Enantioselective total synthesis of (R)-strongylodiols A and B

Article abstract of DOI:10.1016/S0040-4020(03)00905-0

We describe an expeditious enantioselective total synthesis of the acetylenic marine natural products (R)-strongylodiols A and B. Central to the strategy is the use of Zn(OTf)₂, amine base, and N-methyl ephedrine to mediate the direct addition of a 1,3-diyne to two long-chain aliphatic aldehydes in useful selectivities and yields.

Full text of DOI:10.1016/S0040-4020(03)00905-0

Tetrahedron 59 (2003) 6813–6817
Enantioselective total synthesis of (R)-strongylodiols A and B
*
¨
Stefan Reber, Thomas F. Knopfel and Erick M. Carreira
¨ ¨ ¨
Laboratorium fur Organische Chemie, ETH-Honggerberg HCI H337, CH-8093 Zurich, Switzerland
Received 30 January 2003; revised 3 June 2003; accepted 3 June 2003
Abstract—We describe an expeditious enantioselective total synthesis of the acetylenic marine natural products (R)-strongylodiols A and B.
Central to the strategy is the use of Zn(OTf)2, amine base, and N-methyl ephedrine to mediate the direct addition of a 1,3-diyne to two long-
chain aliphatic aldehydes in useful selectivities and yields.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
noting that the fact that the reaction can be conducted under a
wide range of concentrations and catalyst loadings is a key
advantage of the process, as it permits optimization of the
reaction conditions for a wide range of substrates.
The in situ activation of hydrocarbons to give reactive
intermediates that can participate in useful C–C bond
forming reactions is an important area of investigation in
chemical synthesis. In this respect, we have recently
developed and studied reaction methodology that effects
the activation and nucleophilic addition reaction of one of the
simplest class of hydrocarbons, namely, terminal acetylenes.
We have documented that a wide range of terminal
acetylenes can undergo metallation when exposed to Zn(II)
and amine base.1,2 The putative metallation reaction occurs
at ambient temperature and yields a metal acetylide that
participates in aldehyde and nitrone addition reactions
(Scheme 1). Remarkably, the metallation/deprotonation
reaction is not adversely affected when amino alcohol
ligands are present, indeed, the presence of amino alcohols
leads to a ligand-accelerated process. When the amino
alcohol is optically active, enantioenriched products can be
generated in the aldehyde addition reactions. We have
demonstrated that the reaction can be executed not only with
stoichiometric quantities of Zn(II), base and ligand but also,
more recently, with catalytic amounts of each.1j It is worth
As part of our ongoing studies to expand the scope of the
process with aldehydes, we have been involved in the study
and use of reactions with unusual acetylenes as reaction
partners. In this respect, we have been interested in
examining whether conjugated 1,3-diynes could be utilized
in the transformation.
For any acetylene to be successfully employed in addition
reactions two key criteria must be met: (1) the terminal
alkyne must participate in the activation/deprotonation
sequence involving Zn(II), and (2) the metal alkynylide
must be sufficient reactive in nucleophilic additions to the
desired electrophiles vis a vis competing side-reactions such
as oligomerization.
The combined efforts of groups in Japan and The
Netherlands in the search for biologically active compounds
from marine invertebrates has led to the isolation and
characterization of new long-chain acetylenic alcohols
named strongylodiols A, B, and C (Fig. 1).3 Although a
number of propargylic alcohols had been isolated
previously, they have been found mostly in racemic form.
In this respect, the fact that the strongylodiols were isolated
from the sponge genus Strongylophora in non-racemic form
represents an unusual case. In addition to the interesting
taxonomic implications suggested by these compounds,
they were also determined to possess activity against tumor
cell lines (DLD-1 and MOLT-4). Because related acetylenic
compounds isolated from other sponges also possess
interesting biological activity, the investigation of general
synthetic routes that provide access to a large range of
related structures is certainly warranted. Indeed, a synthesis
Scheme 1.
