Hydroxyl-Assisted trans-Reduction of 1,3-Enynes: Application to the Formal Synthesis of (+)-Aspicilin

Article abstract of DOI:10.1055/s-0035-1562381

1,3-Enynes are hardly amenable to trans-hydrometalation reactions, because they tend to bind the standard ruthenium catalysts too tightly. However, catalysts comprising a [Cp?Ru-Cl] unit allow such compounds to be used, provided they contain an OH group next to the triple bond. This aspect is illustrated by a formal synthesis of the lichen-derived macrolide aspicilin. The required macrocyclic enyne precursor was formed by an efficient ring-closing alkyne metathesis reaction.

Full text of DOI:10.1055/s-0035-1562381

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
S. Schaubach et al.
Paper
Synthesis
Hydroxyl-Assisted trans-Reduction of 1,3-Enynes: Application to
the Formal Synthesis of (+)-Aspicilin
Sebastian Schaubacha
hydroxyl-assisted
Kenichi Michigamia,b
Alois Fürstner*a
ruthenium-catalyzed
O
O
alkyne-trans-reduction
O
O
OH
a Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,
45470 Mülheim/Ruhr, Germany
b Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo
060-0812, Japan
OH
HO
RCAM
OH
OH
literature
fuerstner@kofo.mpg.de
O
Dedicated to Prof. Dieter Enders on the occasion of his 70th birthday
(+)-aspicilin
O
Received: 21.06.2016
HO
Accepted: 21.06.2016
Published online: 04.07.2016
DOI: 10.1055/s-0035-1562381; Art ID: ss-2016-z0442-op
OH
OH
O
Abstract 1,3-Enynes are hardly amenable to trans-hydrometalation
reactions, because they tend to bind the standard ruthenium catalysts
too tightly. However, catalysts comprising a [Cp*Ru–Cl] unit allow such
compounds to be used, provided they contain an OH group next to the
triple bond. This aspect is illustrated by a formal synthesis of the lichen-
derived macrolide aspicilin. The required macrocyclic enyne precursor
was formed by an efficient ring-closing alkyne metathesis reaction.
ref. 6
ref. 4
O
RO
(+)-aspicilin (1)
O
O
O
O
A
OR
B
Key words alkyne metathesis, enynes, hydrostannation, molybde-
num alkylidynes, natural products, ruthenium, trans-reduction
O
Ever since the structure of (+)-aspicilin (1) has been elu-
cidated,1,2 this lichen-derived macrolide3 serves as a popu-
lar testing ground for methodological innovations.4–21 In
line with this tradition, we saw an opportunity to scruti-
nize two catalytic transformations under investigation in
our laboratory by implementing them into a formal synthe-
sis of this prominent target.
O
C
OR
O
OR
D
O
Of particular interest to us was the question whether a
diene of type A can be reached by trans-reduction of an
enyne precursor C,22 which in turn could be made by ring-
closing alkyne metathesis (RCAM)23,24 of a readily available
substrate of type D (Scheme 1). If successful, this approach
intercepts the total synthesis of 1 reported by Oppolzer and
co-workers, who showed that diene A (R = H) can be effi-
ciently converted into the final target by a sequence of hy-
droxyl-directed epoxidation followed by acetate-assisted
epoxide opening.6 Interestingly, the more conventional cis-
reduction of C to diene B also provides access to 1, as the
historically first total synthesis of aspicilin by Quinkert et
al. passed through this particular intermediate: however,
the osmylation of B had proven only modestly effec-
tive.4,20,25
Scheme 1 Retrosynthetic analysis of (+)-aspicilin (1) involving a
RCAM/semi-reduction sequence
The envisaged key step C → A, however, bore consider-
able risk. Classical methods for the trans-reduction of
alkynes using dissolving metal conditions are obviously in-
adequate in this case. Ruthenium-catalyzed trans-hydro-
metalation22,26–32 and trans-hydrogenation33 reactions, as
the best current alternatives, show a broad scope, but in-
variably encounter limitations when applied to substrates
capable of serving as potential 4- or 6-electron donors. 1,3-
Enynes E and related compounds, as well as the derived 1,3-
diene products, fall into this category and have therefore
proven problematic in the past (Scheme 2). Their inertia is
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
S. Schaubach et al.
Paper
Synthesis
most likely caused by the formation of stable adducts of
type F and/or G, which trap the catalyst,34,35 especially
when working with [Cp*Ru(MeCN)]PF6 or related cationic
complexes that have dominated the field until recently.27
substrate 4 comprising a primary alkyl bromide is notewor-
thy; yet, one might suspect that the yield of only 65% indi-
cates some material loss by competing N-alkylation of this
chiral ligand.
[Cu(MeCN)4]PF6 (5 mol%)
bipyridine (5 mol%), NMI (10 mol%)
X
Br
[Cp*Ru]
R3MH
R
Ru
O
HO
R
TEMPO (5 mol%), air, MeCN
no / slow
turnover
Ru
R
R
R
91%
R
4
2 X = OH
3 X = Br
HBr, toluene
reflux, 73%
R3M
G
F
E
[Cp*Ru]
Zn(OTf)2, Et3N, propyne
Br
TBSCl, imidazole
Br
TBSO
(+)-N-methylephedrine
HO
[Cp*RuCl]
R
OH
R
HO
Ru
Cl
Ru
CH2Cl2, 0 °C to r.t.
