Weinreb Amide Based New Synthetic Equivalents for Convenient Access to Immunosuppressive Agent FTY720 and Analogues

Sivaraman Balasubramaniam; Senthilmurugan Annamalai; Indrapal Singh Aidhen

doi:10.1055/s-2007-990961

LETTER

Weinreb Amide Based New Synthetic Equivalents for Convenient Access to Immunosuppressive Agent FTY720 and Analogues

Sivaraman Balasubramaniam, Senthilmurugan Annamalai, Indrapal Singh Aidhen*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
Fax: +91(44)22574202; e-Mail: isingh@iitm.ac.in;

Abstract

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Abstract

Three new synthetic equivalents containing Weinreb amide functionality for the central core of FTY720, an immunosuppressive agent, have been developed. These synthetic equivalents enabled incorporation of the polar head group of FTY720, through Julia, Wittig, and Horner-Wadsworth-Emmons reactions and also allowed for variation in the chain length of the lipophilic side chain in target, through the Weinreb amide functionality therein. The use of tris(hydroxymethyl)aminomethane, commercially available at low cost for the polar head group offers a distinct advantage. Convenient reactions and simple functional group interconversions in good to high yield highlight the strength of the new route developed for the synthesis of clinically important FTY720.

Key words

FTY720 - Weinreb amide - sulfone - olefination

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References

References and Notes

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For previous syntheses of FTY720, see:

3a Adachi K. Kohara T. Nakao N. Arita M. Chiba K. Mishina T. Sasaki S. Fujita T. Bioorg. Med. Chem. Lett. 1995, 5: 853

3b Kiuchi M. Adachi K. Kohara T. Inoguchi M. Hanano T. Aoki Y. Mishina T. Arita M. Nakao N. Ohtsuki M. Hoshino Y. Teshima K. Chiba K. Sasaki S. Fujita T. J. Med. Chem. 2000, 43: 2946

3c Durand P. Peralba P. Sierra F. Renaut P. Synthesis 2000, 505

3d Kalita B. Barua NC. Bezbarua M. Bez G. Synlett 2001, 1411

For recent syntheses of FTY720, see:

4a Kim S. Lee H. Lee M. Lee T. Synthesis 2006, 753

4b Sugiyama S. Arai S. Kiriyama M. Ishii K. Chem. Pharm. Bull. 2005, 53: 100

4c Seidel G. Laurich D. Fürstner A. J. Org. Chem. 2004, 69: 3950

For FTY720-related compounds, see:

4d Kiuchi M. Adachi K. Tomatsu A. Chino M. Takeda S. Tanaka Y. Maeda Y. Sato N. Mitsutomi N. Sugahara K. Chiba K. Bioorg. Med. Chem. 2005, 13: 425

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4g Hinterding K. Cottens S. Albert R. Zecri F. Buehlmayer P. Spanka C. Brinkmann V. Nussbaumer P. Ettmayer P. Hoegenauer K. Gray N. Pan S. Synthesis 2003, 1667

4h Hinterding K. Albert R. Cottens S. Tetrahedron Lett. 2002, 43: 8095

5 Sivaraman B. Aidhen IS. Synlett 2007, 959

N-Methoxy-N-methyl amides are popularly called as Weinreb amides. For reviews on Weinreb amide chemistry, see:

6a Singh J. Satyamurthi N. Aidhen IS. J. Prakt. Chem. 2000, 342: 340

6b Mentzel M. Hoffmann HMR. J. Prakt. Chem. 1997, 339: 517

6c Sibi MP. Org. Prep. Proced. Int. 1993, 25: 15

7 Mickel SJ. Niederer D. Daeffler R. Osmani A. Kuesters E. Schmid E. Schaer K. Gamboni R. Chen W. Loeser E. Kinder FR. Konigsberger K. Prasad K. Ramsey TM. Repic O. Wang R.-M. Florence G. Lyothier I. Paterson I. Org. Process Res. Dev. 2004, 8: 122

