Synthesis of hydroxy-substituted unsaturated fatty acids and the amino-acid insect-derivative volicitin

Article abstract of DOI:10.1016/S0040-4039(02)02640-0

An efficient synthesis of N-(17S-hydroxylinolenoyl)-L-glutamine (volicitin), a chemical elicitor from the herbivore-pest beet armyworm is presented. The synthesis, which utilizes a copper-catalyzed acetylene coupling, links (S)-3,6-heptadiyne-2-ol with a C-8 propargylic iodine methyl ester to form the (S)-17-hydroxylinolenate skeleton. By substituting different heptadiyne-2-ol groups, a series of methylene interrupted polyacetylene analogues were generated.

Full text of DOI:10.1016/S0040-4039(02)02640-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 831–833
Synthesis of hydroxy-substituted unsaturated fatty acids and the
amino-acid insect-derivative volicitin
Han-Xun Wei, Christopher L. Truitt and Paul W. Pare´*
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA
Received 29 October 2002; accepted 20 November 2002
Abstract—An efficient synthesis of N-(17S-hydroxylinolenoyl)-L-glutamine (volicitin), a chemical elicitor from the herbivore-pest
beet armyworm is presented. The synthesis, which utilizes a copper-catalyzed acetylene coupling, links (S)-3,6-heptadiyne-2-ol
with a C-8 propargylic iodine methyl ester to form the (S)-17-hydroxylinolenate skeleton. By substituting different heptadiyne-2-ol
groups, a series of methylene interrupted polyacetylene analogues were generated. © 2003 Elsevier Science Ltd. All rights
reserved.
N-(17S-Hydroxylinolenoyl)-
L
-glutamine is the first bio-
Several synthetic schemes have been reported for volic-
itin, with the goal to synthesize sufficient material for
structural confirmation.4 In each case, the preparation
of the methylene-interrupted polyacetylene a-linolenic
acid backbone was based on either Grignard reagent
coupling of propargylic bromides followed by catalytic
hydrogenation to form unconjugated double bonds
units and/or (Z)-selective Wittig olefination.4 The cou-
pling of the fatty acid moiety to the amino acid took
place in the final step. These literature procedures gave
over-all yields of ca. 0.1–33% or complex product mix-
tures.4 In our experience, such synthetic routes are not
chemical elicitor to be isolated and characterized from
insects that triggers defense responses in plants.1 It was
originally isolated from the regurgitant of the herbi-
vore-pest beet armyworm (Spodoptera exigua) and
since has been found in other Lepidopteran species.2
This fatty acid derivative, referred to as volicitin, acti-
vates genes in corn seedlings (Zea may) for the synthe-
sis of terpenoids and the nitrogen containing metabolite
indole, as well as the subsequent release of C-10 and
C-15 volatile components from the aerial portion of
insect-damaged plants.3
Scheme 1. Reagents and conditions: (i) 2 equiv. (A), 2 equiv. EtMgBr, 10% CuCl, THF, rt, 15 h; (ii) P2–Ni, H2, EtOH, rt, 6 h;
(iii) 10 equiv. LiOH, THF–H2O (1:1, v/v), rt, 12 h; (iv) NEt3, THF, ClCO2Et, −10°C 20 min, then Gln, NaOH, rt, 25 min.
* Corresponding author. Tel.: 1-806-742-3062; fax: 1-806-742-1289; e-mail: paul.pare@ttu.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02640-0

