A General Approach to the Asymmetric Synthesis of Unsaturated Lipidic α-Amino Acids. the First Synthesis of α-Aminoarachidonic Acid

Full text of DOI:10.1021/jo9715128

J . Org. Chem. 1998, 63, 3741-3744
3741
Sch em e 1
A Gen er a l Ap p r oa ch to th e Asym m etr ic
Syn th esis of Un sa tu r a ted Lip id ic r-Am in o
Acid s. Th e F ir st Syn th esis of
r-Am in oa r a ch id on ic Acid
George Kokotos,† J ose´ M. Padro´n,‡ Toma´s Mart´ın,‡
William A. Gibbons,§ and V´ıctor S. Mart´ın*,‡
Department of Chemistry, Laboratory of Organic Chemistry,
University of Athens, Panepistimiopolis,
the properties of lipidic amino acids and related lipid
mimetics have been reviewed.8
15771 Athens, Greece, Instituto Universitario de
Bio-Orga´nica “Antonio Gonza´lez”, Universidad de La
Laguna, Carretera de La Esperanza, 2, 38206 La Laguna,
Tenerife, Spain, and Department of Pharmaceutical
Chemistry, The School of Pharmacy, University of London,
29-39 Brunswick Square, London, WC1N 1AX, UK
Approaches using regioselective functionalization of
readily available chiral building blocks, e.g. derivatives
of natural amino acids, are especially attractive for the
synthesis of unnatural amino acids. L-Glutamic acid is
an inexpensive starting material, which may be modified
selectively at the γ-carboxylic acid function after suitable
protection of the R-amino group.9 Our strategy for the
synthesis of chiral unsaturated lipidic amino acids is
based on the regioselective functionalization of the suit-
ably protected glutamic acid γ-aldehyde.
Received August 13, 1997
In tr od u ction
Nonproteinogenic, nonnatural R-amino acids have
increasingly attracted the attention of numerous disci-
plines in connection with the design and synthesis of
potential constituents of pharmaceuticals, for example
enzyme inhibitors, and of optically active starting ma-
terials for a variety of synthetic applications. In conse-
quence, a large effort has been devoted to the preparation
of amino acids in the enantiomerically pure form of either
configuration, a subject already covered by general
reviews.1-3
Here we report on a simple, efficient, and general
method to prepare unsaturated R-amino fatty acids in
their enantiomeric forms, which eventually can be trans-
formed into the saturated products by simple hydrogena-
tion. We have illustrated these procedures by the
synthesis of R-amino arachidonic acid 1 (Scheme 1). The
synthesis of such substances should provide us with a
general methodology to gain access to analogues and,
importantly, to permit the analysis of structure-activity
relationships.
On the other hand, particular attention has been
focused on lipidic acids and their involvement in signal
transduction and medicine. Thus, arachidonic acid acts
both as a modulator and messenger, particularly of
signals triggered at the level of cell membranes.4,5 The
fatty acids in the cell membranes determine many of
their physical properties, modulate the configuration of
all the membrane-associated proteins, and are able to
influence directly or indirectly almost every second
messenger system which controls cell function. Unsuit-
able concentrations of 20- and 22-carbon essential fatty
acids in cell membrane phospholipids and inappropriate
ratios between the n - 6 and n - 3 essential fatty acids
may be the ultimate causal factors in coronary heart
disease and peripheral vascular disease.6
Resu lts a n d Discu ssion s
Our strategy was based on the possibility of building
the chain using Wittig-type reactions from aldehydes
such as 3 that could be obtained from acids such as
glutamic acid. This approach permitted both conver-
gence in the synthetic procedure and stereoselectivity in
the formation of the double bond. Although the synthesis
of aldehyde 3 from glutamic acid is known,10 we explored
a new and more direct method that permitted us to easily
increase the scale of the reaction. Thus, (S)-glutamic acid
was perbenzylated under known conditions11 to yield the
diester 4. When this product was submitted to reduction
with DIBAL under controlled conditions (1.1 equiv, -78
°C, 1 h), the aldehyde 3 (P ) P′ ) Bn) was obtained in
87% isolated yield (Scheme 2). Although the synthesis
of this aldehyde is a promising result, its use for the
synthesis of unsaturated amino acid would be drastically
limited because of the cleavage of the N,N-dibenzyl
protecting group.12 In light of these results it was decided
to further explore the method by changing the protecting
groups in the starting unit. Thus, the dimethyl N-Boc-
glutamate 5 was reduced under the above conditions
To combine structural features of amino acids with
those of fatty acids, we have prepared chiral lipidic
R-amino acids which are unnatural R-amino acids with
saturated long aliphatic side chains.7 The synthesis and
† University of Athens
‡ Universidad de La Laguna
§ University of London
(1) Barrett, G. C. Chemistry and Biochemistry of the Amino Acids;
Chapman and Hall, London, 1985.
