Diastereoselective 1, 4-Conjugate Addition of Alkyl Cuprates to Methyl

Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Diastereoselective 1,4-Conjugate Addition of Alkyl Cuprates to Methyl Cyclopent-1-enecarboxylates Staffan Karlsson,*,† Philip Cornwall,‡ Angéle Cruz,† Fritiof Pontén,† Maria Fridén-Saxin,§ and Andrew Turner‡ †

Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, SE-431 83 Mölndal, Sweden Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Macclesfield SK10 2NA, United Kingdom § Medicinal Chemistry, Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca Gothenburg, SE-431 83 Mölndal, Sweden ‡

S Supporting Information *

ABSTRACT: Starting from readily available homochiral Vince lactam, trisubstituted cyclopentanes were obtained utilizing conjugate addition of alkyl cuprates as an efficient approach to introduce different side chains. Although the 1,4-conjugate addition reactions gave the products as mixtures of diastereomers, an epimerization approach followed by crystallization furnished the stereoisomerically pure cyclopentanes.

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special cases,3 have not been employed in reactions with esters of type 3, and thus, we believed that such a strategy would be difficult to use in this case.4 The 1,4-conjugate addition of alkyl cuprates to α,β-unsaturated esters is well-known in the literature, and the starting materials for generation of the cuprates are often commercially available as either the alkyllithium or alkyl Grignard reagent. For this reason, we found this approach to be the most promising method for developing a sustainable large-scale procedure. At the same time, we were aware of the fact that the addition of alkyl cuprates to esters conjugated to an endocyclic double bond had been very little explored, which can be explained by the fact that such α,β-unsaturated esters are of lower reactivity compared with mono- and disubstituted alkenes.5 It is also well-known that the benzyl cuprates required for this study are short-lived species and that Wurtz coupling is a common side reaction.6 Therefore, benzyl cuprates are rarely used in conjugate additions and to our knowledge have not been reported in reactions with esters conjugated to cyclopentenes. For these reasons, we feared that it would be challenging to develop an efficient route and that an extended screen of conditions would be needed to find suitable conditions to prepare compounds 1 and 2. Furthermore, a low stereoselectivity in the conjugate addition/protonation sequence could in the worst case require time-consuming chromatographic purifications of the diastereomeric mixtures obtained. However, we aimed for a reaction between the alkyl cuprate and α,β-unsaturated ester 3 in which the alkyl cuprate would exclusively or with high selectivity add from the Re face of alkene 3 (Scheme 2). Even though the distance from the reacting center to the Boc-protected aminomethyl substituent is remote, we hoped that sufficient shielding of the Si face would result in a diastereoselectivity

INTRODUCTION In one of our drug development projects, (+)-Vince lactam was used as a starting material for the synthesis of trisubstituted cyclopentanes that constituted important building blocks for further transformation into bioactive compounds. After extensive screening for biological activity of drug candidates incorporating these moieties, the benzyl-substituted cyclopentane 1 and the isobutyl-substituted compound 2 were selected as key building blocks for the synthesis of two drug candidates (Scheme 1). To enable preclinical studies for these two compounds, hundreds of grams of the two building blocks 1 and 2 were required within a short time frame. It was envisaged that compound 2 would be readily accessible via a Heck-type reaction of α,β-unsaturated ester A, prepared from (1S,4R)-(+)-Vince lactam, and an alkenyl halide such as 1-bromo-2-methylprop-1-ene followed by reduction of the double bonds of intermediate B to give C (Scheme 1, approach i). Deprotection of C to give D followed by further transformations would give compound 2. By means of this strategy for the introduction of the isobutyl side chain, a highly diastereoselective Heck-type reaction was recently demonstrated.1 Although this method worked well on a small scale, it suffered from the need for a troublesome protecting group, which required hydroxylamine for its removal, and a nonselective hydrogenation of the double bonds.1 Moreover, such an approach cannot be applied for introduction of the benzyl side chain to give 1. Thus, we searched for a more general alternative approach where both the benzyl and isobutyl side chains could be introduced efficiently with good diastereoselectivity. We reasoned that a 1,4-conjugate addition of a metallo-organic reagent to α,β-unsaturated ester 3, readily available from compound 4, could potentially fulfill these criteria (Scheme 1, approach ii). Although Rh(I) catalysis of the addition of various aromatic boronic acids to α,β-unsaturated esters has successfully been reported,2 alkylboronic acids, with the exception of a few © XXXX American Chemical Society

