A versatile enantioselective strategy toward L-C-nucleosides: A total synthesis of L-showdomycin

Article abstract of DOI:10.1021/jo990195x

Strategies for the synthesis of nucleosides that can provide either L or D isomers become more important as a result of the increasing number of such compounds that are therapeutically useful. The lower toxicity and reduced susceptibility toward metabolism of the L isomers make them particularly interesting. A strategy toward the C-nucleoside analogues has been explored in the context of the synthesis of L-showdomycin. The route involves an asymmetric desymmetrization using palladium catalysis of cis-2,5-diacyloxy- 2,5-dihydrofurans available in one step from furan, with carbon nucleophiles. Nucleophilic synthons for a maleimide unit and a methoxycarbonyl unit have been designed. Two sequential palladium-catalyzed reactions introduce both substituents with excellent chemo-, regio-, diastereo-, and enantioselectivity. The presence of a double bond in this doubly alkylated compound at C-3 and C-4 allows easy structural variation. The use of an ester as a hydroxymethyl precursor also introduces a diversity element as well as having importance in its own right. The successful completion of a synthesis of L-showdomycin validates this approach as a viable strategy to C- nucleosides.

Full text of DOI:10.1021/jo990195x

J . Org. Chem. 1999, 64, 5427-5435
5427
A Ver sa tile En a n tioselective Str a tegy Tow a r d L-C-Nu cleosid es: A
Tota l Syn th esis of L-Sh ow d om ycin
Barry M. Trost* and Lara S. Kallander
Department of Chemistry, Stanford University, Stanford, California 94305-5080
Received February 2, 1999
Strategies for the synthesis of nucleosides that can provide either L or D isomers become more
important as a result of the increasing number of such compounds that are therapeutically useful.
The lower toxicity and reduced susceptibility toward metabolism of the L isomers make them
particularly interesting. A strategy toward the C-nucleoside analogues has been explored in the
context of the synthesis of L-showdomycin. The route involves an asymmetric desymmetrization
using palladium catalysis of cis-2,5-diacyloxy-2,5-dihydrofurans available in one step from furan,
with carbon nucleophiles. Nucleophilic synthons for a maleimide unit and a methoxycarbonyl unit
have been designed. Two sequential palladium-catalyzed reactions introduce both substituents with
excellent chemo-, regio-, diastereo-, and enantioselectivity. The presence of a double bond in this
doubly alkylated compound at C-3 and C-4 allows easy structural variation. The use of an ester as
a hydroxymethyl precursor also introduces a diversity element as well as having importance in its
own right. The successful completion of a synthesis of L-showdomycin validates this approach as a
viable strategy to C-nucleosides.
The therapeutic value of nucleosides and their ana-
logues have drawn attention to the need for new strategic
approaches to their synthesis. Furthermore, easy access
to both enantiomeric series is proving more important
as the therapeutic advantages for the L-series compared
to the D-series are being increasingly demonstrated.1-3
Reduced tendency for enzymatic metabolism can increase
bioavailability and, thus, potency. Further, the potential
for higher specificity of mammalian enzymes for process-
ing of nucleic acids may also reduce toxicity. Such
benefits have been demonstrated for the treatment of the
human immunodeficiency virus (HIV) with the L-nucleo-
side analogues L-3TC2 and L-ddC.3 The recent work with
the C-nucleosides L-9-deazaadenosine and the dideoxy
analogue indicate the growing interest in this area,4
particularly with respect to C- rather than O-glycosyl-
ation reactions.
tions5 and is based upon the desymmetrization of cis-2,5-
diacyloxy-2,5-dihydrofuran (1), available in one step by
oxidation of furan.7 Simply by choice of ligand, substitu-
tion of either prochiral leaving group leading to either
enantiomeric series, 2 or 3, may be accomplished (eq 1).8
In developing a new strategy for the synthesis of
nucleosides, we focused on the ability to generate either
enantiomer equally well. Our strategy derives from the
development of asymmetric palladium-catalyzed reac-
By choosing appropriate nucleophiles, nucleosides may
be readily accessed. For example, by using purine or
pyrimidine bases, both D- and L-nucleosides have been
prepared.6 It should be pointed out that desymmetriza-
tion of diesters such as 1 with hydrolytic enzymes does
not work due to instability of the lactol product.
(1) (a) J urovcik, M.; Holy, A. Nucl. Acids Res. 1976, 3, 2143. (b) Nair,
V.; J ahnke, T. S. Antimicrob. Agents Chemother. 1995, 39, 1017. (c)
Koszalka, G. W.; Daluge, S. M.; Boyd, F. L. Ann. Rep. Med. Chem.
1998, 33, 163.
The applicability of this strategy to C-nucleosides
would expand its scope significantly. We chose showdo-
mycin (4) because of its interesting biological activity as
an antibiotic and antitumor agent, yet its development
is, in part, limited by its toxicity.9 Thus, access to
(2) (a) Coates, J . A. V.; Cammack, N.; J enkinson, H. J .; Mutton, I.
M.; Pearson, B. A.; Storer, R.; Cameron, J . M.; Penn, C. R. Antimicrob.
Agents Chemother. 1992, 36, 202. (b) Schinazi, R. F.; Chu, C. K.; Peck,
A.; McMillan, A.; Mathis, R.; Cannon, D.; J eong, L.-S.; Beach, J . W.;
Choi, W.-B.; Yeola, S.; Liotta, D. C. Antimicrob. Agents Chemother.
1992, 36, 672.
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E.; Cheng, Y.-C. J . Med. Chem. 1994, 37, 798. (b) Gosselin, G.; Schinazi,
R. F.; Sommadossi, J .-P.; Mathe, C.; Bergogne, M.-C.; Aubertin, A.-
M.; Kirn, A.; Imbach, J .-L. Antimicrob. Agents Chemother. 1994, 38,
1292. (c) Gosselin, G.; Boutow, V.; Griffon, J .-F.; Pavia, G.; Pierra, C.;
Imbach, J .-L.; Aubertin, A.-M.; Schinazi, R. F.; Faraj, A.; Sommadossi,
J .-P. Nucleosides Nucleotides 1997, 16, 1389. (d) Lin, T.-S.; Luo, M.-
Z.; Liu, M.-C. Tetrahedron Lett. 1994, 36, 3477. (e) Chen, S. H.; Li, X.;
Li, J .; Niu, C.; Carmichael, E.; Doyle, T. W. J . Org. Chem. 1997, 62,
3449. (f) J ung, M. E.; Kretschik, O. J . Org. Chem. 1998, 63, 2975.
(4) (a) Lee, C. S.; Du, J .; Chu, C. K. Nucleosides Nucleotides 1996,
15, 1223. (b) Liang, C.; Ma, T.; Cooperwood, J . S.; Du, J .; Chu, C. K.
Carbohydr. Res. 1997, 303, 33.
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(6) (a) Trost, B. M.; Shi, Z. J . Am. Chem. Soc. 1996, 118, 3037. (b)
For the carbacyclic analogues, see: Trost, B. M.; Madsen, R.; Guile,
S. D.; Elia, A. E. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1569. Trost,
B. M.; Madsen, R.; Guile, S. D. Tetrahedron Lett. 1997, 38, 1707.
(7) Elming, N.; Claason-Kass, N. Acta Chem. Scand. 1952, 6, 535.
(8) (a) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J . Am. Chem.
Soc. 1992, 114, 9327. (b) Trost, B. M.; Van Vranken, D. L. Angew.
Chem., Int. Ed. Engl. 1992, 31, 228.
(9) Nishimura, H.; Mayama, M.; Komatsu, Y.; Kato, H.; Shimsoka,
N.; Tanaka, Y. J . Antibiot., Ser. A 1964, 17, 148.
10.1021/jo990195x CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

5428 J . Org. Chem., Vol. 64, No. 15, 1999
Trost and Kallander
Sch em e 1. Retr osyn th etic An a lysis
L-showdomycin (en t-4) would provide the ability to
evaluate the biological properties of its mirror image.
Showdomycin demonstrated a broad range of inhibitory
effects toward the growth of Gram-positive and Gram-
negative bacteria.9 In E. coli, showdomycin inhibits
growth by obstructing the membrane transport of nutri-
ents.10 Showdomycin has also demonstrated antitumor
activity. It inhibits the growth of Ehrlich ascites tumor
cells in vivo and HeLa cells in vitro.11 Showdomycin
expressed a 2-fold selective toxicity for L1210 leukemia
cells over bone marrow progenitor cells. This selectivity
was enhanced by the addition of cytidine, a nontoxic
competitive substrate.12
Several studies have been done to elucidate showdo-
mycin’s specific mechanism of action as an antibiotic and
antitumor agent. The growth-inhibiting properties of
showdomycin on E. coli were reversed by preincubation
with RNA, DNA, and thiols but not other biologically
relevant compounds.10 Since these results imply that the
alkylating ability of the maleimide aglycon is important
for activity, it was postulated that showdomycin inacti-
vates membrane proteins by alkylating available thi-
ols,6,13 although this theory has been challenged.14,15
Further studies will be necessary to clarify the mecha-
nism(s) of showdomycin’s biological activity.
