A Photochemical Route to 3- and 4âHydroxy ... - ACS Publications

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Cite This: J. Org. Chem. 2018, 83, 527−534

A Photochemical Route to 3- and 4‑Hydroxy Derivatives of 2‑Aminocyclobutane-1-carboxylic Acid with an all-cis Geometry Zong Chang,† France Boyaud,† Régis Guillot,‡ Thomas Boddaert,† and David J. Aitken*,† †

CP3A Organic Synthesis Group, ICMMO, CNRS UMR 8182, Université Paris Sud, Université Paris Saclay, 15 rue Georges Clemenceau, 91405 Orsay Cedex, France ‡ Services Communs, ICMMO, CNRS UMR 8182, Université Paris Sud, Université Paris Saclay, 15 rue Georges Clemenceau, 91405 Orsay Cedex, France S Supporting Information *

ABSTRACT: Short gram-scale syntheses of both enantiomers of 2-amino-3-hydroxycyclobutane-1-carboxylic acid and of 2amino-4-hydroxycyclobutanecarboxylic acid with an all-cis geometry are described. The sequences feature highly endo-selective [2 + 2]-photocycloaddition reactions followed by fully regioselective ring opening/Hofmann rearrangement/nitrogen protection, in a consecutive or one-pot protocol, followed by efficient resolution using a chiral oxazolidinone.

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Scheme 1. Synthetic Approach toward the Target Molecules

yclobutanes are of considerable interest in organic chemistry, due to their strained molecular skeletons and the resulting intrinsic chemical reactivity.1 Cyclobutane rings appear in a wide array of natural products and bioactive derivatives,2 and they are especially useful as intermediates for chemical synthesis.3 Multiply functionalized cyclobutanes have been a focal point in recent studies on molecular diversity4 and have been proposed as mechanophores,5 while particular examples have served as modulators of glycopeptide conformation6 or as selective ligands for therapeutically relevant biological receptors.7 In relation to our own studies on peptidomimetics,8 we required access to a cyclobutane scaffold bearing three functional groupsacid, amine and alcoholat consecutive positions on the ring and with an all-cis geometry; the target structures were the 3- and 4-hydroxy derivatives of 2aminocyclobutane-1-carboxylic acid (3-HACBC and 4HACBC, respectively) (Scheme 1). Synthetic approaches to cyclic β-amino acids9 and cyclobutane β-amino acids in particular9b have been reviewed, but it transpires that the present targets are virtually unknown: a racemic 3-HACBC derivative was once prepared in low yield and as a mixture of diastereoisomers via an acyl nitrene insertion approach,10 while a urea derivative of racemic all-cis 4-HACBC was prepared in several steps from 4-benzyloxy-2-pyrone but could not be decarbamoylated without isomerization.11 Neither of these approaches was appealing so we sought a more robust synthesis © 2017 American Chemical Society

of the targets and endeavored to obtain them in enantiomerically pure form. [2 + 2]-Photocycloaddition reactions constitute a powerful entry to multifunctional cyclobutanes,12−14 so we decided to examine the photochemical reaction between an alkyl vinyl ether and a cyclic derivative of maleic acid: either maleimide15 or maleic anhydride.5a,13a,16 Our rationale was that the bicyclic photoproducts should be formed preferentially with an endo configuration, by analogy with MO calculations on the reaction of maleic anhydride with vinyl acetate,16g as well as the mechanistic proposal by Griesbeck for Received: October 30, 2017 Published: December 1, 2017 527

DOI: 10.1021/acs.joc.7b02559 J. Org. Chem. 2018, 83, 527−534

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The Journal of Organic Chemistry

facilitated selective hydrolysis/Hofmann rearrangement/amine protection in a consecutive process18 and provided racemic N,O-diprotected 3-HACBC, (±)-5, in 81% yield (Scheme 2). Of particular note was the complete regioselectivity of the first step, in which hydrolysis occurred through attack of water at the least hindered carbonyl group leading to an amide function in the vicinal position with respect to the tert-butoxy group. This expedient synthesis provided the all-cis trifunctionalized cyclobutane in only two chemical steps and 54% yield from commercially available starting materials. Resolution of (±)-5 was achieved using a chiral, nonracemic oxazolidinone as a resolving agent.13b,19 (R)-4-Phenyloxazolidin-2-one was fully satisfactory, in terms of coupling efficiency, simplicity of diastereoisomer separation, and then cleavage of the auxiliary, allowing us to establish a straightforward protocol for the resolution of (±)-5 on 25 mmol (7.2 g) scale (Scheme 3). Acid activation using pivaloyl chloride followed by addition of the lithium salt of the oxazolidinone provided the expected diastereoisomers (−)-6a and (−)-6b in 93% combined yield. These two derivatives were easily separated in a single chromatographic operation, and the chiral oxazolidinone was removed from each (and could be recovered for recycling) upon treatment with LiOOH, to give (−)-5 and (+)-5 in 94% and 90% yields, respectively. The N,O-protection group suite was, by design, acid labile. Gratifyingly, each enantiomer of 5 was fully deprotected using trifluoroacetic acid, providing the corresponding enantiomers of the target all-cis-3-HACBC, (+)-(1R,2R,3S)-7, and (−)-(1S,2S,3R)-7, in near-quantitative yields (Scheme 3). It was of note that the unprotected form 7 turned out to be more stable than unsubstituted ACBC and can be stored for months under argon at −20 °C and even for days in aqueous solution. The absolute configurations of the compounds described in this series were deduced from the X-ray diffraction analysis of a single crystal of amide (−)-8, obtained by condensation of compound (+)-5 and (R)-(p-nitrophenyl)ethylamine (Figure 1). We then turned our attention to the synthesis of 4-HACBC. Here, maleic anhydride 2b was used as the enone component and tert-butyl vinyl ether 1c was retained as the alkene partner for the [2 + 2]-photocycloaddition. The reaction of 2b and 1c under the same conditions as those used above for 2a (acetonitrile solvent, acetophenone photosensitizer) furnished oxabicyclo[3.2.0]heptanedione 9c as a single diastereoisomer but in only 25% NMR yield.20 After some experimentation, an optimized protocol was established: when a 30 mM solution of 2b (6 mmol) and 1.5 equiv of 1c in acetone was irradiated

the [2 + 2]-photocycloaddition reaction between vinyl ethers and cyclopentenone, wherein the endo geometry is favored by the 1,4-biradical prior to cyclization.17 The photoproducts would then serve as useful intermediates leading to either allcis-3-HACBC or all-cis-4-HACBC via controlled regioselective chemical transformations (Scheme 1). We began our studies with the synthesis of 3-HACBC. The first step was the [2 + 2]-photocycloaddition reaction between an alkyl vinyl ether 1 and maleimide 2a, and we investigated the influence of the steric bulk of the alkene on the reaction yield and diastereoselectivity, using ethyl-, n-butyl, and tert-butyl vinyl ethers (1a, 1b, and 1c, respectively). An acetonitrile solution of maleimide 2 (6 mmol) with 1.5 equiv of vinyl ether and 0.1 equiv of acetophenone as a photosensitizer was irradiated using a 400 W Hg-vapor lamp in a 200 mL Pyrex reaction vessel for 4 h, to furnish the corresponding diastereoisomeric azabicyclo[3.2.0]heptandiones 3a−c and 4a−c in 85−97% overall yields; the isomers were separated conveniently by chromatography (Scheme 2). The reaction was Scheme 2. Synthesis of N,O-Diprotected all-cis-3-HACBC, (±)-5

efficient in all three cases, and the diastereoselectivity was directly related to the bulk of the alkyl radical of the vinyl ether, ranging from 2.0:1 for 1a to 4.1:1 for 1c. As anticipated, the major diastereoisomers 3a−c had an endo configuration, and this was established for compound 3c by a single crystal X-ray diffraction analysis (Scheme 2). For preparative purposes, tert-butyl vinyl ether 1c was retained and the photochemical reaction was conducted on 30 mmol scale without erosion of yield or diastereoselectivity, allowing facile access to multigram quantities (4 g in a typical run) of compound 3c. In order to install the amine and carboxylic acid functions, 3c was treated with bromine in basic medium followed by addition of di-tert-butyl dicarbonate, which

