Nucleophilic phosphine-catalyzed iodocyclization of isoprenoids bearing an oxygen terminal group

Article abstract of DOI:10.3987/COM-09-S(E)1

The nucleophilic phosphine-catalyzed diastereoselective iodocyclization of linear isoprenoids bearing an oxygen terminal group was investigated. TBDMS ether of homogeraniol and TBDMS ester of homogeranic acid were successfully converted to the correspondi

Full text of DOI:10.3987/COM-09-S(E)1

HETEROCYCLES, Vol. 82, No. 1, 2010
249
HETEROCYCLES, Vol. 82, No. 1, 2010, pp. 249 - 255. © The Japan Institute of Heterocyclic Chemistry
Received, 29th November, 2009, Accepted, 22nd January, 2010, Published online, 25th January, 2010
DOI: 10.3987/COM-09-S(E)1
NUCLEOPHILIC PHOSPHINE–CATALYZED IODOCYCLIZATION OF
ISOPRENOIDS BEARING AN OXYGEN TERMINAL GROUP
Akira Sakakura,a) Gakujun Shomi,b) Atsushi Ukai,b) and Kazuaki
Ishihara*,b),c)
a) EcoTopia Science Institute, Nagoya University, Chikusa, Nagoya, 464-8603
Japan
b) Graduate School of Engineering, Nagoya University, Chikusa, Nagoya,
464-8603 Japan; e-mail: ishihara@cc.nagoya-u.ac.jp
c) JST, CREST, Chikusa, Nagoya, 464-8603 Japan
Abstract
–
The nucleophilic phosphine-catalyzed diastereoselective
iodocyclization of linear isoprenoids bearing an oxygen terminal group was
investigated. TBDMS ether of homogeraniol and TBDMS ester of homogeranic
acid were successfully converted to the corresponding iodopolycyclic products in
the presence of a catalytic amount of triphenylphosphine with complete
diastereoselectivity.
Diastereoselective halocyclizations induced by the electrophilic addition of a halonium ion to an
unactivated alkene are powerful tools in organic synthesis.1,2 Since these halocyclizations are still
conducted under harsh reaction conditions with more than stoichiometric amounts of reagents, the
development of effective catalysts that can promote halocyclizations under mild conditions is in high
demand. In this context, we recently developed a catalytic diastereoselective iodocyclization of
isoprenoids bearing an aryl terminal group.3 Catalytic amounts of nucleophilic phosphorous(III)
compounds activate N-iodosuccinimide (NIS) and react with the terminal carbon-carbon double bond of
4-homogeranyltoluene (1), which induces diastereoselective cyclization to give 2 in excellent yield
(Scheme 1).4 Highly nucleophilic phosphorous(III) compounds such as tributylphosphine (PBu3) show
good catalytic activities in CH2Cl2. During the course of our study, we found that the reactivity of
nucleophilic phosphine-catalyzed iodocyclization significantly depended on the structure and
nucleophilicity of the terminal functional group. We report here the nucleophilic phosphine-catalyzed
iodocyclization of isoprenoids bearing an oxygen terminal group.

