One-Pot γ-Lactonization of Homopropargyl Alcohols via Intramolecular Ketene Trapping

Article abstract of DOI:10.1021/acs.orglett.1c00840

A one-pot γ-lactonization of homopropargyl alcohols via an alkyne deprotonation/boronation/oxidation sequence has been developed. Oxidation of the generated alkynyl boronate affords the corresponding ketene intermediate, which is trapped by the adjacent hydroxy group to furnish the γ-lactone. We have optimized the conditions as well as examined the substrate scope and synthetic applications of this efficient one-pot lactonization.

Full text of DOI:10.1021/acs.orglett.1c00840

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Letter
One-Pot γ‑Lactonization of Homopropargyl Alcohols via
Intramolecular Ketene Trapping
Daichi Yamane,† Haruna Tanaka,† Akihiro Hirata,† Yumiko Tamura, Daichi Takahashi,
Yusuke Takahashi, Tohru Nagamitsu,* and Masaki Ohtawa*
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ABSTRACT: A one-pot γ-lactonization of homopropargyl alco-
hols via an alkyne deprotonation/boronation/oxidation sequence
has been developed. Oxidation of the generated alkynyl boronate
affords the corresponding ketene intermediate, which is trapped by
the adjacent hydroxy group to furnish the γ-lactone. We have
optimized the conditions as well as examined the substrate scope
and synthetic applications of this efficient one-pot lactonization.
ive-membered cyclic esters, i.e., γ-lactones (γ-butyrolac-
alcohols5 via hydroboration/oxidation followed by further
oxidation of the lactols over multiple steps. The latter
approaches are based on the intramolecular cyclization of
1
Ftones), are important bioactive molecules
and useful
building blocks for various interesting target molecules.2 γ-
Lactones are often synthesized by intramolecular cyclizations
of the corresponding hydroxycarboxylic acid (seco acid) or its
esters;3 however, functional group interconversions (FGIs) are
needed to prepare these precursors. On the other hand, γ-
lactonizations of homopropargyl alcohols involving stepwise
and direct approaches have been developed (Figure 1). In the
former case, γ-lactones are produced from lactols derived from
homopropargyl alcohols4 or the corresponding homoallyl
̈
alkyne-derived metal vinylidene intermediates. Dotz et al. have
reported the first reaction of this type, in which isolable
chromium vinylidene intermediates are formed from homo-
propargyl alcohols and subsequently oxidized with ceric
ammonium nitrate (CAN) to afford γ-lactones.6 After this
report, several catalytic one-pot cyclizations of metal vinylidene
intermediates (Ru cat.,7 Au cat.8) have been reported.
Although this approach can be carried out under mild
conditions and exhibits a wide substrate generality, tran-
sition-metal catalysts which are not readily available are still
required.
In a previous study on the synthesis of (−)-bilobalide,9 we
have developed a novel γ-lactonization of homopropargyl
alcohols (Figure 2). The construction of γ-lactone 7 from
homopropargyl alcohol 6 was attempted using both stepwise
(entries 1 and 2) and direct lactonization (entries 37 and 48a)
strategies; however, both approaches provided low or no yield
of lactone 7, most likely due to the steric hindrance. Next, we
attempted the γ-lactonization of the ketene intermediate10
generated from acetylide using the Li salt of tert-butyl
hydroperoxide (TBHP),11 but the oxidation did not proceed
(entry 5). In another previous work, we have reported the
Received: March 10, 2021
Published: March 22, 2021
Figure 1. Previously reported lactonization strategies for propargyl
alcohols and the approach used in this study.
https://doi.org/10.1021/acs.orglett.1c00840
© 2021 American Chemical Society
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Figure 2. Discovery of new lactonization.
direct hydroxylation of pyridine via a lithiation/boronation
(B(OMe)3)/oxidation (m-chloroperoxybenzoic acid (m-
CPBA)) sequence.12 If this reaction could also be applied to
the sp carbon, it would represent a new method of ketene
generation via alkyne hydroxylation.13 As expected, subjecting
homopropargyl alcohol 6 to these conditions gave lactone 7 as
the exclusive product in 55% yield (entry 6).
Nevertheless, this lactonization procedure uses common and
inexpensive reagents and an easy one-pot sequence.14 There-
fore, it represents a new and useful alternative procedure to
obtain γ-lactones from various homopropargyl alcohols. Our
optimized conditions and instructive deviations are shown in
Figure 3.