Scheme 3. Synthesis of Both Enantiomers of all-cis-3-HACBC, (+)-7 and (−)-7

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(R)-4-Phenyloxazolidin-2-one was once again employed as the resolving agent. Transformation of (±)-10 into diastereoisomers (−)-11a and (−)-11b was achieved on gram scale in 90% combined yield, and the two derivatives were separated easily by chromatography. Removal of the chiral oxazolidinone from (−)-11a using LiOOH gave a high yield of (−)-(1R,2R,4S)-10 after 6 h. Compound (−)-11b, however, was less reactive, and a considerably longer reaction time was required to remove the chiral auxiliary. A competing hydrolysis of the heterocyclic ring was in evidence, and the required compound (+)-(1S,2S,4R)-10 was isolated in 61% yield, accompanied by the byproduct (−)-12 in 28% yield (Scheme 5). (−)-10 and (+)-10 were stable compounds but, in constrast with the regioisomeric 3-HACBC series, attempts to deprotect them resulted only in degradation (Scheme 5).21 The free hydroxy amino acid form of 4-HACBC, 13, suffers from an intrinsic instability, most likely due to the presence of one electron-withdrawing group and two vicinal electron-donating groups on the cyclobutane ring, which probably facilitates rapid and irreversible ring opening.22 As shown in Scheme 5, the absolute configurations of the compounds involved in this series were deduced from the X-ray diffraction analysis of a single crystal of derivative (−)-11a. For our purposes, the N,O-diprotected forms of the target HACBCs were fully adequate, but we verified that orthogonal protecting groups could also be installed if required. To this end, (±)-5 and (±)-10 were transformed efficiently into the corresponding benzyl esters, (±)-14 and (±)-15, respectively. Each of these derivatives was selectively N-deprotected using cold, dilute trifluoroacetic acid and then reprotected using FmocCl in a one-pot sequence to give (±)-16 and (±)-17 in a very good yields (Scheme 6).

Figure 1. X-ray crystal structure of amide (−)-8.

using a 400 W Hg-vapor lamp in a 200 mL Pyrex reaction vessel for 4 h, 9c was obtained in 89% NMR yield,20 again as a single diastereiosomer; acetone plays the role of both solvent and photosensitizer (Scheme 4). A minor inconvenience with Scheme 4. Synthesis of N,O-Diprotected all-cis-4-HACBC, (±)-10

this otherwise highly satisfactory result was the reactivity of the anhydride function of 9c, which precluded purification on silica gel. We therefore continued the synthetic sequence using the almost pure crude material. A one-pot ammonolysis/Hofmann rearrangement/amine protection protocol was conducted on 9c to furnish racemic N,O-diprotected 4-HACBC, (±)-10. Once again, complete regioselectivity of the first step was in evidence, characterized by the attack of ammonia at the least hindered carbonyl group. The subsequent Hofmann rearrangement was most efficient when carried out using PIFA in an acetonitrile/water mixture. This synthesis provided the diastereomerically pure trifunctionalized cyclobutane in four chemical steps and a single final purification in 30% overall yield and in half-gram scale from commercially available starting materials (Scheme 4).

Scheme 6. Preparation of Orthogonally Protected 3-HACBC and 4-HACBC, (±)-16 and (±)-17

Scheme 5. Synthesis of Both Enantiomers of N,O-Diprotected all-cis-4-HACBC, (−)-10 and (+)-10

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triethylamine (1.2 equiv) in THF (20 mL/mmol) was added pivaloyl chloride (1.05 equiv) dropwise. The mixture was stirred at 0 °C for 1 h to form the mixed anhydride and then cooled to −78 °C. In a separate flask, a cold (−40 °C) solution of (R)-4-phenyloxazolidin-2-one (1.0 equiv) in THF (5 mL/mmol) was treated with a hexane solution of nBuLi (1.0 equiv) and stirred for 5 min. The resulting solution was cooled to −78 °C and added by rapid cannulation to the cooled (−78 °C) solution of the mixed anhydride. Residual metalated oxazolidinone was taken up by rinsing with dry THF and added to the cooled reaction mixture. After 1 h, the reaction mixture was warmed up to room temperature and treated with saturated NaHCO3 (25 mL/ mmol). THF was removed under reduced pressure, and the remaining aqueous solution was extracted with dichloromethane (3 × 15 mL/ mmol). The combined organic phases were washed with brine (15 mL/mmol), dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography to afford the two diastereoisomers 6 and 11. General Procedure C for Oxazolidinone Cleavage. To an icecold solution of the indicated diastereoisomer 6 or 11 (1 equiv) in a 1:4 mixture of water and THF (25 mL/mmol) was added a 35% w/w solution of H2O2 (6 equiv). The resulting mixture was stirred at 0 °C for 5 min, and then a solution of LiOH·H2O (2 equiv) in water (1 mL/mmol) was added. The mixture was stirred at 0 °C for 4 h/6 h (or overnight after warming up to room temperature), and then a saturated aqueous solution of Na2SO3 (12 mL/mmol) and a saturated aqueous solution of NaHCO 3 (12 mL/mmol) were added successively. THF was removed under reduced pressure, and the residual aqueous solution was washed with dichloromethane (24 mL/ mmol) to remove and recycle the chiral auxiliary. The aqueous solution was then acidified to pH 4 with an aqueous solution of HCl (1 M) and extracted with dichloromethane (3 × 10 mL/mmol). The combined organic extracts were dried over MgSO4, filtrated, and evaporated under reduced pressure to give nonracemic product 5 or 10. General Procedure D for TFA Deprotection. To cold (0 °C) trifluoroacetic acid (10 mL/mmol) the protected amino acid 5 (1 equiv) was added in one portion, the temperature was raised to room temperature slowly, and the mixture was stirred overnight at room temperature. Trifluoroacetic acid was removed under reduced pressure, and the residue was applied to a column of Dowex 50WX8 cation exchange resin (200−400 mesh) and eluted using 1 M NH4OH to afford the free amino acid 7. General Procedure E for Benzylic Protection. To a solution of protected ACBC 5 or 10 (1 equiv) and BnOH (3 equiv) in dichloromethane DMAP (0.2 equiv) and DCC (1.2 equiv) were added at 0 °C, and the mixture was stirred for 1 h at this temperature. After warming up to room temperature, the reaction mixture was stirred for 20 h at room temperature. After filtration, the solvent was removed under reduced pressure, ethyl acetate was added, and the mixture was washed with brine, 1 M HCl solution, brine, 5% NaHCO3 solution, and brine successively. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography to afford the benzyl ester 14 or 15. General Procedure F for Fmoc Protection. To a solution of benzyl ester 14 or 15 in dichloromethane (20 mL/mmol) trifluoroacetic acid (30 equiv) was added at 0 °C and stirred at this temperature. The reaction was followed by TLC analysis, and saturated Na2CO3 (10 mL/mmol) was added after starting material disappeared. Then, FmocCl (1.5 equiv) in dioxane (13 mL/mmol) was added, and the temperature was raised to room temperature slowly, followed then by stirring at this temperature overnight. The mixture was diluted with H2O, and the dioxane was evaporated carefully. The residue was extracted with dichloromethane, and the combined organic phases were washed with brine and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography to afford the desired product 16 or 17. (±)-cis-endo-6-(Methoxy)-3-azabicyclo[3.2.0]heptane-2,4dione 3a and (±)-cis-exo-6-(ethoxy)-3-azabicyclo[3.2.0]heptane-2,4-dione 4a. General procedure A, using maleimide 2a

These robust and expedient protocols provide access to stable N,O-protected derivatives of enantiomerically pure all-cis3-HACBA and all-cis-4-HACBC for the first time. The combined overall yield for (−)-5 and (+)-5, isolated on gram scale in four steps from commercially available staring materials, was 45% (25% and 20%, respectively), while the combined overall yield for (−)-10 and (+)-10 in six steps from commercially available staring materials, was 20% (13% and 7%, respectively). Handling and storage of the title compounds in protected form is advisible: while the free hydroxyl amino acid form of the former (7) is sufficiently stable to be stored and characterized, the latter (13) is not and undergoes rapid degradation.

