Stereoselective synthesis of fully protected (S)-1,7-dioxaspiro[5,5]undec-4-ene derivatives of sugars

Article abstract of DOI:10.1002/ejoc.200300025

Perbenzylated 1,7-dioxaspiro[5,5]undec-4-ene derivatives of sugars are obtained in three steps, starting from fully protected glycono-1,5-lactones. The procedure is based on the attack of a lithiated dithiinyl reagent (6) on the starting δ-glyconolactone.

Full text of DOI:10.1002/ejoc.200300025

FULL PAPER
Stereoselective Synthesis of Fully Protected (S)-1,7-Dioxaspiro[5,5]undec-4-ene
Derivatives of Sugars
Romualdo Caputo,[a] Umberto Ciriello,[a] Pasquale Festa,[a] Annalisa Guaragna,*[a]
Giovanni Palumbo,[a] and Silvana Pedatella[a]
Dedicated to Prof. L. Mangoni on his 70th birthday
Keywords: Spiro compounds / Carbohydrates / Lactones / Dithiins
Perbenzylated 1,7-dioxaspiro[5,5]undec-4-ene derivatives of
rocyclization of which is then accomplished with BF3·Et2O.
sugars are obtained in three steps, starting from fully pro- The fully protected unsaturated spiroacetals can be smoothly
tected glycono-1,5-lactones. The procedure is based on the
attack of a lithiated dithiinyl reagent (6) on the starting δ-
glyconolactone. The C-glycosidation leads to the sole ther-
modynamically more stable α-hemiacetal derivative, the spi-
desulfurized for the purpose of any further elaborations of
the free double bond.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
In a recent paper[1] we reported a new stereoselective syn-
thesis of 1,6-dioxaspiro[4,5]dec-3-enes of common sugars,
starting from the corresponding fully protected glyconolac-
tones.
For these reasons we considered modifying our former
synthetic approach in order to devise a new and reliable
method for the preparation of 1,7-dioxaspiro[5,5]undec-4-
ene derivatives of sugars, in which we are interested to per-
form a new synthesis of avermectin B1a.
Under our conditions only the products having (S) con-
figuration at the spiro carbon atom were formed in the C-
glycosidation step, and that was likely due to the addition
of a rather bulky 1,4-dithiinyl reagent 1 onto the carbonyl
group of the starting glyconolactones. In fact, C-glycosid-
ation reactions often suffer from poor facial selectivity of
the nucleophile attack leading to mixtures of both dia-
stereomeric C-glycosides.[2,3] Indeed, the (S) stereochem-
istry at the spirocentre represents an interesting synthetic
outcome inasmuch as such a configuration is that shown by
a wide group of natural products[4,5] containing a symmetri-
cally disposed 1,7-dioxaspiro[5,5]undecene spiroacetal mo-
tif. Specifically, the calcium-binding ionophore[6] A 23187
and the group of potent anthelmintic antibiotics comprising
the avermectins[7] and milbemycins[8] offer awe-inspiring ex-
amples of such structures.
Results and Discussion
The procedure we reported to prepare 1,6-dioxaspiro[4,5-
]dec-3-enes was based on the nucleophilic attack of 3-C-
lithiated (5,6-dihydro-1,4-dithiin-2-ylmethoxy)(4-methoxy-
phenyl)methane (1) onto the carbonyl group of a δ-glycono-
lactone. The dithiinyl reagent 1, devised in our laboratory,
acts as an allylic alcohol anion equivalent and leads to
three-carbon elongations of suitable electrophiles by intro-
duction of a fully protected hydroxypropenyl moiety.
Hence, in order to synthesize 1,7-dioxaspiro[5,5]undec-4-
ene derivatives of sugars we needed a new dithiinyl reagent,
namely 3-{3-[(4-methoxybenzyl)oxy]propyl}-5,6-dihydro-
1,4-dithiin-2-yl)lithium (6), that is a one-carbon homolog
of 1.
[a]
`
Dipartimento di Chimica Organica e Biochimica, Universita di
However, such a compound could not be prepared di-
rectly from methyl/ethyl acetoacetate[9] and a special syn-
thetic path had to be devised.
The preparation turned out not to be as trivial as ex-
pected and more than one attempt at the synthesis was un-
Napoli Federico II
4 Via Cynthia, 80126 Napoli, Italy
E-mail: guaragna@unina.it
[b]
Consorzio Interuniversitario Nazionale, La Chimica per
l’Ambiente
`
5/12 Via della Liberta, 30175 Marghera (VE), Italy
Eur. J. Org. Chem. 2003, 2617Ϫ2621
DOI: 10.1002/ejoc.200300025
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2617

R. Caputo, U. Ciriello, P. Festa, A. Guaragna, G. Palumbo, S. Pedatella
FULL PAPER
successful: eventually 6 was obtained, as outlined in
Scheme 1, starting from the monobenzoyl ester of the com-
mercially available 1,4-butanediol. The initial benzoic ester
protection was chosen because of its resistance under the
acidic conditions occurring during the ring-expansion step
leading to dithiin 5a from its parent dithiolane 4. The ben-
zoic ester was then removed and replaced by the 4-meth-
oxybenzyl ether (MPM) protection which is more suitable
for the spiro-ring closure conditions: as a matter of fact, the
MPM protection is unaffected by butyllithium and, there-
fore, 5c could be directly lithiated to afford the final dithii-
nyl reagent 6.
Scheme 2. Coupling and spirocyclization of sugars. i. THF, Ϫ78
°C; ii. BF3·Et2O, CH2Cl2, room temp.; iii. Raney (Ni), THF,
room temp.
1
10aϪc on the basis of H NMR comparison experiments
which showed a NOE between 5-H and 11-H in both gluco-
and galacto-spiroacetals (10a,c) (see Exp. Sect.). The NOE
was instead absent in the manno-spiroacetal 10b, thus ruling
out the possibility of (R) configuration at the spiro centres.
