General [4 + 1] Cyclization Approach to Access 2,2-Disubstituted Tetrahydrofurans Enabled by Electrophilic Bifunctional Peroxides

Article abstract of DOI:10.1021/acs.orglett.9b02012

A general [4 + 1] cyclization reaction of carbonyl nucleophiles with 2-iodomethylallyl peroxides, which function as unique electrophilic oxygen synthons, for the synthesis of a broad range of 2,2-disubstituted tetrahydrofurans is achieved under operationally simple conditions. The unprecedented asymmetric version of such reaction is also realized via chiral auxiliary-assisted cyclization, thus providing a distinct approach to access chiral tetrahydrofurans with high diastereoselectivities. The new method can be applied to the synthesis of core structure of posaconazole drug.

Full text of DOI:10.1021/acs.orglett.9b02012

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
General [4 + 1] Cyclization Approach To Access 2,2-Disubstituted
Tetrahydrofurans Enabled by Electrophilic Bifunctional Peroxides
Min Gao,†,§ Yukun Zhao,†,§ Chen Zhong,† Shengshu Liu,† Pengkang Liu,† Qi Yin,† and Lin Hu*,†,‡
†Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, China
‡Guangdong Provincial Key Lab of Nano-Micro Material Research, School of Chemical Biology and Biotechnology, Peking
University Shenzhen Graduate School, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: A general [4 + 1] cyclization reaction of
carbonyl nucleophiles with 2-iodomethylallyl peroxides, which
function as unique electrophilic oxygen synthons, for the
synthesis of a broad range of 2,2-disubstituted tetrahydrofur-
ans is achieved under operationally simple conditions. The
unprecedented asymmetric version of such reaction is also
realized via chiral auxiliary-assisted cyclization, thus providing
a distinct approach to access chiral tetrahydrofurans with high
diastereoselectivities. The new method can be applied to the synthesis of core structure of posaconazole drug.
etrahydrofurans are a class of fundamentally important
heterocycles widely found in numerous biologically
Scheme 1. Background and Our Synthetic Strategy
T
important natural products and drug molecules (Figure 1).1
Figure 1. Representative structures of tetrahydrofuran-containing
natural products and drugs.
Among those synthetic methods established,2 cycloaddition
reactions provide an attractive and powerful strategy for the
one-step synthesis of these compounds.1,2 To date, such a
cyclization strategy predominantly focuses on the [3 + 2]
processes,3−5 such as the transition-metal- or Lewis-acid-
catalyzed cycloaddition reactions of carbonyl ylides,3 cyclo-
propanes,4 and trimethylenemethane5 (Scheme 1a, paths a and
b). As an alternative strategy, [4 + 1] cyclization reactions,
however, have been far less investigated.6,7 Currently, a few
isolated examples including transition-metal-catalyzed metal-
locarbene O−H insertion−Michael addition, O−H insertion−
aldol, and O−H insertion−Conia-ene cascades have been
reported by Hu,6a Moody,6c Hatakeyama,6e and Sharma,6f,g
respectively (Scheme 1a, path c). Accordingly, the develop-
ment of new [4 + 1] cyclization reactions remains an unmet
challenge.
Herein we describe a highly efficient formal [4 + 1]
cyclization reaction, a tandem C−C and C−O bond-forming
process wherein the C−O bond is constructed via an
unconventional electrophilic alkoxylation strategy, for the
synthesis of a wide range of functionalized 2,2-disubstituted
tetrahydrofurans from various carbonyl nucleophiles 2 and
bifunctional 2-iodomethylallyl peroxides 3 in a single step.
