Platinum-catalyzed synthesis of β-keto tetrahydropyrans and cyclic dienolethers

Article abstract of DOI:10.1002/asia.201100113

A platinum upgrade: Zeise's dimer [{Cl₂Pt(CH₂CH ₂)}₂] catalyzes the activation of linear propargylic alcohols and esters. Depending on the presence of a suitably placed alcohol group proximal or distal to the pr

Full text of DOI:10.1002/asia.201100113

COMMUNICATION
DOI: 10.1002/asia.201100113
Platinum-Catalyzed Synthesis of b-Keto Tetrahydropyrans and Cyclic
Dienolethers
Qiren Liang, Mingxing Qian, Mina Razzak, and Jef K. De Brabander*[a]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
Nature has presented us with a seemingly innumerable
range of oxygen-containing cyclic frameworks, challenging
organic chemists to devise efficient, mild, and increasingly
general procedures for their preparation.[1] Many interesting
molecular architectures have been identified as recurring
challenges; our continued efforts in the areas of metal-cata-
lyzed hydroalkoxylation of alkynes,[2] propargylic substitu-
tions, and cycloisomerization of propargylic esters[3] have led
us to address some of these challenges. Previously, we dem-
onstrated that w-hydroxy propargylic acetates of type 1
could undergo a gold-catalyzed cycloisomerization to form
the corresponding enolacetates 2, as well as undergoing plat-
inum-catalyzed propargylic substitution to ethers of type 3
(Scheme 1).[3] The former transformation provided entry to
synthetically useful b-keto tetrahydropyran building blocks,
such as 4, after methanolysis of the enolacetates 2, thereby
establishing a platform from which to synthesize more-com-
plex polyketide natural products bearing the 1,3-dioxygena-
tion pattern. Recently, Jung and Floreancig reported a route
to b-keto tetrahydropyrans via a gold-catalyzed cyclization
of w-hydroxy propargylic ethers.[4,5] Whilst this method is
very useful, we postulated that we could access these b-keto
tetrahydropyrans directly from propargylic alcohols (1!4;
R=H), thereby eliminating the need to activate the propar-
gylic alcohol via etherification or esterification. Further-
more, we also wanted to investigate the possibility of engag-
ing the propargylic unit in a cyclization with a pendant nu-
cleophile embedded within a tether located distal from the
propargylic center (5). We postulated that this operation
would lead to cyclic dienolethers 6, an important structural
motif used as synthetic intermediates and present in a
number of natural products, such as the anti-inflammatory
falconensins[6] and the heart-blocking agent anhydrocuna-
niol.[7] Herein, we report the successful execution of these
objectives.
During an initial screen to discover catalysts that would
perform the direct cycloisomerization of propargylic alco-
hols, we found Zeiseꢀs dimer, [{Cl2PtACHTUNGRTNEUNG(CH2CH2)}2], to be su-
perior to other systems trialed, including gold(I) systems. As
shown in Table 1, the platinum(II)-catalyzed cycloisomeriza-
tion of propargylic alcohols into b-keto tetrahydropyrans
occurs under mild conditions (CH2Cl2, RT, open to air), with
a broad substrate scope for internal alkynes. Terminal al-
kynes failed to give the desired b-keto tetrahydropyrans
(Table 1, entry 1), as did substrates with sterically encumber-
ing substituents on the alkyne (e.g., TMS, tBu; Table 1, en-
tries 3 and 4), resulting in recovery of starting material and
some decomposition. However, aromatic (Table 1, entry 2),
cycloalkyl (Table 1, entry 5), and alkyl substituents (Table 1,
entries 6–8) were converted in very good yields (greater
than 80%). The scope of this method was easily extended to
prepare other classes of heterocycles. The inclusion of addi-
tional oxygen atoms into the tether (Table 1, entries 9–12)
provided access to 1,4-dioxanes, whilst nitrogen inclusion
Scheme 1. Proposed synthesis of b-keto tetrahydropyrans and cyclic dien-
olethers.
