An Efficient Petasis Boronic–Mannich Reaction of Chiral Lactol Derivatives Prepared from d-Araboascorbic Acid

Abstract

Optically active polyhydroxy trans-1,2-amino alcohols were efficiently synthesized in good to excellent yields by the Petasis­ boronic–Mannich reaction of an amine, an organoboronic acid, and a chiral lactol, which was prepared from d-araboascorbic acid or its diastereomer. Further transformations of the resulting Petasis products were investigated in detail to obtain chiral building blocks containing three continuous stereogenic centers.

Multicomponent reactions are highly efficient and atom-economical,[1] and are frequently used to construct various compound libraries in medicinal chemistry. After the pioneering work on multicomponent reactions reported by Petasis,[2] many groups have reported on the Petasis boronic–Mannich (PBM) reaction over the last two decades.[3] Various combinations of each component (amine, aldehyde, and organoboronic acid) in the PBM reaction have been widely studied, and this has allowed the diversity-oriented synthesis of nitrogen-containing molecules.[4] When an α-hydroxy aldehyde is used in the PBM reaction,[2d] [5] the reaction proceeds with high diastereoselectivity due to the assistance of an α-hydroxy directing group, and gives a product with a trans-1,2-amino alcohol unit,[6] which is a useful building block for the synthesis of natural products.[7] [8] Despite the utility of this valuable reaction, this powerful synthetic method has not been used extensively; enantiopure α-hydroxyaldehydes are not easy to prepare[9] or handle due to their keto–enol tautomerization, which also results in a loss of enantiopurity. To further expand the structural diversity of Petasis products, alternative sources of an α-hydroxyaldehyde equivalent are still of great interest in synthetic organic chemistry. Thus, simply structured chiral lactols[2d] [4] and carbohydrates,[10] which are more stable and easier to handle than α-hydroxyaldehydes, have been frequently used in the PBM reaction (Scheme [1]).

In the course of our previous research,[11] we became interested in the use of the PBM reaction as a key step in the synthesis of biologically active molecules. This motivated us to develop the PBM reaction of a densely functionalized chiral lactol, having a four carbon unit with three continuous stereogenic centers, prepared from d-araboascorbic acid (Scheme [1]). The newly designed chiral lactol has several features: (a) A pent-3-ylidene moiety improves the lipophilicity[12] and the stability of the 1,2-diol protection to avoid acetal migration during lactol synthesis. (b) The sterically hindered pent-3-ylidene moiety is expected to be stable under the PBM reaction conditions. (c) The product derived from such a chiral lactol can already embed various functional groups and protecting groups, which situationally allows orthogonal functionalization. In this paper, we report the details of the preparation of chiral lactols and their use in the PBM reaction to provide an array of chiral polyhydroxy trans-1,2-amino alcohol derivatives. The further transformation of the obtained Petasis products is also demonstrated.

Initially, we synthesized the chiral protected lactol, the substrate for the PBM reaction, starting from d-araboascorbic acid (Scheme [2]). A readily available d-araboascorbic acid was treated with 3,3-dimethoxypentane[12] in the presence of a catalytic amount of 4-toluenesulfonic acid monohydride in N,N-dimethylformamide to afford pure protected lactone 1 without purification. Oxidative cleavage of 1 with potassium carbonate and hydrogen peroxide,[13] followed by extraction of the crude product under acidic conditions (pH 4), afforded the crude 2 in 39% yield (2 steps). The unpurified α-hydroxy carboxylic acid 2 was then effectively protected with 2,2-dimethoxypropane without the use of a catalyst in refluxing benzene to afford lactone 3 in 79% yield. When the reaction was carried out in the presence of a catalytic amount of 4-toluenesulfonic acid monohydride in N,N-dimethylformamide at 40 °C, undesirable acetal migration and intramolecular cyclization were observed to give 4.[14] Finally, the lactone 3 was subjected to reducing conditions with diisobutylaluminum hydride in dichloromethane at –78 °C, and the desired lactol 5a was obtained in 91% yield. Due to the lability of 5a towards silica gel chromatography, 5a was used in the PBM reaction without further purification.

Since the chiral lactol 5a was efficiently prepared, the PBM reaction was carried out with benzhydrylamine (6), trans-2-phenylvinylboronic acid (7), and chiral lactol 5a as a model reaction in refluxing methanol for 24 hours (Table [1]). The reaction proceeded smoothly, and the desired product 8a was obtained in 93% isolated yield with complete diastereoselectivity (entry 1), and was obtained in 87% yield with one equivalent each of 6 and 7 at room temperature for one hour (entry 2). Surprisingly, the use of a shorter reaction time (10 min) under identical conditions also gave the desired product 8a in 91% isolated yield. According to these results, the selected combination (5a, 6, and 7) showed good reactivity for the PBM reaction.

Table 1 PBM Reaction of Chiral Lactol 5a with Amine 6 and Organoboronic Acid 7

Entry	6 and 7 (equiv)	Temp (°C)	Time	Yield (%)
1	2.0	reflux	24 h	93
2	1.0	25	1 h	87
3	1.0	25	10 min	91

Next, various combinations of chiral lactol, amine, and boron reagent were examined (Scheme [3]). The reaction of lactol 5a and 7 with allylamine also gave the Petasis product 8b in 69% isolated yield. The reaction of 5a and 7 with secondary amines including dibenzylamine, N-allylbenzylamine, and diallylamine also efficiently proceeded to give 8c, 8d, and 8e in good to excellent yields. The use of 4-methoxyphenylboronic acid instead of 7 in this reaction gave 8f in 80% yield. Furthermore, the reaction of diacetonide-protected lactol 5b or 5c (diastereomer of 5a) with 6 and 7 also afforded the desired products 8g and 8h in 66% and 65% yields, respectively. The chiral lactols 5a–c allowed us to prepare a series of polyhydroxy trans-1,2-amino alcohols with three continuous stereogenic centers.

Next, to demonstrate the synthetic utility of the PBM product 8a, various functional group transformations were examined (Scheme [4]). Protection of the hydroxy group in 8a under usual silylation conditions gave TBS ether 9 in 99% yield, and regioselective reductive acetal cleavage was then efficiently promoted by titanium(IV) chloride and triethylsilane to afford alcohol 10 in 90% yield with >98% regioselectivity. In this reaction, the order of the addition of titanium(IV) chloride and triethylsilane is very important to achieve regioselective acetal cleavage with high regioselectivity. When titanium(IV) chloride was added to a mixture of 9 and triethylsilane, the product 10 was selectively obtained. In contrast, when triethylsilane was added to a mixture of 9 and titanium(IV) chloride, a mixture of 10 and 12 was obtained in 55% and 33% yields, respectively. Interestingly, the order in which the reagents were added changed the selectivity of the reductive acetal cleavage, even if the same reagents were used. The oxidation reaction of the resulting primary hydroxy group of 10 under various conditions (Dess–Martin oxidation, TEMPO oxidation, AZADO oxidation, Swern oxidation, Parikh–Doering oxidation, DMSO/Ac₂O oxidation, and DMSO/P₂O₅ oxidation) did not proceed at all. We assumed that the Lewis basic nitrogen (-NHCHPh₂) might interfere with oxidation. The TBS ether was removed with tetrabutylammonium fluoride (>99% yield), and the resulting diol 11 was treated with di-tert-butyl dicarbonate and triethylamine in the presence of a catalytic amount of 4-(dimethylamino)pyridine to give the cyclic carbamate 13 in 78% yield. Finally, the Boc group on the primary hydroxy group was removed by hydrolysis to yield the alcohol 14, which was easily crystallized and subjected to X-ray structural analysis. As shown in Figure [1], the relative stereochemistry of the 1,2-amino alcohol is in the trans configuration, and thus the absolute stereochemistry was determined to be (2R,3S,4S) based on d-araboascorbic acid.

