Enantioselective synthesis of cis-3-oxy-2,2,6,6-tetrasubstituted tetrahydropyrans

Article abstract of DOI:10.1055/s-2006-933141

A synthesis of cis-3-oxy-2,2,6,6-tetrasubstituted tetrahydropyrans has been achieved in an easy and straightforward way. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-933141

LETTER
939
Enantioselective Synthesis of cis-3-Oxy-2,2,6,6-tetrasubstituted
Tetrahydropyrans
S
ynthesis of cis-3-
a
O
xy-2,2,6,
v
i
ute
d
T
e
d
trahydropyrans Díez,* Marta G. Núñez, R. F. Moro, W. Lumeras, Isidro S. Marcos, P. Basabe, Julio G. Urones
Departamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1–5, 37008 Salamanca, Spain
Fax +34(923)294574; E-mail: ddm@usal.es
Received 30 November 2005
Schreiber et al.8 described a mercury transetherification–
cyclisation leading to cis- and trans-fused cyclic pyrano-
pyrans. Suárez et al.9 described a rearrangement of
spiroacetals to give cis-fused 1,6-dioxadecalines and re-
cently Martin et al.10 described the synthesis of cis-2-
alkyl-3-oxy-tetrahydropyran units as building blocks for
new ionophores, starting from tri-O-acetyl-D-galactal.
The most frequently used reaction for obtaining these
systems is the Michael addition of an alcohol to a,b-unsat-
urated esters to give cis-2-alkyl-3-oxy-tetrahydropyrans
as described by Gung et al.11 and Martín et al.12 Other
methods for the synthesis of this kind of compound are the
cyclisation of vinylstannanes with trifluoromethane-
sulfonic acid13 or cyclisation of w-oxo-g-alkoxyallyl-
boronates, which cyclise to cis-disubstituted vinyl
tetrahydropyrans.14 Very recently a version of the Michael
addition has been reported using trans-hydroxy enones
to give cis-2,3-disubstituted tetrahydropyrans by Taylor
et al.15
Abstract: A synthesis of cis-3-oxy-2,2,6,6-tetrasubstituted tetrahy-
dropyrans has been achieved in an easy and straightforward way.
Key words: Sharpless epoxidation, nitriles, tetrahydropyrans,
cyclisation, iodine
Tetrahydropyrans are present in many biologically active
compounds,1 for example in (+)-decarestrictine L,2 an
inhibitor of cholesterol biosynthesis, in antimitotic mac-
rolides such as spongistatin,3 and in fused tetrahydropyran
ring systems from the backbone of brevetoxin B4 and
maitotoxin.5 In these structures the tetrahydropyran units
are generally trans-fused. The less usual cis-fused pyrano-
pyrans are present in natural products such as elatenyne
(1)6 and halichondrin B (2), which has received much at-
tention due to its extraordinary in vitro and in vivo anti-
tumour activity (Figure 1).7
H
H
H
Br
O
In an earlier study we were able to synthesise cis-2-alkyl-
3-oxy-tetrahydropyran 4 in a totally stereoselective way
from olefin 3 (Scheme 1).16 All attempts to extend the side
chain were unsuccessful, so, as we were interested in
enantioselectively obtaining cis-3-oxy-2,2,6,6-tetrasub-
stituted tetrahydropyrans that could be used as synthons
for new ionophores, it was decided to carry out the cycli-
sation in a slightly more complicated substrate and study
the stereoselectivity of the reaction.
O
Br
H
H
H
elatenyne (1)
Me
Me
O
H
H
H
H
H
O
O
O
O
H
H
O
H
O
O
O
H
O
HO
HO
O
H
O
O
O
The starting material for our study is the tosylate 5, previ-
ously obtained by us,16 whose absolute stereochemistry
was established in a Sharpless epoxidation17 step, so both
enantiomers are readily available (Scheme 2). Treatment
of 5 with NaCN in HMPA,18 followed by deprotection of
the tetrahydropyranyl group with p-TsOH in MeOH gave
the a,b-unsaturated nitrile 6 in high yield. After benzyla-
tion under the usual conditions, reduction of the nitrile
group to the alcohol was done with DIBAL-H19 in two
steps. The first reduction gives the aldehydes 8 and 9,
which were separated by column chromatography. The
stereochemistry of the double bond in 9 was established
by the NOE between the methyl and the olefinic hydrogen
shown in Scheme 2. Once separated, both aldehydes were
submitted separately to a further DIBAL-H reduction to
give diols 10 and 11 in 80% and 78% yield, respectively.
Me
O
Me
HO
halichondrin B (2)
Figure 1
OH
OH
I
a
99%
O
OH
3
4
Scheme 1 Reagents and conditions: a) I2, NaHCO3, MeCN, 0 °C.
With compounds 10 and 11 available in sufficient quanti-
ty, it was decided to study the iodine-mediated cyclisation
of these compounds.
SYNLETT 2006, No. 6, pp 0939–0941
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-933141; Art ID: D36005ST
© Georg Thieme Verlag Stuttgart · New York
0
4.
0
4.
2
0
0
6

