Catalytic Enantioselective Ring-Opening Reactions of
Cyclopropanes
Vincent Pirenne,
†
Bastian Muriel
†
and Jerome Waser*
†
These authors contributed equally to this work.
Laboratory of Catalysis and Organic Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique
Fédérale de Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland.
ABSTRACT: This review describes the development of enantioselective methods for the ring-
opening of cyclopropanes. Both approaches based on reaction of non-chiral cyclopropanes and
(dynamic) kinetic resolutions and asymmetric transformations of chiral substrates are presented.
The review is organized according to substrate classes, starting by the more mature field of Donor-
Acceptor cyclopropanes. Emerging methods for enantioselective ring-opening of Acceptor- or
Donor-only cyclopropanes are then presented. The last part of the review describes the ring-
opening of more reactive three-membered rings substituted with unsaturations, with a particular
focus on vinylcyclopropanes, alkylidenecyclopropanes and vinylidenecyclopropanes. In the last
two decades, the field has grown from a proof of concept stage to a broad range of methods for
accessing enantio-enriched building blocks, and further extensive developments can be expected
in the future.
Contents
1. INTRODUCTION ........................................................... 1
2. DONOR-ACCEPTOR CYCLOPROPANES ................ 2
2.1. ANNULATION REACTIONS ....................................... 2
2.1.1. (3+2) Annulations ....................................... 2
2.1.2. (3+3) Annulations ....................................... 6
2.1.3. Other annulations ....................................... 8
2.2. RING-OPENING REACTIONS ..................................... 9
2.2.1. Addition of heteroatom nucleophiles ......... 9
2.2.2. Friedel-Crafts alkylations .......................... 10
2.2.3. Base-mediated fragmentation.................. 11
2.3. OTHER RING-OPENING/CLOSING PROCESSES ............ 12
2.3.1. Cloke-Wilson rearrangement .................... 12
2.3.2. Ring opening/cyclization with primary
amines .................................................................. 12
2.3.3. Via enamine catalysis ............................... 13
2.3.4. Other ......................................................... 13
3. ACCEPTOR-ACTIVATED CYCLOPROPANES ......14
3.1. ANNULATION REACTIONS ..................................... 14
3.2. RING-OPENING REACTIONS ................................... 16
3.2.1. Via nucleophile/base catalysis .................. 16
3.2.2. Via enamine catalysis ............................... 16
4. DONOR-ACTIVATED CYCLOPROPANES ..............17
5. VINYLCYCLOPROPANES ..........................................18
5.1. (3+2) ANNULATIONS........................................... 18
5.1.1. Palladium catalysis ................................... 19
5.1.2. Synergistic palladium-amine catalysis ...... 24
5.1.3. Rhodium catalysis ..................................... 25
5.1.4. Thiyl radical catalysis ................................ 26
5.2. (5+2) ANNULATIONS .......................................... 27
5.3. (4+3) ANNULATIONS .......................................... 28
5.4. RING EXPANSION ................................................ 28
5.5. RING-OPENING REACTIONS ................................... 29
6. ALKYLIDENECYCLOPROPANES ............................ 30
6.1. ANNULATION REACTIONS ..................................... 30
6.2. RING EXPANSIONS .............................................. 31
6.3. RING-OPENING / DIFUNCTIONALIZATION ................. 33
7. VINYLIDENECYCLOPROPANES ............................. 34
8. CONCLUSION AND OUTLOOK ................................ 36
1. Introduction
Cyclopropanes, as smallest carbocycles, have always attracted
the attention of chemists. The presence of tortional and angle
strain for a total of about 115 KJ mol
-1
sets the stage for ring-
opening reactions to access functionalized chiral building
blocks.
1
Even with the presence of ring-strain, the carbon-
carbon bonds remain kinetically stable, so that catalysts were
developed to achieve ring-opening under mild conditions. This
synthetic strategy is attractive, as many methods are now
available for accessing cyclopropanes stereoselectively.
Therefore, the most common approach for accessing
enantioenriched building blocks from cyclopropanes is through
their stereospecific (enantio- and/or diastereospecific) ring-
opening.
