Synthetic techniques and intermediates for polyhydroxy, dienyl lactone derivatives

Synthetic methods for lactone-containing compounds such as the discodermolides are provided, as are compounds which mimic the chemical and/or biological activity thereof, and methods and intermediates useful in their preparation.

FIELD OF THE INVENTION
 This invention relates to lactone-containing compounds such as
 discodermolide, to compounds which mimic the chemical and/or biological
 activity thereof, and to methods and intermediates useful in their
 preparation.
 BACKGROUND OF THE INVENTION
 In 1990, Gunasekera and co-workers at the Harbor Branch Oceanographic
 Institute reported the isolation of (+) -discodermolide (1), an
 architecturally novel metabolite of the marine sponge Discodermia
 dissoluta (0.002% w/w). (See, Gunasekera, et al., J. Org. Chem. 1990, 55,
 4912. Correction: J. Org. Chem. 1991, 56, 1346).
 ##STR1##
 Initial studies revealed that (+)-discodermolide suppresses both the
 two-way mixed-lymphocyte reaction and the concanavalin A-induced
 mitogenesis of murine splenocytes in vitro with no associated
 cytotoxicity. Moreover, (+)-1 suppresses the in vivo graft-vs.-host
 splenomegaly response induced by injection of parental splenocytes into F1
 recipient mice, with potency intermediate between those of cyclosporin A
 and FK506. (Longley, et al., Transplantation 1991, 52, 650; Longley, et
 al., Transplantation 1991, 52, 656; Longley, et al. Ann. N.Y. Acad. Sci.
 1993, 696, 94). These findings stimulated the recent discovery that (+)-1
 arrests cell development at the M phase by binding and stabilizing mitotic
 spindle microtubules; thus discodermolide resembles taxol in its mode of
 action, but the microtubule binding affinity of 1 is much higher. (ter
 Haar, et al., Biochemistry 1996, 35, 243; Hung, et al., Chemi. & Biol.
 1996, 3, 287). These and other results suggest that (+)-discodermolide
 holds considerable promise as an anticancer agent. The scarcity of natural
 material however has precluded a complete evaluation of its biological
 profile.
 The absolute configuration of discodermolide remained undefined until
 Schreiber et al. synthesized both antipodes of 1. (Nerenberg, et al. J.
 Am. Chem. Soc. 1993, 115, 12621; Hung, et al., Chem. & Biol. 1994, 1, 67).
 Interestingly, the unnatural (-) antipode also displays significant
 immunosuppressant activity.
 There is, therefore, a need for improved synthetic methods for the
 preparation of polyhydroxy, dienyl lactones such as the discodermolides,
 as well as a need for compounds having similar chemical and/or biological
 activity.
 OBJECTS OF THE INVENTION
 It is one object of the present invention to provide polyhydroxy, dienyl
 lactones and mimics thereof.
 It is a further object to provide processes for the preparation of such
 compounds and their mimics.
 It is another object of this invention to provide intermediates useful in
 such processes.
 SUMMARY OF THE INVENTION
 These and other objects are satisfied by the present invention, which, in
 one aspect, provides synthetic methods for the discodermolides and other
 polyhydroxylactones. In preferred embodiments, such methods involve
 contacting a phosphonium salt of formula I:
 ##STR2##
 with base and an alkylthiol of formula II:
 ##STR3##
 to form a diene of formula III:
 ##STR4##
 wherein:
 R.sub.1, R.sub.2, R.sub.3, R.sub.7, R.sub.8, R.sub.11, R.sub.12 and
 R.sub.13 are, independently, C.sub.1 -C.sub.10 alkyl;
 R.sub.6 is H or C.sub.1 -C.sub.10 alkyl;
 X is a halogen;
 Z, Z.sub.1, and Z.sub.2 are, independently, O, S or NR';
 R.sub.4, R.sub.9, R.sub.14, and R.sub.15 are, independently, acid labile
 hydroxyl protecting groups;
 R.sub.5 is C.sub.6 -C.sub.14 aryl;
 Y is O, S or NR';
 R' and R.sub.16 are, independently, hydrogen or C.sub.1 -C.sub.6 alkyl; and
 R.sub.18 is C.sub.6 -C.sub.14 aryl.
