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DOI: https://doi.org/10.24820/ark.5550190.p011.111 Page 96 ©AUTHOR(S)
The Free Internet Journal
for Organic Chemistry
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Organic Chemistry
Arkivoc 2020, part i, 96-116
Organosilanes in the synthesis of saturated heterocycles
Carlos Díez-Poza, Laura Fernández-Peña, Alberto Cherubin, Juan Lión-Villar, and Asunción Barbero*
Department of Organic Chemistry, Faculty of Science, Campus Miguel Delibes, 47011 Valladolid, Spain
Email: asuncion.barbero@uva.es
Received 11-15-2019 Accepted 01-09-2020 Published on line 05-04-2020
Abstract
This account summarizes the studies towards the synthesis of saturated heterocycles using the chemistry of
organosilanes. Two different synthetic approaches are described: a) the acid-mediated cyclization of
unsaturated silyl alcohols and b) the silyl-Prins (or silyl-aza-Prins) cyclization of silylated alkenols. The effect of
substitution on the selectivity of the annulation process is evaluated.
Keywords: Heterocycles, silyl-Prins reaction, cyclization, organosilanes, stereoselection, domino processes
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Table of Contents
1. Introduction
2. Synthesis of Oxacycles by Electrophilic Cyclization of Silyl Alkenols
2.1 Synthesis of five-membered oxacycles by hydroalkoxylation of allylsilyl alcohols
2.2 Synthesis of five-membered oxacycles by hydroalkoxylation of vinylsilyl alcohols
2.3 Synthesis of six-membered oxacycles by hydroalkoxylation of vinylsilyl alcohols
3. Synthesis of Oxacycles by silyl-Prins Cyclization
3.1 Synthesis of seven-membered oxacycles
3.2 Synthesis of eight-membered oxacycles
4. Synthesis of Azacycles by Silyl-aza-Prins Cyclization
5. Conclusion
6. Acknowledgements
References
1. Introduction
Saturated heterocycles are important scaffolds with interesting biological properties, which are present in a
wide variety of natural products. For instance, tetrahydrofurans appear in the structures of natural bioactive
molecules including squalene-derivatives with cytotoxic activity such as glabrescol,1 polyethers isolated from
the wood of Spathelia glabrescens, or amphidinolactone B,2 a macrolide isolated from the marine
dinoflagellate Amphidinium sp. Moreover, new molecules with this substructure are discovered almost every
year, like the recently described leoligin (Figure 1), a lignan isolated from the roots of edelweiss
(Leontopodium nivale spp. alpinum) possessing antiinflammatory properties and being a compound relevant
for cardiovascular disease.3
Of the many natural products containing six-membered oxacycles, 2,2,5-trisubstituted tetrahydropyrans
are especially abundant. An example is the natural malyngolide,4 an antibiotic extracted from the
cyanobacterium Lyngbya majuscula, which shows activity against Mycobacterium smegmatis and
Streptococcus pyogenes. Others are the 2,5-disubstituted rhopaloic acids A and B,5 isolated from a marine
sponge Rhopaloeides sp. which exhibit potent inhibitory activity against the embryonic development of the
starfish Asterina pectinifera or the recently isolated ecteinamycin (Figure 1),6 which has neuroprotective,
antibacterial and antimetastatic activities.
Similarly, a plethora of examples of oxepanes can be found in the structures of biologically active
compounds.7 Among them raspacionin8 is a triterpenoid isolated from the marine sponge Raspaciona
aculeata, which shows anticancer activity against the MCF-7 tumor cell line. Another example is aplysistatin
(Figure 1),9 found in algae of the genus Laurencia, which inhibits the progression of murine lymphocytic
leukemia P-388 and has antimalarial and antiinflammatory activities.10 Last in the series, oxocanes are also
present as structural elements in some natural products such as ansellone B,11 a sesterterpenoid isolated from
a sponge identified as Phorbas sp.
Regarding aza heterocycles, azepanes can be found in molecules like balanol,12 a potent PKC inhibitor
isolated from Verticillium balanolides, or ophiocordin,13 which was isolated from Cordyceps ophioglossoides
and has antifungal activity.
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Figure 1
Numerous synthetic approaches have been proposed for the synthesis of these fascinating structures.
Among them, the electrophilic cyclization of alkenols and the Prins cyclization have been recognized as some
of the most efficient ring-forming reactions.
