1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains

Lynch, Christopher L.; Willoughby, Christopher A.; Hale, Jeffrey J.; Holson, Edward J.; Budhu, Richard J.; Gentry, Amy L; Rosauer, Keith G.; Caldwell, Charles G.; Chen, Ping; Mills, Sander G.; MacCoss, Malcolm; Berk, Scott C.; Chen, Liya; Chapman, Kevin T.; Malkowitz, Lorraine; Springer, Martin S.; Gould, Sandra L.; DeMartino, Julie A.; Siciliano, Salvatore; Cascieri, Margaret A.; Carella, Anthony; Carver, Gwen; Holmes, Karen; Schleif, William A.; Danzeisen, Renee; Hazuda, Daria; Kessler, Joseph; Lineberger, Janet; Miller, Michael D.; Emini, Emilio A.

doi:10.1016/s0960-894x(02)00829-6

Cited by 49 publications

(12 citation statements)

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“…A case study from a recent Merck campaign demonstrates the power of a concurrent RCC strategy for modularly generating C(sp 3 )–rich scaffolds (Fig. 3B) such as 87a and 87b (33, 34). In the original preparation, the absence or presence of fluorine atoms dictates the starting materials and methods used.…”

mentioning

confidence: 99%

Modular radical cross-coupling with sulfones enables access to sp ³ -rich (fluoro)alkylated scaffolds

Merchant

Edwards

Qin

et al. 2018

Science

189

119

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Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron-induced variants of this reaction class have proven particularly useful in the formation of C(sp)-C(sp) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents. This method's tolerance of fluoroalkyl substituents proved particularly advantageous for the streamlined preparation of pharmaceutically oriented fluorinated scaffolds that previously required multiple steps, toxic reagents, and nonmodular retrosynthetic blueprints. Five specific sulfone reagents facilitate the rapid assembly of a vast set of compounds, many of which contain challenging fluorination patterns.

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confidence: 99%

Modular radical cross-coupling with sulfones enables access to sp ³ -rich (fluoro)alkylated scaffolds

Merchant

Edwards

Qin

et al. 2018

Science

189

119

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“…[1] As ar esult, the incorporation of aC F 2 group into organic compounds at benzylic positions has become one of the useful strategies for modification of biologically active compounds (Figure 1). [2] Fore xample,a pplication of this strategy led to ad ifluorinated nitric oxide synthase (NOS) inhibitor (I) for chronic neurodegenerative pathologies with improved oral bioactivity compared to its parent compound. [2a] Ar emark-ably improved metabolic stability of urea transporter B(UT-B) inhibitor (II), used for edema, has also resulted from replacement of benzylic CH 2 with CF 2 .…”

mentioning

confidence: 99%

Nickel‐Catalyzed Difluoroalkylation of (Hetero)Arylborons with Unactivated 1‐Bromo‐1,1‐difluoroalkanes

2016

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“…Furthermore, the crucial fluorination step utilized HF and provided no opportunity for synthetic modularity (i.e., variable F incorporation), a vital aspect of expedited discovery campaigns. While the two-electron synthons from polar retrosynthetic analysis seem straightforward because they originate from carbonyl chemistry, the lack of chemoselectivity limits its overall efficiency . Whereas incorporation of F atoms usually dictates the focus of a retrosynthetic analysis, RCC simplifies and modularizes the approach as it treats such functionality no differently than any other substituent (such as a methyl group).…”

Section: Strategic Applications Of Radical Cross-couplingmentioning

confidence: 99%

Radical Retrosynthesis

2018

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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...

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1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains

Cited by 49 publications

References 11 publications

Modular radical cross-coupling with sulfones enables access to sp ³ -rich (fluoro)alkylated scaffolds

Modular radical cross-coupling with sulfones enables access to sp ³ -rich (fluoro)alkylated scaffolds

Nickel‐Catalyzed Difluoroalkylation of (Hetero)Arylborons with Unactivated 1‐Bromo‐1,1‐difluoroalkanes

Radical Retrosynthesis

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1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains

Cited by 49 publications

References 11 publications

Modular radical cross-coupling with sulfones enables access to sp 3 -rich (fluoro)alkylated scaffolds

Modular radical cross-coupling with sulfones enables access to sp 3 -rich (fluoro)alkylated scaffolds

Nickel‐Catalyzed Difluoroalkylation of (Hetero)Arylborons with Unactivated 1‐Bromo‐1,1‐difluoroalkanes

Radical Retrosynthesis

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Modular radical cross-coupling with sulfones enables access to sp ³ -rich (fluoro)alkylated scaffolds

Modular radical cross-coupling with sulfones enables access to sp ³ -rich (fluoro)alkylated scaffolds