Interrupted carbonyl-olefin metathesis via oxygen atom transfer

Article abstract of DOI:10.1126/science.aar8238

Some of the simplest and most powerful carbon-carbon bond forming strategies take advantage of readily accessible ubiquitous motifs: carbonyls and olefins. Here we report a fundamentally distinct mode of reactivity between carbonyls and olefins that differs from established acid-catalyzed carbonyl-ene, Prins, and carbonyl-olefin metathesis reaction paths. A range of epsilon, zeta-unsaturated ketones undergo Br?nsted acid-catalyzed intramolecular cyclization to provide tetrahydrofluorene products via the formation of two new carbon-carbon bonds. Theoretical calculations and accompanying mechanistic studies suggest that this carbocyclization reaction proceeds through the intermediacy of a transient oxetane formed by oxygen atom transfer. The complex polycyclic frameworks in this product class appear as common substructures in organic materials, bioactive natural products, and recently developed pharmaceuticals.

Full text of DOI:10.1126/science.aar8238

RESEARCH
in dichloroethane, the desired metathesis pro-
duct 16 was obtained in 71% yield. We initially
ORGANIC CHEMISTRY
3
postulated that iron(III) triflate [Fe(OTf) ] could
function as a stronger Lewis acid catalyst to
further improve the yield of the carbonyl-olefin
metathesis product 16. However, subjecting the
Interrupted carbonyl-olefin
metathesis via oxygen atom transfer
3
same aryl ketone 14 to 10 mol % Fe(OTf) re-
sulted in the formation of a new product, in 55%
yield, that was identified as tetrahydrofluorene
17. We hypothesized that this new compound
likely arose from an intermediate carbocation
that subsequently underwent Friedel-Crafts alkyl-
ation with the pendant aromatic ring to form
the tricyclic core. This outcome is in stark con-
1
1
1
2
Jacob R. Ludwig , Rebecca B. Watson *, Daniel J. Nasrallah *, Joseph B. Gianino ,
1
1
1
Paul M. Zimmerman , Ren A. Wiscons , Corinna S. Schindler †
Some of the simplest and most powerful carbon-carbon bond forming strategies take
advantage of readily accessible ubiquitous motifs: carbonyls and olefins. Here we report a
fundamentally distinct mode of reactivity between carbonyls and olefins that differs from
established acid-catalyzed carbonyl-ene, Prins, and carbonyl-olefin metathesis reaction
paths. A range of epsilon, zeta-unsaturated ketones undergo Brønsted acid–catalyzed
intramolecular cyclization to provide tetrahydrofluorene products via the formation of two
new carbon-carbon bonds. Theoretical calculations and accompanying mechanistic studies
suggest that this carbocyclization reaction proceeds through the intermediacy of a
transient oxetane formed by oxygen atom transfer. The complex polycyclic frameworks
in this product class appear as common substructures in organic materials, bioactive
natural products, and recently developed pharmaceuticals.
3
trast to the reactivity observed in FeCl -catalyzed
carbonyl-olefin metathesis, which proceeds via an
asynchronous, concerted mechanism and does not
involve carbocations as essential intermediates.
As such, this result indicated that altering the
catalytic system, which we ultimately discovered
to be Brønsted acid catalyzed, provides access to
a distinct reaction pathway relying on carboca-
tion intermediates. The combined importance of
the tetrahydrofluorene products obtained along
with the distinct reactivity observed upon Brønsted
acid catalysis of aryl ketone 14 prompted us to
further optimize this reaction, explore the sub-
strate scope, and investigate the reaction mech-
anism of this transformation.
Thorough optimization involved the evalua-
tion of various Lewis and Brønsted acids, solvents,
and reaction times and ultimately led to the fol-
lowing optimal reaction conditions: 5 mol % triflic
acid (TfOH) at 80°C in degassed benzene (see
supplementary materials for details).
Initial efforts to explore the scope of this trans-
formation focused on investigating the effect
of varying the olefin substitution (Fig. 2A). The
trisubstituted olefins 18 and 19 provided the cor-
responding tetrahydrofluorene product in 85 and
86% yield, respectively. Phenyl-substituted olefin
20 and exocyclic olefins 21 to 23 proved to be
viable substrates, with the latter leading to spi-
rocyclic tetrahydrofluorene products. Specifi-
cally, piperidine 23 bearing a para-trifluoromethyl
phenylsulfonylamide underwent efficient cycliza-
tion in 87% yield, demonstrating the potential for
the incorporation of heteroatoms into the poly-
cyclic scaffold. Aryl ketones 24 and 25, in-
corporating either a 1,2-di-substituted olefin or a
1,1-di-chlorinated olefin, failed to undergo the de-
sired transformation, suggesting that two carbon-
based substituents are required to increase the
nucleophilicity of the olefin.