Keywords: strongylodiol; hydrocarbon; metallation.
*
Corresponding author. Tel.: þ41-1-632-2830; fax: þ41-1-632-1328;
e-mail: carreira@org.chem.ethz.ch
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00905-0

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S. Reber et al. / Tetrahedron 59 (2003) 6813–6817
equivalent of BuLi in THF/HMPA was exposed to 9, the
alcohol 11 was isolated in 65% yield. Interestingly, the use
of protected forms of 9, such as the corresponding O-SiMe3
or O-THP analogs, gave considerably poorer results, with
the former proving unreactive and the latter affording
product, albeit in only 31% yield. Oxidation of 11 furnished
aldehyde 12 which was used in the synthesis of strongyldiol
B. Alternatively, semihydrogenation of 11 gives a cis alkene
which following oxidation provided aldehyde 13, which
was used in the synthesis of strongylodiol A (Scheme 3).
With both aldehydes 12 and 13 in hand, the stage was set for
examination of the key diyne addition reaction and
completion of the syntheses. Although the addition reaction
required some experimentation in order to identify optimal
conditions, we subsequently observed that the use of excess
Zn(II), ligand, and Et3N (4 equiv. each) and slow addition of
the aldehyde successfully provided adducts 14 and 15 in
68% yield/80% ee and 62% yield/82% ee, respectively
Figure 1.
of strongylodiol A relying on the Sharpless asymmetric
epoxidation reaction of allylic alcohol precursor has been
reported.4 Herein we document the successful use a 1,3-
diyne in the addition reactions to two aldehydes, leading to
facile synthesis of strongylodiols A and B.
2. Results and discussion
Our interest in developing efficient strategies towards the
strongylodiols provided us a unique opportunity to examine
the question of whether 1,3-diynes would participate in
Zn(II)-mediated activation and enantioselective aldehyde
addition reactions. At the outset of our investigations, it was
not clear whether such conjugated 1,3-dinynes would be
suitable substrates, as such diynes and the corresponding
metallated counterparts are known to be susceptible to
decomposition through oligomerization.
Scheme 3.
Our studies commenced with 1,4-dihydroxy-2-butyne,
which is an inexpensive commodity readily converted to
the corresponding 1,4-dichlorobutyne 4 upon treatment with
thionyl chloride in pyridine.5 The transformation of this
dichloride into protected silyl ether 7 is conveniently
effected upon exposure of 4 to 3 equiv. of NaNH2 and
trapping of the putative acetylide 5 with formaldehyde to
afford 6,6 which is in turn without purification protected
(TBDMSCl, imidazole), leading to 7 in 39% yield over
three steps (Scheme 2).
The synthesis of the long-chain hydrocarbon portion of
strongylodiols A and B commences with decanediol 8.
Conversion of 8 to hydroxy bromide 9 was carried out by
treatment of 8 with HBr in refluxing benzene for 28 h.7
When a solution of lithiated 1-decyne (10) containing an
Scheme 4.
Scheme 2.
Scheme 5.

S. Reber et al. / Tetrahedron 59 (2003) 6813–6817
6815
(Schemes 4 and 5). The enantioselectivity of the addition
reactions in each case was assayed by Mosher’s method.8
The syntheses of strongylodiols A and B were brought to
completion upon desilylation of 14 and 15 with TBAF,
affording (R)-strongylodiol B (2) and (R)-strongylodiol A
(1) in 90 and 85% yields, respectively.
