Improved synthesis of key fragments for the preparation of natural product incednine

Article abstract of DOI:10.1016/j.tet.2019.130604

A shorter and more efficient synthesis of three key fragments that have been previously described for the preparation of the polyenic macrolactam aglycon of natural product incednine isolated from Actinomyces sp. has been developed. These fragments have been prepared with higher levels of selectivity when compared to the already published procedure.

Full text of DOI:10.1016/j.tet.2019.130604

Tetrahedron 75 (2019) 130604
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Improved synthesis of key fragments for the preparation of natural
product incednine
*
ꢀ
ꢀ
Sandra Sarceda, Jose A. Souto, Daniel Otero, Angel R. de Lera, Marta Domínguez ,
Rosana Alvarez
**
ꢀ
ꢀ
Departamento de Química Organica, Facultade de Química, CINBIO and IIS Galicia Sur, Universidade de Vigo, E-36310, Vigo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2019
Received in revised form
3 September 2019
Accepted 11 September 2019
Available online 16 September 2019
A shorter and more efficient synthesis of three key fragments that have been previously described for the
preparation of the polyenic macrolactam aglycon of natural product incednine isolated from Actinomyces
sp. has been developed. These fragments have been prepared with higher levels of selectivity when
compared to the already published procedure.
© 2019 Elsevier Ltd. All rights reserved.
Keywords:
Natural products
Incednine
Polyenic macrolactams
Cross coupling reactions
1. Introduction
sugar moiety and the methyl substituents and the precise func-
tioning of the enzymatic machinery [4,6,9].
Polyenic macrolactams comprise a growing family of natural
products isolated from actinomycetes that generally feature a 20 to
26 membered-ring macrolactam having two stereochemically
defined polyene regions separated by hydroxyl-substituted frag-
ments. Among the several substituents attached to the unsaturated
chains, methoxy, methyl and longer (branched) alkyl groups can be
found, whereas some of the hydroxyl groups can be further func-
tionalized with a sugar moiety. Compounds with polyenic macro-
lactam substructures display a plethora of interesting biological
activities. Among them, heronamide C (2) [1,2] was shown to
induce abnormal cell wall morphology in fission yeast by targeting
saturated hydrocarbon chains in lipid membranes, silvalactam (4)
[3] has been described as a potent antitumor agent, and incednine
(1) [4e6] has been reported as a potent inhibitor of the anti-
apoptotic function of Bcl-xL, an oncoprotein that is found overex-
pressed in many cancers [7,8] (Fig. 1).
Two synthetic approaches to incednine have been developed by
Toshima and co-workers and two more publications have been
released describing the synthesis of the disaccharide fragment,
which allowed to unambiguously confirm its structure and to ac-
cess enough material for further biological studies (Scheme 1)
[10e14].
Their first contribution to the development of a total synthesis
of 1 [10] in 2009 described the preparation of pentaenoic ester
fragment 7 that included as key steps a Sharpless asymmetric
epoxidation-ring opening reaction to render the chiral diol and
carbonyl olefination reactions for the generation of the double
bonds. Despite reaching the targeted molecule, this approach
comprises 25 steps of a linear synthetic sequence. Furthermore, the
non-complete stereoselectivity observed in some of the reported
transformations (i.e. 90% ee for the Sharpless epoxidation, 9:1 E/Z
ratio for the Wittig reaction) required the separation of the ob-
tained stereoisomers (including the use of a chiral resolving reagent
for isolation of the enantiomerically pure diol). A protecting group
exchange (a dioxolane was replaced by a bis-silyl ether for the diol
protection) was required due to incompatibility with some of the
reaction conditions performed along the synthetic sequence.
Later on, the same authors improved the route to fragment 7
and completed the synthesis of the aglycon 6 of incednine (1) [11].
The biogenetic pathway for the 24-membered ring macrolactam
of incednine (1) has been determined in vivo based on the incor-
poration of labeled components, thus clarifying the origin of the
* Corresponding author.
** Corresponding author.
E-mail address: mseoane@uvigo.es (M. Domínguez).
https://doi.org/10.1016/j.tet.2019.130604
0040-4020/© 2019 Elsevier Ltd. All rights reserved.

2
S. Sarceda et al. / Tetrahedron 75 (2019) 130604
(RCM) to perform the macrocyclisation by means of C18 ¼ C19
double bond formation. This approach solved some of the previ-
ously mentioned selectivity problems for the stereocontrolled
generation of double bonds and avoided the use of unstable in-
termediates but the preparation of these compounds yet required
long synthetic routes from commercially available starting
materials.
Despite the very elegant solution to the problems encountered
during the synthesis of 6, further efforts to prepare this compound
that considers the development of
a sustainable and atom
economical synthetic strategy avoiding, or at least reducing, the use
of hazardous chemicals and protecting groups, while preferentially
employing catalytic reaction for the generation of targeted mole-
cules in a selective manner, are fully justified [15]. This consider-
ation prompted us to describe a new approach to the preparation of
the three key intermediates used in the synthesis of incednam (6).
Our synthetic plan aimed to improve the efficiency of the global
route reducing the number of steps required for the preparation of
the targeted molecules, and prioritising the use of catalytic re-
actives and highly selective transformations (Scheme 2).
Fig. 1. Selection of natural products belonging to the macrolactam family (the absolute
configuration of 4 and 5 is not yet known).
The former was prepared following a chiral pool strategy using
methyl-L-lactate as chiral component by titanium-mediated Evans
2. Results/discussion
aldol addition rendering the desired anti product in a 10:1 d.r., thus
avoiding the previously mentioned step required for the chiral
resolution of diols and affording the desired pentaenoic ester 7 in a
slightly shorter, although yet linear, 22-step sequence. For the
preparation of the upper tetraene fragment 8, the authors devised a
convergent synthetic approach that implied a Wittig olefination for
the generation of the natural product C18¼C19 double bond. Albeit
highly selective, the transformation rendered 8 in low yield (32%)
and the compound had to be used immediately after preparation
due to its intrinsic instability.
Already described fragment 9 [10,11] could be prepared in a
convergent manner following the synthetic pathway described in
Schemes 3 and 4. After protection of (Z)-3-methylpent-2-en-4-yn-
1-ol Z-19 as 4-methoxybenzoate, we took advantage of Sharpless
asymmetric dihydroxylation reaction with AD-mix a, following a
methodology previously described by our group [16] that allows
the isolation of the corresponding diols starting from (Z)-alkenes, to
render compound 23 with high yield and enantioselectivity [17].
Furthermore, the prepared compound could be isolated in enan-
tiopure form after crystallisation. The obtained diol 23 was pro-
tected as silyl ether [11] and subsequently 24 was transformed into
the corresponding terminal stannane 25 in a regio- and stereo-
selective manner and in good yield (95%), by a palladium-mediated
hydrometallation reaction [18]. The observance of a coupling con-
stant of J ¼ 19.2 Hz between the vicinal hydrogens confirmed the E
geometry of the olefin. At this point, the cleavage of the PMBz group
resulted more difficult than anticipated. The use of previously
described methodologies that involve basic conditions (i.e. MeLi,
KOH) resulted either in decomposition or deprotection followed by
silyl group migration from the secondary (C2) to the primary (C1)
alcohol [17]. To our delight, we found that addition of DIBAL-H
smoothly afforded the deprotected primary alcohol 26 in 83%
yield (Scheme 3).
An improved total synthesis of incednam was more recently
reported [12], which took advantage of the ring-closing metathesis
The synthesis of iododienoate 29 starting from 3,3-
Scheme 2. Retrosynthetic analysis of incednam (6) leading to key fragments 9, 16 and
18.
Scheme 1. Previously described synthetic strategies for the preparation of 6 [10e12].

S. Sarceda et al. / Tetrahedron 75 (2019) 130604
3
paper motivation, compound 9 could be transformed into 7 in 5
steps with good overall yield and selectivity following a synthetic
pathway previously described by Toshima et al. [10].