The interesting biological activity of showdomycin has
inspired multiple synthetic studies; both racemic16 and
enantiomerically pure17-19 showdomycin have been syn-
thesized. Most synthetic approaches build upon the
biogenetic precursor, D-ribose, by forming a diastereo-
selective anomeric carbon-carbon bond.17 Although some
very short syntheses of showdomycin have been realized
by this method, few analogues can be prepared in this
manner. Alternatively, the total synthesis of showdomy-
cin from noncarbohydrate starting materials provides
access to a broader range of analogues. The only method
to date in which the enantioselectivity was introduced
catalytically to synthesize showdomycin from noncarbo-
hydrate starting materials was an enzymatic desym-
metrization in which the enantiomeric excess was moder-
ate.19 In this paper, we report a short and versatile
synthesis of (-)-showdomycin predicated on the highly
selective palladium-catalyzed desymmetrization of eq 1.
Since the absolute stereochemistry is set by the chiral
ligand, either enantiomer of the final product is equally
accessible simply by choosing the correct enantiomer of
the ligand. Thus, a synthesis of ent-showdomycin also
constitutes a strategy for the synthesis of the natural
enantiomer as well. Proceeding through a 2,5-dihydro-
furan intermediate also provides easy access to numerous
analogues similar to the types of structural modifications
found in several clinically important antiviral nucleoside
analogues.
Syn th etic Str a tegy
Scheme 1 outlines the retrosynthetic analysis wherein
the 2,5-dihydrofuran 6 is a key intermediate derived from
the dibenzoate 7 and the two side chain fragments that
evolve from 8 and 9. The latter has previously been
shown by us to provide access to a carboxylic acid
function that can be reduced to a hydroxymethyl unit.6
The maleimide fragment of showdomycin can derive by
elimination of the elements of benzenesulfinic acid from
8. Therein also lies the problemsthe ease of this elimina-
tion since the sulfone stabilized anion must be able to
be generated and serve as a nucleophile prior to any
elimination. In principle, either unit, 8 or 9, can be
introduced in either order. The lability of 8 toward
elimination suggests it should be introduced later rather
than earlier, but both protocols were examined.
(10) (a) Yoshihide, K.; Kentaro, T. Agric. Biol. Chem. 1968, 32, 1021.
Nishimura, H.; Yoshihide, K. J . Antibiot. 1968, 21, 250. (b) Roy-
Burman, S.; Huang, Y. H.; Visser, D. W. Biochem. Biophys. Res.
Commun. 1971, 42, 445.
(11) Matsuura, S.; Shiratori, O.; Katagiri, K. J . Antibiot. Ser. A 1964,
17, 234.
(12) (a) Rabinovitz, M.; Uehara, Y.; Vistica, D. T. Science 1979, 206,
1085. (b) Uehara, Y.; Fisher, J . M.; Rabinovitz, M. Biochem. Pharmacol.
1980, 29, 2199. (c) Uehara, Y.; Rabinovits, M. Biochem. Pharmacol.
1981, 30, 3165.
Allylic Alk yla tion
(13) Roy-Burman, P. Recent Results Cancer Res. 1970, 25, 80.
(14) Roy-Burman, S.; Ryo-Burman, P.; Visser, D. W. Cancer Res.
1968, 28, 1605.
(15) Niedzwicki, J . G.; El Kouni, M. H.; Chu, S. H.; Cha, S. Biochem.
Pharmacol. 1983, 32, 399.
(16) (a) J ust, G.; Liak, T. J .; Lim, M.-I.; Potvin, P.; Tsantrizos, Y. S.
Can. J . Chem. 1980, 58, 2024. (b) Kozikowski, A. P.; Ames, A. J . Am.
Chem. Soc. 1981, 103, 3923.
(17) For some examples starting from ribose, see: (a) Barton, D. H.
R.; Ramesh, M. J . Am. Chem. Soc. 1990, 112, 891. (b) Barrett, A. G.
M.; Broughton, H. B.; Attwood, S. V.; Gunatilaka, A. A. L. J . Org.
Chem. 1986, 51, 495. (c) Katagiri, N.; Haneda, T.; Takahashi, N.
Nucleic Acids Res. 1984, 15, 37. (d) Gonzalez, M. S. P.; Aciego, R. M.
D.; Herrera, F. J . L. Tetrahedron 1988, 44, 3715. (e) Stewart, A. O.;
Williams, R. M. J . Am. Chem. Soc. 1985, 107, 4289.
(18) For other asymmetric syntheses, see: (a) Kang, S. H.; Lee, S.
B. Chem. Commun. 1995, 1017. (b) Kang, S. H.; Lee, S. B. Tetrahedron
Lett. 1995, 36, 4089; (c) 1993, 34, 1955. (d) Takayama, H.; Iyobe, A.;
Koizumi, T. Chem. Pharm. Bull. 1987, 35, 433. (e) Sato, T.; Hayakawa,
Y.; Noyori, R. Bull. Chem. Soc. J pn. 1984, 57, 2515.
(19) Ito, Y.; Shibata, T.; Arita, M.; Sawai, H.; Ohno, M. J . Am. Chem.
Soc. 1981, 103, 6739.
Maleimide synthon 8 was prepared to investigate its
utility as a carbon nucleophile for allylic alkylation
reactions. It was decided to protect the imide nitrogen
with the p-methoxybenzyl group to prevent N-alkylation,
a side reaction observed in the unprotected case. As
shown in Scheme 2, thiophenol underwent smooth con-
jugate addition to maleimide. Oxidation with hydrogen
peroxide in acetic acid generated the desired sulfone 10
in 83% yield for the two steps. To reduce the number of
steps, a Michael addition with sodium benzenesulfinate
to maleimide was explored (Scheme 2). Though this
reaction is reversible, the reaction is driven by the
precipitation of 10 in a buffered aqueous medium. After
filtration and drying, no further purification of 10 was
necessary. Protection of the imide with an alkyl group
without undue elimination was successful utilizing Mit-

Enantioselective Strategy toward L-C-Nucleosides
J . Org. Chem., Vol. 64, No. 15, 1999 5429
Sch em e 2. Syn th esis of Nu cleop h ilic Ma leim id e
Syn th on
Sch em e 3. Alter n a tive Syn th esis of Key
Dih yd r ofu r a n In ter m ed ia te
sunobu conditions.20 In this way, sulfonylsuccinimide 8
was prepared in three steps in 50% overall yield or in
two steps in an overall 46% yield.
To test the viability of using sulfone 8 as a nucleophile,
it was treated with sodium hydride in THF at 0 °C. After
10 min, a white solid precipitated (eq 2). To establish the
desired carbon adduct 16. By changing the solvent to
THF, 16 was formed exclusively.
The absolute stereochemistry of product 16 was pre-
dicted on the basis of precedence and subsequently
verified by completion of the synthesis.8 For both the
major and minor diastereomers, the enantiomeric excess
was determined to be 92% by chiral HPLC. This high
enantioselectivity was obtained without optimization.
The diastereoselectivity does not affect the synthesis of
showdomycin because this stereocenter will be lost when
the sulfone is eliminated. Nevertheless, it is of some
interest since induction of chirality at the prostereogenic
center of a nucleophile is an important dimension of
asymmetric palladium-catalyzed reactions.22
A second regio- and diastereoselective allylic alkylation
reaction of 16 with the known protected tartronic acid
96 was explored. Since the chiral product is formed
through a chirality transfer, an achiral ligand can be used
for this reaction. As shown in eq 4, the reaction proceeded
identity of this solid, in particular to explore whether it
was sodium benzenesulfinate or the desired anion 11, it
was exposed to methyl iodide. Indeed, the desired meth-
ylated product 12 was isolated in excellent yield.
The heterocyclic substrate 76,7 was reacted with nu-
cleophile 11 using a catalyst derived from palladium
complex 13 and the R,R configuration of chiral ligand
14.8 A strong solvent effect was discovered. Using a
biphasic mixture, the only product was determined to be
the sulfone adduct 15 (eq 3). This indicates that the polar
to introduce the tartronate forming the key intermediate
6 with complete regio- and diastereocontrol. The yield
may reflect sensitivity of the substrate and/or product
to base catalyzed eliminations.
