Diversity-generation from an allenoate–enone coupling: syntheses of azepines and pyrimidones from common precursors

Tetrahedron 61 (2005) 6309–6314

Diversity-generation from an allenoate–enone coupling: syntheses of azepines and pyrimidones from common precursors Catherine A. Evans, Bryan J. Cowen and Scott J. Miller* Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467-3860, USA Received 3 December 2004; revised 26 January 2005; accepted 4 March 2005 Available online 3 May 2005

Abstract—Amine-catalyzed coupling reactions of allenoate esters and a,b-unsaturated carbonyls lead to a diverse range of a,a 0 disubstituted allenoates. With appropriately substituted monomers, intermolecular reactions can lead to pyrimidone products. Alternatively, with amine substituted allenoates, a 7-endo-dig cyclization can be carried out such that a divergent pathway is observed that leads to azepine scaffolds. q 2005 Elsevier Ltd. All rights reserved.

1. Introduction Catalytic reactions that lead to products of different structures from common precursors can be of utility in diversity-oriented syntheses. While five- and six-membered nitrogen-containing heterocycles are arguably the most prevalent azacycles found in natural products and natural product derivatives, the intriguing biological activity of numerous natural products containing seven- and eightmembered azacycles has made them attractive targets for synthesis also.1,2 Furthermore, the ability to access members of each ring size from a common acyclic precursor seemed to us an important challenge. During our examination of the scope of the quinuclidine-catalyzed addition of allenic esters to a,b-unsaturated carbonyl compounds (Eq. 1),3,4 we realized that this reaction provided an opportunity to use the allenic ester products as a platform for diversity generation of this type.5

(1)

2. Results and discussion As a first step to achieving 7-membered azacycles, we Keywords: Heterocycle; Quinuclidine; Azacycle. * Corresponding author. Tel.: C617 552 3620; fax: C617 552 2473; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.03.106

needed to examine the scope of the allenic ester/enone coupling to include nitrogen functionalized monomers. We thus demonstrated that vinyl ketones derived from N-protected amino acids were suitable coupling partners in this reaction. As such, we found that enone 2 could be coupled to allenoate 1 to deliver substituted allenoate 3 in 78% isolated yield under the influence of quinuclidine (10 mol%, Eq. 2).6

(2) The reaction proved efficient for a range of substrates ultimately derived from a-amino acids, as is shown in Table 1. In addition to benzyl substituted a-amino ketone derivative 2, the isopropyl substituted derivative 4 serves as an excellent substrate affording allenoate 5 in 86% yield (entry 2). Heterocycle-substituted substrates also participate in the reaction. For example, pyrrolidine derivative 6 yields allenoate 7 in 80% yield (entry 3); piperidine analog 8 results in compound 9 in 76% yield (entry 4). 2,5-Disubstitution is also tolerated on the pyrrolidine as compound 10 undergoes conversion to 11 in 80% yield (entry 5). With the ability to access allenoate-substituted a-amino vinyl ketones from the chiral pool, we set out to show that cyclization of the coupled products could lead to the synthesis of a range of chiral azepines.7 Following the

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Table 1. Substrate scope for coupling of allenoate esters to a,b-unsaturated carbonyl compoundsa Entry

Substrate

Yieldb

Product

1

78% 2

3

86%

2 4

5

80%

3 6

7

4

76% 8

9

5

80% 10

a b

11

All reactions were conducted at room temperature in PhCH3 for 24 h in the presence of quinuclidine (10 mol %). Yields refer to isolated yield after silica gel chromatography.

Table 2. Substrate scope for 7-endo-dig cyclization to deliver azepinesa Entry

Substrate

Product

1

Yieldb

90% 3 16

95%

2 5 17

3

97% 7 18

4

96% 11

19

82%

5 9 20 a

BOC-group cleavage was achieved with TFA prior to cyclization. All reactions were then conducted at reflux in CH3CN for 14 h in the presence of Hu¨nig’s base. See Experimental for details. b Yields refer to isolated material.

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pioneering work of Mukai in this arena,8 amine deprotection was projected to lead to the desired azepine scaffold through addition of nitrogen to the electron-deficient sp-carbon of the allenic esters. This intramolecular 7-endo-dig cyclization, followed by isomerization is depicted in Eq. 3.