Appropriately protected 14 was re-subjected to Dess–Martin oxidation conditions, and the desired aldehyde 15 was obtained in 91% yield. These results indicate that protection of the trans-1,2-amino alcohol unit was required for oxidation of the primary alcohol. Presumably, this is due to a change in conformation of the Petasis product and a decrease in the Lewis basicity of nitrogen.

Next, we intended to transform an alkene moiety derived from trans-2-phenylvinylboronic acid (7) (Scheme [5]). Compound 13 was subjected to standard ozonolysis conditions, followed by dimethyl sulfide reduction to give the desired aldehyde 16 in 98% yield. The Horner–Wadsworth­–Emmons reaction of 16 proceeded smoothly to afford ester 17 in 94% yield. Finally, hydrolysis of the Boc group (98% yield) and Dess–Martin oxidation (>99% yield) both worked well to give aldehyde 19. The overall process from the Petasis product 8a gave 15 or 19 in excellent yields. To the best of our knowledge, this is the first example of the use of a highly functionalized chiral lactol prepared from d-araboascorbic acid in the diaste­reoselective PBM reaction.

In conclusion, we have developed an efficient PBM reaction of chiral lactols with three continuous stereogenic carbons, which can provide an array of chiral polyhydroxy trans-1,2-amino alcohol derivatives in good to excellent yields. Furthermore, we also demonstrated transformation of the PBM product through the use of regioselective acetal cleavage, oxidation of a primary alcohol, and ozonolysis. The current examples demonstrate the potential of the PBM reaction in the construction of highly functionalized biologically active chiral molecules. Further transformations of 15 and 19 to more important molecules, such as oseltamivir phosphate, are now underway.

NMR spectra were recorded in CDCl₃ on Varian 400-MR (¹H 400 MHz, ¹³C 100 MHz), Varian 600 System (¹H 600 MHz, ¹³C 150 MHz), and Jeol ECS-400 (¹H 400 MHz, ¹³C 100 MHz) spectrometers; ¹H NMR spectra are relative to residual CHCl₃ (δ = 7.26), ¹³C NMR spectra are relative to CHCl₃ (δ = 77.0). IR spectra were measured with a Jasco FT/IR-4100 spectrophotometer or Shimadzu IRAffinity-1 spectrophotometer. Melting points were recorded on a Sansyo Meltingpoint SMP-300. HRMS was performed on a Jeol JMS-700 MStation FAB-MS (positive mode) at the Mass Spectrometry Facility (Okayama University). Specific rotation was measured with Polarimeter Jasco DIP-1000. TLC was carried out by using Merck precoated silica gel F₂₅₄ plates (thickness 0.25 mm). Flash column chromatography was carried out on Kanto Chemical silica gel 60N (40–50 μm). Unless otherwise noted, all reactions were carried out under an argon atmosphere. MeCN, CH₂Cl₂, and toluene were distilled over CaH₂. MeOH was distilled over Mg and stored with molecular sieves. Anhyd THF, DMF, and benzene were purchased from Wako Pure Chemical Industries. DIBAL-H was purchased from Aldrich. Unless otherwise noted, all materials were purchased from commercial suppliers and used without further purification. CCDC 1008043 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html.

(5R)-5-[(4R)-2,2-Diethyl-1,3-dioxolan-4-yl]-3,4-dihydroxyfuran-2(5H)-one (1)

To a solution of d-araboascorbic acid (20.0 g, 114 mmol) in DMF (56.8 mL) was added 3,3-dimethoxypentane (16.4 g, 136 mmol) and TsOH·H₂O (0.66 g, 3.40 mmol). The mixture was stirred at r.t. for 24 h. The reaction was quenched with Et₃N (0.64 mL, 4.54 mmol) and extracted with Et₂O. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to give 1 (22.0 g, 90.2 mmol, 79%) as a colorless solid. Compound 1 was used for the next reaction without further purification; mp 83–84 °C; [α]_D ²⁰ –15.6 (c 0.5, acetone).

IR (KBr): 3481, 2973, 1762, 1664, 1134 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 4.67 (d, J = 6.9 Hz, 1 H), 4.24 (dt, J = 6.9, 5.1 Hz, 1 H), 4.14 (dd, J = 9.0, 6.3 Hz, 1 H), 4.00 (dd, J = 9.0, 5.1 Hz, 1 H), 1.74 (q, J = 7.5 Hz, 2 H), 1.64 (q, J = 7.5 Hz, 2 H), 0.94 (t, J = 7.5 Hz, 3 H), 0.90 (t, J = 7.5 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 170.5, 151.4, 118.7, 115.1, 76.2, 74.4, 66.2, 29.1, 28.5, 8.2, 8.0.

HRMS (FAB): m/z [M + H]⁺ calcd for C₁₁H₁₇O₆: 245.1025; found: 245.1052.

(2R)-2-[(4R)-2,2-Diethyl-1,3-dioxolan-4-yl]-2-hydroxyacetic Acid (2)

To a solution of 1 (22.0 g, 90.2 mmol) in H₂O (120 mL) was added K₂CO₃ (34.5 g, 250 mmol) and the mixture was cooled to 0 °C. 30 wt% H₂O₂ (22.0 mL, 272 mmol) was slowly added to the mixture so as not to exceed 20 °C. The resulting mixture was stirred at r.t. for 15 h. The reaction was quenched with aq HCl while adjusting pH 4 and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to give a colorless oil (9.0 g, 44.0 mmol, 49%) and used in the next reaction without further purification; [α]_D ²⁰ –2.7 (c 1.0, acetone).

IR (KBr): 3422, 2976, 1736, 1464, 1082 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 4.33–4.27 (m, 2 H), 4.11 (dd, J = 8.7, 6.4 Hz, 1 H), 4.03 (dd, J = 8.7, 5.6 Hz, 1 H), 1.74–1.62, (m, 4 H), 0.92 (t, J = 7.4 Hz, 3 H), 0.89 (t, J = 7.4 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.8, 114.7, 76.1, 70.4, 66.0, 29.2, 28.5, 8.1, 7.9.

HRMS (FAB): m/z [M + H]⁺ calcd for C₉H₁₇O₅: 205.1076; found: 205.1067.

(4R)-4-[(4R)-2,2-Diethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-1,3-dioxolan-5-one (3)

To a solution of 2 (8.7 g, 43 mmol) in benzene (143 mL) was added 2,2-dimethoxypropane (26.8 g, 258 mmol). The mixture was stirred at 100 °C for 14 h with a Dean–Stark trap packed with molecular sieves 4 A. The mixture was evaporated in vacuo and purified by column chromatography (silica gel, hexane–Et₂O, 4:1) to afford 3 (8.3 g 0.34 mmol, 79%) as a colorless liquid; [α]_D ²⁰ –15.2 (c 1.0, acetone­).

IR (KBr): 2976, 1796, 1464, 1134, 919 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 4.54 (d, J = 3.2 Hz, 1 H), 4.39 (dt, J = 6.9, 3.2 Hz, 1 H), 4.05 (dd, J = 15.3, 8.1 Hz, 1 H), 4.03 (dd, J = 15.3, 8.1 Hz, 1 H), 1.70–1.60 (m, 7 H), 1.56 (s, 3 H), 0.89 (t, J = 7.5 Hz, 3 H), 0.89 (t, J = 7.5 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 169.9, 114.2, 111.2, 75.2, 73.7, 64.5, 29.1, 28.8, 26.6, 26.4, 7.9, 7.8.

HRMS (FAB): m/z [M + H]⁺ calcd for C₁₂H₂₁O₃: 245.1389; found: 245.1388.

