Claisen self-condensation/decarboxylation as the key steps in the synthesis of C2-symmetrical 1,7-dioxaspiro[5.5]undecanes

Article abstract of DOI:10.1016/j.tetlet.2005.07.073

A convenient method for the synthesis of functionalised 1,7-dioxaspiro[5.5]undecanes using acid-catalysed spiroketalisations of substituted dihydroxyketones is described. The dihydroxyketones were readily prepared from appropriately substituted hydroxy es

Full text of DOI:10.1016/j.tetlet.2005.07.073

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6195–6198
Claisen self-condensation/decarboxylation as the key steps in
the synthesis of C2-symmetrical 1,7-dioxaspiro[5.5]undecanes
Bas Lastdrager, Mattie S. M. Timmer, Gijsbert A. van der Marel and
Herman S. Overkleeft*
Leiden Institute of Chemistry, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands
Received 25 April 2005; revised 4 July 2005; accepted 15 July 2005
Abstract—A convenient method for the synthesis of functionalised 1,7-dioxaspiro[5.5]undecanes using acid-catalysed spiroketalisa-
tions of substituted dihydroxyketones is described. The dihydroxyketones were readily prepared from appropriately substituted
hydroxy esters via Claisen self-condensation followed by decarboxylation.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Spiroketals are found as structural entities in many bio-
logically active compounds isolated from a variety of
natural sources, including insects, microbes, fungi,
plants and marine organisms.1 The vast majority of
the spiroketal frameworks found in natural products
are composed of spiro[5.5], spiro[4.5] and spiro[4.4] ring
systems (see Fig. 1, for representative examples). The
cytotoxic polyether okadaic acid (1) was isolated in
1981 from two marine sponges.2 It acts as an inhibitor
of protein phosphatases3 and is associated with diar-
rhetic shellfish poisoning.4 The first total synthesis of
okadaic acid, containing two 1,7-dioxaspiro[5.5]un-
decane ring systems and one 1,6-dioxaspiro[4.5]decane
fragment, was accomplished in 1986 by Isobe et al.5
The first spiroketal identified from insects was chalcogran
(2-ethyl-1,6-dioxaspiro[4.4]nonane, 2). It was isolated as
a mixture of isomers from the bark beetle Pityogenes
chalcographus and found to be the principle component
of the aggregation pheromone.6 One of the most wide-
spread spiroketal compounds found in nature is 2,8-di-
methyl-1,7-dioxaspiro[5.5]undecane (3a,b), present in
several species of fruit flies, bees, wasps, ants and bee-
tles.7 Several reports have appeared in the literature
describing the synthesis of 2,8-dihydroxymethyl-1,7-
dioxaspiro[5.5]undecanes (4a,b), versatile intermediates
for the construction of 6,6-spiroketals as prevalent
structural elements in many natural products, and also
as the starting point for the development of natural
product derived compound libraries.8 For example, spiro-
ketal 4b has been evaluated for its biological activities
such as the inhibition of microtubule assembly and
induction of apoptosis in human breast cancer cells.9
OH
O
H
H
H
O
O
HO
O
O
O
OH
H
H
The vast majority of synthetic efforts in the preparation
of spiroketal entities are focussed on the general ring
systems depicted in Figure 1. Strategies towards spiro-
ketal synthesis are based on two general approaches. The
most common route is the intramolecular acid-catalysed
ketalisation of dihydroxyketones or equivalents thereof.
The second approach makes use of a preformed ring,
followed by the addition of a carbon chain containing
the necessary oxygen function to effect cyclisation. The
main focus in all the strategies concerns the installation
of the spiro centre from a ketone. Several represen-
tative examples to obtain the requisite carbonyl source,
destined to be the spiro carbon, involve the use of
O
O
H
H
OH
OH
1
R
R
R
R
O O
O O
O
O
2
3a R = H
4a R = OH
3b R = H
4b R = OH
Figure 1.
*
Corresponding author. Tel.: +31 71 5274342; fax: +31 71 5274307;
e-mail: h.s.overkleeft@chem.leidenuniv.nl
0040-4039/$ - see front matter ꢀ 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.073

