Cu-mediated Stille reactions of sterically congested fragments: Towards the total synthesis of zoanthamine

Article abstract of DOI:10.1016/j.tet.2005.06.005

A study on the Stille reaction of alkenyl iodides and stannanes with structural resemblance to retrosynthetic fragments of a projected total synthesis of the marine alkaloid zoanthamine was carried out. A range of reaction conditions was examined, and a p

Full text of DOI:10.1016/j.tet.2005.06.005

Tetrahedron 61 (2005) 8013–8024
Cu-mediated Stille reactions of sterically congested fragments:
towards the total synthesis of zoanthamine
*
Thomas E. Nielsen, Sebastian Le Quement, Martin Juhl and David Tanner
Department of Chemistry, Technical University of Denmark, Kemitorvet, Building 201, DK-2800 Kgs. Lyngby, Denmark
Received 11 April 2005; revised 17 May 2005; accepted 2 June 2005
Available online 23 June 2005
Abstract—A study on the Stille reaction of alkenyl iodides and stannanes with structural resemblance to retrosynthetic fragments of a
projected total synthesis of the marine alkaloid zoanthamine was carried out. A range of reaction conditions was examined, and a protocol
developed by Corey utilizing excess copper(I) chloride and lithium chloride was found to be most efficient. The methodology was
successfully applied to join two major fragments of the zoanthamine skeleton.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
and C22 methyl groups on the C ring.8 However, more than
20 years after the initial discovery went by before Miyashita
and co-workers recently reported the first total synthesis of
norzoanthamine in 41 steps in an overall yield of 3.5%.9
Since their discovery,1 the zoanthamine alkaloids (Fig. 1)
have been intensively investigated targets in marine natural
product chemistry.2 Yet, the mechanism of biological action
and the biosynthetic origin of these fascinating molecular
entities remain uncertain. Several related compounds have
been isolated from Zoanthus sp.,3 and a range of synthetic
studies have been carried out, most notably with focus on
the construction of the unusual double hemiaminal core of
zoanthamine (1) and norzoanthamine (2).4 Other studies
have dealt with the synthesis of the AB ring system of
norzoanthamine,5 the ABC ring systems of zoanthamine6
and zoanthenol,7 and the incorporation of the quarternary C9
It is not only the unique and challenging structural topology
that has made the zoanthamine alkaloids attractive targets
for synthetic organic chemists. The zoanthamine alkaloids
have also been reported to exhibit a range of interesting
biological properties. For example, zoanthamine (1) has
displayed potent inhibitory activity towards phorbol
myristate acetate induced inflammation of the mouse
ear,10 and norzoanthamine (2) has been reported to be a
potent inhibitor of growth of murine leukemia cells.11 Also
Figure 1. Representative zoanthamine alkaloids.
Keywords: Zoanthamine; Stille coupling.
*
Corresponding author. Tel.: C45 45 25 21 88; fax: C45 45 93 39 68; e-mail: dt@kemi.dtu.dk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.005

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T. E. Nielsen et al. / Tetrahedron 61 (2005) 8013–8024
osteoporosis may be prevented, as indicated by the
observation of significant suppression of bone weight
decrease and weakening in ovariectomized mice treated
with norzoanthamine (2).12
present in either fragments B and C of the Stille coupling.
Furthermore, C20 of fragment C may be either at the ketone
or alcohol stage, anticipating that each oxidation state
displays fundamentally different steric and electronic
properties, which should greatly affect the coupling process.
Finding the optimal combination (stannane/halide, and
alcohol/ketone) for the proposed Stille coupling represents
the major research objective of the present study. Since
stannanes may be easily converted to halides by halodes-
tannylation reactions, it was decided to follow synthetic
strategies directed towards each fragment in its stannylated
form.
Palladium-catalyzed Stille reactions of organic electrophiles
with organostannane reagents represent straightforward and
highly effective methods for carbon–carbon bond formation
in total syntheses of natural products.13 Despite having lost
some of its popularity to environmentally more benign
protocols,14 the Stille reaction remains a significant tool for
the assembly of advanced and often highly complex
fragments. Bearing in mind the unique functional group
tolerance, mild reaction conditions and high reliability of
this coupling process, in addition to a variety of well-
established routes towards organo-stannanes,15 we decided
to investigate the coupling of two sterically congested major
fragments B and C (Fig. 2) via the Stille reaction in a
projected total synthesis of the marine alkaloid
zoanthamine.16
2. Results and discussion
The synthesis of fragment B commenced with a Pd-
catalyzed hydrostannation of methyl propiolate (Scheme 1).
In their original report,17 Guibe et al. reported a 100%
´
regioselectivity in favour of the a-stannylated product at rt.
However, in our hands 10–15% of other regioisomers were
also formed. Only by lowering the temperature to 0 8C, and
adding tributyltin hydride dropwise, were we able to
exclusively obtain the desired a-regioisomer 10. Sub-
sequent reduction to the alcohol 11 was conveniently
effected with DIBAL-H (complete conversion and excellent
purity according to crude NMR), although isolated yields of
11 varied. Initial attempts to isolate the stannylated acrylic
aldehyde 12 from the subsequent TPAP-oxidation failed.
Flash column chromatography on various commercial
sources of silica gel or fluorisil, with miscellaneous eluent
systems, including co-elution with triethylamine, was tried,
but all combinations resulted in decomposition, and only
traces of the pure compound could be isolated. We
discovered that demetallated silica gel prepared according
to the procedure described in Section 4 was a strict
A crucial disconnection in the proposed retrosynthesis of
zoanthamine suggests the late-stage multi-condensation
reaction of advanced intermediate 6. Removal of the
protecting groups of 6 in acid media is expected to facilitate
a one-pot formation of the double hemiaminal core of 1, as
first suggested by Tanner et al. and elegantly demonstrated
in model studies by Kobayashi and co-workers.4a,b,d Arrival
at advanced intermediate 6 requires the proper assembly of
fragments A, B and C. The Stille coupling between
fragments B (C6–C10) and C (C11–C22) should set up the
olefin geometries of 8 for a subsequent intramolecular
Diels–Alder reaction. This is expected to give the desired
stereochemistries at both C12 and C21 of zoanthamine, with
the stereochemistry at C19 as a key controlling element. In
principle, the halide or stannane functionality could be
Figure 2. Major fragments A, B and C in the retrosynthesis of zoanthamine: XZhalide or metal; YZSnR3 or I; PGZprotecting group; R1,R2ZO, or R1ZOH,
R2ZH.

T. E. Nielsen et al. / Tetrahedron 61 (2005) 8013–8024
8015
˚
Scheme 1. Synthesis of fragment B (15–16): (a) Bu3SnH, Pd(PPh3)2Cl2 (0.5 mol%), THF, 0 8C; (b) DIBAL-H, THF, K78 8C; (c) TPAP (7 mol%), NMO, 4 A
˚
MS, CH2Cl2, rt; (d) ethylvinyl ether, Hg(OAc)2 (3 mol%); (e) 12, Yb(fod)3 (17 mol%), 4 A MS, 30 8C; (f) I2, CH2Cl2, rt, then n-Bu4NPh2PO2, CH2Cl2, rt.
requirement in the purification of 12. The key step in the
synthesis of fragment B was the subsequent lanthanide-
catalyzed inverse electron demand Diels–Alder (IEDDA)
reaction, where benzyl vinyl ether was found to be an
excellent dienophile, providing fragment B as the stable
dihydropyrane 15, in 94% yield with a readily removable
protecting group (Bn). The addition of molecular sieves
17, starting with protection of the secondary hydroxyl
group as the TBDMS ether 18. Removal of the Piv
protecting group with DIBAL-H afforded primary alcohol
19, which was smoothly converted to the corresponding
aldehyde 20 with the Dess–Martin periodinane. Addition
of lithium acetylide 21 to the aldehyde gave propargylic
alcohol 22 as a 2:1 diastereomeric mixture, which was
hydrostannated according to the method of Greeves,20
thus providing fragment C variant 23. Ketone counterpart
24 could be obtained via the TPAP procedure
(Scheme 2).
˚
(4 A) proved to be crucial in obtaining reproducible yields.
Benzyl vinyl ether 14 was conveniently prepared by
transetherification of ethyl vinyl ether with benzyl alcohol
via Hg(II)-catalysis.18 Iododestannylation with iodine gave
the stable halide 16 in excellent yield, even on gram scale.
For the purification of 15 and 16, the use of demetallated
silica gel was mandatory, and removal of tributylstannyl
iodide by-products from crude 16 could only be accom-
plished by treatment with tetrabutylammonium diphenyl-
phosphinate (n-Bu4NPh2PO2) as a tin scavenger.19
In a model study, alkenyl stannane 27 was easily
iododestannylated with iodine to provide alkenyl iodide
29 or TPAP-oxidized to the a,b-unsaturated ketone 28
(Scheme 3). Surprisingly, stannylated derivatives 23 and 24
could not be converted into the corresponding alkenyl
iodides 25 and 26, the major products deriving instead from
desilylation of the TBDMS-protected secondary alcohol
Fragment C was synthesized from known16,20b compound
Scheme 2. Synthesis of fragment C (23–24): (a) TBDMSCl, imidazole, DMF; (b) DIBAL-H, CH2Cl2, K78 8C; (c) Dess–Martin periodinane, CH2Cl2, rt;
˚
(d) 21, THF, K78 8C; (e) Bu3SnH, Pd(P(o-Tol)3)2Cl2 (1 mol%), THF, rt; (f) TPAP (16 mol%), NMO, 4 A MS, CH2Cl2, rt; (g) I2, CH2Cl2, rt.

