23-O-substituted 5-O-mycaminosyltylonide derivatives

Abstract

There are described novel 5-O-mycaminosyltylonide (OMT) analogs possessing increased antibacterial activity toward Gram positive and Gram negative bacteria as well as macrolide resistant Gram positives and pharmaceutically acceptable compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier. Also described are a method for treating bacterial infections by administering to a patient a pharmaceutical composition containing a therapeutically-effective amount of a compound of the invention, and processes for the preparation of such compounds

1 . A compound represented by the Formula:  
       
         
           
           
               
               
           
         
         wherein  
         A is selected from the group consisting of: 
 (1) —CHO or a protected aldehyde;  
 (2) —CN;  
 (3) —CH=N—NR 6 R 7 , wherein R 6  and R 7  are each independently selected from the group consisting of: 
 (a) hydrogen;  
 (b) C 1 -C 6 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;  
 (c) C 2 -C 6 -alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;  
 (d) C 2 -C 6 -alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic; and  
 (e) R 6  and R 7 , taken together with the nitrogen atom to which they are connected, form a 3- to 7-membered ring which may optionally contain a hetero-function selected from the group consisting of: —O—, —NH—, —N(C 1 -C 6 -alkyl)-, —N(aryl)-, —N(heteroaryl)-, —S—, —S(O)—, and —S(O) 2 —;  
 
 (4) —CH=N—OR 6 , wherein R 6  is as previously defined;  
 (5) —CH 2 X, wherein X is selected from the group consisting of: 
 (a) hydroxy or protected hydroxy;  
 (b) halogen;  
 (c) —NR 6 R 7 , wherein R 6  and R 7  are as previously defined;  
 (d) —NR 6 C(O)—R 8 , wherein R 6  is as previously defined and R 8  is selected from the group consisting of: 
 i. hydrogen;  
 ii. C 1 -C 6 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;  
 iii. C 2 -C 6 -alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;  
 iv. C 2 -C 6 -alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;  
 v. aryl;  
 vi. substituted aryl;  
 vii. heterocyclic; and  
 viii. substituted heterocyclic;  
 
 (e) —NR 6 C(O)—NR 7 R 8 , wherein R 6 , R 7 , and R 8  are as previously defined;  
 (f) —NR 6 —NR 7 R 8 , wherein R 6 , R 7  and R 8  are as previously defined;  
 (g) —NR 6 —NR 7 C(O)—R 8 , wherein R 6 , R 7  and R 8  are as previously described;  
 (h) —S(O) n —R 9 , wherein R 9  is selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, and wherein n=0, 1 or 2;  
 (i) —S(O) n —(C 1 -C 6 -alkyl), optionally substituted with one or more substituents selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein n is as previously defined;  
 (j)—S(O) n —(C 2 -C 6 -alkenyl), optionally substituted with one or more substituents selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein n is as previously defined;  
 (k) —S(O) n —(C 2 -C 6 -alkynyl), optionally substituted with one or more substituents selected from the group consisting of: aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein n is as previously defined; and  
 (l) —O-M-Y, 
 where M is selected from:  
 i. absent,  
 ii. —C(O)—,  
 iii. —C(O)N(R 6 )—, wherein R 6  is as previously defined,  
 iv. C 1 -C 6 -alkyl-N(R 6 )—, wherein R 6  is as previously defined,  
 v. C 2 -C 6 -alkenyl-N(R 6 )—, wherein R 6  is as previously defined, or  
 vi. C 2 -C 6 -alkynyl-N(R 6 )—, wherein R 6  is as previously defined,  
 and wherein Y is selected from:  
 i. hydrogen,  
 ii. C 1 -C 6 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, —OR 6 , aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein R 6  is as previously defined,  
 iii. C 2 -C 6 -alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, —OR 6 , aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein R 6  is as previously defined,  
 iv. C 2 -C 6 -alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, —OR 6 , aryl, substituted aryl, heterocyclic, and substituted heterocyclic, wherein R 6  is as previously defined,  
 v. aryl,  
 vi. substituted aryl,  
 vii. heterocyclic, or  
 viii. substituted heterocyclic; and  
 
 
 (6) heterocyclic or substituted heterocyclic;  
 
