Highly stereoselective lodolactonization of 4,5-allenoic acids - An efficient synthesis of 5-(1′-Iodo-1′(Z)-alkenyl)-4,5-dihydro-2(3H)- furanones

Article abstract of DOI:10.1002/chem.200801363

In this paper, it is reported that the efficient iodolactonization of 4,5-allenoic acid with I₂ in cyclohexane in the presence or absence of K₂CO₃ afforded 5-(1′-iodo-1′(Z)-alkenyl)-4, 5-dihydro-2(3H)-furanones highly stereo-selectively. However, the reaction of axially optically active 4,5-allenoic acids (R)-(-)-5a and (R)-(-)-5b with I₂ afforded the corresponding products with a serious loss of chirality. This problem was solved by conducting the iodolactonization with N-iodosuccinimide in CH₂Cl₂ in the presence of Cs ₂CO₃; however, the Z/E selectivity is somewhat lower. The pure optically active Z products were prepared by subsequent kinetic resolution with Sonogashira coupling. The reaction of thesubstrates with a substituent at the 3-position of the starting 4,5-allenoic acids afforded the trans-4,5-disubstituted γ-butyrolactones as the only products. The reaction of the 4,5-allenoic acids (S)-(+)-11, (R)-(-)-11, and (S)-(+)-lm with a center chirality at the 3-position afforded the trans products with very high enantiopurity and up to 98:2 Z/E selectivity regardless of the axial chirality of the allene moiety.

Full text of DOI:10.1002/chem.200801363

DOI: 10.1002/chem.200801363
Highly Stereoselective Iodolactonization of 4,5-Allenoic Acids—An Efficient
Synthesis of5-(1 ’-Iodo-1’(Z)-alkenyl)-4,5-dihydro-2(3H)-furanones
Xinpeng Jiang, Chunling Fu,* and Shengming Ma*[a]
Dedicated to Professor Xiyan Lu on the occasion of his 80th birthday
Abstract: In this paper, it is reported
that the efficient iodolactonization of
4,5-allenoic acid with I2 in cyclohexane
in the presence or absence of K2CO3
afforded 5-(1’-iodo-1’(Z)-alkenyl)-4,5-
dihydro-2(3H)-furanones highly stereo-
selectively. However, the reaction of
axially optically active 4,5-allenoic
acids (R)-(À)-5a and (R)-(À)-5b with
I2 afforded the corresponding products
with a serious loss of chirality. This
problem was solved by conducting the
iodolactonization with N-iodosuccini-
mide in CH2Cl2 in the presence of
Cs2CO3; however, the Z/E selectivity is
somewhat lower. The pure optically
active Z products were prepared by
subsequent kinetic resolution with So-
nogashira coupling. The reaction of the
substrates with a substituent at the 3-
position of the starting 4,5-allenoic
acids afforded the trans-4,5-disubstitut-
ed g-butyrolactones as the only prod-
ucts. The reaction of the 4,5-allenoic
acids (S)-(+)-1l, (R)-(À)-1l, and (S)-
(+)-1m with a center chirality at the 3-
position afforded the trans products
with very high enantiopurity and up to
98:2 Z/E selectivity regardless of the
axial chirality of the allene moiety.
Keywords:
acids
·
allenes
·
·
iodolactonization
stereoselectivity
·
lactones
Introduction
zation reactions of g-allenoic acids with a,b-unsaturated car-
bonyl compounds; and intramolecular cyclization of g-(p-al-
lylmolybdenum) carboxylic acids.[12] In addition, by using N-
heterocyclic carbene as catalyst, the reaction of a,b-unsatu-
rated aldehydes with 1,2-dicarbonyl compounds[13] or alde-
hydes[14] could also afford g-butyrolactones. Another route
toward the formation of this important skeleton is a formal
[2+2+1] cycloaddition of an alkene, an aldehyde or ketone
functionality, and carbon monoxide by using a catalytic
amount of Ti catalyst.[15] In this paper, we wish to disclose
our recent observation that 4,5-allenoic acids may be iodo-
lactonized efficiently providing a highly stereoselective syn-
thesis of g-butyrolactones.[16]
g-Butyrolactones are important subunits that are present in
a large variety of natural products and biologically active
compounds.[1] These very attractive biological properties
prompted organic chemists to develop a series of methods
for the synthesis of g-butyrolactones. The most notable
methods are as follows: the intramolecular transesterifica-
tion of g-hydroxyesters;[2] the reagent-controlled stereoselec-
tive halolactonizaton[3] or manganese acetate mediated cycli-
zation[4] of 4-pentenoic acid derivatives; lactonization of 4-
pentynoic acids catalyzed by AuCl,[5] [Pd
cubane-type MoNiS4 clusters;[7] lactonization of g-allenoic
acids catalyzed by Pd(OAc)2 or mediated by N-bromosucci-
nimide,[8] or cationic gold(I) complexes;[9] cationic [CpRu-
(NCCH3)3]PF6-[10] or Pd(OAc)2-[11] promoted coupling cycli-
(PPh3)4],[6] or
AHCTREUNG
U
A
Results and Discussion
We tried the reaction of dodeca-4,5-dienoic acid (1a)[8] with
I2 in the first instance. In MeCN, the reaction could afford
the five-membered 5-(1’-iodo-1’(Z)-octenyl)-4,5-dihydro-
2(3H)-furanone (2a) in 92% yield. The formation of 7-
membered lactone 3a was not observed, which indicates
that the iodolactonization reaction is highly regioselective;
however, the stereoselectivity for the carbon–carbon double
bond in 2a is poor (Z/E 87:13; Table 1, entry 1). When the
reaction was conducted at a lower temperature in the pres-
[a] X. Jiang, Prof. Dr. C. Fu, Prof. Dr. S. Ma
Laboratory of Molecular Recognition and Synthesis
Department of Chemistry, Zhejiang University
Hangzhou 310027, Zhejiang, Peopleꢀs Republic of China
Fax : (+86)21-6260-9305
E-mail: masm@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801363. It contains full ex-
1
perimental details and copies of H NMR, 13C NMR, and HPLC spec-
tra of all compounds.
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FULL PAPER
Table 1. The iodolactonization of g-allenoic acid 1a with I2.
Table 2. Iodolactonization of 4,5-allenoic acids 1 with I2.
Entry
1
Conditions[a] Yield of
Z/E[c]
Entry Solvent
T [oC]
t
Yield of 2a [%][a] Z/E[a,b]
2 [%][b]
R1
R2
R3
1
CH3CN
RT
40 min
19 h
9287:13
2CH
3
4
5
6
3CN/H2O[c] À30
73
80
91
89
84
99
100
94
92:8
91:9
97:3
96:4
96:4
97:3
95:5
97:3
1
2
3
4
5
6
7
8
9
nC6H13
nC5H11
nC4H9
CH3
C2H5
H
H
H
H
H
H
H
H
À
À
H (1a)
H (1b)
H (1c)
H (1d)
nC4H9 (1e)
nC4H9 (1 f)
nC4H9 (1 f)
H (1g)
A
A
A
A
A
A
B
A
B
B
83 (2a)
85 (2b)
85 (2c)
79 (2d)
75 (2e)
19 (2 f)[d]
87 (2 f)
98:2
98:2
97:3
98:2
99:1
–
–
–
–
–
DMSO
toluene
CHCl3
CH2Cl2
CH2Cl2
RT
RT
RT
RT
À20
À20
RT
RT
RT
RT
RT
48 min
40 min
35 min
50 min
2.5 h
7
8
[d]
CH2Cl2
2.5 h
H
9
10
11
ClCH2CH2Cl
cyclohexane
hexane
40 min
45 min
30 min
50 min
35 min
À
(CH2)5
trace (2g)[d]
73 (2g)
88 (2h)
9298:2
70
À
(CH2)5
H (1g)
98:2
10
C2H5
C2H5 H (1h)
[e]
12cyclohexane
9298:2
9297:3
13
cyclohexane[f]
[a] Conditions A: I2 (1.5 equiv), cyclohexane, RT, 1 h; conditions B: I2
(1.5 equiv), K2CO3 (1 equiv), cyclohexane, RT, 1 h. [b] Isolated yield.
