Z-selective intramolecular Horner-Wadsworth-Emmons reaction for the synthesis of macrocyclic alkenes

Article abstract of DOI:10.1016/j.tetlet.2011.01.043

The Z-selective intramolecular Horner-Wadsworth-Emmons reaction of the substrates 7-12 (RO)₂P(O)CHR′CO₂Et (R′ = (CH₂)_nCHO) (R = Ph or o-tBuC₆H₄) gives the 13-18-membered cyclic alkenes selectively (up to Z:E = 97:3) in good yields using NaH in THF under high dilution conditions.

Full text of DOI:10.1016/j.tetlet.2011.01.043

Tetrahedron Letters 52 (2011) 1284–1287
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Z-Selective intramolecular Horner–Wadsworth–Emmons reaction
for the synthesis of macrocyclic alkenes
⇑
Kaori Ando , Kaori Sato
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The Z-selective intramolecular Horner–Wadsworth–Emmons reaction of the substrates 7–12
(RO)2P(O)CHR0CO2Et (R0 = (CH2)nCHO) (R = Ph or o-tBuC6H4) gives the 13–18-membered cyclic alkenes
selectively (up to Z:E = 97:3) in good yields using NaH in THF under high dilution conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 27 November 2010
Revised 23 December 2010
Accepted 11 January 2011
Available online 20 January 2011
The Horner–Wadsworth–Emmons (HWE) modification of the
The intramolecular HWE reaction substrates were planned to be
prepared by alkylation of the phosphonate reagents 6 with alkyl io-
dides, which were prepared as follows (Scheme 3). The commer-
cially available diols were mono-protected as the THP ethers and
followed by tosylation using Tanabe’s procedure8 to give 3b
and 3c in 96–98% yields. On the other hand, tosylation using TsCl
and pyridine gave 3a in a moderate 78% yield. Both 3b and 3c were
converted into the ethers by the reaction with diols in the presence
of NaH in DMSO and the following tosylation gave the tosylates
3d–3g. Pentadecanolide was subjected to the base-catalyzed
transesterification and the resulting hydroxy group was protected
as the THP ether 4. The ethyl ester group was reduced with LiAlH4
followed by tosylation to give the tosylate 3h. These tosylates 3a
and 3d–3h were converted into the corresponding iodides 5a–5f
by nucleophilic substitution with NaI.
Wittig reaction is a widely used method for the preparation of a,b-
unsaturated esters.1 After the first reports by Stork and Nakamura
and by Nicolaou et al. in 1979,2 the intramolecular HWE reaction
has been one of the most reliable macrocyclization procedures.
These reactions gave E-
with high selectivity. Since there are many bioactive macrolides
containing the Z- ,b-unsaturated lactone moiety, we started our re-
a,b-unsaturated lactones or cyclic ketones
a
search on the Z-selective intramolecular HWE reaction. Recently, we
reported the Z-selective intramolecular HWE reaction for the
synthesis of macrocyclic lactones (Scheme 1).3,4 When the
x-formy-
lated HWE substrates 1 were added to a THF suspension containing
3 equiv of NaH at 0 °C or NaI-DBU at room temperature over 1-10 h,
the intramolecular HWE reaction occurred to give 12–18-mem-
bered ring lactones in 61–99% yields with 95–100% Z selectivity.
There is another type of intramolecular HWE reaction as shown in
Scheme 2. This type of intramolecular HWE reaction has been used
for the synthesis of bioactive compounds5,6 such as (+)-Desepoxyas-
perdiol,5a (ꢀ)-Asperdiol,5b and Anisomelic acid.6a,b Only a limited
number of the intermolecular HWE reaction with the phosphonate
HWE reagents 6a,4c 6b,9 6c, and 6d were alkylated with the
above iodides 5a–5f by using NaH in DMSO, followed by deprotec-
tion of the THP ethers and oxidation with PCC to give the intramo-
lecular HWE substrates 7–12 (Scheme 4). Since these substrates
were not so stable, the substrates were stored in a freezer and used
within 1 week.
