Synthesis of volicitin: A novel three-component Wittig approach to chiral 17-hydroxylinolenic acid

Article abstract of DOI:10.1039/a902020i

A short stereoselective synthesis of both enantiomers of N-(17-hydroxylinolenoyl)-L-glutamine (volicitin) 12, an elicitor of plant volatile biosynthesis from beet armyworm salivary secretion, is described; the protected 17-hydroxylinolenic acid 4 moiety o

Full text of DOI:10.1039/a902020i

Synthesis of volicitin: a novel three-component Wittig approach to chiral
17-hydroxylinolenic acid
Georg Pohnert,* Thomas Koch and Wilhelm Boland*
Max-Planck-Institut für Chemische Ökologie, Tatzendpromenade 1a, D-07745 Jena, Germany.
E-mail: pohnert@ice.mpg.de
Received (in Liverpool, UK) 10th March 1999, Accepted 22nd April 1999
A short stereoselective synthesis of both enantiomers of N-
(17-hydroxylinolenoyl)-l-glutamine (volicitin) 12, an elici-
tor of plant volatile biosynthesis from beet armyworm
salivary secretion, is described; the protected 17-hydroxy-
linolenic acid 4 moiety of volicitin 12 was prepared in a one
pot bis-Wittig reaction.
different reactivity of the bis-functional ylide 9 and the
monofunctional intermediates like 10. Thus, if only 1 equiv. of
aldehyde 1 was added to a cold solution (2100 °C) of the bis-
ylide 9, generated from the bis-phosphonium salt with 2.1
equiv. of KHMDS,7 a preferential formation of the mono-ylide
10 was observed after slow warming to 220 °C. Recooling to
278 °C and addition of 1 equiv. of aldehyde 3 afforded the
cross-coupled product 4 in high yield. According to GLC-MS
analysis, the amount of the two symmetric products 5 and 6 was
less than 20% of the product mixture. Furthermore, the amount
of symmetric coupling products could be suppressed even more
efficiently by using the aluminium alkoxide 8, generated by
reduction of TBDMS-protected d- or l-lactic acid methyl ester
7 with DIBAL-H at low temperature, as the first carbonyl
equivalent (Scheme 2).8
Plants are able to respond to herbivore damage by de novo
biosynthesis of a characteristic blend of volatiles that attracts
the natural enemies of the attacking insect.1 Feeding on the leaf
is accompanied by introduction of salivary secretions that may
contain high and/or low molecular weight compounds activat-
ing the plant’s defense. Established elicitors are a b-glucosidase
from the regurgitant of Pieris brassicae caterpillars2 and the
recently identified N-(17-hydroxylinolenoyl)-l-glutamine (vo-
licitin) 12 from beet armyworm oral secretion.3 Like the
microbial metabolite coronatine, which strongly induces vola-
tile biosynthesis in plants,4 volicitin 12 is also an amphiphilic
compound that consists of a nonpolar lipid moiety joined to an
amino acid by an amide linkage. First experiments with
synthetic volicitin revealed that biological activity is highly
(Ph)3P
P(Ph)3
9
OMe
ii
CO2Me
i
OAlBui2
OTBDMS
OTBDMS
dependent on the stereochemistry of the amino acid.3
A
7
8
conjugate of (±)-17-hydroxylinolenic acid and l-glutamine
proved to be highly active, while the corresponding conjugate
with d-glutamine was virtually inactive. The configuration of
the 17-hydroxy group of the fatty acid has not been addressed to
date.
CO2R
PPh3
iii
7
OTBDMS
OTBDMS
4 R = Me
11 R = H
10
iv
Here we report an efficient synthesis of both enantiomers of
TBDMS protected 17-hydroxylinolenic acid methyl ester 4
based on a novel three component bis-Wittig approach.
Subsequent deprotection and coupling with l-glutamine yielded
both volicitin diastereomers (17R)- and (17S)-12, respec-
tively.
According to Scheme 1, the fatty acid skeleton is readily
assembled in a single operation via a bis-Wittig approach, based
on the Z-hex-3-ene-1,6-diol-derived symmetric bifunctional
Wittig salt 2.5 In order to suppress the formation of symmetric
by-products 5 and 6, resulting from statistical coupling of the
three components 1,6 2 and 3, the reaction conditions were
carefully optimised. While addition of a 1 : 1 mixture of the
aldehydes 1 and 3 to the ylide 9 resulted in the expected
statistical product ratio of 4, 5 and 6, successive addition of the
aldehydes to 9, in conjunction with optimised temperatures
during the stepwise reaction, afforded high yields of the
protected 17-hydroxylinolenic acid 4. This result suggested
O
C
CO2H
v
N
CONH2
H
OH
12
Scheme 2 Reagents and conditions: i, DIBAL-H, Et2O, 278 °C; ii, 9
[prepared from 2 in THF using 2 equiv. KN(SiMe3)2, 278 to 0 °C], 278 °C,
add 8, warm to room temp.; iii, 278 °C, 3, warm to room temp.; iv, LiOH,
THF–H2O; v, NEt3, THF, ClCO2Et, 210 °C, then Gln, NaOH, room
temp.
During warming to room temperature, the silylated aldehyde
1 is presumably slowly released from the intermediate alumin-
ium complex 8 and reacts instantaneously with the bis-ylide 9 to
give the ylide 10. After 30 min at room temperature, the solution
was recooled (278 °C), before 1.2 equiv. of the 9-oxo ester 3
were added. Following work-up, the silylated (17R)- or (17S)-
hydroxylinolenic acid 4 could be isolated in 42% overall yield.†
Less than 10% of the symmetrical coupling products 5 and 6
could be detected. Use of the configurationally stable alumin-
ium complex 8 had the additional advantage that the sensitive
chiral C3 synthon 1 reacted without racemisation under the basic
Wittig conditions. Both products, (17S)- and (17R)-4, proved to
be of > 97% ee by Mosher ester analysis of the end products
(17S)- and (17R)-12 (volicitin).‡ 13C NMR analysis revealed
the configuration of the 9- and 15-double bonds to be of > 95%
Z.
O
O
Br–Ph3P+
P+Ph3Br–
+
+
R1
H
R2
H
1
2
3
R1
R1
base
5
+
R2
R1
4
Saponification of 4 with aqueous LiOH in THF7 afforded
TBDMS protected 17-hydroxylinolenic acid 11 in 86% yield.
Coupling of 11 with glutamine was achieved using the ethyl
carbonate mixed anhydride method. Acidic workup of the crude
R2
R2
R1 = CH(OTBDMS)Me
2 = (CH2)7CO2Me
6
R
Scheme 1
Chem. Commun., 1999, 1087–1088
1087