 In another embodiment, compounds of formula I are contacted with compounds
 of the following formula XXIII:
 ##STR5##
 to form a diene of formula XXXXX:
 ##STR6##
 In another aspect, the methods of the invention involve producing an alkene
 of formula IV.
 ##STR7##
 This can be accomplished by contacting an organometallic reagent of formula
 Va:
 ##STR8##
 with a vinyl halide of formula VIa:
 ##STR9##
 wherein M is Li, Cu, Mg, or Zn and R.sub.10 is an acid stable hydroxyl
 protecting group and all other variables are as defined above.
 Alternatively, a vinyl halide of formula Vb:
 ##STR10##
 can be contacted with an organometallic compound of formula VIb:
 ##STR11##
 In yet another aspect, the methods of the invention involve compounds
 having formula VII.
 ##STR12##
 by contacting a diene of formula VIIIa:
 ##STR13##
 with an organometallic compound having formula Va wherein R.sub.24 is
 hydrogen and R.sub.25 is hydrogen or an acid stable hydroxyl protecting
 group. Alternatively, an organometallic compound having formula VIIIb can
 be contacted with a vinyl halide having formula Vb.
 ##STR14##
 The methods of the invention also involve producing dienes having formula
 VIIIa by contacting phosphonium salts having formula IX:
 ##STR15##
 with base and alkylthiol compounds having formula II.
 The present invention also provides synthetic intermediates which are
 useful in the preparation of polyhydroxylactones, including the compounds
 having formulas I-IX and X:
 ##STR16##
 wherein:
 R.sub.19, R.sub.20, R.sub.21 and R.sub.22 are, independently, C.sub.1
 -C.sub.10 alkyl; and
 R.sub.23 is C.sub.7 -C.sub.15 aralkyl.
 The present invention also provides compounds which mimic the chemical
 and/or biological activity of the discodermolides. In preferred
 embodiments, such compounds have formula XI:
 ##STR17##
 where
 R.sub.30 is substituted or unsubstituted C.sub.1 -C.sub.10 alkyl or a
 moiety formula XII or XIII:
 ##STR18##
 where A is C.sub.1 -C.sub.20 alkyl, --CH.sub.2 NH(T) or a moiety of formula
 XIV:
 ##STR19##
 wherein
 T is peptide having 1 to about 10 amino acids;
 R.sub.32, R.sub.40, R.sub.42, R.sub.43, R.sub.46, R.sub.47, and R.sub.48
 are, independently, hydrogen or C.sub.1 -C.sub.6 alkyl;
 R.sub.41 is a side chain of an amino acid;
 W.sub.1 and W.sub.2 are, independently, --OR.sub.49 or --NHP.sub.1 ;
 P.sub.1 is hydrogen or an amine protecting group;
 R.sub.33 and R.sub.36 are, independently, hydrogen, C.sub.1 -C.sub.10
 alkyl, --OR.sub.50, .dbd.O or together form --CH.sub.2 --CH.sub.2 --;
 R.sub.34 and R.sub.35 are, independently, hydrogen or together form
 --C(H).dbd.C(H)--C(H).dbd.C(H)--;
 R.sub.39 is --OR.sub.51 or --CH.sub.2 --R.sub.51 ;
 R.sub.31 and R.sub.44 are, independently, C.sub.1 -C.sub.10 alkyl;
 Q.sub.1 and Q.sub.2 are, independently, hydrogen, --OR.sub.Q, --NHR.sub.52,
 --OC(.dbd.O)NH.sub.2 or together form --O--C(O)--NH--;
 R.sub.Q is hydrogen or a hydroxyl protecting group;
 R.sub.51 is substituted or unsubstituted C.sub.6 -C.sub.14 aryl,
 tetrahydropyranyl, furanosyl, pyranosyl (e.g., tetramethylfucosyl,
 tetramethylmannosyl, tetramethylgaractosyl and tetramethylglucosyl),
 C.sub.3 -C.sub.10 lactonyl or 2-pyranonyl;
 R.sub.45 is C.sub.1 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkyl, C.sub.6
 -C.sub.14 aryl, C.sub.2 -C.sub.10 heterocycloalkyl, C.sub.3 -C.sub.10
 cycloalkyl, or C.sub.7 -C.sub.15 aralkyl; and
 R.sub.49, R.sub.50, and R.sub.52 are, independently, hydrogen or C.sub.1
 -C.sub.6 alkyl.