Received: June 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02012
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Letter
Importantly, by incorporating a chiral auxiliary group into the
reaction substrates, this approach could be flexibly switched to
the asymmetric synthesis of chiral tetrahydrofurans with high
stereoselectivities under operationally simple and mild
conditions (Scheme 1b). Also, these 2,2-disubstituted
tetrahydrofuran scaffolds are found in the core structures of
many biologically important natural products and drugs, such
as posaconazole, dysiherbaine, azaspirene, scedapins E, and
aspergilline A (Figure 1).8
Traditionally, the C−O bond in ether compounds was
overwhelmingly constructed via the reaction of nucleophilic
oxygen with an electrophilic carbon center.2 Conversely, the
construction of such a bond from the corresponding carbon
nucleophiles and the electrophilic oxygen center has been
significantly underdeveloped.9 It has been long known that
dialkyl peroxides could function as electrophilic oxygen sources
to react with a stoichiometric amount of organometallic
reagents such as Grignard reagents to furnish ether
compounds,10 but the application of such an electrophilic
alkoxylation strategy to the synthesis of oxygen heterocycles,
for example, the tetrahydrofurans, was very rare. To the best of
our knowledge, only one single example of using the reaction
of cyclohexanone and tert-butyl iodopropyl peroxide 5a for the
synthesis of spirotetrahydrofuran has been reported, by
Dussault et al. in 2014.9c We envision that this tandem C−C
and C−O bond-forming reaction possesses untapped potential
for tetrahydrofuran synthesis; however, the generality of such a
unique approach remains unknown. In particular, the
corresponding asymmetric reactions have not been reported
to date.
In fact, in our initial investigations, we found that reactions
of 5a with commonly used nucleophiles such as ester 2ac and
acyclic ketone 2ag failed to generate the target tetrahydrofuran
products under the same conditions as in Dussault’s case.
Moreover, reactions of 5a with synthetically more versatile 1,3-
dicarbonyl nucleophiles such as β-keto esters 2a and 2i were
also unsuccessful. Only O-alkylation or C-alkylation by-
products were formed, even after extensive trials of varying
the structures of peroxides and basic conditions (Scheme 2;
see the Supporting Information (SI) for details). Apparently,
these results indicated that the realization of such distinct [4 +
1] cyclization reactions with a broad substrate scope required
more efforts to search suitable peroxides, which should
accumulate the merits of sufficient reactivities on both
electrophilic carbon and electrophilic oxygen sites as well as
the sufficient stability under basic conditions, to enable the
tandem C−C and C−O bond-forming process to proceed
effectively.
For this reason, we next turned our attention to other peroxy
structures and speculated that allyl peroxide 3a11 bearing both
allylic carbon and peroxide functionalities might serve as a
suitable four-atom synthon to engage in the [4 + 1]
cyclizations with one-carbon nucleophiles such as 1,3-
dicarbonyl compounds. Indeed, to our delight, this peroxide
smoothly underwent the cyclization reaction with ethyl
acetoacetate 2a in the presence of excessive KOH in DMF
and delivered the desired tetrahydrofuran product 1a in 49%
yield (Table 1, entry 1). We reckon that the unique reactivity
a
Table 1. Optimization of the Reaction Conditions
b
entry
time (h)
solvent
base (equiv)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1
1
1
1
1
1
1
1
1
1
1
1
4
12
DMF
THF
CH3CN
DCM
KOH (3.0)
KOH
KOH
KOH
KOH
49
35
42
10
17
71
61
15
61
53
0
acetone
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
KOH
CsOH (3.0)
LiOH (3.0)
Cs2CO3 (3.0)
K3PO4 (3.0)
K2HPO4 (3.0)
KOH (3.0)
KOH (2.0)
KOH (2.0)
c
81
94
60
c
cd
,
14
a
Reaction conditions: 2a (0.1 mmol), 3a (0.1 mmol), and base in
b
c
indicated solvent at rt. Isolated yield. 1.5 equiv of 2a was used.
d
Reaction was carried out at 0 °C.
of 3a may be attributed to the more “soft” allylic carbon12 and
the more reactive O−O bond,13 together with the favorable
entropy effect14 in this molecule, to allow the sequential C−C
and C−O bonds to be formed effectively. This promising
result encouraged us to further optimize the conditions to
improve the yield of the reaction. To this end, we first
evaluated the influence of solvents on the reaction and revealed
that ethyl acetate was the optimum one, which increased the
reaction yield to 71% (Table 1, entries 1−6). Then, the
influence of the base was examined. All of the other tested
bases, including CsOH, LiOH, Cs2CO3, K3PO4, and K2HPO4,
however, proved to be inferior to KOH (Table 1, entries 7−
11). Finally, after increasing 2a to 1.5 equiv and decreasing
KOH to 2 equiv, the reaction became very clean at room
temperature, and the yield was optimized to 94% (Table 1,
entries 12−14).
