A Two-Carbon Homologation of Aldehydes and Ketones Using Ynamides

Lingfeng You; Ziyad F. Al-Rashid; Ruth Figueroa; Sunil K. Ghosh; Gang Li; Ting Lu; Richard P. Hsung

doi:10.1055/s-2007-984513

LETTER

A Two-Carbon Homologation of Aldehydes and Ketones Using Ynamides

Lingfeng You, Ziyad F. Al-Rashid, Ruth Figueroa, Sunil K. Ghosh, Gang Li, Ting Lu, Richard P. Hsung*
Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, 777 Highland Avenue, 7111 Rennebohm Hall, Madison, WI 53705, USA
Fax: +1(608)2625345; e-Mail: rhsung@wisc.edu;

Abstract

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Abstract

Reactions of ynamides with Lewis acid activated aldehydes, enals, or ketones in the formation of acrylic amides are described here. The overall process is an equivalent of a two-carbon homologation of aldehydes or ketones and is selective for the E-isomer.

Key words

two-carbon homologation - ynamide - torquoselective ring opening - oxetene - E-acrylic amides

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References

References and Notes

For reviews on ynamides, see:

1a Zificsak CA. Mulder JA. Hsung RP. Rameshkumar C. Wei L.-L. Tetrahedron 2001, 57: 7575

1b Mulder JA. Kurtz KCM. Hsung RP. Synlett 2003, 1379

1c Katritzky AR. Jiang R. Singh SK. Heterocycles 2004, 63: 1455

2a For the synthesis of ynamides, see: Tracey MR. Hsung RP. Antoline JA. Kurtz KCM. Shen L. Slafer BW. Zhang Y. In Science of Synthesis, Houben-Weyl Methods of Molecular Transformations Weinreb SM. Georg Thieme Verlag; Stuttgart: 2005. Chap. 21.4.

2b Frederick MO. Mulder JA. Tracey MR. Hsung RP. Huang J. Kurtz KCM. Shen L. Douglas CJ. J. Am. Chem. Soc. 2003, 125: 2368

2c Zhang Y. Hsung RP. Tracey MR. Kurtz KCM. Vera EL. Org. Lett. 2004, 6: 1151

2d Dunetz JR. Danheiser RL. Org. Lett. 2003, 5: 4011

2e Couty S. Barbazanges M. Meyer C. Cossy J. Synlett 2005, 906

3 For a special issue dedicated to the chemistry of ynamides, see the Tetrahedron Symposium-In-Print on Chemistry of Electron-Deficient Ynamines and Ynamides: Tetrahedron 2006, 62: 3771-3938

For leading references on chemistry of ynamides, see:

4a Tanaka K. Takeishi K. Noguchi K. J. Am. Chem. Soc. 2006, 128: 4586

4b Couty S. Meyer C. Cossy J. Angew. Chem. Int. Ed. 2006, 45: 6726

4c Dunetz JR. Danheiser RL. J. Am. Chem. Soc. 2005, 127: 5776

4d Riddell N. Villeneuve K. Tam W. Org. Lett. 2005, 7: 3681

4e Zhang Y. Tetrahedron Lett. 2005, 46: 6483

4f Chechik-Lankin H. Livshin S. Marek I. Synlett 2005, 2098

For our recent works on ynamides, see:

5a Zhang X. Li H. You L. Tang Y. Hsung RP. Chem. Commun. 2007, in press

5b Tracey MR. Oppenheimer J. Hsung RP. J. Org. Chem. 2006, 71: 8629

5c Zhang X. Li H. You L. Tang Y. Hsung RP. Adv. Synth. Catal. 2006, 348: 2437

5d Zhang X. Hsung RP. You L. Org. Biomol. Chem. 2006, 6: 2679

5e Zhang X. Zhang Y. Huang J. Hsung RP. Kurtz KCM. Oppenheimer J. Petersen ME. Sagamanova IK. Tracey MR. J. Org. Chem. 2006, 71: 4170

5f Zhang Y. Hsung RP. Zhang X. Huang J. Slafer BW. Davis A. Org. Lett. 2005, 7: 1047

