Increasing the structural span of alkyne metathesis

Article abstract of DOI:10.1002/chem.201302320

A new generation of alkyne metathesis catalysts, which are distinguished by high activity and an exquisite functional group tolerance, allows the scope of this transformation to be extended beyond its traditional range. They accept substrates that were previously found problematic or unreactive, such as propargyl alcohol derivatives, electron-deficient and electron-rich acetylenes of various types, and even terminal alkynes. Moreover, post-metathetic transformations other than semi-reduction increase the structural portfolio, as witnessed by the synthesis of a annulated phenol derivative via ring-closing alkyne metathesis (RCAM) followed by a transannular gold-catalyzed Conia-ene reaction. Further examples encompass a post-metathetic transannular ketone-alkyne cyclization with formation of a trisubstituted furan, a ruthenium-catalyzed redox isomerization, and a Meyer-Schuster rearrangement/oxa-Michael cascade. These reaction modes fueled model studies toward salicylate macrolides, furanocembranolides, and the cytotoxic macrolides acutiphycin and enigmazole A; moreover, they served as the key design elements of concise total syntheses of dehydrocurvularin (27) and the antibiotic agent A26771B (36). Ask for more! Many possibilities exist to take advantage of alkyne metathesis. In addition to the approved semi-reduction to stereodefined olefins, it is shown how to convert the products primarily formed into aromatic or heteroaromatic rings, enones, Michael adducts, or β-ketolactones. At the same time, new types of substrates were engaged, including electron-rich, electron-poor, and terminal alkynes, as well as propargyl alcohol derivatives. Copyright

Full text of DOI:10.1002/chem.201302320

FULL PAPER
DOI: 10.1002/chem.201302320
Increasing the Structural Span of Alkyne Metathesis
Peter Persich, Josep Llaveria, Rudy Lhermet, Teresa de Haro, Robert Stade,
Azusa Kondoh, and Alois Fꢀrstner*[a]
Abstract: A new generation of alkyne
metathesis catalysts, which are distin-
guished by high activity and an exqui-
site functional group tolerance, allows
the scope of this transformation to be
extended beyond its traditional range.
They accept substrates that were previ-
ously found problematic or unreactive,
such as propargyl alcohol derivatives,
electron-deficient and electron-rich
acetylenes of various types, and even
terminal alkynes. Moreover, post-meta-
thetic transformations other than semi-
reduction increase the structural port-
folio, as witnessed by the synthesis of a
annulated phenol derivative via ring-
closing alkyne metathesis (RCAM) fol-
lowed by a transannular gold-catalyzed
Conia-ene reaction. Further examples
encompass a post-metathetic transan-
nular ketone–alkyne cyclization with
formation of a trisubstituted furan, a
ruthenium-catalyzed redox isomeriza-
tion, and a Meyer–Schuster rearrange-
ment/oxa-Michael cascade. These reac-
tion modes fueled model studies
toward salicylate macrolides, furano-
cembranolides, and the cytotoxic mac-
rolides acutiphycin and enigmazole A;
moreover, they served as the key
design elements of concise total synthe-
ses of dehydrocurvularin (27) and the
antibiotic agent A26771B (36).
Keywords: alkyne metathesis
·
gold · molybdenum · natural prod-
ucts · total synthesis · transannular
reactions
Introduction
Significant advances in catalyst design has brought new im-
petus for applications of alkyne metathesis in general and
ring-closing alkyne metathesis (RCAM) in particular.[1,2] In
this context, complexes 1–3 are particularly noteworthy as
they combine excellent reactivity with an outstanding func-
tional group tolerance (Scheme 1).[3] These molybdenum al-
kylidynes endowed with triarylsilanolate ligands are readily
prepared on a multigram scale, turned out to be thermally
quite robust, and can be rendered bench-stable upon com-
plexation with phenanthroline. Since the adduct formation is
reversible on contact with simple metal salts, the active spe-
cies can be conveniently released on demand and its exqui-
site activity profile be harnessed even by a less experienced
practitioner.[3] The reactions are best performed in the pres-
ence of molecular sieves (MS 5 ꢀ). This additive sequesters
the released 2-butyne formed as the generic by-product
from methyl capped alkyne substrates; as a consequence,
full conversion can often be reached at or even below ambi-
ent temperature, which makes the application of static
vacuum or other inconvenient reaction set-ups unnecessa-
ry.[3]
Scheme 1. Assortment of commonly used alkyne metathesis catalysts; for
a comprehensive discussion, see ref. [1a]; Ar = Ph, pMeO-C6H4-; R =
tBu, 2,6-dimethylphenyl.