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HETEROCYCLES, Vol. 82, No. 1, 2010
O
P(III) compound
(30 mol%)
ClSO3H
+
I N
i-PrNO2
–78 °C, 4 h
PBu3: 99% yield
PPh3: 67% yield
P(OPh)3: 51% yield
CH2Cl2, –78 °C, 24 h
then –40 °C, 6 h
I
H
O
(1.1 equiv)
1
2
Scheme 1. Nucleophilic phosphine-catalyzed iodocyclization of an isoprenoid (previous work)
O
I
N
O
O
O
R3P
I
O
R3P
I
N
O
+
TBDMS N
Ph
O
4a
O
O
O
N
O
O
+
+
!
!
OTBDMS
TBDMS
R3P
I
O
Ph
3a
Ph
5a
Scheme 2. Proposed catalytic cycle for the nucleophilic phosphine-catalyzed iodolactonization of 3a
We chose 4-substituted 4-pentenoic acids 3 as model substrates for iodolactonization.5 As a terminal
group, tert-butyldimethylsilyl (TBDMS) ester would be suitable. As shown in Scheme 2, the TBDMS
ester group of 3a would react with the iodonium ion moiety of 5a, and the TBDMS group would be
spontaneously trapped by the succinimide anion to give iodolactone 4a. According to our working
hypothesis, we first examined the catalytic activity of PPh3 toward the 5-exo-trig iodolactonization of 3a
(Table 1). The reaction was conducted with 1.2 equiv. of NIS in toluene at –40 °C. The catalytic
activity highly depended on the amount of triphenylphosphine (PPh3). Very interestingly, the best result
(54% yield) was obtained when 30 mol% of PPh3 was used (entry 4). The use of larger amounts
(40–100 mol%) of PPh3 decreased the yield of 4a (entries 5–7). Interestingly, the catalytic activities of
highly nucleophilic PBu3 and tri(cyclohexyl)phosphine [P(c-C6H11)3] were quite low (entries 8 and 9) in
contrast to the iodocyclization of 4-homogeranyltoluene (Scheme 1). Triphenyl phosphite [P(OPh)3]
showed a slightly higher activity than PPh3 (entry 10).
Based on our preliminary work, it is conceivable that the reactivity of 3 depends on the terminal
functional group. The reactivity of tert-butyl ester 3b was slightly lower than that of TBDMS ester 3a.

HETEROCYCLES, Vol. 82, No. 1, 2010
251
The reaction of 3b proceeded at –20 °C and gave 4b in 49% yield (entry 11). We next examined the
catalytic iodolactonization of TBDMS ester of 4-substituted 4-pentenoic acids 3c–3f. The reaction was
conducted with NIS (1.2 equiv) in the presence of PPh3 (30 mol%) in toluene. Compound 3c (R = H),
which has a monosubstituted carbon–carbon double bond, showed low reactivity and gave 4b in 34%
yield, even though the reaction was conducted at 0 °C (entry 12). In contrast, compounds 3d–3f, which
have 1,1-disubstituted carbon–carbon double bonds, were successfully converted to 4d–4f at –40 °C
(entries 13–15). In particular, compound 3d bearing a less bulky methyl group at the 4-position showed
good reactivity (entry 13). The high nucleophilicity of the carbon–carbon double bond in 3 would be
important for obtaining 4 in high yield.
Table 1. Catalytic Activities of Nucleophilic Phosphorous Compounds Toward the Iodolactonization of 3
O
O
P(III) compound
I
O
O
+
I
N
OPG
R
toluene, –40 °C, 24 h
R
O
(1.2 equiv)
3
4
Entry
1
2
3
4
5
6
7
8
Substrate 3 (R, PG)
3a (Ph, TBDMS)
3a (Ph, TBDMS)
3a (Ph, TBDMS)
3a (Ph, TBDMS)
3a (Ph, TBDMS)
3a (Ph, TBDMS)
3a (Ph, TBDMS)
3a (Ph, TBDMS)
3a (Ph, TBDMS)
3a (Ph, TBDMS)
3b (Ph, t-Bu)
P(III) Compound [mol%]
—
PPh3 [10]
PPh3 [24]
PPh3 [30]
Yield (%) of 4
0
3
33
54
14
6
0
6
3
65
49
34
71
33
59
PPh3 [40]
PPh3 [60]
PPh3 [100]
PBu3 [30]
P(c-C6H11)3 [30]
P(OPh)3 [30]
PPh3 [30]
9
10
11a
12b
13
14
15
3c (H, TBDMS)
3d (Me, TBDMS)
3e (Bn, TBDMS)
3f (c-C6H11, TBDMS)
PPh3 [30]
PPh3 [30]
PPh3 [30]
PPh3 [30]
a The reaction was conducted at –20 °C. b The reaction was conducted at 0 °C.
Although it is unclear why the use of large amounts of PPh3 decreased their activity, we can propose the
explanation in Scheme 3. When the reaction was conducted in the presence of 40–100 mol% of PPh3,
PPh3 might attack the iodonium ion moiety of 5a to give phosphonium ion intermediate 6a, which would
be converted back to 3a by aqueous workup (path a).6,7 Alternatively, the equilibrium between 3a and
5a might strongly favor the regeneration of 3a in the presence of large amounts of PPh3 (path c). In
contrast, the intramolecular cyclization of 5a successfully proceeded in the presence of 30 mol% of PPh3

