Synthesis of γ-Sanshool and hydroxy-γ-Sanshool

Article abstract of DOI:10.1055/s-0034-1379215

Members of the family of polyunsaturated amide compounds known as the sanshools are found in various Zanthoxylum species such as Sichuan (or Szechuan) peppercorns (huajiao). γ-Sanshool and hydroxy-γ-sanshool have been synthesized from simple building bloc

Full text of DOI:10.1055/s-0034-1379215

LETTER
▌2787
lSetyternthesis of γ-Sanshool and Hydroxy-γ-sanshool
γ-Sanshool
Xuanshu Xia, Patrick H. Toy*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Fax +85228571586; E-mail: phtoy@hku.hk
Received: 31.07.2014; Accepted after revision: 05.09.2014
isomers, or only modest (40–56%) yield of the desired
product.16 Therefore, it seems that the synthesis by Crom-
bie and Fisher possibly suffered from similar issues. Fur-
thermore, both syntheses utilized amide-functionalized
Abstract: Members of the family of polyunsaturated amide com-
pounds known as the sanshools are found in various Zanthoxylum
species such as Sichuan (or Szechuan) peppercorns (huajiao). γ-
Sanshool and hydroxy-γ-sanshool have been synthesized from sim-
ple building blocks using an alkyne to (E,E)-1,3-diene isomeriza- phosphonate reagents in the HWE reactions, which result-
tion reaction to stereoselectively install the (E,E)-2,4-diene group of
the key synthetic intermediate (2E,4E,8Z,10E,12E)-tetradecapen-
taenoic acid, which in turn was converted into both γ-sanshool and
intermediate directly amenable to the synthesis of ana-
hydroxy-γ-sanshool by reaction with the appropriate amines.
ed in dienamide products. Thus, these two routes only re-
sulted in the synthesis of 1 and do not involve an
logues of it in which the N-substituent varies, as it does in
2. With these issues regarding this pervious work in mind,
we felt that it would be useful to design a synthesis of 1 in
Key words: alkenes, alkynes, isomerization reactions, natural
products, Wittig reactions
which the issue of stereoisomers in the 2,4-diene group is
eliminated and that involves a carboxylic acid, which
could also be used to generate not only 2, but a library of
The sanshools are a family of polyunsaturated fatty acid
amides found in various Zanthoxylum species that has re-
other amide analogues as well.
cently attracted the interest of a broad cross-section of the
Our retrosynthetic strategy for 1, and thus 2, is depicted in
Scheme 2. As outlined above, carboxylic acid 3 was tar-
geted as the key synthetic intermediate since it could con-
ceivably be converted into a wide range of amides, and it
scientific community (Figure 1).1 For example, hydroxy-
α-sanshool (HAS) is responsible for the numbing/tingling
sensation one experiences when eating Sichuan (or Szech-
uan) peppercorns (huajiao),2 and this finding has led to in-
might be prepared from alkynoate 4 using a stereoselec-
terest in understanding the details of its mechanism of
tive alkyne to (E,E)-1,3-diene isomerization reaction,17,18
action3 and in developing various medicinal,4 agricultur-
followed by saponification. The alkyne group of 4 could
al,5 food,6 and cosmetic7 applications for it. However,
presumably be formed by a Corey–Fuchs reaction on al-
while HAS has been relatively widely studied, it is rather
dehyde 5 using methyl chloroformate to trap the acetylide
difficult to obtain it in pure form.8 While much less is
known regarding the other sanshools,9 γ-sanshool (1) has
been found to inhibit human acyl-CoA cholesterol acyl-
O
transferase-1, with an IC50 of 12 μM.10 Thus, in order to
N
increase the availability of the sanshools for wider study,
H
R
we have initiated a program to synthesize them in stereo-
chemically pure form and have recently reported a synthe-
sis of HAS that can be performed on a gram scale.11–14
In this report, we describe the synthesis of 1 and hydroxy-
γ-sanshool (2) from a common carboxylic acid inter-
mediate.
α-sanshool: R = H
hydroxy-α-sanshool: R = OH
O
N
H
R
The synthesis of 1 has been previously described by two
groups, and in both syntheses a Horner–Wadsworth–Em-
mons (HWE) reaction was used to construct the 2,4-diene
group (Scheme 1).15,16 In the report published nearly 30
years ago by Crombie and Fisher, several synthetic strat-
egies were described, but in the preferred route the C2–C3
double bond was formed from a HWE reaction.15a The au-
thors did not discuss the stereoselectivity of this HWE re-
action, but in the subsequent synthesis of 1 described by
Igarashi et al., a similar HWE reaction used to form the
C4–C5 double bond resulted in either a mixture of E and Z
β-sanshool: R = H
hydroxy-β-sanshool: R = OH
O
N
H
R
γ-sanshool (1): R = H
hydroxy-γ-sanshool (2): R = OH
O
N
H
R
δ-sanshool: R = H
hydroxy-δ-sanshool: R = OH
SYNLETT 2014, 25, 2787–2790
Advanced online publication: 16.10.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379215; Art ID: st-2014-w0644-l
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Sanshool compounds

