Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-Acylazetidines

A new synthetic route to N-alkyl-2-acylazetidines was developed through a highly stereoselective addition of organolithiums to N-alkyl-2-oxazolinylazetidines followed by acidic hydrolysis of the resulting oxazolidine intermediates. This study revealed an unusual reactivity of the C=N bond of the oxazoline group when reacted with organolithiums in a non-polar solvent such as toluene. The observed reactivity has been explained considering the role of the nitrogen lone pair of the azetidine ring as well as of the oxazolinyl group in promoting a complexation of the organolithium, thus ending up with the addition to the C=N double bond. The high level of stereoselectivity in this addition is supported by DFT calculations and NMR investigations, and a model is proposed for the formation of the oxazolidine intermediates, that have been isolated and fully characterized. Upon acidic conditions, the oxazolidine moieties were readily converted into 2-acylazetidines. This synthetic approach has been applied for the preparation of highly enantioenriched 2-acylazetidines starting from chiral not racemic N-alkyl-2-oxazolinylazetidines.

Introduction

The four-membered saturated heterocycle azetidine is a valuable scaffold exploited in several active research areas (Singh et al., 2008; Couty and Evano, 2009; Antermite et al., 2017). The strain and dynamic phenomena associated to the azetidine ring allows exploring new chemical space for organic synthesis and drug discovery purposes (Degennaro et al., 2014a,b; De Ceglie et al., 2011). Recently, different approaches have been reported for the synthesis of azetidine derivatives for targeting lead compounds and bioisosteres for drug discovery (Couty et al., 2004; Ferraris et al., 2007; Pérez-Faginas et al., 2011). Despite the great interest for this small-sized heterocycle, some structural motifs, such as 2-ketoazetidines, seems to be poorly investigated. Biologically active compounds, incorporating the 2-acylazetidine moiety, include natural products such as alkaloids found in the genus Daphniphyllum (Kobayashi and Kubota, 2009) as well as 2-aroylazetidines known as potent inhibitors of dipeptidyl peptidase IV (DPP-IV) (Ferraris et al., 2004), a proline-specific serine protease used as target in several therapeutic areas such as diabetes (Weber, 2004) pain (Ronai et al., 1999), and cognition enhancement (During et al., 2003; Figure 1).

FIGURE 1

Figure 1. Examples of 2-acylazetidine motif in natural products and biologically active compounds.

Methods for the preparation of 2-acylazetidines could be traced back to 1969 with the first synthesis reported by Cromwell, by cyclization of 2,4-dibromoketones with primary amines (Scheme 1, A) or the addition of organolithiums to azetidines carboxylic acids (Rodebaugh and Cromwell, 1969, 1971; Kulkarni and Cromwell, 1977; Arnould et al., 1980; Scheme 1, B). Selected examples, for the stereoselective synthesis of 2-acylazetidines, include the nucleophilic addition of aryllithiums (Couty and Prim, 2002) and Grignard reagents (Couty et al., 2011) to optically active 2-cyanoazetidines (Scheme 1, E) or the addition of Grignard reagents to enantiopure Weinreb amides prepared from methyl 1-phenylethylazetidine-2-carboxylates (Ma et al., 2007; Scheme 1, C). Recently, the synthesis of 2-acylazetidines, by a one-pot tetramethylguanidine/I₂-mediated formal [2+2] cycloaddition reaction of α-amidomalonate with enones, has been reported by Miao and Sun (Miao et al., 2013; Scheme 1, F). Yadav reported the ring expansion of aziridines, employing phenacyl bromide derivatives via in situ generated ammonium ylides in a silica gel-water reaction medium (Garima et al., 2010; Scheme 1, D).

SCHEME 1

Scheme 1. Reported synthesis of 2-acylazetidines.

In 2011, our group reported an intriguing approach for the synthesis of 2-ketoaziridines exploiting an unprecedented reactivity profile of chiral 2-oxazolinylaziridines when subjected to reaction with organolithiums (Degennaro et al., 2011). This work focused on a regioselective α-lithiation of optically active N-phenylethyl-2-oxazolinylaziridines by using a strong base such as n-buthyllithium (n-BuLi) in a coordinating solvent (THF) at −78°C within 1 h. The resulting lithiated species proved to be chemically and configurationally stables, under the experimental conditions, and were trapped with electrophiles in highly stereoselective manner (Scheme 2, path A). In particular, this study demonstrated the presence of a mixture of two equilibrating invertomers for N-alkyl-2-oxazolinylaziridines as a result of the nitrogen inversion (Capriati et al., 2002; Luisi et al., 2005; Scheme 2). It was demonstrated by NMR and DFT calculations, that the dynamics at nitrogen was dependent on the nature of the substituent at the C2 of the azetidine ring. A dynamic model was proposed to account for a diverse and unexpected reactivity observed in a non-polar solvent such as toluene. In fact, as a consequence of a competing complexation of the organolithium reagent with the lone pair of the aziridine nitrogen led to an unusual attack to the C=N bond of the oxazoline ring with consequent formation of an oxazolidine intermediate, useful precursor of the corresponding 2-acylaziridine (Scheme 2, path B). Better results in term of yield and stereoselectivity were obtained by reacting C2-substituted oxazolinylaziridines with organolithiums in toluene and at higher temperature (0°C). Therefore, this model suggests that controlling the nitrogen dynamics, in these systems, could be possible to address the reactivity providing both α-substituted aziridines and 2-ketoaziridines.

SCHEME 2

Scheme 2. Example of reactivity controlled by dynamics in small nitrogenated heterocycles.

Inspired by these preliminary results on 2-oxazolinylaziridines, highlighting the role of nitrogen dynamics on the reactivity of this three-membered heterocycles, we were keen to build on this ground a stereoselective synthesis of 2-ketoazetidines, likely starting from the corresponding 2-oxazolinyl azetidines (Scheme 2). We are glad to report herein the results obtained in this investigation.

Results and Discussion

Substrates Synthesis

The first step for the synthesis of 2-oxazolinylazetidines 4a (R, R)-4b and (R, S)-4b, reported in Scheme 3, involved the reaction of methyl 2,4-dibromobutanoate 1, commercially available, with a suitable primary amine. When ester 1 was reacted with benzylamine, azetidinylester 2a was obtained in high yield, and, by subsequent treatment with 2-amino-2-methylpropanol, n-hexyllithium, in presence of catalytic amount of LaCl₃ afforded hydroxamide 3a (Jang et al., 2015; Scheme 3). The last step consisted in an intramolecular cyclization of hydroxamide 3a mediated by diethylaminosulfur trifluoride at low temperature, that provided the desired oxazoline 4a. A similar protocol was applied to the preparation of 2-methylcarboxylates (R, R)-2b, and (R, S)-2b, by using (R)-1-phenylethylamine as chiral not racemic amine, to yield orthogonally protected and chromatographically separable diastereomeric mixture of esters in 64% yield in 1:1 ratio. Hydroxamides (R, R)-3b and (R, S)-3b where separately synthesized as previously described for amide 3a and, in the case of amide (S, S)-3b, prepared from (S)-1-phenylethylamine, the structure has been solved by X-Ray analysis, confirming the chemical structure and the absolute stereochemistry of the compound (see Supplementary Material). Finally, the cyclization step yielded 2-oxazolinylazetidines (R, R)-4b and (R, S)-4b, as single diastereoisomers, each with excellent enantiomeric ratio (er = 98:2).

SCHEME 3

Scheme 3. Substrates synthesis.

Optimization Study and Scope

According to a recent report by Couty and coworkers, the addition of organolithiums or Grignard reagents to azetidine carboxylic esters (R, S)-2b, occurred with low chemoselectivity, providing the corresponding tertiary alcohol as the main product (Couty et al., 2011). This prompted us to consider the approach reported in Scheme 2 as an alternative route to 2-acylazetidines. We started our investigation considering the reaction of azetidine 4a with n-BuLi in toluene (Table 1). Pleasingly, oxazolidine 5a was the sole product observed in these experiments with no evidence for the α-deprotonation of the azetidine ring.

TABLE 1

Table 1. Reaction of azetidine 4a with n-BuLi.

By adding n-BuLi at room temperature, within 20 min, azetidine 5a was obtained in 30% yield, after aqueous work up, as a 82:18 mixture of diastereomers (Table 1, No. 1). With the aim to improve both yield and diastereoselectivity, the reaction was conducted at lower temperature. To our delight, running the reaction at −78°C furnished the product 5a in high yield and as single diastereoisomer (Table 1, No. 4). The use of an excess n-BuLi, considerably lowered the yields, giving also a complex mixture of products (Table 1, No. 5-6). We considered the conditions in No. 4 as optimal for the examination of the reaction scope. Under optimized conditions, the nucleophilic addition of n-hexylLi, MeLi and EtLi proceeded in highly stereoselective manner affording compounds 5b-d as single diastereoisomer with satisfactory yields (Scheme 4). By using PhLi as nucleophile, the reaction required longer times (3 h) and product 5e was obtained with 82% yield and 98:2 dr. Surprisingly, the reaction with 2-thienyllithium did not afford any product, even keeping the reaction up to 6 h at −78 and 0°C, presumably as a consequence of the presence of ethereal solvents, namely THF, in 2-thienyllithium solution. Based on these results, the same protocol (i.e., toluene, −78°C), was tested using optically active oxazolinylazetidine (R, R)-4b. Unexpectedly, the addition reaction was not observed at −78°C, but full conversion was obtained running the reaction at 0°C in 20 min, obtaining oxazolidine 6a in 86% yield as a single diastereomer (dr > 98:2) and highly enantioenriched (er = 98:2). The modified conditions were also employed for preparing in good yield and diastereoselectivity oxazolidines 6b-d, and 7a-d starting from oxazolinylazetidine (R, R)-4b and (R, S)-4b, respectively (Scheme 4).

SCHEME 4

Scheme 4. Oxazolidine synthesis.

Proposed Model for the Stereoselective Addition

The high stereoselectivity observed for the C=N addition prompted us to consider the stereochemistry at the quaternary stereogenic center of the oxazolidine ring. All attempts to get suitable crystals for X-ray analysis were unsuccessful, and NOESY experiments were inconclusive. Based on our previous experience on the stereochemical assignments in three and four-membered heterocycles by using DFT calculations and NMR predictions, we decided to pursue this approach for solving this stereochemical puzzle (Azzena et al., 2018). The diastereoiomers (R, R, R)-6c and (R, R, S)-6c were considered. A relaxed potential energy surface (PES) scan of the dihedral angles C₄₃N₁₆C₁₇C₁₉ and O₂C₃C₁₁C₁₂, which define the relative position of the two substituents (oxazolidine ring and benzyl group) on the azetidinyl ring, was performed. All other parameters were allowed to vary freely during the PES scan; the single point energies were calculated at DFT/B3LYP/3-21G level in vacuo. After conformational minimization, the lowest energy conformers of the two diastereoisomers was subjected to fully unconstrained geometry optimization at SMD/DFT/B3LYP/6-311++G(d,p) level, followed by vibrational analysis. The free energy values provided by the vibrational analysis calculations indicated that diastereoisomer (R, R, R)-6c was 3.8 Kcal/mol more stable with respect to (R, R, S)-6c. At the end, optimized structures were used for prediction of nuclear shieldings using the gauge independent atomic orbital (GIAO) approach. GIAO NMR calculations were performed at SMD(CHCl₃)/DFT/ MPW1PW91/gen level and the shielding tensors (σ_calc) scaled to obtain the predicted chemical shifts (δscal, see Supplementary Material). The NMR chemical shifts (δ) were calculated as the differences of isotropic shielding constants (σ) with respect to the TMS (tetramethylsilane) reference, calculated at the same level of theory. The pcS-2 basis set, specifically designed for NMR shielding constant calculations (Jensen, 2008), was used for H and C atoms and 6-311++G(d,p) for N and O atoms. For indirect spin-spin coupling constants J_HH calculation, we selected the SMD/DFT/B3LYP/6-311++G(d,p) level of theory, a good compromise between accuracy and computational cost. Indeed in our earlier studies, we noticed the performance of this method in predicting proton and carbon NMR shieldings as well as the spin–spin coupling constants J_HH (Azzena et al., 2011; Carroccia et al., 2014; Zenzola et al., 2014; Degennaro et al., 2015a,b; Pisano et al., 2016)_. All calculations were performed with the Gaussian 09 program at DFT level and the solvent effect was modeled using the self-consistent reaction field (SCRF) calculations within the SMD model (Marenich et al., 2009; Supplementary Material). The statistical parameters CMAE and R² of δ_scaled/δ_expt were determined to establish the consistency between the theoretical and experimental magnetic parameters of the two possible diastereoisomers, and the best fit in all cases was found for the diastereoisomer (R, R, R)-6c (see Supplementary Material). In Figure 2 the comparison between experimental and calculated ¹H NMR spectra of azetidine 6c is reported. A better match can be assessed between the real and calculated spectra of (R,R,R)-6c (Figures 2A,B).

