Tandem Wittig-intramolecular Diels-Alder cycloaddition of ester-tethered 1,3,9-decatrienes under microwave heating

Article abstract of DOI:10.1016/j.tet.2010.10.088

Intramolecular Diels-Alder (IMDA) cycloaddition of the ester-tethered 1,3,9,-decatrienes possessing a carbonyl substituent at C10 has been investigated under controlled microwave heating (MeCN, 180 °C) to afford a variety of 3,4,4a,7,8,8a-hexahydroisochromen-1-ones in 53-89% yields and in 64:36-79:21 ratios for the cis and trans isomers. Under the same microwave heating conditions, a tandem Wittig-IMDA cycloaddition, starting from the α-bromoacetates of 3,5-hexadien-1-ols and glyoxalate/phenylglyoxal hydrates in the presence of PPh₃ and 2,6-lutidine, has been demonstrated, furnishing 3,4,4a,7,8,8a-hexahydroisochromen-1-one adducts in 73-91% yields in favor of the cis isomers. During this tandem process, three consecutive carbon-carbon bonds in the end products were efficiently formed with the aid of microwave irradiation within short reaction times.

Full text of DOI:10.1016/j.tet.2010.10.088

Tetrahedron 67 (2011) 179e192
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem Wittigeintramolecular DielseAlder cycloaddition of
ester-tethered 1,3,9-decatrienes under microwave heating
,b,
Jinlong Wu a, Xiuqing Jiang a, Jingjing Xu a, Wei-Min Dai a
*
a Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
b Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 August 2010
Received in revised form 22 October 2010
Accepted 29 October 2010
Available online 5 November 2010
Intramolecular DielseAlder (IMDA) cycloaddition of the ester-tethered 1,3,9,-decatrienes possessing
a carbonyl substituent at C10 has been investigated under controlled microwave heating (MeCN, 180 ꢀC)
to afford a variety of 3,4,4a,7,8,8a-hexahydroisochromen-1-ones in 53e89% yields and in 64:36e79:21
ratios for the cis and trans isomers. Under the same microwave heating conditions, a tandem Wit-
tigeIMDA cycloaddition, starting from the a-bromoacetates of 3,5-hexadien-1-ols and glyoxalate/phe-
nylglyoxal hydrates in the presence of PPh3 and 2,6-lutidine, has been demonstrated, furnishing
3,4,4a,7,8,8a-hexahydroisochromen-1-one adducts in 73e91% yields in favor of the cis isomers. During
this tandem process, three consecutive carbonecarbon bonds in the end products were efficiently
formed with the aid of microwave irradiation within short reaction times.
Keywords:
1,3,9-Decatriene
Intramolecular DielseAlder cycloaddition
Microwave
1-Oxo-3,4,4a,7,8,8a-hexahydro-1H-
isochromene
Ó 2010 Elsevier Ltd. All rights reserved.
Wittig olefination
1. Introduction
R1
1
R1
1
R1
1
R3
R2
R3
R5
O
CO2Et
10
Intramolecular DielseAlder (IMDA) cycloaddition is a versatile
synthetic tool for enabling formation of polycyclic skeletons of
structural complexity and has been widely used in total synthesis
of natural products.1 For example, IMDA cycloaddition of the es-
ter-tethered 1,3,9-decartrienes 4a,b have been studied under
thermal,2,3 Lewis acid catalysis, and non-conventional conditions4
to afford the bicyclic lactones, such as 7 from 4b (Fig. 1). This type
of IMDA cycloaddition has been applied in total synthesis of al-
kaloids, such as lycorine2c and stenine,3c,4b and eleuthesi-
des.2def,3d It has been established that cycloaddition of the trienes
4a normally take place at higher temperatures (200e250 ꢀC)2
than the trienes 4b possessing a C10-activating group. The latter
undergo cycloaddition at 100e150 ꢀC3 or even at room tempera-
ture.3d The cis-fused bicyclic lactones are preferably formed under
thermal conditions5 but improved diastereoselectivity can be
achieved under Lewis acid catalysis4 or using ionic liquids as the
reaction media,4h giving a single adduct in most cases. A boatlike-
cis (-endo) transition state5a is energetically favored to form the cis
adduct while the diastereoselectivity can be enhanced by in-
corporating a bulky R4 substituent at C6 of 4.3d We have reported
9
O
9
4
R4
4
4
8
8
8
N
5
R2
O
O
5
7
O
O
Bn
5
7
7
3: R2 = H, Me
R3 = Me, Ph
1: R4, R5 = H, C(O)X
X = OMe, OEt, Ph
2: R1 = Me, Ph
R3
1
3
9
6
X
8
O
R1
5
10
R2
R4
O
4a: X = H, alkyl, aryl; 4b: X = C(O)R5
R1
R1
O
O
R2
R2
Br
CH(OH)2
R5
O
PPh3, 2,6-lutidine
O
+
O
MeCN, 180 °C
1−1.5 h, MW
R5
O
R3
R3
R4
5
R4
6
7
Fig. 1. Structures of the tethered 1,3,8-nonatrienes (1 and 2) and 1,3,9-decatrienes (3
and 4) and the tandem WittigeIMDA cycloaddition for formation of 3,4,4a,7,8,8a-
hexahydroisochromen-1-ones 7.
* Corresponding author. Tel./fax: þ86 571 87953128; e-mail addresses: chdai@
zju.edu.cn, chdai@ust.hk (W.-M. Dai).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.088

180
J. Wu et al. / Tetrahedron 67 (2011) 179e192
IMDA cycloadditions of the ester-tethered 1,3,8-nonatrienes 16a
and 26b and the hydroxamate-tethered 1,3,9-decatrienes 36c un-
der controlled microwave heating. A tandem WittigeIMDA cy-
cloaddition of the trienes 1 has been developed. As a continuation
of our studies on the tandem reaction protocol, we report here on
microwave-assisted IMDA cycloaddition of the C10-activated tri-
enes 4b and one-pot synthesis of the bicyclic lactones 7 starting
2.1. Microwave-assisted IMDA cycloadditions of ester-
tethered 1,3,9-decatrienes
Fumaric and maleic acid monomethyl/monoethyl esters 17/1811
and 19/2012 were used to synthesize the ester-tethered 1,3,9-dec-
atrienes possessing an ester activating group at C10 (Scheme 2). The
E-substituted diesters 21aef were obtained in 79e93% yields by
condensation of 17/18 with the diene alcohols 9, 11, 12, 14, and 16 in
the presence of DCCeDMAP in CH2Cl2 at room temperature for 3 h
(entries 1e6, Table 1). Similarly, the Z-substituted diesters 22aef
were obtained in 56e71% yields from 19/20 and the diene alcohols
in the presence of DIC/i-Pr2NEt/DMAP6a,13 in CH2Cl2 at 0 ꢀC for 1 h
(entries 7e12, Table 1).14 Among these diesters, thermal IMDA cy-
cloaddition of (E)-21a,b and (Z)-22a have been reported (Scheme
2); the values of diastereomer ratio (dr) for 23a/24a and 23b/24b
are 83:17 (110 ꢀC in PhMe)5c and 86:14 (70 ꢀC in an ionic liquid),4h
from 3,5-hexadien-1-yl
a-bromoacetates 5 and glyoxalate or
phenylglyoxal hydrates 6 (Fig. 1).
2. Results and discussion
We prepared (E)-3,5-hexadien-1-ol (9) from ethyl sorbate (8)
according to the literature procedure (Scheme 1).4i,7 Treatment of 8
with LDA/HMPA followed by aqueous quenching gave the corre-
sponding deconjugate diene ester, which was then reduced by
LiAlH4 to furnish 9 in 70% overall yield. The diene alcohols 11e13
were synthesized in 68e91% yields by the Wittig olefination using
3-hydroxypropyltriphenylphosphonium bromide (10).8 An in-
separable mixture of (3E,5E)- and (3Z,5E)-isomers was obtained for
11 and 12,9 while 1310 was formed as a single (3E,5E)-isomer. Ox-
idation of 13 by DesseMartin periodinane (DMP) followed by re-
action of the aldehyde with MeMgCl afforded the racemic alcohol
14 in 47% overall yield (not optimized). Finally, the racemic alcohol
16 was synthesized in 50% yield from 3-hydroxy-2-methylpropyl-
triphenylphosphonium bromide (15) in a similar manner as de-
scribed above for 10.
respectively, while dr for 25a/26a is 70:30 (132 ꢀC in PhCl).5c
A
slightly lower dr (78:22) was reported for 23a/24a in refluxing
xylene (bp¼ca. 140 ꢀC).3c We heated the diester (E)-21a at 180 ꢀC in
MeCN with microwave irradiation in a closed pressurized vial to
afford 23a/24a in 80% combined yield and in 79:21 dr (entry 1,
Table 1). Thus, we confirmed that the cis-fused bicyclic lactone 23a
is the major adduct within the reaction temperatures ranged from
110 to 180 ꢀC albeit the diastereoselectivity decreased slightly with
increased temperatures. This temperature effect on diaster-
eoselectivity was also observed in the cycloaddition of (E)-21b. We
recorded 77:23 dr for 23b/24b at 180 ꢀC (entry 2, Table 1) as
compared to 86:14 dr reported at 70 ꢀC in an ionic liquid.4h The
improved diastereoselectivity might also be contributed by using
the ionic liquid. In contrast, the IMDA cycloaddition of (Z)-22a,b
seems insensitive to reaction temperature; we obtained
74:26e75:25 dr for the adducts 25a/26a and 25b/26b at 180 ꢀC,
respectively, while 70:30 dr was reported at 132 ꢀC for 25a/26a5c
(entries 7 and 8, Table 1).
IMDA cycloaddition of (E)-21c,d and (Z)-22c,d was performed
under the same microwave heating conditions (Scheme 2). We
found that the (3Z,5E)-hexadien-1-yl isomers of (E)-21c,d and (Z)-
22c,d could not undergo the cycloaddition, and thus, they were
recovered after the reaction. Yields of the adducts were then
calculated according to the ratios of (3E,5E)-hexadien-1-yl iso-
mers in the mixed trienes (E)-21c,d and (Z)-22c,d (entries 3, 4, 9,
and 10, Table 1). The diastereoselectivity for (E)-21c,d is
71:29e75:25, being similar to the value of 77:23 obtained for (E)-
21b (entries 2e4, Table 1). It implies that the C1-substituent
(R1¼H, Me, Ph) is not influential on IMDA cycloaddition of the (E)-
series of diesters. However, lower dr (64:36) was observed for the
C1ePh-substituted (Z)-22d, which also gave poorer yield (53%) for
25d/26d (entry 4, Table 1). The relative stereochemistry of the
major adduct 23d was determined by X-ray crystal structural
analysis.15 The structures of other adducts were assigned
analogously.
1. LDA (2 eq), HMPA
THF, −78 °C, 1.5 h;
then H2O−HOAc
O
Me
OEt
OH
OH
OH
2. LiAlH4, THF
(70% for 2 steps)
9
8
R2
n-BuLi (2 eq)
THF, 0 °C, 0.5 h;
R1
Br-Ph3P+
R2
R1
11−13
10
CHO
0 °C, 2−2.5 h
R1
R2
yield (%)
E,E:Z,E
Me
Ph
Me
H
H
Me
11, 68
79:21
12, 93
13, 91
73:27
100:0
1. DMP, NaHCO3
CH2Cl2, rt, 2 h
Inoue and co-workers3e examined the thermal IMDA cycload-
dition of the ester-tethered 1,3,9-decatrienes of the type 21 (R3¼H,
R4¼Me, R5¼Me or OEt) at 100e135 ꢀC. Only one pair of cis/trans
adducts of the types 23 and 24 was formed with diaster-
eoselectivity of 70:30e80:20. The results suggest that the cyclo-
addition occurs via two boatlike-cis (-endo) and boatlike-trans
(-exo) transition states5a where R4 (¼Me) sits in an equatorial po-
sition (see TS-I and TS-II in Fig. 2). Kurth and co-workers demon-
strated that the bulky C6et-Bu substituent could serve as an
excellent endo and boat director, furnishing a singlet adduct via TS-
I.3d We carried out the thermal IMDA cycloaddition of (E)-21f and
(Z)-22f and obtained only one pair of cis/trans adducts 23f/24f and
25f/26f, respectively (entries 6 and 12, Table 1). For the adducts
23f/24f a comparable diastereoselectivity (dr¼72:28) to the liter-
ature data was observed while formation of the adducts 25f/26f
Me
Me
Me
Me
Me
OH
OH
2. MeMgCl, THF
−78 °C, 2 h
13
14
(47% for 2 steps)
n-BuLi (2 eq)
THF, 0 °C, 0.5 h;
Me
Me
Br-Ph3P+
OH
OH
Me
CHO
0 °C, 2 h (50%)
Me
15
Me
Me
16
Scheme 1. Synthesis of the diene alcohols 9, 11e14, and 16.

J. Wu et al. / Tetrahedron 67 (2011) 179e192
181
R3
R3
5
O
R3
9
7
O
1
3
17 or 18
19 or 20
8
OH
2
6
R1
O
R5
R1
R1
DCC, DMAP
CH2Cl2, rt, 3 h
DIC, i-Pr2NEt, DMAP
CH2Cl2, 0 °C, 1 h
10
R2
R4
4
R2
R4
O
R2
R4
22a−f
O
O
R5
21a−f
9: R1 = R2 = R3 = R4 = H
11: R1 = Me, R2 = R3 = R4 = H
12: R1 = Ph, R2 = R3 = R4 = H
14: R1 = R2 = R4 = Me, R3 = H
16: R1 = R2 = R3 = Me, R4 = H
MeCN, 180 °C
0.5−1.5 h, MW
MeCN, 180 °C
1.5−2.5 h, MW
R1
O
H
O
R1
O
H
O
R1
O
H
O
R1
O
H
O
R2
R2
R2
R2
R5
O
R5
O
R5
O
R5
O
+
+
H
H
H
H
R3
R3
O
R3
R3
O O
R4
R4
24a−f
trans (minor)
R5
R4
25a−f
cis (major)
R4
HO
R5
HO
23a−f
cis (major)
26a−f
trans (minor)
O
19: R5 = OMe
20: R5 = OEt
17: R5 = OMe
18: R5 = OEt
Me
O
Me
O
H
O
Me
O
H
O
Me
O
H
Me
Me
Me
Me
OEt
O
OEt
OEt
O
OEt
O
H
O
O
+
+
H
H
Me
H
H
Me
O
Me
Me
24e'
26e'
23e'
25e'
cis (major)
trans (minor)
trans (minor)
cis (major)
Scheme 2. Synthesis and microwave-assisted IMDA cycloaddition of ester-tethered 1,3,9-decatrienes 21aef and 22aef.
was less diastereoselective (dr¼65:35) as compared to the cyclo-
addition of (Z)-22c possessing the same C1-substituent (R1¼Me)
(entry 12 vs entry 9, Table 1).
cycloaddition mixtures of both (E)-21e and (Z)-22e (entries 5 and
11, Table 1). By referred to the above-mentioned results reported
by Taguchi and co-workers,4d,e we tentatively assigned the two
major adducts of (E)-21e as the cis-isomers 23e and 23e0, and the
two minor adducts as the trans-isomers 24e and 24e0. All four
adducts are formed via the boatlike transition states shown in
Fig. 2 with TS-I and TS-II being favored over TS-I0 and TS-II0, re-
spectively. The estimated dr for the two cis-adducts 23e and 23e0
is 77:23, which is close to that reported by Taguchi and co-workers
for the C10-unactivated decatriene.4d,e Similarly, the four adducts
from (Z)-22e are considered derived from the same types of
Taguchi and co-workers4d,e reported IMDA cycloaddition of an
ester-tethered 1,3,9-decatriene possessing a C5eMe substituent
(R3¼Me, X¼H) under thermal and Lewis acid catalysis conditions.
Diastereoselectivity of 83:17e88:12 was observed for two cis-
fused adducts formed via TS-I and TS-I0. Adducts via TS-II and TS-
II0 were not observed, being consistent with the selectivity order
(i-Pr>H>CO2Me/CO2Et>COMe) for substituent X at C10.3e It is not
surprising that four stereoisomers were detected in the crude
Table 1
Results of synthesis and microwave-assisted IMDA cycloaddition of ester-tethered 1,3,9-decatrienes 21aef and 22aef
Entry
R1
R2
R3
R4
R5
Diesters
Yield (%)
Lactones
ta (h)
Yieldb (%)
cis:trans ratioc
1
2
3
4
5
6
H
H
Me
Ph
Me
Me
H
H
H
H
Me
Me
H
H
H
H
Me
H
H
H
H
H
H
Me
OMe
OEt
OEt
OEt
OEt
OEt
(E)-21a
(E)-21b
(E)-21c
(E)-21d
(E)-21e
(E)-21f
79
83
23aþ24a
23bþ24b
23cþ24c
23dþ24d
23eþ24e
23fþ24f
1.5
0.5
1
1
1
80
79:21 (83:17)d,e
77:23 (86:14)f
71:29
80
89g
92g
93
82h
71h
87
75:25
86:14 (23e0:24e0¼73:27)i
72:28
84
1
89
7
8
9
10
11
12
H
H
Me
Ph
Me
Me
H
H
H
H
Me
Me
H
H
H
H
Me
H
H
H
H
H
H
Me
OMe
OEt
OEt
OEt
OEt
OEt
(Z)-22a
(Z)-22b
(Z)-22c
(Z)-22d
(Z)-22e
(Z)-22f
66
62
25aþ26a
25bþ26b
25cþ26c
25dþ26d
25eþ26e
25fþ26f
2.5
1.5
2
2
2
78
76
74:26 (70:30)d
75:25
72:28
56g
62g
67
80h
53h (86)i
85
64:36 (62:38)i
78:22 (25e0:26e0¼77:23)j
65:35
71
2
71
a
IMDA cycloadditions were carried out in MeCN at 180 ꢀC for the indicated time in a closed pressurized vial with temperature measured by an IR sensor.
b
c
Combined yields of the isolated adducts.
The ratio was determined by 1H NMR spectrum of the crude product mixture.
d
The numbers in the parentheses are taken from Ref. 5c. The IMDA cycloaddition was carried out in PhMe (110 ꢀC, 22 h) and PhCl (132 ꢀC, 72 h) for (E)-21a and (Z)-22a,
respectively.
e
The adducts 23a and 24a were obtained in 52% and 15% yields (dr¼78:22) in refluxing xylene for 5 h as reported in Ref. 3c.
f
The number in the parenthesis is taken from Ref. 4h. The adducts were obtained in 86% combined yield in [emim]BF4 at 70 ꢀC for 7 h.
Obtained as an inseparable mixture of (3E,5E)- and (3Z,5E)-dien-1-yl esters.
g
h
i
Calculated according to the (3E,5E)-dien-1-yl ester. The (3Z,5E)-dien-1-yl ester was recovered after the IMDA cycloaddition.
The numbers in the parentheses are obtained for the IMDA reaction carried out at 200 ꢀC for 2 h in MeCN using isomeric pure (Z)-22d. The latter was prepared from the
isomeric pure 12 (see Ref. 9).
j
Four inseparable diastereomers were found in the crude products due to the C5 stereogenic carbon attached with R3 (¼Me). The cis:trans ratios were tentatively assigned
according to the isomer ratios (23e:24e:23e0:24e0¼64:10:19:7 and 25e:25e:25e0:25e0¼54:15:24:7) measured by 1H NMR spectra of the crude products.