The preparation of fragment 18 (Scheme 5) started with the
Lewis acid-assisted ring opening of enantiopure 2-methyloxirane
[23], with the anion of trimethylsilyl acetylene [24] to render the
homopropargylic alcohol, which was quantitatively transformed
into the corresponding silyl ether 30. Then, the alkyne terminus of
30 was transformed into the stereochemically pure (Z)-vinylsilane
31 via hydroboration-methylation-carbodemetallation reaction as
previously described by Nozaki and coworkers [25,26]. Subsequent
halogenation, using treatment with bromine followed by sodium
methoxide, afforded the (E)-bromoalkene 32 in 87% yield The ge-
ometry of the double bond was confirmed by NOE experiments.
Then, fluoride-assisted silyl ether deprotection followed by Mit-
sunobu reaction using phthalimide as nucleophile rendered the
corresponding derivative 34 in good yield while maintaining the
stereochemical integrity present in the starting material [17]. Stille
vinylation, using conditions previously developed by Farina et al.
[27], eventually afforded 18 in 87% yield.
Scheme 3. Synthesis of fragment 26.
Finally, fragment 16 was straightforwardly prepared by stan-
nylcupration of (E)ꢀ19 to yield the trans dienylstannane 35 in good
yield and selectivity [28], followed by a quantitative MnO2 oxida-
tion of the allylic alcohol of 35 to dienal 36 and Wittig reaction to
afford trienylstannane 16 in 67% yield (Scheme 6) [29].The E-ge-
ometry of the double bond formed in the stannylcupration reaction
was validated by the value of the coupling constant (J ¼ 19.3 Hz)
between the newly formed olefin hydrogens.
3. Conclusion
Scheme 4. Formal synthesis of fragment 7.
In summary, we have developed a shorter and more efficient
synthesis, with the longest linear sequence of 10 steps, of fragments
9, 16, and 18, which have been reported as key building blocks for
the preparation of the incednine aglycon (6). Our methodology
allows the isolation of enough amount of targeted fragments,
considerably reduces the number of steps for their preparation, and
prioritises the use of highly selective catalytic transformation for
the preparation of key intermediates which could be eventually
used for the total synthesis of incednam (6) as previously described
in the literature [11,12].
diethoxypropyne 20 was achieved by sequential stannylcupration
and acid-catalysed acetal cleavage [19], leading to the isolation of
aldehyde 27 in 83% combined yield, which was transformed into
the corresponding iododienyl ester 29 by HWE reaction, followed
by tin-iodine exchange using N-iodosuccinimide as iodine source
[20], in good overall yield (73%) and high stereoselectivity, in
agreement with data previously reported [19]. Subsequently,
compounds 26 and 29 were merged by Stille coupling using reac-
tion conditions previously described by Fürstner and coworkers
[21] leading to targeted trienyl ester 9 in 68% yield (Scheme 4). The
spectroscopy data of 9 matched those originally published by
Toshima et al. [11] (Table 1) [22]. Although out of the reach of this
4. Experimental section
Solvents were dried using a Puresolv™ solvent purification
system. HPLC grade solvents were used for the HPLC purification.
All other reagents were commercial compounds of the highest
purity available. If not specified, all reactions were carried out
Table 1
Comparison of 1HNMR data (
d, ppm) of synthesized 9 with that previously described
by Toshima et al. [11]
1H-NMR (synthesized)
(400 MHz, CDCl3)
1H-NMR (ref. 11)
(500 MHz, CDCl3)
7.27e7.19 (m, 1H)
6.53e6.47 (m, 2H)
6.31e6.22 (m, 1H)
5.86 (d, J ¼ 15.2 Hz, 1H)
4.22 (q, J ¼ 7.2 Hz, 2H)
7.26e7.18 (m, 1H)
6.52e6.49 (m, 2H)
6.30e6.24 (m, 1H)
5.86 (d, J ¼ 15.5 Hz, 1H)
4.22 (q, J ¼ 7.0 Hz, 2H)
3.77 (ddd, J ¼ 10.3, 6.3, 3.5 Hz, 1H)
3.62 (ddd, J ¼ 10.4, 7.6, 4.2 Hz, 1H)
3.55 (dd, J ¼ 6.3, 4.3 Hz, 1H)
2.71 (dd, J ¼ 7.5, 3.7 Hz, 1H)
1.98 (s, 3H),
3.77 (ddd, J ¼ 10.6, 6.3, 3.8 Hz, 1H
3.62 (ddd, J ¼ 10.6, 7.7, 4.3 Hz, 1H)
3.56 (dd, J ¼ 6.3, 4.3 Hz, 1H)
2.71 (dd, J ¼ 7.7, 3.8 Hz, 1H)
1.98 (s, 3H)
1.38 (s, 3H)
1.39 (s, 3H)
1.31 (t, J ¼ 7.0 Hz, 3H)
1.32 (t, J ¼ 7.0 Hz, 3H)
1.01e0.87 (m, 18H)
0.96e0.91 (m, 18H)
0.64e0.52 (m, 12H)
0.61e0.52 (m, 12H)
Scheme 5. Synthesis of fragment 18.

4
S. Sarceda et al. / Tetrahedron 75 (2019) 130604
4.2. (2S,3R)-2,3-Dihydroxy-3-methylpen-4-yn-1-yl 4-
Methoxybenzoate (23)
To an emulsion of K3Fe(CN)6 (44.7 g, 114.8 mmol), K2CO3 (15.9 g,
114.8 mmol), (DHQ)2PHAL (0.3 g, 0.38 mmol), K2OsO4$2H2O
(0.141 g, 0.38 mmol) and Me2SO4NH2 (4.1 g, 42.1 mmol) in tBuOH/
H2O (278 mL, 1:1, v/v), a solution of (Z)-3-methylpent-2-en-4-yl 4-
methoxybenzoate (22) (8.81 g, 38.26 mmol) in tBuOH/H2O (100 mL,
1:1, v/v) was added and the mixture was stirred at 5 ꢁC for 48 h.
Na2SO3 (60 g) was added and the resulting mixture was stirred for
an additional hour at 25 ꢁC. The mixture was extracted with CH2Cl2
(3x) and the combined organic layers were washed with 1 M NaOH
(3x), dried (Na2SO4) and the solvent was removed. The residue was
purified by column chromatography (silica gel, 50:50 hexane/
EtOAc) and recrystallization (94% ee on the residue; 99% ee after
crystallisation) to afford 6.1 g (60%) of a white solid identified as
Scheme 6. Synthesis of fragment 16.
under an argon atmosphere and protected from light. Those not
involving aqueous reagents were carried out in oven-dried glass-
ware. All solvents and anhydrous solutions were transferred
through syringes and cannulae previously dried in the oven for at
least 12 h and kept in a desiccator. For reactions at low temperature,
ice-water (0 ꢁC) or CO2/acetone systems (ꢀ78 ꢁC) were used. For
temperatures different from previously mentioned ones, a Haake
EK90 Immersion Cooler (ꢀ90 to ꢀ15 ꢁC) was used. Analytical TLC
was performed on aluminium plates with Merck Kieselgel 60F254
and visualized by UV irradiation (254 nm) or by staining with an
acid solution of phosphomolibdic acid and ethanol. Flash column
chromatography was carried out using Merck Kieselgel 60
(230e400 mesh) under pressure. UV/Vis spectra were recorded
with a Cary 100 Bio spectrophotometer in CH2Cl2. IR spectra were
obtained on a JASCO FTIR 4200 spectrophotometer from a diamond
ATR probe. Specific rotations were measured on a JASCO P-1020
polarimeter with a Na lamp. Ee determinations were performance
in a Waters HPLC (Waters™ 717 plus autosample, 515 HPLC pump
and 996 photodiode Array Detector) with chiral columns (Chiralcel
OD-H 0.46 cm ꢂ 15 cm or Chiralpak IA 1 cm ꢂ 25 cm). HRMS (ESIþ)
were measured with an Apex III FT ICR mass spectrometer (Bruker
(2S,3R)-2,3-dihydroxy-3-methylpen-4-yn-1-yl 4-methoxybenzoate
[25]
(23). [
a]
ꢀ22.6ꢁ (c 0.96, MeOH). m.p.: 127-128 ꢁC (hexane/
D
EtOAc). 1H-NMR (400.13 MHz, CDCl3):
d
8.01 (d, J ¼ 8.6 Hz, 2H), 6.93
(d, J ¼ 8.6 Hz, 2H), 4.61 (dd, J ¼ 12.1, 3.2 Hz, 1H), 4.53 (dd, J ¼ 12.1,
7.4 Hz, 1H), 3.89e3.81 (m, 1H), 3.87 (s, 3H), 2.94 (s, 1H), 2.89 (app d,
J ¼ 6.3 Hz, 1H), 2.53 (s, 1H), 1.59 (s, 3H) ppm. 13C-NMR (100.62 MHz,
CDCl3): d 167.0,163.8,132.0 (2x),122.1,113.9 (2x), 84.4 (s), 76.2, 73.9,
69.3, 66.2, 55.6, 26.1 ppm. IR (NaCl):
y 3500e3100 (br, OeH), 3291
(m, C^≡CeH), 2983 (m, CeH), 2839 (w, CeH), 2113 (w, C^≡C),
1705 (s, C]¼O), 1606 (s), 1259 (s), 1171 (s) cmꢀ1. HRMS (ESIþ):
Calcd. for C14H17O5 ([MþH]þ), 265.1070; found, 265.1071.
