DOI: 10.1002/cctc.201801201
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Reviews

Very Important Paper

Generation of Gold(I) Carbenes by Retro-Buchner Reaction:
From Cyclopropanes to Natural Products Synthesis
´
Mauro Mato,[a, b] Cristina Garcıa-Morales,[a, b] and Antonio M. Echavarren*[a, b]

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The gold(I)-catalyzed retro-Buchner (decarbenation, retrocyclopropanation) reaction of 7-substituted cycloheptatrienes has
emerged as a safe and powerful alternative for the generation
of gold(I) carbenes. These carbenes can cyclopropanate alkenes,
take part in intramolecular reactions, or engage in higher

cycloadditions with different partners, giving rise to a wide
range of relevant structures. This review covers the developments made on the generation of gold(I) carbenes via
decarbenation reactions, and the applications of these reactions
in organic synthesis.

1. Introduction

spectroscopically and structurally characterized.[8,9] These recent
findings have provided new insight into the electronic structure
of the AuÀC bond in these key gold(I) intermediates. Ultimately,
experimental and theoretical work has shown that the nature
of gold(I) carbenes is better accounted for as a continuum that
ranges from metal-stabilized singlet carbenes to metal-coordinated carbocations.[6c,7]
Gold(I) carbenes can be generated through different
methods in catalytic transformations (Scheme 2). Among these

Over the past two decades, homogeneous gold(I) catalysis has
arisen as one of the most powerful tools for the construction of
molecular complexity. Since its dawn in 1998, when a
groundbreaking report on the gold(I)-catalyzed hydration of
alkynes was published,[1] gold catalysis became a hot topic in
organic chemistry. Due to its p-Lewis acidity, cationic gold(I)
complexes have been extensively used to selectively activate p
CÀC bonds, especially alkynes, triggering chemical transformations that give rise to complex structures that are difficult to
access by other means, in an atom-economic fashion.[2] The
total synthesis of biologically relevant products stands out
among the applications that have been found for these new
methodologies based on homogeneous gold catalysis.[3]
Many gold(I)-catalyzed transformations have been proposed
to proceed via highly electrophilic cationic gold(I) carbenes as
intermediates (Scheme 1).[2,4,5] Despite the importance of these

Scheme 1. Carbocation and carbene resonance forms used to describe gold
(I) carbenes. L = phosphines, phosphites or NHC carbene ligands among
others.

intermediates, their structure is somewhat controversial and
has been interpreted by different authors as gold(I)-stabilized
carbocations or gold(I) carbenes (Scheme 1).[6,7] The extension
of the p-backbonding interaction, which is at the core of the
discussion, influences the relative contributions of the carbene
and the carbocation resonance forms, and therefore, the
reactivity of these electrophilic species. These different interpretations can be understood because it was not until recently
that examples of well-defined cationic gold(I) carbenes were

Scheme 2. General methods for the catalytic generation of gold(I) carbenes.

strategies, the cycloisomerization of 1,n-enynes has attracted
special attention to the synthetic community, and has been
extensively explored in many different contexts.[2f,h,j,10]
Other examples include the cycloaddition of diene-allenes
to form gold vinylidene intermediates,[11] the 1,2-acyloxy
migration of propargylic carboxylates or ethers,[12] and the
nucleophilic addition of N-oxides or sulfoxides to electrophilic
(h2-alkyne)gold(I) complexes.[13,14] In addition to reactions involving alkynes, transformations based on gold(I)-catalyzed decomposition of diazocompounds,[5,15] and opening of cyclopropenes[16] have also been proposed to form these highly
electrophilic species.
Driven by the high interest of the scientific community on
the plethora of transformations that are proposed to take place

[a] M. Mato, C. García-Morales, Prof. Dr. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ)
Barcelona Institute of Science and Technology (BIST)
Av. Països Catalans 16
43007 Tarragona (Spain)
E-mail: aechavarren@iciq.es
[b] M. Mato, C. García-Morales, Prof. Dr. A. M. Echavarren
Departament de Química Analítica i Química Orgànica
Universitat Rovira i Virgili
C/Marcel·li Domingo s/n
43007 Tarragona (Spain)
This manuscript is part of the Anniversary Issue in celebration of 10 years of
ChemCatchem.

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through metal carbene intermediates, great efforts have been
made to generate them in an efficient manner. In spite of this
fact, most strategies present limitations, such as lack of generality (very specific substrates are employed, such as 1,n-enynes),
the requirement of potentially undesired functional groups that
end up in the reaction products, or the preparation and
handling of potentially dangerous materials, such as diazo
compounds.
In 2008, Chen and coworkers observed for the first time the
formation and reactivity of a gold carbene via retro-cyclopropanation in gas phase, using electrospray ionization tandem
mass spectroscopy.[17,18] Two years later, our group reported the
first formation of gold(I) carbenes in solution via retro-cyclopropanation reaction.[19] Soon after, based on this initial finding,
a general methodology for the cyclopropanation of olefins
based on the retro-Buchner reaction of 7-aryl-1,3,5-cycloheptatrienes was developed.[20] This retro-cyclopropanation (decarbenation) process represents a safe and general way of generating
gold(I) carbenes without the need of introducing stabilizing or
undesired functional groups.
Following these initial results, a wide range of synthetic
methodologies were developed based on the generation of
gold(I) carbenes by retro-cyclopropanation. In this review, we

cover the different transformations that were discovered over
the past 10 years through the generation of gold(I) carbenes
via retro-cyclopropanation, especially using the retro-Buchner
reaction of 7-substituted cycloheptatrienes.

2. Historical Perspective
2.1. The Buchner Ring Expansion
The Buchner ring expansion is the reaction of a diazo
compound, originally ethyl diazoacetate (1), with an arene,
such as benzene, to form a cycloheptatriene (Scheme 3). This

Scheme 3. Buchner ring expansion of benzene.

Mauro Mato was born in Ferrol (Spain) in
1993. He completed his B.Sc. in Chemistry at
˜
the University of A Coruna in 2016, and his
M.Sc. on Synthesis, Catalysis, and Molecular
Design at the Rovira i Virgili University
(Tarragona, Spain) in 2017, receiving in both
degrees the Extraordinary Award (best academic record of each year). Then he started
his Ph.D. studies under the supervision of Prof.
Antonio M. Echavarren at the Institute of
Chemical Research of Catalonia (ICIQ), where
he works on new methods for the generation
of metal carbenes.

the Institute of Organic Chemistry of the CSIC
in Madrid. In 1992 he returned to the UAM as
a Professor of Organic Chemistry and in 2004
he moved to Tarragona as a Group Leader at
the Institute of Chemical Research of Catalonia
(ICIQ). He has been Liebig Lecturer (Organic
Division, German Chemical Society, 2006),
Abbot Lecturer in Organic Chemistry (University of Illinois at Urbana-Campaign, 2009),
Schulich Visiting Professor (Technion, Haifa,
2011), Sir Robert Robinson Distinguished Lecturer (University of Liverpool, 2011), Novartis
Lecturer in Organic Chemistry (Massachusetts
Institute of Technology, 2015) and Kurt Alder
Lecturer 2017 (University of Cologne). In 2012
he got a European Research Council Advanced
Grant. Prof. Echavarren is a member of the
International Advisory Board of Organic &
Biomolecular Chemistry, Chemical Society Reviews, Advanced Synthesis and Catalysis, and
Organic Letters, member of the Editorial Board
of Chemistry European Journal, and Associate
Editor of Chemical Communications. He is a
Fellow of the Royal Society of Chemistry. He
received the 2004 Janssen-Cylag Award in
Organic Chemistry and the 2010 Gold Medal
of the Royal Spanish Chemical Society and an
Arthur C. Cope Scholar Award from the ACS.
He is the President of the Spanish Royal
Society of Chemistry (RSEQ).

