Synthesis of Chiral Five-, Six-, and Seven-Membered Heterocycles from (S)-3-Hydroxy-γ-butyrolactone

Abstract

Chiral small molecules such as amino alcohols and their heterocyclic derivatives are useful building blocks for asymmetric synthesis and the preparation of biologically active compounds. Using a common starting material derived from carbohydrate, the (S)-3-hydroxy-γ-butyrolactone, we have synthesized several five-, six-, and seven-membered nitrogen-containing chiral heterocycles. These include (S)-3-benzyloxypyrrolidine, a protected 6-substituted morpholin-3-one and its homologous 1,4-oxazepan-3-one, and 6-trityloxymethyl tetrahydro-1,3-oxazine-2-thiones. These chiral small heterocycles were synthesized from the lactone via efficient cyclization reactions. Their syntheses and characterization are reported here.

Chiral nitrogen and oxygen-containing heterocycles are important intermediates for the preparation of many biologically active compounds including natural products and medicinally relevant molecules. Among these, five- and six-membered-ring heterocycles are especially useful either as core structures for biologically active molecules [¹] or as ligands for asymmetric synthesis. [²] [³] Among five-membered-ring heterocycles, functionalized 3-hydroxypyrrolidines are very useful moieties found in many biologically interesting compounds. [4] [5] Figure  [¹] shows several examples of medicinally active compounds containing various heterocyclic structures. Compounds 1 and 2 contain the 3-hydroxypyrrolidine core structure. The cyclohexylpyrrolidinol 1 and its analogues are ion channel modulating compounds and are also useful for the treatment of arrhythmia. [4] Compound 2 is a human 5-HT_1D receptor antagonist, which has significance in neurological disorder treatment. [5] Several other disubstituted pyrrolidines also exhibit both serotonergic activity [6] and phosphodiesterase 10A inhibition. [7] The six-membered-ring morpholinones or morpholines contained in compounds 3-6 are heterocyclic compounds that are of medicinal importance as well; they are present in many drug classes either as core structures or as functional groups that improve pharmacokinetic properties. [8] Compound 3 is a selective rat 5-hydroxytryptamine_1B (5-HT_1B) receptor antagonist. [9] The aminomethyl morpholine 4 has shown activity against checkpoint kinase 1 (CHK1), [¹0] and may have applications in anticancer therapies. Another important class of nitrogen containing heterocycles is the cyclic carbamates. These functional groups are also found in several drug molecules, for instance, 5-aminomethyl oxazolidinone is the core structure of the orally available factor Xa inhibitor rivaroxaban (5) [¹¹] and antibacterial agent linezolid (6). [¹²] We have previously demonstrated that the 6-aminomethyloxazinan-2-one derivatives also have important antibacterial activities. [¹] [¹³] Other oxazinan-2-one compounds have been explored as inhibitors of the 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which may have implications in the treatment of obesity and insulin resistance. Compound 7 is an example of this class of compounds. [¹4] The analogous thiocarbamate functional group also has shown interesting biological relevance. Compound 8 is a nonsteroidal progesterone receptor agonist; its fluorinated analogues have been applied in breast tumor imaging. [¹5] [¹6]

Because of their importance in the preparation of biologically active compounds, there have been many studies for the synthesis of these heterocycles and their derivatives. [¹7-³²] Chiral amino alcohols are often used for the synthesis of heterocycles that are of biological relevance or that are used as ligands for asymmetric synthesis. In recent years, a versatile building block, (S)-3-hydroxy-γ-butyrolactone, has found many applications in organic synthesis. It is a commercially available compound that can be synthesized readily in large scale from carbohydrate feed stock such as starch or lactose. [³³] The lactone has been converted into 1,2- and 1,3-amino alcohols and their derivatives via very efficient methods. [³4] [³5] Using the (S)-3-hydroxy-γ-butyrolactone (9) as the starting material, we report here new and efficient synthetic routes to several protected small molecule heterocycles including the protected five-membered-ring pyrrolidine 10, 6-hydroxymethylmorpholin-3-one 11, 7-hydroxymethyl-1,4-oxazepan-3-one 12, and the six-membered-ring oxazinan-2-thione 13 (Figure  [²] ).

The protected 3-hydroxypyrrolidine 10 can be synthesized from the lactone in a few steps. As shown in Scheme  [¹] , the lactone was protected with a benzyl group under slightly acidic conditions to give compound 14a, ring-opening with ammonia in water afforded the amide 15a in nearly quantitative yield. Subsequent reduction of the amide afforded the key intermediate 1,4-amino alcohol 16a. Protection of the primary amino group in 16a gave trifluoroacetamide 17, which was then converted into the mesylate 18. Treating 18 with sodium hydride in THF directly produced the desired protected product (S)-3-benzyloxypyrrolidine (10). The trifluoromethyl group was released during the workup procedure. This procedure of converting the lactone into the protected pyrrolidine is very efficient and nearly all steps gave good to excellent yields. Therefore, this is a new and convenient route for the synthesis of pyrrolidine derivatives from carbohydrate raw materials.

During the synthesis, we also attempted to prepare a seven-membered-ring cyclic carbamate 19. We had hoped that direct treatment of the 1,4-amino alcohol 16 with 1,1′-carbonyldiimidazole (CDI) would afford compound 19, similarly to our previous synthesis of the six-membered-ring oxazinan-2-one by cyclization of the corresponding 1,3-amino alcohol. [²7] However, this cyclization reaction did not work for the 1,4-amino alcohol 16. Other methods of forming the cyclic carbamate were then tried in several attempts, including the conversion of the amino group into the corresponding open-chain carbamate using benzyl chloroformate or Boc anhydride, followed by base treatment to afford the cyclization product. However, none of these conditions were able to produce the seven-membered-ring carbamate 19.

