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DOI: 10.1055/s-0030-1260064
Chemodivergent Synthesis of 7-Aryl/alkyl-6-hydroxy-1,4-oxazepan-5-ones and 2-[Aryl/alkyl(hydroxy)methyl]morpholin-3-ones from a Common Epoxyamide Precursor
Publication History
Publication Date:
09 June 2011 (online)
Abstract
We present here a regiospecific synthesis of 7-alkyl- or 7-aryl-6-hydroxy-1,4-oxazepan-5-ones and 2-[aryl(hydroxy)methyl]- or 2-(1-hydroxyalkyl)morpholin-3-ones from a diastereomeric mixture of trans-3-alkyl- or -3-aryl-N-(2-hydroxyethyl)-N-(1-phenylethyl)oxirane-2-carboxamides. This chemodivergent synthesis is easily controlled by an appropriate choice of cyclization reaction conditions.
Key words
chemoselectivity - cyclization - alkoxide - oxazepan-5-ones - morpholin-3-ones
Six- and seven-membered nitrogen-oxygen-containing chiral heterocycles are general scaffolds classically associated with diverse biological activity. [¹] In addition, these heterocycles frequently exhibit several stereogenic centers. As a consequence, intensive effort has been devoted towards the development of efficient strategies for their synthesis. In our ongoing work on the asymmetric synthesis of nitrogen heterocycles, [²] we have reported an expeditious access to chiral nonracemic epoxyamides. [³] Epoxyamides are known to be versatile intermediates in organic synthesis [4] offering an extensive range of synthetic possibilities. [5] Among them, the use of controlled intramolecular nucleophilic ring closure [6] could deliver, in a straightforward manner, 1,4-oxazepan-5-ones and/or morpholin-3-ones with potential biological interest. In this work, we report that epoxyamide 1 can indeed lead to both heterocyclic scaffolds using a controlled set of reaction conditions (Scheme [¹] ).
Chiral sulfonium salt 3 was synthesized in three steps starting from (S)-phenylethylamine (2) in 77% overall yield (Scheme [²] ).
With the chiral sulfonium salt 3 in hand, the asymmetric epoxidation with benzaldehyde was then investigated (Table [¹] ). Standard basic conditions (KOH, t-BuOK, or NaH as the base) [³] [7] proved to be inappropriate with this substrate, as the NMR analysis of the crude reaction only showed traces of the corresponding epoxyamide. Best results were obtained when sulfonium salt 3 was treated with DBU, in dichloromethane, from 0 ˚C to room temperature (entry 5) giving the corresponding diastereomeric mixture of trans-epoxyamides 4a/4b in 92% yield. The NMR spectra show the presence of an E vs. Z rotameric mixture of each diastereomer. The exclusive formation of the trans adducts was confirmed by the magnitude of the coupling constants of the epoxides (J = 2.1 and 1.6 Hz).
Scheme 1 Divergent synthesis of nitrogen heterocycles from epoxyamide 1
Scheme 2 Reagents and conditions: (a) ethylene oxide, H2O, sonication, 20 min, 91%; (b) bromoacetyl bromide, Et3N, CH2Cl2, -10 ˚C; (c) Me2S, CH2Cl2, r.t., 77% from (S)-phenylethylamine (2).
The detection by ¹H NMR spectroscopy of the corresponding morpholinone 4c in the crude reaction mixture when using inorganic bases such as potassium hydroxide (entry 3), suggests that the formation of the alkoxide rather than the sulfur ylide might be favored under these cyclization conditions, whereas DBU cleanly generated the reactive ylide when the reaction was performed from 0 ˚C to room temperature (Table [¹] ).
The asymmetric epoxidation of chiral sulfonium salt 3 with several aromatic aldehydes was then investigated (Table [²] ). In the case of vanillin, the asymmetric epoxidation was unsuccessful; however, high yields of 11a/11b were obtained when the hydroxy function was protected with a tosyl group (entry 7). The asymmetric epoxidation with aliphatic aldehydes was tested giving the corresponding epoxyamides 12a/12b and 13a/13b in good yields (entries 8 and 9).
As the separation of the diastereomers proved to be difficult at this stage, access to the oxazepanone moiety via a 7-endo-tet ring closure was investigated. Oxirane ring opening of epoxyamides has been reported using various Lewis acids, such as: ZnCl2, [8] MgI2, [9] ZrCl4, [¹0] TFA or Sc(OTf)3, [¹¹] and Zn(OTf)2 or Cu(OTf)2. [¹²] Although a double substitution reaction pathway has been proposed in the presence of magnesium iodide, [9] trans-epoxyamides 4a/4b, led in our hands to the diastereomeric mixture of 1,4-oxazepan-5-ones 14a/14b, coming from the direct SN2 opening reaction in a low yield (Table [³] , entry 1), in agreement with results reported by Ohnmacht et al. [¹¹]
The use of trifluoroacetic acid activation led to 1,4-oxazepan-5-ones 14a/14b in better yield (Table [³] , entry 2,). This reaction proved to be highly sensitive to the electron density of the aromatic moiety. Thus, only traces of 1,4-oxazepan-5-ones 15a/15b were obtained with epoxyamides containing an electron-withdrawing group (entry 3) even using prolonged reaction times. In contrast, 1,4-oxazepan-5-ones 20a/20b was obtained in 73% yield (entry 4). Lewis acid activation was then investigated in order to increase the reaction yields. The best results were obtained in the presence of 20 mol% copper(II) triflate, leading to the desired 1,4-oxazepan-5-ones 14a/14b-21a/21b in good to excellent yields, even in the presence of deactivating groups on the aromatic ring. This condition also was tested with epoxyamides containing an aliphatic group affording the corresponding 1,4-oxazepan-5-ones 22a/22b and 23a/23b in excellent yields (entries 13 and 14).
Diastereomers were easily separated at this stage by chromatographic purification (yielding for entry 7; 16a, 50% and 16b, 42%). Fortunately, the major diastereomer 16a crystallized, enabling the determination of its absolute configuration and securing the presence of the 1,4-oxazepan-5-one ring by X-ray diffraction analysis (Figure [¹] ).
Figure 1 X-ray ORTEP diagram of compound 16a
We then explored the access to the morpholinone ring based on a regiospecific 6-exo-tet ring closure under basic conditions.
In this way, Liebscher [8] reported the intramolecular opening of oxirane carboxamide using DBU in boiling ethanol forming predominantly the corresponding morpholinone derivative, however when we applied this methodology to the corresponding diastereomeric mixture of trans-epoxyamides even using prolonged reaction times, we obtained the desired morpholinone in low yield.
The use of bases such as potassium hydroxide and potassium tert-butoxide led only to degradation of the starting material. Better results were obtained when we used a new procedure based on the in situ sodium alkoxide formation by the treated of epoxyamides 4a/4b with sodium in anhydrous tetrahydrofuran (Table [4] , entry 1). [¹³] The total conversion of the starting material was observed after 20 minutes. The NMR analysis of the crude reaction showed exclusively the presence of the corresponding diastereomeric mixture of 2-[hydroxy(phenyl)methyl]-4-(1-phenylethyl)morpholin-3-ones 24a/24b in 95% yield.
Diastereomers were easily separated at this stage by chromatographic purification (yields of separated diastereomers: 57% for 24a and 38% for 24b). Fortunately, the major diastereomer 24a crystallized, enabling the determination of its absolute configuration and the confirmation of the presence of the morpholinone ring by X-ray diffraction analysis (Figure [²] ).
Figure 2 X-ray ORTEP diagram of compound 24a
Epoxyamides 5a/5b-13a/13b were reacted with sodium, affording the corresponding morpholin-3-ones 25a/25b-33a/33b in good to excellent yields, even in the presence of deactivating groups on the aromatic ring (Table [4] ). Even, the use of epoxyamides 8a/8b (entry 5) gave the corresponding morpholinones 28a/28b in good yields despite the presence of two chlorine atoms which could represent a combination of unfavorable steric and electronic effects. Also, the use of epoxyamides 9a/9b (entry 6) led to the corresponding morpholinones 29a/29b in 85% yield. Epoxyamides containing an aliphatic group 12a/12b and 13a/13b also gave the corresponding morpholinones 32a/32b and 33a/33b in excellent yields (entries 9 and 10).
The divergent pathways for the regiospecific ring-closure reactions can be explained as follows. Under basic conditions, the cyclization through the epoxide opening follows an exo mode, as a six-membered transition state is more favored than a seven-membered one, in accordance with Baldwin’s rules. [¹4] The use of acidic activation favors a later transition state, having a positive charge developing, at the benzylic position for aromatic epoxyamides or at the more stabilized carbon by inductive effect for aliphatic epoxyamides, and therefore favors the formation of the oxazepanone skeleton via a 7-endo-tet process. This mechanism also explains the influence of the aromatic substitution in the cyclization process.
Finally, we performed the removal of chiral auxiliary from 1,4-oxazepan-5-one 14a in two steps. In the first step, compound 14a was reduced with borane-dimethyl sulfide complex, affording the cyclic amine 34 in 91% yield. Finally, compound 34 was selectively N-debenzylated when it was treated under transfer hydrogenation condition to give the desired 7-phenyl-1,4-oxazepan-6-ol 35 in 90% yield (Scheme [³] ).
Scheme 3
In summary, we have developed a new strategy to build in a high yielding, highly functionalized, and regiospecific manner chiral 1,4-oxazepan-5-ones and morpholin-3-ones starting from chiral trans-epoxyamides. This strategy opens a new, versatile, and scalable access to chiral six- and seven-membered N,O-heterocycles for further pharmacological investigations.
All moisture-sensitive reactions were performed using syringe-septum cap techniques under an N2 atmosphere and all glassware was dried in an oven at 80 ˚C for 2 h prior to use. Reactions at -10 ˚C, 0 ˚C were performed using ultra cold equipment (Mod. SEV CRYO1-80). Melting points were measured by a hot stage melting point apparatus (uncorrected). Optical rotations were measured with a Perkin-Elmer 341 polarimeter, using a 1-dm cell with a total volume of 1 mL and are referenced Na d-line. For flash chromatography, Silica Gel 60, 0.063-0.2 mm/70-230 mesh ASTM was employed; PE = petroleum ether. ¹H NMR spectra were recorded using a Varian VX400 (400 MHz) spectrometer relative to TMS (in CDCl3) as internal standard. ¹³C NMR spectra were recorded using a Varian VX400 (100 MHz) spectrometer and referenced to the residual CHCl3 signal. X-ray diffraction data were obtained by using an Oxford Diffraction Gemini Atlas CCD diffractometer, with graphite-monochromatic MoKα radiation (λ = 0.71073 Å). CrysAlis RED program was used to collect and refine cell, CrysAlis RED program was used to reduce data, and SHELXL97 program was used to solve structure and refine it. Exact mass (HRMS) spectra were recorded with a Jeol JEM-AX505HA instrument at a voltage of 70 eV. Infrared spectra were obtained on a Nicolet FT-IR Magna 750 spectrophotometer.
