Custom synthesis of substituted butenolides, dihydropyranones, and α-E-alkylidenelactones via alkenylalumination

Article abstract of DOI:10.1016/j.tetlet.2011.06.103

Alkenylalumination of aldehydes with [α-(ethoxycarbonyl)-β-(t- butyldimethylsilyloxyalkyl)alkenyl]diisobutylaluminum provides the corresponding α-Z-alkylidene-β′-hydroxy esters, which upon protection and treatment with trifluoroacetic acid lactonizes to f

Full text of DOI:10.1016/j.tetlet.2011.06.103

Tetrahedron Letters 52 (2011) 4985–4988
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Custom synthesis of substituted butenolides, dihydropyranones,
and
a-E-alkylidenelactones via alkenylalumination
⇑
P. Veeraraghavan Ramachandran , Debarshi Pratihar, Garrett Garner, B. China Raju
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkenylalumination of aldehydes with [
sobutylaluminum provides the corresponding
and treatment with trifluoroacetic acid lactonizes to furnish
a
-(ethoxycarbonyl)-b-(t-butyldimethylsilyloxyalkyl)alkenyl]dii-
-Z-alkylidene-b0-hydroxy esters, which upon protection
-acetoxyalkyl butenolides (n = 1) and dihy-
dropyranones (n = 2) in 40% overall yield. Conjugate addition to these lactenones and concurrent acetate
Received 27 May 2010
Revised 21 June 2011
Accepted 27 June 2011
Available online 2 July 2011
a
a
elimination constitute a general and stereospecific synthesis of the corresponding
lactones.
a-E-alkylidene
Keywords:
Alkenylalumination
Butenolides
Ó 2011 Elsevier Ltd. All rights reserved.
Dihydropyranones
Lactones
1,4-Addition
a
,b-Unsaturated carbonyl moieties, such as butenolides, pyra-
nones, -alkylidene- -butyrolactones, and -d-valerolactones, are
structural motifs found in a multitude of natural products.1
Alkylidene-
-lactones display a variety of biological activities,2
syntheses of a variety of
a-Z- or E-alkyl(aryl)idene-b,c-disubsti-
a
c
tuted-c-butyrolactones were achieved via either a crotylboration-
a
-
cyclization16 or a crotylboration-oxonia-Cope rearrangement-cycli-
zation17 of aldehydes and alkenylalumination-cyclization of oxir-
c
including COX-2 inhibition, nuclear factor
j
B inhibition,3 and
anes.18 A simple synthesis of
a-alkylidene-d-valerolactones was
increased cellular resistance to oxidant injury in HepG2 cells.4
Accordingly, there has been considerable interest in the
achieved via the conjugate addition of ketone enolates to function-
alized allyl acetates.19
development of efficient protocols for the preparation of
a
-alkyl-
In continuation, we sought a more versatile, tailored process for
idene butyrolactones, during the past three decades.5 These in-
a
-alkylidene lactones of varying ring sizes and substitutions. We
envisioned a general synthesis of b0-substituted-
-unsubstituted-
-E-alkylidene- -butyrolactones, and -d-valerolactones via the
clude free-radical annelation of phenyl selenocarbonates,6
c
Horner-Wadsworth-Emmons condensations of
lactones,7 the Wittig reaction of
-(triphenylphosphoranylid-
ene)lactones8 or Wittig-Horner condensation of
-(dimethoxy-
a-phosphono
a
c
a
alkenylalumination of aldehydes using customized reagents. These
latter reagents were formed through the hydroalumination of TBS-
protected hydroxy alkynoates (Scheme 2). This process was also
meant to provide a general route for the synthesis of functionalized
butenolides and dihydropyranones. The results of our study are
presented herein.
a
phosphonyl)lactones,9 the
a-formylation of lactones, followed by
aldol type condensation,10 etc. Recently, the Cossy11 and Howell12
groups independently reported a cross metathesis protocol for the
synthesis of b,c-unsubstituted-a-E-alkylidene-c-butyrolactones.
