Stereoselective synthesis of (E)- and (Z)-3-hydroxy-2-methyl-1-alkenyl iodides by base-promoted ring-opening of iodomethylated epoxides

Article abstract of DOI:10.1016/j.tetlet.2006.05.023

Both (E)- and (Z)-3-hydroxy-2-methyl-1-alkenyl iodides were stereoselectively synthesized from iodomethylated epoxides by treatment with sodium hexamethyldisilazane in DMF and with LDA in THF (or lithium 2,2,6,6-tetramethylpiperidide in THF), respectively

Full text of DOI:10.1016/j.tetlet.2006.05.023

Tetrahedron Letters 47 (2006) 4843–4848
Stereoselective synthesis of (E)- and
(Z)-3-hydroxy-2-methyl-1-alkenyl iodides by base-promoted
ring-opening of iodomethylated epoxides
Takahiro Ichige, Daisuke Matsuda and Masaya Nakata*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
Received 14 April 2006; revised 2 May 2006; accepted 8 May 2006
Available online 30 May 2006
Abstract—Both (E)- and (Z)-3-hydroxy-2-methyl-1-alkenyl iodides were stereoselectively synthesized from iodomethylated epoxides
by treatment with sodium hexamethyldisilazane in DMF and with LDA in THF (or lithium 2,2,6,6-tetramethylpiperidide in THF),
respectively.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
the iodomethylated epoxide 1a (1.0 equiv) with the an-
ion derived from t-butyl acetate (4.0 equiv) and LDA
(4.0 equiv) in 20:1 THF–HMPA afforded the desired
product 2 in 78% yield. When this reaction was repeated
using 2.0 equiv of t-butyl acetate and 4.0 equiv of LDA,
2 was obtained in only 37% yield accompanied by a 41%
yield of vinyl iodide 3a (E:Z = 30:70). It is reasonable to
assume that the latter compound was obtained by the
base-promoted ring-opening of 1a through a b-elimina-
tion pathway. In general, vinyl iodides are versatile
intermediates in natural products syntheses. Under the
conceptually similar reaction conditions, vinyl chlo-
rides2 and, in the special cases, vinyl bromide,3 and vinyl
fluoride4 have been prepared. However, to the best of
our knowledge, there are no precedents of producing
vinyl iodides under similar reaction conditions.5 In this
letter, we report the stereoselective synthesis of
(E)- and (Z)-3-hydroxy-2-methyl-1-alkenyl iodides by
the base-promoted ring-opening of iodomethylated
epoxides.
During the course of our synthetic studies of biscembra-
noid marine natural products,1 we encountered an inter-
esting reaction (Scheme 1). A substitution reaction of
2. Results and discussion
Using 1a6 as a model compound, we first examined the
reaction conditions that afford vinyl iodide 3a as the
major product (Table 1). To a solution of 1a (1.0 equiv)
in THF was added LDA (1.5 equiv) at ꢀ78 ꢁC, and the
mixture was warmed to 0 ꢁC during a period of 1 h.
After work-up, the crude products were analyzed by
1H NMR spectroscopy. It was found that besides the
Scheme 1. Reaction of the iodomethylated epoxide 1a with the anion
species.
Keywords: Vinyl iodides; Epoxides; Base-promoted ring-opening; Syn
elimination; Anti elimination.
*
Corresponding author. Tel.: +81 45 566 1577; fax: +81 45 566 1551;
e-mail: msynktxa@applc.keio.ac.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.023

