Macrolactonization of Alkynyl Alcohol through Rh(I)/Yb(III) Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b02858

A catalytic macrolactonization through oxidative cyclization of alkynyl alcohol by synergistic transition-metal and Lewis-acid catalysis was developed. Because the alkynyl alcohol substrates involved in this method are different from the seco acids that are used in conventional macrolactonization methods, the current method provides a strategically distinct entry to macrolactones. In addition to the operational simplicity, this macrolactonization protocol proceeds at relatively high concentration, precluding the need for high dilution or slow addition procedures.

Full text of DOI:10.1021/acs.orglett.8b02858

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Macrolactonization of Alkynyl Alcohol through Rh(I)/Yb(III) Catalysis
Wen-Wen Zhang,†,‡ Tao-Tao Gao,‡ Li-Jin Xu,*,† and Bi-Jie Li*,‡
†Department of Chemistry, Renmin University of China, Beijing 100084, China
‡Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing 100084, China
S
* Supporting Information
ABSTRACT: A catalytic macrolactonization through oxidative cyclization of
alkynyl alcohol by synergistic transition-metal and Lewis-acid catalysis was
developed. Because the alkynyl alcohol substrates involved in this method are
different from the seco acids that are used in conventional macrolactonization
methods, the current method provides a strategically distinct entry to
macrolactones. In addition to the operational simplicity, this macrolactonization protocol proceeds at relatively high
concentration, precluding the need for high dilution or slow addition procedures.
acrolactone structures exist in numerous natural
products and bioactive molecules.1 Many of them
carboxylic acid for the macrolactonization. Because an alkyne
group is usually stable under many conditions,11 protection of
the alkyne is not necessary during the synthesis. Therefore, this
strategy provides the advantage of avoiding the multistep
synthesis of the seco acids and tedious manipulation of the
carboxylic acid (Scheme 1).
M
have significant medicinal and biological activities. Due to the
importance of the macrocyclic structures, a range of macro-
lactonization methods have been developed in the past
decades.2 Among them, macrolactonization of seco-acid is a
prominent strategy for the synthesis of macrolide, which has
been practiced in a large number of total syntheses.3 However,
there are several inherent limitations associated with traditional
macrolactonization methods. For example, a stoichiometric
amount of activating reagents are required for the activation of
either the acid or the hydroxyl group.2,3 In addition, to
minimize intermolecular dimerization, highly diluted con-
ditions or slow addition protocols are required.4 These
limitations continue to stimulate the development of novel
methods for the synthesis of macrolactones.
Scheme 1. Macrolactonization of Alkyne
Transition metal catalyzed macrocyclization provides a
distinct opportunity for the preparation of macrolactones.5
For example, ring-closing metathesis6 and cross-coupling
reactions4d,f,7 enable efficient synthesis of macrolactones.8
Compared to these catalytic methods that construct the
macrolactone through formation of the C−C bond of the
backbone, strategies to synthesize macrolactone through
transition metal catalyzed C−O bond formation have been
rather limited.9 In 2006, White and co-workers reported a
seminal work on Pd-catalyzed macrolactonization of alkenyl
acid through C−H functionalization.9a−c Recently, the Breit
group has developed a novel macrolactonization method
through atom-economical Rh-catalyzed addition of carboxylic
acid to unsaturated C−C bonds.9d,e Both of these methods
involve the use of carboxylic acid as the cyclization precursor.
