Synthesis of enantiomeric 9-(2′,3′,4′-trihydroxybutyl)adenine derivatives from L-ascorbic and D-isoascorbic acids

Article abstract of DOI:10.1016/S0040-4020(03)00991-8

L-Ascorbic and D-isoascorbic acids were employed in syntheses of 9-(2′,3′,4′-trihydroxybutyl)adenines protected at 3′ and 4′ oxygens (all four enantiomers) and at 2′ oxygen (2′S,3′R and 2′S,3′S enantiomers).

Full text of DOI:10.1016/S0040-4020(03)00991-8

Tetrahedron 59 (2003) 6075–6081
Synthesis of enantiomeric 9-(20,30,40-trihydroxybutyl)adenine
derivatives from L-ascorbic and D-isoascorbic acids
*
Andrzej E. Wroblewski and Wiesl⁄awa Karolczak
´
´ ´ ´ ´
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Institute of Chemistry, Medical University of L⁄ odz, 90-151 L⁄ odz,
Muszyn˜skiego 1, Poland
Received 13 March 2003; revised 27 May 2003; accepted 19 June 2003
Abstract—L-Ascorbic and D-isoascorbic acids were employed in0syntheses of 9-(20,30,40-trihydroxybutyl)adenines protected at 30 and 40
oxygens (all four enantiomers) and at 20 oxygen (20S,30R and 20S,3 S enantiomers).
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
For the synthesis of the enantiomers of 3 several strategies
have been developed. Initially, the terminal hydroxy group
of a tetritol derivative was transformed into the amino
group, which was next incorporated as N(9) of the adenine
ring.2,3,6 Reduction of esters of (2R,3R) and (2S,3S)-1
afforded (20R,30S)8 and (20S,30R)-3,2,3,8,9 respectively. Alky-
lation of adenine with four-carbon chirons has als0o been
successfully explored in synthesis of (20R,30R) and (2 S,30S)-
3, i.e. enantiomers having threo configuration. To this end,
suitably protected 4-O-tosyl-D(or L)-threitols were obtained
in multi-step procedures from D-(or L)-arabinitol,7 D-
mannitol7 or diethyl L-tartrate.8 Five and six-carbon chirons
prepared from D-xylose, L-arabinose and D-mannose were
also applied in synthesis of N(9) alkylated adenines.7
Several purine acyclonucleosides have been known for their
antiviral activity.1 A natural product, 4-(6-amino-9H-purin-
9-yl)-4-deoxy-D-erythronic acid (D-eritadenine) 1, showed a
marked hypocholesterolemic effect2,3 and is extremely
potent inhibitor of S-adenosyl-L-homocysteine hydrolase.4
Discovery of antiviral activity of (20S)-9-(20,30-dihydroxy-
propyl)adenine 25 has prompted studies on the synthesis of
other N(9)-substituted adenines and guanines possessing
polyhydroxyalkyl chains. Among them, the stereoisomers
of 9-(20,30,40-trihydroxybutyl)adenine 3 have attracted a
great deal of attention from both synthetic6 – 11 and
biological activity12–14 points of views.
Keywords: purine acyclonucleosides; alkylation of adenine; stereoisomers.
*
Corresponding author. Fax: þ48-42-678-8398; e-mail: aewplld@ich.pharm.am.lodz.pl
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00991-8

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A. E. Wroblewski, W. Karolczak / Tetrahedron 59 (2003) 6075–6081
6076
However, a two-step degradation sequence (NaIO4 diol
oxidation and NaBH4 reduction) was required to shorten the
alkyl chain. Finally DIBAL-H reduction of 20,30-O-iso-
propylidene adenosine15 followed by degradation seems to
be a method of choice for the synthesis of (20S,30R)-3.9–11
When the intermediate aldehyde from the degradation0step
was subjected to a base-catalysed epimerisation, (20S,3 S)-3
was obtained.11
ascorbic acid 4 was employed as a starting material.
Preserving the configurations at C(4) and C(5) of 4 would
lead to (20S,30S)-3, whil0e one inversion of configuration is
required to obtain (2 R,30S)-3. Similar approach was
envisioned for the synthesis of (20S,30R)-3 and (20R,30S)-3
starting from D-isoascorbic acid 5 (Scheme 1).
For the alkylation of adenine three different pathways were
applied: nucleophilic displacement of terminal mesylates7,8
and openings of terminal epoxides16 or carbonates17
(Schemes 2–4).
In this paper, we would like to present a new synthetic strategy
for the synthesis of all of the suitably protected enantiomers of
3 based on alkylation of adenine with four-carbon chirons
prepared from L-ascorbic 4 and D-isoascorbic acids 5.
L-Ascorbic acid 4 was transformed into the protected a-
hydroxyester (2R,3S)-6 in 78% yield according to the
literature procedure.18 Reduction of (2R,3S)-6 with a
sodium borohydride–lithium chloride mixture19 led quan-
titatively to the known diol (2S,3S)-7.20,21 In the presence of
carbonyldiimidazole22 the crystalline cyclic carbonate
(2S,3S)-8 was formed from the diol in 80% yield. Alkylation
of0adenine with (2S,3S)-8 in DMF at 1208 for the 38 h led to
(2 S,30S)-9 in 71% yield.
2. Results and discussion
In order to secure the S configuration at C(30) of 3, L-
When the known epoxide (2S,3R)-1220,23 was subjected to
the reaction with adenine in the 0 presence of cesium
carbonate at 1208C for 68 h, (20R,30S)-9 was obtained in
80% yield. For the synthesis of 2 -O-benzyl derivative
(20S,30S)-15 the recently reported24 mesylate 13 was used as
a starting material. Thus, alkylation of adenine with 13 in
DMF at 1408C0for 20 h in the presence of cesium carbonate
afforded (20S,3 S)-14 in 58% yield. Standard deprotection of
(20S,30S)-14 led to crystalline (20S,30S)-15 as a tetrahydrate.
