Intermediates and improved processes for the preparation of neplanocin A
AssigneeChisso Corporation
InventorsNaoyuki Yoshida, Kunio Ogasawara
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Abstract
Intermediate compounds, including 2-(t-butyldimethylsilyloxymethyl)-3,4-[(dimethylmethylene)dioxy]-5-hydroxy-tricyclo[5.2.1.02,6]dec-8-ene, which are useful for the synthesis of neplanocin A having strong antitumor activity. Improved processes for the preparation of neplanocin A, starting from optically active 2-hydroxymethyl-5-hydroxy-tricyclo[5.2.1.02,6]deca-3,8-diene and via a key step comprising a retro-Diels-Alder reaction of the above intermediate.
Claims25
A compound of formula (1)
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- wherein R1 and R2 are independently hydrogen or an alkanoyl group of 2-20 carbons.
A compound of formula (2)
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- wherein X is halogen.
A compound of formula (3)
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- wherein X is halogen and Y is a protecting group.
A compound of formula (4)
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- wherein X is halogen and Y is a protecting group.
A compound of formula (5)
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- wherein X is halogen and Y is a protecting group.
A compound of formula (6)
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- wherein Y is a protecting group.
A compound of formula (7)
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- wherein Y is a protecting group.
A compound of formula (8)
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- wherein Y is a protecting group.
A compound of formula (9)
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- wherein Y is a protecting group.
A compound of formula (10)
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- wherein Y is a protecting group.
A process for preparing an optically active compound of formula (1′)
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- which comprises subjecting a racemic compound of formula (11)
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- to a transesterification with an acylating agent in the presence of a hydrolase to optically resolve the racemic compound into an optically active diester of formula (12)
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- wherein R3 is an alkyl group of 1-19 carbons, and a monoester of formula (13)
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- wherein R3 is as defined above, followed by alcoholysis.
A process for the preparation of neplanocin A which comprises the steps of:
- (a) reacting a compound of formula (1′)
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- with a halogenating agent, to form a compound of formula (2)
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- 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)
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- 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) (4)
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- wherein X and Y are as defined above;
- (d) reacting the compound (4) with a ketalizing agent, to form a compound of formula (5)
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- wherein X and Y are as defined above;
- (e) treating the compound (5) with a dehalogenating agent, to form a compound of formula (6)
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- wherein Y is as defined above;
- (f) subjecting the compound (6) to a retro-Diels-Alder reaction, to form a compound of formula (7)
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- wherein Y is as defined above;
- (g) treating the compound (7) with an oxidizing agent, to form a compound of formula (8)
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- wherein Y is as defined above;
- (h) reducing the compound (8) with a reducing agent, to form a compound of formula (9)
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- wherein Y is as defined above;
- (i) subjecting the compound (9) to a Mitsunobu reaction, to form a compound of formula (10)
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- wherein Y is as defined above, followed by deprotection.
A process for preparing a compound of formula (7)
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- wherein Y is a protecting group, which comprises subjecting a compound of formula (6)
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- wherein Y is a protecting group, to a retro-Diels-Alder reaction.
Dependencies are inferred from the claim text.