Our group has long been devoted to the application of organosilicon compounds14 to the synthesis of
carbo- and heterocycles.15,16 In this account, we mainly intend to give an overview of our contributions to the
synthesis of different sized heterocycles through these two methodologies.
2. Synthesis of Oxacycles by Electrophilic Cyclization of Silyl Alkenols
The electrophilic cyclization of unsaturated alcohols has been found to be an efficient tool for the preparation
of different types of cyclic ethers. This procedure usually relies on the use of mercury salts,17 halogens18 and
selenium reagents19 to promote the addition to the olefin. However, only few examples have been reported
for the corresponding cyclization of alkenols mediated by either Brønsted20,21 or Lewis acids,22,23 mainly due to
associated drawbacks such as side reactions and the lack of generality.24
In this framework, we decided to develop a general approach to the synthesis of cyclic ethers of different
ring size, focussing on the use of activated alkenyl moieties (such as alkenyl silanes), which may be able to
circumvent said limitations of the alkene activation methodology. We expected that the well-known ability of
silicon to stabilize carbocations in the β-position will favour the cyclization. Accordingly, we chose two
different groups, allyl and vinyl silanes.
2.1. Synthesis of five-membered oxacycles by hydroalkoxylation of allylsilyl alcohols
The starting allylsilyl alcohols required for the study were readily prepared in two steps using self-developed
methodology of silylcupration of allene and trapping of the intermediate cuprate with α,β-unsaturated
carbonyl compounds, to produce allylsilyl aldehydes or ketones of general structure 1. Further reduction with
LiAlH4 affords a mixture of the respective allylsilyl alcohols 2 and 3 in high yields (Scheme 2).25
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Scheme 2
The acid-mediated cyclization of these allylsilyl alcohols furnishes the corresponding tetrahydrofurans 4
and 5 (Error! Reference source not found.) with both Brønsted (TsOH) and Lewis acid (AlCl3), although yields
are generally higher in the reaction with Brønsted acids.26 The stereoselectivity of the process depends on the
substitution pattern of the starting silyl alkenol. Thus, while moderate selectivity (dr up to 73:27) is obtained
with primary alcohols bearing an allylic substituent (R2≠H; R1=H) for the stereoisomer with a 2,3-trans
relationship between R2 and the silyl group, equimolar mixtures of diastereomers are obtained when using
alcohols with R2=H and R1≠H. The best stereoselectivities are observed for secondary alcohols bearing allylic
substituents (R1 and R2≠H).
Scheme 2
A plausible mechanism for this cyclization involves the initial protonation of the hydroxyl group to form an
oxonium ion, which in turn delivers the proton to the double bond anti to the silyl group. The corresponding
β-silyl carbocation thus formed (in which the C-Si bond is parallel to the empty p orbital) is then trapped by the
nucleophilic hydroxy group opposite to the silyl group. The favorable formation of stereoisomer 4 can be
rationalized by studying the two possible reactive conformations (I and II) (Scheme 3). As shown, the
unfavorable 1,3-diaxial interaction present in conformation II explains the preferred formation of isomer 4
from conformation I.
An interesting aspect to be studied in this cyclization is the influence of the nature of the silyl moiety in
the selectivity of the process. For that purpose, Hosomi27,28 and our group chose vinylsilanes as the substrates.
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Scheme 3
2.2. Synthesis of five-membered oxacycles by hydroalkoxylation of vinylsilyl alcohols
The use of less reactive nucleophiles, such as vinylsilanes, in the hydroalkoxylation cyclization implies the need
of higher temperatures for the reaction to take place. Moreover, the stereoselectivity of the ring forming
process is substantially improved when vinylsilyl alcohols are used instead of the allylsilyl derivatives.
A thorough study was performed to evaluate the effect of the substitution pattern of the starting alcohol
in the selectivity of the process.29 It was found that the presence of an allylic substituent on the vinylsilyl
alcohol was essential to obtain total stereocontrol in the cyclization (towards the 2,3-trans-disubstituted
tetrahydrofuran). In fact, the ring annulation of secondary alcohols lacking this type of substituents provide
only moderate selectivity towards the 2,3-trans-disubstituted stereoisomer. The stereocontrolled preparation
of 2,3,5-trisubstituted tetrahydropyrans was easily achieved from alcohols with both R1 and R2≠H (Scheme 4).