Starting from D-isoascorbic acid 5 the hydroxyester
(2R,3R)-6 was prepared in 55% overall yield.25 Sodium
borohydride–lithium chloride reduction19 of (2R,3R)-6 led
to the diol (2R,3S)-7,26,27 which was transformed into the
Scheme 1. Retrosynthesis of enantiomers of 3.
Scheme 2. Reagents and conditions: (a) NaBH4–LiCl, THF–EtOH, 208C, 16 h; (b) Im2CO, CH2Cl2, 208C, 16 h; (c) adenine, NaOH, DMF, 1208C, 38 h; (d)
TsCl, pyridine, 08C, 16 h; (e) K2CO3, methanol; (f) adenine, Cs2CO3, DMF, 1208C, 46 h; (g) adenine, DMF, 1408C, 20 h; (h) HCl, dioxane, 208C, 24 h.

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A. E. Wroblewski, W. Karolczak / Tetrahedron 59 (2003) 6075–6081
6077
Scheme 3. Reagents and conditions: (a) NaBH4–LiCl, THF–EtOH, 208C, 16 h; (b) Im2CO, CH2Cl2, 208C, 16 h; (c) adenine, NaOH, DMF, 1208C, 38 h.
Scheme 4. Reagents and conditions: (a) TsCl, pyridine, 08C, 16 h; (b) NaBH4–LiCl, THF–EtOH, 208C, 16 h; (c) K2CO3–methanol, 208C, 30 h; (d) adenine,
Cs2CO3, 1208C, 46 h; (e) BnBr, Ag2O, 208C, 23 h; (f) MsCl, pyridine, 208C, 23 h; (g) adenine, Cs2CO3, DMF, 1408C, 20 h; (h) HCl, dioxane, 208C, 24 h.
cyclic carbonate (2R,3S)-8 (Scheme 3). Alkylation of
adenine with the carbonate was accomplished in the same
way as described for (20S,30S)-9 providing the epimeric
(20S,30R)-9 in 85% yield.
nucleophilic substitution and protection of C(2) hydroxyls
and leads to retention of configuration at C(2). As an
alternative to aluminum hydride23 the same reducing
mixture (NaBH4–LiCl) was found effective in reduction
of esters in the presence of a tosyl group, thus allowing
conversion of an a-hydroxyester subunit into a terminal
epoxide with inversion of configuration in three steps. Due
to poor nucleophilicity of adenine its alkylation was
performed as the last step of the reaction sequence.
Methyl (2R,3R)-3,4-O-cyclohexylidene-1-hydroxybutano-
ate (2R,3R)-1625 was used as a key 0 intermediate in the
synthesis of (20R,30R)-20 and (20S,3 R)-15 (Scheme 4).
Under standard conditions the hydroxyester was trans-
formed into the tosylate (2R,3R)-17. The ester group in
(2R,3R)-17 was reduced with a sodium borohydride–
lithium chloride mixture19 to give the hydroxytosylate
(2R,3S)-18, which was treated with potassium carbonate in
methanol to produce the epoxide (2R,3R)-19. Alkylation of
adenine with the epoxide led to (20R,30R)-20 in 55% yield.
4. Experimental
4.1. General
1H and 13C NMR spectra were taken in CDCl3 on the Varian
Mercury-300 spectrometer at 300 and 75.5 MHz, respect-
ively. IR spectral data were measured on an Infinity MI-60
FT-IR spectrometer. Melting points were determined on a
Boetius apparatus and are uncorrected. Elemental analysis
were performed by the Microanalytical Laboratory of this
Faculty on a Perkin–Elmer PE 2400 CHNS analyzer.
Polarimetric measurements were conducted on a Perkin–
Elmer 241 MC apparatus.
To synthesise (20S,30R)-15 the hydroxy group in (2R,3R)-16
was benzylated, the ester function in (2R,3R)-21 was
reduced with a sodium borohydride–lithium chloride
mixture19 and the hydroxymethyl group in (2R,3S)-22 was
subjected to mesylation. The mesylate (2R,3S)-23 was
reacted with adenine in the presence of cesium carbonate at
1408C to give (20S,30R)-24 in 51% yield. Hydr0olysis of the
cyclohexylidene group led to amorphous (20S,3 R)-15 as the
tetrahydrate.
The following adsorbents were used: column chromatog-
raphy, Merck silica gel 60 (70–230 mesh); analytical TLC,
Merck TLC plastic sheets silica gel 60 F254. TLC plates
were developed in various chloroform: methanol solvent
systems. Visualisation of spots was effected with iodine
vapours.
3. Conclusions
The elaborated strategies incorporate several synthetic
shortcuts and improvements over existing procedures. A
sodium borohydride–lithium chloride mixture was used
instead of lithium aluminum hydride21,28 to efficiently
reduce a-hydroxyesters to terminal diols with a non-
aqueous workup. Transformation of terminal diols into
carbonates results simultaneously in activation of C(1) for
4.1.1. (2S,3S)-1,2-O-Isopropylidenebutane-1,2,3,4-tetrol,
(2S,3S)-7. A solution of (2R,3S)-618 (0.513 g, 2.70 mmol) in
THF–ethanol (1:2, 12 mL) containing anhydrous LiCl
(0.34 g, 8.1 mmol) was cooled to 08C and, while stirred,

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6078
NaBH4 (0.30 g, 8.1 mmol) was added portionwise. The
reaction mixture was stirred overnight at room temperature
and quenched with acetone (1.5 mL). After 30 min the
suspension was diluted with chloroform (50 mL), anhydrous
MgSO4 (3 g) was added and filtered through a layer of
Celite 535. The clear solution was evaporated to leave pure
(2S,3S)-7 (0.430 g, 98%) as a colourless oil. [a]2D0¼þ5.2
(c¼2.0, methanol). IR (film): n¼3399 (br), 2988, 2927,
1372, 1155 cm21. 1H NMR (CDCl3): d¼1.37 and 1.45 (6H,
2s), 2.44 (2H, brs), 3.61–3.73 (3H, m), 3.86 (1H, dAB,
JAB¼8.1 Hz, J¼6.6 Hz), 4.05 (1H, dAB, JAB¼8.1 Hz,
J¼6.6 Hz), 4.15–4.21 (1H, m). 13C NMR (CDCl3):
d¼25.56, 26.72, 64.09, 65.99, 72.30, 76.73, 109.68. Anal.
