Total Synthesis of Callyspongiolide, Part 2: The Ynoate Metathesis/cis-Reduction Strategy

Article abstract of DOI:10.1002/chem.201804988

The macrocyclic core of the cytotoxic marine natural product callyspongiolide (1) was forged by ring-closing alkyne metathesis (RCAM) of an ynoate precursor using a molybdenum alkylidyne complex endowed with triarylsilanolate ligands as the catalyst. This result is remarkable in view of the failed attempts documented in the literature at converting electron deficient alkynes with the aid of more classical catalysts. The subsequent Z-selective semi-reduction of the resulting cycloalkyne by hydrogenation over nickel boride required careful optimization in order to minimize overreduction and competing dehalogenation of the compound's alkenyl iodide terminus as needed for final attachment of the side chain of 1 by Sonogashira coupling. The required cyclization precursor itself was prepared via Kocienski olefination.

Full text of DOI:10.1002/chem.201804988

A Journal of
Accepted Article
Title: Total Synthesis of Callyspongiolide, Part 2 The Ynoate
Metathesis / cis-Reduction Strategy
Authors: Alois Fürstner, Bernhard Wölfl, and Guillaume Mata
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201804988
Link to VoR: http://dx.doi.org/10.1002/chem.201804988
Supported by

10.1002/chem.201804988
Chemistry - A European Journal
Total Synthesis of Callyspongiolide, Part 2:
The Ynoate Metathesis / cis-Reduction Strategy
Bernhard Wölfl, Guillaume Mata, and Alois Fürstner*
Abstract: The macrocyclic core of the cytotoxic marine natural product callyspongiolide (1) was forged by ring
closing alkyne metathesis (RCAM) of an ynoate precursor using a molybdenum alkylidyne complex endowed
with triarylsilanolate ligands as the catalyst. This result is remarkable in view of the failed attempts documented
in the literature at converting electron deficient alkynes with the aid of more classical catalysts. The subsequent
Z-selective semi-reduction of the resulting cycloalkyne by hydrogenation over nickel boride required careful
optimization in order to minimize overreduction and competing dehalogenation of the compound’s alkenyl
iodide terminus as needed for final attachment of the side chain of 1 by Sonogashira coupling. The required
cyclization precursor itself was prepared via Kocienski olefination.
Introduction
The marine macrolide callyspongiolide (1) encodes promising biological activity in a rather unique molecular
framework.[1] Most notably, the compound’s high cytotoxicity against different human cancer cell lines seems to
be the result of a caspase-independent and hence probably non-apoptotic mode of action. Three independent
total syntheses of this target were reported to date,[2,3,4,5] which corrected the absolute configuration originally
attributed to the macrolide core of 1 by the isolation team and firmly established the configuration of the C21
chiral center in the side chain, which had defied unambiguous assignment before.[1]
For our longstanding interest in bioactive marine natural products,[6] we wished to develop an independent
access route to this promising lead compound. As reported in the accompanying paper,[7] our approach had
originally predicated on the formation of the macrocyclic ring by ring closing alkyne metathesis (RCAM)[8,9] at the
C10-C11 bond followed by trans-reduction of the cycloalkyne primarily formed (D  C  A) (Scheme 1).
Whereas the metathesis step worked nicely, the projected trans-addition of R3EH (E = Sn, Si) was
unsatisfactory,[10,11] most likely because the methyl branches adjacent to the triple bond in C prevent reactive
encounter of the sterically hindered substrate with the required bulky [Cp*Ru]-based catalyst (Cp* =
pentamethylcyclopentadienyl).[12]
*
B. Wölfl, Dr. G. Mata, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
Supporting Information for this article can be found on the WWW under ###################
1
This article is protected by copyright. All rights reserved.

