RES EARCH
RESEARCH ARTICLE SUMMARY
◥
ORGANIC CHEMISTRY
A solution to the anti-Bredt olefin synthesis problem
Luca McDermott†, Zach G. Walters†, Sarah A. French‡, Allison M. Clark‡, Jiaming Ding‡,
Andrew V. Kelleghan, K. N. Houk, Neil K. Garg*
INTRODUCTION: The p-bonds in unsaturated or-
RATIONALE: The study of ABOs began at the
dawn of the 20th century with Julius Bredt’s
derivatization studies of the camphane and
pinane ring systems. These studies eventually
led to Bredt’s 1924 conclusion that a carboncarbon double bond could not arise from the
branching positions of the carbon bridge, which
is now known as “Bredt’s rule” in the context of strained systems. Despite Bredt’s conclusion, many endeavors toward generating
ABOs transiently have been made over the
past century. These studies support the existence of ABOs but also suggest that ABOs
are often unstable and prone to decomposition. ABOs are still often considered inaccessible synthetic intermediates per modern
resources. A solution to the long-standing problem of accessing and intercepting ABOs would
challenge Bredt’s rule, provide a new entryway to access substituted bridged bicycles,
and highlight the potential of strategically
leveraging geometrically distorted alkenes for
use in chemical synthesis.
RESULTS: Inspired by the Kobayashi approach
toward benzyne and its successful application
to other strained intermediates, we evaluated
silyl (pseudo)halide precursors to a number of
different ABOs. Treatment of these precursors
with a fluoride source, such as Bu4NF or CsF/
Bu4NBr, in the presence of a suitable trapping
agent, led to cycloadducts indicative of an
ABO being generated in situ and undergoing
trapping. This strategy was applied to several
bicyclic ring systems, such as [3.2.1], [2.2.2],
and [2.2.1] ABOs. In all cases, we evaluated the
geometric distortion associated with the ABO
p-bond using density functional theory computations, showing that the alkenes of ABOs
Bredt’s original findings
Me
Me
OH
strained ABOs can be made and intercepted
in situ, thus providing a solution to the longstanding problem of ABO generation and trapping. Additionally, our findings highlight the
potential of strategically leveraging the heightened reactivity of geometrically distorted alkenes
for broad use in synthesis.
▪
Department of Chemistry and Biochemistry, University of
California, Los Angeles, CA 90095, USA.
*Corresponding author. Email: neilgarg@chem.ucla.edu
†These authors contributed equally to this work.
‡These authors contributed equally to this work.
Cite this article as L. McDermott et al., Science 386,
eadq3519 (2024). DOI: 10.1126/science.adq3519
READ THE FULL ARTICLE AT
https://doi.org/10.1126/science.adq3519
Anti-Bredt olefins accessed in this study
1902–1924 (Bredt)
Me
Me
CONCLUSION: These studies show that highly
Me
Me
Me
O
O
Br
Br
Me
Me
Me
“Gibt Nicht”
Stereochemical transfer study
Bredt’s rule – 1924
“A carbon double bond cannot occur
at the branching positions of the
carbon bridge (the bridgeheads)”
*
Br
*
H
SiMe 3
>95% ee
Me4NF
DMF, 23°C
H
H
~98% ee
Bredt’s rule (1924) and anti-Bredt olefins generated in this study. Summary of Bredt’s original findings from the early 1900s and the establishment of
Bredt’s rule (left). Examples of ABOs synthesized in this study, all of which were validated through trapping experiments (right, top). Transfer of point chirality in a
precursor to point chirality in the product by way of an axially chiral intermediate provides experimental evidence for the intermediacy of the twisted [2.2.2] ABO
(right, bottom). Me, methyl; DMF, N,N′-dimethylformamide; ee, enantiomeric excess.
McDermott et al., Science 386, 509 (2024)
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ganic molecules are typically associated with
having well-defined geometries that are conserved across diverse structural contexts. Nonetheless, these geometries can be distorted, leading
to heightened reactivity of the p-bond. Although
p-bond–containing compounds with bent geometries are well utilized in synthetic chemistry, the corresponding leveraging of p-bond–
containing compounds that display twisting
or pyramidalization remains underdeveloped.
One of the most notorious classes of p-bond–
containing compounds that feature twisting
and pyramidalization are anti-Bredt olefins
(ABOs), which conventional wisdom maintains
are difficult or impossible to access. We sought to
realize a solution to the long-standing problem of synthesizing and manipulating ABOs.
indeed display twisting and pyramidalization.
In the context of a [2.2.1] ABO, we show that
this geometrically distorted structure could be
used in a variety of trapping experiments, including (4+2), (2+2), (3+2), and (5+2) cycloadditions. These trapping experiments show that
ABOs can provide access to structurally complex products, including those that bear functional handles poised for further manipulation.
Computational studies were performed to
better understand the high reactivity of ABOs,
with a focus on the [2.2.1] bicyclic structure.
These studies support the notion that ABOs
have distinctly olefinic character and react in
a concerted asynchronous cycloaddition with
dienes such as anthracene. Stereochemical
studies on the [2.2.2] bicyclic system show that
point chirality present in a precursor can be
transmitted to deliver point chirality in a cycloadduct by way of an axially chiral intermediate.