4844
T. Ichige et al. / Tetrahedron Letters 47 (2006) 4843–4848
Table 1. Reaction of 1a with LDA
Entry
Equiv of LDA
Additive (equiv)
Ratio of the productsa
Yield (%) of 3ab
E-3a:Z-3a:4a:5a
E-3a:Z-3a
1
2
3
4
5
6
1.5
3.0
1.5
1.5
1.5
1.5
—
—
2:86:12:0
0:0:14:86
40:40:11:9
41:26:10:23
46:24:10:20
52:20:11:17
2:98
—
50:50
61:39
66:34
72:28
80
54c
50
55
48
52
HMPA (3.0)
HMPA (6.0)
HMPA (12)
HMPA (24)
a The ratio of the products was based on 1H NMR analysis of the crude products.
b Isolated yield of the mixture of E-3a and Z-3a after silica-gel column chromatography.
c Isolated yield of 5a.
desired vinyl iodides, E-3a and Z-3a,7 the deiodinated
allylic alcohol 4a7 was obtained and the ratio of E-
3a:Z-3a:4a was 2:86:12 (entry 1). The E:Z ratio of 3a
was 2:98 and the isolated yield of the mixture of E-3a
and Z-3a was 80%.8 These are the best conditions to
date producing Z-3a as the major product.9 Compound
4a was derived via the base-promoted dehalogenative
ring-opening of 1a. When 3.0 equiv of LDA was used,
the major product was alkyne 5a7 (54%, entry 2). Alkyne
5a would be derived from vinyl iodides, E-3a and Z-3a,
via deprotonation, a-elimination (alkylidenecarbene for-
mation), and the 1,2-alkyl shift mechanism (Scheme
2).10,11 The amount of HMPA as an additive affected
the E:Z ratio; the larger the amount of HMPA, the lar-
ger the E:Z ratio (up to 72:28, entries 3–6).
3a:Z-3a reached 95:5 albeit in moderate isolated yields
(entries 4 and 5). When the solvent was changed to
DMF, the isolated yields increased to 64% (LHMDS)
and 73% (NHMDS) (entries 7 and 8). The bis(trimethyl-
silyl)amino-substituted byproduct 6a7 was also pro-
duced. KHMDS was ineffective in all cases (entries 6
and 9). Alternatively, when 3.0 equiv of NHMDS was
used in DMF at ꢀ60 ꢁC for 12 h, a 77% yield of a
96:4 mixture of E-3a and Z-3a was obtained (entry
10). In all cases using the HMDS bases, no alkyne 5a
was observed.
In addition, other reagents were surveyed. As antici-
pated, only the deiodinated allylic alcohol 4a was quanti-
tatively obtained by the treatment of 1a with 1.2 equiv of
n-BuLi (THF, ꢀ78 to 0 ꢁC, 1 h). Organoaluminum
amides,12 such as diethylaluminum diisopropylamide
and diethylaluminum 2,2,6,6-tetramethylpiperidide (benz-
ene, 0 ꢁC, 0.5 h), also gave 4a as the major product. In
contrast, lithium 2,2,6,6-tetramethylpiperidide (LTMP)
proved to be an alternative for LDA (THF, ꢀ20 ꢁC,
15 min, 81%, E-3a:Z-3a:4a:5a = 2:83:10:5, E-3a:Z-3a =
2:98).
We next examined the hexamethyldisilazane bases
(Table 2). Lithium, sodium, and potassium hexamethyl-
disilazanes (LHMDS in THF, NHMDS in THF, and
KHMDS in toluene, respectively) had no effect in
THF (entries 1–3). In contrast, gratifyingly, in the pres-
ence of HMPA, both LHMDS and NHMDS were effec-
tive for the synthesis of E-vinyl iodide; the ratio of E-
The formation of allylic alcohols from the reaction of
epoxides with amide bases in a relatively nonpolar
solvent (such as THF) appears to proceed by a b-elimi-
nation pathway and also syn elimination is operative
during this transformation (Fig. 1).13 An amide base
would preferentially coordinate to the epoxide on the
hydrogen substituent side (R1 = Me, R2 = alkyl,
R3 = H), as depicted in Figure 1, due to steric factors.13
Among the two transition state models, TS-A would be
preferable to TS-B; because TS-B experiences a substan-
tial nonbonded interaction between the methyl (R1) and
iodine substituents. In contrast, the use of an additive
(such as HMPA) or a more polar solvent (such as
DMF) precludes a significant association with weakly
basic epoxides; therefore, the typical E2 reaction
Scheme 2. Probable mechanism for formation of 5a from 3a.