γ-Lactonization of 1a under the “standard conditions” gave
the desired product 3a in 79% yield, accompanied by a small
amount of the starting material 1a (entry 1), and a scale-up of
this reaction (entry 2) is easily possible. The optimum time
and temperature for the boronation with B(OMe)3 were
determined to be 2 h at 0 °C (entries 3−5). The oxidation of
the alkynyl boronate intermediate at low temperature (−78
°C) provided 3a in 28% yield, together with a large amount of
unreacted alcohol 1a (entry 6). Variation of the reagents used
in the deprotonation and boronation steps indicated that more
basic (not nucleophilic) and less bulky reagents were most
suitable for this conversion (entries 7 and 8). Next, various
oxidants were examined. Neutral and basic oxidants, such as
TBHP (entry 9) or t-BuOOLi11 (entry 10), did not provide
the desired lactone 3a. When the slightly acidic oxidants
triazox15 and Oxone were used, lactone 3a was obtained in
21% and 44% yield, respectively, although some uncharac-
terized byproducts were generated (entries 11 and 12). At this
point, we focused on the recovered alcohol 1a from each trial
due to the stability of the alkynyl boronate intermediate.
Brown has reported that the protonation of alkynyl boronate
occurs easily in the presence of proton sources such as
alcohols, water, and acids.16 Commercially available m-CPBA
contains 30−40% water and 4−5% m-chlorobenzoic acid (m-
CBA) as stabilizers; therefore, anhydrous m-CPBA and
purified m-CPBA17 were prepared and used for the
lactonization, but the results remained unchanged (entries 12
and 13). This result indicates that m-CPBA and m-CBA
promote the generation and protonation of the alkynyl
boronate intermediate. A more detailed discussion of the
proposed reaction mechanism is presented later in the
Figure 3. Optimization of the reaction conditions.
manuscript (Figure 5). The influence of the number of
equivalents of the reagents (lithium bis(trimethylsilyl)amide
(LHMDS)/B(OMe)3 and m-CPBA) was examined, and we
found that the yield was maintained even when the amounts of
both reagents were reduced to three equivalents (entries 14
and 15).
The optimized conditions were found to be applicable to the
synthesis of γ-lactones from a wide range of homopropargyl
alcohol substrates (Figure 4). Methoxy-, methyl-, chlorine-,
bromine-, cyano-, and substituted phenyl groups were
tolerated, regardless of the substitution position (3a−m);
however, due to the rapid oxidation of the amino group,
lactone 3l could not be obtained. Synthesis of the
monosubstituted γ-lactones 3n−s including heteroaromatic
rings was successfully achieved. Various disubstituted γ-
lactones were also obtained in moderate yield (3t−ab).
Notably, this reaction can also be applied to substrates with
unsaturated bonds, which indicates that the oxidation of the
alkynylboronate intermediates by m-CPBA is faster than the
oxidation of unsaturated bonds.
Then, we applied this reaction to the relatively short
synthesis of spironolactone (Scheme 1). Spironolactone has
been semisynthesized from steroidal precursors using a variety
of industrial methods; in the context of our study, the Ciba-
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Scheme 1. Application to the Short Synthesis of
Spironolactone (12)
following lactonization gave the Ciba-Geigy γ-lactone 11
intermediate in 83% yield in two steps from dehydroepien-
drosterone (9) without compromising the unsaturated bonds.
γ-Lactone 11 was subjected a sequential oxidation followed by
the conjugate addition of thioacetic acid to afford spirono-
lactone (12) (for details, see the SI). Thus, the present
lactonization represents a short synthetic route (5 steps) from
dehydroepiendrosterone (9) to spironolactone (12), showing
that this method can be applied to the synthesis of various
drugs and natural products containing γ-lactones.
A plausible mechanism of this reaction is shown in Figure 5.
The starting material, homopropargyl alcohol 1, is deproto-
nated by LHMDS to afford dilithium species 13. Next,
B(OMe)3 is applied to form borate intermediate 14, and the
subsequent addition of m-CPBA or its contaminant m-CBA
Figure 4. Substrate scope.
Geigy method should be mentioned, as it constructs γ-lactone
11 from dehydroepiendrosterone (9) in 5 steps, followed by 3
steps to produce spironolactone (12) industrially.18 Sub-
sequently, we applied our new lactonization method in an
attempt to improve the synthesis of 12. The homopropargyl
intermediate 10 was obtained in 85% yield by treating
dehydroepiendrosterone (9) with an in situ-prepared propargyl
Grignard reagent in the presence of mercury(II) chloride. The
Figure 5. Plausible mechanism of the reaction.
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promotes the dissociation of MeOH from the borate to give
alkynyl boronate or alkynyl boronic acid 15. The oxidation of
14 does not proceed when TBHP or t-BuOOLi is used as the
oxidant (Figure 3, entries 8 and 9); therefore, the presence of
an acid to dissociate one MeOH from alkynyl boronate seems
to be essential for this reaction. The resulting intermediate 15
is rapidly oxidized by m-CPBA to form ynol boronate or
boronic acid 16, and the intramolecular cyclization of the
adjacent hydroxyl group to the protonated ketene intermediate
5 gives the corresponding lactone 3.19 One problem in this
reaction is the potentially fast protonation of 15 to give starting
material 1. The protonation of 15 depends on the pKa of the
proton source;16 however, it should be difficult to completely
suppress the protonation due to the requirement of a proton
(or Lewis acid) for the desorption of one molecule of MeOH
from the alkynylborate intermediate in situ. Despite this
limitation, this approach is a useful and simple functional-
group-conversion method for the lactonization of homopro-
pargylic alcohols in one pot with readily available reagents.