calcd for C7H14O4 (162.18): C, 51.83; H, 8.70. Found: C,
51.66; H, 9.01.
calcd for C8H12O5 (188.18): C, 51.06; H, 6.42. Found: C,
51.35; H, 6.46.
4.1.5. (20S,30S)-9-(30,40-O-Isopropylidene-20,30,40-tri-
hydroxybutyl)adenine, (20S,30S)-9. To a solution of
(2S,3S)-8 (0.475 g, 2.53 mmol) in DMF (5 mL), adenine
(0.31 g, 2.3 mmol) was added followed by solid NaOH
(15 mg, 0.38 mmol). The reaction mixture was kept at
1208C for 38 h. The solvent was removed in vacuo, and the
residue was coevaporated with toluene (3£15 mL). The
crude product was extracted with methanol (10 mL), the
solution was concentrated and subjected to chromatography
on a silica gel column with chloroform–methanol (4:1, 0v/v).
Appropriate fractions were collected to give (20S,3 S)-9
(0.454 g, 71%) as a white powder, which was recrystallised
from methanol–petroleum ether (colourless plates). Mp
180–1818C. [a]2D0¼240.8 (c¼1.0, methanol). IR (KBr):
n¼3215, 3167, 2978, 2471, 1706, 1658, 1569, 1371, 1065,
4.1.2. (2R,3S)-1,2-O-Isopropylidenebutane-1,2,3,4-tetrol,
(2R,3S)-7. In a similar manner as described for (2S,3S)-7,
from (2R,3R)-625 (0.62 g, 3.2 mmol), pure (2R,3S)-7
1
862 cm21. H NMR (CD3OD): d¼1.35 and 1.44 (6H, 2s),
(0.397 g, 75%) was obtained as
a
colourless oil.
3.94 (1H, dAB, JAB¼7.8 Hz, J¼6.6 Hz), 3.96 (1H, ddd,
J¼9.3, 3.6, 3.3 Hz), 4.08 (1H, dAB, JAB¼7.8 Hz,
J¼6.9 Hz), 4.15 (1H, ddd, J¼6.9, 6.6, 3.6 Hz), 4.24 (1H,
dAB, JAB¼14.1 Hz, J¼9.3 Hz), 4.38 (1H, dAB,
JAB¼14.1 Hz, J¼3.3 Hz), 8.11 (1H, s), 8.20 (1H, s). 13C
NMR (CD3OD): d¼25.64, 26.73, 48.14, 66.51, 70.27,
78.04, 110.79, 119.88, 143.64, 150.68, 153.54, 157.16.
Anal. calcd for C12H17N5O3 (279.29): C, 51.60; H, 6.14; N,
25.08. Found: C, 51.91; H, 5.93; N, 25.06.
[a]2D0¼þ7.4 (c¼3.5, methanol). IR (film): n¼3381, 2984,
2879, 1372, 1067 cm21. 1H NMR (CDCl3): d¼1.36 and 1.43
(6H, 2s), 2.12 (1H, t, J¼5.8 Hz), 2.49 (1H, d, J¼4.7 Hz),
3.60–3.70 (1H, m), 3.70–3.85 (2H, m), 3.91–4.00 (1H, m),
4.04–4.13 (2H, m). 13C NMR (CDCl3): d¼25.36, 26.85,
63.84, 66.58, 72.63, 76.22, 109.51. Anal. calcd for C7H14O4
(162.18): C, 51.83; H, 8.70. Found: C, 51.59; H, 8.74.
4.1.3. (2S,3S)-1,2-O-Isopropylidenebutane-1,2,3,4-tetrol
3,4-cyclic carbonate, (2S,3S)-8. To a solution of (2S,3S)-7
(0.43 g, 2.6 mmol) in CH2Cl2 (8 mL) freshly calcinated
molecular sieves A4 (2 g) were added and the suspension
was stirred at room temperature for 30 min. Carbonyldi-
imidazole (0.45 g, 2.8 mmol) was then added portionwise
and the reaction mixture was stirred overnight. Sieves were
filtered off, and the residue was partitioned between CH2Cl2
and water. The organic phase was dried over MgSO4 and
concentrated. The crude product was recrystallised from
chloroform: hexanes to give the cyclic carbonate (2S,3S)-8
(0.40 g, 80%) as colourless needles. Mp 134.5–1358C.
