Synthesis of functionalized 4-methylenetetrahydropyrans by oxidative activation of cinnamyl or benzyl ethers

Article abstract of DOI:10.1016/j.tetlet.2012.03.041

Oxidative activation of benzyl or cinnamyl ether bearing allylsilane derivatives using a catalytic amount of DDQ and 2 equiv of CAN in the presence of PPTS provided functionalized 4-methylenetetrahydropyrans in good yields and excellent diastereoselectivi

Full text of DOI:10.1016/j.tetlet.2012.03.041

Tetrahedron Letters 53 (2012) 2568–2570
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Synthesis of functionalized 4-methylenetetrahydropyrans by oxidative
activation of cinnamyl or benzyl ethers
⇑
Arun K. Ghosh , Xu Cheng
Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Oxidative activation of benzyl or cinnamyl ether bearing allylsilane derivatives using a catalytic amount
of DDQ and 2 equiv of CAN in the presence of PPTS provided functionalized 4-methylenetetrahydro-
pyrans in good yields and excellent diastereoselectivity. The reaction could be applied to the synthesis
of a variety of substituted tetrahydropyran derivatives.
Received 21 February 2012
Revised 7 March 2012
Accepted 10 March 2012
Available online 16 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Methylenetetrahydropyrans
Sakurai reaction
Cyclization
Stereoselective
Allylsilane
Functionalized 4-methylenetetrahydropyrans are embedded in
many biologically important natural products including anticancer
agents such as zampanolide, enigmazole A, and phorboxazole.1–3
Previous construction of such substituted tetrahydropyran deriva-
tives involved the synthesis of 4-oxotetrahydropyran followed by
olefination of the ketone.4–7 A number of asymmetric methodolo-
gies have been developed over the years that incorporated the
exo-olefin directly. These include, a Mukaiyama Aldol-Prins cas-
cade reaction developed by Rynchnovsky and co-workers,8 and
intramolecular Sakurai cyclizations by Marko and co-workers,9
Keck et al.,10 and Floreancig and co-workers.11 Recently, in the con-
text of our synthesis of (À)-zampanolide, we have developed a re-
lated intramolecular oxidative cyclization protocol using DDQ and
a Bransted acid to construct the substituted 4-methylenetetrahyd-
ropyran subunit.12 As shown in Scheme 1, b-cinnamyloxyester 1
was efficiently converted into allylsilane 2. Treatment of 2 with
DDQ and PPTS at À38 °C in acetonitrile for 3 h afforded 3 in 81%
yield as a single diastereomer. Encouraged by the observed high
diastereoselectivity of the oxidative Sakurai-type cyclization pro-
cess, we have now investigated the scope of this reaction with a
variety of different substrates. Furthermore, we examined this
reaction at a lower temperature as well as using a catalytic amount
of DDQ along with other stoichiometric oxidants. Herein, we report
the results of our studies in which a range of functionalized 4-
methylenetetrahydropyrans were synthesized diastereoselectively
using a catalytic amount of DDQ and 2 equiv of ceric ammonium
nitrate (CAN).
A number of related oxidative protocols have been reported in
the literature. Floreancig and co-workers reported a C–H activation
protocol for the synthesis of a 4-oxo-tetrahydropyran with an alke-
nyl acetate as an intramolecular nucleophilic cyclization group.13
She and co-workers recently reported a Prins type methodology
and introduced bromine into the pyran ring.14 For our studies, a
model substrate 4a with allylsilane and cinnamyl ether functional-
TBDPS
TBDPS
Ph
Ph
O
O
O
O
O
CeCl3
TMSCH2MgCl
81%
EtO
TMS
2
1
DDQ, PPTS
CH3CN,
-38 °C, 3 h
81%
TBDPS
O
Ph
Ref. 12
Steps
(-)-Zampanolide
O
3
⇑
Corresponding author.
E-mail address: akghosh@purdue.edu (A.K. Ghosh).
Scheme 1. Oxidative cyclization leading to substituted-4-methylenetetrahydro-
2H-pyran 3.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.041