[a] Dr. Q. Liang, Dr. M. Qian, Dr. M. Razzak, Prof. J. K. De Brabander
Department of Biochemistry
and Simmons Comprehensive Cancer Center
University of Texas Southwestern Medical Center at Dallas
5323 Harry Hines Boulevard, Dallas, Texas 75390-9038 (USA)
Fax : (+1)214-648-0320
ꢀ
E-mail: jef.debrabander@utsouthwestern.edu
(N Boc, Table 1, entries 13–15) generated morpholines. The
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Chem. Asian J. 2011, 6, 1958 – 1960

Table 1. Cycloisomerization of diols 7 to b-keto heterocycles 8.[a,b]
philic oxygen atom protected as a silylether, we were able to
isolate the expected Meyers–Schuster rearrangement prod-
uct 11a (15%) in addition to the cycloisomerization product
8 f (45%; Scheme 3). In addition, subjecting 11a to the stan-
dard conditions yielded b-keto tetrahydropyran 8 f in 40%
yield (55% recovered 11a), presumably via the unprotected
hydroxyenone 11b. The attempted independent formation
of hydroxyenone 11b via deprotection of silylether 11a
(Bu4NF, THF, RT) resulted in direct formation of b-keto tet-
rahydropyran 8 f. Similar attempts to prepare hydroxyenone
11b independently from the corresponding phosphine ylide
and 5-hydroxypentanal resulted in the formation of 8 f fol-
lowing flash chromatography on silica gel of the crude mate-
rial. These results suggest that the cycloisomerization of
propargylic alcohols 7a–o may occur via a Meyer–Schuster
rearrangement, followed by an exceedingly facile intramo-
lecular oxa-Michael addition.
Entry
7
R1
R2
X
t [h] Yield [%][c] cis/trans
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7 f
H
Ph
TMS
tBu
H
H
H
H
H
H
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
4
2
4
4
2
0.5
0.5
1
36
6
6
6
12
48
36
0[e]
–
–
–
–
86
0[d]
0[d]
c-Hex
95
–
CH
3A
7h PhCH2CH2
3A
93
88
82[e]
64
88
50
53
80
67
60
–
>95:5
–
7g CH CHTUNGTRENNUNG(CH2)5 Et
H
H
H
9
7i
Ph
3A(CH2)5
3A
CH3A(CH2)5 Ph
7m PhCH2CH2
7n Ph
–
–
5:1
8:1
–
10
11
12
13
14
15
7j
CH
N
O
O
O
7k CH
7l
C
C
ꢀ
H
H
N Boc
ꢀ
N Boc
–
7:1
ꢀ
7o PhCH2CH2 Et N Boc
Next, we wanted to explore a new mode of cyclo-reorgan-
ization of propargylic esters. Reasoning that a metal-activat-
ed propargylic ester unit could well be attacked by a nucleo-
phile embedded within the tether distal from the propargylic
center, we envisioned such a strategy as a potential route to
[a] Reaction conditions: 0.15m substrate in CH2Cl2, RT. [b] For entries 9–
15, CSA (1 equiv) was added. [c] Yield of isolated product. [d] The mass
balance recovery was predominantly (>60%) starting material. [e] The
propargylic-substitution product was also isolated (8% yield). Boc=tert-
butoxycarbonyl; CSA=camphorsulfonic acid.
scope of this transformation, in-
corporating various substitution
patterns in the tether with dif-
ferent heteroatoms, is vast. In
addition, the high cis selectivity
when R2 ¼H heightens its syn-
thetic utility (Table 1, entries 7,
Scheme 3. A plausible Meyers–Schuster rearrangement/oxa-Michael addition sequence. brsm=based on recov-
ered starting material.
11, 12, 15).
In one instance, we isolated
small quantities (ca. 8% yield)
of a propargylic substitution product in addition to the b-
keto oxacycle (Table 1, entry 7). To explore a potential sce-
nario where the ketones could result from the platinum-cat-
alyzed hydration of intermediate tetrahydropyranyl alkynes
by the presence of adventitious water,[8] we subjected an in-
dependently prepared alkyne 9[3] to the standard conditions
with added water (5 equiv). As shown in Scheme 2, ketone
the preparation of cyclic conjugated dienolethers (Scheme 1,
5!6). There are few methods for the preparation of these
potentially important synthons in the literature, including
for example, the palladium-catalyzed Hiyama-type coupling
of silanols,[10] molybdenum-[11] and palladium-catalyzed[12] al-
kylations, Diels–Alder cycloadditions,[13] and Knoevenagel
condensations of sugar-derived unsaturated aldehydes.[14]
Whilst these methods remain valid, a cyclo-reorganization
approach would deliver these materials from readily accessi-
ble starting materials under operationally friendly condi-
tions. As shown in Table 2, we were pleased that this hy-
pothesis was confirmed by treatment of propargylic acetates
12a–d with a catalytic amount of Zeiseꢀs dimer (5 mol%,
THF, RT, 30 min). This approach thus constitutes a syntheti-
cally useful and atom-economical entry to dienolethers 13a–
d, which were obtained in high yields (72–81%) and high E-
selectivity (>96:4). There remains scope for the introduc-
tion of handles to allow further manipulation, and accord-
ingly increasing the viability of this methodology in, for ex-
ample, medicinal chemistry programs.
