Pseudoephedrine as a Practical Chiral Auxiliary for the Synthesis of Highly Enantiomerically Enriched Carboxylic Acids, Alcohols, Aldehydes, and Ketones

Myers, Andrew G.; Yang, Bin; Chen, Hou; McKinstry, Lydia; Kopecky, and David J.; Gleason, James L.

doi:10.1021/ja970402f

Cited by 579 publications

(458 citation statements)

References 50 publications

Supporting

Mentioning

432

Contrasting

Unclassified

Order By: Relevance

“…16 To access derivatives 16−19 a stereoselective synthesis was developed as depicted in Scheme 2 for compound 18. Stereoselective pseudoephedrine enolate alkylation according to the methodology of Myers 17 and subsequent reduction yielded alcohol 26 in 91% ee, which was converted to iodide 27. The second stereogenic center was introduced using Schollkopf bis-lactimether methodology 18 (94% de for 29).…”

mentioning

confidence: 99%

Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists

Galley

Beurier

Décoret

et al. 2016

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

2-Aminooxazolines were discovered as a novel structural class of TAAR1 ligands. Starting from a known adrenergic compound 1, structural modifications were made to obtain highly potent and selective TAAR1 ligands such as 12 (RO5166017), 18 (RO5256390), 36 (RO5203648), and 48 (RO5263397). These compounds exhibit drug-like physicochemical properties, have good oral bioavailability, and display in vivo activity in a variety of animal models relevant for psychiatric diseases and addiction. KEYWORDS: TAAR1 agonist, 2-aminooxazoline, SAR, schizophrenia T race amines (TAs) are metabolites of amino acids with structural similarity to biogenic amines and represent the endogenous ligands of the trace amine associated receptor 1 (TAAR1). 1,2 Dysregulation of TAs in the brain has been linked to a variety of psychiatric diseases and selective TAAR1 ligands have gained much interest as potential therapeutics for depression, schizophrenia, bipolar disorder, ADHD, and psychostimulant addiction. 3 The modulatory role of this G protein-coupled receptor on monoaminergic neurotransmission has recently been investigated and confirmed by characterization of a transgenic mouse line overexpressing TAAR1 in central nervous system neurons. 4 Further efforts were made to identify potent and selective TAAR1 agonists with favorable pharmacokinetic properties in order to prove the modulatory effect on dopaminergic signaling in vivo. 5 In an endeavor to discover a novel and selective TAAR1 chemotype, we considered application of the SOSA approach (Selective Optimization of Side Activities) to adrenergic ligands as a viable lead identification strategy. 6 Structural similarity of TAAR1 agonists with adrenergic agonists was already known from our previous work 5 pointing toward a similarity of the binding regions of both receptors. 7,8 Therefore, we searched the literature and in-house databases for adrenergic ligands reported as drugs or development candidates, whereupon the alpha 2 adrenergic receptor partial agonist S18616 from Servier (1) caught our attention. 9 Pleasingly, testing this candidate revealed (besides its expected activity at the human α 2A receptor) a high functional activity at human TAAR1 (EC 50 = 15 nM). 10 A medicinal chemistry optimization program was then started aiming for compounds selective for TAAR1, where the known TAAR1 pharmacophore motif (aromatic moiety linked to a basic headgroup) of S18616 was kept, but the linker region was modified by opening the central six-membered ring (Figure 1). For all such derived compounds selectivity data was obtained by measuring functional activity at the human TAAR1 receptor (EC 50 hTAAR1) and in addition at the human adrenergic α 2A receptor (hα 2A ) (Table 1).All 2-aminooxazolines were synthesized from the corresponding amino alcohols 15 and cyanogen bromide in the presence of a base as depicted in Scheme 1. The enantiomerically pure amino alcohols were obtained from the chiral pool (e.g., via reduction of amino acids or their derivatives). The procedures are describ...

