Synthesis of β,β-disubstituted γ-butyrolactones by chemo-selective oxidation of 1,4-diols and γ-hydroxy olefins with rucl3/NaIO4

Article abstract of DOI:10.1055/s-0034-1379614

Substituted γ-butyrolactones represent an important group of structural fragments commonly found in natural products, receptor ligands, and drug molecules. Interest in preparing a library of substituted γ-butyrolactones and finding that limited routes to β-substituted lactones exist, led to the development of an efficient approach for the synthesis of β,β-disubstituted γ-butyrolactones. Readily prepared substituted 1,4-diols and γ-hydroxy olefins were treated with the -RuCl₃/NaIO₄ oxidation system to provide the target β,β-disubstituted γ-butyrolactones in modest to good yields. The reaction goes through a lactol intermediate that was isolated and characterized for selected compounds. The approach supplies an efficient and versatile method for the synthesis of these important heterocyclic structures. Importantly, the present work is the first report that demonstrates the ability of RuCl₃/NaIO₄ to selectively oxidize primary hydroxyl groups in the presence of secondary alcohols to prepare lactones in good yields.

Full text of DOI:10.1055/s-0034-1379614

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 661–665
letter
661
R. Gao et al.
Letter
Synlett
Synthesis of β,β-Disubstituted γ-Butyrolactones by Chemo-
selective Oxidation of 1,4-Diols and γ-Hydroxy Olefins with
RuCl3/NaIO4
Rong Gao
R2
R3
O
O
R1
R1
R2
R2
R1
R1
R1
RuCl3
NaIO4
RuCl3
NaIO4
Rong Fan
OH
OH
Daniel J. Canney*
O
O
R2
R2
R1
R2
R3
Temple University School of Pharmacy, Department of Pharma-
ceutical Sciences and Moulder Center for Drug Discovery Re-
search, 3307 N Broad Street, Philadelphia, PA 19140, USA
R1
R1
OH
R1 = H, alkyl, aryl
2 = H, aryl
R1 = H, alkyl, aryl
47–81%
48–83%
+
1
2
(
1
5
7
)
0
7
5
6
2
0
canney@temple.edu
2 = H, alkyl
R
R
R
3 = alkyl, aryl
Received: 29.09.2014
Accepted after revision: 03.11.2014
Published online: 07.01.2015
novel amino alcohol based Ir bifunctional complex.4 Both
the Dyatkin and the Suzuki methods required the prepara-
tion of catalytic complexes from expensive starting materi-
als. The reduction of the corresponding cyclic anhydrides
with metal hydrides could also provide the β,β-disubsti-
tuted γ-butyrolactones with moderate yield.5 To date,
however, no efficient, economical, and versatile route to
β,β-disubstituted γ-butyrolactones using readily available
starting materials has been reported.
DOI: 10.1055/s-0034-1379614; Art ID: st-2014-r0818-l
Abstract Substituted γ-butyrolactones represent an important group
of structural fragments commonly found in natural products, receptor
ligands, and drug molecules. Interest in preparing a library of substitut-
ed γ-butyrolactones and finding that limited routes to β-substituted
lactones exist, led to the development of an efficient approach for the
synthesis of β,β-disubstituted γ-butyrolactones. Readily prepared sub-
stituted 1,4-diols and γ-hydroxy olefins were treated with the
RuCl3/NaIO4 oxidation system to provide the target β,β-disubstituted
γ-butyrolactones in modest to good yields. The reaction goes through a
lactol intermediate that was isolated and characterized for selected
compounds. The approach supplies an efficient and versatile method
for the synthesis of these important heterocyclic structures. Important-
ly, the present work is the first report that demonstrates the ability of
RuCl3/NaIO4 to selectively oxidize primary hydroxyl groups in the pres-
ence of secondary alcohols to prepare lactones in good yields.
O
Ph
OH
O
RuCl3, NaIO4
81%
Ph
Ph
Ph
6c
3c
O
Ph
Ph
Key words lactones, cyclization, ruthenium, alkenes, diols
RuCl3, NaIO4
83%
OH
O
Ph
1 Introduction
Ph
OH
Substituted γ-butyrolactones are commonly found in
natural products that exhibit a broad array of biological ef-
fects including antibiotic, anthelmintic, antifungal, antitu-
mor, antiviral, anti-inflammatory and cytostatic properties.
These molecules are also important structural fragments in
drugs as well as serving as key synthetic intermediates.1
Due to their extensive occurrence in natural products and
their broad range of biological activity, a great deal of effort
has been directed at the development of methods for lac-
tone synthesis.1,2 In spite of these efforts, few methods are
available for the preparation of β,β-disubstituted γ-butyro-
lactones. Doyle and Dyatkin reported a dirhodium(II)-cata-
lyzed reaction to form β-spirolactones from cycloalkyl-
methyl diazoacetates in moderate to high yield.3 Suzuki et
al. reported an oxidative lactonization of 1,4-diols using a
5a
7a
Scheme 1 Oxidation of 1,4-diol and γ-hydroxy olefins to γ-butyrolac-
tones
Our continued interest in the synthesis of lactone-based
bioactive ligands requires efficient routes to lactones with
diverse substitutions at the β-position.6 In the past decade,
the use of commercially available, inexpensive RuCl3/NaIO4
as a versatile and efficient oxidation system has expanded
to include many transformations in organic synthesis.
These include, but are not limited to, oxidations of alkenes
to aldehydes or acids;7 and oxidation of alcohols to alde-
hydes, ketones or acids.8 Despite the large number of publi-
cations on RuCl3/NaIO4-related chemistry, there are few re-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 661–665

