Rapid library synthesis of amphiphiles based on a dioxinone scaffold and identification of nonlamellar liquid crystals

Article abstract of DOI:10.1055/s-0034-1379184

Linear and branched amphiphiles with different lengths of lipids and different numbers of hydroxyl groups were rapidly synthesized based on a dioxinone scaffold. The liquid crystalline (LC) properties of the synthesized amphiphiles in excess water were investigated by polarizing optical microscopy and small-angle X-ray scattering (SAXS) analysis. Novel β-keto ester based amphiphiles that formed non-lamellar, inverted LC phases were identified.

Full text of DOI:10.1055/s-0034-1379184

2806▌
LETTER
lRettaerpid Library Synthesis of Amphiphiles Based On a Dioxinone Scaffold and
Identification of Nonlamellar Liquid Crystals
Rapid Library Synthesis of Amphiphiles
Shinichiro Fuse,*a Kentarou Nakamura,a Yuto Mifune,a Hironori Marubayashi,b Ichiro Hijikuro,c Shuichi Nojima,b
Hiroshi Tanaka,a Takashi Takahashid
a
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552, Japan
Fax +81(3)57342884; E-mail: sfuse@apc.titech.ac.jp
b
Department of Organic and Polymeric Materials, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1-H125
Ookayama, Meguro-ku, Tokyo 152-8552, Japan
Fax +81(3)57342888; E-mail: snojima@polymer.titech.ac.jp
c
ChemGenesis Incorporated, 4-10-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan
Fax +81(3)56525578; E-mail: ihijikuro@chemgenesis.com
d
Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama-shi 245-0066, Japan
Fax +81(45)8591382; E-mail: ttak@ym.hamayaku.ac.jp
Received: 04.08.2014; Accepted after revision: 29.08.2014
yl-1,3-dioxin-4-one10 and its derivatives are attractive as
Abstract: Linear and branched amphiphiles with different lengths
molecular scaffolds for assembling building blocks be-
of lipids and different numbers of hydroxyl groups were rapidly
cause they provide multiple reaction centers for various
synthesized based on a dioxinone scaffold. The liquid crystalline
(LC) properties of the synthesized amphiphiles in excess water were
chemical modifications.11 Recently, we reported the effi-
investigated by polarizing optical microscopy and small-angle cient synthesis of multisubstituted β-keto amides via a se-
X-ray scattering (SAXS) analysis. Novel β-keto ester based amphi-
philes that formed non-lamellar, inverted LC phases were identi-
fied.
quential four-component coupling approach that was
based on a dioxinone scaffold.12
Herein, we report the synthesis of a small library identify-
ing novel amphiphiles that form inverted hexagonal and
cubic phases in excess water at ambient temperature via a
multicomponent coupling approach based on a dioxinone
Key words: multicomponent reaction, combinatorial chemistry, al-
kylation, nucleophilic addition, palladium
scaffold.
Amphiphiles that form nonlamellar liquid crystalline
Our preliminary study indicated that the ratio between the
total number of carbon atoms in the lipids A (= NCA) and
B (= NCB) to the number of hydroxyl groups in alcohol C
(= NOH) was important for the LC properties of amphi-
philes (Figure 1). We assumed that 0.8 ≤ (NCA + NCB)/(NCA
+ NCB + NOH) would be suitable for forming liquid crys-
tals. We planned to construct a small library that would
meet the above criteria via a sequential multicomponent
coupling approach based on a dioxinone scaffold toward
the identification of novel nonlamellar liquid crystals
(Figure 1). The first step, nucleophilic alkylation of diox-
inone with lipids A (geranyl group, tetrahydrofarnesyl
group, phytyl group, or none), would afford the alkylated
dioxinone products. The following retro-Diels–Alder re-
action of dioxinone under heating conditions would gen-
erate highly active acylketene in situ. The nucleophilic
addition of alcohols C [protected glycerol, pentaerythri-
tol,13 or branched oligoglycerol (BGL14)] toward the acyl-
ketene would afford β-keto esters, and a subsequent
Tsuji–Trost coupling with lipids B (geranyl group × 1, or
× 2, or none) and the final removal of protecting groups
from building blocks C would afford the desired amphi-
philes in short steps. This approach allowed us to obtain
both linear and branched amphiphiles with various
lengths of lipids and various numbers of alcohols in short
steps.