90%
Cl
R
5
6
toluene, –78 °C to r.t.
65%, 94% ee
H
R
R
O
J
I
H
R
1. Mg, THF
R3MH
HO
[Cp*RuCl]
2. (S)-propylene oxide
Li2CuCl4 (4 mol%)
–40 °C to r.t.
OTBS
7
HO
R
H
71%
R
Scheme 3 Preparation of the alcohol building block
MR3
K
alpha/trans-addition
The derived TBS-ether 6 was converted into the corre-
sponding functionalized Grignard reagent, which served
well in the subsequent copper-catalyzed opening of (S)-
propylene oxide. Esterification of the resulting alcohol 7
with the readily available acid 10 furnished product 11 in
readiness for macrocyclization (Scheme 4).
Scheme 2 Top: 1,3-enynes and 1,3-dienes interfere with catalyst turn-
over, especially when using cationic [Cp*Ru]+ fragments; bottom: inter-
ligand hydrogen bonding between a 1,3-enyne flanked by a hydroxyl
group and the polarized bond [Ru–Cl] might provide access to a reac-
tive coordination mode and hence allow catalytic trans-hydrometala-
tion to proceed; M = Si, Ge, Sn
Alkyne metathesis in general and ring-closing alkyne
metathesis (RCAM) in particular have witnessed consider-
able progress in recent years.23 Molybdenum alkylidyne
complexes endowed with triarylsilanolate ligands have a
significant share for their high activity and remarkable
functional group tolerance;39,40 at the same time, they al-
lowed the substrate scope to be considerably increased.41 In
this context, it is noteworthy that earlier catalyst genera-
tions had failed with propargyl alcohol derivatives as well
as with electron-deficient alkyne substrates,42 whereas
complex 12 and relatives proved effective in a number of
exigent cases.43 Compound 11, however, is the first sub-
strate to comprise both of these demanding structural ele-
ments. Therefore, it is deemed rewarding that cyclization of
11 proceeded quantitatively within 10 minutes reaction
time44 on treatment with catalytic amounts of 12 in reflux-
ing toluene to give the 18-membered lactone 13 in 91%
yield on a 500 mg scale. This favorable result, however, is
critically dependent on the proper reaction conditions:
while the chosen catalyst is fully operative at ambient tem-
perature, only the corresponding cyclic head-to-tail dimer
was formed. This divergent outcome is thought to reflect
the entropic component of the cyclization process and has
precedent in previous work from our laboratory.45
In this context, our recent discovery might prove rele-
vant that substrates bearing protic substituents synergize
with catalysts comprising an intact [Ru–Cl] bond.31 Experi-
mental evidence suggests that this effect is due to an ensu-
ing interligand hydrogen bonding, which imposes direc-
tionality on the actual hydrometalation step. In the case of
1,3-enyne substrates H with a flanking OH group, this fa-
vorable interaction might help to avoid the unproductive
chelate I, but rather enforce a reactive coordination mode J
and hence allow trans-addition with formation of products
K to proceed. As the envisaged key intermediate C en route
to 1 contains this exact substructure, it provides a stringent
test to probe this aspect.
The synthesis started from the cheap decane-1,10-diol
(2), which was transformed on multigram scale into 10-
bromodecanal (4) in two straightforward steps; it is em-
phasized that the copper-catalyzed Stahl oxidation of 3
proved highly effective and convenient on scale (Scheme
3).36 Although only few cases are documented in the litera-
ture in which propyne had been used as nucleophile in
asymmetric Carreira alkynylation reactions,32a,37,38 this
transformation proceeded well to afford product 5 with
high optical purity (94% ee). As this transformation relies
on the use of (+)-N-methylephedrine, the compatibility of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
S. Schaubach et al.
Paper
Synthesis
16, which are often subject to ring contraction and/or isom-
erization when approached by olefin metathesis.49 The abil-
ity of complex 12 to rigorously distinguish between alkenes
and alkynes precludes any such complication.50
Bu3SnC≡CMe
O
7, DCC, DMAP
O
[PdCl2(MeCN)2] (4 mol%)
RO
EtO
I
CH2Cl2, 93%
DMF, 91%
LiOH
8
9 R = Et
aq THF/EtOH
91%
10 R = H
Ar
All reactions using anhyd solvents were carried out under argon in
flame-dried glassware. The solvents were purified by distillation over
the drying agents indicated and were transferred under Ar: THF, Et2O
(Mg/anthracene), CH2Cl2, toluene (Na/K), MeOH (Mg, stored over MS
3Å); DMF, MeCN, and Et3N were dried by an adsorption solvent puri-
fication system based on molecular sieves. TLC: Macherey-Nagel pre-
coated plates (POLYGRAM® SIL/UV254); Flash chromatography:
Merck silica gel 60 (40–63 μm) with predistilled or HPLC grade sol-
vents. Analytic HPLC: Shimadzu LC-2020, Column: 50 mm Eclipse
Plus C8, 3.0 mm. NMR: Spectra were recorded on a Bruker AV 400
spectrometer in the solvents indicated; chemical shifts (δ) are given
in ppm relative to TMS, coupling constants (J) in Hz. The solvent sig-
nals were used as references and the chemical shifts converted to the
TMS scale (CDCl3: δC = 77.16; residual CHCl3 in CDCl3: δH = 7.26). IR:
12 (10 mol%)
Mo
Ph3SiO
Ph3SiO
OSiPh3
O
OTBS
O
5 Å MS, toluene, 110 °C
91%
11
Bu3SnH
O
[Cp*RuCl]4 (2 mol%)
O
SnBu3
OH
O
O
CH2Cl2, 66%
OR
Spectrum One (PerkinElmer) spectrometer, wavenumbers in cm–1
.