662
R. Gao et al.
Letter
Synlett
ports on the oxidative lactonization of γ-hydroxy olefins.
Most of the reports that exist mention lactones as side
products in attempts to synthesize lactols.9 Senanayake and
co-workers used RuCl3/NaIO4 to oxidize γ-hydroxy olefin to
a lactone in 61% yield, but reported only one example with
no details of the procedure disclosed.10 During the course of
our research, the RuCl3/NaIO4 oxidation system was found
to preferentially oxidize terminal alkenes over hydroxyl
groups in γ-hydroxy olefins; and primary hydroxyl groups
over secondary alcohols in 1,4-diols to provide lactones in
good yields (Scheme 1). Herein, we report the application
of this reagent system to the chemoselective oxidation of
γ-hydroxy olefins and 1,4-diols to the corresponding γ-bu-
tyrolactones. To the best of our knowledge, the ability of
RuCl3/NaIO4 to selectively oxidize primary hydroxyl groups
in the presence of secondary alcohols to prepare lactones
has not been demonstrated. Importantly, both series of
γ-butyrolactones were synthesized from readily available
and economical starting materials (allylic esters/acids) pro-
viding great convenience (Scheme 2).
Cl3/NaIO4 oxidation system in MeCN–H2O provided the al-
dehyde. The crude products were then reduced using NaBH4
in anhydrous MeOH to give mixtures of target lactones 4
and hydroxy esters in moderate to good yield. The mixtures
were treated with TsOH in MeCN overnight to cyclize re-
maining hydroxy ester. The α,α-disubstituted lactones 4
were obtained in good yield following purification by chro-
matography on silica gel. Lactones 4 were then treated with
DIBAL and various Grignard reagents at –70 °C to give the
desired 1,4-diols (Scheme 3; 5a–e).
2.2 Screening of Solvents Systems
Solvents are known to have a great impact on reaction
outcomes for the RuCl3/NaIO4 oxidation system.11 In an ef-
fort to identify an effective solvent combination for the re-
action, several commonly utilized solvent mixtures were
screened.8 The results of those screening experiments are
shown in Table 1. When a mixture of H2O–1,2-dichlo-
roethane was used as solvent, the target product was
formed in 27% yield. The use of a H2O–MeCN–CCl4 solvent
combination improved the reaction yield to 35%. Replacing
the CCl4 with EtOAc did not improve the reaction yield. The
use of a H2O–MeCN mixture was found to provide the high-
est yield (81%) of the mixtures tested and thus was used for
oxidation reactions involving 1,4-diols and γ-hydroxy ole-
fins.
O
R1
OH
O
R1
R1
R1
O
R1
R1
R3
O
R2
O
R1
R1
Table 1 Oxidation of Compound 3c with RuCl3/NaIO4 with Various Sol-
vents Systems
OH
O
R1
R1
Entry
Solvents
Yielda
R2
OH
R1, R2, R3 = alkyl
1
2
3
4
H2O–1,2-dichloroethane
H2O–MeCN–CCl4
H2O–MeCN–EtOAc
H2O–MeCN
27%
35%
31%
81%
Scheme 2 Retrosynthetic analysis of β,β-disubstituted γ-butyrolac-
tones
a Isolated yield.
2 Results and Discussion
2.1 Synthesis of Substrates: γ-Hydroxy Olefins and
1,4-Diols
2.3 Oxidative Lactonization of γ-Hydroxy Olefins
The aim of the present work was to develop a general,
robust, and economical synthesis of β,β-disubstituted γ-bu-
tyrolactones that requires minimal chromatographic sepa-
rations. The starting materials included commercially avail-
able, inexpensive α,α-disubstituted esters/acids (Scheme 3;
1a–d). Treatment of 1 with allyl bromide in the presence of
LDA at reduced temperature (–70 °C) gave the allylic
esters/acids 2 which were common intermediates for both
γ-hydroxy olefins and 1,4-diols. Reducing 2 with LiAlH4
provided the γ-hydroxy olefins (Scheme 3; 3a–c) in good
yields. On the other hand, treatment of 2 with the Ru-
The RuCl3/NaIO4 system chemoselectively oxidizes
alkenes in the presence of primary hydroxyl groups to give
the corresponding β,β-disubstituted γ-butyrolactones in
good yields (Table 2, entries 1–3). Consistent with observa-
tions made above with the oxidation of 1,4-diols, the sys-
tem was less effective when the hydroxyl group is at a car-
bon α to an aromatic ring where the formation of keto acids
is observed.12 Four-substituted aromatic functional groups
such as CF3 and Cl did not affect the yield of the reaction
(see entries 4–6 in Table 2).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 661–665