8 Aldehyde 2, a crystalline solid, was conveniently prepared in high overall yield by a literature-known, two-step synthetic procedure, using cheap and commercially available tris(hydroxymethyl)aminomethane (TRIS) as the starting material. See: Ooi H. Ishibashi N. Iwabuchi Y. Ishihara J. Hatakeyama S. J. Org. Chem. 2004, 69: 7765

For reviews on Julia olefination, see:

9a Blakemore PR. J. Chem. Soc., Perkin Trans. 1 2002, 2563

9b Kelly SE. Comp. Org. Synth. 1991, 1: 792

10

4-{(Benzo[ d ]thiazol-2-ylsulfonyl)methyl}- N -methoxy- N -methylbenzamide (4) Yield 85-88%; R _f = 0.35 (hexane-ethyl acetate, 6:4); colorless crystals, mp 142-145 °C. ¹H NMR (400 MHz, CDCl₃): δ = 3.32 (s, 3 H), 3.47 (s, 3 H), 4.79 (s, 2 H), 7.33 (d, 2 H, J = 8.0 Hz), 7.56-7.62 (m, 3 H), 7.63-7.69 (m, 1 H), 7.94 (d, 1 H, J = 8.0 Hz), 8.26 (d, 1 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 32.6, 59.7, 60.1, 121.3, 124.6, 126.8, 127.2, 127.8, 127.9, 129.8, 133.9, 136.1, 151.6, 164.1, 168.0. IR (CH₂Cl₂): 1152, 1332, 1469, 1639, 2929, 2972 cm^-1. HRMS (EI): m/z calcd for C₁₇H₁₆N₂O₄S₂ [M + H]⁺: 377.0630; found: 377.0618.

11a Tunoori AR. White JM. Georg GI. Org. Lett. 2000, 2: 4091

11b

p-Toluic acid was converted to its acid chloride using more economical SOCl₂ and reacted with N-methoxy-N-methyl amine hydrochloride in the presence of 3.0 equiv of Et₃N, yield 88-92%.

