A Synthesis of 1,4-Disubstituted Imidazolidin-2-ones from Fused-Ring Aziridines

Abstract

As part of an antibacterial drug discovery project, we were interested in preparing bioisosteric replacement analogues of 4,5-disubstituted oxazolidinones. One such isosteric replacement is the imidazolidinone ring system. Here, we report the development of a general synthesis of 1,4-disubstituted imidazolidinones that takes advantage of the base-catalyzed rearrangement of amino­methyl-substituted oxazolidinones.

Cyclic urea moieties are found in many molecules ranging from chiral auxiliaries to biologically active molecules. Some examples of the biological activity of molecules containing the imidazolidin-2-one moiety include: protease inhibitors, [¹] anti-ischemic agents, [²] kinase modulators, [³] muscarinic receptor antagonists, [4] and anti-Leishmaniasis agents. [5] Imidazolidin-2-ones are also useful chiral auxiliaries in highly diastereoselective alkylation, aldol and Diels-Alder reactions. [6]

Cyclic ureas are most commonly constructed by treatment of a 1,2-diamine with phosgene [7] or its derivatives. [8] Other approaches to the synthesis of imidazolidin-2-ones include the Pd-catalyzed carboamination of N-allylureas, [9] and intramolecular cyclization of urea derived from a 1,2-aminoalcohol and an isocyanate. [¹0] A good approach to a wide range of saturated imidazolidinones uses a Michael type reaction involving isocyanates or amines containing an α,β-unsaturated ester functional group, [¹¹] or modified Hofmann rearrangement of amino acids in the presence of iodine. [¹²] Rearrangement of an oxazolidinone to imidazolidinone has also been observed. [¹³] We report herein an approach to the synthesis of 1,4-disubstituted imidazolidin-2-ones through a one-pot reaction of fused ring aziridines with primary amines.

The synthesis and reactions of fused-ring aziridines have been previously studied in our laboratory. [¹4] For example, the reaction of 1 with N-phenylpiperazine has been shown to provide oxazolidinone 2 in good yield (Scheme  [¹] ). Acylation of 2 has lead to a series of high-affinity RNA-binding molecules 3. [¹5]

A study on the scope of the reaction of aziridine 1 with a series of amines was initiated in order to generate a broad series of derivatives of 3. As part of this study, the reaction of 1 with an excess of benzylamine was left stirring for several days (Scheme  [²] ). When the reaction was worked up a mixture of 2a and 4a was obtained.

Given the bioisosteric similarity of the resulting imidazolidinone ring to oxazolidinone 3, we decided to investigate the scope and utility of this reaction. Whereas the rearrangement of similar aminomethyl substituted oxazolidinones to the corresponding imidazolidinones have been reported, both reports provided only a single example of this reaction. [¹³]

Realizing that this product came about through an intramolecular cyclization of the amine on to the oxazolidinone ring, an investigation was undertaken to establish the optimal reaction conditions. Given that the original reaction conditions provided a mixture of the oxazolidinone and imidazolidinone, an examination of the conditions necessary to convert the racemic oxazolidinone 2a into the imidazolidinone 4a was first examined (Scheme  [³] ).

The original procedure that provided imidazolidinone 4a involved the use of an excess of amine with N,N-dimethylformamide (DMF) as solvent. However, the use of an excess of amine was not suitable in terms of developing a more general method. We therefore decided to replace the excess amine with a more easily removable base and chose to examine both inorganic and organic bases. The use of the rather high-boiling solvent DMF was also somewhat problematic and other polar, yet lower boiling solvents, were also examined. A few examples of solvents and bases examined are shown in Table  [¹] . Acetonitrile (MeCN) quickly emerged as a highly effective solvent in these initial studies. Coupled with K₂CO₃ as a base, a 63% yield of 4a was obtained, albeit after a 68 hours reaction time. Increasing the amount of K₂CO₃ provided a slightly improved yield of 72%, while completely eliminating the K₂CO₃ provided roughly the same yield upon doubling the reaction time. Other solvents were less useful in this reaction. For example, the use of dioxane provided no product even upon increasing the reaction temperature to 102 ˚C. Bases such as Et₃N were also useful, providing 4a in 61% yield. Systems involving KOH in methanol or potassium tert-butoxide (t-BuOK) in DMF also proved to be excellent base/solvent conditions. Unlike the other bases examined, both of these bases provided excellent yields upon decreasing the amount of added base to 10 mol%.

With optimal reaction conditions for the conversion of 2 into 4 in hand, a one-pot method for the conversion of racemic 1 into the imidazolidinone 4 was re-examined. Two solvents were chosen: acetonitrile and DMF. Whereas methanol was a useful solvent for the rearrangement reaction, it is not suitable for the initial aziridine opening as it was expected to participate in the ring-opening reaction itself. [¹4a] A summary of the optimal conditions are provided in Scheme  [4] . In either acetonitrile or DMF, the amine was added to aziridine 1 and stirred for approximately 18 hours (at which point TLC analysis indicated that the starting aziridine was consumed) at room temperature. Base was then added and the reaction was warmed. Optimal conditions using acetonitrile as solvent required the use of 500 mol% K₂CO₃, which provided 72% overall yield of imidazolinone from 1. Using DMF as solvent and t-BuOK as a base provided an improved yield of 82% of 4a from 1.

Having developed a general method for the direct conversion of 1 into the corresponding imidazolidinone 4, the scope of the ring-opening/rearrangement reaction was investigated. A series of both aliphatic and aromatic amines containing a variety of substitution patterns were examined in the reaction. All reactions were carried out as outlined in Scheme  [4] ; the amine was added to the aziridine in DMF and, after 18-24 hours (typically overnight), t-BuOK was added and the reaction was heated to 50 ˚C until complete (typically 8 h).

Table 2 Scope of the Reaction

Compound	Amine	Yield (%)
4a	BnNH2	82
4b	4-MeOC6H4CH2NH2	75
4c	n-C6H13NH2	68
4d	i-BuNH2	62
4e	t-BuNH2	51
4f	c-C6H11NH2	65
4g	1,2,3,4-tetrahydronaphthylamine	83
4h	CH2=CHCH2NH2	51
4i	HCºCCH2NH2	53
4j	PhCH2CH2NH2	78
4k	MeOCH2CH2NH2	76
4l	HOCH2CH2NH2	50
4m	CH3CH(OH)CH2NH2	65
4n	HOCH2CH(OH)CH2NH2	72
4o	PhNH2 a	47
4p	4-MeOC6H4NH2 a	41
a t-BuOK (100 mol%), 2 h, MW 120 ˚C.

A variety of aliphatic amines (substituted benzylamine, n-hexylamine, isobutylamine, cyclohexylamine, methoxyethylamine, allylamine, propargylamine) all provided the expected imidazolidinone in good yields under the standard reaction conditions. More sterically hindered amines such as tert-butylamine and 1,2,3,4-tetrahydronaphthyl­amine both required extended reaction times for the rearrangement reaction to occur. The presence of an alcohol functionality is compatible with the reaction conditions and amino alcohols provided the expected imidazolidinones 4l, 4m, and 4n in generally good yields. Rearrangement of oxazolidinones containing aniline substituents did not occur under the standard conditions even with heating (72 h at 60 ˚C, or 4 h at 100 ˚C under microwave irradiation). An equimolar amount of t-BuOK and heating for two hours at 120 ˚C (MW) finally provided the imidazolidinones 4o and 4p in moderate yield.

The trityl protecting group can be conveniently removed by the use of Dowex 50 WX8-100 ion-exchange resin in methanol. As shown in Scheme  [5] , shaking the reaction mixture for 15 hours at room temperature provided a series of diols 5 in generally excellent yields. The diol product was easily separated from triphenylmethane by short column chromatography after filtration of the resin.