663
R. Gao et al.
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Synlett
O
1a: R1 = Ph, R2 = Et
R1
1b: R1 = Me, R2 = Me
OR2
1c: R1–R1 = –CH2(CH2)2CH2–, R2 = H
1d: R1–R1 = –CH2(CH2)3CH2–, R2 = H
R1
R1
R1
LDA
OH
LiAlH4
Br
86–90%
O
γ-hydroxy olefins
3a: R1 = Ph
3b: R1–R1 = –CH2(CH2)2CH2–
3c: R1–R1 = –CH2(CH2)3CH2–
R1
R1
OR2
R3
O
1. RuCl3, NaIO4
2. NaBH4
3. TsOH
R1
R1
2a: R1 = Ph, R2 = Et
R1
5a: R1 = Ph, R3 = Me
5b: R1 = Ph, R3 = Et
5c: R1 = Ph, R3 = n-Pr
5d: R1 = Me, R3 = Ph
OH
2b: R1 = Me, R2 = Me
DIBAL-H, RMgBr
66–75%
O
R1
2c: R1–R1 = –CH2(CH2)2CH2–
2d: R1–R1 = –CH2(CH2)3CH2–
OH
4a: R1 = Ph
4b: R1 = Me
5e: R1 = Me, R3 = 4-FC6H4CH2
1,4-diols
Scheme 3 Preparation of γ-hydroxy olefins and 1,4-diols from allylic esters/acids
Table 2 Oxidative Lactonization of 1,4-Diols and γ-Hydroxy Olefins
Entry Substrate
Product
Yielda Entry Substrate
Product
Yielda
Ph
Ph
Ph Ph
HO
O
OH
OH
1
72%
9
73%
62%
O
O
HO
5c
3a
O
7c
6a
O
Ph
2
73% 10
Ph
O
OH
O
O
7d
HO
5d
6b
3b
O
O
F
F
OH
OH
OH
O
Ph
O
Ph
3
81% 11
67%
Ph
6c
O
Ph
3c
5e
7e
OH
OH
O
O
O
OH
4
52% 12
48%
74%
6d
Cl
5f
3d
Cl
7f
OH
Ph
Ph
Ph
Ph
O
O
Cl
O
5
50% 13
OH
O
HO
5g
7f
Cl
3e
7g
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 661–665

