An improved synthetic preparation of anti conformationally constrained acyclic nucleosides

Article abstract of DOI:10.1081/SCC-100103324

Practical large-scale synthesis of anti conformationally constrained acyclic nucleosides has been attained from the coupling of lithiated 2,4-dimethoxy-5,6-dimethylpyrimidine with 1,3-bis(tert-butyldiphenylsilyloxy)-propan-2-one, followed by the sequentia

Full text of DOI:10.1081/SCC-100103324

This article was downloaded by: [Eindhoven Technical University]
On: 19 October 2014, At: 21:36
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number:
1072954 Registered office: Mortimer House, 37-41 Mortimer Street,
London W1T 3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
AN IMPROVED SYNTHETIC
PREPARATION OF ANTI
CONFORMATIONALLY
CONSTRAINED ACYCLIC
NUCLEOSIDES
Kuo-Tsao Yang & Ling-Yih Hsu a
a School of Pharmacy , National Defense Medical
Center , Taipei, Taiwan, ROC
Published online: 09 Nov 2006.
To cite this article: Kuo-Tsao Yang & Ling-Yih Hsu (2001) AN IMPROVED SYNTHETIC
PREPARATION OF ANTI CONFORMATIONALLY CONSTRAINED ACYCLIC NUCLEOSIDES,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:6, 893-898, DOI: 10.1081/SCC-100103324
To link to this article: http://dx.doi.org/10.1081/SCC-100103324
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our
platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,
completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.

The accuracy of the Content should not be relied upon and should be
independently verified with primary sources of information. Taylor and
Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 31(6), 893–898 (2001)
AN IMPROVED SYNTHETIC
PREPARATION OF ANTI
CONFORMATIONALLY CONSTRAINED
ACYCLIC NUCLEOSIDES
Kuo-Tsao Yang1 and Ling-Yih Hsu2,*
1Army Kin-Men Hospital, Kin-Men, ROC
2School of Pharmacy, National Defense Medical Center,
Taipei, Taiwan, ROC
ABSTRACT
Practical large-scale synthesis of anti conformationally
constrainedacyclic nucleosieds has been attainedfrom
the coupling of lithiated 2,4-dimethoxy-5,6-dimethylpyrimi-
dine with 1,3-bis(tert-butyldiphenylsilyloxy)-propan-2-one,
followedby the sequential reactions of methylthiomethylation,
ring cyclization, hydrolysis, and desilylation.
Modified nucleosides and oligonucleotides have attracted much inter-
est due to their potential use as antineoplastic and antiviral agents. Over the
years, a major part of our research efforts has been directed towards the
synthesis of a new class of modified anti conformationally constrained acyc-
lic nucleoside.1–9
2
Some of them showedmoderate activity against HIV
or certain
cancer cell lines.5,6 More recently, this modified nucleoside was also used
as building units for oligonucleoside8,9 synthesis. In connection with our
* Corresponding author.
893
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

894
YANG AND HSU
ongoing research program on exploring potent antineoplastic andantiviral
agents, we requiredgram quantities of 3,3-Bis(hydroxymethyl)-5-methyl-
1H,3H,4H,7H-pyrimido-[1,6-c][1,3] oxazine-6,8-dione (6),2 a key intermedi-
ate in the synthesis of modified anti conformationally constrained acyclic
nucleoside.
In the synthesis of title compound1,3-bis- O-protected-1,3-dihydroxy-
acetone can serve as a building block of two geminal or vicinal hydro-
xymethyl group at the conformationally constrainednucleoside skeleton.
In previous work, synthesis of 1,3-bis-O-protected-1,3-dihydroxyacetone
2
was startedfrom 1,3-idbenzyloxy-2-propanol
that was oxidized to the
corresponding ketone with the N-chlorosuccinimide/dimethylsulfoxide.
The obtainedoily ketone was purifiedby distillation in a kugelrohr appa-
ratus under high vacuum or column chromatography. Although the syn-
thesis was straightforward, these two procedures resulted in a repulsive,
garlic-like odor, time-consuming purification, and low yield, and were not
practically applicable for large-scale preparation. Alternatively, 1,3-bis
(tert-butyldiphenylsilyloxy)propan-2-one (1) was selectedin the present
work. Protection of the hydroxy group of easily accessible 1,3-dihydrox-
yacetone with tert-butylchlorodiphenylsilane gave 1 as a white solid, which
was easily purifiedfrom crystallization (Hexane/AcOEt) in high yield
(83%). This procedure circumvented the unpleasant odor and time-con-
suming purification steps, andobtainedhigh-yieldproduct. We thought
shouldbe superior to 1,3-dibenzyloxy-2-propanone in the synthesis of title
1
compound. Treatment of 2,4-dimethoxy-5,6-dimethylpyrimidine with
n-butyllithium in dry tetrahydrofuran at ꢀ70ꢁC gave lithio derivative,
which was reactedwith 1 at ꢀ70ꢁC to afford 2. Compound( 2), a solid

