The Ireland–Claisen rearrangement strategy towards the synthesis of the schizophrenia drug, (+)-asenapine

Anugu, Raghunath Reddy; Mainkar, Prathama S.; Sridhar, Balasubramanian; Chandrasekhar, Srivari

doi:10.1039/c5ob02047f

Cited by 20 publications

(12 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This near-symmetric molecule has been challenging to prepare enantioselectively as the two aromatic systems differ only in one chlorine substituent. It is therefore hard to envisage a cycloaddition that could be rendered enantioselective for the preparation of 102 , and only one enantioselective approach has been reported (16 steps) 26 . In contrast, 102 could be prepared in formally six steps from B 2 with complete enantiocontrol by a strategy that could also be used to make an array of near-symmetric analogs.…”

mentioning

confidence: 99%

Building C(sp3)-rich complexity by combining cycloaddition and C–C cross-coupling reactions

Chen

Barton

Lin

et al. 2018

Nature

View full text Add to dashboard Cite

Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres, cycloaddition reactions have featured in numerous total syntheses and are a key component in the education of chemistry students. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp manner. Despite the ability of cycloadditions to introduce multiple carbon sp centres in a single step, they are less used. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.

show abstract

mentioning

confidence: 99%

Building C(sp3)-rich complexity by combining cycloaddition and C–C cross-coupling reactions

Chen

Barton

Lin

et al. 2018

Nature

View full text Add to dashboard Cite

show abstract

“…The use of this RCC strategy exploited the modular nature of cross-couplings to install similarly functionalized arenes where selectivity issues could be mitigated . It is instructive to compare the radical-based route to a more conventional polar analysis as was reported by Chandrasekhar in 2016 . Initially, allylic alcohol 161 (synthesized in 10 steps) was esterified with acid 162 under Mitsunobu conditions, thereby setting the stage for an Ireland–Claisen rearrangement, which proceeded with 9:1 selectivity.…”

Section: Strategic Applications Of Radical Cross-couplingmentioning

confidence: 95%

“…43 It is instructive to compare the radical-based route to a more conventional polar analysis as was reported by Chandrasekhar in 2016. 47 Initially, allylic alcohol 161 (synthesized in 10 steps) was esterified with acid 162 under Mitsunobu conditions, thereby setting the stage for an Ireland− Claisen rearrangement, which proceeded with 9:1 selectivity. The resultant acid was methylated, and oxidative cleavage of the intermediate olefin provided an aldehyde.…”

Section: Accounts Of Chemical Researchmentioning

confidence: 99%

Radical Retrosynthesis

2018

View full text Add to dashboard Cite

In The Logic of Chemical Synthesis, E. J. Corey stated that the key to retrosynthetic analysis was a "wise choice of appropriate simplifying transforms" ( Corey , E. J. ; Cheng , X.-M. The Logic of Chemical Synthesis ; John Wiley : New York , 1989 ). Through the lens of "ideality", chemists can identify opportunities that can lead to more practical, scalable, and sustainable synthesis. The percent ideality of a synthesis is defined as [(no. of construction rxns) + (no. of strategic redox rxns)]/(total no. of steps) × 100. A direct consequence of designing "wise" or "ideal" plans is that new transformations often need invention. For example, if functional group interconversions are to be avoided, one is faced with the prospect of directly functionalizing C-H bonds ( Gutekunst , W. R. ; Baran , P. S. Chem. Soc. Rev. 2011 , 40 , 1976 ; Brückl , T. ; et al. Acc. Chem. Res. 2012 , 45 , 826 ). If protecting groups are minimized, methods testing the limits of chemoselectivity require invention ( Baran , P. S. ; et al. Nature 2007 , 446 , 404 ; Young , I. S. ; Baran , P. S. Nat. Chem. 2009 , 1 , 193 ). Finally, if extraneous redox manipulations are to be eliminated, methods directly generating key skeletal bonds result ( Burns , N. Z. ; et al. Angew. Chem., Int. Ed. 2009 , 48 , 2854 ). Such analyses applied to total synthesis have seen an explosion of interest in recent years. Thus, it is the interplay of aspirational strategic demands with the limits of available methods that can influence and inspire ingenuity. E. J. Corey's sage advice holds true when endeavoring in complex molecule synthesis, but together with the tenets of the "ideal" synthesis, avoiding concession steps leads to the most strategically and tactically optimal route ( Hendrickson , J. B. J. Am. Chem. Soc. 1975 , 97 , 5784 ; Gaich , T. ; Baran , P. S. J. Org. Chem. 2010 , 75 , 4657 ). Polar disconnections are intuitive and underlie much of retrosynthetic logic. Undergraduates exposed to multistep synthesis are often taught to assemble organic molecules through the combination of positively and negatively charged synthons because, after all, opposites attract. Indeed, the most employed two-electron C-C bond forming reactions today are those based upon either classical cross-coupling reactions (e.g., Suzuki, Negishi, or Heck) or polar additions (aldol, Michael, or Grignard). These reactions are the mainstay of modern synthesis and have revolutionized the way molecules are constructed due to their robust and predictable nature. In contrast, radical chemistry is sparsely covered beyond the basic principles of radical chain processes (i.e., radical halogenation). The historical perception of radicals as somewhat uncontrollable species does not help the situation. As a result, synthetic chemists are not prone to make radical-based strategic bond disconnections during first-pass retrosynthetic analyses. Recent interest in the use of one-electron radical cross-coupling (RCC) methods has been fueled by the realization of their uniquely chemoselective profiles a...

show abstract

“…In 2016, Chandrasekhar published a synthesis of asenapine ( 122 ) in optically pure form employing a Ireland–Claisen rearrangement as the key step (Scheme 27 ). 32 Starting from commercially available ( S )-ethyl lactate 123 , chiral pyrrolidine 124 was obtained in twelve steps. The dihydrooxepin ring was closed under Ullmann conditions to afford the desired natural product (+)-asenapine ( 122 ) in 71% yield and 94% ee.…”

Section: Dihydrooxepin Productsmentioning

confidence: 99%

Total Synthesis of Oxepin and Dihydrooxepin Containing Natural Products

Sokol¹,

Magauer²

2021

Synthesis

View full text Add to dashboard Cite

The construction of oxepin and dihydrooxepin containing natural products represents a challenging task in total synthesis. In the last decades, a variety of synthetic methods have been reported for the installation of these structural motifs. Herein, we provide an overview of synthetic methods and strategies to construct these motifs in the context of natural product synthesis and highlight the key steps of each example.1 Introduction2 Oxepin Natural Products3 Dihydrooxepin Natural Products3 Brønsted or Lewis acid Catalyzed Cyclization3.2 Radical Cyclization3.3 Substitution and Addition Cyclization3.4 Sigmatropic Rearrangement3.5 Oxidative Methods3.6 Transition Metal Catalyzed Cyclization4 Summary

show abstract

The Ireland–Claisen rearrangement strategy towards the synthesis of the schizophrenia drug, (+)-asenapine

Abstract: (±)-Asenapine, sold in the market as Saphris/Sycrest for the treatment of bipolar disorders, is synthesized in an optically pure form involving an Ireland-Claisen rearrangement as the key step. This approach allows access to all diastereomers.

Cited by 20 publications

References 18 publications

Building C(sp3)-rich complexity by combining cycloaddition and C–C cross-coupling reactions

Building C(sp3)-rich complexity by combining cycloaddition and C–C cross-coupling reactions

Radical Retrosynthesis

Total Synthesis of Oxepin and Dihydrooxepin Containing Natural Products

Contact Info

Product

Resources

About