soln (100 ml). The layers were separated and the water
phase was extracted with CH2Cl2 (2£100 ml). The com-
bined organic layers were washed with brine (50 ml) and
dried over Na2SO4. Evaporation of the solvent in vacuo and
FC (silicagel 150 g, hexanes); gave 2.3 g (39% from 4) of 7
1
as a pale yellow oil, which was stored at 48C. H NMR
(300 MHz, CDCl3) d 0.05 (s, 6H), 0.95 (s, 9H), 2.18 (s, 1H),
4.40 (s, 2H). 13C NMR (75 MHz, CDCl3) d 20.5 (CH3),
18.3 (C), 25.8 (CH3), 51.9 (CH2), 67.6 (CH), 67.8 (C),
69.0 (C), 75.0 (C). FT-IR (thin film, cm21): 3310 (m), 2957
(s), 2931 (s), 2859 (s), 2712 (w), 2066 (w), 1772 (m),
1366 (m), 1258 (s), 1140 (s), 1087 (s), 1006 (m), 939 (w),
837 (s).
We have described a simple procedure for the preparation
of alk-2,4-yne-1,6-diols that is convenient and operation-
ally simple. Given the fact that the strongylodiols have
been shown to possess antineoplastic activity, ready
access to these and related compounds provides avenues
for investigations. Moreover, the 1,6-diols that are
isolated can serve as useful building blocks for the
synthesis of value-added materials. Additional studies are
in progress and results will be reported as they become
available.
3.1.3. Icos-11-yn-1-ol (11).10 A well stirred solution of 10
(100 mg; 0.73 mmol) in THF (2 ml) at 2788C was treated
dropwise with BuLi (0.90 ml of 1.6 M solution in hexanes;
1.5 mmol). After 30 min 9 (170 mg; 0.720 mmol) in THF/
HMPA (1 ml; 4:1) was added. After 2 h at 2788C and 16 h
at 238C the reaction was quenched with sat. aq. NH4Cl soln
(3 ml). The mixture was extracted with ether (3£10 ml).
The combined organic layers were washed with brine
(10 ml), dried over Na2SO4 and concentrated in vacuo. FC
(20 g silicagel; hexanes–EtOAc¼20:1) gave 140 mg (65%)
of 11 as a colorless oil. 1H NMR (300 MHz, CDCl3) d 0.87
(t, 3H, J¼6.9 Hz), 1.20–1.60 (m, 30H), 2.10 (t, 4H,
J¼6.9 Hz), 3.60 (t, 2H, J¼6.9 Hz). 13C NMR (75 MHz,
CDCl3) d 14.2 (CH3), 18.8 (CH2), 22.7 (CH2), 25.8 (CH2),
28.9 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2),
29.6 (CH2), 29.6 (CH2), 29.7 (CH2), 29.7 (CH2), 31.9 (CH2),
32.0 (CH2), 32.9 (CH2), 63.0 (CH2), 80.2 (C), 80.2 (C).
Mass spectroscopy (EI): calculated for C20H38O (M)þ
294.29, found 294.30.
3. Experimental
3.1. General
All reactions were performed using oven-dried glassware
under an atmosphere of dry nitrogen. Toluene was distilled
and dried before use. Reagents were purchased from Fluka,
Aldrich or ACROS chemical companies, and used without
further purification except aldehydes which were distilled
before use. Chromatographic purification of products was
accomplished using forced flow chromatography on silica
gel 60. NMR spectra were recorded on a Varian Mercury
300 operating at 300 and 75.5 MHz for 1H and 13C,
respectively, and referenced to the internal solvent signals.
IR spectra were recorded on a Perkin–Elmer Spectrum RX I
FT-IR spectrometer as thin film unless otherwise noted.
Optical rotations were measured on a JASCO DID-1000
digital polarimeter. Thin layer chromatography was per-
formed using silica gel 60 F254 TLC plates and visualized
either with ultraviolet light or stain with CAM-Stain. Mass
spectra were carried out by the Massenspecktroskopie
service of the Laboratorium fu¨r Organische Chemie at
ETH, Zu¨rich.
3.1.4. Icos-11-ynal (12).9 A solution of oxalyl chloride
(100 mg; 0.788 mmol) in CH2Cl2 at 2788C was treated
dropwise with DMSO (112 ml; 1.58 mmol) and (11)
(120 mg; 0.408 mmol). After 15 min at 2788C Et3N
(300 ml; 2.31 mmol) was added. The reaction was allowed
to warm up at 238C and quenched after 3 h with sat. aq.