[a]2D0¼þ29.9 (c¼1.3, methanol). IR (KBr): n¼2990, 2935,
4.1.6. (20S,30R)-9-(30,40-O-Isopropylidene-20,30,40-tri-
hydroxybutyl)adenine, (20S,30R)-9. In a similar way as
described for (20S,30S)-9, from (2R,3S)-8 (0.357 g,
1.90 mmol), and 0adenine (0.257 g, 1.90 mmol), the adenine
derivative (20S,3 R)-9 (0.450 g, 85%) was obtained as a
white powder. Mp 194–1958C. [a]2D0¼220.5 (c¼1.2,
methanol). IR (KBr): n¼3473, 3363, 3241, 2986, 2933,
1689, 1638, 1305, 1070 cm21. 1H NMR (CD3OD): d¼1.33
and 1.42 (6H, 2s), 3.81–4.20 (5H, m), 4.54 (1H, dd, J¼14.3,
2.9 Hz), 8.11 (1H, s), 8.19 (1H, s). 13C NMR (CD3OD):
d¼25.60, 27.16, 48.37, 67.99, 72.01, 78.39, 111.01, 119.79,
143.69, 150.85, 153.52, 157.07. Anal. calcd for
C12H17N5O3 (279.29): C, 51.60; H, 6.14; N, 25.08. Found:
C, 51.53; H, 6.21; N, 24.87.
1
2904, 1786, 1160, 1073, 1052 cm21. H NMR (CDCl3):
d¼1.37 and 1.44 (6H, 2s), 3.99 (1H, dAB, JAB¼8.7 Hz,
J¼6.3 Hz), 4.14 (1H, dAB, JAB¼8.7 Hz, J¼6.6 Hz), 4.26
(1H, ddd, J¼6.6, 6.3, 2.4 Hz), 4.48 (1H, dAB, JAB¼8.4 Hz,
J¼6.0 Hz), 4.51 (1H, dAB, JAB¼8.4 Hz, J¼8.1 Hz), 4.72
(1H, ddd, J¼8.1, 6.0, 2.4 Hz). 13C NMR (CDCl3): d¼25.40,
26.04, 64.95, 66.42, 74.78, 75.17, 110.62, 153.83. Anal.
calcd for C8H12O5 (188.18): C, 51.06; H, 6.42. Found: C,
51.00; H, 6.48.
4.1.7. Methyl (2R,3S)-3,4-O-isopropylidene-2,3,4-trihy-
droxy-3-O-(p-toluenesulfonyl)butanoate, (2R,3S)-10. To
a cooled (258C) solution of (2R,3S)-6 (2.76 g, 14.5 mmol)
in dry pyridine (10 mL), tosyl chloride (2.76 g, 14.5 mmol)
was added portionwise and the reaction mixture was left at
08C overnight. The solution was poured into ice–water. The
solid was filtered off, thoroughly washed with water and air-
dried to give a crude product (4.027 g, 81%), which was
recrystallised from chloroform–hexanes (colourless nee-
dles). Mp 62–638C. [a]2D0¼þ28.9 (c¼2.7, methanol). IR
4.1.4. (2R,3S)-1,2-O-Isopropylidenebutane-1,2,3,4-tetrol
3,4-cyclic carbonate, (2R,3S)-8. In a similar way as
described for (2S,3S)-8, from (2R,3S)-7 (0.54 g,
3.4 mmol) and carbonyldiimidazole (0.60 g, 3.7 mmol),
the cyclic carbonate (2R,3S)-8 (0.444 g, 71%) was
obtained as a colourless very viscous oil. [a]2D0¼211.9
(c¼1.8, methanol). IR (film): n¼2990, 2935, 2891, 1787,
1
(KBr): n¼2999, 2937, 1762, 1367, 1178 cm21. H NMR
(CDCl3): d¼1.29 and 1.30 (6H, 2s), 2.45 (3H, s), 3.70 (3H,
s), 3.74 (1H, dd, J¼9.3, 5.1 Hz), 4.03 (1H, dd, J¼9.3,
6.3 Hz), 4.57 (1H, ddd, J¼9.3, 6.3, 5.1 Hz), 4.83 (1H, d,
J¼5.1 Hz), 7.35 (2H, d, J¼8.7 Hz), 7.84 (2H, d, J¼8.7 Hz).
13C NMR (CDCl3): d¼21.98, 25.39, 26.18, 53.05, 65.30,
74.82, 76.96, 110.73, 128.29, 129.83, 132.97, 145.34,
166.93. Anal. calcd for C15H20O7S (344.31): C, 52.31; H,
5.97. Found: C, 52.43; H, 6.09.
1
1161, 1074, 1053 cm21. H NMR (CDCl3): d¼1.36 and
1.43 (6H, 2s), 3.92 (1H, dAB, JAB¼9.0 Hz, J¼3.6 Hz,),
4.16 (1H, dAB, JAB¼9.0 Hz, J¼6.3 Hz), 4.20–4.28 (1H,
m), 4.40–4.59 (3H, m). 13C NMR (CDCl3): d¼24.85,
26.72, 66.20, 66.80, 74.98, 75.96, 110.55, 154.55. Anal.

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6079
4.1.8. Methyl (2R,3S)-3,4-O-cyclohexylidene-2,3,4-trihy-
droxy-3-O-(p-toluenesulfonyl)butanoate, (2R,3R)-17. In a
similar manner as described for (2R,3S)-10, from (2R,3R)-
16 (0.657 g, 2.81 mmol) and tosyl chloride (0.570 g,
3.00 mmol), (2R,3R)-17 (1.05 g, 96%) was obtained as a
colourless oil. [a]2D0¼þ6.4 (c¼1.6, methanol). IR (film):
n¼2936, 2862, 1757, 1371, 1096 cm21. 1H NMR (CDCl3):
d¼1.25–1.42 (2H, m), 1.45–1.57 (8H, m), 2.45 (3H, s),
3.64 (3H, s), 3.93 (1H, dAB, JAB¼9.0 Hz, J¼4.6 Hz), 4.00
(1H, dAB, JAB¼9.0 Hz, J¼6.0 Hz), 4.35 (1H, ddd, J¼6.1,
6.0, 4.6 Hz), 4.79 (1H, d, J¼6.1 Hz), 7.35 (2H, d,
J¼8.3 Hz), 7.80 (2H, d, J¼8.3 Hz). 13C NMR (CDCl3):