In contrast, there are only few reports on the preparation of
a
-
The required alkynoates were prepared in 90–92% yield from
the TBS-protected alkyn-1-ols via deprotonation with n-butyllith-
ium at ꢀ78 °C, followed by a treatment with ethyl chloroformate
in tetrahydrofuran (THF). Ethyl 4-(tert-butyldimethylsilyloxy)but-
2-ynoate and ethyl 5-(tert-butyldimethylsilyloxy)pent-2-ynoate
were transformed to the corresponding alkenylaluminum reagents
1 and 2 via hydroalumination with DIBAL-H/NMO complex in THF
at 0 °C.20 Reagent 1 was mixed with benzaldehyde (3a) and stirred
alkylidene valerolactones.13
Inefficient, multi-step protocols, poor yields, and or poor E/Z
selectivity currently encountered in a-alkylidene lactone syntheses
call for new and improved methods.14 As part of an ongoing project
in the pursuit of anti-inflammatory and anti-cancer molecules,15 we
recently reported several protocols for the synthesis of a-methylene
and E- and Z-alkylidene-c- and d-lactones. These involved the alke-
nylalumination of aldehydes as the first step (Scheme 1).16–19 The
for 8 h at 0 °C. Acidic workup provided the a-alkylidene-b-hydro-
xy-b-phenyl ester (4a) in 58% overall yield (Scheme 2).21 The gen-
erality of this process was then demonstrated by carrying out the
reaction with 4-NO2PhCHO, (3b) as well as an aliphatic aldehyde,
⇑
Corresponding author. Tel.: +1 765 494 5303; fax: +1 765 494 0239.
E-mail address: chandran@purdue.edu (P. Veeraraghavan Ramachandran).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.103

4986
P. Veeraraghavan Ramachandran et al. / Tetrahedron Letters 52 (2011) 4985–4988
O
R
O
Ar
100%Z
CO2Et
O
R
R
O
DIBAL-H/
NMO
THF, 2 h
i-Bu2AlO
O
i-Bu2Al
OEt
OEt
Ar
Ar
BF3-Et2O
R
O
R = H
O
R'CHO
R
Ar
100%E
AcCl, Et3N
OLi
O
O
O
R1
OAc
CO2Me
R'
CO2Me
R2
R1
R'
R2
R1
R'
R2
O
O
O
TFA or
Yb(OTf)3
X = EDG
strong LA
O
O
O
R'
trans-
R'
CHO
O
CHO
X
X
OMe
R'
O
B
O
O
X = EWG
O
R'
weak/strong LA
In(OTf)3
R'
cis-
X = EDG
weak LA
X
Scheme 1. Alkenylalumination route to a-alkylidene/methylene-c- and d-lactones.
The preparation of butenolides and dihydropyranones from 4
was completed by the following transformation sequence: Treat-
ment of allylic alcohol 4a with acetyl chloride and pyridine in
dichloromethane afforded the allylic acetate 6a in 90% yield. Addi-
tion of trifluoroacetic acid (TFA), followed by heating the mixture
to reflux for 2 h resulted in both the removal of the TBS group
and concurrent lactonization to provide the butenolide 8a in 88%
yield—an overall yield of 50% for three steps. This protocol was
then extended to allylic alcohols 4b and 4c to yield the correspond-
ing acetates 6b and 6c and butenolides 8b and 8c, respectively
(Scheme 4, Table 2).
O
O
OH O
i-BuO
Al
CO2R
AcO
R
R
OR
OTBS
i-Bu
OR
OTBS
O
O
R
OTBS
Scheme 2. Retrosynthetic analysis of b0-substituted-
idene- -butyrolactones.
c
-unsubstituted-
a
-E-alkyl-
c
cyclohexanecarboxaldehyde (ChxCHO, 3c). The product hydroxy
esters 4b and 4c were obtained in 73% yield and 54% yield, respec-
tively. The results are summarized in Table 1. These same alde-
hydes, when treated with reagent 2, provided the corresponding
alcohols 5a–c, the precursors for the synthesis of pyranones and
d-valerolactones (Scheme 3, Table 1).
