Synthesis of anellated carbasugars from (-)-quinic acid

Article abstract of DOI:10.1016/S0008-6215(02)00411-1

(3R,4R,5R)-3-[(tert-Butyl-dimethylsilyl)oxy]-4,5-(isopropylidenedioxy)-1- cyclohexanone (2) reacted with carbon disulfide and methyl iodide in the presence of sodium hydride to furnish (3R,4R,5R)-5-[(tert-butyl-dimethylsilyl)oxy]-3,4-(isopropylidenedioxy)-2- [bis(methylthio)methylene]-1-cyclohexanone (3). 2 and N,N-dimethylformamide dimethyl acetal afforded (2E,3R,4R,5R)-5-[(tert-butyl-dimethylsilyl)oxy]-2-(dimethylaminomethylene)- 3,4-(isopropylidenedioxy)-1-cyclohexanone (4). These push-pull activated methylenecyclohexanones 3 and 4 underwent a ring closure reaction with hydrazine hydrate and methylhydrazine, respectively, to give pyrazoloanellated carbasugars. Treatment of 3 with formamidinium, acetamidinium and benzamidinium salts, respectively, in the presence of sodium methanolate yielded three (5R,6R,7R)-7-[(tert-butyl-dimethylsilyl)oxy]-5,6,7,8-tetrahydro-5,6- (isopropylidenedioxy)benzo[d]pyrimidines.

Full text of DOI:10.1016/S0008-6215(02)00411-1

Carbohydrate Research 338 (2003) 293–298
www.elsevier.com/locate/carres
Note
Synthesis of anellated carbasugars from (−)-quinic acid
Lidcay Herrera,a Holger Feist,a Manfred Michalik,b Jose´ Quincoces,c Klaus Pesekea,*
aFachbereich Chemie, Uni6ersita¨t Rostock, D-18051 Rostock, Germany
bInstitut fu¨r Organische Katalyseforschung, Buchbinderstraße 5–6, D-18055 Rostock, Germany
cUni6ersidade Bandeirante de Sa˜o Paulo, Rua Maria Candida, 1813, Vila Guilherme, Sao Paulo, CEP: 02071-013, Brazil
Received 6 June 2002; received in revised form 30 September 2002; accepted 13 October 2002
Dedicated to Professor Dr. Rainer Radeglia on the occasion of his 65th birthday
Abstract
(3R,4R,5R)-3-[(tert-Butyl-dimethylsilyl)oxy]-4,5-(isopropylidenedioxy)-1-cyclohexanone (2) reacted with carbon disulfide and
methyl iodide in the presence of sodium hydride to furnish (3R,4R,5R)-5-[(tert-butyl-dimethylsilyl)oxy]-3,4-(isopropylidenedioxy)-
2-[bis(methylthio)methylene]-1-cyclohexanone (3). 2 and N,N-dimethylformamide dimethyl acetal afforded (2E,3R,4R,5R)-5-
[(tert-butyl-dimethylsilyl)oxy]-2-(dimethylaminomethylene)-3,4-(isopropylidenedioxy)-1-cyclohexanone (4). These push–pull
activated methylenecyclohexanones 3 and 4 underwent a ring closure reaction with hydrazine hydrate and methylhydrazine,
respectively, to give pyrazoloanellated carbasugars. Treatment of 3 with formamidinium, acetamidinium and benzamidinium salts,
respectively, in the presence of sodium methanolate yielded three (5R,6R,7R)-7-[(tert-butyl-dimethylsilyl)oxy]-5,6,7,8-tetrahydro-
5,6-(isopropylidenedioxy)benzo[d]pyrimidines. © 2002 Published by Elsevier Science Ltd.
Keywords: (−)-Quinic acid; Benzo[c]pyrazoles; Benzo[d]pyrimidines, a-Oxoketene-S,S-acetals; Push–pull alkenes
Modifications of monosaccharides to increase their
stability towards enzymes and yet retain their biological
properties have led to the development of carbohydrate
mimics. Replacement of the ring oxygen by a carbon
atom creates a carbasugar (pseudosugar) species. The
synthesis of carbasugars is a topic of interest in relation
to elucidation of the biological role of carbohydrates
and their use as drugs.1–10 Furthermore, anellated cyclic
monosaccharide derivatives have attracted great inter-
est in organic synthesis11–15 because of their biological
importance, for example as antibiotics, cancero-
statics16–18 or as inhibitors of different glycosidases.19,20
Here we report the preparation of carbasugars with a
push–pull substituted exocyclic CꢀC double bond from
a cyclohexanone derivative having a-methylene groups
activated by the adjacent carbonyl function. These
push–pull activated carbasugars could be used as pre-
cursors for syntheses of pyrazolo- and pyrimidoanel-
lated carbasugars.
