WO1998009601A2

WO1998009601A2 - Process to prepare pharmaceutical compounds

Info

Publication number: WO1998009601A2
Application number: PCT/US1997/015668
Authority: WO
Inventors: Andrew H. Fray; Michael J. Martinelli; Eric D. Moher
Original assignee: Eli Lilly And Company; University Of Hawaii; Wayne State University
Priority date: 1996-09-06
Filing date: 1997-09-05
Publication date: 1998-03-12
Also published as: IL128643A0; EP0934250A2; HUP0000212A3; EP0934250A4; IL128643A; JP2001500128A; WO1998009601A3; AU4334397A; BR9711695A; HUP0000212A2; KR20010029475A; CA2264527A1

Abstract

This invention provides novel cryptophycin compounds and a process for preparing cryptophycin compounds.

Description

PROCESS TO PREPARE PHARMACEUTICAL COMPOUNDS

This invention relates to the fields of pharmaceutical and organic chemistry and provides a process for preparing cryptophycin compounds useful as anti- microtubule agents.

Cryptophycin compounds can be useful for the treatment of cancer and neoplasms, and are thus useful pharmaceutical agents. The literature discloses a protocol for cyclizing certain cryptophycin compounds. Barrow, R. A.; Hemscheidt, T.; Liang, J.; Paik, S . ; Moore, R. E.; Tius, M. A. J. Am. Chem . Soc . 1995, 11 7, 2479. This three-step sequence (hereinafter "Barrow synthetic sequence") commenced with the conversion of trichloroethyl ester to the corresponding carboxylic acid using zinc and acetic acid. Conversion of crude to the amino carboxylate was accomplished with trifluoroacetic acid followed by an aqueous basic work-up. In the final step, ring closure was achieved in the presence of pentafluorophenyldiphenylphosphinate (FDPP) in N,N- dimethylformamide to provide the desired product 3 (3 is illustrated infra , in Scheme 1 to provide further clarification) (61% after chromatography) .

In contrast, the presently claimed process provides a shorter (two-steps) process which is more adaptable for large scale or commercial preparation of the macrocyclic core of cryptophycin derivatives. The claimed process can reduce reagent expense, as well as minimize the potential waste-stream issues associated with the use of certain reagents in the Barrow synthetic sequence. Further, purification via the claimed process may be accomplished without chromatography, which is expensive and difficult to implement on a large scale.

The presently claimed invention provides a process for preparing a compound of Formula II

wherein

Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, d-Ci? alkyl, C?-Cι₂ alkenyl, C₆-C_1? alkynyl, NR⁵¹R⁵², COR⁵ , OR⁵', and Formula Ar'

R >5³1¹ is selected from the group consisting of hydrogen and C- C₃ alkyl;

R⁵ is selected from the group consisting of hydrogen and d~ C₃ alkyl;

R⁵³ is selected from the group consisting of Cι~Cι₂ alkyl; R⁵⁴ is selected from the group consisting of hydrogen, d~C₆ alkyl, Ci-dalkyl (R^{5 '}R^57"R^57'" ) , simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4- ( tert-butyldimethylsiloxy) - benzyltriphenylphosophonium, COOR⁵⁷, P0₃H, S0₃H, S0₂R^5Θ, N(R⁵⁹)R⁶⁰,

NHCHR⁶¹', CN, NO?, halogen, OR⁶², CH₂(0)R⁶", -

R"

CH_?OC(0)R , CH₂N(R 9^y6^e \)R>9^y6^b' , COR ,100 (d-dalkyl)OR 100 and

SR 63 , R⁹⁵ is selected from the group consisting of -R⁹⁸NH₃; R^9b and R^96' are each independently selected from the group consisting of hydrogen and d-C₆ alkyl, -R⁹⁷NH₃, and -R⁹⁹ NR^99' R^99"; R⁹⁷ is selected from the group consisting of Cι-C_fe alkyl; R⁹⁸ is selected from the group consisting of d-Ce alkyl; R⁹⁹ is d-C₆ alkyl;

R^99' and R^9C" ^' are each independently selected from the group consisting of hydrogen and Cι-C₆ alkyl; R¹⁰⁰ is selected from the group consisting of hydrogen, and _{s i ( R}1 0 , _R1 02_R10_{3 )} .

R¹⁰¹ is Cι -C₆ alkyl ;

R^{: o?} i s d-Ce, alkyl ;

R¹⁰³ is C -C₆ al kyl ; R¹⁰⁴ is selected from the group consisting of C ( 0) d -C₆ alkylN (R^10fa) (R⁵⁹) R⁶⁰, C ( 0) d-C₆ alkylN⁺ , fused bicyclic, and

NHR¹⁰⁵N (R¹⁰⁶) (R⁵⁹) R⁶⁰;

R¹⁰⁵ is selected from the group consisting of C(0,d-C₆ alkyl,

Cι-C₆ alkyl; R¹⁰⁶ is selected from the group consisting of hydrogen, -d alkyl, C(0)OR¹⁰⁷;

R¹⁰⁷ is selected from the group consisting of hydrogen, d^_d alkyl, CR¹⁰⁸ R¹⁰⁹ R^no

R¹⁰⁸ is selected from the group consisting of hydrogen and Cι-C₆ alkyl;

R¹⁰⁹ is selected from the group consisting of hydrogen and

Cι-C₆ alkyl;

R¹¹⁰ is selected from the group consisting of hydrogen and d-C₆ alkyl; R⁵⁵ is selected from the group consisting of hydrogen, Cι-C₆ alkyl, C (R^57'R^57"R^57'" ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR⁵⁷, P0₃H, S0₃H, S0₂R⁵⁸,

NR⁵⁹R⁶⁰, NHOR⁶¹, NHCHR^61', CN, N0₂, halogen, OR⁶², and SR⁶³; R^5b i s selected from the group consisting of hydrogen, Cι -C_b al kyl , C ( R ^{7 '} R^{57 "} R^{57" '} ) , simple unsubstituted aromat ic, simple substituted aromatic , phenyl , COOR^f57 , P0₃H, S0₃H, S0₂R⁵⁸ ,

NR⁵⁹R^b0, NHOR^bl , NHCHR⁶¹' , (d-C₆) alkylNR⁵⁹R⁶ , CN, N0₂, halogen, OR¹⁰⁴ , CR¹⁰⁴ , OR⁶² , and SR⁶³ ;

R^ is selected from the group cons i sting o f hydrogen and d -

C₁₂ al kyl ;

R^57' is selected from the group consisting of hydrogen, halogen, and C1-C12 alkyl; R^57" is selected from the group consisting of hydrogen, halogen, and C~Cι₂ alkyl;

R^57'" is selected from the group consisting of hydrogen, halogen, and d-C₁₂ alkyl;

R⁵⁸ is selected from the group consisting of hydrogen and Cj- C_1? alkyl;

R⁵⁹ is selected from the group consisting of hydrogen, (Cι~

C_fc) alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC) ;

R⁶⁰ is selected from the group consisting of hydrogen and (Ci-d) alkyl;

R⁶¹ is selected from the group consisting of hydrogen, OR¹'⁴,

CH₂NHR⁶⁵, NHR^65' and fluorenylmethoxycarbonyl (FMOC);

R^61' is selected from the group consisting of hydrogen, OR⁶⁴,

CH₂NHR⁶⁵, NHR⁶ and fluorenylmethoxycarbonyl (FMOC) ; R^6? is selected from hydrogen, and d-C_b alkyl;

R^62' is selected from hydrogen, OH, OR⁶², and d~C_b alkyl;

R^bi is selected from hydrogen and Cj-d, alkyl;