Received: December 1, 2017

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DOI: 10.1021/acs.oprd.7b00374 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Scheme 1. Synthetic Strategies To Obtain Compounds 1 and 2

Scheme 2. 1,4-Conjugate Addition of Alkyl Cuprates To Obtain 5 and 6

furnished compound 4, which was purified through vacuum distillation (Scheme 3).8 In the subsequent steps, we found that

good enough for large-scale preparations to give, after protonation, compounds 5 and 6 as the major diastereomers. We had some support for a high π-facial selectivity since good results were recently reported starting from an analogous α,βunsaturated ester but using other nucleophiles.7 In the subsequent protonation step, nonselective protonation of the enolate due to steric hindrance of the newly created stereogenic center would give the undesired 1S,2R,4R epimers of 5 and 6. In that event, we envisaged a process where these isomers could be epimerized to the thermodynamically more stable and desired 1R,2R,4R isomers through treatment with a strong base. Finally, to obtain the stereoisomerically pure isomers of 1 and 2, we wanted to avoid chromatography and instead find good conditions for a final crystallization of the free acids or salts thereof.

Scheme 3. Methylation of (+)-Vince Lactam Followed by a Telescoped Three-Step Sequence to Compound 3

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RESULTS AND DISCUSSION Development of a Telescoped Route to 3. For the study of 1,4-conjugate addition of alkyl cuprates to α,β-unsaturated ester 3, we first needed a practical large-scale route to prepare compound 3. For medicinal chemistry needs, a strategy including methylation of (+)-Vince lactam followed by esterification, Boc protection, and isomerization of the double bond using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was used. For large-scale manufacturing, we wanted to avoid the time-consuming isolation of all intermediates and develop a telescoped sequence instead. We believed that all of the steps from 4 to 3 could be performed in the same solvent, avoiding time-consuming extractions and purifications of the intermediates. Starting from (+)-Vince lactam, methylation using MeI

methanol could be used as the solvent for the esterification, Boc protection, and isomerization steps. Fortunately, no purification other than extraction of 3 was needed to obtain a chemical purity good enough for further transformations (90% w/w). The three-step telescoped sequence gave consistent results also on a large scale, with an overall yield from 4 to 3 of 84% (Scheme 3). Development of a Large-Scale Route to 1/7. We began our study to identify a method for the synthesis of compound 1 and hoped that these conditions would also be suitable for the preparation of 2. A literature search revealed that benzyl cuprates obtained from CuI and Grignard reagents have been successfully used in 1,4-conjugate additions to various B



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Figure 1. Expansion of the 3.50−3.80 ppm region of the crude 1H NMR spectra after 1,4-conjugate addition of benzyl cuprate to 3 (left) and after treatment with sodium methoxide (right).

conjugated double bonds.9 In the presence of trimethylsilyl chloride (TMSCl) as an additive, enhanced reactivity of a weakly reactive α,β-unsaturated ester is sometimes observed.10 We intended to apply the same type of conditions in the reaction with 3. Starting from commercially available benzylmagnesium chloride, we obtained the corresponding cuprate by adding sequentially CuI and N,N,N′,N′-tetramethylethylenediamine (TMEDA). This was followed by the addition of TMSCl and substrate 3. We chose to use NMR spectroscopy to monitor this reaction. At about −30 °C, reaction took place, and almost full conversion of alkene 3 was obtained within 10 h (Figure 1). Even though the result was encouraging, the NMR spectrum recorded on the crude mixture after protonation and extraction with methyl tert-butyl ether (MTBE) was complex with several overlapping signals. It was concluded that no or little reaction had occurred on the ester moiety, which otherwise had resulted in loss of signals in the CH3O−CO region in the NMR spectrum. Also, the disappearance of the alkene shift indicated that reaction had occurred at the right position. Thus, we concluded that compound 5 had been obtained, albeit as a mixture of diastereomers. After comparison with the spectrum of an authentic sample of 5, it was found that the desired diastereomer 5 did not correspond to the major peak but rather to a minor peak at 3.59 ppm (Figure 1). Even though this result was discouraging, we reasoned that the protonation of the intermediate enolate was probably kinetically favored from the side opposite to the newly generated stereocenter, furnishing the 1S,2R,4R isomer of 5. The other two minor peaks at 3.60 and 3.72 ppm were believed to correspond to the (1S,2S,4R) and (1R,2S,4R) isomers of 5, respectively. To verify this hypothesis, an epimerization of the tentative 1S,2R,4R isomer of 5 was planned to obtain the thermodynamically more stable 1R,2R,4R-configured 5. Thus, the crude mixture of 5 was treated with MeOH and a catalytic amount of sodium methoxide. Gratifyingly, it was observed that after several hours of stirring at 40−50 °C, the 1S,2R,4R isomer was slowly converted to the desired 1R,2R,4R isomer of 5 to give an approximately 95:5 diastereomeric mixture in favor of the desired one (Figure 1). The π-facial selectivity of ∼90:10 in the cuprate addition resulted in two additional minor diastereomers, and we next focused on finding suitable conditions to purge the three minor diastereomers from the crude mixture of 5. A crystallization of ester 5 was planned, but since we were not able to identify good conditions for this, the transformation to the corresponding acid 1 was performed instead. This gave us the opportunity to either directly find conditions for crystallization of carboxylic acid 1 or salts thereof. Thus, the