FIGURE 2

Figure 2. (A) Calculated spectrum of (R,R,R)-6c; (B) Real spectrum of (R,R,R)-6c; (C) Calculated spectrum of (R,R,S)-6c.

Based on the results obtained by DFT calculations, we assumed that the configuration at the new created stereocentre of 6c might be (R). With the aim to rationalize the stereochemical outcome of the nucleophilic addition of organolithiums to the C=N double bond of the oxazoline ring, we considered the stereodynamic model proposed for oxazolinylaziridines (Scheme 2). Assuming that oxazolinylazetidines could show dynamic phenomena associated with both nitrogen inversion and ring puckering (Parisi et al., 2016), the stereochemistry of substrates (R, R)-4b and (R, S)-4b was first assessed by NOESY experiments (see Supplementary Material). This stereochemical evaluation demonstrated a trans relationship between the nitrogen substituent and the oxazoline ring. Considering such stereochemical arrangement, the two lone pairs belonging to both azetidine and oxazoline nitrogens could likely be oriented in such a way to promote an easy formation of a complex with the organolithium reagent (Scheme 5). Under these stereochemical restrictions, it is reasonable to foresee the nucleophilic addition of the organolithium to the most accessible face of the planar C=N bond, resulting an (R) configuration at the new stereocenter starting from (R, R)-4b, and (S) configuration starting from (R, S)-4b (Scheme 5). On the basis of this model, the absolute configuration for compounds 6a-d and 7a-b have been supposed to be (R,R,R) and (R,S,S), respectively. Similar reasoning can be made for azetidine 4a leading to adducts 5a-e with (R,^*R^*) relative configuration. It is worth pointing out that, in striking contrast to what previously observed for aziridines, where a preferential α-lithiation took place under similar reaction conditions, with the nucleophilic addition occuring in 15–20% extent and low stereoselectivity, in the case of oxazolinylazetidines α-lithiation was never observed even at higher temperature. It is reasonable to assume that such peculiar stereoelectronic requirements realized with azetidines prevented the deprotonation event, leading to a stable complex prone to undergo exclusively nucleophilic addition to the C=N double bond.

SCHEME 5

Scheme 5. Proposed model.

Synthesis of 2-acylazetidines

All the products 5a-e were isolated by flash chromatography, even though a partial and expected hydrolysis of the oxazolidine moiety in acidic media by silica gel occurred. This evidence prompted us to explore a mild and easy acidic hydrolysis by using silica gel in dichloromethane. Treatment of 5a-d with SiO₂ in dichloromethane (DCM) as solvent for 3 h afforded N-alkyl-2-acylazetidines 8a-d in quantitative yields (Scheme 6). The oxazolidine 5e resulted unreactive under these conditions, and all the attempts to hydrolyze the cyclic aminal failed. Similarly, the hydrolytic protocol was applied to compounds 6a-c and 7b giving good yields of 2-acylazetidines 9a-c and 10b, respectively, in enantiopure form as confirmed by HPLC analysis (see Supplementary Material). A partial epimerization for azetidine 9c in acidic media by silica gel has been observed, leading to the formation of corresponding diastereoisomer 10c (dr = 50/50). Moreover, complete hydrolysis of oxazolidines 7a and 7c taken place already during purification by chromatography on silica gel giving satisfactory yields of 2-acylazetidines 10a and 10c. The absolute stereochemistry of all optically active compounds was assigned according to data reported in the literature (Couty et al., 2011).

SCHEME 6

Scheme 6. Synthesis of 2-acylazetidines.

Conclusions

We have demonstrated that in an apolar solvent, such as toluene, different organolithiums were capable to give an unexpected regio- and stereoselective addition at the C=N bond of the oxazoline group of N-alkyloxazolinylazetidines. Different 1,3-oxazolidinyl azetidines formed in high yield and resulted useful precursors of 2-acylazetidines by acidic hydrolysis. The expected deprotonation event in α position with respect to oxazoline ring did not take place in this conditions. With the aim to rationalize the mechanism and the stereochemical outcome of the addition reaction, a stereodynamic model has been proposed, taking into consideration complexation and dynamic phenomena associated with the azetidine's nitrogen inversion. The configuration assignment, performed on oxazolidinyl azetidines as intermediates by NMR and DFT calculations, resulted mandatory for the validation of proposed model. Even though the stereochemical information generated in the addition reaction is lost in the hydrolysis of oxazolidine ring, this work furnishes an outstanding example of reactivity controlled by dynamics of small nitrogenated heterocycles. Work is in progress to further explore the reactivity of 2-oxazolinylazetidines with organolithium in coordinating solvents.

Materials and Methods

General Information

Flash chromatography was performed using 70–230 mesh Al₂O₃ (either neutral or basic activity II-IV), with the indicated solvent system according to standard techniques. Analytical thin layer chromatography (TLC) was carried out on precoated 0.25 mm thick plates of Kieselgel 60 F254; visualization was accomplished by UV light (254 nm) or by spraying a solution of 5 % (w/v) ammonium molybdate and 0.2 % (w/v) cerium(III) sulfate in 100 ml 17.6 % (w/v) aq. sulphuric acid and heating to 200°C for some time until blue spots appear. Infrared spectra (v_max, FT-IR) were recorded in reciprocal centimeters (cm⁻¹). Nuclear magnetic resonance spectra were recorded on 300 or 500 MHz spectrometers. The frequency used to record the NMR spectra is given in each assignment and spectrum (¹H NMR at 300 or 500 MHz; ¹³C NMR at 101 MHz or 176 MHz). Chemical shifts for ¹H NMR spectra are recorded in parts per million with the residual protic solvent resonance as the internal standard (CDCl₃: δ = 7.27 ppm). Data are reported as follows: chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet and bs = broad singlet), coupling constant (in Hz), integration and assignment]. ¹³C NMR spectra were recorded with complete proton decoupling. Chemical shifts are reported in parts per million with the residual protic solvent resonance as the internal standard (CDCl₃: δ = 77.0 ppm). Assignments of ¹H and ¹³C spectra were based upon the analysis of δ and J values, as well as DEPT, COZY and HSQC experiments where appropriate. All reactions involving air sensitive reagents were performed under nitrogen in oven-dried glassware using syringe-septum cap technique. All organolithiums are commercially available by Sigma Aldrich and were titrated before use. All other chemicals were commercially available and used without further purification. Enantiomeric excess was assessed by HPLC (Chiralcel ODH, ADH). Diastereomeric ratio was assessed by GC-MS or ¹H NMR analysis on the reaction crude.

Synthesis of Substrates

Methyl 1-benzyl-2-azetidinecarboxylate 2a

According to procedure reported in literature (Nocquet et al., 2012).

¹H NMR (500 MHz, CDCl₃) δ 7.45–7.14 (m, 5H, Ar-H overlapping CHCl₃), 3.80 (d, J = 12.6 Hz, 1H, CH2Ph), 3.74 (t, J = 8.4 Hz, 1H, CHCO), 3.63 (s, 3H, CH₃), 3.59 (d, J = 12.6 Hz, 1H, CH2Ph), 3.34–3.29 (m, 1H, NCH₂), 2.94 (ddd, J = 9.2, 7.8, 6.9 Hz, 1H, NCH₂), 2.41–2.32 (m, 1H, NCH₂CH₂), 2.21 (dtd, J = 10.5, 8.1, 2.4 Hz, 1H, NCH₂CH₂).

Methyl 1-[(1R)-methyl]Benzylazetidine-(2R)-carboxylate (R,R)-2b

According to procedure reported in literature (Starmans et al., 1998).

¹H NMR (300 MHz, CDCl₃) δ 7.37–7.14 (m, 5H, Ar-H), 3.84–3.65 (m, 4H, CHCOOCH₃), 3.45 (q, J = 6.6 Hz, 1H, CHCH₃), 3.11 (ddd, J = 8.2, 7.7, 2.9 Hz, 1H, NCH₂), 2.80 (td, J = 8.3, 7.1 Hz, 1H, NCH₂), 2.36–2.10 (m, 2H, NCH₂CH₂), 1.22 (d, J = 6.6 Hz, 1H, CHCH₃).

Methyl 1-[(1R)-methyl]Benzylazetidine-(2S)-carboxylate (R,S)-2b

According to procedure reported in literature (Starmans et al., 1998).

¹H NMR (500 MHz, CDCl₃) δ 7.33–7.14 (m, 5H, Ar-H), 3.63–3.52 (m, 2H, CHCO and NCHH), 3.40–3.29 (m, 4H, CHPh and OCH₃), 3.04–2.96 (m, 1H, NCHH), 2.36–2.24 (m, 1H NCH₂CH₂), 2.13 (dtd, J = 10.4, 8.0, 2.3 Hz, 1H, NCH₂CH₂), 1.28 (d, J = 6.5 Hz, 1H, CHCH₃).

1-benzyl-N-(1-hydroxy-2-methylpropan-2-yl)azetidine-2-carboxamide 3a

General procedure A: To a perfectly dry flask charged with LaCl₃ (587 mg, 2.40 mmol) was dried by heating under reduced pressure. Then, toluene dry (50 mL) and 2-amino-2-methylpropan-1-ol (4.11 g, 46.13 mmol) were added and after cooling to 0°C, n-hexyllithium (2.0 M in hexane, 23.0 mL, 46.13 mmol) was added dropwise and the reaction was heated to 100°C for 15 min. The solution was cooled to room temperature and methyl 1-benzylazetidine-2-carboxylate 2a (3.78 g, 18.45 mmol) was added and the mixture was stirred over night. The reaction was quenched with water (1 mL) and filtered over celite. The organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure to afford the product as a brown oil (4.50 g, yield 93%).

FT-IR (film) cm⁻¹ 3321, 3054, 2984, 2932, 2856, 2305, 1649, 1532, 1454, 1422, 1265, 1071, 909, 738, and 705.

¹H NMR (500 MHz, CDCl₃) δ 7.35–7.27 (m, 3H, Ar-H), 7.25–7.20 (m, 2H, Ar-H), 7.04 (bs, 1H, NH), 5.08 (bs, 1H, OH), 3.66 (d, J = 12.3 Hz, 1H, CH₂Ph), 3.62 (t, J = 8.6 Hz, 1H, CH), 3.51 (d, J = 12.3 Hz, 1H, CH₂Ph), 3.45–3.38 (m, 2H, CH₂OH and NCH₂), 3.31 (d, J = 11.6 Hz, 1H, CH₂OH), 3.08 (dd, J = 16.2, 8.7 Hz, 1H, NCH₂), 2.47–2.38 (m, 1H, NCH₂CH₂), 2.08–1.95 (m, 1H, NCH₂CH₂), 1.15 (s, 1H, CH₃), 0.96 (s, 1H, CH₃).

¹³C NMR (126 MHz, CDCl₃) δ 173.9 (C = O), 137.4 (Ar-C_q), 129.1(2 x Ar-C), 128.9 (2 x Ar-C), 127.8 (Ar-C), 70.9 (CH₂OH), 66.9 (CH), 62.7 (CH₂Ph), 55.5 (C_q), 51.0 (NCH₂), 24.7 (CH₃), 24.4 (CH₃), 23.2 (NCH₂CH₂).

HRMS (ESI-TOF) [M+Na]⁺ calculated for C₁₅H₂₂N₂NaO₂: 285.1579, found 285.1558.

