Asymmetric synthesis of cytotoxic sponge metabolites R-strongylodiols A and B and an analogue

Article abstract of DOI:10.1016/j.tet.2005.05.034

The asymmetric synthesis of the marine sponge natural products R-strongylodiols A R-1 and B R-2, using a minimum protection strategy, is described. Two approaches were examined and the Noyori asymmetric reduction of ynones was found to be successful for installing the chirality of the natural products. Analogue R-32 was also prepared. In addition, asymmetric alkynylation of aldehydes is briefly reviewed.

Full text of DOI:10.1016/j.tet.2005.05.034

Tetrahedron 61 (2005) 7219–7232
Asymmetric synthesis of cytotoxic sponge metabolites
R-strongylodiols A and B and an analogue
James E. D. Kirkham, Timothy D. L. Courtney, Victor Lee and Jack E. Baldwin
* *
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
Received 4 April 2005; revised 29 April 2005; accepted 12 May 2005
Available online 13 June 2005
Abstract—The asymmetric synthesis of the marine sponge natural products R-strongylodiols A R-1 and B R-2, using a minimum protection
strategy, is described. Two approaches were examined and the Noyori asymmetric reduction of ynones was found to be successful for
installing the chirality of the natural products. Analogue R-32 was also prepared. In addition, asymmetric alkynylation of aldehydes is briefly
reviewed.
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
IMR-90 and DLD-1 cells. The gross structures of 1–3 were
determined by a combination of NMR and mass
spectrometry analysis and through the application of the
modified Mosher’s method. Four related compounds,
strongylodiols D–G, were subsequently found from the
Research on marine natural products over the last two
decades has revealed that sponges are prolific sources of
novel and diverse long-chain, polyacetylenic metabolites.
Many exhibit potent and varied bioactivities, as well as
important ecological roles. Strongylodiols A 1, B 2 and C 3
1
4
same source.
2
are three such natural products isolated from the Okinawan
marine sponge of the genus Strongylophora by Iguchi and
The first total synthesis of strongylodiol A R-1 was reported
by Yadav et al. The key step in Yadav’s synthesis involved
5
3
co-workers. Interestingly, compounds 1–3 were found to
exist as enantiomeric mixtures (R/S ratio 91:9 for 1, 97:3 for
the use of strongly basic conditions to effect the b-elimin-
ation of a chiral epoxychloride to install the requisite
acetylenic alcohol. Hence, their method is unsuitable in the
synthesis of strongylodiol B R-2 due to the likelihood of
triple bond isomerization. Their choice of 1,10-decanediol
as starting material and sequential chain extension at either
end resulted in the heavy use of protecting group chemistry.
Thus Yadav’s synthesis is rather complicated for a
compound with a relatively simple molecular structure.
2 and 84:16 for 3) with the R-enantiomer as the major
component in each compound. The enantiomeric mixtures
of 1–3 were found to be cytotoxic towards MOLT-4,
6
Recently Carreira completed the synthesis of R-1 and R-2
via the asymmetric alkynylation of aldehydes. Carreira’s
synthesis is succinct, however, the ee of their asymmetric
addition products were only approximately 80%. We have
7
previously communicated our results and herein we
disclose the full details of our investigation into the
asymmetric synthesis of R-1 and R-2 based on a minimal
protection strategy. We first investigated the synthesis of
R-2 due to its simpler structure.
Keywords: Sponge; Asymmetric reduction; Alkyne; Zinc triflate; N-
Methylephedrine.
2. Results and discussion
*
Corresponding authors. Tel.: C44 1865 275653; fax: C44 1865 275674.
V.L.); e-mail addresses: victor.lee@chem.ox.ac.uk;
jack.baldwin@chem.ox.ac.uk
The retrosynthetic analysis of strongylodiol B R-2 is
outlined in Figure 1. This investigation was initiated prior
(
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.034

7220
J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
Figure 1. Retrosynthetic analysis of strongylodiol B 2.
6
to the publication of Carreira’s results. It was anticipated
Oxidation of alcohol 9 was effected with o-iodoxybenzoic
1
1
that fragments 4 and 5 would be coupled by a Cadiot–
Chodkiewicz reaction via a copper alkynylide derived from
acid (IBX) in THF/DMSO to deliver aldehyde 8 in 86%
yield. 3-Bromoprop-2-yn-1-ol 4 was prepared in 75% yield
by the addition of propargyl alcohol 13 to a solution of
8
4
. Fragment 4 would be prepared by bromination of
9
9
propargyl alchol 13. Fragment 5 would be constructed
from protected acetylene R-6, itself derived from the
enantioselective addition of commercially available tri-
methylsilylacetylene 7 to aldehyde 8 using the conditions of
bromine and KOH in water (Scheme 1). Although literature
described the instability of 4 towards shock and heat we
found that 4 could be purified by flash chromatography
without any difficulty.
1
0
11
Carreira et al. Aldehyde 8 would be formed by oxidation
of the corresponding alcohol 9, itself synthesized by the
nucleophilic displacement of alkyl iodide 10 by the dianion
We initially investigated the Carreira method of asymmetric
addition of alkynylides to aldehydes. It is documented that
simple unbranched aliphatic aldehydes are not highly
effective substrates in the Carreira reaction. However, the
concomitant formation of a carbon–carbon bond and a
chiral centre was deemed to offset the aforementioned
disadvantage. The Carreira reaction was examined with
trimethylsilylacetylene 7 and dodecanal 14 by treatment
with an amine base and chiral ligand (C)-N-methyl-
1
2
of alkynol 11. Alkynol 11 would be derived from
commercially available 9-dodecyn-1-ol 12 by a zipper
reaction.
1
3
Alcohol 11 was prepared by isomerization of commercially
available 12 using lithium 3-aminopropanamide in the
presence of potassium tert-butoxide in 92% yield, following
1
4
the protocol of Abrahams et al. This method was reported
1
to be more convenient than other literature protocols.
ephedrine 16 in the presence of Zn(OTf) (Scheme 2).
2
5
Double deprotonation of 11 with 2 equiv of n-BuLi in
DMPU/THF generated the corresponding dianion, which
was subsequently quenched with 1-iodooctane 10 to afford
alcohol 9. A difficulty with this step was that the dianion had
a tendency to cause the reaction to ‘freeze out’. Therefore
the reaction was occasionally removed from the cold bath to
thaw out the frozen mixture. Notwithstanding this minor
problem the alkylation product was obtained in 54% yield.
A mixture of Zn(OTf)2 and (C)-N-methylephedrine in
toluene was stirred at 23 8C for 2 h resulting in a white
suspension. A solution of 7 in toluene was added via
cannula and the mixture stirred for a further 18 h in an
attempt to solubilize the reagents. However, no further
solubilization was observed. Aldehyde 14 was added
leading to isolation of adduct 15 in !5% yield containing
impurities and with variable reproducibility. It was
t
, KO Bu, H
Scheme 1. Synthesis of aldehyde 8 and fragment 4. Reagents and conditions: (a) LiHN(CH
DMPU, then 10, K20 8C; (c) IBX, DMSO, THF, rt; (d) Br2(liq), KOH, H O, K12 8C.
2
)
3
NH
2
2
N(CH
2
)
3
NH
2
, rt; (b) n-BuLi (2 equiv), THF,
2
Scheme 2. Attempted asymmetric addition reaction using the conditions of Carreira et al. and Jiang et al. Reagents and conditions: (a) Zn(OTf)
triethylamine (2.1 equiv), 16 (2.1 equiv), toluene; (b) Zn(OTf) (1.0 equiv), 17 (1.0 equiv), triethylamine (1.1 equiv), toluene.
2
(2.0 equiv),
2

J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
7221
Figure 2. Second retrosynthetic analysis of strongylodiol B R-2.
conceived that the failure of the reaction might have been
attributed to the facile enolisation of the aldehyde and so use
of a weaker base than triethylamine was attempted.
However, neither 2,6-lutidine nor pyridine was found to
be effective in mediating the desired reaction. Marshall
insoluble gum and addition of triethylamine led to no
change in the physical state of the reactants. Addition of
trimethylsilylacetylene 7 and aldehyde 14 to the reaction
mixture and stirring overnight resulted in no reaction. On
subsequent attempts THF was added to the heterogeneous
mixture in an effort to solubilize the gum; this was
successful. Unfortunately, no reaction was observed.
1
6
et al. later reported an unsuccessful attempt in modifying
the Carreira reaction with H u¨ nig’s base.
Subsequent attempts to form a homogeneous mixture were
made in which the Zn(OTf) was thoroughly powdered and
Several further attempts were made to form a homogeneous
solution by varying the commercial source of Zn(OTf) , by
2
2
1
7
dried before addition to a mixture of 7 and 16. Toluene
was added and the mixture stirred for 2 h, again resulting in
a white suspension. Addition of triethylamine and 14 to the
suspension and heating at 60 8C did not lead to a
homogeneous mixture and no product formation was
observed.
further powdering and drying the Zn(OTf) , and by allowing
2
the Zn(OTf) and chiral ligand 17 to congeal before stirring
2
and heating. Unfortunately, all attempts were unsuccessful.
Consequently, a different approach to the synthesis of
strongylodiols A R-1 and B R-2 was adopted. During the
course of our new investigation we were pleasantly
surprised that the Carreira group reported the successful
synthesis of strongylodiols A R-1 and B R-2 using the chiral
alkynylide addition approach, albeit an excess of Zn(OTf)2,
chiral ligand and base (4 equiv each) were required to
1
6,18
A literature survey
revealed examples of failed Carreira
reactions on aliphatic aldehydes which consolidated our
belief that this reaction was not suitable in our synthesis. We
were then attracted by a similar method recently reported by
1
9
Jiang et al. in which the asymmetric alkynylation of an
aliphatic aldehyde using chiral ligand 17 were described in
excellent yields and enantioselectivities. Amino-alcohol
6
deliver the products in acceptable ee and yields. Therefore
it would appear that these types of chiral zinc acetylide
21,22
addition reactions are highly substrate sensitive.
1
procedure and the enantioselective addition of trimethyl-
7 was therefore synthesized according to literature
2
0
silylacetylene 7 to dodecanal 14 was attempted as described
by Jiang et al. (Scheme 2).
2.1. Revised synthetic route
1
9
Our revised synthetic route involved introducing the chiral
centre at C-6 via the asymmetric reduction of ynone 18
(Fig. 2). It was anticipated that R-6 could be obtained by
performing a Noyori asymmetric transfer hydrogenation
reaction on ynone 18 using chiral ruthenium catalyst 24 in
propan-2-ol. Ynone 18 could be obtained by oxidation of
racemic alcohol rac-6, itself obtained by the nucleophilic
addition of trimethylsilylacetylene 7 to aldehyde 8. Chiral
Jiang et al. had described the mixture of Zn(OTf) and chiral
2
ligand 17 in toluene as a ‘solution’ and that the
enantioselective addition reaction took place in a ‘homo-
geneous phase’. However, we observed great difficulty in
forming a solution of Zn(OTf) and chiral ligand 17 in
2
toluene: a yellow suspension always resulted. Sonification
and heating of the suspension led to coagulation into an
3
Scheme 3. Synthesis of chiral ruthenium catalyst 24. Reagents and conditions: (a) EtOH, 120 8C under reflux; (b) p-TsCl (1 equiv), Et N, THF, 0 8C; (c) KOH,
DCM, rt.

7222
J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
Scheme 4. Synthesis of strongylodiol B R-2. Reagents and conditions: (a) trimethylsilylacetylene 7, n-BuLi, THF, K12 8C; (b) IBX, DMSO, THF, rt; (c) 24,
i-PrOH, 30 8C, rt; (d) NH F, MeOH, 67 8C; (e) 4, CuCl, NH OH$HCl, EtNH , MeOH, rt.
4
2
2
2
8
8
ruthenium catalyst 24 was therefore synthesized according
to literature procedure.
afford 5 in 91% yield. Cadiot–Chodkiewicz coupling of 5
and 2-bromopropyn-1-ol 4 delivered R-2 in 82% yield
(
Scheme 4).
Formation of bis-arene complex 21 was achieved in
approximately 60% yield by heating ruthenium (III)
chloride 19 and a-phellandrene 20 in EtOH under reflux,
The synthesis of strongylodiol R-1 commenced with a
2
9
Lindlar hydrogenation of 9 in benzene to afford 25 in 95%
yield, which was oxidised to aldehyde 26 in 87% yield by
IBX in THF/DMSO. Reaction of aldehyde 26 with lithium
trimethylsilylacetylide delivered rac-27 in 76% yield.
Oxidation of rac-27 with IBX afforded a 93% yield of
ynone 28 and subsequent chiral reduction of 28 with catalyst
24 in propan-2-ol gave R-27 in 97% yield with O95% ee.
Removal of the trimethylsilyl group from R-27 was effected
with ammonium fluoride in methanol to deliver terminal
acetylenic alcohol 29 in 91% yield, which was coupled with
4 to afford R-1 in 80% yield (Scheme 5).
2
3
as described by Bennet et al. It was observed that the
expected aromatic double-doublet signal in the H NMR
1
spectrum of 21 was nearly 1 ppm downfield of the literature
value. Subsequent X-ray diffraction studies confirmed the
structure of 21 and that the literature data is incorrect.
Formation of chiral ligand 23 was achieved in 71% yield by
the selective mono-tosylation of 22, as described by Tietze
2
4
et al. Synthesis of chiral ruthenium catalyst 24 was
achieved in 94% yield following the protocol of Noyori
2
5
et al. (Scheme 3). We observed that the preparation of
chiral ruthenium catalyst 24 did not require the use of a
Schlenk technique. Although catalyst 24 contained some
impurities it was subsequently proven that the 24 we
prepared was highly effective in asymmetric reduction
reactions.
2.2. Synthesis of an analogue of strongylodiols A, B and
C
An analogue of the strongylodiols, R-32, was prepared since
reactions subsequent to the formation of 8 in the synthesis of
strongylodiol B R-2 were first tested on a model system
based on commercially available dodecanal 14. Aldehyde
14 was converted to rac-15 in 85% yield, which was
oxidised to 30 in 98% yield. 30 was subject to an
asymmetric reduction to yield R-15 in O95% ee and 88%
yield, which was deprotected to give 31 in 98% yield.
Cadiot–Chodkiewicz coupling of 31 and 4 afforded R-32 in
84% yield (Scheme 6). Comparison of the optical rotation
Synthesis of strongylodiol R-2 continued by the addition of
lithium trimethylsilylalkynide to aldehyde 8 to give rac-6 in
86% yield, which was subjected to IBX oxidation to give
ynone 18 in 87% yield. Asymmetric reduction of 18 with
2
catalyst 24 in propan-2-ol delivered R-6 in 97% yield. The
6
1
9
ee of R-6 was O95% as determined by F NMR analysis of
its Mosher’s esters. The terminal trimethylsilyl group in
R-6 was removed by ammonium fluoride in methanol to
2
7
Scheme 5. Synthesis of strongylodiol A R-1. Reagents and conditions: (a) Lindlar’s catalyst, quinoline, H
(c) trimethylsilylacetylene 7, n-BuLi, THF, K12 8C; (d) 24, i-PrOH, 30 8C, rt; (e) NH F, MeOH, 67 8C; (f) 4, CuCl, NH
2
, benzene, rt; (b) IBX, DMSO, THF, rt;
OH$HCl, EtNH , MeOH, rt.
4
2
2

