Chiral pool synthesis of 4a-substituted carbocyclic cyclopentanoid nucleoside precursors, I

Article abstract of DOI:10.1515/znb-1999-0816

A suitable protected D-ribono-1,4-lactone derivative has been used for the straightforward chiral pool synthesis of cyclopentanoid nucleoside precursors. Thus, epoxidation followed by deoxygenation or regioselective ring opening led to nucleoside precurso

Full text of DOI:10.1515/znb-1999-0816

Chiral Pool Synthesis of 4a-Substituted Carbocyclic Cyclopentanoid
Nucleoside Precursors, I
Rene C suk*a, Petra Dörrb, Martin Kühnb, Claus Krieger0, and M ikhael Y. Antipind
a Institut für Organ. Chemie, Martin-Luther-Universität Halle-Wittenberg,
Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany
h Pharmazeutisch-Chemisches Institut. Universität Heidelberg, Im Neuenheimer Feld 364,
D-69120 Heidelberg. Germany
c Max-Planck-Institut für Medizinische Forschung, Jahn-Straße 29, D-69120 Heidelberg,
Germany
d Institute of Organoelement Compounds, Russian Academy of Science,
Vavilow St. 28 B-334, Moscow 117813. Russia
* Reprint requests to Prof. Dr. R. Csuk. E-mail: csuk@chemie.uni-halle.de
Z. Naturforsch. 54b, 1068-1078 (1999); received May 21, 1999
Nucleosides, Carbohydrates, X-Ray Data
A suitable protected D-ribono-1,4-lactone derivative has been used for the straightforward
chiral pool synthesis of cyclopentanoid nucleoside precursors. Thus, epoxidation followed by
deoxygenation or regioselective ring opening led to nucleoside precursors modified at the
positions C(4), C(4a) and C(4,4a) as well as side-chain modified derivatives. The structures
of the key intermediates were determined by X-ray analyses.
Introduction
Results and Discussion
Natural nucleosides and their analogues have
been widely studied as potential fungicidal, antitu-
mor and antiviral agents. However, since these nu-
cleosides are substrates for enzymatic degrada-
tions a number of modifications have been carried
out on both, the hetero-cycle and the sugar por-
tion to avoid or at least to slow down these deacti-
vating processes. Thus, the replacement of the oxy-
gen of the furan ring by a methylene group leads
to the synthesis of carbocyclic analogues of nucle-
osides. Since then, carbocyclic analogues of sugars
have attracted considerable attention as potential
inhibitors of carbohydrate metabolism. A number
of carbocyclic nucleosides [1 -3 ] have been re-
ported as potential anti-HIV [4, 5] and anti-HBV
[6] agents. A m ong them, the cyclopentanoid deriv-
ative carbovir [4, 7], is one of the most interesting
compounds. In the course of our ongoing efforts
toward the synthesis of carbocyclic nucleoside an-
alogues we set out to develop an approach to five-
membered sugars possessing a suitable functional
group at the C(4a’)-position. To obtain enantio-
merically pure materials a chiral pool approach
starting from D-ribono-1,4-lactone was chosen.
Thus, the cyclopentene derivative (3a R , 6a R )-
6-benzyloxymethyl-2,2-dimethyl-4,6a-dihydro-
3aH -cyclopenta[d][l,3]dioxol-4-one [(-)-l] [8] has
been used quite successfully as a valuable starting
material for the synthesis of various nucleoside an-
alogues [9, 10]. During the course of developing
new cyclopentanoid antitumor agents we became
interested in the synthesis of derivatives carrying
additional substituents at the positions 4 and/or 4a
(carbohydrate numbering has been used through-
out this work for convenience) and 1 seemed to
be an ideal starting material since it can be synthe-
sized in large amounts by a chiral pool approach
starting from 5-0-benzyl-2,3-0-isopropylidene-D -
ribono-1,4-lactone (2) [11, 12]. Chain elongation
at the anomeric centre with dimethyl lithiomethyl-
phosphonate [8, 13] gave in 84% yield the corre-
sponding phosphonate 3 that was treated with so-
dium m ethoxide to afford the acyclic phosphonate
4. W hereas oxidations with C r0 3 [13], DMSO/
(CF3C 0 ) 20 [14], Swern oxidation [15] as well as
oxidations using PDC or PDC failed to give good
yields on a larger preparative scale, oxidation of 4
with Dess-M artin’s periodinane [16-19] gave ac-
cess to 5 as well as a byproduct that was shown
to be an inseparable 1:1 mixture of the anomeric
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R. Csuk et al. • 4a-Substituted Carbocyclic Cyclopentanoid Nucleoside Precursors, I
phosphonates 6 and 7. The compounds 6/7 are
characterized by the presence of a tert-butyl group
reospecific manner with
a
newly created ste-
reogenic centre possessing (-S)-configuration. Pro-
tection of the hydroxy function in with
in the
NM R spectrum at d = 1.48/1.49 ppm,
8
respectively. The anomeric carbon shows
d
=
chlorotriisopropylsilane/pyridine in the presence
of catalytical amounts of D M A P afforded the
[l,3]dioxol 9 in 90% yield. Under similar condi-
tions 10 was obtained.
The epoxidation of 8 with ra-CPBA [20-23] at
room temperature led to a 1:2 mixture of the two
epoxides 11 and 12.
To establish the absolute configuration at the
newly created stereogenic centres, 9 was epoxi-
dized under the same conditions to afford the ep-
oxide 13. Although the similarity in the spectral
data between 13 and 11 indicated that both com -
pounds possess the same absolute configuration at
the stereogenic centres, these spectral data al-
lowed no unambiguous assignment. Therefore,
both, 12 and 11 were silylated and gave 14 and
13, the latter of which has been identical in every
respect with that material obtained from the epox-
idation reaction of 9.Treatment of the epoxides 11
and 12 with 2,4-dinitrobenzoyl chloride afforded
the nitrobenzoates 15 and 16, and the absolute
48.46/50.60 ppm with !JCP = 128 Hz whereas for
the acetalic C(5) a 3Jc,p A 5 Hz was measured.
Inspection of Dreiding m odels revealed that a re-
ize e attack of ter/-butanol onto C(5) in 5 should
dominate over a si-face attack due to the presence
of the isopropylidene acetal, therefore 6/7 should
possess a (S)-configuration at the acetalic centre.
Chromatographic fractions that contained an ex-
cess of either 6 or 7 showed fast equilibrium in
solution to afford again a 1:1 mixture of these
compounds.
Cyclization [13] of 5 afforded a mixture of (+)-
and (-)-l that was easily separated to yield the
pure enantiomer (-)-l and racemic (±)-l. 1 is
characterized by its IR spectrum by a carbonyl sig-
nal at v = 1722 cm -1; the olefinic H-C(4a) is found
at Ö = 6.22 ppm showing an allylic coupling to
H a ,b-C(5) of 1.5 Hz. Reduction of 1 at 0 °C with
sodium borohydride in the presence of cerium(III)
chloride [13] gave after a re-face attack 8 in a ste-
OMe
BnO
OMe
BnO.