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R. Gao et al.
Letter
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Table 2 (continued)
Entry Substrate
Product
Yielda Entry Substrate
Product
Yielda
70%
OH
O
O
F3C
6
47% 14
O
O
OH
OH
F3C
3f
6f
O
HO
5h
7h
7i
OH
O
Ph
Ph
OH
O
7
83% 15
74%
Ph
Ph
5a
OH
O
5i
7a
Ph
Ph
OH
8
72%
Ph
OH
O
Ph
O
7b
5b
a Isolated yield.
2.4 Oxidative Lactonization of 1,4-Diols
nism may explain the chemoselectivity observed through-
out the series since the lactol would serve as a protective
intermediate to prevent the hydroxyl group from oxidation.
A variety of 1,4-diols can be transformed to the corre-
sponding β,β-disubstituted γ-butyrolactones with the
RuCl3/NaIO4 system in good yields (Table 2, entries 7–11).
To further demonstrate the scope and limitation of this ap-
proach, other readily prepared substrates were evaluated
(entries 12–15). The oxidation reactions using this system
displayed good chemoselectivity for primary hydroxyl
groups in the presence of non-benzylic secondary alcohol
(Table 2, entries 7–9, 11 and 13–15). The reaction tolerated
some degree of steric hindrance near the primary hydroxyl
groups (Table 2, entries 13–15) as well as the secondary hy-
droxyl groups (Table 2, entries 7–9). This method became
less effective for benzylic secondary alcohol (Table 2, en-
tries 10 and 12).
O
OH
OH
O
Ph
Ph
O
Ph
Ph
Ph
Ph
3c
8a
6c
OH
O
Ph
Ph
OH
O
O
Ph
Ph
Ph
9a
Ph
OH
5a
7a
Scheme 4 Lactol intermediates are formed during the oxidation
2.5 Reaction Mechanism
3 Conclusion
Oxidative lactonization using other oxidation systems
has been reported to proceed via two steps: the initial che-
moselective oxidation to the hydroxy aldehyde (which is in
equilibrium with the corresponding lactol), followed by fur-
ther oxidation to the lactone.4,13 RuCl3/NaIO4-mediated oxi-
dation of γ-hydroxy olefins and 1,4-diols showed the initial
formation of an intermediate lactol species which is then
further oxidized to the lactone (Scheme 4). The formation
of the lactol intermediate was confirmed by quenching the
reaction after 20 minutes and isolating the corresponding
components (8a and 9a) from the mixtures. This mecha-
In summary, γ-butyrolactones are important intermedi-
ates in organic synthesis and are useful fragments in the
drug discovery process. Currently available synthetic routes
to β,β-disubstituted γ-butyrolactones have limited scope
and yields are often poor. The present work involved the de-
velopment of a robust and economical synthesis of these
important synthetic intermediates from easily accessible
1,4-diols and γ-hydroxy olefins.14 The routes described
herein provide facile synthetic routes to a variety of import-
ant synthetic intermediates that may find utility in organic
synthesis and drug discovery efforts.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 661–665