J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
7223
Scheme 6. Test reactions of the model system. Reagents and conditions: (a) trimethylsilylacetylene 7, n-BuLi, THF, K12 8C; (b) IBX, DMSO, THF, rt; (c) 24,
i-PrOH, 30 8C, rt; (d) NH F, MeOH, 67 8C; (e) 4, CuCl, NH OH$HCl, EtNH , MeOH, rt.
4
2
2
data of R-1, R-2 and R-32 indicated that the magnitude and
sign of the rotation is almost independent of both chain
length and chain functionality.
5. Experimental
5.1. General
1
13
H NMR and C NMR spectra were recorded on Varian
Gemini 200 (200 MHz), Br u¨ ker DPX200 (200 MHz),
Br u¨ ker DPX400 (400 MHz) and Br u¨ ker AMX500
3
. A comment on the Carreira asymmetric alkynylation
reaction
(500 MHz) spectrometers at ambient temperatures and are
reported in parts per million (ppm). H NMR coupling
1
Since Carreira’s initial report of the asymmetric alkynyl-
ation of aldehydes the synthetic community has expressed
mixed opinion about the effectiveness of this reaction. There
are research groups that have successfully applied this
reaction to synthesis, yet the number of failed Carreira
reactions reported is considerable.
1
3
constants (J) are recorded to the nearest 0.5 Hz. C NMR
spectra were recorded on Varian Gemini 200 (50.3 MHz),
Br u¨ ker DPX200 (50.3 MHz), Br u¨ ker DPX400 (100.6 MHz)
and Br u¨ ker AMX500 (125.8 MHz) spectrometers at
ambient temperatures and are reported in parts per million
3
0
1
6,18
(
experiments were utilized when necessary for the assign-
ppm). A combination of COSY, HMQC and DEPT
Literature survey has revealed clues to the apparent
discrepancies of the Carreira reactions as observed by
various groups. Firstly, the Garcia group noticed that the
source and particle size of the Zn(OTf) can have an effect
2
on the yield of the reaction.
1
13
19
ment of H and C chemical shifts. F spectra were
recorded on Br u¨ ker DPX250 (235 MHz) and Br u¨ ker
DPX400 (376 MHz) spectrometers at ambient temperatures
1
13
19
1
7b
and are reported in parts per million (ppm). H, C and
NMR spectra are referenced to the residual solvent peak.
F
Secondly, the Tanaka
and Garcia group deemed it necessary to
2
2,30b,c,h–j
17
group
vigorously dry the Zn(OTf) prior to reaction. This is in
2
Low resolution mass spectra were recorded using a TRIO-1
GCMS spectrometer, Micromass Platform (APCI) spec-
trometer, Micromass Autospec spectrometer (CI ) and a
contrast to Carreira who reported that the asymmetric
alkynylation reaction is reasonably tolerant to moisture.
1
0,31
C
C
Micromass ZAB spectrometer (CI , EI); only molecular
ions (M ), fragments from molecular ions and other major
Since the Carreira reaction is essentially a heterogeneous
mixture it is tempting to speculate that the reaction takes
C
3
2
peaks are reported. High resolution spectra were recorded
on a Micromass Autospec spectrometer and are accurate to
G10 ppm.
place on the surface of the Zn(OTf) particles. The surface
2
morphology and particle size of Zn(OTf) may vary from
2
source to source, methods of preparation and degree of
dryness. All these factors can affect the outcome of the
reaction. Since the mechanism of this reaction is not well
understood, it is impossible to predict the applicability of
this reaction to target synthesis with a great degree of
confidence.
All melting points were determined using a Cambridge
Instruments Gallene III hot stage melting point apparatus
and are uncorrected.
Optical rotations were recorded on a Perkin–Elmer 241
polarimeter using a 10 cm path length cell.
4
. Conclusion
Infrared spectra were recorded on a Perkin–Elmer Paragon
1000 Fourier Transform spectrometer as a thin film between
NaCl plates, a nujol emulsion between NaCl plates or KBr
In conclusion, we have developed an efficient synthesis of
R-1 and R-2 without the deliberate use of protecting groups.
The spectral data and specific rotation values of both R-1
and R-2 are in excellent agreement with their corresponding
literature values. We have also demonstrated that the Noyori
reduction of ynones 18, 28 and 30 were achieved with high
ee and high yields. In addition, compound 11 could be a
useful intermediate in the syntheses of other members of the
disks; absorption maxima (nmax) of the major peaks are
reported in cm
K1
.
Elemental analyses were performed by Elemental Analysis
Limited.
Thin layer chromatography (TLC) was performed using
Merck aluminium foil backed plates pre-coated with silica
4
strongylodiols.

7224
J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
gel 60 F254 (1.05554). Visualisation was effected by
quenching of UV fluorescence (lmaxZ254 nm), staining
with 10% w/v ammonium molybdate in 1 M H SO ,
which was purified by flash chromatography (95% DCM,
5% MeOH) on a silica column to yield (1S,2S)-3-tert-
butyldimethylsilyloxy-2-N,N-dimethylamino-1-p-nitro-
phenyl-propan-1-ol (0.658 g, 1.86 mmol, 47%) as a yellow
2
4
followed by heating. Retention factors (R ) are reported to
f
2
0
two decimal places. Column chromatography refers to flash
chromatography and was performed on ICN silica 32–63,
˚
oil.
6
6
0 A.
5.2.3. Di-m-chloro-bis[chloro(h -1-isopropyl-4-methyl-
benzene)ruthenium (II)] (21). A solution of ruthenium
(III) chloride hydrate 19 (35–40% Ru) (3.00 g, approxi-
mately 13 mmol) in EtOH (150 ml) was treated with
a-phellandrene 20 (15 ml) and heated under reflux at
120 8C for 4 h. The solution was allowed to cool to ambient
temperature and the red-brown crystalline product was
filtered off. Additional product was obtained by concentrat-
ing the orange-yellow filtrate under reduced pressure to
approximately half-volume, refrigerating overnight and
filtering off the crystals. Drying in vacuo afforded 21
(2.39 g, 3.90 mmol, approximately 60%) as deep-purple
All operations involving air-sensitive reagents were per-
formed under an inert atmosphere of dry argon using
syringes, oven-dried glassware. Anhydrous tetrahydrofuran
(
THF) was distilled over sodium/benzophenone ketyl under
nitrogen. Anhydrous dichloromethane (DCM) was distilled
from calcium hydride under nitrogen. Triethylamine,
dimethyl formamide (DMF), toluene, chloroform and
dimethyl sulfoxide (DMSO) were distilled from calcium
˚
hydride under argon or reduced pressure and stored over 4 A
molecular sieves under argon. Propane-1,3-diamine was
stirred over barium oxide, distilled under reduced pressure
K1
crystals; decomp. O200 8C; nmax/cm (nujol) 319 (s), 287
(s), 266 (s), 247 (s), 232 (s), 204 (s), 169 (w), 154 (m), 139
˚
and stored over 4 A molecular sieves under argon.
a-Phellandrene was distilled under reduced pressure and
˚
stored over 4 A molecular sieves under argon. Commercial
C
C
(m), 123 (m), 108 (m); m/z Probe EI 576.9 ([M(KCl)] ,
Ru Cl C H , 100%); d (400 MHz, CDCl ) 1.25 (12H, d,
2
3
20 28
H
3
solutions of n-BuLi were titrated against 1,3-diphenyl-
acetone-p-toluenesulfonylhydrazone in THF prior to use.
PE 30–40 refers to the fraction of light petroleum ether
boiling between 30 and 40 8C, and was distilled before use.
All water used was distilled except where otherwise
indicated. Solvents were evaporated on a B u¨ chi R110
Rotavaporator.
JZ7.0 Hz, –CH(CH ) ), 2.13 (6H, s, Ar-CH ), 2.89 (2H,
3 2 3
septet, JZ7.0 Hz, –CH(CH ) ), 5.32 (4H, d, JZ5.0 Hz,
3
2
–C H ), 5.44 (4H, d, JZ5.0 Hz, –C H ); d (100.6 MHz,
6
4
6
4
C
CDCl ) 18.91 (2C, Ar-CH ), 22.12 (2C, Ar-CH(CH ) ),
30.58 (2C, Ar-CH(CH ) ), 80.48 (4C, ArC-H), 81.26 (4C,
3
3
3 2
3
2
ArC-H), 96.70 (2C, ArC-C), 101.1 (2C, ArC-C); micro-
analysis found CZ39.20, HZ4.60, Ru Cl C H requires
2
2 20 28
CZ39.23, HZ4.61.
5
5
.2. Synthesis of chiral ligands 34 and 24
5
.2.4. N-((1R,2R)-2-Amino-1,2-diphenylethyl)-4-methyl-
.2.1. (1S,2S)-2-(Dimethylamino)-1-(4-nitrophenyl)pro-
benzenesulfonamide (23). To a solution of 22 (0.805 g,
3.79 mmol, 1 equiv) in anhydrous THF (32 ml) at 0 8C was
added anhydrous triethylamine (1.6 ml) via syringe. A
solution of p-TsCl (0.725 g, 3.80 mmol, 1 equiv) in
anhydrous THF (8 ml) at 0 8C was added over 30 min via
syringe pump and the mixture stirred overnight at 0 8C.
Removal of solvent in vacuo afforded a white solid, which
was quenched with NaHCO3(aq) (sat., 60 ml) and extracted
with DCM (4!15 ml). The combined organic layers were
pane-1,3-diol. A mixture of (1S,2S)-2-amino-3-(p-nitro-
phenyl)propane-1,3-diol (1.01 g, 4.76 mmol), aqueous
formaldehyde (37–40%, 1.5 ml) and formic acid (98%,
2
continuous stirring for 22 h. An effervescence of CO was
observed almost immediately. Removal of solvent in vacuo
afforded a yellow residue, which was neutralized with
NaOH(aq) (1 M, 6 ml) and extracted with DCM (3!15 ml).
The organic phases were combined and washed with
.0 ml) was heated under reflux at 110 8C under argon with
2
washed with NaCl(aq) (sat., 20 ml), dried over Na SO4(s) and
2
NaCl(aq) (sat., 10 ml) and dried over Na SO4(s). Removal
2
concentrated to dryness in vacuo to afford the crude product,
which was purified by flash chromatography (EtOAc) on a
silica column to yield 23 (0.983 g, 2.69 mmol, 71%) as a
of solvent in vacuo afforded the crude product, which was
purified by flash chromatography (90% DCM, 10% MeOH)
on a basic alumina column to yield (1S,2S)-2-N,N-
dimethylamino-1-p-nitrophenyl-propane-1,3-diol (1.02 g,
†
3
3
white solid; mp 125–125.5 8C, lit. mp 125–126 8C ;
2
D
5
25
[a]
max/cm (KBr) 3349 (m), 3284 (m), 3151 (m, br), 2919
w), 2864 (m), 1599 (m), 1495 (m), 1455 (m), 1322 (m),
ZK36.7 (c 1.0, CHCl ), lit. [a] vary considerably;
3 D
K1
2
0
4
.25 mmol, 89%) as a yellow crystalline solid.
n
(
5
.2.2. (1S,2S)-3-(tert-Butyldimethylsilyloxy)-2-(dimethyl-
1155 (s), 1094 (m), 1062 (m), 1019 (m), 937 (w), 898 (m),
838 (w), 813 (m), 767 (s), 699 (s), 670 (m); m/z Probe
amino)-1-(4-nitrophenyl)propan-1-ol (17). To a stirred
solution of (1S,2S)-2-N,N-dimethylamino-1-p-nitrophenyl-
propane-1,3-diol (0.946 g, 3.95 mmol, 1 equiv) and imida-
zole (0.338 g, 4.96 mmol, 1.26 equiv) in DCM (6 ml) under
argon and immersed in a salt-ice bath at K12 8C was added
a solution of TBDMSCl (0.621 g, 4.12 mmol, 1.04 equiv) in
DCM (2 ml, 2!2 ml wash) via cannula. The reaction was
stirred at ambient temperature for 3 h, diluted with DCM
C
C
C
ES 367.1 ([MH] , 100%), HRMS found [MH] Z
367.1469, C21 S requires 367.1480; d (400 MHz,
CDCl ) 1.51 (2H, br s, –NH ), 2.33 (3H, s, –pC CH ),
4.14 (1H, d, JZ5.5 Hz, –CHNH ), 4.40 (1H, d, JZ5.5 Hz,
–CHNHSO pC CH ), 6.98 (2H, d, JZ8.0 Hz,
–pC CH ), 7.05–7.25 (10H, m, –C ), 7.32 (2H, d,
JZ8.0 Hz, –pC CH ); d (100.6 MHz, CDCl ) 21.38
(1C, –pC CH ), 60.52 (1C, –CHNH ), 63.24 (1C,
–CHNHSO pC CH ), 126.5 (2C, ArC-H), 126.8 (2C,
H
N
2
O
23
2
H
H
4
3
2
6
3
2
H
2
6
4
3
H
4
H
6 5
6
3
H
4
6
3
C
3
(20 ml) and quenched with NH Cl
H O) before being extracted with DCM (3!10 ml). The
(5 ml sat. in 40 ml
(aq)
6
H
4
3
2
4
H
4
2
2
6
3
combined organic phases were washed with NaHCO3(aq)
ArC-H), 127.0 (2C, ArC-H), 127.3 (1C, ArC-H), 127.4 (1C,
(sat., 10 ml), NaCl(aq) (sat., 10 ml) and dried over Na SO4(s).
2
Removal of solvent in vacuo afforded the crude product,
†
A small amount of ditosylated product was also observed.

