Concise synthesis of (+)-serinolamide A

Article abstract of DOI:10.1016/j.tetlet.2013.09.084

Serinolamide A, isolated from a species of marine cyanobacteria, exhibits a moderate agonist effect and selectivity for the CB₁ cannabinoid receptor, which is unusual for marine natural products. Herein, we reported a highly efficient enantiospecific first total synthesis of (+)-serinolamide A from l-serine in nine steps with 30% overall yield. The synthesis method provides a facile, practicable, and economical approach for the preparation of other similar endocanabinoid lipids.

Full text of DOI:10.1016/j.tetlet.2013.09.084

Accepted Manuscript
Concise Synthesis of (+)-Serinolamide A
Ya-Ru Gao, Shi-Huan Guo, Zhuan-Xiang Zhang, Shuai Mao, Yan-Lei Zhang,
Yong-Qiang Wang
PII:
S0040-4039(13)01649-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.09.084
TETL 43584
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
30 July 2013
9 September 2013
19 September 2013
Please cite this article as: Gao, Y-R., Guo, S-H., Zhang, Z-X., Mao, S., Zhang, Y-L., Wang, Y-Q., Concise Synthesis
of (+)-Serinolamide A, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.09.084
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Ya-Ru Gao, Shi-Huan Guo, Zhuan-Xiang Zhang, Shuai Mao, Yan-Lei Zhang, Yong-Qiang Wang*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Concise Synthesis of (+)-Serinolamide A
Ya-Ru Gao, Shi-Huan Guo, Zhuan-Xiang Zhang, Shuai Mao, Yan-Lei Zhang, Yong-Qiang Wang*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, P. R. China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, CAS, Shanghai 200032, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Serinolamide A, isolated from a species of marine cyanobacteria, exhibits a moderate agonist
effect and selectivity for the CB cannabinoid receptor, which is unusual for marine natural
1
Received in revised form
Accepted
products. Herein, we reported a highly efficient enantiospecific first total synthesis of (+)-
serinolamide A from L-serine in 9 steps with 30% overall yield. The synthesis method provides
Available online
a
facile, practicable and economical approach for the preparation of other similar
endocanabinoid lipids.
Keywords:
2009 Elsevier Ltd. All rights reserved.
Total Synthesis
Serinolamide A
L-serine
Fatty acid
Endocanabinoid lipids
The discovery of specific cannabinoid receptors (CB
1
and
Wittig reaction, and the amine part would be synthesized from
chiral serine.
1
CB has launched the quest for endogenous ligands.
2
)
Anandamide (1) (Figure 1) is the first reported endogenous
metabolite isolated by Devane et al. in 1992, which adjusts the
Traditionally, (R)-2-amino-3 methoxyproan-1-ol (8) was
synthesized from D-serine though Meyers’ method (Scheme
release of neurotransmitters through binding to the CB
1
and CB
2
5j,8
1,2
2). It is known that D-serine is much more expensive than L-
receptors.
Recently, two new endocanabinoid lipids
9
serine, moreover, large excess of diisobutylaaluminum hydride
serinolamide A (2) and propenediester (3) were reported by
3
(DIBAL)(3.0eq) was used for the reduction of oxazoline to
produce alcohol in the method. So we conceived using common
L-serine as starting material to develop a facile, practicable and
economical method for the synthesis of (R)-(8).
Gutiérrez et al.. Serinolamide A (2) was isolated from marine
cyanobacteria Lyngbya majuscule collected in Papua New
Guinea and propenediester (3) was obtained from Oscillatoria sp.
collected in Panama. Serinolamide A (2) displayed a moderate
agonist effect and selectivity for the CB
1
cannabinoid receptor,
After careful studies we found an ideal method for the
preparation of (R)-(8) (Scheme 3). Esterification of L-serine,
followed by protection of amino group gave product 5 in 90%
whereas propenediester (3) was completely inactive at all tested
3
concentrations. Noticeably, only a few marine natural products
8b
have been reported to show such affinity and selectivity for the
yield over two steps. Methyl derivative 6 was prepared in 67%
yield by etherification of 5 with iodomethane activated by
4
CB
1
receptor. Furthermore, the cannabimimetic effects in vivo
10
make serinolamide
A
(2) attractive from
a
therapeutic
2 4
Ag O. Reduction of 6 with NaBH gave alcohol 7 in 85% yield.
perspective. Therefore, we sought to develop a convergent route
to serinolamide A (2) that could facilitate subsequent structure-
activity relationship studies via the synthesis of structural
variants.
