Crystal structures of dolastatin 16, dolamethylleuine and dolaphenvaline, and methods for preparing dolamethylleuine and dolaphenvaline
AssigneeArizona Board of Regents, A Body Corporate of the State of Arizona Acting for and On Behalf of Arizona State University
InventorsGeorge R. Pettit, Thomas Smith, Jun-Ping Xu, Delbert Herald
Life of this patent
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Abstract
The present invention relates to the crystal structures of dolastatin 16, dolamethylleuine and dolaphenvaline. The present invention also relates to processes for preparing dolamethylleuine and dolaphenvaline. The present invention further relates to computer readable medium with crystal structural data and/or information stored thereon.
Claims20
A crystal comprising dolastatin 16:
- wherein said crystal is in space group P2(1);
- and said crystal has unit cell dimensions of a=10.844 (5) Å, b=16.133 (5) Å, c=16.050 (5) Å, α=90.000 (5)°, β=104.062 (5)°, γ=90.000 (5)°, V=2720.4 (17) Å3.
A crystallizable composition comprising dolastatin 16, wherein the crystallizable composition forms crystals that are of X-ray diffraction quality.
Dolastatin 16 having the X-ray crystal structure of FIG. 1.
A method of obtaining a crystal of dolastatin 16, comprising the steps of:
- (a) combining dolastatin 16 with a crystallization solution to produce a crystallizable composition;
- and
- (b) subjecting the crystallizable composition to conditions that promote crystallization, thereby obtaining said crystal.
A method for making Z-dolamethylleuine:
- comprising the steps of:
- (a) converting benzyloxy-carbonyl valine 4 to a diazoketone 5:
- (b) converting diazoketone 5 to ester 6:
- (c) converting ester 6 to α-methylated ester 7:
- and
- (d) deprotecting α-methylated ester 7 to make Z-dolamethylleuine:
A crystal comprising Z-dolamethylleuine, wherein said crystal is in space group P2(1);
- and said crystal has unit cell dimensions of a=7.2182 (2) Å, b=8.5374 (3) Å, c=12.1649 (4) Å, α=90.00°, β=99.722 (2)°, γ=90.00°, V=738.89 (4) Å3.
A crystallizable composition comprising Z-dolamethylleuine, wherein the crystallizable composition forms crystals that are of X-ray diffraction quality.
Z-Dolamethylleuine having the X-ray crystal structure of FIG. 2.
A method of obtaining a crystal of Z-dolamethylleuine, comprising the steps of:
- (a) combining Z-dolamethylleuine with a crystallization solution to produce a crystallizable composition;
- and
- (b) subjecting the crystallizable composition to conditions that promote crystallization, thereby obtaining said crystal.
A method for making TFA-dolaphenvaline:
- comprising the steps of:
- (a) condensing N-trifluoroacetylglycine 11 with alcohol 12 to provide allylic ester 13:
- (b) converting allylic ester 13 to γ,δ-unsaturated amino acid 14:
- (c) converting y,6-unsaturated amino acid 14 to t-butyl ester 16:
- (d) oxidizing t-butyl ester 16 to t-butyl ester ketone 18:
- (e) converting t-butyl ester ketone 18 to lactone 19:
- and
- (f) converting lactone 19 to TFA-dolaphenvaline 20:
A crystal comprising TFA-dolaphenvaline, wherein said crystal is in space group P 1 21 1;
- and said crystal has unit cell dimensions of a=7.9918 (5) Å, b=6.3850 (5) Å, c=13.4458 (11) Å, α=90°, β=103.1810 (10)°, γ=90°, V=668.03 (9) Å3.
A crystallizable composition comprising TFA-dolaphenvaline, wherein the crystallizable composition forms crystals that are of X-ray diffraction quality.
TFA-Dolaphenvaline having the X-ray crystal structure of FIG. 3.
A method of obtaining a crystal of TFA-dolaphenvaline, comprising the steps of:
- (a) combining TFA-dolaphenvaline with a crystallization solution to produce a crystallizable composition;
- and
- (b) subjecting the crystallizable composition to conditions that promote crystallization, thereby obtaining said crystal.
A non-transitory computer readable medium comprising crystal structural data and/or information of dolastatin 16 stored thereon
A computer system comprising:
- (a) a non-transitory computer readable medium comprising data storage material encoded with the computer-readable data;
- (b) a working memory for storing instructions for processing the computer-readable data;
- and
- (c) a central-processing unit coupled to the working memory and to the computer-readable medium for processing the computer-readable data and generating structures.
A method for designing an analog of dolastatin 16 comprising:
- (a) providing on a computer system a three-dimensional structure of dolastatin 16;
- and
- (b) employing software comprised by the computer system to design the analog.
Dependencies are inferred from the claim text.