2788
X. Xia, P. H. Toy
LETTER
Crombie and Fisher route:15
O
P
O
EtO
EtO
O
O
N
MEMO
1
H
MEMO
N
H
H
n-BuLi
E and Z isomers?
62% yield
Igarashi et al. route:16
O
O
Fe(CO)3
Fe(CO)3
EtO
EtO
P
O
N
O
1
H
N
H
H
base
mixture of E and Z isomers
or 40–54% yield
Scheme 1 Previous synthetic routes towards 1
intermediate to install the ester moiety. Aldehyde 5 in turn by reaction with triphenylphospine, and this in turn was
might be generated by adjusting the oxidation state of es- used in a Wittig reaction with aldehyde 7 using excess
ter 6, which itself might be synthesized via a Z-selective Cs2CO3 in warm CH2Cl2 to afford ester 6 as a mixture of
Wittig reaction between commercially available sorbalde- Z and E stereoisomers (ca. 3:1 ratio). These were not sep-
hyde (7) and the phosphonium salt derived from 8.
arated, and the mixture was directly reduced using
DIBAL-H to afford aldehyde 5 in high yield. Next, con-
version of aldehyde 5 into alkynoate 4 was achieved in a
three-stage Corey–Fuchs procedure using methyl chloro-
formate as the electrophile in good overall yield. Gratify-
ingly, the envisioned isomerization of 4 proceeded with
high stereoselectivity in the presence of the combination
of triphenylphospine and phenol in warm toluene to afford
penultimate intermediate 10 in high yield. Saponification
of 10 afforded solid carboxylic acid 3, which could be re-
crystallized to a high level of stereochemical homogeneity
using a combination of CHCl3 and hexane. Finally, amide
formation using the appropriate amine afforded 120 and
221 in 28% and 29% overall yield, respectively, from 8. It
should be noted that commercially available 7 is labeled
as being ‘predominantly trans,trans’, and is approximate-
O
N
H
R
1: R = H
2: R = OH
O
H2N
+
OH
R
R = H or OH
3
1
ly a 5:1 mixture of stereoisomers according to H NMR
O
O
analysis. Thus, the relatively modest 63% yield for the sa-
ponification of 10 to form carboxylic acid 3 is quite re-
spectable since the isomers formed due to the impurity of
7 and during the Wittig reaction are removed during this
step.
OMe
H
5
4
O
In summary, we report a concise, stereoselective, and
high-yielding route for the synthesis of both 1 and 2 from
simple and commercially available building blocks. Nota-
bly, carboxylic acid 3 can be recrystallized to purity, and
its use as the immediate precursor to 1 and 2 allows for the
synthesis of amide analogues of these natural products.
We are currently investigating the application of our pre-
viously reported methods for using polymer-supported re-
agents and catalysts in Wittig22 and alkyne-
isomerization23 reactions to the synthesis of 3, and it is
hoped that this work will further facilitate the study of the
sanshools by making them and their analogues more eas-
ily available.
O
H
7
OEt
+
O
Br
6
OEt
8
Scheme 2 Retrosynthetic analysis for 1 and 2
The successful implementation of our synthetic plan is
presented in Scheme 3.19 Alkyl halide 8 was converted
into the corresponding phosphonium salt 9 in high yield
Synlett 2014, 25, 2787–2790
© Georg Thieme Verlag Stuttgart · New York