182
J. Wu et al. / Tetrahedron 67 (2011) 179e192
R2
H
H
O
Ph3P
R2
H
Ph3P+Br-
5a
1
R3
O
R1
MeCN, rt, 12 h
H
1
H
R1
R3
H
5
27
H
O
5
H
H
6
X
H
H
6
R4
R4
RCOCH(OH)2, 2,6-lutidine
O
H 10
O
10
MeCN, rt, 2−4 h
X
H
H
O
O
O
R
O
TS-II: boatlike-trans
TS-I: boatlike-cis
X = C(O)R5
R
O
+
O
O
X = C(O)R5
(E)-21b: R = OEt (74%)
(E)-21h: R = Ph (70%)
(Z)-22b: R = OEt (10%)
(Z)-22h: R = Ph (9%)
24a−f
23a−f
R2
H
H
MeCN, 180 °C, 1.5 h, MW
(90%; 23h:24h = 70:30)
R2
for (E)-21h
H
H
R3
R1
R3
H
R1
H
H
5
O
O
H
O
5
H
X
H
H
Ph
H
Ph
H
H
10
H
O
H
O
O
+
O
10
X
H
H
H
H
O
O
O
TS-II': boatlike-trans
TS-I': boatlike-cis
X = CO2Et
23e'
23h
24h
Scheme 3. Synthesis and IMDA cycloaddition of triene (E)-21h.
X = CO2Et
24e'
similar procedure used in our previous study,6a
a-bromoacetate 5a,
Fig. 2. Illustration of two favorable boatlike transition states for IMDA cycloaddition of
(E)-21aef with relative stereochemistry.
prepared from (E)-3,5-hexadien-1-ol (9) (see Scheme 4), was
treated with PPh3 in MeCN at room temperature for 12 h to give the
corresponding phosphonium salt 27. The latter was reacted with
ethyl glyoxalate or phenylglyoxal hydrate in the presence of 2,6-
lutidine as the base (MeCN, rt, 2e4 h) to afford the trienes (E)-21b,h
and (Z)-22b,h in 70e74% and 9e10% overall yields for the two steps,
respectively. The E/Z ratios are ca. 90:10 for both aldehydes. We
found that (E)-21h underwent spontaneous IMDA cycloaddition at
room temperature, being opposite to the related C9-keto-activated
1,3,8-nonatriene whose Z-isomer gave IMDA adducts at room
temperature.6a Therefore, the freshly prepared (E)-21h was heated
at 180 ꢀC with microwave irradiation to give the adducts 23h and
24h in 90% combined yield and in 70:30 dr as checked by 1H NMR
analysis of the crude reaction mixture.
boatlike transition states shown in Fig. 2 but with altered posi-
tions for C10-H and C10-X. Therefore, our above described results
have established that microwave heating at 180 ꢀC in MeCN could
facilitate IMDA cycloaddition of the ester-tethered 1,3,9-deca-
trienes possessing a C10-ester group. The reaction completes
within 0.5e2.5 h to furnish the adducts in good yields in favor of
the cis-fused adducts. Moreover, we have confirmed that a C6 alkyl
substituent controls diastereoselectivity much efficiently than the
same substituent at C5 of the ester-tethered 1,3,9-decatrienes.
2.2. Microwave-assisted tandem WittigeIMDA cycloadditions
of ester-tethered 1,3,9-decatrienes
The requisite a-bromoacetates 5a,ceg for studying the tandem
protocol were prepared from the 3,5-hexadien-1-ols and bromo-
acetic acid (DCC/DMAP, rt) or bromoacetyl bromide (Et3N, 0 ꢀC) in
85e89% yields (Scheme 4 and Table 2). First, a mixture of 5a, methyl
or ethyl glyoxalate hydrate 6 (R5¼OMe or OEt),16 PPh3, and
Before investigating the tandem WittigeIMDA protocol, step-
wise formation and IMDA cycloaddition of the C10-activated tri-
enes (E)-21b,h were first performed (Scheme 3). According to the
R1
O
H
O
R1
O
H
O
O
C
BrCH2CO2H
R5
CH(OH)2 (6)
R2
R2
R3
R3
R5
O
DCC, DMAP
R5
O
CH2Cl2, rt, 3h
PPh3, 2,6-lutidine
OH
O
R1
R1
Br
+
+
or BrCH2COBr, Et3N
CH2Cl2, 0 °C, 2 h
MeCN, 180 °C
1−2.5 h, MW
R2
R4
R2
R4
O
H
H
R3
R3
R4
R4
24a−h
9: R1 = R2 = R3 = R4 = H
5a,c−g
11: R1 = Me, R2 = R3 = R4 = H
12: R1 = Ph, R2 = R3 = R4 = H
13: R1 = R2 = Me, R3 = R4 = H
14: R1 = R2 = R4 = Me, R3 = H
16: R1 = R2 = R3 = Me, R4 = H
23a−h
R1
O
H
O
R1
O
H
O
Me
O
Me
O
H
O
R2
R2
R5
O
R5
O
Me
Me
OEt
O
OEt
O
H
O
+
+
+
H
H
H
Me
H
Me
R3
R3
R4
R4
26a−h
24e'
23e'
25a−h
Scheme 4. Synthesis and microwave-assisted tandem WittigeIMDA cycloaddition of 3,5-hexadien-1-yl a-bromoacetates 5a,ceg.

J. Wu et al. / Tetrahedron 67 (2011) 179e192
183
Table 2
Results of synthesis and microwave-assisted tandem WittigeIMDA cycloaddition of 3,5-hexadien-1-yl
a
-bromoacetates 5a,ceg
Entry
R1
R2
R3
R4
Acetates
Yield (%)
6: R5
Lactones
ta (h)
Yieldb (%)
drc
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
Me
Me
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
Me
H
H
H
5a
5a
5c
5d
5e
5f
5g
5a
5g
88
d
OMe
OEt
OEt
OEt
OEt
OEt
Ph
23aþ24aþ25aþ26a
23bþ24bþ25bþ26b
23cþ24cþ25cþ26c
23dþ24dþ25dþ26d
23eþ24eþ23e0þ24e0þ25eþ26e
23fþ24fþ25fþ26f
23gþ24gþ25gþ26g
23hþ24hþ25hþ26h
23iþ24i
1.5
1
1
1.5
1
1
78
84
77:18:5:0
72:24:4:0
51:34:8:7
64:27:6:3
53:11:18:10:5:3
63:31:4:0
Me
Ph
Me
Me
Me
H
86d
85d
89
87
86
d
90e
85e
86f
73
1
91
63:33:4:0
Ph
1
77
65:32:3:0
Me
Me
d
dg
2.5h
62 (58)i
88:12 (93:7)i
a
All tandem WittigeIMDA cycloadditions were carried out in MeCN at 180 ꢀC for the indicated time in a closed pressurized vial with temperature measured by an IR sensor.
b
c
d
e
f
Combined yield of the isolated adducts.
The diastereomer ratio (dr) was calculated according to the isolated adducts. For entry 5, dr was estimated by 1H NMR spectrum of the mixed products.
Obtained as an inseparable mixture of (3E,5E)- and (3Z,5E)-dien-1-yl
Calculated according to the (3E,5E)-dien-1-yl -bromoacetate.
Combined yield of all adducts as an inseparable mixture.
Aqueous formaldehyde (37 wt %, 3 equiv) was used instead of 6.
The tandem reaction was performed at 160 ꢀC instead of 180 ꢀC.
The numbers in the parentheses are for the reaction using 37 wt % aqueous formaldehyde (8 equiv) carried out at 110 ꢀC (oil bath) in MeCN for 36 h.
a-bromoacetates.
a
g
h
i
2,6-lutidine in MeCN was heated at 180 ꢀC in a closed pressurized
process vial with microwave irradiation for 1e1.5 h. In both cases,
three adducts were identified among four possible diastereomers
and the two major adducts were formed via (E)-21a and (E)-21b,
respectively (entries 1 and 2, Table 2). The adducts 23a,b, 24a,b, and
25a,b were isolated in the combined yields of 78e84% and their
structures were confirmed by comparison with the authentic
samples synthesized from the pre-isolated trienes (Scheme 2).
These results confirmed that the Wittig olefination at 180 ꢀC gave
ca. 90% E-isomers of the trienes. Moreover, the cis/trans ratios of the
ester adducts 23a/24a (81:19) and 23b/24b (75:25) for the tandem
protocol are almost the same as those observed for the IMDA cy-
cloaddition of the pre-isolated trienes (E)-21a and (E)-21b (entries
1 and 2 in Tables 1 and 2).
isolated in 91% combined yield (entry 7, Table 2). Moreover, the
relative stereochemistry of the trans adduct 24g was confirmed by
X-ray crystallographic analysis as depicted in Fig. 3.17
The C10-unactivated 1,3,9-decatriene 21i (Scheme 5), prepared
from the alcohol 13 and acrylic acid, underwent IMDA cycloaddi-
tion at 160 ꢀC for 3 h in MeCN with microwave irradiation, fur-
nishing the cis and trans adducts 23i and 24i in 65% and 5% yields,
respectively, with 92:8 dr for 23i/24i. The results are consistent
with IMDA cycloaddition of the parent triene 21j carried out in PhCl
(132 ꢀC) for 47 h to afford the corresponding cis and trans adducts
23j and 24j in 70% combined yield and with 23j/24j ratio of
92:8.5c,18 We then investigated the tandem reaction of the
a-bro-
moacetate 5g with 37 wt % aqueous formaldehyde in the presence
of 2,6-lutidine in MeCN at 110 ꢀC (oil bath) for 36 h or at 160 ꢀC for
2.5 h with microwave irradiation. In both cases, the adducts 23i and
24i were isolated in 58e62% combined yields and with dr of
88:12e93:7 (entry 9, Table 2). Better dr was observed for the
cycloaddition at lower temperature. It should be mentioned that
the cis adduct 23i was reported as an intermediate in the synthesis
The tandem WittigeIMDA cycloaddition using C6-Me- and C6-
Ph-substituted 3,5-hexadien-1-yl a-bromoacetates 5c,d and ethyl
glyoxalate hydrate 6 (R5¼OEt) was carried out in a similar fashion
as described above (Scheme 4). Four diastereomers 23c,d, 24c,d,
25c,d, and 26c,d were formed. The ratios of 23c/24c (60:40) and
23d/24d (70:30) are somewhat lower for the tandem protocol
(entries 3 and 4, Table 2 vs entries 3 and 4, Table 1). In both cases,
the trienes derived from the (3Z,5E)-hexadien-1-yl
a-bromoace-
tates were recovered at the end of the reaction and the isolated
yields were calculated according to the (3E,5E)-hexadien-1-yl
bromoacetates 5c,d.
a-
The results of tandem WittigeIMDA cycloaddition starting with
5e,f are summarized in entries 5 and 6 of Table 2. Since four di-
astereomers were observed for the IMDA cycloaddition of both
(E)-21e and (Z)-22e (entries 5 and 11, Table 1), it was expected that
a maximum of eightadducts could be formed. In fact, all fouradducts
23e, 24e, 23e0, and 24e0 from(E)-21e, and two major adducts 25e and
26e from (Z)-22e were isolated as an inseparable mixture in 86%
yield. In contrast, the tandem WittigeIMDA cycloaddition of 5f was
much more selective, providing three adducts 23f, 24f, and 25f in
73% combined yield (entry 6, Table 2). The results are in agreement
with those for IMDA cycloaddition of (E)-21f and (Z)-22f (entries 6
and 12, Table 1). Similar dr was noted for 23e/24e (83:17) and 23f/
24f (67:33) via the tandem protocol (entries 5 and 6, Table 2).
The stepwise reactions starting from the a-bromoacetate 5a as
described in Scheme 3 above were now carried out in one-pot
fashion under microwave heating at 180 ꢀC (entry 8, Table 2). Three
out of the four adducts expected for the trienes (E)-21h and (Z)-22h
were isolated in 77% combined yield. The dr (23h/24h¼67:33) is
close to the ratio of 70:30 recorded for the pre-isolated (E)-21h
(Scheme 3). Similar results were obtained for the tandem reaction
of the
a
-bromoacetate 5g and three adducts 23g, 24g, and 25g were
Fig. 3. X-ray crystal structure of the minor adduct 24g.

