Development of an O-Vinylation-Ring-Closing Metathesis Strategy to Access 3,3′-3,4-Dihydropyrans

Article abstract of DOI:10.1055/s-0036-1588615

Dihydropyrans are common structural motifs that appear in both natural products and pharmaceuticals and are intermediates for the synthesis of tetrahydropyrans. Currently, no reports exist in the literature for the synthesis of 3,3′-differentially disubst

Full text of DOI:10.1055/s-0036-1588615

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
A.-M. Dechert-Schmitt et al.
Letter
Synlett
Development of an O-Vinylation–Ring-Closing Metathesis Strategy
to Access 3,3′-3,4-Dihydropyrans
Anne-Marie Dechert-Schmitt*
Ar/Het
Ar/Het
CO2R
R2
R2
1) alkylation
Shawn Cabral
CO2R
Grubbs II
RO2C
Ar/Het
Daniel W. Kung
benzene
60–70 °C
O
O
2) aldol
readily available
3) O-vinylation
6 examples; 71–95% yield
Ar/Het = Ph, pyridine,
pyrimidine
Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA
anne-marie.dechertschmitt@pfizer.com
R = H, Me
Received: 17.08.2016
Accepted after revision: 09.09.2016
Published online: 05.10.2016
tuted olefins.11 Herein we describe an approach to the syn-
thesis of 3-quaternary dihydropyrans through an O-vinyla-
tion–RCM sequence from hydroxyl alkenes.
DOI: 10.1055/s-0036-1588615; Art ID: st-2016-r0536-l
Our initial approach to the desired dihydropyran was
via an intramolecular ruthenium-catalyzed cycloisomeriza-
tion of the primary alcohol 1 (Scheme 2), a strategy recent-
ly described by Merck in the synthesis of a tetrahydropyran
DPP4 inhibitor.8a The reaction delivered the product in low
yields (<20% in most cases), and the product was difficult to
separate from the triphenylphosphine from the reaction
mixture. We reasoned that our heteroaryl substrate was
problematic and perhaps chelated to the ruthenium metal
center of the catalyst.12
Abstract Dihydropyrans are common structural motifs that appear in
both natural products and pharmaceuticals and are intermediates for
the synthesis of tetrahydropyrans. Currently, no reports exist in the lit-
erature for the synthesis of 3,3′-differentially disubstituted-3,4-dihy-
dro-2-pyrans. We describe an approach employing abundant esters as
starting materials that allows access to these heterocyclic scaffolds
through a unique O-vinylation–RCM sequence.
Key words cyclization, heterocycles, metathesis, ring closure, aldol
reaction
Based on the limited success of known procedures, and
limited strategies to access the desired 3,3′-3,4-dihydropy-
ran, we sought an alternative approach to the synthesis of
Dihydropyrans are privileged heterocyclic structures
that are present in both biologically active natural products
and pharmaceuticals, including zanamivir (anti-flu), the
lamiridosin family of natural products (hepatitis C virus en-
try inhibitor) and laulimalide (anti-cell growth, Figure 1).1
In addition to being biologically relevant, dihydropyrans
are also useful synthetic intermediates for the synthesis of
functionalized tetrahydropyrans.2 Due to their structural
significance and biological profile, various methods have
been developed to access dihydropyrans including [4+2] cy-
cloadditions,3 Prins cyclizations,4 a Michael–hemiacetaliza-
tion approach,5 cascade reactions,6 a dioxanone–Claisen re-
arrangement,7 Trost metal-catalyzed cycloisomerization,8
and ring-closing metathesis (RCM).9 RCM approaches to di-
hydropyran synthesis typically utilize allyl-homoallyl
ethers which provide access to the 3,6-dihydro-2H-pyran
regioisomer (Scheme 1). While RCM of vinyl ethers to ac-
cess dihydropyrans is known with both ruthenium and mo-
lybdenum catalysts,10 only one example producing a 3,3′-
disubstituted dihydropyran has been reported; however,
this approach only demonstrates the RCM to form trisubsti-
OH
CO2Me
HO
H
O
HO
HO
HO
OH
HN
O
Me
HN
NH2
OH
O
NH
Lamiridosins
Zanamivir
anti-flu
hepatitus C virus
entry inhibitor
H
O
HO
H OH
O
Me
O
O
H
H
O
Laulimalide
anti-cell growth
Figure 1 Biologically active dihydropyrans
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
A.-M. Dechert-Schmitt et al.
