Stereoselective synthesis of 1′β-2′,3′-dideoxy-2′-bis(ethoxycarbonyl) methyluridine nucleosides by ring opening of cyclopropanated glycals

Article abstract of DOI:10.1039/a906880e

Cyclopropanations of glycals followed by Lewis acid-mediated glycosylations with 5-substituted uracils afforded 1′β-2′,3′-dideoxy-2′-bis(ethoxycarbonyl) methyluridine nucleosides in a highly regiospecific and stereoselective manner in good yields. The Roy

Full text of DOI:10.1039/a906880e

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Stereoselective synthesis of 1Јꢀ-2Ј,3Ј-dideoxy-2Ј-bis(ethoxy-
carbonyl)methyluridine nucleosides by ring opening of
cyclopropanated glycals
Jinsoo Lim and Yong Hae Kim*
Department of Chemistry, Korea Advanced Institute of Science and Technology,
Taejon, 305 - 701, Korea. E-mail:kimyh@sorak.kaist.ac.kr
Received (in Cambridge, UK) 24th August 1999, Accepted 5th October 1999
Cyclopropanations of glycals followed by Lewis acid-
mediated glycosylations with 5-substituted uracils afforded
1Јꢀ-2Ј,3Ј-dideoxy-2Ј-bis(ethoxycarbonyl)methyluridine
nucleosides in a highly regiospecific and stereoselective
manner in good yields.
A number of 2Ј-C-branched nucleosides bearing 2Ј-deoxy-2Ј-
carbon–carbon bonds have displayed clinically useful chemo-
therapeutic activities1 as well as interesting biochemical proper-
ties such as ribonucleotide reductase inactivation.2 Moreover,
the discovery of a positive correlation between inhibitory activ-
ity against ribonucleotide reductase and antitumor activity3 has
led to mechanism-based molecular design to find potent anti-
tumor agents.4 On the basis of these findings, a lot of 2Ј-C-
branched nucleosides have been synthesized by the use of
modified nucleosides and carbohydrates as well. Although there
are numerous examples of syntheses from intact nucleosides,5
there are surprisingly few reports on the stereocontrolled syn-
thesis of nucleosides using 2Ј-ketoribose requiring multi-step
reactions.6 This may be attributed to the fact that both stereo-
chemically controlled C–C bond formations and glycosylations
cannot be attained concurrently. Quite recently, there have been
reported stereoselective cyclopropanations of glycals,7 which
could serve key intermediates to synthesize 2Ј-C-branched
nucleosides stereoselectively.
Danishefsky and co-workers reported the highly stereo-
controlled synthesis of pyrimidine nucleosides by an opening of
Scheme 1
strained glycal epoxides though the chemical yields are low.8
On the supposition that Lewis acid-mediated direct
glycosylations between nucleobases and cyclopropanated
sugars might be one promising operation to couple nucleo-
bases with sugars, cyclopropanated sugars containing electron-
withdrawing groups were reacted with pyrimidine bases in the
presence of Lewis acid.
In the absence of Lewis acid no coupling product was attained
and starting material was recovered (Table 1, run 1). Treatment
of cyclopropanated sugar 2a–b with trimethylsilyl trifluoro-
methanesulfonate (TMSOTf) produced the desired coupling
product in low yield (run 2), with accompaning byproducts.10
Controlling the temperature and dropwise addition of
TMSOTf did not improve the yield. Lower yields were obtained
using BF3ؒOEt2 (run 3) or ZnI2 (run 4). Glycosylation with
methanesulfonic acid (MSA), however, afforded the desired
product exclusively in low yield (run 5), but starting material
(the free pyrimidine base) remained. We attributed this low
yield to decomposition of the reactive silylated nucleobase to
non-reactive naked nucleobase by MSA. Thus, the reactions
were attempted with more than 1 equivalent of nucleobase to
sugar to improve the yields. Through a series of examinations,
the yields have been optimized with 1 equivalent of MSA and 2
equivalents of nucleobases in acetonitrile at 20 ЊC.11 The results
obtained are summarized in Table 1 (run 6–10, 11–15).
The stereochemistry of the products was defined using
1H-NOE experiments and the ratio of β to α by HPLC (chiral
Daicel OD column, i-PrOH:n-hexane = 1:9, retention time; β
5.51 min, α 5.42 min). There are good correlations between
1Ј-H and 1Љ-H (4.97%) as well as between 1Ј-H and 4Ј-H (0.5%)
of 2Ј-C-branched nucleosides. The coupling reaction appears to
undergo a nucleophilic attack by nucleobase to the anti face of
cyclopropane ring exclusively as shown in Scheme 2.
In this paper, we describe stereocontrolled cyclopropanations
of glycals with diethoxycarbonyl metallocarbenoids with high
stereoselectivity and regiospecific glycosylations of nucleo-
bases to cyclopropanated sugars with extremely high stereo-
selectivity for β-formation of uridines (β:α = > 99:1) as shown
in Scheme 1.
Our initial studies on stereocontrolled cyclopropanations of
glycals sought to improve both high diastereoselectivities and
chemical yields. In the hope of attaining these goals, the reac-
tion conditions were controlled by minimizing the concen-
tration of metallocarbenoid. Decreasing the molar ratios of
diazomalonate and dirhodium tetraacetate (N2C(CO2Et)2 :
Rh2(OAc)4 :glycal = 2:0.01:1) afforded high stereoselectivities
and good yields.9 Accelerated addition of the diazomalonate
resulted in dimerization of diethoxycarbonylcarbene and
lowered the yield. The stereochemistry of the major isomer 2b
was confirmed using 1H-NOE experiments and the ratio of β to
α (<1:99) was determined by HPLC (chiral Daicel OD column,
i-PrOH:n-hexane = 1:9, retention time; β 10.76 min, α 10.81
min). Irradiation of H-4 gave no NOE effect at H-1 and H-2,
which supports the trans conformation of 2b. If the product
had a cis conformation a NOE effect would be observed upon
irradiation of H-4.
A limitation of the reaction is seen with cytosine and purine
bases (run 16). The glycosylations did not arise with these
nucleobases. The reason is uncertain, however, basic amino
groups might bind with Lewis acid preferentially, which would
J. Chem. Soc., Perkin Trans. 1, 1999, 3239–3241
This journal is © The Royal Society of Chemistry 1999
3239