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T. E. Nielsen et al. / Tetrahedron 61 (2005) 8013–8024
Scheme 5. Stille couplings of fragment C model compounds: (a) Ph-I (37),
Pd2dba3$CHCl3 (5 mol%), DMF, 65 8C; (b) CH2]CHSnBu3 (1.1 equiv),
Pd2dba3$CHCl3, TFP, THF, reflux.
Scheme 3. Iododestannylation of fragment C model compounds: (a) TPAP
˚
(7 mol%), NMO, 4 A MS, CH2Cl2, rt; (b) I2, CH2Cl2, rt.
Stannane 15 could not be coupled with alkenyl iodides 29
and 30 under traditional Stille reaction conditions. This
problem appeared to be associated with sterical hindrance,
as indicated by the smooth reaction of vinyltributylstannane
with 29 (Scheme 5).
moiety. Lowering the temperature to 0 8C or changing the
solvent to THF at K78 8C, did not yield the desired
products. This prompted us to prepare the analogous
MOM-protected derivatives. Gratifyingly, stannanes 31
and 32 were converted into the desired alkenyl iodides 33
and 34 (Scheme 4),21, which after rapid purification
(filtration through a small plug of demetallated silica gel)
were used immediately in the subsequent coupling reaction
(Scheme 6).
It was then decided to investigate a recent protocol reported
by Corey for Stille couplings of sterically congested
stannanes (Table 1).23 It was found that use of an excess
of both CuCl and LiCl under rigorously dry and anaerobic
conditions in DMSO using Pd(PPh3)4 as the catalyst,
was far superior to other Cu-mediated Stille couplings
available. Pleasingly, a range of fragment B and C
model compounds could be joined via this procedure
(Table 1). Stannane 15 (fragment B) could be joined
with both alkenyl iodides 29 and 30 in high yields
(Table 1, entries 6 and 8), whereas the coupling of
alkenyl iodide 16 (fragment B) with stannanes 27 and
28 remained problematic (Table 1, entries 2 and 4).
Stille coupling product 38 could be oxidized to the
unsaturated ketone 40 (yield: 67%, via the TPAP/NMO-
procedure similar to that of Schemes 2–4). Further
scope of the reaction conditions was demonstrated by
the coupling of tributylstannyl benzene with alkenyl
iodides 29 and 30, providing the coupling products 35
Having successfully prepared iodinated and stannylated
fragments B (15–16) and C (23–24, 31–34), our attention
turned to the Stille coupling between these fragments.
Attempts to couple alkenyl iodide 16 with stannanes 27 and
28 (readily available fragment C model compounds) failed
completely under a variety of Stille reaction conditions,
where many combinations of ligands (e.g., TFP, PPh3,
AsPh3, Cy2P(2-biphenyl), t-Bu2P(2-biphenyl), P(o-Tol)3),
solvents (e.g., THF, DMF, NMP, toluene) Pd-sources (e.g.,
Pd2dba3$CHCl3, Pd(PPh3)4, Pd(CH3CN)2Cl2, Pd(P(o-
Tol)3)2Cl2), Cu-additives (e.g., CuI, CuBr, CuTC),22 and
reaction temperatures (e.g., rt, reflux) were tried. In parallel
experiments, the coupling of iodobenzene with stannane 27
was examined. Curiously, this coupling proceeded under
ligandless conditions (Scheme 5), albeit in low yield.
˚
Scheme 4. Synthesis of iodinated and stannylated fragment C (31–34): (a) TPAP (7 mol%), NMO, 4 A MS, CH2Cl2, rt; (b) I2, CH2Cl2, 0 8C, then n-
Bu4NPh2PO2, CH2Cl2, rt.

T. E. Nielsen et al. / Tetrahedron 61 (2005) 8013–8024
8017
Table 1. Stille couplings between fragment B and C model compounds via the Corey-modified Stille reaction
Entry
1
R1-I
R2-SnBu3
Coupling product (R1–R2)
Yield (%)a
51
37
27
27
35
2
3
4
5
6
7
8
0
16
37
38
39
37
28
0
16
28
41
40
35
82
81
41
74
29
29
15
41
38
39
30
30
15
11
40
42
9
84
29
a Isolated yield after flash column chromatography.
(yield: 82%) and 39 (yield: 41%), respectively,
(Table 1, entries 5 and 7). Interestingly, stannane 11
was efficiently coupled to alkenyl iodide 29 to provide
the primary alcohol 42 in excellent yield (84%, Table 1,
entry 8).
strategy turned out most efficient for the synthesis of the
Diels–Alder substrate 45. Unfortunately, the coupling
product 43 was rather unstable due to ring-opening of the
dihydropyrane moiety, thus affording the dialdehyde 44.
However, 45 was formed as a stable coupling product in
63% yield (Scheme 6). So far we have not been able to
promote the desired Diels–Alder reaction with 45 (e.g., no
reaction in refluxing toluene, decomposition in refluxing
xylene), but we are continuing our efforts and results will be
reported in due course.
The results of Table 1 pointed to the use of fragment B as the
stannane (15) and fragment C as the alkenyl iodide (freshly
prepared as either 33 from 31, or 34 from 32), for the Stille
reaction towards a Diels–Alder precursor of type 8. The

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T. E. Nielsen et al. / Tetrahedron 61 (2005) 8013–8024
Scheme 6. Coupling of fragments B and C: (a) I2, CH2Cl2, 0 8C, then n-Bu4NPh2PO2, CH2Cl2, rt; (b) 15, Pd(PPh3)4 (10 mol%), LiCl (6 equiv), CuCl (5 equiv),
DMSO, rt, 3 h; (c) heat.
3. Conclusion
University of Bath, England. HRMS was performed at the
Department of Chemistry, University of Copenhagen,
Denmark, and the Department of Chemistry, University of
Bath, England. Molecular mass determinations (high-
resolution mass spectrometry) for substances containing
Bu3Sn are based on 120Sn and typically made on the [MK
Bu]C, unless otherwise stated. All compounds, on which
In summary, efficient synthetic routes towards two major
fragments B and C in a projected total synthesis of the
marine alkaloid zoanthamine have been established. The
methodology allows the preparation of each fragment in its
stannylated and iodinated forms. The relative positions of
the stannyl and iodo moieties were found to be crucial for
the Stille coupling between these fragments. Whereas
fragment B in its iodinated form was completely unreactive
under a range of Stille reaction conditions, the correspond-
ing stannylated form reacted readily with alkenyl iodides
using reaction conditions developed by Corey, utilizing
excess of CuCl and LiCl in DMSO. Fragment B in its
stannylated form reacted smoothly with two iodinated
versions of fragment C (with C20 at either the ketone or
alcohol stage). Although, the resulting allylic alcohol
coupling product 43 was too unstable for further synthetic
manipulations, the a,b-unsaturated coupling product 45 was
found to be stable and constitutes therefore a promising
intermediate for the projected total synthesis of
zoanthamine.
1
HRMS were performed exhibited clean H NMR spectra
and showed one spot on TLC analysis, using UV light, and a
solution of 5–10% phosphomolybdic acid in ethanol for
visualization.
Column chromatography was performed using Amicron
Matrex silica gel (35–70 mm). Demetallated silica gel was
prepared by a modification of the procedure of Harris:24
1 kg of silica gel was mechanically stirred with 2 L of 10%
hydrochloric acid until complete wetting was assured. Upon
this treatment, the aqueous phase turned yellow, presumably
due to the formation of chloro-complexes. The acidic
aqueous phase was decanted off, and the silica subsequently
washed 15–20 times with distilled water by decantation
until pHz4. Subsequently, 1 L of distilled water was added
along with 1 mL of aqueous ammonia (25%). The aqueous
phase was decanted and the silica oven-dried at 150 8C for a
minimum of 24 h prior to use for chromatography. All
solvents were distilled prior to use. THF was distilled under
nitrogen from Na–benzophenone. CH2Cl2 and DMF were
dried over calcium hydride and distilled under nitrogen.
4. Experimental
4.1. General
1H (300 MHz) and 13C (75 MHz) NMR spectra were
recorded using CDCl3 as the solvent, and signal positions
(d-values) were measured relative to the signals for CHCl3
(7.27) and CDCl3 (77.0), respectively. Tin–hydrogen
coupling constants, J(SnH), are given as the 117Sn and
119Sn values, or average values. IR spectra were obtained
for thin films on AgCl plates, and only the strongest/
structurally most important peaks (nmax/cmK1) are listed.
Microanalyses were performed by the Microanalysis
Laboratory, Department of Physical Chemistry, University
of Vienna, Austria, and at the Department of Chemistry,
˚
DMSO was dried over 4 A MS, and degassed (4!) by the
freeze-pump-thaw process (K78 8C-rt, argon). Copper(I)
25
¨
¨
chloride was prepared according to Osterlof. Copper(I)
cyanide and lithium chloride were ovendried prior to use
and used without further purification. Commercially
available compounds were used as received unless
otherwise indicated. All reactions were carried out under
an atmosphere of dry argon using carefully flame-dried
glassware. Argon gas was dried by passage through
phosphorous pentoxide and silica gel.