Scheme 4
Regarding the stereochemical outcome of the cyclization, vinylsilanes (and likewise allylsilanes) always
provide the major stereoisomer with a 2,3-trans configuration. On the basis of these experimental results,
together with DFT calculations, a preferred reactive conformation (III) has been proposed, which avoids the
unfavorable 1,3-allylic interaction shown in the alternative conformation IV. In this case, the cation formed by
addition of a proton from the oxonium ion to the double bond (IIIa) undergoes rotation about the C-C bond by
the shortest pathway in order to locate the C-Si bond parallel to the empty p orbital (IIIb) (Scheme 5).
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Scheme 5
Furthermore, the formation of tetrasubstituted tetrahydrofurans was accomplished when vinylsilyl
alcohols with β-substituted vinylsilanes are used (Scheme 6). However, the cyclization of these substrates
provides now an almost equimolar mixture of stereoisomers, probably due to competing destabilizing steric
effects.
Scheme 6
2.3. Synthesis of six-membered oxacycles by hydroalkoxylation of vinylsilyl alcohols
Due to the scarcity of examples of the synthesis of tetrahydropyrans by acid-mediated cyclization of alkenols,
we decided to take an approach using activated silyl alkenols.30 Fortunately, the reaction of these electron rich
alkenes, in the presence of p-TsOH, furnishes the desired tetrahydropyranyl derivatives in good yields. The
reaction is general for various types of substituted silylated alkenols. Moreover, a remarkable stereocontrol is
observed in this cyclization, providing a single diastereoisomer in most cases (Scheme 7).
Scheme 7
An important substituent effect was again observed for β-substituted vinylsilanes. In this case, the nature
of the substituent on the β-position turned out to play a relevant role, since β-alkyl-substituted vinylsilanes
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undergo cyclization with excellent stereoselectivity, while decreased stereocontrol was observed when the
substituent on the β-position is an aryl group (Scheme 8).
Scheme 8
Interestingly, the presence of a remaining silyl group in the oxacycle allows the possibility of further
chemical modification, which was used to prepare marine drug analogs. (Scheme 9)
Scheme 9
3. Synthesis of Oxacycles by Silyl-Prins Cyclization
Prins cyclization has proven to be a very efficient and reliable methodology for the construction of cyclic
ethers.31,32 The general accepted mechanism for this reaction involves the acid-promoted condensation of an
alkenol with an aldehyde to provide an oxocarbenium ion, which readily undergoes endo-cyclization. The
intermediate cyclic carbocation thus formed is finally trapped by a nucleophile present in the media
(frequently provided by the acid).33 A variation of the classical Prins cyclization, the silyl-Prins cyclization, has
found wide application in heterocyclic chemistry owing to multiple advantages including faster reactions,
higher selectivity of the process or lesser side reactions.34
In the silyl-Prins cyclization an electron-rich silylated alkenol is used as nucleophile in the process. The
overall mechanism is similar to the standard Prins cyclization, except for the fact that the intermediate cyclic
carbocation is now a stabilized cation β to silicon, which preferably undergoes elimination of the silyl group
(and formation of a double bond) rather than by addition of a nucleophile. For instance, this strategy has been
used by Keck in the construction of a key intermediate of cytotoxic macrolide dactylolide35 (Scheme 30). The
high stereoselectivity of this cyclization towards the formation of a single cis-2,6-disubstituted
tetrahydropyran 17 is explained by a preferred chair-like transition state in which all the substituents adopt
the minimum energy conformation.
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Scheme 30
Both strategies, Prins and silyl-Prins cyclization, have been mainly applied to the synthesis of six-
membered oxacycles and less frequently used for the construction of larger-ring heterocycles. Our research
group has recently reported the synthesis of medium-sized oxa- and azacycles by silyl-Prins cyclization of
allylsilyl alcohols.
3.1. Synthesis of seven-membered oxacycles
The synthesis of oxepanes has attracted growing attention in the international scientific community due to
their interesting structure and wide occurrence in a variety of natural products. As already mentioned,
examples of synthesis of seven-membered oxacycles by Prins or silyl-Prins cyclization are not so abundant.
Within the few attempts reported to obtain this type of heterocycles by silyl-Prins cyclization, Suginome and
Ito36 have described an approach to oxepane rings by TMSOTf mediated silyl-Prins cyclization of
enantiomerically enriched silylated alkenols and aldehydes (Scheme 11).
