Protective carbon

DOI: 10.1002/anie.201((will be filled in by the editorial staff))

“This is the peer reviewed version of the following article: Angew. Chem. Int. Ed. 2014, 53, 10416-10419, which has been published in
final form at https://doi.org/10.1002/anie.201406645. This article may be used for non-commercial purposes in accordance with Wiley
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Carbon Dioxide as a Protecting Group: Highly Efficient and Selective
Catalytic Access to Cyclic Cis-Diol Scaffolds**
Victor Laserna, Giulia Fiorani, Christopher J. Whiteoak,* Eddy Martin, Eduardo Escudero-Adán,
Arjan. W. Kleij*
Abstract: The efficient and highly selective formation of a wide range
of (hetero)cyclic cis-diol scaffolds using powerful aminotriphenolatebased metal catalysts is reported. The key intermediates are cyclic
carbonates that are derived in high yield and with high levels of
diastereo- and chemo-selectivity from the parent oxirane precursors
and carbon dioxide (CO2). Deprotection of the carbonate structures
affords synthetically useful cis-diol scaffolds with different ring sizes
incorporating various functional groups. This atom-efficient
methodology allows for simple construction of diol synthons using
cheap and accessible precursors and green metal catalysts, and
showcases the use of CO2 as a temporary protecting group.

stereochemistry (Scheme 1).[4b] We recently reported on powerful
catalyst systems based on aminotriphenolate ligands (M = Fe, Al;
Scheme 1, compounds 1-2) which showed great versatility in the
formation of both cyclic[7d,9] as well as polycarbonates.[10] Moreover,
these systems proved to be highly efficient for the catalytic turnover
of acyclic internal epoxides with ample functionality.

Carbon dioxide (CO ) represents an interesting carbon feed stock
2

for organic synthesis, having a number of attractive features being
renewable, cheap and readily available.[1] Recent progress in the area
of CO2 catalysis[2] has witnessed a spectacular increase in the
application of this C1 synthon providing access to important and
functional chemical intermediates,[3] and precursors for
(bio)renewable plastics.[4] One of the areas of high activity is the
preparation of organic carbonates from oxirane/oxetane precursors
giving rise to five- and six ring-membered cyclic structures.[5] Though
this area has been developed to a sophisticated level,[6] important
challenges remain to be resolved including the efficient conversion of
internal cyclic epoxides[7] and their selective conversion towards the
corresponding cyclic versus polycarbonate. The latter feature is
especially vital to control the stereo-chemical outcome of the reaction
as formation of the cyclic carbonate through a double inversion
pathway leads to retention of the relative configuration at both carbon
centers[8] whereas poly-carbonate formation followed by a
depolymerization/hydrolysis pathway results in opposite

[]

V. Laserna, Dr. G. Fiorani, Dr. C. J. Whiteoak, Dr. E. Martin, E.
Escudero-Adán, Prof. Dr. A. W. Kleij
Institute of Chemical Research of Catalonia (ICIQ)
Av. Països Catalans 16, 43007 – Tarragona (Spain)
Fax: (+)34-977920823
E-mail: akleij@iciq.es; chriswhiteoak@googlemail.com
Homepage: www.iciq.es
Prof. Dr. A. W. Kleij
Catalan Institute for Research and Advanced Studies (ICREA)
Pg. Lluís Companys 23, 08010 Barcelona (Spain)

[]

GF kindly acknowledges financial support from the European
Community through FP7-PEOPLE-2013-IEF project RENOVACARB
(grant agreement N°622587). ICIQ, ICREA and the Spanish
MINECO (CTQ2011-27385) are thanked for financial support. VL
thanks the Generalitat de Catalunya for an FI fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.

Scheme 1. Top: natural compounds with cyclic cis-diol scaffolds; below:
synthetic approach towards cis-diols through intermediate carbonate formation
using metal catalysts 1 and 2.