J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
7225
ArC-H), 128.2 (2C, ArC-H), 128.4 (2C, ArC-H), 129.1 (2C,
ArC-H), 137.2 (1C, ArC-C), 139.3 (1C, ArC-C), 141.4 (1C,
ArC-C), 142.5 (1C, ArC-C); microanalysis found CZ69.17,
HZ6.08, NZ7.74, C H N O S requires CZ68.82, HZ
containing lithium (0.52 g, 74.6 mmol, 3.2 mm wire washed
with petrol) was added propane-1,3-diamine (36 ml,
previously distilled from barium oxide). The mixture was
stirred at ambient temperature for 30 min before heating at
75 8C until the deep blue colour had discharged to afford a
white suspension of the lithium amide. The reaction mixture
2
1 22 2 2
6
.05, NZ7.64.
t
5.2.5. (1R,2R)-(K)-N-Tosyl-1,2-diphenylethane-1,2-dia-
mine[(h -1-isopropyl-4-methylbenzene)ruthenium (II)]
was allowed to cool to ambient temperature and KO Bu
6
(5.88 g, 52.4 mmol) was added to afford a pale yellow
solution which was stirred for 20 min. To this solution was
added 12 (2.5 ml, 2.137 g, 11.7 mmol, 1.0 equiv) in
propane-1,3-diamine (10 ml, 120 mmol, 10 equiv) dropwise
via cannula. The reddish-brown mixture was stirred for
30 min and poured into 100 ml water and 100 g ice before
being extracted with PE 30–40 (3!100 ml), washed with
water (100 ml), KHSO4(aq) (10%, 100 ml) and NaCl(aq) (sat.,
(
(
24). A mixture of 21 (0.306 g, 0.500 mmol, 1 equiv), 23
0.366 g, 1.00 mmol, 2 equiv) and KOH (0.411 g,
7
.33 mmol, 15 equiv) in anhydrous DCM (7 ml) was stirred
under argon at ambient temperature for 5 min. On addition
of water (7 ml) the colour changed from orange to deep
purple. The purple organic layer was washed with water
(
vacuo to yield 24 (0.564 g, 0.941 mmol, 94%) as deep
7 ml), dried over CaH and concentrated to dryness in
2
100 ml) and dried over Na
vacuo afforded the crude product, which was purified by
flash chromatography (50% PE 30–40, 50% Et O) to 11
(1.96 g, 10.76 mmol, 92%) as a waxy solid; R Z0.31 (50%
SO4(s). Removal of solvent in
2
K1
purple crystals; decomp. O80 8C; nmax/cm
(
(KBr) 3441
m, br), 3287 (s), 3064 (m), 2965 (m), 2928 (m), 2861 (m),
2
1
1
800 (w), 1597 (m), 1449 (m), 1388 (m), 1261 (s), 1130 (s),
087 (s), 939 (m), 862 (m), 808 (m), 771 (m), 694 (s), 640
f
K1
PE 30–40, 50% Et O); mpZ28 8C; nmax/cm (KBr) 3287
2
C
C
(
m), 547 (m), 506 (w); m/z Probe ES 601.0 ([MH] ,
(s, br), 2919 (s), 2850 (s), 2114 (w), 1487 (m), 1472 (s),
1462 (s), 1434 (m), 1421 (m), 1356 (m), 1322 (m), 1124
(m); m/z Probe CI (NH ) 200.2 ([MNH ] , 100%), 183.2
C
C H N O SRu, 100%); HRMS found [MH] Z
6
3
1
35
2
2
1
01.1486, C H N O S Ru requires 601.1463; dH
02
C
C
3
1
35
2
2
3
4
C
C
(
400 MHz, toluene-d ) 1.04, 1.09 (3H, d, JZ7.0 Hz,
([MH] , 17%); HRMS found [MNH ] Z200.2011,
4
8
–
–
CH(CH ) ), 1.89 (3H, s, –CH in p-Ts), 2.05 (3H, s,
CH in p-cymene), 2.37 (1H, m, –CH(CH ) ), 3.91 (1H, d,
C
12
H
26NO requires 200.2014; d
1.24–1.62 (16H, m, H-2,3,4,5,6,7,8,9), 1.94 (1H, t, JZ
2.5 Hz, H-12), 2.18 (2H, dt, J Z7.0 Hz, J Z2.5 Hz, H-10),
3.64 (2H, t, JZ6.5 Hz, H-1); d (100.6 MHz, CDCl ) 18.37
(1C, C-10), 25.70 (1C, CH ), 28.45 (1C, CH ), 28.71 (1C,
CH ), 29.05 (1C, CH ), 29.37 (1C, CH ), 29.38 (1C, CH ),
29.50 (1C, CH ), 32.77 (1C, C-2), 63.05 (1C, C-1), 68.02
(1C, C-12), 84.77 (1C, C-11).
H 3
(400 MHz, CDCl )
3
2
3
3
3 2
JZ4.0 Hz, –CHNH), 4.71 (1H, s, –CHN-p-Ts), 4.94, 5.06,
.11, 5.22 (4H, d, JZ5.0 Hz, –C H in p-cymene), 6.42
1
2
5
C
3
6
5
(
1H, br. s, –CHNH), 6.70 (2H, d, JZ8.0 Hz, –C H in p-Ts),
2
2
6
5
7
.00–7.23 (10H, m, p-TsNCH(C H )CH(C H )NH), 7.49
2
2
2
2
6
5
6 5
(
2H, d, JZ8.0 Hz, –C H in p-Ts); microanalysis found
2
6
5
CZ61.76, HZ5.69, NZ4.78, C H N O SRu requires
3
1 34 2 2
CZ62.08, HZ5.71, NZ4.78.
5.3.3. Icos-11-yn-1-ol (9). To a solution of 11 (0.160 g,
5
.3. Synthesis of common intermediates 4 and 9
0.89 mmol) in THF (1 ml) and DMPU (1.15 ml) was added
dropwise a solution of n-BuLi in hexanes (0.83 ml, 2.51 M,
2.08 mmol) via syringe, while cooling to K20 8C. The pale
yellow solution was stirred for 30 min at 0 8C before
1-iodooctane 10 (0.32 ml, 1.80 mmol) was added via
syringe. The reaction mixture sometimes ‘froze out’ and
therefore was temporarily removed from the cold bath to
thaw out. The solution was allowed to warm to ambient
temperature and stirred for a further 30 min before being
poured into NH Cl (sat., 40 ml) to quench and extracted
5
.3.1. 3-Bromoprop-2-yn-1-ol (4). Caution. 1-Halo-
propynes are potentially explosive. Do not heat these
compounds. Perform these operations behind a blast shield.
Do not distil.
Molecular bromine (1.54 ml, 30 mmol, 1 equiv) was added
to a vigorously stirred solution of KOH (4.51 g, 80.3 mmol,
2
.67 equiv) in water (12 ml) at K12 8C. The resultant
4
(aq)
yellow solution was kept at K12 8C and added dropwise to
a stirred solution of propargyl alcohol 13 (1.80 ml,
with a 1:1 mixture of PE 30–40 and Et O (3!20 ml). The
2
combined organics were washed with NaCl(aq) (sat., 20 ml)
and dried over Na SO4(s). Removal of solvent in vacuo
3
0 mmol, 1 equiv) in water (3.9 ml) maintaining a tem-
2
perature of !5 8C. Addition took approximately 1 h, after
which the mixture was stirred for 1 h, allowed to warm to
ambient temperature and stirred again for 1 h. The mixture
afforded the crude product, which was purified by flash
chromatography (96% PE 30–40, 4% Et O) on a silica
2
column to yield 9 (0.142 g, 0.480 mmol, 54%) as a waxy
solid; R Z0.26 (80% benzene, 20% Et O); mpZ40 8C;
was then extracted with Et O (4!20 ml), washed with
2
f
2
K1
Na S O
2
(sat., 1!10 ml) and dried over K CO3(s)
2
.
nmax/cm (KBr) 3289 (s, br), 2920 (s), 2852 (s), 2019 (w),
1460 (s), 1356 (s), 1295 (m), 1260 (m), 1208 (w), 1058 (s),
1021 (s), 998 (m), 967 (m), 919 (m), 860 (w), 724 (s); m/z
2
3(aq)
Removal of solvent in vacuo afforded the crude product,
which was purified by flash chromatography (EtOAc) on a
silica column to yield 4 (3.03 g, 22.4 mmol, 75%) as a pale
C
C
Probe CI (NH ) 312.3 ([MNH ] , 100%); HRMS found
3
4
K1
C
[MNH ] Z312.3255, C H NO requires 312.3266; d
yellow oil; R Z0.19 (65% PE 30–40, 35% Et O); nmax/cm
f
2
4 20 42 H
(
(
(
thin film) 3334 (s, br), 2921 (m), 2867 (m), 2218 (s), 1710
w), 1630 (w), 1424 (m), 1359 (m), 1226 (m), 1050 (s), 990
s), 607 (m); d (400 MHz, CDCl ) 3.50 (1H, t, JZ5.5 Hz,
(400 MHz, CDCl ) 0.87 (3H, t, JZ7.0 Hz, H-20), 1.12–1.80
(28H, m, H-2,3,4,5,6,7,8,9,14,15,16,17,18,19), 2.13 (4H, t,
JZ7.0 Hz, H-10,13), 3.63 (2H, t, JZ6.5 Hz, H-1); dC
3
H
3
–
CDCl ) 45.68 (1C, C-3), 51.52 (1C, C-1), 78.18 (1C, C-2).
OH), 4.26 (2H, d, JZ5.5 Hz, H-1); dC (100.6 MHz,
(100.6 MHz, CDCl ) 14.07 (1C, C-20), 18.73 (2C,
3
3
C-10,13), 22.63 (1C, CH ), 25.71 (1C, CH ), 28.82 (1C,
2
2
CH ), 28.84 (1C, CH ), 29.11 (1C, CH ), 29.14 (1C, CH ),
2
2
2
2
5
.3.2. Dodec-11-yn-1-ol (11). To a two-necked flask
29.15 (1C, CH ), 29.16 (1C, CH ), 29.20 (1C, CH ), 29.38
2 2 2

