Ynamide-Mediated Macrolactonization

Article abstract of DOI:10.1021/acscatal.0c00523

Macrolactonization represents a long-standing challenge for organic chemists. Herein, an ynamide-mediated macrolactonization of seco-acids with the assistance of an acid catalyst is described. Various macrolactones ranging in ring size from medium to large can be prepared by using this method. The notorious issues associated with conventional macrolactonization reactions, such as the racemization/epimerization of seco-acids containing an α-chirality center, and the E/Z isomerization of α,β-unsaturated seco-acids can be avoided using this method. In addition, the ynamide-mediated two-step macrolactonization reaction can be performed in a one-pot manner, thus offering a user-friendly protocol. Cyclodepsipeptides containing both amide and ester bonds can also be constructed using this method as the key step to facilitate the ring closure. The total synthesis of dehydroxy LI-F04a, which contains a cyclic hexadepsipeptide core, has been accomplished using this method.

Full text of DOI:10.1021/acscatal.0c00523

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Letter
Ynamide-Mediated Macrolactonization
Ming Yang, Xuewei Wang, and Junfeng Zhao
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 03 Mar 2020
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Ynamide-Mediated Macrolactonization
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Ming Yang,†§ Xuewei Wang,†§ and Junfeng Zhao†‡*
† College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330022, Jiangxi, P. R. China.
‡ School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, P. R. China.
KEYWORDS: Ynamide coupling reagent, macrolactonization, acid catalysis, racemization-free, cyclodepsipeptide
ABSTRACT: Macrolactonization represents a long-standing challenge for organic chemists. Herein, an ynamide-mediated
macrolactonization of seco-acids with the assistance of an acid catalyst is described. Various macrolactones ranging in ring size from
medium to large can be prepared by using this method. The notorious issues associated with conventional macrolactonization
reactions, such as the racemization/epimerization of seco-acids containing an α-chirality center, and the E/Z isomerization of α,β-
unsaturated seco-acids can be avoided using this method. In addition, the ynamide-mediated two-step macrolactonization reaction
can be performed in a one-pot manner, thus offering a user-friendly protocol. Cyclodepsipeptides can also be constructed using this
method as the key step to facilitate the ring-closing reaction. The total synthesis of dehydroxy LI-F04a, which contains a cyclic
hexadepsipeptide core has been accomplished using this method.
O
Macrolactones are essential structural characters for the
O
Me
OH
Me
OH
biological activity of a broad range of pharmaceuticals,
agrochemicals, and natural products (Figure 1).1 Consequently,
a plethora of macrolactonization strategies have been developed
over the past few decades.2 These methods include transition
metal-catalyzed C-O bond formation,3 C–C bond formation via
ring-closing alkyne4/olefin5 metathesis or alkene coupling
reactions,6 and N-heterocyclic carbene (NHC)-catalyzed
oxidative esterification of aldehydes,7 among others.8 However,
the application of these methods is limited to special cases
because of the difficult availability of their ring closing
precursors and the harsh reaction conditions required to carry
out these transformations. On the other hand, the
macrolactonization of seco-acids constitutes a major approach
toward the synthesis of macrolactones via activation of either
the carboxylic acid or hydroxyl group, or both functionalities.9
In addition, catalytic direct intramolecular dehydration
condensation of seco-acids avoiding the use of stoichiometric
O
Me
Me
Me
OH
H3C
NMe2
Me
Me
O
O
Me
HO
Me
O
O
O
O
O
OMe
Me
Me
Me
OH
O
OH
ErythromycinMe
Amphidinolide T1
O
H2N
HN
H
N
O
O
O
O
O
HO
O
O
C7H15
OH HN
HN
H
N
H
R
N
Me
O
O
NH HN
O
Me
O
Core structure of LI-F family
FR252921
coupling reagents is
a
promising solution for
macrolactonization.10 However, high reaction temperatures and
limited substrate scope render it unsuitable for late-stage
macrolactonization, especially in the total synthesis of complex
macrolactone-based natural products. Among all of the
macrolactonization methods of seco-acids reported to date, the
Yamaguchi–Yonemitsu reaction is the most prevalent.9f
Unfortunately, notorious issues including its high sensitivity to
moisture, base-induced racemization of seco-acids containing
an α-chirality center,11 the Z/E isomerization of α,β-unsaturated
seco-acids,12 and high reaction temperature have rendered this
process non-amenable for complex substrates. Furthermore, the
competitive reaction involving intermolecular esterification
followed by macrolactonization to form a diolide side product
is another concern for practitioners. Macrolactonization
remains as a formidable challenge, in particular for seco-acid
Figure 1. Examples of drugs and natural products
containing macrolactone framework.
substrates containing an α,β-unsaturated carboxylic moiety and
α-chirality center because the Z/E isomerization of α,β-
unsaturated seco-acids and racemization/epimerization the α-
chirality center still are unsolved problems in this field. Owing
to
macrolactonization strategies are always in great demand.