15
TBAF
85%
13 R = TBS
14 R = H
MS (EI): Finnigan MAT 8200 (70 eV), ESI-MS: ESQ3000 (Bruker), accu-
rate mass determinations: Bruker APEX III FT-MS (7 T magnet) or Mat
95 (Finnigan). Optical rotations [α]D were measured with a Perkin-
Elmer Model 343 polarimeter. Unless stated otherwise, all commer-
cially available compounds (Alfa Aesar, Aldrich, Fluka, TCI) were used
as received.
HO
OH
OH
20
ref. 6
CuTC, DMF
83%
O
O
O
OH
16
O
1
10-Bromodecan-1-ol (3)51,52
Scheme 4 Completion of the formal synthesis of (+)-aspicilin (1); Ar =
p-MeOC6H4
HBr (48% in H2O, w/w, 16.3 mL, 138 mmol) was added to a mixture of
decane-1,10-diol (2; 20 g, 115 mmol) and toluene (250 mL). The re-
sulting mixture was stirred at reflux temperature for 16 h. After
reaching r.t. and careful addition of sat. aq Na2S2O3 (50 mL), the aque-
ous layer was extracted with EtOAc (3 × 200 mL). The combined ex-
tracts were dried (MgSO4), filtered, and the solvent was evaporated.
Purification of the residue by flash chromatography (silica gel, hex-
anes/EtOAc, 4:1 to 2:1) afforded the title compound as a colorless oil
(19.8 g, 73%).
With the cyclic enyne 13 in hand, the stage was set to
probe the critical trans-reduction manifold. In line with our
expectation, an effective trans-hydrostannation took place
only after deprotection of the propargylic alcohol group.
Thus, reaction of 14 with Bu3SnH in the presence of catalyt-
ic amounts of [Cp*RuCl]4 in CH2Cl2 cleanly furnished the de-
sired product 15; only traces of an undesired isomer were
detected. The high fidelity with which the tin residue is de-
livered to the proximal C-atom of the reacting triple bond is
confidently ascribed to the steering effect of the free OH
group, which has precedent in our earlier work on rutheni-
um-catalyzed trans-hydrometalation reactions;31 more im-
portantly, the current example advocates the notion that
the protic substituent can render otherwise unreactive sub-
strates amenable to trans-addition. This aspect is deemed
relevant for the further advancement of this field and is
therefore subject to detailed investigations.
Treatment of 15 with CuTC [copper(I) thiophene-2-car-
boxylate] in DMF led to the E,E-configured dienoate 16 that
intercepts the efficient total synthesis of (+)-aspicilin (1)
described by Oppolzer and co-workers.6 In concord with a
rapidly growing number of examples from the literature,
this application shows that RCAM in combination with
alkyne semi-reduction provides a selective and predictable
access to alkenes, dienes, and polyenes of all stereochemical
formats.46–48 This includes conjugated dienes as present in
IR (ATR): 3328, 2924, 2853, 1463, 1437, 1371, 1352, 1256, 1242, 1129,
1055, 899, 756, 722, 644, 562, 505, 465, 445, 428, 417 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.63 (t, J = 6.6 Hz, 2 H), 3.40 (t, J = 6.9
Hz, 2 H), 1.88–1.80 (m, 2 H), 1.60–1.51 (m, 2 H), 1.46–1.24 (m, 13 H).
13C NMR (100 MHz, CDCl3): δ = 63.2, 34.2, 32.92, 32.89, 29.6, 29.49,
29.48, 28.9, 28.3, 25.8.
HRMS-ESI: m/z calcd for [C10H21BrO
+
Na]+: 259.0669; found:
259.0668.
10-Bromodecanal (4)53
10-Bromodecan-1-ol (3; 10.0 g, 42 mmol) and TEMPO (312 mg, 2.0
mmol) were added to a mixture of [Cu(MeCN)4]PF6 (744 mg, 2.0
mmol), 2,2′-bipyridine (312 mg, 2.0 mmol), and 1-methylimidazole
(328 mg, 4.0 mmol) in MeCN (200 mL). The resulting red brown mix-
ture was stirred for 14 h at r.t. under air, causing a color change to
blue. The mixture was filtered through a pad of silica gel and the fil-
trate was evaporated. Purification of the residue by flash chromatog-
raphy (silica gel, hexanes/EtOAc, 20:1 to 10:1) afforded the title com-
pound as a pale red oil (9.0 g, 91%).