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EXPERIMENTAL SECTION

General Experimental. All reagents and solvents were of commercial grade and were used without further purification, with the exception of dichloromethane which was dried over activated alumina, n-BnOH which was distilled from MgSO4, THF which was distilled from sodium/benzophenone, acetonitrile which was distilled from P2O5, triethylamine which was distilled on potassium hydroxide, and maleic anhydride which was recrystallized from chloroform. Flash chromatography was performed on 35−70 μm columns of silica gel (Merk-Chimie SAS). Analytical thin-layer chromatography was carried out on commercial 0.25 mm silica gel plates (EMD, Silica Gel 60F254) which were visualized by UV fluorescence at 254 nm and then revealed using a phosphomolybdic acid solution (10% in EtOH) or a ninhydrin solution (0.3% in n-BuOH). Retention factors (Rf) are given for such TLC analyses. Melting points were determined with a Büchi B-545 apparatus in open capillary tubes and are uncorrected. Optical rotations were measured on a Specord 205 instrument (Analytik-Jena) using a 10 cm quartz cell; values for [α]DT were obtained with the Dline of sodium at the indicated temperature T, using solutions of concentration (c) in units of g·100 mL−1. Fourier-transform Infrared (IR) spectra were recorded on a FT-IR PerkinElmer Spectrum Two spectrophotometer using an ATR diamond accessory; maximum absorbances (ν) are given (in cm−1) only for major functional groups. Nuclear magnetic resonance (NMR) data were acquired on Bruker spectrometers operating at 360/300/250 MHz for 1H and at 90/75/ 63 MHz for 13C. Chemical shifts (δ) are reported in ppm with respect to the residual proton signal in deuterated chloroform (δ = 7.26 ppm) for 1H and with respect to CDCl3 (δ = 77.0 ppm) for 13C. Splitting patterns for 1H and 13C NMR signals are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintuplet), broad singlet (br s), app (apparent), or m (multiplet). Coupling constants (J) are reported in Hz. High-resolution mass spectrometry (HRMS) data were recorded on a Bruker Daltonics MicroTOF-Q spectrometer equipped with an electrospray ionization source in positive mode, with a tandem Q-TOF analyzer. HPLC analyses of samples of compounds 5 and 10 were carried out using an Agilent 1260 Infinity HPLC apparatus equipped with a Phenomenex Lux Cellulose-3 column (250 mm × 4.6 mm; particle size 5 μm) and a UV absorbance (220 nm) detector. Ultrapure water (Rephile PURIST) was used, and all solvents were HPLC grade and were filtered through a 0.45 μm PTFE membrane. Injected solutions were filtered through a 0.22 μm PTFE membrane. HPLC conditions and details on X-ray diffraction analysis data are given in the Supporting Information. General Procedure A for Photochemical Reaction of Vinyl Ether and Maleimide. Maleimide 2a (1 equiv) was introduced into a cylindrical reactor containing acetonitrile (33 mL/mmol) with vinyl ether 1 (1.5 equiv) and acetophenone (0.1 equiv). The mixture was stirred at room temperature, degassed with argon for 30 min, and irradiated with a 400 W medium-pressure Hg lamp fitted with a Pyrex filter and a water-cooling jacket for 4 h. The solvent was evaporated, and the solid residue was purified by flash chromatography to afford compounds 3 and 4. General Procedure B for Oxazolidinone Coupling. To a cold (−78 °C) solution of racemic compound 5 or 10 (1 equiv) and 530


Note


(±)-cis-endo-3-(tert-Butoxy)-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic Acid (±)-5. Bromine (1.59 mL, 30.9 mmol) was dissolved in 20% sodium hydroxide solution (100 mL), and the mixture was cooled to 0 °C. Cycloadduct 3c (6.08 g, 30.9 mmol) was gradually added into the cold alkaline solution, and the mixture was stirred vigorously. The light yellow color solution was further cooled to −5 °C, and sodium hydroxide (3.21 g, 80.34 mmol) was then added; the mixture was then stirred vigorously for 30 min. The mixture was heated to 80 °C in a steam bath and maintained at this temperature for 10 min. Then 36% sodium sulfite solution (1.0 mL) was added, and the mixture was cooled to room temperature, and concentrated HCl was added slowly until pH 9. A solution of Boc2O (7.41 g, 34 mmol) in dioxane (100 mL) was added, and the mixture was stirred overnight to room temperature. A 1 M HCl solution was added until pH 4, the dioxane was evaporated under vacuum, and the residual solution was treated with ethyl acetate (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (4 × 35 mL). The combined organic layers were washed with water (10 mL) and brine solution (10 mL) and dried over MgSO4. The solvent was evaporated under vacuum, and the resulting crude was purified by flash chromatography (ethyl acetate/petrol ether, 30/ 70) to afford (±)-5 as a white solid (7.18 g, 81%). Rf (ethyl acetate/ petrol ether, 50/50): 0.25; Mp: 133−135 °C; IR ν 3420, 3210 br, 1726, 1701; 1H NMR (250 MHz, CDCl3) δ 11.31 (br s, 1H), 6.05− 5.38 (m, 1H), 4.65−4.35 (m, 1H), 4.26 (app q, J = 7.0 Hz, 1H), 3.17− 2.73 (m, 1H), 2.61−2.12 (m, 2H), 1.42 (s, 9H), 1.17 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 175.6, 156.0, 79.7, 74.6, 63.4, 54.9, 37.6, 32.3, 28.1 (3C), 27.9 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H25NNaO5+, 310.1625; found, 310.1620. tert-Butyl ((1R,2S,4R)-2-(tert-butoxy)-4-((R)-2-oxo-4-phenyloxazolidine-3-carbonyl)cyclobutyl)carbamate (−)-6a and tertbutyl ((1S,2R,4S)-2-(tert-butoxy)-4-((R)-2-oxo-4-phenyloxazolidine-3-carbonyl)cyclobutyl)carbamate (−)-6b. General procedure B, using racemic compound 5 (1.0 g, 3.48 mmol), triethylamine (0.58 mL, 4.18 mmol), pivaloyl chloride (0.45 mL, 3.66 mmol), oxazolidinone (0.57 g, 3.48 mmol), and n-BuLi (3.48 mmol). Flash chromatography (ethyl acetate/petrol ether, 25/75) afforded diastereoisomer 6a (0.75 g, 50%) as a white solid and diastereoisomer 6b (0.64 g, 43%) as a white solid. 6a: Rf (ethyl acetate/petrol ether, 25/75): 0.50; Mp: 48−49 °C; [α]D24 −122 (c 0.1, CHCl3); IR ν 3420, 1773, 1695; 1H NMR (300 MHz, CDCl3) δ 7.42−7.27 (m, 5H), 5.41 (d, J = 3.7 Hz, 1H), 5.26−5.18 (m, 1H), 4.70 (app t, J = 8.7 Hz, 1H), 4.58−4.45 (m, 1H), 4.24−4.18 (m, 2H), 4.18−4.05 (m, 1H), 2.60− 2.45 (m, 1H), 2.23−2.05 (m, 1H), 1.46 (s, 9H), 1.17 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 169.5, 156.1, 154.2, 139.6, 129.0 (2C), 128.4, 126.1 (2C), 79.1, 74.7, 70.0, 62.2, 57.8, 57.0, 37.1, 30.3, 28.3 (3C), 27.9 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H32N2NaO6+: 455.2153; found, 455.2145. 6b: Rf (ethyl acetate/ petrol ether, 25/75): 0.10; Mp: 56−58 °C; [α]D26 −24 (c 0.1, CHCl3); IR ν 3419, 1782, 1701; 1H NMR (250 MHz, CDCl3) δ 7.45−7.25 (m, 5H), 5.36 (dd, J = 8.3, 5.0 Hz, 1H), 5.15 (d, J = 6.9 Hz, 1H), 4.88− 4.72 (m, 1H), 4.66 (app t, J = 8.7 Hz, 1H), 4.26 (app q, J = 7.4 Hz, 1H), 4.17 (dd, J = 8.7, 5.0 Hz, 1H), 4.06−3.82 (m, 1H), 2.55−2.35 (m, 1H), 2.30−2.10 (m, 1H), 1.38 (s, 9H), 1.12 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 170.2, 155.8, 153.3, 138.7, 129.1 (2C), 128.3, 125.9 (2C), 79.2, 74.4, 70.1, 63.7, 58.3, 57.0, 37.6, 30.7, 28.3 (3C), 27.9 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H32N2NaO6+, 455.2153; found, 455.2147. (1R,2R,3S)-3-(tert-Butoxy)-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic Acid (−)-5. General procedure C, using diastereoisomer 6a (1.44 g, 3.30 mmol), 35% w/w solution of H2O2 (2.0 mL, 23.5 mmol), and LiOH·H2O (0.33 g, 7.88 mmol), afforded oxazolidinone (0.54 g, 99%) and nonracemic product (−)-5 (0.84 g, 94%) as a white solid. Rf (ethyl acetate/petrol ether, 50/50): 0.25; Mp: 141−143 °C; [α]D23 −103 (c 0.1, CHCl3); IR ν 3415, 3200 br, 1726, 1700; 1H NMR (300 MHz, CDCl3) δ 10.90 (br s, 1H), 6.16−5.30 (m, 1H), 4.65−4.34 (m, 1H), 4.26 (app q, J = 7.0 Hz, 1H), 3.20−2.76 (m, 1H), 2.65−2.20 (m, 2H), 1.43 (s, 9H), 1.17 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 175.5, 156.0, 79.7, 74.5, 63.5, 54.9, 37.6, 32.4, 28.1

