Hydrodealkenylative C(sp3)–C(sp2) bond fragmentation

Article abstract of DOI:10.1126/science.aaw4212

Chemical synthesis typically relies on reactions that generate complexity through elaboration of simple starting materials. Less common are deconstructive strategies toward complexity—particularly those involving carbon-carbon bond scission. Here, we introduce one such transformation: the hydrodealkenylative cleavage of C(sp³)–C(sp²) bonds, conducted below room temperature, using ozone, an iron salt, and a hydrogen atom donor. These reactions are performed in nonanhydrous solvents and open to the air; reach completion within 30 minutes; and deliver their products in high yields, even on decagram scales. We have used this broadly functionality tolerant transformation to produce desirable synthetic intermediates, many of which are optically active, from abundantly available terpenes and terpenoid-derived precursors. We have also applied it in the formal total syntheses of complex molecules.

Full text of DOI:10.1126/science.aaw4212

RESEARCH
atom donor (HAD) under Schreiber conditions
promotes C(sp3)–C(sp2) bond cleavage and sub-
sequent construction of a new C(sp3)–H bond
(16). Given the ubiquity of olefins in terpenes
and other organic molecules, we envision several
applications for this transformation: new retro-
synthetic disconnections to aid total syntheses,
the late-stage diversification of both small and
large biologically active molecules, and the facile
generation of useful value-added compounds from
abundantly available starting materials (Fig. 1C).
The huge difference in price between (–)-isopulegol
and (1S,3R)-3-methylcyclohexanol, used in the
synthesis of androgen modulators, highlights the
contrast between the current accessibility of these
two structurally similar compounds (17–19).
After refining the reaction parameters pro-
moting the fragmentation of the isopropenyl
group in the hydroxy ketone 1a (table S1), we
obtained the desired hydrodealkenylation prod-
uct 2a in 90% yield when using 1.2 equivalents
of ferrous sulfate heptahydrate (as the FeII salt)
and 1.5 equivalents of benzenethiol (as the HAD).
The reaction proceeded rapidly and produced
only diphenyl disulfide, a benign by-product. Ap-
plying the optimized conditions, we investigated
the substrate scope of the hydrodealkenylation.
Table 1 reveals that a number of bicyclic ketones
and enones (1b to 1f) underwent fragmentation
cleanly to give their hydrodealkenylation products
(2b to 2f) in high yields (80 to 94%). We prepared
ORGANIC CHEMISTRY
Hydrodealkenylative C(sp3)–C(sp2)
bond fragmentation
Andrew J. Smaligo, Manisha Swain, Jason C. Quintana,
Mikayla F. Tan, Danielle A. Kim, Ohyun Kwon*
Chemical synthesis typically relies on reactions that generate complexity through
elaboration of simple starting materials. Less common are deconstructive strategies
toward complexity—particularly those involving carbon-carbon bond scission. Here, we
introduce one such transformation: the hydrodealkenylative cleavage of C(sp3)–C(sp2)
bonds, conducted below room temperature, using ozone, an iron salt, and a hydrogen
atom donor. These reactions are performed in nonanhydrous solvents and open to the
air; reach completion within 30 minutes; and deliver their products in high yields, even
on decagram scales. We have used this broadly functionality tolerant transformation
to produce desirable synthetic intermediates, many of which are optically active, from
abundantly available terpenes and terpenoid-derived precursors. We have also applied
it in the formal total syntheses of complex molecules.
common ideal in chemical synthesis is
the assembly of complex molecules from
simple precursors, often accompanied by
the need to install carbon centers with pre-
cisely defined stereochemical arrangements.
kenes in the presence of an alcohol. The resulting
oxyradicals can subsequently engage in various
forms of homolytic cleavage to produce alkenes,
dimers, or halides (11–15). Nevertheless, these
methods often occur with poor efficiencies and/
or have limited utility. We have found that em-
ploying a readily available FeII salt with a hydrogen
A
Despite the bevy of methods available to accom-
plish such goals, sometimes it can be more ef-
ficient to reorganize starting materials already
containing the required complexity and/or stereo-
chemistry into the desired molecular structures.
