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Synlett 2009(10): 1614-1618  
DOI: 10.1055/s-0029-1217328
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Studies on a New Access to Z-Ethylenic Pseudodipeptides Based on Ring-Closing Metathesis: Obtention and Reductive Cleavage of N-Arylsulfonyl Dihydropyridones

Lucie Vandromme, Olivier N’Guyen Van Buu, François Guibé, Sophie Bezzenine-Lafollée
Institut de Chimie Moléculaire et des Matériaux d’Orsay, Laboratoire de Catalyse Moléculaire, UMR 8075, Bât 420, Université Paris-Sud, 91405 Orsay, France
Fax: +33(1)69154680; e-Mail: sbezzenine@icmo.u-psud.fr;
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Publication History

Received 3 February 2009
Publication Date:
02 June 2009 (online)

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Abstract

In the reaction with tert-butyloxycarbonyl anhydride (Boc2O), N-(o-vinylacetyloxy)benzenesulfonyl allylic amines 4a-c undergo concomitant O to N acyl migration to give N-(o-vinyl­acetyloxy)-N-(o-tert-butoxycarbonyloxy)benzenesulfonyl allylic amines 16a-c. In the presence of Grubbs’ second-generation catalyst, 16a-c are converted into N-arylsulfonyl-3,6-dihydropyridones 17a-c. The Boc group was removed from 17b and the resulting 18 was reductively cleaved with LiAlH4 to the ring-opened N-arylsulfonylamino alcohol 20 and with DIBAL to the ring-opened N-arylsulfonylamino aldehyde 21 that are close N-protected precursors of the Z-ethylenic pseudopeptidic analogue of l-Phe-Gly.

Key words

acyl migration - dihydropyridone - N-arylsulfonyl - ring opening - diolefin RCM - pseudopeptides - Z-ethylenic

7

In confirmation of this hypothesis, we found that, upon exposure to an ethereal solution of diazomethane 4 undergoes concomitant rearrangement and methylation to give the O-methyl ether of 4′. By comparison of the NMR spectra (CDCl3) of this ether and 4a we were able to locate, in the spectrum of the latter compound, the signals of 4′ which is present to the extent of ca 3%. The O-methyl ether was in turn found to readily cyclize by RCM in 95% yield into the corresponding dihydropyridone.

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The reaction was carried out at 95 ˚C in a tightly stoppered Schlenk tube in the presence of freshly distilled SOCl2 (1.6 equiv) without solvent and under an argon atmosphere. After 12 h the reaction mixture was cooled to r.t. and pumped out on a vacuum line. The Schlenk tube was reloaded with SOCl2 (1.6 equiv) and heated again at 95 ˚C for 12 h. The process was repeated twice more. The progress of the reaction was conveniently followed by examination of
the ¹H NMR pattern of the aromatic protons. The final crystalline residue was recrystallized from heptane-EtOAc. Yield: 83%.

12

Typical Experimental Procedure: The hydrochloric salt of (S)-α-benzylallylamine (6.76 mmol) and DIPEA (13.5 mmol) were dissolved in anhyd MeCN (20 mL) under an argon atmosphere. To the reaction mixture was added dropwise (o-benzoyloxy)benzenesulfonyl chloride 12 (6.76 mmol) and the reaction mixture was further stirred for 1 h at 0 ˚C and for 10 h at r.t. After evaporation of acetonitrile, the residue was taken up in Et2O and washed with dilute aq HCl and dilute aq sodium bicarbonate. After evaporation, the crude N-(1-benzyl)-(o-benzoyloxy)benzenesulfonamide was dissolved in anhyd MeCN (20 mL) at 0 ˚C. Allylamine (15 mmol) was added dropwise and the reaction mixture was further stirred for 10 h at r.t. After acetonitrile evaporation, the residue was taken up in Et2O. The ethereal solution was extracted with 2 N aq NaOH (2 ×). The aqueous phase was acidified to pH 1-2 with aq HCl and extracted with Et2O. After evaporation, 13b was purified by column chromatog-raphy (silica, cyclohexane-EtOAc, 90:10; yield: 62%).

13

Compounds 13a-c were converted into their O-tributyl-stannyl derivatives by reaction of Bu3SnCl in a two-phase system [HCO3Na (2-3 equiv), Bu3SnCl (1 equiv), Et2O-H2O, the tin phenoxide is recuperated in the organic phase] or by reaction of (Bu3Sn)2O (0.5 equiv, benzene or toluene, azeotropic elimination of H2O). The tin phenoxides were reacted with vinylacetyl chloride in hexane at 60 ˚C for 1-4 h depending on the cases. The O-vinylacetyl derivatives 4a-c progressively separated from the reaction mixture as crystals or as oils that crystallized on cooling. The whole reaction mixtures were then taken up in hexane-MeCN and most of the tin by-products were eliminated in the usual way by repetitive partition between the two solvents. Final purification was achieved by recrystallization (hexane-EtOAc) or column chromatography (silica gel, hexane-

