Stereoselective hydrogenation and ozonolysis of iridoids. Conversion into carbocyclic nucleoside analogues

Article abstract of DOI:10.1021/np990288+

Stereoselective hydrogenation of the iridoids geniposide (9) and aucubin (19) was achieved by using the 1-methyl-1- methoxyethyl ether as a protecting group for the allylic alcohol, as it enhanced the stereoselectivity and prevented undesired hydrogenolysis. Ozonolysis of the hydrogenation product from 9, adoxoside (11), with reductive workup, afforded either a chiral lactone (25) or a chiral polyol (26), depending on the reduction conditions. Polyol 26 was subjected to protecting-group manipulation and subsequent oxidation and reductions to yield cyclopentane building blocks (29-34), which, by Mitsunobu couplings with purines, afforded carbocyclic nucleoside analogues (7, 8, and 35).

Full text of DOI:10.1021/np990288+

1646
J . Nat. Prod. 1999, 62, 1646-1654
Ster eoselective Hyd r ogen a tion a n d Ozon olysis of Ir id oid s. Con ver sion in to
Ca r bocyclic Nu cleosid e An a logu es
Henrik Franzyk*,† and Frank R. Stermitz‡
Department of Organic Chemistry, The Technical University of Denmark, Building 201, DK-2800, Lyngby, Denmark, and
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received J une 11, 1999
Stereoselective hydrogenation of the iridoids geniposide (9) and aucubin (19) was achieved by using the
1-methyl-1-methoxyethyl ether as a protecting group for the allylic alcohol, as it enhanced the
stereoselectivity and prevented undesired hydrogenolysis. Ozonolysis of the hydrogenation product from
9, adoxoside (11), with reductive workup, afforded either a chiral lactone (25) or a chiral polyol (26),
depending on the reduction conditions. Polyol 26 was subjected to protecting-group manipulation and
subsequent oxidation and reductions to yield cyclopentane building blocks (29-34), which, by Mitsunobu
couplings with purines, afforded carbocyclic nucleoside analogues (7, 8, and 35).
The iridoids aucubin (19), catalpol, and asperuloside
have previously been used synthetically as precursors of
cyclopentanoids such as prostaglandins,1-3 methyl jas-
monate,4 and triquinanes.5 Also, the aglucone of geniposide
(9), genipin, has been the starting material in semisyn-
theses of diterpenes from marine algae.6-8 In addition,
iridoid aglucones have been converted into pyridine monot-
erpene alkaloids9 and monoterpene piperidines.10 Although
â-glucosidase is often used for sugar removal, simple acid-
catalyzed hydrolysis of the glucoside bond or oxidative
degradation11 of the sugar moiety may also be employed
to obtain iridoid aglucones. Recently it was demonstrated
that ozonolytic cleavage (with reductive workup) of the enol
ether bond in protected iridoids lacking C-11 gives con-
comitant loss of the sugar moiety to produce partially
protected cyclopentane derivatives.12 In the present work,
we extend this method to the 4-carboxymethyl-substituted
iridoid, adoxoside (11; derived from 9), to obtain poly-
hydroxylated cyclopentane building blocks suitable for the
conversion into carbocyclic nucleosides. So far, only two
such interconversions have been reported.13,14 A number
of hydroxymethyl-substituted nucleosides (e.g., compounds
1-4, listed by Mansour and Storer15), exhibit a variety of
antiviral activities, while compounds 516 and 617 are
inactive against HIV. Hence, the objective was to prepare
the novel carbocyclic homo-N-nucleoside analogues 7 and
8, which seem structurally related to the active compounds
2-4.
Resu lts a n d Discu ssion
Selective Hyd r ogen a tion s. To avoid a competing
ozonolytic cleavage of both double bonds in geniposide (9),
the first step was to hydrogenate the 7,8-double bond
selectively to obtain adoxoside (11). However, this did not
prove to be straightforward. Hydrogenation of olefin 9 with
Pt as a catalyst gave 8-epiadoxoside (10) and adoxoside (11)
in a 5:1 ratio.18 Conversely, our initial hydrogenation of
olefin 9 in the presence of Pd/C in ethanolic triethylamine
afforded almost equal amounts of the epimers 10 and 11
in addition to hydrogenolysis products, as earlier re-
ported.19 In recent synthetic work on iridoids,10,12 ac-
etonides were found to be convenient protecting groups for
polyfunctional iridoids. In the present study, iridoid glu-
cosides having allylic alcohol groups proved prone to
forming stable 1-methyl-1-methoxyethyl ethers (also re-
ferred to as methoxyisopropylidene: MIP) at these posi-
tions. Thus, the MIP group was tried as an inexpensive,
easily introduced, and readily removed protecting group
for glucoside 9 during its hydrogenation. Treatment of 9
with excess 2,2-dimethoxypropane (DMP) in dry acetone,
with pyridinium p-toluenesulfonate (PPTS) as catalyst,
afforded five isolable products, namely acetonides 12-16,
of which 13, 14, and 16 carried a MIP group on the primary
allylic alcohol (See Scheme 1).
To improve the yield of acetonides 14 and 16 (63% and
3%, respectively), more forcing conditions involving sub-
sequent heating of the (above) reaction mixture with
2-methoxypropene were attempted. In this case, acetonides
12 and 13 were separated and subjected to repeated
acetonation under mild conditions. This procedure resulted
* To whom correspondence should be addressed. Tel.: 45 4525 2111.
Fax: 45 4593 3968. E-mail: okhf@pop.dtu.dk.
† Technical University of Denmark.
‡ Colorado State University.
10.1021/np990288+ CCC: $18.00
© 1999 American Chemical Society and American Society of Pharmacognosy
Published on Web 11/04/1999

Carbocyclic Nucleoside Analogues
J ournal of Natural Products, 1999, Vol. 62, No. 12 1647
Sch em e 2. Ozonolysis of Adoxoside (11)
Sch em e 1. Hydrogenation of Allylic MIP Ethers
amine in ethanol proceeded almost exclusively (>98%),
with addition of hydrogen to the more hindered concave
side, but hydrogenation of the 3,4-enol ether was also a
significant side-reaction. Separation of the 7,8-dihydro and
3,4,7,8-tetrahydro compounds was difficult, but was also
unnecessary because the mixture (after deprotection to 11
and 17) could be used in the subsequent ozonolysis.
The utility of the MIP protecting group during hydro-
genation using Pd/C was studied further on a mixture of
aucubin acetonides 21/22. Again, the approach of hydrogen
took place at the more hindered concave face to give
acetonide 24 in high yield (90%; the only isolable product)
after the facile and selective removal of the MIP groups.
Thus, the present protection scheme was shown to be
superior to alternate analogous hydrogenations.21,22 To rule
out that the above-observed selectivity was due to a steric
effect exerted by the protected sugar moiety, both Pt- and
Pd/C-catalyzed hydrogenations were performed on olefin
20. As expected, the 8R-epimer 23 was predominant when
Pt was used (R:â ratio 10:1), while Pd/C catalysis in this
case only afforded an R:â ratio of 1:3 (i.e., between 23 and
24). The 13C NMR signals for C-9 and C-10 were more
lowfield in 8â-epimer 24 as compared to 8R-epimer 23, in
accordance with data for related iridoid epimers.23
The induction of high stereoselectivity with MIP as
protecting group has also been observed in a hydroxyalky-
lation24 and in a carbanion addition to a ketone.25 The MIP
group has been used as a protecting group during hydro-
boration.26 Its simultaneous use as a protecting group (to
avoid hydrogenolysis) and as an aid to enhance stereo-
selectivity during hydrogenation is, to our knowledge,
unprecedented.
Ozon olysis of a n Un p r otected Ir id oid . Next, we
examined the ozonolysis of unprotected adoxoside (11) and
the subsequent in situ reduction of the ozonolysis product.
This proceeded through several less polar intermediates
toward a very polar end-product. At first, the sodium
borohydride reduction was stopped when an intermediate
of moderate polarity prevailed in the product mixture. This
compound was an aglucone-derived C9-lactone (25), the
in 68% and 27% overall yields of 10-MIP acetonides 14 and
16, respectively. The sequence of protection appeared to
involve an initial introduction of a MIP group on the
primary 6′-position20 in the glucose moiety, followed by
rapid cyclization to the 4′,6′-acetonide (i.e., to give 12), and
then protection of the allylic 10-position to give 14. The
five-membered trans-2′,3′-acetonides (e.g., 16) formed only
when forcing conditions were applied. Hydrogenation of
acetonides 14 and 16 in the presence of Pd/C and triethyl-

1648 J ournal of Natural Products, 1999, Vol. 62, No. 12
Franzyk and Stermitz
Sch em e 3. Preparation of Building Blocks
structure of which (except for the orientation of the 4-OH
group) was evident from its NMR spectra. Comparison with
1
the H NMR data of the two 4-epimers (()-iridomyrmecin
(27; J 1a,1b ) 11.8 Hz, J 1a,9 ) 2.6 Hz, J 1b,9 ≈ 0)27 and (()-
isoiridomyrmecin (28; J 1a,1b ) 11.0 Hz, J 1a,9 ) 6.3 Hz, J 1b,9
) 11.0 Hz)28 indicated the 4-OH to be R-positioned in
lactone 25 (J 1a,1b ) 12 Hz, J 1a,9 ) 4 Hz, J 1b,9 ≈ 0). Final
structural proof for 25 was obtained by an X-ray structure
determination. Tetrol 26 was then obtained in good yield
after a slightly longer reduction period for the ozonolysis
mixture, and by the direct reduction of lactone 25 (See
Scheme 2).
Con ver sion in to Car bocyclic Nu cleoside An alogu es.
