Tetrahydrofurans from substituted hex-5-yne-1,4-diols

Article abstract of DOI:10.1055/s-0030-1258109

It was discovered that substituted hex-5-yne-1,4-diols like 16, 28, and 30 undergo a domino sequence of Meyer-Schuster rearrangement followed by Michael addition forming 2,5-disubstituted tetrahydrofurans in presence of PtCl ₂. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258109

LETTER
1789
Tetrahydrofurans from Substituted Hex-5-yne-1,4-diols
T
etrahydrofurans
a
from Subs
r
tituted H
o
e
x-5-yne-1,4
l
-diols in Schwehm, Max Wohland, Martin E. Maier*
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax +49(7071)295135; E-mail: martin.e.maier@uni-tuebingen.de
Received 16 April 2010
R1
Abstract: It was discovered that substituted hex-5-yne-1,4-diols
like 16, 28, and 30 undergo a domino sequence of Meyer–Schuster
rearrangement followed by Michael addition forming 2,5-disubsti-
tuted tetrahydrofurans in presence of PtCl2.
OH
OH
[metal]+
?
O
R1
R2
R2
O
Key words: alkynes, domino reaction, Michael addition, organo-
metallic reagents, rearrangement
OH
2
1
OH
OH
The carbon–carbon triple bond represents an extremely
versatile functional group in organic synthesis. In particu-
lar it can engage in a number of unique transformations.
For example, metallacyclopentenes and metallacyclopen-
tadienes are key intermediates in classical transformations
involving alkynes. But alkynes can also be considered de-
hydrated ketones. The well-known hydration of alkynes is
typically performed in presence of Hg(II) salts and strong
acids.1 In recent years the chemistry of alkynes has been
extended by employing other soft electrophilic metals,
like Au(I) or Pt(II) salts for promoting nucleophilic at-
tack.2 Thus, with internal hydroxyl functions, enol ethers
and related compounds could be obtained from alkynols.3
Furthermore, such metal-promoted additions of internal
oxygen-based nucleophiles have been exploited for some
unique domino reactions.4 Some groups already reported
on the synthesis of spiroacetals5 and bridged ketals6 from
alkynediols. Spiroactals are frequently found in
polyketide-based natural products.7 They provide a
unique shape and curvature for a molecule. In this regard
they can also be considered as a natural scaffold.8 With a
view to the synthesis of the spiroacetal fragment of spi-
rangien A, we conceived the cyclization of substrates con-
H
CO2H
O
H
OH
MeO
O
MeO
OH
spirangien A (3)
OH
5
3
OH
O
Au(I)
9
1
O
HO
non-4-yne-1,3,9-triol (4)
5
Scheme 1 Planned metal-catalyzed cyclization of non-5-yne-1,4,9-
triols to spiroacetals. Structure of spirangien A (3) and example for a
Au(I)-catalyzed spiroacetal formation
could be extended to nitrile 10 via mesylate 9 followed by
substitution with cyanide (78%, 2 steps). A substitution of
the alcohol under Mitsunobu conditions15 (DEAD, ace-
tone cyanohydrin toluene) gave nitrile 10 in 67% yield.
Treatment of nitrile 10 with DIBAL-H (1.4 equiv) in tol-
uene furnished the key aldehyde 11. Part of this aldehyde
was converted to alkyne 13 employing dimethyl 1-diazo-
2-oxopropylphosphonate16 (12) as C-1 building block. In
the next step alkyne 13 was added under Carreira condi-
tions to aldehyde 11 using zinc triflate and (–)-N-methyl-
ephedrine (14) as additives.17 This way a 60% yield of
alkynol 15 could be realized. Cleavage of the two silicon
protecting groups gave rise to undec-6-in-2,5,10-triol
(16). The fact that 16 only shows one set of signals in the
13C NMR spectrum indicates the high selectivity in the
Carreira reaction. Alkynetriol 16, dissolved in toluene,
was then subjected to some metal catalysts. While
Ph3PAgCl and Ph3PAuCl left the substrate unchanged,
PtCl2 (40 mol%) in toluene induced the formation of a
new product. Inspection of the 13C NMR indicated the
lack of an acetal C but the presence of a keto function
(209.3 ppm). Acetylation (Ac2O, pyridine) showed that
one of the OH groups was free. These data, the DEPT and
COSY spectrum led to the conclusion that tetrahydrofuran
taining
a non-5-yne-1,4,9-triol subunit (1 → 2,
Scheme 1). The spirangiens were described in 2005 by
Höfle et al.9 Spirangien A (3) displays potent antifungal
and cytotoxic properties. In addition to the complex high-
ly unsaturated side chain there is a hydroxyl group next to
the spiro acetal function. The known routes to the spirang-
ien spiroacetal rely on the classical acetalization of a dihy-
droxyketone precursor.10,11
A
related substrate
4
containing also a propargylic alcohol substructure was re-
cently reported to cyclize to spiroacetal 5.5c
A corresponding model substrate 16 could be easily as-
sembled from methyl (3R)-hydroxybutanoate12
6
(Scheme 2). Via silylation of the alcohol13 and reduction
of the ester function alcohol 8 was obtained.14 The alcohol
SYNLETT 2010, No. 12, pp 1789–1792
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258109; Art ID: G09810ST
© Georg Thieme Verlag Stuttgart · New York

