Total Synthesis of δ-Sanshool and Analogues Thereof

Article abstract of DOI:10.1055/s-0035-1561580

Two simple synthetic approaches were developed for the total synthesis of δ-sanshool, an isobutylamide characterized by a C₁₄ pentaunsaturated chain with all trans double bonds and proposed as a promising lead for the treatment of type-1 diabetes due to its dual activity on cannabinoid (CB) receptors. The syntheses are based on a suitably protected core fragment derived from 1,4-butanediol. These strategies also enable the preparation of small libraries of chemical analogues modified at either the polyunsaturated alkyl chain or the amidic head for use in SAR studies.

Full text of DOI:10.1055/s-0035-1561580

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
C. Mugnaini, F. Corelli
Paper
Synthesis
Total Synthesis of δ-Sanshool and Analogues Thereof
Claudia Mugnaini*
TBDMSO
Federico Corelli
R1 = isobutyl, isopropyl, cyclopropyl
R2 = vinyl
3 steps
Dipartimento di Biotecnologie Chimica e Farmacia,
O
Università degli Studi di Siena, Via A. Moro 53100 Siena,
Italy
claudia.mugnaini@unisi.it
O
R1
TBDMSO
R2
N
H
H
R
1 = isobutyl
R2 = vinyl, hydrogen, phenyl
3 steps
H
N
TBDMSO
O
Received: 14.01.2016
Accepted after revision: 16.02.2016
Published online: 16.03.2016
pungent sensation.1 This pharmacological activity is be-
lieved to be predominantly elicited by the sanshools (Figure
1) present in the traditional medicine.2
DOI: 10.1055/s-0035-1561580; Art ID: ss-2015-z0025-op
Sanshools are a family of polyunsaturated fatty acid am-
ides (FAA) which differ in the length and in the double bond
geometry of the polyunsaturated chain, and in the potential
presence of a hydroxylated isobutyl chain linked to the am-
ide moiety.3
δ-Sanshool, an isobutylamide characterized by a C14 all-
trans pentaunsaturated chain, was isolated for the first time
in 1997 from Budo-Zanthoxylum fruit and its structure was
assigned by spectral examination.4 Due to its ability to acti-
vate the TRPV1 receptor, δ-sanshool exhibits a pungent
taste5 and has been proposed as an ingredient in formula-
tions to stimulate digestion and enhance nutrient absorp-
tion.6 More recently, starting from extracts from Zantoxy-
lum bungeanum, Moaddel and co-workers have identified
δ-sanshool as a molecule with the desired dual activity, as a
CB1 antagonist and CB2 agonist,7 for the possible therapeu-
tic treatment of type-1 diabetes.8
Abstract Two simple synthetic approaches were developed for the to-
tal synthesis of δ-sanshool, an isobutylamide characterized by a C14
pentaunsaturated chain with all trans double bonds and proposed as a
promising lead for the treatment of type-1 diabetes due to its dual ac-
tivity on cannabinoid (CB) receptors. The syntheses are based on a suit-
ably protected core fragment derived from 1,4-butanediol. These strat-
egies also enable the preparation of small libraries of chemical
analogues modified at either the polyunsaturated alkyl chain or the
amidic head for use in SAR studies.
Key words sanshools, alkamides, trienes, Horner–Wadsworth–Em-
mons reaction, cannabinoid receptors
The genus Zanthoxylum belongs to the family Rutaceae
and is represented by 250 species, mainly distributed in
North America and in East Asia. Many of these species have
been used widely in traditional medicine to treat toothache
and as food spices for their ability to evoke a tingling and
O
O
R
N
H
R
N
H
β-sanshool: R = H
hydroxy-β-sanshool: R = OH
α-sanshool: R = H
hydroxy-α-sanshool: R = OH
O
O
13
11
9
7
5
3
R
R
N
H
N
1
H
14
12
10
8
6
4
2
γ-sanshool: R = H
hydroxy-γ-sanshool: R = OH
δ-sanshool: R = H
hydroxy-δ-sanshool: R = OH
Figure 1 Examples of sanshools
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
C. Mugnaini, F. Corelli
Paper
Synthesis
MEMO
EtMgBr, HC(OEt)3
(OEt)2
MEMO
benzene
84%
H
1
Pd/BaSO4, H2
then aq HCl, 2 h,
20 °C (pH 1.4–1.6)
76%
O
EtO
P
O
EtO
N
H
H
N
MEMO
MEMO
CHO
n-BuLi 62%
O
2
TiCl4
CH2Cl2, –70 °C
90%
H
N
H
N
CBr4, PPh3
77%
HO
Br
O
O
>90%
3
Br
CHO
H
N
H
N
Ph3P
O
O
4
Z-isomer: γ-sanshool, 48%
E-isomer: δ-sanshool, 14%
Scheme 1 Synthesis of γ- and δ-sanshool according to Crombie and Fisher9
For this reason, a larger amount of the identified san-
shool was needed to continue with biological investiga-
tions. However, due to the lack of synthetic procedures for
the preparation of δ-sanshool, a reliable synthetic protocol
needed to be established which could be exploited not only
for the preparation of the target molecule, but also for the
creation of a small library of chemical congeners to be used
as SAR probes.
nation, a Wadsworth–Emmons reaction and a Wittig reac-
tion, respectively, as the key steps. Thus, in this work, a sim-
ilar disconnection approach was maintained. Three main
issues were considered: the attainment of the E-geometry
at the C8–C9 double bond, the commercial availability of
the main building blocks, and the possibility to obtain ana-
logues modified at both the polyunsaturated alkyl chain
and the amide head.
