Stereoselective Synthesis of δ- and ε-Amino Ketone Derivatives from N-tert-Butanesulfinyl Aldimines and Functionalized Organolithium Compounds

The addition of functionalized organolithium compounds derived from 5-chloro-2-methoxy-1-pentene and 6-chloro-2-methoxy-1-hexene to N-tert-butanesulfinyl aldimines imines, and a subsequent hydrolysis of the enol ether moiety, yielded different δ- and ε-amino ketone derivatives, respectively, in moderate yields and diastereoselectivities. The application of these compounds in organic synthesis was demonstrated by the preparation of 2-substituted 6-methylpiperidines in a stereoselective manner, among them natural alkaloids (+)- and (−)-isosolenopsin A.


Introduction
Amino carbonyl compounds are versatile intermediates in organic synthesis to access complex nitrogen-containing molecules. Their usefulness derives from the broad catalogue of synthetic transformations that can be carried out on both the amino and carbonyl moieties. Additionally, some amino carbonyl compounds display biological activity by themselves and have multiple applications in medicinal chemistry. For these reasons, the development of methodologies to prepare amino carbonyl compounds is a topic of great interest in organic synthesis [1]. These compounds usually require the presence of protecting groups of the amino or the carbonyl functionalities to avoid inter-and intramolecular undesired condensations. The preparation of α- [2] and β-amino [3][4][5][6][7][8][9][10][11][12][13] ketones have been extensively studied, and in many of the methodologies leading to these compounds, nucleophilic additions to chiral imines are involved. Among chiral imines, those derived from tert-butanesulfinamide are of special relevance and have been recurrently used in organic synthesis [14][15][16]. For instance, our research group have also accomplished the stereoselective synthesis of α-amino ketone derivatives in moderate yields from β-nitro amine derivatives that were obtained by a coupling reaction of N-tertbutanesulfinyl imines and nitroethane under basic conditions [17] (Scheme 1). On the other hand, we reported the synthesis of β-amino ketones through the nucleophilic addition to these chiral imines of enolates obtained by a copper-catalyzed addition of dialkylzinc reagents to α,β-unsaturated cyclic enones [18][19][20], and more recently by a decarboxylative Mannich coupling with β-keto acids under mild basic conditions [21,22], proceeding these reactions in excellent yields and diastereoselectivities (Scheme 1).
Continuing our interest in the stereoselective synthesis of amino ketone derivatives from chiral N-tert-butanesulfinyl imines, and being aware of the potential interest as synthetic intermediates of these compounds, we decide to explore a new synthetic pathway to access to γ-, δ-and ε-amino ketone derivatives in an enantioenriched form, by performing a diastereoselective addition of a functionalized organolithium compound to these imines. Functionalized organolithium compounds are valuable reagents, because upon reaction with electrophiles, polyfunctionalized molecules are directly produced [23,24]. These organolithium compounds can be prepared from appropriate precursors following classical procedures, the most commonly used are halogen-lithium exchange [25]. Our retrosynthetic analysis for the preparation of these amino ketone derivatives is depicted on Scheme 2, involving lithiation of the corresponding chloroenol ether, which could be prepared from the corresponding chloroalkyne, subsequent reaction with the imine, and final hydrolysis. Scheme 2. Proposed retrosynthetic pathway for the construction of γ-, δ-and ε-amino ketone derivatives.
Continuing our interest in the stereoselective synthesis of amino ketone derivatives from chiral N-tert-butanesulfinyl imines, and being aware of the potential interest as synthetic intermediates of these compounds, we decide to explore a new synthetic pathway to access to γ-, δand ε-amino ketone derivatives in an enantioenriched form, by performing a diastereoselective addition of a functionalized organolithium compound to these imines. Functionalized organolithium compounds are valuable reagents, because upon reaction with electrophiles, polyfunctionalized molecules are directly produced [23,24]. These organolithium compounds can be prepared from appropriate precursors following classical procedures, the most commonly used are halogen-lithium exchange [25]. Our retrosynthetic analysis for the preparation of these amino ketone derivatives is depicted on Scheme 2, involving lithiation of the corresponding chloroenol ether, which could be prepared from the corresponding chloroalkyne, subsequent reaction with the imine, and final hydrolysis. Continuing our interest in the stereoselective synthesis of amino ketone derivatives from chiral N-tert-butanesulfinyl imines, and being aware of the potential interest as synthetic intermediates of these compounds, we decide to explore a new synthetic pathway to access to γ-, δ-and ε-amino ketone derivatives in an enantioenriched form, by performing a diastereoselective addition of a functionalized organolithium compound to these imines. Functionalized organolithium compounds are valuable reagents, because upon reaction with electrophiles, polyfunctionalized molecules are directly produced [23,24]. These organolithium compounds can be prepared from appropriate precursors following classical procedures, the most commonly used are halogen-lithium exchange [25]. Our retrosynthetic analysis for the preparation of these amino ketone derivatives is depicted on Scheme 2, involving lithiation of the corresponding chloroenol ether, which could be prepared from the corresponding chloroalkyne, subsequent reaction with the imine, and final hydrolysis. Scheme 2. Proposed retrosynthetic pathway for the construction of γ-, δ-and ε-amino ketone derivatives.