R⁶⁴ is selected from the group consisting of hydrogen, (Ci-

C₆) alkyl, CH₂NR⁶⁶R⁶⁷; R^G5 is selected from the group consisting of hydrogen and Ci-

C₆ alkyl, NH₂, and fluorenylmethoxycarbonyl (FMOC) ;

R^65' is selected from the group consisting of hydrogen and

Cι-C_fa alkyl, NH₂, and fluorenylmethoxycarbonyl (FMOC) ; R⁶⁶ is selected from the group consisting of hydrogen and Ci- d alkyl and fluorenylmethoxycarbonyl (FMOC) ;

R⁶' is selected from the group consisting of hydrogen and Ci-

C₆ alkyl; R³ is a lower alkyl group;

R⁴ is H or OH;

R⁵ is H or OH;

R⁴ and R⁵ may be taken together to form a second bond between ₃ and d R⁶ is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkyoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring (d-C₆) alkyl, (d-C₈) cycloalkyl, substituted C₃-C₈ cycloalkyl, substituted (C,-C_b) alkyl, a group of the formula III'

and a group of the formula III ' '

R⁷ is selected from the group consisting of NR R^',?, R⁵³NR R^5?, OR⁵³, H and a lower alkyl group; R⁵¹ and R^"'² are independently selected from the group consisting of d^_d alkyl; R⁵³ is d~ C₃ alkyl; R⁸ is H or a lower alkyl group; or R⁷ and R⁸ can form a cyclopropyl ring;

R⁹ is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, lower alkyl-C₃-d cycloalkyl, and benzyl; R¹⁰ is H or a lower alkyl group;

Rⁿ is selected from the group consisting of hydrogen, OH, lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl;

R^ιr', R^l , and R¹ ' are each independently selected from the group consisting of hydrogen, OR¹⁸, halo, NR^18'R^19', N0₂,

OP0₃H₂, OR¹⁹phenyl, SCH₂phenyl, CONH , C0_?H,

and

ZZ;

R¹⁸ is selected from the group consisting of hydrogen, aryl,

Cι-C_b alkyl, C(0)R⁹⁰ and fluorenylmethoxycarbonyl (FMOC); R^18' is selected from the group consisting of hydrogen, (d-

C₆) alkyl and C(0)R^90' ;

R¹⁹ is Ci- alkyl, C(0)R^9n" and fluorenylmethoxycarbonyl

( FMOC) ;

R^19' is selected from the group consisting of hydrogen, (d~ C alkyl, and C (0) R^90'" ;

R⁹⁰, R^90' , R^90" , and R^{90" '} are each independently selected from the group consisting of hydrogen, (Ci-d) alkyl, OR^91' and aryl;

R^91' is selected from the group consisting of (Ci-d) alkyl, aryl, and hydrogen;

R²³ is selected from the group consisting of hydrogen and

(d-d) alkyl;

R³⁰ is hydrogen or Ci- alkyl; or

R^3ϋ may be taken together with the N at C-11 to form a three to seven me bered cyclic ring;

R⁵⁰ is hydrogen or

n is 0, 1, or 2; m is 0, 1, or 2; -1-

p is 0, l,or 2;

X is selected from the group consisting of 0, C, S, NH and alkylamino;

Y is selected from the group consisting of C, O, NH, S, SO,

S0₂ and alkylamino;

Z is selected fromt he group consisting of -(CH₂)_n-, -(CH_?)_P-

0-(CH_?)_m- and (C₃-C₅) cycloalkyl;

ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group; comprising contacting a compound of Formula III

with a solvent and a catalyst of the formula IV

^■ vcat

wherein M is selected from the group consisting of hydrogen, Na, Li, K, and Cs;

X^cat is selected from the group consisting of 0, N, and S; y^cat __s selected from the group consisting of 0, N, and S;

Rca^tl i_s selected from the group consisting of Cι~ C₆ alkyl and aryl; R^cat2 is selected from the group consisting of Cι~

Ce alkyl and aryl.

Additionally, the present invention provides a new cryptophycin compound of Formula III

wherein

Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, C] -Cι₂ al kyl , C₂-C_{J 2} alkenyl, C₂-C₁₂ alkynyl, NRbl^lrR-,52 COR^s OR 53 and Formula Ar'

R⁵¹ is selected from the group consisting of hydrogen and Ci- C₃ alkyl;

R 52 is selected from the group consisting of hydrogen and d^~

C₃ alkyl;

R 53 is selected from the group consisting of Cι-Cι₂ alkyl;

R is selected from the group consisting of hydrogen, Ci- alkyl, d~dalkyl (R^{5 '}R^b7"R^57'" ) , simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4- ( tert-butyldimethylsiloxy) - benzyltriphenylphosophonium, COOR⁵⁷, PO^H, S0₃H, S0₇R^5θ, N(R⁵⁹)R⁶⁰, NHOR⁶¹, NHCHR^61', CN, N0₂, halogen, OR⁶², CH₂(0)R^ε?'

CH₂N(R⁹⁶)R^9b',COR¹⁰⁰, (d-C₆alkyl) OR¹⁰⁰, , and

SR⁶³,

R is selected from the group consisting of -R NH₃; R⁹⁶ and R^96' are each independently selected from the group consisting of hydrogen and Ci- alkyl, -R⁹NH₃, and -R⁹ NR^99'

R^99";

R⁹⁷ is selected from the group consisting of Cι-C_h alkyl;

R⁹⁸ is selected from the group consisting of C]-C_f, alkyl; R⁹⁹ is Ci-Ce alkyl;

R^99' and R^99" are each independently selected from the group consisting of hydrogen and d^_ alkyl;

R¹⁰⁰ is selected from the group consisting of hydrogen, and

Si (R¹⁰¹R¹⁰²R¹⁰³) ; R¹⁰¹ is d-Ce alkyl;

R¹⁰² is d-d alkyl;

R¹⁰³ is d-d alkyl;

R¹⁰⁴ is selected from the group consisting of C(0)Cι-C_b alkylN(R¹⁰⁶) (R⁵⁹)R^B0, C (0) C,-C₆ alkylN⁺, fused bicyclic, and NHR¹⁰⁵N(R¹⁰⁶) (R^f,9)R⁶⁰;

R¹⁰⁵ is selected from the group consisting of C(0)d-C₆ alkyl,

Cι-C_β alkyl;

R¹⁰⁶ is selected from the group consisting of hydrogen, Cι~C₆ alkyl, C(0)OR¹⁰⁷; R¹⁰⁷ is selected from the group consisting of hydrogen, Cι~C alkyl, CR¹⁰⁸ R¹⁰⁹ R¹¹⁰

R¹⁰⁸ is selected from the group consisting of hydrogen and

Ci-d alkyl;

R¹⁰⁹ is selected from the group consisting of hydrogen and d-d alkyl;

R ^o is selected from the group consisting of hydrogen and

Ci-d alkyl; R¹¹¹ is selected from the group consisting of hydrogen, d-C_b alkyl, and C(0)0R¹⁰⁷

R⁵⁵ is selected from the group consisting of hydrogen, d~d alkyl, C (R^57'R^57"R⁵'^"' ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR⁵⁷, P0₃H, S0₃H, S0₂R⁵⁸,

NR⁵⁹R⁶⁰, NHOR⁶¹, NHCHR^61', CN, N0₂, halogen, OR⁶², and SR⁶³;

R⁵⁶ is selected from the group consisting of hydrogen, Cι~d alkyl, C (R ^7'R '^"R^h7'" ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR⁵⁷, P0H, S0₃H, S0_?R⁵⁸, NR^b9R⁶⁰, NHOR⁶¹, NHCHR^61', (C,-C₆) alkylNR^b9R^G0, CN, NO^,, halogen,

