The Dolastatins; 18: Stereospecific Synthesis of Dolaproine

Pettit, George R.; Burkett, Douglas D.; Barkóczy, Jószef; Breneman, G. L.; Pettit, William E.

doi:10.1055/s-1996-4296

Cited by 27 publications

(31 citation statements)

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“…The tripeptide Dov-Val-Dil TFA salt (15) and Boc-Dap (12) were obtained via published methods. 32,33 PyBroP coupling of amine 1a to Boc-Dap (12) followed by Boc deprotection with TFA in DCM afforded compound 14 (Scheme 5). Further coupling resulted in des-Doe D-10 stilbene amide 16.…”

Section: Resultsmentioning

confidence: 99%

“…To a stirred mixture of amine 1a (51 mg, 0.17 mmol), N α -Boc-L-Dap 12 (52 mg, 0.18 mmol, 1.1 eq), 32,33 and PyBroP (87 mg, 0.19 mmol, 1.1 eq) at 0 EC under Ar was added DIPEA (65 µL, 0.37 mmol, 2.2 eq). The reaction mixture was stirred for 1.5 h at rt.…”

Section: 4-methylenedioxy-54′-dimethoxy-3′-(n α -Boc-l-dap)-amido-mentioning

confidence: 99%

“…The solvents were removed in vacuo, and the TFA salt, obtained by Sephadex LH-20 column chromatography (solvent, MeOH), was placed in methanol (1 mL). Sodium methoxide (0.22 mg, 0.41 mmol, 1.8 eq) was added to the reaction mixture, and the white precipitate that formed was collected and reprecipitated from DCM-CH 3 To a stirred mixture of amine 1a (51 mg, 0.17 mmol), N α -Boc-L-Dap 12 (52 mg, 0.18 mmol, 1.1 eq), 32,33 and PyBroP (87 mg, 0.19 mmol, 1.1 eq) at 0 EC under Ar was added DIPEA (65 µL, 0.37 mmol, 2.2 eq). The reaction mixture was stirred for 1.5 h at rt.…”

Section: 4-methylenedioxy-54′-dimethoxy-3′-(n α -L-tyr)-amido-z-stmentioning

confidence: 99%

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Antineoplastic Agents. 515. Synthesis of Human Cancer Cell Growth Inhibitors Derived from 3,4-Methylenedioxy-5,4‘-dimethoxy-3‘-amino-Z-stilbene

et al. 2005

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Further structure-activity relationship (SAR) exploration of 3,4-methylenedioxy-5,4′-dimethoxy-3′-amino-Z-stilbene (1a) derivatives resulted in the efficient synthesis of tyrosine amide hydrochloride 9, two tyrosine amide phosphate prodrugs (3a and 6), and sodium aspartate amide 11. Two additional cancer cell growth inhibitors (14 and 16) were synthesized by employing peptide coupling between amine 1a and the Dap residue of dolastatin 10 (4a) to yield amide 14 followed by to yield peptide 16. The latter represents a combination of stilbene 1a with the des-Doe tetrapeptide unit of the powerful tubulin assembly inhibitor dolastatin 10. Peptide 16 was examined for potential binding to tubulin in the vinca and/or colchicine regions and found to perform primarily as a relative of dolastatin 10. Amide 14 had anticryptococcal and antibacterial activities.We recently completed syntheses of 3'-amino derivatives (1a-b, 1d-j) of combretastatin A-2 (2c) 1 , encouraged by the remarkable success of the potent cancer vascular targeting [2][3][4] that occurs with combretastatin A-4 phosphate prodrug (CA4P) 2h. [5][6][7][8][9][10] Subsequently, we undertook the synthesis and initial anticancer evaluation of two phosphate derivatives (3a,b) of tyrosine stilbene amide 1i. Attachment of the phosphate group at the 3'-phenol position has been investigated in detail in the combretastatin A and B series. 1,[11][12][13] In the present study we chose to use the 4"-hydroxyl group of tyrosine amide 1i for attachment of a phosphate group (3a) as well as obtaining a diphosphoryl derivative (3b) by phosphorylating tyrosine amide 1i at both the amine 14 and hydroxyl groups. A parallel important objective of this research involved employing a tetrapeptide segment of dolastatin 10 (4a) for bonding to the 3′-amino group (1b). Dolastatin 10 (D-10, 4a), isolated 15-17 from the Indian Ocean sea hare Dolabella auricularia, has continued to progress through preclinical 18 and clinical development as an impressive antineoplastic agent. [19][20][21][22] Dolastatin 10 (4a) and various synthetic derivatives also have specific antifungal activity against Cryptococcus neoformans. 23,24 Previous SAR studies have confirmed that D-10 (4a) inhibits microtubule assembly by binding to the β-tubulin subunit near the vinca site. SAR studies have shown the des-Doe tetrapeptide unit (4b, Dov-Val-Dil-Dap) to be necessary for potent anticancer * To whom correspondence should be addressed. bpettit@asu 25,26 We now also report synthesis of the amide representing coupling of amine 1a to Dov-Val-Dil-Dap (4b). Results and DiscussionOur synthesis of the tyrosine stilbene amide 1i 27 presented the opportunity to develop two additional phosphate prodrugs in the combretastatin series. Accordingly, the 4"-phenol and α-amino groups were phosphorylated in one step using dibenzyl phosphite (1i to 5) (Scheme 1). Debenzylation of the resulting phosphate diesters (5) was achieved using bromotrimethylsilane to afford the free acid (3b) which was subsequently converted to sod...