(2) Williams, R. M. Organic Chemistry Series: Synthesis of Optically
Active R-Amino Acids; Baldwin, J . E., Magnus, P. D., Eds.; Pergamon
Press: Oxford, 1989.
(3) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
(4) Sumida, C.; Graber, R.; Nunez, E. A. Prostaglandins Leukotrienes
Essent. Fatty Acids 1993, 48, 117.
(8) Kokotos, G.; Mart´ın, V. S.; Constantinou-Kokotou, V.; Gibbons,
W. A. Amino Acids 1996, 11, 329.
(9) Kokotos, G.; Markidis, T.; Constantinou-Kokotou, V. Synthesis
1996, 1223.
(5) Graber, R.; Sumida, C.; Nunez, E. A. J . Lipid Med. Cell Sign.
1994, 9, 91.
(6) Horrobin, D. F. Prostaglandins Leukotrienes Essent. Fatty Acids
1995, 53, 385.
(10) Bold, G.; Steiner, H.; Moesch, L.; Walliser, B. Helv. Chim. Acta
1990, 73, 405.
(11) Gmeiner, P.; Ka¨rtner, A.; J unge D. Tetrahedron Lett. 1993, 34,
4325.
(7) Kokotos, G.; Padro´n, J . M.; Noula, C.; Gibbons, W. A.; Mart´ın,
V. S. Tetrahedron: Asymmetry 1996, 7, 857.
(12) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons: New York, 1991.
S0022-3263(97)01512-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/08/1998

3742 J . Org. Chem., Vol. 63, No. 11, 1998
Notes
Sch em e 2a
Sch em e 3a
a
BnBr, K2CO3, H2O, ∆; (b) (i) DIBAL, ether, -78 °C, (ii) H2O;
(c) (i) TMSCl, MeOH, (ii) Boc2O, Et3N, MeOH; (d) Boc2O, DMAP,
CH3CN.
a
KN(TMS)2, toluene, -78 °C; (b) (i) HCl, THF, (ii) (Boc)2O,
(Scheme 2). Disappointingly, we were unable, in this
case, to obtain satisfactory results, presumably due to
some participation of the nitrogen. This result led us to
try to minimize the nucleophilic power of the nitrogen
by the introduction of a second Boc group.13 In this case,
when the dimethyl N,N-di-Boc-glutamate 6 was reduced
with DIBAL under our conditions, the aldehyde 7 was
obtained in 85% yield (Scheme 2).
To obtain the desired unsaturated lipidic R-amino
acids, the aldehyde 7 was submitted to usual Wittig
conditions (n-BuLi, THF, -78 °C). However, satisfactory
results were not obtained. This disappointment induced
us to change the Wittig reaction conditions. Encourag-
ingly, using NaN(TMS)2 as base, in THF, the unsaturated
ester was obtained in 10% yield, but even better, when
the generation of the ylide was performed with KN-
(TMS)2, in toluene at 0 °C, and the Wittig reaction
performed at -78 °C, the Z-ester 8 was obtained in 92%
isolated yield.14 This result prompted us to achieve the
synthesis of methyl N,N-di-Boc-(S)-R-amino arachidonate
in a straightforward manner. Thus, when the phospho-
nium salt 915 was submitted to the ylide formation under
the later conditions and reacted with the aldehyde 7, the
protected (S)-R-amino arachidonic acid 10 was obtained
in 88% isolated yield.
