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Intramolecular donor–acceptor cyclopropane

ring-opening cyclizations
Cite this: Chem. Soc. Rev., 2014,
43, 804
Marchello A. Cavitt,† Lien H. Phun† and Stefan France*

Received 5th July 2013
DOI: 10.1039/c3cs60238a
www.rsc.org/csr
Cyclization reactions of donor–acceptor (D–A) cyclopropanes are recognized as versatile methods for con-
struction of carbocyclic and heterocyclic scaffolds. In the literature, many examples of these polarized cyclo-
propanes’ reactivity with nucleophiles, electrophiles, and radicals are prevalent. Although intermolecular
reactivity of donor–acceptor cyclopropanes is widely reported, reviews that center on their intramolecular
chemistry are rare. Thereupon, this tutorial review focalizes on new intramolecular transformations of donor–
acceptor cyclopropanes for cycloisomerizations, formal cycloadditions, umpolung reactions, rearrangements
and ring-opening lactonizations/lactamizations from 2009 to 2013. Furthermore, the role of D–A acceptor
cyclopropanes as reactive subunits in natural product synthesis is underscored.

Key learning points

(1) Bond polarization is central to the controlled reactivity of cyclopropanes.
(2) D–A cyclopropanes participate in intramolecular ring-opening annulations to form interesting and useful ring systems.
(3) The annulation reactions of D–A cyclopropanes have demonstrated application in natural product synthesis.
(4) The stereoelectronics of the cyclopropanes can be readily manipulated to allow for a variety of intramolecular transformations to occur (e.g., umpolung
reactions, cycloadditions).
(5) The field is growing and the potential of these reactions is far from being fully realized.

1. Introduction The utility of an intramolecular design for D–A cyclopropanes

Cyclopropanes are useful synthetic building blocks for organic
chemists. When compared to their corresponding linear counter-
parts or larger ring systems, cyclopropanes are synthetically more
versatile due to their high p character, inherent angle strain, and
intrinsic torsional strain.1 Ring-opening acts as a driving force for
much of the chemistry of cyclopropanes, and bond scission can
be tuned and facilitated by strategic placement of donor and
acceptor substituents for C–C bond polarization. Overall, these
donor–acceptor (D–A) cyclopropanes participate in an incommensur-
able amount of chemistry summarized and reviewed in previous
literature. While particular emphasis is placed on intermolecular
reactivity, examples demonstrating intramolecular transformations
have recently become more frequent. The benefits of intramolecu-
larity for ring-opening cyclization reactions of cyclopropanes include
increased reactivity, milder reaction conditions, better control of
diastereoselectivity, and rapid formation of polycyclic structures.
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta,
Georgia 30332, USA. E-mail: stefan.france@chemistry.gatech.edu;
Fax: +1 404-894-7452; Tel: +1 404-385-1796
† Denotes equal contribution.
was established in the late 1960s and early 1970s. During this
period, Stork2 and Grieco3 pioneered the application of cyclopropyl
ketones with alkyl donors as useful precursors for acid-promoted,
intramolecular cation-olefin cyclizations. Corey reported the first
example of a total synthesis using the Stork cyclopropane cycliza-
tion method in the syntheses of ()-cedrone and ()-cedrol.4
Danishefsky published numerous examples of intramolecular
nucleophilic ring-opening cyclizations to generate functionalized
carbo- and heterocycles.5 Wenkert later showcased the utility of
stronger donor groups, including heteroatom donors.6 These
seminal examples established a foundation for almost 40 years of
work devoted to intramolecular reactions of D–A cyclopropanes.
Due to this wealth of chemistry, we will highlight recent advance-
ments in intramolecular ring-opening cyclization reactions of D–A
cyclopropanes from January 2009 through June 2013.
2. Overview
Cyclopropanes are relatively stable and resistant to bond cleavage
unless activated. Ring activation is accomplished by polarizing one
of the C–C bonds through the attachment of electron-donating

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Fig. 1 Vic- vs. gem-donor–acceptor (D–A) cyclopropanes.
(Donor, D) and electron-accepting groups (Acceptor, A) as substi-
tuents (Fig. 1). Classically, electron-withdrawing functionalities,
such as the carbonyl, sulfonyl and nitro groups, serve as acceptors,
and moieties with electron-rich aryl groups, heteroatoms, alkyl or
alkenyl groups act as donors. Generally, there are two arrangements
for donor and acceptor groups about the cyclopropane ring: vicinal
(1) and geminal positioning (2). Vicinally positioned donor and
acceptor groups act in a controllable, push–pull fashion, resulting in
enhanced polarization of the C–C bond between the two adjacent
groups.7 In contrast, donor and acceptor groups positioned
geminally are not as ‘‘synergistic’’ when compared to their vicinal
counterparts for bond polarization.7 Consequently, gem-D–A cyclo-
propanes will not be discussed in this review.
Marchello A. Cavitt was born in
Detroit, Michigan and reared in
Murray, Kentucky. He obtained
his BS in Chemistry from the
University of Louisville in
2007 and completed an MS in
Chemistry in 2009 from the
University of Michigan. He is
currently a doctoral student at
the Georgia Institute of Technol-
ogy where his research interests
involve methodology develop-
Marchello A. Cavitt ment and natural product synthesis.
Lien H. Phun received her BS in
Chemistry from Emmanuel
College in 2007. She began her
graduate work on the develop-
ment of synthetic methodologies
using cyclopropenes and cyclo-
propanes as reactive subunits
under the direction of Professor
Stefan France at Georgia Tech.
In 2013, she received her PhD.
She is currently a senior chemist
at Arizona Chemical.
Lien H. Phun
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Scheme 1 Reactivity of D–A cyclopropanes.
The push–pull effect induces polarization in the vicinal C–C
bond (Scheme 1), and various pathways for ring-opening are
feasible. If heterolytic ring-opening occurs, a zwitterionic inter-
mediate forms. This dipole is reactive towards electrophiles,
nucleophiles, and dipolarophiles. Many D–A cyclopropane ring-
opening reactions proceed through a synchronous route involving
nucleophilic attack on the electron-deficient carbon with con-
current ring-opening. Another pathway for ring-opening is
homolytic cleavage, which forms a diradical intermediate.
Since this homolytic process often occurs independent of the
substituents’ nature, this chemistry primarily falls outside the
scope of this review. However, one relevant example of a radical
rearrangement in Section 6.2 is included. In the case of
dipolarophiles, a formal cycloaddition is expected and believed
to proceed through a stepwise polar mechanism. This predictable
behavior has led to extensive application of vicinal donor–acceptor
(D–A) cyclopropanes in organic chemistry, prompting researchers
to understand the ring polarization.
In order to quantify the polarizing effect of various donor and
acceptor substituents, Werz conducted a systematic theoretical
investigation by calculating ring enlargement activation barriers
for over 70 D–A cyclopropane combinations (Fig. 2).8 As expected,
smaller transition energies are observed with good donor and
acceptor substituents. For most systems, the donor has greater
impact on the transition state energy than the acceptor. If an
Prof. Stefan France was born in
Bronx, New York, in 1978. He
obtained his BS in Chemistry
from Duke University in 2000. In
2005, he obtained his PhD degree
from Johns Hopkins University
under the guidance of Prof.
Thomas Lectka. Thereafter, he
secured a postdoctoral research
position with Al Padwa at Emory
University. Stefan began his
independent career at Georgia
Stefan France Tech in 2007. His primary
research interests include strained
ring-opening reactions, intramolecular annulations, heterocyclic
chemistry, natural product synthesis, and chemical biology.
Chem. Soc. Rev., 2014, 43, 804--818 | 805
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Chem Soc Rev Tutorial Review