Finally, we applied this lactonization strategy to the synthesis
of 4-, 6-, and 7-membered lactones (Scheme 2). However, we
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00840.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Masaki Ohtawa − Laboratory of Synthetic Natural Products
Chemistry and Medicinal Research Laboratories, School of
Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641,
Japan; orcid.org/0000-0001-7129-012X;
Email: ohtawam@pharm.kitasato-u.ac.jp
Tohru Nagamitsu − Laboratory of Synthetic Natural Products
Chemistry and Medicinal Research Laboratories, School of
Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641,
Japan; orcid.org/0000-0002-4278-4507;
Email: nagamitsut@pharm.kitasato-u.ac.jp
Scheme 2. Attempted Lactonization of Various Alkynyl
Alcohols
Authors
Daichi Yamane − Laboratory of Synthetic Natural Products
Chemistry and Medicinal Research Laboratories, School of
Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641,
Japan
Haruna Tanaka − Laboratory of Synthetic Natural Products
Chemistry and Medicinal Research Laboratories, School of
Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641,
Japan
Akihiro Hirata − Laboratory of Synthetic Natural Products
Chemistry and Medicinal Research Laboratories, School of
Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641,
Japan
Yumiko Tamura − Laboratory of Synthetic Natural Products
Chemistry and Medicinal Research Laboratories, School of
Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641,
Japan
Daichi Takahashi − Laboratory of Synthetic Natural Products
Chemistry and Medicinal Research Laboratories, School of
Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641,
Japan
Yusuke Takahashi − Laboratory of Synthetic Natural
Products Chemistry and Medicinal Research Laboratories,
School of Pharmacy, Kitasato University, Minato-ku, Tokyo
108-8641, Japan
found that only the 6-membered ring lactone 3ad was obtained
from 1ad in moderate yield. The reactions of 1ac and 1ae did
not produce the corresponding lactones 3ac and 3ae and
instead furnished complex mixtures including trace amounts of
methyl esters due to the intermolecular esterification of the
MeOH resulting from B(OMe)3 and the corresponding
carboxylic acid from the ketene intermediate due to the
presence of water as a contaminant of m-CPBA. This result
indicates that (i) the intermediate ketene is highly reactive and
effective for the lactonization of more suitable substrates (e.g.,
γ-lactone precursors), and (ii) it could also be extended to
intermolecular reactions to give carboxylic acids, esters, or
amides in the presence of appropriate acceptors.
In summary, we have reported a useful method for the
lactonization of homopropargyl alcohols via a ketene
intermediate. In this one-pot reaction, which involves a
deprotonation, boronation, and oxidation of a terminal alkyne,
the corresponding γ-lactones are obtained via the intra-
molecular cyclization of the ketene intermediates. This simple
transformation thus represents a useful method for the
oxidation of alkynes that does not require the isolation of
intermediates and can be achieved using commercially
available and inexpensive reagents. This γ-lactonization
exhibits a broad substrate generality and is not only applicable
to various homopropargyl alcohols but also effective for the
short synthesis of pharmaceuticals such as a spironolactone.
The application of this method to intramolecular lactams and
intermolecular reactions is currently in progress in our group.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00840
Author Contributions
†D.Y., H.T., and A.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Kenichiro Nagai and Ms. Noriko Sato (Kitasato
University) for kind measurements of NMR and mass spectra.
We also thank Prof. Ryan A. Shenvi (Scripps Research) for
helpful discussions. We are grateful to Robert M. Demoret and
Meghan A. Baker (Scripps Research) for their help in
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Letter
(13) For other reports on the synthesis of ynolates from alkynes, see:
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7125−7127.
(14) Recently, Zhao et al. have reported an elegant intermolecular
formation of carboxylic acids, esters, and amides via the boronation of
terminal alkynes using a similar method. For details, see: Li, C.; Zhao,
P.; Li, R.; Zhang, B.; Zhao, W. Oxidation of Alkynyl Boronates to
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(15) Yamada, K.; Igarashi, Y.; Betsuyaku, T.; Kitamura, M.; Hirata,
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(16) Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988,
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(17) Horn, A.; Kazmaier, U. Purified mCPBA, a Useful Reagent for
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(18) (a) Larik, F. A.; Saeed, A.; Shahzad, D.; Faisal, M.; El-Seedi, H.;
Mehfooz, H.; Channar, P. A. Synthetic Approaches Towards the
Multi Target Drug Spironolactone and Its Potent Analogues/
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3a. This result indicates that the free hydroxyl group is necessary for
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discovering the lactonization in the synthetic study on
bilobalide.9
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