Et3N, MeOH, (iii) NaOH, dioxane, (iv) CH2N2, ether; (c) DIBAL,
benzene, 0 °C; (d) (i) HCl, THF, (ii) (Boc)2O, Et3N, MeOH; (e)
NaOH, dioxane.
incomplete. Furthermore, the optical rotation of the
obtained free acid changed with time, showing clearly
that racemization had occurred. In light of this result,
we decided to try a different strategy and remove the
protecting groups of the nitrogen in the first stage. Thus,
we treated 8 under acidic conditions to remove the two
N-Boc groups, and the resulting compound was N-Boc
protected. This compound was smoothly hydrolyzed
under alkaline conditions,17 in an almost quantitative
manner, with uniform optical activity (Scheme 3). To
ensure the enantiomeric purity of such a product we
again protected the free acid as the methyl N-Boc-R-
amino ester 11, which was then reduced to the primary
alcohol 12. The 1H NMR and HPLC analysis of the
corresponding (R)- and (S)-Mosher esters showed no
detectable racemization.18
Finally, considering the possibility of using these
compounds in the synthesis of lipidic peptides,7 we
prepared the N-Boc-R-amino arachidonic acid (14) using
the above-described methodology, yielding 14 in 88%
overall yield.19
In summary, we have described a new methodology
which can be used for the synthesis of a wide range of
unsaturated and saturated R-amino acids, with almost
unlimited possibilities, the only potential limitations of
which are the synthesis of the suitable ylide and the
corresponding Wittig reaction. The new compound named
(S)-R-aminoarachidonic acid has been reported for the
first time. Although the methodology presented here has
been described for one enantiomeric series only, the
choice of the proper stereoisomer of glutamic acid permits
the control of the absolute configuration in the final
products.
Although it is known that the cleavage of the protecting
groups in methyl N-Boc-R-amino esters to afford the
corresponding R-amino acids occurs without any epimer-
ization,16 in our case, we were worried about such a
possibility because of the presence of the additional N-Boc
group. To investigate this we submitted 8 to standard
basic conditions to cleave the methyl ester. We found
that even after 48 h, at room temperature, under alkaline
treatment (NaOH, dioxane), the removal of the ester was
(13) Almeida, M. L. S.; Grehn, L.; Ragnarsson, U. J . Chem. Soc.,
Perkin Trans. 1 1988, 1905.
(14) Sreekumar, C.; Darst, K. P.; Still, W. C. J . Org. Chem. 1980,
45, 4260.
(15) The ylide 9 was prepared by refluxing (Ph)3P and (3Z,6Z,9Z)-
n-C5H11(CHdCHCH2)3CH2I in CH3CN. The iodide was synthesized
from the suitable alcohol [(Ph)3P, imidazol, I2], which was obtained by
the hydrogenation (P-2, Ni, H2) of n-C5H11(CHtCH)3CH2OTHP. For
the synthesis of a similar skipped triacetylene, see: An˜orbe, B.; Mart´ın,
V. S.; Palazo´n, J . M.; Trujillo J . M. Tetrahedron Lett. 1986, 29, 681.
(16) Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis;
Springer-Verlag: Berlin, 1984, 177.
(17) Callahan, J . F.; Newlander, K. A.; Bryan, H. G.; Huffman, W.
F.; Moore, M. L.; Yim, N. C. F. J . Org. Chem. 1988, 53, 1727.
(18) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(19) Compound 1 was actually prepared as the intermediate to 14.
However, such a compound was insoluble in most NMR solvents, being
found to be soluble only in CF3CO2D, in which decomposition was
extremely fast.

Notes
J . Org. Chem., Vol. 63, No. 11, 1998 3743
crude was purified by silica gel column chromatography to afford
Exp er im en ta l Section
8 (2.7 g, 87% yield) as an oil: [R]25 ) -26.2 (c 2.18, CHCl3); 1H
D
Ma ter ia ls a n d Meth od s. See ref 20 for details.