To make the synthesis more general for all C-nucleo-
sides, we were also interested in using 9 in the desym-
metrization step (see Scheme 3). With the initial condi-
tions of using 14 as the ligand and cesium carbonate as
the base, a high yield (85%) of product ent-17 of 74% ee
was obtained. The enantioselectivity improved to 78%
(93% yield) upon switching the base to DBU with similar
results being obtained in both acetonitrile and methylene
chloride. On the other hand, by utilizing ligand 18,8 which
we believe creates a tighter pocket, the ee jumped to 90%
using DBU in methylene chloride to give 17.
protic solvent facilitated proton exchange, which led to
the thermodynamically favorable elimination of sulfinate.
The latter then serves as a nucleophile in the palladium-
catalyzed desymmetrization. Sodium benzenesulfinate
has been shown previously to be a good nucleophile in
allylic alkylation reactions.21 The same reaction was
repeated in methylene chloride to give both 15 and the
The alkylated product 17 was a good substrate for a
second allylic alkylation reaction with the sulfonylsuc-
cinimide 8. The conditions employed were the same as
those previously developed except that the achiral bis-
(20) Mitsunobu, O.; Wada, M.; Sano T. J . Am. Chem. Soc. 1972, 94,
679.
(21) Trost, B. M.; Organ, M. O.; O′Doherty, G. A. J . Am. Chem. Soc.
1995, 117, 9662.
(22) (a) Trost, B. M.; Radinov, R.; Grenzer, E. M. J . Am. Chem. Soc.
1997, 119, 7879. (b) Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2635.

5430 J . Org. Chem., Vol. 64, No. 15, 1999
Trost and Kallander
Sch em e 4
(diphenylphosphino)propane (dppp) was substituted as
the ligand. With the dppp ligand, the rate of the allylic
alkylation reaction was faster and the yield was higher
than the corresponding reaction with the chiral ligand.
Part of the reason may derive from the smaller steric
demand of the achiral ligand.
Either of the two carbon nucleophiles shown can be
introduced with good enantioselectivity (g90%) in the
desymmetrization of cis-diester 1. Also, either enantiomer
of the product can be accessed based on the choice of
ligand stereochemistry. It appears that the palladium-
catalyzed allylic alkylation offers an improvement in
enantioselectivity over an alternative enzymatic strategy
previously published for the synthesis of D-showdomy-
cin.19
Sch em e 5
Com p letion of th e Syn th esis
cis-Dihydroxylation of 6 with osmium tetraoxide and
N-methylmorpholine N-oxide (NMO) as the co-oxidant
was low yielding because the N-methylmorpholine byprod-
uct proved basic enough to eliminate some of the sulfone
from product 19. This complication arose partly because
the dihydroxylation was exceptionally slow for this
substrate. By experimenting with buffered conditions and
higher catalyst loading (20 mol %), the dihydroxylation
was achieved efficiently (Scheme 4). The substrate-
controlled dihydroxylation occurred with complete dia-
stereoselectivity; the anti configuration was inferred on
the basis of steric predictions, precedent,6 and by the
observed low vicinal coupling constant between the
protons at C-4 and C-5 (J ) 1.7 Hz). Protection of diol as
the acetonide to form 5 proceeded straightforwardly.
Elimination of the sulfone to form an olefin would be
desirable as early in the synthetic sequence as possible
in order to simplify the mixture of diastereomers. When
substrate 5 was reacted with DBU, two different products
were observed. The kinetic product 20 had the desired
maleimide moiety (eq 5), and the thermodynamic product
21 derived from isomerization of the double bond to the
exocyclic position (eq 6).23 The isomerization is particu-
larly undesirable in our case because the chirality at the
furan carbon is lost. Since the isomerization may be
difficult to avoid, we decided to retain the sulfone as a
“protected olefin” to be removed later in the synthetic
sequence.
(see Scheme 5). With ethyl acetate as the solvent, the
desired hydroxy diacid 22 was isolated in essentially a
quantitative yield. It has been noted previously that
alkoxy-substituted benzylamines are inert to hydro-
genolysis.24 Our results also support this observation; the
p-methoxybenzyl group on the imide nitrogen was not
removed under these hydrogenolysis conditions.
A procedure had been previously developed in our
laboratory to convert a hydroxy diacid to a hydroxy-
methyl.6 This approach could not be used with substrate
22 because triethylamine, a necessary reagent, was able
to induce the elimination of the sulfone and isomerize
the olefin to the undesired exocyclic position. As an
alternative approach, an oxidative decarboxylaton was
considered.25 With a hydroxy diacid, it should be possible
to effect a decarboxylation, a hydration, and a second
decarboxylation in one pot to give the desired acid 23a .
Sodium periodate did form some of the desired product
(35%), but increasing the reaction time or temperature
led to decomposition. Using pure ground lead tetraacetate
was more successful; acid 23a was the major compound
in the crude extract (65-75% yield). Direct reduction of
the resultant acid 23a via activation as the hydroxyben-
zotriazole26 ester worked well. Considering the difficulty
of the two steps, a didecarboxylation and reduction in
the presence of sensitive functionality, an overall yield
of 63% from 5 was very satisfying. Interestingly, per-
forming the oxidative bis-decarboxylation in 2:1 acetone-
methanol gave directly the methyl ester 23b in 69% yield.
The completion of the synthesis of showdomycin from
24 requires removal of the protecting groups. In the
elimination of the sulfone, which unmasks a maleimide,
To remove the benzyl and benzyloxycarbonyl protecting
groups from 5, catalytic hydrogenolysis was employed
(24) Bringmann, G.; Geisler, J .-P.; Geuder, T.; Kunkel, G.; Kinzinger,
L. Liebigs Ann. Chem. 1990, 795.
(25) Yanuka, Y.; Katz, R.; Sarel, S. Tetrahedron Lett. 1968, 1725.
(b) Baer, E. J . Am. Chem. Soc. 1940, 62, 1597.
(26) Trost, B. M.; Hipskind, P. A. Tetrahedron Lett. 1992, 33, 4541.
(23) Ozaki, M.; Kariya, T.; Kato, H.; Kimura, T. Agric. Biol. Chem.
1972, 36, 451-456.

Enantioselective Strategy toward L-C-Nucleosides
J . Org. Chem., Vol. 64, No. 15, 1999 5431
Sch em e 6
adduct. Unfortunately, separating the product from the
DMSO was difficult, and the collected showdomycin with
all the known byproducts only accounted for 51% of the
starting material. Recrystallization of the crude material
afforded a 32% yield of showdomycin as a white solid.
At this time, this last step has not been optimized and
would likely proceed in higher yields.
The proton and carbon NMR and IR data of the
synthetically prepared showdomycin matched the litera-
ture data for the natural product except for the sign of
the rotation.27 The synthesized material had been pre-
pared from a bulk supply of 6, which was only 70%
enantiomerically pure, but enantiopure L-showdomycin
was obtained by a recrystallization from acetone/benzene
to give a crystalline product that had an optical rotation
of -47.8°; this value compares favorably with that of
natural showdomycin except being opposite in sign,
verifying that we had prepared the enantiomer of the
natural product.
one side reaction to keep in mind is the presence of an
unprotected hydroxyl group that is also known to undergo
an intramolecular Michael addition to form a spirocycle.27
This Michael addition was observed when following the
reaction over time by proton NMR. By adding DBU to
the substrate at 0 °C and quenching with monopotassium
phosphate buffer after exactly 1 min, a high yield of the
desired product 25 was obtained (eq 7).
Con clu sion
L-Showdomycin was prepared in 10 synthetic steps
from the know cis-diester 1 by using an enantioselective
palladium-catalyzed allylic alkylation reaction. We dem-
onstrated that a novel sulfone-substituted succinimide
(8) could be used as a nucleophile and elaborated into
maleimide. The palladium-catalyzed desymmetrization
was demonstrated to be efficient with either of two carbon
nucleophiles, giving enantiomeric excesses of g90%. The
remaining stereocenters were efficiently introduced by
a regio- and diastereoselective palladium-catalyzed allylic
alkylation and a diastereoselective dihydroxylation. An
efficient and more general method for the decarboxylation
of a hydroxy diacid was developed with lead tetraacetate
under neutral conditions. Deprotection of the p-meth-
oxybenzyl group and acetonide prior to elimination of the
sulfone avoided most of the side reactions in the elimina-
tion of the sulfone to give L-showdomycin.
