Synthesis of α-alkylidene-δ-valerolactones via the conjugate addition of ketone enolates to functionalized allyl acetates

Article abstract of DOI:10.3987/COM-09-S(S)109

Sequential addition of ketone enolates to allyl acetates bearing an ester, followed by reduction and cyclization provides a variety of substituted α-alkylidene-δ-valerolactones.

Full text of DOI:10.3987/COM-09-S(S)109

HETEROCYCLES, Vol. 80, No. 2, 2010
863
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 863 - 872. © The Japan Institute of Heterocyclic Chemistry
Received, 12th August, 2009, Accepted, 9th November, 2009, Published online, 11th November, 2009
DOI: 10.3987/COM-09-S(S)109
SYNTHESIS OF -ALKYLIDENE--VALEROLACTONES VIA THE
CONJUGATE ADDITION OF KETONE ENOLATES TO
FUNCTIONALIZED ALLYL ACETATES
P. Veeraraghavan Ramachandran* and Annyt Bhattacharyya
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907,
USA.
*E-mail: chandran@purdue.edu
Abstract – Sequential addition of ketone enolates to allyl acetates bearing an
ester, followed by reduction and cyclization provides a variety of substituted
α-alkylidene-δ-valerolactones.
Butenolides, pyranones, -alkylidene--butyrolactones and --valerolactones present in multitude of
natural products display a variety of biological activities.1
Although not as prevalent
as-methylene--butyrolactones, the corresponding -valerolactones are also essential components and
characteristic features of a plethora of natural products.2 Several of these substrates possess novel
pharmacological and interesting biological activities which range from antibiotic to antitumor activity.2
In addition to the biological significance, α-methylene-δ-valerolactones find applications in
carbon-carbon bond forming reactions3 and methylene-bridged disaccharide synthesis.4
Among the α-alkylidene-δ-valerolactones, the synthesis of α-methylene δ-valerolactones is more
common5
and among the several approaches known in the literature, the metal-mediated cyclization of
homoallylic alkynoates6 and carbonylation7 are noteworthy. Other processes include synthesis via the
Horner-Wadsworth-Emmons reaction of α-phosphonolactones8 and the trifluoromethanesulfonic acid
mediated Friedel-Crafts reaction of diethoxyphosphorylacrylic acids.9 Shiozaki and coworkers reported
the synthesis of α-alkylidene-δ-valerolactones from corresponding ketones via aldol condensation on a
δ-valerolactone moiety for the preparation of certain rennin inhibitors.10 Recently Howell and
coworkers reported the synthesis of -alkylidene--butyrolactones via a cross-metathesis reaction in the
presence of Grubbs catalyst and 2,6-dichlorobenzoquinone.11 However, this process was not effective
for the preparation of the corresponding -valerolactones. Singh and Batra reported the preparation of a

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HETEROCYCLES, Vol. 80, No. 2, 2010
series of -aryl--methyl--methylene--valerolactones via a nucleophilic substitution (SN2 process) of
Baylis-Hillman acetates (Scheme 1).12
O
O
O
O
O
OAc
15% aq.
NaOH
reflux
O
(i) NaBH4
(ii) HCl
CO2Me
Ar
CO2H
Ar
O
DABCO
Ar
CO2Me
10 min.
Ar
Scheme 1. Batra synthesis of -aryl--methylene--methyl--valerolactones
As part of our ongoing projects on vinylalumination,13 we envisaged a terse general synthesis of variantly
substituted α-alkylidene-δ-valerolactones via the conjugate addition-elimination of functionalized allylic
acetates (an overall SN2' process) with enolate nucleophiles as delineated in Scheme 2. As can be seen,
this process allows for the incorporation of substitutions at , , and -positions. The successful
synthesis of a variety of - and -substituted α-alkylidene-δ-valerolactones, including the construction of
fused bicyclic valerolactone moieties14 is reported herein.
O
O
R2
OAc
R1
R2
O
CO2Me
CO2Me
R2
R4
R1
R3
R4
R1
R3
O
i-Bu2Al
CO2Me
R2
CO2Me
+
R1
H
R2
Scheme 2. Retrosynthesis for -alkylidene--valerlactones
The required allyl acetates for the present study were prepared via the vinylalumination13 of acetaldehyde
and benzaldehyde, followed by esterification of the resulting alcohols with acetic anhydride in the
presence of pyridine (Scheme 3). These derivatives can be prepared via Baylis-Hillman reaction12,15 as
well.
CO2Me
OAc
DIBAL-H
NMO
(i) R1CHO
i-Bu2Al
CO2Me
CO2Me
R1
(ii) Ac2O, Py
1
2
3a: R1 = Me
3b: R1 = Ph
Scheme 3. Preparation of -alkylidene acetates
Initially, the enolates from various methyl ketones were generated under kinetic conditions (LDA, -78 oC),
which was followed by the addition of a solution of 3a or 3b (Scheme 4). The conjugate addition-
o
elimination process is only initiated at or above 0 C. Subsequent warming of the reaction mixture to
ambient condition and stirring overnight ensures complete consumption of 3a or 3b. It is to be noted