The optimized reaction conditions for the for-
mation of tetrahydrofluorenes proved general for
various electronically and sterically differentiated
aryl ketone substrates (Fig. 2B). Electron-rich
aryl ketones bearing hydroxyl, methoxy, or dioxole
functionalities underwent the desired trans-
formation in good to excellent yields (17, 26,
27, 31, 32, 36, and 42, Fig. 2B). Specifically,
di- and trimethoxy–substituted aryl ketones 26
and 42 provided the desired products in 78 and
90% yield, respectively. A silyl-protected phenol
underwent the desired cyclization with advan-
tageous in situ deprotection to result in 92%
arbonyl and olefin functionalities generally
react together through carbonyl-ene (1–5)
or Prins (5–10) pathways upon activation
with strong Brønsted or Lewis acids. Both
pathways can be accessed from similar
[2+2] cycloadditions such as the Paternò-Büchi
reaction (17–19).
We herein report that these fundamental acid-
mediated transformations between carbonyls and
olefins can be expanded to include an additional
mode of reactivity (IV, Fig. 1A). This transfor-
mation resembles the carbonyl-olefin metathesis
reaction in that it also proceeds via an oxetane (8);
however, its fragmentation pathway is interrupted
to result in the formation of an intermediate
carbocation. This interrupted carbonyl-olefin me-
tathesis path relies on Brønsted acid activation
of carbonyl and olefin functionalities to yield a
complex, carbocyclic framework 9 (20, 21) upon
formation of two carbon-carbon bonds. Whereas
this multiple bond–forming process selectively
yields the tetrahydrofluorene product 9, the pres-
ence of a Brønsted acid has previously been
reported to be detrimental to many Lewis acid–
catalyzed carbonyl-ene and Prins reactions, result-
ing in undesired polymerization and isomerization
of olefins (22). Furthermore, this interrupted
carbonyl-olefin metathesis reaction provides
access to tetrahydrofluorene product 9 in a single
synthetic transformation, whereas current strat-
egies rely on multistep sequences and precious
metal–catalyzed cycloisomerizations (23, 24).
Tetrahydrofluorenes represent key structural
elements in materials science (10) (25) and are
ubiquitous core structures in biologically active
natural products (11) (26). Additionally, tetrahy-
drofluorenes are found in recently developed phar-
maceuticals [Merck’s ERb agonist 12 (27) and
ledipasvir 13 (28), part of Harvoni, Gilead’s two-
component treatment against hepatitis C].
C
substrates 1, depending on the choice of catalyst
and conditions (Fig. 1A). Upon coordination to a
carbonyl, Lewis acids can induce a change in po-
larization that enhances reactivity. Different Lewis
acids can subtly alter the charge distribution in the
resulting Lewis acid–substrate complex (11–14) to
generate a continuum between a stepwise mech-
anism involving carbocationic intermediate 2
and a concerted mechanism via a six-membered
transition state 3 (I, Fig. 1A) (3). The carbonyl-ene
reaction can proceed through either route to
generate homoallylic alcohol 4 upon addition of
an electrophilic carbonyl to an alkene with con-
comitant transfer of an allylic hydrogen atom. In
comparison, the Prins reaction proceeds through
intermediate carbocation 2 that is subsequently
captured by an exogenous nucleophile to provide
the corresponding alcohol 5 (II, Fig. 1A) (5). In a
further modulation of the reactivity between car-
bonyls and olefins, we have recently reported an
iron(III)-catalyzed carbonyl-olefin ring-closing me-
tathesis reaction of substrate 1 to provide cyclo-
hexene product 7 (III, Fig. 1A) (15). Mechanistic
studies supported a concerted, asynchronous
[
2+2]-cycloaddition reaction that does not rely on
carbocation intermediates to form oxetane 6,which
subsequently fragments in an asynchronous,
concerted retro-[2+2]-cycloaddition to provide
the corresponding cyclopentene and -hexene me-
tathesis products (16). In this context, Lewis acid
activation opens access to intermediate oxetanes
that are otherwise restricted to photochemical
During our investigations into the iron(III)-
catalyzed carbonyl-olefin metathesis reaction, we
discovered a complementary mode of reactivity
of aryl ketone 14, depending on the choice of
iron(III) catalyst (Fig. 1B). Specifically, when 14
was converted under the optimal reaction condi-
tions developed for carbonyl-olefin metathesis
1
Department of Chemistry, University of Michigan, Ann Arbor,
2
MI, USA. Advanced Materials and Systems Research, BASF,
Wyandotte, MI, USA.
