Diastereoselective synthesis of α-substituted-γ-butyrolactones of nucleosides via [1,5]-c,h insertion reactions of α-diazomalonates of nucleosides

Article abstract of DOI:10.1039/b000524j

Diastereoselective and regioselective [1,5]-C,H insertion reactions of 2'-deoxy-3'-diazomalonate nucleosides afforded τ-butyrolactones of nucleosides as chiral synthons for the preparation of 2'-C-branched nucleosides.

Full text of DOI:10.1039/b000524j

Diastereoselective synthesis of a-substituted-g-butyrolactones of nucleosides via
[1,5]-C,H insertion reactions of a-diazomalonates of nucleosides†
Jinsoo Lim,a Dong-Joon Choob and Yong Hae Kim*a
a Department of Chemistry, Korea Advanced Institute of Science and Technology, Taejon, 305-701, Korea.
E-mail: kimyh@sorak.kaist.ac.kr
b Department of Chemistry, College of Liberal Arts and Sciences, Kyung Hee University, Seoul, 130-701, Korea
Received (in Cambridge, UK) 18th January 2000, Accepted 23rd February 2000
Published on the Web 17th March 2000
Diastereoselective and regioselective [1,5]-C,H insertion
reactions of 2A-deoxy-3A-diazomalonate nucleosides afforded
t-butyrolactones of nucleosides as chiral synthons for the
preparation of 2A-C-branched nucleosides.
Since oxetanocin1 was isolated and turned out to show potent
antiviral activity such as inhibition of HIV-1 antigens and
infectivity, C-branched nucleosides bearing carbon–carbon
bonds at the furanose rings have attracted considerable attention
as clinically useful chemotherapeutic agents.2 Moreover, the
discovery of a positive correlation between inhibitory activity
against ribonucleotide reductase and antitumor activity,3 has led
to rational drug design to find potent antitumor agents having
C–C bonds at the 2A-positions.4 The key step in the synthesis of
C-branched nucleosides is stereocontrolled C–C bond forma-
tion at the branching site of the ribofuranose ring. However, it
is especially difficult to construct C–C bonds at the 2A-position
of nucleosides. Intramolecular cyclization is a facile and useful
strategy for stereo- and regio-controlled C–C bond formation to
provide g-butyrolactones of nucleosides as a useful chiral
synthon for the synthesis of C-branched nucleosides.5 The g-
butyrolactones of nucleosides are important key intermediates
to manipulate various 2A-C-branched nucleoside analogues.
Recently Camarasa and coworkers reported that g-butyr-
olactones of nucleosides were prepared by intramolecular
radical cyclization in good diastereoselectivities but low yields6
which might result from reductive deoxygenation, which is a
feature of free radical cyclizations. Intramolecular [1,5]-C,H
insertion reactions of a-diazocarbonyl compounds have been
among the most attractive and effective methods for the
construction of functionalized five membered rings.7 Substrates
can be smoothly cyclized without difficulty by dirhodium(II)-
catalyzed C,H-insertion reactions. However, surprisingly, no
successful C,H-insertion reactions in the modification of
ribofuranose ring of nucleosides have been reported. Efficient
construction of a C–C bond at the branching point has been a
difficult task especially at the 2A-position of nucleosides by
currently available methods. Here, we describe diastereose-
lective intramolecular C,H-insertion of 2A-deoxy-3A-a-diazoace-
tates of nucleosides in the presence of a catalytic amount of
dirhodium tetraacetate to [3.3.0] fused lactones (g-butyr-
olactones) of a series of nucleosides having a new chiral center
at an off-template site of the ribofuranose ring, in high yields, as
shown in Scheme 1.
Scheme 1
Scheme 2 Reagents and conditions: i, TBDPSCl, pyridine, rt; ii,
R1C(N2)CO2Me, DMAP, toluene, reflux; iii, (1) EtO2CCH2CO2H, DCC,
DMAP; (2) MsN3, Et3N, MeCN; iv, TsNHNNCHCOCl, Et3N, MeCN.
nucleosides and 2A-deoxy-3A-O-a-(methoxycarbonyl)acetylnu-
cleosides in moderate yields. Diazo transfer of these esters with
methanesulfonyl azide and triethylamine in acetonitrile9 af-
forded the corresponding 3A-diazoester derivatives 1a–4a and
1b–4b in poor yields (ca. 50%). These low yields might be due
to steric hindrance by furanose rings. It was found, however,
that the satisfactory yields (84–96%) of 1a–4a and 1b–4b could
be smoothly obtained using methyl a-diazoacetate derivatives
instead of methylacetate ones, and a-ethoxycarbonylacetates of
nucleosides 1c and 2c were not formed by this procedure. The
desired products 1c and 2c could be obtained by a coupling
reaction of 5A-O-protected-2A-deoxynucleosides 10a,b with
monoethyl malonate followed by diazo transfer in moderate
yields (56–71%), while 2A-deoxy-3A-a-diazoacetates of nucleo-
sides 1d and 2d could be obtained in good yields (78–90%)
using the modified House–Blankey procedure.11
Our initial studies on stereocontrolled C,H-insertion of 2A-
deoxy-3A-a-diazoacetates of nucleosides were performed in the
presence of dirhodium tetraacetate (1.0 mol%) in dichloro-
methane at room temperature. However, only a trace amount of
product was obtained and starting material was recovered. To
improve the yields, when the reaction mixture was refluxed,
high yields of g-butyrolactones of nucleosides 5–8 were
obtained and results obtained are summarized in Table 1.
Moreover, the C,H-insertion of 2A-deoxy-3A-a-diazoacetates
of nucleosides 1–4 afforded the g-butyrolactones of nucleosides
5–8 with high diastereoselectivities. Through the JH–H coupling
constant (J1B–2A 8.8 Hz) between 1B-hydrogen and 2A-hydrogen
of 6b, the stereochemistry of 1B-position of g-butyrolactone of
nucleoside 6b was determined as exo. Irradiation of the
anomeric proton of 6b caused enhancement of the signal for H-
1B (8%), indicating that the configuration at C-1B of 6b was (S).
A possible mechanism for the stereochemical outcomes of g-
For the synthesis of the fused g-butyrolactones of nucleosides
we chose 2A-deoxy-3A-diazoacetates of nucleosides (R1 = H,
MeCO, MeO2C, EtO2C) as templates for [1,5]-C,H insertion
reactions. The general strategy is shown in Scheme 2.
The 5A-position of 2A-deoxynucleosides were protected with
tert-butyldiphenylsilyl chloride in dried pyridine at room
temperature. These 5A-O-protected-2A-deoxynucleoside deriva-
tives 10a–e undergo transesterification8 by reaction with the
corresponding methyl ester to give 3A-O-acetoacetyl-2A-deoxy-
† Electronic supplementary information (ESI) available: NMR data for 2b
and 6b. See http://www.rsc.org/suppdata/cc/b0/b000524j/
DOI: 10.1039/b000524j
Chem. Commun., 2000, 553–554
This journal is © The Royal Society of Chemistry 2000
553