To distinguish between the three primary hydroxyl groups,
the vicinal 3,4-diol system was protected as an acetonide
(i.e., to give 29; 79% yield). Subsequent benzylation29 and
acetonide deprotection afforded the crystalline 30. Oxida-
tive cleavage of the 3,4-diol system in 30 was accomplished
with periodic acid to yield an aldehyde, which was reduced
directly to the corresponding alcohol. With sodium boro-
hydride in methanol at room temperature, extensive
epimerization was observed. A change of solvent to dichlo-
romethane-ethanol and a lowering of the reaction tem-
perature resulted in an excellent yield (92.5%) of pure
epimer 31. Next, a deliberate epimerization of the inter-
mediate aldehyde was attempted, and potassium carbonate
in methanol or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
dichloromethane were found to work equally well. Subse-
quent sodium borohydride reduction (one-pot) of the above
methanolic reaction mixture gave the epimeric benzyl-
protected alcohol 32 in 94% yield. In a similar way, the
unepimerized benzoate-protected alcohol 34 was obtained
in an overall yield of 68% from acetonide 29 (See Scheme
3).
Then, a Mitsunobu coupling on acetonide 29 was per-
formed to prepare a homo-N-nucleoside analogue, we
hoped, with the nucleobase attached to the least-hindered
carbon (i.e., C-10). However, the use of two equivalents of
triphenylphosphine, diethyl azodicarboxylate (DEAD), and
6-chloropurine surprisingly gave a protected bisnucleoside
as the predominant product, but in low yield (ca. 40%).
Increasing the amounts of reagents to four equivalents
improved the yield to ca. 70%. Successive ammonolysis and
deprotection with aqueous acid afforded bisnucleoside
analogue 35. Mitsunobu coupling of 6-chloropurine to
alcohol 34 yielded only the expected product, which, after
ammonolysis, gave nucleoside analogue 8. By contrast, both
a Mitsunobu coupling of 31 with 6-chloropurine and an
attempted preparation of the corresponding triflate re-
sulted in formation of tetrahydrofuran 37 as the main
product. Anchimeric assistance of an appropriately situated
benzyloxy group has previously been observed in displace-
ments of tosylates, mesylates, and triflates, and occasion-
ally in Mitsunobu reactions.30-32 Mitsunobu coupling of
adenine and alcohol 32 afforded benzylated analogue 38,
and subsequent debenzylation with borontrichloride yielded
nucleoside analogue 7 (See Scheme 4.)
analogues prepared here have been tested in HIV and
HSV-1 assays, but they did not exhibit significant antiviral
or cytotoxic activities.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. PPTS was pur-
chased from Aldrich Chemical Co.; DMP, BnBr, adenine, and
6-chloropurine were from Fluka Chemie AG; and Ph3P was
from Merck. Geniposide (9) was a gift from Glico Foods
Corporation. Acetone was distilled and then stirred with CaCl2,
filtered, and stored over 3 Å molecular sieves. THF and
dioxane were freshly distilled from Na. All concentrations were
performed in vacuo. Elemental analyses were performed by
Microanalytical Laboratory, Institute of Physical Chemistry,
Vienna, by Desert Analytics, Tucson, Arizona or by the
Microanalytical Department at the H. C. Ørsted Institute
(University of Copenhagen). Optical rotations were measured
These studies provide additional examples of the useful-
ness of iridoids as chiral synthons. We have shown that
the MIP group serves as an excellent inducer of stereo-
selectivity in hydrogenations of certain allylic alcohols.
Also, an unprotected iridoid (i.e., 11) was ozonolyzed and
subsequently reduced stereoselectively into either a chiral
lactone (25) or a polyol building block (26). These types of
lactones are synthetic precursors of iridoid lactones of the
iridomyrmecin type (e.g., 27 and 28),33 thus establishing a
formal synthesis of substituted analogues. The nucleoside
on
a Perkin-Elmer 241 polarimeter. Melting points are
uncorrected. TLC was performed on Merck Si gel 60 F254
aluminum sheets with detection by charring with H2SO4, or
by UV light when applicable. MPLC was performed on Merck
Lobar Lichroprep RP18 columns. Vacuum-liquid chromatog-
raphy (VLC) was performed on predried (120 °C; >24 h) Merck
Si gel 60H; the column size is given as height × diameter (cm).

Carbocyclic Nucleoside Analogues
J ournal of Natural Products, 1999, Vol. 62, No. 12 1649
Sch em e 4. Preparation of Nucleoside Analogues
4′,6′-O-Isop r op ylid en e-gen ip osid e (12): white hygro-
1
scopic foam, [R]25 -13° (c 1.1, MeOH); H NMR (methanol-
D
d4, 500 MHz) δ 7.51 (1H, d, J 3,5 ) 1 Hz, H-3), 5.80 (1H, br s,
H-7), 5.01 (1H, d, J 1,9 ) 8 Hz, H-1), 4.28 (1H, br d, J a,b ) 14
Hz, H-10a), 4.17 (1H, br d, J a,b ) 14 Hz, H-10b), 3.71 (3H, s,
11-MeO), 3.18 (1H, q-like, J ) 8.5 Hz, H-5), 2.83 (1H, br dd,
J a,b ) 16 Hz, J 5,6a ) 8.5 Hz, H-6a), 2.70 (1H, t, J 1,9 ) J 5,9 ) 8
Hz, H-9), 2.06 (1H, br dd, J a,b ) 16 Hz, J 5,6b ) 8 Hz, H-6b);
sugar signals essentially as for 14; 13C NMR (methanol-d4, 125
MHz) δ 169.4, 153.2, 144.8, 128.5, 112.6, 98.6, 61.4, 51.8, 46.8,
39.8, 36.7; sugar moiety 101.1, 100.8, 75.7, 74.8, 74.7, 68.8,
63.1, 29.4, 19.3; anal. C 55.90%, H 6.37%, calcd for C20H28O10
,
C 56.06%, H 6.60%.
10,6′-Di-O-(1-m eth oxy-1-m eth yleth yl)-gen ip osid e (13):
white foam, [R]25 +22° (c 0.7, MeOH); 1H NMR (methanol-
D
d4, 500 MHz) δ 7.54 (1H, d, J 3,5 ) 1 Hz, H-3), 5.76 (1H, br s,
H-7), 5.07 (1H, d, J 1,9 ) 8 Hz, H-1), 4.12 (1H, br d, J a,b ) 13.5
Hz, H-10a), 4.08 (1H, br d, J a,b ) 13.5 Hz, H-10b), 3.72 (3H, s,
11-MeO), 3.17 (1H, q-like, J ) 8 Hz, H-5), 2.83 (1H, br dd, J a,b
) 16.5 Hz, J 5,6a ) 8.5 Hz, H-6a), 2.67 (1H, t, J 1,9 ) J 5,9 ) 8 Hz,
H-9), 2.00 (1H, br dd, J a,b ) 16.5 Hz, J 5,6b ) 9 Hz, H-6b), 3.22,
1.35, 1.34 (each 3H, s, 10-[Me2C(OMe)]), 4.70 (1H, d, J 1′,2′ ) 8
Hz, H-1′), 3.73 (1H, obsc., H-6a′), 3.49 (1H, dd, J a,b ) 10.5 Hz,
J 5′,6b′ ) 6.5 Hz, H-6b′), 3.37 (1H, t, J 2′,3′ ) J 3′,4′ ) 9.5 Hz, H-3′),
3.36 (1H, obsc., H-5′), 3.26 (1H, t, J 3′,4′ ) J 4′,5′ ) 9.5 Hz, H-4′),
3.25 (1H, br t, J ) 9 Hz, H-2′), 1.31, 1.30 (each 3H, s, 4′,6′-
Me2C); 13C NMR (methanol-d4, 500 MHz) δ 169.5, 153.4, 142.7,
129.0, 112.4, 101.3, 98.5, 60.6, 51.7, 49.1, 46.8, 39.9, 37.0, 24.8;
sugar moiety 101.4, 100.3, 78.1, 76.9, 74.9, 71.8, 61.8, 48.8,
24.7; anal. C 56.37%, H 7.54%, calcd for C25H40O12, C 56.37%,
H 7.58%.
4′,6′-O-Isopr opyliden e-10-O-(1-m eth yl-1-m eth oxyeth yl)-
1
gen ip osid e (14): white foam, [R]23 +2.6° (c 1.2, MeOH); H
D
NMR (methanol-d4, 500 MHz) δ 7.51 (1H, d, J 3,5 ) 1 Hz, H-3),
5.82 (1H, br s, H-7), 5.03 (1H, d, J 1,9 ) 8 Hz, H-1), 4.17 (1H,
br d, J a,b ) 13.5 Hz, H-10a), 4.05 (1H, br d, J a,b ) 13.5 Hz,
H-10b), 3.71 (3H, s, 11-MeO), 3.18 (1H, q-like, J ) 8 Hz, H-5),
2.82 (1H, br dd, J a,b ) 16.5 Hz, J 5,6a ) 8.5 Hz, H-6a), 2.70 (1H,
t, J 1,9 ) J 5,9 ) 8 Hz, H-9), 2.06 (1H, br dd, J a,b ) 16.5 Hz, J 5,6b
) 8 Hz, H-6b), 3.21, 1.36, 1.35 (each 3H, s, 10-[Me2C(OMe)]),
4.78 (1H, d, J 1′,2′ ) 8 Hz, H-1′), 3.85 (1H, dd, J a,b ) 10.5 Hz,
J 5′,6a′ ) 5.5 Hz, H-6a′), 3.74 (1H, t, J a,b ) J 5′,6b′ ) 10.5 Hz, H-6b′),
3.53-3.47 (2H, m, H-3′ and H-4′), 3.33-3.25 (2H, m, H-2′ and
H-5′), 1.50, 1.36 (each 3H, s, 4′,6′-Me2C); 13C NMR (methanol-
d4, 125 MHz) δ 169.4, 153.2, 142.4, 129.1, 112.6, 101.6, 98.8,
60.5, 51.8, 49.1, 47.1, 39.8, 36.6, 24.8; sugar signals 101.3,
100.8, 75.7, 74.9, 74.7, 68.7, 63.1, 29.4, 19.3; anal. C 57.41%,
H 7.60%, calcd for C24H36O11, C 57.58%, H 7.26%.
