Direct macrolactonization of seco acids via hafnium(IV) catalysis

Article abstract of DOI:10.1021/acscatal.5b00082

Efficient direct macrolactonization of seco acids can be catalyzed by Hf(OTf)₄ in high yields, forming water as the sole byproduct. The Hf(OTf)₄ catalyst possesses unique reactivity characteristics relative to other Lewis acids, as it promotes macrolactonization over hydrolysis even in the presence of excess water. In addition to forming a variety of macrolactones and benzolactones (55-90%), intermolecular direct esterifications of carboxylic acids and alcohols were also possible and demonstrated compatibility with common carbamate, silyl ether, alkoxymethyl ether, and acetal protecting groups. All of the macrolactonization and esterification processes developed are operationally simple, "one-pot" reactions that exploit a commercially available catalyst without the need for slow addition or azeotropic techniques.

Full text of DOI:10.1021/acscatal.5b00082

Research Article
pubs.acs.org/acscatalysis
Direct Macrolactonization of Seco Acids via Hafnium(IV) Catalysis
Mylene de Leseleuc and Shawn K. Collins*
̀ ́ ́
Dep
Queb
́
artement de Chimie, Centre for Green Chemistry and Catalysis, Universite
ec H3C 3J7, Canada
́ ́ ́
de Montreal, CP 6128 Station Downtown, Montreal,
́
*
S Supporting Information
ABSTRACT: Efficient direct macrolactonization of seco acids can be
catalyzed by Hf(OTf) in high yields, forming water as the sole byproduct.
4
The Hf(OTf) catalyst possesses unique reactivity characteristics relative to
4
other Lewis acids, as it promotes macrolactonization over hydrolysis even in
the presence of excess water. In addition to forming a variety of
macrolactones and benzolactones (55−90%), intermolecular direct ester-
ifications of carboxylic acids and alcohols were also possible and
demonstrated compatibility with common carbamate, silyl ether, alkox-
ymethyl ether, and acetal protecting groups. All of the macrolactonization
and esterification processes developed are operationally simple, “one-pot”
reactions that exploit a commercially available catalyst without the need for
slow addition or azeotropic techniques.
KEYWORDS: macrolactonization, hafnium, esterification, macrocyclization, Lewis acids, catalysis
acrolactones are one of the most common cyclic motifs
was concurrently distilled away from the reaction mixture as it
formed, thus controlling any unfavorable equilibria.
M
found in Nature. In addition to their application in
1
pharmaceuticals, macrolactones have had a tremendous impact
Current strategies to promote macrolactonization from seco
2
−4
15
on the cosmetic industry.
Macrocyclic musks have attracted
acids involve stoichiometric activation of the carboxylic acid,
increased attention from the perfume industry, as they do not
exhibit the toxicity or bioaccumulation properties associated
with traditional nitro-aromatic and polycyclic musks. In 2011,
which is eventually eliminated as a thermodynamically favorable
leaving group (Figure 1). Some of the more popular strategies
employing this concept for macrolactone synthesis include the
5
16
17
18
Corey−Nicolaou, Boden−Keck, Mitsunobu, and Yama-
it was estimated that the market for flavors and fragrances was
19
6
guchi lactonizations. In each of the above examples, reactions
are normally all conducted under high-dilution conditions and
the stoichiometric byproducts can be toxic and difficult to
remove even via chromatographic separation. The Yamaguchi
macrolactonization has been particularly favored among
synthetic chemists since its inception in 1979, as almost 200
examples of the macrolactonization protocol have been
worth over 21 billion dollars. The production of macrocyclic
musk is of considerable industrial impact; for example, in 2008
7
the production of the 16-membered Exaltolide (2) was on the
8
order of ∼1000 tons. Consequently, synthetic chemists in both
academia and industry have continued to develop new
strategies to prepare macrolactones, where Exaltolide and its
derivatives have often served as targets for new methodologies.
20
9
reported. Recently, modified anhydride reagents inspired by
Olefin metathesis, most recently employing Z-selective
1
0
the Yamaguchi method have attracted increased attention for
catalysts, and C−H functionalization have recently been
21
11
the synthesis of naturally occurring macrolactones. Surpris-
explored for the synthesis of macrocyclic musk-like structures.
Surprisingly, catalysis has rarely been examined for macro-
ingly, efficient catalytic direct macrolactonization of seco acids
8
12,13
is rare and underdeveloped. Herein, we report on a hafnium-
cyclization from the commonly occurring seco acids.
catalyzed macrolactonization protocol for the formation of
macrolactones that produces water as the only byproduct.