The above acetylation-cyclization protocols were then utilized
to prepare a-substituted dihydropyranones (9a–c) from the allylic
acetates (7a–c), which were derived from the allylic alcohols 5a–c
(Table 2).
Having achieved the preparation of
and dihydropyranones, we next focused on their conversion to
the corresponding -alkylidene lactones via a conjugate addition-
a-substituted butenolides
a
Table 1
elimination strategy. As representative examples, the endocyclic
Alkenylalumination of aldehydes with 1 and 2
allylic acetates 8 and 9 were treated with a hydride nucleophile22
i-Bu
Al
OH O
O
to achieve the preparation of b,
erolactones. Accordingly, the addition of NaBH4 to allylic acetate
8a in methanol at 0 °C provided the -alkylidene-b, -unsubstitut-
ed- -butyrolactone 10a in 92% yield within 20 min (Table 2).
c-unsubstituted butyro- and val-
R
OEt
OTBS
RCHO
i-Bu
OEt
Entry
OTBS
a
c
( )n
( )n
c
#
#
R
#
Yield (%)
Examination of the PMR spectrum revealed a chemical shift of d
6.8 ppm for the olefinic proton, thereby confirming the E-stereo-
chemistry of the exocyclic olefin.23 This was then extended to 8b
1
2
3
4
5
6
1
1
1
2
2
2
3a
3b
3c
3a
3b
3c
Ph
p-NO2-Ph
Chx
Ph
p-NO2-Ph
Chx
4a
4b
4c
5a
5b
5c
62
73
54
72
66
55
and 8c in 86–91% yields. Preparation of the
a-alkylidene-d-lac-
tones (11a–c) was similarly achieved from the dihydropyranones
9a–c (Table 2).

P. Veeraraghavan Ramachandran et al. / Tetrahedron Letters 52 (2011) 4985–4988
4987
i-Bu
OH O
CO2Et
O
DIBAL-H
NMO
THF
0 oC, 3 h
(i) n-BuLi
RCHO (3)
Al
R
OEt
OTBS
i-Bu
OEt
OTBS
(ii) ClCO2Et
OTBS
( )n
THF
0 oC, 8 h
( )n
( )n
OTBS
( )n
4: n = 1
5: n = 2
1: n = 1
2: n = 2
Scheme 3. Preparation of reagents and alkenylalumination of aldehydes.
(ppm) (75 MHz, CDCl3): 154.2, 89.5, 72.9, 61.1, 30.6, 25.9, 18.2,
15.9, 13.9, ꢀ5.4.
O
OAc O
OAc
O
CF3CO2H
AcCl, py
NaBH4
R
O
( )n
4, 5
R
OEt
OTBS
R
Preparation of Reagent 1 and reaction of benzaldehyde: DIBAL-H
(0.53 mL, 3.0 mmol) was added, at 0 °C, to a stirred suspension of
NMO (0.42 g, 3.6 mmol) in anhydrous THF (7 mL) and stirred for
1 h. Ethyl 4-(tert-butyldimethylsilyloxy)but-2-ynoate (2.0 mmol)
was then added and stirred at 0 °C for 2 h to prepare 1. Benzalde-
hyde (2.2 mmol) was then added and stirring was continued at 0 °C
for 4 h. The reaction was quenched by the addition of a 10% HCl
solution, followed by EtOAc (20 mL). After stirring for 5 min, the
aqueous layer was extracted with EtOAc (3ꢁ 25 mL) and the com-
bined organic layers were washed with brine, dried (MgSO4), con-
centrated, and purified by column chromatography over Silica gel
(95:5, hexanes:EtOAc) to provide 4a in 62% yield. 1H NMR d
(ppm) (300 MHz, CDCl3): 7.24–7.38 (m, 5H), 6.45 (t, 8.6 Hz, 1H),
5.46 (d, 7.2 Hz, 1H), 4.65 (d, 2H), 4.11 (q, 10.2 Hz, 2H), 2.96 (s,
OH), 1.22 (t, 10.2 Hz, 3H), 0.98 (s, 9 H), 0.09 (s, 6H); 13C NMR d
(ppm) (75 MHz, CDCl3): 167.3, 143.2, 134.2, 129.4, 127.2, 127.6,
70.1, 61.8, 55.1, 26.1, 18.3, 13.9.
