An expedient synthesis of maraviroc (UK-427,857) via C–H functionalizationby T. Aaron Bedell, Graham A.B. Hone, Justin Du Bois, Erik J. Sorensen

Tetrahedron Letters

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Year
2015
DOI
10.1016/j.tetlet.2015.01.074
Subject
Organic Chemistry / Biochemistry / Drug Discovery

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An expedient synthesis of maraviroc (UK-427,857) via C–H functionalization

T. Aaron Bedell, Graham A.B. Hone, Justin Du Bois, Erik J. Sorensen

PII: S0040-4039(15)00089-1

DOI: http://dx.doi.org/10.1016/j.tetlet.2015.01.074

Reference: TETL 45744

To appear in: Tetrahedron Letters

Received Date: 31 December 2014

Revised Date: 8 January 2015

Accepted Date: 11 January 2015

Please cite this article as: Aaron Bedell, T., Hone, G.A.B., Du Bois, J., Sorensen, E.J., An expedient synthesis of maraviroc (UK-427,857) via C–H functionalization, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/ j.tetlet.2015.01.074

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An expedient synthesis of maraviroc (UK427,857) via C-H functionalization

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An expedient synthesis of maraviroc (UK-427,857) via C–H functionalization

T. Aaron Bedell†¶, Graham A. B. Hone†¶, Justin Du Bois‡, Erik J. Sorensen†* †Department of Chemistry, Princeton University, Princeton, NJ 08544, United States ‡Department of Chemistry, Stanford University, Stanford, California 94305, United States ¶

T.A.B. and G.A.B.H. contributed equally to this work ejs@princeton.edu 1. Introduction

As of 2013, there were 35.3 million people worldwide living with human immunodeficiency virus (HIV) and 2 million new infections acquired that year. At the same time, approximately 1.5 million individuals died from acquired immunodeficiency syndrome (AIDS), a rate of three every minute annually.1

Although the number of people currently infected with HIV has continued to grow over the last decade, the number of new infections has also dropped, indicating that HIV/AIDS has transitioned from a death sentence to what can be considered a manageable, chronic condition.2,3 The discovery and subsequent approval of the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine (1, AZT, Retrovir®) (Figure 1) in 1987 transformed the treatment of HIV infection,4 so much so that it has resided on the World Health Organization’s Model Lists of Essential

Medicines since 1998.5 Unfortunately, however, the use of monotherapy rapidly led to the emergence of drug resistant strains. The next leap forward for treatment came with the advent of highly active antiretroviral therapy (HAART) in 1996; this next revolution in HIV treatment was enabled by the synthesis, development, and approval of both new NRTIs, as well as new classes of drugs targeting other stages of the viral life cycle.2-4

Pfizer’s maraviroc (2, UK-427,857, Selzentry®) is a chemokine receptor antagonist that belongs to the fusion/entry inhibitor class. These compounds disrupt viral entry by inhibiting the binding of the HIV virus to CCR-5, a G protein-coupled receptor (GPCR) found primarily in cells of the immune system.6

Maraviroc acts as a CCR-5 antagonist by preventing this binding event, while enfuvirtide (3, Fuzeon®), an injectable polypeptide and the only other approved member of this class, binds a transmembrane protein of HIV (gp41) disrupting the final phase of viral fusion.7 Thus, maraviroc, which received FDA approval in 2007, is the only orally-dosed, small-molecule therapy targeting HIV viral entry.8

Figure 1. Selected FDA-approved HIV drugs

The molecular structure of maraviroc also induced diverse and creative efforts to construct its single, nitrogen-bearing benzylic stereocenter. The pioneering and highly convergent medicinal chemistry9 and process chemistry10,11 syntheses of maraviroc (2) by Pfizer (Scheme 1) utilized an intermolecular

Mannich/enantiomer resolution process to produce β-amino ester 4, a key intermediate that was subsequently employed in

A R TI C LE IN FO A BS TRA C T

Article history:

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A new, concise synthesis of the CCR-5 receptor antagonist maraviroc (UK-427,857) from 3phenyl-1-propanol has been completed in four steps featuring a site-selective C–H functionalization. 2009 Elsevier Ltd. All rights reserved.

Keywords:

C-H functionalization

HIV/AIDS

CCR-5

Maraviroc

Amination 2 coupling reactions with 4,4-difluorocyclohexane-1-carboxylic acid 5 and tropane triazole 612 to complete the synthesis. The subsequent syntheses of maraviroc by the laboratories of

Schaus13 and Cordóva14 retained the logic of Pfizer’s convergent synthesis design and featured chiral catalyst-controlled, asymmetric allylation and aza-Michael reactions, respectively, to establish the absolute configuration of the nitrogen-bearing stereocenter of maraviroc (2).

Scheme 1. Pfizer’s retrosynthetic analysis and key intermediates in prior syntheses of maraviroc (2).

Through our ongoing collaborations with the Center for

Selective C–H Functionalization (CCHF), we were drawn to the concept of constructing the benzylic C–N bond of maraviroc in the course of a Du Bois cyclization of acyclic sulfamate ester 7 (Scheme 2).15, 16-32 In the wake of the pivotal, ring-forming rhodium nitrene C–H insertion reaction (7 → 8), we would capitalize on the activation provided by the sulfonyl tethering element to achieve the final two C–N bond formations (8 → 9 → 2).

Scheme 2. A design for synthesizing maraviroc (2) featuring a Du Bois cyclization and the activation provided by a sulfonyl group.

In relation to the prior syntheses of maraviroc, this strategy would not require any oxidation state adjustments in the ascension to maraviroc (2).33 The simple –SO2– group that would be required for the key Du Bois cyclization would be expelled15 in the course of the final nucleophilic attack of the tropane building block on the terminal carbon of the activated, N-acylated cyclic sulfamate (9 → 2). The realization of this strategy featuring the use of a sulfonyl group as both a traceless directing and activating group in a synthesis of maraviroc (2) is described below.