(0.58 g, 6 mmol) with ethyl vinyl ether 1a (0.86 mL, 9 mmol) and acetophenone (0.07 mL, 0.6 mmol). Ratio endo/exo determined by NMR of crude was 2.0/1.0; flash chromatography (ethyl acetate/ petrol ether, 30/70) afforded the exo-cyclobutane adduct 4a (0.30 g, 30%) as a white solid and endo-cyclobutane adduct 3a (0.68 g, 67%) as a white solid. 3a: Rf (ethyl acetate/petrol ether, 50/50): 0.40; Mp: 54− 56 °C; IR ν 3176, 3064, 1695; 1H NMR (250 MHz, CDCl3) δ 9.62 (s, 1H), 4.53−4.24 (m, 1H), 3.91−3.57 (m, 2H), 3.55−3.34 (m, 1H), 3.20−2.86 (m, 2H), 2.48−2.22 (m, 1H), 1.18 (t, J = 7.0 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ 180.6, 176.3, 69.9, 64.9, 47.2, 33.7, 32.7, 14.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C8H11NNaO3+: 192.0631; found, 192.0633. 4a: Rf (ethyl acetate/petrol ether, 50/50): 0.60; Mp: 74−75 °C; IR ν 3180, 3069, 1700; 1H NMR (250 MHz, CDCl3) δ 9.49 (s, 1H), 4.22−4.09 (m, 1H), 3.71−3.54 (m, 1H), 3.52−3.37 (m, 1H), 3.36−3.21 (m, 2H), 2.72−2.50 (m, 2H), 1.16 (t, J = 7.0 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ 180.3, 177.7, 75.5, 64.2, 49.7, 35.2, 31.2, 14.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C8H11NNaO3+, 192.0631; found, 192.0635. (±)-cis-endo-6-(Butoxy)-3-azabicyclo[3.2.0]heptane-2,4dione 3b and (±)-cis-exo-6-(butoxy)-3-azabicyclo[3.2.0]heptane-2,4-dione 4b. General procedure A, using maleimide 2a (0.58 g, 6 mmol) with butyl vinyl ether 1b (1.17 mL, 9 mmol) and acetophenone (0.07 mL, 0.6 mmol). Ratio endo/exo determined by NMR of crude was 2.5/1.0; flash chromatography (ethyl acetate/ petrol ether, 30/70) afforded the exo-cyclobutane adduct 4b (0.30 g, 25%) as a pale yellow liquid and endo-cyclobutane adduct 3b (0.71 g, 60%) as a white solid. 3b: Rf (ethyl acetate/petrol ether, 50/50): 0.40; Mp: 53−54 °C; IR ν 3157, 3071, 1695; 1H NMR (360 MHz, CDCl3) δ 9.51 (s, 1H), 4.34−4.15 (m, 1H), 3.65−3.50 (m, 2H), 3.27 (app dt, J = 9.0, 6.6 Hz, 1H), 3.05−2.80 (m, 2H), 2.25−2.10 (m, 1H), 1.49−1.39 (m, 2H), 1.34−1.17 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 180.6, 176.3, 70.2, 69.4, 47.2, 33.7, 32.7, 31.3, 18.9, 13.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C10H15NNaO3+: 220.0944; found, 220.0949. 4b: Rf (ethyl acetate/petrol ether, 50/50): 0.60; IR ν 3210, 3075, 1704; 1H NMR (360 MHz, CDCl3) δ 9.44 (s, 1H), 4.11−4.01 (m, 1H), 3.46 (app dt, J = 9.4, 6.6 Hz, 1H), 3.30 (app dt, J = 9.4, 6.6 Hz, 1H), 3.26−3.15 (m, 2H), 2.60−2.45 (m, 2H), 1.57−1.45 (m, 2H), 1.37−1.23 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR (90 MHz, CDCl3) δ 180.4, 177.8, 75.7, 68.5, 49.6, 35.1, 31.2 (2C), 19.1, 13.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C10H15NNaO3+, 220.0944; found, 220.0944. (±)-cis-endo-6-(tert-Butoxy)-3-azabicyclo[3.2.0]heptane-2,4dione 3c and (±)-cis-exo-6-(tert-Butoxy)-3-azabicyclo[3.2.0]heptane-2,4-dione 4c. General procedure A, using maleimide 2a (0.58 g, 6 mmol) with tert-butyl vinyl ether 1c (1.18 mL, 9 mmol) and acetophenone (0.07 mL, 0.6 mmol). Ratio of endo/exo determined by NMR of crude was 4.1/1.0; flash chromatography (ethyl acetate/ petrol ether, 40/60) afforded the exo-cyclobutane adduct 4c (190 mg, 16%) as a white solid and endo-cyclobutane adduct 3c (844 mg, 71%) as a white solid. Alternatively, following general procedure A, using maleimide 2a (2.91 g, 30 mmol) with tert-butyl vinyl ether 1c (5.9 mL, 45 mmol) and acetophenone (0.35 mL, 3 mmol). Ratio endo/exo determined by NMR of crude was 4.0/1.0; flash chromatography (ethyl acetate/petrol ether, 40/60) afforded the exo-cyclobutane adduct 4c (1.05 g, 18%) as a white solid and endo-cyclobutane adduct 3c (3.98 g, 67%) as a white solid. 3c: Rf (ethyl acetate/petrol ether, 40/60): 0.35; Mp: 129−131 °C; IR ν 3221, 3083, 1717; 1H NMR (360 MHz, CDCl3) δ 9.41 (s, 1H), 4.50−4.38 (m, 1H), 3.50−3.40 (m, 1H), 3.00−2.82 (m, 2H), 2.30−2.12 (m, 1H), 1.13 (s, 9H); 13C NMR (90 MHz, CDCl3) δ 180.6, 176.1, 74.9, 63.3, 49.3, 35.4, 33.8, 27.6 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C10H15NNaO3+: 220.0944; found, 220.0944. X-ray: CCDC 1571601. 4c: Rf (ethyl acetate/petrol ether, 40/60): 0.40; Mp: 98−100 °C; IR ν 3229, 3078, 1691; 1H NMR (360 MHz, CDCl3) δ 9.34 (s, 1H), 4.29 (app dt, J = 6.9, 3.4 Hz, 1H), 3.24 (dd, J = 7.0, 3.4 Hz, 1H), 3.16 (ddd, J = 10.6, 6.9, 4.0 Hz, 1H), 2.60−2.40 (m, 2H), 1.16 (s, 9H); 13C NMR (90 MHz, CDCl3) δ 180.5, 177.9, 75.4, 69.1, 52.3, 35.1, 33.3, 28.0 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C10H15NNaO3+, 220.0944; found, 220.0948. 531


