Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Reexamination Certificate
1999-05-25
2001-07-24
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
Reexamination Certificate
active
06265209
ABSTRACT:
This invention relates to compounds, including 2-(t-butyldimethylsilyloxymethyl)-3,4-[(dimethylmethylene)-dioxy]-5-hydroxy-tricyclo[5.2.1.0
2,6
]dec-8-ene and the analogues thereof, which are useful as intermediates for the synthesis of neplanocin A having strong antitumor activity. The invention also relates to improved processes for the preparation of neplanocin A.
BACKGROUND OF THE INVENTION
Neplanocin A is represented by the following formula and one of carbanucleosides having strong antitumor activity, but it is not itself a sufficient drug for the clinical treatment of cancer, because of its strong adverse effect.
Nevertheless, there have been desired improved methods for efficiently preparing neplanocin A and related compounds.
Vandewalle et al. (Synlett, December 1991, 921-922) disclose the synthesis of (−)-neplanocin A starting from L-ribulose in 14 steps and in 15% overall yield. Ohira et al. (Tetrahedron Letters, vol. 36, No. 9, pp. 1537-1538, 1995) disclose the synthesis of (−)-neplanocin A starting from D-ribose modified with the protecting group in 9 steps and in 12% overall yield. Trost et al. (Tetrahedron Letters, vol. 38, No. 10, pp. 1707-1710, 1997) disclose the stereoselective synthesis of (−)-neplanocin A using an asymmetric catalyst in 13 steps and in 4% overall yield. Thus, the above prior processes require more improvement in the process step and yield.
SUMMARY OF THE INVENTION
The present invention provides a group of intermediates useful for the synthesis of neplanocin A and related compounds which improve our flexibility in exploring structural variation of carbanucleosides having potential use including chemotherapeutic agents.
The invention also relates to improved processes for the preparation of neplanocin A in short process step and in high yield, starting from a compound of the following formula (1) and via a compound of the following formula (6).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides new class of the compounds useful as intermediates for the synthesis of neplanocin A, which includes the compounds of the following formulas:
Formula (1)
wherein R
1
and R
2
are independently hydrogen or an alkanoyl group of 2-20 carbons;
Formula (2)
wherein X is halogen;
Formula (3)
wherein X is halogen and Y is a protecting group;
Formula (4)
wherein X is halogen and Y is a protecting group;
Formula (5)
wherein X is halogen and Y is a protecting group;
Formula (6)
wherein Y is a protecting group;
Formula (7)
wherein Y is a protecting group;
Formula (8)
wherein Y is a protecting group;
Formula (9)
wherein Y is a protecting group;
Formula (10)
wherein Y is a protecting group.
Examples of the alkanoyl group of 2-20 carbons for R
1
and R
2
include, but are not limited to, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl, stearoyl, caproyl, enanthoyl, capryloyl and icosanoyl. Examples of the halogen for X are Cl, Br and I.
The protecting groups for Y can include any group known in the art of organic synthesis for the protection of hydroxyl groups. Examples of such protecting group include, but are not limited, to trimethylsilyl, triethylsilyl, t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, methoxymethyl, methoxyethoxymethyl, t-butyl, benzyl, triphenylmethyl, isopropyldimethylsilyl, tribenzylsilyl and triisopropylsilyl.
Specific compounds within formulas (2)-(10) are represented by the following respective formulas (2a)-(10a):
wherein TBS stands for t-butyldimethylsilyl.
The present invention also provides a process for the preparation of neplanocin A which comprises the steps of:
(a) reacting a compound of formula (1′)
with a halogenating agent, to form a compound of formula (2)
wherein X is halogen;
(b) reacting the compound (2) with an agent for the protection of hydroxyl groups, to form a compound of formula (3)
wherein X is as defined above and Y is a protecting group;
(c) treating the compound (3) with an oxidizing agent, to form a compound of formula (4)
wherein X and Y are as defined above;
(d) reacting the compound (4) with a ketalizing agent, to form a compound of formula (5)
wherein X and Y are as defined above;
(e) treating the compound (5) with a dehalogenating agent, to form a compound of formula (6)
wherein Y is as defined above;
(f) subjecting the compound (6) to a retro-Diels-Alder reaction, to form a compound of formula (7)
wherein Y is as defined above;
(g) treating the compound (7) with an oxidizing agent, to form a compound of formula (8)
wherein Y is as defined above;
(h) reducing the compound (8) with a reducing agent, to form a compound of formula (9)
wherein Y is as defined above;
(i) subjecting the compound (9) to a Mitsunobu reaction, to form a compound of formula (10)
wherein Y is as defined above, followed by deprotection.
The process for the preparation of neplanocin A is illustrated below, in order of steps (a) to (i).
Step (a)
Depending on the halogenating agent and the solvent used, the reaction may be carried out at a temperature of about −20 to 20° C., preferably about 0° C., for about 1 to 10 hrs, preferably 2 hrs. As a reaction solvent may be used a halogenated hydrocarbon solvent such as dichloromethane, chloroform and dichloroethane. The halogenating agents such as brominating, chlorinating and iodinating agents are well known in the art of organic synthesis. Examples of such halogenating agents include, but are not limited, to HBr, diphos-Br
2
, N-bromosuccinimide (NBS), thionyl bromide, HCl, diphos-Cl
2
, N-chlorosuccinimide (NCS) and thionyl chloride.
Step (b)
The agents for the protection of hydroxyl groups (called “protecting agent” hereafter) may be selected from any agent known in the art of organic synthesis for the protection of hydroxyl groups, for example, but not limited to halides including chlorides or bromides of trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, methoxymethyl, methoxyethoxymethyl, t-butyl, benzyl, triphenylmethyl, isopropyldimethylsilyl, tribenzylsilyl, triisopropylsilyl or the like.
Depending on the protecting agent and solvent used, the reaction may be carried out at a temperature of about −20 to 40° C., for about 10 to 20 hrs. As a solvent may be used a base such as imidazole, benzimidazole, triethylamine, pyridine and hexamethylene disilazane. A base for fixation of free halogenated hydrogen may also be used as the solvent. Where the protecting agent is each kind of silyl chlorides and methoxyethoxymethyl halides, the above-mentioned bases are used. Where the protecting agent is benzyl halides and methoxymethyl halides, sodium hydride is used as the base. Where the hydroxyl group is protected with t-butyl group, the reaction is carried out with isobutene in the presence of an acid type catalyst such as sulfuric acid.
Step (c)
The oxidizing agents used may be selected from any of a variety of the agents known in the art of synthetic organic chemistry, for example, but not limited to, osmium tetraoxide, potassium permanganate, lead tetraacetate, ruthenium tetraoxide and selenium dioxide+hydrogen peroxide, with osmium tetraoxide being most preferred.
Depending on the oxidizing agent and solvent used, the reaction may be carried out at a temperature of about −20 to 40° C., for about 1 to 30 hrs. As a reaction solvent may be used a polar solvent such as water and tetrahydrofuran (THF). Where the oxidizing agent is catalytically used, the reaction is carried out in the presence of an oxygen source such as methylmorpholine N-oxide.
Step (d)
The ketalizing agents may be selected from acetals such as 2,2-dimethoxypropane, 2,2-diethoxypropane or the like.
Depending on the ketalizing agent, solvent and catalyst used, the reaction may be carried out at a temperature of about −20 to 40° C., preferably around room temperature, for about 15 to 30 hrs. The reaction solvents which may be used are relatively low boiling point solvents (excluding alcohol
Ogasawara Kunio
Yoshida Naoyuki
Chisso Corporation
McDermott & Will & Emery
Saucier Sandra E.
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