1790
C. Schwehm et al.
LETTER
17 was formed from alkynetriol 16. Alcohol 17 and ace-
tate 18 showed the presence of diastereomers (62:38).
OH
OH
10
6
5
2
OR
TBSO
OR
NaCN, DMSO
DIBAL-H, CH2Cl2
OH
CO2Me
undec-6-in-2,5,10-triol (16)
–80 to –20 °C (96%)
50 °C (80%)
6 R = H
8 R = H
MsCl, Et3N
TBSCl
imidazole, DMAP
DMF (94%)
CH2Cl2, –50 °C
(97%)
redox isomerization
Meyer–Schuster
rearrangement
7 R = TBS
9 R = Ms
O
O
(MeO)2P
H
O
OH
OH
OH
OH
12
TBSO
CN
H
TBSO
11
DIBAL-H, toluene
–80 to –5 °C (78%)
N2
K2CO3, MeOH
(84%)
10
O
O
19
19
OH
TBSO
Zn(OTf)2, 14
OTBS
TBSO
toluene, Et3N
aldehyde 11 (60%)
O
O
13
15
17
OH
Scheme 3 Redox isomerization as well as Meyer–Schuster rearran-
gement might explain the formation of furanon 17
OH
PtCl2 (40 mol%)
toluene (69%)
TBAF, THF
(76%)
OH
In order to probe the effect of an inner alkyne versus a ter-
minal one, propargyl alcohol 32 was prepared from alde-
hyde 26a by addition of lithium acetylide (THF, –80 °C)
followed by cleavage of the silyl ether.
16
OH
OR
OH
O
O
NMe2
(–)-N-methylephedrine (14)
For the Bn series we also prepared the isomer where the
triple bond is between the two hydroxyl groups, namely
propargyl alcohol 35. This substrate could be obtained
from 26a via Bestmann–Ohira alkyne formation (82%)
yielding alkyne 33. The corresponding lithium acetylide
(LDA, THF, –80 °C) was added to paraformaldehyde to
provide ultimately propargyl alcohol 35.
17 R = H
Ac2O
pyridine
(96%)
18 R = Ac
Scheme 2 Conversion of butanoate 6 to undec-6-in-2,5,10-triol (16)
and its PtCl2-catalyzed formation of tetrahydrofuran 17
The formation of tetrahydrofuran 17 can be explained by
an intramolecular oxa-Michael addition to enone 19
(Scheme 3). Due to partial symmetry within substrate 16
it was however not possible to distinguish between a met-
al-catalyzed redox isomerization18 or a Meyer–Schuster
rearrangement19 of the central alkynol to the enone.
The five compounds (32, 35, 28a,b, and 30) were then
subjected to a substoichiometric amount of PtCl2 in tolu-
ene at room temperature (Scheme 5). In case of 32 the
classical hydration product, hemiacetal 36 was formed as
a mixture of diastereomers. From propargylic alcohol 35
the tetrahydrofuran would result if a redox isomerization
would be induced by PtCl2. However, with this substrate
a complex mixture of products was formed that was not
further analyzed. In contrast, the hexyne diol 28a fur-
nished a reasonable yield (48%) of 2,5-disubstituted furan
37a. This shows that PtCl2 had induced a Meyer–Schuster
rearrangement prior to the oxa-Michael addition. Better
results were obtained with the combination (Ph3P)AuCl/
AgBF4 in toluene. Under these conditions the tetrahydro-
furan 37a was formed in 74% yield.
Therefore some other substrates were prepared that would
allow to probe the isomerization mechanism. The general
sequence is shown in Scheme 4. Substituted acetalde-
hydes 20a,b were subjected to a one-pot proline-catalyzed
a-aminoxylation, Wittig–Horner reaction and cleavage of
the N–O bond leading to 4-hydroxy enoates 22a,b.20
A
final catalytic hydrogenation furnished the 4-hydroxy
esters 23a,b. For the examples studied, the ee values of
22a,b were very high. Via silylation of the hydroxyl func-
tion, ester reduction and Dess–Martin oxidation, alde-
hydes 26a,b could be secured.
In the same manner substrate 28b could be converted to
the corresponding tetrahydrofuran 37b. The diastereo-
meric ratio was in the range 1:1 (84% yield). The reaction
did also work with the phenyl-substituted substrate 30
producing tetrahydrofuran 38 (50% yield, dr = 1:1).
Using the two aldehydes 26a,b addition of propynyllithi-
um, generated by metalation of propenyl bromide,21 fol-
lowed be removal of the silyl protecting group led to
alkynediols 28 with an inner triple bond. Aldehyde 26a
was also reacted with (phenylethynyl)lithium leading to
propargylic alcohol 29 and after deprotection to 1,7-
diphenylhept-6-yne-2,5-diol (30).
Thus, we could show that metal cations like Pt(II) or Au(I)
are able to promote a formal Meyer–Schuster rearrange-
ment of propargylic alcohols. With a suitably positioned
hydroxyl function a subsequent oxa-Michael addition
Synlett 2010, No. 12, 1789–1792 © Thieme Stuttgart · New York