Most of these reviews primarily describe intermolecular

reactions, although relevant intramolecular examples are included.
Reviews solely discussing intramolecular reactions of D–A
cyclopropanes are rare. To complement the rich literature, this
review will feature recent examples of intramolecular ring-
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opening cyclizations of vic-D–A cyclopropanes that efficiently

provide access to various molecular architectures. Given the
emergence of this growing field, all of the representative
chemistry could not be covered. Therefore, this tutorial over-
view includes recent examples of cycloisomerizations, formal
cycloadditions, umpolung reactions, rearrangements, and ring-
opening lactonizations/lactamizations. In order to emphasize
synthetic utility, each literature example is categorized according
to the product or product scaffold. Equally important, specific
Fig. 2 Insights from Werz’s computational study. applications of intramolecular reactions in natural product
synthesis will be discussed.

additional acceptor and/or donor group is added geminally, the

transition state energies further decrease without significant 3. Cycloisomerizations
influence on reaction enthalpies. Hence, specific combinations
For D–A cyclopropanes, cycloisomerization is a synthetic
of donor and acceptor substituents are predicted to readily promote
approach that involves acid- or transition metal-promoted
ring-expansion while others offer less C–C bond polarization. It
intramolecular ring expansion. For clarification, cyclopropane
is important to note that Werz’s study involves a synchronous
cycloisomerizations are divided into three main reaction
polar ring-enlargement mechanism as opposed to a heterolytic
classes: (1) furan-, pyrrole-, and thiophene-forming reactions;
ring-opening (transition state energies were large). Similarly,
(2) formal homo-Nazarov cyclizations; and (3) nucleophilic
when intermediates involving diradicals were modeled, transi-
ring-opening cyclizations.
tion state energies were substantial.
Due to their characteristic reactivity and synthetic potential, 3.1. Furan-, pyrrole-, and thiophene-forming reactions
D–A cyclopropanes have garnered a considerable amount of
D–A cyclopropanes are powerful building blocks for the synthesis of
attention. Wherefore, a number of reviews on the synthesis and
five-membered ring heterocycles via cycloisomerization reactions.
reactivity of D–A cyclopropanes were published in the last decade.
These cycloisomerizations occur via two primary approaches:
In 2003, Reissig discussed synthetic applications of vicinally-
(1) where the acceptor group [usually C(= X)R, where X = O, NR,
substituted D–A cyclopropane derivatives as intermediates in
or S] contains components to form a new five-membered ring
natural product synthesis with an emphasis on cyclopropane
or (2) where peripheral five-membered ring-formation enables
bond scission.9 Subsequently, in 2007, Pagenkopf et al. noted
ring-opening of the cyclopropane.
advancements in the formation and usage of D–A cyclopropanes
3.1.1. Oligoacetals. In 2009, Werz and co-workers sought to
as dipolarophiles for 1,3-dipolar cycloadditions.10 In 2009, Waser
synthesize anti-fused oligoannelated tetrahydrofuran moieties
highlighted intramolecular ring-opening cyclizations with parti-
using cycloisomerization reactions of in situ-generated D–A
cular emphasis on the formal homo-Nazarov cyclization.11 Like-
cyclopropanes (Scheme 2).20 The reaction sequence consisted of
wise, Kerr and Carson published a tutorial review on methods
Cu(OTf)2-catalyzed double cyclopropanation of furan with ethyl
for formation of functionalized heterocycles from ring-expansion
diazoacetate to form a tricyclic bis-cyclopropane. Subsequent
reactions of cyclopropanes in 2009.12 Then, in 2010, Kerr
LAH reduction gave diol 3. Oxidation using IBX initially
described intramolecular cycloadditions of D–A cyclopropanes
resulted in the formation of transient dialdehyde 4, which
and transformations of the resulting adducts to natural product
targets.13 In 2011, Trushkov et al. rendered an account which
included [3+2]-cycloadditions, reductive ring-openings, nucleophilic
ring-openings/ring-closures, and acid-induced ring-openings.14
Within the same year, Waser15 et al. published a paper on the
synthesis and reactivity of heteroatom-substituted D–A cyclo-
propanes while Reisman16 et al. illuminated the application of
the Büchner reaction for total synthesis. Moreover, in 2012,
Qin17 and Wang18 separately disclosed the versatility of acti-
vated cyclopropanes in natural product synthesis. Afterwards,
in 2013, Njardarson and Mack reported new advancements in
expansions of three- and four-membered rings using various
metal catalysts.19 Scheme 2 Werz’s synthesis of anti-oligoannelated THF moieties.

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Scheme 3 Werz’s synthesis of [n,5]-spiroketals.

readily cycloisomerized to tricyclic bisacetal 5 in 76% yield.