NH4Cl soln (3 ml). The water phase was extracted with
ether (3£10 ml). The combined organic layers were dried
over Na2SO4 and concentrated in vacuo. FC (20 g silicagel;
hexanes–EtOAc¼6:1) afforded 105 mg (90%) of the
aldehyde 12 as a colorless oil. 1H NMR (300 MHz,
CDCl3) d 0.84 (t, 3H, J¼6.9 Hz), 1.20–1.54 (m, 24H),
1.56–1.68 (m, 2H), 2.14 (t, 4H, J¼6.9 Hz), 2.40 (dt, 2H,
J1¼1.8 Hz, J2¼7.4 Hz), 9.80 (t, 1H, J¼1.8 Hz). 13C NMR
(75 MHz, CDCl3) d 14.1 (CH3), 18.8 (CH2), 22.2 (CH2),
22.8 (CH2), 28.9 (CH2), 28.9 (CH2), 29.1 (CH2), 29.2 (CH2),
29.3 (CH2), 29.4 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2),
29.7 (CH2), 31.7 (CH2), 31.9 (CH2), 32.0 (CH2), 44.0 (CH2),
80.1 (C), 80.2 (C), 202.0 (C). FT-IR (thin film, cm21): 2928
(s), 2855 (m), 2713 (w), 1728 (m), 1466 (w). Mass
spectroscopy (EI): calculated for C20H36O (M)þ 292.28,
found 292.30.
3.1.1. Penta-2,4-diyn-1-ol (6). A vigorously stirred sus-
pension of NaNH2 (3.5 g; 90 mmol) in liquid ammonia (ca.
70 ml) at 2788C was treated dropwise with 1,4-dihydroxy-
2-butyne (4) (3.7 g, 30 mmol). Subsequently, a suspension
of paraformaldehyde (0.90 g; 29.9 mmol; dried over P2O5)
in ether (5 ml) was added in one portion. After 3 h the dark
reaction mixture was quenched with ammonium chloride
(4 g). The ammonia was allowed to evaporate. Then the
residue was extracted with portions of CH2Cl2 until the
extracts were colorless. The combined extracts were washed
with brine and dried over Na2SO4. Since 6 is known to be
unstable,11 it was used without further purification. 1H NMR
(300 MHz, CDCl3) d 1.91 (s br, 1H), 2.20 (s, 1H), 4.30 (s,
3H).
3.1.5. (6R)-1-(tert-Butyldimethylsilanyloxy)pentacosa-
2,4,16-triyn-6-ol (14).
(360 mg; 0.990 mmol), (þ)-N-methylephedrine (180 mg;
1.00 mmol) and Et3N (100 mg; 0.988 mmol) in toluene
(2 ml) at 238C was stirred vigorously for 2 h. Then, 7
(49 mg; 0.25 mmol) was added. After 15 min, 12 (73 mg;
A
suspension of Zn(OTf)2
3.1.2. 1-(tert-Butyldimethylsilanyloxy)penta-2,4-diyne
(7). A solution of crude 6 (3.12 g; 38.9 mmol) in CH2Cl2
at 238C was treated with TBSCl (7.14 g; 47.4 mmol) and
imidazole (4.09 g; 60.2 mmol). After ca. 30 min the
resulting suspension was quenched with sat. aq. NH4Cl

6816
S. Reber et al. / Tetrahedron 59 (2003) 6813–6817
0.25 mmol) in toluene (1 ml) was added over 4 h with a
syringe pump. After additional 16 h the reaction was
quenched with sat. aq. NH4Cl soln (3 ml). The mixture
was diluted with ether (10 ml). The water phase was
extracted with ether (3£10 ml). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo.
