A new phenylethyl alkyl amide from the Ambrostoma quadriimpressum Motschulsky

Article abstract of DOI:10.3762/bjoc.7.158

A new phenylethyl alkyl amide, (10R)-10-hydroxy-N-phenethyloctadecanamide (1), was isolated from the beetle Ambrostoma quadriimpressum Motschulsky. The structure of the amide was determined by NMR and MS. The absolute configuration of compound 1 was confirmed by an asymmetric total synthesis, which was started from L-glutamic acid. The construction of the aliphatic chain was accomplished by the selective protection of the hydroxy groups and two-time implementation of the Wittig olefination reaction.

Full text of DOI:10.3762/bjoc.7.158

A new phenylethyl alkyl amide from the
Ambrostoma quadriimpressum Motschulsky
Guolei Zhao, Chao Yang*, Bing Li and Wujiong Xia*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1342–1346.
State Key Lab of Urban Water Resource and Environment & the
Academy of Fundamental and Interdisciplinary Sciences, Harbin
Institute of Technology, Harbin 150080, China
doi:10.3762/bjoc.7.158
Received: 15 July 2011
Accepted: 06 September 2011
Published: 29 September 2011
Email:
Chao Yang* - xyyang@hit.edu.cn; Wujiong Xia* - xiawj@hit.edu.cn
Associate Editor: B. Stoltz
* Corresponding author
© 2011 Zhao et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
asymmetric synthesis; beetle; fatty acid amide; isolation
Abstract
A new phenylethyl alkyl amide, (10R)-10-hydroxy-N-phenethyloctadecanamide (1), was isolated from the beetle Ambrostoma
quadriimpressum Motschulsky. The structure of the amide was determined by NMR and MS. The absolute configuration of com-
pound 1 was confirmed by an asymmetric total synthesis, which was started from L-glutamic acid. The construction of the aliphatic
chain was accomplished by the selective protection of the hydroxy groups and two-time implementation of the Wittig olefination
reaction.
Introduction
The leaf beetle Ambrostoma quadriimpressum Motschulsky chemical communication among beetles [3-6]. Only a limited
(Coleoptera: Chrysomelidae) is a serious pest of elm that exists number of semiochemicals [7-13] are known in leaf beetles. To
primarily in north-eastern China. Adult beetles hibernate over the best of our knowledge, fatty acid amides from terrestrial
the winter and emerge in the spring when their host plant is insects have not been reported so far. In addition, certain marine
most succulent. The developmental stages of beetles are able to organisms [14,15] and mushrooms [16,17] are the only two
defend themselves against predatory attracks, and this defence natural sources of phenylethyl alkyl amides with remarkable
is associated with chemical defensive compounds.
activities, such as cytotoxicity to murine leukemia cells (P-388)
[14] and protective activity against endoplasmic reticulum
Insects are able to produce a vast array of biologically active stress-dependent cell death [17]. In the current study, we report
secondary metabolites, which are used for defence purposes or the isolation of (10R)-10-hydroxy-N-phenethyloctadecanamide
as pheromones. In particular, the chemical defensive phenom- (1), a possible chemical defensive compound from the beetle A.
enon of the beetle has been observed in Coleoptera [1,2]. Over quadriimpressum, and confirmation of its absolute configur-
the last few years, many research efforts have concentrated on ation by total synthesis.
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Beilstein J. Org. Chem. 2011, 7, 1342–1346.
Results and Discussion
Isolation of (10R)-10-hydroxy-N-phenethyl-
octadecanamide (1)
ppm). Correlations obtained from an HMBC spectrum provided
partial evidence to assign a phenylethylamine moiety. The loca-
tion of the OH group in the aliphatic chain was assigned by
EIMS analysis; specifically, evidence was provided by a strong
[M − 113]+ peak at m/z 290 corresponding to the loss of C8H17
(Scheme 1). Hence, compound 1 was confirmed as 10-hydroxy-
N-phenethyloctadecanamide. In addition, compound 1 showed
positive optical rotation ([α]20D +38.5 (c 0.13, CHCl3)). To
confirm the absolute configuration at C(10), an asymmetric total
synthesis was performed.
Petroleum ether extracts from adult A. quadriimpressum were
purified repeatedly by means of silica gel column chromatog-
raphy. Compound 1 was obtained as a white solid. An ion peak
at m/z 403 and an [M − H2O]+ peak at m/z 385 in the EIMS
suggested the presence of an OH group. The molecular formula
of 1 was confirmed as C26H45NO2 (m/z 404.3529, [M + H]+) by
HRMS–ESI analysis. The 1H NMR spectrum showed aromatic
protons [δ 7.33–7.18 (m, 5H)], CH2 groups [δ 3.52 (q, J = 6.4
Hz, 2H), 2.82 (t, J = 6.8 Hz, 2H), 2.11 (t, J = 7.2 Hz, 2H),
1.58–1.05 (m, 24H)], an amide proton [δ 5.39 (br s, 1H)], a CH
group [δ 3.58 (br m, 1H)] and an Me group [δ 0.88 (t, J = 6.8
Hz, 3H)]. The COSY spectrum showed that compound 1 had a
coupled proton spin system CH2CH2NH (δ 5.39, 3.52, 2.82
Synthesis of (10R)-10-hydroxy-N-phenethyl-
octadecanamide (1)
The retrosynthetic analysis of compound 1 is outlined in
