A short synthesis of (S)-(+)-siphonodiol

Article abstract of DOI:10.1016/j.tetasy.2007.05.034

A short synthesis of the enantiomer of the polyacetylenic natural product siphonodiol is described. The synthesis is based on the strategy of taking advantage of the hidden symmetry of the target molecule and minimizing the use of protecting groups, thereby reducing the total number of steps and increasing the overall efficiency.

Full text of DOI:10.1016/j.tetasy.2007.05.034

Tetrahedron: Asymmetry 18 (2007) 1284–1287
A short synthesis of (S)-(+)-siphonodiol
Benjamin W. Gung,* Derek T. Craft and Jessica Truelove
Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA
Received 24 March 2007; revised 15 May 2007; accepted 24 May 2007
Abstract—A short synthesis of the enantiomer of the polyacetylenic natural product siphonodiol is described. The synthesis is based on
the strategy of taking advantage of the hidden symmetry of the target molecule and minimizing the use of protecting groups, thereby
reducing the total number of steps and increasing the overall efficiency.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the symmetry of the structure, which can be applied to
any total synthesis.13 This is especially important for poly-
acetylenic compounds because each extra step means a
large difference in overall yield. Fewer steps can be
achieved if molecular symmetry is used advantageously.
The second consideration was to limit the use of functional
protecting groups. For each protecting group employed,
two additional synthetic steps are generally required.
Therefore, to minimize the synthetic operations, use of pro-
tecting groups needs to be minimized. With these consider-
ations, our retro-synthesis lead to three fragments as shown
in Figure 2. Both fragments 2 and 3 are symmetrical and
the coupling reaction applied to these compounds needs
not be at one specific terminal. Therefore, one needs only
to control the equivalency of the coupling partner and
the operational details of addition, but it is not necessary
to use a protecting group.
Siphonodiol (Fig. 1) was isolated from the marine sponge
Siphonochalina truncata in the gulf of Suruga.1,2 Similar
to other polyacetylenic natural products, a variety of bio-
logical activities have been reported for siphonodiol. The
first total synthesis of the natural siphonodiol was reported
in 2005.3 Herein we report a short synthesis of its enantio-
mer, (S)-(+)-siphonodiol.
OH
OH
SiMe3
Figure 1. The structure of (À)-siphonodiol
truncata.
1 from Siphonochalina
2. Results and discussion
Br
O
Recently, we completed the total syntheses of several poly-
acetylenic natural products including adociacetylene, min-
quartynoic acids, and bidensyneosides.4–10 As previously
reported,11,12 polyacetylenic compounds are sensitive to
light and air and in general are very reactive in Nature.
In order to obtain these natural products efficiently, we
have developed some general strategies for our synthetic
effort. The first consideration was to take advantage of
O
SiMe3
2
3
4
Figure 2. Retrosynthetic analysis: components needed for the synthesis of
siphonodiol.
Compound 2 was recently reported by Lopez et al. in their
work related to the synthesis of callyberynes.14 Compound
3 is commercially available. Compound 4 is one of the
*
Corresponding author. E-mail: gungbw@muohio.edu
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.034