(−)-Quinic acid, a widespread natural compound,
was reacted in three steps to furnish (3R,4S,5R)-3-
hydroxy - 4,5 - (isopropylidenedioxy) - 1 - cyclohexanone
(1).21,22 Silylation of this b-hydroxy ketone with tert-
butyl-chlorodimethylsilane (TBDMSCl) in the presence
of imidazole yielded the (3R,4R,5R)-3-[(tert-butyl-
dimethylsilyl)oxy] - 4,5 - (isopropylidenedioxy) - 1 - cyclo-
hexanone (2) in 80% yield [cf. Ref. 23]. For structure
elucidation of the following compounds it was neces-
sary to assign the signal at l=4.68 (dt) in the 1H NMR
spectrum to H-3 or H-5. The correlations in a NOESY
spectrum for H-4 and H-5 gave the H-5 assignment.
As described earlier,24–26 treatment of deoxysugar
uloses with carbon disulfide and alkyl halide in the
presence of bases afforded the corresponding monosac-
charidic a-oxo ketene dithioacetals. Similarly, the car-
basugar
2 reacted with sodium hydride, carbon
disulfide and methyl iodide in N,N-dimethylformamide
to give the corresponding push–pull functionalized car-
basugar 3 in 79% yield as a yellow syrup. In accordance
with the push–pull effect, in the IR spectrum of this
a-oxo ketene dithioacetal 3 the carbonyl band appeared
at a higher wavelength (1676 cm−1) compared with the
* Corresponding author. Fax: +49-381-4986412
E-mail address: klaus.peseke@chemie.uni-rostock.de (K.
Peseke).
0008-6215/03/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0008-6215(02)00411-1

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L. Herrera et al. / Carbohydrate Research 338 (2003) 293–298
Scheme 1. Syntheses and NOE’s of 3 and 4. Reagents (i) (a) TBDMSC1, imidazole (b) NaHSO4/H2O; (ii) (a) NaH, CS2, Mel,
DMF, (b) H2O; (iii) HC(Ome)2Nme2, toluene.
1H NMR spectrum and the NOE correlation of the
dimethylamino group with H-3 proved reaction of the
6-methylene group in compound 2 with the N,N-
dimethylformamide dimethyl acetal, as well as the E-
configuration of the final product.
In analogy to simple push–pull activated a-oxo
ketene dithioacetals30–32 compound 3 was reacted with
hydrazine hydrate to yield (4R,5R,6R)-6-[(tert-butyl-
dimethylsilyl)oxy] - 4,5,6,7 - tetrahydro - 4,5 - (isopropyli-
denedioxy)-3-methylthio-2H(1H)-benzo[c]pyrazole (5)
as a colourless solid (Scheme 2). The spectroscopic data
clearly verify the formation of compound 5. The mass
spectrum contained a signal for [M+1]+ at m/z 371.
The signals for only one methylthio group at l=2.50
and l=17.1 were found in the 1H and 13C NMR
spectra, respectively. On the other hand, in the 13C
NMR spectrum no signal for a carbonyl group was
present. Due to the fast proton exchange between the
CO band in the starting compound 2 (1724 cm−1).24 In
the 1H and 13C NMR spectra the signals for both
methylthio groups were found at l=2.49–2.37 and
l=19.9, 18.6, respectively. The 13C NMR spectrum of
compound 3 showed an upfield shift for the signal of
C-2 (l=131.0) whereas the signal of C-2% was shifted
downfield (l=157.9) which is typically for push–pull
alkenes.27,28 The alternative attack of carbon disulfide
on C-2 of carbasugar 2 could be excluded by the
comparison of the corresponding signals for H-3 in
compound 3 with the corresponding H-5 signals in
compound 2 (double triplett at l=4.68 for 2 and only
a doublet at l=5.92 for 3). Furthermore, a NOESY
experiment showed a relation between one methylthio
group and H-3 (Scheme 1).
Bredereck et al. reported the reaction of acidic meth-
ylene compounds with acetals of amides to furnish
push–pull substituted alkenes as well.29 In this way
compound 2 was reacted with N,N-dimethylformamide
dimethyl acetal in boiling toluene to afford (2E,3R,
4R,5R)-5-[(tert-butyl-dimethylsilyl)oxy]-2-(dimethyl-
aminomethylene) - 3,4 - (isopropylidenedioxy) - 1 - cyclo-
hexanone (4) as a light yellow solid in 58% yield. In the
1H NMR spectrum signals appeared for a dimethy-
lamino group and H-2% at l=3.19 and l=7.68, respec-
tively. Furthermore, in the 13C NMR spectrum the
shifts of signals for C-2 (l=99.3) and C-2% (l=152.9)
were in accordance with the expected one for such
push–pull substituted carbon atoms. In a similar fash-
ion to compound 3, a doublet for H-3 at l=5.27 in the
Scheme 2. Syntheses of 5–7. Reagents (i) NH2NH2/H2O/
MeOH, reflux; (ii) MeNHNH2/MeOH, reflux.