Scheme 11
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We decided to develop a general approach to the synthesis of oxepanes by silyl-Prins cyclization of
silylated bishomoallylic alcohols. The cyclization of these allylsilyl alcohols with aldehydes in the presence of
TMSOTf (which was the most effective catalyst) proved to be high yielding for a wide variety of vinyl and aryl
(both electron-rich and electron-deficient) aldehydes. Moreover, the reaction proceeded with excellent
diastereoselectivity to afford the all-cis trisubstituted oxepane as a single stereoisomer 22 (Scheme 12).37
Scheme 12
The high stereocontrol of this process can be explained through a mechanism involving both the
formation of a preferred E-oxocarbenium ion and a chair-like transition state (V) in which the substituents
adopt the most stable equatorial conformation (Scheme 13).
Scheme 13
We then determined to carry out a detailed study on the factors that affect the selectivity and the
outcome of the process. To understand the influence of the configuration of the starting alcohol on the
selectivity of the reaction, we initially chose allylsilyl alcohols with a trans-relationship between substituents
R1 and R2. As can be seen in Scheme 14, the silyl-Prins cyclization of alcohols 3 again proceeds under mild
conditions, providing a single diastereoisomeric oxepane 23 (Scheme 14). It should be noted that in this case
two different transition states could be drawn in which either R1 or R2 are equatorial. The formation of a
unique isomer bearing an equatorial R1 group seems to indicate that the close proximity of this group to the
reactive oxocarbenium ion accounts for this effect. These results are consistent with Houk’s calculations38
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which predict that the stereoselectivity associated with the attack of a nucleophile on an oxocarbenium ion is
controlled by the adjacent stereogenic center.
Scheme 14
To further explore this hypothesis, we chose for this cyclization alcohols with R1=H. As shown in Scheme
15, silyl-Prins cyclization of these primary alcohols give oxepanes with consistent high yields, albeit with
reduced stereoselectivity towards the cis-isomer. The lower stereocontrol observed in this case again confirms
the required presence of a stereogenic center α to the oxocarbenium ion for the nucleophilic attack of the
allylsilane to be selective. (Scheme 15)
Scheme 15
Continuing with the study of the effect of number and position of substituents on the starting silyl alkenol,
we selected alcohols where R2 is hydrogen. To our surprise, and under the same conditions, the outcome of
the process was completely different. In this case, the reaction mainly provided a new adduct, which was
shown to be dioxaspirodecane 28.39 The reaction is general for a wide variety of aldehydes (aryl, vinyl and
alkyl) although in some examples small amounts of the corresponding oxepane derivative 29 are obtained
together with the major spiro-compound (Scheme 16).
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Scheme 16
The proposed mechanism for this process is a domino Sakurai-Prins cyclization which involves an initial
Sakurai allylation. In the presence of another molecule of aldehyde, the intermediate homoallylic alkoxide
undergoes Prins cyclization providing a tetrahydropyranyl cation which is intramolecularly captured by the
hydroxyl group present in the molecule (Scheme 17).
Scheme 17
It should be noted that in this three component reaction, three new stereogenic centers have been
created with total stereocontrol (a single stereoisomer is observed). The syn relationship between
substituents at C2 and C6 is easily rationalized through a preferred chair-like transition state in which both
groups adopt the more stable equatorial conformation. However, the configuration of the spiro carbon
indicates a preferred equatorial trapping of the tetrahydropyranyl cation, a result that disagrees with Alder’s
calculation40 which predicts the axial attack of a nucleophile at a tertiary cyclic cation, obtained by Prins
cyclization, as the most favourable pathway. The only difference between our experimental results and Alder’s
calculations is that in our case the trapping is intramolecular while Alder’s theoretical calculations were done
for an intermolecular nucleophilic attack. To gain more insight into these results, we performed theoretical
studies, calculating the minimum energy of the intermediate cyclic cation and the activation energies of the
two possible pathways: the axial and the equatorial nucleophilic attack. As shown in Scheme 18, the activation
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energies of pathways a and b are rather different, which explains the favourable formation of the spirane
corresponding to the axial attack under kinetic conditions.