Furthermore, deconstructive strategies can pro-
vide access to challenging, or otherwise inacces-
sible, molecular structures (1–3). The literature
contains many examples of C–C bond fragmen-
tations (Fig. 1A). Some well-established C(sp2)–
C(sp2) bond scissions are oxidative cleavage (e.g.,
ozonolysis) and olefin metathesis (4–6). There
are also reports of C(sp3)–C(sp3) bond fragmen-
tations (1, 7–9), albeit in much smaller numbers,
but these transformations typically require acti-
vation of the C–C bond through the effects of a
neighboring heteroatom, ring strain, or a leaving
group in the reactant. Nevertheless, general meth-
ods for the functionalization of C(sp3)–C(sp2)
bonds remain elusive. Given the profuse number
of organic molecules containing these linkages,
activation of such bonds in a controllable man-
ner would be extremely useful.
C(sp2)–C(sp2) bond fragmentation
A
B
“hydrodealkylation”
H
metal oxide catalyst
many methods
e.g., ozonolysis,
olefin metathesis
500–600 ˚C
H2, 40–60 atm
C(sp3)–C(sp3) bond fragmentation
“hydrodealkenylation”
H
X
X
O3, ROH;
FeII, HAD
limited methods
requires strain or
activating functionality
O3, ROH
CH2O
OOH
C(sp3)–C(sp2) bond fragmentation
HAD
O
FeII
this work
OR
OR
CH3CO2R
FeIII, OH–
· strategies for total synthesis
C
· late-stage diversification of
bioactive molecules
H
O
O
OH
bevirimat (MPC-4326)
anti-HIV drug
H
The net reaction described here involves cleav-
age of a C(sp3)–C(sp2) bond, followed by forma-
tion of a new C(sp3)–H bond (Fig. 1B). We refer to
this process as hydrodealkenylation, coined with
a nod to the hydrodealkylation process that is
most commonly exemplified in the conversion
of toluene to benzene in the presence of H2 gas
at high temperatures and pressures (10). Our re-
action design was based on previous reports of
FeII transferring an electron to the a-alkoxy hy-
droperoxides generated upon ozonolysis of al-
O
O
H
HO
O
H
(R)-(–)-carvone
(–)-2-pupukeanone
O
· rapid generation of non-trivial compounds from readily-accessible sources
Cl
OH
OH
O
CN
(–)-isopulegol
$14/mol
abundant feedstock
(1S,3R)-3-methyl-cyclohexanol
$193K/mol
androgen modulator
pharmaceutical agent
enantiopure material
Fig. 1. Concept and applications of hydrodealkenylative fragmentation of C(sp3)–C(sp2)
bonds. (A) Deconstructive fragmentation of C–C bonds. (B) Overview and proposed mechanism of
hydrodealkenylation. (C) Applications of hydrodealkenylation. X, activating functionality; R, alkyl group.
Department of Chemistry and Biochemistry, University of
California, Los Angeles, Los Angeles, CA 90095, USA.
*Corresponding author. Email: ohyun@chem.ucla.edu
Smaligo et al., Science 364, 681–685 (2019)
17 May 2019
1 of 5

RESEARCH
| REPORT
both enantiomers of the Wieland-Miescher ketone
(2e and ent-2e), a prevalent synthetic interme-
diate used in more than 50 total syntheses (20),
from the readily accessible dienediones 1e and
ent-1e. Naturally occurring terpenoids were also
viable substrates, providing the hydrodealkeny-
lation products 2g to 2j, valuable building blocks
in both total synthesis and the preparation of
pharmaceutical agents (19, 21–23), in good yields
(79 to 89%). The epoxide in (–)-cis-limonene
oxide (1g) was opened diastereoselectively under
the reaction conditions to furnish the trans-
alkoxy alcohol 2g as the sole product (presum-
ably facilitated by a Lewis-acidic FeIII species).
