Carboxylates as Nucleophiles in the Enantioselective Ring-Opening of Formylcyclopropanes under Iminium Ion Catalysis

Article abstract of DOI:10.1002/chem.201801434

In this work, carboxylic acids, which are typically regarded as poor nucleophiles, are demonstrated to be competent reagents to promote the ring-opening of formylcyclopropanes after activation of the latter through iminium ion formation. Under optimized r

Full text of DOI:10.1002/chem.201801434

A Journal of
Accepted Article
Title: Carboxylates as Nucleophiles in the Enantioselective Ring-
Opening of Formylcyclopropanes under Iminium Ion Catalysis
Authors: Estibaliz diaz, Efraim Reyes, Uxue Uria, Luisa Carrillo, Tomas
Tejero, Pedro Merino, and Jose L. Vicario
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To be cited as: Chem. Eur. J. 10.1002/chem.201801434
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COMMUNICATION
Carboxylates as Nucleophiles in the Enantioselective Ring-
Opening of Formylcyclopropanes under Iminium Ion Catalysis
Estibaliz Díaz,[a] Efraim Reyes,*[a] Uxue Uria,[a] Luisa Carrillo,[a] Tomas Tejero,[b] Pedro Merino*[c] and
Jose L. Vicario*[a]
Dedication ((optional))
Abstract: We have demonstrated that carboxylic acids, which are
typically regarded as poor nucleophiles, are competent reagents to
promote the ring-opening of formylcyclopropanes after activation of
the latter through iminium ion formation. Under optimized reaction
conditions, a variety of γ-acyloxy-substituted aldehydes can be
obtained in high yields and enantioselectivities through the
desymmetrization of substituted meso-formylcyclopropanes in the
presence of a chiral secondary amine as catalyst.
opening of formylcyclopropanes in the presence of a chiral
secondary amine as catalyst, which delivers γ-acyloxy-substituted
aldehydes in excellent yields, diastereo- and enantioselectivities
(Scheme 1).[7] It should be highlighted that a variety of
heteronucleophiles have been previously used to promote ring-
opening on donor-acceptor cyclopropanes,[8] typically requiring
powerful nucleophiles such as amines, azides, halides or
indoles.[7,9] Some precedents demonstrate that Lewis acids are
efficient promoters of the ring-opening event in electrophilic
cyclopropanes,[3] but the ability of organocatalysts to activate
these strained substrates[10] has only been recently documented
and is exclusively limited to two cases (Scheme 1). Sparr and
Gilmour were pioneers in reporting the enantioselective ring-
opening of formylcyclopropanes under iminium activation using
MacMillan-type imidazolidinones as catalysts in the presence of
chloride and N-chlorosuccinimine, leading to α,γ-dichlorinated
aldehydes.[11] Very recently, Werz extended this reaction to the
chlorosulfenylation of formylcyclopropanes with moderate
enantiocontrol.[12] These two reports rely on the use of a chloride
anion as the nucleophilic species that promote the ring-opening
of the cyclopropyliminium ion intermediate[13] and also show the
necessity of an external electrophilic sulfur or halogen source to
quench the enamine formed after the ring-opening reaction as a
common feature, in contrast to the reaction studied herein.[14]
The ring-strain associated to small-size carbocycles can be
utilized to unveil unusual reactivity that enables accessing to
chemical architectures that are typically difficult to obtain through
conventional methodologies.[1] Donor-acceptor cyclopropanes are
a paradigmatic case in which the synergistic nature of the
substituents contributes to the polarization of the C-C bond,
favoring the ring-opening process.[2] Alternatively, cyclopropanes
that only incorporate electron-withdrawing substituents can also
be used as substrates to undergo ring-opening with a nucleophile.