Scheme 2. Platinum(II)-catalyzed hydration of alkyne 9.
8 f was isolated in 92% yield, thus implying the viability of
such a proposal.
Another plausible scenario for the formation of the b-
keto tetrahydropyran products would involve an initial
Meyers–Schuster rearrangement, a known transformation in
transition metal catalysis,[9] followed by an intramolecular
oxa-Michael addition of the intermediate hydroxyenones.
Interestingly, using a control substrate 10, with the nucleo-
Finally, we sought to combine the transformations de-
scribed here into a cascade process. Thus, treatment of prop-
argylic acetate 14, bearing both distal and proximal hydroxyl
Chem. Asian J. 2011, 6, 1958 – 1960
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www.chemasianj.org
1959

J. K. De Brabander et al.
COMMUNICATION
Table 2. Propargylic substitution to dienol ethers 12.[a]
t, J=5.2 Hz), 3.60 (2H, t, J=6.4 Hz), 2.15–2.05 (4H, m), 1.80–1.40 (6H,
m), 0.88 (9H, s), 0.03 ppm (6H, s); 13C NMR (75 MHz, CDCl3): dC =
150.9, 128.5, 125.9, 100.6, 66.0, 63.1, 32.4, 32.2, 26.0, 25.5, 22.5, 20.8, 18.4,
ꢀ5.3 ppm; IR (thin film): n˜max =2938, 2253, 1678, 1465, 1381, 1085 cmꢀ1
;
ESI-MS (m/z) calcd. for C17H32O2Si [M+H]+ 297.2, found 297.2.
Entry 11
R1
R2
R3
Yield 12 E/Z[c]
6-((Tetrahydro-2H-pyran-2-yl)methyl)-3,4-dihydro-2H-pyran 15
[%][b]
To
a
solution of 1,11-dihydroxyundec-6-yn-5-yl acetate 14 (73 mg,
(CH2CH2)}2]
1
2
3
4
11a HO
11b HO
11c EtCH(OH)
N
E
H
H
Et
78
72
81
74
>97:3
96:4
>98:2
>96:4
0.30 mmol) in THF (10 mL) at RT was added [{Cl2PtAHCTUNTGRENNUNG
ACHTUNGTRENNUNG
(8.8 mg, 15.0 mmol, 5 mol%). The solution was stirred for 1 h before
being quenched by the addition Et3N (0.2 mL). The solution was concen-
trated in vacuo and the crude material was purified by flash chromatog-
raphy on silica gel (10:1, hexane/EtOAc) as the mobile phase to yield the
title compound 15 (42 mg, 77%). 1H NMR (400 MHz, CDCl3): dH =4.55
(1H, t, J=3.7 Hz), 4.10–3.90 (3H, m), 3.55–3.40 (2H, m), 2.29 (1H, dd,
J=7.3, 6.7 Hz), 2.10–1.15 ppm (11H, m); 13C NMR (75 MHz, CDCl3):
dC =151.3, 97.3, 75.3, 68.5, 66.1, 41.8, 31.6, 26.0, 23.5, 22.3, 20.2 ppm; IR
(thin film): n˜max =3055, 2939, 2306, 1711, 1551, 1422, 1156, 998 cmꢀ1; ESI-
MS (m/z) calcd. for C11H18O2 [M+H]+ 183.1, found 183.1.
(CH2)3
A
11d o-HOC6H4A(CH2)2
N
ACTHGNURTNE(NUNG CH2)5CH3 o-C6H4
[a] Reaction conditions: 0.02m substrate in THF, RT, 30 min. [b] Yield of
isolated product. [c] Ratio determined by 1H NMR spectroscopy. TBS=
tert-butyldimethylsilyl.
Scheme 4. Cascade cyclization to afford methylene-skipped bis-heterocy-
cles.