In 1985, twelve years before its isolation and characteri-
zation, δ-sanshool was described by Crombie and Fisher as
a side product in the preparation of γ-sanshool, differing
from its δ-isomer by the Z geometry of the C8–C9 double
bond (Scheme 1).9 In this procedure, MEM-protected 4-
pentyn-1-ol 1 was elaborated, in two steps, into MEM-pro-
tected (E)-6-hydroxyhex-2-enal 2 via reaction with ethyl
orthoformate in the presence of a Grignard reagent and
subsequent stereoselective reduction of the triple bond and
pH-controlled deacetalization. Wadsworth–Emmons con-
densation followed by alcohol deprotection gave the key in-
termediate 3, which was readily converted into the corre-
sponding phosphonium salt 4. Wittig reaction with (2E,4E)-
hexa-2,4-dienal afforded the desired product, γ-sanshool,
in 48% yield and the side product, δ-sanshool, in 14% yield.
Therefore, δ-sanshool was obtained in 3% overall yield in
seven steps.
On this basis, a suitably protected core fragment arising
from 1,4-butanediol (fragment B in Figure 2) was selected
as the starting material to be functionalized via two
Wadsworth–Emmons reactions to install the A and C frag-
ments (Figure 2).
H
N
O
A
B
C
core
triene
amide head
Figure 2 Disconnection approach
In a first approach, the introduction of the amide head
and the triene moiety in a C + B + A sequence was pursued.
Introducing the triene moiety at the end of the synthesis
has important advantages including the chemical stability
of the intermediates10,11 and the possibility to produce
structural modifications at the alkyl chain level, while
keeping the amide head unchanged. In particular, the key
synthon 512 (Scheme 2) was obtained by Swern oxidation of
commercially available 4-[(tert-butyldimethyl)silyl]oxybu-
However, the experimental protocol was not included in
the published manuscript. As a result, the synthesis of δ-
sanshool has never been reported in detail.
The synthesis of γ-sanshool proposed by Crombie and
Fisher presented the generation of the C2–C3, C4–C5 and
C8–C9 double bonds by means of a stereoselective hydroge-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
C. Mugnaini, F. Corelli
Paper
Synthesis
tan-1-ol, which without further purification was con-
densed with phosphonate 613 in the presence of LiOH in
THF at reflux temperature11 to give a mixture of the dienes
7 and 8. The ratio of dienes 7/8, evaluated by 1H NMR analy-
sis of the crude mixture, was 5:1 with a total yield of 46% of
the E-isomer 7 (calculated over two steps).
After chromatographic separation, compound 7 was
deprotected with TBAF and the resulting alcohol 3 was con-
verted into the corresponding aldehyde 9 by Swern oxida-
tion. δ-Sanshool was obtained in 20% yield as a single iso-
mer by reacting 9 with phosphonate 1014 in the presence of
n-BuLi in THF at –78 °C. This approach provided the target
compound, δ-sanshool, in five steps and 7% overall yield,
starting from 4-[(tert-butyldimethyl)silyl]oxybutan-1-ol.
OH
TBDMSO
(COCl)2, DMSO
Et3N, CH2Cl2, –78 °C
O
H
TBDMSO
5
OEt
H
EtO
P
N
O
O
6
LiOH, 4 Å MS, THF, reflux
H
N
TBDMSO
O
7: E-isomer 46%
8: Z-isomer 9%
TBAF, THF
0 °C to r.t.
86%
H
N
HO
O
3
(COCl)2, DMSO
Et3N, CH2Cl2, –78 °C
72%
H
O
H
N
O
OEt
OEt
9
OEt
OEt
P
P
O
O
14
10
OEt
OEt
23%
n-BuLi, THF, –78 °C
n-BuLi, THF, –78 °C
P
20%
12%
O
13
n-BuLi, THF, –78 °C
H
H
N
N
O
O
H
N
12
δ-sanshool
O
11
Scheme 2 Synthesis of δ-sanshool and analogues 11 and 12 via the C + B + A sequence
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
C. Mugnaini, F. Corelli
Paper
Synthesis
Similarly, compounds 11 and 12, characterized by a modifi-
cation of the triene portion of δ-sanshool, were obtained by
reacting the common intermediate 9 with the commercial-
ly available phosphonates 13 and 14, respectively. Both re-
actions gave the E-isomer as the sole product in 12% and
23% yields, respectively. The low yields of the Horner–
Wadsworth–Emmons reactions leading to δ-sanshool, 11
and 12 are due to the formation of degradation products
whose synthesis could not be avoided even on slightly
changing the reaction conditions.
sured the possibility to introduce different amide heads as
the final step of the synthesis. Accordingly, phosphonate 10
(Scheme 3) was condensed with aldehyde 5 using sec-BuLi
as the base. All-trans triene 15, obtained as the exclusive
isomer, was deprotected with TBAF and the resulting alco-
hol 16 was oxidized using Swern conditions to give the al-
dehyde 17.