4.3. (2S,3R)-3-Methyl-2,3-bis(triethylsilyl)pent-4-yn-1-yl 4-
Methoxybenzoate (24)
To
a
cooled (0 ꢁC) solution of (2S,3R)-2,3-dihydroxy-3-
methylpen-4-yn-1-yl 4-methoxybenzoate (23) (1.85 g, 7.0 mmol)
in CH2Cl2 (69 mL), 2,6-lutidine (4.9 mL, 42.0 mmol) and TESOTf
(6.3 mL, 28 mmol) were added and the reaction mixture was stirred
for 1 h at 0 ꢁC. The reaction mixture was quenched with a saturated
aqueous solution of NaHCO3 and extracted with Et2O (3x). The
combined organic layers were washed with brine (3x), dried
(Na2SO4) and the solvent was removed. The residue was purified by
column chromatography (silica gel, 97:3 hexane/EtOAc) to afford
1
Daltonics). H NMR spectra were recorded at 25 ꢁC with a Bruker
AMX-400 spectrometer operating at 400.16 MHz with residual
protic solvent as the internal reference [CDCl3,
¼ 7.16 ppm]; chemical shifts ( ) are given in parts per million
(ppm) and coupling constants (J) are given in Hertz (Hz). The proton
d
¼ 7.26 ppm; C6D6,
d
d
spectra are reported as follows: d (multiplicity, coupling constant J,
number of protons). 13C NMR spectra were recorded at 25 ꢁC with
the same spectrometer operating at 100.62 MHz with the central
3.4 g (99%) of a colourless oil identified as (2S,3R)-3-methyl-2,3-
peak of CDCl3
(d
¼ 77.0 ppm); C6D6
(
d
¼ 128.0 ppm) as the internal
[23]
bis(triethylsilyl)pent-4-yn-1-yl 4-methoxybenzoate (24).
[a]
reference. DEPT-135 pulse sequences NMR spectra were used to aid
ꢀ26.7ꢁ (c 1.04, MeOH). 1H-NMR (400.13 MHz, CDCl3):
d 8.02 (d,
in the assignment of signals in the 13C NMR spectra.
D
J ¼ 8.9 Hz, 2H), 6.92 (d, J ¼ 8.9 Hz, 2H), 4.63 (dd, J ¼ 11.3, 2.2 Hz, 1H),
4.27 (dd, J ¼ 11.3, 7.4 Hz, 1H), 4.03 (dd, J ¼ 7.4, 2.2 Hz, 1H), 3.87 (s,
3H), 2.44 (s, 1H), 1.49 (s, 3H), 1.02e0.88 (m, 18H), 0.73e0.63 (m,
12H) ppm. 13C-NMR (100.62 MHz, CDCl3):
d 166.3, 163.3, 131.6 (2x),
122.8, 113.5 (2x), 87.5, 77.0, 73.1, 71.3, 67.0, 55.3, 25.4, 7.0 (3x), 6.9
4.1. (Z)-3-Methylpent-2-en-4-yl 4-Methoxybenzoate (22)
(3x), 6.1 (3x), 5.3 (3x) ppm. HRMS (ESIþ):Calcd. for C26H45O5Si2
([MþH]þ), 493.2800; found, 493.2817. IR (NaCl):
y 3309 (w,
To a solution of (Z)-3-methylpent-2-en-4-yl-1-ol (19) (6.0 g,
62.4 mmol) and Et3N (86.8 mL, 0.62 mol) in CH2Cl2 (300 mL), was
added a solution of p-methoxybenzoyl chloride (16 g, 93.6 mmol)
in CH2Cl2 (300 mL). After stirring for 14 h at 25 ꢁC, the solvent was
removed. The residue was purified by column chromatography
(silica gel, 90:10 hexane/EtOAc) to afford 13.24 g (92%) of a white
solid identified as (Z)-3-methylpent-2-en-yl 4-methoxybenzoate
(22). m.p.: 46-47 ꢁC (hexane/EtOAc). 1H-NMR (400.13 MHz,
C^≡CeH), 2955 (s, CeH), 2912 (m, CeH), 2877 (s, CeH), 1717 (s,
C]¼O), 1607 (s), 1257 (s), 1122 (s), 1007 (m) cmꢀ1
.
4.4. (2S,3R,4E)-3-Methyl-5-(tributylstannyl)-2,3-bis[(triethylsilyl)
oxy]pent-4-en-1-yl 4-Methoxybenzoate (25)
To
a solution of (2S,3R)-3-methyl-2,3-bis((triethylsilyl)oxy)
pent-4-yn-1-yl 4-methoxybenzoate (24) (0.3 g, 0.61 mmol) and
PdCl2(PPh3)2 (8.5 mg, 0.012 mmol) in THF (15.25 mL), was added
dropwise n-Bu3SnH (0.25 mL, 0.91 mmol). After stirring for 10 min,
the solvent was removed. The residue was purified by column
chromatography (silica gel, 97:3 hexane/Et3N) to afford 0.45 g (95%)
of a colorless oil identified as (2S,3R,4E)-3-methyl-5-(tributyl-
CDCl3):
J ¼ 6.6 Hz, 1H), 4.99 (d, J ¼ 6.6 Hz, 2H), 3.86 (s, 3H), 3.23 (s, 1H), 1.94
(s, 3H) ppm. 13C-NMR (100.62 MHz, CDCl3):
166.2, 163.4, 132.6,
d
8.00 (d, J ¼ 7.0 Hz, 2H), 6.91 (d, J ¼ 7.0 Hz, 2H), 5.99 (t,
d
131.7 (2x), 122.6, 122.2, 113.6 (2x), 83.0, 81.5, 63.2, 55.5, 23.1 ppm.
HRMS (ESIþ): Calcd. for C14H15O3 ([MþH]þ), 231.1016; found,
231.1021. IR (NaCl):
y
3290 (m, C^≡CeH), 2955 (m, CeH), 2840 (m,
stannyl)-2,3-bis[(triethylsilyl)oxy]pent-4-en-1-yl 4-methoxybenz
CeH), 1711 (s, C]O), 1607 (s), 1257 (s), 1169 (m) cmꢀ1
.