 In another aspect, the present invention provides processes for preparing
 amides having formula XX:
 ##STR20##
 wherein Ar is C.sub.6 -C.sub.14 aryl comprising the steps of contacting a
 compound having formula XXI:
 ##STR21##
 with a compound having formula XXII:
 ##STR22##
 for a time and under conditions effective to form the amide.
 Also provided are processes for producing compounds of formula XXIII:
 ##STR23##
 comprising the steps of contacting an aldehyde of formula XXIV:
 ##STR24##
 with an enol ether of formula XXV:
 ##STR25##
 in the presence of a titanium salt for a time and under conditions
 effective to form an enone of formula XXVI:
 ##STR26##
 Such enones are then contacted with a reducing agent for a time and under
 conditions effective to form a corresponding enol, which is contacted with
 a compound having formula R-L (wherein L is a leaving group) for a time
 and under conditions effective to form a protected enol. This protected
 enol is contacted with an oxidizing agent for a time and under conditions
 effective to oxidize the carbon--carbon double bond of the protected enol.
 The invention also provides processes for producing halogenated olefins of
 formula XXVII:
 ##STR27##
 by contacting an aldehyde of formula XXVIII:
 ##STR28##
 with an .alpha.-halo sulfone of formula XXIX:
 ##STR29##
 for a time and conditions effective to from the halogenated olefin.
 Also provided are processes for producing halogenated olefins of formula
 XXX:
 ##STR30##
 comprising the steps of contacting a compound of formula XXXI:
 ##STR31##
 with triphenylphosphine and a carbon tetrahalide for a time and under
 conditions effective to form a dihalogenated olefin of formula XXXII:
 ##STR32##
 Such a dihalogenated olefin is contacted with an organometallic compound
 (such as lithium dimethyl cuprate or an alkylzinc compound such as methyl
 zinc chloride or methyl zinc bromide) in the presence of a catalyst for a
 time and under conditions effective to form the halogenated olefin.
 Additional processes of the invention are directed to synthesis of dienes
 of formula XXXIII:
 ##STR33##
 comprising contacting a phosphonium salt of formula XXXIV:
 ##STR34##
 with a base and a compound of formula XXXV.
 ##STR35##
 for a time and under conditions effective to form the diene.
 The invention also provides processes for producing a compound of formula
 XXXVI:
 ##STR36##
 comprising contacting a compound of the formula XXXVII:
 ##STR37##
 wherein J is C.sub.1 -C.sub.10 alkyl, C.sub.6 -C.sub.14 aryl, C.sub.2
 -C.sub.10 heterocycloalkyl. or C.sub.2 -C.sub.10 heterocycloalkenyl
 (preferably 4-methoxyphenyl, 4-hydroxyphenyl, 2-pyridyl, 3-pyridyl, or
 4-pyridyl) with a phosphonium salt of formula XXXIV:
 ##STR38##
 and base.
 The invention also provides synthetic intermediates having formulas
 XXXIII-XXXXV:
 ##STR39##
 ##STR40##
 The present invention also provides methods for inhibiting mammalian cell
 proliferation by contacting mammalian cells with a compound according to
 the invention or by administering a compound according to the invention
 (or a pharmaceutical composition comprising such a compound) to a mammal
 suffering from undesired cell proliferation. Also provided are methods for
 inhibiting rejection of a transplanted organ in a mammal comprising
 administering a compound or composition according to the invention to a
 mammalian organ recipient.
 The present invention also provides process for forming a halogenated
 olefin of formula:
 ##STR41##
 wherein:
 R.sub.6 is selected from H and C.sub.1 -C.sub.6 alkyl;
 R.sub.7 and R.sub.8 are independently C.sub.1 -C.sub.10 alkyl;
 R.sub.9 is an acid labile hydroxyl protecting group;
 R.sub.10 is a protecting group labile to DDQ; and,
 X is halogen;
 the process comprising contacting an aldehyde of formula:
 ##STR42##
 with a compound of formula R.sub.6 (R.sub.18).sub.3 PX and X.sub.2 in the
 presence of base, wherein R.sub.18 is C.sub.6 -C.sub.14 aryl, for a time
 and conditions effective to form the halogenated olefin.