10.1002/chem.201804988
Chemistry - A European Journal
Scheme 1. Two approaches to callyspongiolide based on RCAM followed by semi-reduction; R = generic protecting group; X
= halide; the bent drawing of the alkyne units throughout this paper is for convenience only and has no physical meaning
Confronted with this impasse, the synthesis blueprint was adjusted such that the Z-configured enoate became
the strategic site of disconnection (Scheme 1). This structural motif might be formed by RCAM of an alkynoate
precursor followed by ordinary Lindlar-type reduction (F  E  A). While the second step of this approach was
deemed fairly safe in view of the plethora of canonical Z-selective semi-hydrogenation reactions (and synthetic
equivalents thereof) known in the literature,[13,14] the projected ring closure of an ynoate derivative actually bore
considerable risk. The very few attempted metathesis reactions to substrates of this type using the classical
Schrock catalyst [(tBuO)3WCC(Me3)] had invariably failed.[ 15 , 16 ] Only after the advent of molybdenum
2
This article is protected by copyright. All rights reserved.

10.1002/chem.201804988
Chemistry - A European Journal
alkylidynes endowed with triarylsilanolate ligands as a new generation of catalysts with a largely improved
application profile[17,18] became ynoate ring closure possible. The few recorded examples, however, are hardly
more than proof-of-concept as they led to entirely unstrained and basically unfunctionalized macrocycles;[19,20]
despite the lack of any serious molecular constraints in these model studies, cyclodimerization infringed with the
formation of a 14-membered ring.[19] Yet, the risk associated with the plan to forge the equally 14-membered
core of callyspongiolide by ynoate ring closure/semi-reduction was offset by the opportunity to explore a
frontier of alkyne metathesis while trying to establish a productive route to this important lead compound. Since
this study had been initiated before the absolute stereochemistry of callyspongiolide was corrected, we targeted
ent-1 as the structure originally proposed by the isolation team.[1] Adaptation to the natural series, however,
would meet no difficulty.
Results and Discussion
Preparation of the Building Blocks. Based on ample experience with the Kocienski variant of the Julia olefination
as late-stage maneuver in total synthesis,[21,22,23] we resorted to this reaction for the formation of the C10C11
double bond; moreover, this step has precedent in the total syntheses of 1 reported by the Ye and the Gosh
groups.[2,3] The preparation of the required sulfone 10 commenced with the mono-silylation of but-2-en-1,4-diol
(2), which gave good results on scale when carried out at low temperature (Scheme 2). Sharpless epoxidation of
the resulting product furnished compound 3 (93% ee),[24,25] which underwent a highly selective hydroxy-directed
ring opening with MeMgBr/CuI to give multigram quantities of diol 4 in excellent yield.[25]
Scheme 2. a) TBSCl, NaH, THF, 69%; b) Ti(OiPr)4 (24 mol%), L-(+)-diethyl tartrate (30 mol%), tBuOOH, CH2Cl2,
20°C, 88% (93% ee); c) MeMgBr, CuI (30 mol%), Et2O/THF, 20°C, 91%; d) MeOC6H4CH(OMe)2, PPTS (10 mol%),
CH2Cl2, 85%; e) TBAF, THF, 88%; f) (COCl)2, DMSO, Et3N, CH2Cl2, 78°C; g) H3CC(=O)C(=N2)P(=O)(OMe)2, NaOMe,
THF, 78°C  50°C, 74% (over both steps); h) Bu3SnH, AIBN, benzene, reflux, 84% (E:Z = 8:1); i) Dibal-H, CH2Cl2,
0°C, 68%; j) I2, CH2Cl2, 0°C  RT, 94%; k) 1-phenyl-1H-tetrazole-5-thiol, DEAD, PPh3, quant.; l) aq. H2O2,
3
This article is protected by copyright. All rights reserved.

