Iodine(III)-Mediated Contraction of 3,4-Dihydropyranones: Access to Polysubstituted γ-Butyrolactones

Article abstract of DOI:10.1021/acs.orglett.9b01893

Functionalized γ-butyrolactones are privileged structures in the field of medicinal chemistry; they are found in numerous natural products and synthetic compounds with diverse biological activities. The oxidative ring contraction of 3,4-dihydropyran-2-one derivatives represents a promising yet underappreciated strategy to access these compounds. To the best of our knowledge, very few examples of this strategy have been reported, with limited investigation of the influence of stereogenic centers on the starting dihydropyranones. We investigated the iodine(III)-mediated contraction of a representative set of dihydropyranone derivatives. The method gives rapid access to functionalized γ-butyrolactones in good yields. The reaction scope was investigated, and the method was found to support various levels of substituents, even enabling access to sterically congested quaternary centers. The stereoselectivity was investigated using chiral substrates and a chiral iodine(III) reagent.

Full text of DOI:10.1021/acs.orglett.9b01893

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iodine(III)-Mediated Contraction of 3,4-Dihydropyranones: Access to
Polysubstituted γ‑Butyrolactones
Robin Dagenais,† Tommy Lussier,† and Claude Y. Legault*
́
Centre in Green Chemistry and Catalysis, Department of Chemistry, University of Sherbrooke, 2500 boul. de l’Universite,
́
Sherbrooke, Quebec J1K 2R1, Canada
S
* Supporting Information
ABSTRACT: Functionalized γ-butyrolactones are privileged structures in
the field of medicinal chemistry; they are found in numerous natural
products and synthetic compounds with diverse biological activities. The
oxidative ring contraction of 3,4-dihydropyran-2-one derivatives represents a
promising yet underappreciated strategy to access these compounds. To the
best of our knowledge, very few examples of this strategy have been
reported, with limited investigation of the influence of stereogenic centers
on the starting dihydropyranones. We investigated the iodine(III)-mediated
contraction of a representative set of dihydropyranone derivatives. The method gives rapid access to functionalized γ-
butyrolactones in good yields. The reaction scope was investigated, and the method was found to support various levels of
substituents, even enabling access to sterically congested quaternary centers. The stereoselectivity was investigated using chiral
substrates and a chiral iodine(III) reagent.
he γ-butyrolactone motif (Scheme 1a, 1) is a privileged
structure in the field of medicinal chemistry; it is found in
been invested in developing stereoselective methodologies.8
Our group has been involved in the development of
iodine(III)-mediated processes to access chiral nonracemic
α-functionalized carbonyl compounds.9 These products are of
particular interest because of their ubiquity in nature and
potential in synthesis. In our initial work in this area, we
reported chiral iodoarene precatalysts to promote the direct
enantioselective α-tosyloxylation of ketone compounds.10 This
has been an area of active research in the past 20 years, as α-
tosyloxy ketones are high-value chiral precursors.11 More
recently, to solve the long-standing selectivity problem
involved with this methodology, we reported that enol ester
derivatives can serve as enol surrogates,12 much like silyl enol
ethers, initially reported by Moriarty et al.13 and more recently
by Wirth et al.14 The enol esters can be easily converted to
their corresponding α-tosyloxy ketone derivatives under
stoichiometric (eq 1) and catalytic conditions.
T
Scheme 1. (a) Useful γ-Butyrolactones and (b) Concept of
Oxidative Contraction of Dihydropyranones
numerous natural products and synthetic compounds with
diverse biological activities.1 Consequently, efforts have been
devoted to developing methods to access this high-value
scaffold.2 One promising yet underappreciated strategy has
been the oxidative ring contraction of 3,4-dihydropyran-2-ones
(Scheme 1b, 2 → 3). To the best of our knowledge, very few
examples of this strategy have been reported,3,4 with very
limited investigation of the stereocontrol from R3 or R4. Recent
developments, particularly in the field of NHC organo-
catalysis,5 are giving access to numerous chiral nonracemic
3,4-dihydropyran-2-one derivatives, making this strategy quite
relevant.