 The present invention also provides a process for forming a triene of
 formula:
 ##STR43##
 wherein:
 R.sub.1, R.sub.2, R.sub.7, and R.sub.8 are independently C.sub.1 -C.sub.10
 alkyl;
 R.sub.3 and R.sub.6 are independently selected from hydrogen and C.sub.1
 -C.sub.6 alkyl;
 R.sub.4 and R.sub.9 are independently acid labile hydroxyl protecting
 groups;
 R.sub.25 is an acid stable hydroxyl protecting group; and
 R.sub.10 is a hydroxyl protecting group;
 the process comprising contacting an aldehyde of formula:
 ##STR44##
 with a compound of formula Ph.sub.2 PCH.sub.2 CH.dbd.CH.sub.2 in the
 presence of a base and a compound of formula Ti(O--R.sub.27).sub.4,
 wherein R.sub.27 is C.sub.1-6 alkyl; followed by treatment with R.sub.28 X
 wherein R.sub.28 is C.sub.1-6 alkyl and X is a halogen, for a time and
 under conditions effective to form the triene.
 The present invention also provides a process comprising contacting a
 triene of formula:
 ##STR45##
 with a compound of formula:
 ##STR46##
 wherein X is a first halogen and R.sub.26 is selected from C.sub.6-14 aryl
 and C.sub.1-6 alkyl, to form a triene alcohol of formula:
 ##STR47##
 and;
 contacting the triene alcohol with Y.sub.2 in the presence of
 P(R.sub.18).sub.3 and a base, wherein R.sub.18 is C.sub.6-14 aryl and Y is
 a second halogen, under conditions to form a compound of formula:
 ##STR48##
 The present invention also provides a process of forming an aldehyde of
 formula:
 ##STR49##
 the process comprising contacting a compound of formula:
 ##STR50##
 wherein:
 R.sub.1, R.sub.2, R.sub.7, and R.sub.8 are independently C.sub.1 -C.sub.10
 alkyl;
 R.sub.3 and R.sub.6 are independently selected from hydrogen and C.sub.1
 -C.sub.6 alkyl;
 R.sub.4 and R.sub.9 are independently acid labile hydroxyl protecting
 groups; and
 R.sub.10 is a trityl group;
 with hydride to form an alcohol of formula:
 ##STR51##
 oxidizing the alcohol to form the aldehyde.
 The present invention also provides a process for forming a tetraene of
 formula:
 ##STR52##
 wherein:
 R.sub.1, R.sub.2, R.sub.7, and R.sub.8 are independently C.sub.1 -C.sub.10
 alkyl;
 R.sub.3, R.sub.6, and R.sub.16 are independently selected from hydrogen and
 C.sub.1 -C.sub.6 alkyl;
 R.sub.4 and R.sub.9 are independently an acid labile hydroxyl protecting
 group;
 R.sub.25 is an acid stable hydroxyl protecting group; and
 J is selected from:
 ##STR53##
 wherein R.sub.32 is C.sub.1 -C.sub.6 alkyl and R.sub.33 is an acid labile
 hydroxyl protecting group;
 the process comprising contacting a compound of the formula:
EQU J-CHO
 with a phosphonium salt of the formula:
 ##STR54##
 wherein R.sub.18 is C.sub.6 -C.sub.14 aryl, in the presence of a base for a
 time and under conditions effective to form the tetraene.
 The present invention also provides a process for forming a tetraene of
 formula:
 ##STR55##
 wherein:
 R.sub.1, R.sub.2, R.sub.7 and R.sub.8 are independently C.sub.1 -C.sub.10
 alkyl;
 R.sub.3, R.sub.6, and R.sub.16 are independently selected from hydrogen and
 C.sub.1 -C.sub.6 alkyl; and
 J is selected from:
 ##STR56##
 ##STR57##
 wherein R.sub.32 is C.sub.1 -C.sub.6 alkyl and R.sub.33 is H;
 the process comprising contacting an alcohol of formula:
 ##STR58##
 wherein R.sub.4, R.sub.9, and R.sub.33 are acid labile hydroxyl protecting
 groups, with an isocyanate of the formula:
EQU X.sub.3 CC(.dbd.O)NCO
 wherein X is a halogen, to form a carbamate intermediate;
 contacting the carbamate intermediate with neutral alumina to form a
 carbamate of formula:
 ##STR59##
 and;
 removing the acid labile hydroxyl protecting groups by contacting the
 carbamate with acid in a protic solvent to form the tetraene.