Of note, the resulting azepines are somewhat acid sensitive and cannot be purified by conventional silica gel chromatography, although they are stable to purification with basic alumina if necessary.

(3)

In order to further examine the utility of the substituted allenoate products as starting points for diverse products, we sought to examine their chemistry for delivering diverse pyrimidones in analogy to the precedent of Acheson (Eq. 4).10 For example, allenoate esters could be condensed with 2-amino thiazoles to deliver pyrimidones of various structures.

Despite the potential acid-sensitivity of the allenoate moiety, the BOC-protected substrates proved to be excellent precursors to the azepine scaffold. In fact, a one-pot deprotection/cyclization was identified after minor experimentation. The a-amino acid-derived allenes were subjected to standard TFA deprotection conditions (1:1 TFA/ CH2Cl2, 23 8C, 30 min), followed by reaction concentration to provide the intermediate amine salts. The deprotected residue was then redissolved in acetonitrile, followed by the addition of excess Hu¨nig’s base, at which point the solution was heated to reflux for 14 h. After workup, the desired azepines could be isolated without additional purification (Table 2). For example, benzyl-substituted allenoate 3 could be converted to azepine 16 in 90% isolated yield (entry 1). Likewise, isopropyl-substituted derivative 5 delivers azepine 17 in 95% yield (entry 2). The cyclic derivatives were also found to be excellent substrates for the conversion. Pyrrolidines 7 and 11 were converted to the corresponding azepines 18 and 19 in 97% and 96% yield, respectively (entries 3 and 4).9 In addition, piperidine analog 9 afforded the corresponding 6,7-ring system 20 in 82% isolated yield.

(4)

Since the allenoate/enone coupling reaction delivers a-substituted allenoates of various structures, we were pleased to find that a variety of starting materials proceed through the condensation efficiently. As shown in Table 3, both simple ketone derived substrates, as well as those derived from a-amino acids serve with similar efficiency in the condensation. For example, substrates 21 and 23 prepared in our earlier study prove to deliver the corresponding pyrimidones 22 and 24 in excellent yields (84 and 87%, respectively; entries 1 and 2).11 Spirocyclic allenoate 25 also delivers the corresponding pyrimidone 26, albeit in somewhat reduced yield (50%, entry 3). Finally, a-amino ketone 27 is also a suitable precursor, affording pyrimidone 28 in 71% yield (entry 4).

Table 3. Allenoate condensation with 2-aminothiazole to deliver pyrimidonesa Entry

Substrate

Product

Yieldb

84%

1 21

22

87%c

2 23 24

50%d

3 25 26

71%

4 27 a

28

Entries 2–4 were conducted in a sealed tube at 80 8C for 36 h. Entry 1 was conducted in a sealed tube at 80 8C for 24 h. Yields refer to isolated yield after silica gel chromatography. Each entry refers to the average of two runs. c Compound 24 was obtained as a mixture of diastereomers (w1:1). d Compound 26 was also obtained by recrystallization. b