´
Cristina Garcıa-Morales was born in Moguer
(Huelva, Spain) in 1990. After a one-year
period as an Erasmus student at Strathclyde
University (Glasgow, United Kingdom), she
received her B.S. degree in Chemistry from
Universidad de Huelva (Huelva, Spain) in 2013.
After earning her MSc at the Universitat Rovira
i Virgili (Tarragona, Spain) she has been a PhD
student in the group of Prof. Antonio M.
Echavarren at the Institute of Chemical Research of Catalonia (ICIQ), where she works on
enantioselective gold(I) catalysis and the characterization of highly reactive gold(I) carbenes.
Prof. Dr Antonio M. Echavarren was born in
Bilbao (Spain) and received his PhD at the
´
Universidad Autonoma de Madrid (UAM, 1982)
˜
with Prof. Francisco Farina. After a postdoctoral stay in Boston College with Prof. T. Ross
Kelly, he joined the UAM as an Assistant
Professor. Following a two years period as a
NATO-fellow with Prof. John K. Stille in Fort
Collins (Colorado State University), he joined

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reaction was first reported by Eduard Buchner (not to be
¨
confused with Ernst Buchner, the industrial chemist that
¨
invented the Buchner funnel)[21] and Theodor Curtius, in 1885.[22]
The original reaction involves first a thermal or photochemical
decomposition of the diazo compound generating a free
carbene (2) while nitrogen is released. This carbene can
cyclopropanate benzene giving a norcaradiene derivative (3),
which undergoes a 6-electron disrotatory electrocyclic opening
to form a cycloheptatriene (4).
Nowadays, the aforementioned harsh thermal or photochemical conditions are usually avoided, and instead, metalbased catalytic systems are employed, using mainly copper or
rhodium complexes.[23] The use of this strategy allows for an
excellent control of the regioselectivity during the carbene
addition, resulting in the exclusive formation of the kinetic nonconjugated 7-substituted-1,3,5-cycloheptatriene.[22c,23]
The Buchner reaction has found different applications in
synthesis over the years.[24] An excellent example was reported
by Mander and coworkers, who used a rhodium-catalyzed
Buchner ring expansion to accomplish the total synthesis of
(+)-hainanolidol and (+)-harringtonolide, two diterpenoids that
display a tropone ring in their skeleton (Scheme 4).[25]

The position of this equilibrium is largely dictated by the
nature of the substituents on the different positions of the
cycloheptatriene or norcaradiene ring. Thus, for example, while
simple 1,3,5-cycloheptatriene 7 is almost exclusively in the CHT
form under standard conditions, the introduction of two CN
groups at the 7-position gives rise to a thermodynamically
stable norcaradiene (8).[30b] The nature of the different substituents also determines the geometry of cycloheptatrienes,
which is usually non-planar and undergoes interconversion
between two boat conformations. On the other hand, the ion
that results from the abstraction of a hydride from 1,3,5cycloheptatriene, the tropylium cation, is a planar, 6p electronaromatic species that forms stable salts with different counteranions.[31] These salts, especially tropylium tetrafluoroborate (9),
are easily prepared[32] and can be used to synthesize cycloheptatriene derivatives (Scheme 6).[33] The reaction of tropylium

Scheme 6. Preparation and general reactivity of tropylium tetrafluoroborate.

tetrafluoroborate with carbon-based nucleophiles such as
enolates of acetylketones or malonate esters,[34] inorganic
cyanides,[35] or organometallic reagents[20] gives easy access to a
wide range of non-conjugated 7-substituted-1,3,5-cycloheptatrienes.

Scheme 4. Buchner reaction for the total synthesis of harringtonolide.

2.3. First Examples of the Generation of Carbenes from
Cycloheptatrienes
2.2. Cycloheptatrienes and its Valence Tautomerism
Previous to our discovery of the gold(I)-catalyzed retro-Buchner
reaction, there were very few examples in which carbenes were
released from cycloheptatriene or norcaradiene derivatives.
Thus, it was shown in 1973 that 1,2,4,5,6,7-hexamethyltricyclo
[3.2.0.02,4]hept-6-ene 10, which is in equilibrium with its
norcaradiene tautomer 11, reacts in the presence of [Rh(CO)2
Cl]2 to give hexamethylbenzene quantitatively (Scheme 7).[36]

1,3,5-Cycloheptatriene (CHT) is an organic compound that has
recurrently interested chemists since its first preparations from
tropine or from cycloheptanone more than 100 years ago.[26]
Even though cycloheptatrienes have found some uses in
organic synthesis,[27] photochemistry,[28] and as ligands in
coordination chemistry,[29] one of the main appeals to the
scientific community has been the study of their valence
tautomerism. Monocyclic cycloheptatrienes are in equilibrium
with their corresponding norcaradiene (NCD) tautomers,
through a thermally allowed disrotatory electrocyclic ring
opening (Scheme 5).[30]

Scheme 7. Rh-catalyzed retro-cyclopropanation releasing hexamethylbenzene.

The carbene released on this process could be trapped to some
extent with cyclohexene. Other less methylated substrates were
unsuccessful in affording the corresponding arene, and the
possibility of using the released methylene carbene in any kind
of synthetically useful manner was not clear by the time.

Scheme 5. The cycloheptatrieneÀnorcaradiene equilibrium.

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Twenty years later, as part of a study on the palladium(II)promoted isomerization of 7-substituted 1,3,5-cycloheptatrienes via hydrogen-shift, it was found that the treatment of 7ethoxycarbonyl-1,3,5-cycloheptatriene (12) with 1 equiv. of
Pd(OAc)2 gave ring-contraction products (13 and 14), along
with isomerization products of the starting cycloheptatriene
(16).[37] Interestingly, it was possible to detect traces (4 % yield)
of diethyl maleate 15, a product that could have presumably
been formed by the dimerization of the released palladium
carbene (Scheme 8).

3. Generation of Gold(I) Carbenes by
Retro-Cyclopropanation
3.1. Gold(I)-Carbenes by Retro-Buchner Reaction
In 2010, when we were studying the cycloisomerization of
phenyl-linked 1,6-enynes (18), our group discovered a high
yielding synthesis of naphthalenes (19) through an annulation/
fragmentation process, together with the formation of 20, a
product containing two arylcyclopropane rings (Scheme 10).[19]

Scheme 8. Different products detected after the treatment of 12 with
Pd(OAc)2.

