ChemInform Abstract: Formation of Acetaldehyde Enolate from Vinyl Acetate and Its Reaction with Aromatic and Heterocyclic Aldehydes: An Efficient Synthesis of Enals and Polyenals.

Mahata, Pranab Kumar; Barun, Okram; Ila, H.; Junjappa, H.

doi:10.1002/chin.200049105

Cited by 14 publications

(19 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is noted that the 4-chloro enal 3a was readily prepared from commercially available 4-chlorobenzaldehdye. [20] Moreover, experimentally, the (R)-2b was demonstrated to be efficiently transformed to (R)-baclofen (1a) HCl salt using the same procedures in a gram-scale (Scheme 2).…”

Section: Scheme 2 Synthesis Of (S)-and (R)-baclofens (1)mentioning

confidence: 97%

Highly Enantioselective Organocatalytic Conjugate Addition of Nitromethane to α,β‐Unsaturated Aldehydes: Three‐Step Synthesis of Optically Active Baclofen

Xie

et al. 2007

Adv Synth Catal

131

View full text Add to dashboard Cite

An efficient, organocatalytic, highly enantioselective, conjugate addition reaction of nitromethane with a,b-unsaturated aldehydes has been developed. The process serves as the key step for a practical 3-step synthesis of chiral baclofen, an antispastic drug.Keywords: asymmetric catalysis; asymmetric synthesis; C À C bond formation; Michael addition; organic catalysisThe synthesis of natural products and therapeutics has served as a principal driving force for discovering new synthetic methods. On the other hand, the synthetic value of useful synthetic methods can be quickly established in the context of the efficient preparation of biologically important pharmaceuticals and natural products. Baclofen (1; Figure 1), a potent GABA B receptor agonist, is used for the treatment of spinal cord injury-induced spasm.[1] Despite the fact that the racemic form of baclofen is used in clinical practice, [1a] the (R) enantiomer is the essential active chemical entity and its (S) form is inactive. Accordingly, a great deal of effort has been directed to the synthesis of chiral (R)-baclofen. These methodologies rely on the use of chiral precursors, [2] chiral auxiliaries, [3] and chemical [4] and enzymatic [5] resolutions. Atom-economic asymmetric catalytic strategies including organometallic [6] and organocatalytic [7] systems also have been developed. However, these approaches suffer from long synthetic sequences and the use of not readily available chemicals, thus limiting their practical application for a large-scale synthesis. The synthetic significance is further underscored by the utilization of baclofen as a lead compound for the design of GABA agonists and antagonists to seek new therapeutic agents targeting on the central nervous system (CNS). [1a,8] The analogues of baclofen can potentially be developed for the treatment of a variety of diseases including epilepsy, Huntingtons and Parkinsons diseases, and other psychiatric disorders, such as anxiety and pain. [1a,8] As a consequence, the development of general, efficient synthetic strategies enabling a facile approach to chiral baclofen and its analogues is of considerable significance from the standpoint of the medicinal and organic chemistry. Driven by the lack of such a facile access to this class of compounds, in this communication we disclose a remarkably efficient and practical route for the highly enantioselective synthesis of optically active baclofen in 3 steps from the readily available simple achiral molecules a,b-unsaturated aldehydes and nitroalkanes. The key step relies on a highly efficient organocatalytic enantioselective conjugate addition reaction of nitromethane with a,b-unsaturated aldehydes, which we have successfully developed in the study. This efficient synthetic strategy can be further explored for the rapid preparation of new chiral baclofen analogues in drug discovery.Our synthetic strategy towards chiral baclofen (1) is described in Scheme 1. We hypothesized that compound 1 could be constructed from chiral g-nitro aldehyde 2...

show abstract

Section: Scheme 2 Synthesis Of (S)-and (R)-baclofens (1)mentioning

confidence: 97%

Highly Enantioselective Organocatalytic Conjugate Addition of Nitromethane to α,β‐Unsaturated Aldehydes: Three‐Step Synthesis of Optically Active Baclofen

Xie

et al. 2007

Adv Synth Catal

131

View full text Add to dashboard Cite

show abstract

“…[21] We were unable to reproduce the latter synthesis, even under a variety of experimental conditions. We optimized the preparation of aldehyde 21 adopting the procedure described for the 3,4-dimethoxy analogues, [22] that is, reaction of the commercially available acid 20 with thionyl chloride, followed by reduction of the resulting acyl chloride by LiAlH-(OtBu) 3 in dry THF.…”

Section: Synthesismentioning

confidence: 96%

“…An equimolar mixture (1 mmol) of tetronic acid 15, aldehyde 13, [17] and aniline 14 in EtOH (10 mL) was held at reflux for 1 h. The resulting solid was removed by filtration and recrystallized from MeOH to afford 5 as a white powder (217 mg, 50 %): R f = 0. 13 [19] and aniline 14 in EtOH (7 mL) was held at reflux for 4 h. The resulting solid was removed by filtration, purified by flash chromatography (EtOAc/CH 2 Cl 2 , 1:9), and then recrystallized from EtOH to afford 8 as a white solid (345 mg, 97 %): R f = 0.54 (EtOAc); mp: > 260 8C; (2E)-3-(3,4,5-Trimethoxyphenyl)prop-2-enal (21). A solution of (E)-3,4,5-trimethoxycinnamic acid (20) (2.38 g, 10 mmol) and SOCl 2 (2.2 mL, 30 mmol) in 1,2-dichloroethane (100 mL) was held at reflux for 2 h. The solvent was eliminated under reduced pressure, and the crude resulting yellow solid was dissolved in anhydrous THF (100 mL).…”