This progress notwithstanding, most applications of
alkyne metathesis known to date merely engaged the (cy-
clo)alkynes primarily formed into a subsequent semi-reduc-
tion.[1] In doing so, rigorous control over the configuration
of the newly formed double bond as well as high levels of
selectivity in either geometric series are secured, which con-
temporary olefin metathesis usually cannot guarantee.[4–6]
While this approach therefore remains utterly relevant,[7–10]
it is also clear that alkyne semi-reduction is by no means the
only serviceable post-metathetic transformation. Among the
many conceivable options,[11] the use of “alkynophilic”
[a] Dipl.-Chem. P. Persich, Dr. J. Llaveria, Dr. R. Lhermet,
Dr. T. de Haro, Dr. R. Stade, Dr. A. Kondoh, Prof. Dr. A. Fꢁrstner
Max-Planck-Institut fꢁr Kohlenforschung
45470 Mꢁlheim/Ruhr (Germany)
Fax : (+49)208 306 2994
E-mail: fuerstner@kofo.mpg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302320.
Chem. Eur. J. 2013, 19, 13047 – 13058
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13047

Lewis acid catalysts seems particularly lucrative, which
allow a host of nucleophiles to be added across a triple
bond under notably mild conditions.[12] Although a few
recent case studies took advantage of this tactic,[13–16] many
possibilities remain yet to be explored. It is the purpose of
this article to further increase the span of alkyne metathesis
beyond the stereoselective formation of regular olefins. In
parallel, we were striving to encompass those types of
alkyne substrates that were previously considered problem-
atic or even unreactive; any advance in this regard will
expand the portfolio and coverage of alkyne metathesis
beyond its customary sphere.
model study summarized in Scheme 3. Starting from b-ke-
toester 7,[22] CsF-catalyzed transesterification[23] with
tridec-11-yn-1-ol furnished the envisaged cyclization precur-
sor 8. According to NMR analysis, this compound is notice-
AHCTUNGTREGaNNNU bly enolized and was therefore protected in situ on treat-
ment with TMSCl and Et3N; after evaporation of all volatile
materials, the resulting crude silyl enol ether was subjected
to RCAM with the aid of complex 2a·Et2O (Ar = Ph).
Since the silyl residue was readily cleaved during work up,
no extra step was necessary to secure the desired macrocycle
9 in 90% overall yield.
a
Results and Discussion
Gold-catalyzed transannular functionalization: Several
members of the salicylic- and resorcylic acid macrolide
family, such as radicicol, zearalenone or lasiodiplodin, have
been known for decades (Scheme 2); yet, the interest in
these and related polyketide derivatives grew dramatically
in the recent past when their pronounced and diverse bio-
logical activities were fully recognized.[17] In parallel, new
representatives were discovered which became immediate
targets for total synthesis. As one might expect, most ap-
proaches started with preformed aromatic entities and fo-
cused on the formation of the annulated macrocycle. How-
ever, a complementary approach to resorcylic acid macro-
lides pursued by Danishefsky and co-workers showed that
the de-novo formation of the arene nucleus may be advanta-
geous in certain cases; specifically, these authors used an in-
termolecular Diels–Alder strategy to generate the aromatic
ring only after the macrocycle had been forged.[18]
Scheme 3. a) Tridec-11-yn-1-ol, CsF (10 mol%), toluene, reflux, 83%;
b) TMSCl, Et3N, CH2Cl2; c) 2a·Et2O (Ar = Ph, 10 mol%), toluene, MS
5 ꢀ, 808C, 90%; d) Ph3PAuCl (5 mol%), AgNTf2 (5 mol%), CH2Cl2,
97%; e) DDQ, TMSCl, MeCN, ꢀ20 ! 908C (closed vessel), 67%; DDQ
= 2,3-dichloro-4,5-dicyano-1,4-benzoquinone; MS = molecular sieves; Tf
= trifluoromethanesulfonyl; TMS = trimethylsilyl.
Although 6-endo additions of b-ketoesters across internal
alkynes are known in the literature, there is ample room for
improvement as some of the established procedures are
plagued by by-product formation[24] and/or require stoichio-
metric amounts of a metal promoter.[25] We conjectured that
gold catalysis should be particularly well suited to effect this
special variant of a Conia-ene type reaction.[26,27] In line
with this notion, the transannular cyclization of 9 catalyzed
[28]
by Ph3PAuNTf2 generated in situ proceeded with remark-
able ease to furnish enone 11 as the only product in essen-
tially quantitative yield. It is believed that the reaction af-
fords compound 10 as the primary product, which rearrang-
es instantaneously to the much more stable isomer 11 under
the influence of the carbophilic catalyst.[29]
Scheme 2. Representative resorcylate and salicylate macrolides.
The oxidation of 11 to the corresponding phenol 12
turned out to be rather challenging. The elegant aerobic aro-
matization protocol developed by Stahl and co-workers fur-
nished the desired product, but the yield remained low (32–
43%), despite considerable experimentation.[30] Amongst
the variety of alternative oxidants, the use of DDQ in
MeCN in the presence of TMSCl gave the best results.