More generally, what we have demonstrated is a novel
approach to the synthesis of C-nucleosides. The pal-
ladium-catalyzed enantioselective allylic alkylation has
been used previously with amine nucleophiles to prepare
carbanucleosides and nucleosides, but this is the first
example of a carbon nucleophile in the desymmetrization
of a heterocyclic substrate. With alternative carbon
nucleophiles, other C-nucleosides could be synthesized
by the same method. The second carbon side chain also
is introduced efficiently with complete chemo-, regio-, and
diastereoselectivity using a second palladium-catalyzed
alkylation. Furthermore, utilization of a methoxycarbonyl
group as a precursor to a hydroxymethyl group offers
flexibility for structural diversification of this unit as well
as have intrinsic interest. The 3,4-double bond in the
initial doubly alkylated intermediate represents an op-
portunity for facile variation of the substitution pattern
at these carbons, which has proven of interest for several
clinically important nucleoside analogues. Thus, this
strategy has considerable flexibility to vary structure and
should be a versatile route to the preparation of biologi-
cally interesting natural and unnatural C-nucleosides.
Removal of the p-methoxybenzyl group from 25 proved
to be more difficult than had been expected. By treating
25 with trifluoroacetic acid,28 only the acetonide was
removed. Oxidative cleavage methods to remove the
p-methoxybenzyl group from 25 were also unsuccessful;
ceric ammonium nitrate (CAN)29 decomposed the sub-
strate, and no reaction was observed with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ). To address the
possibility that CAN was decomposing the maleimide
functionality, the deprotection of substrate 24 with CAN
was tried. Indeed, the removal of the p-methoxybenzyl
group to give 26 worked well (Scheme 6).
Returning to the issue of a base-induced sulfone
elimination, the presence of an unprotected imide in 26
(pKa ) 9) slowed the elimination, allowing time for the
competing Michael addition. To avoid the Michael addi-
tion, the acetonide was removed first since the bicyclic
nature of substrate 26 facilitates the Michael addition
by bringing the hydroxyl group proximal to the male-
imide olefin. Aqueous acid cleaved the acetonide to give
diol 27 in a high yield.30
The elimination of the sulfone from 27 was followed
by proton NMR in DMSO-d6; showdomycin was the major
product, along with a small amount (<10%) of unreacted
starting material, the isomerized olefin, and the Michael
(27) Nakagawa, Y.; Kano, H.; Tsukuda, Y.; Koyama, H. Tetrahedron
Lett. 1967, 4105.
(28) Smith, A. B.; Rano, T. A.; Chida, N.; Sulikowski, G. A.; Wood,
J . L. J . Am. Chem. Soc. 1992, 114, 8008.
Exp er im en ta l Section
(29) Ihara, M.; Haga, Y.; Yonekura, M.; Ohsawa, T.; Fukumoto, K.;
Kametani, T. J . Am. Chem. Soc. 1983, 105, 7345.
(30) Sato, T.; Hayakawa, Y. Noyori, R. Bull. Chem. Soc. J pn. 1984,
57, 2515.
Gen er a l Meth od s. Unless otherwise noted, reactions were
run in flame-dried glassware under a positive pressure of
nitrogen gas. The reaction flasks were sealed with rubber

5432 J . Org. Chem., Vol. 64, No. 15, 1999
Trost and Kallander
septa, and the contents were magnetically stirred. Liquids
were transferred by oven-dried syringes or cannulas. Solvents
were fresly distilled under nitrogen prior to use: benzene,
acetonitrile, methylene chloride, and triethylamine from cal-
cium hydride; tetrahydrofuran and diethyl ether from sodium
benzophenone ketyl; acetone from calcium sulfate; and metha-
nol from magnesium methoxide. Flash chromatography was
performed with Kieselgel 60, 230-400 mesh. Analytical thin-
layer chromatography (TLC) was performed on 0.2 mm pre-
coated silica gel plates from Merck, Kieselgel 60, F254. Melting
points were determined using open capillaries on a Thomas-
Hoover unimelt apparatus and are uncorrected. High-resolu-
tion mass spectroscopy was performed by the NIH Mass
Spectral Facility at UC San Francisco on a Kratos MS9
instrument. Elemental analyses were performed by M-H-W
Laboratories, Phoenix, AZ. Optical rotations were measured
on a J ASCO DIP-1000 digital polarimeter.
(50:50 petroleum ether/ethyl acetate) gave a crude oil with a
ratio of starting material to product of 8:92. The product was
purified by flash chromatography (75:25 petroleum ether/ethyl
acetate) to give 24 mg (67%) of 16 as a colorless oil. The
diastereomeric ratio was 7:3 by proton NMR. The diastereo-
mers were separated by flash chromatography (80:20 petro-
leum ether/ethyl acetate) for enantiomeric excess determina-
tion by chiral HPLC. The enantiomeric excess for both the
major and minor diastereomers was 92%. To obtain racemic
16, the same method was used, but dppp was substituted for
the chiral ligand. Rf 0.20 (70:30 petroleum ether/ethyl acetate).
1
IR (neat): 2934, 1714, 1515, 1397, 1325 cm-1. H NMR major
diastereomer (400 MHz, CDCl3): δ 7.79-7.86 (m, 4H), 7.66
(t, J ) 7.4 Hz, 1H), 7.57 (t, J ) 7.3 Hz, 1H), 7.49 (t, J ) 7.6
Hz, 2H), 7.43 (t, J ) 7.6 Hz, 2H), 7.05 (s, 1H), 7.00 (d, J ) 8.6
Hz, 2H), 6.72 (d, J ) 6.1 Hz, 1H), 6.62 (d, J ) 8.7 Hz, 2H),
6.26 (d, J ) 6.1 Hz, 1H), 5.62 (s, 1H), 4.48 (d, J ) 14.4 Hz,
1H), 4.36 (d, J ) 14.3 Hz, 1H), 3.71 (s, 3H), 3.27 (d, J ) 19.2
Hz, 1H), 3.15 (d, J ) 19.1 Hz, 1H). 13C NMR major diastereo-
mer (100 MHz, CDCl3): δ 172.4, 170.1, 164.8, 159.0, 135.2,
133.6, 131.5, 130.3, 129.7, 129.6, 129.4, 129.3, 128.7, 128.5,
126.6, 113.8, 102.0, 84.5, 73.6, 55.1, 42.4, 30.8. Anal. Calcd
for C29H25NO8S: C, 63.61; H, 4.60; N, 2.56. Found: C, 63.62;
H, 4.84; N, 2.42.
Deter m in a tion of En a n tiom er ic Excess for 16. High-
pressure liquid chromatography (HPLC) was used to separate
and quantify the enantiomeric products. A Chiralcel OD
column, cellulose tris(3,5-dimethylphenyl carbamate) on a 10
µm silica gel substrate, was used to separate the enantiomers
on a 250 × 4.6 mm column. A flow rate of 1.0 mL/min was
established with 80:20 2-propanol/n-heptane as the eluting
solvent. The substrate had to be heated to dissolve it in the
eluting solvent before it was applied to the column by injecting
10 µL of a 0.91 mM solution. As the enantiomers were eluted
off the column, they were detected and quantified by UV at
254 nm. The racemic 16 was injected on the column, and four
peaks eluted but with considerable overlap. Therefore, in the
asymmetric case, the diastereomers were separated by flash
chromatography before HPLC analysis. The enantiomers of
the major diastereomer eluted at 21 and 39 min resulting in
an enantiomeric excess of 92%. The enantiomers of the minor
diastereomer eluted at 30 and 38 min also resulting in an
enantiomeric excess of 92%. The major enantiomer for both
diastereomers has the 2S,5S stereochemistry.
P r ep a r a tion of (2S,5S)- a n d (2R,5R)-5-(Diben zyloxy-
ca r b on ylb en zyloxyca r b on yloxy)-2-b en zyloxy-2,5-d ih y-
d r ofu r a n (en t-17 a n d 17). Meth od A (Op tim ized for Yield ,
en t-17). Into a prestirred solution of 7 (500 mg, 1.6 mmol),
bis(η3-allyl)di-µ-chloro-dipalladium (15 mg, 5.0 mol % Pd), and
ligand 14 (83 mg, 15 mol %) in acetonitrile (12 mL) under
argon in a cooled (0 °C) sonicator was cannulated a solution
of 9 (840 mg, 1.9 mmol) and DBU (265 µL, 1.7 mmol) in
acetonitrile (8 mL). The reaction mixture was degassed by
bubbling with argon with sonication for 10 min. The reaction
was sealed and stirred under an argon balloon for 3 h at 0 °C.
Direct application to flash chromatography (50:50 petroleum
ether/ethyl acetate) gave a crude oil. The product was further
purified by flash chromatography (70:30 petroleum ether/ethyl
acetate) to give 930 mg (93%) of en t-17 as a colorless oil. The
enantiomeric excess, determined by chiral HPLC, was 78%.