T. Ichige et al. / Tetrahedron Letters 47 (2006) 4843–4848
Table 2. Reaction of 1a with hexamethyldisilazane bases
4845
Entry
Base (equiv)
Additive (equiv)
Solvent
Temperature (ꢁC)
Time (h)
Ratio of the productsa
Yield (%)of 3ab
E-3a:Z-3a:4a:6a
E-3a:Z-3a
c
c
c
1
2
3
4
5
6
7
8
9
LHMDS (1.5)
NHMDS (1.5)
KHMDS (1.5)
LHMDS (1.5)
NHMDS (1.5)
KHMDS (1.5)
LHMDS (1.5)
NHMDS (1.5)
KHMDS (1.5)
NHMDS (3.0)
—
—
—
THF
THF
THF
THF
THF
THF
DMF
DMF
DMF
DMF
ꢀ78 to 0
ꢀ78 to 0
ꢀ78 to 0
ꢀ78 to 0
ꢀ78 to 0
ꢀ78 to 0
ꢀ60 to 0
ꢀ60 to 0
ꢀ60 to 0
ꢀ60
1
1
1
1
1
1
1
1
1
—:—:—:—
—:—:—:—
—:—:—:—
59:3:13:25
60:3:11:26
—:—:—:—
78:4:9:9
79:4:0:17
—:—:—:—
82:3:2:13
—
—
—
95:5
95:5
—
95:5
95:5
—
—
—
—
42
59
—
64
73
HMPA (6.0)
HMPA (6.0)
HMPA (6.0)
—
—
—
—
d
Decomp.
77
10
12
96:4
a The ratio of the products was based on 1H NMR analysis of the crude products.
b Isolated yield of the mixture of E-3a and Z-3a after silica-gel column chromatography.
c Almost no reaction.
d An as-yet-unidentified byproduct was obtained.
Figure 1. Proposed transition state models for syn elimination.
Figure 2. Proposed transition state models for anti elimination.
(anti elimination) would occur as depicted in Figure 2.13
Among the two transition state models, TS-C
would be preferable to TS-D; because TS-D suffers from
a substantial nonbonded interaction between the lone
pairs of the oxygen and iodine substituents.
Epoxides having the cis substituent to the iodomethyl
group showed a dismissive reactivity under the LDA–
THF conditions (Table 4). When the compounds 1i–k6
were subjected to LDA in THF, E-vinyl iodides were
preferred over Z-vinyl iodides albeit in low isolated
yields (entries 1, 3, and 5). This E-selectivity would be
explained by considering that TS-B is sterically prefera-
ble to TS-A when R3 is not a hydrogen substituent
(Fig. 1). In contrast, under the NHMDS–DMF condi-
tions, the same compounds 1i–k showed an excellent
E-selectivity with good isolated yields (entries 2, 4, and
6).
With the reaction conditions suitable for the stereoselec-
tive synthesis of E- and Z-vinyl iodides in hand, the
scope of this reaction was investigated with various sub-
strates 1b–h6 (Table 3). For the structurally similar tri-
substituted epoxides 1b–f, good yields and
stereoselectivities were obtained (entries 1–10). The
2,2-disubstituted epoxide, which was derived in situ
from 1g by treatment with LiI in THF (rt, 0.5 h) due
to the volatility of the corresponding vinyl iodide (en-
tries 11 and 12), and 1h, having the trityloxymethyl
group instead of the methyl group (entries 13 and
14),14 were also suitable for this reaction.
3. Conclusion
In summary, we have developed the stereoselective syn-
thesis of both (E)- and (Z)-3-hydroxy-2-methyl-1-alkenyl

4846
T. Ichige et al. / Tetrahedron Letters 47 (2006) 4843–4848
Table 3. Reactions of the substrates 1b–h under the optimized conditions
Entry
Substrate 1
Conditions
Ratio of the productsa
Yield (%) of 3b
E-3:Z-3:4:5:6
E-3:Z-3
1c
2
A
B
3:79:9:0:—
92:7:1:—:0
4:96
93:7
80
98
3
4
A
B
1:86:6:7:—
80:6:1:—:13
1:99
93:7
83
62
5
6
A
B
2:79:15:4:—
96:1:3:—:0
3:97
99:1
74
74
7
8
A
B
2:83:11:4:—
96:4:0:—:0
2:98
96:4
76
77
9d
10e
A
B
2:77:11:0:—
82:4:0:—:14
3:97
95:5
77
83
11f
12f
A
B
2:98:0:0:—
93:7:0:—:0
2:98
93:7
76
72
13g,h
14h
A
B
2:89:4:0:—
90:9:1:—:0
2:98
91:9
89
74
a The ratio of the products was based on 1H NMR analysis of the crude products.
b Isolated yield of the mixture of E-3a and Z-3a after silica-gel column chromatography.
c The ratio of E-3b:Z-3b:4b:5b:1b = 3:79:9:0:9.
d The ratio of E-3f:Z-3f:4f:5f:1f = 2:77:11:0:10.
e NHMDS (3.0 equiv), DMF, ꢀ60 ꢁC, 12 h.
f 1g was in situ converted into iodide (Lil, THF, rt, 0.5 h) before subjecting it to the reaction conditions (2.0 equiv of the base was used).
g The ratio of E-3h:Z-3h:4h:5h:1h = 2:89:4:0:5.
h See Ref. 14.
iodides from the same iodomethylated epoxides by
using the different bases: NHMDS in DMF for E-vinyl
iodides and LDA in THF (or LTMP in THF) for Z-
vinyl iodides. This method will be applicable to natural
products syntheses.
4. General procedure
(Table 1, entry 1) To a solution of the iodomethylated
epoxide 1a (100 mg, 0.240 mmol) in dry THF (2.4 mL)
was added LDA (1.49 M in heptane/THF/ethylbenzene,