reagents having
a-substituents larger than a methyl group have
been reported. In these cases, relatively poor stereoselectivity has
been observed for both E- and Z-selective HWE reactions.7 The same
is true for the intramolecular HWE reaction. During the total synthe-
sis of 6-epi-sarsolilide A, Xu et al. obtained the Z product with only
8:3 selectivity in 30% yield using our Z-selective Ph reagent4b–g
(R = Ph in 2).6d On the other hand, almost no product was obtained
under a variety of conditions using Still’s reagent4a (R = CF3CH2 in
2). Since stereo-defined synthesis of carbon–carbon double bonds
with high selectivity is critically important, we decided to establish
satisfactory reaction conditions. Here, we report our results of the
intramolecular HWE reaction giving 13–18-membered ring alkenes
selectively.
The intramolecular HWE reaction of 10 is summarized in Table
1.10 The HWE reaction of 10a (R = Ph) was performed using a pro-
cedure similar to that of the intramolecular HWE reaction of 1.3
That is, a THF solution of 10a was added to a THF suspension con-
taining 3 equiv of NaH over 4 h at room temperature (entry 1). The
15-membered compound 13 was obtained in 88% yield with 78:22
Z selectivity11 (the yield of Z-13 is 69%). Since oligomeric (dimeric
and/or trimeric) cyclic compounds were also obtained in 2% yield,
the reaction was performed at 60 °C. A lower yield and lower selec-
tivity were observed (entry 2). Although NaI-DBU was the most
favorable base for the intramolecular HWE reaction of 1,3 lower
69:31 selectivity was observed for 10a (entry 3). Also, the use of
t-BuONa, t-BuOK, and LiCl-DBU as a base did not improve the
selectivity and/or the yield (entries 4–6). In the presence of the
stronger base t-BuOK, decomposition of 10a occurred. In our
⇑
Corresponding author. Tel./fax: +81 58 293 2674.
E-mail address: ando@gifu-u.ac.jp (K. Ando).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.043

K. Ando, K. Sato / Tetrahedron Letters 52 (2011) 1284–1287
1285
O
NaH, DMSO
Z
(RO)2P(O)CH2CO2Et
3 equiv NaH at 0 °C
5a 5f
-
6a
R = Ph
O
or 3 equiv NaI-DBU at rt
36-94%
6b R = o-tBuC6H4
6c R = Et
(ArO)2P(O)CH2CO2---CHO
n-8
high dilution
THF
6d
R = Me (Me ester)
1 Ar = o-tBuC6H4
(RO)2P(O)CHCO2Et
(CH2)n-1CHO
n = 8-14
95-100% Z
61-99% yield
1) PPTS, EtOH, 75 °C, 66-99%
2) PCC, CH2Cl2, 53-95%
7
8
n = 12 , n = 15
(RO)2P(O)CHCO2Et
(CH2)mO(CH2)n-1CHO
Scheme 1.
Z
(n,m)=(6,6) 9, (9,4) 10, (6,9) 11, (6,10) 12
RO2C
RO2C
E
(RO)2P(O)CHCO2R
CH2-----CHO
Scheme 4.
n
n
2
Scheme 2.