crude mixture of 5 in MeOH was hydrolyzed using NaOH followed by an extractive workup to give the crude mixture of acid 1 as a brown syrup. Since no purifications other than extractions and distillation had been performed in the six-step linear sequence from Vince lactam, various minor impurities had accumulated in the synthesis and made direct crystallization of carboxylic acid 1 challenging. We believed that a salt screen would give us a better chance to identify suitable conditions for crystallization. Fortunately, after screening a small set of amines, we found that dicyclohexylamine (DCHA) formed a crystalline solid with 1 that could be crystallized from MTBE/heptane to give the stereoisomerically pure dicyclohexylammonium salt 7. After some further optimization, isopropyl acetate was selected as the solvent instead, which furnished a nonhygroscopic, easily handled, bench-stable solid. We were now ready to evaluate the new synthetic route to 1/7 for largescale applications, and we were delighted to see that on a kilogram scale, the sequential four-step cuprate addition/ epimerization/hydrolysis/salt formation furnished the stereoisomerically pure salt 7 in 68% overall yield from 3 (Scheme 4). After an acidic extraction of 7, the carboxylic acid 1 was isolated. Scheme 4. Large-Scale Synthesis of Stereoisomerically Pure Compound 7/1

Development of a Large-Scale Route to 2/8. Having established an efficient, stereoselective, large-scale route to building block 1, the task remained to develop a good route also for the analogous compound 2. We learned in the development of the large-scale route to 7 that the excess of copper salt used as well as the additives resulted in a timeconsuming, troublesome workup. Also, the use of tetrahydrofuran (THF) as the reaction solvent made it harder to C



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diastereoselectivity was considered but later abandoned because of time constraints. Additionally, the relative ease of operation of the current method should be balanced against a potentially more diastereoselective but more complex system involving oxidation-sensitive and/or expensive ligands that have to be removed in the workup. We chose instead to spend more time on finding a method for the removal of undesired diastereomers in the subsequent steps. An approach similar to the one used for the synthesis of 1 was employed, and after hydrolysis of ester 6 using NaOH, a screen of various amines for salt formation with the formed carboxylic acid 2 was performed. It was found that (R)-1-phenylethylamine gave a salt with suitable solid properties and that most of the undesired diastereomers were removed in one single crystallization from ethyl acetate. We were ready to apply the new route to 2/8 on a larger scale. Starting from 320 g of α,β-unsaturated ester 3, the conjugate addition of the alkyl cuprate obtained from a catalytic amount of CuI (21 mol %) and isobutyl magnesium bromide (250 mol %) in MTBE as the solvent furnished after protonation the crude ester 6 with ∼85:15 π-facial selectivity. The protonation of the enolate occurred mainly from the “right” side to give predominantly (1R,2R,4R)-6 as the main diastereomer along with the 1S,2R,4R isomer of 6 as the major side product (Scheme 5). To affect epimerization of the