OR¹⁰⁴, CR¹⁰⁴, OR⁶², and SR⁶³;

R⁵⁷ is selected from the group consisting of hydrogen and d- d? alkyl;

R^57' is selected from the group consisting of hydrogen, halogen, and d-C₁₂ alkyl;

R^57" is selected from the group consisting of hydrogen, halogen, and Cι-C₁₂ alkyl;

R^57'" is selected from the group consisting of hydrogen, halogen, and Cι-Cι₂ alkyl; R⁵⁸ is selected from the group consisting of hydrogen and d-

C₁₂ alkyl;

R⁵⁹ is selected from the group consisting of hydrogen, (Ci-

C₆) alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC) ; R⁶⁰ is selected from the group consisting of hydrogen and (d-d) alkyl;

R⁶¹ is selected from the group consisting of hydrogen, OR ,

CH₂NHR^es, NHR^65' and fluorenylmethoxycarbonyl (FMOC);

R^61' is selected from the group consisting of hydrogen, OR⁶⁴, CH₂NHR⁶⁵, NHR^65' and fluorenylmethoxycarbonyl (FMOC) ;

R⁶² is selected from hydrogen, and C^_ alkyl;

R^62' is selected from hydrogen, OH, OR⁶², and Ci-d alkyl;

R⁶³ is selected from hydrogen and Ci- alkyl; R^b4 is selected from the group consisting of hydrogen, (Ci-

C₆) alkyl, CH₂NR⁶⁶R⁶⁷;

R⁶⁵ is selected from the group consisting of hydrogen and d-

C₆ alkyl, NH₂, and fluorenylmethoxycarbonyl (FMOC) ; R^65' is selected from the group consisting of hydrogen and

Cι-C₆ alkyl, NH₂, and fluorenylmethoxycarbonyl (FMOC) ;

R⁶⁶ is selected from the group consisting of hydrogen and d-

C₆ alkyl and fluorenylmethoxycarbonyl (FMOC) ;

R⁶⁷ is selected from the group consisting of hydrogen and d- C_b alkyl;

R^J is a lower alkyl group;

R⁴ is H or OH;

R^' is H or OH;

R⁴ and R⁵ may be taken together to form a second bond between C₁₃ and d₄;

R⁶ is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkyoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring

(Ci-Ce) alkyl, (C₃-C₈) cycloalkyl, substituted C₃-C₈ cycloalkyl, substituted (Ci-d) alkyl, a group of the formula III'

and a group of the formula III''

R⁷ is selected from the group consisting of NR⁵¹R^5?, R⁵³NR⁵¹R⁵¹,

OR⁵³, H and a lower alkyl group; R⁵¹ and R⁵² are independently selected from the group consisting of C₁-C3 alkyl; R⁵³ is Ci- C₃ alkyl;

R⁸ is H or a lower alkyl group; or

R⁷ and R^e can form a cyclopropyl ring;

R⁹ is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, lower alkyl-C₃-C_b cycloalkyl, and benzyl;

R¹⁰ is H or a lower alkyl group;

R¹¹ is selected from the group consisting of hydrogen, OH, lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl; R^lb, R¹⁶, and R¹⁷ are each independently selected from the group consisting of hydrogen, OR¹⁸, halo, NR^18'R^19', N0₂,

OP0₃H₂, OR¹⁹phenyl, SCH henyl, CONH₂, C0H, P0₃H₂, S0₂R²³, and

ZZ;

R¹⁸ is selected from the group consisting of hydrogen, aryl, d-C₆ alkyl, C(0)R⁹⁰ and fluorenylmethoxycarbonyl (FMOC);

R^18' is selected from the group consisting of hydrogen, (Ci-

C₆) alkyl and C(0)R^90';

R¹⁹ is d-Ce alkyl, C(0)R^90" and fluorenylmethoxycarbonyl ( MOC) ; R^:9' is selected from the group consisting of hydrogen, (Ci-

C₆) alkyl, and C(0)R^90"';

R⁹⁰, R^90' , R^90" , and R^90'" are each independently selected from the group consisting of hydrogen, (Ci-Ce) alkyl, OR^91' and aryl; R⁹¹' is selected from the group consisting of (Cι-d) alkyl, aryl, and hydrogen;

R^2J is selected from the group consisting of hydrogen and

(d-d) alkyl; R³⁰ is hydrogen or Cι~C₆ alkyl; or

R³⁰ may be taken together with the N at C-11 to form a three to seven membered cyclic ring; o

R⁵⁰ is hydrogen or ; n is 0 , 1 , or 2 ; m is 0 , 1 , or 2 ; p is 0 , l , or 2 ;

X is selected from the group consisting of 0, C, S, NH and alkylamino; Y is selected from the group consisting of C, 0, NH, S, SO, S0₂ and alkylamino;

Z is selected fromt he group consisting of -(CH₂)_n-, - (CH?) _P- 0-(CH₂)_m- and (C₃-C₅) cycloalkyl;

ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group; or a pharmaceutically acceptable salt or solvate thereof.

As used herein, the term "simple alkyl" shall refer to C_2.-C₇ alkyl wherein the alkyl may be saturated, unsaturated, branched, or straight chain. Examples include, but are in no way limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, propenyl, ethenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, methylated pentyl groups and the like. The term "alkenyl" refers to an alkyl group, as defined above, having from one to three double bonds. The term "alkynyl" refers to an alkyl group, as defined above, having at least one triple bond. It is especially preferred that alkynyl has only one triple bond. The term Ci-C_n> alkyl; wherein n' is an integer from 1 to 12 means an alkyl group having from one to the indicated number of carbon atoms. The Ci-Cn¹ alkyl can be straight or branched chain. As used herein, the term "B-ring Ci-Cβ alkyl" refers to saturated, unsaturated, branched and straight chain alkyl wherein the B-ring Ci-Cβ alkyl group may include up to three (3) non-carbon substituents. Such non-carbon substituents are most preferredly selected from the group) consisting of OH, SCH phenyl, NH₂, CO, CONH₂, C0₂H, P0₃H₂,

S0₂R²¹ wherein R²¹ is selected from hydrogen and C_3.-C₃ alkyl;

As used herein, the term " (Ci-Cβ) alkyl linker" refers to Ci-Cβ alkyl group having from zero to three substituents selected from the group consisting of Cχ-C6 alkyl, NH₂ and amino acid.

As used herein the term "amino acid" means an organic acid containing an amino group. The term includes both naturally occuring and synthetic amino acids, therefore, the amino group can be, but is not required to be, attached to the carbon next to the acid. The term shall refer to, but is in no way limited to (CH ) ₂NH₂COOH, (CH₂) ₃NH₂COOC(CH₃) ₃, CH₂NH₂COOC (CH₃) ₃, CH₂CH (NH₂ ) CH₂COOH, CH₂CH(NH₂)CH₂COOC(CH₃)3, and the like.