The carvone-derived hydroxy ester 1k and diol
1l, both of which have been used in a number of
synthetic applications (24–27), smoothly delivered
their products 2k and 2l, respectively. As antici-
pated, the primary hydroxyl group in the diol 1l
underwent intramolecular trapping of the inter-
mediate carbonyl oxide, producing the acetylated
product 2l. Betulin (1m) and betulinic acid (1n),
naturally occurring triterpenoids displaying wide
biological activities (28), gave the hydrodealke-
nylation products 2m and 2n, respectively. The
hydroxy ketone 1o, containing four stereocenters,
provided the fragmentation product 2o. Facile
conversion of the indanol 1p to 2p illustrated
the excision of the 2-propenyl substituent attached
to a primary alkyl carbon. The substrates 1q to
1t delivered their fragmentation products 2q to
2t in good yields (72 to 86%), further displaying
the potential of this transformation for deriva-
tization of chiral pool–based auxiliaries. We also
converted the ammonium salt 1u to the amino
alcohol 2u after performing a basic workup. As
Table 1. Substrate scope of the hydrodealkenylation. Experiments performed on ≥1.0-mmol scale unless otherwise noted. Yields shown refer to isolated
yields after SiO2 chromatography. See the supplementary materials for experimental details. MeOH, methanol; PhSH, benzenethiol; Me, methyl; Ph, phenyl;
rt, room temperature.
i. O3, MeOH
ii. FeSO4·7H2O, PhSH
H
–78 ˚C
rt, 30 min
1
2
Starting Material
Product
Yield
Starting Material
Product
Yield
Starting Material
Product
Yield
O
O
H
O
O
MeO
90%
85%
85%
O
O
O
O
O
O
H
H
H
OH
1a
OH
2a
H
1g
OH
1o
OH
2o
2g
OH
OH
H
OH
OH
83%
85%
80%
71%
84%
89%*
H
1h
2h
OH
1b
OH
2b
1p
2p
O
O
O
O
PPh2
PPh2
79%
HO
HO
H
H
H
H
H
1c
2c
2d
1i
2i
1q
2q
OH
OH
OH
OH
94%
90%
80%
84%
72%
86%
O
O
O
O
O
O
H
H
1d
1r
OH
2r
OH
1j
2j
O
O
HO
HO
HO
HO
HO
HO
H
H
H
1e
2e
H
CO2Me
OH
CO2Me
1s
2s
1k
2k
2l
O
O
Ph
P
H
O
Ph
91%
91%
O
82%
P
O
O
O
O
O
O
1t
2t
ent-1e
ent-2e
H
1l
O
O
H
H
90%
HO
62%‡
H
N
H
N
OH
OH
X
H
H
HO
HO
H
H
X
H
H
H
1f
2f
2m X = H2 88%
2n X = O 83%†
HO
1u
2u
1m/1n
H
H
...................................................................................................................................................................................................................................................................................................................................................
*100.0-mmol scale.
†0.2-mmol scale.
‡After basic workup.
Smaligo et al., Science 364, 681–685 (2019)
17 May 2019
2 of 5

RESEARCH
| REPORT
validation of the robustness of this reaction,
fragmentation of (–)-isopulegol (1h) on 100-mmol
scale furnished the enantiomerically pure alcohol
2h in 89% yield. Both antipodes are attainable
for every chiral product in Table 1 (except 2d, 2m,
and 2n), owing to the ready accessibility of the
enantiopure terpenoid precursors.
this process furnished a single diastereoisomer
of the bicyclo[3.3.1]nonane ester 4d. The reac-
tion of (–)-caryophyllene oxide (3e) produced the
lactone 4e—the result of epoxide opening (com-
pare with 2g) and subsequent intramolecular
lactonization.
terpenes are, however, prevalent; combined with
hydrodealkenylation, they provide ready access
to variants of this scaffold. (+)-a-Pinene (5b) and
(–)-nopol (5c) produced opposite enantiomers of
the cyclobutylacetaldehyde acetals 6b and ent-6b.
(S)-cis-Verbenol (5d) smoothly dispensed the
corresponding aldol acetal 6d, containing two
stereocenters, and (–)-a-cedrene (5e) provided
the cis-fused octahydropentalene 6e, with three
stereocenters.