EtOAc) of the residue from the MeCN phase. See: Newman W. P.; Synthesis; 1987, 665
Spectroscopic data : Compound 4a: ¹H NMR (250 MHz, CDCl3): δ = 7.90 (1 H, dd, J = 7.8 Hz, J′ = 1.2 Hz), 7.20-7.56 (3 H, m), 6.11-6.14 (1 H, m), 5.64-5.68 (1 H, m), 5.35-5.39 (2 H, m), 5.05-5.11 (2 H, m), 4.75 (1 H, br s, NH), 3.58 (2 H, t, J = 6.0 Hz), 3.37 (2 H, d, J = 7.0 Hz). ¹³C NMR (62.5 MHz, CDCl3): δ = 169.2, 147.5, 134.2, 132.8, 130.3, 128.9, 126.5, 124.7, 120.3, 118.0, 48.9, 39.2. IR (CHCl3): 1773 (C=O), 3368 (NH) cm-¹. MS (CI, NH3): m/z = 298 [M + NH4 +], 282 [MH+].
Compound 4b: ¹H NMR (200 MHz, CDCl3): δ = 6.86-7.90 (9 H, m), 5.90-6.10 (1 H, m), 5.54-5.71 (1 H, m), 5.21-5.33 (2 H, m), 4.92-5.01 (2 H, m), 4.79 (1 H, d, J = 7.3 Hz, NH), 3.95-4.10 (1 H, m), 3.33 (2 H, d, J = 7.2 Hz), 2.80 (2 H, d, J = 6.8 Hz). ¹³C NMR (62.5 MHz, CDCl3): δ = 168.7, 147.3, 136.7, 136.1, 133.8, 129.9, 129.5, 129.4, 128.6, 128.5, 126.9, 126.1, 124.5, 119.9, 116.4, 57.4, 42.0, 39.0.
Compound 4c: ¹H NMR (250 MHz, CDCl3): δ = 6.90-7.80 (9 H, m), 5.76-6.11 (2 H, m), 5.00-5.30 (4 H, m), ca. 5.2
(1 H, NH) 4.80-4.95 (1 H, t, J = 15 Hz), 3.35 (2 H, d, J = 6.9 Hz). ¹³C NMR (62.5 MHz, CDCl3): δ = 168.7, 147.3, 138.9, 136.7, 133.9, 132.4, 130.0, 129.8, 128.7, 127.9, 127.1, 126.1, 124.3, 120.3, 117.1, 60.2, 39.3. IR (liquid film): 1772.2 (C=O), 3294.2 (NH) cm-¹. MS (CI, NH3): m/z = 375 [M + NH4 +], 358 [MH+].

15

The absence of ester IR carbonyl absorption in the range 1750-1700 cm-¹ is coherent with the O-silylated N-acylated structure as represented in 15; the alternative N-silylated O-acylated may be confidently dismissed.

16

Typical Experimental Procedure: To a solution of N-1-benzylallyl-o-(but-3-enoyloxy)benzene-sulfonamide (4b; 1.7 mmol) in anhyd CH2Cl2 (12 mL) were added successively Boc2O (1.72 mmol) and DMAP (0.08 mmol, ca 0.05 equiv). The reaction mixture was then stirred at r.t. with TLC monitoring. After completion, the reaction mixture was diluted with EtOAc and washed successively with aq 1 M HCl and aq NaHCO3. The organic phase was dried, concentrated and the residue was purified by column chromatography (silica gel, cyclohexane-EtOAc, 9:1) to give N-1-benzylallyl-N-but-3-enoyl-(o-tert-butoxycarbonyl-
oxy)benzenesulfonamide (16b) as a colorless oil (yield: 79%).
Spectroscopic data: Compound 16b: ¹H NMR (200 MHz, CDCl3): δ = 7.30-8.03 (9 H, m), 5.91-6.23 (2 H, m), 5.10-5.23 (2 H, m), 4.58-4.90 (2 H, m), 4.50-4.58 (1 H, m), 3.71 (2 H, d, J = 6.8 Hz), 3.31-3.42 (1 H, dd, J = 13.2 Hz, J′ = 9.3 Hz), 3.00-3.09 (1 H, dd, J = 13.2 Hz, J′ = 5.0 Hz), 1.58
(s, 9 H). IR (CHCl3): 1769 (C=O, Boc), 1702.1 (C=O, amide) cm-¹. Compound 16c (yield: 93%): ¹H NMR (200 MHz, CDCl3): δ = 7.30-8.20 (9 H, m), 6.35-6.55 (1 H, m), 5.80-6.00 (1 H, m), 5.76 (1 H, d, J = 6.4 Hz), 5.10-5.20 (2 H, m), 5.00-5.48 (2 H, m), 3.50-3.80 (m, 2 H), 1.58 (s, 9 H). IR (CHCl3): 1769 (C=O, Boc), 1702.1 (C=O, amide) cm-¹.

