A concise and efficient synthesis of spiroketals - Application to the synthesis of SPIKET-P and a spiroketal from bactrocera species

Article abstract of DOI:10.1002/ejoc.201201199

We report the synthesis of spiroketals by sequence of enol ether synthesis and cyclization. The enol ethers were prepared from lactones by a Julia olefination reaction, and the starting chiral lactone was prepared from an industrial intermediate. This route is a concise and efficient way to synthesize naturally occurring and biologically interesting spiroketals. We used this sequence for the preparation of SPIKET-P and a spiroketal from Bactrocera species. Copyright

Full text of DOI:10.1002/ejoc.201201199

FULL PAPER
DOI: 10.1002/ejoc.201201199
A Concise and Efficient Synthesis of Spiroketals – Application to the Synthesis
of SPIKET-P and a Spiroketal from Bactrocera Species
Loic Tomas,[a] Benjamin Bourdon,[a] Jean Claude Caille,[b] David Gueyrard,*[a] and
Peter G. Goekjian*[a]
Keywords: Synthetic methods / Cyclization / Olefination / Spiro compounds / Natural products / Lactones / Enol ethers
We report the synthesis of spiroketals by sequence of enol
ether synthesis and cyclization. The enol ethers were pre-
pared from lactones by a Julia olefination reaction, and the
starting chiral lactone was prepared from an industrial inter-
mediate. This route is a concise and efficient way to synthe-
size naturally occurring and biologically interesting spiroket-
als. We used this sequence for the preparation of SPIKET-P
and a spiroketal from Bactrocera species.
tended this methodology to non-carbohydrate lactones
in the synthesis of the spiroketal fragment of
bistramide A.[4b]
Introduction
Spiroketals are found in many natural products of bio-
logical interest such as marine macrolides, ionophores, and
polyether antibiotics[1] (Figure 1). The synthesis of spiroket-
als has thus attracted considerable attention over the past
decades.[2]
Figure 2. Synthetic route to spiroketals (Btz = benzothiazolyl).
In this paper, we describe how we have used this syn-
thetic strategy for the preparation of two additional spi-
roketals of interest, and so tested the scope of the reaction
with minimally substituted lactones. SPIKET-P (Figure 3)
was rationally designed as a pharmacophore of spongista-
tin,[5] and has shown promising cytotoxicity against human
breast cancer.[6] The second target is a component of the
cephalic secretions of a cleptoparasitic bee.[7]
Figure 1. Structures of spiroketal-containing natural products.
We recently developed a short and convenient route to
sugar-derived spiroketals using modified Julia reagents.[3]
Starting from lactones, enol ethers were synthesized by
treatment with a benzothiazolyl sulfone containing a pro-
tected alcohol. At this stage, the use of an acid-labile pro-
tecting group allowed us to prepare the spiroketals in a
single step in acidic media (Figure 2).[4] We recently ex-
[a] Université de Lyon, Laboratoire Chimie Organique 2, ICBMS -
UMR 5246, Université Claude Bernard Lyon 1,
43 Bd. du 11 Novembre 1918, 69622 Villeurbanne Cedex,
France
Figure 3. Structures of the two synthetic targets.
E-mail: gueyrard@univ-lyon1.fr
goekjian@univ-lyon1.fr
Homepage: http://www.icbms.fr/user/main.asp?num=150
[b] PPG Sipsy, Z. I. La Croix Cadeau,
Results and Discussion
BP 79, 41012 Avrillé, France
Optically active 2-hydroxymethyl lactones such as 4a and
4b are key intermediates for the synthesis of a large number
Supporting information for this article is available on the
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Eur. J. Org. Chem. 2013, 915–920
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915

D. Gueyrard, P. G. Goekjian et al.
FULL PAPER
of natural products,[8] and we felt that it would be of inter-
est to investigate their preparation from [(S)-3,6-dihydro-
2H-pyran-2-yl]methanol (1), which was first synthesized as
an intermediate for the synthesis of the protein kinase C
inhibitor LY 333531.[9] Compound 1 was prepared by PPG
on a large scale using a sequence of hetero-Diels–Alder re-
action and enzymatic resolution.
Compound 1 was protected with a benzyl ether or a
TBDPS (tert-butyldiphenylsilyl) ether protecting group
(Scheme 1). Oxidation with PDC (pyridinium dichromate)
in refluxing 1,2-dichloroethane (DCE) led to a separable
mixture of the desired lactone (i.e., 4) and enone 3.[10] Fi-
nally, unsaturated lactones 4a and 4b were hydrogenated
with Pd on charcoal to give lactones 5a and 5b, respectively,
in quantitative yields.
Scheme 2. Synthesis of SPIKET-P (HMDS = hexamethyldisilazide;
DBU = 1,8-diazabicycloundec-7-ene; p-TSA = p-toluenesulfonic
acid; TBAF = tetrabutylammonium fluoride).
steps and 22% overall yield from dicyclohexylidene-d-
mannitol. A wide range of natural and unnatural spiroket-
als can, in principle, be produced for diversity-orientated
synthesis from a common Julia reagent following this ap-
proach.
Scheme 1. Synthesis of lactones 5a and 5b.
SPIKET-P was prepared as shown in Scheme 2. The spi-
roketal was synthesized from lactone 5a or 5b and sulfone
6[4b] in two steps using our methodology.[3,4] The enol ether
was formed in the presence of LiHMDS and boron trifluo-
ride–diethyl ether at low temperature, and was cyclized di-
rectly in acidic media (p-toluenesulfonic acid in dichloro-
methane) to give the thermodynamic spiroketals 8a and 8b.