If one considers that the dithiinyl compound 5c is quite
stable and can be stored for a long time in the refrigerator
to be lithiated to afford 6 immediately before use, the whole
procedure appears very convenient, being also charac-
terized by clean and high-yielding reactions. The double
bond in the final sulfur-free unsaturated spiroacetals can be
easily saturated by catalytic hydrogenation, or hydroxylated
under stereocontrolled conditions, to synthesise other more
complex dioxaspiroacetal-based compounds.
Scheme 1. Preparation of the lithiated reagent 6. i. PCC, CH2Cl2,
room temp.; ii. polymer-bound DPP /I2, ethanedithiol, MeCN,
room temp.; iii. NBS, CHCl3, room temp.; iv. MeONa, MeOH,
room temp.; v. NaH, MPMCl, DMF, room temp.; vi. BuLi, THF,
Ϫ78 °C
The coupling of 6 with the fully protected δ-glyconolac-
tones 7aϪc, in dry THF at Ϫ78 °C, led to the hemiacetals
8a,c. The stereochemical outputs of the coupling reactions
Experimental Section
1
were confirmed via H NMR experiments and found con-
General: 1H and 13C NMR spectra: Varian Inova 500, Bruker
DRX-400, Varian Gemini 200 spectrometers, CDCl3 unless other-
wise specified, TMS internal standard. Bzli to Bzliv in the 1H NMR
sistent with available literature data.[5,10] Indeed, the hemia-
cetal 8b, coming from the corresponding protected δ-man-
nonolactone 7b, could not be purified to get any of its data are used to indicate proton couplings in the same benzyl ring.
Optical rotations (in CHCl3): Jasco P-1010 (1.0-dm cell). Combus-
tion analyses: PerkinϪElmer Series II 2400, CHNS analyzer. TLC
analyses: silica gel Merck 60 F254 plates (0.2 mm layer thickness).
Column chromatography: Merck Kieselgel 60 (70Ϫ230 mesh). Dry
solvents were distilled immediately before use.
physical data, likely due to the poor stability consequent to
the ∆-2 effect and, from this, the equilibrium between the
cyclic form and the open α,β-unsaturated ketone form. The
cyclizations of the hemiacetals 8a,c, and also of the coup-
ling product coming from 7b, occurred smoothly at room
temperature, with BF3·Et2O in methylene dichloride afford- 4-(Benzoyloxy)-1-butanol (2): Benzoyl chloride (6.43 mL,
55.5 mmol) was added in one portion, at 0 °C, to a magnetically
stirred solution of 1,4-butanediol (4.9 mL, 55.5 mmol) in anhy-
drous pyridine (150 mL). After 2 h at room temperature the 1,4-
butanediol was fully consumed (TLC monitoring). The solution
was neutralized by addition of 2  aq. HCl (250 mL) and the re-
sulting mixture was extracted with CHCl3 (3 ϫ 30 mL). The com-
bined organic layers were washed with water (3 ϫ 30 mL), dried
(Na2SO4), and the solvents evaporated under reduced pressure to
afford an oily residue that, after purification by column chromatog-
raphy on silica gel, gave the pure monobenzoyl ester 2 (8.1 g, 75%)
ing the spiroacetals 9aϪc (Scheme 2). The stereochemistry
of the six-membered ring closure is governed by thermo-
dynamic factors,[1,3] leading to the more stable (R) deriva-
tives, as ascertained by the 1H NMR analysis of the desulfu-
rized spiroacetals.
The dimethylenedisulfur bridge still present in the spiro
compounds 9aϪc could be eventually removed by Raney-
Ni in THF at room temperature.[11]
The (S) stereochemistry at the spirocarbon after sulfur
removal was unambiguously assigned to all the spiroacetals as an oil. C11H14O3 (194.2): calcd. C 68.02, H 7.27; found C 68.13,
2618  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2003, 2617Ϫ2621

Fully Protected (S)-1,7-Dioxaspiro[5,5]undec-4-ene Derivatives of Sugars
H 7.30. 1H NMR (500 MHz): δ ϭ 1.53 (br. s, 1 H, OH), 1.65Ϫ1.98 61.6 (CH2ϪO), 109.8 (C-3), 122.8 (C-2), 126.6 (2 ϫ Cmeta), 127.9
FULL PAPER
(m, 4 H, 2-H and 3-H), 3.75 (t, J1,2 ϭ 6.5 Hz, 2 H, 1-H), 4.38 (t,
(2 ϫ Cortho), 128.6 (Cipso), 131.2 (Cpara), 164.7 (CϭO) ppm.
J
4,3 ϭ 6.5 Hz, 2 H, 4-H), 7.38Ϫ7.61 (m, 3 H, Hpara and Hmeta), 8.07
5,6-Dihydro-1,4-dithiin 5b: Solid MeONa (0.6 g, 11.2 mmol) was
added in one portion, with magnetic stirring and under nitrogen at
room temperature, to a solution of 5a (2.0 g, 7.5 mmol) in MeOH
(15 mL). After 4 h the reaction was quenched with excess glacial
acetic acid and most of the MeOH was removed under reduced
pressure. The crude residue was redissolved by CH2Cl2 (100 mL),
washed with water until neutral, dried (Na2SO4), and the solvents
evaporated under reduced pressure. After purification by column
chromatography on silica gel (CH2Cl2) pure 5b was obtained (1.2 g,
98%), oily. C6H10OS2 (162.2): calcd. C 44.41, H 6.21; found C
(d, 2 H, Hortho) ppm. 13C NMR (300 MHz): δ ϭ 25.1 (C-3), 29.1
(C-2), 62.3 (C-1), 64.6 (C-4), 128.2 (2 ϫ Cmeta), 129.4 (2 ϫ Cortho),
130.2 (Cipso), 132.8 (Cpara), 166.6 (CϭO) ppm.