These authors contributed equally to this work.
*
†
Corresponding author. Email: corinnas@umich.edu
3
using 5 mole % (mol %) iron(III) chloride (FeCl )
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yield of 27; subjection of the corresponding un-
protected phenol also afforded efficient conver-
sion to the desired tetrahydrofluorene 27 in 71%
yield. Aryl ketones bearing electron-neutral tert-
butyl, methyl, naphthyl, or phenyl substitution at
the aromatic moiety provided the corresponding
products in up to 94% yield (28, 37, 43, and 46,
Fig. 2B). Electron-deficient aryl ketones bearing
chlorine or fluorine substitution reacted to form
41 and 47 in 66 and 88% yield, respectively. The
para position of the aromatic subunit was thor-
oughly investigated and found to be widely elec-
tronically tolerant (27 to 29, 32, 33, 35, 37, 39
to 41, 44, 46, and 47, Fig. 2B). Similarly, sub-
stitution at the meta and ortho positions of the
aromatic subunit led to the desired tetrahydro-
fluorene products; however, in the case of meta-
substituted substrates, a mixture of regioisomers
34 and 36 was observed. The optimized reaction
conditions also proved efficient for heteroar-
omatic ketones, resulting in the formation of
benzothiophene 30 in 73% yield and thiophene
38 in 57% yield. Aryl ketones that contained het-
eroatoms distal from the reactive sites proved
viable substrates for the desired transformation,
resulting in the corresponding tetrahydrofluorene
products in up to 59% yield (29, 33, and 35, Fig. 2B).
Fig. 1. Chemistry of carbonyls and olefins. (A) Fundamental acid-catalyzed reactivity modes between carbonyls and olefins. (I) Carbonyl-ene reaction.
II) Prins reaction. (III) Carbonyl-olefin metathesis.; (IV) This work: interrupted carbonyl-olefin metathesis. The importance of the products accessible
in this reactivity mode is showcased below. LA, Lewis acid; R, hydrogen, alkyl, or aryl; Me, methyl; Nu, nucleophile; Ar, aryl. (B) Complementary reactivity
(
modes of aryl ketone 14 are accessible depending on the choice of iron(III)-derived Lewis acid catalyst. The use of FeCl
carbonyl-olefin metathesis product 16, whereas Fe(OTf) results in tetrahydrofluorene 17. rt, room temperature.
3
leads to the formation of the
3
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1
Fig. 2. Substrate scope. Conditions: Ketone (1.0 equivalent; 0.02 M),
TfOH (5 mol %) in benzene at 80°C. See supplementary materials for
additional experimental details. (A) Variation of the alkene substitution.
‡Percent yield and percent conversion determined by H nuclear magnetic
resonance (NMR) using dimethyl terephthalate or mesitylene as an internal
standard. §98% of starting material 25 is recovered. ||Starting material
TBS (tert-butyldimethylsilyl) protected. ¶Percent yield determined by gas
chromatography using dodecane as an internal standard. #Reaction run on a
10.2-mmol scale. **Percent yield and diastereomeric ratio (dr) determined
F
Et, ethyl; Ts, (4-(trifluoromethyl)phenyl)sulfonyl; tBu, tert-butyl. (B) Variation
of the aryl ketone and carbon tether. Bn, benyl; Ph, phenyl. (C) In situ
isomerization of alkenes to expand substrate scope. Footnotes: *4.3:1
mixture of E and Z alkenes. †81% of starting material 24 is recovered.
1
by H NMR using dimethyl terephthalate as an internal standard.
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Advantageously, benzyl ether 29 and phthalimide
3 can be deprotected to provide handles for
further elaboration. Tert-butyl–substituted aro-
matic substrates bearing distinct functionalities
along the carbon backbone resulted in the for-
mation of the desired products 39, 40, and 44
in up to 65% yield, whereas the substrate bearing
minimal substitution also proved viable, provid-
ing the desired tetrahydrofluorene 45 in 55%
yield. Taken together, the substrate scope sug-
gests that the electronics of the aryl ketone and
sterics on the substrate tether do not alter the
efficiency of this transformation. The optimized
reaction conditions also proved amenable to
gram-scale synthesis of 37.