6-Hydroxy-7-substituted-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-ones 4a/4b-13a/13b; General Procedure
To a stirred soln of the diastereomeric mixture of trans-N-(2-hydroxyethyl)-3-substituted-N-[(S)-1-phenylethyl]oxirane-2-carboxamide (0.56 mmol) in MeCN (5 mL) was added Cu(OTf)2 (20% mol) at r.t. The mixture was stirred until the total disappearance of the starting material (20 min). The reaction was quenched by addition of brine (10 mL). The organic phase was separated, dried (anhyd Na2SO4), filtered, and the solvent was removed by evaporation. The resulting diastereomeric mixture was purified via flash column chromatography (silica gel, EtOAc-PE, 1:4).
(-)-(6 R ,7 R )-6-Hydroxy-7-phenyl-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (14a)
Yield: 0.329 mmol (51%); R f = 0.65 (EtOAc-PE, 40:60).
[α]D ²0 -85.8 (c 1.0, CH2Cl2).
IR (KBr): 3380, 1639, 1106, 737 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.59 (d, J = 6.8 Hz, 3 H, CH3), 3.11 (dd, J = 4.1, 16.3 Hz, 1 H, H3), 3.40 (dd, J = 9.9, 16.3 Hz, 1 H, H3), 3.53 (dd, J = 9.9, 12.9 Hz, 1 H, H2), 4.10 (dd, J = 4.1, 12.9 Hz, 1 H, H2), 4.29 (d, J = 9.0 Hz, 1 H, H7), 4.47 (m, 2 H, OH, H6), 6.15 (q, J = 6.8 Hz, 1 H, H1′), 7.24-7.39 (m, 10 H).
¹³C NMR (100 MHz, CDCl3): δ = 16.5, 45.5, 52.6, 70.6, 73.5, 82.2, 127.1-128.7, 139.1, 139.2, 174.4.
HRMS (ESI): m/z [M] calcd for C19H21NO3: 311.1521; found: 311.1541.
(-)-(6 S ,7 S )-6-Hydroxy-7-phenyl-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (14b)
Yield: 0.280 mmol (44%); R f = 0.55 (EtOAc-PE, 40:60).
[α]D ²0 -160 (c 1.0, CH2Cl2).
IR (KBr): 3377, 1642, 1100, 725 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.54 (d, J = 6.9 Hz, 3 H), 2.93 (ddd, J = 0.8, 9.9, 13.0 Hz, 1 H, H3), 3.15 (ddd, J = 0.6, 4.16, 15.8 Hz, 1 H, H2), 3.60 (ddd, J = 0.8, 9.9, 15.8 Hz, 1 H, H2), 3.75 (ddd, J = 0.9, 4.16, 13.0 Hz, 1 H, H3), 4.19 (d, J = 8.7 Hz, 1 H, H7), 4.45 (m, 2 H, OH, H6), 6.17 (q, J = 6.9 Hz, 1 H, H1′), 7.29-7.41 (m, 10 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.3, 44.8, 52.6, 69.8, 73.7, 82.0, 127.4-128.7, 139.2, 174.3.
HRMS (ESI): m/z [M] calcd for C19H21NO3: 311.1521; found: 311.1538.
(-)-(6 R ,7 R )-6-Hydroxy-7-(2-nitrophenyl)-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (15a)
Yield: 0.188 mmol (42%); R f = 0.88 (EtOAc-PE, 40:60).
[α]D ²0 -223.5 (c 1.1, CH2Cl2).
IR (KBr): 3362, 1658, 1530, 1338, 1127 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.61 (d, J = 7.0 Hz, 3 H), 3.10 (dd, J = 4.0, 16.4 Hz, 1 H, H3), 3.38 (dd, J = 10.2, 16.4 Hz, 1 H, H3), 3.58 (dd, J = 10.2, 12.9 Hz, 1 H, H2), 4.16 (dd, J = 4.0, 12.9 Hz, 1 H, H2), 4.39 (m, 2 H, OH, H7), 5.28 (d, J = 8.3 Hz, 1 H, H6), 6.16 (q, J = 7.0 Hz, 1 H), 7.29-7.94 (m, 9 H).
¹³C NMR (100 MHz, CDCl3): δ = 16.6, 45.6, 52.6, 71.0, 74.0, 77.3, 124.2, 127.1-128.77, 132.9, 133.9, 139.1, 173.6.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1402.
(-)-(6 S ,7 S )-6-Hydroxy-7-(2-nitrophenyl)-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (15b)
Yield: 0.160 mmol (36%); R f = 0.53 (EtOAc-PE, 40:60).
[α]D ²0 -35.4 (c 1.1, CH2Cl2).
IR (KBr): 3375, 1654, 1552, 1347 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.54 (d, J = 7.0 Hz, 3 H), 2.95 (dd, J = 10.0, 13.0 Hz, 1 H, H3), 3.17 (dd, J = 3.9, 16.0 Hz, 1 H, H2), 3.58 (dd, J = 10.0, 16.0 Hz, 1 H, H2), 3.78 (dd, J = 3.9, 13.0 Hz, 1 H, H3), 4.32 (dd, J = 4.9, 8.48 Hz, 1 H, H6), 4.41 (d, J = 4.9 Hz, 1 H, OH), 5.24 (d, J = 8.48 Hz, 1 H, H7), 6.17 (q, J = 7.0 Hz, 1 H), 7.29-7.95 (m, 9 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.3, 44.9, 52.6, 70.3, 74.2, 76.3, 124.2, 127.7-128.8, 132.9, 134.0, 139.1, 173.7.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1402.
(-)-(6 R ,7 R )-6-Hydroxy-7-(3-nitrophenyl)-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (16a)
Yield: 0.251 mmol (50%); R f = 0.88 (EtOAc-PE, 40:60).
[α]D ²0 -75.6 (c 1.1, CH2Cl2).
IR (KBr): 3377, 1640, 1536, 1330 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.61 (d, J = 7.0 Hz, 3 H), 3.14 (dd, J = 4.2, 16.4 Hz, 1 H), 3.41 (dd, J = 10.0, 16.4 Hz, 1 H), 3.56 (dd, J = 10.0, 12.9 Hz, 1 H), 4.16 (d, J = 4.2, 12.9 Hz, 1 H), 4.40 (m, 2 H), 4.51 (d, J = 3.5 Hz, 1 H), 6.14 (q, J = 7.0 Hz, 1 H), 7.26-7.41 (m, 5 H), 7.53 (t, J = 7.9 Hz, 1 H), 7.69 (dt, J = 1.2, 7.7 Hz, 1 H), 8.18 (ddd, J = 1.2, 2.2, 8.2 Hz, 1 H), 8.3 (t, J = 1.9 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 16.5, 45.5, 52.8, 70.8, 73.4, 80.0, 122.5, 123.0, 127.1, 128.0, 128.8, 134.0, 138.8, 141.2, 173.7.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1397.
(-)-(6 S ,7 S )-6-Hydroxy-7-(3-nitrophenyl)-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (16b)
Yield: 0.213 mmol (42%); R f = 0.55 (EtOAc-PE, 40:60).
[α]D ²0 -134.4 (c 1.1, CH2Cl2).
IR (KBr): 3370, 1644, 1526, 1347, 1111 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.56 (d, J = 7.0 Hz, 3 H), 2.93 (dd, J = 9.8, 12.9 Hz, 1 H), 3.22 (dd, J = 3.9, 15.9 Hz, 1 H), 3.63 (dd, J = 9.8, 15.9 Hz, 1 H), 3.79 (dd, J = 3.5, 13.1 Hz, 1 H), 4.31 (d, J = 9.0 Hz, 1 H), 4.39 (dd, J = 3.2, 9.0 Hz, 1 H), 4.53 (d, J = 3.5 Hz, 1 H), 6.17 (q, J = 7.0 Hz, 1 H), 7.26-8.29 (m, 9 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.3, 44.8, 52.8, 70.0, 73.6, 80.6, 122.5, 122.9, 127.1, 127.6, 128.2, 128.7, 128.8, 133.9, 141.31, 173.6.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1399.
(-)-(6 R ,7 R )-6-Hydroxy-7-(4-nitrophenyl)-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (17a)
Yield: 0.314 mmol (52%); R f = 0.5 (EtOAc-PE, 30:70).
[α]D ²0 -69.55 (c 1.0, CH2Cl2).
IR (KBr): 3380, 1645, 1526, 1350 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.62 (d, J = 7.0 Hz, 3 H), 3.14 (dd, J = 4.0, 16.4 Hz, 1 H, H3), 3.39 (dd, J = 10.0, 16.4 Hz, 1 H, H3), 3.55 (dd, J = 10.0, 12.8 Hz, 1 H, H2), 4.14 (dd, J = 4.0, 12.8 Hz, 1 H, H2), 4.39 (m, J = 9.0 Hz, 2 H, H7, H6), 4.50 (d, J = 3.6 Hz, 1 H, OH), 6.13 (q, J = 7.0 Hz, 1 H), 7.26-7.56 (m, 7 H), 8.22 (m, 2 H).
¹³C NMR (100 MHz, CDCl3): δ = 16.5, 45.5, 52.8, 70.8, 73.4, 80.9, 123.2, 127.1-128.8, 138.8, 146.3, 147.5, 173.7.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1407.
(-)-(6 S ,7 S )-6-Hydroxy-7-(4-nitrophenyl)-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (17b)
Yield: 0.269 mmol (43%); R f = 0.4 (EtOAc-PE, 30:70).
[α]D ²0 -208.3 (c 1.0, CH2Cl2).
IR (KBr): 3277, 1654, 1555, 1264 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.55 (d, J = 7.0 Hz, 3 H), 2.93 (dd, J = 9.5, 13.1 Hz, 1 H, H3), 3.22 (dd, J = 3.9, 15.8 Hz, 1 H, H2), 3.62 (dd, J = 9.5, 15.8 Hz, 1 H, H2), 3.79 (dd, J = 3.4, 13.1 Hz, 1 H, H3), 4.33 (dd, J = 9.0 Hz, 2 H, H6, H7), 4.50 (d, J = 3.9 Hz, 1 H, OH), 6.16 (q, J = 7.0 Hz, 1 H), 7.32-7.43 (m, 5 H), 7.54 (m, 2 H), 8.21 (m, 2 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.4, 44.8, 52.8, 70.1, 73.6, 80.8, 123.2, 127.7-128.8, 139.0, 146.3, 173.6.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1395.
(-)-(6 R ,7 R )-7-(2,6-Dichlorophenyl)-6-hydroxy-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (18a)
Yield: 0.207 mmol (49%); R f = 0.53 (EtOAc-PE, 10:90).
[α]D ²0 -65.90 (c 1.0, CH2Cl2).