6a Fuks R. Viehe HG. Chem. Ber. 1970, 103: 564

6b Hsung RP. Zificsak CA. Wei L.-L. Douglas CJ. Xiong H. Mulder JA. Org. Lett. 1999, 1: 1237

7 For a review, see: Shindo M. Synthesis 2003, 2275

8a Shindo M. Matsumoto K. Mori S. Shishido K. J. Am. Chem. Soc. 2002, 124: 6840

8b Shindo M. Sato Y. Yoshikawa T. Koretsune R. Shishido K. J. Org. Chem. 2004, 69: 3912

8c Mori S. Shindo M. Org. Lett. 2004, 6: 3945

8d Shindo M. Yoshimura Y. Hayashi M. Soejima H. Yoshikawa T. Matsumoto K. Shishido K. Org. Lett. 2007, 9: in press

For an elegant equivalent of this ynol ethers-homologation through a Meyer-Schuster rearrangement, see:

9a Dudley G. Engel DA. Lopez SS. Synlett 2007, 949

9b Engel DA. Dudley G. Org. Lett. 2006, 8: 4027

10 Kurtz KCM. Hsung RP. Zhang Y. Org. Lett. 2006, 8: 231

11 Rhee JU. Krische MJ. Org. Lett. 2005, 7: 2493

12 Brønsted acids were not effective from the onset in this reaction, and thus, we focused on Lewis acids, although we did not exhaust the Brønsted acid option. In addition, Lewis acids such as TMSX, TiCl₄, BX₃, and MgX₂ had to be avoided because they react with ynamides to give (E)-α-haloenamides. See: Mulder JA. Kurtz KCM. Hsung RP. Coverdale HA. Frederick MO. Shen L. Zificsak CA. Org. Lett. 2003, 5: 1547

13

General Experimental Procedure: To a solution of ynamide 5 (56.0 mg, 0.30 mmol) in CH₂Cl₂ (30 mL) was added hexanal (0.055 mL, 0.45 mmol, 1.5 equiv). The solution was then cooled to -78 °C and a solution of BF₃·OEt₂ (0.20 M in CH₂Cl₂, 0.75 mL, 0.15 mmol) was added carefully dropwise and the reaction was stirred for 10 min at -78 °C. When the TLC analysis showed that the starting ynamide 5 was completely consumed, the reaction mixture was poured into sat aq NaHCO₃ (20 mL). The two phases were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL). The organic layers were combined, dried over Na₂SO₄, and concentrated in vacuo. The resulting crude yellow oil was purified using silica gel flash column chromatography (gradient eluent: 10-20% EtOAc in hexanes) to afford the pure acrylic amide 6 (56.0 mg, 65%) exclusively as the E-isomer and as a colorless oil. 6: R _f 0.34 (25% EtOAc in hexanes); [α]_D ²⁰ 86.0 (c = 0.40, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.24-1.34 (m, 4 H), 1.42-1.50 (m, 2 H), 2.25 (dtd, J = 1.2, 6.8, 7.2 Hz, 2 H), 4.27 (dd, J = 4.0, 8.8 Hz, 1 H), 4.81 (dd, J = 4.0, 8.8 Hz, 1 H), 5.48 (dd, J = 4.0, 8.8 Hz, 1 H), 7.10 (dt, J = 7.2, 15.2 Hz, 1 H), 7.25 (dt, J = 1.2, 15.2 Hz, 1 H), 7.30-7.41 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 13.9, 22.4, 27.7, 31.3, 32.6, 57.7, 69.9, 120.1, 125.9, 128.6, 129.1, 139.1, 152.3, 153.7, 164.7. IR (film): 2929 (w), 1775 (s), 1686 (w), 1634 (w) cm^-1. MS (APCI): m/z (%) = 288.2 (100) [M + H]⁺.