T. E. Nielsen et al. / Tetrahedron 61 (2005) 8013–8024
8019
4.1.1. 2-Tributylstannylacrylic acid methyl ester (10).17
A 2 L three-necked roundbottomed flask equipped with a
magnetic stirring bar, thermometer, and a septum was
charged with freshly prepared bis(triphenylphosphine)-
palladium(II)chloride (716 mg, 1.3 mmol) and methyl
propiolate (17.18 g, 205 mmol). Degassed THF (820 mL)
was added, and the solution was cooled to 0 8C. During
35 min tributyltin hydride (65.4 g, 225 mmol) was added
dropwise, and the solution subsequently stirred at rt for
10 min during, which time the originally light-yellow
solution turned orange-brown. The solvent was quickly
removed by rotary evaporation. The obtained residue was
dissolved in pentane (1.7 L), and washed with CH3CN (2!
100 mL), water (2!200 mL) and brine (200 mL). The
organic phase was isolated, dried over magnesium sulfate,
filtered and rotary evaporated to afford the title compound
10 (83.2 g, quant.) as a red-brown oil: 1H NMR (300 MHz,
CDCl3) d 6.82 (1H, d, JZ3 Hz, J(117SnH)Z106 Hz,
J(119SnH)Z112 Hz), 5.85 (1H, d, JZ3 Hz, J(117SnH)Z
51 Hz, J(119SnH)Z54 Hz), 3.66 (3H, s), 1.56–1.33 (6H, m),
1.33–1.12 (6H, m), 0.94–0.87 (6H, m), 0.86–0.77 (9H, t, JZ
7 Hz); 13C NMR (75 MHz, CDCl3) d 171.1, 146.1, 139.8,
51.9, 29.0, 27.4, 13.8, 10.2.
column packed with demetallated silica gel, and the product
was rapidly eluted (hexane/triethylamine, 100:1) affording
the aldehyde 12 (1.7 g, 70%) as a light brown oil: 1H NMR
(300 MHz, CDCl3) d 9.67 (1H, s, J(117SnH)Z52 Hz,
J(119SnH)Z55 Hz), 6.85 (1H, d, JZ2 Hz, J(117SnH)Z
101 Hz, J(119SnH)Z106 Hz), 6.69 (1H, d, JZ2 Hz,
J(SnH)Z48 Hz), 1.63–1.37 (6H, m), 1.37–1.20 (6H, m),
1.03–0.97 (6H, m), 0.91–0.84 (9H, m, JZ7 Hz); 13C NMR
(75 MHz, CDCl3) d 199.4, 156.7, 148.2, 29.2, 27.4, 13, 9.9.
4.1.4. Benzyl vinyl ether (14).26 A 1000 mL flask equipped
with a Claisen-adapter, thermometer and reflux condenser
fitted with a calcium chloride-tube was charged with freshly
distilled ethyl vinyl ether (400 mL, 301.2 g, 4.2 mol),
benzylalcohol (38.2 mL, 40.0 g, 0.37 mol) and mercuric
acetate (4.0 g, 12.6 mmol). The resulting solution was
refluxed for 14 h, then treated with additional mercuric
acetate (2.0 g, 6.3 mmol) and refluxed for another 4 h. It was
then extracted twice with cold 10% potassium carbonate
solution, dried with potassium carbonate and concentrated
to a light oil. Efficient distillation was achieved using a
10 cm Vigreux column on top of a 10 cm column packed
with small glass rings, to afford benzyl vinyl ether (25.5 g,
51%) as a colourless liquid: bp 128–132 8C/60 Torr (bp 88–
90 8C /25 Torr);27 1H NMR (300 MHz, CDCl3) d 7.40–7.27
(5H, m), d 6.57 (1H, dd, JZ7, 14 Hz), d 4.77 (2H, s), d 4.31
(1H, dd, JZ2, 14 Hz), d 4.08 (1H, dd, JZ2, 7 Hz); 13C
NMR (75 MHz, CDCl3) d 152.9, 137.2, 128.8, 128.2, 128.0,
87.7, 70.4.
4.1.2. 2-Tributylstannylprop-2-en-1-ol (11).17 A three-
necked roundbottomed flask equipped with a magnetic
stirring bar and septa was charged with ester 10 (1.13 g,
3.0 mmol) and THF (18 mL). The solution was cooled to
K78 8C, and dropwise added diisobutylaluminium hydride
(1.0 M in hexanes, 6.2 mL, 6.2 mmol) over 2 h using a
syringe pump, and stirred overnight at rt. Methanol (6 mL)
was added, followed by benzene (15 mL), and water (6 mL).
The mixture was immediately filtered, and the precipitated
aluminum salts were thoroughly washed with methanol. The
filtrate and washings were combined, and the volatiles
removed by rotary evaporation. The residue was dissolved
in pentane (100 mL) and washed with water (10 mL) and
brine (10 mL). The organic phase was dried over
magnesium sulfate, filtered and rotary evaporated to give
a thick, yellow oil, which was subjected to flash column
chromatography on demetallated silica gel (hexane/ethyl
acetate/triethylamine, 100:10:1) to afford the title com-
4.1.5. 2-Benzyloxy-5-tributylstannyl-3,4-dihydro-2H-
pyran (15).
A Schlenk tube was charged with
tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedio-
nato)ytterbium (Yb(fod)3, 210 mg, 0.198 mmol) under
argon, and the flask was heated to 60 8C with stirring for
4 days under high vacuum. The aldehyde 12 (417 mg,
1.2 mmol) dissolved in freshly distilled benzyl vinyl ether
14 was subsequently added together with pulverized MS
˚
4 A (3 g). The solution was stirred overnight at 30 8C,
followed by rapid filtration through a plug of demetallated
silica gel (hexane/ethyl actetate/triethylamine, 40:1:1). The
filtrate and washings were concentrated in vacuo. Benzyl-
vinylether was removed under high vacuum (!0.5 mmHg)
and collected using a freeze trap. The residue was subjected
to flash column chromatography on demetallated silica gel
(hexane/ethyl acetate/triethylamine, 40:1:1), affording dihy-
dropyrane 15 (543 mg, 94%) as a colourless oil: IR
(CDCl3): 2925, 1605, 1455, 1040; 1H NMR (300 MHz,
CDCl3) d 7.39–7.23 (5H, m), 5.99 (1H, dd (app. t), JZ2 Hz,
J(SnH)Z34 Hz), 5.07 (1H, dd (app. t), JZ3 Hz), 4.86 (1H,
d, JZ12 Hz), 4.61 (1H, d, JZ12 Hz), 2.37–2.22 (1H, m),
2.06–1.94 (1H, m), 1.93–1.84 (2H, m), 1.62–1.41 (6H, m),
1.38–1.25 (6H, m), 0.93–0.84 (15H, m, JZ7 Hz); 13C NMR
(75 MHz, CDCl3) d 143.3, 138.6, 128.5, 127.9, 127.7,
109.0, 96.1, 69.5, 29.4, 28.2, 27.6, 21.9, 14.0, 9.3. Anal.
Calcd for C24H40O2Sn: C, 60.13; H, 8.43. Found: C, 60.37;
H, 8.32.
1
pound 11 (0.66 g, 63%) as a colourless liquid: H NMR
(300 MHz, CDCl3) d 5.88 (1H, m, JZ4, 2 Hz, J(SnH)Z
129 Hz), 5.25 (1H, m, JZ4, 2 Hz, J(SnH)Z61 Hz), 4.27
(2H, m, J(SnH)Z29 Hz), 1.61–1.43 (6H, m), 1.41–1.24
(6H, m), 0.97–0.85 (15H, m, JZ7 Hz); 13C NMR (75 MHz,
CDCl3) d 155.0, 123.1, 69.8, 29.4, 27.7, 13.9, 9.8.
4.1.3. 2-Tributylstannanylpropenal (12).16 A 500 mL
roundbottomed flask equipped with a magnetic stirring bar
and a septum was charged with 60 g of freshly activated
˚
(flame dried under high vacuum) finely pulverized 4 A
molecular sieves. Dichloromethane (100 mL) was added,
followed by N-methyl morpholine N-oxide (NMO, 1.50 g,
11.5 mmol), and alcohol 11 (2.50 g, 7.0 mmol). The
solution was stirred for 10 min, then tetra-n-propylammo-
nium perruthenate (TPAP, 115 mg, 0.5 mmol) was added in
one portion, followed by the appearance of a green-brown
colouration. The reaction mixture was stirred overnight, by
which time the solution had become brown, and TLC
showed a complete conversion of the alcohol into one
product. The reaction mixture was applied directly to a
4.1.6. 2-Benzyloxy-5-iodo-3,4-dihydro-2H-pyran (16). A
solution of the stannane 15 (114 mg, 0.24 mmol) in CH2Cl2
(16 mL) was cooled to 0 8C and slowly added a 0.04 M
solution of iodine (60 mg, 0.24 mmol) in CH2Cl2 (7.5 mL).
The addition of iodine was stopped when a permanent red