In terms of synthetic potential, this type of electrophilic
cyclopropanes[3] can be considered as Michael acceptor
homologues, undergoing 1,5-functionalization upon reaction with
a nucleophile in comparison to the standard 1,4-functionalization
achieved on Michael-type reactions (see Scheme 1).[4]
On the other hand, carboxylic acids are typically considered
as poor oxygen-centered nucleophiles that need to react with
potent carbon electrophiles when the corresponding C-O bond
formation is desired. Alternatively, they require for an irreversible
C-O bond forming process for the reaction to be
thermodynamically favored, due to their ability as good leaving
groups.[5] This implies that important organic reactions remain
elusive when the nucleophilic counterpart is a carboxylate anion
like, for example, in the conjugate addition.[6] In this sense, we
wish to present herein that carboxylic acids, despite their limited
ability as nucleophiles, are competent reagents to initiate the ring-
vs
1,4-addition
1,5-addition
R1
R1
R1
R1
R1
R1
EWG
EWG
R2
EWG
EWG
+
+
R2
O
O
R2COOH
R2COOH
O
O
H
R1
O
N
CHO
R1
R1
This
work
H
R2
H
O
R1
R1
H
O
O
R1
O
R2
O
Me
O
Me
N
N
R1
O
[a]
E. Diaz, E. Reyes, U. Uria, L. Carrillo, Prof. Dr. J. L. Vicario
Department of Organic Chemistry II
University of the Basque Country (UPV/EHU)
P.O. Box 644, 48080 Bilbao (Spain)
E-mail: joseluis.vicario@ehu.es; efraim.reyes@ehu.es
T. Tejero
Instituto de Síntesis Química y Catálisis Homogénea (ISQH)
Universidad de Zaragoza CSIC
50009 Zaragoza (Spain)
Bn
Bn
R1
N
Prior
work
R1
N
"
"
H
X
H
H
X
Cl
X=Cl
Cl
R1
(Gilmour)
X=SR
R1
Cl
R1
(Werz)
[b]
[c]
Scheme 1. Electrophilic cyclopropanes as homologous Michael acceptor
equivalents reacting with carboxylates.
P. Merino
Instituto de Biocomputación y Fisica de Sistemas Complejos (BIFI)
Universidad de Zaragoza
50009 Zaragoza (Spain)
The optimization of the reaction conditions was carried out using
formylcyclopropane 1a as model substrate and benzoic acid 2a
as nucleophile (Table 1). We initially surveyed the performance of
MacMillan-type imidazolidinone 3a, which was found to perform
best in the other two examples mentioned earlier.[11,12] However,
E-mail: pmerino@unizar.es
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201801434
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COMMUNICATION
the formation of 4a was observed in very low amount (entry 1). As
an alternative, we tested O-TMS-protected diphenylprolinol 3b,
which is the other archetypical catalyst employed in iminium
activation chemistry.[15] In this case, the desired product was
obtained in moderate yield and low enantiocontrol (entry 2). The
fact that the reaction required a relatively high temperature could
possibly induce desilylation of the catalyst and, for this reason,
other analogues of 3b were surveyed (entries 3-5). All these
derivatives performed similarly in terms of yield but provided
increased enantioselectivity when a bulkier SiPh2Me group was
incorporated (catalysts 3e and 3f, entries 6 and 7). Once a
catalyst providing optimal stereocontrol was identified (catalyst 3f,
entry 7), we moved to modify the conditions with the aim to
increase the yield (entries 7-10). In this sense, while changing the
solvent did not end up in any major improvement (entries 7-9),
using an excess of 2a had a very positive effect (entry 10).
material, although the yield was slightly lower. Other
formylcyclopropanes were also surveyed, observing that, in
general,
good results were obtained for related
benzocyclohexane- cyclopentane- and cycloheptane-fused
substrates (adducts 4n-4p),[16] although the latter two cases
provided the final ring-opening product in somewhat lower
amount, which also provides interesting insights into reaction
mechanism, as it will be discussed afterwards. In addition,
simpler meso-2,3-disubstituted formylcyclopropanes also
reacted efficiently under the optimized conditions (adducts 4q-
4t). Remarkably, the reaction is not only limited to the use of
benzoic acids as nucleophiles, also performing well with other
aliphatic carboxylic acids (adducts 4v and 4w), with the only
exception of acetic acid, for which 4u was obtained in lower yield
because of isolation/purification issues. α-Aminoacids are also
able to undergo this reaction in a clean way and under exclusive
catalyst control with respect to stereocontrol (see 4x and 4y) and
even a β-aminoacid provided the corresponding adduct with
good yield and as a single diastereoisomer (compound 4z).
Table 1. Screening for best reaction conditions[a]
Ph
O
O
H
3a-f
(20%)
CHCl3 50 ºC
O
OH
OHC
+
,
Table 2. Scope of the reaction.[a]
H
O
R1
O
O
CHO
1a
2a
4a
O
3f
mol%)
(20
R2
O
+
H
Ar
Ar
Me
R2
or
80ºC
CHCl3 50 ºC
3b
OH
2a-r
(R=SiMe3)
R1
R1
m
O
R1
4a-z
N
N
-xylene,
Ph 3c
(R=SiEt3)
H
1a-f
OSiPh2Me
2C6H3
Ph
tBuMe
)
2
tBu
Bn
3d
N
N
(R=Si
R2
R1
R2
Ar=3,5-(CF3
CF3CO2 H2
H
)
OR
3e
Me)
(R=SiPh2
R1
R3
3f
3a
O
O
O
O
Entry
Catalyst Solvent
Yield [%][b]
d.r.[c]
e.e. [%][b]
31
O
R1
O
O
O
O
1
3a
3b
3c
3d
3e
3f
CHCl3
8
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
1=R2
e.e.
e.e.