V
(+)-1
(-)-1
9
R = TIPS
10 R = TBDMS
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R. Csuk et al. ■4a-Substituted Carbocyclic Cyclopentanoid Nucleoside Precursors. I
1070
an expected epoxide 18 but the 'H NM R spectrum
showed a triplet at d = 6.24 with J - 1.9 Hz, and
in the 13C NM R spectrum two signals at d - 117.7
and d = 149.9 ppm indicated the presence of an
olefinic double bond. The oxidation of a,ß-unsatu-
rated ketones to a-epoxy-ketones and their re-
arrangement to enol lactones is well documented;
nevertheless no products corresponding to this re-
action were found in our experiments. To gain an
unambiguous structural assignment, however, suit-
able crystals of 17 were grown and subjected to a
X-ray analysis whose results are depicted in Fig. 2.
configuration of the latter was determined by a X-
ray analysis; the atomic coordinates, bond lengths
and angles, torsion angles and thermal paramters
are available on request from the Director of the
Cambridge Crystallographic Centre, University
Chemical Laboratory, Lensfield Road, Cambridge
CB21EW. The main results of this X-ray analysis
are depicted in Fig. 1. Therefore, the assignment
of the absolute configuration of all stereogenic
centres was possible for compounds 11-16, respec-
tively.
Interestingly enough, treatment of (±)-l with
ra-CPBA gave rise in 70% yield to a product 17 Therefore, 17 results from a Baeyer-Villiger-oxida-
whose elem ental analysis corresponded well with tion of 1.
Fig. 1. X-ray analysis of 16: C23H22N2O 10, mono-
clinic, space group P2\. unit cell dimensions: a =
10.517(3) Ä, b = 14.277(4) A, c - 15.604(3) Ä, a =
90°, ß = 90.23(2)°, y = 90°, F (000) = 1016; 3979
independent reflections measured, 2639 observed
F2 = 0.993, final R indices: [I > 2a (I)]: R = 0.0688,
Rw = 0.1525; Z = 4; colorless prism; crystal size
0.4 x 0.3 x 0.3 mm: C(4)-C(4a) = 1.518(12)Ä,
C(4)-C(5)= 1.476(11)A, C(2>C(3) = 1.542(10)A,
C(l)-C(2)
1.494(11)A, 0(3)-C(4a)
=
1.552(12)A,
C(l)-C(4a)
1.448(10)A, C(l)-
=
=
0(4) - 1.451(9)A, C(3)-C(4) - 1.507(12)A; C(4a)-
0(3)-C(4) = 63.1(5)°, 0(3)-C(4)-C(5) = 113.3(6)°,
0(3)-C(4)-C(3) = 111.4(7)°, 0(3)-C(4a)-C(4) =
58.6(5)°.
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R. Csuk et al. ■4a-Substituted Carbocyclic Cyclopentanoid Nucleoside Precursors, I
1071
V
18
droxy group using Mitsunobu conditions [24, 25]
without affecting the epoxide moiety. Thus, reac-
tion of 12 with triphenylphosphine, diethyl azodi-
carboxylate and 6-chloropurine gave 19 in 62%
yield after chromatographic purification [26-31].
The
NM R spectrum of 19 showed - as com -
pared to the spectrum of 12 - two additional sig-
nals at d = 8.19 and 8.62 ppm resulting from the
presence of the purine moiety and in the IR
spectrum the signal of the hydroxy group was
missing. The synthetic potential of these novel syn-
thetic precursors for the synthesis of cyclopenta-
noid nucleoside analogues is currently under in-
vestigation in our laboratories.
Fig. 2. X-ray analysis of 17: C16H 180 5, monoclinic, space
group P2j/n, unit cell dimensions: a = 9.225(5) A, b =
9.318(5) A, c = 17.572(4) Ä, ß = 96.74(4)°, F (000) = 616;
2942 independent measured, 1964 reflections observed,
I > 3.0 cx(I), 257 parameters refined; R = 0.043, Rw =
0.053; colorless prism; Z - 4-} crystal size 0.2 x 0.2 x
0.3 mm; C(l)-0(6) = 1.341(3)A, C(l)-C(2) = 1.458(3)A,
C (l)-0(1) = 1.205(3)A, C(2)-C(3) - 1.317(2)A, C(3)-
C(4) = 1.494(2)A, C(4)-C(5) = 1.499(3)A, C(5)-0(6) -
Experimental
General methods'. [32]
1.446(2)A; 0 (6)-C (l)-0(l)
= 118.4(2)°, C(2)-C(l)-
Dimethyl(6-0-benzyl-l-deoxy-3,4-0-isopropyl-
idene-ß-D-ribo-hex-2-ulofuranosyl)-phosphonate
(3)
0(1) = 123.2(2)°, C(l)-C(2)-C(3) = 118.2(2)°, C(2)-C(3)-
C(4) = 118.2(2)°, C(5)-C(4)-C(3) = 114.9(1)°, 0(6)-C(5)-
C(4) = 113.6(2)°, C(5)-0(6)-C(l) = 121.4(2), 0(6)-C (l)-
C(2) = 118.4(2)°.
To
a solution of freshly distilled dimethyl
methylphosphonate (24.0 g, 193.5 mmol) in dry
TH F (200 ml) at -7 8 °C n-butyllithium (120 ml,
1.6 M in hexane) was added within 40 min. After
stirring for an additional 30 min at -7 8 °C a solu-
tion of 2 (21.4 g, 77 mmol) in dry THF (200 ml)
was slowly added. Stirring was continued for an
Compound 12 itself seem s to be a valuable in-
termediate for the synthesis of C(4a’) substituted
nucleoside analogues and it could be subjected to
a nucleophilic displacement reaction at the hy-
12
19
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1072
R. Csuk et al. • 4a-Substituted Carbocyclic Cyclopentanoid Nucleoside Precursors, I
additional 15 min, then a saturated aqueous solu-
tion of ammonium chloride (25 ml) was added, the
reaction mixture was diluted with diethyl ether
(500 ml), the organic layer was separated, and the
(c, 1.0 CHC13); R f - 0.12 (hexane/ethyl acetate
1:1); (Lit.: [a]g> -8 .2 ° (c, 1.0 CHC13) [13]); !H
NM R (300 MHz, CDC13): (3 = 7.39-7.25 (m, 5 H,
H-C(ar)); 4.61 (d , 1 H, J = 6.2 Hz, H-C(3)), 4.55
aqueous phase was extracted with ether ( 1 0
x
(s, 2 H, CH (ar)), 4.22 (d d , 1 H, 7 = 6.2, 6.5 Hz,
2
100 ml). The combined organic phases were
washed with brine (100 ml), dried (M gS 04), and
the solvent was removed under reduced pressure.