940
D. Díez et al.
LETTER
OBn
CN
OBn
OH
OBn
CH2OH
9
O
a
a
b
6
2
OTs
CH2OH
94%
O
2'
O
77%
80%
1'
OH
THPO
OH
b
CN
I
12
16
5
7
6
95%
c
OBn
CHO
65%
OBn
OBn
H
O
+
17
CHO
c
41%
OH
OH
CHO
H
9
8
OBn
COOH
10
: 1
O
d
80%
d
78%
d
66%
O
O
O
19
OBn
18
OBn
H
Scheme 4 Reagents and conditions: a) HSnBu3, AIBN, C6H6,
reflux; b) (COCl)2, DMSO, Et3N, CH2Cl2, –60 °C; c) O2 (air, 24 h);
d) H2, Pd/C, EtOH, r.t.
CH2OH
OH
OH
CH2OH
10
11
Scheme 2 Reagents and conditions: a) NaCN, HMPA, r.t.; p-TsOH,
MeOH, r.t.; b) NaH, BnBr, TBAI, THF, r.t.; c) DIBAL-H, CH2Cl2,
–78 °C; d) DIBAL-H, CH2Cl2, –78 °C.
expected. The structure of alcohol 16 has been established
previously and, as the only difference between 16 and 20
is the stereochemistry of C-2, the structure for 20 is shown
in Scheme 5, and so the stereochemistry for all the tetra-
hydropyrans at C-2 is determined. The stereochemistry of
the iodide in C-1¢ for all the tetrahydropyrans was estab-
lished based on mechanistic grounds.
When compound 10 was submitted to treatment with
iodine under kinetic conditions,20 two tetrahydropyrans
(12 and 13) were obtained in a ratio of 93:7 in good
yield.21 When 11 was submitted to the same conditions
two different tetrahydropyrans (14 and 15) were obtained
with practically no stereoselectivity (ratio of products
9:10, Scheme 3).
OBn
a
a
12
14
CH2OH
94%
O
OBn
CH2OH
OBn
CH2OH
16
a
+
10
88%
O
O
OBn
CH2OH
I
I
a
a
12
13
13
15
60%
O
93
OBn
CH2OH
:
7
20
OBn
a
+
11
Scheme 5 Reagents and conditions: a) HSnBu3, AIBN, C6H6,
CH2OH
83%
O
O
reflux.
I
I
14
15
The stereochemistry of these compounds can be under-
stood by comparing the proposed transition states as
shown in Figure 2.
9
:
10
Scheme 3 Reagents and conditions: a) I2, NaHCO3, MeCN, 0 °C.
Considering the conformational preferences of C1-oxy-
genated acyclic chiral alkenes for the C–C eclipsed con-
formation as described by Gung et al.,25 and supposing an
equatorial disposition of the benzyloxy group in the tran-
sition state, transition state I is more favourable than II for
the cyclisation of the trans alcohol, but transition states
III and IV are much the same due to the interaction of the
-CH2OH with the benzyloxy group in III.
Determination of the stereochemistry of these compounds
was as follows. Compound 12 was reduced with HSnBu3
to give the alcohol 16. This compound was oxidised under
Swern conditions22 to give aldehyde 17 in 95% yield.
When compound 17 was left in a flask open to the air the
acid 18 was obtained in moderate yield, and, if acid 18
was deprotected with H2 on Pd/C, the reaction led to the
lactone 19 (Scheme 4).23 This compound shows a NOE
between the hydrogen of C-3 and Me on C-2. In this
manner the stereochemistry of C-2 was assured.
Thus, a new synthesis of cis-3-oxy-2,2,6,6-tetrasubstitut-
ed tetrahydropyrans, synthons for the synthesis of iono-
phores or other uses in chemistry, has been described. The
fact that the compounds can be obtained in satisfactory
overall yield in both enantiomeric forms adds more versa-
tility to the procedure.
Having established the stereochemistry of compound 12
at C-2, we proceeded to do the same with the other three
remaining tetrahydropyrans. Reduction with HSnBu324 of
the four tetrahydropyrans gave two diols (16 and 20) as
Synlett 2006, No. 6, 939–941 © Thieme Stuttgart · New York