To obtain racemic 17, the same method was used but dppp
was substituted for the chiral ligand. Rf 0.21 (80:20 petroleum
ether/ethyl acetate). IR (neat): 3065, 3034, 2959, 1755, 1455,
1382 cm-1. 1H NMR (300 MHz, CDCl3): δ 8.07 (d, J ) 8.0 Hz,
2H), 7.46 (t, J ) 7.6 Hz, 1H), 7.16-7.37 (m, 17H), 7.06 (s, 1H),
6.32 (d, J ) 6.0 Hz, 1H), 6.00 (d, J ) 6.0 Hz, 1H), 5.63 (s, 1H),
5.11-5.28 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 165.7, 164.2,
163.8, 153.7, 134.6, 134.5, 133.0, 130.8, 130.0, 129.7, 128.6,
128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 101.8, 87.4, 84.2, 70.4,
P r ep a r a tion of 3-P h en ylsu lfon ylsu ccin im id e (10). To
maleimide (5.0 g, 51.5 mmol) in water (100 mL) were added
monopotassium phosphate buffer (10% aqueous, 84 mL, 61.8
mmol) and sodium benzenesulfinate (9.30 g, 56.7 mmol). The
mixture was stirred at room temperature for 1 h, during which
time a white solid precipitated. The solid was filtered and
evaporated in vacuo to give 9.11 g (74%) of 10. Mp: 156-158
°C. Rf: 0.27 (50:50-petroleum ether:ethyl acetate). IR (neat):
3264, 1793, 1724, 1346, 1312 cm-1 1H NMR (400 MHz,
.
CDCl3): δ 9.34 (s, 1H), 7.79 (d, J ) 7.9 Hz, 2H), 7.59 (t, J )
7.3 Hz, 1H), 7.47 (t, J ) 7.6 Hz, 2H), 4.49 (m, 1H), 3.02 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 174.3, 169.2, 135.9, 134.8,
129.3, 128.9, 64.1, 31.0. HRMS (m/e): calcd for C10H9NO4S
239.0252, found 239.0252.
P r epar ation of 3-P h en ylsu lfon yl-N-(4-m eth oxyben zyl)-
su ccin im id e (8). To a cooled solution (-78 °C) of 10 (1.78 g,
7.4 mmol), triphenylphosphine (1.95 g, 7.4 mmol), and 4-meth-
oxybenzyl alcohol (925 µL, 7.4 mmol) in THF (37 mL, 0.2 M)
was added diisopropyl azodicarboxylate (1.46 ml, 7.4 mmol).
The mixture was then transferred to an ice bath. The reaction
turned from yellow to orange within 10 min, and TLC (50:50
petroleum ether/ethyl acetate) indicated that the starting
material had been consumed. The reaction mixture was poured
into ethyl acetate/petroleum ether (200 mL, 50:50 mixture),
and the organic products were filtered through a silica plug
(200 mL), using ethyl acetate/petroleum ether (800 mL, 50:50
mixture) washes to collect the crude product. After evaporation
in vacuo, the yellow oil was dissolved in methanol (50 mL)
and cooled for 24 h in the refrigerator. The newly formed white
crystals were filtered to give 1.28 g (48%) of 8. On a smaller
scale (556 mg), purification by flash chromatography gave 504
mg (61%) of 8: Mp: 136-138 °C (methanol). Rf: 0.46 (50:50
petroleum ether/ethyl acetate). IR (neat): 2940, 1712, 1514,
1
1397, 1326 cm-1. H NMR (400 MHz, CDCl3): δ 7.84 (d, J )
8.3 Hz, 2H), 7.68 (t, J ) 8.6 Hz, 1H), 7.54 (d, J ) 7.5 Hz, 2H),
7.21 (d, J ) 8.7 Hz, 2H), 6.78 (d, J ) 8.7 Hz, 2H), 4.53 (s, 2H),
4.30 (dd, J ) 9.6, 3.7 Hz, 1H), 3.76 (s, 3H), 3.30 (dd, J ) 19.1,
3.8 Hz, 1H), 3.02 (dd, J ) 19.1, 9.6 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 172.5, 168.2, 159.4, 136.2, 134.8, 130.1, 129.2,
126.9, 113.9, 63.2, 55.2, 42.5, 29.8. HRMS (m/e): calcd for
C
18H17NO5S 359.0827, found 359.0821.
P r epar ation of (2S,5S)-2-[3′-P h en ylsu lfon yl-N′-(4-m eth -
oxyb en zyl)su ccin im id -3′-yl]-5-b en zoyloxy-2,5-d ih yd r o-
fu r a n (16). To sodium hydride (68% oil, 3.9 mg, 0.097 mmol)
in a cooled sonicator bath (0 °C) was added 8 (46 mg, 0.13
mmol) in THF (300 µL). The mixture was degassed with argon
while bubbling ensued for 3-5 min. A prestirred solution of 7
(20 mg, 0.064 mmol), bis(η3-allyl)di-µ-chlorodipalladium31 (0.5
mg, 5 mol % Pd), and ligand 14 (3.0 mg, 15%) in THF (300
µL) under argon was cannulated into the solution of nucleo-
phile in the sonicator. Additional THF was added to help wash
all the material into the reactive flask (200 µL, 0.08 M overall).
The reaction mixture was degassed by bubbling with argon
with sonication for 10 min. The mixture was sealed and stirred
for 4 h at 0 °C. Direct application to flash chromatography
68.2, 68.1. Anal. Calcd for C36H30O10
Found: C, 69.55; H, 4.91.
: C, 69.45; H, 4.86.
Meth od B (Op tim ized for En a n tiom er ic Excess, 17).
Into a prestirred solution of 7 (25 mg, 0.082 mmol), bis(η3-
allyl)di-µ-chlorodipalladium (1.5 mg, 10 mol % Pd), and ligand
18 (10 mg, 15 mol %) in methylene chloride (320 µL) under
(31) Tatsuno, Y.; Yoshida, T.; Otsuka, S. Inorg. Synth. 1990, 28, 342.

Enantioselective Strategy toward L-C-Nucleosides
J . Org. Chem., Vol. 64, No. 15, 1999 5433
argon in a cooled (0 °C) sonicator was cannulated a solution
of 9 (43 mg, 0.098 mmol) and DBU (13.5 µL, 0.090 mmol) in
methylene chloride (500 µL). The reaction mixture was de-
gassed by bubbling with argon with sonication for 10 min. The
reaction was sealed and stirred under an argon balloon for 3
h at 0 °C and then 2 h at room temperature. Direct application
to flash chromatography gave a crude oil with both product
and unreacted starting material. The product was further
purified by flash chromatography (70:30 petroleum ether/ethyl
acetate) to give 28 mg (54%) of 17 as a colorless oil. The
starting material was separated from excess 9 by hydrogena-
tion and silica filtration to give 7.0 mg of 7, making the overall
yield 74% based on recovered starting material. The enantio-
meric excess, determined by chiral HPLC, was 90%. This
material was identical spectroscopically to the material above.
Deter m in a tion of En a n tiom er ic Excess for 17. HPLC
was used to separate and quantify the enantiomeric products.
A Chiralpak AD column, amylose tris(3,5-dimethylphenyl
carbamate) on a 10 µm silica gel substrate, was used to
separate the enantiomers on a 250 × 4.6 mm column. A flow
rate of 1.0 mL/min was established with 85:15 2-propanol/n-
heptane as the eluting solvent. The substrate had to be heated
to dissolve it in the eluting solvent before it was applied to
the column by injecting 10 µL of a 0.80 mM solution. As the
enantiomers were eluted off the column, they were detected
and quantified by UV at 254 nm. The enantiomers eluted at
24 min (2S,5S) and 35 min (2R,5R). The enantiomeric excess
was determined to be 90%.
P r ep a r a tion of (2S,3S,4R,5R)-5-(Diben zyloxyca r bon yl-
ben zyloxyca r bon yloxy)-2-[3′-p h en ylsu lfon yl-N′-(4-m eth -
oxybenzyl)succinim id-3′-yl]-3,4-dih ydr oxytetr ah ydr ofu r an
(19). To a solution of 6 (617 mg, 0.72 mmol) in methylene
chloride (0.5 M, 1.43 mL) were added monopotassium phos-
phate buffer (10% aqueous, 2.91 mL), osmium tetraoxide (0.19
M solution, 755 µL), and NMO (500 mg, 4.27 mmol). After the
two-phase mixture was stirred vigorously for 24 h at room
temperature, a solution of sodium metabisulfite (10% aqueous,
10 mL) was added, and the mixture was stirred for 1 h. The
organic products were extracted with methylene chloride (3
× 10 mL). The combined organic products were dried over
magnesium sulfate, filtered, and evaporated in vacuo. The
product was purified by flash chromatography (50:50 petro-
leum ether/ethyl acetate) to give 570 mg (89%) of 19 as a foamy
colorless glass. Rf 0.35 (50:50 petroleum ether/ethyl acetate).