Inspired by this precedent and in continuation of our own
early investigations in this field,[19,20] we considered that
macrocyclization by ring-closing alkyne metathesis
(RCAM)[21] followed by a transannular addition of an ap-
propriate soft C-nucleophile across the triple bond might
open an entirely different entry. This idea was tested by the
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Alkyne Metathesis
FULL PAPER
Another model study was undertaken to investigate
whether transannular reactions of macrocyclic b-ketoesters
comprising a triple bond in their framework might ultimate-
ly provide access to furanocembranoids (Scheme 4).[31] A se-
quence of two conventional alkylation reactions converted
methyl acetoacetate (13) into product 14, which was trans-
formed into the corresponding silyl enol ether prior to ring-
closure; the desired macrocycle 15 was obtained in respecta-
ble yield. Exposure of this compound to catalytic AuCl3 in
refluxing methanol[32] resulted in clean transannular attack
of the enol oxygen atom with formation of the desired furan
ring. It is pointed out that product 16 maps onto the frame-
work of pukalide or iopholide and congeners.[31]
nable to the arguably more challenging RCAM reactions as
well.
To this end, the ester derivatives 17 differing in the nature
and steric demand of the protecting groups for the propar-
gylic alcohol subunit were reacted with complex 2a·Et2O
(Ar = Ph) as one of the most active and selective alkyne
metathesis catalysts known to date (Scheme 5, Table 1).
Scheme 5. RCAM of propargyl alcohol derivatives followed by a redox
isomerization: a) see Table 1; b) pTsOH·H2O, MeOH, 92% (from 18a, R
= TBS); c) 19 (10 mol%), InACHTNUGTRNEUNG(OTf)3 (10 mol%), camphorsulfonic acid
(17 mol%), THF, reflux, 79%; Ts = p-toluenesulfonate (tosyl).
Table 1. RCAM of propargyl alcohol derivatives.[a]
Entry
Substrate
R
c [m]
T [8C]
Yield [%]
1
2
3
4
5
17a
17a
17b
17b
17c
TBS
TBS
Ac
Ac
MOM
0.017
0.002
0.017
0.002
0.002
RT
100
RT
80
69[b]
74[b,c]
56
86
79
80
[a] Unless stated otherwise, all reactions were performed with 10 mol%
of complex 2a·Et2O (Ar = Ph) in toluene in the presence of MS 5 ꢀ. [b]
Ca. 20% of a cyclic dimer was detected. [c] Using 15 mol% of catalyst;
Ac = acetyl; MOM = methoxymethyl; TBS = tert-butyldimethylsilyl.
Gratifyingly, the cyclization reactions proceeded smoothly,
affording the desired macrocycles 18 in respectable yields,
although the catalyst loading was not optimized at this
stage. Compound 17a bearing a bulky OTBS group adjacent
to one of the alkynes furnished variable amounts of a cyclic
dimer in addition to the desired product 18a. In view of the
sterically demanding ancillary ligands on the catalyst, it is
hardly surprising that the reaction is responsive to steric hin-
drance about the triple bonds to be metathesized.[35] Cleav-
age of the silyl group of 18a followed by a ruthenium-cata-
lyzed redox isomerization[36] furnished enone 20 in high
yield.
Yet another possibility to take advantage of the compati-
bility of propargylic substrates with RCAM is outlined by
the model study directed towards the highly cytotoxic mac-
rolide enigmazole A (Scheme 6).[37] Our approach engaged
the readily available diyne 21 (diastereomeric mixture)[38]
into ring-closure on treatment with catalytic amounts of
complex 1 under high dilution conditions. Oxidative cleav-
age of the PMB-ether in the resulting product 22 followed
by treatment with catalytic [(Ph3P)AuNTf2] gave the tetra-
hydropyran derivative 24 as a single diastereomer in excel-
lent yield, which can be isolated as such or directly convert-
Scheme 4. a) NaH, then BuLi, THF, then 11-bromo-2-undecyne, 08C !
RT, 53%; b) NaH, 1-bromo-2-butyne, THF, 08C
!
RT, 64 %;
c) (i) TMSCl, Et3N, CH2Cl2; (ii) 2·Et2O (Ar = Ph) (2ꢃ5 mol%), toluene,
MS 5 ꢀ, 808C, 66%; d) AuCl3 (7 mol%), MeOH, reflux, 67%.
