220249-56-9

Upstream product

• 18162-48-6 tert-butyldimethylsilyl chloride 
• 220249-55-8 (3S,4R)-1-(4-methoxybenzyloxy)-4-(trifluoromethyl)hex-5-en-3-ol 
• 135362-69-5 3-(4-methoxybenzyl)oxypropan-1-ol 
• 824-94-2 p-methoxybenzyl chloride 
• 128461-65-4 3-(p-methoxybenzyloxy)propanal 
• 69739-34-0 t-butyldimethylsiyl triflate 
• 849619-01-8 1-(4-methoxybenzyloxy)-4-methylhex-5-en-3-ol 

Downstream Products

• 123-11-5 4-methoxy-benzaldehyde 
• 311341-98-7 (3S,4R)-3-(tert-butyldimethylsilyloxy)-4-methylhex-5-en-1-ol 

Relevant academic research and scientific papers

BIOCATALYTIC SYNTHESIS OF CRYPTOPHYCIN ANTICANCER AGENTS

The disclosure provides cryptophycin intermediates, cryptophycin analogs, and cryptophycin chimeric molecules useful in treating cancer, as well as methods of producing these compounds and methods of treating cancer.

A versatile chemoenzymatic synthesis for the discovery of potent cryptophycin analogs

The cryptophycins are a family of macrocyclic depsipeptide natural products that display exceptionally potent antiproliferative activity against drug-resistant cancers. Unique challenges facing the synthesis and derivatization of this complex group of molecules motivated us to investigate a chemoenzymatic synthesis designed to access new analogs for biological evaluation. The cryptophycin thioesterase (CrpTE) and the cryptophycin epoxidase (CrpE) are a versatile set of enzymes that catalyze macrocyclization and epoxidation of over 20 natural cryptophycin metabolites. Thus, we envisioned a drug development strategy involving their use as standalone biocatalysts for production of unnatural derivatives. Herein, we developed a scalable synthesis of 12 new unit A-B-C-D linear chain elongation intermediates containing heterocyclic aromatic groups as alternatives to the native unit A benzyl group. N-Acetyl cysteamine activated forms of each intermediate were assessed for conversion to macrocyclic products using wild type CrpTE, which demonstrated the exceptional flexibility of this enzyme. Semipreparative scale reactions were conducted for isolation and structural characterization of new cryptophycins. Each was then evaluated as a substrate for CrpE P450 and its ability to generate the epoxidized products from these substrates that possess altered electronics at the unit A styrenyl double bond position. Finally, biological evaluation of the new cryptophycins revealed a des-β-epoxy analog with low picomolar potency, previously limited to cryptophycins bearing epoxide functionality.

Studies toward the Synthesis of Amphidinolide C1: Stereoselective Construction of the C(1)-C(15) Segment

An enantioselective synthesis of the C(1)-C(15) segment of the marine natural product amphidinolide C has been accomplished by a route that includes a stereoselective boron-Wittig reaction to furnish a trisubstituted alkenylboronate. In addition, the rout

Direct generation of acyclic polypropionate stereopolyads via double diastereo- and enantioselective iridium-catalyzed crotylation of 1,3-diols: Beyond stepwise carbonyl addition in polyketide construction

Under the conditions of transfer hydrogenation employing the cyclometalated iridium catalyst (R)-I derived from [Ir(cod)Cl]2, allyl acetate, 4-cyano-3-nitrobenzoic acid, and the chiral phosphine ligand (R)-SEGPHOS, α-methylallyl acetate engages 1,3-propanediol (1a) and 2-methyl-1,3-propanediol (1b) in double carbonyl crotylation from the alcohol oxidation level to deliver the C2-symmetric and pseudo-C 2-symmetric stereopolyads 2a and 3a, respectively, with exceptional control of anti-diastereoselectivity and enantioselectivity. Notably, the polypropionate stereopentad 3a is formed predominantly as 1 of 16 possible stereoisomers. Desymmetrization of 3a is readily achieved upon iodoetherification to form pyran 4. The direct generation of 3a enables a dramatically simplified approach to previously prepared polypropionate substructures, as demonstrated by the synthesis of C19-C27 of rifamycin S (eight steps, originally prepared in 26 steps) and C19-C25 of scytophycin C (eight steps, originally prepared in 15 steps). The present transfer hydrogenation protocol represents an alternative to chiral auxiliaries, chiral reagents, and premetalated nucleophiles in polyketide construction.

Synthesis and cytotoxicity studies of new cryptophycin analogues

Two analogues of cryptophycin were synthesized and biologically evaluated for their in-vitro cytotoxicities against several solid tumors and leukemia cell lines. The results revealed that both analogues exhibited a broad range of cytotoxic activity with observed IC50 values in the μM-range, and compound 4 was more effective than compound 3 in most assays studied.

Cryptophycin affinity labels: Synthesis and biological activity of a benzophenone analogue of cryptophycin-24

An efficient synthesis of a C16 side chain benzophenone analogue of cryptophycin-24 using a crotylboration reaction and Heck coupling as key steps is described. In an in vitro tubulin assembly assay, the benzophenone analogue of the β isomer (IC50/s

Total synthesis of cryptophycin-24 (arenastatin A) amenable to structural modifications in the C16 side chain

Two efficient protocols for the synthesis of tert-butyl (5S,6R,2E,7E)-5-[(tert-butyldimethylsilyl)-oxy]-6-methyl-8-phenyl-2,7-octadie noate, a major component of the cryptophycins, are reported. The first utilized the Noyori reduction and Frater alkylation of methyl 5-benzyloxy-3-oxopentanoate to set two stereogenic centers, which became the C16 hydroxyl and C1' methyl of the cryptophycins. The second approach started from 3-p-methoxybenzyloxypropanal and a crotyl borane reagent derived from (-)-α-pinene to set both stereocenters in a single step and provided the dephenyl analogue, tert-butyl (5S,6R,2E)-5-[(tert-butyldimethylsilyl)oxy]-6-methyl-2,7-octadienoate, in five steps. This compound was readily converted to the 8-phenyl compound via Heck coupling. The silanyloxy esters were efficiently deprotected and coupled to the C2-C10 amino acid fragment to provide desepoxyarenastatin A and its dephenyl analogue. The terminal olefin of the latter was further elaborated via Heck coupling. Epoxidation provided cryptophycin-24 (arenastatin A).

Enantioselective synthesis of a 3'-dephenylcryptophycin synthon

An enantioselective synthesis of tert-butyl (5S,6R)-(E)-5-tert- butyldimethylsilyloxy-6-methyl-2,7-octadienoate, a precursor for the synthesis of the antimitotic macrolides cryptophycin A and arenastatin A (cryptophycin-24), is presented. The key step in the reaction sequence features a crotyl boration that sets both stereocenters that become the C16 hydroxyl and C1' methyl in the cryptophycins. Homologation of the terminal olefin via a Heck reaction is presented.