1
IR (neat): 3494, 2956, 1756, 1715, 1515, 1397 cm-1. H NMR
major diastereomer (400 MHz, CDCl3): δ 7.70 (d, J ) 8.3 Hz,
2H), 7.63 (t, J ) 8.0 Hz, 1H), 7.07-7.45 (m, 19H), 6.74 (d, J )
8.5 Hz, 2H), 5.10-5.19 (m, 4H), 4.77 (d, J ) 13.1 Hz, 1H),
4.68-4.71 (m, 2H), 4.58 (d, J ) 5.7 Hz, 1H), 4.47 (d, J ) 1.7
Hz, 1H), 4.37 (d, J ) 14.0 Hz, 1H), 4.31-4.35 (m, 1H), 4.20 (d,
J ) 14.3 Hz, 1H), 3.72 (d, J ) 3.7 Hz, 1H), 3.66 (s, 3H), 3.37
(d, J ) 18.8 Hz, 1H), 3.23 (d, J ) 18.8 Hz, 1H), 2.90 (d, J )
1.2 Hz, 1H). 13C NMR major diastereomer (100 MHz, CDCl3):
δ 172.1, 169.9, 163.6, 163.3, 159.2, 152.8, 135.2, 134.4, 134.2,
133.7, 130.5, 130.1, 129.1, 128.7, 128.5, 128.2, 128.0, 127.9,
126.8, 113.8, 84.9, 84.1, 79.2, 73.7, 72.0, 71.2, 70.8, 68.6, 68.1,
55.1, 42.3, 30.5. Anal. Calcd for C47H43NO15S: C, 63.15; H, 4.85;
N, 1.57. Found: C, 63.05; H, 4.90; N, 1.73.
P r ep a r a tion of (2S,5R)-5-(Diben zyloxyca r bon ylben -
zyloxyca r bon yloxy)-2-[3′-p h en ylsu lfon yl-N′-(4-m eth oxy-
ben zyl)-su ccin im id -3′-yl]-2,5-d ih yd r ofu r a n (6). Meth od
A: F r om su bstr a te 17. To a suspension of sodium hydride
(68% oil, 45 mg, 2.6 mmol) in THF (7 mL) placed in a cooled
sonicator bath (0 °C) was added 8 (616 mg, 3.4 mmol) in THF
(7 mL). The mixture was degassed with argon while bubbling
ensued for 3-5 min. A prestirred solution of 17 (534 mg, 1.7
mmol), bis(η3-allyl)di-µ-chlorodipalladium (7.8 mg, 5 mol % Pd),
and dppp (27 mg, 15 mol %) in THF (7 mL) under argon was
cannulated into the solution of the nucleophile in the sonicator.
Additional THF was added (27 mL). The reaction mixture was
degassed by bubbling with argon with sonication at 0 °C for
10 min. The mixture was sealed and stirred for 3 h at 0 °C.
Direct application to flash chromatography (50:50 petroleum
ether/ethyl acetate) and evaporation in vacuo gave a crude oil.
The product was further purified by flash chromatography (70:
30 petroleum ether/ethyl acetate) to give 617 mg (84%) of 6 as
a foamy colorless glass. Rf 0.77 (50:50 petroleum ether/ethyl
acetate). IR (neat): 3035, 2956, 1757, 1718, 1515, 1397, 1279
P r ep a r a tion of (2S,3S,4R,5R)-5-(Diben zyloxyca r bon -
ylben zyloxycar bon yloxy)-2-[3′-ph en ylsu lfon yl-N′-(4-m eth -
oxyben zyl)su ccin im id -3′-yl]-3,4-d ih yd r oxya ceton id e-tet-
r a h yd r ofu r a n (5). To a solution of 19 (570 mg, 0.64 mmol)
in methylene chloride (6.3 mL, 0.1 M) were added 2,2-
dimethoxypropane (313 µL, 2.56 mmol) and PPTS (16 mg,
0.064 mmol). The mixture was warmed to 35 °C and stirred
for 24 h, sealed with a nitrogen balloon. The solvent was
evaporated in vacuo, and the residue was applied to flash
chromatography for purification (70:30 petroleum ether/ethyl
acetate). The product was collected, and the solvents were
evaporated in vacuo to give 549 mg (92%) of 5 as a foamy
colorless glass. Rf 0.43 (70:30 petroleum ether/ethyl acetate).
IR (neat): 2936, 1759, 1715, 1515, 1398, 1250, 1151, 1083 cm-1
.
1H NMR major diastereomer (400 MHz, CDCl3): δ 7.89 (d, J
) 8.5 Hz, 2H), 7.66 (t, J ) 8.0 Hz, 1H), 7.48 (t, J ) 8.2 Hz,
2H), 7.10-7.40 (m, 17H), 6.78 (d, J ) 8.7 Hz, 2H), 5.05-5.18
(m, 6H), 4.83-4.90 (m, 2H), 4.71 (d, J ) 12.3 Hz, 1H), 4.49 (d,
J ) 2.5 Hz, 1H), 4.37-4.45 (m, 2H), 3.65 (s, 3H), 3.38 (d, J )
18.8 Hz, 1H), 3.28 (d, J ) 18.8 Hz, 1H), 1.60 (s, 3H), 1.33 (s,
3H). 13C NMR major diastereomer (100 MHz, CDCl3): δ 172.4,
170.5, 163.5, 163.1, 152.8, 135.0, 134.9, 134.4, 134.3, 134.2,
134.1, 131.5, 130.6, 129.7, 128.9, 128.7, 128.6, 128.5, 128.4,
128.3, 128.2, 128.1, 127.9, 126.8, 114.9, 113.9, 84.2, 82.5, 80.9,
80.4, 73.1, 70.9, 68.6, 68.2, 55.0, 42.4, 30.3, 29.7, 27.2, 25.3.
Anal. Calcd for C50H47NO15S: C, 64.30; H, 5.07; N, 1.50.
Found: C, 64.34; H, 5.23; N, 1.49.
1
cm-1. H NMR major diastereomer (400 MHz, CDCl3): δ 7.70
(d, J ) 7.3 Hz, 2H), 7.57 (t, J ) 7.4 Hz, 1H), 7.31-7.46 (m,
4H), 7.15-7.30 (m, 5H), 6.78 (d, J ) 8.7 Hz, 2H), 6.37 (d, J )
6.4 Hz, 1H), 6.08 (d, J ) 6.1 Hz, 1H), 5.62 (s, 1H), 5.37 (s,
1H), 5.14-5.26 (m, 4H), 4.99 (s, 2H), 4.39 (d, J ) 14.3 Hz,
1H), 4.20 (d, J ) 14.3 Hz, 1H), 3.73 (s, 3H), 3.63 (d, J ) 19.3
Hz, 1H), 3.09 (d, J ) 19.3 Hz, 1H). 13C NMR major diastereo-
mer (100 MHz, CDCl3): δ 172.1, 169.9, 163.8, 162.9, 158.9,
152.9, 134.8, 134.5, 134.4, 134.2, 134.1, 130.2, 129.9, 129.8,
128.9, 128.8, 128.7, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0,
127.5, 126.9, 113.6, 86.9, 84.2, 83.5, 73.9, 70.5, 68.2, 67.9, 54.9,
41.9, 30.0. Anal. Calcd for C47H41NO13S: C, 65.65; H, 4.81; N,
1.63. Found: C, 65.47; H, 4.91; N, 1.81.
P r ep a r a tion of (2S,3S,4R,5R)-2-[N′-(4-Meth oxyben zyl)-
m aleim id-3′-yl]-5-(diben zyloxycar bon ylben zyloxycar bon -
yloxy)-3,4-d ih yd r oxya ceton id etetr a h yd r ofu r a n (20). To
a solution of 5 (49 mg, 0.052 mmol) in chloroform (5 mL, 0.01
M) was added DBU (8.7 µL, 0.057 mmol). The mixture was
stirred at room temperature for 10 min. The reaction mixture
was directly applied to flash chromatography for purification
(70:30 petroleum ether/ethyl acetate). The product was col-
lected, and the solvents were evaporated in vacuo to give 23
mg (55%) of 20 as a colorless oil. Rf 0.15 (80:20 petroleum ether:
Meth od B: F r om Su bstr a te 16. Into a prestirred solution
of 16 (31 mg, 0.057 mmol), bis(η3-allyl)di-µ-chlorodipalladium
(0.5 mg, 2.5 mol % Pd), and dppp (1.7 mg, 7.5 mol %) in
acetonitrile/THF (1:1, 1 mL) under argon was cannulated a
solution of 9 (30 mg, 0.068 mmol) and cesium carbonate (22
mg, 0.068 mmol) in acetonitrile/THF (1:1, 1 mL). The reaction
mixture was degassed by bubbling with argon with sonication
for 10 min. The reaction was sealed and stirred under an argon
balloon for 27 h. Direct application to flash chromatography
(50:50 petroleum ether/ethyl acetate) gave a crude oil. The
product was further purified by flash chromatography (80:20
petroleum ether/ethyl acetate) to give 31 mg (66%) of 6 as an
oil. This material was identical spectroscopically to the mate-
rial above.
ethyl acetate). IR (neat): 2938, 1756, 1710, 1514, 1402 cm-1
.