Not unexpectedly, the overall yield was higher with the less
labile benzyl group. These compounds were deprotected to
give SPIKET-P in six steps and overall yields of 18% (with
TBDPS protection) and 22% (with benzyl protection) from
(S)-(3,6-dihydro-2H-pyran-2-yl)methanol (1).
We then turned our attention to valerolactone, which was
expected to be more challenging, due to the absence of
either electronic or Thorpe–Ingold effects in the hemiketal
anion intermediate.
Unexpectedly, treatment of a mixture of valerolactone,
sulfone, and boron trifluoride–diethyl ether with LiHMDS
at –78 °C gave the enol ether directly, and treatment with
DBU was not required in this case (Scheme 3). The Julia
olefination–cyclization sequence thus provided the thermo-
dynamic spiroketal 10 in 60% yield. The homologation re-
action was performed by oxidation of the primary alcohol,
and reaction of the resulting aldehyde with the Ohira–Best-
Scheme 3. Synthesis of the spiroketal from Bactrocera species.
Conclusions
We have developed an original, general, and stereoselec-
mann reagent to deliver the terminal alkyne 12, which was tive route to spiroketals from lactones via an intermediate
hydrogenated to give the natural compound (i.e., 13). The enol ether. We report the preparation of lactones 4 and 5
spiroketal from Bactrocera species was thus prepared in 12 from an industrial intermediate, although additional in-
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A Concise and Efficient Synthesis of Spiroketals
phenylsilane (1.4 mL, 5.26 mmol, 1.2 equiv.) were added to a solu-
tion of (S)-dihydropyranylmethanol (500 mg, 4.39 mmol, 1 equiv.)
in N,N-dimethylformamide (8 mL) at 0 °C. The resulting solution
was stirred at room temperature for 12 h. The mixture was then
poured into water and extracted with ethyl acetate. The combined
organic extracts were washed with water and brine, and dried with
anhydrous MgSO4. After filtration and concentration in vacuo, the
crude product was purified over silica gel (95:5 petroleum ether/
ethyl acetate) to give 2b (1.53 g, 4.35 mmol, 98%) as a slightly yel-
low oil. 1H NMR (CDCl3, 300 MHz): δ = 1.09 (m, 9 H), 2.05–2.07
(m, 2 H, 4-H), 3.61–3.71 (m, 2 H, 6-H), 3.78–3.83 (m, 1 H, 5-H),
4.19–4.20 (m, 2 H, 1-H), 5.70–5.74 (m, 1 H, 2-H), 5.82–5.85 (m, 1
H, 3-H), 7.37–7.41 (m, 6 H), 7.69–7.71 (m, 4 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 135.60 (CH), 133.1 (C), 130.2 (CH), 128.1
(CH), 126.9 (CH, C-2), 124.4 (CH, C-3), 74.3 (CH, C-5), 67.2
(CH2, C-6), 65.8 (CH2, C-1), 27.5 (CH2, C-4), 26.8 (CH3), 19.7 (C)
ppm.
vestigations into the control of the regiochemistry of the
oxidation reaction are needed. We applied this methodology
to the preparation of two spiroketals of interest: SPIKET-
P, and a spiroketal from Bactrocera species.
Experimental Section
General Remarks: Reactions were carried out in dried glassware
and under an argon atmosphere. All reactions were magnetically
stirred and monitored by thin-layer chromatography (TLC) on sil-
ica gel 60 F254 (Merck) plates using either UV light or 10% H2SO4
solution in ethanol to visualize the compounds. Solvents were dis-
tilled and dried from sodium benzophenone ketyl for tetra-
hydrofuran, and from calcium hydride for dichloromethane. Other
dry solvents were purchased from commercial suppliers and used
without further purification. Flash chromatography was performed
on silica gel (40–60 μm) purchased from Acros Organics. Yields
refer to chromatographically and spectroscopically pure com-
pounds unless otherwise noted. 1H and 13C NMR spectra were
recorded at 23 °C with a Bruker Avance DRX300 spectrometer.
Chemical shifts are referenced to the residual peaks of the solvent
(CDCl3: 7.26 ppm for 1H and 77.16 ppm for 13C). The following
abbreviations are used to denote the multiplicities: s = singlet, d =
doublet, dd = doublet of doublets, t = triplet, m = multiplet, and
br. s = broad singlet. NMR solvents were purchased from Euriso-
Top (Saint Aubin, France). Low resolution mass spectra (ESI) and
HRMS were recorded in positive ion mode using a Thermo Finni-
gan LCQ spectrometer.
(S)-5,6-Dihydro-6-[methoxy(tert-butyl)diphenylsilyl]pyran-2-one (4b)
and
one (3b):
(S)-2-{[(tert-Butyldiphenylsilyl)oxy]methyl}-2H-pyran-4(3H)-
mixture of pyridinium dichromate (1.433 mg,
A
6.65 mmol, 3 equiv.) and powdered molecular sieves (3 Å) was
added to a solution of compound 2b (780 mg, 2.22 mmol, 1 equiv.)
in freshly distilled dichloroethane (7 mL). The reaction mixture was
stirred at reflux for 4 h, then diluted with diethyl ether (100 mL),
and finally passed through a pad of silica gel, which was washed
with diethyl ether. Removal of the solvent in vacuo and purification
by flash chromatography over silica gel (8:2 petroleum ether/ethyl
acetate) gave lactone 4b (521 mg, 1.42 mmol, 65%) as a colorless
oil and ketone 3b (73 mg, 0.20 mmol, 9%)as a colorless oil.