The ease of operation, efficiency, and functional-
group compatibility of the hydrodealkenylation
were further confirmed through its application
in the formal syntheses of several biologically active
natural products (Fig. 2). In a notable example—
en route to the isotwistane sesquiterpenoid (–)-2-
pupukeanone—we generated the bicyclic ketoester
2v directly from 1v in 78% yield. Previously, this
conversion required six steps and gave the prod-
uct in only 28% overall yield (32). In another
example, we obtained the ketoester 2w, an in-
termediate leading to (–)-seychellene, directly
from its precursor 1w in 81% yield. Although our
net yield was slightly lower than that reported
for the five-step route (91%), the simplicity of our
We further elaborated the substrate scope by
converting various cycloalkenes (5) to ethylene
glycol acetals of the aldehydes (6), involving the
loss of a two-carbon (or more) unit as a methyl
ester during FeII-mediated reductive fragmen-
tation (Table 3). Because of the volatility of the
aldehyde products, we protected them imme-
diately and isolated them as 1,3-dioxolanes.
Methylcyclohexene (5a) cleanly delivered the
acetal of pentanal 6a. More compelling is the
ability to generate optically active products from
readily available and enantiomerically pure ter-
pene and terpenoid starting materials. Although
cyclobutane moieties are particularly valuable syn-
thetic intermediates and are also present in many
natural products, enantioselective preparations of
these ring systems can be challenging, especially
when compared with those of smaller and larger
carbocycles (29–31). Cyclobutane-containing bridged
To amplify the synthetic utility of this hydro-
dealkenylation, we extended it to other types of
C(sp3)–C(sp2) linkages. Table 2 reveals that start-
ing materials containing exomethylene units
(3) provided carboxylic ester products (4) after
the loss of a one-carbon unit as formaldehyde.
Methylenecyclohexane (3a) smoothly furnished
methyl hexanoate (4a). The naturally occurring
terpene ( )-camphene (3b) generated a single
diastereoisomer of the cyclopentanecarboxylic
ester 4b. The a-alkoxy hydroperoxide interme-
diate fragmented to generate the tertiary carbon
radical exclusively, rather than the alternative
secondary carbon radical, before hydrogen atom
abstraction. By contrast, (–)-b-pinene (3c) provided
a 1:1 regioisomeric mixture of the products 4c
and 4c′, a result of indiscriminative radical scis-
sion. Subjecting methyleneadamantane (3d) to
Table 2. Generation of esters via C(sp3)–C(sp2) bond fragmenta-
tion. Experiments performed on 2.0-mmol scale. Yields shown refer to
isolated yields after SiO2 chromatography. See the supplementary
materials for experimental details. r.r., regioisomeric ratio.
Table 3. Generation of masked aldehydes via C(sp3)–C(sp2)
bond fragmentation. Experiments performed on 2.0-mmol scale.
Yields shown refer to isolated yields after SiO2 chromatography.
See the supplementary materials for experimental details. p-TSA,
para-toluenesulfonic acid.
O
i. O3, MeOH
ii. FeSO4·7H2O, PhSH
OMe
i. O3, MeOH
ii. FeSO4·7H2O, PhSH
O
–78 ˚C
rt, 30 min
H
O
H
–78 ˚C
rt, 30 min
R
iii. HOCH2CH2OH, p-TSA
3
4
benzene, reflux, 2 h
5
6
Product
Yield
Starting Material
Product
Yield
Starting Material
O
80%
O
H
OMe
H
71%
O
H
3a
3b
4a
5a
6a
O
O
89%
60%
65%
MeO
O
H
4b
O
5b
6b
O
O
H
+
OMe
83%
(1:1 r.r.)
MeO
OH
H
H
H
3c
4c
4c
5c
ent-6b
O
OMe
O
OH
HO
O
81%
26%
88%
78%
O
H
4d
5d
6d
3d
O
H
O
O
O
O
H
H
H
H
OMe
5e
6e
4e
3e
H
...........................................................................................................................................................
.....................................................................................................................................................
Smaligo et al., Science 364, 681–685 (2019)
17 May 2019
3 of 5

RESEARCH
| REPORT
method obviates the five purifications required by
the former (33). Other examples included one-pot
conversions of the silyloxy dione 1x, an inter-
mediate leading to the sesquiterpenoid perico-
nianone A (34); the dione 1y, an intermediate in
the preparation of the spirocyclic sesquiterpenoid
(–)-7-epibakkenolide-A (35); and the silyloxy ketone
1z, a chiral steroid precursor (36).