1H NMR (400 MHz, CDCl3): δ 7.25-7.37 (m, 17H), 6.80 (d, J
) 8.7 Hz, 2H), 6.47 (s, 1H), 5.12-5.28 (m, 6H), 5.01-5.04 (m,
1H), 4.86-4.88 (m, 1H), 4.75 (d, J ) 2.8 Hz, 1H), 4.62-4.65
(m, 1H), 4.51 (s, 2H), 3.76 (s, 3H), 1.51 (s, 3H), 1.26 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 169.6, 169.5, 164.0, 163.8,
159.1, 151.0, 145.7, 134.5, 134.3, 130.0, 128.7, 128.6, 128.5,
128.4, 128.2, 114.4, 113.9, 86.7, 84.2, 84.1, 81.3, 80.8, 70.7, 70.6,

5434 J . Org. Chem., Vol. 64, No. 15, 1999
Trost and Kallander
68.6, 55.2, 40.8, 27.2, 25.2. Anal. Calcd for C44H41NO13: C,
66.74; H, 5.22; N, 1.77. Found: C, 66.57; H, 5.33; N, 1.72.
P r ep a r a tion of (2S,3S,4R,5R)-5-Hyd r oxym eth yl-2-[3′-
p h en ylsu lfon yl-N′-(4-m et h oxyb en zyl)su ccin im id -3′-yl]-
3,4-d ih yd r oxya ceton id etetr a h yd r ofu r a n (24). To a solu-
tion of 5 (344 mg, 0.37 mmol) in ethyl acetate (0.7 mL, 0.5 M)
was added 10% Pd/C (39 mg). The air in the reaction vessel
was evacuated, and a balloon of hydrogen gas was attached.
The reaction was vigorously stirred over 16 h. The mixture
was filtered through Celite, and the organic products were
evaporated in vacuo to give 220 mg (97%) of 22 as a foamy
colorless glass. IR (neat): 3212, 1745, 1712, 1515, 1401, 1314
24 (32 mg, 0.064 mmol) in chloroform (5 mL) was added DBU
(9.0 µL, 0.064 mmol) in chloroform (1 mL). After the reaction
mixture was stirred for exactly 1 min, monopotassium phos-
phate buffer (10% aqueous, 5 mL) was added. The organic
products were extracted with chloroform (3 × 10 mL), dried
over magnesium sulfate, filtered, and evaporated in vacuo. The
residue was applied to flash chromatography for purification
(20:80 petroleum ether/ethyl acetate). The product was col-
lected, and the solvents were evaporated in vacuo to give 20
mg (86%) of 25 as a colorless oil. Rf 0.66 (diethyl ether). IR
(neat): 3464, 2937, 1707, 1515, 1403 cm-1. 1H NMR (400 MHz,
CDCl3): δ 7.28 (d, J ) 8.6 Hz, 2H), 6.83 (d, J ) 8.6 Hz, 2H),
6.57 (s, 1H), 4.85 (dd, J ) 2.5, 5.9 Hz, 1H), 4.71-4.77 (m, 2H),
4.59 (s, 2H), 4.30 (d, J ) 2.4 Hz, 1H), 3.84 (d, J ) 12.3 Hz,
1H), 3.78 (s, 3H), 3.70 (t, J ) 10.0 Hz, 1H), 3.17 (d, J ) 9.8
Hz, 1H), 1.58 (s, 3H), 1.34 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 170.0, 169.1, 159.3, 145.2, 130.1, 129.5, 128.1, 114.6,
114.0, 85.1, 83.9, 82.4, 80.6, 62.9, 55.2, 41.1, 27.6, 25.3. HRMS
(m/e): calcd for C20H23NO7 389.1475, found 389.1494.
1
cm-1. H NMR major diastereomer (400 MHz, CDCl3): δ 7.86
(d, J ) 7.3 Hz, 2H), 7.64 (t, J ) 6.7 Hz, 1H), 7.45 (t, J ) 7.0
Hz, 2H), 7.12 (d, J ) 7.9 Hz, 2H), 6.81 (d, J ) 8.2 Hz, 2H),
4.75-4.86 (m, 3H), 4.40-4.60 (m, 3H), 3.74 (s, 3H), 3.55 (d, J
) 18.3 Hz, 1H), 3.40 (d, J ) 18.6 Hz, 1H), 1.54 (s, 3H), 1.36 (s,
3H). 13C NMR major diastereomer (100 MHz, CDCl3): δ 175.1,
170.9, 169.5, 169.4, 159.0, 135.2, 134.0, 131.5, 129.4, 128.7,
126.7, 114.8, 114.0, 84.3, 82.9, 81.5, 80.7, 79.5, 73.2, 55.3, 42.4,
30.6, 27.3, 25.3.
To cooled (0 °C) lead tetraacetate (99.9%, 106 mg, 0.24
mmol) was added a cooled solution (0 °C) of 22 (74 mg, 0.12
mmol) in dry acetone (2.4 mL, 0.05 M) and water (2.7 µL, 0.15
mmol). The mixture was allowed to warm to room temperature
over 1.5 h with stirring. Sodium bisulfate (10% aqueous, five
drops), water (10 mL), and brine (10 mL) were added, and the
organic products were extracted with diethyl ether (3 × 10
mL). The combined organic products were dried over magne-
sium sulfate, filtered, and evaporated in vacuo to give a crude
23a , which was used directly in the next step. IR (neat): 3475,
2929, 1710, 1514, 1401 cm-1. 1H NMR major diastereomer (400
MHz, CDCl3): δ 7.81 (d, J ) 7.9 Hz, 2H), 7.68 (m, 1H), 7.49
(t, J ) 7.6 Hz, 2H), 7.20 (d, J ) 8.6 Hz, 2H), 6.81 (d, J ) 8.8
Hz, 2H), 6.25 (br s, 1H), 4.82 (s, 2H), 4.64 (d, J ) 14.4 Hz,
1H), 4.55 (s, 1H), 4.54 (d, J ) 14.0 Hz, 1H), 4.45 (d, J ) 1.8
Hz, 1H), 3.77 (s, 3H), 3.49 (d, J ) 1.9 Hz, 1H), 3.09 (d, J ) 1.9
Hz, 1H), 1.39 (s, 3H), 1.25 (s, 3H). 13C NMR major diastereomer
(100 MHz, CDCl3): δ 172.8, 171.8, 170.8, 159.2, 135.2, 134.2,
131.3, 129.7, 128.7, 126.6, 115.7, 113.8, 84.1, 83.8, 81.3, 80.5,
P r ep a r a tion of (2S,3S,4R,5R)-5-Hyd r oxym eth yl-2-(3′-
ph en ylsu lfon ylsu ccin im id -3′-yl)-3,4-d ih ydr oxya ceton id e-
tetr a h yd r ofu r a n (26). To a cooled solution (0 °C) of 24 (64
mg, 0.20 mmol) in acetonitrile (1.2 mL, 0.1 M) was added
dropwise a cooled solution (0 °C) of CAN (229 mg, 0.42 mmol)
in water (1.2 mL). The reaction mixture was allowed to warm
to room temperature with stirring over 1 h. Ethyl acetate (10
mL) and brine (10 mL) were added, and the organic products
were extracted with ethyl acetate (3 × 10 mL). The combined
organic products were dried over magnesium sulfate, filtered,
and evaporated in vacuo. The residue was applied to flash
chromatography for purification twice (20:80 petroleum ether/
diethyl ether). The product was collected, and the solvents
were evaporated in vacuo to give 35 mg (72%) of 26 as a foamy
glass. Rf 0.21 (50:50 petroleum ether/ethyl acetate). IR (neat):
3507, 3261, 2989, 2937, 1727, 1316 cm-1 1H NMR major
.
diastereomer (400 MHz, CDCl3): δ 8.54 (br s, 1H), 8.03 (d, J
) 7.5 Hz, 2H), 7.73 (t, J ) 7.5 Hz, 1H), 7.56 (t, J ) 7.8 Hz,
2H), 4.75 (d, J ) 2.1 Hz, 2H), 4.34 (d, J ) 2.0 Hz, 1H), 3.99 (d,
J ) 2.1 Hz, 1H), 3.67 (m, 2H), 3.49 (d, J ) 18.6 Hz, 1H), 3.23
(d, J ) 18.8 Hz, 1H), 2.34 (br s, 1H), 1.56 (s, 3H), 1.41 (s, 3H).
