Enantioselective multicomponent synthesis of fused 6-5 bicyclic 2-butenolides by a cascade heterobicyclisation process

Article abstract of DOI:10.1002/chem.201102288

The successive coupling of an alkoxy(aryl/heteroaryl)carbene complex of chromium with either a ketone or an imide lithium enolate and then a 3-substituted (H, TMS, PhCH₂, PhCH₂CH₂, Me) propargylic organomagnesium reagent h

Full text of DOI:10.1002/chem.201102288

FULL PAPER
DOI: 10.1002/chem.201102288
Enantioselective Multicomponent Synthesis of Fused 6–5 Bicyclic 2-
Butenolides by a Cascade Heterobicyclisation Process
Marcos G. Suero,[a] Raquel De la Campa,[a] Laura Torre-Fernꢀndez,[b]
Santiago Garcꢁa-Granda,[b] and Josefa Flꢂrez*[a]
Dedicated to Professor Josꢀ Barluenga
Abstract: The successive coupling of an
alkoxy(aryl/heteroaryl)carbene com-
plex of chromium with either a ketone
or an imide lithium enolate and then
cohol core. The selective formation of
these five- or six-component heterobi-
cyclisation products is the result of the
regioselective integration of the
Grignard reagent as a propargyl frag-
and elimination sequence. By using
lithium enolates of chiral N-acetyl-2-
oxazolidinones and the corresponding
propargylic organocerium reagents,
both enantiomers of these bicyclic het-
erocycles were efficiently prepared
with very high enantiomeric purity. Ar-
chitecturally, these fused bicyclic bute-
nolides are characterised by a highly
unsaturated and oxygenated core and
they exhibit strong blue fluorescence in
solution.
a
3-substituted (H, TMS, PhCH2,
PhCH2CH2, Me) propargylic organo-
magnesium reagent has afforded novel
hydroxy-substituted bicyclic [4.3.0]-g-
alkylidene-2-butenolides with three
modular points that has allowed the ef-
ficient introduction of molecular com-
plexity, including a homopropargylic al-
ment followed by a cascade CO/
alkyne/CO insertion, ketene trapping
Keywords: asymmetric synthesis ·
carbenes · cascade reactions · cycli-
zations · multicomponent reactions
Introduction
We have developed a multicomponent sequential coupling
reaction that involves a one-pot reaction of a chromium al-
koxycarbene complex, a ketone or ester lithium enolate and
allylmagnesium bromide: this allows an efficient diastereo-
selective synthesis of either highly substituted cyclopenta-
nols or 1,4-cyclohexanediols.[4] The key to these transforma-
tions lies in the formally divalent nature of the carbene
carbon atom of the FCCs. After its reaction with an enolate
anion as an electrophile, this carbene carbon atom is trans-
formed into a nucleophilic alkylmetallate reagent that un-
dergoes further transformations with strategically positioned
unsaturated reactive centres in the same molecule. As part
of our ongoing efforts in designing novel multicomponent
cascade reactions mediated by heteroatom-stabilised FCCs,
we decided to explore the behaviour of propargylic organo-
magnesium reagents envisaging that they could undergo dif-
ferent cyclisation processes. Very recently we reported the
introduction of these unsaturated Grignard derivatives, as
allenyl units, into the FCC+imide lithium enolate adduct,
followed by insertion of a carbonyl ligand to produce 4-al-
lenyl-4-hydroxy-2-cyclohexenones.[5] These densely function-
alised carbocycles were prepared in a highly enantioen-
riched form by using chiral N-acetyl-1,3-oxazolidin-2-ones.[6]
Herein we report a new type of multicomponent heterobi-
The design and development of novel multicomponent reac-
tions (MCRs) that provide rapid and economical access to
architecturally complex molecules from simple and readily
available starting materials is a very active area of research
in modern organic chemistry.[1] To achieve this goal,
Group 6 metal heteroatom-stabilised Fischer carbene com-
plexes (FCCs) are particularly important precursors that
À
offer great potential and versatility in carbon carbon and
carbon heteroatom bond-formation processes as well as the
À
possibility of incorporating carbon monoxide from the car-
bonyl ligands.[2] In addition, MCRs represent an efficient
tool for the synthesis of diverse heterocyclic scaffolds, the
most common structural motifs found in numerous natural
products, drugs and pharmaceutically important substan-
ces.[1c,e–h,3]
[a] 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, Asturias (Spain)
Fax : (+34)985-103446
E-mail: jflorezg@uniovi.es
cyclisation strategy that provides bicyclicACTHNUGRTENUNG[4.3.0] 2-buteno-
[b] L. Torre-Fernꢂndez, Prof. Dr. S. Garcꢁa-Granda
Departamento de Quꢁmica Fꢁsica y Analꢁtica
Facultad de Quꢁmica, Universidad de Oviedo
Juliꢂn Claverꢁa, 8, 33006 Oviedo, Asturias (Spain)
lides by the selective inclusion of propargylic organomagne-
sium reagents as a propargylic fragment in the FCC+
ketone or imide lithium enolate adduct and the subsequent
incorporation of two carbonyl ligands. These fused 6–5 bicy-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102288.