[c] The Z/E ratio was determined by 400 MHz 1H NMR spectroscopic
analysis. [d] The yield was determined by 300 MHz H NMR spectroscop-
ic analysis.
[a] Determined by 400 MHz 1H NMR spectroscopic analysis. [b] The
alkene configuration was established by the NOE study. [c] CH3CN/H2O
40:1. [d] K2CO3 (2equiv) was applied as an additive. [e] I 2 (1.5 equiv)
was used. [f] I2 (1.2equiv) was used.
1
ence of H2O, the stereoselectivity was higher (entry 2). In
DMSO, toluene, CHCl3, CH2Cl2, or ClCH2CH2Cl, the reac-
tion also afforded the product (Z)-2a with better stereose-
lectivities (entries 3–9). The best stereoselectivity (Z/E 98:2)
was observed when the reaction was conducted in cyclohex-
ane or hexane at room temperature; however, the yield of
(Z)-2a in cyclohexane is much higher than that in hexane
(compare entry 10 with entry 11). After conducting the reac-
tion with different amounts of I2, conditions A (1.5 equiv of
I2, cyclohexane, RT) were established as the first optimized
reaction conditions (entry 12). The configuration of the C=C
bond in 2a was established by a NOE study (Figure 1).
Figure 2. ORTEP drawing of 2g.
For the synthesis of optically active 4,5-allenoic acids (R)-
(À)-1a and (R)-(À)-1b, optically active propargylic alcohols
(R)-(+)-4a and (R)-(+)-4b[18] were treated with excess
triethyl orthoacetate in the presence of a catalytic amount
of propionic acid. The resulting 3,4-allenoates were then re-
duced with LiAlH4 to form the related alcohols (R)-(À)-5a
and (R)-(À)-5b, which were tosylated and subsequently con-
verted to nitriles (R)-(À)-6a and (R)-(À)-6b. Finally, hydrol-
ysis with NaOH in EtOH/H2O afforded the allenoic acids
(R)-(À)-1a and (R)-(À)-1b (Scheme 1).[19]
Figure 1. NOE study of (Z)-2a, (E)-2a, and 2l.
The scope of the reaction was studied under conditions A.
The results in Table 2indicated that both 6-substituted (en-
tries 1–4, Table 2) and 4,6-disubstituted (entry 5) 4,5-allenoic
acids may be highly regio- and stereoselectively cyclized in
the presence of 1.5 equivalents of I2 affording (Z)-2 in 46–
85% yields. However, the corresponding reactions of 6-un-
substituted (entry 6) and 6,6-disubstituted (entry 8) 4,5-alle-
noic acids afforded the products in relatively low yields. To
our surprise, with the addition of one equivalent of K2CO3
(conditions B), the reaction afforded 2 f–h in much higher
yields (entries 7, 9, and 10). The structures of all the prod-
ucts were further established by the X-ray diffraction study
of 2g (Figure 2).[17]
However, when optically active (R)-(À)-1a was treated
with 1.5 equivalents of I2 in cyclohexane, although the Z/E
selectivity is still high (98:2), the product 2a is racemic,
which indicates that the axial chirality in (R)-(À)-1a was
lost during the cyclization, probably due to the formation of
the p-allylic cation intermediate. Thus, NIS was used instead
of I2 and the corresponding iodolactonization of (R)-(À)-1a
and (R)-(À)-1b in CH2Cl2 afforded butyrolactones (S)-(Z)-
2a (99% ee)/(R)-(E)-2a and (S)-(Z)-2b (98% ee)/(R)-(E)-
2b (Scheme 2). The absolute configuration of the chiral
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9657

S. Ma, C. Fu and X. Jiang
means of the Sonogashira coupling was applied.[20] In this
way, (S)-(+)-(Z)-2b and (R)-(+)-(Z)-2a were prepared in
>98% ee and with 96:4 Z/E selectivity (Scheme 4).
Scheme 4. Kinetic resolution of Z/R and E/S mixtures of 2a and 2b.
Scheme 1. Synthesis of optically active g-allenoic acids (R)-(À)-1a and
(R)-(À)-1b. Ts=tosyl.
Furthermore, when a substituent was introduced at the 3-
position of the substrates, that is, 1i–m, the reaction also af-
forded the products trans-(Z)-2i–m with two chiral centers
highly diastereoselectively (Table 3). The relative trans ste-
reochemistry of these products was established by the NOE
study of 2l (Figure 1).
Table 3. Iodolactonization of g-allenoic acids 1i–m with I2.
Entry
Allenoic acid
R2
Yield of 2 [%][b] Z/E[c] d.r.[c]
R1
d.r.[a]
1
CH3
CH3 (1i)
C2H5 (1j)
2.0:1 82 (2i)
2.2:1 78 (2j)
96:4
97:3
97:3
97:3
97:3
>99:1
>99:1
>99:1
>99:1
>99:1
2CH
3
3
4
5
CH3
nC3H7 (1k) 2.2:1 82 (2k)
3.1:1 76 (2l)
nC6H13 nC3H7 (1m) 2.7:1 80 (2m)
nC4H9 CH3 (1 l)
[a] The d.r. value was determined by inverse gated decoupling 13C NMR
spectroscopic analysis.[21] [b] Isolated yield after flash chromatography.
[c] The Z/E ratio and d.r. value were determined by 1H NMR spectro-
scopic analysis of the crude reaction mixture.
Scheme 2. Intramolecular iodolactonization of optically active 4,5-alleno-
ic acids (R)-(À)-1a and (R)-(À)-1b with I2 or NIS. NIS=N-iodosuccini-
mide.
It is remarkable that this process yields diastereomerically
pure g-butyrolactones despite the low diastereomeric purity
of the starting materials, which suggests that the process is
diastereoconvergent. This was investigated in detail.
To show the potential for the highly diastereoselective
synthesis of optically active compounds, optically active g-al-
lenoic acids (S)-(+)-1l and (S)-(+)-1m were prepared ac-
cording to the chemistry shown in Scheme 5. 3-(Trimethylsi-
lyl)propiolaldehyde[22] was converted to 3,4-allenoic acids
following the procedures developed by Nelson et al.[23] The
resulting optically active b-allenoic acids (Ra,R)-(+)-9a and
(Ra,R)-(À)-9b were then reduced with LiAlH4 to form the
related alcohols (Ra,R)-(À)-10a and (Ra,R)-(À)-10b, which
were tosylated and subsequently converted to nitriles.[24] Fi-
nally, hydrolysis with NaOH in EtOH/H2O afforded the al-
lenoic acids (S)-(+)-1l and (S)-(+)-1m. However, epimeri-
zation of the axial chirality of the allene moiety was ob-
served, which led to the formation of a pair of diastereoiso-
mers. (R)-(À)-1l was prepared similarly by using TMS-qui-
Scheme 3. The anti iodolactonization of (R)-(À)-1a and (R)-(À)-1b with
NIS.
center in the above four products is tentatively assigned
based on the anti nature of the iodolactonization reaction
(Scheme 3). However, the stereoselectivity for the carbon–
carbon double bond in 2a and 2b is poorer. To get the pure
Z isomer, a kinetic resolution of these two products by
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Stereoselective Iodolactonization of 4,5-Allenoic Acids
FULL PAPER
through the common intermediacy of 14-type p-allylic cat-
ionic species, which led to the formation of the thermody-
namically more stable trans products by 1,2-chiral induction.
To confirm this hypothesis, (Ra,R)-(À)-1l was prepared
from the known procedure (Scheme 7).[25]
Scheme 5. Synthesis of optically active g-allenoic acids (S)-(+)-1l and
(S)-(+)-1m. TBAF=tetrabutylammonium fluoride; TMS=trimethylsilyl.
nidine in the first step converting 7 to (3S,4S)-(+)-8a (for
the synthetic scheme with the yield information see
Scheme S1 in the Supporting Information and Scheme 7).