2
An alternative approach is the enantioselective ring-
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Reviews
copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited
and published work see https://pubs.acs.org/doi/10.1021/acs.chemrev.0c00109
opening of cyclopropanes, which has been extensively
investigated since 2005, and is having therefore an increasing
impact in synthetic chemistry. Nevertheless, to the best of our
knowledge, this topic has never been described in a single
dedicated review. Only the specific case of enantioselective
ring-opening of Donor-Acceptor cyclopropanes has been
recently covered.
3
From the point of view of enantioinduction, two strategies can
be followed (Figure 1A):
1) Starting from non-chiral cyclopropane (Class I), either
simple substrates with substituents on a single carbon or more
complex meso-compounds.
2) Using more complex multi-substituted cyclopropanes, which
are themselves chiral (Class II). In this case, kinetic resolutions
or asymmetric transformations can be used to access
enantiopure ring-opening products starting from racemic
cyclopropanes. Nevertheless, the theoretical maximal yield of
such transformations is only 50%. Major efforts have been
consequently invested in the last decades to develop dynamic
processes, allowing to convert the starting material completely
to the desired product.
Figure 1. Methods for stereoinduction (A) and types of
cyclopropanes covered in this review (B).
The choice of chiral catalyst and activation principle is highly
dependent on the structure of the cyclopropanes.
4
Therefore,
this review has been organized along the most important classes
of three-membered rings (Figure 1B). It will start with Donor-
Acceptor (D-A) cyclopropanes (section 2). The inherent push-
pull system in vicinal D-A cyclopropanes polarizes the C-C
bond and strongly facilitates the ring-opening process. Upon
activation, a formal 1,3-zwitterion is formed and can react with
a nucleophile, an electrophile or a multiple bond system leading
to acyclic or cyclic products. This exceptional reactivity has
been widely used in synthetic chemistry and has been covered
by numerous reviews,
5
-
16
with only one dedicated to
enantioselective transformations.
3
The most frequently used
acceptor is by far a diester group, although ketones, nitriles and
nitro groups have been used in some instance. The donors are
most frequently (hetero)aryls and heteroatoms, with some
examples of enolates or enamines. Alkyl groups are only
weakly electron-donating and have not been considered as
donors for this review. Section 3 and 4 will be dedicated to
Acceptor- and Donor-only-activated cyclopropanes
respectively. These classes of substrates are more difficult to
activate and have been less investigated, but recent exciting
progress has been realized, especially based on transition metal
catalysis
17
-
23
or the formation of reactive intermediates, such as
radicals
24
or carbocations. Enantioselective methods have just
started to emerge in this case. Again, carbonyl groups were
most frequently used as acceptors, whereas heteroatoms
dominate as donors. Finally, the last three sections will discuss
special classes of cyclopropanes substituted with C-C
unsaturations: Vinylcyclopropanes (section 5),
alkylidenecyclopropanes (section 6) and
vinylidenecyclopropanes (section 7). The presence of the more
reactive systems opens the way for other types of transition
metal-based activations, which has been described in dedicated
reviews,
25
-
36
none of them specific to asymmetric
transformations however. Cyclopropenes have been only rarely
used in asymmetric ring-opening transformations and are not
covered in this review.
37
2. Donor-Acceptor cyclopropanes
Due to the presence of a highly polarized bond, the catalytic
activation of D-A cyclopropanes is easy and has been
extensively investigated.
3-16
Ring-opening is usually triggered
by a LUMO-lowering Lewis acid catalyst through coordination
of the electron-withdrawing substituent, very often via
chelation to a diester, facilitating the attack by a nucleophile. In
contrast, the HOMO-raising approach (activation of the
electron-donating group) is less frequent and has been mostly
achieved via enamine/enolate formation or Umpolung of
carbonyls with a carbene catalyst. In this section,
enantioselective reactions using D-A cyclopropanes will be
discussed, classified according to the chemical transformation:
annulations, ring-opening reactions, other ring-opening/closing
processes and rearrangements.