This provides experimental support for the
olefinic character present in ABOs.
RES EARCH
RESEARCH ARTICLE
◥
ORGANIC CHEMISTRY
A solution to the anti-Bredt olefin synthesis problem
Luca McDermott†, Zach G. Walters†, Sarah A. French‡, Allison M. Clark‡, Jiaming Ding‡,
Andrew V. Kelleghan, K. N. Houk, Neil K. Garg*
O
rganic molecules that have carbon-carbon
p-bonds are well studied and highly valuable compounds. Synthetic transformations of these unsaturated systems
are some of the most fundamental and
widely applied reactions in organic chemistry.
The presence of p-bonding between atoms
typically forces specific geometries in order to
maximize the bonding interaction between the
p orbitals involved in the p-bond. Although these
geometric constraints resulting from p-bonds
have become “textbook thinking,” deviations
from these standard geometries are sometimes
possible, leading to changes in bonding and,
consequently, reactivity (1). A prominent example of this concept involves “bent” alkynes, which
are now commonly used in biorthogonal chemistry (2, 3) and synthetic chemistry (4–10).
The present study relates to the types of
geometric distortion highlighted in Fig. 1A:
twisting and pyramidalization of alkenes
(11, 12). As shown for ethylene (1), both carbon
termini of an alkene typically adopt a trigonal
planar geometry, where all four directly connected alkene substituents are oriented in the
same plane. The H–C=C–H dihedral angle on
each side of the alkene is 0°. In a “twisted”
alkene, the corresponding dihedral angles deviate from 0°. As alkenes become increasingly
twisted, the p-bond weakens, culminating in a
discrete diradical at 90° of twist (13). Alkenes
2 and 3 are exemplary compounds that display symmetrical twisting due to steric factors
(14, 15). Alternatively, or sometimes concurrently with twisting, pyramidalization can occur
where substituents of an alkene terminus are
positioned in the same direction away from a
Department of Chemistry and Biochemistry, University of
California, Los Angeles, CA 90095, USA.
*Corresponding author. Email: neilgarg@chem.ucla.edu
†These authors contributed equally to this work.
‡These authors contributed equally to this work.
McDermott et al., Science 386, eadq3519 (2024)
typical alkene plane. Examples of compounds
that display pyramidalization include the stable compound 5-cycloparaphenylene ([5]CPP,
4) (16), the natural product haouamine A (5)
(17, 18), and buckminsterfullerene (6) (19). Yet
another example is trans-cyclooctene (7), which
can be isolated but also used productively in
bioorthogonal reactions (20, 21). Despite these
examples, the strategic use of geometrically
distorted alkenes that display twisting, pyramidalization at the alkene termini, or both
remains an underdeveloped area in chemical
synthesis.
One of the most notorious classes of p-bond–
containing compounds that have highly distorted geometries is a subclass of bridgehead
olefins known as “anti-Bredt” olefins (ABOs)
(Fig. 1B) (22–24). The study of these species
began at the dawn of the 20th century with
Julius Bredt’s derivatizations of the camphane
and pinane ring systems. A key result was found
in the dehydrative elimination of the alcohol
present in [2.2.1]-bridged bicycle 8, where
Bredt noted the transformation as gibt nicht
(meaning “there is no”) olefin isomer 9 (25).
Ultimately, these studies led to Bredt’s 1924
conclusion that a carbon-carbon double bond
could not arise from the branching positions
of the carbon bridge (i.e., the bridgehead position) (25). Although this early finding would
not hold for larger ring systems that can allow
for bridgehead olefins to be observed or isolated,
Bredt’s 1924 discovery led to what has now become widely known as “Bredt’s rule,” as recognized by the International Union of Pure and
Applied Chemistry (IUPAC) (26) and many textbooks. More specifically, ABOs are generally
considered to be rare and unstable compounds
that contain a bridgehead alkene within a bicycle that is not “large enough to accommodate the double bond without excessive strain”
(27–30). As will be discussed further herein,
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The p-bonds in unsaturated organic molecules are typically associated with having well-defined
geometries that are conserved across diverse structural contexts. Nonetheless, these geometries can be
distorted, leading to heightened reactivity of the p-bond. Although p-bond–containing compounds with
bent geometries are well utilized in synthetic chemistry, the corresponding leveraging of p-bond–
containing compounds that display twisting or pyramidalization remains underdeveloped. We report
a study of perhaps the most notorious class of geometrically distorted molecules that contain p-bonds:
anti-Bredt olefins (ABOs). ABOs have been known since 1924, and conventional wisdom maintains
that ABOs are difficult or impossible to access. We provide a solution to this long-standing problem. Our
study also highlights the strategic manipulation of compounds that display considerable distortion
arising from the presence of geometrically constrained p-bonds.
ABOs contain alkenes with remarkably distorted
geometries that feature unsymmetrical twisting and pyramidalization of each terminus.
Despite Bredt’s rule, many endeavors toward
generating ABOs transiently have been made
over the past century. Through these attempts,
evidence for the formation of several ABOs has
been reported in the literature using a variety
of different strategies (Fig. 1B). The first successful examples, reported by the laboratories of Marshall (31), Wiseman (32, 33), and
Keese (34), took advantage of elimination
reactions from a suitable precursor to presumably intercept ABOs 10 to 12. Wiseman’s
group was able to observe ABO 10 at –80°C
using nuclear magnetic resonance (NMR) spectroscopy, which remains the only example
of a nonisolable ABO being detected (33, 35).