L. Herrera et al. / Carbohydrate Research 338 (2003) 293–298
295
Scheme 3. Syntheses of 8–11. Reagents (i) MeONa/MeOH, 50 °C; (ii) CF3COOH/H2O.
nitrogen atoms an NH signal was not identified and in
1. Experimental
1.1. General methods
the 13C NMR spectrum the C-7a appeared as broad
signal at l=142.7. The C-3 signal was not displayed
due to exchange broadening.
The a-oxoketene-S,S-acetal 3 and methylhydrazine
Melting points were determined with a Boe¨tius melting
point apparatus and are corrected. Optical rotations
were measured with a Polar LmP (IBZ Meßtechnik)
polarimeter. IR spectra were recorded with a Nicolet
205 FT-IR spectrometer. 1H and 13C NMR spectra
were recorded with a Bruker AC 250 (250.13 MHz and
62.9 MHz, resp.) and a Bruker ARX 300 (300.13 MHz
and 75.5 MHz, resp.). The calibration of spectra was
afforded
the
(4R,5R,6R)-6-[(tert-butyl-dimethylsi-
lyl)oxy]-4,5,6,7-tetrahydro-4,5-(isopropylidenedioxy)-2-
methyl-3-methylthio-2H-benzo[c]pyrazole (6) in 52%
1
yield as colourless crystals. In the H and 13C NMR
spectra only one methylthio signal at l=2.36 and 19.2,
respectively, and one N-methyl signal at l=3.88 and
l=36.4, respectively, were found. The stereochemistry
of this N-methyl group was proved by the NOE with
the neighbouring methylthio group.
Furthermore, the dimethylaminoenone 4 was reacted
with methylhydrazine to furnish the (4R,5R,6R)-6-
[(tert - butyl - dimethylsilyl)oxy] - 4,5,6,7 - tetrahydro-4,5-
(isopropylidenedioxy) - 2 - methyl - 2H - benzo[c]pyrazole
(7) in 69% yield. Similarly to compound 6, the 3-methyl
signal was found at l=3.84 and l=38.9 in the 1H and
13C NMR spectra and the position of the methyl group
with respect to the N atoms was determined by the
NOE with H-3.
1
carried out by means of solvent peaks (CDCl3: l H
1
7.25; l 13C 77.0; acetone-D6: l H 2.04; l 13C 29.7;
DMSO-D6: l 1H 2.50; l 13C 39.7). The 13C NMR
1
signals were assigned by DEPT and/or H,13C correla-
tion spectra. Mass spectra were obtained with an AMD
402/3 spectrometer (AMD Intectra GmbH). Elemental
analyses were performed with a Leco CHNS-932.
Column chromatography was carried out on Silica gel
60 (230–400 mm, Merck). Thin-layer chromatography
(TLC) was performed on Silica gel 60 GF254 foils
(Merck) with detection by UV-light and by charring
with sulphuric acid. Solvents and liquid reagents were
purified and dried according to recommended
procedures.
Treatment of the dimethylaminoenone 4 with form-
amidinium, acetamidinium, and benzamidinium salts,
respectively, in the presence of sodium methanolate in
methanol at 50 °C afforded the corresponding pyrimi-
doanellated carbasugars 8–10 in 30–49% yield (Scheme
1.2.
(3R,4R,5R)-3-[(tert-Butyl-dimethylsilyl)oxy]-4,5-
1
3). In the H and 13C NMR spectra of compound 8 the
(isopropylidenedioxy)-1-cyclohexanone (2) [cf. Ref. 23]
signals at l=8.97 for H-2 and l=158.8 for C-2 confir-
med the successful anellation. Similarly, the corre-
sponding signals for C-2 in the 13C NMR spectra of 9
and 10 were found at l=168.0 and l=165.1(164.2).
For compound 10 we examined the deprotection with
a 60% aqueous solution of trifluoroacetic acid at 22 °C,
which afforded, accompanied by elimination, the
(5R,6S)-5,6-dihydro-5,6-dihydroxy-2-phenyl-benzo[d]-
pyrimidine (11) in 55% yield.
In summary, we have described routes for the synthe-
sis of pyrazolo- and pyrimidoanellated carbasugars
with defined stereochemistry on the basis of push–pull
activated methylenecyclohexanone.