show abstract

mentioning

confidence: 99%

Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists

Galley

Beurier

Décoret

et al. 2016

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

show abstract

“…Another earlier asymmetric route to reduced polypropionates involved diastereoselective conversion of chirons derived from natural sources (8). However, the methods most frequently used now involve either ␣-alkylation of chiral enolates (2,(9)(10)(11)(12) and related nucleophiles (13) or conjugate addition to chiral ␣,␤-unsaturated carboxamides (14,15). Despite the fact that these methods require at least one, and often more than one, equivalent of chiral reagents, some of them, in particular the protocol of Myers et al (11,12), may be viewed as the current benchmarks.…”

mentioning

confidence: 99%

“…However, the methods most frequently used now involve either ␣-alkylation of chiral enolates (2,(9)(10)(11)(12) and related nucleophiles (13) or conjugate addition to chiral ␣,␤-unsaturated carboxamides (14,15). Despite the fact that these methods require at least one, and often more than one, equivalent of chiral reagents, some of them, in particular the protocol of Myers et al (11,12), may be viewed as the current benchmarks. These methods typically require three steps involving (i) asymmetric ␣-alkylation, (ii) reduction of amides to alcohols, and (iii) iodination or similar activation toward enolates for iterative construction of reduced polypropionates.…”

mentioning

confidence: 99%

An efficient and general route to reduced polypropionates via Zr-catalyzed asymmetric C—C bond formation

Negishi

Tan²,

Liang³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

103

View full text Add to dashboard Cite

An efficient and general method for the synthesis of reduced polypropionates has been developed through the application of asymmetric carboalumination of alkenes catalyzed by dichlorobis(1-neomenthylindenyl)zirconium [(NMI) 2ZrCl2]. In this investigation, attention has been focused on those reduced polypropionates that are ␣-monoheterofunctional and either -ethyl or -n-propyl. The reaction of 3-buten-1-ol with triethylaluminum (Et 3 Al) or tripropylaluminum ( n Pr3Al) in the presence of (NMI)2ZrCl2 and isobutylaluminoxane gave, after protonolysis, (R)-3-methyl-1-pentanol as well as (R)-and (S)-3-methyl-1-hexanols in 88 -92% yield in 90 -92% enantiomeric excess in one step. These 3-monomethyl-1-alkanols were then converted to two stereoisomers each of 2,4-dimethyl-1-hexanols and 2,4-dimethyl-1-heptanols via methylalumination catalyzed by (NMI) 2ZrCl2 and methylaluminoxane followed by oxidation with O 2. The four-step (or three-isolation-step) protocol provided syn-2,4-dimethyl-1-alkanols of >98% stereoisomeric purity in Ϸ50% overall yields, whereas (2S,4R)-2,4-dimethyl-1-hexanol of comparable purity was obtained in 40% overall yield. Commercial availability of (S)-2-methyl-1-butanol as a relatively inexpensive material suggested its use in the synthesis of (2S,4S)-and (2R,4S)-2,4-dimethyl-1-hexanols via a three-step protocol consisting of (i) iodination, (ii) zincation followed by Pd-catalyzed vinylation, and (iii) Zr-catalyzed methylalumination followed by oxidation with O 2. This three-step protocol is iterative and applicable to the synthesis of reduced polypropionates containing three or more branching methyl groups, rendering this method for the synthesis of reduced polypropionates generally applicable. Its synthetic utility has been demonstrated by preparing the side chain of zaragozic acid A and the C11-C20 fragment of antibiotics TMC-151 A-F. O ligo-and poly(alkene)s with methyl groups bonded to alternating carbon atoms in the main chain (compound 1 in Fig. 1) are important structural units in both polymer materials chemistry (1) and natural products chemistry. The latter includes those reduced polypropionates that contain (i) two methylbranched asymmetric carbon centers, such as zaragozic acid A (compound 2 in Fig. 1) (2), and (ii) three methyl-branched asymmetric carbon centers, such as antibiotics TMC-151 A-F (compound 3 in Fig. 1) (3). The degree of polymerization of poly(propylene) usually exceeds 10 3 . As a consequence, most of the methyl-branched carbon centers may be considered to be ''virtually achiral,'' rendering their absolute configuration practically insignificant. On the other hand, their relative stereochemistry, termed tacticity, is of crucial importance in various respects. In the cases of reduced polypropionates, where the degree of polymerization is mostly Ͻ10, typically 2-4, both absolute and relative configurations of compound 1 (Fig. 1) are critically important. It is therefore essential to construct each methyl-bearing asymmetric carbon center with the correct absolute configurati...

