Synthesis of carba analogues of deoxy-4-C-(hydroxymethyl)-hexopyranoses, intermediates in the synthesis of carbocyclic nucleosides

Article abstract of DOI:10.1135/cccc20010785

3-O-Benzyl-1,2-O-isopropylidene-α-D-glucofuranose-5,6-O-sulfate (1) was treated with sodium salt of dimethyl malonate to obtain, after hydrolysis, methyl 5-(3-O-benzyl-1,2-O-isopropylidene-α-D-erythrofuranos-4-yl)-2- oxotetrahydrofuran-3-carboxylate (3) w

Full text of DOI:10.1135/cccc20010785

Carbocyclic Nucleosides
785
SYNTHESIS OF CARBA ANALOGUES OF DEOXY-4-C-(HYDROXYMETHYL)-
HEXOPYRANOSES, INTERMEDIATES IN THE SYNTHESIS OF
CARBOCYCLIC NUCLEOSIDES
1,
2
Hubert HŘEBABECKÝ * and Antonín HOLÝ
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
1
2
166 10Prague 6, Czech Republic; e-mail: hubert@uochb.cas.cz, holy@uochb.cas.cz
Received March 2, 2001
Accepted April 20, 2001
3-O-Ben zyl-1,2-O-isopropyliden e-α-D-glucofuran ose-5,6-O-sulfate (1) was treated with sodium
salt of dim eth yl m alon ate to obtain , after h ydrolysis, m eth yl 5-(3-O-ben zyl-1,2-O-
isopropyliden e-α-D-eryth rofuran os-4-yl)-2-oxotetrah ydrofuran -3-carboxylate (3) wh ich was
con verted to th e m ixture of m eth yl (2S,3R,4R)- (7) an d (2R,3R,4R)-2-(acetyloxy)-3-
(ben zyloxy)-4-(form yloxy)-7-oxo-6-oxabicyclo[3.2.1]octan e-1-carboxylate (8). Th e com poun d
7
was reduced with lith ium alum in ium h ydride to give (1R,2R,3R,4S)-3-(ben zyloxy)-
5,5-bis(h ydroxym eth yl)cycloh exan e-1,2,4-triol (9) wh ich was tran sform ed to (1R,2S,4R)-
5,5-bis(h ydroxym eth yl)cycloh exan e-1,2,4-triol (14). Treatm en t of sodium salt of dieth yl
m alon ate with 3-O-ben zyl-5,6-dideoxy-6-iodo-1,2-O-isopropyliden e-α-D-xylo-h exofuran ose
(19) gave dieth yl (3-O-ben zyl-5,6-dideoxy-1,2-O-isopropyliden e-α-D-xylo-h exofuran os-6-
yl)m alon ate (20) wh ich was con verted to (1R,3R)-4,4-bis(h ydroxym eth yl)cycloh exan e-
1,3-diol (28) by a sim ilar procedure to th at used for 14.
Keyw ord s: Carbasugars; Pseudosugars; Carbocyclic h exopyran oses; Substituted 1,1-bis-
(h ydroxym eth yl)cycloh exan es; Carboh ydrates; Cycloh exan es; Cyclitols; Glucose.
Polyh ydroxycycloh exan es can be regarded as carbocyclic sugar an alogues.
An approach to six-m em bered carbocycles open s a syn th etic way to carba
an alogues of n ucleosides with pyran oses an d/or h exitols as sugar m oieties.
Because th e h exitol n ucleosides exh ibit an tiviral activity1, th eir carbocyclic
con gen ers an d cycloh exen e an alogues were prepared2.
In con tin uation of our previous studies3 aim ed at th e syn th eses of
carbocyclic 4′-substituted deoxyn ucleosides with poten tial an tiviral activ-
ity, th is study con cern s syn th eses of 4-C-(h ydroxym eth yl)pseudoh exo-
pyran oses. D-Glucose was ch osen as a startin g com poun d for syn th esis of
th e target com poun ds.
Treatm en t of sulfate4 1 (Sch em e 1) with sodium salt of dim eth yl
m alon ate in dim eth ylform am ide afforded sodium salt of sulfate 2 wh ich
gave directly, on h ydrolysis with 8% aqueous sulfuric acid, a m ixture of
Collect. Czech. Chem. Commun. (Vol. 66) (2001)
doi: 10.1135/cccc20010785

786
Hřebabecký, Holý:
(CH3OOC)2CH
HO
O
OBn
O
O
(CH3OOC)2CH
NaOSO2O
(i)
O2S
O
O
O
O
(ii)
OBn
OBn
4
(iii)
O
O
O
O
1
2
CH3OOC
3
4
*
O
H
5
2
O
O
1
CH3OOC
O
CH3OOC
O
OBn
*
(iv)
O
H
H
O
OCHO
O
O
O
(v)
OH
3
OBn
OBn
CHO
OH
6
5
(vi)
O
O
O
OR
OR
O
RO
RO
OCHO
OCHO
(vii)
OR
OAc
CH3OOC
CH3OOC
OAc
OBn
OBn
OBn
8
7
9, R = H
10, R = Bz
(viii)
OBz
OBz
OR
OR
(ix)
BzO
BzO
RO
OBz
OR
RO
OR
11, R = H
12, R = C(S)SCH3
13, R = Bz
14, R = H
(x)
(xii)
(xi)
(i) (MeOOC)2CH2/NaH/DMF; (ii) 8% aqueous H2SO4/CH2Cl2, 67% of 3, 11% of 4 based on
reacted 1; (iii) 0.1 M MeONa/MeOH; (iv) Dowex 50(H+)/aqueous dioxane; (v) NaIO4/aqueous
dioxane; (vi) (CH3CO)2O/pyridine, 35% of 7, 2.5% of 8 based on reacted 3; (vii) LiAlH4/THF, 79%;
(viii) benzoyl chloride/pyridine, 93%; (ix) Pd/C/MeOH-DMF, 91%; (x) 1. NaH/CS2/DMF, 2. MeI, 90%;
(xi) Bu3SnH/AIBN/toluene, 82%; (xii) 0.1 M MeONa/MeOH, 94%
SCHEME 1
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Carbocyclic Nucleosides
787
lacton e 3 an d diester 4 (67 an d 11% yields, respectively, based on sulfate 1).
Th e diester 4 was con verted to th e lacton e by treatm en t with 0.1
M
m eth an olic sodium m eth oxide. Th e lacton e 3 is an equim olar m ixture of
(3R)- an d (3S)-isom ers. Th e isom ers could n ot be separated by ch rom atogra-
ph y on silica gel. Deketalization of com poun d 3 wh ich was perform ed on
Dowex 50(H+) in aqueous 1,4-dioxan e, afforded an an om eric m ixture of
diols 5. Th is reaction was accom pan ied by partial h ydrolysis of th e m eth yl
ester an d th erefore it was in terrupted wh en TLC revealed th eir h ydrolysis.
Reaction of diols 5 with sodium periodate followed by acetylation gave a
m ixture of cycloh exan e derivatives 7 an d 8. Both isom ers were separated
an d obtain ed in a crystallin e form (35% of 7 an d 2.5% of 8 based on ketal 3).
Because on ly th e (3S)-isom er of aldeh yde 6 was able to un dergo a
cyclization reaction , th e yield of 7 an d 8 was low. Reduction of th e ester 7
to th e correspon din g bis(h ydroxym eth yl) derivative 9 was carried out with
lith ium alum in um h ydride in boilin g tetrah ydrofuran . Ben zoylation of 9 by
treatm en t with ben zoyl ch loride in pyridin e an d subsequen t h ydro-
gen olysis of th e obtain ed ben zoate 10 afforded substituted cycloh exan ol 11
(91% yield). It was con verted in to dith iocarbon ate 12 wh ich was subse-
quen tly treated with tributylstan n an e in th e presen ce of 2,2′-azobis-
(2-m eth ylpropan on itrile), usin g a described5 procedure to give th e deoxy
derivative 13. Both reaction s were facile an d gave h igh yields (90 an d 82%,
respectively). Meth an olysis of com poun d 13 afforded free carba an alogue 14.