Cyclic cis-diol scaffolds are key structural elements of various
naturally occurring compounds such as ()-trihydroxyheliotridine
and Mupirocin (Scheme 1)[11] and are thus interesting synthetic
targets. One of the most well-known methods for cis-diol formation
is based on the Sharpless dihydroxylation of alkene precursors using
osmium catalysis.[12] We envisaged that the catalytic formation of
organic carbonates from cyclic oxiranes and CO2 using earthabundant and cheap metal catalysts followed by deprotection under
basic conditions could offer a useful and alternative sustainable
approach towards cyclic cis-diols.[13] Using this methodology, CO2
has a dual role acting as a temporary protecting group (TPG; Scheme
1) that helps to stir the process stereo-selectivity, and as an oxygen
source. Though various reports exist on diol formation from organic
carbonates,[14] the substrate scope to date remains limited and has
been primarily based on terminal epoxides which are relatively facile
to convert, though cyclic cis-diol formation using CO2 as a key
reagent has rarely been studied.[15] Here we present a general
approach towards functional cyclic cis-diol synthons using a versatile
catalytic strategy that allows for efficient conversion of (internal)

2

(hetero)cyclic
oxirane
substrates,
suppressing
undesired
polycarbonate formation and thus controlling the stereo-selectivity.
Further, this CO2-based methodology allows for a broad substrate
scope and good functional group tolerance, providing a wide range of
accessible and functional cis-diol scaffolds in good to excellent yields.
Our first efforts focused on the chemo-selective conversion of
some benchmark substrates including cyclopentene oxide and
cyclohexene oxide (see Table S1; 1 as catalyst, Supporting
Information) that have previously been shown to easily form
polycarbonates;[10,16] this screening stage afforded useful information
about the required reaction conditions and nature of (co)catalysts and
their loadings to achieve high and selective conversions towards the
cyclic carbonate.[17] Whereas for the conversion of cyclopentene
oxide (Table S1, entries 19) both high selectivity for the cyclic
carbonate and appreciable conversion levels were obtained at 70ºC
(entries 46), for cyclohexene oxide under similar reaction conditions
(entries 1014, 1821) high selectivity towards the (undesired)
polycarbonate was noted. Two important requisites for selective
conversion to the cyclic organic carbonates were revealed upon
further variation of the reaction medium and the relative ratio between
complex 1 or 2 and the nucleophile (NBu4Br), see entries 1517. The
use of a co-solvent (2-butanone) and relative excess of nucleophile
(NBu4X: bromide was generally found to be the best nucleophile)
suppressed multiple, alternate CO2 and/or epoxide insertions that
would lead to undesired polycarbonate formation with the opposite
stereochemistry in the carbonate unit (Scheme 1 and Table 1). Once
the reaction conditions had been optimized,[18] a series of cyclic
oxiranes were screened as substrates to form their respective bi-, triand tetracyclic organic carbonates 3a-3q (Figure 1).
We were pleased to find that the optimized reaction conditions
gave access to a wide range of organic carbonates in high yields and
selectivities using catalysts 1 or 2 and NBu4Br as nucleophile additive,
with catalyst 2 being eventually preferred.[18] In most cases, rather
mild temperatures (70ºC) could be used whereas in the synthesis of
bis-carbonate 3h (66% yield) a somewhat elevated reaction
temperature was required to achieve high conversion of both oxirane
fragments into their respective carbonates. Five-, six- and sevenmembered ring oxiranes were all smoothly converted into their
targeted products (3a-3p), whereas the eight-membered ring
carbonate 3p could only be isolated in 15% yield. This latter result
suggests that activation of larger cycloalkenyl-based epoxides is more
difficult through coordination to the Lewis acid (cf., 2) with the
nucleophilic ring-opening step[19] complicated by the presence of a
relative non-reactive conformation of the oxirane substrate. This was
further supported by using cyclooctadiene oxide as substrate
successfully furnishing carbonate 3q (63%): the presence of a double
bond in the backbone is sufficient to result in significantly higher
conversion and yield of the cyclic carbonate, and likely the result of
a more rigid nature of the substrate backbone which appears to play
an important role. It, however also (slightly) influences the cis/trans
ratio of the carbonate unit (87:13) as testified by the NMR
characteristic patterns of both cis and trans isomers. When the bisoxirane derived from cyclooctadiene was used as substrate, the
oxirane-derived trans-carbonate 3r was isolated in 52% yield having,
as in 3d, a synthetically useful epoxide group incorporated.
Surprisingly, the presence of the epoxide ring in 3r (sp3 versus sp2
hybridized C-centres when compared to 3q) thus directs the
stereoselectivity towards the trans-carbonate.

