Synthesis of glycerol homologues

Article abstract of DOI:10.1055/s-0033-1339185

A series of monoprotected glycerol homologues and triols were prepared in high overall yields (>90%) via the hydroboration-oxidation of the corresponding dienols. Hydroboration with disiamylborane and concomitant alkaline oxidation (NaOH, H₂O₂) was found to be a mild, high-yielding, and highly efficient method for the construction of a variety of glycerol homologues. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339185

2280▌
PAPER
paper
Synthesis of Glycerol Homologues
Synthesis of Glycerol Homologues
Kiran Kumar Thota, Mark L. Trudell*
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Fax +1(504)2806860; E-mail: mtrudell@uno.edu
Received: 04.03.2013; Accepted after revision: 13.05.2013
(e.g., Et2O and THF), halogenated solvents (e.g., CH2Cl2
and CHCl3), and toluene. Therefore it was of interest to
develop an efficient method for the general construction
of a series of glycerol homologues that would facilitate
Abstract: A series of monoprotected glycerol homologues and tri-
ols were prepared in high overall yields (>90%) via the hydrobora-
tion–oxidation of the corresponding dienols. Hydroboration with
disiamylborane and concomitant alkaline oxidation (NaOH, H2O2)
was found to be a mild, high-yielding, and highly efficient method later structural modification of the core triol side chains.
for the construction of a variety of glycerol homologues.
R1
R2
Key words: hydroboration, diols, triols, diene, disiamylborane
OH
OH
R2
R1
OH
N
N
1 R1 = R2 = H
We have recently demonstrated the efficiency of the irid-
ium-catalyzed N-heterocyclization reaction1 for the prep-
aration of novel piperidine alkaloids from 1,5-diols
(Scheme 1).2 More recently Kawahara and co-workers,
demonstrated that nonane-1,5,9-triol (1) could be effi-
ciently converted into quinolizidine in 85% yield (Scheme
1).3
OH
R1
R2
HO
OH
R1
R2
2 R1 = R2 = H
R1
R2
OH
OH
OH
R1
N
R2NH2
R2
3 R1 = R2 = H
N
R2
OH OH
[Cp*IrCl2]2
R1
Scheme 2 Bicyclic amphibian alkaloids
R1
NH3, H2O
OH
OH
OH
N
To achieve this goal we envisaged a hydroboration–oxi-
dation strategy that would give a triol derivative with a
protected secondary hydroxy group (Scheme 3).8 Protec-
tion of the hydroxy moiety of the readily available dienols
49 and 610 and commercially available 5 would provide the
corresponding dienes 7–9. Simultaneous hydroboration–
oxidation of both double bonds of the dienes would then
afford the monoprotected glycerol homologues 10–12.
This strategy would furnish a triol substrate that would
likely have improved solubility in organic solvents and al-
low for further modification of the primary hydroxy bear-
ing appendages.
[Cp*Ir(NH3)3]I2
140 °C
1
85%
Scheme 1 Applications of the iridium-catalyzed N-heterocycliza-
tion reaction
Our interest in exploring the chemistry and biology of
novel amphibian alkaloids has prompted an investigation
to implement this methodology for the construction of
more complex heterocyclic structures. To this end we en-
visaged the application of the iridium-catalyzed N-hetero-
cyclization reaction for the preparation of quinolizidine,
pyrrolizidine, and indolizidine alkaloids from the corre-
sponding triol-based molecular scaffolds (Scheme 2).4
In order to establish the viability of the approach for future
studies, it was of interest to determine whether a series of
hydroxy protecting groups would tolerate the hydrobora-
tion–oxidation reaction. To this end (Scheme 4), the di-
enols 4–6 were converted into a series of silyl ethers 7a–
9a, benzyl ethers 7b–9b, and benzoate esters 7c–9c in
straightforward fashion and in high yields (95–98%).
In an effort to identify precursors for the preparation of
complex triols, we found that nonane-1,5,9-triol (1),3,5
heptane-1,4,7-triol (2),6 and unsymmetrical octane-1,4,8-
triol (3)7 have been reported in the literature. However,
these triols would require sophisticated protecting group
strategies in order to prepare substituted analogues of 1–3
(Scheme 2, R1 and R2 are alkyl groups). In addition, like
glycerol we found the triols 1–3 to be insoluble in ethers
With the dienes in hand, our attention was directed toward
the identification of suitable hydroboration reagents and
conditions to prepare the glycerol homologues.11 Initially,
diene 8a was treated with borane–tetrahydrofuran com-
plex with concomitant alkaline oxidative workup with so-
dium hydroxide/hydrogen peroxide. This afforded an
insoluble material that was impervious to the oxidative
SYNTHESIS 2013, 45, 2280–2286
Advanced online publication: 25.06.2013
DOI: 10.1055/s-0033-1339185; Art ID: SS-2013-M0181-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

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Synthesis of Glycerol Homologues
2281
OH
OR
OR
HO
OH
X
Y
X
Y
X
Y
4 X = Y = (CH2)2
5 X = Y = CH2
6 X = (CH2)2, Y = CH2
7 X = Y = (CH2)2
8 X = Y = CH2
9 X = (CH2)2, Y = CH2
10 X = Y = (CH2)2
11 X = Y = CH2
12 X = (CH2)2, Y = CH2
Scheme 3 Target monoprotected triols
Table 1 Hydroboration–Oxidation of Diene Derivatives 7–9
OR
i, ii or iii
i, ii or iii
i, ii or iii
4
5
6
1) Sia2BH, THF
0 °C to r.t., 18 h
2) EtOH, NaOH
7a–c
OR
OR
H2O2
OR
a R = TBS
b R = Bn
c R = Bz
HO
OH
X
Y
X
Y
10 X = Y = (CH2)2
11 X = Y = CH2
12 X = (CH2)2, Y = CH2
8a–c
7 X = Y = (CH2)2
8 X = Y = CH2
9 X = (CH2)2, Y = CH2
OR
10–12
R
Yield (%)
of 10
Yield (%)
of 11
Yield
(%) of 12
9a–c
Scheme 4 Reagents and conditions: (i) TBSCl, imidazole, CH2Cl2,
0 °C; (ii) NaH, BnBr, DMF, 0 °C; (iii) BzCl, Et3N, DMAP, CH2Cl2,
0 °C to r.t.