(R)-N-(1-hydroxy-2-methylpropan-2-yl)-1-[(R)-1-phenylethyl]azetidine-2-carboxamide (R,R)-3b

According to the general procedure A, starting from (R,R)-2b (800 mg, 3.65 mmol) amide (R,R)-3b was isolated as white solid, 907 mg, yield 90%, mp 107–109°C, ${\text{[α]}}_{\text{D}}^{20}$ = + 69.49° (c = 1, CHCl₃).

FT-IR (KBr, cm⁻¹) ν 3334, 3234, 2969, 2852, 1645, 1538, 1451, 1377, 1282, 1072, 767, 702, and 565.

¹H NMR (500 MHz, CDCl₃): δ 7.70 (s, 1H, NH-OH), 7.34–7.21 (m, 5H, Ar-H), 5.24 (s, 1H, NH - OH), 3.75–3.64 (m, 3H, CH₂OH and NCH), 3.45 (q, J = 6.4 Hz, 1H, CHCH₃), 3.08 (t, J = 8.0 Hz, 1H, CH₂), 2.78 (q, J = 8.0 Hz, 1H, CH₂), 2.38–2.29 (m, 1H, CH₂), 2.00–1.91 (m, 1H, CH₂), 1.36 (s, 3H, CH₃), 1.33 (s, 3H, CH₃), 1.14 (d, J = 6.6 Hz, 3H, CHCH₃).

¹³C NMR (125 MHz, CDCl₃): δ 174.7 (C = O), 142.61 (Ar-C_q), 128.6 (2x Ar-C), 127.4 (Ar-C), 126.9 (2x Ar-C), 70.8 (CH₂OH), 67.3 (CH-Ph), 65.3 (NCH), 55.6 (C_q), 49.6 (CH₂N), 24.8 (CH₃), 24.7 (CH₃), 22.1 (CH₂CH₂CH), 21.2 (CH₃CH).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₆H₂₅N₂O₂: 277.1911, found 277.1917.

(S)-N-(1-hydroxy-2-methylpropan-2-yl)-1-[(R)-1-phenylethyl]azetidine-2-carboxamide (R,S)-3b

According to the general procedure A, starting from (S,R)-2b (860 mg, 3.94 mmol) amide (R,S)-3b was isolated as colorless oil, 979 mg, yield 90%, ${\text{[α]}}_{\text{D}}^{20}$ = −118.15° (c = 0.4, CHCl₃).

FT-IR (film, cm⁻¹) ν 3323, 2969, 2930, 2850, 1651, 1532, 1456, 1380, 1278, 1168, 1071, 709, and 656.

¹H NMR (500 MHz, CDCl₃) δ 7.29 (m, 5H, Ar-H), 6.71 (bs, 1H, NH), 4.99 (t, J = 6.1 Hz, 1H, OH), 3.57 (t, J = 8.6 Hz, 1H, CH-CO), 3.46 (t, J = 7.6 Hz, 1H, CH₂N), 3.40–3.28 (m, 2H, CHPh and CHHN), 3.15–3.05 (m, 2H, CHHN and CHHOH), 2.44–2.27 (m, 1H, CH₂), 1.99–1.86 (m, 1H, CH₂), 1.32 (d, J = 6.6 Hz, 3H, CHCH₃), 1.11 (s, 3H, CH₃), 0.88 (s, 3H, CH₃).

¹³C NMR (126 MHz, CDCl₃): δ 173.9 (C = O), 141.5 (Ar-C_q), 128.9 (2 x Ar-C), 128.2 (Ar-C), 128.0 (2 x Ar-C), 71.0 (CH₂OH), 67.0 (CH-Ph), 66.0 (CHCH₂), 55.3 (C_q), 49.8 (CH₂N), 24.4 (CH₃), 24.1 (CH₃), 22.47 (CH₂CH₂CH), 18.3 (CH₃CH).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₆H₂₅N₂O₂: 277.1911, found 277.1933.

General procedure B (cyclization to 4,5-dihydrooxazole): To a solution of hydroxamide (943 mg, 3.42 mmol) in dry dichloromethane (23 mL) at −78°C, diethylaminosulfur trifluoride (497 μL, 3.76 mmol) was added dropwise and the reaction was stirred for 1 h. Then the reaction was stirred at room temperature overnight. The solution was washed with NaHCO₃ 0.1 M (3 × 7 mL), the organic phase was dried over Na₂SO₄ and the solvent was evaporated under reduced pressure.

2-(1-benzylazetidin-2-yl)-4,4-dimethyl-4,5-dihydrooxazole 4a

According to the general procedure B, dihydrooxazole 4a was isolated as yellow oil by chromatography on alumina (20% AcOEt/hexane, Rf 0.4) (1.18 g, yield 88%).

FT-IR (film, cm⁻¹) 3062, 3027, 2966, 2928, 2865, 1666, 1454, 1363, 1297, 1174, 1004, 935, 735, and 701.

¹H NMR (700 MHz, CDCl₃) δ 7.31–7.27 (m, 4H, Ar-H), 7.22 (t, J = 7.1 Hz, 1H, Ar-H), 3.86 (d, J = 8.0 Hz, 1H, OCH₂), 3.82 (t, J = 8.2 Hz, 1H, azetidine-CH), 3.77 (d, J = 8.0 Hz, 1H, OCH₂), 3.67 (AB system, d, J = 12.6 Hz, 2H, CH₂Ph), 3.41–3.37 (m, 1H, azetidine-CH₂), 3.00 (dt, J = 9.4, 7.4 Hz, 1H, azetidine-CH₂), 2.45–2.37 (m, 1H, azetidine-CH₂), 2.16 (m, 1H, azetidine-CH₂), 1.18 (s, 3H, CH₃), 1.07 (s, 3H, CH₃).

¹³C NMR (126 MHz, CDCl₃): δ 165.2 (C=N), 137.4 (Ar-C_q), 129.4 (2 × Ar-C), 128.3 (2 × Ar-C), 127.2 (Ar-C), 79.23 (oxazoline-CH₂), 66.9 (oxazoline-C_q), 62.8 (CH₂Ph), 61.5 (azetidine-CH), 51.8 (azetidine-CH₂), 28.3 (CH₃), 28.3 (CH₃) 22.0 (azetidine-CH₂).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₅H₂₁N₂O: 245.1654, found 245.1649.

4,4-dimethyl-2-{(R)-1-[(R)-1-phenylethyl]azetidin-2-yl}-4,5-dihydrooxazole (R,R)-4b

According to the general procedure B, dihydrooxazole (R,R)-4b was isolated as light brown oil by chromatography on silica (40% AcOEt/hexane, Rf 0.5) (536 mg, yield 92%), ${\text{[α]}}_{\text{D}}^{20}$ = + 81.20° (c = 1, CHCl₃). (ADH, 99:1 Hex:iPrOH, 1 mL/min).

FT-IR (film, cm⁻¹) ν 2967, 2929, 2869, 1737, 1660, 1493, 1453, 1364, 1175, 1072, 1028, 1004, 975, 764, and 701.

¹H NMR (500 MHz, CDCl₃): δ 7.35–7.26 (m, 4H, Ar-H), 7.24–7.20 (m, 1H, Ar-H), 4.04–3.98 (m, 2H, OCH₂), 3.87 (t, J = 8.1 Hz, 1H, NCH), 3.49–3.40 (m, 1H, CH-Ph), 3.12–3.04 (m, 1H, CH₂), 2.82–2.73 (m, 1H, CH₂), 2.38–2.29 (m, 1H, CH₂), 2.14–2.06 (m, 1H, CH₂), 1.29 (s, 3H, CH₃), 1.28 (s, 3H, CH₃), 1.23 (d, J = 6.4 Hz, 3H, CHCH₃).

¹³C NMR (126 MHz, CDCl₃): δ 166.3 (C=N), 142.9 (Ar-C_q), 128.4 (2 × Ar-C), 127.6 (2 × Ar-C), 127.2 (Ar-C), 79.4 (OCH₂), 68.1 (CH-Ph), 67.0 (C_q), 61.2 (NCH), 50.2 (CH₂), 28.2 (CH₃), 28.2 (CH₃), 21.1 (CHCH₃), 21.07 (CH₂).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₆H₂₃N₂O: 259.1805, found 259.1805.

4,4-dimethyl-2-{(S)-1-[(R)-1-phenylethyl]azetidin-2-yl}-4,5-dihydrooxazole (R,S)-4b

According to the general procedure B, dihydrooxazole (R,S)-4b was isolated as light yellow oil by chromatography on silica (40% AcOEt/hexane, Rf 0.4) (747 mg, yield 94%), ${\text{[α]}}_{\text{D}}^{20}$ = −56.30° (c = 1, CHCl₃). (ADH, 99:1 Hex:iPrOH, 0.5 mL/min).

FT-IR (film, cm⁻¹) ν 2960, 2932, 2874, 1735, 1658, 1497, 1444, 1371, 1168, 1072, 1022, 1010, 985, 760, and 704.

¹H NMR (500 MHz, CDCl₃) δ 7.34–7.16 (m, 5H overlapping CHCl₃, Ar-H), 3.76–3.68 (m, 2H, OCHH and CHCH₂), 3.58–3.49 (m, 2H, OCHH and NCHH), 3.34 (q, J = 6.5 Hz, 1H, CHCH₃), 2.99 (q, J = 7.7 Hz, 1H, OCHH), 2.38–2.27 (m, 1H, CH₂CH), 2.13–2.04 (m, 1H, CH₂CH), 1.26 (d, J = 6.6 Hz, 3H, CH₃CH), 1.03 (s, 1H, CH₃), 0.81 (s, 1H, CH₃).

¹³C NMR (126 MHz, CDCl₃): δ 164.8 (C=N), 142.6 (Ar-C_q), 128.3 (2 × Ar-C), 128.1 (2 × Ar-C), 127.4 (Ar-C), 79.0 (0CH₂), 68.5 (CHPh), 66.5 (C_q), 61.4 (NCH), 50.9 (NCH₂), 28.2 (CH₃), 28.0 (CH₃), 21.3 (CH₂CH), 20.3 (CH₃CH).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₆H₂₃N₂O: 259.1805, found 259.1805.

Addition TO 4,5-dihydrooxazoles

General procedure: To a solution of 2-(1-benzylazetidin-2-yl)-4,4-dimethyl-4,5-dihydrooxazole 4a (1 eq) in dry toluene cooled at −78°C, organolithium (R-Li, 1.1-1.5 eq) was added dropwise. The reaction was stirred for 20 min and quenched with water (1 mL). The crude was extracted with water/ethyl acetate and the collected organic phases were dried over sodium sulfate. The solvent was evaporated under reduced pressure and the alumina chromatography afforded the desire product.

(R^*, R^*)-2-(1-benzylazetidin-2-yl)-2-butyl-4,4-dimethyl-1,3-oxazolidine 5a

According to the General Procedure, the reaction was carried out using 2-(1-benzylazetidin-2-yl)-4,4-dimethyl-4,5-dihydrooxazole 4a (60 mg, 0.25 mmol) in dry toluene (5 mL) and butyllithium (1.15 M in hexane, 235 μL, 0.27 mmol) affording 5a as yellow oil (66 mg, yield 87%, dr = 98:2). R_f 0.9 (20% AcOEt/hexane).

FT-IR (film, cm⁻¹) 3265, 2958, 2928, 2857, 1599, 1463, 1364, 1268, 1142, 1045, 935, 799, and 732.

¹H NMR (500 MHz, CDCl₃) δ 7.31–7.21 (m, 5H, Ar-H), 4.03 (d, J = 13.6 Hz, 1H, CH₂Ph), 3.63 (d, J = 7.6 Hz, 1H, oxazolidine-CH₂), 3.54 (t, J = 8.4 Hz, 1H, CH), 3.41 (d, J = 7.6 Hz, 1H, oxazolidine-CH₂), 3.39 (d, J = 13.6 Hz, 1H, CH₂Ph), 3.15 (m, 1H, azetidine-CH₂), 2.71 (dd, J = 15.6, 8.7 Hz, 1H, azetidine-CH₂), 1.99–1.91 (m, 2H, azetidine-CH₂), 1.80–1.68 (m, 1H, butyl-H), 1.55–1.46 (m, 1H, butyl-H), 1.34 (s, 3H, oxazoline-CH₃), 1.33 (s, 3H, oxazolidine-CH₃), 1.31–1.23 (m, 5H, butyl-H), 0.90 (t, J = 7.0 Hz, 1H, CH₂-CH₃).