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T. E. Nielsen et al. / Tetrahedron 61 (2005) 8013–8024
colouration of the reaction mixture appeared (this was taken
as an indication of complete conversion of the stannane),
and the reaction was stirred for further 30 min. The reaction
mixture was diluted with ether (100 mL) and washed with
satd sodium thiosulfate (2!10 mL), then dried over
magnesium sulfate, filtered and rotary evaporated. The
residue was immediately subjected to flash column
chromatography on demetallated silica (hexane/ethyl acte-
tate, 40:1) to give a colourless oil. Traces of tributylstannyl
iodide were removed by dissolving the oil in ether (50 mL),
followed by addition of tetra-n-butylammonium diphenyl-
phosphinate. The precipitated salts were removed by
filtration. Subsequent rotary evaporation of the volatiles
gave the title compound 16 (61 mg, 84%) as a colourless oil:
IR (CDCl3): 2937, 1634, 1134, 1094, 1017; 1H NMR
(300 MHz, CDCl3) d 7.38–7.25 (5H, m), 6.48 (1H, dd, JZ1,
2 Hz), 5.10 (1H, dd (app. t), JZ3 Hz), 4.75 (1H, d, JZ
12 Hz), 4.52 (1H, d, JZ12 Hz), 2.62–2.48 (1H, dddd, JZ2,
8, 11, 17 Hz), 2.29–2.18 (1H, dddd, JZ1, 5, 6, 17 Hz),
1.95–1.80 (2H, m); 13C NMR (75 MHz, CDCl3) d 143.8,
137.8, 128.6, 128.0 (two signals), 94.7, 69.9, 69.5, 29.0,
28.9. Anal. Calcd for C12H13O2I: C, 45.59; H, 4.14. Found:
C 45.85; H 4.01; HRMS (FAB) calcd for C12H13O2I [MC]
315.9960, found 315.9961.
dried over magnesium sulfate and rotary evaporated to a
residue that was purified by flash column chromatography
(hexane/ethyl acetate, 5:1) to give the title compound 19
(376 mg, 92%) as a colourless oil: [a]2D5 K100.5 (c 2.0,
CH2Cl2); IR (CDCl3): 3420, 2956, 2857, 1644, 1472, 1378,
1
1252, 1031, 935, 890, 835, 805, 774; H NMR (300 MHz,
CDCl3) d 5.45 (1H, m), 4.87 (1H, s), 4.77 (1H, s), 4.40 (1H,
br s), 3.60 (2H, m), 3.09 (1H, m, KOH), 2.71 (1H, ddd, JZ
7, 9, 16 Hz), 2.11–1.88 (2H, m), 1.81 (1H, m), 1.73 (3H, s),
1.68 (3H, s), 1.61–1.54 (1H, m), 1.05 (3H, d, JZ7 Hz), 0.92
(9H, s), 0.11 (6H, s); 13C NMR (75 MHz, CDCl3) d 147.3,
136.1, 124.2, 112.2, 67.3, 65.9, 45.5, 40.9, 36.0, 34.8, 33.4,
26.1, 34.8, 26.1, 22.9, 19.7, 18.4, 16.7, K3.9; HRMS (EI)
calcd for C19H36O2Si [M]C324.2485, found 324.2485.
4.1.9. (R)-2-[(1R,2S,6R)-2-(tert-Butyldimethylsilyloxy)-6-
isopropenyl-4-methylcyclohex-3-enyl]propionaldehyde
(20). A suspension of Dess–Martin periodinane (421 mg,
0.99 mmol) in CH2Cl2 (5 mL) was cooled to 0 8C and stirred
for 5 min. A solution of alcohol 19 (258 mg, 0.79 mmol) in
CH2Cl2 (8 mL) was then dropwise added. After 30 min TLC
indicated complete conversion of the alcohol. The reaction
was quenched with a mixture of 10% sodium thiosulfate
(aq) and sat. sodium bicarbonate (1:1, 10 mL) and stirred
until two homogeneous layers were observed. The resultant
mixture was extracted with CH2Cl2 (3!50 mL) and the
combined organic phases were washed with water (50 mL),
dried over magnesium sulfate and rotary evaporated to a
residue that was further purified by flash column chroma-
tography (hexane/ethyl acetate, 20:1) to give the title
compound 20 (240 mg, 94%) as a colourless oil: [a]D25
K168.9 (c 3.5, CH2Cl2); IR (CDCl3): 2931, 2858, 1719,
1459, 1438, 1379, 1257, 1079, 1032, 935, 880, 837, 805,
778; 1H NMR (300 MHz, CDCl3) d 9.82 (1H, s), 5.48 (1H,
m), 4.90 (1H, s), 4.87 (1H, s), 3.01 (1H, m), 2.41 (1H, m),
2.14–1.92 (2H, m), 1.85 (1H, m), 1.73 (3H, s), 1.71 (3H, s),
1.11 (3H, d, JZ7 Hz), 0.86 (9H, s), 0.07 (3H, s), 0.02 (3H,
s); 13C NMR (75 MHz, CDCl3) d 203.6, 146.0, 136.0, 123.4,
113.9, 65.3, 45.7, 44.1, 40.4, 36.0, 26.0, 23.1, 18.8, 18.3,
12.4, K3.9 (two signals); HRMS (EI) calcd for C19H34O2Si
[M]C322.2328, found 322.2325.
4.1.7. (R)-2-[(1R,2S,6R)-2-(tert-Butyldimethylsilyloxy)-4-
methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl]propyl piva-
late (18). tert-Butyldimethylsilyl chloride (387 mg,
2.57 mmol) and imidazole (583 mg, 8.56 mmol) were
dissolved in DMF (15 mL). Compound 17 (630 mg,
2.14 mmol) was dropwise added and the resultant solution
stirred overnight. Hexane (60 mL) and a mixture of water/
DMF (10:1, 55 mL) was added, and the mixture was
transferred to a separation funnel. The organic phase was
separated, washed with water (4!20 mL) and brine
(20 mL), dried over magnesium sulfate, filtered and
evaporated to give a residue that was further purified by
flash column chromatography (hexane/ethyl acetate, 20:1)
to give the title compound 18 (734 mg, 84%) as a colourless
oil: [a]2D5 K130.8 (c 4.2, CH2Cl2); IR (CDCl3): 2958, 2931,
1
2858, 1728, 1463, 1284, 1254, 1165, 1035, 835, 774; H
NMR (300 MHz, CDCl3) d 5.49 (1H, m), 4.82 (2H, m), 4.33
(1H, m), 4.19–4.14 (1H, dd, JZ4, 11 Hz), 4.11–4.05 (1H,
dd, JZ9, 11 Hz), 2.77–2.68 (2H, ddd, JZ7, 11, 16 Hz),
2.05–1.92 (3H, m), 1.71 (3H, s), 1.67 (3H, s), 1.61–1.55
(1H, m), 1.19 (9H, s), 1.05 (3H, d, JZ7 Hz), 0.91 (9H, s),
0.10 (3H, s), 0.09 (3H, s); 13C NMR (75 MHz, CDCl3) d
178.5, 146.7, 136.5, 124.1, 112.9, 68.3, 66.2, 44.6, 40.1,
38.7, 36.3, 33.3, 27.3, 26.1, 23.0, 18.9, 18.3, K3.6 (two
signals); HRMS (EI) calcd for C24H44O3Si [M]C408.3060,
found 408.3076.
4.1.10. (R)-7-(tert-Butyldimethylsilyloxy)-2-[(1R,2S,6R)-
2-(tert-butyldimethylsilyloxy)-6-isopropenyl-4-methyl-
cyclohex-3-enyl]hept-4-yn-3-ol (22). To a solution of
freshly distilled but-3-yn-1-ol (92 mg, 0.5 mmol) in THF
(3 mL) was added dropwise n-butyllithium (1.6 M in
hexanes, 0.31 mL, 0.5 mmol) at K78 8C. The reaction
mixture was stirred at K78 8C for 30 min, and then at
K30 8C for another 30 min, before recooling to K78 8C and
dropwise addition of aldehyde 20 (161 mg, 0.5 mmol).
After stirring for 1 h at K78 8C, the reaction mixture was
allowed to reach rt. A mixture of ether (10 mL) and sat.
sodium bicarbonate (10 mL) was added and the organic
layer separated and washed with brine (2!5 mL), then
dried over magnesium sulfate, filtered and rotary evapor-
ated. The residue was purified by flash column chromato-
graphy on silica gel (hexane/ethyl acetate, 20:1) to give the
title compound 22 (241 mg, quant.) as a colourless oil (2:1
diastereomeric mixture): [a]2D5 K46 (c 1.0, CH2Cl2); IR
(CDCl3): 3336, 2928, 2857, 1742, 1379, 1256, 1106, 1006,
890, 838, 778, 733, 668; 1H NMR (300 MHz, CDCl3) d 5.39
(1H, br s), 4.87 (1H, m), 4.77–4.69 (1H, m), 4.68–4.54 (1H,
4.1.8. (R)-2-[(1R,2S,6R)-2-(tert-Butyldimethylsilyloxy)-6-
isopropenyl-4-methylcyclohex-3-enyl]propan-1-ol (19).
A solution of compound 18 (515 mg, 1.26 mmol) in
CH2Cl2 (50 mL) was prepared and cooled to K78 8C. The
solution was then dropwise added diisobutylaluminum
hydride (1 M in hexanes, 3.15 mL, 3.15 mmol). After
45 min, TLC indicated complete reaction, and an aqueous
solution of Rochelle salt (50 mL) was added. The resultant
mixture was stirred at rt for 1 h. The separated aqueous
phase was extracted with CH2Cl2 (3!100 mL) and the
combined organic phases were washed with brine (100 mL),