a
b
c
TBS
Bn
96
97
95
96
97
95
96
98
96
Bz
workup. Subsequently the yield of any hydroxylated ma-
terial was low (< 20%). Similar results were obtained with
borane–dimethyl sulfide complex. The formation of in-
tractable material was avoided with the dialkylborane re-
agents, dicyclohexylborane and 9-BBN. However, these
reagents gave low yields (<50% yield of hydroxylated
material) and mixtures of regioisomers resulting from the
introduction of the hydroxy group at C2 and/or C6 of 8a.
Based upon these results it was clear that the dialkylbo-
rane reagents offered the best chance for success if we
could better control the regiochemistry of the reaction.
Previous studies by Dobner and co-workers were success-
ful in preparing long-chain diols from the corresponding
dienes using disiamylborane.12 In light of these results, we
investigated the utility of disiamylborane, generated in
situ from borane–dimethyl sulfide complex and 2-methyl-
but-2-ene. Treatment of 8a with disiamylborane followed
by oxidation with alkaline hydrogen peroxide afforded the
silyl-protected glycerol homologue 11a in 95% isolated
yield (Table 1). Under these conditions we observed no
formation of insoluble materials and the high yield was
quite satisfying given our previous results with the dicy-
clohexylborane and 9-BBN. In addition, we were unable
to detect the formation of regioisomers resulting from C2
and/or C6 hydroxylation. Based upon the success of this
reaction, we employed disiamylborane for the preparation
of a series of monoprotected glycerol homologues. These
results are summarized in Table 1.
ester based protecting groups. In addition, the monopro-
tected glycerol homologues 10a–c, 11a–c, and 12a–c
were found to be readily soluble in a variety of solvents
that could be used in future transformations. These sol-
vents include tetrahydrofuran, dichloromethane, chloro-
form, and toluene.
To demonstrate the utility of the selected protecting
groups for the preparation of glycerol homologues, 10a–c,
11a–c, and 12a–c were converted into the corresponding
triols. As illustrated in Scheme 5, the silyl ethers 10a, 11a,
and 12a were treated with tetrabutylammonium fluoride
in tetrahydrofuran to furnish the triols 1, 2, and 3, respec-
tively, in high yields (97–99%). In addition, hydrogenol-
ysis over palladium hydroxide on carbon of the benzyl
ethers 10b, 11b, and 12b afforded the triols 1, 2, and 3 in
quantitative yields (97–99%). Finally, the triols 1, 2, and
3, were easily obtained by hydrolysis of the benzoate es-
ters 10c, 11c, and 12c (96–98% isolated yields).
With the monoprotected glycerol homologues in hand, we
selected the TBS homologue 11a for further conversion
into a substituted homologue. As illustrated in Scheme 6,
oxidation of diol 11a with excess Dess–Martin periodin-
ane reagent furnished the dialdehyde 13 in 80% yield. The
dialdehyde 13 was then treated with excess methylmagne-
sium bromide to afford the diol 14 in 81% yield. Removal
of the TBS-protecting group was then achieved with tetra-
butylammonium fluoride to give the triol 15 in 95% yield.
We were pleased with the efficiency of the oxidation, al-
kylation and deprotection sequence to furnish the substi-
tuted triol 15 in 58% overall yield (five steps) from
commercially available dienol 5.
Overall, the disiamylborane-mediated hydroboration–
oxidation was very effective in providing high yields
(>95%) of the monoprotected glycerol homologues 10a–c,
11a–c, and 12a–c. Clearly the reaction conditions were
tolerant of the three protecting groups that were evaluated
(TBS, Bn, and Bz). Thus, this approach should be readily
adaptable to other silyl ethers, substituted benzyl ethers or
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2280–2286

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K. K. Thota, M. L. Trudell
PAPER
OR
OH
i, ii or iii
i, ii or iii
HO
OH
HO
OH
10a–c
1
OR
OH
HO
OH
HO
OH
11a–c
2
OR
OH
i, ii or iii
HO
HO
OH
OH
12a–c
3
Scheme 5 Reagents and conditions: (i) TBAF, THF, r.t.; (ii) H2 (1 atm), Pd(OH)2/C, MeOH, r.t.; (iii) KOH, MeOH, r.t.
Na2SO4), and concentrated under reduced pressure. The residue was
OTBS
i
purified by flash chromatography (4% EtOAc–hexane) to furnish 4
11a
O
O
1
(4.6 g, 90%) as a colorless oil. H and 13C The spectroscopic data
were consistent with those reported previously for this compound.9
13 (80%)
OR
Octa-1,7-dien-4-ol (6)
ii, iii
HO
OH
A dry 250-mL 2-necked round-bottom flask was filled with a solu-
tion of 1 M allylmagnesium bromide in Et2O (17 mL, 18 mmol) un-
der an argon atmosphere. The mixture was cooled to –78 °C and
pent-4-enal (1.0 g, 12 mmol) was added dropwise. The mixture was
stirred and allowed to warm to r.t. overnight. Sat. NH4Cl (20 mL)
was added and the mixture stirred for 1 h. The organic layer was
separated, washed with brine solution, then dried (anhydrous
Na2SO4), and concentrated under reduced pressure. The residue was
purified by flash chromatography (5% EtOAc–hexane) to furnish 6
(1.41 g, 94%) as a colorless oil. The spectroscopic data were consis-
tent with those reported previously for this compound.10
14 R = TBS (81%)
15 R = H (95%)
Scheme 6 Reagents and conditions: (i) Dess–Martin periodinane,
CH2Cl2, 0 °C to r.t., 6 h; (ii) MeMgBr, THF, –78 °C to r.t., 3 h; (iii)
TBAF, THF, r.t.
