Mild acetal cleavage using B-chlorocatecholborane in the synthesis of rearrangement-sensitive 2-arachidonoylglycerol

Article abstract of DOI:10.1016/j.tetlet.2012.04.039

A mild method for the cleavage of an acetal to afford a rearrangement sensitive diol using B-chlorocatecholborane was developed for the synthesis of the endogenous cannabinoid neurochemical messenger 2-arachidonoylglycerol. The tendency for rearrangement of 2-arachidonoylglycerol to the corresponding 1-arachidonoylglycerol was precluded with this reagent. Features of the partial recyclization to an isomeric acetal provide mechanistic detail.

Full text of DOI:10.1016/j.tetlet.2012.04.039

Tetrahedron Letters 53 (2012) 3825–3827
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mild acetal cleavage using B-chlorocatecholborane in the synthesis
of rearrangement-sensitive 2-arachidonoylglycerol
⇑
Michael J. Roche, Seth M. Madren, C. Ray Tallent, F. Ivy Carroll, Herbert H. Seltzman
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild method for the cleavage of an acetal to afford a rearrangement sensitive diol using B-chloro-
catecholborane was developed for the synthesis of the endogenous cannabinoid neurochemical messenger
2-arachidonoylglycerol. The tendency for rearrangement of 2-arachidonoylglycerol to the corresponding
1-arachidonoylglycerol was precluded with this reagent. Features of the partial recyclization to an iso-
meric acetal provide mechanistic detail.
Received 21 February 2012
Accepted 6 April 2012
Available online 16 April 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Acetal cleavage
Mild conditions
Sensitive probe
Mechanism
2-Arachidonoylglycerol
Introduction
MEM ethers, benzylcarbamates, methyl and benzyl ethers, and es-
ters with the B-bromo reagent.8,9 The methylenedioxy acetal is
The use of acetals to protect either aldehyde or diol moieties in
organic synthesis often pivots on the vulnerability of other func-
tional groups in the target structure to the acetal cleavage meth-
od.1,2 The potential cleavage conditions (acid hydrolysis or
exchange, oxidation, hydrogenation, etc.) may be incompatible
with other functionality in the substrate and preclude its use. Thus,
the availability of alternative cleavage chemistries extends the util-
ity of acetal protection by providing reagents/methods with differ-
ent functional group compatibilities.
In this context, boron halides have been employed for the cleav-
age of oxygen-linked groups. The reactive parent trihalides, typi-
fied by boron trichloride, cleave methyl ethers, acetates,
glycoside linkages, ethylenedioxy ketals, and methylenedioxy and
benzylidenedioxy acetals.3 Milder and more selective boron ha-
lides such as dimethylboron bromide and diphenylboron bromide
cleave most cyclic and acyclic acetals and ketals and the acetal
derivatives methoxymethyl (MOM) and methoxyethoxymethyl
(MEM) ethers at À78 °C while methyl ethers and tetrahydropyra-
nyl (THP) ethers are stable until 0–25 °C and esters remain sta-
ble.4–6 The sulfur containing heterocyclic haloborane 2-chloro-
1,3,2-dithioborolan cleaves MEM ethers, acetonides, and benzyli-
dene acetals at À78 °C while methylene acetals, THP ethers, esters,
and methyl and benzyl ethers are stable.7 The yet milder oxygen
containing heterocyclic B-halocatecholboranes (Br, Cl) require
ambient temperature for the effective cleavage of MOM and
resistant to cleavage. The B-chloro reagent is less reactive requiring
24–48 h for benzyl ethers versus 18 h with the bromo reagent. The
chloro reagent has been used to cleave benzyl ethers in the synthe-
sis of 2-arachidonoylglycerol (2-AG) but suffered the production of
a minor amount (<5%) of rearranged product 1-arachidonoylglyc-
erol (1-AG).10 The mildness of B-chlorocatecholborane suggested
itself for even more selective cleavage of acetals without inducing
rearrangement of the sensitive 2-AG.
2-AG is an endogenous neurochemical messenger for the can-
nabinoid receptors that has been the subject of extensive study
to elucidate the functions of this major neurochemical system.11
It is prone to rearrangement to 1-arachidonoylglycerol (1-AG) un-
der the mildest provocations of reaction conditions and even room
temperature storage in various biologically compatible solvents.12
Separation of these isomers is ineffective on a preparative scale,
leaving mixtures that could compromise the interpretation of bio-
logical studies. Its synthesis has been reported employing different
protected forms of glycerol10,13–15 or from glycidol.16 While the
glycidol method16 and the phenylboronate method14 are the least
prone to rearrangement in the final deblocking step (<1% as deter-
mined by 1H NMR or HPLC analyses, respectively), the silyl13 and
benzyl10 protected glycerol approaches experience ꢀ5% of rear-
rangement, demonstrating the sensitivity of this molecule to
deblocking conditions and identifying it as a probe of the mildness
of reaction conditions.
We report here the use of B-chlorocatecholborane (1) for acetal
cleavage of cis-arachidonoylbenzylidene glycerol (cis-ABG) that
demonstrates the mildness of the reagent on an especially sensitive
⇑
Corresponding author.
E-mail address: hhs@rti.org (H.H. Seltzman).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.039