O
4m
57%, 92%
R
=Me;
=
93%
74%,
84%,
4j
4k
1=R2=R3
1=R2
e.e.
e.e.
4a R
=H;
77%, 92%
=H; R3=F;
91%
76%,
R
iPr;
91%
1=R2
1
2
CHCl3
43
33
41
40
40
28
<5
32
77
51
e.e.
e.e.
86%
4b
4c
4d
4e
4f
R
R
R
2
e.e.
4l
R =OMe; R =H;
89%
81%,
1=R2
=H; R3=NO
2; 80%,
93%
3
CHCl3
61
1=R2
e.e.
e.e.
O
=H; R3=Me;
2-NO
2-NO2C6H4
45%,
95%
O
2C6
H4
2=R3
1
R =F, R
=H;
75%,
O
O
2=R3
e.e.
95%
1
4
CHCl3
13
R =OH, R
=H;
79%,
e.e.
=H;
92%
81%,
O
H
O
H
2=R3
1
4g
4h
4i
R =NO2
1
R
2=R3
,
e.e.
e.e.
R =Me, R
1=R3
=H;
44%,
93%
92%
5
CHCl3
70
4n
71%, 89%
4o
40%, 66%
R
=H, R2=OMe;
72%,
e.e.
e.e.
6
CHCl3
92
O
2-NO2C6H4
2-NO2C6H4
Ph
O
O
Ph
O
Et
O
Ph
O
Et
O
O
7
3f
Toluene
THF
90
O
O
O
O
H
H
H
H
Et
Et
Ph
8
3f
n.d.
89
4p
44%, 82%
4q
4r
4s
e.e.
2-NO2C6H4
e.e.
Me
e.e.
e.e.
38%, 91%
74%, 92%
38%, 94%
9
3f
ClCH2CH2Cl
CHCl3
O
O
O
O
Ph
H
Cl
Ph
O
O
O
O
10[e
3f
92
O
O
O
O
H
Ph
4t
83%, 96%
H
H
[a] Reaction carried out in a 0.25 mmol scale of 1a, using 1 eq. of 2a and 20
mol% of catalyst.. [b] Yield of pure product after column chromatography. [c]
Determined by NMR analysis of the crude reaction mixture. [d] Determined by
HPLC analysis of the corresponding primary alcohol obtained after reduction
(see Supporting Information). [e] Reaction carried out using 3 equiv. of 2a.
4u
26%, 90%
4v
79%, 91%
4w
73%, 87%
e.e.
O
e.e.
O
e.e.
O
e.e.
NHBoc
NHBoc
O
O
O
NHBoc
O
H
O
H
O
With optimized conditions in hand, we next evaluated the scope
of this transformation. As it can be seen in Table 2, the reaction
performed well with a variety of benzoic acid derivatives
(compounds 4a to 4l), providing better results when electron-
withdrawing substituents were placed at the aryl moiety and also
furnishing the desired adduct efficiently regardless the position
H
4x
d.r. 11:1
4y
d.r. 11:1
4z
d.r. 18:1
67%,
88%,
60%,
[a] Reaction carried out in a 0.25 mmol scale of 1a-f, using 1.5-3.0 eq. of 2a-
r and 20 mol% of 3f. e.e. was determined by HPLC analysis of the
corresponding primary alcohol obtained after reduction.
of the substituent at the aryl ring. Moreover, when
heteroaromatic substrate such as 2-furanecarboxylic acid was
a
DFT calculations were carried out in order to gain further insight
into the mechanism of the reaction and on the origin of
employed, adduct 4m was obtained as highly enantiopure
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10.1002/chem.201801434
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stereocontrol. The proposal follows the iminium activation
concept, i.e. condensation of 1a with the catalyst involves
activation of the former towards ring-opening through an
increment on the C-C bond polarity. The reaction would therefore
start with the formation of hemiaminal HA and generation of
iminium ion would take place promoted by benzoic acid that
participates in the abstraction of hydroxyl group (TS1), leading to
the formation of an encounter pair IM in which a water molecule
that stabilizes the ion pair is present.[17] From the two carbon
atoms of the cyclopropane moiety that can be attacked by
benzoate anion leading to the two possible enantiomers (through
formation of a contact ion pair[20] explains the inversion of
configuration and also the observed differences in reactivity
between 2a and cyclopentane- and cycloheptane-fused
formylcyclopropanes, for which their lower reactivity is attributed
to the lower stability of the incipient carbocation. This observation
is in agreement with the observed differences in the stability of
cyclohexyl, cyclopentyl and cycloheptyl carbocations calculated
through solvolysis of the corresponding 1-arylcycloalkanols.[21]
V(O12)
IM
TS2, the rate-limiting step) calculations showed
a clear
preference (4.0 kcal/mol) for the pathway leading to the
experimentally observed enantiomer.