The three-step (cyclopropanation, reduction, and oxidation/ Scheme 4 Werz’s oligopyrrole synthesis.

cycloisomerization) sequence was repeated three additional times

to ultimately generate oligoacetal 6 in an all-anti-arrangement, the
first of its kind.
3.1.2. [n,5]-Spiroketals. Spiroketals are commonly synthe-
sized using hetero-Diels–Alder reactions and cross couplings.21
To expand the synthetic approaches to these privileged struc-
tures, Werz designed a methodology that uses cyclopropane
cycloisomerizations to form [n,5]-spiroketals 9 (n = 5 or 6)
(Scheme 3).21 IBX-oxidation of hydroxymethyl cyclopropanes 8
Scheme 5 Werz’s synthesis of bisthiophenes and thioacetals.
with 10 mol% of Yb(OTf)3 afforded spiroketals 9 in low to good
yields (26–87%). Product analysis revealed that the configuration
of the spirocenter was not conserved in the transformation with and loss of water furnished the desired products. Interestingly,
IBX and Yb(OTf)3. As a result, the main reaction pathway for when the temperature was lowered to 25 1C in CH2Cl2 or by
most of the precursors is believed to proceed through an employing electron-withdrawing appendages, ‘‘cage-like’’ struc-
asynchronous mechanism, forming zwitterionic intermediate tures 21a were afforded in fair yield. For this transformation,
12, which would enable the erosion of stereochemistry at the Lawesson’s reagent was proposed to act as a Lewis acid for
spirocenter. Alternatively, Dess–Martin periodinane preserved thioacetal formation. In the same report, Werz demonstrated
the stereochemistry and supported a synchronous mechanism. that selenium-containing cage-like products 21b were obtained
With this procedure, pyran- and monosaccharide-derived spiro- when Woollins’ reagent was chosen as the selenium source.
ketals were readily prepared through ring expansion of D–A 3.1.5. N,O-Bisacetals and N-Boc-pyrroles. In a full paper,
cyclopropane derivatives. Werz et al. published a protocol for formation of N,O-bisacetals and
3.1.3. Oligopyrroles. Expanding upon their oligoacetal pyrroles from the analogous pyrrolidine substrate 22 (Scheme 6).24
methodology, Werz and co-workers divulged a unique approach By subjecting biscyclopropane 22 to p-toluenesulfonic acid in
for the synthesis of 3,3 0 -linked bispyrroles and oligopyrroles THF at 80 1C for 30 min, N,O-bisacetals 23 were prepared in fair
(Scheme 4).22 Treatment of diketones 13 with excess primary to excellent yields (when R1 = Me or Ph). When R1 = H, pyrroles
amines, carbamates or sulfonamides and 5 mol% p-TsOH or 24 were observed in 80–93% yield after cyclopropane ring-
AcOH in benzene at reflux afforded 3,3 0 -linked bispyrroles 14 in opening and rapid aromatization.
19–90% yield. The reaction proceeds via the bisimine 15 which 3.1.6. Fused furans and pyrroles. Sarpong and co-workers
undergoes cycloisomerization and water loss to give bispyrroles disclosed a tungsten-catalyzed heterocycloisomerization approach
14. When extended oligoacetalic diketones, as in 17, were to 4,5-dihydro-benzo[b] furans and indoles (Scheme 7).25 When
employed as starting materials, oligopyrroles 18 were obtained keto[4.1.0]bicycles 25a were treated with W(CO)5THF (10 mol%)
in one step with modest yields. Given the intrinsic instability of
these oligopyrroles, synthetic yields decrease dramatically as
the number of pyrrole units increases.
3.1.4. Bisthiophenes and caged thioacetals. Werz also pub-
lished examples of the formation of 3,3 0 -linked bisthiophenes
(Scheme 5).23 Cyclopropanes 19 were treated with 2.2 equiv. of
Lawesson’s reagent in toluene at 100 1C or benzene at 80 1C to
afford 20 in 19–56% yield. Subsequent thioketone formation Scheme 6 Werz’s synthesis of N,O-acetals and pyrroles.

