Palladium-catalyzed enantioselective synthesis of carbanucleosides

Article abstract of DOI:10.1021/ja9938837

A general strategy has been developed for enantioselective synthesis of diverse carbanucleosides. The key step is a Pd(0)-catalyzed enantioselective allylic amination of cis-3,5-dibenzoyloxycyclopent-2-ene 10a with the nucleobase. With guanine-derived nuc

Full text of DOI:10.1021/ja9938837

J. Am. Chem. Soc. 2000, 122, 5947-5956
5947
Palladium-Catalyzed Enantioselective Synthesis of Carbanucleosides
Barry M. Trost,* Robert Madsen, Simon D. Guile, and Brian Brown
Contribution from the Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
ReceiVed NoVember 1, 1999. ReVised Manuscript ReceiVed April 18, 2000
Abstract: A general strategy has been developed for enantioselective synthesis of diverse carbanucleosides.
The key step is a Pd(0)-catalyzed enantioselective allylic amination of cis-3,5-dibenzoyloxycyclopent-2-ene
10a with the nucleobase. With guanine-derived nucleobase 13 and chiral ligand 9, a 93-96% ee was obtained,
while 6-chloropurine and chiral ligand 8 gave 94% ee. The reaction was followed by a second Pd(0)-catalyzed
allylic alkylation with phenylsulfonyl(nitro)methane 6. The nitrosulfone, thus obtained, served as a versatile
intermediate for divergent synthesis in which the phenylsulfonyl(nitro)methyl group is a surrogate for the
hydroxymethyl side chain. With the guanine-derived nucleobase 13, (-)-carbovir was obtained in only four
steps from 10a. With 6-chloropurine as an adenine equivalent, the obtained nitrosulfone intermediate 26 could
be converted into both (-)-aristeromycin and (-)-neplanocin A as well as their 2′,3′-diepi isomers.
Carbanucleosides have been the focus of much recent
attention in the development of new antiviral and antitumor
therapeutic agents.1,2 Due to the absence of a glycosidic linkage,
carbanucleosides are chemically more stable and not subject to
the phosphorylases that cleave the N-glycosidic linkage in
conventional nucleosides. Many carbanucleosides that exhibit
potent and selective biological activity have now been identi-
fied.1,2 During a large search for new antiviral agents, particu-
larly for the treatment of human immunodeficiency virus (HIV),
(-)-carbovir 1 was discovered3 and subsequently shown to
possess significant in vitro activity as an inhibitor of HIV reverse
transcriptase.4 The adenosine analogues (-)-aristeromycin 2 and
(-)-neplanocin A 3, isolated from Streptomyces citricolor5 and
Ampullariella regularis,6 respectively, are also strong antiviral
agents due to their potent inhibition of the cellular enzyme
S-adenosyl homocysteine hydrolase.7 In addition, (-)-neplano-
cin A has been shown to possess anticancer activity especially
against leukemia.8 Because of their pharmaceutical importance,
these compounds have been the subject of many studies and a
number of total and formal syntheses have been reported.2,9-11
Although none of these three carbanucleosides has been
developed into a drug, they have paved the way for the
development of analogues that are more effective and less toxic
therapeutic agents. One example is the cyclopropylamino
derivative of (-)-carbovir, abacavir 4, which has a higher oral
bioavailability than the parent compound and is now in phase
III clinical trials for HIV treatment.12 Another example is the
cytosine analogue of neplanocin A, cyclopentenyl cytosine 5,
which is in clinical development for cancer treatment.13 In any
search for analogues, it is important to have an efficient synthetic
(9) For previous syntheses of (-)-carbovir, see: (a) Olivo, H. F.; Yu, J.
J. Chem. Soc., Perkin Trans. 1 1998, 391. (b) Mart´ınez, L. E.; Nugent, W.
A.; Jacobsen, E. N. J. Org. Chem. 1996, 61, 7963. (c) Crimmins, M. T.;
King, B. W. J. Org. Chem. 1996, 61, 4192. (d) Hildbrand, S.; Troxler, T.;
Scheffold, R. HelV. Chim. Acta 1994, 77, 1236. (e) Hodgson, D. M.;
Witherington, J.; Moloney, B. A. J. Chem. Soc., Perkin Trans. 1 1994,
3373. (f) Nokami, J.; Matsuura, H.; Nakasima, K.; Shibata, S. Chem. Lett.
1994, 1071. (g) Asami, M.; Takahashi, J.; Inoue, S. Tetrahedron: Asymmetry
1994, 5, 1649. (h) Trost, B. M.; Li, L.; Guile, S. D. J. Am. Chem. Soc.
1992, 114, 8745. (i) Evans, C. T.; Roberts, S. M.; Shoberu, K. A.;
Sutherland, A. G. J. Chem. Soc., Perkin Trans. 1 1992, 589. (j) Peel, M.
R.; Sternbach, D. D.; Johnson, M. R. J. Org. Chem. 1991, 56, 4990. (k)
Jones, M. F.; Myers, P. L.; Robertson, C. A.; Storer, R.; Williamson, C. J.
Chem. Soc., Perkin Trans. 1 1991, 2479.
(10) For previous syntheses of (-)-aristeromycin, see: (a) Boyer, S. J.;
Leahy, J. W. J. Org. Chem. 1997, 62, 3976. (b) Burlina, F.; Favre, A.;
Fourrey, J.-L.; Thomas, M. Bioorg. Med. Chem. Lett. 1997, 7, 247. (c)
Csuk, R.; Do¨rr, P. Tetrahedron 1995, 51, 5789. (d) Tanaka, M.; Yoshioka,
M.; Sakai, K. J. Chem. Soc., Chem. Commun. 1992, 1454. (e) Yoshikawa,
M.; Okaichi, Y.; Cha, B. C.; Kitagawa, I. Tetrahedron 1990, 46, 7459. (f)
Wolfe, M. S.; Anderson, B. L.; Borcherding, D. R.; Borchardt, R. T. J.
Org. Chem. 1990, 55, 4712. (g) Arita, M.; Adachi, K.; Ito, Y.; Sawai, H.;
Ohno, M. J. Am. Chem. Soc. 1983, 105, 4049. (h) Also see: refs 9b and 9h
as well as Matthews, D. P.; Edwards, M. L.; Mehdi, S.; Koehl, J. R.; Woloo,
J. A.; McCarthy, N. R. Bioorg. Med. Chem. Lett. 1993, 3, 165.
(11) For previous syntheses of (-)-neplanocin A, see: (a) Yoshida, N.;
Kamikubo, T.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 4677. (b)
Niizuma, S.; Shuto, S.; Matsuda, A. Tetrahedron 1997, 53, 13621. (c) Ohira,
S.; Sawamoto, T.; Yamato, M. Tetrahedron Lett. 1995, 36, 1537. (d) Hill,
J. M.; Hutchinson, E. J.; Le Grand, D. M.; Roberts, S. M.; Thorpe, A. J.;
Turner, N. J. J. Chem. Soc., Perkin Trans. 1 1994, 1483. (e) Vanhessche,
K.; Bello, C. G.; Vandewalle, M. Synlett 1991, 921. (f) Bestmann, H. J.;
Roth, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 99. (g) Marquez, V. E.;
Lim, M.-I.; Tseng, C. K.-H.; Markovac, A.; Priest, M. A.; Khan, M. S.;
Kaskar, B. J. Org. Chem. 1988, 53, 5709. (h) Medich, J. R.; Kunnen, K.
B.; Johnson, C. R. Tetrahedron Lett. 1987, 28, 4131 and refs 10f and 10g.
(12) Foster, R. H.; Faulds, D. Drugs 1998, 55, 729.
(1) Agrofoglio, L. A.; Challand, S. R. Acyclic, Carbocyclic and L-
Nucleosides; Kluwer Academic Publishers: Dordrecht, 1998.
(2) For recent reviews, see: Crimmins, M. T. Tetrahedron 1998, 54,
9229. Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.;
Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611; Borthwick, A. D.;
Biggadike, K. Tetrahedron 1992, 48, 571.
(3) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17.
(4) Orr, D. C.; Figueiredo, H. T.; Mo, C.-L.; Penn, C. R.; Cameron, J.
M. J. Biol. Chem. 1992, 267, 4177.
(5) Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi, T.;
Mizuno, K. J. Antibiot. 1968, 21, 255; Kishi, T.; Muroi, M.; Kusaka, T.;
Nishikawa, M.; Kamiya, M.; Mizuno, K. Chem. Pharm. Bull. 1972, 20,
940.
(6) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.; Otani,
M. J. Antibiot. 1981, 34, 359.
(7) Wolfe, M. S.; Borchardt, R. T. J. Med. Chem. 1991, 34, 1521; De
Clercq, E. Biochem. Pharmacol. 1987, 36, 2567.
(8) Niitsu, N.; Yamamoto-Yamaguchi, Y.; Kanatani, Y.; Shuto, S.;
Matsuda, A.; Umeda, M.; Honma, Y. Exp. Hematol. 1997, 25, 1296.
(13) Agbaria, R.; Kelley, J. A.; Jackman, J.; Viola, J. J.; Ram, Z.;
Oldfield, E.; Johns, D. G. Oncol. Res. 1997, 9, 111.
10.1021/ja9938837 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/09/2000

5948 J. Am. Chem. Soc., Vol. 122, No. 25, 2000
Trost et al.
