Regioselective addition of 1,3-dicarbonyl dianions to carbonyl compounds: One pot lactonization and ketalization of-hydroxy-keto esters to protected pyrone derivatives

Article abstract of DOI:10.1071/CH12062

A simple and efficient strategy for the synthesis of 6-substituted-2-pyrone derivatives, by BF₃OEt₂ mediated one pot cyclization and keto-protection of-hydroxy-keto esters, obtained via regioselective addition of 1,3-dicarbonyl diani

Full text of DOI:10.1071/CH12062

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2012, 65, 1262–1270
Full Paper
http://dx.doi.org/10.1071/CH12062
Regioselective Addition of 1,3-Dicarbonyl Dianions
to Carbonyl Compounds: One Pot Lactonization
and Ketalization of d-Hydroxy-b-keto Esters
to Protected Pyrone Derivatives
A B
,
A
A
Manas K. Ghorai,
Sandipan Halder, and Sauvik Samanta
A
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India.
Corresponding author. Email: mkghorai@iitk.ac.in
B
A simple and efficient strategy for the synthesis of 6-substituted-2-pyrone derivatives, by BF3ꢀOEt2 mediated one pot
cyclization and keto-protection of d-hydroxy-b-keto esters, obtained via regioselective addition of 1,3-dicarbonyl dianion
of ethyl acetoacetate to aldehydes and ketones is described.
Manuscript received: 1 February 2012.
Manuscript accepted: 16 February 2012.
Published online: 2 May 2012.
dihydro-4H-pyran-4-ones.[9a] Dieter et al. have used an acid
catalyzed cyclization of vinylogous thiol esters for the synthesis
of a-pyrones,[9b] but these methods have limitations in terms of
the yield of the addition product as well as formation of
the dehydrated product in the cyclization step. Langer et al. have
also described a FeCl3 catalyzed cyclization approach for the
synthesis of 6-aryl substituted 2,3-dihydro-4H-pyran-4-ones
from d-hydroxy-b-diketones.[9c]
Hence, development of a suitable procedure for the synthesis
of pyrones in higher yields, with control over dehydration
processes, is necessary for further functionalization of the
pyrone ring. In this context Ley et al. have reported an interest-
ing strategy involving a tandem cyclization of propargylic
carbonyl compounds to the corresponding dithiol protected
pyrone derivatives.[10]
Introduction
Di- and tetrahydropyrones are abundant in many naturally
occurring compounds with significant medicinal and biological
activities.[1] Furthermore, this ring structure as a representative
intermediate has been exploited for several important oxacyclic
and other oxygen containing molecules.[2] In particular, kurzi-
lactone,[3] cryptofoline, and obolactone[4] (Fig. 1) are well
known in the literature for exhibiting antifungal and cytotoxic
activities. Several protocols have been devised for the synthesis
of pyrone moieties. These methods include hetero Diels–Alder
reactions,[5] metal catalyzed oxidative cyclizations,[6] and ring
closing metathesis reactions.[4,7] In this context Light et al. have
for the first time used d-hydroxy-b-keto esters, the addition
product of a 1,3-dicarbonyl dianion of a b-keto ester with an
aldehyde, for the synthesis of pyrone derivatives via a
HCl/MeOH mediated cyclization approach.[8] Similarly,
Peterson and co-workers have also reported a p-toluenesulfonic
acid (PTSA) catalyzed cyclization approach to afford
In another approach the reactivity of 1,3-dicarbonyl dianion
has been prudently exploited for the synthesis of a variety of
heterocyclic scaffolds. Several research groups have made
O
O
OH
O
O
O
OH OH
Kurzilactone 1
(ϩ)-Cryptofoline
O
O
O
O
H
Obolactone 1
Fig. 1. Some dihydropyrone containing natural products.
Journal compilation Ó CSIRO 2012
www.publish.csiro.au/journals/ajc

Oxacycles Pyrones
1263
remarkable efforts in this particular field for the development of
newer synthetic routes.[11,12] In this perspective Langer and
co-workers have made significant contribution towards the
synthesis of a number of heterocyclic frameworks through the
utilization of the 1,3-dicarbonyl dianion.[13] Previously we have
reported the synthesis of 2-substituted piperidines and diaster-
eopure 2,4-disubstituted azetidine derivatives from d-amino-
b-keto esters obtained via the regioselective addition of
1,3-dicarbonyl dianion of ethyl acetoacetate to N-tosyl
aldimines.[14] In continuation of our research in enolate[15] and
dianion chemistry, we anticipated that six membered oxa-cycles
could easily be made through a similar strategy using different
carbonyl electrophiles. The addition of the dianion generated
from ethyl acetoacetate to carbonyl electrophiles would lead to
the formation of d-hydroxy-b-keto esters, which could be
further converted to 2-substituted pyrone derivatives upon
protection of the ketone group followed by cyclization. To our
gratification we have successfully developed a Lewis acid
(BF3ꢀOEt2) catalyzed one pot lactonization-ketalization
strategy to furnish 6-substituted-4-keto protected pyrone
derivatives in good yield, though alternate cyclization methods
were reported earlier.[16]
this work and synthesis of bioactive pyrone molecules using this
approach is underway.
