Ha-Soon Choi

Total Synthesis of the CP Molecules CP-263,114 and CP-225,917— Part 1: Synthesis of Key Intermediates and Intelligence Gathering

A synthetic labyrinth endowed with countless obstacles, yet filled with numerous hidden treasures, had to be overcome to reach the CP molecules CP-263,114 (1) and CP-225,917 (2). Their complex molecular frameworks coupled with the array of sensitive functionalities present amount to a formidable synthetic challenge. Moreover, these compounds possess interesting biological properties. Although the first synthetic strategies ended before the goals were achieved, in spite of careful preparation and numerous model studies, enough information was gathered en route to enable a revised approach to be formulated, which finally culminated in success.

Crystal structures of human HSP90α-complexed with dihydroxyphenylpyrazoles

Abstract A series of dihydroxyphenylpyrazole compounds were identified as a unique class of reversible Hsp90 inhibitors. The crystal structures for two of the identified compounds complexed with the N-terminal ATP binding domain of human Hsp90α were determined. The dihydroxyphenyl ring of the compounds fits deeply into the adenine binding pocket with the C2 hydroxyl group forming a direct hydrogen bond with the side chain of Asp93. The pyrazole ring forms hydrogen bonds to the backbone carbonyl of Gly97, the hydroxyl group of Thr184 and to a water molecule, which is present in all of the published HSP90 structures. One of the identified compounds (G3130) demonstrated cellular activities (in Her-2 degradation and activation of Hsp70 promoter) consistent with the inhibition of cellular Hsp90 functions.

Catalytic asymmetric allylation of aldehydes with BINOL-Ti(IV) complex accelerated by i-PrSSiMe3

Abstract Practical and efficient catalytic asymmetric allylation reaction of achiral aldehydes with allyltri-n-butylstannane in the presence of chiral Lewis acid catalyst has been achieved by the use of accelerator, i-PrSSiMe3. This system exhibited not only dramatically accelerating reactivity but also significantly increasing catalytic ability.

A Novel Route to the Fused Maleic Anhydride Moiety of CP Molecules

A seven-step cascade reaction-in which selective mesylation, epoxide formation, epoxide lysis, cyclization, reiterative oxidation, and nitrogen-oxygen exchange occur sequentially-facilitates the construction of the maleic anhydride moiety of CP molecules 1 and 2 (>93% yield per step). Unstable intermediates of this reaction sequence were detected, providing evidence for the proposed mechanism and resulting in the discovery of a new chemical entity.

(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.

Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.

Diastereoselective synthesis of highly functionalized tetrahydropyrans from the cyclic vinyl acetal with aldehydes mediated by lewis acid catalyst

Abstract A new method for constructing substituted tetrahydropyrans from the conjunction of 6-ethylthio-3,4-dihydro-2-methoxy-2 H -pyran with aldehydes in the presence of 10 mol % SnCl 4 is described. This reaction is highly stereocontrolled and allows various functionalities to be incorporated at tetrahydropyran ring.

CATALYTIC ASYMMETRIC PROP-2-YNYLATION INVOLVING THE USE OF THE BIFUNCTIONAL SYNERGETIC REAGENT ET2BSPRI

Efficient catalytic asymmetric prop-2-ynylation of achiral aldehydes with allenyltributylstannane promoted by a BINOL–Ti IV complex (10 mol%) is achieved with high enantioselectivity by the use of Et 2 BSPr i .

Bifunctional molecular accelerator for catalytic asymmetricallylation: R2MSR′ (M = B, Al) as a useful synergeticreagent

Dramatic acceleration of the catalytic process of asymmetric allylation of achiral aldehydes is observed by the utilization of the bifunctional synergetic reagents R 2 MSR′ (M = B, Al).

Self-regulated molecular rearrangement: diastereoselective zwitterionic aza-Claisen protocol

Treatment of N-but-2-enylpiperidine with acyl halides in the presence of K2CO3 afforded the corresponding Claisen products with high diastereoselectivity depending on the E or Z but-2-enyl geometry.