(S)-6-(Benzyloxymethyl)tetrahydro-2H-pyran-2-one (5a): [(S)-3,6-
Dihydro-2H-pyran-2-yl]methanol (1 g, 8.77 mmol) was dissolved in
anhydrous DMF (44 mL) under argon, and the solution was cooled
to 0 °C. Imidazole (299 mg, 4.39 mmol, 0.5 equiv.) was added in
portions, and then NaH (60% in mineral oil; 702 mg, 17.54 mmol,
2 equiv.) was added. After 20 min, benzyl bromide (2.16 mL,
13.16 mmol, 1.5 equiv.) was added, and the mixture was stirred at
room temperature until complete conversion of the starting mate-
rial was observed. The reaction was quenched by the addition of
methanol (5 mL), and extracted with dichloromethane (3ϫ
50 mL). The organic extracts were combined, washed with water
(4ϫ 50 mL) and brine (50 mL), and then dried with MgSO4, and
filtered. The solvents were evaporated in vacuo. After purification
over silica gel (eluent petroleum ether/EtOAc, 9:1), 2a (1.40 g,
6.86 mmol, 78%) was obtained, and the analytical data were iden-
tical to those described in the literature.[11]
1
Data for 4b: H NMR (CDCl3, 300 MHz): δ = 1.09 (m, 9 H), 2.43
(dddd, J = 1.1, 4.6, 5.6, 18.5 Hz, 1 H, 4-H), 2.59 (app ddt, J = 2.7,
2.7, 10.9, 18.5 Hz, 1 H, 4-H), 3.85 (d, J = 4.9 Hz, 2 H, 6-H), 4.52
(dddd, J = 4.7, 4.7, 4.7, 9.4 Hz, 1 H, 5-H), 6.01 (ddd, J = 1.1, 2.6,
9.7 Hz, 1 H, 2-H), 6.89 (ddd, J = 2.7, 5.7, 9.7 Hz, 1 H, 3-H), 7.34–
7.52 (m, 6 H), 7.65–7.69 (m, 4 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 163.3 (C, C-1), 144.4 (CH, C-3), 136.0 (CH), 133.0
(C), 130.2 (CH), 128.2 (CH), 121.2 (CH, C-2), 74.3 (CH, C-5), 65.9
(CH2, C-6), 27.8 (CH2, C-4), 27.2 (CH3), 19.7 (C) ppm.
1
Data for 3b: H NMR (CDCl3, 300 MHz): δ = 1.07 (s, 9 H), 2.44
(ddd, J = 1.1, 3.7, 16.9 Hz, 1 H, 4-H), 2.82 (app dd, J = 13.9,
16.9 Hz, 1 H, 4-H), 3.82 (dd, J = 11.4, 4.5 Hz, 1 H, 6-H), 3.92 (dd,
J = 11.4, 3.9 Hz, 1 H, 6-H), 4.49 (dddd, J = 4.0, 4.1, 4.1, 13.5 Hz,
1 H, 5-H), 5.41 (dd, J = 6.0, 1.1 Hz, 1 H, 2-H), 7.50–7.32 (m, 7 H,
1-H), 7.70–7.61 (m, 4 H) ppm.
Compound 2a (2 g, 9.80 mmol) was dissolved in dichloroethane
(33 mL) under argon, and molecular sieves (3 Å, 11 g) and PDC
(11 g, 29.4 mmol, 3 equiv.) were added. The reaction mixture was
stirred at reflux for 24 h. The crude mixture was cooled, diluted
with diethyl ether (250 mL) and filtered through a pad of Celite.
After evaporation under reduced pressure, the residue was purified
over silica gel (eluent petroleum ether/EtOAc, 8:2 to 1:1) to give
starting material (17%), 4a (1.18 g, 5.40 mmol, 55%), and 3a
(642 mg, 2.90 mmol, 30%). The analytical data were identical to
those reported in the literature.[12]
(S)-(tert-Butyldiphenylsiloxymethyl)tetrahydro-2H-pyran-2-one (5b):
A solution of 14 (634 mg, 1.73 mmol, 1 equiv.) and Pd-C (10%;
10 mg, 0.08 mmol, 0.05 equiv.) in ethyl acetate (7 mL) was stirred
under a positive pressure of H2 for 24 h. The mixture was then
diluted with diethyl ether, and passed through a pad (5 cm) of Ce-
lite, which was then washed with ethyl acetate. Removal of the sol-
vent in vacuo and purification by flash chromatography over silica
gel (8:2 petroleum ether/ethyl acetate) gave lactone 5b (623 mg,
1.69 mmol, quantitative) as a white solid. 1H NMR (CDCl3,
300 MHz): δ = 1.07 (m, 9 H), 1.67–1.70 (m, 2 H, 3-H), 1.91–2.00
(m, 2 H, 4-H), 2.39–2.50 (m, 1 H, 2-H), 2.55–2.65 (m, 1 H, 2-H),
3.75 (dd, J = 4.0, 9.6 Hz, 1 H, 6-H), 3.80 (dd, J = 3.2, 9.6 Hz, 1
H, 6-H), 4.36–4.43 (m, 1 H, 5-H), 7.37–7.47 (m, 6 H), 7.65–7.69
(m, 4 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 171.6 (C, C-1),
135.6 (CH), 133.5 (C), 135.8 (CH), 128.2 (CH), 80.4 (CH, C-5),
65.7 (CH2, C-6), 30.0 (CH2, C-2), 26.9 (CH3), 24.6 (CH2, C-4), 19.4
(C), 18.5 (CH2, C-3) ppm. MS (ESI): m/z = 391 [M + Na]+. HRMS
(ESI): calcd. for [M + Na]+ 391.1700; found 391.1699.