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Scheme 7 Tungsten-catalyzed heterocycloisomerization approach.
and 3.0 equiv. of NEt3, 4,5-dihydrobenzo[b]furans 26 were
obtained in 81–98% yield. Similarly, 4,5-dihydroindoles 27 were
produced in 57–80% yield from corresponding oximes 25b. When
bicyclo[5.1.0] substrates 25c or 25d are used, cycloheptene-2,3-
fused furan 28 or pyrrole 29 is formed. By incorporating a D–A
cyclopropyl subunit, the method tolerates alkyl and heteroatom
substituents, and the products can be easily functionalized.
If the proposed mechanism is examined, using 25a as an
example, the transformation is purported to involve formation
of metallo-vinylidene 30, which engages the proximal heteroatom
to provide zwitterionic species 31 (Scheme 8). Upon proto-
demetalation, spiro-fused tricycle 32 arises. Ultimately, cyclo-
propane ring-opening followed by proton transfer with concomitant
aromatization affords product 26.
3.1.7. c-Butyrolactones. Melnikov and co-workers reported
a chemo-, regio-, and stereoselective protocol for the isomeriza-
tion of 2-arylcyclopropane-1,1-dicarboxylates 34 (Scheme 9).26
Lewis acid-promoted ring-opening furnished three different
products (35–37). While the paper focused on the preparation
of styrylmalonates 35, g-butyrolactone 37 was seen under a
range of Lewis acidic conditions. For instance, 37 was obtained
in 78% yield with BF3Et2O (1.2 equiv.) in chlorobenzene, in
Scheme 8 Purported mechanism for heterocycloisomerization.
Scheme 9 Lewis acid-induced isomerization of cyclopropanes 34.
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Scheme 10 Corey’s synthesis of ketolactones and bislactones.
81% yield with SnCl4 (1.2 equiv.) in dichloromethane, or in 77%
yield with Sn(OTf)2 (10 mol%) in nitromethane. Formation of
37 proceeds via cycloisomerization of 34 into a dihydrofuran
followed by acetal hydrolysis/tautomerization.
3.1.8. Ketolactones and bislactones. Similarly, Corey et al.
reported an acid-catalyzed cycloisomerization of cyclopropyl
esters to ketolactones 42/43 and bislactones 44/45 with moderate
to good yields (61–86%) (Scheme 10).27 The D–A cyclopropanes
(38–41) were treated with 3.0 equiv. of TMSOTf and 1.5 equiv. of
water in i-PrNO2 with temperatures varying from 23 1C to 110 1C.
TMSOTf-promoted ring-opening followed by intramolecular
trapping by the oxygen of the pendant ester moiety provided
the lactone products 42–45 after hydrolysis.
3.2. Formal homo-Nazarov cyclizations
When treated with an acid promoter, cyclopropyl aryl (or hetero-
aryl) ketones and cyclopropyl vinyl ketones undergo ring-opening/
Friedel–Crafts annulations to generate a-tetralones, cyclohexe-
nones, and heteroaryl-fused cyclohexanones (Scheme 11).11
The mechanistic pathway involves cyclopropane ring-opening
to afford acyclic cation 47 followed by adjacent p-attack to give
six-membered oxyallyl cation 48. Quenching of the charge
yields 49. Due to homology with the classic Nazarov cyclization
(formation of a five-membered oxyallyl cation), transformations
of these cyclopropanes were termed the ‘‘homo-Nazarov cycli-
zation’’. Prior to 2007, a few examples of this methodology were
published. Recent developments in the field have offered new
reports and applications.
3.2.1. Cyclohexenones. Most historical examples of the formal
homo-Nazarov cyclization utilized stoichiometric amounts of
Brønsted or Lewis acids to promote reactivity. To address this
issue, Waser reported the first instance of non-stoichiometric
acid catalysis in the formal homo-Nazarov cyclization using
dihydropyran- and dihydrofuran-substituted cyclopropyl ketones
Scheme 11 The formal homo-Nazarov cyclization.
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Scheme 12 Waser’s Brønsted acid-catalyzed formal homo-Nazarov
cyclization.
50 (Scheme 12).28 Since most Lewis acids gave polymerization
of the starting materials, certain Brønsted acids proved to be
viable alternatives. Acidity of the catalyst appeared to have a strong
influence on the reaction outcome; stronger acids resulted in
decomposition of the starting material while weaker acids were
unable to achieve full conversion. A stepwise mechanism was
proposed where ring-opening is rate-determining. Tautomerization
of the enol intermediate is postulated to be important for catalysis.
The optimized conditions of p-TsOH (20 mol%) in acetonitrile
at room temperature afforded the desired cyclohexenones 51 in
15–99% yield. For cyclization, electron-rich aromatic donor
substituents were necessary. In the absence of a heteroatom
donor in the a-position, no reaction was observed unless a silyl
directing group was present at the b 0 -position.
3.2.2. Tetrahydro-1H-carbazol-1-ones. Waser probed the
reaction by using the p-system of a heteroaryl substituent as
the pendant nucleophile (Scheme 13). When the heteroaryl
subunit is a protected or unprotected 2-indole, cyclization
readily occurs to provide fused cyclohexanone 54 in quantita-
tive yield. Conversely, when other heteroaryl groups were
employed, no desired cyclization product was observed using
the optimized conditions.
3.2.3. Formal synthesis of ()-aspidospermidine. Waser then
explored amines as donor groups for the formal homo-Nazarov
cyclization with the 2-indolyl group as the p-nucleophile.29 Upon
cyclopropane ring-opening, the transient iminium ion is trapped
by the adjacent indole. Intriguingly, when the indole nitrogen is
unprotected, catalyst and solvent selection have a direct impact on
product outcomes (Scheme 14). With Cu(OTf)2 (15–25 mol%) in
acetonitrile, the anticipated formal homo-Nazarov products 57
were produced in high yields (88–95%). In contrast, when catalytic
p-TsOH in CH2Cl2 was used, N,N-acetal product 58 was observed
as a result of an attack of the indole nitrogen on the iminium
intermediate. This approach was later employed in the total
synthesis of goniomitine (Section 3.3.3). Aminal 58 was smoothly
converted to tetracycle 57 with Cu(OTf)2. Cbz-cleavage furnished
the free amine, providing a known intermediate for the total
synthesis of aspidospermidine.
Scheme 13 Brønsted acid-catalyzed heteroaromatic formal homo-
Nazarov cyclization.
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Scheme 14 Catalytic selective cyclizations of aminocyclopropanes.
3.2.4. Dihydronaphthalenes. In an informal expansion of
the methodology, Nishii and co-workers reported a strategy to
access 1-aryl-1,2-dihydronaphthalene-3-carboxylic acid esters
60 from methyl (arylhydroxymethyl) cyclopropanecarboxylates
59 with Lewis and Brønsted acids (Scheme 15).30 Various Lewis
acids promoted regioselective ring expansion with Sc(OTf)3 and
BF3Et2O being optimal. Electron-donating substituents on the
aryl rings were well-tolerated to produce dihydronaphthalene
products 60 in fair to high yields (60–99%).
Mechanistically, the reaction resembles the formal homo-
Nazarov cyclization (Scheme 16). First, the Lewis acid activates
the hydroxyl group for carbocation formation. Ring-opening
generates cationic species 63, which is directly analogous to
acyclic aryl formal homo-Nazarov intermediate 64. Finally,
intramolecular Friedel–Crafts alkylation provides the observed