d¼21.98, 23.92, 24.10, 25.23, 34.78, 36.27, 52.84, 65.39,
74.48, 77.01, 111.37, 128.29, 129.88, 132.79, 145.45,
167.15. Anal. calcd for C18H24O7S (384.37): C, 56.24; H,
6.29. Found: C, 56.56; H, 6.57.
A solution of (2R,3S)-18 (0.700 g) in methanol (3 mL) was
stirred with anhydrous K2CO3 (0.291 g, 2.11 mmol) at room
temperature for 30 h. After addition of saturated NH4Cl, the
solution was concentrated in vacuo. Water (5 mL) was
added to the residue, the aqueous phase was then extracted
with CH2Cl2 (3£10 mL) and the organic extracts were dried
over MgSO4 and concentrated. The crude product was
chromatographed on a silica gel column with chloroform–
methanol (200:1, v/v) to give (2R,3R)-19 (0.240 g, 67%) as
a colourless oil. [a]2D0¼223.6 (c¼0.7, methanol). IR (film):
1
n¼2935, 2860, 1449, 1368, 1163, 1102 cm21. H NMR
(CDCl3): d¼1.30–1.45 (2H, m), 1.45–1.70 (8H, m), 2.68
(1H, dd, J¼5.1, 2.7 Hz), 2.79 (1H, dd, J¼5.1, 4.2 Hz), 3.03
(1H, ddd, J¼5.1, 4.2, 2.7 Hz), 3.84 (1H, dd, J¼8.0, 6.2 Hz),
3.98 (1H, ddd, J¼6.5, 6.2, 5.1 Hz), 4.09 (1H, dd, J¼8.0,
6.5 Hz). 13C NMR (CDCl3): d¼24.07, 24.22, 25.36, 35.28,
36.25, 44.12, 52.37, 65.77, 76.01, 110.69. Anal. calcd for
C10H16O3 (184.23): C, 65.19; H, 8.76. Found: C, 64.96; H,
8.80.
4.1.9. (2S,3S)-1,2-O-Isopropylidene-3-O-(p-toluenesul-
phonyl)butane-1,2,3,4-tetrol, (2S,3S)-11. A solution of
(2R,3S)-10 (1.376 g, 4.000 mmol) in THF–EtOH (1:2,
18 mL) containing anhydrous LiCl (0.504 g, 12.0 mmol)
was cooled to 258C and NaBH4 (0.444 g, 12.0 mmol) was
added at this temperature portionwise. The reaction mixture
was stirred at room temperature overnight, treated with
acetone (8 mL) and after 30 min diluted with chloroform.
Anhydrous MgSO4 (3 g) was added and the suspension was
vigorously stirred for 1 h and filtered through a layer of
Celite 535. Solvents were evaporated and the crude product
was chromatographed on a silica gel column with chloro-
form–methanol (50:1) to give (2S,3S)-11 (1.165 g, 93%) as
a colourless oil. [a]2D0¼þ9.9 (c¼1.1, methanol). IR (film):
n¼3452, 2993, 2931, 1355, 1178 cm21. 1H NMR (CDCl3):
d¼1.27 and 1.28 (6H, 2s), 2.17 (1H, brs), 2.45 (3H, s), 3.80
and 3.82 (2H, AB part of ABX, JAB¼12.9 Hz, J¼5.1,
4.3 Hz), 3.88 (1H, dAB, JAB¼9.0 Hz, J¼5.7 Hz), 4.01 (1H,
dAB, JAB¼9.0 Hz, J¼6.9 Hz), 4.31 (1H, ddd, J¼6.9, 5.7,
4.8 Hz), 4.57 (1H, ddd, J¼5.1, 4.8, 4.3 Hz), 7.33–7.37 and
7.82–7.86 (4H, m). 13C NMR (CDCl3): d¼21.72, 25.28,
26.09, 62.08, 65.35, 74.49, 81.68, 110.04, 128.08, 129.80,
133.29, 145.10. Anal. calcd for C14H20O6S (316.30): C,
53.07; H, 6.50. Found: C, 52.89; H, 6.49.
4.1.11. 9-[(20R,30S)-20,30,40-Trihydroxy-30,40-O-isopropyl-
idenebutyl]adenine, (20R,30S)-9. A mixture of the epoxide
(2S,3R)-12 (0.144 g, 1.00 mmol), adenine (0.135 g,
1.00 mmol), DMF (3 mL) and cesium carbonate (0.40 g,
1.2 mmol) was stirred at 1208C for 46 h. After cooling the
suspension was filtered and the subsequent solution was
concentrated in vacuo (0.1 mm Hg) and the residue was
coevaporated with toluene (3£3 mL). The crude product
was purified on a silica gel column with chloroform–
methanol (4:1, v/v) to give (20R,30S)-9 (0.223 g, 80%),
which was recrystallised from methanol–petroleum ether
(colourless needles). Mp 176–1788C. [a]2D0¼þ8.8 (c¼3.6,
methanol). IR (KBr): n¼3291, 2926, 1701, 1652, 1072,
1
669 cm21. H NMR (CD3OD): d¼1.33 and 1.42 (6H, 2s),
3.86 (1H, dt, J¼8.4, 3.0 Hz), 3.9–4.1 (3H, ABC system),
4.15 (1H, dd, JAB¼14.4 Hz, J¼8.4 Hz), 4.54 (1H, dd,
JAB¼14.4 Hz, J¼3.0 Hz), 8.11 (1H, s), 8.19 (1H, s). 13C
NMR (CD3OD): d¼26.34, 27.92, 49.13, 68.73, 72.74,
79.15, 111.71, 120.54, 144.44, 151.60, 154.26, 157.82.