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Results and Discussion
6–5 Bicyclic g-alkylidenebutenolides from ketone enolates:
Our initial study began by examining the feasibility of the
reaction with ketone lithium enolates 2 and propargylic or-
ganomagnesium reagents 3 (R3 =H, TMS, PhCH2, Me),
which were generated from the corresponding propargylic
bromide and magnesium (0.4 mol% HgCl2, Et2O, 0 8C). We
found that the successive reaction of a chromium methoxy-
carbene complex 1 with a methyl ketone lithium enolate 2
and then with propargylmagnesium bromide (3a) or a 3-sub-
stituted propargylmagnesium bromide 3b–d, conducted
under the reaction conditions indicated in Table 1, led selec-
Scheme 1. Five- and six-component synthesis of novel fused 6–5 bicyclic
g-alkylidene-2-butenolides by sequential coupling of three starting mate-
rials.
Table 1. Selective synthesis of 6–5 bicyclic g-alkylidene-2-butenolides 4 from ketone lithium enolates.[a]
clic heterocycles were also gen-
erated with very high stereoin-
duction from chiral imide eno-
lates (Scheme 1).
The fused 6–5 bicyclic g-alk-
ACHTUNGTRENNUNGylidene-2-butenolide core fea-
ture, marked in bold in
Scheme 1,[7] is a synthetically
important structural unit that is
present in various natural prod-
ucts that display a wide range
of biological activity.[8] Among
the few synthetic methods re-
ported for the construction of
compounds containing this key
structural element,[9] one finds
the cyclisation of chromium car-
Entry
1
R1
2[b]
2a[d]
2b
R2
3
R3
4
Yield [%][c]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1b
1c
1d
1d
1d
1d
1e
1a
1d
1 f
Ph
Ph
Ph
Me
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3c
3d
3a
3a
3a
3a
H
H
H
H
H
H
H
H
H
H
H
H
TMS
TMS
TMS
PhCH2
Me
H
4a
4b
4c
4d
4e
4 f
4g
4h
4i
69
88
82
71
78
77
88
86
58
80
88
78
77
86
65
87
75
40
58
74
48
1-cyclopentenyl
2c
2d
Ph
2-furyl
Me
iPr
2-furyl
Me
Ph
2-naphthyl
2-naphthyl
p-ClC6H4
2-furyl
2-furyl
2-furyl
2-furyl
2-thienyl
Ph
2-furyl
3-thienyl
5-TMS-2-furyl
5-TMS-2-furyl
Ph
2a[d]
2e[d]
2d
2a[d]
2e[d]
2 f
iPr
10[e]
11[e]
12
Ph C C
4j
4k
4l
À ꢀ
À ꢀ
2g
2h
2i
2j
2d
2i
2k
TMS C C
bene
complexes
bearing
1,4-benzodioxan-6-yl
À
a
carbon carbon triple bond 13
14
tBu
cyclopropyl
2-furyl
tBu
1-adamantyl
Me
4m
4n
4o
4p
4q
4a
4r
appropriately positioned in the
alkyl or alkoxy groups bonded
to the carbene carbon atom.
Annulation of these derivatives
occurred by cascade insertion
reactions of CO and alkyne in-
duced by the addition of a nu-
cleophile (hydride, alkoxide, al-
kyllithium or alkylmagnesium
compound) to the carbene
carbon atom.[10,11] However, not
one of these methods repre-
15
16
17
18
19
20
21
1g
1g
1aW
1a
1a
1h
2a[d]
2eK[f]
2i[g]
2e[i]
Ph
Ph
iPr
tBu
iPr
H
H
H
[h]
–
[j]
ꢀ
tBuC C
–
[a] Reagents and conditions: 1) 2a,c,e–h (1.2 equiv), À788C, 15 min or 2b,d,i–k,eK (1.2 equiv), À78 to À558C,
45 min; 2) 3 (1.5 equiv), À78 to À558C, 5 h and then 208C, 30 min; 3) NH4Cl (saturated aqueous solution,
20 mL). [b] Enolates 2b–d,f–k were prepared from the corresponding ketone and lithium diisopropylamide
(LDA; THF, À788C, 1 h). [c] Yield of the isolated, analytically pure product based on carbene complex 1.
[d] Enolates 2a,e were prepared from the corresponding trimethylsilyl enol ether (2-(trimethylsilyloxy)pro-
pene or 2-(trimethylsilyloxy)-3-methyl-1-butene, respectively) and BuLi (THF, 08C, 30 min). [e] In these ex-
periments, the reaction conditions in the second step were as follows: 3a (1.5 equiv), À78 to 208C, 24 h.