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3. Conclusions The allenoate/enone condensation has thus been demonstrated to be an effective reaction with expanded substrate scope. The efficacy of a-amino acid derived vinyl ketones as substrates also significantly increases the utility of the reaction since it sets up a subsequent 7-endo-dig cyclization to allow for efficient synthesis of azepines. In combination with precedented condensation chemistry such as the reaction of allenoate with 2-amino thiazoles, the potential utility of the chemistry of allenoates as diversity-generating templates is supplemented. This starting material has now been shown to participate efficiently in a wide range of chemistry, including phosphine-catalyzed cycloadditions12 and other powerful annulations.13,14 In addition, our previous studies of amine-catalyzed couplings to enones set up threecomponent couplings with Baylis–Hillman adducts.3 The present study now adds azepine and pyrimidone syntheses to expand the utility of these starting materials. 4. Experimental 4.1. General Proton NMR spectra were recorded on Varian 400 or 500 spectrometers. Proton chemical shifts are reported in ppm (d) relative to internal tetramethylsilane (TMS, d, 0.0). Spectral data is reported as follows: chemical shift (multiplicity (singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m)), coupling constants (J) (Hz), integration). Carbon NMR spectra were recorded on a Varian 400 MHz (100 MHz) or Varian 300 MHz (75 MHz) spectrometer with complete proton decoupling. Carbon chemical shifts are reported in ppm (d) relative to the residual solvent signal (CDCl3, d 77.16). NMR data were collected at 25 8C, unless otherwise indicated. Infrared spectra were obtained on a Perkin–Elmer Spectrum 1000 spectrometer. Analytical thin-layer chromatography (TLC) was performed using Silica Gel 60 F254 pre-coated plates (0.25 mm thickness), TLC Rf values are reported and visualization was accomplished by irradiation with a UV lamp and/or staining with cerium ammonium molybdinate (CAM) solutions. Flash column chromatography was performed using Silica Gel 60A (40 mm) from Scientific Adsorbents Inc. High resolution mass spectra were obtained from Mass Spectrometry Facilities at Boston College (Chestnut Hill, MA). The method of ionization is given in parentheses. All reactions were carried out under a nitrogen atmosphere employing oven- and flame-dried glassware. Solvents were distilled over appropriate drying reagents prior to use. 4.2. Preparation of compounds 4.2.1. General procedure for the coupling of allenic esters to amino vinyl ketones. a,b-Unsaturated ketone 4 (165 mg, 0.780 mmol) was dissolved in 8.00 mL of toluene and buta-2,3-dienoic acid benzyl ester (163 mL, 0.940 mmol) was added. Quinuclidine (8.70 mg, 0.078 mmol) was then added. The reaction was stirred for 24 h at 23 8C, at which point the crude reaction mixture was