NMR spectra were recorded on Bruker AM-500 or AC-300P
and Varian Inova 500 or Mercury 300 spectrometers. Chemical
shifts are given in parts per million (ppm) using the solvent
peaks as internal standards (CDCl3: δH ) 7.27, δC ) 77.0,
methanol-d4: δH ) 3.31, δC ) 49.0, DMSO-d6: δH ) 2.50, δC
) 39.5). Coupling constants are given in Hertz. For all
compounds 1H NMR signals were assigned by homonuclear
decoupling experiments or by COSY, while 13C NMR signals
were assigned from HETCOR spectra or HSQC spectra. In the
NMR spectra a prime (′) denotes sugar positions in the
glucosides, while (′) and (′′) denote the purine moieties in the
nucleoside analogues. Carbocyclic nucleoside analogues were
tested against HIV and HSV-1 virus at the Department of
Virology, The Danish Serum Institute, Copenhagen.34,35
Gen ip osid e Aceton id es 12-16. Geniposide (9, 10.0 g) and
PPTS (1.0 g) were suspended in dry Me2CO-DMP (1:1, 200
mL), and the mixture was stirred at room temperature for 12
h, when more DMP (50 mL) was added. After an additional
24 h, Et3N (2 mL) was added and the mixture concentrated.
The residue was purified on a VLC column (5.5 × 8.5 cm).
Elution with hexanes-Me2CO (10:1 to 1.5:1) yielded, succes-
sively, acetonides 16 (0.45 g, 3%), 15 (0.17 g, >95% purity,
1.4%), 14 (8.08 g, 63%), and a mixture of 12 and 13 (2.82 g,
26%). The last fraction was further purified by VLC eluting
with hexanes-Me2CO (3:1 to 1.8:1) to give 13 (0.35 g, >95%
purity), 12 (1.72 g, >95% purity), and pure 12 (0.74 g).
Similarly, analytical samples of 13 and 15 were obtained by
repeated VLC.
2′,3′:4′,6′-Di-O-isop r op ylid en e-gen ip osid e (15): white
1
foam, [R]25 -18° (c 0.8, MeOH); H NMR (methanol-d4, 500
D
MHz) δ 7.52 (1H, d, J 3,5 ) 1 Hz, H-3), 5.81 (1H, br s, H-7),
5.06 (1H, d, J 1,9 ) 7.5 Hz, H-1), 4.26 (1H, br d, J a,b ) 14 Hz,
H-10a), 4.17 (1H, br d, J a,b ) 14 Hz, H-10b), 3.72 (3H, s, 11-
MeO), 3.19 (1H, q-like, J ) 8.5 Hz, H-5), 2.84 (1H, br dd, J a,b
) 16.5 Hz, J 5,6a ) 8.5 Hz, H-6a), 2.70 (1H, t, J 1,9 ) J 5,9 ) 8 Hz,
H-9), 2.07 (1H, br dd, J a,b ) 16.5 Hz, J 5,6b ) 8 Hz, H-6b), sugar
signals essentially as for 16; 13C NMR (methanol-d4, 125 MHz)
δ 169.3, 153.0, 144.7, 128.6, 112.6, 98.6, 61.3, 51.8, 46.8, 39.7,
36.7; sugar signals 112.9, 100.8, 99.6, 78.9, 73.8, 71.2, 63.1,
29.3, 26.9, 26.6, 19.5; anal. C 58.95%, H 7.09%, calcd for
C
23H32O10, C 58.95%, H 6.90%.
2′,3′:4′,6′-Di-O-isop r op ylid en e-10-O-(1-m eth yl-1-m eth -
oxyeth yl)-gen ip osid e (16): white foam, [R]25 -2.8° (c 0.9,
D
1
MeOH); H NMR (methanol-d4, 500 MHz) δ 7.52 (1H, d, J 3,5
) 1 Hz, H-3), 5.83 (1H, br s, H-7), 5.05 (1H, d, J 1,9 ) 8 Hz,
H-1), 4.13 (1H, br d, J a,b ) 13 Hz, H-10a), 4.07 (1H, br d, J a,b
) 13 Hz, H-10b), 3.72 (3H, s, 11-MeO), 3.18 (1H, q-like, J )
8.5 Hz, H-5), 2.83 (1H, br dd, J a,b ) 16 Hz, J 5,6a ) 9 Hz, H-6a),
2.69 (1H, t, J 1,9 ) J 5,9 ) 8 Hz, H-9), 2.06 (1H, br dd, J a,b ) 16
Hz, J 5,6b ) 8.5 Hz, H-6b), 3.22, 1.36, 1.35 (each 3H, s, 10-[Me2C-
(OMe)]), 5.22 (1H, d, J 1′,2′ ) 8 Hz, H-1′), 3.95 (1H, t, J 3′,4′
J 4′,5′ ) 9 Hz, H-4′), 3.88 (2H, m, 2 × H-6′), 3.72 (1H, t, J 2′,3′
)
)
J 3′,4′ ) 9 Hz, H-3′), 3.42 (1H, dd, J 2′,3′ ) 9 Hz, J 1′,2′ ) 8 Hz,
H-2′), 3.34 (1H, m, H-5′), 1.53, 1.36 (each 3H, s, 4′,6′-Me2C),
1.45, 1.44 (each 3H, s, 2′,3′-Me2C); 13C NMR (methanol-d4, 125

1650 J ournal of Natural Products, 1999, Vol. 62, No. 12
Franzyk and Stermitz
MHz) δ 169.3, 153.0, 142.3, 129.7, 112.7, 101.5, 98.5, 60.5, 51.8,
49.2, 46.9, 39.8, 36.7, 24.9, 24.8; sugar moiety 113.0, 100.8,
99.4, 78.9, 73.9, 71.2, 63.2, 29.4, 26.9, 26.7, 19.5; anal. C
60.14%, H 7.67%, calcd for C27H40O11, C 59.98%, H 7.47%.
Alter n a te P r ep a r a tion of Gen ip osid e Aceton id es 14
a n d 16. Geniposide (9, 12.0 g) and PPTS (1.5 g) in dry Me2-
CO-DMP (1:1, 300 mL) was kept for 14 h at room temperature
followed by 1.5 h at 50 °C, when more DMP (50 mL) and PPTS
(1.0 g) were added. After a further 3 h at 50 °C, followed by
12 h at room temperature, 2-methoxypropene (9 mL) was
added in three portions over the next 6 h. Then the mixture
was heated to 50 °C for 1.5 h, when Et3N (10 mL) was added.
Concentration gave a residue that was purified by VLC as
above to give 16 (3.62 g, 22%) and 14 (8.51 g, 55%). Fractions
of 12 and 13 were combined (4.00 g) and then dissolved in dry
Me2CO-DMP (1:1.25, 125 mL) with PPTS (0.50 g) added. After
the mixture was stirred at room temperature for 45 h and
subsequently at 50 °C for 1 h, Et3N (2.5 mL) was added, and
the mixture was concentrated. The residue was purified by
VLC to give additional amounts of 16 (0.91 g, 5%) and 14 (2.01
g, 13%).
Ad oxosid e (11) fr om Aceton id e 14. Acetonide 14 (13.3
g) in EtOH (150 mL) and Et3N (15 mL) was hydrogenated for
4.5 h in the presence of 5% Pd/C (0.75 g). The catalyst was
filtered off on activated charcoal over Celite, and the cake was
eluted further with EtOAc (500 mL). The filtrates were
concentrated and the residue heated to 45-50 °C in 5%
aqueous HOAc for 3 h. The solvent was removed and the
residue purified by MPLC. Elution with H2O-MeOH (2:1)
yielded 11 (7.13 g, 69%).36
signals essentially as for 21; anal. C 55.56%, H 6.75%, calcd
for C18H26O9, C 55.94%, H 6.80%.
4′,6′-O-Isopr opyliden e-10-O-(1-m eth yl-1-m eth oxyeth yl)-
1
a u cu bin (21): H NMR (methanol-d4, 500 MHz) δ 6.32 (1H,
dd, J 3,4 ) 6 Hz, J 3,5 ) 2 Hz, H-3), 5.78 (1H, m, H-7), 5.11 (1H,
dd, J 3,4 ) 6 Hz, J 4,5 ) 4 Hz, H-4), 4.81 (1H, d, J 1,9 ) 8 Hz,
H-1), 4.41 (1H, ddt, J ) 5.5, 4, 2 × 2 Hz, H-6), 4.23 (1H, br d,
J a,b ) 14.5 Hz, H-10a), 3.99 (1H, br d, J a,b ) 14.5 Hz, H-10b),
2.86 (1H, t, J ) 8 Hz, H-9), 2.64 (1H, dddd, J ) 7.5, 5.5, 4, 2
Hz, H-5), 3.21, 1.36, 1.35 (each 3H, s, 10-[Me2C(OMe)]), 4.74
(1H, d, J 1′,2′ ) 8 Hz, H-1′), 3.86 (1H, dd, J a,b ) 10.5 Hz, J 5′,6a′
) 5.5 Hz, H-6a′), 3.74 (1H, t, J a,b ) J 5′,6b′ ) 10.5 Hz, H-6b′),
3.53-3.46 (2H, H-3′ and H-4′), 3.32-3.24 (2 H, H-2′ and H-5′),
1.49, 1.38 (each 3H, s, 4′,6′-Me2C); 13C NMR (methanol-d4, 125
MHz) δ 145.5, 141.5, 130.9, 105.8, 101.6, 98.2, 82.9, 60.4, 49.1,
48.2, 46.3, 24.8, 24.7; sugar moiety 100.8 (2 C), 75.8, 74.9, 74.8,
68.6, 63.1, 29.4, 19.2.