These early studies provided an initial guide
as to which bridgehead olefins may be observed on the basis of ring size. A key study,
relevant to our own and discussed in more
detail below, is the 1977 report by the Chan
laboratory on the [2.2.2] ABO 13 (36). Further
studies from the 1990s by the laboratories of
Wiberg (37), Platz (38), and Eguchi (39) took
advantage of carbene rearrangements of suitable precursors to generate ABOs 14 to 16.
These studies support the existence of ABOs
but also suggest that ABOs are often unstable
and prone to decomposition. Reported yields
of the few trapping experiments mostly range
from 10 to 40%. Additionally, various undesired reactions of the transient ABOs have
been proposed on the basis of experimental
observations, such as rearrangements (36),
retro–Diels-Alder reactions (40), and dimerizations (33). More recently, in 2019, Wang
and Ma used a base-mediated b-elimination to
transiently generate a bridgehead enone in a
[3.2.1] bicycle (41), thus providing an advance
in the field.
Given its relevance to our own studies, the
aforementioned 1977 study by Chan and Massuda
attempting the fluoride-mediated generation
of ABO 13 deserves special attention (Fig. 1C).
The authors prepared silyl bromide 19 as a
potential precursor, but their numerous attempts
at ABO generation predominantly led to undesired rearrangement pathways. For example,
treatment of 19 with benzyltrimethylammonium
fluoride in the presence of cyclohexene (18) gave
17. It was surmised that ABO formation may
have occurred before skeletal rearrangement.
One promising result indicative of ABO formation was described, wherein the use of nitrone
20 as a trapping agent led to (3+2) cycloadduct
21, although an isolated yield was not reported.
Thus, the Chan and Massuda study provides a
glimmer of hope but also suggests various challenges that may have hampered further studies
over the subsequent decades.
Despite seminal studies showing that Bredt’s
rule can be violated in some cases, ABOs have
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Fig. 1. Geometric distortions of unsaturated compounds and historical perspective of anti-Bredt olefins. (A) Twisting of alkene and pyramidalization of carbon
termini. (B) Historical timeline of anti-Bredt olefins. (C) Prior efforts to generate anti-Bredt olefins using silyl halide precursors.
largely remained disregarded and are typically
still considered inaccessible synthetic intermediates. We attribute this to prior efforts being scattered across several decades, mixed results in
attempted ABO generation and trapping, modest yields in successful trapping reactions, and
harsh reaction conditions used to generate
ABOs in many cases as well as the general
McDermott et al., Science 386, eadq3519 (2024)
notoriety of Bredt’s rule. Herein, we describe
a solution to the long-standing problem of accessing and intercepting anti-Bredt olefins.
Geometric distortion of anti-Bredt olefin 12
and precursor synthesis
At the outset of our studies, we analyzed the
ground-state structure of [2.2.1] ABO 12 using
1 November 2024
density functional theory (DFT). Although modern resources suggest that ABO 12 is “too
unstable to form” (42), we were sufficiently
encouraged by the prior studies by Keese and
Krebs to pursue this ABO (Fig. 2A) (34). Earlier
computational studies of ABOs, including those
by Maier and Schleyer (43), Novak (44), and
Krenske and Williams (23), were performed
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Fig. 2. Structural analysis of [2.2.1] ABO 12 and synthesis of a precursor for ABO generation.
(A) Structural features of 12 with respect to the geometric distortion about the C–C double bond. Olefin
strain energy calculated at the CCSD(T)/cc-pVTZ level of theory. Ground-state geometry calculated
at the wB97XD/def2-TZVP level of theory. (B) Synthetic route to isomers 27 and epi-27 from acrylate 22.
(C) Syntheses of silyl sulfonates 28, 29a, and epi-29a. Diastereomeric silyl nonaflate epi-29a is not a
viable ABO precursor experimentally, likely because of an unfavorable torsion angle that precludes formation
of the ABO p-bond as suggested by calculated structures 29b and epi-29b (OTf and Me3Si substituents
used to simplify computations). Calculations were performed at the wB97XD/def2-TZVP level of theory.
(D) Survey of reaction conditions for generation and trapping of ABO 12.
over several decades using theoretical methods
that were available at the time; however, theoretical studies addressing the twisting, pyramidalization, and electronic structure of ABOs
at more contemporary levels of theory warrant investigation. As such, we calculated the
ground-state structure of 12 and other ABOs
using several methods and basis sets. Results
are provided in the supplementary materials,
and our findings obtained using wB97XD/def2TZVP, the preferred functional used for studying
other strained intermediates (8, 45), are shown
in the main text. An oversimplified yet common
explanation for the inaccessibility of ABOs is
that a trans-alkene (C3–C2=C1–C6) is embedded
within the ring system. Although strain energies
do not necessarily correlate with stability and
should therefore only be used as a guide (46),
an olefin strain energy of 54.2 kcal/mol was
calculated for 12, which was not considered
detrimental for ABO generation and trapping
(47). Additionally, the predicted C=C bond
length is 1.35 Å, consistent with a bond order
of 1.86 determined by natural bond orbital
(NBO) analysis (48).