As used herein, the term "carbohydrate" refers to a class of substituents made up of carbon, hydrogen, and oxygen wherein hydrogen and oxygen are in the same proportions as in water or nearly the proportions as water. The term "carbohydrate" further refers to an aldehyde or ketone alcohol or a compound which on hydrolysis produces and aldehyde or ketone. The term "carbohydrate" is as commonly understood by the skilled artisan. For example,, the term refers to, but is in no way limited to, Cι₂H ₂0n and C₆H₁₀O₅. As used herein, the term "amino sugar" refers to a carbohydrate group containing from one to three amino substituents at any available position on the carbohydrate molecule . As used herein, the term "saccharide" refers to carbohydrate subunits to form disaccharides or polysaccharides . The term means for example, but in no way limited to, lactose, maltose, sucrose, fructose, starch, and the like. As used herein, the term "substituted phenyl" shall refer to a phenyl group with from one to three non- hydrocarbon substituents which may be independently selected from the group consisting of simple alkyl, Cl, Br, F, and I. As used herein, the term "substituted benzyl" shall refer to a benzyl group with from one to three non- hydrocarbon substitutents which may be independently selected from the group consisting of simple alkyl, Cl, Br, F, and I wherein such substituents may be attached at any available carbon atom. As used herein "B-ring heterocyclic group" refers to aromatic or unsaturated rings which contain one or more non-carbon substituent selected from the group consisting of oxygen, nitrogen, and sulfur. Especially preferred B-ring heterocyclic groups are selected from, but not limited to, the group consisting of

20

R²⁰ is selec ed from hydroge alkyl. wherein R²⁰ is selected from hydrogen and Ci-Cβ alkyl.

It is especially preferred that "B-ring heteroaromatic group" refers to a substituent selected from the group consisting of:

As used herein "cycloalkyl" refers to a saturated C-C cycloalkyl group wherein such group may include from zero to three substituents selected from the group consisting of C₁-C₃ alkyl, halo, and OR²² wherein R²² is selected from hydrogen and C₁-C₃ alkyl. Such substituents may be attached at any available carbon atom. It is especially preferred that cycloalkyl refers to substituted or unsubstituted cyclohexyl.

As used herein "Lower alkoxyl group" means any alkyl group of one to five carbon atoms bonded to an oxygen atom. As used herein "lower alkyl group" means an alkyl group of one to five carbons and includes linear and non- linear hydrocarbon chains, including for example, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, and methylated pentyl groups. As used herein "allylically substituted alkene" means any alkene having from one to seven carbon atoms which contains an alkyl substitution on it. As used herein the term "unsaturated lower alkyl" means a lower alkyl group as defined supra , wherein from one to two double bonds are present in the unsaturated lower alkyl substituent. A preferred unsaturated lower alkyl is -CH₂-CH=CH . The term "lower alkyl-C₃~C₅ cycloalkyl" refers to C-C alkyl substituted with a C₃-C₅cycloalkyl group. A preferred lower alkyl-C₃~C₅ cycloalkyl group is -CH₂-cyclopropyl; wherein the group is attached to the cryptophycin core structure at R⁹ via the CH₂.

As used herein "epoxide ring" means a three- membered ring whose backbone consists of two carbons and an oxygen atom. As used herein, "aziridine ring" means a three-me bered ring whose backbone consists of two carbon atoms and a nitrogen atom. As used herein "sulfide ring" means a three-membered ring whose backbone consists of two carbon atoms and a sulfur atom. As used herein "episulfide ring" means a three-membered ring whose backbone consists of two carbon atoms and a sulfur atom. As used herein "sulfate group" means a five membered ring consisting of a carbon- carbon-oxygen-sulfur-oxygen backbone with two additional oxygen atoms connected to the sulfur atom. As used herein "cyclopropyl ring" means a three member ring whose backbone consists of three carbon atoms. As used herein, "monoalkylphosphate ring" means a five membered ring consisting of a carbon-carbon-oxygen-phosphorous-oxygen backbone with two additional oxygen atoms, one of which bears a lower alkyl group, connected to the phosphorous atom.

As used herein, "simple unsubstituted group" refers to common aromatic rings having 4n+2 π electrons in a monocyclic conjugated system, for example, but not limited to: furyl, pyrrolyl, thienyl, pyridyl and the like, or a bicyclic conjugated system, for example but not limited to mdolyl or naphthyl. As used herein "simple substituted aromatic group" refers to a phenyl group substituted with a single group selected from the group consisting of halogen and lower alkyl group.

As used herein, the term "fused bicyclic" refers to two joined ring systems which are optionally independently saturated, unsaturated, or aromatic. Such groups include but are in no way limited to naphthyl, groups which fuse an unsaturated ring with an aromatic ring, groups having a heterocyclic group fused with a heteroaromatic group, and a heterocyclic group fused with an aromatic group. The fused bicyclic is optionally substituted with one or more substituents selected from the group consisting of Ci- alkyl and halogen.

As used herein, "heteroaromatic group" refers to aromatic rings which contain one or more non-carbon atoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. It is most preferred that the heteroaromatic group will have from three to eight members in the ring. It is especially preferred that the number of non-carbon members will be from one to three.

As used herein, the term "heterocyclic" refers to saturated or unsaturated rings containing one or more non carbon atoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. It is most preferred that the heterocyclic group will have from three to eight members m the ring. It is especially preferred that the number of non-carbon members will be from one to three.

As used herein, "halogen" or "halo" refers to those members of the group on the periodic table historically known as halogens. Methods of halogenation include, but are not limited to, the addition of hydrogen halides, substitution at high temperature, photohalogenation, etc., and such methods are known to the skilled artisan. Especially preferred halogens are chloro, bromo, fluoro, and lodo . For some purposes within the scope of this invention, chloro, bromo and fluoro are especially preferred halogens.

Compounds of Formula III are particularly useful for the preparation of cryophycin compounds.

The starting material corresponding to a compound of Formula 1 as illustrated in Scheme 1 can be prepared using the disclosures available to the skilled artisan. See Barrow, id. The processes for preparing compound 2 as illustrated in Scheme 1' used TFA; however, the artisan will recognize that alternative agents can be used in this process. Likewise, the basic workup uses sodium hydroxide; however, the artisan will appreciate that other basic agents can be effective as well.

The processes to prepare the compounds of this invention most preferably are completed m the presence of a solvent. The skilled artisan can select appropriate solvents using known methodologies. While in no way limiting the scope of the present invention, some preferred solvents are provided for the guidance of the artisan, including, but not limited to, a solvent selected from the group consisting of toluene, N,N-dιmethylformamide, ethyl acetate, tetrahydrofuan, and acetonitrile. The reaction time is related to the starting materials and operating temperature. The optimum reaction time for a given process is, as always, a compromise which is determined by considering the competing goals of throughput, which is favored by short reaction times, and maximum yield, which is favored by long reaction times.

The process of this invention can be further illustrated by the following Scheme 1' :

And more particularly, Scheme 1:

catalyst ►

Toluene, rt

As illustrated above, the catalyst is most preferrably selected from the group consisting of alky and aryl substituted metal carboxylates, carboxylic acids, and other bifunctional compounds according to the Formula IV. Especially preferred catalysts are selected from the group consisting of 2-hydroxyρyridine, tetrabutylammonium cyanide and sodium benzoate/n-tetrabutylNHS0₄.

The following is provided to further illustrate the advantages of the claimed process:

As shown in Table 1, 2-hydroxypyridine (entries 2-4) and tetrabutylammonium benzoate (entry 5) have been shown to significantly accelerate the macrolactamization process. In contrast, ring closure was very slow when the reaction was allowed to stir at room temperature without catalyst (entry 1) . Although not listed in Table 1, tetrabutylammonium cyanide (NaBu₄NCN + NaCN) also promoted macrolactamization of 2. As shown in Table 1, the 2 and 3 refer to the structures of Scheme 1 wherein Ar is phenyl. TABLE 1

Example 1 Cryptophycin-51 (3) .