The residue was subjected to column chromatog-
H -C(4)), 3.92 (ddd, 1 H, J = 3.2, 6.0, 6.5 Hz, H-
C(5)), 3.81 (d, 3 H, 7 = 2.7 Hz, POCH3), 3.78 (d ,
3 H. 7 = 2.7 Hz, PO C H 3), 3.72 (dd, 1 H , 7 = 3.2,
9.9 Hz, H b-C(
H a -C( )), 3.45 (dd, 1 H, 7 = 14.3, 22.4 Hz, H B-
C (l)), 3.35 (dd, 1 H. 7 = 14.3, 22.4 Hz, H A-C(1)),
2.70 (bs, 1 H, exchangeable with D 0 , HO-C(5)),
1.43 ( 5, 3 H, CH (isopropyl)), 1.34 (5, 3 H, CH3-
6
)), 3.58 (dd, 1 H, 7 = 6.0, 9.9 Hz,
raphy (silica gel, hexane/ethyl acetate
1
:1
) to af-
6
ford 3 (25.9 g, 84%) as a colorless oil that crystal-
lized upon refrigeration: m.p. 56 °C; [a]^ -13.7°
(c, 1.1 CHC13); R F - 0.18 (hexane/ethyl acetate
1:1); (Lit.: m.p. 5 4 -5 6 °C; [a ]$ -1 4 ° (c, 0.9
2
3
(isopropyl)); 13C NM R (75 MHz. CDC13): (3 =
201.33 (d, 7Cp = 6.7 Hz, C(2)), 137.69 (s, C„(ar)),
128.25, 127.63 127.59 (d, Q (ar)), 111.21 (s, C^iso-
propyl)), 82.64 (dd, JCP = 2.3 Hz, C(4)), 77.36 (d,
CHCI
7.37-7.29 (m, 5 H, H-C(ar)), 6.23 (5, exchangeable
with D 0 , 1 H, H O -C(2)), 4.77 (d , 1 H, 7 = 6.2 Hz,
H -C(3)), 4.54 (s, 2 H, CH (ar)), 4.47 (d, 1 H, J =
3
) [13]); ]H NM R (250 MHz, DM SO-d6): (3 =
2
2
C (5)), 73.43 (t, CH
C( )), 53.13 (dq, JCP = 5.4 Hz, PO CH 3), 53.03 (dq,
7CP = 6.7 Hz, PO C H 3), 37.20 (dt, 7CP = 131.0 Hz,
C (l)), 26.95 (q, CH (isopropyl)), 25.98 (q, CH3-
2
(ar)), 71.55 (d, C(3)), 70.82 (t,
5.0 Hz, H -C(5)), 4.15 (t, 1 H, 7 = 6.2 Hz, H -C(4)),
3.64 (d , 3 H, 7H p = 7.4 Hz, POCH3)), 3.60 (d , 3 H,
7Hp = 7.4 Hz, PO CH 3)), 3.58-3.46 (m, 2 H, H A B-
6
3
C(
CH
6
)), 2.30-2.42 (m, 2 H, H A.B-C(1)), 1.38 (s, 3 H,
(isopropyl)), 1.29 (s, 3 H, CH (isopropyl));
(isopropyl)); MS (FAB, glycerol): 403; MS (FAB,
glycerol + LiCl): 409.
3
3
13C NM R (62 MHz, DM SO-d6): (3 = 138.23 (s,
C ^ar)), 127.52, 127.59, 128.25, (d , Q (ar)), 111.70
(s, Cq (isopropyl)), 104.99 (s, C (2)), 85.20 (d d ,
7Cp = 4.2 Hz C(3)), 82.88, 83.72 (d , C(5),C(4)),
Analysis for C 18
H 2 7 0 8P (402.38)
Calcd C 53.73 H 6.76%,
Found C 53.55 H 6.83%.
71.53, 72.33 (t, C(
Hz, PO CH 3), 51.64 (,dq, 7Cp = 6.2 Hz, POCH3),
31.53 (dt, JCP = 139.2 Hz, C (l)), 26.45 (q , CH
(isopropyl)), 25.15 (q , CH (isopropyl)); MS (FAB,
glycerol): 385; MS (FAB, glycerol + LiCl): 409.
6
), CH
2
(ar)), 52.49 (dq, JCP = 6.l
Dimethyl(6-0-benzyl-l-deoxy-3,4-0-isopropyl-
idene-D-erythro-2,5-hexodiulosyl)-phosphonate
3
(5)
3
To a solution of 4 (10.1 g, 25 mmol) in abs. di-
chloromethane (100 ml) a solution of Dess-Mar-
tin's periodinane (10.7 g, 26 mmol) in abs. dichlo-
Analysis for C i
8
H
2 7 0 8P (402.38)
Calcd
C 53.73 H 6.76% ,
romethane ( 1 0
0
ml) was added in several portions.
Found C 53.90 H 6.99% .
Dry tert-butanol (2.0 g, 27 mmol) was added and
stirring was continued at 25 °C until tic indicated
the absence of any starting material. After dilution
with diethylether (500 ml), a saturated aqueous so-
lution of sodium hydrogencarbonate (500 ml) was
added, the phases were separated, the organic
layer was extracted with diethylether (4 x 200 ml)
and the combined organic phases were dried
(M gS 04); the solvent was removed under reduced
pressure and the residue subjected to column
chromatography (silica gel, hexane/ethyl acetate
5:1 —* 3:1 —*• 2:1) to afford 5 (7.6 g, 76% ) as an oil;
[a]o -17.5° (c, 1.5 CHC13); R f = 0.42 (ethyl ace-
tate); (Lit.: [a]g> -14.1° (c, 1.0 CHC13) [13]); !H
NM R (250 MHz, CDC13): (3 = 7.38-7.25 (m, 5 H,
H -C(ar)), 4.84 (t, 1 H, 7 = 5,7 Hz, H -C(3)), 4.75 (t,
Dimethyl(6-0-benzyl-l-deoxy-3,4-0-isopropyl-
idene-D-ribo-2-hexulosyl)-phosphonate (4)
To a solution of 3 (16.0 g, 40 mmol) in dry m eth-
anol (80 ml) a solution of sodium methoxide in
methanol [freshly prepared from sodium (2.4 g,
1 0 0 mmol) in abs. methanol ( 1 0
0
ml)] was added
and the mixture was stirred for 2 days at 25 °C,
then neutralized by the careful addition of glacial
acetic acid and the solvent was removed under re-
duced pressure. The residue was partioned be-
tween ethyl acetate (500 ml) and water (250 ml),
the organic layer was separated and the aqueous
phase was extracted with ethyl acetate ( 1 0
x
100 ml). The combined organic layers were
washed with brine, dried (M gS 04), the solvent was
removed and the residue subjected to chromatog-
raphy (silica gel, hexane/ethyl acetate 3:1 — 1:1 —^
0:1) to afford 4 (14.2 g, 89%) as an oil; [a]& -7.9°
1 H. 7 = 5.7 Hz, H C (4)), 4.63 (s, 2 H, CH
4.48 (d, 1 H. 7 = 18.4 Hz, H B-C( )), 4.40 (d, 1 H.
7 = 18.3 Hz. H a -C( )), 3.83 (d , 3 H, 7 = 1.9 Hz,
PO C H 3), 3.79 (d, 3 H. 7 = 1.9 Hz. PO CH 3), 3.54
2
(ar)),
6
6
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R. Csuk et al. • 4a-Substituted Carbocyclic Cyclopentanoid Nucleoside Precursors, I
1073
(dd, 1 H, J = 14.2, 22.4 Hz, H B-C(1)), 3.29 (dd, 1
H, J = 14.2, 22.5 Hz, H A-C(1)), 1.42 (s, 6 H, 2 x
80.02 (d, C(7a)), 73.99 (d, C(3a)), 73.20 (t,
CH (ar)), 73.02 (t, CH (O B n)), 53.58 (dq, JCP =
6.7 Hz, PO C H 3), 53.30 (dq, JCP = 6.4 Hz, POCH3),
50.60 (dd, JCP 128.1 Hz, C( )), 27.88 (q,
CH (terr-butylj), 27.22, 26.26 (q, 2 x C H 3).
2
2
CH (isopropyl)); 13C NM R (75 MHz, CDC13): ö =
3
204.49 (s, C(5)), 199.38 (d , JCP = 7.0 Hz, C(2)),
136.77 (s, Cq(ar)), 128.36, 127.87, 127.83 (d,
Q (ar)), 112.93 (s, C ^isopropyl)), 81.45, 79.36 (d,
=
6
3
Data for 7. - !H NM R (300 MHz, CDC13): d =
7.30-7.40 (m, 5 H, H-C(ar)), 4.68 (d, 1 H, J = 6 . 8
C(2), C(3)), 73.31 (t, CH
2
(ar)), 72.54 (t, C( )),
6
Hz, H-C(3a)) 4.77 (ddd, 1 H, J = 5.3,
H -C(7a)), 4.63 (s, 2 H, CH (ar)), 4.53 (d, 1 H, / =
18.5 Hz, H A-CH (O Bn)), 4.42 (d, 1 H, J = 18.5
Hz, H B-CH (O Bn)), 3.81, 3.77 (d, 3 H, J = 2.6 Hz,
POCH3), 3.45 (dd, 1 H, J = 5.3, 22.9 Hz, H -C ( )),
1.48 (s, 9 H, CH (terr-butyl)), 1.46, 1.34 ( , 3 H, 2 x
CH3); 13C NM R (75 M Hz, CDCI ): (3 = 204.58 (s,
6
.
