Synthesis of (E)- and (Z)-α-alkylidene-γ-aryl-γ- butyrolactones via alkenylalumination of oxiranes

Article abstract of DOI:10.1021/ol702079f

(Chemical Equation Presented) Alkenylalumination of substituted styrene oxides with [α-(ethoxycarbonyl)alkenyl]diisobutylaluminum, in the presence of BF₃·Et₂O, affords the corresponding (Z)-α-alkylidene-γ-aryl-γ-hydroxy esters in 81-

Full text of DOI:10.1021/ol702079f

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4753-4756
Synthesis of (E)- and
(Z)- -Alkylidene- -aryl-γ-butyrolactones
r
γ
via Alkenylalumination of Oxiranes
P. Veeraraghavan Ramachandran,* Garrett Garner, and Debarshi Pratihar
Department of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
chandran@purdue.edu
Received August 23, 2007
ABSTRACT
Alkenylalumination of substituted styrene oxides with [
corresponding (Z)- -alkylidene- -aryl- -hydroxy esters in 81
with trifluoroacetic acid, provides isomerically pure (Z)- -alkylidene-
alkylidene hydroxyl esters using LDA, followed by protonation using a bulky proton source, such as BHT, provides a simple route to the
r
-(ethoxycarbonyl)alkenyl]diisobutylaluminum, in the presence of BF3
100% Z-selectivity. Chromatographic separation of isomers, followed by lactonization
-aryl- -butyrolactones in 53 78% overall yield. Isomerization of the (Z)-
‚Et2O, affords the
r
γ
γ
−
r
γ
γ
−
corresponding
r-(E)-alkylidene-γ-phenyl-γ-hydroxy esters in 72−78% yield, which were cyclized to obtain the corresponding (E)-butyrolactones
in 78 85% yield.
−
Interest in naturally occurring and synthetic R-alkylidene-
γ-butyrolactones is surging1 as several of them have been
identified to display anti-inflammatory COX-2 inhibition, as
well as phytotoxic and cytotoxic activities.2 The binding of
a series of suitably substituted γ-butyrolactones, particularly,
γ-substituted-R-alkylidene-γ-butyrolactones, which are ana-
logues of diacylglycerol (DAG) lactones, to protein kinase
C (PK-C) displays an enhanced affinity due to the R-alkyli-
dine group.3 This family of lactones has also been tapped
for their potential as versatile synthons.4 Even though there
are several protocols for their synthesis,1,5 very few offer
simple, direct routes.
We had previously reported the preparation of (Z)- or (E)-
R-alkylidene-γ-alkyl-γ-butyrolactones via a crotylboration-
oxonia-Cope process.6 This method is restricted to the
preparation of γ-alkyl derivatives since γ-aryl derivatives
undergo a carbocation-mediated rearrangement to provide
cis- or trans-â,γ-disubstituted-R-methylene-γ-butyrolactones
(4) Oh, S.; Jeong, I. H.; Shin, W.-S.; Wang, Q.; Lee, S. Bioorg. Med.
Chem. Lett. 2006, 16, 1656.
(5) (a) Katsumi, I.; Kondo, H.; Yamashita, K.; Hidaka, T.; Hosoe, K.;
Yamashita, T.; Watanabe, K. Chem. Pharm. Bull. 1986, 34, 121. (b)
Shaikenov, T. E.; Adekenov, S. M.; Williams, R. M.; Baker, F. L.; Prasad,
N.; Madden, T. L.; Newman, R. Oncol. Rep. 2001, 8, 173. (c) Nattrass, G.
S.; Diez, E.; McLachlan, M. M.; Dixon, D. J.; Ley, S. V. Angew. Chem.,
Int. Ed. 2005, 44, 580. (d) Biel, M.; Kretsovali, A.; Karatzali, E.;
Papamatheakis, J.; Giannis, A. Angew. Chem., Int. Ed. 2004, 43, 3974. (e)
Gonzalea, A. G.; Silva, M. H.; Pardon, J. I.; Leon, F.; Reyes, E.; Alvarez-
Mon, M.; Pivel, J. P.; Quintana, J.; Estevez, F.; Bermejo, J. J. Med. Chem.
2002, 45, 2358. (f) Trost, B. M.; Corte, J. R. Angew. Chem., Int. Ed. 1999,
38, 3664. (g) Trost, B. M.; Corte, J. R.; Gudiksen, M. S. Angew. Chem.,
Int. Ed. 1999, 38, 3662.
(1) (a) Tesaki, S.; Kikuzaki, H.; Yonemori, S.; Nakatani, N. J. Nat. Prod.
2001, 64, 515. (b) Moise, J.; Arseniyadis, S.; Cossy, J. Org. Lett. 2007, 9,
1695 and references cited therein. (c) Raju, R.; Allen, L.; Le, T.; Taylor,
C.; Howell, A. Org. Lett. 2007, 9, 1699. (d) Oh, S.; Jeong, I. H.; Shin,
W.-S.; Wang, Q.; Lee, S. Bioorg. Med. Chem. Lett. 2006, 16, 1656.
(2) (a) Janecki, T.; Blaszczyk, E.; Janecka, A.; Krajewaska, U.; Rozalski,
M. J. Med. Chem. 2005, 48, 3516. (b) Huang, W. C.; Chan, S. T.; Yang,
T. L.; Tzeng, C. C.; Chen, C. C. Carcinogenesis 2004, 25, 1925.
(3) (a) Kang, J. H.; Peach, M. L.; Pu, Y.; Lewin, N. E.; Nicklaus, M.
C.; Blumberg, P. M.; Marquez, V. E. J. Med. Chem. 2005, 48, 5738. (b)
Tamamura, H.; Bruno, B.; Nacro, K.; Nancy, E. L.; Blumberg, P. M.;
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10.1021/ol702079f CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/18/2007