The synthesis of acylated derivatives of the imidazolidinones was of interest for the preparation of analogues of RNA-binding oxazolidinones (e.g., 3). The first attempt at acylation of the secondary hydroxy group of imidazolidinone 4a was carried out under standard conditions, using 200 mol% benzoyl chloride with triethylamine and 4-(N,N-dimethylamino)pyridine (DMAP) in dichloro­methane. This provided a single diacylated product in which both the secondary alcohol and the free nitrogen of the imidazolidinone ring were benzoylated. Decreasing the amount of benzoyl chloride to 110 mol% provided a mixture of mono- and diacylated products. Decreasing the amount of triethylamine to 100 mol% from 200 mol% provided 6a, with no observable diacylation products, in 51% yield. Unfortunately, the use of these conditions with other acid chlorides proved ineffective, with mixtures of the mono- and diacylated products being obtained. Further decreases in the amount of triethylamine used yielded no significant improvements in the ratio of mono- to di­acylated products.

Acid anhydrides were next examined as potential acylating agents. Using the partially optimized conditions for the benzoylation as a starting point, the reaction of 4a with 105 mol% benzoic anhydride with a catalytic amount of DMAP in dichloromethane provided a mono-benzoylated product 6a in 71% isolated yield. Additional carboxylic acid anhydrides, acetic, propionic and isobutyric all worked well, providing the corresponding esters in excellent yields (Scheme  [6] ).

In addition to the synthesis of esters, the conversion of alcohols 4 into the corresponding carbamate was also of interest. Using the same successful general conditions used for the synthesis of esters 6 did not provide any of the expected products. The reaction of 4a with PhNCO provided a mixture of mono- and disubstituted products without complete consumption of the starting alcohol 4a. The use of CuCl as a carbamoylation catalyst proved far more successful. The reaction of 4a with 150 mol% PhNCO and a large excess of CuCl (500 mol%) provided 7a in 85% yield.

The trityl group from the acylated derivatives 6 and 7 could be readily removed with HCl, providing the corresponding alcohols 8a-d in good yields. No acyl group migration was observed based upon the ^¹H NMR spectra of the hydroxymethyl group.

Based upon their similarity to previously reported oxazolidinone RNA-binding agents, [¹5] imidazolidinones 8a-d were examined for their ability to disrupt tRNA binding to T box antiterminator model RNA using a previously described fluorescence anisotropy assay. [¹6] This tRNA-antiterminator RNA interaction is a critical component of the T box riboswitch transcription regulatory mechanism found in many Gram positive bacteria and is a potential antibacterial target. [¹7] In the presence of ligand (100 µM), the observed changes in the anisotropy were: -56% (8a), -38% (8b), -19% (8c) and -13% (8d). Based on these results, compounds 8a and 8b significantly disrupt the tRNA-antiterminator RNA complex. In addition, an apparent structure-activity trend was evident since the carbamate compounds 8c and 8d were less effective at disrupting the complex than the ester analogues 8a and 8b. These results indicate that further study of these imidazolidinone derivatives may be useful in identifying novel RNA-binding ligands.

In conclusion, we have demonstrated that 1,4-disubstituted imidazolidin-2-ones can be easily prepared from fused-ring aziridine with a variety of primary amines, using a one-pot aziridine ring-opening/rearrangement sequence. This method is efficient, uses readily available materials, and provides imidazolidinones and their derivatives in a simple manner.

All chemicals were purchased from the usual commercial suppliers and used without further purification unless noted. All amines were freshly distilled before use, t-BuOK was freshly sublimed before use, CuCl was freshly purified before use. [¹8] CH₂Cl₂ was dried using a SOLVTEK column purification system. All reactions were carried out under an argon atmosphere. TLC was performed using Whatman Flexible Plates Al Sil G/UV; visualization was achieved by UV absorbance or by staining with iodine or a 5% ethanolic solution of phosphomolybdic acid. Chromatography refers to flash chromatography on 32-63D 60Å silica gel according to the method of Still. [¹9] IR spectra were obtained neat. The purity of all compounds were determined by HPLC analysis with a Shimadzu LC-10AT chromatograph equipped with a UV or ELS detector employing a Discovery-C8 column (15 cm × 4.6 mm × 5 µm; Supelco) at a flow rate of 1 mL/min. ^¹H, ^¹³C NMR and 2D NMR (COSY and HMQC-GP) spectra were recorded with a Bruker Avance 300 MHz NMR spectrophotometer and were referenced to TMS as an internal standard. All yields refer to analytically pure compounds. All compounds prepared were racemic mixtures, the R*/S* nomenclature is used to denote relative stereochemistry. [²0]

(4 R *,5 S *)-4-[(Benzylamino)methyl]-5-[(trityloxy)methyl]oxazolidin-2-one (2a)

To a solution of racemic aziridine 1 [¹5d] [¹4c] (0.1 g, 0.27 mmol) in CH₂Cl₂ (3 mL) was added benzylamine (35 mg, 0.32 mmol). The reaction was stirred for 18 h, concentrated, and purified by chromatography to provide oxazolidinone 2a.

Yield: 0.10 g (81%); white solid; mp 120.2-120.8 ˚C; R _f  = 0.20 (hexanes-EtOAc, 1:1); t _R  = 7.725 min (100%; 254 nm; 50% MeCN-H₂O, gradient started at 2 min increased to 90% MeCN-H₂O at 5 min).

IR (film): 3286, 1751, 1489 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 2.65 (AB dd, J _AB = 23.6 Hz, δ_A = 2.62, J = 12.2, 6.9 Hz, δ_B = 2.68, J = 12.2, 5.1 Hz, 2 H), 3.30 (AB dd, J _AB = 49.2 Hz, δ_A = 3.22, J = 10.3, 4.4 Hz, δ_B = 3.36, J = 10.3, 4.6 Hz, 2 H), 3.68 (m, 1 H), 3.72 (s, 2 H), 4.37 (dt, J = 9.5, 4.6 Hz, 1 H), 5.98 (s, 1 H), 7.20-7.31 (m, 15 H), 7.40-7.44 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 52.7, 53.9, 54.8, 64.4, 79.2, 87.1, 127.3, 127.4, 128.1, 128.2, 128.6, 128.8, 139.9, 143.6, 159.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₃₀N₂O₃Na⁺: 501.2149; found: 501.2148.

Preparation of Imidazolidin-2-ones 4; General Procedure

Racemic aziridine 1 and the primary amine (105 mol%) were dissolved in DMF (0.4 M) at r.t. (or 50 ˚C for anilines). The reaction mixture was stirred until the starting material was consumed (reaction monitored by TLC analysis; 16-24 h). After completion of the ring-opening process, t-BuOK (10 mol%; 100 mol% for anilines) was added. The reaction mixture was then heated at 50 ˚C until the reaction was complete (TLC analysis; 8-24 h or 2 h at 120 ˚C, MW for anilines). After cooling, the reaction was partitioned between CH₂Cl₂ and H₂O. After separation, the organic phase was washed twice with H₂O, brine, dried over MgSO₄, concentrated, and purified by chromatography. All purified compounds were analyzed by HPLC (214 nm; 30% MeCN-H₂O, gradient started at 1 min increased to 90% MeCN-H₂O at 10 min, unless otherwise noted).

( R* )-1-Benzyl-4-[( S* )-1-hydroxy-2-(trityloxy)ethyl]imidazolidin-2-one (4a)

Aziridine 1 (0.31 g, 0.82 mmol) provided 4a.

Yield: 0.32 g (82%); white solid; mp 72.0-73.7 ˚C; R _f  = 0.20 (hexanes-EtOAc, 1:4); t _R  = 11.858 min (99.7%).

