Synthesis of novel conformationally locked carbocyclic nucleosides derived from 5,5- and 6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol

Article abstract of DOI:10.1135/cccc20050519

(1R*,2R*,3R*,4S*)-3-Amino-6,6-bis(hydroxymethyl) bicyclo[2.2.1]heptan-2-ol (13) was prepared from (bicyclo[2.2.1]hept-5-ene-2,2- diyl)dimethyl dibenzoate (7) via cis-diol 8, cyclic sulfate 10, and azide 12. (1R*,2R*,3S*,4S*)-3-Amino-6,6-bis(hydroxymethyl) bicyclo[2.2.1]-heptan-2-ol (18) and (1R*;2S*,3S*,4S*)-3- amino-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (19) were obtained by addition of chromyl azide to double bond of 7, Chromatographic separation, debenzoylation and hydrogenation of resulting azides 14 and 16. The amines 13, 18, and 19 were used to build (1R*,2R*,3R*,4S*)- (21a), (1R*,2R*,3S*,4S*)-3-(6-chloro-9H-purin-9-yl)-6, 6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (21b), and (1R*,2S*, 3S*,4S*)-3-(6-chloro-9H-purin-9-yl)-5,5-bis(hydroxymethyl)bicyclo[2. 2.1]heptan-2-ol (21c), respectively. Ammonolysis of these compounds led to 6-amino-9H-purine derivatives 22a-22c. 6-(Dimethylamino)-9H-purine analogues 23a-23c and 6-(cyclopropylamino)-9H-purine analogues 24a-24c were prepared by aminolysis of 21a-21c. Reaction of amines 13, 18, and 19 with ethyl N-((2E)-3-ethoxymethacryloyl)carbamate afforded thymine derivatives 28a-28c.

Full text of DOI:10.1135/cccc20050519

Novel Conformationally Locked Carbocyclic Nucleosides
519
SYNTHESIS OF NOVEL CONFORMATIONALLY LOCKED
CARBOCYCLIC NUCLEOSIDES DERIVED FROM 5,5- AND
6,6-BIS(HYDROXYMETHYL)BICYCLO[2.2.1]HEPTAN-2-OL
1,
2
3
Hubert HŘEBABECKÝ *, Milena MASOJÍDKOVÁ and Antonín HOLÝ
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
1
2
166 10 Prague 6, Czech Republic; e-mail: hubert@uochb.cas.cz, masojid@uochb.cas.cz,
holy@uochb.cas.cz
3
Received March 4, 2005
Accepted April 12, 2005
(1R*,2R*,3R*,4S*)-3-Am in o-6,6-bis(h ydroxym eth yl)bicyclo[2.2.1]h eptan -2-ol (13) was pre-
pared from (bicyclo[2.2.1]h ept-5-en e-2,2-diyl)dim eth yl diben zoate (7) via cis-diol 8, cyclic
sulfate 10, an d azide 12. (1R*,2R*,3S*,4S*)-3-Am in o-6,6-bis(h ydroxym eth yl)bicyclo[2.2.1]-
h eptan -2-ol (18) an d (1R*,2S*,3S*,4S*)-3-am in o-5,5-bis(h ydroxym eth yl)bicyclo[2.2.1]h eptan -
2-ol (19) were obtain ed by addition of ch rom yl azide to double bon d of 7, ch rom atograph ic
separation , deben zoylation an d h ydrogen ation of resultin g azides 14 an d 16. Th e am in es 13,
18, an d 19 were used to build (1R*,2R*,3R*,4S*)- (21a), (1R*,2R*,3S*,4S*)-3-(6-ch loro-9H-
purin -9-yl)-6,6-bis(h ydroxym eth yl)bicyclo[2.2.1]h eptan -2-ol (21b), an d (1R*,2S*,3S*,4S*)-3-
(6-ch loro-9H-purin -9-yl)-5,5-bis(h ydroxym eth yl)bicyclo[2.2.1]h eptan -2-ol (21c), respectively.
Am m on olysis of th ese com poun ds led to 6-am in o-9H-purin e derivatives 22a–22c. 6-(Di-
m eth ylam in o)-9H-purin e an alogues 23a–23c an d 6-(cyclopropylam in o)-9H-purin e an alogues
24a–24c were prepared by am in olysis of 21a–21c. Reaction of am in es 13, 18, an d 19 with
eth yl N-((2E)-3-eth oxym eth acryloyl)carbam ate afforded th ym in e derivatives 28a–28c.
Keyw ord s: Azides; Am in es; Cyclic sulfates; Nucleosides; Carbocyclic n ucleosides; Purin es;
Pyrim idin es; Nucleobases; Alken es; Azidoh ydroxylation ; An tivirals.
Nucleoside an alogues play an im portan t role in ph arm acology, m ain ly as
an tiviral an d an titum oral drugs. Carbocyclic n ucleoside an alogues h ave
also attracted atten tion sin ce th e n atural com poun ds aristerom ycin 1 (1)
an d n eplan ocin A2 (2) were foun d to exh ibit sign ifican t biological effects.
Carbocyclic n ucleosides in com parison with th e furan ose-derived an alogues
h ave in creased resistan ce to en zym atic degradation as well as decreased tox-
icity3. Prom in en t syn th etic carbocyclic n ucleosides are th e an ti-HIV com -
poun ds carbovir4 (3) an d abacavir5 (Ziagen TM) (4). Th e class of carbocyclic
n ucleoside an alogues still possesses a large an d un exploited poten tial for
developm en t of n ew ph arm aceuticals.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)
doi:10.1135/cccc20050519

520
Hřebabecký, Masojídková, Holý:
N
N
NH2
N
NH2
N
HO
HO
HO
N
N
N
N
HO
OH
HO
OH
1
2
N
N
NH
N
O
NH
N
HO
N
N
N
NH2
NH2
3
4
Syn th esis of n ovel con form ation ally locked carbocyclic n ucleosides with
th e 2-oxabicyclo[2.2.1]h eptan e rin g system (as precursors of locked
carbocyclic n ucleic acids) was recen tly described6. Bisph osph ate of th e
2-iodo-(6-m eth ylam in o)purin e an alogue con tain in g th is rin g system dis-
played poten t bin din g affin ity at th e h um an P2Y1 receptor7.
Th e bicyclo[2.2.1]h eptan e (n orborn an e) rin g, like oxabicyclo[2.2.1]h ep-
tan e, is a con form ation ally locked carbapen tofuran ose an d/or carbah exo-
pyran ose rin g system s. Recen tly, we reported th e syn th esis of n ovel racem ic
con form ation ally locked carbocyclic purin e n ucleoside an alogues derived
from 5-oxatricyclo[4.2.1.03,7]n on an e-3-m eth an ol8. On ly ch loropurin e (5a)
an d (cyclopropyl)purin e (5b) derivatives exh ibit certain activity in tests for
an ti-HIV-1 an d -HIV-2 activity in h um an T-lym ph ocyte (CEM) cells. How-
ever, th eir activity correspon ds with th eir cytotoxicity.
N
X
N
HO
N
N
O
5a, X = Cl
5b, X =
HN
Th is study con cern s syn th eses of n ovel carbocyclic n ucleosides derived
from 5,5- an d 6,6-bis(h ydroxym eth yl)bicyclo[2.2.1]h eptan -2-ol. Th e target
com poun ds, wh ich are sh own in Fig. 1, were syn th esized from com m er-
cially available bicyclo[2.2.1]h ept-5-en e-2,2-dim eth an ol (6).
Alcoh ol 6 was ben zoylated an d th en cis-h ydroxylated with OsO4 in th e
yield 87% of cis-diol 8. 4-Meth ylm orph olin e 4-oxide was used as don or of
oxygen 9. Th e diol 8 was treated with th ion yl ch loride in eth er at room tem -
perature to give a m ixture of sulfites 9 (95%). Th e m ixture of stereoisom ers,
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Novel Conformationally Locked Carbocyclic Nucleosides
521
wh ich differ in orien tation of th e S=O bon d, was n ot separated; th e ratio of
1
isom ers (1:1) was determ in ed by H NMR spectroscopy. Th e m ixture of sul-
fites 9 was con verted to sulfate 10 followin g th e procedure of Gao an d
Sh arpless10. Treatm en t of sulfate 10 with lith ium azide in dim eth ylform -
am ide at 150 °C for 8 h afforded, after h ydrolysis with a m ixture of tetra-
h ydrofuran , sulfuric acid, an d water, azido derivative 11 (77%), wh ich was
deprotected with m eth an olic sodium m eth oxide to give free azide 12 (78%).
Hydrogen ation of azide 12 usin g palladium h ydroxide on carbon as catalyst
gave am in e 13 (85%) (Sch em e 1).
Steroidal alken es h ave been reported11 to give vicin al trans-h ydroxy
azides upon treatm en t with th e in situ gen erated ch rom yl azide from so-
dium azide an d ch rom ium trioxide in acetic acid. An an alogous reaction of
an alken e with azidotrim eth ylsilan e an d ch rom ium trioxide in dich loro-
m eth an e led to α-azidoketon es12. Th e reaction of alken e 7 with sodium
azide an d ch rom ium trioxide in acetic acid was in ten ded as an altern ative
O
X
H3C
N
N
NH
N
N
O
N
HO
HO
HO
HO
OH
OH
O
HN
O
CH3
HO
N
X
N
HO
N
N
N
OH
OH
OH
OH
O
CH3
N
X
HN
O
N
N
N
N
HO
HO
OH
OH
OH
OH
X = Cl, NH2, N(CH3)2,
HN
FIG. 1
Novel carbocyclic n ucleosides
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

522
Hřebabecký, Masojídková, Holý:
O
HO
HO
O
S
O
OBz
OBz
OBz
OR
(ii)
(iii)
OBz
OR
6, R = H
9
8
(i)
(iv)
7, R = Bz
HO
O
HO
O
S
O
OR
OR
OH
OH
(v)
OBz
(vii)
O
OBz
N3
NH2
10
13
11, R = Bz
12, R = H
(vi)
(i) BzCl/pyridine, 91%; (ii) OsO3/4-methylmorpholine 4-oxide/acetone/H2O, 87%;
(iii) SOCl2/ether, 95%; (iv) NaIO4/RuCl3/MeCN/CCl4/H2O, 90%; (v) LiN3/DMF,
150 °C, 77%; (vi) 0.1 M MeONa/MeOH, 78%; (vii) H2, Pd(OH)2/C, 85%
SCHEME 1
way for th e preparation of azide 11. But, surprisin gly, th is reaction afforded
azides 14 (37%) an d 16 (15%) as m ain products besides of a n on -separable
m ixture of m an y m in or by-products as a result of th e rin g-in vertin g
Wagn er–Meerwein rearran gem en t (for som e exam ples of th e rearran ge-
m en t, cf. lit.13). Deprotection of azides 14 an d 16 with m eth an olic sodium
m eth oxide followed by h ydrogen ation on palladium h ydroxide gave am in es
18 (83%) an d 19 (76%), respectively (Sch em e 2).
N3
(i)
HO
N3
OR
OR
OR
7
+
OR
16, R = Bz
OH
14, R = Bz
15, R = H
(ii)
(ii)
17, R = H
(iii)
(iii)
H2N
HO
H2N
OH
OH
OH
OH
OH
18
19
(i) CrO3/NaN3/AcOH, 37% of 14, 15% of 16; (ii) 0.1 M MeONa/MeOH,
83% of 15, 79% of 17; (iii) H2/Pd(OH)2/C, 83% of 18, 76% of 19
SCHEME 2
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Novel Conformationally Locked Carbocyclic Nucleosides
523
Con version of am in e 13, 18 or 19 to th e 6-ch loropurin e derivatives was
perform ed by described procedures8,14. Couplin g of th e am in es with
4,6-dich loropyrim idin -5-am in e in eth an ol in th e presen ce of trieth ylam in e
gave pyrim idin ylam in o derivative 20a (74%), 20b (81%), an d 20c (84%).