Scheme 2. The target molecule is disconnected into two frag-
ments, 2 and 3. The intermediate fragment 2 would be readily
Scheme 1: Chemical structure of compound 1 and mass spectral analysis.
Scheme 2: Retrosynthetic analysis of (R)-1.
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Beilstein J. Org. Chem. 2011, 7, 1342–1346.
Scheme 3: (a) BnOH, H2SO4; NaNO2, AcOH; CH2N2, 35% in 3 steps. (b) TBDPSCl, imidazole, 100%. (c) Pd/C, H2; BH3·THF, 95% in 2 steps. (d)
TBDMSCl, imidazole, 100%. (e) Dibal-H, 86%. (f) PCC, 94%. (g) C7H15PPh3Br, n-BuLi, 75%. (h) PPTS, 98%.
prepared from the commercially available ε-caprolactone. The tive removal of the TBS group with pyridinium tosylate gave 12
crucial fragment 3 would be constructed from the intermediate in 98% yield [21].
4 through Wittig olefination. The polyhydroxy compound 4
would be obtained from L-glutamic acid by selective protection. With the alcohol 12 in hand, our next step was to synthesize the
phosphonium salt 15 [22,23] (Scheme 4). Therefore, ε-capro-
Our synthesis started from the ready available L-glutamic acid, lactone was hydrolyzed with 5% NaOH to give hydroxy acid 13
as shown in Scheme 3. On the basis of the preceding literature in quantitative yield, which was reacted with PBr3 in CH2Cl2 to
[18-20], the hydroxy diester 5 was obtained in 35% yield afford compound 14 in 82% yield. Treatment of 14 with PPh3
(BnOH, H2SO4; NaNO2, AcOH; CH2N2). Protection of the sec- in CH3CN gave the phosphonium salt 15 in 98% yield.
ondary alcohol with the TBDPS group gave compound 6 in
quantitative yield. The following debenzylation and reduction
with BH3·THF afforded alcohol 7 in 95% isolated yield. Then
primary alcohol 7 was protected again with TBDMSCl to give
compound 8 in 100% yield. An initial attempt to synthesize
compound 9 by reduction of 8 with LiAlH4, however, resulted
in the deprotection of the TBDPS group. Alternatively, the
alcohol 9 could be obtained by reduction with diisobutylalu-
minium hydride (Dibal-H) in 86% yield, which was then
Scheme 4: (a) 5% NaOH, 100%. (b) PBr3, 82%. (c) PPh3, 98%.
converted to the corresponding aldehyde 10 by oxidation with
PCC. Wittig olefination of aldehyde 10 with n-heptylidenetri-
phenylphosphonium bromide in the presence of n-BuLi gave The construction of the aliphatic chain was achieved according
adduct 11 as an (E/Z)-mixture (E/Z = 1:5) in 75% yield. Selec- to the synthetic plan shown in Scheme 5. Oxidation of the
Scheme 5: (a) PCC, 96%. (b) LDA, 15, 72%. (c) DCC, DMAP, phenylethylamine, 80%. (d) Pd/C, H2, 100%. (e) TBAF, 93%.
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Beilstein J. Org. Chem. 2011, 7, 1342–1346.
alcohol 12 with PCC afforded the corresponding aldehyde 16, 6.4 Hz, 2H), 2.82 (t, J = 6.8 Hz, 2H), 2.11 (t, J = 7.2 Hz, 2H),
followed by a Wittig reaction with salt 15 in the presence of two 1.58–1.05 (m, 24H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100
equiv LDA, which afforded the adduct 17 as an (E/Z)-mixture MHz, CDCl3) δ 173.1, 139.0, 128.8, 128.6, 126.5, 72.0, 40.5,
in 72% yield. The E/Z isomers of 17 were not separated because 37.5, 37.5, 36.8, 35.7, 31.9, 29.7, 29.6, 29.4, 29.3, 29.2, 25.7,
the olefin geometry has no effect on the synthesis. Therefore, 25.6, 22.7, 14.1; EIMS (m/z): 403, 385, 294, 290, 265, 176, 163,
compound 17 was directly converted to the amide 18 with DCC 122, 104 (base), 91, 83, 69, 55, 43; HRMS–ESI (m/z): [M + H]+
and DMAP in 80% yield. Reduction of the C=C double bond by calcd for C26H45NO2, 404.3529; found, 404.3529.
hydrogenation with Pd/C gave compound 19 in quantitative
yield, which was transferred to the final product (R)-1 in 93%
Supporting Information
yield by removal of the TBDPS group. Both NMR and EIMS
data were in complete agreement with those of the natural pro-
Supporting Information File 1
duct 1. In addition, the synthetic compound (R)-1 showed posi-
tive optical rotation ([α]20D +37.2 (c 0.85, CHCl3)), suggesting
that the absolute configuration of natural product 1 is to be
assigned (R).
Detailed experimental procedures for the synthesis of
compound 1.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-158-S1.pdf]
Conclusion
In summary, a new natural product, (10R)-10-hydroxy-N-
phenethyloctadecanamide (1) from Ambrostoma quadriim-
pressum Motschulsky was identified and synthesized. Further
studies on the biological roles of fatty acid amides are currently
being performed by our group.
Acknowledgements
We are grateful for the financial supports from China NSFC
(Nos. 20802013, 21002018 and 21072038), HIT.NSRIF (Nos.
01107866 and 01107986), the Fundamental Research Funds for
the Central Universities (No. HIT.BRET2.2010001) and
Wenzhou Science and Technology Program (No.G20100056).
Experimental
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at 400 MHz on a Bruker AV-400 instrument. 13C NMR spectra
were recorded at 100 MHz. High-resolution mass spectra were
recorded on an Agilent 1200-6520 Q-TOF electrospray mass
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