loaded directly onto a silica gel column and purified by flash chromatography (gradient 0–40% EtOAc/hexanes) to afford 262 mg (86% yield) of desired product 5 as a clear oil. 4.2.1.1. Characterization data for products in Table 1. Data for 3. 1H NMR (CDCl3, 400 MHz) d 7.31–7.13 (m, 5H), 5.12–5.01 (overlapping m, 4H), 3.07 (dd, JZ13.7, 6.4 Hz, 1H), 2.95, (dd, JZ13.9, 6.6 Hz, 1H), 2.64–2.40 (m, 4H), 1.40 (s, 9H), 1.24 (d, JZ6.2 Hz, 6H); 13C NMR (CDCl3, 100 MHz) d 212.8, 207.5, 166.0, 154.9, 136.0, 129.1, 128.5, 126.8, 99.5, 79.7, 68.7, 60.2, 38.8, 37.9, 28.4, 22.1, 21.9; IR (film, cmK1) 3368, 2980, 2935, 1965, 1941, 1709, 854; TLC Rf 0.32 (20% EtOAc/hexanes); Exact mass calcd for [C23H31NO5Na]C requires m/z 424.2100. Found 424.2104 (ESIC). Data for 5. 1H NMR (CDCl3, 400 MHz) d 7.36–7.27 (m, 5H), 5.22–5.12 (overlapping d, s, and t, JtripletZ3.1 Hz, 5H), 4.27 (dd, JZ4.0, 8.8 Hz, 1H), 2.72–2.52 (m, 4H), 2.14 (m, 1H), 1.43 (s, 9H), 0.98 (d, JZ6.6 Hz, 3H), 0.75 (d, JZ 6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 213.2, 207.8, 166.3, 155.6, 135.8, 128.3, 127.9, 127.7, 99.0, 80.0, 79.5, 66.6, 64.1, 38.7, 30.2, 28.4, 22.3, 20.0, 16.7; IR (film, cmK1) 3377, 2971, 2934, 1966, 1938, 1710, 861; TLC Rf 0.33 (20% EtOAc/hexanes); Exact mass calcd for [C23H31NO5Na]C requires m/z 424.2100. Found 424.2101 (ESIC). Data for 7 (rotamers). 1H NMR (CDCl3, 400 MHz) d 5.15 (m, 2H), 4.34–4.18 (overlapping m and q, 3H), 3.60–3.41 (m, 2H), 2.72–2.60 (m, 2H), 2.56–2.51 (m, 2H), 2.21–2.08 (m, 1H), 1.96–1.80 (m, 2H), 1.46 and 1.40 (2s, 9H), 1.28 (t, JZ7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 212.9, 208.4, 208.2, 166.4, 154.3, 153.5, 99.4, 99.2, 80.0, 79.6, 79.5, 65.1, 64.5, 61.0, 46.8, 46.7, 37.3, 36.7, 30.0, 28.9, 28.4, 28.3, 24.4, 23.7, 22.2, 21.8, 14.3; IR (film, cmK1) 2979, 2935, 1967, 1941, 1709, 858; TLC Rf 0.24 (20% EtOAc/hexanes); Exact mass calcd for [C18H27NO5Na]C requires m/z 360.1778. Found 360.1787 (ESIC). Data for 9. 1H NMR (CDCl3, 400 MHz) d 5.15 (m, 2H), 4.74–4.58 (broad m, 1H), 4.20 (q, JZ7.0 Hz, 2H), 4.09– 3.94 (m, 1H), 2.91–2.52 (m, 5H), 2.19 (d, JZ13.2 Hz. 1H), 1.62 (m, 5H), 1.46 (s, 9H), 1.28 (t, JZ7.0 Hz, 3H); IR (film, cmK1) 2983, 2947, 2875, 1975, 1951, 1714, 874; TLC Rf 0.38 (20% EtOAc/hexanes); Exact mass calcd for [C19H29NO5Na]C requires m/z 374.1935. Found 374.1943 (ESIC). Data for 11 (rotamers). 1H NMR (CDCl3, 400 MHz) d 5.15 (m, 2H), 4.39–4.37 (m, 1H), 3.99–3.89 (m, 1H), 3.75–3.74 (2 s, 3H), 2.74–2.54 (m, 1H), 2.54–2.52 (m, 2H), 2.22–2.10 (m, 1H), 1.95–1.62 (m, 4H), 1.45 and 1.38 (2 s, 9H), 0.87 (m, 3H); 13C NMR (CDCl3, 100 MHz) d 212.9, 207.5, 207.3, 166.6, 153.9, 152.9, 98.8, 98.6, 79.4, 79.4, 79.3, 79.2, 64.7, 64.3, 58.2, 57.8, 51.9, 51.9, 37.4, 37.0, 34.1, 33.4, 31.6, 29.4, 29.4, 29.3, 29.0, 28.2, 28.1, 27.8, 27.1, 26.8, 26.4, 26.3, 26.1, 22.4, 22.0, 21.7; IR (film, cmK1) 2954, 2929, 2856, 1966, 1946, 1718, 855; TLC Rf 0.32 (20% EtOAc/hexanes); Exact mass calcd for [C26H43NO5Na]C requires m/z 472.3039. Found 472.3049 (ESIC). 4.2.2. General procedure for the cyclization of allenic esters to azepines. Allene 7 (130 mg, 0.380 mmol) was dissolved in 4.00 mL TFA/CH2Cl2 (1:1 v/v) and stirred at

