Formal total synthesis of kendomycin by way of alkyne metathesis/gold catalysis

Article abstract of DOI:10.1002/chem.201304580

In an attempt to study the ability of the latest generation of alkyne metathesis catalysts to process sterically hindered substrates, two different routes to the bacterial metabolite kendomycin (1) were explored. Whereas the cyclization of the overcrowded

Full text of DOI:10.1002/chem.201304580

DOI: 10.1002/chem.201304580
Full Paper
&
Organic Synthesis
Formal Total Synthesis of Kendomycin by Way of Alkyne
Metathesis/Gold Catalysis
Laura Hoffmeister, Peter Persich, and Alois Fꢀrstner*[a]
Abstract: In an attempt to study the ability of the latest
generation of alkyne metathesis catalysts to process sterical-
ly hindered substrates, two different routes to the bacterial
metabolite kendomycin (1) were explored. Whereas the cyc-
lization of the overcrowded arylalkyne 39 and related sub-
strates turned out to be impractical or even impossible, ring
closure of the slightly relaxed diyne 45 was achieved in ex-
cellent yield under notably mild conditions with the aid of
the molybdenum alkylidyne 2 endowed with triphenylsilano-
late ligands. The resulting cycloalkyne 46 was engaged into
a gold-catalyzed hydroalkoxylation, which led to benzofuran
47 that had already previously served as a late-stage inter-
mediate en route to 1.
on several occasions.[6,9,11j] Although this transformation seems
to be an obvious choice in view of its outstanding creden-
tials,[12–16] attempted formation of the ansa-frame of 1 by RCM
was surprisingly difficult or even met with failure; only after
careful conformational design of the cyclization precursor and/
or probing of various sites of disconnection has olefin meta-
thesis been successfully implemented.[6,9] It is perhaps ironic,
however, that the direct formation of the D13, 14 E-alkene was in
vain, despite several independent attempts: although it was
possible to close the macrocycle by RCM at this site, the unde-
sired Z-isomer was invariably and exclusively formed.[6,9,11j] The
fact that the subsequent inversion of the double bond geome-
try required a four-step sequence painfully illustrates that in-
herently E-selective metathesis catalysts are urgently needed
but currently unknown.[17]
Introduction
The kendomycin ((ꢀ)-TAN 2162) (1)[1–3] case nicely illustrates
the stimulus that a natural product endowed with pronounced
bioactivity and a challenging molecular architecture can pro-
vide.[4] No less than six different total or formal total syntheses
were disclosed during the last decade in addition to a signifi-
cant number of model studies.[5–11] Collectively, these efforts re-
flect the challenges posed by this secondary metabolite isolat-
ed from various Streptomyces
strains, which embodies a rather
unique
quinone-methide/lactol
chromophor within a carbogenic
ansa-framework. Even the first syn-
thetic forays had already indicated
that closure of this macrocyclic
It is against this backdrop that our approach to kendomycin
(1) must be seen. Recent progress in catalyst design prompts
us to advocate the use of alkyne metathesis in general and
ring-closing alkyne metathesis (RCAM) in particular as notewor-
thy alternatives to the more commonly practiced metathesis of
olefins.[18] This methodology is arguably most serviceable when
combined with alkyne-specific post-metathetic transforma-
tions. Of the many possibilities, it seems particularly lucrative
to invoke carbophilic Lewis acid catalysts based on platinum
or gold,[19,20] as they allow alkynes to be engaged as privileged
substrates into a host of different transformations.
scaffold might be difficult because
of conformational peculiarities that
originate from the restricted rota-
tion about the pseudo-C-glycosidic
C4aꢀC5 bond connecting the densely functionalized pyran and
the aromatic sector.[11]
Although this forecast basically proved correct, various crea-
tive solutions were found in the following tournament. In the
event, kendomycin succumbed to macrocyclizations as distinct
as C-glycosidation,[5] Prins reaction,[8] Barbier-type carbonyl ad-
dition,[7] lactonization/photo-Fries rearrangement,[9] and Dçtz
benzannulation,[10] although with largely different efficiency.
Furthermore, ring-closing olefin metathesis (RCM) was invoked
In the present context, we envisaged that a sequence of
RCAM[21] followed by noble-metal-catalyzed hydroalkoxylation
should open access to the known benzofuran A, which has
previously served as the penultimate intermediate en route to
1 (Scheme 1).[4] Whereas our experiences with the cyclization
of benzofuran rings by addition of a phenolic ꢀOH group onto
a lateral alkyne partner made us optimistic for the projected
case,[22,23] the formation of the required cycloalkyne precursor
definitely needed careful consideration.
[a] L. Hoffmeister, P. Persich, Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/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.201304580.