temperature. Hydrolysis with sat. NH4Cl, extraction with Et2O and column
chromatography on SiO2 yielded the protected ester 4 as a colourless,
viscous liquid. Yield: 161 mg (42%).
‡ Both enantiomers of 12 were esterified with excess (R)-(2)-a-methoxy-
a-(trifluoromethyl)phenylacetyl chloride in the presence of DMAP and
Et3N (ref. 10). After the reaction was complete (no starting material could
be detected via NMR analysis) the ee of 12 was determined by integration
of the isolated 17-hydroxylinolenic acid C(18)-methyl doublet [d 1.35 for
product resulted in simultaneous deprotection, and pure volici-
tin 4 could be separated from excess glutamine by RP-MPLC-
chromatography.§ The significance of the chiral centre for the
induction of plant volatile biosynthesis is currently being
evaluated. Detailed results together with information on the
mode of signaling of the compound will be presented else-
where.
The three-component Wittig reaction described here opens a
new and highly versatile route to the skipped triene sub-
structures occurring in a large variety of natural products. The
central building block 2 is readily available on a multi-gram
scale,5 and one-pot product formation with good stereoselectiv-
ities allows its universal use as a building block in the synthesis
of highly unsaturated fatty acids and related compounds. Like
the previously introduced di-n-butyl-1-stannacyclohexa-
2,5-diene9 as a bifunctional building block for the formation of
skipped dienes, the bis-Wittig approach also has universal
potential, allowing the direct assembly of at least three
homoconjugated double bonds from simple precursors in a
single operation.
(17S)-12 and d 1.42 for (17R)-12].
22
589
§ Selected data for 12: [a]52829 +3 (c 0.83, CH2Cl2) [(17S)-12]; [a] 24.0
(c 0.82, CH2Cl2) [(17R)-12]; dH (CD3OD, 500 MHz) 5.3–5.17 (m, 6H), 4.50
(dq, 1H, J 6.8, 6.36), 4.25 (dd, 1H, J 4.8, 3.9), 2.75 (m, 2H), 2.69 (t, 2H, J
5.8), 2.21–2.16 (m, 2H), 2.12 (t, 2H, J 7.3), 2.07–1.95 (m, 1H), 1.95 (q, 2H,
J 6.5), 1.87–1.77 (m, 1H), 1.49 (t, 2H), 1.29–1.18 (m, 10H), 1.07 (d, 3H, J
6.36); dC (CD3OD, 125 MHz), 176.761, 175.404, 174.169, 134.418,
130.237, 128.657, 128.190, 127.690, 127.680, 63.396, 52.376, 35.867,
31.799, 29.704, 29.339, 29.269, 29.227, 27.623, 27.177, 25.868, 25.787,
25.519, 22.970. See ref. 3 for mass spectroscopic data.
1 M. K. Stowe, T. C. J. Turlings, J. H. Loughrin, W. J. Lewis and J. H.
Tumlinson, Proc. Natl. Acad. Sci. U.S.A., 1995, 92, 23 and references
cited therein.
Financial support by the Deutsche Forschungsgemeinschaft
(SPP 716) Bonn, and the Fonds der Chemischen Industrie,
Frankfurt, is gratefully acknowledged. We thank the BASF,
Ludwigshafen, and the Bayer AG, Leverkusen, for generous
supplies of chemicals and solvents and Dr N. J. Oldham for
proof-reading of the manuscript.
2 M. L. Mattiacci, M. Dicke and M. A. Posthumus, Proc. Natl. Acad. Sci.
U.S.A., 1995, 92, 2036.
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mental details for the preparation of 2 will be reported elsewhere.
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5180.
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Notes and references
† Experimental procedure: A cold (278 °C) suspension of the Wittig salt 2
(700 mg, 0.91 mmol) in dry THF (15 ml) was treated with KN(SiMe3)2 in
hexane (3.8 ml of a 0.5 M solution). The solution was allowed to warm to
0 °C, stirred for 10 min and recooled (278 °C). An ethereal solution of the
aluminate 8 (2.3 ml, 0.4 M, pre-cooled to 278 °C) was added (ref. 6,8). The
mixture was allowed to warm to room temperature and stirring was
continued for 1 h before recooling to 278 °C. Then, a solution of 3 (203 mg
in 1 ml THF) was added and the mixture was allowed again to reach room
Communication 9/02020I
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Chem. Commun., 1999, 1087–1088