A convenient access to thermodynamically nonstabilised spiroketal isomers: The first synthesis of (Z)-7-methyl-1,6-dioxaspiro[4.5]decane

Article abstract of DOI:10.1016/j.tetlet.2005.09.085

Functionalised hydroxy α-alkynones were transformed to the corresponding spiroketals by a one-pot cascade consisting of palladium-catalysed hydrogenation of the triple bond, hydroxyl group deprotection and spirocyclisation under mild nonacidic conditions. The reaction does not rely upon thermodynamic control to set the configuration of the ketal stereocentre so that both the anomerically stabilised and nonstabilised isomers are similarly accessible.

Full text of DOI:10.1016/j.tetlet.2005.09.085

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7923–7926
A convenient access to thermodynamically nonstabilised
spiroketal isomers: the first synthesis of
(
Z)-7-methyl-1,6-dioxaspiro[4.5]decane
a
a
b
a
a,
*
ˇ
Jan Doubsk y´ , David Saman, Ji rˇ ´ı Zedn ´ı k, So nˇ a Va sˇ ´ı cˇ kov a´ and Bohum ´ı r Koutek
a
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic
b
Department of Physical and Macromolecular Chemistry, Charles University, 120 00 Prague 2, Czech Republic
Received 15 August 2005; revised 6 September 2005; accepted 15 September 2005
Available online 29 September 2005
Abstract—Functionalised hydroxy a-alkynones were transformed to the corresponding spiroketals by a one-pot cascade consisting
of palladium-catalysed hydrogenation of the triple bond, hydroxyl group deprotection and spirocyclisation under mild nonacidic
conditions. The reaction does not rely upon thermodynamic control to set the configuration of the ketal stereocentre so that both
the anomerically stabilised and nonstabilised isomers are similarly accessible.
ꢀ
2005 Elsevier Ltd. All rights reserved.
The spiroketal (sub)unit forms an important structural
motif of many biologically active natural products from
various sources, including plants, marine organisms,
ones. According to our strategy, in contrast to a partly
similar strategy described previously, the spiroketalisa-
6
tion occurs under mild, nonacidic conditions. This im-
plies that isomerisation at the spirocentre is not likely
to happen, thus making our protocol well suited to the
synthesis of isomeric mixtures with a unique ratio of less
stable/more stable diastereoisomers.
1
fungi and insects. A main strategy for its construction
has been the classical acid-catalysed intramolecular cyc-
lisation of the corresponding keto-diol precursors or
1
,2
their equivalents. Consequently, control of the stereo-
chemistry at the anomeric centre was, almost exclu-
sively, based on the relative thermodynamic stabilities
of the different isomers in the acid-catalysed spiroketal-
isation step. When all factors that control spirocyclisa-
tion, that is, a maximum anomeric effect and minimum
steric interactions are reinforcing, a thermodynamically
In this letter, we describe an adaptation of our previ-
4
ously described strategy and demonstrate its potential
as a method for the preparation of stereoisomeric 7-
methyl-1,6-dioxaspiro[4.5]decanes 1, 2,7-dimethyl-1,6-
dioxaspiro[4.5]decanes 2 and 2,8-dimethyl-1,7-dioxa-
spiro[5.5]undecanes 3. Our intention was to construct
these spiroketals in a simple fashion with particular
attention to the synthesis of the intrinsically less stable
diastereoisomers.
(
anomerically) favoured isomer forms as the major or
even exclusive product.
Although most of the biologically active spiroketals
have the thermodynamically stabilised configuration,
1
a,c,3
exceptions from this regularity have been described
Scheme 1 illustrates the synthesis of 7-methyl-1,6-dioxa-
spiro[4.5]decane 1. Treatment of (± )-4 with hydrogen in
the presence of 10% palladium on charcoal in EtOH or
EtOAc solutions resulted in a smooth and reproducible
one-pot formation of a 7:3–3:2 (by gas chromatography)
separable mixture of the major (E)-spiroketal (± )-1a to-
gether with the minor (Z)-isomer (± )-1b in about 75–
indicating a need for further nonstabilised spiroketal-
4
targeted synthetic efforts. Recently, we have developed
a new high yielding strategy towards the construction of
[
4.4], [4.5], [5.5] and [5.6] spiroketal structures starting
5
from easily available benzyl protected hydroxy a-alkyn-
78% yields (Table 1). Significantly, the two isomers were
Keywords: Spiroketals; a-Alkynones; Diastereoselective synthesis;
successfully separated and isolated by column chroma-
tography under carefully controlled conditions (silica
Nonstabilised isomers.