184
J. Wu et al. / Tetrahedron 67 (2011) 179e192
6 (R3¼Ph), and other reagents were obtained commercially and
Me
O
used as received. Fumaric acid monomethyl ester 17,11 maleic acid
monomethyl ester 1912 and monoethyl ester 20,12 methyl glyox-
alate hydrate 6 (R3¼OMe),16 and ethyl glyoxalate hydrate 6
(R3¼OEt)16 were prepared according to the reported procedures.
The microwave-assisted reactions summarized in Tables 1 and 2,
and Schemes 3 and 5 were carried out on an Emrys creator (single-
mode microwave reactor) from Personal Chemistry AB (now under
Biotage AB, Uppsala, Sweden) with temperature measured by an
external IR sensor. The microwave-assisted reaction time is the
hold time at the final temperature.
Ph3P
Ph3P+Br-
5g
Me
O
H2O−MeCN
160 °C, 2.5 h, MW
or 110 °C, 36 h
28
CH2(OH)2
2,6-lutidine
Wittig
R
O
O
R
IMDA
21i: R = Me
21j: R = H
R
R
4.2. (E)-Hexa-3,5-dien-1-ol (9)4i,7
R
R
CH2=CHCO2H
DCC, DMAP
CH2Cl2, rt
H
O
H
O
(21i,
59%)
O
O
+
To a solution of diisopropyl amine (3.5 mL, 25.0 mmol) in dry
THF (12 mL) cooled at ꢁ10 ꢀC under a nitrogen atmosphere was
added a solution of n-BuLi (10 mL, 2.5 M in hexanes, 25.0 mmol)
followed by stirring for 30 min at the same temperature. The re-
sultant LDA solution was then cooled to ꢁ78 ꢀC, and, after adding
HMPA (4 mL), was stirred for another 20 min at ꢁ78 ꢀC.
H
H
13
23i: R = Me
24j: R = H
24i: R = Me
24j: R = H
Scheme 5. One-pot synthesis of 23i and 24i from 5g and formaldehyde.
To the above prepared LDAeHMPA solution was added a solu-
tion of ethyl sorbate (8, 1.50 mL, 10.0 mmol) in dry THF (5 mL). After
stirring at ꢁ78 ꢀC for 1.5 h, the reaction was quenched by adding
a mixed solution of water (22 mL) and acetic acid (4 mL). The re-
action mixture was extracted with hexane (30 mLꢂ3) and the
combined organic layer was washed with saturated aqueous
NaHCO3 and brine, dried over anhydrous Na2SO4, filtered off, and
concentrated under reduced pressure to give the crude deconjugate
ester, which was used for next reaction without purification.
To a suspension of LiAlH4 (532.0 mg,14 mmol) in dry THF (30 mL)
cooledin an iceewaterbath undera nitrogenatmospherewasadded
a solution of the above crude deconjugate ester in dry THF (5 mL).
The resultant mixture was then stirred at room temperature for
overnight (12 h). The reaction mixture was cooled in an iceewater
bath and the reaction was quenched by carefully adding small
amount of water. A saturated aqueous solution of potassium sodium
tartratewas added to the above mixture followed bystirring at room
temperature till the mixture became clear. The mixture was
extracted with EtOAc (30 mLꢂ3) and the combined organic layer
was washed with brine, dried over anhydrous Na2SO4, filtered off,
and concentrated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, eluted with 20% EtOAc
in PE) to give the alcohol 9 (686.0 mg, 70% for the two steps) as
a colorless oil;4i,7 Rf¼0.39 (25% EtOAc in hexane); IR (film) 3345,
of the oxaspirobicyclic tetronic acid unit related to tetronothiodin,
a CCK-B receptor antagonist.10
3. Conclusion
In summary, we have examined the intramolecular DielseAlder
(IMDA) cycloaddition of a series of ester-tethered 1,3,9-decatrienes
in MeCN at 160e180 ꢀC under controlled microwave heating.
Stereoselectivity has been found to be similar to that reported for
the thermal reactions carried out at lower temperatures. In general,
the trienes 4 (Fig. 1) give slightly higher dr than the corresponding
(9Z)-isomers in favor of the cis-adducts.5c Influence of the sub-
stituents on stereoselectivity varies: (a) dr increases for R1 at C1 in
the order of Me (71:29)<Ph (75:25)<H (77:23); (b) R4 at C6 con-
trols stereoselectivity better than R3 at C5; and (c) dr increases for X
at C10 in the order of COPh (70:30)zCO2Me/CO2Et
(71:29e77:23)<<H (92:8, at 160 ꢀC). Moreover, we have estab-
lished a microwave-assisted tandem WittigeIMDA cycloaddition
protocol.6a Starting from 3,5-hexadien-1-yl
a-bromoacetates 5,
hydrated glyoxalate, phenylglyoxal, or formaldehyde, PPh3, and
2,6-lutidine, 3,4,4a,7,8,8a-hexahydroisochromen-1-ones are pre-
pared in 62e91% yields by heating in MeCN at 160e180 ꢀC for
1e2.5 h with microwave irradiation. The main pair of cis/trans ad-
ducts are derived from the trienes 4 formed in situ in the tandem
process. Three consecutive carbonecarbon bonds with up to four
new stereogenic centers are installed onto the end products,
demonstrating the high efficiency of the microwave-assisted
synthesis.
2919, 2865,1648,1603,1050 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 6.33
(ddd, J¼16.8,10.4,10.4 Hz,1H), 6.16 (dd, J¼15.2,10.4 Hz,1H), 5.68 (dt,
J¼15.2, 7.2 Hz, 1H), 5.14 (d, J¼16.8 Hz, 1H), 5.02 (d, J¼10.0 Hz, 1H),
3.69 (t, J¼6.4 Hz, 2H), 2.36 (dt, J¼6.4, 6.4 Hz, 2H), 1.50 (br s, 1H, OH);
13C NMR (100 MHz, CDCl3)
d 136.8, 133.7, 130.6, 115.9, 61.9, 35.9; MS
(EIþ) m/z 98 (Mþ, 20), 97 (MþꢁH, 36), 71 (56), 59 (100).
4. Experimental
4.3. General procedure A for synthesis of 3,5-hexadien-1-ols
4.1. General methods
11e13 via Wittig reaction of 10
1H and 13C NMR spectra were recorded in CDCl3 or DMSO-d6
(400, or 500 MHz for 1H and 100 or 125 MHz for 13C, respectively).
IR spectra were taken on an FT-IR spectrophotometer. Mass spectra
(MS) were measured by the ESIþ or EIþ method. Melting points are
uncorrected. Silica gel plates pre-coated on glass were used for
thin-layer chromatography using UV light, or 7% ethanolic phos-
phomolybdic acid and heating as the visualizing methods. Silica gel
was used for flash column chromatography. Yields refer to chro-
matographically and spectroscopically (1H NMR) homogeneous
materials. Petroleum ether (PE) of 60e90 ꢀC fraction was used in
this work. Fumaric acid monoethyl ester 18, phenylglyoxal hydrate
To a suspension of (3-hydroxypropyl)triphenylphosphonium
bromide (10)8 (4.010 g, 10.0 mmol) in dry THF (25 mL) cooled in an
iceewater bath (ca. 0 ꢀC) was added a solution of n-BuLi (8.0 mL,
2.5 M in hexanes, 20.0 mmol) followed by stirring for 0.5 h at the
same temperature. To the resultant mixture was added the alde-
hyde (12.0 mmol) in dry THF (5 mL) and the mixture was stirred for
another 2e2.5 h at 0 ꢀC. The reaction was quenched by adding
saturated aqueous ammonium chloride. The aqueous layer was
extracted with Et2O (10 mLꢂ2) and the combined organic layer was
washed with brine, dried over Na2SO4, and evaporated under re-
duced pressure. The residue was purified by flash column

J. Wu et al. / Tetrahedron 67 (2011) 179e192
185
chromatography (silica gel, eluted with 20% EtOAc in PE) to give the
3,5-hexadien-1-ols 11e13 in 68e91% yields (see Scheme 1).
added pyridine (2.42 mL, 20 mmol) and p-toluenesulfonyl chloride
(3.15 g, 16.5 mmol) followed by stirring at room temperature for
overnight (12 h). The reaction was quenched with saturated
aqueous NH4Cl, and the resultant mixture was extracted with
EtOAc (100 mLꢂ3). The combined organic layer was washed with
10% aqueous HCl, saturated aqueous NaHCO3, and brine, and dried
over anhydrous Na2SO4. The solid was filtered off and filtrate was
condensed under reduced pressure. The residue was purified by
flash column chromatography (silica gel, eluted with gradient from
20% EtOAc in PE to 100% EtOAc) to give, along with the bis-tosylate,
the mono-tosylate (2.500 g, 68%) as a colorless oil; 1H NMR
4.3.1. (3E,5E)-Hepta-3,5-dien-1-ol (11). Prepared according to the
general procedure A in 68% yield as a yellow oil; an inseparable
mixture of two geometrical isomers [(3E,5E)/(3Z,5E)¼79:21];
Rf¼0.39 (20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3)
d 6.35
(dd, J¼13.6, 12.4 Hz, 0.21H), 6.14e5.99 (m, 1.79H), 5.73 (dq, J¼14.8,
6.8 Hz, 0.21H), 5.63 (dq, J¼14.4, 6.4 Hz, 0.79H), 5.51 (dt, J¼14.4,
7.6 Hz, 0.79H), 5.28 (dt, J¼10.4, 6.8 Hz, 0.21H), 3.68e3.63 (m, 2H),
2.45 (dt, J¼6.8, 6.8 Hz, 0.42H), 2.32 (dt, J¼6.8, 6.8 Hz, 1.58H), 1.78 (d,
J¼6.2 Hz, 0.63H), 1.73 (d, J¼6.8 Hz, 2.37H), 1.51 (br s, 1H, OH).
(400 MHz, CDCl3)
(d, J¼5.6 Hz, 2H), 3.60e3.49 (m, 2H), 2.45 (s, 3H), 2.04e1.96 (m, 1H),
0.92 (d, J¼6.8 Hz, 3H) (OH signal is not identified).
d
7.79 (d, J¼7.6 Hz, 2H), 7.35 (d, J¼8.4 Hz, 2H), 4.02
4.3.2. (3E,5E)-6-Phenylhexa-3,5-dien-1-ol (12)9. Prepared accord-
ing to the general procedure A in 93% yield as a yellow oil; an in-
separable mixture of two geometrical isomers [(3E,5E)/(3Z,5E)¼
73:27]; Rf¼0.44 (25% EtOAc in hexane); 1H NMR (400 MHz, CDCl3)
A solution of the above mono-tosylate (4.150 g,17.0 mmol) and LiI
(2.70 g, 20.4 mmol) in dry THF (150 mL) was heated under reflux for
30 min. After cooling, the resultant yellow suspension was filtered
off through a plug of Celite with washing by EtOAc. The combined
filtrate was diluted with EtOAc (200 mL), washed with water and
brine, dried over anhydrous Na2SO4, filtered, and condensed under
reduced pressure. The residue was purified by flash column chro-
matography (silica gel, eluted with gradient from 9% to 50% EtOAc in
PE) to give the mono-iodide (2.860 g, 84%) as a colorless oil; 1H NMR
d
7.43e7.19 (m, 5H), 7.08 (dd, J¼15.6, 11.2 Hz, 0.27H), 6.77 (dd,
J¼15.6,10.8 Hz, 0.73H), 6.58 (d, J¼15.6 Hz, 0.27H), 6.49 (d, J¼15.6 Hz,
0.73H), 6.34e6.29 (m, 1H), 5.80 (dt, J¼14.8, 7.6 Hz, 0.73H), 5.54
(dt, J¼10.8, 7.6 Hz, 0.27H), 3.75e3.70 (m, 2H), 2.58 (dt, J¼6.8, 6.8 Hz,
0.54H), 2.43 (dt, J¼6.8, 6.8 Hz, 1.46H) (OH signal is not identified).
4.3.3. (3E,5E)-5-Methylhepta-3,5-dien-1-ol (13)10. Prepared accord-
ing to the general procedure A in 91% yield as a yellow oil; Rf¼0.38
(20% EtOAc in hexane); IR (film) 3366 (br), 2921, 2875, 1651, 1633,
(400 MHz, CDCl3)
1.70e1.62 (m, 1H), 0.98 (d, J¼6.4 Hz, 3H).
d
3.52 (m, 2H), 3.29 (d, J¼5.6 Hz, 2H),1.88 (br s,1H),
A solution of the above mono-iodide (200.0 mg, 1.0 mmol) and
PPh3 (314.6 mg, 1.2 mmol) in dry MeCN (10 mL) was heated under
reflux for 40 h. The solvent was removed under reduced pressure to
give a white solid. The solid was washed with toluene and ether
until PPh3 was completely removed. The solid was thoroughly dried
in a vacuum oven (100 ꢀC) to give the phosphonium salt 15
(374.5 mg, 81%) as a white solid.
1435, 1379, 1048 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 6.12 (d,
J¼15.6 Hz, 1H), 5.51e5.43 (m, 2H), 3.62 (t, J¼6.4 Hz, 2H), 2.32 (dt,
J¼6.8, 6.8 Hz, 2H), 2.17 (br s, 1H), 1.70e1.67 (m, 6H); 13C NMR
(100 MHz, CDCl3) d 137.6, 134.1, 125.6, 122.2, 62.1, 36.1, 13.6, 11.9; MS
(EIþ) m/z 126 (Mþ, 34), 109 (MþꢁOH, 52), 95 (96); HRMS (EIþ) calcd
for C8H14O (Mþ) 126.1045, found 126.1041.
The alcohol 16 was prepared, by following the general procedure
A as described in Section 4.2 above, in 50% yield from the phospho-
nium salt 15 and trans-2-methyl-2-butenal as a yellow oil; Rf¼0.47
(25% EtOAc in hexane); IR (film) 3354 (br), 2959, 2923, 1453, 1380,
4.4. (4E,6E)-6-Methylocta-4,6-dien-2-ol (14)
To a solution of the alcohol 13 (940.0 mg, 7.5 mmol) in dry
CH2Cl2 (40 mL) was added solid NaHCO3 (5.040 g, 60.0 mmol) and
DesseMartin periodinane (0.3 M in CH2Cl2, 30 mL, 10.0 mmol). The
resultant mixture was stirred at room temperature for 2 h and
the reaction was quenched with saturated aqueous Na2S2O3. The
mixture was extracted with EtOAc (50 mLꢂ3) and the combined
organic layer was washed with brine, dried over anhydrous Na2SO4,
filtered, and condensed under reduced pressure. The crude alde-
hyde was used for the next step without further purification.
To a solution of the above aldehyde in dry THF (20 mL) under
a nitrogen atmosphere cooled at ꢁ78 ꢀC was added a solution of
MeMgCl (0.33 M, 35.5 mL, 11.7 mmol) followed by stirring at the
same temperature for 2 h. The reaction was quenched with satu-
rated aqueous NH4Cl, and the resultant mixture was extracted with
EtOAc (30 mLꢂ3) and the combined organic layer was washed with
brine, dried over anhydrous Na2SO4, filtered, and condensed under
reduced pressure. The residue was purified by flash column chro-
matography (silica gel, eluted with 20% EtOAc in PE) to give the
alcohol 14 (490.8 mg, 47% for the two steps) as a yellow oil; Rf¼0.52
(25% EtOAc in hexane); IR (film) 3374 (br), 2969, 2920, 1454, 1377,
1033 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
6.16 (d, J¼15.6 Hz, 1H), 5.52
(q, J¼6.4 Hz,1H), 5.36 (dd, J¼15.2, 8.0 Hz,1H), 3.52 (dd, J¼10.8, 5.6 Hz,
1H), 3.40 (dd, J¼10.8, 8.0 Hz, 1H), 2.45e2.33 (m, 1H), 1.80e1.60 (br
s, 1H), 1.73e1.70 (m, 6H), 1.02 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d
136.1, 134.0, 128.5, 126.0, 67.5, 39.9, 16.7, 13.7, 12.0; MS (EIþ)
m/z 140 (Mþ, 25), 109 (100); HRMS (EIþ) calcd for C9H16O (Mþ)
140.1201, found 140.1205.
4.6. General procedure B for synthesis of a-bromoacetates
5a,ceg
To a suspension of the alcohol (9, 11e14, or 16) (1.5 mmol), 4-
dimethylaminopyridine (DMAP, 0.15 mmol), and bromoacetic acid
(2.0 mmol) in dry CH2Cl2 (15 mL) cooled in an iceewater bath (0 ꢀC)
under a nitrogen atmosphere was added N,N0-dicyclohexylcarbo-
diimide (DCC, 2.0 mmol) in one portion. After stirring for 30 min at
0
ꢀC, the reaction was allowed to warm up to room temperature
followed by stirring for another 3 h. Celite was added to the reaction
vessel and the mixture, after stirring for 30 min, was then filtered off
with washing by CH2Cl2. The combined filtrate was evaporated un-
der reduced pressure and the residue was purified by flash column
chromatography (silica gel, eluted with 5e10% EtOAc in PE) to pro-
1125, 1076 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
6.14 (d, J¼16.0 Hz,
1H), 5.55e5.47 (m, 2H), 3.86e3.78 (m, 1H), 2.30e2.14 (m, 2H), 1.79
(br s, 1H), 1.72e1.69 (m, 6H), 1.19 (d, J¼6.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d
138.3, 134.1, 125.9, 122.2, 67.4, 42.7, 22.7, 13.7,
vide the a-bromoacetates 5a,ceg. The latter could be prepared from
12.0; MS (EIþ) m/z 140 (Mþ, 17), 81 (100); HRMS (EIþ) calcd for
the alcohols and bromoacetyl bromide in the presence of Et3N in
CH2Cl2 at 0 ꢀC for 2 h. But the acylation should be quenched at 0 ꢀC in
order to suppress decomposition of the dienes by the acidic species
in the reaction mixture. The yields of 5a,ceg are listed in Table 2.
C9H16O (Mþ) 140.1201, found 140.1194.
4.5. (3E,5E)-2,5-Dimethylhepta-3,5-dien-1-ol (16)
To a solution of 2-methyl-1,3-propanediol (1.350 g, 15.0 mmol)
4.6.1. (E)-Hexa-3,5-dien-1-yl
the alcohol 9 according to the general procedure B in 88% yield as
a-bromoacetate (5a). Prepared from
in dry CH2Cl2 (100 mL) cooled in an iceewater bath (ca. 0 ꢀC) was