O
( )n
CH2Cl2
rt, 1 h
CH2Cl2
reflux, 2 h
MeOH
0 oC, 20 min
( )n
8
9
: n = 1
: n = 2
6
7
: n = 1
: n = 2
10: n = 1
11: n = 2
Scheme 4. Preparation of a-alkylidene-c-butyrolactones and -d-valerolactones.
Table 2
Preparation of butenolides/dihydropyranones and
a-methylene-
c
- and d-lactones
OAc O
OAc
O
O
R
O
R
OEt
OTBS
R
O
Entry
( )n
( )n
( )n
#
R
Yield (%)
#
Yield (%)
#
Yield (%)
1
2
3
4
5
6
6a
6b
6c
7a
7b
7c
Ph
p-NO2-Ph
Chx
Ph
p-NO2-Ph
Chx
90
88
84
77
83
84
8a
8b
8c
9a
9b
9c
83
89
88
73
76
84
10a
10b
10c
11a
11b
11c
92
86
91
89
89
91
(b) (Z)-Ethyl 2-(acetoxy(phenyl)methyl)-4-(tert-butyldimethylsi-
lyloxy)but-2-enoate (6a): 4a (2.0 mmol) dissolved in CH2Cl2
(5 mL) was cooled to 0 °C, followed by the addition of pyridine
(0.20 mL, 2.5 mmol). After stirring for 5 min, acetyl chloride
(0.16 mL, 2.3 mmol) was added dropwise, and the solution stirred
for 2 h. Water (50 mL) was then added and the product was ex-
tracted with CH2Cl2 (3ꢁ 25 mL). The organic layers were combined,
washed with brine, dried (MgSO4), concentrated, and purified via
silica gel chromatography (95:5 hexane/EtOAc) to afford 6a in
90% yield. 1H NMR d (ppm) (300 MHz, CDCl3): 7.35 (m, 5H), 6.64
(d, 5.1 Hz, 1H), 6.34 (t, 4.9 Hz, 1H), 4.70 (d, 3.2 Hz, 2H), 4.13 (q,
10.5 Hz, 2H), 2.11 (s, 3H), 1.21 (t, 10.5 Hz, 3H), 0.90 (s, 9H), 0.07
(s, 6H); 13C NMR d (ppm) (75 MHz, CDCl3): 169.4, 167.3, 142.5,
134.7, 129.3, 127.3, 127.1, 76.6, 62.1, 61.0, 53.0, 26.0, 21.4, 18.5,
14.3.
In conclusion, we have developed an efficient route for the
preparation of substituted butenolides and dihydropyranones, in
good overall yields through the use of alkenylaluminum reagents,
which were prepared from readily available acetylenic alcohols.
Hydride addition, and concurrent acetate elimination to these
lactenones provides a general and stereospecific synthesis of the
corresponding a-E-alkylidene-c-butyro- and d-valerolactones. We
are currently working to further expand this protocol to include
greater functionality and ring systems.