When optically active compounds (S)-(+)-1l, (S)-(+)-1m,
and (R)-(À)-1l were treated with I2 under conditions A,
(4S,5S)-(+)-(Z)-2l, (4S,5S)-(+)-(Z)-2m, and (4R,5R)-(À)-
(Z)-2l were isolated in 86, 72, and 82% yields with 99% ee,
respectively (Scheme 6). The absolute configurations of the
newly formed chiral centers in the above three products
were assigned based on the trans orientation of the two sub-
stituents and the center chirality at the 3-position of the
starting acids (S)-(+)-1l, (S)-(+)-1m, and (R)-(À)-1l. Thus,
consistent with the results in Scheme 2, under I2/cyclohexane
conditions, it is believed that the reaction proceeded
Scheme 7. Synthesis of optically active g-allenoic acid (Ra,R)-(À)-1l.
DCC=1,3-dicyclohexylcarbodiimide; DMAP=4-dimethylaminopyridine.
In addition, (Sa,R)-(+)-1l was prepared by preparative
HPLC separation of the benzyl ester of (R)-(À)-1l, followed
by hydrolysis of (Sa,R)-(+)-13a (Scheme 8). The absolute
configuration of the diastereomer related to peak 2was de-
termined to be Ra,R by comparison with the sign of the spe-
cific optical rotation of (Ra,R)-(À)-13a prepared in
Scheme 7. Based on this, the absolute configuration of the
diastereomer related to peak 1 was assigned as (Sa,R).
It is interesting to observe that both (Sa,R)-(+)-1l and
(Ra,R)-(À)-1l indeed afforded the same product (4R,5R)-
Scheme 6. Iodolactonization of optically active 4,5-allenoic acids (S)-(+)-
1l, (S)-(+)-1m, and (R)-(À)-1l with I2.
Scheme 8. Synthesis of optically active g-allenoic acids (Sa,R)-(+)-1l.
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S. Ma, C. Fu and X. Jiang
ethyl undeca-3,4-dienoate (5.6457 g, 26.9 mmol) in THF (25 mL) was
added dropwise to an ice-cold suspension of LiAlH4 (1.3310 g,
34.9 mmol) in anhydrous THF (25 mL) under N2. After 1.2h, the reac-
tion was complete, as determined by TLC analysis, and it was quenched
by slow addition of H2O, extracted with 60 mL of ethyl ether, and then
filtered to remove the solid. The resulting mixture was extracted with
ether and the combined organic layers were washed with water and
brine, dried over Na2SO4, filtered, evaporated, and purified by chroma-
tography on silica gel to afford 5a (3.8973 g, 86%). Oil; 1H NMR
(400 MHz, CDCl3): d=5.19–5.12(m, 1H), 5.12–5.04 (m, 1H), 3.70 (t, J=
6.2 Hz, 2H), 2.28–2.21 (m, 2H), 2.02–1.95 (m, 2H), 1.64 (s, 1H), 1.43–
1.21 (m, 8H), 0.88 ppm (t, J=6.8 Hz, 3H); this compound was used in
the next step without further characterization.
Synthesis of dodeca-4,5-dienenitrile (6a): pTsCl (22.2 g, 0.12 mol) was
added in several portions to an ice-cooled solution of 5a (6.5161 g,
0.039 mol) in dry pyridine (50 mL) at 0–48C with an ice/water bath.
After 4 h, the mixture was poured into ice/water and the resulting mix-
ture was extracted with ether (50 mL”3). The combined organic layers
were washed with water and brine, dried over Na2SO4, filtered, and then
concentrated in vacuum. The product was then used in the next step
without further purification. NaCN (2.0526 g, 0.042 mol) was added to a
mixture of the tosylate prepared above and anhydrous DMSO (30 mL)
at 208C. The reaction mixture was stirred for 25 h at this temperature,
quenched with H2O (30 mL), and extracted with ether (30 mL”3). The
organic layers were washed with water and brine, dried over Na2SO4, fil-
tered, evaporated, and purified by chromatography on silica gel to afford
6a (5.0199 g, the combined yield from 5a to 6a is 73%). Oil; 1H NMR
(400 MHz, CDCl3): d=5.31–5.20 (m, 1H), 5.20–5.10 (m, 1H), 2.42 (t, J=
7.0 Hz, 2H), 2.35–2.28 (m, 2H), 2.06–1.97 (m, 2H), 1.45–1.20 (m, 8H),
0.88 ppm (t, J=6.6 Hz, 3H); this compound was used in the next step
without further characterization.
Scheme 9. Iodolactonization of optically active 4,5-allenoic acids (Sa,R)-
(+)-1l and (Ra,R)-(À)-1l with I2.
(Z)-2l as expected, which further supported our hypothesis
(Scheme 9).
Conclusion
We have demonstrated an efficient and highly stereoselec-
tive iodolactonization reaction of 4,5-alkadienoic acids with
NIS in CH2Cl2 or I2 in cyclohexane. When a chiral center
was installed at the 3-position of the 4,5-allenoic acids, the
iodolactonization reaction with I2 in cyclohexane at room
temperature provided trans-5-(1’-iodo-1’(Z)-alkenyl)-4-sub-
stituted butyrolactones with very high diastereoselectivity.
However, the axial chirality in (R)-(À)-1a and (R)-(À)-1b
could not be transformed into the center chirality of the
products by conducting the iodolactonization with I2. In-
stead, NIS was applied to produce the optically active prod-
ucts (S)-(+)-2a and (S)-(+)-2b with a relatively low Z/E se-
lectivity in CH2Cl2. The pure optically active Z isomers may
be prepared by kinetic resolution through Sonogashira cou-
pling. Compared with other reports related to the cycliza-
tion of allenoic acids, the method described here enjoys the
advantage of more easily available/cheap reagents, higher Z
stereoselectivity, referring to the formation of the C=C bond
in the product, efficient axial chirality transfer, and excellent
1,2-chiral induction. Further studies in this area is being pur-
sued in our laboratory.
Synthesis of dodeca-4,5-dienoic acid (1a): A mixture of dodeca-4,5-diene-
nitrile (2.0040 g, 11.3 mmol), ethanol (15 mL), and NaOH solution (4.0 g
in 5.2mL of H 2O, 100 mmol) was stirred at 808C for 5 h. The mixture
was concentrated in vacuum and the residue was quenched with water
(20 mL). The aqueous solution was extracted with ether to remove neu-
tral impurities. The aqueous layer was then acidified with 5% HCl (aq.)
to pH 1 and extracted with ether (30 mL”3). The ether extraction was
washed with water and brine, dried over Na2SO4, filtered, and then con-
centrated in vacuum. Chromatography on silica gel (petroleum ether/
ethyl acetate 5:1) of the crude product afforded 1a (2.1065 g, 95%). Oil;
1H NMR (300 MHz, CDCl3): d=9.82(brs, COOH, 1H), 5.21–5.09 (m,
2H), 2.48 (t, J=7.1 Hz, 2H), 2.36–2.23 (m, 2H), 2.03–1.90 (m, 2H), 1.46–
1.16 (m, 8H), 0.88 ppm (t, J=6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=203.6, 179.6, 92.9, 89.2, 33.1, 31.7, 29.1, 28.84, 28.82, 23.5, 22.6,
14.1 ppm; IR (neat): n˜ =3030, 2957, 2927, 2856, 1964, 1712, 1435, 1336,
1278, 1211, 1173 cmÀ1; MS (70 ev, EI): m/z (%): 196 (0.46) [M]+, 12 6
(100); HRMS: m/z: calcd for C12H20O2Na: 219.1356 [M++Na]; found:
219.1351.
