Enantioselective synthesis of (10S)- and (10R)-methyl-anandamides

Article abstract of DOI:10.1016/j.tet.2012.05.010

For the development of novel endocannabinoid templates with potential resistance to hydrolytic and oxidative metabolism, we are targeting the bis-allylic carbons of the arachidonoyl skeleton. Toward this end, we recently disclosed the synthesis and prelim

Full text of DOI:10.1016/j.tet.2012.05.010

Tetrahedron 68 (2012) 6329e6337
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Enantioselective synthesis of (10S)- and (10R)-methyl-anandamides
,
y
y
*
*
Spyros P. Nikas , Marsha D’Souza , Alexandros Makriyannis
Center for Drug Discovery, Northeastern University, 116 Mugar Life Sciences Building, 360 Huntington Avenue, Boston, MA 02115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
For the development of novel endocannabinoid templates with potential resistance to hydrolytic and
oxidative metabolism, we are targeting the bis-allylic carbons of the arachidonoyl skeleton. Toward this
end, we recently disclosed the synthesis and preliminary biological data for the (13S)-methyl-ananda-
mide. We report now the total synthesis of the (10S)- and (10R)-methyl-counterparts. Our synthetic
approach is stereospecific, efficient, and provides the analogs without the need for resolution. Peptide
coupling, P-2 nickel partial hydrogenation, and cis-selective Wittig olefination are the key steps.
Ó 2012 Published by Elsevier Ltd.
Received 11 March 2012
Received in revised form 30 April 2012
Accepted 2 May 2012
Available online 24 May 2012
Keywords:
Methyl-anandamide
Endocannabinoids
Lipids
Enantioselective synthesis
1. Introduction
becomes important when FAAH or MGL are inhibited and when
endocannabinoid biosynthesis is activated following tissue dam-
The endogenous arachidonic acid (Ia) derivatives N-arach-
idonoylethanolamine (AEA, anandamide, Ib) and 2-arachidonoyl
glycerol (2-AG, Ic, Fig. 1) are synthesized on demand in response
to elevations of intracellular calcium, and are the two key lipid
modulators that act on CB1 and CB2 cannabinoid receptors.1e3 Both
CB1 and CB2 are members of the superfamily of G-protein-coupled
receptors4e7 and they are implicated in a wide array of patho-
physiological processes including inflammation,8 nociception,9e11
neuroprotection,12e15 memory,16 anxiety,17 feeding,18,19 and cell
proliferation.20,21 Following their synthesis and release, the endo-
cannabinoids AEA and 2-AG are removed from their sites of action
by cellular uptake and degraded by enzymes. In most tissues, fatty
acid amide hydrolase (FAAH) is the enzyme responsible for AEA
hydrolysis, and monoacylglycerol lipase (MGL) is the major
metabolizing enzyme for 2-AG.22,23 In addition to hydrolysis, the
presence of an arachidonoyl moiety in both AEA and 2-AG suggests
the conspicuous possibility that endocannabinoids may be metab-
olized by the plethora of oxygenases that act on arachidonic acid.
Investigations into this possibility have shown that a subset of
oxidative enzymes of the arachidonate cascade, such as lip-
oxygenases (LOX), cyclooxygenase-2 (COX-2), and cytochrome P450
catalyze the biotransformation of AEA and 2-AG into eicosanoid-
related metabolites.24e29 Apart from the hydrolytic deactivation of
AEA and 2-AG, the alternative COX-2 oxidative deactivation
age.30,31 Also, in platelets, which lack significant COX-2 and FAAH
activity a lipoxidative pathway of AEA deactivation predominates.26
As a part of our ongoing program in cannabinoid medicinal
chemistry, we turned our attention into the development of novel
endocannabinoid prototypes that possess CB receptor binding af-
finity as well as metabolic stability to the action of COX-2 and LOX.
The novel analogs can enhance our understanding regarding the
stereoelectronic requirements for CB receptor binding and aid in
* Corresponding authors. Tel.: þ1 617 373 4200; fax: þ1 617 373 7493; e-mail
addresses: s.nikas@neu.edu (S.P. Nikas), a.makriyannis@neu.edu (A. Makriyannis).
y
Fig. 1. Structures of arachidonic acid and endocannabinoid analogs.
These authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2012 Published by Elsevier Ltd.
doi:10.1016/j.tet.2012.05.010

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S.P. Nikas et al. / Tetrahedron 68 (2012) 6329e6337
the discovery of more potent and selective cannabinergic drug
candidates and fatty acid oxygenase (e.g., COX-2 and LOX) in-
hibitors. They can also serve as biochemical/pharmacological tools
to explore the connection between the endocannabinoid and the
COX-2 and LOX systems, and to define the physiological significance
of the oxidative metabolism of endocannabinoids.
Earlier work from our laboratory has shown that one of the most
successful and convenient ways to ‘shut off’ the enzymatic hydro-
lysis of AEA is the addition of a methyl substituent near the met-
abolic hot spot of the substrate (e.g., (R)-methanandamide, Id).32e34
It has also been shown that COX-2 and LOX mediated metabolism of
arachidonic acid and its derivatives begins with abstraction of
a hydrogen radical from the bis-allylic carbons 7, 10, or 13
(Fig. 1).35e38 Therefore, we considered that introduction of a methyl
group at the bis-allylic positions might preserve cannabinoid ac-
tivity while blocking the oxidative metabolism by COX-2 and LOX
enzymes. In this regard, we recently described the synthesis and
preliminary biological evaluation of (13S)-methyl anandamide
(Ie).39 With the aim of exploring all three bis-allylic positions and
establishing structureeactivity relationships (SAR) for the hitherto
unknown, methyl-substituted arachidonoyl chain, we report here
our efforts toward the total synthesis of the (10S)- and (10R)-
methyl-anandamides. Our synthetic approach is stereospecific, ef-
ficient, and provides the analogs without the need for resolution. A
detailed SAR study along with a full biological evaluation of the
synthesized analogs will be reported in due course.
Scheme 1. Synthesis of chiral aldehydes 3 and 4.
with DesseMartin periodinane produced 3 in 88% yield. Similarly,
the enantiomeric aldehyde 440 was synthesized from Roche ester 10.
Construction of the required alkenyl phosphonium salt 5 is
summarized in Scheme 2. Protection of the acetylenic alcohol 13
afforded terminal alkyne 14 (95% yield), which was metalated with
n-BuLi and quenched with excess ethylene oxide to give the two
carbon homologated alcohol 15 in 75% yield. As reported earlier,41
we also observed that ethylene oxide opening with lithium acety-
lides (e.g., TBDPSO(CH2)4C^CLi) in the presence of boron tri-
fluoride etherate has low reproducibility, especially on large scale,
and requires freshly distilled catalyst. Use of hexamethylphos-
phoramide,42 which strongly coordinates to lithium cations, is
a robust alternative to carry out this conversion. Partial hydroge-
nation of alkyne 15 over P-2 nickel catalyst39 afforded the corre-
sponding Z alkene 16 in 86% yield (3J3He4H¼10.5 Hz). Treatment of
this material with the PPh3/CBr4 system gave bromide 17 (81%
yield). However, deprotection with TBAF at 0 ꢀC produced the de-
sirable bromide 18 (Rf¼0.32, 30% AcOEt in hexane, 41% yield) along
with significant amounts of the elimination byproduct 19 (Rf¼0.27,
30% AcOEt in hexane, 32% yield). We also observed that large excess
of TBAF reagent and elevated temperature favor the formation of
19. After our experimental exercise, the problem was solved by
carrying out the reaction in the presence of acetic acid at 0 ꢀC.