4′,6′-O-Isop r op ylid en e-6-O-(1-m eth yl-1-m eth oxyeth yl)-
1
a u cu bin (22): H NMR (methanol-d4, 500 MHz) δ 6.31 (1H,
dd, J 3,4 ) 6 Hz, J 3,5 ) 2 Hz, H-3), 5.77 (1H, m, H-7), 5.06 (1H,
dd, J 3,4 ) 6.5 Hz, J 4,5 ) 4 Hz, H-4), 4.86 (1H, d, J 1,9 ) 8 Hz,
H-1), 4.49 (1H, ddt, J ) 5.5, 4, 2 × 2 Hz, H-6), 4.30 (1H, br d,
J a,b ) 15.5 Hz, H-10a), 4.15 (1H, br d, J a,b ) 15.5 Hz, H-10b),
2.89 (1H, m, H-9), 2.73 (1H, m, H-5), 3.25, 1.36, 1.35 (each
3H, s, 6-[Me2C(OMe)]), sugar signals as for 21; 13C NMR
(methanol-d4, 125 MHz) δ 148.1, 141.5, 129.7, 105.7, 101.6,
97.7, 82.1, 61.4, 49.1, 47.5, 44.4, 25.7, 25.6; remaining signals
as for 21; acetonides 21/22: white foam, [R]21 -99° (c 0.2,
D
MeOH); anal. C 57.38%, H 7.51%, calcd for C22H34O10, C
57.63%, H 7.47%.
Ad oxosid e (11) fr om Aceton id e 16. Compound 16 (4.77
g) was hydrogenated as above for 24 h to give a crude product
(4.60 g), which was deprotected as above for 3 h to give a crude
5:1 mixture of adoxoside (11) and the 3,4-dihydro compound
17 (3.45 g), which was used directly for ozonolysis (see below).
10-Cin n a m oyla u cu bin (18, Isoscr op h u la r iosid e). Fresh
aerial parts of Penstemon teucrioides (1.5 kg)37 were homog-
enized with 95% EtOH (6.5 L). After filtration, the cake was
eluted with MeOH (3.0 L). The combined filtrates were
concentrated and the residue partitioned in H2O-Et2O (1:1,
1.6 L). The aqueous layer was concentrated to ca. 200 mL and
was then extracted with EtOAc (8 × 400 mL). Concentration
of the organic layers gave a residue (29.5 g), that was treated
with Al2O3 (400 g) on a Bu¨chner funnel. Elution with H2O (2.0
L) and concentration of the filtrates gave a residue, which was
dissolved in MeOH (250 mL) and filtered through activated
charcoal (ca. 5 g). Removal of the solvent gave crude 18 (13.9
g).37
10r-4′,6′-O-Isop r op ylid en e-3,4,7,8-tetr a h yd r oa u cu bin
(23). Acetonide 20 (493 mg) in EtOH (5 mL) and Et3N (50 µL)
was hydrogenated for 12 h in the presence of Pt (from 25 mg
PtO2). The catalyst was filtered off on activated charcoal/Celite,
eluting the cake with Me2CO (50 mL). Concentration of the
filtrates gave a residue (487 mg) that was purified on a VLC
column (3 × 3 cm). Elution with hexane-Me2CO (2:1 to 1:1.3)
gave first a 1:1.5 mixture of acetonides 23/24 (121 mg, 24%);
then came pure 23 (311 mg, 62%): mp 157-158 °C (from Me2-
CO-hexanes), [R]20D -120° (c 0.9, MeOH); 1H NMR (methanol-
d4, 500 MHz) δ 5.15 (1H, d, J 1,9 ) 4 Hz, H-1), 4.04 (1H, br dd,
J ) 9, 4 Hz, H-6), 3.97 (1H, ddd, J ) 12, 8.5, 3.5 Hz, H-3a),
3.75 (1H, dd, J a,b ) 11 Hz, J 8,10a ) 7 Hz, H-10a), 3.53 (1H,
obsc., H-10b), 3.50 (1H, obsc., H-3b), 2.47 (1H, br sextet, J )
8 Hz, H-8), 2.30 (1H, m, H-9), 2.27 (1H, m, H-5), 1.85 (1H, br
d, J ) 9 Hz, H-7a), 1.84 (1H, dd, J ) 9, 1.5 Hz, H-7b), 1.62
(1H, m, H-4a), 1.37 (1H, m, H-4b), 4.67 (1H, d, J 1′,2′ ) 8 Hz,
H-1′), 3.88 (1H, dd, J a′,b′ ) 10.5 Hz, J 5′,6a′ ) 5.5 Hz, H-6a′), 3.76
(1H, t, J ) 10.5 Hz, H-6b′), 3.54-3.46 (2H, m, H-3′ and H-4′),
3.28 (1H, dd, J 2′,3′ ) 9 Hz, J 1′,2′ ) 8 Hz, H-2′), 3.25 (1H, m,
H-5′), 1.51, 1.38 (each 3H, s, 4′,6′-Me2C); 13C NMR (methanol-
d4, 125 MHz) δ 95.5, 76.3, 65.6, 60.2, 45.0, 43.1, 42.2, 38.0,
26.2; glucose moiety 99.5, 75.8, 75.0, 74.8, 68.6, 63.1, 29.4, 19.3;
anal. C 55.56%, H 7.56%, calcd for C18H26O9, C 55.36%, H
7.76%.
Hyd r ogen a tion of Aceton id e 20 w ith P d /C a s Ca ta lyst.
Acetonide 20 (100 mg) in MeOH (5 mL) and Et3N (0.14 mL)
was hydrogenated (as described below for 24) for 24 h in the
presence of 5% Pd/C (15 mg). NMR of the crude product (101
mg, quant.) showed a 1:3 ratio between 23 and 24 (data given
above and below).
10â-4′,6′-O-Isop r op ylid en e-3,4,7,8-t et r a h yd r oa u cu b in
(24). A mixture of acetonides 21/22 (176 mg) in MeOH (10 mL)
and Et3N (0.28 mL) was hydrogenated for 24 h in the presence
of 5% Pd/C (25 mg). The mixture was filtered on charcoal over
Celite eluting further with EtOAc (75 mL). Concentration of
the filtrate gave a residue (181 mg), which was treated with
1% aqueous HOAc-THF (1:1, 10 mL) for 2 days. Then Et3N
(0.2 mL) was added, and the mixture was concentrated. The
residue was purified as described for 23 to give acetonide 24
Au cu bin (19). To crude 18 (4.46 g) in H2O (30 mL) was
added 1M NaOH (15 mL), and the mixture was stirred at room
temperature for 2 h. Then HOAc was added till pH 6.5, and
then solid NaHCO3 was added until pH 8.5. The mixture was
then purified by MPLC. Elution with H2O-MeOH (15:1)
yielded 19 (2.20 g, 68%).
Au cu bin Aceton id es 20 a n d 21/22. Aucubin (19, 527 mg,
1.52 mmol) and anhydrous CuSO4 (527 mg) were suspended
in dry Me2CO (40 mL), and then PPTS (53 mg, 0.21 mmol)
was added. The mixture was cooled to 0 °C, and DMP (2.0 mL,
16.3 mmol) was added. Stirring at 0-5 °C was continued for
4 days. Then Et3N (0.2 mL) was added, and the mixture was
diluted with EtOAc and filtered through a layer of Na2SO4.
The filtrate was concentrated to give a residue that was
purified on a VLC column (3 × 3 cm). Elution with hexanes-
Me2CO (4:1 to 1:1) yielded a 4:1 mixture of acetonides 21/22
(217 mg, 31%) and 20 (238 mg, 40%).
4′,6′-O-Isop r op ylid en e-a u cu bin (20): white foam, [R]20
D
-124° (c 0.7, MeOH); 1H NMR (methanol-d4, 500 MHz) δ 6.32
(1H, dd, J 3,4 ) 6 Hz, J 3,5 ) 2 Hz, H-3), 5.76 (1H, m, H-7), 5.12
(1H, dd, J 3,4 ) 6 Hz, J 4,5 ) 4 Hz, H-4), 4.79 (1H, d, J 1,9 ) 7.5
Hz, H-1), 4.42 (1H, ddt, J ) 5.5, 4, 2 × 2 Hz, H-6), 4.31 (1H,
br d, J a,b ) 15.5 Hz, H-10a), 4.15 (1H, br d, J a,b ) 15.5 Hz,
H-10b), 2.87 (1H, br t, J ) 7.5 Hz, H-9), 2.64 (1H, dddd, J )
7.5, 5.5, 4, 2 Hz, H-5), 1.50, 1.37 (each 3H, s, 4′,6′-Me2C); other
sugar signals as for 21; 13C NMR (methanol-d4, 125 MHz) δ
147.8, 141.6, 130.5, 105.8, 98.1, 82.9, 61.5, 47.9, 46.6; sugar
(135 mg, 90%): mp 187-188 °C (from MeOH-EtOH-hex-
1
anes), [R]20 -98° (c 0.8, MeOH); H NMR (methanol-d4, 500
D
MHz) δ 5.13 (1H, br s, H-1), 4.00 (1H, dt, J a,b ) J 3a,4b ) 11.5
Hz and J 3a,4a ) 2.5 Hz, H-3a), 3.91 (1H, br d, J ) 5.5 Hz, H-6),
3.57 (1H, dd, J a,b ) 10.5 Hz, J 8,10a ) 6 Hz, H-10a), 3.51 (1H,

Carbocyclic Nucleoside Analogues
J ournal of Natural Products, 1999, Vol. 62, No. 12 1651
dd, J a,b ) 10.5 Hz, J 8,10b ) 6.5 Hz, H-10b), 3.48 (1H, obsc.,
H-3b), 2.29 (1H, m, H-7a), 2.28 (1H, m, H-5), 2.21 (1H, m, H-8),
1.98 (1H, br dd, J ) 9, 7 Hz, H-9), 1.47 (1H, m, H-4a), 1.39
(1H, m, H-7b), 1.30 (1H, m, H-4b), 4.64 (1H, d, J 1′,2′ ) 8 Hz,
H-1′), 3.86 (1H, dd, J a′,b′ ) 10.5 Hz, J 5′,6a′ ) 5.5 Hz, H-6a′), 3.76
(1H, t, J a′,b′ ) J 5′,6b′ ) 10.5 Hz, H-6b′), 3.52-3.48 (2H, m, H-3′
and H-4′), 3.30 (1H, dd, J 2′,3′ ) 9 Hz, J 1′,2′ ) 8 Hz, H-2′), 3.24
(1H, ddd, J 5′,6b′ ) 10.5 Hz, J 4′,5′ ) 9.5 Hz and J 5′,6a′ ) 5.5 Hz,
H-5′), 1.50, 1.38 (each 3H, s, 4′,6′-Me2C); 13C NMR (methanol-
d4, 125 MHz) δ 96.6, 77.7, 67.2, 59.3, 44.1, 43.5, 41.7, 37.1,
25.5; sugar signals 100.7, 99.4, 75.9, 75.2, 74.9, 68.6, 63.2, 29.4,
19.3; anal. C 55.32%, H 7.76%, calcd for C18H26O9, C 55.36%,
H 7.76%.