IR (ATR): 2926, 2854, 2716, 1723, 1463, 1409, 1390, 1245, 1111, 846,
723, 643, 560 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
S. Schaubach et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 9.77 (t, J = 1.8 Hz, 1 H), 3.42 (t, J = 6.8
Hz, 2 H), 2.44 (td, J = 7.4, 1.8 Hz, 2 H), 1.90–1.81 (m, 2 H), 1.68–1.59
(m, 2 H), 1.47–1.37 (m, 2 H), 1.36–1.27 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ = 202.7, 43.9, 33.9, 32.8, 29.21, 29.18,
29.1, 28.7, 28.1, 22.1.
(2S,13R)-13-(tert-Butyldimethylsilyloxy)hexadec-14-yn-2-ol (7)
Mg turnings (250 mg, 10.3 mmol) and I2 (20 mg) were vigorously
stirred under argon atmosphere for 14 h at 90 °C. After reaching r.t.,
the activated Mg powder was suspended in THF (5 mL) and the sus-
pension stirred at reflux temperature for 1 h. A solution of bromide 6
(2.0 g, 5.14 mmol) in THF (2 mL) was added over 2 min and stirring
continued at reflux temperature for 1 h. The resulting mixture was
cooled to –40 °C and Li2CuCl4 (0.1 M in THF, 2 mL, 0.2 mmol, 4 mol%)
was introduced. (S)-Propylene oxide (407 mg, 7.0 mmol, 0.49 mL) was
added dropwise over 5 min and the mixture was allowed to reach r.t.
over 14 h. The reaction was quenched with sat. aq NH4Cl (5 mL), the
aqueous layer was extracted with EtOAc (3 × 50 mL), the combined
extracts were dried (MgSO4), filtered, and the solvent was evaporated.
Purification of the residue by flash chromatography (silica gel, hex-
anes/EtOAc, 50:1 to 20:1) afforded the title compound as a colorless
oil (1.35 g, 71%); [α]D20 +32.6 (c = 1, CHCl3).
HRMS-ESI: m/z calcd for [C10H19BrO
+
Na]+: 257.0510; found:
257.0512.
(R)-13-Bromotridec-2-yn-4-ol (5)
Et3N (3.90 mL, 27.9 mmol) was added dropwise to a suspension of
Zn(OTf)2 (10.1 g, 27.9 mmol) and (+)-N-methylephedrine (5.0 g, 27.9
mmol) in toluene (120 mL). The colorless suspension was stirred for 2
h at r.t. before the mixture was cooled to –78 °C and liquid propyne
(ca. 4 mL) was added via cannula from a Schlenk tube at –78 °C. The
mixture was allowed to reach r.t. over the course of 1 h. A solution of
aldehyde 4 (5.48 g, 23.3 mmol) in toluene (10 mL) was added drop-
wise over 4 h and stirring continued for 14 h at r.t. before the reaction
was quenched with sat. aq NH4Cl (20 mL). The aqueous layer was ex-
tracted with EtOAc (3 × 150 mL). The remaining aqueous layer was
acidified to pH 2 by the addition of aq 2 M HCl and extracted with
EtOAc (150 mL). The combined extracts were dried (MgSO4), filtered,
and the solvent was evaporated. Purification of the residue by flash
chromatography (silica gel, hexanes/EtOAc, 10:1) afforded the title
IR (ATR): 3355, 2925, 2854, 1744, 1463, 1407, 1389, 1361, 1341, 1250,
1083, 1005, 939, 834, 775, 721, 666, 559 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.32–4.25 (m, 1 H), 3.84–3.74 (m, 1 H),
1.82 (d, J = 2.1 Hz, 3 H), 1.65–1.55 (m, 2 H), 1.49–1.33 (m, 5 H), 1.32–
1.23 (m, 14 H), 1.18 (d, J = 6.2 Hz, 3 H), 0.90 (s, 9 H), 0.11 (s, 3 H), 0.09
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 81.3, 79.9, 68.4, 63.4, 39.5, 39.1, 29.8,
29.7, 29.4, 26.0, 26.0, 25.9, 25.4, 23.6, 18.5, 3.7, –4.3, –4.9.
20
compound as a colorless oil (4.15 g, 65%, 94% ee); [α]D –0.8 (c = 1,
CHCl3).
HRMS-ESI: m/z calcd for [C22H44O2Si
+
Na]+: 391.3000; found:
IR (ATR): 3434, 2924, 2854, 2219, 1734, 1674, 1454, 1441, 1352, 1323,
1260, 1200, 1135, 1119, 1076, 1022, 988, 904, 868, 811, 723, 543, 428
391.3003.
cm–1
.