For th e syn th esis of th e target diol 28, 3-O-ben zyl-5-deoxy-1,2-O-iso-
propyliden e-α-D-xylo-h exofuran ose (17) was used as a startin g com poun d.
Because syn th eses of 17 reported in th e literature6 are n ot suitable for
large-scale preparation , 17 was obtain ed by deoxygen ation of 6-O-ben zoyl-
3-O-ben zyl-1,2-O-isopropyliden e-α-D-glucofuran ose7 (15) as follows: m on o-
ben zoate 15 was first con verted in to dith iocarbon ate 16 (91% yield) wh ich
was th en treated with tributylstan n an e in th e peresen ce of 2,2′-azo-
bis(2-m eth ylpropan on itrile) to give, after m eth an olysis of th e ben zoyl
group, 5-deoxyglucose 17 in th e yield of 76% (Sch em e 2).
BzO
HO
BzO
HOCH2CH2
CH3SC(S)O
O
O
O
(ii)
(i)
OBn
OBn
OBn
O
O
O
O
O
O
15
16
17
Bn = benzyl, Bz = benzoyl
(i) 1. CS2/NaH/DMF, 2. MeI, 91%; (ii) 1. Bu3SnH/AIBN/toluene, 2. 0.1 M MeONa/MeOH, 76%
SCHEME 2
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788
Hřebabecký, Holý:
Treatm en t of 5-deoxyglucose 17 with tosyl ch loride in pyridin e afforded
tosylate 18 (92% yield) an d subsequen t n ucleoph ilic displacem en t of th e
tosyl group by iodin e gave 5,6-dideoxy-6-iodoglucose 19 in th e yield of
79% (Sch em e 3). Reaction of th e iodo derivative 19 with sodium salt of
dim eth yl m alon ate in dim eth ylform am ide led to m alon ate 20 (87% yield).
Its deketalization with Dowex 50(H+) in aqueous 1,4-dioxan e, oxidation
with sodium periodate an d acetylation afforded a m ixture of (2R)- an d
(2S)-diesters 21 (41% yield). In th is case, deketalization was n ot accom pa-
n ied by ester h ydrolysis. Th e diastereom eric m ixture 21 was treated with
lith ium alum in um h ydride in boilin g tetrah ydrofuran givin g a m ixture of
(3R)- an d (3S)-diols 22 in th e yield of 41%. Attem pts to separate of diesters
21 an d diols 22 by ch rom atograph y failed. However, th e ben zoates 23 an d
24 obtain ed from th e m ixture of diols by reaction with ben zoyl ch loride in
RCH2CH2
(C2H5OOC)2CHCH2CH2
O
O
(i)
OBn
OBn
D-glucose
O
O
O
O
20
18, R = OTs
19, R = I
(iii)
(ii)
(iv)
BzO
C2H5OOC
C2H5OOC
HO
OBz
OCHO
OH
(vi)
(v)
BzO
HO
HO
OBn
OBn
OBz
24
OBn
AcO
21
22
BzO
BzO
RO
RO
BzO
BzO
OBz
OR
OBz
(vii)
OBz
OR
OBz
OR
OBn
(ix)
25, R = H
26, R = C(S)SCH3
27, R = Bz
28, R = H
23
(viii)
(x)
(i) TsCl/pyridine, 92%; (ii) NaI/MeCOEt, 89%; (iii) (EtOOC)2CH2/NaH/DMF, 87%; (iv) 1. Dowex
50(H+)/aqueous dioxane, 2. NaIO4/aqueous dioxane, 3. (CH3CO)2O/pyridine, 41%;
(v) LiAlH4/THF, 84%; (vi) benzoyl chloride/pyridine, 62% of 23, 19% of 24; (vii) Pd/C/MeOH-DMF,
95%; (viii) 1. NaH/CS2/DMF, 2. MeI, 79%; (ix) Bu3SnH/AIBN/toluene, 95%; (x) MeONa/MeOH, 85%
SCHEME 3
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Carbocyclic Nucleosides
789
pyridin e, were easily separated by ch rom atograph y on silica gel (62% yield
of 23 an d 19% yield of 24). Th e ben zyl group in com poun d 23 was re-
m oved by h ydrogen olysis an d th e resultin g cycloh exan ol 25 was con verted
to dith iocarbon ate 26 by th e above procedure (see com poun d 12). Treat-
m en t of 26 with tributylstan n an e in th e presen ce of 2,2′-azobis(2-m eth yl-
propan on itrile) afforded ben zoate 27 wh ich was m eth an olyzed to give diol
28 in th e yield of 85%.
Th e structure of th e cycloh exan e derivatives 7, 8, 10, 23 an d 24 was de-
term in ed by 1H NMR spectroscopy. Couplin g con stan ts of cycloh exan es 7
(J(2,3) = J(3,4) = 8.5 Hz), 10 (J(2,3) = J(3,4) = 8.5 Hz), 23 (J(2,3) = 8.8 Hz an d
J(3,4) = 8.5 Hz) an d con stan ts of th e isom eric com poun ds 8 (J(2,3) = 4.6 Hz
an d J(3,4) = 8.8 Hz) an d 24 (J(2,3) = 3.2 Hz an d J(3,4) = 7.2 Hz) correspon d
with (2S)-con figuration of th e com poun ds 7, 10, 23 an d (2R)-con figuration
of th e isom ers 8 an d 24.
In con clusion , n ew carba an alogues of 2-deoxy-4-C-(h ydroxym eth yl)-
h exopyran oses were syn th esized as in term ediates in n ucleoside syn th eses
startin g from in expen sive D-glucose.
EXPERIMENTAL
Th e m eltin g poin ts were determ in ed on a Kofler block an d are un corrected. Optical
rotation s were obtain ed at 20 °C with a Perkin –Elm er 241 polarim eter an d are given in
.
10–1 deg cm 2 g–1 1H NMR spectra (δ, ppm ; J, Hz) were recorded with Varian UNITY 200 in -
strum en t in h exadeuteriodim eth yl sulfoxide, with tetram eth ylsilan e as in tern al stan dard.
Colum n Ch rom atograph y was perform ed on 30–60 µm silica gel (Service Laboratories of th e
In stitute) an d th in -layer ch rom atograph y (TLC) on Silufol UV 254 foils (Kavalier, Votice).
Solven ts were evaporated at 2 kPa an d bath tem perature 30–60 °C. Th e com poun ds prepared
were dried over ph osph orus pen toxide at 13 Pa. Lith ium alum in ium h ydride was used as a
1
M solution in tetrah ydrofuran e, supplied by Aldrich .