2,3-O-Isopentylidene-d-erythronolactone (4)[14]

To a solution of 2 (210 mg, 1.04 mmol) in DMF (5.20 mL) was added 3,3-dimethoxypentane (178 mg, 1.25 mmol, 93% purity) and TsOH·H₂O (5.60 mg, 29.0 μmol). The mixture was stirred at 40 °C for 19 h. Since starting material 2 remained, 3,3-dimethoxypentane (355 mg, 2.5 mmol, 93% purity) was added, and the resulting mixture was stirred for 3 h at 40 °C. After the addition of a large excess of 3,3-dimethoxypentane (1.48 g, 10.4 mmol, 93% purity) to the mixture, it was continuous stirred for 14 h at 40 °C. The reaction was quenched with Et₃N (4.2 mg, 0.041 mmol) and H₂O (20 mL). The aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane–EtOAc, 2:1) to afford 4 (168 mg, 0.900 mmol, 88%) as a colorless oil; [α]_D ²⁰ –101.5 (c 1.0, acetone).

IR (KBr): 2976, 1786, 1465, 1185, 1107 cm^–1.

¹H NMR (400 MHz, CDCl₃) δ 4.88 (dd, J = 5.7, 3.7 Hz, 1 H), 4.75 (d, J = 5.7 Hz, 1 H), 4.47 (d, J = 11.0 Hz, 1 H), 4.39 (dd, J = 11.0, 3.7 Hz, 1 H), 1.69 (q, J = 6.4 Hz, 2 H), 1.64 (q, J = 6.4 Hz, 2 H), 0.90 (t, J = 7.4 Hz, 3 H), 0.88 (t, J = 7.4 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.9, 118.3, 75.7, 74.9, 70.4, 29.7, 29.3, 8.2, 7.3.

HRMS (FAB): m/z [M + H]⁺ calcd for C₉H₁₅O₄: 187.0970; found: 187.0969.

(4R)-4-[(4R)-2,2-Diethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-1,3-dioxan-5-ol (5a); Typical Procedure

A solution of 3 (0.74 g 3.0 mmol) in dry CH₂Cl₂ (0.83 mL) was stirred at –78 °C; 1 M DIBAL-H in CH₂Cl₂ (6.0 mmol, 6.0 mL) was added dropwise over 2 min. The mixture was stirred at –78 °C for 2.5 h. After complete consumption of 3 (TLC monitoring), the reaction was quenched with 1 M HCl and extracted with Et₂O. The combined organic phases were dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was a colorless oil (0.68 g, 2.74 mmol, 91%) and it was used in the next reaction without further purification. The lactols 5b and 5c were also prepared from corresponding lactones using same procedure. The lactols 5a, 5b, and 5c (all new compounds) were too unstable to collect various spectral data for characterization.

(1S,2S,E)-2-(Benzhydrylamino)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-4-phenylbut-3-en-1-ol (8a); Typical Procedure

To a solution of 5a (0.38 g, 1.6 mmol) in MeOH (6.5 mL) was added benzhydrylamine (6, 0.53 mL, 3.1 mmol) and trans-2-phenylvinylboronic acid (7, 0.46 g, 3.1 mmol); the mixture was stirred at 100 °C for 24 h. The mixture was evaporated in vacuo and extracted with Et₂O. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane–EtOAc, 4:1) to afford 8a (0.66 g 1.44 mmol, 93%) as a brown oil; [α]_D ²⁰ +40.1 (c 1.0, acetone).

IR (KBr): 3450, 2972, 1710, 1492, 917 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.40–7.19 (m, 15 H), 6.45 (d, J = 16.0 Hz, 1 H), 6.17 (dd, J = 16.0, 8.9 Hz, 1 H), 4.95 (s, 1 H), 4.07 (dt, J = 6.6, 6.4 Hz, 1 H), 4.00 (dt, J = 8.2, 1.0 Hz, 1 H), 3.90–3.85 (m, 2 H), 3.37 (dd, J = 8.9, 4.2 Hz, 1 H), 2.57 (s, 1 H), 1.65–1.55 (m, 4 H), 0.86 (t, J = 7.4 Hz, 3 H), 0.85 (t, J = 7.4 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.1, 143.1, 136.6, 133.9, 128.6, 128.5, 127.7, 127.6, 127.2, 127.2 (3), 127.1, 126.5, 112.7, 74.2, 66.8, 63.6, 60.5, 29.5, 29.1, 8.2, 8.0.

HRMS (FAB): m/z [M + Na]⁺ calcd for C₃₀H₃₅NO₃Na: 480.2515; found: 480.2518.

(1S,2S,E)-2-(Allylamino)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-4-phenylbut-3-en-1-ol (8b)

Following the typical procedure using 5a (51.5 mg, 0.21 mmol), allylamine (31.0 μL, 0.41 mmol), and 7 (65.9 mg, 0.45 mmol) in refluxing MeOH for 15 h gave 8b (47.7 mg, 0.144 mmol, 69%) as a brown oil; [α]_D ²² +16.3 (c 0.26, CH₂Cl₂).

IR (neat): 3445, 2972, 2356, 1078, 918, 754, 694 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.40 (d, J = 8.8 Hz, 2 H), 7.32 (t, J = 7.2 Hz, 2 H), 7.27–7.24 (m, 1 H), 6.61 (d, J = 16.0 Hz, 1 H), 6.16 (dd, J = 16.0, 8.8 Hz, 1 H), 5.96–5.86 (m, 1 H), 5.20 (dd, J = 17.6, 1.2 Hz, 1 H), 5.13 (dd, J = 10.0, 1.2 Hz, 1 H), 4.07 (dd, J = 7.6, 6.4 Hz, 1 H), 4.01 (t, J = 6.4 Hz, 1 H, 3.90 (dd, J = 7.6, 6.8 Hz, 1 H), 3.78 (dd, J = 7.6, 3.6 Hz, 1 H), 3.54 (dd, J = 9.6, 7.6 Hz, 1 H), 3.34 (dd, J = 14.4, 6.0 Hz, 1 H), 3.23 (dd, J = 14.4, 6.0 Hz, 1 H), 2.31 (br s, 2 H), 1.66 (qd, J = 7.2, 3.2 Hz, 2 H), 1.58 (q, J = 7.2 Hz, 2 H), 0.88 (dt, J = 22.0, 7.2 Hz, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 136.6, 136.3, 133.9, 128.5, 127.7, 126.9, 126.4, 116.4, 112.8, 76.3, 73.7, 67.7, 62.4, 49.5, 29.6, 29.1, 8.2, 8.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₃₀NO₃: 332.2220; found: 332.2221.

(1S,2S,E)-2-(Dibenzylamino)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-4-phenylbut-3-en-1-ol (8c)

Following the typical procedure using 5a (51.3 mg, 0.21 mmol), dibenzylamine (80 μL, 0.42 mmol), and 7 (62.5 mg, 0.42 mmol) in refluxing MeOH for 17 h gave 8c (63.9 mg, 0.136 mmol, 65%) as a yellow oil; [α]_D ²⁰ +123.9 (c 0.23, acetone).

IR (KBr): 3463, 2929, 1602, 1495, 698 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.19 (m, 15 H), 6.52 (d, J = 15.9 Hz, 1 H), 6.31 (dd, J = 15.9, 9.6 Hz, 1 H), 4.32 (dt, J = 7.1, 4.2 Hz, 1 H), 4.15 (dd, J = 7.3, 4.2 Hz, 1 H), 3.87 (d, J = 14.0 Hz, 2 H), 3.50 (dt, J = 8.0, 1.5 Hz, 1 H), 3.42 (d, J = 14.0 Hz, 2 H), 3.13 (dd, J = 9.6, 7.3 Hz, 1 H), 2.27 (s, 1 H), 1.62–1.52 (m, 4 H), 1.21 (s, 1 H), 0.84 (t, J = 7.5 Hz, 3 H), 0.82 (t, J = 7.5 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 139.4, 136.6, 135.7, 129.0, 128.6, 128.4, 127.8, 127.2, 126.6, 124.4, 112.3, 76.9, 71.5, 64.5, 63.5, 55.0, 29.5, 29.1, 8.2, 8.0.

