Synthesis of cyclic alkenylsiloxanes by semihydrogenation: A stereospecific route to (Z)-alkenyl polyenes

Article abstract of DOI:10.1002/chem.201403255

Cyclic alkenylsiloxanes were synthesized by semihydrogenation of alkynylsilanes - a reaction previously plagued by poor stereoselectivity. The silanes, which can be synthesized on multigram scale, undergo Hiyama-Denmark coupling to give (Z)-alkenyl polyene motifs found in bioactive natural products. The ring size of the silane is crucial: five-membered cyclic siloxanes also couple under fluoride-free conditions, whilst their six-membered homologues do not, enabling orthogonality within this structural motif.

Full text of DOI:10.1002/chem.201403255

DOI: 10.1002/chem.201403255
Communication
&
Cross-Coupling
Synthesis of Cyclic Alkenylsiloxanes by Semihydrogenation: A
Stereospecific Route to (Z)-Alkenyl Polyenes
Bryony L. Elbert, Diane S. W. Lim, Haraldur G. Gudmundsson, Jack A. O’Hanlon, and
Edward A. Anderson*[a]
Abstract: Cyclic alkenylsiloxanes were synthesized by
semihydrogenation of alkynylsilanes—a reaction previous-
ly plagued by poor stereoselectivity. The silanes, which
can be synthesized on multigram scale, undergo Hiyama–
Denmark coupling to give (Z)-alkenyl polyene motifs
found in bioactive natural products. The ring size of the
silane is crucial: five-membered cyclic siloxanes also
couple under fluoride-free conditions, whilst their six-
membered homologues do not, enabling orthogonality
within this structural motif.
Alkenylsilanes are valuable reagents in organic synthesis.[1]
Among many applications, their use in Hiyama–Denmark
cross-coupling[2] offers advantages over conventional Stille and
Scheme 1. Strategy for the preparation of cyclic alkenylsiloxanes, and exam-
Suzuki methods, as organosilanes are non-toxic, stable to a vari-
ety of synthetic transformations and can be prepared from in-
expensive starting materials. Cyclic alkenylsiloxanes (1,
Scheme 1)[3] are particularly attractive Hiyama substrates, be-
cause they give specific control over the stereochemistry of
a (Z)-alkene, the geometry of which is “protected” in the cyclic
form. Polyenes containing disubstituted (Z)-alkenes are
common in bioactive natural products, such as the anticancer
protein phosphatase inhibitors in Scheme 1,[4] and the efficient
synthesis of these motifs is an important goal. Despite this, the
cross-coupling of cyclic alkenylsiloxanes has received less at-
tention[5] than their acyclic counterparts,[6,7] likely due to re-
strictions in their preparation.[8] The principle approaches em-
ployed to date include ring-closing metathesis, which requires
the air- and moisture-sensitive Schrock catalyst,[5] intramolecu-
lar hydrosilylation, which is limited to internal alkynes,[9] and al-
kynylsilane enyne metathesis.[10] The latter two methodologies
afford trisubstituted alkenes, and are therefore less applicable
to natural products of the types depicted in Scheme 1.
ples of (Z)-alkene-containing bioactive natural products.
has not been explored for the synthesis of (Z)-alkenylsiloxanes,
in which hydrogenation of an alkynylsiloxane 2 (Scheme 2)
should give a (Z)-alkenylsilane, which in the case of substrate 2
could then undergo intramolecular capture by a proximal alco-
hol to form 1. Herein, we report the realization of this chemis-
try, and the subsequent cross-coupling of these important si-
lanes, including applications to syntheses of the polyene seg-
ments of the bioactive natural products in Scheme 1.