T. E. Nielsen et al. / Tetrahedron 61 (2005) 8013–8024
8021
m), 4.48–4.31 (1H, m), 3.72 (2H, t, JZ7 Hz), 2.94 (1H, m),
2.71–2.62 (1H, m), 2.47–2.40 (2H, m), 2.13–1.81 (4H, m),
1.76 (3H, s), 1.67 (3H, s), 1.14–1.06 (3H, m), 0.93–0.89
(18H, app. s), 0.14–0.06 (12H, app. s); 13C NMR (75 MHz,
CDCl3) d 147.8, 147.1, 135.9, 135.6, 124.4, 124.0, 111.8,
82.1, 82.0, 81.1, 68.6, 68.3, 66.1, 64.3, 62.1, 43.6, 41.2,
41.0, 39.6, 39.1, 34.6, 33.6, 26.0, 25.9, 23.2, 22.7, 20.7,
20.5, 18.4, 18.3, 14.9, 14.4, K4.0, K4.2, K4.4; HRMS (EI)
calcd for C29H54O3Si2 [M]C506.3611, found 506.3608.
(1H, m), 2.87–2.78 (1H, m), 2.72–2.61 (1H, m), 2.51–2.42
(2H, m), 2.14–1.85 (2H, m), 1.81 (3H, s), 1.71 (3H, s), 1.55–
1.44 (6H, m), 1.40–1.27 (6H, m), 1.05–0.84 (36H, m), 0.07
(6H, s), 0.01 (3H, s), K0.05 (3H, s); 13C NMR (75 MHz,
C6D6) d 201.6, 161.5, 147.8, 141.4, 134.4, 125.4, 110.4, 69.2,
63.6, 43.9, 42.7, 40.8, 40.1, 31.4, 29.6, 27.8, 26.6, 26.3, 22.9,
22.1, 19.0, 18.7, 15.4, 14.0, 10.4, K4.4, K4.7, K4.9; HRMS
(FAB) calcd for C37H71O3Si2Sn [M KC4H9]C739.3964,
found 739.3969.
4.1.13. 5-(tert-Butyldimethylsilyloxy)-1-cyclohexyl-3-
iodopent-2-en-1-ol (28). A solution of the known
b-stannylated allylic alcohol 27 (176 mg, 0.3 mmol) in
CH2Cl2 (30 mL) was cooled to 0 8C, and a solution of iodine
(76 mg, 0.3 mmol) in CH2Cl2 (15 mL) was added dropwise
until a permanent red colouration was observed. The
reaction mixture was stirred for further 30 min, before
pouring the reaction mixture into sat. sodium thiosulfate
(15 mL). The red-pink organic phase became immediately
colourless when washed with sat. sodium thiosulfate (2!
10 mL) and brine (10 mL). The organic phase was dried
over magnesium sulfate, and evaporated in vacuo. The
residue was purified by flash column chromatography on
silica gel (hexane/ethyl acetate, 20:1) to give the title
compound 28 (124 mg, 98%) as a slightly pink oil (the pink
colouration disappeared when the compound was main-
tained under a slight vacuum): IR (CDCl3): 3448, 2928,
4.1.11. (R)-7-(tert-Butyldimethylsilyloxy)-2-[(1R,2S,6R)-
2-(tert-butyldimethylsilyloxy)-6-isopropenyl-4-methyl-
cyclohex-3-enyl]-5-tributylstannylhept-4-en-3-ol (23). To
a solution of dichlorobis(tri-o-tolylphosphine)-palla-
dium(II) (5 mg, 0.025 mmol) and propargylic alcohol 22
(253 mg, 0.5 mmol) in THF (6 mL) was added dropwise
tributyltin hydride (218 mg, 0.75 mmol) during 0.5 h. The
reaction mixture was stirred at rt for 1 h, and another
amount of tributyltin hydride (218 mg, 0.75 mmol) was
dropwise added during 0.5 h, followed by stirring overnight.
The reaction mixture was added ether (15 mL), and filtered
through a pad of Celite. The volatiles were removed in
vacuo, and the residue was purified by flash column
chromatography on silica gel (hexane/ethyl acetate, 20:1)
giving the title compound 23 (311 mg, 78%) as a colourless
oil (2:1 diastereomeric mixture): [a]2D5 K25.9 (c 1.2,
CH2Cl2); IR (CDCl3): 2956, 2927, 2856, 1644, 1377,
1
1
1628, 1471, 1450, 1256, 1102, 1009, 927, 834, 777; H
1254, 1076, 939, 890, 837; H NMR (300 MHz, CDCl3) d
NMR (300 MHz, CDCl3) d 6.43 (1H, d, JZ8 Hz), 4.04–
3.95 (1H, m, JZ8 Hz), 3.83–3.67 (2H, m), 2.94 (1H, ddd,
JZ4, 5, 14 Hz), 2.74 (1H, d, JZ1 Hz), 2.57 (1H, ddd, JZ4,
5, 14 Hz), 1.97–1.86 (1H, m), 1.80–1.62 (4H, m), 1.50–0.80
(6H, m), 0.92 (9H, s), 0.12 (6H, 2!s); 13C NMR (75 MHz,
C6D6) d 147.0, 103.8, 73.4, 61.3, 43.5, 42.9, 29.1, 26.5, 26.4,
26.2, 18.8,, K5.2 (two signals). Anal. Calcd for
C17H33IO2Si: C, 48.11; H, 7.84. Found: C, 48.37; H, 7.80.
5.74–5.59 (1H, m), 5.54–5.45 (1H, m), 4.92–4.74 (2H, m),
4.44–4.27 (2H, m), 4.13C3.14 (1H, m, KOH), 3.64–3.49
(2H, m), 2.79–2.62 (2H, m), 2.43–2.36 (1H, m), 2.19–1.71
(4H, m), 1.77 (3H, 2!s), 1.68 (3H, 2!s), 1.54–1.41 (6H,
m), 1.40–1.25 (6H, m), 1.04 (3H, d, JZ7 Hz), 0.94–0.85
(15H, m), 0.91 (18H, s), 0.122 (6H, app. s), 0.07 (6H, s); 13C
NMR (75 MHz, CDCl3) d 148.7, 146.6, 142.1, 139.9, 136.3,
136.1, 124.5, 124.4, 112.3, 70.0, 69.2, 68.3, 67.4, 63.2, 62.9,
45.4, 42.1, 40.9, 40.6, 40.4, 40.0, 36.8, 35.4, 29.2, 27.4,
26.2, 26.1, 23.0, 22.8, 20.5, 20.0, 18.5, 18.4, 14.8, 13.7,
12.6, 9.8, K3.8, K3.9, K4.1, K5.2; HRMS (FAB) calcd
for C37H73O3Si2Sn [MKC4H9]C 741, 4120, found
740.4121.
4.1.14. 5-(tert-Butyldimethylsilyloxy)-1-cyclohexyl-3-
iodopent-2-en-1-one (30). To a slurry of freshly activated
˚
and finely pulverized 4 A molecular sieves (1.5 g) in
CH2Cl2 (3 mL) was added NMO (41 mg, 0.3 mmol) and a
solution of the b-iodinated allylic alcohol 28 (64 mg,
0.15 mmol) in CH2Cl2 (1 mL). The reaction mixture was
stirred for 10 min, before the addition of TPAP (2!2.5 mg,
0.014 mmol). The reaction mixture was stirred overnight,
and diluted with CH2Cl2 (50 mL) before filtering off the
molecular sieves, which was washed with further amounts
of CH2Cl2 (3!25 mL). The combined organic phases were
evaporated, then added the smallest possible amount of
CH2Cl2 to redissolve the thick, dark oil, which was purified
by flash column chromatography on silica gel (hexane/ethyl
acetate, 25:1) to give the title compound 30 (49 mg, 77%) as
a colourless oil: IR (CDCl3): 2929, 1690, 1583, 1256, 1105,
836, 776; 1H NMR (300 MHz, CDCl3) d 7.11 (1H, s), 3.79
(2H, t, JZ6 Hz), 3.27 (2H, dt, JZ1, 6 Hz), 2.35–2.21 (1H,
m), 1.91–1.61 (4H, m), 1.40–0.81 (6H, m), 0.89 (9H, s),
0.07 (6H, s); 13C NMR (75 MHz, CDCl3) d 200.6, 139.5,
124.1, 62.5, 51.2, 44.4, 28.2, 25.9, 25.8, 25.6, 18.3, K5.3.
Anal. Calcd for C17H31IO2Si: C, 48.34; H, 7.40. Found: C,
48.35; H, 7.11.
4.1.12. (R)-7-(tert-Butyl-dimethyl-silyloxy)-2-[(1R,2S,6R)-
2-(tert-butyl-dimethyl-silanyloxy)-6-isopropenyl-4-
methyl-cyclohex-3-enyl]-5-tributylstannyl-hept-4-en-3-
one (24). To a slurry of freshly activated and finely
˚
pulverized 4 A molecular sieves (2 g) in CH2Cl2 (10 mL)
was added NMO (115 mg, 0.85 mmol) and a solution of the
b-stannylated allylic alcohol 23 (399 mg, 0.5 mmol) in
dichloromethane (2 mL). The reaction mixture was stirred
for 10 min, before the addition of tetra-n-propylammonium
perruthenate (26 mg, 0.08 mmol). The reaction mixture was
stirred overnight and diluted with CH2Cl2 (20 mL) before
filtering off the molecular sieves, which was washed with
further amounts of CH2Cl2 (3!10 mL). The combined
organic phases were evaporated, and the residue was
purified by flash column chromatography on silica gel
(hexane/ethyl acetate; 20:1) to give the title compound 24
(322 mg, 81%) as a colourless oil: [a]2D5 K21.5 (c 1.3,
CH2Cl2); IR (CDCl3): 2956, 2928, 2856, 2362, 1686, 1464,
1377, 1253, 1091, 1006, 836; 1H NMR (300 MHz, CDCl3) d
6.38 (1H, s, J(SnH)Z68 Hz), 5.21 (1H, br s), 4.81 (1H, br s),
4.59 (1H, br s), 4.23 (1H, br s), 3.78–3.56 (2H, m), 3.08–2.98
4.1.15. 5-(tert-Butyldimethylsilyloxy)-1-cyclohexyl-3-
phenylpent-2-en-1-ol (35). A solution of alkenyl stannane