Letter
Synlett
1. base
2. K2CO3, allyl bromide
R2
Ar/Het
Previous methods:
[4+2] cyclization
O
Het
MeO2C
CO2t-Bu
R
3. TFA
NO2
RO
O
X
Ref. 3
3
4
5
R
OSiR3
N
O
R
N
2,3-dihydro-4H-
pyran-4-one
N
CO2Me
CO2Me
Prins cyclization
O
5aa
5bb
Ref. 4
50% over 3 steps
65% over 3 steps
O
Alternative preparation of aryl ester
R2
R
O
OEt
R
O
OEt
5,6-dihydro-
2H-pyrans
R1
Br
LiHMDS
R2
Ar/Het
RCM approach
MeO2C
R
THF
6
–78 °C to rt
5
Ref. 9
Cl
R
O
O
R
R
R
H
H
H
H
3,6-dihydro-2H-
pyrans
CO2Me
CO2Me
CO2Me
RCM approach II
R
5c
84% yield
5d
81% yield
5e
42% yield
Ref. 10
R
Scheme 3 Preparation of the aryl ester. Base: a NaH; b K2CO3.
O
O
R = H, alkyl
This work:
for the formation of the product on the various substrates
shown. Less acidic substrates such as the methyl phenyl ac-
etate gave comparable yields using LiHMDS as a base com-
pared to sodium methoxide. Attempts to perform the aldol
reaction with other aldehydes under various conditions
were unsuccessful, presumably due to the increased steric
demands of the product (Scheme 4).
R
R
R'
R'
O
O
3,3-differentially
disubstituted
3,4-dihydro-2H-
pyran
Scheme 1 Synthetic approaches to dihydropyrans
Ar/Het
R2
R2
Ar/Het
paraformaldehyde
R1
NaOMe
DMF or DMSO
60–70 °C
R1
CO2Et
N
HO
CO2Et
5
7
CpRu(PPh3)2Cl, NaHCO3,
N-hydroxysuccinimide,
NO2
N
N
O
NBu4PF6, PPh3
N
N
N
CO2Me
DMF, 80 °C
N
CO2Me
CO2Me
CO2Me
CO2Me
HO
1
2
HO
HO
HO
low yields
poor reproducibility
7aa
64% yield
7ba,c
7cc,d
48% yield
57% yield
Cl
Scheme 2 Cycloisomerization approach to access dihydropyran
CO2Me
dihydropyrans through the use of an O-vinylation–RCM se-
quence. The O-vinylation precursors were prepared from
the aryl halides via a three-step sequence: SNAr with
malonate 3 and aryl halide 4, allylic alkylation, and decar-
boxylation under acidic conditions to deliver product 5. Al-
ternatively, alkylation of aryl acetic acid derivatives 6 with
allyl bromide or methallyl bromide delivered the aryl allyl
ester precursors 5 in a reliable manner (Scheme 3).
With the aryl allyl esters 5 in hand, the bishomoallylic
alcohol 7 was installed using an aldol reaction of parafor-
maladehyde. Several bases were explored, including tri-
ethylamine, LDA, LiHMDS, but the most general base for the
reaction was found to be sodium methoxide, which allowed
CO2Me
HO
HO
7db,c
48% yield
7eb
51% yield
Scheme 4 Aldol reaction with paraformaldehyde. a DMSO, 60 °C; b DMF,
70 °C; c average of two runs; d DMSO, 75 °C.
Our next step was the O-vinylation of primary alcohols
7. Historically, O-vinylation has been accomplished through
the use of stoichiometric quantities of mercury or hydro-
etherification of acetylene.13 Modern methods have shown
that several metals catalyze this reaction and circumvent
the use of mercury or the harsh conditions associated with
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
A.-M. Dechert-Schmitt et al.
Letter
Synlett
acetylene hydroetherification.14 We explored several meth-
ods (Ir, Pd, Au/Ag) and found that both the palladium- and
gold/silver-catalyzed reactions delivered the desired prod-
uct 8 successfully, while the iridium catalyst proved to be
unsuitable (Scheme 5).14e In the case of the gold/silver reac-
tion,14g the reaction was slow and required 72 hours to ob-
tain an acceptable yield, with acetal byproduct formation
also occurring. Attempts to improve the yield by increasing
the temperature and changing the reaction solvent resulted
in no appreciable yield increase.14g
Ar/Het
R1
R2
Ar/Het
R1
R2
Grubbs II catalyst
(5 mol%)
benzene
60–70 °C
O
N
O
9
8
NO2
N
N
CO2Me
CO2Me
CO2Me
O
O
O
9a
81% yield
9b
91% yield
9c
71% yield
Pd(TFA)2
Ar/Het
Cl
Cl
R2
(5–10 mol%)
Ar/Het
R1
R2
R1
4,7-diphenyl-
1,10-phenanthroline
O
HO
CO2Me
H
CO2Me
O
(solvent)
7
8
O
O
O
Et3N, 75 °C
9d
92% yield
9e
95% yield
9f
MeO2C
O
MeO2C
O
N
N
MeO2C
O
78% yield
NO2
Scheme 6 RCM with Grubbs second-generation catalyst
N
8a
57% yielda
8b
8c
60% yield
hol 12 could be prepared using BEMP as a catalyst in 80%
yield.16 The silyl-protected 3-hydroxy tetrahydropyran 13
was prepared using a hydroboration–oxidation sequence
followed by protection with TESOTf to deliver a 1.7:1 mix-
ture of diastereomers in 38% yield over two steps.