8
, 11.1 Hz,
53.18 (d q ,J c p = 4.6 Hz, POCH3), 53.17 (dq,JCP =
2.9 Hz, P O C H 3 ), 36.97 (<fr, JC P = 130,1 Hz, C (l)),
2
2
26.13 (q, CH
pyl)); MS (ei, 80 eV, 180 °C): 385 (0.6%), 324
(0.1% ), 309 (0.3% ), 292 ( %), 251 (12.0%), 193
3
(isopropyl)), 26.00 (q, CH
3
(isopro-
2
6
.6
6
(18.0% ), 151 (37.7% ), 124 (16.4% ), 109 (19.5%),
91 (100% ).
3
5
3
C(7)), 165.26 (ds, JCP = 5.1 Hz, C(4)), 137.02 (s,
C^ar)), 128.25, 127.82, 127.74 (d, Q (ar)), 111.14
(s, C(2)), 82.83 (s, Cq(tert-buty\)), 79.87 (d, C(7a)),
Analysis for C 18
H 2 5 0 8P (400.36)
Calcd C 54.00 H 6.29% ,
Found C 54.21 H 6.39% .
74.03 (d, C(3a)), 73.15 (t, CH
CH (O Bn)), 53.34 (dq, JCP = 6.7 Hz, PO CH
53.24 (dq, Jc P = 6.4 Hz, PO CH 3), 48.46 (dd, JCP =
128.1 Hz, C( )), 27.81 (q, C H 3(tert-buty\)), 26.64,
2
(ar)), 72.65 (t,
2
3
),
(7flR,6RS,3aS,) Dimethyl(4-benzyloxymethyl-4-
tert-butoxy-2,2-dimethyl-7-oxo-tetrahydro-[l,3]-
dioxolo[4,5-c]pyran-6-yl)-phosphonate (6) and (1)
6
26.05 (q, 2 x CH3).
To
a
solution
of periodinane
(745 mg,
I.76 mmol) in abs. dichloromethane (7 ml) a solu-
tion of 4 (180 mg, 0.45 mmol) in abs. dichloro-
m ethane (5 ml) was added in one portion. After
the addition of dry rert-butanol (200 mg, 2.7 mmol)
stirring at 25 °C was continued for 7 h, then the
reaction was diluted with diethylether ( 2 0 0 ml)
and a saturated aqueous solution of sodium hy-
drogencarbonate (150 ml) was added. Work up as
above and chromatography (silica gel, hexane/
ethyl acetate 5:1 —* 3:1 —* 2:1) gave a 1:1 mixture
of 6/7 (151 mg, 71% ) as a semicrystaline oil; m.p.:
35 °C; MS (ei, 80 eV, 105 °C): 472 (M, 0.6%), 457
(M -C H 3, 0.7% ), 416 (1.4% ), 399 (2.7%), 366
(3aS,4S,6aK)6-(Benzyloxymethyl)-2,2-dimethyl-
4,6a-dihydro-3aH-cyclopenta[d][l,3]dioxol-4-ol
(8)
To
a
-2 0 °C cold solution of ( - ) - l (1.0 g,
• 7 H 20 (1.12 g, 3.01 mmol)
3.65 mmol) and CeCl
3
in methanol (7 ml) sodium borohydride (0.15 g,
3.94 mmol) was added in several portions and the
mixture was allowed to warm to 25 °C. The pH
was adjusted to 5 by the addition of acetic acid,
water (15 ml) was added and the mixture was ex-
tracted with diethylether (3 x 30 ml). The com -
bined organic layers were washed with brine, dried
(M gS 04), and the solvent was removed under re-
duced pressure. The residue was purified by col-
umn chromatography (silica gel, hexane/ethyl ace-
tate 10:1) to afford 8 (0.95 g, 94%); [a]&° +20.4° (c,
1.6 CHC13); R f = 0.64 (hexane/ethyl acetate 1:1);
*H NM R (300 MHz, CDC13): (3 = 7.33-7.24 (m, 5
H, H-C(ar)), 5.82 (d, 1 H, J = 1.5 Hz, H -C(5)),
(2.3% ), 341 (6.1% ), 310 (10.1% ), 267 (8 6
(15.9% ), 209 (95.1% ), 191 ( %), 165 (15.2%),
151 (21.8% ), 127 (14.4% ), 91 (100%); By repeated
.8
%), 223
6 .6
chromatography a temporarily separation of
7 could be achieved.
6
and
Data for
0.70 (ethyl acetate). Data for
6
. - R F = 0.76 (ethyl acetate), 7 R F =
. - 'H NMR (300
6
MHz, C D C I3 ): <3 = 7.29-7.40 (m, 5 H, H-C(ar)),
4.99 (ddd, 1 H, J = 5.6, 6.9, 9.0 Hz, H-C(7a)), 4.68
(d, l H , / = 5.6 Hz, H-C(3a)), 4.63 (d, 2 H, J =
4.97 (d, 1 H, J = 5.4 Hz, H -C (
5.5 Hz, H -C(3a)), 4.58 (s, 3 H, CH
4.16 (5, 2 H, CH (O B n)), 2.76 (d, 1 H, / = 9.2 Hz,
OH), 1.43, 1.40 (s, 3 H, 2 x C H 3); 13C NM R (62.89
MHz, CD Cl3): d = 142.34 , C( )), 137.84 (s,
6
a)), 4.77 (t, l H , / =
2
(ar)), H-C(4)),
2.2 Hz, CH
2
(ar)), 4.51 (d, 1 H, J = 18.2 Hz, H A-
2
CH
CH
2
(O Bn)), 4.40 (d, 1 H,
(O B n)), 3.81, 3.77 (d,
J
3
=
H,
18.2 Hz, H B-
2.6 Hz,
)),
(ferf-butyl)), 1.44, 1.32 (s, 3 H, 2 x
-C(2)); 13C NM R (75 MHz, CDC13): (3 =
2
J
=
(
5
6
PO CH
1.49 (s, 9 H, CH
CH
3
), 3.25 (dd, 1 H, J = 9.0, 21.1 Hz, H-C(
6
Cq(ar)), 131.24 (d, C(5)), 128.30,127.50 (d, Cf(ar)),
112.40 (s, C (2)), 82.92, 77.69, 73.21 (d , C(4), C(3a),
3
3
C(
6
a)), 72.81 (t, CH
2
(ar)), 66.16 (t, CH (O Bn)),
2
203.90 (s, C (7)), 164.97 (ds, JCP = 5.8 Hz, C(4)),
137.09 (s, Cq(ar)), 128.26, 127.83, 127.75 (d,
Ct(ar)), 111.07 (s, C(2)), 82.50 (s, Cq(tert-butyl)),
27.58, 26.56 (q, 2 x CH3); MS (ei, 80 eV, 150 °C):
278 (1.4% ), 263 (4.3% ), 220 (5.7% ), 168 (5.2%),
110 (6.1% ), 107 (10.4% ), 92 (15.8% ), 91 (100%).