Herein, we report the first ynamide-mediated
the
importance
of
macrolactones,
efficient
macrolactonization under very mild reaction conditions.
Our group recently disclosed that α-acyloxyenamides formed
from the hydroacyloxylation of ynamides using carboxylic ac
ids are effective acyl donors for amide and peptide
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Scheme 1. Proposed ynamide-mediated macrolactonization
with the assistance of acid catalysis.
tion of N-methyl ynetoluenesulfonamide (MYTsA) and seco-
acid 1j, was employed as a model substrate in our preliminary
studies. Various acid catalysts were evaluated and the results
summarized in Table 1. To our delight, both Lewis and
Brönsted acids were effective in catalyzing the
macrolactonization with Brönsted acids exhibiting better
results. p-Toluenesulfonic acid monohydrate (PTSA·H2O) was
identified to be the
H
O
H
Me
N
Ts
H
O
O
Me
N
Me
N
H
O
H
O
H
Ts
OH
Ts
O
O
H
O
H
H
Scheme 2. Scope of the macrolactonization reaction.a
-H
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Me
N
O
Ts
+
O
Ac
Ts
N
O
O
Me
HO
OH
O
bond formation.13 With the success on the amide bond forming
reaction in hand, we were stimulated to investigate the
ynamide-mediated macrolactonization reaction, which presents
a greater challenge due to the weak nucleophilicity of the
hydroxyl group compared to the amino group. It was notable
that the protection of the side chain hydroxyl group in Tyr, Ser,
or Thr was not necessary, thereby indicating that the
esterification reaction between the α-acyloxyenamide and
hydroxyl group does not occur under peptide bond forming
conditions. Interestingly, during our subsequent study of the
solvent effect on the aminolysis step, we detected an
esterification side-product when weakly acidic trifluoroethanol
was used as the reaction solvent. Meanwhile, computational
studies have illustrated that the ynamide-mediated amide bond
forming reaction can be accelerated in the presence of an acid
catalyst.14 In addition, the acid catalyst facilitates proton
transfer by lowering the energy barrier of the ester exchange
reaction of vinyl esters.15 We therefore envisioned that
ynamides16 will be promising coupling reagents for the
macrolactonization with the assistance of an acid catalyst
(Scheme 1).
1
3
Ts
OH
O
N
2
Me
pTsOH•H O
Ts
O
N
DCM, rt
DCM, rt
Me
2
O
O
O
O
O
9
O
O
O
7
Me
10
8
O
b
b
2a
3a
2b
3b
2c
2d
3d
98%
98%, 100 mM
90%
76%
92%
96%, 100 mM
3c
85%, 5 mM
95%, 5 mM
O
O
O
O
O
O
O
O
12
11
11
12
b
b
2e
2f
3f
2g
3g
2h
3h
98%
98%
91%, 5 mM
69%
76%
76%, 5 mM
3e
91%, 5 mM
76%, 5 mM
O
O
O
13
O
15
13
O
O
b
b
Active ester α-acyloxyenamides can be easily obtained from
their corresponding ynamide and carboxylic acid. Therefore, α-
acyloxyenamide 2j, which was formed via the hydroacyloxyla
2i
2j
3j
2k
3k
87%
92%
94%
93%, 5 mM
3i
89%, 5 mM
91%, 5 mM
O
O
17
O
O
O
O
O
Table 1. Optimization of the macrolactonization reaction
conditions.a
O
16
O
O
16
O
O
b
2l
2m 75%
2n 75%
90%
3m
3n
,
98%, 10 mM
91% 5 mM
Ph
NH
3l
92%, 5 mM
OH
Me
5
13
O
O
Cat.