Experimental
General Procedure for the Synthesis
of d-Hydroxy-b-keto Ester (4a–k)
To a solution of diisopropylamine (0.66 mL, 4.7 mmol) in
1.5 mL of dry THF was added n-BuLi (2.94 mL, 4.7 mmol)
[1.6 M solution in hexane] at 08C and stirred for 30 min. The
solution changed to light yellow, where it was cooled to ꢁ508C
and ethyl acetoacetate (0.3 mL, 2.35 mmol) was addedand stir-
red for a further 1 h to generate the dianion. Aldehydes or
ketones (0.94 mmol) in 0.5 mL of THF were added to the reac-
tion mixture and the stirring was continued for an additional
3–4 h at the same temperature. After completion of the reaction
as monitored by TLC, the reaction mixture was quenched with
saturated aqueous ammonium chloride. The organic and the
aqueous layers were separated, and the aqueous layer was
extracted with ethyl acetate (3 ꢂ 5 mL). The combined organic
extracts were washed with brine, dried over anhydrous sodium
sulfate, and evaporated under reduced pressure. The crude
reaction mixture was purified by flash column chromatography
on silica gel (230–400 mesh) using 10 % ethyl acetate in
petroleum ether to obtain pure d-hydroxy-b-keto ester 4a–j.
Results and Discussion
Our study began with the generation of the dianion 2 from ethyl
acetoacetate by treatment with LDA (2.0 equiv.) at ꢁ508C in
THF followed by reaction with benzaldehyde to afford the
corresponding d-hydroxy-b-keto ester 4a in 98 % yield (Table 1,
entry 1). The strategy was generalized for other aldehydes and
further extended to different ketones. In all cases the reactions
proceeded smoothly with excellent yields of the products
(Table 1).
Ethyl 5-Hydroxy-3-oxo-5-phenylpentanoate (4a)
The general procedure described above was followed to
afford 4a (218.2 mg, 98 % yield) as a light yellow liquid,
Rf 0.33 (20 % ethyl acetate in petroleum ether); IR nmax (neat,
cmꢁ1) 3473, 3063, 3031, 2982, 2932, 1740, 1713, 1650, 1494,
1453, 1408, 1368, 1319, 1267, 1193, 1156, 1095, 1030, 941,
853, 803, 756, 701; 1H NMR (500 MHz, CDCl3) d 1.26 (t, 3H,
J ¼ 7.1 Hz), 2.86–3.05 (m, 2H), 3.47 (s, 2H), 4.18 (q, 2H,
J ¼ 7.1 Hz), 5.18 (dd, 1H, J ¼ 3.1, 9.3 Hz), 7.27–7.37 (m, 5H);
13C NMR (125 MHz, CDCl3) d 14.1, 49.9, 51.6, 61.5, 69.8,
125.6, 127.8, 128.6, 142.5, 166.8, 202.9.
We have extended this protocol towards the synthesis of a
non-racemic addition product 4k; for this purpose chiral
Garner’s aldehyde was introduced as an electrophile. After the
reaction the addition product was obtained as a mixture diaster-
eomers (40 : 1) which were separated after protection of the –OH
functionality as a tert-butyldimethylsilyl (TBDMS) ether
(Table 1, entry 11). In the next step, attempted protection of
the keto functionality in the addition product 4a was made by
treatment with ethanediol in the presence of PTSA; unfortunately,
the product decomposed under the harsh reaction conditions.
As an alternative, we tried a milder reaction where the
substrate was treated with ethylene glycol in the presence of a
catalytic amount of BF3ꢀOEt2 in CH2Cl2 at 08C to room
temperature for 18–20 h.[17] To our great delight, the cyclized
2-pyrone product 5a was obtained with protected ketone func-
tionality in the same pot with good yield (Table 2, entry 1). This
protocol was further generalized for other d-hydroxy-b-keto
esters 4b –j and the result is shown in Table 2. Addition products
4i and 4j underwent lactonization without further keto protec-
tion under the same reaction conditions, and the corresponding
4-ketolactones 5i and 5j were obtained (Table 2, entry 9 and
entry 10) in good yields. Crystal structures of 5b, 5d, and 5e as
representative examples are shown in Fig. 2.
Ethyl 5-(2-Bromophenyl)-5-hydroxy-3-
oxopentanoate (4b)
The general procedure described above was followed to
afford 4b (207 mg, 76 % yield) as a colourless liquid, Rf 0.35
(20 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
)
3440, 3054, 3031, 2967, 2932, 1735, 1705, 1647, 1494, 1453,
1398, 1368, 1267, 1193, 1163, 1030, 964, 850, 803, 759, 701,
577, 544; 1H NMR (400 MHz, CDCl3) d 1.27 (t, 3H, J ¼ 6.8 Hz),
2.73–2.82 (m, 1H), 3.09 (dd, 1H, J ¼ 2.0, 17.6 Hz), 3.49 (s, 2H),
4.19 (q, 2H, J ¼ 6.8 Hz), 5.48 (dd, 1H, J ¼ 2.0, 9.8 Hz),
7.10–7.15 (m, 1H), 7.30–7.35 (m, 1H), 7.49 (d, 1H, J ¼ 7.8 Hz),
7.58–7.62 (m, 1H)13C NMR (100 MHz, CDCl3) d 14.1,
49.7, 49.8, 61.6, 68.7, 121.2, 127.3, 127.9, 129.1, 132.6,
141.4, 166.7, 202.7.