ACYCLIC NUCLEOSIDES
895
product, was easily purified from crystallization (MeOH) and obtained in
high yield (75%). By contrast, the similar 1,3-dibenzyloxy product in pre-
vious synthesis was an oily product that required time-consuming column
chromatography purification andyieldwas low (60%). Conversion of the
hydroxy group of 2 to the corresponding methylthiomethyl ether of 3 was
accomplishedby treating 2 with a mixture of acetic anhydride and anhy-
drous dimethyl sulfoxide at room temperature for 36 h. Ring closure of 3
was accomplished with iodine in dry tetrahydrofuran at room temperature
to give 4. Treatment of 4 with 2 N sodium hydroxide in dioxane at reflux
overnight to give 5. Desilylation of 5 with tetrabutylammonium fluoride
in tetrahydrofuran at room temperature afforded 6. By contrast, 6 in
previous synthesis2 was obtainedfrom the intermeiadte containing
the protected1,3-dibenzyloxy groups by hydrogenation in the presence
of 20% palladium on carbon in methanol at high hydrogen pressure
(50 psi), but this methodwas not practically applicable for large-scale
preparation.
In conclusion, we have developed an improved and practical
procedure for the synthesis of anti conformationally constrained acyclic
nucleosides using 1,3-bis(tert-butyldiphenylsilyloxy)propan-2-one (1) as a
building block of two geminal hydroxymethyl groups in place of 1,3-diben-
zyloxy-2-propanol. This selecting circumventedseveral limitations of
unpleasant odor, time-consuming purification, and high-pressure hydroge-
nation, andprovidedan easily purifiedway andhigh yieldof the target
compound.
EXPERIMENTAL
Melting points were taken on a BUCHI 530 apparatus andare
uncorrected. The silica gel used for chromatography was silica gel 60 70-
230 mesh (E. Merck, Darmstadt, Germany). TLC was performed on pre-
scoredDC-Alufolien Kieselgel 60F
(E. Merck, Darmstadt, Germany).
254
Compounds were visualized by illuminating under UV light (254 nm).
Evaporations were carriedout at <50 ꢁC using a rotary evaporator at
1
reduced pressure (water aspirator). Solvent ratios are reported as v/v. H
and 13C NMR spectra were obtainedat Varian 300 NMR spectrometer.
Where necessary, deuterium exchange experiments were used to obtain
proton shift assignments. Analytical samples were dried under reduced
pressure at 78ꢁC in the presence of P2O5 for at least 12 h unless otherwise
specified. Elemental analyses were obtained from a Perkin-Elmer 2400
elemental analyzer.