Compound 1 (as illustrated by Scheme 1 supra . ) (10.2 g,

11.2 ol) was cooled to 0 °C and dissolved in trifluoroacetic acid (TFA) (50 mL) . The resulting solution was stirred at 0 °C for 30 min and was then concentrated under reduced pressure. The resultant syrup was diluted with toluene (250 L) and washed with IN NaOH (2x100 mL) using brine (50 mL) to break up emulsions. The aqueous extracts were back-extracted with fresh toluene (1x50 L) and the organic phases were combined and dried (MgS0₄) . TLC analysis indicated no trace of starting 1. The filtered solution of amino ester 2 was diluted to 500 mL and 2-hydroxypyridine (5.34, 56.2 mmoles) was added. The resulting clear, pale yellow solution was allowed to stir at room temperature for 14 h. The reaction mixture became turbid so the suspension was diluted with CH2CI2 (250 mL) to assure solubility of product. The mixture was washed with saturated, aqueous NaHC0₃ (3 x 100 mL) and brine (1 x 100 L) . The aqueous extracts were back-extracted with CH₂CI₂ (1 x 100 mL) and the organic extracts were combined, dried (MgS0₄ ) , and concentrated to a thick syrup. A solution of hexanes and EtOAc (100 mL, 1:1 v/v) was added and the solution was cooled to 0 °C. Spontaneous crystallization occurred after 30 min. The mixture was filtered, and the filtrate was concentrated and induced to crystallize two additional times. The collected crops were combined to give 5.04 g (69%) of compound 3 (LSN 354504) as a white powder. HPLC (85:15 CH₃CN / H₂0, 0.05% TFA in both organic and aqueous phases; flow 1 mL / min; wavelength: 225 nm; column: Zorbax SB-C18) R_t = 6.09 min 95% pure. ^XH NMR (300 MHz, CDCI₃) d 7.32-7.17 (m, 8H) ; 7.04 (dd, 1H, J= 2.2, 8.4); 6.82 (d, 1H, J = 8.5); 6.76 (m, 1H) ; 6.39 (d, 1H, J= 15.9); 5.99 (dd, 1H, J = 8.8, 15.8); 5.73 (dd, 1H, J = 2.3, 16.4); 5.50 (d, 1H, J = 7.8); 5.03 (m, 1H) ; 4.83 (dd, 1H, J = 3.3, 9.9); 4.73 (ABq, 1H, J= 6.4); 3.86 (s, 3H) ; 3.39 (dd, 1H, J= 8.6, 13.5); 3.10 (m, 2H) ; 2.53 (m, 2H) ; 2.36 (m, 1H) ; 1.62 (m, 3H) ; 1.21 (s, 3H) ; 1.14 (s, 3H) ; 1.11 (d, 3H, J = 6.9) ; 0.71 (app. t, 6H, J = 6.0) .

Claims

We claim:

A compound of Formula III

wherein

Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, -Cι alkyl, d-Cι₂ alkenyl, C₂-C_1? alkynyl, NR^!,'R^:;, COR^'2, OR^'", and Formula Ar-'

Rbl is selected from the group consisting of hydrogen and C--

C, alkyl;

R² is selected from the group consisting of hydrogen and d-

C₃ alkyl;

S3 is selected from the group consisting of Ci-Ci: alkyl;

54 is selected from the group consisting of hydrogen, C.--C. alkyl, d-dalkyl (R^Γ,7'R^{5 "}R"^{" '} ) , simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4- ( tert-butyldimethylsiloxy) - benzyltriphenylphosophonium, COOR", P0.,H, SdH, S0_?R^5δ,

N(R^jy)R^b , NH0R ,6^b1 , NHCHR ,6^b1^l , CN, N0₂, halogen, OR , CH₂(0)Rc: ' CH_rOC(0)R CH_?N(R'^b)R^yt , COR¹nr (d-C.-.alkyl)OR, 1 Of

and

R⁹⁵ is selected from the group consisting of -R⁹⁸NH,;

R^9b and R^96' are each independently selected from the group consisting of hydrogen and Ci-d. alkyl, -R NH,, and -R NR

R^99";

R^9/ is selected from the group consisting of Ci-d alkyl;

R⁹⁸ is selected from the group consisting of C-,-d, alkyl;

R⁹⁹ is Ci-d alkyl;

R^{9 '} and R⁹"^" are each independently selected from the group consisting of hydrogen and C_ι~d- alkyl;

R^10ϋ is selected from the group consisting of hydrogen, and _{si (R}:o-_!Rio2_Rim_{) ;}

101 is d-d alkyl

10? is Ci-d alkyl

103 is Ci- alkyl

R 104 is selected from the group consisting of C(0)d-C, alkylN(R^luc) (R^j9)R^b , C(0)d-d alkylN⁺, fused bicyclic, and

NHR^10!,N(R¹⁰") (R⁵ )R⁶⁰, R^lor' is selected from the group consisting of C(0)C-C alkyl, Ci-d alkyl;

R 106 is selected from the group consisting of hydrogen, C-.-C, alkyl, C(0)0R 107 ,

R¹ is selected from the group consisting of hydrogen, C--C. alkyl, CR ,1¹08 R ,1¹0'⁾ R .n' o

R ,1^J0^U8^D is selected from the group consisting of hydrogen and Ci-d; alkyl;

R 109 is selected from the group consisting of hydrogen and d-d alkyl;

Rno is selected from the group consisting of hydrogen and

Ci-d alkyl; R^: is selected from the group consisting of hydrogen, Ci-C, alkyl, and C(0)OR¹⁰⁷

R⁵⁵ is selected from the group consisting of hydrogen, Ci-C, alkyl, C (R^r''^'R⁵⁷"R⁵⁷" ' ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR^'7, P0₃H, SO^H, S0-R³ ,

NR^:,9R^b0, NHOR⁶¹, NHCHR^61', CN, NO,, halogen, OR'" , and SR^C'\-

^*R ^b is selected from the group consisting of hydrogen, C.-C. alkyl, C (R⁵'^'R^{5 "}R^57' " ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl,

PO.H, SO,H, SO R^ri, NR⁵⁹R⁶⁰, NHOR⁶¹, NHCHR^61', (d -C₆) alkylNR^R^' , CN, N0 , halogen,

OR¹⁰", CR ^'\ OR⁶², and SR°;

R^h' is selected from the group consisting of hydrogen and C -

Ci: alkyl;

R^57' is selected from the group consisting of hydrogen, halogen, and C]-Cι₂ alkyl;

R^^" is selected from the group consisting of hydrogen, halogen, and d -Cι₂ alkyl ;

R⁵⁷'^" is selected from the group consisting of hydrogen, halogen, and d -C₁₂ alkyl ; R^~>a is selected from the group cons i st ing o f hydrogen and C -

Ci ; alkyl ;

R⁵⁹ is selected from the group consisting of hydrogen, (C,-

C_b) alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC); R^6ϋ is selected from the group consisting of hydrogen and (d-d) alkyl;

R⁶¹ is selected from the group consisting of hydrogen, OR^υ" ,

CH₂NHR⁶\ NHR⁶ and fluorenylmethoxycarbonyl (FMOC);

R^61' is selected from the group consisting of hydrogen, OR^b" ,

NHR⁶⁵' and fluorenylmethoxycarbonyl (FMOC);

R⁶² is selected from hydrogen, and Ci-d alkyl;

R^62' is selected from hydrogen, OH, OR"^', and d-d, alkyl;

R⁶³ is selected from hydrogen and d.-C, alkyl; R^b is selected from the group consisting of hydrogen, (d- d ) alkyl , CH₂NR^6bR⁶⁷ ;

R⁶⁵' is selected from the group consisting of hydrogen and d

Co alkyl, NH₂, and fluorenylmethoxycarbonyl (FMOC) ;

R 65' is selected from the group consisting of hydrogen and

Ci-Cβ alkyl, NH₂, and fluorenylmethoxycarbonyl

R 66 is selected from the group consisting of hydrogen and C

C₆ alkyl and fluorenylmethoxycarbonyl (FMOC) ;