2.1. Annulation reactions
D-A cyclopropanes have been widely used in annulation
reactions for which enantioselective versions were first
developed as compared to ring-opening reactions. Due to the
importance of five-membered carbocycles and heterocycles,
studies have focused on enantioselective (3+2) annulations with
different π-systems such as silyl enol ethers, carbonyl
compounds or imines. Enantioselective (3+3) annulations have
also been investigated with nitrones or azomethine imines.
Finally, less common annulations, such as (4+3) or (2+2)
processes, were also reported.
2.1.1. (3+2) Annulations
Enantioselective annulation reactions with an achiral
cyclopropane system (acceptor-activated cyclopropane) were
first described in 2005 by Sibi and co-workers (vide infra).
Following this pioneering work, an important breakthrough was
achieved by the group of Johnson with chiral D-A
cyclopropanes. They reported in 2009 the enantioselective
synthesis of tetrahydrofurans derivatives through a dynamic
kinetic asymmetric (3+2) annulation of racemic D-A
cyclopropanes and aldehydes (Scheme 1).
38
The development
of this DYKAT (DYnamic Kinetic Asymmetric
Transformation) strategy was later highlighted in a
Perspective.
39
Initial studies revealed that the p-methoxyphenyl
(PMP) substituted diester cyclopropane was best suitable for a
DYKAT as it undergoes fast ring opening under Lewis acid
coordination. After examination of several pyBOX
(bis(oxazolinyl)pyridyl) ligands with MgI
2
as catalyst, 1
provided the tetrahydrofuran derivatives with the highest
enantiopurity. Electron-rich, cinnamyl and aliphatic aldehydes
undergo the annulation reaction with activated cyclopropanes
such as p-methoxyphenyl and 2-thienyl substituted
cyclopropanes furnishing cycloadducts such as 2-4 in good
yields and enantioselectivities.
Scheme 1. Dynamic kinetic asymmetric (3+2) annulation of
racemic D-A cyclopropanes and aldehydes reported by
Johnson and co-workers.
38
Racemization/epimerization of the starting material or a
reaction intermediate is needed for a DYKAT process. The
phenyl-substituted D-A cyclopropane (R
1
= Ph) is not reactive
enough to allow racemization and is therefore suitable only for
a kinetic resolution. Reaction on the racemic phenyl-substituted
D-A cyclopropane revealed that the (S)-enantiomer reacts
faster. Based on this observation and the stereochemistry of the
product, the authors proposed a stereochemical model involving
a magnesium-cyclopropane chelate complex displaying
octahedral geometry (Figure 2). Even though steric interactions
might occur between the tBu and the aryl group in the complex
formed by the S enantiomer (complex I), the aldehyde’s
approach suffers from unfavorable steric interactions with the
aryl group in the complex formed by the R substrate (complex
II), leading to slower reaction.
Figure 2. Proposed stereochemical model for the addition of
aldehydes to activated D-A cyclopropanes.
The same group applied the DYKAT to the synthesis of 2,5-cis-
substituted pyrrolidines from racemic cyclopropanes and (E)-
aldimines (Scheme 2).
40
Previous observations by Kerr and
Tang showed that an N-benzyl protecting group for aldimines
favors a cis selectivity.
41
,
42
Using MgI
2
with pyBOX 1 and
alkoxy-substituted benzyl protecting groups, good yields and
selectivities could be already obtained. By screening various 4-
X-tBupyBOX ligands, 4-Br-tBupyBOX (5) was finally
selected, as it furnished the pyrrolidine from challenging
electron-rich aldimines with the highest yield and selectivity.
Yields and enantioselectivities were high with both electron-
rich and –neutral aryl aldimines to give pyrrolidines such as 6-
8. However, electron-poor aryl, alkenyl and aliphatic aldimines
were not successful in this transformation.
Scheme 2. Asymmetric (3+2) annulation of D-A
cyclopropanes with aldimines reported by Johnson and co-
workers.