HRMS (FAB): m/z [M + H]⁺ calcd for C₃₁H₃₈NO₃: 472.2852; found: 472.2869.

(1S,2S,E)-2-[Allyl(benzyl)amino]-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-4-phenylbut-3-en-1-ol (8d)

Following the typical procedure using 5a (0.56 g, 2.25 mmol), N-allylbenzylamine (0.72 mL, 4.50 mmol), and 7 (0.67 g, 4.50 mmol) in refluxing MeOH for 6 h gave 8d (0.84 g, 2.00 mmol, 89%) as a yellow oil; [α]_D ²³ +115.1 (c 1.0, CH₂Cl₂).

IR (neat): 3472, 2970, 1495, 1454, 914, 752, 694 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.43 (d, J = 7.2 Hz, 2 H), 7.37–7.32 (m, 6 H), 7.29–7.25 (m, 2 H), 6.59 (d, J = 16.0 Hz, 1 H), 6.30 (dd, J = 16.0, 9.6 Hz, 1 H), 5.94–5.83 (m, 1 H), 5.22 (d, J = 16.4 Hz, 1 H), 5.21 (d, J = 10.8 Hz, 1 H), 4.28 (t, J = 5.6 Hz, 1 H), 4.11 (t, J = 5.6 Hz, 1 H), 3.92 (d, J = 14.0 Hz, 1 H), 3.85 (t, J = 8.0 Hz, 1 H), 3.74 (t, J = 8.0 Hz, 1 H), 3.50 (d, J = 14.0 Hz, 1 H), 3.38 (dd, J = 14.4, 4.8 Hz, 1 H), 3.31 (dd, J = 9.6, 6.4 Hz, 1 H), 3.09 (dd, J = 14.4, 7.6 Hz, 1 H), 1.69–1.58 (m, 4 H), 0.89 (t, J = 7.2 Hz, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 139.4, 136.6, 135.6, 135.2, 128.7, 128.4, 128.3, 127.6, 127.0, 126.4, 117.9, 112.3, 76.6, 71.4, 65.3, 64.1, 54.6, 53.4, 29.4, 29.0, 8.1, 7.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₃₆NO₃: 422.2690; found: 422.2690.

(1S,2S,E)-2-(Diallylamino)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-4-phenylbut-3-en-1-ol (8e)

Following the typical procedure using 5a (51.5 mg, 0.21 mmol), diallylamine (50.0 μL, 0.41 mmol), and 7 (64.8 mg, 0.44 mmol) in refluxing MeOH for 15 h gave 8e (63.0 mg, 0.170 mmol, 81%) as a pale yellow oil; [α]_D ²⁴ +94.4 (c 1.0, CH₂Cl₂).

IR (neat): 3445, 2972, 2359, 1599, 1078, 750, 694 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.40 (d, J = 7.2 Hz, 2 H), 7.33 (t, J = 7.2 Hz, 2 H), 7.27–7.25 (m, 1 H), 6.56 (d, J = 16.0 Hz, 1 H), 6.24 (dd, J = 16.0, 9.6 Hz, 1 H), 5.87–5.77 (m, 2 H), 5.20 (d, J = 6.4 Hz, 2 H), 5.17 (s, 2 H), 4.17 (q, J = 6.4 Hz, 1 H), 4.07–4.02 (m, 2 H), 3.88 (t, J = 8.0 Hz, 1 H), 3.40–3.35 (m, 3 H), 3.10 (dd, J = 14.4, 7.2 Hz, 2 H), 1.69–1.56 (m, 4 H), 0.88 (dt, J = 18.4, 7.6 Hz, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 136.7, 135.6, 134.8, 128.5, 127.6, 126.4, 125.0, 117.6, 112.5, 76.5, 71.4, 66.1, 64.5, 53.4, 29.5, 29.1, 8.2, 7.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₃₄NO₃: 372.2533; found: 372.2535.

(1S,2S,E)-2-(Benzhydrylamino)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-2-(4-methoxphenyl)ethan-1-ol (8f)

Following the typical procedure using 5a (50.1 mg, 0.20 mmol), 6 (69.0 μL, 0.40 mmol), and 4-methoxyphenylboronic acid (60.8 mg, 0.40 mmol) in refluxing MeOH for 1.5 h gave 8f (74.8 mg, 0.162 mmol, 80%) as a pale yellow oil; [α]_D ²³ +57.9 (c 0.26, CH₂Cl₂).

IR (neat): 3445, 2970, 2358, 1508, 1080, 744, 700 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.33–7.20 (m, 12 H), 6.90 (d, J = 8.8 Hz, 2 H), 4.68 (s, 1 H), 4.05–3.95 (m, 1 H), 3.84–3.73 (m, 7 H), 1.65–1.51 (m, 4 H), 0.83 (td, J = 7.6, 4.8 Hz, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 159.1, 143.8, 142.6, 130.5, 129.6, 128.5, 128.4, 127.7, 127.2, 127.1, 127.0, 113.8, 112.6, 76.7, 74.5, 66.6, 63.3, 61.3, 55.1, 29.5, 29.0, 8.2, 8.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₃₆NO₄: 462.2639; found: 462.2640.

(1S,2S,E)-2-(Benzhydrylamino)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-phenylbut-3-en-1-ol (8g)

Following the typical procedure using 5b (43.7 mg, 0.20 mmol), 6 (69.0 μL, 0.40 mmol), and 7 (59.2 mg, 0.40 mmol) in refluxing MeOH for 21 h gave 8g (57.0 mg, 0.133 mmol, 66%) as a yellow-brown oil; [α]_D ²⁵ +81.3 (c 0.25, CH₂Cl₂).

IR (neat): 3445, 2986, 2359, 1456, 1063, 845, 748, 696 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.43–7.19 (m, 15 H), 6.45 (d, J = 16.0 Hz, 1 H), 6.21 (dd, J = 16.0, 9.2 Hz, 1 H), 4.98 (s, 1 H), 4.11–4.06 (m, 1 H), 3.97–3.90 (m, 3 H), 3.41–3.39 (m, 1 H), 1.37 (s, 3 H), 1.31 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.0, 143.0, 136.6, 133.9, 128.6, 128.5, 127.6, 127.3, 127.1, 127.0, 126.5, 126.4, 108.8, 76.5, 73.8, 66.1, 63.7 (d, J = 7.4 Hz), 63.3 (d, J = 8.4 Hz), 60.2, 26.6 (d, J = 16.2 Hz), 25.3 (d, J = 12.4 Hz).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₃₂NO₃: 430.2377; found: 430.2379.

(1S,2R,E)-2-(Benzhydrylamino)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-4-phenylbut-3-en-1-ol (8h)

Following the typical procedure using 5c (49.8 mg, 0.20 mmol), 6 (69.0 μL, 0.40 mmol), 7 (59.5 mg, 0.40 mmol) in refluxing MeOH for 21 h gave 8h (60.0 mg, 0.131 mmol, 65%) as a yellow oil; [α]_D ²¹ +141.1 (c 0.25, CH₂Cl₂).