58% yielda
MeO2C
MeO2C
O
Cl
O
8d
64% yielda
8e
73% yield
N
N
O
Scheme 5 Pd-catalyzed O-vinylation. a Average of two runs.
NH
O
12
RCM with Grubbs second-generation catalyst delivered
the dihydropyrans in excellent yields, with no dimerization
or other byproducts being detected (Scheme 6). It is worth
noting that enol ethers are generally poor substrates in
cross-metathesis reactions with ruthenium–alkylidene cat-
alysts.15 However, the intramolecular RCM is highly favor-
able likely due to initial insertion into the terminal olefin
followed by ring closure. To explore the possibility of a
Thorpe–Ingold effect in the substrates below, the des-ester
substrate was prepared and subjected to the RCM condi-
tions. The product 9f was generated in 78% yield with no
appreciable formation of byproducts, indicating that the
quaternary center likely does not have a strong effect on the
RCM reaction.
OH
N
N
N
(a)
(d)
Et3SiO
N
N
(b)
(c)
NH
9b
CO2Me
N
O
13
O
11
N
H
N
10
O
Scheme 7 Elaboration of the dihydropyran. Reagents and conditions:
(a) BEMP, ethanolamine, MeCN, 40 °C (80%); (b) 1) N2H4–H2O, MeOH,
70 °C, 2) MeCN, 150 °C, MW (66%, 2 steps); (c) 1) 9-BBN, THF, then
MeOH, pH 8 buffer, H2O2, 2) TESOTf, 2,6-lutidine (38%, 2 steps); (d)
NaOH, THF (62%).
To further demonstrate the utility of the approach to ac-
cess 3,4-dihydropyrans, the pyrimidine 9a was further
elaborated into compounds of synthetic interest (Scheme
7). The methyl ester could be hydrolyzed and decarboxylat-
ed using 1 M NaOH in THF at 0 °C to deliver the des-ester 10
in 62% yield. The ester could also be transformed into a
1,2,4-triazole 11 by first treatment with hydrazine-hydrate
followed by addition of acetonitrile under microwave con-
ditions. Following a procedure by Caldwell, the amido alco-
In summary, we have developed a novel strategy to ac-
cess 3,3′-disubstituted 3,4-dihydro-2-pyrans using robust
chemistry that is tolerant of N-heterocycles.17 In this se-
quence, a readily accessed aryl allyl ester is subjected to an
aldol reaction with paraformaldehyde. The resultant prima-
ry alcohol is O-vinylated under palladium-catalyzed condi-
tions, and subjected to a high yielding RCM with Grubbs
second-generation catalyst. Further elaboration of the
products has allowed for highly substituted dihydropyrans
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
A.-M. Dechert-Schmitt et al.
Letter
Synlett
and tetrahydropyrans to be accessed. Moreover, our ap-
proach allows access to 3,3′-disubstituted 3,4-dihydropy-
rans which are not commonly accessible through the stan-
dard methods to access other dihydropyrans.
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Acknowledgment
Andy Tsai, Matt Dowling, and Kevin Hesp are gratefully acknowledged
for their help in preparing this manuscript.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588615.
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(17) Example Experimental Procedure for the Preparation of 9c
Methyl 2-(Hydroxymethyl)-2-phenylpent-4-enoate (7c)
An oven-dried vial equipped with a stir bar was charged with
methyl 2-phenylpent-4-enoate (5c, 700 mg, 3.68 mmol) and
paraformaldehyde (365 mg, 4.05 mmol). The vial was purged
with nitrogen for 15 min, then DMSO (7.36 mL, 0.05 M) was
added followed by NaOMe (219 mg, 4.05 mmol) at 25 °C. The
reaction was heated to 75 °C for 16 h. The reaction was then
poured into HCl solution (1 M, 20 mL), extracted with EtOAc (3
× 15 mL). The combined organic extracts were concentrated
under reduced pressure and purified via column chromatogra-
phy (0–70% EtOAc–heptane) to provide the product (422.4 mg,
52%). The reaction was run a second time and a yield of 61% was
obtained.
Alternatively, similar yields could be obtained using LiHMDS as
a base. An oven-dried round-bottom flask equipped with a stir
bar was charged with methyl 2-phenylpent-4-enoate (5c, 700
mg, 3.68 mmol). The flask was purged with nitrogen and to this
was added THF (0.5 M, 7.36 mL). The reaction was cooled to –78
°C, and LiHMDS (1 M in THF, 4.05 mmol, 4.05 mL) was added
dropwise over 15 min. The reaction was aged for 15 min, then
paraformaldehyde was added (365 mg, 4.05 mmol), and the
reaction was warmed to 25 °C for 16 h. The reaction mixture
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

E
A.-M. Dechert-Schmitt et al.