12 Aïssa C. J. Org. Chem. 2006, 71: 360

13

General Procedure for Olefination
A suspension of sulfone (0.3 mmol), aldehyde (0.33 mmol, 1.1 equiv), and K₂CO₃ (0.9 mmol, 3 equiv) in a mixture of THF (1.8 mL) and DMF (0.6 mL; 3:1 mixture) was heated at 70 °C for 17 h. After completion of the reaction, THF was evaporated and the reaction mixture was quenched with H₂O and then extracted with EtOAc. The washed organic layer was dried over anhyd Na₂SO₄, filtered, concentrated, and then purified by silica gel flash chromatography. The spectral and analytical details for selected compounds are given below.
4-[4-(5,5-Dimethyl-1,3-dioxan-2-yl)styryl]- N -methoxy- N -methylbenzamide (8c) Yield 64% (E:Z = 3:1). E-Isomer: R _f = 0.35 (hexane-EtOAc, 7:3); white crystalline solid, mp 121-124 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.73 (s, 3 H), 1.22 (s, 3 H), 3.28 (s, 3 H), 3.48 (s, 3 H), 3.58 (d, 2 H, J = 10.8 Hz), 3.70 (d, 2 H, J = 11.2 Hz), 5.32 (s, 1 H), 7.03 (d, 1 H, J = 16.0 Hz), 7.10 (d, 1 H, J = 16.4 Hz), 7.41-7.46 (m, 6 H), 7.62 (d, 2 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 20.8, 22.0, 29.2, 32.8, 60.0, 76.7, 100.4, 125.0, 125.6, 127.1, 127.6, 127.8, 129.1, 131.9, 136.5, 137.2, 138.6, 168.5. Z-Isomer: R _f = 0.42 (hexane-EtOAc, 7:3); colorless viscous liquid. ¹H NMR (400 MHz, CDCl₃): δ = 3.27 (s, 3 H), 3.49 (s, 3 H), 3.57 (d, 2 H, J = 10.4 Hz), 3.69 (d, 2 H, J = 11.2 Hz), 5.28 (s, 1 H), 6.51 (d, 1 H, J = 12.4 Hz), 6.57 (d, 1 H, J = 12.4 Hz), 7.17-7.21 (m, 4 H), 7.30 (d, 2 H, J = 8.0 Hz), 7.46 (d, 2 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 20.9, 22.1, 29.2, 33.0, 59.9, 76.7, 100.6, 125.2, 127.3, 127.5, 127.8, 128.6, 130.2, 131.6, 136.4, 136.6, 138.6, 168.7. IR (CH₂Cl₂): 1097, 1383, 1417, 1638, 2850, 2954 cm^-1. HRMS (EI): m/z calcd for C₂₃H₂₇NO₄ [M + H]⁺: 382.2018; found: 382.2029.
N -Methoxy- N -methyl-4-(2-nitrostyryl)benzamide (8d) Yield 70% (E:Z = 9:1); R _f = 0.4 (hexane-EtOAc,7:3); yellow solid, mp 60-63 °C. ¹H NMR (400 MHz, CDCl₃): δ (E-isomer) = 3.38 (s, 3 H), 3.58 (s, 3 H), 7.09 (d, 1 H, J = 16.0 Hz), 7.42-7.46 (m, 1 H), 7.57 (d, 2 H, J = 8.4 Hz), 7.62 (d, 1 H, J = 7.6 Hz), 7.67 (d, 1 H, J = 16.4 Hz), 7.73 (d, 2 H, J = 8.4 Hz), 7.77 (d, 1 H, J = 7.2 Hz), 7.98-8.00 (m, 1 H); δ (Z-isomer, nonoverlapped signals) = 3.32 (s, 3 H), 3.52 (s, 3 H), 6.77 (d, 1 H, J = 12.0 Hz), 6.97 (d, 1 H, J = 12.0 Hz), 7.49 (d, 2 H, J = 8.0 Hz), 7.81 (d, 1 H, J = 8.0 Hz), 7.93 (d, 1 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ (E-isomer) = 33.2, 60.5, 124.4, 124.8, 126.1, 127.8, 127.9, 128.4, 132.2, 132.4, 132.7, 133.3, 138.2, 147.6, 168.8; δ (Z-isomer, nonoverlapped signals) = 60.6, 124.3, 128.2, 130.4, 131.7, 132.8. IR (CH₂Cl₂): 1264, 1345, 1523, 1635, 3054 cm^-1. HRMS (EI): m/z calcd for C₁₇H₁₆N₂O₄ [M + H]⁺: 313.1188; found: 313.1194.