FC (20 g silicagel; hexanes–EtOAc¼20:1) afforded 83 mg
(68%) of 14. ee: 80 % as determined by 19F NMR analysis
of the corresponding Mosher ester: d 271.54 (minor),
722 (m). Mass spectroscopy (EI): calculated for C20H40O
(M)þ 296.31, found 296.27.
3.1.8. Icos-11-enal (13).9 A solution of oxalylchloride
(100 mg; 0.788 mmol) in CH2Cl2 at 2788C was treated
dropwise with DMSO (112 ml; 1.58 mmol) and 16 (102 mg;
0.346 mmol). After 15 min at 2788C Et3N (300 ml;
2.31 mmol) was added. The reaction was allowed to warm
up at 238C and quenched after 3 h with sat. aq. NH4Cl soln
(3 ml). The water phase was extracted with ether (3£10 ml).
The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. FC (20 g silicagel; hexanes–
EtOAc¼6:1) afforded 94 mg (92 %) of the aldehyde 13 as
1
271.83 (major). [a]D24¼23.89 (c¼1.24, CHCl3). H NMR
(300 MHz, CDCl3) d 0.12 (s, 6H), 0.84–0.95 (m, 12H),
1.23–1.51 (m, 26H), 1.66–1.76 (m, 2H), 1.86 (s, br, 1H),
2.10–2.18 (m, 4H), 4.38–4.42 (m, 3H). 13C NMR (75 MHz,
CDCl3) d 25.1 (CH3), 14.2 (CH3), 18.4 (C), 18.9 (CH2),
22.8 (CH2), 25.1 (CH2), 25.8 (CH3), 27.7 (CH2), 28.9 (CH2),
29.0 (CH2), 29.2 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2),
29.7 (CH2), 31.9 (CH2), 32.0 (CH2), 37.6 (CH2), 52.1 (CH2),
62.9 (CH), 68.8 (C), 69.1 (C), 78.2 (C), 79.8 (C), 80.2 (C).
FT-IR (thin film, cm21): 3418 (w, br), 2926 (s), 2855 (m),
1464 (w), 1363 (w), 1255 (w), 1091 (m), 836 (m), 778 (w).
Mass spectroscopy (HRMS, MALDI): calculated for
C31H54O2Si (MþNa)þ 509.3791, found 509.3796.
1
a colorless oil. H NMR (300 MHz, CDCl3) d 0.84 (t, 3H,
J¼3.9 Hz), 1.20–1.39 (m, 24H), 1.56–1.68 (m, 2H), 2.14
(m, 4H), 2.40 (dt, 2H, J1¼1.9 Hz, J2¼7.4 Hz), 5.35 (m, 2H),
9.8 (t, 1H, J¼1.9 Hz). 13C NMR (75 MHz, CDCl3) d 14.3
(CH3), 22.2 (CH2), 22.8 (CH2), 27.3 (CH2), 27.3 (CH2), 29.3
(CH2), 29.4 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6
(CH2), 29.9 (CH2), 32.0 (CH2), 44.0 (CH2), 129.7 (CH),
129.9 (CH), 202.7 (C). FT-IR (thin film, cm21): 3300 (s, br),
2924 (s), 2848 (s), 1462 (m), 1354 (w), 1320 (w), 1064 (m),
1030 (m), 964 (w), 726 (w), 1122 (w), 959 (w). Mass
spectroscopy (EI): calculated for C20H38O (M)þ 294.29,
found 294.24.
3.1.6. (6R)-Pentacosa-2,4,16-triyne-1,6-diol (strongylo-
diol B) (2). A solution of 14 (50 mg; 0.10 mmol) in THF
(2 ml) at 238C was treated with TBAF (0.12 ml; 1.0 M soln
in THF; 0.12 mmol). After 20 min the reaction was
quenched with sat. aq. NH4Cl soln (5 ml). The mixture
was diluted with ether (10 ml). The water phase was
extracted with ether (3£10 ml). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo.