3826
M. J. Roche et al. / Tetrahedron Letters 53 (2012) 3825–3827
O
O
O
O
B Cl
O
O
O
O
O
1
O
Cl
O
B
O
2
cis-ABG
24%
58%
O
O
H2O
O
O
HO
HO
O
O
O
2-AG
3
B
O
7%
H2O
X
O
O
O
O
HO
OH
O
O
trans-ABG
1-AG
Scheme 1. 2-Acyl glycerol acetal deblocking pathways with B-chlorocatecholborane.
transformation while also affording an improved quality of product
of current interest. Furthermore, the product distribution from the
reaction provides some insight into the mechanism of this acetal
cleavage reaction (Scheme 1).
formed from 2-acylglycerols via stabilization like that proposed
here for the borate ester 2.17
This work demonstrates the utility of B-chlorocatecholborane
for the mild and effective cleavage of a benzylidene acetal moiety
in an especially sensitive transformation suggesting its potential
application with other acetals where its mildness can preclude side
reactions. 2-AG of improved purity, necessary for unambiguous
interpretation of biological experiments, was obtained compared
to a previously reported method10 as well as an improved synthe-
sis compared to an earlier method.14
When the cis-ABG was treated with 2.5 equiv of B-chloro-
catecholborane (CH2Cl2, 0 °C, 2.5 h) followed by workup with
MeOH/H2O, HPLC analysis showed the formation of 2-AG (58%),
1-AG (<1%, not detected), cis-ABG (24%), and trans-ABG (6.8%).
Based on the recovered acetals, the yield of 2-AG was 85%. The ab-
sence of 1-AG in the worked up reaction is evidence of the gentle
but the effective cleavage of acetals with B-chlorocatecholborane.
The observation of the trans-isomer (trans-ABG), when none
was present in the starting material, can be understood in terms
of ring opening of cyclic acetal followed by ring closure during
hydrolysis of the boron ester during work up. This process is sim-
ilar to that reported with dimethylboron bromide which affords an
Experimental
cis-Arachidonoylbenzylidene glycerol (cis-ABG)
Under anhydrous conditions, arachidonic acid (75 mg, 0.25
mmol) in 3 mL dry CH2Cl2 was cooled under nitrogen to 0 °C and
treated with oxalyl chloride in CH2Cl2 (0.45 mL of 2.0 M) and two
drops of DMF to produce gas evolution. The solution was stirred
for 30 min at room temperature, and an aliquot was quenched with
MeOH and analyzed by TLC (SiO2, EtOAc/hexane 2:3, phosphomo-
lybdic acid detection). Methyl arachidonate but no arachidonic
acid was observed, indicating complete conversion to the arachido-
noyl chloride). The volatiles were removed in vacuo and the resi-
due blanketed with nitrogen and dissolved in 3 mL of dry CH2Cl2
and cooled to À72 °C. Pyridine (45 mg, 0.57 mmol) was added fol-
lowed by cis-O-benzylidene glycerol (88 mg, 0.49 mmol, 2 equiv)
in 2 mL of CH2Cl2. The reaction was stirred and warmed to room
temperature overnight under N2 and then filtered through a 1 g
SiO2 Sep-Pak followed by elution with 3 mL CH2Cl2. Chromatogra-
phy of the product concentrate on another 1 g SiO2 Sep-Pak eluting
with 5 mL CH2Cl2 afforded 91 mg of cis-ABG as a resin, (0.188
mmol, 76% TY).
intermediate
the case of the benzylidene acetal in this work, a similar ring closure
of the putative -chloroether leads to a mixture of the cis- and trans-
a
-bromoether that then recyclizes to the acetal.4,à In
a
benzylidene acetals.
The cis- and trans-acetals obtained upon workup suggests a
mechanism of recyclization that is likely proceeding via stereose-
lective processes via a non-chiral center (i.e. carbocation 3). The
greater preponderance of the cis versus the trans isomer is also
consistent with this interpretation since the cis-acetal isomer is
more thermodynamically stable than the trans and is preferentially
HPLC analyses were conducted on a Reversed Phase C-18 Waters Radial Pak
(10
lm, 8 mm  10 cm), 95% MeOH/H2O, 2 mL/min, 215 nm. Quantitation was via a
comparison of peak areas of the gravimetric reaction mixture solution to standard
curves of absorption versus amount injected for 2-AG and cis-ABG (trans-ABG was
assumed to have the same UV response as the cis-ABG).
à
Attempted in situ hydroxide cleavage of the intermediate
a-chloroether with
1H NMR (CDCl3, 250 MHz) d 7.48–7.51 (m, 2H, Ar), 7.34–7.40
(m, 3H, Ar), 5.55 (s, 1H,), 5.34–5.39 (m, 8H, olefin H), 4.71 (s, 1H,
CH), 4.25–4.30 (d, J = 13 Hz, 2H, CH2O), 4.13–4.19 (d, J = 13 Hz,
tetra-n-butylammonium hydroxide did not improve the overall conversion to 2-AG,
affording cleavage of the arachidonyl ester, in contrast to its success with other boron
halides and non-ester acetals.5