The groups of Takahashi and Dai have achieved macro-
lactonization through Pd-catalyzed carbonylation reactions.9f−h
The presence of a carboxylic acid in the cyclization precursor
could complicate the synthesis. Usually the acid must be
protected before functional group manipulation, and the
protecting group needs to be removed before the macro-
lactonization event.3 In connection with our interest in alkyne
functionalization,10 we sought to use alkyne as a surrogate of
We envisioned that an oxidative macrolactonization of
alkynyl alcohol could be achieved by transition metal catalysis
through intermediacy of a ketene. Specifically, transition
metal12 such as Rh13 and Ru14 could interact with the alkyne
to afford a metal vinylidene (Scheme 2). Further oxygenation
of the vinylidene complex would afford a ketene intermedia-
te.14d−f,15 Intramolecular trapping of the ketene by the alcohol
group would afford the macrolactone product.16 Although an
Received: September 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02858
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a
Scheme 2. Proposed Macrolactonization of Alkynyl Alcohol
Table 1. Development of Catalytic Macrolactonization
yield
entry
1
catalyst
ligand
oxidant
additive
(%)
Rh(COD)2OTf (4-F-
N-Oxide 1
−
36
C6H4)3P
(4-F-
C6H4)3P
Ph3P
(4-MeO-
C6H4)3P
(4-F-
C6H4)3P
(4-F-
C6H4)3P
(4-F-
C6H4)3P
(4-F-
C6H4)3P
(4-F-
C6H4)3P
(4-F-
C6H4)3P
2
Rh(COD)2BF4
N-Oxide 1
−
39
3
4
Rh(COD)2BF4
Rh(COD)2BF4
N-Oxide 1
N-Oxide 1
−
−
34
35
elegant example of catalytic intermolecular oxidative ester-
ification of alkyne has been developed by Lee and co-
workers,15d a catalytic macrolactonization through oxidative
alkyne functionalization is unknown.14a,b We report here a Rh
and Yb-cocatalyzed cyclization of alkynyl alcohol for the
synthesis of a range of macrolactones. Significantly, this
macrolactonization method proceeds efficiently at relatively
high concentration. High dilution or slow addition protocol is
not necessary.4 Moreover, the alkynyl alcohol substrate
involved in this method is distinct from the seco acids that
are used in traditional macrolactonization. This method
provides a possible alternative retrosynthetic planning to
macrolactone molecules.
b
5
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
N-Oxide 1
N-Oxide 1
N-Oxide 1
N-Oxide 1
N-Oxide 2
N-Oxide 3
Zn(OTf)2
In(OTf)3
Yb(OTf)3
AgOTf
48
45
70
42
<5
66
b
6
b
7
b
8
b
9
Yb(OTf)3
Yb(OTf)3
b
10
a
Reaction conditions: alkyne (0.20 mmol) in CH3CN (6 mL). Yields
b
We began our studies by testing the viability of the designed
intramolecular lactonization from alkynyl alcohol (Scheme 3).
1
determined by H NMR using CH2Br2 as an internal standard. 10
mol % of additive.
Scheme 3. Catalytic Macrolactonization of Alkynyl Alcohol
facilitate this key step by addition of a Lewis acid to enhance
the electrophilicity of the ketene. To test this proposal, a series
of Lewis acids were evaluated (entries 5−8). When a catalytic
amount of ytterbium triflate was added, a dramatic increase of
the yield was observed (entry 7). Under these conditions, less
than 5% of dimerization product was generated. Importantly,
this reaction could be conducted at much higher concentration
than many other conventional macrolactonization methods.4
As a comparison, Yamaguchi macrocyclization of the seco acid
that forms 2c proceeded with 11% of product and 84% of
dimerization. Switching the oxidant from pyridine N-oxide to
4-nitropyridine N-oxide resulted in low yield (entry 9). Other
analogues including 4-methoxy pyridine N-oxide were slightly
less effective than the parent pyridine N-oxide (entry 10).
To probe the generality of this macrolactonization method,
the cyclizations of a series of alkynyl alcohols were conducted
(Scheme 4). The cyclization of a secondary alcohol worked as
well (2d). Benzene and cyclohexane fused alkynyl alcohols
underwent catalytic macrolactonization to afford the products
2e−2h in good yields. To see if this structural bias is a requisite
for the macrolactonization, we tested the reactivities of
substrates that contain only ester linkages. Cyclization of
alkynyl alcohols 1i and 1j also delivered macrolactones 2i and
2j in good yields. Moreover, a lineal alkynyl alcohol without
any conformational bias underwent smooth macrocyclization
(2k). In addition to alkyl alkyne, macrocyclization of an
aromatic alkyne proceeded well (2l). These results demon-
strate the structural flexibility of the substrates in this catalytic
macrolactonization process.
a
Yield determined by GC using dodecane as an internal standard.
b
Isolated yield.