B. W. Gung et al. / Tetrahedron: Asymmetry 18 (2007) 1284–1287
1285
Br
O
O
(S)-4
O
+ bis-coupling product
(see expt.)
CuI, piperidine,
O
3
5
°
0 C
5%
52%
p-TsOH
NBS, AgNO3
Br
°
MeOH, 50 C, 21h
Acetone, 2h
90%
OH
OH
OH
7
6
97%
OH
TMS
1. TBAF, THF, 1h
2. CuCl, NH2OH-HCl
7, EtNH2, MeOH
OH
OH
48%
TMS
(+)-1
2
Scheme 1.
frequently observed functional group motifs in polyacety-
lenic natural products.15 We have developed a synthesis
of this useful building block starting from 2,3-isopropylid-
ene–glyceraldehyde, which involved the formation of a
dibromoolefin intermediate followed by the elimination
of 1 M amount of HBr.15 Since D-mannitol is less expensive
than L-mannitol, as a study for proof of the concept, we
employed the readily available enantiomer of 4 in this short
synthesis of (S)-(+)-siphonodiol.
the enantiomer of the natural siphonodiol. It was reported
that natural siphonodiol was highly unstable.2 In our
hands, (S)-1 survived silica gel column chromatographic
separation and a postal trip to a mass spectrometry facility.
Overnight 13C NMR data collection did not show any
change in peak appearance. This is consistent with our pre-
vious experience related to polyacetylenic natural products,
that is, they are fairly stable once the structure is com-
pletely assembled and purified. On the other hand, poly-
acetylenic intermediates with terminal diyne or triynes are
extremely unstable.
Starting from the commercially available diyne 3, a cop-
per(I) catalyzed coupling with bromoalkyne (S)-415 affor-
ded the desired diyne 5 along with 5% of the bis-coupling
by-product (Scheme 1).16 Although the concurrent produc-
tion of the bis-coupling product reduced the yield of the
desired product, the separation was straightforward. In
practice it was more efficient than conducting the coupling
with a one-end protected diyne followed by deprotection.
3. Conclusion
In conclusion, by adopting a strategy to minimize the use
of protecting groups and by taking advantage of the hidden
symmetry of the target molecule we have completed a short
synthesis of the enantiomer of the natural product siphono-
diol. This synthesis took only four linear steps and afforded
the (+)-siphonodiol in 22% overall yield. Currently we are
planning to use this general strategy to the total synthesis
of more challenging natural products.
The terminal alkyne was converted to bromoalkyne after
removal of the acetonide protecting group for the diol.17
The final step involved a one-pot deprotection-cross cou-
pling operation. The symmetrical alkyne 2 was treated with
2.2 equiv of tetrabutylammonium fluoride in THF for 1 h,
followed by the addition of bromoalkyne 7. The slow addi-
tion of 1 equiv of 7 over 1 h led to a coupling reaction at
only one-end of alkyne 2 despite the TMS groups at both
terminals being removed. The cross coupling was under
the classical Cadiot–Chodkiewicz conditions yielding the
enantiomer of the natural siphonodiol in 48% (unoptim-
ized). A small amount of the additional, more polar mate-
rial was shown on TLC, which presumably was the bis
coupling product, but was not characterized. We believe
a better yield is possible for this final coupling reaction
through optimization. The spectroscopic data of the major
product obtained through this synthesis are consistent with
4. Experimental
4.1. General
All reactions were carried out under an atmosphere of
nitrogen in oven-dried glassware with magnetic stirring.
Reagents were purchased from commercial sources and
used directly without further purification. Methylene chlo-
ride was dried over P2O5 and freshly distilled before use.
Purification of the reaction products was carried out by
flash chromatography using silica gel 40–63 lm (230–