R⁶' is selected from the group consisting of hydrogen and d- d alkyl;

R³ is a lower alkyl group; R is H or OH; R⁵ is H or OH;

R⁴ and R⁵ may be taken together to form a second bond between C_]3 and C₁₄;

R is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkyoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring

(Ci-Cfi) alkyl, (d-d) cycloalkyl, substituted C₃-C₈ cycloalkyl, substituted (Ci- ) alkyl, a group of the formula III'

and a group of the formula III¹':

III R' is selected from the group consisting of NR⁵¹R², R^jNR^M3. ,

OR^'^, H and a lower alkyl group; R^M and R^{' '} arc independently selected from the group consisting of Ci-d alkyl; R^"'¹ is C -

C₃ alkyl; R^B is H or a lower alkyl group; or

R' and R⁸ can form a cyclopropyl ring;

R⁹ is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, lower alkyl-d-d, cycloalkyl, and benzyl; R^j0 is H or a lower alkyl group;

R¹¹ is selected from the group consisting of hydrogen, OH, lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl;

R¹⁵, R^lb, and R¹⁷ are each independently selected from the group consisting of hydrogen, OR¹", halo, NR^18'R^1Q', N0₂,

OP0₃H₂, 0R¹⁹phenyl, SCH.phenyl, CONH,, C0₂H, PO.H. , S0₂R \ and

ZZ;

R^1B is selected from the group consisting of hydrogen, aryl, d-d alkyl, C(0)R⁹⁰ and fluorenylmethoxycarbonyl (FMOC); R^18' is selected from the group consisting of hydrogen, (C - d) alkyl and C (O)R^90' ;

R¹⁹ is Cι~ alkyl, C(0)R⁹"^" and fluorenylmethoxycarbonyl ( FMOC) ;

R^19' is selected from the group consisting of hydrogen, (C-- C_G) alkyl, and C (0) R^90'" ;

R^q°, R^90' , R^90" , and R^90'" are each independently selected from the group consisting of hydrogen, (Ci-C,,) alkyl, OR^91' and aryl;

R^91' is selected from the group consisting of (C]-C_b) alkyl , aryl, and hydrogen;

R²³ is selected from the group consisting of hydrogen and (C,-d) alkyl;

R³⁰ is hydrogen or Cι~C_fi alkyl; or R³⁰ may be taken together with the N at C-11 to form a three to seven membered cyclic ring;

R⁵⁰ is hydrogen or

n is 0, 1, or 2;

p is 0, 1 , or 2;

X is selected from the group consisting of O, C, S, NH and alkylamino;

Y is selected from the group consisting of C, 0, NH, S, SO,

SO; and alkylamino;

Z is selected fromt he group consisting of -(CH,),,-, -(CH, ) -

0-(CH₂),_r- and (d-d) cycloalkyl;

2. A compound of Claim 1 wherein the compound of

Formula III is defined as follows:

wherein

Ar is phenyl or any simple unsubstituted or substituted aromatic or heteroaromatic group, C₁-C₁₂ alkyl, C₁-C₁₂ alkene, C₁-C₁₂ alkyne, NR⁵¹R⁵², OR⁵³, Formula Ar '

R⁵¹ is selected from the group consisting of hydrogen and

C₁-C3 alkyl;

R⁵² is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

R⁵³ is selected from the group consisting of C₁-C₁₂ alkyl ^•

R⁵⁴ is selected from the group consisting of hydrogen, C|-C alkyl, simple aromatic, phenyl, COOR⁵⁷, PO₃H, SO₃H, S0₂R^5£ ,

NR⁵⁹R⁶⁰, NHOR⁶¹, NHCHR⁶¹', CN, N0₂, halogen, OR⁶², and SR⁶³; R⁵⁵ is selected from the group consisting of hydrogen, Cχ-C₀ alkyl, simple aromatic, phenyl, COOR⁵⁷, PO₃H, SO₃H, S0₂R⁵⁸,

NR⁵⁹R⁶⁰, NHOR⁶¹, NHCHR⁶¹', CN, N0₂, halogen, OR⁶², and SR⁶³;

R⁵⁶ is selected from the group consisting of hydrogen, Ci-Cβ alkyl, simple aromatic, phenyl, COOR⁵⁷, PO₃H, SO3H, S0₂R⁵ , NR⁵⁹R⁶⁰, NHOR⁶¹, NHCHR⁶¹', CN, N0₂, halogen, OR⁶^, and SR^6Ξ ;

R⁵⁷ is selected from the group consisting of hydrogen and

C₁-C₁₂ alkyl;

R⁵⁸ is selected from the group consisting of hydrogen and

C1-C12 alkyl; R⁵⁹ is selected from the group consisting of hydrogen, (Cj.-

Cς, ) alkyl and fluorenylmethoxycaronyl (FMOC);

R⁶⁰ is selected from the group consisting of hydrogen and (Cι-C₆) alkyl;

R⁶¹ is selected from the group consisting of hydrogen, OR⁶⁴, CH₂NHR⁶⁵, NHR⁶⁵ and fluorenylmethoxycaronyl (FMOC);

R⁶¹' is selected from the group consisting of hydrogen, OR⁶⁴, CH₂NHR⁶⁵, NHR⁶⁵ and fluorenylmethoxycaronyl (FMOC) ; R⁶² is selected from hydrogen and Cχ-C₆ alkyl; R⁶³ is selected form hydrogen and Ci-Cβ alkyl; R⁶⁴ is selected from the group consisting of hydrogen, (C|- C₆) alkyl, CH₂NR⁶⁶R⁶⁷ R⁶⁵ is selected from the group consisting of hydrogen and

Ci-C_δ alkyl, NH₂, and fluorenylmethoxycaronyl (FMOC) ;

R⁶⁶ is selected from the group consisting of hydrogen and

Ci-Ce alkyl and fluorenylmethoxycaronyl (FMOC);

R⁶⁷ is selected from the group consisting of hydrogen and

Cι-C₆ alkyl;

R³ is a lower alkyl group;

R⁴ is H or OH;

R⁴ and R⁵ may be taken together to form a second bond between C₁₃ and C₁₄;

R⁶ is selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl , or dihaloalkoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B- ring (Ci-Cβ) alkyl, (C₃-C₈) cycloalkyl, substituted C3-C8 cycloalkyl, substituted (Ci-Cβ) alkyl, a group of the formula III' :

' and a group of the formula III

",

R⁷ is H or a lower alkyl group;

R⁸ is H or a lower alkyl group;

R⁹ is H or a lower alkyl group;

R¹⁰ is H or a lower alkyl group;

R¹¹ is selected from the group consisting of H, OH, simple alkyl, phenyl, substituted phenyl, benzyl, and substituted benzyl; R¹⁵, R¹⁶, and R¹⁷ are each independently selected from the group consisting of hydrogen, (C₁-C₆) lkyl , OR¹⁸, halo, NR¹⁸'R¹⁹', N0₂, OPO₄H₂, OR¹⁹phenyl, SCH₂phenyl, CONH₂, C0₂H, PO₃H₂, S0₂R²³, and ZZ; R¹⁸ is selected from the group consisting of hydrogen, aryl, and C₁-C6 alkyl; R¹⁸' is selected from the group consisting of hydrogen and

(Ci-Ce) alkyl; R¹⁹ is Ci-Cβ alkyl; R¹⁹' is selected from the group consisting of hydrogen and

(Ci-Ce) alkyl; R²³ is selected from the group consisting of hydrogen and

(C1-C3) alkyl; R³⁰ is hydrogen or Ci-Cβ alkyl;

R⁵⁰ is hydrogen or

; n is 0, 1 , or 2

m is 0, 1 , or 2

X is 0, NH or alkylamino;

Y is C, 0, NH, S, SO, S0₂ or alkylamino;

Z is selected from the group consisting of -(CH₂)_n~/

- (CH₂)_p-0- (CH₂)_m- and (C₃-C₅) cycloalkyl ;

ZZ is selected from the group consisting of an aromatic group and a substituted aromatic group; or a pharmaceutically acceptable salt thereof.