Section: Chemistrymentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of the First Podophyllotoxin Analogues as Potential Vascular‐Disrupting Agents

et al. 2010

View full text Add to dashboard Cite

We designed and synthesized two novel series of azapodophyllotoxin analogues as potential antivascular agents. A linker was inserted between the trimethoxyphenyl ring E and the tetracyclic ABCD moiety of the 4-aza-1,2-didehydropodophyllotoxins. In the first series, the linker enables free rotation between the two moieties; in the second series, conformational restriction of the E nucleus was considered. We have identified several new compounds with inhibitory activity toward tubulin polymerization similar to that of CA-4 and colchicine, while displaying low cytotoxic activity against normal and/or cancer cells. An aminologue and a methylenic analogue were shown to disrupt endothelial cell cords on Matrigel at subtoxic concentrations, and an original assay of drug washout allowed us to demonstrate the rapid reversibility of this effect. These two new analogues are promising leads for the development of vascular-disrupting agents in the podophyllotoxin series.

show abstract

“…Substrates 3b-d were prepared by Wittig reactions, while compound 3e was prepared by refluxing 2-naphthaldehyde, vinyl acetate and Ba(OH) 2 in THF. 15 With the exception of the reaction performed on (E)-3-(4-nitrophenyl)acrylaldehyde (3d) all processes showed good yields and good diastereo-and enantioselectivities. Moreover in each case the major isomer 4 could be recovered by chromatography on silica gel as a single diastereomer (de >99%).…”

mentioning

confidence: 97%

Enantioselective Methoxyselenenylation of α,β-Unsaturated Aldehydes

Santi¹,

Santoro²,

Tomassini³

et al. 2009

Synlett

View full text Add to dashboard Cite

In this communication we propose a convenient methodology to effect the asymmetric methoxyselenenylation of b-aryl a,b-unsaturated aldehydes using as electrophilic reagent an optically pure sulfur-containing selenenyl chloride. Mechanistic aspects of the reaction were investigated and simple manipulations to prepare optically pure derivatives are reported.Organoselenium compounds are very useful reagents in organic synthesis and they have been extensively used in a wide range of reactions, varying from cationic, radical and anionic transformations, to rearrangements and eliminations. 1 During the last decades the design of enantiomerically pure diselenides and their use as electrophilic reagents precursors have emerged as practical and powerful tools for the stereoselective preparation of chiral molecules. 1-3 We reported the synthesis of a new class of enantiopure sulfur-containing diselenides and their synthetic applications to promote enantioselective selenium addition reactions to unsaturated substrates. 4 Electrophilic reagents generated starting from diselenide 1 were successfully employed to prepare enantiomerically enriched alcohols, 5 ethers, 5 azides, 6 heterocycles 7 as well as for the kinetic resolution of allylic alcohols. 8 All the investigated reactions showed a very high facial selectivity, higher than those obtained with the corresponding nitrogen-or oxygen-containing reagents. 3 We demonstrated also that the facial selectivity is strongly correlated to the nonbonding interaction established between the electrophilic selenium and the sulfur atom in compounds like 2. 9 This compound is an air-stable solid that can be easily prepared starting from diselenide 1 by treatment with SO 2 Cl 2 and crystallization from diethyl ether (Scheme 1). It can be successfully used in a large series of asymmetric conversions. [5][6][7][8][9] In this communication the first efficient asymmetric methoxyselenenylation of a,b-unsaturated aldehydes is reported. Paulmier and co-workers have already described a methodology for the methoxyselenenylation of these substrates using PhSeCl in MeOH at -30 °C. 10 The authors claim that this process proceeds through a dimethylacetal intermediate, which undergoes electrophilic selenomethoxylation via seleniranium ion intermediate. This process, however, occurs with poor regio-and stereoselectivity and it is strongly conditioned by the nature of the substrate.In order to find the best reaction conditions preliminary experiments were carried out starting from cinnamaldehyde (3a) using the Ar*SeCl 2 as electrophilic selenenylating reagent at different temperatures and evaluating also the effect of MgSO 4 as an additive. The results are summarized in Table 1.All of the reactions led to the formation of four enantiomerically pure diastereomers 4a-7a, one of which in much higher yield (4a). Only this major isomer could be purified from the reaction mixture by flash chromatograScheme 1 Preparation of chiral electrophilic selenium reagent S M e S e ) 2 E t 2

show abstract

ChemInform Abstract: Formation of Acetaldehyde Enolate from Vinyl Acetate and Its Reaction with Aromatic and Heterocyclic Aldehydes: An Efficient Synthesis of Enals and Polyenals.

Cited by 14 publications

References 1 publication

Highly Enantioselective Organocatalytic Conjugate Addition of Nitromethane to α,β‐Unsaturated Aldehydes: Three‐Step Synthesis of Optically Active Baclofen

Highly Enantioselective Organocatalytic Conjugate Addition of Nitromethane to α,β‐Unsaturated Aldehydes: Three‐Step Synthesis of Optically Active Baclofen

Design, Synthesis, and Biological Evaluation of the First Podophyllotoxin Analogues as Potential Vascular‐Disrupting Agents

Enantioselective Methoxyselenenylation of α,β-Unsaturated Aldehydes

Contact Info

Product

Resources

About