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room temperature for 30 min. At this point the solvent was removed by azeotroping with toluene (3!20 mL) under vacuum at 80 8C. The crude residue was dissolved in 5 mL acetonitrile and DIPEA was added (204 mL, 1.14 mmol). The reaction mixture was heated to reflux for 14 h. After cooling, the reaction was concentrated, redissolved in CH2Cl2 (50 mL) and washed with sat. NaHCO3 (1! 10 mL). The organic layer was dried over Na2SO4 and concentrated to yield the desired azepine 18 in 97% yield (87 mg) as a yellow oil. 4.2.2.1. Characterization data for products in Table 2. Data for 16. 1H NMR (CDCl3, 400 MHz) d 7.26–7.10 (m, 5H), 4.93 (m, 1H), 4.23 (m, 1H), 3.54 (bd, JZ2.6 Hz, 1H), 3.18 (dd, JZ4.0, 14.7, 1H), 2.85–2.59 (m, 5H), 1.99 (s, 3H), 1.25 (d, JZ1.8 Hz, 3H), 1.24 (d, JZ1.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 208.3, 168.5, 154.1, 136.7, 128.7, 128.6, 126.7, 99.4, 66.5, 63.5, 41.2, 35.7, 23.8, 23.5, 22.2, 22.1; IR (film, cmK1) 3352, 3035, 2985, 2938, 1725, 1685, 1669, 1598; Exact mass calcd for [C18H23NO3Na]C requires m/z 324.1576. Found 324.1579 (ESIC). Data for 17. 1H NMR (CDCl3, 400 MHz) d 7.38–7.24 (m, 5H), 5.15, (dd, JZ12.8, 14.3 Hz, 2H), 3.84 (t, JZ5.1 Hz, 1H), 3.67 (d, JZ3.7 Hz, 1H), 2.95–2.83 (m, 2H), 2.72–2.58 (m, 2H), 2.34 (m, 1H), 2.29 (s, 3H), 0.99 (d, JZ7.0 Hz, 3H), 0.94 (d, JZ6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 207.8, 168.7, 155.6, 136.9, 128.3, 127.8, 127.6, 98.4, 67.7, 65.4, 41.9, 27.8, 24.0, 23.8, 19.6, 17.9; IR (film, cmK1) 3368, 2962, 2934, 2873, 1718, 1686; Exact mass calcd for [C18H23NO3Na]C requires m/z 324.1576. Found 324.1573 (ESIC). Data for 18. 1H NMR (CDCl3, 400 MHz) d 4.42 (d, JZ 7.7 Hz, 1H), 4.08 (q, JZ7.1 Hz, 2H), 3.36 (m, 2H), 2.96 (m, 1H), 2.80 (m, 1H), 2.46 (m, 3H), 2.40 (s, 3H), 1.83–1.53 (m, 3H), 1.27 (t, JZ7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 207.2, 169.6, 157.5, 98.1, 67.2, 59.3, 49.4, 40.8, 25.2, 25.0, 23.5, 19.8, 14.6; IR (film, cmK1) 2977, 2855, 2874, 1721, 1674, 1558; Exact mass calcd for [C13H20NO3]C requires m/z 238.1443. Found 238.1442 (ESIC). Data for 19. 1H NMR (CDCl3, 400 MHz) d 4.40 (d, JZ 7.7 Hz, 1H), 3.89 (m, 1H), 3.68 (s, 3H), 3.02–2.87 (m, 2H), 2.55–2.37 (m, 2H), 3.40 (s, 3H), 2.08–2.01 (m, 1H), 1.81– 1.71 (m, 1H), 1.62 (m, 1H), 1.50–1.40 (m, 1H), 1.24–1.13 (m, 16H), 0.88 (t, JZ6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 208.6, 170.0, 156.9, 99.9, 68.6, 54.5, 50.8, 40.4, 36.7, 31.9, 30.1, 29.6, 29.6, 29.3, 26.2, 25.9, 24.0, 22.7, 18.6, 14.2; IR (film, cmK1) 2930, 2855, 1725, 1685, 1560; Exact mass calcd for [C21H36NO3]C requires m/z 350.2695. Found 350.2693 (ESIC). Data for 20. 1H NMR (CDCl3, 400 MHz) d 4.15 (q, JZ 7.0 Hz, 2H), 3.56 (d, JZ12.5 Hz, 1H), 2.92 (m, 1H), 2.57– 2.42 (m, 4H), 2.29 (s, 3H), 2.13 (m, 1H), 1.62–1.47 (m, 5H), 1.28 (t, JZ7.7 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 209.5, 169.2, 158.3, 107.6, 64.2, 59.5, 45.9, 40.9, 26.2, 25.9, 24.5, 20.5, 19.8, 14.4; IR (film, cmK1) 2938, 2868, 2851, 1719, 1690, 1572; Exact mass calcd for [C14H22NO3]C requires m/z 252.1600. Found 252.1601 (ESIC). 4.2.3. General procedure for allenoate condensation with 2-aminothiazole to deliver pyrimidones. To a solution of

