Flow synthesis of (3R)- and (3S)-(E)-1-iodohexa-1,5-dien-3-ol: Chiral building blocks for natural product synthesis

Article abstract of DOI:10.1246/cl.180475

A concise procedure to prepare optically active (3R)- and (3S)-(E)-1-iodohexa-1,5-dien-3-ol was developed. Ethyl (E)-3-iodoacrylate was converted to racemic (E)-1-iodohexa-1,5-dien-3-ol under flow and batch conditions via successive half reduction followed by Grignard reaction. Kinetic resolution of the racemic alcohol was achieved under flow conditions by using lipase packed in a column to afford (3S)-(E)-1-iodohexa-1,5-dien-3-ol and corresponding (3R)-acetate. Removal of the acetyl group was also carried out under flow conditions by using ion exchange resin packed in a column and (3R)-(E)-1-iodohexa-1,5-dien-3-ol was obtained after simple evaporation of the eluent.

Full text of DOI:10.1246/cl.180475

Advance Publication Cover Page
Flow Synthesis of (3R)- and (3S)-(E)-1-Iodohexa-1,5-dien-3-ol:
Chiral Building Blocks for Natural Product Synthesis
Sota Katayama, Tomoyuki Koge, Satoko Katsuragi, Shuji Akai, and Tohru Oishi*
Advance Publication on the web June 30, 2018
doi:10.1246/cl.180475
© 2018 The Chemical Society of Japan
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Publication manuscripts.

1
Flow Synthesis of (3R)- and (3S)-(E)-1-Iodohexa-1,5-dien-3-ol:
Chiral Building Blocks for Natural Product Synthesis
Sota Katayama,1 Tomoyuki Koge,1 Satoko Katsuragi,2 Shuji Akai,2 and Tohru Oishi*1
1Department of Chemistry, Faculty and Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395,
Japan, 2Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
E-mail: oishi@chem.kyushu-univ.jp
1
2
3
4
5
6
7
8
9
A concise procedure to prepare optically active (3R)-
51 passing through the tube (tube length = 200 cm), the
52 reaction mixture was poured into a mixture of Et2O and
53 aqueous solution of Rochellet salt at 0 °C.
54
55
56
57
58
and (3S)-(E)-1-iodohexa-1,5-dien-3-ol was developed. Ethyl
(E)-3-iodoacrylate was converted to racemic (E)-1-
iodohexa-1,5-dien-3-ol under flow and batch conditions via
successive half reduction followed by Grignard reaction.
Kinetic resolution of the racemic alcohol was achieved
under flow conditions by using lipase packed in a column to
afford (3S)-(E)-1-iodohexa-1,5-dien-3-ol and corresponding
(3R)-acetate. Removal of the acetyl group was also carried
10 out under flow conditions by using ion exchange resin
11 packed in a column and (3R)-(E)-1-iodohexa-1,5-dien-3-ol
12 was obtained after simple evaporation of the eluent.
59
60
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62
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64
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66
67
68
69
70
13
Optically active (3R)- and (3S)-(E)-1-iodohexa-1,5-
14 dien-3-ol ((R)-1 and (S)-1) are useful chiral building blocks
15 for the synthesis of natural products (Figure 1).1-4 During the
16 course of our synthetic studies of amphidinol 3,5 we have
17 reported a concise synthesis of (R)-1 and (S)-1 via kinetic
18 resolution of racemic alcohol dl-1.5a
19
20
21
71
72 Scheme 2. Half reduction of ester 2 with DIBALH under flow
73 conditions.
74
22
23
24 Figure 1. Structure of (3R)- and (3S)-(E)-1-iodohexa-1,5-dien-5-ol
75 As shown in Table 1, mixing a solution of 2 in toluene (0.20
76 M) with a solution of DIBALH in toluene (0.24 M) resulted
77 in the formation of aldehyde 3 with concomitant formation
78 of alcohol 4 in a 63 : 37 ratio without recovery of 2 as
79 determined by 1H NMR analysis (entry 1). When the solvent
80 was changed to CH2Cl2 (entry 2), the ratio of 3 was
81 dramatically improved (3 : 4 : 2 = 93 : 4 : 3). It is postulated
82 that DIBALH forms dimer in less polar solvent such as
83 hexane, but dissociation of the dimer occurred in CH2Cl2.
84 Therefore, reactivity of DIBALH in CH2Cl2 was higher than
85 that in hexane.
25 ((R)-1 and (S)-1), and the corresponding racemic alcohol (dl-1).
26
27
Although dl-1 was synthesized via Grignard reaction
28 of aldehyde 3 with allylmagnesium bromide, half reduction
29 of ester 2 with DIBALH giving aldehyde 3 was not
30 reproducible (34-83%) with concomitant formation of
31 byproduct 4 and recovery of 2, and handling of 3 was
32 difficult because of the volatile and labile property (Scheme
33 1). Herein, we report practical procedure for synthesizing
34 dl-1 by using microflow reactors,6 and concise preparation
35 of (R)-1 and (S)-1 under flow conditions.
36
37
38
86
87 Table 1. Half reduction of 2 with DIBALH under the flow conditions.
ratio / %a
entry
solvent A / X M
solvent B / Y M
3 : 4 : 2
39
40
1
2
toluene / 0.20
CH2Cl2 / 0.20
hexane / 0.50
CH2Cl2 / 0.84
CH2Cl2 / 0.84
CH2Cl2 / 1.0
toluene / 0.24
CH2Cl2 / 0.24
hexane / 0.70
hexane / 1.0
hexane / 1.0
hexane / 1.0
63 : 37 : 0
93 : 4 : 3
88 : 12 : 0
73 : 6 : 21
93 : 7 : 0
78 : 14 : 8
41 Scheme 1. Unsuccessful half reduction of ester 2 with DIBALH under
42 the batch conditions.
43
3
44
It is reported that half reduction of esters was
4
45 successfully achieved by using microflow reactor by Eisai7
46 and Jamison8 group, therefore, we applied the method to our
47 system (Scheme 2). A solution of 2 in solvent A and a
48 solution of DIBALH in solvent B were transferred (tube
49 length = 100 cm) and mixed through a microflow reactor
50 (Comet X-01)9 at a rate for 5.0 mL/min at −78 °C, and after
5b
6b
88 aThe ratio was determined by 1H NMR analysis. bTwo micromixers
89 were directly connected in series.