In conclusion, we have shown that the hydroboration–ox-
idation of monoprotected dienols with disiamylborane is tert-Butyldimethylsiloxydienes 7a, 8a, and 9a; General Proce-
dure
a mild, high-yielding, and highly efficient method for the
To a solution of dienol (1 equiv) in CH2Cl2 (20 mL), imidazole (2
equiv) was added at r.t., and mixture was stirred for 15 min. To the
construction of glycerol homologues. Further conversion
of a monoprotected glycerol homologue into a more high-
ly substituted triol derivative proceeded in high overall
yield. Having established an efficient route for the prepa-
ration of novel triols, the synthesis of structurally novel
amphibian alkaloids is currently under investigation and
will be reported in due course.
stirred solution, a solution of TBSCl (1.5 equiv) in CH2Cl2 (5 mL),
was added slowly at 0 °C and stirring was continued overnight. The
mixture was poured into H2O (50 mL) and extracted with CH2Cl2 (3
× 50 mL). The combined organic layers were dried (anhydrous
Na2SO4), and concentrated under reduced pressure. The residue was
purified by flash chromatography (silica gel) to afford the desired
TBS ether.
5-(tert-Butyldimethylsiloxy)nona-1,8-diene (7a)
All chemicals were purchased from Aldrich Chemical Company
and used as received unless otherwise noted. TLC employed silica
gel (250 μm) on glass plates purchased from Sorbent Technologies.
Visualization was achieved with UV light, I2, or phosphomolybdic
acid. Compounds were purified by flash chromatography on silica
gel 60 Å (230–400 mesh) purchased from Sorbent Technologies. 1H
NMR (400 MHz) and 13C NMR (100 MHz) were recorded on a
Varian-400 MHz nuclear magnetic resonance spectrometer at r.t. in
CDCl3 or D2O relative to TMS (1H) or CDCl3 (13C, δ = 77.0). Atlan-
tic Microlab, Inc., Norcross, GA performed all CHN microanalyses.
Prepared from 4 (1.0 g, 7.1 mmol), imidazole (1.0 g, 14 mmol), and
TBSCl (1.6 g, 11 mmol). Purification by flash chromatography (1%
EtOAc–hexane) furnished a colorless oil; yield: 1.8 g (98%).
1H NMR (400 MHz, CDCl3): δ = 5.85–5.74 (m, 2 H), 5.03–4.90 (m,
4 H), 3.72–3.65 (m, 1 H), 2.12–2.04 (m, 4 H), 1.54–1.50 (m, 4 H),
0.89 (s, 9 H), 0.05 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 139.1, 114.5, 71.4, 36.4, 29.7,
26.1, 18.3, –4.2.
4-(tert-Butyldimethylsiloxy)hepta-1,6-diene (8a)
Nona-1,8-dien-5-ol (4)
Prepared from 5 (1.0 g, 7.1 mmol), imidazole (1.0 g, 14 mmol), and
TBSCl (1.6 g, 11 mmol). Purification by flash chromatography (1%
EtOAc–hexane) furnished a colorless oil; yield: 1.8 g (98%).
To a dry 250-mL 2-neck round-bottom flask, Mg turnings (2.7 g,
110 mmol) were added under an argon atmosphere and this was fol-
lowed by the addition of anhydrous THF (40 mL). To the stirred so-
lution, 4-bromobut-1-ene (5.0 g, 37 mmol) was added slowly at r.t.
and the mixture was stirred for 1 h. The mixture was cooled to 0 °C
and ethyl formate (1.5 mL, 19 mmol) was added dropwise, then it
was stirred at r.t. overnight. Sat. NH4Cl (40 mL) was added at 0 °C
and stirring was continued for a further 3 h. The organic layer was
separated, washed with brine solution, then dried (anhydrous
1H NMR (400 MHz, CDCl3): δ = 5.85–5.76 (m, 2 H), 5.06–5.02 (m,
4 H), 3.74 (p, J = 5.8 Hz, 1 H), 2.27–2.15 (m, 4 H), 0.89 (s, 9 H),
0.05 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 135.5, 117.1, 72.0, 41.7, 26.1,
18.4, –4.3.
Synthesis 2013, 45, 2280–2286
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Synthesis of Glycerol Homologues
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4-(tert-Butyldimethylsiloxy)octa-1,7-diene (9a)
tography (2% EtOAc–hexane) furnished a colorless oil; yield: 1.9 g
(91%).
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 7.2 Hz, 2 H), 7.57 (t,
J = 7.2 Hz, 1 H), 7.45 (t, J = 7.2 Hz, 2 H), 5.83–5.77 (m, 2 H), 5.19–
5.16 (m, 1 H), 5.04–4.95 (m, 4 H), 2.16–2.12 (m, 4 H), 1.88–1.75
(m, 4 H).
Prepared from 6 (1.0 g, 8.0 mmol), imidazole (1.1 g, 15 mmol), and
TBSCl (1.8 g, 12 mmol). Purification by flash chromatography (1%
EtOAc–hexane) furnished a colorless oil; yield: 1.9 g (97%).
1H NMR (400 MHz, CDCl3): δ = 5.84–5.75 (m, 2 H), 5.05–4.92 (m,
4 H), 3.71 (p, J = 6.0 Hz, 1 H), 2.22 (t, J = 4.0 Hz, 2 H), 2.17–2.01
(m, 2 H), 1.57–1.50 (m, 2 H), 0.89 (s, 9 H), 0.091 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 139.1, 135.4, 117.0, 114.5, 71.6,
42.1, 36.2, 29.9, 26.1, 18.3, –4.3.