[f] Enolate 2eK was prepared from the corresponding ketone (3-methyl-2-butanone) and potassium bis-
sents
a multicomponent ap-
proach. The new synthetic
method presented in this paper
combines three readily avail-
able starting materials, provides
enantiomerically pure com-
pounds and is a significant ex-
pansion of the currently known
methods for the synthesis of 6–
G
(trimethylsilyloxy)-3,3-dimethyl-1-butene and BuLi (THF, 08C, 30 min). [h] Compound 5 was isolated. [i] In
this experiment, enolate 2e was generated from 3-methyl-2-butanone and LDA (THF, À788C, 1 h). [j] Com-
pound 6 was isolated.
5
bicyclic g-alkylidenebuteno-
lides.
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Bicyclic Butenolides by Cascade Heterobicyclisation
FULL PAPER
tively, after hydrolysis and decoordination of the metal spe-
cies by exposure to air and light, to the corresponding bicy-
clic g-alkylidenebutenolide 4. This reaction proceeded effi-
ciently with different aryl and heteroaryl FCCs and dis-
played an excellent generality of the ketone component
with significant structural variation in the R2 group (alkyl,
aryl, heteroaryl, alkenyl, alkynyl) being tolerated (Table 1,
entries 1–17). In general, the addition of ketone lithium eno-
lates 2[12] to carbene complexes 1 takes place almost instan-
taneously at low temperature (À788C) to produce a clear
and immediate disappearance of the red colour of the car-
bene-complex solution and the formation of an orange-
yellow solution. In the cases of enolates 2b,d,i–k (R2 =1-cy-
clopentenyl, 2-furyl, tBu, cyclopropyl, 1-adamantyl) it was
necessary to raise the temperature from À78 to À558C over
45 min to achieve a complete consumption of the starting
carbene complex 1 (Table 1, entries 2, 4, 7, 13–17). Either
steric (greater size of R2) or electronic effects (extended p
conjugation) could be invoked to account for this lower re-
activity. The organomagnesium reagents 3 were added at
low temperature (À788C) and after stirring for 5 h between
À78 and À558C, the reaction mixture was warmed to room
temperature and stirred for an additional 30 min. The
Grignard component 3 (R3 =H, TMS, PhCH2, Me) was se-
lectively incorporated into the FCC+ketone enolate adduct
as a propargyl unit.[13] The regiochemical selectivities ob-
served in our work as a function of the nature of the sub-
stituent R3 at the acetylene terminus are consistent with re-
ported results.[14] The regiochemical preference in the reac-
tion of 2-butynylmagnesium bromide (3d, R3 =Me) with the
adduct formed between complex 1g and 1-adamantyl
methyl ketone enolate 2k, which contains a sterically hin-
dering group (Table 1, entry 17), was the reverse of that ob-
served in our previous work with imide enolates.[5] The reac-
tion performed with tungsten carbene complex 1aW, which
was sequentially treated with acetone lithium enolate (2a)
and propargylmagnesium bromide (3a) under otherwise
identical reaction conditions, afforded the expected g-alkyli-
denebutenolide 4a, but with lower chemical yield (Table 1,
see entries 1 and 18). It is known that tungsten complexes
are less prone to undergo carbonyl insertion than their chro-
mium counterparts.[15] Modification of the metal in the eno-
late anion did not alter the course of the reaction. Thus, the
experiment conducted with phenylcarbene complex 1a, po-
tassium enolate 2eK and propargylmagnesium bromide (3a)
analogously provided bicyclic 2-butenolide 4r (Table 1,
entry 19). On the other hand, two different reaction prod-
ucts were isolated when either an enolate anion with a steri-
cally bulky substituent or an alkynylcarbene complex were
employed. In the former case, treatment of phenylcarbene
complex 1a with tert-butyl methyl ketone lithium enolate
(2i) and then with propargylmagnesium bromide (3a) pro-
duced 4-methylidenecyclopentanol 5 as a single diastereoiso-
mer (Table 1, entry 20).[16] In the latter case, under similar
experimental conditions, the reaction of alkynylcarbene
complex 1h, isopropyl methyl ketone lithium enolate (2e)
and propargylmagnesium bromide (3a) yielded the open-
chain enediyne derivative 6 also as a single diastereoisomer
(Table 1, entry 21). Both of these compounds (cyclic 5 and
acyclic 6) have incorporated the carbon frameworks of the
three starting materials into their structures.