Rin g closure of 20a–20c with trieth yl orth oform ate in th e presen ce of con -
cen trated h ydroch loric acid gave 6-ch loropurin e derivatives 21a (79%), 21b
(89%), an d 21c (89%), respectively. Th e ch loropurin es were am m on olysed
with liquid am m on ia at 75 °C to give aden in e derivatives 22a (79%), 22b
(86%), an d 22c (84%) wh ich , in turn , were treated with dim eth yl-
am m on ium N,N-dim eth ylcarbam ate to afford 6-(dim eth ylam in o)purin e
23a (95%), 23b (85%), an d 23c (84%) or am in olysed with cyclopropyl-
am in e to yield 6-(cyclopropylam in o)purin e 24a (89%), 24b (88%), an d 24c
(84%) (Sch em e 3). Th e reaction s of am in e 13, 18, an d 19 with acyl-
carbam ate 26 in 1,4-dioxan e at 100 °C (Sch em e 4) yielded com poun ds
27a–27c wh ich were, with out isolation , treated with Dowex 50 (H+) to give
th ym in e derivatives 28a (48%), 28b (34%), an d 28c (57%). Acylcarbam ate
26 was prepared from 1-eth oxyprop-1-en e by th e treatm en t with ch loro-
carbon yl isocyan ate followed by eth an ol usin g th e procedure described for
eth yl N-((2E)-3-eth oxy-2-eth ylprop-2-en oyl)carbam ate15
.
Cl
X
N
H2N
N
(i)
(ii)
N
N
13, 18 or 19
N
R
HN
R
N
20
21, X = Cl
22, X = NH2
(iii)
(iv)
OH
(v)
HO
OH
OH
23, X = NMe2
a, R =
b, R =
24, X =
HN
HO
OH
OH
c, R =
OH
OH
(i) 4,6-dichloropyrimidin-5-amine/TEA/ETOH, 100 °C, 74% of 20a, 81% of 20b,
and 84% of 20c; (ii) 1. CH(OEt)3/HCl, 2. THF/H2O/HCl, 89% of 21a, 79% of 21b,
and 89% of 21c; (iii) NH3 (l), 75 °C, 79% of 22a, 86% of 22b, and 84% of 22c;
(iv) Me2NCOO-Me2NH+, 95% of 23a, 85% of 23b, and 84% of 23c;
(v) cyclopropylamine, 89% of 24a, 88% of 24c, and 86% of 24c
SCHEME 3
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

524
Hřebabecký, Masojídková, Holý:
O
O
(ii)
H3C
NH
H3C
O
NH
13, 18 or 19
+
COOEt
O
HN
R
O
26
(i)
27
(iii)
O
O
25
H3C
NH
N
R
28
O
HO
OH
OH
a, R =
HO
OH
OH
OH
OH
b, R =
c, R =
OH
(i) 1. ClCONCO/Et3N, 2. EtOH, 68%; (ii) 1,4-dioxane;
(iii) Dowex 50 (H+), 48% of 28a, 34% of 28b, and 50% of 28c
SCHEME 4
Th e structure of th e prepared com poun ds was determ in ed by 1H an d
13C NMR spectroscopy. Couplin g con stan ts J(H,H) were obtain ed by usin g
decouplin g experim en ts. Assign m en t of th e sign als to proton s an d carbon
atom s in NMR spectra of th e key in term ediates 12, 15, an d 17 was per-
form ed by HSQC. Th e structure of th ese com poun ds was determ in ed on th e
basis of th e observed lon g-ran ge in teraction s C–H (HMBC). Th e foun d
stron g lon g-ran ge C–H in teraction s in HMBC experim en ts are given in
Fig. 2. Th e literature16 sh ows th e followin g values of couplin g con stan ts
J(2,3) an d J(1,2) of 2,3-substituted n orborn an es: J(2 exo,3 exo) = 9–10 Hz,
J(2 en do,3 en do) = 6–7 Hz, J(2 exo,3 en do) = 2.5–5 Hz, J(1,2 exo) = 3–4 Hz,
an d J(1,2 en do) = 0–2 Hz. Th e followin g values of correspon din g couplin g
con stan ts were foun d for th e prepared com poun ds: J(2 en do,3 exo) =
1.5–2.2 Hz an d J(1, 2en do) ≈ 1.0 Hz for com poun ds 12, 13, 20a, 21a, 22a,
23a, 24a, and 28a, J(2 endo,3 endo) = 5.9–6.1 Hz and J(1,2 endo) = 1.0–1.5 Hz
for compounds 15, 18, 20b, 21b, 22b, 23b, 24b, and 28b, and J(2 exo,3 endo) =
1.7–2.8 Hz an d J(1,2 exo) = 4.2–4.6 Hz for com poun ds 17, 19, 20c, 21c,
22c, 23c, 24c, an d 28c.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Novel Conformationally Locked Carbocyclic Nucleosides
525
In con clusion , n ovel racem ic con form ation ally locked carbocyclic
n ucleoside an alogues of aden in e, 6-(dim eth ylam in o)purin e, 6-(cyclopropyl-
am in o)purin e, an d th ym in e derived from 5,5- an d 6,6-bis(h ydroxym eth yl)-
bicyclo[2.2.1]h eptan -2-ol were prepared from com m ercially available bicyclo-
[2.2.1]h ept-5-en e-2,2-dim eth an ol. Th e target com poun ds 21a–21c, 22a–22c,
23a–23c, 24a–24c, an d 28a–28c were tested for in h ibition of cell growth of
th e followin g cell cultures: m ouse leukem ia L1210 cells (ATCC CCL 240),
h um an cervix carcin om a HeLaS3 cells (ATCC CCL 2.2), h um an prom yelo-
cytic leukem ia HL60 cells (ATCC CCL 240), an d h um an T lym ph oblastoid
CCRF-CEM cell lin e (ATCC CCL 119). Non e of th e com poun ds exh ibited
sign ifican t activity17
.
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Kofler block an d are un corrected. Mass spectra were re-
corded on a ZAB-EQ (VG An alytical) spectrom eter usin g FAB (ion ization by Xe, acceleratin g
voltage 8 kV, glycerol m atrix). NMR spectra (δ, ppm ; J, Hz) were m easured on a Varian
UNITY 500 in strum en t (500 MHz for 1H an d 125.7 MHz for 13C) in h exadeuteriodim eth yl
sulfoxide (referen ced to th e solven t sign al). Colum n ch rom atograph y was perform ed on
Silica gel 60 (Fluka) 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 36–60 °C; th e com poun ds
were dried at 13 Pa an d 50 °C.
HO
OH
HO
N3
OH
6
2
6
5
Ha
OH
3
3
Ha
OH
H
5
N3
Hb
Hb
Hb
6
2
N3
3
OH
OH
H
a
5
H
OH
FIG. 2
Stron g lon g-ran ge C–H in teraction s in HMBC experim en ts
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

526
Hřebabecký, Masojídková, Holý:
(Bicyclo[2.2.1]h ept-5-en e-2,2-diyl)dim eth yl Diben zoate (7)
Ben zoyl ch loride (5.6 m l, 48 m m ol) was added to a stirred an d cooled solution of n or-
born en e derivative 6 (3.08 g, 20 m m ol) in pyridin e (40 m l) an d th e m ixture was left at room
tem perature overn igh t. Water (3 m l) was th en added an d, after 15 m in , th e solven t was
evaporated. Th e residue was partition ed between eth yl acetate (200 m l) an d water (100 m l).
Th e organ ic ph ase was wash ed with water (100 m l), 5% h ydroch loric acid (50 m l), 10%
aqueous KHCO3 (3 × 100 m l), dried over an h ydrous sodium sulfate, an d th e solven t was
evaporated. Crystallization of th e residue from eth an ol–petroleum eth er afforded 6.60 g
(91%) of diben zoate 7, m .p. 63–65 °C. For C23H22O4 (362.4) calculated: 76.22% C, 6.12% H;
foun d: 76.16% C, 6.11% H. FAB MS, m/z: 363 [M + H]. 1H NMR: 1.01 dd, 1 H, J(6b,7b) = 2.6,
Jgem = 12.3 (H-6b); 1.42 dm , 1 H, Jgem = 8.8 (H-7b); 1.69 dd, 1 H, J(6a,1) = 3.7 (H-6a); 1.72 dm ,
1 H (H-7a); 2.90 m , 1 H (H-1); 2.95 m , 1 H (H-4); 4.02 d, 1 H an d 4.22 d, 1 H, Jgem = 11.0
(CH2O); 4.51 s, 2 H (CH2O); 6.15 dd, 1 H, J(3,2) = 5.7, J(3.4) = 3.0 (H-3); 6.29 dd, 1 H,
J(2,1) = 3.0 (H-2); 7.48 m , 4 H, 7.63 m , 2 H, an d 7.95 m , 4 H (H-arom .). 13C NMR: 32.94
(C-6); 42.20 (C-1); 46.01 (C-4); 46.30 (C-5); 47.00 (C-7); 134.42 (C-2); 138.05 (C-3); 128.89,
4 C, 129.32, 4 C, 113.47, 129.81, 129.82, 133.49, 165.66, an d 165.79 (arom .).
((1R*,4S*,5S*,6R*)-5,6-Dih ydroxybicyclo[2.2.1]h eptan e-2,2-diyl)dim eth yl Diben zoate (8)
A m ixture of th e bicyclo[2.2.1]h epten e derivative 7 (10.87 g, 30 m m ol), aceton e (600 m l),
water (60 m l), an aqueous solution of 4-m eth ylm orph olin e 4-oxide (50%, 42 m l), an d os-
m ium tetroxide (30 m g) was stirred at room tem perature overn igh t. Th e resultin g solution
was evaporated an d th e residue was partition ed between eth yl acetate (400 m l) an d water
(300 m l). Th e aqueous layer was extracted with eth yl acetate (300 m l) an d th e collected ace-
tate layers were wash ed with water (200 m l), dried over an h ydrous sodium sulfate, an d evap-
orated. Crystallization of th e residue from eth an ol afforded 10.33 g (87%) of 8, m .p.
124–125.5 °C. For C23H24O6 (396.4) calculated: 69.68% C, 6.10% H; foun d: 69.46% C,
5.98% H. FAB MS, m/z: 397 [M + H]. 1H NMR: 1.06 dd, 1 H, J(3b,7a) = 2.1, Jgem = 13.2
(H-3b); 1.45 dd, 1 H, J(3a,4) = 4.8 (H-3a); 1.49 dm , 1 H, Jgem = 10.6 (H-7b); 1.79 dm , 1 H
(H-7a); 2.02 brdq, 1 H, J(4,1) ≈ J(4,7a) ≈ J(4,7b) = 1.5 (H-4); 2.19 m , 1 H (H-1); 3.67 brdt,
1 H, J(5,7b) = 1.2 (H-5); 3.96 brddd, 1 H, J(6,7b) = 1.2, J(6,5) = 5.7, J(6,OH) = 4.6 (H-6);
4.16 d, 1 H an d 4.41 d, 1 H, Jgem = 11.5 (CH2O); 4.22 d, 1 H an d 4.31 d, 1 H, Jgem = 11.1
(CH2O); 4.64 d, 1 H, J(OH,5) = 5.4 (5-OH); 4.78 d, 1 H (6-OH); 7.46 t, 2 H, 7.49 t, 2 H,
7.62 t, 1 H, 7.64 t, 1 H, 7.92 d, 2 H, an d 7.95 d, 2 H (H-arom .). 13C NMR: 30.75 (C-7); 33.10
(C-3); 42.87 (C-2); 43.84 (C-4); 47.57 (C-1); 65.40 (CH2O); 67.56 (CH2O); 68.69 (C-5); 73.10
(C-6); 128.88, 2 C, 128.90, 2 C, 129.28, 2 C, 129.35, 2 C, 129.72, 129.74, 133.50, an d 133.54
(C-arom .); 165.68 (C=O); 165.80 (C=O).