Additionally, Gassman and Johnson reported in 1976 the
cleavage of cyclopropanes to form metal carbenes with low
efficiency by using highly electrophilic PhWCl3/RAlCl2 (R = Et,
Cl), demonstrating the possibility of carrying out a cyclopropane–olefin cross-metathesis.[38] Furthermore, it was also
possible to carry out a retro-cyclopropanation of highly strained
bicyclo[1.1.0]butanes with Ni(0) or Rh(I) via oxidative addition
reactions.[39]
Without the need of transition metals, free carbenes could
also be generated by retro-cyclopropanation of phenanthrene
derivatives such as 17 under photochemical conditions
(Scheme 9).[40]

Scheme 10. Synthesis of naphthalenes by annulationÀfragmentation of
phenyl-linked 1,6-enynes. Structure of the two cationic phosphine complexes
usually employed in the gold(I)-catalyzed retro-Buchner reaction.

Scheme 9. Generation of carbenes from phenanthrene derivatives under
photochemical conditions.

Scheme 11. Annulation–fragmentation mechanism of 1,6-enynes. [LAuL’] + = A.

This retro-cyclopropanation reaction resembles a special
case of a retro-Buchner process, in which the starting cycloheptatriene derivative is fused to two aromatic rings (17),
releasing phenanthrene instead of a simple arene. These
reactions have been further studied recently by other groups,
using both experimental and theoretical methods.[41] However,
the difficulty of the preparation of this type of phenanthrene
derivatives makes this way of generating carbenes impractical
for its application in organic synthesis. It was not until
homogeneous gold(I) catalysis came into play that the generation of carbenes via retro-Buchner reaction could be applied
in the development of new useful synthetic methodologies.

These results are consistent with a mechanism proceeding
through a 6-endo-dig cyclization of the 1,6-enyne promoted by
gold to form cyclopropyl gold(I) carbene 21 (Scheme 11),
followed by a 1,2-H shift to form alkenyl gold(I) complex 22,
which after protodeauration is in equilibrium with 23.[19] This
intermediate, which can also be considered as a benzo-fused
electron-rich norcaradiene, then undergoes a retro-cyclopropanation process, releasing the main reaction product
(naphthalene 19) and aryl gold(I) carbene 24. The free gold(I)
carbene 24 may then cyclopropanate another unit of 23,
delivering the corresponding biscyclopropane.
This mechanism was further supported by the synthesis and
isolation of metal-free intermediate 23 and its treatment with
5 mol % of cationic gold(I) complex [(JohnPhos)Au(MeCN)]SbF6,

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3.2. Gold(I)-Carbenes by Retro-Cyclopropanation in Gas
Phase
In an effort to gain insight into the nature of benzylidene gold
(I) species, Chen and coworkers reported characterization of
[(IMes)AuCHPh] + in the gas phase.[17] This cationic species was
generated from a phosphonium ylide complex (25) as a suitable
gold(I) carbene precursor via collision-induced dissociation of
PPh3 (Scheme 12). To complete the structural assignment, they
investigated the reactivity displayed by this species in the
presence of alkenes, demonstrating that 26 presents a typical
metallocarbene behavior by promoting cyclopropanation, alkene loss and, even more interestingly, “cyclopropane metathesis”.
To further understand the three reaction pathways, the
group of Chen prepared a family of p-substituted gold
benzylidene complexes, [(IMes)AuCHAr] + (Ar = p-XC6H4, where
X = OMe, Me, Ph, F, H, Cl, Br, CO2Me, CF3, CN, SO2Me) in gas
phase.[43] Experimental data, kinetic studies, and DFT calculations supported that the open chain species 28 was a common
intermediate for all the processes (Scheme 13).[44] Complex 28
can further undergo cyclopropane ring-closing, generating
stable (h2-cyclopropane)gold(I) complexes (29). The cyclopropane dissociation from 29 only took place upon collision
activation and, in fact, this step was found to be rate
determining of the cyclopropanation reaction. Instead of
releasing cyclopropane, after collision activation, complex 29
can return to open-chain intermediate 28, from which two
different events can occur. First, it can revert to the initial
adduct 30 that can further release the initial alkene. Alternatively, ring closing leading to the formation of a metallacyclobutane species 32 can take place. After a few internal
rearrangements, a new gold(I) carbene 33 is generated
together with an alkene resulting from a formal alkene metathesis reaction. To be more precise, the authors named this
process “cyclopropane metathesis” and represents the first
example of the generation of gold(I) carbenes via gold(I)promoted retro-cyclopropanation in the gas-phase. The socalled “cyclopropane metathesis” resembles the gold(I)-catalyzed retrocyclopropanation that takes place in the retroBuchner reaction reported by our group (Scheme 10).[19] In the
following years, both the groups of Chen and Gronert
demonstrated that the same reactivity patterns were displayed
by gold(I) benzylidenes bearing other ancillary ligands.[45]

Scheme 13. Mechanisms proposed for the three reaction pathways found
for benzylidene gold(I) complexes in gas phase.

Scheme 12. Generation and reactivity of aryl gold(I) carbene 26 in gas
phase.

giving 45 % yield of naphthalene 19 and 38 % yield of
biscyclopropane 23.[19] These results demonstrated, for the first
time, the feasibility of generating gold(I) carbenes in solution
from cycloheptatriene/norcaradiene derivatives. Furthermore, in
2015, Hashmi and coworkers reported a rearrangement of
diynes to give naphthalenes, which presumably proceeds
though a cycloisomerization phase, an alkyl migration, and
finally a decarbenation (retro-Buchner) of a benzo-fused
norcaradiene.[42]

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3.3. Alternative Methods for the Generation of Aryl Gold(I)
Carbenes in Solution
Carbenoids are species structurally related to metallocarbenes.
More precisely, they contain a sp3 carbon bound both to a
metal and to a leaving group (Scheme 14).[7a,46] After removal of
the leaving group, a formal metallocarbene is generated, which
can transfer the carbene moiety onto a substrate.
The first examples of gold(I) carbenoids were reported
30 years ago.[47] At that time, it was shown that carbenoids
were able to take part on typical metal carbene reactions upon

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4. Cyclopropanation via Retro-Buchner
Reaction of Cycloheptatrienes
4.1. Cyclopropanation with Aryl Gold(I) Carbenes
Scheme 14. Structural relationship between metal carbenoids and metal
carbenes. L = ligand.