Procedures for the preparation of optically active g-allenoic acids[26] (R)-
(À)-1a, (R)-(À)-1b, (S)-(+)-1l, (S)-(+)-1m, and (Ra,R)-(À)-1l
Preparation ofoptically active g-allenoic acid[19a] (R)-(À)-1a
Synthesis of (R)-(À)-dodeca-4,5-dienenitrile ((R)-(À)-6a): Following the
procedure for the preparation of 5a, the reaction of (R)-(+)-nonyn-3-ol
((R)-(+)-4a) (4.0693 g, 29 mmol, 99% ee, [a]2D0 =+4.6 (c=1.92in
CHCl3)), EtCOOH (1.5 mL, d=0.99 gmLÀ1, 1.49 g, 0.020 mol), and MeC-
Experimental Section
A
Typical procedure for the preparation of g-allenoic acids[8] 1a–m
(4.1724 g). The product was used in the next step without further charac-
terization. A solution of this ester (4.1724 g, 19.9 mmol) in THF (30 mL)
was treated with LiAlH4 (0.7990 g, 21 mmol) in anhydrous THF (30 mL)
to afford (R)-(À)-5a (2.4345 g, the crude combined yield from (R)-(+)-
4a to (R)-(À)-5a is 50%). The product was used in the next step without
further characterization. Following the procedure for the preparation of
6a, the reaction of (R)-(À)-5a (1.6055 g, 10 mmol), pTsCl (5.7 g,
30 mmol), and dry pyridine (20 mL) afforded the tosylate, which was
used in the next step without further purification. The reaction of the to-
sylate prepared above and NaCN (0.5584 g, 11.4 mmol) in anhydrous
DMSO (20 mL) afforded (R)-(À)-6a (1.3584 g, the combined yield from
Preparation ofdodeca-4,5-dienoic acid (1a)
Synthesis of undeca-3,4-dien-1-ol (5a): A mixture of nonyn-3-ol (4a)
(7.0010 g, 0.05 mol), EtCOOH (1 mL, d=0.99 gmLÀ1, 0.99 g, 0.013 mol),
and MeC
at 1308C for 5 h with a Dean–Stark apparatus to remove the in situ
formed EtOH and the excess MeC(OEt)3. After removing most of the
(OEt)3 (30 mL, d=0.876 gmLÀ1, 26.28 g, 0.16 mol) was heated
AHCTREUNG
compounds with low boiling points, the mixture was cooled to RT and
then purified by chromatography on silica gel to afford ethyl undeca-3,4-
dienoate (9.8926 g, crude yield: 94%). The product was used in the next
step without further characterization. A solution of the above prepared
9660
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 9656 – 9664

Stereoselective Iodolactonization of 4,5-Allenoic Acids
FULL PAPER
(R)-(À)-5a to (R)-(À)-6a is 66%). Oil; [a]2D0 =À69.2( c=0.99 in CHCl3);
1H NMR (300 MHz, CDCl3): d=5.32–5.20 (m, 1H), 5.20–5.08 (m, 1H),
2.42 (t, J=6.8 Hz, 2H), 2.35–2.24 (m, 2H), 2.06–1.95 (m, 2H), 1.47–1.16
(m, 8H), 0.87 ppm (t, J=6.3 Hz, 3H); this compound was used in the
next step without further characterization.
1H), 1.99–1.90 (m, 2H), 1.57 (brs, 1H), 1.48–1.24 (m, 4H), 1.00 (d, J=
6.9 Hz, 3H), 0.90 (t, J=7.1 Hz, 3H), 0.08 ppm (s, 9H); this compound
was used in the next step without further characterization.
Synthesis of (S)-(À)-3-methyldeca-4,5-dienenitrile ((S)-(À)-11a): Follow-
ing the procedure for the preparation of (R)-6b, a mixture of (Ra,R)-(À)-
10a (0.7625 g, 3.4 mmol) and anhydrous pyridine (15 mL) was treated
with pTsCl (in two portions: 1.9899+0.9936 g, 15.7 mmol) to afford the
tosylate, which was used in the next step without further purification.
The reaction of the tosylate prepared above and NaCN (0.1701 g,
3.9 mmol) in anhydrous DMSO (10 mL) afforded (Ra,S)-3-methyl-6-tri-
methylsilyldeca-4,5-dienenitrile, which was used in the next step without
further purification. A solution of tetrabutylammonium fluoride in THF
(3.0 mL, 1m) was added to a solution of this nitrile in of anhydrous THF
(10 mL). The mixture was stirred at 308C for 40 min, diluted with ether,
and washed with a saturated aqueous solution of ammonium chloride.
The organic layers were dried over Na2SO4, filtered, and concentrated.
The residue was purified by flash chromatography on silica gel to afford
(S)-(À)-11a[24] (195.1 mg, the combined yield from (Ra,R)-10a to (S)-(À)-
11a is 35%). Oil; [a]2D0 =À9.1 (c=0.51 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=5.32–5.23 (m, 1H), 5.17–5.10 (m, 1H), 2.60–2.49 (m, 1H),
2.41 (dd, J1 =16.5, J2 =6.2Hz, 1H), 2.32 (dd, J1 =16.5, J2 =6.8 Hz, 1H),
2.07–1.98 (m, 2H), 1.44–1.29 (m, 4H), 1.20–1.15 (m, 3H), 0.90 ppm (t,
J=7.2Hz, 3H); this compound was used in the next step without further
characterization.
Synthesis of (R)-(À)-dodeca-4,5-dienoic acid ((R)-(À)-1a): Following the
procedure for the preparation of 1a, the reaction of (R)-(À)-6a (0.7106 g,
4.0 mmol), ethanol (10 mL), and NaOH solution (3.0 g in 4 mL of H2O,
75 mmol) afforded (R)-(À)-1a (0.5703 g, 72%). Oil; [a]2D0 =À71.4 (c=
1.06 in CHCl3); 1H NMR (300 MHz, CDCl3): d=10.45 (brs, 1H;
COOH), 5.21–5.08 (m, 2H), 2.53–2.41 (m, 2H), 2.38–2.22 (m, 2H), 2.01–
1.87 (m, 2H), 1.44–1.16 (m, 8H), 0.88 ppm (t, J=6.8 Hz, 3H).
Preparation of( S)-3-methyldeca-4,5-dienoic acid ((S)-(+)-1l)
Synthesis of (3R,4R)-(À)-3-methyl-4-(trimethylsilyl)ethynyloxetan-2-one
((3R,4R)-(À)-8a):[23a] A solution of N,N-diisopropylethylamine (2.49 g,
20 mmol) and O-trimethylsilylquinine (0.3402g, 0.8 mmol) in anhydrous
CH2Cl2 (25 mL) was added to a suspension of MgCl2 (0.7614 g, 8 mmol)
in anhydrous diethyl ether (12mL). Then a solution of 7[6] (1.0107 g,
8 mmol) in anhydrous CH2Cl2 (5 mL) was added at À808C. After being
stirred at À808C for 40 min, a solution of propionyl chloride (1.5348 g,
17 mmol) in anhydrous CH2Cl2 (5 mL) was then added over 3 h by a sy-
ringe pump at this temperature. The reaction mixture was stirred for
14.5 h at À808C and then quenched by adding a saturated aqueous
NH4Cl solution (25 mL). The resulting mixture was extracted with diethyl
ether (200 mL”3) and the combined organic extracts were washed suc-
cessively with H2O and brine, dried over Na2SO4, filtered, and concen-
trated. The residue was purified by flash chromatography on silica gel
(petroleum ether (30–608C)/ethyl ether 10:1) to afford (3R,4R)-(À)-8a
Synthesis of (S)-(+)-3-methyldeca-4,5-dienoic acid ((S)-(+)-1l): Following
the procedure of 6a, the reaction of (S)-(À)-11a (0.1951 g, 1.2mmol),
ethanol (8 mL), and NaOH solution (2.0 g in 2.6 mL of H2O, 50 mmol)
afforded (S)-(+)-1l (0.1688 g, 77%). Oil; [a]2D0 =+19.0 (c=0.93 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=9.94 (brs, 1H; COOH), 5.23–
5.09 (m, 2H), 2.73–2.60 (m, 1H), 2.55–2.39 (m, 1H), 2.37–2.21 (m, 1H),
2.05–1.90 (m, 2H), 1.46–1.24 (m, 4H), 1.08 (d, J=6.3 Hz, 3H), 0.89 ppm
(t, J=6.9 Hz, 3H).
1
(1.0794 g, 73%). Colorless oil; [a]2D0 =À12.9 (c=1.26 in CHCl3); H NMR
(400 MHz, CDCl3): d=5.12(d, J=6.4 Hz, 1H), 3.92–3.81 (m, 1H), 1.42
(d, J=7.6 Hz, 3H), 0.21 ppm (s, 9H).
