Synthesis of γ-Lactones Utilizing Ketoacids and Trimethylsulfoxonium Iodide

Article abstract of DOI:10.1021/acs.orglett.9b01852

The Johnson-Corey-Chaykovsky epoxidation is one of the oldest methods for the synthesis of terminal epoxides from carbonyl compounds. Herein we present a simplified extension of the Johnson-Corey-Chaykovsky epoxidation, where ketoacids are employed as the substrates and commercially available trimethylsulfoxonium iodide is employed as the carbon-atom homologating reagent. A variety of lactones are produced in a single step in synthetically useful yields.

Full text of DOI:10.1021/acs.orglett.9b01852

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of γ‑Lactones Utilizing Ketoacids and
Trimethylsulfoxonium Iodide
Ierasia Triandafillidi, Anatoli Savvidou, and Christoforos G. Kokotos*
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis,
Athens 15771, Greece
S
* Supporting Information
ABSTRACT: The Johnson−Corey−Chaykovsky epoxidation is one of the oldest methods for the synthesis of terminal
epoxides from carbonyl compounds. Herein we present a simplified extension of the Johnson−Corey−Chaykovsky epoxidation,
where ketoacids are employed as the substrates and commercially available trimethylsulfoxonium iodide is employed as the
carbon-atom homologating reagent. A variety of lactones are produced in a single step in synthetically useful yields.
Because of the importance of the lactone moiety, a variety of
synthetic pathways have been reported for their synthesis,
utilizing as starting materials a plethora of compounds, like
unsaturated hydrocarbons,10 alcohols,11 or carboxylic acids.12
A very common approach is the intramolecular lactonization of
organic compounds to γ-lactones, utilizing a variety of metal
catalysts13 or organocatalysts.14
Our group has focused on the implementation of green
strategies for the synthesis of compounds via new reactions
employing either organocatalysis15 or photocatalysis.16 Herein
we contribute to the synthesis of lactones via an alternative and
complementary methodology (Scheme 1). Because of our
uring the last 60 years, organo-sulfur compounds have
Dattracted the attention of the scientific community as
valuable intermediates in the synthesis of various organic
compounds and as key components of numerous reactions.1 In
particular, sulfur ylides have been recognized for their
important role as a source of carbanions.2 The Johnson−
Corey−Chaykovsky epoxidation is among the oldest methods
for the synthesis of structurally diverse terminal oxiranes from
aldehydes or ketones.3 Several modifications of the reaction
have been investigated via the alteration of the base, the
medium of the reaction, or the insertion group.4 Very recently,
attention has been diverted to asymmetric variations of the
reaction, employing chiral sulfides,5 and its applications in
asymmetric catalysis with chiral catalysts.6 In this work, we
extend the limits of the Corey−Chaykovsky epoxidation to the
synthesis of lactones.
Scheme 1. Synthetic Pathways for the Synthesis of Lactones
2
Lactones are important intermediates in organic synthesis
and have been widely employed for the preparation of
antimicrobial compounds,7 compounds of biological impor-
tance,8 and a variety of useful building blocks9 (Figure 1).
knowledge of oxidation and especially epoxidation,15 we have
reported the synthesis of lactones 2 from 1 via a two-step
process involving a Wittig olefination, followed by an
organocatalytic epoxidation−cyclization (Scheme 1, top).15c
We have also provided photocatalytic alternatives, starting
from either alkenes and iodoacetic acid16d or Michael
Received: May 28, 2019
Figure 1. Utility of the lactone’s skeleton.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01852
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acceptors and alcohols.16b However, it would be highly
desirable if we could provide a one-step procedure for the
direct transformation of 1 to lactones 2. Herein we saw an
opportunity that sulfur ylides provide17 to perform such a task.
We initiated our study utilizing ketoacid 1a in an attempt to
identify the optimum reaction conditions for the synthesis of γ-
lactone 2a (Table 1). In the beginning, sodium hydride was
Scheme 2. Substrate Scope for the Synthesis of γ-Lactones
from Ketoacids
Table 1. Optimization of the Reaction Conditions for the
a
Synthesis of γ-Lactones from Ketoacids
b
entry
base (equiv)
solvent (M)
yield (%)
1
2
3
4
5
6
7
8
NaH (1.2)
NaH (1.2)
NaH (1.2)
NaH (1.2)
KtOBu (1.2)
n-BuLi (1.2)
KHMDS (1.2)
DBU (1.2)
NaH (2.4)
NaH (3.6)
NaH (3.6)
NaH (3.6)
THF (0.2)
0
9
CH2Cl2 (0.2)
MeCN (0.2)
DMSO (0.2)
DMSO (0.2)
DMSO (0.2)
DMSO (0.2)
DMSO (0.2)
DMSO (0.2)
DMSO (0.2)
DMSO (0.4)
DMSO (0.1)
traces
55
27
51
5
0
9
68
76
41
70
10
11
12
a
Reaction conditions for lactonization: ketoacid (1.0 equiv),
trimethylsulfoxonium iodide (3.0 equiv), base, solvent at 0 °C for 1
b
h, and then rt for 20 h. Isolated yield.
employed as the base to form in situ the sulfur ylide, and
several solvents were tested, but the desired lactone was not
obtained in satisfactory yield (Table 1, entries 1−3). When
DMSO was used as the solvent, lactone 2a was afforded in
good yield (Table 1, entry 4). Various organic bases were then
tested along with trimethylsulfoxonium iodide, with sodium
hydride leading to the highest yield (Table 1, entries 5−8).
Because trimethylsulfoxonium iodide is employed, a common
cheap base can be employed for the deprotonation rather than
a stronger organic base, which is required for sulfonium ylides
(pKa Me3S(O)I = 18.2, pKa Me3S = 24.5 (in DMSO)).18
Furthermore, an increase in the equivalents of the base
afforded lactone 2a in better yield (Table 1, entries 9 and 10).