dihydronaphthalene product 60a. Of note, the reaction rate
is directly related to the alkene stereochemistry in inter-
mediate 63. If the Z-alkene is produced, then cyclization
proceeds readily; however, the E-intermediate slows the con-
version. Furthermore, halogenated Lewis acids, such as TiCl4
and SnCl4, caused chlorination of benzyl cation 63, resulting in
lowered yields of 60a.
Scheme 15 Ring expansions of methyl 2-phenyl-1-(arylhydroxymethyl)-
cyclopropanes.
Scheme 16 Nishii’s proposed mechanism.
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3.2.5. Cyclohexanols and cyclohexenones. Building on the
accomplishments in the area, the France group sought to
explore the reactivity of the formal homo-Nazarov reaction in
further detail.31 In an attempt to improve the overall reaction
scope, cyclopropyl vinyl ketones bearing a secondary acceptor
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(such as an ester or ketone) in the a 0 -position were envisioned
as substrates (Scheme 17). The secondary acceptor group is
postulated to coordinate with Lewis acids, generating a six-
membered chelate that facilitates ring-opening by lowering the
activation barrier for C–C bond cleavage.8 Upon p-nucleophilic
attack, the acceptor group polarizes the resulting cyclic oxyallyl
cation by localizing charge density on the a-carbon, providing
predictable reaction outcomes.
The study began with cyclopropyl vinyl b-ketoesters containing
an electron-rich aromatic donor group and an unactivated alkene.
Upon subjecting a model substrate (derived from 2-butene) to a
screen of Lewis acids in a catalytic amount (30 mol%), In(OTf)3
efficiently catalyzed the formal homo-Nazarov cyclization in full
conversion to afford two products: methylene cyclohexanol 66
and cyclohexenone 67 in 75% combined yield in a 3 : 2 ratio of
exocyclic to endocyclic alkene (Scheme 18).31 The product ratio
can be influenced through strategic installation of a silyl group.
For instance, a b 0 -silyl group (as in 68) results in selective
formation of exocyclic alkene 69 (92% yield). Other unactivated
alkenes demonstrate similar reactivity (B75% yield, 3 : 2 ratio),
while an a 0 -oxygen allows for efficient cyclization (93% yield).
More importantly, when unactivated or electron-poor aromatic
donor groups are used, cyclization proceeds, albeit with low-
ered yields and longer reaction times.
3.2.6. Heteroaryl-fused cyclohexanones. The France group
expanded the In-catalyzed method to include cyclopropyl
heteroaryl b-ketoesters (Scheme 19).32 Cyclopropanes 70 and 71
Scheme 17 Formal homo-Nazarov reaction with a secondary cyclopro-
pane acceptor.
Scheme 18 In(OTf)3-catalyzed alkenyl formal homo-Nazarov cyclization.
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Scheme 19 In(OTf)3-catalyzed heteroaromatic formal homo-Nazarov
cyclization.
were efficiently converted into 2,3-hetero-fused cyclohexanones
72 and 73 in good to high yields (61–91%) with only 5 mol% of
the catalyst. Interestingly, when the 2-bromo thienyl substrate
was employed, cyclization at the thiophene 4-position afforded
the 3,4-heteroaryl ring-fused product in 56% yield. A large array
of heteroaromatics were reacted, including 2- and 3-furans,
thiophenes, indoles, and benzofurans.
Since both the cyclopropanation and homo-Nazarov cyclization
steps occur in CH2Cl2, the development of a one-pot procedure
was conceived in which rhodium and indium catalysis would
transpire in tandem (Scheme 20). As a representative example,
when a-diazoester 74 was subjected to Rh2esp2 (1 mol%) and
In(OTf)3 (0.2 mol%), the desired ring-fused cyclohexanone 75
was obtained in 56% yield.
3.3. Nucleophilic ring-opening annulations
D–A cyclopropanes can undergo both direct and formal homo-
conjugate addition reactions in the presence of nucleophiles.
Depending on the extent of polarization, nucleophiles can react
with the cyclopropane in either an SN2-type or SN1-type fashion.
If the cyclopropane is substituted with an oxygen or a nitrogen
donor, oxonium or iminium intermediates are generated
and readily react with nucleophiles. When the nucleophile is
tethered to the cyclopropane, a new ring is formed upon
intramolecular attack. Several groups have exploited this reac-
tivity by using a range of tethered carbon-and nitrogen-based
nucleophiles.
3.3.1. Total synthesis of ()-vincorine. Over the past ten years,
the Qin group has developed nucleophilic ring-opening annulation
methods to construct distinct indoline alkaloid frameworks via
cascade or stepwise cyclopropanation/ring-opening/iminium
cyclization (CRI) reactions of indolylcyclopropanocarboxylates.33
Scheme 20 Tandem cyclopropanation/formal homo-Nazarov cyclization.
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Scheme 21 Qin’s total synthesis of ()-vincorine.
This design was applied to achieve the first total synthesis of
the akuammiline alkaloid, ()-vincorine (80), in 31 steps with an
overall yield of 1% (Scheme 21). The reaction presumably
proceeds through an unstable cyclopropane intermediate 77
that undergoes ring-opening and iminium cyclization with the
pendant amine to obtain tetracycle 79.
3.3.2. Formal total synthesis of (+)-fawcettimine. In another
example of a total synthesis using an intramolecular nucleo-
philic ring-opening cyclization, Jung and Chang disclosed an
enantioselective formal total synthesis of the Lycopodium
alkaloid (+)-fawcettimine (81) in which the key transformation
is the diastereospecific intramolecular attack of a silyl enol ether
on an activated D–A cyclopropane (Scheme 22).34 The enantio-
pure cyclopropane-1,1-diester 82 was synthesized and subjected
to a catalytic amount (20 mol%) of Sc(OTf)3 to yield the desired
hydrindanone product 84 in 77% as a single diastereomer.
This process proceeded via an ‘‘SN2-like’’ mechanism with full
retention of stereochemistry at the cyclopropyl center. Krapcho
decarbalkoxylation gave the known ester 85 which is eight steps
removed from completion of the total synthesis.
3.3.3. Total synthesis of ()-goniomitine. Waser and co-workers
disclosed a simple modification of their homo-Nazarov reaction
(Section 3.2.3) en route to the total synthesis of an anti-proliferative
agent, goniomitine (86), starting from aminocyclopropane 87
(Scheme 23).25 Upon ring-opening with catalytic p-TsOH, iminium
Scheme 22 Jung’s enantioselective formal total synthesis of (+)-fawcettimine.
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Scheme 23 Waser’s total synthesis of ()-goniomitine.
ion intermediate 88 is generated and subsequently trapped by
the indole nitrogen providing the tetracyclic core 89 of gonio-
mitine in 93% yield. A sequence of reduction, acetylation, and
deprotection furnished goniomitine (86) in thirteen linear steps
with an overall yield of 11% from d-valerolactam.
3.3.4. Dihydropyrido[1,2-a]indoles. France et al. revealed
an efficient and modular approach to hydropyrido[1,2-a]indole-
6(7H)-ones 93 via a Lewis acid-catalyzed domino ring-opening/
Friedel–Crafts alkylation sequence (Scheme 24).35 When cyclo-
propyl b-amidoesters 90 were subjected to 30 mol% In(OTf)3 in