2
1
2
3
4
5
6
7
8
9
However, price of the DIBALH solution in CH2Cl2 is three
times expensive than that in toluene or hexane. Therefore,
hexane solution was used, and concentration of 2 and
DIBALH was increased to 0.50 M and 0.70 M, respectively,
aiming for the large scale synthesis (entry 3). As a result,
acceptable ratio of 3 was obtained (3 : 4 = 88 : 12). Next, we
planned to use the commercially available 1.0 M DIBALH
solution in hexane directly, and solvent for 2 was changed to
CH2Cl2 (0.84 M) to increase the solubility at low
60
Having dl-1 in hand, lipase catalyzed kinetic resolution
61 under flow conditions was examined.10 The advantages of
62 using flow system with solid catalyst are as follows: 1) it is
63 easy to recover and reuse the catalyst, 2) reaction time can
64 be shortened because of higher catalyst/substrate ratio, and
65 3) once the reaction conditions are optimized, optical
66 resolution can be performed continuously and reproducibly.
67 After prescreening of lipases, CALB was selected and
68 packed in a column and a solution of dl-1 in vinyl acetate
10 temperature (entry 4). However, the considerable amount of
11 2 remained (3 : 4 : 2 = 73 : 6 : 21). Although attempts to
12 improve the ratio of 3 by prolong the resident time were
13 unsuccessful, we found that direct connection of two
14 micromixers in series was effective to result in the
15 formation of 3 in high selectivity (3 : 4 = 93 : 7, entry 5). In
16 this reaction, mixing of the substrate and reagent is very
17 important. Only one micromixer is not enough to complete
18 the mixing of them. When the concentration of 2 was
19 increased to 1.0 M, the yield of 3 was decreased (3 : 4 : 2 =
20 78 : 14 : 8). Therefore, we decided that conditions in entry 5
21 was most suitable.
69 was eluted (Scheme 4).
70
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73
74
75
76
77
78
79
80
22
Having succeeded in the half reduction of 2, synthesis
81
23 of dl-1 was examined without isolation of the aldehyde 3.
24 Although one flow synthesis was examined by mixing the
82 Scheme 4. Lipase catalyzed kinetic resolution of dl-1 under flow
83 conditions.
25 solution of 3 with allylmagnesium bromide, the low
84
26 solubility of the resulting alkoxide under the reaction
27 conditions was problematic to cause choking the flow
28 system. Therefore, flow and batch conditions were applied
29 as shown in Scheme 3 for large scale synthesis. The half
85
As shown in Table 2, 0.68 g of lipase (CALB) was
86 packed in a column (ϕ5 mm × 10 mm), and a solution of dl-
87 1 in vinyl acetate (0.30 M) was eluted at a rate of 10 mL/h at
88 50 °C (entry 1). The ratio of the resulting (S)-1 and (R)-7
1
30 reduction of 2 (70.2 g) was carried out under the optimized
89 was determined by H-NMR analysis to be 51 : 49 and
31 conditions by using two microflow reactors in series (Table
32 1, entry 5), and plunger pumps were used for feeding the
33 solutions. The resulting reaction mixture was poured into a
34 solution of allylmagnesium bromide 5 in Et2O (1.05 M) at
35 −78 °C. After completing the flow reaction, the resulting
36 reaction mixture was allowed to warm up to 0 °C to afford
37 dl-1 in 93% (64.9 g) yield with concomitant formation of
38 small amount of 4 (7%) without byproduct 6.
90 enantiomeric excess was determined by HPLC analysis
91 using chiral column to be 91.0%ee and 90.0%ee,
92 respectively. Next, the reaction was carried out at 60 °C, and
93 the ratio of (S)-1 : (R)-7 was 44 : 56 in 96.8%ee and
94 74.5%ee, respectively (entry 2). When the flow rate was
95 increased to 12 mL/h at 60 °C, the ratio of (S)-1 : (R)-7 was
96 45 : 55 in 97.2%ee and 80.4%ee, respectively (entry 3).
97
39
40
41
98 Table 2. Lipase catalyzed kinetic resolution of dl-1. a
temp / °C
ratio / %b
ee%c
flow rate /
mL/h
entry
(S)-1 : (R)-7
(S)-1 (R)-7
42
43
44
45
1
2
3
10
10
12
50
60
60
51 : 49
44 : 56
45 : 55
91.0 90.0
96.8 74.5
97.2 80.4
46
47
48
49
50
51
52
53
54
99 dA column of ϕ5 mm × 10 mm was used. bThe ratio was determined
100 by 1H NMR analysis (600 MHz). cThe enantiomeric excess was
101 determined by HPLC analysis using Chiralpak AD, ϕ4.6 ×250 mm,
102 0.3% 2-propanol in hexane, 1.0 mL/min, 254 nm.
103
104
The final step of the synthesis is removal of the acetyl
105 group of (R)-7, which was also carried out under flow
106 conditions. Although removal of acetates are usually carried
107 out under batch conditions by using K2CO3 in methanol,
108 quenching, extraction, and evaporation sequence is required
109 after the reaction. We planned to apply flow chemistry for
110 this purpose by using anion exchange resin as a base
55
56
57 Scheme 3. Sequential DIBALH reduction of 2 under flow conditions
58 and Grignard reaction with 5 under batch conditions without isolation
59 of aldehyde 3. BPR: back pressure regulator.