Chem. Eur. J. 2014, 20, 4396 – 4402
4396
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Results and Discussion
Preparation of the polyketide chain
In line with the intentions spelled out above, we pur-
sued a pragmatic route to the aldehyde fragment 5,
which was best prepared on scale in five high yield-
ing operations
starting from b-citronellene
(Scheme 2).[31] In passing, however, it is noted that 5
has also been made from the lactic acid ester 6 by
the elegant zinc-catalyzed triflate alkylation chemistry
developed by the Breit group,[32] which furnished the
coupling product 8 in respectable yield (Scheme 3).
Acid cleavage of the tert-butyl ester gave the corre-
sponding lactone 9 that was transformed into the
gem-dichloroolefin 10 by following a literature proce-
dure.[33] Treatment of this compound with MeLi in
the presence of [Cu(acac)2] engendered fragmenta-
tion with formation of the nonterminal alkyne 11
Scheme 1. Retrosynthetic analysis of kendomycin (1) based on RCAM followed by benzo-
furan formation by noble-metal-catalyzed hydroalkoxylation; kendomycin numbering
scheme.
RCAM is best performed with the aid of the molybdenum al-
kylidyne [(Ph3SiO)3MoꢁCAr] (Ar=ꢀC6H4OMe) (2) or related
complexes recently developed by our group.[24–26] Because
these catalysts exhibit an outstanding functional group toler-
ance and usually operate under mild conditions, they allow
rather fragile compounds to be handled.[27,28] Therefore it
Scheme 2. a) O3, CH2Cl2, ꢀ788C, then Me2S; b) HC(OMe)3, K10-montmorilo-
nite, 75% (over both steps); c) 4-dimethylaminopyridinium bromide perbro-
mide, 08C!RT, DMAP, CH2Cl2, 87%; d) LiHMDS, THF, 508C, 90%; e) BuLi, MeI,
THF/DMPU, ꢀ788C!RT, then aq. HCl, 95%; DMAP=4-dimethylaminopyri-
dine; LiHMDS=lithium hexamethyldisilazide; DMPU=1,3-dimethyl-3,4,5,6-
tetrahydro-2(1H)pyrimidinone.
seemed unlikely that the substitution pattern of kendomycin
would pose any problems. Yet, limitations are to be expected
for sterically hindered alkynes since the three fairly bulky tri-
phenylsilanolate ligands about the operative alkylidyne in 2
might obstruct efficient substrate binding in such cases.[26,29,30]
This issue seemed particularly daunting in the projected forma-
tion of cycloalkyne B, in which the arylalkyne subunit is ortho-
disubstituted on the aromatic end and a-branched at the ali-
phatic side.
Therefore it appeared prudent to consider an alternative
entry that remits some of this steric burden. To this end, we
contemplated a tactic based on ring contraction by photo-
Fries rearrangement of an ester precursor of type C, which fol-
lows the beautiful lead previously described by the Mulzer
group for a related intermediate.[9] Yet, the topology of the
meta-bridging ansa chain in C implies that such a cycloalkyne
is strained and hence its formation by RCAM also potentially
problematic.
Scheme 3. a) Tf2O, 2,6-lutidine, CH2Cl2, 08C, 85%; b) ZnCl2 (5 mol%), THF,
08C, 66%; c) trifluoroacetic acid, CH2Cl2, 66%; d) CCl4, PPh3, THF, reflux, 71%;
e) MeLi, Cu(acac)2 (10 mol%), Et2O, 92%; f) TEMPO (5 mol%), bipyridine
(5 mol%), [Cu(MeCN)4]BF4 (5 mol%), N-methylimidazole, MeCN, air, 96%;
Tf=trifluoromethanesulfonyl; acac=acetylacetonato; TEMPO=2,2,6,6-tetra-
methyl-piperidin-1-oxyl, free radical.
It was these open chemical questions that let us venture
into the total synthesis of kendomycin. As the major goal, our
study intended to interrogate the new alkyne metathesis cata-
lysts as to the tolerable steric hindrance. To gain the necessary
material however, it was planned to take ample advantage of
the knowledge gathered in the literature for the preparation of
the required building blocks as well as for the envisaged end
game.[4–11] Gratifyingly, a single polyketide segment D can
serve both of the conceived routes to 1, which reduces the
necessary preparative burden. As outlined below, this concep-
tual frame finally gave rise to a concise approach to this exi-
gent target, while illustrating the power of alkyne metathesis
when applied in concert with gold catalysis.
without noticeable epimerization of the a-chiral center.[34]
A
copper- and TEMPO-cocatalyzed air oxidation then gave the
targeted aldehyde 5.[35] Although this route was also satisfacto-
ry in terms of yield, it is distinctly longer than the “chiral pool”
strategy shown in Scheme 2 and therefore not competitive in
this particular case.[36]
Chem. Eur. J. 2014, 20, 4396 – 4402
www.chemeurj.org
4397
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 4. a) Sn(OTf)2, Et3N, CH2Cl2, ꢀ788C, 57%; b) Me4NBH(OAc)3, MeCN/
HOAc, ꢀ50!ꢀ108C, 80%; c) LiOH, H2O2, THF/H2O, 99%; d) 2,2-dimethoxy-
propane, camphorsulfonic acid (10 mol%), 90%; e) PhMe2SiLi, CuCN, THF,
ꢀ78!08C, 93%; f) NIS, 2,6-lutidine, hexafluoroisopropanol, 08C, 97%;
NIS=N-iodosuccinimide.