With this in mind, we envisioned that iodine(III) reagents
could serve to promote the contraction of 3,4-dihydropyran-2-
ones 2 to the corresponding γ-butyrolactones 3 (Scheme 1b,
[Ox] = iodine(III) reagent). Additionally, we hypothesized
that they could provide unique reactivity and selectivity
In the field of oxidative methodologies, hypervalent iodine
compounds have become reagents.6 They tend to have lower
environmental impact.7 In particular, numerous efforts have
Received: June 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01893
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
profiles. In this communication, we report our preliminary
investigation of the iodine(III)-mediated oxidative contraction
of 3,4-dihydropyranones to their corresponding polysubsti-
tuted γ-butyrolactone products as well as an investigation of
the effect of steric and electronic modifications on both the
substrate and the iodine(III) reagent on the stereoselectivity.
We initially selected a small set of dihydropyranones to
investigate the feasibility of the reaction. The substrates (2a−f)
were made using reported synthetic routes.15 We submitted
these compounds to the standard oxidation protocol previously
developed for enol esters, using a slight excess of [(hydroxy)-
tosyloxyiodo]benzene (HTIB) at room temperature. The
results are illustrated in Scheme 2. Gratifyingly, when
Figure 1. Iodine(III) reagents used for the study.
a
Table 1. Screening of Conditions
a
Scheme 2. Preliminary Scope
b
c
entry
reagent
solvent
time (min) yield of 3g (%)
trans:cis
d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
HTIB
HTIB
HTIB
HTIB
HTIB
DIB
DIB
4a
4b
4c
4c
4d
MeCN
MeCN
MeCN
CH2Cl2
CHCl3
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
MeCN
MeCN
CCl4
240
15
5
20
20
60
5
30
30
30
60
30
180
720
720
80
75
77
82
80
72
75
83
82
82
81
75
45
77
61
4.7:1
4.5:1
4.3:1
7.8:1
5.4:1
4.5:1
3.4:1
3.8:1
3.7:1
6.0:1
7.5:1
5.6:1
1.9:1
1.1:1
1.1:1
e
f
g
4e
Br2
m-CPBA
CH2Cl2
a
Unless otherwise stated, the reaction was performed at room
b
a
b
temperature using 0.1 equiv of TsOH·H2O as the additive. Isolated
Isolated yields are reported. 0.1 equiv of TsOH·H2O was added to
c
c
the reaction mixture. The yield was determined by 1H NMR analysis
using an internal standard.
yields of combined diastereoisomers. Diastereomeric ratios were
d
determined by 1H NMR analysis of the crude products. The reaction
e
was performed without an additive. Additive: TsOH·H2O (1 equiv).
f
g
Additive: MsOH·H2O (2 equiv). Additive: H2SO4·H2O (2 equiv).
dihydropyranone 2a (R1 = Ph, R2 = H) was submitted to
the contraction conditions, it was converted to the
corresponding γ-butyrolactone 3a within 4 h using a slight
excess of HTIB. In analogy to our work with acyclic enol
esters, the addition of a catalytic quantity of TsOH·H2O
drastically increased the rate of the reaction, leading to
completion in 20 min. The method tolerates an enolizable
alkyl group at the R1 position (3c), the lower yield being due
to product volatility. We evaluated the possibility of making γ-
butyrolactones bearing quaternary centers (R2 ≠ H) using
substrates 2d−f. The desired products were obtained, albeit in
lower yields. Almost no elimination product was observed in
the crude products, in contrast to the results observed with
acyclic enol esters.9
With these promising results in hand, we investigated
substrates bearing a stereogenic center α to the enol to
measure the level of achievable diastereoselectivity. Substrate
2g was first used to assess the effect of the reaction conditions
on the selectivity. Iodine(III) reagents 4a−e16 were synthe-
sized and used for the investigation to explore the effect of the
nature of the iodine(III) reagent on the selectivity (Figure 1).