Cyclopropanes have attracted much attention from the
scientific community, not only because of its applications as
reactive intermediates in synthetic chemistry,[50] but also
because they can be found in many biologically relevant natural
or synthetic products.[51] Cyclopropanes are often prepared by
trapping carbenes with alkenes, using different transition
metals as catalysts, including gold.[52]
In 2011, our group reported a general method for the
cyclopropanation of styrenes and stilbenes via gold(I)-catalyzed
generation of carbenes by retro-Buchner reaction of 7-aryl1,3,5-cyclohepatrienes (Table 1).[20]

release of the leaving group in solution. Since then, the studies
regarding these species have been mainly focused on complexes of the type [LAuCH2X] and their reactivity.[48]
As descried in the previous section, Chen developed a
strategy to generate [LAuCHAr] + carbenes in gas-phase based
on the loss of PPh3 from their [LAuCHArPPh3] + counterparts
(Scheme 12).[17,43,44,45] To transfer this approach to solution, they
installed a SO2-imidazolylidene moiety as leaving group, which
undergoes thermal dissociation to release SO2 gas and
imidazolylidene (Scheme 15).[49] Following this methodology,

Table 1. Selected examples of the aryl-cyclopropanation reaction. a The cis
or endo diastereoisomer was obtained as major product.

Scheme 15. Stoichiometric cyclopropanation of p-methoxystyrene with gold
(I) carbene precursors. DIPP = 2,6-diisopropylphenyl.

they prepared a family of complexes bearing NHC and
JohnPhos ligands. The formation of aryl gold(I) carbenes from
these precursors was tested in the presence of p-methoxystyrene at 120 8C. The expected cyclopropanes (as cis and trans
mixtures in different ratios) were obtained, supporting the
formation of carbene intermediates at high temperatures.
In 2017, as part of a study on chloromethyl gold(I)
carbenoids, our group reported the preparation of a chlorobenzyl gold(I) complex bearing JohnPhos as ligand (36).[48] Upon
chloride abstraction with TMSOTf at 25 8C, the carbenoid was
completely consumed through a bimolecular coupling generating cis- and trans-stilbene together with 1,2,3-triphenylcyclopropane, which arises from the cyclopropanation of the previously
formed alkenes (Scheme 16).

A variety of substituents are tolerated in both the aryl
cycloheptatriene and in the alkene. This provides an access to
1,2,3-trisubstitued cyclopropanes, which are not easily prepared
by other methods. When styrenes are employed, poor to good
diastereoselectivities can be achieved favoring the cis product
in most cases.
Additionally, it was possible to perform the same cyclopropanation intramolecularly, giving the expected cyclopropylindane 37 in quantitative yield, exclusively as the exo
diastereoisomer (Scheme 17, upper reaction).[20] Using a related
substrate (Scheme 17, bottom reaction), 8 % yield of intramolecular C(sp3)ÀH insertion product of the corresponding aryl
gold(I) carbene was observed (38) under the same reaction
conditions.
In regards to the starting substrates, a wide range of 7-aryl1,3,5-cycloheptatrienes can be easily prepared by reaction of
Grignard (ArMgBr) or organolithium reagents (ArLi) with
commercially
available
tropylium
tetrafluoroborate
(Scheme 18).[33]

Scheme 16. Activation of aryl gold(I) carbenoids with TMSOTf in solution.

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Table 2. Representative scope of the vinyl cyclopropanation of styrenes
and other related activated alkenes.

Scheme 17. Intramolecular cyclopropanation and CÀH insertion.

Scheme 18. Procedure for the synthesis of 7-aryl- or 7-styrylcycloheptatrienes.

4.2. Cyclopropanation with Vinyl Gold(I) Carbenes
The mechanism of this transformation was studied both
experimentally and computationally, giving rise to a consistent
stereochemical model for the cyclopropanation, in which pÀp
stabilizing interactions lead to cis diastereoselectivity (Figure 1).
The reaction starts by the retro-Buchner reaction of the
norcaradiene, which involves the cleavage of the two CÀC
bonds in complex II. The cleavage of the first CÀC bond to give
cationic TSII-III is the rate-limiting step of the reaction. The
cyclopropanation of styrene by carbene V proceeds through an
asynchronous concerted mechanism, with an energy difference
of 3.1 kcal · molÀ1 favoring the cis cyclopropane over the trans
product. This difference can be partially attributed to the
electronic non-covalent pÀp stabilizing interactions in the cisTS(VIa-VIIa) and its absence in the trans-TS(VIa-VIIa).

Among all cyclopropanes, vinylcyclopropanes are of special
interest because of their rich downstream chemistry,[50] undergoing rearrangements to cyclopentenes, cycloadditions, and
other metal-catalyzed transformations.[53] They are also common motifs in natural products and active pharmaceuticals.[54]
Although some 7-styryl-1,3,5-cycloheptatrienes can be prepared using tropylium tetrafluoroborate as shown in
Scheme 18, a more reliable and general method is based on the
use of the Julia-Kocienski olefination employing sulfone 39
(Scheme 19).[55]

Scheme 19. Synthesis of 7-vinyl-1,3,5-cycloheptatrienes by Julia-Kocienski
olefination.

5. Higher Cycloadditions of Gold(I) Carbenes
via Retro-Buchner Reaction

Sulfone 39 can be prepared in multi-gram scale and stored
indefinitely. Treatment of this reagent with LiHMDS followed by
the addition of commercially available aldehydes or ketones
allows the synthesis of a wide range of 7-vinyl and 7-styryl1,3,5-cycloheptatrienes, which can be also employed to generate gold(I) carbenes by retro-Buchner reaction (Table 2).[55]
In the presence of 5 mol % of a cationic gold complex such
as [(tBuXPhos)Au(MeCN)]SbF6, these substrates undergo a
retro-Buchner reaction at 75 8C releasing benzene and generating vinyl or styryl gold(I) carbenes that can cyclopropanate
styrenes and other related activated alkenes, such as indenes,
chromenes, or N-vinylphthalimides. This reaction generally
proceeds efficiently and with good diastereocontrol, favoring
the formation of the corresponding cis-vinylcyclopropanes
(Table 2).[55]

5.1. Formal (4 + 1) Cycloaddition of Methylenecyclopropanes
and Cyclobutenes with Aryl Gold(I) Carbenes

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Apart from (2 + 1) cyclopropanations of alkenes, it was found
that gold(I) carbenes generated by retro-Buchner reaction can
engage in higher cycloadditions with different unsaturated
partners.
In 2014, we reported that 7-aryl-1,3,5-cycloheptatrienes and
methylenecyclopropanes[56] react under gold(I) catalysis to give
arylcyclopentenes (Table 3).[57]
A range of aryl groups can be efficiently transferred in the
carbene fragment using down to only 1 mol % of [(JohnPhos)
Au(MeCN)]SbF6 in up to 0.5 g scale. Not only aryl methylenecyclopropanes can be employed, but also alkyl methylenecyclo-

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Figure 1. Calculated energies for the gold(I)-catalyzed retro-Buchner reaction and cyclopropanation. Energies in kcal·molÀ1. M06/6-31G(d)/M06/6-311 + G(2d,p)
(C, H, N, O, P) and SDD (Au) levels of theory, using JohnPhos as the phosphine ligand and SMD = dichloromethane for solvent effects. For specific details on
the computational study, see the original publication.[55]

Table 3. Representative scope of the (4 + 1) cycloaddition of gold(I)
carbenes with methylenecyclopropanes.