(LC) phases such as the inverted hexagonal phase and the
inverted cubic phase are garnering considerable attention,
because they retain an extremely high surface area com-
pared with the lamellar LC phase, and can solubilize hy-
drophobic, hydrophilic, and amphiphilic compounds.1
The nonlamellar liquid crystals show promise as biomi-
metics,2 as matrices for protein crystallization,3 and in
particular, as drug carriers.4 The best known nonlamellar
LC drug carrier is glycerol monooleate, which can form
an inverted cubic phase.4a,5
However, the further use of nonlamellar liquid crystals in
science and technology has been hampered by a limited
number of reported amphiphiles that can form inverted
hexagonal and cubic phases in water.6 Accurate theoreti-
cal predictions for the LC properties of amphiphiles have
not been simple, although the critical packing parameter7
has been useful for a qualitative estimation of the LC
properties. Combinatorial chemistry8 is useful when the
rational design of molecules is difficult. Molecular scaf-
folds that allow orthogonal structural modifications are
highly valuable in combinatorial library synthesis for drug
discovery and material development.9 The 2,2,6-trimeth-
SYNLETT 2014, 25, 2806–2813
Advanced online publication: 20.10.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
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2
0
9
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DOI: 10.1055/s-0034-1379184; Art ID: st-2014-u0650-l
© Georg Thieme Verlag Stuttgart · New York

LETTER
Rapid Library Synthesis of Amphiphiles
2807
Figure 1 Synthesis of β-keto ester based amphiphiles library via a sequential multicomponent coupling approach using a dioxinone scaffold
The first step involved the nucleophilic alkylation of the hydronerolidol (2), and isophytol (3) afforded allyl bro-
2,2,6-trimethyl-1,3-dioxin-4-one (7) with alkyl bromides mide 4 as a sole E-isomer, and 5 and 6 as a mixture of E-
4–6 (Scheme 1).15 The bromination of geraniol (1), tetra- and Z-isomers. The obtained allyl bromides 4–6 were
a)
OH
geraniol (1)
OH
OH
a)
a)
R
Br
tetrahydronerolidol (2)
isophytol (3)
= R: 4
= R: 5
= R: 6
O
O
O
7
O
O
R
+
O
O
O
O
b)
(E)
(Z)
+
R
O
O
R
O
isomer a
isomer b
isomer c
= R: 8
= R: 9
= R: 10
Scheme 1 Nucleophilic alkylation of 2,2,6-trimethyl-1,3-dioxin-4-one (7) with alkyl bromides 4–6. Reagents and conditions: (a) PBr3, THF,
0 °C, 0.5 h; (b) (i-Pr)2NH, n-BuLi, 7, CuBr·Me2S, –78 °C to 0 °C, 1 h for 4, 2.5 h for 5, 1 h for 6, 64% in 2 steps for 8 (8a:8b:8c = 86:0:14),
54% in 2 steps for 9 (9a:9b:9c = 66:23:11), 58% in 2 steps for 10 (10a:10b:10c = 72:14:14).
© Georg Thieme Verlag Stuttgart · New York
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S. Fuse et al.
LETTER
used for the following nucleophilic alkylation without fur- The third step involved the Tsuji–Trost coupling16 be-
ther purification. The alkylation of the dioxinone 7 at its tween β-keto esters 14–18, and geranylmethylcarbonate17
γ-position afforded the desired alkylated dioxinones 8–10 (24) as shown in Scheme 2 and Scheme 3. We controlled
in satisfactory yields. In all cases, generation of SN2′ prod- the number of geranyl groups that were introduced into
ucts 8c–10c was observed by 1H NMR analyses (≤9%). In the β-keto esters by altering the quantity of 24 that was
the cases of 9 and 10, generation of Z-isomers 9b and 10b used in the coupling reaction. Monogeranylated products
was observed by 1H NMR analyses (12% and 8%, respec- 25 and 28–30 were obtained by using one equivalent of 24
tively). The alkylated dioxinones 8–10 were used for the against β-keto esters. Digeranylated products 26, 27, and
second step without the isolation of either component.
31–33 were obtained by using 2.5 equivalents of 24
against β-keto esters. Most of the products were obtained
as a mixture of E- and Z-isomers, and it was difficult to de-
termine the ratio of the isomers from NMR analyses.