Scheme 5. a) Isobutene, H2SO4 cat., CH2Cl2, 92%; b) LiAlH4, THF, ꢀ788C, 80%;
c) I2, PPh3, imidazole, Et2O/MeCN, 88%; d) 25, LDA, LiCl, THF, ꢀ788C!RT,
96%; e) LDA, BH3·NH3, THF, 08C, 96%; f) TPAP cat., NMO, MS 4 ꢂ, CH2Cl2,
08C!RT, 72%; g) CBr4, PPh3, Zn, CH2Cl2, 68%; h) BuLi, MeI, THF, ꢀ788C!RT,
99%; i) i) trifluoroacetic acid, CH2Cl2; ii) KOH, MeOH/H2O, 88%; j) I2, PPh3, imi-
dazole, Et2O/MeCN, 95%; k) i) tBuLi, 26, Et2O; ii) 17, K3PO4, [PdCl2(dppf)]
(10 mol%), DMF/H2O, quant.; l) LiOH, THF, MeOH, H2O, 90%; LDA=lithium
diisoprpylamide; TPAP=tetra-n-propylammonium perruthenate; NMO=N-
methylmorpholine-N-oxide; MS=molecular sieves; dppf=1,1’-bis(diphenyl-
phosphino)ferrocene.
In analogy to a literature precedent,[9] a tin-aldol reaction of
5 with the Evans keto-imide 12 furnished compound 13 in
high yield,[37] which was subjected to a 1,3-anti reduction with
tris(acetoxy)borohydride (Scheme 4).[38] Hydrolytic cleavage of
the auxiliary resulted in lactone formation upon work up,
which was inconsequential as treatment of 14[5] with 2,2-dime-
thoxypropane under acidic condition led to concomitant trans-
esterification and acetal formation. The transformation of 15
thus formed into the alkenyl iodide 17 was best achieved by
silylcupration[39,40] followed by iodine-for-silicon exchange.[41]
Although this tactic is one step longer than hydrozirconation/
iodination, it was found much more reliable and also higher
yielding.
The necessary coupling partner 22 derives from Roche ester
18, which was first converted into iodide 19 by standard
means (Scheme 5). A subsequent Myers alkylation followed by
reductive cleavage of the auxiliary gave product 20 basically as
a single diastereomer,[42] which was readily elaborated into
alkyne 21 by oxidation[43] and a subsequent Corey–Fuchs
alkyne formation.[44] Acid treatment followed by reaction of the
resulting alcohol with PPh3/I2 in basic medium furnished the
required building block 22 in excellent overall yield. A note-
worthy aspect of potentially more general interest is the use of
the tert-butyl ether moiety, which is a somewhat underrepre-
sented alcohol protecting group even though it is cheap, easy
to introduce, robust against many reagents, yet readily cleaved
in acidic medium. Anyhow, its use provided a nicely scalable
and inexpensive solution for the present case.
Scheme 6. a) BzCl, Et3N, THF, 08C, 89%; b) NIS, H2SO4 cat., HOAc, 94%;
c) KOH, MeOH, 80%; d) NBS, MeCN, ꢀ108C, 49–81%; e) DIBAl-H, CH2Cl2;
f) MOMCl, DBU, acetone, 61% (over both steps); g) propynylmagnesium bro-
mide, ZnBr2, [Pd(PPh3)4] (40 mol%), THF, reflux, 82%; h) pTsOH cat., MeOH;
i) PtCl2 (20 mol%), toluene, 708C, 82% (over both steps); j) BuLi, THF, then
isobutyraldehyde, 788C, 96%; k) 2 (18 mol%), 2-octyne, MS 5 ꢂ, toluene,
1008C, 54% (91% brsm); NBS=N-bromosuccinimide; DIBAl-H=di-isopropyl-
aluminum hydride; MOM=methoxymethyl; DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene; Ts=p-toluenesulfonyl; brsm=based on recovered start-
ing material.
Next, fragments 17 and 22 were combined by way of the 9-
MeO-9-borabicyclo[3.3.1]nonane (9-MeO-9-BBN) variant of the
Suzuki coupling that has already served previous syntheses of
kendomycin well.[5,8,10] Parenthetically, we note that this meth-
odology originates from our laboratory[45] and later found ex-
tensive use by us and others.[46] As expected, it furnished prod-
uct 23 in essentially quantitative yield as the last common in-
Chem. Eur. J. 2014, 20, 4396 – 4402
www.chemeurj.org
4398
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
termediate of the two envisaged
RCAM-based routes toward ken-
domycin (1).
Exploration of route A
After considerable experimenta-
tion it was found that an ade-
quate hexasubstituted benzene
derivative of type E can be
formed as shown in Scheme 6.