Meth yl 5-(3-O-Ben zyl-1,2-O-isopropyliden e-α-D-eryth rofuran os-4-yl)-
2-oxotetrah ydrofuran -3-carboxylate (3)
Sodium h ydride (60% dispersion in m in eral oil, 4.8 g, 120 m m ol) was added un der argon at
0 °C to a stirred solution of dim eth yl m alon ate (15 m l, 131 m m ol) in dim eth ylform am ide
(400 m l) an d, after stirrin g at 0 °C for 15 m in , a solution of sulfate4 1 (37.2 g, 100 m m ol) in
dim eth ylform am ide (150 m l) was added. Th e m ixture was stirred at room tem perature for
2 h an d th en th e solven t was evaporated. Th e solution of th e residue in water (400 m l) was
wash ed with eth yl acetate (2 × 100 m l) an d th e aqueous solution was evaporated. Th e m ix-
ture of th e residue, dich lorom eth an e (300 m l) an d 8% aqueous sulfuric acid (120 m l) was
stirred at room tem perature for 15 h ; th e organ ic layer was th en separated, wash ed with wa-
ter (2 × 100 m l), dried over an h ydrous sodium sulfate, an d th e solven t was taken down . Th e
residue was dissolved in 0.1 M m eth an olic sodium m eth oxide (400 m l) an d th e solution was
set aside overn igh t at room tem perature. Dowex 50(H+) was added to n eutralize th e reaction
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

790
Hřebabecký, Holý:
m ixture, th e resin was filtered off, wash ed with m eth an ol, an d th e com bin ed filtrates were
evaporated to give 30.6 g (78%) of 3 as an equim olar m ixture of (3R)- an d (3S)-isom ers. For
C
20H24O8 (392.4) calculated: 61.22% C, 6.16% H; foun d: 61.23% C, 6.26% H. 1H NMR
(CDCl3): 1.32 s, 6 H, 1.48 s, 3 H an d 1.51 s, 3 H (2 × C(CH3)2); 2.60–2.84 m , 4 H (2 × H-4);
3.61–3.79 m , 2 H (2 × H-3); 3.80 s, 3 H an d 3.81 s, 3 H (2 × CH3O); 4.05 d, 1 H, J(3′,4′) = 3.4
an d 4.10 d, 1 H, J(3′,4′) = 3.4 (2 × H-3′); 4.25–4.31 m , 2 H (2 × H-4′); 4.55 d, 2 H an d 4.68 d,
2 H, Jgem = 11.6 (2 × CH2Ph ); 4.62 d, 1 H, J(2′,1′) = 3.4 an d 4.63 d, 1 H, J(2′,1′) = 3.7 (2 ×
H-2′); 5.92 d, 1 H an d 5.94 d, 1 H (2 × H-1′); 7.27–7.40 m , 10 H (H-arom .).
In a sm all-scale experim en t, a m ixture of 3 an d diester 4 (150 m g) prior to m eth an olysis
was separated by silica gel ch rom atograph y (eth yl acetate–toluen e, 1 : 3) to afford 3
(120 m g) an d dim eth yl m alon ate 4 (19 m g).
Dimethyl (3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-α-D-glucofuranos-6-yl)malonate (4). For
C
21H28O9 (424.5) calculated: 59.42% C, 6.65% H; foun d: 59.19% C, 6.47% H. 1H NMR
(DMSO-d6): 1.24 s, 3 H an d 1.39 s, 3 H (C(CH3)2); 1.81 ddd, 1 H, J(6a′,CH) = 4.9, J(6a′,5′) =
9.2, J(6a′,6b′) = 14.0 (H-6a′); 2.14–2.30 m , 1 H (H-6b′); 3.64 s, 3 H an d 3.65 s, 3 H (2 ×
CH3O); 3.70 t, 1 H, J(CH,6b′) = 4.9 (CH); 3.68–3.84 m , 2 H (H-4′, H-5′); 3.91 d, 1 H, J(3′,4′) =
3.1 (H-3′); 4.56 d, 1 H an d 4.65 d, 1 H, Jgem = 11.6 (CH2Ph ); 4.67 d, 1 H (H-2′); 4.98 d, 1 H,
J(OH,5′) = 6.7 (5′-OH); 5.82 d, 1 H, J(1′,2′) = 3.7 (H-1′); 7.33 m , 5 H (H-arom .).
Meth yl (2S,3R,4R)- (7) an d (2R,3R,4R)-2-(Acetyloxy)-3-(ben zyloxy)-
4-(form yloxy)-7-oxo-6-oxabicyclo[3.2.1]octan e-1-carboxylate (8)
A m ixture of 3 (7.84 g, 20 m m ol), dioxan e (53 m l), water (32 m l), an d Dowex 50 (H+ form ,
15 m l) was stirred at 80 °C for 6 h . Th en th e resin was filtered off, wash ed with dioxan e,
an d th e solven t was evaporated. A solution of th e residue in eth yl acetate (300 m l) was
wash ed with water (100 m l), 10% aqueous potassium h ydrogen carbon ate (100 m l), dried
over an h ydrous sodium sulfate, an d th e solven t was evaporated. To a stirred solution of th e
residue in dioxan e (100 m l), a saturated solution of sodium periodate (85 m l) was added
dropwise durin g 20 m in . Th e in soluble portion was filtered off an d wash ed with dioxan e.
Th e com bin ed filtrates were evaporated to on e th ird of th e origin al volum e an d partition ed
between eth yl acetate (300 m l) an d water (100 m l). Th e organ ic ph ase was separated,
wash ed with water (100 m l), dried over an h ydrous sodium sulfate, an d th e solven t was
evaporated. Acetic an h ydride (6 m l, 64 m m ol) was added to a solution of th e residue in
pyridin e (75 m l) an d th e solution was set aside at room tem perature for 2 days. Meth an ol
(5 m l) was added an d, after 15 m in , th e solven t was evaporated. A solution of th e residue in
eth yl acetate (200 m l) was wash ed with water (3 × 75 m l), dried over an h ydrous sodium
sulfate an d taken down . Ch rom atograph y on a colum n of silica gel (800 g) in toluen e–eth yl
acetate (3 : 1) an d crystallization from m eth an ol afforded 200 m g (2.5%) of com poun d 8
an d 2.75 g (35%) of com poun d 7.
Compound 7: M.p. 116.5–117.5 °C. For C19H20O9 (392.4) calculated: 58.16% C, 5.14% H;
foun d: 57.97% C, 5.19% H. [α]D –50.3 (c 0.77, ch loroform ). 1H NMR (CDCl3): 2.03 s, 3 H
(CH3CO); 2.25 d, 1 H, J(8a,8b) = 13.1 (H-8a); 2.86 dd, 1 H, J(8b,5) = 6.7 (H-8b); 3.77 s, 3 H
(CH3O); 3:89 t, 1 H, J(3,2) = J(3,4) = 8.5 (H-3); 4.63 s, 2 H (CH2-ben zyl); 4.82 dd, 1 H,
J(5,4) = 1.2 (H-5); 5.06 ddd, 1 H, J = 0.9 (H-4); 5.57 d, 1 H (H-2); 7.21–7.34 m , 5 H
(H-arom .); 8.01 s, 1 H (CH=O).
Compound 8: M.p. 120–121 °C. For C19H20O9 (392.4) calculated: 58.16% C, 5.14% H;
foun d: 58.13% C, 5.17% H. [α]D –168.2 (c 0.786, ch loroform ). 1H NMR (CDCl3): 2.10 s, 3 H
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Carbocyclic Nucleosides
791
(CH3CO); 2.71 d, 1 H, J(8a,8b) = 12.6 (H-8a); 2.96 ddd, 1 H, J(8b,2) = 1.6, J(8b,5) = 6.4
(H-8b); 3.79 dd, 1 H, J(3,2) = 4.6, J(3,4) = 8.8 (H-3); 3.83 s, 3 H (CH3O); 4.40 d an d 4.74 d,
Jgem = 10.9 (CH2-ben zyl); 4.90 dd, 1 H, J = 1.1 (H-5); 5.10 d, 1 H (H-4); 6.18 dd, 1 H (H-2);
7.22–7.38 m , 5 H (H-arom .); 8.05 s, 1 H (CH=O).