Scheme 18
3.2. Synthesis of eight-membered oxacycles
An even more challenging goal is the synthesis of eight-membered-ring ethers by Prins cyclization. Within the
scarce precedents in this field, Overman41 was the first to describe the preparation of oxocenes by Prins
cyclization. The reaction of 5-hexenyl acetals, mediated by Lewis acids, is highly stereoselective (a single
diastereoisomer is formed) although yields tend to be low unless the vinylic R substituent is a phenylthio
group (Scheme 19).
Scheme 19
Our research group has recently reported a general methodology for the synthesis of polysubstituted
oxocanes by silyl-Prins cyclization of silylated tris-homoallylic alcohols 30 and aldehydes.42 The reaction is
general and high-yielding for several types of aldehydes, including arylic (both electron-rich and electron-
deficient) and vinylic aldehydes. Moreover, a single cis-2,5-disubstituted oxocane 31 is obtained in every case,
which seems to indicate a preferred transition state with these two substituents in pseudo-equatorial
conformation. It should be noted that the initial silylated alcohol bears a gem-dimethyl group,43 which we
think determines the success of this cyclization (the so-called Thorpe-Ingold effect) (Scheme 20).
Pathway c
Pathway d
equatorial
axial
6.92 kcal/mol
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Scheme 20
In order to examine the effect of the allylic substituent on the reaction, we next chose a tris-homoallylic
alcohol lacking this type of substituent. As can be seen in Scheme 21, the reaction again follows a completely
different pathway, now providing dioxaspiroundecanes through a domino Sakurai-Prins cyclization.
Scheme 21
Thus, two types of reaction pathway are observed in the acid-mediated cyclization of bis- and tris-
homoallylic alcohols, depending on the substitution of the alcohol. Presumably, steric effects account for this
substitution pattern. We envisioned that, apart from steric effects, the nature of the Lewis acid may have a
great influence. Since the previous reactions were done using TMSOTf as a Lewis acid, we decided to check the
chemical behaviour of the reaction in the presence of other Lewis acids, from which BF3·OEt2 gave interesting
results. As can be seen in Scheme 22, the reaction of tris-homoallylic alcohols, lacking an allylic substituent,
with aldehydes in the presence of BF3·OEt2 selectively provides oxocanyl derivatives (none of the
corresponding dioxaspiroundecane is observed). Although this catalyst effect remains to be rationalized, the
most favourable pathway will be determined by the ease with which the Sakurai reaction (the initial step of
the domino process leading to dioxaspiroundecanes) or the formation of the oxocarbenium ion (the initial step
of the direct silyl-Prins cyclization) take place.
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Scheme 22
Contemporary with our work, Ghosh et al.44 have described an approach to the synthesis of oxocenes
through a two component Prins cyclization. Under optimized conditions (using TMSOTf in THF) they were able
to obtain 2,4,8-trisubstituted oxocenes 36 with excellent stereoselectivity to form the 2,8-cis diastereoisomer,
although in low yields unless R2 is a nitro group (Scheme 23).
Scheme 23
4. Synthesis of Azacycles by Silyl-Prins Cyclization
The synthesis of nitrogen heterocycles by Prins cyclization is called aza-Prins cyclization and is significantly less
developed than the standard methodology. The silylated version (the silyl-aza-Prins cyclization) has shown
various advantages such as allowing the use of an array of protected amines or providing more selective
reactions. Two types of protocols have been mainly used in this reaction: the two component cyclization,
which involves the acid-mediated reaction of a homoallylic amine with an aldehyde to give an intermediate
iminium cation. Subsequent 6-endo cyclization will provide a piperidinium cation, that is finally trapped by a
nucleophile present in the media. This approach has been used by Remuson45 in the synthesis of natural
alkaloid (+)-isosolenopsin A. The good diastereoselectivity observed towards the final 2,6-cis piperidine 37 was
explained through the formation of a preferred E-iminium ion intermediate and a chair like transition state of
minimum energy. However, an aza-Cope rearrangement (side reaction) seems to be responsible for the
observed racemization process (Scheme 24).
The second methodology employed in this cyclization involves the use of a single precursor, which in the
presence of the acid catalyst is transformed into the iminium ion required for the cyclization. Speckamp’s
group46 has explored this type of one-component protocol in the synthesis of 2,3-disubstituted piperidines 38.
In this approach, treatment of an α-ethoxy amide with formic acid generates the iminium ion intermediate,
which is then captured by the allylsilane (Scheme 25).