         R 1  and R 2  are each independently selected from the group consisting of: 
 (1) hydrogen;  
 (2) hydroxy;  
 (3) protected hydroxy;  
 (4) —OC(O)—C 1 -C 12 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —OR 6 , and —NR 6 R 7 , wherein R 6  and R 7  are as previously defined;  
 (5) —OR 6 , wherein R 6  is as previously defined;  
 (6) halogen;  
 (7) —NR 6 R 7 , wherein R 6  and R 7  are as previously defined; and  
 (8) R 1  and R 2  taken together are=O;  
 
         R 3  is selected from the group consisting of: 
 (1) hydrogen;  
 (2) a hydroxy protecting group;  
 (3) —C(O)—C 1 -C 12 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —OR 6 , and —NR 6 R 7 , wherein R 6  and R 7  are as previously defined;  
 (4) C 1 -C 6 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —OR 6 , and —NR 6 R 7 , wherein R 6  and R 7  are as previously defined;  
 (5) C 2 -C 6 -alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —OR 6 , and —NR 6 R 7 , wherein R 6  and R 7  are as previously defined; and  
 (6) C 2 -C 6 -alkynyl, optionally substituted with one or more substitutents selected fron the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —OR 6 , and —NR 6 R 7 , wherein R 6  and R 7  are as previously defined;  
 
         R 4  is -M-Y, wherein M and Y are as previously defined;  
         R 5  is -M-Y, wherein M and Y are as previously defined; and  
         R p  is hydrogen or a hydroxy protecting group.  
       
     
     
         2 . A compound according to  claim 1  wherein in Formula I, R 3  is selected from the group consisting of: 
 (1) C 1 -C 6 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —O—R 6  and —NR 6 R 7 , wherein R 6  and R 7  are as defined in  claim 1;     (2) C 2 -C 6 -alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —O—R 6  and —NR 6 R 7 , wherein R 6  and R 7  are as previously defined; and    (3) C 2 -C 6 -alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —O—R 6  and —NR 6 R 7 , wherein R 6  and R 7  are as previously defined.    
     
     
         3 . A compound according to  claim 2  wherein in Formula I, R 1  and R 2  taken together are=O.  
     
     
         4 . A compound according to  claim 3  wherein in Formula I, R 4  is hydrogen.  
     
     
         5 . A compound according to  claim 1  wherein in Formula I, R 4  is selected from the group consisting of: 
 (1) C 1 -C 6 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —O—R 6  and —NR 6 R 7 , wherein R 6  and R 7  are as defined in  claim 1;     (2) C 2 -C 6 -alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —O—R 6  and —NR 6 R 7 , wherein R 6  and R 7  are as previously defined; and    (3) C 2 -C 6 -alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —O—R 6  and —NR 6 R 7 , wherein R 6  and R 7  are as previously defined.    
     
     
         6 . A compound according to  claim 5  wherein in Formula I, R 1  and R 2  taken together are=O.  
     
     
         7 . A compound according to  claim 6  wherein in Formula I, R 3  is hydrogen.  
     
     
         8 . A compound according to  claim 1  wherein in Formula I, R 5  is selected from the group consisting of: 
 (4) C 1 -C 6 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —O—R 6  and —NR 6 R 7 , wherein R 6  and R 7  are as defined in  claim 1;     (5) C 2 -C 6 -alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, O—R 6  and —NR 6 R 7 , wherein R 6  and R 7  are as previously defined; and    (6) C 2 -C 6 -alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, —O—R 6  and —NR 6 R 7 , wherein R 6  and R 7  are as previously defined.    
     
