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10.1002/anie.201913201
Angewandte Chemie International Edition
COMMUNICATION
Oxodealkenylative cleavage of alkene C(sp3)–C(sp2) bonds: A
practical method for introducing carbonyls into chiral pool
materials
Andrew J. Smaligo,[a] Jason Wu,[a] Nikolas R. Burton,[a] Allison S. Hacker,[a] Aslam C. Shaikh,[a] Jason
C. Quintana,[a] Ruoxi Wang,[a] Changmin Xie,[a] and Ohyun Kwon*[a]
Abstract: Herein we report
a
one-pot protocol for the
envisioned that it is possible to prepare carbonyl compounds from
terpene-derived starting materials.
oxodealkenylative introduction of carbonyl functionalities into
terpenes and terpene-derived compounds. This transformation
proceeds via Criegee ozonolysis of an alkene, reductive cleavage of
the resulting α-alkoxy hydroperoxide, trapping of the generated alkyl
radical with TEMPO, and subsequent oxidative fragmentation with
MMPP. Using readily available starting materials from chiral pool, a
variety of carbonyl-containing products have been accessed rapidly in
good yields.
functional group occurrence in natural products
O
O
O
Br
Cl
R
R
R
R′
R
R
H
1.5%
39.9%
15.9%
6.0%
2.4%
1.8%
bromide
alkene
ketone
enone
aldehyde
chloride
halide-to-carbonyl conversion
Inokuchi and Kawafuchi [5]
X
TEMPO
R
O
TEMPONa
X = Cl or Br
mCPBA
Natural products have had a longstanding influence on both the
natural world and society.[1] In particular, they have played an
important role in drug development, with approximately 65% of
FDA-approved small-molecule drugs being, in some way,
dependent on natural products.[2] Nature’s chiral pool is also
frequently exploited in enantiospecific synthesis, especially in the
total synthesis of small and complex molecules of biological
relevance.[3] One interesting facet relevant to these context is the
prevalence of alkenes (39.9%) relative to that of ketones (15.9%),
enones (6.0%), and aldehydes (2.4%) found in natural products
(Scheme 1).[4] With the chiral pool materials being useful in many
types of chemical processes, a simple method for the conversion
of natural alkenes into carbonyl-containing compounds would be
highly valuable.
R
R′
R′
R
R′
oxodealkenylation
O3, MeOH;
aq. FeSO4·7H2O, TEMPO;
MMPP
CHO
O
– operationally simple
– open to air
– non-anhydrous solvent
– introduction of carbonyl groups
– natural product diversification
1
2
CO2Me
O3, MeOH
CHO
–TEMPOH
CHO
CHO
R′CO3H
FeII, TEMPO
O
OOH
OMe
ONR2
ONR2
–FeIII, OH–
–R′CO2H
CO2Me
CO2Me
Scheme 1. Prevalence of functional groups in natural products, halide-to-
carbonyl conversion, and the oxodealkenylative process. Magnesium
bis(monoperoxyphthalate) hexahydrate, MMPP.
In 2004, Inokuchi and Kawafuchi reported a simple protocol for
the conversion of alkyl halides to carbonyl-containing compounds
(Scheme 1).[5] This process involves SN2 displacement of an alkyl
halide with the anion of 2,2,6,6-tetramethylpiperidin-1-yl (TEMPO)
and subsequent m-chloroperoxybenzoic acid (mCPBA)-mediated
oxidation of the O-alkyl TEMPO intermediate to give the
corresponding carbonyl compound. While only a few natural
products contain halide functionalities (chloride, 1.8%; bromide,
1.5%), terpenes and terpenoids are abundant.[6] Because these
natural alkenes can be converted into O-alkyl TEMPO
intermediates through redox-based radical processes, we
In this paper, we report a simple one-pot protocol for the cleavage
of an alkene C(sp3)–C(sp2) bond followed by formation of a C=O
bond. The reaction involves several steps: ozonolysis of an
alkene 1, Fe(II)-mediated single-electron-transfer (SET)-based
reduction of the intermediate α-alkoxy hydroperoxide, alkoxy
radical-induced β-fragmentation, trapping of the resultant alkyl
radical with a persistent radical TEMPO,[7] and subsequent
oxidation, ultimately providing the carbonyl-containing product 2
(Scheme 1). This transformation proceeds under mild reaction
conditions and open to the air, employs common terpenes and
terpene derivatives as starting materials, and is tolerant of
functional groups that are typically prone to degradation and/or
reaction in acidic, basic, and/or oxidative conditions (e.g., β-
hydroxy ketones, acetals, enones, ketones, alcohols).
Furthermore, the initial oxidant (ozone) is renewable, the ferrous
salt (FeSO4·7H2O) is plentiful,[8] and the terminal oxidant (MMPP)
is less expensive and more stable than similar peracids.[9]
[a]
A. J. Smaligo, J. Wu, N. R. Burton, A. S. Hacker, Dr. A. C. Shaikh, J.
C. Quintana, R. Wang, Dr. C. Xie, Prof. Dr. O. Kwon.
Department of Chemistry & Biochemistry
University of California – Los Angeles
Los Angeles CA 90095-1569, United States
E-mail: ohyun@chem.ucla.edu
Supporting information for this article is given via a link at the end of
the document.
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