1286
B. W. Gung et al. / Tetrahedron: Asymmetry 18 (2007) 1284–1287
400 mesh) unless otherwise stated. Reactions were moni-
tored by 1H NMR and/or thin-layer chromatography.
Visualization was accomplished with UV light, staining
with 5% KMnO4 solution followed by heating or with
p-anisaldehyde in EtOH solution. Chemical shifts were
recorded in ppm (d) using tetramethylsilane (H, C) as the
internal reference. Data are reported as (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet; inte-
gration; coupling constant(s) in Hz). Optical rotations were
measured using Autopol III. Melting points were measured
with a Gallenkamp melting point apparatus. Infrared spec-
tra were recorded on a Perkin–Elmer 1600 series FTIR for
liquids and on a Perkin–Elmer Spectrum 2000 FTIR for
solids. High-resolution mass spectra were recorded at the
Ohio State University.
17.8, 18.5, 26.1, 26.3, 27.3, 65.3, 66.0, 69.7, 69.9, 70.7,
73.7, 80.9, 83.1, 110.8. HRMS calcd for C23H24O2 + Na,
355.1674; found, 355.1676. (2S,14S)-1,2,14,15-Diisopropyl-
idene-3,5,10,12-Pentadecatetrayne 5a: [a]D = +59.8 (c
1
0.016, CHCl3). H NMR (300 MHz, CDCl3): d 1.33 (6H,
s), 1.46 (6H, s), 1.65–1.77 (2H, m), 2.36–2.41 (4H, t,
J = 6.9), 3.92 (2H, m), 4.10 (2H, m), 4.72 (2H, m). 13C
NMR (75 MHz, CDCl3): d 18.7, 26.1, 26.9, 65.6, 66.1,
70.0, 73.8, 77.9, 80.6, 110.9. HRMS calcd for
C21H24O4 + Na, 363.1572; found, 363.1572.
4.4. (2S)-Undeca-3,5,10-triyne-1,2-diol 6
In a 100 ml round bottomed flask under an atmosphere
of nitrogen with magnetic stirring were added 24 ml
of MeOH, (2S)-1,2-isopropylidene-3,5,10-undecatriyne
(261 mg, 1.2 mmol), and p-toluenesulfonic acid (23 mg,
0.12 mmol). The flask was equipped with a condenser
and heated to 50 ꢁC. The reaction mixture was allowed to
stir at this temperature for 21 h after which TLC indicated
that the reaction was complete. NaHCO3 (200 mg,
2.4 mmol) was then added and the mixture stirred for
15 min. The solids were removed by filtration and the sol-
vent was removed under reduced pressure. The residue was
purified over silica gel (40–50% EtOAc/Hex) to afford
206 mg (97%) of a white solid. [a]D = +41.4 (c 0.06,
4.2. (S)-(+)-3,4-O-Isopropylidene-1-bromobut-1-yn-3,4-diol
4
In a 200 ml round bottomed flask under an atmosphere of
nitrogen, (3S)-3,4-O-isopropylidene-1,1-dibromobut-1-en-
3,4-diol 818 (3.5 g, 12.3 mmol) was added in 120 ml of dry
THF. The solution was cooled to À100 ꢁC and NaHMDS
(1 M, 14.7 ml, 14.7 mmol) was added dropwise via a syr-
inge. After 1 h, TLC indicated that the starting material
had all disappeared. The reaction was diluted with 100 ml
of ether and washed twice with saturated NH4Cl solution.
The aqueous layer was extracted with ether and the com-
bined organic layers were washed with brine, dried over
MgSO4, and the solvent was removed under reduced pres-
sure. The residue was purified over silica gel (2–5% EtOAc/
1
CHCl3). Mp = 59–61 ꢁC. H NMR (300 MHz, CDCl3): d
1.75 (2H, m), 1.97 (1H, t, J = 2.6 Hz), 2.28 (2H, m) 2.40
(2H, t, J = 7.0 Hz), 3.64 (2H, m), 4.4–4.5 (1H, m). 13C
NMR (75 MHz, CDCl3): d 17.4, 18.2, 26.9, 63.3, 64.7,
66.2, 69.3, 70.8, 73.6, 80.7, 82.9.
Hex) to provide 2.17 g (86%) of
a colorless oil.
[a]D = +36.1 (c 0.10, CHCl3), [a]D = +29.9 (c 0.10,
MeOH). H NMR (200 MHz, CDCl3): d 1.4 (3H, s), 1.5
1
4.5. (2S)-11-Bromo-undeca-3,5,10-triyne-1,2-diol
(3H, s), 3.9 (1H, dd, J = 6.1, 4.3 Hz), 4.1 (1H, dd,
J = 6.4, 1.7 Hz), 4.7 (1H, dd, J = 4.5, 1.6 Hz). 13C NMR
(75 MHz, CDCl3): d 110.4, 79.0, 69.9, 66.4, 46.1, 26.1,
25.6. IR (film) 2900, 2253, 1253, 1096.
To
a
solution of (2S)-undeca-3,5,10-triyne-1,2-diol
(139 mg, 0.79 mmol) in 6.6 ml of acetone was added
AgNO3 (27 mg, 0.16 mmol) followed by NBS (170 mg,
0.95 mmol). After stirring at rt for 2 h, TLC indicated that
the starting material had been consumed. The reaction
mixture was diluted with ether (15 ml) and water (15 ml).
The aqueous layer was extracted with ether (3 · 15 ml)
and the combined organic layers were washed with brine.
The solution was dried over MgSO4 and the solvent re-
moved under reduced pressure. The residue was purified
over silica gel (40% EtOAc/Hex) to yield 178 mg (90%)
4.3. (2S)-1,2-Isopropylidene-3,5,10-undecatriyne 5
In a 50 ml round bottomed flask under an atmosphere of
N2 with magnetic stirring was added piperidine (15 ml),
1,6-heptadiyne (570 mg, 6.20 mmol), and CuI (71 mg,
0.37 mmol). The mixture was cooled to 0 ꢁC using an ice
bath and (2S)-4-bromo-1,2-isopropylidene-3-butyne (310
mg, 1.55 mmol) was then added via a syringe over a period
of 1 h. The reaction was allowed to stir for 2 h at 0 ꢁC and
TLC indicated that the reaction was complete. A saturated
solution of NH4Cl (10 ml) was then added under vigorous
stirring. The mixture was extracted with CH2Cl2
(3 · 15 ml). The combined organic layers were washed with
brine and dried over MgSO4. The solvent was removed un-
der reduced pressure and the residue purified over silica gel
(5–10% EtOAc/Hex) to afford 174 mg (52%) of a colorless
oil 5, and 26 mg (5%) of a colorless oil 5a. (2S)-1,2-Isoprop-
ylidene-3,5,10-undecatriyne 5: [a]D = +58.3 (c 0.04,
CHCl3). 1H NMR (200 MHz, CDCl3): d 1.40 (3H, s),
1.52 (3H, s), 1.80 (2H, m), 2.01 (1H, t, J = 2.6 Hz), 2.31
(2H, dt, J = 2.6, 6.8 Hz), 2.39 (2H, t, J = 6.8 Hz), 3.93
(1H, dd, J = 8.1, 6.1 Hz), 4.13 (1H, dd, J = 8.1, 6.3 Hz),
4.79 (1H, t, J = 6.2 Hz). 13C NMR (75 MHz, CDCl3): d
of
a white solid. [a]D = +24.0 (c 0.009, CHCl3).
Mp = 61–62 ꢁC. 1H NMR (300 MHz, CDCl3): d 1.76
(2H, m), 2.29–2.46 (4H, m), 3.67–3.81 (2H, m), 4.49–4.54
(1H, m). 13C NMR (75 MHz, CDCl3): d 18.7, 19.1, 27.1,
64.0, 65.3, 66.6, 71.4, 73.8, 77.6, 79.1, 81.1. HRMS calcd
for C11H11BrO2 + Na, 276.9840; found, 276.9836.
4.6. (S)-(+)-Siphonodiol
In a 25 ml round bottomed flask under an atmosphere of
N2 were added 1 ml of THF and (3Z,9Z)-1,12-bis(trimeth-
ylsilyl)dodeca-3,9-diene-1,11-diyne (200 mg, 0.66 mmol).
TBAF (1.45 ml, 1.45 mmol, 1 M in THF) was then added
dropwise at rt via syringe. The solution was stirred for
1 h after which TLC indicated that the starting material
had been consumed. The reaction mixture was then cooled