Synthesis of N-tert-Butanesulfinyl δ-Amino Ketone Derivatives 7
Chiral sulfinyl imine 5a, derived from benzaldehyde and (R)-tert-butanesulfinamide, was chosen as the model substrate to optimize the reaction conditions to perform the addition to sulfinyl imines 5 of the organolithium compound 4b, generated from 5-chloro-2methoxypent-1-ene (2b) in the presence of excess of lithium metal, and a substoichiometric amount of 4,4′-di-tert-butylbiphenyl (DTBB). The product that results from this addition after hydrolysis with water (6a) was found to be slightly unstable, so it was directly transformed into the corresponding diastereomeric N-tert-butanesulfinyl δ-amino ketone derivatives 7a or 7a' under slightly acidic conditions. These compounds were easier to handle and were separated by means of column chromatography (Table 1). Firstly, it was studied the effect of the solvent, in which imine 5a was dissolved, on the diastereoselectivity of the addition of a solution of organolithium compound 4b in THF at −78 °C. The best result in terms of stereoselectivity (70:30 dr) was obtained when imine 5a was dissolved in toluene (Table 1, entry 3). At this point, we assumed that the major diastereoisomer (7a) was the one that is formed by addition of the organolithium reagent 4b to the Re-face of imine 5a with (RS)-configuration via an open transition state (Table 1) [27], in accordance with previous results of our research group [28,29]. Moreover, we found that the addition of the imine 5a to the solution of the organolithium compound 4b in THF resulted in an enhanced diastereoselectivity (Table 1, entry 4). The formation of the organolithium compound 4b was also accomplished using Et2O as solvent, and without the presence of DTBB. However, after adding imine 5a to the resulting ethereal solution containing functionalized organolithium compound 4b, the stereochemical outcome of the reaction was slightly worse than in the previous case, when THF was employed as solvent (Table 1, entry 5). It is known that the addition of Grignard reagents to these chiral sulfinyl imines proceeds with higher levels of diastereocontrol than in the case of organolithium derivatives [16]. However, all the attempts to prepare the corresponding organomagnesium compound from chloromethoxyalknes 2 failed, due probably to their instability and the demanding reaction conditions (sonication, higher temperatures, bases as additives) [30]. On the other hand, bromoalkynes of type 1 are not commercially available. As 4-chloro-2-methoxybut-1-ene (2a) was not produced in significant amounts, it was not possible to access N-tert-butanesulfinyl γ-amino ketone derivatives using this methodology.