CH2Cl2 at room temperature or 1,2-dichloroethane at reflux,
dihydropyrido[1,2-a]indole-6(7H)-ones 93 were obtained in
modest to excellent yields (31–99%) with some diastereoselectivity
(from 2 : 1 trans : cis dr to >20 : 1 dr). The suggested mechanism
involves cyclopropane ring-opening followed by an intramolecular
Friedel–Crafts alkylation at the 2-position of the indole to generate
the lactam ring of the dihydropyrido[1,2-a]indole-6(7H)-ones.
To date, this method has been applied to a diverse set of
N-acyl indolyl substrates to determine the scope and limitations
(Fig. 3). The method is amenable to a variety of functionalities
including alkyl and aryl halides, protected amines, ethers, silyl
groups, and thioethers. Cyclic and acyclic heteroatom donor groups
(O, N, and S) readily cyclized to their respective products. A second
donor group resulted in rate enhancement as a result of additional
stabilization and steric influence. Hence, cyclopropanes with
gem-dialkyl substituents afforded spirocyclic compounds and
quarternary center formation.
Moreover, pyrido[1,2-a]indoles can be directly obtained
from bromocyclopropanes 90 (Scheme 25). For instance, when
bromocyclopropane 94 was treated with In(OTf)3, pyrido-
[1,2-a]indole 95 was obtained in 29% yield. The product presumably
arises from a nucleophilic ring-opening cyclization followed by
Scheme 24 Acid-catalyzed domino ring-opening/Friedel–Crafts alkyla-
tion sequence of N-indolyl cyclopropyl b-amidoesters.
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Fig. 3 Cyclopropyl b-amidoesters’ substrate scope.
Scheme 25 Domino cyclopropane ring-opening annulation/aromatization.
Scheme 26 Molchanov’s base-promoted b-lactam formation.
aromatization via rapid HBr elimination. Similar eliminations
were observed with ethers, thioethers, and amine substituents.
3.3.5. b-Lactams. Molchanov et al. designed the synthesis of
b-lactams from spirocyclopropane isoxazolidines 96 (Scheme 26).36
Deprotonation of the amide proton in 96 with t-BuOK initiated
the ring-opening cyclization to afford b-lactams 97 with
an azeto[2,3-d]isoxazolidine core in 50–80% yield. Both alkyl
and aryl substituents were tolerated about the isoxazolidine
moiety.
4. Formal cycloadditions
The use of D–A cyclopropanes for formal 1,3-dipolar cycloaddi-
tions is well-documented for intermolecular cases.9,12–15,17,18
Despite Snider’s report on the intramolecular [3+2] cycloaddi-
tion of cyclopropane-1,1-diesters with alkenes in 1986,36 it was
not until the past six years that intramolecular dipolar cyclo-
additions of cyclopropanes reappeared in the literature. Since
then, various groups have demonstrated the utility of these
intramolecular cycloadditions. This approach has proven to be
a formidable tool for the synthesis of natural products as
various tethered dipolarophiles (e.g. alkenes, alkynes, nitrones,
imines, aldehydes and ketones) will react to give polycyclic
structures with diverse frameworks in one step. The use of an
acid activator is normally required and has resulted in the
development of numerous catalytic protocols.
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In the following section, recent examples of intramolecular
formal 1,3-dipolar cycloadditions will be presented. In most
cases, the reactions are polar in nature and involve nucleophilic
ring-opening of the cyclopropane to generate a transient
electrophilic species with subsequent nucleophilic attack by
the pendant carbanionic moiety. For rare cases in which complete
ring-opening of the D–A cyclopropane occurs to give a 1,3-dipole
prior to engaging the dipolarophile, the transformation is
expected to be concerted.
4.1. Amino alcohols
For the past 10 years, the Kerr lab has published an appreciable
amount of work on the reactivity of D–A cyclopropanes in
formal [3+2] and [3+3] cycloadditions with nitrones, imines,
oxime ethers, hydrazones and allyl silanes.13 More recently,
Kerr began exploring the utility of intramolecularity for these
cycloadditions. In 2009, Kerr and Dias reported an intra-
molecular formal homo-[3+2]-dipolar cycloaddition of in situ-
generated nitrone cyclopropane-1,1-diesters 99 (Scheme 27).37
A domino cyclopropane ring-opening/annulation was initiated
by the oxygen of the nitrone (prepared from cyclopropane
aldehydes 98) to form 2-oxa-3-azabicyclo[2.2.2]octanes 101 in
fair to excellent yields (60–98%). 101 was readily reduced with
Zn–AcOH to afford 1,4-aminoalcohols 102 in 69–92% yield.
When the aldehyde tether length was limited to two carbon
units, only the [2.2.2] ring system was accessible. Nonetheless,
the incorporation of aliphatic, alkenyl and aromatic (hetero-
aromatic) moieties as the linker was well tolerated.
4.2. Pyrazolidines
Kerr similarly displayed the application of cyclopropyl hydrazones
in intramolecular formal dipolar cycloadditions (Scheme 28).38
Hydrazinoethyl 1,1-cyclopropanediesters 103 were converted to
their corresponding hydrazones. The hydrazones were further
reacted to prepare cis- and trans-pyrazolidines 104 in modest to
excellent yields (16–90%). The cis–trans-isomeric ratios could be
Scheme 27 Intramolecular homo-[3+2]-dipolar nitrone-cyclopropane
cycloaddition.
Scheme 28 Stereodivergent synthesis of fused bicyclopyrazolidines.
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controlled by preferential formation of the E- or Z-azaiminium
intermediates governed by the order of addition of the aldehyde
and Yb(OTf)3. If the aldehyde is added followed by the catalyst,
trans-adduct 104b is the major product. Conversely, cis-adduct 104a
was obtained preferentially when the catalyst was added first. When
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the Boc group was replaced with a methyl carbamate, the selectivity
was improved for the 2,5-cis-pyrazolidines significantly. Following
Krapcho decarbalkoxylation, pyrazolidine adducts 104 were readily
converted to pyrrolidines via N–N cleavage with SmI2.
4.3. Total synthesis of FR901483
In another paper, Kerr and Carson disclosed the total synthesis of
the immunosuppressive alkaloid FR901483 (105) where the key step
involved an intramolecular imine/cyclopropane formal cycloaddition
(Scheme 29).39 The main pyrrolidine-forming reaction was per-
formed by the addition of a dilute solution of paraformaldehyde
and Yb(OTf)3 to cyclopropane 106 in 1,2-dichloroethane at 70 1C.
The resulting imine 107 attacks the cyclopropane to generate
iminium intermediate 108 and the pendant malonate anion. Anion
attack on the iminium provides the aza-tricyclic core 109 in 67%
yield. In the absence of paraformaldehyde, direct cyclopropane ring-
opening by the amino group was not observed. With the core
assembled, the synthesis of FR901483 (105) was completed in
18 linear steps over the entire reaction sequence.
4.4. Oxa- and aza-[n.2.1] skeletons
Inspired by the work of Snider and Kerr, Wang and co-workers
reported a Lewis acid-catalyzed intramolecular [3+2] cross-
cycloaddition (IMCC) of cyclopropane-1,1-diesters with carbo-
nyls and imines (110 or 111) to form bridged bicyclo[n.2.1] ring
systems (Scheme 30).40 When D–A cyclopropanes containing
tethered aldehydes or ketones were subjected to 20 mol% of