O
N
Ph
diolide
Ts
7
DCM, rt
O
O
O
3j'
O
NH
olide
3j
2j
NH
O
O
O
O
O
16
16
O
3j´(%)
entry
catalyst
Sc(OTf)3
Yb(OTf)3
3j (%)
23
16
1
2
5
7
2o
3o
2p
3p
2q
3q
87%
88%
89%
c
81%, 5 mM, 98% ee
93%, 20 mM, >99:1 dr
72%, 20 mM, 98% ee
19
NH
3
4
Cu(OTf)2
CuOTf
35
32
43
42
63
34
67
91
6
7
HN
O
O
O
O
NH
19
5
Zn(OTf)2
Bi(OTf)3
CSA
10
8
O
O
O
6
16
7
13
18
6
8
Fe(OTf)3
PTSA·H2O
PTSA·H2O
2r
3r
2s
3s
81%
72%, 20 mM, >99:1 dr
70%
80%, 20 mM, >99:1 dr
9
10b
aReaction conditions: First step: 1 (0.1–0.4 mmol), MYTsA (1.1 equiv.),
DCM (1–2 mL), rt, 1–24 h; Second step: 2 (0.1–0.4 mmol), PTSA·H2O (15
0
aReaction conditions: 2j (0.08 mmol), Cat. (15 mol%), DCM (10 mL), rt.
b
mol%), rt, 0.3–4 h. CuCl (15 mol%) was added as a catalyst in the first
b
Isolated yield. The reaction was performed at a concentration of 5 mM.
step; cOne-pot, two-step reaction; Isolated yield.
CSA = camphorsulfonic acid.
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best catalyst (Table 1, entry 9). Unlike conventional macrolac
To further illustrate its potential for application in the
synthesis of complex natural macrolactones, the total synthesis
of cyclodepsipeptide was studied using the ynamide-mediated
macrolactonization as the late stage ring-closing step. The LI-F
family of macrolides produced by Bacillus (Paenibacillus)
species exhibit significant antifungal activity and contain a
cyclic hexadepsipeptide core that can be theoretically
constructed via an intramolecular cyclization at any of the
amide or ester bonds in its structure.17 However, the
intermolecular esterification of peptide fragments sometimes
tends to be challenging, and thus the macrolactonization of a
linear peptide precursor becomes an attractive strategy to
construct the ester bond as well as to close the ring of
cyclodepsipeptides.18 For example, Jolliffe and co-workers
accomplished the total synthesis of LI-F04a using a
tonization reactions, which are sensitive to moisture, this
transformation can be performed in the presence of small
amount of water from the monohydrate catalyst. It is notable
that a low yield of the diolide side product 3j’ was formed when
the macrolactonization reaction was performed at
a
concentration of 8 mM with respect to α-acyloxyenamide 2j
(Table 1, entry 9). Interestingly, the formation of the diolide
side product could be suppressed completely by performing the
reaction at a lower substrate concentration (5 mM) (Table 1,
entry 10).
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With the optimized reaction conditions in hand, the substrate
scope of the ynamide-mediated macrolactonization was
investigated. Initially, the α-acyloxyenamide derivatives of a
variety of seco-acids were prepared upon mixing the acids with
MYTsA in dichloromethane (DCM).13a All the α-
acyloxyenamides were stable and can be easily purified,
characterized, and stored with no deterioration being detected
after storage in a fridge for two months. However, the
hydroacyloxylation of seco-acids containing a long aliphatic
chain became sluggish because of their weaker acidity.
Fortunately, this situation could be remedied by using 15% mol
CuCl as the catalyst (see supporting information Table S1 for
Table 2. Comparative study.a
O
Trt
N
H
H
HN
N
OtBu
OH
O
O
O
H
H
O
tBuO
O
O
OH
N
N
O
O
N
N
N
H
O
HN
H
H
19
HN
O
O
O
N
H
O
Cbz
Cbz
NHTrt
NH HN
Cbz-Thr-DVal-Val-Dallo-Thr(tBu)-DAsn(Trt)-DAla-OH
details). Scheme
2
shows that the acid-catalyzed
O
III
Core structure of LI-F family
macrolactonization reaction proceeds smoothly to give the
expected macrolactones in good to excellent yield for a broad
range of seco-acids. Unlike conventional macrolactonization
reactions that must be carried out at a seco-acid concentration
of ≤1 mM, our ynamide-mediated macrolactonization can be
performed at a α-acyloxyenamide concentration in the range of
5–100 mM without any noticeable formation of the diolide side-
product. This superiority will be more attractive for large-scale
reactions that require large volume of solvent. Using this
protocol, macrolactone 3i was obtained in 89% yield, while 22%
of 3i accompanied with 24% of the diolide side-product was
obtained when ethoxyacetylene was used as the coupling
I
III:III’b
yieldc
34%
drb
entry reaction conditions
DCC, DMAP, CSA,
1
98:2
89:11
CHCl3, rt, 4 h
EDCI, HOAT, DMAP,
CHCl3, rt, 4 h
2
69:31
90:10
>99:1
78:22
46:54
21:79
>99:1
13%
20%
33%
38%
12%
5%
37:63
23:77
69:31
93:7
HBTU, DMAP, CHCl3,
2 h
3
TBTU, HOAT, DMAP,
CH2Cl2, 1 h