Synthesis of (Ra,R)-(À)-2-methyl-5-(trimethylsilyl)nona-3,4-dienoic acid
((Ra,R)-9a): 1,2-Dibromoethane (60 mL, 0.7 mmol) was added to a mix-
ture of magnesium turnings (0.8477 g, 35 mmol) in anhydrous THF
(10 mL) under nitrogen. Upon the initiation of the Grignard reaction, a
solution of nBuBr (2.057 g, 15 mmol) in THF (25 mL) was then added
dropwise over 15 min at RT. After being stirred for 30 min, the resulting
Grignard reagent solution (14 mL, 6.02mmol) was added dropwise to a
mixture of (3R,4R)-(À)-8a (365.2mg, 2.0 mmol), CuCN (18.8 mg,
0.2mmol), and anhydrous lithium bromide (40.5 mg, 0.46 mmol) in anhy-
drous THF (20 mL) at À788C within 20 min. After being stirred at
À788C for additional 20 min, the reaction was quenched with a saturated
aqueous NH4Cl solution (50 mL). The resulting mixture was extracted
with ethyl acetate (200 mL”2) and the combined organic extracts were
successively washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated. The residue was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate 40:1 to 5:1) to afford (Ra,R)-(+)-9a as
a colorless oil (397.6 mg, 83%). Oil; [a]2D0 =+22.3 (c=1.53 in CHCl3);
1H NMR (300 MHz, CDCl3): d=11.30 (brs, 1H), 5.13–4.90 (m, 1H),
3.20–2.97 (m, 1H), 1.96 (td, J1 =7.4, J2 =3.0 Hz, 2H), 1.46–1.27 (m, 4H),
1.24 (d, J=6.9 Hz, 3H), 0.89 (t, J=7.1 Hz, 3H), 0.08 ppm (s, 9H); this
compound was used in the next step without further characterization.
The d.r. value of (S)-1l was determined after its conversion to the corre-
sponding benzyl ester.
Synthesis of benzyl (S)-(+)-3-methyldeca-4,5-dienoate ((S)-(+)-13a): Fol-
lowing the procedure for the benzylation of (Ra,R)-1l, the reaction of
(S)-1l (9.8 mg, 0.05 mmol), BnOH (17.8 mg, 0.16 mmol), DMAP (5.1 mg,
0.04 mmol), and DCC (14.4 mg, 0.07 mmol) in CH2Cl2 (1 mL) afforded
(S)-(+)-13a (12.0 mg, 82%), d.r.=1.2:1; the d.r. value was determined by
HPLC (Chiralcel AS-H column, rate=0.5 mLminÀ1
iPrOH 100:0, l=214 nm, tR
(minor)=27.1, (major)=32.4). [a]2D0 =+12.1
, eluent=hexane/
AHCTREUNG
1
(c=0.475 in CHCl3); H NMR (300 MHz, CDCl3): d=7.42–7.29 (m, 5H),
5.20–5.06 (m, 4H), 2.76–2.63 (m, 1H), 2.50–2.40 (m, 1H), 2.36–2.24 (m,
1H), 2.01–1.89 (m, 2H), 1.41–1.27 (m, 4H), 1.05 (d, J=6.9 Hz, 3H),
0.93–0.84 ppm (m, 3H); IR (neat): n˜ =1961, 1738, 1499, 1455, 1378,
1159 cmÀ1; MS (70 ev, EI): m/z (%): 272 (0.57) [M+], 69 (100); HRMS:
m/z: calcd for C18H24O2Na: 295.1669 [M++Na]; found: 295.1666.
Synthesis of benzyl (R)-(À)-3-methyldeca-4,5-dienoate ((R)-(À)-13a):
Following the procedure for the preparation of (Ra,R)-(À)-13a, the reac-
tion of (R)-(À)-1l (52.8 mg, 0.29 mmol), BnOH (92.5 mg, 0.86 mmol),
DMAP (27.5 mg, 0.23 mmol), and DCC (65.1 mg, 0.32 mmol) in CH2Cl2
(1.8 mL) afforded (R)-(À)-13a (69.9 mg, 89%, d.r.=1.2:1; HPLC (Chir-
alcel OJ-H column, rate=0.7 mLminÀ1, eluent=hexane/iPrOH 99:1, l=
Synthesis
((Ra,R)-(À)-10a): K2CO3 (1.1472g, 8.3 mmol) and MeI (0.42mL,
6.8 mmol) were added sequentially to solution of (Ra,R)-(+)-9a
of
(Ra,R)-(À)-2-methyl-5-(trimethylsilyl)nona-3,4-dien-1-ol
214 nm, tR
A
a
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.40–7.29 (m, 5H), 5.20–5.06
(m, 4H), 2.74–2.61 (m, 1H), 2.52–2.39 (m, 1H), 2.36–2.22 (m, 1H), 2.01–
1.88 (m, 2H), 1.42–1.26 (m, 4H), 1.08–1.02 (m, 3H), 0.92–0.84 ppm (m,
3H); IR (neat): n˜ =1961, 1740, 1498, 1456, 1377, 1261, 1155 cmÀ1; MS
(70 ev, EI): m/z (%): 272 (0.57) [M+], 139 (100); HRMS: m/z: calcd for
C18H24O2Na: 295.1669 [M++Na]; found: 295.1666.
(1.0191 g, 4.2mmol) in DMF (10 mL). The resulting mixture was then
stirred for 105 min at 108C. After being stirred at this temperature, the
mixture was quenched with H2O (5 mL) and extracted with ethyl ether
(50 mL”3). The combined organic layers were washed with H2O, brine,
dried over Na2SO4, and filtered. After evaporation of the solvent, chro-
matography on silica gel afforded (Ra,R)-methyl 2-methyl-5-(trimethylsi-
lyl)nona-3,4-dienoate (0.9813 g, crude yield: 91%). It was used in the
next step without further purification. Following the procedure for the
preparation of (R)-5a, a solution of ester (0.9484 g, 3.7 mmol) in anhy-
drous THF (15 mL) was added to a suspension of LiAlH4 (0.1819 g,
4.8 mmol) in anhydrous THF (20 mL) to afford (Ra,R)-(À)-10a (0.7875 g,
93%). Oil; [a]2D0 =À0.6 (c=0.81 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=4.68 (dt, J1 =6.6, J2 =3.2 Hz, 1H), 3.55–3.37 (m, 2H), 2.40–2.24 (m,
Preparation of( Sa,R)-(+)-3-methyldeca-4,5-dienoic acid ((Sa,R)-(+)-1l):
The two isomers (Sa,R)-(+)-13a and (Ra, R)-(À)-13a were separated by
using
a ,
CHIRALPAK IC column (25 cm”2 cm), rate=9 mLminÀ1
eluent=hexane/ethyl acetate 98:2, l=214 nm, injection=2mL ( C=
1 mgmLÀ1): peak 1, tR =13.7; peak 2, tR =15.0. The two portions collected
were kept over dry ice. After evaporation of the solvent, pure isomers
were obtained.
Chem. Eur. J. 2008, 14, 9656 – 9664
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9661

S. Ma, C. Fu and X. Jiang
1
A
ganic extracts were successively washed with H2O and brine, dried over
Na2SO4, filtered, and then concentrated. The residue was purified by
flash chromatography on silica gel to afford (Ra,S)-2-methylnona-3,4-di-
enoic acid (0.0415 g, 80%). Colorless oil; [a]2D0 =À110.9 (c=1.21 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=9.78 (brs, 1H), 5.35–5.20 (m,
2H), 3.21–3.04 (m, 1H), 2.09–1.90 (m, 2H), 1.44–1.31 (m, 4H), 1.27 (d,
J=7.2Hz, 3H), 0.89 ppm (t, J=7.1 Hz, 3H); it was used in the next step
without further purification. Following the procedure for the preparation
of (R)-(À)-5a, a solution of the dienoic acid prepared above (0.3229 g,
1.9 mmol) in anhydrous ether (3 mL) was added to a suspension of
LiAlH4 (0.1441 g, 3.8 mmol) in anhydrous ether (15 mL) to afford (Ra,S)-
(À)-10a (0.1284 g, 43%). Oil; [a]2D0 =À82.3 (c=0.39 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=5.21–5.11 (m, 1H), 5.10–5.01 (m, 1H), 3.48 (d, J=
6.3 Hz, 2H), 2.39–2.28 (m, 1H), 2.03–1.92 (m, 2H), 1.91 (brs, 1H), 1.43–
1.24 (m, 4H), 0.95 (d, J=6.9 Hz, 3H), 0.88 ppm (t, J=7.1 Hz, 3H); this
compound was used in the next step without further characterization.