to provide 2091 unique reflections (Rint ) 0.024). All non-
hydrogen atoms were refined by using anisotropic displace-
ment parameters. Hydrogen atoms were defined in idealized
positions.
Tetr ol 26; Ozon olysis of Ad oxosid e (11). Pure glucoside
11 (5.29 g, 13.6 mmol) in CH2Cl2-MeOH (2:1, 120 mL) was
cooled to -78 °C and then treated with O3 for 30 min. Then
N2 was passed through the solution for 15 min, at which time
NaBH4 (1.54 g, 40.7 mmol) and EtOH (60 mL) were added.
After 1.5 h, the cooling to -78 °C was stopped, and after an
additional 2 h at room temperature, HOAc (6 mL) was added.
Repeated concentration with MeOH gave a residue that was
purified by VLC. Elution with hexane-Me2CO (1:1) gave tetrol
La cton e 25; P r ep a r a tion fr om Aceton id e 14. Acetonide
14 (5.60 g) in EtOH (185 mL) and Et3N (5.60 g) was
hydrogenated for 12 h in the presence of 5% Pd/C (0.28 g).
Workup and deprotection, as described for 11, afforded a crude
5:1 mixture of 11 and 17 (4.64 g). An aliquot (3.95 g, 10.2
mmol) of this mixture was dissolved in CH2Cl2-MeOH (2:1,
90 mL), cooled to -78 °C, and then treated with O3 for 15 min.
After purging the solution with Ar for 15 min, NaBH4 (0.92 g,
24.3 mmol) and EtOH (50 mL) were added. After 2.5 h, the
cooling was stopped, and, after an additional 1.5 h at room
temperature, HOAc (4 mL) was added. When a clear solution
was obtained, it was concentrated, and the residue was
partitioned between EtOAc (200 mL) and brine-saturated
NaHCO3 (2:1, 90 mL). The aqueous layer was extracted further
with EtOAc (5 × 150 mL). The organic layers were dried (Na2-
SO4) and concentrated to a residue (1.31 g), which was purified
on a VLC column (4 × 4 cm). Elution with hexane-Me2CO
(10:1 to 2:1) and then Me2CO afforded impure lactone 25 (273
mg, 16% from 14), lactone 25 (885 mg, 53%), and then a
mixture (112 mg) containing 17 and a small amount of tetrol
26 (see below). Recrystallization from Me2CO-hexane gave
26 (1.80 g, 70%) as a hygroscopic syrup: [R]21 -18° (c 0.5,
D
MeOH); 1H NMR (methanol-d4, 500 MHz) δ 3.78 (1H, dd, J a,b
) 10.5 Hz, J 8,10a ) 7.5 Hz, H-10a), 3.68-3.63 (2H, m, H-3a
and H-4), 3.50-3.42 (3H, m, 2 × H-1 and H-3b), 3.44 (1H, obsc.,
H-10b), 2.13-2.02 (2H, m, H-5 and H-9), 1.89-1.82 (2H, m,
H-7a and H-8), 1.65 (1H, m, H-6a), 1.34 (1H, m, H-6b), 1.27
(1H, m, H-7b); 13C NMR (methanol-d4, 125 MHz) δ 73.9, 67.1,
66.7, 63.9, 46.2, 46.1 (2 C), 29.1, 28.9.
Tetr ol 26; Red u ction of La cton e 25. To lactone 25 (955
mg, 5.13 mmol) in EtOH (40 mL) was added NaBH4 (194 mg,
5.13 mmol). After the mixture was stirred at room temperature
for 2.5 h, HOAc (1 mL) was added. The mixture was then
concentrated, and the residue was concentrated twice with
MeOH. The resulting residue was purified by VLC to yield
tetrol 26 (910 mg, 93%).
Tetr ol Aceton id e 29. Tetrol 26 (3.56 g, 18.7 mmol) was
dissolved in dry Me2CO (220 mL), and PPTS (165 mg),
anhydrous CuSO4 (2.20 g), and DMP (1.65 mL) were added.
After 6 h, the mixture was concentrated to ca. 50 mL. The
residual solution was then diluted with EtOAc (150 mL) and
washed with brine-saturated NaHCO3 (1:1, 60 mL). The
aqueous layer was extracted with more EtOAc (2 × 100 mL).
The combined organic layers were dried (Na2SO4) and con-
centrated. The residue was purified on a VLC column (6 × 7
cm). Elution with hexane-Me2CO (10:1 to 6:1) yielded ac-
an analytical sample of 25: mp 154-155 °C, [R]23 +196° (c
D
1
0.8, MeOH); H NMR (methanol-d4, 500 MHz) δ 4.60 (1H, d,
J 4,5 ) 7 Hz, H-4), 4.42 (1H, dd, J a,b ) 12 Hz, J 1a,9 ) 4 Hz, H-1a),
4.26 (1H, br d, J a,b ) 12 Hz, H-1b), 3.62 (1H, dd, J a,b ) 11 Hz,
J 8,10a ) 6 Hz, H-10a), 3.56 (1H, dd, J a,b ) 11 Hz, J 8,10b ) 6.5
Hz, H-10b), 2.88 (1H, m, H-5), 2.24 (1H, ddd, J ) 12, 9.5, 4
Hz, H-9), 1.98 (1H, m, H-8), 1.93 (1H, m, H-6a), 1.79 (1H, m,
H-7a), 1.24 (1H, m, H-7b), 1.19 (1H, m, H-6b); 13C NMR
(methanol-d4, 125 MHz) δ 177.3, 69.7 (2 C), 65.6, 47.9, 42.9,
42.0, 30.0, 29.7; anal. C 58.11%, H 7.57%, calcd for C9H14O4,
C 58.04%, H 7.59%.
etonide 29 (3.48 g, 81%): colorless oil, [R]23 -1.3° (c 0.9,
D
MeOH); 1H NMR (methanol-d4, 500 MHz) δ 4.10 (1H, ddd, J 4,5
) 10 Hz, J 3b,4 ) 8 Hz, J 3a,4 ) 5.5 Hz, H-4), 4.03 (1H, dd, J a,b
8 Hz, J 3a,4 ) 5.5 Hz, H-3a), 3.85 (1H, dd, J a,b ) 11 Hz, J 1a,9
)
)
5.5 Hz, H-1a), 3.53 (1H, dd, J a,b ) 11 Hz, J 1b,9 ) 7.5 Hz, H-1b),
3.52 (1H, obsc., H-10a), 3.51 (1H, t, J a,b ) J 3b,4 ) 8 Hz, H-3b),
3.49 (1H, obsc., H-10b), 2.11 (1H, m, H-5), 2.05 (1H, m, H-8),
2.02 (1H, m, H-9), 1.90 (1H, m, H-7a), 1.62 (1H, m, H-6a), 1.35
(1H, m, H-7b), 1.33 (1H, m, H-6b), 1.37, 1.33 (each 3H, s,
3,4-Me2C); 13C NMR (methanol-d4, 125 MHz) δ 110.0, 77.7,
70.4, 67.0, 63.7, 47.8, 47.1, 46.4, 29.4, 28.7, 27.1, 26.1; anal. C
62.29%, H 9.76%, calcd for C12H22O4, C 62.58%, H 9.63%.