oate (25). [
a]
ꢀ17.0ꢁ (c 1.14, MeOH). 1H-NMR (400.13 MHz,
[23]
D

S. Sarceda et al. / Tetrahedron 75 (2019) 130604
5
C6D6):
d
8.24 (d, J ¼ 6.9 Hz, 2H), 6.66 (d, J ¼ 6.9 Hz, 2H), 6.49 (d, JH-
resulting mixture was stirred at 80 ꢁC for 16 h. When completion
was judged by TLC analysis, the reaction was quenched by addition
of a saturated aqueous solution of NaHCO3. The aqueous layer was
extracted with Et2O (3x) and the combined organic layers were
washed with brine (3x), dried (Na2SO4) and solvent was evapo-
rated. The residue was purified by column chromatography (silica
gel, 98:2 hexane/triethylamine) to afford 11.2 g (83%) of a yellow oil
characterized as (E)-(3-tributylstannyl)acrylaldehyde (27). 1H-NMR
¼ 19.2 Hz, JH-Sn ¼ 73.0 Hz, 1H), 6.41 (d, JH-H ¼ 19.2 Hz, JH-
H
¼ 66.5 Hz, 1H), 5.06 (d, J ¼ 11.5 Hz, 1H), 4.61 (dd, J ¼ 11.5, 7.4 Hz,
Sn
1H), 4.17 (d, J ¼ 7.4 Hz, 1H), 3.11 (s, 3H), 1.78e1.55 (m, 6H), 1.48 (s,
3H), 1.47e1.36 (m, 6H), 1.15e1.02 (m, 24H), 1.02e0.96 (m, 9H),
0.79e0.68 (m, 12H) ppm. 13C-NMR (100.62 MHz, CDCl3):
d 166.3,
163.5, 150.2, 131.8 (2x), 126.5, 122.6, 113.7 (2x), 77.2, 75.9, 67.2, 55.5,
29.2 (2JC-Sn ¼ 20.4 Hz, 3x), 27.4 (3JC-Sn ¼ 55.2 Hz, 3x), 24.8, 13.8 (3x),
9.52 (1J1C1-9 ¼ 342.9 Hz, 1JC11-7Sn ¼ 329.2 Hz, 3x), 6.99 (6x), 5.21 (6x)
(400.13 MHz, C6D6):
d
9.36 (d, J ¼ 7.4 Hz, 1H), 7.32 (d, JH-H ¼ 19.2 Hz,
Sn
ppm. HRMS (ESIþ): Calcd. for C38H72O5Si2SnNa ([MþNa]þ),
J
¼ 57.5 Hz,
J
¼ 55.0 Hz, 1H), 6.70 (dd, JH-H ¼ 19.2, 7.4 Hz,
2 119
2 117
H- Sn
3 119
H- Sn
807.3839; found, 807.3835. IR (NaCl):
y
2955 (s, CeH), 2927 (m,
J
¼ 52.1 Hz, 3JH11-7Sn ¼ 49.6 Hz, 1H), 1.55e1.35 (m, 6H), 1.34e1.21
H- Sn
CeH), 2874 (m, CeH), 1717 (s, C]¼O), 1607 (m), 1257 (s), 1111 (s),
(m, 6H), 0.96e0.80 (m, 12H) ppm. 13C-NMR (100.62 MHz, C6D6):
1009 (m), 749 (m) cmꢀ1
.
d
192.2
(JC-Sn ¼ 71.9 Hz),
160.3
(1JC11-9Sn ¼ 296.7 Hz
117
[1],J
¼ 283.4 Hz), 148.4, 29.3 (2JC-Sn ¼ 21.2 Hz, 3x), 27.6 (3JC-
C- Sn
¼ 55.9 Hz,
4.5. (2S,3R,4E)-3-Methyl-5-(tributylstannyl)-2,3-bis[(triethylsilyl)
oxy]pent-4-en-1-ol (26)
3x),
13.9
(3x),
9.91
(1JH11-9Sn ¼ 342.6 Hz,
Sn
1 117
J
¼ 326.5 Hz, 3x) ppm. HRMS (ESIþ) m/z (%): Calcd. for
H- Sn
C
15H31O119Sn ([MþH]þ), 347.13937; found, 347.13875. IR (NaCl):
y
To a cooled (ꢀ78 ꢁC) solution of (2S,3R,4E)-3-methyl-5-(tribu-
tylstannyl)-2,3-bis[(triethylsilyl)oxy]pent-4-en-1-yl 4-methoxyb
enzoate (25) (1.38 g, 2.09 mmol) in CH2Cl2 (29 mL), was added
DIBAL-H (5.23 mL,1.0 M in hexane, 5.23 mmol). After stirring for 4 h
at ꢀ78 ꢁC, the reaction mixture was diluted with Et2O (30 mL) and
allowed to reach 0 ꢁC. Then, H2O (0.21 mL), a 15% aqueous solution
of NaOH (0.21 mL) and H2O (0.53 mL) were added sequentially. The
mixture was warmed up to 25 ꢁC and stirred for 15 min, Na2SO4 was
added and the solution was stirred for a further 15 min. The
resulting suspension was filtered through a pad of Celite®, washed
with Et2O and the solvent was evaporated. The residue was purified
by flash column chromatography (silica gel compacted with 98:2
hexane/Et3N, then 95:5 hexane/EtOAc) to afford 0.91 g (83%) of a
2957 (s, CeH), 2925 (s, CeH), 2852 (m, CeH), 1690 (s, C]¼O), 1461
(m), 1377 (w), 1189 (w), 1072 (m), 992 (w), 960 (w), 871 (w), 800
(w), 744 (w), 665 (m) cmꢀ1
.
4.7. Ethyl (2E,4E)-2-Methyl-5-(tributylstannyl)penta-2,4-dienoate
(28)
To a cooled (0 ꢁC) solution of ethyl 2-(diethoxyphosphoryl)
propanoate (27) (1.43 mL, 6.66 mmol) in THF (25 mL) was added
dropwise n-BuLi (2.56 mL, 2.49 M in THF, 6.37 mmol). After stirring
at that temperature for 0.5 h, a solution of (E)-3-(tributylstannyl)
acrylaldehyde (2.0 g, 5.8 mmol) in THF (5 mL) was added and the
mixture was stirred for 3 h. H2O was added and the mixture was
extracted with CH2Cl2 (3x). The combined organic layers were dried
(Na2SO4) and the solvent was removed. The residue was purified by
column chromatography (silica gel, 96:2:2 hexane/EtOAc/Et3N) to
afford 2.43 g (98%) of a colorless oil identified as ethyl (2E,4E)-2-
methyl-5-(tributylstannyl)penta-2,4-dienoate (28). 1H NMR
colorless oil identified as (2S,3R,4E)-3-methyl-5-(tributylstannyl)-
[24]
2,3-bis[(triethylsilyl)oxy]pent-4-en-1-ol (26). [
a]
ꢀ16.8ꢁ (c
D
1.04, MeOH). 1H-NMR (400.13 MHz, C6D6):
d
6.40 (d, JH-H ¼ 19.3 Hz,
JH-Sn ¼ 74.0 Hz, 1H), 6.31 (d, JH-H ¼ 19.3 Hz, JH-Sn ¼ 66.8 Hz, 1H),
4.04e3.97 (m, 1H), 3.89e3.78 (m, 1H), 3.75 (t, J ¼ 5.1 Hz, 1H),
2.34e2.25 (m, 1H), 1.71e1.58 (m, 6H), 1.44 (s, 3H), 1.43e1.35 (m,
6H), 1.14e0.93 (m, 33H), 0.75e0.61 (m, 12H) ppm. 13C-NMR
(400.13.16 MHz, C6D6):
d
7.51 (d, J ¼ 10.7 Hz, 1H), 7.06 (dd, JH-
¼ 18.6, 10.7 Hz, 1H), 6.71 (d, JH-H ¼ 18.6 Hz, JH-Sn ¼ 68.3 Hz, 1H),
H
(100.62 MHz, C6D6):
d
154.6, 127.1, 80.6, 78.8, 64.7, 29.7 (2JC-
4.07 (q, J ¼ 7.1 Hz, 2H), 2.05 (s. 3H), 1.71e1.44 (m, 6H), 1.43e1.28 (m,
¼ 20.5 Hz, 3x), 27.9 (3JC-Sn ¼ 55.4 Hz, 3x), 21.4, 14.0 (3x), 9.7 (3x),
6H), 1.12e0.85 (m, 18H) ppm. 13C NMR (100.62 MHz, (CD3)2CO):
Sn
7.4 (1J1C1-9 ¼ 342.1 Hz,
J
¼ 327.1 Hz, 3x), 7.3 (3x), 7.2 (3x), 5.7
d
168.6, 145.4, 142.9, 140.5 (1JC-Sn ¼ 72.4 Hz), 126.7, 60.9, 28.8 (2JC-
¼ 20.9 Hz, 3x), 27.9 (3JC-Sn ¼ 53.8 Hz, 3x), 14.7, 14.0 (3x), 12.9, 10.2
1 117
Sn
C- Sn
(3x) ppm. HRMS (ESIþ): Calcd. for C30H66O3Si1219SnNa ([MþNa]þ),
Sn
673.3469; found, 673.3443. IR (NaCl):
y
3571 (w, OeH), 2955 (s,
(1J1C1-9 ¼ 347.9 Hz, 1J1C1-7Sn ¼ 332.6 Hz, 3x) ppm. HRMS (ESIþ): Calcd.