Dihydropyranone 2g was submitted to various oxidative
contraction conditions. The results are described in Table 1.
Under the standard oxidation protocol, described in Scheme 2,
a good yield of the contraction product 3g was obtained, with a
selectivity of 4.7:1 in favor of the trans diastereoisomer. The
relative stereochemistry of the major diastereoisomer was
unambiguously assigned using X-ray diffraction analysis.
A catalytic amount of TsOH·H2O increased the reaction
rate and had a marginal effect on the diastereoselectivity. It was
possible to obtain an extremely fast reaction (∼5 min) by using
a stoichiometric quantity of TsOH·H2O, with a slight decrease
in diastereoselectivity. We currently hypothesize that the role
of TsOH·H2O is to increase the effective concentration of the
reactive iodine(III) species.9 We obtained increased selectiv-
ities in less polar solvents (Table 1, entries 4 and 5). HTIB
equivalents can be generated in situ from (diacetoxyiodo)-
benzene (DIB) and a strong acid (entries 6 and 7). The use of
MsOH resulted in almost identical diastereoselectivity, where-
as lower selectivity was obtained using sulfuric acid.
We evaluated the use of HTIB derivatives 4a−e (Table 1,
entries 8−13). The influence of the electronic properties of the
iodine(III) reagent led to a small cost in terms of selectivity.
Conversely, the use of bulkier reagents (entries 10−12) led to
an increase in selectivity. We evaluated the use of a less polar
solvent with the most selective reagent (4c); it did lead to an
increase in selectivity (entry 11) but did not surpass what
could be obtained with HTIB under the same conditions
(entry 4). We also investigated the effect of lower reaction
temperature with both HTIB and 4c, but it did not result in
increased selectivity. The partial solubility of the iodine(III)
B
DOI: 10.1021/acs.orglett.9b01893
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reagents could explain this surprising behavior. Finally, we
investigated the oxidative contractions reported in the
diphenyl-2-pyrone, as separation proved difficult. We evaluated
the influence of 1,2-allylic strain on the selectivity using a
substrate possessing methyl groups at both R2 and R3. A drastic
increase in selectivity (product 3p was obtained as a single
diastereoisomer) was observed compared with model substrate
2g. We then evaluated the effect of substitution at R4/R5. As
could be expected, no selectivity was obtained. Interestingly, an
allyl moiety was tolerated under the reaction conditions (3r).
The presence of a quaternary center α to the lactone
carbonyl is felt, however, as the oxidation rate is lower, leading
to reaction times of up to 1 h (products 3s and 3t).
Interestingly, the phenyl migration product 5 could be isolated
in 11% yield when 2t was subjected to the oxidation
conditions.17 In contrast to substrate 2p, addition of a
stereocenter at R4 while having a stereocenter at R3 (substrate
2u) resulted in lowered selectivity compared with 2g. Finally, it
is noteworthy that the contraction is easily scalable; performing
a 15 mmol scale contraction of 2g provided pure trans-3g in
75% isolated yield.
3
literature using Br2 (entry 14) and m-CPBA4 (entry 15) as
the oxidants. Interestingly the selectivities were modest; the
use of a bulkier iodine(III) reagent is thus clearly advantageous
to access synthetically useful selectivities.
We explored the scope using HTIB in both MeCN and
CH2Cl2. The results are illustrated in Scheme 3. We first
a
Scheme 3. Substrate Scope Study
We propose a mechanism to account for the trans selectivity
and formation of side product 5 (Scheme 4). We expect the
Scheme 4. Proposed Mechanism
a
Isolated yields of combined products are reported. Selectivities
(trans:cis) were determined by 1H NMR analysis of the crude
products. Isolated yield of the pure trans product. The reaction was
performed in CH2Cl2. The reaction was performed in CH2Cl2 on a
15 mmol (2.8 g) scale. Combined yield of trans-3o and 5,6-diphenyl-
b
c
d
e
2-pyrone (1:1.5).
iodine(III) reagent to react preferentially with the alkene face
trans to the substituent at R3, leading preferentially to Int-1 (or
species with identical relative configuration). Less polar
solvents would result in stronger electrostatic interactions,
leading to shorter substrate···iodine(III) distances and better
facial discrimination. A water molecule would then attack at C2
or C6 on Int-1, leading to either Int-2A or Int-2B, respectively.