Di-O-ben zyl-tetr ol 30. To acetonide 29 (1.49 g, 6.47 mmol)
in dry THF (40 mL) was added NaH (0.93 g, 50% oil-
suspension, 19.4 mmol) under Ar and cooling to 0 °C. After 15
min at 0 °C and then 15 min at room temperature, Bu4NI (717
mg, 1.94 mmol) and BnBr (2.31 mL, 19.4 mmol) in THF (10
mL) were added. The mixture was stirred at room temperature
for 2 days, when additional amounts of NaH (186 mg, 50%
oil-suspension, 3.87 mmol), Bu4NI (72 mg, 0.19 mmol), and
BnBr (0.23 mL, 1.94 mmol) were added. After an additional 1
day, the mixture was diluted with EtOAc (100 mL), and then
brine (50 mL) was added cautiously. The aqueous layer was
extracted with more EtOAc (100 mL). The combined organic
layers were dried (Na2SO4) and concentrated. The residue was
hydrolyzed in a mixture of 1M HCl (50 mL) and THF (100
mL) for 1 day at room temperature. The mixture was then
concentrated to ca. 100 mL, diluted with EtOAc (100 mL), and
saturated NaHCO3 (50 mL) was added. The organic layer was
washed with brine-saturated NaHCO3 (1:1, 2 × 50 mL) and
was then dried (Na2SO4) and concentrated. The residue was
purified on a VLC column (4 × 4 cm). Elution with hexane-
Me2CO (9:1) yielded diol 30 (1.86 g, 77.5%): needles (hexane-
3,4-Dih yd r oa d oxosid e (17): Repeated VLC gave an ana-
lytical sample: mp 147-148 °C (from MeOH), [R]23 -49° (c
D
1
0.6, MeOH); H NMR (methanol-d4, 500 MHz) δ 5.26 (1H, br
s, H-1), 4.03 (1H, t, J a,b ) J 3a,4 ) 11 Hz, H-3a), 3.68 (3H, s,
11-MeO), 3.63 (1H, dd, J a,b ) 11 Hz, J 3b,4 ) 4.5 Hz, H-3b), 3.56
(1H, dd, J a,b ) 11 Hz, J 8,10a ) 5.5 Hz, H-10a), 3.50 (1H, dd, J a,b
) 11 Hz, J 8,10b ) 6.5 Hz, H-10b), 2.60 (1H, m, H-5), 2.53 (1H,
dt, J 3a,4 ) J 4,5 ) 11 Hz, J 3b,4 ) 4.5 Hz, H-4), 2.16 (1H, m, H-8),
1.93 (1H, m, H-7a), 1.80 (1H, br dd, J ) 10, 6 Hz, H-9), 1.68
(1H, ddd, J ) 13, 9.5, 5.5 Hz, H-6a), 1.63 (1H, m, H-6b), 1.47
(1H, dddd, J ) 13, 9.5, 6, 3 Hz, H-7b), 3.86 (1H, dd, J a′,b′ ) 12
Hz, J 5′,6a′ ) 2 Hz, H-6a′), 3.63 (1H, dd, J a′,b′ ) 12 Hz, J 5′,6b′
)
5.5 Hz, H-6b′), 3.37 (1H, br t, J ) 9 Hz, H-3′), 3.28 (1H, br t,
J ) 9.5 Hz, H-4′), 3.27 (1H, obsc., H-5′), 3.23 (1H, dd, J 2′,3′
)
9 Hz, J 1′,2′ ) 8 Hz, H-2′); 13C NMR (methanol-d4, 125 MHz) δ
175.1, 95.9, 66.4, 60.2, 52.3, 46.4, 43.4, 42.3, 38.6, 30.2, 26.4;
glucose moiety 99.0, 74.8, 78.0, 71.6, 78.1, 62.7; anal. C 51.87%,
H 7.35%, calcd for C17H28O10, C 52.02%, H 7.21%.
X-r a y Cr ysta llogr a p h ic An a lysis of 25.38 Compound 25
crystallized in the trigonal space group P32 a ) 7.5812 (4), c
) 13.4709 (9) Å, V ) 670.51 (7) Å3, Z ) 3 and with a calculated
density of 1.383 g/cm3. The structure was solved by direct
methods (Brucker AXS SHELXTL vers. 5.03) and refined on
F2, using all data by a full-matrix, weighted least-squares
process (R ) 0.054 and wR2 ) 0.112). Intensity data were
collected on a Brucker AXS SMART CCD system using M0-
KR (λ ) 0.7107). Intensities were integrated from a series of
frames covering more than a hemisphere of reciprocal space.
Absorption corrections were applied by using SADABS (Tmax
) 0.98 and Tmin ) 0.61). The reflections obtained were merged
EtOAc), mp 67-68 °C, [R]23 +6.7° (c 0.9, MeOH). 1H NMR
D
(methanol-d4, 500 MHz) δ 3.66 (1H, dd, J a,b ) 9.5 Hz, J 1a,9
)
7 Hz, H-1a), 3.62 (2H, obsc., H-3a and H-4), 3.50 (1H, dd, J a,b
) 9.5 Hz, J 1b,9 ) 5.5 Hz, H-1b), 3.42 (1H, dd, J a,b ) 9.5 Hz,

1652 J ournal of Natural Products, 1999, Vol. 62, No. 12
Franzyk and Stermitz
J 8,10a ) 7 Hz, H-10a), 3.41 (1H, obsc., H-3b), 3.37 (1H, dd, J a,b
) 9.5 Hz, J 8,10b ) 7 Hz, H-10b), 2.27 (1H, m, H-9), 2.13 (1H,
m, H-8), 2.04 (1H, m, H-5), 1.87 (1H, m, H-7a), 1.62 (1H, m,
H-6a), 1.33 (1H, m, H-6b), 1.28 (1H, m, H-7b), 7.33-7.24 (10H,
m, 2 × PhCH2), 4.51, 4.48 (each 2H, s, 2 × PhCH2); 13C NMR
(methanol-d4, 125 MHz) δ 139.9, 139.5, 129.4, 128.9, 128.8,
75.7, 74.3, 73.9, 72.6, 66.8, 46.3, 44.1, 43.4, 29.3, 28.9; anal. C
74.86%, H 8.30%, calcd for C23H30O4, C 74.56%, H 8.16%.
Di-O-ben zyl-tr iol 31. Diol 30 (270 mg, 0.729 mmol) was
dissolved in dry THF (10 mL), and then H5IO6 (183 mg, 0.802
mmol) in dry THF (10 mL) was added. The mixture was stirred
at room temperature for 15 min and then diluted with EtOAc
(100 mL), and saturated aqueous NaHCO3 (50 mL) was added.
The aqueous layer was extracted with more EtOAc (100 mL).
The combined EtOAc phases were dried (Na2SO4) and con-
centrated. The residue was dissolved in CH2Cl2 (25 mL), and
the solution was cooled to -78 °C. Then EtOH (7 mL) and
NaBH4 (30 mg, 0.802 mmol) were added. After 1 h at -78 °C,
more NaBH4 (45 mg, 1.20 mmol) was added. The temperature
was then allowed to reach 10 °C during the next 19 h, at which
point the mixture was neutralized with HOAc (0.25 mL), and
then CH2Cl2 (50 mL) and aqueous saturated NaHCO3 (35 mL)
were added. The aqueous layer was extracted with more CH2-
Cl2 (50 mL), and the combined organic layers were dried (Na2-
SO4) and concentrated. The residue was purified on a VLC
column (3 × 3 cm). Elution with hexane-EtOAc (10:1 to 7:1)
yielded 31 (237 mg, 95.5%), [R]23D +29° (c 0.8, MeOH); 1H NMR
(methanol-d4, 500 MHz) δ 3.67 (1H, dd, J a,b ) 11 Hz, J 4a,5 ) 7
Hz, H-4a), 3.54 (1H, dd, J a,b ) 9.5 Hz, J 1a,9 ) 7.5 Hz, H-1a),
3.50 (1H, dd, J a,b ) 9.5 Hz, J 1b,9 ) 5.5 Hz, H-1b), 3.47 (1H, dd,
J a,b ) 11 Hz, J 4b,5 ) 7.5 Hz, H-4b), 3.46 (1H, dd, J a,b ) 9 Hz,
J 8,10a ) 6.5 Hz, H-10a), 3.38 (1H, dd, J a,b ) 9 Hz, J 8,10b ) 6.5
Hz, H-10b), 2.22 (1H, m, H-5), 2.11 (1H, m, H-9), 2.07 (1H, m,
H-8), 1.88 (1H, m, H-7a), 1.73 (1H, m, H-6a), 1.45 (1H, m,
H-6b), 1.33 (1H, m, H-7b), 7.33-7.24 (10 H, m, 2 × PhCH2),
4.48, 4.47 (each 2H, s, 2 × PhCH2); 13C NMR (methanol-d4,
125 MHz) δ 140.0, 139.7, 129.4, 128.9, 128.8, 128.5, 75.6, 74.2,
74.0, 72.0, 63.5, 45.5, 45.0, 43.4, 29.3, 29.2; anal. C, 77.61%,
H 8.29%, calcd for C22H28O3, C 77.39%, H 8.35%.
CO3 (1:1, 50 mL). The EtOAc-phase was dried (Na2SO4) and
concentrated. The residue (2.02 g) was purified on a VLC
column (3.5 × 4 cm). Elution with hexane and then hexane-
Me2CO (8:1 to 5:1) afforded 33 (1.47 g, 80%) as a colorless
syrup: [R]23D +4.3° (c 0.3, MeOH); 1H NMR (methanol-d4, 500
MHz) δ 4.68 (1H, dd, J a,b ) 10.5 Hz, J 1a,9 ) 4 Hz, H-1a), 4.36
(1H, dd, J a,b ) 10.5 Hz, J 1b,9 ) 9 Hz, H-1b), 4.31 (1H, dd, J a,b
) 10.5 Hz, J 8,10a ) 6 Hz, H-10a), 4.24 (1H, dd, J a,b ) 10.5 Hz,
J 8,10b ) 8 Hz, H-10b), 3.68 (1H, dd, J a,b ) 11 Hz, J 3a,4 ) 3 Hz,
H-3a), 3.64 (1H, m, H-4), 3.47 (1H, dd, J a,b ) 11 Hz, J 3b,4 ) 6
Hz, H-3b), 2.59 (2H, m, H-8 and H-9), 2.28 (1H, m, H-5), 2.11
(1H, m, H-7a), 1.80, 1.53 (each 1H, m, 2 × H-6), 1.50 (1H, m,
H-7b), 8.00-7.40 (10H, m, 2 × Ph-CO); 13C NMR (methanol-
d4, 125 MHz) δ 168.2, 168.1, 134.2, 131.5, 130.5, 129.6, 73.6,
69.3, 67.1, 66.7, 45.4, 43.2, 29.0, 28.7; anal. C 69.24%, H 6.49%,
calcd for C23H26O6, C 69.33%, H 6.58%.
