Article pubs.acs.org/OPRD
An Asymmetric Synthesis of a Chiral Sulfone Acid with Concomitant Hydrolysis and Oxidation to Enable the Preparation of a Glucokinase Activator Amy C. DeBaillie,*,† Nicholas A. Magnus,† Michael E. Laurila,† James P. Wepsiec,† J. Craig Ruble,‡ Jeffrey J. Petkus,‡ Radhe K. Vaid,† Jeffry K. Niemeier,† Joseph F. Mick,† and Thomas Z. Gunter† †
Chemical Product Research and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
‡
ABSTRACT: This contribution describes the demonstration of an asymmetric synthesis of a glucokinase activator via protonation of the enolate generated from an alkylaryl ketene and (R)-pantolactone. Additionally, a one-pot hydrolysis/oxidation protocol with lithium hydroperoxide was developed to afford a chiral sulfone acid without degradation of the labile stereocenter.
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INTRODUCTION It is estimated that 346 million people worldwide have diabetes, and the World Health Organization (WHO) anticipates that diabetes deaths will double between 2005 and 2030.1 Of the three types of diabetes, type 2 is the most common form and is characterized by the body’s inability to control glucose.2 The glucose-phosphorylating enzyme, glucokinase, has been identified as a promising drug target for type 2 diabetes and has led to the development of several glucokinase activators.3 The glucokinase activator (GKA), (R)-1 (Figure 1), was developed as a potential therapeutic agent for the treatment of
substrate to catalyst ratio (s/c) of 2000 to 1 was required. Sulfone acid (R)-3 was obtained in 86% ee and was upgraded to >99% ee via recrystallization. A charcoal-absorbent treatment was required to remove residual rhodium, which led to significant yield loss. Since it had been reported that pantolactone adds to ketenes to yield esters with high stereoselectivity6−8 and the reagent is readily available,9 we investigated its utilization in the asymmetric synthesis of glucokinase activator (R)-1. We chose to target the synthesis of (R)-3 and utilize the amide coupling conditions as described by Prosidion.5 To that end, chiral sulfone acid (R)-3 would be generated from the addition of (R)-pantolactone to the ketene produced from racemic sulfide acid 5 and subsequent hydrolysis and oxidation of ester 4 (Figure 2). To investigate this approach, an efficient synthesis of racemic sulfide acid 5 was developed from sulfide α-ketoester 710 (Scheme 2). Wittig olefination of 7 with the ylide generated from phosphonium iodide 8 and lithium hexamethyldisilazide (LiHMDS) gave sulfide acrylic esters 9 as a 55:45 mixture of E:Z isomers, which contained residual triphenylphosphine oxide that could be removed in the subsequent step. Hydrolysis of the (E/Z)-sulfide acrylic esters, 9, cleanly gave the (E/Z)sulfide acrylic acids 10 in a 89% yield.11 The hydrogenation of (E/Z)-sulfide acrylic acids 10 to yield sulfide acid 5 proved to be challenging and required less than ideal substrate-to-catalyst loadings (Scheme 3, Table 1).12 Pd/ C required a 3:1 s/c, 150 psig (1034 kPa), and 75 °C to completely consume 10 (entries 1 and 2). Wilkinson’s catalyst, (RuCl(PPh3)3), (entries 3 and 4) and [Rh(dippf)(cod)]BF4 (entries 5−8) were found to be effective at reducing the olefin without being sufficiently poisoned; however, at least one equivalent of triethylamine was necessary to suppress hydrogenation of the cyclopropyl moiety to give 11 (Scheme 3).12 Using preformed [Rh(dippf)(cod)]BF4 at a 200:1 s/c, 5 was obtained in a 84% yield after recrystallization on a 100-g scale
Figure 1. Glucokinase activator (R)-1.
type 2 diabetes. It was designed to lower blood glucose levels by increasing the uptake of glucose in the liver and increasing insulin secretion from the pancreas. Herein, we describe the demonstration of an asymmetric synthesis of glucokinase activator (R)-1 via protonation of the enolate generated from an alkylaryl ketene and (R)-pantolactone4 followed by concomitant hydrolysis and oxidation.