Condensation of aldehyde 17 with phosphonate 6 using
LiOH in THF at reflux afforded δ-sanshool in 85% yield (14%
overall yield in four steps starting from phosphonate 10).
The putative cis isomer was obtained in trace amount after
chromatographic purification and was not characterized.
Similarly, condensation of aldehyde 17 with phosphonates
In a second approach, δ-sanshool was obtained accord-
ing to the same disconnection route but combining the
three fragments in an A + B + C fashion (Scheme 3). This en-
OEt
P
OEt
O
10
43%
5, s-BuLi, THF, –78 °C
OTBDMS
15
TBAF, THF
0 °C to r.t.
77%
OH
16
(COCl)2, DMSO
60%
Et3N, CH2Cl2, –78 °C
O
H
OEt
P
H
OEt
P
H
EtO
N
EtO
N
17
O
O
O
O
18
19
LiOH, 4 Å MS, THF, reflux
LiOH, 4 Å MS, THF, reflux
80%
70%
O
O
N
N
H
H
20
21
OEt
H
EtO
P
N
O
O
85%
6
LiOH, 4 Å MS, THF, reflux
O
N
H
δ-sanshool
Scheme 3 Synthesis of δ-sanshool and analogues 20 and 21 via the A + B + C sequence
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
C. Mugnaini, F. Corelli
Paper
Synthesis
OEt
P
H
OEt
P
OEt
1. P(OEt)3, 120 °C
2. KOH, H2O
EtO
N
R-NH2
EtO
OH
Br
R
HOBt, EDC
CH2Cl2
O
O
O
O
O
6, R = isobutyl
18, R = isopropyl
41%
55%
22
19, R = cyclopropyl 20%
Scheme 4 Synthesis of phosphonates 6, 18 and 19
18 and 19 allowed the preparation of two analogues of δ-
sanshool modified at the amide level (compounds 20 and
21, respectively).
This second approach, though preferable in terms of ste-
reoselectivity and general yields, proved to be less conve-
nient because of the chemical instability of the intermedi-
ates. These had to be stored at low temperature in the ab-
sence of light and oxygen, and had to be prepared and used
rapidly in subsequent reactions.
Phosphonates 6, 18 and 19 were prepared from ethyl 4-
bromocrotonate by an Arbuzov reaction,13 hydrolysis of the
ester moiety15 and subsequent reaction of carefully dried
acid 22 with the appropriate amine in the presence of EDC
and HOBt (Scheme 4).11
The double bond geometry of the new compounds was
assigned by decoupling experiments and comparison of the
1H NMR spectrum of synthesized δ-sanshool with data re-
ported in the literature (see the Supporting Information).
In conclusion, for the first time, a simple synthetic ap-
proach has been described for the total synthesis of δ-san-
shool and the preparation of derivatives modified either at
the lipophilic tail of the molecule or at the amide head.
However, the newly synthesized compounds proved to be
extremely unstable even when stored at –15 °C under ni-
trogen and in the absence of light. This behavior raises the
issue of their biological evaluation which must be per-
formed rapidly on freshly purified materials in order to en-
sure the robustness of the experimental outcomes. Addi-
tional studies to modify the structural skeleton of δ-san-
shool are ongoing in our laboratories with the aim of
obtaining molecules endowed with increased chemical sta-
bility.
tions: gas flow = 0.8 mL/min; temperature: 80 °C (5 min), 80–280 °C
(10 °C/min), 280 °C (10 min). Elemental analysis was performed using
a Perkin-Elmer PE 2004 elemental analyzer and the obtained data for
C, H, and N are within 0.4% of the calculated values.
(2E,4E)-8-[(tert-Butyldimethylsilyl)oxy]-N-isobutylocta-2,4-di-
enamide (7) and (2E,4Z)-8-[(tert-Butyldimethylsilyl)oxy]-N-isobu-
tylocta-2,4-dienamide (8)
Oxalyl chloride (9.7 mL, 2 M in CH2Cl2, 19.5 mmol) was diluted in
CH2Cl2 (100 mL) and the reaction mixture was cooled to –78 °C.