¹³C NMR (176 MHz, CDCl₃) δ 138.8 (Ar-C_q), 128.4 (2 × Ar-C), 128.3 (2 × Ar-C), 126.9 (Ar-C), 100.6 (OC_qNH), 77.4 (OCH₂), 68.7 (CH), 62.9 (CH₂Ph) 62.8 (butyl-CH₂), 59.6 (butyl-CH₂), 50.52 (NCH₂), 36.9 (butyl-CH₂), 29.9 (oxazolidine-CH₃), 29.1 (oxazolidine-CH₃), 28.0 (butyl-CH₂), 26.51 (butyl-CH₂), 23.55 (butyl-CH₂), 20.9 (NCH₂CH₂), 14.17 (butyl-CH₃).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₉H₃₁N₂O: 303.2436, found 303.2428.

(R^*, R^*)-2-(1-benzylazetidin-2-yl)-2-hexyl-4,4-dimethyl-1,3-oxazolidine 5b

According to the General Procedure, the reaction was carried out using 2-(1-benzylazetidin-2-yl)-4,4-dimethyl-4,5-dihydrooxazole 4a (70 mg, 0.29 mmol) in dry toluene (6 mL) and hexyllithium (1.25 M in hexane, 255 μL, 0.32 mmol) affording 5b as yellow oil (58 mg, yield 60%, dr = 98:2), R_f 0.9 (20% AcOEt/hexane).

¹H NMR (500 MHz, CDCl₃) δ 7.41–7.10 (m, 5H, Ar-H overlapping CHCl₃ signal), 4.03 (d, J = 13.5 Hz, 1H, CH₂Ph), 3.63 (d, J = 7.5 Hz, 1H, oxazolidine-H), 3.54 (t, J = 8.5 Hz, 1H, CH), 3.44 – 3.33 (m, 2H, CH₂Ph and oxazolidine-H), 3.17–3.12 (m, 1H, azetidine-CH₂), 2.70 (q, J = 8.0 Hz, 1H, azetdine-CH₂), 1.94 (m, 2H, azetdine-CH₂), 1.77–1.68 (m, 1H, hexyl-CH₂), 1.49 (t, J = 10.3 Hz, 1H, hexyl-CH₂), 1.34 (s, 3H, oxazoline- CH₃), 1.32 (s, 3H, oxazoline-CH₃), 1.31–1.23 (m, 9H, hexyl-CH₂), 0.88 (t, J = 6.2 Hz, 3H, CH₂-CH₃).

¹³C NMR (126 MHz, CDCl₃) δ 138.7 (Ar-C_q), 128.4 (2 × Ar-C), 128.3 (2 × Ar-C), 126.9 (Ar-C) 100.6 (OC_qN), 77.4 (oxazolidine-CH₂), 68.6 (azetidine-CH), 62.8 (CH₂Ph), 59.6 (oxazolidine-C_q), 50.5 (azetidine-CH₂), 37.2 (hexyl-CH₂), 31.9 (hexyl-CH₂), 30.15 (hexyl-CH₂), 29.11 (oxazolidine-CH₃), 28.05 (oxazolidine-CH₃), 24.3 (hexyl-CH₂), 22.7 (hexyl-CH₂), 20.9 (azetidine-CH₂), 14.25 (hexyl-CH₃).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₂₁H₃₅N₂O: 331.2749, found 331.2743.

(R^*, R^*)-2-(1-benzylazetidin-2-yl)-2,4,4-trimethyl-1,3-oxazolidine 5c

According to the General Procedure, the reaction was carried out using 2-(1-benzylazetidin-2-yl)-4,4-dimethyl-4,5-dihydrooxazole 4a (50 mg, 0.21 mmol) in dry toluene (5 mL) and methyllithium (1.1 M in diethoxy methane, 210 μL, 0.23 mmol) affording 2-(1-benzylazetidin-2-yl)-2,4,4-trimethyloxazolidine 5c as yellow oil (37 mg, yield 70%, dr = 98:2). R_f 0.9 (5% AcOEt/hexane).

FT-IR (film, cm⁻¹) 3029, 2963, 2928, 2853, 1637, 1454, 1371, 1261, 1044, 797, and 748.

¹H NMR (300 MHz, CDCl₃): δ 7.39–7.11 (m, 5H, Ar-H overlapping CHCl₃ signal), 4.01 (d, J = 13.6 Hz, 1H, CH₂Ph), 3.68 (d, J = 8.2 Hz, 1H, OCH₂), 3.43–3.33 (m, 3H, CH₂Ph, OCH₂ and azetidine-CH), 3.15 (t, J = 6.5 Hz, 1H, azetidine-CH₂), 2.73 (q, J = 7.9 Hz, 1H, azetidine-CH₂), 2.02–1.86 (m, 2H, azetidine-CH₂), 1.34 (s, 6H, oxazolidine-CH₃), 1.25 (s, 1H, CH₃).

¹³C NMR (126 MHz, CDCl₃) δ 138.7 (Ar-C_q), 128.4 (2 × Ar-C), 128.4 (2 × Ar-C), 127.0 (Ar-C), 98.8 (OC_qN), 77.7 (OCH₂), 70.8 (azetidine-CH), 62.6 (CH₂Ph), 59.9 (oxazoline-C_q), 50.2 (azetidine-CH₂), 28.8 (oxazolidine-CH₃), 27.5 (oxazolidine-CH₃), 23.5 (CH₃), 20.8 (azetidine-CH₂).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₆H₂₅N₂O: 261.1967, found 261.1957.

(R^*, R^*)-2-(1-benzylazetidin-2-yl)-2-ethyl-4,4-dimethyl-1,3-oxazolidine 5d

According to the General Procedure, the reaction was carried out using 2-(1-benzylazetidin-2-yl)-4,4-dimethyl-4,5-dihydrooxazole 4a (120 mg, 0.49 mmol) in dry toluene (10.5 mL) and ethyllithium (0.1 M in benzene/cyclohexane, 5.4 mL, 0.54 mmol) affording 2-(1-benzylazetidin-2-yl)-2-ethyl-4,4-dimethyloxazolidine 5d as colorless oil (78 mg, yield 58%, dr = 98:2). R_f 0.9 (10% AcOEt/hexane).

FT-IR (film, cm⁻¹) 3267, 2963, 2927, 2855, 1455, 1366, 1260, 1208, 1045, 916, 798, 734, and 697.

¹H NMR (500 MHz, CDCl₃) δ 7.34–7.27 (m, 4H, Ar-H), 7.25–7.20 (m, 1H, Ar-H), 4.03 (d, J = 13.6 Hz, 1H, oxazolidine-CH₂), 3.62 (d, J = 7.7 Hz, 1H, CH₂Ph), 3.56 (t, J = 8.5 Hz, 1H, azetidine-CH), 3.42 (d, J = 7.7 Hz, 1H, CH₂Ph), 3.39 (d, J = 13.6 Hz, 1H, oxazolidine-CH₂), 3.15 (td, J = 6.8, 3.8 Hz, 1H, azetidine-CH₂), 2.76–2.68 (m, 1H, azetidine-CH₂), 1.98–1.91 (m, 2H, azetidine-CH₂), 1.84–1.74 (m, 1H, CH₂CH₃), 1.52 (tt, J = 14.4, 7.2 Hz, 1H, CH₂CH₃), 1.34 (s, 3H, oxazolidine-CH₃), 1.32 (s, 3H, oxazolidine-CH₃), 0.91 (t, J = 7.6 Hz, 3H, CH₂CH₃).

¹³C NMR (126 MHz, CDCl₃) δ 138.7 (Ar-C_q), 128.4 (2 × Ar-C), 128.3 (2 × Ar-C), 126.9 (Ar-C), 100.7 (OC_qN), 77.3 (OCH₂), 68.1 (azetidine-CH), 62.8 (CH₂Ph), 59.6 (C_q), 50.5 (azetidine-CH₂), 29.5 (CH₂CH₃), 29.0 (oxazolidine-CH₃), 28.1 (oxazoline-CH₃), 20.8 (azetidine-CH₂), 8.68 (CH₂CH₃).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₇H₂₇N₂O: 275.2123, found 275.2113.

(R^*, R^*)-2-(1-benzylazetidin-2-yl)-4,4-dimethyl-2-phenyl-1,3-oxazolidine 5e

According to the General Procedure, the reaction was carried out using 2-(1-benzylazetidin-2-yl)-4,4-dimethyl-4,5-dihydrooxazole 4a (73 mg, 0.30 mmol) in dry toluene (7 mL) and phenyllithium (1.0 M in dibutyl ether, 330 μL, 0.33 mmol) affording 2-(1-benzylazetidin-2-yl)-4,4-dimethyl-2-phenyloxazolidine 5e as colorless oil (79 mg, yield 82%, dr = 98:2). R_f 0.9 (5% AcOEt/hexane).

FT-IR (film, cm⁻¹) 3262, 3084, 3061, 3028, 3001, 2963, 2928, 2857, 1953, 1887, 1812, 1652, 1494, 1453, 1366, 1235, 1038, 941, 738, and 700.

¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, J = 8.1, 2H, Ar-H), 7.35–7.21 (m, 8H, Ar-H), 4.17 (d, J = 13.4 Hz, 1H, CH₂Ph), 3.51–3.41 (m, 4H, HCHPh, oxazolidine-CH₂ overlapping azetidine-CH), 3.18–3.09 (m, 1H, azetidine-CH₂), 2.63 (dd, J = 16.2, 7.7 Hz, 1H, azetidine-CH₂), 1.96 (dt, J = 17.9, 9.0 Hz, 1H, azetidine-CH₂), 1.52 (dtd, J = 10.2, 7.9, 2.1 Hz, 1H, azetidine-CH₂), 1.38 (s, 3H, CH₃), 0.93 (s, 3H, CH₃).

¹³C NMR (176 MHz, CDCl₃) δ 143.1 (Ar-C_q), 138.9 (Ar-C_q), 128.5 (2 × Ar-C), 128.4 (2 × Ar-C), 127.8 (2 x Ar-C), 127.4 (Ar-C), 126.9 (Ar-C), 126.9 (2 × Ar-C), 101.2 (OC_qN), 77.3 (OCH₂), 70.8 (CH), 62.6 (CH₂Ph), 60.1 (C_q), 49.7 (azetidine-CH₂), 28.00 (CH₃), 27.9 (CH₃), 20.6 (azetidine-CH₂).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₂₁H₂₇N₂O: 323.2123, found 323.2109.

(R)-2-butyl-4,4-dimethyl-2-{(R)-1-[(R)-1-phenylethyl]azetidin-2-yl}-1,3-oxazolidine 6a

According to the General Procedure, the reaction was carried out using dihydrooxazole (R,R)-4b (50 mg, 0.19 mmol) in dry toluene (3 mL) and butyllithium (1.15 M in hexane, 235 μL, 0.28 mmol) affording 6a as a pale yellow oil, yield 86%, 53 mg, dr = 95:5, ${\text{[α]}}_{\text{D}}^{20}$ = + 59.15° (c = 1, CHCl₃).

FT-IR (film, cm⁻¹) ν 3412, 3028, 2960, 2930, 2860, 1492, 1453, 1380, 1260, 1227, 1164, 1047, 968, 859, 761, and 701.

¹H NMR (500 MHz, CDCl₃) δ 7.35–7.30 (m, 2H, Ar-H), 7.29–7.22 (m, 3H, Ar-H), 3.65 (m, 2H, CHPh and OCH₂), 3.58 (d, J = 7.8 Hz, 1H, OCH₂), 3.49 (t, J = 8.5 Hz, 1H, NCH), 3.00–2.95 (m, 1H, NCH₂), 2.67 (q, J = 8.8 Hz, 1H, NCH₂), 1.92–1.70 (m, 3H, 2 x NCH₂CH₂ and butyl-H), 1.49–1.35 (m, 8H, 2 × butyl-H and 2 x oxazolidin-CH₃), 1.30 (d, J = 6.9 Hz, 3H, CHCH₃), 1.29–1.24 (m, 2H, butyl-H), 1.23–1.16 (m, 1H, butyl-H), 0.87 (t, J = 7.2 Hz, 3H, butyl-CH₃).