obtain clear, well-separated phases in the extraction. In the synthesis of 2, we planned to utilize an approach similar to the one used for the preparation of 1 but to address the aforementioned issues. We aimed for a process in which we could have as few additives as possible and ideally use only a substoichiometric amount of the copper salt to simplify the workup. Starting from a Grignard reagent and various α,βunsaturated esters, the enantioselective conjugate addition of alkyl cuprates using a catalytic amount of CuI and various TolBINAP ligands has been described in the literature.11 We found this approach more attractive compared with the method used for the analogue 1 for several reasons: (i) only a catalytic amount of CuI was needed; (ii) a chiral ligand in a catalytic amount as an additive could potentially enhance the diastereoselectivity; and (iii) the reaction could be run in non-water-miscible ethereal solvents instead of THF, meaning that concentration of the reaction mixture prior to extraction was probably not required. Fortunately, in this case the starting Grignard reagent required for the transformation to the corresponding cuprate was commercially available either as isobutylmagnesium bromide or chloride in ethereal solvents. Gratifyingly, our first attempts starting from a 2 M solution of isobutylmagnesium bromide with catalytic amounts of CuI and a TOL-BINAP ligand as an additive in MTBE as the solvent furnished the desired ester 6 with ∼85:15 π-facial selectivity. Although a low selectivity of the protonation of the enolate was observed, it was in favour of the desired one.12 Surprisingly, TMSCl as an additive as used in the preparation of 1 was not necessary for the reaction to occur. As with 1, the reaction was easily monitored by NMR spectroscopy by recording the spectrum of the crude mixture after protonation (Figure 2).

Scheme 5. Large-Scale Synthesis of Stereoisomerically Pure Compound 8/2

1S,2R,4R diastereomer of 6 to the desired one, the crude mixture of 6 was treated with sodium methoxide in MeOH, which resulted in ∼90% conversion to the desired 1R,2R,4R isomer. After a direct telescoped hydrolysis of this ester, the crude acid 2 was obtained, and after an extractive workup of this, purification was performed through salt formation with (R)-1-phenylethylamine. One crystallization from ethyl acetate furnished a 96:4 diastereomeric mixture of 8, and after recrystallization of this salt, better then 99:1 stereoisomeric purity was obtained. The overall yield from compound 3 was lower (48%) compared with the yield obtained for the analogous compound 7 (68%), which was mainly explained by the somewhat lower π-facial selectivity in the cuprate addition and a less efficient crystallization of the final salt. An acidic extraction of 8 using KHSO4/MTBE furnished carboxylic acid 2 as a viscous oil. Determination of the Relative Configuration of 7/8. To determine the relative configuration of the three substituents on the cyclopentane ring in 7 and 8, a number of 2D NMR experiments were performed on both salts 7 and 8. As depicted

Figure 2. Expansion of the 3.60−3.75 ppm region of the 1H NMR spectra of (i) the crude mixture of 6 after conjugate addition of the isobutyl cuprate to 3 (purple) and (ii) after treatment with MeONa/ MeOH (green).

Using the same strategy as for compound 1, we were then able to epimerize most of the 1S,2R,4R diastereomer of 6 to obtain the thermodynamically more stable one using sodium methoxide in MeOH. By applying the other enantiomer of the ligand, we did not observe a significant change in π-facial selectivity, which made us suspect that the ligand probably was of no importance. To confirm this hypothesis, a control experiment was performed in the absence of a chiral ligand, and as anticipated, we found that the π-facial selectivity was unchanged. An extended screen of other ligands to improve the D