7226
J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
(1C, CH ), 29.45 (1C, CH ), 29.54 1C, CH ), 31.82 (1C,
CH ), 32.78 (1C, CH ) 63.04 (1C, C-1), 80.18, 80.23 (2C,
C-11,12).
(1H, d, JZ5.5 Hz, –OH), 2.14 (4H, t, JZ7.0 Hz, H-12,15),
4.35 (1H, apparent q, JZ5.5 Hz, H-3); dC (100.6 MHz,
CDCl ) K0.14 (3C, Si(CH ) ), 14.09 (1C, C-22), 18.74 (2C,
2
2
2
2
2
3
3 3
C-12,15), 22.65 (1C, CH ), 25.08 (1C, C-5), 28.84 (1C,
2
5
5
.4. Synthesis of strongylodiol B R-2
.4.1. Icos-11-ynal (8). To a stirred solution of IBX
CH ), 28.85 (1C, CH ), 29.11 (1C, CH ), 29.13 (1C, CH ),
2 2 2 2
2
(1C, CH
9.15 (1C, CH ), 29.19 (1C, CH ), 29.21 (1C, CH ), 29.41
2
2
2
), 29.44 (1C, CH
), 31.83 (1C, CH
), 37.69 (1C,
2
2
2
(
0.281 g, 1.00 mmol, 2 equiv) in DMSO (3 ml) under
C-4), 62.90 (1C, C-3), 80.19, 80.24 (2C, C-13.14), 89.26,
106.90 (2C, C-1,2).
argon was added 9 (0.142 g, 0.481 mmol, 1 equiv) in
anhydrous THF (1 ml, 2!0.5 ml wash) via cannula. The
reaction mixture was stirred for 3 h, after which water
5.4.3. 1-(Trimethylsilyl)docosa-1,13-diyn-3-one (18). To
a stirred solution of IBX (0.038 g, 0.135 mmol, 1.5 equiv) in
DMSO (3 ml) under argon was added rac-6 (0.035 g,
0.090 mmol, 1 equiv) in anhydrous THF (0.5 ml, 2!0.5 ml
wash) via cannula. The reaction mixture was stirred for 3 h,
after which water (12 ml) was added. In a few minutes a
white precipitate had formed which was removed by
filtration through a sintered glass funnel. The residue was
washed with cold EtOAc (6 ml). The combined organics
were extracted with EtOAc (4!10 ml), washed with
(
12 ml) was added. In a few minutes a white precipitate had
formed which was removed by filtration through a sintered
glass funnel. The residue was washed with cold EtOAc
(
(
6 ml). The combined organics were extracted with EtOAc
4!10 ml), washed with NaCl(aq) (sat., 10 ml) and dried
over Na SO4(s). Removal of solvent in vacuo afforded the
2
crude product, which was purified by flash chromatography
(
(
2
96% PE 30–40, 4% Et O) on a silica column to yield 8
2
0.121 g, 0.415 mmol, 86%) as a white solid; mp 2K5–1
5.5 8C; R Z0.14 (96% PE 30–40, 4% Et O); nmax/cm
NaCl(aq) (sat., 10 ml) and dried over Na
of solvent in vacuo afforded the crude product, which was
purified by flash chromatography (94% PE 30–40, 6% Et O)
on a silica column to yield 18 (0.030 g, 0.078 mmol, 87%)
as a colourless oil; R Z0.53 (90% PE 30–40, 10% Et O);
(KBr) 2929 (s), 2855 (s), 2151 (w), 1680 (s),
2
SO4(s). Removal
f
2
(
(
(
KBr) 2952 (s), 2930 (s), 2848 (s), 2746 (m), 2359 (w), 1709
s), 1466 (m), 1424 (w), 1407 (m), 1393 (m), 1302 (w), 1231
w), 1062 (w), 892 (w), 724 (m), 696 (m), 668 (w), 527 (w);
2
C
C
m/z Probe CI (NH ) 310.3 ([MNH ] , 100%); HRMS
3
f
2
4
C
found [MNH ] Z310.3112, C H NO requires 310.3110;
K1
nmax/cm
4
20 40
d (400 MHz, CDCl ) 0.86 (3H, t, JZ6.5 Hz, H-20), 1.18–
1466 (m), 1406 (w), 1352 (w), 1332 (w), 1252 (s), 1217 (w),
1116 (m), 1081 (m), 847 (s),762 (m), 723 (w), 704 (w), 621
(w); m/z Probe CI (NH ) 406.4 ([MNH ] , 100%) 389.3
H
3
1
.40 (20H, m, H-4,5,6,7,8,15,16,17,18,19), 1.60 (2H, qui,
C
C
JZ7.0 Hz, H-3), 1.40–1.50 (4H, m, H-9,14), 2.11 (4H, t,
JZ7.0 Hz, H-10,13), 2.39 (2H, dt, J Z7.5 Hz, J Z2.0 Hz,
3
4
C
C
([MH] , 88%); HRMS found [MNH ] Z406.3466,
1
2
4
H-2), 9.75 (1H, t, JZ2.0 Hz, H-1); d (100.6 MHz, CDCl )
C
25
H48NOSi requires 406.3505; d
(400 MHz, CDCl )
H 3
C
3
1
CH ), 22.62 (1C, CH ), 28.76 (1C, CH ), 28.83 (1C, CH ),
4.06 (1C, C-20), 18.70, 18.71 (2C, C-10,13), 22.03 (1C,
0.25 (9H, s, K(CH ), 0.88 (3H, t, JZ7.0 Hz, H-22), 1.15–
1.42 (m, 20H, H-6,7,8,9,10,17,18,19,20,21), 1.42–1.52 (4H,
m, H-11,16), 1.66 (2H, quintet, JZ7.0 Hz, H-5), 2.14 (4H, t,
)
3 3
2
2
2
2
2
9.04 (1C, CH ), 29.09 (2C, CH ), 29.10 (1C, CH ), 29.11
2
2
2
(
CH ), 31.81 (1C, CH ), 43.86 (1C, C-2), 80.09, 80.21 (2C,
C-11,12), 202.8 (1C, C-1).
1C, CH ), 29.13 (1C, CH ), 29.19 (1C, CH ), 29.27 (2C,
JZ7.0 Hz, H-12,15), 2.55 (2H, t, JZ7.5 Hz, H-4); d
(100.6 MHz, CDCl ) K0.80 (3C, –Si(CH ), 14.06 (1C,
C-22), 18.71 (2C, C-12,15), 22.62 (1C, CH ), 23.88 (1C,
C
2
2
2
)
3 3
2
2
3
2
C-5), 28.77 (1C, CH ), 28.82 (1C, CH ), 28.88 (1C, CH ),
2
2
2
5
.4.2. 1-(Trimethylsilyl)docosa-1,13-diyn-3-ol (rac-6). To
a stirred solution of trimethylsilylacetylene 7 (0.120 ml,
.865 mmol, 1.03 equiv) in anhydrous THF (4 ml) at
K12 8C was added n-BuLi (2.12 M in hexanes, 0.410 ml,
.865 mmol, 1.03 equiv) under argon. After stirring for 1 h
at K12 8C a pre-cooled solution of 8 (0.246 g, 0.840 mmol,
equiv) in anhydrous THF (1 ml, 2!0.5 ml wash) at
29.05 (1C, CH
(1C, CH
CH ), 31.80 (1C, CH
2
), 29.09 (1C, CH
2
), 29.13 (1C, CH
2
), 29.18
), 29.23 (1C, CH
), 29.27 (1C, CH ), 29.65 (1C,
2
2
2
0
2
2
), 45.25 (1C, C-4), 80.12, 80.22 (2C,
C-13,14), 97.48, 102.0 (2C, C-1,2), 188.0 (1C, C-3).
0
5.4.4. (R)-1-(Trimethylsilyl)docosa-1,13-diyn-3-ol (R-6).
To a solution of 18 (0.132 g, 0.340 mmol, 1 equiv) in de-
gassed isopropyl alcohol (1 ml) was added catalyst 24
(0.003 g, 0.005 mmol, 0.15 equiv) in one portion. The
mixture was stirred for 18 h at 30 8C under argon before
being concentrated to dryness in vacuo to afford the crude
product. The crude product was purified by flash chroma-
1
K12 8C was added dropwise via cannula. The reaction
mixture was stirred for 1.5 h, then quenched with NH Cl
(sat., 5 ml) and water (5 ml) before being extracted with
Et O (3!20 ml). The combined organic phases were
washed with NaCl(aq) (sat., 10 ml) and dried over
Na SO4(s). Removal of solvent in vacuo afforded the
4
(aq)
2
tography (90% PE 30–40, 10% Et O) on a silica column to
2
2
crude product, which was purified by flash chromatography
(
yield R-6 (0.129 g, 0.330 mmol, 97%, O95% ee) as a
colourless oil; R Z0.18 (90% PE 30–40, 10% Et O);
90% PE 30–40, 10% Et O) on a silica column to yield
2
f
2
2
5
K1
rac-6 (0.283 g, 0.724 mmol, 86%) as a colourless oil; R Z
[a] ZK1.1 (c 0.95, CHCl ); nmax/cm (thin film) 3389
f
D 3
K1
0
3
.27 (90% PE 30–40, 10% Et O); nmax/cm
(thin film)
350 (w, br), 2928 (s), 2855 (s), 2360 (w), 2171 (w), 1465
(m), 2928 (s), 2855 (s), 2358 (m), 2360 (m), 2172 (w), 1456
(m), 1333 (w), 1249 (m), 1026 (m), 843 (s), 760 (m); m/z
2
C
C
(
(
3
m), 1332 (m), 1250 (m), 1022 (m), 843 (s), 760 (m), 721
w), 699 (w); m/z Probe CI (NH ) 408.4 ([MNH ] , 32%)
Probe CI (NH ) 408.4 ([MNH ] , 100%); HRMS
3 4
C
C
C
found [MNH ] Z408.3592, C H NOSi requires
4 25 50
3
4
C
73.3 (55%), 310.3 (100%); HRMS found [MNH ] Z
408.3662; dH (400 MHz, CDCl3) 0.18 (9H, s,
–Si(CH ) ), 0.89 (3H, t, JZ7.0 Hz, H-22), 1.22–1.42
4
4
08.3663, C H NOSi requires 408.3662; d (400 MHz,
2
5
50
H
3 3
CDCl ) 0.18 (9H, s, –Si(CH ) ), 0.89 (3H, t, JZ7.0 Hz,
(m, 20H, H-6,7,8,9,10,17,18,19,20,21), 1.42–1.54 (6H, m,
H-5,11,16), 1.63–1.76 (2H, m, H-4), 1.80 (1H, d, JZ5.0 Hz,
–OH), 2.14 (4H, t, JZ5.0 Hz, H-12,15), 4.35 (1H, apparent
3
3 3
H-22), 1.22–1.42 (m, 20H, H-6,7,8,9,10,17,18,19,20,21),
1
.42–1.54 (6H, m, H-5,11,16), 1.63–1.76 (2H, m, H-4), 1.80