*
Corresponding author. Tel.: +420 220 183 201; fax: +420 220 183
82; e-mail: koutek@uochb.cas.cz
5
gel deactivated with 6% of water, 6:1 pentane/Et O)
2
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.085

7924
J. Doubsk y´ et al. / Tetrahedron Letters 46 (2005) 7923–7926
OBn
OBn
a
a
HO
HO
up to 80%
up to 78%
O
O
(
±)-4
5
(
S)-4
O
O
O
+
+
+
O
O
O
O
O
O
O
(
±)-2a
(±)-2b
(±)-2c
(
±)-1a
(±)-1b
(5R,7S)-1b
Scheme 2. Reagents and conditions: (a) H
2
(1 atm), 10% Pd/C, rt (for
(
5S,7S)-1a
further details see Table 1).
Scheme 1. Reagents and conditions: (a) H
2
(1 atm), 10% Pd/C, rt (for
further details see Table 1).
OBn
a
HO
up to 79%
Table 1. Synthesis of spiroketals
O
a
b
Entry
1
Alkynone
Conditions
Product
(± )-1a
± )-1b
(± )-1a
± )-1b
(5S,7S)-1a
5R,7S)-1b
(± )-2a
Yield (%)
6
c
(± )-4
EtOAc, 14 h
55 (76)
(
23
O
+
+
O
2
3
4
(± )-4
(S)-4
5
EtOH, 11 h
EtOH, 11 h
EtOAc, 32 h
45 (61)
30 (11)
O
O
O
O
(
(
±)-3a
(±)-3b
(±)-3c
(66)
(9)
(
2
Scheme 3. Reagents and conditions: (a) H (1 atm), 10% Pd/C, rt (for
further details see Table 1).
21
21
38
(
(
± )-2b
± )-2c
the presence of the two secondary methyl groups. Thus,
the reaction of (± )-5 afforded 2,7-dimethyl-1,6-dioxa-
spiro[4.5]decane 2 as a 1:1:2 mixture of (± )-2a, (± )-2b
and (± )-2c (according to NMR analysis (± )-2c is an
inseparable 1:1 mixture of two (7Z)-isomers), while
the reaction of (± )-6 led to the formation of 2,8-di-
methyl-1,7-dioxaspiro[5.5]undecane 3 as a mixture of
± )-3a, (± )-3b and (± )-3c in the ratio of 3:5:2. The
results are summarised in Table 1. While no characteris-
tic analytical data for the (7Z)-isomer(s) 2c could be
5
6
7
5
6
6
EtOH, 15 h
EtOAc, 24 h
EtOH, 32 h
(± )-2a
19 (27)
19 (25)
39 (21)
(
(
± )-2b
± )-2c
8
d
(± )-3a
23 (30)
38 (30)
d
(
(
± )-3b
± )-3c
15
(
(± )-3a
24 (27)
39 (31)
16 (13)
(
(
± )-3b
± )-3c
found in the literature, the corresponding data for
a
Starting from 1 mmol of alkynone.
GC yields. Numbers in parentheses refer to the isolated yields after
liquid chromatography.
After acidification of the reaction mixture and distillation. Starting
from 50.8 mmol of the alkynone.
After acidification of the reaction mixture and liquid chromato-
graphy.
9
(
Z,Z)-isomer 3c have been published previously and
b
agree with those obtained in this work.
c
The conformations of spiroketals 1 and 2 were deter-
mined on the basis of standard 1D and 2D NMR tech-
niques (Table 2). Although, due to rather complex
spectra of these mono- and disubstituted spiroketals,
we were not able to detect sufficiently clear diagnostic
NOESY cross-peaks to confirm the conformations
d
yielding 61% of (± )-1a and 11% of (± )-1b. Both isomers
were of sufficient purity to allow a full characterization
by IR and NMR measurements and mass spectrometry.