The structures of compounds 4–6, including the relative
stereochemistries of products 5 and 6, were unambiguously
established by 1D and 2D NMR spectroscopy[17] (the latter
was performed on compounds 4a,f, 5 and 6). Furthermore,
a single-crystal X-ray diffraction analysis of products 4 f,m[18]
confirmed the bicyclic g-alkylidenebutenolide structure of
products 4 (see the Supporting Information). The chemical
arrangement of these bicyclic 2-butenolides represents the
assembly of five reacting components through the efficient
À
À
formation of five new C C bonds and one C O bond in
a single-pot operation starting from three materials. The car-
bene ligand, two carbonyl ligands (located in the lactone
functional group of 4), the enolate framework and a propar-
gylic unit (embedded in the butenolide and cyclohexene
rings of 4 as a 3C synthon) have come together through
a formal intermolecular [2E +2P +1C +1CO]/intramolecular
[19]
[2P +2CO +1CO
]
cascade heterobicyclisation process. The
three independent inputs (R1, R2, R3) present in the final
products 4 offer a modular means to reaching structural di-
versity and complexity. The bicyclic products 4 feature an
À
a,b-unsaturated lactone ring conjugated with a C C double
bond at the g position in addition to an aromatic ring at-
tached to this unsaturation. This extended p-conjugated
system gives rise to the fluorescent properties of these mole-
cules; compounds 4 show intense blue fluorescence in solu-
tion and on TLC plates under a hand-held UV/Vis lamp
(l=365 nm).[20]
6–5 Bicyclic g-alkylidenebutenolides from imide enolates—
asymmetric synthesis: Next we explored the analogous cou-
pling reaction but with imide enolates. First, we studied the
performance of 3-acetyloxazolidin-2-one lithium enolate
(7a; prepared with LDA in THF at À788C) and 3-substitut-
ed propargylic organomagnesium reagents 3a,b,e (R2 =H,
TMS, PhCH2CH2, prepared as previously mentioned). The
results summarised in Table 2 show that the successive treat-
ment of an aryl- or heteroarylACTHNUGRTNEUNG(methoxy)carbene complex
1 with imide lithium enolate 7a (1.2 equiv) and then with
Grignard reagent 3a,b,e (2.6 equiv) under the experimental
conditions described[21] provided directly, and after hydroly-
sis and decoordination of the metal species, hydroxy- and
propargyl-substituted bicyclicACHTUNGTRNEUNG
[4.3.0] 2-butenolides rac-8.[22]
Propargylmagnesium bromide (3a, R2 =H), 3-trimethylsilyl-
propargylmagnesium bromide (3b, R2 =TMS) and 5-phenyl-
2-pentynylmagnesium bromide (3e, R2 =PhCH2CH2) al-
lowed the efficient and remarkable synthesis of bicyclic g-al-
kylidenebutenolides rac-8a,b, rac-8c–k and rac-8l,m, respec-
tively (Table 2, entries 1–13). The reaction of complex 1g,
lithium enolate 7a and 3-trimethylsilylpropargylmagnesium
bromide (3b) provided a mixture of propargyl-substituted 2-
butenolide rac-8k (major product, 53%) and allenyl-substi-
tuted 2-butenolide
9 (minor product, 20%; Table 3,
entry 11). This minor structural isomer 9 results from the si-
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J. Flꢀrez et al.
Table 2. Selective synthesis of bicyclic 2-butenolides rac-8 from imide
lithium enolates.[a]
Entry
1
R1
3
R3
rac-8
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1d
1a
1b
1h
1i
1c
1j
1k
1e
Ph
2-furyl
Ph
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
H
H
rac-8a
rac-8b
rac-8c
rac-8d
rac-8e
rac-8 f
rac-8g
rac-8h
rac-8i
rac-8j
rac-8k
68
75
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
67 (38)[c]
81
Scheme 2. Enantioselective synthesis of bicyclic 2-butenolides ent-8. Re-
agents and conditions: 1) 7c (1.2 equiv), À788C, 15 min; 2) 10b,e
(2.6 equiv), À788C, 30 min, then À558C, 12 h and then À55 to 208C, 8 h;
3) NH4Cl (saturated aqueous solution, 20 mL).
2-naphthyl
p-MeOC6H4
p-TBSOC6H4
p-ClC6H4
p-BrC6H4
p-CF3C6H4
2-thienyl
65
78
77
89
9
79
rectly to a mixture of complex 1a and enolate 7b, a complex
reaction mixture was formed with no clearly identifiable
products. In addition, none of the reactions performed with
unsubstituted propargyl organocerium reagent 10a (R3 =H),
which was added to a reaction mixture of carbene complex
1a and lithium enolate 7b, provided the expected buteno-
lide, instead furnishing a mixture of unidentifiable prod-
ucts.[24]
Accordingly, addition at low temperature of a carbene
complex 1 to a THF solution of lithium enolate 7b (derived
from the S enantiomer of 3-acetyl-4-benzyl-2-oxazolidinone
and prepared with LDA in THF at À788C) followed by
treatment with organocerium reagent 10b or 10e and hy-
drolysis at room temperature produced bicyclic 2-buteno-
10
11
12
13
71
1g 5-TMS-2-furyl 3b
1e 2-thienyl
1g 5-TMS-2-furyl 3e PhCH2CH2 rac-8m 88
53[d]
80
3e PhCH2CH2 rac-8l
[a] Reaction conditions: 1) 7a (1.2 equiv), À788C, 15 min; 2) 3
(2.6 equiv), À788C, 30 min, then À558C, 12 h and then À55 to 208C, 8 h;
3) NH4Cl (saturated aqueous solution, 20 mL). [b] Yield of isolated pure
product based on carbene complex 1. [c] Chemical yield obtained when
this experiment was performed with only 1.1 equiv of organomagnesium
reagent 3b. [d] Compound 9 (20% yield) was also isolated in this experi-
ment. TBS=tert-butyldimethylsilyl.