LETTER
γ-Sanshool
2789
O
Ph
P
O
Ph3P (1.0 equiv)
7 (1.0 equiv), Cs2CO3 (4.0 equiv)
O
Ph
OEt
Br
OEt
CHCl3, reflux, 48 h
CH2Cl2, 45 °C, 24 h
OEt
Br Ph
8
9, 95%
6, 93% (3:1 Z/E)
O
O
H
DIBAL-H (1.1 equiv)
PhMe, –78 °C, 2 h
1. Ph3P (4.8 equiv), CBr4 (2.4 equiv), CH2Cl2, 0 °C, 45 min
OMe
2. n-BuLi (2.4 equiv), THF, –78 °C, 3 h
3. methyl chloroformate (1.4 equiv), THF, –78 °C to r.t., 4 h
5, 88%
4, 68%
O
O
Ph3P (1.0 equiv)
phenol (1.0 equiv)
1. NaOH (5.0 equiv), MeOH, 50 °C, 2 h
OMe
OH
2. HCl (aq)
PhMe, 55 °C, 16 h
10, 90%
3, 63%
H2N
H2N
O
N
or
(1.5 equiv)
OH
TEA (2.0 equiv), HBTU (1.5 equiv)
MeCN–CHCl3, 30 min
H
R
1: R = H, 95% (28% overall yield)
2: R = OH, 97% (29% overall yield)
Scheme 3 Synthesis of 1 and 2
Watanabe, T.; Kubota, K. Biosci. Biotechnol. Biochem.
2005, 69, 1951.
Acknowledgement
This research was supported financially by the University of Hong
Kong and the Research Grants Council of the Hong Kong S. A. R.,
P. R. of China (Project No. HKU 705510P).
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at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2787–2790

2790
X. Xia, P. H. Toy
LETTER
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(20) Characterization Data for 11c
1H NMR (400 MHz, CDCl3): δ = 0.92 (d, 6 H, J = 6.5 Hz),
1.78 (d, 3 H, J = 6.5 Hz), 1.81 (q, 1 H, J = 6.5 Hz), 2.25 (t, 2
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= 14.0 Hz, J2 = 7.0 Hz), 5.81 (d, 1 H, J = 15.2 Hz), 5.85 (s,
1 H), 5.99–6.20 (m, 5 H), 6.29–6.33 (m, 1 H), 7.17 (dd, 1 H,
J1 = 14.6 Hz, J2 = 10.7 Hz). 13C NMR (100 MHz, CDCl3): δ
= 18.4, 20.2, 27.2, 28.7, 33.0, 47.0, 122.4, 125.4, 128.9,
129.5, 130.0, 130.1, 132.0, 133.4, 141.0, 141.8, 166.5. MS:
m/z calcd for C18H27NO: 273.2; found: 273.2.
(21) Characterization Data for 21e
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3.33 (d, 2 H, J = 5.9 Hz), 5.35 (dt, 1 H, J1 = 10.1 Hz, J2 = 7.5
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= 15.0 Hz), 5.99–6.02 (m, 5 H), 6.29–6.36 (m, 1 H), 7.19
(dd, 1 H, J1 = 15.0 Hz, J2 = 10.4 Hz). 13C NMR (100 MHz,
CDCl3): δ = 18.4, 27.1, 27.3, 33.0, 50.6, 71.0, 121.9, 125.4,
128.8, 129.6, 130.0, 130.1, 131.9, 133.5, 141.6, 142.4,
167.7. MS: m/z calcd for C18H27NO2: 289.2; found: 289.2.
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