Imidazole (1.70 g, 25 mmol) and TBDMSCl (2.26 g, 15
mmol) were added to a solution of (3R,4R,5R)-5-hy-
droxy - 3,4 - (isopropylidenedioxy) - 1 - cyclohexanone21,22
(1, 1.86 g, 10 mmol), in DMF (25 mL). The reaction
mixture was stirred for 12 h at 22 °C, then diluted with
chloroform (100 mL), washed with 3% aqueous
NaHSO4 (50 mL) and three times with water (100 mL),
dried with Na2SO4 and evaporated. The residue was
purified by column chromatography (toluene/ethyl ace-
tate 10:1) to yield 2.40 g (80%) of 2 as a colourless
solid; TLC: toluene/ethyl acetate 2:1 Rf: 0.75; mp 34–
36 °C; [h]2D1: +100.1 (c 1.0, CHCl3); IR (capillary):

296
L. Herrera et al. / Carbohydrate Research 338 (2003) 293–298
1724 cm−1 (CO); 1H NMR (250.1 MHz, CDCl3): l
81–83 °C; [h]2D1: +266.3 (c 1.0, CHCl3); IR (KBr): 1651
3
3
1
4.68 (dt, 1H, J4,5ꢀ7.1 Hz, J5,6ꢀ3J5,6%ꢀ3.5 Hz, H-5);
cm−1 (CO); H NMR (300.1 MHz, CDCl3): l 7.68 (s,
2
3
4.23–4.12 (m, 2H, H-4, H-3); 2.73 (dd, 1H, J6,6%ꢀ17.5
1H, H-2%); 5.27 (d, 1H, J3,4ꢀ6.0 Hz, H-3); 4.09–4.03
3
Hz, J5,6ꢀ3.5 Hz, H-6); 2.63 (dd, 2H, H-2a, H-6%); 2.35
(m, 2H, H-4, H-5); 3.19 (s, 6H, NMe2); 2.62 (dd, 1H,
2J6,6%ꢀ16.2 Hz, 3J5,6ꢀ3.3 Hz, H-6); 2.29 (m, 1H, H-6%);
1.47, 1.38 (2s, 2×3H, CMe2); 0.85 (s, 9H, CMe3); 0.07,
0.05 (2s, 2×3H, SiMe2); 13C NMR (75.5 MHz,
CDCl3): l 193.9 (C-1); 152.9 (C-2%); 107.6 (CMe2); 99.3
(C-2); 78.3 (C-4); 71.5 (C-3); 69.3 (C-5); 43.4 (NMe2);
43.2 (C-6); 27.8 (1×CMe2); 25.5 (CMe3); 24.9 (1×
CMe2); 18.0 (CMe3); −4.7, −4.8 (SiMe2); MS, EI
(m/z): 355 [M]+; Anal. Calcd for C18H33NO4Si: C
60.75; H 9.28; N 3.94. Found: C 61.03; H 9.42; N 4.12.
2
3
4
(ddd, 1H, J2,2%ꢀ17.5 Hz, J2%,3ꢀ3.7 Hz, J2%,4ꢀ2.0
Hz, H-2%); 1.42, 1.35 (2s, 2×3H, CMe2); 0.84 (s, 9H,
CMe3); 0.07, 0.04 (2s, 2×3H, SiMe2); 13C NMR (62.9
MHz, CDCl3): l 207.6 (C-1); 108.7 (CMe2); 75.2 (C-4);
72.4 (C-5); 68.8 (C-3); 41.9 (C-2); 40.2 (C-6); 26.3
(1×CMe2); 25.6 (CMe3); 23.9 (1×CMe2); 17.9
(CMe3); −5.0 (2×SiMe2); MS, CI (m/z): 301 [M+
1]+; Anal. Calcd for C15H28O4Si: C 59.96; H 9.39.
Found: C 60.20; H 9.30.
1.3. (3R,4R,5R)-5-[(tert-Butyl-dimethylsilyl)oxy]-3,4-
(isopropylidenedioxy)-2-[bis(methylthio)methylene]-1-
cyclohexanone (3)
1.5. (4R,5R,6R)-6-[(tert-Butyl-dimethylsilyl)oxy]-
4,5,6,7-tetrahydro-4,5-(isopropylidenedioxy)-3-
methylthio-2H(1H)-benzo[c]pyrazole (5)
A solution of 2 (0.30 g, 1.0 mmol), carbon disulfide
(0.18 mL, 3.0 mmol) and methyl iodide (0.25 mL, 4.0
mmol) in anhyd DMF (10 mL) was cooled to 0 °C.
Then sodium hydride (0.08 g, 2.0 mmol, 60%) was
added. The mixture was stirred for 1 h at 0 °C, then
poored onto ice water and extracted three times with
CHCl3 (50 mL). The combined organic layers were
washed with water, dried (Na2SO4) and concentrated.