14

For other representative characterizations, see: 7: R _f 0.19 (25% EtOAc in hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 0.89 (t, J = 6.4 Hz, 3 H), 1.24-1.36 (m, 4 H), 1.44-1.53 (m, 2 H), 2.28 (dt, J = 6.4, 7.2 Hz, 2 H), 4.07 (dd, J = 7.6, 8.4 Hz, 2 H), 4.42 (dd, J = 7.6, 8.4 Hz, 2 H), 7.16 (dt, J = 6.4, 15.6 Hz, 1 H), 7.25 (dt, J = 1.2, 15.6 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 13.8, 22.3, 27.6, 31.2, 32.5, 42.6, 61.9, 119.8, 151.7, 153.4, 165.2. IR (film): 2928 (w), 2859 (w), 1773 (s), 1683 (m), 1643 (w), 1623 (w), 1386 (w), 1359 (m) cm^-1. MS (APCI): m/z (%) = 212.2 (100) [M + H]⁺.
8: R _f 0.35 (25% EtOAc in hexanes); mp 88-91 °C; [α]_D ²⁰ -36.9 (c = 0.15, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 4.31 (dd, J = 4.0, 9.2 Hz, 1 H), 4.73 (dd, J = 8.8, 9.2 Hz, 1 H), 5.56 (dd, J = 4.0, 8.8 Hz, 1 H), 7.30-7.41 (m, 6 H), 7.48 (dd, J = 7.6, 7.6 Hz, 1 H), 7.57-7.64 (m, 2 H), 7.79 (d, J = 16.0 Hz, 1 H), 7.94 (d, J = 0.8, 16.0 Hz, 1 H), 8.12 (d, J = 8.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 58.1, 70.2, 117.1, 126.2, 128.9, 128.9, 129.1, 129.4, 131.0, 134.7, 139.4, 146.9, 154.1, 165.0. IR (film): 3064 (w), 1775 (s), 1687 (m), 1619 (w) cm^-1. MS (APCI): m/z (%) = 294.2 (100) [M + H]⁺.
9: R _f 0.34 (25% EtOAc in hexanes); [α]_D ²⁰ -159 (c = 0.90, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.60-0.70 (m, 2 H), 0.94-1.02 (m, 2 H), 1.64-1.74 (m, 1 H), 4.26 (dd, J = 4.0, 8.8 Hz, 1 H), 4.69 (dd, J = 8.8, 8.8 Hz, 1 H), 5.48 (dd, J = 4.0, 8,8 Hz, 1 H), 6.54 (dd, J = 10.4, 15.2 Hz, 1 H), 7.29-7.34 (m, 3 H), 7.34-7.39 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 9.5, 9.6, 15.6, 58.0, 70.1, 117.3, 126.2, 128.8, 129.4, 139.5, 154.0, 157.6, 164.7. IR (film): 1770 (s), 2928 (w), 1681 (w), 1623 (w), 1379 (w) cm^-1. MS (APCI): m/z (%) = 258.2 (100) [M + H]⁺.
10: R _f 0.48 (25% EtOAc in hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 5.22 (s, 2 H), 7.05 (d, J = 15.2 Hz, 1 H), 7.32-7.44 (m, 10 H), 7.71 (d, J = 15.6 Hz, 1 H), 7.92-7.96 (m, 2 H), 8.24-8.27 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 50.1, 117.1, 124.3, 128.0, 128.5, 128.7, 129.3, 129.4, 129.7, 131.4, 134.2, 136.3, 145.5, 148.1, 150.7, 166.4. IR (film): 1775 (w), 1683 (m), 1619 (m), 1532 (m), 1350 (s) cm^-1. MS (APCI): m/z (%) = 423.1 (100) [M + H]⁺.