G
(minor)=9.930, (Ra,R)-(À)-13a)):
ACHTREUNG
(300 MHz, CDCl3): d=7.42–7.28 (m, 5H), 5.20–5.06 (m, 4H), 2.76–2.63
(m, 1H), 2.46 (dd, J1 =15.3, J2 =6.9 Hz, 1H), 2.29 (dd, J1 =15.2, J2 =
7.7 Hz, 1H), 2.01–1.89 (m, 2H), 1.41–1.27 (m, 4H), 1.05 (d, J=6.9 Hz,
3H), 0.88 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=202.4,
172.5, 136.0, 128.5, 128.2, 128.16, 95.7, 93.3, 66.1, 41.3, 31.3, 30.0, 28.6,
22.2, 20.3, 13.9 ppm; IR (neat): n˜ =1961, 1737, 1498, 1456, 1379, 1351,
1263, 1161 cmÀ1; MS (70 ev, EI): m/z (%): 272 (0.54) [M+], 141 (100);
HRMS: m/z: calcd for C18H24O2: 272.1776 [M+]; found: 272.1775; HPLC
Synthesis of (Ra,R)-(À)-3-methyldeca-4,5-dienoic acid ((Ra,R)-(À)-1l):
Following the procedure for the preparation of (R)-(À)-6a, a mixture of
(Ra,S)-(À)-10a (0.1284 g, 0.8 mmol) and anhydrous pyridine (1 mL) was
treated with pTsCl (0.4785 g, 2.5 mmol) to afford the tosylate, which was
used in the next step without further purification. The reaction of the to-
sylate prepared above and NaCN (0.0482g, 0.96 mmol) in anhydrous
DMSO (2mL) afforded ( Ra,S)-3-methyldeca-4,5-dienenitrile, which was
used in the next step without further purification. Following the proce-
dure for the preparation of 6a, the reaction of (Ra,S)-3-methyldeca-4,5-
dienenitrile (0.0814 g, 0.5 mmol), ethanol (2mL), and NaOH solution
(0.4 g in 0.6 mL of H2O, 10 mmol) afforded (Ra, R)-(À)-1l (0.0660 g, the
combined yield from (Ra,S)-(À)-10a to (Ra,R)-(À)-1l is 43%). Oil;
[a]2D0 =À74.9 (c=1.34 in CHCl3); 1H NMR (300 MHz, CDCl3): d=10.65
(brs, 1H; COOH), 5.21–5.09 (m, 2H), 2.73–2.60 (m, 1H), 2.44 (dd, J1 =
15.6, J2 =7.0 Hz, 1H), 2.23 (dd, J1 =15.6, J2 =7.3 Hz, 1H), 2.05–1.90 (m,
2H), 1.46–1.24 (m, 4H), 1.08 (d, J=6.6 Hz, 3H), 0.89 ppm (t, J=7.2Hz,
3H); 13C NMR (75 MHz, CDCl3): d=202.4, 179.3, 95.5, 93.4, 41.2, 31.3,
29.8, 28.6, 22.2, 20.3, 13.9 ppm; IR (neat): n˜ =1962, 1710, 1458, 1410,
1378, 1294 cmÀ1; MS (70 ev, EI): m/z (%): 182(1.90) [M +], 140 (100);
HRMS: m/z: calcd for C11H18O2: 182.1307 [M+]; found: 182.1307.
(Chiralcel OJ-H column, rate=0.7 mLminÀ1
99:1, l=214 nm, tR(minor)=9.377 ((Sa,R)-(+)-13a), tR
((Ra,R)-(À)-13a)): peak 2: d.r. >98:2.
,
eluent=hexane/iPrOH
(major)=9.930
A
ACHTREUNG
The absolute configuration of the isomer related to peak 2was deter-
mined as (Ra,R) by comparison with the specific optical rotation of
(Ra,R)-(À)-13a prepared on p. S47 in the Supporting Information. The
absolute configuration of the isomer related to peak 1 was then assigned
as Sa,R.
Synthesis of (Sa,R)-(+)-3-methyldeca-4,5-dienoic acid ((Sa,R)-(+)-1l):
LiOH·H2O (8 mg, 0.18 mmol) was added to a solution of (Sa,R)-(+)-13a
(16 mg, 0.06 mmol) prepared above in H2O (0.3 mL) and MeOH
(0.6 mL). After being stirred for 12h at 30 8C, the reaction was complete
as detected by TLC analysis (eluent=petroleum ether/ethyl acetate 5:1).
The mixture was then adjusted with 5% HCl (aq.) to pH 1 and extracted
with ether (30 mL”3). The ether layer was subsequently washed with
water and brine, dried over Na2SO4, filtered, and then concentrated
under vacuum. Chromatography on silica gel (petroleum ether/ethyl ace-
tate 20:1) of the crude product afforded (Sa,R)-(+)-1l (7.1 mg, 66%).
Oil; [a]2D0 =+45 (c=1.00 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
5.21–5.09 (m, 2H), 2.73–2.58 (m, 1H), 2.45 (dd, J1 =15.6, J2 =6.9 Hz,
1H), 2.29 (dd, J1 =15.6, J2 =7.2 Hz, 1H), 2.05–1.90 (m, 2H), 1.46–1.24
(m, 4H), 1.08 (d, J=6.9 Hz, 3H), 0.89 ppm (t, J=7.1 Hz, 3H), the acidic
proton is missing here in this spectrum; 13C NMR (75 MHz, CDCl3): d=
202.4, 178.7, 95.6, 93.5, 41.0, 31.3, 29.7, 28.6, 22.2, 20.2, 13.9 ppm; IR
(neat): n˜ =1962, 1710, 1458, 1410, 1378, 1293 cmÀ1; MS (70 ev, EI): m/z
Synthesis of benzyl (Ra,R)-(À)-3-methyldeca-4,5-dienoate ((Ra,R)-(À)-
13a): BnOH (16.9 mg, 0.165 mmol) and DMAP (5.4 mg, 0.044 mmol)
were added sequentially to
a
solution of (Ra,R)-(À)-1l (8.9 mg,
0.055 mmol) in CH2Cl2 (1 mL). Then DCC (13.6 mg, 0.06 mmol) was
added at 08C. After being stirred for 23.5 h at RT, the reaction was over
as determined by TLC analysis and the resulting mixture was diluted
with ether (10 mL) and transferred to a round-bottomed flask and evapo-
rated. The residue was purified by chromatography on silica gel to afford
(Ra,R)-(À)-13a (13.3 mg, 100%, d.r.=96/4; HPLC (Chiralcel OJ-H
column, rate=0.5 mLminÀ1, eluent=hexane/iPrOH 99:1, l=214 nm, tR-
(%): 182(3.54)
[
M+], 81 (100); HRMS: m/z: calcd for C11H18O2:
A
182.1307 [M+]; found: 182.1308.