FC (20 g silicagel; hexanes–EtOAc¼4:1) afforded 34 mg
(90 %) of 2 as a white solid. [a]2D4¼26.2 (c¼0.42, CHCl3),
lit.: 27.1 (c¼0.42, CHCl3)3. 1H NMR (300 MHz, CDCl3) d
0.88 (t, 3H, J¼6.9 Hz), 1.21–1.51 (m, 26H), 1.66–1.76 (m,
2H), 2.14 (t, 4H, J¼6.9 Hz), 4.39 (s, 2H), 4.41 (t, 1H,
J¼6.9 Hz). 13C NMR (75 MHz, CDCl3) d 14.2 (CH3), 18.5
(CH2), 22.8 (CH2), 25.1 (CH2), 28.9 (CH2), 29.0 (CH2), 29.2
(CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (CH2), 29.7
(CH2), 31.9 (CH2), 32.0 (CH2), 37.5 (CH2), 51.5 (CH2), 62.8
(CH), 68.8 (C), 69.8 (C), 80.2 (C), 80.5 (C). FT-IR (thin
film, cm21): 3299 (w, br), 2927 (m), 2849 (s), 1354 (w),
1320 (w), 1030 (w). Mass spectroscopy (HRMS, MALDI):
calculated for C25H40O2 (MþNa)þ 395.2926, found
395.2923. Mp 498C.
3.1.9. (6R)-1-(tert-Butyldimethylsilanyloxy)pentacos-16-
ene-2,4-diyn-6-ol (15). A suspension of Zn(OTf)2 (360 mg;
0.990 mmol), (þ)-N-methylephedrine (180 mg; 1.00 mmol)
and Et3N (100 mg; 0.988 mmol) in toluene (2 ml) at 238C
was stirred vigorously for 2 h. Then, 7 (49 mg; 0.25 mmol)
was added. After 15 min, 13 (74 mg; 0.25 mmol) in toluene
(1 ml) was added over 4 h with a syringe pump. After
additional 16 h the reaction was quenched with sat. aq.
NH4Cl soln (3 ml). The mixture was diluted with ether
(10 ml). The water phase was extracted with ether
(3£10 ml). The combined organic layers were dried over
Na2SO4 and concentrated in vacuo. FC (20 g silicagel;
hexanes–EtOAc¼20:1) afforded 76 mg (62%) of 15. ee:
82% as determined by 19F NMR analysis of the correspond-
ing Mosher ester: d 271.52 (minor), 271.81 (major).
[a]2D4¼29.15 (c¼0.44, CHCl3). 1H NMR (300 MHz,
CDCl3) d 0.12 (s, 6H), 0.84–0.95 (m, 12H), 1.23–1.51
(m, 26H), 1.66–1.76 (m, 2H), 1.86 (d, 1H, J¼6.9 Hz),
2.10–2.18 (m, 4H), 4.38–4.42 (m, 3H), 5.30–5.41 (m, 2H).