10.1002/chem.201804988
Chemistry - A European Journal
(NH4)6Mo7O24 (50 mol%), EtOH, 72%; DEAD = diethyl azodicarboxylate; PPTS = pyridinium p-toluenesulfonate;
TBAF = tetra-n-butylammonium fluoride; TBS = tert-butyldimethylsilyl
The derived p-methoxybenzylidene acetal was readily transformed into aldehyde 5, which proved rather
sensitive and epimerization-prone.[26] Although 5 could be elaborated via Takai olefination[27,28] into an adequate
alkenyl iodide, as necessary for the later attachment of the side chain of callyspongiolide, this reaction required
a large excess of CrCl2; moreover, the subsequent reductive acetal opening with Dibal-H to give the targeted
compound 8 also proved surprisingly troublesome. Therefore we pursued an alternative route to this compound,
in which aldehyde 5 was first transformed into the corresponding terminal alkyne 6 on treatment with
Bestmann-Ohira reagent[29] which had to be preactivated with NaOMe prior to addition of the aldehyde to avoid
epimerization.[30,31] The alkenylstannane formed by hydrostannation of alkyne 6 under free radical conditions
underwent reductive opening of the p-methoxybenzylidene acetal ring to give the desired regioisomer 7 as the
major product in appreciable yield.[32] Since the subsequent tin/iodine exchange also worked well, this detour
was clearly the more practical and scalable route to compound 8. Two routine steps then sufficed to complete
the synthesis of sulfone 10 as necessary for fragment coupling.
Scheme 3. a) O2, [Cu(MeCN)4]BF4 (5 mol%), 2,2’-bipyridine (5 mol%), TEMPO, NMI, MeCN, 97%; b) CBr4, PPh3,
CH2Cl2, 92%; c) LiBH4, MeOH, Et2O, 97%; d) TBSOTf, 2,6-lutidine, CH2Cl2, 98%; e) nBuLi, MeI, THF, 78°C  RT,
96%; f) HFpyridine, pyridine, THF, 63% (77% brsm); g) (COCl)2, DMSO, iPr2NEt, CH2Cl2, 78°C; h) 10, LiHMDS,
DMF, 78°C, 57% (E/Z = 15:1); i) DDQ, CH2Cl2, phosphate buffer (pH 7.4), 63%; j) 2-butynoic acid, DIC, DMAP,
CH2Cl2, 87%; DDQ = 2,3-dichloro-5,6-dicyanobenzoquinone; DIC = N.N’-diisopropylcarbodiimide; DMAP = 4-
(dimethylamino)pryridine; LiHMDS = lithium hexamethyldisilazide; TEMPO = 2,2,6,6-tetramethylpiperidin-1-oxyl
radical; Tf = trifluoromethanesulfonyl
4
This article is protected by copyright. All rights reserved.

10.1002/chem.201804988
Chemistry - A European Journal
The required aldehyde partner was attained by adaptation of a fragment synthesis described in the
accompanying paper.[7] To this end, the readily available butyrolactone derivative 12 was subjected to Stahl
oxidation[33] and the resulting aldehyde transformed into dibromoolefin 13 by standard means (Scheme 3).[34]
Reduction of the lactone moiety, persilylation of the resulting diol, and treatment of compound 14 thus formed
with nBuLi/MeI afforded alkyne 15 in good yield. Not unexpectedly, however, the selective cleavage of the
primary TBS-ether in 15 proved delicate and was best accomplished with HFpyridine in THF/pyridine by
stopping the reaction prior to full conversion in order to minimize global desilylation (although the resulting diol
can be recycled, if necessary). The crude aldehyde derived from 16 by Swern oxidation[35] was subjected to the
Kocienski olefination without delay.[21,22] Careful optimization of the reaction conditions showed the use of
LiHMDS as the base and DMF as the solvent to be optimal; for the sake of robustness and yield, a slight excess of
the lithiated sulfone 10 (1.45-1.5 equiv.) was used, which could be largely recovered after work-up. Under these
conditions, the olefination was clean and well reproducible, furnishing alkene 17 with high selectivity for the
required E-isomer (57%, E/Z = 15:1). Oxidative cleavage of the PMB-group[36] under buffered conditions followed
by DIC-mediated esterification of the resulting secondary alcohol with 2-butynoic acid furnished diyne 18 in
readiness for macrocyclization.
Ynoate Metathesis and Completion of the Total Synthesis. Despite the largely missing precedent for alkyne
metathesis reactions of ynoates in general (vide supra), treatment of compound 18 with the molybdenum
alkylidyne complex 22 resulted in fast, clean and essentially quantitative ring closure at ambient temperature
when carried out in the presence of molecular sieves (5 Å) to scavenge the released 2-butyne;[17] the desired
cycloalkyne 19 was isolated in analytically pure form in 96% yield (Scheme 4). This remarkable outcome further
attests to the maturity that alkyne metathesis has reached in recent years as well as to the excellent application
profile of this class of alkyne metathesis catalysts previously developed in our laboratory.[17,18] Moreover, the
ease of formation of 19 shows that metathesis of ynoates and related electron deficient substrates certainly
warrants more detailed investigation.
The remarkable chemoselectivity of catalyst 22, which activates triple bonds under mild conditions but leaves
alkenes of all sorts untouched, is best appreciated when compared with the application profile of the standard
reagents or catalysts used for the semi-reduction of alkynes.[14] Compound 19 is a particularly stringent test
because of possible overreduction at three different sites and the daunting cleavage of the CI bond at the
alkenyl iodide terminus.[37] In fact, an initial survey quickly showed that standard Lindlar hydrogenation,[38] the
use of activated zinc dust,[39,40] and even reduction over nickel boride[41] all furnished product mixtures
comprising appreciable amounts of the corresponding dehalogenated product (up to 18% by HPLC/MS).[42]
Focusing on the use of nickel boride (generated from Ni(OAc)24H2O, NaBH4 and ethylenediamine),[41] as the
arguably most promising starting point,[37,43] the evolution of the product distribution was monitored with time.
These control experiments showed that overreduction and deiodination rapidly increased once the alkyne was
5
This article is protected by copyright. All rights reserved.