((3aR*,4R*,7S*,7aS*)-2-Oxoh exah ydro-2λ4-4,7-m eth an o-1,3,2-ben zodioxath iole-
5,5-diyl)dim eth yl Diben zoate (9)
Th ion yl ch loride (13 m l) was added to a stirred suspen sion of diol 8 (7.93 g, 20 m m ol) in
eth er (130 m l) an d th e m ixture was stirred at room tem perature for 3 h . Th e resultin g solu-
tion was evaporated an d a solution of th e residue in eth yl acetate (250 m l) was wash ed with
water (100 m l) an d 10% aqueous sodium h ydrogen carbon ate (3 × 100 m l), dried over an h y-
drous sodium sulfate an d th e solven t was evaporated. Th e obtain ed product (8.40 g, 95%)
was used in th e n ext step with out purification . An an alytical sam ple was purified by ch ro-
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m atograph y on a silica gel colum n with toluen e–eth yl acetate (4:1). For C23H22O7S (442.5)
calculated: 62.43% C, 5.01% H, 7.25% S; foun d: 62.59% C, 5.13% H, 7.23% S. FAB MS, m/z:
443 [M + H]. 1H NMR: isom er A: 1.24 dd, 1 H, J(6b,CH2) = 2.5, Jgem = 13.7 (H-6b); 1.45 dm ,
1 H, Jgem = 11.6 (CHaH); 1.63 dd, 1 H, J(6a,7) = 5.0 (H-6a); 1.74 dpen t, 1 H, J(CHbH,7) ≈
J(CHbH,7a) ≈ J(CHbH,3a) ≈ J(CHbH,4) = 1.4 (CHbH); 2.47 brdq, 1 H, J(7,7a) ≈ J(7,CHbH) = 1.5
(H-7); 2.71 brs, 1 H (H-4); 5.18 brdd, 1 H, J(7a,3a) = 5.5 (H-7a); 5.29 brdd, 1 H, J(3a,4) = 1.0
(H-3a); isom er B: 1.16 dd, 1 H, J(6b,CHaH) = 2.6, Jgem = 13.7 (H-6b); 1.65 dd, 1 H, J(6a,7) =
5.0 (H-6a); 1.78 dpen t, 1 H, J(CHbH,7) ≈ J(CHbH,7a) ≈ J(CHbH,3a) ≈ J(CHbH,4) = 1.4, Jgem
=
13.7 (CHbH); 2.16 dm , 1 H (CHaH); 2.52 brdq, 1 H, J(7,7a) ≈ J(7,CHaH) = 1.5 (H-7); 2.74 brs,
1 H (H-4); 4.91 brdd, 1 H, J(7a,3a) = 6.1 (H-7a); 5.11 brdd, 1 H, J(3a,4) = 1.0 (H-3a); isom er A +
isom er B: 4.11 d, 2 H an d 4.51 d, 2 H, Jgem = 11.8 (CH2O); 4.30 d, 2 H an d 4.43 d, 2 H,
Jgem = 12.0 (CH2O); 4.31 d, 2 H an d 4.40 d, 2 H, Jgem = 11.4 (CH2O); 4.34 d, 2 H an d 4.38 d,
2 H, Jgem = 11.4 (CH2O); 7.46 m , 8 H, 7.92 m , 4 H, an d 7.95 m , 8 H (H-arom .). Th e ratio A:B
was foun d 1:1.
((3aR*,4R*,7S*,7aS*)-2,2-Dioxoh exah ydro-2λ4-4,7-m eth an o-1,3,2-ben zodioxath iole-
5,5-diyl)dim eth yl Diben zoate (10)
To a stirred ice-cool solution of sulfite 9 (7.96 g, 18 m m ol) in aceton itrile (45 m l) an d tetra-
ch lorom eth an e (23 m l), water (83 m l), sodium periodate (7.90 g) an d ruth en ium (III) ch lo-
ride h ydrate (25 m g) were added. Th e m ixture was stirred at 0 °C for 20 m in an d at room
tem perature for 10 m in . Addition al am oun t of sodium periodate (3.94 g) was th en added,
th e m ixture was stirred at room tem perature for 30 m in an d th en diluted with eth yl acetate
(500 m l). Th e organ ic layer was separated, wash ed with water (3 × 200 m l), dried over an h y-
drous sodium sulfate, an d filtered th rough a silica gel pad (150 g). Silica gel was wash ed
with eth yl acetate an d th e collected filtrates were evaporated. Crystallization of th e residue
from eth an ol afforded 7.43 g (90%) of sulfate 10, m .p. 152–153 °C. For C23H22O8S (458.5)
calculated: 60.25% C, 4.84% H, 6.99% S; foun d: 60.07% C, 4.75% H, 6.86% S. FAB MS, m/z:
459 [M + H]. 1H NMR: 1.27 dd, 1 H, J(6b,CH2) = 2.4, Jgem = 13.8 (H-6b); 1.71 dd, 1 H, J(6a,7) =
5.2 (H-6a); 1.87 dm , 1 H (CHaH); 2.01 dpen t, 1 H, J(CHbH,7) ≈ J(CHbH,7a) ≈ J(CHbH,3a) ≈
J(CHbH,4) = 1.5, Jgem = 11.6 (CHbH); 2.64 brdq, 1 H, J(7,7a) = 1.2, J(7,CHaH) = 1.5 (H-7);
2.87 m , 1 H (H-4); 4.25 d, 1 H an d 4.48 d, 1 H, Jgem = 12.0 (CH2O); 4.31 d, 1 H an d 4.37 d,
1 H, Jgem = 11.4 (CH2O); 5.35 brdd, 1 H, J(7a,3a) = 5.4, J(7a,CHbH) = 1.5 (H-7a); 5.51 brdd, 1 H,
J(3a,4) = 1.0 (H-3a). 13C NMR: 30.36 (CH2); 30.44 (C-6); 40.86 (C-7); 42.77 (C-5); 44.54
(C-4); 64.98 (CH2O); 67.05 (CH2O); 83.80 (C-7a); 85.78 (C-3a); 128.84, 2 C, 128.88, 2 C,
129.40, 4 C, 129.50, 129.61, an d 133.57, 2 C (C-arom .); 165.48 (C=O); 165.69 (C=O).
((1R*,4S*,5R*,6R*)-5-Azido-6-h ydroxybicyclo[2.2.1]h eptan e-2,2-diyl)dim eth yl
Diben zoate (11)
A solution of sulfate 10 (6.88 g, 15 m m ol) an d lith ium azide (2.94 g, 60 m m ol) in dim eth yl-
form am ide (100 m l) was h eated at 150 °C for 8 h an d evaporated to dryn ess. A m ixture of
th e residue, tetrah ydrofuran (60 m l), sulfuric acid (3 m l) an d water (3 m l) was stirred at
room tem perature overn igh t an d th en n eutralized with sodium h ydrogen carbon ate. Th e
m ixture was partition ed between eth yl acetate (350 m l) an d water (150 m l), th e organ ic
layer was separated, wash ed with water (2 × 100 m l), dried over an h ydrous sodium sulfate,
an d evaporated. Ch rom atograph y of th e residue on a silica gel colum n (250 g) in toluen e–
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Hřebabecký, Masojídková, Holý:
eth yl acetate (4:1) gave 4.84 g (77%) of azide 11. For C23H23N3O5 (421.5) calculated: 65.55% C,
5.50% H, 9.97% N; foun d: 65.75% C, 5.65% H, 9.79% N. FAB MS, m/z: 422 [M + H].
1H NMR: 1.39 ddd, 1 H, J(3a,4) = 3.7, J(3a,5) = 1.2, Jgem = 13.4 (H-3a); 1.42 brdd, 1 H,
J(3b,7a) = 2.1 (H-3b); 1.75 brdq, 1 H, J(7b,1) ≈ J(7b,4) = 1.7, J(7b,6) = 2.0, Jgem = 11.0 (H-7b);
1.80 brdq, 1 H, J(7a,1) ≈ J(7a,4) = 1.4 (H-7a); 2.24 m , 1 H (H-1); 2.48 ddq, 1 H, J(4,1) = 1.4,
J(4,5) = 4.8 (H-4); 3.74 brt, 1 H, J(6,5) = 2.0 (H-6); 3.79 brdq, 1 H, J(5,1) = 1.0 (H-5); 4.22 d,
1 H an d 4.47 d, 1 H, Jgem = 11.5 (CH2O); 4.26 d, 1 H an d 4.36 d, 1 H, Jgem = 11.2 (CH2O);
5.30 brs, 1 H (6-OH); 7.46 t, 2 H, 7.48 t, 2 H, 7.62 t, 1 H, 7.64 t, 1 H, 7.92 d, 2 H, an d 7.94 d,
2 H (H-arom .). 13C NMR: 28.93 (C-3); 32.92 (C-7); 39.87 (C-4); 42.89 (C-2); 48.50 (C-1);
65.26 (CH2O); 67.56 (CH2O); 72.23 (C-5); 73.36 (C-6); 128.86, 4 C, 129.31, 2 C, 129.42, 2 C,
129.67, 129.69, 133.52, an d 133.54 (C-arom .); 165.67 (C=O); 165.83 (C=O).
((1R*,4S*,5S*,6R*)-5-Azido-6-h ydroxybicyclo[2.2.1]h eptan e-2,2-diyl)dim eth yl
Diben zoate (14) an d ((1R*,4S*,5R*,6R*)-6-Azido-5-h ydroxybicyclo[2.2.1]-h eptan e-
2,2-diyl)dim eth yl Diben zoate (16)
Ch rom ium (VI) oxide (1.1 g, 11 m m ol) was added to a stirred ice-cool m ixture of acetic acid
(85 m l), alken e 7 (3.96 g, 10 m m ol) an d sodium azide (14 g). Th e m ixture was warm ed to
room tem perature, stirred for 30 m in , filtered an d evaporated. A solution of th e residue in a
m ixture of tetrah ydrofuran (40 m l), sulfuric acid (2 m l) an d water (2 m l) was set aside at
room tem perature for 1 h an d th en n eutralized with solid sodium h ydrogen carbon ate. Th e
in soluble portion was filtered off with a Celite pad, wash ed with tetrah ydrofuran an d th e
collected filtrates were evaporated. A solution of th e residue in eth yl acetate was left at
≈4 °C overn igh t an d th e deposited precipitate was filtered off with a Celite pad, wash ed with
eth yl acetate an d th e collected filtrates were evaporated. Ch rom atograph y of th e residue on
silica gel (300 g) in eth yl acetate–toluen e afforded 1.55 g (37%) of azide 14 an d 653 m g
(15%) of azide 16.
Compound 14: For C23H23N3O5 (421.5) calculated: 65.55% C, 5.50% H, 9.97% N; foun d:
65.82% C, 5.54% H, 9.75% N. FAB MS, m/z: 422 [M + H]. 1H NMR: 1.15 dd, 1 H, J(3b,7a) =
2.6, Jgem = 13.2 (H-3b); 1.52 dd, 1 H, J(3a,4) = 4.8 (H-3a); 1.61 dpen t, 1 H, J(7b,1) ≈ J(7b,5) ≈
J(7b,6) ≈ J(7b,4) = 1.5, Jgem = 10.7 (H-7b); 1.89 dm , 1 H, J(7a,1) ≈ J(7a,1) = 1.5 (H-7a);
2.21 brdq, 1 H, J(4,1) = 1.5 (H-4); 2.28 m , 1 H (H-1); 3.59 brdd, 1 H, J(5,4) = 1.0, J(5,6) = 6.0
(H-5); 4.18 d, 1 H an d 4.43 d, 1 H, Jgem = 11.6 (CH2O); 4.22 d, 1 H an d 4.33 d, 1 H, Jgem
=
11.2 (CH2O); 4.25 brddd, 1 H, J(6,1) = 1.0, J(6,OH) = 5.1 (H-6); 5.30 d, 1 H (6-OH); 7.45 t,
2 H, 7.49 t, 2 H, 7.62 t, 1 H, 7.65 t, 1 H, 7.90 d, 2 H, an d 7.95 d, 2 H (H-arom .). 13C NMR:
32.00 (C-7); 34.33 (C-3); 42.01 (C-4); 42.69 (C-2); 48.36 (C-1); 65.42 (CH2O); 65.50 (C-5);
67.49 (CH2O); 70.99 (C-6); 128.88, 2 C, 128.89, 2 C, 129.28, 2 C, 129.40, 2 C, 129.68,
129.72, 133.53, an d 133.56 (C-arom .); 165.68 (C=O); 165.78 (C=O).
Compound 16: For C23H23N3O5 (421.5) calculated: 65.55% C, 5.50% H, 9.97% N; foun d:
65.75% C, 5.49% H, 9.78% N. FAB MS, m/z: 422 [M + H]. 1H NMR: 1.32 dd, 1 H, J(3b,4) =
4.2, J(3b,5) = 1.0, Jgem = 12.8 (H-3b); 1.58 dm , 1 H, Jgem = 10.6 (H-7b); 1.69 dd, 1 H, J(3a,7b) =
2.1 (H-3a); 1.76 brdq, 1 H, J(7a,1) ≈ J(7a,4) ≈ J(7a,6) = 1.7 (H-7a); 2.32 brtq, 1 H, J(4,1) ≈
J(4,7b) = 1.5, J(4,5) = 4.6 (H-4); 2.36 m , 1 H (H-1); 3.64 brt, 1 H, J(6,1) = 0.5, J(6,5) = 1.8
(H-6); 3.87 brt, 1 H, J(5,1) = 1.0, J(5,6) = 1.6, J(5,OH) = 3.4 (H-5); 4.29 d, 1 H an d 4.37 d, 1 H,
Jgem = 11.2 (CH2O); 4.38 d, 1 H an d 4.55 d, 1 H, Jgem = 11.5 (CH2O); 5.50 d, 1 H (5-OH);
7.44 d, 2 H, 7.47 d, 2 H, 7.60 t, 1 H, 7.62 t, 1 H, an d 7.92 d, 4 H (H-arom .). 13C NMR: 27.65
(C-3); 33.27 (C-7); 41.95 (C-4); 43.65 (C-2); 46.28 (C-1); 65.55 (CH2O); 67.62 (C-6); 67.72
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(CH2O); 128.87, 4 C, 129.28, 2 C, 129.31, 2 C, 129.66, 2 C, 133.52, an d 133.55 (C-arom .);
165.65 (C=O); 165.86 (C=O).