A. K. Ghosh, X. Cheng / Tetrahedron Letters 53 (2012) 2568–2570
2569
ities was prepared in gram quantities. Our choice of this model was
based upon the fact that a cinnamyl ether functionality can be in-
stalled readily as described previously.12
DDQ
Ph
O
Ph
O
(20 mol%)
CAN, PPTS
-38 °C
The etherification substrate, the b-hydroxyester can be conve-
niently prepared in optically active form utilizing Noyori hydroge-
nation with very high enantioselectivity.15 Also, the styrenyl side
chain can be selectively differentiated from other olefins for fur-
ther synthetic manipulation.16 Allylsilane 4a was prepared by an
aldol reaction of isovaleraldehyde and ethyl acetate followed by
etherification and subsequent conversion to the silane derivative
as described previously for compound 2.12
( )-4a
TMS
( )-5a
- OTs
Ph
70%
O
DDQ-2H
DDQ
H
H
SiMe3
6
As shown in Table 1, we investigated a variety of oxidative C–H
activation conditions for an effective Sakurai-type cyclization reac-
tion. We attempted cyclization of 4a with 1.5 equiv of DDQ and
1.5 equiv of InCl3 in CH2Cl2 at À78 °C. These conditions, within a
3 h period resulted in 4-methylenetetrahydropyran 5a in 40% yield
(Table 1). Encouraged by this result, we then examined conditions
using a catalytic amount of DDQ (20 mol %) and a stoichiometric
amount of various oxidants to decrease the amount of organochlo-
ride byproducts.17 We were also interested in using inexpensive
and other readily available oxidants. In order to improve oxidant
solubility, acetonitrile was used instead of CH2Cl2 and the reaction
temperature was optimized to À38 °C. As can be seen, under these
reaction conditions, oxidants KMnO4, MnO2, and PhI(OAc)2 were
ineffective (entries 2–4). However, the use of a catalytic amount
(20 mol %) of DDQ and 2 equiv of ceric ammonium nitrate (CAN)
in the presence of PPTS (2 equiv) for 16 h provided tetrahydropy-
ran 5a exclusively in 70% yield after chromatography (entry 5).
The presence of PPTS was essential with DDQ/CAN combinations
as the corresponding reaction in the absence of PPTS resulted in
the decomposition of the starting material (entry 7). Our at-
tempted optimization with pyridine however, resulted in a signif-
icantly slower reaction. Thus, PPTS is necessary for this oxidative
cyclization, however, the exact role of PPTS is unclear. The assign-
ment of cis-stereochemistry was established based upon extensive
1H NMR NOESY experiments of 5a. The stereochemical outcome of
this oxidative cyclization can be rationalized based upon the Zim-
mermann–Traxler18 transition state 6 shown in Scheme 2. As
shown, the C2-cinnamyl substituent in the incipient tetrahydropy-
ran ring assumes an equatorial position which explains the stereo-
chemistry of the newly created asymmetric center in product 5a.
After optimization of the reaction conditions, we examined the
scope of this catalytic process with a variety of allylsilane/benzyl/
cinnamyl ether substrates. The results are shown in Table 2. As can
be seen, an electron rich 4-methoxy cinnamyl substrate provided
5b in very good yield (entry 1). A furyl allyl substrate under the
Ce3+
Ce4+
Scheme 2. Possible reaction pathway with a catalytic amount of DDQ.
above catalytic conditions provided significant decomposition of
product 5c. Therefore, this cyclization was carried out using
1.5 equiv of DDQ to provide 5c within 30 min in 61% isolated yield.
We have also examined a 4-methoxy benzyl derivative which pro-
vided 5d in 81% yield (entry 3). The scope of the reaction was
investigated with a benzyl ether side chain and an alcohol side
chain. As shown, the side chain benzyl ether was stable during
the cyclization reaction and product 5e was obtained in 79% yield
(entry 4). Also, the cyclization proceeded smoothly in the presence
of a primary alcohol (entry 5). Substrates 4g and 4h containing vi-
nyl and chlorine substituents provided very clean cyclization prod-
ucts 5g and 5h, respectively (entries 6 and 7). The presence of a
bulky t-butyl side chain did not diminish the reactivity and the
resulting tetrahydropyran derivative 5i was obtained in very good
yield (entry 8). A PMB type substrate 4j also gave rise to the cy-
clized product 5j in good yield and selectivity (entry 9). The oxida-
tive cyclization also proceeded in a manner of annulation to
provide the bicyclic derivative 5k (entry 10). The reaction with
an (E)-(3-alkoxybut-1-enyl)benzene substrate afforded tetrahy-
dropyran 5l with a quaternary center in 63% yield as a mixture
(dr = 4.7:1) of diastereomers. The mixture was separated by silica
gel chromatography and 5l with i-trans Bu and Me groups was
the major isomer. After the exploration of cyclization substrate
scope, we carried out the cyclization reaction in gram scale using
optically active material. Substrate 2 (Scheme 1) was prepared in
97% ee as described previously.12 Subsequent oxidative cyclization
was carried out in 1.8 g scale by treating 2 with DDQ/CAN/PPTS in
acetonitrile at À38 °C to yield the 4-methylenetetrahydropyran
derivative 3 in 71% yield and 97% ee.19 This tetrahydropyran deriv-
ative was previously converted into (À)-zampanolide.12
Table 1
The screening of cyclization conditionsa
Ph
O
Ph
O
conditions
TMS
(+)-4a
(+)-5a
Entry
Condition
DDQ (1.5 equiv), InCl3 (1.5 equiv), CH2Cl2, À78 °C
Time (h)
Yield (%)
1
2
3
4
5
6
7
3
24
24
24
16
24
0.5
40b
DDQ (20 mol %), KMnO4 (1.5 equiv), PPTS (1.5 equiv) in MeCN, À38 °C
DDQ (20 mol %), MnO2 (1.5 equiv), PPTS (1.5 equiv) in MeCN, À38 °C
DDQ (20 mol %), PhI(OAc)2 (1.5 equiv), PPTS (1.5 equiv) in MeCN, À38 °C
DDQ (20 mol %), CAN (2 equiv), PPTS (2 equiv) in MeCN, À38 °C
CAN (2 equiv), PPTS (2 equiv) in MeCN, À38 °C
<10c
<10c
<10c
70b
NRd
DDQ (20 mol %), CAN (2 equiv) in MeCN, À38 °C
Decomp
a
b
c
All the reactions were carried out in the presence of 4 Å MS.
Yield after chromatography.
Conversion yield by 1H NMR.
d
NR, no reaction.