Under these neutral conditions, 18 was produced in 83% yield
without any contamination with 19. Oxidation of the primary al-
cohol 18 to the carboxylic acid 20 employing Zhao’s elegant
method,43 followed by TMSCHN2 esterification gave methyl ester
2144,45 in 77% yield over two steps. A lower overall yield (63%) was
obtained when conversion of 18 to 20 was carried out using Jones
oxidation. Heating of 21 (72e75 ꢀC) with triphenylphosphine in dry
acetonitrile for four days furnished phosphonium salt 544 in 91%
yield after purification.
2. Results and discussion
Our retrosynthetic analysis involves methyl esters 2a and 2b as
the key precursors from which (10S)- and (10R)-methyl-ananda-
mides (1a and 1b, respectively) would be produced through pep-
tide coupling (Fig. 2). Retrosynthetic disconnection at the double
bonds adjacent to the chiral center provides four convergent frag-
ments: the phosphonium salts 5 and 6, and the chiral aldehydes 3
and 4 that possess the S and R configuration corresponding to the
C10 stereogenic centers of 1a and 1b, respectively. The synthetic
direction could be completed through Wittig olefination reactions.
Similarly the requisite C12eC20 fragment 645 was synthesized in
two steps and high overall yield (Scheme 3) through conversion of
alcohol 22 to bromide 23 (94% yield) and reaction with triphenyl-
phosphine in refluxing acetonitrile for seven days (72% yield). The
reaction time for the synthesis of phosphonium salt 6, is longer
when compared to the time required for the preparation of 5. Per-
haps, this is due to slightly different solubility of bromides 21 and 23
in acetonitrile. Our attempts to minimize the reaction time during
the preparation of phosphonium salts 5 and 6 using microwave
heating46 resulted in reduction of the purity of the products.
The assembly of the phosphonium salts 5 and 6 with chiral al-
dehyde 3 into (10S)-methyl-anandamide 1a is outlined in Scheme
4. Treatment of 5 with KHMDS at ꢁ78 to ꢁ60 ꢀC and coupling of
the resulting ylide with aldehyde 3 at ꢁ115 ꢀC gave TBDPS ether 24
(46% yield). Based on 1H NMR analysis (see Supplementary data),
Fig. 2. Retrosynthetic analysis of (10S)- and (10R)-methyl-anandamides.
Synthesis of chiral aldehyde 3 was carried out by following our
recently reported procedures (Scheme 1).39 Briefly, silylation of
commercially available methyl ester 7 gave the TBDPS ether 8 (95%
yield), which upon reduction with diisobutylaluminum hydride led
to aldehyde 3 (60% yield) and alcohol 9 (38% yield). Oxidation of 9
this Wittig reaction afforded the
Z olefin exclusively with

S.P. Nikas et al. / Tetrahedron 68 (2012) 6329e6337
6331
Scheme 2. Synthesis of alkenyl phosphonium salt 5.
Scheme 3. Synthesis of alkenyl phosphonium salt 6.
Scheme 4. Synthesis of (10S)-methyl-anandamide 1a.
3J8He9H¼10.5 Hz. Cleavage of the silyl ether 24 with TBAF produced
alcohol 25 in 92% yield. Interestingly, in the 1H NMR spectrum of 25,
all four double bond protons are well separated with coupling
constants 3J5He6H and 3J8He9H equal to 10.5 Hz (see Supplementary
data), which confirms a Z relationship between the hydrogen atoms
of the 5He6H and 8He9H spin systems. Exposure of 25 to
DesseMartin periodinane delivered aldehyde 26, which was used
immediately, without purification, in a Wittig reaction with phos-
phonium bromide 6, under salt free conditions, to give (10S)-
methyl-arachidonate 2a (39% yield from 25). Saponification of 2a
with lithium hydroxide in THF/H2O led to acid 27 (86% yield), which
was coupled with 2-(tert-butyldiphenylsilyloxy)ethanamine (29) to
give amide 30 (74% yield) by using the carbonyldiimidazole acti-
vation procedure. Desilylation of 30 with TBAF produced the req-
uisite (10S)-methyl-anandamide (1a) in 83% yield. The structure of
1a was established using 1D and 2D NMR experiments (COSY, HSQC
and NOESY, given under Supplementary data). NOESY interactions
between 10H and 13H confirm the Z stereochemistry for the
C11]C12 double bond, which was installed earlier in the arach-
idonate structure during the synthesis of the methyl ester 2a.

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S.P. Nikas et al. / Tetrahedron 68 (2012) 6329e6337
The enantiomer (10R)-methyl-anandamide (1b) was synthe-
Shield 400WB plus (1H at 400 MHz, 13C at 100 MHz), or on a Varian
500 (1H at 500 MHz, 13C at 125 MHz), or on a Varian 600 (1H at
600 MHz, 13C at 150 MHz), or on a Bruker Ultra Shield 700WB plus
(1H at 700 MHz, 13C at 175 MHz) spectrometers and chemical shifts
sized in a similar fashion (Scheme 5). Thus, Wittig olefination of
aldehyde 4 with phosphonium bromide 5 gave the Z product 31.
Deprotection with TBAF followed by oxidation with DesseMartin
periodinane led to intermediate aldehyde 33, which was used im-
mediately in the next step. Combination of 33 and the ylide derived
from 6 and KHMDS, resulted in the formation of the methyl ester
precursor 2b. The synthesis of 1b was completed by following: (a)
methyl ester hydrolysis, (b) coupling with protected ethanolamine
29 and (c) desilylation using TBAF.
are reported in units of d relative to internal TMS. Multiplicities are
indicated as br (broadened), s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet) and coupling constants (J) are reported in
hertz (Hz). Low and high-resolution mass spectra were performed
in School of Chemical Sciences, University of Illinois at Urbana-
Champaign. Mass spectral data are reported in the form of m/z
Scheme 5. Synthesis of (10R)-methyl-anandamide 1b.
3. Conclusion
(intensity relative to base¼100). Elemental analyses were obtained
in Baron Consulting Co., Milford, CT.
In summary, to explore the bio-actions, the receptor-appropriate
conformation(s), and the metabolic stability of a novel arachidonoyl
chain substituted with methyl groups at the bis-allylic positions, we
report here the enantioselective total synthesis of (10S)- and (10R)-
methyl-anandamides. Our approach involves P-2 nickel partial hy-
drogenation, cis-selective Wittig olefination and peptide coupling
as the key steps. A detailed SAR study and a full biological evaluation
of the analogs described here are currently underway.