8022
T. E. Nielsen et al. / Tetrahedron 61 (2005) 8013–8024
27 (59 mg, 0.1 mmol), iodobenzene (20 mg, 0.1 mmol)
tris(dibenzylideneacetone)dipalladium(0)chloroform complex
(5.2 mg, 0.005 mmol) in DMF (2 mL) was heated to 65 8C
overnight. Upon cooling, the DMF was removed by rotary
evaporation, and the resulting residue was purified by flash
column chromatography on silica gel (hexane/ethyl acetate,
20:1) to give the title compound 35 (14 mg, 38%) as a
yellow oil: IR (CDCl3): 3446, 2929, 1711, 1492, 1471,
1450, 1257, 1090, 1006, 911; 1H NMR (300 MHz, CDCl3) d
7.42–7.23 (5H, m), 5.90 (1H, d, JZ8 Hz), 4.18 (1H, ddd,
JZ2, 8, 15 Hz), 3.70 (1H, m), 3.51 (1H, m), 2.97 (1H, m),
2.74 (1H, m), 2.61 (1H, d, JZ2 Hz), 2.03 (1H, d, JZ13 Hz),
1.86–0.91 (10H, m), 0.89 (9H, s), 0.01 (6H, s); 13C NMR
(75 MHz, CDCl3) d 141.9, 140.1, 138.4, 128.3, 127.2, 126.7,
71.9, 61.3, 43.7, 33.4, 29.0, 26.7, 26.2, 26.0, 18.5, K5.5;
HRMS (FAB) calcd for C23H37OSi [MKOH]C357.2601,
found 357.2590.
chromatography on silica gel (hexane/ethyl acetate) to give
the coupling product.
4.3. Analytical data for Stille coupling products
4.3.1. 3-(6-Benzyloxy-5,6-dihydro-4H-pyran-3-yl)-5-
(tert-butyldimethylsilyloxy)-1-cyclohexylpent-2-en-1-ol
(38). Yellow oil (diastereomeric mixture): IR (CDCl3):
3424, 2929, 2855, 1720, 1654, 1629, 1451, 1257, 1090, 908;
1H NMR (300 MHz, CDCl3) d 7.40–7.26 (5H, m), 6.53 (1H,
d, JZ4 Hz), 5.55 (1H, t, JZ8 Hz), 5.07 (1H, m), 4.83 (1H,
d, JZ12 Hz), 4.62 (1H, d, JZ12 Hz), 4.07 (1H, m), 3.71
(2H, m), 2.71 (1H, m), 2.80–0.91 (17H, m), 0.89 (9H, s),
0.06 (6H, s); 13C NMR (75 MHz, CDCl3) d 138.8, 138.6,
137.8, 137.7, 136.8, 136.5, 128.2, 127.7 (two signals), 127.6
(two signals), 127.4, 127.3, 114.1 (two signals), 95.7, 95.5,
71.4, 71.2, 69.5 (two signals), 62.2, 62.0, 43.8, 43.7, 32.7,
30.5, 30.3, 29.1 (two signals), 29.0, 26.7, 26.4, 26.2 (two
signals), 26.1 (three signals), 26.0, 25.9, (three signals),
25.8, 25.3, 18.6, 18.0, 17.9, 11.4, K5.4 (four signals);
HRMS (FAB) calcd for C29H45O3Si [MKOH]C469.3138,
found 469.3105.
4.1.16. (E)-3-[2-(tert-Butyldimethylsilyloxy)ethyl]-1-
cyclohexylpenta-2,4-dien-1-ol (36). A solution of alkenyl
iodide 28 (42 mg, 0.10 mmol), trifurylphosphine (4.6 mg,
0.02 mmol) and tris(dibenzylideneacetone)-dipalladium(0)-
chloroform complex (5.2 mg, 0.005 mmol) in THF (2 ml)
was stirred at rt for 10 min, before dropwise addition of
vinyltributylstannane (35 mg, 0.11 mmol). The resulting
solution was stirred overnight at reflux, then filtered through
a pad of Celite, and concentrated by rotary evaporation. The
residue was purified by flash column chromatography on
silica gel (hexane/ethyl acetate, 15:1) to give the title
compound 36 (20 mg, 61%) as a colourless oil: IR (CDCl3):
3446, 2926, 1472, 1451, 1257, 1096, 1004, 895, 836, 777;
1H NMR (300 MHz, CDCl3) d 6.29 (1H, dd, JZ11, 18 Hz),
5.70 (1H, d, JZ8 Hz), 5.17 (1H, d, JZ18 Hz), 5.04 (1H, d,
JZ11 Hz), 4.07 (1H, app. t, JZ7 Hz), 3.80, 3.62 (2H, m),
2.73–2.61 (2H, m), 2.51 (1H, ddd, JZ5, 5, 14 Hz), 1.97
(1H, m), 1.81–0.79 (10H, m), 0.89 (9H, s), 0.06 (6H, 2!s);
13C NMR (75 MHz, CDCl3) d 139.7, 137.4, 136.5, 112.4,
71.4, 61.6, 43.5, 29.7, 29.0, 28.8, 26.7, 26.1, 18.6, K5.3.
Anal. Calcd for C19H36O2Si: C, 70.31; H, 11.18. Found: C,
69.92; H, 10.80.
4.3.2. 5-(tert-Butyldimethylsilyloxy)-1-cyclohexyl-3-phe-
nylpent-2-en-1-one (39). Yellow oil: IR (CDCl3): 2929,
1678, 1596, 1449, 1257, 1102, 909; H NMR (300 MHz,
1
CDCl3) d 7.58–7.29 (5H, m), 6.52 (1H, s), 3.77 (2H, t, JZ
6 Hz), 3.25 (2H, t, JZ7 Hz), 2.45 (1H, m), 1.97–0.82 (10H,
m), 0.83 (9H, s), 0.02 (6H, s); 13C NMR (75 MHz, CDCl3) d
203.8, 156.1, 142.3, 128.7, 128.3, 127.1, 124.8, 62.8, 52.1,
35.2, 28.7, 26.0, 25.9, 25.8, 25.7, 18.2, K5.4. Anal. Calcd
for C23H36O2Si: C, 74.14; H, 9.74. Found: C, 74.42; H, 9.41.
4.3.3. 3-(6-Benzyloxy-5,6-dihydro-4H-pyran-3-yl)-5-
(tert-butyldimethylsilyloxy)-1-cyclohexylpent-2-en-1-
one (40). Yellow oil: IR (CDCl3): 3450, 2930, 1723, 1668,
1
1614, 1564, 1162, 1092; H NMR (300 MHz, CDCl3) d;
7.41–7.24 (5H, m), 7.13 (1H, s), 6.10 (1H, s), 5.16 (1H, t,
JZ3 Hz), 4.84 (1H, d, JZ12 Hz), 4.64 (1H, d, JZ12 Hz),
3.77 (2H, t, JZ7 Hz), 3.00 (2H, t, JZ6 Hz), 2.47–0.90
(17H, m), 0.89 (9H, s), 0.04 (6H, s); 13C NMR (75 MHz,
CDCl3) d203.5, 154.2, 147.0, 128.4, 127.8, 127.7, 117.6, 115.3,
95.9, 69.8, 63.8, 52.3, 31.7, 31.6, 29.0, 26.0, 25.9, 17.7, K5.3;
HRMS (FAB) calcd for C29H44O4Si [MKC6H11]C401.2148,
found 401.2133.
4.2. General procedure for Cu-mediated Stille
reactions23
A 30 mL Schlenck-tube was charged with lithium chloride
(31 mg, 0.74 mmol) and flame-dried under high vacuum.
Upon cooling, tetrakis(triphenylphosphine)-palladium(0)
(28 mg, 0.03 mmol) and copper(I) chloride (61 mg,
0.62 mmol) were added, and the mixture was degassed
(4!) under high-vacuum with an argon purge. DMSO
(2 mL) was introduced with concomitant stirring, followed
by the addition of the iodide (0.12 mmol) and the stannane
(0.15 mmol). The resulting mixture was rigorously degassed
(4!) by the freeze-thaw process (K78 8C to rt, Ar). The
reaction mixture was stirred at rt for 1 h, then heated to
60 8C and left under stirring overnight. The reaction mixture
was then allowed to reach rt, and diluted with ether (15 mL)
and washed with a mixture of brine and 5% aqueous
ammonium hydroxide (5 mL, 1:1). The aqueous layer was
further extracted with ether (2!10 mL) and the combined
organic layers were washed with water (2!10 mL), then
brine (10 mL), dried over sodium sulfate and rotary
evaporated. The residue was then purified by flash column
4.3.4. 2-(tert-Butyldimethylsilyloxy)ethyl]-1-cyclohexyl-
4-methylenepent-2-ene-1,5-diol (42). Yellow oil: IR
(CDCl3): 3406, 2929, 1450, 1257, 1090, 910, 835, 734;
1H NMR (300 MHz, CDCl3) d 5.76 (1H, d, JZ8 Hz, 5.25
(1H, s), 5.16 (1H, s), 4.30 (2H, s), 4.08 (1H, t, JZ8 Hz),
3.69 (2H, m), 2.73 (2H, m), 2.52 (1H, m), 2.06–0.91 (10H,
m), 0.89 (9H, s), 0.06 (6H, s); 13C NMR (75 MHz, CDCl3) d
147.0, 136.9, 132.2, 112.4, 71.5, 64.4, 61.8, 43.6, 31.6, 28.9,
26.6, 26.2, 26.0, 18.6, K5.4. Anal. Calcd for C20H38O3Si:
C, 67.74; H, 10.80. Found: C, 67.52; H, 10.78.
4.3.5. (2E)-2-((S,4E)-1-(tert-Betyldimethylsilyloxy)-6-
((1S,2S,6R)-2-(methoxymethoxy)-4-methyl-6-(prop-1-
en-2-yl)cyclohex-3-enyl)hept-4-en-3-ylidene)pentanedial
(44). Following Section 4.2 using alkenyl iodide 33 (62 mg,
0.11 mmol), freshly prepared from 31 according to a
procedure similar to that of Section 4.1.13 and purified by