show abstract

“…Rearrangement of 14 followed by trapping of the ketene with (+)-pseudoephedrine gave the homologated amide 15 in 80% yield. At this stage, the C12 methyl bearing stereocenter was introduced with high selectivity using Myers pseudoephedrine derived auxiliary 11 and afforded 16 in 96% yield. The magnitude of diastereoselectivity of the alkylation was determined to be >10:1 after reductive removal of the auxiliary using lithium amidotrihydroborate (LAB).…”

Section: Nih Public Access Author Manuscriptmentioning

confidence: 99%

Total Synthesis of Herboxidiene/GEX 1A.

Zhang

Panek

2007

ChemInform

View full text Add to dashboard Cite

A convergent enantioselective synthesis of herboxidiene/GEX 1A (1) is described, which features a double stereodifferentiating crotylation, [4+2]-annulation and a silicon-based sp 2 -sp 2 crosscoupling to assemble the conjugated diene.Herboxidiene/GEX 1A (1), a secondary metabolite originally isolated from Streptomyces sp. A7847, displayed selective phytotoxicity against a range of broadleaf annual weeds while remaining harmless to coplanted wheat. 1 In a search for new antitumor agents, 1 was reisolated from a fermentation culture broth with five other structurally related GEX 1 members (2-6, Figure 1). 2 While several members of this family showed potent cytotoxicity (IC 50 values ranging from 3.7 nM to 0.99 μM) against several human tumor cell lines in vitro, GEX 1A is the only one possessing antitumor activity in vivo. The entire family of GEX 1 compounds displayed cytotoxicity via up-regulating luciferase reporter gene expression as well as inducing both G1 and G2/M arrest in human tumor cell line The stereochemical assignment of 1 was obtained through a combination of degradation studies, partial synthesis and crystallographic analysis. 4 The class of natural products possesses several synthetically challenging structural features, including the trisubstituted tetrahydropyran core, the conjugated diene moiety and the poly-oxygenated side chain. Two total syntheses and several synthetic approaches toward herboxidiene/GEX 1A have recently been published. 5 Herein, we describe a convergent enantioselective total synthesis of herboxidiene/GEX 1A (1) that makes use of organosilane based bond construction methodology in three crucial ways (Scheme 1). The first disconnection at C9-C10 leads to a functionalized pyran core and an oxygenated side chain. We anticipated using a silicon-assisted sp 2 -sp 2 cross-coupling for panek@bu.edu. Supporting Information Available Experimental details and new selected spectral for all new compounds. This material is available free of charge in the Internet at http://pubs.acs.org. the union of intermediates 7 and 8. In this plan, the conjugated (E, E)-diene could be accessed with high levels of selectivity. Dihydropyran 7 could be obtained from syn-silane reagent 9 and the silyl-substituted methacrolein 10 utilizing our stereoselective [4+2]-annulation strategy. 6 Further, we hoped that side chain 11 could be rapidly constructed from silane reagent (S)-12 and α-silyloxy acetal (S)-13. NIH Public AccessSynthesis of the C10-C19 fragment was initiated with a double stereodifferentiating crotylation 7 based on the use of a newly developed crotylsilane reagent (S)-12 that bears a fully substituted stereocenter (Scheme 2). 8 Since the C18 hydroxyl would be properly configured for a directed epoxidation later in the synthesis, we chose (S)-silyloxy acetal 13, as the crotylation electrophile. 9 Thus, a matched crotylation between (S)-12 and (S)-13 promoted by TMSOTf, provided the desired syn-homoallylic ether 11 containing a trans trisubstituted olefin in 62% yield and high dias...

show abstract

Pseudoephedrine as a Practical Chiral Auxiliary for the Synthesis of Highly Enantiomerically Enriched Carboxylic Acids, Alcohols, Aldehydes, and Ketones

Cited by 579 publications

References 50 publications

Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists

Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists

An efficient and general route to reduced polypropionates via Zr-catalyzed asymmetric C—C bond formation

Total Synthesis of Herboxidiene/GEX 1A.

Contact Info

Product

Resources

About