6196
B. Lastdrager et al. / Tetrahedron Letters 46 (2005) 6195–6198
nucleophilic additions to lactones,10 1,3-dithianes,11
dimethylhydrazones,12 nitroalkanes,13 aldol condensa-
tion products14 and hetero Diels–Alder reactions.15 Cla-
isen self-condensation of appropriately functionalised
hydroxy esters, followed by decarboxylation and spiro-
ketal formation, presents an efficient alternative for the
preparation of C2-symmetrical spiroketals, including
4a. Rather surprisingly, this strategy has not been fully
exploited to date.16
agency of lithium chloride and water in dimethyl sulfo-
xide18 to give C2-symmetrical ketone 10 in 94% yield.
Unmasking of the diol functionalities by treatment with
acid followed by intramolecular cyclisation led to the
formation of spiroketal 4a as a single isomer in quanti-
tative yield.19
Next, the use of 1,2:5,6-di-O-isopropylidene-D-mannitol
(11) was investigated in the synthesis of hydroxy substi-
tuted spiroketals 16 (Scheme 2). Periodate assisted diol
cleavage of 11, immediately followed by Horner Wads-
worth Emmons olefination, gave a,b-unsaturated ester
12 in 96% yield over two steps.20 At this stage, by anal-
ogy with the conditions described in Scheme 1, satura-
tion of the double bond in 12 was achieved through
palladium-catalysed hydrogenation leading to the for-
mation of ester 13 (94%). Claisen self-condensation of
ester 13 produced b-ketoester 14 in 58% yield. Decar-
boxylation of 14 with the LiCl/H2O/DMSO system
furnished ketone 15 in a yield of 92%. Acid mediated
tandem deprotection/cyclisation resulted in the forma-
Here, we report the synthesis of a set of chiral C2-
symmetrical 1,7-dioxaspiro[5.5]undecane ring systems.
Key to our strategy is the realisation that suitable
dihydroxyketone precursors amenable to acid-catalysed
spiroketalisation are readily available via Claisen
self-condensation of chiral, protected hydroxy esters,
followed by decarboxylation.
As a first example, the synthesis of spiroketal 4a com-
mences with reduction of the carboxylate functions of
(S)-malic acid (5) with borane–methyl sulfide complex
followed by protection of the vicinal diol as the isoprop-
ylidene acetal, providing protected (S)-butanetriol
derivative 6 in 83% over two steps (Scheme 1).17 The
requisite ester function was installed by a sequential
Swern oxidation/Wittig olefination procedure. Treat-
ment of 6 with oxalyl chloride, dimethyl sulfoxide and
diisopropylethylamine in dichloromethane followed by
chain elongation of the crude aldehyde using triphenyl-
phosphoranylidene acetate in dichloromethane, resulted
in the formation of E-alkene 7 in 81% yield. Hydrogena-
tion of 7 over palladium on carbon afforded saturated
ester 8 in an 88% yield. Claisen self-condensation of 8
was effected by slow addition of excess lithium hexa-
methyldisilazane (LHMDS) and tetramethylethylenedi-
amine (TMEDA) over a period of 2 h at 0 ꢁC,
providing b-ketoester 9 in an 84% yield.16c Decarboxyl-
ation of methyl ester 9 proceeded smoothly under the
tion of
a thermodynamic mixture of spiroketals
(16a–c) in an overall yield of 76% (prolonged exposure
to TFA did not result in a shift towards one of the
individual spiroketals).
It was reasoned that replacement of the secondary
hydroxyl groups in 15 with an amine functionality, as in
21, would lead to 6,6-spiroketal 22 as the single product.
In a two step procedure the carboxylic acid moiety in
glutamic acid derivative 17 was selectively reduced in
the presence of the methyl ester (Scheme 3).21 Treatment
of 17 with N-methylmorpholine (NMM) and ethyl chlo-
roformate yielded the corresponding mixed anhydride
O
OH
O
i
O
O
O
OEt
O
OH
11
O
OH
O
O
O
O
O
i
ii
HO
12
13
OH
O
O
S
OMe
OH
O
6
7
ii
5
iii
O
R
O
O
O
O
O
O
iii
O
O
OEt
HO
O
O
iv
O
O
O
O
O
O
OMe
OH
8
14 R = CO2Et
15 R = H
MeO
9
iv
v
v
HO
OH
OH
vi
O O
S
S
O
O
O
S
O O
O
O
O
O
O
S
S
HO
OH
OH
10
4a
16a
16b
16c
Scheme 1. Reagents and conditions: (i) (a) BH3ÆMe2S, THF, 0 ꢁC to rt,
15h; (b) acetone, p-TsOH, 17 h, rt, 83% (2 steps); (ii) (a) (COCl)2,
DMSO, DiPEA, DCM, ꢀ78 ꢁC, 2 h; (b) Ph3P@CHCO2Me (1.4 equiv),
DCM, 0 ꢁC to rt, 15h, 81% (2 steps); (iii) H 2, 10% Pd–C (cat.), EtOH,
24 h, rt, 88%; (iv) LHMDS (1.0 M in hexanes, 2.5equiv), TMEDA
(5.0 equiv), THF, 0 ꢁC, 2 h, 84%; (v) LiCl (3.8 equiv), DMSO, H2O,
reflux, 10 min, 94%; (vi) HOAc/H2O (3:2), rt, 90 min, quant.
Scheme 2. Reagents and conditions: (i) (a) NaIO4 (1.2 equiv), 5% aq
NaHCO3, rt, 1 h; (b) (EtO)2POCH2CO2Et, 6 M aq K2CO3, rt, 17 h,
96% (2 steps); (ii) H2, 10% Pd–C (cat.), EtOH, 45min, 94%; (iii)
LHMDS (2.0 equiv), TMEDA (4.0 equiv), THF, 0 ꢁC, 2.5h, 58%; (iv)
LiCl (3.8 equiv), DMSO, H2O, reflux, 5min, 92%; (v) HOAc/H 2O
(3:2), rt, 90 min, 76%.