(c) (2-Oxo-2,5-dihydrofuran-3-yl)(phenyl)methyl acetate (8a): 6a
(2.0 mmol) was dissolved in CH2Cl2 (3 mL), followed by the drop-
wise addition of CF3COOH (0.22 mL, 3.0 mmol). The mixture was
then refluxed under N2 atmosphere until TLC showed a complete
conversion to a more polar product (Rf 0.4 in 1:1 hexane/EtOAc)
(2 h). The reaction was cooled to room temperature, followed by
the addition of saturated aqueous NaHCO3 (10 mL). The product
was then extracted with CH2Cl2, the organic layers were combined,
dried (MgSO4), concentrated, and purified by silica gel chromatog-
raphy (70:30 hexane/EtOAc) to afford 8a in 83% yield. 1H NMR d
(ppm) (300 MHz, CDCl3): 7.41 (m, 6H), 6.58 (s 1H), 4.82 (s, 2H),
2.13 (s, 3H); 13C NMR d (ppm) (75 MHz, CDCl3): 171.2, 169.5,
146.8, 133.9, 130.2, 129.2, 128.8, 127.2, 70.1, 21.0.
(d) (E)-3-benzylidenedihydrofuran-2(3H)-one (10a): MeOH
(5 mL) was added to 8a (1.0 mmol) and cooled to 0 °C. NaBH4 (0.
038 g, 1.0 mmol) was added slowly (Caution: foaming) and the solu-
tion was stirred for 20 min. The solvent was removed by rotoevapo-
ration and EtOAc (10 mL) was added and the solution was extracted
with water (3ꢁ 5 mL). The organic layer was dried (MgSO4), and
purified over silica gel (70:30 hexane/EtOAc) to provide 92% of
10a. 1H NMR d (ppm) (300 MHz, CDCl3): 7.66–7.38 (m, 6H), 7.28
(s, 1H), 4.50 (t, 10.3 Hz, 2H), 3.27 (m, 2H); 13C NMR d (ppm)
(75 MHz, CDCl3): 170.4, 139.1, 135.3, 131.8, 128.9, 128.2, 65.4, 28.2.
Experimental
Preparation of (E)-3-benzylidenedihydrofuran-2(3H)-one (10a)
is represented.
(a) Preparation of (Z)-ethyl 4-(tert-butyldimethylsilyl)-2-(hydro-
xy(phenyl)methyl)but-2-enoate (4a).
Preparation of Ethyl 4-(tert-butyldimethylsilyloxy)but-2-ynoate:
Prop-2-yn-1-ol (2 mmol) and tert-butyldimethylsilyl chloride
(2 mmol) were mixed in DMF in the presence of imidazole
(2 mmol) as a base,24 for 6 h. Aqueous work and purification by Sil-
ica gel chromatography provided tert-Butyldimethyl(prop-2-ynyl-
oxy)silane (2.0 mmol), which was dissolved in THF (5 mL) and
cooled to ꢀ78 °C. n-BuLi (2.1 mmol, 0.84 mL) was added dropwise,
and the solution was stirred for 2 h, followed by the dropwise addi-
tion of ClCO2Et (2.5 mmol, 0.24 mL) and stirring was continued for
12 h at ꢀ78 °C. The reaction mixture was quenched with a 10%
solution of HCl and extracted with EtOAc (3ꢁ 25 mL). The com-
bined organic extracts were dried (MgSO4), concentrated, and puri-
fied via column chromatography (95:5 hexane/EtOAc) to provide
ethyl 4-(tert-butyldimethylsilyloxy)but-2-ynoate in 88% yield. 1H
NMR d (ppm) (300 MHz, CDCl3): 4.48 (s, 2H), 4.28 (q, 10.5 Hz,
2H), 1.40 (t, 10.5 Hz, 3H), 0.98 (s, 9H), 0.09 (s, 6H). 13C NMR d

4988
P. Veeraraghavan Ramachandran et al. / Tetrahedron Letters 52 (2011) 4985–4988
Perez, R. M. B. J. Org. Chem. 1985, 50, 5257; (d) Tanaka, K.; Tamura, N.; Kaji, A.
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