Initial investigations with alkynylsilane 2a (Table 1, entry 1)
gave unexpectedly high levels of the undesired (E)-alkenylsi-
lane 3a, and significant over-reduction—a result that corre-
lates with previous reports into the inconsistent selectivity of
alkynylsilane hydrogenation.[12] In seeking a solution to this
problem, we were drawn to a footnote in a report by Panek
and Clark[13] in which hydrogenation of a phenyldimethylsilylal-
kynyl propargylic acetate exhibited high (Z)-selectivity. To our
delight, reaction of the acetate derivative 2b of our alkynylalk-
oxysilane (Table 1, entry 2) gave cyclic alkenylsiloxane 1a in
high yield (75%, diastereomeric ratio (d.r.)=96:4) following in
situ acetate solvolysis/cyclization, with the reaction remaining
efficient on multigram scale (Table 1, entry 3). Benzoate ester
2c also displayed high selectivity; however, difficulties in the
purification of 1a from methyl benzoate by-product reduced
the isolated yield (entry 4).[14] A solvent screen identified tolu-
ene as the optimum choice: alcohol and ester solvents
(Table 1, entries 6–9) gave fast reaction times, but were prone
Prominent among methods for the stereoselective formation
of disubstituted (Z)-alkenes[11] is the semi-reduction of alkynes,
typified by Lindlar hydrogenation.[12] Surprisingly, this strategy
[a] B. L. Elbert, D. S. W. Lim, H. G. Gudmundsson, J. A. O’Hanlon,
Dr. E. A. Anderson
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA, U.K.
Fax: (+44)1865-285002
E-mail: edward.anderson@chem.ox.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403255.
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Table 1. Optimization of the stereoselective semihydrogenation of prop-
argylic alkynylsilanes.[a]
Table 2. Scope of semihydrogenation of alkynylsilanes.[a]
Entry Substrate
t
Product
Yield [%][b]
Entry
Substrate
Solvent
t
1a:(E)-3a[b]
Yield [%][c]
1
2
2 h
3 h
80
80
1
2
3
4
5
6
7
8
2a
2b
2b
2c
2b
2b
2b
2b
2b
2b
2b
toluene
toluene
toluene
toluene
benzene
MeOH
EtOH
iPrOH
EtOAc
THF
8 min
50 min
50 min
25 min
50 min
8 min
8 min
15 min
15 min
1.5 h
52:48
96:4
96:4[d]
96:4
96:4
89:11
95:5
42
75
80[d]
20[e]
73
3
4
1 h
73
72[f]
75[f]
76[f]
66[f]
76
40 min
62[c,d]
93:7
9
10
11
87:13
95:5
86:14[g]
5
4 h
4 h
79
THF
1.5 h
49[g]
[a] Reactions were performed with 0.15 mmol of 2, 0.1m, 1 atm H2 (bal-
loon). [b] Determined by H NMR spectroscopic analysis of the crude reac-
tion mixture. [c] Isolated yield. [d] 2.2 g of 2b. [e] PhCO2Me by-product
complicated purification, resulting in lower yield. [f] Variable amounts of
over-hydrogenation were observed. [g] 500 mg of 2b.
1
6
2h
94[e]
7
8
9.5 h
2 h
67[c]
76[c]
to over-reduction, whilst THF led to inconsistent Z/E ratios on
scale-up (entries 10, 11).
With optimized conditions now in hand, we explored the
scope of the hydrogenation/cyclization sequence (Table 2). A
wide range of five-membered siloxanes were obtained in high
yield, demonstrating the tolerance of branched side chains
(1d, Table 2, entry 1), and common protecting groups (1e and
f, Table 2, entries 2 and 3, the latter being synthesized in enan-
tioenriched form by Noyori transfer hydrogenation of the cor-
responding ketone).[15] The benzylic product 1g (entry 4)
proved to be more challenging to obtain, as partial reduction
of the benzylic CÀO bond was observed. However, employing
the benzylic alcohol and more reactive alkynylsilanol (substrate
2g) with a lower catalyst loading smoothly accessed 1g, pro-
viding that cyclohexene was used as a sacrificial co-solvent to
prevent over-reduction in this rapid reaction.[16] The height-
ened reactivity of the silanol over the isopropoxysilane may re-
flect either a reduced steric effect, or potentially complexation
of this free hydroxyl to the catalyst, as has been proposed in
other reactions.[17]
9
10
11
1 h
1 h
15 min
71
66
73
12
10 min
50 min
79
13
65
[a] Reaction conditions: n=0: 20 mol% quinoline; then K2CO3, MeOH/cyc-
lization. n=1: 50 mol% quinoline; then concentrated, MeOH was added;
passed through K2CO3 plug to cyclize. [b] Isolated yield. [c] Cyclohexene
was used as co-solvent (PhMe/C6H10 10:1). [d] 1 mol% [Pd], 50 mol%
quinoline. [e] Cyclized by using PPTS in CH2Cl2/toluene. [Si]=SiEt2OiPr.