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1074
R. Csuk et al. • 4a-Substituted Carbocyclic Cyclopentanoid Nucleoside Precursors, I
(3aS,4S,6aR)6-(Benzyloxy-methyl)-4-(triiso-
propylsilyloxy)-2,2-dimethyl-4,6a-dihydro-3aH-
cyclopenta[d][l,3]-dioxol (9)
solvents were removed under reduced pressure to
yield a residue, subjected to column chromatogra-
phy (silica gel, hexane/ethyl acetate 2 0
:1 ) to afford
10 (1.05 g, 90%); +18.6° (c, 1.6 CHC13), R F = 0.71
(hexane/ethyl acetate 3:1); ’H NM R (300 MHz,
CDCU): d = 7.35-7.22 (m, 5 H, H -C(ar)), 5.72 (s,
1 H, H-C(4a)), 4.87 (m, 1 H), 4.64 (m, 2 H ), 4.45
To a solution of 8 (500 mg, 1.81 mmol) in dry
pyridine (4 ml) containing 4-dimethylaminopyri-
dine (250 mg, 2.0 mmol) triisopropylchlorosilane
(420 mg, 2.2 mmol) was added and the mixture
stirred at 25 °C for 24 h. After dilution of this sus-
pension with dichloromethane (15 ml) and ice
water (5 ml) the layers were separated and the
aqueous layer was extracted with dichloromethane
(3 x 25 ml); the combined organic layers were
washed with brine, dried (M gS 04), the solvent was
removed and the residue subjected to chromatog-
raphy (silica gel, hexane/ethyl acetate 50:1) to af-
ford 9 (778 mg, 99.0% ) as an oil; [a]^ +6.3 (c, 1.0,
CHC13), R f = 0.43 (hexane/ethyl acetate 10:1); 'H
NM R (300 MHz, CDC13): Ö = 7.17-7.27 (m, 5 H,
H -C(ar)), 5.68 (s, 1 H, H -C(5)), 4.81 (d , l H , i =
(s, 2 H, CH
2
(ar)), 4.16 (s, 2 H, H
2
C(5)), 1.41 ( , 3
5
H, CH (isopropyl)), 1.37 (
3
5
, 3 H, CH3(isopropyl)),
0.93 (*,'9 H, CH3(/m -butyl)), 0.13 (s, 6 H, 2 x CH 3-
Si); 13C NM R (62 MHz, CDC13): <5 = 141.82 (s,
C(4)), 138.18 (s, C(?(ar)), 131.72, 128.40, 127.70,
127.65 (d, C,(ar), C(4a)), 112.22 (s, C<7(isopropyl)),
82.93, 79.00, 74.61 (d, C (l), C(2), C (3)), 72.91(r,
CH2(ar)), 66.63 (t, C(5)), 27.47 (q, C H 3(isopro-
pyl)), 26.88 (q, CH3(isopropyl)), 25.88 (q,
CH3(ferr-butyl)), 18.41 ( 5, Cq(rerf-butyl)), -4.47 (q,
CH3-Si), -4.85 (q, CH3-Si); MS (80 eV, 115 °C): 376
(M-14, 0.3%), 375 (M-15, 1%), 332 (M -tert-butyl
9.7%).
5.6 Hz, H -C(
H, J = 5.6 Hz, H -C (3a)), 4.48 (s, 2 H, CH
4.09 (s, 2 H, CH (O Bn)), 1.31, 1.30 (s, 3 H, 2 x
CH3), 1.03 (s, 18 H, CH -TIPS), 0.98 (s, 3 H, CH-
TIPS); 13C NM R (62 MHz, CDC13): öd = 141.98 (s,
C( )), 138.36 ( 5, Cg(ar)), 132.26 (d , C(5)), 128.34,
127.94 (d, Q (ar)), 112.44 (s, C(2)), 83.28, 79.49,
74.81 (d , C(4), C(3a), C( a)), 73.30 (t, CH (ar)),
66.94 (t, CH (O B n)), 27.99, 26.49 (q , 2 x CH ,);
18.42 (q , CH (TIPS)), 12.84 (d , CH(TIPS)); MS
(ei, 80 eV, 120 °C): 417 (M -C H 3, 0.4% ), 331 (M -
C H ,-(2 isopropyl), 11.5%) 301 (5.7% ), 240
6
a)), 4.64 (m, 1 H, H -C(4)), 4.61 (r, 1
Analysis for C22H 340 4Si (390.59)
2
(ar)),
Calcd
C 67.65 H 8.77%,
2
Found C 67.27 H 8.64%.
3
6
(4aS)4,4a-Anhydro-5-0-benzyl-4a-carba-2,3-0-
isopropylidene-ß-L-lyxofiiranose - (1S,2S,3S,4R,5S)-
2-benzyloxymethyl-7,7-dimethyl-6,8,9-trioxa-tricyclo-
[3.3.123]nonan-4-ol (11) and (4a RJ 4,4a-anhydro-5-
0-benzyl-4a-carba-2,3-0-isopropylidene-ß-D-ribo-
furanose = (lS,2R,3R,4R,5S)-2-Benzyloxymethyl-
7,7-dimethyl-6,8,9-trioxa-tricyclo [3.3.12’3]nonan-4-ol
6
2
2
3
x
(M -C H 3- (2 x isop rop yl)-B n, 2.0% ), 225 (2.0% ), (12)
201 (1.9% ), 183 (4.4% ), 155 (5.5% ), 131 (3.3% ),
103 (3.5% ), 91 (100% ).
To a solution of 8 (1.10 g, 3.98 mmol) in dichlo-
romethane (25 ml) m-CPBA (70% , 1.88 g,
7.61 m mol) was added and the mixture stirred for
12 h. Work up was performed as described for 13,
followed by chromatography (silica gel, hexane/
ethyl acetate 10:1 —> 6:1 —*■2:1) to give 11 (0.35 g,
30%) and 12 (0.76 g, 65%). Data for 11. - [a]^°
+11.8° (c, 1.4 CHCI3); R f = 0.46 (hexane/ethyl ace-
tate 4:1); !H NMR (300 MHz, CDC13): (5 = 7 .3 6 -
7.25 (m, 5 H, H-C(ar)), 4.78 (dd, 1 H, J = 1.1, 5.7
Hz, H -C(3)), 4.62 (s, 2 H, CH2(ar)), 4.53 (virt. t, 1
H, J = 5.7 Hz, H-C(2)), 4.17 (d, 1 H, J = 11.9 Hz,
H a -C(5)), 4.11 (d , 1 H, J = 5.9 Hz, H -C (l)), 3.57
Analysis for C2 5
H 4 6 0 4Si (432.68)
Calcd C 69.40 H 9.32% ,
Found C 69.54 H 9.21% .
(lS,2R,3R)4-(Benzyloxy-methyl)-l-0-(tert-butyl-
dimethylsilyl)-2,3-0-isopropylidene-cyclopent-4-
ene = (3aR,4S,6aR) 6-(benzyloxy-methyl)-4-(tert-
butyldimethylsilyloxy)-2,2-dimethyl-3a,6a-dihydro-
cyclopenta[l,3]-dioxol (10)
To a solution of
8
(0.829 g, 3.00 mmol) in abs.