Sn
CeH), 2925 (m, CeH), 2875 (m, CeH), 1102 (m), 1001 (m), 742
for C20H39O1219Sn ([MþH]þ), 431.1970; found, 431.1977. IR (NaCl):
y
(s) cmꢀ1
.
2956 (s, CeH), 2926 (s, CeH), 1707 (s, C]O), 1263 (s), 1253 (s) cmꢀ1
.
UV (MeOH): lmax 274 nm.
4.6. (E)-(3-Tributylstannyl)acrylaldehyde (27)
4.8. Ethyl (2E,4E)-2-Methyl-5-iodopenta-2,4-dienoate (29)
To a cooled (ꢀ78 ꢁC) solution of CuCN (4.18 g, 46.83 mmol) in
THF (100 mL) was added n-BuLi (43.5 mL, 2.15 M in THF,
93.63 mmol) and the resulting mixture was stirred at 25 ꢁC for
20 min. The temperature was cooled down again to ꢀ78 ꢁC and n-
Bu3SnH (25.3 mL, 93.63 mmol) was added. After stirring for 30 min,
3,3-diethoxyprop-1-yne (20) (5.6 mL, 39.00 mmol) in THF (60 mL)
was added and the reaction was stirred at ꢀ78 ꢁC for 30 min. Dry
methanol was added dropwise while stirring, keeping the tem-
perature at ꢀ78 ꢁC during 30 min and then at 0 ꢁC for 10 min. The
reaction was quenched by addition of a saturated aqueous solution
of NH4Cl and extracted with Et2O (3x). The combined organic layers
were washed with brine (3x), dried (Na2SO4) and the solvent was
evaporated to afford a yellow oil identified as (E)-tributyl(3,3
diethoxyprop-1-en-1-yl)stannane which was used in the next step
without further purification.
To a cooled (0 ꢁC) solution of ethyl (2E,4E)-2-methyl-5-(tribu-
tylstannyl)penta-2,4-dienoate (28) (250 mg, 0.58 mmol) in CH3CN
(12 mL), NIS (131 mg, 0.0.58 mmol) was added and the mixture was
stirred at 0 ꢁC for 1 h. Then, a saturated aqueous solution of Na2S2O3
and a saturated aqueous solution of NaHCO3 were added and the
aqueous layer was extracted with Et2O (3x). The combined organic
layers were washed with water (2x), brine (2x), dried (Na2SO4) and
the solvent was removed. The residue was purified by column
chromatography (silica gel, 96:2:2 hexane/EtOAc/Et3N) to afford
140 mg (90%) of a colorless oil identified as ethyl (2E,4E)-2-methyl-
5-iodopenta-2,4-dienoate (29). 1H NMR (400.13 MHz, C6D6):
d 7.09
(dd, J ¼ 14.1, 11.6 Hz, 1H), 6.96 (dd, J ¼ 11.6, 1.4 Hz, 1H), 6.11 (d,
J ¼ 14.1 Hz, 1H), 3.99 (q, J ¼ 7.2 Hz, 2H), 1.60 (d, J ¼ 1.4 Hz, 3H), 0.96
(t, J ¼ 7.1 Hz, 3H) ppm.13C NMR (100.62 MHz, C6D6):
d 167.5, 141.1,
To a solution of (E)-tributyl(3,3 diethoxyprop-1-en-1-yl)stan-
nane (16.35 g, 39.00 mmol) in acetone (150 mL) and water (10 mL),
p-toluenesulfonic acid (0.74 g, 3.90 mmol) was added and the
136.8, 88.0, 60.7, 14.3, 12.9 ppm. HRMS (ESIþ): Calcd. for C8H12IO2
([MþH]þ), 266.9877; found, 266.9872. IR (NaCl):
y 2958 (m, CeH),
2929 (m, CeH), 2857 (w, CeH), 1708 (s, C]¼O), 1255 (s), 1103

6
S. Sarceda et al. / Tetrahedron 75 (2019) 130604
(s) cmꢀ1
.
395.2237. IR (NaCl): y 2960 (m, CeH), 2930 (m, CeH), 2896 (w,
CeH), 2858 (m, CeH), 2177 (m, C^≡C), 1427 (m), 1249 (m), 1110 (s),
4.9. Ethyl (2E,4E,6E,8R,9S)-8,9-Bis(triethylsilyloxy)-10-hydroxy-
842 (s) cmꢀ1
.
2,8-dimethyldeca-2,4,6-trienoate (9)
4.11. (4R,4Z)-tert-Butyldiphenyl-(5-(trimethylsilyl)hex-4-en-2-yl)
To a round-bottomed flask containing (Ph2PO2)(NBu4) (91 mg,
0.20 mmol) was added a solution of stannane (26) (113 mg,
0.22 mmol) and iodide (29) (48 mg, 0.18 mmol) in DMF (0.663 mL),
followed by addition of CuTC (38 mg, 0.20 mmol) and Pd(PPh3)4
(21 mg, 0.020 mmol). After stirring at 25 ꢁC for 1 h, the reaction was
cooled down to 0 ꢁC and quenched by addition of water. The
mixture was extracted with Et2O (3x) and the combined organic
layers were washed with H2O (3x), dried (Na2SO4) and the solvent
was removed. The residue was purified by column chromatography
(silica gel, 98:2 hexane/Et3N) to afford 51 mg (68%) of a colorless oil
oxy-silane (31)
To a cooled (0 ꢁC) solution of cyclohexene (4.16 g, 50.0 mmol) in
THF (20.3 mL), was added borane (25.3 mL, 1 M in THF, 25.3 mmol).
After stirring for 75 min at 0 ꢁC, a solution of (R)-tert-butyldiphenyl-
(5(trimethylsilyl)pent-4-yn-2-yl-oxy-silane (30) (5.0 g, 12.7 mmol)
in THF (16 mL) was added. The resulting mixture was stirred
overnight at 25 ꢁC, whereupon 1-hexene (3 mL, 23.7 mmol) was
added. The homogeneous solution was cooled down to 0 ꢁC and
methyl lithium (27.4 mL, 1.6 M in Et2O, 43.83 mmol) was added. The
resulting solution was stirred for 30 min, whereupon freshly
distilled methyl iodide (39.3 mL, 63.13 mmol) was added. After
stirring for 48 h at 25 ꢁC, the solution was diluted with Et2O
(804 mL), cooled down to 0 ꢁC and a 1 M aqueous solution of NaOH
(26.1 mL, 26.1 mmol) and H2O2 (1.73 mL, 30% w/w, 20.14 mmol)
were added. After stirring for 1 h at 25 ꢁC, the layers were sepa-
rated. The organic layer was washed with a 10% aqueous solution of
Na2S2O3 (2x), a 1 M solution of NaOH (2x), a 10% aqueous solution
of citric acid (2x), a saturated solution of NaHCO3 (2x) and brine
(2x), dried (Na2SO4) and the solvent was removed. The residue was
purified by column chromatography (silica gel, gradient from 99:1
to 98:2 hexane/EtOAc) to afford 4.0 g (88%) of a colorless oil iden-
identified as ethyl (2E,4E,6E,8R,9S)-8,9-bis(triethylsilyloxy)-10-
[20]
hydroxy-2,8-dimethyldeca-2,4,6-trienoate (9). [
a
]
ꢀ4.5ꢁ (c
D
0.53, CHCl3). 1H-NMR (400.13 MHz, CDCl3):
d
7.27e7.19 (m, 1H),
6.53e6.47 (m, 2H), 6.31e6.22 (m, 1H), 5.86 (d, J ¼ 15.2 Hz, 1H), 4.22
(q, J ¼ 7.2 Hz, 2H), 3.77 (ddd, J ¼ 10.3, 6.3, 3.5 Hz, 1H), 3.62 (ddd,
J ¼ 10.4, 7.6, 4.2 Hz, 1H), 3.55 (dd, J ¼ 6.3, 4.3 Hz, 1H), 2.71 (dd,
J ¼ 7.5, 3.7 Hz, 1H), 1.98 (s, 3H), 1.38 (s, 3H), 1.31 (t, J ¼ 7.0 Hz, 3H),
1.01e0.87 (m, 18H), 0.64e0.52 (m, 12H) ppm. 13C-NMR
(100.62 MHz, CDCl3): d 168.5, 143.4, 138.6, 138.0, 129.6, 128.2, 127.6,
79.0, 77.2, 64.4, 60.8, 20.8, 14.5, 12.9, 7.1 (3x), 7.0 (3x), 6.7 (3x), 5.2
(3x) ppm. HRMS (ESIþ): Calcd. for C26H50NaO5Si2 ([MþNa]þ),
521.3058; found, 521.3081. IR (NaCl):
y 3535 (m, OeH), 2955 (s,
CeH), 2878 (s, CeH), 1705 (s, C]¼O), 1246 (s), 1104 (s) cmꢀ1
.
tified as (2R,4Z)-tert-butyldiphenyl-(5-(trimethylsilyl)hex-4-en-2-
yl)oxy-silane (31).