1H NMR (300 MHz, CDCl3): d=7.42–7.29 (m, 5H), 5.20–5.06 (m, 4H),
2.76–2.62 (m, 1H), 2.47 (dd, J1 =15.4, J2 =6.9 Hz, 1H), 2.30 (dd, J1 =15.4,
J2 =7.7 Hz, 1H), 2.02–1.89 (m, 2H), 1.40–1.29 (m, 4H), 1.06 (d, J=
6.9 Hz, 3H), 0.89 ppm (t, J=7.2Hz, 3H).
Preparation of( Ra,R)-(À)-3-methyldeca-4,5-dienoic acid ((Ra,R)-(À)-1l)
Synthesis of (3S,4S)-(À)-3-methyl-4-ethynyloxetan-2-one ((3S,4S)-(À)-
12a):[25] A solution of tetrabutylammonium fluoride in THF (14.0 mL,
Typical procedure for the preparation of 4,5-dihydro-2(3H)-furanones
((Z)-2a–m)
1m, 14 mmol) was added to
a solution of (3S,4S)-(+)-8a (2.3543 g,
13 mmol) in 20 mL of anhydrous THF. The mixture was stirred at 08C
for 25 min, and then the resulting mixture was filtered through a 1.5 cm
plug of silica gel, eluting with CH2Cl2. The filtrate was concentrated and
purified by flash chromatography on silica gel (petroleum ether (30–
5-(1’-Iodo-1’(Z)-octenyl)-4,5-dihydro-2(3H)-furanone
(Z-2a):
I2
(114.3 mg, 0.45 mmol, solid) was added to a solution of 1a (59.3 mg,
0.3 mmol) in cyclohexane (4 mL) with stirring at RT. After the reaction
was complete as determined by TLC (eluent: petroleum ether/ethyl ace-
tate 5:1), it was quenched with H2O (6 mL), which was followed by the
addition of sat. aqueous Na2S2O3 (4 mL). The resulting mixture was ex-
tracted with ether (20 mL”3), washed with brine, dried over Na2SO4,
and filtered. After evaporation of the solvent, the Z/E ratio of the prod-
ucts was determined to be 98:2by 400 MHz 1H NMR spectroscopic anal-
ysis. Chromatography on silica gel (petroleum ether/ethyl acetate 5:1) of
the crude product afforded (Z)-2a (81 mg, 83%, Z/E 98:2). Oil;
1H NMR (400 MHz, CDCl3): d=6.02(td, J1 =6.6, J2 =1 Hz, 1H), 4.76 (t,
J=7.0 Hz, 1H), 2.70–2.58 (m, 1H), 2.58–2.45 (m, 1H), 2.45–2.33 (m,
1H), 2.21–2.08 (m, 3H), 1.45–1.34 (m, 2H), 1.34–1.16 (m, 6H), 0.86 ppm
(t, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=176.4, 138.5, 106.9,
608C)/ether 5:1) to afford (3S,4S)-(À)-12a (0.7234 g, 51%). Oil; [a]D20
=
À5.4 (c=0.70 in CHCl3); 1H NMR (300 MHz, CDCl3): d=5.13 (dd, J1 =
6.6, J2 =2.1 Hz, 1H), 3.95–3.85 (m, 1H), 2.84 (d, J=2.1 Hz, 1H),
2.44 ppm (d, J=7.8 Hz, 3H).
Synthesis of (Ra,S)-(À)-2-methylnona-3,4-dien-1-ol ((Ra,S)-(À)-10a):
(3S,4S)-(À)-12a (34.1 g, 0.3 mmol) was added to a solution of CuBr·SMe2
(6.8 mg, 0.03 mmol) and dimethylsulfide (0.2mL) in anhydrous THF
(3.5 mL). Then the Grignard reagent solution (0.65 mL, 1m in THF,
0.65 mmol) was added dropwise to the mixture at À788C within 5 min.
After being stirred at À788C for additional 20 min, the reaction was
quenched with a saturated aqueous NH4Cl solution (10 mL). The result-
ing mixture was extracted with ether (30 mL”3) and the combined or-
9662
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Chem. Eur. J. 2008, 14, 9656 – 9664

Stereoselective Iodolactonization of 4,5-Allenoic Acids
FULL PAPER
84.3, 35.5, 31.5, 28.8, 28.6, 28.0, 27.9, 22.5, 14.0 ppm; IR (neat): n˜ =2955,
2926, 2855, 1785, 1640, 1457, 1316, 1180, 1024 cmÀ1; MS (70 ev, EI): m/z
(%): 322 (30.18) [M+], 111 (100); elemental analysis calcd (%) for
C12H19IO2: C 44.74, H 5.94; found: C 44.74, H 6.01.
Acknowledgements
Financial support from the National Natural Science Foundation of
China (no. 20572093) and the Zhejiang Provincial Natural Science Foun-
dation of China (Y 404262) is greatly appreciated. S. Ma is a Qiu Shi ad-
junct professor at Zhejiang University. We thank Mr. Y. Deng for repro-
ducing the results presented in entry 2of Table 2, entry 5 of Table 3, and
the formation of (4S,5S)-(Z)-2m from (S)-1m in Scheme 6.
Typical procedure for the iodocyclization of 1 f–h in the presence of I2
and K2CO3
5-Butyl-5-(1’-iodo-1’-vinyl)-4,5-dihydro-2(3H)-furanone
(2 f):
K2CO3
(43.7 mg, 0.3 mmol) was added to a solution of 1 f (50.5 mg, 0.3 mmol) in
cyclohexane (4 mL). After stirring for 20 min, I2 (116.0 mg, 0.45 mmol,
solid) was added, and the mixture was stirred for a further 1 h. The re-
sulting mixture was quenched sequentially with H2O (6 mL) and sat.
aqueous Na2S2O3 (4 mL), extracted with ether (25 mL”3), washed with
brine, dried over Na2SO4, and then filtered. After evaporation of the sol-
vent, the residue was purified by flash chromatography on silica gel (pe-
troleum ether/ethyl acetate 5:1) to afford 2 f (76.9 mg, 87%). Oil;
1H NMR (400 MHz, CDCl3): d=6.43 (d, J=2.2 Hz, 1H), 5.91 (d, J=
2.2 Hz, 1H), 2.55–2.43 (m, 3H), 2.14–2.01 (m, 2H), 1.73–1.64 (m, 1H),
1.42–1.20 (m, 4H), 0.90 ppm (t, J=7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=176.1, 126.9, 111.4, 90.2, 38.6, 33.2, 28.1, 25.5, 22.5, 13.8 ppm;
[1] a) M. S. Maier, D. I. G. Marimon, C. A. Stortz, M. T. Adler, J. Nat.
Prod. 1999, 62, 1565; b) S.-C. Lee, G. D. Brown, J. Nat. Prod. 1998,
61, 29; c) J. D. Connolly, R. A. Hill, Dictionary of Terpenoids, Vol. 1,
Chapman and Hall, London, 1991, p. 476.
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Ponte, P. S. Bonatto, Tetrahedron: Asymmetry 2003, 14, 3253.
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L. X. Gao, W. P. Mai, A. X. Xia, F. Wang, S. B. Zhang, J. Org. Chem.
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Kaptein, R. D. Zorzi, L. Randaccio, P. Scrimin, G. Licini, Org. Lett.
2007, 9, 2365.
IR (neat): n˜ =2956, 2930, 2871, 1784, 1611, 1456, 1183, 1090, 1024 cmÀ1
;
MS (70 ev, EI): m/z (%): 294 (0.36) [M+], 237 (100) [M+ÀC4H9];
HRMS: m/z: calcd for C10H15IO2: 294.0111 [M+]; found: 294.0130.
[4] D. G. Hulcoop, J. W. Burton, Chem. Commun. 2005, 4687.
[5] E. Genin, P. Y. Toullec, S. Antoniotti, C. Brancour, J.-P. GenÞt. , V.
Michelet, J. Am. Chem. Soc. 2006, 128, 3112.
Typical procedure for the preparation of optically active 5-(1’-iodo-1’-al-
kenyl)-4,5-dihydro-2(3H)-furanones (R)-2a and (R)-2b
[6] Z. Huo, N. T. Patil, T. Jin, N. K. Pahadi, Y. Yamamoto, Adv. Synth.
Catal. 2007, 349, 680.
[7] I. Takei, Y. Wakebe, K. Suzuki, Y. Enta, T. Suzuki, Y. Mizobe, M.
Hidai, Organometallics 2003, 22, 4639.
[8] C. Jonasson, A. Horvµth, J.-E. Bäckvall, J. Am. Chem. Soc. 2000,
122, 9600.
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496.
[10] B. M. Trost, A. McClory, Org. Lett. 2006, 8, 3627.
[11] G. Liu, X. Lu, Tetrahedron Lett. 2003, 44, 127.
[12] A. J. Pearson, E. F. Mesaros, Org. Lett. 2001, 3, 2665.