The residue was purified by column chromatography
(toluene/ethyl acetate 15:1) to yield 0.32 g (79%) of 3 as
a yellow syrup; TLC: toluene/ethyl acetate 10:1 Rf:
0.53; [h]2D1: −75.5 (c 1.0, CHCl3); IR (capillary): 1676
A mixture of 3 (0.40 g, 1.0 mmol) and hydrazine
hydrate (0.15 mL, 3.0 mmol) in anhyd methanol (10
mL) was heated at reflux for 30 min., the reaction
mixture was cooled and the solvent was evaporated
under vacuum. The residue was purified by column
chromatography (toluene/ethyl acetate 1:2) to yield 0.11
g (30%) of 5 as colourless solid; TLC: toluene/ethyl
acetate 3:1 Rf: 0.36; mp 127–129 °C; [h]2D1: +30.5 (c
1.0, CHCl3); IR (KBr): 3195 cm−1 (NH); 1H NMR
3
(250.1 MHz, CDCl3): l 5.17 (d, 1H, J4,5ꢀ5.5 Hz,
H-4); 4.30–4.18 (m, 2H, H-5, H-6); 2.95 (dd, 1H,
3
2J7,7%ꢀ16.0 Hz, J6,7ꢀ4.0 Hz, H-7); 2.61 (dd, 1H,
cm−1 (CO); H NMR (250.1 MHz, CDCl3): l 5.92 (d,
2J7,7%ꢀ16.0 Hz, 3J6,7%ꢀ5.8 Hz, H-7%); 2.50 (s, 3H, SMe);
1.44, 1.32 (2s, 2×3H, CMe2); 0.82 (s, 9H, CMe3); 0.09,
0.05 (2s, 2×3H, SiMe2); 13C NMR (62.9 MHz,
CDCl3): l 142.7 (br, C-7a); 114.9 (C-3a); 109.5 (CMe2);
78.2 (C-5); 69.5, 68.7 (C-4, C-6); 27.9 (1×CMe2); 27.8
(C-7); 26.1 (1×CMe2); 25.5 (CMe3); 17.8 (CMe3); 17.1
(SMe); −4.4, −4.6 (SiMe2); C-3 not displayed due to
exchange broadening; MS, CI (m/z): 371 [M+1]+;
Anal. Calcd for C17H30N2O3SSi: C 55.14; H 8.11; N
7.57; S 8.64. Found: C 55.08; H 8.30; N 7.49; S 8.50.
1
3
3
1H, J3,4ꢀ7.5 Hz, H-3); 4.24 (dt, 1H, J3,4ꢀ7.5 Hz,
3J4,5ꢀ4J4,6%ꢀ2.5 Hz, H-4); 4.05 (m, 1H, H-5); 2.81 (dd,
2
3
1H, J6,6%ꢀ16.8 Hz, J5,6ꢀ2.2 Hz, H-6); 2.49–2.37 (m,
7H, H-6%, 2×SMe); 1.43, 1.41 (2s, 2×3H, CMe2); 0.78
(s, 9H, CMe3); 0.03, 0.01 (2s, 2×3H, SiMe2); 13C
NMR (62.9 MHz, CDCl3): l 195.0 (C-1); 157.9 (C-2%);
131.0 (C-2); 108.7 (CMe2); 77.3 (C-4); 75.5 (C-3); 68.6
(C-5); 42.6 (C-6); 26.4 (1×CMe2); 25.6 (CMe3); 24.2
(1×CMe2); 19.9, 18.6 (2×SMe); 17.8 (CMe3); −4.9,
−5.0 (SiMe2); MS, CI (m/z): 405 [M+1]+; Anal.
Calcd for C18H32O4S2Si: C 53.46; H 7.92; S 15.84.
Found: C 53.63; H 8.07; S 15.92.
1.6. (4R,5R,6R)-6-[(tert-Butyl-dimethylsilyl)oxy]-4,5,6,7-
tetrahydro-4,5-(isopropylidenedioxy)-2-methyl-3-
methylthio-2H-benzo[c]pyrazole (6)
1.4. (2E,3R,4R,5R)-5-[(tert-Butyl-dimethylsilyl)oxy]-2-
(dimethylaminomethylene)-3,4-(isopropylidenedioxy)-1-
cyclohexanone (4)
A mixture of 3 (0.404 g, 1.0 mmol) and methylhy-
drazine (0.16 mL, 3.0 mmol) was reacted as described
before. The residue was purified by column chromatogr-
aphy (toluene/ethyl acetate 3:1) to yield 0.20 g (52%) of
6 as colourless crystals; TLC: toluene/ethyl acetate 3:1
Rf: 0.57; mp 47–49 °C; [h]2D1: +57.1 (c 1.0, CHCl3); IR
(KBr): 1549 cm−1 (CꢁC); 1H NMR (250.1 MHz,
To a solution of 2 (0.6 g, 2.0 mmol) in anhyd toluene
(20 mL) was added N,N-dimethylformamide dimethyl-
acetal (1.33 ml, 10 mmol). After 5 h under reflux the
mixture was allowed to cool to 20 °C and after that the
solvent was evaporated under vacuum. The residue was
purified by column chromatography (toluene/ethyl ace-
tate 1:1) to yield 0.41 g (58%) of 4 as a light yellow
solid. TLC: toluene/ethyl acetate 1:1; Rf: 0.17; mp
3
CDCl3): l 5.19 (d, 1H, J4,5ꢀ5.3 Hz, H-4); 4.27–4.16
(m, 2H, H-5, H-6); 3.88 (s, 3H, NMe); 2.92 (dd, 1H,
3
2J7,7%ꢀ15.8 Hz, J6,7ꢀ3.8 Hz, H-7); 2.58 (dd, 1H,
2J7,7%ꢀ15.8 Hz, 3J6,7%ꢀ6.1 Hz, H-7%); 2.36 (s, 3H, SMe);

L. Herrera et al. / Carbohydrate Research 338 (2003) 293–298
297
3
1.44, 1.32 (2s, 2×3H, CMe2); 0.82 (s, 9H, CMe3); 0.08,
0.04 (2s, 2×3H, SiMe2); 13C NMR (62.9 MHz,
CDCl3): l 146.3 (C-7a); 134.2 (C-3); 117.9 (C-3a); 109.4
(CMe2); 78.6 (C-5); 70.1 (C-6); 69.6 (C-4); 36.4 (NMe);
29.0 (C-7); 28.2, 26.3 (CMe2); 25.7 (CMe3); 19.2 (SMe);
18.0 (CMe3); −4.7, −4.8 (SiMe2); MS, CI (m/z): 385
[M+1]+; Anal. Calcd for C18H32N2O3SSi: C 56.21; H
8.39; N 7.28; S 8.34. Found: C 56.08; H 8.52; N 7.12; S
8.22.