The benzyl protecting group was optimal for the scheme. The hydroxy group of the lactone could be protected using trityl chloride to afford compound 14b, and the subsequent ammonia ring-opening gave compound 15b in excellent yield. However, reduction of amide 15b using LiAlH₄ did not afford the desired amino alcohol product 16b, instead, the amide decomposed rapidly under LiAlH₄ treatment, mostly leading to eliminated intermediates and intractable mixture of by-products. We speculate that the trityl group is too bulky for the reaction to proceed as planned; under even mild basic conditions, elimination is favored over reduction. The benzyl group, on the other hand, causes much less steric hindrance and the amide reduction could be carried out successfully.

From amino alcohol 20, [²6] which was synthesized from the lactone 9, 3,6-disubstituted 3-morpholinones can be synthesized (Scheme  [²] ). Treating compound 20 with a slight excess of bromoacetic anhydride afforded the O- and N-acylated product, and the ester was selectively hydrolyzed using sodium bicarbonate at room temperature to give β-hydroxyamide 21 quantitatively. It was then cyclized using sodium hydroxide in dichloromethane under refluxing condition to afford the trityl-protected morpholinone 11. Other conditions were tried for the cyclization of 21 such as using K₂CO₃, Na₂CO₃, and NaOH in THF, which all failed to give the desired product in good yield. The trityl group can be removed to afford the free 6-hydroxymethylmorpholin-3-one (22) in excellent yield, giving us a free hydroxy group that can be further functionalized. The nitrogen in 11 can be functionalized as well by N-alkylation, reductive amination, or N-arylation reactions to synthesize thrombin inhibitor analogous to compound 1. The morpholinone can also be reduced to give the corresponding 6-trityl-protected hydroxymethylmorpholine 23, another useful moiety in the synthesis of biologically active compounds.

Seven-membered homologues of 11 were also synthesized using a similar method. As shown in Scheme  [³] , amino alcohol 24 was converted into the corresponding bromoacetamide 25, followed by an intramolecular SN₂ reaction to afford the 7-trityl-protected hydroxymethyl-1,4-oxazepan-3-ones 12 (≡ 26a) and 26b. When R = H, the cyclization reaction worked well, however, when R = Bn, the cyclization from the bromo compound gave a poorer yield of 26b, probably due to steric hindrance of the benzylamide. However, this issue can be circumvented by alkylating the already cyclized oxazepan-3-one 12 (≡ 26a) to obtain substituted products such as 26c and 26d in good yields. These novel seven-membered-ring heterocycles are expected to be valuable building blocks in the synthesis of biologically active compounds.

Besides the cyclic amides, several sulfur-containing cyclic carbamate derivatives were also synthesized using amino alcohols derived from the lactone 9. As shown in Scheme  [4] , treating amino alcohol 24a with thiocarbonyldiimidazole (TCDI) afforded the trityl-protected 6-trityl­oxymethyltetrahydro-1,3-oxazine-2-thione 13 smoothly in 88% yield. From this compound, we attempted alkylation on the nitrogen to obtain the N-ethyl-alkylated compound 28, however, the reaction only led to the sulfur-alkylated product 27 as the main product. An alternative route was then used for the preparation of N-alkylated analogues. Starting from the amino alcohol 24c, cyclization with TCDI afforded the ethyl-substituted product 28. Deprotection of the trityl group led to compound 29, which can be converted into the corresponding mesylate and then alkylated with various halides to generate a small molecule library for the screening of biological activities.

In conclusion, using amino alcohols derived from (S)-3-hydroxy-γ-butyrolactone, we have synthesized several nitrogen-containing heterocycles. These include the (S)-3-benzyloxypyrrolidine, which was obtained from the corresponding 1,4-amino alcohol. Starting from 1,3-amino alcohol derivatives obtained from the lactone, 6-hydroxymethylthiaoxazinanone, 6-hydroxymethylmorpholin-3-one, and 7-hydroxymethyl[1,4]oxazepan-3-one were synthesized efficiently. Since the lactone 9 can be prepared from readily available starch or lactose in a one-pot reaction, the methods reported here represent access to important chiral molecules using affordable and renewable carbohydrates as starting materials. These compounds are expected to be useful in the preparation of medicinally important compounds.

General chemicals and reagents were purchased from Sigma-Aldrich or VWR International and used directly. The optically pure lactone was provided by Afid Therapeutics. NMR spectra were recorded using a 400 MHz Varian NMR spectrometer and a Bruker 250 MHz NMR spectrometer. High-resolution mass spectrometry data were measured on the Q-Tof UE521 of the Mass Spectrometry lab at the University of Illinois at Urbana Champaign after the low-resolution masses were confirmed. The ionization technique used was ESI (electrospray ionization) in ES+ mode. Melting points were measured using a Fisher-Jones melting point apparatus. Optical rotations were measured using a Rudolph Autopol III 6768MFG 1991 polarimeter; the concentrations reported here are in g/100 mL.

( S )-3-Benzyloxy-γ-butyrolactone (14a)

(S)-3-Hydroxy-γ-butyrolactone (9; 0.400 g, 4.90 mmol) was dissolved in 1,4-dioxane (5 mL) in a round-bottomed flask. Then, benzyl 2,2,2-trichloroacetimidate (1.48 g, 5.88 mmol) and trifluoroacetic acid (0.056 g, 0.49 mmol) were added to the flask. The reaction mixture was stirred at r.t. for 16 h, and then partitioned between EtOAc (150 mL) and H₂O (100 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (2 × 200 mL). The combined organic phases were washed with brine (200 mL) and dried (Na₂SO₄). The solvent was removed on a rotovap and the residue was purified by silica gel flash column chromatography (hexane-EtOAc, 4:1). The pure product was obtained as a colorless oil; yield: 0.64 g (85%, 3.33 mmol); [α]_D ^²5 -27.6 (c = 1.2, CHCl₃).