3
Fig. 3. Mechanistic investigations. (A) Possible mechanistic alternatives in the Brønsted acid–catalyzed formation of tetrahydrofluorenes from aryl
ketones. (B) Density functional theory studies of the reaction pathway comparing carbonyl-ene reactivity to a pathway relying on a transient oxetane.
G, free energy. (C) Three-dimensional representations of intermediates and transition states.
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Fig. 4. Proposed mechanism and application. (A) Mechanistic hypothesis for interrupted carbonyl-olefin metathesis reaction. (B) Investigation of
mechanistic probe molecules. (C) Synthesis of intermediates to access known and new ledipasvir analogs. HCV, hepatitis C virus.
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Subsequent efforts focused on further expand-
ing the scope of this transformation to include
state 62, following the initial mechanistic hypoth-
esis (Fig. 3B), and (ii) a single-elementary step
pathway passing through transition state 64 and
oxetane 65 (Fig. 3B) (30). The latter path was
found to have an energy barrier 9.3 kcal/mol lower
than that of the carbonyl-ene reaction, which sug-
gests that it is the preferred reaction path. This
lower-energy pathway yields benzylic carbocation
intermediate 66 and constitutes a direct oxygen
atom transfer between two carbons (C-1 and C-3
in 66, Fig. 3B). Electronically, conversion of 61 to
66 is enabled by an asynchronous, concerted path
that is best conceptualized as two distinct transitions
connected by an unstable oxetane intermediate 65.
Figure 3, B and C, highlights the asynchronous
nature of this path by showing the transition
state 64 as the highest-energy point, which forms
oxetane 65 and subsequently fragments through
an energetically favorable ring-opening to result
in benzylic carbocation intermediate 66. The sec-
ond electronic change in this reaction path is
barrierless, due to the instability of the proton-
ated oxetane 65 when compared to its fragmen-
tation product 66.
This Brønsted acid–catalyzed mode of reactivity
complements the previously established Lewis
acid–catalyzed carbonyl-olefin metathesis reac-
tion that relies on intermediate oxetanes. How-
ever, under Brønsted acid catalysis, fragmentation
of the transient oxetane interrupts the carbonyl-
olefin metathesis pathway and results in a new
reactive intermediate, benzylic carbocation 66. As
such, the transience of 65 suggests a direct oxygen
atom transfer that represents a distinct reactivity
mode between carbonyls and olefins to provide
benzylic carbocations (Fig. 3A, pathway IV).
Taking into account the experimental and
computational results obtained, we propose the
following reaction mechanism for the Brønsted
acid–catalyzed interrupted carbonyl-olefin metath-
esis reaction (Fig. 4A). Protonation of aryl ketone
56 initiates intramolecular oxygen atom transfer
via transition state 68 to form intermediate
benzylic carbocation 60. Elimination and sub-
sequent protonation of the resulting allylic al-
cohol provides 69, which can then undergo
dehydration to produce carbocation 70. This
highly stabilized allylic carbocation undergoes a
final Friedel-Crafts alkylation to form the tetra-
hydrofluorene product 71. This hypothesis was
subsequently tested by the independent synthe-
sis of two probe molecules—specifically, tertiary
alcohols 60a and 70a (Fig. 4B). Diol 60a and
allylic alcohol 70a are both able to undergo a
Friedel-Crafts alkylation to provide tetrahydro-
fluorene product 74 upon treatment with TfOH,
which supports carbocations 60 and 70 as po-
tential intermediates. However, at lower reaction
temperatures, Friedel-Crafts alkylation does not
proceed and carbocation 70 is quenched via elim-
ination to result in diene 72. Further isomeri-
zation of diene 72 provides an experimentally
observed skipped diene 73 as a shunt product
(supplementary materials). Alternative pathways
for the formation of skipped diene 73 were in-
vestigated computationally but were found to be
higher in energy. Upon exposure to the optimized
reaction conditions, skipped diene 73 reengages
in the reaction pathway to give rise to the tetra-
hydrofluorene product exclusively (see supple-
mentary materials for experimental details).
The tetrahydrofluorene products obtained in
our one-step, multiple bond–forming transforma-
tion can be readily oxidized to the corresponding
fluorene compounds in up to 99% yield using
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone)
(supplementary materials). The synthetic value of
this cyclization-oxidation sequence has been dem-
onstrated in the synthesis of a key fluorene inter-
mediate toward a biologically active ledipasvir
analog (Fig. 4C) (28). Importantly, the interrupted
carbonyl-olefin metathesis reaction enables rapid
entry to aromatic fluorene moieties bearing dis-
tinctive substitution patterns that are difficult to
access with currently available synthetic methods.
Specifically, symmetric and asymmetric analogs
are accessible using the same fluorene core.