4-(3,4-Dimethoxystyryl)- N -methoxy- N -methyl Benzamide (8e) Yield 66% (E:Z = 3:1); R _f = 0.37 (hexane-EtOAc, 7:3); yellow viscous liquid. ¹H NMR (400 MHz, CDCl₃): δ (E-isomer) = 3.28 (s, 3 H), 3.49 (s, 3 H), 3.82 (s, 3 H), 3.86 (s, 3 H), 6.78 (d, 1 H, J = 8.0 Hz), 6.89 (d, 1 H, J = 16.4 Hz), 6.97-6.99 (m, 2 H), 7.04 (d, 1 H, J = 16.0 Hz), 7.43 (d, 2 H, J = 8.4 Hz), 7.62 (d, 2 H, J = 8.4 Hz); δ (Z-isomer, nonoverlapped signals) = 3.26 (s, 3 H), 3.46 (s, 3 H), 3.54 (s, 3 H), 3.77 (s, 3 H), 6.43 (d, 1 H, J = 12.4 Hz), 6.51 (d, 1 H, J = 12.4 Hz), 6.65-6.68 (m, 2 H), 6.72-6.74 (m, 1 H), 7.24 (d, 2 H, J = 8.4 Hz), 7.47 (d, 2 H, J = 8.4 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 33.8, 55.8, 55.9, 61.1, 108.8, 111.2, 120.3, 121.9, 125.7, 128.2, 128.5, 128.8, 130.2, 131.2, 132.3, 139.9, 149.1, 149.3, 169.5; δ (Z-isomer non-overlapped signals) = 55.5, 55.8, 60.9, 110.9, 111.7, 125.8, 127.9, 128.6, 129.4, 130.0, 140.2, 148.3, 148.4, 169.6. IR (CH₂Cl₂): 1264, 1514, 1635, 3053 cm^-1. HRMS (EI): m/z calcd for C₁₉H₂₁NO₄ [M + H]⁺: 328.1549; found: 328.1546.
tert -Butyl {3-[4-Methoxy(methyl)carbamoyl]styryl}-1 H -indole-1-carboxylate (8f) Yield 56% (E:Z = 3:2); Rf = 0.27 (hexane-EtOAc, 7:3); pale yellow viscous liquid. ¹H NMR (400 MHz, CDCl₃): δ (E-isomer) = 1.70 (s, 9 H), 3.38 (s, 3 H), 3.58 (s, 3 H), 7.21 (d, 1 H, J = 17.2 Hz), 7.32-7.38 (m, 4 H), 7.55 (d, 2 H, J = 8.4 Hz), 7.72 (d, 2 H, J = 8.4 Hz), 7.77 (s, 1 H), 7.90 (d, 1 H, J = 7.2 Hz), 8.20 (d, 1 H, J = 8.0 Hz); δ (Z-isomer, nonoverlapped signals) = 3.33 (s, 3 H), 3.52 (s, 3 H), 6.68-6.75 (m, 2 H), 7.08-7.12 (m, 1 H), 7.23-7.29 (m, 2 H), 7.35 (d, 2 H, J = 8.4 Hz), 7.48 (s, 1 H), 7.56 (d, 2 H, J = 8.4 Hz), 8.11 (d, 1 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ (E-isomer) = 28.2, 33.8, 61.1, 84.1, 115.5, 118.7, 119.9, 121.7, 123.1, 124.5, 124.8, 125.6, 127.8, 128.5, 128.9, 132.4, 140.1, 149.5, 169.6; δ (Z-isomer, nonoverlapped signals) = 83.8, 115.1, 117.0, 121.5, 122.5, 124.4, 128.3, 129.2, 130.4, 132.6, 135.2. IR (CH₂Cl₂): 1261, 1457, 1604, 1723, 2853, 2923, 2956 cm^-1. HRMS (EI): m/z calcd for C₂₄H₂₆N₂O₄ [M + H]⁺: 407.1971; found: 407.1981.
4-[2-(Furan-2-yl)vinyl]- N -methoxy- N -methyl Benzamide ( 8g)
Yield 75% (E:Z = 5:4); Rf = 0.3 (hexane-EtOAc, 7:3); yellow viscous liquid. ¹H NMR (400 MHz, CDCl₃): δ (E-isomer) = 3.26 (s, 3 H), 3.46 (s, 3 H), 6.18-6.23 (m, 1 H), 6.29-6.37 (m, 4 H), 6.85 (d, 1 H, J = 16.0 Hz), 6.94 (d, 1 H, J = 16.4 Hz), 7.37-7.41 (m, 4 H), 7.56-7.60 (m, 3 H); δ (Z-isomer, nonoverlapped signals) = 3.27 (s, 3 H), 3.48 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ (E-isomer) = 33.8, 61.0, 109.5, 111.8, 118.0, 125.7, 126.0, 128.8, 132.6, 139.4, 142.5, 152.9, 169.5; δ (Z-isomer, nonoverlapped signals) = 110.7, 111.3, 118.9, 126.7, 128.1, 128.3, 139.8, 141.9, 151.7, 169.7. IR (CH₂Cl₂): 1378, 1416, 1639, 2929 cm^-1. HRMS (EI): m/z calcd for C₁₅H₁₅NO₃ [M + H]⁺: 258.1130; found: 258.1138.

