Butenolide synthesis by molybdenum-mediated hetero-Pauson-Khand reaction of alkynyl aldehydes

Article abstract of DOI:10.1021/ja0684186

The highly reactive complex Mo(CO)₃(DMF)₃ promotes the CO gas-free cyclocarbonylation of 1,5- and 1,6-alkynyl aldehydes under very mild reaction conditions to provide fused butenolides in good yields. This novel Mo-mediated hetero-Pa

Full text of DOI:10.1021/ja0684186

Published on Web 01/04/2007
Butenolide Synthesis by Molybdenum-Mediated Hetero-Pauson-Khand
Reaction of Alkynyl Aldehydes
Javier Adrio* and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad Auto´noma de Madrid,
Cantoblanco 28049 Madrid, Spain
Received November 23, 2006; E-mail: javier.adrio@uam.es; juancarlos.carretero@uam.es
Table 1. Screening of Reaction Conditions for the Hetero-PKR of
The Pauson-Khand reaction (PKR), the formal transition-metal-
the Model Substrate 1
mediated three-component cycloaddition of an alkyne, an alkene,
and carbon monoxide, constitutes one of the most useful and
convergent methods for cyclopentenone synthesis.1 In contrast, the
hetero variant of this process,2 and especially that involving the
use of a carbonyl partner instead of the alkene component, has been
entry
metal complex
conditions
yield (%)a
much less studied despite the synthetic and natural product relevance
of the resulting butenolide unit.3 The first isolated example of this
strategy was reported by Buchwald in 1996 by a low-yielding
titanocene-mediated cyclocarbonylation of an alkynyl ketone under
a carbon monoxide atmosphere.2a One year later, Murai described
a more general protocol by the Ru-catalyzed hetero-PKR of alkynyl
aldehydes under a carbon monoxide atmosphere and a high
temperature (160 °C).4 However, as an important drawback, this
procedure cannot be applied to terminal alkynes. To the best of
our knowledge, the only CO gas-free carbonylation of alkynes and
aldehydes to give butenolides has been recently reported by
Morimoto using a Rh-catalyzed process, albeit this procedure is
limited to intermolecular processes involving formaldehyde as the
carbonyl partner.5
Recently, we reported that the readily available molybdenum
complex Mo(CO)3(DMF)3 efficiently promotes the intramolecular
PKR of enynes in the absence of any promoter.6 Extending the
synthetic relevance of this highly reactive molybdenum carbonyl
complex, we describe herein a very mild and general CO gas-free
procedure for the synthesis of fused R,â-butenolides by the hetero-
PKR of alkynyl aldehydes.
1
2
3
4
Co2(CO)8
Mo(CO)6
Mo(CO)3(CN)3
Mo(CO)3(DMF)3
NMO, rt, CH2Cl2, 16 h
toluene, DMSO, 100 °C, 16 h
THF, rt, 3 h
0
0
53
71
THF, rt, 15 min
a Isolated yield after column chromatography.
Table 2. Mo-Mediated Hetero-PKR of 1,5-Yne Aldehydes
entry
X
R
substrate
time (min)
product
yield (%)a
1
2
3
4
5
6
7
C(CO2Et)2
C(CO2Et)2
C(CO2Et)2
N-Boc
N-Boc
CH2
Ph
Me
H
Ph
H
1
3
15
15
2
4
71
63
61
70
66
68
60
5
15
6
7
15
8
9
11
13
15
120
120
10
12
14
Ph
H
CH2
a Isolated yield after column chromatography.
(entries 6 and 7). Disappointingly, no cyclization at all was observed
when an alkynyl ketone substrate was tested under the same reaction
conditions.9
As a starting point, the alkynyl aldehyde 1 was selected as a
model substrate for the cyclocarbonylation process (Table 1).
Preliminary experiments showed that no reaction was observed
when stoichiometric amounts of Co2(CO)8 or Mo(CO)6 were used
under usual cobalt- or molybdenum-mediated PKR conditions7
(entries 1 and 2). On the contrary, in the presence of the
commercially available complex Mo(CO)3(CH3CN)3, the reaction
occurred at room temperature in THF8 to provide the butenolide 2
in 53% yield after 3 h (entry 3), showing the necessity of having
labile ligands at the molybdenum atom. To our delight, the complex
Mo(CO)3(DMF)3 proved to be even more reactive (15 min) and
efficient (71% yield, entry 4).
With these optimal reaction conditions in hand, Table 2 sum-
marizes the results obtained in the hetero-PKR of a variety of 5-yne
aldehydes. Remarkably, in contrast to the previously reported Ru-
catalyzed cyclocarbonylation process,4 where alkyne disubstitution
is required, this Mo-promoted reaction led to the butenolide adducts
in high yields (60-71%) with both terminal (entries 3, 5, and 7)
and disubstituted alkynes (entries 1, 2, 4, and 6). It is also interesting
to note that the presence of substituents in the tether to restrict the
conformational mobility of the substrate is not necessary for the
success of the cyclization, albeit higher reaction times are required
Next, we extended the procedure to the cyclocarbonylation of
6-yne aldehydes (Table 3). Although the reaction also occurred
mildly under the standard reaction conditions, with these substrates,
a variable amount of the exo-methylene alcohol B, the result of a
noncarbonylative reductive cyclization, was formed as a minor
product. In an attempt to inhibit this competitive process, several
additives were studied.10 Interestingly, the use of Et3B as a Lewis
acid additive11 produced a significant enhancement of the selectivity
in favor of the butenolide formation. Under these new reaction
conditions, the five tested yne aldehydes provided the corresponding
butenolides in satisfactory isolated yields (63-73%), regardless of
the substitution at the tether and alkyne terminus (entries 3-7).