13C NMR major diastereomer (100 MHz, CDCl3): δ 173.7,
171.2, 135.2, 134.4, 131.6, 128.6, 115.1, 83.9, 82.3, 81.3, 81.1,
74.5, 62.0, 32.1, 27.2, 25.3. HRMS (m/e): calcd for C17H18NO8S
(M+ - CH3) 396.0753, found 396.0770.
72.8, 55.2, 42.7, 31.5, 27.2, 25.3. HRMS (m/e): calcd for C26H27
-
NO10S 545.1356, found 545.1361.
To crude 23a (approximately 0.12 mmol) was added 1,3-
dicyclohexylcarbodiimide (49 mg, 0.24 mmol), 1-hydroxybenzo-
triazole (42 mg, 0.31 mmol), and THF (6 mL, 0.02 M). The
mixture was stirred at room temperature for 5 h, during which
time a white solid formed. The reaction was cooled to -10 °C
with a brine-ice bath, and lithium borohydride (2 M in THF,
90 µL, 0.18 mmol) was added. The reaction mixture was then
warmed to room temperature over 1 h. Triethylamine hydro-
chloride (30% aqueous, five drops), water (10 mL), and sodium
bisulfate (10% aqueous, 10 drops) were added, and the organic
products were extracted with diethyl ether (3 × 10 mL). The
combined organic products were dried over magnesium sulfate,
filtered, and evaporated in vacuo. The residue was applied to
flash chromatography for purification twice (diethyl ether), to
separate the product from the dicyclohexylurea. The product
was collected, and the solvents were evaporated in vacuo to
give 40 mg (63% over two steps) of 24 as a colorless foamy
glass. Rf 0.36 (50:50 petroleum ether/ethyl acetate). IR (neat):
P r ep a r a tion of (2S,3S,4R,5R)-5-Hyd r oxym eth yl-2-(3′-
p h en ylsu lfon ylsu ccin im id -3′-yl)-3,4-d ih yd r oxyt et r a h y-
d r ofu r a n (27). To 26 (46 mg, 0.11 mmol) in an ice bath was
added dropwise a cooled solution (0 °C) of trifluoroacetic acid
in water (80:20, 0.5 mL). After 20 min of stirring at 0 °C, the
mixture was dried by a silica gel filtration (ethyl acetate then
acetone). All the organic products were collected and evapo-
rated to remove the trifluoroacetic acid. The residue was
applied to flash chromatography for purification (ethyl ace-
tate). The product was collected, and the solvents were
evaporated in vacuo to give 35 mg (84%) of 27 as a foamy glass.
Rf 0.24 (ethyl acetate). IR (neat): 3460, 3072, 2935, 1724, 1313
1
cm-1. H NMR major diastereomer (300 MHz, acetone-d6): δ
10.46 (br s, 1H), 8.04 (d, J ) 7.3 Hz, 2H), 7.84 (t, J ) 7.4 Hz,
1H), 7.67 (t, J ) 7.8 Hz, 2H), 4.34-4.46 (m, 4H), 4.14 (dd, J )
11.7, 5.7 Hz, 1H), 3.95 (t, J ) 5.2 Hz, 1H), 3.57-3.73 (m, 3H),
3.33 (d, J ) 18.6 Hz, 1H), 3.21 (d, J ) 18.6 Hz, 1H). 13C NMR
major diastereomer (100 MHz, acetone-d6): δ 174.4, 172.4,
136.4, 135.8, 132.1, 129.7, 84.1, 82.8, 75.8, 72.0, 71.9, 61.6, 32.7.
HRMS (m/e): calcd for C9H12NO6 (M+ - PhSO2) 230.0664,
found 230.0670.
3532, 2936, 1712, 1515, 1399, 1316 cm-1 1H NMR major
.
diastereomer (400 MHz, CDCl3): δ 7.84 (d, J ) 7.3 Hz, 2H),
7.68 (t, J ) 7.5 Hz, 1H), 7.48 (t, J ) 7.9 Hz, 2H), 7.25 (d, J )
9.1 Hz, 2H), 6.82 (d, J ) 8.8 Hz, 2H), 4.64-4.69 (m, 3H), 4.53
(d, J ) 14.3 Hz, 1H), 4.37 (d, J ) 4.7 Hz, 1H), 3.92 (d, J ) 3.0
Hz, 1H), 3.77 (s, 3H), 3.46-3.52 (m, 3H), 3.06 (d, J ) 18.6 Hz,
1H), 1.79 (t, J ) 5.3 Hz, 1H), 1.54 (s, 3H), 1.36 (s, 3H). 13C
NMR major diastereomer (100 MHz, CDCl3): δ 172.9, 171.0,
159.6, 134.9, 134.8, 131.5, 129.9, 128.4, 127.0, 115.1, 113.8,
83.9, 82.9, 81.2, 81.1, 73.2, 62.1, 55.3, 42.6, 31.6, 27.3, 25.3.
Anal. Calcd for C26H29NO9S: C, 58.75; H, 5.50; N, 2.63.
Found: C, 58.56; H, 5.65; N, 2.67.
P r ep a r a tion of (2S,3S,4R,5R)-5-Hyd r oxym eth yl-2-(2′,5′-
d ioxo-2′,5′-d ih yd r op yr r ol-3′-yl)-3,4-d ih yd r oxytetr a h yd r o-
fu r a n (L-Sh ow d om ycin ). To a solution of 27 (18 mg, 0.047
mmol) in DMSO (11.2 mL, 4.2 mM) was added DBU (7.1 µL,
0.047 mmol). The reaction mixture was not stirred, but was
manually shaken once every 30 min for 2 h. Trifluoroacetic
acid (20 µL) was then added to quench the base, and the
solvents were removed by a Kuglerohr vacuum distillation (100
°C, 0.3 mmHg). The residue was applied to flash chromatog-
raphy for purification twice (ethyl acetate). The crude product
P r ep a r a tion of (2S,3S,4R,5R)-5-Hyd r oxym eth yl-2-[N′-
(4-m e t h oxyb e n zyl)m a le im id -3′-yl]-3,4-d ih yd r oxya ce -
ton id etetr a h yd r ofu r a n (25). To a cooled solution (0 °C) of

Enantioselective Strategy toward L-C-Nucleosides
J . Org. Chem., Vol. 64, No. 15, 1999 5435
(5.5 mg) consisted of showdomycin and trace amounts (<10%)
of unreacted starting material and the isomerized showdomy-
cin, inseparable by chromatography. The reaction and workup
had been optimized following the reaction by NMR in DMSO-
d6, and showdomycin was shown to be the only major product,
but the collected material only accounted for 51% of the
starting material. Showdomycin was recrystallized from acetone/
benzene to give 3.5 mg (32%) of showdomycin as a white solid,
verified to be pure showdomycin by spectroscopic methods. The
material had been prepared from 17 that was only 70% ee.
The sulfone elimination reaction was run a second time (35
mg, 0.093 mmol), and the crude product (11.2 mg) was
recrystallized from acetone/benzene to give 3.5 mg (16%) of
enantiopure material. Mp: 144-145 °C (D isomer lit.27 mp
(dd, J ) 2.8, 12.0 Hz, 1H), 3.43 (dd, J ) 4.0, 12.1 Hz, 1H). 13C
NMR (100 MHz, DMSO-d6): δ 171.8, 171.7, 148.9, 128.6, 83.2,
77.4, 74.7, 70.4, 60.8;.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health, General Medical Sciences, and the
National Science Foundation for their generous support
of our programs. Mass spectra were provided by the
Mass Spectrometry Facility, University of San Fran-
cisco, supported by the NIH Division of Research
Resources.
153-154 °C, lit.18a,b mp 150-151 °C), [R]26 -47.8° (c ) 0.35,
1
D
Su p p or tin g In for m a tion Ava ila ble: Copies of IR and H
H2O, lit.27 [R]26 +49.9°). IR (KBr): 3462, 3405, 3232, 1769,
and 13C NMR spectra of 8, 10, 26, 27, and en t-4. This material
D
1703, 1640 cm-1. 1H NMR (400 MHz, DMSO-d6/AcOD): δ 6.72
(d, J ) 1.8 Hz, 1H), 4.53 (dd, J ) 1.7, 3.5 Hz, 1H), 3.94 (t, J )
4.0 Hz, 1H), 3.84 (dt, J ) 2.7, 6.5 Hz, 1H), 3.73 (m, 1H), 3.59
is available free of charge via the Internet at http://pubs.acs.org.
J O990195X