Removal of the Boc group with trifluroacetic acid (TFA)
produced (R)-(8) in quantitative yield, which could be used
directly without purification.
In a parallel sequence, oxidation of 1-tetradecyl alchohol 9
with PCC yielded tetradecanal 10 in 92% yield, which was then
The structure of serinolamide A (2) is similar to some other
5
cyanobacterium6 metabolites,
such
as
malyngamides ,
added
to
the
ylide
generated
by
treating
the
7
11
semiplenamides and hermitamides , which bear a long fatty acid
chain bonded to an amine moiety. Herein, we report a concise
and economical enantiospecific first total synthesis of
serinolamide A (2).
triphenylphosphonium salt 11 with NaHMDS, afforded 12 in
73% yield (Scheme 4). Unfortunately, the synthetic fatty acid 12
was a 3:1 E/Z mixture which couldn’t be separated by column
chromatography. Some other efforts had been tried (such as
optimizing solvent, base and temperature, etc.), but the E/Z ratio
couldn’t be improved.
As shown in the retrosynthesis (Scheme 1), serinolamide A
(2) is derived from methylation of compound 4, which is divided
into two parts, the fatty acid 12 and the derivative of serinol 8.
The formation of fatty acid moiety would be achieved through
Then we changed our synthetic strategy into reduction of
alkyne sub-unit. Luckily, we made a few attempts to obtain the

2
Tetrahedron
single configuration of fatty acid 12 with high yield and
1424; (f) Kan, Y.; Sakamoto, B.; Fujita, T.; Nagai, H. J. Nat.
Prod. 2000, 63, 1599-1602; (g) Appleton, D. R.; Sewell, M. A.;
Berridge, M. V.; Copp, B. R. J. Nat. Prod. 2002, 65, 630-631; (h)
McPhail, K. L.; Gerwick, W. H. J. Nat. Prod. 2003, 66, 132-135;
minimum number of steps. As depicted in Scheme 5, the
coupling of 1-bromotridecane 13 and pent-4-yn-1-ol using excess
n-BuLi in hexamethylphosphoramide (HMPA) and THF afforded
4 in 86% yield. It is noteworthy that the product of hydroxyl
group coupling with 1-bromotridecane would be formed
(i) Nogle, L. M.; Gerwick, W. H. J. Nat. Prod. 2003, 66, 217-220;
12
1
(j) Chen, J.; Li, Y.; Cao, X. P. Tetrahedron: Asymmetry 2006, 17,
933-941; (k) Chen, J.; Fu, X. G.; Zhou, L.; Zhang, J. T.; Qi, X. L.;
Cao, X. P. J. Org. Chem. 2009, 74, 4149-4157.
(a) Han, B.; Mcphail, K. L.; Ligresti, A.; Marzo, V. D.; Gerwick,
W. H. J. Nat. Prod. 2003, 66, 1364-1368; (b) Davies, I. R.;
Cheeseman, M.; Niyadurupola, D. G.; Bull, S. D. Tetrahedron
Lett. 2005, 46, 5547-5549; (c) Das, B.; Damodar, K.; Bhunia, N.;
Shashikanth, B. Tetrahedron lett. 2009, 50, 2072-2074.
exclusively when 1 equiv n-BuLi was used. Gratifyingly,
reduction of 14 with LiAlH gave alkene 15 with complete E-
configuration in 96% yield. Oxidation of 15 with PDC obtained
the fatty acid (E)-12 in 92% yield.
6
7
.
.