11: R _f 0.43 (25% EtOAc in hexanes); [α]_D ²⁰ 29.2 (c = 0.15, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.84 (t, J = 7.2 Hz, 3 H), 1.20-1.28 (m, 4 H), 1.33-1.41 (m, 2 H), 2.19 (ddd, J = 1.6, 7.6, 15.2 Hz, 2 H), 4.17 (dd, J = 6.8, 9.2 Hz, 1 H), 4.63 (dd, J = 8.8, 8.8 Hz, 1 H), 5.44 (dd, J = 6.8, 8.8 Hz, 1 H), 6.23 (t, J = 7.8 Hz, 1 H), 7.17-7.21 (m, 2 H), 7.27-7.35 (m, 5 H), 7.35-7.42 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 22.3, 28.5, 28.8, 31.4, 58.1, 69.6, 126.6, 127.6, 127.8, 128.8, 129.0, 129.6, 134.3, 136.1, 137.9, 140.1, 152.6, 169.7. IR (film): 2957 (w), 1787 (s), 1688 (m) cm^-1. MS (APCI): m/z (%) = 364.2 (100) [M + H]⁺.
12: R _f 0.48 (30% EtOAc-hexanes); mp 152-154 °C; [α]_D ²⁵ -15.3 (c = 0.60, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 2.20 (d, J = 1.5 Hz, 3 H), 4.34 (dd, J = 7.5, 8.5 Hz, 1 H), 4.80 (t, J = 9.0 Hz, 1 H), 5.59 (dd, J = 7.5, 8.5 Hz, 1 H), 7.11 (s, 1 H), 7.37-7.47 (m, 10 H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.5, 58.7, 70.2, 126.6, 128.6, 128.7, 129.2, 129.5, 129.8, 131.9, 135.8, 137.2, 138.1, 153.7, 171.8. IR (thin film): 3059 (w), 1782 (s), 1678 (s), 1357 (m), 1323 (m) cm^-1. MS (APCI): m/z (%) = 308 (100) [M + H]⁺.
13: R _f 0.40 (20% EtOAc-hexanes); mp 103-105 °C; [α]_D ²⁵ -28.3 (c = 0.90, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.91-0.96 (m, 3 H), 1.31-1.39 (m, 4 H), 1.47-1.58 (m, 2 H), 1.92 (s, 3 H), 2.19-2.27 (m, 2 H), 4.27 (dd, J = 7.5, 8.5 Hz, 1 H), 4.74 (t, J = 9.0 Hz, 1 H), 5.53 (dd, J = 7.5, 8.5 Hz, 1 H), 6.28 (ddd, J = 1.5, 7.5, 7.5 Hz, 1 H), 7.38-7.53 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 13.5, 14.3, 22.8, 28.3, 28.8, 31.8, 58.7, 70.0, 126.6, 129.1, 129.4, 130.7, 138.2, 142.0, 153.8, 171.4. IR (thin film): 2927 (w), 2858 (w), 1789 (s), 1679 (s), 1325 (m) cm^-1. MS (APCI): m/z (%) = 302 (100) [M + H]⁺.
15: R _f 0.34 (25% EtOAc in hexanes); [α]_D ²⁰ 70.0 (c = 0.90, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 4.20 (dd, J = 7.0, 9.0 Hz, 1 H), 4.65 (dd, J = 9.0, 9.0 Hz, 1 H), 5.39 (dd, J = 1.0, 10.0 Hz, 1 H), 5.47 (dd, J = 6.5, 9.0 Hz, 1 H), 5.57 (dd, J = 1.0, 16.5 Hz, 1 H), 6.55 (ddd, J = 10.0, 11.0, 16.5 Hz, 1 H), 6.69 (d, J = 11.0 Hz, 1 H), 7.20-7.24 (m, 2 H), 7.30-7.36 (m, 5 H), 7.37-7.43 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 58.5, 70.0, 125.0, 127.0, 128.2, 128.4, 129.3, 129.4, 130.2, 132.8, 134.3, 136.5, 136.6, 138.0, 152.9, 169.8. IR (film): 1782 (s), 1680 (w) cm^-1. MS (APCI): m/z (%) = 320.2 (100) [M + H]⁺.