Deprotection of Ben zoates 11, 14, an d 16
A solution of ben zoate 11, 14 or 16 (4.21 g, 10 m m ol) in 0.1 M m eth an olic sodium m eth -
oxide (45 m l) was set aside at room tem perature overn igh t. Th e solution was n eutralized
with Dowex 50 (H+), th e resin was filtered off, wash ed with m eth an ol, an d th e collected fil-
trates an d wash in gs were evaporated. Th e precipitated crystals were filtered off an d wash ed
with eth er.
(1R*,2R*,3R*,4S*)-3-Azido-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (12): Yield 1.67 g
(78%), m .p. 112–113.5 °C. For C9H15N3O3 (213.2) calculated: 50.69% C, 7.09% H, 19.71% N;
foun d: 50.75% C, 7.25% H, 19.69% N. FAB MS, m/z: 214 [M + H]. 1H NMR: 0.94 dd, 1 H,
J(5b,7a) = 2.6, Jgem = 12.9 (H-5b); 1.07 ddd, 1 H, J(5a,3) = 1.6, J(5a,4) = 4.3 (H-5a); 1.48 ddt,
1 H, J(7b,1) ≈ J(7b,4) = 1.7, J(7b,2) = 2.2, Jgem = 10.5 (H-7b); 1.62 ddt, 1 H, J(7a,1) ≈ J(7a,4) =
1.5, J(7a,5b) = 2.6 (H-7a); 1.87 brs, 1 H (H-1); 2.29 br tq, 1 H, J(4,1) = 1.5, J(4,3) = 4.8 (H-4);
3.18 dd, 1 H, J(CH,OH) = 5.2 an d 3.41 dd, 1 H, J(CH,OH) = 5.6, Jgem = 10.4 (CH2O); 3.24 dd,
1 H, J(CH,OH) = 5.4 an d 3.50 dd, 1 H, J(CH,OH) = 4.0, Jgem = 10.6 (CH2O); 3.67 brdq, 1 H,
J(3,1) = 1.0, J(3,2) = 1.5 (H-3); 3.75 brdt, 1 H, J(2,1) = 1.0, J(2,OH) = 3.9 (H-2); 4.40 dd, 1 H
(CH2OH); 4.50 t, 1 H, J(CH2,OH) = 5.4 (CH2OH); 5.00 d, 1 H (2-OH). 13C NMR: 28.35 (C-5);
32.88 (C-7); 39.80 (C-4); 45.48 (C-6); 48.16 (C-1); 61.78 (CH2O); 64.79 (CH2O); 72.88 (C-3);
73.22 (C-2).
(1R*,2R*,3S*,4S*)-3-Azido-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (15): Yield 1.76 g
(83%), m .p. 81–82 °C. For C9H15N3O3 (213.2) calculated: 50.69% C, 7.09% H, 19.71% N;
foun d: 50.68% C, 7.26% H, 19.52% N. FAB MS, m/z (rel.%): 214 (100) [M + H], 165 (21).
1H NMR: 0.68 brdd, 1 H, J(5b,7a) = 2.4, Jgem = 12.8 (H-5b); 1.19 dd, 1 H J(5a,4) = 4.6 (H-5a);
1.34 brdpen t, 1 H, J(7b,1) ≈ J(7b,2) ≈ J(7b,3) ≈ J(7b,4) = 1.5, Jgem = 10.3 (H-7b); 1.73 brdq,
1 H, J(7a,1) ≈ J(7a,4) = 1.7 (H-7a); 1.91 brs, 1 H (H-1); 2.08 brdq, 1 H, J(4,1) = 1.5 (H-4);
3.13 dd, 1 H, J(CH,OH) = 5.0 an d 3.38 dd, 1 H, J(CH,OH) = 5.5, Jgem = 10.7 (CH2O); 3.14 dd,
1 H, J(CH,OH) = 5.2 an d 3.43 dd, 1 H, J(CH,OH) = 4.3, Jgem = 10.7 (CH2O); 3.29 brdd, 1 H,
J(3,2) = 6.1, J(3,7b) = 1.6 (H-3); 4.23 ddt, J(2,1) = 1.0, J(2,7b) = 1.5, J(2,OH) = 5.1 (H-2);
4.47 t, J(OH,CH2) = 4.7 (CH2OH); 4.50 t, J(OH,CH2) = 5.3 (CH2OH); 4.98 d, 1 H (2-OH).
13C NMR: 32.05 (C-7); 33.97 (C-5); 42.17 (C-4); 45.29 (C-6); 48.01 (C-1); 62.22 (CH2O);
64.85 (CH2O); 66.07 (C-3); 71.24 (C-2).
(1R*,2S*,3S*,4S*)-3-Azido-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (17): Yield 1.69 g
(79%), m .p. 137–138 °C. For C9H15N3O3 (213.2) calculated: 50.69% C, 7.09% H, 19.71% N;
foun d: 50.70% C, 7.20% H, 19.53% N. FAB MS, m/z: 214 [M + H]. 1H NMR: 1.03 ddd, 1 H,
J(6b,1) = 4.4, J(6b,2) = 1.2, Jgem = 12.6 (H-6b); 1.20 dd, 1 H, J(6a,7b) = 2.3 (H-6a); 1.38 ddt,
1 H, J(7b,1) = J(7b,4) = 1.5, Jgem = 10.5 (H-7b); 1.51 ddt, 1 H, J(7a,1) = J(7a,4) = 1.6, J(7a,3) =
2.7 (H-7a); 1.95 m , 1 H (H-4); 2.15 brtq, 1 H, J(1,2) = 4.6 (H-1); 3.19 dd, 1 H, J(CH,OH) = 5.1
an d 3.45 dd, 1 H, J(CH,OH) = 5.6, Jgem = 10.4 (CH2O); 3.39 dd, 1 H, J(CH,OH) = 5.6 an d
3.43 dd, 1 H, J(CH,OH) = 4.3, Jgem = 10.9 (CH2O); 3.60 brt, 1 H, J(3,2) = 1.7, J(3,4) = 1.0
(H-3); 3.77 ddq, 1 H, J(2,4) = 1.2, J(2,OH) = 3.7 (H-2); 4.44 dd, 1 H (CH2OH); 4.55 t,
J(OH,CH2) = 5.4 (CH2OH); 5.22 d, 1 H (2-OH). 13C NMR: 26.83 (C-6); 33.25 (C-7); 42.04
(C-1); 45.84 (C-4); 46.25 (C-5); 61.80 (CH2O); 65.16 (CH2O); 67.69 (C-3); 77.77 (C-2).
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Preparation of Am in es 13, 18, an d 19
Hydrogen was bubbled th rough a stirred m ixture of azide 12, 15 or 17 (1.49 g, 7 m m ol),
m eth an ol (25 m l), an d palladium h ydroxide on carbon (20% Pd, 75 m g) for 3 h . Th e cata-
lyst was filtered off an d wash ed with m eth an ol. Th e collected filtrates an d wash in gs were
evaporated. Th e residue was crystallized from eth an ol.
(1R*,2R*,3R*,4S*)-3-Amino-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (13): Yield 1.11 g
(85%), m .p. 151–154 °C. For C9H17NO3 (187.2) calculated: 57.73% C, 9.15% H, 7.48% N;
foun d: 57.62% C, 9.17% H, 7.19% N. FAB MS, m/z: 188 [M + H]. 1H NMR: 0.85 ddd, 1 H,
J(5a,3) = 1.1, J(5a,4) = 4.4, Jgem = 12.7 (H-5a); 1.23 dd, 1 H, J(5b,7a) = 2.4 (H-5b); 1.35 ddt,
1 H, J(7b,1) ≈ J(7b,4) = 1.5, J(7b,2) = 1.8, Jgem = 11.0 (H-7b); 1.57 ddt, 1 H, J(7a,1) ≈ J(7a,4) =
1.3, J(7a,5b) = 2.4 (H-7a); 1.81 m , 1 H (H-1); 1.95 brtq, 1 H, J(4,1) = 1.6, J(4,3) = 4.4 (H-4);
2.80 brd, 1 H, J(3,1) = 1.0 (H-3); 3.15 d, 1 H an d 3.36 d, 1 H, Jgem = 10.4 (CH2O); 3.42 d, 1 H
an d 3.53 d, 1 H, Jgem = 10.6 (CH2O); 3.48 brt, 1 H, J(2,3) = 1.6 (H-2); 3.50 brs, 3 H (NH2,
OH); 4.35 brs, 1 H (OH); 4.50 brs, 1 H (OH). 13C NMR: 26.64 (C-5); 33.61 (C-7); 41.99 (C-4);
45.73 (C-6); 49.30 (C-1); 62.61 (CH2O); 63.62 (C-3); 65.94 (CH2O); 76.37 (C-2).
(1R*,2R*,3S*,4S*)-3-Amino-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (18): Yield 1.09 g
(83%), m .p. 154–156 °C. For C9H17NO3 (187.2) calculated: 57.73% C, 9.15% H, 7.48% N;
foun d: 57.76% C, 9.24% H, 7.37% N. FAB MS, m/z: 188 [M + H]. 1H NMR: 0.61 dd, 1 H,
J(5b,7a) = 2.4, Jgem = 12.6 (H-5b); 1.13 dd, 1 H, J(5a,4) = 4.5 (H-5a); 1.17 dpen t, 1 H, J(7b,1) ≈
J(7b,2) ≈ J(7b,3) ≈ J(7b,4) = 1.5, Jgem = 10.2 (H-7b); 1.53 brdq, 1 H (H-7a); 1.77 brdq, 1 H,
J(4,1) = 1.6 (H-4); 1.82 brs, 1 H (H-1); 2.71 brdd, 1 H, J(3,7b) = 1.6 (H-3); 3.13 d, 1 H an d
3.38 d, 1 H, Jgem = 10.4 (CH2O); 3.17 d, 1 H an d 3.42 d, 1 H, Jgem = 10.6 (CH2O); 3.40 brs,
2 H (NH2); 3.77 brd, J(2,1) = 1.3 (H-2); 4.40 brs, 3 H (3 × OH). 13C NMR: 30.90 (C-7); 34.97
(C-5); 44.98 (C-4); 45.51 (C-6); 47.38 (C-1); 56.55 (C-3); 62.29 (CH2O); 65.06 (CH2O); 68.30
(C-2).
(1R*,2S*,3S*,4S*)-3-Amino-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (19): Yield 934 m g
(76%), m .p. 180–182 °C. For C9H17NO3 (187.2) calculated: 57.73% C, 9.15% H, 7.48% N;
foun d: 57.52% C, 9.30% H, 7.38% N. FAB MS, m/z: 188 [M + H]. 1H NMR: 0.89 ddd, 1 H,
J(6b,1) = 4.4, J(6b,2) = 1.3, Jgem = 12.4 (H-6b); 1.19 dd, 1 H, J(6a,7b) = 2.3 (H-6a); 1.33 ddt,
1 H, J(7b,1) = J(7b,4) = 1.7, Jgem = 10.4 (H-7b); 1.56 ddt, 1 H, J(7a,1) = J(7a,4) = 1.7 (H-7a);
1.61 m , 1 H (H-4); 2.01 brtq, 1 H, J(1,2) = 4.6, J(1,4) = 1.5 (H-1); 2.72 brt, 1 H, J(3,2) = 2.2
(H-3); 3.17 d, 1 H an d 3.41 d, 1 H, Jgem = 10.4 (CH2O); 3.40 brs, 2 H (NH2); 3.45 d, 1 H an d
3.52 d, 1 H, Jgem = 10.4 (CH2O); 3.46 brd, 1 H (H-2); 4.25 brs, 1 H, 4.45 brs, 1 H, an d 4.65 brs,
1 H (3 × OH). 13C NMR: 26.86 (C-6); 32.37 (C-7); 42.20 (C-1); 46.27 (C-5); 49.35 (C-4); 56.81
(C-3); 62.46 (CH2O); 65.78 (CH2O); 81.62 (C-2).