4
12
With the key acid (E)-12 and amine 8 in hand, condensation
(a) Tan, L. T.; Okino, T.; Gerwick, W. H. J. Nat. Prod. 2000, 63,
952–955; (b) Elyashberg, M. E.; Blinov, K. A.; Williams, A. J.;
Martirosian, E. R.; Molodtsov, S. G. J. Nat. Prod. 2002, 65, 693–
was achieved using dicyclohexylcarbodiimide (DCC) and
pyridine to afford amide 4. Unfortunately, methylation with
CH I and NaH failed to give the N-methyl product 2, forming the
5j
13
7
03; (c) Molodtsov, S. G.; Elyashberg, M. E.; Blinov, K. A.;
3
Williams, A. J.; Martirosian, E. E.; Martin, G. E.; Lefebvre, B. J.
Chem. Inf. Comput. Sci. 2004, 44, 1737–1751; (d) Virolleaud, M.
A.; Menant, C.; Fenet, B.; Piva, O. Tetrahedron Lett. 2006, 47,
instead product 16 from O-methylation (Scheme 6).
A simple solution was to install the methyl group on the amine
before condensation with fatty acid (Scheme 7). First, protection
of the primary hydroxyl group with tert-butydimethylsilyl
chloride (TBDMSCl) produced the corresponding silyl ether 17
I and
NaH afforded 18 in quantitative yield. After deprotection of
Boc group of compound 18 under TFA/CH Cl conditions, we
obtained two products 19 and 20. The mixture of products 19 and
0 without purification and separation under the condensation
condition ((1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
5
127-5130.
(a) Meyers, A. I.; Schmidt, W.; McKennon, M. J. Synthesis 1993,
50-262; (b) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis,
8
9
.
.
2
N. Synthesis 1994, 31-33.
The prices of L-serine and D-serine in Acros Organics – part of
Thermo Fisher Scientific: L-serine 232 CNY / 100 g, D-serine
14
in 91% yield. Subsequently N-methyl action using CH
3
13
2799 CNY / 100 g.
2
2
1
1
0. Passiniemi, M.; Koskinen, A. M. P. Synthesis 2010, 2816-2822.
1. Mesguiche, V.; Valls, R.; Piovetti, L.; Peiffer, G. Tetrahedron
Lett. 1999, 40, 7473-7476.
2. Narayan, R. S.; Borhan, B. J. Org. Chem. 2006, 71, 1416-1429.
3. Bigot, A.; Dau, M. E. T. H.; Zhu, J. P. J. Org. Chem. 1999, 64,
2
1
1
hydrochloride (EDC), 1-Hydroxy-1H-benzotriazole (HOBt),
6
283-6296.
N,N-Diisopropylethylamine (DIPEA)) could afford two
1
4. Franco, D.; Gómez, M.; Jiménez, F.; Muller, G.; Rocamora, M.;
15
corresponding products 2 and 21. Then 21 was treated with
tetrabutyl ammonium fluoride (TBAF ) to smoothly convert into
the final natural product 2. The overall yield from 18 to 2 was
Maestro, M. A.; Mahía. J. Organometallics 2004, 23, 3197-3209.
15. Brodmann, T.; Janssen, D.; Kalesse, M. J. Am. Chem. Soc. 2010,
132, 13610–13611.
1
13
6
4%. The spectroscopic data ( H NMR, C NMR, IR, HRMS) as
well as rotation vales of the synthetic sample 2 were in good
agreement with the reported data.
Supplementary Material
3
Supplementary data associated with this article can be found,
in the online version, at doi:
In conclusion, (+)-serinolamide A (2) has been synthesized
for the first time in 9 steps from L-serine with 30% overall yield.
The synthesis method provides
a facile, practicable and
economical approach to the preparation of other similar
endocanabinoid lipids.
O
OH
N
H
1: Anandamide
Acknowledgments
OH
O
This research was supported by National Natural Science
Foundation of China (NSFC-20872183, 20972126, 21272185;
J1210057), the Program for New Century Excellent Talents in
University of the Ministry of Education China (NCET-10-0937),
and Education Department of Shaanxi Provincial Government
O
N
2: Serinolamide A
O
O
O
(09JK776).
O
3: Propenediester
References and notes
Figure 1 Compound 1, 2 and 3
1
2
.
.
Lambert, D. M.; Fowler, C. J. J. Med. Chem. 2005, 48, 5059-
087.