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RESULTS AND DISCUSSION The goal of this research was to demonstrate a cost-effective, asymmetric synthesis of glucokinase activator (R)-1 with the potential for scale-up. Previous quantities of the active pharmaceutical ingredient (API), (R)-1, had been prepared via a synthesis devised by Prosidion Ltd. that utilized an enantioselective hydrogenation to set the labile chiral center (Scheme 1).5 In order to convert (E)-acrylic acid 2 to chiral sulfone acid (R)-3, 750 psig (5171 kPa) of hydrogen and a © 2012 American Chemical Society
Received: May 27, 2012 Published: August 13, 2012 1538
dx.doi.org/10.1021/op300139g | Org. Process Res. Dev. 2012, 16, 1538−1543
Organic Process Research & Development
Article
Scheme 1. Prosidion’s synthesis of (R)-1
Figure 2. Retrosynthetic analysis of glucokinase activator (R)-1.
Scheme 2. Synthesis of (E/Z)-sulfide acrylic acids 10
Scheme 3. Hydrogenation of (E/Z)-sulfide acrylic acids 10
Table 1. Hydrogenation of (E/Z)-sulfide acrylic acids 10 to yield racemic sulfide acid 5 entry
catalyst
pressure (psig H2)
temp (°C)
time (h)
conversion/yield
1 2 3 4a 5b,c 6b 7b 8b
5% Pd/C Degussa type (8:1 s/c) 5% Pd/C Degussa type (3:1 s/c) RhCl(PPh3)3 (30:1 s/c) RhCl(PPh3)3 (30:1 s/c) [Rh(dippf)(cod)]BF4 (200:1 s/c) 0.1 mol % Rh with dippf ligand prepared from [Rh(cod)2]CF3SO3 0.1 mol % Rh with dippf ligand prepared from [Rh(nbd)Cl]2 0.1 mol % Rh with dippf ligand prepared from [Rh(cod)2]BF4
150 150 50 50 50 50 50 50
75 75 50 50 24 24 24 24
12 12 24 18 24 16 16 16
1:1 mixture of 10:5 by 1H NMR 100% conversion by 1H NMR 1:0.55 mixture of 5:11 by 1H NMR 100% conversion by 1H NMR 84% isolated yield 100% by HPLC 100% by HPLC 100% by HPLC
a
3.0 equiv of TEA. b1.0 equiv of TEA. cEtOH was utilized as the reaction solvent. Entries 1−4 and 6−8 were conducted in MeOH.
(entry 5). The substrate-to-catalyst loading was further improved to 1000:1 via the in situ preparation of the catalyst in MeOH with 1.0 equiv of triethylamine at 24 °C and 50 psig (345 kPa) (entries 6−8). With 5 in hand, the selectivity of the protonation of the enolate generated from the sulfide alkylaryl ketene 13 and (R)pantolactone (6) could be evaluated. Treatment of 5 with
oxalyl chloride and catalytic DMF in toluene generated the acid chloride 12 (Scheme 4). The reaction solution was cooled to 0 °C, and 3 equiv of dimethylethylamine6 was added to generate 13. Addition of a solution of 6 in toluene to 13 at −78 °C generated sulfide ester 4 in 98% yield and 88% de as determined by HPLC. Additionally, it was shown that changing the reaction solvent to THF (instead of toluene) gave sulfide 1539
dx.doi.org/10.1021/op300139g | Org. Process Res. Dev. 2012, 16, 1538−1543
Organic Process Research & Development
Article
Scheme 4. Addition of (R)-pantolactone (6) to the ketene (13) generated from racemic sulfide acid 5
sulfide oxidation state. The hydrolysis of 4 to chiral sulfide acid 14 was initially investigated with hydroxide sources (LiOH, NaOH, or KOH in THF/H2O) (Scheme 5). Comparison of the diastereomeric and enantiomeric excess data indicated that ∼10% erosion of the stereocenter was occurring under these conditions. Surprisingly, upon exposure of 4 to lithium hydroperoxide,13 oxidation of the sulfide to the sulfoxide and sulfone was observed in addition to the desired hydrolysis. Furthermore, a more concentrated reaction (5−7 vols) with 4 equiv of LiOH and 8 equiv of H2O2 enabled complete hydrolysis with concomitant oxidation to yield sulfone acid (R)3 without erosion of the stereocenter. We hypothesize that intermediate peracids derived from sulfide ester 4 and pantolactone are the active oxidants generated under the lithium hydroperoxide conditions. To test this theory, sulfide acid 5 was exposed to the lithium hydroperoxide reaction conditions, and