10.1002/chem.201804988
Chemistry - A European Journal
consumed; the amount of added ethylenediamine, in contrast, had little effect on the outcome. This differential
reactivity suggested that addition of an adequate sacrificial alkene to the mixture might allow the problem to be
remedied. While the use of excess cyclohexene failed to give a better product ratio, iodoacrylate 23 as a proper
mimic of the actual substrate proved effective: in its presence (3 equiv.), dehalogenation as well as
overreduction of the precious cycloalkyne 19 were reliably reduced to as little as  4% and  12% (NMR),
respectively; importantly, no increase in deiodination of the desired product 20 was noticed on prolonged
stirring (HPLC/MS). Since 20 was easily separated from all other organic components, this protocol was deemed
a practical solution for an otherwise hardly manageable selectivity problem.
Scheme 4. a) 22 (15 mol%), toluene, MS 5Å, RT, 96%; b) Ni(OAc)24H2O, NaBH4, ethylenediamine, H2, 23, EtOH,
0°C  RT; c) camphorsulfonic acid, CH2Cl2/MeOH; d) chlorosulfonyl isocyanate, CH2Cl2, then aq. THF, 76% (over
three steps); e) 24, Pd(PPh3)4 (10 mol%), CuI, iPr2NEt, THF, 80%; Ar = p-methoxyphenyl
With a robust access to 20 secured, the total synthesis of callyspongiolide was completed by cleavage of the
remaining TBS-ether and installation of the conspicuous carbamate functionality.[44,45] In the final step the side
chain was attached via Sonogashira coupling[46,47] of 21 with alkyne 24, for which an efficient asymmetric
synthesis is outlined in the accompanying paper.[7] The analytical and spectral data of our synthetic samples of
callyspongiolide were in excellent accord with those reported in the literature,[1-4] except that we had been
misled at the outset of our project by the mis-assigned absolute configuration in the original report to pursue
the non-natural enantiomer ent-1.[1]
6
This article is protected by copyright. All rights reserved.