We then performed several experiments to
support the mechanistic involvement of a free
carbon radical in these hydrodealkenylations and
establish the possibility of engaging the radical
intermediate in other useful transformations
(Fig. 3). Subjecting (1S)-(+)-3-carene to the reaction
conditions generated the corresponding cyclo-
propylcarbinyl radical, with subsequent rearrange-
ment, hydrogen atom abstraction, and dioxolane
protection supplying a 1:0.85 mixture of the prod-
ucts 6f and 6f′ in 87% yield. When we substituted
TEMPO (2,2,6,6-tetramethylpiperidin-1-yl) for the
HAD, we obtained the TEMPO adducts 7a and
7a′ in a combined isolated yield of 91%. Single-
crystal x-ray diffraction of the major product 7a
confirmed the equatorial stereochemistry of the
aminoxyl group. Similarly, employing diphenyl
disulfide as a radical trap produced the thioethers
8a and 8a′ in a combined isolated yield of 40%.
For this transformation, the diastereoselectivity
was higher (8:1 diastereomeric ratio), and the
major product again displayed an equatorial—in
this case, phenylthio—group.
We envision that the straightforward nature
of the hydrodealkenylation, performed with in-
expensive and commercially available reagents
and instruments, will engender innovations in
synthesis and the use of chiral pool–based start-
ing materials. Fundamentally, this unusual discon-
nection should prove useful in both retrosynthetic
analyses and late-stage synthetic modifications.
H
O
“standard conditions”
i. O3, MeOH ii. FeSO4·7H2O, PhSH
–78 ˚C rt, 30 min
78%
previously 6 steps (28%)
O
O
(32)
CO2Me
CO2Me
2v
1v
(–)-2-pupukeanone
(a) O3, MeOH (b) Ac2O, Et3N, DMAP (c) K2CO3, MeOH
(d) PCC, silica gel (e) (CH2SH)2, BF3·OEt2 (f) Raney Ni, EtOH
O
O
H
O
R
R
standard
conditions
standard
O
O
(34)
(33)
conditions
HO
H
O
80%
81%
HO
CO2Me
CO2Me
OTBS R = (CH2)2COCH3
OTBS
periconianone A
1w
2w
(–)-seychellene
O
1x
2x
previously 5 steps (91%)
previously 3 steps (67%)
HO
O
O
standard
O
standard
conditions
(36)
OTBS
R
R
O
H
(35)
conditions
O
75%
78%
R = CH2COCH3
OTBS
H
1z
2z
H
2y
1y
(–)-7-epibakkenolide-A
MeO
previously 4 steps (47%)
previously 3 steps (49%)
chiral steroid
Fig. 2. Applications of hydrodealkenylation in total synthesis. Experiments performed on 1.0-mmol scale. Yields shown refer to isolated yields
after SiO2 chromatography. See the supplementary materials for experimental details. Ac2O, acetic anhydride; Et3N, triethylamine; DMAP,
4-dimethylaminopyridine; PCC, pyridinium chlorochromate; BF3·OEt2, boron trifluoride diethyl etherate; EtOH, ethanol; TBS, tert-butyldimethylsilyl.
Fig. 3. Observations
consistent with
the intermediacy of
a carbon radical.
i. O3, MeOH
ii. FeSO4·7H2O, PhSH
H
O
O
–78 ˚C
rt, 30 min
+
O
O
iii. HOCH2CH2OH, p-TSA
H
Experiments performed
on ≥0.5-mmol scale.
Yields shown refer to
isolated yields after
SiO2 chromatography.
See the supplementary
materials for experimen-
tal details. d.r., diastere-
omeric ratio; Ph2S2,
diphenyl disulfide;
benzene, reflux, 2 h
5f
87% 6f/6f
(1:0.85 r.r.)
i. O3, MeOH
ii. FeSO4·7H2O, TEMPO
N
O
–78 ˚C
rt, 30 min
O
O
O
O
OH
1a
OH
91% 7a/7a
(4:1 d.r.)