Ethyl 5-(3-Bromophenyl)-5-hydroxy-3-
oxopentanoate (4c)
The general procedure described above was followed to
afford 4c (218 mg, 80 % yield) as a light yellow liquid, Rf 0.36
(20 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
Conclusion
)
In conclusion we have developed a simple strategy for the
synthesis of 6-substituted, 4-keto protected, 2-pyrone deriva-
tives via a Lewis acid-catalyzed cyclization of d-hydroxy-b-
keto ester, obtained by regioselective addition of 1,3-dicarbonyl
dianion to aldehydes and ketones. The asymmetric version of
3454, 2981, 2926, 1740, 1713, 1650, 1596, 1570, 1473, 1409,
1369, 1317, 1260, 1191, 1095, 1070, 1028, 884, 785, 695;
1H NMR (400 MHz, CDCl3) d 1.22 (t, 3H, J ¼ 7.3 Hz)
2.82–2.94 (m, 2H), 3.42 (s, 2H), 4.14 (q, 2H, J ¼ 7.1 Hz),
5.05–5.12 (m, 1H), 7.13–7.22 (m, 2H), 7.35 (d, 1H, J ¼ 7.8 Hz),

1264
M. K. Ghorai, S. Halder, and S. Samanta
Table 1. Synthesis of d-hydroxy-b-keto esters by regioselective addition of 1,3-dianion of ethyl acetoacetate to aldehydes/ketones
O
O
O
O
OLi OLi
R1R2CO (3), THF
Ϫ50ЊC, 3 h
O
LDA, THF
R1
R2
O
O
Ϫ50ЊC, 1 h
OH
1
2
4
Yield: 75–98 %
Entry
Aldehyde or ketone (3)
3a: R1 ¼ Ph, R2 ¼ H
Addition product (4)
Yield [%]A
O
O
O
1
98
4a
Ph
Br
OH
O
O
O
2
3b: R1 ¼ 2-Br-C6H4, R2 ¼ H
76
OH
4b
O
O
O
O
3c: R1 ¼ 3-Br-C6H4, R2 ¼ H
80
Br
3
OH
O
4c
O
4
3d: R1 ¼ 4-Cl-C6H4, R2 ¼ H
75
OH
4d
Cl
O
O
O
5
3e: R1 ¼ 4-CN-C6H4, R2 ¼ H
81
OH
4e
NC
O
O
O
H3C
H3C
6
7
8
3f: R1 ¼ Me, R2 ¼ Me
3g: R1 ¼ Et, R2 ¼ Me
3h: R1 ¼ R2–(CH2)4–
88
83
4f
OH
O
O
O
H3CH2C
H3C
4g
OH
O
O
O
95
OH 4h
(Continued)

Oxacycles Pyrones
1265
Table 1. (Continued)
Entry
Aldehyde or ketone (3)
Addition product (4)
Yield [%]A
O
O
O
O
9
3i: R1 ¼ R2–(CH2)4–
90
4i
OH
O
O
O
Ph
10
3j: R1 ¼ Ph, R2 ¼ Et
87
H3CH2C
OH
O
4j
O
O
N
11B
57C
OTBDMS
O
N
3k: R1 ϭ
, R2 ϭ H
Boc
4k
Boc
AYields of isolated products after column chromatographic purification.
BThe –OH group of the addition product was protected as a TBDMS ether and the diastereomers were separated.
CIsolated product after two steps; dr 40 : 1 (confirmed by the yield of the isolated diastereomers).
7.47 (s, 1H); 13C NMR (100 MHz, CDCl3) d 14.0, 49.8, 51.4,
61.6, 69.1, 122.7, 124.3, 128.7, 128.8, 130.1, 130.8, 144.8,1
166.7, 202.6.
3516, 2977, 2935, 1742, 1709, 1648, 1467, 1369, 1318, 1238,
1178, 1096, 1031, 985, 938, 910, 854, 810, 779; 1H NMR
(400 MHz, CDCl3) d 1.21–1.30 (m, 9H), 2.72 (s, 2H), 3.32
(s, 1H), 3.44 (s, 2H), 4.12–4.21 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 14.0, 29.3, 50.5, 53.7, 61.4, 69.7, 166.8, 204.2.
Ethyl 5-(4-Chlorophenyl)-5-hydroxy-3-
oxopentanoate (4d)
The general procedure described above was followed
to afford 4d (190 mg, 75 % yield) as a light yellow liquid,
Rf 0.27 (20 % ethyl acetate in petroleum ether); IR nmax (neat,
cmꢁ1) 3456, 2982, 2929, 1740, 1714, 1651, 1492, 1445, 1408,
1369, 1318, 1241, 1192, 1155, 1091, 1031, 1014, 940, 831, 718;
1H NMR (500 MHz, CDCl3) d 1.26 (t, 3H, J ¼ 6.3 Hz),
2.85–2.99 (m, 2H), 3.46 (s, 2H), 4.18 (q, 2H, J ¼ 7.4 Hz),
5.14–5.16 (m, 1H), 7.25–7.33 (m, 4H); 13C NMR (125 MHz,
CDCl3) d 14.1, 49.8, 51.5, 61.7, 69.2, 127.2, 128.8, 133.5, 141.0,
166.9, 202.9.