13C NMR (75 MHz, CDCl3) d 25.3 (CH3), 14.3 (CH3), 18.4
(C), 22.8 (CH2), 25.1 (CH2), 25.7 (CH3), 27.3 (CH2), 29.3
(CH2), 29.4 (CH2), 29.6 (CH2), 29.9 (CH2), 32.0 (CH2), 37.6
(CH2), 52.1 (CH2), 62.9 (CH), 68.9 (C), 69.1 (C), 78.2 (C),
79.8 (C), 129.8 (CH), 129.9 (CH). FT-IR (thin film, cm21):
3306 (w, br), 2926 (s), 2854 (s), 1463 (m), 1363 (w), 1257
(w), 1091 (m), 836 (m), 780 (w), 722 (w). Mass
3.1.7. Icos-11-en-1-ol.10 A suspension of Lindlar catalyst
(10 mg), 11 (160 mg; 0.544 mmol) and freshly distilled
quinoline (20 ml) in hexanes (2 ml) at 238C was stirred
vigorously under a hydrogen atmosphere (approx. 1 bar;
balloon). After 1 h the solid was separated by filtration. The
organic layer was diluted with hexanes (10 ml), washed
with HCl (10 ml, 0.1N in water), sat. aq. NaHCO3 soln
(10 ml) and dried over Na2SO4. Evaporation of the solvent
gave 156 mg (95 %) of the alcohol 16. 1H NMR (300 MHz,
CDCl3) d 0.87 (t, 3H, J¼6.9 Hz), 1.20–1.40 (m, 27H),
1.50–1.61 (m, 2H), 1.95–2.95 (m, 4H), 3.62 (t, 2H,
J¼6.9 Hz), 5.35–5.40 (m, 2H). 13C NMR (75 MHz,
CDCl3) d 14.2 (CH3), 22.8 (CH2), 25.8 (CH2), 27.3 (CH2),
28.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.8 (CH2),
30.9 (CH2), 32.0 (CH2), 32.9 (CH2), 63.1 (CH2), 129.7
(CH), 129.8 (CH). FT-IR (thin film, cm21): 3339 (w, br),
3005 (w), 2924 (s), 2854 (s), 1466 (m), 1378 (w), 1058 (m),
spectroscopy
(HRMS,
MALDI):
calculated
for
C31H56O2Si (MþNa)þ 511.3947, found¼511.3949.
3.1.10. (6R)-Pentacos-16-ene-2,4-diyne-1,6-diol
(strongylodiol A)3 (1). A solution of (15) (50 mg;
0.10 mmol) in THF (2 ml) was treated at 238C with TBAF
(0.12 ml of 1.0 M soln in THF; 0.12 mmol). After 20 min
the reaction was quenched with sat. aq. NH4Cl soln (5 ml).
The mixture was diluted with ether (10 ml). The water phase
was extracted with ether (3£10 ml). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo.

S. Reber et al. / Tetrahedron 59 (2003) 6813–6817
6817
3, 4319. (h) Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3,
¨
4319. (i) Fassler, R.; Frantz, D.; Oetiker, J.; Carreira, E. M.
FC (20 g silicagel; hexanes–EtOAc¼4:1) afforded 32 mg
(85%) of 1 as a viscous colorless oil. [a]2D4¼210.9 (c¼1.11,
CHCl3), lit.: 27.2 (c¼1.11, CHCl3).3 1H NMR (300 MHz,
CDCl3) d 0.88 t, 3H, J¼6.9 Hz), 1.21–1.51 (m, 26H), 1.66–
1.76 (m, 2H), 1.98–2.06 (m, 4H), 4.39 (s, 2H), 4.41 (t, 1H,
J¼6.9 Hz), 5.38–5.40 (m, 2H). 13C NMR (75 MHz, CDCl3)
d 14.2 (CH3), 20.9 (CH2), 22.8 (CH2), 25.1 (CH2), 27.3
(CH2), 29.3 (CH2), 29.6 (CH2), 29.8 (CH2), 32.0 (CH2), 37.5
(CH2), 51.5 (CH2), 62.8 (CH), 68.8 (C), 69.8 (C), 80.5 (C),
129.7 (CH), 129.8 (CH). FT-IR (thin film, cm21): 3307 (m,
br), 3004 (w), 2924 (s), 2851 (s), 2255 (w), 2161 (w), 1652
(w) 1463 (m), 1354 (w), 1319 (w), 1065 (m), 1028 (m), 966
(w), 901 (w).
Angew. Chem. Int. Ed. 2002, 41, 3054. (j) Sans Diez, R.;
Adger, B.; Carreira, E. M. Tetrahedron 2002, 58, 8341.
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Acknowledgements
We thank the ETH, SNF, Eli Lilly, Merck, and F. Hoffmann-
LaRoche for their generous support of our research
program.
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