previous study, we found ortho-substituted phenyl reagents (R =
o-MeC6H4 and o-iPrC6H4 in 6) showed higher Z selectivity than
the Ph reagent 6a.4c After that, Touchard et al. reported the
improvement of selectivity at 0 °C using the o-tBuC6H4 reagent
6b.9,12,3 In the presence of 3 equiv of NaH, the o-tBuC6H4 reagent
10b reacted to give 13 in 47% yield with 95:5 selectivity at room
temperature (entry 7). Generally, the reactivity of the o-tBuC6H4
reagents is lower than that of the Ph reagents because of steric ef-
fects.3,9 When the reaction of 10b was performed at 60 °C, an im-
proved yield of 63% was obtained with 97:3 Z selectivity (entry
8). The reaction using NaI-DBU again gave much lower selectivity
than that using NaH (entries 10 and 11). Thus, Z-13 was prepared
by the reaction of 10a in a high yield with moderate 78:22 selectiv-
ity or by the reaction of 10b with higher 97:3 selectivity in a mod-
erate yield using 3 equiv of NaH in THF. On the other hand, the
reaction of the Et reagent 10c gave only low yields and low E selec-
tivity using LiCl-DBU in MeCN13 or LDA in toluene (entries 12 and
13). The crude mixture contained 13% of 10c in entry 12, while
there was no 10c left in entry 13. The use of NaH in THF gave
low Z selectivity (entry 14). Although the use of the smaller tri-
methyl phosphonoacetate reagent 10d gave improved yields, the
selectivity was low in the presence of LiCl-DBU in MeCN or NaH
in THF (entries 15 and 16).
1) DHP, PPTS, THF, 60 °C
50-55%
TsO(CH2)nOTHP
HO(CH2)nOH
n = 6,9,12
2) TsCl, Et3N, Me3N/HCl
MeCN, 96, 98%
3a
3c
3b
n=6
n=12,
n=9
1) HO(CH2)mOH, NaH
DMSO, 45-79%
TsO(CH2)mO(CH2)nOTHP
3b or 3c
2) TsCl, Et3N, Me3N/HCl
MeCN, 93-98%
3d
3e
3g
(n,m) = (6,6)
, (9,4)
,
3f
(6,9) , (6,10)
1) EtONa, EtOH, 86%
pentadecanolide
EtO2C(CH2)14OTHP
2) DHP, PPTS, THF
60 °C, 93%
4
1) LiAlH4, ether, 96%
TsO(CH2)15OTHP
2) TsCl, Et3N, Me3N/HCl, MeCN, 99%
3h
NaI, acetone
I(CH2)nOTHP I(CH2)mO(CH2)nOTHP
3a or
3d 3h
5c
(n,m) = (6,6) , (9,4)
5d
5f
-
,
n = 15 5a
5b
reflux, 89-99%
5e
(6,9)
(6,10)
n = 12
Scheme 3.
Table 1
Intramolecular HWE reaction of 10
EtO2C
EtO2C
base
(3 eq)
(RO)2P(O)CHCO2Et
15
15
O
(CH2)4O(CH2)8CHO
O
10a R = Ph, 10b R = o-tBuC6H4
10c R = Et, 10d R = Me (Me ester)
Z-13
E-13
Entry
10
Solvent
Base
Conditiona
Yield 13 (%)
Oligomer (%)
Z:E
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
10a
10a
10a
10a
10a
10a
10b
10b
10b
10b
10b
10c
10c
10c
10d
10d
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
MeCN
Toluene
THF
MeCN
THF
NaH
NaH
rt, 4 h
60 °C, 4 h
rt, 4 h
rt, 4 h
rt, 4 h
88
79
83
81
23
75
47
63
41
66
64
40
8
2
78:22
75:25
69:31
70:30
80:20
72:28
95:5
—
—
—
—
—
—
—
—
3
—
6
20
11
2
NaI-DBU
t-BuONa
t-BuOK
LiBr-DBU
NaH
NaH
NaH
NaI-DBU
NaI-DBU
LiCl-DBU
LDA
rt, 4 h
rt, 4 h
60 °C, 4 h
Reflux, 4 h
rt, 4 h
60 °C, 4 h
60 °C, 4 h
rt, 2 h
60 °C, 4 h
60 °C, 4 h
60 °C, 4 h
97:3
92:8
86:14
85:15
42:58
38:62
62:38
48:52
72:28
NaH
LiCl-DBU
NaH
47
58b
65b
—
a
The addition was carried out over the specified time. The final concentration was 0.01 mol Lꢀ1
The corresponding Me ester was obtained.