The strain is further understood by considering the two geometric distortions that result
from the confinement of the alkene to the
rigid bicyclic ring system: twisting and pyramidalization. When considering an unstrained,
typical alkene, the expected dihedral angle of
cis substituents on opposite termini is 0°. However, in the case of the alkene of ABO 12, the
dihedral angle is 22° for C7–C1=C2–C3 and 49°
for C6–C1=C2–H. The average twist angle, defined as tau (t), is 35.5°, reflecting substantial
geometric distortion due to twisting (24). As
a result of this twisting, the orbitals involved in
p-bonding still overlap, but they are misaligned
(49). With regard to pyramidalization, the sum
of angles between substituents around a typical
alkene carbon should be 360°. In the case of 12,
these angles are considerably lower owing to
pyramidalization of the carbon termini involved
in the ABO p-bond. The pyramidalization angles (Fp) at C1 and C2 are calculated to be 20.1°
and 11.6°, respectively (50). Thus, the overall
geometry at the C1 terminus of the alkene is
reminiscent of a tetrahedral geometry rather
than a trigonal planar geometry. These factors
showcase the extreme geometric distortion
seen in ABO 12 compared with a classic alkenecontaining structure and highlight why ABO
generation has remained a major challenge.
Moreover, these geometric distortions have a
pronounced impact on reactivity, as will be discussed later.
To pursue the synthesis and trapping of ABOs,
we opted to revisit Kobayashi-type elimination
chemistry (4). The implementation of this approach was considered challenging given Chan
and Massuda’s previously discussed findings
(Fig. 1C). Moreover, generating other strained
intermediates through the Kobayashi approach
RES EARCH | R E S E A R C H A R T I C L E
McDermott et al., Science 386, eadq3519 (2024)
72.2° (torsion angles are presumed to be comparable in the corresponding fluoride-bound
silicate complexes given the rigidity of the bicycle). Additionally, these stereochemical requirements support a concerted syn-elimination for
the generation of ABO 12 from 29a, which
differs from what has been proposed for the
corresponding formation of benzyne (52).
Anti-Bredt olefin generation and
trapping experiments
Select findings for the generation and trapping of ABO 12 from precursors 28 and 29a
are shown in Fig. 2D, wherein a given precursor was treated with anthracene (30) in the
presence of a fluoride source (53). The formation of cycloadduct 31 would be indicative of
ABO 12 being generated in situ and undergoing trapping, analogous to how the intermediacy of other transient strained compounds
is usually validated (4). Using silyl triflate 28,
we found that some product formation was
observed using tetrabutylammonium fluoride
(TBAF) in N,N′-dimethylformamide (DMF) at
23°C (entry 1). Lowering the temperature to 0°C
led to a slightly increased yield, presumably
because of slower generation of the strained
intermediate (entry 2) (54). Improved results were
seen using silyl nonaflate 29a (entry 3), which
we hypothesize is due to increased hydrolytic
stability relative to 28 (55–57). Other perturbations, such as switching the solvent to acetonitrile (MeCN) or changing the fluoride source to
tetramethylammonium fluoride (TMAF), led
to lower yields of 31 (entries 4 and 5, respectively). We also examined the use of cesium fluoride
(CsF) as the fluoride source. After experimentation, we found that the use of CsF and the
fluoride-solubilizing agent tetrabutylammonium bromide (TBAB) in toluene at 120°C delivered 31 in excellent yield (entry 6). We posit
that the addition of TBAB leads to slow generation of TBAF in situ, which, in turn, leads to
slow and controlled formation of the transient
ABO. The higher temperature increases fluoride
dissolution and is not considered necessary for
ABO trapping. Thus, two optimal sets of conditions were identified for generation and trapping of ABO 12 from nonaflate 29a: TBAF in
DMF at 0°C or CsF and TBAB in toluene at
120°C. Throughout our studies, only the depicted diastereomer of 31 has been observed;
the reasoning for this observation is discussed
later in this manuscript.
Nonaflate 29a could be used in a variety of
ABO generation and trapping experiments,
demonstrating the versatility of ABO 12 and
its capability of undergoing various types of
cycloadditions (Fig. 3). Reactions proceeded
using the aforementioned optimal reaction
conditions, with the preferred fluoride source
for a given experiment being determined empirically. We found that electron-rich dienes,
such as furans 34 or 36 and pyrroles 38 or
1 November 2024
40, can be used in (4+2) cycloadditions and give
rise to fused heteroatom-containing bicycles
35, 37, 39, and 41 (entries 1 through 4, respectively). Diastereoselectivities are generally
modest (i.e., ranging from 1.2:1 to 4:1). Electronpoor diene 42 is also a competent trapping
agent, as shown by the formation of 43 in
72% yield (entry 5); of note, 42 reacted with
improved diastereoselectivity (9:1 d.r.). Both
(2+2) and (3+2) cycloadditions are also viable,
as shown by experiments that used unsymmetric trapping agents. With regard to (2+2)
cycloadditions, both acrylate 44 and indene
(46) are competent trapping agents, as shown
by product 45, which is a protected amino acid
derivative, and cyclobutane 47 (entries 6 and 7,
respectively). Notably, only a single constitutional isomer is observed in each case (58).