(400.13 MHz, CDCl3): d 7.70e7.65 (m, 4H), 7.44e7.33 (m, 6H), 5.93
[28]
[
a
]
þ28.1ꢁ (c 1.00, MeOH). 1H-NMR
D
4.10. (2R)-tert-Butyldiphenyl-(5-(trimethylsilyl)pent-4-yn-2-yl)
oxy-silane (30)
(t, J ¼ 7.4 Hz, 1H), 3.90e3.81 (m, 1H), 2.38e2.30 (m, 1H), 2.28e2.21
(m, 1H), 1.72 (s, 3H), 1.05 (s, 9H), 1.03 (d, J ¼ 6.1 Hz, 3H), 0.08 (s, 9H)
To a cooled (ꢀ78 ꢁC) solution of trimethylsilylacetylene (2.03 g,
20.66 mmol) in THF (62.3 mL), n-BuLi (14.5 mL, 1.48 M in THF,
21.52 mmol) was added dropwise. After stirring at that tempera-
ture for 1.5 h, a solution of (R)-propylene oxide (21) (1.0 g,
17.22 mmol) in THF (12.4 mL) and trifluoroboro-etherate (3.24 mL,
25.23 mmol) were sequentially added. After stirring for
3 h at ꢀ78 ꢁC, the reaction mixture was diluted with Et2O and a
saturated aqueous solution of NH4Cl was slowly added. The
resulting mixture was extracted with Et2O (3x). The combined
organic layers were washed with brine (3x), dried (Na2SO4) and the
solvent was removed. The residue was purified by column chro-
matography (silica gel, gradient from 90:10 to 80:20 hexane/Et2O)
to afford 3.05 g (94%) of a colorless oil identified as (R)-5-(trime-
thylsilyl)pent-4-yn-2-ol which was used in the next step without
further manipulation.
ppm. 13C-NMR (100.62 MHz, CDCl3):
d 139.1, 136.2, 136.1 (2x), 136.0
(2x), 135.0, 134.6, 129.6, 129.5, 127.6 (2x), 127.5 (2x), 70.1, 41.8, 27.2
(3x), 25.0, 23.5, 19.4, ꢀ0.1 (3x) ppm. HRMS (ESIþ): Calcd. for
C
25H39OSi2 ([MþH]þ), 411.2534; found, 411.2532. IR (NaCl):
y 2930
(s, CeH), 2856 (m, CeH), 1427 (m), 1220 (s), 1110 (s), 835 (s) cmꢀ1
.
4.12. (2R,4E)-(5-Bromohex-4-en-2-yl)-tert-butyldiphenyloxy-
silane (32)
To a cooled (ꢀ78 ꢁC) solution of (2R,4Z)-tert-butyldiphenyl-(5-
(trimethylsilyl)hex-4-en-2-yl)oxy-silane (31) (2.0 g, 4.87 mmol) in
CH2Cl2 (10.4 mL), was added a 2 M solution of Br2 in CH2Cl2
(3.12 mL, 6.23 mmol and stirred for 1 h. Subsequently, MeOH
(6.23 mL) and solid Na2SO3 were added to the cooled solution. The
resulting light yellow solution was poured into a 10% aqueous so-
lution of Na2SO3 and extracted with Et2O (3x). The combined
organic layers were washed with brine (3x), dried (Na2SO4) and the
solvent was removed. The residue was dissolved in CH2Cl2 (31.2 mL)
and cooled down to 0 ꢁC. A freshly prepared solution of NaOMe
(7.3 mL, 7.3 mmol) in MeOH (7.3 mL) was added and the mixture
was stirred for 1 h at 0 ꢁC and 2 h at 25 ꢁC, whereupon a 10%
aqueous solution of citric acid was added. The aqueous layer was
extracted with Et2O (3x). The combined organic layers were
washed with H2O (3x) and brine (3x), dried (Na2SO4) and the sol-
vent was removed. The residue was purified by column chroma-
tography (silica gel, 99:1 hexane/EtOAc) to afford 1.77 g (87%) a
To a cooled (0 ꢁC) solution of (R)-5-(trimethylsilyl)pent-4-yn-2-
ol (0.203 g, 1.3 mmol) in DMF (0.65 mL) were sequentially added
imidazole (0.115 g, 1.68 mmol) and TBDPSCl (0.437 mL, 1.68 mmol)
and the reaction mixture was stirred for 12 h at 25 ꢁC. The reaction
mixture was diluted with Et2O and a saturated aqueous solution of
NaCl was added. The aqueous layer was extracted with Et2O (3x).
The combined organic layers were washed with H2O (3x), dried
(Na2SO4) and the solvent was removed. The residue was purified by
column chromatography (silica gel, 95:5 hexane/EtOAc) to afford
0.506 g (99%) of a colorless oil identified as (R)-tert-butyldiphenyl-
(5-(trimethylsilyl)pent-4-yn-2-yl)oxy-silane (30).
[26]
[a
]
þ29.4ꢁ (c 1.04, MeOH). 1H-NMR (400.13 MHz, CDCl3):
colorless oil identified as (2R,4E)-(5-bromohex-4-en-2-yl)-tert-
D
[24]
d
7.72e7.62 (m, 4H), 7.45e7.33 (m, 6H), 4.03e3.95 (m, 1H), 2.40 (dd,
butyldiphenyloxy-silane (32). [
a
]
þ19.7ꢁ (c 0.98, MeOH). 1H-
D
J ¼ 16.6, 5.2 Hz, 1H), 2.32 (dd, J ¼ 16.6, 6.8 Hz, 1H), 1.16 (d, J ¼ 6.0 Hz,
NMR (400.13 MHz, CDCl3): d 7.69e7.65 (m, 4H), 7.45e7.34 (m, 6H),
3H), 1.05 (s, 9H), 0.12 (s, 9H) ppm. 13C-NMR (100.62 MHz, CDCl3):
5.81 (t, J ¼ 7.8 Hz, 1H), 3.90e3.81 (m, 1H), 2.21e2.13 (m, 1H), 2.08 (s,
3H), 2.11e2.02 (m, 1H), 1.07 (d, J ¼ 6.1 Hz, 3H), 1.05 (s, 9H) ppm. 13C-
d
136.1 (2x), 136.0 (2x), 134.5, 134.2, 129.8, 129.7, 127.7 (2x), 127.6
(2x), 104.5, 86.3, 68.3, 30.7, 27.1 (3x), 23.1, 19.4, 0.23 (3x) ppm.
NMR (100.62 MHz, CDCl3): d 136.0 (2x), 135.9 (2x), 134.6, 134.2,
HRMS (EIþ): Calcd. for C24H35OSi2 ([MþH]þ), 395.2221; found,
129.8, 129.7, 128.8, 127.7 (2x), 127.6 (2x), 120.9, 68.8, 39.5, 27.1 (3x),

S. Sarceda et al. / Tetrahedron 75 (2019) 130604
7
79
23.4, 23.2, 19.3 ppm. HRMS (ESIþ): Calcd. for C22
H
BrOSi
2.93e2.76 (m,1H), 2.52e2.37 (m, 1H),1.60 (s, 3H),1.35 (d, J ¼ 7.3 Hz,
3H) ppm. 13C-NMR (100.62 MHz, C6D6):
168.2 (2x), 141.5, 136.8
30
([MþH]þ), 417.1244; found, 417.1262. IR (NaCl):
y
2932 (m, CeH),
d
2858 (m, CeH), 1427 (m), 1222 (s), 1111 (s), 994 (m) cmꢀ1
.