Table 3. Enantioselective synthesis of bicyclic 2-butenolides 8 from imide lithium eno-
lates.[a]
multaneous introduction of the organomagnesium
reagent as both a propargyl and an allenyl fragment
into the same molecule.
The structures of the bicyclic compounds rac-8,
which, in addition to the g-alkylidene-2-butenolide
skeleton, contain a tertiary homopropargylic-alco-
hol unit, combines the carbene ligand, the enolate
framework, two propargyl fragments and two car-
bonyl groups, six reacting components that have
been joined together with the formation of six new
Entry
1
R1
10
R3
8
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
1a
1b
1h
1i
1c
1j
1e
1g
1g
Ph
10b
10b
10b
10b
10b
10b
10b
10b
10e
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
8c
8d
8e
8 f
8g
8h
8j
70
73
69
70
77
63
88
75
80
98
98
96
À
À
C C bonds and one C O bond.
2-naphthyl
p-MeOC6H4
p-TBSOC6H4
p-ClC6H4
p-BrC6H4
2-thienyl
We next examined the enantioselective synthesis
of compounds rac-8 by using chiral imide enolates
7b,c and found that both enantiomers of the het-
98 [d]
99
99
98
99
99
A
ACHTUNGTRENNUNGbicyclic structures are readily accessible with
a
5-TMS-2-furyl
5-TMS-2-furyl
8k
8m
PhCH2CH2
Scheme 2). To be successful in this asymmetric syn-
thesis it was necessary to employ propargylic orga-
nocerium reagents 10, which were generated by
transmetallation of the corresponding propargylic
[a] Reaction conditions: 1) 7b (1.2 equiv), À788C, 15 min; 2) 10 (2.6 equiv), À788C,
30 min, then À558C, 12 h and then À55 to 208C, 8 h; 3)3) NH4Cl (saturated aqueous
solution, 20 mL). [b] Yield of isolated pure product based on carbene complex 1.
[c] Enantiomeric excess determined by HPLC analysis on a chiral stationary phase
(Chiralcel OD-H or ChiralPak IC column) and compared with the corresponding rac-
emic mixture rac-8. [d] Recovery of the chiral auxiliary (S)-4-benzyl-2-oxazolidinone
organomagnesium compounds
3
with CeCl3
(1.2 equiv) in THF at 08C for 1 h.[23] When proparg-
yl organomagnesium reagents 3a,b were added di- was accomplished in 81% yield by flash column chromatography.
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Bicyclic Butenolides by Cascade Heterobicyclisation
FULL PAPER
lides
8
as almost enantiomerically pure compounds
(Table 3). Similar experiments carried out with enolate
anion 7c, prepared from the R enantiomer of 3-acetyl-4-
benzyl-2-oxazolidinone (treatment with LDA in THF at
À788C), also occurred with high asymmetric induction in
the generation of the quaternary stereogenic centre to
afford the corresponding enantiomers of compounds 8 (ent-
8d,g,l; Scheme 2). These bicyclic heterocycles 8, which like-
wise incorporate the above-mentioned fluorophore scaffold
g-(2-arylalkylidene)-2-butenolide, are also blue-light-emit-
ting molecules that display deep-blue fluorescence in solu-
tion.[25]
The structures of compounds 8 were determined by 1D
and 2D NMR spectroscopy[17] (the latter experiments were
performed on compounds rac-8a and rac-8l). In addition,
single-crystal X-ray diffraction analysis of butenolide rac-8a
confirmed the structural assignment.[26] The absolute config-
urations of compounds 8 (Table 3) and ent-8 (Scheme 2)
were assigned by analogy with our previous results,[5] but
they have not been confirmed.[27]
The TMS groups bonded to the alkynyl and alkenyl posi-
tions of products 8c,g and ent-8d were easily removed by
treatment with tetrabutylammonium fluoride (TBAF) trihy-
drate in THF (Scheme 3). These reactions proceeded very
Scheme 4. Mechanistic pathway for the formation of 6–5 bicyclic g-alkyli-
dene-2-butenolides 8.