IR (film): 3327, 1697, 1489 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 2.55 (d, J = 7.8 Hz, 1 H), 3.11 (AB dd, J _AB = 61.1 Hz, δ_A = 3.00, J = 8.8, 7.4 Hz, δ_B = 3.21, J = 8.8 Hz, 2 H), 3.20 (AB dd, J _AB = 35.8 Hz, δ_A = 3.12, J = 9.9, 4.8 Hz, δ_B = 3.22, J = 9.9, 4.4 Hz, 2 H), 3.51 (m, 1 H), 3.73 (m, 1 H), 4.32 (AB d, J _AB = 47.9 Hz, δ_A = 4.26, J = 15.0 Hz, δ_B = 4.37, J = 15.0 Hz, 2 H), 4.66 (s, 1 H), 7.21-7.32 (m, 14 H), 7.36-7.40 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 46.8, 47.6, 52.4, 65.2, 72.0, 87.4, 127.5, 127.7, 128.1, 128.2, 128.7, 128.8, 137.1, 143.6, 161.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₃₀N₂O₃Na⁺: 501.2149; found: 501.2147.

( R* )-4-[( S* )-1-Hydroxy-2-(trityloxy)ethyl]-1-(4-methoxybenzyl)imidazolidin-2-one (4b)

Aziridine 1 (0.31 g, 0.82 mmol) provided 4b.

Yield: 0.31 g (75%); yellow solid; mp 70.3-71.4 ˚C; R _f  = 0.20 (hexanes-EtOAc, 1:4); t _R  = 11.692 min (99.9%).

IR (film): 3333, 1697, 1612, 1512, 1489 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 2.83 (d, J = 7.6 Hz, 1 H), 3.08 (AB dd, J _AB = 45.1 Hz, δ_A = 2.97, J = 8.9, 7.3 Hz, δ_B = 3.19, J = 9.0 Hz, 2 H), 3.16 (AB dd, J _AB = 29.5 Hz, δ_A = 3.13, J = 9.9, 4.8 Hz, δ_B = 3.21, J = 9.9, 4.9 Hz, 2 H), 3.51 (m, 1 H), 3.71 (m, 1 H), 3.78 (s, 3 H,), 4.24 (AB d, J _AB = 42.8 Hz, δ_A = 4.18, J = 14.8 Hz, δ_B = 4.30, J = 14.8 Hz, 2 H), 4.78 (s, 1 H), 6.83 (d, J = 8.6 Hz, 2 H), 7.14 (d, J = 8.6 Hz, 2 H), 7.20-7.31 (m, 9 H), 7.36-7.40 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 46.4, 46.8, 52.1, 55.3, 65.0, 71.7, 87.2, 114.0, 127.3, 128.0, 128.5, 128.9, 129.4, 143.4, 159.1, 161.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₂H₃₂N₂O₄Na⁺: 531.2254; found: 531.2252.

( R* )-1-Hexyl-4-[( S* )-1-hydroxy-2-(trityloxy)ethyl]imidazolidin-2-one (4c)

Aziridine 1 (0.30 g, 0.81 mmol) provided 4c.

Yield: 0.26 g (68%); white solid; mp 120.4-121.8 ˚C; R _f  = 0.35 (hexanes-EtOAc, 5:95); t _R  = 12.800 min (100%).

IR (film): 3333, 2924, 2854, 1697, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.27 (m, 6 H), 1.44 (quint, J = 6.6 Hz, 2 H), 2.54 (d, J = 8.1 Hz, 1 H), 3.02-3.37 (m, 6 H), 3.57 (m, 1 H), 3.76 (m, 1 H), 4.46 (s, 1 H), 7.23-7.34 (m, 9 H), 7.40-7.43 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 14.2, 22.8, 26.6, 27.6, 31.7, 43.4, 47.1, 52.3, 65.2, 71.7, 87.3, 127.5, 128.2, 128.7, 143.7, 161.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₀H₃₆N₂O₃Na⁺: 495.2618; found: 495.2617.

( R* )-4-[( S* )-1-Hydroxy-2-(trityloxy)ethyl]-1-isobutylimidazolidin-2-one (4d)

Aziridine 1 (0.30 g, 0.80 mmol) provided 4d.

Yield: 0.22 g (62%); white solid; mp 178.2-178.6 ˚C; R _f  = 0.20 (hexanes-EtOAc, 1:4); t _R  = 11.783 min (99.9%).

IR (film): 3348, 2924, 2870, 1697, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 0.88 (d, J = 6.7 Hz, 3 H), 0.89 (d, J = 6.7 Hz, 3 H), 1.80 (m, 1 H), 2.42 (d, J = 8.3 Hz, 1 H), 2.93 (AB dd, J _AB = 23.0 Hz, δ_A = 2.91, J = 13.7, 7.4 Hz, δ_B = 2.96, J = 13.7, 7.6 Hz, 2 H), 3.21 (AB dd, J _AB = 27.0 Hz, δ_A = 3.16, J = 10.3, 4.8 Hz, δ_B = 3.25, J = 9.8, 4.8 Hz, 2 H), 3.25 (AB dd, J _AB = 60.0 Hz, δ_A = 3.15, J = 9.1, 7.5 Hz, δ_B = 3.36, J = 8.9 Hz, 2 H), 3.58 (m, 1 H), 3.77 (m, 1 H), 4.40 (s, 1 H), 7.23-7.35 (m, 9 H), 7.39-7.43 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 20.2, 27.1, 47.8, 51.1, 52.2, 65.3, 71.6, 87.4, 127.5, 128.3, 128.7, 143.6, 162.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₃₂N₂O₃Na⁺: 467.2305; found: 467.2296.

( R* )-1-( tert -Butyl)-4-[( S* )-1-hydroxy-2-(trityloxy)ethyl]imidazolidin-2-one (4e)

Aziridine 1 (0.30 g, 0.80 mmol) provided 4e.

Yield: 0.18 g (51%); white solid; mp 175.4-176.3 ˚C; R _f  = 0.42 (hexanes-EtOAc, 5:95); t _R  = 11.883 min (100%).

IR (film): 3348, 3055, 1682, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 1.32 (s, 9 H), 2.44 (d, J = 8.3 Hz, 1 H), 3.20 (AB dd, J _AB = 35.0 Hz, δ_A = 3.16, J = 9.8, 4.6 Hz, δ_B = 3.25, J = 9.8, 4.8 Hz, 2 H), 3.28 (AB dd, J _AB = 56.7 Hz, δ_A = 3.19, J = 8.3 Hz, δ_B = 3.37, J = 8.7 Hz, 2 H), 3.55 (m, 1 H), 3.66 (m, 1 H), 4.36 (s, 1 H), 7.23-7.35 (m, 9 H), 7.40-7.43 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ= 27.8, 45.7, 52.0, 53.1, 65.5, 71.4, 87.3, 127.5, 128.2, 128.7, 143.7, 162.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₃₂N₂O₃Na⁺: 467.2311; found: 467.2304.

( R* )-1-Cyclohexyl-4-[( S* )-1-hydroxy-2-(trityloxy)ethyl]imidazolidin-2-one (4f)

Aziridine 1 (0.31 g, 0.82 mmol) provided 4f.

Yield: 0.25 g (65%); white solid; mp 181.3-182.8 ˚C; R _f  = 0.20 (hexanes-EtOAc, 1:4); t _R  = 12.250 min (99.5%).

IR (film): 3333, 2932, 2854, 1682, 1489, 1450 cm^-¹.

^¹H NMR (CDCl₃, 300 MHz): δ = 1.01-1.11 (m, 1 H), 1.18-1.36 (m, 4 H), 1.63-1.78 (m, 5 H), 2.46 (d, J = 8.1 Hz, 1 H), 3.10-3.34 (m, 4 H), 3.53-3.78 (m, 3 H), 4.40 (s, 1 H), 7.26-7.35 (m, 9 H), 7.40-7.43 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 25.4, 25.5, 30.0, 30.5, 42.6, 50.9, 52.4, 65.0, 71.5, 87.2, 127.3, 128.0, 128.6, 143.5, 161.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₀H₃₄N₂O₃Na⁺: 493.2462; found: 493.2460.