896
YANG AND HSU
1,3-Bis-[(tert-butyldiphenylsilyloxy)]propan-2-one (1)
ꢁ
To a chilled(0 C) solution of 1,3-dihydroxyacetone (8.1 g, 90 mmol)
and dimethylaminopyridine (2.57 g, 21 mmol) in dry pyridine (100 mL), tert-
butylchlorodiphenylsilane (50 g, 182 mmol) was added over a period of 1 h.
The resulting mixture was stirredunder nitrogen at room temperature for
four days. The reaction mixture was poured over crushed ice and left over-
night. The precipitate was taken out anddissolvedin AcOEt. The filtrate
was extractedwith AcOEt (3 ꢂ 150 mL). The combinedorganic extract was
washedwith 1 N HCl (3 ꢂ 150 mL) andwater (3 ꢂ 150 mL), dried over
sodium sulfate, and evaporated under reduced pressure to give a white
solid. Recrystallization (AcOEt/Hexane) afforded 1 (42.4 g, 83%): m.p.
99ꢁ–100ꢁC (lit. 100ꢁ–101ꢁC).10
6-[2-[(1,3-Bis-(tert-butyldiphenylsilyloxy)-2-hydroxy)propyl]methyl]-
2,4-dimethoxy-5-methylpyrimidine (2)
Under nitrogen atmosphere n-butyllithium (1.6 M, 35 mL, 56 mmol)
was added dropwise to a solution of 2,4-dimethoxy-5,6-dimethylpyrimidine
(8.43 g, 50 mmol) in dry tetrahydrofuran (100 mL) at ꢀ70ꢁC. The mixture
was raisedto ꢀ55ꢁC andstirredfor 30 m. Compound( 1) (29 g, 51 mmol)
was added and the stirring continued for 2 h. The solution was neutralized
with acetic acid to pH 7, and the solvent was removed under reduced press-
ure. The residue was partitioned between ethyl acetate and water. The
organic layer was separeted, dried over sodium sulfate, and concentrated
to give the product. Crystallization (MeOH) afforded 2 (27.5 g, 75%): Rf
0.35 (Hexane/AcOEt ¼ 4/1); m.p. 77ꢁ–79ꢁC; H NMR (300 MHz, CDCl3)ꢀ
1
7.6–7.3(m, 20H, Ph), 5.75(s, 1H, OH), 4.01(s, 4H, OCH2), 3.79, 3.78(s, 3H
each, OCH3), 2.99(s, 2H, CH2-6), 2.00(s, 3H, CH3), 1.30–1.01(s, 18H,
t-butyl); MS (m/z): 735 (Mþ); Anal. calcd. for C43H54N2O5Si2(735.08):
C, 70.26%; H,7.40%; N, 3.81%. Found: C, 69.94%; H, 7.36%; N, 3.68%.
6-[2-[(1,3-Bis(tert-butyldiphenylsilyloxy)-
2-methylthiomethyloxy)propyl]methyl]-2,4-dimethoxy-
5-methylpyrimidine (3)
Acetic anhydride (25 mL) was added to a mixture of 2 (40.1 g,
54 mmol) in dry DMSO (250 mL). The solution was stirred at room tem-
perature for 36 h. The solution was extractedwith CHCl andwashedwith
3
brine andwater. The organic layer was driedover MgSO 4 andconcentrated

ACYCLIC NUCLEOSIDES
897
to an oily residue. This residue was purified by flash chromatography on
silica gel with 9:1 hexane-AcOEt as eluant to give 30.2 g of 3 (70%). Rf 0.25
1
(Hexane/AcOEt ¼ 9/1); H NMR(300 MHz, CDCl3)ꢀ 7.6–7.3(m, 20H, Ph),
4.80(s, 2H, CH2OS), 4.08, 4.02(s, 3H each, OCH3), 3.98, 3.58(s, 2H each,
CH2O), 3.14(s, 2H, CH2-6), 2.12(s, 3H, SCH3), 2.08(s, 3H, CH3), 1.02–1.3(s,
18H, t-butyl). Anal. calcd. for C45H58N2O5SSi2 (795.21): C, 67.97%;
H,7.35%; N, 3.52%. Found: C, 67.64%; H, 7.61%; N, 3.87%.
3,3-Bis(tert-butyldiphenylsilyloxymethyl)-6-methoxy-5-methyl-1H,
3H,4H-pyrimido[1,6-c][1,3]oxazine-8-one (4)
Iodine (12 g, 94 mmol) was added to a mixture of 3 (26 g, 32 mmol) in
dry THF (150 mL). The mixture was stirred at room temperature for 64 h. A
5% aq. sodium sulfite solution was added until the brown color of the
mixture disappeared and the resulting solution was extracted with
CH2Cl2. The combinedextracts were washedwith brine andwater, dried
over MgSO4, andconcentratedin vacuo. Crystallization (MeOH) afforded
4
(22 g, 94%): Rf 0.2 (CHCl3/AcOEt/n-hexane ¼ 10:10:1); m.p. 121ꢁ–122ꢁC;
1H NMR(300 MHz, CDCl3)ꢀ 7.60–7.26(m, 20H, Ph), 5.56(s, 2H, NCH2O),
3.99(s, 3H, OCH3), 3.59(s, 2H, CH2O), 3.54(s, 2H, CH2O), 3.06(s, 2H, CH2-
4), 1.93(s, 3H, CH3), 1.07, 1.01, 0.95(s, 6H each, t-butyl); Anal. calcd. for
C43H53O5N2Si2(733.07): C, 70.45%; H, 7.15%; N, 3.82%. Found: C,
70.54%; H, 7.48%; N, 3.63%.
3,3-Bis(tert-butyldiphenylsilyloxymethyl)-5-methyl-1H,3H,4H,7H-
pyrimido-[1,6-c][1,3]-oxazine-6,8-dione (5)
A solution of 4 (26 g, 32 mmol) in 2 N NaOH/dioxane (1/1, 300 mL)
was stirredunder reflux overnight. The solvent was removedin vacuo. The
residue was taken up in EtOAc. The solution was neutralized by Dowex-X2
(Hþ form) to pH 7, andthen filtered. The filtrate was concentratedto give a
white powder. Crystallization (MeOH) afforded 5 (10.2 g, 72%): Rf 0.32
(CHCl3/AcOEt ¼ 4:1); m.p. 82ꢁ–84ꢁC; 1H NMR(300 MHz, CDCl3)
ꢀ
9.17(s, 1H, NH), 7.60–7.26(m, 20H, Ph), 5.43(s, 2H, NCH2O), 3.58(s, 2H,
CH2O), 3.55(s, 2H, CH2O), 3.11(s, 2H, H2-4), 1.94(s, 3H, CH3), 1.07–0.95
(m, 18H, t-butyl); MS (m/z): 720 (Mþ); Anal. calcd. for
C42H51O5N2Si2(719.05): C, 70.16%; H, 7.01%; N, 3.90%. Found: C,
69.74%; H, 6.98%; N, 3.98%.