Figure 1. Substrate scope in the formation of cyclic carbonates 3a-3r. General
conditions used (deviations mentioned in the Figure): 18 h, 70ºC, p(CO2) = 10
bar, 2-butanone (MEK) as solvent (0.5-2.0 mL), NBu4Br ([Br]) as co-catalyst
using either 1 ([Fe]) or 2 ([Al]) as catalysts (amounts indicated). Reported yields
are based on the isolated compounds. Apart from some indicated cases, the
carbonate configuration was >98% cis. Fg stands for functional group. Reported
dr values were calculated from analysis of 1H and/or 13C NMR spectra and relate
to the relative configuration of the carbonate unit and C6 ring substituent.

Interestingly, the catalyst system based on 1 or 2 tolerates a
number of useful functionalities including ether (3b), oxirane (3d, 3r),
endo- and exo-cyclic double bonds (3f, 3j and 3q), trimethoxysilyl
(3l) and ester (3m) groups. Remarkably, the tetracyclic carbonate
product 3d is obtained from its corresponding bis-oxirane derivative
without affecting the other epoxide unit and thus provides clean
access to a difunctional intermediate.[20] Of further note are the
preparation of the substituted bicyclic carbonates 3h-3m for which
straightforward analysis by NMR spectroscopy was more challenging
due to the presence of three stereocentres in these molecules; however,
for a representative example we were able to separate the set of
diastereoisomers (3m) by column chromatography (Figure S1) and
have analysed one of these (i.e., the minor isomer 3ma; ester group

3

equatorial) by X-ray analysis;[21] the other, major diastereoisomer
3mb (ester group axial) was isolated as a viscous liquid (see for
details Supporting Information). The combined data was used to
assign both isomers present in the isolated product, and also
confirmed the cis nature of the carbonate unit.

and (diastereo)selectivity with the preparation of their cis organic
carbonate precursors being the key to success. The selective
formation of cyclic carbonate versus poly(carbonate) (cf., Scheme 1)
from cyclic epoxides infers that two consecutive SN2 reactions take
place preserving the initial relative configuration of the two carbon
centers in the oxirane unit leading to cis-diol formation after basic
treatment. This double inversion mechanistic pathway leading to the
carbonate intermediate has been studied and suggested independently
by various groups.[22]
The current approach is characterized by the use of accessible,
air-stable and powerful catalysts derived from aminotriphenolate
complexes incorporating cheap and earth-abundant metals, and the
use of carbon dioxide as a temporary protecting group. These
attractive features combined with the simple operational
characteristics of this catalytic methodology (no special precautions
warranted) may give a valuable starting point for the synthesis of triand even tetra-substituted cis-diol synthons, and may stimulate the
advancement of alternative asymmetric preparations of this important
class of organic compounds.

Experimental Section

Figure 2. Formation of cis-diol products 4a-4r from precursors 3a-3r. General
conditions used: 3 h, rt, NaOH (5 equiv) in H2O; for 4m K2CO3 (3 equiv. in MeOH)
was used. Reported yields are based on the isolated compounds. Apart from
some indicated cases, the diol configuration was >98% cis. Fg stands for
functional group. Reported dr values were calculated from analysis of 1H and/or
13
C NMR spectra and relate to the relative configuration of the carbonate unit and
C6 ring substituent, except for 4r. Note that further details for the analysis of 4r
are provided in the Supporting Information.