Macrolactones formed via condensation of the corresponding
seco acid are equilibrium-controlled processes, where the
reverse hydrolysis reaction can be problematic. While in an
analogous intermolecular esterification the alcohol can be
added in large excess (often as the solvent) in order to push
unfavorable equilibria toward the formation of the desired
DISCOVERY OF A HF(IV)-CATALYZED
MACROLACTONIZATION
■
In developing an ideal direct macrolactonization of seco acids,
1
4
several goals were identified. First, an operationally simple,
ester, the stoichiometry of the alcohol and acid functionalities
13a
“
one-pot” process was desired which avoided the use of
in macrolactonization remains fixed in a 1:1 ratio. In 1936,
azeotropic techniques (drying tubes, Dean−Stark traps) and
Carothers reported a Lewis acid catalyzed transesterification
process for the formation of macrolactone 2. Following thermal
polymerization of the seco acid 1, MgCl was used to promote
Received: January 15, 2015
2
“back-biting” of the oligomer to afford macrolactone 2, which
©
XXXX American Chemical Society
1462
DOI: 10.1021/acscatal.5b00082
ACS Catal. 2015, 5, 1462−1467

ACS Catalysis
Research Article
Figure 2. Optimization of a Lewis acid catalyzed macrolactonization
process. Footnotes for the entries are as follows. (a) Isolated yields
following silica gel chromatography; the remaining mass balance was
unreacted 1 unless otherwise noted. (b) No trace of 1 was isolated. (c)
Polymerization of 1 was observed. (d) Lower catalyst loadings
Figure 1. Traditional macrolactonization strategies.
provided lower yields. When 2.5 mol % Hf(OTf) was used, 72% of 2
4
and 27% reisolated 1 were obtained. At a concentration of 10 mM,
3
2% of 2 was obtained along with a complex mixture of cyclic and
slow-addition/high-dilution apparatus (syringe pumps). Sec-
ond, the direct macrolactonization would produce water as the
only byproduct. These goals present significant challenges for
catalysis, as a suitable Lewis acid must not only possess
sufficient acidity to activate the macrocyclization but must also
retain that reactivity even as the reaction media becomes
increasingly “contaminated” by water. An additional require-
ment is that the Lewis acid must also refrain from catalyzing
hydrolysis of the desired macrolactone. Although a thorough
investigation surveying a wide variety of Lewis acids from across
the periodic table was envisioned, particular focus in the
present study was placed on lanthanide-based Lewis acids,
including Lewis acids based on elements of groups III and IV
that have demonstrated the ability to promote Lewis acid
acyclic dimers. Lowering the temperature resulted in low conversions,
even when the catalyst loading was increased.
Next, Lewis acids from groups III and IV, including
lanthanide-based Lewis acids, were investigated. Given the
success of electrophilic triflate catalysts for macrocyclization of
1, Sc(OTf) (45%), Sm(OTf) (21%), Dy(OTf) (13%), and
Yb(OTf) (38%) were evaluated and showed encouraging but
low yields (Figure 2, entries 22−25). Interestingly, when
Hf(OTf) was used, an 83% yield of the macrolactone 2 was
isolated. Yamamoto and co-workers reported that efficient
direct intermolecular esterifications using low loadings of
HfCl (THF) were possible, albeit under azeotropic reflux.
Disappointingly, when the hafnium-based catalysts
HfCl (THF)2 and Hf(O-n-Bu)4 were investigated in the
protocol without the use of azeotropic techniques, only low
yields were obtained (entries 26 and 27). Given the success of
the Hf(OTf) complex, the possibility of catalysis via in situ
formed HOTf was investigated. In a control reaction, it was
found that HOTf did catalyze the macrolactonization (1 → 2),
albeit in much lower yield (39% vs 83% with Hf(OTf)4).
3
3
3
3
4
2
4
25,26
4
2
22
catalysis in aqueous media. The macrolactonization of seco
acid 1 to provide Exaltolide 2 was selected as a model substrate
for cyclization (Figure 2). The investigations began with various
oxophilic Lewis acid catalysts. Although these Lewis acids are
known to react readily with water, no precautions to exclude
water (such as adding drying tubes or molecular sieves) were
taken and no slow-addition techniques were exploited (Figure
4
4
2
3
2
). As expected, titanium, iron, magnesium, boron, and
aluminum catalysts in general did not afford any of the desired
macrolactone 2 (entries 1−10), and either quantitative recovery
of the starting material 1 was observed or the highly acidic
conditions caused decomposition of 1. Some productive
macrocyclization was observed copper-based catalysts were
used. While CuCl2 and CuBr2 did not promote any
macrolactonization, both Cu(OAc) and Cu(OTf) resulted
Consequently, macrolactonization using Hf(OTf) with added
4
(i-Pr) NEt (50 mol % or 10 equiv of base with respect to
2
Hf(OTf) ) to quench traces of protic acids was performed. In
4
the macrolactonization with added base, the desired macro-
27
lactone 2 was isolated in 79% yield. The almost identical
yields obtained in either the presence or absence of added base
suggests that successful macrolactonization is due to catalysis
via the Hf-based Lewis acid.