Benzoylation of commercial 27
was followed by iodination,
which occurred regioselectively
trans to the methoxy substitu-
ent. At this stage, the bulky
iodide shields the adjacent ester
such that hydrolysis with K2CO3
in aqueous MeOH solely unveils
one phenol site, which provides
the necessary activation for the
introduction of a second halide
at the remaining open ortho po-
sition. To this end, 29 was treat-
ed with NBS to give product 30
in somewhat variable yield after
reductive cleavage of the re-
maining benzoate. Compound
30 was then MOM-protected
prior to a regioselective attach-
ment of the yet missing propyn-
Scheme 7. a) MeNH(OMe)·HCl, iPrMgCl, THF, ꢀ258C!RT, 78%; b) DIBAl-H, THF, ꢀ788C; c) 31, nBuLi, THF,
ꢀ788C!RT, 70% (over both steps); d) Ac2O, DMAP, pyridine, 55%; e) Dess–Martin periodinane, CH2Cl2, 97%; f) aq.
HCl, MeOH, 77%; g) MOMCl, iPrNEt2, CH2Cl2, 73%; h) 2 (2ꢃ30 mol%), toluene, reflux, ꢂ62%, see text.
yl moiety by Negishi cross-coupling at the iodide site to give
the functional hexasubstituted arene fragment 31.[47]
the price of a very high catalyst loading; all other attempts at
cyclization of the shown precursors with the help of 2 or other
alkyne metathesis catalysts such as 41[51] resulted in either no
reaction, the production of acyclic dimers and/or gradual de-
composition.[52] What is more, even the formation of 40 turned
out to be fairly erratic, which definitely meant that route A
(Scheme 1) does not provide a competitive solution for the
kendomycin problem. Hence we conclude that metathesis of
aryl alkynes flanked by bulky and/or potentially coordinating
substituents at both ortho-positions, though not excluded,[50] is
currently not yet sufficiently robust.
A few model reactions were performed at this stage to ex-
plore the likelihood of the projected end game. In line with
our expectations, MOM-cleavage followed by treatment of the
resulting phenol with catalytic amounts of PtCl2 furnished the
corresponding benzofuran 32 in good yield.[22] Likewise, lithi-
um-for-halogen exchange and reaction with an a-branched ali-
phatic aldehyde worked well to give adduct 33, whereas addi-
tion of the organolithium intermediate to an analogous Wein-
reb amide[48] was low yielding (not shown). Finally, the out-
come of an alkyne cross metathesis[49] of the hindered sub-
strate 31 with 2-octyne catalyzed by the molybdenum
alkylidyne 2[25] was encouraging, though certainly not optimal;
yet, such a crowded arylalkyne substrate had never been suc-
cessfully metathesized before. Additional control experiments
also augured well for the projected ring closure.[50]
Metacyclophane/ring-contraction pathway
As a consequence, we increased our efforts to explore the al-
ternative gateway to kendomycin (route B). The preparation of
an appropriate phenol derivative basically reiterates the acyla-
tion and subsequent iodination chemistry outlined above, in
that 27 could be cleanly transformed into compound 43
(Scheme 8). By virtue of steric hindrance, a selective acetate
cleavage with K2CO3 in aqueous MeOH solely unveiled the
proper phenol site for the attachment of the polyketide seg-
ment 24 to give ester 44. Only at this point the missing
second alkyne unit was installed by another variant of the
Suzuki coupling,[53] which generates an appropriate alkynylbor-
on donor in situ from propynyl sodium and cheap
Based on the gathered intelligence, the polyketide sector 23
was first transformed into the corresponding aldehyde 35,
which was then reacted with the lithiated arene segment to
give product 36 in good yield. This compound was elaborated
into a panel of possible cyclization precursors as shown in
Scheme 7. Unfortunately, none of them proved viable, despite
considerable experimentation. Suffice it to say that only diyne
39 could be transformed into the desired macrocyclic mono-
mer 40, even though at an impractically high dilution and for
Chem. Eur. J. 2014, 20, 4396 – 4402
www.chemeurj.org
4399
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Mulzer and co-workers.[9] Their
subsequent ring contraction by
a photo-Fries rearrangement[55]
could be nicely reproduced, fur-
nishing ketone 48 in good yield;
suffice it to say that the analyti-
cal and spectral data of either
compond were in excellent
agreement with those reported
in the literature (see Supporting
Information).[9] The remaining
steps to the target have also
been repeated, even though
only in a cursory manner on
small scale, as they merely echo
established chemistry.[9]
Conclusion
The advent of a new generation
of catalysts, as exemplified by
the molybdenum alkylidyne
2,[24–26] entails a significant push
for alkyne metathesis in practical
and strategic terms.[18] They
allow most common functional
groups to be handled and hence
enable applications to densely
functionalized and fairly elabo-
rate compounds, as witnessed
by the present case study as
well as by a number of earlier
examples from this and other
Scheme 8. a) AcCl, Et3N, THF, ꢀ78!08C, 90%; b) NIS, AcOH, H2SO4 cat., 99%; c) K2CO3, MeOH/H2O, 97%; d) 24,
EDCI·HCl, DMAP, CH2Cl2, 77%; e) propynyl sodium, B(OMe)3, [PdCl2(Ph3P)2] (10 mol%), tBuXPhos (20 mol%), THF,
reflux, 78%; f) 2 (5 mol%), toluene, MS 5 ꢂ, 95%; g) K2CO3, MeOH, 08C, 86%; h) 50 (10 mol%), CH2Cl2, 79%; i) hu
(high pressure mercury gas lamp, 125 W), cyclohexane, 85%; j) NaBH4, MeOH; k) aq. HCl, MeOH, 89% (over both
steps); l) ref. [9]; EDCI=1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide; tBuXPhos=2-di-tert-butylphosphino-
2’,4’,6’-triisopropyl-1,1’-biphenyl.