IR (neat): 3445, 2972, 2342, 1599, 1456, 1078, 750, 694 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.44–7.18 (m, 15 H), 6.36 (d, J = 16.0 Hz, 1 H), 6.18 (dd, J = 16.0, 9.2 Hz, 1 H), 4.99 (s, 1 H), 4.22–4.18 (m, 1 H), 3.98 (t, J = 8.0 Hz, 1 H), 3.86 (t, J = 8.0 Hz, 1 H), 3.63 (br s, 1 H), 3.32 (br s, 1 H), 1.68 (qd, J = 7.2, 3.2 Hz, 2 H), 1.61 (t, J = 7.2 Hz, 2 H), 0.89 (dt, J = 16.8, 7.2 Hz, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.4, 142.6, 136.4, 133.8, 128.6, 127.7, 127.6, 127.2, 127.0, 126.9, 126.5, 126.4, 113.1, 72.2, 66.2, 63.3, 63.1, 60.5, 29.6, 29.1, 8.1, 8.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₃₆NO₃: 458.2690; found: 458.2694.

(1S,2S,E)-2-(Benzhydrylamino)-1-(tert-butyldimethylsiloxy)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-4-phenylbut-3-ene (9)

To a solution of 8a (94.5 mg, 0.21 mmol) in DMF (1.05 mL) was added TBSCl (95.0 mg, 0.63 mmol) and imidazole (42.8 mg, 0.63 mmol). The mixture was stirred at 80 °C for 24 h. The reaction was quenched with 1 M aq HCl aq and extracted with Et₂O. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane–EtOAc, 10:1) to afford 9 (117 mg 0.20 mmol, 99%) as a colorless oil; [α]_D ²⁰ +43.7 (c 1.0, acetone).

IR (KBr): 3345, 2930, 1360, 1060, 777 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.38–7.15 (m, 15 H), 6.40 (d, J = 16.0 Hz, 1 H), 6.12 (dd, J = 16.0, 9.0 Hz, 1 H), 4.89 (s, 1 H), 4.12–3.98 (m, 2 H), 3.99 (dd, J = 5.6, 2.8 Hz, 1 H), 3.83 (t, J = 7.3, 1 H), 3.35 (dd, J = 8.9, 2.7 Hz, 1 H), 1.91 (s, 1 H), 1.63–1.52 (m, 4 H), 0.87–0.82 (m, 15 H), 0.11 (s, 3 H), 0.01 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.8, 143.6, 137.1, 133.1, 128.6, 128.5, 128.4, 128.3, 127.7, 127.5, 127.2, 126.9, 126.8, 126.4, 112.3, 76.7, 67.0, 63.4, 61.4, 29.7, 28.6, 26.0, 18.2, 8.3, 8.2, -4.3, -3.9.

HRMS (FAB): m/z [M + H]⁺ calcd for C₃₆H₅₀NO₃Si: 572.3560; found: 572.3565.

(2R,3S,4S,E)-4-(Benzhydrylamino)-3-(tert-butyldimethylsil­oxy)-2-(pentan-3-yloxy)-6-phenylhex-5-en-1-ol (10)

A solution of 9 (497 mg, 0.90 mmol) in CH₂Cl₂ (9.0 mL) was cooled to –45 °C and Et₃SiH (0.42 mL, 2.7 mmol) was added. The mixture was stirred at –45 °C for 5 min and 1 M TiCl₄ in CH₂Cl₂ (2.7 mL, 2.7 mmol) was added; the mixture was stirred for 19 h. The reaction was quenched with sat. aq NaHCO₃ and extracted with Et₂O. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane–EtOAc­, 10:1) to afford 11 (450.0 mg 0.081 mmol, 90%) as a colorless oil; [α]_D ²⁰ +33.1 (c 1.0, acetone).

IR (KBr): 3437, 2928, 1600, 1253, 777 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.18 (m, 15 H), 6.42 (d, J = 16.0 Hz, 1 H), 6.16 (dd, J = 16.0, 9.0 Hz, 1 H), 4.90 (s, 1 H), 3.94 (br d, J = 3.8 Hz, 1 H), 3.86 (dd, J = 11.5, 9.0 Hz, 1 H), 3.58–3.52 (m, 1 H), 3.48–3.37 (m, 2 H), 3.25–3.15 (m, 1 H), 1.59 (br s, 1 H), 1.52–1.29 (m, 4 H), 1.26 (s, 1 H), 0.85 (t, J = 7.4 Hz, 3 H), 0.85 (s, 9 H), 0.71 (t, J = 7.4 Hz, 3 H), 0.07 (s, 3 H), –0.05 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.2, 142.0, 136.5, 134.1, 128.7, 128.6, 128.4, 127.9, 127.8 (2), 127.3, 127.0, 126.8, 126.5, 80.8, 78.4, 63.2, 62.6, 57.9, 26.5, 26.1, 25.9, 18.2, 10.1, 9.3, –4.4, –5.4.

HRMS (FAB): m/z [M + H]⁺ calcd for C₃₆H₅₂NO₃Si: 574.3716; found: 574.3708.

(2R,3S,4S,E)-4-(Benzhydrylamino)-2-(pentan-3-yloxy)-6-phen­ylhex-5-ene-1,3-diol (11)

A solution of 10 (28 mg, 0.049 mmol) in THF (0.49 mL) was stirred at 0 °C and 1 M TBAF solution (74 μL, 0.074 mmol) was added and the solution was brought to r.t. The mixture was stirred for 2.5 h and after that, the reaction was quenched with sat aq NH₄Cl and extracted with Et₂O. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane–EtOAc, 2:1) to afford 11 (24 mg, 0.051 mmol, >99%) as a colorless oil; [α]_D ²² +76.2 (c 0.3, acetone).

IR (KBr): 3439, 2926, 1599, 1492, 746 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.37–7.31 (m, 8 H), 7.28–7.24 (m, 6 H), 7.19–7.15 (m, 1 H), 6.36 (d, J = 16.0 Hz, 1 H), 6.22 (dd, J = 16.0, 9.2 Hz, 1 H), 4.96 (s, 1 H), 3.91 (t, J = 4.3 Hz, 1 H), 3.78 (dd, J = 11.8, 7.8 Hz, 1 H), 3.62–3.57 (m, 2 H), 3.52 (quint, J = 3.8 Hz, 1 H), 3.20 (quint, J = 5.7 Hz, 1 H), 1.49–1.33 (m, 4 H), 0.83 (t, J = 7.4 Hz, 3 H), 0.74 (t, J = 7.4 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 136.4, 134.8, 128.7, 128.6, 128.5, 127.9, 127.7, 127.3, 127.1, 126.6, 126.5, 80.9, 77.1, 76.8, 74.7, 63.4, 60.3, 59.7, 26.2, 26.0, 9.5, 9.4.

HRMS (FAB): m/z [M + H]⁺ calcd for C₃₀H₃₈NO₃: 460.2852; found: 460.2878.

(2R,3S,4S,E)-4-(Benzhydrylamino)-3-(tert-butyldimethylsil­oxy)-1-(pentan-3-yloxy)-6-phenylhex-5-en-2-ol (12)

A solution of 9 (69.8 mg, 0.12 mmol) in CH₂Cl₂ (1.2 mL) was cooled to –45 °C and 1 M TiCl₄ in CH₂Cl₂ (0.36 mL, 0.36 mmol) was added. The mixture was stirred at –45 °C for 5 min and Et₃SiH (57.0 μL, 0.36 mmol) was added and stirring was continued for 2 h. The reaction was quenched with sat. aq NaHCO₃ and extracted with Et₂O. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane–EtOAc, 10:1) to afford 10 (38.4 mg 0.067 mmol, 55%) and 12 (23.1 mg 0.040 mmol, 33%) both as colorless oils.

12

[α]_D ²⁵ +73.5 (c 0.25, CH₂Cl₂).