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Table 1 Dirhodium(II) tetraacetate catalyzed formation of 5–8
Scheme 4 Reagents and conditions: i, (PhO)2CO, NaHCO3, DMF; ii,
TsHNNNCHCOCl, Et3N, MeCN; iii, Rh2(OAc)4, CH2Cl2, reflux; iv, NaH,
MeCN.
[1,5]-C,H insertion reactions of a-diazo-g-butyrolactones of
nucleosides.
Furthermore, this reaction can be applied to the synthesis of
(E)-2A-deoxy-2A-(carboxymethylene)-5A-O-trityluridine-3A,2A-g-
lactone 17, a chiral synthon in the synthesis of 2A-C-branched
nucleosides.
This work was supported by the Center for Molecular Design
and Synthesis at Korea Advanced Institute of Science and
Technology.
Notes and references
Scheme 3
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butyrolactones of nucleosides 5–8 is proposed as shown in
Scheme 3.
The unfavorable steric hindrance between the anomeric
proton and the methyl ester in endo transition state 12 drives the
equilibrium to the left to the exo transition state 11, which gives
the (S) conformer (exo adduct, 5–8) stereoselectively. When
pure 6b was refluxed in CH2Cl2 for 10 h, no epimerization
occurred.
The g-butyrolactones of the nucleosides described above can
be considered as useful chiral synthons for the synthesis of C-
branched nucleosides. In connection with biologically inter-
esting nucleosides containing the 2A-methylene moiety, for
instance (E)-FMC3 and (E)-2A-deoxy-2A-(carboxymethylene)-
5A-O-trityluridine-3A,2A-g-lactone 17,12 the synthesis of 17 was
attempted by employing C,H-insertion of the 2A,5A-cyclouridine
derivative 14 as shown in Scheme 4.
Cyclization of 5A-O-trityluridine 13 by basic diphenylcarbo-
nate gave the 2A,5A-cyclouridine 14 in 81% yield. Exposure of 14
to the House–Blankey protocol afforded the corresponding
diazo compound 15, which could be converted to the g-
butyrolactone of uridine 16 in 65% yield. Product 17 could be
smoothly obtained by an elimination reaction with sodium
hydride in 85% yield.
In conclusion, we have achieved the new stereoselective
syntheses of a-substituted-g-butyrolactones of nucleosides via
Communication b000524j
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Chem. Commun., 2000, 553–554