IR (KBr): 3383, 2975, 1646, 1437, 1320, 1109, 775, 735, 701 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.61 (d, J = 7.1 Hz, 3 H), 3.10 (dd, J = 4.2, 16.3 Hz, 1 H, H3), 3.50 (dd, J = 9.9, 16.3 Hz, 1 H, H3), 3.55 (dd, J = 9.9, 12.7 Hz, 1 H, H2), 4.15 (dd, J = 4.2, 12.7 Hz, 1 H, H2), 4.38 (d, J = 4.3 Hz, 1 H, H7), 5.19 (d, J = 9.3 Hz, 1 H, OH), 5.25 (dd, J = 4.3, 9.3 Hz, 1 H, H6), 6.14 (q, J = 7.1 Hz, 1 H, H1′), 7.13-7.39 (m, 8 H).
¹³C NMR (100 MHz, CDCl3): δ = 16.6, 45.4, 52.4, 70.6, 71.5, 78.6, 127.1-130.0, 134.0, 134.5, 136.4, 139.0, 174.5.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found: 379.0775.
(-)-(6 S ,7 S )-7-(2,6-Dichlorophenyl)-6-hydroxy-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (18b)
Yield: 0.176 mmol (42%); R f = 0.41 (EtOAc-PE, 10:90).
[α]D ²0 -187.4 (c 1.0, CH2Cl2).
IR (KBr): 3385, 2980, 1646, 1435, 1390, 1110, 778, 740, 701 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.53 (d, J = 7.0 Hz, 3 H), 2.91 (dd, J = 9.8, 13.0 Hz, 1 H, H3), 3.16 (dd, J = 3.6, 15.9 Hz, 1 H, H2), 3.63 (dd, J = 9.8, 15.9 Hz, 1 H, H2), 3.76 (dd, J = 3.6, 13.0 Hz, 1 H, H3), 4.37 (d, J = 4.3 Hz, 1 H, H7), 5.13 (d, J = 9.2 Hz, 1 H, OH), 5.21 (dd, J = 4.3, 9.2 Hz, 1 H, H6), 6.16 (q, J = 7.0 Hz, 1 H), 7.12-7.41 (m, 8 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.3, 44.8, 52.5, 70.8, 70.9, 78.5, 127.7-130.1, 134.0, 139.2, 174.5.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found: 379.0770.
(-)-(6 R ,7 R )-7-(3,4-Dichlorophenyl)-6-hydroxy-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (19a)
Yield: 0.247 mmol (47%); R f = 0.88 (EtOAc-PE, 50:50).
[α]D ²0 -83.4 (c 1.0, CH2Cl2).
IR (KBr): 3393, 1642, 1464, 1113, 739 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.61 (d, J = 7.1 Hz, 3 H), 3.10 (dd, J = 4.1, 16.4 Hz, 1 H, H3), 3.35 (dd, J = 9.8, 16.4 Hz, 1 H, H3), 3.50 (dd, J = 9.8, 12.9 Hz, 1 H, H2), 4.10 (dd, J = 3.9, 12.9 Hz, 1 H, H2), 4.22 (d, J = 9.0 Hz, 1 H, OH), 4.36 (dd, J = 4.1, 9.0 Hz, 1 H, H6), 4.48 (d, J = 4.1 Hz, 1 H, H7), 6.11 (q, J = 7.1 Hz, 1 H), 7.18-7.49 (m, 8 H).
¹³C NMR (100 MHz, CDCl3): δ = 16.4, 45.4, 52.7, 70.6, 73.3, 80.7, 127.0-132.2, 138.8, 139.4, 173.7.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found: 379.0773.
(-)-(6 S ,7 S )-7-(3,4-Dichlorophenyl)-6-hydroxy-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (19b)
Yield: 0.211 mmol (40%); R f = 0.79 (EtOAc-PE, 50:50).
[α]D ²0 -143.6 (c 1.0, CH2Cl2).
IR (KBr): 3397, 1642, 1460, 1390, 1114, 739 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.53 (d, J = 7.0 Hz, 3 H), 2.89 (dd, J = 9.4, 13.1 Hz, 1 H, H3), 3.18 (dd, J = 3.8, 15.8 Hz, 1 H, H2), 3.57 (dd, J = 9.4, 15.8 Hz, 1 H, H2), 3.73 (dd, J = 3.8, 13.1 Hz, 1 H, H3), 4.15 (d, J = 9.0 Hz, 1 H, OH), 4.33 (dd, J = 4.0, 9.0 Hz, 1 H, H6), 4.49 (d, J = 4.0 Hz, 1 H, H7), 6.15 (q, J = 7.0 Hz, 1 H), 7.19 (dd, J = 2.0, 8.2 Hz, 1 H), 7.38-7.48 (m, 7 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.3, 44.8, 52.7, 69.9, 73.6, 80.6, 127.0-129.9, 139.0, 139.4, 173.7.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found: 379.0778.
(-)-(6 R ,7 R )-7-[4-(Benzyloxy)-3-methoxyphenyl]-6-hydroxy-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (20a)
Yield: 0.104 mmol (52%); R f = 0.53 (EtOAc-PE, 40:60).
[α]D ²0 -139.8 (c 1.0, CH2Cl2).
IR (KBr): 3380, 2924, 1634, 1511, 1460, 1265, 1106 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.53 (d, J = 7.08 Hz, 3 H), 2.91 (dd, J = 9.8, 12.9 Hz, 1 H, H3), 3.16 (dd, J = 3.9, 15.7 Hz, 1 H, H2), 3.59 (dd, J = 9.8, 15.7 Hz, 1 H, H2), 3.73 (dd, J = 3.7, 12.9 Hz, 1 H, H3), 3.90 (s, 3 H, OCH3), 4.15 (d, J = 8.6 Hz, 1 H, OH), 4.45 (m, 2 H, H6, H7), 5.14 (s, 2 H, CH2Ph), 6.16 (q, J = 7.08 Hz, 1 H, H1′), 6.85-6.92 (m, 3 H), 7.25-7.42 (m, 10 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.4, 44.8, 52.6, 55.9, 69.8, 70.9, 73.7, 81.9, 110.8, 113.4, 119.9, 127.2-128.8, 132.4, 137.2, 139.2, 148.0, 149.4, 174.3.
HRMS (ESI): m/z [M] calcd for C27H29NO5: 447.2046; found: 447.2080.
(-)-(6 S ,7 S )-7-[4-(Benzyloxy)-3-methoxyphenyl]-6-hydroxy-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (20b)
Yield: 0.088 mmol (44%); R f = 0.37 (EtOAc-PE, 40:60).
[α]D ²0 -62.8 (c 1.0, CH2Cl2).
IR (KBr): 3390, 2929, 1634, 1509, 1455, 1270, 1110 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.59 (d, J = 7.08 Hz, 3 H), 3.09 (dd, J = 4.0, 16.3 Hz, 1 H, H3), 3.38 (dd, J = 9.8, 16.3 Hz, 1 H, H3), 3.51 (dd, J = 9.8, 12.7 Hz, 1 H, H2), 3.90 (s, 3 H, OCH3), 4.09 (dd, J = 4.0, 12.7 Hz, 1 H, H2), 4.22 (d, J = 8.5 Hz, 1 H, OH), 4.48 (m, 2 H, H6, H7), 5.14 (s, 2 H, CH2Ph), 6.13 (q, J = 7.08 Hz, 1 H, H1′), 6.86-6.94 (m, 3 H), 7.26-7.43 (m, 10 H).
¹³C NMR (100 MHz, CDCl3): δ = 16.53, 45.55, 52.65, 55.91, 70.60, 70.90, 73.50, 82.12, 110.79, 113.45, 120.0, 127.1-132.3, 137.2, 139.1, 148.1, 149.4, 174.4.
HRMS (ESI): m/z [M] calcd for C27H29NO5: 447.2046; found: 447.2080.
(-)-(6 R ,7 R )-6-Hydroxy-7-[3-methoxy-4-(tosyloxy)phenyl]-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (21a)
Yield: 0.155 mmol (52%); R f = 0.68 (EtOAc-PE, 50:50).
[α]D ²0 -52.3 (c 1.0, CH2Cl2).
IR (KBr): 3449, 2929, 1642, 1371, 1177, 1112, 855 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.59 (d, J = 7.1 Hz, 3 H), 2.42 (s, 3 H, CH3-Ph), 3.10 (dd, J = 4.0, 16.3 Hz, 1 H, H3), 3.37 (dd, J = 9.8, 16.3 Hz, 1 H, H3), 3.51 (dd, J = 9.8, 12.7 Hz, 1 H, H2), 3.56 (s, 3 H, OCH3), 4.10 (dd, J = 3.5, 12.7 Hz, 1 H, H2), 4.22 (d, J = 8.8 Hz, 1 H, OH), 4.41 (m, 2 H, H6, H7), 6.12 (q, J = 7.1 Hz, 1 H, H1′), 6.86-6.90 (m, 2 H), 7.11 (d, J = 8.2 Hz, 1 H), 7.26-7.36 (m, 8 H), 7.74 (d, J = 8.3 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 16.5, 21.6, 45.4, 52.7, 55.5, 70.6, 73.4, 76.7, 81.6, 111.8, 123.5, 127.1, 127.9, 128.6, 128.8, 129.3, 139.3, 144.8, 151.4, 174.0.
HRMS (ESI): m/z [M] calcd for C27H29NO7S: 511.1665; found: 511.1691.
(-)-(6 S ,7 S )-6-Hydroxy-7-[3-methoxy-4-(tosyloxy)phenyl]-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (21b)
Yield: 0.132 mmol (46%); R f = 0.57 (EtOAc-PE, 50:50).
[α]D ²0 -120.3 (c 1.0, CH2Cl2).
IR (KBr): 3421, 2929, 1638, 1365, 1112, 860 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.53 (d, J = 7.08 Hz, 3 H), 2.42 (s, 3 H, CH3-Ph), 2.89 (dd, J = 9.4, 13.0 Hz, 1 H, H3), 3.17 (dd, J = 3.9, 15.7 Hz, 1 H, H2), 3.56 (s, 3 H, OCH3), 3.58 (m, 1 H), 3.72 (m, 1 H), 4.15 (d, J = 8.9 Hz, 1 H, OH), 4.36 (dd, J = 4.0, 8.9 Hz, 1 H, H6), 4.44 (d, J = 4.0 Hz, 1 H, H7), 6.14 (q, J = 7.08 Hz, 1 H, H1′), 6.87 (m, 2 H), 7.11 (m, 1 H), 7.26-7.39 (m, 8 H), 7.73 (d, J = 8.3 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.4, 21.6, 44.7, 52.7, 55.5, 69.8, 73.6, 81.4, 111.8, 119.7, 123.5, 127.6, 128.1, 128.6, 128.8, 129.3, 139.1, 139.3, 144.8, 151.4, 174.0.