N
H
Ph
Ph
OTMS
V(C4,N5)
V(C3,C4)
H
4a
O
H
Ph
1a
Ph
Ph
N
O
O
H
OTMS
H
3b
N
V(C1,O6)
P60
V(C1,C3)
V(N10)
Ph
Ph
H
TMSO
N
OTMS
Ph Ph
O
H
O
O
TS2
H
H
O
H
Ph
PhCO2H
2a
HA
EN
N
Ph
Ph
H
H
Figure 1. ELF analysis for the formation of 4a.
N
OTMS
Ph
TMSO
Ph
H
H
O
O
Finally, the synthetic applicability of the reaction was
demonstrated by the different chemical manipulations that can be
carried out o substrate 4a as model. In particular, reduction of the
aldehyde is straightforward to the corresponding primary alcohol
5a and hydrolysis of 4a delivered the corresponding γ-
hydroxyaldehyde as an equilibrating mixture of closed and open-
chain isomers that, after oxidation, led to γ-lactone 6a. Moreover,
the synthetic potential of this reaction as a tool in synthesis was
demonstrated with the preparation of speciosin H (Scheme 3),
which is a metabolite isolated from the basidiomycete fungus
Hexagonia speciosa that grows in subtropical areas of China.[22]
O
H
H
O
Ph
O
H
Ph
TS1
TS2
N
Ph
O
TMSO Ph
O
H
H
Ph
O
O
H
IM
Scheme 2. Proposed catalytic cycle for the reaction.
The formation of the intermediate EN might be considered as a
SN2-type reaction but a close inspection of TS2 and the
associated IRC showed a slight asynchronicity in the process (see
SI). We carried out a topological analysis of the electron
localization function,[18] recently evidenced as a useful tool for
assessing the synchronicity of organic reactions.[19] Figure 1
shows the evolution of electronic populations along the reaction
coordinate from ion pair IM into EN through TS2 for selected
bonds and atoms (for the full topological analysis see SI). When
the cyclopropane C1-C3 bond is broken (point 56), both N5 and
C3-C4 bond increase their electronic population. Simultaneously,
population of C4-N5 bond decreases to single bond values,
indicating the opening of the cyclopropane ring and concomitant
evolution of the iminium ion towards the enamine. However, O12
remains with the same electron population and it is only at point
72 when it decreases as a consequence of the C1-O6 bond
formation, revealed by the electron density appearing between
those atoms. The observed gap between C1-C3 breaking (point
62) and C1-O6 formation (point 72) reveals the formal existence
of a carbocation (not stable enough to be located as a minimum)
forming an intimate ion pair and thus consisting of an inverting-
SN1 process rather a typical SN2 mechanism. Since there are no
intermediates, the reaction proceeds through a single kinetic step
and it should be considered a concerted asynchronous process
since two events are identified along the reaction coordinate. The
O
Ph
O
Ph
H
O
O
O
O
NaBH4
1. NaOMe, MeOH
OH
, Pyridine
2. CrO3
MeOH
93%
O
H
6a
61%
5a
4a
CHO
H
O
Ar
O
Ar
O
O
ent-
O
3f
H
O
O
mol%)
,
O
(20
O
pTSA
neat, r.t.
+
Ar
OH
CHCl3 50 ºC
H4
O
(Ar=2-OHC6
)
H
94%
8
2f
1g
7
93%
m
-CPBA,
NaHCO3
CH2Cl2
Ar
d.r. >20:1;
93%
d.r. 1.6:1
e.e.
92%
r.t.
,
O
Ar
O
,
,
1. Ph3P=CMe2
THF,
1. LiBH4
THF, -30ºC
OH
O
r.t.
O
O
O
O
HCl
concd.
2.
2. LAH
HO
O
HO
H
Acetone/H2O
82%
9
10
H
Speciosin
72%
isolated
(59%
yield)
Scheme 3. Synthetic manipulations carried out on 4a and total synthesis of
Speciosin H.