B. Lastdrager et al. / Tetrahedron Letters 46 (2005) 6195–6198
6197
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HNZ
HNZ
i
HO
OMe
HO
OMe
O
O
O
17
18
ii
NZ
R
ZN
NZ
iii
O
O
O
OMe
6. Francke, W.; Heemann, V.; Gerken, B.; Renwick, J. A. A.;
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O
´
Vite, J. P. Naturwissenschaften 1977, 64, 590–591.
19
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21 R = H
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iv
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v
O O
ZHN
NHZ
22
Scheme 3. Reagents and conditions: (i) (a) NMM, ClCO2Et, THF,
ꢀ10 ꢁC, 10 min; (b) NaBH4 (3.0 equiv), 0 ꢁC, 30 min, 83% (2 steps); (ii)
dimethoxypropane, acetone, p-TsOH, rt, 17 h, 94%; (iii) LHMDS
(1.0 M in hexanes, 2.5equiv), TMEDA (5.0 equiv), THF, 0 ꢁC, 3 h
72%; (iv) KOH (2.5equiv), MeOH/H 2O (1:1), reflux, 1 h, 79%; (v)
HOAc/H2O (1:1), reflux, 3 h, 90%.
which was subsequently reduced with sodium borohy-
dride furnishing alcohol 18 in 83% yield. Installation
of the isopropylidene group gave oxazolidine 19 (94%),
of which Claisen self-condensation under the conditions
previously described afforded b-ketoester 20 in a yield of
72%. Saponification of 20 at elevated temperature gave
the corresponding b-ketoacid which immediately under-
went decarboxylation yielding ketone 21 in 79%. Acidic
removal of the isopropylidene protecting groups and
concomitant cyclisation provided amine protected spiro-
ketal 22 in a yield of 90%.22
14. Barun, O.; Sommer, S.; Waldmann, H. Angew. Chem., Int.
Ed. 2004, 43, 3195–3199.
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described in the literature: (a) Baker, R.; Herbert, R.;
Howse, P. E.; Jones, O. T. J. Chem. Soc., Chem. Commun.
1980, 52–53; (b) Bo¨hrer, G.; Knorr, R.; Bo¨hrer, P. Chem.
Ber. 1990, 123, 2161–2166; (c) Austad, B. C.; Hart, A. C.;
Burke, S. D. Tetrahedron 2002, 58, 2011–2026.
In conclusion, we have presented a new route for the
stereoselective synthesis of functionalised 1,7-dioxa-
spiro[5.5]undecane ring systems. These C2-symmetrical
spiroketals were efficiently obtained via acid-catalysed
cyclisation of dihydroxyketones which are readily avail-
able from the Claisen self-condensation of suitably
substituted hydroxy esters. The scope of our strategy
in the preparation of unsymmetrical spiroketals and
their implementation as chiral scaffolds is currently
under investigation.
´
17. Hanessian, S.; Ugolini, A.; Dube, D.; Glamyan, A. Can. J.
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18. Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.;
Jahngen, E. G. E., Jr.; Lovey, A. J.; Stephens, W. P. J.
Org. Chem. 1978, 43, 138–147.
Acknowledgement
19. All analytical data of compound 4a are in full agreement
with those reported in the literature (see Refs. 8b,f).
This work was financially supported by the Council for
Chemical Sciences of the Netherlands Organisation for
Scientific Research (NWO-CW).
20
½aꢁD +59.0 (c 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): d
3.75(m, 2H, H-2, H-7), 3.60 (dd, 2H, J = 3.4 Hz,
J = 11.4 Hz, 2 · CHCH2OH), 3.51 (dd, 2H, J = 6.9 Hz,
J = 11.4 Hz, 2 · CHCH2OH), 2.54 (s, 2H, 2 · OH), 1.99–
1.82 (qt, 2H, J = 4.2 Hz, J = 13.2 Hz, H-4a, H-10a), 1.67–
1.58 (m, 4H, H-4b, H-5a, H-10b, H-11a), 1.51 (m, 2H, H-
3a, H-9a), 1.41 (m, 2H, H-5b, H-11b), 1.28 (dq, 2H,
J = 3.8 Hz, J = 12.8 Hz, H-3b, H-9b). 13C NMR
(75MHz, CDCl 3): d 96.0 (C-6), 72.0 (C-2, C-8), 66.1
(2 · CH2OH), 35.1 (C-5, C-11), 26.4 (C-3, C-9), 18.2 (C-4,
References and notes
1. (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617–
1661; (b) Fletcher, M. T.; Kitching, W. Chem. Rev. 1995,
95, 789–828; (c) Mead, K. T.; Brewer, B. N. Curr. Org.
Chem. 2003, 7, 227–256.