Formation of 5 would originate from a 1,2-phenyl shift18 on
Int-2B. This is observed only for 2t (R1 = Ph, R3 = H, R4 =
Bn); the increased steric bulk near C2 could force the attack of
H2O at C6, providing a kinetic preference for the formation of
Int-2B. Alternatively, the Thorpe−Ingold effect could increase
the effective concentration of Int-2B. Finally, we propose that
the desired trans product is obtain by SN2 attack from the free
acid on Int-2A (blue arrow). It does suggest that the α-
tosyloxylation (red arrow), leading to Int-3, is not dominant in
this reaction.
investigated the effect of different substitution patterns on an
aromatic ring at the R1 position. In analogy to our work on
enol acetates,9 we found that dihydropyranones bearing an
electron-rich aromatic ring (substrates 2h, 2i, 2k, and 2l) were
much more reactive toward HTIB, the reaction being complete
within minutes. The crude products presented noticeable
degradation, but surprisingly, this increased reactivity was also
met with increased selectivity. In analogy, substrates possessing
more electron-deficient aromatic rings (2j and 2m) were less
reactive and less selective. Increasing the size of the R3 group
resulted in a noticeable enhancement of the selectivity with
respect to 2g (R3 = Me), affording up to 12.5:1 in CH2Cl2 for
2n (R3 = i-Pr). Contraction of 2o, bearing a phenyl at R3,
provided the desired lactone product as a single diaster-
eoisomer (trans-3o) along with 5,6-diphenyl-2-pyrone as a
major side product originating from phenyl migration.17 We
have reported the combined yield for trans-3o and 5,6-
Our method compares favorably with known methods to
access γ-butyrolactones by direct oxidative cyclization of
C
DOI: 10.1021/acs.orglett.9b01893
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Letter
acyclic keto acids.11d,f,19 We investigated lactonization of
substrates 6a−c; the results are presented in Scheme 5. The
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.9b01893.
Scheme 5. Lactonization of Keto Acids
Experimental procedures and NMR spectra for all new
compounds (PDF)
Accession Codes
CCDC 1919362 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 e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
method requires higher temperature and longer reaction times,
but lactone 3a could be obtained in high yield from 6a.
Substrate 6b, with two enolizable positions, resulted in the
formation of numerous side products, thus yielding the desired
lactone 3c in only 30% yield. Finally, the oxidative
lactonization of keto acid 6c resulted in the desired lactone
3g in 84% yield, but with no diastereoselectivity. The oxidative
contraction of 3,4-dihydropyran-2-ones thus provides numer-
ous advantages in terms of both reaction rate and selectivity.
Finally, on the basis of our success in the enantioselective
conversion of enol esters to enantioenriched α-tosyloxy
ketones, we performed a preliminary evaluation of an
enantioselective variant of the oxidative contraction of
dihydropyranone 2a (Scheme 6). Lactone 3a was obtained
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: claude.legault@usherbrooke.ca.
ORCID
Claude Y. Legault: 0000-0002-0730-0263
Author Contributions
†R.D. and T.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
Scheme 6. Enantioselective Conditions
ACKNOWLEDGMENTS
■
This work was supported by the National Science and
Engineering Research Council (NSERC) of Canada, the
Canada Foundation for Innovation (CFI), the FRQNT Centre
in Green Chemistry and Catalysis (CGCC), and the Universite
de Sherbrooke. We thank Antoine Jobin-Des Lauriers for
preliminary results.
́
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