romethane have appeared,12 although they are known to resist
lactonization by simple acid or base hydrolysis.13 Accord-
ingly, the R-methylene-γ-hydroxy ester was dissolved in
dichloromethane and treated with TFA for 2 h at rt to achieve
γ-phenyl-R-methylene-γ-butyrolactone (4a) in 88% isolated
yield (Scheme 3). The generality of the R-methylene-γ-aryl-
Scheme 1. Preparation of R-Alkylidene or
R-Methylene-γ-butyrolactones
Scheme 3. Vinylalumination and Lactonization of Styrene
Oxide
(Scheme 1).7 We have designed an approach for the synthesis
of the R-alkylidene-γ-aryl derivatives via the alkenylalumi-
nation8 of oxiranes9 or cyclic sulfates (Scheme 2) to over-
come the above limitation. The results of our study follows.
Scheme 2. Retrosynthetic Analysis
γ-butyrolactone synthesis was demonstrated by applying the
epoxide opening-lactonization sequence to 4-chloro- (2b),
4-fluoro- (2c), and 4-bromostyrene oxides (2d) to provide
the corresponding homoallylic alcohols in 84, 77, and 81%
yields, respectively, and the resultant butyrolactones in 93,
91, and 83% yields, respectively (Table 1).
The reaction of [R-(ethoxycarbonyl)vinyl]diisobutyl-
aluminum (1), prepared via the hydroalumination of ethyl
propiolate with Dibal-H-NMO complex10 and styrene oxide
(2a) in tetrahydrofuran (THF) at room temperature (rt), failed
to proceed even after 24 h. A solvent study was then
conducted, involving diethyl ether, toluene, and pentane, but
yielded no positive results. The lack of reactivity could be
attributed to the complexation of NMO with aluminum,8
preventing the necessary coordination of the epoxide. Indeed,
our earlier studies have shown that the alkenylalumination
of ketones can only be achieved with 1 in the presence of 1
equiv of BF3-Et2O.8,10
Table 1. Vinylalumination and Lactonization of Substituted
Styrene Oxidesa
homoallyl alcohol
yieldb
γ-lactone
yieldb
styrene oxide
entry
No.
X
No.
(%)
No.
(%)
After screening different Lewis acids, such as Me3Al,
Sc(OTf)3, In(OTf)3, Zn(OTf)2, Ti(OiPr)4, and BF3‚OEt2, it
was evident that only BF3‚Et2O was able to sufficiently
activate the epoxide for the vinylalumination. A 1.3 equiv
of BF3‚OEt2 was optimal, and additional equivalents did not
increase the 82% yield of the homoallylic alcohol, ethyl
4-hydroxy-2-methylene-4-phenylbutanoate (3a).
Surprisingly, the reaction of the cyclic sulfate, prepared
from styrene,11 did not undergo vinylalumination even under
the influence of Lewis acid catalysts.
1
2
3
4
2a
2b
2c
2d
H
Cl
F
3a
3b
3c
3d
82
84
77
81
4a
4b
4c
4d
88
93
91
83
Br
a Reaction conditions: styrene oxide 2 (3.0 mmol), BF3‚Et2O (2.6 mmol)
in 1 (2.0 mmol, in THF) at 0 °C for 8 h. Alcohol 3 (3.0 mmol),
trifluoroacetic acid (3.3 mmol) in CH2Cl2 at rt for 2-10 h. b Isolated yields
after chromatography.
We now focused on expanding this protocol to include
the alkenylaluminum reagents owing to the importance of
R-alkylidene-γ-butyrolactones. (Z)-[R-(Ethoxycarbonyl)-â-
methylvinyl]diisobutylaluminum (5), prepared via the hy-
droalumination of ethyl-2-butynoate with Dibal-H-NMO
complex in THF,10 also reacted with styrene oxides 2a-d
in the presence of BF3‚Et2O, providing homoallylic alcohols
6a-d in 76-82% yield with a Z/E ratio of 3:1 (Scheme 4,
Recently, reports on the lactonization of hydroxy esters
of the type 3a using trifluoroacetic acid (TFA) in dichlo-
(7) Ramachandran, P. V.; Pratihar, D.; Biswas, D. Org. Lett. 2006, 8,
3877.
(8) Ramachandran, P. V.; Rudd, M. T.; Burghardt, T. E.; Ram Reddy,
M. V. J. Org. Chem. 2003, 68, 9310.
(9) For cleavage of oxiranes with aluminum reagents, see: (a) Boireau,
G.; Abenhaim, D.; Henry-Basch, E. Tetrahedron 1980, 36, 3061. (b)
Boireau, G.; Abenha´ım, D.; Bernardon, C.; Henry-Basch, E.; Sabourault,
B. Tetrahedron Lett. 1975, 30, 2521. (c) Lundeen, A. J; Oehlschlager, A.
C. J. Organomet. Chem. 1970, 25, 337.
(10) Ramachandran, P. V.; Ram Reddy, M. V.; Rudd, M. T. Chem.
Commun. 1999, 19, 1979.
(12) (a) Zhou, J.; Jia, Y.; Yao, X.; Wu, S. Synth. Commun. 1996, 26,
2397. (b) Adam, W.; Groer, P.; Saha-Moller, C. R. Tetrahedron: Asymmetry
2000, 11, 2239.
(11) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538.
(13) Marino, J.; Linderman, R. J. J. Org. Chem. 1983, 48, 4621.
4754
Org. Lett., Vol. 9, No. 23, 2007