Synthesis of N-tert-Butanesulfinyl δ-Amino Ketone Derivatives 7
Chiral sulfinyl imine 5a, derived from benzaldehyde and (R)-tert-butanesulfinamide, was chosen as the model substrate to optimize the reaction conditions to perform the addition to sulfinyl imines 5 of the organolithium compound 4b, generated from 5-chloro-2methoxypent-1-ene (2b) in the presence of excess of lithium metal, and a substoichiometric amount of 4,4 -di-tert-butylbiphenyl (DTBB). The product that results from this addition after hydrolysis with water (6a) was found to be slightly unstable, so it was directly transformed into the corresponding diastereomeric N-tert-butanesulfinyl δ-amino ketone derivatives 7a or 7a under slightly acidic conditions. These compounds were easier to handle and were separated by means of column chromatography (Table 1). Firstly, it was studied the effect of the solvent, in which imine 5a was dissolved, on the diastereoselectivity of the addition of a solution of organolithium compound 4b in THF at −78 • C. The best result in terms of stereoselectivity (70:30 dr) was obtained when imine 5a was dissolved in toluene ( Table 1, entry 3). At this point, we assumed that the major diastereoisomer (7a) was the one that is formed by addition of the organolithium reagent 4b to the Re-face of imine 5a with (R S )-configuration via an open transition state (Table 1) [27], in accordance with previous results of our research group [28,29]. Moreover, we found that the addition of the imine 5a to the solution of the organolithium compound 4b in THF resulted in an enhanced diastereoselectivity (Table 1, entry 4). The formation of the organolithium compound 4b was also accomplished using Et 2 O as solvent, and without the presence of DTBB. However, after adding imine 5a to the resulting ethereal solution containing functionalized organolithium compound 4b, the stereochemical outcome of the reaction was slightly worse than in the previous case, when THF was employed as solvent (Table 1, entry 5). It is known that the addition of Grignard reagents to these chiral sulfinyl imines proceeds with higher levels of diastereocontrol than in the case of organolithium derivatives [16]. However, all the attempts to prepare the corresponding organomagnesium compound from chloromethoxyalknes 2 failed, due probably to their instability and the demanding reaction conditions (sonication, higher temperatures, bases as additives) [30]. On the other hand, bromoalkynes of type 1 are not commercially available.  was added to a solution of sulfininyl imine 5a in the solvent and conditions indicated in each case. c Sulfinyl imine 5a was added to a solution of the organolithium compound 4b in the solvent and conditions that are indicated in each case. d The formation of 4b was carried out without the presence of DTBB and in Et2O as solvent.
The addition of the organolithium compound 4b was then studied on a variety of tert-butanesulfinyl imines 5, employing the optimal conditions found for imine 5a (Table  1, entry 4). As in the optimization of the reaction conditions, the products of the addition 6 were directly transformed into the corresponding N-tert-butanesulfinyl δ-amino ketone derivatives 7, which are more stable and easier to separate by means of column chromatography. Products 7 were isolated in moderate to good yields, obtaining the best result in the case of the aromatic sulfinyl imine 5a ( Figure 1). Additionally, the ratio of diastereoisomers 7 and 7' was always ranging approximately between 2:1 and 3:1 (7:7' ratio), except in the case of the highly hindered sulfinyl imine 5c, derived from isobutyraldehyde, in which the minor diastereoisomer 7c' was isolated in low yield and was pure enough to be properly characterized (Table 1, compounds 7c and 7c'). This methodology allowed access to the corresponding enantiomers ent-7 and ent-7' of these N-tert-butanesulfinyl δamino ketone derivatives by using as starting materials (SS)-N-tert-butanesulfinyl imines ent-5, at it was exemplified for imines ent-5a and ent-5e derived from benzaldehyde and dodecanal, respectively. As a limitation, halogen atoms, ester, nitrile and carbonyl groups will not be tolerated in these transformations, due to the extremely reductive reaction medium ( Figure 1).

Entry
Reaction Conditions Diastereomeric Ratio a 7a 7a The addition of the organolithium compound 4b was then studied on a variety of tert-butanesulfinyl imines 5, employing the optimal conditions found for imine 5a (Table 1, entry 4). As in the optimization of the reaction conditions, the products of the addition 6 were directly transformed into the corresponding N-tert-butanesulfinyl δ-amino ketone derivatives 7, which are more stable and easier to separate by means of column chromatography. Products 7 were isolated in moderate to good yields, obtaining the best result in the case of the aromatic sulfinyl imine 5a ( Figure 1). Additionally, the ratio of diastereoisomers 7 and 7 was always ranging approximately between 2:1 and 3:1 (7:7 ratio), except in the case of the highly hindered sulfinyl imine 5c, derived from isobutyraldehyde, in which the minor diastereoisomer 7c was isolated in low yield and was pure enough to be properly characterized (Table 1, compounds 7c and 7c ). This methodology allowed access to the corresponding enantiomers ent-7 and ent-7 of these N-tert-butanesulfinyl δ-amino ketone derivatives by using as starting materials (S S )-N-tert-butanesulfinyl imines ent-5, at it was exemplified for imines ent-5a and ent-5e derived from benzaldehyde and dodecanal, respectively. As a limitation, halogen atoms, ester, nitrile and carbonyl groups will not be tolerated in these transformations, due to the extremely reductive reaction medium ( Figure 1).