(2x), 133.6 (2x), 132.4 (2x), 129.0, 123.0 (2x), 111.5, 47.5, 33.2, 18.3,
11.9 ppm. HRMS (ESIþ): Calcd. for C16H18NO2 ([MþH]þ), 256.1332;
4.13. (2R,4E)-5-Bromohex-4-en-2-ol (33)
found, 256.1328. IR (NaCl): y 2979 (m, CeH), 2938 (m, CeH), 1772
(m), 1709 (s), 1362 (s) cmꢀ1
.
To a cooled (0 ꢁC) solution of (2R,4E)-(5-bromohex-4-en-2-yl)-
tert-butyldiphenyloxy-silane (32) (1.87 g, 4.48 mmol) in THF
(73.4 mL), was added TBAF (8.96 mL, 1 M in THF, 8.96 mmol) and
the resulting mixture was stirred for 30 min at 0 ꢁC and for 4 h at
25 ꢁC. The reaction mixture was quenched with a saturated
aqueous solution of NaHCO3 and then extracted with Et2O (3x). The
combined organic layers were washed with brine (3x), dried
(Na2SO4) and the solvent was evaporated. The residue was purified
by column chromatography (silica gel, gradient from 90:10 to 80:20
4.16. (2E,4E)-3-Methyl-5-(tributylstannyl)penta-2,4-dien-1-ol (35)
To a cooled (ꢀ78 ꢁC) suspension of CuCN (1.89 g, 21.1 mmol) in
THF (32.8 mL) n-BuLi (30.8 mL, 44.4 mmol,1.44 M) was added. After
stirring for 10 min, Bu3SnH (12 mL, 44.4 mmol) was added and the
reaction mixture was stirred for 10 min. A solution of (E)-3-
methylpent-2-en-4-yn-1-ol (E-19) (1.01 g, 10.6 mmol) in THF
(10.6 mL) was added and the temperature was raised to ꢀ30 ꢁC.
After stirring for 30 min, Et2O and a mixture of NH4Cl and NH3 (5:1
v/v) were added and the reaction mixture was extracted with Et2O
(3x). The combined organic layers were washed with brine (3x),
dried (Na2SO4) and the solvent was removed. The residue was
purified by column chromatography (silica gel, 90:7:3 hexane/
EtOAc/Et3N) to afford 3.7 g (90%) of a colorless oil identified as
(2E,4E)-3-methyl-5-(tributylstannyl)penta-2,4-dien-1-ol (35). 1H-
hexane/EtOAc) to afford 0.685 g (85%) of a colorless oil identified as
[26]
(2R,4E)-5-bromohex-4-en-2-ol (33). [
a]
ꢀ5.4ꢁ (c 1.01, MeOH).
D
1H-NMR (400.13 MHz, CDCl3):
d
5.90 (t, J ¼ 7.8 Hz, 1H), 3.91e3.82
(m, 1H), 2.25 (s, 3H), 2.23e2.14 (m, 2H), 1.21 (d, J ¼ 6.2 Hz, 3H) ppm.
13C-NMR (100.62 MHz, CDCl3)
128.3, 121.8, 67.3, 39.3, 23.6,
22.9 ppm. HRMS (EIþ): Calcd. for C6H BrO ([M]þ), 179.9973; found,
d
81
11
179.9981. IR (NaCl):
y 3500-3000 (br,OeH), 2969 (m, CeH), 2921
(m, CeH), 1651 (m), 1059 (m) cmꢀ1
.
NMR (400.13 MHz, C6D6):
d
6.81 (d, JH-H ¼ 19.3 Hz, JH-Sn ¼ 64.7 Hz,
1H), 6.38 (d, JH-H ¼ 19.3 Hz, JH-Sn ¼ 69.4 Hz, 1H), 5.62 (t, J ¼ 6.2 Hz,
1H), 4.01 (t, J ¼ 6.1 Hz, 2H), 1.65 (s, 3H), 1.68e1.57 (m, 6H), 1.39 (h,
J ¼ 7.3 Hz), 1.08e0.98 (m, 6H), 0.94 (t, J ¼ 7.3 Hz), 0.42 (s, 1H) ppm.
4.14. (2S,4E)-2-(5-Bromohex-4-en-2-yl)-isoindoline-1,3-dione (34)
To a cooled (0 ꢁC) solution of triphenylphosphine (0.89 g,
3.41 mmol) in THF (24 mL), DIAD (0.72 mL, 3.41 mmol) was added
and the mixture was stirred at 25 ꢁC until cloudiness appeared. The
reaction mixture was cooled down to 0 ꢁC and a solution of (2R,4E)-
5-bromohex-4-en-2-ol (33) (0.47 g, 2.62 mmol) in THF (3 mL) and
phthalimide (0.5 g, 3.41 mmol) were sequentially added. After
stirring for 6.5 h at 25 ꢁC, the solvent was evaporated. The residue
was purified by column chromatography (silica gel, 95:5 hexane/
13C-NMR (100.62 MHz, C6D6):
d 151.3, 136.9, 131.8, 127.0, 59.5, 29.7
(2JC-Sn ¼ 21.0 Hz, 3x), 27.8 (3JC-Sn ¼ 53.8 Hz, 3x), 14.0 (3x), 12.0, 9.9
(1J1C1-9 ¼ 342.5 Hz, 1J1C1-7Sn ¼ 327.9 Hz, 3x) ppm. HRMS (ESIþ): Calcd.
Sn
C
(NaCl):
for
18H36NaO119Sn ([MþNa]þ), 411.1683; found, 411.1677. IR
y
3500-3100 (br, OeH), 2957 (m, CeH), 2919 (m, CeH), 2859
(m, CeH), 1461 (m), 989 (s) cmꢀ1
.
4.17. (2E,4E)-3-Methyl-5-(tributylstannyl)penta-2,4-dienal (36)
EtOAc) to afford 0.59 g (73%) of a colourless oil identified as (2S,4E)-
[26]
2-(5-bromohex-4-en-2-yl)-isoindoline-1,3-dione (34).
[
a
]
To a cooled (0 ꢁC) solution of alcohol (35) (60 mg, 0.155 mmol) in
THF (3.0 mL) were added MnO2 (0.24 g, 2.79 mmol) and Na2CO3
(0.3 g, 2.79 mmol) and the mixture was stirred at room temperature
for 2 h. Then, the reaction was filtered through a pad of Celite™ and
the solvent was removed to isolate 59 mg (99%) of a colourless oil
identified as (2E,4E)-3-methyl-5-(tributylstannyl)penta-2,4-dienal
(36) which was used in the next step without further purification.
D
þ74.4ꢁ (c 1.02, MeOH). 1H-NMR (400.13 MHz, CDCl3):
d 7.84e7.80
(m, 2H), 7.74e7.69 (m, 2H), 5.78 (t, J ¼ 7.7 Hz, 1H), 4.45e4.36 (m,
1H), 2.83e2.72 (m, 1H), 2.57e2.43 (m, 1H), 2.18 (s, 3H), 1.49 (d,
J ¼ 7.0 Hz, 3H) ppm. 13C-NMR (100.62 MHz, CDCl3):
d 168.4 (2x),
134.1 (2x), 131.9 (2x), 128.3, 123.3 (2x), 122.3, 46.7, 34.1, 23.5,
79
18.3 ppm. HRMS (ESIþ): Calcd. for C14
H
BrN2O ([MþH]þ),
15
308.0281; found, 308.0285. IR (NaCl):
y
2977 (w, CeH), 2937 (w,
1H-NMR (400.13 MHz, C6D6):
d
9.99 (d, J ¼ 7.7 Hz, 1H), 6.83 (d, JH-
CeH), 1709 (s, C]O), 1360 (m) cmꢀ1
.
¼ 19.4 Hz, JH-Sn ¼ 61.8 Hz, 1H), 6.64 (d, JH-H ¼ 19.3 Hz, JH-
¼ 59.3 Hz, 1H), 5.92 (t, J ¼ 7.7 Hz, 1H), 1.72 (s, 3H), 1.64e1.45 (m,
H
Sn
4.15. (2R,4E)-2-(5-Methylhept-4-en-2-yl)-isoindoline-1,3-dione
(18)
6H), 1.39 (h, J ¼ 7.3 Hz, 6H), 0.98e0.88 (m, 15H) ppm. 13C-NMR
(100.62 MHz, C6D6): d
190.5, 152.9, 149.6, 139.8, 129.9, 29.5 (2JC-
¼ 20.9 Hz, 3x), 27.7 (3JC-Sn ¼ 54.9 Hz, 3x), 14.0 (3x), 12.1, 10.0
Sn
A solution of Pd2dba3 (4.2 mg, 0.004 mmol) and triphenylarsine
(10.4 mg, 0.032 mmol) in NMP (1.95 mL) was stirred at room tem-
perature for 5 min. Then, a solution of bromide (34) (50 mg,
0.162 mmol) in NMP (0.81 mL) was added and the resulting mixture
(1J1C1-9 ¼ 346.1 Hz, 1J1C1-7Sn ¼ 330.5 Hz, 3x) ppm. HRMS (ESIþ): Calcd.