13C NMR (100 MHz, CDCl3): δ = 166.4, 138.0, 133.0, 130.8, 129.8,
128.6, 115.2, 74.1, 33.7, 29.8.
Hepta-1,6-dien-4-yl Benzoate (8c)
Benzyloxydienes 7b, 8b, and 9b; General Procedure
Prepared from 5 (1.0 g, 9.0 mmol), Et3N (3.7 mL, 27 mmol, DMAP
(0.1 g), and BzCl (1.2 mL, 10 mmol). Purification by flash chroma-
tography (2% EtOAc–hexane) furnished a colorless oil; yield: 1.8 g
(92%).
To a solution of NaH (1.4 equiv) in anhydrous DMF, the dienol (1
equiv) was added dropwise at 0 °C. The mixture was stirred for 15
min, and then BnBr (1.1 equiv) was added. The mixture was al-
lowed to warm to r.t. and stirred overnight. Excess NaH was
quenched by addition of ice at 0 °C and the mixture was stirred for
10 min. The mixture was poured into H2O, extracted with EtOAc (3
× 50 mL). The combined organic layers were washed with H2O and
brine solution, dried (anhydrous Na2SO4), and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy (silica gel) to furnish the desired benzyl ether.
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 7.2 Hz, 2 H), 7.55 (t,
J = 7.6 Hz, 1 H), 7.43 (t, J =7.6 Hz, 2 H), 5.88–5.78 (m, 2 H), 5.22
(p, J = 6.0 Hz, 1 H), 5.15–5.07 (m, 4 H), 2.47 (t, J = 6.4 Hz, 4 H).
13C NMR (100 MHz, CDCl3): δ = 166.3, 133.7, 133.1, 130.8, 129.8,
128.6, 118.3, 73.3, 38.2.
Octa-1,7-dien-4-yl Benzoate (9c)
Prepared from 6 (1.0 g, 9.0 mmol), Et3N (3.7 mL, 27 mmol), DMAP
(0.1 g), and BzCl (1.2 mL, 10 mmol). Purification by flash chroma-
tography (2% EtOAc–hexane) furnished a colorless oil; yield: 1.9 g
(91%).
5-(Benzyloxy)nona-1,8-diene (7b)
Prepared from 4 (1.2 g, 9.0 mmol), NaH (0.31 g, 13 mmol), and
BnBr (1.7 g, 10 mmol). Purification by flash chromatography (2%
EtOAc–hexane) furnished a colorless oil; yield: 1.8 g (90%).
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 7.2 Hz, 2 H), 7.56 (t,
J = 7.2 Hz, 1 H), 7.44 (t, J = 7.2 Hz, 2 H), 5.88–5.77 (m, 2 H), 5.23–
5.17 (m, 1 H), 5.13–4.95 (m, 4 H), 2.46 (t, J = 6.4 Hz, 2 H), 2.21–
2.10 (m, 2 H), 1.88–1.72 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 166.4, 137.9, 133.7, 133.0, 130.8,
129.8, 128.4, 118.4, 115.2, 73.6, 38.9, 33.1, 29.8.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.26 (m, 5 H), 5.86–5.77 (m,
2 H), 5.04–4.94 (m, 4 H), 4.50 (s, 2 H), 3.47–3.41 (m, 1 H), 2.17–
2.11 (m, 4 H), 1.72–1.54 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 139.1, 138.9, 128.5, 128.0, 127.7,
114.8, 77.1, 33.3, 29.8
4-(Benzyloxy)hepta-1,6-diene (8b)
Prepared from 5 (1.0 g, 9.0 mmol), NaH (0.32 g, 13 mmol), and
BnBr (1.7 g, 10 mmol). Purification by flash chromatography (2%
EtOAc–hexane) furnished a colorless oil; yield 1.6 g (90%).
Diols 10a–c, 11a–c, and 12a–c; General Procedure
A 250-mL, round-bottom flask was charged with borane–DMS
complex (4.4 equiv) under an argon atmosphere and cooled to –10
°C. A solution of 2 M 2-methylbut-2-ene in THF (8.8 equiv) was
added dropwise and the mixture was stirred for 2 h at 0 °C. A solu-
tion of the diene (1 equiv) in anhydrous THF (10 mL) was added
dropwise at 0 °C. The mixture was then allowed to warm to r.t. and
stirred for 18–24 h until no of the diene was observed by TLC.
EtOH (50 equiv), 6 M NaOH (6 equiv), and H2O2 (25 equiv, 30%)
were added slowly and the mixture was heated to 50 °C for 1–3 h
(until the white solid suspension dissolved). After cooling to r.t., the
mixture was extracted with Et2O (3 × 50 mL). The combined organ-
ic layers were dried (anhydrous Na2SO4) and concentrated under re-
duced pressure. The residue was purified by flash chromatography
to furnish the desired monoprotected glycerol homologue.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.26 (m, 5 H), 5.87–5.81 (m,
2 H), 5.08–5.06 (m, 4 H), 4.56 (s, 2 H), 3.52 (p, J = 6.0 Hz, 1 H),
2.34 (t, J = 6.6 Hz, 4 H).
13C NMR (100 MHz, CDCl3): δ = 138.9, 135.1, 128.5, 127.9, 127.7,
117.3, 78.4, 71.2, 38.3.
4-(Benzyloxy)octa-1,7-diene (9b)
Prepared from 6 (1.1 g, 9.0 mmol), NaH (0.31 g, 13 mmol), and
BnBr (1.7 g, 10 mmol). Purification by flash chromatography (2%
EtOAc–hexane) furnished a colorless oil; yield: 1.7 g (91%).