(3+2) cycloadditions proceed using nitrone
48 or nitrile oxide 50 delivering isoxazolidine
49 and isoxazoline 51 as the major cycloadducts, respectively (entries 8 and 9, respectively).
Finally, trapping of in situ–generated ABO 12
with oxidopyridinium 52 in a (5+2) cycloaddition provides [3.2.1] azabicycle 53, again with
high selectivity for the constitutional isomer
shown (entry 10). The results shown in Fig. 3
not only validate that ABO 12 can be generated
but also showcase the breadth of reactions that
can be used as a means to synthesize functionalized bicyclic products.
Anti-Bredt olefins of different ring sizes are
also accessible (Fig. 4). The ABOs are depicted,
and, for each, we have evaluated the geometric
distortion associated with the ABO p-bond
using DFT computations. The average twist
angle and the pyramidalization angle for the
bridgehead carbon are provided for each ABO
and highlight the unusual structures of these
compounds. Routes to suitable precursors to
each ABO accessed are shown in the supplementary materials, with the choice of silyl
substituent typically being made on the basis
of synthetic efficiency. Despite not being able
to access a halide precursor to ABO 12 (see Fig.
2B discussion), we generally found the opposite to be true in efforts to prepare other ABO
precursors. More specifically, silyl halides 54
were typically accessible synthetically, rather
than the corresponding silyl sulfonates (59). In
our efforts to validate ABO generation, anthracene (30) was used as a trapping agent to give
cycloadducts 56, with the preferred fluoride
source (i.e., TBAF, CsF, or TMAF) being determined empirically. Use of monoterpene-derived
[2.2.1] ABO 57 furnishes enantioenriched cycloadduct (+)-58 (entry 1). Two isomers of a [3.2.1]
ABO are accessible, 59 and 61, as gleaned by
the formation of products 60 and 62, respectively (entries 2 and 3). The intermediacy of
[2.2.2] ABO 63 is also confirmed by the formation of fused [2.2.2] bicycle 64 (entry 4).
In addition, functionalized derivatives of ABO
59 are tolerated. Generation and trapping of
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typically requires a dihedral angle of 0° between
the C–Si bond and the C–leaving group bond.
The corresponding syn-elimination to give alkenes in rigid systems, such as bicycles, where
this dihedral angle cannot be 0° (Fig. 2C) bears
little precedent (36). Thus, it remained uncertain
as to whether the kinetic barriers required to
achieve such eliminations could be overcome,
given the poor orbital alignment seen in the
ground state. Nonetheless, we designed plausible ABO precursors and synthetic routes, with
the hope of probing some of the aforementioned
challenges and unknowns.
The precursors to ABO 12 that we envisioned
were prepared as shown in Fig. 2, B and C.
Known silyl acrylate 22 was treated with diphenyl diselenide in the presence of sodium
borohydride to provide conjugate addition
product 23. Addition of two equivalents of allylmagnesium bromide (24), followed by ringclosing metathesis, afforded cyclopentenol 25.
Subsequent radical cyclization (51) was achieved
by treatment of 25 with tris(trimethylsilyl)silane
(TTMSS) and azobisisobutyronitrile (AIBN) at
elevated temperature, thus furnishing [2.2.1]
bicycle 27 and epi-27 [1.7:1 diastereomeric
ratio (d.r.)]. These epimers presumably arise
from radical intermediate 26. Fortuitously,
they were separable using chromatography
and could be carried forward independently.
Sulfonylation reactions were used to furnish
triflate 28, nonaflate 29a, and epi-29a (Fig.
2C). In addition to sulfonylation, several attempts to synthesize the corresponding halides
were made, but these attempts were unsuccessful. Nonetheless, access to the aforementioned
precursors allowed us to evaluate different types
of sulfonate leaving groups as well as the role
of relative stereochemistry. The relative stereochemistry issue is notable, as typical Kobayashi
elimination chemistry (e.g., arynes, cyclic alkynes, cyclic allenes) is not complicated by
such considerations. We ultimately found that
the relative stereochemistry was crucial.
More specifically, as will be discussed in the
“Stereochemical considerations” section, precursor 29a undergoes reaction successfully
under some conditions. However, epi-29a was
found to be unreactive toward conditions for
ABO generation and trapping. Even under
forcing conditions, recovery of starting material or decomposition was observed primarily
with no evidence of ABO generation. These
findings can be explained by considering the
torsion angles between the silyl and sulfonate
substituents. More specifically, we computationally evaluated the structures of 29b and
epi-29b to gauge the plausibility of overlap between the relevant s- and s*-orbitals implicated in ABO generation, wherein the –OTf and
–SiMe3 groups were used to simplify calculations. The structure of 29b features a relatively
smaller angle of 32.2°, whereas epi-29b features a much larger and prohibitive angle of
RES EARCH | R E S E A R C H A R T I C L E
diene 65 leads to cycloadduct 66, highlighting
the heightened reactivity of the bridgehead
alkene, compared with the relatively unstrained
alkene (entry 5). Finally, interception of dibromocyclopropane ABO 67, epoxide ABO 69, or
dimethylketal ABO 71 gives rise to products
68, 70, and 72 in good yields (entries 6 to 8,
respectively).