Sn
for C18H34NaO119Sn ([MþNa]þ), 409.1527; found, 409.1525. IR
(NaCl):
y 2955 (m, CeH), 2923 (m, CeH), 2850 (m, CeH), 1663 (s,
C]¼O), 1203 (m) cmꢀ1
.
stirred for
a
further 10 min at 25 ꢁC. Stannane (0.06 mL,
0.195 mmol) was added and the mixture was deoxygenated prior to
stirring at 70 ꢁC for 4.5 h. An aqueous solution of KF was added and
the resulting mixture was stirred for a further 10 min at 25 ꢁC. The
aqueous layer was extracted with Et2O (3x), the combined organic
layers were washed with H2O (3x), dried (Na2SO4) and the solvent
was evaporated. The residue was purified by column chromatog-
raphy (silica gel, 95:5 hexane/EtOAc) to afford 36 mg (87%) of a
4.18. (1E,3E,5E)-3-Methylhex-1,3,5-trien-1-tributylstannane (16)
To solution of methyltriphenylphosphonium bromide
a
(100 mg, 0.279 mmol) in THF (0.25 mL) was added NaHMDS
(0.248 mL, 1 M in THF, 0.248 mmol) and the mixture was stirred at
25 ꢁC for 30 min. Then, the mixture was cooled down to ꢀ60 ꢁC and
HMPA (0.041 mL, 0.233 mmol) was added. After stirring for 10 min,
the mixture was cooled down to ꢀ78 ꢁC and a solution of aldehyde
36 (60 mg, 0.155 mmol) in THF (1.9 mL) was added and the reaction
was stirred at ꢀ78 ꢁC for an additional 1.5 h. Then, hexane was
added and the organiclayer washed with brine (3x), H2O (3x), dried
(Na2SO4) and the solvent was removed. The residue was purified by
colourless oil identified (2R,4E)-2-(5-methylhept-4-en-2-yl)-iso-
[24]
indoline-1,3-dione (18). [
a
]
þ32.3ꢁ (c 0.5, MeOH). 1H-NMR
D
(400.13 MHz, C6D6):
d
7.47 (dd, J ¼ 5.7, 3.2 Hz, 2H), 7.03 (dd, J ¼ 5.6,
3.2 Hz, 2H), 6.19 (dd, J ¼ 18.1, 11.0 Hz, 1H’), 5.33 (t, J ¼ 8.1 Hz, 1H),
4.93 (d, J ¼ 18.1 Hz, 1H), 4.77 (d, J ¼ 11.0 Hz, 1H), 4.49e4.30 (m, 1H),

8
S. Sarceda et al. / Tetrahedron 75 (2019) 130604
[5] Y. Futamura, R. Sawa, Y. Umezawa, M. Igarashi, H. Nakamura, K. Hasegawa,
M. Yamasaki, E. Tashiro, Y. Takahashi, Y. Akamatsu, M. Imoto, J. Am. Chem. Soc.
130 (2008) 1822e1823.
[6] M. Takaishi, F. Kudo, T. Eguchi, J. Antibiot. 66 (2013) 691e699.
[7] A. Ashkenazi, W.J. Fairbrother, J.D. Leverson, A.J. Souers, Nat. Rev. Drug Discov.
16 (2017) 273e284.
[8] J.L. Yap, L. Chen, M.E. Lanning, S. Fletcher, J. Med. Chem. 60 (2017) 821e838.
[9] M. Takaishi, F. Kudo, T. Eguchi, Org. Lett. 14 (2012) 4591e4593.
[10] T. Ohtani, H. Kanda, K. Misawa, Y. Urakawa, K. Toshima, Tetrahedron Lett. 50
(2009) 2270e2273.
[11] T. Ohtani, S. Tsukamoto, H. Kanda, K. Misawa, Y. Urakawa, T. Fujimaki,
M. Imoto, Y. Takahashi, D. Takahashi, K. Toshima, Org. Lett. 12 (2010)
5068e5071.
column chromatography (silica gel, 98:2 hexane/Et3N) to afford
40 mg (67%) of a colorless oil identified as (1E,3E,5E)-3-methylhex-
1,3,5-trien-1-tributylstannane (16). 1H-NMR (400.13 MHz, CDCl3):
d
6.72 (ddd, J ¼ 16.8, 11.2, 10.3 Hz, 1H), 6.59 (d, JH-H ¼ 19.2 Hz, JH-
¼ 63.4 Hz, 1H), 6.31 (d, JH-H ¼ 19.3 Hz, JH-Sn ¼ 67.4 Hz, 1H), 6.07 (d,
Sn
J ¼ 11.2 Hz, 1H), 5.28 (d, J ¼ 16.8 Hz, 1H), 5.14 (d, J ¼ 10.1 Hz, 1H),1.88
(s, 3H), 1.65e1.40 (m, 6H), 1.41e1.18 (m, 6H), 1.10e0.83 (m, 15H)
ppm. 13C-NMR (100.62 MHz, CDCl3):
d 150.6, 137.2, 133.6, 131.4,
129.0 (1JC11-9 ¼ 387.3 Hz,
J
¼ 368.6 Hz), 117.8, 29.3 (2JC-
1 117
Sn
C- Sn
¼ 20.5 Hz, 3x), 27.5 (3JC-Sn ¼ 55.1 Hz, 3x), 13.8 (3x), 12.2, 9.71
Sn
(1JC11-9 ¼ 343.2 Hz, 1JC11-7Sn ¼ 328.2 Hz, 3x) ppm. IR (NaCl):
y 2956 (s,
[12] A. Takada, K. Uda, T. Ohtani, S. Tsukamoto, D. Takahashi, K. Toshima,
J. Antibiot. 66 (2013) 155e159.
[13] T. Ohtani, S. Sakai, A. Takada, D. Takahashi, K. Toshima, Org. Lett. 13 (2011)
6126e6129.
Sn
CeH), 2924 (s, CeH), 1460 (m), 985 (m) cmꢀ1
.
[14] J.R. Abbott, W.R. Roush, Org. Lett. 15 (2013) 62e64.
[15] P.T. Anastas, J.C. Warner, Green Chemistry : Theory and Practice, Oxford
University Press, 1998.
[16] S. Alvarez, R. Alvarez, A.R. de Lera, Tetrahedron: Asymmetry 15 (2004)
839e846.
Acknowledgments
We thank the Spanish MINECO (SAF2016-77620-RFEDER),
Xunta de Galicia (Consolidacion GRC ED431C 2017/61 from
DXPCTSUG; ED-431G/02-FEDER “Unha maneira de facer Europa” to
CINBIO, a Galician research center 2016e2019).
ꢀ
[17] See Supporting Information for further details
ꢀ
[18] P. Le Menez, I. Berque, V. Fargeas, J. Ardisson, A. Pancrazi, Synlett (1994)
998e1000.
ꢀ
ꢀ
ꢀ
[19] N. Fontan, B. Vaz, R. Alvarez, A.R. de Lera, Chem. Commun. 49 (2013)
2694e2696.
Appendix A. Supplementary data
[20] P. Wipf, P.D.G. Coish, J. Org. Chem. 64 (1999) 5053e5061.
[21] A. Fürstner, J.-A. Funel, M. Tremblay, L.C. Bouchez, C. Nevado, M. Waser,
J. Ackerstaff, C.C. Stimson, Chem. Commun. (2008) 2873e2875.
[22] For comparison of 13C NMR of synthesized 9 with previously described by
Toshima et al. see SI
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2019.130604.
[23] M. Tokunaga, J.F. Larrow, F. Kakiuchi, E.N. Jacobsen, Science 277 (1997)
936e938.
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