To enlarge the structural scope of this Mo-mediated cyclocar-
bonylation, we turned our attention to the synthesis of chiral
nonracemic butenolides from readily available enantiopure R-sub-
stituted yne aldehydes (Table 4). Thus, aldehyde 25 was readily
prepared in three steps from (S)-ethyl lactate and subjected to the
usual hetero-PKR conditions, providing the butenolide 26 as the
only detectable product in good yield (68%) and high exo selectivity
(exo/endo ) 92:8, entry 1).12 An even better chemical and
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J. AM. CHEM. SOC. 2007, 129, 778-779
10.1021/ja0684186 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Mo-Mediated Hetero-PKR of 1,6-Yne Aldehydes
In summary, we have developed an efficient and general Mo-
mediated cyclocarbonylation of 1,6- and 1,7-yne aldehydes. This
novel hetero-PKR occurs under very mild conditions in the absence
of a carbon monoxide gas atmosphere. Starting from readily
available chiral aldehydes, highly valuable, enantiomerically pure
fused butenolides are obtained.
entry
X
R
substrate
additive
product
A:Ba
yield (%)b
Acknowledgment. Financial support by the Ministerio de
Educacio´n y Ciencia (MEC, BQU2003-0508), Consejer´ıa de
Educacio´n de la CAM, and the Universidad Auto´noma de Madrid
(UAM/CAM (08/PPQ/001)) is gratefully acknowledged. J.A. thanks
the MEC for a Ramon y Cajal contract.
1
2
3
4
5
6
7
C(CO2Et)2
C(CO2Et)2
C(CO2Et)2
C(CO2Et)2 Me
N-Boc
H
H
H
15
15
15
17
19
21
23
16
16
16
18
20
22
24
82:18
88:12
92:8
>98:<2
>98:<2
93:7
69
65
63
73
72
70
65e
Et3Bc
Et3Bd
Et3Bd
Et3Bd
Et3Bd
Et3Bd
H
Ph
H
N-Boc
C(SO2Ph)2
Supporting Information Available: Experimental procedures,
characterization data of new compounds, copies of NMR spectra, and
X-ray crystallography data of exo-34 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
90:10
a Determined by 1H NMR of the crude mixtures. b Isolated yield in adduct
A after column chromatography. c 10 mol % of Et3B. d 100 mol % of Et3B.
e Yield in A + B mixture.
References
Table 4. Mo-Mediated Hetero-PKR of Enantiomerically Pure Yne
Aldehydes
(1) For a recent review on PKR, see: Struebing, D.; Beller, M. In Transition
Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-
VCH: Weinheim, Germany, 2004; pp 619-632.
(2) Main versions of oxa-hetero-PKR and related processes. For Ti-mediated
cyclocarbonylation of alkenyl ketones and aldehydes, see: (a) Kablaoui,
N. M.; Hicks, H. A.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 5818-
5819. (b) Crowe, W. E.; Vu, A. T. J. Am. Chem. Soc. 1996, 118, 1557-
1558. (c) Kablaoui, M.; Hicks, H. A.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 4424-4431. (d) Mandal, S. K.; Amin, S. R.; Crowe, W. E. J.
Am. Chem. Soc. 2001, 123, 6457-6458. For Ru-catalyzed cyclocarbo-
nylation of allenyl aldehydes and ketones, see: (e) Kang, S.-K.; Kim,
K.-J.; Hong, Y.-T. Angew. Chem., Int. Ed. 2002, 41, 1584-1586. For
Ni-mediated cyclocarbonylation of alkenyl aldehydes, see: (f) Ogoshi,
S.; Oka, M.; Kurosawa, H. J. Am. Chem. Soc. 2004, 126, 11802-11803.
For Mo-mediated cyclocarbonylation of allenyl or cyclopropylidenyl
aldehydes, see: (g) Yu, C.-M.; Hong, Y.-T.; Yoon, S.-K.; Lee, J.-H. Synlett
2004, 1695-1698. (h) Yu, C.-M.; Hong, Y.-T.; Lee, J.-H. J. Org. Chem.
2004, 69, 8506-8509.
entry
X
R1
R2
substrate
product
exo:endoa
yield (%)
1
2
3
4
5
O
O
O
Me
Me
Me
iPr
H
25
27
29
31
33
26
28
30
32
34
92:8
>98:<2
>98:<2
14:86
68b
71
Me
Ph
H
76
N-Boc
N-Boc
62b
73c
iPr
Ph
30:70
a Determined by 1H NMR of the crude mixtures. b Yield in the mixture
exo/endo after column chromatography. c Yield of 51 and 22% of endo and
exo adducts, respectively, after column chromatography.