NMR (CHCl3) δ 0.88 (t, J ) 6.8 Hz, 3 H), 1.25 (bs, 24 H), 1.49
(s, 18 H), 1.90 (m, 1 H), 2.00 (dd, J ) 13.6, 6.8 Hz, 2 H), 2.08
(dd, J ) 14, 7.2 Hz, 2 H), 2.15 (m, 1H), 3.71 (s, 3 H), 4.86 (dd, J
) 8.8, 4.8 Hz, 1 H), 5.38 (m, 2H); 13C NMR (CHCl3) δ 14.1 (q),
22.7 (t), 24.0 (t), 27.3 (t), 28.0 (q), 29.3 (t), 29.4 (t), 29.5 (t), 29.6
(t), 29.7 (t), 30.1 (t), 31.9 (t), 52.1 (q), 57.7 (d), 83.0 (s), 128.1 (d),
131.3 (d), 152.1 (s), 171.4 (s); IR (CHCl3) (cm-1) 2928, 2855, 1787,
1698, 1458, 1144; MS m/ z (relative intensity) 382 (M - 157)+
P r ep a r a tion of Dim eth yl (S)-2-ter t-Bu toxyca r bon yla m i-
n op en ta n ed ioa te (5). To a stirred solution of (S)-glutamic acid
(1.47 g, 10 mmol) in dry MeOH (26 mL) was added Me3SiCl (5.6
mL, 44 mmol) at 0 °C. The temperature was allowed to reach
rt and the mixture was stirred overnight. Then, Et3N (9 mL,
65 mmol) and Boc2O (2.4 g, 11 mmol) were added and the
resulting mixture stirred until the evolution of gas was com-
pleted. The solvent was evaporated under reduced pressure, and
the residue was triturated and washed with ether (3 × 100 mL).
The combined filtrates were concentrated, to provide a crude
that was purified by silica gel chromatography to yield 5 (2.6 g,
(4), 339 (30), 280 (83), 156 (10), 133 (100). Anal. Calcd for C31H57
-
NO6: C, 68.96; H, 10.65; N, 2.60. Found: C, 68.67; H, 10.88;
N, 2.65.
P r ep a r a tion of Meth yl (5Z,8Z,11Z,14Z,2S)-2-Di-ter t-bu -
toxyca r bon yla m in oeicosa -5,8,11,14-tetr a en oa te (10). The
general conditions used above to obtain 8 were applied by using
915 on a 594 mg (1 mmol) scale, yielding 10 (390 mg, 88% yield)
95% yield) as an oil: [R]25 ) +12.9 (c 2.00, CHCl3); 1H NMR
D
(CDCl3) δ 1.40 (s, 9 H), 1.91 (m, 1H), 2.14 (m, 1H), 2.37 (m, 2
H), 3.64 (s, 3 H), 3.70 (s, 3 H), 4.29 (bs, 1 H), 5.14 (bs, 1 H); 13
C
as an oil: [R]25 ) -27.7 (c 2.00, CHCl3); 0.88 (t, J ) 6.2 Hz, 3
NMR (CDCl3) δ 27.7 (t), 28.2 (q), 30.0 (t), 51.7 (q), 52.3 (q), 52.8
(d), 79.9 (s), 155.3 (s), 172.6 (s), 173.1 (s); IR (CHCl3) (cm-1) 3436,
3025, 1737, 1503, 1369, 1167; MS m/ z (relative intensity) 276
(M + 1)+ (1), 219 (22), 187 (25), 116 (99), 84 (86), 57 (100). Anal.
Calcd for C12H21NO6: C, 52.35; H, 7.69; N, 5.09. Found: C,
52.26; H, 7.81; N, 5.05.
P r ep a r a tion of Dim eth yl (S)-2-Di-ter t-bu toxyca r bon yl-
a m in op en ta n ed ioa te (6). To a stirred solution of 5 (2.5 g, 9
mmol) and DMAP (220 mg, 1.8 mmol) in dry CH3CN (30 mL)
was added Boc2O (2.2 g, 9.9 mmol) at room temperature. The
reaction became slightly red with gas evolution. The mixture
was stirred for 2 h, after which time TLC showed that some
starting material still remained. Then, more Boc2O (1.1 g, 4.9
mmol) was added and the mixture was additionally stirred
overnight. The solvent was evaporated, and the crude purified
D
H), 1.30 (m, 6 H), 1.93 (m, 1 H), 2.03 (m, 2 H), 2.15 (m, 3 H),
2.81 (m, 6 H), 3.70 (s, 3 H), 4.87 (dd, J ) 8.5, 4.4 Hz, 1 H), 5.36
(m, 8 H); 13C NMR (CHCl3) δ 14.0 (q), 22.5 (t), 24.0 (t), 25.6 (t),
27.2 (t), 27.9 (q), 29.3 (t), 30.0 (t), 31.5 (t), 52.1 (q), 57.6 (d), 83.0
(s), 127.5 (d), 127.8 (d), 128.1 (d), 128.2 (d), 128.6 (d), 128.7 (d),
129.0 (d), 130.4 (d), 152.1 (s), 171.3 (s); IR (CHCl3) (cm-1) 3011,
2932, 2860, 1787, 1457; MS m/ z (relative intensity) 378 (M -
155)+ (1), 276 (3), 184 (7), 156 (11), 142 (55), 128 (100). Anal.
Calcd for C31H51NO6: C, 69.76; H, 9.63; N, 2.62. Found: C,
69.70; H, 9.90; N, 2.76.
Exp er im en t To P r ove th a t th e Wh ole Sequ en ce of th e
P r otectin g Gr ou p Clea va ge Over th e Di-Boc-r-Am in o
Ester s Does Not Ca u se Ra cem iza tion . P r ep a r a tion of
Meth yl (5Z,2S)-2-ter t-Bu toxyca r bon yla m in oeicos-5-en oa te
(11) a n d ter t-Bu tyl (S)-[(4Z)-(1-Hyd r oxym eth yln on a d ec-4-
en yl]ca r ba m a te (12). To a stirred solution of 8 (300 mg, 0.56
mmol) in THF (5 mL) was added HCl (5.2 N solution in dry THF,
5.3 mL, 27.8 mmol) at room temperature. The stirred mixture
was monitored by TLC until complete conversion. The solvent
was evaporated and the residue was treated with THF (2 × 5
mL) and evaporated. The solid residue was triturated, washed
with ether (5 mL), and dried. Then, it was dissolved in a 10:1
mixture of MeOH:Et3N (6 mL) and treated with Boc2O (134 mg,
0.6 mmol) at room temperature. The mixture was stirred until
no gas evolution was observed (≈3 h). The solvent was evapo-
rated and the crude was purified by silica gel chromatography
by silica gel chromatography, yielding 6 (3.32 g, 98% yield) as
1
an oil: [R]25 ) -37.2 (c 2.15, CHCl3); H NMR (CDCl3) δ 1.49
D
(s, 18 H), 2.17 (m, 1 H), 2.40 (m, 2 H), 2.46 (m, 1 H), 3.67 (s, 3
H), 3.71 (s, 3 H), 4.93 (dd, J ) 9.2, 4.4 Hz, 1 H); 13C NMR (CDCl3)
δ 25.2 (t), 27.9 (q), 30.6 (t), 51.6 (q), 52.2 (q), 57.3 (d), 83.3 (s),
151.9 (s), 170.8 (s), 173.1 (s); IR (CHCl3) (cm-1) 3024, 1789, 1742,
1699, 1370; MS m/ z (relative intensity) 376 (M + 1)+ (3), 320
(58), 264 (42), 220 (100), 176 (100). Anal. Calcd for C17H29NO8:
C, 54.37; H, 7.79; N, 3.73. Found: C, 54.64; H, 7.92; N, 3.73.
P r ep a r a tion of Meth yl (S)-2-Di-ter t-bu toxyca r bon yla m i-
n o-5-oxop en ta n oa te (7). To a stirred solution of 6 (1 g, 2.7
mmol) in dry ether (27 mL) was added dropwise DIBAL (3 mL,
1.0 M in hexane, 3 mmol) to -78 °C. The reaction mixture was
stirred for 5 min. It was then quenched with H2O (0.4 mL) and
allowed to warm to room temperature. The mixture was stirred
for 30 min, dried over MgSO4 and filtered through a pad of
Celite. The solvent was evaporated and the residue was purified
by silica gel column chromatography, to yield 7 (790 mg, 85%
yield) as an oil: [R]25D ) -35.3 (c 2.25, CHCl3); 1H NMR (CDCl3)
δ 1.48 (s, 18 H), 2.16 (m, 1 H), 2.52 (m, 2 H), 2.59 (m, 1 H), 3.71
(s, 3 H), 4.87 (dd, J ) 9.6, 5.2 Hz, 1 H), 9.76 (s, 1 H);13C NMR
(CDCl3) δ 22.5 (t), 27.9 (q), 40.5 (t), 52.2 (q), 57.3 (d), 83.4 (s),
152.0 (s), 170.7 (s), 200.9 (d); IR (CHCl3) (cm-1) 3028, 2984, 1789,
1370, 1231, 1144; MS m/ z (relative intensity) 302 (M - 43) (1),
to obtain 11 (244 mg, 99% yield) as an oil: [R]25 ) +16.3 (c
D
1.23, CHCl3); 1H NMR (CHCl3) δ 0.87 (t, J ) 7.0 Hz, 3 H), 1.25
(bs, 24 H), 1.43 (s, 9 H), 1.68 (m, 1 H), 1.84 (m, 1 H), 2.00 (m, 2
H), 2.08 (m, 2 H), 3.72 (s, 3 H), 4.29 (bs, 1 H), 5.01 (bs, 1 H),
5.30 (m, 1 H), 5.39 (m, 1 H); 13C NMR (CHCl3) δ 14.0 (q), 22.6
(t), 23.1 (t), 27.2 (t), 27.3 (t), 28.2 (q), 29.3 (t), 29.5 (t), 29.6 (t),
29.8 (t), 31.8 (t), 31.9 (t), 32.6 (t), 52.1 (q), 53.1 (d), 79.7 (s), 127.5
(d), 131.5 (d), 155.3 (s), 173.3 (s); IR (CHCl3) (cm-1) 3442, 2928,
1740, 1712, 1501, 1368; MS m/ z (relative intensity) 383 (M -
57)+ (7), 366 (8), 339 (34), 156 (13), 142 (18), 133 (100). Anal.
Calcd For C26H49NO4: C, 71.01; H, 11.24; N, 3.11. Found: C,
70.98; H, 11.51; N, 3.09.
206 (15), 174 (37), 162 (35), 128 (100). Anal. Calcd for C16H27
-
To prove that the hydrolysis of the methyl ester does not cause
any racemization, 11 (100 mg, 0.23 mmol) was dissolved in
dioxane (1 mL) and treated with NaOH (1 M aqueous solution,
6.2 mL, 6.2 mmol) at room temperature. The reaction mixture
was stirred overnight. Then, HCl (3 M) was added at 0 °C until
pH ≈ 2 was reached, and the mixture was extracted with EtOAc
(4 × 5 mL). The combined organic phases were washed with
10 mL of a saturated solution of brine, dried, and evaporated in
vacuo. The residue was dissolved in ether (10 mL) and treated
with an ether solution of diazomethane until a yellow color
persisted. Then a few drops of acetic acid were added to destroy
the excess of diazomethane. The reaction mixture was washed
with a saturated solution of NaHCO3 (5 mL) and brine (5 mL),
dried, and evaporated. The residue was purified by column
chromatography to give 11 (90 mg, 90% overall yield) with a
specific rotation almost similar to that previously obtained. This
batch of 11 was used to obtain 12 in accordance with the
following procedure.
NO7: C, 55.64; H, 7.88; N, 4.06. Found: C, 55.45; H, 8.10; N,
4.09.