Anal. calcd for C12H17O3N5 (279.29): C, 51.60; H, 6.14; N,
25.08. Found: C, 51.25; H, 6.38; N, 24.92.
4.1.10. (2R,3R)-1,2-O-Cyclohexylidene-3,4-epoxybutane-
1,2-diol, (2R,3R)-19. A solution of (2R,3R)-17 (0.836 g,
2.18 mmol) in THF–EtOH (1:2, 12 mL) containing anhy-
drous LiCl (0.273 g, 6.51 mmol) was cooled to 08C and
NaBH4 (0.240 g, 6.51 mmol) was added at this temperature
portionwise. The reaction mixture was stirred at room
temperature overnight, treated with acetone (2 mL) and
after 30 min diluted with chloroform (30 mL). Anhydrous
MgSO4 (2 g) was added and the suspension was vigorously
stirred for 1 h and filtered through a layer of Celite 535.
Solvents were evaporated to give crude (2R,3S)-18
(0.700 g) as a colourless very viscous oil of sufficient purity
to be used in the next step. IR (film): n¼3412, 2926, 2854,
4.1.12. 9-[(20R,30R)-30,40-O-Cyclohexylidene-20,30,40-tri-
hydroxybutyl]adenine, (20R,30R)-20. In a similar manner
as described for (20R,30S)-9, from (2R,3R)-19 (0.25 g,
1.3 mmol), adenine (0.20 g, 1.5 mmol), DMF (5 mL) and
Cs2CO3 (0.65 g, 2.0 mmol), (20R,3R0)-20 (0.246 g, 55%) was
obtained as a white powder. Mp 185–1868C. [a]2D0¼þ25.9
(c¼0.7, methanol). IR (KBr): n¼3338, 3199, 2931, 2544,
1619, 1574, 1479, 1340, 1232, 1094 cm21 1H NMR
.
(CD3OD): d¼1.38–1.41 (2H, m), 1.43–1.70 (8H, m), 3.91
(1H, dAB, JAB¼7.8 Hz, J¼6.9 Hz), 3.96(1H, ddd, J¼8.4, 3.9,
3.6 Hz), 4.05 (1H, dAB, JAB¼7.8 Hz, J¼6.6 Hz), 4.14 (1H,
ddd, J¼6.9, 6.6, 3.9 Hz), 4.26 (1H, dAB, JAB¼14.1 Hz,
J¼8.4 Hz), 4.37 (1H, dAB, JAB¼14.1 Hz, J¼3.6 Hz), 8.11
(1H, s), 8.19 (1H, s). 13C NMR (CD3OD): d¼25.03, 25.19,
26.47, 35.84, 37.02, 48.23, 66.25, 70.25, 77.67, 111.28,
119.90, 143.66, 150.77, 153.54, 157.18. Anal. calcd for
C15H21O3N5 (319.36): C, 56.41; H, 6.62; N, 21.93. Found: C,
56.56; H, 6.44; N, 21.78.
1
1365, 1097 cm21. H NMR (CDCl3): d¼1.30–1.40 (2H,
m), 1.50–1.65 (8H, m), 2.10–2.30 (1H, brs), 2.46 (3H, s),
3.68–3.83 (2H, m), 3.90 (1H, dAB, JAB¼12.7 Hz,
J¼3.6 Hz), 3.99 (1H, dd, J¼8.5, 6.3 Hz), 4.21 (1H, ddd,
J¼7.3, 6.3, 5.1 Hz), 4.52 (1H, ddd, J¼7.3, 4.4, 3.6 Hz),
7.26–7.38 and 7.79–7.84 (4H, m). 13C NMR (CDCl3):
d¼21.97, 23.93, 24.17, 25.27, 34.73, 36.36, 62.37, 66.21,
73.75, 82.39, 110.73, 127.94, 130.03, 133.43, 145.34.
4.1.13. (2R,3S)-3-O-Benzyl-1,2-O-cyclohexylidene-4-O-
(methanesulphonyl)butane-1,2,3,4-tetrol, (2R,3S)-23. To

´
A. E. Wroblewski, W. Karolczak / Tetrahedron 59 (2003) 6075–6081
6080
a solution of (2R,3R)-16 (1.40 g, 6.08 mmol) in CH2Cl2
(30 mL) freshly calcinated molecular sieves 4A (6 g) were
added followed by Ag2O (2.25 g, 9.73 mmol). This suspen-
sion was treated with benzyl bromide (2.08 g, 12.2 mmol) in
several portions and vigorously stirred at room temperature
for 23 h. The reaction mixture was filtered through a layer of
Celite 535, and the solution was concentrated in vacuo
(0.1 mm Hg) to leave crude (2R,3R)-21 (2.11 g) as an
yellowish oil, which was used in the next step without
purification. IR (film): n¼3030, 2924, 2854, 1745 cm21. 1H
NMR (CDCl3): d¼1.30–1.50 (2H, m), 1.50–1.70 (8H, m),
3.76 (3H, s), 3.95–4.06 (3H, m), 4.32 (1H, ddd, J¼6.5, 6.0,
5.0 Hz), 4.49 and 4.66 (2H, AB system, JAB¼11.7 Hz),
7.25–7.40 (5H, m).
column with chloroform–methanol (50:1 to 4:1, v/v) to give
(20S,30S)-14 (0.465 g, 58%) as a white powder which was
recrystallised from methanol–hexanes (colourless plates).