M. J. Roche et al. / Tetrahedron Letters 53 (2012) 3825–3827
3827
2H, CH2O), 2.78–2.82 (m, 6H, 7,10,13 @CH2@), 2.42–2.48 (t,
trans-1,3 Arachidonyl benzylidene glycerol (trans-ABG)
J = 7.5 Hz, 2H, 2-CH2), 2.00–2.18 (m, 4H, 4, 16-CH2), 1.69–1.80 (p,
2 H, J = 7.4 Hz, 3-CH2), 1.17–1.37 (m, 6H,17-19-CH2), 0.85–0.90 (t,
J = 6.7 Hz, 3H, 20-CH3).
1H NMR (CDCl3, 250 MHz) d 7.46–7.49 (m, 2H, Ar), 7.35–7.38
(m, 3H, Ar), 5.45 (s, 1H,), 5.34–5.41 (m, 8H, olefin H), 4.97–5.10
(sept, J = 5 Hz, 1H, CH), 4.35–4.42 (m, 2H, equatorial CH2O), 3.65–
3.73 (t, J = 9.9 Hz, 2H, axial CH2O), 2.80–2.87 (m, 6H, 7,10,13
@CH2@), 2.30–2.36 (t, J = 7.5 Hz, 2H, 2-CH2), 2.05–2.14 (m, 4H, 4,
16-CH2), 1.65–1.77 (p, 2 H, J = 7.3 Hz, 3-CH2), 1.31–1.39 (m,
6H,17-19-CH2), 0.87–0.92 (t, J = 6.9 Hz, 3H, 20-CH3).
2-Arachidonoylglycerol
cis-ABG (1,000 mg, 2.07 mmol) was added to B-chloro-
catecholborane (800 mg, 5.18 mmol) in CH2Cl2 (25 mL) at 0 °C un-
der nitrogen and protected from light. After stirring 2.5 h, TLC
(SiO2, 30% EtOAc/hexane, phosphomolybdic acid detection) showed
reformed starting material (on a MeOH/H2O quenched reaction ali-
quot, which would have reconverted the ring opened intermediate
back to the acetal). Workup involved dilution with CH2Cl2 (25 mL)
and washing (3 Â 50 mL) with degassed MeOH/H2O 1:1 to a final
neutral pH. The CH2Cl2 phase was dried over Na2SO4, concentrated
in vacuo at ambient temperature to 825 mg of an oil that contained
459 mg of 2-AG/<1% 1-AG (58%, 85% based on recovered acetal mix-
ture c/t-ABG by HPLC analysis). The oil was chromatographed on
40 g of silica gel with a 0–100% EtOAc/hexane linear gradient over
12 void volumes to afford 30 mg of trans-ABG, 200 mg of cis-ABG,
and 347 mg of 97% pure 2-AG containing 3% 1-AG that was gener-
ated by the silica gel chromatography (44% isolated yield; 58%
based on recovered cis- and trans-ABG).
Acknowledgement
This work was supported on Contracts N01DA-3-7736 and
N01DA-8-7763 from the National Institute on Drug Abuse.
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