A solution of lactone 4a (708 mg, 3.25 mmol) in ethyl acetate
(13 mL) was stirred at room temperature for 45 min under a hydro-
gen atmosphere with palladium on charcoal. The reaction mixture
was filtered to give compound 5a (714 mg, 3.25 mmol, quantita-
tive). The data were consistent with those reported in the litera-
ture.[13]
(S)-Dihydropyranylmethoxy(tert-butyl)diphenylsilane (2b): Imid-
azole (598 mg, 8.77 mmol, 2.0 equiv.) and tert-butyl(chloro)di-
Eur. J. Org. Chem. 2013, 915–920
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D. Gueyrard, P. G. Goekjian et al.
FULL PAPER
2-{3-[(S)-6-(Benzyloxymethyl)tetrahydro-2H-pyran-2-ylidene]-
propyl}-1,4-dioxaspiro[4.5]decane (7a): Benzothiazolyl sulfone 6
(250 mg, 0.65 mmol, 1.2 equiv.) was added to a solution of lactone
5a (119 mg, 0.54 mmol, 1 equiv.) and BF3·Et2O (68 μL, 0.54 mmol,
1 equiv.) in THF (1 mL) at room temperature . The mixture was
cooled to –78 °C, and lithium hexamethyldisilazide (1 m in THF;
1 mL, 1.00 mmol, 2 equiv.) was added dropwise. The reaction mix-
ture was stirred at –78 °C for 30 min, quenched by the addition of
water at –78 °C, diluted with ethyl acetate, stirred at room tempera-
ture for 15 min, and extracted with ethyl acetate. The organic ex-
tracts were combined, washed with brine, and dried with anhydrous
sodium sulfate. After filtration and evaporation in vacuo, the resi-
due was dissolved in THF (5 mL), and 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (161 μL, 1.08 mmol, 2 equiv.) was added over 10 min.
The reaction mixture was stirred at room temperature for 30 min,
then it was concentrated in vacuo and the residue was purified by
flash chromatography over alumina (9:1 petroleum ether/ethyl acet-
ate) to give compound 7a (114.6 mg, 0.30 mmol, 55%) as a color-
1090, 1045, 1018, 984, 950, 923, 907, 841, 820, 734, 697 cm–1. [α]D
= +32.3 (c = 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ = 7.35–
7.25 (m, 5 H, H Ar), 4.60 (s, 2 H, PhCH2O), 3.88–3.74 (m, 2 H, 2-
H and 8-H), 3.60 (m, 1 H, 1Јa-H), 3.52–3.42 (m, 1 H, 1Јb-H), 3.50
(dd, J = 10.2, 5.7 Hz, 1 H, 1ЈЈa-H), 3.44 (dd, J = 10.2, 4.8 Hz, 1
H, 1ЈЈb-H), 2.01 (br. s, 1 H, OH), 2.03–1.81 (m, 2 H), 1.68–1.54
(m, 5 H), 1.51–1.21 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 139.0 (C), 128.7 (CH), 127.9 (CH), 127.8 (CH), 96.5 (C), 74.0
(CH2), 73.7 (CH2), 70.0 (CH), 69.2 (CH), 66.6 (CH2), 35.7 (CH2),
35.5 (CH2), 27.8 (CH2), 26.9 (CH2), 18.9 (CH2), 18.6 (CH2) ppm.
MS (ESI+): m/z = 329.1 [M + Na]+, 307.0 [M + H]+. HRMS
(ESI+): calcd. for [M + Na]+ 329.1729; found 329.1729.
{(2S,6S,8S)-8-[(tert-Butyldiphenylsilyloxy)methyl]-1,7-dioxaspiro-
[5.5]undecan-2-yl}methanol (8b): Following the same procedure as
for 8a, the crude mixture was purified over silica gel (eluent petro-
leum ether/EtOAc, 8:2) to give spiroketal 8b (180 mg, 0.40 mmol,
92%) as a pale yellow oil. Rf (SiO2, petroleum ether/EtOAc, 8:2) =
0.53. IR: ν = 3485, 2934, 2858, 1741, 1590, 1473, 1458, 1428, 1373,
˜
less oil. IR: ν = 2933, 2860, 1722, 1676, 1497, 1450, 1364, 1331,
˜
1239, 1226, 1112, 1089, 1074, 1045, 982, 949, 922, 840, 823, 802,
739, 701, 690 cm–1. [α]D = +9.5 (c = 1.0, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 7.75–7.71 (m, 4 H), 7.40–7.32 (m, 6 H), 3.87–3.73
(m, 2 H, 2-H and 8-H), 3.68 (dd, J = 10.3, 6.2 Hz, 1 H), 3.60 (dd,
J = 11.3, 3.4 Hz, 1 H), 3.58 (dd, J = 10.4, 4.5 Hz, 1 H), 3.49 (dd,
J = 11.1, 6.8 Hz, 1 H), 2.17 (br. s, 1 H, OH), 1.93 (m, 1 H), 1.68–
1.57 (m, 5 H), 1.48–1.25 (m, 6 H), 1.07 (s, 9 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 135.8 (CH), 134.0 (C), 129.7 (C), 127.7
(CH), 127.7 (CH), 96.1 (C), 70.4 (CH), 69.5 (CH), 67.5 (CH2),
66.4 (CH2), 35.5 (CH2), 35.3 (CH2), 27.1 (CH2), 26.9 [(CH3)3], 26.6
(CH2), 19.7 (C), 19.4 (CH2), 18.7 (CH2) ppm. MS (ESI+): m/z =
477.2 [M + Na]+. HRMS (ESI+): calcd. for [M + Na]+ 477.2437;
found 477.2437.