(4 R* )-4-[( S* )-1-Hydroxy-2-(trityloxy)ethyl]-1-(1,2,3,4-tetrahydronaphthalen-1-yl)imidazolidin-2-one (4g)

Aziridine 1 (0.30 g, 0.81 mmol) provided 4g.

Yield: 0.35 g (83%); yellow solid; mp 87.5-89.0 ˚C; R _f  = 0.54 (hexanes-EtOAc, 1:4); t _R  = 12.517 min (99.8%).

IR (film): 3333, 2932, 2870, 1682, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 1.67-2.04 (m, 4 H), 2.55 (d, J = 7.3 Hz, 1 H), 2.74 (m, 2 H), 2.81-3.28 (m, 4 H), 3.54 (m, 1 H), 3.70 (m, 1 H), 4.62 and 4.69 (2 × s, 1 H), 5.16 (m, 1 H), 7.07-7.17 (m, 4 H), 7.21-7.32 (m, 9 H), 7.34-7.40 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 21.9, 22.0, 27.4, 28.0, 29.7, 43.0, 50.5, 50.6, 52.3, 52.6, 65.2, 65.3, 71.8, 72.1, 87.4, 87.5, 126.4, 126.5, 127.1, 127.5, 127.7, 128.3, 128.7, 129.4, 134.9, 135.2, 138.4, 138.5, 143.6, 162.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₄H₃₄N₂O₃Na⁺: 541.2462; found: 541.2462.

( R* )-1-Allyl-4-[( S* )-1-hydroxy-2-(trityloxy)ethyl]imidazolidin-2-one (4h)

Aziridine 1 (0.31 g, 0.82 mmol) provided 4h.

Yield: 0.18 g (51%); yellow solid; mp 157.3-157.8 ˚C; R _f  = 0.42 (hexanes-EtOAc, 1:4); t _R  = 11.258 min (99.6%).

IR (film): 3333, 2924, 2878, 1697, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 2.37 (d, J = 8.1 Hz, 1 H, OH), 3.21 (AB dd, J _AB = 31.2 Hz, δ_A = 3.17, J = 9.8, 4.8 Hz, δ_B = 3.26, J = 9.8, 4.7 Hz, 2 H), 3.22 (AB dd, J _AB = 66.2 Hz, δ_A = 3.11, J = 8.6 Hz, δ_B = 3.33, J = 9.0 Hz, 2 H), 3.57 (m, 1 H), 3.75 (AB dd, J _AB = 33.0 Hz, δ_A = 3.72, J = 15.8, 5.8 Hz, δ_B = 3.79, J = 15.9, 5.4 Hz, 2 H), 3.76 (m, 1 H), 4.47 (s, 1 H), 5.17 (m, 2 H), 5.71 (m, 1 H), 7.23-7.34 (m, 9 H), 7.39-7.42 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 46.3, 46.9, 52.3, 65.2, 71.8, 87.4, 117.9, 127.5, 128.2, 128.7, 133.3, 143.6, 161.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₂₈N₂O₃Na⁺: 451.1992; found: 451.1990.

( R* )-4-[( S* )-1-Hydroxy-2-(trityloxy)ethyl]-1-(prop-2-yn-1-yl)imidazolidin-2-one (4i)

Aziridine 1 (0.30 g, 0.80 mmol) provided 4i.

Yield: 0.18 g (53%); yellow solid; mp 73.0-74.5 ˚C; R _f  = 0.50 (hexanes-EtOAc, 1:4); t _R  = 11.042 min (99.6%).

IR (film): 3294, 2924, 2878, 1697, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 2.21 (t, J = 2.5 Hz, 1 H), 2.61 (d, J = 7.9 Hz, 1 H), 3.23 (AB dd, J _AB = 33.2 Hz, δ_A = 3.19, J = 9.9, 4.7 Hz, δ_B = 3.28, J = 9.9, 4.7 Hz, 2 H), 3.34 (AB dd, J _AB = 68.6 Hz, δ_A = 3.22, J = 8.6 Hz, δ_B = 3.45, J = 8.8 Hz, 2 H), 3.60 (m, 1 H), 3.79 (m, 1 H), 3.96 (AB dd, J _AB = 20.0 Hz, δ_A = 3.95, J = 17.6, 2.4 Hz, δ_B = 3.97, J = 17.9, 2.4 Hz, 2 H), 4.76 (s, 1 H), 7.23-7.35 (m, 9 H), 7.40-7.43 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 33.1, 46.2, 52.1, 64.9, 71.6, 72.4, 87.2, 127.4, 128.1, 128.5, 143.4, 160.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₂₆N₂O₃Na⁺: 449.1836; found: 449.1833.

( R* )-4-[( S* )-1-Hydroxy-2-(trityloxy)ethyl]-1-phenethylimidazolidin-2-one (4j)

Aziridine 1 (0.30 g, 0.81 mmol) provided 4j.

Yield: 0.31 g (78%); yellow solid; mp 163.1-164.2 ˚C; R _f  = 0.36 (hexanes-EtOAc, 5:95); t _R  = 12.117 min (99.8%).

IR (film): 3348, 2923, 2870, 1670, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 2.34 (d, J = 8.2 Hz, 1 H), 2.79 (t, J = 7.3 Hz, 2 H), 3.14 (AB dd, J _AB = 63.2 Hz, δ_A = 3.03, J = 7.5 Hz, δ_B = 3.24, J = 8.8 Hz, 2 H), 3.16 (AB dd, J _AB = 33.7 Hz, δ_A = 3.11, J = 9.8, 4.7 Hz, δ_B = 3.21, J = 9.8, 4.9 Hz, 2 H), 3.40 (m, 2 H), 3.50 (m, 1 H), 3.70 (m, 1 H), 4.42 (s, 1 H), 7.19-7.21 (m, 3 H), 7.23-7.35 (m, 11 H), 7.38-7.41 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 34.4, 44.9, 47.6, 52.4, 65.1, 71.7, 87.3, 126.7, 127.5, 128.2, 128.7, 128.7, 128.9, 139.1, 143.7, 161.7.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₂H₃₂N₂O₃Na⁺: 515.2311; found: 515.2318.

( R* )-4-[( S* )-1-Hydroxy-2-(trityloxy)ethyl]-1-(2-methoxyethyl)imidazolidin-2-one (4k)

Aziridine 1 (0.30 g, 0.80 mmol) provided 4k.

Yield: 0.27 g (76%); white solid; mp 140.9-142.3 ˚C; R _f  = 0.27 (hexanes-EtOAc, 5:95); t _R  = 10.675 min (99.9%).

IR (film): 3348, 2924, 2878, 1697, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 2.50 (d, J = 7.8 Hz, 1 H), 3.14-3.30 (m, 4 H), 3.32 (s, 3 H), 3.35-3.55 (m, 4 H), 3.55-3.62 (m, 1 H), 3.74-3.81 (m, 1 H), 4.40 (s, 1 H), 7.23-7.35 (m, 9 H), 7.39-7.43 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 43.3, 48.5, 52.4, 58.9, 65.1, 71.6, 71.7, 87.3, 127.5, 128.3, 128.7, 143.6, 161.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₃₀N₂O₄Na⁺: 469.2098; found: 469.2090.

( R* )-4-[( S* )-1-Hydroxy-2-(trityloxy)ethyl]-1-(2-hydroxyethyl)imidazolidin-2-one (4l)

Aziridine 1 (0.30 g, 0.80 mmol) provided 4l.

Yield: 0.17 g (50%); white solid; mp 59.8-61.6 ˚C; R _f  = 0.55 (CH₂Cl₂-MeOH, 9:1); t _R  = 2.400 min (99.8%).

IR (film): 3348, 2924, 2878, 1682, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 2.83 (br s, 1 H), 3.03 (br s, 1 H), 3.16-3.34 (m, 6 H), 3.61 (m, 1 H), 3.71 (t, J = 4.9 Hz, 2 H), 3.80 (m, 1 H), 4.63 (s, 1 H), 7.23-7.35 (m, 9 H), 7.40-7.43 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 46.2, 48.1, 52.4, 60.3, 64.8, 71.9, 87.1, 127.3, 128.0, 128.6, 143.5, 162.7.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₂₈N₂O₄Na⁺: 455.1941; found: 455.1939.