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B. Lastdrager et al. / Tetrahedron Letters 46 (2005) 6195–6198
C-10). IR (thin film): 3377, 2937, 1225, 1082, 1045, 1014,
982 cmꢀ1 HRMS (ESI) calcd for [C11H20O4+H]+:
217.1434. Found: 217.1437.
J = 4.6 Hz, J = 9.8 Hz, H-2a, H-8a), 3.44 (m, 2H, H-3,
.
H-9), 3.18 (m, 2H, H-2b, H-8b), 1.64 (m, 6H, H-4a, H-4b,
H-5a, H-10a, H-10b, H-11a), 1.50 (dd, 2H, J = 4.6 Hz,
J = 13.0 Hz, H-5b, H-11b). 13C NMR (100 MHz, DMSO-
d6): d 155.5 (C@OCBz), 137.0 (CqCBz), 128.3, 127.8
(CHarom), 93.2 (C-6), 65.3 (CH2CBz), 62.1 (C-2, C-8), 46.3
(C-3, C-9), 33.7 (C-5, C-11), 24.7 (C-4, C-10). IR: 3300,
20. Marshall, J. A.; Trometer, J. D.; Cleary, D. G. Tetra-
hedron 1989, 45, 391–402.
21. Kokotos, G. Synthesis 1990, 299–301.
22. Analytical data of compound 22: amorphous white solid.
20
1
½aꢁD +12.0 (c 0.1, CHCl3). H NMR (400 MHz, DMSO-
d6, 333 K): d 7.40–7.27 (m, 10H, CHarom), 7.05(2H,
2 · NH), 5.01 (m, 4H, 2 · CH2Bn), 3.51 (dd, 2H,
2953, 1684, 1545, 1439, 1312, 1292, 1084, 1024, 964 cmꢀ1
.
HRMS (ESI) calcd for [C25H30N2O6+H]+: 455.2177.
Found: 455.2175.