10.1002/chem.201804988
Chemistry - A European Journal
Conclusions
A project that had originally intended to merely establish an efficient entry into the cytotoxic marine macrolide
callyspongiolide gradually turned into a much broader investigation into scope and limitations of contemporary
alkyne metathesis and relevant downstream chemistry. Overall, the status of RCAM was found highly
satisfactory in that this transformation allowed the macrocyclic ring of the target to be closed with similar
efficiency at either the C2-C3 or the C10C11 site. In this context it is of note that this study provides the first
convincing illustration that even complex ynoates succumb to productive alkyne metathesis, a transformation
that had previously met with failure using the classical alkyne metathesis catalysts.[15,16] This favorable outcome
nicely illustrates the excellent performance of the latest generation of molybdenum alkylidyne complexes
endowed with triarylsilanolate ligands.[17,18]
The maturity of alkyne metathesis manifest in these examples stands in certain contrast to the difficulties
encountered during the subsequent semi-reduction of the cycloalkyne products thus formed. The emerging field
of ruthenium catalyzed trans-addition chemistry as a gateway to E-alkenes, though successfully used in the
context of natural product synthesis on many occasions,[11,48] obviously finds an important limitation when it
comes to applications to sterically hindered triple bonds. Even the stereo-complementary formation of Z-alkenes
by canonical Lindlar-type reduction, however, still faces considerable and in part unsolved problems when
polyfunctional substrates need to be addressed.[14] Although these challenges were ultimately mastered and a
robust entry into callyspongiolide was established, this total synthesis project revealed significant gaps in
methodological coverage and inspires investigations into better catalysts for stereoselective alkyne semi-
reduction.[49] Work along these lines is underway in our laboratory.
Experimental Section
All experimental details can be found in the Supporting Information. The material includes compound
characterization data and copies of spectra of new compounds.
Acknowledgements
Generous financial support by the Swiss National Science Foundation (fellowship to G. M.) and the MPG is
gratefully acknowledged. We thank the analytical departments of our Institute for excellent support.
7
This article is protected by copyright. All rights reserved.

10.1002/chem.201804988
Chemistry - A European Journal
For the Table of Contents
First of its kind: Alkynes as electron deficient as ynoates had basically defied productive metathesis
for decades; the latest generation of molybdenum alkylidynes, however, now allowed ynoate
metathesis to be used as the corner stone of a productive entry into the marine macrolide
callyspongiolide, which shows promising cytotoxic properties.
Keywords: alkyne metathesis  macrolides  molybdenum alkylidynes  natural products  total
synthesis
8
This article is protected by copyright. All rights reserved.