J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
7227
C
C
q, JZ6.0 Hz, H-3); dC (100.6 MHz, CDCl ) K0.14 (3C,
([MNH ] , 17%); HRMS found [MNH ] Z390.3379,
4 4
3
–
Si(CH ) ), 14.10 (1C, C-22), 18.74 (2C, C-12,15), 22.65
C H NO requires 390.3372; dH (400 MHz, CDCl3)
25 44 2
3
3
(
CH ), 29.11 (1C, CH ), 29.12 (1C, CH ), 29.13 (1C, CH ),
1C, CH ), 25.09 (1C, C-5), 28.85 (1C, CH ), 28.86 (1C,
0.88 (3H, t, JZ7.0 Hz, H-25), 1.18–1.52 (26H, m,
H-8,9,10,11,12,13,14,19,20,21,22,23,24), 1.64–1.80 (2H,
m, H-7), 2.13 (4H, t, JZ7.0 Hz, H-15,18), 2.49 (2H, br s,
–OH), 4.34 (2H, s, H-1), 4.42 (1H, t, JZ6.5 Hz, H-6); dC
2
2
2
2
2
2
2
9.15 (1C, CH ), 29.19 (1C, CH ), 29.22 (1C, CH ), 29.42
2 2 2
(1C, CH ), 29.45 (1C, CH ), 31.84 (1C, CH ), 37.69 (1C,
2 2 2
C-4), 62.90 (1C, C-3), 80.19, 80.25 (2C, C-13.14), 89.26,
(100.6 MHz, CDCl ) 14.09 (1C, C-25), 18.73 (2C,
C-15,18), 22.64 (1C, CH ), 25.01 (1C, CH ), 28.83 (1C,
3
1
06.9 (2C, C-1,2).
2
2
CH ), 28.84 (1C, CH ), 29.10 (2C, CH ), 29.14 (2C, CH ),
2
2
2
2
5
.4.5. (R)-Docosa-1,13-diyn-3-ol (5). To a solution of R-6
0.123 g, 0.315 mmol, 1 equiv) in MeOH (1.5 ml) was
29.16 (1C, CH ), 29.20 (1C, CH ), 29.41 (1C, CH ), 29.42
(1C, CH ), 31.82 (1C, CH ), 37.40 (1C, C-7), 51.29 (1C,
2 2
C-1), 62.76 (1C, C-6), 68.82, 69.73 (2C, C-3,4), 77.53,
80.24, 80.30, 80.46 (4C, C-2,5,16,17); microanalysis found
2
2
2
(
added NH F (0.117 g, 3.15 mmol, 10 equiv) in one portion.
The mixture was stirred overnight at 67 8C under argon
before being diluted with water (10 ml) and extracted with
4
CZ80.74, HZ10.95, C25H O requires CZ80.59, HZ
40 2
Et O (4!10 ml). The combined organic layers were
2
10.82.
washed with NaCl(aq) (sat., 10 ml) and dried over
Na SO4(s). Removal of solvent in vacuo afforded the
crude product, which was purified by flash chromatography
5.5. Synthesis of strongylodiol A R-1
2
(
(
(
(
2
1
1
80% PE 30–40, 20% Et O) on a silica column to yield 5
2
5.5.1. (Z)-Icos-11-en-1-ol (25). To a solution of 9 (0.128 g,
0.436 mmol) and anhydrous benzene (2 ml) were added
Lindlar’s catalyst (0.053 g) and quinoline (0.040 ml) under
argon. The mixture was stirred under H2(g) (1 atm, balloon)
at ambient temperature for 2 h. The mixture was filtered
through cellulose and washed with benzene (50 ml). The
combined filtrate was washed with KHSO4(aq) (1%, 10 ml),
neutralised with NaHCO3(aq) (sat., 10 ml), washed with
NaCl(aq) (sat., 10 ml) and dried over MgSO4(s). Removal of
solvent in vacuo afforded the crude product which was
purified by flash chromatography (80% PE 30–40, 20%
0.091 g, 0.287 mmol, 91%) as a white solid; R Z0.19
f
2
5
80% PE 30–40, 20% Et O); mp 44–44.5 8C; [a] ZC1.0
2
D
K1
c 0.74, CHCl ); nmax/cm
(KBr) 3340 (s, br), 3278 (s),
956 (s), 2930 (s), 2949 (s), 2848 (s), 2360 (w), 1636 (w),
3
466 (s), 1426 (w), 1384 (w), 1312 (w), 1262 (w), 1102 (m),
059 (m), 1021 (m), 977 (m), 935 (w), 898 (w), 856 (w), 803
(w), 723 (m), 685 (m), 668 (m), 553 (w), 470 (w); m/z Probe
CI (NH ) 336.3 ([MNH ] , 100%); HRMS found
C
C
3
4
C
[
(
MH] Z319.2999, C H O requires 319.3001; d
22 39 H
400 MHz, CDCl ) 0.89 (3H, t, JZ6.5 Hz, H-22), 1.22–
3
1
.42 (m, 20H, H-6,7,8,9,10,17,18,19,20,21), 1.42–1.54 (6H,
m, H-5,11,16), 1.63–1.76 (2H, m, H-4), 1.81 (1H, d, JZ
.5 Hz, KOH), 2.14 (4H, t, JZ7.0 Hz, H-12,15), 2.47 (1H,
d, JZ2.0 Hz, H-1), 4.38 (1H, apparent dq, J Z6.0 Hz, J Z
Et O) on a silica column to yield 25 (0.124 g, 0.417 mmol,
2
95%) as a colourless oil; R Z0.38 (50% PE 30–40, 50%
f
K1
Et O); nmax/cm (thin film) 3338 (m, br), 3005 (m), 2924
(s), 2853 (s), 1656 (w), 1465 (m), 1378 (m), 1058 (m), 967
5
2
1
2
C
C
2.0 Hz, H-3); dC (100.6 MHz, CDCl ) 14.10 (1C, C-22),
18.74 (2C, C-12,15), 22.65 (1C, CH ), 24.98 (1C, C-5),
2
(m), 722 (m); m/z Probe CI (NH ) 314.3 ([MNH ] ,
3 4
3
C
2
100%); HRMS found [MNH ] Z314.3408, C H NO
4 20 44
8.82 (1C, CH ), 28.85 (1C, CH ), 29.11 (1C, CH ), 29.12
2
requires 314.3423; dH (400 MHz, CDCl ) 0.87 (3H, t,
JZ6.5 Hz,
2
2
3
(1C, CH ), 29.13 (1C, CH ), 29.15 (1C, CH ), 29.19 (1C,
CH ), 29.21 (1C, CH ), 29.41 (1C, CH ), 29.44 (1C, CH ),
3
H-20),
1.18–1.40
(26H,
m,
H-
2
2
2
2
2
2
2
3,4,5,6,7,8,9,14,15,16,17,18,19), 1.57 (2H, qui, JZ7.0 Hz,
H-2), 1.94–2.09 (4H, m, H-10,13), 3.64 (2H, t, JZ6.5 Hz,
H-1), 5.31–5.42 (2H, m, H-11,12); d (100.6 MHz, CDCl )
1.83 (1C, CH ), 37.63 (1C, C-4), 62.33 (1C, C-3), 72.82
2
(
1C, C-1), 80.19, 80.26 (2C, C-13.14), 84.98 (1C, C-2).
C
3
14.07 (1C, C-20), 22.65, (1C, CH ), 25.72 (2C, CH ), 27.18
(2C, C-10,13), 29.14 (1C, CH
2
2
5
.4.6. (R)-Pentacosa-2,4,16-triyne-1,6-diol (R-2). To a
2
), 29.29 (1C, CH ), 29.41
2
mixture of 5 (0.079 g, 0.247 mmol, 1 equiv), anhydrous
CuCl powder (0.003 g, 0.030 mmol, 0.12 equiv, cat.), 33%
methanolic ethylamine (0.325 ml, 1.88 mmol, 7.5 equiv)
and hydroxylamine hydrochloride (0.010 g, 0.144 mmol,
(1C, CH
CH ), 29.63 (1C, CH
31.88 (1C, CH ), 32.79 (1C, C-2), 63.05 (1C, C-1), 129.8,
2
), 29.50 (1C, CH
2
), 29.54 (1C, CH
2
), 29.58 (1C,
), 29.67 (1C, CH
2
), 29.74 (1C, CH
),
2
2
2
2
129.9 (2C, C-11,12).
0
0
.58 equiv) in MeOH (0.5 ml) was added 4 (0.047 g,
.35 mmol, 1.40 equiv) via cannula over 30 min. The
5.5.2. (Z)-Icos-11-enal (26). To a stirred solution of IBX
(0.463 g, 1.65 mmol, 2 equiv) in DMSO (3 ml) under argon
was added 25 (0.232 g, 0.781 mmol, 1 equiv) in anhydrous
THF (2 ml, 2!0.5 ml wash) via cannula. The reaction
mixture was stirred for 3 h, after which water (12 ml) was
added. In a few minutes a white precipitate had formed
which was removed by filtration through a sintered glass
funnel. The residue was washed with cold EtOAc (6 ml).
The combined organics were extracted with EtOAc (4!
10 ml), washed with NaCl(aq) (sat., 10 ml) and dried over
yellow suspension was stirred at ambient temperature for
h before being diluted with water (10 ml) and extracted
with Et O (3!20 ml). The combined organic layers were
3
2
washed with NaHSO4(aq) (1%, 10 ml) and NaCl(aq) (sat.,
10 ml), and dried over Na SO4(s). Removal of solvent in
2
vacuo afforded the crude product, which was purified by
flash chromatography (50% PE 30–40, 50% Et O) on a
2
silica column to yield R-2 (0.076 g, 0.20 mmol, 82%) as a
white solid; R Z0.19 (50% PE 30–40, 50% Et O); mp 58–
f
2
22
2
5
5
0
8.5 8C; [a] ZK7.1 (c 0.90, CHCl ), lit. [a] ZK7.1 (c
Na SO4(s). Removal of solvent in vacuo afforded the crude
2
D
3
D
3
.42, CHCl ) ; nmax/cm (KBr) 3305 (s, br), 2931 (s), 2848
K1
product, which was purified by flash chromatography (96%
PE 30–40, 4% Et O) on a silica column to yield 26 (0.201 g,
3
(s), 2361 (w), 2343 (w), 1463 (s), 1439 (m), 1428 (m), 1354
m), 1320 (m), 1292 (w), 1280 (w), 1265 (w), 1222 (w), 1224
2
0.682 mmol, 87%) as a white solid; R Z0.12 (96% PE 30–
f
K1
(
(
w), 1104 (w), 1064 (s), 1049 (m), 1030 (s), 980 (w), 964
m), 934 (m), 900 (w), 856 (m); m/z Probe CI (NH ) 390.4
40, 4% Et O; nmax/cm
(thin film) 3004 (w), 2925 (s),
2854 (s), 2112 (w), 1728 (m), 1465 (m), 1409 (w), 1378 (w),
2
C
3

7228
J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
C
302 (w), 968 (w), 722 (w); m/z Probe CI (NH ) 312.3
1
on a silica column to yield 28 (0.189 g, 0.485 mmol, 93%)
as a colourless oil; R Z0.38 (95% PE 30–40, 5% Et O);
3
C
C
(
C H NO requires 312.3266; d (400 MHz, CDCl3)
[MNH ] ); HRMS found [MNH ] Z312.3253,
4
4
f
2
K1
nmax/cm
(thin film) 3004 (m), 2925 (s), 2854 (s), 2151
2
0
42
H
0
.88 (3H, t, JZ6.5 Hz, H-20), 1.18–1.40 (24H, m,
H-4,5,6,7,8,9,14,15,16,17,18,19), 1.63 (2H, qui, JZ
.0 Hz, H-3), 2.01–2.07 (4H, m, H-10,13), 2.42 (2H, dt,
J Z7.5 Hz, J Z2.0 Hz, H-2), 5.28–5.21 (2H, m, H-11,12),
(w), 1681 (s), 1465 (m), 1406 (m), 1353 (w), 1252 (s), 1217
(w), 1112 (m), 1082 (m), 846 (s), 761 (m), 722 (w), 665 (w);
C
C
7
m/z Probe CI (NH ) 408.4 ([MNH ] , 100%); HRMS
3 4
C
found [MNH ] Z408.3654, C H NOSi requires
1
2
4
25 50
9
.77 (1H, t, JZ2.0 Hz, H-1); d (100.6 MHz, CDCl ) 14.08
408.3662; d (400 MHz, CDCl ) 0.25 (9H, s, –Si(CH ) ),
C
3
H 3 3 3
(
(
(
1C, C-20), 22.06 (1C, C-3), 22.66 (1C, CH ), 27.16, 27.18
2C, C-10,13), 29.14 (1C, CH ), 29.23 (1C, CH ), 29.30
0.89 (3H, t, JZ7.0 Hz, H-22), 1.24–1.42 (m, 24H,
H-6,7,8,9,10,11,16,17,18,19,20,21), 1.58–1.73 (m, 2H, H-
5), 1.92–2.10 (4H, m, H-12,15), 2.55 (2H, t, JZ7.5 Hz, H-
4), 5.30–5.41 (m, 2H, H-13,14); dC (100.6 MHz, CDCl3)
K0.78 (3C, –Si(CH ) ), 14.09 (1C, C-22), 22.66 (1C, CH ),
2
2
2
1C, CH ), 29.32 (1C, CH ), 29.37 (1C, CH ), 29.44 (1C,
2
2
2
CH ), 29.50 (1C, CH ), 29.72 (1C, CH ), 29.74 (1C, CH ),
2
3
1
2
2
2
1.88 (1C, CH ), 32.56 (1C, CH ), 43.89 (1C, C-2), 129.8,
2 2
29.9 (2C, C-11,12), 202.9 (1C, C-1).
3 3
2
23.91 (1C, C-5), 27.18 (2C, CH ), 28.92 (1C, CH ), 29.26
2 2
(1C, CH ), 29.30 (3C, CH ), 29.38 (1C, CH ), 29.46 (1C,
CH
45.29 (1C, C-4), 97.51, 102.4 (2C, C-1,2), 129.8, 129.9 (2C,
C-13,14), 188.1 (1C, C-3).
2
2
2
5
2
.5.3. (Z)-1-(Trimethylsilyl)docos-13-en-1-yn-3-ol (rac-
7). To a stirred solution of trimethylsilylacetylene 7
0.098 ml, 0.708 mmol, 1.03 equiv) in anhydrous THF
2
), 29.50 (1C, CH
2
), 29.74 (2C, CH
2
), 31.89 (1C, CH ),
2
(
(
4 ml) at K128 was added n-BuLi (1.28 M in hexanes,
0
.553 ml, 0.708 mmol, 1.03 equiv) under argon. After
stirring for 1 h at K12 8C a pre-cooled solution of 26
0.201 g, 0.687 mmol, 1 equiv) in anhydrous THF (1 ml,
!0.5 ml wash) at K12 8C was added dropwise via
cannula. The reaction mixture was stirred for 1.5 h, then
quenched with NH Cl (sat., 5 ml) and water (5 ml)
5.5.5. (R,Z)-1-(Trimethylsilyl)docos-13-en-1-yn-3-ol
(R-27). To a solution of 28 (0.028 g, 0.072 mmol, 1 equiv)
in de-gassed isopropyl alcohol (1 ml) was added catalyst 24
(0.0024 g, 0.004 mmol, 0.06 equiv) in one portion. The
mixture was stirred overnight at 30 8C under argon before
removal of solvent in vacuo and purification by flash
(
2
4
(aq)
before being extracted with Et O (3!20 ml). The combined
2
chromatography (90% PE 30–40, 10% Et
column to yield R-27 (0.027 g, 0.070 mmol, 97%, O95%
ee) as a colourless oil; R Z0.28 (80% PE 30–40, 20%
2
O) on a silica
organic phases were washed with NaCl(aq) (sat., 10 ml) and
dried over Na SO4(s). Removal of solvent in vacuo afforded
2
f
2
5
K1
the crude product, which was purified by flash chromato-
graphy (90% PE 30–40, 10% Et O) on a silica column to
yield rac-27 (0.283 g, 0.721 mmol, 76%) as a colourless oil;
Et O); [a] ZK1.2 (c 1.02, CHCl ); nmax/cm (thin film)
2 D 3
3324 (w, br), 3005 (w), 2925 (s), 2854 (m), 2172 (w), 1466
(m), 1406 (w), 1378 (w), 1333 (w), 1250 (s), 1019 (m), 843
2
K1
C
R Z0.16 (90% PE 30–40), 10% Et O; nmax/cm (thin film)
(s), 760 (m), 722 (w), 700 (w); m/z Probe CI (NH ) 393.4
3
f
2
C
C
3
326 (w, br), 3005 (m), 2925 (s), 2854 (s), 2172 (w), 1466
m), 1406 (w), 1378 (w), 1250 (s), 1017 (m), 909 (w), 844
([MH] , 100%); HRMS found [MH] Z393.3553,
49OSi requires 393.3553; d (400 MHz, CDCl ) 0.18
(9H, s, –Si(CH ), 0.89 (3H, t, JZ7.0 Hz, H-22), 1.22–1.39
(
(
(
C
25
H
H
3
C
s), 760 (m), 735 (m), 700 (m); m/z Probe CI (NH ) 410.4
[MNH ] ); HRMS found [MNH ] Z410.3827,
)
3 3
3
C
C
(m, 24H, H-6,7,8,9,10,11,16,17,18,19,20,21), 1.39–1.54
(2H, m, H-5), 1.65–1.75 (2H, m, H-4), 1.79 (1H, d, JZ
5.0 Hz, –OH), 1.99–2.03 (4H, m, H-12,15), 4.36 (1H,
apparent q, JZ5.5 Hz, H-3), 5.31–5.41 (2H, m, H-13,14);
4
4
C H NOSi requires 410.3818; d (400 MHz, CDCl3)
2
5
52
H
0
1
1
.18 (9H, s, –Si(CH ) ), 0.89 (3H, t, JZ7.0 Hz, H-22),
.22–1.38 (m, 24H, H-6,7,8,9,10,11,16,17,18,19,20,21),
.38–1.50 (2H, m, H-5), 1.63–1.76 (2H, m, H-4), 1.81
3 3
d
(100.6 MHz, CDCl
C-22), 22.67 (1C, CH
C-10,13), 29.20 (1C, CH
CH ), 29.51 (3C, CH ), 29.76 (2C, CH
) K0.13 (3C, –Si(CH
), 25.09 (1C, C-5), 27.19 (2C,
), 29.31 (3C, CH ), 29.48 (1C,
), 31.89 (1C, CH ),
) ), 14.11 (1C,
C
3
3 3
(
(
1H, d, JZ5.5 Hz, –OH), 1.93–2.08 (4H, m, H-12,15), 4.35
1H, apparent q, JZ4.5 Hz, H-3) 5.29–3.41 (2H, m,
H-13,14); dC (100.6 MHz, CDCl3) K0.14 (3C,
2
2
2
2
2
2
2
–
Si(CH ) ), 14.09 (1C, C-22), 22.66 (1C, CH ), 25.08
3
37.69 (1C, C-4), 62.91 (1C, C-3), 89.26, 106.9 (2C, C-1,2),
129.9 (2C, C-13,14).
3
2
‡
(1C, C-5), 27.19 (2C, C-12,15), 29.20 (1C, CH ), 29.30 (1C,
CH ), 29.48 (1C, CH ), 29.50 (1C, CH ), 29.63 (1C, CH ),
2
2
2
2
2
2
9.75 (1C, CH ), 31.89 (1C, CH ), 32.59 (1C, CH ), 37.69
2
5.5.6. (R,Z)-Docos-13-en-1-yn-3-ol (29). To a solution of
R-27 (0.125 g, 0.318 mmol, 1 equiv) in MeOH (2 ml) was
2
2
(
1
1C, C-4), 62.90 (1C, C-3), 89.24, 106.9 (2C, C-1,2), 129.8,
29.9 (2C, C-13,14).
added NH
The mixture was stirred for 18 h at 67 8C under argon before
being diluted with water (10 ml) and extracted with Et
(4!10 ml). The combined organic layers were washed with
NaCl(aq) (sat., 10 ml) and dried over Na SO4(s). Removal of
F (0.117 g, 3.18 mmol, 10 equiv) in one portion.
4
5.5.4. (Z)-1-(Trimethylsilyl)docos-13-en-1-yn-3-one (28).
To a stirred solution of IBX (0.292 g, 1.04 mmol, 2 equiv)
in DMSO (3 ml) under argon was added rac-27 (0.205 g,
0
wash) via cannula. The reaction mixture was stirred for 3 h,
after which water (12 ml) was added. In a few minutes a
white precipitate had formed which was removed by
filtration through a sintered glass funnel. The residue was
washed with cold EtOAc (6 ml). The combined organics
were extracted with EtOAc (4!10 ml), washed with
O
2
2
.522 mmol, 1 equiv) in anhydrous THF (1 ml, 2!0.5 ml
solvent in vacuo afforded the crude product, which was
purified by flash chromatography (80% PE 30–40, 20%
Et
91%) as a white solid; R
O) on a silica column to yield 29 (0.091 g, 0.287 mmol,
Z0.19 (80% PE 30–40, 20%
2
f
2
5
Et O); mp 44–44.5 8C; [a] ZC1.6 (c 1.60, CHCl ); nmax/
2 D 3
K1
cm (KBr) 3311 (s), 3005 (m), 2924 (s), 2853 (s), 2361
(w), 2341 (w), 1653 (w), 1465 (m), 1404 (m), 1378 (m),
1308 (m), 1025 (m), 722 (m), 655 (m), 627 (m), 556 (w),
NaCl(aq) (sat., 10 ml) and dried over Na SO4(s). Removal
2
of solvent in vacuo afforded the crude product, which was
purified by flash chromatography (95% PE 30–40, 5% Et O)
‡
Can be resolved as 129.85 and 129.90.
2