(1R,2R,3R,4S)-3-(Ben zyloxy)-5,5-bis(h ydroxym eth yl)cycloh exan e-1,2,4-triol (9)
A solution of ester 7 (5.89 g, 15.0 m m ol) in tetrah ydrofuran (45 m l) was slowly added
dropwise to a stirred boilin g 1 M solution of lith ium alum in ium h ydride (45 m l) in an argon
atm osph ere. Th e m ixture was refluxed for 2 h , cooled an d eth yl acetate (6 m l) was added,
after 15 m in followed by water. Th e m ixture was taken down an d th e residue was extracted
with warm eth yl acetate (5 × 30 m l). Th e solid residue was air-dried an d m ixed with 90%
aqueous m eth an ol. Th e in soluble portion was filtered off th rough a Celite pad an d wash ed
with m eth an ol. Th e com bin ed extract an d filtrates were taken down an d th e residue was
ch rom atograph ed on a silica gel colum n (400 g) in eth yl acetate–aceton e–eth an ol–water
(36 : 6 : 5 : 3) to give 3.59 g (79%) of th e h ydroxy derivative 9. For C15H22O6 (298.3) calcu-
lated: 60.39% C, 7.43% H; foun d: 60.11% C, 7.62% H. [α]D –32.8 (c 1.280, water). 1H NMR
(DMSO-d6): 1.47 dd, 1 H, J(6a,1) = J(6b,1) = 3.7, Jgem = 15.0 (2 × H-6); 3.19–3.68 m , 7 H (2 ×
CH2, H-1, H-3, H-4); 3.75–3.82 m , 1 H (H-2); 4.46 t, 1 H, J = 5.5 (CH2OH); 4.50 t, 1 H, J =
5.5 (CH2OH); 4.60 d, 1 H, J = 6.7 (OH); 4.65 d, 1 H, J = 5.5 (OH); 4.75 s, 2 H (CH2Ph );
4.94 d, 1 H, J = 4.3 (OH); 7.23–7.44 m , 5 H (H-arom .).
(2S,3R,4R,5R)-2,3,5-Tris(ben zoyloxy)-3-(ben zyloxy)-1,1-bis[(ben zoyloxy)-
m eth yl]cycloh exan e (10)
Th e h ydroxy derivative 9 (3.43 g, 11.5 m m ol) was dissolved in pyridin e (70 m l) an d taken
down . To
a solution of th e residue in pyridin e (70 m l), ben zoyl ch loride (8.1 m l,
69.8 m m ol) was added un der coolin g. Th e m ixture was set aside at room tem perature for
50 h an d cooled down to 0 °C. Water (4.5 m l) was th en added an d after 10 m in th e m ixture
was con cen trated, an d th e residue was partition ed between eth yl acetate (300 m l) an d water
(100 m l). Th e organ ic ph ase was wash ed with water, 5% h ydroch loric acid, water an d 10%
aqueous potassium h ydrogen carbon ate (100 m l each ), th en dried over an h ydrous sodium
sulfate, an d th e solven t was evaporated. Ch rom atograph y of th e residue on a silica gel col-
um n (500 g) in toluen e–eth yl acetate (91 : 9) gave 8.76 g (93%) of ben zoate 10. For
C
50H42O11 (818.9) calculated: 73.34% C, 5.17% H; foun d: 73.15% C, 5.27% H. [α]D –52.0
(c 0.636, ch loroform ). 1H NMR (CDCl3): 2.20 dd, 1 H, J(6a,5) = 3.1, J(6a,6b) = 15.3 (H-6a);
2.76 dd, 1 H, J(6b,5) = 5.2 (H-6b); 4.42 d, 1 H an d 4.62 d, 1 H, Jgem =11.6 (CH2); 4.53 t, 1 H,
J(3,2) = J(3,4) = 8.5 (H-3); 4.68 d, 1 H an d 4.74 d, 1 H, Jgem = 11.0 (CH2); 4.82 s, 2 H (CH2);
5.60 dd, 1 H, J(4,5) = 3.4 (H-4); 5.87 m , 1 H (H-5); 5.91 d, 1 H (H-2); 6.99–7.11 m , 5 H
(H-arom . ben zyl); 7.29–7.55 m , 15 H an d 7.72–8.03 m , 10 H (H-arom . ben zoyl).
(1R,2S,5R,6S)-2,5,6-Tris(ben zoyloxy)-3,3-bis[(ben zoyloxy)m eth yl]cycloh exan -1-ol (11)
Ben zyl derivative 10 (8.19 g, 10.0 m m ol) was h ydrogen ated in a m ixture of m eth an ol
(60 m l) an d dim eth ylform am ide (15 m l) over Pd/C (10%, 1.5 g) at atm osph eric pressure for
45 h . Th e catalyst was rem oved by filtration th rough a Celite pad, wash ed with m eth an ol,
an d th e com bin ed filtrates were taken down . Th e residue was dissolved in eth yl acetate
(200 m l) an d th e solution was wash ed with water (2 × 100 m l), 5% aqueous sodium
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h ydrogen carbon ate solution (50 m l), dried over an h ydrous sodium sulfate, an d th e solven t
was evaporated. Yield 6.63 g (91%) of alcoh ol 11. For C43H36O11 (728.8) calculated:
70.87% C, 4.98% H; foun d: 70.87% C, 5.03% H. [α]D –38.9 (c 1.426, ch loroform ). 1H NMR
(DMSO-d6): 2.41 dd, 1 H, J(4a,5) = 2.0, J(4a,4b) = 15.4 (H-4a); 2.64 dd, 1 H, J(4b,5) = 4.1
(H-4b); 4.43 brs, 2 H (CH2); 4.56 m , 1 H, J(1,2) = 8.9, J(1,6) = 9.2, J(1,OH) = 5.6 (H-1);
4.76 d, 1 H an d 4.99 d, 1 H, Jgem = 11.8 (CH2); 5.46 dd, 1 H, J(6,5) = 3.4 (H-6); 5.66 d, 1 H
(H-2); 5.77 m , 1 H (H-5); 5.91 d, 1 H (1-OH); 7.28–8.01 m , 25 H (H-arom .).
(2S,3R,4S,5R)-2,4,5-Tris(ben zoyloxy)-1,1-bis[(ben zoyloxy)m eth yl]-3-
{[(m eth ylsulfan yl)th iocarbon yl]oxy}cycloh exan e (12)
Carbon disulfide (3.1 m l, 51.5 m m ol) was added to a solution of alcoh ol 11 (5.83 g,
8.0 m m ol) in dim eth ylform am ide (25 m l) an d, after coolin g to 0 °C, sodium h ydride (60%
dispersion in m in eral oil, 1.06 g, 26.5 m m ol) was added. After stirrin g at 0 °C for 30 m in ,
m eth yl iodide (6.1 m l, 98 m m ol) was added, th e m ixture was stirred at 0 °C for an oth er
30 m in an d th en warm ed up to room tem perature durin g an oth er 30 m in . Water (280 m l)
was added an d th e m ixture was extracted with eth yl acetate (280 m l). Th e organ ic layer was
wash ed with water (3 × 200 m l), dried with an h ydrous sodium sulfate, an d th e solven t was
evaporated. Ch rom atograph y on a silica gel colum n (800 g) in toluen e–eth yl acetate (93 : 7)
gave 5.90 g (90%) of dith iocarbon ate 12. For C45H38O11S2 (818.9) calculated: 66.00% C,
4.68% H, 7.83% S; foun d: 66.22% C, 4.70% H, 7.66% S. [α]D –99.1 (c 0.565, ch loroform ).
1H NMR (DMSO-d6): 2.29 s, 3 H (SCH3); 2.54 dd, 1 H, J(6a,5) = 1.5 (H-6a); 2.76 dd, 1 H,
J(6b,5) = 2.8, J(6b,6a) = 15.1 (H-6b); 4.43 d, 1 H an d 4.49 d, 1 H, Jgem = 11.6 (CH2O); 4.81 d,
1 H an d 5.03 d, 1 H, Jgem = 11.8 (CH2O); 5.87 m , 1 H (H-5); 6.06 dd, 1 H, J(4,3) = 10.2,
J(4,5) = 3.5 (H-4); 6.25 d, 1 H, J(2,3) = 10.4 (H-2); 7.20 t, 1 H (H-3); 7.21–7.87 m , 25 H
(H-arom .).