HETEROCYCLES, Vol. 80, No. 2, 2010
865
o
that the reaction is prohibitively slow even at 0 C. Extensive experimentation confirmed that the
presence of excess base or HMPA does not have any beneficial effect on the reaction and that THF is the
solvent of choice.
OAc
O
O
OLi
CO2Me
CO2Me
R1
LDA, -78oC
THF
R4
R4
R4
R3
3a: R1= Me
3b: R1 = Ph
R3
R3
R1
R3 = H, alkyl, aryl, -CH2-
R4= alkyl, aryl, (-CH2-)n
4 : R3 = H, R1 = CH3
5 : R3 = H, R1 = Ph
6 : R3 = alkyl, aryl, (CH2)n
R1 = CH3
7 : R3 = alkyl, aryl, (CH2)n
R1 = Ph
Scheme 4. Preparation of -alkylidene--keto esters
The oxoesters (4a-d and 5a-5c) from methyl ketones (R3=H, Scheme 4) were obtained in moderate
1
(52-65%) yields. The H NMR analysis of all of the products (4a-d and 5a-c) indicated 90% E
geometry for the olefin. The C2-symmetric bis-adducts derived from the deprotonation of 4 or 5 were
also obtained in 10-20% yield. The availability of the base for the deprotonation of 4 or 5 could be
presumably from the reversibility of the enolate formation. The formation of the bis adduct could be
considerably controlled under optimum conditions (1.2 equivalent of LDA), although it could not be
completely suppressed. The results are summarized in Table 1.
Table 1. Conjugate addition-elimination of methyl ketone enolates.a
entry acetate
#
R2COCH3
keto ester
structureb
#
% yieldc
65
R2
Ph
O
O
O
O
1
3a
3a
3a
3a
4a
CO2Me
CO2Me
CO2Me
CO2Me
Ph
2
3
4
2-Thiophenyl 4b
52
57
63
S
Me
4c
t-Bu
4d
tBu

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HETEROCYCLES, Vol. 80, No. 2, 2010
O
5
6
7
3b
3b
3b
2-Naphthyl
i-Pr
5a
5b
5c
54
61
56
CO2Me
Ph
Ph
Ph
O
O
CO2Me
CO2Me
p-Tol
aThe additions were carried out at -78 oC and warmed overnight to rt.
bE:Z ratio 90:10. The diastereomer ratio was determined by 1H NMR. cIsolated yield.
Compared to the methyl ketones, other classes of ketones such as ethyl, n-propyl, benzyl and alicyclic
ketones generated keto esters in much better yields with similar E:Z ratio as observed for 4 and 5. The
keto-adducts from propiophenone (6a,7a), n-butyrophenone (6b,7b), deoxybenzoin (6c,7c),
cyclopentanone (6d,7d), and cyclohexanone (6e) are among the representatives. The alicyclic
derivatives of keto esters (6d, 6e and 7d) could be successfully generated under analogous reaction
conditions. The formation of the bisadducts, as observed for 4a-d and 5a-c, does not occur for
keto-adducts 6a-d, 7a-d, presumably due to the steric congestion at the newly generated ternary
stereocenter in these adducts. The results are summarized in Table 2.
Table 2. Conjugate addition-elimination of several classes of ketone enolates.a
entry acetate
#
R2COCH2R3
keto ester
structureb
R2
Ph
R3
#
% yieldc
82
O
O
O
1
3a
3a
3a
Me
6a
CO2Me
Ph
Ph
Ph
2
3
Ph
Ph
Et
6b
6c
85
91
CO2Me
CO2Me
Et
Ph
Ph