ORTEP of 7a
i. O3, MeOH
ii. FeSO4·7H2O, Ph2S2
ORTEP, Oak Ridge
thermal ellipsoid plot.
–78 ˚C rt, 30 min
S
OH
OH
1a
40% 8a/8a
(8:1 d.r.)
Smaligo et al., Science 364, 681–685 (2019)
17 May 2019
4 of 5

RESEARCH
| REPORT
Furthermore, the ease with which these carbon-
centered radicals can be trapped opens a gateway
for employing common alkenes, seldom used as
radical precursors, in a plethora of known radical
transformations.
16. A. J. Smaligo, S. Vardhineedi, O. Kwon, ACS Catal. 8,
5188–5192 (2018).
17. Based on current list price of (–)-isopulegol, CAS 89-79-2
(Sigma–Aldrich).
18. Based on current list price of (1S,3R)-3-methylcyclohexanol,
CAS 24965-92-2 (Advanced ChemBlocks and PharmaBlock).
19. L.-Y. Hu et al., Androgen modulators, U.S. Patent
US20060009427, Jan 12, 2006.
20. B. Bradshaw, J. Bonjoch, Synlett 23, 337–356 (2012).
21. K.-F. Cheng, K.-P. Chan, T.-F. Lai, J. Chem. Soc., Perkin Trans.
1 1991, 2461–2465 (1991).
22. Z. Zhu et al., Preparation of imidazolidin-2-imines and their
analogs as aspartyl protease inhibitors for treating various
diseases, U.S. Patent US20080200445, Aug 21, 2008.
23. T. D. Aicher et al., Preparation of heterocyclic compounds as
glucokinase activators, U.S. Patent US20090247526,
Oct 1, 2009.
34. R. Liffert, A. Linden, K. Gademann, J. Am. Chem. Soc. 139,
16096–16099 (2017).
35. A. Srikrishna, T. J. Reddy, Tetrahedron 54, 11517–11524
(1998).
36. S. Pogrebnoi, F. C. E. Saraber, B. J. M. Jansen, A. de Groot,
Tetrahedron 62, 1743–1748 (2006).
ACKNOWLEDGMENTS
REFERENCES AND NOTES
We thank the UCLA Molecular Instrumentation Center for the NMR
spectroscopy, mass spectrometry, and x-ray diffraction (S. I.
Khaan) instrumentation. Funding: Financial support for this study
was provided by the NIH (R01GM071779). Author contributions:
A.J.S. and O.K. conceived of the study, designed the experiments,
and analyzed the data. A.J.S., M.S., J.C.Q., M.F.T., and D.A.K.
performed the experiments. A.J.S. and O.K. wrote the manuscript.
Competing interests: A.J.S. and O.K. are listed as inventors on
an initial patent application filed by the Regents of the University of
California (U.S. Provisional Patent Application No. 62/810,271).
Data and materials availability: Experimental procedures,
optimization data, and characterization data are available in the
supplementary materials. Crystallographic data are available free
of charge from the Cambridge Crystallographic Data Centre under
reference number CCDC 1874958.
1. J. B. Roque, Y. Kuroda, L. T. Göttemann, R. Sarpong, Nature
564, 244–248 (2018).
2. T. J. Osberger, D. C. Rogness, J. T. Kohrt, A. F. Stepan,
M. C. White, Nature 537, 214–219 (2016).
3. B. M. Rosen et al., Angew. Chem. Int. Ed. 49, 7002–7005
(2010).
4. P. S. Bailey, Chem. Rev. 58, 925–1010 (1958).
5. A. H. Hoveyda, A. R. Zhugralin, Nature 450, 243–251 (2007).
6. G. C. Vougioukalakis, R. H. Grubbs, Chem. Rev. 110, 1746–1787
(2010).
7. I. Marek, A. Masarwa, P.-O. Delaye, M. Leibeling, Angew. Chem.
Int. Ed. 54, 414–429 (2015).
8. Z. Nairoukh, M. Cormier, I. Marek, Nat. Rev. Chem. 1, 0035
(2017).
9. G. Fumagalli, S. Stanton, J. F. Bower, Chem. Rev. 117,
9404–9432 (2017).