4.1.1. 6-[(tert-Butyldiphenylsilyl)oxy]hex-1-yne (14).47 To a solution
of 5-hexyn-1-ol (13) (14.2 g,144.7 mmol) and dried imidazole (12.8 g,
188.1 mmol) in anhydrous CH2Cl2 (180 mL) at 0 ꢀC under an argon
atmosphere, was added a solution of tert-butyldiphenylsilyl chloride
(43.8 g,159.2 mmol) in 10 mL CH2Cl2 dropwise. The reaction mixture
was stirred for 1 h at 0 ꢀC and 1 h at room temperature. On com-
pletion, the reaction was quenched with saturated aqueous sodium
bicarbonate solution and extracted with CH2Cl2. The combined or-
ganic extracts were washed with brine, dried (MgSO4) and concen-
trated under reduced pressure. Purification by flash column
chromatography on silica gel (10e20% diethyl ether in hexanes) gave
44.1 g (95% yield) of 14 as a colorless oil. 1H NMR (500 MHz, CDCl3)
4. Experimental
4.1. General
All reagents and solvents were purchased from Aldrich Chemical
Company, unless otherwise specified, and used without further
purification. All anhydrous reactions were performed under a static
argon or nitrogen atmosphere in flame-dried glassware using
scrupulously dry solvents. Flash column chromatography employed
silica gel 60 (230e400 mesh). All compounds were demonstrated
to be homogeneous by analytical TLC on pre-coated silica gel TLC
d
7.68(d, J¼7.2Hz, 4H, 2-H, 6-H, Ph), 7.42 (t, J¼7.2Hz, 2H, 4-H, Ph), 7.38
(t, J¼7.2 Hz, 4H, 3-H, 5-H, Ph), 3.68 (t, J¼6.0 Hz, 2H, eCH2Oe), 2.19 (td,
J¼7.0, 2.5 Hz, 2H, eCH2eC^CH), 1.93 (t, J¼2.5 Hz,1H, eCH2eC^CH),
1.71e1.60 (m, 4H, eCH2eCH2e), 1.05 (s, 9H, eC(CH3)3e). 13C NMR
(100 MHz, CDCl3) d 135.8 (Ph), 134.2 (]C(Si)e),129.8 (Ph),127.8 (Ph),
84.7 (C^CH), 68.5 (^CH), 63.5 (eCH2Oe), 31.8, 27.2 (eC(CH3)3), 25.7,
19.4, 18.4. Mass spectrum (ESI) m/z (relative intensity) 359 (MþþNa,
37), 337 (MþþH, 100), 239 (95), 135 (42). Exact mass (ESI) calculated
for C22H29OSi (MþþH), 337.1988; found, 337.1992.
plates (Merck, 60 F245 on glass, layer thickness 250
mm), and
chromatograms were visualized by phosphomolybdic acid or
KMnO4 staining. Melting points were determined on a micro-
melting point apparatus and are uncorrected. Optical rotations
were recorded on a Rudolph DigiPol 781 polarimeter. NMR spectra
were recorded in CDCl3, unless otherwise stated, on a Bruker Ultra
4.1.2. 8-[(tert-Butyldiphenylsilyl)oxy]oct-3-yn-1-ol (15). To a stirred
solution of 14 (5.0 g, 15.6 mmol) in dry THF (78 mL) at ꢁ78 ꢀC under
an argon atmosphere, was added n-BuLi (12.5 mL, 31.2 mmol, 2.5 M

S.P. Nikas et al. / Tetrahedron 68 (2012) 6329e6337
6333
solution in hexanes) dropwise followed by the addition of HMPA
(previously dried over 4 A molecular sieves). The reaction temper-
was removed under reduced pressure at 30 ꢀC and the residue was
purified by flash column chromatography on silica gel (1e2%
diethyl ether in hexanes) to give 1.54 g (81% yield) of 17 as a col-
ꢀ
ature was raised to 0 ꢀC and stirring was continued for 1.5 h. Ethylene
oxide (7.7 mL, 156 mmol) was added at the same temperature and
the reaction mixture was stirred for an additional 5 h. On comple-
tion, the mixture was quenched by the addition of saturated aque-
ous NH4Cl at ꢁ78 ꢀC, then warmed at room temperature, and
extracted with diethyl ether. The combined organic extracts were
washed with brine, dried (MgSO4), and concentrated under reduced
pressure at 30 ꢀC. Purification by flash column chromatography on
silica gel (20e50% diethyl ether in hexanes) afforded 4.45 g (75%
orless oil. 1H NMR (500 MHz, CDCl3)
d
7.66 (d, J¼7.2 Hz, 4H, 2-H, 6-
H, Ph), 7.42 (t, J¼7.2 Hz, 2H, 4-H, Ph), 7.38 (t, J¼7.2 Hz, 4H, 3-H, 5-H,
Ph), 5.51 (dtt, J¼10.5, 7.0, 1.5 Hz, 1H, ]CH(CH2)2Br), 5.36 (dtt,
J¼10.5, 7.0, 1.5 Hz, 1H, eCH]), 3.66 (t, J¼6.3 Hz, 2H, eCH2Oe), 3.35
(t, J¼6.3 Hz, 2H, eCH2Br), 2.58 (dt, J¼7.0, 7.0 Hz, 2H, eCH2CH2Br),
2.03 (dt, J¼7.0, 7.0 Hz, 2H, eCH2eCH]), 1.57 (quintet, J¼6.5 Hz, 2H,
eCH2e), 1.44 (quintet, J¼6.5 Hz, 2H, eCH2e), 1.05 (s, 9H,
eC(CH3)3e). 13C NMR (100 MHz, CDCl3)
d 135.8 (Ph), 134.3
yield) of 15 as a colorless oil. 1H NMR (500 MHz, CDCl3)
d
7.66 (d,
(]C(Si)e), 133.1 (eCH]CHe), 129.7 (Ph), 127.8 (Ph), 126.2 (eCH]
CHe), 63.9 (eCH2Oe), 32.7, 32.3, 31.0, 27.3, 27.1 (eC(CH3)3), 25.9,
19.4. Mass spectrum (EI) m/z (relative intensity) 389 (Mþþ2-
C(CH3)3, 22), 387 (MþꢁC(CH3)3, 22), 263 (25), 261 (25), 109 (100).
Mass spectrum (ESI) m/z (relative intensity) 469 (Mþþ2þNa, 100),
467 (MþþNa, 100). Exact mass (ESI) calculated for C24H33BrOSiNa
(MþþNa), 467.1382; found, 467.1396.
J¼7.2 Hz, 4H, 2-H, 6-H, Ph), 7.42 (t, J¼7.2 Hz, 2H, 4-H, Ph), 7.38 (t,
J¼7.2 Hz, 4H, 3-H, 5-H, Ph), 3.67 (t, J¼6.0 Hz, 2H, eCH2OH
or eCH2OTBDPS), 3.66 (t, J¼6.0 Hz, 2H, eCH2OTBDPS or eCH2OH),
2.42 (tt, J¼6.5, 2.5 Hz, 2H, eCH2eC^Ce), 2.17 (tt, J¼6.5, 2.5 Hz,
2H, eC^CeCH2e), 1.72 (t, J¼6.5 Hz, 1H, OH), 1.68e1.56 (m,
4H, eCH2eCH2e), 1.05 (s, 9H, eC(CH3)3e). 13C NMR (100 MHz,
CDCl3)
d 135.8 (Ph), 134.2 (]C(Si)e), 129.8 (Ph), 127.8 (Ph), 84.5
(eC^CH), 77.2 (^CH),63.6 (eCH2Oe), 61.6 (eCH2Oe), 32.0, 27.1
(eC(CH3)3), 25.6, 23.4, 19.4, 18.7. Mass spectrum (ESI) m/z (relative
intensity) 403 (MþþNa, 100), 303 (15). Exact mass (ESI) calculated
for C24H32O2NaSi (MþþNa), 403.2069; found, 403.2068.
4.1.5. (Z)-8-Bromooct-5-en-1-ol (18). To a solution of 17 (1.5 g,
3.36 mmol) in dry THF (67 mL) at 0 ꢀC, under an argon atmosphere,
was added acetic acid (1.78 mL, 31.2 mmol), followed by tetra-n-
butylammonium fluoride (4.37 mL, 1 M solution in THF) dropwise.
The reaction mixture was stirred at 0 ꢀC until completion of the
reaction (12 h) and then it was quenched with saturated aqueous
NH4Cl, and extracted with diethyl ether. The combined organic ex-
tracts were washed with brine, dried (MgSO4) and the solvent was
evaporated under reduced pressure at 33 ꢀC. The residue was puri-
fied by flash column chromatography on silica gel (20e40% ethyl
acetate in hexanes) to give 578 mg of 18 as a colorless oil in 83% yield.