HRMS (ESI): m/z [M] calcd for C27H29NO7S: 511.1665; found: 511.1687.
(-)-(6 R ,7 R )-6-Hydroxy-4-[( S )-1-phenylethyl]-7-propyl-1,4-oxazepan-5-one (22a)
Yield: 0.2 mmol (54%); R f = 0.82 (EtOAc-PE, 30:70).
[α]D ²0 -87.3 (c 1.0, CH2Cl2).
IR (KBr): 2957, 1639, 1111 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 0.92 (t, J = 7.2 Hz, 3 H), 1.37 (m, 2 H), 1.53 (d, J = 7.0 Hz, 3 H), 1.58 (m, 2 H), 1.89 (m, 1 H), 2.98 (dd, J = 4.0, 16.1 Hz, 1 H), 3.17-3.37 (m, 2 H), 3.97 (dd, J = 4.0, 12.7 Hz, 1 H), 4.12 (dd, J = 4.2, 8.9 Hz, 1 H), 4.45 (d, J = 4.3 Hz, 1 H), 6.08 (q, J = 7.0 Hz, 1 H), 7.23-7.36 (m, 5 H).
¹³C NMR (100 MHz, CDCl3): δ = 13.9, 16.3, 18.0, 34.0, 45.5, 52.2, 70.1, 73.3, 79.3, 127.0, 127.6, 128.5, 139.1, 175.0.
HRMS (ESI): m/z [M] calcd for C16H23NO3: 277.1678; found: 277.1680.
(-)-(6 S ,7 S )-6-Hydroxy-4-[( S )-1-phenylethyl]-7-propyl-1,4-oxazepan-5-one (22b)
Yield: 0.165 mmol (44%); R f = 0.71 (EtOAc-PE, 30:70).
[α]D ²0 -254.4 (c 1.0, CH2Cl2).
IR (KBr): 2957, 1638, 1112 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 0.90 (t, J = 7.3 Hz, 3 H), 1.33 (m, 2 H), 1.49 (d, J = 7.1 Hz, 3 H), 1.54 (m, 1 H), 1.87 (m, 1 H), 2.73 (dd, J = 10.0, 13.0 Hz, 1 H), 3.06 (dd, J = 4.0, 15.7 Hz, 1 H), 3.22 (td, J = 2.8, 8.7 Hz, 1 H), 3.41 (dd, J = 10.0, 15.7 Hz, 1 H), 3.62 (dd, J = 4.0, 13.0 Hz, 1 H), 4.09 (dd, J = 3.5, 8.9 Hz, 1 H), 4.46 (d, J = 3.8 Hz, 1 H), 6.11 (q, J = 7.1 Hz, 1 H), 7.27-7.38 (m, 5 H).
¹³C NMR (100 MHz, CDCl3): δ = 14.3, 15.6, 18.37, 34.4, 45.1, 52.6, 69.7, 73.9, 79.5, 127.9, 128.2, 128.9, 139.5, 175.3.
HRMS (ESI): m/z [M] calcd for C16H23NO3: 277.1678; found: 277.1680.
(-)-(6 R ,7 R )-7-Butyl-6-hydroxy-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (23a)
Yield: 0.2 mmol (54%); R f = 0.86 (EtOAc-PE, 30:70).
[α]D ²0 -61.65 (c 1.0, CH2Cl2).
IR (KBr): 2957, 1638, 1112 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 0.90 (t, J = 7.2 Hz, 3 H), 1.3 (m, 3 H), 1.53 (d, J = 7.0 Hz, 3 H), 1.58 (m, 2 H), 1.93 (m, 1 H), 2.97 (dd, J = 3.9, 16.1 Hz, 1 H), 3.17-3.37 (m, 3 H), 3.98 (dd, J = 3.8, 12.6 Hz, 1 H), 4.13 (dd, J = 4.4, 8.8 Hz, 1 H), 4.45 (d, J = 4.4 Hz, 1 H), 6.08 (q, J = 7.0 Hz, 1 H), 7.23-7.36 (m, 5 H).
¹³C NMR (100 MHz, CDCl3): δ = 14.0, 16.3, 22.6, 27.0, 31.7, 45.5, 52.2, 70.1, 73.3, 79.5, 127.0, 127.6, 128.5, 139.1, 175.0.
HRMS (ESI): m/z [M] calcd for C17H25NO3: 291.1833; found: 291.1843.
(-)-(6 S ,7 S )-7-Butyl-6-hydroxy-4-[( S )-1-phenylethyl]-1,4-oxazepan-5-one (23b)
Yield: 0.164 mmol (44%); R f = 0.76 (EtOAc-PE, 30:70).
[α]D ²0 -197.1 (c 1.0, CH2Cl2).
IR (KBr): 2957, 1638, 1112 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 7.3 Hz, 3 H), 1.29 (m, 3 H), 1.49 (d, J = 7.08 Hz, 3 H), 1.54 (m, 2 H), 1.91 (m, 1 H), 2.73 (dd, J = 10.0, 12.9 Hz, 1 H), 3.05 (dd, J = 4.0, 15.7 Hz, 1 H), 3.21 (td, J = 2.9, 8.7 Hz, 1 H), 3.41 (dd, J = 10.0, 15.7 Hz, 1 H), 3.62 (dd, J = 4.0, 12.9 Hz, 1 H), 4.10 (dd, J = 3.5, 8.9 Hz, 1 H), 4.46 (d, J = 4.1 Hz, 1 H), 6.13 (q, J = 7.08 Hz, 1 H), 7.28-7.38 (m, 5 H).
¹³C NMR (100 MHz, CDCl3): δ = 14.0, 15.2, 22.6, 27.0, 31.7, 44.8, 52.2, 69.4, 73.5, 79.4, 127.5, 127.8, 128.5, 139.2, 175.0.
HRMS (ESI): m/z [M] calcd for C17H25NO3: 291.1833; found: 291.1843.
2-[Hydroxymethyl]-4-[( S )-1-phenylethyl]morpholin-3-ones 24a/24b-33a/33b; General Procedure
To a stirred suspension of Na (14-18 mg) in anhyd THF (3.5 mL), was added a soln of the corresponding trans-diastereomeric mixture of epoxyamide (0.64 mmol) in anhyd THF (5.0 mL) at r.t. The resulting mixture was stirred until the total conversion of the starting material. Finally, the reaction was filtered and quenched by addition of aq brine (20 mL) and the organic phase was separated, dried (anhyd Na2SO4), filtered, and the solvent was removed by evaporation. The resulting diastereomeric mixture was purified via flash column chromatography (silica gel, EtOAc-PE, 1:1).
(-)-(2 S )-2-[( S )-Hydroxy(phenyl)methyl]-4-[( S )-1-phenylethyl]morpholin-3-one (24a)
Yield: 0.333 mmol (57%); R f = 0.51 (EtOAc-PE, 40:60).
[α]D ²0 -144 (c 1.1, CH2Cl2).
IR (KBr): 3405, 1630, 1447, 701 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.40 (d, J = 7.2 Hz, 3 H), 2.67 (d, J = 12.2 Hz, 1 H, H5), 3.17 (td, J = 4.1, 11.5 Hz, 1 H, H6), 3.42 (td, J = 2.9, 11.5 Hz, 1 H, H6), 3.80 (ddd, J = 1.3, 3.9, 11.8 Hz, 1 H, H5), 4.28 (d, J = 7.1 Hz, 1 H, H2), 4.99 (d, J = 7.1 Hz, 1 H, H1′′), 6.02 (q, J = 7.2 Hz, 1 H), 7.26-7.45 (m, 10 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.0, 39.9, 49.8, 63.0, 74.4, 78.8, 127.1-128.5, 138.9, 139.9, 168.4.
HRMS (ESI): m/z [M] calcd for C19H21NO3: 311.1521; found: 311.1539.
(+)-(2 R )-2-[( R )-Hydroxy(phenyl)methyl]-4-[( S )-1-phenylethyl]morpholin-3-one (24b)
Yield: 0.283 mmol (38%); R f = 0.35 (EtOAc-PE, 40:60).
[α]D ²0 +1.53 (c 1.0, CH2Cl2).
IR (KBr): 3416, 1623, 1454, 700 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.49 (d, J = 7.1 Hz, 3 H), 2.78 (m, 1 H, H5), 2.92 (dt, J = 2.7, 12.6 Hz, 1 H, H5), 3.61 (td, J = 3.2, 10.12, 11.9 Hz, 1 H, H6), 3.80 (ddd, J = 2.7, 4.15, 11.9 Hz, 1 H, H6), 4.32 (d, J = 7.0 Hz, 1 H, H1′′), 5.03 (d, J = 7.0 Hz, 1 H, H2), 5.97 (q, J = 7.1 Hz, 1 H, H1′), 7.05-7.44 (m, 10 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.0, 40.4, 49.9, 63.0, 74.4, 79.1, 127.3-128.5, 138.5, 140.0, 168.2.
HRMS (ESI): m/z [M] calcd for C19H21NO3: 311.1521; found: 311.1537.
(+)-(2 S )-2-[( S )-Hydroxy(2-nitrophenyl)methyl]-4-[( S )-1-phenylethyl]morpholin-3-one (25a)
Yield: 0.363 mmol (52%); R f = 0.85 (EtOAc-PE, 50:50).
[α]D ²0 +113.3 (c 1.1, CH2Cl2).
IR (KBr): 3374, 1627, 1528, 737 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.58 (d, J = 7.2 Hz, 3 H), 2.75 (m, 1 H), 3.39 (m, 2 H), 3.78 (m, 1 H), 3.99 (d, J = 8.8 Hz, 1 H, H1′′), 5.53 (br, 1 H, OH), 5.86 (d, J = 8.8 Hz, 1 H, H2), 6.06 (q, J = 7.2 Hz, 1 H), 7.23-7.37 (m, 5 H), 7.26 (td, J = 1.6, 7.6, 8.0 Hz, 1 H), 7.64 (td, J = 0.8, 7.6, 8.0 Hz, 1 H), 7.81 (dd, J = 0.8, 1.2, 8.2 Hz, 1 H), 7.99 (dd, J = 1.2, 1.6, 7.8 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.3, 40.0, 50.2, 63.1, 68.4, 78.5, 123.8, 127.2-128.7, 132.8, 134.6, 138.9, 168.9.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1390.
(-)-(2 R )-2-[( R )-Hydroxy(2-nitrophenyl)methyl]-4-[( S )-1-phenylethyl]morpholin-3-one (25b)
Yield: 0.309 mmol (44%); R f = 0.68 (EtOAc-PE, 50:50).
[α]D ²0 -169 (c 1.1, CH2Cl2).