898
YANG AND HSU
3,3-Bis-(hydroxymethyl)-5-methyl-1H,3H,4H,7H-pyrimido
[1,6-c][1,3]oxazine-6,8-dione (6)
Tetrabutylammonium fluoride (12.12 g, 46.4 mmol) was added into a
solution of 5 (16 g, 23.2 mmol) in THF (250 mL). The mixture was stirredat
room temperature for 2 h andthen concentratedto give a white product.
Crystallization (MeOH) afforded 6 (5.0 g, 88%): m.p. 197ꢁ–198ꢁC (lit.
197ꢁ–198ꢁC).2
ACKNOWLEDGMENTS
We thank Dr. Leroy B. Townsendfor supplying 2,4-dimethoxy-5,6-
dimethyl pyrimidine as a gift for starting material for chemical synthesis.
This investigation is supportedby a research grant from the National
Science Council of the Republic of China (No. NSC 88-2314-B-016-046).
REFERENCES
1. Hsu, L.Y.; Wise, D.S.; Drach, J.C.; Townsend, L.B. Chin. Pharm. J.
1991, 43, 275.
2. Hsu, L.Y.; Wise, D.S.; Kucera, L.S.; Drach, J.C.; Townsend, L.B.
J. Org. Chem. 1992, 57, 3354.
3. Hsu, L.Y.; Wise, D.S.; Shannon, W.M.; Drach, J.C.; Townsend, L.B.
Nucleosides and Nucleotides 1994, 13, 563.
4. Hsu, L.Y.; Wise, D.S.; Drach, J.C.; Townsend, L.B. Nucleosides and
Nucleotides 1996, 15, 1481.
5. Hsu, L.Y.; Chang, Y.M.; Lin, C.H.; Drach, J.C. Nucleosides and
Nucleotides 1996, 15, 1835.
6. Hsu, L.Y.; Lin, C.H. Heterocycles 1996, 43, 2687.
7. Hsu, L.Y.; Kang, Y.F.; Drach, J.C. Heterocycles 1998, 48, 2163.
8. Hsu, L.Y.; Yang, K.T. Nucleosides and Nucleotides 1999, 18, 1261.
9. Hsu, L.Y.; Yang, K.T. Nucleosides and Nucleotides 1999, 18, 2031.
10. Sharma, R.; Jeewoo, L.; Wang, S.; George, W.A. J. Med. Chem. 1996,
39, 19.
Receivedin Japan April 17, 2000