14

( E )- tert -Butyl (5-{4-[Methoxy(methyl)carbamoyl]sty-ryl}-2,2-dimethyl-1,3-dioxan-5-yl)carbamate (9) Yield 70%; R _f = 0.35 (hexane-EtOAc, 6:4); colorless solid, mp 115-118 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.36 (s, 9 H), 1.38 (s, 3 H), 1.40 (s, 3 H), 3.26 (s, 3 H), 3.45 (s, 3 H), 3.82-3.92 (m, 4 H), 5.27 (br s, 1 H), 6.23 (d, 1 H, J = 16.4 Hz), 6.48 (d, 1 H, J = 16.4 Hz), 7.30 (d, 2 H, J = 8.0 Hz), 7.56 (d, 2 H, J = 8.4 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 19.6, 27.4, 28.3, 33.7, 53.0, 60.9, 66.0, 79.6, 98.3, 125.9, 128.6, 129.5, 130.0, 132.9, 138.8, 154.8, 169.4. IR (CHCl₃): 1166, 1456, 1637, 1712, 2851, 2921 cm^-1. HRMS (EI): m/z calcd for C₂₂H₃₃N₂O₆ [M + H]⁺): 421.2339; found: 421.2348.

15

General Procedure for the Addition of Grignard Reagent, R ^¹ MgBr to the Weinreb Amides 9 and 14 To a stirred solution of 9 or 14 (0.7 mmol) in anhyd THF (3 mL), the appropriate solution of alkyl or arylmagnesium bromide (4.2 mmol, 6 equiv) in anhyd THF (5 mL) was added under inert atmosphere at -10 °C and the mixture was stirred for 3 h between -10 °C and 0 °C. Subsequent hydrolysis was achieved by cautious addition of sat. NH₄Cl solution. The aqueous layer was extracted with EtOAc, dried over Na₂SO₄, and concentrated to furnish the crude product, which was purified by silica gel column chromatography using hexane-EtOAc (85:15) to afford ketones 10a-e and 15, respectively. The spectral and analytical details for selected compounds are given below.
( E )- t e rt -Butyl [5-(4-Heptanoylstyryl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamate (10b) Yield 65%; R _f = 0.4 (hexane-EtOAc, 7:3); colorless solid, mp 86-89 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.89 (t, 3 H, J = 7.2 Hz), 1.29-1.35 (m, 6 H), 1.44 (s, 9 H), 1.48 (s, 3 H), 1.49 (s, 3 H), 1.68-1.74 (m, 2 H), 2.94 (t, 2 H, J = 7.6 Hz), 3.91-4.01 (m, 4 H), 5.27 (br s, 1 H), 6.35 (d, 1 H, J = 16.4 Hz), 6.58 (d, 1 H, J = 16.4 Hz), 7.43 (d, 2 H, J = 8.0 Hz), 7.90 (d, 2 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 14.0, 19.4, 22.5, 24.3, 27.7, 28.4, 29.0, 31.9, 38.6, 53.1, 66.1, 79.8, 98.4, 126.5, 128.5, 129.5, 131.0, 136.1, 140.9, 154.8, 200.0. IR (CHCl₃): 1167, 1466, 1601, 1682, 1716, 2853, 2923 cm^-1. HRMS (EI): m/z calcd for C₂₆H₄₀NO₅ [M + H]⁺: 446.2906; found: 446.2899.
( E )- tert -Butyl [2,2-Dimethyl-5-(4-octanoylstyryl)-1,3-dioxan-5-yl]carbamate (10d) Yield 75%; R _f = 0.4 (hexane-EtOAc, 7:3); colorless solid, mp 83-86 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, 3 H, J = 7.2 Hz), 1.28-1.38 (m, 8 H), 1.44 (s, 9 H), 1.47 (s, 3 H), 1.49 (s, 3 H), 1.70-1.74 (m, 2 H), 2.93 (t, 2 H, J = 7.2 Hz), 3.91-4.00 (m, 4 H), 5.25 (br s, 1 H), 6.35 (d, 1 H, J = 16.4 Hz), 6.58 (d, 1 H, J = 16.4 Hz), 7.43 (d, 2 H, J = 8.4 Hz), 7.90 (d, 2 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 14.0, 19.5, 22.6, 24.5, 27.6, 28.4, 29.0, 29.3, 32.8, 38.6, 53.1, 66.1, 79.8, 98.4, 126.5, 128.4, 129.5, 131.0, 136.1, 140.9, 154.8, 199.9. IR (CHCl₃): 1168, 1456, 1603, 1685, 1719, 2853, 2923 cm^-1. HRMS (EI): m/z calcd for C₂₇H₄₂NO₅ [M + H]⁺: 460.3063; found: 460.3076.
( E )- tert -Butyl [5-(4-Benzoylstyryl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamate (10e) Yield 72%; R _f = 0.4 (hexane-EtOAc, 7:3); colorless solid, mp 109-112 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.45 (s, 9 H), 1.48 (s, 3 H), 1.50 (s, 3 H), 3.92-4.01 (m, 4 H), 5.24 (br s, 1 H), 6.37 (d, 1 H, J = 16.4 Hz), 6.61 (d, 1 H, J = 16.4 Hz), 7.45-7.50 (m, 4 H), 7.57-7.59 (m, 1 H), 7.76-7.79 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.5, 27.7, 28.4, 53.1, 66.1, 79.8, 98.4, 126.2, 128.2, 129.5, 129.9, 130.0, 132.3, 136.5, 137.7, 140.6, 154.8, 196.1. IR (CHCl₃): 1165, 1494, 1601, 1655, 1711, 2927, 2976 cm^-1. HRMS (EI): m/z calcd for C₂₆H₃₂NO₅ [M + H]⁺: 438.2280; found: 438.2281.