IR (KBr): 3365, 1630, 1510, 724 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.54 (d, J = 7.1 Hz, 3 H), 2.98 (m, 2 H, H5, H6), 3.59 (td, J = 3.4, 8.8, 12.0 Hz, 1 H, H5), 3.75 (dt, J = 3.7, 11.8 Hz, 1 H, H6), 4.02 (d, J = 8.4 Hz, 1 H, H1′′), 5.53 (br, 1 H, OH), 5.86 (d, J = 8.4 Hz, 1 H, H2), 6.04 (q, J = 7.1 Hz, 1 H, H1′), 7.29-7.45 (m, 6 H), 7.64 (m, 1 H), 7.82 (dd, J = 1.2, 8.0 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.2, 40.5, 50.3, 62.9, 68.4, 78.5, 123.8, 127.3-128.8, 132.8, 134.7, 138.3, 168.8.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1385.
(-)-(2 S )-2-[( S )-Hydroxy(3-nitrophenyl)methyl]-4-[( S )-1-phenylethyl]morpholin-3-one (26a)
Yield: 0.204 mmol (49%).
[α]D ²0 -134 (c 1.1, CH2Cl2); R f = 0.79 (EtOAc-PE, 50:50).
IR (KBr): 3414, 2926, 1628, 1528, 1347 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.50 (d, J = 7.1 Hz, 3 H), 2.77 (m, 1 H), 3.32 (td, J = 4.2, 11.5 Hz, 1 H), 3.47 (td, J = 2.9, 11.5 Hz, 1 H), 3.87 (ddd, J = 1.4, 4.2, 11.8 Hz, 1 H), 4.19 (d, J = 7.7 Hz, 1 H, H1′′), 5.08 (d, J = 7.7 Hz, 1 H, H2), 5.51 (br, OH), 6.06 (q, J = 7.2 Hz, 1 H, H1′), 7.28-7.37 (m, 5 H), 7.51 (t, J = 7.9 Hz, 1 H), 7.81 (m, 1 H), 8.16 (m, 1 H), 8.34 (m, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.2, 40.0, 50.1, 63.2, 73.5, 78.3, 122.6, 127.1-128.7, 133.7, 138.7, 142.3, 168.3.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1389.
(-)-(2 R )-2-[( R )-Hydroxy(3-nitrophenyl)methyl]-4-[( S )-1-phenylethyl]morpholin-3-one (26b)
Yield: 0.174 mmol (41%); R f = 0.41 (EtOAc-PE, 50:50).
[α]D ²0 -0.6 (c 1.1, CH2Cl2).
IR (KBr): 3378, 2940, 1640, 1527, 1330 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.53 (d, J = 7.1 Hz, 3 H), 2.86 (m, 1 H), 3.00 (dt, J = 2.4, 12.6 Hz, 1 H), 3.67 (m, 1 H), 3.86 (ddd, J = 2.3, 4.1, 11.9 Hz, 1 H), 4.22 (d, J = 7.4 Hz, 1 H, H1′′), 5.09 (d, J = 7.4 Hz, 1 H, H2), 6.00 (q, J = 7.1 Hz, 1 H, H1′), 7.15-7.35 (m, 5 H), 7.49 (t, J = 7.9 Hz, 1 H), 7.78 (d, J = 7.6 Hz, 1 H), 8.1 (m, 1 H), 8.33 (m, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.0, 40.3, 50.1, 63.0, 73.4, 78.4, 122.7, 127.2-128.7, 133.8, 138.2, 142.3, 168.0.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1389.
(-)-(2 S )-2-[( S )-Hydroxy(4-nitrophenyl)methyl]-4-[( S )-1-phenylethyl]morpholin-3-one (27a)
Yield: 0.341 mmol (48%); R f = 0.8 (EtOAc-PE, 50:50).
[α]D ²0 -75.4 (c 1.0, CH2Cl2).
IR (KBr): 3450, 2925, 1630, 1528, 1340 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.49 (d, J = 7.2 Hz, 3 H), 2.75 (m, 1 H), 3.29 (td, J = 4.2, 11.6 Hz, 1 H), 3.47 (td, J = 2.9, 11.6 Hz, 1 H), 3.85 (ddd, J = 1.4, 4.1, 11.8 Hz, 1 H), 4.19 (d, J = 7.5 Hz, 1 H), 5.09 (d, J = 7.5 Hz, 1 H), 6.05 (q, J = 7.2 Hz, 1 H), 7.28-7.37 (m, 5 H), 7.64 (m, 2 H), 8.19 (m, 2 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.5, 40.3, 50.4, 63.5, 73.9, 78.7, 123.3, 127.4-129.0, 139.0, 147.8, 168.4.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1387.
(+)-(2 R )-2-[( R )-Hydroxy(4-nitrophenyl)methyl]-4-[( S )-1-phenylethyl]morpholin-3-one (27b)
Yield: 0.290 mmol (42%); R f = 0.44 (EtOAc-PE, 50:50).
[α]D ²0 +12.8 (c 1.0, CH2Cl2).
IR (KBr): 3398, 2929, 1630, 1526, 1347 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.52 (d, J = 7.1 Hz, 3 H), 2.82 (m, J = 4.2, 10.4, 12.5 Hz, 1 H), 3.00 (dt, J = 2.6, 12.6 Hz, 1 H), 3.65 (m, J = 3.2, 10.4, 11.9 Hz, 1 H), 3.85 (ddd, J = 2.3, 4.3, 11.9 Hz, 1 H), 4.24 (d, J = 7.1 Hz, 2 H), 5.12 (d, J = 7.1 Hz, 1 H), 6.98 (q, J = 7.1 Hz, 1 H), 7.14-7.34 (m, 5 H), 7.61 (m, 2 H), 8.16 (m, 2 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.1, 40.3, 50.2, 63.1, 73.6, 78.6, 123.0, 127.3-128.6, 138.3, 147.4, 167.8.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found: 356.1389.
(-)-(2 S )-2-[( S )-(2,6-Dichlorophenyl)hydroxymethyl]-4-[( S )-1-phenylethyl]morpholin-3-one (28a)
Yield: 0.170 mmol (21%); R f = 0.86 (EtOAc-PE, 50:50).
[α]D ²0 -6.3 (c 0.9, CH2Cl2).
IR (KBr): 3401, 2930, 1635, 1464, 1135, 1063, 1037 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.60 (d, J = 7.1 Hz, 3 H), 2.83 (td, J = 3.2, 12.4 Hz, 1 H), 3.37 (ddd, J = 3.9, 9.2, 12.6 Hz, 1 H), 3.55 (ddd, J = 3.1, 9.2, 12.0 Hz, 1 H), 3.88 (td, J = 3.6, 11.9 Hz, 1 H), 5.01 (d, J = 9.6 Hz, 1 H), 5.41 (d, J = 1.2 Hz, 1 H), 5.76 (dd, J = 1.1, 9.6 Hz, 1 H), 6.11 (q, J = 7.1 Hz, 1 H), 7.14 (dd, J = 7.6, 8.4 Hz, 1 H), 7.29-7.39 (m, 7 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.3, 40.3, 50.0, 63.1, 71.0, 74.7, 127.2, 127.8, 128.7, 129.3, 133.8, 138.8, 169.6.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found: 379.0755.
(-)-(2 R )-2-[( R )-(2,6-Dichlorophenyl)hydroxymethyl]-4-[( S )-1-phenylethyl]morpholin-3-one (28b)
Yield: 0.145 mmol (19%); R f = 0.77 (EtOAc-PE, 50:50).
[α]D ²0 -5.3 (c 0.9, CH2Cl2).
IR (KBr): 3401, 2930, 1635, 1464, 1135, 1063, 1037 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.57 (d, J = 7.1 Hz, 3 H), 2.93 (ddd, J = 3.9, 7.5, 12.5 Hz, 1 H), 3.17 (ddd, J = 3.5, 5.1, 12.5 Hz, 1 H), 3.69 (ddd, J = 3.5, 7.5, 11.9 Hz, 1 H), 3.84 (ddd, J = 3.9, 5.1, 11.9 Hz, 1 H), 5.06 (d, J = 9.6 Hz, 1 H), 5.39 (d, J = 1.3 Hz, 1 H), 5.78 (dd, J = 1.3, 9.6 Hz, 1 H), 6.12 (q, J = 7.1 Hz, 1 H), 7.13-7.42 (m, 8 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.1, 40.5, 50.0, 62.6, 70.8, 74.5, 122.9, 127.3, 127.8, 128.7, 129.4, 133.9, 138.6, 169.6.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found: 379.0759.
(-)-(2 S )-2-[( S )-(3,4-Dichlorophenyl)hydroxymethyl]-4-[( S )-1-phenylethyl]morpholin-3-one (29a)
Yield: 0.217 mmol (45.5%); R f = 0.47 (EtOAc-PE, 50:50).
[α]D ²0 -129.0 (c 1.0, CH2Cl2).
IR (KBr): 3401, 2930, 1635, 1464, 1135, 1063, 1037 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.47 (d, J = 7.2 Hz, 3 H), 2.73 (m, 1 H), 3.26 (td, J = 4.1, 11.5 Hz, 1 H), 3.45 (td, J = 2.9, 11.5 Hz, 1 H), 3.84 (ddd, J = 1.5, 4.1, 11.8 Hz, 1 H), 4.15 (d, J = 7.4 Hz, 1 H), 4.94 (d, J = 7.4 Hz, 1 H), 6.04 (q, J = 7.2 Hz, 1 H), 7.28-7.37 (m, 5 H), 7.64 (m, 2 H), 8.19 (m, 2 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.2, 40.0, 50.0, 63.2, 73.3, 78.5, 127.0-131.9, 138.8, 140.5, 168.2.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found: 379.0766.
(+)-(2 R )-2-[( R )-(3,4-Dichlorophenyl)hydroxymethyl]-4-[( S )-1-phenylethyl] morpholin-3-one (29b)
Yield: 0.185 mmol (39.5%); R f = 0.17 (EtOAc-PE, 50:50).
[α]D ²0 +3.0 (c 1.0, CH2Cl2).
IR (KBr): 3398, 2929, 1635, 1460, 1130, 1050, 1028 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.51 (d, J = 7.1 Hz, 3 H), 2.81 (m, J = 4.2, 10.4, 12.6 Hz, 1 H), 2.95 (dt, J = 2.5, 12.6 Hz, 1 H), 3.64 (ddd, J = 3.2, 10.4, 11.9 Hz, 1 H), 3.85 (ddd, J = 2.4, 4.2, 11.9 Hz, 1 H), 4.21 (d, J = 7.0 Hz, 1 H), 4.97 (d, J = 7.0 Hz, 1 H), 5.97 (q, J = 7.1 Hz, 1 H), 7.10 (m, 2 H), 7.26-7.39 (m, 5 H), 7.57 (d, J = 1.9 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.0, 40.4, 50.1, 63.1, 73.3, 78.7, 127.2-132.0, 138.3, 140.4, 167.9.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found: 379.0770.
