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1. (WO1991005804) CATALYSIS OF DIELS-ALDER REACTIONS, METHODS AND CATALYSTS THEREFOR
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WHAT IS CLAIMED IS:
1. A catalyst molecule comprising an
antibody combining site that catalyzes the formation of a cyclic reaction product from a Diels-Alder [4+2] cycloaddition/fragmentation reaction of a dienophile molecule containing a reactive multiple bond and a conjugated cyclic diene molecule in which said cyclic reaction product has a formed ring containing five or six atoms and at least two conjugated endocyclic double bonds, said conjugated diene molecule having a structure that includes a fugitive leaving group within a five- or six-membered ring, said catalyst molecule immunoreacting with an antigen whose structure (i) includes a [2.2.1] or [2.2.2] bicyclic ring system absent from the reaction product and (ii) contains at least one endocyclic double bond fewer in said bicyclic ring system than the number of endocyclic double bonds present in the reaction product.

2. The catalyst molecule according to claim

1 wherein said catalyst molecule is an intact antibody molecule.

3. The catalyst molecule according to claim 1 wherein said dienophile molecule has a cyclic
structure.

4. The catalyst molecule according to claim 1 wherein said fugitive leaving group forms a gaseous compound upon the formation of the reaction product.

5. The catalyst molecule according to claim 1 wherein said dienophile includes an electron
withdrawing substituent moiety relative to hydrogen that is located alpha to said reactive multiple bond.

6. A catalyst molecule comprising an
antibody combining site that catalyzes the formation of a cyclic reaction product from the reaction of a cyclic dienophile molecule with a cyclic diene molecule and in which said cyclic reaction product contains a five- or six-membered ring formed by said reaction and that includes at least two endocyclic conjugated double bonds, said dienophile molecule containing a reactive multiple bond and including a moiety that is electron-withdrawing relative to hydrogen located at a position alpha to said reactive multiple bond, said conjugated diene molecule having a structure that includes a fugitive leaving group that forms a gaseous compound upon formation of said cyclic reaction product and that is present within a five- or six-membered ring, and said catalyst molecule immunoreacting with an antigen whose structure (i) includes a [2.2.1] or [2.2.2] bicyclic ring system absent from the reaction product and (ii) containing at least one endocyclic double bond fewer in said bicyclic ring system than the number of endocyclic double bonds present in the reaction product.

7. The catalyst molecule according to claim 6 that is an intact antibody.

8. The catalyst molecule according to claim 6 wherein said antigen has a structure that corresponds to the formula


wherein X is isologous to said fugitive leaving group,
R7 and R8 each contain a total of 1 to about 50 atoms, and each is selected from the group consisting of hydrogen, an electron-withdrawing group relative to hydrogen, and an electron-donating group relative to hydrogen, or R7 and R8 together form a ring containing up to eight atoms, and
R1, R2, R3, R4, R5 and Rδ are independently selected from the group consisting of hydrogen, halogen, C1-C6 lower alkyl, substituted C1-C6 lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, C1-C6 lower alkenyl, and C1-C6 substituted lower alkenyl, or

R5 and R6 are absent and replaced by a double bond.

9. The catalyst molecule according to claim 8 wherein R1, R2, R3 and R4 are chloro, R5 and R6 are hydrogen, R7 and R8 together form a ring containing five atoms, and X is a -CC12- group.

10. The catalyst molecule according to claim 8 wherein primary amine groups present in said catalyst are protected from reaction with the diene, dienophile or the reaction product.

11. The catalyst molecule according to claim 8 wherein said catalyst molecule is secreted by
hybridoma 1E9 having the ATCC accession number HB
10261^

12. A method of forming a cyclic reaction product having a five- or six-membered ring that
includes at least two endocyclic conjugated double bonds comprising the steps of: (a) admixing a dienophile molecule having a reactive multiple bond and a cyclic conjugated diene molecule having a structure that includes a fugitive leaving group within a five- or six-membered ring with a catalyst molecule in a liquid composition to form a reaction mixture, said catalyst molecule
comprising a monoclonal antibody combining site-containing molecule that catalyzes said reaction and immunoreacts with an antigen whose structure (i)
includes a [2.2.1] or [2.2.2] bicyclic ring system absent from the reaction product and (ii) contains at least one endocyclic double bond per molecule fewer in said bicyclic ring system than the number of endocyclic double bonds present in the reaction product; and
(b) maintaining said reaction mixture for a time period sufficient for the reaction product to form.

13. The method according to claim 12
including the further step of recovering the reaction product.

14. The method according to claim 12 wherein said catalyst molecule is an intact antibody molecule.

15. The method according to claim 12 wherein said dienophile has a cyclic structure.

16. The method according to claim 12 wherein said cyclic reaction product is a cyclohexadiene derivative, and including the further step of oxidizing cyclohexadiene derivative reaction product to a benzene derivative.