[13] V. Nair, S. Vellalath, M. Poonoth, R. Mohan, E. Suresh, Org. Lett.
2006, 8, 507.
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14370; b) C. Burstein, F. Glorius, Angew. Chem. 2004, 116, 6331;
Angew. Chem. Int. Ed. 2004, 43, 6205; c) W. Ye, G. Cai, Z. Zhuang,
X. Jia, H. Zhai, Org. Lett. 2005, 7, 3769.
[15] a) S. K. Mandal, S. R. Amin, W. E. Crowe, J. Am. Chem. Soc. 2001,
123, 6457; b) W. E. Crowe, A. T. Vu, J. Am. Chem. Soc. 1996, 118,
1557.
Optically active 5-(1’-iodo-1’-octenyl)-4,5-dihydro-2(3H)-furanone (mix-
ture of( S)-(Z)-2a and (R)-(E)-2a): Cs2CO3 (667.8 mg, 2mmol) was
added to a solution of (R)-(À)-1a (396.0 mg, 2mmol) in CH 2Cl2 (24 mL)
with stirring at RT. NIS (677.2mg, 3 mmol) was then added to the mix-
ture at À608C. After 10 h, another 0.5 equivalents of NIS (0.2251 g,
1 mmol) was added at À608C. After the reaction was complete, as deter-
mined by TLC (eluent=petroleum ether/ethyl acetate 5:1), the resulting
mixture was warmed up to RT and quenched sequentially with H2O
(10 mL) and a sat. aqueous solution of Na2S2O3 (6 mL). The mixture was
then extracted with ether (25 mL”3), washed with brine, and then dried
over Na2SO4. After filtration, evaporation of the solvent and chromatog-
raphy on silica gel (petroleum ether/ethyl acetate/CH2Cl2 6:1:1) afforded
2a (575.8 mg, 89%, (S)-(Z)-2a/(R)-(E)-2a 85:15, (S)-(Z)-2a: 99% ee;
HPLC (Chiralcel OJ-H column, rate=0.5 mLminÀ1
iPrOH 90:10, l=254 nm, tR(minor)=14.8, (major)=15.8)). Oil; H NMR
, eluent=hexane/
1
AHCTREUNG
(400 MHz, CDCl3): d=6.44 (t, J=7.6 Hz, 0.15H), 6.04 (td, J1 =7.0, J2 =
0.9 Hz, 0.85H), 4.89 (t, J=7.0 Hz, 0.15H), 4.79 (t, J=7.0 Hz, 0.85H),
2.78–2.61 (m, 1H), 2.61–2.48 (m, 1H), 2.48–2.33 (m, 1H), 2.25–2.08 (m,
3H), 1.48–1.36 (m, 2H), 1.36–1.20 (m, 6H), 0.88 ppm (t, J=6.8 Hz, 3H);
this Z/E mixture was submitted to the kinetic resolution without further
characterization.
[16] For our recent results on the halolactonization of allenoic acid see:
a) C. Fu, S. Ma, Eur. J. Org. Chem. 2005, 3942; b) S. Ma, S. Wu,
Chem. Commun. 2001, 441; c) S. Ma, S. Wu, Tetrahedron Lett. 2001,
42, 4075; d) S. Ma, Z. Shi, Z. Yu, Tetrahedron Lett. 1999, 40, 2393;
e) S. Ma, Z. Shi, Z. Yu, Tetrahedron 1999, 55, 12137; f) S. Ma, S. Wu,
J. Org. Chem. 1999, 64, 9314; g) S. Ma, Z. Shi, J. Org. Chem. 1998,
63, 6387.
Typical procedure for the kinetic resolution of (R)-(Z)- and (S)-(E)-iso-
mers ofoptically active products 2a and 2b
(S)-(+)-5-(1’-Iodo-1’(Z)-octenyl)-4,5-dihydro-2(3H)-furanone
(Z)-2a): solution of Et2NH (8.3 mg, 0.11 mmol), prop-2-yn-1-ol
(5.4 mg, 0.096 mmol), and mixture of (S)-(Z)-2a and (R)-(E)-2a
(95.8 mg, 0.3 mmol) in CH3CN (1 mL) were added to a mixture of CuI
(2.1 mg, 0.011 mmol, 3.5 mol%) and [PdCl2(PPh3)2] (7.4 mg, 0.011 mmol,
((S)-(+)-
A
a
[17] Crystal data for compound 2g: C11H15IO2; MW =306.13; monoclinic;
AHCTREUNG
space group=P2(1)/c; final
R indices=[I>2s(I)], R1 =0.0576,
3.5 mol%). The mixture was stirred at 38C with an ice/water bath for 1 h
under nitrogen. After the reaction was complete, as determined by GC
analysis, the resulting mixture was quenched with H2O (10 mL), diluted
with ether (10 mL), separated, extracted with ether (3”30 mL), washed
with brine, and then dried over Na2SO4. Filtration, evaporation, and pu-
rification by chromatography on silica gel (petroleum ether/ethyl acetate
6:1) afforded (S)-(+)-(Z)-2a (70.9 mg, 74%, Z/E 98:2, 99% ee; HPLC
wR2 =0.1303; a=28.562(16), b=5.262(3), c=7.779(4) Š; a=90, b=
90, g=90o; V=1169.1.0(11) Š3; Z=4; 1calcd =1.739 gcmÀ3; reflec-
tions collected/unique: 6317/2274 (Rint =0.1153); parameters: 131.
CCDC-663501 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(Chiralcel OJ-H column, rate=0.5 mLminÀ1
, eluent=hexane/iPrOH
[18] D. Xu, Z. Li, S. Ma, Tetrahedron Lett. 2003, 44, 6343.
[19] For the synthesis of optically active g-allenoic acid from optically
active propargylic alcohol, see: a) K. Mori, T. Nukada, T. Ebata, Tet-
rahedron 1981, 37, 1343; b) R. A. Brawn, J. S. panek, Org. Lett.
2007, 9, 2689.
90:10, l=254 nm, tR
(minor)=17.2, (major)=18.3)). [a]2D0 =+16.4 (c=
A
0.95 in CHCl3); the 1H NMR spectroscopic data are the same as those
for racemic (Z)-2a.
[20] For kinetic resolution by using Sonogashira coupling, see: a) S. Ma,
Z. Ma, Synlett 2006, 8, 1263; b) B. P. AÇdreini, A. Carpita, R. Rossi,
Tetrahedron Lett. 1986, 27, 5533; for recent reviews of Sonogashira
reactions, see: c) R. Chinchilla, C. Nµjera, Chem. Rev. 2007, 107,
Chem. Eur. J. 2008, 14, 9656 – 9664
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9663

S. Ma, C. Fu and X. Jiang
874; d) H. Doucet, J.-C. Hierso, Angew. Chem. 2007, 119, 850;
Angew. Chem. Int. Ed. 2007, 46, 834; for a seminal paper on the So-
nogashira reaction, see: K. Sonogashira, Y. Tohda, N. Hagihara, Tet-
rahedron Lett. 1975, 16, 4467.
[24] When we removed the TMS group by treatment with TBAF in
THF, this desilylation led to serious loss of axial chirality. For a simi-
lar example, see: C. Rameshkumar, R. P. Hsung, Angew. Chem.
2004, 116, 62 5;Angew. Chem. Int. Ed. 2004, 43, 615.
[25] Z. Wan, S. G. Nelson, J. Am. Chem. Soc. 2000, 122, 10470.
[26] S. Arseniyadis, J. Gore, M. L. Roumestant, Tetrahedron 1979, 35,
353.
[21] J. N. Shooiery, Prog. NMR Spectrosc. 1977, 11, 79.
[22] N. J. Harris, J. J. Gajewski, J. Am. Chem. Soc. 1994, 116, 6121.
[23] a) C. Zhu, X. Shen, S. G. Nelson, J. Am. Chem. Soc. 2004, 126, 5352;
b) Z. Liu, A. S. Wasmuth, S. G. Nelson, J. Am. Chem. Soc. 2006, 128,
10352.
Received: July 5, 2008
Published online: September 9, 2008
9664
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Chem. Eur. J. 2008, 14, 9656 – 9664