( , 1 H, H-C(4a)), 3.53 (d, 1 H, J = 11.9 Hz, H B-
5
dichloromethane (5 ml) dry pyridine (1.5 ml,
18.6 mmol), D M A P (100 mg, 0.8 mmol) and tert-
butyldimethylchlorosilane (0.60 g, 4.0 mmol) were
added and the mixture was stirred for 15h. Then
the suspension was diluted with dichloromethane
(25 ml) and ice water (10 ml). The layers were sep-
arated, the aqueous phase was extracted with di-
chloromethane (3 x 50 ml), the combined organic
phases washed with brine, dried (M g S 0 4), and the
C(5)), 2.9 (bs, 1 H, O H ), 1.52, 1.40 (s, 3 H, 2 x
CH,(isopropyl)); 13C NM R (75 MHz, CDC1,): (3 =
137.63 (5, C^(ar)), 128.15, 127.48 (d, C,(ar)), 113.21
(s, C^isopropyl)), 79.80, 79.16 (d, C (l), C(2)),
73.25 (t, CH.(ar)), 68.17 (d, C(3)), 67.60 (s, C(4)),
66.37 (t, C(5)), 63.40 (d, C(4a)), 26.13, 24.49 (q, 2 x
CH3(isopropyl)); MS (ei, 80 eV, 110 °C): 293
(M +l, 0.6% ), 292 (M, 3.5%), 277 (M -C H 3.
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1075
R. Csuk et al. • 4a-Substituted Carbocyclic Cyclopentanoid Nucleoside Precursors, I
15.8%), 171 (8.3%), 110 (20.6%), 107 (21.6% ), 101
(35.2% ), 91 (100%).
CH3(isopropyl)), 1.10 (s, 3 H, CH-TIPS), 1.05 (s,
18 H, CH3-TIPS); 13C NM R (75 MHz, CDC13): d -
137.79 (s, C^(ar)), 128.13, 127.48 (d, C,(ar)), 113.06
( 5, C<7(isopropyl)), 82.06, 79.23 (d, C (l), C(2)),
73.13 (t, CH2(ar)), 70.38 (d, C(3)), 67.90 (s, C(4)),
66.44 (t, C(5)), 64.14 (d, C(4a)), 26.59, 25.78 (q, 2 x
CH3(isopropyl)), 17.88 (q, CH 3(TIPS)), 17.69 (q,
CH3(TIPS)), 12.16 (d, CH(TIPS)); MS (ei, 80 eV,
140 °C): 448 (M, 0.5% ), 433 (M -C H 3, 6.9%), 405
(28.3% ), 347 (41.1% ), 185 (8.0% ), 157 (5.9% ), 103
(13.9% ), 92 (23.3% ), 91 (100%).
Analysis for C l6H20O 5 (292.33)
Calcd
C 65.74 H 6.89% ,
Found C 65.58 H 6.81% .
Data for 12. - [a]$ +46.9° (c, 1.1 CHC13); R F =
0.15 (hexane/ethyl acetate 4:1); ]H NM R (300
M Hz, CDC13): (3 = 7.42-7.27 (m, 5 H, H-C(ar)),
4.76 (d , l H , i = 6.8 Hz, H -C(3)), 4.64 (d, 1 H, J =
11.8 Hz, H A-CH?(ar)), 4.52 (d , 1 H, J = 11.8 Hz,
H B-CH2(ar)), 4.53-4.50 (m, 1 H, H -C(2)), 4.17
(dd, 1 H, J = 1.5, 6.1 Hz, H -C (l)), 3.81 (d , 1 H, J =
11.3 Hz, H a -C(5)), 3.62 (d, 1 H, J = 11.3 Hz, H B-
C (5)), 3.56 (virt. (, 1 H , i = 1.2 Hz, H -C(4a)), 1.59
(s, 3 H, CH3(isopropyl)), 1.48 (d, 1 H, J = 3.2, OH),
1.33 (s, 3 H, CH3(isopropyl)); 13C NM R (75 MHz,
CDCI3): (3 = 137.44 (s, Cq(ar)), 128.25, 127.72 (d,
Ct(ar)), 114.25 (s, Cf/(isopropyl)), 78.45, 76.92 (d,
C (l), C(2)), 73.48 (t, CH2(ar)), 69.66 (d, C(3)),
67.69 (t, C(5)), 65.95 (d, C(4a)), 65.25 (s, C(4)),
26.34, 25.85 (q, 2 x CH 3(isopropyl)); MS (ei, 80
eV, 110 °C): 292 (M, 1.2%), 277 (M -C H 3 13.1%),
171 (7.7% ), 128 (9.5%), 127 (10.5%), 101 (17.5% ),
91 (100% ).
Analysis for C25H4o0 5Si (448.26)
Calcd
C 66.93 H 8.99%,
Found C 66.84 H 8.82% .
(4aR)4,4a-Anhydro-5-0-benzyl-4a-carba-l-0-
(triisopropylsilyl)-2,3-0-iso-propylidene-ß-D-
ribofuranose = (7S,2R,JR,4 R,5S)-2-benzyloxy-
methyl-7,7-dimethyl-4-triisopropylsdyloxy-6,8,9-
trioxa-tricyclo[3.3.12-3Jnonane (14)
To a solution of 12 (540 mg, 1.85 mmol) in dry
pyridine (1 ml) at 25 °C triisopropylchlorosilane
(535 mg, 2.78 m mol)
and
D M A P
(450 mg,
3.68 mmol) were added, and the mixture was
stirred for 6h. After addition of dichloromethane
(15 ml) and ice water (5 ml), the aqueous phase
was extracted with dichloromethane (3 x 25 ml),
the combined organic layers were washed with
brine (10 ml), dried (M g S 0 4), the solvent was re-
m oved in vacuo and the residue subjected to chro-
matography (silica gel, hexane/ethyl acetate 50:1
-* 10:1) to afford 14 (733 mg, 88.3%) as a colorless
oil; [aB 0 +15.9° (c, 1.0, CHC13), R F= 0.73 (hexane/
ethyl acetate 2.5:1); JH NM R (300 MHz, CDC13):
Ö = 7.25-7.35 (m, 5 H, H-C(ar)), 4.67 (d, 1 H, J =
6.6 Hz, H -C (3)), 4.65 (d, 1 H, J = 11.7 Hz, H A-
CH2(ar)), 4.51 (d, 1 H, J = 11.7 Hz, H B-CH2(ar)),
4.44 (dt, 1 H, J = 1.1, 6.4 Hz, H -C(2)), 4.30 (d, 1
H, J = 11.4 Hz, H A-C(5)), 3.61 (d, l H , i = 11.4
Hz, H B-C(5)), 3.47 (d, 1 H, J = 1.3 Hz, H-C(4a)),
I.59, 1.30 (s, 3 H, 2 x CH3(isopropyl)), 1.10 (5, 18
Analysis for C 16H 20O 5 (292.33)
Calcd
C 65.74 H 6.89% ,
Found C 65.72 H 6.94% .