     
         9 . A compound acording to  claim 1  which is selected from the group consisting of: 
 Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =4-quinoline-carboxyl and R p =H;    Compound of Formula I; A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =3-pyridyl-acetyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 H, R 4 =H, R 5 =3-pyridine-propionyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =3-pyridine-acrylyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH 2  and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NHPhenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-p-tolyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-4-methylthiophenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-4-methoxyphenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-4-dimethylaminophenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-4-phenoxyphenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-4-cyanophenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-4-nitrophenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-α,α,α-trifluoro-p-tolyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-4-fluoro-3-nitrophenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-3,4-difluorophenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-3,5-difluorophenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-4-acetylphenyl and R p =H;    Compound of formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-(4-fluoro)phenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-(4-chloro)phenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NH-(4-bromo)phenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NHCH 2 Phenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NHCH 2 CH 2 Phenyl and R 1 =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NHCH 2 CH 2 Br and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NHCH 2 CHCH 2  and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =C(O)NHCH 2 CHCH-3-quinolyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =CH 2 OCH 3  and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =CH 2 OCH 2 Phenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =CH 2 OCH 2 Phenyl, R 4 =H, R 5 =CH 2 OCH 2 Phenyl and R 1 =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =CH 3  and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =CH 2 CCH and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =(CH 2 ) 4 Br and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =CH 2 CHCHCH 2 Cl and R p =H;    Compound of formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =CH 2 Phenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =CH 2 CHCH 2  and R p =H Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =CH 2 CHCH 2 , R 4 =H, R 5 =CH 2 CHCH 2  and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =H, R 5 =CH 2 CHCH-(3-quinolyl) and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CH 2 CHCH-(3-quinolyl) and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =(t-butoxycarboxy)-3-(3-quinolyl), R 5 =CH 2 -phenyl, and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CH 2 CHCH 2 , R 5 =H and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CHCHCH 2 -3-quinolyl, R 5 =H and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CHCHCH 2 -3-quinolyl, R 5 =—C(O)NH-Phenyl and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CH 3 , R 5 =H and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CH 2 -phenyl, R 5 =H and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CH 2 -phenyl, R 5 =H and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CH 2 CCH, R 5 =CH 3  and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =2-fluoro-3-nitrobenzyl, R 5 =CH 3  and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 5 =(2-pyridyl)thiophenyl, R 5 =CH 3  and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CH 2 CC-(3-quinolyl), R 5 =CH 3  and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CH 2 CC-(3-pyrimidyl), R 5 =CH 3  and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CH 2 CC-(3-pyridinyl), R 5 =CH 3  and R p =H;    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CH 2 CHCH-(3-pyrimidinyl), R 5 =CH 3  and R p =H; and    Compound of Formula I: A=—CHO, R 1  and R 2  taken together are=O, R 3 =H, R 4 =CH 2 CH 2 CH 2 -(3-pyrimidinyl), R 5 =CH 3  and R p =H.    
     
     
         10 . A pharmaceutical composition for treating bacterial infections comprising a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt, ester or prodrug thereof in combination with a pharmaceutically acceptable carrier.  
     
     
         11 . A method for treating bacterial infections comprising administering to an animal in need of such treatment a pharmaceutical composition containing a therapeutically-effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt, ester or prodrug thereof.  
     
     
         12 . A process for the preparation of a compound represented by Formula I as defined in  claim 1  comprising: 
 (1) reacting a compound represented by the formula:                        wherein R p  is a hydroxy protecting group, with:    i. an acetalating agent at a pH between 1 to 4 in an alcoholic solvent; and    ii. treating with one or more silylating agent(s), optionally with the addition of a catalyst in an aprotic solvent at a temperature between 0C and 50° C. for 1 to 48 hours;    to provide a compound represented by the formula:                          wherein R p   1 , R p   3  and R p   4  are each a hydroxy protecting group, and R′ and R″ are each C 1 -C 6 -alkyl or when taken together are —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —;      (2) treating the compound from step (1) with an acid in an organic solvent at a temperature between 0° C. and 50° C. for 1 to 24 hours to provide a compound represented by the formula:                           wherein R p , R p   1 , R p   3 , R′ and R″ are as previously defined;    (3) reacting the compound from step (2) with an alkylating agent represented by the formula R 4 X, wherein X is a halogen or sulphonyl group and R 4  is as defined in  claim 1 , in the presence of a base in an aprotic solvent at a temperature between −20° C. and 60° C., and then treating with an acid in an organic solvent at a temperature between room temperature and 100° C. for 1 to 48 hours to provide a compound represented by the formula:                           wherein R p , R p   3 , R 4 , R′ and R″ are as previously defined; and    (4) reacting the compound from step (3) with an alkylating agent in an aprotic solvent at a temperature between −20° C. and 100° C. in the presence of a base, optionally in the presence of water and a phase transfer catalyst, to provide a compound represented by the formula:                        wherein R p , R p   3 , R 4 , R 5 R′ and R″ are as previously defined, optionally deprotecting the compound from step (4) by:    i. treating with an aqueous acid in an organic solvent at a temperature from 0° C. to 100° C. for 1 to 24 hours; and    ii. stirring in methanol at a temperature between room temperature and reflux temperature for 4 to 24 hours;      to provide a compound represented by Formula I where A is —CHO, R 1  and R 2  taken together are=O, R 3  is hydrogen and R 4 , R 5  and R p  are as defined in  claim 1 .    
     