186
J. Wu et al. / Tetrahedron 67 (2011) 179e192
a pale yellow oil; Rf¼0.62 (25% EtOAc in hexane); IR (film) 2961,
1738, 1282, 1164, 1005 cmꢁ1; 1H NMR (400 MHz, CDCl3)
6.31 (ddd,
CH2Cl2 (20 mL) cooled in an iceewater bath (0 ꢀC) under a nitrogen
atmosphere, was added N,N0-dicyclohexylcarbodiimide (DCC,
2.2 mmol) in one portion. After stirring for 30 min at the same
temperature, the reaction mixture was allowed to warm up to room
temperature followed by stirring for another 3 h. Celite was added
to the reaction vessel and the mixture, after stirring for 30 min, was
then filtered off with washing by CH2Cl2. The combined filtrate was
evaporated under reduced pressure and the residue was purified by
flash column chromatography (silica gel, eluted with 9% EtOAc in
PE) to provide the product (E)-21aef. The yields are given in Table 1.
d
J¼16.4, 10.4, 10.4 Hz, 1H), 6.14 (dd, J¼14.8, 10.8 Hz, 1H), 5.65
(dt, J¼15.2, 6.8 Hz, 1H), 5.15 (d, J¼16.8 Hz, 1H), 5.04 (d, J¼10.0 Hz,
1H), 4.22 (t, J¼6.4 Hz, 2H), 3.83 (s, 2H), 2.46 (dt, J¼6.8, 6.8 Hz, 2H);
13C NMR (100 MHz, CDCl3)
d 167.2, 136.6, 133.8, 128.9, 116.3, 65.2,
31.6, 25.7; MS (ESIþ) m/z 241 (MþNaþ, 100), 218 (MþHþ, 26); HRMS
(EIþ) calcd for C8H11BrO2 217.9942 (Mþ), found 217.9927.
4.6.2. (3E,5E)-Hepta-3,5-dien-1-yl
a-bromoacetate (5c). Prepared
from the alcohol 11 according to the general procedure B in 86%
yield as a pale yellow oil; an inseparable mixture of two geo-
metrical isomers [(3E,5E)/(3Z,5E)¼77:23]; Rf¼0.73 (20% EtOAc in
4.7.1. Methyl (E)-hexa-3,5-dien-1-yl fumarate [(E)-21a]5c. Prepared
from the alcohol 9 according to the general procedure C in 79% yield
as a colorless oil; Rf¼0.70 (25% EtOAc in hexane); IR (film) 2954,
hexane); 1H NMR (400 MHz, CDCl3)
d
6.30 (dd, J¼13.2, 12.8 Hz,
0.23H), 6.12e5.98 (m, 1.77H), 5.74 (dq, J¼14.8, 6.8 Hz, 0.23H), 5.64
(dq, J¼14.8, 6.8 Hz, 0.77H), 5.48 (dt, J¼14.8, 6.8 Hz, 0.77H),
5.28e5.21 (m, 0.23H), 4.20 (t, J¼6.8 Hz, 2H), 3.83 (s, 2H), 2.54
(dt, J¼6.8, 6.8 Hz, 0.46H), 2.42 (dt, J¼6.8, 6.8 Hz, 1.54H), 1.79 (d,
J¼6.8 Hz, 0.69H), 1.74 (d, J¼6.4 Hz, 2.31H).
1730, 1646, 1437, 1301, 1260, 1157, 1009 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
6.84 (br s, 2H), 6.30 (ddd, J¼16.8, 10.0, 10.0 Hz, 1H), 6.13
(dd, J¼15.2, 10.4 Hz, 1H), 5.65 (dt, J¼14.8, 6.8 Hz, 1H), 5.13 (d,
J¼16.8 Hz, 1H), 5.02 (d, J¼10.4 Hz, 1H), 4.24 (t, J¼6.8 Hz, 2H), 3.80
(s, 3H), 2.46 (dt, J¼6.8, 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
165.4, 164.8, 136.6, 133.6 (2ꢂ), 133.3, 129.1, 116.3, 64.4, 52.3, 31.7;
4.6.3. (3E,5E)-6-Phenylhexa-3,5-dien-1-yl
a-bromoacetate (5d). Prepared
MS (EIþ) m/z 211 (MþHþ, 5), 113 (72), 105 (70), 80 (100).
from the alcohol 12 according to the general procedure B in 85% yield as
a pale yellow oil; an inseparable mixture of two geometrical isomers
[(3E,5E)/(3Z,5E)¼79:21]; Rf¼0.63 (20% EtOAc in hexane); 1H NMR
4.7.2. Ethyl (E)-hexa-3,5-dien-1-yl fumarate [(E)-21b]4h,i. Prepared
from the alcohol 9 according to the general procedure C in 83% yield
as a colorless oil; Rf¼0.71 (25% EtOAcin hexane); IR (film) 2961,1732,
(400 MHz, CDCl3)
d
7.44e7.20 (m, 5H), 7.03 (dd, J¼15.6, 11.2 Hz, 0.21H),
6.75 (dd, J¼15.6, 10.4 Hz, 0.79H), 6.58 (d, J¼15.6 Hz, 0.21H), 6.49
(d, J¼15.6 Hz, 0.79H), 6.33e6.27 (m, 1H), 5.76 (dt, J¼15.2, 7.2 Hz, 0.79H),
5.52e5.46 (m, 0.21H), 4.26 (t, J¼6.4 Hz, 2H), 3.85 (s, 1.58H), 3.83 (s,
0.42H), 2.68 (dt, J¼7.2, 7.2 Hz, 0.42H), 2.53 (dt, J¼6.8, 6.8 Hz, 1.58H).
1652, 1259, 1162, 1038 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 6.84 (br s,
2H), 6.30 (ddd, J¼16.8, 10.0, 10.0 Hz, 1H), 6.13 (dd, J¼15.2,
10.4 Hz,1H), 5.66 (dt, J¼15.2, 6.8 Hz,1H), 5.14 (d, J¼17.2 Hz,1H), 5.03
(d, J¼10.0 Hz,1H), 4.28e4.20 (m, 4H), 2.47 (dt, J¼6.8, 6.8 Hz, 2H),1.31
(t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
164.9 (2ꢂ),136.6,133.8,
d
4.6.4. (3E,5E)-2,5-Dimethylhepta-3,5-dien-1-yl
a-bromoacetate (5e).
133.6, 133.3, 129.1, 116.3, 64.3, 61.3, 31.7, 14.0; MS (EIþ) m/z 225
(MþHþ,19),179 (71),127 (79),105 (100), 79 (96); HRMS (ESIþ) calcd
for C12H16O4Naþ (MþNaþ) 247.0946, found 247.0937.
Prepared from the alcohol 16 according to the general procedure B in
87% yield as a yellow oil; Rf¼0.61 (17% EtOAc in hexane); IR (film)
2967, 1738, 1281, 1165, 1110 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 6.11
(d, J¼16.0 Hz, 1H), 5.50 (q, J¼6.8 Hz, 1H), 5.39 (dd, J¼15.6, 7.2 Hz,1H),
4.10 and 4.01 (ABqd, J¼10.0, 7.2 Hz, 2H), 3.83 (s, 2H), 2.65e2.54 (m,
1H), 1.71 (br s, 6H), 1.07 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
4.7.3. Ethyl (3E,5E)-hepta-3,5-dien-1-yl fumarate [(E)-21c]. Prepared
from the alcohol 11 according to the general procedure C in 89%
yield as a colorless oil; an inseparable mixture of two geometrical
isomers [(3E,5E)/(3Z,5E)¼77:23]; Rf¼0.71 (20% EtOAc in hexane); 1H
d
167.2, 135.5, 134.1, 127.1, 126.1, 70.4, 36.2, 25.9, 17.0, 13.7 12.0; HRMS
(EIþ) calcd for C11H17BrO2 260.0412 (Mþ) and 262.0391 (Mþþ2),
NMR (400 MHz, CDCl3)
d
6.83 (s, 2H), 6.30 (dd, J¼14.0, 11.6 Hz,
found 260.0416 and 262.0396.
0.23H), 6.11e5.98 (m, 1.77H), 5.74 (dq, J¼14.8, 6.8 Hz, 0.23H), 5.63
(dq, J¼14.0, 6.8 Hz, 0.77H), 5.49 (dt, J¼14.4, 6.8 Hz, 0.77H), 5.28
(dt, J¼11.6, 6.8 Hz, 0.23H), 4.28e4.20 (m, 4H), 2.55 (dt, J¼6.8, 6.8 Hz,
0.46H), 2.43 (dt, J¼6.8, 6.8 Hz, 1.54H), 1.78 (d, J¼6.4 Hz, 0.69H), 1.73
(d, J¼7.2 Hz, 2.31H), 1.31 (t, J¼6.8 Hz, 3H).
4.6.5. (4E,6E)-6-Methylocta-4,6-dien-2-yl a-bromoacetate (5f). Prepared
from the alcohol 14 according to the general procedure B in 89% yield as
a yellow oil; Rf¼0.50 (11% EtOAc in hexane); IR (film) 2981, 2933, 1738,
1283, 1171, 1109 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
6.10 (d, J¼15.0 Hz,
Ethyl (3Z,5E)-hepta-3,5-dien-1-yl fumarate was recovered from
IMDA cycloaddition given in entry 3 of Table 1. 1H NMR (400 MHz,
1H), 5.50e5.41 (m, 2H), 4.99 (tq, J¼6.5, 6.5 Hz, 1H), 3.79 (s, 2H),
2.42e2.30 (m, 2H), 1.71e1.70 (m, 6H), 1.25 (d, J¼7.0 Hz, 3H); 13C NMR
CDCl3)
d
6.84 (s, 2H), 6.30 (dd, J¼14.4, 11.6 Hz, 1H), 6.07 (dd, J¼11.2,
(125 MHz, CDCl3)
d
166.7, 138.1, 134.1, 125.9, 120.6, 72.9, 39.0, 26.3, 19.2,
10.4 Hz, 1H), 5.74 (dq, J¼14.8, 6.4 Hz, 1H), 5.25 (dt, J¼10.4, 6.8 Hz,
1H), 4.28e4.21 (m, 4H), 2.55 (dt, J¼6.8, 6.8 Hz, 2H),1.79 (d, J¼6.8 Hz,
3H), 1.32 (t, J¼7.2 Hz, 3H).
13.7 12.0; HRMS (EIþ) calcd for C11H17BrO2 260.0412 (Mþ) and
262.0391 (Mþþ2), found 260.0414 and 262.0387.
4.6.6. (3E,5E)-5-Methylhepta-3,5-dien-1-yl
a
-bromoacetate(5g). Prepared
4.7.4. Ethyl (3E,5E)-5-phenylhexa-3,5-dien-1-yl fumarate [(E)-21d].
Prepared from the alcohol 13 according to the general procedure C
in 92% yield as a colorless oil; an inseparable mixture of two geo-
metrical isomers [(3E,5E)/(3Z,5E)¼74:26]; Rf¼0.62 (20% EtOAc in
from the alcohol 13 according to the general procedure B in 86% yield as
a pale yellow oil; Rf¼0.68 (20% EtOAc in hexane); IR (film) 2959, 2913,
1738, 1280, 1163, 1110 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 6.13 (d,
J¼16.0 Hz, 1H), 5.51e5.43 (m, 2H), 4.21 (t, J¼6.8 Hz, 2H), 3.83 (s, 2H), 2.45
hexane); 1H NMR (400 MHz, CDCl3)
d 7.43e7.19 (m, 5H), 7.03 (dd,
(dt, J¼6.8, 6.8 Hz, 2H), 1.71e1.70 (m, 6H); 13C NMR (100 MHz, CDCl3)
J¼14.8, 10.8 Hz, 0.26H), 6.89e6.84 (m, 2H), 6.77 (dd, J¼16.0, 10.0 Hz,
0.74H), 6.58 (d, J¼15.2 Hz, 0.26H), 6.49 (d, J¼15.6 Hz, 0.74H),
6.33e6.26 (m, 1H), 5.77 (dt, J¼14.8, 7.6 Hz, 0.74H), 5.50 (dt, J¼10.8,
7.6 Hz, 0.26H), 4.30e4.21 (m, 4H), 2.69 (dt, J¼6.8, 6.8 Hz, 0.52H),
2.54 (dt, J¼6.8, 6.8 Hz, 1.48H), 1.33e1.24 (m, 3H).
d
167.2, 137.7, 134.0, 126.1, 120.8, 65.8, 31.9, 25.9, 13.7, 12.0; HRMS (EIþ)
calcd for C10H15BrO2 246.0255 (Mþ), found 246.0258.
4.7. General procedure C for synthesis of E-substituted 1,3,9-
decatrienes (E)-21aef and 21i
4.7.5. Ethyl (3E,5E)-2,5-dimethylhepta-3,5-dien-1-yl fumarate [(E)-
21e]. Prepared from the alcohol 16 according to the general pro-
cedure C in 93% yield as a colorless oil; Rf¼0.68 (11% EtOAc in
hexane); IR (film) 2978, 1724, 1646, 1297, 1259, 1154, 1031 cmꢁ1; 1H
To a solution of the alcohol (9, 11, 12, 14, or 16) (1.5 mmol), 4-
dimethylaminopyridine (DMAP, 0.15 mmol), and fumaric acid
monomethyl ester 1711 or monoethyl ester 1811 (2 mmol) in dry