3
1
2
3
4
5
6
7
8
9
catalyst.11 The advantage is the simple operation, i.e. only
evaporation of the solvent is required for isolation of the
product if the starting material is consumed completely. As
shown in Scheme 5, a solution of the acetate (R)-7 in
methanol was passed through ion-exchange resin (DOWEX
1×4 50-100 Mesh) packed in a column (ϕ5 mm × 10 mm),
which was washed with water, 1.0 M NaOH, water, and
methanol prior to use (conversion of Cl− form to MeO−
form).
49 followed by Grignard reaction. Kinetic resolution of the
50 racemic alcohol with lipase was achieved under flow
51 conditions to give (3S)-(E)-1-iodohexa-1,5-dien-3-ol and
52 corresponding (3R)-acetate. Removal of the acetyl group
53 was also carried out under flow conditions with ion
54 exchange resin packed in a column and (3S)-(E)-1-
55 iodohexa-1,5-dien-3-ol was obtained after simple
56 evaporation of the solvent.
57
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11
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14
15
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17
18
19
20
58 This work was supported in part by JSPS KAKENHI Grant
59 Numbers JP15K13645, JP24106735, and JP16H01159 in
60 Middle Molecular Strategy.
61
62 Supporting
Information
is
available
on
63 http://dx.doi.org/10.1246/cl.******.
64 References
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21 Scheme 5. Removal of acetyl group of (R)-7 under flow conditions
22 with ion-exchange resin packed in a column.
3
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24 As shown in Table 3, (R)-7 in methanol (0.1 M) was passed
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5d
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b
40 aA column of ϕ5 mm × 10 mm was used. The ratio was determined
41 by 1H NMR analysis (600 MHz). cThe column used in entry 3 was
42 reused. dThe column used in entry 4 was reused.
43
44 In conclusion, optically active (3R)- and (3S)-(E)-1-
45 iodohexa-1,5-dien-3-ol was synthesized under flow
46 conditions. Ethyl (E)-3-iodoacrylate was converted to
47 racemic (E)-1-iodohexa-1,5-dien-3-ol under flow and batch
48 conditions via successive half reduction with DIBALH
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