The second step involved the nucleophilic addition of al-
cohols 11–13 toward in situ generated acyl ketenes from
dioxinones 7–10 (Table 1). The retro Diels–Alder reaction
of the dioxinones proceeded under heating conditions The final step involved acidic deprotection for the prepa-
(toluene, reflux) to afford highly electrophilic acyl ration of amphiphiles 34–4818 (Scheme 4). Fifteen target
ketenes. The nucleophilic addition of alcohols 11–13 pro- amphiphiles were obtained in good to excellent yields.
ceeded in high yields. In most cases, the isomer originat- Most of the products were obtained as a mixture of E- and
ing from the SN2′ product in the first step could be Z-isomers.
removed by silica gel column chromatography, whereas
Z-isomers could not be separated.
All the obtained compounds were treated with excess wa-
ter and stirred well with a spatula. As a result, highly vis-
cous and clear liquids were obtained for two compounds,
Table 1 Nucleophilic Addition of Alcohols 11–13 toward In Situ Generated Acyl Ketenes from Dioxinones 7–10a
O
O
O
O
O
O
O
O
•
R1
7
HO
HO
O
O
O
O
O
O
O
O
R1
11
HO
O
O
= R1: 8
= R1: 9
= R1: 10
O
13
12
O
O
R2
R1
O
14–23
Entry
Dioxinone
Alcohol
Time
Product
Yieldb
1
2
7
7
11
12
11
12
13
11
12
11
12
13
3.5 h
4 h
14
15
16
17
18
19
20
21
22
23
quant.
82%
90%
83%
93%
70%
80%
91%
85%
95%
3
8
2 h
4
8
4 h
5
8
2 h
6
9
2 h
7
9
2.5 h
2 h
8
10
10
10
9
2 h
10
2.5 h
a Reaction conditions: 7, 8, 9, or 10, and 11, 12, or 13, toluene, reflux.
b Isolated yields.
Synlett 2014, 25, 2806–2813
© Georg Thieme Verlag Stuttgart · New York

LETTER
Rapid Library Synthesis of Amphiphiles
2809
35 and 37, which is a feature of an inverted cubic phase.
Three compounds, 42, 44, and 48, afforded viscous and
white liquid, which is a feature of an inverted hexagonal
phase. Three compounds 34, 36, and 38, afforded a less
viscous and white liquid, which is a feature of a lamellar
liquid crystal. We observed no signs of LC phase forma-
tion in other compounds.
O
O
OMe
24
a
O
O
O
O
O
R
R
O
O
O
= R: 14
= R: 15
Polarizing optical microscopy analysis of 35 at room tem-
perature showed no obvious texture. This result indicated
that 35 had formed an inverted cubic phase, because a cu-
bic phase is isotropic, and, therefore, no texture should be
observed (for the details for polarizing optical microscopy
analysis of 34–38, 42, 44, and 48, see supporting informa-
tion).
O
= R: 25
O
O
O
O
O
O
R
O
b
Small-angle X-ray scattering (SAXS) analysis of the eight
compounds, 34–38, 42, 44, and 48, was performed at
room temperature (20 °C), as shown in Figure 2 and Fig-
ure 3. In the SAXS pattern of the compound 35, there were
four reflections that corresponded to d spacings of 6.04,
5.26, 3.32, and 3.16 nm (Figure 2, a). The relative posi-
tions of these reflections were √6:√8:√20:√22, which
were in good agreement with the (211), (220), (420), and
(332) reflections of an inverted cubic phase with Ia3d
symmetry.
O
= R: 26
= R: 27
O
O
O
O
Scheme 2 Tsuji–Trost coupling between β-keto esters 14 and 15 and
geranylmethylcarbonate (24). Reagents and conditions: (a) geranyl-
methylcarbonate (24; 1 equiv), Pd2(dba)3 (2.5 mol%), dppe (10
mol%), THF, 60 °C, 9 h for 25, 65%; (b) geranylmethylcarbonate (24;
2.5 equiv), Pd2(dba)3 (2.5 mol%), dppe (10 mol%), THF, 60 °C, 15 h
for 26, 13 h for 27, 86% for 26, 90% for 27.
O
O
= R: 28
O
O
OMe
24
a
O
O
O
O
O
R
R
O
O
= R: 29
= R: 30
O
O
O
O
= R: 16
= R: 17
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
= R: 31
= R: 32
= R: 18
O
R
O
b
O
O
O
O
O
O
O
O
O
= R: 33
Scheme 3 Tsuji–Trost coupling between β-keto esters 16–18 and geranylmethylcarbonate (24). Reagents and conditions: (a) geranylmethyl-
carbonate (24; 1 equiv), Pd2(dba)3 (2.5 mol%), dppe (10 mol%), THF, 60 °C, 9 h for 28, 13 h for 29, 11 h for 30, 63% for 28, 57% for 29, 77%
for 30; (b) geranylmethylcarbonate (24; 2.5 equiv), Pd2(dba)3 (2.5 mol%), dppe (10 mol%), THF, 60 °C, 4 h for 31, 11 h for 32, 16 h for 33,
97% for 31, 96% for 32, 96% for 33.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2806–2813

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S. Fuse et al.
LETTER
O
O
a
R
R
O
O
16, 19–23, 25–33
34–48
O
O
O
O
OH
OH
OH
OH
OH
OH
O
O
O
O
= R
O
= R
OH
= R
= R
O
O
O
= R
= R
OH
OH
O
O
O
O
O
O
OH
O
OH
O
34 (91%)
OH
OH
O
35 (78%)
O
O
O
OH
OH
OH
O
OH
OH
36 (86%)
37 (71%)
O
O
O
OH
OH
OH
OH
38 (56%)
O
O
O
OH
OH
OH
O
39 (95%)
O
O
O
O
O
O
OH
OH
O
O
O
OH
OH
OH
O
OH
OH
40 (quant.)
41 (quant.)
42 (72%)
O
O
O
O
O
OH
O
OH
OH
OH
OH
43 (88%)
44 (92%)
OH
O
O
O
O
O
OH
OH
OH
O
OH
O
OH
O
45 (96%)
O
O
OH
OH
OH
OH
46 (70%)
O
O
O
O
O
OH
OH
OH
O
47 (98%)
48 (98%)
Scheme 4 Acidic deprotection to obtain aimed amphiphiles. Reagents and conditions: (a) TFA, THF–H2O, 60 °C, 20 h for 34, 35, and 37, 50
°C, 7 h for 36, 60 °C, 10 h for 38, and 42, 50 °C, 2 h for 39, 50 °C, 24 h for 40, 41, and 43, 50 °C, 10 h for 44, 60 °C, 14 h for 45, 50 °C, 48 h
for 46, 60 °C, 8 h for 47, 60 °C, 2 h for 48.
Synlett 2014, 25, 2806–2813
© Georg Thieme Verlag Stuttgart · New York

LETTER
Rapid Library Synthesis of Amphiphiles
2811
Figure 2 SAXS patterns for the cubic phase of (a) compound 35, and
for the inverted cubic–inverted hexagonal mixed phase of (b) com-
pound 37
Figure 4 The relationship between the structures of amphiphiles and
their LC phases. NCA and NCB refer to the number of the carbon atoms
in the lipids A and B, respectively. NOH is the number of the hydroxyl
group in the alcohol C. The green, purple, and blue areas show per-
centages of NCA, NCB, and NOH in NCA + NCB + NOH, respectively. ‘L,’
‘C,’ and ‘H’ indicate the ‘lamellar phase,’ ‘inverted cubic phase,’ and
‘inverted hexagonal phase,’ respectively.
All the results, including polarizing optical microscopy
and SAXS analyses, supported the formation of an invert-
ed cubic phase for compound 35. As for the SAXS pattern
of compound 37, eight reflections corresponding to d
spacings of 5.87, 5.51, 4.79, 4.13, 3.38, 3.17, 2.92, and
2.75 nm appeared (Figure 2, b). The relative positions of
the six Bragg peaks were √2:√3:√4:√6:√8:√9, all of which
were in good agreement with the (110), (111), (200),
(211), (220), and (300) reflections of an inverted cubic
phase with Pn3m symmetry. The relative positions of the
remaining two Bragg peaks were 1*:√3*, which were in
good agreement with the (10), and (11) reflections of an
inverted hexagonal phase. This result indicated that com-
pound 37 had formed an inverted cubic–inverted hexago-
nal mixed phase.
Figure 3 SAXS patterns for the lamellar phase of (a) compounds 34,
36, and 38, and for the inverted hexagonal phase of (b) compounds 42,
44, and 48
In the SAXS pattern of compounds 34, 36, and 38, there
were two or three reflections that corresponded to d spac-
ings of 4.55 and 2.23 nm for 34; 4.26 and 2.13 nm for 36;
4.75, 2.38, and 1.59 nm for 38 (Figure 3, a). The relative
positions of these peaks were 1:2:3, which were in good
agreement with the reflections of a lamellar phase. In the
SAXS patterns of compounds 42, 44, and 48, three reflec-
tions appeared corresponding to d spacings of 2.97, 1.71,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2806–2813

2812
S. Fuse et al.
LETTER
(c) Larsson, K. Curr. Opin. Colloid Interface Sci. 2000, 5,
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and 1.48 nm for 42; 3.13, 1.81, and 1.57 nm for 44; and,
3.42, 1.98, and 1.71 nm for 48 (Figure 3, b). The relative
positions of these peaks were 1:√3:2, which were in good
agreement with the (10), (11), and (20) reflections of an
inverted hexagonal phase. The result indicated com-
pounds 34, 36, and 38 formed a lamellar phase, whereas,
compounds 42, 44, and 48 formed an inverted hexagonal
phase.
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The structure–LC phase relationships were considered
based on the results shown in Figure 4. The green, purple,
and blue areas show the percentages of NCA, NCB, and NOH
against NCA + NCB + NOH, respectively.
All the lamellar phase and inverted cubic phase liquid
crystals were found in linear compounds with no lipid B,
The percentage of NCA against NCA + NOH seemed to be a
critical factor that determined the lamellar phase or invert-
ed cubic phase.
Compounds 35 and 37 (partially) had both formed an in-
verted cubic phase, and both contained more than 88% of
NCA against NCA + NOH. Compounds 34, 36, and 38 had all
formed the lamellar phase, and all contained less than
87% of NCA against NCA + NOH. All the inverted hexagonal
liquid crystals were found in branched compounds that
contained lipid B. Interestingly, compounds 42, 44, and
48 had formed an inverted hexagonal phase and contained
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We have demonstrated the rapid synthesis of a small li-
brary of amphiphiles based on a dioxinone scaffold. Both
linear and branched amphiphiles with different lengths of
lipids and different numbers of hydroxyl groups were pre-
pared in good yields in short steps. The LC properties of
the synthesized amphiphiles in an excess amount of water
were investigated by polarizing optical microscopy and
SAXS analyses. We identified novel β-keto ester based
amphiphiles that form non-lamellar LC phases in an ex-
cess amount of water. These would be valuable in the fu-
ture development of useful drug carriers.
Acknowledgment
The authors thank Mr. Shintaro Nakagawa, Tokyo Institute of Tech-
nology, for helping with the SAXS analysis, and Ms. Saki Naka-
mura, Tokyo Institute of Technology, for helping with the initial
synthetic study. The authors also thank the New Energy and Indu-
strial Development Organization (NEDO) for financial support.
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References and Notes
(1) (a) Chang, D. P.; Nylander, T. Nonlamellar Lipid Liquid
Crystalline Structures at Interfaces, In Self-Assembled
Supramolecular Architectures: Lyotropic Liquid Crystals;
Garti, N.; Somasundaran, P.; Mezzenga, R., Eds.; John
Wiley & Sons, Inc: Hoboken, 2012. (b) Yang, D.; Armitage,
B.; Marder, S. R. Angew. Chem. Int. Ed. 2004, 43, 4402.
Synlett 2014, 25, 2806–2813
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hattori, H.; Matsumura, K.; Itou, T.; Kawamura, T.; Kita, T.;
Rapid Library Synthesis of Amphiphiles
2813
chromatography on silica gel to give products 8, 9, or 10 as
a mixture of isomers.
Nishida, H.; Arakaki, N. Bioorg. Med. Chem. Lett. 2012, 22,
5051.
General Procedure for the Preparation of β-Keto Esters:
To stirred solutions of dioxinone 7, 8, 9, or 10 (1.00 equiv),
solutions of alcohol 11, 12, or 13 in anhyd toluene were
added at r.t. under an argon atmosphere. After being stirred
at 130 °C, the reaction mixtures were cooled and
(15) (a) Heinemann, C.; Demuth, M. J. Am. Chem. Soc. 1997,
119, 1129. (b) Cramer, N.; Buchweitz, M.; Laschat, S.; Frey,
W.; Baro, A.; Mathieu, D.; Richter, C.; Schwalbe, H. Chem.
Eur. J. 2006, 12, 2488. (c) Graalfs, H.; Fröhlich, R.; Wolff,
C.; Mattay, J. Eur. J. Org. Chem. 1999, 1999, 1057.
(16) (a) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.;
Takahashi, K. J. Org. Chem. 1985, 50, 1523. (b) Tsuji, J.;
Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 4387.
(c) Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95,
292.
concentrated in vacuo. The residue was purified by column
chromatography on silica gel to give products 14, 15, 16, 17,
18, 19, 20, 21, 22, or 23 as a mixture of E- and Z-isomers.
General Procedure for the Preparation of Branched
Lipids: To stirred solutions of β-keto ester 14, 15, 16, 17, or
18 (1.00 equiv) and geranylmethylcarbonate (24; 1.0 or 2.5
equiv) in anhyd THF were added Pd2(dba)3 (0.0250 equiv)
and dppe (0.100 equiv) at r.t. under an argon atmosphere.
After being stirred at 60 °C, the reaction mixtures were
cooled, filtered through Celite and concentrated in vacuo.
The residue was purified by column chromatography on
silica gel to give products 25, 26, 27, 28, 29, 30, 31, 32, or
33 as a mixture of E- and Z-isomers.
General Procedure for Acidic Deprotection: To a stirred
solution of protected alcohols (1.00 equiv) in THF–H2O
(4:1) was added TFA (1.10–2.00 equiv) at r.t. under an argon
atmosphere. After being stirred at 50 °C or 60 °C, the
reaction mixture was cooled and concentrated in vacuo. The
residue was purified by column chromatography on silica
gel to give the desired amphiphiles.
(17) Guzman-Martinez, A.; Hoveyda, A. H. J. Am. Chem. Soc.
2010, 132, 10634.
(18) General Procedure for the Preparation of Alkylated
Dioxinones: To a stirred solution of alcohol 1, 2, or 3 (1.00
equiv) in anhyd THF was added a solution of PBr3 (0.400
equiv) in anhyd THF dropwise at 0 °C under an argon
atmosphere. After being stirred at the same temperature for
30 min, the reaction mixture was poured into H2O, also at 0
°C. The aqueous layer was extracted with two portions of
Et2O. The combined extract was washed with brine, dried
over MgSO4, filtered and concentrated in vacuo. The residue
was used in the next reaction without further purification.
To a stirred solution of (i-Pr)2NH (2.40 equiv) in anhyd THF
was added n-BuLi (1.60 M solution in hexane, 2.20 equiv)
dropwise at –78 °C under an argon atmosphere. After being
stirred at 0 °C for 30 min, 2,2,6-trimethyl-1,3-dioxin-4-one
(7; 2.00 equiv) in anhyd THF was added dropwise at –78 °C
under an argon atmosphere. After being stirred at 0 °C for
30 min, CuBr·Me2S (1.00 equiv) in anhyd THF was added at
–78 °C under an argon atmosphere. After being stirred at 0
°C for 30 min, crude alkyl bromide 4, 5, or 6 in anhyd THF
was added dropwise at –78 °C under an argon atmosphere.
After being stirred at 0 °C, the reaction mixture was poured
into sat. aq NH4Cl at 0 °C. The aqueous layer was extracted
with three portions of Et2O. The combined extract was
washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by column
48 (major isomer): 1H NMR (400 MHz, CDCl3): δ = 5.15
(quint, J = 4.8 Hz, 1 H), 5.02–5.09 (m, 4 H), 4.88 (t, J = 6.6
Hz, 2 H), 3.79 (d, J = 4.8 Hz, 4 H), 3.66–3.73 (br, 8 H), 3.48
(br, 2 H), 2.76–2.88 (br, 4 H), 2.58 (br s, 4 H), 2.46 (t, J = 7.3
Hz, 2 H), 2.23 (dt, J = 7.3, 7.3 Hz, 2 H), 1.93–2.05 (m, 12 H),
1.67 (s, 9 H), 1.59–1.60 (m, 18 H). 13C NMR (100 MHz,
CDCl3): δ = 207.7, 171.8, 139.2, 136.5, 131.6, 131.4, 124.1,
123.9, 122.4, 117.7, 81.1, 72.2, 67.9, 63.5, 62.4, 62.2, 39.9,
39.7, 39.3, 30.2, 26.7, 26.5, 25.6, 22.2, 17.7, 16.3, 16.0. FT-
IR (KBr): 3405, 2926, 1710, 1445, 1377, 1277, 1217, 1124,
1050, 833 cm–1. HRMS (ESI–TOF): m/z [M + H]+ calcd. for
C43H73O9: 733.5255; found: 733.5240.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2806–2813

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