Practical asymmetric synthesis of β-hydroxy γ-amino acids via complimentary aldol reactions

Pandya, Bhaumik A.; Dandapani, Sivaraman; Duvall, Jeremy R.; Rowley, Ann; Mulrooney, Carol A.; Ryba, Troy D.; Dombrowski, Michael T.; Harton, Marie; Young, Damian W.; Marcaurelle, Lisa A.

doi:10.1016/j.tet.2011.06.043

Cited by 9 publications

(6 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The TBS- and Boc-protecting groups were selected on the basis of their compatibility with a variety of downstream transformations. As we required substantial quantities (∼500 g) of the aldol intermediates for library production and future follow-up studies, significant effort went into developing a practical and robust method for their large-scale preparation . As outlined in Scheme , the syn- aldol reaction of aldehyde 9 with Evans’ oxazolidinone (−)- 10a was successful for the generation of (−)- 11a using dibutylboron triflate as a solution in toluene along with dichloromethane as a co-solvent (1:1).…”

Section: Resultsmentioning

confidence: 99%

An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors

et al. 2010

Self Cite

View full text Add to dashboard Cite

An aldol-based ‘build/couple/pair’ (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti- aldol reactions were performed to produce four stereoisomers of a Boc protected γ-amino acid. In addition both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes, namely: nucleophilic aromatic substitution (SNAr), Huisgen [3+2] cycloaddition and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields providing a variety of skeletons ranging in size from 8- to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on solid-phase to yield a 14,400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships (SSAR) was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.

show abstract

Section: Resultsmentioning

confidence: 99%

An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…to ensure that moderate-to-high coverage of library sequences was readily achievable in widely available and relatively low cost NGS experiments, and 3) to ensure a manageable cost for acquisition of raw materials to enable library production and follow-up studies. We therefore selected 61 multifunctional compounds to serve as skeletons, [36][37][38][39][40][41][42] all comprising secondary amines (Fmoc-, Boc-or Ns-protected) and an aryl halide (Br or I), which we envisioned using for on-DNA diversification (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Diversity-oriented synthesis encoded by deoxyoligonucleotides

Hudson

Westphal

Richter

et al. 2022

Preprint

View full text Add to dashboard Cite

Diversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, a direct result of which has been to elucidate novel biological mechanisms of action. Running in parallel to the development of DOS over the past few decades, DNA-encoded libraries (DELs) have emerged as an effective and efficient screening strategy to identify protein binders. Yet, despite recent advancements in this field most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here we describe the design, synthesis and validation experiments performed for a 3.7 million-member DEL using diverse skeleton architectures derived from DOS to achieve structural diversity beyond that afforded by varying appendages alone. We will make this encoded collection available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery.

show abstract

“…81 Marcaurelle et al devised a highly robust aldol strategy to increase skeletal diversity of macrocyclic compounds by introducing several stereocenters in the 'build' phase. 82,83 These products were coupled to both L-and D-alaninol by amide coupling followed by amide reduction to provide the complete matrix of all eight stereoisomers ( Figure 9, 9-1). This quickly allowed for the incorporation of stereo-structure/activity relationship (SSAR) in the compound collection.…”

Section: Algorithmic Strategies 21 Build/couple/pairmentioning

confidence: 99%

Strategies for the Diversity-Oriented Synthesis of Macrocycles

et al. 2019

View full text Add to dashboard Cite

Macrocycles have long been recognized as useful chemical entities for medicine, with naturally occurring and synthetic macrocycles clinically approved for use as prescription drugs. Despite this promise, the synthesis of collections of macrocycles has been historically challenging due to difficulties in the formation of large rings. Diversity-Oriented Synthesis (DOS) emerged in the early 2000s as a powerful strategic solution to the construction of diverse molecular libraries. This review details the various strategies developed within the field of DOS for the synthesis of macrocycle libraries, utilizing modern synthetic methodology to deliver structurally diverse collections of macrocyclic molecules, and the exploration of their therapeutic potential.

show abstract

Practical asymmetric synthesis of β-hydroxy γ-amino acids via complimentary aldol reactions

Cited by 9 publications

References 38 publications

An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors

An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors

Diversity-oriented synthesis encoded by deoxyoligonucleotides

Strategies for the Diversity-Oriented Synthesis of Macrocycles

Contact Info

Product

Resources

About