(4 R* )-4-[( S* )-1-Hydroxy-2-(trityloxy)ethyl]-1-(2-hydroxypropyl)imidazolidin-2-one (4m)

Aziridine 1 (0.30 g, 0.80 mmol) provided 4m.

Yield: 0.23 g (65%); white solid; mp 50.4-52.1 ˚C; R _f  = 0.24 (EtOAc-MeOH, 98:2); t _R  = 9.917 min (97.8%).

IR (film): 3348, 2924, 2870, 1697, 1682, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 1.14 (d, J = 6.3 Hz, 3 H), 2.94-3.35 (m, 6 H), 3.07 (d, J = 5.6 Hz, 1 H), 3.43-3.60 (m, 2 H), 3.76-3.79 (m, 1 H), 3.81-3.94 (m, 1 H), 4.82 (s, 1 H), 7.22-7.33 (m, 9 H), 7.40-7.43 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 20.5, 20.6, 48.4, 49.2, 51.1, 51.6, 52.2, 52.4, 64.8, 65.7, 66.5, 71.7, 71.8, 87.0, 87.1, 127.1, 127.2, 127.9, 128.0, 128.4, 128.5, 143.3, 143.4, 162.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₃₀N₂O₄Na⁺: 469.2098; found: 469.2095.

(4 R* )-1-(2,3-Dihydroxypropyl)-4-[( S* )-1-hydroxy-2-(trityl­oxy)ethyl]imidazolidin-2-one (4n)

Aziridine 1 (0.30 g, 0.81 mmol) provided 4n.

Yield: 0.27 g (72%); white solid; mp 68.3-70.8 ˚C; R _f  = 0.45 (CH₂Cl₂-MeOH, 9:1); t _R  = 9.450 min (97.8%).

IR (KBr): 3404, 2924, 2877, 1682, 1494, 1449 cm^-¹.

^¹H NMR (500 MHz, CD₃OD): δ = 3.08-3.32 (m, 5 H), 3.49 (m, 2 H), 3.56-3.62 (m, 2 H), 3.71-3.74 (m, 1 H), 3.78-3.83 (m, 1 H), 5.50 (s, 1 H), 7.25-7.35 (m, 9 H), 7.45-7.49 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 46.1, 46.3, 48.8, 49.2, 52.5, 52.6, 64.1, 64.2, 65.0, 70.2, 70.5, 72.2, 72.3, 87.2, 127.4, 128.1, 128.6, 143.7, 163.0, 163.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₃₀N₂O₅Na⁺: 485.2047; found: 485.2039.

4-(1-Hydroxy-2-trityloxyethyl)-1-phenylimidazolidin-2-one (4o)

Aziridine 1 (0.31 g, 0.82 mmol) provided 4o.

Yield: 0.18 g (47%); white solid; mp 198.9-199.4 ˚C; R _f  = 0.34 (hexanes-EtOAc, 1:1); t _R  = 12.058 min (100%).

IR (KBr): 3428, 2883, 1685, 1600, 1500 cm^-¹.

^¹H NMR (300 MHz, DMSO-d ₆): δ = 3.08 (AB dd, J _AB = 34.4 Hz, δ_A = 3.03, J = 9.7, 5.1 Hz, δ_B = 3.13, J = 9.7, 5.8 Hz, 2 H, CH₂), 3.40 (br s, 1 H, OH), 3.54-3.58 (m, 2 H), 3.70-3.82 (m, 2 H), 5.24 (s, 1 H), 6.93-6.98 (m, 2 H), 7.34-7.36 (m, 10 H), 7.41-7.48 (m, 8 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 46.5, 50.8, 65.2, 71.2, 86.1, 116.5, 121.2, 126.9, 127.8, 128.3, 128.5, 140.6, 143.8, 158.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₀H₂₈N₂O₃Na⁺: 487.1991; found: 487.1984.

( R* )-4-[( S* )-1-Hydroxy-2-(trityloxy)ethyl]-1-(4-methoxyphenyl)imidazolidin-2-one (4p)

Aziridine 1 (0.30 g, 0.80 mmol) provided 4p.

Yield: 0.16 g (41%); white solid; mp 233.2-234.4 ˚C; R _f  = 0.37 (hexanes-EtOAc, 1:1); t _R  = 11.825 min (99.0%).

IR (KBr): 3422, 2930, 1693, 1513, 1485 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 2.44 (d, J = 8.1 Hz, 1 H), 3.28 (AB dd, J _AB = 32.4 Hz, δ_A = 3.24, J = 10.0, 4.6 Hz, δ_B = 3.34, J = 9.9, 4.7 Hz, 2 H), 3.68 (AB dd, J _AB = 47.7 Hz, δ_A = 3.61, J = 8.8, 7.2 Hz, δ_B = 3.77, J = 9.0 Hz, 2 H), 3.63-3.69 (m, 1 H), 3.78 (s, 3 H), 3.84-3.89 (m, 1 H), 4.76 (br s, 1 H), 6.86 (d, J = 9.1 Hz, 2 H), 7.24-7.38 (m, 17 H).

^¹³C NMR (75 MHz, DMSO-d₆): δ = 46.8, 50.9, 55.2, 65.2, 71.3, 86.1, 113.8, 118.3, 126.9, 127.8, 128.4, 133.9, 143.8, 154.0, 158.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₃₀N₂O₄Na⁺: 517.2098; found: 517.2089.

Synthesis of Diols 5; General Procedure

To a solution of imidazolidinone 4 in MeOH (0.3 M), Dowex 50 WX8-100 ion-exchange resin (50 wt%) was added at r.t. The reaction mixture was shaken until TLC showed the reaction was complete (18-24 h). The reaction was the filtered, concentrated, and purified by chromatography to provide 5. All diols were analyzed by HPLC (214 nm; 5% MeCN-H₂O, gradient started at 2 min increased to 20% MeCN-H₂O at 5 min and 50% MeCN-H₂O at 10 min, unless otherwise noted).

( R* )-1-Benzyl-4-[( S* )-1,2-dihydroxyethyl]imidazolidin-2-one (5a)

Trityl ether 4a (100 mg, 0.21 mmol) provided 5a.

Yield: 41 mg (82%); white solid; mp 94.2-95.2 ˚C; R _f  = 0.39 (CH₂Cl₂-MeOH, 9:1); t _R  = 11.292 min (99.7%).

IR (KBr): 3356, 2907, 2860, 1690, 1506, 1467 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 3.24 (AB dd, J _AB = 66.1 Hz, δ_A = 3.13, J = 8.9, 6.9 Hz, δ_B = 3.35, J = 9.2 Hz, 2 H), 3.51-3.69 (m, 3 H), 3.73-3.80 (m, 1 H), 4.04 (br s, 1 H), 4.32 (AB d, J _AB = 60.5 Hz, δ_A = 4.24, J = 15.2 Hz, δ_B = 4.40, J = 15.2 Hz, 2 H), 4.67 (br s, 1 H), 6.00 (s, 1 H), 7.21-7.34 (m, 5 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 47.1, 47.4, 52.1, 64.1, 73.3, 127.6, 127.9, 128.7, 136.7, 162.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₁₆N₂O₃Na⁺: 259.1053; found: 259.1050.

( R* )-4-[( S* )-1,2-dihydroxyethyl]-1-hexylimidazolidin-2-one (5c)

Trityl ether 4c (99 mg, 0.21 mmol) provided 5c.

Yield: 44 mg (91%); white solid; mp 108.5-109.8 ˚C; R _f  = 0.24 (CH₂Cl₂-MeOH, 9:1); t _R  = 3.783 min (98.8%).