¹³C NMR (126 MHz, CDCl₃): δ 142.2 (Ar-C) 128.2 (2 × Ar-C), 128.2 (2 × Ar-C), 127.0 (Ar-C), 100.7 (NHC_qO), 77.2 (OCH₂), 65.4 (NCH), 64.2 (CHCH₃), 59.3 (oxazolidine-C_q), 46.2 (NCH₂), 35.9 (butyl-CH₂), 30.0 (oxazolidine-CH₃), 28.9 (oxazolidine-CH₃), 26.3 (butyl-CH₂), 23.5 (butyl-CH₂), 20.9 (CHCH₃), 20.1 (NCH₂CH₂), 14.2 (butyl-CH₃).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₂₀H₃₃N₂O: 317.2587, found 317.2587.

(R)-2-hexyl-4,4-dimethyl-2-{(R)-1-[(R)-1-phenylethyl]azetidin-2-yl}-1,3-oxazolidine 6b

According to the General Procedure, the reaction was carried out using dihydrooxazole (R,R)-4b (60 mg, 0.23 mmol) in dry toluene (4 mL) and hexyllithium (2.0 M in hexane, 170 μL, 0.35 mmol) affording 6b as yellow oil, 66 mg, yield 83%, dr = 95:5, R_f 0.9 (20% AcOEt/hexane), ${\text{[α]}}_{\text{D}}^{20}$ = + 69.49° (c = 1, CHCl₃).

FT-IR (film, cm⁻¹) ν 3261, 2959, 2927, 2856, 1492, 1454, 1380, 1265, 1210, 1164, 1047, 928, 851, 761, 701, and 665.

¹H NMR (500 MHz, CDCl₃) δ 7.35–7.30 (m, 2H, Ar-H), 7.28–7.22 (m, 3H, Ar-H), 3.67–3.61 (m, 2H, CHPh and OCH₂), 3.58 (d, J = 7.8 Hz, 1H, OCH₂), 3.49 (t, J = 8.5 Hz, 1H, NCH), 3.00–2.95 (m, 1H, NCH₂), 2.67 (q, J = 8.8 Hz, 1H, NCH₂), 1.93–1.70 (m, 3H, NCH₂CH₂ and hexyl-H), 1.49–1.40 (m, 1H, hexyl-H), 1.39 (s, 3H, oxazolidine-CH₃), 1.36 (s, 3H, oxazolidine-CH₃), 1.32–1.21 (m, 9H, CHCH₃ and 6 × hexyl-H), 0.87 (t, J = 7.0 Hz, 3H, hexyl-CH₃).

¹³C NMR (126 MHz, CDCl₃) δ 142.2 (Ar-C_q), 128.2 (2 × Ar-C), 128.2 (2 × Ar-C), 127.0 (Ar-C), 100.7 (NHC_qO), 77.2 (OCH₂), 65.4 (NCH), 64.2 (CHCH₃), 59.3 (oxazolidine-C_q), 46.2 (NCH₂), 36.2 (hexyl-CH₂), 31.9 (hexyl-CH₂), 30.1 (oxazolidine-CH₃), 30.0 (hexyl-CH₂), 28.9 (oxazolidine-CH₃), 24.1 (hexyl-CH₂), 22.7 (hexyl-CH₂), 20.9 (CHCH₃), 20.1 (NCH₂CH₂), 14.2 (hexyl-CH₃).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₂₂H₃₇N₂O: 345.2900, found 345.2894.

(R)-2,4,4-trimethyl-2-{(R)-1-[(R)-1-phenylethyl]azetidin-2-yl}-1,3-oxazolidine 6c

According to the General Procedure, the reaction was carried out using dihydrooxazole (R,R)-4b (50 mg, 0.19 mmol) in dry toluene (3 mL) and methyllithium (1.0 M in diethoxymethane, 290 μL, 0.29 mmol) affording oxazolidine 6c as yellow oil, 36 mg, yield 70%, dr = 95:5). R_f 0.9 (5% AcOEt/hexane). ${\text{[α]}}_{\text{D}}^{20}$ = + 69.10° (c = 1, CHCl₃).

FT-IR (film, cm⁻¹) ν 3258, 2965, 2928, 2861, 1707, 1452, 1371, 1262, 1230, 1166, 1046, 846, and 701.

¹H NMR (300 MHz, CDCl₃) δ 7.37–7.20 (m, 5H, Ar-H overlapping CHCl₃), 3.72 (d, J = 7.7 Hz, 1H, OCH₂), 3.64 (q, J = 6.8 Hz, 1H, CHPh), 3.53 (d, J = 7.7 Hz, 1H, OCH₂), 3.34 (t, J = 8.5 Hz, 1H, NCH), 2.99 (dd, J = 12.4, 6.1 Hz, 1H, NCH₂), 2.69 (td, J = 8.9, 7.1 Hz, 1H, NCH₂), 1.85 (td, J = 8.8, 6.0 Hz, 2H, NCH₂CH₂), 1.39 (s, 1H, oxazolidine-CH₃), 1.38 (s, 1H, oxazolidine-CH₃), 1.31 (d, J = 6.9 Hz, 1H, CHCH₃), 1.21 (s, 1H, oxazolidine-CH₃).

¹³C NMR (126 MHz, CDCl₃) δ 142.1 (Ar-C_q), 128.3 (2 × Ar-C), 128.2 (2 × Ar-C), 127.1 (Ar-C), 99.0 (OC_qNH), 77.5 (OCH₂), 67.6 (NCH), 64.1 (CHPh), 59.6 (oxazolidine-C_q), 46.1 (NCH₂), 29.7 (oxazolidine-CH₃), 28.4 (oxazolidine-CH₃), 23.0 (oxazolidine-CH₃), 20.8 (CHCH₃), 20.2 (NCH₂).

HRMS (ESI-TOF) [M+Na]⁺ calculated for C₁₇H₂₆N₂NaO: 297.1943, found 297.1946.

(R)-4,4-dimethyl-2-phenyl-2-{(R)-1-[(R)-1-phenylethyl]azetidin-2-yl}-1,3-oxazolidine 6d

According to the General Procedure, the reaction was carried out using dihydrooxazole (R,R)-4b (50 mg, 0.19 mmol) in dry toluene (3 mL) and phenyllithium (1.0 M in dibutyl ether, 290 μL, 0.29 mmol) affording oxazolidine 6d as colorless oil, 62 mg, yield 95%, dr = 95:5). R_f 0.8 (10% AcOEt/hexane). ${\text{[α]}}_{\text{D}}^{20}$ = + 40.10° (c = 1, CHCl₃). (ADH, 99.5:0.5 Hex:iPrOH + 0.2% DEA, 0.3 mL/min).

FT-IR (film, cm⁻¹) ν 3257, 3026, 2927, 2865, 1450, 1382, 1268, 1200, 1164, 1039, 961, 851, 752, 720, 701, and 647.

¹H NMR (500 MHz, CDCl₃) δ 7.62–7.58 (m, 2H, Ar-H), 7.37–7.20 (m, 8H, Ar-H), 3.75–3.68 (m, 1H, CHPh), 3.55 (d, J = 7.5 Hz, 1H, OCH₂), 3.47–3.38 (m, 2H, NCH and OCH₂), 3.01–2.90 (m, 1H, NCH₂), 2.60–2.52 (m, 1H, NCH₂), 1.87–1.77 (m, 1H, NCH₂CH₂), 1.44 (s, 3H, oxazolidine-CH₃), 1.41 (d, J = 6.7 Hz, 1H, CHCH₃), 1.33–1.23 (m, 1H, NCH₂CH₂), 0.99 (s, 1H, oxazolidine-CH₃).

¹³C NMR (126 MHz, CDCl₃) δ 142.9 (Ar-C_q), 142.5 (Ar-C_q), 128.2 (2 × Ar-C), 128.2 (2 × Ar-C), 127.6 (2 × Ar-C), 127.4 (Ar-C), 127.3 (2 × Ar-C), 125.8 (Ar-C), 101.2 (NHC_qO), 77.1 (OCH), 68.0 (NCH), 64.4 (CHPh), 59.9 (oxazolidine-C_q), 45.9 (NCH₂), 28.6 (2 × oxazolidine-CH₃), 21.2 (CHCH₃), 19.8 (NCH₂CH₂).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₂₂H₂₉N₂O: 337.2274, found 337.2277.

(S)-2-hexyl-4,4-dimethyl-2-{(S)-1-[(R)-1-phenylethyl]azetidin-2-yl}-1,3-oxazolidine 7a

According to the General Procedure, the reaction was carried out using dihydrooxazole (R,S)-4b (80 mg, 0.31 mmol) in dry toluene (3 mL) and hexyllithium (1.6 M in hexane, 290 μL, 0.46 mmol) affording 7a as yellow oil, 96 mg, yield 90%, dr = 95:5, R_f 0.8 (30% AcOEt/hexane ${\text{[α]}}_{\text{D}}^{20}$ = −8.30° (c = 1, CHCl₃).

FT-IR (film, cm⁻¹) ν 3259, 2960, 2928, 2857, 1453, 1380, 1365, 1196, 1173, 1047, 930, 773, and 699.

¹H NMR (500 MHz, CDCl₃) δ 7.34–7.27 (m, 4H, Ar-H), 7.23–7.18 (m, 1H, Ar-H), 3.85 (q, J = 6.8 Hz, 1H, CHPh), 3.79 (t, J = 8.3 Hz, 1H, NCH), 3.53 (d, J = 7.6 Hz, 1H, OCH), 3.25 (d, J = 7.6 Hz, 1H, OCH), 3.19 (dd, J = 15.3, 8.6 Hz, 1H, NCH₂), 2.93 (td, J = 7.9, 3.0 Hz, 1H, NCH₂), 1.95–1.88 (m, 2H, NCH₂CH₂), 1.74–1.64 (m, 1H, hexyl-H), 1.51–1.42 (m, J = 13.0, 8.4 Hz, 1H, hexyl-H), 1.41–1.20 (m, 14H, CHCH₃, oxazolidine-CH₃ and 8 × hexyl-H), 1.19 (s, J = 8.0 Hz, 3H, oxazolidine-CH₃), 0.88 (t, J = 6.9 Hz, 3H, hexyl-CH₃).

¹³C NMR (126 MHz, CDCl₃) δ 144.3 (Ar-C_q), 128.2 (2 × Ar-C), 127.2 (2 × Ar-C), 126.6 (Ar-C), 100.7 (OC_qNH), 77.1 (OCH₂), 64.3 (NCH), 59.4 (oxazolidine-C_q), 58.9 (CHPh), 42.9 (NCH₂), 36.9 (hexyl-CH₂), 31.9 (hexyl-CH₂), 30.2 (hexyl-CH₂), 29.6 (oxazolidine-CH₃), 28.6 (oxazolidine-CH₃), 24.2 (hexyl-CH₂), 22.8 (hexyl-CH₂), 20.6 (NCH₂CH₂), 14.2 (hexyl-CH₃), 13.8 (CHCH₃).

HRMS (ESI-TOF) [M+Na]⁺ calculated for C₂₂H₃₆N₂NaO: 367.2725, found 367.2718.

(S)-4,4-dimethyl-2-phenyl-2-{(S)-1-[(R)-1-phenylethyl]azetidin-2-yl}-1,3-oxazolidine 7d

According to the General Procedure, the reaction was carried out using dihydrooxazole (R,S)-4b (50 mg, 0.19 mmol) in dry toluene (3 mL) and phenyllithium (1.0 M in dibutyl ether, 290 μL, 0.29 mmol) affording oxazolidine 7b as yellow oil, 59 mg, yield 90%, dr = 95:5). R_f 0.7 (30% AcOEt/hexane). ${\text{[α]}}_{\text{D}}^{20}$ = −3.09 (c = 0.5, CHCl₃). (LUX-1, 99.5:0.5 Hex:iPrOH + 0.2% DEA, 0.5 mL/min).

FT-IR (film, cm⁻¹) ν 3060, 3027, 2966, 2929, 2866, 1687, 1493, 1451, 1366, 1273, 1233, 1036, 742, and 700.