17

Spectroscopic data: Compound 17b: ¹H NMR (200 MHz, CDCl3): δ = 7.27-8.25 (9 H, Ar, m), 5.84-5.93 (1 H, m), 5.64-5.72 (1 H, m), 5.40-5.53 (1 H, m), 3.10-3.31 (2 H, m), 2.46-2.59 (1 H, dd, J = 21.5 Hz, J′ = 5.1 Hz), 1.90-2.02
(1 H, dd, J = 21.5 Hz, J′ = 2.9 Hz), 1.58 (s. 9H). ¹³C NMR (62.5 MHz, CDCl3): δ = 168.4, 147.7, 135.3, 135.0, 132.4, 131.6, 130.8, 128.3, 127.0, 125.9, 125.7, 122.9, 84.8, 59.4, 42.8, 33.8, 27.6. IR (CHCl3): 1770 (C=O, Boc), 1694 (C=O, amide) cm-¹. [α]D ²0 +113.3 (c = 1, CHCl3).
Compound 17c: ¹H NMR (200 MHz, CDCl3): δ = 8.16 (1 H, dd, J = 8.0 Hz, J′ = 1.5 Hz), 7.64 (1 H, td, J = 15.0 Hz, J′ = 1.5 Hz), 7.30-7.45 (7 H, m), 6.24-6.28 (1 H, m), 5.71-6.16 (2 H, m), 2.90-3.31 (2 H, m), 1.63 (9 H, s). ¹³C NMR (62.5 MHz, CDCl3): δ = 167.9, 147.8, 140.3, 134.9, 132.5, 129.1, 128.1, 127.6, 126.2, 126.1, 125.9, 124.2, 119.9, 84.9, 62.2, 34.1, 27.8. IR (CHCl3): 1770.5 (C=O, Boc), 1699.3 (C=O, lactam) cm-¹.

18

Experimental Procedure: To a solution of 18 (40 mg, 0.116 mmol) in THF (2 mL) was added LiAlH4 (4 mg, 0.116 mmol, 1 equiv) at r.t. The reaction was stirred for 3 h and quenched with a solution of 0.1 M HCl. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were dried with MgSO4 and concentrated in vacuo. The resulting oil was then chromatographed on silica gel column (EtOAc-heptane, 20:80) to give the alcohol 20. Yield: 74% (30 mg, 0.086 mmol).
Compound 20: ¹H NMR (300 MHz, CDCl3): δ = 8.71 (1 H, s), 6.96-7.56 (m, 9 H), 5.31-5.42 (2 H, m), 4.91-4.94 (1 H, br d, NH), 4.23-4.32 (1 H, m), 3.45 (2 H, t, J = 6.4 Hz), 2.91 (1 H, dd, J = 13.5 Hz, J′ = 6.0 Hz), 2.78 (1 H, dd, J = 13.5 Hz, J′ = 7.9 Hz), 1.91-2.11 (2 H, 2 × symmetrical m). ¹³C NMR (75 MHz, CDCl3): δ = 155.2, 136.2, 135.3, 130.9, 129.7, 129.6, 128.7, 128.6, 127.1, 123.2, 120.5, 118.8, 61.6, 52.5, 42.2, 30.8. HRMS (ESI): m/z [M + Na+] calcd for C18H21O4NNaS: 370.1068; found: 370.10787.

19

Experimental Procedure: To a stirred solution of 18 (50 mg, 0.146 mmol) in THF (2 mL) at -78 ˚C was added slowly a 1.1 M solution of diisobutylaluminum hydride in cyclo-hexane (0.4 mL, 0.44 mmol, 3 equiv). The solution was warmed to 0 ˚C and quenched with a solution of 0.1 M HCl. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The combined organic phases were dried with MgSO4 and concentrated in vacuo. The resulting oil was then chromatographed on silica gel column (EtOAc-heptane, 30:70). Compound 21 was obtained as a 85:15 mixture of the two possible diastereo-isomers. Yield: 60% (32 mg, 0.088 mmol).
Spectroscopic data: Compound 21 (major diastereoisomer): ¹H NMR (360 MHz, CDCl3): δ = 7.80 (1 H, dd, J = 8.1 Hz, J′ = 1.5 Hz), 7.44-7.47 (1 H, m), 7.19-7.35 (5 H, m), 6.92 (1 H, d, J = 8.6 Hz), 6.17-6.19 (1 H, m), 5.76-5.82 (2 H, m), 4.20-4.22 (1 H, m), 3.41 (1 H, dd, J = 13.1 Hz, J′ = 2.8 Hz), 3.11 (1 H, dd, J = 13.2 Hz, J′ = 8.3 Hz), 2.41-2.57 (1 H, m), 2.18-2.24 (1 H, m). ¹³C NMR (75 MHz, CDCl3): δ = 134.2, 134.1, 130.4, 129.4, 128.5, 128.0, 127.3, 126.5, 125.2, 124.7, 122.3, 121.7, 119.7, 119.5, 118.2, 83.9, 54.9, 42.9, 24.6. HRMS (ESI): m/z [MH+ - H2O] calcd for C18H18O3NS: 328.1002; found: 328.10030.