1279, 1233, 1163, 1099, 1069, 1041, 1028, 929, 908, 847, 828, 735,
697 cm–1. [α]2D5 = +27.4 (c = 1.0, CHCl3). H NMR ([D]6acetone,
1
300 MHz): δ = 1.38 (m, 2 H), 1.45–1.65 (m, 13 H), 1.83–1.93 (m,
1 H), 1.95–2.07 (m, 4 H), 3.44 (dd, J = 7.2, 7.2 Hz, 1 H, 10-H),
3.57 (dd, J = 4.8, 10.4 Hz, 1 H, 6-H), 3.63 (dd, J = 5.4, 10.2 Hz, 1
H, 6-H), 3.96–4.01 (m, 3 H, 5-H and 11-H), 4.49 (m, 1 H, 7-H),
4.58 (s, 2 H), 7.25–7.38 (m, 5 H) ppm. 13C NMR ([D]6acetone,
75 MHz): δ = 154.8 (C, C-1), 140.2 (C), 129.5 (CH), 128.7 (CH),
128.6 (CH), 109.8 (C), 96.2 (CH, C-7), 76.7 (CH, C-5), 75.7 (CH,
C-10), 74.1 (CH2, C-11), 73.6 (CH2, C-6), 70.1 (CH2), 37.9 (CH2),
36.5 (CH2), 35.2 (CH2), 34.4 (CH2), 26.4 (CH2), 25.5 (CH2), 25.1
(CH2), 25.0 (CH2), 24.5 (CH2), 20.9 (CH2) ppm. MS (ESI): m/z =
409 [M + Na]+. HRMS (ESI): calcd. for [M + Na]+ 409.2355;
found 409.2357.
[(2S,8S)-8-(Hydroxymethyl)-1,7-dioxaspiro[5.5]undec-2-yl]meth-
anol (SPIKET-P): A mixture of spiroketal 8a (23.5 mg, 0.08 mmol,
1 equiv.) and Pd(OH)2 (20 mg) in ethanol (4 mL) was stirred under
a positive pressure of H2 for 16 h. The mixture was diluted with
diethyl ether, and passed through a pad (5 cm) of Celite, which was
washed with ethyl acetate. The solvent was evaporated in vacuo,
and the crude product was purified by flash chromatography over
silica gel (70:30 petroleum ether/ethyl acetate) to give SPIKET-P
({(2S)-6-[3-(1,4-Dioxaspiro[4.5]decan-2-yl)propylidene]tetrahydro-
2H-pyran-2-yl}methoxy)(tert-butyl)diphenylsilane (7b): Following
the same procedure as for 7a, the crude mixture was purified over
basic alumina (eluent petroleum ether/EtOAc, 95:5) to obtain 7b
(224 mg, 0.42 mmol, 31%) as a colorless oil. Rf (SiO2, petroleum
ether/EtOAc, 8:2) = 0.90. IR: νmax = 2932, 2857, 1741, 1676, 1473,
˜
1462, 1448, 1428, 1390, 1363, 1332, 1280, 1235, 1163, 1104, 1069,
1044, 1006, 976, 930, 908, 848, 823, 796, 739, 700 cm–1. [α]D
=
(14.7 mg, 0.07 mmol, 90%) as a colorless oil. IR: ν = 3380, 2931,
˜
1463, 1454, 980 cm–1. [α]2D5 = +62.9 (c = 0.9, CHCl3). 1H NMR
(CDCl3, 300 MHz): δ = 1.19–1.54 (m, 6 H, 2-H, 4-H, 7-H, and 9-
H), 1.54–1.68 (m, 4 H, 2-H, 3-H, 7-H, and 8-H), 1.89 (qt, J = 4.2,
13.0 Hz, 2 H, 3-H and 8-H), 2.18 (br. s, 2 H, OH), 3.50 (dd, J =
6.9, 11.3 Hz, 2 H, 6-H and 11-H), 3.50 (dd, J = 6.9, 11.3 Hz, 2 H,
6-H and 11-H), 3.78–3.69 (m, 2 H, 5-H and 10-H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 96.2 (C, C-1), 69.9 (CH, C-5 and C-10),
66.3 (CH2, C-6 and C-11), 35.4 (CH2, C-2 and C-7), 26.5 (CH2, C-
4 and C-9), 18.4 (CH2, C-3 and C-8) ppm. MS (CI): m/z = 217
[M + H]+. Analytical data consistent with those reported in the
literature.[14]
+18.2 (c = 1.0, CHCl3). 1H NMR ([D]6acetone, 300 MHz): δ =
7.79–7.75 (m, 4 H, H-Ar), 7.49–7.45 (m, 6 H, H-Ar), 4.49 (m, 1 H,
7-H), 4.09–3.92 (m, 3 H), 3.84 (dd, J = 10.6, 4.9 Hz, 1 H, 6a-H),
3.80 (dd, J = 10.6, 5.1 Hz, 1 H, 6b-H), 3.44 (t, J = 7.2 Hz, 1 H,
10-H), 2.14–1.98 (m, 6 H), 1.72–1.47 (m, 12 H), 1.38 (m, 2 H), 1.08
[s, 9 H C(CH3)3] ppm. 13C NMR ([D]6acetone, 75 MHz): δ = 154.0
(C), 135.9 (CH), 133.9 (C), 130.1 (CH), 128.1 (CH), 108.9 (C), 95.2
(CH), 76.2 (CH), 75.8 (CH), 69.2 (CH2), 66.7 (CH2), 37.0 (CH2),
35.6 (CH2), 34.4 (CH2), 33.5 (CH2), 26.7 [(CH3)3], 25.2 (CH2), 24.2
(CH2), 24.2 (CH2), 24.1 (CH2), 23.7 (CH2), 20.1 (CH2), 19.4 (C)
ppm. MS (ESI+): m/z = 557.3 [M + Na]+. HRMS (ESI+): calcd.
for [M + Na]+ 557.3063; found 557.3062.