Propargylic alcohol derivatives: Propargyl alcohols and de-
rivatives thereof are attractive substrates for alkyne meta-
thesis as they provide many opportunities for post-metathet-
ic transformations.[33] A close survey of the literature, how-
ever, shows that such compounds have hardly ever been
tested; in fact, it is by no means clear that they will qualify
since the formation of a metal alkylidyne—which is known
to be nucleophilic at carbon[34]—adjacent to a potential leav-
ing group might simply result in the extrusion of the propar-
gylic substituent and, in doing so, destroy the catalyst. Only
recently have a few examples of successful alkyne cross-
metathesis (ACM) reactions been reported, using the latest
generation of molybdenum–alkylidyne complexes endowed
with triarylsilanolate ligands.[3] This precedent encouraged
us to study whether propargylic alcohol derivatives are ame-
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A. Fꢁrstner et al.
of the popular ring-closing alkene metathesis (RCM) to the
formation of macrocyclic enones are surprisingly rare.[42,43]
Total synthesis of dehydrocurvularin: To further scrutinize
this notion, we targeted dehydrocurvularin (27), a macrolide
antibiotic endowed with phytotoxic and nematicidal activity
as well as appreciable cytotoxicity.[44] Although this com-
pound is known for decades,[45] no total synthesis has been
published,[46,47] even though its saturated sibling curvularin
(26) had served as a prominent
target in the past.[48,49]
Since the enone substructure
of 27 is part of a 12-membered
ring and hence any cycloalkyne
precursor necessarily strained,
the macrocyclization by RCAM
as well as the rearrangement
chemistry are deemed fairly
Scheme 6. Model study towards enigmazole A based on a sequence of
RCAM followed by a Meyer–Schuster rearrangement/transannular hy-
droalkoxylation cascade: a) 1 (Ar = pMeOC6H4-, 12 mol%), toluene, MS
5 ꢀ, 808C, 95%; b) DDQ, CH2Cl2, pH 7 buffer, 97%; c) Ph3PAuNTf2
(5 mol%), CH2Cl2, 95%; d) K2CO3, MeOH, 78% (over two steps).
challenging. In fact, additional intelligence had suggested
that an approach to dehydrocurvularin via a Meyer–Schus-
ter rearrangement might be stereo-unselective.[50] Therefore
we opted for the redox route shown in Scheme 7, which
commenced with formylation of the commercial aryl bro-
mide 28 followed by addition of propynylmagnesium bro-
mide and protection of the resulting alcohol with a TBS
group. The residual bromide in 30 allowed for the rapid at-
tachment of the entire ester side chain by a palladium-cata-
lyzed enolate arylation reaction. After some experimenta-
tion, it was found that this transformation was best achieved
by deprotonation of acetate 31 with TMPZnCl·LiCl, fol-
lowed by palladium-catalyzed cross-coupling of the resulting
enolate.[51] Gratifyingly, the resulting diyne derivative 32
could be cyclized in good yield by RCAM, although the
somewhat less encumbered complex 6 (Scheme 1), activated
in situ on treatment with CH2Cl2 as previously described by
our group,[52] had to be used for optimal results.[53] It was
necessary to perform the reaction in refluxing toluene; the
need for such forcing conditions and a high catalyst loading
is ascribed to the very strained and distorted nature of the
incipient cycloalkyne 33.
ed into ketone 25 upon saponification of the crude material.
The allenyl acetate 23 primarily formed by the gold-cata-
lyzed Meyer–Schuster rearrangement[39] is subject to a spon-
taneous transannular hydroalkoxylation mediated by the
very same catalyst; the net outcome is synthetically equiva-
lent to enone formation followed by an oxa-Michael addi-
tion.[40] The structure of 25 in the solid state confirms the
diequatorial substitution of the resulting tetrahydropyran
moiety and hence the validity of this model for a projected
total synthesis of enigmazole A (Figure 1). Further studies
towards this particular target will be reported in due course.
As evident from the structure in the solid state (Figure 2),
the alkyne subunit deviates from linearity; perhaps more
ꢀ
consequential is the fact that the bulky OTBS ether is
forced into a pseudo-axial orientation on the macrocyclic
frame in order to avoid an even less favorable eclipsing sit-
uation with the methoxy group at the a-position of the ben-
zene ring. This particular conformation, which orients the
ꢀ
C1 O1 bond almost perpendicularly to the plane of the
very electron rich arene, renders the silyl ether an excellent
leaving group and lowers the barrier to formation of a
highly stabilized carbocation. In any case, attempted depro-
tection of 33 under standard conditions led to instantaneous
decomposition; gratifyingly though, the use of TASF in
aqueous DMF allowed the silyl ether to be cleaved in essen-
tially quantitative yield.[54,55] The resulting alcohol is no less
sensitive than its silylated precursor, in particular under
(Lewis) acidic conditions. As a result, all attempts to engage
Figure 1. Structure of compound 25 in the solid state.[41]
Although only modestly complex in structural terms,
these model studies showcase that macrocyclic enones and
derivatives thereof are well within reach of RCAM. This
new gateway is deemed a valuable addendum to the syn-
thetic repertoire, in particular since successful applications
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Alkyne Metathesis
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Figure 2. Structure of cycloalkyne 33 in the solid state; the C4–C6 region
of the alkyl chain is disordered.[41]
molybdenum–alkylidyne complexes 1–3 endowed with tri-
phenylsilanolate groups.[3] With this precedent in mind, it
seemed reasonable to dissect (ꢀ)-A26771B at its a-hydroxy-
ketone site, which should be accessible in optically pure
form from a precursor with an enyne conjugated to an ester
moiety or a surrogate thereof (Scheme 8).