Scheme 29 Kerr’s total synthesis of FR901483.
Scheme 30 Lewis acid-catalyzed intramolecular [3+2] cross-cycloaddition
(IMCC).
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Sc(OTf)3, Yb(OTf)3, or SnCl4 in 1,2-dichloroethane, oxabicyclo[n.2.1]
skeletons 114 (n = 2, 3, or 4) were formed in 27–96% yield. When the
same reactions were carried out in toluene with aryl and alkyl
amines over 4 Å molecular sieves, the desired azabicyclo[n.2.1]
products 115 were obtained in 75–84% yield.
4.5. Formal synthesis of platensimycin
This IMCC approach was applied to the formal total synthesis of
platensimycin (116, Scheme 31).40 Treatment of cyclopropane-1,1-
diester 117 with Sc(OTf)3 afforded the formal [3+2] cycloadduct
118 in 87% yield. Subsequent decarbalkoxylation formed almost
exclusively the endo-isomer 119 in 79% yield. 119 was converted
into the known intermediate 120 which was used to complete the
synthesis of platensimycin.
4.6. Total synthesis of bruguierol A
Wang and co-workers applied a similar [3+2] IMCC approach to
the total synthesis of ()-bruguierol A (121), which contains an
8-oxabicyclo[3.2.1]octane skeleton (Scheme 32).41 The target
was obtained in ten steps with an overall yield of B17%.
4.7. Acetal[n.2.1] skeletons
Adaptation of the method allowed for construction of the acetal-
[n.2.1] skeleton (Scheme 33).42 Alkoxy cyclopropane-1,1-diesters
Scheme 31 Formal synthesis of platensimycin.
Scheme 32 Wang’s synthesis of bruguierol using an IMCC approach.
Scheme 33 IMCC approach toward acetal[n.2.1]skeletons.
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124 readily underwent a TESOTf-catalyzed intramolecular [3+2]
cycloaddition in nitromethane to generate either acetal pro-
ducts 125 or 4-hydroxycyclohexanones 126 depending on the
length of the linker. For linkers with n = 1 and 2, acetals 124
were generated in 28–94% yield. Exo/endo ratios were substrate-
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dependent. Acetal reduction of 125 with TiCl4 and Et3SiH
provided cyclic b-hydroxycarbonyl compound 127. For shorter
linkers (n = 0), product 126 was obtained in 50–95% yield as
predominantly the endo-isomer (up to >95 : 5 dr). The method
was used to construct 2,8-dioxabicyclic[3.2.1] skeletons as well.
4.8. Komaroviquinone core construction
In the same report, Wang showcased the synthesis of the
tricyclic icetexane diterpenoid 6-7-6 core skeleton, which is
present in komaroviquinone (128, Scheme 34).43 The reaction
of cyclopropane 129 (prepared in four steps from o-bromobenzyl
bromide) with PdCl2(MeCN)2 (5 mol%) generated ketone inter-
mediate 130 which readily underwent the [3+2] IMCC reaction to
provide 131 in 81% as a 91 : 9 exo/endo dr. 131 was used to access
the 6-7-6 tricyclic core 132.
4.9. Cyclopenta[c]chromenes
Alkynes have also been utilized in intramolecular [3+2] cyclo-
additions with D–A cyclopropanes.44 In one representative
example, Liang and co-workers obtained cyclopenta[c]-
chromenes 134 from cyclopropane 133a in moderate to high
yields (48–94%) with Sc(OTf)3 (10 mol%) as the Lewis acid
catalyst (Scheme 35).44 Although electron-rich and electron-poor
Scheme 34 Construction of the icetexane diterpenoid 6-7-6 tricyclic
core skeleton.
Scheme 35 Intramolecular [3+2] alkyne-cyclopropane cycloaddition.
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aryl groups were well-tolerated on the alkyne, aliphatic and
terminal alkynes failed to furnish the cycloaddition products.
Finally, tetrahydroquinoline 135 was obtained in 83% yield
when substituted anilino cyclopropane 133b was subjected to
the reaction conditions.
5. Umpolung reactions
Umpolung reactions have long served as useful tools for
synthetic chemists to manipulate functional groups. For
example, N-heterocyclic carbenes (NHCs) will promote umpolung
reactivity for the carbonyl moiety, essentially making it a donor
group. For cyclopropanes bearing aldehydes, ring-opening
can be catalyzed by NHCs through this umpolung chemical
reactivity. This approach is particularly useful for formation of
pyrone derivatives.
Dihydro-a-pyrones
You and co-workers demonstrated that 2-acyl-1-formylcyclo-
propanes underwent intramolecular tandem redox lactoniza-
tion with NHC catalysts.45 Several NHCs were screened, and the
optimal reaction conditions chosen were 5 mol% of triazolium
salt 137, 30 mol% DBU, and 4 Å molecular sieves in dioxane at
65 1C (Scheme 36). The generality of the reaction was tested
using various 2-acyl-1-formylcyclopropanes 136. 3,4-Dihydro-a-
pyrones 138 were formed in moderate to high yields (50–92%).
R2 can be aliphatic as well as aromatic; R1 was mainly limited to
aryl groups. When an alkyl substituent (t-butyl) was present at
R1, the pyrone was obtained in a significantly lower yield (30%).
You also showed that optically active 3,4-dihydro-a-pyrones are
readily prepared from enantioenriched cyclopropanes without
loss of optical purity. Finally, a one-pot synthesis of 3,4-dihydro-
a-pyrones 138 from allylic alcohols was disclosed.
6. Rearrangements
Rearrangements represent an expedient method to access
complex chemical frameworks in an atom-economical manner.
Rearrangements can readily occur upon ring-opening of strained
systems such as cyclopropanes. Moreover, the polarized nature
of D–A cyclopropanes allows for strategic design and use of
Scheme 36 You’s NHC-catalyzed ring-expansion of formylcyclopropanes.
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rearrangement reactions that generate new rings. Rearrange-
ments involving cyclopropanes are normally categorized into
three major classes: (1) rearrangements of vinylcyclopropanes; (2)
acid-promoted rearrangements; and (3) radical rearrangements.
The first class, vinylcyclopropane rearrangements, is outside
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the scope of this review article. Despite representing well-
studied synthetic methods for the construction of complex ring
systems,46 vinylcyclopropane rearrangements are much less
influenced by the placement of donor and acceptor groups
as compared to D–A cyclopropanes. Furthermore, these trans-
formations are believed to occur through either a diradical-
mediated two-step process or an orbital symmetry-controlled
pericyclic mechanism. Given reactivity differences, vinylcyclo-
propane rearrangements will not be discussed in further
detail. Instead, two distinctive examples of an acid-promoted
rearrangement and a radical rearrangement of D–A cyclo-
propanes are presented.
6.1. Acid-promoted rearrangements
Skeletal rearrangements may occur upon cleavage of the D–A
cyclopropane C–C bond on treatment with acid. As one highly
electrophilic center is generated, an adjacent group can migrate,
generating a more stabilized intermediate. For D–A cyclopropanes,
substitution with heteroatoms provides the necessary stabilization
of the electrophilic center to promote rearrangement. One
representative example is shown below.
Pyrrolidinones and pyrro[2,3-c]quinolines. Reiser published
an efficient access to cis-4,5-disubstituted pyrrolidinones 142 in
a catalytic Sc(OTf)3-catalyzed multicomponent approach using