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obtained. The mixture was filtered, and the solid was rinsed with methyl ethyl ketone (500 mL). The filtrate was concentrated to a pale-yellow oil, which was distilled under reduced pressure (bp 58 °C/0.3 mbar) to give the title compound 4 as a clear, colorless oil (99 g, 804 mmol, 98% w/ w, 90% yield). Analytical data were in accordance with those given in the literature.13 (R)-Methyl 4-(tert-Butoxycarbonyl(methyl)amino)cyclopent-1-enecarboxylate (3). Compound 4 (83.6 g, 679 mmol) was dissolved in 450 mL of a methanolic solution of hydrogen chloride (2 M) prepared from acetyl chloride (70.6 g, 900 mmol) and MeOH (400 mL), and the solution was stirred at 20 °C for 20 h. The brownish mixture was cooled to −5 °C, and triethylamine (235 mL, 1695 mmol) was slowly added during 1 h while the reaction temperature was maintained below 10 °C. At a reaction temperature of 10−20 °C, this was followed by portionwise addition of di-tert-butyl dicarbonate (178 g, 817 mmol). The mixture was stirred at 20 °C for 1 h, after which DBU (405 mL, 2708 mmol) was added. The solution was stirred at 20 °C for 65 h. MTBE (700 mL) and water (800 mL) were added. The aqueous layer was extracted with MTBE (500 mL), and the pooled organic phase was carefully washed with 4 M aqueous HCl (500 mL), 8% aqueous NaHCO3 (500 mL), and finally water (500 mL). The organic layer was concentrated, and residual water was azeotropically removed using EtOAc (2 × 100 mL). This yielded the title compound as a brown oil (162 g, 90% w/w, 84% overall yield), which was used as such in the next step without further purification. 1H NMR (500 MHz, DMSO, 90 °C): δ 1.42 (s, 9H); 2.46−2.55 (m, 2H); 2.68 (s, 3H); 2.72−2.80 (m, 2H), 3.69 (s, 3H); 4.79 (tt, J = 9.1, 5.6 Hz, 1H); 6.67−6.72 (m, 1H). 13 C NMR (126 MHz, 90 °C, DMSO): δ 28.6, 29.9, 35.6, 37.4, 51.5, 54.6, 79.2, 134.6, 141.8, 155.1, 164.7. HRMS: [M + Na]+ m/z calcd for C13H21NNaO4 278.1363, found 278.1355. Dicyclohexylammonium (1R,2R,4R)-2-Benzyl-4-(tertbutoxycarbonyl(methyl)amino)cyclopentanecarboxylate (7). A dry 100 L reactor was charged with CuI (1880 g, 9.87 mol) followed by the addition of anhydrous THF (21 L). The resulting suspension was cooled to −2 °C, and TMEDA (1.55 L, 10.34 mol) was slowly added during 20 min. The mixture was cooled to −60 °C, and a 2 M solution of BnMgCl in THF (4.70 L, 9.4 mol) was slowly added during 80 min while the reaction temperature was maintained at −60 to −56 °C. TMSCl (2.98 L, 23.5 mol) was added within 10 min, with the reaction temperature maintained at −60 °C to −58 °C. A solution of 3 (1200 g, 90% w/w, 4.23 mol) in THF (2 L) was added during 10 min. The jacket temperature was ramped to −30 °C during 30 min, and the mixture was stirred at that temperature for 10 h, after which full conversion of 3 was obtained. A solution of acetic acid (2.02 L, 35 mol) in THF (2 L) was slowly added during 1 h while the reaction temperature was maintained at 0 to −5 °C. Water (24 L) and MTBE (20 L) were added, and the mixture was allowed to attain 20 °C. Precipitated copper salts at the interface prevented clean separation of the layers. Removal of copper salts through filtration was attempted but abandoned because of blockage of the filter. The aqueous layer was extracted with MTBE (10 L). The pooled organic layer was washed with brine (3 L). The somewhat inhomogeneous organic layer was then filtered through 750 g of Celite followed by concentration. Residual water was azeotropically removed using toluene (2 × 5 L) to yield crude ester 5, where the undesired diastereomer

in Figure 3, a positive nuclear Overhauser effect (NOE) was observed between protons Ha and Hd in both 7 and 8,

Figure 3. Proposed configuration of 7 (R = Bn) and 8 (R = i-Bu) through 2D NOESY experiments. The blue arrows indicate key selected interactions.

supporting a cis relationship between the carbamate and the carboxylic acid substituents. Other key interactions were between Hb and Hd and also a positive NOE between the N−CH3 protons and both Hc and He, suggesting a trans relationship between the R substituent and the other two substituents.

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CONCLUSION A practical approach involving diastereoselective 1,4-conjugate addition of alkyl cuprates to an α,β-unsaturated endocyclic ester (3) to give stereoisomerically pure 1,2,4-trisubstituted cyclopentanes was developed. The reactions were demonstrated on a multi-hundred-gram scale and gave consistent results. Chromatography was avoided, being replaced with salt formation with homochiral amines followed by crystallization.