Reduction of silanol 2h (Table 2, entries 5, 6) illustrates a tol-
erance of free alcohols in the reaction. This substrate also pro-
vides a choice of products: by using a basic methanolysis
workup, solely five-membered siloxane 1h was obtained,
whereas exposure of the crude reaction mixture to mild acidic
conditions (pyridinium p-toluenesulfonate (PPTS), CH2Cl2/tolu-
ene) instead afforded exclusively the six-membered ring 1i.
Similar regioselectivity was observed in the case of 2j, which
gave the five-membered siloxane 1j directly, without trace of
the six-membered isomer (Table 2, entry 7). These examples
demonstrate a predictable differentiation between proximal al-
cohol functionalities, which could be useful for further manipu-
lations of the cyclic products. It was found that acetylation
prior to reduction was unnecessary for homopropargylic or
hindered propargylic alcohols; hence, five- and six-membered
siloxanes 1k–p could be obtained in good yields directly from
the corresponding alcohols (Table 2, entries 8–13). As the latter
reductions again proceeded more rapidly than the esterified
substrates, a higher quinoline loading (50 mol%) was required
to prevent over-hydrogenation. Siloxane 1o was obtained as
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Table 3. Hiyama cross-coupling of cyclic alkenylsiloxane 1a.[a]
Entry [Pd]
Activator (equiv)
Solvent, T Yield
[8C]
5aaa:6:7[c]
[%][b]
1
2
3
4
5
6
7
8
9
[allylPdCl]2 TBAF·3H2O (3.0)
[Pd(dba)2] TBAF·3H2O (3.0)
[allylPdCl]2 TASF (3.0)
[allylPdCl]2 TBAT (3.0)
[allylPdCl]2 CsF (3.0)
[Pd(PPh3)4] Ag2O (2.0)
[allylPdCl]2 KOH (3.0)
[Pd(dba)2] KOSiMe3 (2.5)
[Pd(dba)2] KOSiMe3
THF, RT
THF, RT
THF, RT
THF, RT
DMF, 70
THF, 60
MeOH, RT 16[e]
DME,[f] RT 47
DME,[f] 60 65
72
65
44
0[d]
47
11
100:0:0
85:15:0
99:1:0
–
87:13:0
30:36:34
90:10:0
57:18:25
84:11:5
(2.5)+10 equiv H2O
[a] Reaction conditions: 0.22 mmol 1a, 0.22 mmol 4a, 0.3m. [b] Isolated
yield. [c] Determined by 1H NMR spectroscopic analysis of the crude reac-
tion mixture. [d] No reaction. [e]>80% iodide homocoupling was ob-
served. [f] 0.16m. TBAF=tetrabutylammonium fluoride; TASF=tris(dime-
thylamino)sulfonium difluorotrimethylsilicate; TBAT=tetrabutylammoni-
um difluorotriphenylsilicate.
Scheme 2. Cross-coupling of cyclic alkenylsiloxanes under fluoride- and
base-activated conditions. Reactions performed with one equivalent each of
silane/iodide unless otherwise stated. [a] 1.5 equiv iodide was used. [b] Reac-
tion time 48 h. [c] No reaction was observed, see text.
a single enantiomer from 2o (prepared by ring opening of the
corresponding non-racemic terminal epoxide)[15] demonstrating
that enantioenriched six-membered cyclic siloxanes are also
easily accessed.