2
2
in unsatisfactory yields of macrocycle 2 (25 and 54% yields,
respectively). While AgOTf and ZrCl (THF) did provide low
As stated previously, no precautions were taken to exclude or
remove water from the reaction media during the macro-
lactonization reactions. Hence, efficient Lewis acid catalysis not
only must be able to promote macrolactonization in high yields
but must also be able to do so in the presence of water without
4
2
yields of the macrolactone 2 (22 and 13%, respectively), other
transition-metal-based Lewis acids displayed little reactivity
even with other electrophilic complexes of Zr, Zn, Pd, Ni, and
Co.
1
463
DOI: 10.1021/acscatal.5b00082
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Research Article
catalyzing the reverse hydrolysis reaction. Consequently, all
Lewis acid catalysts that displayed some activity for macro-
cyclization were re-evaluated in two additional control
reactions. First, the macrolactonization was performed under
the identical reaction conditions utilized in the catalyst survey,
but the reaction solvent (PhMe) was pretreated with an excess
of water (200 equiv). Under these conditions, the majority of
the complexes which demonstrated some measure of activity
for direct macrolactonization were now significantly inhibited
Table 1. Substrate Scope of the Hf(OTf) -Catalyzed
4
Macrolactonization
(
isolated yields in 2 shown in red; Figure 3). Gratifyingly, the
Figure 3. Evaluation of various Lewis acids for a catalytic
macrolactonization strategy. The most efficient complex is judged to
have yields of macrocyclization under the optimized conditions (blue)
and under the optimized reaction conditions in the presence of excess
water (red) and provide high recovered yields of macrolactone 2 under
hydrolysis conditions (green). Footnotes are as follows. (a) All entries
represent isolated yields following silica gel chromatography. (b) The
reisolated yield of 2 remained high (>80%) even when 1000 equiv of
a
Isolated yields following flash chromatography.
rings such as the 16- and 17-membered macrolactones 2 and 5
29
were isolated in higher yields (83% and 87%, respectively).
The yields of the macrolactones obtained via Hf catalysis are
either comparable to or higher than those obtained using
stoichiometric methods. Cardenas and co-workers prepared the
13-, 16-, and 17-membered macrolactones using a Boden−
Keck-type method in 69−78% yield, but stoichiometric
amounts of EDC, HOBt, and DMAP and high-dilution/slow-
addition techniques were required. Recently, Zhang and co-
workers reported a hypervalent iodine(III) reagent for the
preparation of macrolactones 2, 3, and 5 in 56−94% yields.
Although the iodine-based reagent was recyclable, the
added H O was used.
2
Hf(OTf) catalyst maintained the same level of reactivity (83%
4
yield of macrolactone 2). Second, all active Lewis acid catalysts
were evaluated for their ability to catalyze the hydrolysis of
macrolactone 2. Exaltolide 2 was resubmitted to the macro-
cyclization conditions with added excess water (500 equiv) for
30
31
2
4 h, and then the remaining macrolactone was isolated
(
isolated yields of recovered 2 in green; Figure 3). In general,
most catalysts promoted some degree of hydrolysis of the
macrolactone 2. Once again, the Hf-based Lewis acids
demonstrated ideal reactivity patterns for direct macro-
lactonization, as they were poor hydrolysis catalysts and greater
than 80% of 2 could be reisolated, even when 1000 equiv of
excess water was added.