laboratories.[27–30,56]
somewhat crowded
Yet,
the
ligand
sphere in 2, casted by the triaryl-
silanolate ligands, suggests that
limitations might be encoun-
tered with sterically hindered
substrates. The two different
B(OMe)3.[46,54] Despite the heavy functionalization, this method
worked well and furnished diyne 45 in respectable yield in
readiness for macrocyclization by ring-closing alkyne metathe-
sis.
routes to kendomycin (1) and the accompanying model stud-
ies described above elaborate on this aspect.
Whereas the intermolecular cross-metathesis of the over-
crowded arylalkyne 31 bearing bulky substituents on either
side ortho to the reacting triple bond could be enforced in
a preparatively meaningful yield, the intramolecular versions
trying to engage substrates 36–39 were either impractical or
even impossible. A relatively small relaxation of the steric pres-
sure, however, greatly improved the outcome as evident from
the surprisingly smooth cyclization of diyne 45 to the meta-
bridging and somewhat strained cycloalkyne 46. This transfor-
mation was instrumental for yet another total synthesis of ken-
domycin, a bacterial metabolite that had already served as
a prominent target in the past.[4–11] Although we appreciate
that step-counting is not always an unambiguous exercise and
certainly not the only relevant index, the present synthesis of
1 is one of the shortest entries into this particular ansamycin
In striking contrast to the difficulties outlined in the previous
section, the cyclization of the meta-bridged cyclophane deriva-
tive 45 proceeded with exceptional ease. Thus, exposure of
diyne 45 to complex 2 (5 mol%)[25] furnished the desired prod-
uct within 1 h at ambient temperature in essentially quantita-
tive and well reproducible yield. The crude material was direct-
ly subjected to saponification of the remaining acetate. While
treatment of this compound with PtCl2 did not engender cycli-
zation of the benzofuran ring, the use of more electrophilic
cationic gold complexes smoothly triggered this second key
transformation. Best results were obtained with [Au-
(JohnPhos)]OTs (50) as the catalyst in CH2Cl2. Compound 47 in-
tercepts the total synthesis of kendomycin (1) published by
Chem. Eur. J. 2014, 20, 4396 – 4402
www.chemeurj.org
4400
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Org. Lett. 2005, 7, 4161–4164; j) T. Sengoku, D. Uemura, H. Arimoto,
Chem. Lett. 2007, 36, 726–727.
[12] T. M. Trnka, R. H. Grubbs, Acc. Chem. Res. 2001, 34, 18–29.
[13] a) A. Fꢀrstner, Angew. Chem. 2000, 112, 3140–3172; Angew. Chem. Int.
Ed. 2000, 39, 3012–3043; b) A. Fꢀrstner, Chem. Commun. 2011, 47,
6505–6511.
derivative known to date. This fact corroborates the notion
that alkyne metathesis, in particular when aligned with noble
metal catalysis,[57] opens many opportunities and deserves con-
sideration in other challenging settings in the future.
[14] K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005, 117, 4564–
4601; Angew. Chem. Int. Ed. 2005, 44, 4490–4527.
[15] Metathesis in Natural Product Synthesis: Strategies, Substrates and Cata-
lysts (Eds.: J. Cossy, S. Arseniyadis, C. Meyer), Wiley-VCH, Weinheim,
2010.
[16] For the first examples of macrocyclizations with Grubbs-type catalysts,
see: a) A. Fꢀrstner, K. Langemann, J. Org. Chem. 1996, 61, 3942–3943;
b) A. Fꢀrstner, N. Kindler, Tetrahedron Lett. 1996, 37, 7005–7008; c) A.
Fꢀrstner, K. Langemann, Synthesis 1997, 792–803; d) A. Fꢀrstner, K. Lan-
gemann, J. Am. Chem. Soc. 1997, 119, 9130–9136; e) A. Fꢀrstner, T.