Scheme 2. Initial Investigations
With the optimal conditions in hand, the substrate scope of
this transformation was then evaluated. As shown in Table 2,
this cyclization reaction is very general. A wide range of
aliphatic and aromatic β-keto esters, regardless of the structural
and electronic properties of substituents on both ester and
carbonyl sides, uneventfully provided the tetrahydrofuran
B
DOI: 10.1021/acs.orglett.9b02012
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Letter
a
To further expand the reaction scope, the structural
tolerance of the peroxide part was next evaluated. As shown
in Table 3, phenyl-substituted allyl peroxide 3b smoothly
Table 2. Substrate Scope for Reactions of 2 with 3a
a
Table 3. Substrate Scope for Substituted Peroxide 3b
a
Reaction conditions: 2 (0.3 mmol), 3b (0.2 mmol), and KOH (0.4
b
mmol) in EtOAc (1.0 mL) at rt for 2−12 h. Cs2CO3 was used.
c
DMF was used as solvent.
cyclized with a range of nucleophiles such as acetoacetate,
benzoylacetate, β-keto phosphonate, and β-keto sulfonate
under standard conditions to afford the corresponding
tetrahydrofuran products 11a−d in good yields. Notably, the
E/Z mixture exiting in peroxide 3b had no influence on the
cyclization reaction, which indicated that the reaction tolerated
substituted peroxides very well.
Encouraged by the generality and mild conditions of the
above reactions, we are particularly interested in developing an
asymmetric version of such cyclization reactions for the
synthesis of chiral 2,2-disubstituted tetrahydrofurans.5c,6 We
envisioned that the most straightforward strategy might rely on
the incorporation of a chiral auxiliary into the reaction
substrates to control the stereoselectivities of the cyclizations.
However, this unprecedented asymmetric cyclization may be
challenging because the tandem cyclization process may
involve two reverse reaction pathways, that is, the C−C →
C−O bond sequence or the C−O → C−C bond sequence,
which will consequently generate the tetrahydrofuran products
with low diastereomeric ratios (dr’s), even in the presence of
chiral auxiliaries. Therefore, control experiments were first
performed to elucidate the mechanism of the reaction. When
treating benzoyl acetate 2i with 3a under standard conditions,
we observed that the C-alkylation intermediate 12 was initially
formed in the early stage of the reaction. After resubmitting
this intermediate to the same reaction conditions, we were able
to isolate the final product 1i in 76% overall yield (Scheme 3).
a
Unless otherwise noted, reaction conditions: 2 (0.75 mmol), 3a (0.5
mmol), and KOH (1.0 mmol) in EtOAc (2.5 mL) at rt for 0.5−12 h.
b
c
d
Cs2CO3 was used. DMF was used as solvent. KOtBu as base and
THF as solvent were used.
products in good to excellent yields (Table 2, 1a−q). In
addition, other types of nucleophiles, such as 1,3-dicarbonyl
compounds, β-keto amide, cyanoacetate, β-keto phosphonates,
and β-keto sulfonates, were all compatible for this cyclization
reaction (Table 2, 1r−z). It is noteworthy that tetrahydrofuran
products 1v−z bearing phosphonate- or sulfonate-containing
quaternary carbons have never been previously prepared,
which may exhibit biologically interesting properties. Mean-
while, spirotetrahydrofuran 1aa and alkynyl product 1ab could
also be generated from indolinone and α-alkynyl ester
substrates in good yields. Importantly, by slightly modifying
the reaction conditions to a stronger KOtBu base, the less
reactive ester and ketone substrates, including 2ac and 2ag that
were not able to react with peroxide 5a in our initial studies,
also successfully underwent the cyclization with 3a and
provided the synthetically valuable products with satisfactory
yields (Table 2, 1ac−ah). For example, compound 1ad is the
structural core of antifungal drug posaconazole.8c
Scheme 3. Control Experiments
These observations confirmed that the tandem process mainly
proceeded via the C−C → C−O bond sequence, which
supports the possibility of developing the asymmetric version
of such reactions.
