) A. L.
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