3. A compound of Claim 1 wherein Ar is selected from the group consisting of phenyl, aromatic, or simple substituted aromatic.

4. A compound of Claim 2 wherein Ar is a parafluoro substituted phenyl ring.

5. A compound of Claim 1 wherein R ^> is hydrogen,

R⁷ and R⁸ are each methyl, X is 0, Y is 0, and R^ϋ is a group

of the formula Λ

6. A compound of Claim 1 wherein R Hi is hydrogen, one of R⁷ and R⁸ is methyl, X is 0, Y is 0, and R^rf is a.

group of the formuil.a

7. A process for preparing a compound of Formula II

wherein

Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, d-d_ alkyl, C_-C . alkenyl, C₂-C_ι2 alkynyl, NR⁵¹R^r' , COR^, 0R^'\ and Formula Ar'

R is selected from the group consisting of hydrogen and C - d alkyl;

R^j2 is selected from the group consisting of hydrogen and C - d alkyl;

R⁵³ is selected from the group consisting of Cι-C_ι? alkyl;

R⁵⁴ is selected from the group consisting of hydrogen, C -C alkyl, d-C₆alkyl (R^57'R^57"R^57'") , simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4- ( ert-butyldimethylsiloxy) - benzyltriphenylphosophonium, COOR' , POjH, S0₃H, SO-R , N(R ⁾)R ⁰, NHOR⁶¹, NHCHR^61', CN, NO.., halogen, OR⁶', CH_r(0)R^62'

R¹'

CH_?OC CH₂N(R^9b)R^9b' ,COR^lϋn, (d-d alkyl ) OR¹⁰", , and

SR⁶²; R^9'J is selected from the group consisting of -R^'"NH ;

R^9b and R^96' are each independently selected from the group consisting of hydrogen and Ci-d alkyl, -R⁹'NH₍, and -R⁹⁹ NR⁹"^'

R^9'" ^' ;

R⁹⁷ is selected from the group consisting of Ci-d alkyl; R^9B is selected from the group consisting of Ci-d alkyl;

R⁹⁹ is Ci-C,. alkyl;

R^99' and R^9<1" are each independently selected from the group consisting of hydrogen and Ci-d alkyl;

R¹⁰⁰ is selected from the group consisting of hydrogen, ard Si(R^ιnιR¹⁰R¹⁰³);

R¹⁰¹ is Ci-d alkyl;

R^lo: is Ci-d, alkyl;

R¹⁰³ is Ci-d alkyl;

R¹⁰⁴ is selected from the group consisting of C(0)C.-C, alkylN(R^κ"') (R^', )R^f°, C(0)Cι-C„ alkylN^f, fused bicyclic, and

NHR¹⁰⁵N(R¹⁰⁶) (R^'j9)R ^(l;

R^10'' is selected from the group consisting of C(0)d-d alkyl, d-d alkyl;

R¹⁰⁶ is selected from the group consisting of hydrogen, C,-C alkyl, C(0)0R¹⁰⁷;

R¹⁰' is selected from the group consisting of hydrogen, Ci-C. alkyl, CR¹⁰⁸ R¹⁰⁹ R¹¹⁰

R¹⁰⁸ is selected from the group consisting of hydrogen and

Cι-C_b alkyl; R^loq is selected from the group consisting of hydrogen and

Ci-d alkyl; R¹¹⁰ is selected from the group consisting of hydrogen and

Ci- alkyl;

R"⁵ is selected from the group consisting of hydrogen, C-,-C, alkyl, C (R ^7'R^57"R-'^7' " ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR⁵⁷, P0₃H, SO,H, S0₂R^i,β,

NR⁵⁹R⁶⁰, NHOR⁶¹, NHCHR^61', CN, N0₂, halogen, OR⁶², and SR^υ";

R ^€ is selected from the group consisting of hydrogen, Ci-C, alkyl, C ( R^^' R^{51 "} R^{^}'^{1 "} ' ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR^5'1, PdH, S0₃H, S0₂R^5H, NRⁱR⁶°, NHOR⁶¹, NHCHR^61', (d-C₆) alkylNR⁵⁹R⁶⁰, CN, N0₂, halogen,

OR¹⁰⁴, CR¹⁰\ OR⁶², and SR⁶³;

R⁵⁷ is selected from the group consisting of hydrogen and C--

C₁₂ alkyl;

R^57' is selected from the group consisting of hydrogen, halogen, and C1-C12 alkyl;

R⁵'^" is selected from the group consisting of hydrogen, halogen, and Cι-C_T2 alkyl;

R^{^'"} is selected from the group consisting of hydrogen, halogen, and Cι-Cι₂ alkyl; R⁵⁸ is selected from the group consisting of hydrogen and C--

Ci; alkyl;

R^*13 is selected from the group consisting of hydrogen, (d-

C₆) alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC); R^oC is selected from the group consisting of hydrogen and

(d-d) alkyl;

R⁶¹ is selected from the group consisting of hydrogen, OR⁶⁴,

NHR⁶ and fluorenylmethoxycarbonyl (FMOC);

R^61' is selected from the group consisting of hydrogen, OR^6'1,

NHR^65' and fluorenylmethoxycarbonyl (FMOC);

R⁶² is selected from hydrogen, and Cι-C_c alkyl;

R^62' is selected from hydrogen, OH, OR^b2, and Ci-C,-, alkyl;

R⁶³ is selected from hydrogen and C_:-C,; alkyl; R64 is selected from the group consisting of hydrogen, (Ci d) alkyl, CH_?NR^b6R⁶

R^b is selected from the group consisting of hydrogen and C - d alkyl, NH_?, and fluorenylmethoxycarbonyl (FMOC);

R⁶ is selected from the group consisting of hydrogen and

Cι-C₆ alkyl, NH , and fluorenylmethoxycarbonyl (FMOC);

R^6<r is selected from the group consisting of hydrogen and C - d alkyl and fluorenylmethoxycarbonyl (FMOC);

R⁶⁷ is selected from the group consisting of hydrogen and C - d alkyl;

R * I S a lower alkyl group ;

R⁴ is H or OH;

R⁴ and R⁵ may be taken together to form a second bond between d< and d„;

R^b is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl , halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkyoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring

(Ci-d) alkyl, (d-C_n) cycloalkyl , substituted d-C_H cycloalkyl, substituted (Cι~C_b) alkyl, a group of the formula III'

and a group of the formula III''

III R' is selected from the group consisting of NR^slR^rι2, R^,J,NR⁵¹R^' ,

OR", H and a lower alkyl group; R^M and R^^*' are independently selected from the group consisting of - alkyl; R" is C--

C₃ alkyl; R° is H or a lower alkyl group; or

R' and R⁸ can form a cyclopropyl ring;

R⁹ is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, lower alkyl-d-d cycloalkyl, and benzyl; R¹⁰ is H or a lower alkyl group;

R¹⁵, R"⁶, and R¹⁷ are each independently selected from the group consisting of hydrogen, OR¹⁸, halo, NR^lh"R^1< , N0₂,

OP0₃H₂, OR^1?phenyl, SCH₂phenyl, CONH_., CO.-H, P0₃H₂,

and

ZZ;