10.1002/chem.201804988
Chemistry - A European Journal
1
C.-D. Pham, R. Hartmann, P. Bohler, B. Stork, S. Wesselborg, W. Lin, D. Lai, P. Proksch, Org. Lett.
2014, 16, 266-269.
2
3
J. Zhou, B. Gao, Z. Xu, T. Ye, J. Am. Chem. Soc. 2016, 138, 6948-6951.
a) A. K. Ghosh, L. A. Kassekert, Org. Lett. 2016, 18, 3274-3277; b) A. K. Ghosh. L. A. Kassekert, J.
D. Bungard, Org. Biomol. Chem. 2016, 14, 11357-11370.
4
5
F. Manoni, C. Rumo, L. Li, P. G. Haran, J. Am. Chem. Soc. 2018, 140, 1280-1284.
For studies towards callyspongiolide, see: a) A. Athe, A. Sharma, K. Marumudi, S. Ghosh, Org.
Biomol. Chem. 2016, 14, 6769-6779; b) E. Matousova, P. Koukal, B. Formanek, M. Kotera, Org.
Lett. 2016, 18, 5656-5659; c) G. Reddy Ramidi, J. S. Yadav, D. K. Mohapadra, Tetrahedron Lett.
2018, 59, 3579-3582.
6
For our most recent contributions, see ref. [23a] and the following: a) M. Heinrich, J. J. Murphy,
M. K. Ilg, A. Letort, J. Flasz, P. Philipps, A. Fürstner Angew. Chem. Int. Ed. 2018, 57, 13575-13581;
Angew. Chem. 2018, 130, 13763-13769; b) C.-X. Zhuo, A. Fürstner, J. Am. Chem. Soc. 2018, 140,
10514-10523; c) A. Ahlers, T. de Haro, B. Gabor, A. Fürstner, Angew. Chem. Int. Ed. 2016, 55,
1406-1411; Angew. Chem. 2016, 128, 1428-1433.
7
8
9
G. Mata, B. Wölfl, A. Fürstner, accompanying paper in this issue.
A. Fürstner, Angew. Chem. Int. Ed. 2013, 52, 2794-2819; Angew. Chem. 2013, 125, 2860-2887.
For recent applications of RCAM to natural product synthesis reported by other groups, see the
following for leading references: a) K. J. Ralston, H. C. Ramstadius, R. C. Brewster, H. S. Niblock,
A. N. Hulme, Angew. Chem. Int. Ed. 2015, 54, 7086-7090; Angew. Chem. 2015, 127, 7192-
7196;b) L.-D. Guo, X.-Z. Huang, S.-P. Luo, W.-S. Cao, Y.-P. Ruan, J.-L. Ye, P.-Q. Huang, Angew.
Chem. Int. Ed. 2016, 55, 4064-4068; Angew. Chem. 2016, 128, 4132-4136; c) G. Herstad, P. P.
Molesworth, C. M. Miller, T. Benneche, M. A. Tius, Tetrahedron 2016, 72, 2084-2093; d) R. K.
Boeckman, H. Wang, K. W. Rugg, N. E. Genung, K. Chen, T. R. Ryder, Org. Lett. 2016, 18, 6136-
6139; e) J. Burnley, W. R. Jackson, A. J. Robinson, J. Org. Chem. 2015, 80, 9057-9063; f) C. M.
Neuhaus, M. Liniger, M. Stieger, K.-H. Altmann, Angew. Chem. Int. Ed. 2013, 52, 5866-5870;
Angew. Chem. 2013, 125, 5978-5983.
10
11
12
B. M. Trost, Z. T. Ball, J. Am. Chem. Soc. 2005, 127, 17644-17655.
T. G. Frihed, A. Fürstner, Bull. Chem. Soc. Jpn. 2016, 89, 135-160.
a) S. M. Rummelt, K. Radkowski, D.-A. Roşca, A. Fürstner, J. Am. Chem. Soc. 2015, 137, 5506-
5519; b) D.-A. Roşca, K. Radkowski, L. M. Wolf, M. Wagh, R. Goddard, W. Thiel, A. Fürstner, J.
Am. Chem. Soc. 2017, 139, 2443-2455; c) S. M. Rummelt, A. Fürstner, Angew. Chem. Int. Ed.
2014, 53, 3626-3630; Angew. Chem. 2014, 126, 3700-3704.
9
This article is protected by copyright. All rights reserved.