Devane, W. A.; Hanuš, L.; Breuer, A.; Pertwee, R. G.; Stevenson,
L. A.; Griffin, G.; Gibson, D.; Mandelbaum, A.; Etinger, A.;
Mechoulam, R. Science 1992, 258, 1946−1949.
5
3
4
.
.
Gutiérrez, M.; Pereira, A. R.; Debonsi, H. M.; Ligresti, A.; Marzo,
V. D.; Gerwick, W. H. J. Nat. Prod. 2011, 74, 2313-2317.
Tidgewell, K.; Clark, B. T.; Gerwick, W. H. In Comprehensive
Natural Products Chemistry, 2nd ed.; Moore, B.; Crews, P., Eds.;
Pergamon Press: Oxford, UK, 2010; pp 141−188.
5
.
(a) Todd, J. S.; Gerwick, W. H. Tetrahedron Lett. 1995, 36, 7837-
7840; (b) Wu, M.; Milligan, K. E.; Gerwick, W. H. Tetrahedron
1
997, 53, 15983-15990; (c) Kan, Y.; Fujita, T.; Nagai, H.;
Sakamoto, B.; Hokama, Y. J. Nat. Prod. 1998, 61, 152-155; (d)
Milligan, K. E.; Márquez, B.; Williamson, R. T.; Davies-Coleman,
M.; Gerwick, W. H. J. Nat. Prod. 2000, 63, 965-968; (e)
Gallimore, W. A.; Scheuer, P. J. J. Nat. Prod. 2000, 63, 1422-

3
OH
O
O
O
N
O
2
C13H27
OH
OH
O
1
2
OH
DCC, pyridine
CH2Cl2, 25%
O
+
C13H27
N
H
O
CH2OH
O
N
H
4
4
H2N
8
NaH, DMF/THF
CH3I, 99%
OH
O
+
O
O
OH
C13H27
OH
H2N
O
O
1
2
8
O
O
C13H27
N
H
C13H27
N
16
2
O
O
OH
Scheme 6 Unexpected product of 13
O
+
BrPh3P
C13H27
H
OH
OH
H2N
1
0
11
L-serine
CH2OH
CH2OTBDMS
O
Scheme 1 Retrosynthesis
TBDMSCl
NaH, CH3I
THF, DMF
O
imidazole
BocHN
BocN
BocHN
CH2Cl2, 91%
99%
7
17
O
OH
OH
MeO2C
1
2
) AcCl, MeOH
OTBDMS
O
OH
O
1
2
) DIBAH
CH OTBDMS
2
H2N
N
O
)
OEt
NH
TFA, CH2Cl2
) NaH, MeI
O
+
D-serine
Ph
HN
HN
Ph
1
9
1
8
20
MeOH2C
N
CH2OH
O
HCl
12, EDC
HOBt, DIPEA
CH2Cl2
12, EDC
O
H2N
HOBt, DIPEA
CH Cl
R)-8
2
2
(
Ph
OH
Scheme 2 Meyers’ systhesis of (R)-8
OTBDMS
O
O
TBAF, THF
O
O
C13H27
N
C13H27
N
2
1
(64% yield from 18)
O
OH
OH
COOMe
OH
Ag2O, CH3I
1
) CH3COCl, CH3OH
BocHN
BocHN
Scheme 7 Synthesis of (+)-serinolamide A (2)
H2N
CH3COCH3, 67%
2
) (Boc)2O, Et3N,
CH3CN, 90%
L-serine
5
CH2OH
O
CH2OH
NaBH4
H2O/CH3OH (1:1)
COOMe
TFA
2
O
O
H2N
BocHN
CH Cl
2
8
5%
7
8
6
Scheme 3 Synthesis of (R)-8
O
O
PCC, CH2Cl2
11, NaHMDS
C14H29OH
C13H27
10
H
C13H27
OH
9
2%
dimethylbenzene
3%
12
E/Z=3:1
9
7
Scheme 4 Synthesis of 12
HO
C13H27
LiAlH , diglyme
OH
4
C13H27Br
n-BuLi, HMPA, THF
THF, 96%
14
13
86%
O
PDC, DMF
C13H27
OH
C13H27
OH
92%
15
12
Scheme 5 Synthesis of (E)-12