Ethyl 5-Hydroxy-5-methyl-3-oxoheptanoate (4g)
The general procedure described above was followed to
afford 4g (158 mg, 83 % yield) as a light yellow liquid, Rf 0.40
(20 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
3449, 2929, 1738, 1716, 1668, 1498, 1467, 1408, 1369, 1334,
1270, 1178, 1150, 1091, 1054, 1024, 948, 831, 756, 690;
1H NMR (400 MHz, CDCl3) d 0.88 (t, 3H, J ¼ 7.3 Hz), 1.16
(s, 3H), 1.24 (t, 3H, J ¼ 6.8 Hz), 1.48–1.58 (m, 2H), 2.69 (q, 2H,
J ¼ 17.1 Hz), 3.45 (s, 2H), 4.20 (q, 2H, J ¼ 7.1 Hz); 13C NMR
(100 MHz, CDCl3) d 8.1, 14.1, 25.3, 26.1, 34.6, 44.2, 48.5, 51.7,
81.5, 166.9, 200.8.
)
Ethyl 5-(4-Cyanophenyl)-5-hydroxy-3-
oxopentanoate (4e)
Ethyl 4-(1-Hydroxycyclopentyl)-3-oxobutanoate (4h)
The general procedure described above was followed to
afford 4e (199 mg, 81 % yield) as a colourless liquid, Rf 0.27
(20 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
3441, 2987, 2930, 2906, 2229, 1737, 1713, 1610, 1550, 1508,
1451, 1409, 1375, 1327, 1273, 1240, 1194, 1174, 1137, 1081,
1
1059, 1019, 951, 849, 826, 733; H NMR (400 MHz, CDCl3)
d 1.20 (t, 3H, J ¼ 7.1 Hz), 2.86–2.88 (m, 2H), 3.41 (s, 2H),
4.01–4.15 (m, 2H), 5.16–5.19 (m, 1H), 7.40–7.58 (m, 4H);
13C NMR (100 MHz, CDCl3) d 14.0, 49.7, 51.2, 61.7, 69.1,
112.5, 118.6, 126.7, 132.4, 147.8, 166.6, 202.4.
The general procedure described above was followed to
afford 4h (191 mg, 95 % yield) as a light yellow liquid, Rf
0.48 (20 % ethyl acetate in petroleum ether); IR nmax (neat,
cmꢁ1) 3523, 2962, 2874, 1741, 1710, 1647, 1369, 1320, 1239,
1184, 1095, 1029, 954, 856; 1H NMR (400 MHz, CDCl3) d 1.26
(t, 3H, J ¼ 7.1 Hz), 1.48–1.49 (m, 2H), 1.58–1.61 (m, 2H),
1.78–1.83 (m, 4H), 2.85 (s, 2H), 3.44 (s, 2H), 4.18 (q, 2H,
J ¼ 7.1 Hz); 13C NMR (100 MHz, CDCl3) d 14.7, 21.5, 36.3,
50.7, 52.5, 62.0, 70.6, 167.1, 202.4.
)
Ethyl 5-Hydroxy-5-methyl-3-oxohexanoate (4f)
Ethyl 4-(1-Hydroxycyclohexyl)-3-oxobutanoate (4i)
The general procedure described above was followed to
afford 4f (156 mg, 88 % yield) as a light yellow liquid, Rf 0.36
The general procedure described above was followed to
afford 4i (193 mg, 90 % yield) as a light yellow liquid, Rf 0.43
(20 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
)
(20 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
)

1266
M. K. Ghorai, S. Halder, and S. Samanta
.
Table 2. BF3 OEt2 catalyzed cyclization of d-hydroxy-b-keto esters to synthesize 6-substituted-4-protected-2-pyrones
OH
O
O
O
O
BF3·OEt2,
OH
O
R1
R2
Yield: up to 65 %
R1
R2
CH2Cl2, 0ЊC to rt
OH
4
O
O
18 to 20 h
5
Entry
4
Cyclized product (5)
Yield [%]A
O
O
1
4a: R1 ¼ Ph, R2 ¼ H
55
Ph
Br
O
5a
O
O
O
2
4b: R1 ¼ 2-Br-C6H4, R2 ¼ H
52
O
O
5b
O
O
Br
3
4c: R1 ¼ 3-Br-C6H4, R2 ¼ H
65
O
5c
O
O
O
O
O
4
4d: R1 ¼ 4-Cl-C6H4, R2 ¼ H
62
O
5d
Cl
O
5
4e: R1 ¼ 4-CN-C6H4, R2 ¼ H
58
O
O
5e
NC
O
O
H3C
H3C
6
4f: R1 ¼ Me, R2 ¼ Me
58
O
O
5f
O
O
H3CH2C
H3C
7
4g: R1 ¼ Et, R2 ¼ Me
56
O
O
5g
(Continued)

Oxacycles Pyrones
1267
Table 2. (Continued)
Entry
4
Cyclized product (5)
Yield [%]A
O
O
8
4h: R1 ¼ R2 ¼ –(CH2)4–
55
O
O
O
5h
O
9B
4i: R1 ¼ R2 ¼ –(CH2)5–
60
O
5i
O
Ph
H3CH2C
10B
4j: R1 ¼ Ph, R2 ¼ Et
63
O
O
5j
AYields of isolated products after column chromatographic purification.
BThe product was obtained as unprotected 4-keto lactone.