10.1002/chem.201804988
Chemistry - A European Journal
13
a) A. M. Kluwer, C. J. Elsevier, in Handbook of Homogeneous Hydrogenation (Eds.: J. G. de Vries,
C. J. Elsevier) Vol. 1, Wiley-VCH, Weinheim, 2007, pp. 375-411; b) H.-U. Blaser, A. Schnyder, H.
Steiner, F. Rössler, P. Baumeister, in Handbook of Heterogeneous Catalysis (Eds.: G. Ertl, H.
Knözinger, F. Schüth, J. Weitkamp,), 2nd ed., Vol. 7, Wiley-VCH, Weinheim, 2008, pp. 3284-3308;
c) P. N. Rylander, Hydrogenation Methods; Academic Press, London, 1985.
C. Oger, L. Balas, T. Durand, J.-M. Galano, Chem. Rev. 2013, 113, 1313-1350.
A. Fürstner, O. Guth, A. Rumbo, G. Seidel, J. Am. Chem. Soc. 1999, 121, 11108-11113.
A. Gollner, K.-H. Altmann, J. Gertsch, J. Mulzer, Chem. Eur. J. 2009, 15, 5979-5997.
J. Heppekausen, R. Stade, R. Goddard, A. Fürstner, J. Am. Chem. Soc. 2010, 132, 11045-11057.
a) J. Heppekausen, R. Stade, A. Kondoh, G. Seidel, R. Goddard, A. Fürstner, Chem. Eur. J. 2012,
18, 10281-10299; b) S. Schaubach, K. Gebauer, F. Ungeheuer, L. Hoffmeister, M. K. Ilg, C. Wirtz,
A. Fürstner, Chem. Eur. J. 2016, 22, 8494-8507; c) R. Lhermet, A. Fürstner, Chem. Eur. J. 2014, 20,
13188-13193.
14
15
16
17
18
19
20
P. Persich, J. Llaveria, R. Lhermet, T. de Haro, R. Stade, A. Kondoh, A. Fürstner, Chem. Eur. J.
2013, 19, 13047-13058.
For a related RCAM of a 2-en-4-ynoate, see: S. Schaubach, K. Michigami, A. Fürstner, Synthesis
2017, 49, 202-208.
21
22
23
P. R. Blakemore, W. J. Cole, P. J. Kocieński, A. Morley, Synlett 1998, 26-28.
C. Aïssa, Eur. J. Org. Chem. 2009, 1831-1844.
For advanced applications from our group, see: a) F. Anderl, S. Größl, C. Wirtz, A. Fürstner,
Angew. Chem. Int. Ed. 2018, 57, 10712-10717; Angew. Chem. 2018, 130, 10872-10877; b) A.
Fürstner, M. Albert, J. Mlynarski, M. Matheu, E. DeClercq, J. Am. Chem. Soc. 2003, 125, 13132-
13142; c) A. Fürstner, C. Aïssa, C. Chevrier, F. Teplý, C. Nevado, M. Tremblay, Angew. Chem. Int.
Ed. 2006, 45, 5832-5837; Angew. Chem. 2006, 118, 5964-5969; d) A. Fürstner, S. Flügge, O.
Larionov, Y. Takahashi, T. Kubota, J. Kobayashi, Chem. Eur. J. 2009, 15, 4011-4029; e) A. Fürstner,
F. Feyen, H. Prinz, H. Waldmann, Tetrahedron 2004, 60, 9543-9558.
24
25
26
N. Bhunia, B. Das, Synthesis 2015, 47, 1499-1509.
A. W. Eppley, N. I. Totah, Tetrahedron 1997, 53, 16545-16552.
I. Shiina, M. Hashizume, Y. Yamai, H. Oshiumi, T. Shimazaki, Y. Takasuna, R. Ibuka, Chem. Eur. J.
2005, 11, 6601-6608.
27
28
29
K. Takai, Org. React. 2004, 64, 253-612.
A. Fürstner, Chem. Rev. 1999, 99, 991-1045.
S. Müller, B. Liepold, G. J. Roth, H. J. Bestmann, Synlett 1996, 521-522.
10
This article is protected by copyright. All rights reserved.