the silanolate activator, which is significantly moderated by
water.[5c,24]
Having established robust, scalable methods to generate
cyclic alkenylsiloxanes, we turned our attention to their appli-
cation in Hiyama cross-coupling reactions, in which we were
particularly intrigued to probe the effect of ring size on reactiv-
ity (Table 3). By using Denmark’s conditions for fluoride-activat-
ed coupling ([allylPdCl]2/tetra-n-butylammonium fluoride
(TBAF)),[5a,b,18] we were pleased to find that the reaction of
equimolar amounts of siloxane 1a and vinyl iodide 4a gave al-
lylic diene 5aa in good yield, as a single geometrical isomer
(entry 1); other catalysts and fluoride sources (entries 2–5)[19]
were found to be inferior. We next undertook a study of fluo-
ride-free cross-coupling, which would lead to greater function-
al group tolerance; to the best of our knowledge, fluoride-free
couplings have not been reported for cyclic alkenylsiloxanes of
this type.[20,21] In contrast, a number of conditions have been
developed to achieve basic activation of other alkenylsilanes;[2c]
selected examples of these, applied to our system, are shown
With conditions for both fluoride-promoted and fluoride-free
cross-coupling established, a selection of (Z)-alkenyl styrenes
and dienes were prepared, with variation of siloxane ring size,
substituent and iodide coupling partner (Scheme 2). Reaction
with iodobenzene gave (Z)-allylic alcohols as single isomers in
excellent yields with alkyl and aryl-substituted five-membered
cyclic siloxanes under both sets of conditions (5ba, bd, bg).[25]
Alkyl-substituted vinyl iodides 4c and d were also found to be
competent coupling partners, giving good yields of E,Z-dienes
(5ca and dg). Notably, the cross-coupling of siloxane 1e,
which features a primary TBS ether, gave 5ae and be under
fluoride-free conditions without deprotection of the TBS
group, demonstrating compatibility with this commonly em-
ployed fluoride/acid sensitive functionality.
Although six-membered siloxane 1o coupled efficiently with
fluoride promotion to give homoallylic alcohols 5ao and bo in
high yield, no cross-coupling was observed under fluoride-free
conditions, from which 1o was recovered untouched. This
result opens exciting possibilities for the orthogonal cross-cou-
pling of five- and six-membered cyclic alkenylsiloxanes,[26] and
is likely related to the greater ring strain of the five-membered
ring.[14,27] To definitively illustrate this orthogonality, equimolar
amounts of five-membered siloxane 1 f, six-membered siloxane
1o and an iodide were subjected to fluoride-free coupling con-
ditions (Scheme 3). We were delighted to find that both aryl
and vinyl iodides reacted selectively with the five-membered
substrate 1 f, with the inert six-membered siloxane returned in
high yield in both cases.
in Table 2 (entries 6–9).[22] The most promising results were ob-
[23]
tained with 2.5 equivalents of KOSiMe3
and 5 mol%
[Pd(dba)2] in dimethoxyethane (DME), which gave a modest
yield of 5aa (entry 8), although desilylation (6) and silane ho-
mocoupling (7) were found to compete. Hypothesizing that
these by-products might arise from the enhanced basicity of
KOSiMe3 under anhydrous conditions, we were pleased to find
that the addition of 10 equivalents of water to the reaction al-
leviated these problems (entry 9), albeit requiring heating to
608C to attain full conversion. It seems that the success of fluo-
ride-free coupling thus depends crucially on the solvation of
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cifically cross-coupled to form (Z)-alkene-containing products,
the additional observation of ring size-dependent orthogonal
Hiyama–Denmark reactivity under base-promoted conditions
offers exciting synthetic opportunities. The preparation of the
diene/triene segments of representative anticancer polyketide
natural products illustrates the value and applicability of this
chemistry in organic synthesis.
Experimental Section
Scheme 3. Orthogonal cross-coupling of five-membered silane 1 f in the
presence of six-membered silane 1o (1 equiv each) with PhI (4b) or 4a
(1 equiv) under fluoride-free conditions. [a] KOSiMe3 added in portions.