R^lβ is selected from the group consisting of hydrogen, aryl,

Ci-d alkyl, C(0)R⁹⁰ and fluorenylmethoxycarbonyl (FMOC); R^18' is selected from the group consisting of hydrogen, (C,-

Cc) alkyl and C(0)R^90';

R¹⁹ is Ci-d alkyl, C(0)R⁹ⁿ" and fluorenylmethoxycarbonyl

( FMOC) ;

R^19' is selected from the group consisting of hydrogen, (d- C₆) alkyl, and C(0)R^90"';

R⁹⁰, R^90' , R^90" , and R^{90' "} are each independently selected from the group consisting of hydrogen, (d-d,) alkyl , OR⁹'^' and aryl;

R^91' is selected from the group consisting of (Ci-C alkyl, aryl, and hydrogen;

R²³ is selected from the group consisting of hydrogen and

(d-d) alkyl;

R³⁰ is hydrogen or Cι~C₆ alkyl ; or R³⁰ may be taken together with the N at C-11 to form a three to seven membered cyclic ring;

R⁵⁰ is hydrogen or

n is 0, 1, or 2; m is O, 1, or 2 ; p is 0, 1 , or 2;

X is selected from the group consisting of O, C, S, NH and alkylamino;

Y is selected from the group consisting of C, 0, NH, S, SO, S0₂ and alkylamino;

Z is selected fromt he group consisting of -(CH₂),,-, -(CH )_:- 0-(CH )_n- and (d-d,) cycloalkyl;

with a solvent and a catalyst of the formula IV

_ιy wherein M is selected from the group consisting of hydrogen, Na, Li, K, and Cs;

X^cat is selected from the group consisting of O, N, and S; y^cat __s selected from the group consisting of 0, N, and S;

R^catl __s selected from the group consisting of Cj_.- C Q alkyl and aryl;

R^cat2 is selected from the group consisting of Cι~ C₆ alkyl and aryl.

8. A process of Claim 7 wherein the solvent is selected from the group consisting of toluene, N,N- dimethylformamide, ethyl acetate, tertrahydrofuran and acetonitrile .

9. A process of Claim 7 wherein the Formula II compound is defined as follows

wherein

Ar is phenyl or any simple unsubstituted or substituted aromatic or heteroaromatic group, C]_-Cι alkyl, C₁-C₁₂ alkene, C₁-C₁₂ alkyne, NR⁵¹R⁵², OR⁵³, Formula Ar '

R⁵¹ is selected from the group consisting of hydrogen and

C1-C₃ alkyl;

R⁵² is selected from the group consisting of hydrogen and

C1-C3 alkyl;

R⁵³ is selected from the group consisting of C1-C12 alkyl;

R⁵⁴ is selected from the group consisting of hydrogen, d-Co alkyl, simple aromatic, phenyl, COOR⁵⁷, PO₃H, SO₃H, S0₂R^5e ,

_NR5⁹ _R ⁶⁰ _/ NHOR⁶¹, NHCHR⁶¹', CN, N0₂, halogen, OR⁶², and SR⁶³;

R⁵⁵ is selected from the group consisting of hydrogen, Cj.-Cc alkyl, simple aromatic, phenyl, COOR⁵⁷, P0₃H, SO₃H, S0₂R^b ,

R⁵⁶ is selected from the group consisting of hydrogen, C₁-C0 alkyl, simple aromatic, phenyl, COOR⁵⁷, PO₃H, SO₃H, S0₂R⁵ , NR⁵⁹R⁶⁰, NHOR⁶¹, NHCHR⁶¹', CN, N0₂, halogen, OR⁶², and SR^6Ξ;

R⁵⁷ is selected from the group consisting of hydrogen anc.

C1-C12 alkyl;

R⁵⁸ is selected from the group consisting of hydrogen and

C1-C12 alkyl; R⁵⁹ is selected from the group consisting of hydrogen, (C^'ι-

Cβ) alkyl and fluorenylmethoxycaronyl (FMOC);

R⁶⁰ is selected from the group consisting of hydrogen and (Cι-C₆) alkyl;

R⁶¹ is selected from the group consisting of hydrogen, OR⁶⁴, CH₂NHR⁶⁵, NHR⁶⁵ and fluorenylmethoxycarony i (FMOC);

R⁶¹' is selected from the group consisting of hydrogen, OR⁶⁴, CH₂NHR⁶⁵, NHR⁶⁵ and fluorenylmethoxycaronyl (FMOC); R⁶² is selected from hydrogen and Ci-C_δ alkyl; R⁶³ is selected form hydrogen and Ci-Ce alkyl;

R⁶⁴ is selected from the group consisting of hydrogen, C₆) alkyl, CH₂NR⁶⁶R⁶⁷ R⁶⁵ is selected from the group consisting of hydrogen and

Ci-Cβ alkyl, NH₂, and fluorenylmethoxycaronyl (FMOC);

R⁶⁶ is selected from the group consisting of hydrogen and

Cι~C₆ alkyl and fluorenylmethoxycaronyl (FMOC);

R⁶⁷ is selected from the group consisting of hydrogen and

C₁-C6 alkyl;

R³ is a lower alkyl group;

R⁴ is H or OH;

R⁵ is H or OH;

R⁴ and R⁵ may be taken together to form a second bond between C ₃ and Cι ;

R⁶ is selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, fi^¬ ring (Ci-C_δ) alkyl, (C₃-C₈) cycloalkyl , substituted C3-C8 cycloalkyl, substituted (Ci-C_δ) alkyl, a group of the formula III* :

' and a group of the formula III

",

R⁷ is H or a lower alkyl group;

R⁸ is H or a lower alkyl group;

R⁹ is H or a lower alkyl group;

R¹⁰ is H or a lower alkyl group;

R¹¹ is selected from the group consisting of H, OH, simple alkyl, phenyl, substituted phenyl, benzyl, and substituted benzyl; R¹⁵, R¹⁶, and R¹⁷ are each independently selected from the group consisting of hydrogen, (Ci-Cβ) alkyl , OR¹⁸, halo, NR¹⁸'R¹⁹', N0₂, OP0 H₂, 0R¹⁹phenyl, SCH₂phenyl, CONH₂, C0₂H, P0₃H₂, S0₂R²³, and ZZ; R¹⁸ is selected from the group consisting of hydrogen, aryi, and Ci-Cβ alkyl; R¹⁸' is selected from the group consisting of hydrogen and

(Ci-Ce) alkyl; R¹⁹ is Cι-C₆ alkyl; R¹⁹' is selected from the group consisting of hydrogen and

(Cι-C₆) alkyl;

R²³ is selected from the group consisting of hydrogen and

(C1-C₃) alkyl; R³⁰ is hydrogen or Ci-Cβ alkyl;

R⁵⁰ is hydrogen or

; n is 0, 1, or 2; p is 0, 1, or 2;

q is 2, 3, or 4; X is O, NH or alkylamino;

Y is C, 0, NH, S, SO, S0₂ or alkylamino;

Z is selected from the group consisting of -(CH₂)n^~>

- (CH₂)_p-0- (CH₂)_m- and (C3-C5) cycloalkyl;

ZZ is selected from the group consisting of an aromatic group and a substituted aromatic group.

10. A process of Claim 7 wherein the solvent is toluene .

11. A process of Claim 7 wherein Ar is aromatic or substituted aromatic.

12. A process of Claim 7 wherein R³' is hydrogen,

R⁷ and R^b are each methyl, X is 0, Y is 0, and R^c ' is a group

of the formula Λ

13. A process of Claim 7 wherein R is hydrogen, one of R' and R⁸ is methyl, X is 0, Y is 0, and Rⁿ is a

group of the formula A