2-[3-(Tetrahydro-2H-pyran-2-ylidene)propyl]-1,4-dioxaspiro[4.5]-
decane (9): BF3·Et2O (279 μL, 2.20 mmol, 1 equiv.) was added to a
solution of δ-valerolactone (200 μL, 220 mg, 2.20 mmol) and 2-[3Ј-
(1,4-dioxaspiro[4.5]decan-2-yl)propylsulfonyl]benzo[d]thiazole (6)
(1.00 g, 2.64 mmol, 1.2 equiv.) in distilled THF (11 mL) under ar-
gon. The mixture was cooled to –78 °C, and LiHMDS (1 m in
THF; 4.39 mL, 4.39 mmol, 2 equiv.) was added. After 30 min at
–78 °C, the reaction mixture was quenched by the addition of water
(500 μL), and diluted with ethyl acetate. The solution was dried
with sodium sulfate, filtered, and evaporated to give a pale yellow
solid. This residue was purified by flash chromatography over basic
[(2S,6S,8S)-8-(Benzyloxymethyl)-1,7-dioxaspiro[5.5]undecan-2-yl]-
methanol (8a): para-Toluenesulfonic acid (21 mg, 0.11 mmol,
0.5 equiv.) was added to the mixture of enol ethers 7a (83.5 mg,
0.22 mmol, 1 equiv.) in dichloromethane (3 mL). The reaction mix-
ture was stirred at room temperature for 25 min, then the solvent
was evaporated in vacuo, and the crude product was purified by
flash chromatography over silica gel (70:30 petroleum ether/ethyl
acetate) to give spiroketal 8a (61.2 mg, 0.20 mmol, 94%) as a color-
less oil. R (SiO , petroleum ether/EtOAc, 7:3) = 0.32. IR: ν =
˜
max
f
2
3446, 2937, 2868, 1721, 1497, 1454, 1365, 1280, 1225, 1204, 1166,
918
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 915–920

A Concise and Efficient Synthesis of Spiroketals
alumina (eluent petroleum ether/EtOAc, 95:5) to give enol ether 9
(348 mg, 1.31 mmol, 60%) as a colorless oil. Rf (SiO2, petroleum
721 cm–1. [α]D = +52.7 (c = 1.0, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 4.42 (dt, J = 11.3, 2.2 Hz, 1 H, 2-H), 3.71 (m, 1 H,
8a-H), 3.65–3.59 (m, 1 H, 8b-H), 2.42 (d, J = 2.2 Hz, 1 H, 1Ј-H),
2.01–1.78 (m, 3 H), 1.73–1.65 (m, 1 H), 1.63–1.37 (m, 8 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 96.5 (C), 84.3 (C), 72.2 (CH),
61.0 (CH2), 60.3 (CH), 35.8 (CH2), 35.1 (CH2), 32.1 (CH2), 25.5
(CH2), 18.8 (CH2), 18.7 (CH2) ppm. MS (CI): m/z = 181.2 [M +
H]+. HRMS (CI): calcd. for [M + H]+ 181.1229; found 181.1230.
ether/EtOAc, 8:2) = 0.71 and 0.76. IR: ν
= 2932, 2862, 1675,
˜
max
1449, 1389, 1364, 1347, 1280, 1233, 1163, 1143, 1102, 1064, 1042,
978, 929, 909, 848, 827, 814, 761, 658 cm–1. [α]D = +7.1 (c = 1.0,
CHCl3). 1H NMR ([D6]acetone, 300 MHz): δ = 4.50 (t, J = 3.5 Hz,
1 H, 5-H), 4.13–4.02 (m, 2 H), 3.97 (dd, J = 5.1, 5.1 Hz, 2 H), 3.48
(dd, J = 7.2, 6.6 Hz, 1 H, 8-H), 2.04–1.98 (m, 4 H), 1.82–1.74 (m,
2 H), 1.65–1.51 (m, 12 H), 1.45–1.39 (m, 2 H) ppm. 13C NMR
([D6]acetone, 75 MHz): δ = 155.1 (C), 109.5 (C), 96.0 (CH), 76.4
(CH), 69.9 (CH2), 66.7 (CH2), 37.6 (CH2), 36.2 (CH2), 35.1 (CH2),
34.1 (CH2), 26.1 (CH2), 24.9 (CH2), 24.7 (CH2), 24.2 (CH2), 23.4
(CH2), 21.0 (CH2) ppm. MS (CI): m/z = 267.2 [M + H]+ HRMS
(ESI+): calcd. for [M + H]+ 267.1960; found 267.1960.