Di-O-ben zoyl-tr iol 34. Dibenzoate 33 (0.61 g, 1.53 mmol)
was dissolved in THF (20 mL), and then H5IO6 (0.38 g, 1.67
mmol) in dry THF (30 mL) was added. The mixture was stirred
at room temperature for 30 min and then diluted with EtOAc
(150 mL) and saturated aqueous NaHCO3 (75 mL). The organic
layer was washed with brine (75 mL), dried (Na2SO4), and
concentrated. The residue (0.71 g) was dissolved in CH2Cl2 (60
mL), and the solution was cooled to -78 °C. Then EtOH (25
mL) and NaBH4 (64 mg, 1.68 mmol) were added, and after
1.5 h at -78 °C, more NaBH4 (32 mg, 0.84 mmol) was added.
After an additional 1 h at -78 °C, HOAc (0.6 mL) was added.
The mixture was allowed to reach room temperature during
4 h, when the mixture was diluted with CH2Cl2 (100 mL) and
then washed with brine (50 mL). The organic layer was dried
(Na2SO4) and concentrated. The residue (0.65 g) was purified
on a VLC column (3 × 3 cm). Elution with hexane and then
hexane-Me2CO (10:1 and 9:1) yielded 34 (0.48 g, 85%) as a
colorless syrup: [R]22D +19° (c 0.7, MeOH); 1H NMR (methanol-
d4, 500 MHz) δ 4.52 (1H, dd, J a,b ) 11 Hz, J 1a,9 ) 5.5 Hz, H-1a),
4.38 (1H, dd, J a,b ) 11 Hz, J 1b,9 ) 6.5 Hz, H-1b), 4.32 (2H, d,
J 8,10 ) 6.5 Hz, 2 × H-10), 3.74 (1H, dd, J a,b ) 10.5 Hz, J 4a,5
)
6.5 Hz, H-4a), 3.61 (1H, dd, J a,b ) 10.5 Hz, J 4b,5 ) 7 Hz, H-4b),
2.43 (1H, m, H-8), 2.42 (1H, m, H-9), 2.41 (1H, m, H-5), 2.06
(1H, m, H-7a), 1.90, 1.61 (each 1H, m, 2 × H-6), 1.50 (1H, m,
H-7b), 7.98 (4H, br d, J ) 8.5 Hz, Ph-CO), 7.56 (2H, br t, J )
8.5 Hz, Ph-CO), 7.42 (4H, m, Ph-CO); 13C NMR (methanol-d4,
125 MHz) δ 168.0, 134.1, 131.4, 130.4, 129.5, 69.2, 66.4, 63.2,
45.3, 44.1, 42.8, 29.2, 28.8; anal. C 71.58%, H 6.60%, calcd for
Di-O-ben zyl-tr iol 32. Diol 30 (0.90 g, 2.43 mmol) was
oxidized as above. The crude aldehyde was dissolved in MeOH
(100 mL) and then anhydrous K2CO3 (1.00 g) was added. After
the mixture was stirred at room temperature for 4 h (clear
solution), NaBH4 (100 mg, 2.65 mmol) was added. After an
additional 16 h, HOAc (1 mL) was added, and then the mixture
was concentrated. The residue was dissolved in EtOAc (150
mL), which was washed twice with brine-saturated NaHCO3
(1:1, 80 mL). The EtOAc-phase was dried (Na2SO4) and
concentrated. The residue was purified on a VLC column (4 ×
4 cm). Elution with hexane and then hexane-Me2CO (20:1 and
C
22H24O5, C 71.72%, H 6.57%.
Bisn u cleosid e An a logu e 35. Acetonide 29 (144 mg, 0.625
mmol), Ph3P (656 mg, 2.50 mmol), and 6-chloropurine (387 mg,
2.50 mmol) in dry THF (7 mL) were cooled to 0 °C, when a
solution of DEAD (0.38 mL, 2.45 mmol) in dry THF (3 mL)
was added dropwise. After 15 min, the cooling bath was
removed, and after a total of 2 h the mixture was concentrated
(to ca. 2 mL) and loaded onto a VLC column (3.5 × 3 cm).
Elution with hexane-Me2CO (6:1 to 2:1) gave protected
bisnucleoside (226 mg, 72%) contaminated with ca. 5% Ph3-
15:1) gave di-O-benzyl-triol 32 (0.78 g, 94%): [R]22 +19.5° (c
D
1.1, MeOH); 1H NMR (methanol-d4, 500 MHz) δ 3.54 (1H, dd,
J a,b ) 9 Hz, J 1a,9 ) 6 Hz, H-1a), 3.52 (1H, dd, J a,b ) 10.5 Hz,
J 4a,5 ) 6 Hz, H-4a), 3.47 (1H, dd, J a,b ) 9 Hz, J 8,10a ) 6 Hz,
H-10a), 3.44 (1H, dd, J a,b ) 9 Hz, J 1b,9 ) 6.5 Hz, H-1b), 3.41
(1H, dd, J a,b ) 10.5 Hz, J 4b,5 ) 7 Hz, H-4b), 3.36 (1H, dd, J a,b
) 9 Hz, J 8,10b ) 7.5 Hz, H-10b), 2.02 (1H, m, H-8), 1.92 (1H,
m, H-5), 1.74 (2H, m, H-6a and H-7a), 1.61 (1H, m, H-9), 1.46
(2H, m, H-6b and H-7b), 7.48-7.22 (10 H, m, 2 × PhCH2),
4.48-4.45 (4H, m, 2 × PhCH2); 13C NMR (methanol-d4, 125
MHz) δ 139.9, 139.8, 129.4, 129.3, 128.7, 128.6, 128.5, 75.2,
74.9, 74.1, 74.0, 66.7, 47.6, 47.0, 44.4, 29.6, 29.4; anal. C
77.27%, H 8.44%, calcd for C22H28O3, C 77.61%, H 8.29%.
Di-O-ben zoyl-tetr ol 33. Acetonide 29 (1.06 g, 4.60 mmol)
was dissolved in CH2Cl2-pyridine (4:1, 15 mL), and then BzCl
(1.34 mL, 11.5 mmol) was added. The mixture was kept at 4
°C for 19 h and subsequently at room temperature for 2 h. Ice
was then added to the reaction mixture, and after 30 min, the
mixture was diluted with CH2Cl2 (50 mL) and then washed
successively with 2M H2SO4, H2O, and saturated NaHCO3
(each 40 mL). Concentration of the organic layer yielded a
residue (2.23 g), which was treated with 1M aqueous HCl (30
mL) in THF (70 mL) at room temperature for 34 h. Then
EtOAc (150 mL) was added to the mixture; the organic layer
was separated and washed twice with brine-saturated NaH-
1
PO. H NMR (DMSO-d6, 500 MHz) δ 4.34 (1H, dd, J a,b ) 13.5
Hz, J 1a,9 ) 6 Hz, H-1a), 4.10 (1H, dd, J a,b ) 13.5 Hz, J 1b,9 ) 11
Hz, H-1b), 4.08 (1H, obsc., H-4), 4.04 (1H, obsc., H-3a), 4.01
(1H, obsc., H-10a), 3.99 (1H, obsc., H-10b), 3.55 (1H, t, J a,b
)
J 3b,4 ) 7.5 Hz, H-3b), 2.69 (1H, m, H-9), 2.40 (1H, m, H-8),
2.33 (1H, m, H-5), 2.04 (1H, m, H-7a), 1.70 (1H, m, H-6a), 1.50
(1H, m, H-6b), 1.38 (1H, m, H-7b), 1.31, 1.18 (each 3H, s, 3,4-
Me2C), 8.48, 8.42 (each 1H, s, H-8′ and H-8′′), 8.46, 8.43 (each
1H, s, H-2′ and H-2′′); 13C NMR (DMSO-d6, 125 MHz) δ 108.2,
75.1, 68.6, 47.8, 44.5, 44.1, 42.2, 41.0, 27.8, 26.7, 26.2, 25.5;
purine signals 151.4, 151.1, 150.8, 148.8, 148.7, 147.3, 146.9,
130.5, 130.3. An aliquot of the protected nucleoside (140 mg)
was treated with liquid NH3 (20 mL) in a steel vessel at 50 °C
for 3 days. After evaporation of the NH3, the residue was
treated with 0.5M aqueous HCl (10 mL) at 4 °C for 1.5 days.
After neutralization with solid NaHCO3, the mixture was
concentrated to 5 mL and loaded onto an MPLC column.
Elution with H2O-MeOH (2:1) afforded unprotected bis-
nucleoside 35 (94 mg, 80%): mp 185-186 °C (from H2O-
MeOH), [R]20 -107° (c 0.5, H2O); 1H NMR (DMSO-d6, 500
D
MHz) δ 4.67 (1H, d, J ) 5 Hz, 4-OH), 4.52 (1H, t, J ) 5.5 Hz,

Carbocyclic Nucleoside Analogues
J ournal of Natural Products, 1999, Vol. 62, No. 12 1653
3-OH), 4.39 (1H, dd, J a,b ) 13.5 Hz, J 1a,9 ) 4.5 Hz, H-1a), 3.98
(1H, dd, J a,b ) 13.5 Hz, J 1b,9 ) 12 Hz, H-1b), 3.75 (1H, dd, J a,b
) 13.5 Hz, J 8,10a ) 8 Hz, H-10a), 3.64 (1H, dd, J a,b ) 13.5 Hz,
J 8,10b ) 7.5 Hz, H-10b), 3.53 (1H, obsc., H-4), 3.52 (1H, obsc.,
H-3a), 3.36 (1H, obsc. by HDO-peak, H-3b), 2.50 (1H, obsc. by
DMSO-d5 peak, H-9), 2.27 (1H, m, H-8), 2.22 (1H, m, H-5),
1.81 (1H, m, H-7a), 1.70 (1H, m, H-6a), 1.46 (1H, m, H-6b),
1.31 (1H, m, H-7b), 8.05, 7.90 (each 1H, s, H-2′ and H-2′′), 7.94,
7.73 (each 1H, s, H-8′ and H-8′′), 7.08, 7.05 (each 2H, br s,
6′-NH2 and 6′′-NH2); 13C NMR (DMSO-d6, 125 MHz) δ 71.5,
65.7, 47.1, 43.7, 42.7, 41.0, 27.2, 26.0; purine signals 155.8,
155.7, 152.2, 152.1, 149.8, 149.3, 140.6, 140.3, 118.8, 118.5;
anal. C 49.59%, H 5.90%, N 30.22%, calcd for C19H24N10O2‚
2H2O, C 49.56%, H 6.13%, N 30.42%.