16a Fürstner A. Leitner A. Méndez M. Krause H. J. Am. Chem. Soc. 2002, 124: 13856

16b Fürstner A. Leitner A. Angew. Chem. Int. Ed. 2002, 41: 609

16c

See also ref. 4c and references cited therein.

Reagents and conditions:

17a

PPh₃ (1.2 equiv), acetone, reflux, 6 h, 80%;

17b

P(OEt)₃ (1.5 equiv), toluene, 110 °C, 8 h, 60%.
{4-[Methoxy(methyl)carbamoyl]benzyl}(triphenyl)phos-phonium Bromide (12)
Yield 80%; R _f = 0.2 (MeOH-CHCl₃, 3:7); white solid. ¹H NMR (400 MHz, CDCl₃): δ = 3.32 (s, 3 H), 3.57 (s, 3 H), 5.06 (d, 2 H, J _HP = 15.2 Hz), 7.12 (d, 2 H, J = 8.0 Hz), 7.49 (d, 2 H, J = 8.0 Hz), 7.69-7.76 (m, 12 H), 7.90-7.94 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 30.3, 30.8, 61.7, 118.5, 119.4, 129.6, 131.5, 131.8, 131.9, 132.0, 135.3, 135.5, 135.7, 136.6, 170.7. IR (CHCl₃): 1165, 1368, 1645, 3026 cm^-1.
Diethyl {4-[Methoxy(methyl)carbamoyl]benzyl}phos-phonate (13) Yield 60%; R _f = 0.1 (hexane-EtOAc, 3:7), colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ = 1.25 (t, 6 H, J = 6.8 Hz), 3.18 (d, 2 H, J _HP = 22.0 Hz), 3.35 (s, 3 H), 3.55 (s, 3 H), 4.00-4.06 (m, 4 H), 7.34 (dd, 2 H, J = 2.4, 8.0 Hz), 7.65 (d, 2 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 16.3, 33.6 (d, J _CP = 140 Hz), 33.7, 60.9, 62.2, 128.5, 129.4, 132.5, 134.5, 169.5. IR (CHCl₃): 1019, 1220, 1380, 1633, 2981 cm^-1. HRMS (EI): m/z calcd for C₁₄H₂₃NO₅P [M + H]⁺: 316.1314; found: 316.1317.