O
N
C
H
Br
O
C
Cl
O
C
H
H
5b
5d
5e
CCDC No. 864222
CCDC No. 864223
CCDC No. 864224
Fig. 2. X-ray crystal structures of 5b, 5d, and 5e.
3519, 2932, 2858, 1742, 1707, 1647, 1447, 1407, 1368, 1319,
1
1239, 1170, 1097, 1030, 987, 965, 853; H NMR (400 MHz,
CDCl3) d 1.20–1.58 (m, 13H), 2.64 (s, 2H), 3.40 (s, 2H), 4.14
(q, 2H, J ¼ 6.9 Hz); 13C NMR (100 MHz, CDCl3) d 14.0, 21.1,
25.6, 37.5, 50.9, 52.8, 61.5, 70.8, 166.9, 204.4.
(m, 2H), 3.24 (s, 2H), 3.95 (s, 1H), 4.09 (q, 2H, J ¼ 7.3 Hz),
7.14–7.31 (m, 5H); 13C NMR (100 MHz, CDCl3) d 7.6, 14.0,
35.8, 47.2, 50.8, 52.5, 61.5, 125.3, 126.7, 128.0, 166.6, 204.3.
Tert-butyl-4-(1-(tert-butyldimethylsilyloxy)-5-
ethoxy-3,5-dioxopentyl)-2,2-dimethyloxazolidine-
3-carboxylate (4k)
Ethyl 5-Hydroxy-3-oxo-5-phenylheptanoate (4j)
The general procedure described above was followed to
afford 4j (216 mg, 87 % yield) as a light yellow liquid, Rf 0.30
The general procedure described above was followed to
afford tert-butyl 4-(5-ethoxy-1-hydroxy-3,5-dioxopentyl)-2,2-
dimethyloxazolidine-3-carboxylate. The addition product
(0.60 mmol) was dissolved in a mixture of pyridine and
dichloromethane (1 : 2) and cooled to 08C before addition of
t-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf).
The reaction mixture was warmed to room temperature and
(20 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
)
3513, 3060, 3027, 2977, 2967, 2881, 1741, 1708, 1649, 1494,
1463, 1447, 1369, 1317, 1261, 1161, 1095, 1078, 1030, 961,
855, 795, 762, 702; 1H NMR (400 MHz, CDCl3) d 0.68 (t, 3H,
J ¼ 7.3 Hz),1.18(t, 3H, J ¼ 7.3 Hz), 1.68–1.82 (m, 2H), 2.88–3.28

1268
M. K. Ghorai, S. Halder, and S. Samanta
stirred for an additional 12 h. After completion of the reaction as
monitored by TLC, the reaction mixture was quenched with
saturated aqueous ammonium chloride. The organic and the
aqueous layers were separated, and the aqueous layer was
extracted with dichloromethane (3 ꢂ 5 mL). The combined
organic extracts were washed with brine, dried over anhydrous
sodium sulfate, and evaporated under reduced pressure. The
crude reaction mixture was purified by flash column chroma-
tography on silica gel (230–400 mesh) using 5 % ethyl acetate in
petroleum ether to obtain pure 4k (103 mg, 57 % isolated yield
of the major diastereomer, diastereomeric ratio 40 : 1) as a light
yellow liquid, Rf 0.32 (5 % ethyl acetate in petroleum ether);
[a]2D5 ¼ ꢁ21.4 (c 0.12 in CHCl3); IR nmax (neat, cmꢁ1) 3373,
2927, 2856, 1746, 1698, 1652, 1463, 1369, 1317, 1254, 1172,
1096, 1054, 1019, 837, 776; 1H NMR (500 MHz, CDCl3)
d 0.02–0.14 (m, 6H), 0.83–0.97 (m, 9H), 1.26 (t, 3H, J ¼ 7.2 Hz),
1.43–1.63 (m, 17H), 2.71–2.76 (m, 1H) 3.44 (s, 2H), 3.81–3.91
(m, 1H), 4.01–4.02 (m, 2H), 4.14–4.20 (m, 2H); 13C NMR
(100 MHz, CDCl3) d ꢁ4.4, 14.0, 17.9, 22.9, 25.6, 27.0, 28.4,
29.3, 31.9, 37.0, 49.6, 64.1, 80.3, 166.9, 200.2; HRMS (ESI)
calcd for C23H44NO7Si (MþHþ): 474.2887, found 474.2885.
(m, 1H), 2.78–2.92 (m, 2H), 3.93–4.09 (m, 4H), 5.74 (dd, 1H,
J ¼ 3.2, 12.0 Hz), 7.11–7.15 (m, 1H), 7.29–7.33 (m, 1H), 7.45–
7.49 (m, 2H); 13C NMR (100 MHz, CDCl3) d 39.7, 41.4, 64.9,
105.4, 121.0, 127.4, 128.0, 129.7, 132.9, 137.9, 168.8; HRMS
(ESI) calcd for C13H14BrO4 (MþHþ): 313.0075, found:
313.0070.
9-(3-Bromophenyl)-1,4,8-trioxaspiro[4.5]decan-
7-one (5c)
The general procedure described above was followed to
afford 5c (85 mg, 65 % yield) as colourless thick liquid, Rf
0.50 (40 % ethyl acetate in petroleum ether); IR nmax (neat,
cmꢁ1) 3064, 2924, 1745, 1620, 1597, 1572, 1476, 1431, 1367,
1340, 1253, 1230, 1126, 1097, 1075, 1050, 1013, 982, 948, 861,
827, 786, 731; 1H NMR (400 MHz, CDCl3) d 2.0–2.20 (m, 2H),
2.73–2.88 (m, 2H), 3.89–4.04 (m, 4H), 5.36 (dd, 1H, J ¼ 3.2,
12.2 Hz), 7.17–7.25 (m, 2H), 7.39–7.52 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 41.4, 64.9, 65.0, 105.4, 122.8, 124.5,
129.1, 130.3, 131.7, 140.9, 168.6; HRMS (ESI) calcd for
C13H14BrO4Na (MþNaþ): 334.9894, found: 334.9893.
9-(4-Chlorophenyl)-1,4,8-trioxaspiro[4.5]decan-
7-one (5d)
General Procedure for the Synthesis of Protected Pyrone
Derivatives from d-Hydroxy-b-keto Ester (5a–j)
The general procedure described above was followed to
afford 5d (70 mg, 62 % yield) as a light yellow solid, mp 78–
828C; Rf 0.48 (40 % ethyl acetate in petroleum ether); IR nmax
(KBr, cmꢁ1) 2911, 1746, 1626, 1494, 1416, 1382, 1344, 1289,
1271, 1245, 1107, 1088, 1077, 1047, 1012, 966, 948, 886, 846,
824, 749; 1H NMR (500 MHz, CDCl3) d 2.0–2.20 (m, 2H), 2.60–
2.90 (m, 2H), 3.90–4.01 (m, 4H), 5.37 (dd, 1H, J ¼ 3.4, 12.0 Hz),
7.23–7.31 (m, 4H); 13C NMR (125 MHz, CDCl3) d 42.0, 65.6,
65.7, 78.2, 106.1, 128.0, 129.8, 135.1, 135.7, 169.4; HRMS
(ESI) calcd for C13H14ClO4 (MþHþ): 269.0580, found:
269.0587.
The addition product 4a–j (0.42 mmol) was dissolved in 2.0 mL
dichloromethane and cooled to 08C before addition of 1,2-
ethanediol (0.18 mL, 3.36 mmol) and BF3ꢀOEt2 (0.03 mL,
0.21 mmol) (diluted in 0.5 mL dichloromethane and cooled to
08C) . The reaction mixture was warmed to room temperature
and stirred for 18–20 h. After completion of the reaction, mon-
itored by TLC, the reaction mixture was quenched with cold
water. The organic and aqueous layers were separated, and the
aqueous layer was extracted with dichloromethane (3 ꢂ 5 mL).
The combined organic extract was washed with brine and dried
over anhydrous sodium sulfate. After filtration and removal of
the solvent under reduced pressure, the crude reaction mixture
was purified by flash column chromatography on silica gel
(230–400 mesh) using 20 % ethyl acetate in petroleum ether to
obtain pure 5a–j.
4-(9-Oxo-1,4,8-trioxaspiro[4.5]decan-7-yl)
benzonitrile (5e)
The general procedure described above was followed to
afford 5e (63 mg, 58 % yield) as a white solid, mp 83–858C;
Rf 0.40 (40 % ethyl acetate in petroleum ether); IR nmax (KBr,
cmꢁ1) 3441, 2906, 2235, 1731, 1631, 1551, 1467, 1422, 1379,
1343, 1270, 1254, 1233, 1208, 1149, 1108, 1073, 1043, 1011,
9-Phenyl-1,4,8-trioxaspiro[4.5]decan-7-one (5a)
The general procedure described above was followed to
afford 5a (55 mg, 55 % yield) as a colourless thick liquid, Rf
0.51 (40 % ethyl acetate in petroleum ether); IR nmax (neat,
cmꢁ1) 3064, 3034, 2976, 2927, 2894, 1743, 1614, 1498, 1477,
1455, 1343, 1254, 1234, 1207, 1127, 1082, 1047, 1011, 979,
948, 842, 723; 1H NMR (400 MHz, CDCl3) d 2.06–2.21 (m, 2H),
2.75–2.90 (m, 2H), 3.90–4.02 (m, 4H), 5.39 (dd, 1H, J ¼ 3.4,
11.7 Hz), 7.27–7.38 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 41.3, 64.8, 64.9, 78.3, 105.5, 125.9, 128.6, 128.7, 138.5,
168.9; HRMS (ESI) calcd for C13H15O4 (MþHþ): 235.0970,
found: 235.0970.
1
979, 948, 902, 851, 819, 734; H NMR (500 MHz, CDCl3)
d 2.02–2.10 (m, 1H), 2.21–2.26 (m, 1H), 2.78–2.95 (m, 2H),
3.94–4.20 (m, 4H), 5.49 (dd, 1H, J ¼ 2.9, 11.9 Hz), 7.48 (d, 2H,
J ¼ 8.6 Hz), 7.67 (d, 2H, J ¼ 8.3 Hz); 13C NMR (125 MHz,
CDCl3) d 41.2, 41.3, 64.9, 65.0, 76.7, 105.2, 112.4, 118.3,
126.5, 135.5, 143.8, 168.3; HRMS (ESI) calcd for
C14H13NO4Na (MþNaþ): 282.0742, found: 282.0743.
9,9-Dimethyl-1,4,8-trioxaspiro[4.5]decan-7-one (5f)
The general procedure described above was followed to
afford 5f (45 mg, 58 % yield) as a colourless liquid, Rf 0.34
9-(2-Bromophenyl)-1,4,8-trioxaspiro[4.5]decan-
7-one (5b)
(40 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
2980, 2933, 1733, 1703, 1626, 1446, 1407, 1380, 1360, 1284,
)
The general procedure described above was followed to
afford 5b (68 mg, 52 % yield) as a light yellow solid, mp 116–
1188C; Rf 0.48 (40 % ethyl acetate in petroleum ether); IR nmax
(KBr, cmꢁ1) 3060, 2956, 2884, 1740, 1618, 1490, 1456, 1432,
1341, 1234, 1210, 1133, 1079, 1034, 1011, 980, 932, 840, 715;
1H NMR (400 MHz, CDCl3) d 1.81–1.88 (m, 1H), 2.38–2.43
1232, 1177, 1113, 1089, 1032, 1016, 999, 978, 949, 932, 872,
1
811, 794; H NMR (400MHz, CDCl3) d 1.42 (s, 6H), 1.96
(s, 2H), 2.68 (s, 2H), 3.85–3.95 (m, 4H); 13C NMR (100 MHz,
CDCl3) d 29.6, 40.6, 43.3, 64.5, 89.9, 105.7, 169.3; HRMS (ESI)
calcd for C9H15O4 (MþHþ): 187.0970, found: 187.0979.

Oxacycles Pyrones
1269
9-Ethyl-9-methyl-1,4,8-trioxaspiro[4.5]decan-
7-one (5g)
(d) M. Kobayashi, K. Higuchi, N. Murakami, H. Tajima, S. Aoki,
Tetrahedron Lett. 1997, 38, 2859. doi:10.1016/S0040-4039(97)00482-6
(e) R. Pereda-Miranda, M. Fragoso-Serrano, C. M. Cerda-Garc´ıa-Rojas,
Tetrahedron 2001, 57, 47. doi:10.1016/S0040-4020(00)00987-X
(f) G. E. Raoelison, C. Terreaux, E. F. Queiroz, F. Zsila, M. Simonyi,
S. Antus, A. Randriantsoa, K. Hostettmann, Helv. Chim. Acta 2001,
84, 3470. doi:10.1002/1522-2675(20011114)84:11,3470::AID-
HLCA3470.3.0.CO;2-K
The general procedure described above was followed to
afford 5g (47 mg, 56 % yield) as a colourless liquid, Rf 0.39
(40 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
2976, 2926, 1733, 1698, 1645, 1462, 1383, 1361, 1327, 1274,
)
1
1224, 1164, 1101, 1017, 979, 949, 795; H NMR (400MHz,
CDCl3) d 0.85–0.97 (m, 5H), 1.38 (s, 3H), 1.83–2.01 (m, 2H),
2.56–2.69 (m, 2H), 3.87–3.93 (m, 4H); 13C NMR (100 MHz,
CDCl3) d 8.1, 26.4, 35.2, 40.8, 44.148.4, 64.4, 83.3, 105.8,
169.3; HRMS (ESI) calcd for C10H16O4Na (MþNa): 223.0946,
found: 223.0948.
(g) J. E. Moses, J. E. Baldwin, R. M. Adlington, Tetrahedron Lett.
2004, 45, 6447. doi:10.1016/J.TETLET.2004.06.125
(h) P. Kasaplar, O. Yılmazer, A. C¸ ag˘ır, Bioorg. Med. Chem. 2009, 17,
¨
311. doi:10.1016/J.BMC.2008.10.069
(i) M. Daoubi, C. Pinedo-Rivilla, M. B. Rubio, R. Hermosa, E. Monte,
Tetrahedron 2009, 65, 4834. doi:10.1016/J.TET.2009.04.051
(j) A. Tanaka, N. Hamada, Y. Fujita, T. Itoh, Y. Nozawa, M. Iinuma,
M. Ito, Bioorg. Med. Chem. 2010, 18, 3133. doi:10.1016/J.BMC.2010.
03.034
(k) L. V. Puyvelde, N. De Kimpe, M. Chagnon-Dube´, Y. Boily,
F. Borremans, N. Schamp, J. O. Anteunis, Phytochemistry 1981, 20,
2753. doi:10.1016/0031-9422(81)85280-6
(l) L. V. Puyvelde, N. De Kimpe, Phytochemistry 1998, 49, 1157.
doi:10.1016/S0031-9422(98)00112-5
(m) S. E. Drewes, B. M. Sehlapelo, R. Hornmmscott-Shaw, P. Sandow,
Phytochemistry 1995, 38, 1427. doi:10.1016/0031-9422(94)00828-H
(n) M. T. Davies-Coleman, D. E. A. Ravett, Phytochemistry 1995, 38,
791. doi:10.1016/0031-9422(95)93874-F
(o) D. M. Boalino, J. B. Connolly, S. McLean, W. F. Reynolds,
W. F. Tinto, Phytochemistry 2003, 64, 1303. doi:10.1016/
J.PHYTOCHEM.2003.08.017
(p) L. D. Juliawaty, Y. Watanabe, M. Kitajima, S. A. Achmad,
H. Takayama, N. Aimi, Tetrahedron Lett. 2002, 43, 8657.
doi:10.1016/S0040-4039(02)02181-0
(q) Y. Deng, M. J. Balunas, J.-A. Kim, D. D. Lantvit, Y.-W. Chin,
H. Chai, S. Sugiarso, L. B. S. Kardono, H. H. S. Fong, J. M. Pezzuto,
S. M. Swanson, E. J. C. de Blanco, A. D. Kinghorn, J. Nat. Prod. 2009,
72, 1165. doi:10.1021/NP9001724
(r) S. Senthil-Nathan, M.-Y. Choi, C.-H. Paik, K. Kalaivani,
Chemosphere 2008, 72, 1393. doi:10.1016/J.CHEMOSPHERE.2008.