Scheme 1. Stategies to Carbanucleosides Based on Pd-Catalyzed Allylic Alkylation
route that is not only short and enantioselective but also
divergent so that modifications can easily be introduced.
synthesis using the cycloaddition of bis-benzoate 10a with 6 as
the enantiodiscriminating step.9h However, introduction of the
hydroxymethyl side chain and the nucleobase did require a
significant number of steps. Since the nucleobase is introduced
late in the sequence, this strategy is useful to access a series of
analogues in which this unit is variedsas is desired in a
medicinal chemistry program. A desire to streamline the route
led to the development of a third generation synthesis.15 In this
strategy, the nucleobase is introduced directly in the enantio-
discriminating step followed by a second regio- and diastereo-
selective Pd(0)-catalyzed alkylation to introduce the phenylsul-
fonyl(nitro)methyl side chain. Two key questions that needed
to be resolved involve the ability to use the nucleobases in the
enantiodiscriminating step and to employ the initial alkylation
product in a further Pd(0)-catalyzed allylic alkylation without
loss of the nucleobase. Here, we report a full account of this
third generation carbanucleoside synthesis exemplified by the
synthesis of (-)-carbovir, (-)-aristeromycin, and (-)-neplano-
cin A as well as the 2′,3′-diepi analogues of the latter two.
Our long time interest in palladium-catalyzed allylic alkyl-
ations has led us to develop several strategies for the synthesis
of carbanucleosides.9h,14,15 The key steps are two Pd(0)-catalyzed
alkylations on an activated cyclopentene skeleton to introduce
the nucleobase and the hydroxymethyl side chain. In our first
generation synthesis the nucleobase (Nu) was first reacted with
cyclopentadiene monoepoxide (Scheme 1).14 Then, a second
Pd(0)-catalyzed alkylation with the anion of phenylsulfonyl-
(nitro)methane (6) introduced a one-carbon side chain which
can be converted into the hydroxymethyl group. Although rather
short, this synthesis gives racemic carbanucleosides.14 Our
development of a series of chiral modular ligands 7-916,17
Results and Discussion
Synthesis of (-)-Carbovir. We have previously examined
the asymmetric allylic alkylation (AAA) reaction wherein bis-
benzoate 10a18 was reacted with a variety of nucleophiles in
the presence of Pd(0) and chiral ligand 7.17 The asymmetric
induction in this case should in principle be independent of the
nucleophile. This also seems to be true for simple nucleophiles
such as malonates,16 sulfinates,19 azide,20 and amines16 which
all give high yields and ee’s in the alkylation reaction. In
accordance with our model for this system, the (S,S)-ligand 7
in all cases preferentially ionizes the pro-R leaving group.
However, nucleobases behave differently and show a remarkable
effect on the catalytic turnover and the enantioselectivity,
probably as a result of their ability to coordinate with palladium.
(14) Trost, B. M.; Kuo, G.-H.; Benneche, T. J. Am. Chem. Soc. 1988,
110, 621.
(15) Trost, B. M.; Madsen, R.; Guile, S. D. Tetrahedron Lett. 1997, 38,
1707; Trost, B. M.; Madsen, R.; Guile, S. D.; Elia, A. E. H. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1569.
(16) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc.
1992, 114, 9327.
(17) Trost, B. M. Acc. Chem. Res. 1996, 29, 355.
(18) Available in two steps from cyclopentadiene: Kaneko, C.; Sugimoto,
A.; Tanaka, S. Synthesis 1974, 876; Deardorff, D. R.; Myles, D. C.;
MacFerrin, K. D. Tetrahedron Lett. 1985, 26, 5615.
(19) Trost, B. M.; Organ, M. G.; O’Doherty, G. A. J. Am. Chem. Soc.
1995, 117, 9662.
(20) Trost, B. M.; Stenkamp, D.; Pulley, S. R. Chem. Eur. J. 1995, 1,
568.
allowed the development of an asymmetric second-generation

Synthesis of Carbanucleosides
J. Am. Chem. Soc., Vol. 122, No. 25, 2000 5949
Table 1. AAA Reaction of 10a with 11
Table 2. AAA Reaction of 10a with 13
yield (%)
14a
[R]D (CH2Cl2) (deg)
of 14
yield (%)
16a
17 18 of 16
49 (57) 13 NI
ee (%)
entry
ligand
15
entry [η3-C3H5PdCl]2 (%) 9 (%) temp.
1
2
3
7
8
9
29 (48)
39 (53)
28 (31)
21
13
32
-48
-95
-132
1
2
3
2.5
2.5
1.5
7.5 rt
90
96
93
7.5 0 °C 50 (54)
4.5 0 °C 59 (70)
8
7
21
16
a Yields in parantheses are based on recovered 10a.
a Yields in parentheses are based on recovered 10a. NI ) not isolated.
For the synthesis of (-)-carbovir, a guanine equivalent was
needed for the enantiodiscriminating step. Guanine itself is
extremely insoluble in organic solvents, and as a result, 2-amino-
6-chloropurine (11) is often used as a substitute. We have
successfully employed this equivalent in Pd(0)-catalyzed allylic
alkylations with achiral ligands without complications. In
addition, a base was needed for the enantioselective allylic
amination. The choice of base proved to have a significant
influence on the conversion using ligand 8 and nucleobase 11
(eq 1). Tertiary amine bases were superior to inorganic bases
Scheme 2. Asymmetric Synthesis of (-)-Carbovira
a (a) 1% Pd2dba3‚CHCl3, 8% PPh3, 6, Et3N, THF, rt, 97%. (b)
Me2NC(NH)NMe2, TBA-oxone, Na2CO3, MeOH, CH2Cl2, rt, 71%. (c)
Ca(BH4)2, THF, then aq. NH3, rt, 61%.
2, entries 2 and 3), yield (up to 70%), and ee (up to 96%) as
well as a better ratio between the N-9 and the N-7 product.
One recrystallization from EtOAc enhanced the ee to more than
98%. Surprisingly, the doubly alkylated product 18 was also
isolated. The formation of this may, in part, contribute to the
higher ee by imposing a partial kinetic resolution of the
monoalkylated product after the initial enantiodiscriminating
allylic alkylation.
such as sodium hydride and cesium carbonate. In particular,
the more sterically hindered amine bases gave better conversion.
In the series triethylamine, diisopropylethylamine and 1,2,2,6,6-
pentamethylpiperidine (pempidine), the yield of the allylation
product more than doubled. As a result, pempidine was selected
as the base of choice. An even more profound influence was
observed with the choice of ligand. Although no ee has been
determined at this point, the measured optical rotations clearly
show that ligand 9 is superior to 7 and 8 (Table 1). Bicyclic
ligand 9 presumably has a larger P-Pd-P bite angle than 7
and 8.16 However, these results are still surprising because
ligands 7 and 8 have previously given excellent yields and ee’s
with the simpler nucleophiles mentioned above.17 As indicated
in Table 1, both products of N-9 and N-7 alkylation were
isolated. Especially for ligand 9, this ratio was not satisfactory.
Consequently, other purine nucleophiles were investigated that
would give more of the desired N-9 product. The C-6 substituent
was changed from chlorine to more sterically demanding groups
in an effort to block the N-7 position. Introducing the TMS-
ethoxy group as in 1221 gave, in fact, only one regioisomer in
the alkylation, but only in about 20% yield. A much more
gratifying result was obtained with diphenylcarbamate 1322
where the electron-donating ability of the 2-amino group has
at the same time been reduced by acetylation (eq 2, Table 2).
Having prepared enantiopure 16 the hydroxymethyl side chain
can now be introduced in three steps (Scheme 2). A second
Pd(0)-catalyzed alkylation with phenylsulfonyl(nitro)methane
(6) and triethylamine gives nitrosulfone 19 as a 1:1 diastereo-
meric mixture almost quantitatively. Previous work relied upon
ozonolysis to cleave the nitrosulfone to the estersan oxidation
protocol not compatible with the double bond. Thereby, we
developed a new protocol for this transformation.20 Chemose-
lective oxidation of the tetramethylguanidine salt with tetrabu-
tylammonium oxone23 (TBA-oxone) in MeOH/CH2Cl2 buffered
with sodium carbonate gave methyl ester 20 in 71% yield. The
ee’s in Table 2 were determined from this methyl ester by NMR
spectroscopy using Eu(hfc)3 as the chiral shift reagent. Reduction
of the ester with calcium borohydride24 followed by an aqueous
ammonia workup to remove the guanine-protecting groups then
generated (-)-carbovir in 61% yield. Employing lithium boro-
hydride in lieu of calcium borohydride gave a slightly lower
yield. The spectral data and the optical rotation were in
A 57% yield of the desired N-9 alkylation product 16 was
obtained in 90% ee. Lowering the reaction temperature from
room temperature to 0 °C gave higher catalytic turnover (Table
(21) Gundersen, L.-L.; Benneche, T.; Rise, F.; Gogoll, A.; Undheim, K.
Acta Chem. Scand. 1992, 46, 761.
(22) Prepared in a one-pot procedure from guanine: Robins, M. J.; Zou,
R.; Guo, Z.; Wnuk, S. F. J. Org. Chem. 1996, 61, 9207.
(23) Trost, B. M.; Braslau, R. J. Org. Chem. 1988, 53, 532.
(24) Daluge, S.; Vince, R. J. Org. Chem. 1978, 43, 2311.

5950 J. Am. Chem. Soc., Vol. 122, No. 25, 2000
Trost et al.
Table 4. AAA Reaction of 10a with Uracil and Analoguesa
yield (%) ee (%)
ligand 24 25 24
Scheme 3. Asymmetric Alkylation with Adenine
Equivalenta
entry nucleophile solvent
base
1
2
3
4
23a
23a
23c
23c
23c
23c
23c
23c
23c
23b
THF
THF
CH2Cl2 NONE
(C2H5)3N
(C2H5)3Al
8
8
8
8
8
8
8
8
7
8
-
-
-
43
-
94
-
trace 10
trace 22
CH2Cl2 (C2H5)3N
-
98
98
5
DMF
DMF
DMF
DMF
DMF
DMF
(C2H5)3N
i-Pr2NEt
(C2H5)3N
(C2H5)3N
(C2H5)3N
(C2H5)3N
50
27
52
54
55
36
27
10
trace 97
11
-
-
6
7b
8c
9
97
96
N.D.