was purified on a VLC column (3 × 3 cm). Elution with hexane,
CHCl3, and CHCl3-MeOH (10:1 to 8:1) yielded nucleoside
analogue 8 (59 mg, 35%) as well as only partially debenzoy-
lated product. The latter was treated with NaOMe-MeOH at
room temperature for 2 h, and was purified as above to give
an additional amount of nucleoside analogue 8 (75 mg, 44%):
mp 167-168 °C (from EtOH-MeOH), [R]21D +22° (c 0.6, H2O);
1H NMR (DMSO-d6, 500 MHz) δ 4.70 (1H, t, J ) 4.5 Hz, 10-
OH), 4.58 (1H, t, J ) 5 Hz, 1-OH), 4.30 (1H, dd, J a,b ) 13.5
Hz, J 4a,5 ) 5.5 Hz, H-4a), 4.05 (1H, dd, J a,b ) 13.5 Hz, J 4b,5
)
11 Hz, H-4b), 3.53 (1H, m, H-1a), 3.48 (1H, dt, J a,b ) 10.5 Hz,
J ) 5 Hz, H-1b), 3.29 (2H, m, 2 × H-10), 2.56 (1H, m, H-5),
1.87 (2H, m, H-8 and H-9), 1.78 (1H, m, H-7a), 1.30, 1.25 (2H,
m, 2 × H-6), 1.18 (1H, m, H-7b); 13C NMR (DMSO-d6, 125
MHz) δ 64.8, 61.2, 45.8, 43.8, 43.6, 41.7, 28.5, 26.8; purine
signals 155.8, 152.2, 149.6, 140.9, 118.6; anal. C 56.45%, H
6.86%, N 25.04%, calcd for C13H19N5O2, C 56.30%, H 6.91%, N
25.25%.
P r otected Nu cleosid e An a logu e 38. A mixture of com-
pound 32 (259 mg, 0.761 mmol), Ph3P (399 mg, 1.52 mmol),
and adenine (206 mg, 1.52 mmol) was stirred in dry dioxane
(10 mL) under Ar. Then DEAD (0.23 mL, 1.48 mmol) in
dioxane (2 mL) was added. The mixture was stirred at room
temperature for 19 h, then concentrated, redissolved in EtOAc
(6 mL), and loaded onto a VLC column (3 × 3 cm). Elution
with hexane and then hexane-Me2CO (5:1 to 2:1) gave
Ack n ow led gm en t. This work was supported by NSF
grant CHE9619213 to F.R.S. and by the Danish National
Research Councils (grant no. 9501145) to H.F. We thank Prof.
S. Isoe for obtaining the geniposide, Dr. S. M. Miller for the
X-ray study, and Dr. C. M. Nielsen for performing the antiviral
tests.
compound 38 (240 mg, 68.5%): mp 122-123 °C (from hexane-
1
Me2CO), [R]21 +31° (c 0.8, MeOH); H NMR (DMSO-d6, 500
D
MHz) δ 4.22 (1H, dd, J a,b ) 13.5 Hz, J 4a,5 ) 6.5 Hz, H-4a),
4.05 (1H, dd, J a,b )13.5 Hz, J 4b,5 ) 8.5 Hz, H-4b), 3.41 (1H,
dd, J a,b ) 9.5 Hz, J 8,10a ) 5.5 Hz, H-10a), 3.33 (1H, dd, J a,b
Su p p or tin g In for m a tion Ava ila ble: Tabulated 13C NMR data
for all new compounds as well as supplementary reproductions of
selected NMR spectra of tetrol 26, bisnucleoside 35, and bicyclic
tetrahydrofuran 37; experimental procedure for the preparation of 37;
crystallographic data for lactone 25. This material is available free of
charge via the Internet at http://pubs.acs.org.
)
9.5 Hz, J 8,10b ) 7.5 Hz, H-10b), 3.31 (1H, dd, J a,b ) 9.5 Hz,
J 1a,9 ) 6 Hz, H-1a), 3.28 (1H, dd, J a,b ) 9.5 Hz, J 1b,9 ) 6.5 Hz,
H-1b), 2.35 (1H, pentet-like, J ) 7.5 Hz, H-5), 1.99 (1H, pentet-
like, J ) 7 Hz, H-8), 1.67 (1H, pentet-like, J ) 6.5 Hz, H-9),
1.65 (1H, m, H-7a), 1.49 (1H, m, H-6a), 1.45 (1H, m, H-7b),
1.37 (1H, m, H-6b), 8.14 (1H, s, H-2′), 8.09 (1H, s, H-8′), 7.17
(2H, br s, 6′-NH2), 7.35-7.24 (10H, m, 2 × Ph-CH2), 4.46, 4.43
(each 1H, d, J ) 13.5 Hz, Ph-CH2), 4.36, 4.33 (each 1H, d, J )
13.5 Hz, Ph-CH2); 13C NMR (DMSO-d6, 125 MHz) δ 138.7,
138.5, 128.2, 127.3, 127.2, 73.3, 72.5, 72.0, 47.0, 45.6, 43.0. 42.4,
28.8, 27.8; purine signals 155.9, 152.3, 149.7, 140.9, 118.7;
anal. C 70.60%, H 6.69%, N 15.08%, calcd for C27H31N5O2, C
70.87%, H 6.83%, N 15.31%.
Refer en ces a n d Notes
(1) Berkowitz, W. F.; Choudry, S. C.; Hrabie, J . A. J . Org. Chem. 1982,
47, 824-829.
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902.
Nu cleosid e An a logu e 7. Compound 38 (152 mg, 0.332
mmol) in CH2Cl2 (16 mL) was cooled to -78 °C, and then 1M
BCl3 in CH2Cl2 (4 mL) was added under Ar. The mixture was
stirred at -78 °C for 6 h and was subsequently allowed to
warm to -25 °C during 1 h. Then MeOH (8 mL) was added,
and the cooling bath was removed. When the mixture reached
room temperature it was concentrated. The residue was
concentrated three times with more MeOH and was then
partitioned between EtOAc (50 mL) and H2O (25 mL). The
aqueous layer was concentrated, and the residue was purified
on a VLC column (3 × 3 cm). Elution with hexane, CHCl3,
and CHCl3-MeOH (10:1 to 8:1) yielded nucleoside analogue
(6) Isoe, S.; Ge, Y.; Yamamoto, K.; Katsumura, S. Tetrahedron Lett. 1988,
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(7) Ge, Y.; Kondo, S.; Katsumura, S.; Nakatani, K.; Isoe, S. Tetrahedron
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7 (89 mg, 97%): mp 169-170 °C (from EtOH-MeOH), [R]21
D
+14.5° (c 0.4, H2O); 1H NMR (DMSO-d6, 500 MHz) δ 4.67 (1H,
t, J ) 4.5 Hz, OH), 4.62 (1H, t, J ) 5 Hz, OH), 4.19 (1H, dd,
J a,b ) 14 Hz, and J 4a,5 ) 6 Hz, H-4a), 4.01 (1H, dd, J a,b ) 14
Hz, and J 4b,5 ) 9 Hz, H-4b), 3.34-3.24 (4H, m, 2 × H-10 and
2 × H-1), 2.24 (1H, sextet-like, J ) 7.5 Hz, H-5), 1.78 (1H,
sextet-like, J ) 6.5 Hz, H-8), 1.54 (1H, m, H-7a), 1.40 (3H, m,
H-6a, H-7b and H-9), 1.29 (1H, m, H-6b), 8.12 (1H, s, H-2′),
8.11 (1H, s, H-8′), 7.17 (2H, br s, 6′-NH2); 13C NMR (DMSO-
d6, 125 MHz) δ 64.4, 63.7, 48.3, 47.1, 45.2, 42.9, 28.7, 27.4;
purine signals 155.8, 152.2, 149.6, 141.0, 118.5; anal. C
56.13%, H 6.72%, N 25.11%, calcd for C13H19N5O2, C 56.30%,
H 6.91%, N 25.25%.
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Nu cleosid e An a logu e 8. A mixture of dibenzoate 34 (225
mg, 0.611 mmol), Ph3P (321 mg, 1.22 mmol), and 6-chloro-
purine (189 mg, 1.22 mmol) was stirred in dry THF (4 mL).
Then DEAD (185 µL, 1.19 mmol) in THF (1.5 mL) was added
under Ar. The mixture was stirred at room temperature for
12 h, when the mixture was concentrated, redissolved in CH2-
Cl2 (4 mL), and loaded onto a VLC column (3 × 3 cm). Elution
with hexane and then hexane-Me2CO (10:1 to 8:1) gave a
mixture of product and Ph3PO (0.42 g), which was treated
directly with liquid NH3 at 45-50 °C for 3 days. The residue
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1654 J ournal of Natural Products, 1999, Vol. 62, No. 12
Franzyk and Stermitz
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(38) Atomic coordinates, thermal parameters, bond distances and angles,
and observed and calculated factors have been deposited with the
Cambridge Crystallographic Centre and can be obtained upon request
from the Director, CCDC, University Chemistry Laboratory, 12 Union
Road, Cambridge, CB2 1EZ, U.K.; fax +44-(0)1223-336033 or e-mail
deposit@ccdc.cam.ac.uk.
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1153.
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