4-Benzoyloxybutanal (3): A solution of 2 (6.0 g, 30.9 mmol) in an-
hydrous CH2Cl2 (15 mL) was added in one portion, at room tem-
perature, to a magnetically stirred suspension of pyridinium chlor-
ochromate (PCC) (10.0 g, 46.4 mmol) and Celite 545 (10.0 g) in the
same solvent (80 mL). The resulting dark-brown reaction mixture
was kept at room temperature for 1.5 h and then diluted with anhy-
drous Et2O and filtered through a sintered-glass septum funnel.
The solvents were evaporated under reduced pressure and the crude
residue was purified by column chromatography on silica gel
(CH2Cl2) to give the pure aldehyde 3 (5.3 g, 90%), oily. C11H12O3
1
44.20, H 6.25. H NMR (200 MHz): δ ϭ 2.39 (t, J1Ј,2Ј ϭ 6.0 Hz, 2
H, 1Ј-H), 3.12Ϫ3.28 (m, 4 H, 5-H and 6-H), 3.73 (t, J2Ј,1Ј ϭ 6.0 Hz,
2 H, 2Ј-H), 6.01 (s, 1 H, 3-H) ppm. 13C NMR (200 MHz): δ ϭ
24.1, 25.9 (C-5 and C-6), 41.0 (CH2ϪCϭ), 59.3 (CH2ϪO), 109.4
(C-3), 123.1(C-2) ppm.
1
(192.2): calcd. C 68.74, H 6.29; found C 68.95, H 6.31. H NMR
(300 MHz): δ ϭ 2.05Ϫ2.30 (m, 2 H, 3-H), 2.75 (m, 2 H, 2-H),
4.30Ϫ4.51 (m, 2 H, 4-H), 7.38Ϫ7.65 (m, 3 H, Hpara and Hmeta),
8.05 (d, Jortho ϭ 7.9 Hz, 2 H, Hortho), 9.82 (t, J1,2 ϭ 1.3 Hz, 1 H, 1-
H) ppm. 13C NMR (400 MHz): δ ϭ 23.9 (C-3), 30.6 (C-2), 63.8
(C-4), 128.3 (2 ϫ Cmeta), 129.5 (2 ϫ Cortho), 130.2 (Cipso), 133.0
(Cpara), 166.6 (CϭO), 201.0 (C-1) ppm.
5,6-Dihydro-1,4-dithiin 5c: 4-Methoxybenzyl chloride (2.38 mL,
17.6 mmol) dissolved in dry DMF (40 mL) was added dropwise to
a solution of pure 5b (2.2 g, 13.5 mmol) and NaH (0.48 g,
20.3 mmol) in the same solvent (20 mL) that had been kept mag-
netically stirred and under nitrogen atmosphere for 30 min at room
temperature. The stirring was continued for 15 h, and the reaction
mixture was diluted with brine and extracted with Et2O. The com-
bined organic layers, after drying (Na2SO4) and evaporation of the
solvents under reduced pressure, gave a crude product, which after
chromatography on silica gel (petroleum ether/Et2O, 9:1) afforded
the pure oily 5c (3.7 g, 96%). C14H18O2S2 (282.4): calcd. C 59.54,
H 6.42; found C 59.57, H 6.45. 1H NMR (200 MHz): δ ϭ 2.45 (dt,
J1Ј,3 ϭ 0.8, J1Ј,2Ј ϭ 6.9 Hz, 2 H, 1Ј-H), 3.02Ϫ3.22 (m, 4 H, 5-H
and 6-H), 3.55 (t, J2Ј,1Ј ϭ 6.9 Hz, 2 H, 2Ј-H), 3.81 (s, 3 H, OCH3),
4.47 (s, 2 H, OCH2MPM), 5.96 (d, J3,1Ј ϭ 0.8 Hz, 1 H, 3-H), 6.88
(d, Jortho ϭ 8.1 Hz, 2 H, Harom.), 7.28 (d, Jortho ϭ 8.1 Hz, 2 H,
Harom.) ppm. 13C NMR (200 MHz): δ ϭ 25.8, 27.5 (C-5 and C-6),
39.6 (CH2Cϭ), 55.1 (OCH3), 68.4 (CH2-O), 72.5 (OCH2Ar), 110.2
(C-3), 113.6 (2 ϫ Cmeta), 122.1 (C-2), 129.2 (2 ϫ Cortho), 130.0
(Cipso), 150.9 (CϪOCH3) ppm.
2-[3Ј-(Benzoyloxy)propyl]-1,3-dithiolane (4): A solution of 3 (4.3 g,
22.6 mmol) in anhydrous acetonitrile (25 mL) was added via a syr-
inge in one portion to a magnetically stirred suspension of polys-
tyryl diphenylphosphane-iodine complex (22.6 mmol, prepared in
situ) in the same solvent (150 mL), at room temperature and under
dry nitrogen. After 10 min, 1  ethanedithiol in the same solvent
(23 mL) was also added in one portion. The benzoyloxybutanal
was fully consumed (TLC monitoring) within 2 h. Solid K2CO3
(excess) was then added, and the suspension was stirred for a cou-
ple of minutes and finally filtered. The solid was washed with
chloroform (3 ϫ 100 mL) and the combined filtrates, after shaking
with 5  aq sodium thiosulfate (50 mL) and water until neutral,
were evaporated under reduced pressure to leave a residue con-
sisting of practically pure 4 (5.9 g, 98%), oily. C13H16O2S2 (268.4):
calcd. C 58.18, H 6.01; found C 58.32, H 6.04. 1H NMR
(300 MHz): δ ϭ 1.84Ϫ2.10 (m, 4 H, 1Ј-H and 2Ј-H), 3.12Ϫ3.37
Compound 8a. Typical Coupling Procedure: 1.6  BuLi in hexane
(0.9 mL, 1.4 mmol) was added dropwise over 10 min to a stirred
solution of 5c (0.39 g, 1.2 mmol) in anhydrous THF (5 mL), at Ϫ78
°C and under N2. After 40 min, -gluconolactone 7a (0.54 g,
1.0 mmol) dissolved in the same solvent (2 mL) was added drop-
wise via a cannula. The reaction mixture was kept at Ϫ78 °C for
3 h, then quenched with 10% aq. NH4Cl (5 mL) and extracted with
EtOAc (3 ϫ 15 mL). The combined organic layers were dried
(Na2SO4) and the solvents evaporated under reduced pressure.
Chromatography of the crude residue on silica gel (petroleum ether/
EtOAc, 7:3) finally afforded the pure hemiacetal 8a (0.74 g, 90%)
as an oil. [α]2d5 ϭ ϩ5.4 (c ϭ 1.8). C48H52O8S2 (821.0): calcd. C
(m, 4 H, 4-H and 5-H), 4.28Ϫ4.39 (m, 2 H, 3Ј-H), 4.54 (t, J2,1Ј
ϭ
6.3 Hz, 1 H, 2-H), 7.38Ϫ7.62 (m, 3 H, Hpara and Hmeta) 8.04 (d,
Jortho ϭ 8.0 Hz, 2 H, Hortho) ppm. 13C NMR (300 MHz): δ ϭ 28.1
(C-2Ј), 35.8, 38.3 (C-4 and C-5), 53.0 (C-2), 64.2 (C-3Ј), 128.2 (2
ϫ Cmeta), 129.4 (2 ϫ Cortho), 130.1 (Cipso), 132.7 (Cpara), 166.4 (Cϭ
O) ppm.
5,6-Dihydro-1,4-dithiin (5a): A solution of NBS (6.6 g, 37.4 mmol)
in anhydrous CHCl3 (100 mL) was added in one portion, at room
temperature, to a magnetically stirred solution of pure 1,3-dithiol-
ane 4 (5.0 g, 18.7 mmol) in the same solvent (500 mL). After 16 h 70.22, H 6.38; found C 70.26, H 6.41. 1H NMR (500 MHz, C6D6):
at room temperature saturated aq. NaHCO3 (200 mL) was added. δ ϭ 1.72 (dd, J1Јa,2Јa ϭ 2.4, J1Јa,1Јb ϭ 12.9 Hz, 1 H, 1Ј-Ha),
The organic layer was separated and shaken with 5  aq. sodium
thiosulfate (150 mL), washed with water until neutral, dried
(Na2SO4), and the solvents evaporated under reduced pressure. The
oily residue, chromatographed on a silica gel column (petroleum
ether/Et2O, 9:1) afforded the pure 5,6-dihydro-1,4-dithiin 5a (4.5 g,
2.32Ϫ2.38 (m, 2 H, CH2S), 2.42Ϫ2.48 (m, 1 H, CHaS), 2.83Ϫ2.92
(m, 1 H, CHbS) 3.01Ϫ3.16 (m, 1 H, 2Ј-Ha), 3.22 (s, 3 H, OCH3),
3.40Ϫ3.48 (m, 1 H, 2Ј-Hb), 3.62 (dd, J6a,5 ϭ 1.5, J6a,6b ϭ 11.7 Hz,
1 H, 6-Ha), 3.92 (dd, J6b,5 ϭ 3.4, J6b,6a ϭ 11.7 Hz, 1 H, 6-Hb),
3.98Ϫ4.06 (m, 2 H, 4-H and OCHaMPM), 4.09Ϫ4.16 (m, 2 H, 3-
90%), oily. C13H14O2S2 (266.3): calcd. C 58.62, H 5.30; found C H and OCHbMPM), 4.19Ϫ4.22 (m, 1 H, 5-H), 4.34 (d, J2,3
ϭ
58.76, H 5.36. 1H NMR (300 MHz): δ ϭ 2.72 (dt, J1Ј,3 ϭ 0.8,
9.3 Hz, 1 H, 2-H), 4.38Ϫ4.46 (m, 1 H, 1Ј-Hb), 4.58 (d, Ja,b
ϭ
J1Ј,2Ј ϭ 6.6 Hz, 2 H, 1Ј-H), 3.98Ϫ3.26 (m, 4 H, 5-H and 6-H), 4.45 12.7 Hz, 1 H, Bzli-Ha), 4.63 (d, Ja,b ϭ 10.2 Hz, 1 H, Bzlii-Ha), 4.74
(t, J2Ј,1Ј ϭ 6.6 Hz, 2 H, 2Ј-H), 6.15 (s, 1 H, 3-H), 7.38Ϫ7.60 (m, 3 (d, Ja,b ϭ 11.2 Hz, 1 H, Bzliii-Ha), 4.80 (d, Jb,a ϭ 12.7 Hz, 1 H,
H, Hpara and Hmeta), 8.05 (d, Jortho ϭ 7.8 Hz, 2 H, Hortho) ppm. 13
C
Bzli-Hb), 4.87 (d, Jb,a ϭ 10.2 Hz, 1 H, Bzlii-Hb), 4.89 (d, Ja,b
ϭ
NMR (200 MHz): δ ϭ 24.3, 25.9 (C-5 and C-6), 37.0 (CH2ϪCϭ), 11.7 Hz, 1 H, Bzliv-Ha), 4.94 (d, Jb,a ϭ 11.2 Hz, 1 H, Bzliii-Hb),
Eur. J. Org. Chem. 2003, 2617Ϫ2621
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. Caputo, U. Ciriello, P. Festa, A. Guaragna, G. Palumbo, S. Pedatella
5.01 (d, Jb,a ϭ 11.7 Hz, 1 H, Bzliv-Hb), 6.42 (br. s, 1 H, OH), 6.65 1H NMR (500 MHz, C6D6): δ ϭ 1.72 (dd, J3a,2b ϭ 1.6, J3a,3b
FULL PAPER
ϭ
(d, Jortho ϭ 8.8 Hz, 2 H, Harom.), 7.02Ϫ7.61 (m, 22 H, Harom.) ppm. 16.2 Hz, 1 H, 3-Ha), 2.10Ϫ2.19 (m, 1 H, CHaS), 2.28Ϫ2.38 (m, 2
13C NMR (300 MHz): δ ϭ 26.3 (CH2Cϭ), 31.3, 36.0 (2 ϫ CH2S), H, 3-Hb and CHbS), 2.41Ϫ2.48 (m, 1 H, CHaS), 2.81Ϫ2.88 (m, 1
55.1 (OCH3), 67.8, 68.1, 68.5, 71.0, 73.2, 73.4, 74.9, 75.5, 75.9, 78.3,
H, CHbS), 3.28 (dd, J2a,3b ϭ 4.7, J2a,2b ϭ 11.0 Hz, 1 H, 2-Ha),
81.6, 83.5 (4Ј-CH2Bzl, CH2O, OCH2MPM, C-2, C-3, C-4, C-5, C- 3.67Ϫ3.73 (m, 1 H, 2-Hb), 3.76 (d, J12a,12b ϭ 10.5 Hz, 1 H, 12-Ha),
6), 99.3 (C-1), 113.6 (2 ϫ CmetaMPM), 127.1Ϫ129.4 (22 ϫ Carom.
CipsoMPM, 2 ϫ Cϭ), 137.8, 138.2, 138.5, 138.9 (4 ϫ Cipso), 159.2
(CϪOMe) ppm.
,
3.84 (d, J11,10 ϭ 2.6 Hz, 1 H, 11-H), 3.94Ϫ4.01 (m, 2 H, 8-H and
12-Hb), 4.31 (dd, J10,11 ϭ 2.6, J10,9 ϭ 9.4 Hz, 1 H, 10-H), 4.42 (t,
J9,10 ϭ 9.4 Hz, 1 H, 9-H), 4.51 (d, Ja,b ϭ 12.0 Hz, 1 H, Bzli-Ha),
4.55 (d, Jb,a ϭ 12.0 Hz, 1 H, Bzli-Hb), 4.61 (d, Ja,b ϭ 12.1 Hz,1 H,
Under the same conditions:
-Galactonolactone 7c: (89%), oily. [α]2d5
Compound 8c, from d ϭ
Bzlii-Ha), 4.65 (d, Ja,b ϭ 11.5 Hz, 1 H, Bzliii-Ha), 4.85 (d, Ja,b
ϭ
11.0 Hz, 1 H, Bzliv-Ha), 4.88 (d, Jb,a ϭ 11.0 Hz, 1 H, Bzliv-Hb),
4.91 (d, Jb,a ϭ 11.5 Hz, 1 H, Bzliii-Hb), 4.99 (d, Jb,a ϭ 12.1 Hz, 1
H, Bzlii-Hb), 7.00Ϫ7.65 (m, 20 H, Harom.) ppm. 13C NMR
(300 MHz): δ ϭ 27.8 (C-3), 31.3, 31.9 (2 ϫ CH2S), 58.1 (C-2), 69.4
(C-12), 72.6, 73.7, 74.2, 74.6 (4 ϫ CH2Bzl), 74.8, 75.3, 80.2, 81.8
(C-8, C-9, C-10, C-11), 97.4 (C-6), 122.3 (C-4), 125.5 (C-5),
Ϫ1.02 (c ϭ 1.1). C48H52O8S2 (821.0): calcd. C 70.22, H 6.38; found
C 70.18, H 6.34. 1H NMR (500 MHz, C6D6): δ ϭ 1.89 (d, J1Јa,1Јb ϭ
15.1 Hz, 1 H, 1Ј-Ha), 2.32Ϫ2.40 (m, 2 H, CH2S), 2.41Ϫ2.48 (m, 1
H, CHaS), 2.77Ϫ2.86 (m, 1 H, CHbS), 3.14 (m, 1 H, 2Ј-Ha), 3.26
(s, 3 H, OCH3), 3.46Ϫ3.54 (m, 1 H, 2Ј-Hb), 3.67 (dd, J6a,5 ϭ 5.4,
J6a,6b ϭ 8.8 Hz, 1 H, 6-Ha), 3.90 (t, J6b,6a ϭ J6b,5 ϭ 8.8 Hz, 1 H,
6-Hb), 4.01 (m, 1 H, 4-H), 4.05 (d, Ja,b ϭ 11.3 Hz, 1 H, OCH-
aMPM), 4.12 (dd, J3,4 ϭ 2.9, J3,2 ϭ 9.8 Hz, 1 H, 3-H), 4.16 (m, 2
H, 3-H and OCHbMPM), 4.26 (d, Ja,b ϭ 11.7 Hz, 1 H, Bzli-Ha),
4.33 (d, Jb,a ϭ 11.7 Hz, 1 H, Bzli-Hb), 4.34Ϫ4.38 (m, 1 H, 1Ј-Hb),
4.39Ϫ4.44 (m, 1 H, 5-H), 4.48 (d, Ja,b ϭ 11.7 Hz, 1 H, Bzlii-Ha),
4.61 (d, Jb,a ϭ 11.7 Hz, 1 H, Bzlii-Hb), 4.67 (d, Ja,b ϭ 10.7 Hz, 1
H, Bzliii-Ha), 4.68 (d, Ja,b ϭ 11.7 Hz, 1 H, Bzliv-Ha), 4.72 (dd, J2,3 ϭ
9.8, J2,4 ϭ 1.5 Hz, 1 H, 2-H), 4.91 (d, Jb,a ϭ 10.7 Hz, 1 H, Bzliii-
Hb), 5.12 (d, Jb,a ϭ 11.7 Hz, 1 H, Bzliv-Hb), 6.22 (br. s, 1 H, OH),
6.65 (d, Jortho ϭ 8.8 Hz, 2 H, Harom.), 7.02Ϫ7.48 (m, 22 H, Harom.).
13C NMR (300 MHz): δ ϭ 27.4 (CH2ϪCϭ), 31.2, 36.0 (2 ϫ CH2S),
55.2 (OCH3), 68.1, 68.4, 69.4, 72.6, 72.8, 73.1, 73.4, 74.2 (4 ϫ
CH2Bzl, CH2O, OCH2MPM, C-5, C-6), 74.5, 78.6 81.0 (C-2, C-3,
127.2Ϫ128.5 (20 ϫ Carom.), 138.8, 139.0, 139.1, 139.3 (4 ϫ Cipso
)
ppm.
Compound 9c from 8c: 88%, oily. [α]2d5 ϭ Ϫ29.1 (c ϭ 1.3).
C40H42O6S2 (682.9): calcd. C 70.35, H 6.20; found C 70.39, H 6.16.
1H NMR (500 MHz, C6D6): δ ϭ 1.57 (dd, J3a,2b ϭ 1.5, J3a,3b
ϭ
16.1 Hz, 1 H, 3-Ha), 2.27Ϫ2.34 (m, 1 H, CHaS), 2.36Ϫ2.42 (m, 1
H, CHbS), 2.44Ϫ2.57 (m, 3 H, CH2S and 3-Hb), 3.44 (dd, J2a,3b
4.5, J2a,2b ϭ 10.6 Hz, 1 H, 2-Ha), 3.68 (dd, J12a,8 ϭ 5.4, J12a,12b
ϭ
ϭ
8.8 Hz, 1 H, 12-Ha), 3.76Ϫ3.84 (m, 2 H, 2-Hb and 12-Hb), 3.97
(dd, J9,8 ϭ 1.2, J9,10 ϭ 2.7 Hz, 1 H, 9-H), 4.11 (dd, J10,9 ϭ 2.7,
J10,11 ϭ 10.0 Hz, 1 H, 10-H), 4.17 (ddd, J8,9 ϭ 1.2, J8,12a ϭ 5.4,
J8,12b ϭ 6.8 Hz, 1 H, 8-H), 4.22 (d, Ja,b ϭ 11.8 Hz, 1 H, Bzli-Ha),
4.27 (d, Jb,a ϭ 11.8 Hz, 1 H, Bzli-Hb), 4.48 (d, Ja,b ϭ 11.8 Hz, 1 H,
C-4), 99.8 (C-1), 113.7 (2 ϫ CmetaMPM), 126.9, 129.4 (22 ϫ Carom.
ipsoMPM, 2 ϫ Cϭ), 138.1, 138.5, 139.0, 139.6 (4 ϫ Cipso), 159.2
(CϪOMe) ppm.
,
Bzlii-Ha), 4.59 (d, Jb,a ϭ 11.8 Hz, 1 H, Bzlii-Hb), 4.65 (d, Ja,b
ϭ
C
11.8 Hz, 1 H, Bzliii-Ha), 4.88 (d, J11,10 ϭ 10.0 Hz, 1 H, 11-H), 4.91
(d, Ja,b ϭ 11.2 Hz, 1 H, Bzliv-Ha), 5.02 (d, Jb,a ϭ 11.2 Hz, Bzliv-
Hb), 5.13 (d, Jb,a ϭ 11.8 Hz, 1 H, Bzliii-Hb), 7.02Ϫ7.48 (m, 20 H,
Harom.) ppm. 13C NMR (300 MHz): δ ϭ 27.7 (C-3), 29.0, 31.2 (2
ϫ CH2S), 58.3 (C-2), 68.6 (C-12), 70.4, 72.9, 73.3, 74.0 (4 ϫ
CH2Bzl), 74.5, 75.5, 78.0, 80.8 (C-8, C-9, C-10, C-11), 98.7 (C-6),
119.9 (C-4), 126. 7 (C-5), 127.0Ϫ128.2 (20 ϫ Carom.), 137.9, 138.7,
139.0, 139.2 (4 ϫ Cipso) ppm.
Spirocyclization of Hemiacetal 8a to Compound 9a. Typical Pro-
cedure: A solution (3% v/v in CH2Cl2) of BF3·Et2O (0.2 mL) was
added carefully to a magnetically stirred solution of hemiacetal 8a
(0.81 g, 1.0 mmol) in CH2Cl2 (14 mL) at room temperature. After
1 h, the reaction was quenched with Et3N (0.03 mL, 0.2 mmol) and
the organic layer was washed with water and dried (Na2SO4). The
solvents were evaporated under reduced pressure to afford a crude
residue, and chromatography on a silica-gel column (petroleum
ether/EtOAc, 8:2) afforded the pure spiroacetal 9a (0.58 g, 87%),
oily. [α]2d5 ϭ Ϫ28.0 (c ϭ 0.7). C40H42O6S2 (682.9): calcd. C 70.35,
Compound 10a. Typical Desulfurization Procedure: A solution of
spiroacetal 9a (0.1 g, 0.15 mmol) in THF (3 mL) was added in one
portion to a stirred suspension of Raney-Ni (W2) (1.5 g, wet) in
the same solvent (2 mL) at room temperature. The suspension was
stirred for 35 min (TLC monitoring) and the solid was then filtered
off and washed with EtOAc. The filtrate was neutralized with satu-
rated aq. Na2CO3 and extracted with EtOAc (3 ϫ 15 mL). The
combined organic layers were washed with water until neutral,
dried (Na2SO4), and the solvents evaporated under reduced press-
ure to afford a crude residue. Chromatography of the latter on a
silica gel column (petroleum ether/EtOAc, 8:2) gave the pure sulfur-
free spiroacetal 10a (0.07 g, 79%) as an oil. [α]2d5 ϭ ϩ29.3 (c ϭ 0.5).
C38H40O6 (592.7): calcd. C 77.00, H 6.80; found C 77.06, H 6.84.