Mꢀller, Synlett 1997, 1010–1012; f) A. Fꢀrstner, T. Gastner, H. Weintritt,
J. Org. Chem. 1999, 64, 2361–2366; g) A. Fꢀrstner, T. Mꢀller, J. Am.
Chem. Soc. 1999, 121, 7814–7821.
Experimental Section
All experimental details can be found in the Supporting Informa-
tion. The material includes compound characterization and copies
of spectra of new compounds.
Acknowledgements
Generous financial support by the MPG and the Fonds der
Chemischen Industrie is gratefully acknowledged. We thank all
analytical departments of our Institute for the excellent sup-
port of our program, in particular Mrs B. Gabor for her assis-
tance with the analysis of several NMR spectra. Dr. G. Valot is
recognized for the preparation of some model compounds.
[17] A. Fꢀrstner, Science 2013, 341, 1229713.
[18] a) A. Fꢀrstner, Angew. Chem. 2013, 125, 2860–2887; Angew. Chem. Int.
Ed. 2013, 52, 2794–2819; b) A. Fꢀrstner, P. W. Davies, Chem. Commun.
2005, 2307–2320.
[19] a) D. J. Gorin, F. D. Toste, Nature 2007, 446, 395–403; b) A. Fꢀrstner,
P. W. Davies, Angew. Chem. 2007, 119, 3478–3519; Angew. Chem. Int. Ed.
2007, 46, 3410–3449; c) E. Jimꢅnez-NfflÇez, A. M. Echavarren, Chem. Rev.
2008, 108, 3326–3350; d) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180–
3211; e) Y. Yamamoto, J. Org. Chem. 2007, 72, 7817–7831.
Keywords: alkynes · gold · metathesis · molybdenum · natural
products
[20] a) A. Fꢀrstner, Chem. Soc. Rev. 2009, 38, 3208–3221; b) M. Rudolph,
A. S. K. Hashmi, Chem. Soc. Rev. 2012, 41, 2448–2462.
[21] a) A. Fꢀrstner, G. Seidel, Angew. Chem. 1998, 110, 1758–1760; Angew.
Chem. Int. Ed. 1998, 37, 1734–1736; b) A. Fꢀrstner, O. Guth, A. Rumbo,
G. Seidel, J. Am. Chem. Soc. 1999, 121, 11108–11113.
[22] A. Fꢀrstner, P. W. Davies, J. Am. Chem. Soc. 2005, 127, 15024–15025.
[23] A. Fꢀrstner, E. K. Heilmann, P. W. Davies, Angew. Chem. 2007, 119, 4844–
4847; Angew. Chem. Int. Ed. 2007, 46, 4760–4763.
[24] J. Heppekausen, R. Stade, R. Goddard, A. Fꢀrstner, J. Am. Chem. Soc.
2010, 132, 11045–11057.
[25] J. Heppekausen, R. Stade, A. Kondoh, G. Seidel, R. Goddard, A. Fꢀrstner,
Chem. Eur. J. 2012, 18, 10281–10299.
[1] a) Y. Funahashi, N. Kawamura, T. Ishimaru, Jpn. Kokai Tokkyo Koho 1996,
08231551 (Chem. Abstr. 1996, 125, 326518); b) Y. Funahashi, T. Ishimaru,
N. Kawamura, Jpn. Kokai Tokkyo Koho 1996, 08231552 (Chem. Abstr.
1997, 126, 6553); c) M. H. Su, M. Hosken, B. J. Hotovec, T. L. Johnston, U.
S. Patent 5728727 (Chem. Abstr. 1998, 128, 239489).
[2] a) H. B. Bode, A. Zeeck, Perkin 1 2000, 323–328; b) H. B. Bode, A. Zeeck,
Perkin 1 2000, 2665–2670.
[3] For studies on the mode of action, see: a) Y. A. Elnakady, M. Rohde, F.
Sasse, C. Backes, A. Keller, H.-P. Lenhof, K. J. Weissman, R. Mꢀller, Chem-
BioChem 2007, 8, 1261–1272; b) C. O. Janssen, S. Lim, E. P. Lo, K. F. Wan,
V. C. Yu, M. A. Lee, S. B. Ng, M. J. Everett, A. D. Buss, D. P. Lane, R. S.
Boyce, Bioorg. Med. Chem. Lett. 2008, 18, 5771–5773; c) for the biosyn-
thesis, see: S. C. Wenzel, H. B. Bode, I. Kochems, R. Mꢀller, ChemBioChem
2008, 9, 2711–2721.
[4] Review: H. J. Martin, T. Magauer, J. Mulzer, Angew. Chem. 2010, 122,
5746–5758; Angew. Chem. Int. Ed. 2010, 49, 5614–5626.
[5] Y. Yuan, H. Men, C. Lee, J. Am. Chem. Soc. 2004, 126, 14720–14721.
[6] a) A. B. Smith, E. F. Mesaros, E. A. Meyer, J. Am. Chem. Soc. 2005, 127,
6948–6949; b) A. B. Smith, E. F. Mesaros, E. A. Meyer, J. Am. Chem. Soc.