J. Wu et al. / Tetrahedron 67 (2011) 179e192
187
NMR (400 MHz, CDCl3)
d
6.86 and 6.81 (ABq, J¼16.8 Hz, 2H), 6.11
5.66 (dt, J¼15.6, 6.8 Hz, 1H), 5.14 (d, J¼17.2 Hz, 1H), 5.02 (d, J¼10.4 Hz,
1H), 4.28e4.22 (m, 4H), 2.47 (dt, J¼6.8, 6.8 Hz, 2H), 1.31 (t, J¼7.2 Hz,
(d, J¼16.0 Hz, 1H), 5.49 (q, J¼6.4 Hz, 1H), 5.39 (dd, J¼16.0, 7.2 Hz,
1H), 4.25 (q, J¼7.2 Hz, 2H), 4.12 and 4.03 (ABqd, J¼10.4, 7.2 Hz, 2H),
2.63e2.56 (m, 1H), 1.70 (br s, 6H), 1.31 (t, J¼7.2 Hz, 3H), 1.07
3H); 13C NMR (100 MHz, CDCl3)
d 165.1, 165.1, 136.6, 133.4, 129.9,
129.5, 129.3, 116.1, 64.3, 61.1, 31.5, 13.9; MS (EIþ) m/z 224 (Mþ, 4), 179
(12), 127 (15), 105 (45), 99 (38), 80 (100); HRMS (ESIþ) calcd for
C12H16O4Naþ (MþNaþ) 247.0946, found 247.0942.
(d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
165.0 (2ꢂ), 135.4,
134.0, 133.6, 133.5, 127.3, 126.1, 69.6, 61.3, 36.2, 17.1, 14.1, 13.7, 12.0;
MS (ESIꢁ) m/z 265 (MꢁH, 100); HRMS (ESIþ) calcd for C15H22O4Naþ
(MþNaþ) 289.1416, found 289.1407.
4.8.3. Ethyl (3E,5E)-hepta-3,5-dien-1-yl maleate [(Z)-22c]. Prepared
from the alcohol 11 according to the general procedure D in 56%
yield as a colorless oil; an inseparable mixture of two geometrical
isomers [(3E,5E)/(3Z,5E)¼78:22]; Rf¼0.65 (20% EtOAc in hexane);
4.7.6. Ethyl (4E,6E)-6-methylocta-4,6-dien-2-yl fumarate [(E)-21f].
Prepared from the alcohol 14 according to the general procedure C
in 84% yield as a colorless oil; Rf¼0.65 (14% EtOAc in hexane); IR
(film) 2980, 2936, 1723, 1647, 1296, 1259, 1156, 1034 cmꢁ1; 1H NMR
1H NMR (400 MHz, CDCl3)
d
6.29 (dd, J¼13.6, 12.8 Hz, 0.22H), 6.22
(s, 2H), 6.11e5.98 (m, 1.78H), 5.73 (dq, J¼14.8, 6.8 Hz, 0.22H), 5.63
(dq, J¼14.4, 6.8 Hz, 0.78H), 5.49 (dt, J¼14.4, 7.2 Hz, 0.78H), 5.25 (dt,
J¼10.4, 6.8 Hz, 0.22H), 4.27e4.19 (m, 4H), 2.55 (dt, J¼6.8, 6.8 Hz,
0.44H), 2.42 (dt, J¼6.8, 6.8 Hz, 1.56H), 1.77 (d, J¼6.4 Hz, 0.66H), 1.73
(d, J¼6.4 Hz, 2.34H), 1.32e1.25 (m, 3H).
(400 MHz, CDCl3)
d
6.82 (s, 2H), 6.09 (d, J¼15.2 Hz, 1H), 5.47e5.40
(m, 2H), 5.07e5.00 (m, 1H), 4.25 (q, J¼7.2 Hz, 2H), 2.45e2.30 (m,
2H), 1.70 (br s, 6H), 1.30 (t, J¼7.2 Hz, 3H), 1.26 (d, J¼6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 165.1,164.5,138.1,134.1,134.0,133.4,125.9,
120.8, 71.9, 61.3, 39.2, 19.3, 14.1, 13.7, 12.0; MS (ESIþ) m/z 555
(2MþNaþ, 38), 289 (MþNaþ, 100); HRMS (ESIþ) calcd for
C15H22O4Naþ (MþNaþ) 289.1416, found 289.1409.
4.8.4. Ethyl (3E,5E)-5-phenylhexa-3,5-dien-1-yl maleate [(Z)-22d].
Prepared from the alcohol 12 according to the general procedure D in
62% yield as a colorless oil; an inseparable mixture of two geometrical
1
4.7.7. (3E,6E)-6-Methylhapta-4,6-dien-2-yl acrylate (21i). Prepared
from the alcohol 13 and acrylic acid according to the general pro-
cedure C in 59% yield as a colorless oil; Rf¼0.63 (4.8% EtOAc in PE);
isomers [(3E,5E)/(3Z,5E)¼72:28]; Rf¼0.58 (20% EtOAc in hexane); H
NMR (400 MHz, CDCl3)
d
7.43e7.21 (m, 5H), 7.03 (dd, J¼14.8, 10.8 Hz,
0.28H), 6.75 (dd, J¼15.6, 10.8 Hz, 0.72H), 6.57 (d, J¼16.0 Hz, 0.28H),
6.48 (d, J¼15.6 Hz, 0.72H), 6.35e6.23 (m, 3H), 5.77 (dt, J¼14.8, 7.6 Hz,
0.72H), 5.50 (dt, J¼10.8, 7.2 Hz, 0.28H), 4.29e4.23 (m, 4H), 2.69 (dt,
J¼7.2, 7.2 Hz, 0.56H), 2.53 (dt, J¼6.8, 6.8 Hz, 1.44H), 1.33e1.26 (m, 3H).
IR (film) 2955, 2920, 1727, 1636, 1408, 1272, 1187, 1059 cmꢁ1 1H
;
NMR (400 MHz, CDCl3)
d
6.38 (dd, J¼17.2, 1.6 Hz, 1H), 6.14e6.07 (m,
2H), 5.79 (dd, J¼10.4, 1.6 Hz, 1H), 5.52e5.44 (m, 2H), 4.18 (t,
J¼6.8 Hz, 2H), 2.44 (dt, J¼6.8 Hz, 2H), 1.70 (s, 3H), 1.67 (d, J¼7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3)
d
166.0, 137.3; 134.0; 130.4; 128.4;
4.8.5. Ethyl (3E,5E)-2,5-dimethylhepta-3,5-dien-1-yl maleate [(Z)-
22e]. Prepared from the alcohol 16 according to the general pro-
cedure D in 67% yield as a colorless oil; Rf¼0.54 (11% EtOAc in
hexane); IR (film) 2978, 1732, 1645, 1404, 1211, 1163, 1027 cmꢁ1; 1H
125.6; 121.2; 64.0; 32.0; 13.5; 11.8; HRMS (EIþ) calcd for C11H16O2
(Mþ) 180.1150, found 180.1150.
4.8. General procedure D for synthesis of Z-substituted 1,3,9-
decatrienes (Z)-22aef
NMR (400 MHz, CDCl3)
d
6.23 (br s, 2H), 6.10 (d, J¼15.6 Hz, 1H),
5.50e5.49 (q, J¼6.8 Hz, 1H), 5.40 (dd, J¼15.6, 7.2 Hz, 1H), 4.24 (q,
J¼7.2 Hz, 2H), 4.11 and 4.01 (ABqd, J¼10.8, 6.8 Hz, 2H), 2.64e2.54
(m, 1H), 1.70 (br s, 6H), 1.30 (t, J¼7.2 Hz, 3H), 1.06 (d, J¼6.8 Hz, 3H);
To a solution of maleic acid monomethyl ester 19 or monoethyl
ester 2012 (3.0 mmol) in dry CH2Cl2 (10 mL) was added N,N0-dii-
sopropylcarbodiimide (DIC, 1.5 mmol) and the mixture was stirred
at 0 ꢀC for 1 h. The insoluble urea was filtered off through a plug of
Celite and the filtrate was added to a solution of the alcohol (9, 11,
12, 14, or 16) (1.0 mmol) in dry CH2Cl2 (6 mL), followed by addition
of i-Pr2NEt (DIEA, 3.0 mmol) and 4-dimethylaminopyridine (DMAP,
0.1 mmol). The resultant mixture was stirred at 0 ꢀC for 1 h. The
reaction mixture was diluted with CH2Cl2 and successively washed
with saturated aqueous NH4Cl and brine. The organic layer was
dried over anhydrous Na2SO4, filtered, and evaporated under re-
duced pressure. The residue was purified by column chromatog-
raphy (silica gel, eluted with 9% EtOAc in PE) to provide the product
(Z)-22aef. The yields are given in Table 1.
13C NMR (100 MHz, CDCl3)
d 165.3, 165.2, 135.3, 134.1, 129.9, 129.6,
127.5, 125.9, 69.6, 61.2, 36.0, 17.2, 14.0, 13.7, 11.9; MS (ESIþ) m/z 555
(2MþNaþ, 100), 289 (MþNaþ, 54); HRMS (ESIþ) calcd for
C15H22O4Naþ (MþNaþ) 289.1416, found 289.1408.
4.8.6. Ethyl (4E,6E)-6-methylocta-4,6-dien-2-yl maleate [(Z)-22f].
Prepared from the alcohol 14 according to the general procedure D
in 71% yield as a colorless oil; Rf¼0.50 (17% EtOAc in hexane); IR
(film) 2982, 2935, 1723, 1642, 1403, 1384, 1213, 1166, 1028 cmꢁ1; 1H
NMR (500 MHz, CDCl3)
d
6.20 (br s, 2H), 6.09 (d, J¼16.0 Hz, 1H),
5.49e5.42 (m, 2H), 5.04 (sextet, J¼6.0 Hz,1H), 4.24 (q, J¼7.0 Hz, 2H),
2.44 and 2.31 (ABqdd, J¼21.0, 7.0, 7.0 Hz, 2H), 1.70 (s, 3H), 1.70 (d,
J¼6.5 Hz, 3H), 1.30 (t, J¼7.5 Hz, 3H), 1.26 (d, J¼6.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3)
d 165.2, 164.7, 137.9, 134.2, 130.1, 129.5, 125.7,
4.8.1. Methyl (E)-hexa-3,5-dien-1-yl maleate [(Z)-22a]5c. Prepared
from the alcohol 9 according to the general procedure D in 66%
yield as a pale yellow oil; Rf¼0.42 (18% EtOAc in hexane); IR (film)
121.0, 71.9, 61.1, 39.0, 19.1, 14.0, 13.7, 12.0; MS (ESIþ) m/z 555
(2MþNaþ, 100), 289 (MþNaþ, 70); HRMS (ESIþ) calcd for
C15H22O4Naþ (MþNaþ) 289.1416, found 289.1406.
2955, 1732, 1651, 1436, 1398, 1218, 1163, 1006 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
d
6.29 (ddd, J¼16.8, 10.0, 10.0 Hz, 1H), 6.24 (s, 2H),
4.9. General procedure E for synthesis of the ester-tethered
1,3,9-decatrienes via Wittig olefination
6.12 (dd, J¼15.2, 10.4 Hz, 1H), 5.65 (dt, J¼14.8, 7.2 Hz, 1H), 5.13 (d,
J¼16.8 Hz, 1H), 5.01 (d, J¼10.0 Hz, 1H), 4.22 (t, J¼7.2 Hz, 2H), 3.77
(s, 3H), 2.46 (dt, J¼6.8, 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
A
solution of (E)-hexa-3,5-dien-1-yl
a-bromoacetate 5a
d
165.6, 165.1, 136.6, 133.5, 129.8, 129.6, 129.3, 116.1, 64.3, 52.1, 31.5;
(0.30 mmol) and PPh3 (0.33 mmol) in MeCN (10 mL) was stirred at
room temperature for overnight (12 h). The reaction mixture was
evaporated under reduced pressure to give a white solid, which was
washed with dry benzene (9 mLꢂ3) and dried in vacuum to provide
quantitatively the salt 27. The phosphonium salt was used without
further purification.
MS (EIþ) m/z 113 (C5H5Oþ3 , 100), 80 (47).
4.8.2. Ethyl (E)-hexa-3,5-dien-1-yl maleate [(Z)-22b]. Prepared from
the alcohol 9 according to the general procedure D in 62% yield as
a colorless oil; Rf¼0.69 (25% EtOAc in hexane); IR (film) 2983, 1731,
1645, 1405, 1212, 1162, 1006 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
6.30
A solution of the above phosphonium salt 27 (0.20 mmol), ethyl
glyoxalate or phenylglyoxal hydrate (0.22 mmol), and 2,6-lutidine
(dt, J¼17.2, 10.4 Hz, 1H), 6.23 (s, 2H), 6.14 (dd, J¼15.2, 11.2 Hz, 1H),