Scheme 7. a) DMF, POCl3, 908C, then KOH, RT, 91%; b) propynylmag-
nesium bromide, THF, 08C ! RT, 93%; c) TBSCl, imidazole, DMF,
98%; d) 3-pentynylmagnesium bromide, CuCN (10 mol%), THF, ꢀ788C
! RT, 97 %; e) Ac2O, Et3N, DMAP (20 mol%), CH2Cl2, 98%; f) (i) 31,
TMPZnCl·LiCl, THF; (ii) 30, PdACHTNUTRGNENG(U OAc)2 (5 mol%), SPhos (10 mol%),
THF, 508C, 62%; g) 6 (50 mol%), CH2Cl2, toluene, reflux, 79%;
h) TASF, aq. DMF, 97%; i) MnO2, CH2Cl2, 77%; j) CrCl2, THF/H2O
(1:1), 71% (E-35, + 7% of Z-isomer); k) Al, I2, toluene, 908C, then 35,
TBAI, toluene, 08C, 60%; DMAP = 4-dimethylaminopyridine; TASF =
tris(dimethylACHTUNGTRENNUNGamino)sulfonium difluorotrimethylsilicate; TBAI = tetra-n-
butylammonium iodide; TMP = 2,2,6,6-tetramethylpiperidinyl.
this compound into a ruthenium-catalyzed redox isomeriza-
tion[36] were in vain, despite considerable experimentation.
However, the problem could be fixed by an oxidation/reduc-
tion sequence,[56] which gave dehydrocurvularin dimethyl
ether 35 in good yield and high selectivity (E/Z ꢁ10:1).
Cleavage of the methyl groups with AlI3 generated in situ[57]
completed the total synthesis of dehydrocurvularin (27) in
optically pure form (9 steps, longest linear sequence, 13%
overall yield).
Scheme 8. Retrosynthetic analysis of (ꢀ)-A26771B.
The required alcohol component 37 was prepared by a
copper-catalyzed ring-opening of optically pure (R)-propen-
oxide with 9-undecynylmagnesium bromide (Scheme 9). Es-
terificaton with hex-2-en-4-ynoic acid under standard condi-
tions furnished diyne 38, which reacted without incident on
exposure to complex 1 at elevated temperatures. The result-
ing product, however, was found to be the cyclodimer 39
rather than the desired cyclic monomer. This outcome could
not be changed by increasing the dilution; it remained the
only detectable product even at 0.0001m concentration.
Compound 39 was formed as a single head-to-tail isomer;
this connectivity pattern is evident from the spectral data
and was unambiguously confirmed by single crystal X-ray
diffraction (Figure 3).
Electron deficient enynes—total synthesis of the antibiotic
(ꢀ)-A26771B: The antibiotic (ꢀ)-A26771B, derived from
the fungus Penicillium turbatum,[58–60] provides an excellent
opportunity to explore whether triple bonds conjugated to
an electron withdrawing group are amenable to alkyne
metathesis. Very little is known about the reactivity of such
substrates: whereas two attempted RCAM reactions of alky-
noates with the help of the classical Schrock tungsten alkyli-
dyne complex 4 met with failure (see below),[61,62] alkyne
cross-metathesis (ACM) reactions of the somewhat less elec-
tron-deficient ethyl hex-2-en-4-ynoate with simple alkyne
partners proceeded in decent yields when catalyzed by the
To overcome this pronounced inherent bias, we envisaged
the use of an acetylenic aldol motif as surrogate for the
enyne moiety (Scheme 10).[63] The appropriate diyne 40
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A. Fꢁrstner et al.
Table 2. Catalyst screening and optimization of the RCAM reaction
leading to product 41.[a]
Entry Catalyst T [8C] t [h] Conversion [%][c] 41 [%] Dimer [%][d]
1
2
3
4
5
6
3[b]
3[b]
2
2
1
RT
80
RT
80
RT
80
6
8
4
3
1.5
1
93
89
>98
>98
>98
>98
65
78
72
95
90
92
20
10
10
–
6
–
1
[a] Unless stated otherwise, all reactions were performed with 5 mol% of
catalyst in toluene in the presence of MS 5 ꢀ. [b] Using 10 mol% of cat-
alyst which was activated with ZnCl2 (10 mol%) at 808C for 40 min prior
1
to the addition of the substrate. [c] Determined by H NMR of the crude
product. [d] According to GC/MS; the exact structure was not deter-
mined because the product is a mixture of several diastereomers.