2006, 128, 5292–5299.
[26] P. Persich, J. Llaveria, R. Lhermet, T. de Haro, R. Stade, A. Kondoh, A.
Fꢀrstner, Chem. Eur. J. 2013, 19, 13047–13058.
[27] a) K. Micoine, A. Fꢀrstner, J. Am. Chem. Soc. 2010, 132, 14064–14066;
b) V. Hickmann, M. Alcarazo, A. Fꢀrstner, J. Am. Chem. Soc. 2010, 132,
11042–11044; c) V. Hickmann, A. Kondoh, B. Gabor, M. Alcarazo, A.
Fꢀrstner, J. Am. Chem. Soc. 2011, 133, 13471–13480; d) K. Micoine, P.
Persich, J. Llaveria, M.-H. Lam, A. Maderna, F. Loganzo, A. Fꢀrstner,
Chem. Eur. J. 2013, 19, 7370–7383.
[28] a) C. M. Neuhaus, M. Liniger, M. Stieger, K.-H. Altmann, Angew. Chem.
2013, 125, 5978–5983; Angew. Chem. Int. Ed. 2013, 52, 5866–5870;
b) B. J. Smith, G. A. Sulikowski, Angew. Chem. 2010, 122, 1643–1646;
Angew. Chem. Int. Ed. 2010, 49, 1599–1602; c) M. Fouchꢅ, L. Rooney,
A. G. M. Barrett, J. Org. Chem. 2012, 77, 3060–3070; d) M. G. Nilson, R. L.
Funk, Org. Lett. 2010, 12, 4912–4915.
[7] J. T. Lowe, J. S. Panek, Org. Lett. 2008, 10, 3813–3816.
[8] a) K. B. Bahnck, S. D. Rychnovsky, J. Am. Chem. Soc. 2008, 130, 13177–
13181; b) K. B. Bahnck, S. D. Rychnovsky, Chem. Commun. 2006, 2388–
2390.
[29] J. Willwacher, N. Kausch-Busies, A. Fꢀrstner, Angew. Chem. 2012, 124,
12207–12212; Angew. Chem. Int. Ed. 2012, 51, 12041–12046.
[30] G. Valot, C. S. Regens, D. P. O’Malley, E. Godineau, H. Takikawa, A. Fꢀrst-
ner, Angew. Chem. 2013, 125, 9713–9717; Angew. Chem. Int. Ed. 2013,
52, 9534–9538.
[9] a) T. Magauer, H. J. Martin, J. Mulzer, Angew. Chem. 2009, 121, 6148–
6152; Angew. Chem. Int. Ed. 2009, 48, 6032–6036; b) T. Magauer, H. J.
Martin, J. Mulzer, Chem. Eur. J. 2010, 16, 507–519.
[10] K. Tanaka, M. Watanabe, K. Ishibashi, H. Matsuyama, Y. Saikawa, M.
Nakata, Org. Lett. 2010, 12, 1700–1703.
[31] a) A. Fꢀrstner, D. De Souza, L. Parra-Rapado, J. T. Jensen, Angew. Chem.
2003, 115, 5516–5518; Angew. Chem. Int. Ed. 2003, 42, 5358–5360;
b) A. Fꢀrstner, D. De Souza, L. Turet, M. D. B. Fenster, L. Parra-Rapado, C.
Wirtz, R. Mynott, C. W. Lehmann, Chem. Eur. J. 2007, 13, 115–134.
[32] C. Studte, B. Breit, Angew. Chem. 2008, 120, 5531–5535; Angew. Chem.
Int. Ed. 2008, 47, 5451–5455.
[33] M. Lakhrissi, Y. Chapleur, J. Org. Chem. 1994, 59, 5752–5757.
[34] a) For the conversion of lactone-derived gem-dichloroolefins into non-
terminal alkynes on treatment with MeLi, see: K. Lehr, R. Mariz, L. Le-
seurre, B. Gabor, A. Fꢀrstner, Angew. Chem. 2011, 123, 11575–11579;
Angew. Chem. Int. Ed. 2011, 50, 11373–11377; b) K. Lehr, A. Fꢀrstner, Tet-
rahedron 2012, 68, 7695–7700; c) this reaction can be largely improved
[11] For fragment syntheses and model studies, see: a) H. J. Martin, M.
Drescher, H. Kꢄhlig, S. Schneider, J. Mulzer, Angew. Chem. 2001, 113,
3287–3289; Angew. Chem. Int. Ed. 2001, 40, 3186–3188; b) M. M. B.
Marques, S. Pichlmair, H. J. Martin, J. Mulzer, Synthesis 2002, 2766–
2770; c) S. Pichlmair, M. M. B. Marques, M. P. Green, H. J. Martin, J.