Gen er a l P r oced u r e for th e Syn th esis of Z-Un sa tu r a ted
r-Am in o Acid s by a Wittig Rea ction over Meth yl (S)-2-Di-
ter t-bu toxyca r bon yla m in o-5-oxo-p en ta n oa te (7). P r ep a -
r a tion of Meth yl (5Z,2S)-2-Di-ter t-bu toxyca r bon yla m in o-
eicos-5-en oa t e (8). To a stirred suspension of pentadecyl-
triphenylphosphonium bromide (3.85 g, 7 mmol) in dry toluene
(40 mL) under argon was added dropwise KN(TMS)2 (12.8 mL,
0.5 M solution in toluene, 6.4 mmol) at 0 °C. After 15 min the
flask was cooled to -78 °C and 7 (2 g, 5.8 mmol) in toluene (5
mL) was added dropwise. The reaction mixture was stirred for
2 h, after which time TLC showed complete conversion. Then,
the reaction mixture was quenched with a saturated aqueous
solution of NH4Cl (50 mL) and extracted with ether (3 × 10 mL).
The combined organic phases were washed with brine (50 mL),
dried over MgSO4, and filtered and the solvent evaporated. The
To a slurry of 11 (42 mg, 0.1 mmol) in dry benzene (5 mL)
was added dropwise DIBAL (200 µL, 1.0 M in hexane, 0.2 mmol)
at 0 °C. The reaction mixture was stirred for 5 min. It was
(20) Rodr´ıguez, C. M.; Mart´ın, T.; Mart´ın, V. S. J . Org. Chem. 1994,
59, 4461.

3744 J . Org. Chem., Vol. 63, No. 11, 1998
Notes
then quenched with H2O (0.4 mL) and allowed to warm to room
temperature. The mixture was stirred for 30 min, dried over
MgSO4, and filtered through a pad of Celite. The solvent was
evaporated and the residue was purified by silica gel column
P r ep a r a tion of (5Z,8Z,11Z,14Z,2S)-2-ter t-Bu toxyca r bo-
n yla m in oeicosa -5,8,11,14-tetr a en oic Acid (14). To a stirred
solution of 13 (26.3 mg, 0.061 mmol) in dioxane (1 mL) was
added NaOH (1 M aqueous solution, 6.2 mL, 6.2 mmol) at room
temperature. The reaction mixture was stirred overnight.
Then, HCl (3 M) was added at 0 °C until pH ≈ 2 was reached,
and the mixture was extracted with EtOAc (4 × 5 mL). The
combined organic phases were washed with 10 mL of a saturated
solution of brine, dried, and evaporated in vacuo, and the residue
was purified by column chromatography to give 14 (23.1 mg,
chromatography, to yield 12 (34 mg, 85% yield) as an oil: [R]25
D
) -11.3 (c 2.01, CHCl3); 1H NMR (CDCl3) δ 0.87 (t, J ) 7.0 Hz,
3 H), 1.25 (bs, 24 H), 1.43 (s, 9 H), 1.57 (m, 2 H), 2.00 (m, 2 H),
2.09 (m, 2 H), 2.67 (bs, 1 H), 3.53 (m, 1 H), 3.65 (m, 2 H), 4.68
(d, J ) 7.28 Hz, 1 H), 5.31 (m, 1 H), 5.39 (m, 1 H); 13C NMR
(CHCl3) δ 14.1 (q), 22.6 (t), 23.1 (t), 27.2 (t), 27.3 (t), 28.2 (q),
29.3 (t), 29.5 (t), 29.6 (t), 29.8 (t), 31.8 (t), 31.9 (t), 32.6 (t), 52.9
(d), 66.0 (t), 79.7 (s), 128.3 (d), 131.5 (d), 156.6 (s); IR (CHCl3)
(cm-1) 3691, 3442, 2855, 1712, 1504, 1368; MS m/ z (relative
intensity) 354 (M - 57)+ (3), 300 (26), 268 (18), 57 (100). Anal.
Calcd For C25H49NO3: C, 72.94; H, 12.00; N, 3.40. Found: C,
72.88; H, 12.03; N, 3.36.