T. E. Nielsen et al. / Tetrahedron 61 (2005) 8013–8024
8023
rapid filtration through a small plug of silica gel, the reaction
with lithium chloride (25 mg, 0.59 mmol), copper chlor-
ide(I) (49 mg, 0.49 mmol), tetrakis(triphenylphosphine)pal-
ladium(0) (11 mg, 0.01 mmol) and stannane 13 (58 mg,
0.12 mmol) gave after flash column chromatography on
silica gel (hexane/ethyl acetate; 20:1) the coupling product
43 (30 mg, 40%, two steps from 31) as a slightly yellow oil
(diastereomeric mixture). The coupling product rapidly
decomposed, and the resulting mixture was purified by flash
column chromatography on silica gel (hexane/ethyl acetate;
20:1) to afford the title compound 44 (20 mg, 81%) as a
colourless oil: [a]D25 K76.8 (c 0.5, CH2Cl2); IR (CDCl3):
3155, 2930, 2254, 1794, 1719, 1654, 1618, 1560, 1466,
1381, 1258, 1096, 1039, 912, 742, 651; 1H NMR (300 MHz,
CDCl3) d 10.13 (1H, s), 9.76 (1H, t, JZ2 Hz), 7.34 (1H, m),
6.79 (1H, q, JZ8 Hz), 6.35 (1H, d, JZ16 Hz), 5.68 (1H, br
s), 4.85 (1H, s), 4.77 (1H, s), 4.69 (1H, d, JZ7 Hz), 4.56
(1H, d, JZ7 Hz), 4.21 (1H, br s), 3.73 (2H, m), 3.36 (3H, s),
3.07–2.91 (2H, m), 2.75–2.60 (3H, m), 2.47–2.40 (2H, m),
2.03 (2H, m), 1.71 (6H, s), 1.20 (3H, d, JZ6 Hz), 0.96–0.86
(1H, m), 0.85 (9H, s), 0.00 (6H, s); 13C NMR (75 MHz,
CDCl3) d 201.8, 192.0, 151.2, 146.5, 145.0, 138.7, 138.4,
135.7, 125.4, 121.1, 113.4, 95.1, 69.9, 62.6, 55.8, 45.1, 43.4,
41.0, 37.7, 36.9, 30.0, 25.9, 23.2, 18.6, 18.2, 17.8,K5.4;
HRMS (FAB) calcd for C30H50O5Si [M]C518.3428, found
518.3424.
financial support. TEN thanks Thomas Rossmeier (Univer-
sity of Regensburg, Germany) for experimental assistance.
References and notes
1. Rao, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.; Venkata-
teswaelu, Y.; Rosser, R. M.; Faulkner, D. J.; Chen, M. H. M.;
Clardy, J. J. Am. Chem. Soc. 1984, 106, 7983–7984.
2. (a) Rahman, A.-U.; Choudhary, M. I. In Alkaloids, Vol. 52;
Academic: New York, 1999; pp 233–260. (b) Kuramoto, M.;
Arimoto, H.; Uemura, D. Mar. Drugs 2004, 1, 39–54.
3. For isolation and characterization of zoanthamine alkaloids:
consult: (a) Uramoto, M.; Hayashi, K.; Yamaguchi, K.; Yada,
M.; Tsuji, T.; Uemura, D. Bull. Chem. Soc. Jpn. 1998, 71,
771–779. (b) Atta-ur-Rahman; Alvi, K. A.; Abbas, S. A.;
Choudhary, M. I.; Clardy, J. Tetrahedron Lett. 1989, 30,
´ ´
6825–6828. (c) Daranas, A. H.; Fernandez, J. J.; Gavın, J. A.;
Norte, M. Tetrahedron 1998, 54, 7891–7896. (d) Daranas,
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A. H.; Fernandez, J. J.; Gavın, J. A.; Norte, M. Tetrahedron
1999, 55, 5539–5546. (e) Nakamura, H.; Kawase, Y.;
Maruyama, K.; Murai, A. Bull. Chem. Soc. Jpn. 1998, 71,
781–787.
4. (a) Hikage, N.; Furukawa, H.; Takao, K.; Kobayashi, S.
Tetrahedron Lett. 1998, 39, 6237–6240. (b) Hikage, N.;
Furukawa, H.; Takao, K.; Kobayashi, S. Tetrahedron Lett.
1998, 39, 6241–6244. (c) Williams, D. R.; Cortez, G. S.
Tetrahedron Lett. 1998, 39, 2675–2678. (d) Hikage, N.;
Furukawa, H.; Takao, K.; Kobayashi, S. Chem. Pharm. Bull.
2000, 48, 1370–1372.
4.3.6. (R,4E)-5-(6-(Benzyloxy)-5,6-dihydro-4H-pyran-3-
yl)-7-(tert-butyldimethyloxy)-2-((1R,2S,6R)-2-(methoxy-
methoxy)-4-methyl-6-(prop-1-en-2-yl)cyclohex-3-enyl)
hept-4-en-3-one (45). Following Section 4.2 using alkenyl
iodide 34 (75 mg, 0.13 mmol), freshly prepared from 32
according to a procedure similar to that of Section 4.1.13
and purified by rapid filtration through a small plug of silica
gel, the reaction with lithium chloride (53 mg, 1.26 mmol),
copper chloride(I) (104 mg, 1.05 mmol), tetrakis(triphenyl-
phosphine)palladium(0) (22 mg, 0.02 mmol) and stannane
13 (121 mg, 0.25 mmol) gave after flash column chroma-
tography on silica gel (hexane/ethyl acetate; 20:1) the
coupling product 45 (83 mg, 63%, two steps from 32) as a
5. Williams, D. R.; Brugel, T. A. Org. Lett. 1999, 2, 1023–1026.
6. (a) Tanner, D.; Andersson, P. G.; Tedenborg, L.; Somfai, P.
Tetrahedron 1994, 50, 9135–9144. (b) Ghosh, S.; Rivas, F.;
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Fischer, D.; Gonzalez, M. A.; Theodorakis, E. A. Org. Lett.
2004, 6, 941–944.
7. Hirai, G.; Oguri, H.; Moharram, S. M.; Koyama, K.; Hirama,
M. Tetrahedron Lett. 2001, 42, 5783–5787.
8. Hirai, G.; Oguri, H.; Hirama, M. Chem. Lett. 1999, 141–142.
9. Miyashita, M.; Sasaki, M.; Sakai, M.; Tanino, K. Science
2004, 495–499.
1
colourless oil: H NMR (500 MHz, CDCl3) d 7.37–7.26
(5H, m), 7.08 (1H, s), 6.05 (1H, s), 5.32 (1H, br s), 5.14–
5.12 (1H, m), 4.85–4.80 (2H, m), 4.65 (1H, s), 4.62 (1H, d,
JZ12 Hz), 4.42 (1H, dd, JZ3 Hz), 4.27 (1H, dd, JZ5,
7 Hz), 4.04 (1H, br s), 3.77 (2H, app. t, JZ6 Hz), 3.26 (3H,
d, JZ2 Hz), 3.02 (1H, dddd, JZ7, 7, 7, 13 Hz), 2.85 (1H,
dddd, JZ2, 7, 7, 9 Hz), 2.72–2.66 (1H, m), 2.53–2.48 (2H,
m), 2.38 (1H, dddd, JZ6, 11, 17, 17 Hz), 2.18 (1H, dddd,
JZ5, 5, 17, 17 Hz), 2.08–1.92 (3H, m), 1.88–1.82 (1H, m),
1.79 (3H, s), 1.73 (3H, s), 1.05 (3H, d, JZ6 Hz), 0.88 (9H,
m), 0.03 (6H, s); 13C NMR (75 MHz, CDCl3) d 204.1,
152.6, 146.5, 138.1, 135.1, 128.3, 127.3, 127.0, 122.4,
120.0, 115.5, 95.9, 95.5, 93.4, 72.4, 64.2, 54.9, 45.4, 40.7,
39.8, 31.9, 26.3, 23.2, 21.8, 18.3, 16.7, K5.2; HRMS (EI)
calcd for C37H56NaO6Si [MCNa]C647.3744, found
647.3481.
10. (a) Rao, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.;
Venkatateswaelu, Y.; Rosser, R. M.; Faulkner, D. J. J. Org.
Chem. 1985, 50, 3757–3760. (b) Rao, C. B.; Rao, D. V.; Raju,
V. S. N.; Sullivan, B. W.; Faulkner, D. J. Heterocycles 1989,
28, 103–106.
11. Fukuzawa, S.; Hayashi, Y.; Uemura, D.; Nagatu, A.; Yamada,
K.; Ijuin, Y. Heterocycl. Commun. 1995, 1, 207–214.
12. Yamaguchi, K.; Yada, M.; Tsuji, T.; Kuramoto, M.; Uemura,
D. Biol. Pharm. Bull. 1999, 22, 920–924.
13. For selected reviews on the Stille reaction, consult: (a) Stille,
J. K. Angew Chem., Int. Ed. Engl. 1986, 25, 508–524. (b)
Mitchell, T. N. Synthesis 1992, 803–815. (c) Farina, V.;
Krishnamurthy, V.; Scott, W. J. Org. React. 1998, 50, 1–652.
(d) Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin
Trans. 1 1999, 1235–1246. (e) Espinet, P.; Echavarren, A. M.
Angew. Chem. 2004, 43, 4704–4734.
Acknowledgements
14. For an overview of metal-catalyzed cross-coupling reactions,
see: Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998.
15. For an overview of organotin chemistry, see Davies, A. G.
Organotin Chemistry; VCH: Weinheim, 1997.
The Technical University of Denmark, The Torkil Holm
Foundation, The Fam. Hede Nielsen Foundation and The
Lundbeck Foundation are gratefully acknowledged for