(3) (a) Bruckner, R. Curr. Org. Chem. 2001, 5, 679-718. γ-Butyrolactones
are present in about 10% of all natural products. See: (b) Seitz, M.; Reiser,
O. Curr. Opin. Chem. Biol. 2002, 6, 453-458.
(4) Chantani, N.; Morimoto, T.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc.
1998, 120, 5335-5336.
Scheme 1. Synthesis of the (+)-Dihydrocanadensolide Epimer 35
(5) Fuji, K.; Morimoto, T.; Tsutsumi, K.; Kakiuchi, K. Chem. Commun. 2005,
3295-3297.
(6) Adrio, J.; Rodr´ıguez-Rivero, M.; Carretero, J. C. Org. Lett. 2005, 7, 431-
434.
(7) For leading references on Mo-mediated PKR of enynes, see: (a)
Brummond, K. M.; Curran, D. P.; Mitasev, B.; Fischer, S. J. Org. Chem.
2005, 70, 1745-1753. (b) Cao, H.; Van Ornui, S. G.; Deschamps, J.;
Flippen-Anderson, J.; Laib, F.; Cook, J. M. J. Am. Chem. Soc. 2005, 127,
933-935.
(8) Lower yields were obtained in other solvents, such as toluene, CH2Cl2,
or CH3CN.
stereochemical outcome was obtained with the phenyl- and methyl-
substituted alkynes 27 and 29, which provided the exo adducts with
complete selectivity (entries 2 and 3). In contrast, the N-Boc
aldehydes derived from L-valine (31 and 33, entries 4 and 5) led to
the corresponding butenolides with similar yields but reversed
diastereoselectivity, showing the sensitivity of the exo/endo ratio
to the substitution at the R-position and tether.13 We also checked
that the hetero-PKR takes place without racemization at the
R-position of aldehydes 29 and 33, as confirmed by the very high
enantiopurity of the butenolides 30 and endo-34 (96 and 98% ee,
respectively, HPLC).
To highlight its synthetic potential, this highly convergent
approach to the synthesis of bicyclic butenolides was finally applied
to the straightforward synthesis of an epimer of dihydrocanaden-
solide (35), a biologically active bislactone metabolite isolated from
Penicillium canadense (Scheme 1).14 The exposure of the enan-
tiomerically pure aldehyde 36 to the usual Mo-mediated reaction
conditions afforded the butenolide 37 (61% yield) with complete
exo selectivity. Hydrogenation of the C-C double bond followed
by Ru-catalyzed ether-to-ester oxidation under Sharpless’ condi-
tions15 gave rise to the bislactone 35 as a single stereoisomer in
80% overall yield.
(9) No reaction at all occurred when diethyl 2-(2-oxopropyl)-2-propargyl-
malonate was used as substrate.
(10) For example, the addition of isopropanol or water produced a decrease in
the reaction yield, while the use of PPh3 did not significantly affect the
A/B selectivity.
(11) For an example of the use of boranes as Lewis acid in metal-mediated
aldehyde cyclizations, see: Yu, C.-M.; Youn, J.; Lee, M.-K. Org. Lett.
2005, 7, 3733-3736.
(12) The endo/exo configurational assignment was established by 1H NMR
experiments and by X-ray diffraction analysis of exo-34 (see Supporting
Information for details).
(13) Although the Co-mediated PKR of allylic-substituted 1,6-enynes is usually
exo selective (see for instance (a) Magnus, P.; Principe, L. M. Tetrahedron
Lett. 1985, 26, 4851-4854. (b) Mukai, C.; Kim, J. S.; Sonobe, H.;
Hanaoka, M. J. Org. Chem. 1999, 64, 6922-6832), some examples of
endo selective PKR have been reported (see for instance (c) Adrio, J.;
Rodriguez-Rivero, M.; Carretero, J. C. Angew. Chem., Int. Ed. 2000, 39,
2906-2909. (d) Rios, R.; Perica`s, M. A.; Moyano, A.; Maestro, M. A.;
Mahia, J. Org. Lett. 2002, 4, 1205-1208).
(14) For the isolation of dihydrocanadensolide, see: (a) McCorkindale, N. J.;
Wright, J. L.; Brian, P. W.; Clarke, S. M.; Hutchinson, S. A. Tetrahedron
Lett. 2001, 42, 6183-6186. (b) Kato, M.; Kageyama, M.; Tanaka, R.;
Kuwahara, K.; Yoshikoshi, A. J. Org. Chem. 1975, 40, 1932-1941. For
recent synthesis, see: (c) Mulzer, J.; Kattner, L. Angew. Chem., Int. Ed.
1990, 29, 679-680. (d) Chen, M.-J.; Narkunan, K.; Liu, R.-S. J. Org.
Chem. 1999, 64, 8311-8311. (e) Sharma, G. V. M.; Gopinath, T.
Tetrahedron 2003, 59, 6521-6530.
(15) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936-3938.
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