cyclopropapyrrolines 141, furaldehydes 139 and aromatic
amines 140 (Scheme 37).47 The proposed mechanism involves
an initial Povarov reaction of aldimine 143 (formed in situ) onto
pyrroline 141 to form polycyclic cyclopropane 143. Sc(OTf)3-
mediated cyclopropane ring opening followed by furan migra-
tion gives 146 which undergoes rearomatization via C–N bond
Scheme 37 Reiser’s rearrangement approach to pyrrolidinones.
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Scheme 38 Reiser’s synthesis of dihydropyrro[2,3-c]quinolines.
cleavage to generate quinoline intermediate 147. Subsequent
Boc hydrolysis and lactamization affords pyrrolidinone 142. At
ambient temperature, both endo-144 and exo-144 are produced
in 3.5 : 1 dr and can be readily separated. When other aryl
aldehydes 148 are used in the place of furaldehydes, no rearrange-
ment products were observed (Scheme 38). Conversely, stable
polycyclic imines 150 were formed as diastereomeric mixtures in
good yields (53–70%) via cyclopropane ring-opening. Interestingly,
a stable imine was observed in the case of furaldehydes when the
exo-isomer is subjected to Sc(OTf)3 under reflux conditions,
whereas subjecting endo-144 to Sc(OTf)3 under reflux conditions
gave pyrrolidinones 142.
6.2. Radical rearrangements
D–A cyclopropanes will undergo homolytic cleavage about the
polarized C–C bond when either the donor or acceptor group
bears an unpaired electron. When this process transpires
intramolecularly, radical recombination will generate new
skeletal frameworks. Along these lines, Molchanov reported
the radical rearrangements of D–A cyclopropanes resulting from
the 1,3-dipolar cycloaddition of ketonitrones with 3-acceptor
alkylidenecyclopropanes.48
6.2.1. Azetoquinolines. Cycloaddition reactions (toluene
under reflux) between Feist’s ester 152 (an alkylidenecyclopro-
pane) and ketonitrones 151 afforded azetoquinolines 154 in up
to 54% yield along with minor side products 155 (Scheme 39). The
reaction proceeds through the corresponding 5-spirocyclopropane-
isoxazolidine cycloadduct 153, which rearranges to give products
154 and 155. When the reaction was performed in benzene under
reflux, 153 was formed in 79% yield with a small amount (3%)
of 1,2,5,6-tetrahydropyridine 155. Adduct 153 was quantitatively
transformed to 155 by heating in p-xylene.
The authors attributed the formation of the rearrangement
products 154 and 155 to spirocyclopropanes 153 undergoing
thermally induced Brandi–Guarna rearrangements,48 which
involves a radical cyclopropane ring-opening (Scheme 40).
Ring closure of the resulting biradicals 157 or 158 forms either
Scheme 39 Cycloaddition-rearrangement cascade of nitrones 151 and
Feist’s ester 152.
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Scheme 40 Proposed mechanism for formation of products 154 and 155.
Scheme 41 Proposed mechanism for formation of pyrroloquinoline 161.
six-membered tetrahydropyridines 155 or eight-membered azo-
cinones 159. Transannular nucleophilic attack of the nitrogen
on the keto group generates azetoquinolines 154.
6.2.2. Pyrrolo[1,2-a]quinolines. Alternatively, when gem-
inal acceptor-substituted alkylidenecyclopropanes 160 were
reacted with ketonitrones 151a, pyrrolo[1,2-a]quinolines 161
were obtained in 32–81% yield (Scheme 41).48 Product 161
was envisioned to arise through an analogous azetoquinoline
intermediate 163 that undergoes ring-opening and cyclocon-
densation to give 161.
7. Ring-opening lactonizations/
lactamizations
Ring-opening can initiate intramolecular ring-formation at
peripheral sites within a molecule. Here, an internal nucleo-
phile reacts directly with the acceptor unit to generate a new
ring as compared to reacting at the polarized cyclopropane C–C
bond. Stabilization of the ring-opened intermediate is usually
accomplished by employing heteroatom donor substituents.
7.1. Tetrahydropyranones and lactones
Gharpure and co-workers reported a series of tandem ring-opening/
lactonization reactions of cyclopropafuranols 165 (Scheme 42).49
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Scheme 42 Tandem ring-opening reactions of cyclopropafuranones.
Scheme 43 Tandem ring-opening/lactonizations with various nucleophiles.
Upon treatment with TMSOTf, 165 undergoes cyclopropane ring-
opening and subsequent lactonization of the pendant ester onto
the proximal alcohol. This sequence leaves a transient oxonium
intermediate that is readily trapped with nucleophiles. When
Et3SiH is used to trap the oxonium, furafuranones 167a and
167b are obtained in 85 and 88% yield, respectively. When
mCPBA was substituted for Et3SiH, furofuradiones 168a and
168b were produced in 89% and 64% yield, respectively.
The tandem ring-opening-lactonization sequence was shown
to be very general, and various nucleophiles were used to access
substituted lactones (169–171) and pyranone derivatives 172
(Scheme 43).
7.2. Piperidones and fused-lactones
In 2012, Gharpure published a related report on the tandem
ring-opening/lactamization behavior of cyclopropapyrrolidines
173 (Scheme 44).50 As with the earlier lactonization report,
TMSOTf, in the presence of various trapping agents, promoted
the analogous tandem ring-opening/lactamization reaction and
gave products 175–177 in good to excellent yields (70–92%) with
high diastereoselectivities (>19 : 1 dr). The reactive species for
Scheme 44 Ring-opening reactions of cyclopropapyrrolidines.
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these tandem reactions is iminium 174 which is attacked by
various nucleophiles.
8. Conclusions and outlook
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Donor–acceptor (D–A) cyclopropanes are very useful privileged
structures in organic synthesis. Their inherent ring strain,
coupled with substituent-controlled C–C bond polarization/
cleavage, has led to a host of interesting transformations.
As discussed, these D–A cyclopropanes readily participate in
intramolecular ring-opening cyclizations ranging from cyclo-
isomerizations and cycloadditions to rearrangements and ring
expansions. This breadth of chemistry and multiple modes of
intramolecular reactivity allow for the synthesis of simple
carbo- and heterocycles as well as complex polycycles and
natural products. Controllable intramolecular reactivity often
enables high selectivities. In particular, good diastereocontrol
can be obtained whereas enantiocontrol remains a formidable
challenge. The future of this chemistry will rest on the develop-
ment of reliable enantioselective methods. In summary, the
intramolecular ring-opening cyclizations of D–A cyclopropanes
serve as powerful tools in synthesis with foreseeable applications
in medicinal chemistry, chemical biology, materials science and
the pharmaceutical industry.
Acknowledgements
S.F. gratefully acknowledges financial support from the National
Science Foundation (CAREER Award CHE-1056687). L.H.P. thanks
the Georgia Tech CD4 for a GAANN Fellowship. M.A.C. thanks the
National Science Foundation for a graduate fellowship, Georgia
Tech for a Presidential Fellowship and the MacArthur Foundation
for a Sam Nunn Security Fellowship.
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