Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1991-03-29
1993-06-15
Brown, Johnnie R.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 2714, 536 2854, 536 282, C07H 19073, C07H 1173
Patent
active
052200035
DESCRIPTION:
BRIEF SUMMARY
B OHOB? described above, i.e., it is reacted with a silylated base in the presence of a trialkylsilyl triflate and then de-protected. For example, dideoxydidehydrothymidine (d.sub.4 T) is prepared by reacting the above-described hydroxy-protected 2,3-dideoxy-2,3-didehydroribofuranoside with silylated thymine, and deprotecting the hydroxyl group on the primary carbon to obtain d.sub.4 T.
Those skilled in the art will appreciate that the compounds described above--3'-substituted-2'3'-dideoxynucleosides; 2',3'-dideoxynucleosides; 2',3'-dideoxy-2'3'didehydronucleosides; the modified ribofuranoside precursors thereof, and the like--can be prepared as both the D- and L-enantiomers, and that the compounds are separable into .alpha.- and .beta.-anomers.
L-2'-deoxynucleosides
The present invention also provides a synthetic route to L-2'-deoxynucleosides, which can be polymerized to enantio-DNA.("anti-sense" DNA). Synthesis of L-2'-dideoxynucleosides proceeds as follows: The epoxy alcohol (2S,3S) 3-(2,2-dimethoxyethyl)oxiranemthanol is reacted with benzyl alcohol in the presence of titanium (IV) tetraisopropoxide to obtain 3-benzyloxy-5,5-dimethoxypentane-1,2-diol: ##STR24##
The benzyloxy diol is dissolved in dichloromethane and treated with dilute acid (in a manner similar to that described above) to obtain a 2,3-deoxy-3-0-benzylribofuranoside having the formula ##STR25##
This compound is treated with benzyl bromide, in the presence of a base, to obtain a hydroxy-protected L-ribofuranoside having the formula ##STR26##
The hydroxy-protected L-ribofuranoside is converted to an L-2'-deoxynucleoside using Vorbruggen or Hilbert-Johnson technology, i.e., the compound is treated with a silylated base in the presence of a trialkylsilyl triflate, and both hydroxyl groups de-protected to obtain a mixture of .alpha.- and .beta.-anomers of an L-2'-deoxynucleoside: ##STR27## wherein B is a purine or pyrimidine base.
Such a nucleoside is separated into .alpha.- and .beta.-anomers by flash chromatography or similar technique. The .beta.-anomer has the formula: ##STR28## and is polymerized into enantio-DNA using known techniques.
The following examples describe in detail syntheses illustrative of the present invention. It will be apparent to those skilled in the art that many modifications, both of material and methods, may be practiced without departure from the purpose and intent of this disclosure.
EXAMPLE 1
(E) and (Z) (1.3-butadien-1-yl)oxytrimethylsilane
To a solution of crotonaldehyde (31.8 g, 0.454 mole) and triethylamine (51.4 g, 1.1 eq) in benzene at 25.degree. C., was added hydroquinone (0.95 g) and zinc chloride (0.75 g) rapidly with efficient stirring. This was followed by the addition of freshly distilled trimethylsilyl chloride (46 ml, 0.9 eq) over 1-2 minutes, whereupon a white precipitate rapidly formed. After stirring the mixture for 30 minutes at 25.degree. C., a further 0.2 eq of trimethylsilyl chloride were added. The reaction was then warmed to 70.degree. C. and stirred at this temperature for 12 hours. It was then cooled to 0.degree. C., quenched by addition of saturated aq. NaHCO.sub.3 (75 ml), poured into a separatory funnel, and the organic layer separated. The aqueous layer was extracted with further portions of benzene (3.times.50 ml), the organic extracts combined, washed with 10% KHSO.sub.4, and the benzene removed in vacuo to leave a dark brown liquid. Distillation through a short Vigreaux column yielded 28.4 g (46%) of pure 1-trimethylsilyloxy-1,3-butadiene as a colorless liquid (bp 78.degree.-80.degree. C./68 mm Hg). .sup.1 H NMR (200 MHz, CDCl.sub.3): .delta. 6.66(1H,d,J=11.9 Hz), 6.35(1H,dt,J=17.1, 10.6Hz), 5.84(1H,t,J=11.4 Hz), 5.11(1H,dd,J=16.8, 1.8 Hz), 4.94(1H,dd,J=10.3, 1.8 Hz), 0.37(9H, s).
.sup.13 C NMR (50 MHz,CDCl.sub.3): .delta.144.56, 133.22, 114.44, 111.96, -0.53.
EXAMPLE 2
(E) 5,5-Dimethoxypent-2-enal
To a mixture of 1-trimethylsilyloxy-1,3-butadiene (14.57 g, 0.1 mol) and trimethyl orthoformate (10 855 g, 0.1 mol) stirring in dichloromethane (500 ml) was added ZnCl.su
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Hughe
Gardiner John M.
Jung Michael E.
Brown Johnnie R.
Crane L. Eric
The Regents of the University of California
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