Letter
Synlett
was then poured into HCl (1 M, 15 mL), extracted with EtOAc (3
× 15 mL), dried over MgSO4, and concentrated. The crude mate-
rial was purified via column chromatography (0–60% EtOAc–
heptane) to provide the product as a clear oil (407 mg, 50%). 1H
NMR (400 MHz, CDCl3): δ = 2.16 (br s, 1 H). 2.91–2.89 (dd, J = 7.2
Hz, 1 Hz, 1 H), 3.75 (s, 3 H) 4.10–4.01 (q, J = 11.4 Hz, 2 H), 5.21–
5.10 (m, 2 H), 5.82–5.71 (m, 1 H), 7.40–7.28 (m, 5 H). 13C NMR
(101 MHz, CDCl3): δ = 28.47, 52.19, 56.00, 66.37, 118.82, 126.70,
127.37, 128.64, 133.58, 139.64, 175.20. ESI-HRMS: m/z calcd for
H), 5.11–5.06 (m, 2 H), 5.59–5.52 (m, 1 H), 6.47–6.43 (dd, J =
14.4, 6.7 Hz, 1 H), 7.29–7.24 (m, 3 H), 7.36–7.34 (m, 2 H). 13C
NMR (101 MHz, CDCl3): δ = 37.81, 52.24, 54.05, 69.03, 86.64,
119.21, 126.32, 127.29, 128.55, 133.04, 139.55, 151.62, 173.93.
ESI-HRMS: m/z calcd for C15H18O3 [M + Na]: 269.12; found:
269.11.
Methyl 3-Phenyl-3,4-dihydro-2H-pyran-3-carboxylate (9c)
To a vial equipped with a stir bar was added methyl 2-phenyl-2-
[(vinyloxy)methyl]pent-4-enoate (8c, 139 mg, 0.56 mmol) in
benzene (8.06 mL, 0.07 M). The reaction mixture was sparged
with nitrogen for 15 min at which point Grubbs II catalyst (24
mg, 0.028 mmol) was added. The vial was sealed, and the reac-
tion was heated to 70 °C for 16 h. The reaction mixture was con-
centrated under reduced pressure and purified via column
chromatography (0–50% EtOAc–heptane) to provide the
C13H16O3 [M + H]: 243.10; found: 243.09.
Methyl 2-Phenyl-2-[(vinyloxy)methyl]pent-4-enoate (8c)
To a vial equipped with a stir bar was added Pd(TFA)2 (3.15 mg,
0.00949 mmol, 1 mol%) and 4,7-diphenyl-1,10-phenanthroline
(3.15 mg, 1 mol%). Butyl vinyl ether (1 mL) was added, and the
reaction mixture was aged 15 min. Methyl 2-(hydroxymethyl)-
2-phenylpent-4-enoate (7c, 209 mg, 0.949 mmol) was added in
butyl vinyl ether (1.5 mL) followed by Et3N (13.2 μL, 10 mol%) at
25 °C. The reaction was heated to 75 °C for 48 h and then con-
centrated under reduced pressure. The crude reaction mixture
was purified via MPLC (0–15% EtOAc–heptane) to provide the
product (139 mg, 60%) as a clear oil. 1H NMR (400 MHz, CDCl3):
δ = 2.93–2.92 (d, J = 7.6 Hz, 2 H), 3.69 (s, 3 H), 4.01–4.00 (dd, J =
7.0, 1.8 Hz, 1 H), 4.13–4.11 (d, J = 9.4 Hz, 1 H), 4.26–4.24 (m, 2
1
product as a clear oil (88 mg, 71%). H NMR (400 MHz, CDCl3):
δ = 2.66–2.38 (m, 1 H), 2.87–2.81 (m, 1 H), 3.61 (s, 3 H), 4.10–
4.08 (d, J = 10.5 Hz, 1 H), 4.55–4.52 (dd, J = 10.7, 2.1 Hz, 1 H),
4.78–4.74 (ddd, J = 6.0, 4.5, 3.1 Hz, 1 H), 6.31–6.29 (dt, J = 6.1,
1.8 Hz, 1 H), 7.29–7.17 (m, 5 H). 13C NMR (101 MHz, CDCl3): δ =
29.37, 46.64, 52.54, 69.82, 99.36, 125.92, 127.61, 128.79,
139.58, 143.75, 173.58. ESI-HRMS: m/z calcd for C13H14O3 [M +
Na]: 241.08; found: 241.08.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E