Mp 172–1748C. [a]2D0¼245.4 (c¼1.6, methanol). IR
(KBr): n¼3295, 3126, 2981, 1674, 1606, 1309, 1078,
1
698 cm21. H NMR (CD3OD): d¼1.37 and 1.46 (6H, 2s),
3.92 (1H, ddd, J¼9.0, 5.7, 3.9 Hz), 4.00 (1H, dAB,
JAB¼8.4 Hz, J¼6.9 Hz), 4.13 (1H, dAB, JAB¼8.4 Hz,
J¼6.6 Hz), 4.16–4.33 (3H, m), 4.30 (1H, d, J¼11.7 Hz),
4.55 (1H, d, J¼11.7 Hz), 6.90–6.97 (2H, m), 7.05–7.13
(3H, m), 8.01 (1H, s), 8.11 (1H, s). 13C NMR (CD3OD):
d¼25.70, 26.87, 45.82, 66.48, 74.36, 77.43, 77.87, 110.81,
119.92, 128.71, 129.01, 129.18, 138.56, 143.52, 150.49,
153.40, 157.08. Anal. calcd for C19H23N5O3·0.25H2O
(369.23): C, 61.03; H, 6.33; N, 18.73. Found: C, 61.06; H,
6.22; N, 18.82.
To a solution of (2R,3R)-21 (2.11 g) in a mixture of THF–
ethanol (1:2, 50 mL) anhydrous LiCl (0.590 g, 14.0 mmol)
was added. The reaction mixture was cooled to 08C and
NaBH4 (1.08 g, 28.5 mmol) was added portionwise. After
stirring at room temperature for 21 h acetone (8 mL) was
injected. The crude product was diluted with CH2Cl2
(50 mL), vigorously stirred with powdered MgSO4 (4 g)
and filtered through a layer of Celite 535. The solution was
concentrated in vacuo to give crude (2R,3S)-22 (1.55 g) as
an almost colourless oil sufficiently pure to be used in the
4.1.15. 9-[(20S,30R)-20-O-Benzyl-30,40-O-cyclohexylidene-
20,30,40-trihydroxybutyl]adenine,0(20S,30R)-24. In a similar
manner as described for (20S,3 S)-14, from (2R,3S)-23
(0.759 g, 2.05 mmol), adenine (0.280 g, 2.05 mmol) and
Cs2CO3 (1.3 g, 4.0 mmol), (20S,30R)-24 (0.427 g, 51%) was
obtained as an yellowish oil. [a]2D0¼232.4 (c¼1.3,
methanol). IR (film): n¼3325, 2937, 2862, 1614, 1576,
1
1481, 748, 700 cm21. H NMR (CD3OD): d¼1.35–1.48
next step. IR (film): n¼3342, 2926, 2854, 744, 700 cm21
.
(2H, m), 1.51–1.69 (8H, m), 3.88 (1H, dd, J¼8.4, 6.0 Hz),
3.92 (1H, ddd, J¼6.6, 5.4, 3.3 Hz), 4.16 (1H, ddd, J¼6.6,
6.0, 5.4 Hz), 4.26 (1H, dd, J¼14.4, 7.5 Hz), 4.43 (1H, AB,
JAB¼11.4 Hz), 4.46 (1H, dd, J¼14.4, 3.6 Hz), 4.55 (1H,
AB, JAB¼11.4 Hz), 7.00–7.08 (2H, m), 7.10–7.18 (3H, m),
8.04 (1H, s), 8.14 (1H, s). 13C NMR (CD3OD): d¼25.01,
25.22, 26.40, 35.66, 37.30, 45.60, 66.89, 73.94, 76.81,
78.08, 111.22, 119.85, 128.79, 129.12, 129.20, 138.60,
143.39, 150.79, 153.48, 157.07. Anal. calcd for
C22H27N5O3 (409.47): C, 64.52; H, 6.64; N, 17.10. Found:
C, 64.21; H, 6.44; N, 17.01.
1H NMR (CDCl3): d¼1.30–1.50 (2H, m), 1.50–1.70 (8H,
m), 2.13 (1H, brs), 3.45–3.55 (1H, m), 3.60–3.77 (1H, m),
3.77–3.95 (2H, m), 4.02–4.12 (2H, m), 4.6–4.7 (2H, m),
7.25–7.40 (5H, m).
To a cooled 258C solution of (2R,3S)-22 (1.55 g) in CH2Cl2
(10 mL) containing dry pyridine (1.3 mL), mesyl chloride
(0.79 g, 6.9 mmol) was added dropwise. After 23 h of
stirring at room temperature the reaction mixture was
diluted with CH2Cl2 (13 mL) and washed with water.
Aqueous layer was extracted with CH2Cl2 (2£10 mL) and
combined organic extracts were washed with brine and
dried over MgSO4. Solvents were evaporated and the
residual pyridine was removed by coevaporation with
toluene. The crude product was purified on a silica gel
column with methylene chloride–methanol (100:1, v/v) to
give (2R,3S)-23 (0.759 g, 34%) as a colourless oil.
[a]2D0¼þ16.1 (c¼0.9, methanol). IR (film): n¼3030, 2937,
4.1.16. 9-[(20S,30S)-20-O-Benzyl-20,30,400-trihydroxybutyl]-
adenine, (20S,30S)-15. A mixture of (2 S,30S)-14 (0.667 g,
1.81 mmol), dioxane (15 mL) and aqueous HCl (1 M/L,
19.3 mL) was stirred at room temperature for 24 h,
evaporated in vacuo and coevaporated with dioxane
(3£5 mL). The residue was recrystallised from methanol–
petroleum ether to give (20S,30S)-15 (0.487 g, 82%) as
colourless crystals. Mp 165–1668C. [a]2D0¼265.3 (c¼1.5,
methanol). IR (KBr): n¼3259, 3100, 2923, 1691, 1423,
1
2862, 1176, 744, 700 cm21. H NMR (CDCl3): d¼1.30–
1.50 (2H, m), 1.50–1.70 (8H, m), 3.01 (3H, s), 3.61 (1H,
ddd, J¼7.3, 4.6, 2.4 Hz), 3.86 (1H, m), 4.05–4.15 (2H, m),
4.32 (1H, dd, J¼11.1, 4.6 Hz), 4.61 (1H, dd, J¼11.1,
2.4 Hz), 4.58 and 4.76 (2H, AB system, JAB¼11.5 Hz),
7.25–7.30 (5H, m). 13C NMR (CDCl3): d¼23.96, 24.24,
25.28, 34.77, 36.70, 37.67, 66.77, 69.01, 73.02, 73.90,
78.19, 110.39, 128.14, 128.16, 128.59, 137.32. Anal. calcd
for C18H26O6S (370.45): C, 58.37; H, 7.07. Found: C, 58.24;
H, 7.05.