1H NMR (400 MHz, CDCl3): δ = 7.35–7.26 (m, 5 H), 5.88–5.76 (m,
2 H), 5.06–4.94 (m, 4 H), 4.58 (d, J = 11.6 Hz, 1 H), 4.48 (d, J =
11.6 Hz, 1 H), 3.48 (p, J = 6.0 Hz, 1 H), 2.34–2.20 (m, 2 H), 2.16–
2.08 (m, 2 H), 1.62–1.57 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 139.0, 138.8, 135.1, 128.6, 128.0,
127.7, 117.2, 114.8, 78.1, 71.2, 38.5, 33.3, 29.9.
5-(tert-Butyldimethylsiloxy)nonane-1,8-diol (10a)
Prepared from 7a (0.51 g, 2.0 mmol), BH3·DMS (0.75 mL, 8.0
mmol), and 2 M 2-methylbut-2-ene in THF (7.3 mL, 16 mmol). The
oxidation used EtOH (5.5 mL), 6 M NaOH (1.8 mL), and H2O2
(30%, 3.7 mL). Purification by flash chromatography (50% EtOAc–
hexane) furnished a colorless oil; yield: 0.56 g (96%).
Dienyl Benzoates 7c, 8c, and 9c; General Procedure
To a solution of dienol (1 equiv) in CH2Cl2 (20 mL), Et3N (3 equiv)
was added along with catalytic amount of DMAP (10%). The mix-
ture was stirred for 30 min at r.t. The solution was cooled to 0 °C
and BzCl (1.1 equiv) was added and the mixture was stirred over-
night at r.t. The mixture was poured into H2O (50 mL) and extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were
washed with H2O (2 × 50 mL), brine (50 mL), dried (anhydrous
Na2SO4), and concentrated under reduced pressure. The residue was
purified by flash chromatography (silica gel) to furnish the desired
benzoate esters.
1H NMR (400 MHz, CDCl3): δ = 3.68–3.63 (m, 1 H), 3.66–3.62 (t,
J = 6.4 Hz, 4 H), 1.59–1.52 (m, 4 H), 1.49–1.42 (m, 4 H), 1.40–1.30
(m, 4 H), 0.88 (s, 9 H), 0.04 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 72.3, 63.2, 36.9, 33.2, 26.1, 21.6,
18.4, –4.2.
Anal. Calcd for C15H34O3Si: C, 62.01; H, 11.80. Found: C, 61.75;
H, 11.68.
5-(Benzyloxy)nonane-1,8-diol (10b)
Prepared from 7b (0.46 g, 2.0 mmol), BH3·DMS (0.75 mL, 8
mmol), and 2 M 2-methylbut-2-ene in THF (7.3 mL, 16 mmol). The
oxidation used EtOH (5.5 mL), 6 M NaOH (1.8 mL), and H2O2
Nona-1,8-dien-5-yl Benzoate (7c)
Prepared from 4 (1.0 g, 9.0 mmol), Et3N (3.7 mL, 27 mmol), DMAP
(0.1 g), and BzCl (1.2 mL, 10 mmol). Purification by flash chroma-
© Georg Thieme Verlag Stuttgart · New York
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2284
K. K. Thota, M. L. Trudell
PAPER
(30%, 3.7 mL). Purification by flash chromatography (60% EtOAc–
hexane) furnished a colorless oil; yield: 0.52 g (97%).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.25 (m, 5 H), 4.49 (s, 2 H),
3.59 (t, J = 6.4 Hz, 4 H), 3.39 (p, J = 6.0 Hz, 1 H), 1.90 (br s, 2 H),
1.61–1.34 (m, 12 H).
13C NMR (100 MHz, CDCl3): δ = 139.1, 128.6, 128.0, 127.7, 79.1,
71.1, 62.9, 33.7, 33.0, 21.7.
4-(tert-Butyldimethylsiloxy)octane-1,8-diol (12a)
Prepared from 9a (0.48 g, 2.0 mmol), BH3·DMS (0.75 mL, 8.0
mmol), and 2 M 2-methylbut-2-ene in THF (7.3 mL, 16 mmol). The
oxidation used EtOH (5.5 mL), 6 M NaOH (1.8 mL), and H2O2
(30%, 3.7 mL). Purification by flash chromatography (50% EtOAc–
hexane) furnished a colorless oil; yield: 0.53 g (96%).
1H NMR (400 MHz, CDCl3): δ = 3.73 (p, J = 5.6 Hz, 1 H), 3.64 (t,
J = 5.6 Hz, 4 H), 1.65–1.56 (m, 4 H), 1.54–1.47 (m, 4 H), 1.43–1.31
(m, 2 H), 0.89 (s, 9 H), 0.06 (s, 6 H).
Anal. Calcd for C16H26O3·H2O: C, 67.57; H, 9.92. Found: C, 67.98;
H, 9.69.
13C NMR (100 MHz, CDCl3): δ = 72.1, 63.4, 63.1, 36.5, 33.5, 33.1,
28.0, 26.1, 21.8, 18.3, –4.3.
1,5-Dihydroxynonane-5-yl Benzoate (10c)
Prepared from 7c (0.49 g, 2.0 mmol), BH3·DMS (0.75 mL, 8 mmol),
and 2 M 2-methylbut-2-ene in THF (7.3 mL, 16 mmol). The oxida-
tion used EtOH (5.5 mL), 6 M NaOH (1.8 mL), and H2O2 (30%, 3.7
mL). Purification by flash chromatography (60% EtOAc–hexane)
furnished a colorless oil; yield: 0.53 g (95%).
1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 6.8, Hz, 2 H), 7.55 (t,
J = 7.2 Hz, 1 H), 7.43 (t, J = 7.2 Hz, 2 H), 5.19–5.12 (m, 1 H), 3.62
(t, J = 6.4 Hz, 4 H), 1.77–1.65 (m, 4 H), 1.63–1.51 (m, 4 H), 1.49–
1.39 (m, 4 H).