(2R,4S,5R)-2,4,5-Tris(ben zoyloxy)-1,1-bis[(ben zoyloxy)m eth yl]cycloh exan e (13)
A 1 M tributylstan n an e solution in toluen e (8 m l) an d 2,2′-azobis(2-m eth ylpropan on itrile)
(300 m g, 1.8 m m ol) were added to a boilin g solution of dith iocarbon ate 12 (4.09 g,
5.0 m m ol) in toluen e (40 m l). After 30 m in reflux, th e m ixture was taken down an d th e res-
idue was ch rom atograph ed on a colum n of silica gel (450 g) in toluen e–eth yl acetate (93 : 7)
to give 2.92 g (82%) of deoxy derivative 13. For C43H36O10 (712.8) calculated: 72.46% C,
5.09% H; foun d: 72.40% C, 5.12% H. [α]D –14.6 (c 0.884, ch loroform ). 1H NMR (CDCl3):
2.11 dd, 1 H, J(6a,5) = 3.2, J(6a,6b) = 15.1 (H-6a); 2.49–2.78 m , 2 H (2 × H-3); 2.82 dd, 1 H,
J(6b,5) = 6.0 (H-6b); 4.45 d, 1 H an d 4.61 d, 1 H, Jgem = 11.6 (CH2O); 4.83 d, 1 H an d 4.88 d,
1 H, Jgem = 11.9 (CH2O); 5.52–5.60 m , 1 H (H-4); 5.69 dd, 1 H, J(2,3a) = 4.6, J(2,3b) = 9.2
(H-2); 5.73 m , 1 H (H-5); 7.2–7.59 m , 15 H an d 7.71–8.01 m , 10 H (H-arom .).
(1R,2S,4R)-5,5-Bis(h ydroxym eth yl)cycloh exan e-1,2,4-triol (14)
Ben zoate 13 (713 m g, 1.0 m m ol) was dissolved un der stirrin g in 0.1 M m eth an olic sodium
m eth oxide (9 m l) an d th e solution was set aside at room tem perature overn igh t. Th e m ix-
ture was th en n eutralized with Dowex 50(H+), th e resin was filtered off, wash ed with m eth a-
n ol, an d th e com bin ed filtrates were evaporated. Colum n ch rom atograph y on silica gel
(25 g) in eth yl acetate–aceton e–eth an ol–water (15 : 3 : 4 : 3) afforded 180 m g (94%) of
h ydroxy derivative 14. For C8H16O5 (192.2) calculated: 49.99% C, 8.39% H; foun d:
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793
49.68% C, 8.68% H. [α]D –17.0 (c 0.672, water). 1H NMR (DMSO-d6): 1.30 dd, 1 H, J(6a,1) =
3.9, J(6a,6b) = 14.1 (H-6a); 1.50 dd, 1 H, J(6b,1) = 6.7 (H-6b); 1.61 dt, 1 H, J(3a,2) = J(3a,4) =
3.8, J(3a,3b) = 12.8 (H-3b); 1.83 dt, 1 H, J(3b,2) = J(3b,4) = 8.1 (H-3b); 3.25–366 m , 7 H (2 ×
CH2O, H-2, H-4, H-5); 4.23 t, 1 H, J(OH,CH2) = 5.5 (CH2OH); 4.41 t, 1 H, J(OH,CH2) = 5.3
(CH2OH); 4.46 d, 1 H, J = 4.6 (OH); 4.58 d, 2 H, J = 6.1 (2 × OH).
6-O-Ben zoyl-3-O-ben zyl-1,2-O-isopropyliden e-5-O-[(m eth ylsulfan yl)-
th iocarbon yl]-α-D-glucofuran ose (16)
Carbon disulfide (17.5 m l, 0.29 m ol) was added to a solution of glucose derivative7 15
(18.65 g, 45 m m ol) in dim eth ylform am ide (135 m l) an d, after coolin g to 0 °C, sodium h y-
dride (60% dispersion in m in eral oil, 6.0 g, 0.15 m ol) was added. After stirrin g at 0 °C for
30 m in , m eth yl iodide (35 m l, 0.56 m ol) was added an d th e m ixture was stirred at 0 °C for
30 m in an d th en warm ed up to room tem perature durin g an oth er 30 m in . Water (1.5 l) was
added an d th e m ixture was extracted with eth yl acetate (1.7 l). Th e organ ic layer was
wash ed with water (3 × 1.5 l), dried with an h ydrous sodium sulfate, an d th e solven t was
evaporated. Ch rom atograph y of th e residue on a silica gel colum n (1.2 kg) in toluen e–eth yl
acetate (93 : 7) gave 22.7 g (91%) of dith iocarbon ate 16. For C25H28O7S2 (504.6) calculated:
59.50% C, 5.59% H, 12.71% S; foun d: 59.32% C, 5.70% H, 12.63% S. [α]D –54.8 (c 1.521,
ch loroform ). 1H NMR (CDCl3): 1.33 s, 3 H an d 1.49 s, 3 H (C(CH3)2); 2.15 s, 3 H (SCH3);
4.06 d, 1 H, J(3,4) = 3.1 (H-3); 4.52 d, 1 H an d 4.60 d, 1 H, Jgem = 11.9 (CH2Ph ); 4.56 dd, 1 H,
J(6a,5) = 4.3, J(6a,6b) = 12.8 (H-6a); 4.62 d, 1 H, J(2.1) = 3.7 (H-2); 4.70 dd, 1 H, J(4,5) = 7.9
(H-4); 5.05 dd, 1 H, J(6b,5) = 1.8 (H-6b); 5.96 d, 1 H (H-1); 6.23 m , 1 H (H-5); 7.30 s, 5 H
(H-arom . ben zyl); 7.38–7.59 m , 3 H an d 8.01–8.05 m , 2 H (H-arom . ben zoyl).
3-O-Ben zyl-5-deoxy-1,2-isopropyliden e-α-D-xylo-h exofuran ose (17)
2,2′-Azobis(2-m eth ylpropan on itrile) (1.5 g, 9.1 m m ol) was added to a boilin g solution of
dith iocarbon ate 16 (22.2 g, 44 m m ol) an d tributylstan n an e (90 m m ol) in toluen e (300 m l).
Th e m ixture was refluxed for addition al 30 m in , cooled, an d th e solven t was evaporated. A
solution of th e residue in 0.1 M m eth an olic sodium m eth oxide (200 m l) was set aside over-
n igh t, n eutralized with 10% h ydroch loric acid an d taken down . Th e residue was partition ed
between eth yl acetate (1 l) an d water (0.5 l). Th e organ ic layer was wash ed with water
(500 m l), dried over an h ydrous sodium sulfate, an d th e solven t was evaporated. Ch rom atog-
raph y of th e residue on a silica gel colum n (1 kg) in toluen e–eth yl acetate (9 : 1) gave 9.85 g
(76%) of com poun d 17. For C16H22O5 (294.4) calculated: 65.29% C, 7.53% H; foun d:
65.11% C, 7.58% H. 1H NMR spectrum was iden tical with th at of th e com poun d prepared
accordin g to ref.6b
.