Semihydrogenation of propargylic acetates
Palladium on CaCO3 (5 wt% Pd, 0.05 equiv) was added to a stirred
solution of acetate (1.0 equiv) and quinoline (0.2 equiv) in toluene
(0.1m). The resulting solution was stirred under an atmosphere of
hydrogen (balloon) for the indicated period until completion as
monitored by TLC. The mixture was then filtered through Celite
and concentrated. The crude residue was redissolved in methanol,
then K2CO3 (2–3 equiv) was added, and the mixture was stirred vig-
orously for 3 h. The reaction was then diluted with Et2O, washed
twice with water, dried (MgSO4) and concentrated. The residue was
purified by rapid flash column chromatography on a short column
of silica gel to give the oxasiloles as colourless oils, which are sensi-
tive to silica gel. Typically, 4–5 cm of silica gel (or 8–9 gmmolÀ1 of
crude) was employed, and the crude mixture was loaded onto
a layer of sand (2–3 cm) prior to elution (petroleum ether/Et2O
19:1).
To underline the synthetic value of this chemistry, we ad-
dressed the preparation of the polyene segments of three bio-
logically active natural products featuring (Z)-allylic alcohols
(see Scheme 1). Although several total syntheses of fostriecin
have been reported,[28] the majority have used Stille coupling
to assemble the polyene moiety, and/or required the protec-
tion of both allylic alcohols. Our methodology (Scheme 4) al-
lowed the construction of the sensitive Z,Z,E-triene 8 (C9ÀC18
fragment of fostriecin) from enantioenriched silane 1 f and
dienyl iodide 4e, without the need to protect either allylic al-
cohol (66%). Equally pleasing was the success of the challeng-
ing cross-coupling of 1 f with the electron-rich, hindered (Z)-
vinyl iodide 4 f, which gave the C9ÀC21 fragment 9 of phos-
lactomycin B (52%).[29,30] Finally, although much synthetic at-
tention[31] has been focused on the synthesis of (E,E)-dienes in
the bitungolide family, no work on the more challenging C9À
C21 portion of bitungolide C, featuring a Z,E-diene and trisub-
stituted arene, has been reported to date. We were therefore
pleased that 10 could be prepared (without the need for
masking of the free phenol), which to our knowledge repre-
sents the first synthesis of this bitungolide fragment.
Fluoride-promoted cross-coupling
A degassed solution of TBAF·3H2O (1m solution in THF, 3.0 equiv)
was added to the silane (1.0 equiv), iodide (1.0 equiv) and allylpal-
ladium chloride dimer (0.025 equiv) at room temperature. The mix-
ture was stirred for 24–48 h in the dark, then the reaction was di-
luted with CH2Cl2 and filtered through a plug of silica gel. The fil-
trate was concentrated, and the residue purified by flash-column
chromatography to give the cross-coupled product.
Base-promoted cross-coupling
In summary, we have established a robust, general route to
cyclic alkenylsiloxanes based on the Lindlar hydrogenation of
alkynylsilane alcohols and esters, which solves a long-standing
selectivity issue in alkynylsilane reduction chemistry. Although
A degassed solution of potassium trimethylsilanolate (98 wt%, as
a 0.42m solution in DME, 2.5 equiv) was added to the silane
(1.0 equiv), iodide (1.0 equiv), water (10.0 equiv) and bis(dibenzyli-
deneacetone)palladium (0.05 equiv) at room temperature. The mix-
ture was heated to 608C for 24 h in the dark, then it was cooled to
room temperature, diluted with Et2O and filtered through a plug
of silica gel. The filtrate was concentrated, and the residue purified
by flash-column chromatography to afford the cross-coupled
product.
Acknowledgements
We thank the EPSRC (EP/E055273/1, Advanced Research Fel-
lowship to E.A.A.) and A*STAR for a National Science Scholar-
ship (D.L.).
Keywords: alkynes · cross-coupling · hydrogenation · natural
products · silanes
Scheme 4. Bioactive natural-product fragments prepared by fluoride-pro-
moted cross-coupling of 1 f. Reaction conditions: common to all:
TBAF·3H2O (3 equiv), [allylPdCl]2 (5 mol%); (a) RT, 48 h; (b) H2O (10 equiv),
508C, 24 h; c) 508C, 24 h.
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[27] It is interesting to note that reaction of the acyclic alkenylsilane (Z)-
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yield of coupled product under fluoride promotion, and was unreactive
using KOTMS, illustrating further orthogonality and the benefit of both
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Received: April 25, 2014
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Published online on June 4, 2014
Chem. Eur. J. 2014, 20, 8594 – 8598
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