LETTER
Synthesis of cis-3-Oxy-2,2,6,6-tetrasubstituted Tetrahydropyrans
Doubek, D. L.; Schmidt, J. M.; Cerny, R. L.; Hooper, J. N.
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I
BnO
I
OH
BnO
OH
CH2OH
CH2OH
I
II
OBn
CH2OH
OBn
CH2OH
O
O
I
I
12
13
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Martin, V. S. J. Org. Chem. 1997, 62, 4584.
CH2OH
I
BnO
OH
BnO
OH
I
HOH2C
IV
III
OBn
OBn
CH2OH
(13) Gevorgyan, V.; Kadota, I.; Yamamoto, Y. Tetrahedron Lett.
1993, 34, 1313.
CH2OH
O
O
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I
I
15
14
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2001, 1013.
Figure 2
Acknowledgment
(17) Katsuki, T.; Martín, V. S. Org. React. 1996, 48, 1.
(18) Wright, J. N.; Calder, M. R.; Akhtar, M. J. Chem. Soc.,
Financial support for this work came from the Spanish MEC
(CTQ2005-06813/BQU) and Junta de Castilla y León (Spain)
(SA045A05). The authors thank also Dr. A. M. Lithgow for the
NMR spectra and Dr. César Raposo for the mass spectra. M.G.N. is
grateful for a FPU doctoral fellowship of the Spanish MEC.
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(21) Spectroscopic Data for Compound 12.
[a]D20 +22.5 (c 1.0, CHCl3). IR (film): 3460 (br), 2970–2870,
1454, 1377, 1221, 1069, 974, 731, 696 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.46–7.30 (5 H, m, Ph), 4.85 (1 H, dd,
J = 3.4, 10.1 Hz, H-1¢), 4.58 (1 H, d, J = 10.8 Hz, OCH2Ph,
HA), 4.48 (1 H, d, J = 10.8 Hz, OCH2Ph, HB), 4.09 (1 H, m,
HA-2¢), 3.94 (1 H, m, HB-2¢), 3.43 (1 H, m, H-3), 2.05–1.85
(4 H, m, H-4, H-5), 1.51 (3 H, s, H-9), 1.26, 1.22 (3 H each,
s, H-7 and H-8) ppm. 13C NMR (100 MHz, CDCl3): d =
18.33 (C-4), 20.13 (C-9), 27.44 (C-7), 29.34 (C-5), 32.81 (C-
8), 39.12 (C-1¢), 66.70 (C-2¢), 71.15 (PhCH2), 74.04 (C-6),
75.98 (C-3), 127.47 (Phpara), 127.69 (Phortho), 128.25
(Phmeta), 138.45 (Phipso) ppm. HMRS (EI): m/z calcd for
C17H26O3I: 405.0927 [M + H]+; found: 405.0944.
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Synlett 2006, No. 6, 939–941 © Thieme Stuttgart · New York