In the presence of rhodium catalyst and 4-picoline N-oxide, the
oxidative cyclization proceeded smoothly to afford six and
seven-membered lactones 2a and 2b. However, significantly
lower yield was obtained when a macrocyclization was
attempted (2c). The dramatic difference between the
cyclization of a small ring size lactone and a macrolactone
highlighted the difficulty in achieving a catalytic macro-
lactonization reaction.
Subsequent effort was devoted to identify suitable reaction
conditions for the macrolactonization (Table 1). Conducting
the reaction at 80 degree and 33 mM concentration provided
the macrolactonization product in 36% yield (entry 1). A
similar yield was obtained when a cationic rhodium complex
with a different anion was used (entry 2). Perturbation of the
electronic effect of the ligand did not lead to increase of the
yield (entries 3, 4). Because the macrolactonization involves
the acylation of the alcohol by the ketene, we sought to
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a
Scheme 4. Scope of Catalytic Macrolactonization
Scheme 5. Functional Group Tolerance of Catalytic
Macrolactonization
a
a
Reaction conditions: alkyne (0.2 mmol), in CH3CN (6 mL).
Isolated yields were reported.
(eq 1). Thus, the cooperative catalysis enables the synthesis of
unusually large ring systems.
a
Reaction conditions: alkyne (0.2 mmol), in CH3CN (6 mL). c = 33
mM. Isolated yields were reported.
Further experiments probed the functional group tolerance
of this macrocyclization reaction (Scheme 5). An array of
alkynyl alcohols were cyclized under the catalytic conditions to
afford functionalized macrolactones 2m−2r. Functional groups
including ester, alkene, acetal, amide and carbamate were
tolerated. In addition, a protected amino acid in the backbone
did not interfere with the macrolactonization (2r). The
capability to synthesize functionalized macrolactone with
various ring sizes demonstrates the synthetic value of this
method.
To further test the potential of this catalytic macro-
lactonization, we investigated the possibility to cyclize an
extra-large ring. Under the catalytic conditions, cyclization of
1s delivered a 33-membered macrolactone 2s in a good yield
Many macrolactone natural products contain a 1,3-benzo
fused structure.17 Thus, cyclization of 1,3-benzo fused alkynyl
alcohol was conducted. The catalytic macrolactonization of 1t
proceeded to give the desired product in a synthetically useful
yield (eq 2). These results further highlight the synthetic utility
of the catalytic macrolactonization.
C
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Traditional macrolactonization methods are usually con-
ducted at highly diluted conditions in order to minimize
intermolecular reaction.4 In contrast, current catalytic macro-
lactonization can be conducted at relatively high concentration
(Scheme 6). The yield of macrolactonization did not drop
functionalized macrolactones. This macrolactonization pro-
ceeds at relatively high concentration, alleviating the need for
diluted conditions or slow addition. Current method provides
a new strategy for the retrosynthetic analysis of complex
macrolactone molecules. Further studies to understand the
mechanism and enhance the catalytic activity are ongoing in
our laboratory.
Scheme 6. Effect of the Reaction Concentration
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02858.
Experimental procedures, characterization of new
compounds, crystallographic data and spectroscopic
data (PDF)
Accession Codes
CCDC 1857692−1857693 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
significantly when the concentration was increased from 17
mM to 100 mM. Synthetically useful yield could be obtained
even when the concentration was increased to 200 mM. This
concentration is higher than those for many uncatalyzed and
catalyzed macrolactonization reactions.9a−g
*E-mail: 20050062@ruc.edu.cn.
*E-mail: bijieli@mail.tsinghua.edu.cn.
ORCID
The intermediacy of a rhodium vinylidene species was
probed by deuterium labeling studies (Scheme 7). Consistent
Li-Jin Xu: 0000-0003-4067-8898
Bi-Jie Li: 0000-0001-8528-8514
Notes
Scheme 7. Deuterium Labeling Experiments
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Grant No. 21672122) and National
Program for Thousand Young Talents of China.
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