DMSO (2.8 mL, 39 mmol) was slowly added followed, after 15 min, by
the dropwise addition of 4-[(tert-butyldimethylsilyl)oxy]butan-1-ol
(3.0 mL, 13 mmol) in CH2Cl2 (15 mL). After the solution had been
stirred for 45 min at –78 °C, Et3N (8.1 mL, 58.5 mmol) was added. Af-
ter 1 h, the mixture was allowed to warm gradually to 0 °C, kept at
this temperature for an additional 30 min, and then quenched by the
addition of sat. aq NaHCO3 solution (50 mL). The mixture was allowed
to rest overnight and the two phases were separated. The aq layer was
extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered and the solvent evaporated to
give aldehyde 5 (yellow oil, 3.0 g), which was used in the next reaction
without further purification. A solution of phosphonate 6 (5.4 g, 19.5
mmol) in THF (50 mL) was added to a suspension of LiOH (1.6 g, 39.0
mmol) in dry THF (50 mL) in the presence of 4 Å molecular sieves. Af-
ter 10 min, a solution of aldehyde 5 (3.0 g) in THF (15 mL) was added
and the mixture was heated at reflux temperature for 2.5 h. After
cooling, the mixture was filtered and evaporated to dryness. The
crude residue was purified by column chromatography (PE–Et2O, 2:1)
to give compounds 7 (1.9 g, 6.0 mmol) and 8 (390 mg, 1.2 mmol) in
46% and 9% yields, respectively.
Compound 7
White solid; mp 78–80 °C.
1H NMR (400 MHz, CDCl3): δ = 7.14 (dd, J = 14.5 Hz, J = 10.1 Hz, 1 H),
6.11–5.96 (m, 2 H), 5.68 (d, J = 15.0 Hz, 1 H), 5.45 (br s, 1 H), 3.64 (t, J =
6.2 Hz, 2 H), 3.10 (t, J = 6.1 Hz, 2 H), 2.15 (q, J = 7.1 Hz, 2 H), 1.73 (sept,
J = 6.7 Hz, 1 H), 1.56 (quin, J = 7.0 Hz, 2 H), 0.86 (s, 3 H), 0.85 (s, 3 H),
0.82 (s, 9 H), –0.03 (s, 6 H).
Reagents were purchased from commercial suppliers and were used
without further purification. Anhydrous reactions were run under
dry N2 (positive pressure). Merck silica gel 60 was used for flash chro-
matography (23–400 mesh). Melting points were determined on a
Gallenkamp apparatus and are uncorrected. 1H NMR and 13C NMR
spectra were recorded at 400 and 100 MHz on a Bruker Avance
DPX400 spectrometer. Chemical shifts are reported relative to te-
tramethylsilane at 0.00 ppm. Mass spectral (MS) data were obtained
using an Agilent 1100 LC/MSD VL system (G1946C) with a 0.4 mL/min
flow rate using a binary solvent system of MeOH–H2O (95:5). Mass
spectra were acquired either in positive or in negative mode scanning
over the mass range of 105–1500. UV detection was monitored at 254
nm. GC–MS data were collected on a Varian Saturn 2000 GC–MS
equipped with a VF-5 ms capillary column, using the following condi-
13C NMR (100 MHz, CDCl3): δ = 166.3, 142.4, 141.2, 128.5, 121.9, 62.3,
46.9, 31.8, 29.2, 28.6, 25.9, 20.1, 18.3, –5.3.
GC–MS: tR = 23.18 min, m/z = 268 [M – t-Bu]+.
Anal. Calcd for C18H35NO2Si: C, 66.41; H, 10.84; N, 4.30. Found: C,
66.52; H, 10.85; N, 4.29.
Compound 8
Colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.45 (dd, J = 14.5 Hz, J = 11.7 Hz, 1 H),
6.00 (t, J = 11.1 Hz, 1 H), 5.77 (d, J = 14.8 Hz, 1 H), 5.73–5.67 (m, 1 H),
5.59 (br s, 1 H), 3.54 (t, J = 6.4 Hz, 2 H), 3.09 (t, J = 6.4 Hz, 2 H), 2.27 (q,
J = 7.5 Hz, 2 H), 1.73 (sept, J = 6.7 Hz, 1 H), 1.60–1.51 (m, 2 H), 0.85 (s,
3 H), 0.84 (s, 3 H), 0.81 (s, 9 H), –0.03 (s, 6 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
C. Mugnaini, F. Corelli
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 166.3, 139.3, 135.7, 126.6, 124.0, 62.5,
47.0, 32.6, 28.6, 25.9, 24.6, 20.1, –5.3.
GC–MS: tR = 22.46 min, m/z = 268 [M – t-Bu]+.
Et2O (3 × 10 mL). The combined organic layers were dried over anhy-
drous Na2SO4, filtered and the solvent was removed under vacuum.
The crude residue was purified by column chromatography.
HRMS (EI): m/z [M]+ calcd for C18H35NO2Si: 325.24; found: 325.25.
δ-Sanshool
Yield: 73 mg (20%) (eluent: PE–EtOAc, 7:3); white solid; mp 129–
132 °C.