Analogous results were obtained when starting with the
optically active (S)-4. As expected, the reaction afforded
a mixture of (5S,7S)-1a (ee 99%) and (5R,7S)-1b (de
a
Table 2. Selected NMR data of spiroketals 1 and 2
1a
1b
2a
2b
2c
d
d
H
C
(a-Hax
(C7)
)
4.02
65.89
3.50
69.01
4.17
65.46
4.22
65.15
3.47–3.55
8
8%, ee 99%) with isolated yields of 66% and 9%, respec-
68.67
69.19
10.2
2.7
tively. These reactions demonstrate, to the best of our
knowledge, the first synthesis of the very unstable con-
tra-thermodynamic (Z)-isomer 1b.
7
3
Jaa
11.3
2.3
9.9
2.8
11.2
2.3
11.4
2.3
3
J
ae
d
C
(C5)
104.98 105.95 105.24 104.99 105.29
05.76
1
The strategy was similarly successful in transforming the
alkynones 5 (Scheme 2) and 6 (Scheme 3) both of which
are mixtures of diastereoisomeric racemic pairs due to
a
Measured in C D , at 500 MHz (for 1H) and 125 MHz (for 13C),
6
6
chemical shifts are given in ppm and coupling constants in hertz.

J. Doubsk y´ et al. / Tetrahedron Letters 46 (2005) 7923–7926
7925
OH
R
4
3J
3J
HO
ae
ae
O
O
7
R
α
-Hax
α
-Hax
H+
O
β
-Heq
β
-Heq
- H O
2
O
O
Me
-Hax
Me
Hax
3Jaa
3J
aa
-
β
β
CH
3
H C
3
O
+
OH
O
OH
H
1a
R=H
a,b R=Me
1b R=H
2c R=Me
A
B
2
Figure 1. Structure of spiroketals 1 and 2.
CH
3
depicted in Figure 1, the observed coupling constants
for H7 (Table 2) unambiguously indicate that this pro-
ton is predominantly axial (7-Me equatorial) in all iso-
H
H C HO
O
3
H C
O
=
3
HO
>
HO
H
HO
O
H
CH3
O
mers, thus supporting the presented structures. The
3
lower values of J for the (7Z)-isomers 1b and 2c
A
1
A
2
B
1
B
2
aa
can be explained by a small distortion of the chair geom-
etry. Furthermore, there are several characteristic trends
1
13
in the H and C NMR spectra (Table 2) that mirror
3
c,9–11
1a
>
1b
1a:1b = 1:1
earlier findings.
The chemical shifts of the axially-
oriented H7 are one of the most distinctive features.
When the H7 is in a 1,3-diaxial relationship with the
C–O bond, the resonance is shifted downfield for the
Scheme 4. Proposed mechanism of the kinetically controlled forma-
tion of spiroketal 1.
(
7E)-isomers compared to the (7Z)-isomers. Also
the differences in chemical shifts of C7 caused by the
well known c-effect are significant and argue for the sug-
gested structures. Somewhat controversially, although
mentioned in the literature,3c,10 trends in the chemical
shifts of the spirocarbon C5, where (E)-isomers of spiro-
ketals usually show resonances shifted to a slightly lower
frequency (upfield), are consistent with our observa-
tions, especially for 1a and 1b.
Accordingly, the formation of, for example, [4.5] spiro-
ketal isomers 1 from 4 is assumed to occur via intramole-
cular dehydrative ketalisation of the pre-formed
12
dihydroxyketone 7, whose protonation promotes the
formation of two oxocarbenium ion intermediates A
and B (Scheme 4). Although the oxocarbenium ion A
can actually exist in two conformations (both conforma-
tions leading to energetically equivalent protonated spi-
roketals) that (showed in Scheme 4) with the methyl
group in an equatorial position should be, due to steric
reasons, explicitly favoured. The formation of oxocarben-
ium ions A and B would then be followed by a stereo-
electronically controlled antiperiplanar attack by the
hydroxyl group either from the lower or upper side
Importantly, the (E)/(Z) isomer ratio was found to
remain unchanged under our mild conditions, while
the mixture of 1a and 1b was very rapidly (<5 min)
equilibrated upon treatment with hydrochloric acid to
give the spiroketal 1a as sole product. To a certain
extent, isomer 1b also undergoes conversion to 1a dur-
ing the isolation work-up; this explains the discrepancy
between the initial and isolated diastereoisomer ratio
affording the respective chair-like (A ) and twist-boat-
1
like (A ) transition states. Assuming an early transition
2
1b
1
state,
the A ! A conversion benefits from steric
1
(
Table 1). The same 1b ! 1a conversion was observed
interactions and would be slightly favoured over the
during storage both neat and as solutions in nonpolar
solvents. On the other hand, 1b is relatively stable in
polar solvents (EtOH or EtOAc) where it may be stored
without significant changes for at least several weeks.