HETEROCYCLES, Vol. 80, No. 2, 2010
867
O
4
5
3a
3a
-CH2- (CH2-)2 6d
-CH2- (CH2-)3 6e
76
62
CO2Me
CO2Me
CO2Me
O
O
O
O
6
7
8
9
3b
3b
3b
3b
Ph
Ph
Ph
Me
Et
7a
7b
7c
61
73
80
69
Ph
Ph
Ph
Me
Ph
CO2Me
Et
Ph
Ph
CO2Me
CO2Me
Ph
Ph
O
-CH2- (CH2-)2 7d
Ph
aThe additions were carried out at -78 oC and warmed overnight to rt.
bE:Z ratio 90:10. The diastereomer ratio was determined by 1H NMR. cIsolated yield.
Chemoselective reduction of the α-alkylidene oxoesters to the corresponding hydroxyesters could be
effected quantitatively with Sodium borohydride. Substrates 6a-e and 7a, 7c and 7d underwent
reduction with varied diastereoselectivity. The diastereoselectivity was not determined at this point
since the alcohol has a tendency to lactonize during aqueous workup. Attempted silica-gel
chromatography resulted in partial lactonization of the hydroxyl ester. As a consequence, they were
submitted to an acidic environment without further purification and the cyclization to the lactones
occurred instantaneously.
O
O
CO2Me
i) NaBH4
R1
O
R4
R3
R4
ii) PTSA/CH2Cl2 reflux, < 0.5 h
R1
R3
Scheme 5. Preparation of -alkylidene--valerolactones

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HETEROCYCLES, Vol. 80, No. 2, 2010
Thus, 4a-d, 5a-c, 6a-e and 7a, 7c, 7d generated the lactones 8a-d, 9a-c, 10a-e and 11a, 11c, 11d,
respectively, in high yields over two steps (Scheme 5). The alkyl substituent at the α-position
predominantly governs the hydride approach from the si face of the prochiral carbonyl carbon, thus
favoring the formation of the syn-alcohol. Thus, while 10a and 10c were formed as 2:1 and 1:1 mixture
of diastereomers respectively, lactones 10b and 11b were generated with high cis-selectivity. The
1
diastereomeric ratio was determined from H NMR coupling constants. The lactone 11a and the
cyclopentanone-derived lactones 10d and 11c were formed excusively as anti isomers.16 The lactone
10e, obtained from cyclohexanone, was an inseparable diastereomeric mixture in the ratio of 2:1.14 The
yields and the diastereomeric ratios of the lactones are summarized in Table 3.
Table 3. Preparation of α-alkylidene-δ-valerolactones
entry keto ester
#
lactone
#
structurea
% yieldb
74
dr
cis trans
1
4a
4b
8a
nac
na
O
O
Ph
O
2
8b
53
na
na
O
O
S
3
4
4c
8c
69
82
na
na
na
na
O
O
4d
8d
O
t-Bu
O
5
6
5a
5b
9a
9b
80
65
na
na
na
na
Ph
O
O
Ph
O
i-Pr

HETEROCYCLES, Vol. 80, No. 2, 2010
869
O
O
7
5c
9c
77
na
na
Ph
O
O
8
9
6a
6b
10a
10b
70
68
2
1
O
O
+
Ph
Ph
O
>99
<1
O
Ph
Et
O
O
10
6c
10c
74
1
1
O
O
+
Ph
Ph
Ph
Ph
11
12
13
6d
6e
7a
10d
10e
11a
63
59
76
<1
1
>99
2
O
O
+
O
O
O
O
O
<1
>99
Ph
Ph
O
Ph
O
14
15
7c
11c
11d
58
62
24
<1
1
O
Ph
Ph
Ph
O
7d
>99
O
aE:Z ratio: 95:5. The diastereomer ratio was determined by 1H NMR.
bIsolated yields. bNot applicable