IR (KBr): 3564, 3445, 3061, 2928, 1495, 1253, 1099, 702 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.31 (m, 10 H), 7.28–7.22 (m, 4 H), 7.19–7.15 (m, 1 H), 6.35 (d, J = 16.0 Hz, 1 H), 6.13 (dd, J = 16.0, 9.0 Hz, 1 H), 4.93 (s, 1 H), 3.97–3.89 (m, 2 H), 3.64 (dd, J = 9.6, 3.6 Hz, 1 H), 3.42 (dd, J = 9.2, 8.0 Hz, 1 H), 3.35 (dd, J = 9.2, 4.0 Hz, 1 H), 3.13 (quint, J = 5.6 Hz, 1 H), 1.48 (sext, J = 7.2 Hz, 4 H), 0.90–0.84 (m, 15 H), 0.10 (s, 3 H), 0.0 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.6, 14301, 136.9, 133.1, 128.6, 128.6, 128.5, 128.3, 127.7, 127.4, 127.2, 127.0, 126.8, 126.4, 82.3, 76.5, 69.8, 63.4, 61.6, 25.9 (16.3 Hz), 18.2, 9.7, 9.4.

(R)-2-{(4S,5S)-3-Benzhydryl-2-oxo-4-[(E)-styryl]oxazolidin-5-yl}-2-(pentan-3-yloxy)ethyl tert-Butyl Carbonate (13)

A solution of 11 (516 mg, 1.12 mmol) in CH₂Cl₂ (11.2 mL) was added Boc₂O (0.54 mL, 2.4 mmol), Et₃N (0.33 mL, 2.4 mmol), and DMAP (42 mg, 0.34 mmol). The mixture was stirred at r.t. for 3 h. The reaction was quenched with 1 M aq HCl and extracted with Et₂O. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane–EtOAc, 5:1) to afford 13 (513 mg 0.88 mmol, 78%) as a brown oil; [α]_D ²⁰ +104.4 (c 1.0, acetone).

IR (KBr): 1767, 1600, 1494, 1159, 750 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.30–7.23 (m, 5 H), 7.24–7.16 (m, 7 H), 7.14–7.11 (m, 1 H), 7.07–7.03 (m, 2 H), 6.14 (dd, J = 16.0, 9.5 Hz, 1 H), 6.08 (s, 1 H), 6.00 (d, J = 16.0 Hz, 1 H), 4.66 (dd, J = 8.3, 5.5 Hz, 1 H), 4.36 (dd, J = 9.5, 8.3 Hz, 1 H), 4.23 (dd, 11.8, 5.5 Hz, 1 H), 4.06 (dd, J = 11.8, 4.0 Hz, 1 H), 3.83 (q, J = 5.4 Hz, 1 H), 3.26 (sept, J = 4.4 Hz, 1 H), 1.58–1.39 (m, 12 H), 1.34–1.28 (m, 1 H), 0.85 (t, J = 7.4 Hz, 3 H), 0.71 (t, J = 7.4 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 157.0, 153.1, 138.6, 138.2, 135.6 (2), 128.8 (2), 128.5, 128.3, 128.2, 127.7, 127.6 (2), 126.5, 123.6, 82.5, 81.2, 75.8, 74.1, 64.5, 61.6, 60.9, 27.6, 26.0, 25.4, 9.6, 9.1.

HRMS (FAB): m/z [M + Na]⁺ calcd for C₃₆H₄₃NO₆Na: 608.2988; found: 608.2985.

(4S,5S)-3-Benzhydryl-5-[(R)-2-hydroxy-1-(pentan-3-yloxy)ethyl]-4-[(E)-styryl]oxazolidin-2-one (14)

A solution of 13 (220 mg, 0.38 mmol) in MeCN–6 M aq HCl (2:1, 5.0 mL) was stirred at r.t. for 36 h. The reaction was quenched with 1 M aq NaOH to neutralize the mixture and extracted with CH₂Cl₂. The combined organic phases were washed with brine, dried (MgSO_4­), filtered, and concentrated under reduced pressure to give 14 (185 mg, 0.38 mmol, 98%) as a colorless solid and this material was used in the next reaction without further purification; mp 145–146 °C; [α]_D ²⁴ +129.4 (c 0.5, acetone).

IR (KBr): 3397, 2968, 1742, 1653, 754 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.34–7.19 (m, 12 H), 7.15–7.11 (m, 1 H), 7.09–7.06 (m, 2 H), 6.09 (s, 1 H), 6.04–5.97 (m, 2 H), 4.73 (t, J = 7.2 Hz, 1 H), 4.38 (t, J = 7.8 Hz, 1 H), 3.80–3.69 (m, 3 H), 3.27–3.20 (m, 1 H), 1.85 (br, 1 H), 1.54–1.45 (m, 1 H), 1.41 (sept, J = 7.4 Hz, 2 H), 1.31–1.22 (m, 1 H), 0.84 (t, J = 7.4 Hz, 3 H), 0.69 (t, J = 7.4 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 156.8, 138.6, 138.5, 135.6, 135.2, 129.0, 128.5, 128.4, 128.3 (2), 128.2, 127.8, 127.6, 126.5, 123.4, 80.5, 76.6, 75.2, 61.7, 61.1 (2), 25.9, 25.5, 9.4, 9.2.

HRMS (FAB): m/z [M + H]⁺ calcd for C₃₁H₃₆NO₄: 486.2644; found: 486.2672.

(S)-2-{(4S,5S)-3-Benzhydryl-2-oxo-4-[(E)-styryl]oxazolidin-5-yl}-2-(pentan-3-yloxy)acetaldehyde (15)

A solution of 14 (185 mg, 0.39 mmol) in CH₂Cl₂ (3.8 mL) was added Dess–Martin periodinane (0.20 g, 0.47 mmol). The mixture was stirred at r.t. for 3 h. The reaction was quenched with sat. aq NaHCO₃ and sat. aq Na₂SO₃, and extracted with Et₂O. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane–EtOAc, 3:2) to afford 15 (166 mg 0.34 mmol, 91% yield from 13) as a yellow oil; [α]_D ²² +30.6 (c 1.8, acetone).

IR (KBr): 3483, 2967, 1770, 1702, 748 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.50 (s, 1 H) 7.36 (d, J = 7.9 Hz, 2 H), 7.28–7.17 (m, 11 H), 7.04–7.02 (m, 2 H), 6.30 (dd, J = 16.1, 9.4 Hz, 1 H), 6.15 (s, 1 H), 5.96 (d, J = 16.1 Hz, 1 H), 4.90 (dd, J = 9.4, 3.0 Hz, 1 H), 4.31 (t, J = 9.4 Hz, 1 H), 4.13 (d, J = 3.0 Hz, 1 H), 3.38–3.29 (m, 1 H), 1.70–1.59 (m, 4 H), 1.03 (t, J = 7.4 Hz, 3 H), 0.91 (t, J = 7.4 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 202.8, 157.1, 138.7, 137.3, 137.0, 135.3, 129.7, 128.7, 128.5, 128.3, 128.2, 128.1, 128.0, 127.5, 126.5, 124.9, 85.0, 83.4, 77.7, 61.7, 60.3, 26.0, 25.2, 10.1, 9.0.

HRMS (FAB): m/z [M + H]⁺ calcd for C₃₁H₃₄NO₄: 484.2488; found: 484.2483.

(R)-2-[(4R,5S)-3-Benzhydryl-4-formyl-2-oxooxazolidin-5-yl]-2-(pentan-3-yloxy)ethyl tert-Butyl Carbonate (16)

A solution of 13 (453 mg, 0.94 mmol) in CH₂Cl₂–MeOH (4:1, 9.4 mL) was cooled to –78 °C, and ozone was bubbled through it until the solution had a blue coloration. Then Me₂S (1.73 mL, 23.4 mmol) was added, and the solution was brought to r.t. for 10 min. The mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane–EtOAc, 3:1) to afford 16 (377 mg, 0.92 mmol, 98%) as a colorless oil; [α]_D ²⁴ +120.2 (c 0.085, acetone).

