Diverging DOS Strategy Using an Allene-Containing Tryptophan Scaffold and a Library Design that Maximizes Biologically Relevant Chemical Space While Minimizing the Number of Compounds

Abstract

A diverging diversity-oriented synthesis (DOS) strategy using an allene-containing tryptophan as a key starting material was investigated. An allene-yne substituted derivative of tryptophan 12 gave indolylmethylazabicyclooctadiene 17 when subjected to a microwave-assisted allenic [2 + 2] cycloaddition reaction. This same tryptophan-derived precursor afforded an indolylmethyldihydrocyclopentapyridinone 14 when subjected to a rhodium(I)-catalyzed cyclocarbonylation reaction and an indolylmethylpyrrolidinocyclopentenones 16 when reacted with molybdenum hexacarbonyl. Construction of allenic tetrahydro-β-carboline scaffolds via a Pictet-Spengler reaction and subsequent silver(I)-catalyzed cycloisomerization afforded tetrahydroindolizinoindoles (21). Attachment of allene and alkyne groups to the tetrahydro-β-carboline followed by a microwave-assisted allenic [2 + 2] cycloaddition reaction provided tetrahydrocyclobutaindoloquinolizinones 24 and the tetrahydrocyclopentenone indolizinoindolone 26 when reacted with molybdenum hexacarbonyl. These six scaffolds were used as a template for the construction of a virtual library of 11,748 compounds employing 44 indoles, 12 aldehydes, and 51 alkynes. Diversity analyses using a combination of cell-based chemistry space computations using BCUT (Burden (B) CAS (C) Pearlman at the University of Texas (UT)) metrics and Tanimoto coefficient (Tc) similarity calculations using two-dimensional (2D) fingerprints showed that the compounds in the virtual library occupied new chemical space when compared to the 327,000 compounds in the molecular libraries small molecule repository (MLSMR). A subset of fifty-three compounds was identified from the virtual library using the DVS package of Sybyl 8.0; this subset represents the most diverse compounds within the chemical space defined by these compounds and will be synthesized and screened for biological activity.

Network Measures for Chemical Library Design

“…Painter et al. [] have used BCUT metrics [Pearlman and Smith, ; Stanton, ] to analyze the structural diversity of a virtual library, with the objective of designing molecules that explored new regions of chemical space in a DOS strategy. They employed a large virtual library of 11,748 compounds constructed from different scaffolds obtained from a DOS strategy.…”

Combinatorial Chemistry Online

“…A recent paper describes the use of an allenecontaining tryptophan as a key starting material in the generation of a DOS library. 1 This paper describes a diversification strategy that focused on the cyclocarbonylation and carbocyclisation reactions of allene or alkyne groups substituted onto an indole framework. Indoles were used because they occur frequently in natural products and also in synthetically derived bioactive molecules.…”

The Pictet-Spengler Reaction Updates Its Habits

“…Chiral catalysts derived from BINOL [40,44,45] and SPINOL [49] (phosphoric acids and thiourea derivatives) stand out among the usual Brønsted acids: TFA [35,42,47,57], HCl [58], 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) [59], 2,4,6-trichloro-1,3,5-triazine (TCT) [54], H 2 SO 4 [50], MeSO 3 H [52], TsOH [58], and mild catalysts, such as phosphate buffer [30,39] and microwave irradiation [61].…”

“…N-substituted aryl ethylamines 20 [27,31,35,36,39,40], allene-containing-tryptophan 21 [42], trifluoromethylated precursors 22 [55], and spirocyclic lactams embodying Trp 23 [56] were the most interesting amine substrates. Conversely, isatins 24 [44][45][46], enaminone 25 [52], (S)-2,3-O-isopropylidene-L-glyceraldehyde 26 [53], pyridoxal 27 [60], L/D-amino aldehydes 28 [57,63], and 11 C-labeled formaldehyde 29 [58] were the most notable carbonyl components (Figure 1).…”