Anal. Calcd for C14H32O3Si: C, 60.82; H, 11.67. Found: C, 60.80;
H, 11.80.
4-(Benzyloxy)octane-1,8-diol (12b)
Prepared from 9b (0.43 g, 2.0 mmol), BH3·DMS (0.75 mL, 8
mmol), and 2 M 2-methylbut-2-ene in THF (7.3 mL, 16 mmol). The
oxidation used EtOH (5.5 mL), 6 M NaOH (1.8 mL), and H2O2
(30%, 3.7 mL). Purification by flash chromatography (70% EtOAc–
hexane) furnished a colorless oil; yield: 0.49 g (98%).
1H NMR (400 MHz, CDCl3): δ = 7.35–7.26 (m, 5 H), 4.54 (d, J =
11.6 Hz, 1 H), 4.50 (d, J = 11.6 Hz, 1 H), 3.64 (t, J = 6.4 Hz, 4 H),
3.48–3.42 (m, 1 H), 1.58–1.38 (m, 10 H).
13C NMR (100 MHz, CDCl3): δ = 166.7, 133.1, 130.8, 129.8, 128.6,
74.9, 62.9, 34.2, 32.7, 21.8.
Anal. Calcd for C16H24O4·0.5 H2O: C, 66.40; H, 8.73. Found: C,
66.00; H, 8.69.
13C NMR (100 MHz, CDCl3): δ = 138.8, 128.6, 128.1, 127.8, 78.9,
71.1, 63.3, 63.1, 33.5, 33.1, 30.4, 28.7, 21.8.
4-(tert-Butyldimethylsiloxy)-heptane-1,7-diol (11a)
Anal. Calcd for C15H24O3·H2O: C, 66.64; H, 9.69. Found: C, 67.00;
H, 9.38.
Prepared from 8a (1.0 g, 5.0 mmol), BH3·DMS (1.7 mL, 22 mmol),
and 2 M 2-methylbut-2-ene in THF (17.6 mL, 44 mmol). The oxi-
dation used EtOH (13 mL), 6 M NaOH (4.4 mL), and H2O2 (30%,
5.3 mL). Purification by flash chromatography (50% EtOAc–
hexane) furnished a colorless oil; yield: 1.1 g (96%).
1,8-Dihydroxyoctan-4-yl Benzoate (12c)
Prepared from 9c (0.46 g, 2.0 mmol), BH3·DMS (0.75 mL, 8.0
mmol), and 2 M 2-methylbut-2-ene in THF (7.3 mL, 16 mmol). The
oxidation used EtOH (5.5 mL), 6 M NaOH (1.8 mL), and H2O2
(30%, 3.7 mL). Purification by flash chromatography (75% EtOAc–
hexane) furnished a colorless oil; yield: 0.51 g, (96%).
1H NMR (400 MHz, CDCl3): δ = 3.78–3.76 (m, 1 H), 3.62–3.60 (m,
4 H), 2.34 (br s, 2 H), 1.62–1.52 (m, 8 H), 0.88 (s, 9 H), 0.06 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 72.1, 63.2, 33.2, 28.5, 26.1, 18.3,
–4.3.
1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 7.2 Hz, 2 H), 7.55 (t,
J = 7.6 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 2 H), 5.20–5.15 (m, 1 H), 3.68–
3.60 (m, 4 H), 1.76–1.41 (m, 10 H).
Anal. Calcd for C13H30O3Si: C, 59.49; H, 11.52. Found: C, 59.23;
H, 11.26.
13C NMR (100 MHz, CDCl3): δ = 166.7, 133.1, 130.7, 129.8, 128.6,
74.7, 62.8, 62.7, 34.3, 32.7, 30.8, 28.7, 21.8.
4-(Benzyloxy)heptane-1,7-diol (11b)
Prepared from 8b (0.4 g, 2.0 mmol), BH3·DMS (0.75 mL, 8 mmol),
and 2 M 2-methylbut-2-ene in THF (7.3 mL, 16 mmol). The oxida-
tion used EtOH (5.5 mL), 6 M NaOH (1.8 mL), and H2O2 (30%, 3.7
mL). Purification by flash chromatography (70% EtOAc–hexane)
furnished a colorless oil; yield: 0.46 g (97%).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.25 (m, 5 H), 4.51 (s, 2 H),
3.61–3.59 (t, J = 5.6 Hz, 4 H), 3.50–3.48 (m, 1 H), 2.31 (br s, 2 H),
1.67–1.58 (m, 8 H).
Anal. Calcd for C15H22O4·0.5 H2O: C, 65.43; H, 8.42. Found: C,
65.38; H, 8.47.
TBS Deprotection of 10a, 11a, and 12a; General Procedure
A solution 1 M solution of TBAF in THF (2 equiv) was add to a so-
lution of tert-butyldimethylsiloxy diol (1 equiv) in anhydrous THF
(10 mL) at r.t. and the mixture was stirred overnight. The mixture
was concentrated under reduced pressure and the residue was puri-
fied by flash chromatography (10% MeOH–EtOAc) to furnish the
corresponding triol in nearly quantitative yield.
13C NMR (100 MHz, CDCl3): δ = 138.5, 128.6, 128.1, 127.9, 78.8,
71.1, 63.0, 30.2, 28.6.
Debenzylation of 10b, 11b, and 12b; General Procedure
The benzyloxy diol (1 g) in anhydrous MeOH (5 mL) was added to
a solution of 10% Pd(OH)2 on carbon (10% wt) and stirred for 3–4
h under an atmosphere of H2 (1 atm). After all of the starting mate-
rial was consumed (TLC) the catalyst was filtered, concentrated un-
der reduced pressure, and dried under high vacuum (0.133 mbar) at
r.t. to furnish the triol in nearly quantitative yield.