(2S,6S)-2-Ethyl-1,7-dioxaspiro[5.5]undecane (13): Pd on charcoal
(7 mg) was added to
a solution of compound 12 (50 mg,
0.39 mmol) in methanol (1.3 mL), and the mixture was stirred un-
der a hydrogen atmosphere overnight at room temperature. After
filtration through Celite, the pad was washed with dichlorometh-
ane. The filtrates were combined, and the solvent was evaporated
under reduced pressure to give compound 13 (51 mg, 0.39 mmol,
quantitative) as a colorless oil. 1H NMR (CDCl3): δ = 3.72–3.34
(m, 3 H), 1.93–1.75 (m, 2 H), 1.64–1.32 (m, 11 H), 1.22–1.08 (m,
1 H), 0.98 (t, J = 6.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 95.3 (C), 70.4 (CH), 60.4 (CH2), 35.9 (CH2), 35.4 (CH), 30.9
(CH2), 29.3 (CH2), 25.5 (CH2), 18.8 (CH2), 18.6 (CH2), 10.3 (CH3)
ppm. HRMS (EI): calcd. for [M]+ 184.1463; found 184.1458.
{(2S,6S)-1,7-Dioxaspiro[5.5]undecan-2-yl}methanol (10): Following
the same procedure as for compound 8a, the crude mixture was
purified over silica gel (eluent petroleum ether/EtOAc, 8:2). Spi-
roketal 10 (301 mg, 1.62 mmol, quantitative) was obtained as a col-
orless oil. R (SiO , petroleum ether/EtOAc, 8:2) = 0.23. IR: ν
˜
max
f
2
= 3436, 2938, 2870, 1439, 1383, 1280, 1258, 1227, 1210, 1182, 1146,
1119, 1092, 1076, 1059, 1046, 1021, 988, 949, 919, 894, 875, 862,
847, 806, 734 cm–1. [α]D = +77.4 (c = 1.0, CHCl3). 1H NMR
(CDCl3, 300 MHz): δ = 3.71 (m, 1 H, 8a-H), 3.64–3.52 (m, 2 H, 2-
H and 8b-H), 3.58 (dd, J = 11.2, 3.5 Hz, 1 H, 1Јa-H), 3.47 (dd, J
= 7.0, 11.3 Hz, 1 H, 1Јb-H), 2.43 (br. s, 1 H, OH), 1.91–1.71 (m, 2
H), 1.60 (m, 1 H), 1.57–1.16 (m, 9 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 95.9 (C), 70.1 (CH2), 66.6 (CH2), 60.8 (CH2), 35.9
(CH2), 35.7 (CH2), 26.8 (CH), 25.6 (CH2), 18.9 (CH2), 18.5 (CH2)
ppm. MS (CI): m/z = 187 [M + H]+. HRMS (CI): calcd. for [M +
H]+ 187.1333; found 187.1334.
Supporting Information (see footnote on the first page of this arti-
1
cle): H NMR spectra of compounds 4a, 4b, 5a, 5b, 7b, 9, and 11,
1
and H and 13C NMR spectra of compounds 7a, 8a, 8b, SPIKET-
P, 10, 12 and 13 are available.
Acknowledgments
The authors would like to thank the French Ministère de l’Enseig-
nement Supérieur et de la Recherche for a grant to L. T.. acknow-
ledge The European Union (EU) is thanked for a grant (to B. B.)
within the European Integrated Project (contract number LSHB-
CT-2004-503467).
(2S,6S)-1,7-Dioxaspiro[5.5]undecane-2-carbaldehyde (11): Oxalyl
chloride (2 m in dichloromethane; 1.44 mmol, 2 equiv.) was cooled
to –78 °C under argon. A solution of anhydrous DMSO (205 μL,
2.88 mmol, 4 equiv.) in dichloromethane (600 μL) was added drop-
wise. Then alcohol 10 (134 mg, 0.72 mmol, 1 equiv.) in dichloro-
methane was added. After 15 min at –78 °C, Et3N (600 μL,
4.32 mmol, 6 equiv.) was added, and the reaction mixture was
warmed to room temperature. The mixture was extracted with di-
ethyl ether (3ϫ 25 mL). The organic extracts were combined,
washed with brine (20 mL), dried with Na2SO4, and filtered, and
the solvents were evaporated in vacuo. Purification of the residue
on silica gel (eluent petroleum ether/EtOAc, 8:2) gave aldehyde 11
(99 mg, 75%) as a colorless oil. The aldehyde could also be used
without further purification. 1H NMR (CDCl3, 300 MHz): δ = 9.67
(s, 1 H, 1Ј-H), 4.03 (d, J = 12.1 Hz, 1 H), 3.59 (d, J = 6.4 Hz, 2
H), 1.85–1.21 (m, 12 H) ppm.
[1] a) W. Francke, W. Kitching, Curr. Org. Chem. 2001, 5, 233–
251; b) J. E. Aho, P. M. Pihko, T. K. Rissa, Chem. Rev. 2005,
105, 4406–4440.
[2] a) F. Perron, K. F. Albizati, Chem. Rev. 1989, 89, 1617–1661;
b) K. T. Mead, B. N. Brewer, Curr. Org. Chem. 2003, 7, 227–
256; c) S. Favre, P. Vogel, S. Gerber-Lemaire, Molecules 2008,
13, 2570–2600; d) M. C. Mc Leod, M. A. Brimble, D. C. K.
Rathwell, Z. E. Wilson, T. Y. Yuen, Pure Appl. Chem. 2012, 84,
1379–1390.
[3] a) D. Gueyrard, R. Haddoub, A. Salem, N. Said Bacar, P. G.
Goekjian, Synlett 2005, 520–522; b) B. Bourdon, M. Corbet,
P. Fontaine, P. G. Goekjian, D. Gueyrard, Tetrahedron Lett.
2008, 49, 747–749.