Ethyl (E)-Hex-2-en-4-ynoate (9)54
1H NMR (400 MHz, CDCl3): δ = 4.35–4.29 (m, 1 H), 3.42 (t, J = 6.9 Hz, 2
H), 1.85 (d, J = 2.1 Hz, 3 H), 1.89–1.80 (m, 2 H), 1.72–1.60 (m, 3 H),
1.47–1.36 (m, 4 H), 1.35–1.25 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ = 81.1, 80.6, 62.9, 38.3, 34.2, 33.0, 29.6,
29.5, 29.4, 28.9, 28.3, 25.3, 3.7.
[PdCl2(MeCN)2] (60.8 mg, 0.21 mmol) was added to a solution of ethyl
(E)-3-iodoacrylate (8;55 1.20 g, 5.0 mmol) and tributyl(prop-1-yn-1-
yl)stannane (1.71 g, 5.2 mmol) in DMF (10 mL) and the resulting mix-
ture was stirred for 14 h at r.t.. Aq KF (0.5 M, 20 mL) and EtOAc (20
mL) were added and stirring was continued for 2 h. After filtration,
the aqueous layer was extracted with EtOAc (3 × 30 mL). The com-
bined extracts were dried (MgSO4), filtered, and the solvent was
evaporated. Purification of the residue by flash chromatography (sili-
ca gel, hexanes/EtOAc, 50:1 to 20:1) afforded the title compound as a
colorless oil (630 mg, 91%).
HRMS-ESI: m/z calcd for [C13H23BrO
+
Na]+: 297.0825; found:
297.0826.
(R)-[(13-Bromotridec-2-yn-4-yl)oxy](tert-butyl)dimethylsilane (6)
TBSCl (2.86 g, 19.0 mmol) was added to a solution of alcohol 5 (3.6 g,
13.1 mmol) and imidazole (2.66 g, 39.0 mmol) in CH2Cl2 (100 mL) at
0 °C. The cooling bath was removed and the mixture stirred for 2 h at
r.t. before the reaction was quenched with sat. aq NH4Cl (30 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 50 mL), the combined
extracts were dried (MgSO4), filtered, and the solvent was evaporated.
Purification of the residue by flash chromatography (silica gel, hex-
anes/EtOAc, 50:1) afforded the title compound as a colorless oil (4.57
g, 90%); [α]D20 +24.5 (c = 1, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 6.72 (dq, J = 15.8, 2.5 Hz, 1 H), 6.13 (dd,
J = 15.8, 0.6 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 2.02 (dd, J = 2.5, 0.6 Hz, 3
H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.3, 129.4, 126.2, 96.3, 77.2, 60.8,
14.3, 4.9.
HRMS-ESI: m/z calcd for [C8H10O2 + Na]+: 161.0575; found: 161.0573.
(E)-Hex-2-en-4-ynoic Acid (10)
IR (ATR): 2927, 2855, 2238, 1716, 1586, 1463, 1389, 1360, 1341, 1250,
LiOH (479 mg, 20.0 mmol) was suspended in a mixture of THF (10
mL), H2O (10 mL) and EtOH (2 mL). Ester 9 (950 mg, 6.88 mmol) was
added and the mixture was stirred for 1 h at r.t. After the addition of
sat. aq NH4Cl (10 mL), the pH was adjusted to 2 by addition of aq 2 M
HCl. The aqueous layer was extracted with EtOAc (3 × 50 mL), the
combined extracts were dried (MgSO4), filtered, and the solvent was
evaporated. The title compound was isolated as a colorless solid (690
mg, 91%); mp 175–177 °C.
1154, 1075, 1005, 939, 834, 775, 723, 666, 647, 563 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.36–4.28 (m, 1 H), 3.40 (t, J = 6.9 Hz, 2
H), 1.82 (d, J = 21.0 Hz, 3 H), 1.88–1.81 (m, 2 H), 1.65–1.55 (m, 2 H),
1.46–1.34 (m, 4 H), 1.33–1.24 (m, 8 H), 0.90 (s, 9 H), 0.11 (s, 3 H), 0.09
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 81.3, 79.9, 63.3, 39.1, 34.2, 33.0, 29.6,
29.5, 29.4, 28.9, 28.3, 26.0, 25.4, 18.4, 3.7, –4.3, –4.9.
IR (ATR): 2925, 2582, 2216, 1674, 1614, 1452, 1421, 1310, 1279, 1210,
HRMS-ESI: m/z calcd for [C19H37BrOSi + Na]+: 411.1691; found:
411.1689.
1172, 1033, 962, 921, 865, 677, 539, 422 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 11.92 (br s, 1 H), 6.82 (dq, J = 15.8, 2.5
Hz, 1 H), 6.14 (d, J = 15.8 Hz, 1 H), 2.05 (d, J = 2.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.7, 129.0, 128.6, 98.6, 77.1, 5.1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
S. Schaubach et al.
Paper
Synthesis
HRMS-ESI: m/z calcd for [C6H5O2]–: 109.0295; found: 109.0295.
residue by flash chromatography (silica gel, hexanes/EtOAc, 20:1 to
4:1) afforded the title compound as a colorless solid (243 mg, 85%);
mp 62−63 °C; [α]D20 +61.1 (c = 1, CHCl3).