Scheme 3. Removal of the TMS groups. Formation of bicyclic 2-buteno-
lides 8a,n and ent-8o.
anion 7b to the carbene carbon atom of complex 1 provides
lithium alkylpentacarbonylchromate intermediate A. The
subsequent regioselective nucleophilic addition of substitut-
ed propargyl organocerium reagent 10 to the exocyclic car-
bonyl group of the N-acyl-2-oxazolidinone moiety of A led
to lithium pentacarbonyl-5-alkynylchromate intermediate B.
This process allows removal of the chiral auxiliary group
with concomitant incorporation of two propargyl units.[31]
efficiently with preservation of the stereocentre to yield
highly enantioenriched butenolides 8a,n and ent-8o (the
enantiomeric purity of these derivatives was verified by
HPLC analysis on a chiral support: ChiralPak IC or Chiral-
cel OD-H column).[28] This two-step procedure gave access
to the chiral non-racemic butenolides 8 and ent-8 with R3 =
H, which could not be directly formed by using propargyl
organocerium reagent 10a, as stated before.[29,30]
À
The presence of a C C triple bond at the 5-position with re-
À
spect to the C Cr s bond in chromate complex B is a struc-
Reaction mechanism: A mechanistic pathway that accounts
for the formation of 6–5 bicyclic g-alkylidenebutenolides 4,
8 and 9 is exemplified by the formation of highly enantio-
merically enriched compounds 8 from chiral imide lithium
enolate 7b and is illustrated in Scheme 4. In accordance
with our previous results,[5] nucleophilic addition of enolate
tural feature held in common with that of chromate inter-
mediates generated after nucleophile addition to the car-
bene carbon atom of 5-alkynylcarbene complexes.[10] There-
fore complex B could undergo similar intramolecular struc-
tural transformations. 1) Insertion of a carbonyl ligand into
3
À
the C
N
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J. Flꢀrez et al.
ACHTUNGTRENNUNGtetracarbonylchromate complex C. 2) Intramolecular inser-
À
tion into the C(O) Cr s bond of the suitably positioned
alkyne group affords tetracarbonyl-3-oxoalkenylchromate
intermediate D, which is in equilibrium with tetracarbonyl-
b-oxyalkenylcarbene complex E. The diastereoselectivity of
this cyclisation reaction would be controlled as shown in in-
termediate C by chelation of the lithium cation to both sp3-
hybridised oxygen atoms of the chain.[4c,5,32] 3) A second car-
bonyl ligand insertion process taking place in this case into
À
the chromium carbene carbon double bond of complex E
produces (b-oxyalkenylketene)tricarbonylchromium com-
plex F, which undergoes annulation by intramolecular nucle-
ophile trapping of the chromium-bound ketene unit to give
2-oxyfuran derivative G.[33] 4) A final lithium methoxide
elimination with simultaneous generation of the g-alkyli-
dene-2-butenolide core leads to tricarbonylchromium-bound
intermediate H, which, after hydrolysis and metal decoordi-
nation, affords the corresponding bicyclic butenolide 8. The
sense of asymmetric induction observed in these reactions
can be rationalised by invoking a six-membered chair-like
transition-state model I (Zimmerman–Traxler-type) for the
initial addition reaction, which indicates a chelated enolate
approaching the carbene complex from the less hindered
face (Scheme 4). The formation of a minor amount of chro-
mate complex J, which incorporates both a propargyl and an
allenyl chain from the same propargylic organomagnesium
reagent 3 f and undergoes selective cyclisation through the
alkyne unsaturation, may explain the isolation of butenolide
9.
On the other hand, a similar cascade reaction pathway
starting with intermediates A’ and B’ would explain the for-
mation of bicyclic butenolides 4 from ketone lithium eno-
lates (Scheme 5). The diastereoselectivity presumably ob-
served in the reaction of the initial adduct A’ with a propar-
gylic organomagnesium reagent 3 (R3 =H, TMS, PhCH2,
Me) to give intermediate B’ may arise from the lower-
energy chelation-controlled transition state with a chair-like
conformation (approach topology K) in which the lithium
and magnesium atoms are coordinated to both carbonyl and
methoxy group oxygen atoms and the pentacarbonylchromi-
um substituent is in an equatorial position. Addition of the
organomagnesium reagent to the less-hindered face of the
carbonyl group (back face in model K) then gives intermedi-
ate B’.[4b] The mechanism of the reactions of propargyl/allen-
yl organometallics with carbonyl compounds is thought to
be a cyclic SE2’ process, which affords allenic/homopropar-
gylic products, respectively.[14a] Accordingly, an allenyl struc-
ture is assumed for the organomagnesium reactive spe-
cies.[34]
Scheme 5. Mechanism proposed for the formation of compounds 4, 5 and
6.