^¹H NMR (400 MHz, CDCl₃): δ = 7.30-7.38, (m, 5 H), 4.56 (d, J = 11.7 Hz, 1 H), 4.52 (d, J = 11.7 Hz, 1 H), 4.34-4.40 (m, 3 H), 2.60-2.72 (m, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 175.5, 136.9, 128.6, 128.2, 127.7, 73.8, 73.1, 71.2, 35.0.

The NMR data matched with the values reported in the literature. [³6]

( S )-3-Trityloxy-γ-butyrolactone (14b)

To a stirred solution of 9 (1.00 g, 9.8 mmol) in THF (20 mL) were added trityl chloride (3.00 g, 10.8 mmol) and pyridine (1.74 mL, 19.6 mmol). The reaction mixture was stirred at 50 ˚C for 48 h, after which the reaction mixture was partitioned between EtOAc (200 mL) and H₂O (150 mL). The aqueous phase was extracted with EtOAc (2 × 200 mL). The organic phases were combined, washed with brine (100 mL), and dried (Na₂SO₄). After filtration and concentration of the solution on the rotavap, the crude residue was purified by silica gel flash column chromatography using a gradient of hexane-EtOAc (16:1 to 6:1) to give the final compound as a white solid; yield: 3.27 g (97%, 9.49 mmol); mp 92-93 ˚C; [α]_D ^²5 -10.1 (c = 10, EtOAc).

^¹H NMR (400 MHz, CDCl₃): δ = 7.52-7.43 (m, 6 H), 7.40-7.28 (m, 9 H), 4.51 (m, 1 H), 3.86 (dd, J = 5.9, 9.9 Hz, 1 H), 3.80 (dd, J = 4.4, 9.9 Hz, 1 H), 2.34 (dd, J = 5.5, 17.9 Hz, 1 H), 2.29 (dd, J = 7.0, 17.9 Hz, 1 H).

^¹³C NMR (101 MHz, CDCl₃): δ = 175.3, 143.6, 128.4, 128.1, 127.5, 87.8, 73.3, 69.4, 35.6.

HRMS: m/z calcd for C₂₃H₂₀O₃ + Na [M + Na]⁺: 367.1310; found: 367.1310.

( S )-3-Benzyloxy-4-hydroxybutanamide (15a)

To a solution of 14a (600 mg, 3.12 mmol) in THF (5 mL) was added NH₄OH (218 mg, 6.24 mmol) and the reaction mixture was stirred overnight. The mixture was diluted with CH₂Cl₂ (25 mL) and the solvent phases were separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 25 mL). The combined organic phases were washed with brine (20 mL) and dried (Na₂SO₄). After filtration, the solution was concentrated on a rotovap. The obtained residue was purified using silica gel flash chromatography (hexane-EtOAc, 3:1) to afford the pure product as a semi-solid; yield: 1.06 g (98%, 5.06 mmol); [α]_D ^²5 -23.4 (c = 1.3, CHCl₃).

^¹H NMR (400 MHz, CDCl₃): δ = 7.30-7.37 (m, 5 H), 4.61 (s, 2 H), 3.93-3.98 (m, 1 H), 3.78 (dd, J = 4.0, 11.7 Hz, 1 H), 3.62 (dd, J = 4.3, 11.7 Hz, 1 H), 2.48-2.58 (m, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 173.3, 137.7, 128.6, 128.0, 127.9, 76.6, 72.2, 63.5, 38.2.

HRMS: m/z calcd for C₁₁H₁₅NO₃ + Na [M + Na]⁺: 232.0950; found: 232.0948.

( S )-4-Hydroxy-3-(trityloxy)butanamide (15b)

To a stirred solution of 14b (1.00 g, 2.80 mmol) in THF (10 mL) was added NH₄OH (0.969 mL, 27.7 mmol). The reaction mixture was stirred at r.t. overnight, then diluted with CH₂Cl₂ (100 mL), and the organic layer was washed with H₂O (70 mL). The aqueous layer was extracted with CH₂Cl₂ (2 × 100 mL). The organic phases were combined, washed with brine (50 mL), and dried (Na₂SO₄). After filtration and concentration on the rotovap, the crude mixture was purified by silica gel flash chromatography using a gradient of hexane-CH₂Cl₂-acetone (8:1:1 to 2:1:1) to give the pure product as a semi-solid; yield: 1.03 g (99%, 2.84 mmol); mp 135.0-136.0 ˚C; [α]_D ^²5 +14.2 (c = 1.7, EtOAc).

^¹H NMR (400 MHz, CDCl₃): δ = 7.49 (d, J = 7.3 Hz, 6 H), 7.30 (m, 9 H), 5.52 (s, 2 H, NH₂), 4.00 (m, 1 H), 3.52 (m, 2 H), 2.91 (m, 1 H, OH), 2.02 (dd, J = 3.7, 14.7 Hz, 1 H), 1.94 (dd, J = 7.0, 14.7 Hz, 1 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 173.7, 144.3, 128.7, 128.1, 127.4, 87.4, 70.8, 64.3, 38.4.

HRMS: m/z calcd for C₂₃H₂₄NO₃ [M + H]⁺: 362.1756; found: 362.1769.

( S )-4-Amino-2-(benzyloxy)butan-1-ol (16a)

To a stirred suspension of LiAlH₄ (0.0597 g, 11.9 mmol) in anhyd THF (10 mL) at 0 ˚C was added slowly the amide 15a (0.500 g, 2.39 mmol). The solution was brought to r.t. and refluxed for 6 h under anhydrous conditions. The reaction was quenched with cold MeOH (10 mL) and diluted with CH₂Cl₂ (20 mL). The solution was filtered through a pad of Celite and concentrated on the rotovap. The crude product was purified by silica gel flash chromatography (2% MeOH in CH₂Cl₂) to afford pure amino alcohol 16a as a semi-solid; yield: 0.370 g (79%, 1.88 mmol); [α]_D ^²5 -18.7 (c = 1.0, CHCl₃).