2570
A. K. Ghosh, X. Cheng / Tetrahedron Letters 53 (2012) 2568–2570
Table 2
access to a variety of functionalized 4-methylenetetrahydropyrans
in very good yield and excellent diastereoselectivity.
Substrate scope of oxidative cyclizationa
Entry
Product
Time (h)
16
Yield (%)
75
Acknowledgment
MeO
O
Financial support by the National Institutes of Health is grate-
fully acknowledged.
1
5b
Supplementary data
O
O
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.03.041.
2
3
0.5
61b
5c
MeO
References and notes
O
14
81
5d
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Singh, A. J.; Kanakkanthara, A.; Halfihi, T.; Northcote, P. T.; Miller, J. H. J. Med.
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McMahon, J. B.; Gustafson, K. R. J. Am. Chem. Soc. 2010, 132, 10278–10285.
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4
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79
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5e
OH
O
O
O
O
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more details, please see Supplementary data).
Cl
5i
5j
OMe
Representative example: 4-Methylenetetrahydropyran 3: To a suspension of
DDQ (147 mg, 20 mol %), PPTS (1.63 g, 6.48 mmol), CAN (3.51 g, 6.48 mmol),
O
O
9
10
11
16
10
3
73
and 4 Å MS (3.6 g) in MeCN (120 mL) was added
3.24 mmol). The suspension was stirred at À38 °C for 16 h and quenched with
Et3N (1 mL). The mixture was filtered through silica gel column with
a solution of 2 (1.8 g,
a
hexanes/ethyl acetate (v/v = 95:5) as the eluent. The concentrated product was
purified by silica gel chromatography with hexanes/ethyl acetate (v/v = 95:5)
as eluent to give 4-methylenetetrahydropyran 3 as an oil (1.17 g, 71%). The
analysis data comply with the reported value.12
79
4-Methylenetetrahydropyran 5a: To a suspension of 4a (33 mg, 0.1 mmol) and
4 Å MS (100 mg) in MeCN (4 mL) was added DDQ (4.5 mg, 20 mol %), PPTS
(50.4 mg, 0.2 mmol) and CAN (110 mg, 0.2 mmol) at À38 °C. Then the mixture
was stirred at À38 °C until TLC showed full conversion. Et3N (0.2 mL) was
added. The mixture was filtered through a short silica gel pad with hexanes/
ethyl acetate (v/v = 97:3) as eluent to give crude product that was purified by
silica gel chromatography with hexanes/ethyl ether = 97:3 as eluent to give 5a
as colorless oil (17.9 mg, 70%).
5k
O
*
63b
Me
(dr =4.7:1)
5l
1H NMR (400 MHz, CDCl3) d 7.40–7.21 (m, 5H), 6.62 (d, J = 16 Hz, 1H), 6.26 (dd,
J = 5.9, 16.0 Hz, 1H), 4.77 (s, 2H), 3.97–3.93 (m, 1H), 3.46–3.40 (m, 1H), 2.35 (d,
J = 13.2 Hz, 1H), 2.23 (d, J = 13.2 Hz, 1H), 2.15 (t, J = 13.2 Hz, 1H), 1.97 (t,
J = 12.7 Hz, 1H), 1.91–1.83 (m, 1H), 1.64–1.57 (m, 1H), 1.33–1.26 (m, 1H), 0.93
(d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H).
a
DDQ (20 mol %), CAN (2 equiv), PPTS (2 equiv), 4 Å MS, MeCN, À38 °C.
DDQ (1.5 equiv), PPTS (1.5 equiv), 4 Å MS, MeCN, À38 °C.
b
13C NMR (100 MHz, CDCl3) d 144.5, 136.8, 130.1, 128.4, 127.4, 126.4, 108.6,
78.6, 45.3, 41.0, 40.9, 24.3, 23.0, 22.5.
In summary, we have developed a useful oxidative protocol for
a Sakurai-type cyclization using a catalytic amount of DDQ and
2 equiv of CAN and PPTS as a promoter. The protocol provides
IR (thin film, cmÀ1) 2954, 1732, 1652, 1500, 1315, 1133, 1079, 965, 890, 745,
692. Rf = 0.35, hexanes/ethyl ether = 98:2 UV. MS (EI) m/z 256 (M+).