832
H.-X. Wei et al. / Tetrahedron Letters 44 (2003) 831–833
Table 1.
well suited for gram scale synthesis, nor appropriate for
modifying the length or terminal group of the fatty acid
backbone
for
studying
structure–reactivity
relationships.
We report here an efficient protocol for the preparation
of v-hydroxy unsaturated fatty acids based on a
cuprous chloride-catalyzed coupling of 3,6-heptadiyne-
2-ol derivatives with a C-8 propargylic iodine methyl
ester to form 17-hydroxylinolenate skeletons. The gen-
eral synthetic route outlined in Scheme 1, allows for
facile modifications to the fatty acid skeleton and an
overall yield for the four-step procedure at ca. 37%.
The key step in this synthetic strategy was the coupling
of (A) with C-8 propargylic iodide (B) to form the C-17
triynol (C). The most common coupling approach for
forming such a methylene-interrupted polyacetylene
carbon chain is based on cuprous chloride-catalyzed
Grignard coupling of a protected diynol with a unit
containing propargylic bromine7,8 or other similar
methods.9 However, we found that such protocols were
not well suited for gram-scale synthesis. We then exam-
ined Becker’s procedure,10 in which similar triacetylene
alcohols were obtained in ca. 55% yield through the
condensation of a C-9 propargylic iodine with 2,5-
hexadiyne-1-ol.
Since the experimental protocol was not provided, we
tested several conditions before establishing that with
10 mol% of CuCl as catalyst, our key intermediate,
C-17 triynol liquid (C) was obtained in 56% yield (the
off red color may have been to a contamination of a
conjugated product. This step relies on the coupling of
the Grignard reagent derived from 3,6-heptadiyne-2-ol
(A)11 with a C-8 propargylic iodine (B).12 Catalytic
hydrogenation of (C) using P2ꢀNi as the catalyst,13
yielded the corresponding (Z,Z,Z)-trienol (D) as a yel-
lowish liquid and that product was then converted to
17-hydroxylinolenic acid (E) in 90% yield using
bromine while the other reaction parameters were
unchanged.
By using commercially available (S)-(−)-3-butyn-2-ol as
the substrate in the formation of 3,6-heptadiyne-2-ol,
optically active 17-hydroxylinolenic acid was generated
in the natural-product S-configuration originally iso-
lated from beet armyworms.15 In conclusion, a simple
synthesis of volicitin16 in four steps is presented here
which proceeds with an overall yield of 37%.
aqueous LiOH in THF. Coupling of (E) with
L-glu-
tamine to give volicitin was achieved by a modified
ethylcarbonate mixed anhydride method14 in 82% yield
for this final step.
With this successful procedure in hand, a series of
analogues of (C) were synthesized by the same Grig-
nard coupling reaction as shown in Scheme 2. Results
shown in Table 1 indicate that increasing the carbon
chain length R-group from methyl to isopropyl, sec-
butyl, isobutyl, or n-hexyl (entries 2–5) did not signifi-
cantly effect the coupling reaction albeit, the adding of
the benzyl or cyclohexyl unit did slightly decrease the
yields (entries 6–7). It is noteworthy that the yield of
(C) was diminished to less then 30% if the C-8 propar-
gylic iodine was substituted with the C-8 propargylic
Acknowledgements
We thank D. Purkiss for expert NMR support. NMR
instrumentation was purchased by NSF (CHE-
9808436); project financial support was provided by
NRI/USDA (grant c35320-9378) and The Herman
Frasch Foundation for Chemical Research.
Scheme 2.

H.-X. Wei et al. / Tetrahedron Letters 44 (2003) 831–833
833
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16. Selected date for intermediates and volicitin: (B):1H
NMR (CDCl3, 300 MHz) l 3.71 (t, J=2.4 Hz, 2H), 3.66
(s, 3H), 3.30 (t, J=9 Hz, 2H), 2.18 (m, 2H), 1.63 (m, 2H),
1
1.46 (m, 2H), 1.32 (m, 6H); (D): H NMR (CDCl3, 300
MHz) l 5.34–5.43 (m, 6H), 4.69 (m, 1H), 3.66 (s, 3H),
2.82–2.86 (m, 4H), 2.31 (t, J=7.4 Hz, 2H), 2.02–2.05 (m,
2H), 1.60–1.66 (m, 2H), 1.29–1.40 (m, 8H), 1.20 (d,
J=7.2 Hz, 3H); (E): 1H NMR (CDCl3, 300 MHz) l
5.32–5.45 (m, 6H), 4.64–4.72 (m, 1H), 2.78–2.89 (m, 4H),
2.32 (t, J=7.4 Hz, 2H), 2.04–2.11 (m, 2H), 1.60–1.69 (m,
2H), 1.28–1.39 (m, 8H), 1.20 (d, J= 7.2 Hz, 3H). Volic-
1
itin: H NMR (CD3OD, 500 MHz): l 1.06 (d, J=6.5 Hz,
3H), 1.18–1.28 (m, 10H), 1.49 (t, J=7.2 Hz, 2H), 1.77–
1.87 (m, 1H), 1.96 (q, J=6.5 Hz, 2H), 1.96–2.07 (m, 1H),
2.12 (t, J=7.2 Hz, 2H), 2.20–2.17 (m, 2H), 2.69–2.75 (m,
4H), 4.25 (dd, J=4.8, 4.0, 1H), 4.48 (dq, J=6.8, 6.2),
5.15–5.32 (m, 6H); 13C NMR (CD3OD, 125 MHz): l
22.9, 25.4, 25.8, 25.9, 63.2, 127.7, 127.8 128.1, 128.7,
130.2, 134.3, 174.1, 175.4, 176.8