4.1.3. (Z)e8-[(tert-Butyldiphenylsilyl)oxy]oct-3-en-1-ol
(16). To
a stirred solution of Ni(OAc)2 (2.24 g, 9.0 mmol) in dry MeOH
(178 mL) at room temperature under an argon atmosphere, was
added NaBH4 (0.4 g, 10.6 mmol) portionwise. Following the addi-
tion, the argon atmosphere was replaced with hydrogen. To the
black suspension was added ethylenediamine (0.9 mL), stirring was
continued for 5 min and then a solution of 15 (2.0 g, 5.3 mmol) in
dry MeOH (20 mL) was added. The reaction mixture was hydroge-
nated until the TLC analysis indicated total consumption of the
starting material (2 h). The catalyst was filtered off through Celite
pad, and the filtrate was diluted with diethyl ether and brine. The
organic phase was separated and the aqueous phase extracted five
times with diethyl ether, and the combined organic layer was
washed with brine. Then, the aqueous phases were reextracted with
diethyl ether and the ethereal layer was washed with brine. The
combined organic phase was dried (MgSO4) and evaporated under
reduced pressure at 38 ꢀC. The residue was again diluted with
diethyl ether/brine and the organic phase was separated. The
aqueous phase was extracted with diethyl ether and the combined
organic layer was washed with brine, dried (MgSO4) and concen-
trated in vacuo (38 ꢀC). Purification by flash column chromatogra-
phy on silica gel (10e30% diethyl ether in hexanes) afforded 1.73 g
1H NMR (500 MHz, CDCl3)
d
5.53 (dtt, J¼10.5, 7.0, 1.5 Hz, 1H, ]
CH(CH2)2Br), 5.38 (dtt, J¼10.5, 7.0, 1.5 Hz, 1H, eCH]), 3.66 (t,
J¼6.5 Hz, 2H, eCH2OH), 3.37 (t, J¼7.0 Hz, 2H, eCH2Br), 2.63 (dt, J¼7.0,
7.0 Hz, 2H, eCH2CH2Br), 2.09 (dt, J¼7.0, 7.0 Hz, 2H, eCH2eCH]),1.59
(m as quintet, J¼7.0 Hz, 2H, eCH2e),1.46 (m as quintet, J¼7.0 Hz, 2H,
eCH2e). 13C NMR (100 MHz, CDCl3)
d 132.8 (eCH]CHe), 126.4
(eCH]CHe), 63.0 (eCH2Oe), 32.6, 32.5, 31.0, 27.3, 25.8. Mass
spectrum (CI) m/z (relative intensity) 207 (MþþH, 2%),189 (MþꢁOH,
5%), 188 (3), 187 (3), 127 (MþþH-Br, 10), 109 (100). Exact mass (ESI)
calculated for C8H16BrO (MþþH), 207.0385; found, 207.0395.
When the above procedure was carried out without acetic acid,
two major compounds were isolated and identified: (a) (Z)-8-
bromooct-5-en-1-ol (18, 41% yield, Rf¼0.32, 30% AcOEt in hexane)
and (b) (Z)-octa-5,7-dien-1-ol48 (19, 32% yield, Rf¼0.27, 30% AcOEt
in hexane). (Z)-Octa-5,7-dien-1-ol (19) 1H NMR (500 MHz, CDCl3)
d
6.63 (ddd, J¼16.5, 11.0, 10.5 Hz, 1H, 7-H), 6.02 (dd, J¼11, 10.5 Hz,
(86% yield) of 16 as a colorless oil. 1H NMR (500 MHz, CDCl3)
d
7.66
1H, 6-H), 5.45 (dtd, J¼10.5, 8.0, 1.0 Hz, 1H, 5-H), 5.18 (dd, J¼16.5,
1.5 Hz, 1H, 8-H), 5.09 (d, J¼10.5 Hz, 1H, 8-H), 3.65 (t, J¼6.5 Hz, 2H,
eCH2Oe), 2.23 (dt, J¼8.0, 7.5 Hz, 2H, 4-H), 1.65e1.57 (m, 2H,
eCH2e), 1.51e1.42 (m, 2H, eCH2e).
(d, J¼7.2 Hz, 4H, 2-H, 6-H, Ph), 7.42 (t, J¼7.2 Hz, 2H, 4-H, Ph), 7.38
(t, J¼7.2 Hz, 4H, 3-H, 5-H, Ph), 5.54 (dtt, J¼10.5, 7.0, 1.5 Hz, 1H, ]
CH(CH2)2Oe), 5.36 (dtt, J¼10.5, 7.0, 1.5 Hz, 1H, eCH]), 3.66
(t, J¼6.5 Hz, 2H, eCH2Oe), 3.62 (t, J¼6.5 Hz, 2H, eCH2OH), 2.30 (dt,
J¼7.0, 7.0 Hz, 2H, eCH2CH2OH), 2.05 (dt, J¼7.0, 7.0 Hz, 2H,
eCH2eCH]), 1.57 (quintet, J¼6.5 Hz, 2H, eCH2e), 1.44 (quintet,
J¼6.5 Hz, 2H, eCH2e), 1.04 (s, 9H, eC(CH3)3e). 13C NMR (100 MHz,
4.1.6. (Z)-8-Bromooct-5-enoic acid (20). To a stirred mixture of 18
(512 mg, 2.5 mmol) in acetonitrile (9 mL) and water (3 mL) at 0 ꢀC
was added 1 mL of Zhao’s reagent every 30 min until completion of
reaction (3.5 h). A stock solution of Zhao’s reagent was prepared by
dissolving 0.63 g H5IO6 and 1.27 g CrO3 in 1.9 mL H2O and 4.4 mL
CH3CN. The reaction was quenched with Na2HPO4 (20 mg in 1 mL
H2O) and diluted with diethyl ether. The organic phase was sepa-
rated and the aqueous phase extracted with diethyl ether. The
combined organic layer was washed with brine, dried (MgSO4) and
the solvent was evaporated under reduced pressure at 33 ꢀC. Pu-
rification by flash column chromatography on silica gel (30e40%
ethyl acetate in hexanes) gave 464 mg (85% yield) of 2044,45 as an
CDCl3)
d 135.8 (Ph), 134.3 (]C(Si)e), 133.50 (eCH]CHe), 129.7
(Ph),127.8 (Ph),125.4 (eCH]CHe), 64.0 (eCH2Oe), 62.6 (eCH2Oe),
32.4, 31.0, 27.3, 27.1 (eC(CH3)3), 26.1, 19.5. Mass spectrum (ESI) m/z
(relative intensity) 405 (MþþNa, 100). Exact mass (ESI) calculated
for C24H34O2NaSi (MþþNa), 405.2226; found, 405.2229.