Scheme 20. Proposed mechanism for the formal (4 + 1) cycloaddition.
[LAuL’] + = gold complex A.

pathway to the one occurring in the gas phase for the
cyclopropanation/retro-cyclopropanation of enol ethers with
gold(I) carbenes reported by Chen and coworkers.[17] The
mechanism of this triple gold(I)-catalyzed transformation was
further investigated computationally by another group, obtaining results consistent with the experimental observations.[59]
The hypothesis that cyclobutenes are indeed intermediates
in this process was confirmed by the development of a similar
methodology, under the same reaction conditions, but using
cyclobutenes instead of methylenecyclopropanes (Table 4).[57]
Not only monosubstituted cyclobutenes could be employed, but also trisubstituted ones, allowing further expanding
the scope of the (4 + 1) cycloaddition obtaining cyclopentenes
with different substituents in good yields.

propanes were tolerated, although in these cases, mixtures of
regioisomers ranging from 1.5 : 1 to 10 : 1 were obtained.[57]
This formal (4 + 1) cycloaddition proceeds via triple gold(I)
catalysis. The first steps involve a metal-catalyzed isomerization
of methylenecyclopropanes to cyclobutenes, a ring-expansion
process that had been reported before using Pt(II) or Pd(II)[58]
(Scheme 20, left cycle).
The second part is the gold(I)-catalyzed retro-Buchner
reaction to generate aryl gold(I) carbene 40, which reacts with
the cyclobutene to form bicyclo[2.1.0]pentane-gold(I) complex
41 (Scheme 20, right cycle). Opening of the cyclopropane leads
to a cationic intermediate (42) that further evolves by 1,2-H
shift to give the reaction product after deauration. The cyclopropanation of the cyclobutene probably follows a similar
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Table 4. Representative scope of the (4 + 1) cycloaddition of gold(I)
carbenes with cyclobutenes.

Scheme 22. Intramolecular (4 + 1) cycloaddition and preparation of polyarene fragments. [LAuL’] + = [(IPr)Au(PhCN)]SbF6 (5 mol %).

Au(MeCN)]SbF6 gives rise to a very wide range of highly
substituted indenes in moderate to good yields.[62] The reaction
is general and tolerates substituents of different nature in the
transferred aryl moiety, or even different aromatic units such as
naphthalenes or phenanthrenes. Different alkyl substituents can
be introduced by using different allene derivatives. Employing
cyclic allenes is especially interesting since they afford spirocyclic indene structures difficult to access by other methods
(Table 5).
In a similar manner, 7-styryl-1,3,5-cycloheptatrienes reacted
with allenes at 100 8C in the presence of 5 mol % of [(tBuXPhos)
Au(MeCN)]SbF6 through a formal (3 + 2) cycloaddition giving
rise to highly substituted cyclopentadienes (Table 6).[62] Cyclopentadienes are relevant substrates, mainly as reactive diene
components in the Diels–Alder reaction and as ligands in
organometallic chemistry.[65] A range of highly substituted
cyclopentadienes could be accessed, including both electronpoor and electron-rich aryl derivatives. As in the case of
indenes, this methodology proves to be suitable for the
synthesis of spirocyclic structures.
The proposed mechanism for these two transformations
takes place in a very similar fashion.[62] In both cases, the first
step is the gold(I)-catalyzed retro-Buchner reaction of the

Cyclobutenes can be prepared by a gold(I)-catalyzed [2 + 2]
cycloaddition reaction of alkynes with alkenes.[60] By optimizing
the reaction conditions, it was possible to combine both
processes and develop a one-pot [2 + 2]–(4 + 1) sequence. This
strategy allowed obtaining complex structures in a single
reaction flask from very simple substrates: a cycloheptatriene,
an alkyne, and an alkene, using 10 mol % of [(JohnPhos)
Au(MeCN)]SbF6 as the only catalyst (Scheme 21).[61]

Scheme 21. One pot [2 + 2]–(4 + 1) sequential cycloadditions.

An intramolecular version of the (4 + 1) cycloaddition of an
aryl gold(I) carbene with a methylenecyclopropane starting
from substrate 44 was also developed, giving access to a
polyarene fragment (45).[57] Furthermore, product 46 could be
used to prepare a bigger polyarene fragment (47) via light
induced cyclization (Scheme 22).[57]

Table 5. Selected examples of the (3 + 2) cycloaddition of aryl gold(I)
carbenes with allenes to give indenes.

5.2. Formal (3 + 2) Cycloaddition of Allenes with Aryl and
Styryl Gold(I) Carbenes
Aryl gold(I) carbenes generated by retro-Buchner reaction can
also engage in a formal (3 + 2) cycloaddition with allenes to
give rise to indenes.[62] Indenes are important motifs present in
many relevant natural products,[63] and are also used as building
blocks for organic synthesis or organometallic chemistry.[64]
The reaction of 7-aryl-1,3,5-cycloheptrienes with 1,1-dialkylallenes at 120 8C in the presence of 5 mol % of [(JohnPhos)
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clic double bond of 50 with concomitant deauration would
directly furnish the indene.
In the case of the synthesis of cyclopentadienes
(Scheme 23, bottom cycle), cyclization of 53 would give 54,
which is finally isomerized to the corresponding product. Using
short reaction times, it is possible to isolate and characterize
intermediates 54 by GCÀMS and 1H NMR, further confirming
the proposed reaction pathway.

6. Intramolecular Reactivity of Gold(I)
Carbenes and Further Transformations
6.1. Intramolecular Synthesis of Indenes and Fluorenes
Right after the discovery of the aryl-cyclopropanation through
gold(I) carbenes via retro-Buchner reaction, our group developed a range of transformations involving intramolecular
reactivity of different substrates, based mainly in FriedelÀCraftstype trapping of the carbene intermediates.[66] This led to two
general methodologies to synthesize indenes and fluorenes,
allowing access to a rich variety of structures that arise from
different modifications of the starting substrates.
In the presence of 5 mol % of [(tBuXPhos)Au(MeCN)]SbF6,
substrates such as 55 undergo a retro-Buchner reaction,
generating gold(I) carbenes 56 that can react intramolecularly
with the alkenes to give carbocationic intermediates such as
57, which further evolve via 1,2-H shift to form indenes
(Scheme 24).
This transformation was shown to be suitable for the
preparation of a variety of substituted indenes (Table 7).

Scheme 23. Mechanistic proposal for the (3 + 2) cycloaddition of aryl or
styryl gold(I) carbenes with allenes. [LAuL’] + = A or B (5 mol %).

corresponding aryl or styryl cycloheptatriene to release carbenes 48 or 52, respectively (Scheme 23). Each carbene undergoes electrophilic attack at the central carbon atom of the
allenes to give allyl cationic species 49 and 53. In the first case
(for the indene synthesis, Scheme 23, upper cycle), intramolecular electrophilic aromatic substitution gives intermediate
50, which can undergo rearomatization and protonolysis of the
AuÀC bond to form 51 which after isomerization gives the
corresponding indene. Alternatively, protonation of the exocy-

Scheme 24. Proposed mechanism for the formation of indenes via retroBucher reaction.