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EXPERIMENTAL SECTION All reactions were performed under an atmosphere of nitrogen. All reagents were commercially available and were used without further purification. 1H and 13C NMR spectra were measured in CDCl 3 , CD 3 OD, or DMSO-d 6 on a Bruker Avance spectrometer (400−600 MHz; frequency stated in each experiment) at 25 °C, unless otherwise stated. The chemical shifts (δ) are reported in parts per million (ppm), with the residual solvent signal used as a reference. Coupling constants (J) are reported in hertz (Hz). Assays of intermediates and final products are given as percent weight/weight (% w/w) and were determined by 1H NMR measurements using benzyl benzoate as an internal standard. High-resolution mass spectrometry (HRMS) measurements were performed on either a Bruker APEX mass spectrometer or a T-Wave ion mobility mass spectrometer using the electrospray ionization (ESI) technique. (1S,4R)-2-Methyl-2-azabicyclo[2.2.1]hept-5-en-3-one (4). To a suspension of (1S,4R)-2-azabicyclo[2.2.1]hept-5-en-3one (100 g, 898 mmol) and cesium carbonate (673 g, 2066 mmol) in methyl ethyl ketone (1 L) was added iodomethane (84 mL, 1347 mmol). The mantle temperature was set at 35 °C, and the suspension was stirred over the weekend, after which full conversion of the starting material had been E



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(1R,2R,4R)-6 and (1S,2R,4R)-6). Residual water was azeotropically removed using toluene (2 × 500 mL). The mixture was used as such in the next step. Epimerization. To the crude ester 6 were added MeOH (400 mL) and sodium methoxide (28 g, 0.52 mol), and the dark-brown mixture was heated at 40 °C for ∼24 h, after which a ∼ 91:9 diastereomeric mixture of (1R,2R,4R)-6 and (1S,2R,4R)-6 was obtained. The mixture was used as such in the next step. Hydrolysis. To the above crude mixture of ester 6 was added a solution of 50% aqueous sodium hydroxide (56.5 mL, 1.5 mol), and the mixture was stirred at 20 °C for 60 min, after which full conversion to the crude carboxylic acid 2 was obtained. Water (300 mL) was added, and most of the MeOH was removed under reduced pressure. MTBE (300 mL) and heptane (300 mL) were added. The organic layer was extracted with water (100 mL). To the dark-brown pooled aqueous layer was added MTBE (300 mL), and the mixture was cooled in an ice bath. The pH was carefully adjusted to 2.5 using first aqueous 12 M HCl and then 2 M KHSO4. The aqueous layer was extracted with MTBE (100 mL), and the pooled organic layer was washed with water (100 mL) followed by concentration to give crude 2 as a brown viscous oil. Residual water was azeotropically removed using EtOAc (2 × 100 mL). The mixture was used as such in the next step. Crystallization. The crude carboxylic acid 2 was dissolved in ethyl acetate (3.5 L). The mixture was heated to 65 °C, and (R)-1-phenylethanamine (129 mL, 1.0 mol) was slowly added. Seeding crystals of 8 were added, and an immediate but slow precipitation initiated. After an additional 40 min, the mixture was allowed to attain 20 °C during 100 min and was then stirred for an additional 12 h. The mixture was filtered, and the salt collected was washed with EtOAc (4 × 500 mL) to give the salt 8 with >96:4 stereoisomeric purity. A second crystallization from EtOAc (2.5 L) using the same procedure as above furnished stereoisomerically pure (>99:1 dr) salt 8 (227 g, 99% w/w, 0.54 mol, 48% yield). 1H NMR (500 MHz, MeOD, 55 °C): δ 0.90 (d, J = 6.7 Hz, 3H); 0.92 (d, J = 6.7 Hz, 3H), 1.15− 1.23 (m, 1H); 1.38−1.54 (m, 2H); 1.57 (d, J = 6.8 Hz, 3H); 1.59−1.68 (m, 1H); 1.83−1.96 (m, 2H); 2.00−2.09 (m, 1H); 2.18−2.28 (m, 1H); 2.29−2.40 (m, 1H); 2.81 (s, 3H); 4.33 (q, J = 6.8 Hz, 1H); 4.48−4.58 (m, 1H); 7.31−7.47 (m, 5H). 13C NMR (126 MHz, MeOD, 55 °C): δ 22.2, 22.6, 23.8, 27.7, 28.8 (3C), 29.0, 35.4, 35.5, 41.4, 46.7, 52.4, 53.9, 56.5, 80.9, 127.3, 129.4, 130.0, 142.4, 157.7, 182.1. HRMS (free acid 2): [M + H]+ m/z calcd for C16H30NO4 300.2175, found 300.2164. General Method To Liberate the Free Acids 1 and 2 from the Corresponding Salts 7 and 8. Salt 7 or 8 was partitioned between MTBE (∼2 L/mol of salt) and a 0.5 M aqueous KHSO4 solution (∼2 L/mol of salt). The aqueous layer was extracted with MTBE (∼0.2 L/mol of salt). The pooled organic layer was washed with water (∼0.2 L/mol of salt) followed by concentration. Residual water was azeotropically removed using toluene (2 × 0.2 L/mol of salt). (1R,2R,4R)-2-Benzyl-4-(tert-butoxycarbonyl(methyl)amino)cyclopentanecarboxylic Acid (1). Following the general procedure for liberating the free acids, the title compound 1 (795 g, 2.4 mol) was obtained as a highly viscous amber oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H); 1.61− 1.78 (m, 2H); 1.86−1.95 (m, 1H); 2.18 (dt, J = 12.6, 7.2 Hz, 1H); 2.46−2.66 (m, 3H); 2.72 (s, 3H); 2.91 (dd, J = 13.0, 4.9 Hz, 1H); 4.67 (s, 1H); 7.13−7.35 (m, 3H); 7.24−7.29 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 28.1, 28.2, 32.7, 32.9,

