Angewandte
Research Articles
Chemie
macrolactone and macrodiolide attained 1:1 with 10-hydrox-
diolides (13- to 26-membered macrolactones and macro-
ydecanoic acid 1h, providing 2h in 31% yield. Further, the
reaction was compatible with various functional groups,
including triazole, strained 1,3-butadiyne, alkene and diol
diolides in yields ranging from 55 to 98%) by employing
Hf(OTf) as a catalyst. However, those reactions conditions
4
were not compatible with secondary and tertiary aliphatic
alcohols and were less effective with ring sizes smaller than
13-membered rings. In turn, Zhao and co-workers depicted
the use of an ynamide (N-ethynyl-N,4-dimethylbenzenesulfo-
namide) as a reacting agent with the carboxylic acid to deliver
an enamide that undergoes a cyclization with the alcohol in
the presence of p-toluenesulfonic acid. This strategy afforded
7- to 19-membered macrolactones in yields ranging from 52 to
96% over 2 steps. However, not only do the reactions require
the use of an expensive ynamide, but stoichiometric amounts
of N-methyl-N-tosylacetamide were formed, which tends to
make the purification of the products troublesome. Of note,
the possibility of using substrates bearing phenols was not
(
protected or not) moieties, affording the target macro-
lactones in yields ranging from 65% to 89%. The method
could also be applied to secondary aliphatic alcohols and
carboxylic acids (2n–2s) and even challenging 8-membered
[18]
rings such as 2q were obtained in 42% yield. In the case of
1
p, the reaction occurred with retention of configuration. In
[
19]
addition, the framework of resorcylic lactones (2n)
and
cyclodepsipeptide 2s were generated in 76 and 74% yields.
Lastly, tertiary aliphatic alcohols were also tolerated, albeit in
a lower yield (2t, 35%).
The devised strategy is not limited to macrolactonization
of aliphatic hydroxyacids, but was also extended to substrates
[
20]
incorporating phenols,
notably arduous meta-and para-cyclophanes in high yields
2u–2w, 82 to 85%), compounds that have many applications
delivering the target products,
reported in any of those studies. Regarding the preparation of
ꢀ
compound 10 (Musk T ), apart from industrial processes
(
involving the thermal cleavage of oligoesters, the only
macrodilactonization described led to this compound in only
[
21]
in materials science and supramolecular chemistry. Never-
theless, the reaction with phenols proved to be slower as the
reactions required 48 h to reach full conversion. Finally, we
turned our attention to the preparation of macrodiolides
[
24]
20% yield via the use of Brønsted and Lewis acids.
(
compounds 6–11), which are widespread scaffolds in medic-
Scope of Esters
[
22]
inal chemistry.
Their synthesis is known to be more
challenging than the one of macrolactones since two chemical
events (esterification then macrolactonization) are involved
We also investigated intermolecular esterifications (Ta-
ble 3). Once more, this procedure showcased a broad func-
tional group tolerance at a higher concentration when
compared to macrolactonizations (0.1 M). The reaction
proved to be compatible with primary as well as secondary
and tertiary alcohols producing high yields (up to 98%). In
a similar manner, primary, secondary and tertiary carboxylic
acids exhibited the same efficiency. Moreover, we succeeded
to accomplish the mono- acetylation of 1,4-butanediol (14ae)
in 71% yield. Even a poorly nucleophilic alcohol, trifluor-
oethanol, delivered the corresponding ester 14ad in 72%
yield. Reactions of less reactive aryl alcohols such as phenol
and naphthol provided the ester products in 80% and 72%,
respectively, in 48 h. Of note, substrates bearing acid-sensitive
functional groups (TBS, Boc and acetal) were well-tolerated.
Finally, compounds of interest such as amino alcohols (14ag),
amino acids (14ba), carbohydrates (14ah), steroids (14ak)
and fatty acids (14em) underwent esterifications with yields
[
23]
when starting from seco-acids or diacids. We were pleased
to find that 16- to 34-membered macrodiolides could be
rapidly afforded in high yields (up to 89%). Moreover, Musk
ꢀ
ꢀ
T and Zenolide (10 and 11), two compounds with major
industrial applications, were generated in a single step within
4
8 h in 74% and 68% yields.
Comparison with Prior Art
The major strengths of our approach are (i) its compat-
ibility with a large variety of primary, secondary, tertiary
aliphatic alcohols, diols, and phenols, (ii) an inexpensive
activating reagent (pentafluorobenzoyl chloride), and (iii) the
easily removable side-products through a simple aqueous
work-up. The key question is where our method stands
compared to previous reports from the literature featuring
seco-acids, including the methods involving the formation of
a mixed anhydride (e.g., the use of MNBA) and the catalytic
approaches. In the case of MNBA, we compared our data on
[
25]
ranging from 54% to 91%.
Having identified the pentafluorobenzoyl group as an
excellent activating agent for macrolactonization processes,
we next turned to study the origins of its reactivity and
selectivity. In particular, we wondered whether the cyclization
occurred via supramolecular interactions as initially hypothe-
sized. To shed light on the mode of operation of our system,
we conducted experimental studies, which were further
corroborated by Density Functional Theory (DFT) compu-
tations.
[4c]
identical substrates (see Table 1). With respect to tradi-
tional substrates, we noticed that both methods were similarly
efficient. However, in the case of more challenging reactions,
such as the formation of macrodiolides and macrolactones
incorporating a phenol moiety, our method formed products
in significantly higher yields than the previous method, e.g.,
8
4% vs. < 10% yield of 2w and 81% vs. 30% yield of 8,
respectively. Another important factor is that pentafluoro-
[17]
benzoyl chloride is significantly cheaper than MNBA,
Kinetic Studies
without requiring any slow addition of the reagents during
the reaction set-up. More recently, the group of Collins
reported a method to access macrolactones and macro-
First, we studied the kinetics of the reaction of 1a with 1’a
in the presence of triethylamine by H and F NMR
1
19
Angew. Chem. Int. Ed. 2021, 60, 2 – 11
ꢂ 2021 Wiley-VCH GmbH
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These are not the final page numbers!
Ciofini, Ilaria