(1R*,2R*,3R*,4S*)-3-[(5-Am in o-6-ch loropyrim idin -4-yl)am in o]-6,6-bis(h ydroxym eth yl)-
bicyclo[2.2.1]h eptan -2-ol (20a)
A solution of am in e 13 (562 m g, 3 m m ol), 4,6-dich loropyrim idin -5-am in e (984 m g, 6 m m ol),
an d trieth ylam in e (1.8 m l) in eth an ol (18 m l) was h eated in a pressure vessel at 100 °C for
48 h an d, after coolin g, th e precipitated crystals were filtered off an d wash ed with eth an ol
an d eth er. 580 m g (61%) of pyrim idin e 20a was obtain ed. Ch rom atograph y of th e m oth er
liquors on a silica gel colum n in eth yl acetate–aceton e–eth an ol–water (90:15:11:9) afforded
120 m g (13%) of th e sam e com poun d, m .p. 263–265 °C. For C13H19ClN4O3 (314.8) calcu-
lated: 49.60% C, 6.08% H, 11.26% Cl, 17.80% N; foun d: 49.50% C, 6.26% H, 11.11% Cl,
17.58% N. FAB MS, m/z (rel.%): 317/315 (37/100) [M + H], 281 (44). 1H NMR: 0.89 dd, 1 H,
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Novel Conformationally Locked Carbocyclic Nucleosides
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J(5b,7a) = 2.2, Jgem = 13.2 (H-5b); 0.97 ddd, 1 H, J(5a,3) = 1.6, J(5a,4) = 4.4 (H-5a); 1.49 brdq,
1 H, J(7b,1) ≈ J(7b,2) ≈ J(7b,4) = 1.6, Jgem = 10.5 (H-7b); 1.68 dm , 1 H (H-7a); 1.94 m , 1 H
(H-1); 2.53 brtq, 1 H, J(4,1) ≈ J(4,7a) = 1.6, J(4,3) = 4.4 (H-4); 3.20 dd, 1 H, J(CH,OH) = 5.2
an d 3.46 dd, 1 H, J(CH,OH) = 5.5, Jgem = 10.6 (CH2O); 3.43 dd, 1 H, J(CH,OH) = 5.6 an d
3.57 dd, 1 H, J(CH,OH) = 4.3, Jgem = 10.6 (CH2O); 3.70 m , 1 H, J(3,2) = 2.2, J(3,NH) = 4.5
(H-3); 3.93 brdq, 1 H, J(2,1) = 1.0, J(2,OH) = 3.8 (H-2); 4.40 dd, 1 H (CH2OH); 4.53 t, 1 H,
J(OH,CH2) = 5.4 (CH2OH); 4.60 d, 1 H (2-OH); 5.21 brs, 2 H (NH2); 6.61 d, 1 H (NH); 7.74 s,
1 H (H-2′).13C NMR: 27.63 (C-5); 32.83 (C-7); 39.45 (C-4); 45.93 (C-6); 48.10 (C-1); 62.53
(CH2O); 65.35 (C-3); 65.50 (CH2O); 73.35 (C-2); 123.94 (C-5′); 136.97 (C-4′); 145.69 (C-2′);
152.22 (C-6′).
(1R*,2R*,3S*,4S*)-3-[(5-Am in o-6-ch loropyrim idin -4-yl)am in o]-6,6-bis(h ydroxym eth yl)-
bicyclo[2.2.1]h eptan -2-ol (20b) an d (1R*,2S*,3S*,4S*)-3-[(5-Am in o-6-ch loropyrim idin -4-yl)-
am in o]-5,5-bis(h ydroxym eth yl)bicyclo[2.2.1]h eptan -2-ol (20c)
A solution of am in e 18 or 19 (562 m g, 3 m m ol), 4,6-dich loropyrim idin -5-am in e (984 m g,
6 m m ol), an d trieth ylam in e (1.8 m l) in eth an ol (18 m l) was h eated in a pressure vessel at
100 °C for 6 days an d, after coolin g, was taken down . Th e residue was ch rom atograph ed on
a silica gel colum n (50 g) in eth yl acetate–aceton e–eth an ol–water (180:30:23:417) an d crys-
tallized from eth an ol.
Compound 20b: Yield 764 m g (81%), m .p. 220–222 °C. For C13H19ClN4O3 (314.8) calcu-
lated: 49.60% C, 6.08% H, 11.26% Cl, 17.80% N; foun d: 49.35% C, 6.21% H, 11.12% Cl,
17.59% N. FAB MS, m/z (rel.%): 317/315 (36/100) [M + H]. 1H NMR: 0.79 dd, 1 H, J(5b,7a) =
2.4, Jgem = 12.7 (H-5b); 1.20 dd, 1 H, J(5a,4) = 4.4 (H-5a); 1.31 brdpen t, 1 H, J(7b,1) ≈
J(7b,2) ≈ J(7b,3) ≈ J(7b,4) = 1.5, Jgem = 10.2 (H-7b); 1.81 dm , 1 H (H-7a); 1.95 m , 1 H (H-1);
1.99 brdq, 1 H, J(4,1) = 1.3 (H-4); 3.19 dd, 1 H, J(CH,OH) = 5.1 an d 3.42 dd, 1 H, J(CH,OH) =
5.4, Jgem = 10.4 (CH2O); 3.25 dd, 1 H, J(CH,OH) = 5.2 an d 3.51 dd, 1 H, J(CH,OH) = 4.2,
Jgem = 10.6 (CH2O); 3.89 ddd, 1 H, J(3,2) = 6.1, J(3,7b) = 1.3, J(3,NH) = 7.2 (H-3); 4.18 brdd,
1 H, J(2,1) ≈ J(2,7b) = 1.0 (H-2); 4.48 t, 1 H (CH2OH); 4.51 t, 1 H (CH2OH); 4.94 d, J(OH,2) =
4.6 (2-OH); 5.02 brs, 2 H (NH2); 6.38 d, 1 H (NH); 7.74 s, 1 H (H-2′). 13C NMR: 31.85 (C-5);
34.52 (C-7); 42.42 (C-1); 45.44 (C-6); 47.93 (C-4); 57.31 (C-3); 68.64 (C-2); 123.63 (C-5′);
137.67 (C-4′); 146.51 (C-2′); 152.55 (C-6′).
Compound 20c: Yield 840 m g (84%), m .p. 144–146 °C (h ydrate), 250–252.5 °C. For
C
13H19ClN4O3·H2O (332.8) calculated: 46.92% C, 6.36% H, 10.65% Cl, 16.84% N; foun d:
46.93% C, 6.41% H, 10.79% Cl, 16.67% N. FAB MS, m/z (rel.%): 317/315 (35/100) [M + H],
281 (24). 1H NMR: 1.18 ddd, 1 H, J(6b,1) = 4.4, J(6b,2) = 1.2, Jgem = 12.8 (H-6b); 1.29 dd, 1 H,
J(6a,7b) = 2.0 (H-6a); 1.46 dm , 1 H, Jgem = 10.6 (H-7b); 1.51 ddt, 1 H, J(7a,1) ≈ J(7a,4) = 1.3,
J(7a,3) = 2.6 (H-7a); 1.79 m , 1 H (H-4); 2.18 brtq, 1 H, J(1,2) = 4.4, J(1,4) ≈ J(1,7) = 1.3 (H-1);
3.17 dd, 1 H, J(CH,OH) = 5.4 an d 3.46 dd, 1 H, J(CH,OH) = 5.6, Jgem = 10.4 (CH2O); 3.60 dd,
1 H, J(CH,OH) = 3.5 an d 3.68 dd, 1 H, J(CH,OH) = 8.8, Jgem = 11.2 (CH2O); 3.71 dt, 1 H,
J(3,2) = 2.8, J(3,NH) = 5.6 (H-3); 3.94 brq, 1 H, J(2,4) = 1.2, J(2,OH) = 3.4 (H-2); 4.46 t, 1 H,
J(OH,CH2) = 5.5 (CH2OH); 4.48 dd, 1 H (CH2OH); 4.89 d, 1 H (2-OH); 5.20 brs, 2 H (NH2);
6.86 d, 1 H (NH); 7.69 s, 1 H (H-2′). 13C NMR: 26.72 (C-6); 32.93 (C-7); 42.11 (C-1); 46.42
(C-4); 47.13 (C-5); 58.55 (C-5); 62.63 (CH2O); 64.56 (CH2O); 78.18 (C-2); 124.11 (C-5′);
136.50 (C-4′); 145.25 (C-2′); 151.32 (C-6′).
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532
Hřebabecký, Masojídková, Holý:
Preparation of 6-Ch loropurin e An alogues 21a, 21b, an d 21c
Con cen trated h ydroch loric acid (0.7 m l) was added to a stirred m ixture of com poun d 20a
(315 m g, 1 m m ol), 20b (315 m g, 1 m m ol) or 20c (333 m g, 1 m m ol) an d trieth yl orth o-
form ate (15 m l), th e resultin g solution was set aside at room tem perature for 3 days an d
th en evaporated. Th e residue was dissolved in tetrah ydrofuran (9 m l). To th e stirred solu-
tion , 0.5 M h ydroch loric acid (9 m l) was added, th e m ixture was stirred at room tem perature
for 3 h an d th en n eutralized with solid sodium h ydrogen carbon ate. Th e organ ic layer was
separated an d th e aqueous layer was extracted with tetrah ydrofuran (3 × 7 m l). Th e col-
lected organ ic ph ases were dried over an h ydrous sodium sulfate an d evaporated.
(1R*,2R*,3R*,4S*)-3-(6-Chloro-9H-purin-9-yl)-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol
(21a ): Th e residue was crystallized from water. Yield 305 m g (89%), m .p. 141–142 °C
(h ydrate), 198–199.5 °C. For C14H17ClN4O3·H2O (342.8) calculated: 49.05% C, 5.59% H,
10.34% Cl, 16.34% N; foun d: 49.25% C, 5.62% H, 10.38% Cl, 16.41% N. FAB MS, m/z
(rel.%): 327/325 (38/100) [M + H]. 1H NMR: 0.57 dd, 1 H, J(5b,7a) = 2.3, Jgem = 13.7 (H-5b);
1.07 ddd, 1 H, J(5a,3) = 1.6, J(5a,4) = 4.6 (H-5a); 1.70 brdq, 1 H, J(7b,1) ≈ J(7b,4) = 1.6,
J(7b,2) = 2.0, Jgem = 10.5 (H-7b); 1.83 dm , 1 H (H-7a); 2.10 m , 1 H (H-1); 3.15 overlapped
(H-4); 3.15 dd, 1 H, J(CH,OH) = 5.5 an d 3.38 dd, 1 H, J(CH,OH) = 5.5, Jgem = 10.5 (CH2O);
3.22 dd, 1 H, J(CH,OH) = 5.3 an d 3.40 dd, 1 H, J(CH,OH) = 4.5, Jgem = 10.6 (CH2O);
4.29 brdt, 1 H, J(3,1) = 1.0, J(3,2) = 2.2, J(3,4) = 4.3 (H-3); 4.44 dd, 1 H (CH2OH); 4.53 t, 1 H,
J(OH,CH2) = 5.5 (CH2OH); 4.91 brdt, 1 H, J(2,1) = 1.0, J(2,OH) = 3.9 (H-2); 5.22 d, 1 H
(2-OH); 8.77 s, 1 H an d 8.81 s, 1 H (H-2′, H-8′). 13C NMR: 27.73 (C-5); 32.48 (C-7); 40.29
(C-4); 45.85 (C-6); 48.55 (C-1); 62.18 (CH2O); 64.67 (CH2O); 69.54 (C-3); 70.33 (C-2); 131.40
(C-5′); 147.02 (C-8′); 149.28 (C-6′); 151.51 (C-2′); 152.83 (C-4′).
(1R*,2R*,3S*,4S*)-3-(6-Chloro-9H-purin-9-yl)-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol
(21b): Th e residue was crystallized from water. Yield 265 m g (79%), m .p. 207–209 °C. For
C
14H17ClN4O3·0.5H2O (333.8) calculated: 50.38% C, 5.44% H, 10.62% Cl, 16.79% N; foun d:
50.32% C, 5.51% H, 10.44% Cl, 16.68% N. FAB MS, m/z (rel.%): 327/325 (41/100) [M + H].