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HETEROCYCLES, Vol. 82, No. 1, 2010
(path b), as shown in Scheme 2. The finding that highly nucleophilic phosphorous compounds showed
low catalytic activities might also be explained by this mechanism.
O
Ph3P
path a
path b
N
O
O
path c
O
PPh3
TBDMS
O
3a +
3a +
Ph3P I N
O
I
N
I
path c
Ph
5a
O
O
path b
path a
aqueous
workup
O
4
PPh3
Ph
Ph3P=O + HI + 3a
I
OTBDMS
6a
Scheme 3
Many halogenated polycyclic terpenoids possessing a cyclic ether structure have been isolated from
various marine organisms.8 For example, the cytotoxic substance aplysistatin was isolated from the
South Pacific Ocean sea hare Aplysia angasi.9 Luzonenone and luzofuran were isolated from the red
alga Laurencia luzonensis.10 The biosynthesis of these natural products appears to include the halonium
ion-induced polycyclization of linear isoprenoids bearing terminal oxygen groups.11 Catalytic
diastereoselective iodocyclization is one of the most promising methods for the chemical synthesis of
these polycyclic natural compounds, since polycyclic iodoterpenoids can be converted to other
halogenated derivatives by stereospecific transhalogenation.3 Therefore, we next examined the
nucleophilic phosphine-catalyzed iodocyclization of 9 and 10 (Scheme 4).
iodocyclization
O
X
halogen-containing
polycyclic natural terpenoids
X
OPG
I
H
7 (X = H,H)
8 (X = O)
9 (X = H,H)
10 (X = O)
Scheme 4
First, the catalytic iodoetherification of O-protected homogeraniol 9 was examined (Table 2). The
reaction was conducted with NIS in the presence of PPh3 (30 mol%) in CH2Cl2.12 When the reaction of
TBDMS ether 9a was conducted with 1.2 equiv. of NIS, the desired trans-fused dicyclic product 7 was

HETEROCYCLES, Vol. 82, No. 1, 2010
253
obtained in 35% yield as a single diastereomer (entry 1). To improve the yield of 7, the reaction was
conducted with 2.0 equiv. of NIS. As a result, 7 was successfully obtained in 68% yield along with a
small amount of monocyclic product 11a (15%) (entry 2). The reaction of p-methoxyphenyl (PMP)
ether 9b also proceeded to give monocyclic product 11b, which was easily converted to 7 (52%, 3 steps
from 9b) by oxidative deprotection of the PMP group [Ce(NH4)2(NO3)6] followed by Brønsted
acid-promoted cyclization (SnCl4, ClSO3H) (entry 3). The iodolactonization of homogeranic acid esters
10 was also catalyzed by triphenylphosphine to give the corresponding iodocyclic product 8 as a single
diastereomer. As in the case of 3, TBDMS ester 10a was more reactive than tert-butyl ester 10c and
gave 8 in 47% yield along with monocyclic product 12a (11%) (entries 4 and 5).
Table 2. Triphenylphosphine-Catalyzed Iodocyclization of Homogeraniol Derivatives 9 and Homogeranic
Acid Derivatives 10
O
X
O
PPh3 (30 mol%)
X
X
+
+
I
N
OPG
CH2Cl2
–40 °C, 24 h
I
OPG
I
H
H
O
9 (X = H, H)
10 (X = O)
11 (X = H, H)
12 (X = O)
7 (X = H, H)
8 (X = O)
(2 equiv)
Entry
Substrate (PG)
9a (TBDMS)
9a (TBDMS)
9b (PMP)
10a (TBDMS)
10c (t-Bu)
Yield (%)
11, 3
11, 15
11, —
12, 11
12, 17
1a
2
7, 35
7, 68
3
4
5
7, 52b
8, 47
8, 22
a
b
The reaction was conducted with NIS (1.2 equiv.).
deprotection and Brønsted acid-promoted cyclization.
The yield of 7 was evaluated after oxidative
In conclusion, we investigated nucleophilic phosphine-catalyzed diastereoselective iodocyclization with
oxygen terminal groups.13 For the 5-exo-trig iodolactonization of TBDMS esters of 4-substituted
4-pentenoic acids 3, 30 mol% of triphenylphosphine showed moderate catalytic activity under mild
reaction conditions (toluene, –40 °C). TBDMS ether of homogeraniol and TBDMS ester of
homogeranic acid were successfully converted to the corresponding iodopolycyclic products in the
presence of a catalytic amount of triphenylphosphine with complete diastereoselectivity.
ACKNOWLEDGEMENTS
Financial support for this project was provided by MEXT.KAKENHI (20245022), the Toray Science
Foundation, the Global COE Program of MEXT, and JSPS Research Fellowships for Young Scientists
(A.U.).