.
b

1286
K. Ando, K. Sato / Tetrahedron Letters 52 (2011) 1284–1287
Table 2
Intramolecular HWE reaction of 8
base
(3 eq)
EtO2C
EtO2C
(RO)2P(O)CHCO2Et
16
16
(CH2)14CHO
8a R = Ph, 8b R = o-tBuC6H4
8c R = Et, 8d R = Me (Me ester)
Z-14
-14
E
Entry
8
Solvent
Base
Conditiona
Yield 14 (%)
Oligomer (%)
Z:E
1
2
3
4
5
6
7
8a
8a
8a
8b
8c
8d
8d
THF
THF
THF
THF
MeCN
MeCN
THF
NaH
NaH
rt, 4 h
66
72
71
79
11
—
—
6
2
2
91:9
Reflux, 6 h
Reflux, 4 h
60 °C, 4 h
rt, 4 h
60 °C, 4 h
60 °C, 4 h
78:22
80:20
87:13
39:61
37:63
64:36
NaI-DBU
NaH
LiCl-DBU
LiCl-DBU
NaH
23
53b
67b
1
a
The addition was carried out over the specified time. The final concentration was 0.01 mol Lꢀ1
The corresponding Me ester was obtained.
.
b
The results of the intramolecular HWE reaction of 8 are summa-
11% yield. The formation of oligomers was suppressed when the
reaction was performed in refluxing THF and 72% yield of 14 was
obtained however with disappointing 78:22 selectivity (entry 2).
In this reaction, NaI-DBU gave a similar result (entry 3). The
o-tBuC6H4 reagent 8b reacted in the presence of 3 equiv of NaH
at 60 °C to give 14 in 79% yield with 87:13 selectivity (entry 4).
Thus, the 16-membered Z-14 was obtained in a good yield with
good selectivity from either the Ph reagent 8a or the o-tBuC6H4
reagent 8b. On the other hand, E-14 was obtained from the Et
reagent 8c in a low yield and with low selectivity using LiCl-DBU
in MeCN (entry 5). The yield was improved using the smaller Me
reagent 8d but the selectivity was still low (entry 6). The use of
NaH in THF also brought about low Z selectivity for 8d (entry 7).
The reactions of 7, 9, 11, and 12 were similarly performed and
the results are summarized in Figure 1. While the reaction of the
Ph reagent 7a at room temperature gave mainly oligomeric
by-products in 78% yield, the reaction in refluxing THF gave the
13-membered compound 15 in 70% yield with 76:24 Z-selectivity
along with oligomers (11%). The use of the o-tBuC6H4 reagent 7b
brought some improvement of the selectivity, but the yield was
miserable. It seems that the intramolecular HWE reaction is unfa-
vorable for 7 bearing a shorter alkyl chain aldehyde because of ring
strain. The 14-membered cyclic compound Z-16 was more selec-
tively available using the Ph reagent 9a or the o-tBuC6H4 reagent
9b with 84:16 and 87:13 Z selectivity in 69 and 57% yield, respec-
tively. The reaction of the o-tBuC6H4 reagent 11b in the presence of
3 equiv of NaH at 60 °C occurred smoothly to give the 17-
membered compound 17 with 92:8 Z selectivity in 75% yield. The
reaction of the Et reagent 11c using LiCl-DBU in MeCN gave E-17
in 37:63 E selectivity in 56% yield. The 18-membered cyclic com-
pound 18 was also prepared from the o-tBuC6H4 reagent 12b using
NaH in THF at 60 °C in 69% yield with 88:12 selectivity. A similar
89:11 selectivity was obtained from the reaction at room temper-
ature in 65% yield.