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allenoate 23 (35.1 mg, 0.100 mmol) in acetonitrile (1.00 mL) was added 2-aminothiazole (10.1 mg, 0.100 mmol). Upon stirring in a sealed tube, the solution was heated at 80 8C for 36 h. The reaction mixture was concentrated and the crude residue was purified by silica gel chromatography (0–4% MeOH/CH2Cl2) to afford pyrimidone 24 in 82% yield (33.4 mg) as a light orange solid. 4.2.3.1. Characterization data for products in Table 3. Data for 22. 1H NMR (CDCl3, 400 MHz) d 7.71 (d, JZ 7.7 Hz, 1H), 7.58 (t, JZ7.0 Hz, 1H), 7.44 (d, JZ7.7 Hz, 1H), 7.39–7.34 (m, 2H), 6.94 (d, JZ4.7 Hz, 1H), 3.35 (dd, JZ17.2 Hz, 6.6 Hz, 1H) 3.05 (m, 5H), 2.55 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 207.8, 167.5, 163.8, 153.8, 141.7, 136.2, 134.8, 127.3, 126.7, 123.7, 121.7, 120.2, 109.5, 46.6, 33.2, 28.4, 16.3; IR (film, cmK1) 3081, 2927, 1705, 1627, 1609, 1565, 1495, 1422; TLC Rf 0.17 (5% MeOH/CH2Cl2); Exact mass calcd for [C17H14N2O2SNa]C requires m/z 333.0674. Found 333.0675 (ESIC). Data for 24. 1H NMR (CDCl3, 400 MHz) d 7.86 (dd, JZ7.9, 1.3 Hz, 1H), 7.79 (dd, JZ7.9 Hz, 1.8 Hz, 1H), 7.60–7.43 (m, 6H), 7.41–7.25 (m), 7.18–6.98 (m, 5H), 6.80 (m, 2H), 5.77 (s, 1H), 5.45 (d, JZ8.2 Hz, 1H), 3.99 (m, 1H), 3.53 (m, 1H), 3.04 (m, 1H), 2.76 (m, 2H), 2.31 (s, 3H), 2.05 (s, 2H); 13 C NMR (CDCl3, 100 MHz) d (two diastereomers) 194.5, 194.2, 167.0, 166.8, 163.8, 163.6, 160.6, 160.2, 141.1, 141.0, 137.3, 136.6, 136.1, 128.6, 128.5, 128.2, 127.7, 127.2, 126.9, 126.0, 121.8, 121.5, 121.4, 120.6, 120.2, 119.7, 119.1, 118.1, 118.0, 109.2, 84.0, 81.4, 49.1, 47.8, 29.9, 26.4, 22.9, 16.3, 15.8; IR (film, cmK1) 3069, 2924, 2855, 1686, 1628, 1607, 1567, 1496, 1473, 1463, 1423; TLC Rf 0.13 (5% MeOH:CH2Cl2); Exact mass calcd for [C23H19N2O3S]C requires m/z 403.1116. Found 403.1124 (ESIC). Data for 26. 1H NMR (CDCl3, 400 MHz) d 7.77 (dd, JZ7.7, 1.6 Hz, 1H), 7.48 (m, 1H), 7.17 (d, JZ5.1 Hz, 1H), 6.98 (m, 2H), 6.84 (d, JZ4.9 Hz, 1H), 3.25 (dd, JZ13.5 Hz, 3.0 Hz), 2.88 (dd, JZ11.4 Hz, 3.1 Hz, 1H), 2.70–2.64 (m, 1H), 2.27 (m, 1H), 2.16 (m, 1H), 2.05 (s, 3H), 1.98–1.92 (m, 2H), 1.84–1.67 (br m, 4H); 13C NMR (CDCl3, 75 MHz) d 195.9, 167.5, 164.4, 160.1, 141.7, 136.4, 127.2, 122.0, 121.3, 120.2, 119.7, 119.1, 109.7, 93.7, 53.1, 36.9, 36.1, 26.4, 24.8, 24.1, 16.3; IR (film, cmK1) 3068, 2955, 1687, 1632, 1607, 1565, 1495, 1425; TLC Rf 0.15 (5% MeOH:CH2Cl2); Exact mass calcd for [C21H20N2O3SNa]C requires m/z 403.1096. Found 403.1092 (ESIC). Data for 28. 1H NMR (CDCl3, 400 MHz) d 7.30 (d, JZ 4.9 Hz, 1H), 7.20 (m, 3H), 7.07 (d, JZ6.6 Hz, 2H), 6.89 (d, JZ4.9 Hz, 1H), 5.10 (d, JZ7.1 Hz, 1H), 4.43 (m, 1H), 3.12 (dd, JZ14.0 Hz, 5.8 Hz, 1H), 2.90–2.80 (m, 5H), 2.50 (s, 3H), 1.38 (s, 9H); 13C NMR (CDCl3, 100 MHz) d 208.6, 167.1, 163.7, 155.0, 141.2, 136.1, 129.1, 128.4, 126.8, 121.7, 120.7, 109.3, 79.9, 60.4, 37.9, 37.5, 29.9, 28.5, 21.3, 16.1; IR (film, cmK1) 3289, 3094, 3056, 2980, 2924, 1705, 1629, 1616, 1569, 1496, 1455, 1424; TLC Rf 0.18 (5% MeOH/CH2Cl2); Exact mass calcd for [C23H24N6O8SNa]C requires m/z 464.1620. Found 464.1626 (ESIC).