188
J. Wu et al. / Tetrahedron 67 (2011) 179e192
(0.26 mmol) in MeCN (5 mL) was stirred for 2e4 h at room tem-
perature. The reaction mixture was diluted with EtOAc (30 mL) and
washed with 6% aqueous HCl and brine. The organic layer was dried
over anhydrous Na2SO4 and evaporated under reduced pressure.
The residue was purified by flash column chromatography (silica
gel, 9% EtOAc in PE) to give (E)-21b (74%) and (Z)-22b (10%) or (E)-
21h (70%) and (Z)-22h (9%), respectively (see Scheme 3 for detail).
according to the general procedure F, from the triene (E)-21a in 22%
yield as colorless needles; mp 100e101 ꢀC (EtOAcehexane);
Rf¼0.21 (20% EtOAc in hexane); IR (KBr) 2922, 1735 (br), 1432, 1411,
1313, 1199, 1168, 1101, 1066, 1008 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
5.72 (br d, J¼11.6 Hz, 1H), 5.61 (br d, J¼9.2 Hz, 1H), 4.39 (t,
J¼7.2 Hz, 2H), 3.74 (s, 3H), 2.80e2.69 (m, 2H), 2.48e2.44 (m, 2H),
2.29e2.20 (m, 2H), 1.73e1.66 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
175.5, 173.0, 128.5, 125.5, 66.2, 52.0, 43.1, 40.0, 32.9, 29.2, 28.1; MS
4.9.1. (E)-Hexa-3,5-dien-1-yl (E)-4-phenyl-4-oxo-2-butenoate [(E)-
21h]. Prepared from the phosphonium salt 27 and phenylglyoxal
hydrate according to the general procedure E in 70% yield as a color-
less oil; Rf¼0.74 (20% EtOAc in hexane); IR (film) 2958, 1720, 1678,
(EIþ) m/z 210 (Mþ, 8), 178 (MþꢁMeOH, 45), 150 (73), 122 (55), 105
(38), 91 (100), 78 (77).
4.10.3. Methyl (4aS
*
,8R
*
,8aS )-1-oxo-3,4,4a,7,8,8a-hexahydro-1H-
*
1593, 1459, 1299, 1173, 1014 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
isochromene-8-carboxylate (25a)5c. The major adduct obtained,
according to the general procedure F, from the triene (Z)-22a in 58%
yield as a colorless solid; mp 92e93 ꢀC (EtOAc/hexane); Rf¼0.12
(20% EtOAc in hexane); IR (KBr) 2949, 1732 (br), 1433, 1209, 1184,
d
8.02 (d, J¼7.2 Hz, 2H), 7.93 (d, J¼15.6 Hz, 1H), 7.70 (t, J¼7.6 Hz, 1H),
7.57 (dd, J¼7.6, 7.6 Hz, 2H), 6.72 (d, J¼15.6 Hz, 1H), 6.33 (ddd, J¼17.2,
10.0,10.0 Hz,1H), 6.17 (dd, J¼15.2,10.8 Hz,1H), 5.75 (dt, J¼15.6, 6.8 Hz,
1H), 5.15 (d, J¼16.8 Hz, 1H), 5.01 (d, J¼10.4 Hz, 1H), 4.24 (t, J¼6.4 Hz,
1146, 1002 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
5.85 (ddd, J¼7.2, 5.2,
2H), 2.47 (dt, J¼6.8, 6.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6)
d
189.7,
2.4 Hz, 1H), 5.53 (br dd, J¼10.0, 2.4 Hz, 1H), 4.30 (ddd, J¼11.6, 4.8,
4.8 Hz, 1H), 4.21 (ddd, J¼11.6, 10.0, 4.4 Hz, 1H), 3.74 (s, 3H), 3.46
(dd, J¼6.4, 3.2 Hz, 1H), 3.00e2.92 (br s, 1H), 2.63 (ddd, J¼9.6, 6.0,
3.2 Hz, 1H), 2.52e2.32 (m, 2H), 2.21 (dddd, J¼14.0, 10.0, 5.6, 4.0 Hz,
1H), 1.75 (dddd, J¼14.4, 5.6, 5.6, 4.0 Hz, 1H); 13C NMR (100 MHz,
165.3, 137.3 (2ꢂ), 136.5, 134.5, 133.6, 131.8, 130.7, 129.5 (2ꢂ), 129.2
(2ꢂ),116.7, 64.5, 31.7; MS (ESIþ) m/z 279 (MþNaþ,100); HRMS (ESIþ)
calcd for C16H16O3Naþ (MþNaþ) 279.0997, found 279.0986.
4.9.2. (E)-Hexa-3,5-dien-1-yl (Z)-4-phenyl-4-oxo-2-butenoate [(Z)-
22h]. Prepared from the phosphonium salt 27 and phenylglyoxal
hydrate according to the general procedure E in 9% yield as a col-
orless oil; Rf¼0.66 (20% EtOAc in hexane); IR (film) 2958, 2926,
CDCl3) d 173.3, 171.3, 128.4, 127.9, 66.2, 52.0, 41.1, 40.1, 32.6, 28.5,
23.2; MS (EIþ) m/z 210 (Mþ, 3), 178 (MþꢁMeOH, 85), 150 (57), 105
(53), 91 (100), 78 (100).
1724, 1674, 1598, 1449, 1213, 1166, 1005 cmꢁ1
;
1H NMR (400 MHz,
4.10.4. Methyl (4aS
*
,8S
*
,8aR )-1-oxo-3,4,4a,7,8,8a-hexahydro-1H-
*
DMSO-d6)
d
7.87 (d, J¼7.6 Hz, 2H), 7.67 (t, J¼7.6 Hz, 1H), 7.55 (dd,
isochromene-8-carboxylate (26a)5c. The minor adduct obtained,
according to the general procedure F, from the triene (Z)-22a in 20%
yield as a colorless solid; mp 91e92 ꢀC (EtOAc/hexane); Rf¼0.15 (20%
EtOAc in hexane); IR (KBr) 2960, 1727 (br), 1403, 1211, 1174, 1104,
J¼7.6, 7.6 Hz, 2H), 7.27 (d, J¼11.6 Hz, 1H), 6.38 (d, J¼12.0 Hz, 1H),
6.23 (ddd, J¼16.8, 10.0, 10.0 Hz, 1H), 6.02 (dd, J¼14.8, 10.4 Hz, 1H),
5.53 (dt, J¼15.6, 6.8 Hz, 1H), 5.10 (d, J¼16.8 Hz, 1H), 5.00 (d,
J¼10.0 Hz, 1H), 3.98 (t, J¼6.4 Hz, 2H), 2.12 (dt, J¼6.4, 6.4 Hz, 2H); 13C
1066 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 5.72e5.67 (m, 1H), 5.60 (br
NMR (100 MHz, DMSO-d6)
d
194.1, 165.0, 142.4, 137.1, 135.9, 134.1,
d, J¼10.0 Hz,1H), 4.50 (ddd, J¼12.8, 6.8, 4.4 Hz,1H), 4.42 (dd, J¼11.2,
3.6 Hz, 1H), 3.69 (s, 3H), 3.55 (dd, J¼7.2, 3.2 Hz, 1H), 2.94 (br
t, J¼11.2 Hz, 1H), 2.67 (br d, J¼18.8 Hz, 1H), 2.53e2.45 (m, 1H), 2.27
(dd, J¼12.4, 3.6 Hz,1H), 2.04 (dm, J¼18.0 Hz,1H),1.70 (dddd, J¼12.4,
133.2, 130.5, 129.2 (2ꢂ), 128.8 (2ꢂ), 126.0, 116.5, 64.1, 31.3; MS
(ESIþ) m/z 256 (Mþ, 100); HRMS (ESIþ) calcd for C16H16O3Naþ
(MþNaþ) 279.0997, found 279.0990.
12.4,12.4, 6.4 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 173.3,171.4,129.0,
4.10. General procedure F for microwave-assisted IMDA
cycloaddition of (E)-21aef,h,i and (Z)-22aef
126.0, 69.4,. 52.0, 44.7, 37.0, 31.2, 29.8, 28.1; MS (EIþ) m/z 211 (MþHþ,
3),179 (MþeOMe, 85),152 (100), 122 (55), 106 (68), 91 (72), 78 (92).
To a 10-mL pressurized process vial was added the 1,3,9-dec-
atriene (0.30e0.90 mmol) and CH3CN (4 mL). The loaded vial was
then sealed with a cap containing a silicon septum, and put into
the microwave cavity and heated at 180 ꢀC for 0.5e2.5 h. The
reaction mixture was evaporated under reduce pressure. The
residue was checked for adduct isomer ratio by 1H NMR spectrum
and was then purified by flash column chromatography (silica gel,
eluted with 5e20% EtOAc in PE) to give the desired products. The
structures, isomer ratios, and yields are found in Schemes 2, 3, and
5, and Table 1.
4.10.5. Ethyl (4aS
*
,8S
*
,8aS )-1-oxo-3,4,4a,7,8,8a-hexahydro-1H-iso-
*
chromene-8-carboxylate (23b)4h. The major adduct obtained,
according to the general procedure F, from the triene (E)-21b in 62%
yield as a colorless oil; Rf¼0.22 (20% EtOAc in hexane); IR (film)
2980, 2906, 1728 (br), 1274, 1196, 1155, 1093, 1034 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
d
5.85e5.81 (m, 1H), 5.50 (br d, J¼10.0 Hz, 1H),
4.31e4.23 (m, 2H), 4.14 (q, J¼7.0 Hz, 2H), 3.43 (br dd, J¼2.8, 2.8 Hz,
1H), 3.26 (dd, J¼6.4, 2.8 Hz, 1H), 2.89 (br s, 1H), 2.52 (dm, J¼18.2 Hz,
1H), 2.28 (dm, J¼18.8 Hz, 1H), 2.20e2.11 (m, 1H), 1.74e1.67 (m, 1H),
1.23 (t, J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 173.3, 172.1,
127.9, 127.6, 66.3, 60.9, 40.3, 39.0, 28.5, 28.2, 22.9, 14.1; MS (EIþ) m/z
224 (Mþ, 4), 178 (MþꢁEtOH, 31), 150 (65), 122 (20), 105 (39), 91
(87), 78 (100); HRMS (ESIþ) calcd for C12H16O4Naþ (MþNaþ)
247.0946, found 247.0940.
4.10.1. Methyl
(4aS
*
,8S
*
,8aS )-1-oxo-3,4,4a,7,8,8a-hexahydro-1H-
*
isochromene-8-carboxylate (23a)5c. The major adduct obtained,
according to the general procedure F, from the triene (E)-21a in 58%
isolated yield as a colorless oil; Rf¼0.29 (20% EtOAc in hexane); IR (film)
2953, 2920,1731 (br),1436,1275,1155 cmꢁ1;1H NMR (400 MHz, CDCl3)
4.10.6. Ethyl (4aS
*
,8R
*
,8aR )-1-oxo-3,4,4a,7,8,8a-hexahydro-1H-iso-
*
d
5.82 (br dd, J¼4.8, 2.8 Hz,1H), 5.50 (br d, J¼9.6 Hz,1H), 4.34e4.20 (m,
chromene-8-carboxylate (24b). The minor adduct obtained, accord-
ing to the general procedure F, from the triene (E)-21b in 18% yield
as colorless needles; mp 76e78 ꢀC (EtOAc/hexane); Rf¼0.14 (20%
EtOAc in hexane); IR (KBr) 2991, 2932, 1736 (br), 1412, 1255, 1185,
2H), 3.69 (s, 3H), 3.47e3.45 (m, 1H), 3.26 (dd, J¼6.4, 2.8 Hz, 1H),
2.93e2.85 (br s,1H), 2.52 (br d, J¼18.4 Hz,1H), 2.29 (dm, J¼18.4 Hz, 1H),
2.16 (dddd, J¼14.0, 9.6, 5.2, 5.2 Hz, 1H), 1.71 (dddd, J¼14.4, 5.2, 5.2,
5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
173.8, 172.1, 127.8, 127.6, 66.4,
1090, 1038 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 5.73e5.70 (m, 1H),
52.1, 40.3, 38.9, 28.6, 28.2, 22.9; MS (EIþ) m/z 210 (Mþ, 15), 178
(MþꢁMeOH, 100), 150 (97), 122 (42), 105 (74), 91 (95), 78 (96).
5.60 (br d, J¼10.0 Hz, 1H), 4.38 (t, J¼7.2 Hz, 2H), 4.26e4.13 (m, 2H),
2.77e2.68 (m, 2H), 2.51e2.40 (m, 2H), 2.30e2.17 (m, 2H), 1.73e1.64
(m, 1H), 1.28 (t, J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 175.0,
4.10.2. Methyl (4aS
*
,8R
*
,8aR
*
)-1-oxo-3,4,4a,7,8,8a-hexahydro-1H-
173.0, 128.5, 125.5, 66.2, 60.7, 43.0, 40.2, 32.9, 29.2, 28.1, 14.0; MS
isochromene-8-carboxylate (24a)5c. The minor adduct obtained,
(EIþ) m/z 224 (Mþ, 10), 179 (MþꢁOEt, 30), 150 (62), 122 (57), 105

J. Wu et al. / Tetrahedron 67 (2011) 179e192
189
(35), 91 (100), 78 (79). Anal. Calcd for C12H16O4: C, 64.27; H, 7.19,
found: C, 64.20; H, 7.02.
NMR (400 MHz, CDCl3)
d
5.81 (br d, J¼10.0 Hz, 1H), 5.47 (br d,
J¼10.0 Hz, 1H), 4.40e4.26 (m, 2H), 4.18 (q, J¼7.2 Hz, 2H), 3.38 (dd,
J¼7.6, 4.4 Hz, 1H), 3.00 (dd, J¼4.4, 4.4 Hz, 1H), 2.85 (br s, 1H), 2.65
(br s, 1H), 2.08e2.01 (m, 1H), 1.91e1.86 (m, 1H), 1.26 (t, J¼7.2 Hz,
4.10.7. Ethyl
(4aS
*
,8R
*
,8aS )-1-oxo-3,4,4a,7,8,8a-hexahydro-1H-iso-
*
chromene-8-carboxylate (25b). The major adduct obtained, according
to the general procedure F, from the triene (Z)-22b in 57% yield as
colorless needles; mp 80e82 ꢀC (EtOAc/hexane); Rf¼0.21 (20% EtOAc
in hexane); IR (film) 2980, 2925, 1732 (br), 1393, 1207, 1183, 1137,
3H), 1.15 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 172.0, 171.8,
134.5, 126.6, 67.2, 60.4, 44.8, 39.8, 33.0, 30.5, 28.2, 17.9, 14.1; MS
(EIþ) m/z 238 (Mþ, 13), 192 (MþꢁEtOH, 88), 164 (56), 119 (65), 105
(65), 92 (100); HRMS (ESIþ) calcd for C13H18O4Naþ (MþNaþ)
261.1103, found 261.1090.
1034 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 5.83 (br s, 1H), 5.52 (br
d, J¼10.0 Hz, 1H), 4.30e4.26 (m, 1H), 4.21e4.16 (m, 3H), 3.44 (br d,
J¼3.6 Hz, 1H), 2.95 (br s, 1H), 2.62e2.57 (m, 1H), 2.48e2.31 (m, 2H),
2.24e2.15 (m, 1H), 1.76e1.71 (m, 1H), 1.25 (t, J¼7.2 Hz, 3H); 13C NMR
4.10.12. Ethyl (4aS
*
,7R
*
,8S
*
,8aR )-7-methyl-1-oxo-3,4,4a,7,8,8a-hex-
*
ahydro-1H-isochromene-8-carboxylate (26c). The minor adduct
obtained, according to the general procedure F, from the triene (Z)-
22c in 22% yield as a white solid; mp 54e55 ꢀC (EtOAc/hexane);
Rf¼0.22 (20% EtOAc in hexane); IR (KBr) 2961, 1732 (br), 1403, 1231,
(100 MHz, CDCl3) d 172.7,171.3,128.4,127.9, 66.2, 60.7, 41.1, 40.2, 32.7,
28.5, 23.2, 14.0; MS (EIþ) m/z 224 (Mþ, 1), 178 (MþꢁEtOH, 39), 150
(30),105 (25), 91 (56), 78 (100). Anal. Calcd for C12H16O4: C, 64.27; H,
7.19, found: C, 64.23; H, 7.07.
1171, 1080, 1026 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 5.62 (br
d, J¼10.0 Hz, 1H), 5.55 (br d, J¼10.0 Hz, 1H), 4.52e4.38 (m, 2H),
4.19e4.08 (m, 2H), 3.20 (d, J¼2.4 Hz, 1H), 2.94e2.88 (m, 2H), 2.23
(dd, J¼12.0, 3.6 Hz,1H), 2.03 (br d, J¼13.6 Hz,1H),1.75 (dddd, J¼12.8,
12.8,12.8, 6.0 Hz,1H),1.24 (t, J¼7.2 Hz, 3H),1.17 (d, J¼6.8 Hz, 3H); 13C
4.10.8. Ethyl (4aS
*
,8S
*
,8aR )-1-oxo-3,4,4a,7,8,8a-hexahydro-1H-iso-
*
chromene-8-carboxylate (26b). The minor adduct obtained,
according to the general procedure F, from the triene (Z)-22b in 19%
yield as a colorless oil; Rf¼0.26 (20% EtOAc in hexane); IR (film)
NMR (100 MHz, CDCl3)
d 172.6, 171.9, 132.1, 128.1, 69.4, 60.8, 44.3,
2979, 2928, 1731 (br), 1403, 1201, 1168, 1090 cmꢁ1
;
1H NMR
41.5, 32.9, 31.5, 29.8, 22.0, 14.1; MS (EIþ) m/z 238 (Mþ, 1), 193
(MþꢁOEt, 98), 164 (67), 136 (85), 119 (87), 105 (100), 91 (90). Anal.
Calcd for C13H18O4: C, 65.53; H, 7.61; found: C, 65.46; H, 7.63.
(400 MHz, CDCl3)
d
5.70e5.68 (m, 1H), 5.60 (br d, J¼10.0 Hz, 1H),
4.51e4.38 (m, 2H), 4.20e4.09 (m, 2H), 3.52 (dd, J¼7.6, 2.8 Hz, 1H),
2.93 (br t, J¼11.2 Hz, 1H), 2.68 (br d, J¼18.4 Hz, 1H), 2.47 (dm,
J¼18.8 Hz, 1H), 2.26 (dd, J¼11.2, 2.8 Hz, 1H), 2.03 (dm, J¼13.2 Hz,
1H), 1.73 (dddd, J¼13.2, 13.2, 13.2, 6.0 Hz, 1H), 1.24 (t, J¼6.4 Hz, 3H);
4.10.13. Ethyl (4aS
*
,7R
*
,8S
*
,8aS )-1-oxo-7-phenyl-3,4,4a,7,8,8a-hex-
*
ahydro-1H-isochromene-8-carboxylate (23d)14. The major adduct
obtained, according to the general procedure F, from the triene (E)-
21d in 53% yield as colorless needles; mp 119e121 ꢀC (EtOAc/hex-
ane); Rf¼0.17 (20% EtOAc in hexane); IR (KBr) 2990, 2954, 2899,
13C NMR (100 MHz, CDCl3)
d 172.8, 171.4, 129.0, 126.2, 69.4, 60.9,
44.8, 37.2, 31.3, 29.9, 28.1, 14.1; MS (EIþ) m/z 224 (Mþ, 1), 179
(MþꢁOEt, 100), 166 (70), 150 (51), 122 (45), 105 (65), 91 (64), 79
(96); HRMS (ESIþ) calcd for C12H16O4Naþ (MþNaþ) 247.0946, found
247.0940.
1725 (br), 1404, 1374, 1221, 1179, 1087 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
7.31e7.21 (m, 3H), 7.16 (d, J¼6.8 Hz, 2H), 5.87e5.80
(m, 2H), 4.47 (ddd, J¼11.2, 4.4, 4.4 Hz, 1H), 4.33 (ddd, J¼11.2, 3.2,
3.2 Hz, 1H), 4.09e4.01 (m, 2H), 3.87 (dd, J¼8.4, 1.6 Hz, 1H), 3.28
(dd, J¼10.0, 7.2 Hz, 1H), 2.91 (dd, J¼10.0, 8.8 Hz, 1H), 2.80 (br s, 1H),
2.07e2.03 (m,1H),1.91e1.81 (m,1H),1.09 (t, J¼7.2 Hz, 3H); 13C NMR
4.10.9. Ethyl (4aS
*
,7R
*
,8S
*
,8aS )-7-methyl-1-oxo-3,4,4a,7,8,8a-hex-
*
ahydro-1H-isochromene-8-carboxylate (23c). The major adduct
obtained, according to the general procedure F, from the triene (E)-
21c in 58% yield as a colorless oil; Rf¼0.46 (20% EtOAc in hexane); IR
(100 MHz, CDCl3)
d
173.0, 170.6, 141.9, 130.7, 128.5 (2ꢂ), 128.0, 127.8
(film) 2964, 2932, 1732, 1403, 1265, 1179, 1087 cmꢁ1
;
1H NMR
(2ꢂ), 127.1, 68.5, 60.8, 48.0, 44.1, 41.8, 31.6, 27.7, 13.9; MS (EIþ) m/z
300 (Mþ, 2), 254 (MþꢁEtOH, 50), 226 (32),154 (100). Anal. Calcd for
C18H20O4: C, 71.98; H, 6.71; found C, 71.92; H, 6.71. The relative
stereochemistry of 23d has been confirmed by X-ray crystal
structural analysis.15
(400 MHz, CDCl3)
d
5.70 (br d, J¼9.6 Hz, 1H), 5.53 (br d, J¼10.0 Hz,
1H), 4.42e4.30 (m, 1H), 4.29e4.25 (m, 1H), 4.21e4.15 (m, 2H), 3.17
(dd, J¼7.6, 6.8 Hz, 1H), 2.72e2.60 (m, 3H), 2.02e1.95 (m, 1H),
1.77e1.67 (m, 1H), 1.26 (t, J¼7.2 Hz, 3H), 1.02 (d, J¼6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3)
d 173.8, 171.5, 133.4, 126.2, 68.0, 60.9, 46.9,
41.3, 32.3, 31.0, 27.8, 20.3, 14.1; MS (EIþ) m/z 192 (MþꢁEtOH, 52),
164 (47), 105 (49), 92 (100); HRMS (ESIþ) calcd for C13H18O4Naþ
(MþNaþ) 261.1103, found 261.1090.
4.10.14. Ethyl (4aS
*
,7R
*
,8R
*
,8aR )-1-oxo-7-phenyl-3,4,4a,7,8,8a-hex-
*
ahydro-1H-isochromene-8-carboxylate (24d). The minor adduct
obtained, according to the general procedure F, from the triene
(E)-21d in 18% yield as a colorless oil; Rf¼0.19 (20% EtOAc in
hexane); IR (film) 2930, 1732 (br), 1454, 1394, 1273, 1085 cmꢁ1; 1H
4.10.10. Ethyl (4aS
*
,7R
*
,8R
*
,8aR )-7-methyl-1-oxo-3,4,4a,7,8,8a-hex-
*
ahydro-1H-isochromene-8-carboxylate (24c). The minor adduct
obtained, according to the general procedure F, from the triene (E)-
21c in 24% yield as a colorless oil; Rf¼0.40 (20% EtOAc in hexane); IR
NMR (400 MHz, CDCl3)
d
7.31e7.25 (m, 3H), 7.13 (d, J¼6.8 Hz, 2H),
5.89 (dm, J¼10.0 Hz, 1H), 5.77 (ddd, J¼7.2, 4.8, 2.4 Hz, 1H), 4.45
(dd, J¼8.4, 5.2 Hz, 2H), 3.95e3.92 (m, 1H), 3.86e3.73 (m, 2H), 3.13
(dd, J¼12.0, 7.2 Hz, 1H), 2.84 (dd, J¼12.0, 12.0 Hz, 1H), 2.56e2.37
(m, 2H), 1.86e1.77 (m, 1H), 0.96 (t, J¼7.2 Hz, 3H); 13C NMR
(film) 2971, 2927, 1738 (br), 1397, 1316, 1260, 1162, 1086, 1032 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
5.69 (br d, J¼9.6 Hz, 1H), 5.54 (br d,
J¼9.6 Hz, 1H), 4.42e4.38 (m, 2H), 4.23e4.17 (m, 2H), 2.88 (dd,
J¼11.6, 6.4 Hz, 1H), 2.76e2.68 (m, 2H), 2.42e2.25 (m, 2H), 1.67e1.59
(m, 1H), 1.28 (t, J¼7.2 Hz, 3H), 0.93 (d, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d
173.8, 171.7, 139.2, 129.2 (2ꢂ), 128.7, 128.2 (2ꢂ),
128.1, 127.4, 65.3, 60.3, 45.4, 42.9, 37.9, 33.0, 27.7, 13.7; MS (EIþ) m/
z 300 (Mþ, 9), 254 (MþꢁEtOH, 35), 226 (61), 156 (100), 91 (71);
HRMS (ESIþ) calcd for C18H20O4Naþ (MþNaþ) 323.1259; found
323.1252.
(100 MHz, CDCl3)
d 174.1, 173.0, 131.9, 126.8, 65.2, 60.5, 43.5, 38.0,
33.1, 31.0, 27.6, 17.6, 14.2; MS (EIþ) m/z 238 (Mþ, 25), 193 (MþꢁOEt,
100), 163 (72), 149 (70), 119 (50), 105 (50), 91 (52); HRMS (ESIþ)
calcd for C13H18O4Naþ (MþNaþ) 261.1103, found 261.1090.
4.10.15. Ethyl (4aS
*
,7R
*
,8R
*
,8aS )-1-oxo-7-phenyl-3,4,4a,7,8,8a-hex-
*
ahydro-1H-isochromene-8-carboxylate (25d). The major adduct
obtained, according to the general procedure F, from the triene (Z)-
22d in 34% yield as a colorless oil; Rf¼0.38 (25% EtOAc in hexane);
IR (film) 2981, 1728 (br), 1454, 1403, 1247, 1188, 1157, 1086,
4.10.11. Ethyl (4aS
*
,7R
*
,8R
*
,8aS )-7-methyl-1-oxo-3,4,4a,7,8,8a-hex-
*
ahydro-1H-isochromene-8-carboxylate (25c). The major adduct
obtained, according to the general procedure F, from the triene (Z)-
22c in 58% yield as a colorless oil; Rf¼0.15 (20% EtOAc in hexane); IR
1022 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.33e7.20 (m, 5H), 6.03 (dt,
(film) 2977, 2934, 1731 (br), 1402, 1261, 1187, 1090, 1036 cmꢁ1 1H
;
J¼10.4, 2.0 Hz, 1H), 5.86 (dt, J¼10.0, 3.0 Hz, 1H), 4.49 (ddd, J¼10.8,