Table 7. Selected examples of the intramolecular synthesis of indenes.

Table 6. Selected examples of the (3 + 2) cycloaddition of styryl gold(I)
carbenes with allenes to give cyclopentadienes.

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In contrast, when a cis stilbene was employed as starting
substrate (58) under the same reaction conditions, we observed
an intramolecular Buchner ring expansion.[66] Presumably, as a
result of the proximity of the phenyl ring to the gold carbene in
intermediate 59, an intramolecular Buchner reaction occurs
followed, giving 60, which undergoes a disrotatory norcaradiene-to-cycloheptatriene opening and a 1,5-H shift, furnishing
cycloheptatriene 61 (Scheme 25).

Scheme 27. Proposed mechanism for the formation of fluorenes. [LAuL’] + = A (5 mol %).

Table 8. Selected examples of the intramolecular synthesis of fluorenes.

Scheme 25. Intramolecular retro-BuchnerÀBuchner reaction sequence.

Following this approach, it was possible to shed more light
into the mechanism of the gold(I)-catalyzed synthesis of
naphtalenes via annulationÀfragmentation of phenyl-linked 1,6enynes, that was previously discussed in Scheme 11.[19] Thus,
when diene 62 was heated to 120 8C in the presence of 5 mol %
of [(JohnPhos)Au(MeCN)]SbF6 catalyst, it was possible to
observe the formation of both naphthalene and biscyclopropane 63.[66] This can be rationalized by a retro-Buchner reaction,
followed by an intramolecular cyclopropanation of the distal
double bond of the diene, giving tricyclic intermediate 64. This
compound can further evolve through retro-cyclopropanation
releasing naphthalene and generating a free gold(I) carbene
[LAu=CHPh] + that can cyclopropanate another unit of 64
assembling biscyclopropane 63 (Scheme 26).

Wheland intermediate 67. This cationic intermediate further
evolves through a 1,2-H shift to form a fluorene. Some
examples of the scope are highlighted in Table 8. Both electronrich and electron-poor carbene fragments could be delivered
intramolecularly. Interestingly, starting from 2-binaphthylcycloheptatriene, it was possible to obtain 7H-dibenzo[c,g]fluorene
in 67 % yield,[66] in the shortest route reported so far.[67]
Furthermore, as depicted in Scheme 28, this methodology
could be extended to a double annulation, preparing interesting structures,[66] such as indeno[1,2-b]fluorene (69) as a 4 : 1
mixture with indeno[2,1-a]fluorene in 53 % isolated yield from
68.[68]
Generally, aryl carbenes generated by pyrolysis of aryl
diazomethanes undergo formal insertion into the adjacent
ortho position of the XC6H5 ring when X=CH2 or NH, whereas
substrates with X=O or S lead to a Buchner ring expansion. In
our case, substrate 70 gave 9H-xanthene (71).[66] This is the
product of formal insertion of the gold(I) carbene into the ortho
position of the phenyl group. The resulting carbenes could also
be trapped intermolecularly with high yields using trans-

Scheme 26. Intramolecular retro-BuchnerÀBuchner reaction sequence.

When instead of a stilbene, a biphenyl unit is linked to a
cycloheptatriene (65), under gold(I) catalysis, the resulting
carbene is trapped by the second aromatic ring furnishing a
fluorene (Scheme 27[66] Both computational work and experimental evidence support that the trapping occurs via a
FriedelÀCrafts-type reaction of gold(I) carbene 66 to give
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Scheme 28. Double annulation via retro-Buchner reaction.

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bridge of the indene. Supported by DFT calculations, we
hypothesized that the intermediacy of a barbaralyl species,
generated by an initial 1,6-enyne cyclization, could be responsible for the observed reactivity (Scheme 31).[69a]

Scheme 31. Gold-catalyzed isomerization of 7-alkynyl-1,3,5-cycloheptatrienes
to indenes through a barbaralyl cation intermediate.
Scheme 29. Reactivity of o-cycloheptatrienyl phenoxybenzene.

To prove our hypothesis, the trapping by oxidation of the
gold stabilized barbaralyl cation was studied. In the presence of
gold(I) cationic complexes (bearing phosphine or NHC ligands),
under oxidative conditions, these 7-alkynyl-1,3,5-cycloheptatrienes can be cycloisomerized and trapped as barbaralones,[70]
interesting fluxional molecules that have been central to the
understanding of the phenomena of valence tautomerism.[71]
This discovery led to a straightforward synthesis of 1-substituted barbaralones from alkynes and commercially available
tropylium tetrafluoroborate (Table 9).

stilbene to give cyclopropanes such as 72 or with a 1,3diketone giving 73 (Scheme 29).

6.2. Gold(I)-Catalyzed Isomerization of 7-Alkynyl
Cycloheptatrienes: Generation of Barbaralyl Cations
In contrast to aryl or vinyl/styryl derivatives, 7-alkynyl-1,3,5cycloheptatrienes (74) undergo cycloisomerization reactions at
low temperature under gold(I) or gold(III) catalysis leading to
indenes through the generation of stabilized barbaralyl cations.[69] This is another way of generating gold carbenes in
solution from cycloheptatrienes that does not involve a
fragmentation process.
The ratio of regioisomers 75 a/75 b (Scheme 30) is sensitive
to the gold catalyst employed. Gold trichloride, cationic
phosphine-gold(I), and N-heterocyclic carbene-gold(I) complexes led to mixtures of products. However, the pyridine
carboxylate Au(III) complex employed in conditions A
(Scheme 30) gave preferentially 1-aryl-1H-indenes such as 75 a.
On the other hand, using a phosphite gold(I) complex
(Scheme 30, conditions B) led exclusively to 2-aryl-1H-indenes
like 75 b.
This catalyst-controlled regioselectivity allowed to obtain a
wide range of 1- and 2-aryl substituted 1H-indenes just by
using the appropriate gold catalysts for each case. The
formation of 1-substituted indenes involves a remarkable transformation in which the alkyne carbon atoms end up at the

Table 9. Selected examples of the gold(I)-catalyzed oxidative synthesis of
barbaralones. [LAuL’] + = [(IPr)Au(MeCN)]SbF6.

The development of this methodology also allowed to
accomplish a very short total synthesis of bullvalene 78
(another related fluxional compound) in five steps from
commercially available starting materials and 10 % overall yield
(Scheme 32).[70]

Scheme 30. Gold(III)- or gold(I)-catalyzed isomerization of 7-alkynyl-1,3,5cycloheptatrienes to indenes.

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Scheme 32. Synthesis of bullvalone (77) and bullvalene (78).

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furan was monosubstituted, 83 undergoes Z to E isomerization
to give ketone 79. Alternatively, if a 2,5-disusbtituted furan was
used, diene 83 can cyclize by a Michael-type ring closing to
afford 80.