(4aS)4,4a-Anhydro-5-0-benzyl-4a-carba-l-0-
(triisopropylsilyl)-2,3-0-iso-propylidene-ß-L-
lyxofuranose = (lS,2S,3S,4K,5S)-2-benzyloxy-
methy 1-7,7-dimethyl-4-triisopropylsilyloxy-6,8,9-
trioxa-tricyclo[3.3.12JJnonane (13)
To a solution of 9 (500 mg, 1.15 mmol) in dichlo-
romethane (15 ml) m-CPBA (70%, 543 mg,
2.2 mmol) was added, and the mixture was stirred
for 12 h at 25 °C. After dilution with diethyl ether
(10 ml), the mixture was washed with a saturated
aqueous solution of Na2S 0 3 (3 x 10 ml); the ethe-
real phase was washed with sodium hydrogencar-
bonate and brine (10 ml each), dried (M gS 04), the
solvent was evaporated under reduced pressure
and the residue subjected to chromatography (sil-
ica gel, hexane/ethyl acetate 50:1 —* 40:1) to afford
13 (443 mg, 86%); [a]g> -12.0° (c, 1.0 CHC13);
R f = 0.52 (hexane/ethyl acetate 10:1); JH NM R
(300 MHz, CDCI3): <3 = 7.37-7.25 (m , 5 H, H-
C(ar)), 4.66 (dd, 1 H, 7 = 1.0, 5.7 Hz, H -C (3)), 4.63
(s, 2 H, CH2(ar)), 4.50 (t, 1 H, J = 5.6 Hz, H -C(2)),
4.21 (d, 1 H, J = 5.6 Hz, H -C (l)), 4.17 (d, 1 H, J =
11.9 Hz, H a -C(5)), 3.58 (d, 1 H, J = 11.9 Hz, H B-
C(5)), 3.47 (s, 1 H, H-C(4a)), 1.46, 1.36 (s, 3 H, 2 x
H, CH3(TIPS)), 1.09
(5 , 3 H, CH(TIPS)); 13C
NM R (75 MHz, CDC13): (3 = 137.71 (s, C(?(ar)),
128.31, 127.88, 127.72 (d, Q (ar)), 113.74 (s, C ^iso-
propyl)), 78.02 (d, C (l)), 77.52 (d, C(2)), 73.58 (t,
CH2(ar)), 71.38 (d, C(3)), 68.20 (t, C(5)), 65.72 (d,
C(4a)), 63.23 (s, C (4)), 26.62, 25.79 (q, 2 x C H 3-
(isopropyl)), 18.00 (q, CH3(TIPS)), 12.38 (d,
CH(TIPS)); MS (ei, 80 eV, 113 °C): 433 (M -C H 3,
2.5% ), 405 (M -isopropyl, 9.1% ), 347 (9.4% ), 239
(6.3% ), 227 (3.2% ), 199 (4.5% ), 159 (5.5% ), 157
(2.5% ), 131 (5.3% ), 129 (3.8% ), 91 (100%).
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1076
R. Csuk et al. • 4a-Substituted Carbocyclic Cyclopentanoid Nucleoside Precursors, I
phy (silica gel, hexane/ethyl acetate 2.5:1) 16
(297 mg, 90%) was obtained; m.p. 135-136 °C;
[a]o +23.0° (c, 1.2 CHC13); R F = 0.23 (hexane/
ethyl acetate 2:1); 5H NM R (300 MHz, CDC13):
Analysis for C2 5
H oO<;Si (448.26)
4
Calcd
C 66.93 H 8.99%,
H 8.97% .
Found
C
6 6 . 8 6
d = 9.20 (s, 3 H, H -C (2’), H-C(4’), H-C( ’)), 7.27-
7.33 (m, 5 H, H-Car(Bn)), 5.24 {dd, l H , / = 1.7,
5.1, H -C (l)), 4.87-4.91 (m, 2 H, H-C(3), H-C(2)),
6
(4aS)4,4a-Anhydro-5-0-benzyl-4a-carba-2,3-0-
isopropylidene-1 -ö-(3,5-dinitrobenzoyl)-ß-L-
lyxofuranose = (lS,2S,3S,4R,5S)-2-benzyloxy-
methyl-7',7-dimethyl-6,8,9-trioxa-tncyclo[3.3.1.2'3J-
non-4-yl-3,5-dinitrobenzoate (15)
4.66 (d, 1 H, J = 11.8, H A-CH
J = 11.8, H B-CH (Bn)), 3.91 (d, 1 H, J = 11.5, H A-
C (5)), 3.83 ( , 1 H, H-C(4a)), 3.72 {d, 1 H, J = 11.5,
H b-C(5)), 1.56, 1.31 ( , 3 H, x CH (isopropyl));
13C NM R (75 MHz, CDC13): (3 = 162.07 (s, C = 0 ),
2
(Bn)), 4.55 (d, 1 H,
2
5
To a solution of 11 (100 mg, 0.34 mmol) in dry
5
2
3
pyridine
(1 ml)
3,5-dinitrobenzoylchloride
(158 mg, 0.68 mmol) was added, the mixture was
stirred at 25 °C for 30 min, poured onto ice water
(5 ml) and extracted with dichloromethane (3 x
15 ml). The combined organic phases were dried
(M gS 04), the solvent removed under reduced
pressure and residue subjected to chromatography
(silica gel, hexane/ethyl acetate 10:1) to afford 15
(146 mg, 88%) as white crystals; m.p. 128 °C; [a]o
-13.0° (c, 0.9 CHC13); R f = 0.52 (hexane/ethyl ace-
tate 2:1); XH NM R (300 MHz, CDC13): <3 = 9.23 (t,
1 H, J = 2.1, H -C(4')), 9.18 (d, 2 H, J = 2.1, H-
148.42 (s,
C
9
(3’), C<
7
(5’)j, 137.37
(
(
5
,
C ,(B n)),
’)), 128.31,
133.07 ( , C (l')), 129.58 (d, C<?(2’), C
5
9
6
127.77, 127.71 (d, Cf(Bn)), 122.43 (d, C(4’)), 114.96
, Cq(isopropyl)), 78.21 (d, C(2)), 75.98 (d, C(3)),
73.78 (d, C (l)), 73.58 (t, CH (Bn)), 67.40 (t, C(5)),
64.50 (s, C(4)), 62.51 (d, C(4a)), 26.34, 25.89 (q, 2
x CH (isopropyl)); MS (ei, 80 eV, 132 °C): 486 (M,
(
5
2
3
0.03% ), 471 (M -C H 3, 16.7%), 365 (13.2%), 195
(14.5% ), 149 (6.7% ), 111 (9.7%), 91 (100%).
Analysis for C2 3
H
2 2
N
2
O 10 (292.33)
Calcd C 56.79 H 4.56 N 5.76%,
Found C 56.68 H 4.59 N5.49% .
C(
2
’), H -C( ’)), 7.26-7.39 (m, 5 H, H-Car(Bn)),
6
5.32 (d, 1 H, J = 5.6, H -C (l)), 4.83 (dd, 1 H, J =
1.0, 5.6, H -C(3)), 4.76 (t, 1 H, J = 5.5, H -C (2)), 4.66
( ± )-7-(Benzyloxymethyl)-2,2-dimethyl-3a,7a-
dihydro[l,3]dioxolo[4,5-b]pyran-5-one (17)
(s, 2 H, CH
3.85 (s, 1 H, H -C(4a)), 3.73 (d, 1 H, J = 11.9, H B-
C(5)), 1.32, 1.27 (s, 3 H, 2 x CH (isopropyl)); 13C
NM R (75 MHz, CDC13): Ö = 161.21 (s, C = 0 ),
148.56 (s, C(?(3’), C(?(5’), 137.52 (s, C (Bn), 133.12
(s, C (l’)), 129.37 (d, Cq(T), C ’), 128.30, 127.69,
2
(Bn)), 4.26 (d, 1 H , J - 11.9, H A-C(5)),
3
A solution of ( ± ) - l (407 mg, 1.48 mmol) in di-
chloromethane (5 ml) containing m-CPBA (70%,
732 mg, 2.98 mmol) was stirred for 12 h, then the
mixture was diluted with diethyl ether ( 1 0 ml), ex-
9
9
(
6
127.59 (d, Q (B n)), 122.54 (d, C (4’)), 113.64 (s,
C(?(isopropyl)), 79.80 (d, C(2)), 79.03 (d, C(3)),
tracted with saturated aqueous solution of
a
Na S 0 (3 x 10 ml), washed with sodium hy-
2
3
73.55 (t, CH
65.83 (s, C(4)), 60.63 (d , C(4a)), 26.42, 24.81 (q, 2
x CH (isopropyl)); MS (ei, 80 eV, 178 °C): 487
2
(Bn)), 72.38 (d , C (l)), 68.43 (t, C(5)),
drogencarbonate and brine ( 1 0 ml each), dried
(M gS 04), the solvent was evaporated and the resi-
due purified by chromatography (silica gel, hex-
ane/ethyl acetate 10:1) to afford 17 (301 mg,
70.0%); m.p. 5 0 -5 1 °C; R f = 0.44 (hexane/ethyl
acetate 2.5:1); JH NM R (300 MHz, CDC13): (3 -
7.37-7.30 (m, 5 H, H-C(ar)), 6.24 (t, 1 H, / = 1.9
3
(M +l, 1.2%), 486 (M, 5.0% ), 471 (M -C H 3,
15.2%), 365 (8.0% ), 265 (3.1% ), 195 (59.1% ), 149
(15.6% ), 111 (16.8% ), 110 (21.3% ), 91 (100% ).