The anomerically nonstabilised isomers 2c and 3c dis-
played nearly the same chemical behaviour.
A ! A conversion. On the other hand, in the case of
2
B, both pathways leading to transition states B and
1
B are stereoelectronically nearly equivalent. This rea-
2
soning would explain the observed excess (ꢀ20% de
even at the beginning of the reaction) of isomer 1a over
1b (see Table 1). We suppose that the formation of spi-
roketal 2 proceeds similarly furnishing the 2a:2b:2c iso-
mer ratio of about 1:1:2. This ratio may indicate that the
energetic differences in possible pathways are less after
introduction of the second methyl group.
It can be inferred from the above results that the spiro-
ketalisation under prescribed conditions proceeds in a
way similar to that described by Deslongchamps for
the formation of [5.5] spiroketals by kinetically con-
trolled cyclisation of dihydroxyketones or hydroxy-
In conclusion, we have developed a new scalable kineti-
cally controlled approach towards simple spiroketals,
which could be applied to the synthesis of different spi-
roketal isomers, including those lacking anomeric stabil-
isation. The approach is capable of providing the
nonstabilised isomers in relatively large amounts thus
making biological tests of some less-stable spiroketal
insect pheromone components (e.g., 1b) possible for
1
1
enolethers. Additional observations, namely that no
unsaturated spiroketals were detected during the whole
course of these transformations and that the ratio of
isomers 3a:3b:3c = 3:5:2 formed under our conditions
(
Table 1) was essentially identical with that formed by
1
1b
kinetically controlled cyclisation, lend further support
to the kinetically controlled process.

7926
J. Doubsk y´ et al. / Tetrahedron Letters 46 (2005) 7923–7926
the first time (cf. Refs. 1c,3b). Moreover, we believe the
approach holds considerable potential for further syn-
theses of more elaborated spiroketal targets.
H9, 1H), 1.33–1.38 (m, H4, 1H), 1.58–1.61 (m, H3, 1H),
.63–1.67 (m, H10eq, 1H), 1.69–1.71 (m, H9, 1H), 1.91
1
(
ddq, H3, J = 6.1, 8.3 and 11.8 Hz, 1H), 1.94 (dt, H10ax,
J = 4.1 and 12.5 Hz, 1H), 2.07 (ddd, H4, J = 3.9, 8.2 and
1
2.5 Hz, 1H), 3.50 (ddq, H7ax, J = 2.8, 6.2 and 9.9 Hz,
1
H), 3.86 (dt, H2, J = 6.1 and 7.9 Hz, 1H), 4.14 (dt, H2,
Acknowledgements
13
J = 5.8 and 8.1 Hz, 1H). C NMR (125 MHz, C D ):
6
6
d = 20.59 (C9), 21.32 (Me), 23.44 (C3), 31.61 (C8), 32.20
C4), 33.31 (C10), 66.29 (C2), 69.01 (C7), 105.95 (C5).
GC–IR: 2980, 2948, 2889, 1456, 1376, 1214, 1073,
Financial support from the research projects Z4-055-905
and MSM 113100001 is gratefully acknowledged. We
also thank Ms. Jana Ma sˇ kov a´ for performing chro-
matographic analyses.
(
ꢁ
1
20
1010 cm . Compound (5R,7S)-1b: ½aꢂD +25.4 (c 0.156,
Et O).