17. A method of forming a cyclic reaction product that contains a five- or six-membered ring having at least two conjugated endocyclic double bonds comprising the steps of:
(a) admixing a cyclic dienophile
molecule and a cyclic conjugated diene molecule with a catalyst molecule in an aqueous liquid composition to form a reaction mixture, said cyclic dienophile molecule including a double bond that reacts with the two double bonds of said cyclic conjugated diene, said cyclic conjugated diene including a fugitive leaving group in a five- or six-membered ring, said catalyst molecule catalyzing the formation of said cyclic reaction product from said cyclic dienophile and said cyclic conjugated diene and comprising a monoclonal antibody combining site-containing molecule that immunoreacts with an antigen whose structure (i) includes [2.2.1] or [2.2.2] bicyclic ring system absent from the reaction product and (ii) contains at least one endocyclic double bond per molecule fewer in said bicyclic ring system than the number of endocyclic double bonds present in the
reaction product; and
(b) maintaining said reaction mixture under biological conditions for a time period sufficient for the reaction product to form.

18. The method according to claim 17
including the further step of isolating said cyclic reaction product.

19. The method according to claim 18 wherein said cyclic reaction product is a cyclohexadiene derivative, and said reaction mixture is maintained under anaerobic conditions.

20. A catalytic method for increasing the proportion of a preselected cyclic reaction product structural isomer formed in a reaction that forms a plurality of structural isomeric cyclic reaction
products that contain a five- or six-membered ring having at least two conjugated endocyclic double bonds in an uncatalyzed reaction comprising the steps of:
(a) admixing a dienophile molecule having a reactive multiple bond and a cyclic conjugated diene molecule having a structure that includes a fugitive leaving group within a five- or six-membered ring with a catalyst molecule in a liquid composition to form a reaction mixture, at least one of said dienophile molecule and said conjugated diene molecule being asymmetrically substituted, said catalyst molecule comprising a monoclonal antibody combining site-containing molecule that catalyzes said reaction and immunoreacts with an antigen whose structure (i)
includes a [2.2.1] or [2.2.2] bicyclic ring system absent from the reaction product, (ii) contains at least one endocyclic double bond per molecule fewer in said bicyclic ring system than the number of endocyclic double bonds present in the reaction product, and (iii) contains a substituent that corresponds substantially to the asymmetric substituent present in said at least one of said dienophile molecule and said conjugated diene, and that is present at an analogous location in said preselected structural isomeric cyclic reaction product; and
(b) maintaining said reaction mixture for a time period sufficient for the reaction product to form.

21. The method according to claim 20
including the further step of recovering said
preselected cyclic reaction product.

22. A catalytic method for increasing the proportion of a preselected cyclic reaction product stereoisomer formed in a reaction that forms
stereoisomeric cyclic reaction products that contain a five- or six-membered ring having two conjugated
endocyclic double bonds in an uncatalyzed reaction comprising the steps of:
(a) admixing a reactant dienophile molecule having a reactive multiple bond and a reactant cyclic conjugated diene molecule having a structure that includes a fugitive leaving group within a five- or six-membered ring with a catalyst molecule in a liquid composition to form a reaction mixture, said reactant molecules including one or more substituent groups that give rise to possible stereoisomer cyclic reaction products, said catalyst molecule comprising a monoclonal antibody combining site-containing molecule that
catalyzes said reaction and immunoreacts with an antigen whose structure (i) includes a [2.2.1] or [2.2.2] bicyclic ring system absent from the reaction product, (ii) contains at least one endocyclic double bond per molecule fewer in said bicyclic ring system than the number of endocyclic double bonds present in the
reaction product, and (iii) contains one or more
substituents that correspond substantially to said substituent or substituents present in said reactant molecules, and which substituent or substituents are present at an analogous location and stereoconfiguration in said preselected stereoisomeric cyclic reaction product; and (b) maintaining said reaction mixture for a time period sufficient for the reaction product to form.

23. The method according to claim 22
including the further step of recovering said
preselected reaction product.

24. The method according to claim 23 wherein said stereoisomeric reaction product is an entiomer.

25. The method according to claim 22 wherein said reactant cyclic conjugated diene is asymmetrically substituted.

26. The method according to claim 25 wherein said reactant dienophile molecule contains an
asymmetrically substituted carbon-containing double bond and said cyclic reaction product contains a six-membered ring having an endocyclic bond that includes a
tetrahedral carbon atom.

27. A method of preparing a monoclonal antibody combining site-containing molecule capable of catalyzing the formation of a reaction product
containing a five- or six-membered ring and at least two endocyclic double bonds comprising the steps of:
(a) immunizing an animal host with a relatively non-reactive immunogen having a structure that is isologous to the structure of a [4+2]
cycloaddition product formed by reaction of a dienophile molecule containing a reactive multiple bond and a cyclic conjugated diene that includes a fugitive leaving group in a five- or six-membered ring and that is a reactive intermediate in the formation of the reaction product, the structure of said immunogen including a
[2.2.1] or [2.2.2] bicyclic ring structure absent from the reaction product and containing at least one
endocyclic double bond per molecule fewer in said bicyclic ring system than the number of endocyclic double bonds present in the reaction product;
(b) forming hybridoma cells with
antibody-secreting cells from an immunized animal host that secretes antibodies that immunoreact with said immunogen; and
(c) cloning and culturing the hybridoma cells that secrete monoclonal antibodies that
immunoreact with said immunogen.

28. The method according to claim 27
including the further step of recovering said monoclonal antibodies.

29. The method according to claim 28
including the further step of reacting amino groups present in said recovered monoclonal antibodies with protective groups that do not substantially inhibit the reaction catalyzed by said monoclonal antibodies.