40
The breakthrough of Johnson’s work served as inspiration for
many other reports. The initially developed Mg-PyBox catalytic
system was improved and other metals as well as other BOX
ligands have been used. Tang and co-workers developed a
copper-catalyzed enantioselective and diastereoselective
annulation reaction of cyclic enol ethers with racemic D-A
cyclopropanes allowing the synthesis of [n.3.0] carbocycles
(Scheme 3).
43
This reaction was exemplified with five-, six-,
and seven-membered silyl enol ethers with para-
methoxyphenyl- (PMP), 2-thiophenyl-, 3,4,5-
trimethoxyphenyl- (TMP), and alkenyl-substituted D-A
cyclopropanes to give carbocycles such as 10-12. This work
was also extended to benzene-fused silyl enol ethers furnishing
cyclic products such as 13 with high yield and
diastereoselectivities (>99:1). In addition to set the bicyclic
skeleton, this method installs a tertiary alcohol at the ring
junction and at least two stereocenters in one-step with good to
excellent yield and high enantiomeric excess. Key for high
enantiomeric excess was the introduction of a bulky aryl
sidearm group (R) at the bridging carbon atom of the BOX
(bis(oxazoline)) ligand (9) combined with adamantyl ester
groups on the cyclopropanes. It is worth mentioning that a
kinetic resolution could be applied to less reactive
cyclopropanes (e.g. phenyl-substituted).
Scheme 3. Copper-catalyzed (3+2) annulation of cyclic silyl
enol ethers with D-A cyclopropanes reported by Tang and
co-workers.
43
Our group described the first example of a copper-catalyzed
(3+2) annulation reaction of aminocyclopropane 14 with enol
ethers and aldehydes through a DYKAT process (Scheme 4).
44
The same copper catalyst bearing a tBuBOX ligand (15), is used
both for the synthesis of cyclopentanes and tetrahydrofurans.
The stereoselectivity and the efficiency of the reaction were
improved by modifying the substituent on the nitrogen of the
cyclopropane, by increasing the steric hindrance of the
substituent on the ligand and finally by changing the counterion
of the metal catalyst. Thus, the combination of succinimide,
tBuBOX ligand and Cu(ClO
4
)
2
as the copper source furnished
cyclopentylamines, such as 16 or 17, and tetrahydrofuran
derivatives, such as 18 or 19, with excellent yields and good
enantio- and diastereoselectivities.
Scheme 4. Dynamic kinetic asymmetric (3+2) annulation of
aminocyclopropane 14 with enol ethers and aldehydes
reported by Waser and co-workers.
44
A speculative stereochemical model, disclosed in Figure 3, was
also proposed: the nucleophile attack is faster in the complex
formed by the R enantiomer of cyclopropane 14 (complex I)
whereas attack of the nucleophile is blocked by the tert-butyl
substituents of the ligand in the complex formed by the S
enantiomer (complex II).
Figure 3. Proposed speculative stereochemical model for the
(3+2) annulation reaction of aminocyclopropanes. Reproduced
with minor adaptation from Ref. 44, Copyright 2014, American
Chemical Society.
As illustrated above classical π-systems (carbonyl, imines and
olefins) were successfully used in enantioselective (3+2)
annulation reactions with D-A cyclopropanes. More
challenging dearomatization reactions were also studied with
indoles and benzazoles. The group of Tang described a copper-
catalyzed asymmetric (3+2) annulation of indoles with D-A
cyclopropanes leading to enantioenriched C2,C3-fused indoline
products such as 21-23 with excellent yields and
diastereoselectivities (Scheme 5).
45
Again, the modification of
the side-arm group (R = Me and R’ = benzyl) allowed them to
improve the catalyst activity as well as the enantioselectivity.
The cagelike BOX ligand 20 with two tert-butyl groups at the
meta position of the pendant benzyl groups was identified as the
best ligand. The reaction tolerated substitutions on the indole
motif and functionalized alkyl chains at the C3 positions (R
1
)
without major erosion of the enantioselectivity. The scope was
extended to heteroaryl-, alkenyl-, and vinyl-substituted D-A
cyclopropanes with good yields and enantioselectivities.