90% yield) as an oil: [R]25 ) +9.7 (c 0.66, CHCl3); 1H NMR
D
(CDCl3) δ 0.89 (t, J ) 6.8 Hz, 3 H), 1.33 (m, 6 H), 1.44 (s, 9 H),
1.72 (m, 1 H), 1.92 (m, 1 H), 2.05 (m, 2 H), 2.16 (m, 2 H), 2.82
(m, 6 H), 4.28 (bs, 1 H), 5.06 (bs, 1 H), 5.38 (m, 8 H); 13C NMR
(CDCl3) δ 14.0 (q), 22.5 (t), 23.2 (t), 25.6 (t), 26.8 (t), 27.2 (t),
28.3 (q), 29.3 (t), 30.3 (t), 31.5 (t), 32.1 (t), 53.2 (d), 80.2 (s), 127.5
(d), 127.8 (d), 128.0 (d), 128.3 (d), 128.6 (d), 129.4 (d), 130.0 (d),
130.5 (d), 155.7 (s), 177.0 (s); IR (CHCl3) (cm-1) 3525, 2928, 2855,
1735, 1501, 1369; MS m/ z (relative intensity) 363 (M - 57)+
(2), 114 (38), 79 (23), 57 (100). Anal. Calcd for C25H41NO4: C,
71.55; H, 9.85; N, 3.34. Found: C, 71.25; H, 9.86; N, 3.02.
P r ep a r a tion of Meth yl (5Z,8Z,11Z,14Z,2S)-2-ter t-Bu toxy-
car bon ylam in oeicosa-5,8,11,14-tetr aen oate (13). To a stirred
solution of 10 (120 mg, 0.22 mmol) in THF (5 mL) was added
HCl (5.2 N solution in dry THF, 1 mL, 5.2 mmol) at room
temperature. The stirred mixture was monitored by TLC until
complete conversion. The solvent was evaporated and the
residue was treated with THF (2 × 5 mL) and evaporated. The
solid residue was triturated, washed with ether (5 mL), and
dried. Then, it was dissolved in a 10:1 mixture of MeOH:Et3N
(6 mL) and treated with Boc2O (53 mg, 0.24 mmol) at room
temperature. The mixture was stirred until no gas evolution
was observed (≈3 h). The solvent was evaporated and the crude
was purified by silica gel chromatography to obtain 13 (94 mg,
Ack n ow led gm en t. This research was supported by
the DGICYT (PB92-0489, PB95-0751) of Spain, the
Human Capital and Mobility Program (ERBCHRXCT93-
0288) of the European Community, and the Consejer´ıa
de Educacio´n, Cultura y Deportes del Gobierno de
Canarias. J .M.P. and T.M. thank the Gobierno Au-
to´nomo de Canarias, for a fellowship.
97% yield) as an oil: [R]25 ) +16.0 (c 2.08, CHCl3); 1H NMR
D
(CDCl3) δ 0.89 (t, J ) 6.9 Hz, 3 H), 1.30 (m, 6 H), 1.44 (s, 9 H),
1.70 (m, 1 H), 1.86 (m, 1 H), 2.05 (m, 2 H), 2.12 (m, 2 H), 2.81
(m, 6 H), 3.72 (s, 3 H), 4.31 (bs, 1 H), 5.00 (bs, 1 H), 5.37 (m, 8
H); 13C NMR (CDCl3) δ 14.0 (q), 22.5 (t), 23.1 (t), 25.5 (t), 25.6
(t), 27.2 (t), 28.3 (q), 29.3 (t), 29.6 (t), 31.5 (t), 32.5 (t), 52.2 (q),
53.1 (d), 79.8 (s), 127.5 (d), 127.8 (d), 128.0 (d), 128.3 (d), 128.6
(d), 129.2 (d), 129.6 (d), 130.5 (d), 155.3 (s), 173.2 (s); IR (CHCl3)
(cm-1) 3525, 3010, 2932, 2860, 1742, 1698, 1368; MS m/ z
(relative intensity) 377 (M - 57)+ (1), 274 (7), 150 (10), 128 (57),
57 (100). Anal. Calcd for C26H43NO4: C, 72.00; H, 10.00; N, 3.23.
Found: C, 71.57; H, 10.64; N, 3.09.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for the compounds 3-8 and 10-14 and the 1H
NMR spectra for the (R)- and (S)-Mosher esters of 12 (24
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O9715128