Scheme 9. a) 9-Undecynylmagnesium bromide, CuI (10 mol%), THF,
ꢀ788C ! RT, 84%; b) hex-2-en-4-ynoic acid, EDCI, DMAP, CH2Cl2,
08C ! RT, 83 %; c) 1 (Ar = pMeOC6H4-, 10 mol%), toluene, MS 5 ꢀ,
808C, 83%; EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
Scheme 10. a) 3-(Benzoyloxy)-hex-4-ynoic acid, DIAD, PPh3, toluene,
98%; b) see Table 2; c) DBU, toluene, 08C, quant. (E/Z 5:1); d) H2
(1 atm), Lindlar catalyst, quinoline, hexanes, 99%; e) DBU, toluene, RT,
97%; f) AD-mix b, K2OsO4·2 H2O (7 mol%), NaHCO3, methanesulfona-
mide, tBuOH/H2O (1:1), 08C, 81% (dr > 95:5); g) TEMPO, pTsOH,
CH2Cl2, 62%; h) succinic anhydride, DMAP cat., CH2Cl2, 71%; DBU =
Figure 3. Structure of the head-to-tail cyclodimer 39.[41]
could be cyclized without damaging the labile aldol entity to
any noticeable extent. Small amounts of a cyclic dimer were
detected in all runs performed at RT, whereas the formation
of this by-product could be completely suppressed at higher
temperature (Table 2). In line with our expectations, the
neutral molybdenum benzylidyne complex 1 bearing three
triphenylsilanolate groups was most effective in terms of re-
action time and yield.[3] The corresponding ate-complex 2a
(Ar = Ph), which is believed to release the neutral complex
1 in solution,[3] is similarly productive but somewhat slower.
The bench-stable adduct 3 (Ar = pMeOC6H4-), after activa-
tion with ZnCl2 as an appropriate phenanthroline scaveng-
er,[3] also gave good results, although a higher catalyst load-
ing was necessary.
1,8-diazabicycloACHTNUTGRNEUNG[5.4.0]undec-7-ene; DIAD = diisopropyl azodicarboxy-
late; TEMPO = 2,2,6,6-tetramethylpiperidinyloxyl.
Elimination of the benzoate group with formation of the
corresponding cyclic enyne 42 (E/Z 5:1) proceeded quantita-
tively on treatment with DBU at 08C. Although this product
potentially opens a route to (ꢀ)-A26771B, a more conven-
ient entry was found by subjecting the triple bond to Lindlar
reduction[64] prior to benzoate elimination. In this way, diene
44 was secured in isomerically pure form and almost quanti-
tative yield. The subsequent asymmetric dihydroxylation
with AD-mix b[65] proceeded with excellent regio- and ster-
eoselectivity; only the less electron-deficient distal olefin
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Alkyne Metathesis
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bond got oxidized (d.r. >95:5).
The allylic alcohol of 45 could
then be selectively converted
into the corresponding ketone
using TEMPO in acidic medi-
um;[59h] reaction of the remain-
ing hydroxyl group in 46 with
succinic anhydride under stand-
ard conditions completed this
concise and productive total
synthesis of (ꢀ)-A26771B (36)
(8 steps from propenoxide, lon-
gest linear sequence, 25% over-
all yield).
Electron deficient alkynes—
RCAM of ynoates: To the best
of our knowledge, only two at-
tempts were reported at engag-
ing the electron deficient triple
bond of an alkynoate into a
ring-closing alkyne metathesis
reaction. Unfortunately, howev-
er, neither the simple diyne 48a
(n = 1)[61] nor the much more
elaborate substrate 47[62] could
be cyclized on treatment with
the classical tungsten alkylidyne
complex 4,[66] which was the
benchmark catalyst for many
years.
Challenged by this shortfall,
we explored whether the new
molybdenum alkylidynes en-
dowed with silanolate ligands
are more appropriate, since
they had proven effective in
Scheme 11. RCAM reactions of alkynoates: a) 1 (10 mol%), toluene (0.001 m), MS 5 ꢀ, 808C, 66% (49a, n =
1, + 23% of cyclic dimer); 92% (49b, n = 5); 84% (51); b) p-TsOH (5 mol%), MeOH, 85%; c) AuCl3
(2 mol%), MeOH, 96%; MOM = methoxymethyl.
several
challenging
cases
before.[1,3,7,8,13–16] In fact, treat-
ment of a solution of 48a (n =
1) in toluene at 808C with 1 (8–10 mol%, unoptimized) fur-
nished the desired product 49a in respectable 66% yield, to-
gether with some head-to-tail cyclodimer,[67] which was
easily removed by flash chromatography (Scheme 11). Once
again, the product distribution was fairly unresponsive to di-
lution in the tested concentration range (0.004–0.0005m).