3-O-Ben zyl-5-deoxy-1,2-O-isopropyliden e-6-O-tosyl-α-D-xylo-h exofuran ose (18)
A solution of com poun d 17 (9.71 g, 33 m m ol) in pyridin e (150 m l) was evaporated, re-
disolved in pyridin e (100 m l) an d tosyl ch loride (7.63 g, 40 m m ol), an d 4-(dim eth yl-
am in o)pyridin e (250 m g, 2.0 m m ol) were added. Th e m ixture was set aside at room
tem perature overn igh t. Water (5 m l) was added at 0 °C an d, after 10 m in , th e solven t was
evaporated. Th e residue was partition ed between eth yl acetate (500 m l) an d water (100 m l).
Th e organ ic layer was separated an d wash ed with 5% h ydroch loric acid, water an d 5% aque-
ous sodium h ydrogen carbon ate (100 m l each ), dried over an h ydrous sodium sulfate an d
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794
Hřebabecký, Holý:
taken down to give 13.7 g (92%) of tosylate 18. An an alytical sam ple was prepared by ch ro-
m atograph y on a silica gel colum n in toluen e–eth yl acetate (9 : 1). For C23H28O7S (448.5)
calculated: 61.59% C, 6.29% H, 7.15% S; foun d: 61.30% C, 6.36% H, 7.36% S. 1H NMR
(DMSO-d6): 1.24 s, 3 H an d 1.36 s, 3 H (C(CH3)2); 1.92 q, 2 H, J(5,4) = J(5.6) = 6.7 (2 × H-5);
2.40 s, 3 H (CH3); 3.68 d, 1 H, J(3,4) = 3.1 (H-3); 4.01–4.13 m , 3 H (H-4, 2 × H-6); 4.40 d,
1 H an d 4.63 d, 1 H, Jgem = 11.6 (CH2Ph ); 4.69 d, 1 H, J(2,1) = 3.7 (H-2); 5.78 d, 1 H (H-1);
7.25–7.34 m , 5 H (H-arom . ben zyl); 7.45 d, 2 H an d 7.75 d, 2 H, J = 7.9 (H-arom . tosyl).
3-O-Ben zyl-5-deoxy-1,2-O-isopropyliden e-6-iodo-α-D-xylo-h exofuran ose (19)
A solution of tosylate 18 (13.5 g, 30 m m ol) an d sodium iodide (15 g, 100 m m ol) in
butan -2-on e (170 m l) was refluxed for 1 h . After coolin g, th e in soluble portion was filtered
off an d th e solven t was evaporated. Th e residue was dissolved in eth yl acetate (500 m l) an d
th e solution was wash ed with water, aqueous sodium th iosulfate, water, dried over an h y-
drous sodium sulfate an d taken down . Ch rom atograph y on a silica gel colum n (700 g) in
toluen e–eth yl acetate (87 : 13) afforded 10.84 g (89%) of iodo derivative 19. For C16H21IO4
(404.3) calculated: 47.54% C, 5.24% H, 31.39% I; foun d: 47.80% C, 5.27% H, 31.49% I. [α]D
–38.4 (c 1.800, ch loroform ). 1H NMR (CDCl3): 1.33 s, 3 H an d 1.51 s, 3 H (C(CH3)2);
1.99–2.16 m , 1 H (H-5a); 2.22–2.40 m , 1 H (H-5b); 3.11–3.30 m , 2 H (2 × H-6); 3.83 d, 1 H,
J(3,4) = 3.1 (H-3); 4.26 m , 1 H, J(4,5a) = 4.9, J(4,5b) = 8.5 (H-4); 4.48 d, 1 H an d 4.71 d, 1 H,
Jgem = 11.9 (CH2PH); 4.63 d, 1 H, J(2,1) = 4.3 (H-2); 5.91 d, 1 H (H-1); 7.30–7.41 m , 5 H
(H-arom .).
Dieth yl (3-O-Ben zyl-5,6-dideoxy-1,2-O-isopropyliden e-α-D-xylo-h exofuran os-
6-yl)m alon ate (20)
Sodium h ydride (60% dispersion in m in eral oil, 1.2 g, 30 m m ol) was added un der argon at
0 °C to a stirred solution of dieth yl m alon ate (5.0 m l, 33 m m ol) in dim eth ylform am ide
(100 m l) an d, after stirrin g at 0 °C for 15 m in , a solution of iodide 19 (10.11 g, 25 m m ol) in
dim eth ylform am ide (30 m l) was added. Th e m ixture was stirred at room tem perature for 6 h
an d th en th e solven t was evaporated. Th e residue was partition ed between eth yl acetate
(500 m l) an d water (100 m l). Th e organ ic ph ase was wash ed with water (100 m l), dried over
an h ydrous sodium sulfate, an d th e solven t was evaporated. Ch rom atograph y on a colum n
of silica gel (400 g) in toluen e–eth yl acetate (87 : 13) afforded m alon ate 20 (9.50 g, 87%).
For C23H32O8 (436.5) calculated: 63.29% C, 7.39% H; foun d: 63.01% C, 7.42% H. [α]D –35.6
(c 0.772, ch loroform ). 1H NMR (CDCl3): 1.25 t, 6 H, J = 7.3 (2 × CH3); 1.31 s, 3 H and 1.48 s, 3 H
(C(CH3)2); 1.66–2.05 m , 4 H (2 × H-5′, 2 × H-6′); 3.35 t, 1 H, J(2,6′a) = J(2,6′b) = 7.3 (H-2);
3.79 d, 1 H, J(3′,4′) = 3.1 (H-3′); 4.18 q, 4 H, J = 7.3 (2 × CH2Me); 4.10–4.18 m , 1 H (H-4′);
4.49 d, 1 H an d 4.69 d, 1 H, Jgem = 11.9 (CH2PH); 4.61 d, 1 H, J(2′,1′) = 3.7 (H-2′); 5.90 d, 1 H
(H-1′); 7.23–7.36 m , 5 H (H-arom .).
Dieth yl (2R,S,3S,4R)-2-(Acetyloxy)-3-(ben zyloxy)-4-(form yloxy)cycloh exan e-
1,1-dicarboxylate (21)
A m ixture of 20 (8.73g, 20 m m ol), dioxan e (53 m l), water (32 m l) an d Dowex 50 (H+ form ,
15 m l) was stirred at 80 °C for 20 h . Th en th e resin was filtered off, wash ed with dioxan e,
an d th e solven t was evaporated. A solution of th e residue in eth yl acetate (300 m l) was
wash ed with water (100 m l) an d 10% aqueous potassium h ydrogen carbon ate (100 m l), dried
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Carbocyclic Nucleosides
795
over an h ydrous sodium sulfate, an d th e solven t was evaporated. To a stirred solution of th e
residue in dioxan e (100 m l), a saturated solution of sodium periodate (85 m l) was added
dropwise durin g 20 m in . Th e in soluble portion was filtered off an d wash ed with dioxan e.
Th e com bin ed filtrates were con cen trated to about 40 m l an d partition ed between eth yl ace-
tate (300 m l) an d water (100 m l). Th e organ ic ph ase was separated, wash ed with water
(100 m l), dried over an h ydrous sodium sulfate, an d th e solven t was evaporated. A m ixture
of th e residue, pyridin e (60 m l) an d acetic an h ydride (6 m l) was set aside at room tem pera-
ture overn igh t. Meth an ol (5 m l) was added an d, after 15 m in , th e solven t was evaporated. A
solution of th e residue in eth yl acetate (200 m l) was wash ed with water (3 × 100 m l), dried
over an h ydrous sodium sulfate an d taken down . Ch rom atograph y on a colum n of silica gel
(450 g) in toluen e–eth yl acetate (92 : 8) afforded 3.60 g (41%) of 21. For C22H28O9 (436.5)
calculated: 60.54% C, 6.47% H; foun d: 60.31% C, 6.61% H. 1H NMR (CDCl3): 1.17–1.31 m
(2 × CH3 2R + 2S); 1.48–1.59 m (H-6a 2R + 2S); 1.99 s (COCH3 2S); 2.05 s (COCH3 2R);
2.09–2.31 m (2 × H-5, H-6b 2R + 2S); 3.89 dd, J(3,2) = 3.1, J(3,4) = 9.8 (H-3 2R); 4.04–4.33 m
(2 × MeCH2 2R + 2S, H-3 2S); 4.49 d an d 4.78 d, Jgem = 11.6 (CH2Ph 2R); 4.68 d an d 4.71 d,
Jgem = 11.6 (CH2Ph 2S); 4.88–5.09 m (H-4 2R + 2S); 5.37 d (H-2 2S); 6.21 d (H-2 2R);
7.24–7.36 m (H-arom . 2R + 2S); 7.97 s (CHO 2S); 8.03 s (CHO 2R); (2R)-isom er an d (2S)-iso-
m er in th e 1 : 3 ratio.