IR (KBr): 2970, 1734, 1600, 1496, 702 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.93 (d, J = 3.6 Hz, 1 H) 7.37 (t, J = 7.7 Hz, 2 H), 7.35–7.29 (m, 4 H), 7.27–7.23 (m, 2 H), 7.17 (d, J = 7.7 Hz, 2 H), 6.36 (s, 1 H), 4.98 (dd, J = 8.9, 3.4 Hz, 1 H), 4.26 (dd, J = 8.9, 3.4 Hz, 1 H), 4.09–4.02 (m, 2 H), 3.98–3.94 (m, 1 H), 3.38–3.32 (m, 1 H), 1.59–1.33 (m, 13 H), 0.84 (t, J = 7.7 Hz, 3 H), 0.79 (t, J = 7.7 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 196.6, 156.8, 152.9, 138.1, 137.9, 129.9, 129.0 (2), 128.8, 127.8, 127.1, 83.0, 82.9, 78.0, 73.4, 63.7, 63.1, 61.4, 27.7, 25.9, 25.2, 9.5, 9.0.

HRMS (FAB): m/z [M + Na]⁺ calcd for C₂₉H₃₇NO₇Na: 534.2468; found: 534.2439.

Ethyl (E)-3-{(4S,5S)-3-Benzhydryl-5-[(R)-2-(tert-butoxycarbonyloxy)-1-(pentan-3-yloxy)ethyl]-2-oxooxazolidin-4-yl}acrylate (17)

A suspension of NaH (2.3 mg, 0.057 mmol, 60% in mineral oil) in THF (0.24 mL) was added triethyl phosphonoacetate (14.2 μL, 0.072 mmol) at –20 °C. The mixture was stirred at –20 °C for 30 min and the mixture was added to 16 (24 mg, 0.048 mmol) in THF (0.24 mL) and the mixture was stirred for 30 min. The reaction was quenched with sat. aq NH₄Cl and extracted with Et₂O. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane–EtOAc­, 4:1) to afford 17 (27 mg 0.045 mmol, 94%) as a colorless oil; [α]_D ²³ +78.9 (c 0.25, acetone).

IR (KBr): 2972, 1773, 1654, 1495, 748 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.36 (t, J = 6.0 Hz, 2 H), 7.33–7.20 (m, 8 H), 6.65 (dd, J = 15.8, 9.5 Hz, 1 H), 6.20 (s, 1 H), 5.36 (d, J = 15.8 Hz, 1 H), 4.75 (t, J = 7.7 Hz, 1 H), 4.39–4.29 (m, 2 H), 4.14–4.02 (m, 3 H), 3.81–3.76 (m, 1 H), 3.31 (sept, J = 3.9 Hz, 1 H), 1.58–1.35 (m, 12 H), 1.34–1.25 (m, 1 H), 1.23 (t, J = 7.1 Hz, 3 H), 0.87 (t, J = 7.5 Hz, 3 H), 0.79 (t, J = 7.5 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 164.6, 156.6, 153.1, 140.7, 138.4, 138.1, 129.3, 128.5, 128.4, 128.1, 127.9, 127.7, 125.0, 82.6, 80.3, 75.6, 72.5, 63.7, 61.5, 60.4, 58.5, 27.7, 25.9, 25.0, 14.1, 9.5, 9.2.

HRMS (FAB): m/z [M + Na]⁺ calcd for C₃₃H₄₃NO₈Na: 604.2886; found: 604.2909.

Ethyl (E)-3-{(4S,5S)-3-Benzhydryl-5-[(R)-2-hydroxy-1-(pentan-3-yloxy)ethyl]-2-oxooxazolidin-4-yl}acrylate (18)

A solution of 17 (245 mg, 0.41 mmol) in MeCN–6 M aq HCl (2:1, 4.1 mL) was stirred at r.t. for 18 h. The reaction was quenched with 1 M aq NaOH to neutralize mixture and extracted with CH₂Cl₂. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to give 18 (192 mg, 0.40 mmol, 98%) as a colorless oil; [α]_D ²³ +84.9 (c 1.0, acetone).

IR (KBr): 3451, 1763, 1647, 1497, 762 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.36 (t, J = 7.4 Hz, 2 H), 7.32–7.25 (m, 3 H), 7.22 (d, J = 7.4 Hz, 5 H), 6.55 (dd, J = 15.8, 9.3 Hz, 1 H), 6.21 (s, 1 H), 5.32 (d, J = 15.8 Hz, 1 H), 4.79 (t, J = 7.6 Hz, 1 H), 4.36 (dd, 9.3, 7.4 Hz, 1 H), 4.14–4.04 (m, 2 H), 3.85–3.80 (m, 1 H), 3.74 (dd, J = 12.1, 2.4 Hz, 1 H), 3.65–3.61 (m, 1 H), 3.32–3.26 (m, 1 H), 1.57–1.37 (m, 3 H), 1.32–1.22 (m, 4 H), 0.88 (t, J = 7.4 Hz, 3 H), 0.77 (t, J = 7.4 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 164.7, 156.5, 140.4, 138.4 (2), 129.6, 128.6, 128.5, 128.3, 127.7, 127.5, 124.7, 79.9, 76.1, 74.0, 61.4, 60.4, 60.3, 58.5, 25.9, 25.0, 14.2, 9.5, 9.2.

HRMS (FAB): m/z [M + Na]⁺ calcd for C₂₈H₃₅NO₆Na: 504.2362; found: 504.2385.

Ethyl (E)-3-{(4S,5S)-3-Benzhydryl-2-oxo-5-[(S)-2-oxo-1-(pentan-3-yloxy)ethyl]oxazolidin-4-yl}acrylate (19)

A solution of 18 (16 mg, 0.033 mmol) in CH₂Cl₂ (0.33 mL) was added Dess–Martin periodinane (17 mg, 0.040 mmol) at r.t.; the mixture was stirred at r.t. for 6 h. The reaction was quenched with sat. aq NaHCO₃ and sat. aq Na₂SO₃, and extracted with Et₂O. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to give 19 (16 mg, 0.034 mmol, >99%) as a yellow oil; this compound was sufficiently pure without further purification. [α]_D ²⁴ +1.1 (c 0.5, acetone).

IR (KBr): 2976, 1748, 1721, 1395, 710 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.63 (s, 1 H), 7.36–7.25 (m, 8 H), 7.21–7.18 (m, 2 H), 6.95 (dd, J = 15.9, 9.6 Hz, 1 H), 6.19 (s, 1 H), 5.35 (d, J = 15.9 Hz, 1 H), 4.92 (dd, J = 9.6, 3.5 Hz, 1 H), 4.32 (t, J = 9.6 Hz, 1 H), 4.16 (d, J = 3.5 Hz, 1 H), 4.13–4.05 (m, 2 H), 3.43–3.37 (m, 1 H), 1.71–1.58 (m, 4 H), 1.22 (t, J = 7.1 Hz, 3 H), 1.09 (t, J = 7.5 Hz, 3 H), 0.94 (t, J = 7.5 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 202.6, 164.4, 156.8, 142.2, 138.3, 136.9, 129.1, 128.5 (2), 128.3, 128.2, 127.9, 126.7, 85.0, 82.5, 77.0, 61.9, 60.7, 58.4, 26.0, 25.2, 14.1, 10.0, 9.0.