4
HATU, DMAP, CHCl3,
rt, 30 min
5
reagent.15d
Medium-sized
(8–13-membered
ring)
PyBop, DMAP, CH2Cl2,
2 h
macrolactones, which are troublesome to prepare using other
macrolactonization strategies, can also be constructed using this
method (3b–3j). Furthermore, 16-membered ring Exaltolide
(3l), which has been widely used as a fragrant species, can be
prepared efficiently. Notably, α,β-unsaturated seco-acids are
compatible in the reaction and give the target macrolactones (3f
and 3k) in excellent yields with no Z/E isomerization at the C2-
C3 double bond. In addition, this method is applicable to the
preparation of cyclodepsipeptides, which contain both ester and
amide bonds (3o–3s). As expected, an excellent retention of the
optical purity of the α-amino acid residues was observed during
the ynamide-mediated macrolactonization (3o–3s). This feature
offers an alternative approach toward the synthesis of
cyclodepsipeptides by employing macrolactonization rather
than macrolactamization as the final ring-closing step. It was
also found that the ynamide-mediated macrolactonization of
seco-acids can be performed in a one-pot, two-step manner (3p),
in which the α-acyloxyenamide 2p was used directly without
purification, thereby offering an operationally simple procedure.
It should be noted that although the majority of the ynamide-
mediated macrolactonization reactions were performed in a
two-step manner to carefully study the efficiency of both steps,
all the reactions could be conducted in a one-pot, two-step
manner.
6
27:73
92:8c
29:71
PySSPy, PPh3, MeCN,
80 C, 8 h
7
PPh3, DEAD, THF, rt,
48 h
8
6%
2-Methyl-6-nitrobenzoic
anhydride, DMAP, NEt3,
toluene, 25 ℃, slow
9d
nd
(52%)
94:6
addition of I
Ynamide (MYTsA),
PTSA·H2O, CH2Cl2,
rt, 10 min
87%
(92%)
10
>99:1
>99:1
aReaction conditions: Seco-acid
I (0.005 mmol), solvent (2 mL),
b
concentration (2.5 mM); Determined based on analytical HPLC of the
crude reaction mixture; c HPLC yield of III using biphenyl as an internal
standard; the isolated yield is reported in the parentheses. d Data from Ref.
19b. nd = not detected. DCC = N,N'-dicyclohexylcarbodiimide; DMAP =
4-dimethyl-aminopyridine; CSA = camphorsulfonic acid; EDCI = N'-
(Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOAT = 1-
hydroxy-7-azabenzo-triazole; HBTU = 2-(1H-benzotriazole-1-yl)-1,1,3,3-
tetramethyluronium hexafluorophosphate; HATU
= 2-(7-aza-1H-ben-
zotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; PyBop
= benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate;
DEAD = diethyl azodicarboxylate.
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Scheme 3. Total synthesis of dehydroxy LI-F04a
3
4
5
6
7
8
OtBu
Ts
N
Me
DCM, rt
24 h, 97%
OtBu
H
N
OH
O
O
O
OH
H
H
O
O
O
Me
N
H
OH
N
N
O
N
N
N
N
H
N
N
N
H
O
Ts
H
H
O
HN
O
O
H
H
O
O
HN
O
O
Cbz
Cbz
NHTrt
NHTrt
II
I
Cbz-Thr-DVal-Val-Dallo-Thr(tBu)-DAsn(Trt)-DAla-OH
5 mol% PTSA·H2O, CH2Cl2, rt
2.5 mM, 95%, 15 min
9
O
Trt
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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60
N
O
H
H
N
H2N
HN
O
O
tBuO
H
O
O
HN
N
Boc
HO
N
HN
O
1) HATU, iPr2EtN, DMF
19
O
O
N
H
O
R
HO
+
HN
O
N
NH2
O
O
12
NH HN
H
2) TFA:CH2Cl2:H2O
90:5:5
O
19
NH
NH
60% over two steps
V
O
HN
NH
O
III: R = Cbz
O
IV: R = H
O
N
12
NH2
H
VI
Dehydroxy LI-F04a (VI)
40% overall yield over 5 steps
Pd/C, H2
MeOH, rt, 12 h, 73%
modified Yamaguchi macrolactonization approach based on
their intensive screening of conventional macrolactonization
strategies (Table 2, entry 9).19 Their study demonstrated that the
absolute configuration of the D-Ala residue is crucial for the
biological activity, since the inversion of its chirality resulted in
the complete loss of its antifungal activity. Unfortunately,
considerable epimerization of the C-terminal D-Ala residue is
observed under most conventional macrolactonization reaction
conditions.19b We therefore expected that this cyclic
hexadepsipeptide core structure would be an ideal model to
macrolactonization reaction. In addition, no diolide side-
product was detected when the macrolactonization was
performed at a concentration of 2.5 mM (the formation of
dilolide was observed when the concentration was increased to
10 mM). Subsequently, de-protection of III via palladium
catalyzed hydrogenation to afford IV was carried out along with
coupling of side chain V.19b Global de-protection completed the
total synthesis of dehydroxy LI-F04a VI in an overall 40% yield
over five steps.