IR (KBr): 3366, 3060, 2926, 1678, 1505, 1462 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 0.88 (t, J = 6.4 Hz, 3 H), 1.28 (m, 6 H), 1.47 (quint, J = 6.3 Hz, 2 H), 3.00-3.25 (m, 3 H), 3.47-3.60 (m, 3 H), 3.69-3.83 (m, 2 H), 4.44 (br s, 1 H), 4.93 (d, J = 6.2 Hz, 1 H), 5.96 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 14.0, 22.6, 26.4, 27.5, 31.5, 43.3, 47.3, 52.1, 64.0, 73.4, 162.7.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₂₂N₂O₃Na⁺: 253.1523; found: 253.1519.

( R* )-1-Allyl-4-[( S* )-1,2-dihydroxyethyl]imidazolidin-2-one (5h)

Trityl ether 4h (100 mg, 0.23 mmol) provided 5h.

Yield: 41 mg (94%); white solid; mp 116.9-119.1 ˚C; R _f  = 0.16 (CH₂Cl₂-MeOH, 9:1); t _R  = 2.008 min (92.5%).

IR (KBr): 3342, 2928, 2879, 1687, 1498, 1460 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 3.30 (AB dd, J _AB = 76.0 Hz, δ_A = 3.21, J = 8.6, 7.2 Hz, δ_B = 3.46, J = 9.2 Hz, 2 H), 3.55-3.59 (m, 2 H), 3.66-3.73 (m, 2 H), 3.78-3.85 (m, 2 H), 4.48 (br s, 1 H), 4.96 (br d, J = 4.1 Hz, 1 H), 5.16-5.23 (m, 2 H), 5.66-5.79 (m, 1 H), 6.11 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 46.1, 47.1, 52.0, 63.9, 73.5, 117.7, 133.0, 162.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₁₄N₂O₃Na⁺: 209.0897; found: 209.0894.

( R* )-4-[( S* )-1,2-Dihydroxyethyl]-1-(prop-2-yn-1-yl)imidazolidin-2-one (5i)

Trityl ether 4i (100 mg, 0.23 mmol) provided 5i.

Yield: 25 mg (58%); thick oil; R _f  = 0.16 (CH₂Cl₂-MeOH, 9:1); t _R  = 5.216 min (99.0%; ELSD; 50% MeOH-H₂O, gradient started at 5 min, increased to 80% MeOH-H₂O at 10 min).

IR (KBr): 3346, 2923, 2871, 1676, 1494, 1448 cm^-¹.

^¹H NMR (300 MHz, acetone-d ₆): δ = 2.76 (t, J = 2.5 Hz, 1 H), 3.48 (AB dd, J _AB = 59.9 Hz, δ_A = 3.38, J = 8.6, 7.1 Hz, δ_B = 3.58, J = 8.7 Hz, 2 H), 3.58-3.66 (m, 3 H), 3.77-3.84 (m, 1 H), 3.96 (s, 1 H), 3.98 (AB dd, J _AB = 20.2 Hz, δ_A = 3.97, J = 17.6, 2.5 Hz, δ_B = 3.99, J = 17.6, 2.5 Hz, 2 H), 4.22 (d, J = 5.8 Hz, 1 H), 5.88 (s, 1 H).

^¹³C NMR (75 MHz, acetone-d ₆): δ = 33.9, 47.5, 53.3, 64.9, 73.8, 74.8, 80.0, 162.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₁₂N₂O₃Na⁺: 207.0740; found: 207.0741.

Acylation with Anhydrides - Synthesis of Imidazolidin-2-ones 6; General Procedure

To a solution of imidazolidinone 4a and DMAP (10 mol%) in CH₂Cl₂ (1 M) at r.t., a solution of anhydride (105 mol%) in CH₂Cl₂ (1 M) was added. The reaction mixture was stirred for 24 h, concentrated, and purified by chromatography to provide 6. All purified compounds were analyzed by HPLC (214 nm; 30% MeCN-H₂O gradient started at 1 min increased to 90% MeCN-H₂O at 10 min).

( S* )-1-[( R* )-1-Benzyl-2-oxoimidazolidin-4-yl]-2-(trityloxy)ethyl Benzoate (6a)

Alcohol 4a (100 mg, 0.21 mmol) provided 6a.

Yield: 86 mg (71%); white solid; mp 85.4-87.0 ˚C; R _f  = 0.44 (hexanes-EtOAc, 1:1); t _R  = 12.492 min (99.0%).

IR (film): 3225, 3063, 1697, 1596, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 3.19 (AB dd, J _AB = 100.4 Hz, δ_A = 3.0, J = 9.2, 6.1 Hz, δ_B = 3.33, J = 9.3 Hz, 2 H), 3.37 (AB dd, J _AB = 43.0 Hz, δ_A = 3.28, J = 10.8, 4.2 Hz, δ_B = 3.41, J = 10.6, 4.6 Hz, 2 H), 4.15 (dt, J = 10.3, 5.3 Hz, 1 H), 4.25 (AB d, J _AB = 25.5 Hz, δ_A = 4.22, J = 15.0 Hz, δ_B = 4.28, J = 15.0 Hz, 2 H), 4.98 (s, 1 H), 5.11 (dt, J = 4.6 Hz, 1 H), 7.11-7.24 (m, 14 H), 7.34-7.38 (m, 6 H), 7.47 (m, 2 H), 7.60 (m, 1 H), 8.07 (m, 2 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 46.9, 47.6, 50.4, 62.8, 74.4, 87.4, 127.5, 127.6, 128.1, 128.2, 128.6, 128.7, 128.8, 129.7, 130.1, 133.6, 136.8, 143.4, 161.4, 166.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₈H₃₄N₂O₄Na⁺: 605.2411; found: 605.2411.

( S* )-1-[( R* )-1-Benzyl-2-oxoimidazolidin-4-yl]-2-(trityloxy)ethyl Acetate (6b)

Alcohol 4a (100 mg, 0.21 mmol) provided 6b.

Yield: 88 mg (81%); white solid; mp 78.0-80.0 ˚C; R _f  = 0.47 (hexanes-EtOAc, 1:2); t _R  = 12.458 min (98.6%).

IR (film): 3225, 3063, 1744, 1697, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 2.04 (s, 3 H), 3.08 (AB dd, J _AB = 105.0 Hz, δ_A = 2.91, J = 9.2, 6.4 Hz, δ_B = 3.26, J = 9.1 Hz, 2 H), 3.20 (AB dd, J _AB = 29.7 Hz, δ_A = 3.16, J = 10.5, 4.3 Hz, δ_B = 3.24, J = 10.5, 6.2 Hz, 2 H), 4.02 (dt, J = 8.2, 6.5 Hz, 1 H), 4.29 (AB d, J _AB = 26.9 Hz, δ_A = 4.26 J = 14.9 Hz, δ_B = 4.32, J = 14.9 Hz, 2 H), 4.85 (dt, J = 6.1, 4.5 Hz, 1 H), 5.07 (s, 1 H), 7.19-7.37 (m, 20 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 21.1, 46.7, 47.6, 50.2, 62.4, 74.2, 87.3, 127.5, 127.7, 128.2, 128.3, 128.7, 128.8, 137.0, 143.5, 161.5, 170.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₃H₃₂N₂O₄Na⁺: 543.2254; found: 543.2254.

( S* )-1-[( R* )-1-Benzyl-2-oxoimidazolidin-4-yl]-2-(trityloxy)ethyl Isobutyrate (6c)

Alcohol 4a (100 mg, 0.21 mmol) provided 6c.

Yield: 101 mg (88%); white solid; mp 62.7-64.8 ˚C; R _f  = 0.45 (hexanes-EtOAc, 1:1); t _R  = 13.117 min (100.0%).