^¹H NMR (400 MHz, CDCl₃): δ = 7.27-7.34 (m, 5 H), 4.54-4.62 (m, 2 H), 3.65 (dd, J = 5.4, 11.7 Hz, 1 H), 3.62 (dd, J = 4.0, 11.7 Hz, 1 H), 3.56 (q, J = 5.1 Hz, 1 H), 2.89-2.96 (m, 1 H), 2.72-2.78 (m, 1 H), 1.68-1.86 (m, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 138.5, 128.4, 127.7, 127.6, 78.0, 71.1, 63.6, 37.6, 35.3.

HRMS: m/z calcd for C₁₁H₁₈NO₂ [M + H]⁺: 196.1338; found: 196.3333.

( S )- N -[3-(Benzyloxy)-4-hydroxybutyl]-2,2,2-trifluoroacetamide (17)

Compound 16a (0.100 g, 0.510 mmol) was dissolved in THF (2.50 mL) and cooled to 0 ˚C in an ice-bath. Ethyl trifluoroacetate (0.060 mL, 1.0 mmol) was added to the solution and the mixture was stirred at 0 ˚C for 10 min, by which time the reaction was complete. The reaction was quenched by the addition of ice-cold H₂O (5 mL) and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic phases were dried (Na₂SO₄). After filtration and concentration on the rotovap, the crude residue was purified by silica gel flash chromatography using a gradient of hexane-EtOAc (12:1 to 6:1) to afford the pure product as a colorless liquid; yield: 0.143 g (96%, 0.49 mmol); [α]_D ^²5 -22.5 (c = 1, EtOAc).

^¹H NMR (400 MHz, CDCl₃): δ = 7.29-7.50 (m, 5 H), 4.68 (d, J = 11.5 Hz, 1 H), 4.55 (d, J = 11.5 Hz, 1 H), 3.84 (dd, J = 7.3, 4.7 Hz, 1 H), 3.48-3.69 (m, 2 H), 3.29-3.45 (m, 1 H), 1.83-1.93 (m, 1 H), 1.65-1.82 (m, 1 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 157.6, 157.3, 156.9, 156.5, 137.5, 128.7, 128.2, 128.0, 120.1, 117.2, 114.3, 111.5, 77.8, 71.8, 63.3, 37.0, 30.0.

HRMS: m/z calcd for C₁₃H₁₆F₃NO₃ + Na [M + Na]⁺: 314.0980; found: 314.0986; m/z calcd for C₁₃H₁₇F₃NO₃ [M + H]⁺: 292.1161; found: 292.1164.

( S )-2-Benzyloxy-4-(2,2,2-trifluoroacetamido)butyl Methanesulfonate (18)

Compound 17 (0.150 g, 0.51 mmol) was mixed with pyridine (0.41 mL, 5.1 mmol) in anhyd THF (2.00 mL). The solution was cooled to 0 ˚C and MsCl (0.120 mL, 1.53 mmol) was added and the mixture was stirred at r.t. overnight. The mixture was diluted with CH₂Cl₂ (20 mL) and washed with H₂O (3 × 5 mL). The combined organic phases were dried (Na₂SO₄). After filtration and concentration on the rotovap, the crude residue was purified by silica gel flash chromatography with a gradient of hexane-EtOAc (12:1 to 6:1). The pure product was obtained as a colorless liquid; yield: 0.16 g (85%, 0.43 mmol); [α]_D ^²5 -20.2 (c = 1.3, EtOAc).

^¹H NMR (400 MHz, CDCl₃): δ = 7.45-7.30 (m, 5 H), 6.70 (s, 1 H), 4.75 (d, J = 11.4 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 1 H), 4.35 (dd, J = 4.4, 11.0 Hz, 1 H), 4.23 (dd, J = 4.7, 11.0 Hz, 1 H), 3.78 (td, J = 8.4, 4.2 Hz, 1 H), 3.52 (ddd∼dt, J = 6.6, 13.2 Hz, 1 H), 3.35 (ddd∼dt, J = 5.4, 6.6, 13.2 Hz, 1 H), 3.03 (s, 3 H), 1.76-1.94 (m, 2 H).

^¹³C NMR (101 MHz, CDCl₃): δ = 157.3, 156.9, 136.9, 128.7, 128.5, 128.3, 117.1, 114.0, 74.9, 72.5, 69.5, 37.6, 36.8, 30.2.

HRMS: m/z calcd for C₁₄H₁₉F₃NO₅S [M + H]⁺: 370.0936; found: 370.0936.

( S )-3-(Benzyloxy)pyrrolidine (10) [³7]

The mesylate 18 (0.050 g, 0.14 mmol) was dissolved in anhyd THF (1.5 mL). The mixture was cooled to 0 ˚C in an ice-bath, and then NaH (0.0071 g, 0.30 mmol) was added. The reaction mixture was stirred at r.t. for 6 h. The reaction was quenched with ice-cold H₂O (5 mL) and extracted with CH₂Cl₂ (3 × 5 mL). The combined organic phases were dried (Na₂SO₄). After filtration, the solvent was removed on the rotovap and the crude residue was purified by silica gel flash chromatography using a gradient of hexane-EtOAc (12:1 to 6:1). The pure product was obtained as a yellow liquid; yield: 0.023 g (91%, 0.13 mmol); [α]_D ^²5 +2.2 (c = 1.00, EtOH).

^¹H NMR (400 MHz, CDCl₃): δ = 7.28-7.38 (m, 5 H), 4.48 (br s, 2 H), 4.11 (m, 1 H), 3.05-3.18 (m, 1 H), 2.78-2.91 (m, 1 H), 1.84-1.96 (m, 2 H), 1.75-2.07 (m, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 138.3, 128.4, 127.6, 127.6, 80.0, 70.9, 53.2, 45.8, 32.8.