3J6,7ꢀ4.0 Hz, J7,8ꢀ2.8 Hz, H-7); 3.11 (dd, 1H,
3
2J8,8%ꢀ16.5 Hz, J7,8ꢀ2.8 Hz, H-8); 2.84 (ddd, 1H,
3
4
2J8,8%ꢀ16.5 Hz, J7,8%ꢀ4.8 Hz, J6,8%ꢀ1.5 Hz, H-8%);
4
1.42 (t, 3H, JMe,Meꢀ0.6 Hz, CMe2); 1.27 (t, 3H,
4JMe,Meꢀ0.6 Hz, CMe2); 0.73 (s, 9H, CMe3); 0.1, 0.06
(2s, 2×3H, SiMe2); 13C NMR (75.5 MHz, acetone-D6):
l 164.6 (C-8a); 158.8 (C-2); 157.4 (C-4); 129.0 (C-4a);
110.0 (CMe2); 77.8 (C-6); 72.7 (C-5); 70.1 (C-7); 36.6
(C-8); 27.3 (1×CMe2); 25.9 (CMe3); 25.0 (1×CMe2);
18.4 (CMe3); −4.8 (2×SiMe2); MS, CI (m/z): 337
[M+1]+; Anal. Calcd for C17H28N2O3Si: C 60.68; H
8.39; N 8.32. Found: C 60.54; H 8.58; N 8.23.
1.7. (4R,5R,6R)-6-[(tert-Butyl-dimethylsilyl)oxy]-
4,5,6,7-tetrahydro-4,5-(isopropylidenedioxy)-2-methyl-
2H-benzo[c]pyrazole (7)
1.9. (5R,6R,7R)-7-[(tert-Butyl-dimethylsilyl)oxy]-
5,6,7,8-tetrahydro-5,6-(isopropylidenedioxy)-2-
methyl-benzo[d]pyrimidine (9)
A mixture of 4 (0.355 g, 1.0 mmol) and methylhy-
drazine (0.16 mL, 3.0 mmol) was reacted as described
for preparation of 5. The residue was purified by
column chromatography (toluene/ethyl acetate 2:1) to
yield 0.23 g (69%) of 7 as colourless solid; TLC: tolu-
ene/ethyl acetate 2:1 Rf: 0.27; mp 81–83 °C; [h]2D1:
Compound 4 (53 mg, 0.15 mmol) and acetamidinium
hydrochloride (28 mg, 0.3 mmol) was reacted as de-
scribed for preparation of 8. The residue was purified
by column chromatography (toluene/ethyl acetate 1:1)
to yield 17 mg (33%) of 9 as colourless solid; TLC:
toluene/ethyl acetate 1:1 Rf: 0.44; mp 60–62 °C; [h]2D1:
1
+18.6 (c 1.0, CHCl3); IR (KBr): 1564 cm−1 (CꢁC); H
NMR (300.1 MHz, CDCl3): l 7.35 (s, 1H, H-3); 5.18
3
(d, 1H, J4,5ꢀ5.5 Hz, H-4); 4.20–4.12 (m, 2H, H-5,
2
1
H-6); 3.84 (s, 3H, NMe); 2.93 (dd, 1H, J7,7%ꢀ16.0 Hz,
+33.5 (c 1.0, CHCl3); H NMR (300.1 MHz, acetone-
2
3J6,7ꢀ3.8 Hz, H-7); 2.58 (dd, 1H, J7,7%ꢀ16.0 Hz,
3
D6): l 8.51 (s, 1H, H-4); 5.31 (d, 1H, J5,6ꢀ6.5 Hz,
3J6,7%ꢀ7.5 Hz, H-7%); 1.41, 1.36 (2s, 2×3H, CMe2);
0.85 (s, 9H, CMe3); 0.09, 0.06 (2s, 2×3H, SiMe2); 13C
NMR (62.9 MHz, CDCl3): l 146.9 (C-7a); 129.3 (C-3);
113.7 (C-3a); 109.4 (CMe2); 79.3 (C-5); 70.5 (C-6); 69.3
(C-4); 38.9 (NMe); 29.2 (C-7); 28.2, 26.1 (CMe2); 25.7
(CMe3); 18.0 (CMe3); −4.6, −4.7 (SiMe2); MS, CI
(m/z): 339 [M+1]+; Anal. Calcd for C17H30N2O3Si: C
60.32; H 8.93; N 8.28. Found: C 60.18; H 8.82; N 8.12.