Note

The Journal of Organic Chemistry (3C), 27.9 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H25NNaO5+, 310.1625; found, 310.1655. (1S,2S,3R)-3-(tert-Butoxy)-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic Acid (+)-5. General procedure C, using diastereoisomer 6b (1.32 g, 3.06 mmol), 35% w/w solution of H2O2 (1.56 mL, 18.3 mmol), and LiOH·H2O (0.26 g, 6.1 mmol), afforded oxazolidinone (0.50 g, 99%) and nonracemic product (+)-5 (0.79 g, 90%) as a white solid. Rf (ethyl acetate/petrol ether, 50/50): 0.25; Mp: 141−142 °C; [α]D26 +106 (c 0.1, CHCl3); IR ν 3420, 3200 br, 1726, 1700; 1H NMR (250 MHz, CDCl3) δ 11.23 (br s, 1H), 6.20−5.35 (m, 1H), 4.64−4.34 (m, 1H), 4.26 (app q, J = 7.0 Hz, 1H), 3.18−2.80 (m, 1H), 2.60−2.20 (m, 2H), 1.43 (s, 9H), 1.17 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 175.5, 156.1, 79.7, 74.6, 63.5, 55.0, 37.7, 32.5, 28.2 (3C), 27.9 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H25NNaO5+: 310.1625; found, 310.1625. (1R,2R,3S)-2-Amino-3-hydroxycyclobutane-1-carboxylic Acid (+)-7. General procedure C, using protected amino acid (−)-5 (86 mg, 0.3 mmol) in trifluoroacetic acid (3 mL), afforded the free amino acid (+)-7 (39 mg, 99%) as a white solid. Mp: 103−104 °C (dec); [α]D23 +12 (c 0.1, H2O); IR ν 3250 br, 1548; 1H NMR (300 MHz, D2O) δ 4.46−4.34 (m, 1H), 3.88 (dddd, J = 7.0, 6.1, 3.1, 0.8 Hz, 1H), 3.08−2.92 (m, 1H), 2.59 (dddd, J = 12.1, 9.0, 7.2, 3.1 Hz, 1H), 2.20 (dddd, J = 12.1, 10.0, 7.5, 0.8 Hz, 1H), COOH, OH and NH2 are not observed; 13C NMR (63 MHz, D2O (with one drop of dioxane)) δ 179.1, 61.7, 52.0, 34.8, 33.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C5H10NO3+, 132.0655; found, 132.0659. (1S,2S,3R)-2-Amino-3-hydroxycyclobutane-1-carboxylic Acid (−)-7. General procedure C, using protected amino acid (+)-5 (86 mg, 0.3 mmol) in trifluoroacetic acid (3 mL) afforded the free amino-acid (−)-7 (38 mg, 97%) as a white solid. Mp: 103−104 °C (dec); [α]D25 −11 (c 0.1, H2O); IR ν 3250 br, 1552; 1H NMR (250 MHz, D2O) δ 4.48−4.28 (m, 1H), 3.85 (app dt, J = 6.7, 3.0 Hz, 1H), 3.08−2.90 (m, 1H), 2.57 (dddd, J = 12.0, 9.0, 7.4, 3.0 Hz, 1H), 2.17 (ddd, J = 12.0, 10.0, 7.6 Hz, 1H), COOH, OH and NH2 are not observed; 13C NMR (63 MHz, D2O (with one drop of dioxane)) δ 179.1, 61.8, 52.0, 34.9, 33.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C5H10NO3+, 132.0655; found, 132.0659. tert-Butyl ((1S,2R,4S)-2-(tert-Butoxy)-4-(((R)-1-(4-nitrophenyl)ethyl)carbamoyl)cyclobutyl)carbamate (−)-8. To a cold (0 °C) solution of (+)-5 (28.7 mg, 0.1 mmol) in dry dichloromethane (2.5 mL) under argon, HOBt (22.5 mg, 0.14 mmol), (S)-α-methyl-pnitrobenzylamine hydrochloride (22.3 mg, 0.11 mmol), and triethylamine (0.021 mmol, 0.15 mmol) were added successively and stirred at 0 °C for 10 min. After addition of EDCI·HCl (28.7 mg, 0.15 mmol), the mixture was stirred at room temperature for 14 h. Dichloromethane (7.5 mL) was added, and the mixture was then washed with KHSO4 (1 M, 2 mL), saturated NaHCO3 (2 mL), and dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/petrol ether, 30/ 70) to afford the amide (−)-8 (40 mg, 92%) as a white solid. Rf (ethyl acetate/petrol ether, 50/50): 0.40; Mp: 117−119 °C; [α]D25 −86 (c 0.1, CHCl3); IR ν 3437, 3281, 1713, 1643; 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 6.86 (br d, J = 6.5 Hz, 1H), 5.55 (br d, J = 5.5 Hz, 1H), 5.07 (app quint, J = 6.8 Hz, 1H), 4.42−4.32 (m, 1H), 4.25 (app q, J = 7.7 Hz, 1H), 2.95−2.78 (m, 1H), 2.37 (app t, J = 8.7 Hz, 2H), 1.47 (s, 9H), 1.46 (d, J = 8.8 Hz, 3H), 1.17 (s, 9H); 13C NMR (90 MHz, CDCl3) δ 170.4, 157.4, 151.6, 146.8, 126.9 (2C), 123.8 (2C), 80.0, 74.7, 62.2, 54.7, 48.8, 39.1, 32.3, 28.4 (3C), 28.0 (3C), 21.8; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H33N3NaO6+, 458.2262; found, 458.2290. X-ray: CCDC 1571603. (±)-cis-endo-2-(tert-Butoxy)-4-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic Acid (±)-10. Maleic anhydride 2b (0.59 g, 6 mmol) was introduced into a cylindrical reactor containing acetone (200 mL) with tert-butyl vinyl ether 1c (1.18 mL, 9 mmol). The mixture was stirred at room temperature, degassed with argon for 30 min, and irradiated with a 400 W medium-pressure Hg lamp fitted with a Pyrex filter and a water-cooling jacket for 4 h. The solvent was evaporated, and the residue was dissolved in THF (60 mL) in a 250 mL flask. The head space of the flask was flushed with ammonia gas,