The examples shown in Figs. 3 and 4 demonstrate that ABOs provide access to structurally complex products, including those that
bear functional group handles poised for further manipulation. The parent bridged bicycles
that are accessible are commonly seen in natural
products and medicinal agents. For example,
McDermott et al., Science 386, eadq3519 (2024)
Observed diastereomeric ratios (d.r.) and regioselectivities (% r) to indicate
distribution of constitutional isomers are provided, with the major isomer being
depicted. In all cases, the stereochemistry at C2 of the bicycle fragment is as shown
in structure 33. For product 49, 1.3:1 d.r. is observed for the major constitutional
isomer and 6:1 d.r. is observed for the minor constitutional isomer.
ABO-derived compounds such as 60 and 64
share structural features seen in such molecules
of importance (60, 61). Moreover, the methodology provides access to ring-fused bridged bicycles with de novo substitution patterns, which
is notable given the increased desire to access
rigid molecules with a substantial degree of
saturation (62).
Further computational studies related to
reactivity and electronic structure of ABO 12
DFT studies were performed to better understand the high reactivity of ABOs, with a focus
on ABO 12 (Fig. 5A). The transition state for
(4+2) cycloaddition between ABO 12 with
1 November 2024
anthracene (30) was evaluated, and both concerted and stepwise processes were considered. The concerted cycloaddition pathway via
TS-1 has the lowest activation barrier (DG‡ =
15.0 kcal/mol) and is proposed to be operative.
Moreover, the ground-state structure of 12 indicates a low degree of diradical character
(see the supplementary materials). TS-1 reflects a concerted asynchronous process, with
the forming C–C bond being shorter at the
more pyramidalized carbon (C1) of the ABO
(2.43 Å versus 2.70 Å). TS-1 is an early transition state, as is expected for the reaction of a
highly strained compound (63), and the overall reaction is exergonic by 61.9 kcal/mol (64).
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Fig. 3. Scope of trapping reactions with [2.2.1] anti-Bredt olefin 12. Asterisk
symbol indicates the following conditions: 29a (1 equiv), trapping partner (3
to 10 equiv), CsF (10 equiv), TBAB (1 equiv), toluene (0.1 M), 120°C, 14 hours, sealed
vessel. Single-dagger symbol indicates the following conditions: 29a (1 equiv),
trapping partner (2 equiv), TBAF (1 M in THF, 5 equiv), DMF (0.05 M), 0°C, 3 hours.
RES EARCH | R E S E A R C H A R T I C L E
Distortion/interaction–activation strain analysis (DIAS) was also performed (65). Notably,
DE‡dist for the ABO is <1 kcal/mol, suggesting
that the ABO undergoes minimal geometric
change in reaching TS-1. Indeed, comparison
of the ground-state structure of ABO 12 and
the structure of the ABO fragment in TS-1 shows
nearly identical geometries. The pyramidalization
angles at C1 and C2 in TS-1 are 21.0° and 12.9°,
respectively, compared with 20.1° and 11.6°, re-
spectively, in ABO 12. Thus, the ABO geometry
is nearly perfectly predistorted at the p-bond in a
manner that closely resembles the transitionstate geometry. This explains the high reactivity
of 12 and other ABOs.
Computations were performed to identify the
frontier molecular orbitals (FMOs) for ABO 12
and understand their structure (Fig. 5B). The
calculated HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied mo-
lecular orbital) display helicity, as expected,
which arises from the geometric constraints
of the ABO’s twisted alkene. ABO 12 has a
HOMO energy of –8.0 eV and a LUMO energy
of 3.3 eV. To better understand the influence
of twisting and pyramidalization on energetics
and the FMOs, computations were performed
for ethylene (1). In its typical ground-state structure, 1 has a trigonal planar geometry, and the
HOMO and LUMO are as expected for an
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Fig. 4. Validation of anti-Bredt olefins by trapping with anthracene (30).
Different combinations of silyl group and bridgehead leaving group are indicated
in the entry column. Average twist angle (t) and pyramidalization angle at
the bridgehead carbon (Fp) are given for each ABO and were obtained from the
ground-state geometry-optimized structures calculated at the wB97XD/def2TZVP level of theory. Reaction conditions: Asterisk symbol indicates the following
McDermott et al., Science 386, eadq3519 (2024)
1 November 2024
conditions: precursor (1 equiv), anthracene (2 equiv), TMAF (5 equiv), DMF
(0.05 M), 23°C, 2 to 17 hours. Single-dagger symbol indicates the following
conditions: precursor (1 equiv), anthracene (2 equiv), CsF (10 equiv), TBAB
(1 equiv), toluene (0.1 M), 120°C, 14 hours. Double-dagger symbol indicates the
following conditions: precursor (1 equiv), anthracene (2 equiv), CsF (10 equiv),
TBAB (1 equiv), xylene (0.1 M), 140°C, 22 hours.