Synthesis of N-tert-Butanesulfinyl ε-Amino Ketone Derivatives 9
The reaction of 6-chloro-2-methoxyhex-1-ene (2c) with N-tert-butanesulfinyl imines 5 under the same reaction conditions described in the previous section for the synthesis of N-tert-butanesulfinyl δ-amino ketone derivatives 7, led to the homologous ε-amino ketone derivatives 9 ( Figure 2). The highest yield was also obtained working with aromatic aldimine 5a, diastereomeric amino ketone derivatives 9a and 9a being isolated in a combined 82% yield in an almost enantiopure form. Concerning the diastereoselectivity of these transformations, better diastereoselectivities were observed for aromatic and αdisubstituted aldimines 5a and 5c, with near 3:1 diastereomeric ratios. On the other hand, for aliphatic not hindered aldimines, those values of diastereomeric ratio were closer to 2:1 ( Figure 2).

Synthesis of N-tert-Butanesulfinyl ε-Amino Ketone Derivatives 9
The reaction of 6-chloro-2-methoxyhex-1-ene (2c) with N-tert-butanesulfinyl imines 5 under the same reaction conditions described in the previous section for the synthesis of N-tert-butanesulfinyl δ-amino ketone derivatives 7, led to the homologous ε-amino ketone derivatives 9 ( Figure 2). The highest yield was also obtained working with aromatic aldimine 5a, diastereomeric amino ketone derivatives 9a and 9a' being isolated in a combined 82% yield in an almost enantiopure form. Concerning the diastereoselectivity of these transformations, better diastereoselectivities were observed for aromatic and α-disubstituted aldimines 5a and 5c, with near 3:1 diastereomeric ratios. On the other hand, for aliphatic not hindered aldimines, those values of diastereomeric ratio were closer to 2:1 ( Figure 2).  To demonstrate the synthetic utility of N-tert-butanesulfinyl δ-amino ketone derivatives 7, the stereoselective preparation of piperidine ring systems was accomplished in two steps. This methodology consists in an initial desulfinylation under acidic conditions, and a subsequent reduction of the resulting imine intermediate 10 with NaCNBH 3 [31,32]. As a result, 2,6-cis-disubstituted piperidines 11 were isolated in good to excellent yields (Scheme 4). The cis:trans diastereomeric ratio of compounds 11 was excellent in all cases, as determined by GC-MS analysis. It was not possible to determine by HPLC, or GC using chromatographic columns with a chiral packing, the enantiomeric purities of compounds 11e and ent-11e, but we consider that these values should be similar to the diastereomeric ratios of their precursors aminoketone derivatives 7e (>95:5 dr after column chromatography purification). Piperidines 11e and ent-11e [33] are, respectively, the alkaloids (−)-isosolenopsin A and (+)-isosolenopsin A, that have been isolated from the venom of the fire ants of the genus Solenopsis and display cytotoxic, antibacterial, insecticidal and antifungal activity (Scheme 4) [34,35]. It is worth noting that, by comparison of the optical rotation values of these natural products with those reported in the literature, we were able to confirm that the attack of the organolithium compound 4b occurred through the Re-face of chiral sulfinyl imine 5e, to give N-tert-butanesulfinyl δ-amino ketone derivative 7e as the major diastereoisomer, with S configuration at the stereocenter that is formed after this addition, as in piperidine 11e. The opposite configuration of piperidine ent-11e can be explained then by a selective attack of compound 4b through the Si-face of the (S S )-tert-butanesulfinyl imine ent-5e, which is the precursor in this case.