1H NMR (400 MHz, CD3OD): δ = 7.02 (dd, J = 15.1 Hz, J = 10.6 Hz, 1 H),
6.17–6.11 (m, 1 H), 6.04–5.90 (m, 5 H), 5.86 (d, J = 15.1 Hz, 1 H), 5.63–
5.53 (m, 2 H), 2.99 (d, J = 7.0 Hz, 2 H), 2.20–2.14 (m, 4 H), 1.76–1.66
(m, 4 H), 0.85 (s, 3 H), 0.84 (s, 3 H).
13C NMR (100 MHz, CD3OD): δ = 167.7, 141.6, 140.6, 132.1, 131.7,
131.3, 131.1, 130.1, 128.8, 128.3, 122.0, 46.6, 32.4, 31.7, 28.3, 19.1,
16.9.
(2E,4E)-8-Hydroxy-N-isobutylocta-2,4-dienamide (3)
TBAF (1.9 mL, 1 M in THF, 1.9 mmol) was added at 0 °C to a solution of
compound 7 (305 mg, 0.9 mmol) in THF (10 mL). After 5 min, the re-
action mixture was allowed to warm to r.t. and stirred for 3 h. After
evaporation of the solvent, the resulting dark yellow oil was purified
by column chromatography (EtOAc–PE, 2:1 → EtOAc) to give com-
pound 3 (170 mg, 0.8 mmol) as a white solid in 86% yield.
Mp 82–84 °C.
1H NMR (400 MHz, CDCl3): δ = 7.11 (dd, J = 14.9 Hz, J = 10.4 Hz, 1 H),
6.12–5.96 (m, 2 H), 5.72 (d, J = 15.0 Hz, 1 H), 5.67 (br s, 1 H), 3.58 (t, J =
6.4 Hz, 2 H), 3.09 (t, J = 6.2 Hz, 2 H), 2.18 (q, J = 7.2 Hz, 2 H), 1.93 (br s,
1 H), 1.73 (sept, J = 6.7 Hz, 1 H), 0.86 (s, 3 H), 0.84 (s, 3 H).
GC–MS: tR = 14.50 min, m/z = 213 [M – 60]+.
Anal. Calcd for C18H27NO: C, 79.07; H, 9.95; N, 5.12. Found: C, 78.95;
H, 9.97; N, 5.13.
13C NMR (100 MHz, CDCl3): δ = 166.5, 142.0, 141.1, 128.8, 122.1, 62.1,
47.0, 31.7, 29.2, 28.6, 20.1.
(2E,4E,8E)-N-Isobutylundeca-2,4,8,10-tetraenamide (11)
GC–MS: tR = 9.82 min, m/z = 142 [M – 69]+.
Yield: 37 mg (12%) (eluent: PE–EtOAc, 7:3); white solid; mp 98–
100 °C.
Anal. Calcd for C12H21NO2: C, 68.21; H, 10.02; N, 6.63. Found: C, 68.35;
H, 9.99; N, 6.62.
1H NMR (400 MHz, CDCl3): δ = 7.11 (dd, J = 14.8 Hz, J = 10.4 Hz, 1 H),
6.27–6.18 (m, 1 H), 6.11–5.95 (m, 3 H), 5.68 (d, J = 15.0 Hz, 1 H), 5.64–
5.57 (m, 1 H), 5.38 (br s, 1 H), 5.03 (d, J = 17.0 Hz, 1 H), 4.91 (d, J = 10.1
Hz, 1 H), 3.10 (t, J = 6.5 Hz, 2 H), 2.25–2.14 (m, 4 H), 1.78–1.68 (m, 1
H), 0.86 (s, 3 H), 0.85 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.3, 141.7, 141.0, 137.0, 133.7,
131.7, 128.7, 122.2, 115.4, 46.9, 32.5, 31.8, 28.6, 20.1.
(2E,4E)-7-Formyl-N-isobutylhepta-2,4-dienamide (9)
Oxalyl chloride (590 μL, 2 M in CH2Cl2, 1.2 mmol) was diluted in
CH2Cl2 (7 mL) and the mixture was cooled to –78 °C. DMSO (170 μL,
2.3 mmol) was slowly added followed, after 15 min, by the dropwise
addition of compound 3 (165 mg, 0.8 mmol) in CH2Cl2 (3 mL). After
the solution had been stirred for 45 min at –78 °C, Et3N (490 μL, 3.5
mmol) was added. After 1 h, the reaction mixture was allowed to
warm gradually to 0 °C, kept at this temperature for an additional 30
min and then quenched by the addition of sat. aq NaHCO3 solution
(10 mL). The mixture was allowed to rest overnight and the two
phases were separated. The aq layer was extracted with CH2Cl2
(2 × 10 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered and the solvent evaporated. The crude residue was
purified by column chromatography (EtOAc–PE, 2:1) to give 9 (117
mg, 0.5 mmol) as a white solid in 72% yield.
GC–MS: tR = 20.83 min, m/z = 233 [M]+.
Anal. Calcd for C15H23NO: C, 77.21; H, 9.93; N, 6.00. Found: C, 77.38;
H, 9.91; N, 5.99.