T. Ichige et al. / Tetrahedron Letters 47 (2006) 4843–4848
Table 4. Reactions of the substrates 1i–k under the optimized conditions
4847
Entry
Substrate 1
Conditions
Ratio of the productsa
Yield (%) of 3b
E-3:Z-3:4
E-3:Z-3
1c
2
A
B
13:4:62
94:3:3
76:24
97:3
17
86
3d
4
A
B
45:0:18
>99:0:0
>99:1
>99:1
35
96
5e
6
A
B
26:0:59
>99:0:0
>99:1
>99:1
21
94
a The ratio of the products was based on 1H NMR analysis of the crude products.
b Isolated yield of the mixture of E-3a and Z-3a after silica-gel column chromatography.
c The ratio of E-3i:Z-3i:4i:1i = 13:4:62:21.
d The ratio of E-3j:Z-3j:4j:5j:1j = 45:0:18:15:22.
e The ratio of E-3k:Z-3k:4k:1k = 26:0:59:15.
0.242 mL, 0.360 mmol) at ꢀ78 ꢁC and the mixture was
gradually warmed to 0 ꢁC during a period of 1 h. The
reaction was quenched by adding satd aq NH4Cl solu-
tion (1.2 mL) at 0 ꢁC and the resulting mixture was
extracted with EtOAc (2.4 mL · 3). The extracts were
washed with satd aq NaCl solution (2.4 mL), dried over
Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography (10 g of
silica gel, 3:1 hexane/EtOAc) to afford vinyl iodide 3a
(80.2 mg, 80%) as a 2:98 mixture of E- and Z-isomers
extracted with 1:1 hexane–EtOAc (2.5 mL · 3). The
extracts were washed with satd aq NaCl solution
(2.5 mL), dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column
chromatography (10.5 g of silica gel, 3:1 hexane/ethyl
acetate) to afford 3a (76.3 mg, 73%) as a 95:5 mixture
of E- and Z-isomers (a pale yellow syrup). E-3a,
27
Rf = 0.34 (2:1 hexane/ethyl acetate); ½aꢁD +4.85 (c
2.01, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.54–
1.76 (2H, m), 1.64 (3H, s), 1.79 (3H, d, J = 1.0 Hz),
1.92–2.26 (2H, m), 3.80 (3H, s), 3.98 (2H, d,
J = 7.0 Hz), 4.11 (1H, br t, J = 6.0 Hz), 4.43 (2H, s),
5.39 (1H, tq, J = 7.0, 1.5 Hz), 6.24 (1H, s), 6.87 (2H,
d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz); 13C NMR
(75 MHz, CDCl3): d 16.60, 19.80, 32.82, 35.45, 55.37,
66.29, 71.88, 76.23, 78.55, 113.83, 121.53, 129.52,
130.53, 139.58, 150.04, 159.19; MS (EI) m/z 416 (M+);
HRMS (EI) m/z calcd for C18H25O3I (M+) 416.0849,
found 416.0824.
(a pale yellow syrup). Z-3a, Rf = 0.34 (2:1 hexane/ethyl
23
acetate); ½aꢁD ꢀ28.0 (c 2.06, CHCl3); 1H NMR
(300 MHz, CDCl3): d 1.50–1.83 (2H, m), 1.68 (3H, s),
1.87 (3H, d, J = 1.5 Hz), 1.98–2.28 (2H, m), 3.80 (3H,
s), 4.01 (2H, d, J = 7.0 Hz), 4.44 (2H, s), 4.52–4.63
(1H, m), 5.45 (1H, tq, J = 7.0, 1.0 Hz), 5.93 (1H, q,
J = 1.5 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.27 (2H, d,
J = 8.6 Hz); 13C NMR (75 MHz, CDCl3): d 16.68,
18.83, 32.27, 35.49, 55.35, 66.34, 71.83, 74.48, 75.54,
113.81, 121.52, 129.51, 130.58, 139.69, 148.57, 159.16;
MS (EI) m/z 416 (M+); HRMS (EI) m/z calcd for
C18H25O3I (M+) 416.0849, found 416.0819.
Acknowledgments
(Table 2, entry 8) To a solution of the iodomethylated
epoxide 1a (105 mg, 0.252 mmol) in dry DMF
(2.52 mL) was added NHMDS (1.0 M in THF,
0.378 mL, 0.378 mmol) at ꢀ60 ꢁC and the mixture was
gradually warmed to 0 ꢁC during a period of 1 h. The
reaction was quenched by adding satd aq NH4Cl solu-
tion (1.3 mL) at 0 ꢁC and the resulting mixture was
This research was partially supported by a Grant-in-
Aid for the 21st Century COE program ‘KEIO Life
Conjugate Chemistry’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan
(MEXT) and a Grant-in-Aid for Scientific Research
on Priority Areas 17035076 and 18032067 from
MEXT.

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T. Ichige et al. / Tetrahedron Letters 47 (2006) 4843–4848
Chou, S.-S. P.; Kuo, H.-L.; Wang, C.-J.; Tsai, C.-Y.; Sun,
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