1H NMR: 1.03 dd, 1 H, J(5b,7a) = 1.7, Jgem = 12.9 (H-5b); 1.39 dd, 1 H, J(5a,4) = 4.4 (H-5a);
1.59 brdpen t, 1 H, J(7b,1) ≈ J(7b,2) ≈ J(7b,3) ≈ J(7b,4) = 1.5, Jgem = 10.6 (H-7b); 2.06 brs, 1 H
(H-1); 2.18 brdm , 1 H, J(7a,1) ≈ J(7a,4) = 1.3 (H-7a); 2.53 brdq, 1 H, J(4,1) ≈ J(4,3) = 1.3
(H-4); 3.23 dd, 1 H, J(CH,OH) = 5.2 an d 3.47 dd, 1 H, J(CH,OH) = 5.5, Jgem = 10.5 (CH2O);
3.34 dd, 1 H, J(CH,OH) = 5.4 an d 3.59 dd, 1 H, J(CH,OH) = 4.3, Jgem = 10.7 (CH2O);
4.36 ddt, 1 H, J(2,1) = 1.2, J(2,3) = 5.9, J(2,7b) = 1.5, J(2,OH) = 4.5 (H-2); 4.60 t, 1 H,
J(OH,CH2) = 5.4 (CH2OH); 4.64 t, 1 H, J(OH,CH2) = 4.7 (CH2OH); 4.69 brdt, 1 H (H-3);
4.75 d, 1 H (2-OH); 8.58 s, 1 H an d 8.73 s, 1 H (H-2′, H-8′). 13C NMR: 33.67 (C-7); 35.55
(C-5); 41.75 (C-4); 45.46 (C-6); 48.23 (C-1); 60.82 (C-3); 62.42 (CH2O); 65.01 (CH2O); 69.57
(C-2); 130.44 (C-5′); 146.98 (C-8′); 148.63 (C-6′); 151.29 (C-2′);152.74 (C-4′).
(1R*,2S*,3S*,4S*)-3-(6-Chloro-9H-purin-9-yl)-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol
(21c): Th e residue was ch rom atograph ed on a silica gel colum n (30 g) in eth yl acetate–
aceton e–eth an ol–water (95:15:9:6). Yield 290 m g (89%), m .p. 180–183 °C. For C14H17ClN4O3
(324.8) calculated: 51.78% C, 5.28% H, 10.92% Cl, 17.25% N; foun d: 51.95% C, 5.42% H,
10.98% Cl, 17.01% N. FAB MS, m/z (rel.%): 327/325 (41/100) [M + H], 291 (33). 1H NMR:
1.15 ddd, 1 H, J(6b,1) = 4.4, J(6b,2) = 1.0, Jgem = 12.8 (H-6b); 1.46 dd, 1 H, J(6a,7b) = 2.1
(H-6a); 1.71 brdt, 1 H, J(7a,1) ≈ J(7a,4) = 1.2, J(7a,3) = 2.6, Jgem = 10.6 (H-7a); 1.86 dm , 1 H
(H-7b); 2.30 m , 1 H (H-4); 2.32 brtq, 1 H, J(1,2) = 4.2, J(1,4) ≈ J(1,7) = 1.2 (H-1); 3.30 dd,
1 H, J(CH,OH) = 5.2 an d 3.47 dd, 1 H, J(CH,OH) = 5.6, Jgem = 10.5 (CH2O); 3.67 dd, 1 H,
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Novel Conformationally Locked Carbocyclic Nucleosides
533
J(CH,OH) = 5.0 an d 3.47 dd, 1 H, J(CH,OH) = 5.0, Jgem = 10.6 (CH2O); 4.48 t, 1 H,
J(OH,CH2) = 5.0 (CH2OH); 4.50 brq, 1 H, J(2,3) = 2.8, J(2,4) = 1.0 (H-2); 4.56 t, 1 H,
J(OH,CH2) = 5.4 (CH2OH); 4.63 brt, 1 H (H-3); 5.27 d, 1 H, J(OH,2) = 4.0 (2-OH); 8.79 s, 1 H
an d 8.89 s, 1 H (H-2′, H-8′). 13C NMR: 26.83 (C-6); 33.81 (C-7); 42.41 (C-1); 46.69 (C-4);
47.34 (C-5); 61.93 (CH2O); 62.52 (C-3); 64.54 (CH2O); 77.55 (C-2); 131.21 (C-5′); 146.08
(C-8′); 149.21 (C-6′); 151.50 (C-2′); 152.32 (C-4′).
Am m on olysis of 6-Ch loropurin es 21a, 21b, an d 21c
Liquid am m on ia (10 m l) was added to a stirred suspen sion of a 6-ch loropurin e (0.5 m m ol)
in m eth an ol (2 m l) at –70 °C an d th e m ixture was h eated in an autoclave at 75 °C for 48 h .
Am m on ia was evaporated an d th e residue was crystallized from water.
(1R*,2R*,3R*,4S*)-3-(6-Amino-9H-purin-9-yl)-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol
(22a): Yield 124 m g (79%), m .p. 290–293 °C. For C14H19N5O3·0.5H2O (314.4) calculated:
53.49% C, 6.41% H, 22.28% N; foun d: 53.69% C, 6.42% H, 22.13%N. FAB MS, m/z (rel.%):
306 (100) [M + H], 275 (48). 1H NMR: 0.54 dd, 1 H, J(5b,7a) = 2.3, Jgem = 13.6 (H-5b);
1.07 ddd, 1 H, J(5a,3) = 1.6, J(5a,4) = 4.6 (H-5a); 1.67 brdq, 1 H, J(7b,1) ≈ J(7b,4) = 1.6,
J(7b,2) = 2.0, Jgem = 10.5 (H-7b); 1.79 dm , 1 H (H-7a); 2.07 m , 1 H (H-1); 3.04 brtq, 1 H,
J(4,1) ≈ J(4,7a) = 1.6, J(4,3) = 4.3 (H-4); 3.20 dd, 1 H, J(CH,OH) = 5.2 an d 3.40 dd, 1 H,
J(CH,OH) = 5.6, Jgem = 10.5 (CH2O); 3.23 dd, 1 H, J(CH,OH) = 5.2 an d 3.45 dd, 1 H,
J(CH,OH) = 4.4, Jgem = 10.6 (CH2O); 4.17 brdq, 1 H, J(3,1) = 1.0, J(3,2) = 2.2 (H-3); 4.46 dd,
1 H (CH2OH); 4.52 t, 1 H, J(OH,CH2) = 5.4 (CH2OH); 4.78 brdt, 1 H, J(2,1) = 1.0, J(2,OH) =
3.9 (H-2); 5.12 d, 1 H (2-OH); 7.22 brs, 2 H (NH2); 8.13 s, 1 H an d 8.22 s, 1 H (H-2′, H-8′).
13C NMR: 27.82 (C-5); 32.49 (C-7); 40.30 (C-4); 45.94 (C-6); 48.28 (C-1); 62.08 (CH2O);
64.63 (CH2O); 68.74 (C-3); 70.39 (C-2); 119.38 (C-5′); 139.97 (C-8′); 150.48 (C-4′); 152.49
(C-2′); 156.18 (C-6′).
(1R*,2R*,3S*,4S*)-3-(6-Amino-9H-purin-9-yl)-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol
(22b): Yield 135 m g (86%), m .p. 301–303.5 °C. For C14H19N5O3·0.5H2O (314.4) calculated:
53.49% C, 6.41% H, 22.28% N; foun d: 53.28% C, 6.45% H, 21.99% N. FAB MS, m/z (rel.%):
306 (100) [M + H], 136 (32). 1H NMR: 0.98 dd, 1 H, J(5b,7a) = 2.6, Jgem = 12.8 (H-5b);
1.35 dd, 1 H, J(5a,4) = 4.3 (H-5a); 1.56 brdpen t, 1 H, Jgem = 10.5 (H-7b); 2.04 m , 1 H (H-1);
2.14 dm , 1 H (H-7a); 2.36 brdq, 1 H, J(4,1) ≈ J(4,7) = 1.5, J(4,5a) = 4.3 (H-4); 3.23 dd, 1 H,
J(CH,OH) = 5.3 an d 3.47 dd, 1 H, J(CH,OH) = 5.5, Jgem = 10.4 (CH2O); 3.33 dd, 1 H,
J(CH,OH) = 4.9 an d 3.58 dd, 1 H, J(CH,OH) = 4.3, Jgem = 10.7 (CH2O); 4.29 brddt, 1 H,
J(2,1) ≈ J(2,7b) = 1.2, J(2,3) = 6.0, J(2,OH) = 4.6 (H-2); 4.56 brdt, 1 H, J(3,4a) ≈ J(3,7b) = 1.2
(H-3); 4.59 t, 1 H, J(OH,CH2) = 5.4 (CH2OH); 4.62 t, 1 H, J(OH,CH2) = 4.6 (CH2OH); 4.75 d,
1 H (2-OH); 7.12 brs, 2 H (NH2); 8.02 s, 1 H an d 8.11 s, 1 H (H-2′, H-8′). 13C NMR: 33.71
(C-7); 35.85 (C-5); 42.40 (C-4); 45.46 (C-6); 48.23 (C-1); 59.74 (C-3); 62.36 (CH2O); 64.93
(CH2O); 69.61 (C-2); 118.13 (H-5′); 140.31 (H-8′); 150.20 (C-4′); 152.18 (C-2′); 155.96 (C-6′).
(1R*,2S*,3S*,4S*)-3-(6-Amino-9H-purin-9-yl)-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol
(22c): Yield 128 m g (84%), m .p. 269–270 °C. For C14H19N5O3 (305.3) calculated: 55.07% C,
6.27% H, 22.94% N; foun d: 54.94% C, 6.42% H, 22.70% N. FAB MS, m/z (rel.%): 306 (100)
[M + H], 136 (57). 1H NMR: 1.16 ddd, 1 H, J(6b,1) = 4.4, J(6b,2) = 1.2, Jgem = 12.7 (H-6b);
1.43 dd, 1 H, J(6a,7b) = 2.0 (H-6a); 1.65 brddt, 1 H, J(7a,1) ≈ J(7a,4) = 1.2, J(7a,3) = 2.3, Jgem
=
10.6 (H-7a); 1.80 dm , 1 H, J(7b,1) ≈ J(7b,4) = 1.2 (H-7b); 2.09 brs, 1 H (H-4); 2.30 brtq, 1 H,
J(1,2) = 4.2, J(1,4) = 1.2 (H-1); 3.27 dd, 1 H, J(CH,OH) = 5.3 an d 3.46 dd, 1 H, J(CH,OH) =
5.6, Jgem = 10.5 (CH2O); 3.68 dd, 1 H, J(CH,OH) = 4.6 an d 3.76 dd, 1 H, J(CH,OH) = 6.2,
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Hřebabecký, Masojídková, Holý:
Jgem = 11.0 (CH2O); 4.45 brt, 1 H, J(3,2) = 2.8 (H-3); 4.52 dd, 1 H (CH2OH); 4.54 t, 1 H,
J(OH,CH2) = 5.4 (CH2OH); 4.56 brq, 1 H, J(2,4) = 1.1, J(2,OH) = 3.9 (H-2); 5.20 d, 1 H
(2-OH); 7.24 brs, 2 H (NH2); 8.14 s, 1 H an d 8.33 s, 1 H (H-2′, H-8′). 13C NMR: 26.73 (C-6);
33.41 (C-7); 42.38 (C-1); 47.19 (C-4); 47.43 (C-5); 61.42 (C-3); 62.06 (CH2O); 64.45 (CH2O);
76.84 (C-2); 119.24 (C-5′); 139.19 (C-8′); 149.87 (C-4′); 152.43 (C-2′); 156.21 (C-6′).
Preparation of 6-(Dim eth ylam in o)purin es 23a, 23b, an d 23c
A ch loropurin e (0.5 m m ol) was dissolved un der stirrin g in dim eth ylam m on ium N,N-di-
m eth ylcarbam ate (1.5 m l), th e solution was set aside at room tem perature for 5 h an d th en
evaporated. Th e residue was crystallized from water.