4.1.4. (Z)-[(8-Bromooct-5-en-1-yl)oxy](tert-butyl)diphenylsilane
(17). To a solution of 16 (1.64 g, 4.3 mmol) and carbon tetrabromide
(2.85 g, 8.6 mmol) in dry CH2Cl2 (21 mL) at 0 ꢀC under an argon
atmosphere, was added dried triphenylphosphine (2.25 g,
8.6 mmol) portionwise. The reaction mixture was stirred for 1 h at
oil. 1H NMR (500 MHz, CDCl3)
CH(CH2)2Br), 5.38 (dtt, J¼11.0, 7.0, 1.5 Hz, 1H, eCH]), 3.37
(t, J¼7.0 Hz, 2H, eCH2Br), 2.63 (dt, J¼7.0, 7.0 Hz, 2H, eCH2CH2Br),
d
5.53 (dtt, J¼11.0, 7.0, 1.5 Hz, 1H, ]
0
ꢀC and for 2 h at room temperature. On completion, the solvent

6334
S.P. Nikas et al. / Tetrahedron 68 (2012) 6329e6337
2.38 (t, J¼7.0, 7.0 Hz, 2H, eCH2eCOOH), 2.12 (dt, J¼7.0, 7.0 Hz, 2H,
eCH2eCH]), 1.73 (quintet, J¼7.0 Hz, 2H, eCH2eCH2eCOOH). 13C
portionwise. The reaction mixture was stirred for 1 h at 0 ꢀC and for
2 h at room temperature. On completion, the solvent was removed
under reduced pressure at 30 ꢀC and the residue was purified by
flash column chromatography on silica gel (1e2% diethyl ether in
hexanes) to give 6.8 g (94% yield) of 2349 as a colorless oil. 1H NMR
NMR (100 MHz, CDCl3)
d 179.7 (eCOOH), 131.7 (eCH]CHe), 127.4
(eCH]CHe), 33.5, 32.6, 31.0, 26.9, 24.6. Mass spectrum (EI) m/z
(relative intensity) 222 (Mþþ2, 0.2), 220 (Mþ, 0.2), 204 (Mþþ2-
H2O, 1), 202 (MþꢁH2O, 1), 176 (Mþþ2-H2O-CO, 2), 174 (MþꢁH2O,
eCO, 2), 162 (Mþþ2-H2O, eCO, eCH2, 18), 160 (MþꢁH2O, eCO,
eCH2, 18), 140 (MþꢁBr, 86), 123 (39), 81 (100). Mass spectrum (ESI)
m/z (relative intensity) 245 (Mþþ2þNa, 100), 243 (MþþNa, 100),
127 (45), 125 (45). Exact mass (ESI) calculated for C8H13BrO2Na
(MþþNa), 242.9997; found, 243.0004.
(500 MHz, CDCl3)
d
5.53 (dtt, J¼10.5, 7.0, 1.5 Hz, 1H, 3-H), 5.36 (dtt,
J¼10.5, 7.0, 1.5 Hz, 1H, 4-H), 3.36 (t, J¼7.0 Hz, 2H, eCH2Br), 2.61 (dt,
J¼7.0, 7.0 Hz, 2H, eCH2eCH2Br), 2.03 (dt, J¼7.0, 7.0 Hz, 2H, ]
CHeCH2e(CH2)3eCH3), 1.40e1.24 (m and sextet overlapping, 6H, 6-
H, 7-H, 8-H, especially 1.36 sextet, J¼7.0 Hz, 2H), 0.89 (t, J¼7.5 Hz,
3H, eCH2CH3). Mass spectrum (ESI) m/z (relative intensity) 205
(MþþH, 15), 163 (15), 123 (92), 55 (100). Exact mass (EI) calculated
for C7H17Br(Mþ), 204.0514; found, 204.0504.
4.1.7. (5Z)-8-Bromo-5-octenoic methyl ester (21). To a stirred solu-
tion of 20 (0.35 g,1.58 mmol) in 1:4 mixture of methanol (4 mL) and
diethyl ether (16 mL) at 0 ꢀC under an argon atmosphere, was
added trimethylsilyldiazomethane (1.02 mL, 2.05 mmol, 2.0 M so-
lution in hexane). After 20 min, the reaction was quenched with
saturated aqueous NH4Cl and diluted with diethyl ether. The or-
ganic phase was separated and the aqueous layer was extracted
with diethyl ether. The combined organic layer was washed with
brine, dried (MgSO4) and concentrated under reduced pressure at
25 ꢀC. Purification by flash column chromatography on silica gel
(0e10% diethyl ether in hexanes) afforded 338 mg (91% yield) of
4.1.10. [(3Z)-3-Nonen-1-yl]triphenylphosphonium bromide (6). A
stirred mixture of 23 (5 g, 24.37 mmol) and dried triphenylphos-
phine (12.78 g, 48.74 mmol) in anhydrous acetonitrile (48 mL) was
heated (72e75 ꢀC) for 7 days under argon. Solvent evaporation and
purification by flash column chromatography on silica gel (3%
methanol in methylene chloride) gave 8.2 g (72% yield) of 645 as
a colorless gum. The product was rigorously dried in high vacuo for
6 h at 40e42 ꢀC, and used in the next step. 1H NMR (500 MHz,
CDCl3)
d
7.88 (m as dd, J¼12.5, 7.5 Hz, 6H, 2-H, 6-H, ePPh3), 7.80 (m
2144,45 as a colorless oil. 1H NMR (500 MHz, CDCl3)
d 5.50 (dtt,
as td, J¼7.5, 1.8 Hz, 3H, 4-H, ePPh3), 7.70 (m as td, J¼7.5, 4.2 Hz, 6H,
J¼11.0, 7.0, 1.5 Hz, 1H, ]CH(CH2)2Br), 5.42 (dtt, J¼11.0, 7.0, 1.5 Hz,
1H, eCH]), 3.68 (s, 3H, eCOOCH3), 3.39 (t, J¼7.0 Hz, 2H, eCH2Br),
2.61 (dt, J¼7.0, 7.0 Hz, 2H, eCH2CH2Br), 2.33 (t, J¼7.5 Hz, 2H,
eCH2eCOOe), 2.10 (dt, J¼7.0, 7.0 Hz, 2H, eCH2eCH]), 1.71 (quin-
tet, J¼7.0 Hz, 2H, eCH2eCH2eCOOe). 13C NMR (100 MHz, CDCl3)
3-H, 5-H, ePPh3), 5.57 (dtt, J¼11.0, J¼7.0, 1.5 Hz, 1H,
]
CH(CH2)2PþPh3), 5.39 (dtt, J¼11.0, 7.0, 1.5 Hz, 1H, eCH]), 3.95 (dt,
J¼12.0, 8.0 Hz, 2H, eCH2PþPh3), 2.49e2.41 (m, 2H,
eCH2eCH2ePþPh3), 1.75 (quintet, J¼7.0 Hz, 2H, eCH]CHeCH2e),
1.26e1.17 (m, 4H, eCH2e), 1.16e1.10 (m, 2H, eCH2e), 0.84 (t,
J¼7.0 Hz, 3H, eCH2eCH3). Mass spectrum (ESI) m/z (relative in-
tensity) 387 (MþꢁBr, 100). Exact mass (ESI) calculated for
C27H32P(MþꢁBr), 387.2242; found, 387.2249.
d
174.1 (>C]O), 131.8 (eCH]CHe), 127.2 (eCH]CHe), 51.7
(eOCH3), 33.5, 32.6, 30.9, 26.9, 24.8. Mass spectrum (EI) m/z (rel-
ative intensity) 236 (Mþþ2, 1), 234 (Mþ, 1), 205 (Mþþ2-MeO, 5),
204 (Mþþ2-MeOH, 3), 203 (MþꢁMeO, 5), 202 (MþꢁMeOH, 3), 176
(Mþþ2-MeOH, eCO, 4), 174 (MþꢁMeOH, eCO, 4), 162 (Mþþ2-
MeOH, eCO, eCH2, 11), 160 (MþꢁMeOH, eCO, eCH2, 11), 160
(MþꢁMeOH, eCO, eCH2, 11), 155 (MþþHeBr, 42), 154 (MþꢁBr, 32),
123 (MþꢁBr, eOMe, 79), 74 (100). Exact mass (ESI) calculated for
C9H15BrO2 (Mþ), 234.0255; found, 234.0244.