1H NMR (500 MHz, C6D6): δ ϭ 1.18Ϫ1.37 (m, 1 H, 3Ha),
1.98Ϫ2.09 (m, 1 H, 3Hb), 3.41 (d, J11,10 ϭ 9.8 Hz, 1 H, 11-H), 3.55
1
H 6.20; found C 70.38, H 6.17. H NMR (500 MHz, C6D6): δ ϭ
1.55 (dd, J3,2 ϭ 1.4, J3a,3b ϭ 16.3 Hz, 1 H, 3-Ha), 2.30Ϫ2.42 (m, 2
H, CH2S), 2.44Ϫ2.58 (m, 3 H, 3-Hb and CH2S), 3.45 (dd, J2a,3b
4.9, J2a,2b ϭ 10.7 Hz, 1 H, 2-Ha), 3.65 (dd, J12,8 ϭ 1.5, J12a,12b
11.2 Hz, 1 H, 12-Ha), 3.74 (ddd, J2b,3a ϭ 1.4, J2b,3b ϭ 9.3, J2b,2a
ϭ
ϭ
ϭ
10.7 Hz, 1 H, 2-Hb), 3.84 (dd, J12,8 ϭ 3.9, J12b,12a ϭ 11.2, 1 H, 12-
Hb), 3.90 (t, J9,8 ϭ J9,10 ϭ 9.8 Hz, 1 H, 9-H), 4.05 (ddd, J8,12a
ϭ
1.4, J8,12b ϭ 3.9, J8,9 ϭ 9.8 Hz, 1 H, 8-H), 4.48 (d, Ja,b ϭ 12.2 Hz,
1 H, Bzli-Ha), 4.68 (d, Jb,a ϭ 12.2 Hz, 1 H, Bzli-Hb), 4.70 (d, Ja,b ϭ
11.3 Hz, 1 H, Bzlii-Ha), 4.82 (d, Ja,b ϭ 11.7 Hz, 1 H, Bzliii-Ha),
4.88Ϫ4.95 (m,
4 H, Bzlii-Hb and Bzliii-Hb and Bzliv-Ha,b),
7.02Ϫ7.43 (m, 20 H, Harom.) ppm. 13C NMR (300 MHz): δ ϭ 27.6
(C-3), 29.6, 31.3 (2 ϫ CH2S), 58.3 (C-2), 68.6 (C-12), 72.2, 73.3,
74.9, 75.3, 75.6, 78.1, 81.3, 83.3 (4 ϫ CH2Bzl, C-8, C-9, C-10, C-
11), 98.2 (C-6), 115.7 (C-4), 119.4 (C-5), 127.5Ϫ128.2 (20 ϫ Carom.),
138.2Ϫ138.7 (4 ϫ Cipso) ppm.
(dd, J2a,3b ϭ 5.76, J2a,2b ϭ 10.7 Hz, 1 H, 2-Ha), 3.68 (dd, J12a,8
ϭ
1.95, J12a,12b ϭ 10.7 Hz, 1 H, 12-Ha), 3.72Ϫ3.81 (m, 2 H, 2-Hb and
12-Hb), 3.87 (t, J9.8 ϭ J9,10 ϭ 9.3 Hz, 1 H, 9-H), 4.09 (m, 1 H, 8-
H), 4.31 (dd, J10,9 ϭ 9.3, J10,11 ϭ 9.8 Hz, 1 H, 10-H), 4.34 (dd,
Ja,b ϭ 12.2 Hz, 1 H, Bzli-Ha), 4.45 (d, Ja,b ϭ 12.2 Hz, 1 H, Bzli-
The following spiroacetals were also obtained under the same con-
ditions:
Compound 9b from 8b: 87%, oily. [α]2d5 ϭ Ϫ22.6 (c ϭ 0.4).
Hb), 4.55 (d, Ja,b ϭ 11.2 Hz, 1 H, Bzlii-Ha), 4.68 (dd, Jb,a ϭ Ja,b
11.2 Hz, 2 H, Bzlii-Hb and Bzliii-Ha), 4.82 (d, Ja,b ϭ 11.2 Hz, 1 H,
Bzliv-Ha), 4.92 (d, Jb,a ϭ 11.2 Hz, 1 H, Bzliv-Hb), 4.98 (d, Jb,a
ϭ
ϭ
C40H42O6S2 (682.9): calcd. C 70.35, H 6.20; found C 70.39, H 6.19. 11.2 Hz, 1 H, Bzliii-Hb), 5.50 (td, J5,3 ϭ 1.0, J5,4 ϭ 10.26 Hz, 1 H,
2620  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2003, 2617Ϫ2621

Fully Protected (S)-1,7-Dioxaspiro[5,5]undec-4-ene Derivatives of Sugars
5-H), 5.70 (dd, J4,3a ϭ 5.8, J4,5 ϭ 10.2 Hz, 1 H, 4-H), 7.01Ϫ7.18
FULL PAPER
Hb), 5.08 (d, Jb,a ϭ 11.2 Hz, Bzliv-Hb), 5.58 (dd, J5,3b ϭ 1.9, J5,4
ϭ
(m, 20 H, Harom.) ppm, [5-H, 11 H: NOE effect]. 13C NMR 10.2 Hz, 1 H, 5-H), 5.68 (dd, J4,3a ϭ 5.8, J4,5 ϭ 10.2 Hz, 1 H, 4-
(400 MHz): δ ϭ 24.6 (C-3), 58.6 (C-2), 69.3 (C-12), 71.5, 73.8, 75.3, H), 7.01Ϫ7.45 (m, 20 H, Harom.) ppm, [5-H, 11 H: NOE effect].
75.7, 76.1, 78.7, 83.3, 83.6 (4 ϫ CH2Bzl, C-8, C-9, C-10, C-11),
96.1 (C-6), 127.9Ϫ129.0 (C-4, 20 ϫ Carom.), 130.8 (C-5), 138.5, 73.2, 73.4, 74.5 (4 ϫ CH2Bzl), 74.9, 75.3, 79.2, 80.3 (C-8, C-9, C-
13C NMR (200 MHz): δ ϭ 29.6 (C-3), 58.2 (C-2), 68.8 (C-12), 69.7,
138.6, 138.8, 139.6 (4 ϫ Cipso) ppm.
10, C-11), 95.9 (C-6), 127.2Ϫ128.2 (20 ϫ Carom.), 128.5 (C-4), 130.0
(C-5), 138.0, 138.2, 138.4, 138.8 (4 ϫ Cipso) ppm.
The following desulfurized spiroacetals were also obtained under
the same conditions:
Compound 10b from 9b: 77%, oily. [α]2d5 ϭ ϩ18.4 (c ϭ 0.1).