enediyne derivative 6 can be rationalised by assuming the
formation of the corresponding lithium 5-hexynylchromate
complex B’’’ with a linear alkynyl group at C-1. This inter-
mediate B’’’, which presumably adopts a more extended
chain conformation (smaller steric requirement of the C-
1 alkyne substituent), seems to undergo lithium methoxide
elimination to provide non-heteroatom-stabilised alkynylcar-
bene complex M, which would then undergo decomposition
by a formal 1,2-proton shift. This last process could occur by
a deprotonation to give lithium alkenylchromate complex N
2
À
followed by protonation of the C
G
rectly to the Z isomer 6. The favoured configuration of in-
termediate N would be expected to have the bulky (CO)5Cr
fragment and the large tertiary alcohol chain group trans to
one another.[35]
The formation of 4-methylenecyclopentanol
5 would
result from the evolution of intermediate B’’ through an in-
tramolecular carbometallation reaction of the terminal
alkyne group to afford intermediate L and, after hydrolysis,
product 5 (Scheme 5). The presence of the bulky tert-butyl
group could induce a more folded chain conformation and
Conclusion
3
À
therefore favour the insertion of the alkyne into the C
G
We have established a novel five- or six-component tandem
heterobicyclisation approach for the synthesis of fused 6–5
Cr s bond over CO insertion. In addition, the isolation of
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Bicyclic Butenolides by Cascade Heterobicyclisation
FULL PAPER
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ly available starting materials: carbene complex, ketone or
imide enolate and a propargylic organomagnesium reagent
that is selectively incorporated as a propargyl moiety. This
strategy was performed in a single-pot operation and offers
a rapid and efficient procedure for the introduction of three
points of structural diversity into these potentially useful
heterocycle scaffolds, which in addition are novel fluores-
cent core skeletons. Both enantiomers of these products
were prepared in highly enantioenriched form by using
chiral N-acetyl-2-oxazolidinone lithium enolates. The con-
struction of these fused heterocyclic compounds involves the
selective sequential coupling of the three starting materials
followed by a cascade double annulation process in which
an alkyne group and two carbonyl ligands are the key struc-
tural elements. To the best of our knowledge this is the first
multicomponent and highly enantioselective pathway to
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ic handle for further coupling or derivatisation.
Experimental Section
Full experimental details can be found in the Supporting Information.
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Acknowledgements
We are grateful to Prof. J. Barluenga, University of Oviedo, for his con-
stant support and helpful discussions. This work was financially supported
by the Ministerio de Ciencia e Innovaciꢀn of Spain (MICINN, grant nos.
CTQ2007-61048/BQU and CTQ2010-16790). M.G.S. and R.D.C. thank
the MEC of Spain for FPU predoctoral fellowships. We thank also Prof.
P. J. Campos and Dr. R. Alonso (University of La Rioja) for help with X-
ray analysis and Prof. J. M. Costa and A. M. Coto (University of Oviedo)
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[9] For the cyclisation of cyclic 1,3-bis(trimethylsilyloxy)-1,3-butadienes
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will be isolated but with
a
lower chemical yield (see Table 2,
entry 3). This same behaviour was observed in an analogous reac-
tion carried out with allylmagnesium bromide (1.1 equiv) instead of
propargylmagnesium bromide 3a, which provided the corresponding
cyclic derivative shown in the scheme in a chemical yield of only
43% (compared with 85% when 2.6 equiv were employed; see
refs. [4a,b]). These results will be reported separately.
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À
[11] Most of the structures prepared by this method lack the carbon
carbon double bond at the g position of the butenolide ring.
[12] These lithium enolates 2 can be prepared either from the corre-
sponding ketone and LDA or from the corresponding trimethylsilyl
enol ether and BuLi. Both procedures are equally valid in this heter-
obicyclisation process.
[24] To the best of our knowledge organocerium reagent 10a (R3 =H)
has not been described previously. To prepare this derivative,
Grignard compound 3a (R3 =H) was treated with CeCl3 (1.2 equiv)
in THF at 08C for 1 h and also at À788C for the same period of
time.
[25] Compound 8k exhibits high fluorescence emission with excitation
and emission wavelengths at 395 and 466 nm, respectively, and
a large Stokes shift coupled to high brightness and good photostabil-
ity (the fluorescence data were measured in CH2Cl2). See the Sup-
porting Information.
[13] The regioselectivity of the reactions of propargylmetals with carbon-
yl compounds, which remains an important challenge in organic syn-
thesis, seems to be controlled both by the structural nature (prop-
argyl-allenyl isomers) of the reactive organometallic species in-
volved in the reaction and by the nature of the electrophilic reaction
partner.
[14] a) H. Yamamoto 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. Rodrꢁ-
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K. Miyoshi, Y. Kobayashi, Org. Lett. 2007, 9, 3535–3538, and refer-
ences therein.
[26] L. Torre-Fernꢂndez, M. G. Suero, S. Garcꢁa-Granda, Acta Crystal-
logr. E 2010, 66, o2834.