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Section: Resultsmentioning

confidence: 99%

Section: 4-methylenedioxy-54′-dimethoxy-3′-(n α -Boc-l-dap)-amido-mentioning

confidence: 99%

Section: 4-methylenedioxy-54′-dimethoxy-3′-(n α -L-tyr)-amido-z-stmentioning

confidence: 99%

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Antineoplastic Agents. 515. Synthesis of Human Cancer Cell Growth Inhibitors Derived from 3,4-Methylenedioxy-5,4‘-dimethoxy-3‘-amino-Z-stilbene

et al. 2005

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“…Aldol reaction strategies for the construction of Dap precursor 8 (Equation 1) 6 and Dil precursors 10a,b (Equation 2) 9 employing chiral auxiliaries in the presence ( 7a and 7c ) and absence ( 7b ) of α-functionality.…”

Section: Figurementioning

confidence: 99%

Samarium Iodide-Mediated Reformatsky Reactions for the Stereoselective Preparation of β-Hydroxy-γ-amino Acids: Synthesis of Isostatine and Dolaisoleucine

Nelson

Burke

2011

J. Org. Chem.

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The synthesis of β-hydroxy-γ-amino acids via SmI2-mediated Reformatsky reactions of α-chloroacetyloxazolidinones with aminoaldehydes is reported. Diastereoselective coupling is demonstrated to depend on the absolute configuration of the Evans chiral auxiliary employed in the reaction, allowing erythro or threo products to be obtained selectively. The potential utility of the methodology is exemplified by the facile synthesis of biologically relevant N-Boc-isostatine (2b) and N-Boc-dolaisoleucine (3c).

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“…On the other hand, O-methylation of 1075 with diazomethane in the presence of trimethyloxonium tetrafluoroborate gave the methyl ether derivative 1077, which by cleavage of the chiral auxiliary under the same conditions afforded N-Boc-dolaproline (2S,2 0 R,3 0 R)-1073 in 83% yield (Scheme 268). 386 On the other hand, cobalt-triphenylphosphine-promoted Reformatsky reaction between N-Boc-L L-prolinal 1060a and (4R,5S)-3-(2-bromopropionyl)-4-methyl-5-phenyloxazolidin-2-one 1078 gave b-hydroxy amide 1075 in 70% and high stereoselectivity, which was converted in dolaproline (Dap) 1073 under an identical protocol to that described above (Scheme 269). 387 Genet et al 388 have reported an efficient multigram-scale synthesis of enantiomerically pure N-Boc-iso-dolaproline 1083 using a dynamic kinetic resolution (DKR).…”

Section: Synthesis Of C N B;c Derivativesmentioning

confidence: 99%