(2S,13R)-13-[(tert-Butyldimethylsilyl)oxy]hexadec-14-yn-2-yl (E)-
Hex-2-en-4-ynoate (11)
IR (ATR): 3266, 2922, 2850, 2215, 1702, 1622, 1611, 1460, 1378, 1351,
1302, 1271, 1188, 1155, 1128, 1107, 1077, 1021, 979, 871, 755, 719,
Alcohol 7 (1.50 g, 4.07 mmol), DCC (887 mg, 4.3 mmol), and DMAP
(10 mg, 0.82 mmol) were successively added at 0 °C to a solution of
acid 10 (473 mg, 4.07 mmol) in CH2Cl2 (10 mL). After stirring for 2 h at
0 °C, the mixture was filtered through a pad of silica gel. Sat. aq NH4Cl
(5 mL) was added and the aqueous layer was extracted with CH2Cl2
(2 × 20 mL). The combined extracts were dried (MgSO4), filtered, and
the solvent was evaporated. Purification of the residue by flash chro-
matography (silica gel, hexanes/EtOAc, 100:1 to 50:1) afforded the ti-
tle compound as a colorless oil (1.75 g, 93%); [α]D20 +35.9 (c = 1, CHCl3).
585, 499, 410 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.75 (dd, J = 15.9, 2.1 Hz, 1 H), 6.24 (d,
J = 15.9 Hz, 1 H), 5.04–4.94 (m, 1 H), 4.61–4.54 (m, 1 H), 2.05–1.16 (m,
24 H).
13C NMR (100 MHz, CDCl3): δ = 165.3, 132.3, 124.4, 99.9, 82.8, 72.9,
63.1, 36.6, 34.2, 29.8, 29.7, 29.5, 29.2, 29.1, 28.5, 25.4, 23.9, 20.2.
HRMS-ESI: m/z calcd for [C18H28O3]–: 291.1668; found: 291.1966.
IR (ATR): 2926, 2854, 2222, 2120, 1712, 1463, 1359, 1300, 1256, 1180,
(3E,5E,7R,18S)-7-Hydroxy-18-methyl-6-(tributylstannyl)oxacy-
clooctadeca-3,5-dien-2-one (15)
1164, 1078, 1005, 961, 835, 776, 720, 667, 516 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.71 (dq, J = 15.8, 2.4 Hz, 1 H), 6.12 (d,
J = 15.8 Hz, 1 H), 5.00–4.90 (m, 1 H), 4.32–4.25 (m, 1 H), 2.02 (d, J = 2.4
Hz, 3 H), 1.81 (d, J = 2.1 Hz, 3 H), 1.66–1.54 (m, 3 H), 1.54–1.24 (m, 17
H), 1.23 (d, J = 6.3 Hz, 3 H), 0.90 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.0, 130.1, 125.9, 96.1, 81.3, 79.9,
77.3, 71.6, 63.4, 39.1, 36.1, 29.70, 29.66, 29.59, 29.4, 26.0, 25.5, 25.4,
20.1, 18.4, 4.9, 3.7, –4.4, –4.9.
[{Cp*RuCl}4] (10 mg, 9.0 μmol, 2 mol%) was added to a solution of
compound 14 (150 mg, 0.51 mmol) in CH2Cl2 (2.5 mL). A solution of
Bu3SnH (163 mg, 0.56 mmol) in CH2Cl2 (1 mL) was then added drop-
wise over 5 min. After stirring for 2 h at r.t., the solvent was evaporat-
ed. Purification of the residue by flash chromatography (silica gel,
hexanes/EtOAc, 20:1 to 10:1) afforded the title compound as a pale
yellow oil (196 mg, 66%). A second fraction containing the cis-isomer
20
HRMS-ESI: m/z calcd for [C28H48O3Si
+
Na]+: 483.3266; found:
was also isolated and purified by preparative HPLC (8 mg, 3%); [α]D
483.3265.
–31.7 (c = 1, CHCl3).
IR (ATR): 3464, 2953, 2922, 2852, 1707, 1688, 1619, 1565, 1460, 1376,
1354, 1258, 1186, 1125, 1072, 1019, 976, 903, 863, 757, 716, 666,
(7R,18S,E)-7-[(tert-Butyldimethylsilyl)oxy]-18-methyloxacyclooc-
tadec-3-en-5-yn-2-one (13)
595, 536, 504 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25 (dd, J = 15.1, 11.5 Hz, 1 H), 6.81 (d,
J = 11.6 Hz, JSn–H = 54.8 Hz, 1 H), 5.78 (d, J = 15.0 Hz, 1 H), 5.05 (dqd,
J = 9.3, 6.3, 2.9 Hz, 1 H), 4.31 (dt, J = 9.3, 3.4 Hz, JSn–H = 26.1 Hz, 1 H),
1.71–1.58 (m, 2 H), 1.54–1.38 (m, 9 H), 1.35–1.06 (m, 22 H), 1.05–0.91
(m, 9 H), 0.84 (t, J = 7.3 Hz, 9 H).
13C NMR (100 MHz, CDCl3): δ = 167.7, 166.8, 144.5, 137.0, 123.2, 80.3,
71.3, 36.1, 35.2, 29.9, 29.8, 29.5, 29.28, 29.25, 29.01, 28.96, 27.6, 25.2,
23.9, 20.6, 13.8, 11.8.