. Selected analytical data. Compound (± )-2c: H NMR
500 MHz, C D ): d = 1.14–1.26 (m, H8, 2H), 1.25 (d,
2
1
8
(
6
6
Z,Z-7-Me, J = 6.1 Hz, 3H), 1.28 (d, E,Z-7-Me,
J = 6.2 Hz, 3H), 1.30 (d, E-2-Me, J = 6.2 Hz, 3H), 1.30–
Supplementary data
1
2
1
.35 (m, E-H3, 1H), 1.32–1.36 (m, H10, 1H), 1.32–1.37 (m,
· H8 + 2 · H9, 4H),1.45 (d, Z-2-Me, J = 6.1 Hz, 3H),
.55–1.60 (m, H10, 1H), 1.62–1.66 (m, H4, 2H), 1.65–1.76
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.2005.
0
9.085. A general procedure and analytical data for
(
m, H9, 2H), 1.70–1.82 (m, Z-H3, 1H), 1.89–1.96 (m, H4,
2H), 1.99–2.05 (m, H3, 2H), 2.03–2.06 (m, H10, 1H), 2.20
ddd, H10, J = 1.9, 7.1 and 12.4 Hz, 1H), 3.47–3.55 (m,
H7ax, J = 2.7, 6.2 and 10.2 Hz, 2H), 4.20 (m, Z-H2, 1H),
spiroketals 1, 2 and 3 are included.
(
1
3
References and notes
6 6
4.52 (m, E-H2, 1H). C NMR (125 MHz, C D ): d =
2
0.39 (Z,Z-7-Me), 20.56 (C9), 20.69 (C9), 21.36 (E-2-Me),
1
. For reviews of spiroketals, see: (a) Perron, F.; Albizati, K.
F. Chem. Rev. 1989, 89, 1617–1661; (b) Jacobs, M. F.;
Kitching, W. Curr. Org. Chem. 1998, 2, 395–436; (c)
Francke, W.; Kitching, W. Curr. Org. Chem. 2001, 5, 233–
21.70 (E,Z-7-Me), 22.31 (Z-2-Me), 31.26 (C3), 31.29 (C3),
31.66 (C8), 31.79 (C8), 32.61 (C10), 32.84 (C10), 33.91
(C4), 33.93 (C4), 68.67 (C7), 69.19 (C7), 73.22 (E-C2),
75.24 (Z-C2), 105.29 (C5), 105.76 (C5). GC–IR: 2979,
ꢁ1
251; (d) Mead, K. T.; Brewer, B. N. Curr. Org. Chem.
2946, 2878, 1459, 1379, 1220, 1076, 1012 cm .
2
003, 7, 227–256.
9. Kitching, W.; Lewis, J. A.; Perkins, M. V.; Drew, R.;
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Org. Chem. 1989, 54, 3893–3902.
2
3
. Ghosh, S. K.; Hsung, R. P.; Liu, J. J. Am. Chem. Soc.
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. (a) Chen, J.; Fletcher, M. T.; Kitching, W. Tetrahedron:
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11. (a) Deslongchamps, P.; Rowan, D. D.; Pothier, N.; Sauv e´ ,
T.; Saunders, J. K. Can. J. Chem. 1981, 59, 1105–1121; (b)
Pothier, N.; Goldstein, S.; Deslongchamps, P. Helv. Chim.
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1
3
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ˇ
4
5
6
7
. Doubsk y´ , J.; Streinz, L.; Saman, D.; Zedn ´ı k, J.; Koutek,
B. Org. Lett. 2004, 6, 4909–4911.
+
12. The origin of acid catalysis (H or Lewis acid) essential for
. Doubsk y´ , J.; Streinz, L.; Le sˇ etick y´ , L.; Koutek, B. Synlett
the acetal formation still remains unclear. Some plausible
explanations are: trace amounts of acetic acid present as
impurity in the solvents, acidic nature of the glassware
used or small traces of HCl present in the palladium
catalyst (cf. Ref. 13).
2003, 937–942.
. Jacobson, R.; Taylor, R. J.; Williams, H. J.; Smith, L. R.
J. Org. Chem. 1982, 47, 3140–3142.
1
. Selected analytical data. Compound (± )-1b: H NMR
(
500 MHz, C
6
D
6
): d = 1.15–1.20 (m, H8, 1H), 1.29–1.34
13. Brimble, M. A.; Park, J. H.; Taylor, C. M. Tetrahedron
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(
m, H8, 1H), 1.30 (d, Me, J = 6.2 Hz, 3H), 1.32–1.36 (m,