Acknowledgements
groups, with 0.5 mol% of [{Cl2PtACHTNUTRGEN(UNG CH2CH2)}2] delivered the
Financial support was provided by the Robert A. Welch Foundation
(Grant I-1422), Reata Pharmaceuticals, and the NIH (Grant CA90349).
methylene-skipped bis-heterocycle 15 in 77% yield
(Scheme 4); this bis-heterocycle is a structural motif found
in bryostatin[15] and exiguolide.[16]
In conclusion, we have demonstrated that appropriately
substituted propargylic alcohols and acetates can serve as
viable linear starting materials for a platinum(II)-catalyzed
cyclo-reorganization approach to b-keto oxacycles and cyclic
dienolethers in good yields. Mechanistic studies and expan-
sion of the substrate scope of both these new transforma-
tions are currently underway in our laboratory.
Keywords: cycloisomerization · dienolethers · platinum ·
tetrahydropyrans · transition metal catalysis
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Experimental Section
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[5] Jung and Floreancig demonstrated that homopropargylic ethers can
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However, this process remains limited to terminal alkynes.
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Typical Procedure for the Cycloisomerization to b-Keto Tetrahydropyrans
To a solution of 7-phenylhept-6-yne-1,5-diol 7b (62 mg, 0.3 mmol) in
CH2Cl2 (2 mL) at RT was added [{Cl2PtACHTNUTRGEN(UNG CH2CH2)}2] (0.9 mg, 1.5 mmol,
0.5 mol%). The resulting solution was stirred for 2 h before being
quenched by the addition of Et3N (0.2 mL). The solution was concentrat-
ed in vacuo and the resulting crude material was purified by flash chro-
matography on silica gel (95:5, hexane/EtOAc) to afford 1-phenyl-2-(tet-
rahydro-2H-pyran-2-yl)ethanone 8b as a colorless oil (53 mg, 0.26 mmol,
86%). 1H NMR (400 MHz, CDCl3): dH =8.00–7.40 (5H, m), 4.00–3.90
(2H, m), 3.55–3.40 (1H, m), 3.33 (1H, dd, J=15.9, 6.7 Hz), 2.96 (1H, dd,
J=15.9, 5.5 Hz), 1.85–1.20 ppm (6H, m); 13C NMR (75 MHz, CDCl3):
dC =198.3, 137.2, 133.0, 128.5, 128.2, 74.3, 68.6, 45.3, 32.0, 25.8, 23.3 ppm;
IR (thin film): n˜max =3155, 2940, 2253, 1684, 1449, 1084, 971 cmꢀ1; ESI-
MS (m/z) calcd. for C13H16O2 [M+Na]+ 227.1, found 227.0.
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Typical Procedure for the Propargylic Substitution to Cyclic Dienolethers
To a solution of 1-((tert-butyldimethylsilyl)oxy)-11-hydroxyundec-6-yn-5-
yl acetate 12a (107 mg, 0.3 mmol) in THF (15 mL) at RT was added
[{Cl2PtACHTUNGTRENNUNG(CH2CH2)}2] (8.8 mg, 15.0 mmol, 5.0 mol%). The resulting solution
was stirred for 30 min before being quenched by the addition of Et3N
(0.2 mL). The solution was concentrated in vacuo and the resulting crude
material was purified by flash chromatography on silica gel (95:5,
hexane/EtOAc) to afford (E)-tert-butyl((6-(3,4-dihydro-2H-pyran-6-
[13] S.-S. P. Chou, C.-Y. Tsai, J. Org. Chem. 1988, 53, 5305–5308.
[14] a) I. Rudloff, M. Michalik, A. Montero, K. Peseke, Synthesis 2001,
1686–1682; b) A. Bari, S. Milicevic, H. Feist, D. Michalik, M. Mi-
chalik, K. Peseke, Synthesis 2005, 2758–2764.
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[16] S. Ohta, M. M. Uy, M. Yanai, E. Ohta, T. Hirata, S. Ikegami, Tetra-
hedron Lett. 2006, 47, 1957–1960.
yl)hex-5-en-1-yl)oxy)dimethylsilane 13a as
a colorless oil (68 mg,
0.23 mmol, 78%). 1H NMR (400 MHz, CDCl3): dH =5.91 (1H, dt, J=
15.5, 8.1 Hz), 5.74 (1H, d, J=15.5 Hz), 4.68 (1H, t, J=4.0 Hz), 4.05 (2H,
Received: February 5, 2011
Published online: May 4, 2011
1960
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Chem. Asian J. 2011, 6, 1958 – 1960