In conclusion, carboxylic acids are proficient pronucleophiles for
inducing the ring-opening of formylcyclopropanes under iminium
activation. In the presence of chiral catalyst 3f the reaction
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10.1002/chem.201801434
Chemistry - A European Journal
COMMUNICATION
catalysis see b) Y. Xia, L. Lin, F; Chang, X. Fu, X. Liu, X. Feng, Angew.
Chem. Int. Ed. 2015, 54, 13748.
proceeds with excellent yields and stereoselectivities, providing γ-
acyloxy-substituted aldehydes after the ring-opening process.
The reaction is wide in scope and includes the possibility of using
α- and β-aminoacids as pronucleophiles, which could open the
possibility of applying this approach to the bioconjugation to
peptide-type molecules. Mechanistic studies also indicate that the
reaction proceeds through an SN2-type process in which the
catalyst is involved in the stereodifferentiation of the two
chemically equivalent electrophilic carbon atoms of the meso-
cyclopropane reagent.
[8]
[9]
Some reviews: a) V. A. Rassadin, Y. Six, Tetrahedron 2016, 72, 4701; b)
A. Pons, T. Poisson, X. Pannecoucke, A. B. Charette, P. Jubault,
Synthesis 2016, 48, 4060
For a focused recent review see: a) E. M. Budynina, K. L. Ivanov, I. D.
Sorokin, M. Y. Melnikov, Synthesis 2017, 49, 3035. For some selected
examples: b) A. Lucht, L. J. Patalag, A. U. Augustin, P. G. Jones, D. B.
Werz, Angew. Chem. Int. Ed. 2017, 56, 10587; c) S. Das, C. G. Daniliuc,
A. Studer, Angew. Chem. Int. Ed. 2017, 56, 11554; d) L. K. B. Garve, P.
G. Jones, D. B. Werz, Angew. Chem. Int. Ed. 2017, 56, 9226; e) J.
Wallbaum, L. K. B. Garve, P. G. Jones, D. B. Werz, Org. Lett. 2017, 19,
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Int. Ed. 2016, 55, 12228; g) S. Das, C. G. Daniliuc, A. Studer, Org. Lett.
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Acknowledgements
This research was supported by Spanish MINECO (FEDER-
CTQ2017-83633-P and FEDER-CTQ2016-76155-R), Basque
Government (IT908-16), UPV/EHU (fellowship to E. D.) and
Government of Aragon. The authors acknowledge resources from
the supercomputers "Memento" and “Cierzo”, technical
assistance provided by BIFI-ZCAM (UZ, Spain)"
Keywords: Asymmetric catalysis · Carboxylic acids ·
Cyclopropanes · Strained molecules · Organocatalysis
[1]
[2]
[3]
For some selected reviews see: a) A. Nikolaev, A. Orellana, Synthesis
2016, 48, 1741; b) V. Ganesh, S. Chandrasekaran, Synthesis, 2016, 48,
4347; c) J. R. Green, V. Snieckus, Synlett 2014, 25, 2258; d) F. De
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[5]
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A. De Meijere, Angew. Chem. Int. Ed. Engl. 1979, 18, 809. See also refs.
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chloride anion show a similar reactivity against α,β-unsaturated iminium
ions
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Li, Q. Wang, Synlett 2009, 1830.
[7]
For one previous example of an enantioselective ring-opening of
cyclopropyl ketones with carboxylic acids under chiral Lewis acid
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10.1002/chem.201801434
Chemistry - A European Journal
COMMUNICATION
T. K. Johansen, P. H. Poulsen, K. S. Halskov, K. A. Jørgensen, Angew.
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[17] Stabilization of iminium ion through binding of the OH leaving group by a
H-bond donor has also been reported to happen with bis-sulfonamides:
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10.1002/chem.201801434
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COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
:
COMMUNICATION
Estibaliz Díaz, Efraim Reyes, Uxue Uria,
Luisa Carrillo, Tomas Tejero, Pedro
Merino* and Jose L. Vicario*
O
R'
O
R
O
Im
HO
OH
2
+
R
CHO
O
H
2
9
R'
2
8
R'
8
examples
>20:1 d.r.
27
R'
Page No. – Page No.
9
CHO
e.e.
high
H
speciosin
Carboxylates as Nucleophiles in the
Enantioselective Ring-Opening of
Formylcyclopropanes under Iminium
Ion Catalysis
Text for Table of Contents
Open up!: Carboxylic acids, which are typically regarded as poor nucleophiles,
are competent reagents to promote the ring-opening of formylcyclopropanes after
activation of the latter through iminium ion formation. In this way, stereodefined
γ-acyloxy-substituted aldehydes are obtained through the desymmetrization of
meso-formylcyclopropanes catalysed by a chiral secondary amine.
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