[4] a) M. Corbet, B. Bourdon, D. Gueyrard, P. G. Goekjian, Tetra-
hedron Lett. 2008, 49, 750–754; b) L. Tomas, D. Gueyrard,
P. G. Goekjian, Tetrahedron Lett. 2010, 51, 4599–4601; c) L.
Tomas, G. Boije af Gennas, M. A. Hiebel, P. Hampson, D.
Gueyrard, B. Pelotier, J. Yli-Kauhaluoma, O. Piva, J. M. Lord,
P. G. Goekjian, Chem. Eur. J. 2012, 18, 7452–7466.
[5] H. Huang, C. Mao, S. T. Jan, F. M. Uckun, Tetrahedron Lett.
2000, 41, 1699–1702.
[6] F. M. Uckun, C. Mao, A. O. Vassilev, H. Huang, S. T. Jan,
Bioorg. Med. Chem. Lett. 2000, 10, 541–545.
[7] a) J. Tengo, G. Bergstrom, A. K. Borg-Karlson, I. Groth, W.
Francke, Z. Naturforsch. C 1982, 37, 376–380; b) J. E. Stok,
C. S. Lang, B. D. Schwartz, M. T. Fletcher, W. Kitching, J. J.
De Voss, Org. Lett. 2001, 3, 397–400.
(2S,6S)-2-Ethynyl-1,7-dioxaspiro[5.5]undecane
(12):
K2CO3
(150 mg, 1.09 mmol, 2 equiv.) and dimethyl 1-diazo-(2-oxopropyl)-
phosphonate (118 mg, 0.61 mmol, 1.2 equiv.) in methanol (1 mL)
were added to a solution of (2S,6S)-1,7-dioxaspiro[5.5]undecane-2-
carbaldehyde (11) (100 mg, 0.51 mmol) in methanol (8 mL) under
argon. The reaction mixture was stirred at room temperature for
2 h. The mixture was extracted with ether (2ϫ 50 mL), and the
combined organic extracts were washed with NaHCO3 (sat. aq.;
25 mL), then brine (25 mL). The organic phase was dried with
MgSO4, filtered, and evaporated under reduced pressure. The resi-
due was purified by flash chromatography on silica gel (eluent pe-
troleum ether/EtOAc, 95:5) to give 12 (98 mg, 0.51 mmol, quantita-
tive) as white needles, m.p. 64–66 °C. Rf (SiO2, petroleum ether/
[8] a) J. Mulzer, E. Oehler, Angew. Chem. 2001, 113, 3961–3964;
Angew. Chem. Int. Ed. 2001, 40, 3842–3846; b) L. C. Dias,
P. R. R. Meira, Tetrahedron Lett. 2002, 43, 8883–8885; c) J. Po-
spisil, I. E. Marko, Tetrahedron Lett. 2006, 47, 5933–5937; d)
EtOAc, 95:5) = 0.39. IR: νmax = 3217, 2944, 2877, 2115, 1451, 1438,
˜
1384, 1355, 1301, 1281, 1254, 1231, 1209, 1181, 1143, 1111, 1091,
1064, 1052, 1043, 1031, 979, 947, 932, 909, 891, 865, 849, 814, 740,
Eur. J. Org. Chem. 2013, 915–920
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
919

D. Gueyrard, P. G. Goekjian et al.
FULL PAPER
M. Kanematsu, M. Yoshida, K. Shishido, Tetrahedron Lett.
2011, 52, 1372–1374.
[9] J. C. Caille, C. K. Govindan, H. Junga, J. Lalonde, Y. Yao, Org.
Process Res. Dev. 2002, 6, 471–476.
[10] F. Bonadies, R. Di Fabio, C. Bonini, J. Org. Chem. 1984, 49,
1647–1649.
ferty, Tetrahedron Lett. 1996, 37, 5649–5652; c) X. Fan, G. R.
Flentke, D. H. Rich, J. Am. Chem. Soc. 1998, 120, 8893–8894;
d) P. Hayes, B. D. Suthers, W. Kitching, Tetrahedron Lett. 2000,
41, 6175–6179; e) A. B. Smith, R. M. Corbett, G. R. Pettit,
J. C. Chapuis, J. M. Schmidt, E. Hamel, M. K. Jung, Bioorg.
Med. Chem. Lett. 2002, 12, 2039–2042; f) A. Sharma, P. Iyer,
S. Gamre, S. Chattopadhyay, Synthesis 2004, 1037–1040; g) B.
Lastdrager, M. S. M. Timmer, G. A. Van der Marel, H. S. Ov-
erkleeft, Tetrahedron Lett. 2005, 46, 6195–6198; h) N. Ardes-
Guisot, B. Ouled-Lahoucine, I. Canet, M. E. Sinibaldi, Tetra-
hedron Lett. 2007, 48, 8511–8513.
[11] S. Aragonès, F. Bravo, Y. Diaz, M. I. Matheu, S. Castillon, Tet-
rahedron: Asymmetry 2003, 14, 1847–1856.
[12] G. E. Keck, X.-Y. Li, C. E. Knutson, Org. Lett. 1999, 1, 411–
413.
[13] N. C. Barua, R. R. Schmidt, Synthesis 1986, 1067–1070.
[14] a) S. Sauret, A. Cuer, J. Gourcy, G. Jeminet, Tetrahedron:
Asymmetry 1995, 6, 1995–2000; b) M. T. Crimmins, S. W. Raf-
Received: September 11, 2012
Published Online: January 10, 2013
920
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 915–920