Scheme 4. Alkenylalumination-Cyclization of Substituted
Scheme 5. Tentative Mechanism for the Predominant
Formation of (Z)-Alkylidene Products via the
Alkenylalumination of Styrene Oxides
Styrene Oxides
We then desired to prepare the corresponding the R-(E)-
alkylidene-γ-aryl-γ-butyrolactones. Isomerization of croto-
nates using LDA is known,14 and a bulky proton source, such
as 2,6-di-tert-butyl-4-methylphenol (BHT), has been em-
ployed to preferentially protonate the less hindered position.
Accordingly, the reaction of (Z)-6a with LDA, followed by
treatment with BHT, provided the isomerized product (E)-
6a in 95% yield. The isomerization process, aided by the
chelation of the lithium to the oxygen anion, is illustrated in
Scheme 6. Lactonization using trifluoroacetic acid, as in the
case of (Z)-6a, provided (E)-7a in 82% yield.
Table 2). The selectivity remained the same with Et2O,
dioxane, and pentane as solvents. A 4:1 selectivity was
achieved in toluene, and this solvent was utilized for further
reactions. A tentative mechanism for the predominant
formation of the Z-isomer is given in Scheme 5.13 Fortu-
nately, the isomers could be readily separated by silica gel
chromatography, and lactonization provided the correspond-
ing isomerically pure R-(Z)-alkylidene-γ-phenyl-γ-butyro-
lactone (Z)-7a-d in 77-85% yields.
Table 2. Alkenylalumination and Lactonization of Substituted
Styrene Oxidesa
Scheme 6. Isomerization-Cyclization of Substituted Styrene
Oxides
homoallyl alcohol
yieldb
lactone
yieldb
styrene
oxide
entry reagent
No.
(%)
No.
(%)
1
2
3
4
5
6
7
8
9
5
5
5
5
5c
5c
5c
5c
8
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
(Z)-6a
(Z)-6b
(Z)-6c
(Z)-6d
(E)-6a
(E)-6b
(E)-6c
(E)-6d
(Z)-9a
(Z)-9b
(Z)-9c
(Z)-9d
76
77
81
82
72
73
77
78
74
72
76
75
(Z)-7a
(Z)-7b
(Z)-7c
(Z)-7d
(E)-7a
(E)-7b
(E)-7c
(E)-7d
(Z)-10a
(Z)-10b
(Z)-10c
(Z)-10d
82
85
84
77
80
85
85
78
79
79
70
74
A direct isomerization of the intermediate from alkenyl-
alumination, without the need for the isolation of the
homoallyl alcohol, provided 61% overall yield of (E)-6a
(Scheme 7). We preferred the isomerization of the isolated
10
11
12
8
8
8
a Reaction conditions: styrene oxide 2 (3.0 mmol), BF3‚Et2O (2.6 mmol)
in 5 or 8 (2.0 mmol, in THF) at 0 °C for 8 h. Alcohol 6 or 9 (3.0 mmol),
trifluoroacetic acid (3.3 mmol) in CH2Cl2 at reflux, for 2-10 h. b Isolated
yields after chromatography. c Reaction conditions: alcohol 5 (3.0 mmol)
added to LDA (12.0 mmol) in THF at -78 °C for 12 h. BHT (12 mmol)
in THF added at -78 °C and warmed to rt.
Scheme 7. One-Pot Alkenylalumination-Isomerization of
Styrene Oxide
However, exclusive Z-selectivity was achieved during the
ring opening of epoxides 2a-d with [R-(ethoxycarbonyl)-
â-phenylvinyl]diisobutylaluminum (8), generated via the
hydroalumination of ethyl-3-phenylpropiolate. The R-ben-
zylidene alcohols (Z)-9a-d obtained in 72-76% yields, upon
lactonization, afforded the corresponding R-benzylidene-γ-
butyrolactones (Z)-10a-d in 70-79% yields (Scheme 4,
Table 2).
Org. Lett., Vol. 9, No. 23, 2007
4755

