An Efficient Enantioselective Synthesis of an Indane Acetic Acid
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TETRAHEDRON: ASYMMETRY Pergamon Tetrahedron: Asymmetry 14 (2003) 3447–3453 An efficient enantioselective synthesis of an indane acetic acid derivative: methyl (2S)-2-[(1S)-5-hydroxy- 2,3-dihydro-1H-inden-1-yl]butanoate Mingbao Zhang,* Lei Zhu and Xin Ma Department of Chemistry Research, Bayer Research Center, West Haven, CT 06516, USA Received 10 June 2003; accepted 17 July 2003 Abstract—We have developed a practical enantioselective synthesis of 1, a novel indane acetic acid derivative with two contiguous stereogenic centers. The key indene acetic acid framework was constructed via a robust, unprecedented Reformatsky process. One stereogenic center was set via a resolution, and the other via a highly diastereoselective hydrogenation of the indene acetic acid. © 2003 Elsevier Ltd. All rights reserved. 1. Introduction stereogenic centers in 1 presented a formidable syn- thetic challenge. Herein we describe an efficient enan- Indane-containing compounds have been of great inter- tioselective synthesis of 1 with both high de and ee. est as synthetic targets due to their biological and pharmacological properties.1–9 Indane-derived chiral ligands have also found application in transition metal- 2. Results and discussion catalyzed processes.10 In connection to a drug discovery project, we required a large quantity of the indane 2.1. Retrosynthetic analysis of 1 acetic acid derivative 1 in enantiomerically pure form. Despite numerous synthetic methods for constructing The retrosynthetic analysis of 1 is shown in Scheme 1. functionalized indanes,1,2,11–13 the two contiguous The benzylic stereogenic center could be derived from the prochiral CC bond in the indene intermediate (S)-3. The chiral indene precursor could in turn be obtained by resolution of the corresponding racemate. We envisioned that racemic 3 could be obtained via the Reformatsky reaction14 of 5-methoxy-1-indanone 2,a commercially available starting material. The success of this strategy hinged on a robust Reformatsky process Scheme 1. * Corresponding author. Tel.: (203) 812-5906; fax: (203) 812-2452; e-mail: [email protected] 0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2003.07.021 3448 M. Zhang et al. / Tetrahedron: Asymmetry 14 (2003) 3447–3453 and the ability to perform a diastereoselective reduction develop a robust process for the Reformatsky reaction. of the indene precursor (S)-3 that would set the ben- A pattern emerged from careful analysis of the results zylic carbon to the desired (S)-configuration. from our initial survey of the Reformatsky conditions. We observed that if a small amount of product was 2.2. Synthesis of 1 formed as detected by TLC, then the reaction always proceeded rapidly to completion. While the induction We previously reported a novel, carboxylate-directed, period for the reaction varied, production of the end diastereoselective, homogeneous hydrogenation of product was consistent. This observation prompted us cyclic b,g-unsaturated carboxylic acids with Wilkinson’s to investigate a ‘seeding process’. A small-scale batch catalyst.15 With this methodology, the racemic indene (typically 1–10 g of the indanone) was carried to com- acetic acid 3a was hydrogenated smoothly via its tri- pletion, and this reaction mixture was used without ethyl amine salt to yield the corresponding indane workup as ‘seed’ for the next larger batch. As expected, acetic acid in greater than 199:1 diastereoselectivity in the larger batch proceeded to completion rapidly after favor of the desired racemic diastereomer 4. We envi- addition of the ‘seed’. The bulk of the reaction mixture sioned that hydrogenation of enantiomerically pure (S)- (ca. 90%) was then transferred to another vessel via a 3a using this method would deliver the corresponding Teflon tube for workup. The reaction flask was subse- single diastereomer (S,S)-4. quently charged with a new batch of starting material, and the reaction was repeated iteratively until the 2.2.1. Reformatsky reaction to construct the indene ace- desired amount of product was produced. Interestingly, tic acid framework. The requisite racemic indene acetic a tightly closed sample of the ‘seed’ was effective in acid precursor 3a was prepared by saponification of the promoting Reformatsky reaction of similar substrates indene ester 3b. Synthesis of 3b was achieved via the after being kept for 5 months on the bench. While the Reformatsky reaction of 5-methoxy-1-indanone 2 and nature of the catalytic cycle and of the catalyst itself is methyl 2-bromobutyrate using ‘Barbier-type’ conditions not clear at this point, we nevertheless believe that this in tetrahydrofuran (Scheme 2). During our initial work observation could be generally valuable. on the Reformatsky reaction, the reaction was not reproducible: under very similar