Given the unique ability of Hf(OTf)4 to catalyze the
macrolactonization reaction, the synthesis of various macro-
lactones was investigated under the optimized conditions
procedure still required stoichiometric DMAP and PPh as
coreagents and subsequent purification/separation of the
3
associated byproducts (PPh O) was necessary. Given the
3
abundance and biological activity of benzolactone natural
32
products, the synthesis of four different macrocycles with
benzoic acid cores was investigated. The 14- and 16-membered
macrolactones 6 and 7 were each isolated in good yields (90%
and 84%, respectively). The presence of an alkyne spacer in the
analogous macrolactone 8 was well tolerated, although the
product was isolated in a lower yield (56%). When the ring size
was increased, the 26-membered ring 9 was isolated in 72%
yield. The synthesis of other 17-membered macrolactones
(
Table 1). The medium 13-membered macrolactone 4 was
28
prepared in 55% yield (the smaller 11-membered macrocycle
could not be formed under the optimized conditions). Larger
3
1
464
DOI: 10.1021/acscatal.5b00082
ACS Catal. 2015, 5, 1462−1467

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Research Article
3
3
related to the isoambrettolide family of musks was also
primary alcohols over secondary or tertiary alcohols or primary
amines to provide the ester 15.
35
investigated (entries 9 and 10). Macrolactonization afforded
(
9Z)-isoambrettolide 10 in good yield (72%) without any
In an effort to understand the reactivity of the Hf(OTf)4
complex in direct macrolactonization, several control experi-
ments were performed (Scheme 1). The intermolecular
isomerization of the cis-olefin. Protection of the diol moiety of
erythro-aleuritic acid as its bis-pivaloate ester and subsequent
macrocyclization afforded the macrolactone 11 in 73% yield.
Finally, macrolactonization of more strained rings, such as the
Scheme 1. Investigations into the Mechanism of the Hf(IV)-
Catalyzed Esterification
1
,3-diyne containing 21-membered macrolactone 12, also
proceeded in high yield (86%). The Hf(OTf) -catalyzed
4
protocol also evaluated in the cyclization of structures has
enolizable stereocenters and steric bulk adjacent to the reacting
carboxylic acid. The 19-membered macrolactone 13 derived
from iso-leucine was cyclized in 74% yield. Similarly, the 22-
membered dipeptide macrocycle 14 was formed in 57% yield.
Both macrocycles 13 and 14 were obtained without any
observed epimerization.
To further probe the functional group tolerance of the
Hf(OTf) -catalyzed macrolactonization, several intermolecular
4
esterifications were performed (Table 2). The esterification of a
Table 2. Evaluation of Functional and Protecting Group
Compatibility in the Hf(OTf) -Catalyzed Esterifications
4
esterification of 1-pentanoic acid with 1-pentanol was
performed with both Hf(OTf) and Dy(OTf) . The stability
4
3
and catalytic activity of Dy(OTf) in water are largely attributed
3
to the cation’s large ionic radii and favorable hydrolysis
22c
constants. Although Hf-derived Lewis acids do not possess
the same hydrolytic stability as the lanthanide triflates, both
Hf(OTf) and Dy(OTf) provided identical yields of the ester
4
3
1
5 (∼99%). Interestingly, when the esterification of benzamide
with 1-nonanol was examined under identical reaction
conditions, only Hf(OTf) promoted the formation of the
4
36
ester 29 (58% yield). The useful Lewis acidity of Hf-based
complexes for a variety of transformations is well docu-
37
mented. Finally, esterification of 1-pentanoic acid was carried
out with a secondary alcohol (3-pentanol). While Hf(OTf) did
4
afford any of the desired product, Dy(OTf) provided a 60%
3
yield of ester 28. As a whole, these preliminary studies suggest
that the direct esterification/macrolactonization is influenced
by the Lewis acidity, hydrolytic stability, and steric bulk of the
catalyst.
A protocol for an efficient direct Hf(IV)-catalyzed macro-
lactonization of seco acids has been described. Following a
a
b
Yields following flash chromatography. With added Hu
̈
nig’s base
(
50 mol %).
survey of >25 various Lewis acids, Hf(OTf) was identified as
4
the most efficient catalyst, promoting macrolactonization in
high yields at relatively high concentrations (5 mM). Further
investigations into the activity of the Hf(OTf)4 complex
simple aliphatic acid and alcohol to provide the ester 15
occurred in quantitative yield (99%, entry 1). Esterification
provided Boc-, tosyl-, and Cbz-protected glycine derivatives in
good yields (72%). Both TBS- and TIPS-protected silyl ethers
were utilized in the esterification to afford the corresponding
esters 19 and 20 in 66 and 62% yields, respectively (entries 5
demonstrated that (1) Hf(OTf) is significantly more efficient
4
relative to other Lewis acids in catalyzing direct macro-
lactonization, even in the presence of excess water, and (2)
Hf(OTf) is a poor catalyst for the hydrolysis of macrolactones.