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6. Compound 3a might be regenerated from 6a through the nucleophilic attack on the iodine atom by
OH–, S2O32– or something else.
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small amount (ca. 10%) of phosphonium salt I–PPh3+. The intermediate 6a might be too moisture
sensitive to be detected by NMR analysis.
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12. General procedure for the iodocyclization of homogeraniol derivatives 9 and homogeranic acid
derivative 10: To a solution of triphenylphosphine (30 mol%) and 9 or 10 (0.10 mmol) in CH2Cl2
(1 mL) was added NIS (2.0 equiv.) at –78 °C, and the mixture was stirred at –78 °C for 0.5 h and
then at –40 °C for 24 h. The reaction mixture was quenched with Na2S2O3 (3 mL) and extracted
with EtOAc (5 mL ! 3). The combined organic layer was dried over Mg2SO4, filtered and
concentrated in vacuo. The crude product was purified by column chromatography on silica gel

HETEROCYCLES, Vol. 82, No. 1, 2010
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with a 30:1 mixture of hexane–EtOAc. 7: oil; IR (neat) 2872, 1455, 1376, 1140, 1064, 1008 cm–1;
1H NMR (300 MHz, CDCl3) ! 0.97 (s, 3H), 1.04 (s, 3H), 1.13 (s, 3H), 1.42–1.62 (m, 2H), 1.73 (m,
1H), 1.8–2.0 (m, 2H), 2.14–2.31 (m, 1H), 2.37–2.45 (m, 1H), 3.52–3.66 (m, 2H), 4.08 (dd, J = 4.2,
13
12.9 Hz, 1H); C NMR (100 MHz, CDCl3) ! 19.6, 20.0, 25.7, 32.5, 35.5, 38.7, 40.9, 48.9, 54.3,
64.6, 78.9; HRMS (EI) calcd for C11H19IO (M+) 294.0481, found 294.0499. 8: oil; IR (neat) 1772,
1
1457, 1387, 1188, 1132 cm–1; H NMR (300 MHz, CDCl3) ! 1.04 (s, 6H), 1.39 (s, 3H), 1.78–1.92
13
(m, 2H), 2.09–2.59 (m, 5H), 4.08 (dd, J = 4.8, 12.9 Hz, 1H); C NMR (100 MHz, CDCl3) ! 19.6,
20.4, 30.8, 32.0, 34.8, 38.2, 39.9, 44.7, 52.8, 84.8, 175.2; HRMS (EI) calcd for C11H17IO2 (M+)
308.0273, found 308.0285.
13. Triphenylphosphine could not be recovered because it was oxidized to triphenylphosphine oxide by
unreacted NIS through aqueous workup.