1
1225, 1056, 703 cm21. H NMR (CD3OD): d¼3.68–3.85
(3H, m), 4.07 (1H, ddd, J¼8.4, 4.8, 3.0 Hz), 4.27 (1H, d,
J¼12.0 Hz), 4.39 (1H, dAB, JAB¼14.4 Hz, J¼8.4 Hz), 4.45
(1H, dAB, JAB¼14.4 Hz, J¼4.8 Hz), 4.60 (1H, d,
J¼12.0 Hz), 6.96–7.03 (2H, m), 7.04–7.11 (3H, m), 8.19
(1H, s), 8.25 (1H, s). 13C NMR (CD3OD): d¼47.05, 63.52,
73.13, 74.45, 77.37, 119.57, 128.62, 128.95, 129.59, 138.64,
144.59, 146.31, 150.04, 151.36. Anal. calcd for
C16H19N5O3·4H2O (401.41): C, 47.87; H, 5.79; N, 17.45.
Found: C, 47.96; H, 6.01; N, 17.50.
4.1.14. 9-[(20S,30S)-20-O-Benzyl-30,40-O-isopropylidene-
20,30,40-trihydroxybutyl]adenine, (20S,30S)-14. To a solu-
tion of (2S,3S)-13 (0.716 g, 2.17 mmol) in DMF (10 mL)
adenine (0.290 g, 2.17 mmol) and Cs2CO3 (1.40 g,
4.34 mmol) were added and the reaction mixture was stirred
at 1408C for 20 h. Solids were filtered off and solvents were
removed in vacuo followed by coevaporation of toluene
(3£3 mL). The crude product was purified on a silica gel
4.1.17. 9-[(20S,30R)-20-O-Benzyl-20,30,40-trihydroxybutyl]
adeni0ne, (20S,30R)-15. In a0 similar manner as described for
(200S,30S)-15, from (20S,3 R)-24 (0.167 g, 0.450 mmol),
(2 S,3 R)-15 (0.076 g, 51%) was obtained as an amorphous
solid after crystallisation from methanol. Mp 109–1118C.
[a]2D0¼239.3 (c¼2.1, methanol). IR (KBr): n¼3253, 3065,

´
A. E. Wroblewski, W. Karolczak / Tetrahedron 59 (2003) 6075–6081
6081
2879, 1705, 1452, 1219, 1052, 748 cm21. 1H NMR (CD3OD):
d¼3.66–3.80 (3H, m), 3.90–3.96 (1H, m), 4.37 (1H, AB,
J¼11.7 Hz), 4.41 (1H, dd, J¼14,7, 8.1 Hz), 4.57 (1H, AB,
J¼11.7 Hz), 4.58 (1H, dd, J¼14.7, 3.3 Hz), 7.00–7.04 (2H,
m), 7.05–7.18 (3H, m), 8.23 (1H, s), 8.25 (1H, s). 13C NMR
(CD3OD): d¼46.13, 64.01, 72.92, 73.28, 77.62, 119.47,
128.65, 129.01, 129.51, 138.65, 144.61, 146.46, 150.27,
151.36. Anal. calcd for C16H19N5O3·4H2O (401.41): C, 47.87;
H, 5.79; N, 17.45. Found: C, 47.97; H, 5.80; N, 17.12.
11. Hirota, K.; Monguchi, Y.; Sajiki, H.; Sako, M.; Kitade, Y.
J. Chem. Soc., Perkin Trans. 1 1998, 941–946.
12. De Clercq, E.; Holy, A. J. Med. Chem. 1979, 22, 510–513.
13. Holy, A.; Votruba, I.; De Clercq, E. Coll. Czech. Chem.
Commun. 1985, 50, 245–261.
14. Slama, K.; Holy, A. Acta Entomol. Bohemoslov. 1988, 85,
94–106.
15. Kitade, Y.; Hirota, K.; Maki, Y. Tetrahedron Lett. 1993, 34,
4835–4836.
16. Martin, J. C.; Smee, D. F.; Verheyden, J. P. H. J. Org. Chem.
1985, 50, 755–759.
Acknowledgements
17. Schultze, L. M.; Chapman, H. H.; Dubree, N. J. P.; Jones, R. J.;
Kent, K. M.; Lee, T. T.; Louie, M. S.; Postich, M. J.; Prisbe,
E. J.; Rohloff, J. C.; Yu, R. H. Tetrahedron Lett. 1998, 39,
1853–1856.
´ ´
Financial support from Medical University of L⁄ odz (502-
13-683) is gratefully acknowledged. We thank Dr Dorota
G. Piotrowska for her assistance in NMR spectroscopy.
18. Wei, C.; De Bernardo, S.; Tengi, J. P.; Borgese, J.; Weigele,
M. J. Org. Chem. 1985, 50, 3462–3467.
19. Bergmeier, S. C.; Set, P. P. J. Org. Chem. 1997, 62,
2671–2674.
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