reaction conditions, 2.2.2. Resolution of the indene acetic acid 3a. With a yields ranged from near quantitative to zero where the process in hand for generating racemic 3b, we next indanone starting material 2 was completely recovered. explored its resolution and resolution of its hydrolysis The predictability of the Reformatsky reaction has product, 3a. Our initial focus was enzymatic remained a major challenge for organic chemists since hydrolysis19,20 of the indene ester 3b using the Altus the reaction was first reported more than a century screening kit ChiroScreen-EH (Scheme 3). An enzy- ago.16,17 While it is generally accepted that activation of matic resolution of the ester would highly be advanta- the zinc improves reliability, very few of the numerous geous if the desired enantiomer undergoes hydrolysis literature procedures are universally effective.18 Fur- selectively. Under this circumstance, the saponification thermore, most reported zinc activation methods of 3b to 3a would not be required prior to resolution. require use of additional reagents which inevitably end Among the numerous enzymes screened, Mucor meihei up as impurities in the reaction.14 Our initial results lipase showed high enantioselectivity. Even at 100 wt% were also inconsistent. Thus, to enhance the success of enzyme loading, the hydrolysis stopped at ca. 50% our overall synthetic strategy for 1, we needed to conversion after overnight stirring. The acid was iso- Scheme 2. Conditions: (a) zinc powder, methyl 2-bromobutyrate, THF, 60°C; (b) 1N HCl; (c) KOH (3 equiv.)/MeOH. Scheme 3. M. Zhang et al. / Tetrahedron: Asymmetry 14 (2003) 3447–3453 3449 lated with 98% ee. Unfortunately, these conditions M HCl to liberate the free (S)-indene acid 3. The afforded the undesired (R)-3a enantiomer, as indicated results are summarized in Table 1. Several points are by chiral HPLC. It is important to note that this chiral worth noting. Lower mole ratios of quinine:3a resulted acid would no longer undergo hydrogenation under our in higher ee, but lower yields (entries 1–5). At a stoi- diastereoselective, homogeneous hydrogenation condi- chiometric ratio (1:1), a substantial amount of the tions with Wilkinson’s catalyst, presumably due to undesired (R)-enantiomer crystallized (entry 6). The residual enzyme impurities that poisoned the catalyst. optimal ratio of quinine:3a was set at 0.77 for the The chiral ester (S)-3b, recovered from the enzymatic large-scale runs. Under these conditions, reproducibly resolution racemized when we tried to hydrolyze it to high ee and yields were obtained from a single recrys- the corresponding acid (S)-3a. Based on these results, tallization (entries 8 and 9). we abandoned the enzymatic resolution approach. 2.2.3. Diastereoselective hydrogenation. Carboxylate- Chemical resolution of the indene acid (±)-3a was car- directed hydrogenation15 of (S)-3a with Wilkinson’s ried out with quinine in acetonitrile (Scheme 4). In this catalyst in ethanol/tetrahydrofuran (9:1) at 60 psi case, the desired (S)-enantiomer formed a less soluble hydrogen pressure afforded the (S,S)-indane acid inter- diastereomeric salt with quinine and was conveniently mediate 4 in >99% de and no loss of ee. At this point, isolated and purified by recrystallization. The salt was the stereoselective elaboration of the target was com- then dissolved in dichloromethane and washed with 1 plete (Scheme 5). Scheme 4. Table 1. Chemical resolution of (±)-3a using quinine Entry Quinine:3a (mole ratio) 3a conc. (M) Agitation Ee (%) Yield (%)g 1a 0.50 0.29Magnetic 97.3 25.0 2a 0.50 0.57 Magnetic 98.5 22.7 3a 0.580.29 Magnetic 92.9 35.9 4a 0.64 0.29 Magnetic 93.0 40.9 5b 0.50 0.29 Mechanical 92.8 23.4 6b 1.0 0.29 Mechanical67.6 58.0 7c,f 0.710.29 Mechanical 98.1 27.8 8d,f 0.77 0.27 Mechanical 97.4 35.4 9e,f 0.77 0.28 Mechanical 96.4 32.2 a Resolution was carried out on 4.9 mmol scale. b Resolution was carried out on 9.8 mmol scale. c Resolution was carried out on 0.245 mol scale. d Resolution was carried out on 1.29 mol scale. e Resolution was carried out on 1.64 mol scale. f After one recrystallization. g Isolated yield (based on racemate). 3450 M. Zhang et al. / Tetrahedron: Asymmetry 14 (2003) 3447–3453 4. Experimental 4.1. General Starting materials 2, as well as all other reagents used in this synthesis were purchased commercially and used without purification. Enantiomeric excess of intermedi- ates (R)-3a and (S)-3a, and (S,S)-4 was determined by chiral HPLC analysis using a Chiracel AD analytical Scheme 5. Conditions: (a): ClRh(PPh3)3, 5 mol%, Et3N (1.5 column. NMR spectroscopic data were recorded on a equiv.), EtOH/THF (9:1), 60 psi H2. Varian (300 MHz) NMR spectrometer. Coupling con- stants are reported in hertz (Hz). Optical rotation and IR measurements, and elemental analyses were per- formed by Robertson Microlit labs. Melting point was recorded on a Mel-Temp II uncorrected.