Under the optimized reaction conditions, aryl
ketone 75 yields tetrahydrofluorene 76, which
upon subsequent oxidation results in fluorene
77. This intermediate (77) can be further ad-
vanced to known symmetric ledipasvir derivative
78, with a hepatitis C virus GT1b replicon EC50
(median effective concentration) value of 14 pM,
or an unknown asymmetric analog 79 (28).
The developed interrupted carbonyl-olefin me-
tathesis reaction complements the repertoire of
well-established reactions between carbonyls and
olefins and provides entry into the formation of
complex, polycyclic tetrahydrofluorenes in a sin-
gle synthetic step relying on TfOH as an in-
expensive catalyst.
1,1-disubstituted alkenes that are readily accessi-
ble via Wittig olefination or hydroarylation strat-
egies (Fig. 2C). Isomerization of these alkenes in
situ under Brønsted acid catalysis results in the
corresponding 1,2,2-trisubstituted analogs that
subsequently enable facile access to tetrahydro-
fluorene products bearing distinct substitution
at the central five-membered ring. Specifically,
aryl ketones bearing electron-rich and neutral
substituents proved viable substrates in the
isomerization-cyclization sequence and provided
the corresponding tetrahydrofluorene products
in up to 76% yield (48 to 55, Fig. 2C). Varying the
electronics of the alkene itself was tolerated with
both electron-poor (50 and 51) and -neutral (52
and 53) styrene derivatives, which underwent the
desired transformation in up to 70% yield. This in
situ isomerization-cyclization sequence is not only
limited to terminal styrene derivatives but also
tolerates the alkene-bearing aliphatic substituents
(
54). Modest diastereoselectivity (3:2 diastereo-
meric ratio) was observed for tetrahydrofluorene
5, demonstrating the potential for this mode
5
of reactivity to be used in the development of
stereoselective methods.
On the basis of the literature precedent of
transformations between carbonyls and olefins,
we initially considered a mechanistic hypothesis
relying on a carbonyl-ene reaction to form alco-
hol 57 upon nucleophilic addition between the
carbonyl and olefin functionalities of 56 (Fig. 3A).
However, this initial mechanistic hypothesis
proved inconsistent with experimental data (sup-
plementary materials), and other potential mech-
anistic alternatives were evaluated. In addition to
a concerted carbonyl-ene reaction path (I, Fig. 3A),
intermediate carbocation 58 could result from
a nucleophilic addition between the carbonyl
and olefin moieties in 56, in accordance with
established Prins reactivity (II, Fig. 3A). A third
alternative would be the formation of oxetane
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Ludwig et al., Science 361, 1363–1369 (2018)
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2
2
2
2
SUPPLEMENTARY MATERIALS
7
www.sciencemag.org/content/361/6409/1363/suppl/DC1
Materials and Methods
Figs. S1 to S7
Tables S1 to S4
References (31–64)
NMR Spectra
(
fellowships to C.S.S.). J.R.L. and R.B.W. thank the National
1
Science Foundation for predoctoral fellowships. P.M.Z. thanks the
National Science Foundation (CHE-1551994). Author
contributions: J.R.L., R.B.W., D.J.N., and C.S.S. devised the
experiments and prepared the manuscript for publication. D.J.N.
conducted the theoretical investigations. J.B.G. performed initial
experiments, P.M.Z. provided guidance in theoretical
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20 December 2017; accepted 25 July 2018
10.1126/science.aar8238
investigations, and R.A.W. conducted x-ray crystallographic
Ludwig et al., Science 361, 1363–1369 (2018)
28 September 2018
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Interrupted carbonyl-olefin metathesis via oxygen atom transfer
Jacob R. Ludwig, Rebecca B. Watson, Daniel J. Nasrallah, Joseph B. Gianino, Paul M. Zimmerman, Ren A. Wiscons and
Corinna S. Schindler
Science 361 (6409), 1363-1369.
DOI: 10.1126/science.aar8238
Two ways out of an oxetane
Oxetanes are highly reactive four-membered rings that contain three carbon atoms and an oxygen atom.
Recently, they were implicated as transient intermediates in Lewis acid−catalyzed intramolecular metathesis reactions of
ketones with olefins. Ludwig et al. now report that by replacing the Lewis acid with a strong Brønsted acid, they can
change the course of the oxetane ring-opening. In a so-called interrupted metathesis, the oxygen atom migrates and then
departs through dehydration, while the remaining carbon framework cyclizes to form tetrahydrofluorene compounds.
Science, this issue p. 1363
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