10. R. Schmidt et al., in Ullmann’s Encyclopedia of Industrial
Chemistry (Wiley-VCH, 2015).
11. J. Kumamoto, H. D. De La Mare, F. F. Rust, J. Am. Chem. Soc.
82, 1935–1939 (1960).
24. S. F. Oliver et al., Angew. Chem. Int. Ed. 42, 5996–6000
(2003).
25. L. Sun et al., J. Med. Chem. 53, 7864–7868 (2010).
26. V. Navickas, D. B. Ushakov, M. E. Maier, M. Ströbele,
H.-J. Meyer, Org. Lett. 12, 3418–3421 (2010).
27. H. Yang, Y. Gao, X. Qiao, L. Xie, X. Xu, Org. Lett. 13, 3670–3673
(2011).
28. S. Alakurtti, T. Mäkelä, S. Koskimies, J. Yli-Kauhaluoma, Eur. J.
Pharm. Sci. 29, 1–13 (2006).
29. Y. Xu, M. L. Conner, M. K. Brown, Angew. Chem. Int. Ed. 54,
11918–11928 (2015).
30. S. Poplata, A. Tröster, Y.-Q. Zou, T. Bach, Chem. Rev. 116,
9748–9815 (2016).
31. T. P. Yoon, Acc. Chem. Res. 49, 2307–2315 (2016).
32. A. Srikrishna, P. R. Kumar, S. J. Gharpure, Tetrahedron Lett.
42, 3929–3931 (2001).
SUPPLEMENTARY MATERIALS
science.sciencemag.org/content/364/6441/681/suppl/DC1
Materials and Methods
Figs. S1 to S3
Table S1
Characterization Data
References (37–100)
12. H. E. De La Mare, J. K. Kochi, F. F. Rust, J. Am. Chem. Soc. 83,
2013 (1961).
13. S. Murai, N. Sonoda, S. Tsutsumi, Bull. Chem. Soc. Jpn. 37,
1187–1190 (1964).
14. S. Schreiber, J. Am. Chem. Soc. 102, 6163–6165 (1980).
15. T. J. Fisher, P. H. Dussault, Tetrahedron 73, 4233–4258 (2017).
18 December 2018; accepted 14 March 2019
10.1126/science.aaw4212
33. A. Srikrishna, G. Ravi, Tetrahedron 64, 2565–2571 (2008).
Smaligo et al., Science 364, 681–685 (2019)
17 May 2019
5 of 5

Hydrodealkenylative C(sp3)−C(sp2) bond fragmentation
Andrew J. Smaligo, Manisha Swain, Jason C. Quintana, Mikayla F. Tan, Danielle A. Kim and Ohyun Kwon
Science 364 (6441), 681-685.
DOI: 10.1126/science.aaw4212
Excising an olefin
Plants produce an abundance of structurally complex terpene compounds that are useful precursors to
pharmaceuticals and other fine chemicals. However, the carbon frameworks of these compounds constrain the available
pathways for diversification. Smaligo et al. now show that successive treatment with ozone, an iron oxidant, and a
hydrogen-atom donor can cleanly cleave pendant olefins from terpenes and related compounds (see the Perspective by
Caille). Breaking the bond between saturated and double-bonded carbon centers offers a direct route to desirable chiral
intermediates from readily available, inexpensive precursors.
Science, this issue p. 681; see also p. 635
ARTICLE TOOLS
http://science.sciencemag.org/content/364/6441/681
SUPPLEMENTARY
MATERIALS
http://science.sciencemag.org/content/suppl/2019/05/15/364.6441.681.DC1
RELATED
CONTENT
http://science.sciencemag.org/content/sci/364/6441/635.full
REFERENCES
This article cites 96 articles, 0 of which you can access for free
http://science.sciencemag.org/content/364/6441/681#BIBL
PERMISSIONS
http://www.sciencemag.org/help/reprints-and-permissions
Use of this article is subject to the Terms of Service
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement of
Science, 1200 New York Avenue NW, Washington, DC 20005. 2017 © The Authors, some rights reserved; exclusive
licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. The title
Science is a registered trademark of AAAS.