(1R,2S,3R,S)-2-(Ben zyloxy)-4,4-bis(h ydroxym eth yl)cycloh exan e-1,3-diol (22)
Ester 21 (2.18 g, 5 m m ol) dissolved in tetrah ydrofuran (20 m l) was slowly added dropwise to
a stirred refluxin g 1 M solution of lith ium alum in ium h ydride (25 m l) in argon atm osfere.
After addition al 2 h reflux, th e m ixture was cooled an d eth yl acetate (4 m l) was added, fol-
lowed after 15 m in by water (15 m l). Th e m ixture was taken down an d th e residue was ex-
tracted with warm eth yl acetate (5 × 30 m l). Th e solid residue was air-dried an d m ixed with
90% aqueous m eth an ol (60 m l). Th e in soluble portion was filtered off th rough a Celite pad
an d wash ed with h ot m eth an ol. Th e com bin ed extracts an d filtrates were taken down an d
th e residue was ch rom atograph ed on a silica gel colum n (350 g) in eth yl acetate–ace-
ton e–eth an ol–water (100 : 15 : 6 : 4) givin g 1.18 g (84%) of com poun d 22. For C15H22O5
(282.3) calculated: 63.81% C, 7.85% H; foun d: 63.50% H, 8.01% H. 1H NMR (DMSO-d6):
1.11–1.64 m (2 × H-5, 2 × H-6 3R + 3S); 3.16–3.60 m (2 × CH2O, H-2 3R + 3S, H-1, H-3 3S);
3.68–3.82 m (H-1 3R); 3.89 dd, J(3,2) = 3.05, J(3,OH) = 4.3 (H-3 3R); 4.19 t, J(CH2,OH) = 5.2
(CH2OH 3R); 4.28–4.84 m (CH2OH 3S, 2 × CH2OH, 1-OH, 3-OH, 2 × CH2Ph 3R + 3S);
7.22–7.44 m (H-arom ); after exch an ge with D2O: 4.50 d an d 4.59 d, Jgem = 12.2 (CH2Ph 3R);
4.69 d an d 4.74 d, Jgem = 11.3 (CH2Ph 3S); (2R)-isom er an d (2S)-isom er in th e 1 : 3 ratio.
(2S,3S,4R)- (23) an d (2R,3S,4R)-2,4-Bis(ben zoyloxy)-1,1-bis[(ben zoyloxy)m eth yl]-
3-(ben zyloxy)cycloh exan e (24)
A m ixture of isom eric tetrah ydroxy derivatives 22 (1.13 g, 4.0 m m ol) was codistilled with
pyridin e (15 m l), redissolved in pyridin e (12 m l), an d ben zoyl ch loride (2.4 m l, 20.7 m m ol)
was added un der coolin g. Th e m ixture was set aside at room tem perature for 2 days, water
(1 m l) was added at 0 °C an d, after 10 m in , con cen trated in vacuo. Th e residue was parti-
tion ed between eth yl acetate (100 m l) an d water (50 m l). Th e organ ic ph ase was wash ed
with water (100 m l), 5% h ydroch loric acid (100 m l), water (50 m l) an d 10% aqueous potas-
sium h ydrogen carbon ate (50 m l), th en dried over an h ydrous sodium sulfate, an d th e solven t
was evaporated. Ch rom atograph y of th e residue on a silica gel colum n (300 g) in toluen e–
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Hřebabecký, Holý:
eth yl acetate (96 : 4) gave ben zoate 24 (527 m g, 19%) an d, after crystallization from m eth a-
n ol, 1.74 g (62%) of ben zoate 23.
Compound 23: M.p. 141–142 °C. For C43H38O9 (698.8) calculated: 73.91% C, 5.48% H;
foun d: 74.13% C, 5.36% H. [α]D –38.8 (c 0.752, ch loroform ). 1H NMR (CDCl3): 1.74–2.34 m ,
4 H (2 × H-5, 2 × H-6); 4.18 dd, 1 H, J(3,2) = 8.8, J(3,4) = 8.5 (H-3); 4.45 d, 1 H an d 4.57 d,
1 H, Jgem = 11.6 (CH2); 4.61 d, 1 H an d 4.69 d, 1 H, Jgem = 11.1 (CH2); 4.67 d, 1 H an d
4.92 d, 1 H, Jgem = 11.6 (CH2); 5.29 ddd, 1 H, J(4,5a) = 4.9, J(4,5b) = 9.2 (H-4); 5.79 d, 1 H
(H-2); 6.94–7.07 m , 5 H (H-arom . ben zyl); 7.28–7.60 m , 12 H an d 7.92–8.03 m , 8 H
(H-arom .).
Compound 24: Colourless foam . For C43H38O9 (698.8) calculated: 73.91% C, 5.48% H;
foun d: 73.64% C, 5.59% H. [α]D –25.9 (c 0.804, ch loroform ). 1H NMR (CDCl3): 1.79–2.44 m ,
4 H (2 × H-5, 2 × H-6); 4.07 dd, 1 H, J(3,2) = 3.2, J(3,4) = 7.2 (H-3); 4.47–4.73 m , 6 H (3 ×
CH2); 5.52 m , 1 H, ΣJ = 18.3 (H-4); 6.04 d, 1 H (H-2); 7.08–7.61 m , 17 H an d 7.98–8.06 m , 8 H
(H-arom .).
(1S,2S,6R)-2,6-Bis(ben zoyloxy)-3,3-bis[(ben zoyloxy)m eth yl]cycloh exan -1-ol (25)
Ben zyl derivative 23 (1.40 g, 2.0 m m ol) was h ydrogen ated in a m ixture of m eth an ol (12 m l)
an d dim eth ylform am ide (6 m l) over Pd/C (10%, 250 m g) at atm osph eric pressure for 50 h .
