Ngiap-Kie Lim

Single-Step Synthesis of 5,6,7,8-Tetrahydroindolizines via Annulation of 2-Formylpiperidine and 1,3-Dicarbonyl Compounds.

An expedient single-step synthesis of 5,6,7,8-tetrahydroindolizines has been achieved via the annulation of commercially available 2-formylpiperidine hydrochloride and 1,3-dicarbonyl compounds in THF in the presence of pyrrolidine and 4 Å molecular sieves. A variety of β-ketoesters, ketones, and amides participated in this annulation chemistry, affording the desired 5,6,7,8-tetrahydroindolizines in moderate to good yields.

Highly Stereoselective Synthesis of Tetrasubstituted Acyclic All-Carbon Olefins via Enol Tosylation and Suzuki–Miyaura Coupling

A highly stereocontrolled synthesis of tetrasubstituted acyclic all-carbon olefins has been developed via a stereoselective enolization and tosylate formation, followed by a palladium-catalyzed Suzuki-Miyaura cross-coupling of the tosylates and pinacol boronic esters in the presence of a Pd(OAc)2/RuPhos catalytic system. Both the enol tosylation and Suzuki-Miyaura coupling reactions tolerate an array of electronically and sterically diverse substituents and generate high yield and stereoselectivity of the olefin products. Judicious choice of substrate and coupling partner provides access to either the E- or Z-olefin with excellent yield and stereochemical fidelity. Olefin isomerization was observed during the Suzuki-Miyaura coupling. However, under the optimized cross-coupling reaction conditions, the isomerization was suppressed to <5% in most cases. Mechanistic probes indicate that the olefin isomerization occurs via an intermediate, possibly a zwitterionic palladium carbenoid species.

Two-Step Synthesis of 3,4-Dihydropyrrolopyrazinones from Ketones and Piperazin-2-ones

An expedient two-step synthesis of 3,4-dihydropyrrolopyrazinones has been achieved via a Vilsmeier-Haack reaction of ketones, followed by an annulation of the corresponding chloroaldehydes with commercially available piperazin-2-ones. A variety of cyclic and acyclic ketones and piperazin-2-ones participated in this two-step chemistry, affording the desired 3,4-dihydropyrrolopyrazinones in up to 78% yield.

Synthesis of a Selective Estrogen Receptor Degrader via a Stereospecific Elimination Approach

An efficient synthesis of a selective estrogen receptor degrader, GDC-0810, bearing a challenging stereodefined (E)-tetrasubstituted all-carbon olefin core, is reported. The described synthetic route involves a highly diastereoselective addition of an arylmagnesium reagent 3a to ketone 4, yielding the key tertiary alcohol 2a in >99:1 dr. The corresponding tert-butyl carbonate derivative was identified among other leaving groups to provide the desired olefin geometry in a 98:2 E/Z ratio via a concerted elimination. A four-step telescoped process was then developed starting from the tertiary alcohol 2a to produce GDC-0810 API as a pyrrolidine salt in 70% yield.

Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin

We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E: Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.

Synthesis of Highly Stereodefined Tetrasubstituted Acyclic All-Carbon Olefins via a Syn-Elimination Approach.

An efficient synthesis of stereodefined tetrasubstituted acyclic all-carbon olefins has been developed via a bis(2,6-xylyl)phosphate formation of stereoenriched tertiary alcohols, followed by in situ syn-elimination of the corresponding phosphates under mild conditions. This chemistry tolerates a wide variety of electronically and sterically diverse substrates and generates the desired tetrasubstituted olefins in high yields and stereoselectivities (>95:5) in most cases. This stereocontrolled olefin synthesis has been applied to the synthesis of anticancer drug tamoxifen in three steps from commercially available 1,2-diphenylbutan-1-one in 97:3 stereoselectivity and 78% overall yield.

CCDC 1586657: Experimental Crystal Structure Determination

Related Article: Ngiap-Kie Lim, Patrick Weiss, Beryl X. Li, Christina H. McCulley, Stephanie R. Hare, Bronwyn L. Bensema, Teresa A. Palazzo, Dean J. Tantillo, Haiming Zhang, and Francis Gosselin|2017|Org.Lett.|19|6212|doi:10.1021/acs.orglett.7b03141

CCDC 1586659: Experimental Crystal Structure Determination

Related Article: Ngiap-Kie Lim, Patrick Weiss, Beryl X. Li, Christina H. McCulley, Stephanie R. Hare, Bronwyn L. Bensema, Teresa A. Palazzo, Dean J. Tantillo, Haiming Zhang, and Francis Gosselin|2017|Org.Lett.|19|6212|doi:10.1021/acs.orglett.7b03141

CCDC 1586641: Experimental Crystal Structure Determination

Related Article: Ngiap-Kie Lim, Patrick Weiss, Beryl X. Li, Christina H. McCulley, Stephanie R. Hare, Bronwyn L. Bensema, Teresa A. Palazzo, Dean J. Tantillo, Haiming Zhang, and Francis Gosselin|2017|Org.Lett.|19|6212|doi:10.1021/acs.orglett.7b03141