190
J. Wu et al. / Tetrahedron 67 (2011) 179e192
4.4, 2.4 Hz, 1H), 4.36 (ddd, J¼12.0, 12.0, 2.8 Hz, 1H), 3.87e3.75
(m, 2H), 3.69e3.60 (m, 2H), 3.33 (dd, J¼9.2, 5.6 Hz, 1H), 2.85e2.76
(m, 1H), 2.35 (dddd, J¼12.8, 12.8, 12.8, 4.4 Hz, 1H), 1.87 (dm,
J¼14.0 Hz, 1H), 0.82 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
J¼12.8, 10.0, 10.0 Hz, 1H), 1.74e1.67 (m, 1H), 1.72 (s, 3H), 1.39 (d,
J¼6.4 Hz, 3H), 1.28 (t, J¼7.2 Hz, 3H), 0.96 (d, J¼7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3)
d 174.7, 173.0, 137.5, 122.3, 72.4, 60.5, 44.3,
37.0, 35.6, 35.3, 33.6, 21.8, 21.0, 15.8, 14.2; MS (EIþ) m/z 266 (Mþ,
16), 220 (MþꢁEtOH, 57), 192 (40), 177 (48), 147 (95), 119 (77), 107
(100), 91 (81); HRMS (EIþ) calcd for C15H22O4 (Mþ) 266.1518,
found 266.1522.
d
171.7, 171.6, 141.3, 129.7, 128.3 (2ꢂ), 128.0 (2ꢂ), 127.4, 126.7, 69.5,
60.1, 46.9, 42.5, 41.1, 32.6, 26.9, 13.4; HRMS (TOF-CIþ) calcd for
C18H21Oþ4 (MþHþ) 301.1440, found 301.1437.
4.10.16. Ethyl (4aS
*
,7R
*
,8S
*
,8aR
*
)-1-oxo-7-phenyl-3,4,4a,7,8,8a-hex-
4.10.21. Ethyl (3S
*
,4aS
*
,7S
*
,8R
*
,8aS )-3,6,7-trimethyl-1-oxo-3,4,4a,7,8,8a-
*
ahydro-1H-isochromene-8-carboxylate (26d). The minor adduct
obtained, according to the general procedure F, from the triene
(Z)-22d in 19% yield as a colorless solid; mp 95e96 ꢀC (EtOAc/
hexane); Rf¼0.39 (25% EtOAc in hexane); IR (KBr) 2992, 2918, 1724
hexahydro-1H-isochromene-8-carboxylates (25f). The major adduct
obtained, according to the general procedure F, from the triene
(Z)-22f in 46% yield as a colorless oil; Rf¼0.52 (33% EtOAc in
hexane); IR (film) 2975, 2937, 1732 (br), 1447, 1386, 1226, 1192,
(br), 1450, 1407, 1244, 1220, 1194, 1068, 1029 cmꢁ1
;
1H NMR
1097, 1035 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 5.17 (br s, 1H),
(400 MHz, CDCl3)
d
7.36e7.24 (m, 5H), 5.92 (ddd, J¼9.6, 1.6, 1.2 Hz,
4.45e4.42 (m, 1H), 4.21e4.08 (m, 2H), 3.30 (dd, J¼10.0, 5.0 Hz,
1H), 2.93e2.84 (m, 2H), 2.58e2.51 (m, 1H), 2.05 (dd, J¼14.0,
7.0 Hz, 1H), 1.71 (s, 3H), 1.37e1.32 (m, 1H), 1.34 (d, J¼7.0 Hz, 3H),
1.24 (t, J¼7.5 Hz, 3H), 1.15 (d, J¼7.5 Hz, 3H); 13C NMR (125 MHz,
1H), 5.80 (ddd, J¼11.6, 4.0, 2.8 Hz, 1H), 4.52e4.40 (m, 2H),
4.27e4.16 (m, 3H), 3.44 (d, J¼2.8 Hz, 1H), 3.07e3.00 (m, 1H), 2.25
(dd, J¼12.0, 3.2 Hz, 1H), 2.14 (dm, J¼12.8 Hz, 1H), 1.81 (dddd,
J¼12.4, 12.4, 12.4, 6.4 Hz, 1H), 1.31 (t, J¼7.2 Hz, 3H); 13C NMR
CDCl3)
d 172.6, 172.2, 138.2, 122.1, 74.5, 60.4, 44.5, 38.1, 37.0, 34.1,
(100 MHz, CDCl3)
d
172.1, 171.5, 142.9, 130.7, 128.7 (2ꢂ), 128.0 (2ꢂ),
32.3, 21.5, 21.1, 16.4, 14.1; MS (EIþ) m/z 266 (Mþ, 21), 220
(MþꢁEtOH, 72), 192 (41), 147 (86), 119 (49), 107 (100), 91 (76);
HRMS (EIþ) calcd for C15H22O4 (Mþ) 266.1518, found 266.1519.
127.7, 127.0, 69.3, 61.1, 46.1, 43.2, 40.4, 31.4, 29.8, 14.1; MS (EIþ) m/z
300 (Mþ, 5), 254 (MþꢁEtOH, 66), 226 (100), 198 (65), 181 (62), 167
(52), 154 (45), 91 (46). Anal. Calcd for C18H20O4: C, 71.98; H, 6.71;
found C, 71.88; H, 6.68.
4.10.22. Ethyl (3R
*
,4aS
*
,7S
*
,8S
*
,8aR )-3,6,7-trimethyl-1-oxo-3,4,4a,7,8,8a-
*
hexahydro-1H-isochromene-8-carboxylates (26f). The minor adduct
obtained, according to the general procedure F, from the triene
(Z)-22f in 25% yield as a colorless oil; Rf¼0.58 (33% EtOAc in
hexane); IR (film) 2976, 2935, 1732 (br), 1454, 1380, 1220, 1183,
4.10.17. Ethyl 4,6,7-trimethyl-1-oxo-3,4,4a,7,8,8a-hexahydro-1H-iso-
chromene-8-carboxylates (23e, 24e, 23e0, 24e0). An inseparable
mixture of four adducts obtained, according to the general pro-
cedure F, from the triene (E)-21e in 87% yield as a colorless oil. The
ratio of 23e/24e/23e0/24e0 is 60:10:19:7 as measured by 1H NMR
1156, 1127, 1028 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 5.24 (br s,
1H), 4.72 (qdd, J¼6.5, 6.5, 4.0 Hz, 1H), 4.18e4.08 (m, 2H), 3.12 (d,
J¼3.0 Hz, 1H), 3.10e3.04 (m, 1H), 2.65 (q, J¼7.0 Hz, 1H), 2.27 (dd,
J¼12.0, 3.0 Hz, 1H), 1.86 (ddd, J¼13.3, 5.5, 4.0 Hz, 1H), 1.80e1.74
(m, 1H), 1.70 (br s, 3H), 1.45 (d, J¼7.0 Hz, 3H), 1.24 (t, J¼7.5 Hz,
spectrum of the crude products. 1H NMR (400 MHz, CDCl3)
d 5.35
(br s, 0.19H), 5.30 (br s, 0.64H), 5.27 (br s, 0.10H), 5.21 (br s, 0.07H)
(for the vinyl protons of the four diastereomeric adducts).
3H), 1.20 (d, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 172.9,
4.10.18. Ethyl 4,6,7-trimethyl-1-oxo-3,4,4a,7,8,8a-hexahydro-1H-iso-
chromene-8-carboxylates (25e, 26e, 25e0, 26e0). An inseparable
mixture of four adducts obtained, according to the general pro-
cedure F, from the triene (Z)-22e in 85% yield as a colorless oil. The
ratio of 25e/26e/25e0/26e0 is 54:15:24:7 as measured by 1H NMR
172.5, 137.6, 123.7, 74.7, 60.7, 44.6, 40.0, 37.0, 35.2, 27.9, 22.0, 21.9,
20.5, 14.1; MS (EIþ) m/z 266 (Mþ, 5), 220 (MþꢁEtOH, 47), 192
(45), 147 (100), 119 (85), 107 (89), 91 (67); HRMS (EIþ) calcd for
C15H22O4 (Mþ) 266.1518, found 266.1522.
spectrum of the crude products. 1H NMR (400 MHz, CDCl3)
d
5.44
4.10.23. (4aS
*
,8S
*
,8aS )-8-Benzoyl-3,4,4a,7,8,8a-hexahydro-1H-iso-
*
(br s, 0.24H), 5.25 (br s, 0.15H), 5.22 (br s, 0.54H), 5.20 (br s, 0.07H)
(for the vinyl protons of the four diastereomeric adducts).
chromene-1-one (23h). The major adduct obtained, according to
the general procedure F, from the triene (E)-21h in 63% yield as
a colorless solid; mp 95e96 ꢀC (EtOAc/hexane); Rf¼0.33 (20% EtOAc
4.10.19. Ethyl (3S
*
,4aS
*
,7S
*
,8S
*
,8aS
*
)-3,6,7-trimethyl-1-oxo-3,4,4a,7,8,8a-
in hexane); IR (KBr) 2958, 2908, 1725, 1683, 1445, 1265, 1148 cmꢁ1
;
hexahydro-1H-isochromene-8-carboxylates (23f). The major adduct
obtained, according to the general procedure F, from the triene
(E)-21f in 64% yield as a colorless oil; Rf¼0.41 (25% EtOAc in
hexane); IR (film) 2981, 1731, 1715, 1446, 1250, 1224, 1150,
1H NMR (400 MHz, CDCl3)
d
7.93 (d, J¼7.2 Hz, 2H), 7.57 (t, J¼7.2 Hz,
1H), 7.48 (dd, J¼7.6, 7.6 Hz, 2H), 5.88e5.84 (m, 1H), 5.54 (dd, J¼10.4,
2.0 Hz, 1H), 4.46e4.45 (m, 1H), 4.30 (dd, J¼9.2, 4.0 Hz, 2H), 3.20
(dd, J¼7.2, 2.0 Hz, 1H), 2.94 (br s, 1H), 2.46e2.44 (m, 2H), 2.17e2.09
1037 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
5.28 (br s, 1H), 4.45e4.38
(m, 1H), 1.77e1.71 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 201.1, 172.3,
(m, 1H), 4.26e4.11 (m, 2H), 3.08 (dd, J¼8.4, 8.4 Hz, 1H), 2.66e2.52
(m, 3H), 1.94 (ddd, J¼10.8, 3.2, 3.2 Hz, 1H), 1.68 (s, 3H), 1.36 (d,
J¼6.4 Hz, 3H), 1.32 (br d, J¼14.0 Hz, 1H), 1.26 (t, J¼7.2 Hz, 3H), 1.02
135.3, 132.9, 128.7 (2ꢂ), 128.3 (2ꢂ), 127.4, 127.2, 66.4, 41.0, 40.5,
28.4, 28.2, 23.2; MS (EIþ) m/z 256 (Mþ, 11), 228 (MþꢁCO, 15), 183
(11), 151 (90), 105 (100), 77 (83). Anal. Calcd for C16H16O3: C, 74.98;
H, 6.29; found C, 74.92; H, 6.07.
(d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 174.3, 172.3, 137.1,
122.1, 76.3, 60.9, 47.5, 40.4, 36.4, 35.7, 32.0, 21.6, 21.2, 17.9, 14.1; MS
(EIþ) m/z 266 (Mþ, 5), 220 (MþꢁEtOH, 90), 192 (65), 177 (57), 151
(100), 133 (77), 119 (71), 106 (100), 91 (95); HRMS (EIþ) calcd for
C15H22O4 (Mþ) 266.1518, found 266.1516.
4.10.24. (4aS
*
,8R
*
,RaS )-8-Benzoyl-3,4,4a,7,8,8a-hexahydro-1H-iso-
*
chromene-1-one (24h). The minor adduct obtained, according to
the general procedure F, from the triene (E)-21h in 27% yield as
a colorless solid; mp 74e76 ꢀC (EtOAc/hexane); Rf¼0.22 (20% EtOAc
4.10.20. Ethyl (3R
*
,4aS
*
,7S
*
,8R
*
,8aR
*
)-3,6,7-trimethyl-1-oxo-3,4,4a,7,8,8a-
in hexane); IR (KBr) 2924, 1733, 1679, 1296, 1206, 1178 cmꢁ1 1H
;
hexahydro-1H-isochromene-8-carboxylates (24f). The minor adduct
obtained, according to the general procedure F, from the triene
(E)-21f in 25% yield as a colorless oil; Rf¼0.53 (25% EtOAc in
hexane); IR (film) 2976, 2935, 1732 (br), 1449, 1385, 1256, 1186,
NMR (400 MHz, CDCl3)
d
8.02 (d, J¼7.6 Hz, 2H), 7.57 (t, J¼7.6 Hz,1H),
7.48 (dd, J¼7.6, 7.6 Hz, 2H), 5.77e5.74 (m,1H), 5.68 (d, J¼9.6 Hz,1H),
4.44e4.40 (m, 2H), 3.81 (ddd, J¼16.0, 5.2, 5.2 Hz, 1H), 3.10 (dd,
J¼12.0, 11.2 Hz, 1H), 2.63e2.55 (m, 1H), 2.50e2.44 (m, 1H), 2.33
(dddd, J¼13.6, 8.0, 8.0, 8.0 Hz, 1H), 2.20e2.12 (m, 1H), 1.78e1.69 (m,
1122, 1054 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 5.25 (br s, 1H),
4.63e4.58 (m, 1H), 4.20 (q, J¼7.0 Hz, 2H), 2.83 (dd, J¼12.0, 6.0 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 202.7, 173.6, 136.5, 132.9, 128.5
1H), 2.75 (dd, J¼12.0, 12.0 Hz, 1H), 2.50e2.29 (m, 2H), 1.92 (ddd,
(3ꢂ), 128.3 (2ꢂ),125.5, 65.7, 43.2, 40.7, 32.8, 29.8, 27.8; MS (EIþ) m/z