4.1.11. (10R,5Z,8Z)-11-[(tert-Butyldiphenylsilyl)oxy]-10-methyl-un-
deca-5,8-dienoic methyl ester (24). To a solution of 5 (415 mg,
0.834 mmol) in dry THF (4 mL) at ꢁ78 ꢀC under an argon atmo-
sphere was added potassium bis(trimethylsilyl)amide (0.79 mL,
1.0 M solution in THF) dropwise. The mixture was stirred at ꢁ78 ꢀC
to ꢁ60 ꢀC for 45 min, to ensure complete formation of the orange
ylide, and then it was cooled to ꢁ115 ꢀC. Subsequently, a solution of
aldehyde 3 (136 mg, 0.417 mmol) in dry THF (1 mL) was added
dropwise. The reaction mixture was stirred for 15 min at ꢁ115 ꢀC,
and then it was warmed to ꢁ20 ꢀC over a period of 2.5 h. The re-
action mixture was then cooled to ꢁ78 ꢀC and quenched with
a saturated aqueous sodium bicarbonate solution. The mixture was
warmed to room temperature, extracted with diethyl ether and the
combined organic extracts were washed with brine, dried (MgSO4)
and concentrated in vacuo. Purification by flash column chroma-
tography on silica gel (5e7% diethyl ether in hexane) gave 24 as
4.1.8. [(3Z)-8-Methoxy-8-oxo-3-octen-1-yl]triphenylphosphonium
bromide (5). A stirred mixture of 21 (300 mg, 1.27 mmol) and dried
triphenylphosphine (667 mg, 2.54 mmol) in anhydrous acetonitrile
(6 mL) was heated (72e75 ꢀC) for four days under argon. Solvent
evaporation and purification by flash column chromatography on
silica gel (0e15% methanol in methylene chloride) gave 576 mg (91%
yield) of 544 as a colorless gum. The product was rigorously dried in
high vacuo for 6 h at 40e42 ꢀC, and used in the next step. 1H NMR
(500 MHz, CDCl3)
d
7.88 (m as dd, J¼12.6, 7.8 Hz, 6H, 2-H, 6-H,
ePPh3), 7.81 (m as td, J¼7.8, 1.8 Hz, 3H, 4-H, ePPh3), 7.71 (m as td,
J¼7.8, 4.2 Hz, 6H, 3-H, 5-H, ePPh3), 5.65 (dtt, J¼11.0, 7.0, 1.5 Hz, 1H,
]CH(CH2)2PþPh3), 5.37 (dtt, J¼11.0, 7.0,1.5 Hz,1H, eCH]), 3.96 (dt,
J¼12.0, 8.0 Hz, 2H, eCH2PþPh3), 3.61 (s, 3H, eCOOCH3), 2.48e2.46
(m, 2H, eCH2eCH2PþPh3), 2.21 (t, J¼7.5 Hz, 2H, eCH2eCOOe), 1.87
(dt, J¼7.0, 7.0 Hz, 2H, eCH2eCH]), 1.58 (quintet, J¼7.5 Hz, 2H,
colorless oil in 46% yield (89 mg). ½a D26
ꢁ17.48 (c 0.2 g/100 mL in
ꢂ
CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.66 (d, J¼7.8 Hz, 4H, 2-H, 6-H,
Ph), 7.44 (t, J¼7.2 Hz, 2H, 4-H, Ph), 7.37 (t, J¼7.2 Hz, 4H, 3-H, 5-H, Ph),
5.37e5.28 (m, 3H, 5-H, 6-H, 8-H), 5.19 (tdd, J¼10.5, 9.5,1.0 Hz,1H, 9-
H), 3.66 (s, 3H, eCOOCH3), 3.46 (dd, J¼10.0, 6.0 Hz, 1H, 11-H), 3.46
(dd, J¼10.0, 7.0 Hz,1H,11-H), 2.81e2.73 (m,1H,10-H), 2.72e2.64 (m,
2H, 7-H), 2.30 (t, J¼7.5 Hz, 2H, 2-H), 2.07 (dt, J¼6.5, 6.5 Hz, 2H, 4-H),
1.69 (quintet, J¼7.5 Hz, 2H, 3-H), 1.05 (s, 9H, eC(CH3)3), 1.00 (d,
eCH2eCH2eCOOe). 13C NMR (100 MHz, CDCl3)
d 174.1 (>C]O),
135.2 (C40, Ph), 134.1 (d, J¼9.2 Hz, C20, C60, Ph), 131.3 (eCH]
CHe(CH2)2P Ph3), 130.7 (d, J¼11.5 Hz, C30, C50, Ph), 127.5 (d,
J¼13.8 Hz, eCH]CHe(CH2)2P), 118.6 (d, J¼85.5 Hz, C10, Ph), 51.7
(eOCH3), 33.5, 26.8, 24.7, 23.0 (d, J¼49 Hz, eCH2P), 20.7. Mass
spectrum (ESI) m/z (relative intensity) 417 (MþꢁBr,100). Exact mass
(ESI) calculated for C27H30O2P(MþꢁBr), 417.1983; found, 417.1973.
J¼6.5 Hz, 3H, >CHeCH3). 13C NMR (100 MHz, CDCl3)
d 174.23 (>C]
O), 135.9, 134.2, 133.3, 129.7, 129.5, 128.9, 128.3, 127.8, 68.8, 51.6,
35.0, 33.7, 27.1, 26.8, 26.1, 25.0, 19.5, 17.7. Mass spectrum (ESI) m/z
(relative intensity) 465 (MþþH, 23), 387 (MþꢁPh, 100). Exact mass
(ESI) calculated for C29H41O3Si (MþþH), 465.2825; found, 465.2827.
4.1.9. (3Z)-1-Bromo-3-nonene (23). To a stirred solution of (3Z)-3-
nonen-1-ol (5 g, 35.15 mmol) and carbon tetrabromide (11.6 g,
35.15 mmol) in dry CH2Cl2 (170 mL) at 0 ꢀC under an argon atmo-
sphere, was added dried triphenylphosphine (9.17 g, 35.15 mmol)
4.1.12. (10R,5Z,8Z)-11-Hydroxy-10-methyl-undeca-5,8-dienoic
methyl ester (25). To a stirred solution of 24 (85 mg, 0.183 mmol) in
dry THF (3 mL), under an argon atmosphere at 0 ꢀC, was added TBAF

S.P. Nikas et al. / Tetrahedron 68 (2012) 6329e6337
6335
(0.25 mL, 0.25 mmol, 1 M solution in THF) dropwise. Stirring was
continued for 10 min at 0 ꢀC and for 1.5 h at room temperature. The
reaction mixture was quenched with a saturated aqueous NH4Cl
solution at 0 ꢀC and extracted with AcOEt. The combined organic
extracts were washed with brine, dried (MgSO4) and concentrated
under reduced pressure at 37 ꢀC. The crude material was purified by
flash column chromatography on silica gel (15e45% ethyl acetate in
hexane) to afford 25 (38 mg, 92% yield) as a colorless viscous liquid.
4H, 7-H, 13-H), 2.32 (t, J¼7.0 Hz, 2H, 2-H), 2.11 (dt, J¼7.0, 7.0 Hz, 2H,
4-H), 2.05 (dt, J¼7.5, 7.5 Hz, 2H, 16-H), 1.71 (quintet, J¼7.5 Hz, 2H, 3-
H), 1.39e1.24 (m, 6H, 18-H, 19-H, 17-H), 1.02 (d, J¼7.0 Hz,
3H, >CHeCH3), 0.89 (t, J¼7.0 Hz, 3H, 20-H). 13C NMR (100 MHz,
CDCl3)
d 174.2 (>C]O), 135.0 (eCH]), 134.7 (eCH]), 130.7
(eCH]), 129.3 (eCH]), 129.1 (eCH]), 127.9 (eCH]), 126.6
(eCH]), 126.2 (eCH]), 51.6 (OCH3), 33.7, 31.7, 30.8, 29.9, 29.5,
27.4, 26.8, 26.0, 25.0, 22.7, 22.1, 14.2 (C-20). Mass spectrum (ESI) m/z
(relative intensity) 355 (MþþNa, 100), 333 (MþþH, 72). Exact mass
(ESI) calculated for C22H36O2Na (MþþNa), 355.2613; found,
355.2618, and calculated for C22H37O2 (MþþH), 333.2794; found,
333.2797.