16: R _f 0.52 (33% EtOAc in hexanes); mp 146-149 °C; [α]_D ²⁵ -59.0 (c = 0.5, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.77 (s, 3 H), 1.13 (d, J = 8.0 Hz, 1 H), 1.35 (s, 3 H), 2.13 (s, 1 H), 2.41-2.51 (m, 3 H), 2.66 (t, J = 6.4 Hz, 1 H), 4.27 (dd, J = 3.6, 8.8 Hz, 1 H), 4.69 (dd, J = 8.8, 8.8 Hz, 1 H), 5.51 (dd, J = 3.6, 8.8 Hz, 1 H), 6.08 (s, 1 H), 7.23 (d, J = 15.2 Hz, 1 H), 7.26-7.39 (m, 5 H), 7.42 (d, J = 15.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.0, 26.3, 31.4, 33.1, 38.0, 40.8, 41.5, 58.1, 70.1, 113.4, 126.1, 128.8, 129.4, 136.8, 139.5, 146.7, 146.8. 154.1, 165.6. IR (neat): 2976 (br m), 1778 (s), 1679 (s), 1494 (s), 1422 (s), 1384 (s) cm^-1. MS (APCI): m/z (%) = 338.2 (100) [M + H]⁺.
17: R _f 0.19 (20% EtOAc-hexanes); [α]_D ²³ -188.0 (c = 0.25, CH₂Cl₂). ¹H NMR (400 MHz CDCl₃): δ = 1.51 (m, 1 H), 1.74 (s, 3 H), 1.92 (ddd, J = 2.4, 5.2, 12.4 Hz, 1 H), 2.15 (m, 2 H), 2.26 (ddd, J = 2.4, 5.2, 12.4 Hz, 1 H), 2.37 (m, 2 H), 4.26 (dd, J = 4.0, 8.8 Hz, 1 H), 4.68 (t, J = 8.8 Hz, 1 H), 4.71 (m, 1 H), 4.75 (t, J = 1.6 Hz, 1 H), 5.51 (dd, J = 4.0, 8.8 Hz, 1 H), 6.22 (t, J = 2.4 Hz, 1 H), 7.23 (d, J = 15.6 Hz, 1 H), 7.30-7.34 (m, 3 H), 7.35-7.39 (m, 2 H), 7.40 (d, J = 15.6 Hz, 1 H). ¹³C NMR (100 MHz CDCl₃): δ = 21.0, 24.8, 27.1, 32.2, 40.8, 58.1, 70.1, 109.4, 114.2, 126.2, 128.8, 129.4, 135.6, 139.5, 140.2, 149.1, 149.8, 154.0, 165.5. IR (neat): 2919 (m), 1773 (s), 1680 (m), 1600 (s), 1383 (m), 1334 (s) cm^-1. MS (APCI): m/z (%) = 338.2 (100) [M + H]⁺.
18: R _f 0.29 (50% EtOAc in hexanes); colorless oil; [α]_D ²⁰ -43.8 (c = 0.53, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 2.05 (s, 3 H), 2.07 (s, 3 H), 2.11 (s, 3 H), 4.16 (dd, J = 6.4, 12.1 Hz, 1 H), 4.22 (dd, J = 3.9, 12.1 Hz, 1 H), 4.29 (dd, J = 4.0, 8.9 Hz, 1 H), 4.72 (t, J = 8.9 Hz, 1 H), 5.22 (ddd, J = 3.9, 4.8, 6.5 Hz, 1 H), 5.50 (dd, J = 3.9, 8.8 Hz, 1 H), 5.59 (ddd, J = 1.1, 5.0, 6.3 Hz, 1 H), 6.03 (dd, J = 6.4, 15.4 Hz, 1 H), 6.52 (ddd, J = 1.3, 10.6, 15.4 Hz, 1 H), 7.27-7.43 (m, 7 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.8, 20.9, 21.0, 57.9, 61.8, 70.2, 71.5, 71.6, 122.3, 126.1, 128.9, 129.4, 132.1, 135.8, 139.0, 144.4, 153.8, 164.5, 169.6, 170.1, 170.6. IR (neat): 3475 (w), 2963 (w), 1775 (m), 1738 (s), 1682 (m), 1606 (m), 1370 (m), 1350 (m), 1330 (m), 1214 (s), 1043 (s), 1013 (s) cm^-1. MS (APCI): m/z (%) = 460 (2) [M + H]⁺, 400 (35) [M - HOAc]⁺, 340 (100) [M - 2 × HOAc]⁺, 298 (5), 164 (10).