Diyne 11 (500 mg, 1.09 mmol) was added to a suspension of molecu-
lar sieves 5Å (flame dried, 8 g) in toluene (800 mL) and the resulting
mixture was stirred for 1 h at r.t. The mixture was then warmed to
110 °C before a solution of complex 12 (110 mg, 0.106 mmol, 10
mol%) in toluene (2 mL) was added over 2 min. After stirring for 10
min at this temperature, the suspension was filtered through a plug of
Celite, which was carefully rinsed with EtOAc (50 mL). The combined
filtrates were evaporated and the residue was purified by flash chro-
matography (silica gel, hexanes/EtOAc, 100:1 to 50:1) to give the title
compound as a colorless oil (400 mg, 91%); the product contained ca.
8% of the dimeric macrocycle and was used without further purifica-
tion for the next step.
119Sn NMR (186 MHz, CDCl3): δ = –56.0.
HRMS-ESI: m/z calcd for [C30H56O3Sn
+
H]+: 585.3329; found:
585.3324.
IR (ATR): 2927, 2855, 1715, 1619, 1462, 1360, 1299, 1254, 1178, 1153,
1125, 1083, 1006, 982, 960, 940, 835, 777, 717, 669 cm–1
.
(3E,5Z,7R,18S)-7-Hydroxy-18-methyl-6-(tributylstannyl)oxacy-
clooctadeca-3,5-dien-2-one [(5Z)-15]
1H NMR (400 MHz, CDCl3): δ = 6.75 (dd, J = 15.8, 2.1 Hz, 1 H), 6.21 (d,
J = 15.8 Hz, 1 H), 5.06–4.93 (m, 1 H), 4.54 (ddd, J = 7.5, 4.8, 2.1 Hz, 1
H), 1.77–1.62 (m, 3 H), 1.61–1.17 (m, 17 H), 1.23 (d, J = 6.3 Hz, 3 H),
0.92 (s, 9 H), 0.12 (s, 3 H), 0.10 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.5, 131.8, 124.9, 101.2, 82.1, 72.8,
63.6, 37.6, 34.2, 29.9, 29.8, 29.5, 29.2, 28.6, 25.9, 25.8, 25.5, 23.8, 20.3,
–4.5, –4.8.
Minor isomer formed in the reaction described above, which was iso-
lated and purified by preparative HPLC (8 mg, 3%).
IR (ATR): 3500, 2953, 2923, 2854, 1710, 1691, 1569, 1460, 1419, 1376,
1357, 1337, 1268, 1186, 1125, 1072, 1021, 979, 893, 876, 845, 804,
769, 722, 665, 596, 548, 505, 435, 408 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.51 (ddt, J = 15.2, 11.0, 3.3 Hz, 1 H),
6.33 (dd, J = 11.2, 1.6 Hz, JSn–H = 30.8 Hz, 1 H), 5.81 (d, J = 15.0 Hz, 1 H),
5.18 (ddp, J = 9.5, 6.3, 3.1 Hz, 1 H), 5.03 (t, J = 7.3 Hz, JSn–H = 32.0 Hz, 1
H), 1.65–1.11 (m, 37 H), 0.99–0.92 (m, 5 H), 0.89 (t, J = 7.3 Hz, 9 H).
HRMS-ESI: m/z calcd for [C24H42O3Si
+
Na]+: 429.2799; found:
429.2795.
(7R,18S,E)-7-Hydroxy-18-methyloxacyclooctadec-3-en-5-yn-2-
one (14)
13C NMR (100 MHz, CDCl3) δ = 167.5, 166.5, 138.7, 134.6, 121.2, 72.2,
69.6, 37.8, 36.0, 29.8, 29.2, 28.7, 28.4, 27.7, 27.6, 26.6, 25.3, 24.2, 21.0,
13.9, 10.9.
119Sn NMR (186 MHz, CDCl3): δ = –40.2.
HRMS-ESI: m/z calcd for [C30H56O3Sn + Na]+: 607.3148; found:
TBAF (1 M in THF, 2 mL, 2 mmol) was added at 0 °C to a solution of
compound 13 (400 mg, 0.98 mmol) in THF (5 mL) and the mixture
was stirred for 2 h till r.t. was reached The reaction was quenched
with sat. aq NH4Cl (1 mL) and H2O (1 mL) and the aqueous layer was
extracted with EtOAc (3 × 30 mL). The combined extracts were dried
(MgSO4), filtered, and the filtrate was evaporated. Purification of the
607.3143.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
S. Schaubach et al.
Paper
Synthesis
(3E,5E,7R,18S)-7-Hydroxy-18-methyloxacyclooctadeca-3,5-dien-2-
one (16)
(14) Dubost, C.; Markó, I. E.; Ryckmans, T. Org. Lett. 2006, 8, 5137.
(15) Yadav, J. S.; Rao, T. S.; Ravindar, K.; Reddy, B. V. S. Synlett 2009,
2828.