and the mixture was stirred at room temperature under an ammonia atmosphere for 1 h. THF was removed under reduced pressure, and the residue was dissolved with a 1:1 mixture of water and acetonitrile (216 mL). PIFA (3.87 g, 9 mmol) was added, and the mixture was stirred for 15 min at room temperature. Pyridine (1.45 mL, 18 mmol) was then added, and the mixture was stirred at room temperature for 4 h. Acetonitrile was evaporated carefully, and the residual aqueous solution was basified with NaOH solution (2 M) to pH 9. Boc2O (1.70 g, 7.8 mmol) solution in dioxane (108 mL) was added, and the mixture was stirred overnight at room temperature. Dioxane was evaporated carefully, and the residual aqueous solution was acidified with HCl (1 M) to pH 4, followed by extraction with ethyl acetate (4 × 120 mL). The combined organic phases were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/petrol ether, 25/75) to afford the compound (±)-10 (0.52 g, 30%) as a white solid. Rf (ethyl acetate/petrol ether, 50/50): 0.40; Mp: 125−126 °C; IR ν 3389, 3100 br, 1691, 1652; 1H NMR (300 MHz, CDCl3) δ 11.66 (s, 1H), 6.60−5.40 (m, 1H), 4.20−3.78 (m, 2H), 3.68−3.43 (m, 1H), 2.72−2.50 (m, 1H), 2.50−2.24 (m, 1H), 1.38 (s, 9H), 1.13 (s, 9H); 13 C NMR (90 MHz, CDCl3) δ 175.8, 155.2, 79.6, 74.9, 61.1, 54.7, 40.5, 38.3, 28.3 (3C), 27.8 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H25NNaO5+, 310.1625; found, 310.1619. tert-Butyl ((1R,2R,3S)-3-(tert-Butoxy)-2-((R)-2-oxo-4-phenyloxazolidine-3-carbonyl)cyclobutyl)carbamate (−)-11a and tert-Butyl ((1S,2S,3R)-3-(tert-butoxy)-2-((R)-2-oxo-4-phenyloxazolidine-3-carbonyl)cyclobutyl)carbamate (−)-11b. General procedure B, using racemic compound 10 (1.84 g, 6.4 mmol), triethylamine (1.06 mL, 7.68 mmol), pivaloyl chloride (0.82 mL, 6.7 mmol), oxazolidinone (1.04 g, 6.4 mmol), and n-BuLi (6.4 mmol). Flash chromatography (ethyl acetate/petrol ether, 15/85) afforded diastereoisomer (−)-11a (1.38 g, 50%) as a white solid and diastereoisomer (−)-11b (1.11 g, 40%) as a white solid. 11a: Rf (ethyl acetate/petrol ether, 25/75): 0.50; Mp: 115−116 °C; [α]D25 −27 (c 0.1, CHCl3); IR ν 3420, 1769, 1695; 1H NMR (300 MHz, CDCl3) δ 7.45−7.28 (m, 5H), 6.20 (br d, J = 9.0 Hz, 1H), 5.49 (dd, J = 8.7, 3.5 Hz, 1H), 4.84 (dddd, J = 8.5, 7.5, 3.4, 0.8 Hz, 1H), 4.61 (t, J = 8.5 Hz, 1H), 4.23 (dd, J = 8.7, 3.4 Hz, 1H), 4.20−4.02 (m, 2H), 2.63 (dddd, J = 11.1, 8.0, 6.1, 3.5 Hz, 1H), 2.24−2.06 (m, 1H), 1.37 (s, 9H), 1.14 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 171.7, 155.0, 153.3, 139.4, 129.1 (2C), 128.5, 125.6 (2C), 78.9, 74.4, 69.8, 61.3, 57.2, 51.4, 42.5, 39.3, 28.2 (3C), 27.9 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H32N2NaO6+: 455.2157; found, 455.2144. X-ray: CCDC 1571602. 11b: Rf (ethyl acetate/petrol ether, 25/75): 0.40; Mp: 135− 136 °C; [α]D26 −189 (c 0.1, CHCl3); IR ν 3394, 1786, 1700; 1H NMR (300 MHz, CDCl3) δ 7.48−7.28 (m, 5H), 6.06 (br s, 1H), 5.43 (dd, J = 8.6, 3.4 Hz, 1H), 4.84 (app dt, J = 8.1, 3.3 Hz, 1H), 4.66 (t, J = 8.6 Hz, 1H), 4.30−4.00 (m, 3H), 2.60 (dddd, J = 11.1, 8.1, 6.3, 3.4 Hz, 1H), 2.26−2.15 (m, 1H), 1.40 (s, 9H), 1.15 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 171.5, 155.0, 152.9, 138.8, 128.8 (2C), 128.2, 125.5 (2C), 79.0, 74.6, 70.0, 62.2, 57.8, 52.1, 42.7, 39.3, 28.3 (3C), 28.1 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H32N2NaO6+, 455.2157; found, 455.2144. (1R,2S,4R)-2-(tert-Butoxy)-4-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic Acid (−)-10. General procedure C, using diastereoisomer (−)-11a (1.65 g, 3.8 mmol), 35% w/w H2O2 solution (1.96 mL, 22.9 mmol), and LiOH·H2O (0.32 g, 7.6 mmol) afforded oxazolidinone (0.57 g, 92%) and nonracemic product (−)-10 (0.92 g, 84%) as a white solid. Rf (ethyl acetate/petrol ether, 50/50): 0.40; Mp: 158−159 °C; [α]D25 −13 (c 0.25, CHCl3) IR ν 3433, 3120 br, 1713, 1669; 1H NMR (300 MHz, CDCl3) δ 10.05 (br s, 1H), 5.62 (br s, 1H), 4.20−3.94 (m, 2H), 3.68−3.50 (m, 1H), 2.78−2.60 (m, 1H), 2.58−2.25 (m, 1H), 1.44 (s, 9H), 1.20 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 175.6, 155.2, 79.6, 74.8, 61.1, 54.7, 40.5, 38.3, 28.3 (3C), 27.8 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H25NNaO5+, 310.1625; found, 310.1621. (1R,2S,4R)-2-(tert-Butoxy)-4-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic Acid (+)-10 and tert-Butyl ((1S,2S,3R)-3-(tert-Butoxy)-2-(((R)-2-hydroxy-1-phenylethyl)carbamoyl)cyclobutyl)carbamate (−)-12. General procedure C, 532


Note


= 11.0, 7.6, 7.5, 3.4 Hz, 1H), 1.17 (s, 9H); 13C NMR (90 MHz, CDCl3) δ 171.1, 156.0, 144.2, 143.8, 141.3, 141.2, 135.9, 128.5 (2C), 128.4 (2C), 128.1, 127.7 (2C), 127.1 (2C), 125.3, 125.2, 119.9 (2C), 74.8, 67.0, 66.7, 63.5, 55.7, 47.2, 37.6, 32.3, 28.1 (3C); HRMS (ESITOF) m/z: [M + Na]+ Calcd for C31H33NNaO5+, 522.2251; found, 522.2254. (±)-cis-endo-Benzyl-benzyl-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)cyclobutane-1-carboxylate (±)-17. General procedure F, using racemic compound 15 (75 mg, 0.2 mmol), trifluoroacetic acid (0.46 mL, 6 mmol), and FmocCl (77.4 mg, 0.3 mmol). Deprotection with trifluoroacetic acid in dichloromethane took 4 h approximately at 0 °C. Flash chromatography (pentane/ ether, 80/20) afforded the Fmoc protected benzyl ester 17 (98 mg, 98%) as a white solid. Rf (dichloromethane/ether, 98/2): 0.40; Mp: 106−108 °C; IR ν 3410, 1715; 1H NMR (360 MHz, CDCl3) δ 7.76 (d, J = 7.1 Hz, 2H), 7.58 (dd, J = 7.1, 1.7 Hz, 2H), 7.44−7.28 (m, 9H), 6.13 (d, J = 10.0 Hz, 1H), 5.26 (A of AB quartet, J = 12.2 Hz, 1H), 5.16 (B of AB quartet, J = 12.2 Hz, 1H), 4.40−4.25 (m, 2H), 4.23− 4.00 (m, 3H), 3.73−3.62 (m, 1H), 2.73−2.60 (m, 1H), 2.53 (app dd, J = 19.8, 10.5 Hz, 1H), 1.10 (s, 9H); 13C NMR (90 MHz, CDCl3) δ 171.3, 155.7, 143.9, 143.8, 141.2 (2C), 135.6, 128.5 (2C), 128.4 (2C), 128.2, 127.6 (2C), 127.0 (2C), 125.1 (2C), 119.9 (2C), 74.4, 66.9, 66.4, 61.6, 54.7, 47.1, 40.8, 38.9, 27.8 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C31H33NNaO5+, 522.2251; found, 522.2252.