Mulzer, Org. Lett. 2003, 5, 4657–4659; d) M. P. Green, S. Pichlmair,
M. M. B. Marques, H. J. Martin, O. Diwald, T. Berger, J. Mulzer, Org. Lett.
2004, 6, 3131–3134; e) J. Mulzer, S. Pichlmair, M. P. Green, M. M. B. Mar-
ques, H. J. Martin, Proc. Natl. Acad. Sci. USA 2004, 101, 11980–11985;
f) T. Sengoku, H. Arimoto, D. Uemura, Chem. Commun. 2004, 1220–
1221; g) J. D. White, H. Smits, Org. Lett. 2005, 7, 235–238; h) J. T. Lowe,
J. S. Panek, Org. Lett. 2005, 7, 1529–1532; i) D. R. Williams, K. Shamim,
Chem. Eur. J. 2014, 20, 4396 – 4402
www.chemeurj.org
4401
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
upon addition of adequate metal catalysts: K. Lehr, projected Ph.D.
thesis, Technische Universitꢄt Dortmund.
[35] J. M. Hoover, S. S. Stahl, J. Am. Chem. Soc. 2011, 133, 16901–16910.
[36] Unfortunately, the required tert-butyl ester 6 is currently not commer-
cial and requires three steps to make starting from l-(+)-lactic acid.
[37] a) D. A. Evans, J. S. Clark, R. Metternich, V. J. Novack, G. S. Sheppard, J.
Am. Chem. Soc. 1990, 112, 866–868; b) D. A. Evans, H. P. Ng, J. S. Clark,
D. L. Rieger, Tetrahedron 1992, 48, 2127–2142.
[38] D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. Soc. 1988, 110,
3560–3578.
[39] I. Fleming, T. W. Newton, F. Roessler, J. Chem. Soc. Perkin Trans. 1 1981,
2527–2532.
[51] a) A. Fꢀrstner, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc. 1999, 121,
9453–9454; b) A. Fꢀrstner, C. Mathes, C. W. Lehmann, Chem. Eur. J.
2001, 7, 5299–5317.
[52] Some representative results are specified in the Supporting Informa-
tion.
[53] Although propynylation at this stage adds one step to the longest
linear sequence, this timing proved better than introduction of the
alkyne on the arene prior to esterification, because the steric hindrance
of the iodide is essential for selective saponification of the distal acetate
and hence exclusive formation of phenol 43.
[40] For a previous application to total syntheses by our group, see: A.
Fꢀrstner, E. Kattnig, O. Lepage, J. Am. Chem. Soc. 2006, 128, 9194–9204.
[41] E. A. Ilardi, C. E. Stivala, A. Zakarian, Org. Lett. 2008, 10, 1727–1730.
[42] a) A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky, J. L. Glea-
son, J. Am. Chem. Soc. 1997, 119, 6496–6511; b) A. G. Myers, B. H. Yang,
H. Chen, J. L. Gleason, J. Am. Chem. Soc. 1994, 116, 9361–9362; c) A. G.
Myers, B. H. Yang, Org. Synth. 2000, 77, 22–28.
[43] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis 1994, 639–
666.
[54] A. Fꢀrstner, K. Nikolakis, Liebigs Ann. 1996, 2107–2113.
[55] P. Magnus, C. Lescop, Tetrahedron Lett. 2001, 42, 7193–7196.
[56] For other pertinent cases of total synthesis based on RCAM in concert
with noble metal catalysis, see ref. [30] and the following: a) S. Benson,
M.-P. Collin, A. Arlt, B. Gabor, R. Goddard, A. Fꢀrstner, Angew. Chem.
2011, 123, 8898–8903; Angew. Chem. Int. Ed. 2011, 50, 8739–8744;
b) W. Chaładaj, M. Corbet, A. Fꢀrstner, Angew. Chem. 2012, 124, 7035–
7039; Angew. Chem. Int. Ed. 2012, 51, 6929–6933; c) L. Brewitz, J. Llave-
ria, A. Yada, A. Fꢀrstner, Chem. Eur. J. 2013, 19, 4532–4537.
[57] A. Fꢀrstner, Acc. Chem. Res. 2014, in press (DOI: 10.1021/ar4001789).
[44] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769–3772.
[45] a) A. Fꢀrstner, G. Seidel, Tetrahedron 1995, 51, 11165–11176; b) for an
independent report, see: J. A. Soderquist, K. Matos, A. Rane, J. Ramos,
Tetrahedron Lett. 1995, 36, 2401–2402.
[46] G. Seidel, A. Fꢀrstner, Chem. Commun. 2012, 48, 2055–2070.
[47] E. Negishi, L. Anastasia, Chem. Rev. 2003, 103, 1979–2018.
[48] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815–3818.
[49] A. Fꢀrstner, C. Mathes, Org. Lett. 2001, 3, 221–223.
[50] In this context, the ease with which the following more flexible model
compound could be cyclized even at ambient temperature is notewor-
thy:
Received: November 22, 2013
Published online on March 3, 2014
Chem. Eur. J. 2014, 20, 4396 – 4402
www.chemeurj.org
4402
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim