An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy

Article abstract of DOI:10.1021/jo005535p

A general and efficient synthesis of carbocyclic and hexenopyranosyl nucleosides has been developed. The strategy combines three key transformations: an asymmetric aldol addition to establish the relative and absolute configuration of the pseudosugar, a ring-closing metathesis to construct the pseudosugar ring, and a Trost-type palladium(0)-mediated substitution to assemble the pseudosugar and the aromatic base. Carbovir, abacavir, and their 2'-methyl derivatives as well as hexenopyranosyl nucleoside analogues have been prepared by this sequence.

Full text of DOI:10.1021/jo005535p

J . Org. Chem. 2000, 65, 8499-8509
8499
An Efficien t, Gen er a l Asym m etr ic Syn th esis of Ca r bocyclic
Nu cleosid es: Ap p lica tion of a n Asym m etr ic Ald ol/Rin g-Closin g
Meta th esis Str a tegy
Michael T. Crimmins,* Bryan W. King, William J . Zuercher, and Allison L. Choy
Venable and Kenan Laboratories of Chemistry, The University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
crimmins@email.unc.edu
Received J une 6, 2000
A general and efficient synthesis of carbocyclic and hexenopyranosyl nucleosides has been developed.
The strategy combines three key transformations: an asymmetric aldol addition to establish the
relative and absolute configuration of the pseudosugar, a ring-closing metathesis to construct
the pseudosugar ring, and a Trost-type palladium(0)-mediated substitution to assemble the pseudo-
sugar and the aromatic base. Carbovir, abacavir, and their 2′-methyl derivatives as well as hexeno-
pyranosyl nucleoside analogues have been prepared by this sequence.
In tr od u ction
Herdewijn has also prepared two series of pyranosyl
analogues 3 and 4, which, like carbocyclic nucleosides,
lack the labile anomeric linkage to the aromatic base.11,12
Many synthetic approaches to carbocyclic nucleosides
rely on the use of cyclopentadiene for the source of the
carbocyclic sugar.13 The advantages of using cyclopenta-
The development of agents that function as nontoxic,
selective inhibitors of kinases and polymerases for the
control of viral diseases has been the focus of intense
research.1 However, despite significant progress, the need
continues for new replication inhibitors of the human
immunodeficiency virus (HIV), herpes simplex virus
(HSV), Epstein-Barr virus (EBV), human cytomegalo-
virus (CMV), hepatitis B virus (HBV), and other viruses.
The ongoing problem of drug resistance adds substan-
tially to this need.2 Nucleoside analogues that are good
substrates for cellular kinases, but resistant to other host
enzymes, such as phosphorylases, are essential for the
development of useful therapeutic agents. Replacement
of the oxygen in the sugar portion of the nucleoside with
a methylene unit results in carbocyclic nucleoside ana-
logues that are highly resistant to phosphorylases.3 While
the carbocyclic analogue of adenosine was first described
by Shealy4 in 1966, the discovery that the natural
carbocyclic nucleosides aristeromycin5,6 and neplanocin
A7 display antibiotic and antitumor activity sparked the
search for other carbocyclic nucleoside analogues with
biological activity. Subsequently, other synthetic carbo-
cyclic nucleosides have shown significant potential as
new antiviral (as well as antitumor) agents.8 Particularly,
carbovir (1)9 and abacavir (Ziagen, 2)10 have been shown
to be inhibitors of HIV replication, the causative agent
for the acquired immune deficiency syndrome (AIDS).13
(6) For synthetic approaches to aristeromycin, see: (a) Boyer, S. J .;
Leahy, J . W. J . Org. Chem. 1997, 62, 3976-3980. (b) Burlina, F.; Favre,
A.; Fourrey, J .-L.; Thomas, M. Bioorg. Med. Chem. Lett. 1997, 7, 247-
250. Burlina, F.; Clivio, P.; Fourrey, J .-L.; Riche, C.; Thomas, M.
Tetrahedron Lett. 1994, 35, 8151-8152. (c) Ohira, S.; Sawamoto, T.;
Yamata, M.; Tetrahedron Lett. 1995, 36, 1537-1538. (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) Van-
hessche, K.; Bello, C. G.; Vandewalle, M. Synlett 1991, 921. (f)
Bestman, H. J .; Rith, 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, 5709-5714.
(h) Medich, J . R.; Kunnen, K. B.; J ohnson, C. R. Tetrahedron Lett. 1987,
28, 4131.
(7) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.;
Otani, M. J . Antibiot. 1981, 34, 359-366.
(8) (a) Crimmins, M. T. Tetrahedron 1998, 54, 9229-9272. (b) Zhu,
X. F. Nucleosides Nucleotides Nucleic Acids 2000, 19, 651-690.
(9) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17-21.
(10) Abacavir (Ziagen) is the carbocyclic nucleoside formerly known
as 1592U89: (a) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W.
H.; St. Clair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N.; Reardon, J .
E.; Dornsfife, R. E.; Averett, D. R. Krenitsky, T. A. Antimicrob. Agents
Chem. 1997, 41, 1082-1093. (b) “Therapeutic Nucleosides”. Daluge,
S. M. U.S. Patent 5,034,394, 1991. Daluge, S. M.; Martin, M. T.; Sickles,
B. R.; Livingston, D. A. Nucleosides Nucleotides Nucleic Acids 2000,
19, 297-327.
(11) Verheggen, I.; Van Aerschot, A.; Toppet, S.; Snoeck, R.; J anssen,
G.; Balzarini, J .; De Clercq, E.; Herdewijn, P. J . Med. Chem. 1993, 36,
2033-2040.
(12) Luyten, I.; Herdewijn, P. Tetrahedron 1996 52, 9249-9262.
(13) For previous syntheses of carbovir and ziagen, see ref 9 and:
(a) Trost, B. M.; Madsen, R. M.; Guile, S. D.; Brown, B. J . Am. Chem.
Soc. 2000, 122, 5947-5956. (b) Olivo, H. F.; Yu, J . J . Chem. Soc., Perkin
Trans. 1 1998, 391.; (c) Martine´z, L. E.; Nugent, W.; J acobsen, E. N.
J . Org. Chem. 1996, 61, 7963. (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.; J ohnson, M. R. J . Org. Chem. 1991, 56, 4990.
(k) J ones, M. F.; Myers, P. L.; Robertson, C. A.; Storer, R.; Williamson,
C. J . Chem. Soc., Perkin Trans. 1 1991, 2479. (l) Berrenger, T.;
Langlois, Y. Tetrahedron Lett. 1995, 36, 5523-5526. (m) J ung, M. E.;
Rhee, H. J . Org. Chem. 1994, 59, 4719-4720.
(1) (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571-
623. (b) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand,
S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611-10670. (c)
Huryn, D.; Okabe, M. Chem. Rev. 1992, 92, 1745-1768. (d) Mansour,
T. S.; Storer, R. Curr. Pharm. Des. 1997, 3, 227-264.
(2) Kavlick, M. F.; Shirasaka, T.; Kojima, E.; Pluda, J . M.; Hiu, F.,
J r.; Yarchoan, R.; Mitsuya, H. Antiviral Res. 1995, 28, 133-146.
(3) Marquez, V.; Lim, M. Med. Res. Rev. 1986, 6, 1. Roberts, S.;
Biggadike, K.; Borthwick, A.; Kirk, B. In Topics in Medicinal Chem-
istry; Leeming, P. R., Ed.; Royal Society of Chemistry: London, 1988;
p 172. Bricaud, H.; Herdewijn, P.; DeClerq, E. Biochem. Pharmacol.
1983, 3583.
(4) Shealy, Y. F.; Clayton, J . D. J . Am. Chem. Soc. 1966, 88, 3885-
3887. Shealy, Y. F.; Clayton, J . D. J . Am. Chem. Soc. 1969, 91, 3075-
3083. Shealy, Y. F.; Clayton, J . D. J . Pharm. Sci. 1973, 62, 1432.
(5) (a) Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi,
T.; Mizuno, K. J . Antibiot. 1968, 21, 255-271.
10.1021/jo005535p CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/17/2000

8500 J . Org. Chem., Vol. 65, No. 25, 2000
Crimmins et al.
Sch em e 1
Sch em e 2
diene are that the five-membered carbocyclic structure
is already intact and it is a very inexpensive starting
material. There are disadvantages as well. To accomplish
an enantioselective synthesis, introduction of chirality
upon the carbocyclic ring must be accomplished by means
of an asymmetric bond forming reaction, by a desymme-
trization process of a meso intermediate, or by classical
resolution. The ability to prepare a variety of substituted
analogues is also somewhat limited.
the rapid assembly of hexenopyranosyl nucleosides 4
through a palladium(0)-mediated substitution. Herein,
we report the details concerning the use of this strategy
in the synthesis of carbocyclic as well as other substituted
nucleoside analogues.
We recently reported an efficient and general strategy
for the synthesis of carbocyclic nucleosides 1 and 2 based
on an asymmetric aldol/ring-closing metathesis strategy.
This strategy holds the advantage of establishing the
asymmetry of the molecule prior to ring closure, thus
opening the possibility of introduction of substitution on
the five-membered ring.14 We sought to exploit the aldol-
metathesis approach to allow greater flexibility in the
preparation of a variety of 2′ substituted analogues as
well as heterocyclic analogues. Our approach to carbo-
cyclic nucleoside analogues involves a combination of
three powerful reactions in retrosynthetic order: (1)
Trost-type allylic substitution of an allylic ester with the
purine or pyrimidine base to assemble the nucleoside
base and the pseudo-sugar,15 (2) ring-closing metathesis
(RCM) to form the pseudo sugar ring,16 and (3) asym-
metric aldol addition to control the relative and absolute
stereochemistry of the pseudo-sugar17 (Scheme 1). The
palladium-catalyzed coupling of the pseudosugar frag-
ment 5 (or its allylic regioisomer) with an aromatic base
via an π-allyl intermediate is a well-established, conver-
gent approach to nucleosides.18 The appropriate func-
tionalized precursors 5 have been previously prepared
by a variety of methods from cyclopentadiene,6b,13d,e,f,i,19
but can also be formed in a straightforward manner by
RCM of a diene 6, the stereochemistry of which is
established through an asymmetric aldol addition.
The strategy described above might also be applied to
the construction of other nucleoside analogues by incor-
poration of a heteroatom into the sugar moiety as
illustrated in Scheme 2. Initiating the strategy with a
glycolate chiral auxiliary 9 could allow the stereoselective
preparation of the diene 8. Metathesis of the diene 8
would provide the allylic ester 7, which could result in
Resu lts
Syn th esis of Ca r bovir 1 a n d Aba ca vir 2. The
synthesis of carbocyclic nucleosides 1 and 2 began with
acylation of the lithium anion of (S)-4-benzyl-2-oxazoli-
dinone with 4-pentenoic pivalic mixed anhydride to afford
10 in nearly quantitative yield (Scheme 3). Use of our
titanium tetrachloride and (-)-sparteine protocol20 to
generate the chlorotitanium enolate of 10 followed by
addition of acrolein resulted in diastereoselective syn
aldol addition to produce the aldol adduct 11 in 82% yield
[>99% de, [R]24 +50.6 (c ) 0.89, CHCl3)]. Exposure of
D
11 to 1 mol % (PCy3)2Cl2RudCHPh in CH2Cl2 at 25 °C
led to cyclopentenol 12 (97% yield), which was then
reduced to diol 13 in 78% yield with LiBH4 (>99.6% ee
by chiral HPLC of the bis-(p-toluate) ester).21 While allylic
alcohols have been known to undergo isomerization in
the presence of the Grubbs catalyst,22 the presence of the
allylic alcohol in 11 does not adversely effect the ring-
closing metathesis in this case. Diol 1313l was readily
converted to the diacetate 146b by exposure to acetic
anhydride, triethylamine and 4-(dimethylamino)pyridine.
The dicarbonate 15 was accessed by treatment of the diol
with methyl chloroformate in dichloromethane with
pyridine as the base.13l Interestingly, if triethylamine was
(19) (a) Bajorek, J . J .; Battaglia, R.; Pratt, G.; Sutherland, J . K. J .
Chem. Soc., Perkin Trans. 1 1974, 1243. Pawson, H.; Maass, U. Chem.
Ber. 1981, 114, 346. (b) Popescu, A.; Hornfeldt, A.-B.; Gronowitz, S.;
J ohansson, N. G. Nucleosides Nucleotides 1995, 14, 1233-1249. (c)
Saville-Stones, E. A.; Turner, R. M.; Lindell, S. D.; J ennings, N. S.;
Head, J . C.; Carver, D. S. Tetrahedron 1994, 50, 6695-6704. (d)
MacKeith, R. A.; McCague, R., Olivo, H. F.; Palmer, C. F., Roberts, S.
M. J . Chem. Soc., Perkin Trans. 1 1993, 313-314. (e) Gundersen, L.-
L.; Benneche, T.; Undheim, K. Tetrahedron Lett. 1992, 33, 1085-1088.
(f) Gundersen, L.-L.; Benneche, T.; Rise, F.; Gogoll, A.; Undheim, K.
Acta Chem. Scand. 1992, 46, 761-771. (g) Hildbrand, S.; Leumann,
C.; Scheffold, R. Helv. Chim. Acta 1996, 79, 702-709. (h) Hodgson, D.
M.; Witherington, J .; Moloney, B. A. Tetrahedron: Asymmetry 1994,
5, 337-338. (i) Dhanda, A.; Knutsen, L. J . S.; Nielsen, M.-B.; Roberts,
S. M.; Varley, D. R. J . Chem. Soc., Perkin Trans. 1 1999, 3469-3475.
(20) Crimmins, M. T.; King, B. W.; Tabet, E. A. J . Am. Chem. Soc.
1997, 119, 7883-7884.
(14) Crimmins, M. T.; King, B. W. J . Org. Chem. 1996, 61, 4192-
4193.
(15) Trost, B. M.; Kuo, G.-H.; Benneche, T. J . Am. Chem. Soc. 1988,
110, 621-622.
(16) (a) Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995,
28, 446-454. (b) Furstner, A. Top. Catal. 1997, 4, 285-299. (c) Naota,
T.; Takaya, H.; Murahashi, S.-I. Chem. Rev. 1998, 98, 2599-2660.
(17) (a) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc.
1981, 103, 2127-2129. (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M.
T.; Urpi, F. J . Am. Chem. Soc. 1991, 113, 1047-1049. (c) Yan, T.-Y.;
Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J . Am. Chem. Soc. 1993,
115, 2613-2621. (d) Ahn, K. H.; Lee, S.; Lim, A. J . Org. Chem. 1992,
57, 5065-5066. (e) Bonner, M. P.; Thornton, E. R.; J . Am. Chem. Soc.
1991, 113, 1299-1308. (f) Oppolzer, W.; Lienard, P. Tetrahedron Lett.
1993, 34, 4321-4324.
(21) It was imperative to remove trace amounts of ruthenium from
the metathesis reaction since any residual ruthenium catalyzed
hydrogenation of the cyclopentene olefin in the during the lithium
borohydride reduction. Apparently, the hydrogen generated during the
reduction, in combination with the trace ruthenium resulted in
hydrogenation of the alkene.
(18) For
a thorough discussion of the use of π-allylpalladium
chemistry for the convergent assembly of carbocyclic nucleosides, see
ref 8a.
(22) Ackerman, L.; El Tom, D.; Fu¨rstner, A. Tetrahedron 2000, 56,
2195-2202.

Synthesis of Carbocyclic Nucleosides
J . Org. Chem., Vol. 65, No. 25, 2000 8501
Sch em e 3
Sch em e 5
thought to be coordinating to the metal center, thus
stabilizing the intermediate ruthenium alkylidine. Since
the next step was to remove the auxiliary, we opted to
reverse the order of the sequence and reductively remove
the auxiliary prior to the olefin metathesis. Exposure of
aldol adduct 19 to sodium borohydride in aqueous THF
produced the diol 21 in 77% yield. Acetylation of the diol
with acetic anhydride followed by treatment of the
diacetate with the Grubbs catalyst produced the diacetate
14 in 83% overall yield.
In a similar approach, the non-Evans syn aldol adduct
24 was prepared in 79% yield by enolization of the
acyl oxazolidinethione 23 with 2 equiv of titanium tetra-
chloride in the presence of diisopropylamine followed by
addition of crotonaldehyde. In contrast to the Evans syn
aldol adduct 19, the diene 24 underwent efficient ring-
closing metathesis when treated with Cl2(PCy3)2Rud
CHPh. There is apparently a difference in the ability of
the thiocarbonyl to coordinate to the metal in the
intermediate alkylidine in the Evans syn and non-Evans
syn diastereomers 19 and 24. The ultimate result is that
the non-Evans syn diastereomer 24 can be processed to
the required diol 13 as shown in Scheme 5 by metathesis
of the diene 24 followed by reductive removal of the
auxiliary.
Sch em e 4
With ready access to the diacetate 14, the dicarbonate
15 and the cyclic carbonate 16, evaluation of the Pd-
catalyzed coupling with both 2-amino-6-chloropurine
26 and 2-amino-6-(cyclopropylamino)purine 27 was in-
vestigated (Schemes 6 and 7). While Pd(0)-catalyzed
assembly of carbocyclic nucleosides from allylic acetates
and carbonates and purine bases is well-established,18
the use of cyclopropylaminopurine 27 had not been
previously investigated. Reaction of diacetate 14 with
2-amino-6-chloropurine in the presence of Pd(PPh3)4 and
NaH in 1:1 THF/DMSO at 45 °C yielded an 86:14 mixture
of the chloropurine acetate 28a 13m and its N7 isomer
29a (65% isolated yield of 28a ). The analysis of the N7
used as the base in the methyl chloroformate acylation,
cyclic carbonate 1613d resulted.
In an effort to avoid the use of lithium borohydride to
remove the oxazolidinone auxiliary because of the cost,
the use of the oxazolidinethione 17 as the chiral auxiliary
was investigated since oxazolidinethiones are known to
be more easily cleaved.23 Attachment of the 4-pentenoate
proceeded as before to give the acyl oxazolidinethione
18 in 99% yield (Scheme 4). Again, through the use of
(-)-sparteine as the base with titanium tetrachloride as
the Lewis acid, the Evans syn aldol 19 resulted in high
yield with excellent diastereoselectivity. Unfortunately,
attempts to execute the Grubbs metathesis on diene 19
were disappointing. Yields were generally low due to poor
conversion. The thiocarbonyl of the oxazolidinethione was
1
and N9 coupling products is readily accomplished by H
NMR, since the proton at the 8-position of the purine is
well separated and easily distinguished in the two regio-
isomers. The C-8 proton of the N9 isomer (ca. δ 7.85 ppm)
is typically upfield of the N7 isomer (ca. δ 8.05 ppm). The
problem of N9-N7 regioselectivity is a common problem
in classic Vorbruggen coupling of purines with sugars,24
but the issue has only recently been recognized in Pd-
catalyzed couplings.
This extremely important observation was noted by
Benneche and Gunderson.19e-f They noted that not only
(24) (a) Vorbruggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber.
1981, 114, 1234-1255. (b) Vorbruggen, H.; Hofle, G. Chem. Ber. 1981,
114, 1256-1268.
(23) Nagao, Y.; Yagi, M.; Ikedo, T.; Fujita, E. Tetrahedron Lett. 1982,
23, 201-204.

8502 J . Org. Chem., Vol. 65, No. 25, 2000
Crimmins et al.
Sch em e 6
F igu r e 1. Nucleoside analogues.
6-(cyclopropylamino)purine 27 was utilized as the nu-
cleophile in the coupling reaction. Exposure of 27 and
diacetate 14 to 10 mol % Pd(PPh3)4 and NaH in DMSO
resulted in a 95:5 mixture of N9/N7 regioisomers 30 and
31 (Scheme 7). The N9 isomer 30 was obtained in 62%
yield after silica gel chromatography and was readily
hydrolyzed to 2 with NaOH.
Syn th esis of 2′-Meth yl Der iva tives of Ca r bovir
a n d Aba ca vir . The advantages of enzymatic stability
and improved bioavailability of carbocyclic nucleosides
is counter-balanced by substantial changes in the con-
formation of carbocyclic nucleosides relative to natural
nucleosides and their analogues. Removal of the ring
oxygen eliminates the possibility for anomeric stabiliza-
tion of the axially oriented C-N bond and also removes
the gauche interaction between the C4′-O bond and the
C3′-OH bond. The result is a dramatic change in the
conformation obtained in the five membered ring pseu-
dorotational cycle. The preferential C2′-endo,3′-exo (south-
ern) and C3′-endo,2′-exo (northern) conformations are not
favored in analogous carbocyclic nucleosides.25 The 1′-
exo conformation that places the base in a pseudoequa-
torial orientation is preferred. This conformational change
is a likely reason for the lack of biological activity of many
carbocyclic nucleosides, possibly due to poor processing
to the triphosphates by cellular or viral kinases or
because of poor recognition of the triphosphate by the
appropriate polymerase. As a consequence of the noted
conformational observations, the activity of carbocyclic
nucleoside antiretroviral agents has been correlated with
conformation.26 For example, Marquez and co-workers
demonstrated that Carba-T, a conformationally unre-
stricted pyrimidine carbocyclic nucleoside, showed poor
activity against HSV-I and II (Figure 1).27 Locking the
Sch em e 7
did coupling of purines with allylic esters and carbonates
give a mixture of N9 and N7 isomers of the products, but
also incorporation of larger groups at the 6 position of
the purine can substantially alter the regioselectivity of
the coupling reaction. Earlier and some subsequent
reports fail to recognize this limitation of the direct
coupling, although it is a common problem in natural
nucleoside synthesis. As expected, use of the cyclic
carbonate 16 in the coupling reaction with 26 led to a
similar result (71% yield of an 85:15 N9/N7 mixture of
system into a northern E conformation by cyclopropane
2
annulation led to pronounced antiretroviral activity of
N-methano Carba-T (Figure 2). A similar annulation that
biased the system into a southern 2E conformation
produced poor antiretroviral activity for S-methano Car-
ba-T in the same assay. Additionally, it has been dem-
onstrated by Painter that AZT-triphosphate and thymi-
dine triphosphate both adopt a similar (northeastern) 4′-
exo conformation when bound to reverse transcriptase;
thus, conformationally biased carbocyclic nucleosides that
exist in a northern or northern-like 4′-exo conformation
could be viable antivirals.28-30
1
28c:13d29c as determined by H NMR), but the dicarbon-
ate 15 gave only a 74:26 mixture, albeit in higher yield
(68% of N9 isomer 28b13f after purification) and at room
temperature without the need for external base. Treat-
ment of the chloropurine 28a with cyclopropylamine in
EtOH followed by hydrolysis of the acetate (NaOH, H2O)
produced abacavir 2 in 81% overall yield identical to that
previously reported.10,13 Alternatively, direct hydrolysis
of 28a with NaOH produced carbovir 1 in 68% yield
consistent with reported literature data.9,13
(25) Kalman, A.; Koritsanszky, T.; Beres, J .; Sagi, G. Nucleosides
Nucleotides 1990, 9, 235-243.
(26) It should be noted that the action of nucleoside drugs involves
multiple enzymatic steps, each of which may exhibit distinct confor-
mational selectivity. For a comprehensive review of the defining terms
for nucleoside conformations, see: Saenger, W. Principles of Nucleic
Acid Structure; Springer-Verlag: New York, 1984.
On the basis of the observations of Benneche and
Gundersen,19e,f it was anticipated that the N9/N7 regi-
oselectivity might be improved by first incorporating the
cyclopropylamino group at the 6-position. Thus, 2-amino-
(27) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.; Wang,
J . Y.; Wagner, R. W.; Matteucci, M. D. J . Med. Chem. 1996, 39, 3739-
3747.
(28) Painter, G. R.; Aulabaugh, A. E.; Andrews, C. W. Biochem.
Biophys. Res. Commun. 1993, 191, 1166-1171.

Synthesis of Carbocyclic Nucleosides
J . Org. Chem., Vol. 65, No. 25, 2000 8503
Sch em e 8
F igu r e 2. Conformationally restricted carbocyclic nucleosides.
Sch em e 9
F igu r e 3. Conformations of 2′-substituted cyclopentenes.
We thus set out to bias abacavir and carbovir into more
northern-like conformations, which would require a
pseudoaxially oriented base. We anticipated that the
addition of a 2′-methyl group would lead to enhanced A1,2
strain with the purine and force the base to be pseudo-
axial. Molecular modeling on a simple system (cis-3-
amino-5-methylcyclopentene) supports this argument:31
with no olefinic substitution, the conformation possessing
pseudoequatorial substituents is thermodynamically fa-
vored by 0.4 kcal mol-1 over the pseudoaxial conformation
by calculated MM2 energies (Figure 3). Addition of a 2′-
methyl group reverses the conformational bias; the
pseudoaxial conformation is favored by 0.4 kcal mol-1
.
In the carbocyclic nucleoside systems of interest, the
presence of purine ring systems instead of a simple amino
group should lead to additional conformation bias, and
the ∆∆G of 0.8 kcal mol-1 in the model system should
serve as a lower limit.
Construction of 2′-methyl analogues would be difficult
through traditional strategies for carbocyclic nucleoside
synthesis, because of their reliance upon cyclopentadiene
as starting material. However, 2′-alkyl derivatives were
thought to be accessible by the previously described aldol/
RCM route through the use of methacrolein or other
R-substituted acroleins in the aldol reaction. Thus, the
synthesis of 2′-methyl derivatives of abacavir and car-
bovir began with the formation of the titanium enolate
of 18 with 1.1 equiv TiCl4 and 2.5 equiv (-)-sparteine
followed by exposure to methacrolein to form the Evans
syn aldol adduct 32 in 86% yield (Scheme 8).20 Alterna-
tively, under slightly different conditions for the aldol
addition (2.1 equiv of TiCl4 and 1.1 equiv of EtN-i-Pr2),
the non-Evans syn aldol adduct 33 was obtained in 81%
yield. Reductive removal of the chiral auxiliary in 32
or 33 was accomplished with LiBH4 to form diol 34 which
was acylated to provide the corresponding diacetate
or dicarbonate. Lithium borohydride was utilized since
LiBH4 gives slightly higher yields than sodium boro-
hydride in some cases. Ring-closing metathesis under
standard conditions provided methylcyclopentenes 35
and 36, respectively.
Both the diacetate 35 and dicarbonate 36 were utilized
in the Pd-catalyzed coupling with 2-amino-6-chloropurine
(Scheme 9). Initial results with Pd(PPh3)4 showed sig-
nificantly lower yields than in analogous reactions of
14 and 15. Yields were slightly increased by employing
Pd2(dba)3‚CHCl3/PPh3 as the catalyst, but optimized
conditions for both 35 and 36 involved Pd2(dba)3‚CHCl3/
P(Oi-Pr)3 catalyst system and led to 45% isolated yield
of chloropurine acetate 37 and 59% isolated yield of
chloropurine carbonate 38. 1H NMR analysis of the crude
(29) Van Roey, P.; Salerno, J . M.; Duax, W. L.; Chu, C. K.; Ahn, M.
K.; Schinazi, R. F. J . Am. Chem. Soc. 1988, 110, 2277-2282.
(30) Birnbaum, G. I.; Giziewicz, J .; Gabem, E. J .; Lin, T.-S.; Prusoff,
W. H. Can. J . Chem. 1987, 65, 2135-2139.
(31) Molecular mechanics calculations were performed with MM2
parameters.

8504 J . Org. Chem., Vol. 65, No. 25, 2000
Crimmins et al.
Sch em e 10
Sch em e 11
product mixtures indicated no N7 isomer was formed in
the reaction of 35 whereas an 85:15 N9/N7 isomer ratio
resulted in the reaction of 36. Again, the C-8 purine
proton was diagnostic in analysis of the regioisomers.
Functionalization of 37 and 38 to the 2′-methyl deriva-
tives of abacavir and carbovir proceeded as in the earlier
synthesis. Thus, exposure of 37 to cyclopropylamine in
EtOH at reflux followed by basic hydrolysis formed 40
in 73% yield. Direct hydrolysis of 38 afforded 41 in 68%
yield.
Sch em e 12
The issue of N9/N7 regioselectivity in the purine
coupling step is influenced by the steric properties of the
incoming nucleophile as well as those of the allylic
intermediate. Increased steric interaction upon approach
of the purine nucleophile, such as the 6-cyclopropylamino
group in 27 or the 2′-methyl group of 35, favors the
desired N9 isomer. Additionally, the nature of the leaving
group affected the N9/N7 selectivity; with the allylic
acetates 14 and 35, NaH was used to form the purine
anion prior to π-allyl formation while the purine anion
was generated in situ during reactions with allylic
carbonates (such as 15 and 36). Preformation of the
purine anion may limit the extent of reversibility of
nucleophilic attack on the π-allyl complex, suggesting the
N9 isomer is the kinetic product.
Syn th esis of a D-th r eo-Hex-3′-en opyr an osyl Nu cleo-
sid e. With a general strategy to the synthesis of carbo-
cyclic nucleosides completed, it was thought that a
similar approach might be applied to other nucleoside
analogues. The initial approach to the synthesis of
hex-3′-enopyranosyl nucleoside analogue 42 was based
on the strategy employed in the synthesis of the carbo-
cyclic nucleoside analogues as shown in Scheme 10. A
palladium-catalyzed coupling of a substituted purine
with dibenzoate 43 was planned for the convergent
construction of the nucleoside analogue. Dibenzoate 43
would be prepared in high enantiomeric purity from the
asymmetric aldol adduct 44 by a ring-closing metathesis
reaction. The aldol product 44 was to be obtained through
an asymmetric aldol addition to establish the relative
and absolute configuration of the new stereogenic centers.
The required acyl oxazolidinone or oxazolidinethione
would be obtained from allyloxy acetic acid 45 and the
appropriate chiral auxiliary.
anhydride in high yield to provide the acyl oxazolidinone
46. Enolization of 46 with titanium tetrachloride and
(-)-sparteine followed by addition of crotonaldehyde
produced the aldol adduct 44 in 75% yield with a
diastereoselectivity of >97:3. Exposure of diene 44 to
5 mol percent of Grubbs' ruthenium carbene gave the
cyclic ether 47 in 95% yield. Reductive removal of the
auxiliary with sodium borohydride-lithium chloride
provided the somewhat water-soluble diol 48. Conversion
of the diol 48 to the diacetate 49 with acetic anhydride
and pyridine set the stage for the palladium catalyzed
coupling to the purine base. Unfortunately, attempts to
couple 2-amino-6-chloropurine 26 and diacetate 49 in the
presence of (Ph3P)4Pd were completely unsuccessful.
At this juncture it seemed appropriate to address not
only the issue of the palladium catalyzed coupling, but
also the problem of the water solubility of diol 48. Due
to the water solubility of diol 48 it was decided to remove
the chiral auxiliary and protect the diol prior to the
ring closing metathesis reaction. Thus, reduction of the
acyl oxazolidinone 44 with sodium borohydride-lithium
chloride gave diol 50 (81% yield) which was significantly
less water-soluble than diol 48. Acylation of the diol with
benzoyl chloride gave the dibenzoate 51 in 85% yield. The
diene 51 smoothly underwent ring-closing metathesis to
yield the dibenzoate 43 in 95% yield upon exposure to
the Grubbs catalyst (Scheme 12).
The allyloxyacetic acid was readily prepared by expo-
sure of allyl alcohol to sodium hydride in THF followed
by treatment with the sodium carboxylate of bromoacetic
acid. The resultant carboxylic acid was quantitatively
converted to the mixed anhydride by exposure to pivaloyl
chloride in THF-diethyl ether (Scheme 11). The oxazoli-
dinone 18 was acylated with R-allyloxyacetyl pivaloyl
With ready access to the dibenzoate 43, the palladium
catalyzed coupling with 2-amino-6-chloropurine was again
attempted. While use of (Ph3P)4Pd once again failed to
produce the nucleoside analogue, use of Pd2(dba)3-CHCl3
as the palladium (0) source resulted in isolation of the
coupling product 52 in 79% yield, based on recovered

Synthesis of Carbocyclic Nucleosides
J . Org. Chem., Vol. 65, No. 25, 2000 8505
separated and the aqueous layer was washed with ether. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated. The residue was purified
by filtration through a pad of silica gel (3:1 hexanes/ethyl
acetate) to give 25.88 g (100%) of the title compound 10 as a
colorless oil. 1H NMR (250 MHz, CDCl3) δ: 2.42 (m, 2H); 2.72
(dd, J ) 9.7, 13 Hz, 1H); 3.03 (m, 2H); 3.29 (dd, J ) 13, 4 Hz,
1H); 4.15 (m, 2H); 4.65 (m, 1H); 5.07 (m, 2H); 5.86 (m, 1H);
7.12-7.37 (m, 5H). 13C NMR (100 MHz, CDCl3) δ: 28.17, 34.78,
37.9, 55.14, 66.2, 115.7, 127.3, 128.9, 129.4, 135.2, 136.7, 153.4,
172.5. IR (film): 1790, 1708 cm-1. [R]24D: +64.2° (c ) 0.83,
CHCl3). Anal. Calcd for C15H17O3N: C, 69.48; H, 6.61; N, 5.40.
Found: C, 69.20; H, 6.65; N, 5.33.
Sch em e 13
[3(2S,3R),4S]-3-(2-Allyl-3-h yd r oxyp en t-4-en oyl)-4-ben -
zyloxa zolid in -2-on e (11). A solution of the 4S-benzyl-3-pent-
4-enoyloxazolidin-2-one 10 (4.00 g, 15 mmol) in 70 mL of
dichloromethane was cooled to 0 °C. Titanium tetrachloride
(1.86 mL, 17 mmol) was added dropwise, producing a yellow
precipitate. After 5 min, (-)-sparteine (8.85 mL, 39 mmol) in
10 mL of dichloromethane was added dropwise, resulting in a
red-black solution. The solution was stirred at 0 °C for 20 min
and then cooled to -78 °C. Freshly distilled acrolein (1.54 mL,
23 mmol) in 2 mL of dichloromethane was then added
dropwise. When addition was complete, the mixture was
warmed to 0 °C for 30 min. Half-saturated ammonium chloride
was added, the mixture was filtered through Celite, and the
layers were separated. The aqueous layer was extracted twice
with dichloromethane. The combined organic extracts were
dried over sodium sulfate and concentrated. Purification of the
residue by flash chromatography (3:1 hexanes/ethyl acetate)
afforded 3.98 g (82%) of 11 as a viscous, colorless oil. 1H NMR
(250 MHz, CDCl3) δ: 2.38-2.61 (band, 3H); 2.62 (dd, J ) 10.5,
13 Hz, 1H); 3.28 (dd, J ) 13, 4 Hz, 1H); 4.13 (m, 2H); 4.22 (m,
1H); 4.42, (m, 1H); 4.69 (m, 1H); 4.98-5.37 (m, 4H); 5.72-
5.96 (m, 2 H); 7.12-7.34 (m, 5H). 13C NMR (100 MHz, CDCl3)
δ: 31.89, 37.87, 47.23, 55.4, 65.88, 73.13, 116.6, 117.1, 127.2,
128.8, 129.3, 135.1, 135.2, 137.2, 153.4, 174.3. IR (film): 3500,
1780 cm-1. [R]24D: +50.6° (c ) 0.89, CHCl3). Anal. Calcd for
starting material. Subsequent exposure of 52 to cyclo-
propylamine in ethanol at reflux followed by basic
hydrolysis of the benzoate provided the nucleoside 42 in
good yield (Scheme 13).
Con clu sion
An efficient, enantioselective synthesis of carbocyclic
nucleoside and hex-3′-enopyranosyl nucleoside analogues
has been accomplished by exploiting a novel asymmetric
aldol-olefin metathesis sequence for the asymmetric
construction of the sugar fragment of the nucleoside. A
direct palladium catalyzed coupling of the sugar to the
purine allows for the highly convergent assembly of the
nucleoside analogue. The general approach described
here should be adaptable to a variety of nucleoside
analogues.
C
18H21O4N: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.65; H,
Exp er im en ta l Section
6.74; N, 4.40.
[3(1R,2R)4S]-4-Ben zyl-3-(2-h yd r oxycyclop en t -3-en e-
Gen er a l P r oced u r es. All reactions involving air- and/or
water-sensitive reagents were carried out under an atmo-
sphere of N2 using oven-dried glassware. Unless otherwise
noted, reagents were obtained from commercial suppliers and
used without further purification. Cl2(PCy3)2RudCHPh was
prepared according to a modified procedure of Grubbs and co-
workers.32 Et2O, THF, and CH2Cl2 were purified according to
the method of Grubbs and co-workers.33 Et3N, EtNi-Pr2,
DMSO, and pyridine were distilled from CaH2. Purification
by silica gel chromatography was performed by the method of
Still using Scientific Adsorbents Incorporated 40 micron flash
silica gel.34 Optical rotations were measured at ambient
temperature.
4S-Ben zyl-3-p en t-4-en oyloxa zolid in -2-on e (10). To a
cooled solution (-78 °C) of 4-pentenoic acid (10.0 g, 100 mmol)
and 14.7 mL (105 mmol) of triethylamine in 800 mL of diethyl
ether was added 12.35 mL (100 mmol) of pivaloyl chloride.
After 5 min, the bath was removed and replaced by an ice-
water bath. The heterogeneous mixture was mechanically
stirred at 0 °C for 1 h. In a separate flask, a solution of 17.7
g (100 mmol) of (S)-4-benzyl-2-oxazolidinone in 120 mL of THF
was cooled to -78 °C whereupon 63.1 mL (101 mmol) of 1.6
M n-butyllithium in hexanes was added slowly. This solution
was stirred for 10 min at -78 °C. The flask containing the
mixed anhydride was cooled to -78 °C, and the lithiated
oxazolidinone was transferred via cannula into the mixed
anhydride. After being stirred at -78 °C for 15 min, the
reaction mixture was warmed to 0 °C and stirred for 30 min.
After the reaction was quenched with water, the layers were
ca r b on yl)oxa zolid in -2-on e (12). To
a solution of the
[3(2S,3R),4S]-3-(3-hydroxy-2-allyl-1-oxo-4-pentenyl)-4-benzyl-
2-oxazolidinone 11 (767 mg. 2.43 mmol) in 15 mL of dichloro-
methane under argon was added 40 mg of benzylidine(bis-
tricyclohexylphosphine)ruthenium(II) dichloride. The dark
mixture was stirred at 25 °C for 30 min, whereupon TLC
showed complete reaction. Air was bubbled through the
mixture for 3 h to oxidize the remaining catalyst. The solution
was concentrated, and the residue was purified by flash
chromatography to give 679 mg (97%) of 12 as a colorless oil.
1H NMR (250 MHz, CDCl3) δ: 2.00 (br, 1H); 2.48 (m, 1H); 2.76
(dd, J ) 10.5, 13 Hz, 1H); 3.12 (m, 1H); 3.31 (dd, J ) 13, 4 Hz,
1H); 4.15 (m, 2H); 4.45 (m, 1H); 4.69 (m, 1H); 5.09, (m, 1H);
5.74 (m, 1H); 6.02 (m, 1H); 7.15-7.36 (m, 5H). 13C NMR (100
MHz, CDCl3) δ: 33.19, 38.07, 47.03, 55.49, 66.2, 77.23, 127.2,
128.8, 129.3, 131.1, 134.7, 135.4, 153.6, 172.1. IR (film): 3480,
1780, 1700 cm-1. [R]24D: -92.5° (c ) 0.795, CHCl3). Anal. Calcd
for C16H17O4N: C, 66.88; H, 5.96; N, 4.88. Found: C, 66.79;
H, 5.92; N, 4.79.
(1R,5R)-5-Hyd r oxym eth yl-2-cyclop en ten -1-ol (13). A
solution of [3(1R,2R)4S]-4-benzyl-3-[(2-hydroxy-3-cyclopenten-
1-yl)carbonyl]-2-oxazolidinone 12 (339 mg, 1.18 mmol) in 11
mL of THF was cooled to 0 °C, and 0.105 mL of methanol was
added. Lithium borohydride solution (1.30 mL of a 2 M
solution, 2.6 mmol) was added, and gas evolution was ob-
served. After being stirred for 1 h at 0 °C, the reaction was
quenched by the addition of 3.5 mL of 10% sodium hydroxide
solution. Diethyl ether was added, and the layers were
separated. The aqueous layer was extracted with ethyl acetate,
and the combined organic extracts were washed with brine,
dried over sodium sulfate, filtered, and concentrated. Flash
chromatography of the residue provided 102 mg (78%) of the
diol 13 as a pale yellow oil. 1H NMR (250 MHz, CDCl3) δ:
2.03-2.49 (band, 3H); 3.33 (br s, 2H); 3.71 (m, 2H); 4.82 (m,
(32) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996,
118, 100.
(33) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J . Organometallics 1996, 15, 1518.
(34) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

8506 J . Org. Chem., Vol. 65, No. 25, 2000
Crimmins et al.
1H); 5.74 (m, 1H); 5.92 (m, 1H). 13C NMR (100 MHz, CDCl3)
δ: 33.54, 42.49, 62.59, 77.61, 132.4, 135.0. IR (film): 3600-
3000 (broad) cm-1. [R]24D: -125.1° (c ) 0.47, CH2Cl2). The
sample was identical in all respects to an authentic sample.
The diol was converted to its bis-p-toluate and analyzed by
chiral HPLC on a Chiralcel OD column eluting with 4%
ethanol-heptane. Optical purity was determined to be >99%
by this method. S,S-Enantiomer elution time ) 5.9 min; R,R-
enantiomer elution time ) 7.6 min.
reaction mixture immediately turned dark red. After 5 min,
(-)-sparteine (0.69 mL, 3.02 mmol) was added and the reaction
mixture darkened further. The solution was stirred for 20 min
to ensure complete enolate formation before cooling to -78 °C.
Freshly distilled crotonaldehyde (0.15 mL, 1.81 mmol) was
added dropwise. Clean formation of a more polar species was
observed after 20 min. The reaction was quenched by addition
of half-saturated NH4Cl and was extracted with CH2Cl2. The
organic extracts were dried over MgSO4, concentrated under
vacuum, and purified by silica gel chromatography to yield 19
as a white crystalline solid, 313 mg, 78%. 1H NMR (200 MHz,
CDCl3) δ: 7.28 (m, 5H); 5.51-6.02 (m, 3H); 5.35 (dt, J ) 5.7,
8.5 Hz, 1H); 5.0-5.19 (m, 1H); 4.94 (m, 1H); 4.42 (brt, J ) 5.7
Hz, 1H); 4.26 (m, 2H); 3.24 (dd, J ) 3, 12 Hz, 1H); 2.69 (dd,
J ) 12, 9.5 Hz, 1H); 2.38-2.52 (m, 3H); 1.72 (d, J ) 6 Hz,
3H).
Dia ceta te 14, Cyclic Ca r bon a te 16, a n d Dica r bon a te
15. To a solution of diol 13 in CH2Cl2 at 0 °C under nitrogen
was added 2.2 equiv of either triethylamine (for the diacetate
and the cyclic carbonate) or pyridine (for the dicarbonate). The
acylating agent (3.0 equiv) was then added dropwise followed
by a catalytic amount of N,N-dimethylaminopyridine (DMAP).
After 1.5-2.0 h, the reaction was quenched with 5% HCl
solution and the layers were separated. The organic layer was
washed with saturated NaHCO3 solution and brine, dried over
sodium sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (15% EtOAc/Hexanes) to give
diacetate 14 (90% yield), cyclic carbonate 16 (52% yield), or
dicarbonate 15 (90% yield).
[3(2S,3R),4R]-3-(2-Allyl-3-h ydr oxy-4-m eth ylh ex-4-en oyl)-
4-ben zyloxa zolid in -2-th ion e 24. To a stirring solution of
acyloxazolidinethione 23 (247 mg, 0.897 mmol) in CH2Cl2 (5
mL) at 0 °C was added TiCl4 (0.20 mL, 1.79 mmol). The
solution immediately turned red and was allowed to stir for 5
min before the addition of EtN-i-Pr2 (0.19 mL, 1.08 mmol).
After 20 min, the reaction mixture was cooled to -78 °C, and
freshly distilled crotonaldehyde (0.11 mL, 1.35 mmol) was
added. After being stirred for 1 h at -78 °C and an additional
1 h at 0 °C, the reaction was quenched by the addition of half-
saturated NH4Cl and was extracted with CH2Cl2. The organic
fractions were dried over MgSO4, concentrated under vacuum,
and purified by silica gel chromatography to yield 24 as a white
Dia ceta te 14.6b 1H NMR (250 MHz, CDCl3) δ: 2.0 (s, 3H);
2.02 (s, 3H); 2.14-2.30 (m, 1H); 2.39-2.55 (m, 1H); 2.58-2.78
(m, 1H); 4.02-4.28 (dd, J ) 6.8, 8.1, 11.1 Hz, 2H); 5.68-5.75
(m, 1H); 5.79-5.85 (m, 1H); 6.02-6.10 (m, 1H). 13C NMR (100
MHz, CDCl3) δ: 170.9, 170.5, 136.7, 129.4, 78.04, 63.34, 39.49,
34.61, 21.01, 20.83. IR: 1740 (broad), 1370, 1235, 1035. [R]24
-178.0° (c ) 0.45, CH2Cl2).
:
D
1
Cyclic Ca r bon a te 16.13d 1H NMR (250 MHz, CDCl3) δ:
2.31-2.48 (m, 1H); 2.57-2.73 (m, 1H); 2.84-3.01 (m, 1H); 4.01
(dd, J ) 5.1, 11.0 Hz, 1H); 4.31 (dd, J ) 4.3, 11.0 Hz, 1H);
crystalline solid, 227 mg, 73%. H NMR (200 MHz, CDCl3) δ:
7.29 (m, 5H); 5.57-5.91 (m, 3H); 5.28 (dt, J ) 5.7, 8.5 Hz, 1H);
4.95-5.0.14 (m, 1H); 4.94 (m, 1H); 4.53 (brt, J ) 5.7 Hz, 1H);
4.28 (m, 2H); 3.26 (dd, J ) 3, 12 Hz, 1H); 2.75 (dd, J ) 12, 9.5
Hz, 1H); 2.41-2.65 (m, 3H); 1.72 (d, J ) 6 Hz, 3H).13C NMR
(100 MHz, CDCl3) δ: 17.27, 31.86, 37.09, 47.03, 59.5, 69.71,
72.93, 116.3, 126.8, 128.0, 128.4, 128.9, 130.01, 134.7, 135.0,
174.4, 185.1; IR (film): 3450, 1690 cm-1. [R]24D: +153.6 ° (c )
1.39, CH2Cl2). Anal. Calcd for C19H23NO3S: C, 66.06; H, 6.71;
N, 4.05. Found: C, 65.79; H, 6.63; N, 4.01.
5.46-5.55 (m, 1H); 5.79-5.87 (m, 1H); 6.08-6.15 (m, 1H). 13
C
NMR (100 MHz, CDCl3) δ: 151.5, 137.5, 128.9, 87.45, 68.2,
35.01, 33.77. IR: 1750, 1620 cm-1. [R]24D: -145.2° (c ) 0.44,
CH2Cl2).
Dica r bon a te 15.13l 1H NMR (250 MHz, CDCl3) δ: 2.20-
2.32 (m, 1H); 2.42-2.57 (m, 1H); 2.66-2.81 (m, 1H); 3.73 (s,
3H); 3.77 (s, 3H); 4.20 (dd, J ) 5.9, 11.0 Hz, 1H); 4.33 (dd, J
) 6.9, 11.0 Hz, 1H); 5.60 (m, 1H); 5.88-5.92 (m, 1H); 6.10-
6.15 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 155.7, 155.3,
137.7, 129.0, 82.05, 66.81, 54.79, 54.68, 39.89, 34.58. IR: 1745
(broad), 1440. [R]24D: -148.5° (c ) 0.46, CH2Cl2).
[4S,2R,3R]-(4-Ben zyl-2-th ioxooxazolidin -3-yl)(2-h ydr oxy-
cyclop en t-3-en yl)m eth a n on e 25. To a solution of the aldol
adduct 24 (3.715 g, 10.8 mmol) in 74 mL of dichloromethane
under argon was added 177 mg of benzylidine(bis-tricyclo-
hexylphosphine)ruthenium(II) dichloride. The dark mixture
was stirred at 40 °C for 1 h, whereupon TLC showed complete
reaction. Air was bubbled through the mixture for overnight
to oxidize the remaining catalyst. Concentration followed by
flash chromatography gave 2.43 g (74%) of cyclopentene 25
4S-1-(4-Ben zyl-2-th ioxooxa zolid in -3-yl)p en t-4-en -1-on e
18. To a cooled solution (-78 °C) of 4-pentenoic acid (2.26 g,
22.6 mmol) and 3.30 mL (23.7 mmol) of triethylamine in 180
mL of diethyl ether was added 2.78 mL (22.6 mmol) of pivaloyl
chloride. After 5 min, the bath was removed and replaced by
an ice-water bath. The heterogeneous mixture was mechani-
cally stirred at 0 °C for 1 h. In a separate flask, a solution of
4.9 g (22.6 mmol) of (S)-4-benzyl-2-oxazolidinethione in 27 mL
of THF was cooled to -78 °C, whereupon 14.25 mL (22.8 mmol)
of 1.6 M n-butyllithium in hexanes was added slowly. This
solution was stirred for 10 min at -78 °C. The flask containing
the mixed anhydride was cooled to -78 °C, and the lithiated
oxazolidinethione was transferred via cannula into the mixed
anhydride. After being stirred at -78 °C for 15 min, the
reaction mixture was warmed to 0 °C and stirred for 30 min.
Water was added, the layers were separated, and the aqueous
layer was washed with ether. The combined organic layers
were washed with brine, dried over sodium sulfate, filtered,
and concentrated. The residue was purified by filtration
through a pad of silica gel (3:1 hexanes/ethyl acetate) to give
1
as a colorless oil. H NMR (200 MHz, CDCl3) δ: 7.28 (m, 5H);
6.03 (m, 1H); 5.80 (m, 1H); 5.49 (brt, J ) 7 Hz, 1H); 5.16 (m,
1H); 4.97 (m, 1H); 4.29 (m, 2H); 3.32 (dd, J ) 3, 12 Hz, 1H);
3.11 (m, 1H); 2.75 (dd, J ) 12, 9.5 Hz, 1H); 2.49 (m, 1H); 2.22
(d, J ) 8.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 33.87, 37.0,
46.52, 59.88, 69.85, 78.0, 126.8, 128.4, 129.0, 130.07, 133.6,
135.1, 172.6, 185.1. IR (film): 3450, 1690 cm-1. [R]24D: +396.2°
(c ) 0.84, CH2Cl2). Anal. Calcd for C16H17NO3S: C, 63.35; H,
5.65; N, 4.62. Found: C, 63.42; H, 5.70; N, 4.58.
Ch lor op u r in e Aceta te 28a .13m To a solution of hexane-
washed sodium hydride (3.04 mmol, 0.122 g of 60% NaH) in 5
mL of dimethyl sulfoxide under nitrogen was added 2-amino-
6-chloropurine (2.89 mmol, 0.490 g). The mixture was heated
at 45 °C for 15 min. After the mixture was cooled to room
temperature, tetrakis(triphenylphosphine)palladium(0) (5.0
mol %, 0.15 mmol, 0.167 g) was added followed by the addition
of diacetate 14 (2.89 mmol, 0.573 g) in 5 mL of THF. The
mixture was heated at 45 °C overnight. The mixture was
allowed to cool to room temperature and was quenched with
water. The solution was extracted five times with ethyl acetate.
The combined organic layers were washed with water and
concentrated. Purification by flash chromatography afforded
0.275 g of starting material and 0.298 g 65% based on
recovered starting material) of the N-9 isomer 28a .13m 1H NMR
(250 MHz, CDCl3) δ: 1.59-1.76 (m, 1H); 2.20 (s, 3H); 2.71-
2.90 (m, 1H); 3.08-3.21 (m, 1H); 4.50-4.61 (dd, J ) 4.3, 4.7,
10.0 Hz, 2H); 5.31 (m, 2H); 5.49-5.59 (m, 1H); 5.82-5.90 (m,
1
4.74 g (81%) of the title compound 18 as a pale yellow oil. H
NMR (250 MHz, CDCl3) δ: 7.28 (m, 5H); 5.91 (m, 1H); 5.0-
5.18 (m, 2H); 3.22-3.62 (m, 3H); 2.75 (dd, J ) 10, 13.3 Hz,
1H); 2.48 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 28.07,
36.557, 37.32, 59.6, 70.1, 115.4, 127.1, 128.7, 129.1, 135.0,
136.4, 172.9, 185.1. IR (film): 1700 cm-1. [R]24D: +119.8 ° (c
) 0.99, CH2Cl2). Anal. Calcd for C15H17NO2S: C, 65.43; H, 6.22;
N, 5.09. Found: C, 65.32; H, 6.23; N, 5.00.
[3(2S,3R),4S]-3-(2-Allyl-3-h ydr oxy-4-m eth ylh ex-4-en oyl)-
4-ben zyloxa zolid in -2-th ion e 19. To a stirring solution of
acyloxazolidinethione 18 (313 mg, 1.21 mmol) in CH2Cl2
(5 mL) at 0 °C was added TiCl4 (0.146 mL, 1.33 mmol). The

Synthesis of Carbocyclic Nucleosides
J . Org. Chem., Vol. 65, No. 25, 2000 8507
1H); 6.09-6.14 (m, 1H); 7.79 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ: 170.9, 159.0, 153.4, 151.2, 140.4, 137.8, 129.8, 125.5,
4.73-4.88 (m, 1H); 5.48-5.58 (m, 1H); 5.63-5.72 (m, 1H);
5.85-5.91 (m, 1H); 6.03-6.10 (m, 1H); 7.49 (s, 1H). 13C NMR
(100 MHz, CDCl3) δ: 170.8, 159.9, 156.1, 150.8, 136.8, 135.1,
130.6, 114.7, 66.37, 58.52, 44.25, 35.01, 23.55, 20.72, 7.23. IR
(film): 3580-3000(br), 1735 cm-1. [R]24D: -41.0° (c ) 0.39,
CH2Cl2).
66.11, 59.44, 44.4, 34.52, 20.83. IR: 3560-3060, 1735 cm-1
[R]24D: -88.6° (c ) 0.43, CH2Cl2).
.
Ch lor op u r in e Ca r bon a te 28b13f a n d Ch lor op u r in e Al-
coh ol 28c. To a solution of 2-amino-6-chloropurine (0.378
mmol, 0.064 g) in 1 mL of dimethyl sulfoxide under nitrogen
was added tetrakis(triphenylphosphine)palladium(0). Dicar-
bonate 15 (0.378 mmol, 0.087 g) or cyclic carbonate 9 was then
added in 1 mL of THF. After being stirred for 2 h, the reaction
was quenched with water. The mixture was extracted five
times with ethyl acetate. The combined organic layers were
washed with water and concentrated. Purification by flash
chromatography afforded 0.083 g (68%) of chloropurine car-
bonate 28b. 1H NMR (250 MHz, CDCl3) δ: 1.68-1.79 (m, 1H);
2.74-2.90 (m, 1H); 3.10-3.24 (m, 1H); 3.75 (s, 3H); 4.19 (dd,
J ) 5.3, 10.6 Hz, 1H); 4.29 (dd, J ) 4.7, 10.6 Hz, 1H); 5.21 (m,
2H); 5.50-5.60 (m, 1H); 5.82-5.89 (m, 1H); 6.08-6.12 (m, 1H);
7.83 (s, 1H) 13C NMR (100 MHz, CDCl3) δ: 158.8, 155.7, 153.3,
151.1, 140.7, 137.1, 130.2, 125.5, 69.26, 59.30, 54.85, 44.43,
34.00. IR (film): 3500-3100(br), 1745 cm-1. [R]24D: -64.6° (c
) 0.28, CH2Cl2).13f
[3(2S,3R),4S]-3-(2-Allyl-3-h yd r oxy-4-m eth ylp en t-4-en o-
yl)-4-ben zyloxa zolid in e-2-th ion e (32). To a stirring solution
of acyloxazolidinethione 18 (8.30 g, 30.1 mmol) in CH2Cl2 (200
mL) at 0 °C was added TiCl4 (3.46 mL, 31.6 mmol). The
reaction mixture immediately turned dark red. After 5 min,
(-)-sparteine (17.3 mL, 75.4 mmol) was added, and the
reaction mixture darkened further. The solution was stirred
20 min to allow complete enolate formation before being cooled
to -78 °C. Freshly distilled methacrolein (2.74 mL, 33.2 mmol)
was added dropwise. Clean formation of a more polar species
(Rf 0.16, 25% EtOAc in hexanes) was observed after 20 min.
The reaction was quenched by addition of half-saturated
NH4Cl and was extracted with CH2Cl2. The organic fractions
were dried over MgSO4, concentrated under vacuum, and
purified by silica gel chromatography (30-50% EtOAc in
hexanes elution) to yield 32 as a white crystalline solid, 8.94
1
Ch lor op u r in e Alcoh ol 28c.13d Same procedure as above.
g, 86%. H NMR (200 MHz, CDCl3) δ: 1.78 (s, 3); 2.41-2.73
1
Yields range from 61% to 65%. H NMR (250 MHz, CDCl3) δ:
(m, 3); 2.67 (dd, 1, J ) 13.4, 10.6 Hz); 3.26 (dd, 1, J ) 13.3, 3.1
Hz); 4.17-4.32 (m, 2); 4.42-4.46 (m, 1); 4.86-5.16 (m, 5);
5.36-5.45 (m, 1); 5.84-6.05 (m, 1); 7.18-7.36 (m, 5). 13C NMR
(100 MHz, CDCl3) δ: 19.21, 31.09, 37.70, 44.64, 60.32, 70.04,
74.60, 112.46, 117.31, 127.42, 129.01, 129.37, 135.19, 135.30,
144.09, 175.90, 185.22. IR (film): 3500, 1685 cm-1. [R]D: +38.2
(c 0.44, CH2Cl2). Anal. Calcd for C19H23NO3S: C, 66.06; H, 6.71.
Found: C, 66.29; H, 6.89.
1.90-2.03 (m, 1H); 2.69-2.89 (m, 1H); 3.00-3.18 (m, 1H);
3.66-3.90 (m, 3H); 5.20 (m, 2H); 5.41-5.58 (m, 1H); 5.75-
5.82 (m, 1H); 6.10-6.19 (m, 1H); 7.89 (s, 1H). 13C NMR (100
MHz, CDCl3) δ: 158.7, 153.1, 151.2, 141.8, 139.1, 129.6, 125.5,
64.61, 60.66, 47.66, 33.19. IR: 3560-3000, 1610 cm-1. [R]24
-80.0° (c ) 0.62, CH3OH).13d
:
D
(-)-1592U89 2.10 To a stirred solution of chloropurine
acetate 28a (0.117 mmol, 0.036 g) in 1 mL of ethanol was
added cyclopropylamine (1.17 mmol, 0.081 mL). The mixture
was heated at reflux for 5 h. After the mixture was cooled to
room temperature, 0.234 mL of a 1 N NaOH solution was
added. The mixture was stirred overnight and concentrated.
Purification by flash chromatography provided 0.027 g (81%)
of 1592U89 2 identical to that previously reported.9 1H NMR
(250 MHz, DMSO-d6) δ: 0.50-0.70 (m, 4H); 1.49-1.63 (m, 1H);
2.52-2.69 (m, 1H); 2.83 (br m, 1H); 3.01 (br m, 1H); 3.42 (m,
2H); 4.75 (m, 1H); 5.38 (m, 1H); 5.78-5.90 (m, 3H); 6.02-6.12
(m, 1H); 7.29 (d, J ) 4.2 Hz, 1H); 7.59 (s, 1H). 13C NMR (100
MHz, DMSO-d6) δ: 159.9, 155.8, 150.9, 137.8, 134.7, 129.9,
113.5, 63.98, 58.01, 47.58, 34.19, 23.76, 6.324. IR (film): 3590-
3000 (br), 1590 (br) cm-1. [R]24D: -37.5° (c ) 0.51, CH3OH).
(-)-Ca r bovir 1.9 A solution of chloropurine acetate 28a
(0.286 mmol, 0.088 g) in 5 mL of a 0.5 N NaOH solution was
heated at reflux for 5 h. After being cooled to room tempera-
ture, the solution was neutralized with 5 mL of a 0.5 M HCl
solution. Concentration and purification by column chroma-
tography afforded 0.048 g (68%) of (-)-carbovir 1 identical to
that previously reported.9 1H NMR (250 MHz, DMSO-d6) δ:
1.49-1.61 (m, 1H); 2.50-2.65 (m, 1H); 2.78-2.90 (m, 1H);
3.38-3.48 (m, 2H); 4.68-4.74 (m, 1H); 5.28-5.39 (m, 1H);
5.80-5.89 (m, 1H); 6.06-6.12 (m, 1H); 6.42 (s, 2H); 7.58 (s,
1H); 10.52 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 156.7,
153.3, 150.6, 138.1, 134.9, 129.6, 116.6, 63.9, 58.39, 47.59,
34.24.
Aceta te-Cyclop r op yla m in op u r in e 30. To a stirred solu-
tion of sodium hydride (0.375 mmol, 0.009 g) in 1 mL of
dimethyl sulfoxide under nitrogen was added 2-amino-6-cyclo-
propylaminopurine (0.313 mmol, 0.059 g). The solution was
heated at 45 °C for 15 min. After the mixture was cooled to
room temperature, tetrakis(triphenylphosphine)palladium(0)
(0.031 mmol, 0.036 g) was added followed by the addition
of diacetate 14 (0.313 mmol, 0.062 g) in 1 mL of THF. The
mixture was heated at 45 °C overnight. The mixture was
allowed to cool to room temperature and was quenched by the
addition of water. The mixture was extracted five times with
ethyl acetate. The combined organic layers were washed with
water and concentrated. Purification by flash chromatography
provided 0.064 g (62%) of acetate 30. 1H NMR (250 MHz,
CDCl3) δ: 0.55-0.62 (m, 2H); 0.79-0.90 (m, 2H); 1.57-1.70
(m, 2H); 2.03 (s, 3H); 2.73-2.90 (m, 1H); 2.91-3.04 (m, 1H);
3.05-3.19 (m, 1H); 4.02-4.20 (dd, J ) 4.7 Hz, 5.3, 10.1, 2H);
[3(2S,3R),4R]-3-(2-Allyl-3-h yd r oxy-4-m eth ylp en t-4-en o-
yl)-4-ben zyloxa zolid in -2-th ion e (33). To a stirring solution
of acyloxazolidinethione 23 (1.31 g, 4.76 mmol) in CH2Cl2 (30
mL) at 0 °C was added TiCl4 (1.04 mL, 9.52 mmol). The
solution immediately turned red and was allowed to stir for 5
min before the addition of EtN-i-Pr2 (0.91 mL, 5.24 mmol).
After 20 min, the reaction mixture was cooled to -78 °C, and
freshly distilled methacrolein (0.43 mL, 5.24 mmol) was added.
After being stirred for 1 h at -78 °C and an additional 1 h at
0 °C, the reaction was quenched by the addition of half-
saturated NH4Cl and was extracted with CH2Cl2. The organic
fractions were dried over MgSO4, concentrated under vacuum,
and purified by silica gel chromatography (5-10% EtOAc in
hexanes elution) to yield 33 as a white crystalline solid, 1.20
1
g, 74%. H NMR (200 MHz, CDCl3) δ: 1.82 (s, 3); 2.32-2.60
(m, 2); 2.66 (d, 1, J ) 3.2 Hz); 2.72 (dd, 1, J ) 13.4, 10.0 Hz);
3.26 (dd, 1, J ) 13.4, 3.5 Hz); 4.17-4.33 (m, 2); 4.58 (br s, 1);
4.83-5.08 (m, 4); 5.15 (br s, 1); 5.33 (dt, 1, J ) 9.6, 4.8);
5.73-5.93 (m, 1); 7.18-7.36 (m, 5). 13C NMR (100 MHz, CDCl3)
δ: 19.52, 31.04, 37.72, 44.79, 60.19, 70.34, 73.98, 112.56,
117.00, 127.45, 129.01, 129.37, 135.11, 135.48, 143.99, 176.28,
185.39. IR (film): 3500, 1790 cm-1. HRMS for C19H23NNaO3S
[MNa]+: calcd 368.1296, found 368.1277. [R]D: +81.4 (c 0.76,
CH2Cl2).
(3S,4R)-4-H yd r oxym et h yl-2-m et h yl-1,6-h ep t a d ien -3-
ol (34). To a stirring solution of aldol adduct 32 (1.65 g, 4.78
mmol) and MeOH (0.25 mL, 6.21 mmol) in Et2O (50 mL, 0.1
M) at 0 °C was added LiBH4 (3.10 mL of a 2.0 M solution in
THF, 6.21 mmol) dropwise. The reaction was stirred 1.5 h and
then quenched by the slow addition of 15% NaOH. The
resulting solution was extracted with Et2O until no diol was
observed by TLC in the aqueous layer. The organic fractions
were combined, dried over MgSO4, concentrated under vacuum,
and purified by silica gel chromatography (30% EtOAc in
hexanes elution) to yield diol 34 as a clear, colorless oil, 0.694
1
g, 93%. H NMR (200 MHz, CDCl3) δ: 1.66 (s, 3); 1.69-1.79
(m, 1); 1.96-2.12 (m, 2); 3.08 (br s, 2); 3.68 (d, 2, J ) 4.8 Hz);
4.25 (d, 1, J ) 3.4 Hz); 4.89-5.07 (m, 4); 5.65-5.86 (m, 1). 13
C
NMR (100 MHz, CDCl3) δ: 19.21, 28.77, 41.87, 63.64, 76.73,
111.12, 116.25, 137.18, 145.65. IR (film): 3600-3100 cm-1
[R]D: -4.3 (c 0.53, CH2Cl2).
.
(3S,4R)-3-Acetoxy-4-a cetoxym eth yl-2-m eth ylcyclop en -
ten e (35). To a stirring solution of diol 34 (56 mg, 0.36 mmol)
in CH2Cl2 at 25 °C were added Ac2O (0.10 mL, 1.1 mmol), EtN-

8508 J . Org. Chem., Vol. 65, No. 25, 2000
Crimmins et al.
i-Pr2 (0.16 mL, 0.90 mmol), and DMAP (4.4 mg, 0.036 mmol).
After 1 h, the reaction was quenched with 5% HCl (10 mL)
and extracted with CH2Cl2 (15 mL). The organic layers were
combined, washed with saturated aqueous NaHCO3, dried over
Na2SO4, and concentrated. The resulting yellow oil was
purified by silica gel chromatography (10 to 25% EtOAc in
hexanes), affording the diacetate as a clear, colorless oil, 72
mg, 95%. 1H NMR (200 MHz, CDCl3) δ: 1.70 (s, 3); 2.02 (s, 3);
2.05 (s, 3); 1.94-2.15 (m, 2); 2.21-2.31 (m, 1); 3.95 (d, 2, J )
6.0 Hz); 4.90-5.06 (m, 4); 5.23 (d, 1, J ) 5.4 Hz); 5.62-5.83
(m, 1). 13C NMR (100 MHz, CDCl3) δ: 18.58, 20.82, 20.98,
30.90, 38.68, 63.23, 76.23, 113.76, 117.06, 135.62, 141.14,
170.00, 170.93. IR (film): 1740, 1640 cm-1. [R]D: -4.2 (c 0.44,
CH2Cl2). Anal. Calcd for C13H20O4: C, 64.98; H, 8.39. Found:
C, 65.13; H, 8.47. To a solution of the diacetate from above
(0.280 g, 1.16 mmol) in CH2Cl2 (80 mL) at reflux was added
Cl2(PCy3)2RudCHPh (0.045 g, 0.055 mmol). The reaction was
allowed to proceed overnight. The solvent was removed under
vacuum, and the residue was purified by silica gel chroma-
tography (10 to 15% EtOAc in hexanes) to yield the product
as a clear, colorless oil, 239 mg, 97%. 1H NMR (200 MHz,
CDCl3) δ: 1.65 (s, 3); 1.98 (s, 3); 2.01 (s, 3); 2.02-2.17 (m, 1);
2.31-2.46 (m, 1); 2.62-2.81 (m, 1); 3.96-4.14 (m, 2); 5.59 (s,
1); 5.69 (d, 1, J ) 7.6 Hz). 13C NMR (100 MHz, CDCl3) δ: 13.94,
20.81, 20.89, 33.92, 39.90, 63.42, 79.87, 129.67, 138.12, 170.77,
170.94. IR (film): 1740 cm-1. [R]D: -50.9 (c 0.49, CH2Cl2). Anal.
Calcd for C11H16O4: C, 62.25; H, 7.60. Found: C, 62.15; H,
7.59.
(3S,4R)-4-H yd r oxym et h yl-2-m et h yl-1,6-h ep t a d ien -3-
ol Bis(m eth yl ca r bon a te). To a stirring solution of diol 34
(69 mg, 0.44 mmol) in CH2Cl2 (10 mL) at 0 °C were added
ClCO2Me (0.17 mL, 2.2 mmol), pyridine (0.18 mL, 2.2 mmol),
and DMAP (11 mg, 0.088 mmol). The reaction mixture was
allowed to warm to room temperature and was then stirred 4
h. The reaction was quenched with 5% HCl and extracted with
CH2Cl2. The organic layers were combined, washed with
saturated aqueous NaHCO3, dried over Na2SO4, and concen-
trated. The resulting yellow oil was purified by silica gel
chromatography (10-25% EtOAc in hexanes), affording the
biscarbonate as a clear, colorless oil, 103 mg, 86%. 1H NMR
(200 MHz, CDCl3) δ: 1.72 (s, 3); 2.01-2.16 (m, 2); 2.27-2.37
(m, 1); 3.74 (s, 3); 3.75 (s, 3); 4.06 (d, 2, J ) 5.2 Hz); 4.97-5.02
(m, 3); 5.06-5.09 (m, 2); 5.62-5.83 (m, 1). 13C NMR (100 MHz,
CDCl3) δ: 18.33, 30.43, 38.99, 54.81, 66.43, 80.23, 114.56,
117.51, 135.18, 140.65, 155.03, 155.59. IR (film): 1750, 1640
cm-1. HRMS for C13H20NaO6 [MNa]+: calcd 295.1158, found
295.1145. [R]D: -4.8 (c 0.63, CH2Cl2).
(3S,4R)-3-Met h oxyca r b on yloxy-4-m et h oxyca r b on yl-
oxym eth yl-2-m eth ylcyclop en ten e (36). 1H NMR (200 MHz,
CDCl3) δ: 1.69 (s, 3); 2.07-2.22 (m, 1); 2.33-2.47 (m, 1); 2.69-
2.87 (m, 1); 3.75 (s, 3); 3.78 (s, 3); 4.05-4.27 (m, 2); 5.53-5.60
(m, 2). 13C NMR (100 MHz, CDCl3) δ: 13.87, 33.76, 40.04,
54.64, 54.70, 66.93, 84.37, 130.15, 137.48, 155.54, 155.71. IR
(film): 1750 cm-1. HRMS for C11H16NaO6 [MNa]+: calcd
267.0845, found 267.0831. [R]D: -53.8 (c 0.44, CH2Cl2).
(3S,5R)-Acetoxym eth yl-1-m eth yl-5-(2-a m in o-6-ch lor o-
p u r in -9-yl)cyclop en ten e (37). To a solution of hexane-
washed NaH (16 mg of a 60% dispersion in mineral oil, 0.40
mmol) in DMSO (1.5 mL) was added 2-amino-6-chloropurine
26 (68 mg, 0.40 mmol). The mixture was heated to 45 °C for
15 min and then cooled to room temperature. Concurrently,
P(O-i-Pr)3 (0.039 mL, 0.16 mmol) was added to a stirring
suspension of Pd2(dba)3‚CHCl3 (21 mg, 2.0 µmol) in THF (1.0
mL) and stirred for 15 min, at which time the solution was
homogeneous and green-yellow in color. The THF solution was
transferred via cannula to the DMSO solution, and the cyclic
diacetate 35 (81 mg, 0.38 mmol) was added in THF (0.5 mL).
The reaction mixture was heated at 45 °C overnight and then
was quenched with water. The resulting mixture was extracted
with EtOAc. The organic layers were combined, washed with
water, and concentrated. Purification by silica gel chromatog-
raphy (Et2O elution) yielded recovered starting diacetate 35
(25 mg) as well as the product 37: 55 mg, 45%. 1H NMR
(200 MHz, CDCl3) δ: 1.57 (s, 3); 1.71-1.84 (m, 1); 2.07 (s, 3);
2.73-2.89 (m, 1); 3.06-3.14 (m, 1); 4.17 (d, J ) 5.6, 2 Hz);
5.11 (br s, 1); 5.32-5.40 (m, 1); 5.69-5.73 (m, 1); 7.76 (s, 1).
13C NMR (100 MHz, CDCl3) δ: 13.74, 20.98, 34.74, 43.04,
62.18, 66.65, 125.54, 131.61, 138.54, 140.91, 151.25, 153.63,
158.92, 171.10. IR (film): 3500-3100, 1730, 1620 cm-1; HRMS
for C14H16ClN5NaO2 [MNa]+: calcd 344.0890, found 344.0894.
[R]D: -29.7 (c 0.39, CH2Cl2).
(3S ,5R )-Me t h oxyca r b on yloxym e t h yl-1-m e t h yl-5-(2-
a m in o-6-ch lor op u r in -9-yl)cyclop en ten e (38). To a stirring
suspension of Pd2(dba)3‚CHCl3 (32 mg, 0.031 mmol) in THF
(1.5 mL) was added P(O-i-Pr)3 (0.060 mL, 0.24 mmol). The
reaction was stirred for 20 min before being transferred via
cannula to a stirring solution of cyclic dicarbonate 36 (149 mg,
0.61 mmol) and 2-amino-6-chloropurine (103 mg, 0.61 mmol)
in DMSO (1.5 mL). The reaction mixture was heated to 45 °C
overnight and then was quenched with water. The resulting
mixture was extracted with EtOAc. The organic layers were
combined, washed with water, and concentrated. Purification
by silica gel chromatography (50 to 100% EtOAc in hexanes)
yielded the nucleoside analogue 38 as a white crystalline solid,
122 mg, 59%. 1H NMR (200 MHz, CDCl3) δ: 1.56 (s, 3); 1.78-
1.91 (m, 1); 2.74-2.90 (m, 1); 3.06-3.18 (m, 1); 3.78 (s, 3);
4.18-4.34 (m, 2); 5.09 (br s, 2); 5.32-5.42 (m, 1); 5.68-5.71
(m, 1); 7.84 (s, 1). 13C NMR (100 MHz, CDCl3) δ: 13.67, 34.23,
43.17, 54.95, 62.13, 69.79, 125.45, 130.90, 139.04, 141.25,
151.21, 153.67, 155.85, 158.90. IR (film): 3500-3100, 1750,
1610 cm-1. HRMS for C14H16ClN5NaO3 [MNa]+ calcd 360.0839,
found 360.0818. [R]D: -41.1 (c 0.36, CH2Cl2).
(-)-2′-Meth yl 1592U89 40. To a stirring solution of chloro-
purine carbonate 38 (84 mg, 0.26 mmol) was added cyclopro-
pylamine (0.090 mL, 1.3 mmol). The reaction was heated to
reflux for 15 min, at which time TLC showed clean conversion
to a more polar intermediate (Rf 0.08, EtOAc). After the
mixture was cooled to room temperature, 0.5 M NaOH (4 mL)
was added, and the reaction mixture was heated to reflux for
2 h. The solvent was removed under vacuum, and the residue
was purified by silica gel chromatography to yield the product
40 as a white crystalline solid, 54 mg, 73%. 1H NMR (200 MHz,
DMSO-d6) δ: 0.55-0.68 (m, 4); 1.46 (s, 3); 1.58-1.73 (m, 1);
2.53-2.66 (m, 1); 2.73-2.84 (m, 1); 2.96-3.07 (m, 1); 3.41-
3.46 (m, 1); 4.70-4.76 (m, 1); 5.19-5.27 (m, 1); 5.68 (s, 1); 5.81
(s, 2); 7.30 (d, J ) 4.4, 1 Hz); 7.59 (s, 1). 13C NMR (100 MHz,
DMSO-d6) δ: 6.40, 13.51, 23.81, 34.66, 46.26, 60.49, 64.42,
113.42, 131.85, 135.20, 138.02, 151.28, 155.88, 160.8. IR
(film): 3600-3000 (br), 1590 (br) cm-1. HRMS for C15H21N6O
[MH]+: calcd 301.1777, found 301.1784. [R]D: -62.8 (c 0.58,
MeOH).
(-)-2′-Met h ylca r b ovir 41. A stirring solution of chloro-
purine acetate 37 (0.050 g, 0.16 mmol) in 0.5 M NaOH (3 mL)
was heated to reflux for 6 h. The solution was cooled to room
temperature, and solvent was removed under vacuum. The
residue was purified by silica gel chromatography (5-10%
MeOH in CH2Cl2) to yield the product 41 as a white crystalline
1
solid, 24 mg, 60%. H NMR (200 MHz, DMSO-d6) δ: 1.46 (s,
3); 1.56-1.70 (m, 1); 2.53-2.65 (m, 1); 2.72-2.81 (m, 1); 3.42
(t, 2, J ) 5.4 Hz); 4.68 (t, 1, J ) 5.1 Hz); 5.13-5.22 (m, 1);
5.68-5.70 (m, 1); 6.41 (br s, 2); 7.58 (s, 1); 10.54 (s, 1). 13C
NMR (100 MHz, DMSO-d6) δ: 13.48, 34.71, 46.28, 60.84, 64.31,
116.41, 132.18, 135.39, 137.68, 151.14, 153.49, 156.82. IR
(film): 3400-3200, 1693, 1637 cm-1. HRMS for C12H14N5NaO2
[MNa]+: calcd 284.1123, found 284.1135. [R]D: -61.0 (c 0.31,
MeOH).
(3R)-3-Allyloxya cetyl-4-ben zyloxa zolid in -2-on e (46). A
solution of the allyloxyacetic acid (5.48 g, 42.1 mmol) and
triethylamine (6.2 mL, 44.2 mmol) in 350 mL of ether was
added to a flask fitted with a mechanical stirrer, and the
mixture was cooled to -78 °C. Pivaloyl chloride (5.44 mL, 44.2
mmol) was added slowly over 15 min, and the resultant
mixture was stirred for 5 min at -78 °C and then warmed to
0 °C for 1 h. In a separate flask, (S)-4-benzyl-2-oxazolidinone
(7.46 g, 42.1 mmol) in 50 mL of THF was cooled to -78 °C,
and n-BuLi (26.0 mL, 42.5 mmol) was added dropwise. After
addition was complete, the mixture was stirred at -78 °C for
10 min. The solution of mixed anhydride was recooled to -78
°C, and the lithiated oxazolidinone was then transferred via
cannula into the mixed anhydride. After being stirred for 15

Synthesis of Carbocyclic Nucleosides
J . Org. Chem., Vol. 65, No. 25, 2000 8509
min at -78 °C, the mixture was warmed to 0 °C for 30 min.
The reaction was quenched with water and warmed to 25 °C.
The aqueous layer was extracted with ether, and the combined
extracts were washed with brine, dried over Na2SO4, and
concentrated in vacuo. Purification by flash chromatography
2-Hyd r oxym eth yl-3,6-d ih yd r o-2H-p yr a n -3-ol (Diben -
zoa te) 43. To a solution of the dibenzoate 51 (977 mg. 2.57
mmol) in 100 mL of dichloromethane under argon was added
42 mg of benzylidine(bis-tricyclohexylphosphine)ruthenium(II)
dichloride. The dark mixture was stirred at 25 °C for 2 h,
whereupon TLC showed complete reaction. Air was bubbled
through the mixture for 3 h to oxidize the remaining catalyst.
Concentration followed by purification of the residue by flash
chromatography gave 826 mg (95%) of 43 as a colorless oil,
95%. 1H NMR (200 MHz, CDCl3) δ: 8.03 (m, 4H); 7.53 (m,
2H); 7.41 (m, 4H); 6.15 (d, J ) 3 Hz, 2H); 5.42 (brs, 1H); 4.62
(dd, J ) 13, 6.5 Hz, A of ABX, 1H); 4.48 (d, J ) 13, 5.8 Hz, B
of ABX, 1H); 4.41 (dd, J ) 17.6, 1 Hz, A of ABX, 1H); 4.26 (dd,
J ) 17.6, 2 Hz, B of ABX, 1H); 4.12 (m, 1H). 13C NMR (100
MHz, CDCl3) δ: 63.8, 65.0, 65.8, 74.0, 122.2, 128.4, 128.5,
129.7, 129.8, 129.9, 132.6, 133.1, 133.2, 180.2, 182.4. IR
(neat): 1720 cm-1. [R]24D: -233.3° (c ) 0.47, CH2Cl2). HRMS
for C20H18NO5Na [M+ + Na]+: calcd 361.1052, found 361.1039.
[2S,5S]-[5-(2-Am in o-6-cyclop r op yla m in op u r in -9-yl)-
5,6-d ih yd r o-2H -p yr a n -2-yl]m et h ylb en zoa t e (49). To a
solution of hexane-washed NaH (16 mg of a 60% dispersion
in mineral oil, 0.40 mmol) in DMSO (1.5 mL) was added
2-amino-6-chloropurine 26 (62 mg, 0.37 mmol). The mixture
was heated to 45 °C for 15 min and then cooled to room
temperature. Dibenzoate 43 (124 mg, 0.37 mmol) in 2 mL of
THF was added followed by Pd2(dba)3‚CHCl3 (38 mg, 0.037
mmol) and PPh3 (9.7 mg 0.37 mmol). The reaction mixture was
heated to 45 °C overnight and then was quenched with water.
The resulting mixture was extracted with EtOAc. The organic
layers were combined, washed with water, and concentrated.
Purification by silica gel chromatography (50 to 100% EtOAc
in hexanes) yielded the dibenzoate 50 mg (40%) plus the
nucleoside analogue 52 as a white crystalline solid 67 mg, 48%
(79% based on recovered starting material). 1H NMR (200
MHz, CDCl3) δ: 8.05 (m, 2H); 8.00 (s, 1H); 7.53 (m, 3H); 6.26
(d, J ) 10.5 Hz, 1H); 6.09 (dd, J ) 10.5, 4.8 Hz, 1H); 5.13 (brs,
2H); 5.13 (brs, 2H); 4.92 (m, 1H); 4.54 (m, 3H); 4.12 (d, J ) 12
Hz, A of ABX, 1H); 4.01 (dd, J ) 12, 3 Hz, 1H). Anal. Calcd
for C23H24N5: C, 72.61; H, 6.36; O, 21.03. Found: C, 72.33; H,
6.22; N, 20.81.
1
provided 10.0 g (82%) of acyloxazolidinone 46. H NMR (250
MHz, CDCl3) δ: 7.27 (m, 5H); 5.96 (m, 1H); 5.28 (m, 2H); 4.68
(m, 1H); 4.67 (s, 2H); 4.23 (m, 2H); 4.16 (d, J ) 5.7 Hz, 2H);
3.32 (dd, J ) 3, 8, 9.5 Hz, 1H); 2.79 (dd, J ) 9, 5, 13 Hz, 1H).
13C NMR (CDCl3) δ: 37.69, 54.73, 67.22, 69.53, 72.48, 118.2,
127.4, 129.0, 129.4, 133.7, 134.9, 153.3, 170.2. IR (neat): 1780
cm-1. Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09.
Found: C, 65.40; H, 6.11; N, 5.22.
[3(2S,3R),4R]-3-(2-Allyloxy-3-h yd r oxyh ex-4-en oyl)-4-
ben zyloxa zolid in -2-on e 44. A solution of the allyloxyacetyl
oxazolidinone 46 (2.75 g, 10 mmol) in 50 mL of dichloro-
methane was cooled to 0 °C. Titanium tetrachloride (1.2 mL,
11 mmol) was added dropwise, producing a yellow precipitate.
After 5 min, (-)-sparteine (5.67 mL, 25 mmol) in 10 mL of
dichloromethane was added dropwise, resulting in a red-black
solution. The solution was stirred at 0 °C for 20 min and then
cooled to -78 °C. Freshly distilled crotonaldehyde (1.24 mL,
1.05 g, 15 mmol) in 2 mL of dichloromethane was then added
dropwise. When addition was complete, the mixture was
warmed to 0 °C for 30 min, whereupon half-saturated am-
monium chloride was added. The mixture was filtered through
Celite and the layers were separated. The aqueous layer was
extracted twice with 50 mL of dichloromethane. The combined
organic extracts were dried over sodium sulfate and concen-
trated. Purification of the residue by flash chromatography
afforded 3.00 g (87%) of 44 as a viscous, colorless oil. 1H NMR
(250 MHz, CDCl3) δ: 7.27 (m, 5H); 5.91 (m, 1H); 5.74 (q, J )
5.2 Hz, 1H); 5.59 (m, 1H); 5.28 (m, 2H); 5.18 (d, J ) 4.9 Hz);
4.67 (m, 1H); 4.32(brs, 1H); 4.14 (m, 3H); 3.35 (dd, J ) 3, 11
Hz, 1H); 2.79 (dd, J ) 7.8, 11 Hz, 1H); 1.70 (d, J ) 5.2 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ: 17.67, 37.70, 55.60, 66.81,
72.27, 73.61, 79.81, 118.54, 127.43, 128.96, 129.30, 129.38,
133.91, 134.99, 153.31, 170.70. IR (neat): 3490, 1760, 1710
cm-1. HRMS for C19H23NO5Na [M+ + Na]+: calcd 368.1474,
found 368.1468.
(2R,3R)-2-Allyloxy-h ep t-4-en e-1,3-d iol (50). To a stirring
solution of aldol adduct 44 (1.30 g, 3.76 mmol) and methanol
(0.20 mL, 4.88 mmol) in diethyl ether (30 mL, 0.1 M) at 0 °C
was added LiBH4 (2.44 mL of a 2.0 M solution in THF, 4.88
mmol) dropwise. The reaction was stirred for 1.5 h and then
quenched by the slow addition of 15% NaOH (30 mL). The
resulting solution was extracted with diethyl ether until no
diol was observed by TLC in the aqueous layer. The organic
fractions were combined, dried over MgSO4, concentrated
under vacuum, and purified by silica gel chromatography (30%
EtOAc in hexanes elution) to yield diol 50 as a clear, colorless
[2S,5S]-[5-(2-Am in o-6-cyclop r op yla m in o-p u r in -9-yl)-
5,6-d ih yd r o-2H -p yr a n -2-yl]m et h a n ol 42. To a stirring
solution of chloropurine benzoate 52 (54 mg, 0.14 mmol) in
1 mL of absolute ethanol was added cyclopropylamine (0.10
mL, 1.4 mmol). The reaction was heated to reflux for 5 h, at
which time TLC showed complete conversion to a more polar
intermediate. After the mixture was cooled to room temper-
ature, 0.5 M NaOH (4 mL) was added, and the reaction
mixture was heated to reflux for 2 h. The solvent was removed
under vacuum, and the residue was purified by silica gel
chromatography to yield the product 42 as a white crystalline
solid, 17 mg, 40%. 1H NMR (200 MHz, CDCl3) δ: 7.70 (s, 1H);
6.15 (d, J ) 11 Hz, 1H); 6.12 (brs, 1H); 6.03 (dd, J ) 11, 5 Hz,
1H); 4.82 (s, 1H); 4.78 (m, 1H); 4.38 (brs, 1H); 4.02 (dd, J )
12, 3 Hz, A of ABX, 1H); 3.94 (dd, J ) 12, 3 Hz, B of ABX,
1H); 3.83 (m, 1H); 3.70 (dd, J ) 12.5, 4.8 Hz, B of BABX, 1H);
2.90 (brs, 1H); 0.78 (m, 2H); 0.51 (m, 2H). Anal. Calcd for
1
oil, 0.569 g, 88%. H NMR (200 MHz, CDCl3) δ: 5.91 (m, 1H);
5.77 (q, J ) 6.4 Hz, 1H); 5.50 (m, 1H); 5.26 (m, 2H); 4.17 (m,
2H); 3.68 (m, 2H); 3.32 (m, 1H); 2.8 (d, J ) 3.7 Hz, 1H); 2.51
(brt, J ) 4.8 Hz, 1H); 1.73 (d, J ) 6 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ: 17.77, 61.20, 71.86, 72.64, 81.96, 117.48,
129.37, 129.60, 134.49. IR (film): 3600-3100 cm-1. Anal. Calcd
for C9H16O3: C, 62.77; H, 9.36. Found: C, 62.85; H, 9.46.
(2R,3R)-2-Allyloxyh ep t-4-en e-1,3-d iol Diben zoa te 51.
To a stirring solution of diol 50 (569 mg, 3.31 mmol) in 30 mL
of CH2Cl2 at 25 °C was added benzoyl chloride (0.961 mL, 1.16
g, 8.28 mmol), Et3N (1.4 mL, 9.9 mmol), and DMAP (12 mg,
0.1 mmol). After 12 h, the reaction was quenched with 5% HCl
(10 mL) and extracted with CH2Cl2. The organic layers were
combined and washed with saturated aqueous NaHCO3, dried
over Na2SO4, and concentrated. The resulting yellow oil was
purified by silica gel chromatography (10-25% EtOAc in
hexanes), affording the dibenzoate 51 (1.068 g, 85%) as a clear,
colorless oil that was used directly in the metathesis reaction.
1H NMR (200 MHz, CDCl3) δ: 8.08 (m, 4H); 7.54 (m, 2H); 7.41
(m, 4H); 5.58-6.10 (m, 4H); 5.21-5.42 (m, 2H); 4.57 (dd, J )
4, 11.5 Hz, A of ABX, 1H); 4.41 (dd, J ) 6, 11.5 Hz, B of ABX,
1H); 4.23 (dq, J ) 5, 1.5 Hz, 1H); 3.95 (ddd, J ) 4, 5, 9.5 Hz,
1H); 1.72 (dd, J ) 6, 2 Hz, 3H). IR (neat): 1720, 1603, 1264
C
14H18N6O2: C, 55.62; H, 6.00; N, 27.80; O, 10.58. Found: C,
55.44; H, 6.020; N, 27.99.
Ack n ow led gm en t. Fellowship support from the
Department of Education (for B.W.K.) and the National
Institutes of Health (for W.J .Z.) is gratefully acknowl-
edged. This work was supported in part by grant
from the Glaxo-Wellcome UNC Collaborative Research
Program.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for
obtained compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
cm-1
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J O005535P