6 of 9
RES EARCH | R E S E A R C H A R T I C L E
ordinary p-bond. The HOMO energy is –10.2 eV
and the LUMO energy is 4.9 eV. To gauge
the influence of twisting alone, ethylene was
constrained to a geometry reflecting the same
average twisting (t) of 35° seen in ABO 12 but
without allowing for pyramidalization of the
carbon termini (66). This twisted form, 1-T, is
16.1 kcal higher in energy. The HOMO energy
increases by 0.9 eV and the LUMO energy decreases by 0.7 eV upon twisting. Lastly, pyramidalization of the carbon termini was added,
using the analogous geometric constraints seen
in ABO 12, leading to 1-ABO. Significant strain
is present in 1-ABO, arising from geometric
constraints and poor orbital overlap. The energy
of this conformer is 30.8 kcal/mol higher compared with the energy of 1-T and 47.1 kcal/mol
higher compared with the energy of 1. Thus,
McDermott et al., Science 386, eadq3519 (2024)
present in ABO 12 on energetics and frontier molecular orbitals. Geometry
optimizations were performed at the wB97XD/def2-TZVP level of theory.
MO structures and energies were obtained at the HF/6-31G(d) level of theory.
(C) Explanation for diastereoselectivity in the formation of 31. Calculations
were performed at the B3LYP/6-311+G(d,p) level of theory. (D) ABO 63 and
its enantiomer ent-63 are depicted with a mirror plane. Use of enantioenriched
silyl bromide (+)-73 leads to enantioenriched cycloadduct (+)-64 in high
optical yield.
both twisting and pyramidalization seen in the
ABO geometry lead to higher energy structures,
with the latter contributing more. Whereas the
HOMO energy remains nearly the same, the
LUMO energy for 1-ABO is 2.8 eV (compared
with 4.2 eV in 1-T and 4.9 eV in 1), further
reflecting the pronounced impact of pyramidalization in the ABO geometry. The higher
HOMO energy seen in 1-T and 1-ABO relative
to 1 can be attributed to the lesser overlap of the
atomic orbitals that form the p-bond. This
reduced overlap decreases the level of mixing
that can be possible, which results in the HOMO
being higher in energy and the LUMO being
lower in energy. The increase in free energy
DGrel, the lowering of the LUMO energy, and
raising of the HOMO energy resulting from
geometric distortion, as seen in our study of
1 November 2024
twisting and pyramidalization of ethylene, are
presumably large contributions to the increased
reactivity seen in ABOs (67).
Stereochemical considerations
Several considerations regarding stereochemistry warrant discussion. The first pertains to the
diastereoselectivities seen in trappings of ABOs
with respect to the new stereocenter formed
on the ABO fragment. As shown earlier and as
depicted in Fig. 5C, trapping of ABO 12 with
anthracene (30) proceeds stereospecifically to
give 31. Epi-31 is not observed, and the same
sense of diastereoselectivity is seen in all trapping reactions in considering the newly formed
C2 stereocenter. The pathway leading to epi31 would presumably require epimerization at
C2 of ABO 12 to give epi-12, before trapping by
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Fig. 5. Studies pertaining to reactivity, electronic structure, and stereochemistry of ABOs. (A) A concerted asynchronous cycloaddition is proposed
for the formation of cycloadduct 31. ABO 12 is predistorted in a manner
that resembles the geometry seen in TS-1, leading to a facile reaction. Calculations were performed at the wB97XD/def2-TZVP/SMD(DMF) level of theory.
(B) FMOs of ABO 12, with structures reoriented to best visualize the alkene
portion of the molecule. Calculations of stepwise geometric distortions of
ethylene are used to assess the influence of the twisting and pyramidalization
RES EARCH | R E S E A R C H A R T I C L E
Conclusions
These studies show that anti-Bredt olefins can
be used as versatile synthetic intermediates
for the preparation of functionalized bridged
bicyclic molecules, thus providing a solution to
the long-standing problem of anti-Bredt olefin
generation and trapping. Additionally, the studies
described herein highlight the potential of strategically leveraging the heightened reactivity of
McDermott et al., Science 386, eadq3519 (2024)
geometrically distorted alkenes for broad use in
chemical synthesis.
Materials and methods summary
Unless stated otherwise, reactions were conducted in flame-dried glassware under an atmosphere of nitrogen, and commercially obtained
reagents were used as received unless otherwise specified. Anhydrous solvents were either
freshly distilled or passed through activated
alumina columns, unless otherwise stated. Noncommercially available substrates were synthesized according to known preparations or
following protocols specified in the experimental procedures section of the supplementary
materials. 1H NMR, 13C NMR, and 19F NMR
spectra were recorded on Bruker spectrometers
and are reported relative to the residual solvent
signal. Data for supercritical fluid chromatograms are reported in enantiomeric excess.
Diastereomeric ratios and regioselectivities
were determined by 1H NMR analysis of crude
reaction mixtures. Further details on the materials and methods used can be found in the
supplementary materials.
Initial computational structures were prepared in Spartan’20 v1.1.5 and optimized using
molecular mechanics. All DFT calculations
were performed using Gaussian 16. Geometry
optimizations were performed with ⍵B97XD
with the def2-TZVP basis set unless noted otherwise. All geometries were verified as stationary points on the potential energy surface and
characterized as transition states or minima
by frequency calculations. GoodVibes (v3.2)
with quasi-harmonic entropy and enthalpy
treatment (frequency cutoff value: 100 cm−1)
was used to obtain corrected Gibbs free energies and enthalpies at 298.15 K and 1 atm.