665
R. Gao et al.
Letter
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Acknowledgment
(9) Arnone, A.; Bravo, P.; Frigerio, M.; Mele, A.; Vergani, B.; Viani, F.
Eur. J. Org. Chem. 1999, 2149.
The authors are grateful to Temple University Graduate School (R.G.,
University Fellowship; D.J.C., Grant-in-Aid of Research), and the
Dean’s Office, School of Pharmacy, for generous financial support and
to Dr. Abou-Gharbia and Rogelio Martinez (Moulder Center for Drug
Discovery Research) for access to instrumentation and helpful discus-
sions.
(10) Senanayake, C.; Larsea, R. D.; Bill, T. J.; Liu, J.; Corley, E. G.;
Reider, P. J. Synlett 1994, 199.
(11) Zimmermann, F.; Meux, E.; Mieloszynski, J.; Lecuireb, J.; Oget,
N. Tetrahedron Lett. 2005, 46, 3201.
(12) The formation of keto acids is observed based on LC–MS analy-
sis of the reaction mixture.
(13) Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.; Abrams, J.
N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57.
Supporting Information
(14) General Procedure for 6a–6f: To a stirred mixture of γ-
hydroxy olefins (3a–3f, 3.16 mmol), RuCl3 stock solution [(4.51
mL, 0.035 M in H2O), MeCN (81 mL) and distilled H2O (9 mL),
NaIO4 (4.06 g, 18.96 mmol)] was added in portions over a period
of 30 min at r.t. The suspension was allowed to stir at r.t. over-
night. The reaction was quenched with sat. aq solution of
Na2S2O3 and the two layers were separated. The aqueous layer
was extracted with EtOAc (3 × 100 mL). The combined organic
layer was washed with brine, dried over anhyd MgSO4, filtered,
and concentrated. The residue was purified by flash column
chromatography to give desired aldehyde product (silica gel,
EtOAc–hexanes, 0–25%).
Supporting
information
is
available
online
at
http://dx.doi.org/10.1055/s-0034-1379614. Included are the general
procedures for 3a–3c and 5a–5i, as well as characterization data for
3a–3c, 5a–5i, 6a–6f, 7a–7i, 8a and 9a.
S
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p
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ortiInfogrmoaitn
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rmoaitn
References and Notes
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(2) (a) El Ali, B.; Alper, H. Synlett 2000, 161. (b) Collins, I. J. Chem.
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(3) Doyle, M. P.; Dyatkin, A. B. J. Org. Chem. 1995, 60, 3035.
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(5) Kayser, M. M.; Morand, P. Can. J. Chem. 1978, 56, 1524.
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(b) Ahungena, A.; Canney, D. J. Med. Chem. Res. 2005, 14, 404.
(c) Ahungena, A.; Gabriel, J. L.; Canney, D. J. Med. Chem. Res.
2003, 12, 481.
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(b) Milne, C.; Powell, A.; Jim, J.; Nakeeb, M. A.; Smith, C. P.;
Micklefield, J. J. Am. Chem. Soc. 2006, 128, 11250. (c) Yang, D.;
Zhang, C. J. Org. Chem. 2001, 66, 4814.
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2009, 131, 6354. (d) Miller, M. J.; Walz, A. J.; Zhu, H.; Wu, C.;
Moraski, G.; Möllmann, U.; Tristani, E. M.; Crumbliss, A. L.;
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2-Oxaspiro[4.4]nonan-3-one (6a): colorless oil, yield: 72%. 1H
NMR (400 MHz, CDCl3): δ = 4.10 (s, 2 H), 2.44 (s, 2 H), 1.69 (m, J
= 5.2, 2.5 Hz, 8 H). 13C NMR (101 MHz, CDCl3): δ = 177.2, 78.6,
47.7, 41.4, 36.9, 24.4.
General Procedure for 7a–7i: To a stirred mixture of 1,4-diols
(3.16 mmol), RuCl3 stock solution [(4.51 mL, 0.035 M in H2O),
MeCN (81 mL) and distilled H2O (9 mL), NaIO4 (4.06 g, 18.96
mmol)] was added in portions over a period of 30 min at r.t. The
suspension was allowed to stir at r.t. overnight. The reaction
was quenched with sat. aq solution of Na2S2O3 and the two
layers were separated. The aqueous layer was extracted with
EtOAc (3 × 100 mL). The combined organic layer was washed
with brine, dried over anhyd MgSO4, filtered, and concentrated.
The residue was purified by flash column chromatography to
give the desired aldehyde product (silica gel, EtOAc–hexanes: 0–
25%).
5-Methyl-4,4-diphenyldihydrofuran-2(3H)-one (7a): colorless
semisolid, yield: 81%. 1H NMR (400 MHz, CDCl3): δ = 7.13–7.32
(m, 6 H), 7.05–7.13 (m, 2 H), 6.94 (m, 2 H), 5.34 (q, J = 6.4 Hz, 1
H), 3.41 (d, J = 16.9 Hz, 1 H), 2.88 (d, J = 16.9 Hz, 1 H), 1.06 (d, J =
6.5 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 175.3, 145.1, 142.1,
129.0, 128.6, 128.1, 127.4, 127.3, 127.1, 82.4, 55.5, 43.0, 17.9.
HRMS (CI): m/z [M + H] calcd for C17H16O2: 253.1229; found:
253.1225.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 661–665

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