Scheme 5. Copper-catalyzed asymmetric (3+2) annulation
of indoles with D-A cyclopropanes reported by Tang and co-
workers.
45
The authors also proposed a tentative stereochemical model
based on the square-planar geometry of bisoxazoline copper
complexes (Figure 4). The enantioinduction was explained by
the favored approach of the Si face of the indole to the (R)-
cyclopropane in complex I, thus avoiding steric interactions
present in the complex II formed by the S enantiomer.
Figure 4. Proposed stereochemical model for the addition of
indoles to activated D-A cyclopropanes.
Enantioselective dearomative (3+2) annulations of
benzothiazoles with D-A cyclopropanes were described by You
and co-workers (Scheme 6).
46
Here also, the DYKAT strategy
was successfully applied leading to enantioenriched
hydropyrrolo-thiazoles. The tBu-PYBOX ligand combined
with MgI
2
gave the best enantioselectivity when the reaction
was performed at 0 °C in chlorobenzene. Overall, excellent
yields and good ee values were obtained for electron-rich or
electron-deficient aryl cyclopropanes and benzothiazoles to
give products such as 24-26. The authors also applied the same
catalytic system in a kinetic resolution process.
Scheme 6. Dearomative (3+2) annulations of D-A
cyclopropanes with benzothiazoles reported by You and co-
workers.
46
The same group published later a dearomative (3+2) annulation
reaction of benzazoles with aminocyclopropanes (Scheme
7A).
47
Enantioenriched hydropyrrolo-benzazoles containing
quaternary stereocenters were obtained via a kinetic resolution
using Cu(OTf)
2
as the copper source and the tBuBOX ligand.
The use of succinimidyl cyclopropane 27 in excess (4 equiv.)
was crucial to reach good yields and excellent
enantioselectivities. Concerning the scope, benzothiazoles and
benzoxazoles were suitable substrates giving dearomatized
products such as 28-30 in high yields and enantioselectivities.
Benzimidazoles showed some limitations, giving products such
as 31 in only moderate yield and enantioselectivity. This
catalytic asymmetric dearomatization (CADA) reaction was
also applied by Guo and co-workers to purines generating
enantioenriched dearomatized purine frameworks such as 33-
35 (Scheme 7B).
48
This (3+2) annulation was also found to be
chemoselective when N9-alkenyl-substituted purines were
used. The annulation products on the C=C double bond at the
N9-position were not observed.
Scheme 7. Enantioselective dearomative (3+2) annulations
of benzazoles reported by You and co-workers (A) and of
purines by Guo and co-workers (B) with
aminocyclopropane 27.
47,48
In addition, Baneerje and Verma attempted to apply their
racemic (3+2) annulation of D-A cyclopropanes with enamines
to a dynamic kinetic asymmetric version.
49
Unfortunately, low
enantio- and diastereoselectivity were obtained.
All the examples above consist in the activation of the
cyclopropane by a LUMO-lowering catalyst using a chiral
metal complex. In (3+2) annulation reactions, only two reports
described the HOMO-raising activation of cyclopropanes
through organocatalysis. First, a remarkable enantioselective
organocatalytic (3+2) annulation of racemic D-A
cyclopropylketones with nitroolefins was described by
Jørgensen and co-workers based on a new nucleophilic
activation mode of D-A cyclopropanes combined with
electrophilic activation of the nitroolefins using bifunctional
urea-amine catalyst 36 (Scheme 8).
50
Racemic di-cyano
cyclopropylketones were activated by the basic pyrrolidine in
36, whereas the thiourea lowered the LUMO of the nitroolefin.
From bifunctional derivatives obtained by varying the tertiary
amine and the electronic properties of the aromatic ring on the
urea, the para-NO
2
-substituted thiourea 36 delivered
cycloadducts such as 37-40 in best yields and ee values, ranging
from 66 to 91%, which can be improved to 99% by
recrystallization. The electron-withdrawing ability of the NO
2
benzene substituent had a crucial role in increasing the
hydrogen-donor character of the thiourea, leading to enhanced
reactivity.