homoallyl alcohols to the one-pot synthesis since we
achieved consistently higher overall yields. All of the (Z)-
alcohols (Z)-6b-d were converted to (E)-6b-d and lacton-
ized to (E)-7b-d in 78-85% yields.
Finally, we examined the alkenylalumination of 2,3-
disubstituted oxiranes (e.g., stilbene oxide) with 1 for the
preparation of â,γ-disubstituted-R-methylene-γ-butyrolac-
tones. Interestingly, both (E)- and (Z)-stilbene oxides pro-
vided the trans-lactone, 12, in 62% overall yield and >95%
diastereoselectivity (Scheme 8). The formation of trans-12
from both oxiranes can be rationalized via the formation of
the benzylic carbocation in the presence of BF3‚Et2O during
alkenylalumination, followed by the formation of the ther-
modynamic hydroxy ester, anti-11.
In conclusion, we have achieved a convenient and general
synthesis of R-(Z)-4-hydroxy-2-alkylidene-4-arylbutanoates
via alkenylalumination of the corresponding 2-aryloxiranes
using [R-(ethoxycarbonyl)alkenyl]diisobutylaluminum in the
presence of BF3-Et2O. The corresponding R-(E)-4-hydroxy-
2-alkylidene-4-arylbutanoates were achieved via the isomer-
ization of the alkenylalumination intermediate or the homo-
allylic alcohol with LDA, followed by quenching with BHT.
These hydroxy esters were lactonized using trifluoroacetic
acid to provide the corresponding R-(E)- or R-(Z)-alkylidene-
γ-phenyl-γ-butyrolactones in high yields. This reaction is
amenable to scale-up and should find applications in natural
product syntheses.
Scheme 8. Alkenylalumination of 2,3-Disubstituted Oxiranes
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL702079F
(14) Iwasa, S.; Yamamoto, M.; Kohmoto, S.; Yamada, K. J. Org. Chem.
1991, 56, 2849.
4756
Org. Lett., Vol. 9, No. 23, 2007