½
a 2D6
ꢂ
83.11 (c 0.139 g/100 mL in CHCl3). 1H NMR (500 MHz, CDCl3)
d
5.49 (dtd, J¼10.5, 7.5, 1.2 Hz, 1H, 8-H), 5.40 (td, J¼10.5, 7.0 Hz, 1H,
6-H or 5-H), 5.35 (td, J¼10.5, 7.0 Hz, 1H, 5-H or 6-H), 5.16 (tdd,
J¼10.5, 10.0, 1.5 Hz, 1H, 9-H), 3.67 (s, 3H, eCOOCH3), 3.49 (ddd,
J¼12.0, 8.0, 6.0 Hz, 1H, 11-H), 3.35 (ddd, J¼12.0, 8.5, 4.5 Hz, 1H, 11-
H), 2.83 (dd, J¼7.5, 7.5 Hz, 2H, 7-H), 2.73 (m as septet, J¼6.5 Hz, 1H,
10-H), 2.33 (t, J¼7.0 Hz, 2H, 2-H), 2.11 (dt, J¼7.5, 7.5 Hz, 2H, 4-H),
1.70 (quintet, J¼7.5 Hz, 2H, 3-H), 1.51 (dd, J¼6.0, 4.5 Hz, 1H, OH),
4.1.15. (10S,5Z,8Z,11Z,14Z)-10-Methyl-eicosa-5,8,11,14-tetraenoic acid
(27). To a stirred solution of 2a (15 mg, 0.045 mmol) in dry THF
(1 mL) at room temperature, under an argon atmosphere, was added
1 M aqueous LiOH solution (0.09 mL). Stirring was continued for
24 h, and then the reaction mixture was acidified with 5% HCl to pH
3, and lipophilic products were extracted with Et2O. The combined
organic extracts werewashed with brine and dried (MgSO4). Solvent
evaporation under reduced pressure at 37e40 ꢀC gave pure acid 27
(12.4 mg, 86% yield) as a colorless oil, which was used in the next
step without further purification. 1H NMR (500 MHz, CDCl3)
0.96 (d, J¼6.5 Hz, 3H, >CHeCH3). 13C NMR (100 MHz, CDCl3)
d 174.1
(>C]O), 132.8 (C-9 or C-8), 130.4 (C-8 or C-9), 129.4 (C-6 or C-5),
129.2 (C-5 or C-6), 68.1 (CH2OH), 51.8 (OCH3), 35.4, 33.9, 27.0, 26.4,
25.1, 17.4. Mass spectrum (ESI) m/z (relative intensity) 249 (MþþNa,
100). Exact mass (ESI) calculated for C13H22O3Na (MþþNa),
249.1465; found, 249.1468.
4.1.13. (10R,5Z,8Z)-10-Methyl-11-oxo-undeca-5,8-dienoic methyl es-
ter (26). To a solution of alcohol 25 (38 mg, 0.168 mmol) in dry
CH2Cl2 (3.5 mL) at 0 ꢀC under an argon atmosphere, was added
DesseMartin periodiane (DMP) (142 mg, 0.336 mmol) and the
resulting suspension was warmed to room temperature and stirred
for 45 min. An additional amount of DMP (21 mg, 0.05 mmol) was
added at 0 ꢀC and stirring was continued for 30 min at room tem-
perature to ensure total consumption of alcohol 25. The reaction
mixture was quenched by adding a mixture of Na2S2O3 (10% in H2O)
and saturated NaHCO3 (1:1) and diluted with diethyl ether. The
slurry was filtered through Celite, the organic phase separated and
the aqueous phase was extracted with diethyl ether. The combined
organic layer was washed with saturated NaHCO3, brine, and dried
(MgSO4). Solvent evaporation under reduced pressure at 36e40 ꢀC
provided the sensitive crude product 26 as a colorless oil, which was
d 5.43e5.31 (m, 4H, eCH]CHe), 5.31e5.21 (m, 4H, eCH]CHe),
3.48 (ddq as sextet, J¼6.5 Hz, 1H, 10-H), 2.88e2.76 (m, 4H, 7-H, 13-
H), 2.38 (t, J¼7.5 Hz, 2H, 2-H), 2.13 (dt, J¼7.5, 7.5 Hz, 2H, 4-H), 2.05
(dt, J¼7.0, 7.0 Hz, 2H, 16-H), 1.72 (quintet, J¼7.5 Hz, 2H, 3-H),
1.39e1.24 (m, 6H,18-H,19-H,17-H),1.03 (d, J¼7.0 Hz, 3H, >CHeCH3),
0.89 (t, J¼7.0 Hz, 3H, 20-H). Mass spectrum (ESI) m/z (relative in-
tensity) 341 (MþþNa, 100), 319 (MþþH, 45). Exact mass (ESI) cal-
culated for C21H34O2Na (MþþNa), 341.2457; found, 341.2456, and
calculated for C21H35O2 (MþþH), 319.2637; found, 319.2638.
4.1.16. 2-[(tert-Butyldiphenylsilyl)oxy]ethanamine (29). To a solu-
tion of ethanolamine (28) (1 g, 16.4 mmol) and dried imidazole
(2.44 mg, 36.1 mmol) in anhydrous CH3CN (80 mL) at 0 ꢀC under an
argon atmosphere, was added tert-butyldiphenylsilyl chloride
(4.95 mg, 18.0 mmol) dropwise. The reaction mixture was stirred
for 30 min at 0 ꢀC and then quenched with a saturated aqueous
sodium bicarbonate solution, diluted with water and extracted
with CH2Cl2. The combined organic extracts were washed with
brine, dried (MgSO4) and concentrated in vacuo. The crude oil was
purified by flash column chromatography on silica gel (10% MeOH
in CH2Cl2) to afford 2939 (4.64 g, 95%) as a colorless oil. 1H NMR
used in the next step immediately. 1H NMR (500 MHz, CDCl3)
d 9.53
(d, J¼1.5 Hz, 1H, eCHO), 5.64 (dtd, J¼10.5, 7.5 Hz, 1.2 Hz, 1H, 8-H),
5.42e5.34 (m, 2H, 6-H, 5-H), 5.25 (ttd, J¼10.5, 10.0, 1.5 Hz, 1H, 9-H),
3.67 (s, 3H, eCOOCH3), 3.37 (m as quintet, J¼8.0 Hz, 1H, 10-H),
2.86e2.78 (m, 2H, 7-H), 2.33 (t, J¼7.0 Hz, 2H, 2-H), 2.11 (dt, J¼7.5,
7.5 Hz, 2H, 4-H), 1.71 (quintet, J¼7.5 Hz, 2H, 3-H), 1.19 (d, J¼6.5 Hz,
3H, >CHeCH3). Mass spectrum (ESI) m/z (relative intensity) 247
(MþþNa,100), 225 (MþþH,10),175 (34). Exact mass (ESI) calculated
for C13H20O3Na (MþþNa), 247.1310; found, 247.1309.