Synthesis of Piperidines 11 and Azepanes 13 from N-tert-Butanesulfinyl Amino Ketone Derivatives 7 and 9
To demonstrate the synthetic utility of N-tert-butanesulfinyl δ-amino ketone derivatives 7, the stereoselective preparation of piperidine ring systems was accomplished in two steps. This methodology consists in an initial desulfinylation under acidic conditions, and a subsequent reduction of the resulting imine intermediate 10 with NaCNBH3 [31,32]. As a result, 2,6-cis-disubstituted piperidines 11 were isolated in good to excellent yields (Scheme 4). The cis:trans diastereomeric ratio of compounds 11 was excellent in all cases, as determined by GC-MS analysis. It was not possible to determine by HPLC, or GC using chromatographic columns with a chiral packing, the enantiomeric purities of compounds 11e and ent-11e, but we consider that these values should be similar to the diastereomeric ratios of their precursors aminoketone derivatives 7e (>95:5 dr after column chromatography purification). Piperidines 11e and ent-11e [33] are, respectively, the alkaloids (−)isosolenopsin A and (+)-isosolenopsin A, that have been isolated from the venom of the fire ants of the genus Solenopsis and display cytotoxic, antibacterial, insecticidal and antifungal activity (Scheme 4) [34,35]. It is worth noting that, by comparison of the optical rotation values of these natural products with those reported in the literature, we were able to confirm that the attack of the organolithium compound 4b occurred through the Re-face of chiral sulfinyl imine 5e, to give N-tert-butanesulfinyl δ-amino ketone derivative 7e as the major diastereoisomer, with S configuration at the stereocenter that is formed after this addition, as in piperidine 11e. The opposite configuration of piperidine ent-11e can be explained then by a selective attack of compound 4b through the Si-face of the (SS)tert-butanesulfinyl imine ent-5e, which is the precursor in this case. Azepane ring systems are also easily accessible from N-tert-butanesulfinyl ε-amino ketone derivatives 9 employing the same methodology that was used for the synthesis of piperidines 11, starting from N-tert-butanesulfinyl δ-amino ketone derivatives 9. In this case, azepanes 13a and ent-13a were obtained in excellent yields and enantiopurities. Reduction of cyclic imine intermediate 12 took place with poorer diastereoselectivity than for six-membered cyclic imines 10, leading in this case to a 85:15 cis:trans diastereomeric ratio. However, the enantiopurity of compounds 13a and ent-13a was analyzed by GC (see in Supplementary Materials) using a column containing a chiral stationary phase and both Azepane ring systems are also easily accessible from N-tert-butanesulfinyl ε-amino ketone derivatives 9 employing the same methodology that was used for the synthesis of piperidines 11, starting from N-tert-butanesulfinyl δ-amino ketone derivatives 9. In this case, azepanes 13a and ent-13a were obtained in excellent yields and enantiopurities. Reduction of cyclic imine intermediate 12 took place with poorer diastereoselectivity than for six-membered cyclic imines 10, leading in this case to a 85:15 cis:trans diastereomeric ratio. However, the enantiopurity of compounds 13a and ent-13a was analyzed by GC (see in Supplementary Materials) using a column containing a chiral stationary phase and both showed excellent enantiomeric ratios (Scheme 5). Azepane ring systems are also easily accessible from N-tert-butanesulfinyl ε-amino ketone derivatives 9 employing the same methodology that was used for the synthesis of piperidines 11, starting from N-tert-butanesulfinyl δ-amino ketone derivatives 9. In this case, azepanes 13a and ent-13a were obtained in excellent yields and enantiopurities. Reduction of cyclic imine intermediate 12 took place with poorer diastereoselectivity than for six-membered cyclic imines 10, leading in this case to a 85:15 cis:trans diastereomeric ratio. However, the enantiopurity of compounds 13a and ent-13a was analyzed by GC (see in Supplementary Materials) using a column containing a chiral stationary phase and both showed excellent enantiomeric ratios (Scheme 5).
Infrared spectra (IR) were obtained with an ATR Jasco FT/IR-4100, without previous preparation of the sample. The frequencies are given in cm −1 . Optical rotations were measured using a Jasco P-1030 polarimeter with a thermally jacketed 5 cm cell at approximately 23 °C and concentrations (c) are given in g/100 mL. Low-resolution mass spectra (LRMS) were obtained in the electron impact mode (EI) with an Agilent MS5973N spectrometer with a SIS (Scientific Instrument Services) direct insertion probe (73DIP-1) at 70 eV, and with an Agilent GC/MS5973N spectrometer in the electron impact mode (EI) at 70 eV. In both cases, fragment ions are given in m/z with relative intensities (%) in parentheses. High-resolution mass spectra (HRMS) were also carried out in the electron impact mode (EI) at 70 eV on an Agilent 7200 spectrometer equipped with a time of flight (TOF) analyzer and the samples were introduced through a direct insertion probe, or through an Agilent GC7890B. NMR spectra were recorded at 300 or 400 MHz for 1 H NMR and at 75 or 100 MHz for 13 C NMR with a Bruker AV300 Oxford or a Bruker AV400 spectrometers, Scheme 5. Synthesis of azepanes 13a from N-tert-butanesulfinyl amino ketone derivative 9a.