C38H40O6 (592.7): calcd. C 77.00, H 6.80; found C 70.04, H 6.85.
1H NMR (500 MHz, C6D6): δ ϭ 1.15Ϫ1.25 (m, 1 H, 3-Ha),
1.82Ϫ1.92 (m, 1 H, 3-Hb), 3.35 (dd, J2a,3b ϭ 6.3, J2a,2b ϭ 10.7 Hz,
1 H, 2-Ha), 3.63Ϫ3.68 (m, 2 H, 10-H and 12-Ha), 3.72Ϫ3.78 (m, 2
H, 2-Hb and 12-Hb), 3.96Ϫ4.02 (m, 1 H, 8-H), 4.15Ϫ4.23 (m, 2 H,
9-H and 11-H), 4.34 (d, Ja,b ϭ 12.2 Hz, 1 H, Bzli-Ha), 4.39Ϫ4.52
(m, 5 H, Bzli-Hb and Bzlii-Ha and Bzliii-Ha and Bzliv-Ha,b), 4.84 (d,
Jb,a ϭ 11.7 Hz, 1 H, Bzlii-Hb), 4.86 (d, Ja,b ϭ 11.7 Hz, 1 H, Bzliii-
Hb), 5.57 (dd, J4,3a ϭ 5.8, J4,5 ϭ 10.3 Hz, 1 H, 4-H), 6.16 (dd,
Acknowledgments
1H and 13C NMR spectra were obtained at Centro Interdiparti-
`
mentale di Metodologie Chimico-Fisiche, Universita di Napoli
Federico II, and Lab. of Consorzio Interuniversitario Nazionale
La Chimica per lЈAmbiente (INCA). The Inova 500 Varian instru-
ment was used in the frame of a project by INCA (M.I.U.R., L.
488/92, Cluster 11-A).
[1]
R. Caputo, A. Guaragna, G. Palumbo, S. Pedatella, F. Solla,
Eur. J. Org. Chem. 2002, 534Ϫ536.
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5,3b ϭ 1.4, J5,4 ϭ 10.3 Hz, 1 H, 5-H), 6.99Ϫ7.35 (m, 20 H, Harom.)
[2]
Y. Du, R. J. Linhardt, Tetrahedron 1998, 54, 9913Ϫ9959.
ppm, [5-H, 11 H: no NOE effect]. 13C NMR (200 MHz): δ ϭ 29.6
(C-3), 57.6 (C-2), 69.5 (C-12), 72.3, 72.6, 73.2, 74.8 (4 ϫ CH2Bzl),
74.9, 75.0, 78.5, 81.4 (C-8, C-9, C-10, C-11), 95.5 (C-6), 126. 5
(C-4), 127.3Ϫ128.1 (20 ϫ Carom.), 128.5 (C-5), 138.2Ϫ138.6 (4 ϫ
[3]
S. Hanessian, A. Ugolini, Carbohydr. Res. 1984, 130, 261Ϫ269.
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F. Perron, K. F. Albizati, Chem. Rev. 1989, 89, 1617Ϫ1661.
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P. A. V. van Hooft, M. A. Leeuwenburgh, H. S. Overkleeft,
G. A. van der Marel, C. A. A. van Boeckel, J. H. van Boom,
Tetrahedron Lett. 1998, 39, 6061Ϫ6064.
M. O. Chaney, P. V. Demarco, N. D. Jones, J. L. Occolowitz,
Cipso) ppm.
[6]
Compound 10c from 9c: 78%, oily. [α]2d5 ϭ ϩ10.1 (c ϭ 0.1).
C38H40O6 (592.7): calcd. C 77.00, H 6.80; found C 77.04, H 6.85.
1H NMR (500 MHz, C6D6): δ ϭ 1.20Ϫ1.32 (m, 1 H, 3-Ha),
2.08Ϫ2.18 (m, 1 H, 3-Hb), 3.56 (dd, J2a,3b ϭ 5.9, J2a,2b ϭ 10.7 Hz,
1 H, 2-Ha), 3.75 (dd, J12a,8 ϭ 5.8, J12a,12b ϭ 8.8 Hz, 1 H, 12-Ha),
3.78Ϫ3.86 (m, 2 H, 2-Hb, and 12-Hb), 3.98 (br. s, 1 H, 9-H), 4.14
(br. s, 1 H, 10-H), 4.20Ϫ4.25 (m, 2 H, 8-H and 11-H), 4.26 (d,
Ja,b ϭ 11.7 Hz, 1 H, Bzli-Ha), 4.32 (d, Jb,a ϭ 11.7 Hz, 1 H, Bzli-
Hb), 4.48 (d, Ja,b ϭ 11.7 Hz, 1 H, Bzlii-Ha), 4.55 (d, Ja,b ϭ 11.2 Hz,
1 H, Bzliii-Ha), 4.60 (d, Jb,a ϭ 11.7 Hz, 1 H, Bzlii-Hb), 4.62 (d,
Ja,b ϭ 11.2 Hz, 1 H, Bzliv-Ha), 4.78 (d, Jb,a ϭ 11.2 Hz, 1 H, Bzliii-
J. Am. Chem. Soc. 1974, 96, 1932Ϫ1933.
[7]
S. J. Danishefsky, D. M. Armistead, F. E. Wincott, H. G.
Selnick, R. Hungate, J. Am. Chem. Soc. 1987, 109, 8117Ϫ8119.
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Swain, J. Chem. Soc., Chem. Commun. 1983, 829Ϫ831.
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[8]
[9]
2369Ϫ2376.
[10]
´
ˆ
M. E. Lasterra Sanchez, V. Michelet, I. Besnier, J. P. Genet,
Synlett 1994, 705Ϫ708.
R. Caputo, G. Palumbo, S. Pedatella, Tetrahedron 1994, 50,
7265Ϫ7268.
[11]
Received January 21, 2003
Eur. J. Org. Chem. 2003, 2617Ϫ2621
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2621