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T. E. Nielsen et al. / Tetrahedron 61 (2005) 8013–8024
16. Tanner, D.; Tedenborg, L.; Somfai, P. Acta Chem. Scand.
1997, 51, 1217–1223.
´
17. Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55,
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21. Alkenyl iodides 33 and 34 were found to be unstable upon
overnight storage in the fridge, where significant amounts of
decomposed material appeared.
18. Although, Hg(OTfa)2 has been reported to suppress formation
of cross-products (Matysiak, S.; Fitznar, H.; Schnell, R.;
Pfleiderer, W. Helv. Chim. Acta 1998, 81, 1545–1566. ) and
generally give cleaner transetherification reactions than
Hg(OAc)2, the opposite trend was observed. Thus,
Hg(OAc)2 gave a clean conversion into the desired product
14 (51% isolated yield after purification), whereas Hg(OTfa)2
converted O80% of the benzyl alcohol into by-products. Prior
to its use, benzyl vinyl ether was carefully purified by flash
chromatography on silica gel to remove any traces of
benzaldehyde (1% according to NMR).
22. For pioneering reports on Cu(I)-mediated Stille reactions,
consult: (a) Marino, J. P.; Long, J. K. J. Am. Chem. Soc. 1988,
110, 7916–7917. (b) Liebeskind, L. S.; Fengl, R. J. Org. Chem.
1990, 55, 5359–5364.
23. Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 7600–7605.
24. Hubbard, J. S.; Harris, T. M. J. Org. Chem. 1981, 46, 2566–2570.
¨
¨
25. Osterlof, J. Acta Chim. Scand. 1950, 4, 374–385.
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27. Christol, H.; Cristau, H.-J.; Soleiman, M. Synthesis 1975,
736–738.