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Acknowledgements This research is supported by National Science Foundation (CHE-0236591). In addition, we are grateful to Merck Research Laboratories and Pfizer Global Research for support. S. J. M. is a Fellow of the Alfred P. Sloan Foundation and a Camille Dreyfus Teacher-Scholar.

6.

References and notes

7.

1. For an excellent review on 7, 8, and 9-membered azacycle synthesis and natural products, see (a) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131–9166. (b) O’Hagan, D. Nat. Prod. Rep. 1997, 637–652. 2. For a discussion on the novel biological activity of glucosederived 7-membered azasugars, see: Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.; PrakashaReddy, J. J. Org. Chem. 2004, 69, 4760–4766. 3. Evans, C. A.; Miller J. Am. Chem. Soc. 2003, 125, 12394–12395. 4. The quinuclidine-catalyzed reaction initiates through conjugate addition, in analogy to the amine-catalyzed Baylis– Hilman reaction. For a review, see: Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–891. 5. For several key references to nucleophilic catalysis via conjugate addition of P-nucleophiles, see (a) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933–7935. (b) Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 1 1993, 1921–1923. (c) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119, 7595–7596. (d) Trost, B. M.; Dake, G. R. J. Org. Chem. 1997, 62, 5670–5671. (e) Wang, L.-C.; Luis, A.-L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402–2403. (f) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404–2405. (g) Wang,

8.

9.

10.

11. 12.

13. 14.

J.-C.; Ng, S.-S.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 3682–3683. Vinyl ketone derivatives of a-amino acids are readily obtained in analogy to the following precedents: (a) Spaltenstein, A.; Leban, J. J.; Huang, J. J.; Reinhardt, K. R.; Viveros, O. H.; Sigafoos, J.; Crouch, R. Tetrahedron Lett. 1996, 37, 1343–1346. (b) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818. (c) At this stage, we have not evaluated the extent to which racemization may have occurred at any step in the sequences. For recent reviews concerning syntheses of 7- and 8-membered azacycles, see: (a) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238. (b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127–2198. (a) Mukai, C.; Yamashita, H.; Hanaoka, M. Org. Lett. 2001, 3, 3385–3387. (b) Mukai, C.; Ukon, R.; Kuroda, N. Tetrahedron Lett. 2003, 44, 1583–1586. (c) Mukai, C.; Kobayashi, M.; Kubota, S.; Takahashi, Y.; Kitagaki, S. J. Org. Chem. 2004, 69, 2128–2136. As noted in Ref. 6, product racemization has not yet been evaluated in these sequences. Circumstantially, we note that product 19 was isolated without erosion of diastereomeric purity. (a) Acheson, R. M.; Bite, M. G.; Cooper, M. W. J. Chem. Soc., Perkin Trans. 1 1976, 1908–1911. (b) Doad, G. J. S.; Okor, D. I.; Scheinmann, F.; Bates, P. A.; Hursthouse, M. B. J. Chem. Soc., Perkin Trans. 1 1988, 2993–3003. Compound 24 is isolated as a mixture of diastereomers (w1:1 cis/trans) after pyrimidone formation. (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535–544 and references therein. (b) Du, Y.; Lu, X.; Yu, Y. J. Org. Chem. 2002, 67, 8901–8905. Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716–4717. Zhu, X.-F.; Henry, C. E.; Wang, J.; Dudding, T.; Kwon, O. Org. Lett. 2005, 7, 1387–1390.