(16) Wang, C.-Y.; Hou, D.-R. J. Chin. Chem. Soc. 2012, 59, 389.
(17) Reddy, C. R.; Rao, R. R.; Sujitha, P.; Kumar, C. G. Eur. J. Org. Chem.
2012, 1819.
CuTC (65 mg, 0.34 mmol) was added to a solution of stannane 15 (100
mg, 0.17 mmol) in DMF (2 mL) and the resulting mixture was stirred
for 1 h at r.t. before H2O (5 mL) was added. The aqueous layer was ex-
tracted with EtOAc (3 × 10 mL), the combined extracts were dried
(MgSO4), filtered, and the solvent was evaporated. Purification of the
residue by flash chromatography (silica gel, hexanes/EtOAc, 10:1 to
(18) Gandi, V. R. Tetrahedron 2013, 69, 6507.
(19) Saidhareddy, P.; Ajay, S.; Shaw, A. K. RCS Adv. 2014, 4, 4253.
(20) Formal synthesis: Zhang, H.; Yu, E. C.; Torker, S.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2014, 136, 16493.
(21) For syntheses of the enantiomer, see: (a) Waanders, P. P.; Thijs,
L.; Zwanenburg, B. Tetrahedron Lett. 1987, 28, 2409. (b) Solladie,
G.; Fernandez, I.; Maestro, C. Tetrahedron: Asymmetry 1991, 2,
801.
(22) For a review on trans-reduction and trans-hydrometalations of
alkynes in the context of total synthesis, see: Frihed, T. G.;
Fürstner, A. Bull. Chem. Soc. Jpn. 2016, 89, 135.
(23) Fürstner, A. Angew. Chem. Int. Ed. 2013, 52, 2794.
(24) (a) Fürstner, A.; Seidel, G. Angew. Chem. Int. Ed. 1998, 37, 1734.
(b) Fürstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc.
1999, 121, 9453. (c) Fürstner, A.; Mathes, C.; Lehmann, C. W.
Chem. Eur. J. 2001, 7, 5299.
20
4:1) afforded the title compound as a colorless oil (42 mg, 83%); [α]D
+14.2 (c = 1, CHCl3).
IR (ATR): 3412, 2925, 2854, 1701, 1644, 1618, 1460, 1355, 1296, 1260,
1178, 1124, 999, 910, 883, 730, 647, 411 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24 (dd, J = 15.4, 10.9 Hz, 1 H), 6.32
(dd, J = 15.2, 10.9 Hz, 1 H), 6.07 (dd, J = 15.2, 7.9 Hz, 1 H), 5.85 (d,
J = 15.4 Hz, 1 H), 5.02 (dqd, J = 9.4, 6.3, 3.2 Hz, 1 H), 4.27 (td, J = 8.3,
3.7 Hz, 1 H), 1.82–1.73 (m, 1 H), 1.69–1.54 (m, 4 H), 1.50–1.37 (m, 2
H), 1.28 (d, J = 6.3 Hz, 3 H), 1.33–1.12 (m, 14 H).
13C NMR (100 MHz, CDCl3): δ = 166.6, 145.1, 143.6, 128.4, 122.6, 73.3,
71.5, 35.5, 35.4, 29.7, 29.14, 29.10, 29.05, 28.8, 24.8, 23.4, 20.6.
HRMS-ESI: m/z calcd for [C18H30O3 + Na]+: 317.2087; found: 317.2087.
(25) This step might be improved in view of the advances in dihy-
droxylation chemistry since the publication of this paper; as
our prime interest, however, related to the trans-reduction
chemistry, we refrained from investigating this possibility.
(26) Trost, B. M.; Ball, Z. T. Synthesis 2005, 853.
(27) (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726.
(b) Trost, B. M.; Ball, Z. T.; Jöge, T. J. Am. Chem. Soc. 2002, 124,
7922. (c) Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003,
5, 1895. (d) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127,
17644. (e) Trost, B. M.; Ball, Z. T.; Jöge, T. Angew. Chem. Int. Ed.
2003, 42, 3415.
Acknowledgment
Generous financial support by the MPG, the Fonds der Chemischen
Industrie (Kekulé stipend to S.S.) and JSPS (predoctoral fellowship to
K.M.) is gratefully acknowledged. We thank the analytical depart-
ments of our Institute for excellent support.
Supporting Information
(28) (a) Fürstner, A.; Radkowski, K. Chem. Commun. 2002, 2182.
(b) Lacombe, F.; Radkowski, K.; Seidel, G.; Fürstner, A. Tetrahe-
dron 2004, 60, 7315.
Copies of spectra of new compounds for this article is available online
at http://dx.doi.org/10.1055/s-0035-1562381.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(29) Sundararaju, B.; Fürstner, A. Angew. Chem. Int. Ed. 2013, 52,
14050.
(30) Rummelt, S. M.; Fürstner, A. Angew. Chem. Int. Ed. 2014, 53,
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(31) Rummelt, S. M.; Radkowski, K.; Rosca, D.-A.; Fürstner, A. J. Am.
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Chem. Int. Ed. 2015, 54, 6241. (b) Sommer, H.; Fürstner, A. Org.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G