(-)-(2 S )-2-{( S )-[4-(Benzyloxy)-3-methoxyphenyl]hydroxymethyl}-4-[( S )-1-phenylethyl]morpholin-3-one (30a)
Yield: 0.072 mmol (40.5%); R f = 0.25 (EtOAc-PE, 90:10).
[α]D ²0 -87.0 (c 1.1, CH2Cl2).
IR (KBr): 3418, 2927, 1640, 1511, 1265, 1138, 699 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.44 (d, J = 7.2 Hz, 3 H), 2.72 (dt, J = 1.9, 12.2 Hz, 1 H), 3.25 (dd, J = 4.1, 11.5, 1 H), 3.48 (dd, J = 2.9, 11.4 Hz, 1 H), 3.86 (ddd, J = 1.6, 4.0, 11.8 Hz, 1 H), 3.91 (s, 3 H), 4.25 (d, J = 7.5, 1 H), 4.90 (d, J = 7.5 Hz, 1 H), 5.07 (br, 1 H), 5.15 (s, 2 H), 6.04 (q, J = 7.2 Hz, 1 H), 6.87 (m, 2 H), 7.07 (d, J = 1.8 Hz, 1 H), 7.25-7.44 (m, 10 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.2, 40.1, 49.9, 55.9, 63.2, 70.8, 74.4, 78.8, 110.8, 113.2, 120.0, 127.2, 127.7, 127.8, 128.5, 128.7, 133.2, 137.2, 139.1, 147.9, 149.3, 168.8.
HRMS (ESI): m/z [M] calcd for C27H29NO5: 447.2046; found: 447.2051.
(+)-(2 R )-2-{( R )-[4-(Benzyloxy)-3-methoxyphenyl]hydroxymethyl}-4-[( S )-1-phenylethyl]morpholin-3-one (30b)
Yield: 0.061 mmol (34.5%); R f = 0.11 (EtOAc-PE, 90:10).
[α]D ²0 +7.0 (c 1.0, CH2Cl2).
IR (KBr): 3418, 2927, 1640, 1511, 1265, 1138, 699 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.51 (d, J = 7.0 Hz, 3 H), 2.82 (m, 1 H), 2.96 (dt, J = 2.7, 12.5 Hz, 1 H), 3.65 (td, J = 3.2, 11.9 Hz, 1 H), 3.84 (dd, J = 2.8, 7.9 Hz, 1 H), 3.87 (s, 3 H), 4.30 (d, J = 7.2 Hz, 1 H), 4.95 (d, J = 7.2 Hz, 1 H), 5.1 (s, 2 H), 5.99 (q, J = 7.0 Hz, 1 H), 6.86 (m, 2 H), 7.0 (m, 1 H), 7.25-7.44 (m, 10 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.0, 40.4, 49.9, 55.9, 63.0, 70.8, 74.3, 79.0, 111.0, 113.1, 120.2, 127.2-128.6, 137.2, 138.5, 148.0, 149.3, 168.4.
HRMS (ESI): m/z [M] calcd for C27H29NO5: 447.2046; found: 447.2055.
(-)-(2 S )-2-{( S )-[3-Methoxy-4-(tosyloxy)phenyl]hydroxymethyl}-4-[( S )-1-phenylethyl]morpholin-3-one (31a)
Yield: 0.116 mmol (46%); R f = 0.2 (EtOAc-PE, 50:50).
[α]D ²0 -88.4 (c 1.0, CH2Cl2).
IR (KBr): 3449, 1642, 1271, 1177, 700 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.46 (d, J = 7.2 Hz, 3 H), 2.43 (s, 3 H), 2.73 (m, 1 H), 3.25 (td, J = 4.1, 11.5 Hz, 1 H), 3.46 (td, J = 2.9, 11.8 Hz, 1 H), 3.56 (s, 3 H), 3.85 (ddd, J = 1.5, 4.0, 11.8 Hz, 1 H), 4.17 (d, J = 7.4 Hz, 1 H), 4.93 (d, J = 7.4 Hz, 1 H), 6.03 (q, J = 7.2 Hz, 1 H), 6.94 (dd, J = 1.9, 8.3 Hz, 1 H), 7.0 (d, J = 1.8 Hz, 1 H), 7.10 (d, J = 8.2 Hz, 1 H), 7.26-7.39 (m, 6 H), 7.74 (d, J = 8.3 Hz, 2 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.2, 21.6, 40.1, 50.0, 55.5, 63.2, 74.1, 78.6, 111.6, 119.9, 123.1, 127.2-129.3, 137.9, 138.9, 140.3, 144.9, 151.4, 168.5.
HRMS (ESI): m/z [M] calcd for C27H29NO7S: 511.1665; found: 511.1684.
(+)-(2 R )-2-{( R )-[3-Methoxy-4-(tosyloxy)phenyl]hydroxymethyl}-4-[( S )-1-phenylethyl]morpholin-3-one (31b)
Yield: 0.098 mmol (39%); R f = 0.06 (EtOAc-PE, 50:50).
[α]D ²0 +4.2 (c 1.0, CH2Cl2).
IR (KBr): 3450, 1643, 1271, 1177, 700 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.52 (d, J = 7.0 Hz, 3 H), 2.43 (s, 3 H), 2.8 (ddd, J = 4.3, 10.0, 12.6 Hz, 1 H), 2.97 (dt, J = 2.6, 12.6 Hz, 1 H), 3.53 (s, 3 H), 3.61 (m, 2 H), 3.82 (ddd, J = 2.6, 4.1, 11.8 Hz, 1 H), 4.19 (d, J = 7.5 Hz, 1 H), 4.94 (d, J = 7.3 Hz, 1 H), 5.98 (q, J = 7.0 Hz, 1 H), 6.93 (dd, J = 1.8, 8.3 Hz, 1 H), 6.90 (d, J = 1.8 Hz, 1 H), 7.08-7.15 (m, 3 H), 7.26-7.36 (m, 5 H), 7.74 (d, J = 8.3 Hz, 1 H).
¹³C NMR (100 MHz, CDCl3): δ = 15.1, 21.6, 40.5, 50.1, 55.5, 63.0, 73.9, 78.7, 111.8, 120.0, 123.2, 127.2-129.3, 140.3, 144.9, 151.4, 168.3.
HRMS (ESI): m/z [M] calcd for C27H29NO7S: 511.1665; found: 511.1687.
(-)-2 S )-2-[( S )-1-Hydroxybutyl]-4-[( S )-1-phenylethyl)morpholin-3-one (32a)
Yield: 0.15 mmol (46%); R f = 0.80 (EtOAc-PE, 50:50).
[α]D ²0 -194.2 (c 1.0, CH2Cl2).
IR (KBr): 3415, 2955, 1626 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 7.0 Hz, 3 H), 1.44 (m, 2 H), 1.53 (d, J = 7.2 Hz, 3 H), 1.60 (m, 2 H), 2.78 (dt, J = 1.9, 11.8 Hz, 1 H), 3.41 (td, J = 4.2, 11.1 Hz, 1 H), 3.56 (td, J = 2.9, 11.1 Hz, 1 H), 3.70 (s, 1 H), 3.93-4.0 (m, 2 H), 4.35 (s, 1 H), 6.06 (q, J = 7.2 Hz, 1 H), 7.27-7.37 (m, 5 H).
¹³C NMR (100 MHz, CDCl3): δ = 14.0, 15.2, 18.1, 34.5, 40.1, 49.6, 63.0, 71.7, 78.8, 127.1, 127.6, 128.5, 139.1, 169.0.
HRMS (ESI): m/z [M] calcd for C16H23NO3: 277.1678; found: 277.1680.
(-)-(2 R )-2-[( R )-1-Hydroxybutyl]-4-[( S )-1-phenylethyl]morpholin-3-one (32b)
Yield: 0.126 mmol (49%); R f = 0.58 (EtOAc-PE, 50:50).
[α]D ²0 -71.25 (c 1.0, CH2Cl2).
IR (KBr): 3415, 2955, 1626 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 7.1 Hz, 3 H), 1.39-1.51 (m, 2 H), 1.53 (d, J = 7.0 Hz, 3 H), 1.55-1.67 (m, 2 H), 2.94 (td, J = 4.3, 12.5 Hz, 1 H), 3.03 (dt, J = 2.9, 12.3 Hz, 1 H), 3.71 (ddd, J = 3.4, 10.1, 11.7 Hz, 1 H), 3.92 (ddd, J = 2.6, 4.2, 11.8 Hz, 1 H), 3.97 (dd, J = 7 Hz, 1 H), 4.32 (br, 1 H), 6.0 (q, J = 7.0 Hz, 1 H), 7.27-7.38 (m, 5 H).
¹³C NMR (100 MHz, CDCl3): δ = 14.0, 15.0, 18.1, 34.7, 40.4, 49.8, 62.9, 71.7, 78.7, 127.3, 127.7, 128.5, 138.7, 169.1.
HRMS (ESI): m/z [M] calcd for C16H23NO3: 277.1678; found: 277.1680.
(-)-(2 S )-2-[( S )-1-Hydroxypentyl)-4-[( S )-1-phenylethyl]morpholin-3-one (33a)
Yield: 0.153 mmol (44%); R f = 0.76 (EtOAc-PE, 50:50).
[α]D ²0 -162.2 (c 1.0, CH2Cl2).
IR (KBr): 3415, 2955, 1626 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 0.91 (t, J = 7.3 Hz, 3 H), 1.35 (m, 4 H), 1.53 (d, J = 7.2 Hz, 3 H), 1.69 (m, 1 H), 2.78 (dt, J = 2.0, 12.0 Hz, 1 H), 3.4 (td, J = 4.2, 11.4 Hz, 1 H), 3.56 (td, J = 2.9, 11.4 Hz, 1 H), 3.69 (s, 1 H), 3.96 (m, 3 H), 4.35 (s, 1 H), 6.06 (q, J = 7.2 Hz, 1 H), 7.26-7.37 (m, 5 H).
¹³C NMR (100 MHz, CDCl3): δ = 13.9, 15.2, 22.6, 27.0, 32.1, 40.21, 49.6, 63.0, 71.9, 78.8, 127.1, 127.6, 128.5, 139.1, 169.0.
HRMS (ESI): m/z [M] calcd for C17H25NO3: 291.1834; found: 291.1838.
(-)-(2 R )-2-[( R )-1-Hydroxypentyl]-4-[( S )-1-phenylethyl]morpholin-3-one (33b)
Yield: 0.125 mmol (36%); R f = 0.54 (EtOAc-PE, 50:50).
[α]D ²0 -98.75 (c 1.0, CH2Cl2).