J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
7229
C
96 (w), 474 (m), 460 (m); m/z Probe CI (NH ) 338.3
4
and then at K12 8C for 1 h, before being quenched with
NH Cl (sat., 25 ml) and extracted with Et O (3!20 ml).
The combined organic layers were washed with NaCl(aq)
3
C
C
(
C H NO requires 338.3423; d (400 MHz, CDCl ) 0.89
[MNH ] , 100%); HRMS found [MNH ] Z338.3411,
4
4
4
(aq)
2
2
2
44
H
3
(
3H, t, JZ6.5 Hz, H-22), 1.22–1.40 (m, 24H,
H-6,7,8,9,10,11,16,17,18,19,20,21), 1.40–1.52 (2H, m,
(sat., 20 ml) and dried over Na SO4(s). Removal of solvent
2
in vacuo afforded the crude product, which was purified by
flash chromatography (90% PE 30–40, 10% Et O) on a
H-5), 1.67–1.76 (2H, m, H-4), 1.83 (1H, s, –OH), 2.02
(
2
5
C-22), 22.66 (1C, CH ), 24.98 (1C, CH ), 27.18 (2C, CH ),
2
(5C, CH ), 29.75 (2C, CH ), 31.88 (1C, CH ), 37.64 (1C,
C-4), 62.33 (1C, C-3), 72.79 (1C, C-1), 85.00 (1C, C-2),
1
2
4H, apparent q, JZ6.0 Hz, H-12,15), 2.47 (1H, d, JZ
silica column to yield rac-15 (1.30 g, 4.61 mmol, 85%) as a
pale yellow oil; R Z0.22 (90% PE 30–40, 10% Et O); nmax/
.0 Hz, H-1), 4.37 (1H, apparent q, JZ6.0 Hz, H-3), 5.31–
.40 (2H, m, H-13,14); d (100.6 MHz, CDCl ) 14.09 (1C,
f
2
K1
cm (thin film) 3326 (m, br), 2924 (s), 2855 (s), 2173 (m),
1466 (m), 1407 (m), 1378 (m), 1334 (m), 1250 (s), 1128
(m), 1028 (m), 843 (s), 760 (m), 721 (m), 699 (m), 666 (m);
C
3
2
2
2
9.21 (1C, CH ), 29.27 (1C, CH ), 29.30 (2C, CH ), 29.49
2 2 2
C
C
m/z Probe CI (NH ) 300.3 ([MNH ] , 20%), 282.2
3 4
2
2
2
C
([MH] , 31%), 265.2 (42%), 191.2 (79%), 90.1 (61%), 73.0
C
29.8, 129.9 (2C, C-13,14).
(100%); HRMS found [MNH ] Z300.2711, C H NOSi
4
17 38
requires 300.2723; dH (400 MHz, CDCl ) 0.18 (9H, s,
–Si(CH ) ), 0.88 (3H, t, JZ7.0 Hz, H-14), 1.18–1.38 (16H,
3
5
.5.7. (R,Z)-Pentacosa-16-en-2,4-diyne-1,6-diol (R-1). To
3
3
a mixture of 29 (0.042 g, 0.132 mmol, 1 equiv), anhydrous
CuCl powder (0.003 g, 0.030 mmol, 0.12 equiv, cat.),
methanolic ethylamine (2.03 M, 0.470 ml, 0.954 mmol,
m, H-6,7,8,9,10,11,12,13), 1.38–1.52 (2H, m, H-5), 1.60–
1.78 (2H, m, H-4), 1.87 (1H, d, JZ5.5 Hz, –OH), 4.35 (1H,
apparent q, JZ6.0 Hz, H-3); dC (100.6 MHz, CDCl3)
K0.14 (3C, –Si(CH ) ), 14.10 (1C, C-14), 22.67 (1C,
7
0
.5 equiv) and hydroxylamine hydrochloride (0.050 g,
.730 mmol, 5.5 equiv) in MeOH (0.5 ml) was added 4
3
3
CH ), 25.08 (1C, C-5), 29.19 (1C, CH ), 29.33 (1C, CH ),
2 2 2
(
0.037 g, 0.270 mmol, 2.0 equiv) via cannula over 30 min.
29.48 (1C, CH ), 29.52 (1C, CH ), 29.62 (1C, CH ), 29.63
2 2 2
The yellow suspension was stirred at ambient temperature
for 3 h before being diluted with water (10 ml) and extracted
with Et O (3!20 ml). The combined organic layers were
(1C, CH ), 31.90 (1C, CH ), 37.68 (1C, C-4), 62.89 (1C,
2 2
C-3), 89.24, 106.93 (2C, C-1,2).
2
washed with NaHSO4(aq) (1%, 10 ml) and NaCl(aq) (sat.,
10 ml) and dried over Na SO4(s). Removal of solvent in
2
vacuo afforded the crude product, which was purified by
5.6.2. 1-Trimethylsilyl-tetradec-1-yn-3-one (30). To a
stirred solution of IBX (0.151 g, 0.541 mmol, 1.5 equiv)
in DMSO (3 ml) under argon was added rac-15 (0.101 g,
0.356 mmol, 1 equiv) in anhydrous THF (0.5 ml, 2!0.5 ml
wash) via cannula. The reaction mixture was stirred for 3 h,
after which water (12 ml) was added. In a few minutes a
white precipitate had formed which was removed by
filtration through a sintered glass funnel. The residue was
washed with cold EtOAc (6 ml). The combined organics
were extracted with EtOAc (4!10 ml), washed with
flash chromatography (50% PE 30–40, 50% Et O) on a
2
silica column to yield R-1 (0.039 g, 0.105 mmol, 80%) as a
white solid; R Z0.25 (50% PE 30–40, 50% Et O); mp 56–
f
2
2
5
22
5
1
2
1
6.5 8C; [a] ZK7.1 (c 1.04, CHCl ), lit. [a] ZK7.2 (c
D 3 D
3 K1
.11, CHCl ) ; nmax/cm
(KBr) 3296 (m, br), 3003 (m),
3
920 (s), 2847 (s), 1463 (s), 1442 (m), 1406 (m), 1352 (m),
318 (m), 1064 (s), 1031 (s), 965 (m), 901 (m), 806 (m); m/z
C
C
Probe CI (NH ) 392.4 ([MNH ] , 100%), 312.3 (76%);
3
NaCl(aq) (sat., 10 ml) and dried over Na SO4(s). Removal
2
4
C
HRMS found [MNH ] Z392.3532, C H NO requires
4
25 46
2
of solvent in vacuo afforded the crude product, which was
purified by flash chromatography (97% PE 30–40, 3% Et O)
3
92.3529; dH (400 MHz, CDCl ) 0.89 (3H, t JZ7.0 Hz,
3
2
H-25), 1.22–1.39 (24H, m, H-9,10,11,12,13,14,19,
0,21,22,23,24), 1.39–1.50 (2H, m, H-8), 1.65–1.80 (2H,
on a silica column to yield 30 (0.099 g, 0.352 mmol, 98%)
as a colourless oil; R Z0.38 (97% PE 30–40, 3% Et O);
2
f
2
K1
m, H-7), 1.90–2.10 (6H, m, 2!-OH, H-15,18), 4.35 (2H, s,
H-1), 4.39–4.47 (1H, m, H-6), 5.31–5.41 (m, 2H, H-16,17);
d (100.6 MHz, CDCl ) 14.11 (1C, C-25), 22.67 (1C, CH ),
nmax/cm (thin film) 2926 (s), 2856 (s), 2151 (w), 1679 (s),
1462 (m), 1408 (w), 1358 (w), 1253 (m), 1219 (w), 1334
(m), 1096 (m), 851 (s), 762 (m), 709 (w), 620 (w); m/z Probe
C
3
2
C
C
C
2
5.00 (1C, CH ), 27.19 (1C, CH ), 29.19 (1C, CH ), 29.28
2
CI (NH ) 298.3 ([MNH ] , 100%), 281.2 ([MH] , 65%);
3 4
2
2
C
(
CH ), 29.75 (3C, CH ), 31.89 (1C, CH ), 37.44 (1C, C-7),
1C, CH ), 29.30 (2C, CH ), 29.47 (1C, CH ), 29.50 (3C,
HRMS found [MH] Z281.2295, C H OSi requires
2
2
2
17 33
2
2
2
281.2301; d (400 MHz, CDCl ) 0.25 (9H, s, –Si(CH ) ),
H
3
3 3
5
7
1.41 (1C, C-1), 62.82 (1C, C-6), 68.80, 69.80 (2C, C-3,4),
7.48, 80.51 (2C, C-2,5), 129.9 (2C, C-16,17); micro-
0.88 (3H, t, JZ7.0 Hz, H-14), 1.20–1.36 (16H, m,
H-6,7,8,9,10,11,12,13), 1.66 (2H, quintet, JZ7.0 Hz,
H-5), 2.55 (2H, t, JZ7.5 Hz, H-4); dC (100.6 MHz,
CDCl ) K0.78 (3C, –Si(CH ) ), 14.08 (1C, C-14), 22.65
§
analysis found CZ79.73, HZ10.93, C H O requires
CZ80.16, HZ11.30.
2
5 42 2
3
3 3
(1C, CH ), 23.92 (1C, C-5), 28.91 (1C, CH ), 29.29 (1C,
2 2
5
.6. Synthesis of R-32, an analogue of strongylodiol B R-2
CH ), 29.30 (1C, CH ), 29.39 (1C, CH ), 29.56 (1C, CH ),
2 2 2 2
29.57 (1C, CH ), 31.88 (1C, CH ), 45.28 (1C, C-4), 97.50,
102.03 (2C, C-1,2), 188.1 (1C, C-3).
2 2
5
.6.1. 1-Trimethylsilyl-tetradec-1-yn-3-ol (rac-15). To a
stirred solution of 7 (0.750 ml, 5.42 mmol, 1 equiv) in
anhydrous THF (2 ml) at K12 8C was added n-BuLi
5.6.3. (3R)-1-Trimethylsilyl-tetradec-1-yn-3-ol (R-15).
To a solution of 30 (0.069 g, 0.244 mmol, 1 equiv) in de-
gassed isopropyl alcohol (2.5 ml) was added catalyst 24
(0.0015 g, 0.0025 mmol, 0.01 equiv) in one portion. The
mixture was stirred for 18 h at 30 8C under argon before
being concentrated to dryness in vacuo to afford the crude
product. The crude product was purified by flash chroma-
(
2.02 M in hexanes, 2.68 ml, 5.41 mmol, 1 equiv) under
argon. After stirring for 1 h at K12 8C a pre-cooled solution
of 14 (1.20 ml, 5.44 mmol, 1 equiv) in anhydrous THF
(2 ml, 2!0.5 ml wash) at K12 8C was added via cannula.
The reaction mixture was maintained at K78 8C for 30 min,
§
Can be resolved as 129.85 and 129.93.
tography (85% PE 30–40, 15% Et O) on a silica column to
2