03.037
1,4,8-Trioxadispiro[4.3.4.1]tetradecane-7-one (5h)[18]
The general procedure described above was followed to
afford 5h (49 mg, 55 % yield) as a light yellow liquid, Rf 0.38
(40 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
)
2987, 2964, 1740, 1636, 1542, 1472, 1415, 1383, 1334, 1278,
1232, 1208, 1172, 1122, 1078, 1048, 1028, 988, 972, 922, 870,
832, 785, 634; 1H NMR (400MHz, CDCl3) d 1.63–2.11
(m, 10H), 2.74 (s, 3H), 3.91–3.96 (m, 4H); 13C NMR (100 MHz,
CDCl3) d 23.6, 40.0, 41.2, 41.8, 64.6, 90.9, 169.4; HRMS (ESI)
calcd for C11H17O4 (MþHþ): 213.1127, found: 213.1126.
1-Oxaspiro[5.5]undecane-2,4-dione (5i)
The general procedure described above was followed to
afford 5i (46 mg, 60 % yield) as a light yellow liquid, Rf 0.51
(40 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
2956, 1735, 1636, 1446, 1407, 1382, 1355, 1284, 1232, 1217,
)
1175, 1120, 1089, 1024, 1016, 999, 978, 966, 954, 872, 832, 770,
1
641; H NMR (400MHz, CDCl3) d 1.19–1.82 (m, 10H), 2.60
(s, 2H), 3.35 (s, 2H); 13C NMR (100 MHz, CDCl3) d 21.4, 24.6,
36.8, 44.4, 49.4, 80.4, 167.3, 200.8; HRMS (ESI) calcd for
C10H15O3 (MþHþ): 183.1021, found: 183.1027.
[2] (a) I. Fleming, A. Barbero, D. Walter, Chem. Rev. 1997, 97, 2063.
doi:10.1021/CR941074U
6-Ethyl-6-phenyldihydro-2H-pyran-2,4(3H)-dione (5j)
The general procedure described above was followed to
afford 5j (58 mg, 63 % yield) as a light yellow liquid, Rf 0.39
(40 % ethyl acetate in petroleum ether); IR nmax (neat, cmꢁ1
2971, 2925, 2854, 1727, 1663, 1618, 1494, 1450, 1410, 1332,
1260, 1226, 1174, 1090, 1018, 972, 894, 829, 804, 760, 701;
1H NMR (400MHz, CDCl3) d 0.80–0.84 (m, 3H), 1.96–1.99
(m, 2H), 1.83–2.01 (m, 2H), 2.79–2.89 (m, 2H), 3.16–3. 31
(m, 2H), 7.22–7.33 (m, 5H); 13C NMR (100 MHz, CDCl3) d 8.4,
35.3, 36.3, 45.9, 47.4, 124.3, 125.9, 128.5, 130.1, 167.8; HRMS
(ESI) calcd for C13H13O3 (MꢁHþ): 217.0865, found: 217.0867.
(b) M. M. Faul, B. E. Huff, Chem. Rev. 2000, 100, 2407. doi:10.1021/
CR940210S
(c) P. F. Hudrlik, A. M. Hudrlik, G. Nagendrappa, T. Yimenu, E. T.
Zellers, E. Chin, J. Am. Chem. Soc. 1980, 102, 6894. doi:10.1021/
JA00542A061
(d) K. Afarinkia, M. J. Bearpark, A. Ndibwami, J. Org. Chem. 2005,
70, 1122. doi:10.1021/JO048213K
(e) A. Kumar, F. V. Singh, A. Goel, Tetrahedron Lett. 2007, 48, 8223.
doi:10.1016/J.TETLET.2007.09.084
(f) V. Bertacche, A. Contini, E. Erba, D. Nava, P. Trimarco,
Tetrahedron 2007, 63, 9652. doi:10.1016/J.TET.2007.07.022
(g) Farhanullah, F. Samrin, V. J. Ram, Tetrahedron 2009, 65, 1635.
doi:10.1016/J.TET.2008.12.041
)
Acknowledgements
[3] B. Jiang, Z. Chen, Tetrahedron: Asymmetry 2001, 12, 2835.
doi:10.1016/S0957-4166(01)00506-7
[4] J. Zhang, Y. Li, W. Wang, X. She, X. Pan, J. Org. Chem. 2006, 71,
MKG is grateful to IIT-Kanpur and DST, India for financial support. SH and
SS are thankful to UGC and CSIR, India, respectively, for their research
fellowships.
2918. doi:10.1021/JO060028E
[5] (a) K. A. Jørgensen, Angew. Chem. Int. Ed. 2000, 39, 3558.
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