IR (KBr): 3415, 2955, 1626 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 0.91 (t, J = 7.2 Hz, 3 H), 1.35 (m, 4 H), 1.53 (d, J = 7.1 Hz, 3 H), 1.67 (m, 1 H), 2.94 (td, J = 4.3, 10.0 Hz, 1 H), 3.03 (dt, J = 2.6, 12.4 Hz, 1 H), 3.71 (td, J = 3.4, 10.0 Hz, 1 H), 3.90-3.99 (m, 3 H), 4.31 (br, 1 H), 6.0 (q, J = 7.1 Hz, 1 H), 7.27-7.32 (m, 5 H).
¹³C NMR (100 MHz, CDCl3): δ = 14.0, 14.9, 22.7, 27.0, 32.3, 40.4, 49.7, 62.9, 71.9, 78.7, 127.3, 127.7, 128.5, 138.7, 169.1.
HRMS (ESI): m/z [M] calcd for C17H25NO3: 291.1834; found: 291.1838.
(+)-(6 S ,7 R )-7-Phenyl-4-[( S )-1-phenylethyl]-1,4-oxazepan-6-ol (34)
To a stirred soln of 1,4-oxazepan-5-one 14a (0.138 g, 0.443 mmol) in anhyd THF (6 mL) at 0 ˚C, under N2, was added BH3˙SMe2 (0.084 g, 1.10 mmol). The mixture was stirred at r.t. for 12 h. Later, the reaction was quenched with MeOH (6 mL) and stirred for 1 h. Finally, the solvent was evaporated under reduced pressure, and the crude was purified via flash chromatography column giving the desired compound 34 (0.120 g, 0.403 mmol, 91%) as a white oil; R f = 0.7 (EtOAc-PE, 50:50).
[α]D ²0 +12.0 (c 1.0, CH2Cl2).
IR (KBr): 3416, 2930, 1451, 700 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 1.42 (d, J = 6.8 Hz, 3 H), 2.71 (m, 2 H), 2.86 (m, 2 H), 3.78-3.91 (m, 3 H), 4.0 (dt, J = 2.6, 13.0 Hz, 1 H), 4.70 (d, J = 2.0 Hz, 1 H), 7.17-7.35 (m, 10 H).
¹³C NMR (100 MHz, CDCl3): δ = 16.4, 50.9, 55.0, 63.4, 69.4, 74.7, 87.4, 125.8, 127.0, 127.2, 127.5, 128.1, 128.2, 141.5, 142.2.
HRMS (ESI): m/z [M] calcd for C19H23NO2: 297.1729; found: 297.1731.
(-)-(6 S ,7 R )-7-Phenyl-1,4-oxazepan-6-ol (35)
To a stirred suspension of 10% Pd-C (0.08 g) in abs EtOH (6 mL) at r.t. was added 1,4-oxazepan-6-ol 34 (0.08 g, 0.286 mmol). To the resulting mixture, ammonium formate (0.09 g, 1.42 mmol) was added and the mixture was refluxed for 5 min. Finally, the mixture was filtered through a path of diatomite and the solvent was eliminated in vacuo giving the desired compound 35 (0.252 mmol, 90%); R f = 0.31 (EtOAc-MeOH, 50:50).
[α]D ²0 -14.7 (c 1.0, CH2Cl2).
IR (KBr): 3381, 2924, 1597, 1130, 1070, 1020 cm-¹.
¹H NMR (400 MHz, CDCl3): δ = 3.11 (m, 1 H), 3.2 (m, 2 H), 3.97-4.03 (m, 1 H), 4.13 (m, 2 H), 4.70 (d, J = 3.2, Hz, 1 H), 6.29 (br, 2 H), 7.23-7.38 (m, 5 H).
¹³C NMR (100 MHz, CDCl3): δ = 48.9, 49.8, 68.4, 74.5, 86.9, 125.8, 127.6, 128.4, 140.7.
HRMS (ESI): m/z [M] calcd for C11H15NO2: 193.1103; found: 193.1105.
Acknowledgment
We are grateful to CONACyT (Project 83185) for financial support, D.M.A.S. thanks CONACyT for the scholarship (169011).
- 1a
Witjman R.Vink MKS.Schoemaker HE.van Delft FL.Blaauw RH.Rutjes FPJ. Synthesis 2004, 641 - 1b
Herreros E.Almela MJ.Lozano S.De las Heras FG.Gargallo-Viola D. Antimicrob. Agents Chemother. 2001, 45: 3132 - 2a
Terán JL.Gnecco D.Galindo A.Juárez J.Bernès S.Enríquez RG. Tetrahedron: Asymmetry 2001, 12: 357 - 2b
Gnecco D.Vázquez E.Galindo A.Terán JL.Orea L.Bernès S.Enríquez RG. ARKIVOC 2003, (xi): 185 - 2c
Roa LF.Gnecco D.Galindo A.Terán JL.Bernès S. Tetrahedron: Asymmetry 2004, 15: 847 - 2d
Roa LF.Gnecco D.Galindo A.Terán JL. Tetrahedron: Asymmetry 2004, 15: 3393 - 2e
Castro A.Juárez J.Gnecco D.Terán JL.Galindo A.Bernès S.Enríquez RG. Tetrahedron: Asymmetry 2005, 16: 949 - 2f
Castro A.Juárez J.Gnecco D.Terán JL.Orea L.Bernès S. Synth. Commun. 2006, 36: 935 - 2g
Castro A.Ramírez J.Juárez J.Terán JL.Orea L.Galindo A.Gnecco D. Heterocycles 2007, 71: 2699 - 2h
Gnecco D.Lumbreras AM.Terán JL.Galindo A.Juárez JR.Orea ML.Castro A.Enríquez RG.Reynolds WF. Heterocycles 2009, 78: 2589 - 2i
Palillero A.Terán JL.Gnecco D.Juárez JR.Orea ML.Castro A. Tetrahedron Lett. 2009, 50: 4208 - 3
Aparicio DM.Terán JL.Gnecco D.Galindo A.Juárez JR.Orea ML.Mendoza A. Tetrahedron: Asymmetry 2009, 20: 2764 - 4a
Sarabia F.Martín-Gálvez F.García-Castro M.Chammaa S.Sánchez-Ruiz A.Tejón-Blanco JF. J. Org. Chem. 2008, 73: 8979 - 4b
Diéz D.Núñez MG.Antón AB.García P.Moro RF.Garrido NM.Marcos IS.Basade P.Urones JG. Curr. Org. Synth. 2008, 5: 186 - 4c
Pino-González MS.Oña N. Tetrahedron: Asymmetry 2008, 19: 721 - 4d
More SS.Vince R. J. Med. Chem. 2008, 51: 4581 - 4e
Aggarwal VK.Charmant JPH.Fuentes D.Harvey JN.Hynd G.Ohara D.Picoul W.Robiette R.Smith C.Vasse J.-L.Winn CL. J. Am. Chem. Soc. 2006, 128: 2105 - 4f
Sarabia F.Sánchez-Ruiz A.Chammaa S. Bioorg. Med. Chem. 2005, 13: 1691 - 4g
Pino-González MS.Assiego C.López-Herrera FJ. Tetrahedron Lett. 2003, 44: 8353 - 4h
Aggarwal VK.Hynd G.Picoul W.Vasse J.-L. J. Am. Chem. Soc. 2002, 124: 9964 - For opening of epoxyamides with nitrogen nucleophiles, see:
- 5a
Valpuesta-Fernández M.Durante Lanes P.López Herrera FJ. Tetrahedron Lett. 1995, 36: 4681 - 5b
Azzena F.Crotti P.Favero L.Pineschi M. Tetrahedron 1995, 51: 13409 - 5c
Izquierdo I.Plaza MT.Robles R.Mota AJ. Tetrahedron: Asymmetry 2000, 11: 4509 - 5d
Martín-Ortiz L.Chammaa S.Pino-González MS.Sánchez-Ruiz A.García-Castro M.Assiego C.Sarabia F. Tetrahedron Lett. 2004, 45: 9069 - For opening of epoxyamides with halides, see:
- 5e
Righi G.Rumboldt G.Bonini C. Tetrahedron 1995, 51: 1340 - 5f
Righi G.Pescatore G.Bonadies F.Bonini C. Tetrahedron 2001, 57: 5649 - 5g
Fringuelli F.Pizzo F.Vaccaro L. J. Org. Chem. 2001, 66: 4719 - For opening of epoxyamides with sulfides, see:
- 5h
Caron M.Sharpless KB. J. Org. Chem. 1985, 50: 1557 - 5i
Behrens CH.Sharpless KB. J. Org. Chem. 1985, 50: 5696 - 5j
Chong JM.Sharpless KB.
J. Org. Chem. 1985, 50: 1560 - 5k
Deng B.-L.Demillequand M.Laurent M.Touillaux R.Belmans M.Kemps L.Cérésiat M.Marchand-Brynaert J. Tetrahedron 2000, 56: 3209 - 5l
Sasaki M.Tanino K.Miyashita M. J. Org. Chem. 2001, 66: 5388 - 5m
Cossy J.Bellosta V.Hamoir C.Desmurs J.-R. Tetrahedron Lett. 2002, 43: 7083 - 5n
Aggarwal VK.Hynd G.Picoul W.Vasse J.-L. J. Am. Chem. Soc. 2002, 124: 9964 - For opening of epoxyamides with selenides, see:
- 5o
Gruttadauria M.Aprile C.D’Anna F.Lo Meo P.Riela S.Noto R. Tetrahedron 2001, 57: 6815 - For opening of epoxyamides with organometallics, see:
- 5p
Sarabia García F.Pedraza Cebrián GM.Heras López A.López Herrera FJ. Tetrahedron 1998, 54: 6867 - 5q
Schneider C.Brauner J. Tetrahedron Lett. 2000, 41: 3043 - 5r
Concellón JM.Bardales E. Org. Lett. 2003, 5: 4783 - For regiospecific opening of epoxyamides with hydrides, see:
- 5s
Kakei H.Nemoto T.Ohshima T.Shibasaki M. Angew Chem. Int. Ed. 2003, 43: 3117 - 6a
Pino-González MS.Assiego C.Ona N. Tetrahedron: Asymmetry 2008, 19: 932 - 6b
Yang L.Deng G.Wang D.-X.Huang Z.-T.Zhu J.-P.Wang M.-X. Org. Lett. 2007, 9: 1387 - 6c
Pino-González MS.Assiego C. Tetrahedron: Asymmetry 2005, 16: 199 - 6d
Assiego C.Pino-González MS.López-Herrera FJ. Tetrahedron Lett. 2004, 45: 2611 - 6e
Pino-González MS.Assiego C.López-Herrera FJ. Tetrahedron Lett. 2003, 44: 8353 - 6f
Valpuesta M.Durante P.López-Herrera FJ. Tetrahedron 1993, 49: 9547 - 7a
Furukawa N.Sugihara Y.Fujihara H. J. Org. Chem. 1989, 54: 4222 - 7b
Li A.-H.Dai L.-X.How X.-L.Huang Y.-Z.Li F.-W. J. Org. Chem. 1996, 61: 489 - 7c
Zhou Y.-G.Hou X.-L.Dai L.-X.Xia L.-J.Tang M.-H. J. Chem. Soc., Perkin Trans. 1 1999, 77 - 7d
Julienne K.Metzner P.Henyron V. J. Chem. Soc., Perkin Trans. 1 1999, 731 - 7e
Hayakawa R.Shimizu M. Synlett 1999, 1328 - 7f
Zanardi J.Leriverend C.Aubert D.Julienne K.Metzner P. J. Org. Chem. 2001, 66: 5620 - 7g
Saito T.Akiba D.Sakairi M.Kanazawa S. Tetrahedron Lett. 2001, 42: 57 - 7h
Winn CL.Bellanie B.Goodman JM. Tetrahedron Lett. 2002, 43: 5427 - 7i
Aggarwal VK.Winn CL. Acc. Chem. Res. 2004, 37: 611 - 8
Woydowski K.Liebscher J. Tetrahedron 1999, 55: 9205 - 9
Karikomi M.Watanabe S.Kimura Y.Uyehara T. Tetrahedron Lett. 2002, 43: 1495 - 10
Sarabia F.Sánchez-Ruiz A. Tetrahedron Lett. 2005, 46: 1131 - 11
Becker CW.Dembofsky BT.Hall JE.Jacobs RT.Pivonka DE.Ohnmacht CJ. Synthesis 2005, 2549 - 12
Sekar G.Singh VK. J. Org. Chem. 1999, 64: 287 - 14
Baldwin J. E. Chem. Commun. 1976, 734
References
When sodium was changed to lithium, the corresponding morpholin-3-one was obtained; however, prolonged reaction times were required.