Analysis for C2 3
H
2 2
N
2
O 10 (292.33)
Hz, H -C (
4.61 (s, 2 H, CH
C(3a)), 4.30 (dd, 1 H, J
6
)), 5.90 (d, 1 H, J = 3.7 Hz, H-C(7a)),
(ar)), 4.42 (d, 1 H, J = 3.9 Hz, H-
1.9, 15.9 Hz, H A-
(O B n)), 4.25 (dd, 1 H, J = 1.9, 15.9 Hz, H B-
(O Bn)), 1.50, 1.44 (s, H, 2 x CH 3); 13C NM R
Calcd C 56.79 H 4.56 N 5.76% ,
Found C 56.75 H 4.59 N 5.57%.
2
=
CH
CH
2
(4aR)4,4a-Anhydro-5-0-benzyl-4a-carba-2,3-0-
isopropylidene-1 -0-(3,5-dinitrobenzoyl)-d-D-
ribofuranose - (lS,2R,3S,4R,5S)-2-benzyloxy-
methyl-7\7-dimethyl-6,8,9-trioxa-tricyclo[3.3.1.2’?/-
non-4-yl-3,5-dinitrobenzoate (16)
2
3
(75 MHz, CDC13): <3 = 160.57 (s, C(5)), 149.89 (s,
C (7)), 139.91 (s, C ,(ar)), 128.35, 127.87, 127.55 (d,
Cf(ar)), 117.72 (d , C(
C(3a)), 73.08 (t, CH
6 8 . 6 8 (d, C(7a)), 27.64, 26.20 (q, 2 x CH
6
)), 113.09 (s, C(2)), 99.26, (d,
(ar)), 69.17 (t, CH (O Bn)),
); MS (ei,
2
2
To a solution of 12 (200 mg, 0.68 mmol) in dry
3
80 eV, 65 °C): 290 (M, 0.1%), 275 (M -C H 3, 3.8%),
247 (M -isopropyl, 0.3%), 233 (13.7%), 187
(1.5% ), 184 (2.4% ), 159 (3.9% ), 126 (95.9%), 107
(53.1% ), 97 (37.4% ), 91 (100%).
pyridine
(1 ml)
3,5-dinitrobenzoylchloride
(315 mg, 1.37 mmol) was added, the mixture was
stirred at 25 °C for 30 min. Work up was per-
formed as described for 15 and after chromatogra-
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1077
R. Csuk et al. • 4a-Substituted Carbocyclic Cyclopentanoid Nucleoside Precursors, I
Analysis for C 1 6
H
1 8
0
5
(290.32)
1 H, J = 11.8 Hz, H B-CH
2
(O B n)), 3.65 (d, 1 H, J =
Calcd C 66.20 H 6.25% ,
Found C 66.13 H 6.20% .
1.4 Hz, H -C(3)), 1.61, 1.29 (s, 3 H,
NM R (75 MHz, CDC13): <5 = 151.83 (d, C (2’)),
151.33 (s, C( ')), 151.05 (s, C (4’)), 144.35 (d,
C( ’)), 137.41 (s, Cg(Bn)), 131.78 (s, C (5’)), 128.21,
127.66, 127.60, 127.59 (d, C,(Bn)), 113.96 (j, C(7)),
86.81 (d, C(5)), 79.69 (d, C (l)), 73.30 (t, CH (Bn)),
69.57 (s, C(2)), 66.76 (t, CH (O Bn)), 63.25 (d,
2
x CH ,)); 13C
6
8
(lS,2R,3R,4R,5S)-4-(6-Chloro-9H-purin-9-yl)-2-
benzyloxymethyl-7,7-dimethyl-6,8,9-trioxa-tricyclo
[3.3.12JJnonane (19)
2
2
To a solution of triphenylphosphine (430 mg,
C(3)), 59.30 (d , C(4)), 26.17, 25.36 (q, 2 x CH 3);
MS (ei, 80 eV, 191 °C): 430 (M+2, 0.5% ), 429
(M + l, 0.3% ), 428 (M, 1.7%), 415 (7.2% ), 414
(4.8% ), 413 (M -CH 3, 20.1% ), 324 (2.5% ) 322
(7.3% ), 307 (3.6% ), 264 (10.2% ), 249 (3.3% ), 237
(3.5% ), 235 (4.9% ), 209 (5.3% ), 207 (13.5% ), 199
(3.2% ), 197 (10.3% ), 157 (10.2% ), 155 (30.2% ),
1.64 m m ol)
1.64 m m ol) in abs. THF (12 ml) at 25 °C a solution
of diethyl azodicarboxylate (0.27 ml, 95%,
and
6
-chloropurine
(262 mg,
1.64 m m ol) in abs. THF was slowly added, and the
mixture was stirred for 1 h. Then a solution of 12
(400 mg, 1.37 mmol) in abs. THF (5 ml) was
added, stirred for 3 days, the solvents were re-
moved under reduced pressure and the residue
subjected to chromatography (silica gel, hexane/
ethyl acetate 3:1) to afford 19 (364 mg, 62%) as
viscous oil; [a]^ -4.2°; R F = 0.25 (hexane/ethyl
acetate 1:1); ’H NM R (300 MHz, CDC13): (3 = 8.62
153 (
6
.8 %), 126 (17.9% ), 110 (12.1% ), 91 (100%);
HRM S calcd. for:
found: 428.1252.
C
2 1
H
2 1
N
4
O4 CI: 428.1251;
Acknowledgements
Financial support by the European Communi-
ties (SC I*-CT92-0780) and the Fonds der Chem-
ischen Industrie is gratefully acknowledged; we
are indebted to Dr. P. Rosyk for his help with the
manuscript and to Professor Dr. R. Neidlein,
Pharmazeutisch-Chemisches Institut, Universität
Heidelberg, for his encouragement.
(5, 1 H, H -C (2’)), 8.19 (5, 1 H, H-C( ’)), 7.28-7.33
8
(m, 5 H, H -Car(Bn)), 5.32 (d , 1 H, / = 7.0 Hz, H-
C (l)), 5.09 (s, 1 H, H -C(4)), 4.80 (d , 1 H, J = 7.0
Hz, H -C (5)), 4.66 (d, 1 H, J = 11.8 Hz, H A-
CH
2
(B n)), 4.60 (d, 1 H, J = 11.8 Hz, H B-CH
2
(Bn)),
4.02 (d, 1 H, J = 11.8 Hz, H A-CH
2
(O Bn)), 3.92 (d,
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