Gratifyingly, the larger homologue 49b (n = 5) was formed
under the same conditions as a single compound in excellent
yield, with virtually no cyclodimer being detected in the
crude mixture. This rewarding outcome may inspire applica-
tions to natural product synthesis, as illustrated by the con-
version of ynoate rac-50[38] into cycloalkyne 51 containing an
appropriately located silyl ether. After unmasking, the hy-
droxyl group in 52 is poised for a transannular oxa-Michael
addition, which was best effected under the aegis of AuCl3
in MeOH as an alkynophilic catalyst.[68] Under these condi-
tions, the corresponding ketal 53 is formed in excellent yield
as a single diastereomer, which corresponds to the core
structure of the potently cytotoxic macrolide acutiphycin.[69]
Electron-rich alkynes and ring-opening/alkyne cross-meta-
thesis: Much like their electron-deficient relatives, electron
rich acetylene derivatives have hardly ever been used as
substrates for alkyne metathesis.[70] Therefore, a selection of
such compounds was prepared and subjected to alkyne
cross-metathesis (ACM) reactions in the presence of com-
plex 1 as the arguably most selective catalyst known to
date.[3] Although a simple alkynyl ether, -thio ether and
sulfur-containing ynamine failed to react under the standard
conditions (Figure 4), we were pleased by the good results
obtained with a moderately bulky alkynylsilane,[71] -phos-
phine and -phosphineoxide; even a phosphine-gold complex
could be transformed by ACM with 5-decyne without dam-
aging the organometallic entity (Table 3). Furthermore, the
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13053

A. Fꢁrstner et al.
kynes to be productively metathesized and competing poly-
merization to be largely suppressed, provided that even the
intermolecular reactions are performed under high dilu-
tion.[75,76]
Although the available dataset is small and further inves-
tigations are warranted, one may speculate that the reduced
basicity of the fluorinated alkoxide ligands in 5 disfavors the
fatal transannular proton abstraction and hence opens a
window of opportunity for productive cycloreversion of the
metallacyclic intermediate. Under this premise, complex 1
might also qualify as catalyst, since the basicity of silanolates
is also significantly lower than that of regular alkoxides.[77]
This is in fact the case (Table 4): in line with the results of
Tamm et al.,[75] high dilution was necessary to ensure good
results even in intermolecular settings; moreover, a rigor-
ously anhydrous reaction medium was mandatory. Therefore
all reactions were carried out in the presence of MS 4 ꢀ/
5 ꢀ, which are meant to seques-
Figure 4. Electron-rich alkynes that were unreactive under the standard
conditions.
reactivity of these substrates could be harnessed in an un-
precedented mode: whereas ring-closure by RCAM is well
established, ring-opening alkyne metathesis has so far been
restricted to polymerization reactions.[72] However, entries 3
and 6 illustrate that even a fairly unstrained cycloalkyne un-
dergoes ring-opening/alkyne cross-metathesis when treated
with an alkynylsilane or –phosphine in the presence of com-
plex 1.
ter traces of moisture as well as
the released acetylene, respec-
tively. Under these conditions, a
set of alkyne metathesis reac-
Table 3. Alkyne metathesis reactions of electron rich substrates.[a]
Entry
Substrate
Partner
mol%
T [8C]
Product
Yield [%]
1
2
2
2
RT
RT
93
5-decyne
71
tions of terminal alkyl alkynes
were accomplished with appre-
ciable yields that are compara-
ble to the literature results ob-
3
10
60
77
tained with the fluorinated al-
kylidyne complex 5.[75]
Of particular note are the as
yet unprecedented cross-meta-
4
5
2
2
60
52
79[b]
5-decyne
RT
thesis reactions of terminal al-
kynes with propynyl(trimethyl)-
silane, which turned out to be
6
5
60
36
particularly productive (entries
6, 7, 12, 15, 16). This transfor-
mation represents a new way of
7
8
5-decyne
5-decyne
2
5
RT
RT
67
introducing
a silyl protecting
group onto a terminal alkyne,
which is compatible with func-
tional groups that might not
subsist under conventional sily-
lation conditions.[78]
92
[a] All reactions were performed with complex 1 (Ar = p-MeOC6H4-) in toluene in the presence of MS 5 ꢀ.
[b] The product contains traces of the corresponding phosphine oxide formed upon air oxidation during work
up.