¹H NMR (500 MHz, CDCl₃) δ 7.59–7.55 (m, 2H, Ar-H), 7.39–7.21 (m, 8H, Ar-H overlapping CHCl₃), 3.96 (q, J = 6.8 Hz, 1H, CHPh), 3.64 (t, J = 8.3 Hz, 1H, NCH), 3.32 (d, J = 7.3 Hz, 1H, OCH₂), 3.16 (d, J = 7.3 Hz, 1H, OCH₂), 3.06 (dt, J = 15.1, 7.5 Hz, 1H, NCH₂), 2.97–2.90 (m, 1H, NCH₂), 1.94 (tt, J = 17.4, 8.7 Hz, 1H, NCH₂CH₂), 1.47–1.36 (m, 4H, CHCH₃ and NCH₂CH₂), 1.24 (s, 3H, oxazolidine-CH₃), 0.86 (s, 3H, oxazolidine-CH₃).

¹³C NMR (126 MHz, CDCl₃) δ 144.4 (Ar-C_q), 143.2 (Ar-C_q), 128.9 (2 × Ar-C), 127.7 (2 × Ar-C), 127.5 (2 × Ar-C), 127.4 (Ar-C), 127.1 (2 × Ar-C), 126.6 (Ar-C_q), 101.2 (OC_qNH), 76.9 (OCH₂) 67.3 (NCH), 59.9 (oxazolidine-C_q), 59.8 (CHPh), 42.7 (NCH₂), 28.5 (oxazolidine-CH₃), 28.0 (oxazolidine-CH₃), 20.2 (NCH₂CH₂), 14.6 (CHCH₃).

HRMS (ESI-TOF) [M+Na]⁺ calculated for C₂₂H₂₈N₂NaO: 359.2099, found 359.2092.

Hydrolysis of 1,3-oxazolidines

General Procedure: To a solution of oxazolidines 5a-d, 6a-c and 7b (0.16 mmol, 1 eq) in dichloromethane, silica (150 mg) was added. The reaction was stirred for 3 h at room temperature. The crude was filtered and the solvent was evaporated under reduced pressure to obtain the desire product.

1,3-Oxazolidines 7a and 7c undergo quantitative hydrolysis to corresponding acyl derivatives 10a and c during the chromatography on silica gel.

1-(1-benzylazetidin-2-yl)pentan-1-one 8a

According to the General Procedure, the reaction was carried out using oxazolidine 5a (50 mg, 0.16 mmol), ketoazetidine 8a was obtained as colorless oil (33 mg, yield 90%).

FT-IR (film, cm⁻¹) 2957, 2926, 2854, 1711, 1455, 1360, 1260, 1029, 913, 801, 747, and 700.

¹H NMR (500 MHz, CDCl₃): δ 7.33–7.23 (m, 5H, Ar-H overlapping CHCl₃ signal), 3.73 (d, J = 12.5 Hz, 1H, CH₂Ph), 3.68 (t, J = 8.6 Hz, 1H, azetidine-CH), 3.58 (d, J = 12.5 Hz, 1H, CH₂Ph), 3.35–3.30 (m, 1H, azetidine-CH₂), 2.94 (dd, J = 16.2, 8.0 Hz, 1H, azetidine-CH₂), 2.53 (ddd, J = 17.5, 8.6, 6.3 Hz, 1H, butyl-CH₂), 2.28-2.12 (m, 3H, azetidine-CH₂ and butyl-CH₂), 1.50–1.36 (m, 2H, butyl-CH₂), 1.25-1.19 (m, 2H, butyl-CH₂), 0.86 (t, J = 7.4 Hz, 3H, CH₃).

¹³C NMR (126 MHz, CDCl₃): δ 212.0 (C = O), 137.2 (Ar-C_q), 129.0 (2 x Ar-C), 128.4 (2 x Ar-C), 127.3 (Ar-C), 71.33 (azetidine-CH), 62.9 (CH₂Ph), 50.8 (azetidine-CH₂), 37.7 (butyl-CH₂), 25.1 (butyl-CH₂), 22.3 (butyl-CH₂), 21.8 (azetidine-CH₂), 13.9 (CH₃).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₅H₂₂NONa: 254.1521, found 254.1510.

1-(1-benzylazetidin-2-yl)heptan-1-one 8b

According to the General Procedure, the reaction was carried out using from oxazolidine 5b (50 mg, 0.15 mmol), ketoazetidine 8b was obtained as colorless oil (35 mg, yield 90%).

FT-IR (film, cm⁻¹) 2926, 2853, 1707, 1454, 1364, 1460, 1028, 912, 802, 735, and 699. ¹H NMR (500 MHz, CDCl₃): δ 7.36–7.22 (m, 5H, Ar-H overlapping CHCl₃ signal), 3.73 (d, J = 12.6 Hz, 1H, CH₂Ph), 3.68 (t, J = 8.7 Hz, 1H, azetidine-CH), 3.58 (d, J = 12.5 Hz, 1H, CH₂Ph), 3.34–3.29 (m, 1H, azetidine-CH₂), 2.94 (dd, J = 16.2, 8.0 Hz, 1H, azetidine-CH₂), 2.53 (ddd, J = 17.5, 8.5, 6.3 Hz, 1H, hexyl-CH₂), 2.28–2.11 (m, 3H, azetidine-CH₂ and hexyl-CH₂), 1.50–1.40 (m, 2H, hexyl-CH₂), 1.30–1.17 (m, 6H, hexyl-CH₂), 0.87 (t, J = 7.0 Hz, 3H, CH₃).

¹³C NMR (126 MHz, CDCl₃): δ 212.2 (C = O), 137.5 (Ar-C_q), 129.2 (2 x Ar-C), 128.5 (2 x Ar-C), 127.5 (Ar-C), 71.5 (azetidine-CH), 63.1 (CH₂Ph), 51.0 (azetidine-CH₂), 31.8 (hexyl-CH₂), 29.9 (hexyl-CH₂), 29.1 (hexyl-CH₂), 23.2 (hexyl-CH₂), 22.7 (hexyl-CH₂), 21.9 (azetidine-CH₂), 14.2 (CH₃).

HRMS (ESI-TOF) m/z: calcd for C₁₇H₂₅NONa [M+Na]⁺ 282.1834; found 282.1828.

1-(1-benzylazetidin-2-yl)ethanone 8c

According to the General Procedure, the reaction was carried out using oxazolidine 5c (50 mg, 0.19 mmol) in dichloromethane (1 mL) affording 2-acylazetidine 8c as yellow oil, yield 95%, 32 mg, dr = 95:5).

FT-IR (film, cm⁻¹) 3086, 3062, 3028, 2965, 2930, 2867, 1955, 1881, 1734, 1658, 1652, 1531, 1454, 1162, 1069, and 914.

¹H NMR (700 MHz, CDCl₃) δ 7.33–7.23 (m, 5H, Ar-H overlapping CHCl₃ signal), 3.73 (d, J = 12.6 Hz, 1H, CH₂Ph), 3.66 (dd, J = 14.5, 5.8 Hz, 1H, azetidine-CH), 3.59 (d, J = 12.6 Hz, 1H, CH₂Ph), 3.34–3.31 (m, 1H, azetidine-CH₂), 2.94 (ddd, J = 9.3, 8.0, 6.9 Hz, 1H, azetidine-CH₂), 2.23 (dtd, J = 10.8, 8.3, 2.5 Hz, 1H, azetidine-CH₂), 2.18 (ddd, J = 19.4, 10.5, 8.9 Hz, 1H, azetidine-CH₂), 2.05 (s, 3H, CH₃).

¹³C NMR (176 MHz, CDCl₃): δ 210.5 (C = O), 137.4 (Ar-C_q), 129.1 (2 × Ar-C), 128.5 (2 × Ar-C), 127.5 (Ar-C), 71.8 (azetidine-CH), 63.2 (CH₂Ph), 51.0 (azetidine-CH₂), 25.7 (CH₃), 21.8 (azetidine-CH₂).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₂H₁₆NO: 190.1232, found 190.1226.

1-(1-benzylazetidin-2-yl)propan-1-one 8d

According to the General Procedure, the reaction was carried out using oxazolidine 5d (50 mg, 0.18 mmol), ketoazetidine 8d was obtained as yellow oil (33 mg, yield 90%).

FT-IR (film, cm⁻¹) 3063, 3029, 2964, 2928, 2875, 1955, 1709, 1634, 1495, 1454, 1404, 1241, 1077, 1028, 735, and 700.

¹H NMR (500 MHz, CDCl₃): δ 7.36–7.22 (m, 5H, Ar-H overlapping CHCl₃ signal), 3.75 (d, J = 12.6 Hz, 1H, CH₂Ph), 3.69 (t, J = 8.6 Hz, 1H, azetidine-CH), 3.57 (d, J = 12.6 Hz, 1H, CH₂Ph), 3.33–3.28 (m, 1H, azetidine-CH₂), 2.93 (q, J = 7.5 Hz, 1H, azetidine-CH₂), 2.60 (dq, J = 18.4, 7.3 Hz, 1H, COCH₂), 2.35–2.11 (m, 3H, azetidine-CH₂ and COCH₂), 0.95 (t, J = 7.3 Hz, 3H, CH₃).

¹³C NMR (75 MHz, CDCl₃): δ 212.6 (C = O), 137.6 (Ar-C_q) 129.1 (2 x Ar-C), 128.5 (2 x Ar-C), 127.5 (Ar-C), 71.4 (azetidine-CH), 63.1 (CH₂Ph), 51.1 (azetidine-CH₂), 31.4 (COCH₂), 22.0 (azetidine-CH₂), 7.33 (CH₃).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₃H₁₈NO: 204.1388, found 204.1381.

1-{(R)-1-[(R)-1-phenylethyl]azetidin-2-yl}pentan-1-one 9a

Starting from oxazolidine 6a (50 mg, 0.16 mmol), ketoazetidine 9a was obtained as pale yellow oil. (35 mg, yield 90%), er = 98:2 (LUX-1, 99:1 Hex:iPrOH + 0.5% DEA, 0.5mL/min). ${\text{[α]}}_{\text{D}}^{20}$ = + 149.46° (c = 1, CHCl₃).

FT-IR (KBr, cm⁻¹) ν 3391, 3028, 2960, 2930, 2871, 1705, 1493, 1453, 1371, 1282, 1029, 760, and 701.

¹H NMR (500 MHz, CDCl₃): δ 7.36–7.29 (m, 4H, Ar-H), 7.25–7.21 (m, 1H, Ar-H), 3.72 (t, J = 8.7 Hz, 1H, CHCO), 3.39 (q, J = 6.6 Hz, 1H, CHPh), 3.14–3.05 (m, 1H, NCH₂), 2.80–2.60 (m, 3H, NCHH and COCH₂), 2.21–2.12 (m, 1H, NCH₂CH₂ overlapping acetone), 2.10–2.00 (m, 1H, NCH₂CH₂), 1.66–1.54 (m, 2H, COCH₂CH₂), 1.40–1.31 (m, 2H, COCH₂CH₂CH₂), 1.12 (d, J = 6.6 Hz, 3H, CHCH₃), 0.94 (t, J = 7.4 Hz, 1H, CH₂CH₃).

¹³C NMR (126 MHz, CDCl₃): δ 212.6 (CO), 143.1 (Ar-C_q), 128.5 (2 x Ar-C), 127.4 (2 x Ar-C), 127.3 (Ar-C), 71.3 (CHCO), 67.7 (CHPh), 50.0 (NCH₂), 37.4 (COCH₂), 25.7 (COCH₂CH₂), 22.6 (CH₂CH₃), 21.4 (CH₃CH), 21.1 (NCH₂CH₂), 14.1 (CH₂CH₃).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₆H₂₄NO: 246.1858, found 246.1852.

1-{(R)-1-[(R)-1-phenylethyl]azetidin-2-yl}heptan-1-one 9b

Starting from oxazolidine 6b (50 mg, 0.145mmol), ketoazetidine 9b was obtained as pale yellow oil (30 mg, yield 75%). ${\text{[α]}}_{\text{D}}^{20}$ = +102.22° (c = 0.7, CHCl₃) (ADH, 99:1 Hex:iPrOH, 0.5 mL/min).

FT-IR (KBr, cm⁻¹) ν 2958, 2928, 2854, 1706, 1493, 1452, 1370, 1282, 1068, 1029, 60, and 700.