J. Wu et al. / Tetrahedron 67 (2011) 179e192
191
256 (Mþ, 44), 151 (25), 105 (100), 77 (94). Anal. Calcd for C16H16O3:
C, 74.98; H, 6.29; found: C, 74.91; H, 6.23.
obtained, according to the general procedure G, from the
a
-bro-
moacetate 5g and phenylglyoxal hydrate in 31% yield as a white
solid; Rf¼0.36 (25% EtOAc in hexane); IR (KBr) 2970, 2937, 1743,
4.10.25. (4aS
*
,7S
*
,8aR
*
)-6,7-Dimethyl-3,4,4a,7,8,8a-hexahydro-1H-
1682, 1449, 1299, 1171 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 8.01 (d,
isochromene-1-one (23i). The major adduct obtained, according to
the general procedure F, from the triene (E)-21i in 65% yield as
a colorless oil; Rf¼0.30 (20% EtOAc in hexane); IR (film) 2961, 1731
J¼7.6 Hz, 2H), 7.57 (t, J¼7.2 Hz, 1H), 7.47 (dd, J¼7.6, 7.2 Hz, 2H),
5.35 (br s, 1H), 4.46e4.42 (m, 2H), 3.89 (dd, J¼11.2, 5.6 Hz, 1H),
3.06 (dd, J¼12.0, 12.0 Hz, 1H), 2.52e2.23 (m, 3H), 1.74 (s, 3H),
1.69e1.60 (m, 1H), 0.85 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz,
(br), 1444, 1399, 1247, 1213, 1089, 1066 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
5.27 (br s, 1H), 4.38 (ddd, J¼11.2, 4.4, 4.4 Hz, 1H), 4.24 (ddd,
CDCl3)
d
200.3, 174.7, 137.9, 136.5, 133.0, 128.7 (2ꢂ), 128.3 (2ꢂ),
J¼10.8, 10.8, 3.2 Hz, 1H), 2.78 (ddd, J¼10.8, 6.0, 3.6 Hz, 1H), 2.55 (br
s,1H), 2.23e2.17 (m,1H), 2.06 (ddd, J¼13.2, 4.8, 4.4 Hz,1H),1.84 (dq,
J¼14.4, 3.6 Hz,1H), 1.77e1.70 (m, 1H), 1.68 (s, 3H), 1.67e159 (m, 1H),
122.5, 65.0, 45.2, 38.0, 35.6, 33.8, 27.7, 22.0, 15.7; MS (EIþ) m/z 284
(Mþ, 20), 179 (25), 150 (15), 133 (20), 105 (100), 77 (65). Anal. Calcd
for C18H20O3: C, 76.03; H, 7.09; found C, 76.05; H, 7.03. The relative
stereochemistry of 24g has been confirmed by X-ray crystal
structural analysis.17
1.02 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 174.4, 140.3,
122.6, 68.8, 39.7, 33.6, 32.9, 27.5, 21.1, 19.2; MS (EIþ) m/z 180 (Mþ,
78), 152 (MþꢁCO, 47), 121 (40), 107 (100), 93 (100), 79 (66); HRMS
(ESIþ) calcd for C11H17O2 (MþHþ): 181.1229; found 181.1216.
Acknowledgements
4.10.26. (4aS
*
,7S
*
,8aS )-6,7-Dimethyl-3,4,4a,7,8,8a-hexahydro-1H-
*
The Laboratory of Asymmetric Catalysis and Synthesis is
established under the Cheung Kong Scholars Program of The Min-
istry of Education of China. This work is supported in part by the
research grants from The National Natural Science Foundation of
China (Grant No. 20572092), Zhejiang University, and Zhejiang
University Education Foundation. The authors thank Mr. Jianming
Gu of the X-ray crystallographic facility of Zhejiang University for
assistance on crystal structure analysis. Dr. Jian Jin is thanked for
helping on some experiments.
isochromene-1-one (24i). The minor adduct obtained, according to
the general procedure F, from the triene (E)-21i in 5% yield as
a white solid; mp 72e74 ꢀC (EtOAc/hexane); Rf¼0.38 (20% EtOAc in
hexane); IR (KBr) 2961, 1732 (br), 1454, 1399, 1273, 1191, 1124,
1078 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 5.25 (s, 1H), 4.45e4.32 (m,
2H), 2.40e2.01 (m, 5H), 1.74 (dd, J¼12.8, 6.4 Hz, 1H), 1.70e1.64
(m, 1H), 1.69 (s, 3H), 1.08 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3)
d 174.4, 139.9, 123.4, 68.0, 38.5, 35.2, 33.5, 30.1, 29.2, 21.8,
19.8; MS (EIþ) m/z 180 (Mþ, 35), 152 (MþꢁCO, 37), 135 (55), 121
(40), 107 (100), 93 (80), 79 (51); HRMS (ESIþ) calcd for C11H17O2
(MþHþ): 181.1229; found 181.1219.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.02.096. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
4.11. General procedure G for microwave-assisted tandem
WittigeIMDA cycloaddition
To a 10-mL pressurized process vial was added the 3,5-hex-
adien-1-yl a-bromoacetate 5 (0.30 mmol), PPh3 (0.39 mmol), 2,6-
References and notes
lutidine (0.39 mmol), methyl/ethyl glyoxalate or phenylglyoxal
hydrate 6 (0.9 mmol), and MeCN (4 mL). The loaded vial was then
sealed with a cap containing a silicon septum, and put into the
microwave cavity and heated at 180 ꢀC for 1e1.5 h. The reaction
mixture was diluted with EtOAc and washed with saturated
aqueous NH4Cl and brine. The organic layer was dried over anhy-
drous Na2SO4, filtered, and evaporated under reduce pressure. The
residue was checked for adduct isomer ratio by 1H NMR spectrum
and was then purified by flash column chromatography (silica gel,
eluted with 10e20% EtOAc in PE) to give the desired products. The
structures, isomer ratios, and yields are found in Scheme 4 and
entries 1e8 of Table 2. For the reaction in entry 9 of Table 2, 37 wt %
aqueous formaldehyde solution (0.9 mmol) was used and the re-
action was carried out at 160 ꢀC for 2.5 h.
1. For selected reviews on IMDA reaction, see: (a) Taber, D. F. Intramolecular
DielseAlder and Alder Ene Reactions; Springer: Berlin, 1984; (b) Fallis, A. G. Can. J.
Chem. 1984, 62, 183e234; (c) Ciganek, E. Org. React. 1984, 32, 1e374; (d) Craig, D.
Chem. Soc. Rev. 1987, 187e238; (e) Roush, W. R. In Advances in Cycloaddition;
Curran, D. P., Ed.; JAI: Greenwich, CT, 1990; Vol. 2, pp 91e142; (f) Roush, W. R. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.;
Pergamon: Oxford, 1991; Vol. 5, pp 513e550; (g) Craig, D. Stereoselective
Synthesis (Houben-Weyl) No E21c In Methods of Organic Chemistry, 4th ed.;
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schumann, E., Eds.; Thieme: Stutt-
gart, 1995, pp 2872e2904; (h) Fallis, A. G. Acc. Chem. Res. 1999, 32, 464e474; (i)
Bear, B.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001, 40, 820e849; (j)
Stocking, E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42, 3078e3115; (k)
Takao, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779e4807.
2. For thermal IMDA of ester-tethered 1,3,9-decatrienes, see: (a) Martin, S. F.;
Williamson, S. A.; Gist, R. P.; Smith, K. M. J. Org. Chem. 1983, 48, 5170e5180; (b)
Nugent, W. A.; Thorn, D. L.; Harlow, R. L. J. Am. Chem. Soc. 1987, 109, 2788e2796;
(c) Hoshino, O.; Ishizaki, M.; Kamei, K.; Taguchi, M.; Nagao, T.; Iwaoka, K.;
Sawaki, S.; Umezawa, B.; Iitaka, Y. J. Chem. Soc., Perkin Trans. 1 1996, 571e580;
(d) Jung, M. E.; Huang, A.; Johnson, T. W. Org. Lett. 2000, 2, 1835e1837; (e)
4.11.1. (4aS
ahydro-1H-isochromene-1-one (23g). The major adduct obtained,
according to the general procedure G, from the -bromoacetate 5g
*
,7S
*
,8S
*
,8aS
*
)-8-Benzoyl-6,7-dimethyl-3,4,4a,7,8,8a-hex-
ꢀ
Ritter, N.; Metz, P. Synlett 2003, 2422e2424; (f) Bruyere, H.; Samaritani, S.;
Ballereau, S.; Tomas, A.; Royer, J. Synlett 2005, 1421e1424.
a
3. For thermal IMDA of ester-tethered 1,3,9-decatrienes possessing a C10-acti-
vating group, see: (a) Boeckman, R. K., Jr.; Demko, D. M. J. Org. Chem. 1982, 47,
1789e1792; (b) Mori, K.; Gupta, A. K. Tetrahedron 1985, 41, 5295e5299; (c)
Chen, C.-Y.; Hart, D. J. J. Org. Chem. 1993, 58, 3840e3849; (d) Kim, P.; Hantz, M.
H.; Kurth, M. J.; Olmstead, M. M. Org. Lett. 2000, 2, 1831e1834; (e) Inoue, S.; Yin,
C.; Kosugi, H.; Nabeta, A.; Sakai, Y.; Honda, K.; Hoshino, Y. Bull. Chem. Soc. Jpn.
2008, 81, 1308e1314.
4. For IMDA of ester-tethered 1,3,9-decatrienes under Lewis acid catalysis or non-
conventional conditions, see: (a) Alexakis, A.; Jachiet, D.; Toupet, L. Tetrahedron
1989, 45, 6203e6210; (b) Chen, C.-Y.; Hart, D. J. J. Org. Chem. 1990, 55,
6236e6240; (c) Saito, A.; Ito, H.; Taguchi, T. Org. Lett. 2002, 4, 4619e4621; (d)
Saito, A.; Yanai, Y.; Taguchi, T. Tetrahedron 2004, 60, 12239e12247; (e) Saito, A.;
Yanai, H.; Sakamoto, W.; Takahashi, K.; Taguchi, T. J. Fluorine Chem. 2005, 126,
709e714; (f) Yanai, H.; Saito, A.; Taguchi, T. Tetrahedron 2005, 61, 7087e7093;
(g) Taguchi, T.; Saito, A.; Yanai, H. Chem. Rec. 2007, 7, 167e179; (h) Yanai, H.;
Ogura, H.; Taguchi, T. Org. Biomol. Chem. 2009, 7, 3657e3659 For IMDA cyclo-
addition catalyzed by an N-protonated chiral oxazaborolidine, see: (i) Zhou, G.;
Hu, Q.-Y.; Corey, E. J. Org. Lett. 2003, 5, 3979e3982 Also see Refs. 2e,3c.
and phenylglyoxal hydrate in 60% yield as a colorless oil; Rf¼0.46
(25% EtOAc in hexane); IR (film) 2967, 2918, 1728, 1682, 1447, 1272,
1169, 1149 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.96 (d, J¼7.6 Hz, 2H),
7.56 (t, J¼7.2 Hz, 1H), 7.47 (dd, J¼7.6, 7.2 Hz, 2H), 5.17 (br s, 1H),
4.40e4.25 (m, 3H), 3.16 (dd, J¼8.0, 3.2 Hz, 1H), 2.86 (br s, 1H), 2.49
(q, J¼7.6 Hz, 1H), 2.10e2.01 (m, 1H), 1.78e1.68 (m, 1H), 1.73 (s, 3H),
1.18 (d, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 201.2, 172.8,
140.3, 135.7, 133.0, 128.8 (2ꢂ), 128.4 (2ꢂ), 121.2, 66.5, 49.0, 39.0,
34.2, 29.6, 28.5, 22.2, 20.1; MS (ESIþ) m/z 307 (MþNaþ, 100); HRMS
(ESIþ) calcd for C18H20O3Naþ (MþNaþ) 307.1310; found 307.1296.
4.11.2. (4aS
*
,7S
*
,8R
*
,8aR
*
)-8-Benzoyl-6,7-dimethyl-3,4,4a,7,8,8a-
minor adduct
hexahydro-1H-isochromene-1-one (24g). The

192
J. Wu et al. / Tetrahedron 67 (2011) 179e192
5. For computational calculations on IMDA of ester-tethered 1,3,9-decatrienes,
12. Sabitha, G.; Srividya, R.; Yadav, J. S. Tetrahedron 1999, 55, 4015e4018. Also see Ref.11.
13. Paulvannan, K.; Jacobs, J. W. Tetrahedron Lett. 1999, 55, 7433e7440.
14. The E- and Z-substituted diesters of the diene alcohol 13 were prepared sim-
ilarly. But the results are not included here because their IMDA adducts could
not be separated by flash column chromatography.
see: (a) Tantillo, D. J.; Houk, K. N.; Jung, M. E. J. Org. Chem. 2001, 66, 1938e1940;
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L. C. H.; Turner, C. I.; Jones, G. A.; Willis, A. C.; Paddon-Row, M. N.; Sherburn, M.
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M. S.; Paddon-Row, M. N. Org. Biomol. Chem. 2008, 6, 513e522.
6. (a) Wu, J.; Sun, L.; Dai, W.-M. Tetrahedron 2006, 62, 8360e8372; (b) Wu, J.; Yu,
H.; Wang, Y.; Xing, X.; Dai, W.-M. Tetrahedron Lett. 2007, 48, 6543e6547; (c)
Wang, Y.; Wu, J.; Dai, W.-M. Synlett 2009, 2862e2866.
15. Jiang, X. Q.; Wu, J.-L. Acta Crystallogr. 2010, E66, o1367.
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Sik, V.; Storer, R. J. Chem. Soc., Perkin Trans. 1 1995, 2419e2425; (b) Bailey, P. D.;
Smith, P. D.; Pederson, F.; Clegg, W.; Rosaira, G. M.; Teat, S. J. Tetrahedron Lett.
2002, 43, 1067e1070.
7. Martin, S. F.; Tu, C.-Y.; Chou, T.-S. J. Am. Chem. Soc. 1980, 102, 5274e5279.
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1529e1562.
9. Wu, P.-L.; Chung, T.-H.; Chou, Y. J. Org. Chem. 2001, 66, 6585e6594.
10. Page, P. C. B.; Vahedi, H.; Batchelor, K. J.; Hindley, S. J.; Edgar, M.; Beswick, P.
Synlett 2003, 1022e1024.
17. The X-ray crystal data (excluding structure factors) of compound 24g, given in
Fig. 3, have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no CCDC 785558. Copy of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: þ44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
18. The adducts 23j/24j were obtained from the triene 21j in 42% combined yield
and in 90:10 dr by heating in xylene at 210 ꢀC for 5 h as reported in Ref. 2a.
11. Spate, S. M.; Stone, H. J. Org. Chem. 1958, 23, 1559e1560.