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Scheme 24
Scheme 25
As already mentioned, both Prins and silyl-Prins cyclization have been mainly applied to the synthesis of
five- or six-membered azacycles. In this context, our research group decided to study an approach to the
preparation of seven-membered azacycles by silyl-Prins cyclization.47 This type of compound occurs in both
natural and synthetic compounds with biological activity, such as the natural product ophiocordin48 (an
antifungal antibiotic isolated from submerged cultures of Cordyceps ophioglossoides) or synthetic
trihydroxyazepanes, which have demonstrated good glycosidase inhibitory potency.49
Our approach to these interesting structures started with the synthesis of the initial silylated bis-
homoallylic amines by silylcupration of allene and capture of the intermediate with enones, followed by
reductive amination. Within the numerous Lewis acids tested for this cyclization, InCl3 was found to be the
only effective catalyst for the process.50 The reaction is general and high yielding for various types of
aldehydes (both α,β-unsaturated and aromatic aldehydes). Moreover, 2,6-trans-disubstituted azepanes 40
were always the predominant stereoisomers, with selectivities ranging from moderate (80:20) to excellent
(>95:5). (Scheme 26)
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Scheme 26
The stereoselectivity of this reaction seems to be controlled by the preferential formation of a more stable
Z-iminium ion which undergoes 7-endo cyclization through a chair-like transition state with the substituents in
the minimum energy conformation (Scheme 27).
Scheme 27
5. Conclusions
This account summarizes our recent results concerning the synthesis of differently sized oxa- and azacycles
starting from organosilanes. Two different methodologies have been used to prepare these scaffolds: the acid-
mediated cyclization of silylated alkenyl alcohols and the silyl-Prins (or silyl-aza-Prins) cyclization of silyl
alkenols (or silyl alkenamines). The influence of structural factors in the stereochemistry of these processes
has been studied and mechanistic rationales have been proposed.
6. Acknowledgements
We thank the “Junta de Castilla y León” (VA294P18) for financial support. C.D.-P. acknowledges a predoctoral
Grant (Q4718001C), funded by the European Social Fund and the “Junta de Castilla y León”.
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Authors’ Biographies
Asunción Barbero was born in Burgos (Spain) and studied Chemistry at the University of Valladolid. Later, she
undertook her PhD studies at the same University (Prof. Pulido), being recognized with the Doctorate
Extraordinary Award. She then held a Marie Curie Postdoctoral Fellowship working for two years at the
University of Cambridge under the supervision of Prof. Ian Fleming in the study of stereocontrol in organic
synthesis using silicon chemistry. After returning to Valladolid, she was first appointed as Assistant Professor
and then promoted to Associate Professor (2001) and to Full Professor (2019). She has co-authored around 60
high impact scientific publications and has delivered several invited and plenary lectures in international
conferences. Her current interests include the use of organosilanes in the synthesis of carbo- and
heterocycles.
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Carlos Díez-Poza received his B.Sc. in Chemistry in 2015 and his Master’s degree in 2016 from the University of
Valladolid. Currently he is a Ph.D. student in the same University under the supervision of Prof. Asunción
Barbero. He has spent two short research stays with Prof. Opatz (University of Mainz) and Prof. D’Hooghe
(University of Ghent). He is co-author of various papers, reviews and book chapters. His research interests
include the synthesis of heterocycles by silyl-Prins cyclizations.
Laura Fernández-Peña obtained her B.Sc. in Chemistry in 2018 from the University of Valladolid and her
Master’s degree in 2019 from the Autonomous University of Madrid. At present she is a Ph.D. student at the
University of Valladolid under the supervision of Prof. Asunción Barbero working in the use of organosilanes
for the synthesis of various types of heterocycles.
Alberto Cherubin holds a Bachelor’s degree in chemistry from the University of Genova and a Master’s degree
in Chemical Science from the same University. In 2018 he moved to the University of Valladolid, starting a
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project aiming the preparation of oxacycles from alkenylsilanes under the supervision of Prof. Barbero.
Currently he is a research technician at the University of Valladolid.
Juan Lión-Villar completed his undergraduate studies in chemistry and his master’s degree at the University of
Valladolid. He then moved to the Higher Council for Scientific Research (CSIC) in Madrid where he is working
as research technician.