¹H NMR (500 MHz, CDCl₃): δ 7.39–7.29 (m, 4H, Ar-H), 7.27–7.22 (m, 1H, Ar-H overlapping CHCl₃), 3.72 (t, J = 8.6 Hz, 1H, NCH), 3.39 (q, J = 6.5 Hz, 1H, CHPh), 3.10 (dd, J = 11.0, 4.3 Hz, 1H, NCH), 2.86–2.58 (m, 3H, NCHH and COCH₂), 2.22–2.11 (m, 1H, NCH₂CH₂), 2.10–2.01 (m, 1H, NCH₂CH₂), 1.64–1.54 (m, 2H, hexyl-CH₂), 1.37–1.28 (m, 6H, hexyl-CH₂), 1.12 (d, J = 6.6 Hz, 3H, CHCH₃), 0.90 (t, J = 6.7 Hz, 3H, hexyl-CH₃).

¹³C NMR (126 MHz, CDCl₃): δ 212.7 (C = O), 143.1 (Ar-C_q), 128.5 (2 × Ar-C), 127.5 (2 × Ar-C), 127.3 (Ar-C), 71.4 (NCH), 67.7 (CHPh), 50.0 (NCH₂), 37.8 (hexyl-CH₂), 31.9 (hexyl-CH₂), 29.2 (hexyl-CH₂), 23.5 (hexyl-CH₂), 22.7 (hexyl-CH₂), 21.5 (CHCH₃), 21.1(NCH₂CH₂), 14.2 (hexyl-CH₃).

HRMS calcd. for C₁₈H₂₇NNaO [M+Na]⁺ 296.1990; found 296.1978.

1-{(R)-1-[(R)-1-phenylethyl]azetidin-2-yl}ethanone 9c

Starting from oxazolidine 6c (50 mg, 0.18 mmol), ketoazetidine 9c was obtained as pale yellow oil (37 mg, yield 90%).

FT-IR (KBr, cm⁻¹) ν 2968, 2929, 2850, 1705, 1493, 1453, 1354, 1282, 1245, 1172, 1072, 758, and 701.

¹H NMR (500 MHz, CDCl₃): δ 7.35–7.29 (m, 4H, Ar-H), 7.27–7.22 (m, 1H, Ar-H), 3.69 (t, J = 8.7 Hz, 1H, CHCO), 3.40 (q, J = 6.6 Hz, 1H, CHPh), 3.13–3.08 (m, 1H, NCH₂), 2.78 (dd, J = 16.4, 8.0 Hz, 1H, NCH₂), 2.34 (s, 3H, CH₃CO), 2.22–2.02 (m, 2H, CH₂CH), 1.13 (d, J = 6.6 Hz, 3H, CHCH₃). ¹³C NMR (126 MHz, CDCl₃): δ 211.2 (CO), 143.1 (Ar-C_q), 128.5 (2 × Ar-C), 127.4 (2 × Ar-C), 127.3 (Ar-C), 71.6 (CHCO), 67.7 (CHPh), 50.0 (NCH₂), 25.4 (CH₃CO), 21.4 (CH₃CH), 20.9 (NCH₂CH₂). HRMS (ESI-TOF) [M+Na]⁺ calculated for C₁₃H₁₇NNaO: 226.1208, found 226.1200.

1-{(S)-1-[(R)-1-phenylethyl]azetidin-2-yl}pentan-1-one 10a

Pale yellow oil. er = 98:2 (LUX-1, 99:1 Hex:iPrOH + 0.5% DEA, 0.5 mL/min). ${\text{[α]}}_{\text{D}}^{20}$ = −26.61° (c = 1, CHCl₃).

FT-IR (KBr, cm⁻¹) ν 2959, 2930, 2871, 1705, 1493, 1453, 1373, 1303, 1276, 1159, 1028, 760, and 701.

¹H NMR (500 MHz, CDCl₃): δ 7.26–7.17 (m, 5H, Ar-H), 3.63 (t, J = 8.6 Hz, 1H, CHCO), 3.52 (td, J = 7.3, 2.8 Hz, 1H, NCH₂), 3.31 (q, J = 6.5 Hz, 1H, CHPh), 2.98 (dd, J = 16.0, 8.4 Hz, 1H, NCH₂), 2.12–2.06 (m, 2H, NCH₂CH₂), 2.05–1.97 (m, 1H, COCH₂), 1.92–1.83 (m, 1H, COCH₂), 1.29 (d, J = 6.6 Hz, 3H, CHCH₃), 1.22–0.98 (m, 4H, CH₂CH₂CH₃), 0.76 (t, J = 7.2 Hz, 3H, CH₂CH₃).

¹³C NMR (126 MHz, CDCl₃): δ 211.1 (CO), 142.0 (Ar-C_q), 128.4 (2 × Ar-C), 128.4 (2 × Ar-C), 127.8 (Ar-C), 70.9 (CHCO), 68.5 (CHPh), 50.6 (NCH₂), 38.3 (COCH₂), 25.3 (COCH₂CH₂), 22.3 (COCH₂CH₂CH₂), 21.1 (NCH₂CH₂), 19.4 (CHCH₃), 14.0 (CH₂CH₃).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₆H₂₄NO: 246.1858, found 246.1852.

1-((S)-1-((R)-1-phenylethyl)azetidin-2-yl)heptan-1-one 10b

Starting from oxazolidine 7b (50 mg, 0.145 mmol), ketoazetidine 10b was obtained as pale yellow oil (36 mg, yield 90%), ${\text{[α]}}_{\text{D}}^{20}$ = −10.81° (c = 0.3, CHCl₃). (LUX-1, 99:1 Hex:iPrOH +0.5% DEA, 0.5 mL/min).

FT-IR (KBr, cm⁻¹) ν 2957, 2928, 2855, 1705, 1453, 1372, 1302, 1276, 1159, 1082, 1029, and 701.

¹H NMR (500 MHz, CDCl₃): δ 7.38–7.29 (m, 1H, Ar-H), 7.27–7.10 (m, 4H, 4 × Ar-H overlapping CDCl₃), 3.63 (t, J = 8.5 Hz, 1H, NCH), 3.53 (td, J = 7.3, 2.7 Hz, 1H, NCH₂), 3.32 (q, J = 6.6 Hz, 1H, CHPh), 2.99 (dd, J = 15.9, 8.6 Hz, 1H, NCH₂), 2.13–1.97 (m, 3H, hexyl-H and NCH₂), 1.88 (ddd, J = 17.5, 8.8, 5.9 Hz, 1H, hexyl-H), 1.33–1.08 (m, 9H, 6 × hexyl-H and CHCH₃), 1.06–0.99 (m, 2H, hexyl-H), 0.85 (t, J = 7.3 Hz, 3H, hexyl-H).

¹³C NMR (126 MHz, CDCl₃): δ 211.1 (C = O), 142.0 (Ar-C_q), 128.4 (2 × Ar-C), 128.4 (2 × Ar-C), 127.8 (Ar-C), 71.0 (NCH), 68.5 (CHPh), 50.6 (NCH₂), 38.6 (hexyl-C), 31.7 (hexyl-C), 28.9 (hexyl-C), 23.1 (hexyl-C), 22.6 (hexyl-C), 21.1 (NCH₂CH₂), 19.4 (CHCH₃), 14.2 (hexyl-C).

HRMS (ESI-TOF) [M+H]⁺ calculated for C₁₈H₂₇NNaO: 296.1990, found 296.1985.

1-{(S)-1-[(R)-1-phenylethyl]azetidin-2-yl}ethanone 10c

Pale yellow oil. Yield 80%. ${\text{[α]}}_{\text{D}}^{20}$ = −3.52° (c = 0.3, CHCl₃).

FT-IR (KBr, cm⁻¹) ν 2965, 2928, 2851, 1706, 1493, 1453, 1352, 1244, 1167, 1030, and 702.

¹H NMR (500 MHz, CDCl₃): δ 7.35–7.30 (m, 1H, Ar-H), 7.28–7.20 (m, 4H, Ar-H overlapping CHCl₃), 3.59 (t, J = 8.6 Hz, 1H, NCH), 3.52 (td, J = 7.4, 2.7 Hz, 1H, NCH₂), 3.32 (q, J = 6.6 Hz, 1H, CHPh), 3.04–2.97 (m, 1H, NCH₂), 2.15–2.02 (m, 2H, NCH₂CH₂), 1.69 (s, 3H, COCH₃), 1.30 (d, J = 6.5 Hz, 3H, CHCH₃).

¹³C NMR (126 MHz, CDCl₃): δ 207.1 (C = O), 142.7 (Ar-C_q), 128.5 (2 × Ar-C), 128.4 (2 × Ar-C), 128.0 (Ar-C), 71.5 (NCH), 68.3 (CHPh), 50.6 (NCH₂), 25.5 (COCH₃), 20.8 (NCH₂CH₂), 19.2 (CHCH₃).

HRMS (ESI-TOF) [M+Na]⁺ calculated for C₁₃H₁₇NNaO: 226.1208, found 226.1202.

X-ray Structural Study of Compound (S,S)-3b

Colorless needles of compound (S,S)-3b were obtained by slow evaporation of solvent (Methanol) at room temperature. A single crystal (dimensions 0.500 × 0.350 × 0.220 mm) was selected and mounted on a glass fiber for the X-ray diffraction measurements. The X-ray diffraction experiment was carried out at room temperature by a Bruker-Nonius KappaCCD single crystal diffractometer, equipped with a charge-coupled device (CCD detector), using monochromatized MoKα radiation (λ 0.71073 Å). The automatic data collection was performed by the COLLECT software, cell determination and refinement by DIRAX and data reduction by EVAL. Absorption effects were corrected by SADABS program via a semi-empirical approach. Additional software used: WinGX21 for preparing the material for publication. The structure was solved by direct methods by using SIR2014 program and refined via full-matrix least squares on F2 by SHELXL2014/7. Non-hydrogen atoms were refined anisotropically. The hydrogen atoms were placed at calculated positions and refined isotropically using a riding model approximation with the displacement parameters set to Uiso(H) = 1.5·Ueq(C) in the case of methyl carbon and to Uiso(H) = 1.2·Ueq(C) for all other carbon atoms where Ueq is the equivalent isotropic displacement parameter of carbon. The compound (S,S)-3b belongs to the monoclinic crystal system with cell lengths (a 7.422(1); b 11.655(3); c 10.382(7); alpha 90; beta 110.40(1); gamma 90). Cell volume 841.8(2) Å3; Z 2. ρcalc 1.090 g/cm³; space group p21. A total of 3,806 reflections were collected at 298 K in the θ range from 3.410 to 27.489°, of which 2254 were observed (I > 2σ(I)). The final values of agreement factors were R 7.34 and wR 17.02% with a number of refined parameters was 187 and the maximum and minimum residual densities were Δρmax 0.52 and Δρmin −0.60. The complete crystallographic information on compound (S,S)-3b has been deposited at the Cambridge Crystallographic Data Center (deposit CCDC 1947700).

Data Availability

All datasets generated for this study are included in the manuscript/Supplementary Files.