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tert -Butyl (5-{4-[Methoxy(methyl)carbamoyl]styryl}2,2-dimethyl-1,3-dioxan-5-yl)carbamate (9 + Z -isomer) Yield 70% (Z:E = 3:1); R _f = 0.35 (hexane-EtOAc, 6:4); colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ (Z-isomer) = 1.32 (s, 3 H), 1.38 (s, 9 H), 1.45 (s, 3 H), 3.37 (s, 3 H), 3.56 (s, 3 H), 3.77 (d, 2 H, J = 11.6 Hz), 3.88-3.94 (m, 2 H), 5.20 (br s, 1 H), 5.65 (d, 1 H, J = 12.8 Hz), 6.68 (d, 1 H, J = 12.8 Hz), 7.30 (d, 2 H, J = 8.0 Hz), 7.64 (d, 2 H, J = 8.0 Hz); δ (E-isomer, nonoverlapped signals) = 3.35 (s, 3 H), 3.53 (s, 3 H), 3.88-3.94 (m, 4 H), 5.27 (br s, 1 H), 6.23 (d, 1 H, J = 16.4 Hz), 6.48 (d, 1 H, J = 16.4 Hz), 7.39 (d, 2 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ (Z-isomer) = 18.8, 19.4, 20.9, 27.6, 28.3, 33.7, 52.5, 60.9, 65.8, 79.4, 98.1, 125.9, 128.6, 129.5, 130.0, 132.9, 140.1, 154.4, 169.4; δ (E-isomer, nonoverlapped signals) = 53.0, 66.0, 98.3, 127.9, 131.5, 132.6, 138.8. IR (CHCl₃): 1166, 1456, 1637, 1712, 2851, 2921 cm^-1. HRMS (EI): m/z calcd for C₂₂H₃₃N₂O₆ [M + H]⁺: 421.2339; found: 421.2348.

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tert -Butyl (5-{4-[Methoxy(methyl)carbamoyl]pheneth-yl}-2,2-dimethyl-1,3-diox-an-5-yl)carbamate (14) Yield 95%; R _f = 0.35 (hexane-EtOAc, 6:4); colorless solid, mp 89-91 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.42 (s, 3 H), 1.44 (s, 3 H), 1.48 (s, 9 H), 1.98-2.02 (m, 2 H), 2.58-2.62 (m, 2 H), 3.35 (s, 3 H), 3.55 (s, 3 H), 3.69 (d, 2 H, J = 12.0 Hz), 3.90 (d, 2 H, J = 12.0 Hz), 5.01 (br s, 1 H), 7.21 (d, 2 H, J = 8.0 Hz), 7.60 (d, 2 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 18.9, 27.4, 28.3, 28.6, 32.3, 32.8, 50.6, 59.9, 65.2, 78.4, 97.4 126.1, 126.9, 127.5, 130.6, 143.9, 153.9, 168.8. IR (CHCl₃): 1164, 1453, 1638, 1710, 2934, 2976 cm^-1. HRMS (EI): m/z calcd for C₂₂H₃₅N₂O₆ [M + H]⁺: 423.2495; found: 423.2486.

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tert -Butyl [2,2-Dimethyl-5-(4-octanoylphenethyl)-1,3-dioxan-5-yl]carbamate (15) Yield 70%; R _f = 0.4 (hexane-EtOAc, 7:3); colorless solid, mp 60-63 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, 3 H, J = 6.8 Hz), 1.25-1.35 (m, 8 H), 1.42 (s, 3 H), 1.44 (s, 3 H), 1.47 (s, 9 H), 1.70-1.74 (m, 2 H), 1.99-2.11 (m, 2 H), 2.60-2.64 (m, 2 H), 2.92 (t, 2 H, J = 7.2 Hz), 3.69 (d, 2 H, J = 12.0 Hz), 3.89 (d, 2 H, J = 12.0 Hz), 4.95 (br s, 1 H), 7.26 (d, 2 H, J = 8.0 Hz), 7.87 (d, 2 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 13.2, 19.0, 21.7, 23.7, 26.3, 27.6, 28.2, 28.5, 28.8, 30.8, 32.4, 37.7, 50.9, 65.5, 78.8, 97.6, 127.5, 127.7, 134.4, 146.7, 154.1, 199.3. IR (CHCl₃): 1198, 1498, 1606, 1682, 1715, 2856, 2926 cm^-1. HRMS (EI): m/z calcd for C₂₇H₄₄NO₅ [M + H]⁺: 462.3219; found: 462.3229.