B. W. Gung et al. / Tetrahedron: Asymmetry 18 (2007) 1284–1287
1287
to 0 ꢁC and 2.2 ml of MeOH and 2.2 ml of a 70% aqueous
References
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0.03 mmol) and NH2OH–HCl (2 mg, 0.03 mmol) were
added and the reaction was stirred for 10 min. (2S)-11-Bro-
mo-undeca-3,5,10-triyne-1,2-diol (167 mg, 0.66 mmol) in
THF (1.5 ml) was then added via syringe over a period of
1 h. The reaction mixture was stirred for 3 h and then di-
luted with ether (10 ml) and quenched with a saturated
solution of NH4Cl (15 ml). The aqueous layer was ex-
tracted with ether (3 · 15 ml). The combined organic layers
were washed with brine, dried over MgSO4, and the solvent
removed under reduced pressure. The residue was purified
over silica gel (60% EtOAc/Hex) to afford 105 mg (48%) of
a yellow oil. [a]D = +6.5 (c 0.004, MeOH). 1H NMR
(300 MHz, CDCl3): d 1.4–1.59 (4H, m), 1.74–1.81 (2H,
m), 2.31–2.47 (8H, m), 2.92 (1H, br s), 3.09 (1H, d,
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m), 5.44–5.49 (2H, m), 6.0–6.09 (2H, m). 13C NMR
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Acknowledgments
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