10.1002/chem.201804988
Chemistry - A European Journal
30
K. C. Nicolaou, K. C. Fylaktakidou, H. Monenschein, Y. Li, B. Weyershausen, H. J. Mitchell, H. Wei,
P. Guntupalli, D. Hepworth, K. Sugita, J. Am. Chem. Soc. 2003, 125, 15433-15442.
J. Willwacher, A. Fürstner, Angew. Chem. Int. Ed. 2014, 53, 4217-4221; Angew. Chem. 2014, 126,
4301-4305.
31
32
For a close precedent, see: W. P. D. Goldring, G. Pattenden, S. L. Rimmington, Tetrahedron 2009,
65, 6670-6681.
33
34
35
36
37
J. M. Hoover, S. S. Stahl, J. Am. Chem. Soc. 2011, 133, 16901-16910.
E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769-3772.
T. T. Tidwell, Org. React. 1990, 39, 297-572.
K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa, O. Yonemtisu, Tetrahedron 1986, 42, 3021-3028.
For a report describing the cis-reduction of an alkyne with nickel boride without touching an
alkenyl iodide, see: X. Zhang, J. Liu, X. Sun, Y. Du, Tetrahedron 2013, 69, 1553-1558.
H. Lindlar, R. Dubuis, Org. Synth. 1966, 46, 89-91.
38
39
40
41
42
W. Boland, N. Schroer, C. Sieler, M. Feigel, Helv. Chim. Acta 1987, 70, 1025-1040.
J. Willwacher, B. Heggen, C. Wirtz, W. Thiel, A. Fürstner, Chem. Eur. J. 2015, 21, 10416-10430.
C. A. Brown, V. K. Ahuja, J. Org. Chem. 1973, 38, 2226-2230.
Reductive decomplexation of a dicobalthexacarbonyl complex failed; for the method, see: T.
Goto, D. Urabe, K. Masuda, Y. Isobe, M. Arita, M. Inoue, J. Org. Chem. 2015, 80, 7713-7726.
For previous applications of nickel boride to the semi-reduction of cycloalkynes formed by
RCAM, see: a) A. F. Kyle, P. Jakubec, D. M. Cockfield, E. Cleator, J. Skidmore, D. J. Dixon, Chem.
Commun. 2011, 47, 10037-10039; b) V. Hickmann, A. Kondoh, B. Gabor, M. Alcarazo, A.
Fürstner, J. Am. Chem. Soc. 2011, 133, 13471-13480; c) K. Lehr, A. Fürstner, Tetrahedron 2012,
68, 7695-7700.
43
44
45
P. Kočovský, Tetrahedron Lett. 1986, 27, 5521-5524.
a) D. Mailhol, J. Willwacher, N. Kausch-Busies, E. E. Rubitski, Z. Sobol, M. Schuler, M.-H. Lam, S.
Musto, F. Loganzo, A. Maderna, A. Fürstner, J. Am. Chem. Soc. 2014, 136, 15719-15729; b) J.
Willwacher, N. Kausch-Busies, A. Fürstner, Angew. Chem. Int. Ed. 2012, 51, 12041-12046;
Angew. Chem. 2012, 124, 12207-12212.
46
K. Sonogashira, in Metal-catalyzed Cross-coupling Reactions (Eds.: F. Diederich, P. J. Stang),
Wiley-VCH, Weinheim, 1998, pp. 203-229.
47
48
R. Chinchilla, C. Najera, Chem. Soc. Rev. 2011, 40, 5084-5121.
For recent examples from our laboratory, see: a) M. Fuchs, A. Fürstner, Angew. Chem. Int. Ed.
2015, 54, 3978-3982; Angew. Chem. 2015, 127, 4050-4054; b) S. M. Rummelt, J. Preindl, H.
Sommer, A. Fürstner, Angew. Chem. Int. End. 2015, 54, 6241-6245; Angew. Chem. 2015, 127,
11
This article is protected by copyright. All rights reserved.

10.1002/chem.201804988
Chemistry - A European Journal
6339-6343; c) H. Sommer, A. Fürstner, Org. Lett. 2016, 18, 3210-3213; d) H. Sommer, J. Y.
Hamilton, A. Fürstner, Angew. Chem. Int. Ed. 2017, 56, 6161-6165; Angew. Chem. 2017, 129,
6257-6261; e) H. Sommer, A. Fürstner, Chem. Eur. J. 2017, 23, 558-562; f) Y. Kwon, S. Schulthoff,
Q. M. Dao, C. Wirtz, A. Fürstner, Chem. Eur. J. 2018, 24, 109-114; g) X. Mo, A. Letort, D.-A. Roşca,
K. Higashida, A. Fürstner, Chem. Eur. J. 2018, 24, 9667-9674; h) Z. Meng, L. Souillart, B. Monks,
N. Huwyler, J. Herrmann, R. Müller, J. Org. Chem. 2018, 83, 6977-6994.
49
For an advance in terms of mechanistic understanding, see: A. Guthertz, M. Leutzsch, L. M. Wolf,
P. Gupta, S. M. Rummelt, R. Goddard, C. Farès, W. Thiel, A. Fürstner, J. Am. Chem. Soc. 2018,
140, 3156-3168.
12
This article is protected by copyright. All rights reserved.