(2E,4E,8E,10E)-N-Isobutyl-11-phenylundeca-2,4,8,10-tetraen-
amide (12)
Yield: 95 mg (23%) (eluent: PE–EtOAc, 4:1); pale yellow solid; mp
147–149 °C.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.29 (m, 2 H), 7.24–7.20 (m, 2 H),
7.14–7.09 (m, 2 H), 6.66 (dd, J = 15.6 Hz, J = 10.4 Hz, 1 H), 6.38 (d, J =
15.7 Hz, 1 H), 6.18–6.05 (m, 2 H), 6.01–5.95 (m, 1 H), 5.78–5.70 (m, 3
H), 3.08 (t, J = 6.4 Hz, 2 H), 2.21 (s, 4 H), 1.76–1.67 (m, 1 H), 0.85 (s, 3
H), 0.84 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.3, 141.5, 140.8, 137.5, 134.0,
131.3, 130.6, 129.1, 128.9, 128.6, 127.2, 126.4, 126.2, 122.5, 47.0, 32.7,
32.1, 28.6, 20.1.
Mp 80–82 °C.
1H NMR (400 MHz, CDCl3): δ = 9.61 (s, 1 H), 6.98 (dd, J = 15.0 Hz, J =
10.8 Hz, 1 H), 6.35 (br s, 1 H), 6.04–5.98 (m, 1 H), 5.88–5.80 (m, 1 H),
5.76 (d, J = 15.0 Hz, 1 H), 2.98 (t, J = 6.4 Hz, 2 H), 2.43 (t, J = 7.1 Hz, 2
H), 2.34–2.28 (m, 2 H), 1.64 (sept, J = 6.7 Hz, 1 H), 0.76 (s, 3 H), 0.74 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 201.1, 166.1, 140.4, 139.5, 129.4,
123.0, 46.9, 42.7, 28.6, 25.3, 20.1.
MS (ESI): m/z = 310 [M + H]+, 332 [M + Na]+.
Anal. Calcd for C21H27NO: C, 81.51; H, 8.79; N, 4.53. Found: C, 81.34;
H, 8.80; N, 4.54.
MS (ESI): m/z = 210 [M + H]+, 232 [M + Na]+.
Anal. Calcd for C12H19NO2: C, 68.87; H, 9.15; N, 6.69. Found: C, 68.95;
H, 9.16; N, 6.68.
[(4E,6E,8E)-Deca-4,6,8-trienyloxy](tert-butyl)dimethylsilane (15)
sec-BuLi (10 mL, 1.4 M in cyclohexane, 14 mmol) was added dropwise
at –78 °C to a solution of phosphonate 10 (2.94 g, 14 mmol) in THF
(60 mL). After 20 min, a solution of aldehyde 5 (2.26 g, 11 mmol) in
THF (20 mL) was added to the yellow solution. The reaction mixture
turned red and was allowed to warm up gradually to r.t. After 15 h,
the mixture was quenched with sat. NH4Cl solution (50 mL) and the
aq phase was extracted with Et2O (3 × 50 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered and the solvent was
δ-Sanshool, Compounds 11 and 12; General Procedure
n-BuLi (1.1 mL, 1.6 M in hexane, 1.74 mmol) was added dropwise at
–78 °C to a solution of the appropriate phosphonate 10, 13, or 14
(1.74 mmol) in THF (10 mL). After stirring for 30 min, a solution of
aldehyde 9 (280 mg, 1.34 mmol) in THF (4 mL) was added. The reac-
tion mixture was kept at –78 °C for 15 min, and was then allowed to
warm to r.t. during the night. The reaction mixture was quenched
with sat. NH4Cl solution (10 mL) and the aq phase was extracted with
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
C. Mugnaini, F. Corelli
Paper
Synthesis
removed under vacuum. The crude residue was purified by column
chromatography (PE–Et2O, 99:1) to give 1.25 g of 15 (4.7 mmol, 43%
yield) as a colorless oil.
drous Na2SO4, filtered and evaporated to dryness. The crude residue
was purified by column chromatography (EtOAc–MeOH, 10:1) to give
the corresponding amide.
1H NMR (400 MHz, CDCl3): δ = 6.00–5.96 (m, 4 H), 5.62–5.56 (m, 2 H),
3.54 (t, J = 6.3 Hz, 2 H), 2.10–2.04 (m, 2 H), 1.69 (d, J = 6.7 Hz, 3 H),
1.57–1.47 (m, 2 H), 0.82 (s, 9 H), –0.03 (s, 6 H).
Diethyl (E)-3-(Isobutylcarbamoyl)allylphosphonate (6)
Yield: 250 mg (41%); colorless oil.
13C NMR (100 MHz, CDCl3): δ = 133.5, 131.8, 130.7, 130.5, 128.8, 62.5,
32.4, 30.9, 29.1, 25.9, 18.2, –5.3.
GC–MS: tR = 17.17 min, m/z = 209 [M – t-Bu]+.