4
and 6). The addition of Hu
̈
nig’s base (50 mol %) was necessary
A variety of macrolactone and benzolactone skeletons could be
prepared, including important macrocycles for the perfume
industry. Intermolecular direct esterifications of carboxylic acids
and alcohols were also possible and demonstrated compatibility
with common carbamate, silyl ether, alkoxymethyl ether, and
acetal protecting groups. All of the macrolactonization
processes developed are operationally simple, use commercially
available catalysts, and are “one-pot” reactions without the need
for slow-addition or azeotropic techniques. Importantly, the
catalytic process forms environmentally benign water as the
only byproduct. Preliminary investigations demonstrate that the
Lewis acidity, hydrolytic stability. and steric bulk of the catalyst
play important roles in the macrolactonization. The effective-
to avoid cleavage of the TBS and TIPS groups. Similarly,
MOM- and acetate-protected alcohols were also tolerated and
esterification afforded the corresponding esters 21 and 22 in 77
and 89% yields, respectively. Both acetonide-protected diols
and ketone groups were tolerated, and the esters 24 and 23
were obtained in 77 and 92% yields, respectively. The propargyl
ester 25 was compatible with the esterification protocol and
was isolated in 78% yield. Additionally, carboxylic acids
bearing furan and thiophene heterocycles were easily esterified
and the n-pentyl esters 26 and 27 were isolated in 75 and 89%
yields, respectively (entries 10 and 11). The esterification
protocol also demonstrated selectivity for condensation with
34
1
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ACS Catalysis
Research Article
ness of the Hf(IV)-catalyzed macrolactonization should be
highly useful, given the prevalence of macrolactone structures
in pharmaceutically and biologically active products and current
interest in sustainability in reagent selection for industrially
see: (d) Tatsumi, T.; Sakashita, H.; Asano, K. J. Chem. Soc., Chem.
Commun. 1993, 1264−1265. (e) Ookoshi, T.; Onaka, M. Tetrahedron
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(
14) (a) Benz, G. In Comprehensive Organic Synthesis; Trost, B. M.,
3
8,39
Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991. (b) Franklin, A. S. J.
Chem. Soc., Perkin Trans. 1 1998, 2451−2466. (c) Franklin, A. S. J.
Chem. Soc., Perkin Trans. 1 1999, 3537−3554. (d) Otera, J.
Esterification Methods, Reactions and Applications; Wiley-VCH:
Weinheim, Germany, 2003.
relevant processes.
ASSOCIATED CONTENT
Supporting Information
The following file is available free of charge on the ACS
■
*
S
(15) Catalysis has been used to form the activated esters. For
Publications website at DOI: 10.1021/acscatal.5b00082.
examples see: (a) Ohba, Y.; Takatsuji, M.; Nakahara, K.; Fujioka, H.;
Kita, Y. Chem. Eur. J. 2009, 15, 3526−3537. (b) Shiina, I.; Kikuchi, T.;
Sasaki, A. Org. Lett. 2006, 8, 4955−4958. (c) Trost, B. M.; Chisholm, J.
D. Org. Lett. 2002, 4, 3743−3745.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
(
16) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614−
AUTHOR INFORMATION
Corresponding Author
E-mail for S.K.C.: shawn.collins@umontreal.ca.
■
*
5616.
(17) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394−2395.
(18) Kurihara, T.; Nakajima, Y.; Mitsunobu, O. Tetrahedron Lett.
1
(
1
976, 28, 2455−2458.
19) (a) Parenty, A.; Moreau, X.; Campagne, J. M. Chem. Rev. 2006,
06, 911−939. (b) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Notes
The authors declare no competing financial interest.
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989−1993.
(20) A recent search for “Yamaguchi Macrolactonization” on
Scifinder (November 21th, 2014) found 219 reports of its use in
synthesis.
ACKNOWLEDGMENTS
The authors acknowledge the Natural Sciences and Engineering
Research Council of Canada (NSERC), Universite
■
́
de
(
21) 2-Methyl-6-nitrobenzoic anhydride: Shiina, I.; Kubota, M.;
Oshiumi, H.; Hashizume, M. J. Org. Chem. 2004, 69, 1822−1830.
22) (a) Kobayashi, S.; Uchiro, H.; Fujishita, Y.; Shiina, I.;
Montreal, and the Centre for Green Chemistry and Catalysis
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Catherine Bedard and Mr. Jeffrey Santandrea for donation of
(
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(35) See the Supporting Information for additional experiments
involving secondary alcohols.
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(
2
(
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(36) The activation of primary amides to form esters may suggest
that the macrolactonizations proceed via carboxylic acid activation. For
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