When the concentration of DMSO was altered, the yield
decreased (Table 1, entries 11 and 12).
expanded the substrate scope, leading to high yields
(compounds 2m−r).
In an effort to further expand the possibilities of this
protocol, additional substrates were tested, affording a variety
of cyclic products (Scheme 3). Starting from ketoacid 1s under
Scheme 3. Additional Substrate Scope
Having in hand the optimized reaction conditions, we
further explored how the nature of the substrate affects the
reaction outcome (Scheme 2). Various substituents at the para
position of the aromatic ring had no significant impact on the
reaction outcome, leading to similar yields (Scheme 2, 2b−g).
In the case of ortho-substituted ketoacid 1h, the yield dropped,
affording lactone 2h in low yield. The high stereochemical
congestion close to the carbonyl moiety, where the reaction
takes place, probably slows down the desired reaction. The
naphthyl group does not affect the reaction outcome, and
lactone 2i was isolated in 65% yield. Changing the substitution
pattern by using aliphatic moieties did not alter the behavior of
the reaction (Scheme 2, 2j−l). Furthermore, the use of
aliphatic side chains with phenyl or other functional groups
the same reaction conditions, δ-lactone 2s was afforded in
good yield. Thus the method can be extended in the synthesis
of δ-lactones. Finally, another possibility for the synthesis of
lactams is possible because ketoamide 1t was used as a
substrate and γ-lactam 2t was isolated in moderate yield.
Attempts to prepare substituted sulfoxonium or sulfonium salts
and utilize them in our methodology to widen our substrate
scope were met with failure.
To expand the limits of this method, we envisaged the
application of our protocol in a fast total synthesis of the
B
DOI: 10.1021/acs.orglett.9b01852
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
natural product (+)-asperolide C19 in only two steps, starting
from (+)-podocarpic acid (3a) (Scheme 4). Podolactones and
C.24 The alkoxide C undergoes an intramolecular ring opening
of the six-membered ring lactone to the desired γ-lactone 2a.
The alternative mechanism involving epoxide formation,
followed by an SN2-type reaction at a quaternary carbon
atom, seems unlikely to be happening.
Scheme 4. Synthetic Routes to (+)-Asperolide C
In conclusion, an effective and easy-to-handle synthetic
protocol for the synthesis of γ-lactones from ketoacids is
described. Utilizing a modification of the Johnson−Corey−
Chaykovsky reaction, a variety of γ-lactones were synthesized.
A plethora of substituted ketoacids lead to γ- or δ-lactones as
well as lactams in good to excellent yield. An effort to apply our
methodology to the total synthesis of (+)-asperolide C was
demonstrated. Unfortunately, its epimer was obtained, which
opens new avenues to synthesize these compounds that have
never been described or assessed for their biological activity.
ASSOCIATED CONTENT
* Supporting Information
■
S
other related compounds of natural origin show a wide variety
of biological activities.20 Because of this biological activity,
different research groups, in the last years, have accomplished
the total synthesis of the natural product (+)-asperolide C
through many synthetic steps.21 Carreira and coworkers were
the first to report the total synthesis of (+)-asperolide C in 17
steps (Scheme 4).21a In 2016, Yang and coworkers reported
the synthesis of (+)-asperolide C in five steps.21b Utilizing our
methodology, we envisaged a fast two-step assembly of
(+)-asperolide C from commercially available (+)-podocarpic
acid (3a) (Scheme 4). In the first step, ozonolysis of
(+)-podocarpic acid (3a), followed by the reduction of the
resulting hydroperoxide, afforded keto diacid 3b; all data
matched with literature.21b In the final step, the application of
our methodology utilizing trimethylsulfoxonium iodide and
sodium hydride led to product 3c in 24% yield over two steps.
Unfortunately, 3c was not (+)-asperolide C but its epimer.
Because all chiral centers in 3b are fixed and previous
methodologies employed a substrate-controlled epoxidation of
the ester-protected compound, we believe that the free
carboxylate, in conjunction with the sulfur−ylide reactivity,
instead of a peracid, leads to a neighboring-effect-controlled
(electrostatic interaction between the carboxylate and the
ylide22) transition state, which is responsible for this difference.
To summarize the events that take place in this reaction, a
proposed reaction mechanism is shown in Scheme 5.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01852.
Experimental procedures, full optimization data, charac-
terization data, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ckokotos@chem.uoa.gr.
ORCID
Christoforos G. Kokotos: 0000-0002-4762-7682
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support through the
Special Account for Research (ELKE) and the Laboratory of
Organic Chemistry of the National and Kapodistrian
University of Athens. We thank Ms. Iokasti Dodi (Laboratory
of Organic Chemistry, Department of Chemistry, National and
Kapodistrian University of Athens) for preliminary results and
Dr. Dimitra Benaki (Department of Pharmacy, National and
Kapodistrian University of Athens) for her assistance in
acquiring the NMR spectra of 3c. I.T. thanks the Hellenic
Foundation for Research and Innovation (HFRI) and the
General Secretariat for Research and Technology (GSRT) for
an HFRI Ph.D. Fellowship grant (GA14476). Also, COST
Action C−H Activation in Organic Synthesis (CHAOS)
CA15106 is acknowledged for helpful discussions.
Scheme 5. Proposed Reaction Mechanism
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DOI: 10.1021/acs.orglett.9b01852
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