Infrared spectra (IR) were obtained with an ATR Jasco FT/IR-4100, without previous preparation of the sample. The frequencies are given in cm −1 . Optical rotations were measured using a Jasco P-1030 polarimeter with a thermally jacketed 5 cm cell at approximately 23 • C and concentrations (c) are given in g/100 mL. Low-resolution mass spectra (LRMS) were obtained in the electron impact mode (EI) with an Agilent MS5973N spectrometer with a SIS (Scientific Instrument Services) direct insertion probe (73DIP-1) at 70 eV, and with an Agilent GC/MS5973N spectrometer in the electron impact mode (EI) at 70 eV. In both cases, fragment ions are given in m/z with relative intensities (%) in parentheses. High-resolution mass spectra (HRMS) were also carried out in the electron impact mode (EI) at 70 eV on an Agilent 7200 spectrometer equipped with a time of flight (TOF) analyzer and the samples were introduced through a direct insertion probe, or through an Agilent GC7890B. NMR spectra were recorded at 300 or 400 MHz for 1 H NMR and at 75 or 100 MHz for 13 C NMR with a Bruker AV300 Oxford or a Bruker AV400 spectrometers, respectively, using CDCl 3 as solvent, and TMS as internal standard (0.00 ppm). The data are reported as: (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br s = broad signal, coupling constant(s) in Hz, integration). 13 C NMR spectra were recorded with 1 H-decoupling at 100 MHz and referenced to CDCl 3 at 77.16 ppm. DEPT-135 experiments were performed to assign CH, CH 2 and CH 3 .
TLCs were performed on prefabricated Merck aluminum plates with silica gel 60 coated with fluorescent indicator F 254 and were visualized with phosphomolybdic acid (PMA) stain. The R f values were calculated under these conditions. Flash chromatography was carried out on handpacked columns of silica gel 60 (230-400 mesh). GC-MS analysis were carried out in an Agilent 6890N spectrometer with FID detector, helium gas transportation (2 mL/min), injection pressure: 12 psi, temperature in detection an injection blocks: 270 •  Known chiral N-tert-butanesulfinyl imines 5a [36], 5b [37], 5c [36], 5d [38], and 5e [39] were prepared according to the reported procedures, and spectroscopic data are in accordance with the literature.

Synthesis of 2-Methoxy-1-alkenyl Chlorides 2
General Procedure. A solution of Hg(OAc) 2 (0.640 g, 2.0 mmol) in dry methanol (5 mL) was stirred under argon at 23 • C for 5 min. Then, the corresponding alkynyl chloride 1 (2.0 mmol) was slowly added to this solution at 0 • C, and the reaction was stirred at 23 • C for 15 min. After this time, petroleum ether (5 mL) was added to the reaction mixture, and it was cooled to 0 • C, and a solution of NaBH 4 (0.082 g, 2.2 mmol, 1.1 equiv) in NaOH 3M (2 mL) was slowly added. The reaction was stirred at 23 • C for 15 min, and then the layers were separated, and the aqueous layer was extracted with petroleum ether (3 × 10 mL). The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was evaporated under vacuum (15 Torr, <30 • C), leading to the expected compounds 2, which were pure enough to be used for the next step.
5-Chloro-2-methoxypent-1-ene (2b). Following the general procedure, compound 2b was obtained from 5-chloropent-1-yne (1b) as a colorless liquid (99% conversion of 1b into 2b by GC-MS analysis): C 6  General Procedure. To a blue suspension of lithium powder (50 mg, 7.1 mmol) and DTBB (15 mg, 0.05 mmol, 25 mol%) in dry THF (3 mL) was added the corresponding 2-methoxy-1-alkenyl chloride 2 (1.0 mmol) at −78 • C, and the reaction mixture was stirred at this temperature for 1 h. Then the corresponding chiral sulfinyl imine 5 (0.2 mmol) was added dropwise, and the resulting reaction mixture was stirred for 1 h, and allowed to warm up until the temperature reached −40 • C. After that, it was hydrolyzed with water (3 mL), and allowed to warm up to reach the room temperature. Then it was extracted with ethyl acetate (3 × 10 mL), dried over magnesium sulfate and the solvent was evaporated under vacuum (15 Torr). The reaction crude was then dissolved in THF (8 mL) and distilled water was added (36 µL, 36 mg, 2 mmol, 10 equiv) and HCl (2M in Et 2 O, 20 µL, 0.04 mmol, 20 mol%) were successively added at 0 • C, and the reaction mixture was stirred at this temperature for 10 min. After that, it was hydrolyzed with a saturated aqueous solution of NaHCO 3 (10 mL), extracted with ethyl acetate (3 × 10 mL), dried over magnesium sulfate, and the solvent was evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc) to yield pure products 7 and 9.
Author Contributions: A.S. performed chemical synthesis experiments, analyzed results, and wrote the manuscript. F.F. and M.Y. designed chemical synthesis, analyzed results, and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.