6.3. Ring Opening of Furans with Gold(I) Carbenes Generated
by Retro-Buchner Reaction
The reactivity of gold(I) carbene intermediates with furans has
been well studied.[72] It has been shown that under homogeneous gold(I) catalysis, alkynes can react with furans to give rise
to phenols, both intramolecularly[72,73] or intermolecularly
(Scheme 33).[74]

7. Second Generation of Cycloheptatrienes
7.1. The Room Temperature Gold(I)-Catalyzed Retro-Buchner
Reaction
Despite the variety of reactivities that have been explored with
this chemistry, the gold(I)-catalyzed retro-Buchner reaction was
still limited by requiring temperatures in the range of 75–120 8C
for the decarbenation process. This complicates the development of stereoselective transformations, and makes the
methodologies involving a retro-Buchner reaction less attractive
for its application in the functionalization of complex molecules. A solution to this problem came through the design of a
new generation of more reactive cycloheptatrienes that can
undergo a retro-cyclopropanation at room temperature under
gold(I) catalysis. Previous computational work revealed that the
rate-limiting step of the decarbenation of 7-styryl-1,3,5-cycloheptatrienes was the cleavage of the first CÀC of the
corresponding norcaradiene giving a Wheland-type cationic
intermediate (see Figure 1).[55] This led to the hypothesis that
introducing electron donating groups on the cycloheptatriene
ring would lower the energy barrier for the decarbenation
process (Scheme 36).[76]

Scheme 33. Gold(I)-catalyzed intramolecular reaction of alkynes with furans.

We discovered that the electrophilic addition of gold(I)
carbenes to furans followed by ring opening results in the
formation of cyclopentenones, polyenes or polycyclic compounds.[75] These gold(I) carbenes were generated by reactions
of propargyl carboxylates or 1,6-enynes, but also from 7-aryl1,3,5-cycloheptatrienes via retro-Buchner reaction. When a 2substituted furan reacts with an aryl gold(I) carbene, an a,b,g,dunsaturated ketone (79) was formed, whereas if the furan is 2,5disubstituted, indene (80) is formed instead (Scheme 34).

Scheme 36. Working hypothesis for the design of a new generation of more
reactive cycloheptatrienes.
Scheme 34. Opening of furans with gold(I) carbenes via retro-Buchner
reaction.

This theoretical model was backed up by different experimental findings that were already mentioned in the introduction. For example, Scheme 7 shows how a hexamethylnorcardiene can undergo a rhodium-promoted retro-Buchner reaction
to release hexamethylbenzene, although the authors claimed
that lower methylated substrates (in effect, bearing less number
of electron donating groups) did not undergo this transformation.[36] Furthermore, in the synthesis of naphthalenes via
annulation–fragmentation shown in Schemes 10 and 11, intermediate 23, which undergoes an analogous gold(I)-catalyzed
decarbenation at room temperature, can be considered as an
electron-rich norcaradiene derivative. Based on this reasoning,
the synthetic route for the synthesis of 7-styryl-1,3,5-cycloheptatrienes via Julia-Kocienski olefination was adapted for the
preparation of a new generation of more reactive 7-styryl-1,3,5trimethyl-1,3,5-cycloheptatrienes. Second-generation Julia-Kocienski reagent 87 can be obtained as a stable and easy-tohandle white solid in multi-gram scale by a sequence involving

Scheme 35. Proposed mechanism for the opening of furans with gold(I)
carbenes.

Mechanistically, the reaction of the 7-aryl-1,3,5-cycloheptatriene with a cationic gold(I) catalyst generates aryl gold(I)
carbene 81 (Scheme 35).[75] The corresponding furan reacts with
the gold carbene to give rise to cationic intermediate 82, which
further evolves via ring opening, furnishing diene 83. If the
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a Rh(II)-catalyzed ring expansion of mesitylene with ethyl
diazoacetate (EDA), reduction of the ester, Mitsunobu reaction
with
1-phenyl-1H-tetrazole-5-thiol,
and
oxidation
(Scheme 37).[76]
Scheme 38. Cyclopropanation with a vinylogous styryl gold(I) carbene.

7.1. The Zinc(II)-Catalyzed Retro-Buchner Reaction
Besides allowing to overcome the requirement of high temperatures to perform the retro-Buchner reaction, this new generation of cycloheptatrienes solved other limitations of the
process. Remarkably, we discovered that these more reactive
cycloheptatrienes can undergo a decarbenation in the presence
of zinc(II) halides, using simple and cheap ZnBr2 as catalyst for
both the retro-Buchner and the cyclopropanation reaction.[76]
This finding not only allowed swapping the expensive gold
complex for a zinc halide, but also expanding the scope of the
transformation to the cyclopropanation of simple unactivated
alkenes, for which the gold(I)-catalyzed version of the reaction
generally gives poor yields (Table 11).

Scheme 37. Synthesis and reactivity of second-generation Julia-Kocienski
reagent 87.

This strategy was used to prepare a broad range of
trimethylated 7-styryl cycloheptatrienes, that undergo the
retro-BuchnerÀcyclopropanation sequence at room temperature under gold(I) catalysis.[76] The cyclopropanation of
styrenes and other activated olefins takes place in good yields,
comparable to those obtained at high temperature with the
first generation of cycloheptatrienes (Table 10).[55]

Table 11. Representative examples of the zinc(II)-catalyzed cyclopropanation of simple unactivated alkenes.

Table 10. Selected examples of the cyclopropanation at room temperature. Yield (cis/trans ratio) at 25 8C between parenthesis, and yield (cis/
trans ratio) at 75 8C with the first generation of cycloheptatrienes between
brackets.

In addition, it was also found that 1 equiv. of the chiral
Lewis acid that is formed in situ by the addition of ZnEt2 to
enantiomerically pure (R)-6,6-dibromo-BINOL can also cleanly
promote the retro-Buchner reaction of cycloheptatriene 90 at
room temperature. With this system, it was possible to cyclopropanate styrene obtaining 91 in quantitative yield, with
excellent diastereoselectivity and in a 72 : 28 ratio of enantiomers. This is the only example reported to date of an
enantioselective transformation involving the trapping of a
metal carbene generated via retro-Buchner reaction
(Scheme 39).[76]

Improved diastereoselectivities were obtained, especially
with challenging alkenes such as N-vinylphthalimide. Moreover,
when very electron-rich cycloheptatrienes were employed, it
was possible to obtain selectively the cis product at 25 8C, while
at high temperatures (75 8C), the trans one is obtained due to a
cis to trans isomerization of vinylcyclopropanes promoted by
gold that occurs especially fast for these substrates.[55] This
methodology was also applied for the late-stage functionalization of several biologically relevant complex products. Furthermore, in a similar fashion, a (E,E)-dienyl gold(I) carbene could be
generated from 88 and trapped with p-acetylstyrene giving
diene 89 (Scheme 38).[76]

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Scheme 39. Enantioselective cyclopropanation promoted by a BINOLÀZn(II)
complex.