(500 MHz, CDCl3)
d
7.68 (d, J¼7.2 Hz, 4H, 2-H, 6-H, PhH), 7.43 (t,
J¼7.2 Hz, 2H, 4-H, PhH), 7.39 (t, J¼7.2 Hz, 4H, 3-H, 5-H, PhH), 3.70 (t,
J¼5.4 Hz, 2H, eCH2eOTBDPS), 2.83 (t, J¼5.4 Hz, 2H, eCH2eNHe),
2.41 (br s, 2H, eNH2), 1.07 (s, 9H, eC(CH3)3).
4.1.14. (10S,5Z,8Z,11Z,14Z)-10-Methyl-eicosa-5,8,11,14-tetraenoic
methyl ester (2a). To a stirred solution of phosphonium bromide 6
(395 mg, 0.845 mmol) in dry THF (4 mL) at 0 ꢀC under an argon
atmosphere, was added potassium bis(trimethylsilyl)amide
(0.83 mL, 1.0 M solution in THF) dropwise. The mixture was stirred
for 30 min at 0 ꢀC to ensure complete formation of the orange ylide
and then it was cooled to ꢁ78 ꢀC. A solution of crude aldehyde 26 in
dry THF (1 mL) was added dropwise, the reaction mixture was
stirred for 1 h at ꢁ78 ꢀC and then it was quenched by the addition of
saturated aqueous sodium bicarbonate. The mixture was warmed
to room temperature, extracted with diethyl ether, and the com-
bined organic extracts were washed with brine, dried (MgSO4) and
concentrated in vacuo. Purification by flash column chromatogra-
phy on silica gel (0e8% diethyl ether in hexane) gave 21 mg (39%
4.1.17. (10S,5Z,8Z,11Z,14Z)-10-Methyl-eicosa-5,8,11,14-tetraenoic acid
N-{2-[(tert-butyldiphenylsilyl) oxy]ethyl}amide (30). A mixture of
acid 27 (10 mg, 0.031 mmol), and fresh carbonyldiimidazole (15 mg,
0.093 mmol) in dry THF (1 mL) at room temperature under an ar-
gon atmosphere, was stirred for 2 h and then protected ethanol-
amine 29 (37 mg, 0.125 mmol) in THF (0.5 mL) was added. The
reaction mixture was stirred for 1 h and then diluted with water
and ethyl acetate. The organic phase was separated and the aque-
ous phase extracted with AcOEt. The combined organic layer was
washed with brine, dried (MgSO4) and concentrated in vacuo. The
crude product obtained after work up was purified by flash column
chromatography on silica gel (15e25% acetone in hexane), and gave
14 mg (74% yield) of 30 as a colorless oil. 1H NMR (500 MHz, CDCl3)
yield from alcohol 25) of ester 2a as a colorless oil. ½a D26
ꢂ
351.92 (c
5.43e5.31
d
7.63 (d, J¼7.5 Hz, 4H, 2-H, 6-H, Ph), 7.43 (t, J¼7.5 Hz, 2H, 4-H, Ph),
0.087 g/100 mL in CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.38 (t, J¼7.5 Hz, 4H, 3-H, 5-H, Ph), 5.73 (br s, 1H, >NH), 5.43e5.32
(m, 4H, eCH]CHe), 5.31e5.19 (m, 4H, eCH]CHe), 3.74 (t,
J¼6.5 Hz, 2H, eCH2eOTBDPS), 3.48 (m as sextet, J¼7.0 Hz,1H,10-H),
(m, 4H, eCH]CHe), 5.31e5.21 (m, 4H, eCH]CHe), 3.67 (s, 3H,
eCOOCH3), 3.49 (ddq as sextet, J¼6.5 Hz, 1H, 10-H), 2.88e2.75 (m,

6336
S.P. Nikas et al. / Tetrahedron 68 (2012) 6329e6337
3.40 (dt, J¼6.5, 6.5 Hz, 2H, eCH2eNHe), 2.88e2.76 (m, 4H, 7-H, 13-
H), 2.16e2.08 (t and dt overlapping, 4H, 2-H, 4-H), 2.04 (dt, J¼7.2,
7.2 Hz, 2H,16-H),1.68 (quintet, J¼8.0 Hz, 2H, 3-H),1.38e1.24 (m, 6H,
18-H, 19-H, 17-H), 1.07 (s, 9H, eC(CH3)3), 1.02 (d, J¼8.5 Hz, 3H,
>CHeCH3), 0.88 (t, J¼7.0 Hz, 3H, 20-H). Mass spectrum (ESI) m/z
(relative intensity) 600 (MþþH, 100), 522 (MþꢁPh, 52). Exact mass
(ESI) calculated for C39H58NO2Si (MþþH), 600.4237; found,
600.4238.
synthesis was carried out as described for 30 and gave the title
compound in 83% yield. Spectroscopic and physical data were
identical to those of the enantiomer 30.
4.1.25. (10R,5Z,8Z,11Z,14Z)-10-Methyl-eicosa-5,8,11,14-tetraenoic
acid N-(2-hydroxyethyl)amide (1b). The synthesis was carried out
as described for 1a and gave the title compound in 85% yield.
Spectroscopic and physical data were identical to those of the en-
antiomer 1a.
4.1.18. (10S,5Z,8Z,11Z,14Z)-10-Methyl-eicosa-5,8,11,14-tetraenoic acid
N-(2-hydroxyethyl)amide (1a). The synthesis was carried out as
described for 25, using 30 (10 mg, 0.0166 mmol) and TBAF (0.02 mL,
0.02 mmol,1 M solution in THF) in dry THF (1 mL). The reaction was
completed in 1 h and the crude oil obtained after work up was
purified by flash column chromatography on silica gel (57:40:3,
ethyl acetate/hexane/MeOH) to afford 1a (5 mg, 83% yield) as
Acknowledgements
This work was supported by grants from the National Institute
on Drug Abuse, DA009158, DA003801 and DA007215.
a colorless oil. ½a D26
ꢂ
99.27 (c 0.108 g/100 mL in CHCl3). 1H NMR
Supplementary data
(700 MHz, CDCl3)
d 5.87 (br s, 1H, >NH), 5.43e5.32 (m, 4H, eCH]),
Experimental procedures and spectroscopic and physical data
for all compounds. Reproductions of 1H NMR spectra of compounds
24 and 25 in CDCl3 solutions and reproductions of 1H NMR, 13C
NMR, COSY, HSQC and NOESY spectra of compound 1a in CDCl3
solutions. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2012.05.010.
5.30e5.19 (m, 4H, eCH]), 3.73 (t, J¼5.1 Hz, 2H, eCH2eOe), 3.48
(qdd as sextet, J¼7.2 Hz, 1H, 10-H), 3.42 (dt, J¼5.5, 5.5 Hz, 2H,
eCH2eNHe), 2.87e2.75 (m, 4H, 7-H, 13-H), 2.22 (t, J¼7.6 Hz, 2H, 2-
H), 2.12 (dt, J¼7.0, 7.0 Hz, 2H, 4-H), 2.05 (dt, J¼7.4, 7.4 Hz, 2H, 16-H),
1.73 (quintet, J¼7.5 Hz, 2H, 3-H), 1.52 (br s, 1H, OH), 1.38e1.33
(sextet, J¼7.1 Hz, 2H, 17-H), 1.32e1.24 (m, 4H, 18-H, 19-H), 1.02 (d,
J¼6.7 Hz, 3H, >CHeCH3), 0.88 (t, J¼7.1 Hz, 3H, 20-H). 13C NMR
(175 MHz, CDCl3)
d 174.2 (>C]O), 134.8 (eCH]), 134.4 (eCH]),
References and notes
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35.9 (C-2), 31.5 (C-18 or C-19), 30.6 (C-10), 29.3 (C-17), 27.2 (C-16),
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