On the basis of the above results, we next screened several
types of well-known chiral auxiliaries and finally found that a
(+)-camphor-derived and conformationally very rigid chiral
alcohol15 could successfully induce the cyclizations with high
stereoselectivities. As shown in Table 4, asymmetric reactions
of 3a with chiral esters 13a−f, which were readily prepared by
C
DOI: 10.1021/acs.orglett.9b02012
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Letter
difluorophenylacetate 2ad and 3a was easily scaled-up to
afford 1.24 g of 1ad in 66% yield. This intermediate was
subsequently converted to silyl ether 18 after two steps of ester
reduction and hydroxyl tert-butyldimethylsilyl (TBS) protec-
tion. Then, the stereochemistry control of the terminal double
bond turned out to be troublesome in the step of hydro-
boration−oxidation; however, after considerable trials, we were
able to obtain the primary alcohol 19 in 84% yield and 5:1 dr
by treating the TBS-protected substrate 18 with bulky 9-BBN
reagent in THF. The relative configuration of the newly
generated stereocenter in this step was determined by nuclear
Overhauser effect analysis. (See the SI for details.) Next, the
treatment of 19 with MsCl, followed by the nucleophilic
substitution with 4-bromophenol, offered phenyl ether 20 in
64% yield in a one-pot operation. Finally, the removal of the
TBS group, followed by the iodination of the resulting alcohol
21 and nucleophilic substitution of iodide 22 with sodium
triazole salt, smoothly provided the core structure 23 with high
yields, thus completing the formal synthesis of the antifungal
drug posaconazole.18 The racemic synthetic route established
herein could be flexibly transferred to the asymmetric synthesis
of the pharmaceutically more important chiral drug. (See the
SI for our initial results.)
Table 4. Chiral Auxiliary and Substrate-Assisted
Asymmetric Cyclizations
a
a
b
dr was determined by 1H NMR analysis. Absolute and relative
c
configurations were determined by X-ray analysis. Relative
configuration was determined by NOE analysis; see the SI for details.
In conclusion, we have developed a general and formal [4 +
1] cyclization reaction of various carbonyl nucleophiles with
bifunctional 2-iodomethylallyl peroxides, which function as
electrophilic oxygen and carbon synthons, for the synthesis of a
wide range of 2,2-disubstituted tetrahydrofurans with high
yields. Control experiments revealed that this cyclization
reaction probably involved a tandem C−C and C−O bond-
forming process, wherein the critical C−O bond was
constructed via an unconventional electrophilic alkoxylation
strategy. Importantly, the corresponding asymmetric version of
this cyclization, including the unprecedented chiral auxiliary-
assisted asymmetric reactions, has also been successfully
achieved, thus providing a highly efficient and distinct method
for the asymmetric synthesis of chiral tetrahydrofurans.
Furthermore, the practicality and synthetic utility of this new
method were demonstrated by the gram-scale and concise
synthesis of the core structure of antifungal drug posaconazole.
We anticipate that the synthetic strategy established herein
should be applicable to many other useful transformations.
simply exchanging the ethoxy group in achiral esters with the
chiral alcohol,16 generally provided the tetrahydrofuran
products 14a−f with high yields and diastereoselectivities
(7:1 to >20:1 dr). A range of electron-donating and
-withdrawing substrates were well tolerated for this reaction.
Moreover, this asymmetric cyclization strategy was also
applicable to other chiral substrates. For example, chiral
compound 1517 showed excellent asymmetric induction for the
reaction and delivered the product 16 as a single diastereomer
(dr >20:1), although a significant amount of O-alkylation side
product 17 was concomitantly formed during the reaction.
To demonstrate the practicality and synthetic applications of
this new transformation, we carried out a gram-scale synthesis
of compound 1ad (Scheme 4). By using the same conditions
as depicted in Table 2, the reaction of ethyl 2,4-
Scheme 4. Gram-Scale Synthesis and Synthetic Application
to the Core Structure of Posaconazole
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.9b02012.
Experimental procedures and characterization data for
all of the products (PDF)
Accession Codes
CCDC 1917974 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lhu@cqu.edu.cn
D
DOI: 10.1021/acs.orglett.9b02012
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ORCID
Letter
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Lin Hu: 0000-0002-8600-965X
Author Contributions
§M.G. and Y.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from NSFC (21871032),
Chongqing Research Program of Basic Research and Frontier
Technology (cstc2017jcyjAX0375), Fundamental Research
Funds for the Central Universities (2018CDQYYX0041),
Venture & Innovation Support Program for Chongqing
Overseas Returnees (cx2017013), and The Guangdong
Science and Technology Program (2017B030314002).
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Organic Letters
Letter
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compound 3a during the course of this project, organic peroxides are
potentially explosive, and all relating reactions should be cautiously
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F
DOI: 10.1021/acs.orglett.9b02012
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