using diastereoisomer (−)-11b (0.43 g, 1 mmol), 35% w/w H2O2 solution (0.51 mL, 6 mmol), and LiOH·H2O (84 mg, 2 mmol). The first extraction of the aqueous solution (before acidification) afforded after flash chromatography oxazolidinone (74 mg, 45%) and the ring opening product (−)-12 (0.12 g, 28%) as a white solid. The second extraction of the aqueous solution (after acidification) afforded the nonracemic product (+)-10 (0.17 g, 61%) as a white solid. 10: Rf (ethyl acetate/petrol ether, 50/50): 0.40; Mp: 156−157 °C; [α]D23 +13 (c 0.25, CHCl3); IR ν 3433, 3100 br, 1708, 1673; 1H NMR (300 MHz, CDCl3) δ 11.70 (br s, 1H), 5.75 (br s, 1H), 4.26−3.82 (m, 2H), 3.68−3.48 (m, 1H), 2.82−2.57 (m, 1H), 2.56−2.32 (m, 1H), 1.44 (s, 9H), 1.19 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 175.8, 155.2, 79.6, 74.8, 61.1, 54.8, 40.5, 38.4, 28.3 (3C), 27.8 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H25NNaO5+: 310.1625; found, 310.1631. 12: Rf (dichloromethane/methanol, 10/1): 0.25; Mp: 157−158 °C; [α]D25 −41 (c 0.1, CHCl3); IR ν 3485, 3437, 3290, 1700, 1630; 1H NMR (360 MHz, CDCl3) δ 7.86 (br s, 1H), 7.42− 7.22 (m, 5H), 5.95 (br s, 1H), 5.21−5.00 (m, 1H), 4.10−3.98 (m, 1H), 3.98−3.86 (m, 1H), 3.86−3.78 (m, 1H), 3.44 (app dt, J = 7.6, 3.9 Hz, 1H), 2.99 (br s, 1H), 2.75−2.55 (m, 1H), 2.32−2.08 (m, 1H), 1.39 (s, 9H), 1.17 (s, 9H); 13C NMR (90 MHz, CDCl3) δ 171.0, 155.5, 138.9, 128.7 (2C), 127.6, 126.7 (2C), 79.2, 75.2, 66.5, 61.5, 55.8, 52.0, 42.1, 39.7, 28.3 (3C), 27.9 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H34N2NaO5+, 429.2360; found, 429.2356. (±)-cis-endo-Benzyl-3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate (±)-14. General procedure E, using racemic compound 5 (0.57 g, 2.0 mmol), benzyl alcohol (0.62 mL, 6 mmol), DMAP (24.4 mg, 0.2 mmol), and DCC (0.50 g, 2.4 mmol). Flash chromatography (ether/pentane, 20/80) afforded the benzyl ester 14 (0.65 g, 86%) as a white solid. Rf (ethyl acetate/petrol ether, 20/80): 0.70; Mp: 77−78 °C; IR ν 3447, 1727, 1711; 1H NMR (360 MHz, CDCl3) δ 7.38−7.26 (m, 5H), 5.44 (d, J = 6.9 Hz, 1H), 5.13 (A of AB quartet, J = 12.2 Hz, 1H), 4.96 (B of AB quartet, J = 12.2 Hz, 1H), 4.55−4.40 (m, 1H), 4.23 (app q, J = 7.5 Hz, 1H), 2.98 (app dt, J = 10.1, 7.4 Hz, 1H), 2.38−2.52 (m, 1H), 2.29 (dddd, J = 11.0, 7.6, 7.5, 3.4 Hz, 1H), 1.42 (s, 9H), 1.15 (s, 9H); 13C NMR (90 MHz, CDCl3) δ 171.0, 155.5, 135.9, 128.3 (2C), 128.2 (2C), 127.9, 79.2, 74.5, 66.4, 63.2, 55.5, 37.2, 32.2, 28.2 (3C), 27.9 (3C); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H31NNaO5+, 400.2094; found, 400.2110. (±)-cis-endo-Benzyl-2-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate (±)-15. General procedure E, using racemic compound 10 (0.60 g, 2.1 mmol), benzyl alcohol (0.65 mL, 6.3 mmol), DMAP (26 mg, 0.21 mmol), and DCC (0.52 g, 2.5 mmol). Flash chromatography (ether/pentane, 20/80) afforded the benzyl ester 15 (0.72 g, 91%) as a white solid. Rf (ethyl acetate/petrol ether, 20/80): 0.70; Mp: 106−107 °C; IR ν 3437, 1709; 1 H NMR (360 MHz, CDCl3) δ 7.45−7.27 (m, 5H), 5.78 (d, J = 9.4 Hz, 1H), 5.24 (A of AB quartet, J = 12.3 Hz, 1H), 5.13 (B of AB quartet, J = 12.3 Hz, 1H), 4.38−3.95 (m, 2H), 3.62 (app td, J = 7.3, 3.6 Hz, 1H), 2.62 (dddd, J = 11.0, 7.5, 7.3, 3.7 Hz, 1H), 2.47 (app dd, J = 19.8, 11.0 Hz, 1H), 1.41 (s, 9H), 1.08 (s, 9H); 13C NMR (90 MHz, CDCl3) δ 171.1, 154.9, 135.6, 128.4 (2C), 128.3 (2C), 128.0, 79.1, 74.2, 66.1, 61.0, 54.9, 40.7, 38.3, 28.2 (3C), 27.7 (3C); HRMS (ESITOF) m/z: [M + Na]+ Calcd for C21H31NNaO5+, 400.2094; found, 400.2088. (±)-cis-endo-Benzyl-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy)cyclobutane-1-carboxylate (±)-16. General procedure F, using racemic compound 14 (75 mg, 0.2 mmol), trifluoroacetic acid (0.46 mL, 6 mmol), and FmocCl (77.4 mg, 0.3 mmol). Deprotection with trifluoroacetic acid in dichloromethane took 1 h approximately at 0 °C. Flash chromatography (dichloromethane/ether, 98/2) afforded the Fmoc protected benzyl ester 16 (84 mg, 84%) as a white solid. Rf (dichloromethane/ether, 98/2): 0.35; Mp: 118−119 °C; IR ν 3357, 1707; 1H NMR (360 MHz, CDCl3) δ 7.75 (d, J = 7.4 Hz, 2H), 7.62 (dd, J = 12.7, 7.4 Hz, 2H), 7.45−7.22 (m, 9H), 5.72 (d, J = 7.6 Hz, 1H), 5.10 (A of AB quartet, J = 12.3 Hz, 1H), 5.00 (B of AB quartet, J = 12.3 Hz, 1H), 4.63−4.53 (m, 1H), 4.32−4.25 (m, 3H), 4.23−4.17 (m, 1H), 3.08 (app dt, J = 10.1, 7.6 Hz, 1H), 2.51 (app dd, J = 19.8, 11.0 Hz, 1H), 2.36 (dddd, J

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02559. Copies of 1H and 13C NMR spectra, HPLC chromatograms of racemic and nonracemic samples of 5 and 10 (PDF) Crystallographic data for 3c, 8, and 11b (CCDC 1571601−1571603) (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Thomas Boddaert: 0000-0002-3939-4700 David J. Aitken: 0000-0002-5164-6042 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Z.C. is grateful to the China Scholarship Council for the award of a PhD grant. The authors thank Mr J.-P. Baltaze for assistance with NMR studies. This work was funded in part by the French ANR (Project 2011-INTB-1003-01).

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REFERENCES

(1) (a) The Chemistry of Cyclobutanes; Rappoport, Z., Liebman, J. F., Eds.; Wiley: Chichester, U.K., 2005. (b) Anslyn, E. V., Dougherty, D. A. Modern Physical Organic Chemistry; University Science Books: Sausalito, CA, 2006; pp 65−145. (2) (a) Hanson, J. R. Nat. Prod. Rep. 2016, 33, 1227−1238 and previous reviews in this annual series. (b) Hong, Y. J.; Tantillo, D. J. Chem. Soc. Rev. 2014, 43, 5042−5050. (c) Crews, C.; Driffield, M.; Thomas, C. J. Food Compos. Anal. 2012, 26, 1−11. (d) Dembitsky, V. M. J. Nat. Med. 2007, 62, 1−33. (3) (a) Xu, Y.; Conner, M. L.; Brown, M. K. Angew. Chem., Int. Ed. 2015, 54, 11918−11928. (b) Secci, F.; Frongia, A.; Piras, P. P. Molecules 2013, 18, 15541−15572. (c) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 7740−7752. (d) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485− 533