870
HETEROCYCLES, Vol. 80, No. 2, 2010
In conclusion we have demonstrated
a
highly convenient synthesis of
a
variety of
α-alkylidene-δ-valerolactones from readily available synthons. The generality of the methodology has
been demonstrated via the synthesis of a wide range of δ-alkyl/aryl valerolactones and studies on the
stereochemistry at ring junction for fused bicyclic α-alkylidene δ-valerolactones. Current efforts focus
on the enantio- and diastereoselective reduction of the keto esters for the preparation of chiral lactones.
We are also examining ways to improve the yields in the conjugate addition-elimination step.
EXPERIMENTAL
General: Unless otherwise noted, reagents were purchased from commercial suppliers. Tetrahydrofuran
(THF) was distilled from sodium benzophenone ketyl under nitrogen. Diisopropylamine was distilled
over calcium hydride or potassium hydroxide and stored over 4 Ǻ molecular sieves. n-Butyl lithium (2.5
M solution in hexanes) was procured from Aldrich. Thin layer chromatography was performed on
Sorbent Technologies precoated silica gel w/UV254 glass backed (250μm) plates. Silica gel (Sorbent
Technologies 230-400 mesh) was used for flash column chromatography. 1H NMR spectra was recorded
on a Gemini (300 MHz) or Bruker (200 MHz) spectrometer. Spectra was referenced internally to the
residual proton resonance in CDCl3 (δ 7.26 ppm) as the internal standard. Commercially available CDCl3
was stored under 4 Ǻ molecular sieves. Chemical shifts (δ) were reported as parts per million (ppm) in δ
scale downfield from TMS. 13C NMR spectra were recorded on a Gemini 300 spectrometer and
referenced to CDCl3 (δ 77.0 ppm). Coupling constants (J) were reported in Hertz. Spectroscopic data is
presented for representative compounds.
Typical procedure for preparation of α-alkylidene-δ-valerolactone 8a.
Preparation of 4a: To a solution of diisopropylamine (0.33 mL, 2.4 mmoles) in anhydrous THF (1 mL)
o
at -78 C was added n-BuLi (0.96 mL, 2.4 mmol, 2.5 M soln. in hexanes) followed by the addition of a
solution of acetophenone (0.24 g, 2 mmol dissolved in anhydrous THF (3mL) at the same temperature
over a period of 10 minutes. To the resulting mixture was added a solution of 3a (0.34 g, 2 mmol)
dissolved in anhydrous THF (3 mL) and stirred overnight, during which time the reaction mixture
warmed upto ambient temperature. This was then quenched with saturated aqueous ammonium chloride,
extracted with EtOAc, dried (Na2SO4) and concentrated to obtain crude 4a, which was purified by flash
column chromatography using silica-gel (1:9:: EtOAc:hexanes) to obtain 0.30 g (65%) of pure 4a as an
oil. δH(300 MHz; CDCl3): 7.99 (2H, d, J 6.0, ArH), 7.4-7.6 (3H, m, ArH), 6.9 (1H, q, J 7.2, CH3CH=C),
3.75 (s, 3H, OCH3), 3.13-3.08 (2H, m, CH2CH2), 2.76-2.71 (2H, m, CH2CO), 1.86 (d, 3H, J 7.14, CH3)
δC(75 MHz; CDCl3): 199.4, 167.9, 138.9, 136.7, 133, 131.7, 128.5, 128, 51.6, 37.7, 21.4 14.3.
Preparation of 8a: To a solution of 4a (0.1 g, 0.43 mmol) in anhydrous MeOH (3 mL) was added solid
NaBH4 (16.3 mg, 0.43 mmol) under ice-cooling and stirred for 2 h. The reaction mixture was quenched

HETEROCYCLES, Vol. 80, No. 2, 2010
871
with water. Methanol was removed under reduced pressure and the aqueous layer was extracted with
EtOAc, dried (Na2SO4) and concentrated. The contents in the flask was dissolved in CH2Cl2 (5 mL) and
catalytic amount of p-toluenesulfonic acid was added and the solution was refluxed for 30 min. The
reaction was quenched with water, extracted with CH2Cl2, dried (Na2SO4), and purified by flash column
chromatography using silica-gel (1:9::EtOAc:hexanes) to obtain 0.064 g (74%) of 8a as a white
crystalline solid. δH(300 MHz; CDCl3): 7.4-7.2 (6H, m, ArH, CH3CH=C), 5.28 (1H, dd, J 2.34, PhCH),
2.76-2.31 (2H, m, CH2CH2), 2.28-2.18 (1H, m, CH2CHO), 2.10-1.86(1H, m, CH2CHO), 1.83 (d, 3H, J
7.14, CH3).
104, 96, 77.
δC(75 MHz; CDCl3): 166.5, 141.5, 139.6, 128.6, 128.2, 125.9, 125.8 MS (EI) 202(M+),
ACKNOWLEDGEMENTS
We thank the Herbert C. Brown Center for Borane Research for support of this work.
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