Th e catalyst was rem oved by filtration th rough a Celite pad, wash ed with m eth an ol, an d th e
com bin ed filtrates were taken down . Th e residue was dissolved in eth yl acetate (40 m l), th e
solution was wash ed with water (3 × 20 m l), dried over an h ydrous sodium sulfate, an d th e
solven t was evaporated. Yield 1.16 g (95%) of alcoh ol 25. For C36H32O9 (608.7) calculated:
71.04% C, 5.30% H; foun d: 70.89% C, 5.27% H. [α]D –39.9 (c 0.903, ch loroform ). 1H NMR
(CDCl3): 1.74–2.27 m , 4 H (2 × H-4, 2 × H-5); 4.29 m , 1 H, J(1,2) = 9.7, J(1,6) = 9.5, J(1,OH) =
5.5 (H-1); 4.40 d, 1 H an d 4.57 d, 1 H, Jgem = 11.4 (CH2); 4.71 d, 1 H an d 4.96 d, 1 H, Jgem
=
11.9 (CH2); 5.17 m , 1 H, ΣJ = 24.7 (H-6); 5.65 d, 1 H (H-2); 7.28–7.61 m , 12 H an d 7.92–8.06 m ,
8 H (H-arom .).
(2S,3S,4R)-2,4-Bis(ben zoyloxy)-1,1-bis[(ben zoyloxy)m eth yl]-3-{[(m eth ylsulfan yl)-
th iocarbon yl]oxy}cycloh exan e (26)
Carbon disulfide (0.68 m l, 11.3 m m ol) was added to a solution of alcoh ol 25 (1.10 g,
1.8 m m ol) in dim eth ylform am ide (5 m l) an d, after coolin g to 0 °C, sodium h ydride (60%
dispersion in m in eral oil, 239 m g, 6.0 m m ol) was added. After stirrin g at 0 °C for 30 m in ,
m eth yl iodide (1.36 m l, 21.8 m m ol) was added an d th e m ixture was stirred at 0 °C for
30 m in an d th en warm ed up to room tem perature durin g an oth er 30 m in . Water (60 m l)
was added an d th e m ixture was extracted with eth yl acetate (70 m l). Th e organ ic layer was
wash ed with water (3 × 60 m l), dried with an h ydrous sodium sulfate, an d th e solven t was
evaporated. Colum n ch rom atograph y on silica gel (110 g) in toluen e–eth yl acetate (96 : 4)
afforded 994 m g (79%) of dith iocarbon ate 26. For C38H34O9S2 (698.8) calculated: 65.31% C,
4.90% H, 9.18% S; foun d: 65.44% C, 4.86% H, 9.10% S. [α]D –36.0 (c 0.916, ch loroform ).
1H NMR (CDCl3): 1.80–2.43 m , 4 H (2 × H-5, 2 × H-6); 2.73 s, 3 H (SCH3); 4.40 d, 1 H an d
4.52 d, 1 H, Jgem = 11.5 (CH2); 4.73 d, 1 H an d 5.05 d, 1 H, Jgem = 11.9 (CH2); 5.41 m , 1 H,
J(4,5a) = 9.6, J(4,5b) = 4.9 (H-4); 5.90 d, 1 H, J(2,3) = 10.1 (H-2); 6.87 dd, 1 H, J(3,4) = 9.8
(H-3); 7.26–7.61 m , 12 H an d 7.90–8.08 m , 8 H (H-arom .).
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Carbocyclic Nucleosides
797
(2R,4R)-2,4-Bis(ben zoyloxy)-1,1-bis[(ben zoyloxy)m eth yl]cycloh exan e (27)
A 1 M tributylstan n an e solution in toluen e (2.1 m l) an d 2,2′-azobis(2-m eth ylpropan on itrile)
(100 m g, 0.6 m m ol) were added to a boilin g solution of dith iocarbon ate 26 (908 m g,
1.3 m m ol) in toluen e (10 m l). After 30 m in reflux, th e m ixture was evaporated an d th e resi-
due was ch rom atograph ed on a silica gel colum n (110 g) in toluen e–eth yl acetate (93 : 7)
givin g 735 m g (95%) of deoxy derivative 27. For C36H32O8 (592.7) calculated: 72.96% C,
5.44% H; foun d: 72.69% C, 5.45% H. [α]D –45.0 (c 1.084, ch loroform ). 1H NMR (CDCl3):
1.66–2.56 m , 6 H (2 × H-3, 2 × H-5, 2 × H-6); 4.49 d, 1 H an d 4.59 d, 1 H, Jgem = 11.3 (CH2);
4.70 d, 1 H an d 4.95 d, 1 H, Jgem = 11.6 (CH2); 5.25 m , 1 H, J(4,3a) ≈ J(4,3b) ≈ J(4,5a) ≈
J(4,5b) ≈ 4.5 (H-4); 5.59 dd, 1 H, J(2,3a) = 4.6, J(2,3b) = 9.8 (H-2); 7.30–7.58 m , 12 H an d
7.95–8.03 m , 8 H (H-arom .).
(1R,3R)-4,4-Bis(h ydroxym eth yl)cycloh exan e-1,3-diol (28)
Ben zoate 27 (593 m g, 1.0 m m ol) was dissolved un der stirrin g in 0.1 M m eth an olic sodium
m eth oxide (7 m l) an d th e solution was set aside at room tem perature overn igh t. Th e m ix-
ture was n eutralized with Dowex 50(H+), th e resin was rem oved by filtration an d wash ed
with m eth an ol, an d th e com bin ed filtrates were evaporated. Colum n ch rom atograph y on
silica gel (20 g) in eth yl acetate–aceton e–eth an ol–water (16 : 3 : 4 : 2) an d crystallization
from aceton e afforded 150 m g (85%) of h ydroxy derivative 28, m .p. 95.0–95.5 °C. For
C8H16O4 (176.2) calculated: 54.53% C, 9.15% H; foun d: 54.54% C, 9.10% H. [α]D –8.1
(c 0.767, water). 1H NMR (DMSO-d6): 0.89–1.56 m , 5 H an d 1.76–1.86 m , 1 H (2 × H-2, 2 ×
H-5, 2 × H-6); 3.30–3.61 m , 6 H (2 × CH2, H-1, H-3); 4.23 t, 1 H, J(OH,CH2) = 4.9 (CH2OH);
4.42 t, 1 H, J(OH,CH2) = 5.0 (CH2OH); 4.51 d, 1 H, J(OH,CH) = 5.2 (OH); 4.53 d, 1 H,
J(OH,CH) = 5.5 (OH).
The autors are indebted to Ms J. Sklenářová and Ms A. Sterecová for an exellent technical assis-
tance, to Ms J. Křelinová for optical rotation measurements, to Ms M. Snopková and Mr R. Pohl for
recording of the 1H NMR spectra, and to the staff of the Analytical Laboratory of this Institute
(Dr L. Válková, Head) for the elemental analyses. This study is a part of the research project Z4 055 905.
REFERENCES
1. a) Verheggen I., Van Aerschot A., Toppet S., Snoeck R., Janssen G., Balzarini J.,
De Clercq E., Herdewijn P.: J. Med. Chem. 1993, 36, 2033; b) Verheggen I.,
Van Aerschot A., Van Meervelt L., Rozenski J., Wiebe L., Snoeck R., Andrei G.,
Balzarini J., Claes P., De Clercq E., Herdewijn P.: J. Med. Chem. 1995, 38, 826.
2. a) Konkel M. J., Vince R.: Tetrahedron 1996, 52, 799; b) Rosenquist A., Kvarnström I.,
Classon B., Samuelsson B.: J. Org. Chem. 1996, 61, 6282; c) Wang J., Herdewijn P.: J. Org.
Chem. 1999, 64, 7820.
3. a) Hřebabecký H., Masojídková M., Holý A.: Collect. Czech. Chem. Commun. 1998, 63,
2044; b) Hřebabecký H., Holý A.: Collect. Czech. Chem. Commun. 1999, 64, 1485;
c) Hřebabecký H., Holý A.: Collect. Czech. Chem. Commun. 2000, 65, 395.
4. Calvo-Flores F. G., García-Mendoza P., Hernández-Mateo F., Isac-García J., Santoyo-
Gonzáles F.: J. Org. Chem. 1997, 62, 3944.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

798
Hřebabecký, Holý:
5. Wysocki R. J., Jr., Siddiqui M. A., Barchi J. J., Jr., Driscoll J. S., Marquez V. E.: Synthesis
1991, 1005.
6. a) Czernecki S., Georgoulis C., Provelenghiou C.: Tetrahedron Lett. 1975, 2623;
b) Bonini C., Di Fabio R., Sotgiu G., Cavegnero S.: Tetrahedron 1989, 45, 2895.
7. Whistler R. L., Lake W. C.: Methods Carbohydr. Chem. 1972, 6, 286.
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