8. The Retro-Buchner Reaction in Total
Synthesis

Scheme 40. Synthesis of spirocyclic ketone intermediates. [LAuL’] + = [(IPr)
Au(PhCN)]SbF6 (5 mol %).

8.1. Towards the Cycloaurenones and the Dysiherbols
97 a. Finally, oxidative deprotection of the methoxy groups with
cerium ammonium nitrate and 2,6-pyridinedicarboxylic acid Noxide gave quinone 98, which presents the carbon skeleton of
the cycloaurenones (Scheme 41).[62]

As a part of our program to apply new synthetic methodologies
in the synthesis of natural or biologically relevant products.[3d,77]
we designed the first approach for the assembly of the carbon
skeleton of the cycloaurenones and the dysiherbols.[62] Cycloaurenones A–C are three natural products that display a cisdecalin in their carbon skeleton, whereas dysiherbols A–C show
a trans-fused decalin (Figure 2).[78]

Scheme 41. Assembly of the cycloaurenones carbon skeleton (98).

Figure 2. Cycloaurenones A–C and dysiherbols A–C.

These compounds are biogenetically related to other
natural products isolated from sponges,[79] displaying antimicrobial, anti-HIV, anti-inflammatory, anti-proliferative, and antisecretory activities, which have attracted the interest of
synthetic chemists.[80] However, no total synthesis of any of the
cycloaurenones or dysiherbols has been reported so far.
Our approach commenced by the key (3 + 2) cycloaddition
of an aryl gold(I) carbene (generated by retro-Buchner reaction
of cycloheptatriene 92) with allene 93, based on our previously
developed methodology (see Table 5), giving spirocyclic intermediate 94 with 5 mol % of [(IPr)Au(PhCN)]SbF6.[62] Deprotection
and oxidation gave a mixture of ketones 95 a and 95 b in 33 %
yield over the three steps and in a 1 : 1 ratio (Scheme 40).
Each one of the two diastereoisomers 95 a and 95 b can be
separated and used to assembly the skeletons of the cycloaurenones or the dysiherbols, respectively. Reduction of ketone
95 a and subsequent treatment with Ph3PBr2 gave bromide
96 a. Treatment of 96 a with nBu3SnH in the presence of AIBN
triggers a radical cyclization giving 33 % of tetracyclic product
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Scheme 42. Assembly of the dysiherbols carbon skeleton (97 b).

Following the same synthetic strategy, the tetracyclic
carbon skeleton of the dysiherbols (97 b) was obtained in three
steps from intermediate 95 b (Scheme 42).[62]

8.2. Total Synthesis of Laurokamurene B
Laurokamurene B, isolated from the red algae Laurencia
okamurae, is a member of a small family of natural sesquiterpenes which display antifungal and cytotoxic activity.[81] Several
synthetic approaches towards laurokamurene B have been
reported, but the routes are relatively long considering the low

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subsequent reduction of the double bond with diimide, gave
lactobacillic acid in 90 % yield. This represents a very versatile
route, since it could potentially be used to obtain a variety of
both natural or non-natural cyclopropane-containing fatty acids
just by tuning the number or carbon atoms in the aliphatic
chains of the two terminal alkenes.[76]

9. Summary and Outlook
Scheme 43. Total synthesis of laurokamurene B.

Progress in synthetic organic chemistry relies on the discovery
of more efficient new reactions that allow transforming simple
substrates into highly complex molecules. Over the past years,
homogeneous gold(I) catalysis proved to be a powerful tool for
accomplishing such task, by the development of efficient
methodologies that proceed through the generation of highly
reactive carbenes under catalytic conditions. Nevertheless, the
generation of metal carbenes in a general and controlled
manner is still an ongoing challenge, for which metal-catalyzed
retro-cyclopropanation (decarbenation) reactions, such as the
gold(I)-catalyzed retro-Buchner reaction of cycloheptatriene
derivatives, proved to be a powerful alternative. This chemistry
represents a convenient access to aryl or styryl gold(I) carbenes,
that can be trapped efficiently by alkenes, affording cyclopropanes with a broad range of different substituents. Higher
intermolecular cycloadditions or intramolecular reactivity of
these intermediates allow to access complex and relevant
scaffolds such as indenes, fluorenes, cyclopentenes, or cyclopentadienes in a general fashion. The usefulness of these
transformations was proved by its application in total synthesis
of natural products, one of the high-end applications of organic
synthesis. Using more reactive cycloheptatrienes, these reactions can even be carried out at room temperature, and the
feasibility of generating carbenes, not only with gold, but also
with zinc was also recently been demonstrated. This finding
opens a door for the generation of other metal carbenes via
retro-Buchner reaction as an alternative to the traditional
methods based on metal-promoted decomposition of diazo
compounds.

structural complexity of this natural product.[82] Our approach
was based on a (3 + 2) cycloaddition between a styryl gold(I)
carbene and an allene (Scheme 43).[62] The reaction of potassium p-methylstyryltrifluoroborate with tropylium tetrafluoroborate (9) gives cycloheptatriene 99 in almost quantitative
yield. A formal (3 + 2) cycloaddition between 3-methylbuta-1,2diene and the styryl gold(I) carbene generated via retroBuchner reaction from 99 gave rise to cyclopentadiene 100,
which was selectively hydrogenated using Wilkinson’s catalyst
to provide laurokamurene B in 86 % yield. This synthesis of
laurokamurene B requires just three steps from commercially
available starting materials and proceeds in 39 % overall yield.

8.3. Synthesis of Cyclopropane-Containing Fatty Acids
Lactobacillic acid is one of the several cyclopropane-containing
fatty acids that have been isolated from natural sources,[83] and
have attracted the interest of many synthetic organic chemists.[84] After overcoming the reactivity issues related to low
efficiencies on the cyclopropanation of unactivated alkenes via
retro-Buchner reaction by the use of zinc(II) halides, an
straightforward route for the total synthesis of lactobacillic acid
was accomplished (Scheme 44).[76]
The zinc(II)-catalyzed retro-Buchner reaction of secondgeneration cycloheptatriene 101 allowed the diastereoselective
cyclopropanation of 1-octene, assembling the cis-cyclopropane
core of lactobacillic acid (102). A cross-metathesis between 102
and 9-decenoic acid afforded 103 as an E/Z mixture, which after

Acknowledgements
´
We thank Agencia Estatal de Investigacion (AEI)/FEDER, UE
(CTQ2016-75960-P and FPI Fellowship to C.G.M.), Severo Ochoa
Excellence Acreditation 2014–2018 (SEV-2013-0319 and FPI Predoctoral Fellowship to M.M.), the European Research Council
(Advanced Grant No. 321066), the AGAUR (2017 SGR 1257) and
CERCA Program / Generalitat de Catalunya for financial support.

Conflict of Interest
The authors declare no conflict of interest.

Scheme 44. Total synthesis of lactobacillic acid.

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Keywords: gold catalysis · retro-Buchner reaction
cyclopropanation · cycloadditions · total synthesis

·

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Manuscript received: July 24, 2018
Accepted Article published: September 1, 2018
Version of record online: October 5, 2018

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