Author Contributions

PM, MC, and FF have been involved in the synthesis of all compounds with the help of CC. AA and FF performed X-Ray analysis for compound (S,S)-3b. LP performed DFT and NMR calculations. RL and LD supervised this work and wrote the paper.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This research was supported by the project MISE, Horizon 2020 – PON 2014/2020 FARMIDIAB code 338 and Support for research Funds Es. Fin. 2017-18, University of Bari.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchem.2019.00614/full#supplementary-material

References

Antermite, D., Degennaro, L., and Luisi, R. (2017). Recent advances in the chemistry of metallated azetidines Org. Biomol. Chem. 15, 34–50. doi: 10.1039/C6OB01665K

PubMed Abstract | CrossRef Full Text | Google Scholar

Arnould, J. C., Cossy, J., and Pete, J. P. (1980). Reactivite photochimique des α-aminoenones: reactions de cyclisation et nouveau type de reaction dans les α-sulfonamido-cyclohexenones. Tetrahedron 36, 1585–1592. doi: 10.1016/S0040-4020(01)83126-4

CrossRef Full Text | Google Scholar

Azzena, U., Carraro, M., and Pisano, L. (2018). Addressing stereochemistry of heterocyclic compounds by DFT NMR calculations. Chem. Hetrocycl. Comp. 54, 380–388. doi: 10.1007/s10593-018-2279-x

CrossRef Full Text | Google Scholar

Azzena, U., Dettori, G., Pisano, L., Musio, B., and Luisi, R. (2011). BH3 -promoted stereoselective β-lithiation of N-alkyl-2-phenylaziridines. J. Org. Chem. 76, 2291–2295 doi: 10.1021/jo102474u

PubMed Abstract | CrossRef Full Text | Google Scholar

Capriati, V., Degennaro, L., Florio, S., Flavia, R., and Luisi, R. (2002). Stereospecific β-lithiation of oxazolinyloxiranes: synthesis of α,β-epoxy-γ-butyrolactones. Org. Lett. 4, 1551–1554. doi: 10.1021/ol025781i

PubMed Abstract | CrossRef Full Text | Google Scholar

Carroccia, L., Degennaro, L., Romanazzi, G., Cuocci, C., Pisano, L., and Luisi, R. (2014). Straightforward access to 4-membered sulfurated heterocycles: introducing a strategy for the single and double functionalization of thietane 1-oxide. Org. Biomol. Chem. 12, 2180–2184. doi: 10.1039/c4ob00173g

PubMed Abstract | CrossRef Full Text | Google Scholar

Couty, F., Drouillat, B., and Lemée, F. (2011). Ring Expansion of 2-(1-Hydroxyalkyl)azetidines to 4-(2-Chloroethyl)oxazolidinones. Eur. J. Org. Chem. 794–801. doi: 10.1002/ejoc.201001375

CrossRef Full Text | Google Scholar

Couty, F., and Evano, G. (2009). Azetidines: new tools for the synthesis of nitrogen heterocycles Synlett, 19, 3053–3064. doi: 10.1055/s-0029-1218299

CrossRef Full Text | Google Scholar

Couty, F., Evano, G., and Prim, D. (2004). Synthesis of chiral not racemic azetidines. Mini ReV. Org. Chem. 1, 133–148. doi: 10.2174/1570193043488845

CrossRef Full Text | Google Scholar

Couty, F., and Prim, D. (2002). Synthesis of enantiopure 2-acyl azetidines and the application of amino alcohols derived therefrom in enantioselective catalysis. Tetrahedron Asymmet. 13, 2619–2624. doi: 10.1016/S0957-4166(02)00710-3

CrossRef Full Text | Google Scholar

De Ceglie, M. C., Musio, B., Affortunato, F., Moliterni, A., Altomare, A., Florio, S., et al. (2011). Solvent- and temperature-dependent functionalisation of enantioenriched aziridines. Chem. A Eur. J. 17, 286–296. doi: 10.1002/chem.201002172

PubMed Abstract | CrossRef Full Text | Google Scholar

Degennaro, L., Carroccia, L., Parisi, G., Zenzola, M., Romanazzi, G., Fanelli, F., et al. (2015a). Regio- and stereoselective synthesis of sulfur-bearing four-membered heterocycles: direct access to 2,4-disubstituted thietane 1-oxides. J. Org. Chem. 80, 12201–12211. doi: 10.1021/acs.joc.5b02126

PubMed Abstract | CrossRef Full Text | Google Scholar

Degennaro, L., Giovine, A., Carroccia, L., and Luisi, R. (2014a). “Lithium compounds in organic synthesis: from fundamentals to applications,”in Practical Aspects of Organolithium Chemistry, eds R. Luisi and V. Capriati. (Weinheim: VCH Verlag & Co. KGaA, 513–538.

Google Scholar

Degennaro, L., Mansueto, R., Carenza, E., Rizzi, R., Florio, S., Pratt, L. M., et al. (2011). Nitrogen dynamics and reactivity of chiral aziridines: generation of configurationally stable aziridinyllithium compounds. Chem. – Eur. J. 17, 4992–5003. doi: 10.1002/chem.201003424

PubMed Abstract | CrossRef Full Text | Google Scholar

Degennaro, L., Pisano, L., Parisi, G., Mansueto, R., Clarkson, G. J., Shipman, M., et al. (2015b). Nitrogen stereodynamics and complexation phenomena as key factors in the deprotonative dynamic resolution of alkylideneaziridines: a spectroscopic and computational study. J. Org. Chem. 80, 6411–6418. doi: 10.1021/acs.joc.5b00848

PubMed Abstract | CrossRef Full Text | Google Scholar

Degennaro, L., Zenzola, M., Trinchera, P., Carroccia, L., Giovine, A., Romanazzi, G., et al. (2014b). Regioselective functionalization of 2-arylazetidines: Evaluating the ortho-directing ability of the azetidinyl ring and the α-directing ability of the N-substituent. Chem. Commun. 50, 1698–1700. doi: 10.1039/c3cc48555b

PubMed Abstract | CrossRef Full Text | Google Scholar

During, M. J., Cao, L., Zuzga, D. S., Francis, J. S., Fitzsimons, H. L., Jiao, X., et al. (2003). Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat. Med. 9, 1173–1179. doi: 10.1038/nm919

PubMed Abstract | CrossRef Full Text | Google Scholar

Ferraris, D., Belyakov, S., Li, W., Oliver, E., Ko, Y.-S., Calvin, D., et al. (2007). Azetidine-based inhibitors of dipeptidyl peptidase IV (DPP IV). Curr. Top. Med. Chem. 7, 597–608. doi: 10.2174/156802607780090993

PubMed Abstract | CrossRef Full Text | Google Scholar

Ferraris, D., Ko, Y.-,Sen Calvin, D., Chiou, T., Lautar, S., Thomas, B., Wozniak, K., et al. (2004). Ketopyrrolidines and ketoazetidines as potent dipeptidyl peptidase IV (DPP IV) inhibitors. Bioorg. Med. Chem. Lett. 14, 5579–5583. doi: 10.1016/j.bmcl.2004.08.057

PubMed Abstract | CrossRef Full Text | Google Scholar

Garima, P., Srivastava, V. P., and Yadav, L. D. S. (2010). The first example of ring expansion of N-tosylaziridines to 2-aroyl-N-tosylazetidines with nitrogen ylides in an aqueous medium. Green Chem. 12, 1460–1465. doi: 10.1039/C004736H

CrossRef Full Text | Google Scholar

Jang, H. J., Lee, J. T., and Yoon, H. J. (2015). Aziridine in polymers: a strategy to functionalize polymers by ring-opening reaction of aziridine. Polym. Chem. 6, 3387–3391. doi: 10.1039/C5PY00266D

CrossRef Full Text | Google Scholar

Jensen, F. (2008). Basis set convergence of nuclear magnetic shielding constants calculated by density functional methods. J. Chem. Theor. Comp. 4, 719–727. doi: 10.1021/ct800013z

PubMed Abstract | CrossRef Full Text | Google Scholar

Kobayashi, J., and Kubota, T. (2009). The Daphniphyllum alkaloids. Nat. Prod. Rep. 26, 936–962. doi: 10.1039/B813006J

PubMed Abstract | CrossRef Full Text | Google Scholar

Kulkarni, S. B., and Cromwell, N. H. (1977). The synthesis of l-alkyl-2-benzoyl-4-methylazetidine. Configurational and conformational studies. J. Heterocycl. Chem. 14, 981–983. doi: 10.1002/jhet.5570140606

CrossRef Full Text | Google Scholar

Luisi, R., Capriati, V., Florio, S., Di Cunto, P., and Musio, B. (2005). Synthesis and lithiation of oxazolinylaziridines: the N-substituent effect. Tetrahedron 61, 3251–3260. doi: 10.1016/j.tet.2005.01.045

CrossRef Full Text | Google Scholar

Ma, S. H., Yoon, D. H., Ha, H. J., and Lee, K. W. (2007). Preparation of enantiopure 2-acylazetidines and their reactions with chloroformates. Tetrahedron Lett. 48, 269–271. doi: 10.1016/j.tetlet.2006.11.033

CrossRef Full Text | Google Scholar

Marenich, A. V., Cramer, C. J., and Truhlar, D. G. (2009). Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J. Phy. Chem. B 113, 6378–6396. doi: 10.1021/jp810292n

PubMed Abstract | CrossRef Full Text | Google Scholar

Miao, C. B., Dong, C. P., Zhang, M., Ren, W. L., Meng, Q., Sun, X. Q., et al. (2013). Highly Stereoselective, One-Pot Synthesis of Azetidines and 2,4-Dioxo-1,3-diazabicyclo[3.2.0] Compounds Mediated by I2. J. Org. Chem. 78, 4329–4340. doi: 10.1021/jo400181r

PubMed Abstract | CrossRef Full Text | Google Scholar

Nocquet, P.-A., Hazelard, D., and Compain, P. (2012). Synthesis of spirocyclopropyl γ-lactams by tandem intramolecular azetidine ring-opening/closing cascade reaction: synthetic and mechanistic aspects. Tetrahedron 68, 4117–4128. doi: 10.1016/j.tet.2012.03.111

CrossRef Full Text | Google Scholar

Parisi, G., Zenzola, M., Capitanelli, E., Carlucci, C., Romanazzi, G., Pisano, L., et al. (2016). Exploiting structural and conformational effects for a site-selective lithiation of azetidines. Pure Appl. Chem. 88, 631–648. doi: 10.1515/pac-2016-0602

CrossRef Full Text | Google Scholar

Pérez-Faginas, P., Aranda, M. T., García-López, M. T., Snoeck, R., Andrei, G., Balzarini, J., et al. (2011). Synthesis and SAR studies on azetidine-containing dipeptides as HCMV inhibitors. Bioorg. Med. Chem. 19, 1155–1161. doi: 10.1016/j.bmc.2010.12.052

PubMed Abstract | CrossRef Full Text | Google Scholar

Pisano, L., Degennaro, L., Carraro, M., Fanelli, F., Azzena, U., Mastrorilli, P., et al. (2016). Computational NMR as useful tool for predicting structure and stereochemistry of four-membered sulfur heterocycles. Eur. J. Org. Chem. 2016, 3252–3258. doi: 10.1002/ejoc.201600372

CrossRef Full Text | Google Scholar

Rodebaugh, R. M., and Cromwell, N. H. (1969). The synthesis of 1-(t-butyl)-2-benzoylazetidine. J. Heterocycl. Chem. 6, 439–440. doi: 10.1002/jhet.5570060332

CrossRef Full Text | Google Scholar

Rodebaugh, R. M., and Cromwell, N. H. (1971). Conformational isomerism of 2-carboazetidines. J. Heterocycl. Chem. 8, 421–430. doi: 10.1002/jhet.5570080312

CrossRef Full Text | Google Scholar

Ronai, A. Z., Timar, J., Mako, E., Erdo, F., Gyarmati, Z., Toth, G., et al. (1999). Diprotin, an inhibitor of dipeptidyl aminopeptidase IV(EC 3.4.14.5) produces naloxone — reversible analgesia in rats. Life Sci. 64, 145–152. doi: 10.1016/S0024-3205(98)00544-X

PubMed Abstract | CrossRef Full Text | Google Scholar

Singh, G. S., D'hooghe, M., and De Kimpe, N. (2008). Azetidines, Azetines and Azetes: Monocyclic Comprehensive Heterocyclic Chemistry III. Vol. 2. Available online at: http://www.sciencedirect.com/science/referenceworks/9780080449920

Google Scholar

Starmans, W. A. J., Starmans, W. A. J., Walgers, R. W. A., Thijs, L., de Gelder, R., Smits, J. M. M., et al. (1998). Azetidine based Ligands in Boron catalyzed Asymmetric Dies-Alder Reactions. Tetrahedron 54, 4991–5004. doi: 10.1016/S0040-4020(98)00204-X

CrossRef Full Text | Google Scholar

Weber, A. E. (2004). Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J. Med. Chem. 47, 4135–4141. doi: 10.1021/jm030628v

PubMed Abstract | CrossRef Full Text | Google Scholar

Zenzola, M., Degennaro, L., Trinchera, P., Carroccia, L., Giovine, A., Romanazzi, G., et al. (2014). Harnessing the ortho-directing ability of the azetidine ring for the regioselective and exhaustive functionalization of arenes. Chem. Eur. J. 20, 12190–12200. doi: 10.1002/chem.201403141

PubMed Abstract | CrossRef Full Text | Google Scholar