(1S,2R,4R)-5 was the predominant one. The diastereomeric mixture was used as such in the next step. Epimerization. A 25 L reactor was charged with the crude ester 5 from above and MeOH (2.5 L), followed by the addition of sodium methoxide (80 g, 1.48 mol). The mixture was stirred for 72 h at 45 °C. 1H NMR analysis of the crude mixture indicated a diastereomeric ratio of ∼95:5 in favor of the 1R,2R,4R isomer of 5. The mixture was used as such in the next step. Hydrolysis. To the crude mixture of ester 5 at 10 °C was charged a solution of 50% w/w aqueous sodium hydroxide (752 g, 9.40 mol). The mixture was then allowed to attain 20 °C and was stirred for 1 h after full conversion of the hydrolysis was obtained as determined by 1H NMR spectroscopy. Most of the MeOH was removed under reduced pressure, followed by addition of MTBE (14 L) and water (15 L). To the aqueous layer was added MTBE (12 L), followed by careful acidification to pH ∼4 using potassium bisulfate (1407 g, 10.3 mol). The organic layer was washed with water (2 × 10 L), followed by concentration and azeotropic removal of water using MTBE (4 × 2.5 L). This yielded crude carboxylic acid 1 (1351 g, 80% w/ w desired diastereomer, 3.24 mol). The mixture was used as such in the next step. Crystallization. To the crude carboxylic acid 1 from above was charged iPrOAc (13 L), and the mixture was heated to 70 °C. Dicyclohexylamine (635 g, 3.50 mol) was slowly added, followed by seeding with crystals of 7 (∼10 g). After 1 h at 70 °C, the mixture was allowed to attain 20 °C during 3 h, followed by stirring for an additional 12 h. The mixture was filtered, and the solid collected was washed with 50% heptane/ isopropyl acetate (5 L) and then dried under reduced pressure to give the title salt 7 (1501 g, 98% w/w, 2.86 mol, 68% yield from 3) as a colorless solid with stereoisomeric purity of >99%. 1 H NMR (500 MHz, MeOD): δ 1.15−1.26 (m, 2H); 1.30− 1.43 (m, 8H); 1.44 (s, 9H); 1.55 (ddd, J = 13.5, 9.5, 7.4 Hz, 1H); 1.62 (dd, J = 9.2, 7.4 Hz, 1H); 1.68−1.73 (m, 2H); 1.77− 1.90 (m, 5H), 2.02−2.10 (m, 5H); 2.30−2.40 (m, 2H); 2.49− 2.58 (m, 1H); 2.72 (s, 3H); 2.97−3.01 (m, 1H); 3.10−3.17 (m, 2H); 4.42−4.65 (m, 1H); 7.11−7.15 (m, 1H); 7.18−7.25 (m, 4H). 13C NMR (126 MHz, MeOD, 50 °C): δ 24.2, 24.8, 27.4, 27.6, 29.4, 32.9, 34.1, 41.0, 43.8, 52.7, 53.2, 54.7, 79.4, 125.4, 127.8, 128.6, 141.2, 156.2, 181.4. HRMS (free acid 1): [M + Na]+ m/z calcd for C19H27NNaO4 356.1832, found 356.1830. [(1R)-1-Phenylethyl]ammonium (1R,2R,4R)-4-[tertButoxycarbonyl(methyl)amino]-2-isobutylcyclopentanecarboxylate (8). A 10 L reactor was charged with CuI (45.4 g, 0.24 mol) and MTBE (3 L). The grayish suspension was cooled to −25 °C, and a solution of isobutylmagnesium bromide (2 M in Et2O, 1.38 L, 2.76 mol) was slowly added during 20 min while the reaction temperature was maintained below −21 °C. With a mantle temperature set at −19 °C, a solution of 3 (320 g, 90% w/w, 1.12 mol) dissolved in MTBE (500 mL) was added during 1.5 h. The reaction temperature was kept in the interval −15 to −18 °C during this addition. After an additional ∼30 min of stirring at −20 °C, 1H NMR analysis of the crude mixture indicated full conversion of 3 and a π-facial selectivity of ∼85:15. The mixture was rapidly (within 5 min) transferred to a 25 L reactor charged with MTBE (3 L), water (4.5 L), and acetic acid (251 mL, 4.39 mol) at 0 °C. The resulting dark-brown biphasic mixture was stirred for 20 min. The pale-yellow organic layer was washed with water (2 L), followed by polish filtration and concentration to give 6 as a nonviscous pale-yellow oil (∼65:35 diastereomeric mixture of F