HRMS: m/z calcd for C₁₁H₁₆NO [M + H]⁺: 178.1232; found: 178.1230.

( S )-2-Bromo- N -[2-hydroxy-3-(trityloxy)propyl]acetamide (21)

(S)-1-Amino-3-(trityloxy)propan-2-ol (20; 0.990 g, 2.97 mmol) was dissolved in anhyd THF (10.0 mL). The reaction mixture was kept at 0 ˚C and bromoacetic anhydride (0.926 g, 3.56 mmol) and K₂CO₃ (0.820 g, 5.94 mmol) were added to the solution. After stirring at 0 ˚C for 30 min and at r.t. for 2 to 3 h, the K₂CO₃ was filtered off and the THF evaporated on the rotovap. Ice-water (5-10 mL) was then added and the diacetylated product was extracted with EtOAc (3 × 25 mL). After evaporating the EtOAc, the product was directly stirred with NaHCO₃ in a mixture of EtOH, THF, and H₂O (1:1:1) at r.t. for 12 h. The EtOH and THF were removed by concentration on the rotovap and the monoacetylated product was extracted with CH₂Cl₂ (3 × 25 mL). After removing the CH₂Cl₂, the product was obtained as an off-white semi-solid; yield: 1.34 g (99%, 2.95 mmol), which was used without further purification.

^¹H NMR (400 MHz, CDCl₃): δ = 7.54-7.15 (m, 15 H), 6.77 (br s, 1 H), 3.91 (m, 1 H), 3.78 (s, 2 H), 3.54 (m, 1 H), 3.27 (m, 1 H), 3.17 (m, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 166.3, 143.5, 128.5, 127.9, 127.2, 86.9, 69.7, 64.9, 43.1, 28.9.

HRMS: m/z calcd for C₂₄H₂₄BrNO₃ + Na [M + Na]⁺: 476.0837; found: 476.0839.

( S )-6-[(Trityloxy)methyl]morpholin-3-one (11)

The amide 21 (0.211 g, 0.464 mmol) was dissolved in anhyd CH₂Cl₂ (8 mL). NaOH (0.093 g, 2.33 mmol) was added to the solution, which was refluxed for 1.5 h. The solid residue was filtered off and washed with CH₂Cl₂ (˜5 mL), and the organic phase was washed with sat. aq NH₄Cl (2 × 5 mL), H₂O (2 × 5 mL), and brine (5 mL). The aqueous phase was separated and the organic phase dried (Na₂SO₄). After filtration, the solvent was evaporated and the pure product was obtained as a white crystalline solid after drying under high vacuum and used without further purification; yield: 0.139 g (80%, 0.372 mmol); mp 187-187.5 ˚C; [α]_D ^²5 -47.4 (c = 1.04, CH₂Cl₂).

^¹H NMR (250 MHz, CDCl₃): δ = 7.52-7.22 (m, 16 H), 4.29 (d, J = 16.9 Hz, 1 H), 4.17 (d, J = 16.9 Hz, 1 H), 3.87 (m, 1 H), 3.37 (m, 3 H), 3.15 (dd, J = 9.6, 5.9 Hz, 1 H).

^¹³C NMR (63 MHz, CDCl₃): δ = 169.4, 143.4, 128.5, 127.8, 127.1, 86.8, 72.0, 67.4, 63.8, 43.9.

HRMS: m/z calcd for C₂₄H₂₄NO₃ [M + H]⁺: 374.1756; found: 374.1773.

( S )-6-(Hydroxymethyl)morpholin-3-one (22)

Compound 11 (0.090 g, 0.242 mmol) was dissolved in anhyd CH₂Cl₂ (4 mL). The solution was cooled to 0 ˚C for 5 min and trifluoroacetic acid (0.036 mL, 0.485 mmol) was added slowly. The mixture was stirred at r.t. for 4 h. The solvent was then evaporated and MeOH (4 × 1 mL) was successively added and evaporated. The crude mixture was taken up in H₂O (5 mL) and the precipitated trityl salts were filtered off. The aqueous phase was extracted with hexane (2 5 mL) and then dried under N₂ and subsequently under high vacuum. The pure product was obtained as a colorless semi-solid, which was used without further purification; yield: 0.0311 g (98%; 0.237 mmol); [α]_D ^²5 -42.9 (c = 1.04, EtOH).

^¹H NMR (250 MHz, CDCl₃): δ = 6.26 (br s, 1 H), 4.34 (d, J = 16.9 Hz, 1 H), 4.22 (d, J = 16.9 Hz, 1 H), 3.85 (m, 1 H), 3.78 (m, 1 H), 3.68 (dd, J = 11.7, 5.6 Hz, 1 H), 3.47 (m, 1 H), 3.30 (m, 1 H).

^¹³C NMR (63 MHz, CDCl₃): δ = 171.3, 72.9, 66.7, 62.6, 42.5.

( S )-2-(Trityloxymethyl)morpholine (23)

Compound 11 (0.055 g, 0.15 mmol) was dissolved in anhyd THF (5 mL). The solution was cooled to 0 ˚C and stirred for 10 min. LiAlH₄ (0.017 g, 0.45 mmol) was added to the solution under N₂ and the reaction mixture was stirred for 2 h. Ice-water (10 mL) was added to quench the reaction, and the precipitated aluminum salts were filtered off. The THF was evaporated and the product was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers was washed with H₂O (5 mL) and brine (5 mL), then evaporated and the product was dried under N₂ and under vacuum to afford a colorless semi-solid, which was used without further purification; yield: 0.037 g (70%, 0.103 mmol); [α]_D ^²5 +13.0 (EtOH, c = 1.00).