- 1a
Witjman R.Vink MKS.Schoemaker HE.van Delft FL.Blaauw RH.Rutjes FPJ. Synthesis 2004, 641 - 1b
Herreros E.Almela MJ.Lozano S.De las Heras FG.Gargallo-Viola D. Antimicrob. Agents Chemother. 2001, 45: 3132 - 2a
Terán JL.Gnecco D.Galindo A.Juárez J.Bernès S.Enríquez RG. Tetrahedron: Asymmetry 2001, 12: 357 - 2b
Gnecco D.Vázquez E.Galindo A.Terán JL.Orea L.Bernès S.Enríquez RG. ARKIVOC 2003, (xi): 185 - 2c
Roa LF.Gnecco D.Galindo A.Terán JL.Bernès S. Tetrahedron: Asymmetry 2004, 15: 847 - 2d
Roa LF.Gnecco D.Galindo A.Terán JL. Tetrahedron: Asymmetry 2004, 15: 3393 - 2e
Castro A.Juárez J.Gnecco D.Terán JL.Galindo A.Bernès S.Enríquez RG. Tetrahedron: Asymmetry 2005, 16: 949 - 2f
Castro A.Juárez J.Gnecco D.Terán JL.Orea L.Bernès S. Synth. Commun. 2006, 36: 935 - 2g
Castro A.Ramírez J.Juárez J.Terán JL.Orea L.Galindo A.Gnecco D. Heterocycles 2007, 71: 2699 - 2h
Gnecco D.Lumbreras AM.Terán JL.Galindo A.Juárez JR.Orea ML.Castro A.Enríquez RG.Reynolds WF. Heterocycles 2009, 78: 2589 - 2i
Palillero A.Terán JL.Gnecco D.Juárez JR.Orea ML.Castro A. Tetrahedron Lett. 2009, 50: 4208 - 3
Aparicio DM.Terán JL.Gnecco D.Galindo A.Juárez JR.Orea ML.Mendoza A. Tetrahedron: Asymmetry 2009, 20: 2764 - 4a
Sarabia F.Martín-Gálvez F.García-Castro M.Chammaa S.Sánchez-Ruiz A.Tejón-Blanco JF. J. Org. Chem. 2008, 73: 8979 - 4b
Diéz D.Núñez MG.Antón AB.García P.Moro RF.Garrido NM.Marcos IS.Basade P.Urones JG. Curr. Org. Synth. 2008, 5: 186 - 4c
Pino-González MS.Oña N. Tetrahedron: Asymmetry 2008, 19: 721 - 4d
More SS.Vince R. J. Med. Chem. 2008, 51: 4581 - 4e
Aggarwal VK.Charmant JPH.Fuentes D.Harvey JN.Hynd G.Ohara D.Picoul W.Robiette R.Smith C.Vasse J.-L.Winn CL. J. Am. Chem. Soc. 2006, 128: 2105 - 4f
Sarabia F.Sánchez-Ruiz A.Chammaa S. Bioorg. Med. Chem. 2005, 13: 1691 - 4g
Pino-González MS.Assiego C.López-Herrera FJ. Tetrahedron Lett. 2003, 44: 8353 - 4h
Aggarwal VK.Hynd G.Picoul W.Vasse J.-L. J. Am. Chem. Soc. 2002, 124: 9964 - For opening of epoxyamides with nitrogen nucleophiles, see:
- 5a
Valpuesta-Fernández M.Durante Lanes P.López Herrera FJ. Tetrahedron Lett. 1995, 36: 4681 - 5b
Azzena F.Crotti P.Favero L.Pineschi M. Tetrahedron 1995, 51: 13409 - 5c
Izquierdo I.Plaza MT.Robles R.Mota AJ. Tetrahedron: Asymmetry 2000, 11: 4509 - 5d
Martín-Ortiz L.Chammaa S.Pino-González MS.Sánchez-Ruiz A.García-Castro M.Assiego C.Sarabia F. Tetrahedron Lett. 2004, 45: 9069 - For opening of epoxyamides with halides, see:
- 5e
Righi G.Rumboldt G.Bonini C. Tetrahedron 1995, 51: 1340 - 5f
Righi G.Pescatore G.Bonadies F.Bonini C. Tetrahedron 2001, 57: 5649 - 5g
Fringuelli F.Pizzo F.Vaccaro L. J. Org. Chem. 2001, 66: 4719 - For opening of epoxyamides with sulfides, see:
- 5h
Caron M.Sharpless KB. J. Org. Chem. 1985, 50: 1557 - 5i
Behrens CH.Sharpless KB. J. Org. Chem. 1985, 50: 5696 - 5j
Chong JM.Sharpless KB.
J. Org. Chem. 1985, 50: 1560 - 5k
Deng B.-L.Demillequand M.Laurent M.Touillaux R.Belmans M.Kemps L.Cérésiat M.Marchand-Brynaert J. Tetrahedron 2000, 56: 3209 - 5l
Sasaki M.Tanino K.Miyashita M. J. Org. Chem. 2001, 66: 5388 - 5m
Cossy J.Bellosta V.Hamoir C.Desmurs J.-R. Tetrahedron Lett. 2002, 43: 7083 - 5n
Aggarwal VK.Hynd G.Picoul W.Vasse J.-L. J. Am. Chem. Soc. 2002, 124: 9964 - For opening of epoxyamides with selenides, see:
- 5o
Gruttadauria M.Aprile C.D’Anna F.Lo Meo P.Riela S.Noto R. Tetrahedron 2001, 57: 6815 - For opening of epoxyamides with organometallics, see:
- 5p
Sarabia García F.Pedraza Cebrián GM.Heras López A.López Herrera FJ. Tetrahedron 1998, 54: 6867 - 5q
Schneider C.Brauner J. Tetrahedron Lett. 2000, 41: 3043 - 5r
Concellón JM.Bardales E. Org. Lett. 2003, 5: 4783 - For regiospecific opening of epoxyamides with hydrides, see:
- 5s
Kakei H.Nemoto T.Ohshima T.Shibasaki M. Angew Chem. Int. Ed. 2003, 43: 3117 - 6a
Pino-González MS.Assiego C.Ona N. Tetrahedron: Asymmetry 2008, 19: 932 - 6b
Yang L.Deng G.Wang D.-X.Huang Z.-T.Zhu J.-P.Wang M.-X. Org. Lett. 2007, 9: 1387 - 6c
Pino-González MS.Assiego C. Tetrahedron: Asymmetry 2005, 16: 199 - 6d
Assiego C.Pino-González MS.López-Herrera FJ. Tetrahedron Lett. 2004, 45: 2611 - 6e
Pino-González MS.Assiego C.López-Herrera FJ. Tetrahedron Lett. 2003, 44: 8353 - 6f
Valpuesta M.Durante P.López-Herrera FJ. Tetrahedron 1993, 49: 9547 - 7a
Furukawa N.Sugihara Y.Fujihara H. J. Org. Chem. 1989, 54: 4222 - 7b
Li A.-H.Dai L.-X.How X.-L.Huang Y.-Z.Li F.-W. J. Org. Chem. 1996, 61: 489 - 7c
Zhou Y.-G.Hou X.-L.Dai L.-X.Xia L.-J.Tang M.-H. J. Chem. Soc., Perkin Trans. 1 1999, 77 - 7d
Julienne K.Metzner P.Henyron V. J. Chem. Soc., Perkin Trans. 1 1999, 731 - 7e
Hayakawa R.Shimizu M. Synlett 1999, 1328 - 7f
Zanardi J.Leriverend C.Aubert D.Julienne K.Metzner P. J. Org. Chem. 2001, 66: 5620 - 7g
Saito T.Akiba D.Sakairi M.Kanazawa S. Tetrahedron Lett. 2001, 42: 57 - 7h
Winn CL.Bellanie B.Goodman JM. Tetrahedron Lett. 2002, 43: 5427 - 7i
Aggarwal VK.Winn CL. Acc. Chem. Res. 2004, 37: 611 - 8
Woydowski K.Liebscher J. Tetrahedron 1999, 55: 9205 - 9
Karikomi M.Watanabe S.Kimura Y.Uyehara T. Tetrahedron Lett. 2002, 43: 1495 - 10
Sarabia F.Sánchez-Ruiz A. Tetrahedron Lett. 2005, 46: 1131 - 11
Becker CW.Dembofsky BT.Hall JE.Jacobs RT.Pivonka DE.Ohnmacht CJ. Synthesis 2005, 2549 - 12
Sekar G.Singh VK. J. Org. Chem. 1999, 64: 287 - 14
Baldwin J. E. Chem. Commun. 1976, 734
References
When sodium was changed to lithium, the corresponding morpholin-3-one was obtained; however, prolonged reaction times were required.
Scheme 1 Divergent synthesis of nitrogen heterocycles from epoxyamide 1
Scheme 2 Reagents and conditions: (a) ethylene oxide, H2O, sonication, 20 min, 91%; (b) bromoacetyl bromide, Et3N, CH2Cl2, -10 ˚C; (c) Me2S, CH2Cl2, r.t., 77% from (S)-phenylethylamine (2).
Figure 1 X-ray ORTEP diagram of compound 16a
Figure 2 X-ray ORTEP diagram of compound 24a
Scheme 3