In contrast, the result for a
prototype RCAM reaction was
rather disappointing (entry 17),
Terminal alkynes: For many years, productive metathesis of
terminal acetylene derivatives remained a largely unmet
goal because of competing substrate polymerization.[73,74] Al-
though terminal alkynes react with Schrock alkylidyne com-
plexes by the usual [2+2] cycloaddition mode, the resulting
as only a modest yield of the desired macrocycle was se-
cured with 1, whereas complex 5 was reported to effect this
transformation in almost quantitative yield (entry 18).[75]
The comparison of entries 17 and 19 is also quite informa-
tive, as it shows that the outcome could be significantly im-
proved upon incorporation of a single methyl end-cap.
Overall, these preliminary data are encouraging and fur-
ther studies to optimize the catalyst design are ongoing. The
promising start notwithstanding, the practicality of terminal
alkyne metathesis—at the current state of development—
does not (yet) rival the robustness of the metathesis of inter-
nal alkynes.
ꢀ
metallacyclobutadienes undergo formal transannular C H
abstraction with formation of a deprotiometallacycle and
concomitant loss of one of the ancillary ligands that picks
up the released proton.[74,3b] Recently however, Tamm and
co-workers showed that the molybdenum alkylidyne com-
plex 5 (Scheme 1, R = 2,6-dimethylphenyl) endowed with
hexafluoro-tert-butoxide ligands allows aliphatic terminal al-
13054
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Alkyne Metathesis
FULL PAPER
Table 4. Metathesis reactions of terminal alkynes.[a]
Entry
Substrate
Partner
Cat.
Product
Yield [%]
1
2
3
4
5
1
1
5
1
5
79 (X = H)
81 (X = OMe)
92 (X = OMe)[75]
75 (X = Cl)
96 (X = Cl)[75]
6
7
1
1
96 (X = OMe)
94 (X = Cl)
8
9
10
11
1
1
1
1
74 (R = Bn)
82 (R = THP)
67 (R = TBDMS)
– (R = Ts)[b]
12
1
88
13
14
1
1
85 (R = Boc)
42 (R = Ts)
15
16
1
1
93 (R = Boc)
91 (R = Ts)
17
18
1[c]
5
56
95[75]
19
1
82
[a] The reactions were performed with 1 mol% of the catalyst in toluene (0.021 m) at ambient temperature in the presence of MS 4 ꢀ and MS 5 ꢀ. [b]
Polymerization of the substrate only. [c] With 2 mol% of catalyst; Boc = tert-butyloxycarbonyl; Bn = benzyl; TBDMS = tert-butyl-dimethylsilyl; THP =
tetrahydropyranyl.
Conclusion
A26771B and the polyketide dehydrocurvularin, as well as a
series of model studies directed toward other bioactive
target molecules provide a further glimpse of the prepara-
tive potential yet to be harnessed.
The examples presented in this paper illustrate that the
structural span of alkyne metathesis in general and ring-clos-
ing alkyne metathesis in particular goes far beyond the for-
mation of stereodefined olefins by semi-reduction of the
acetylenic products initially formed, which has so far been
the most common application.[1,2,79] Specifically, carbophilic
catalysts were used to bring a host of important structural
motifs into reach, as illustrated by the transannular forma-
tion of carbocyclic and heterocyclic aromatic rings, or by the
swift access to enones and oxy-Michael adducts thereof. At
the same time, the substrate scope has been increased to en-
compass alkynes that had previously hardly ever been used;
this includes secondary propargyl alcohols, alkynoates, eny-
noates, various types of electron rich triple bonds and even
terminal acetylenes. Furthermore, the first examples of ring-
opening/alkyne cross-metathesis reactions are disclosed and
the use of alkyne cross-metathesis as a novel means of intro-
ducing silyl protecting groups to a terminal alkyne substrate
is demonstrated. The total synthesis of the antibiotic
Experimental Section
All experimental details can be found in the Supporting Information.
The material includes compound characterization, crystallographic ab-
stracts for the X-ray structures of products 25, 33 and 39, as well as
copies of pertinent NMR spectra.
Acknowledgements
Generous financial support by the MPG, SusChemSys (Ziel 2 Programm
NRW 2007–2013), the Fonds der Chemischen Industrie, the Alexander-
von-Humboldt Foundation (fellowship to J.L.) and the Swiss National
Foundation (fellowship to T.d.H.) is gratefully acknowledged. We thank
Dr. J. Heppekausen and Dr. K. Micoine for preliminary studies, and the
Analytical Departments of our Institute for excellent support.
Chem. Eur. J. 2013, 19, 13047 – 13058
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13055

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These data can be obtained free of charge from The Cambridge
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cif.
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Alkyne Metathesis
FULL PAPER
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Received: June 18, 2013
Published online: September 3, 2013
13058
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Chem. Eur. J. 2013, 19, 13047 – 13058