(1R*,2R*,3R*,4S*)-3-[6-(Dimethyla mino)-9H-purin-9-yl]-6,6-bis(hydroxymethyl)bicyclo-
[2.2.1]heptan-2-ol (23a): Yield 163 m g (95%), m .p. 225–227 °C. For C16H23N5O3·H2O (342.4)
calculated: 56.13% C, 7.07% H, 20.45% N; foun d: 56.32% C, 7.12% H, 20.65% N. FAB MS,
m/z (rel.%): 334 (100) [M + H], 215 (36). 1H NMR: 0.54 dd, 1 H, J(5b,7a) = 2.3, Jgem = 13.7
(H-5b); 1.05 ddd, 1 H, J(5a,3) = 1.6, J(5a,4) = 4.6 (H-5a); 1.67 brdq, 1 H, J(7b,1) ≈ J(7b,4) =
1.6, J(7b,2) = 2.0, Jgem = 10.5 (H-7b); 1.80 dm , 1 H (H-7a); 2.08 m , 1 H (H-1); 3.02 brtq, 1 H,
J(4,1) ≈ J(4,7a) = 1.5, J(4,3) = 4.2 (H-4); 3.22 dd, 1 H, J(CH,OH) = 5.5 an d 3.40 dd, 1 H,
J(CH,OH) = 5.5, Jgem = 10.5 (CH2O); 3.23 dd, 1 H, J(CH,OH) = 5.1 an d 3.46 dd, 1 H,
J(CH,OH) = 4.4, Jgem = 10.7 (CH2O); 3.25 brs, 6 H (N(CH3)2); 4.20 brdt, 1 H, J(3,1) = 1.0,
J(3,2) = 2.1 (H-3); 4.47 dd, 1 H (CH2OH); 4.52 t, 1 H, J(OH,CH2) = 5.5 (CH2OH); 4.75 brdt,
1 H, J(2,1) = 1.0, J(2,OH) = 4.0 (H-2); 5.12 d, 1 H (2-OH); 8.20 s, 1 H an d 8.24 s, 1 H (H-2′,
H-8′). 13C NMR: 27.68 (C-5); 32.54 (C-7); 34.50 (NCH3); 40.25 (C-4); 45.99 (C-6); 48.28
(C-1); 62.07 (CH2O); 64.63 (CH2O); 68.70 (C-3); 70.39 (C-2); 119.88 (C-5′); 138.73 (C-8′);
151.26 (C-4′); 151.81 (C-2′); 154.41 (C-6′).
(1R*,2R*,3S*,4S*)-3-[6-(Dimethyla mino)-9H-purin-9-yl]-6,6-bis(hydroxymethyl)bicyclo-
[2.2.1]heptan-2-ol (23b ): Yield 145 m g (85%), m .p. 237–239 °C. For C16H23N5O3·0.5H2O
(342.4) calculated: 56.13% C, 7.07% H, 20.45% N; foun d: 56.26% C, 7.16% H, 20.40% N.
FAB MS, m/z (rel.%): 334 (100) [M + H], 164 (67). 1H NMR: 0.98 dd, 1 H, J(5b,7a) = 2.7,
Jgem = 12.8 (H-5b); 1.36 dd, 1 H, J(5a,4) = 4.4 (H-5a); 1.55 brdpen t, 1 H, J(7b,1) ≈ J(7b,2) ≈
J(7b,3) ≈ J(7b,4) = 1.3, Jgem = 10.5 (H-7b); 2.04 m , 1 H (H-1); 2.13 dm , 1 H (H-7a); 2.36 brdq,
1 H, J(4,1) ≈ J(4,7a) = 1.3 (H-4); 3.22 dd, 1 H, J(CH,OH) = 5.2 an d 3.47 dd, 1 H, J(CH,OH) =
5.6, Jgem = 10.4 (CH2O); 3.32 dd, 1 H, J(CH,OH) = 5.0 an d 3.58 dd, 1 H, J(CH,OH) = 4.4,
Jgem = 10.6 (CH2O); 3.45 brs, 6 H (N(CH3)2); 4.30 ddt, 1 H, J(2,1) = 1.2, J(2,3) = 6.0,
J(2,OH) = 4.6 (H-2); 4.58 brdt, 1 H, J(3,7a) = 1.2 (H-3); 4.58 t, 1 H, J(CH2,OH) = 5.4
(CH2OH); 4.61 t, 1 H, J(CH2,OH) = 4.7 (CH2OH); 4.70 d, 1 H (2-OH); 8.02 s, 1 H an d 8.18 s,
1 H (H-2′, H-8′). 13C NMR: 33.66 (C-7); 35.83 (C-5); 38.00, 2 C (N(CH3)2); 42.21 (C-4); 45.46
(C-6); 48.25 (C-1); 59.73 (C-3); 62.33 (CH2O); 64.90 (CH2O); 69.53 (C-2); 118.69 (C-5′);
139.15 (C-8′); 150.97 (C-4′); 151.53 (C-2′); 154.33 (C-6′).
(1R*,2S*,3S*,4S*)-3-[6-(Dimethyla mino)-9H-purin-9-yl]-5,5-bis(hydroxymethyl)bicyclo-
[2.2.1]heptan-2-ol (23c): Yield 140 m g (84%), m .p. 235–236.5 °C. For C16H23N5O3 (333.4) cal-
culated: 57.64% C, 6.95% H, 21.01% N; foun d: 57.52% C, 6.94% H, 20.85% N. FAB MS, m/z
(rel.%): 334 (100) [M + H], 215 (24). 1H NMR: 1.18 ddd, 1 H, J(6b,1) = 4.4, J(6b,2) = 1.1,
Jgem = 12.8 (H-6b); 1.43 dd, 1 H, J(6a,7b) = 2.1 (H-6a); 1.65 brddt, 1 H, J(7a,1) ≈ J(7a,4) = 1.2,
J(7a,3) = 2.7, Jgem = 10.6 (H-7a); 1.73 brdm , 1 H, J(7b,1) = J(7b,4) = 1.2 (H-7b); 2.06 m , 1 H
(H-4); 2.31 brtq, 1 H, J(1,2) = 4.2, J(1,4) ≈ J(1,7) = 1.3 (H-1); 3.26 dd, 1 H, J(CH,OH) = 5.3
an d 3.46 dd, 1 H, J(CH,OH) = 5.6, Jgem = 10.5 (CH2O); 3.45 brs, 6 H (N(CH3)2); 3.69 dd, 1 H,
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J(CH,OH) = 4.5 an d 3.77 dd, 1 H, J(CH,OH) = 6.7, Jgem = 11.0 (CH2O); 4.47 brt, 1 H, J(3,2) =
2.7 (H-3); 4.53 overlapped (H-2); 4.53 t, 1 H, J(OH,CH2) = 5.4 (CH2OH); 4.53 dd, 1 H
(CH2OH); 5.20 d, 1 H, J(OH,2) = 3.9 (2-OH); 8.22 s, 1 H an d 8.36 s, 1 H (H-2′, H-8′).
13C NMR: 26.68 (C-6); 33.28 (C-7); 34.33, 2 C (N(CH3)2); 42.39 (C-1); 47.08 (C-4); 47.46
(C-5); 61.21 (C-3); 62.07 (CH2O); 64.37 (CH2O); 76.73 (C-2); 119.74 (C-5′); 137.77 (C-8′);
150.59 (C-4′); 151.77 (C-2′); 154.44 (C-6′).
Reaction of 6-Ch loropurin es 21a, 21b, an d 21c with Cyclopropylam in e
A solution of a ch loropurin e (0.5 m m ol) in cyclopropylam in e (1.5 m l) was left at room tem -
perature overn igh t an d th en was evaporated.
(1R*,2R*,3R*,4S*)-3-[6-(Cyclopropylamino)-9H-purin-9-yl]-6,6-bis(hydroxymethyl)bicyclo-
[2.2.1]heptan-2-ol (24a): Crystallization of th e residue from water yielded 154 m g (89%) of
24a, m .p. 218–219.5 °C. For C17H23N5O3 (345.4) calculated: 59.12% C, 6.71% H, 20.28% N;
foun d: 58.95% C, 6.74% H, 20.16% N. FAB MS, m/z (rel.%): 346 (100) [M + H], 176 (29).
1H NMR: 0.54 dd, 1 H, J(5b,7a) = 2.0, Jgem = 13.7 (H-5b); 0.61 m , 2 H, 0.70 m , 2 H, an d
3.02 m , 1 H (cyclopropyl); 1.06 ddd, 1 H, J(5a,3) = 1.5, J(5a,4) = 4.5 (H-5a); 1.67 dq, 1 H,
J(7b,1) ≈ J(7b,4) = 1.6, J(7b,2) = 2.0, Jgem = 10.4 (H-7b); 1.80 dm , 1 H (H-7a); 2.08 m , 1 H
(H-1); 3.05 brt, 1 H (H-4); 3.20 dd, 1 H, J(CH,OH) = 4.4 an d 3.40 dd, 1 H, J(CH,OH) = 4.9,
Jgem = 10.5 (CH2O); 3.23 dd, 1 H, J(CH,OH) = 5.5 an d 3.43 dd, 1 H, J(CH,OH) = 4.8, Jgem
=
10.6 (CH2O); 4.18 brdt, 1 H, J(3,1) = 1.0, J(3,4) = 4.2 (H-3); 4.52 t, 1 H, J(OH,CH2) = 5.0
(CH2OH); 4.56 t, 1 H, J(OH,CH2) = 4.6 (CH2OH); 4.78 brdt, 1 H, J(2,1) = 1.0, J(2,3) = 2.0,
J(2,OH) = 3.8 (H-2); 5.12 d, 1 H (2-OH); 7.88 brs, 1 H (NH); 8.22 s, 2 H (H-2′, H-8′).
13C NMR: 6.55, 2 C (2 × CH2); 24.20 (NCH); 27.84 (C-5); 32.50 (C-7); 40.31 (C-4); 45.94
(C-6); 48.28 (C-1); 62.10 (CH2O); 64.64 (CH2O); 68.75 (C-3); 70.43 (C-2); 119.75 (C-5′);
139.82 (C-8′); 150.00 (C-4′); 152.41 (C-2′); 155.71 (C-6′).
(1R*,2R*,3S*,4S*)-3-[6-(Cyclopropylamino)-9H-purin-9-yl]-6,6-bis(hydroxymethyl)bicyclo-
[2.2.1]heptan-2-ol (24b): Ch rom atograph y of th e residue on a silica gel colum n in eth yl
acetate–aceton e–eth an ol–water (90:15:11:9) an d crystallization from eth an ol–eth er afforded
152 m g (88%) of 24b , m .p. 242–244 °C. For C17H23N5O3 (345.4) calculated: 59.12% C,
6.71% H, 20.28% N; foun d: 58.92% C, 6.78% H, 20.01% N. FAB MS, m/z (rel.%): 346 (100)
[M + H], 176 (41). 1H NMR: 0.59 m , 2 H, 0.71 m , 2 H, an d 3.05 m , 1 H (cyclopropyl);
0.98 dd, 1 H, J(5b,7a) = 1.7, Jgem = 12.7 (H-5b); 1.35 dd, 1 H, J(5a,4) = 4.2 (H-5a); 1.55 dm ,
1 H, Jgem = 10.4 (H-7b); 2.04 m , 1 H (H-1); 2.14 dm , 1 H (H-7a); 2.36 brd, 1 H (H-4);
3.23 dd, 1 H, J(CH,OH) = 5.6 an d 3.46 dd, 1 H, J(CH,OH) = 5.4, Jgem = 10.4 (CH2O); 3.33 dd,
1 H, J(CH,OH) = 4.8 an d 3.58 dd, 1 H, J(CH,OH) = 4.2, Jgem = 10.6 (CH2O); 4.30 brdd, 1 H,
J(2,3) = 6.0, J(2,OH) = 4.6 (H-2); 4.57 brd, 1 H (H-3); 4.58 t, 1 H, J(OH,CH2) = 5.5 (CH2OH);
4.61 t, 1 H, J(OH,CH2) = 4.6 (CH2OH); 4.72 d, 1 H (2-OH); 7.75 brs, 1 H (NH); 8.01 s, 1 H
an d 8.21 s, 1 H (H-2′, H-8′). 13C NMR: 6.65, 2 C (CH2); 24.13 (NCH); 33.67 (C-7); 35.82
(C-5); 42.33 (C-4); 45.44 (C-6); 48.23 (C-1); 59.73 (C-3); 62.39 (OCH2); 64.97 (OCH2); 69.60
(C-2); 118.49 (C-5′); 140.10 (C-8′); 149.92 (C-4′); 152.05 (C-2′); 155.55 (C-6′).