3
3
H-5); 4.40 (ddd, 1H, J5,6ꢀ6.5 Hz, J6,7ꢀ4.1 Hz,
4J6,8%ꢀ1.3 Hz, H-6); 4.34 (ddd, 1H, J7,8%ꢀ5.0 Hz,
3
3J6,7ꢀ4.1 Hz, J7,8ꢀ3.0 Hz, H-7); 3.05 (dd, 1H,
3
2J8,8%ꢀ16.4 Hz, J7,8ꢀ3.0 Hz, H-8); 2.77 (ddd, 1H,
3
2J8,8%ꢀ16.4 Hz, J7,8%ꢀ5.0 Hz, J6,8%ꢀ1.3 Hz, H-8%);
3
4
4
2.57 (s, 3H, 2-Me); 1.40 (t, 3H, JMe,Meꢀ0.6 Hz,
CMe2); 1.27 (t, 3H, JMe,Meꢀ0.6 Hz, CMe2); 0.74 (s,
4
9H, CMe3); 0.1, 0.06 (2s, 2×3H, SiMe2); 13C NMR
(75.5 MHz, acetone-D6): l 168.0 (C-2); 164.5 (C-8a);
157.6 (C-4); 125.5 (C-4a); 109.8 (CMe2); 78.0 (C-6);
72.6 (C-5); 70.2 (C-7); 36.8 (C-8); 27.3 (1×CMe2); 25.9
(CMe3); 25.8 (2-Me); 25.1 (1×CMe2); 18.4 (CMe3);
−4.7, −4.8 (SiMe2); MS, CI (m/z): 351 [M+1]+;
Anal. Calcd for C18H30N2O3Si: C 61.68; H 8.63; N 7.99.
Found: C 61.49; H 8.54; N 7.75.
1.8. (5R,6R,7R)-7-[(tert-Butyl-dimethylsilyl)oxy]-
5,6,7,8-tetrahydro-5,6-(isopropylidenedioxy)-benzo[d]-
pyrimidine (8)
To a solution of sodium (7 mg, 0.3 mmol) in methanol
(2 mL) was added formamidinium acetate (31 mg, 0.3
mmol). After stirring for 20 min. at 22 °C this mixture
was dropwise added to another stirred solution of 4 (53
mg, 0.15 mmol) in methanol (2 mL). The resulting
mixture was stirred at 50 °C for 1.5 h (TLC control).
The mixture was cooled to 20 °C, and a saturated
solution of NH4Cl (10 mL) was added. The mixture
was extracted three times with CHCl3 (25 mL). The
combined organic layers were washed with water, dried
(Na2SO4) and concentrated. The residue was purified
by column chromatography (toluene/ethyl acetate 2:1)
to yield 15 mg (30%) of 8 as colourless syrup; TLC:
toluene/ethyl acetate 2:1 Rf: 0.38; [h]2D1: +20.5 (c 1.0,
1.10. (5R,6R,7R)-7-[(tert-Butyl-dimethylsilyl)oxy]-
5,6,7,8-tetrahydro-5,6-(isopropylidenedioxy)-2-phenyl-
benzo[d]pyrimidine (10)
Compound 4 (53 mg, 0.15 mmol) and benzamidinium
hydrochloride (47 mg, 0.3 mmol) was reacted as de-
scribed for preparation of 8. The residue was purified
by column chromatography (toluene/ethyl acetate 10:1)
to yield 30 mg (49%) of 10 as colourless solid; TLC:
toluene/ethyl acetate 10:1 Rf: 0.48; mp 67–69 °C; [h]2D1:
1
+57.9 (c 1.0, CHCl3); H NMR (300.1 MHz, acetone-
1
CHCl3); H NMR (300.1 MHz, acetone-D6): l 8.97 (s,
D6): l 8.74 (s, 1H, H-4); 8.49 (m, 2H, o-Ph); 7.50 (m,
3
3
1H, H-2); 8.64 (s, 1H, H-4); 5.36 (d, 1H, J5,6ꢀ6.5 Hz,
3H, m-, p-Ph); 5.40 (d, 1H, J5,6ꢀ6.5 Hz, H-5); 4.50–
3
3
2
H-5); 4.44 (ddd, 1H, J5,6ꢀ6.5 Hz, J6,7ꢀ4.0 Hz,
4.40 (m, 2H, H-6, H-7); 3.20 (dd, 1H, J8,8%ꢀ16.3 Hz,
4J6,8%ꢀ1.5 Hz, H-6); 4.39 (ddd, 1H, J7,8%ꢀ4.8 Hz,
3J7,8ꢀ2.8 Hz, H-8); 2.94 (ddd, 1H, J8,8%ꢀ16.3 Hz,
3
2

298
L. Herrera et al. / Carbohydrate Research 338 (2003) 293–298
4
3J7,8%ꢀ4.8 Hz, J6,8%ꢀ1.4 Hz, H-8’); 1.44, 1.31 (2s,
2×3H, CMe2), 0.74 (s, 9H, CMe3); 0.12, 0.08 (2s,
2×3H, SiMe2); 13C NMR (75.5 MHz, acetone-D6): l
165.1, 164.2 (C-2, C-8a); 158.0 (C-4); 138.6 (i-Ph); 131.4
(p-Ph); 129.3, 128.8 (o-, m-Ph); 126.8 (C-4a); 110.0
(CMe2); 78.0 (C-6); 72.6 (C-5); 70.3 (C-7); 37.0 (C-8);