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(9) (a) Van Heerden, P. S.; Bezuidenhoudt, B. C. B.; Ferreira, D. Tetrahedron 1996, 52, 12313−12322. (b) Van Heerden, P. S.; Bezuidenhoudt, B. C. B.; Steenkamp, J. A.; Ferreira, D. Tetrahedron Lett. 1992, 33, 2383−2386. (10) For example, see: (a) Alexakis, A.; Berlan, J.; Besace, Y. Tetrahedron Lett. 1986, 27, 1047−1050. (b) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019−6022. (c) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015−6018. (d) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 4025−4028. (e) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 4029−4032. (11) (a) Wang, S.-Y.; Loh, T.-P. Chem. Commun. 2009, 46, 8694− 8703. (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 2002, 3221−3236. (c) Howell, G. P. Org. Process Res. Dev. 2012, 16, 1258− 1272. (12) A control experiment in the absence of CuI showed that the attack of the Grignard reagent mainly occurred at the ester carbonyl position. (13) Bengtsson, C.; Wetzel, A.; Bergman, J.; Brånalt, J. J. Org. Chem. 2016, 81, 708−714.

40.8, 42.9, 48.0, 53.8, 79.4, 125.9, 128.0, 128.7, 139.6, 155.5, 180.4. HRMS: [M + Na]+ m/z calcd for C19H27NNaO4 356.1832, found 356.1830. (1R,2R,4R)-4-(tert-Butoxycarbonyl(methyl)amino)-2isobutylcyclopentanecarboxylic Acid (2). Following the general procedure for liberating the free acids, the title compound 2 (162 g, 0.54 mol) was obtained as a viscous pale-yellow oil. 1H NMR (600 MHz, MeOD): δ 0.89 (d, J = 6.6 Hz, 3H); 0.91 (d, J = 6.6 Hz, 3H); 1.19−1.25 (m, 1H); 1.33− 1.39 (m, 1H); 1.46 (s, 9H); 1.50−1.66 (m, 2H); 1.83−1.95 (m, 2H); 2.04−2.18 (m, 1H); 2.28−2.38 (m, 2H); 2.79 (s, 3H); 4.55 (bs, 1H). 13C NMR (151 MHz, MeOD): δ 22.5, 23.7, 27.6, 28.7, 29.2, 34.6, 35.1, 41.2, 46.4, 50.8, 56.0, 81.1, 157.5, 180.0. HRMS: [M + H]+ m/z calcd for C16H30NO4 300.2175, found 300.2164.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.7b00374. 1 H, 13C, and 2D NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: staff[email protected]. ORCID

Staffan Karlsson: 0000-0002-5302-7157 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Malin Härslätt and Mark Harrison for mass spectrometry analyses. The authors also acknowledge David T. E. Whittaker and Gunnar Grönberg for NMR characterization.

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REFERENCES

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Diastereoselective 1, 4-Conjugate Addition of Alkyl Cuprates to Methyl

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