7230
J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
yield R-15 (0.061 g, 0.215 mmol, 88%, O95% ee) as a
pale yellow oil; R Z0.24 (85% PE 30–40, 15% Et O);
3307 (s, br), 2926 (s), 2848 (s), 2361 (m), 2342 (m), 1636
(w), 1559 (w), 1540 (w), 1507 (w), 1463 (m), 1354 (w),
1316 (w), 1086 (m), 1060 (m), 1030 (s), 964 (w), 668 (m);
f
2
25
K1
[
a] ZK1.6 (c 1.29, CHCl ); nmax/cm (thin film) 3333
D 3
C
C
(
m, br), 2926 (s), 2856 (s), 2172 (m), 1462 (m), 1251 (m),
m/z Probe CI (NH ) 282.2 ([MNH ] , 24%), 264.2
3 4
C
027 (m), 845 (s), 760 (m), 700 (w); m/z Probe CI (NH )
C
C
1
3
3
([MH ], 41%); HRMS found [MNH ] Z282.2440,
3
4
C
C
00.3 ([MNH ] , 100%); HRMS found [MNH ] Z
C H NO requires 282.2433; dH (400 MHz, CDCl3)
4
4
17 32
2
00.2723, C H NOSi requires 300.2723; d (400 MHz,
0.89 (3H, t, JZ7.0 Hz, H-17), 1.20–1.38 (16H, m,
H-9,10,11,12,13,14,15,16), 1.38–1.50 (2H, m, H-8), 1.64–
1.80 (3H, m, H-7, –OH of C-1), 1.90 (1H, d, JZ5.5 Hz,
–OH of C-6), 4.36 (2H, d, JZ5.5 Hz, H-1), 4.44 (1H,
apparent q, JZ6.0 Hz, H-6); d (125.7 MHz, CDCl ) 13.97
1
7
38
H
CDCl ) 0.18 (9H, s, KSi(CH ) ), 0.89 (3H, t, JZ7.0 Hz,
3
3 3
H-14), 1.20–1.38 (16H, m, H-6,7,8,9,10,11,12,13), 1.38–
1
5
.52 (2H, m, H-5), 1.64–1.76 (2H, m, H-4), 1.81 (1H, d, JZ
.5 Hz, –OH), 4.36 (1H, apparent q, JZ6.5 Hz, H-3); dC
C
3
(
C-14), 22.65 (1C, CH ), 25.07 (1C, C-5), 29.19 (1C, CH ),
100.6 MHz, CDCl ) K0.15 (3C, KSi(CH ) ), 14.08 (1C,
(1C, C-17), 22.55 (1C, CH ), 24.89 (1C, C-8), 29.08 (1C,
CH ), 29.21 (1C, CH ), 29.35 (1C, CH ), 29.41 (1C, CH ),
3
3 3
2
2
2
2
2
2
2
2
9.31 (1C, CH ), 29.47 (1C, CH ), 29.51 (1C, CH ), 29.61
2
29.48 (1C, CH ), 29.50 (1C, CH ), 31.78 (1C, CH ), 37.37
2 2 2
2
2
(
C-4), 62.91 (1C, C-3), 89.25, 106.93 (2C, C-1,2).
1C, CH ), 29.63 (1C, CH ), 31.89 (1C, CH ), 37.70 (1C,
(1C, C-7), 51.34 (1C, C-1), 62.75 (1C, C-6), 68.70, 69.74,
77.38, 80.47 (4C, C-2,3,4,5).
2
2
2
5
.6.4. (3R)-Tetradec-1-yn-3-ol (31). To a solution of R-15
0.026 g, 0.092 mmol, 1 equiv) in MeOH (1.5 ml) was
5.7. General procedure for the preparation of MTPA
esters
(
added NH F (0.034 g, 0.920 mmol, 10 equiv) in one
4
portion. The mixture was stirred for 18 h at 67 8C under
argon before being diluted with water (10 ml) and extracted
with Et O (4!10 ml). The combined organic layers were
2
washed with NaCl(aq) (sat., 10 ml) and dried over Na SO4(s).
2
Removal of solvent in vacuo afforded the crude product,
which was purified by flash chromatography (85% PE 30–
To a solution of (R)-(C)-MTPA or (S)-(K)-MTPA
(0.048 g, 0.190 mmol, 4 equiv) in anhydrous hexane
(2 ml) was added DMF (0.015 ml, 0.190 mmol, 4 equiv)
and oxalyl chloride (0.065 ml, 0.760 mmol, 16 equiv). The
solution was stirred under argon for 2 h at ambient
temperature. The organic layer was transferred to another
flask and the solvent removed in vacuo. The residue was
4
0
0
0, 15% Et O) on a silica column to yield 31 (0.019 g,
2
.090 mmol, 98%) as a white solid; mp 28–28.5 8C; R Z
dissolved in anhydrous CHCl
DMAP (0.035 g, 0.285 mmol, 6 equiv) and alcohol
(0.048 mmol, 1 equiv) in CHCl (1 ml, 1!0.5 ml wash)
3
(1 ml) and a solution of
f
2
5
.34 (70% PE 30–40, 30% Et O); [a] ZC1.2 (c 0.95,
2
D
K1
CHCl ); nmax/cm
(KBr) 3299 (m), 3280 (s), 2954 (m),
3
3
2
1
917 (s), 2872 (m), 2848 (s), 2117 (w), 1470 (m), 1428 (w),
376 (w), 1305 (w), 1262 (w), 1128 (w), 1085 (m), 1062
was added via cannula. The reaction was stirred under argon
overnight at ambient temperature before being diluted with
DCM (3 ml). The organic layer was washed with KHSO4(aq)
(sat., 5 ml) followed by NaCl(aq) (sat., 5 ml) and dried over
(
m), 1036 (m), 998 (m), 964 (m), 928 (w), 892 (w), 855 (w),
C
09 (w), 719 (m), 679 (m), 658 (m); m/z Probe CI (NH )
8
2
2
3
C
C
28.2 ([MNH ] , 100%); HRMS found [MNH ] Z
Na
product, which was purified by flash chromatography (98%
PE 30–40, 2% Et O) to yield the Mosher’s ester.
2
SO4(s). Removal of solvent in vacuo afforded the crude
4
4
28.2319, C H NO requires 228.2327; d (400 MHz,
1
4
30
H
CDCl ) 0.89 (3H, t, JZ7.0 Hz, H-14), 1.20–1.38 (16H, m,
2
3
H-6,7,8,9,10,11,12,13), 1.38–1.52 (2H, m, H-5), 1.64–1.76
(
JZ2.0 Hz, H-1), 4.37 (1H, apparent q, JZ6.0 Hz, H-3); dC
2H, m, H-4), 1.84 (1H, d, JZ5.0 Hz, KOH), 2.47 (1H, d,
5.7.1. (S)-MTPA ester of (3R)-1-trimethylsilyl-docosa-
1,13-diyn-3-ol. R-6 (0.010 g, 0.025 mmol) was used
following the general procedure for the preparation of an
(S)-MTPA ester to yield (S)-((R)-1-(trimethylsilyl)docosa-
(
100.6 MHz, CDCl ) 14.06 (1C, C-14), 22.63 (1C, CH ),
3 2
2
4.96 (1C, C-5), 29.18 (1C, CH ), 29.29 (1C, CH ), 29.46
2 2
(
CH ), 31.86 (1C, CH ), 37.62 (1C, C-4), 62.32 (1C, C-3),
1C, CH ), 29.50 (1C, CH ), 29.57 (1C, CH ), 29.59 (1C,
1,13-diyn-3-yl) 3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoate (0.014 g, 0.024 mmol, 96%); dH (400 MHz,
2
2
2
2
2
7
2.76 (1C, C-1), 85.00 (1C, C-2).
CDCl ) 0.17 (9H, s, –Si(CH ) ), 0.89 (3H, t, JZ7.0 Hz,
3
3 3
H-22), 1.22–1.42 (20H, m, H-6,7,8,9,10,17,18,19,20,21),
1.42–1.54 (6H, m, H-5,11,16), 1.77–1.92 (2H, m, H-4), 2.15
5
.6.5. (6R)-Heptadeca-2,4-diyne-1,6-diol (R-32). To a
mixture of 31 (0.040 g, 0.190 mmol, 1 equiv), anhydrous
CuCl powder (0.003 g, 0.030 mmol, 0.16 equiv, cat.), 33%
methanolic ethylamine (0.260 ml, 1.33 mmol, 7 equiv) and
hydroxylamine hydrochloride (0.003 g, 0.043 mmol,
(4H, t, JZ7.0 Hz, H-12,15), 3.57 (3H, s, –OCH
t, JZ7.0 Hz, H-3), 7.39–7.44 (3H, m, –C ), 7.52–7.57
(2H, m, –C ); d (376.6 MHz, CDCl ) K71.84 (F, s).
3
), 5.51 (1H,
H
6 5
H
6
5
F
3
0
0
.23 equiv) in MeOH (0.5 ml) was added 4 (0.036 g,
.267 mmol, 1.41 equiv) via cannula over 30 min. The
5.7.2. (S)-MTPA ester of 1-trimethylsilyl-docosa-1,13-
diyn-3-ol. rac-6 (0.010 g, 0.025 mmol) was used following
the general procedure for the preparation of an (S)-MTPA
ester to yield (S)-1-(trimethylsilyl)docosa-1,13-diyn-3-yl
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (0.014 g,
yellow suspension was stirred at ambient temperature for
h before being diluted with water (10 ml) and extracted
with Et O (3!20 ml). The combined organic layers were
3
2
washed with NaHSO4(aq) (1%, 10 ml) and NaCl(aq) (sat.,
10 ml), and dried over Na SO4(s). Removal of solvent in
vacuo afforded the crude product, which was purified by
0.024 mmol, 96%); dH (400 MHz, CDCl ) 0.16 (50% of
3
9H, s, –Si(CH ) ), 0.18 (50% of 9H, s, –Si(CH ) ), 0.89
3 3
2
3 3
(3H, t, JZ7.0 Hz, H-22), 1.22–1.42 (m, 20H,
H-6,7,8,9,10,17,18,19,20,21), 1.42–1.54 (6H, m,
H-5,11,16), 1.70–1.92 (2H, m, H-4), 2.15 (4H, t, JZ
flash chromatography (50% PE 30–40, 50% Et O) on a
2
silica column to yield R-32 (0.042 g, 0.159 mmol, 84%) as a
white solid; R Z0.19 (50% PE 30–40, 50% Et O); mp 28–
7.0 Hz, H-12,15), 3.57 (50% of 3H, s, KOCH ), 3.61 (50%
of 3H, s, –OCH ), 5.51 (50% of 1H, t, JZ6.5 Hz, H-3), 5.56
f
2
3
2
D
5
K1
2
8.5 8C; [a] ZK7.0 (c 0.99, CHCl ); nmax/cm
(KBr)
3
3

J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
7231
(
50% of 1H, t, JZ6.5 Hz, H-3), 7.37–7.45 (3H, m, –C H ),
Acknowledgements
6
5
7
K71.84 (F, s), K71.51 (F, s).
.52–7.60 (2H, m, KC H ); d (376.6 MHz, CDCl3)
6 5 F
We thank Professor Kazuo Iguchi for providing us with the
spectra of natural strongylodiols A and B.
5
1
.7.3. (S)-MTPA ester of (3R)-1-trimethylsilyl-docosa-
3-en-1-yn-3-ol. R-27 (0.010 g, 0.025 mmol) was used
following the general procedure for the preparation of
an (S)-MTPA ester to yield (S)-((R,Z)-1-(trimethylsilyl)-
docos-13-en-1-yn-3-yl) 3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate (0.013 g, 0.021 mmol, 85%); dH
References and notes
1
2
. Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, R. Nat. Prod. Rep. 2004, 21, 1–49 and previous papers
in this series.
(
400 MHz, CDCl ) 0.16 (9H, –Si(CH ) ), 0.89 (3H, t, JZ
3 3 3
7
1
.0 Hz, H-22), 1.22–1.50 (26H, m, H-5,6,7,8,9,10,
1,16,17,18,19,20,21), 1.77–1.92 (2H, m, H-4), 2.15 (4H,
. (a) Fusetani, N.; Sugano, M.; Matsunaga, S.; Hashimoto, K.
Tetrahedron Lett. 1987, 28, 4311–4312. (b) Wright, A. E.;
McConnell, O. J.; Kohmoto, S.; Lui, M. S.; Thompson, W.;
Snader, K. M. Tetrahedron Lett. 1987, 28, 1377–1379. (c)
Gunasekera, S. P.; Faircloth, G. T. J. Org. Chem. 1990, 55,
t, JZ7.0 Hz, H-12,15), 3.57 (3H, s, –OCH ), 5.31–5.42 (2H,
3
m, H-13,14), 5.51 (1H, t, JZ7.0 Hz, H-3), 7.37–7.45 (3H,
m, –C H ), 7.52–7.58 (2H, m, KC H ); d (376.6 MHz,
CDCl ) K71.85 (3F, s, –CF ).
6
5
6
5
F
3
3
6
223–6225. (d) Patil, A. D.; Kokke, W. C.; Cochran, S.;
5
.7.4. (S)-MTPA ester of 1-trimethylsilyl-docosa-13-en-
-yn-3-ol. rac-27 (0.011 g, 0.028 mmol) was used follow-
Francis, T. A.; Tomszek, T.; Westley, J. W. J. Nat. Prod. 1992,
55, 1170–1177. (e) Isaacs, S.; Kashman, Y.; Loya, S.; Hizi, A.;
Loya, Y. Tetrahedron 1993, 49, 10435–10438. (f) Fusetani,
N.; Li, H.-Y.; Tamura, K.; Matsunaga, S. Tetrahedron 1993,
49, 1203–1210. (g) Li, H.-Y.; Matsunaga, S.; Fusetani, N.
J. Nat. Prod. 1994, 57, 1464–1467. (h) Tsukamoto, S.; Kato,
H.; Hirota, H.; Fusetani, N. J. Nat. Prod. 1997, 60, 126–130.
1
ing the general procedure for the preparation of an
0
(
S)-MTPA ester to yield (2 S)-3,3,3-trifluoro-2-methoxy-2-
phenyl-propionic acid 1-trimethylsilylethynyl-eicos-22-
enyl ester (0.017 g, 0.028 mmol, 100%); dH (500 MHz,
CDCl ) 0.17 (50% of 9H, –Si(CH ) ), 0.18 (50% of 9H,
3
3 3
–
Si(CH ) ), 0.89 (3H, t, JZ7.0 Hz, H-22), 1.22–1.50 (26H,
3. Watanabe, K.; Tsuda, Y.; Yamane, Y.; Takahashi, H.; Iguchi,
K.; Naoki, H.; Fujita, T.; Van Soest, R. W. M. Tetrahedron
Lett. 2000, 41, 9271–9276.
3
3
m, H-5,6,7,8,9,10,11,16,17,18,19,20,21), 1.77–1.92 (2H, m,
H-4), 2.03 (4H, apparent q, JZ7.0 Hz, H-12,15), 3.57 (50%
of 3H, s, –OCH ), 3.61 (50% of 3H, s, –OCH ), 5.31–5.42
3
3
4. Watanabe, K.; Tsuda, Y.; Yamane, Y.; Takahashi, K.; Iguchi,
K.; Naoki, H.; Fujita, T. Tennen Yuki Kagobutsu Toronkai
Koen Yoshishu 2000, 42nd ed., Nippon Kagakkai.
5. Yadav, J. S.; Mishra, R. K. Tetrahedron Lett. 2002, 43,
1739–1741.
(
2H, m, H-13,14), 5.51 (50% of 1H, t, JZ7.0 Hz, H-3), 5.56
(
50% of 1H, t, JZ7.0 Hz, H-3), 7.37–7.44 (3H, m, –C H ),
6
5
7
K71.96 (50% of 3F, s, –CF ), K72.29 (50% of 3F, s,
.53–7.59 (2H, m, KC H ); d (235.4 MHz, CDCl3)
6 5 F
3
–
CF3).
6. Reber, S.; Kn o¨ pfel, T. F.; Carreira, E. M. Tetrahedron 2003,
5
9, 6813–6817.
. Kirkham, J. E. D.; Courtney, T. D. L.; Lee, V.; Baldwin, J. E.
Tetrahedron Lett. 2004, 45, 5645–5647.
7
8
5
1
.7.5. (R)-MTPA ester of (3R)-1-trimethylsilyl-tetradec-
-yn-3-ol. R-15 (0.011 g, 0.039 mmol) was used following
. (a) Brandsma, L. Preparative Acetylene Chemistry, 2nd ed.;
Elsevier: Oxford, 1998. (b) Siemsen, P.; Livingston, R. C.;
Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632–2657.
. Polt, R.; Sames, D.; Churma, J. J. Org. Chem. 1999, 64,
the general procedure for the preparation of an (R)-MTPA
ester to yield (S)-((R)-1-(trimethylsilyl)tetradec-1-yn-3-yl)
3
0
–
,3,3-trifluoro-2-methoxy-2-phenylpropanoate (0.017 g,
.034 mmol, 87%); dH (400 MHz, CDCl ) 0.18 (3H, s,
Si(CH ) ), 0.89 (3H, t, JZ6.5 Hz, H-14), 1.18–1.38 (18H,
9
3
6
147–6158.
0. Frantz, D. E.; F a¨ ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
000, 122, 1806–1807.
1. (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
019–8022. (b) Frigerio, M.; Santagostino, M.; Sputore, S.;
3
3
1
1
m, H-5,6,7,8,9,10,11,12,13), 1.74–1.86 (2H, m, H-4), 3.61
2
(
(
3H, s, –OCH ), 5.56 (1H, t, JZ6.5 Hz, H-3), 7.36–7.44
3H, m, –C H ), 7.55–7.61 (2H, m, –C H ); d (376.6 MHz,
3
6
5
6
5
F
8
CDCl ) K71.50 (F, s).
3
Palmisano, G. J. Org. Chem. 1995, 60, 7272–7276. (c)
Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
1999, 64, 4537–4538.
5
3
.7.6. (R)-MTPA ester of 1-trimethylsilyl-tetradec-1-yn-
-ol. rac-15 (0.010 g, 0.035 mmol) was used following the
12. Mori, K.; Qian, Z.-H. Liebigs Ann. Chem. 1994, 291–295.
13. Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97,
891–892.
general procedure for the preparation of an (R)-MTPA
ester to yield (S)-1-(trimethylsilyl)tetradec-1-yn-3-yl 3,3,3-
trifluoro-2-methoxy-2-phenylpropanoate
0
(0.009 g,
.018 mmol, 51%); dH (400 MHz, CDCl ) 0.16 (50% of
14. Abrahams, S. R.; Shaw, A. G. Org. Synth. Coll. 1993, 8,
146–148.
3
9
H, s, –Si(CH ) ), 0.18 (50% of 9H, s, –Si(CH ) ), 0.89
3
15. (a) Hommes, H.; Brandsma, L. Recl. Trav. Chim. Pays-Bas
1997, 96, 160. (b) Macaulay, S. R. J. Org. Chem. 1980, 45,
734–735.
3
3 3
(3H, t, JZ7.0 Hz, H-14), 1.18–1.38 (18H, m,
H-5,6,7,8,9,10,11,12,13), 1.73–1.92 (2H, m, H-4), 3.57
(
(
50% of 3H, s, –OCH ), 3.61 (50% of 3H, s, –OCH ), 5.51
3
50% of 1H, t, JZ7.0 Hz, H-3), 5.56 (50% of 1H, t, JZ
16. Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2003, 5,
3197–3199.
3
7
.0 Hz, H-3), 7.36–7.44 (3H, m, –C H ), 7.52–7.60 (2H, m,
17. (a) Amador, M.; Ariza, X.; Garcia, J.; Oritz, J. Tetrahedron
Lett 2002, 43, 2691–2694. See: Ref. 16 therein. Ortiz, J.;
Garcia, J. Departament de Quı’mica Orga’nica, Universitat de
6
5
–C H ); d (376.6 MHz, CDCl ) K71.84 (F, s), K71.51 (F,
6 5 F 3
s).

7232
J. E. D. Kirkham et al. / Tetrahedron 61 (2005) 7219–7232
Barcelona. Personal communication. (Note: Carreira pre-
viously stated that these enantioselective addition reactions
are relatively insensitive to the presence of moisture. See: Ref.
2002, 4, 2977–2980. (c) Maezaki, N.; Kojima, N.; Tominaga,
H.; Yanai, M.; Tanaka, T. Org. Lett. 2003, 5, 1411–1414. (d)
Oritz, J.; Ariza, X.; Garcia, J. Tetrahedron: Asymmetry 2003,
14, 1127–1131. (e) Murga, J.; Garc ´ı a-Fortanet, J.; Carda, M.;
Marco, J. A. Tetrahedron Lett. 2003, 44, 1737–1739. (f) More,
J. D.; Finney, N. S. Synlett 2003, 1307–1310. (g) Garc ´ı a-
Fortanet, J.; Murga, J.; Carda, M.; Marco, J. A. Tetrahedron
2004, 60, 12261–12267. (h) Kojima, N.; Maezaki, N.;
Tominaga, H.; Yanai, M.; Urabe, D.; Tanaka, T. Chem. Eur.
J. 2004, 10, 672–680. (i) Maezaki, N.; Hirose, Y.; Tanaka, T.
Org. Lett. 2004, 6, 2177–2180. (j) Maezaki, N.; Tominaga, H.;
Kojima, N.; Yanai, M.; Urabe, D.; Tanaka, T. Chem. Commun.
2004, 406–407. (k) Arndt, H.-D.; Welz, R.; M u¨ ller, S.; Ziemer,
B.; Koert, U. Chem. Eur. J. 2004, 10, 3945–3962. (l) Georges,
Y.; Allenbach, Y.; Ariza, X.; Campagne, J.-M.; Garcia J. Org.
Chem. 2004, 69, 7387–7390. (m) Molander, G. A.; Dehmel, F.
J. Am. Chem. Soc. 2004, 126, 10313–10318. (n) Davidson,
M. H.; McDonald, F. E. Org. Lett. 2004, 6, 1601–1603. Trost,
B. M.; Ameriks, M. K. Org. Lett. 2004, 6, 1601–1603. (o)
Crimmins, M. T.; She, J. J. Am. Chem. Soc. 2004, 126,
12790–12791. (p) Katukojvala, S.; Barlett, K. N.; Lotesta,
S. D.; Williams, L. J. J. Am. Chem. Soc. 2004, 126,
15348–15349. (q) Franchini, L.; Compostella, F.; Donda, A.;
Mori, L.; Colombo, D.; De Libero, G.; Matto, P.; Ronchetti, F.;
Panza, L. Eur. J. Chem. 2004, 4755–4761. (r) Archambaud, S.;
Aphecetche-Julienne, K.; Guingant, A. Synlett 2005, 139–143.
(s) Strand, D.; Rein, T. Org. Lett. 2005, 7, 199–202.
3
1. However, Garcia et al. deemed it necessary to thoroughly
dry the Zn(OTf) to effect a successful reaction. In addition,
Garcia et al. observed that the source of Zn(OTf) affects the
yield of reaction and that the reaction worked best when the
Zn(OTf) is in powder form).
8. (a) Ariza, X.; Garcia, J.; L o´ pez, M.; Montserrat, L. Synlett
001, 120–122. (b) Gung, B. W.; Dickson, H.; Shockley, S.
2
2
2
1
2
Tettrahedron Lett. 2001, 42, 4761–4763. (c) Gung, B. W.;
Dickson, H. D.; Seggerson, S.; Bluhm, K. Synth. Commun.
2002, 32, 2733–2740. (d) Ahmed, A.; Crawford, T.; Gould, S.;
Ha, Y. S.; Hollrah, M.; Noor-E-Ain, F.; Dickman, M. B.;
Dussault, P. H. Phytochemistry 2003, 63, 47–52. (e) Ariza, X.;
Fern a´ ndez, N.; Garcia, J.; L o´ pez, M.; Montserrat, L.; Ortiz, J.
Synthesis 2004, 128–134. (f) Alcaide, B.; Almendros, P.;
Alonso, J. M. J. Org. Chem. 2004, 69, 993–996. (g) Fenster,
M. D. B.; Dake, G. R. Chem. Eur. J. 2005, 11, 639–649. (h)
L o´ pez, F.; Castedo, L.; Mascare n˜ as, J. L. Org. Lett. 2005, 7,
2
87–290.
9. Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun. 2002,
524–1525.
1
1
2
2
2
0. Jiang, B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451–3453.
1. Rozners, E.; Xu, Q. Org. Lett. 2003, 5, 3999–4001.
2. Kojima, N.; Maezaki, N.; Tominaga, H.; Asai, M.; Yanai, M.;
Tanaka, T. Chem. Eur. J. 2003, 9, 4980–4990.
2
2
2
2
2
3. Bennet, M. A.; Huang, T. N.; Matheson, T. W.; Smith, A. K.
Inorg. Synth. 1982, 21, 74–78.
4. Tietze, L. F.; Zhou, Y.; T o¨ pken, E. Eur. J. Org. Chem. 2000,
31. (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687–9688. (Note: it is interesting that in this reference the
experimental procedure details drying of the Zn(OTf) under
2
2247–2252.
heat and vacuum overnight, whereas it is stated within the
body of the text that the reaction is tolerant to moisture.). (b)
Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4,
2605–2606.
5. Haak, K.-J.; Hashiguchi, S.; Akio, F.; Ikariya, F.; Noyori, R.
Angew. Chem., Int. Ed. 1997, 36, 285–288.
6. Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738–8739.
7. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
32. Most documented protocols described the reaction as a
‘mixture’. Three further described the reaction as a ‘slurry’.
(See: Refs. 30e,t,q). Only a single reference described the
2543–2549.
2
8. Kalogerakis, A.; Groth, U. Synlett 2003, 1886–1888.
9. Poulain, S.; Noiret, N.; Nugier-Chauvin, C.; Patin, H. Liebigs
Ann. Chem. 1997, 35–40.
2
formation of a ‘nearly homogeneous’ mixture of Zn(OTf) ,
2
N-methylephedrine and alkyne. (See: Ref. 17a). Interestingly,
the same authors subsequently described the reaction as a
slurry. (See: Ref. 30e).
3
0. (a) . For contributions outside the Carreira group see: Dieter,
R. K.; Yu, H. Org. Lett. 2001, 3, 3855–3858. (b) Maezaki, N.;
Kojima, N.; Asai, M.; Tominaga, H.; Tanaka, T. Org. Lett.
33. Meuzelaar, G. J.; Van-Vliet, M. C. A.; Maat, L.; Sheldon,
R. A. Eur. J. Org. Chem. 1999, 2315–2321.