The next step involved the formation of the cis-diol products from
the carbonate precursors 3a-3r by treatment with a suitable base and
most diol targets were readily formed in good to excellent yields
(Figure 2). The deprotection of carbonate 3l was complicated as the
resulting product was a difficult to interpret mixture of rather
insoluble components. Likely, the silyloxy fragment gives rise to
insoluble gels through cross-hydrolysis. However, basic deprotection
of 3m could be carried out with a weaker base (K2CO3) giving cisdiol 4m selectively in high yield (80%). The yield of tetraol 4h (40%)
was lower than generally observed for the other diol products as its
isolation was obviously more difficult. The oxirane group in 4d
(89%) remained surprisingly unaffected under basic conditions
showing again its high stability. The relative cis-configuration in
these diols was further supported by X-ray analysis of diol derivatives
4c and 4q (see inserts Figure 2).[21] These results clearly show the
generality of this approach toward potentially useful cyclic cis-diol
scaffolds.
In summary, we here present an efficient and practical
methodology towards formation of cyclic cis-diols with ample scope
and functional group tolerance affording these synthons in high yield

Typical procedure for organic carbonate formation: A 30 ml stainless steel
autoclave was charged with epoxide precursor (0.5 g) along with the correct
loading of catalyst and co-catalyst and MEK (0.5 mL). The autoclave was
subjected to three cycles of pressurization and depressurization with CO 2 (0.5
MPa, 5 bar), before final stabilization of pressure to 1.0 MPa (10 bar). The
autoclave was sealed and heated to the required temperature for 18-66 h. After
this time, an aliquot of the crude reaction mixture was collected and analyzed by
1
H NMR spectroscopy to determine the reaction conversion (solvent: CDCl3).
Then, the product was isolated/purified through a silica pad or column
chromatography.
Typical deprotection procedure: The respective carbonate (1 mmol) was
dissolved into 1 M NaOH (5 mL). The mixture was left stirring for 2-3 h, until
complete dissolution of the starting material and formation of a homogeneous,
pale yellow solution was achieved. Hereafter, the diol was extracted with various
portions of EtOAc and isolated by removal of the solvent in vacuo.

Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))

Keywords: aluminium • cyclic epoxides • organic carbonates •
homogeneous catalysis • syn-diol formation

[1]

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[17] As previously reported for the FeIII complex 1, acyclic, internal oxiranes
can also be smoothly converted into their corresponding cyclic
carbonates, see: C. J. Whiteoak, E. Martin, E. Escudero-Adán, A. W.
Kleij, Adv. Synth. Catal. 2013, 355, 2233-2239. As a representative
example, we have used this methodology to access the cyclic carbonate
product starting from cis-2,3-epoxybutane (yield 68%, cis/trans of the
carbonate 99:1) and converted it into its corresponding acyclic cis-diol
(87%). See for details the Supporting Information.
[18] Although Fe-complex 1 was initially used, we found that complex 2
resulted consistently in slightly higher yields and selectivities, and thus
the latter was used throughout the rest of the scoping studies. See also
Table 1, entry 16 versus 15.
[19] F. Castro-Gómez, G. Salassa, A. W. Kleij, C. Bo, Chem. Eur. J. 2013,
19, 6289-6298.
[20] Separate control experiments carried out with an oxirane based on this
subunit (i.e., 3-oxatricyclo[3.2.1.02,4]octane or norbornene oxide) only
gave 6% yield of crude carbonate product after prolonged reaction
times (>3 days) and elevated temperatures (100ºC) showing the
unreactive nature of this oxirane unit. For more details see the
Supporting Information.
[21] Details for structure determined for 3ma (CCDC 1005696), for 4c
(CCDC 1005695) and for 4r (CCDC 1009477) are available from the
CCDC upon request or from the author.
[22] See for instance reference 7a and 19, and the reference in footnote 17.

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Entry for the Table of Contents:

Protective carbon
Victor Laserna, Giulia Fiorani,
Christopher J. Whiteoak,* Eddy Martin,
Eduardo Escudero-Adán, Arjan. W.
Kleij*
__________ Page – Page
Carbon Dioxide as a Protecting Group:
Highly Efficient and Selective Catalytic
Access to Cyclic Cis-Diol Scaffolds

Aminotriphenolate complexes of FeIII
and AlIII are presented as highly efficient
and selective catalysts for the
conversion of functional, cyclic oxiranes
into their organic, cis-carbonates. Basic
hydrolysis of the latter provides a wide
series of useful cyclic cis-diol scaffolds
in high yield. This work demonstrates
the dual use of CO2 as a temporary
protecting group and an oxygen donor
furnishing compounds of potential use in
chemical synthesis.

6