Anal. Calcd for C14H22O3·H2O: C, 65.60; H, 9.44. Found: C, 65.87;
H, 8.91.
1,7-Dihydroxyheptan-4-yl Benzoate (11c)
Prepared from 8c (0.4 g, 2.0 mmol), BH3·DMS (0.75 mL, 8.0
mmol), and 2 M 2-methylbut-2-ene in THF (7.3 mL, 16 mmol). The
oxidation used EtOH (5.5 mL), 6 M NaOH (1.8 mL), and H2O2
(30%, 3.7 mL). Purification by flash chromatography (75% EtOAc–
hexane) furnished a colorless oil; yield: 0.47 g (95%).
Debenzoylation of Dihydroxy Benzoates 10c, 11c, and 12c; Gen-
eral Procedure
1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.4 Hz, 2 H), 7.55 (t,
J = 7.6 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 2 H), 5.24–5.18 (m, 1 H), 3.67
(t, J = 6.0 Hz, 4 H), 1.82–1.76 (m, 4 H), 1.69–1.62 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 166.8, 133.2, 130.6, 129.8, 128.6,
74.6, 62.7, 30.9, 28.6.
To a solution of the benzoate ester (1 equiv) in MeOH (10 mL),
KOH (1.1 equiv) was added and the mixture was stirred for 16 h.
After the starting material had all been consumed (TLC), the mix-
ture was concentrated under reduced pressure and the residue was
purified by flash chromatography (10% MeOH–EtOAc) to furnish
the desired triol in nearly quantitative yield.
Anal. Calcd for C14H20O4·0.5 H2O: C, 64.35; H, 8.10. Found: C,
64.36; H, 8.12.
Synthesis 2013, 45, 2280–2286
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Glycerol Homologues
2285
Nonane-1,5,9-triol (1)
13C NMR (100 MHz, CDCl3): δ = 202.3, 70.1, 39.8, 28.9, 26.0, 18.2,
–4.3
Prepared from 10a (1.1 g, 3.8 mmol) in THF and 1 M TBAF in THF
(7.6 mL, 7.6 mmol). Purification by flash chromatography (10%
MeOH–EtOAc) furnished a colorless oil; yield: 0.65 g (97%).
Anal. Calcd for C13H26O3Si: C, 60.42; H, 10.14. Found: C, 60.33;
H, 10.24.
Prepared from 10b (1.0 g, 3.8 mmol) in MeOH and Pd(OH)2 (0.10
g). Purification by flash chromatography (10% MeOH–EtOAc) fur-
nished a colorless oil; yield: 0.64 g (96%).
5-(tert-Butyldimethylsiloxy)nonane-2,8-diol (14)
To a stirred solution of MeMgBr (3.82 mL, 3.8 mmol) in anhydrous
THF at –78 °C was added dialdehyde 13 (450 mg, 1.7 mmol) in
THF (1 mL); the mixture was stirred for 3 h. Sat. NH4Cl solution (5
mL) was added at 0 °C and the mixture stirred for 1 h. The mixture
was extracted with EtOAc (3 × 10 mL) and the organic layer was
dried (anhydrous Na2SO4),. The mixture was filtered and the sol-
vent was removed under reduced pressure. The residue was purified
by flash chromatography (25% EtOAc–hexane) to furnish 14 (0.40
g, 81%) as a colorless oil.
Prepared from 10c (1.2 g, 4.4 mmol) in MeOH and KOH (0.26 g,
4.6 mmol). Purification by flash chromatography (10% MeOH–
EtOAc) furnished a colorless oil; yield: 0.73 g (95%).
1H NMR (400 MHz, D2O): δ = 3.53–3.50 (m, 1 H), 3.45 (t, J = 6.4
Hz, 4 H), 1.44–1.18 (m, 12 H).
13C NMR (100 MHz, CDCl3): δ = 71.9, 62.9, 37.2, 32.7, 22.0.
Anal. Calcd for C9H20O3·0.75 H2O: C, 56.96; H, 11.42. Found: C,
56.77; H, 11.26.
1H NMR (400 MHz, CDCl3): δ = 3.86–3.75 (m, 2 H), 3.67–3.62 (m,
1 H), 2.38 (s, 2 H), 1.59–1.49 (m, 8 H), 1.20 (d, J = 6.4 Hz, 6 H),
0.90 (s, 9 H), 0.09 (s, 6 H)
13C NMR (100 MHz, CDCl3): δ = 72.5, 72.3, 72.1, 68.5, 68.3, 35.1,
34.9, 34.7, 33.0, 32.4, 26.1, 23.7, 18.3, –4.2, –4.3
Heptane-1,4,7-triol (2)
Prepared from 11a (1.0 g, 3.8 mmol) in THF and 1 M TBAF in THF
(7.6 mL, 7.6 mmol). Purification by flash chromatography (10%
MeOH–EtOAc) furnished as a colorless oil; yield: 0.53 g (95%).
Anal. Calcd for C15H34O3Si: C, 62.01; H, 11.80. Found: C, 61.89;
H, 11.94.
Prepared from 11b (1.0 g, 4.2 mmol) in MeOH and Pd(OH)2 (0.10
g). Purification by flash chromatography (10% MeOH–EtOAc) fur-
nished a colorless oil; yield: 0.61 g (98%).
Nonane-2,5,8-triol (15)
To a stirred solution of 14 (0.43 g, 1.47 mmol) in anhydrous THF
(10 mL) was added 1 M TBAF in THF (1.77 mL, 1.77 mmol) at r.t.
and the mixture was stirred overnight. The mixture was concentrat-
ed under reduced pressure and the residue was purified by flash
chromatography (5% MeOH–EtOAc) to furnish the desired triol 15
(0.26 g, 95% yield) as a colorless oil.