^¹H NMR (250 MHz, CDCl₃): δ = 7.49-7.19 (m, 16 H), 3.86 (m, 1 H), 3.69 (m, 1 H), 3.59 (dd, J = 11.2, 3.4 Hz, 1 H), 3.22 (dd, J = 9.3, 5.1 Hz, 1 H), 3.04 (m, 2 H), 2.81 (m, 2 H), 2.62 (m, 1 H).

^¹³C NMR (63 MHz, CDCl₃): δ = 143.9, 128.6, 127.8, 127.0, 86.5, 75.9, 67.9, 65.1, 49.0, 45.9.

( S )-2-Bromo- N -[3-hydroxy-4-(trityloxy)butyl]acetamide (25a)

(S)-4-Amino-1-(trityloxy)butan-2-ol (24a; 3.85 g, 11.1 mmol) was dissolved in anhyd THF (60 mL). K₂CO₃ (3.06 g, 22.1 mmol), then bromoacetic anhydride (3.80 g, 14.6 mmol) were added and the solution was stirred at r.t. for 5-6 h. The K₂CO₃ was filtered off and the THF was evaporated on the rotovap. The solid residue was purified by silica gel flash chromatography (hexane-CH₂Cl₂-THF 6:3:1) and the pure product was isolated as a white solid; yield: 6.21 g (75%, 8.33 mmol); mp 79.0-80.0 ˚C.

^¹H NMR (400 MHz, CDCl₃): δ = 7.46-7.23 (m, 15 H), 7.18 (s, 1 H), 3.87 (m, 1 H), 3.84 (s, 2 H), 3.58 (m, 1 H), 3.26 (m, 1 H), 3.14 (m, 2 H), 2.93 (br s, 1 H), 1.65 (m, 1 H), 1.56 (m, 1 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 165.7, 143.6, 128.5, 127.8, 127.1, 86.8, 69.8, 67.4, 37.8, 32.0, 29.2.

( S )- N -Benzyl-2-bromo- N -[3-hydroxy-4-(trityloxy)butyl]acet­amide (25b)

(S)-4-(Benzylamino)-1-(trityloxy)butan-2-ol (24b; 0.230 g, 0.530 mmol) was mixed with K₂CO₃ (0.218 g, 1.58 mmol) in THF (3.00 mL) and the mixture was cooled to 0 ˚C. Bromoacetic anhydride (0.205 g, 0.790 mmol) was added and the reaction mixture was stirred at r.t. The mixture was then diluted with CH₂Cl₂ (15 mL), the organic layer was washed with H₂O (3 × 5 mL), and dried (Na₂SO₄). After filtration, the solvent was removed in vacuo and the crude was purified by silica gel flash chromatography (hexane-EtOAc, 3:1). The pure product was obtained as a colorless liquid; yield: 0.207 g (70%, 0.370 mmol).

^¹H NMR (400 MHz, CDCl₃): δ (major rotamer) = 7.17-7.51 (m, 20 H), 4.69 (d, J = 16.9 Hz, 1 H), 4.56 (d, J = 16.9 Hz, 1 H), 3.58-3.76 (m, 3 H), 3.31-3.54 (m, 2 H), 2.99-3.17 (m, 2 H), 2.41 (d, J = 3.3 Hz, 1 H, OH), 1.45-1.70 (m, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ (major rotamer) = 168.1, 143.9, 136.8, 129.1, 128.7, 128.6, 128.0, 127.8, 127.5, 127.3, 127.0, 126.23, 86.6, 67.7, 67.4, 52.2, 48.1, 43.5, 31.3, 26.3.

( S )-7-(Trityloxy)methyl-1,4-oxazepan-3-one (12 ≡ 26a)

(S)-2-Bromo-N-[3-hydroxy-4-(trityloxy)butyl]acetamide (25a; 156 mg, 0.333 mmol) was dissolved in anhyd CH₂Cl₂ (10 mL). NaOH (66.6 mg, 1.67 mmol) was added to the solution and the mixture was stirred for 6 h. The solid residue was filtered off and the organic layer was washed with sat. aq NH₄Cl (2 × 5 mL), then with H₂O (5 mL) and brine (5 mL). After drying (Na₂SO₄) and filtration, the solvent was evaporated and the residue dried under vacuum to afford a fluffy white solid; yield: 107 mg (83%, 0.276 mmol); mp 88-90 ˚C; [α]_D ^²5 -36.2 (c = 1.02, CH₂Cl₂).

^¹H NMR (250 MHz, CDCl₃): δ = 7.41-7.11 (m, 15 H), 6.42 (br s, 1 H), 4.32 (d, J = 15.9 Hz, 1 H), 4.05 (d, J = 15.9 Hz, 1 H), 3.70 (m, 1 H), 3.34 (m, 1 H), 3.20 (dd, J = 9.6, 5.9 Hz, 1 H), 2.94 (dd, J = 9.6, 5.0 Hz, 1 H), 1.92 (m, 1 H), 1.70 (m, 1 H).

^¹³C NMR (63 MHz, CDCl₃): δ = 175.4, 143.8, 128.6, 127.8, 86.6, 79.9, 71.5, 65.8, 39.2, 32.5.

HRMS: m/z calcd for C₂₅H₂₅NO₃ + Na [M + Na]⁺: 410.1732; found: 410.1734.

( S )-4-Benzyl-7-[(trityloxy)methyl]-1,4-oxazepan-3-one (26b)

Compound 25b (0.070 g, 0.13 mmol) was mixed with NaOH (0.025 g, 0.60 mmol) in THF (1.50 mL) and the mixture was heated to reflux for 24 h. The crude was diluted with CH₂Cl₂ (10 mL) and the organic layer was washed with H₂O (3 × 5 mL). The organic phase was dried (Na₂SO₄) and after filtration, the solvent was removed in vacuo. The crude residue was purified by silica gel flash chromatography (hexane-EtOAc, 3:1). The pure product was obtained as a white solid; yield: 0.031 g (50%, 0.065 mmol); mp 145.0-146.5 ˚C; [α]_D ^²5 -29.7 (c = 1.00, EtOH).