10
a All reactions were performed with 3 mol % (dba)3Pd2‚CHCl3 and
7.5 mol % chiral ligand unless noted otherwise. b 1 equiv of (n-
C4H9)4NCl added. c [η3-C3H5PdCl]2 used as Pd source.
these latter conditions, a marginal improvement occurred by
going to the more polar DMF as solvent. Satisfyingly, chiral
HPLC revealed the presence of a single enantiomer in all cases.
However, the use of the BOC group as the leaving group is
not optimal for all cases. For example, use of a pyrimidine base,
thymine or uracil, led only to decomposition of the bis-carbonate
substrate. On the other hand, the bis-benzoate 10a does lead to
successful alkylation with uracil and its derivatives (see eq 3
and Table 4). The absence of a basic leaving group as in the
a (a) For R ) Ph, 1% Pd2dba3‚CHCl3, 3% 8, Et3N, THF, rt, 21a:
53% (76% based on rec. 10), 21b: 4%, 21c: 13%. For R ) OC4H9-t,
2.5 mol % (dba)3Pd2‚CHCl3, 7.5 mol % 8, DMF, rt, 62% 21a. (b)
NaOH, MeOH, THF, rt, 95%. (c) (S)-PhCH(OMe)COOH, DCC,
DMAP, CH2Cl2, rt, quant.
Table 3. AAA Reaction of 10b with 6-Chloropurine
entry
solvent
(C2H5)3N
yield (%)
ee (%)
1
2
3
4
THF
4 equiv
4 equiv
none
23
41
59
62
>98
>98
>98
>98
CH2Cl2
CH2Cl2
DMF
none
accordance with literature values.9 This completes the enanti-
oselective synthesis of (-)-carbovir in only four steps from bis-
benzoate 10a (six steps from cyclopentadiene). Compared to
our second-generation synthesis, only half the number of steps
were required.
Synthesis of (-)-Aristeromycin and (-)-Neplanocin A and
Their 2′,3′-Diepi Isomers. We then turned our attention to the
adenine carbanucleosides. Due to the insolubility of adenine in
organic solvents, we also turned to the 6-chloro analogue as
the nucleophile for the desymmetrization of bis-benzoate 10a
(Scheme 3). Initial experiments with ligand 7 and triethylamine
as base in THF gave poor yield and ee of the desired amination
product 21a. However, switching to ligand 8 satisfactorily solved
these problems. A 53% yield (76% based on recovered 10a) of
21a was isolated. The yield was lower when the reaction was
conducted at 0 °C or when pempidine was used as base. The
ee was determined by hydrolysis to the corresponding alcohol
followed by esterification with (S)-O-methylmandelic acid to
give 22. Examination of the crude ester 22 by NMR spectros-
copy revealed a de of 94%. Recrystallization of 21a from EtOAc
gave material with lower ee. As observed above with the guanine
nucleophiles, products of N-7 (e.g., 21b) and bis-amination (e.g.,
21c) were also obtained here in the desymmetrization reaction,
but in lower yields (4% and 13% respectively).
Since the leaving group can affect the enantioselectivity, we
also examined use of a better leaving group, a carbonate, which,
because ionization could occur at lower temperatures, might
lead to enhanced selectivity. As shown in Scheme 3 and Table
3, the reaction does proceed to completion at room temperature.
The table reveals several trends. Yields increased in switching
from THF to methylene chloride (entries 2 and 3). Best results
were obtained in the absence of base (entries 3 and 4). Under
case of carbonate necessitated the use of a base. Nevertheless,
the reaction did not perceptibly proceed in THF or methylene
chloride with tertiary amine bases. On the other hand, triethy-
laluminum led to the monoalkylation product 24a with excellent
ee (entry 2). Better results were obtained with DMF as solvent,
wherein the desired monoalkylation product of 98% ee could
be obtained in good yield (entry 5) along with a dialkylation
product 25. The assignment of the second alkylation at N-3
rather than O stems from the 13C NMR spectrum which reveals
C-4 at δ 162.8 consistent with the amide function of the
pyrimidin-2,4-dione. The addition of tetra-n-butylammonium
chloride suppresses the formation of the bisalkylation product
25. The use of [η3C3H5PdCl]2 as a palladium source also led to
a decreased amount of dialkylation while preserving a good yield
of the desired product of good ee (entry 8). Usefully, the
standard cyclohexyl ligand 7 gave the best results (entry 9).
Thus, both pyrimidine and purine bases can give quite satisfac-
tory results.
The second Pd(0)-catalyzed alkylation of 21a with 6 to
introduce the one-carbon side chain proceeded straightforwardly
to give nitrosulfone 26 in high yield (Scheme 4). This is a pivotal
intermediate that can be converted into both aristeromycin and
neplanocin A as well as their 2′,3′-diepi isomers. Simple
ammonolysis gave adenine derivative 27, an intermediate in our
previous synthesis of aristeromycin where the crucial dihy-
droxylation requires the use of potassium permanganate under
basic conditions14 to obtain the correct diastereomer.

Synthesis of Carbanucleosides
J. Am. Chem. Soc., Vol. 122, No. 25, 2000 5951
Scheme 6. Retrosynthesis of Neplanocin
Scheme 4. Asymmetric Syntheses of Aristeromycin and
2′,3′-Diepi-Aristeromycina
stereochemistry was established by converting the corresponding
acetonides 30b and 31b initially to the chloropurines 32a and
33a which, upon ammonolysis, of the crude alcohols, provided
the acetonides of (-)-aristeromycin 32b, mp 217-218 °C, [R]D
-38.1° (c 0.77, MeOH)10 and (+)-2′,3′-diepi-aristeromycin 33b,
mp 257-259 °C, [R]D +71.7° (c 0.4, MeOH). After our work,
dihydroxylation of cis-1,4-disubstituted cyclopentenyl systems
with osmium tetroxide has been shown in many but not all cases
to occur predominantly from the face syn to the two allylic
substituents.26 The above also sets the stage for a short
diastereoselective synthesis of 2′,3′-diepi-aristeromycin 35 from
alkene 26 (Scheme 4). Protection of the diol to give 34 (85%)
and ozonolysis of the nitrosulfone in a basic methanolic solution
gave methyl ester 31b in 76% yield. Reduction with DIBAL-H
followed by ammonolysis gave 33b (69%) identical, except for
optical rotation, with the compound from our previous synthe-
sis14 which on hydrolysis with dilute aqueous hydrochloric acid
gives 2′,3′-diepi-aristeromycin 35.
a (a) 0.5% Pd2dba3‚CHCl3, 4% PPh3, 6, Et3N, THF, rt, 95%. (b) aq.
NH3, rt, 75%. (c) 4 steps, ref 14. (d) 5% OsO4, NMO, H2O, CH2Cl2,
rt, 82%. (e) (MeO)2CMe2, acetone, TsOH, rt, 85%. (f) O3, DBU, MeOH,
THF, -78 °C, 76%. (g) DIBAL-H, THF, CH2Cl2, -78 °C, then aq.
NH3, THF, rt, 69%. (h) aq. HCl, ref 14.
Scheme 5. Dihydroxylation Diastereoselectivity of Estera
For neplanocin an endocyclic double bond has to be
introduced. None of the intermediates for the aristeromycins
are functionalized at the 4′ position. The synthesis of neplanocin
envisioned a series of addition-eliminations to introduce the
correct oxidation pattern as depicted in Scheme 6. As noted
above, our early work revealed the diastereoselectivity of the
osmylation proceeded preferentially to give the all cis product
in related systems. Thus, we examined the diastereoselectivity
of the epoxidation since the epoxide more readily would
participate in the subsequent elimination. Epoxidation of nitro-
sulfone 26 with MCPBA gave 36 as a 1:1 diastereomeric
mixture (Scheme 7). Since the starting alkene 26 is a 1:1
diastereomeric mixture because of the nitrosulfone carbon, it
was not possible to ascertain the diastereoselectivity of the
epoxidation. However, removal of this stereogenic center in the
ozonolysis step gave only one product, 37. Here the relative
stereochemistry of the alcohol can be assigned by making the
(S)- and (R)-O-methylmandelates 38 and 39. In general, the
O-methylmandelate ester will adopt a conformation in which
the methoxy group is eclipsed with the carbonyl group. Hereby
the phenyl group will shield one of the adjacent protons Ha or
a (a) Me2NC(NH)NMe2, TBA-oxone, Na2CO3, CH3OH, CH2Cl2, rt,
72%. (b) 5% OsO4, NMO, H2O, CH2Cl2, 74%, dr 1:2 or 7% RuCl3,
NaIO4, CH3CN, H2O, 0 °C, 67%, dr 2:3. (c) CH3C(OCH3)2CH3,
CH3COCH3, TsOH, rt, quant (d) DIBAL-H, THF, CH2Cl2, -78 °C,
then aq. NH3, THF, rt, 62% for 32b, 69% for 33b.
On the other hand, as noted in our earlier synthesis of racemic
aristeromycin, dihydroxylation of alkene 26 catalyzed by
osmium tetroxide gave syn diol 28 as the major product (82%)
and only a small amount (6%) of the corresponding anti epimer
was formed. Dihydroxylation catalyzed by ruthenium tetroxide25
gave more of the anti epimer (28%) but the syn product was
still the major one (53%). In contrast to our earlier work,
permangante oxidation of 27 also gave the syn isomer as the
major product (43%) and the anti as the minor one (12%). To
ascertain the effect of the nitrosulfone group, it was converted
to the ester 29 in a fashion analogous to that employed in our
carbovir sequence (Scheme 5) with excellent chemoselectivity.
Dihydroxylation with osmium tetroxide still produced the anti
diol 30a as the minor epimer but in a larger amount (74%, 30a:
31a, 1:2) compared to the nitrosulfone (anti:syn 1:14). Ruthe-
nium tetroxide gave a slightly more favorable ratio (67%, 30a:
31a 2:3) but the anti epimer was still the minor one. The
1
Hb which then, in the H NMR spectrum, will experience an
upfield shift when compared with the epimeric O-methylman-
delate ester.27 NMR analysis of the two mandelates reveals that
Ha shows an upfield shift when changing from the (S)-mandelate
to the (R)-mandelate, while Hb on the other hand shows a
downfield shift. This is consistent with the assignment of the
two mandelates as 38 and 39, and, consequently, 37 as the
â-hydroxyl epimer. Thus, the epoxidation of 26 occurred
(26) For some recent examples, see: Zhang, D.; Miller, M. J. J. Org.
Chem. 1998, 63, 755; Zhang, D.; Ghosh, A.; Su¨ling, C.; Miller, M. J.
Tetrahedron Lett. 1996, 37, 3799; Popescu, A.; Hornfeldt, A.-B.; Gronowitz,
S.; Johansson, N. G. Nucleosides Nucleotides 1995, 14, 1639; and ref 10b.
Cieplak effect has been proposed as an explanation for this unusual
selectivity, see: Katagiri, N.; Ito, Y.; Kitano, K.; Toyota, A.; Kaneko, C.
Chem. Pharm. Bull. 1994, 42, 2653; Palmer, C. F.; McCague, R.; Ruecroft,
G.; Savage, S.; Taylor, S. J. C.; Ries, C. Tetrahedron Lett. 1996, 37, 4601.
(27) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S.
L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370.
(25) Shing, T. K. M.; Tam, E. K. W.; Tai, V. W.-F.; Chung, I. H. F.;
Jiang, Q. Chem. Eur. J. 1996, 2, 50.

5952 J. Am. Chem. Soc., Vol. 122, No. 25, 2000
Scheme 7. Diastereoselectivity of Epoxidationa
Trost et al.
Scheme 8. A Synthesis of (-)-Neplanocin Aa
a (a) MCPBA, CH2Cl2, rt, 73%. (b) O3, DBU, MeOH, THF, -78
°C′ rt, 67%. (c) (S)-PhCH(OMe)COOH, DCC, DMAP, CH2Cl2, rt, 95%.
(d) (R)-PhCH(OMe)COOH, DCC, DMAP, CH2Cl2, rt, 95%.
selectively syn to the two allylic substituents just like the
dihydroxylation with osmium tetroxide.
Nevertheless, the unsaturated ester 37 is a valuable intermedi-
ate for the synthesis of the neplanocins. To obtain the R-hydroxy
group stereochemistry in neplanocin A, the â-hydroxy group
in 37 was inverted by esterification using a Mitsunobu reaction28
to give nitrobenzoate 40 in 62% yield (Scheme 8). Reduction
with DIBAL-H converted the methyl ester into the primary
alcohol, but left the nitrobenzoate ester unchanged. The latter
was subsequently removed in the workup by transesterification
to MeOH to give diol 41 in 79% yield. Osmium tetroxide-
catalyzed dihydroxylation gave rise to only one tetraol which
easily formed a bis-acetonide 44. Because an acetonide will not
form a trans fused bicyclo[3.3.0] ring system, the dihydroxy-
lation must have taken place exclusively from the R-face to give
the stereochemistry depicted in 42. Interestingly, this is a
complete reversal of the facial selectivity as compared to the
dihydroxylation of 26. Acetylation of tetraol 42 in pyridine gave
triacetate 43. Unfortunately, dehydration of the latter with
phosphorus oxychloride or thionyl chloride29 failed to generate
the desired endocyclic double bond in neplanocin A, but instead
furnished a mixture of all three possible elimination products:
48, 51,30 and the product containing a 3′,4′-endocyclic double
bond. To prevent formation of this latter elimination product, a
2′,3′-O-isopropylidene group was introduced. Chemoselective
removal of one acetonide from bis-acetonide 44 required use
of a bulky Lewis acid such as ferric chloride on silica gel31 to
give diol 45 in 94% yield. Standard acetylation conditions
afforded monoaceate 46 in 91% yield.32 Dehydration of the latter
with phosphorus oxychloride and DMAP in CH2Cl2 gave a 3:4
a (a) p-NO2C6H4COOH, PPh3, DEAD, THF, 0 °C, 62%. (b) DIBAL-
H, THF, CH2Cl2, -78 °C, then Et3N, MeOH, rt, 79%. (c) 2% OsO4,
NMO, acetone, H2O, rt, 89%. (d) Ac2O, pyridine, rt, 71%. (e)
(MeO)2CMe2, TsOH, rt, 71%. (f) FeCl3‚H2O on silica gel, CH2Cl2, rt,
61% (94% based on rec. 44). (g) Ac2O, Et3N, DMAP, CH2Cl2, rt, 91%.
(h) Me3CCOCl, pyridine, rt, 95%. (i) SOCl2, DMF, pyridine, rt, 60%
(+ 8% of 53). (j) NH3, MeOH, rt, 73%. (k) aq. HCl, 80 °C, 91%.
mixture of 4933 and 52.30 To prevent elimination to the exocyclic
olefin, the acetate was replaced by the bulkier pivaloyl-
protecting group. When the dehydration was repeated on pivalate
47 under the same conditions, only a slight improvement in
regioselectivity was obtained, giving a 1:1 mixture of 50 and
53.30 However, by switching to thionyl chloride in pyridine as
dehydrating agent, this selectivity could be improved to 8:1. In
addition, it was discovered that adding 1 equiv of DMF35 to
the mixture led to a significant increase in the rate and the yield
for the dehydration. Under these conditions, a 60% yield could
be obtained of the desired elimination product 50. Ammonolysis
simultaneously removed the pivalate and converted the chlo-
ropurine into the adenine to afford the acetonide 54. Acid
hydrolysis to remove the acetonide completed this asymmetric
(28) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(29) Kirk, D. N.; Shaw, P. M. J. Chem. Soc. C 1970, 182.
(30) The geometry of the exocyclic olefin has not been determined.
(31) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J. Org. Chem.
1986, 51, 404.
(32) This compound has been reported in a previous synthesis of racemic
neplanocin A.33 Unfortunately, the spectral data for 46 are not in accordance
with this literature compound, which has been prepared by addition of
dimethyloxosulfonium methylide to the corresponding acetonide-protected
ketone followed by epoxide ring-opening with potassium acetate. However,
later unrelated work has shown that this particular addition to 2,3-O-
isopropylidene cyclopentanones does actually occur from the same face of
the ketone as the acetonide.34 As a result, we believe the structure of this
reported intermediate in the previous neplanocin synthesis is in fact the
C-4′ epimer of 46.
synthesis of neplanocin A (3), mp 214-5 °C, [R]20 -153.9°
D
(33) Jung, M.; Offenba¨cher, G.; Re´tey, J. HelV. Chim. Acta 1983, 66,
1915.
(34) Marschner, C.; Penn, G.; Griengl, H. Tetrahedron 1993, 49, 5067.
(35) Bosshard, H. H.; Mory, R.; Schmid, M.; Zollinger, H. HelV. Chim.
Acta 1959, 42, 1653.

Synthesis of Carbanucleosides
J. Am. Chem. Soc., Vol. 122, No. 25, 2000 5953
Conclusions
Scheme 9. Synthesis of 2′,3′-Diepi-Neplanocin Aa
A short enantio- and diastereoselective approach for the
synthesis of different carbanucleosides has been developed. The
key step is a Pd(0)-catalyzed enantioselective allylic amination
of bis-benzoate 10a with the nucleobase. Contrary to a vast
number of other nucleophiles including malonates, sulfinates,
azide, and amines, the nucleobase shows a remarkable influence
on this desymmetrization reaction. This might stem from its
ability to serve as a competitive ligand and thereby disrupt the
normal coordination of the palladium. Particularly guanine-
derived nucleobases were problematic and had to be protected
with sterically demanding electron-withdrawing groups in order
to function in the desymmetrization reaction. Also the choice
of ligand played a major role. While our standard ligand 7 gives
excellent results with the simple nucleophiles above, this ligand
gave poor results with purines but quite a satisfactory result
with a pyrimidine. For purines, high ee’s were obtained with
ligands 8 and 9. The desymmetrization reaction is followed by
a second Pd(0)-catalyzed reaction with phenylsulfonyl(nitro)-
methane (6) to introduce the one-carbon side chain. The prospect
of performing both Pd(0)-catalyzed reactions in a single pot
might further simplify the synthesis.
The strategy has resulted in a six-step synthesis of (-)-
carbovir from cyclopentadiene, the shortest synthesis of (-)-
carbovir reported to date.9 By simple exchange of ligand
stereochemistry in the desymmetrization reaction, the corres-
ponding L-carbanucleosides could also be prepared by the same
route. In addition to the strategy providing either enantiomeric
series, analogues can also be easily accessed. The divergence
is demonstrated in the synthesis of (-)-aristeromycin and (-)-
neplanocin A where the same intermediate 26 is used for
preparation of both natural compounds as well as their 2′,3′-
diepi isomers. The alkene intermediates also allow for other
variation of the substituents on the 2′- and 3′-positions. Thus,
the strategy should hold great promise for making diverse
carbanucleosides more readily available as potential chemo-
therapeutic agents.
a (a) DIBAL-H, THF, CH2Cl2, -78 °C, 80% (92% based on rec.