Prepared from 11c (1.0 g, 4.0 mmol) in MeOH and KOH (0.26 g,
4.6 mmol). Purification by flash chromatography (10% MeOH–
EtOAc) furnished a colorless oil; yield: 0.56 g (95%).
1H NMR (400 MHz, D2O): δ = 3.58–3.52 (m, 1 H), 3.47 (t, J = 6.4
Hz, 4 H), 1.56–1.28 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ = 71.9, 63.3, 35.2, 29.5.
1H NMR (400 MHz, D2O): δ = 3.65–3.62 (m, 1 H), 3.48–3.46 (m, 2
H), 1.88 (s, 3 H), 1.33–1.25 (m, 8 H), 1.01–0.97 (m, 6 H)
13C NMR (100 MHz, CDCl3): δ = 72.8, 72.1, 71.6, 68.7, 68.0, 36.5,
Anal. Calcd for C7H16O3·H2O: C, 50.58; H, 10.92. Found: C, 50.85;
H, 10.77.
36.4, 35.2, 35.1, 35.0, 34.6, 33.8, 33.3, 24.0, 23.5
Octane-1,4,8-triol (3)
Anal. Calcd for C9H20O3: C, 61.33; H, 11.44. Found: C, 61.07; H,
11.50.
Prepared from 12a (1.1 g, 3.8 mmol) in THF and 1 M TBAF in THF
(7.6 mL, 7.6 mmol). Purification by flash chromatography (10%
MeOH–EtOAc) furnished a colorless oil; yield 0.61 g (97%).
Prepared from 12b (1.0 g, 4.0 mmol) in MeOH and Pd(OH)2 (0.10
g). Purification by flash chromatography (10% MeOH–EtOAc) fur-
nished a colorless oil; yield: 0.63 g (97%).
Acknowledgment
This research was funded by the National Institute on Drug Abuse
(DA023916) and the University of New Orleans.
Prepared from 12c (1.2 g, 4.5 mmol) in MeOH and KOH (0.26 g,
4.6 mmol). Purification by flash chromatography (10% MeOH–
EtOAc) furnished a colorless oil; yield: 0.71 g (97%).
1H NMR (400 MHz, D2O): δ = 3.53–3.42 (m, 1 H), 3.45 (t, J = 6.4
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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Hz, 4 H), 1.49–1.19 (m, 10 H).
13C NMR (100 MHz, CDCl3): δ = 71.9, 63.3, 62.9, 37.3, 34.8, 32.7,
29.3, 22.1.
References and notes
(1) Fujita, K.; Fujii, T.; Yamaguchi, R. Org. Lett. 2004, 6, 3525.
(2) Miao, L.; DiMaggio, S. C.; Shu, H.; Trudell, M. L. Org. Lett.
2009, 11, 1579.
(3) Kawahara, R.; Fujita, K.; Yamaguchi, R. J. Am. Chem. Soc.
2010, 132, 15108.
(4) For a review of amphibian alkaloids see: (a) Daly, J. W.;
Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556.
(b) Daly, J. J. Med. Chem. 2003, 46, 445.
(5) Schwartz, B. D.; McErlean, C. S. P.; Fletcher, M. T.;
Mazomenos, B. E.; Konstantopoulou, M. A.; Kitching, W.;
De Voss, J. J. Org. Lett. 2005, 7, 1173.
(6) Ito, M.; Osaku, A.; Shiibashi, A.; Ikariya, T. Org. Lett. 2007,
9, 1821.
(7) Colonge, J.; Jeltsch, P. Bull. Soc. Chim. Fr. 1963, 6, 1296.
(8) Green, T. W.; Wutts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
Anal. Calcd for C8H18O3·0.5 H2O: C, 56.11; H, 11.18. Found: C,
56.05; H, 10.95.
4-(tert-Butyldimethylsiloxy)heptane-1,7-dial (13)
To a stirred solution of diol 11a (1.0 g, 3.8 mmol) in anhydrous
CH2Cl2 (25 mL), Dess–Martin periodinane (3.55 g, 8.36 mmol) was
added slowly at 0 °C. The mixture was allowed to warm to r.t. and
then it was stirred until the diol was no longer observed by TLC.
Sat. NaHCO3 (20 mL) was added at 0 °C and a white suspension
was formed. The suspension was then filtered and the organic layer
was dried (anhydrous Na2SO4). The mixture was filtered and con-
centrated under reduce pressure, and the residue was purified by
flash chromatography (10% EtOAc–hexane) to furnish 13 (0.78 g,
80%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 9.78 (s, 2 H), 3.78 (p, J = 5.2 Hz,
1 H), 2.50 (t, J = 7.2 Hz, 4 H), 1.75–1.67 (m, 4 H), 0.87 (s, 9 H),
0.04 (s, 6 H)
© Georg Thieme Verlag Stuttgart · New York
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2286
K. K. Thota, M. L. Trudell
PAPER
(11) For a review of hydroboration chemistry see: Smith, K.;
(9) (a) Nicolai, S.; Waser, J. Org. Lett. 2011, 13, 6324.
(b) Brown, H. C.; Negishi, E.; Dickason, W. C. J. Org.
Chem. 1985, 50, 520.
(10) (a) Chiruta, C.; Jachak, S.; Clive, D. L. J. Tetrahedron Lett.
2007, 48, 3141. (b) Iseki, K.; Mizuno, S.; Kuroki, Y.;
Kobayashi, Y. Tetrahedron 1999, 55, 977.
Pelter, A. In Comprehensive Organic Synthesis; Vol. 8;
Trost, B. M.; Flemming, I., Eds.; Pergamon: Oxford, 1991,
703–732.
(12) Drescher, S.; Meister, A.; Blume, A.; Karlsson, G.; Algren,
M.; Dobner, B. Chem. Eur. J. 2008, 14, 6796.
Synthesis 2013, 45, 2280–2286
© Georg Thieme Verlag Stuttgart · New York