LETTER
Tetrahydrofurans from Substituted Hex-5-yne-1,4-diols
1791
OH
1. EtO)3P(O)CH2CO2Et,
LiCl, DBU, MeCN
O
O
OH
H
D-proline
OH
PtCl2, toluene
r.t., 18 h (30%)
R1
R1
O
Ph
Ph
H
H
Ph-N=O, DMSO
r.t., 2 h
2. Cu(OAc)2, NH4Cl,
MeOH, r.t.
Ph
20
21
O
OH
32
HN
Ph
36
mixture of diastereomers
R1
CO2Et
R1
CO2Et
OH
H2, Pd/C
DIBAL-H
PtCl2, toluene
r.t., 18 h
complex product mixture
CH2Cl2, –80 °C
THF, r.t.
OH
OR2
23 R2 = H
22
TBSCl
35
imidazole, DMAP
DMF
OH
24 R2 = TBS
OH
OTBS
OTBS
O
PtCl2, toluene (48%)
Dess–Martin
CH2Cl2, r.t.
H
O
R1
R1
O
r.t., 18 h
or (Ph3P)AuCl/AgBF4
(74%)
26
Ph
OH
25
OH
28a
37a
Ph
OH
OTBS
Br
O
PtCl2, toluene
r.t., 18 h (84%)
, n-BuLi
TBAF, THF
26
O
R1
THF, –80 °C
OH
28b
37b
27
OH
R1
Ph
OH
Ph
OH
O
(Ph3P)AuCl, AgBF4
r.t., 16 h (50%)
20a–28a Bn
R1
O
20b–28b
Me2CH
28
Ph
OH
OH
30
38
Ph
OTBS
Ph
Scheme 5 Reactions of alkynediols 32 and 35 with PtCl2. Cycliza-
tion of the alkynediols 28a, 28b, and 30 to the tetrahydrofurans 37a,
37b, and 38, respectively, via metal-induced Meyer–Schuster rearran-
gement and oxa-Michael addition
TBAF, THF
Ph
Li
Ph
26a
THF, –40 °C (97%)
(86%)
29
OH
OH
Ph
Ph
30
Acknowledgment
OH
OTBS
TES
Financial support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged.
Li
TES
TBAF, THF
(80%)
Ph
26a
THF, –80 °C (88%)
31
OH
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OH
H
Ph
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Synlett 2010, No. 12, 1789–1792 © Thieme Stuttgart · New York

1792
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LETTER
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Synlett 2010, No. 12, 1789–1792 © Thieme Stuttgart · New York

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