In summary, we have successfully developed an
unprecedented ynamide-mediated macrolactonization. The
macrolactonization of α-acyloxyenamides derived from seco-
acids and carboxylic acids proceeded smoothly in the presence
of an acid catalyst. No epimerization/racemization was
observed during the activation as well as the subsequent ester
exchange reaction for seco-acids containing an α-chirality
center. This strategy is also amenable to α,β-unsaturated seco-
acids and the Z/E isom erization of the C2-C3 double bond often
encountered in conventional macrolactonizations can be
completely avoided. In addition, little or no diolide side-
products were formed for a broad range of seco-acid substrates,
even when the macrolactonization reaction was performed at a
relatively high concentration. Both the activation step and
subsequent ester exchange step were found to be compatible
with a small amount of water. It is notable that this two-step
strategy can be performed in a one-pot manner, thereby
rendering it a convenient protocol. It is foreseeable that this
highly efficient method will find broad application toward the
construction of macrolactones, in particular for ring-closing
seco-acid precursors containing an α-chirality center as well as
an α,β-unsaturated carboxylic moiety.
evaluate
the
potency
of
our
ynamide-mediated
macrolactonization strategy. Meanwhile, a series of coupling
reagents and conventional macrolactonization strategies were
examined using hexapeptide acid I as the substrate to compare
their reaction efficiency (Table 2). As shown in Table 2, not
only significant epimerization, but a remarkable amount of
diolide side product III’ was observed for most of the
conventional macrolactonization strategies studied. These side
reactions resulted
a
very low yield of the target
cyclodepsipeptide. In addition, Mukaiyama and co-workers
reported that the PTSA promoted cyclization of 6-phenyl-2-
pridyl esters originated from 6-phenyl-2-pridone and the
corresponding seco-acids could offer macrolactones 3g, 3i, and
3l in 73%, 99%, and 100% yield, respectively.9j However, no
target cyclized product could be detected when their method
was employed for the cyclization of linear peptide I (data not
shown).
To
our
delight,
our
ynamide-mediated
macrolactonization of I proceeded smoothly to give the target
cyclized product III in an overall 92% yield over two steps
without any detectable epimerization (Table 2, entry 10). Thus,
as shown in Scheme 3, the linear peptide precursor I, which was
synthesized by employing solid-phase peptide synthesis, was
quantitatively converted into active ester II upon treatment with
MYTsA coupling reagent in DCM at room temperature. The
subsequent macrolactonization reaction proceeds smoothly in
the presence of 5 mol% of PTSA·H2O to furnish the target
cyclic hexadepsipeptide III in 95% yield. It should be noted that
the significant epimerization of the C-terminal D-Ala residue
observed in the other macrolactonization strategies studied was
ASSOCIATED CONTENT
Supporting information.
Experimental procedures and characterization data for all reactions
and products, including the 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
completely
avoided
in
our
ynamide-mediated
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Author Contributions
§ These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
9
This work was supported by the National Natural Science
Foundation of China (21778025, 91853114) and the Education
Department of Jiangxi Province (150297).
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SYNOPSIS TOC
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O
Trt
N
H
N
H
OtBu
Ts
HN
OH
O
O
O
N
H
H
O
tBuO
O
O
O
O
N
N
OH
N
Me
N
N
HN
H
H
H
19
DCM, rt
HN
O
O
O
N
H
O
Cbz
O
Cbz
5 mol% PTSA
NH HN
NHTrt
92%
No epimerization
O
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Core structure of LI-F family
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