MS (ESI): m/z [M]+ calcd for C16H30OSi: 266.21; found: 266.23.
1H NMR (400 MHz, CDCl3): δ = 6.67–6.57 (m, 1 H), 5.92–5.87 (m, 1 H),
5.49 (br s, 1 H), 4.04 (q, J = 7.1 Hz, 4 H), 3.09–3.06 (m, 2 H), 2.61 (d, J =
7.7 Hz, 1 H), 2.66 (d, J = 7.7 Hz, 1 H), 1.76–1.69 (m, 1 H), 1.18 (t, J = 7.2
Hz, 6 H), 0.85 (d, J = 6.7 Hz, 6 H).
GC–MS: tR = 20.70 min, m/z = 222 [M – 55]+.
(4E,6E,8E)-Deca-4,6,8-trien-1-ol (16)
Diethyl (E)-3-(Isopropylcarbamoyl)allylphosphonate (18)
TBAF (7.5 mL, 1 M in THF, 7.5 mmol) was added to a solution of com-
pound 15 (1.0 g, 3.8 mmol) in THF (30 mL) at 0 °C. After 5 min, the
temperature was allowed to warm to r.t. and the mixture was stirred
overnight. After solvent evaporation, the crude residue was purified
by column chromatography (Et2O–PE, 2:1) to give compound 16 (443
mg, 2.9 mmol) as a white solid in 77% yield.
Yield: 318 mg (55%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 6.69–6.59 (m, 1 H), 5.86 (dd, J = 4.5 Hz,
J = 15.4 Hz, 1 H), 5.40 (br s, 1 H), 4.06–4.02 (m, 4 H), 2.66 (d, J = 7.7 Hz,
1 H), 2.60 (d, J = 7.7 Hz, 1 H), 1.27–1.23 (m, 7 H), 1.11 (s, 3 H), 1.09 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 164.1, 131.6, 131.5, 129.0, 128.9, 62.1,
Mp 56–57 °C.
1H NMR (400 MHz, CDCl3): δ = 6.06–5.94 (m, 4 H), 5.64–5.55 (m, 2 H),
3.58 (t, J = 6.1 Hz, 2 H), 2.14–2.08 (m, 2 H), 1.69 (d, J = 6.9 Hz, 3 H),
1.63–1.56 (m, 2 H).
41.1, 30.7, 22.4, 16.3.
GC–MS: tR = 19.44 min, m/z = 264 [M + 1]+.
MS (EI): m/z [M]+ calcd for C11H22NO4P: 263.13; found: 263.11.
13C NMR (100 MHz, CDCl3): δ = 133.1, 131.7, 131.2, 131.1, 130.3,
129.1, 62.4, 32.2, 29.1, 18.2.
GC–MS: tR = 13.29 min, m/z = 152 [M]+.
Diethyl (E)-3-(Cyclopropylcarbamoyl)allylphosphonate (19)
Yield: 181 mg (20%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 6.75–6.66 (m, 1 H), 5.87 (dd, J = 4.7 Hz,
J = 15.6 Hz, 1 H), 5.66 (br s, 1 H), 4.12–4.03 (m, 4 H), 2.87–2.72 (m, 1
H), 2.69 (d, J = 7.7 Hz, 1 H), 2.63 (d, J = 7.7 Hz, 1 H), 1.29 (t, J = 7.0 Hz, 6
H), 0.88–0.71 (m, 2 H), 0.57–0.49 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 164.5, 132.0, 129.0, 62.2, 32.7, 25.8,
16.3, 7.6.
Anal. Calcd for C10H16O: C, 78.90; H, 10.59. Found: C 79.01; H, 10.56.
(4E,6E,8E)-Deca-4,6,8-trienal (17)
Oxalyl chloride (2.5 mL, 2 M in CH2Cl2, 4.9 mmol) was diluted in
CH2Cl2 (10 mL) and the mixture was cooled to –78 °C. DMSO (0.8 mL,
9.5 mmol) was slowly added followed, after 15 min, by the dropwise
addition of compound 16 (250 mg, 1.6 mmol) in CH2Cl2 (5 mL). After
the solution had been stirred for 45 min at –78 °C, Et3N (2.3 mL, 16
mmol) was added. After 1 h, the reaction mixture was allowed to
warm gradually to 0 °C, kept at this temperature for an additional 30
min and then quenched by the addition of sat. aq NaHCO3 solution
(15 mL). The mixture was allowed to rest overnight and the two
phases were separated. The aq layer was extracted with CH2Cl2
(2 × 15 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered and the solvent evaporated. The crude residue was
purified by column chromatography (PE–Et2O, 4:1) to give 17 (144
mg, 0.9 mmol) as a colorless oil in 60% yield.
GC–MS: tR = 20.78 min, m/z = 149 [M – 112]+.
MS (ESI): m/z [M + H]+ calcd for C11H21NO4P: 262.11; found: 262.
δ-Sanshool, Compounds 20 and 21; General Procedure
A solution of the appropriate phosphonate 6, 18, or 19 (0.4 mmol) in
THF (1 mL) was added to a suspension of LiOH (34 mg, 0.8 mmol) in
dry THF (5 mL) in the presence of 4 Å molecular sieves. After 20 min, a
solution of aldehyde 17 (30 mg, 0.2 mmol) in THF (1 mL) was added
and the reaction mixture was heated at reflux temperature for 3 h. Af-
ter cooling, the mixture was filtered and evaporated to dryness. The
crude residue was purified by column chromatography (CH2Cl2–
MeOH, 98:2).
1H NMR (400 MHz, CDCl3): δ = 9.69 (s, 1 H), 6.07–5.93 (m, 4 H), 5.65–
5.51 (m, 2 H), 2.46 (t, J = 6.9 Hz, 2 H), 2.37–2.32 (m, 2 H), 1.69 (d, J =
6.9 Hz, 3 H).
δ-Sanshool
13C NMR (100 MHz, CDCl3): δ = 201.8, 133.9, 131.7, 131.6, 131.0,
Yield: 46 mg (85%) (eluent: PE–EtOAc, 7:3).
129.8, 129.6, 43.3, 25.3, 18.2.
MS (ESI): m/z = 151 [M + H]+, 173 [M + Na]+.
HRMS (EI): m/z [M]+ calcd for C10H14O: 150.1; found: 150.11.
The analytical data was consistent with that obtained according to
the procedure outlined in Scheme 2.
(2E,4E,8E,10E,12E)-N-Isopropyltetradeca-2,4,8,10,12-pentaen-
amide (20)
Phosphonates 6, 18 and 19; General Procedure
HOBt (304 mg, 2.2 mmol) and EDC (862 mg, 4.5 mmol) were added to
a solution of 22 (500 mg, 2.2 mmol) in CH2Cl2 (15 mL). After 5 min,
the appropriate amine (4.4 mmol) was added and the reaction mix-
ture was stirred at r.t. for 3 h. Next, H2O (10 mL) was added, the two
phases were separated and the aq phase was extracted with CH2Cl2
(2 × 10 mL). The combined organic extracts were dried over anhy-
Yield: 36 mg (70%); white solid.
1H NMR (400 MHz, CDCl3): δ = 7.12–7.06 (m, 1 H), 6.09–5.96 (m, 6 H),
5.72–5.68 (m, 1 H), 5.61–5.58 (m, 2 H), 5.16 (br s, 1 H), 4.10–5.07 (m,
1 H), 2.16–2.09 (m, 4 H), 1.70 (d, J = 6.7 Hz, 3 H), 1.11 (d, J = 6.4 Hz, 6
H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

H
C. Mugnaini, F. Corelli
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 166.6, 141.0, 139.9, 132.4, 131.7,
131.4, 131.3, 130.1, 129.5, 129.2, 121.7, 44.7, 33.0, 23.2, 18.3.
References
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MS (ESI): m/z = 260 [M + H]+, 282 [M + Na]+.
Anal. Calcd for C17H25NO: C, 78.72; H, 9.71; N, 5.40. Found: C, 78.59;
H, 9.72; N, 5.41.
(2E,4E,8E,10E,12E)-N-Cyclopropyltetradeca-2,4,8,10,12-penta-
enamide (21)
Yield: 41 mg (80%); white solid.
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tes 2011, 60, 1198.
1H NMR (400 MHz, MeOD): δ = 7.03 (dd, J = 10.5 Hz, J =15.1 Hz, 1 H),
6.08–5.94 (m, 6 H), 5.77 (d, J = 15.1 Hz, 1 H), 5.58–5.52 (m, 2 H), 2.73–
2.70 (m, 1 H), 2.20–2.14 (m, 4 H), 1.67 (d, J = 6.8 Hz, 3 H), 0.86–0.75
(m, 2 H), 0.36–0.30 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 165.6, 142.0, 141.1, 132.4, 131.7,
131.4, 131.3, 130.1, 129.2, 128.7, 121.7, 32.7, 32.0, 28.6, 22.7, 18.3.
MS (ESI): m/z = 258 [M + H]+, 280 [M + Na]+.
Anal. Calcd for C17H23NO: C, 79.33; H, 9.01; N, 5.44. Found: C 79.42; H,
8.99; N, 5.43.
(9) Crombie, L.; Fisher, D. Tetrahedron Lett. 1985, 26, 2481.
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Acknowledgment
We thank Ruin Moaddel (National Institute on Aging, Baltimore,
U.S.A.) and Alessia Ligresti and Vincenzo Di Marzo (Istituto di Chimica
Biomolecolare, CNR Pozzuoli, Italy) for helpful discussions. Financial
support from Sienabiotech S.p.A., Siena, Italy is gratefully acknowl-
edged.
(15) Castilho, M. S.; Pavão, F.; Oliva, G.; Ladame, S.; Willson, M.;
Périé, J. Biochemistry 2003, 42, 7143.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561580.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H