(1R*,2S*,3S*,4S*)-3-[6-(Cyclopropylamino)-9H-purin-9-yl]-5,5-bis(hydroxymethyl)bicyclo-
[2.2.1]heptan-2-ol (24c): Ch rom atograph y of th e residue on a silica gel colum n in eth yl
acetate–aceton e–eth an ol–water (95:15:10:8) an d crystallization from m eth an ol–eth er gave
153 m g (86%) of 24c, m .p. 157.5–160 °C. For C17H23N5O3·0.5H2O (354.4) calculated:
57.61% C, 6.83% H, 19.76% N; foun d: 57.74% C, 6.82% H, 19.60% N. FAB MS, m/z (rel.%):
346 (100) [M + H], 176 (36). 1H NMR: 0.61 m , 2 H, 0.72 m , 2 H, an d 3.05 m , 1 H
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(cyclopropyl); 1.17 ddd, 1 H, J(6b,1) = 4.4, J(6b,2) = 1.0, Jgem = 12.8 (H-6b); 1.43 dd, 1 H,
J(6a,7b) = 2.0 (H-6a); 1.65 brdt, 1 H, J(7a,1) ≈ J(7a,4) = 1.2, J(7a,3) = 2.6, Jgem = 10.6 (H-7a);
1.79 dm , 1 H (H-7b); 2.09 m , 1 H (H-4); 2.30 brtq, 1 H, J(1,2) = 4.2, J(1,4) ≈ J(1,7) = 1.2
(H-1); 3.26 dd, 1 H, J(CH,OH) = 5.3 an d 3.46 dd, 1 H, J(CH,OH) = 5.5, Jgem = 10.5 (CH2O);
3.69 dd, 1 H, J(CH,OH) = 4.6 an d 3.77 dd, 1 H, J(CH,OH) = 6.1, Jgem = 11.0 (CH2O); 4.46 brt,
1 H, J(3,2) = 2.8 (H-3); 4.52 dd,1 H (CH2OH); 4.53 t, 1 H, J(CH2,OH) = 5.4 (CH2OH);
4.56 brq, 1 H, J(2,4) = 1.0, J(2,OH) = 3.9 (H-2); 5.20 d, 1 H (2-OH); 7.89 brs, 1 H (NH);
8.24 brs, 1 H an d 8.33 s, 1 H (H-2′, H-8′). 13C NMR: 6.58, 2 C (CH2); 25.00 (NCH); 26.73
(C-6); 33.41 (C-7); 42.39 (C-1); 47.19 (C-4); 47.44 (C-5); 61.42 (C-3); 62.08 (CH2O); 64.46
(CH2O); 76.83 (C-2); 119.62 (C-5′); 139.01 (C-8′); 149.34 (C-4′); 152.34 (C-2′); 155.77 (C-6′).
Eth yl N-((2E)-3-Eth oxym eth acryloyl)carbam ate (26)
1-Eth oxyprop-1-en e (8.85 m l, 80 m m ol) in 1,4-dioxan e (40 m l) was added over 20 m in to a
stirred solution of ch lorocarbon yl isocyan ate (4.8 m l, 60 m m ol) in 1,4-dioxan e (55 m l) at
10 °C. Th e m ixture was stirred for 20 m in , trieth ylam in e (8.4 m l, 60 m m ol) in 1,4-dioxan e
(60 m l) was th en added over 45 m in an d stirrin g was con tin ued for 15 m in . An h ydrous eth -
an ol (4.3 m l, 75 m m ol) was th en added dropwise over 15 m in followed by dioxan e (120 m l)
over 15 m in . Th e m ixture was stirred at 15 °C for 20 m in , th e solid was filtered off, wash ed
with 1,4-dioxan e (40 m l) an d th e com bin ed filtrates were con cen trated to 20 m l. Th e resi-
due was diluted with petroleum eth er (20 m l) an d set aside at 5 °C for 1 h . Th e crystallin e
product was filtered off an d wash ed with petroleum eth er–1,4-dioxan e (5:1, 6 m l). 8.2 g
(68%) of 26 was obtain ed, m .p. 114–116 °C. For C9H15NO4 (201.2) calculated: 53.72% C,
7.51% H, 6.96% N; foun d: 53.54% C, 7.55% H, 6.70% N. FAB MS, m/z (rel.%): 202 (100)
[M + H], 113 (42), 102 (17), 85 (14). 1H NMR: 1.22 t, 3 H an d 1.25 t, 3 H, J(CH3,CH2) = 7.1
(2 × CH3); 1.59 s, 3 H (2-CH3); 4.05 q, 2 H an d 4.09 q, 2 H (2 × CH2); 7.44 s, 1 H (H-3);
10.05 s, 1 H (NH). 13C NMR: 9.28, 14.45, an d 15.49 (3 × CH3); 60.67 (CH2O); 69.45 (CH2O);
108.00 (C-2); 151.76 (C=O); 166.72, 2 C (2 × C=O).
Preparation of Th ym in e An alogues 28a, 28b, an d 28c
A solution of am in e (187 m g, 1 m m ol) an d acylcarbam ate 26 (201 m g, 1 m m ol) in 1,4-di-
oxan e (9 m l) was h eated at 100 °C for 3 h . Dowex 50 (H+, 3 m l) was wash ed with
1,4-dioxan e an d th en added to th e m ixture. Th e m ixture was h eated at 90 °C for 3 h , th e
resin was filtered off, wash ed with m eth an ol an d th e collected filtrates were evaporated. Th e
residue was crystallized from eth an ol.
1-[(1R*,2S*,3S*,4S*)-3-Hydroxy-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-yl]-5-methyl-
pyrimidine-2,4(1H,3H)-dione (28a): Yield 142 m g (48%), m .p. 251–254 °C. For C14H20N2O5
(296.3) calculated: 56.75% C, 6.80% H, 9.45% N; foun d: 56.55% C, 6.79% H, 9.22% N.
FAB MS, m/z (rel.%): 297 (100) [M + H], 279 (35). 1H NMR: 0.80 dd, 1 H, J(6b′,7a′) = 2.2,
Jgem = 13.7 (H-6b′); 1.12 ddd, 1 H, J(6a′,1′) = 4.6, J(6a′,2′) = 1.2 (H-6a′); 1.60 brdq, 1 H,
J(7b′,1′) ≈ J(7b′,4′) = 1.6, J(7b′,3′) = 2.0, Jgem = 10.5 (H-7b′); 1.68 dm , 1 H (H-7a′); 1.79 d, 3 H,
J(CH3,6) = 1.0 (H-6); 1.99 m , 1 H (H-4′); 2.65 brtq, 1 H, J(1′,2′) = 4.2, J(1′,4′) ≈ J(1′,7a′) = 1.6
(H-1′); 3.20 dd, 1 H, J(CH,OH) = 5.3 an d 3.38 dd, 1 H, J(CH,OH) = 5.5, Jgem = 10.5 (CH2O);
3.24 dd, 1 H, J(CH,OH) = 5.1 an d 3.53 dd, 1 H, J(CH,OH) = 4.3, Jgem = 10.7 (CH2O); 3.82 m ,
1 H (H-2′); 4.26 brdt, 1 H, J(3′,2′) = 2.0, J(3′,OH) = 3.5 (H-3′); 4.54 t, 1 H, J(OH,CH2) = 5.4
(CH2OH); 4.60 brt, 1 H, J(OH,CH2) = 4.7 (CH2OH); 4.65 d, 1 H (3′-OH); 7.57 brq, 1 H (H-6);
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11.30 s, 1 H (NH). 13C NMR: 12.32 (CH3); 27.49 (C-6′); 32.73 (C-7′); 39.78 (C-1′); 46.11
(C-5′); 48.16 (C-4′); 62.36 (CH2O); 64.91 (CH2O); 70.26 (C-2′); 71.47 (C-3′); 107.94 (C-5);
139.67 (C-6); 152.30 (C-2); 164.02 (C-4).
1-[(1R*,2R*,3S*,4S*)-3-Hydroxy-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-yl]-5-methyl-
pyrimidine-2,4(1H,3H)-dione (28b): Yield 105 m g (34%), m .p. 200–202 °C. For C14H20N2O5·
0.5H2O (305.3) calculated: 55.07% C, 6.93% H, 9.17% N; foun d: 55.27% C, 6.96% H,
8.99% N. FAB MS, m/z (rel.%): 297 (100) [M + H], 279 (12). 1H NMR: 0.83 dd, 1 H,
J(6b′,7a′) = 2.7, Jgem = 12.7 (H-6b′); 1.32 dd, 1 H, J(6a′,1′) = 4.4 (H-6a′); 1.45 dpen t, J(7b′,1′) ≈
J(7b′,2′) ≈ J(7b′,3′) ≈ J(7b′,4′) = 1.5, Jgem = 10.5 (H-7b′); 1.76 d, 3 H, J(CH3,6) = 1.0 (CH3);
1.90 dm , 1 H (H-7a′); 1.93 m , 1 H (H-4′); 2.26 brdq, 1 H, J(1′,4′) ≈ J(1′,7a′) = 1.5 (H-1′);
3.19 dd, 1 H, J(CH,OH) = 5.2 an d 3.43 dd, 1 H, J(CH,OH) = 5.6, Jgem = 10.5 (CH2O); 3.22 dd,
1 H, J(CH,OH) = 5.0 an d 3.48 dd, 1 H, J(CH,OH) = 4.3, Jgem = 10.5 (CH2O); 4.18 m , 2 H
(H-2′, H-3′); 4.53 t, 1 H, J(OH,CH2) = 5.4 (CH2OH); 4.54 brt, 1 H, J(OH,CH2) = 4.6 (CH2OH);
7.23 brq, 1 H (H-6); 11.11 s, 1 H (NH). 13C NMR: 12.61 (CH3); 33.91 (C-7′); 36.66 (C-6′);
39.86 (C-1′); 45.69 (C-5′); 47.39 (C-4′); 61.29 (C-2′); 62.08 (CH2O); 64.90 (CH2O); 69.83
(C-3′); 107.04 (C-5); 139.34 (C-6); 151.83 (C-2); 164.31 (C-4).
1-[(1R*,2R*,3R*,4S*)-3-Hydroxy-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-yl]-5-methyl-
pyrimidine-2,4(1H,3H)-dione (28c): Yield 149 m g (50%), m .p. 223–226 °C. For C14H20N2O5
(296.3) calculated: 56.75% C, 6.80% H, 9.45% N; foun d: 56.65% C, 6.96% H, 9.19% N.
FAB MS, m/z (rel.%): 297 (100) [M + H], 127 (92). 1H NMR: 1.14 ddd, 1 H, J(5b′,3′) = 0.8,
J(5b′,4′) = 4.5, Jgem = 12.8 (H-5b′); 1.30 dd, 1 H, J(5a′,7b′) = 1.7 (H-5a′); 1.45 dm , 1 H, Jgem
=
10.6 (H-7b′); 1.59 dm , 1 H (H-7a′); 1.80 d, 3 H, J(CH3,6) = 1.1; 2.01 m , 1 H (H-1′); 2.23 brtq,
1 H, J(4′,1′) ≈ J(4′,7a′) ≈ J(4′,7b′) = 1.6, J(4′,3′) = 4.0 (H-4′); 3.23 dd, 1 H, J(CH,OH) = 5.4 an d
3.48 dd, 1 H, J(CH,OH) = 5.6, Jgem = 10.4 (CH2O); 3.54 dd, 1 H, J(CH,OH) = 4.4 an d 3.65 dd,
1 H, J(CH,OH) = 6.9, Jgem = 11.1 (CH2O); 4.10 brt, 1 H, J(2′,1′) = 1.0, J(2′,3′) = 2.7, J(2′,7a′) =
2.0 (H-2′); 4.13 brq, 1 H, J(3′,1′) = 1.0, J(3′,OH) = 3.3 (H-3′); 4.28 dd, 1 H, J(OH,CH2) = 4.4
an d 6.9 (CH2OH); 4.52 t, 1 H, J(OH,CH2) = 5.5 (CH2OH); 4.71 d, 1 H (2′-OH); 1.68 brq, 1 H
(H-6); 11.39 s, 1 H (NH). 13C NMR: 12.24 (CH3); 26.84 (C-5′); 33.24 (C-7′); 42.07 (C-4′);
45.01 (C-1′); 47.82 (C-6′); 61.83 (CH2O); 63.07 (C-2′); 64.29 (CH2O); 76.92 (C-3′); 108.65
(C-5); 137.72 (C-6); 152.45 (C-2); 163.84 (C-4).
The cytostatic activity was studied by Dr I. Votruba from the Institute. His contribution is grate-
fully acknowledged. The authors are indebted to Ms J. Sklenářová for excellent technical assistance
and to the staff of the Analytical Laboratory of the Institute for elemental analyses. This study, a part
of the research project Z4 055 0506, was supported by the Grant Agency of the Czech Republic (grant
No. 203/05/0132).
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