^¹H NMR (400 MHz, CDCl₃): δ = 7.40-7.45 (m, 6 H), 7.20-7.36 (m, 14 H), 4.60 (s, 2 H), 4.54 (d, J = 15.7 Hz, 1 H), 4.26 (d, J = 15.7 Hz, 1 H), 3.73 (m 1 H), 3.46 (ddd, J = 14.6, 8.4, 2.2 Hz, 1 H), 3.30 (ddd, J = 14.6, 8.8, 2.2 Hz, 1 H), 3.24 (dd, J = 5.9, 9.5 Hz, 1 H), 2.98 (dd, J = 9.5, 5.1 Hz, 1 H), 1.82-1.92 (m, 1 H), 1.62-1.74 (m, 1 H).

^¹³C NMR (101 MHz, CDCl₃): δ = 172.3, 143.8, 137.1, 128.6, 128.1, 127.8, 127.5, 127.0, 86.6, 79.2, 71.8, 65.7, 51.6, 45.1, 31.6.

HRMS: m/z calcd for C₃₂H₃₁NO₃ + Na [M + Na]⁺: 500.2202; found: 500.2206.

( S )-4-Methyl-7-[(trityloxy)methyl]-1,4-oxazepan-3-one (26c)

The oxazepanone 26a (≡ 12) (0.126 g, 0.325 mmol) was dissolved in anhyd DMF (1.50 mL) and cooled to 0 ˚C. KOt-Bu (0.077 g, 0.65 mmol) was added to the solution. After stirring at 0 ˚C for 5 min, the reaction mixture was allowed to warm to r.t. and stirred for an additional 50 min, at which point MeI (0.060 mL, 0.94 mmol) was added. The mixture was stirred under anhydrous atmosphere using CaCl₂ drying tube for about 2 h. The reaction mixture was quenched by the addition of dil HCl (˜0.1 M; 5 mL). The product was extracted from the aqueous layer with CH₂Cl₂ (3 × 10 mL) and dried (Na₂SO₄). After filtration, the solvent was removed in vacuo and the crude residue was purified by silica gel flash chromatography (hexane-acetone, 9:1). The pure product was obtained as a light yellow liquid; yield: 0.106 g (82%, 0.265 mmol); [α]_D ^²5 -38.0 (c = 3.9, EtOAc).

^¹H NMR (400 MHz, CDCl₃): δ = 7.51-7.40 (m, 6 H), 7.35-7.20 (m, 9 H), 4.44 (d, J = 15.7 Hz, 1 H), 4.18 (d, J = 15.7 Hz, 1 H), 3.77 (m, 1 H), 3.52 (ddd, J = 14.6, 8.6, 2.1 Hz, 1 H), 3.32-3.42 (m, 1 H), 3.27 (dd, J = 9.5, 5.9 Hz, 1 H), 3.01 (m, 1 H), 2.99 (s, 3 H), 1.98-2.07 (m, 1 H), 1.75-1.88 (m, 1 H).

^¹³C NMR (101 MHz, CDCl₃): δ = 172.1, 143.8, 128.6, 127.8, 127.0, 86.6, 78.8, 71.5, 65.6, 47.5, 36.4, 31.3.

HRMS: m/z calcd for C₂₆H₂₇NO₃ + Na [M + Na]⁺: 424.1889; found: 424.1888.

( S )-4-Ethyl-7-[(trityloxy)methyl]-1,4-oxazepan-3-one (26d)

Compound 26d was prepared from 26b using EtI by a similar method as for the synthesis of compound 26c and the pure product was obtained as a colorless liquid; yield: 0.109 g (77%, 0.262 mmol); [α]_D ^²5 -48.5 (c = 2.4, EtOAc).

^¹H NMR (400 MHz, CDCl₃): δ = 7.41-7.50 (m, 6 H), 7.21-7.35 (m, 9 H), 4.44 (d, J = 15.6 Hz, 1 H), 4.18 (d, J = 15.6 Hz, 1 H), 3.75 (m, 1 H), 3.48-3.57 (m, 1 H), 3.43 (m, 2 H), 3.31-3.40 (m, 1 H), 3.27 (dd, J = 9.5, 5.9 Hz, 1 H), 3.02 (dd, J = 9.5, 5.3 Hz, 1 H), 1.96-2.03 (m, 1 H), 1.71-1.83 (m, 1 H), 1.12 (t, J = 7.1 Hz, 3 H). 

^¹³C NMR (101 MHz, CDCl₃): δ = 171.4, 143.7, 128.5, 127.7, 126.9, 86.4, 79.0, 71.8, 65.6, 45.0, 43.3, 31.9, 12.7.

HRMS: m/z calcd for C₂₇H₂₉NO₃ + Na [M + Na]⁺: 438.2045; found: 438.2050.

( S )-6-[(Trityloxy)methyl]-1,3-oxazinane-2-thione (13)

(S)-4-Amino-1-(trityloxy)butan-2-ol (24a; 0.057g, 0.16 mmol) was mixed with thiocarbonyldiimidazole (TCDI) (0.059 g, 0.32 mmol) in 1,4-dioxane (6.0 mL) and the solution was heated to reflux at 120 ˚C for 24 h. The mixture was diluted with CH₂Cl₂ (10 mL), the organic layer washed with H₂O (2 × 5 mL), and dried (Na₂SO₄). The crude residue was purified by silica gel flash column chromatography using a gradient of hexane-EtOAc (6:1 to 2.5:1). The pure product was obtained as a light yellow solid; yield: 0.055 g (88%, 0.14 mmol); mp 155.0-156.0 ˚C; [α]_D ^²5 +23.3 (c = 2.90, EtOAc).