[27] This assignment is also supported by the sense of asymmetric induc-
tion observed in similar cyclisation reactions conducted with carbene
complexes 1, imide lithium enolate 7b or 7c and allylmagnesium
bromide. In these cases, the absolute stereochemistry was unambigu-
ously determined by X-ray crystallographic analysis of two enantio-
mers (unpublished results from our laboratory).
[28] In a similar way to that presented in Scheme 3, racemic compounds
rac-8c,d,g were transformed into racemic butenolides rac-8a,n,o,
which were used in the HPLC analysis (see the Supporting Informa-
tion).
[15] K. Fuchibe, N. Iwasawa, Chem. Eur. J. 2003, 9, 905–914 and referen-
ces cited therein.
[16] This unexpected result was confirmed by performing the same ex-
periment again under identical reaction conditions; cyclopentanol 5
was isolated in a similar chemical yield (68%).
[17] 1H, 13C, DEPT, HSQC, HMBC, COSY and NOESY NMR spectra
were recorded.
[18] CCDC-831310 (4 f), CCDC-831311 (4m), and CCDC-799611 (rac-
8a) contain 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.
[29] Although bicyclic butenolides 8a and 8p are solid materials we did
not succeed in preparing crystals suitable for single-crystal X-ray
analysis.
[19] Topological identification of the cyclisation reaction, which is used
in a formal sense to describe the number of atoms provided by each
fragment to the final cycloadduct (E=enolate anion, P=propargyl
group, C=carbene ligand, CO=carbonyl ligand).
[20] The fluorescence spectra (excitation and emission spectra recorded
in CH2Cl2) of products 4b,c,e,h,j are provided in the Supporting In-
formation. These compounds display strong blue fluorescence in so-
lution with large Stokes shifts.
[30] The TBS group bonded to the phenolic oxygen of compound 8 f was
selectively removed in the presence of the Csp2- and Csp-bonded
TMS groups by treatment with potassium fluoride. This reaction in
DMF/THF resulted in the formation of butenolide 8p with a phenol
ring. Conservation of the enantiomeric purity was proved by HPLC
analysis on a Chiralcel OD-H column (the racemic derivative rac-8p
was analogously prepared from rac-8 f, see the Supporting Informa-
tion and ref. [29]).
[21] Preliminary studies revealed that in the second step of these experi-
ments it was necessary to extend the reaction time at low tempera-
ture for the cyclisation reaction to reach completion (Table 2:
À788C, 30 min, À558C, 12 h and À55 to 208C, 8 h versus Table 1:
À78 to À558C, 5 h and 208C, 30 min). This protocol is analogous to
that previously established for the multicomponent synthesis of the
4-allenyl-2-cyclohexenones reported in ref. [5].
[22] If these experiments are conducted with only 1 equiv of the
Grignard reagent 3, the corresponding g-alkylidenebutenolide rac-8
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Bicyclic Butenolides by Cascade Heterobicyclisation
FULL PAPER
[31] According to our results, the initial tetrahedral intermediate under-
goes a fast elimination of the oxazolidinone group and in conse-
quence a faster addition of the second organomagnesium (3)/orga-
nocerium (10) equivalent will occur.
[34] Organomagnesium reagents 3, initially prepared as propargyl struc-
ture 3P, may undergo a metallotropic rearrangement to produce al-
lenyl structure 3A.
[32] This lithium ion chelation is proposed on the basis of the results of
our DFT calculations on the mechanism of cyclisation of 5-hexenyl-
chromate intermediates (see ref. [4c]). However, the possibility that
either the magnesium or cerium cations could participate in this
oxygen atom coordination cannot be completely ruled out.
[33] This interaction of the negatively charged oxygen with the central
carbon atom of the ketene moiety has previously been described for
different dicarbonyl–metal complexes, see: a) B. G. Van den Hoven,
B. ElAli, H. Alper, J. Org. Chem. 2000, 65, 4131–4137; b) ref. [10e],
and references therein.
[35] This reaction path has previously been proposed to explain an anal-
ogous transformation, see: C. P. Casey, W. R. Brunsvold, Inorg.
Chem. 1977, 16, 391–396.
Received: July 25, 2011
Revised: January 24, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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J. Flꢀrez et al.
Asymmetric Synthesis
M. G. Suero, R. De la Campa,
L. Torre-Fernꢁndez, S. Garcꢂa-Granda,
J. Flꢃrez* ...................... &&&& — &&&&
Enantioselective Multicomponent
Synthesis of Fused 6–5 Bicyclic 2-Bute-
nolides by a Cascade Heterobicyclisa-
tion Process
Concise, versatile assembly: The use of
three different organometallic com-
pounds has led to the one-pot regiose-
lective coupling of six reacting compo-
nents to yield bicyclic g-alkylidenebu-
tenolides with excellent enantioselec-
tivities (see scheme). These novel het-
erocycles are fluorescent building
blocks with attractive functionalities
for organic synthesis.
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10
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www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!