 The present invention also provides several processes for forming an
 alcohol of formula:
 ##STR60##
 In one process, the process comprises contacting a compound of formula:
 ##STR61##
 with a compound of formula:
 ##STR62##
 wherein R.sub.25 is an acid stable protecting hydroxyl protecting group,
 and R.sub.35 is selected from C.sub.4 alkyl and a halogen, in the presence
 of a metal coupling catalyst for a time and under conditions effective to
 form a coupling product of formula:
 ##STR63##
 and deprotecting the coupling product to form the alcohol.
 In another process, the alcohol is formed by contacting a compound of
 formula:
 ##STR64##
 wherein:
 R.sub.25 is an acid stable protecting hydroxyl protecting group;
 R.sub.35 is selected from CH.sub.2 P(R.sub.18).sub.3 X, CHO,
 --P(.dbd.O)Ph.sub.2, and
 ##STR65##
 X is a halogen; and
 R.sub.18 is C.sub.6-14 aryl;
 with a compound of formula:
EQU J-R.sub.35
 in the presence of a base to form a coupling product of formula:
 ##STR66##
 and deprotecting the coupling product to form the alcohol.
 The present invention also provides a process for forming an alcohol of
 formula:
 ##STR67##
 wherein:
 R.sub.7 and R.sub.8 are independently C.sub.1 -C.sub.10 alkyl;
 R.sub.10 is an acid stable hydroxyl protecting group;
 R.sub.34 is selected from (CH.sub.2).sub.n C.sub.6 -C.sub.14 aryl and
 (CH.sub.2 OCH.sub.2)C.sub.6 -C.sub.14 aryl, wherein the aryl is
 substituted with 0-3 R.sub.35 ;
 R.sub.35 is selected from F, CF.sub.3, Br, Cl, and NO.sub.2 ; and
 n is selected from 0 and 1;
 the process comprising contacting a compound of formula:
 ##STR68##
 with the enolate of a compound of formula:
 ##STR69##
 in the presence of Lewis acid for a time and under conditions effective to
 form the alcohol.
 The present invention also provides intermediate compounds of formula:
 ##STR70##
 wherein:
 R.sub.6 is C.sub.1 -C.sub.4 alkyl;
 R.sub.7 and R.sub.8 are independently C.sub.1 -C.sub.10 alkyl;
 R.sub.9 is an acid labile hydroxyl protecting group;
 R.sub.10 is an acid stable hydroxyl protecting group; and
 X is halogen.
 The present invention also provides intermediate compounds of formula:
 ##STR71##
 wherein:
 R.sub.1, R.sub.2, R.sub.7, and R.sub.8 are independently C.sub.1 -C.sub.10
 alkyl;
 R.sub.3 and R.sub.6 are independently selected from hydrogen and C.sub.1
 -C.sub.6 alkyl;
 R.sub.4 and R.sub.9 are independently acid labile hydroxyl protecting
 groups;
 R.sub.25 is an acid stable hydroxyl protecting group; and
 R.sub.10 is a trityl group; and
 R.sub.29 is selected from OH, CHO, and --CH.dbd.CH--CH.dbd.CH.sub.2.
 The present invention also provides a compound of formula:
 ##STR72##
 wherein:
 R.sub.1, R.sub.2, R.sub.7, and R.sub.8 are independently C.sub.1 -C.sub.10
 alkyl;
 R.sub.3, R.sub.6, and R.sub.16 are independently selected from hydrogen and
 C.sub.1 -C.sub.6 alkyl;
 R.sub.4, R.sub.9, and R.sub.14 are acid labile protecting groups;
 R.sub.40 is selected from OR.sub.28 and OC(.dbd.O)NH.sub.2 ;
 R.sub.25 is an acid stable protecting group; and
 J is selected from:
 ##STR73##
 wherein R.sub.32 is C.sub.1 -C.sub.6 alkyl and R.sub.33 is selected from H
 and an acid labile hydroxy protecting group.