27.4 (1×CMe2); 25.9 (CMe3); 25.1 (1×CMe2); 18.4
(CMe3); −4.7 (2×SiMe2); MS, CI (m/z): 413 [M+
1]+; Anal. Calcd for C23H32N2O3Si: C 66.95; H 7.82; N
6.79. Found: C 66.89; H 7.87; N 7.03.
3. Ferrier, R. J. J. Chem. Soc. Perkin Trans. 1 1979, 1455–
1458.
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1.11. (5R,6S)-5,6-Dihydro-5,6-dihydroxy-2-phenyl-
benzo[d]pyrimidine (11)
Compound 10 (124 mg, 0.3 mmol) was added to an
60% aq solution of CF3COOH (5 mL). The mixture
was stirred at 22 °C for 12 h, then extracted with ethyl
acetate (3×25 ml), and the organic phases were
washed with a saturated aq solution of NaHCO3 (2×
50 mL) and water (2×50 mL), dried (Na2SO4) and
concentrated. The residue was purified by column chro-
matography (ethyl acetate/methanol 10:1) to yield 40
mg (55%) of 11 as white crystals; TLC: ethyl acetate/
methanol 10:1 Rf: 0.57; mp 180–182 °C; [h]2D1: +85.7
11. Do¨tz, K. H.; Ehlenz, R.; Paetsch, D. Angew. Chem., Int.
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5301–5302.
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1994; pp 29–42.
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Liebigs Ann. 1997, 1019–1022.
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Carbohydr. Chem. 1999, 18, 429–439.
1
(c 0.5, MeOH); H NMR (250.1 MHz, DMSO-D6): l
16. Booma, C.; Balasubramanian, K. K. Tetrahedron Lett.
1993, 34, 6757–6760.
17. Al-Abed, Y.; Al-Tel, T. H.; Voelter, W. Tetrahedron
1993, 49, 9295–9306.
18. Mohammad-Ali, A. K.; Chan, T. H.; Thomas, A. W.;
Jewett, B.; Strunz, G. M. Can. J. Chem. 1994, 72, 2137–
2143.
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8.76 (s, 1H, H-4); 8.37 (m, 2H, o-Ph); 7.50 (m, 3H, m-,
p-Ph); 6.66–6.57 (m, 2H, H-7, H-8); 5.47 (d, 1H,
3
3J5,OHꢀ6.0 Hz, OH-5); 5.19 (d, 1H, J6,OHꢀ6.0 Hz,
3
OH-6); 4.67 (t, 1H, J5,6ꢀ5.2 Hz, H-5); 4.29 (m, 1H,
H-6). 13C NMR (62.9 MHz, DMSO-D6): l 162.9, 158.7
(C-2, C-8a); 155.2 (C-4); 142.0 (C-7); 137.5 (i-Ph); 130.8
(p-Ph); 128.8 (m-Ph); 128.0 (C-4a); 127.8 (o-Ph); 127.3
(C-8); 67.2 (C-5); 66.3 (C-6). MS, EI (m/z): 240 [M]+;
Anal. Calcd for C14H12N2O2: C 69.99; H 5.03; N 11.66.
Found: C 69.69; H 5.19; N 11.64.
21. Grewe, R.; Nolte, E. Ann. Chem. 1952, 575, 1–17.
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Acknowledgements
24. Peseke, K.; Feist, H.; Cuny, E. Carbohydr. Res. 1992,
230, 319–325.
Support of this work by the Deutsche Forschungsge-
meinschaft and the Fonds der Chemischen Industrie is
gratefully acknowledged. J. Q. is grateful to the Fun-
dac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo
(FAPESP, Brasil) and the Deutscher Akademischer
Austauschdienst for financial support. L. H. would like
to thank the Deutscher Akademischer Austauschdienst
for a scholarship.
25. Peseke, K.; Thiele, G.; Michalik, M. Liebigs Ann. 1995,
1633–1636.
26. Gomez, M.; Quincoces, J.; Kuhla, B.; Peseke, K.; Reinke,
H. Carbohydr. Chem. 1998, 17, 57–68.
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