^¹H NMR (400 MHz, CDCl₃): δ = 8.07 (br s, 1 H), 7.38-7.48 (m, 6 H), 7.21-7.35 (m, 9 H), 4.40 (m, 1 H), 3.48 (dd, J = 9.9, 4.4 Hz, 1 H), 3.21-3.40 (m, 3 H), 2.12-2.24 (m, 1 H), 1.85-2.03 (m, 1 H).

^¹³C NMR (101 MHz, CDCl₃): δ = 186.9, 143.3, 128.6, 128.0, 127.3, 87.1, 77.5, 64.3, 39.8, 22.5.

HRMS: m/z calcd for C₂₄H₂₃NO₂S [M]⁺: 389.1448; found: 389.1449.

( S )-2-(Ethylthio)-6-[(trityloxy)methyl]-5,6-dihydro-4 H -1,3-oxazine (27)

The thione 13 (0.030 g, 0.077 mmol) was mixed with EtI (0.014 mL, 0.0800 mmol) in anhyd THF (1.00 mL). The reaction mixture was cooled in an ice-bath and KOt-Bu (0.013 g, 0.11 mmol) was added slowly. The mixture was stirred at r.t. for 80 min after which the reaction was complete. Dil HCl (4 mL) was added to quench the reaction and the mixture was extracted with CH₂Cl₂ (3 × 7 mL). The combined organic layers were dried (Na₂SO₄) and after filtration and concentration, the crude residue was purified by silica gel flash chromatography using a gradient of hexane-EtOAc (10:1 to 5:1). The pure product was obtained as a colorless liquid; yield: 0.026 g (81%, 0.062 mmol); [α]_D ^²5 +42.1 (c = 1.70, EtOAc).

^¹H NMR (400 MHz, CDCl₃): δ = 7.50-7.41 (m, 6 H), 7.21-7.36 (m, 9 H), 4.34 (m, 1 H), 3.56-3.35 (m, 2 H), 3.29 (dd, J = 9.9, 5.4 Hz, 1 H), 3.17 (dd, J = 9.9, 4.9 Hz, 1 H), 2.94-2.78 (m, 2 H), 1.97-1.77 (m, 2 H), 1.30 (t, J = 7.3 Hz, 3 H).

^¹³C NMR (101 MHz, CDCl₃): δ = 157.8, 143.7, 128.7, 127.9, 127.1, 86.6, 75.8, 65.5, 43.5, 25.0, 24.7, 14.7.

HRMS: m/z calcd for C₂₆H₂₈NO₂S [M + H]⁺: 418.1841; found: 418.1840.

( S )-3-Ethyl-6-[(trityloxy)methyl]-1,3-oxazinane-2-thione (28)

(S)-4-(Ethylamino)-1-(trityloxy)butan-2-ol (24c; 0.218 g, 0.58 mmol) was mixed with TCDI (0.205 g, 1.16 mmol) in 1,4-dioxane (7.00 mL). The reaction mixture was heated to reflux for 24 h and the mixture was cooled to r.t., diluted with CH₂Cl₂ (20 mL), and the organic layer was washed with H₂O (2 × 10 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography using a gradient of hexane-EtOAc (4:1 to 1:1). The pure product was obtained as a white solid; yield: 0.177 g (73%, 0.42 mmol); mp 170.0-171.0 ˚C; [α]_D ^²5 +25.6 (c = 1.00, CH₂Cl₂).

^¹H NMR (400 MHz, CDCl₃): δ = 7.39-7.46 (m, 6 H), 7.20-7.37 (m, 9 H), 4.37 (m, 1 H), 3.89 (m, 2 H), 3.50 (dd, J = 9.7, 4.4 Hz, 1 H), 3.41-3.29 (m, 2 H), 3.23 (dd, J = 9.6, 7.2 Hz, 1 H), 2.25-2.36 (m, 1 H), 1.95-2.08 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3 H).

NMR (101 MHz, CDCl₃): δ = 185.1, 143.4, 128.5, 127.9, 127.2, 87.0, 76.3, 64.2, 50.6, 44.6, 24.3, 10.9.

HRMS: m/z calcd for C₂₆H₂₇NO₂S [M ]⁺: 417.1761; found: 417.1762.

( S )-3-Ethyl-6-(hydroxymethyl)-1,3-oxazinane-2-thione (29)

The thione 28 (0.100 g, 0.24 mmol) was dissolved in CH₂Cl₂ (3.00 mL) and the solution was cooled to 0 ˚C. Trifluoroacetic acid (0.070 mL, 2.4 mmol) was added and the mixture was stirred at r.t. overnight. The reaction was quenched by the addition of MeOH (3 mL) and the organic phase was washed with H₂O (3 × 3 mL). After drying (Na₂SO₄) and filtration, the solvent was removed in vacuo on the rotovap. The crude residue was purified by silica gel flash chromatography (hexane-CH₂Cl₂-acetone 6:1:1). The pure product was obtained as a colorless liquid; yield: 0.042 g (∼100%, 0.24 mmol).

^¹H NMR (400 MHz, CDCl₃): δ = 4.33 (m, 1 H), 3.81-4.03 (m, 3 H), 3.73 (dd, J = 12.5, 4.8 Hz, 1 H), 3.38-3.52 (m, 2 H), 2.02-2.24 (m, 2 H), 1.30 (t, J = 7.1 Hz, 3 H).

^¹³C NMR (101 MHz, CDCl₃): δ = 185.1, 78.7, 63.4, 50.5, 44.9, 22.9, 10.9.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis. Included are ^¹H and ^¹³C NMR spectra for compounds 10-18, 21-23, and 25-29.

Acknowledgment

We thank Afid Therapeutics for their general gift of the lactone starting material. We also thank the Mass Spectrometry lab at the University of Illinois at Urbana Champaign for their assistance with measuring the HRMS. The research was supported in part by a summer research grant from UNO.

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