IR (film): 3225, 3063, 1736, 1697, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 1.15 (d, J = 6.9 Hz, 3 H), 1.17 (d, J = 6.9 Hz, 3 H), 2.57 (sept, J = 7.0 Hz, 1 H), 3.04 (AB dd, J _AB = 104.6 Hz, δ_A = 2.87, J = 9.2, 6.6 Hz, δ_B = 3.22, J = 9.2 Hz, 2 H), 3.20 (AB dd, J _AB = 50.5 Hz, δ_A = 3.12, J = 10.5, 4.4 Hz, δ_B = 3.27, J = 10.5, 4.4 Hz, 2 H), 3.94-4.06 (m, 1 H), 4.28 (AB d, J _AB = 25.4 Hz, δ_A = 4.25, J = 14.9 Hz, δ_B = 4.30, J = 14.9 Hz, 2 H), 4.79 (s, 1 H), 4.85 (dt, J = 5.8, 4.4 Hz, 1 H), 7.18-7.31 (m, 14 H), 7.34-7.38 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 19.2, 34.3, 46.7, 47.6, 50.3, 62.5, 73.9, 87.2, 127.5, 127.7, 128.2, 128.3, 128.7, 128.8, 136.9, 143.5, 161.5, 176.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₆N₂O₄Na⁺: 571.2567; found: 571.2568.

( E )-( S* )-1-[( R* )-1-Benzyl-2-oxoimidazolidin-4-yl]-2-(trityl­oxy)ethyl But-2-enoate (6d)

Alcohol 4a (100 mg, 0.21 mmol) provided 6d.

Yield: 102 mg (89%); yellow solid; mp 61.4-63.4 ˚C; R _f  = 0.48 (hexanes-EtOAc, 1:1); t _R  = 12.242 min (100.0%).

IR (film): 3225, 3063, 1797, 1659, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 1.90 (dd, J = 6.9, 1.6 Hz, 3 H), 3.09 (AB dd, J _AB = 98.3 Hz, δ_A = 2.93, J = 9.2, 6.3 Hz, δ_B = 3.26, J = 9.3 Hz, 2 H), 3.26 (AB dd, J _AB = 39.0 Hz, δ_A = 3.17, J = 10.4, 4.2 Hz, δ_B = 3.29, J = 10.4, 4.8 Hz, 2 H), 4.05 (dt, J = 9.0, 6.2 Hz, 1 H), 4.28 (AB d, J _AB = 18.6 Hz, δ_A = 4.27, J = 15.1 Hz, δ_B = 4.29, J = 15.1 Hz, 2 H), 4.89-4.94 (m, 2 H), 5.88 (dd, J = 15.5, 1.7 Hz, 1 H), 7.01 (dq, J = 22.4, 6.9 Hz, 1 H), 7.18-7.38 (m, 20 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 18.1, 46.5, 47.3, 50.0, 62.3, 73.5, 87.0, 122.0, 127.2, 127.4, 127.9, 128.4, 128.5, 136.7, 143.2, 146.1, 161.2, 165.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₅H₃₄N₂O₄Na⁺: 569.2411; found: 569.2410.

Synthesis of Carbamates 7; General Procedure

A solution of imidazolidinone 4a, isocyanate (150 mol%), and freshly purified CuCl (500 mol%) in CH₂Cl₂ (1 M) was stirred for 24 h. The solids were filtered off, and the filtrate was concentrated and purified by chromatography to provide 7.

( S* )-1-[( R* )-1-Benzyl-2-oxoimidazolidin-4-yl]-2-(trityloxy)ethyl Phenylcarbamate (7a)

Alcohol 4a (100 mg, 0.21 mmol) provided 7a.

Yield: 106 mg (85%); yellow solid; mp 113.4-114.0 ˚C; R _f  = 0.51 (hexanes-EtOAc, 1:1); t _R  = 13.108 min (100.0%).

IR (film): 3271, 3063, 1736, 1697, 1597, 1551, cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 3.14 (AB dd, J _AB = 85.2 Hz, δ_A = 2.97, J = 9.1, 6.3 Hz, δ_B = 3.25, J = 9.0 Hz, 2 H), 3.28 (AB dd, J _AB = 45.1 Hz, δ_A = 3.24, J = 10.5, 4.1 Hz, δ_B = 3.37, J = 10.5, 4.7 Hz, 2 H), 4.02 (dt, J = 9.1, 6.2 Hz, 1 H), 4.24 (AB d, J _AB = 29.2 Hz, δ_A = 4.22, J = 15.1 Hz, δ_B = 4.26, J = 15.1 Hz, 2 H), 4.77 (dt, J = 5.5, 4.4 Hz, 1 H), 5.83 (s, 1 H), 7.03 (m, 1 H), 7.13-7.27 (m, 16 H), 7.37-7.39 (m, 8 H), 7.55 (br s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 46.8, 47.4, 50.4, 62.8, 74.8, 87.1, 118.8, 123.4, 127.2, 127.5, 127.8, 127.9, 128.5, 128.6, 129.0, 136.6, 137.9, 143.3, 152.9, 161.7.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₈H₃₅N₃O₄Na⁺: 620.2520; found: 620.2507.

( S* )-1-[( R* )-1-Benzyl-2-oxoimidazolidin-4-yl]-2-(trityloxy)ethyl Butylcarbamate (7b)

Alcohol 4a (100 mg, 0.21 mmol) provided 7b.

Yield: 75 mg (62%); white solid; mp 74.0-75.4 ˚C; R _f  = 0.29 (hexanes-EtOAc, 1:1); t _R  = 13.000 min (100.0%).

IR (film): 3302, 3063, 1697, 1535, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 0.92 (t, J = 7.2 Hz, 3 H), 1.26-1.52 (m, 4 H), 3.11 (AB dd, J _AB = 90.5 Hz, δ_A = 2.96, J = 9.2, 6.2 Hz, δ_B = 3.26, J = 9.2 Hz, 2 H), 3.08-3.31 (m, 4 H), 3.97 (dt, J = 8.9, 5.8 Hz, 1 H), 4.29 (s, 2 H), 4.73 (d, J = 4.7 Hz, 1 H), 4.91 (t, J = 5.8 Hz, 1 H), 4.97 (s, 1 H), 7.19-7.38 (m, 20 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 13.6, 13.7 (CH₃), 19.8, 19.9, 31.9, 32.2, 40.3, 40.8, 46.6, 47.3, 50.2, 62.7, 73.9, 86.9, 127.2, 127.4, 127.8, 127.9, 128.4, 128.5, 136.8, 143.3, 155.6, 161.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₆H₃₉N₃O₄Na⁺: 600.2833; found: 600.2820.

( S* )-1-[( R* )-1-Benzyl-2-oxoimidazolidin-4-yl]-2-(trityloxy)ethyl (4-Cyanophenyl)carbamate (7c)

Alcohol 4a (100 mg, 0.21 mmol) provided 7c.

Yield: 79 mg (61%); white solid; mp 121.2-123.0 ˚C; R _f  = 0.46 (hexanes-EtOAc, 1:2); t _R  = 12.700 min (99.8%).

IR (film): 3256, 3063, 1728, 1697, 1604, 1535, 1489, 1450 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 3.12 (AB dd, J _AB = 89.9 Hz, δ_A = 2.96, J = 9.3, 6.5 Hz, δ_B = 3.27, J = 9.4 Hz, 2 H), 3.32 (AB dd, J _AB = 51.8 Hz, δ_A = 3.24, J = 10.6, 3.7 Hz, δ_B = 3.40, J = 10.7, 4.5 Hz, 2 H), 4.05 (dt, J = 9.2, 6.7 Hz, 1 H), 4.20 (AB d, J _AB = 58.8 Hz, δ_A = 4.12, J = 15.2 Hz, δ_B = 4.29, J = 15.2 Hz, 2 H), 4.73 (dt, J = 6.3, 4.0 Hz, 1 H), 6.23 (s, 1 H), 7.07-7.10 (m, 2 H), 7.16-7.26 (m, 12 H), 7.35-7.38 (m, 6 H), 7.43 (d, J = 8.8 Hz, 2 H), 7.50 (d, J = 8.8 Hz, 2 H), 8.68 (s, 1 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 46.8, 47.2, 50.5, 62.7, 75.7, 87.2, 105.8, 118.4, 119.1, 127.3, 127.6, 128.0, 128.5, 128.7, 133.1, 136.2, 142.7, 143.2, 152.6, 162.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₉H₃₄N₄O₄Na⁺: 645.2472; found: 645.2468.