rized in Table 2. Using both high dilution conditions and NaH as a
base at room temperature, the 16-membered compound 14 was
obtained in 66% yield with 91:9 Z-selectivity using the Ph reagent
8a (entry 1). Oligomeric cyclic compounds were also obtained in
base
CO2Et
CO2Et
(3 eq)
(RO)2P(O)CHCO 2Et
(CH2)11CHO
13
13
THF
7a R = Ph, 7b R = o-tBuC6H4
Z-15
E-15
conditions
Z:E yield olygomer
7a
7b
NaH, reflux, 15 h 76:24 70%
11%
28%
NaH, reflux, 6 h
84:16 29%
EtO2C
base
EtO2C
(3 eq)
(RO)2P(O)CHCO2Et
14
14
O
THF
(CH2)6O(CH2)5CHO
O
9a R = Ph, 9b R = o-tBuC6H4
Z-16
E-16
conditions
Z:E yield olygomer
9a
9b
NaH, rt, 4 h
NaH, 60 °C, 4 h
84:16 69%
87:13 57%
16%
4%
CO2Et
CO2Et
base
(3 eq)
(RO)2P(O)CHCO2Et
O
17
17
(CH2)9O(CH2)5CHO
O
E-17
11b R = o-tBuC6H4, 11c R = Et
Z-17
conditions
Z
:
E
yield olygomer
11b
11c
NaH-THF, 60 °C, 4 h
LiCl-DBU-MeCN, 60 °C, 4 h 37:63 56%
92: 8 75%
-
5%
In summary, the intramolecular HWE reaction of the substrates
7–12 (R = Ph or o-tBuC6H4) gives the corresponding 13–18-
membered cyclic alkenes Z-13–Z-18 selectively in good to high
yields using NaH in THF at room to refluxing temperature. The
substrates should be added to a THF suspension containing NaH
over a few hour-period. On the other hand, both the Et or Me re-
agents gave mainly cyclic E compounds by using LiCl-DBU in MeCN
and mainly Z compounds by using NaH in THF with low selectivity.
We believe the Z:E selectivity is kinetically controlled.14 Compared
with the diarylphosphonate reagents, the diethylphosphonate
reagents are less reactive and gave very low yields. Although the
E-selective formation of the macrocyclic compounds are not
CO2Et
CO2Et
18
base
(3 eq)
(RO)2P(O)CHCO 2Et
18
THF
(CH2)10O(CH2)5CHO
12b R = o-tBuC6H4
O
O
E-18
Z-18
conditions
NaH, 60 °C, 4 h
NaH, rt, 4 h
Z:E yield olygomer
12b
12b
88:12 69%
89:11 65%
-
3%
Figure 1.

K. Ando, K. Sato / Tetrahedron Letters 52 (2011) 1284–1287
1287
Tetrahedron Lett. 1986, 27, 2157–2160; (d) Zhang, J.; Xu, X. Tetrahedron Lett.
2000, 41, 941–943.
satisfactory, we succeeded in showing that the Z-selective intra-
molecular HWE reaction is useful for the synthesis of macrocyclic
alkenes.
7. (a) Marshall, J. A.; DeHoff, B. S.; Cleary, D. G. J. Org. Chem. 1986, 51, 1735–
1741; (b) Medina, J. C.; Guajardo, R.; Kyler, K. S. J. Am. Chem. Soc. 1989, 111,
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Acknowledgment
8. Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y. Tetrahedron 1999, 55,
2183.
9. Touchard, F. P.; Capelle, N.; Mercier, M. Adv. Synth. Catal. 2005, 347, 707–
711.
10. A typical procedure for the Z-selective intramolecular HWE reaction (entry 8 in
Table 1): To a stirred suspension of NaH (55%) (0.026 g, 0.60 mmol) in THF
(12 mL) was added a solution of 10b (0.130 g, 0.20 mmol) in THF (8 mL) at
This work was partially supported by Grants-in-Aid for
Scientific Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
References and notes
60 °C over 4 h under Ar atmosphere by a motor-driven syringe and the
resulting mixture was stirred for 0.5 h at the same temperature. The reaction
was quenched with water (15 mL) and extracted with AcOEt (20 mL). The
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