Note

The Journal of Organic Chemistry 1537. (e) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449− 1483. (4) (a) Gutekunst, W. R.; Baran, P. S. J. Org. Chem. 2014, 79, 2430− 2452. (5) (a) Wang, J.; Kouznetsova, T. B.; Boulatov, R.; Craig, S. L. Nat. Commun. 2016, 7, 13433−13440. (b) Wiggins, K. M.; Brantley, J. N.; Bielawski, C. W. ACS Macro Lett. 2012, 1, 623−626. (c) Kryger, M. J.; Munaretto, A. M.; Moore, J. S. J. Am. Chem. Soc. 2011, 133, 18992− 18998. (6) Fernández-Tejada, A.; Corzana, F.; Busto, J. H.; Jiménez-Osés, G.; Peregrina, J. M.; Avenoza, A. Chem. - Eur. J. 2008, 14, 7042−7058. (7) (a) Steri, R.; Rupp, M.; Proschak, E.; Schroeter, T.; Zettl, H.; Hansen, K.; Schwarz, O.; Müller-Kuhrt, L.; Müller, K.-R.; Schneider, G.; Schubert-Zsilavecz, M. Bioorg. Med. Chem. Lett. 2010, 20, 2920− 29123. (b) Liu, Q.; Li, N.; Yuan, Y.; Lu, H.; Wu, X.; Zhou, C.; He, M.; Su, H.; Zhang, M.; Wang, J.; Wang, B.; Wang, Y.; Ma, D.; Ye, Y.; Weiss, H.-C.; Gesing, E. R. F.; Liao, J.; Wang, M.-W. J. Med. Chem. 2012, 55, 250−267. (8) (a) Grison, C. M.; Miles, J. A.; Robin, S.; Wilson, A. J.; Aitken, D. J. Angew. Chem., Int. Ed. 2016, 55, 11096−11100. (b) Grison, C. M.; Robin, S.; Aitken, D. J. Chem. Commun. 2016, 52, 7802−7805. (c) Altmayer-Henzien, A.; Declerck, V.; Farjon, J.; Merlet, D.; Guillot, R.; Aitken, D. J. Angew. Chem., Int. Ed. 2015, 54, 10807−10810. (d) Mansawat, W.; Vilaivan, C.; Balazs, Á .; Aitken, D. J.; Vilaivan, T. Org. Lett. 2012, 14, 1440−1443. (e) Fernandes, C.; Faure, S.; Pereira, E.; Théry, V.; Declerck, V.; Guillot, R.; Aitken, D. J. Org. Lett. 2010, 12, 3606−3609. (9) (a) Kiss, L.; Fülöp, F. Chem. Rev. 2014, 114, 1116−1169. (b) Ortuño, R. M.; Moglioni, A. G.; Moltrasio, G. Y. Curr. Org. Chem. 2005, 9, 237−259. (10) Yuan, P.; Driscoll, M. R.; Raymond, S. J.; Hansen, D. E.; Blatchly, R. A. Tetrahedron Lett. 1994, 35, 6195−6198. (11) Katagiri, N.; Sato, H.; Kaneko, C. Chem. Pharm. Bull. 1990, 38, 288−290. (12) Poplata, S.; Tröster, A.; Zou, Y.-Q.; Bach, T. Chem. Rev. 2016, 116, 9748−9815. (13) Applications of [2 + 2] photocycloadditions for the preparation of functional cyclobutanes in our group: (a) Hernvann, F.; Rasore, G.; Declerck, V.; Aitken, D. Org. Biomol. Chem. 2014, 12, 8212−8222. (b) André, V.; Gras, M.; Awada, H.; Guillot, R.; Robin, S.; Aitken, D. J. Tetrahedron 2013, 69, 3571−3576. (c) Declerck, V.; Aitken, D. J. J. Org. Chem. 2011, 76, 708−711. (d) Declerck, V.; Aitken, D. J. Amino Acids 2011, 41, 587−595. (e) André, V.; Vidal, A.; Ollivier, J.; Robin, S.; Aitken, D. J. Tetrahedron Lett. 2011, 52, 1253−1255. (f) Le Liepvre, M.; Ollivier, J.; Aitken, D. J. Eur. J. Org. Chem. 2009, 2009, 5953− 5962. (g) Mondière, A.; Peng, R.; Remuson, R.; Aitken, D. J. Tetrahedron 2008, 64, 1088−1093. (h) Gauzy, C.; Saby, B.; Pereira, E.; Faure, S.; Aitken, D. J. Synlett 2006, 2006, 1394−1398. (14) For other synthetic approaches to 2-aminocyclobutane-1carboxylic acid derivatives, see: (a) de Nanteuil, F.; Waser, J. Angew. Chem., Int. Ed. 2013, 52, 9009−9013. (b) Meiresonne, T.; Mangelinckx, S.; De Kimpe, N. Org. Biomol. Chem. 2011, 9, 7085− 7091. (c) de Meijere, A.; Limbach, M.; Janssen, A.; Lygin, A.; Korotkov, V. S. Eur. J. Org. Chem. 2010, 2010, 3665−3671. (d) Izquierdo, S.; Martín-Vilà, M.; Moglioni, A. G.; Branchadell, V.; Ortuñ o, R. M. Tetrahedron: Asymmetry 2002, 13, 2403−2405. (e) Martín-Vilà, M.; Muray, E.; Aguado, G. P.; Alvarez-Larena, A.; Branchadell, V.; Minguillón, C.; Giralt, E.; Ortuño, R. M. Tetrahedron: Asymmetry 2000, 11, 3569−3584. (15) For precedents for [2 + 2] photocycloadditions between maleimide and alkenes, see: (a) Kearns, P. S.; Wells, B. K.; Warrener, R. N.; Margetic, D. Synlett 2014, 25, 1601−1605. (b) Conradi, M.; Junkers, T. J. Photochem. Photobiol., A 2013, 259, 41−46. (c) Mittendorf, J.; Kunisch, F.; Matzke, M.; Militzer, H.-C.; Schmidt, A.; Schönfeld, V. Bioorg. Med. Chem. Lett. 2003, 13, 433−436. (d) Shimo, T.; Uezono, T.; Obata, T.; Yasutake, M.; Shinmyozu, T.; Somekawa, K. Tetrahedron 2002, 58, 6111−6116. (e) Booker-Milburn, K. I.; Cowell, J. K.; Jimenez, F. D.; Sharpe, A.; White, A. J. Tetrahedron

1999, 55, 5875−5888. (f) Sakai, T.; Kimura, Y.; Kitasaka, K.; Tsuboi, S.; Uko, M. Jpn. Patent, 1992, JP 04283562A. (16) For synthetic applications of [2 + 2] photocycloadditions between maleic anhydride and alkenes, see: (a) Petz, S.; Wanner, K. T. Eur. J. Org. Chem. 2013, 2013, 4017−4025. (b) Celis, S.; Gorrea, E.; Nolis, P.; Illa, O.; Ortuño, R. M. Org. Biomol. Chem. 2012, 10, 861− 868. (c) Gu, X.; Xian, M.; Roy-Faure, S.; Bolte, J.; Aitken, D. J.; Gefflaut, T. Tetrahedron Lett. 2006, 47, 193−196. (d) Birman, V. B.; Jiang, X.-T. Org. Lett. 2004, 6, 2369−2371. (e) Lescop, C.; Mévellec, L.; Huet, F. J. Org. Chem. 2001, 66, 4187−4193. (f) Aitken, R. A.; Cadogan, J. I. G.; Gosney, I.; Humphries, C. M.; McLaughlin, L. M.; Wyse, S. J. J. Chem. Soc., Perkin Trans. 1 1999, 1, 605−614. (g) Somekawa, K.; Hara, R.; Kinnami, K.; Muraoka, F.; Suishu, T.; Shimo, T. Chem. Lett. 1995, 24, 407−408. (17) (a) Griesbeck, A. G. Synlett 2003, 451−472. (b) Griesbeck, A. G.; Stadtmüller, S.; Busse, H.; Bringmann, G.; Buddrus, J. Chem. Ber. 1992, 125, 933−940. (18) For discussions on the terminology of consecutive reactions, see: (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131−163. (b) Coquerel, Y.; Boddaert, T.; Presset, M.; Mailhol, D.; Rodriguez, J. In Ideas in Chemistry and Molecular Sciences: Advances in Synthetic Chemistry; Pignataro, B., Ed.; Wiley-VCH: Weinheim, 2010; pp 187−202. (19) For previous amino acid resolutions using oxazolidinones, see: (a) Kassir, A. F.; Ragab, S. S.; Nguyen, T. A. M.; Charnay-Pouget, F.; Guillot, R.; Scherrmann, M.-C.; Boddaert, T.; Aitken, D. J. J. Org. Chem. 2016, 81, 9983−9991. (b) Hassoun, A.; Grison, C. M.; Guillot, R.; Boddaert, T.; Aitken, D. J. New J. Chem. 2015, 39, 3270−3279. (c) Awada, H.; Robin, S.; Guillot, R.; Yazbeck, O.; Naoufal, D.; Jaber, N.; Hachem, A.; Aitken, D. J. Eur. J. Org. Chem. 2014, 2014, 7148− 7155. (20) The 1H NMR yields were determined on the crude mixture with 3,5-dichloronitrobenzene as an internal standard. (21) The formation of the trifluoroacetic acid salts was clearly suggested by 1H NMR spectroscopy, but attempts to isolate the zwitterionic forms, following procedure D, resulted in complete degradation. (22) (a) Roy, O.; Faure, S.; Aitken, D. J. Tetrahedron Lett. 2006, 47, 5981−5987. (b) Aitken, D. J.; Gauzy, C.; Pereira, E. Tetrahedron Lett. 2004, 45, 2359−2361.

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