Synthesis of Alcohols 8; General Procedure

To a solution of compound 6 or 7 in CH₂Cl₂ (0.1 M) was added dropwise HCl (1.2 M in EtOAc, 130 mol%). The reaction mixture was stirred at r.t. for 30 min, then saturated aqueous NaHCO₃ was added dropwise to pH 8. The aqueous phase was extracted with CH₂Cl₂-i-PrOH (3:1). The combined organic layers were washed with brine, dried over MgSO₄, concentrated, and purified by chromatography to afford 8.

( S* )-1-[( R* )-1-Benzyl-2-oxoimidazolidin-4-yl]-2-hydroxyethyl Benzoate (8a)

Trityl ether 6a (40 mg, 0.068 mmol) provided 8a.

Yield: 13 mg (56%); white solid; mp 45.7-48.3 ˚C; R _f  = 0.45 (CH₂Cl₂-MeOH, 9:1); t _R  = 7.967 min (97.5%; 214 nm; 30% MeCN-H₂O, gradient started at 1 min increased to 90% MeCN-H₂O at 10 min).

IR (KBr): 3423, 3065, 2360, 1691, 1497 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 2.56 (t, J = 5.7 Hz, 1 H), 3.32 (AB dd, J _AB = 96 Hz, δ_A = 3.16, J = 9.2, 5.9 Hz, δ_B = 3.48, J = 9.3 Hz, 2 H), 3.81-4.00 (m, 2 H), 4.15 (m, 1 H), 4.31 (AB d, J _AB = 27 Hz, δ_A = 4.26, J = 15.0 Hz, δ_B = 4.35, J = 15.0 Hz, 2 H), 5.04 (q, J = 4.0 Hz, 1 H), 5.30 (br s, 1 H), 7.16 (m, 5 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.60 (t, J = 7.4 Hz, 1 H), 8.04 (d, J = 8.3 Hz, 2 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 46.9, 47.4, 50.5, 62.6, 75.5, 127.5, 127.9, 128.6, 129.3, 129.9, 133.6, 136.5, 161.5, 166.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₂₀N₂O₄Na⁺: 363.1315; found: 363.1314.

( S* )-1-[( R* )-1-Benzyl-2-oxoimidazolidin-4-yl]-2-hydroxyethyl Isobutyrate (8b)

Trityl ether 6c (47 mg, 0.085 mmol) provided 8b.

Yield: 18 mg (69%); thick oil; R _f  = 0.38 (EtOAc-MeOH, 10:1); t _R  = 17.858 min (93.8%; 254 nm; 5% MeCN-H₂O, gradient started at 2 min increased to 20% MeCN-H₂O at 5 min and 50% MeCN-H₂O at 10 min).

IR (KBr): 3395, 2974, 2361, 1733, 1694, 1496, 1453 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 1.15 (d, J = 6.9, 6 H), 2.56 (m, 1 H), 3.16 (dd, J = 9.0, 6.1 Hz, 1 H), 3.38 (m, 2 H), 3.68 (m, 2 H), 4.09 (AB dd, J = 38.8 Hz, δ_A = 4.02, J = 11.7, 5.1 Hz, δ_B = 4.15, J = 11.8, 4.1 Hz, 2 H), 4.36 (AB d, J = 41.3, δ_A = 4.29, J = 15, δ_B = 4.43, J = 15 Hz, 2 H), 5.26 (br s, 1 H), 7.24-7.36 (m, 5 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 18.9, 33.9, 46.5, 47.4, 51.6, 65.2, 71.1, 127.6, 128.0, 128.7, 136.6, 161.7, 177.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₂₂N₂O₄Na⁺: 329.1472; found: 329.1465.

( S* )-1-[( R* )-1-Benzyl-2-oxoimidazolidin-4-yl]-2-hydroxyethyl Phenylcarbamate (8c)

Trityl ether 7a (45 mg, 0.075 mmol) provided 8c.

Yield: 20 mg (73%); white solid; mp 162.5-163.5 ˚C; R _f  = 0.40 (CH₂Cl₂-MeOH, 9:1); t _R  = 8.125 min (97.1%; 214 nm; 30% MeCN-H₂O, gradient started at 1 min increased to 90% MeCN-H₂O at 10 min).

IR (KBr): 3403, 3065, 2430, 1689, 1603, 1502 cm^-¹.

^¹H NMR (300 MHz, CD₃OD): δ = 3.36 (AB dd, J _AB = 81.0 Hz, δ_A = 3.23, J = 9.4, 5.8 Hz, δ_B = 3.50, J = 9.5 Hz, 2 H), 3.72 (AB dd, J _AB = 16.3 Hz, δ_A = 3.69, J = 11.8, 5.5 Hz, δ_B = 3.74, J = 11.5, 4.8 Hz, 2 H), 4.04 (m, 1 H), 4.34 (AB d, J = 76.1, 15.1 Hz, 2 H), 4.80 (q, J = 4.9 Hz, 1 H), 4.89 (br s, 1 H), 7.05 (t, J = 7.3 Hz, 1 H), 7.15-7.32 (m, 8 H), 7.44 (d, J = 7.8 Hz, 1 H).

^¹³C NMR (75 MHz, CD₃OD): δ = 47.9, 48.1, 51.2, 62.1, 76.9, 119.8, 124.1, 128.5, 128.8, 129.7, 129.8, 138.2, 140.1, 155.3, 164.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₂₁N₃O₄Na⁺: 378.1424; found: 378.1423.

( S* )-1-[( R* )-1-Benzyl-2-oxoimidazolidin-4-yl]-2-hydroxyethyl Butylcarbamate (8d)

Trityl ether 7b (31 mg, 0.053 mmol) provided 8d.

Yield: 16 mg (84%); white solid; mp 121.8-123.8 ˚C; R _f  = 0.30 (EtOAc-MeOH, 10:1); t _R  = 17.533 min (98.0%; 254 nm; 5% MeCN-H₂O, gradient started at 2 min increased to 20% MeCN-H₂O at 5 min and 50% MeCN-H₂O at 10 min).

IR (KBr): 3367, 3085, 2373, 1694, 1533, 1451 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 0.90 (t, J = 7.2 Hz, 3 H), 1.30 (sext, J = 7.2 Hz, 2 H), 1.44 (m, 2 H), 3.08-3.15 (m, 3 H), 3.42 (t, J = 9.27, 1 H), 3.70-3.79 (m, 3 H), 3.90-3.97 (m, 1 H), 4.33 (s, 2 H), 4.58-4.60 (m, 1 H), 5.61 (t, J = 5.6 Hz, 1 H), 6.07 (s, 1 H), 7.22-7.33 (m, 5 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 13.8, 19.9, 31.8, 40.9, 46.9, 47.3, 50.5, 62.9, 76.4, 127.6, 127.9, 128.7, 136.6, 156.5, 162.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₂₅N₃O₄Na⁺: 358.1737; found: 358.1725.

Acknowledgment

We thank the National Institutes of Health (GM073188) for support of this work. We also thank Ohio University for support of the BioMolecular Innovation and Technology Project.

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  Search in Google Scholar
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  Search in Google Scholar
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  Search in Google Scholar
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  Search in Google Scholar
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  Search in Google Scholar
• 1f Arasappan A, Parekh T, Njoroge FG, Girijavallabhan VM, and Ganguily A. K. inventors; PCT Int. Appl.  WO2001US22828.  ; Chem. Abstr. 2002, 136, 135031
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