HRMS (FAB): m/z [M + H]⁺ calcd for C₂₈H₃₄NO₆: 480.2386; found: 480.2402.

Acknowledgement

This research was partially supported by a Grant-in-Aid for Scientific Research on Innovative Areas ‘Advanced Molecular Transformations by Organocatalysts’ from MEXT (Japan). The authors gratefully thank Division of Instrumental Analysis, Department of Instrumental Analysis & Cryogenics, Advanced Science Research Center, Okayama University for the NMR, high-resolution mass spectrometry measurements (FAB), and X-ray single crystal structural analyses. The authors are also grateful to Ms. Tsugumi Shiokawa and Dr. Hiroko Tada at Division of Instrumental Analysis for high-resolution mass spectrometry measurements (ESI).

• References

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• References

• 1a Zhu J, Bienaymé H. Multicomponent Reactions . Wiley-VCH; Weinheim: 2005
  CrossrefSearch in Google Scholar
• 1b Ramón DJ, Yus M. Angew. Chem. Int. Ed. 2005; 44: 1602
  CrossrefPubMedSearch in Google Scholar
• 1c Dömling A. Chem. Rev. 2006; 106: 17
  CrossrefPubMedSearch in Google Scholar
• 1d de Graaff C, Ruijter E, Orru RV. A. Chem. Soc. Rev. 2012; 41: 3969
  CrossrefPubMedSearch in Google Scholar
• 2a Petasis NA, Akritopoulou I. Tetrahedron Lett. 1993; 34: 583
  CrossrefSearch in Google Scholar
• 2b Petasis NA, Zavialov IA. J. Am. Chem. Soc. 1997; 119: 445
  CrossrefSearch in Google Scholar
• 2c Petasis NA, Goodman A, Zavialov IA. Tetrahedron 1997; 53: 16463
  CrossrefSearch in Google Scholar
• 2d Petasis NA, Zavialov IA. J. Am. Chem. Soc. 1998; 120: 11798
  CrossrefSearch in Google Scholar
• 2e Petasis NA, Boral S. Tetrahedron Lett. 2001; 42: 539
  CrossrefSearch in Google Scholar
• 3 For a review see: Candeias NR, Montalbano F, Cal PM. S. D, Gois PM. P. Chem. Rev. 2010; 110: 6169
  CrossrefPubMedSearch in Google Scholar
• 4a Kumagai N, Muncipinto G, Schreiber SL. Angew. Chem. Int. Ed. 2006; 45: 3635
  CrossrefSearch in Google Scholar
• 4b Ascic E, Le Quement ST, Ishoey M, Daugaard M, Nielsen TE. ACS Comb. Sci. 2012; 14: 253
  CrossrefSearch in Google Scholar
• 5a Prakash GK. S, Mandal M, Schweizer S, Petasis NA, Olah GA. Org. Lett. 2000; 2: 3173
  CrossrefSearch in Google Scholar
• 5b Prakash GK. S, Mandal M, Schweizer S, Petasis NA, Olah GA. J. Org. Chem. 2002; 67: 3718
  CrossrefSearch in Google Scholar
• 5c Prakash GK. S, Mandal M, Schweizer S, Petasis NA, Olah GA. J. Org. Chem. 2002; 67: 6286
  CrossrefSearch in Google Scholar
• 6 For a review see: Bergmeier SC. Tetrahedron 2000; 56: 2561
  CrossrefSearch in Google Scholar
• 7a Tarrade A, Dauban P, Dodd RH. J. Org. Chem. 2003; 68: 9521
  CrossrefSearch in Google Scholar
• 7b Pyne SG, Davis AS, Gates NJ, Hartley JP, Lindsay KB, Machan T, Tang M. Synlett 2004; 2670
  Thieme Connect
• 7c Sugiyama S, Arai S, Ishii K. Tetrahedron: Asymmetry 2004; 15: 3149
  CrossrefSearch in Google Scholar
• 7d Li S, Hui X.-P, Yang S.-B, Jia Z.-J, Xu P.-F, Lu T.-J. Tetrahedron: Asymmetry 2005; 16: 1729
  CrossrefSearch in Google Scholar
• 7e Au CW. G, Pyne SG. J. Org. Chem. 2006; 71: 7097
  CrossrefSearch in Google Scholar
• 7f Falentin C, Beaupère D, Demailly G, Stasik I. Tetrahedron 2008; 64: 9989
  CrossrefSearch in Google Scholar
• 7g Salma Y, Ballereau S, Maaliki C, Ladeira S, Andrieu-Abadie N, Genisson Y. Org. Biomol. Chem. 2010; 8: 3227
  CrossrefPubMedSearch in Google Scholar
• 7h Lee Y.-J, Park Y, Kim M.-h, Jew S.-s, Park H.-g. J. Org. Chem. 2011; 76: 740
  CrossrefPubMedSearch in Google Scholar
• 7i Ghosal P, Shaw AK. J. Org. Chem. 2012; 77: 7627
  CrossrefSearch in Google Scholar
• 8 For a review see: Toure BB, Hall DG. Chem. Rev. 2009; 109: 4439
  CrossrefPubMedSearch in Google Scholar
• 9a Mukaiyama T, Sakito Y, Asami M. Chem. Lett. 1978; 1253
• 9b Mukaiyama T, Sakito Y, Asami M. Chem. Lett. 1979; 705
• 9c Lynch JE, Eliel EL. J. Am. Chem. Soc. 1984; 106: 2943
  CrossrefSearch in Google Scholar
• 9d Okamoto S, Shimazaki T, Kitano Y, Kobayashi Y, Sato F. J. Chem. Soc., Chem. Commun. 1986; 1352
• 9e Ogura K, Tsuruda T, Takahashi K, Iida H. Tetrahedron Lett. 1986; 27: 3665
  CrossrefSearch in Google Scholar
• 9f Corey EJ, Jones GB. Tetrahedron Lett. 1991; 32: 5713
  CrossrefSearch in Google Scholar
• 9g Enders D, Reinhold U. Synlett 1994; 792
  Thieme Connect
• 9h Lassaletta J, Fernández R, Martín-Zamora E, Pareja C. Tetrahedron Lett. 1996; 37: 5787
  CrossrefSearch in Google Scholar
• 9i Gawley RE, Campagna SA, Santiago M, Ren T. Tetrahedron: Asymmetry 2002; 13: 29
  CrossrefSearch in Google Scholar
• 9j Evans P, Leffray M. Tetrahedron 2003; 59: 7973
  CrossrefSearch in Google Scholar
• 10 Davis AS, Pyne SG, Skelton BW, White AH. J. Org. Chem. 2004; 69: 3139
  CrossrefSearch in Google Scholar
• 11a Mandai H, Murota K, Sakai T. Tetrahedron Lett. 2010; 51: 4779
  CrossrefSearch in Google Scholar
• 11b Mandai H, Murota K, Suga S. Heterocycles 2012; 85: 1655
  CrossrefSearch in Google Scholar
• 12 Schmid CR, Bradley DA. Synthesis 1992; 587
  Thieme Connect
• 13 Abushanab E, Vemishetti P, Leiby RW, Singh HK, Mikkilineni AB, Wu DC. J, Saibaba R, Panzica RP. J. Org. Chem. 1988; 53: 2598
  CrossrefSearch in Google Scholar
• 14a Clay MD, Riber D, Fallis AG. Can. J. Chem. 2005; 83: 559
  CrossrefSearch in Google Scholar
• 14b Booth KV, da Cruz FP, Hotchkiss DJ, Jenkinson SF, Jones NA, Weymouth-Wilson AC, Clarkson R, Heinz T, Fleet GW. J. Tetrahedron: Asymmetry 2008; 19: 2417
  CrossrefSearch in Google Scholar

• Supplementary Material