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Table 1 Stereoselective glycosylation with 1 and 2
Run
Base
Sugara
1:2
Lewis acid
Product
Yield (%)b
β:α (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
1:1
1:1
1:1
1:1
1:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
None
0
44
36
15
1a
TMSOTf
BF3OEt2
ZnI2
3a
3a
3a
3a
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
1a
1a
1a
MSAd
MSAd
MSAd
MSAd
MSAd
MSAd
MSAd
MSAd
MSAd
MSAd
MSAd
MSAd
54 (95)
81 (98)
75 (99)
77 (98)
66 (97)
64 (97)
75 (99)
71 (98)
65 (97)
55 (96)
53 (95)
0
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
Cytosine
a 2a: R1 = H, 2b: R2 = TBDPSOCH2. b Isolated yields (conversion yields). c Determined by HPLC (chiral Daicel OD column, iPrOH:n-hexane = 1:9)
and 1H-NOE data. d MSA = methanesulfonic acid.
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Scheme 2 Determination of stereochemistry.
inhibit the activation of the cyclopropane diester, and give rise
to no reaction.
In conclusion, we have achieved the new syntheses of
1Јβ-2Ј,3Ј-dideoxy-2Ј-bis(ethoxycarbonyl)methyluridine nucleo-
sides, which may be used in biochemical studies on ribonucleo-
tide reductase related to ribozyme12 from carbohydrates in a
stereoselective fashion. Furthermore, these 2Ј-C-branched
nucleoside derivatives might display promising chemothera-
peutic activities and we are currently exploring their biological
activities.
8 For examples in strained-ring opening of glycal by nucleobase, see:
K. Chow and S. Danishefsky, J. Org. Chem., 1990, 55, 4211.
9 To a mixture of glycal 7e (1.5 mmol) and dirhodium tetraacetate (15
µmol) in 5 ml of methylene chloride at 25 ЊC under argon atmos-
phere was added dropwise a solution of diethyl diazomalonate (3.0
mmol) in 9 ml of methylene chloride for 10 h via syringe pump. The
reaction mixture was concentrated and separated by column
chromatography on silica gel (230–400 mesh, 3 cm × 20 cm, solvent:
EtOAc–n-hexane = 1:5) to give the cyclopropanated glycal 2b (595.2
mg, 80%, >98% de) as a pale yellow oil; [α]D20 ϩ3.85 (c 1, CHCl3);
νmax(film)/cmϪ1 3017, 2951, 2860, 1756, 1725, 1368, 1130 and 841;
δH(300 MHz; CDCl3; Me4Si) 1.03 (9H, s, Me3CSi), 1.30 (6H, tt,
2 × CO2CH2CH3), 1.62 (1H, m, H-2), 1.93 (2H, m, H-3), 3.77 (3H,
m, H-4,5), 4.13 (1H, d, J 4.2, H-1), 4.95 (4H, qq, 2 × CO2CH3CH3)
and 7.33–7.67 (10H, m, (C6H5)2Si); δC(75 MHz; CDCl3; Me4Si) 14.0
(s), 14.5 (q), 14.6 (q), 19.6 (3 × q), 26.7 (d), 33.6 (t), 53.3 (s), 58.9 (t),
61.6 (t), 62.3 (d), 66.3 (t), 71.1 (d), 127.5–135.6 (Ph2Si), 170.6 (s) and
170.7 (s); HRMS m/z (EI) calc’d. for C28H36O6Si (Mϩ): 496.2281;
found: 496.2269.
Acknowledgements
This work was supported by the Center for Biofunctional
Molecules, Korea Science and Engineering Foundation.
References and notes
1 (a) A. Matsuda, A. Azuma, Y. Nakajima, K. Takenuki, A. Dan,
T. Iino, Y. Yoshimura, N. Minakawa, M. Tanaka and T. Sasaki,
in Nucleosides and Nucleotides as Antitumor and Antiviral Agents,
ed. C. K. Chu and D. C. Baker, Plenum Press, New York, 1993, pp.
1–22 and references therein; (b) H. Awano, S. Shuto, M. Baba, T.
Kira, S. Shigeta and A. Matsuda, Bioorg. Med. Chem. Lett., 1994, 4,
367.
10 Major byproduct was identified as 1,3-bis(2Ј-diethoxycarbonyl)-
methyluridine nucleosides by 1H NMR spectroscopy.
11 To a mixture of nucleobase (0.4 mmol) and cyclopropanated glycal
(0.2 mmol) in 2 ml of acetonitrile was added N,O-bis(trimethyl-
silyl)acetamide (0.88 mmol) at 25 ЊC under argon atmosphere. After
stirring for 1 h, the clear solution was treated with methanesulfonic
acid (0.2 mmol) at this temperature and stirred until the reaction was
2 W. A. van der Donk, G. Yu, D. J. Silva, J. Stubbe, J. R. McCarthy,
3240
J. Chem. Soc., Perkin Trans. 1, 1999, 3239–3241