37). (b) CBr4, PPh3, THF, rt, 78% (95% based on rec. 55). (c) t-BuOOH,
10% VO(acac)2, CH2Cl2, rt, 95%. (d) Zn(Cu), EtOH, ultrasound, 50
°C, 93%. (e) (MeO)2CMe2, acetone, TsOH, rt, 90%. (f) Ac2O, Et3N,
DMAP, CH2Cl2, rt, 98%. (g) 4% OsO4, NMO, H2O, CH2Cl2, rt, then
(f), 65%. (h) POCl3, DMAP, CH2Cl2, 0 °C, 98%. (i) NH3, MeOH, rt,
70%.
(c 0.33, H2O), with spectral and physical data in excellent accord
with those reported for the natural substance.6,11 This strategy
effects the enantioselective synthesis of (-)-neplanocin A in
13 steps from bis-benzoate 10a (15 steps from cyclopentadiene).
Several of the intermediates in the neplanocin synthesis are
useful for preparation of analogues of neplanocin. For example,
we prepared the 2′,3′-diepi analogue which has not been
described previously. Allylic alcohol 37 constitutes an ideal
starting point because it already has the required hydroxy group
stereochemistry. Reduction of the methyl ester to the alcohol
55 (92%) followed by allylic bromination gave bromide 56 in
95% (Scheme 9). Hydroxyl-directed epoxidation36 furnished 57
as a single diastereomer (95%) which, on treatment with zinc,
underwent reductive elimination37 to give diol 58 in 93% yield.
The cis diol stereochemistry was confirmed by preparation of
acetonide 59 which formed easily. However, for further use,
diol 58 was quantitatively converted into diacetate 60. Dihy-
droxylation of the latter also gave a single diastereomer which,
in the workup, was acetylated to give triacetate 61. The
dihydroxylation has presumably occurred from the sterically
least hindered R-face to give the stereochemistry as depicted in
61. Contrary to the difficult dehydration described above,
dehydration of 61 proceeded smoothly to give the desired
endocyclic olefin 62 in near quantitative yield. Ammonolysis
then removed the acetates and converted the chloropurine to
the adenine to form 2′,3′-diepi-neplanocin A 63.
Experimental Section38
(1′R,4′S)-1′-(2-Acetamido-6-(N,N-diphenyl)carbamoyloxypurin-
9-yl)-4′-benzoyloxy-cyclopent-2′-ene (16). To an ice-cold deoxygen-
ated solution of ligand 916 (60 mg, 0.07 mmol) in THF (3 mL) were
added [η3-C3H5PdCl]2 (9 mg, 0.02 mmol) and bis-benzoate 10a18 (500
mg, 1.62 mmol) followed by a deoxygenated solution of 2-acetamido-
6-(N,N-diphenyl)carbamoyloxypurine 1322 (750 mg, 1.93 mmol) and
pempidine (1.1 mL, 6.08 mmol) in DMSO (5 mL). The mixture was
stirred vigorously for 8 h at 0 °C. It was then diluted with chloroform
(50 mL) and washed with water (50 mL). The aqueous phase was
extracted with more chloroform (15 mL), and the combined organic
layers were dried and concentrated. The residue was taken up in ethyl
acetate, and 137 mg of the bis-N-9 product 18 was filtered off. The
filtrate was purified by flash chromatography (2/1 ethyl acetate/hexane
f ethyl acetate f acetone) to afford 82 mg (16%) of recovered bis-
benzoate 10a and 546 mg (59%, 70% based on rec. 10a) of the desired
product 16 as a solid, Rf ) 0.48 (ethyl acetate), ee ) 93%. A sample
(475 mg) was recrystallized from ethyl acetate (3 mL) to afford 370
mg, ee > 98%, mp 156-158 °C, [R]20 -108.8° (c 0.45, CH2Cl2).
D
IR (CDCl3): 3402, 1737, 1729, 1720, 1621, 1587, 1492 cm-1. H
1
NMR (400 MHz, CDCl3): δ 8.05-7.99 (m, 4H), 7.57 (t, J ) 7.3 Hz,
1H), 7.47-7.34 (m, 11H), 7.25 (m, 1H), 6.48 (dt, J ) 1.9, 5.5 Hz,
1H), 6.21 (dd, J ) 2.2, 5.5 Hz, 1H), 5.99 (m, 1H), 5.69 (m, 1H), 3.21
(dt, J ) 7.7, 15.2 Hz, 1H), 2.55 (s, 3H), 2.13 (dt, J ) 3.3, 15.2 Hz,
1H). 13C NMR (101 MHz, CDCl3): δ 170.6, 165.8, 156.0, 154.5, 152.0,
150.2, 142.1, 135.7, 133.8, 133.2, 129.4, 129.0, 128.4, 127.7-125.3,
(36) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136.
(37) Sarandeses, L. A.; Mourin˜o, A.; Luche, J.-L. J. Chem. Soc., Chem.
Commun. 1991, 818.
(38) For general procedures, see ref 19.

5954 J. Am. Chem. Soc., Vol. 122, No. 25, 2000
Trost et al.
120.7, 77.3, 57.3, 38.3, 25.1. Anal. Calcd for C32H26N6O5: C, 66.89;
H, 4.56; N, 14.63. Found: C, 67.00; H, 4.54; N, 14.69.
In addition, 65 mg (7%) of 17 was obtained as a foam, Rf ) 0.53
(1/1 ethyl acetate/acetone).
(m, 1H), 3.77 (s, 3H), 2.91 (dt, J ) 9.1, 14.5 Hz, 1H), 2.54 (s, 3H),
2.29 (dt, J ) 4.9, 14.5 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 173.0,
170.8, 155.9, 154.6, 151.8, 150.3, 142.5, 141.5, 135.2, 132.0, 131.9,
131.8, 131.8, 130.7, 129.0, 128.4, 128.3, 128.0-125.3, 120.7, 59.0,
52.3, 49.5, 34.0, 25.0. Anal. Calcd for C27H24N6O5: C, 63.27; H, 4.72;
N, 16.40. Found: C, 63.09; H, 4.93; N, 16.13.
The ee was determined by 1H NMR (400 MHz) using 10 mg of 20
and 25-30 mg of Eu(hfc)3 in 0.6 mL of CDCl3. The OMe-singlets for
the (1′S,4′R) and (1′R,4′S) enantiomers were observed at 4.30 and 4.22
ppm, respectively.
1
IR (CDCl3): 3402, 1755, 1716, 1689, 1634, 1563, 1492 cm-1. H
NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 8.06 (s, 1H), 7.95 (d, J )
7.6 Hz, 2H), 7.57 (t, J ) 7.3 Hz, 1H), 7.45-7.28 (m, 12H), 6.47 (dt,
J ) 2.0, 5.5 Hz, 1H), 6.14 (dd, J ) 1.8, 5.5 Hz, 1H), 5.89 (m, 1H),
5.34 (m, 1H), 2.74 (dt, J ) 7.7, 15.2 Hz, 1H), 2.65 (s, 3H), 1.80 (dt,
J ) 3.2, 15.2 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ 173.4,
168.9, 165.3, 164.8, 151.9, 150.8, 149.4, 147.3, 135.4, 133.8, 133.5,
129.5, 129.3, 128.7, 128.2-126.3, 110.8, 77.7, 60.6, 38.5, 24.5. LRMS
Calcd for C32H26N6O5: 574.2. Found: 574.2.
(-)-Carbovir (1). A mixture of calcium chloride (200 mg, 1.80
mmol) and sodium borohydride (300 mg, 7.93 mmol) in THF (10 mL)
was stirred for 1 h followed by addition of methyl ester 20 (500 mg,
0.98 mmol). The mixture was stirred for 24 h and then concentrated in
vacuo. To the residue was added concentrated aqueous ammonia (10
mL), and the mixture was stirred overnight. Evaporation of the solvent
gave a semicrystalline residue which was passed through a short path
of silica gel eluting with methanol. The eluate was concentrated and
the residue purified by flash chromatography (7/3 chloroform/methanol)
to afford 147 mg (61%) of 1 as a white solid, Rf ) 0.43, mp 255-257
°C (dec) (H2O), [R]20D -60.1° (c 0.4, MeOH) (Lit.: mp 205-210 °C
(dec),9d 210-220 °C (dec),9i 271-273 °C (dec);9k [R]D -62° (c 0.4,
Furthermore, another 85 mg of 18, raising the total yield of 18 to
222 mg (16%), Rf ) 0.43 (1/1 ethyl acetate/acetone), mp 228-230 °C
(dec) (DMF) was isolated.
IR (KBr): 3349, 1736, 1722, 1622, 1589, 1493, 1444, 1403, 1385,
1320 cm-1. 1H NMR (400 MHz, DMSO-d6): δ 10.70 (s, 2H), 8.66 (s,
2H), 7.51-7.41 (m, 18H), 7.31 (t, J ) 7.2 Hz, 2H), 6.40 (s, 2H), 5.76
(t, J ) 7.6 Hz, 2H), 3.29 (m, 1H), 2.40 (m, 1H), 2.20 (s, 6H). 13C
NMR (101 MHz, DMSO-d6): δ 168.9, 155.0, 154.6, 151.9, 150.2,
144.9, 141.7, 133.9, 129.4, 127.4-126.7, 120.3, 58.5, 38.7, 24.6. Anal.
Calcd for C45H36N12O6: C, 64.28; H, 4.32; N, 19.99. Found: C, 64.12;
H, 4.45; N, 19.74.
MeOH),9a [R]24 -66° (c 0.4, MeOH)9i).
D
IR (KBr): 3600-2600, 1736, 1696, 1636, 1570, 1536, 1483, 1417,
1384 cm-1. 1H NMR (400 MHz, DMSO-d6): δ 10.55 (s, 1H), 7.57 (s,
1H), 6.44 (s, 2H), 6.10 (dt, J ) 2.1, 5.5 Hz, 1H), 5.85 (dt, J ) 2.1, 5.5
Hz, 1H), 5.32 (m, 1H), 4.72 (t, J ) 5.3 Hz, 1H), 3.42 (t, J ) 5.5 Hz,
1H), 2.84 (m, 1H), 2.57 (dt, J ) 8.7, 13.7 Hz, 1H), 1.55 (dt, J ) 5.7,
13.7 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ 156.9, 153.5, 150.8,
(1′R,4′S)-1′-(2-Acetamido-6-(N,N-diphenyl)carbamoyloxypurin-
9-yl)-4′-phenylsulfonyl(nitro)methyl-cyclopent-2′-ene (19). To a
deoxygenated solution of triphenylphosphine (24 mg, 0.09 mmol) in
THF (1 mL) was added Pd2dba3‚CHCl3 (12 mg, 0.01 mmol), and the
mixture was stirred for 20 min. It was then added to a deoxygenated
solution of monobenzoate 16 (600 mg, 1.04 mmol), phenylsulfonyl-
(nitro)methane (6)39 (250 mg, 1.24 mmol), and triethylamine (0.36 mL,
2.58 mmol) in THF (6 mL). After being stirred for 12 h, the reaction
mixture was diluted with chloroform (60 mL) and washed with water
(60 mL). The aqueous phase was extracted with more chloroform (10
mL), and the combined organic layers were dried and concentrated.
The residue was purified by flash chromatography (ethyl acetate) to
give 660 mg (97%) of 19 as a foam (1:1 mixture of diastereomers), Rf
) 0.48, which crystallized from methanol, mp 204-205 °C (dec).
1
138.3, 135.1, 129.7, 116.7, 64.0, 58.5, 47.7, 34.4. IR and H and 13C
NMR are in accordance with literature data.9d
(1′R,4′S)-4′-Benzoyloxy-1′-(6-chloropurin-9-yl)-cyclopent-2′-
ene (21a). To a deoxygenated solution of ligand 816 (1.5 g, 1.90 mmol)
in THF (50 mL) was added Pd2dba3‚CHCl3 (650 mg, 0.63 mmol). After
being stirred for 15 min this solution was added to a deoxygenated
mixture of bis-benzoate 10a18 (17.5 g, 56.8 mmol), 6-chloropurine (11
g, 71.2 mmol), and triethylamine (32 mL, 230 mmol) in THF (170
mL). The reaction was stirred for 5 h at room temperature to give a
clear brown solution. The mixture was concentrated and purified by
flash chromatography (3/2 ethyl acetate/hexane f ethyl acetate f
acetone) to afford 6.02 g of recovered bis-benzoate 10a together with
dibenzylideneacetone. This was crystallized from methanol (5 mL) and
gave 5.2 g of recovered 10a. In addition, 10.3 g (53%, 76% based on
rec. 10a) of the desired product 21a (R ) Ph) was isolated, Rf ) 0.40
IR (CDCl3): 3424, 3399, 1741, 1698, 1620, 1586, 1562, 1492 cm-1
.
1H NMR (400 MHz, CDCl3): δ 8.27 (d, J ) 9.8 Hz, 2H), 8.02 (d, J
) 7.4 Hz, 2H), 7.94 (m, 4H), 7.76 (t, J ) 7.3 Hz, 2H), 7.62 (t, J ) 7.5
Hz, 4H), 7.45-7.25 (m, 20H), 6.57 (dt, J ) 2.1, 5.6 Hz, 1H), 6.44 (bs,
1H), 6.21 (bs, 1H), 5.98 (m, 3H), 5.66 (m, 1H), 5.60 (m, 1H), 4.01 (m,
1H), 3.93 (m, 1H), 3.11 (dt, J ) 8.8, 14.8 Hz, 1H), 2.89 (dt, J ) 8.9,
14.5 Hz, 1H), 2.44 (m, 1H), 2.39 (s, 3H), 2.36 (s, 3H), 2.14 (dt, J )
6.4, 14.5 Hz, 1H). 13C NMR (75.5 MHz, CDCl3): δ 169.5, 169.3, 155.8,
155.7, 154.3, 154.2, 151.4, 151.3, 150.2, 143.2, 143.0, 141.4, 135.3,
135.2, 134.3, 134.1, 133.3, 132.9, 132.5, 132.0, 131.9, 131.7, 129.7,
129.6, 129.3, 129.2, 128.9, 128.3, 128.2, 127.8-125.4, 121.3, 121.3,
102.4, 102.3, 60.8, 59.9, 43.8, 43.5, 33.1, 32.8, 24.7. Anal. Calcd for
C32H27N7O7S: C, 58.80; H, 4.16; N, 15.00. Found: C, 58.85; H, 4.24;
N, 14.80.
(3/7 hexane/ethyl acetate), ee ) 94%, [R]20 -106.8° (c 1.71, CH2-
D
Cl2), mp 90-92 °C (EtOAc).
1
IR (CDCl3): 1717, 1590, 1561, 1334 cm-1. H NMR (300 MHz,
CDCl3): δ 8.78 (s, 1H), 8.28 (s, 1H), 8.02 (m, 2H), 7.60 (dt, J ) 1.3,
7.4 Hz, 1H), 7.46 (m, 2H), 6.57 (dt, J ) 2.0, 5.6 Hz, 1H), 6.30 (dd, J
) 2.4, 5.6 Hz, 1H), 6.04 (dt, J ) 2.5, 7.4 Hz, 1H), 5.87 (m, 1H), 3.25
(ddd, J ) 7.7, 8.0, 15.3 Hz, 1H), 2.16 (dt, J ) 3.0, 15.3 Hz, 1H). 13C
NMR (75 MHz, CDCl3): δ 165.7, 151.8, 151.2, 150.9, 143.3, 136.4,
133.6, 133.3, 131.6, 129.4, 129.3, 128.5, 77.3, 57.4, 38.5. Anal. Calcd
for C17H13ClN4O2: C, 59.92; H, 3.85; N, 16.44. Found: C, 60.16; H,
4.00; N, 16.67.
(1′R,4′S)-1′-(2-Acetamido-6-(N,N-diphenyl)carbamoyloxypurin-
9-yl)-4′-methoxycarbonyl-cyclopent-2′-ene (20). To an ice-cold solu-
tion of nitrosulfone 19 (1.05 g, 1.61 mmol) in methanol (20 mL) was
added tetramethylguanidine (0.24 mL, 1.91 mmol). The mixture was
stirred at 0 °C for 15 min followed by addition of TBA-oxone23 (7.5 g,
36%, 7.59 mmol), sodium carbonate (800 mg, 7.55 mmol), and
dichloromethane (25 mL). The solution was stirred at room temperature
for 16 h. It was then diluted with chloroform (100 mL) and washed
with water (100 mL). The aqueous layer was back-extracted with more
chloroform (30 mL), and the combined chloroform layers were dried
and concentrated. The residue was purified by flash chromatography
(ethyl acetate) to furnish 584.1 mg (71%) of 20 as a solid, Rf ) 0.43,
In addition, 0.74 g (4%) of 21b (R ) Ph), Rf ) 0.41 (ethyl acetate),
mp 120-121 °C (EtOAc) was obtained.
IR (KBr): 3071, 1718, 1597, 1538, 1475, 1450, 1384 cm-1. 1H NMR
(400 MHz, CDCl3): δ 8.90 (s, 1H), 8.39 (s, 1H), 7.95 (d, J ) 7.9 Hz,
2H), 7.57 (t, J ) 7.4 Hz, 1H), 7.43 (t, J ) 7.7 Hz, 2H), 6.62 (m, 1H),
6.37 (dd, J ) 2.3, 5.5 Hz, 1H), 6.11 (m, 1H), 6.02 (m, 1H), 3.28 (p, J
) 7.7 Hz, 1H), 2.13 (dt, J ) 2.7, 15.3 Hz, 1H). 13C NMR (101 MHz,
CDCl3): δ 165.7, 162.0, 152.3, 146.5, 142.7, 137.4, 133.3, 132.6, 129.4,
129.1, 128.4, 121.9, 77.1, 60.3, 39.9. Anal. Calcd for C17H13ClN4O2:
C, 59.92; H, 3.85; N, 16.44. Found: C, 59.72; H, 4.00; N, 16.26.
mp 118-120 °C (EtOAc), [R]20 -61.0° (c 0.5, CH2Cl2).
D
IR (CDCl3): 3398, 1737, 1695, 1620, 1589, 1492 cm-1. H NMR
1
In addition, 2.9 g of recovered 6-chloropurine, Rf ) 0.37 (2/1 ethyl
(400 MHz, CDCl3): δ 8.06 (s, 2H), 7.46-7.24 (m, 10H), 6.25 (dt, J
) 2.2, 5.5 Hz, 1H), 5.96 (dt, J ) 2.3, 5.5 Hz, 1H), 5.74 (m, 1H), 3.79
acetate/acetone) was obtained.
1H NMR (300 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.67 (s, 1H).
In addition, 2.7 g (13%) of 21c, Rf ) 0.36 (1/1 ethyl acetate/acetone),
mp 250-251 °C (dec) (DMF) was isolated.
(39) Wade, P. A.; Hinney, H. R.; Amin, N. V.; Vail, P. D.; Morrow, S.
D.; Hardinger, S. A.; Saft, M. S. J. Org. Chem. 1981, 46, 765.

Synthesis of Carbanucleosides
J. Am. Chem. Soc., Vol. 122, No. 25, 2000 5955
IR (KBr): 1590, 1561, 1495, 1435, 1402, 1382, 1335 cm-1. 1H NMR
(400 MHz, DMSO-d6): δ 8.89 (s, 2H), 8.80 (s, 2H), 6.45 (s, 2H), 5.92
(dd, J ) 6.4, 8.5 Hz, 2H), 3.41 (dt, J ) 8.6, 14.1 Hz, 1H), 2.41 (dt, J
) 6.1, 14.3 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ 151.6, 149.0,
145.8, 134.1, 134.0, 131.2, 58.9, 38.3. Anal. Calcd for C15H10Cl2N8:
C, 48.28; H, 2.70; N, 30.02. Found: C, 48.36; H, 2.54; N, 29.79.
(1′R,4′S)-1′-(6-Chloropurin-9-yl)-4′-phenylsulfonyl(nitro)methyl-
cyclopent-2′-ene (26). To a deoxygenated solution of triphenylphos-
phine (400 mg, 1.52 mmol) in tetrahydrofuran (10 mL) was added
Pd2dba3‚CHCl3 (200 mg, 0.19 mmol), and the mixture was stirred for
15 min. It was then added to a deoxygenated solution of monobenzoate
21a (13.5 g, 39.6 mmol), phenylsulfonyl(nitro)methane (6)39 (9.3 g,
46.2 mmol), and triethylamine (13 mL, 93.3 mmol) in THF (200 mL).
After the mixture stirred for 12 h and was concentrated, the semicrys-
talline residue was taken up in chloroform (350 mL) and washed with
0.2 M hydrochloric acid (300 mL). The aqueous phase was extracted
with more chloroform (50 mL), and the combined organic layers were
dried and concentrated. The residue was purified by flash chromatog-
raphy (ethyl acetate f 3/1 ethyl acetate/acetone) to give 15.8 g (95%)
of 26 as a foam (1:1 mixture of diastereomers), Rf ) 0.40 (ethyl acetate).
IR (CDCl3): 1591, 1558, 1336 cm-1. 1H NMR (200 MHz, CDCl3):
δ 8.72 (s, 2H), 8.14 (s, 1H), 8.13 (s, 1H), 8.00-6.90 (m, 10H), 6.59
(dt, J ) 2.1, 5.7 Hz, 1H), 6.08 (m, 5H), 4.79 (m, 2H), 3.98 (m, 2H),
3.20 (dt, J ) 8.8, 14.9 Hz, 1H), 3.04 (dt, J ) 8.8, 14.6 Hz, 1H), 2.45
(dt, J ) 5.7, 14.9 Hz, 1H), 2.14 (dt, J ) 5.8, 14.5 Hz, 1H). 13C NMR
(101 MHz, CDCl3): δ 151.6, 151.5, 151.2, 151.2, 151.1, 151.0, 143.7,
143.6, 135.6, 135.6, 134.4, 134.3, 134.2, 134.0, 132.2, 132.2, 132.1,
132.0, 129.6, 129.6, 102.9, 102.8, 61.0, 59.8, 44.2, 43.9, 33.8, 33.6.
(1′S,2′S,3′R,4′R)-4′-(6-Chloropurin-9-yl)-1′-phenylsulfonyl(nitro)-
methyl-cyclopentane-2′,3′-diol (28). To a solution of olefin 26 (100
mg, 0.24 mmol) and NMO (50 mg, 0.43 mmol) in dichloromethane (2
mL) was added osmium tetroxide (4% aqueous solution, 80 µL, 0.01
mmol). After the mixture stirred for 5 h and after addition of ethyl
acetate (1 mL), water (1 mL), and sodium bisulfite (30 mg, 0.29 mmol)
and stirring for an additional 30 min, the phases were separated, and
the aqueous phase was extracted with ethyl acetate (3 mL). The
combined organic phases were dried, concentrated, and purified by flash
chromatography (ethyl acetate) to give 88.2 mg (82%) of 28 as a foam,
Rf ) 0.40, mp 227-229 °C (dec) (MeOH).
(1′R,2′R,3′S,4′S)-1′-(6-Chloropurin-9-yl)-2′,3′-epoxy-4′-phenylsul-
fonyl(nitro)methyl-cyclopentane (36). MCPBA (85%, 500 mg, 2.46
mmol) was added to a solution of the olefin 26 (684 mg, 1.63 mmol)
in dichloromethane (10 mL), and the mixture was stirred for 44 h.
Precipitated m-chlorobenzoic acid was filtered off. The filtrate was
concentrated and the residue purified by flash chromatography (1/1
hexane/ethyl acetate) to afford 518 mg (73%) of the epoxide 36 as a
solid, Rf ) 0.49 (ethyl acetate), mp 205-206 °C (acetone, cocrystallized
with 1 equiv of acetone).
IR (KBr): 2950, 1593, 1560, 1449, 1404, 1338 cm-1. 1H NMR (400
MHz, CDCl3)(4:3 mixture of diastereomers): Major diastereomer: δ
8.78 (s, 1H), 8.43 (s, 1H), 7.92 (m, 2H), 7.82 (m, 1H), 7.67 (m, 2H),
5.70 (d, J ) 10.5 Hz, 1H), 5.38 (t, J ) 8.8 Hz, 1H), 3.95 (dd, J ) 1.2,
2.7 Hz, 1H), 3.63 (bd, J ) 1.9 Hz, 1H), 3.41 (bq, J ) 8.0 Hz, 1H),
2.90 (dt, J ) 8.0, 13.5 Hz, 1H), 1.79 (dt, J ) 9.5, 13.5 Hz, 1H). Minor
diastereomer: δ 8.74 (s, 1H), 8.41 (s, 1H), 7.97 (m, 2H), 7.83 (m,
1H), 7.67 (m, 2H), 5.75 (d, J ) 10.8 Hz, 1H), 5.33 (t, J ) 8.8 Hz,
1H), 4.31 (dd, J ) 1.1, 2.7 Hz, 1H), 4.03 (dd, J ) 1.2, 2.7 Hz, 1H),
3.49 (bq, J ) 8.0 Hz, 1H), 2.53 (dt, J ) 8.0, 12.9 Hz, 1H), 1.70 (dt,
J ) 9.5, 12.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) (both diastereo-
mers): δ 152.0, 152.0, 151.5, 151.1, 143.0, 142.9, 135.9, 133.7, 133.5,
131.2, 129.7, 129.7, 129.6, 129.5, 101.8, 101.8, 58.0, 56.4, 55.5, 55.3,
54.3, 53.4, 38.3, 38.1, 29.5, 28.8. Anal. Calcd for C17H14ClN5O5S‚
acetone: C, 48.63; H, 4.08; N, 14.18. Found: C, 48.46; H, 4.19; N,
13.96.
(3′S,4′R)-4′-(6-Chloropurin-9-yl)-3′-hydroxy-1′-methoxycarbonyl-
cyclopent-1′-ene (37). A solution of epoxide 36 (1.5 g, 3.44 mmol)
and DBU (2.5 mL, 16.5 mmol) in THF (130 mL) was stirred at room
temperature for 10 min. Methanol (60 mL) was then added and the
mixture cooled to -78 °C. Ozone was bubbled through over 40 min
until the starting material had disappeared by TLC. The solution was
allowed to warm to room temperature over 3 h and then concentrated.
The residue was dissolved in chloroform (100 mL) and washed with
water (80 mL). The aqueous layer was extracted with more chloroform
(20 mL), and the combined organic layers were dried and concentrated.
The residue was purified by flash chromatography (ethyl acetate) to
furnish 675 mg (67%) of 37 as a solid, Rf ) 0.37, mp 205-206 °C
(EtOAc), [R]20 +147.4° (c 1.04, MeOH).
D
IR (KBr): 3300-3200, 1723, 1592, 1571, 1439, 1407, 1340 cm-1
.
1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.24 (s, 1H), 6.92 (q, J
) 2.0 Hz, 1H), 5.40 (q, J ) 7.2 Hz, 1H), 5.18 (dt, J ) 2.0, 6.4 Hz,
1H), 3.84 (s, 3H), 3.64 (d, J ) 6.5 Hz, 1H), 3.23-3.19 (m, 2H). 13C
NMR (101 MHz, CD3OD): δ 166.1, 153.8, 152.9, 151.0, 148.1, 142.2,
138.2, 132.0, 75.1, 57.4, 52.5, 36.0. Anal. Calcd for C12H11ClN4O3:
C, 48.91; H, 3.76; N, 19.01. Found: C, 48.86; H, 4.00; N, 18.90.
(3′R,4′R)-4′-(6-Chloropurin-9-yl)-1′-methoxycarbonyl-3′-(p-ni-
trobenzoyl)oxy-cyclopent-1′-ene (40). To an ice-cooled solution of
alcohol 37 (100 mg, 0.34 mmol), p-nitrobenzoic acid (100 mg, 0.60
mmol), and triphenylphosphine (150 mg, 0.57 mmol) in THF (3 mL)
was added DEAD (90 µL, 0.57 mmol). The reaction was stirred at 0
°C for 6 h. The mixture was diluted with chloroform (20 mL) and
washed with saturated aqueous sodium bicarbonate (20 mL). The
aqueous layer was extracted with more chloroform (2 mL), and the
combined organic layers were dried and concentrated. The residue was
purified by flash chromatography (3/2 ethyl acetate/hexane) to give
94 mg (62%) of 40 as a foam, Rf ) 0.32, [R]20D -178.3° (c 1, CHCl3).
IR (KBr): 3800-3000, 1594, 1561, 1450, 1329, 1210, 1157, 1085
cm-1. 1H NMR (400 MHz, DMSO-d6) (10:1 mixture of diastereomers,
only data for major diastereomer shown): δ 8.79 (s, 1H), 8.77 (s, 1H),
7.95 (d, J ) 8.0 Hz, 2H), 7.88 (t, J ) 7.5 Hz, 1H), 7.73 (t, J ) 7.8 Hz,
2H), 6.62 (d, J ) 10.8 Hz, 1H), 5.69 (d, J ) 4.0 Hz, 1H), 5.36 (d, J
) 5.5 Hz, 1H), 5.26 (q, J ) 8.0 Hz, 1H), 4.28 (bs, 1H), 3.92 (d, J )
3.7 Hz, 1H), 3.04 (m, 1H), 2.76 (dt, J ) 7.7, 14.9 Hz, 1H), 2.44 (m,
1H). 13C NMR (101 MHz, DMSO-d6): δ 152.6, 151.3, 148.6, 148.3,
135.8, 134.1, 130.4, 129.8, 129.6, 102.2, 73.1, 70.8, 54.4, 37.9, 32.7.
Anal. Calcd for C17H16ClN5O6S: C, 44.99; H, 3.55; N, 15.43. Found:
C, 44.79; H, 3.61; N, 15.30.
(1′S,2′S,3′R,4′R)-4′-(6-Chloropurin-9-yl)-2′,3′-O-isopropylidene-
1′-methoxycarbonyl-cyclopentane-2′,3′-diol (31b). To a solution of
nitrosulfone 34 (87 mg, 0.18 mmol) in methanol (3 mL) and THF (2
mL) was added DBU (50 µL, 0.33 mmol). The solution was cooled to
-78 °C, and ozone was bubbled through over 30 min. After the mixture
was quenched with acetic acid (2 drops) and concentrated to half the
volume, the residue was taken up in chloroform (10 mL) and washed
with water (10 mL). The aqueous phase was extracted with more
chloroform (2 mL), and the combined organic phases were dried,
concentrated, and chromatographed (4/1 ethyl acetate/hexane) to give
47.1 mg (76%) of 31b as a solid, Rf ) 0.40, mp 238-240 °C (EtOAc),
1
IR (CDCl3): 1729, 1592, 1564, 1532, 1443, 1410, 1341 cm-1. H
NMR (400 MHz, CDCl3): δ 8.73 (s, 1H), 8.30 (d, J ) 8.9 Hz, 2H),
8.18 (s, 1H), 8.17 (d, J ) 8.9 Hz, 2H), 6.91 (q, J ) 1.9 Hz, 1H), 6.56
(dq, J ) 2.0, 5.6 Hz, 1H), 5.35 (ddd, J ) 5.6, 6.9, 8.9 Hz, 1H), 3.86
(s, 3H), 3.47 (ddt, J ) 1.9, 8.9, 17.1 Hz, 1H), 3.38 (ddt, J ) 2.0, 6.9,
17.1 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 163.7, 163.4, 151.7,
151.4, 151.3, 150.7, 144.1, 138.3, 136.3, 133.9, 132.1, 130.8, 123.5,
83.6, 60.9, 52.2, 36.0. HRMS Calcd for C19H1435ClN5O6: 443.0633.
Found: 443.0616.
(3′R,4′R)-4′-(6-Chloropurin-9-yl)-3′-hydroxy-1′-hydroxymethyl-
cyclopent-1′-ene (41). To a solution of ester 40 (1.95 g, 4.39 mmol)
in THF (25 mL) and dichloromethane (25 mL) at -78 °C was added
DIBAL-H (1 M hexane solution, 20 mL, 20 mmol). The reaction was
stirred at -78 °C for 1 h and then quenched with ethyl acetate (5 mL).
The mixture was warmed to room temperature and saturated aqueous
[R]20 +66.5° (c 0.9, CHCl3).
D
IR (KBr): 2988, 2949, 1749, 1592, 1562, 1344, 1254, 1205, 1169,
1
1100, 1068, 948 cm-1. H NMR (400 MHz, CDCl3): δ 8.73 (s, 1H),
8.37 (s, 1H), 4.99 (t, J ) 5.5 Hz, 1H), 4.93 (dt, J ) 5.4, 12.8 Hz, 1H),
4.77 (t, J ) 5.0 Hz, 1H), 3.78 (s, 3H), 2.97 (dt, J ) 5.9, 11.9 Hz, 1H),
2.78 (q, J ) 12.5 Hz, 1H), 2.32 (dt, J ) 5.9, 11.9 Hz, 1H), 1.50 (s,
3H), 1.27 (s, 3H). 13C NMR (75.5 MHz, CDCl3): δ 169.7, 151.8, 151.7,
150.9, 144.8, 131.3, 111.7, 79.3, 77.5, 54.5, 52.0, 45.7, 28.1, 25.2, 23.7.
Anal. Calcd for C15H17ClN4O4: C, 51.07; H, 4.86; N, 15.88. Found:
C, 51.15; H, 5.02; N, 16.07.

5956 J. Am. Chem. Soc., Vol. 122, No. 25, 2000
Trost et al.
Rochelle salt (30 mL) and ethyl acetate (60 mL) were added. After the
mixture stirred for 3 h, the phases were separated, and the aqueous
phase was extracted with ethyl acetate (20 mL). The extracts were dried
and concentrated to give 1.9 g of a foam which was taken up in
methanol (50 mL) and triethylamine (1 mL, 7.17 mmol). The mixture
was stirred for 2 h and then concentrated to give a solid residue which
was purified by flash chromatography (1/1 ethyl acetate/acetone) to
afford 920 mg (79%) of 41 as a white solid, Rf ) 0.37, mp 190-191
IR and 1H and 13C NMR data are in accordance with literature
values.6,11
2′,3′-Diepi-Neplanocin A (63). The triacetate 62 (110 mg, 0.27
mmol) was dissolved in a saturated solution of ammonia in methanol
(4 mL). The flask was sealed and the mixture stirred at room
temperature for 4 days. Concentration in vacuo and chromatography
(3/2 ethyl acetate/methanol) gave a syrupy residue which was dissolved
in methanol and poured on a column of Amberlite IRA-400 (OH) ion-
exchange resin (6 mL). The column was eluted with methanol, and
the eluate concentrated to afford 49.5 mg (70%) of 63 as a white solid,
Rf ) 0.30, mp 228-230 °C (H2O/MeOH), [R]20D +16.0° (c 0.33, H2O).
IR (KBr): 3600-2600, 1669, 1648, 1610, 1574, 1480, 1417, 1335,
°C (dec) (MeOH), [R]20 -62.7° (c 0.3, MeOH).
D
IR (KBr): 3600-3000, 3112, 2860, 1592, 1561, 1495, 1436, 1402,
1338, 1206, 1038, 944 cm-1. 1H NMR (400 MHz, DMSO-d6): δ 8.79
(s, 1H), 8.77 (s, 1H), 5.62 (bd, J ) 1.7 Hz, 1H), 5.44 (d, J ) 5.8 Hz,
1H), 5.15 (m, 1H), 4.96 (t, J ) 5.4 Hz, 1H), 4.90 (dt, J ) 6.0, 8.1 Hz,
1H), 4.01 (m, 2H), 2.87-2.77 (m, 2H). 13C NMR (101 MHz, DMSO-
d6): δ 151.9, 151.2, 149.1, 146.9, 144.6, 131.4, 125.8, 79.3, 64.4, 59.7,
36.1. Anal. Calcd for C11H11ClN4O2: C, 49.54; H, 4.16; N, 21.01.
Found: C, 49.30; H, 4.26; N, 20.88.
1
1306 cm-1. H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.90 (s,
1H), 7.18 (s, 2H), 5.71 (s, 1H), 5.41 (bs, 1H), 5.39 (bd, J ) 4.5 Hz,
1H), 4.93 (bs, 2H), 4.38 (d, J ) 5.6 Hz, 1H), 4.33 (t, J ) 5.8 Hz, 1H),
4.23 (d, J ) 15.8 Hz, 1H), 4.12 (d, J ) 15.8 Hz, 1H). 13C NMR (101
MHz, DMSO-d6): δ 155.9, 152.0, 151.9, 149.6, 141.2, 121.5, 118.7,
72.8, 70.8, 58.4, 58.3. HRMS Calcd for C11H13N5O3: 263.1018.
Found: 263.1013.
(-)-Neplanocin A (3). A mixture of acetonide 54 (61.5 mg, 0.20
mmol) in 1 M aqueous hydrochloric acid (15 mL) was stirred at 80 °C
for 6 h and then concentrated in vacuo. The residue was dissolved in
methanol and poured onto a column of Amberlite IRA-400 (OH) ion-
exchange resin (5 mL). The column was eluted with methanol, and
the eluate concentrated to give 48.5 mg (91%) of a white solid, Rf )
Acknowledgment. We thank the National Science Founda-
tion and the General Medical Science Institute of the National
Institutes of Health for their generous support of our programs.
Mass spectra were provided by the Mass Spectrometry facility
at the University of California, San Francisco, supported by the
NIH Division of Research Resources.
0.30 (3/2 ethyl acetate/methanol), mp 214-215 °C (H2O), [R]20
D
-153.9° (c 0.33, H2O) (Lit.: mp 220-222 °C,6 211-213 °C,10f 220-
222 °C,10g 212-213 °C;11g [R]20D -157° (c 0.5, H2O),6 [R]20D -153.3°
(c 0.3, H2O),10f [R]20 -152° (c 0.3, H2O),10g [R]20 -153.8° (c 0.3,
D
D
H2O)11g).
Supporting Information Available: Experimental proce-
dures and characterization data for 14, 15, 21b, 22, 24a, 27,
29, 30a-34, 38, 39, 42-47, 49, 50, and 54-62 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
IR (KBr): 3600-2600, 2930, 1668, 1648, 1612, 1583, 1486, 1420,
1333, 1306, 1256, 1116, 1035 cm-1. 1H NMR (400 MHz, DMSO-d6):
δ 8.11 (s, 1H), 8.05 (s, 1H), 7.20 (bs, 2H), 5.69 (s, 1H), 5.33 (bd, J )
2.5 Hz, 1H), 5.16-4.92 (bs, 3H), 4.42 (d, J ) 5.4 Hz, 1H), 4.30 (t, J
) 5.4 Hz, 1H), 4.11 (m, 2H). 13C NMR (101 MHz, DMSO-d6): δ
156.0, 152.3, 150.1, 149.7, 139.5, 123.4, 119.2, 76.6, 72.2, 64.2, 58.6.
JA9938837