     
         13 . A process for the preparation of a compound represented by Formula I as defined in  claim 1  comprising: 
 (1) reacting a compound represented by the formula:                           wherein R p  is a hydroxy protecting group and R′ and R″ are each C 1 -C 6 -alkyl or when taken together are —CH 2 CH 2 — or —CH 2 CH 2 CH 2 — with an alkylating agent in an aprotic solvent at a temperature between −20° C. and 100° C. in the presence of a base, optionally in the presence of water and a phase transfer catalyst, to provide a compound represented by the formula:                           wherein R p , R′ and R″ are as previously defined and R 5  is as defined in  claim 1;     (2) reacting the compound from step (1) with one or more silylating agent(s), optionally with the addition of a catalyst in an aprotic solvent at a temperature between 0° C. and 50° C. for 1 to 48 hours to provide a compound represented by the formula:                           wherein R p   3  and R p   4  are each a hydroxy protecting group and R 5 , R p , R′ and R″ are as previously defined;    (3) reacting the compound from step (2) with an acid in an organic solvent at a temperature between −20° C. and 110° C. for 1 to 24 hours to provide a compound represented by the formula:                           wherein R 5 , R p   2 , R p   3 , R′ and R″ are as previously defined;    (4) reacting the compound from step (3) with an alkylating agent in an aprotic solvent at a temperature between −20° C. and 100° C. in the presence of a base, optionally in the presence of water and a phase transfer catalyst to provide a compound represented by the formula:                           wherein R p , R p   3 , R 5 , R′ and R″ are as previously defined and R 4  is as defined in  claim 1 , 
 optionally deprotecting the compound from step (4) by:  
 i. treating with an aqueous acid in an organic solvent at a temperature between 0° C. and 100° C. for 1 to 24 hours; and  
 ii. stirring in methanol at a temperature between room temperature and reflux temperature for 4 to 24 hours;  
   to provide a compound represented by Formula I where A is —CHO, R 1  and R 2  taken together are=O, R 3  is hydrogen and R 4 , R 5  and R p  are as defined in  claim 1 .    
     
     
         14 . A process for the preparation of a compound represented by Formula I as defined in  claim 1  comprising: 
 (1) reacting a compound represented by the formula:                           wherein R 5  is as defined in  claim 1 , R p  and R p   3  are each a hydroxy protecting group and R′ and R″ are each C 1 -C 6 -alkyl or when taken together are —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —,    with RCHCHCH 2 O(CO)O-t-Butyl in the presence of a palladium catalyst to provide a compound represented by the formula:                           wherein R is hydrogen, aryl, substituted aryl, heteroaryl or substituted heteroaryl and R 5 , R p , R p   3 , R′ and R″ are as previously defined, optionally reacting the compound from step (1) with a reducing agent, optionally in the presence of a metal catalyst, or under hydrogenation conditions, to provide a compound represented by the formula:                           wherein R, R 5 , R p , R p   3 , R′ and R″ are as previously defined; and    (2) deprotecting the compound of step (1) by: 
 i. treating with an aqueous acid in an organic solvent at a temperature from 0° C. to 100° C. for 1 to 24 hours; and  
 ii. stirring in methanol at a temperature between room temperature and reflux temperature for 4 to 24 hours;  
   to provide a compound represented by Formula I, wherein R 4  is —(CH 2 ) 3 —R or —CH 2 (CH) 2 —R, R is as previously defined, A is —CHO, R 1  and R 2  taken together are=O, R 3  is hydrogen and R 4 , R 5  and R p  are as defined in  claim 1 .    
     
     
         15 . A process for the preparation of a compound represented by the formula:  
       
         
           
           
               
               
           
         
          wherein R p  and R p   3  are each independently hydrogen or a hydroxy protecting group, R′ and R″ are each C 1 -C 6 -alkyl or when taken together are —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —, R is aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R 5  is as defined in  claim 1 , comprising:  
         (1) reacting a compound represented by the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein, R p  and R p   3  are hydroxy protecting groups, and R 5 , R′ and R″ are as previously defined, with an allyl halide or a propargyl halide, optionally reducing the product with a borane or stannane reagent, to give a vinyl borane or vinyl stannane derivative represented by the formula:  
         
           
             
             
                 
                 
             
           
         
          where M is hydrogen, B(OH) 2  or SnBu 3 , and R 5 , R p , R p   3 , R′ and R″ are as previously defined; and  
         (2) reacting the compound from step (a) with a compound represented by the formula R-X wherein R is as previously defined and X is a halide or triflate, in the presence of a palladium catalyst to give a compound represented by the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R, R 5 , R p , R p   3 , R′ and R″ are as previously defined.