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completed (1 h). The reaction mixture was quenched with saturated
aqueous Na2CO3 solution (3 ml) and extracted with ethyl acetate
(3 × 3ml). The combined organic layer was washed with brine (5 ml)
and dried over MgSO4. The crude product was purified by column
chromatography on silica gel ( 230–400 mesh, 3 cm × 20 cm, solvent:
EtOAc–n-hexane = 1:2) to give the product.
All compounds exhibited satisfactory spectral and analytical
properties, including proton and carbon NMR, and FTIR.
Representative spectral data for 1Јβ-2Ј,3Ј-dideoxy-2-bis(ethoxy-
carbonyl)-5Ј-O-(tert-butyldiphenylsilyl)thymidine 4b: νmax(film)/
cmϪ1 3493, 3063, 2983, 1732, 1709, 1695, 1461 and 1273; δH(300
MHz; CDCl3; Me4Si) 1.09 (9H, s, Me3Si), 1.23 (6H, tt, 2 × CO2-
CH2CH3), 1.60 (3H, s, 5-CH3), 1.94–2.35 (2H, m, 3Ј-CH2), 3.34 (1H,
m, H-2Ј), 3.54 (1H, d, J 8.92, CH(CO2Et)2), 3.64 and 3.97 (2H, dd,
5Ј-CH3), 4.11 (1H, m, H-4Ј), 4.20 (4H, qq, 2 × CO2CH3CH3), 6.01
(1H, d, J 7.8, H-1Ј), 7.42 (1H, s, H-6), 7.34–7.68 (10H, m, (C6H5)2Si)
and 9.50 (1H, br s, NH); δC (75 MHz; CDCl3; Me4Si) 12.0 (2 × q),
13.9 (s), 19.3 (q), 27.0 (3 × q), 29.7 (t), 30.2 (d), 42.8 (d), 61.9 (2 × t),
65.7 (t), 77.8 (d), 87.3 (d), 111.2 (s), 127.9 (d), 129.9 (d), 130.0 (d),
132.5 (d), 133.1 (d), 135.3 (d), 135.6 (d), 150.6 (s) and 167.4 (3 × s);
HRMS m/z (FAB) calc’d. for C33H41N2O8Si (Mϩ): 622.2710; found:
622.2739.
12 A. J. Lawrence, J. B. J. Pavey, I. A. O’Neil and R. Cosstick, Tetra-
hedron Lett., 1995, 36, 6341.
Communication 9/06880E
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