Synthetic techniques and intermediates for polyhydroxy,...

Details Synthetic techniques and intermediates for polyhydroxy,... Synthetic techniques and intermediates for polyhydroxy,...

1999-12-07

2001-06-05

Aulakh, C. S. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S416000, C549S419000, C549S273000, C549S293000, C549S294000, C560S129000, C568S579000, C568S626000

Reexamination Certificate

active

06242616

ABSTRACT:

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).
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:
with base and an alkylthiol of formula II:
to form a diene of formula III:
wherein:
R
1
, R
2
, R
3
, R
7
, R
8
, R
11
, R
12
and R
13
are, independently, C
1
-C
10
alkyl;
R
6
is H or C
1
-C
10
alkyl;
X is a halogen;
Z, Z
1
, and Z
2
are, independently, O, S or NR′;
R
4
, R
9
, R
14
, and R
15
are, independently, acid labile hydroxyl protecting groups;
R
5
is C
6
-C
14
aryl;
Y is O, S or NR′;
R′ and R
16
are, independently, hydrogen or C
1
-C
6
alkyl; and
R
18
is C
6
-C
14
aryl.
In another embodiment, compounds of formula I are contacted with compounds of the following formula XXIII:
to form a diene of formula XXXXX:
In another aspect, the methods of the invention involve producing an alkene of formula IV.
This can be accomplished by contacting an organometallic reagent of formula Va:
with a vinyl halide of formula VIa:
wherein M is Li, Cu, Mg, or Zn and R
10
is an acid stable hydroxyl protecting group and all other variables are as defined above. Alternatively, a vinyl halide of formula Vb:
can be contacted with an organometallic compound of formula VIb:
In yet another aspect, the methods of the invention involve compounds having formula VII.
by contacting a diene of formula VIIIa:
with an organometallic compound having formula Va wherein R
24
is hydrogen and R
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.
The methods of the invention also involve producing dienes having formula VIIIa by contacting phosphonium salts having formula IX:
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:
wherein:
R
19
, R
20
, R
21
and R
22
are, independently, C
1
-C
10
alkyl; and
R
23
is C
7
-C
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:
where
R
30
is substituted or unsubstituted C
1
-C
10
alkyl or a moiety formula XII or XIII:
where A is C
1
-C
20
alkyl, —CH
2
NH(T) or a moiety of formula XIV:
wherein
T is peptide having 1 to about 10 amino acids;
R
32
, R
40
, R
42
, R
43
, R
46
, R
47
, and R
48
are, independently, hydrogen or C
1
-C
6
alkyl;
R
41
is a side chain of an amino acid;
W
1
and W
2
are, independently, —OR
49
or —NHP
1
;
P
1
is hydrogen or an amine protecting group;
R
33
and R
36
are, independently, hydrogen, C
1
-C
10
alkyl, —OR
50
, ═O or together form —CH
2
—CH
2
—;
R
34
and R
35
are, independently, hydrogen or together form —C(H)═C(H)—C(H)═C(H)—;
R
39
is —OR
51
or —CH
2
—R
51
;
R
31
and R
44
are, independently, C
1
-C
10
alkyl;
Q
1
and Q
2
are, independently, hydrogen, —OR
Q
, —NHR
52
, —OC(═O)NH
2
or together form —O—C(O)—NH—;
R
Q
is hydrogen or a hydroxyl protecting group;
R
51
is substituted or unsubstituted C
6
-C
14
aryl, tetrahydropyranyl, furanosyl, pyranosyl (e.g., tetramethylfucosyl, tetramethylmannosyl, tetramethylgaractosyl and tetramethylglucosyl), C
3
-C
10
lactonyl or 2-pyranonyl;
R
45
is C
1
-C
6
alkenyl, C
1
-C
6
alkyl, C
6
-C
14
aryl, C
2
-C
10
heterocycloalkyl, C
3
-C
10
cycloalkyl, or C
7
-C
15
aralkyl; and
R
49
, R
50
, and R
52
are, independently, hydrogen or C
1
-C
6
alkyl.
In another aspect, the present invention provides processes for preparing amides having formula XX:
wherein Ar is C
6
-C
14
aryl comprising the steps of contacting a compound having formula XXI:
with a compound having formula XXII:
for a time and under conditions effective to form the amide.
Also provided are processes for producing compounds of formula XXIII:
comprising the steps of contacting an aldehyde of formula XXIV:
with an enol ether of formula XXV:
in the presence of a titanium salt for a time and under conditions effective to form an enone of formula XXVI:
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:
by contacting an aldehyde of formula XXVIII:
with an &agr;-halo sulfone of formula XXIX:
for a time and conditions effective to from the halogenated olefin.
Also provided are processes for producing halogenated olefins of formula XXX:
comprising the steps of contacting a compound of formula XXXI:
with triphenylphosphine and a carbon tetrahalide for a time and under conditions effective to form a dihalogenated olefin of formula XXXII:
Such a dihalogenated olefin is contacted with an organometallic compound (such as lithium dimethyl cuprate or an alkylzinc comp

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