Further details on the methods used can be
found in the supplementary materials.
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anthracene. Using DFT, we compared the energetics and geometries of ABO isomers 12 and
epi-12. Epi-12 was found to be 33.2 kcal/mol
higher in energy. This notable difference in
energy can be attributed to the extreme geometric distortion seen in epi-12. The average
twist angle in epi-12 is 55.5° (compared with
35.5° in 12). Significant pyramidalization is
also observed, with epi-12 displaying pyramidalization angles at C1 and C2 of 21.8° and
18.0°, respectively (the corresponding pyramidalization angles for ABO 12 are 20.1° and 11.6°,
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thus far inaccessible and explains the observed
C2 stereochemistry in cycloadducts such as 31.
A final curiosity related to stereochemistry
pertains to the chirality of [2.2.2] ABO 63 and
the potential to perform an enantiospecific trapping. The geometry-optimized structure of 63
is shown in Fig. 5D, showcasing the twisting
(t = 38.4°) and axial chirality of this ABO. Could
63 be accessed in enantioenriched form and
intercepted in an enantiospecific trapping, or
would enantiomerization to ent-63 occur
competitively? To probe this question, we
synthesized enantioenriched ABO precursor
(+)-73 in >95% enantiomeric excess (see supplementary materials) and subjected it to standard ABO generation and trapping conditions
using anthracene (30). We found that this
experiment delivers cycloadduct (+)-64 in
98% enantiomeric excess, indicative of enantiomerization of ABO 63 not occurring and a
quantitative optical yield (68). It is notable that
the point chirality present in substrate (+)-73
can be transmitted to the point chirality seen
in cycloadduct (+)-64 by way of an axially chiral
intermediate (i.e., ABO 63). The result further
suggests that Kobayashi elimination to form
the ABO likely occurs through a concerted
elimination mechanism, as we depict in Fig. 5D,
rather than a discrete carbanion (see Fig. 2C
discussion). Moreover, our finding supports
the notion that the ABO has distinctly olefinic
character. The calculated alkene bond length in
ABO 63 is 1.35 Å, reflective of a bond order of
1.83 determined by NBO analysis (see supplementary materials). Overall, the experiment
shown in Fig. 5D adds a previously unexplored
dimension to ABO chemistry and demonstrates
that ABOs can be used as unconventional building blocks for the synthesis of complex, enantioenriched compounds.
RES EARCH | R E S E A R C H A R T I C L E
McDermott et al., Science 386, eadq3519 (2024)
one would ordinarily expect. However, we surmise that
pyramidalization at the alkene carbons, especially that of the
C2 carbon, enables improved bonding, ultimately contributing
to the calculated bond order of 1.86.
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course.
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1 November 2024
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which is likely a stabilizing effect (see supplementary materials
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68. Although a transition state for the enantiomerization could not
be located, we suggest that the barrier for enantiomerization
exceeds 19 kcal/mol. This is because the calculated barrier for
the Diels-Alder reaction between 63 and 30 is 16.7 kcal/mol
(see the supplementary materials), and the reaction occurs
with high stereoretention. We also note that conducting the
cycloaddition at 50°C instead of 23°C led to lower yields but no
change in the stereospecificity.
AC KNOWLED GME NTS
Funding: The authors acknowledge funding from the NIH-NIGMS
(R35 GM139593 for N.K.G. and F31- GM148017 to L.M.), the NSF
(DGE-2034835 for A.V.K.), and the Trueblood family (for N.K.G.).
These studies were supported by shared instrumentation grants
from the NSF (CHE-1048804) and the NIH NCRR (S10RR025631).
Calculations were performed on the UCLA Hoffman2 cluster
and at the UCLA Institute of Digital Research and Education
(IDRE). Author contributions: L.M., Z.G.W., S.A.F., A.M.C., J.D.,
and A.V.K. designed and performed the experiments and analyzed
the experimental data. Z.G.W. performed the computational
studies, and K.N.H. provided insight and guidance for the
computational studies. N.K.G. directed the investigations and
prepared the manuscript, with contributions from all authors. All
authors contributed to discussions. Competing interests: The
authors declare that they have no competing interests. Data and
materials availability: Experimental procedures and
characterization data are provided in the supplementary materials.
Correspondence and requests for materials should be addressed
to N.K.G. (neilgarg@chem.ucla.edu). License information:
Copyright © 2024 the authors, some rights reserved; exclusive
licensee American Association for the Advancement of Science.
No claim to original US government works. https://www.science.
org/about/science-licenses-journal-article-reuse
SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.adq3519
Materials and Methods
NMR Spectra
Figs. S1 to S149
Tables S1 to S7
References (69–88)
Submitted 9 May 2024; accepted 30 August 2024
10.1126/science.adq3519
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47. As defined by Maier and Schleyer, olefin strain is calculated by
subtracting the total strain of the parent hydrocarbon from
the total strain of the bridgehead olefin (43). These strain energies
are calculated using homodesmotic equations, and details on these
calculations are provided in the supplementary materials.
48. In considering the poor orbital overlap that arises from alkene
twisting alone, the calculated bond order may be higher than