20a: R _f 0.35 (33% EtOAc-hexanes); mp 128-130 °C; [α]_D ²⁵ -181 (c = 0.84, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.60-1.75 (m, 4 H), 2.50-2.55 (m, 2 H), 2.69-2.74 (m, 2 H), 4.22 (dd, J = 4.4, 8.8 Hz, 1 H), 4.67 (dd, J = 9.0, 9.0 Hz, 1 H), 5.49 (dd, J = 4.0, 8.8 Hz, 1 H), 7.22 (dddd, J = 2.4, 2.4, 2.4, 2.4 Hz, 1 H), 7.30-7.34 (m, 3 H), 7.35-7.40 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 25.6, 26.6, 34.2, 37.1, 57.9, 69.9, 111.0, 126.0, 128.7, 129.4, 139.8, 154.1, 164.5, 174.2. IR (thin film): 3065 (w), 2960 (w), 1772 (s), 1681 (m), 1629 (m), 1378 (s) cm^-1. MS (APCI): m/z (%) = 272 (70) [M + H]⁺, 228 (100), 109 (88). MS (MALDI): m/z calcd for C₁₆H₁₇NO₃: 272.1281; found: 272.1280.
20b: R _f 0.49 (25% EtOAc-hexanes); mp 131-133 °C; [α]_D ²⁵ -119 (c = 1.50, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.44-1.55 (m, 4 H), 1.55-1.63 (m, 2 H), 2.17-2.23 (m, 2 H), 2.55-2.70 (m, 2 H), 4.14 (dd, J = 3.6, 8.8 Hz, 1 H), 4.58 (dd, J = 8.8, 8.8 Hz, 1 H), 5.40 (dd, J = 3.6, 8.8 Hz, 1 H), 6.76 (s, 1 H), 7.21-7.27 (m, 3 H), 7.27-7.33 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 26.4, 28.1, 28.9, 31.0, 38.7, 57.9, 70.0, 113.2, 126.1, 128.7, 129.4, 139.7, 153.9, 164.9, 166.6. IR (thin film): 2934 (w), 1777 (s), 1682 (m), 1627 (br s). MS (APCI): m/z (%) = 286.1 (100) [M + H]⁺.
20c: R _f 0.50 (33% EtOAc-hexanes); mp 134-135 °C; [α]_D ²⁵ -191 (c = 0.97, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.48-1.53 (m, 4 H), 1.60-1.68 (m, 4 H), 2.47 (br dd, J = 6.0, 6.0 Hz, 2 H), 2.73 (dddd, J = 1.6, 6.0, 6.0, 16.4 Hz, 1 H), 2.82 (dddd, J = 1.6, 6.0, 6.0, 16.4 Hz, 1 H), 4.21 (dd, J = 4.0, 8.8 Hz, 1 H), 4.66 (dd, J = 8.8, 8.8 Hz, 1 H), 5.48 (dd, J = 4.0, 8.8 Hz, 1 H), 6.99 (dddd, J = 1.6, 1.6, 1.6, 1.6 Hz, 1 H), 7.29-7.34 (m, 3 H), 7.36-7.40 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 26.5, 28.3, 29.4, 30.0, 33.7, 39.8, 57.9, 69.9, 115.1, 126.0, 128.7, 129.4, 139.8, 154.0, 164.5, 170.8. IR (thin film): 2926 (w), 1779 (s), 1686 (m), 1629 (m), 1377 (s) cm^-1. MS (APCI): m/z (%) = 300(35) [M + H]⁺, 274 (100), 256 (47), 137 (55). MS (MALDI): m/z calcd for C₁₈H₂₁NO₃Na: 322.1414; found: 322.1420.
21: R _f 0.41 (33% EtOAc-hexanes); mp 98-99 ºC; [α]_D ²⁵ -162 (c = 0.65, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 1.01 (dd, J = 7.5, 7.5 Hz, 3 H), 1.12 (dd, J = 7.5, 7.5 Hz, 3 H), 2.25 (qd, J = 1.5, 7.5 Hz, 2 H), 2.46 (dq, J = 7.5, 12.5 Hz, 1 H), 2.54 (dq, J = 7.5, 12.5 Hz, 1 H), 4.22 (dd, J = 4.0, 9.0 Hz, 1 H), 4.67 (dd, J = 9.0, 9.0 Hz, 1 H), 5.49 (dd, J = 4.0, 8.5 Hz, 1 H), 6.91 (dd, J = 1.5, 1.5 Hz, 1 H), 7.30-7.34 (m, 3 H), 7.36-7.40 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 12.2, 13.0, 26.6, 31.6, 57.9, 69.9, 113.7, 126.0, 128.7, 129.4, 139.7, 154.0, 164.6, 170.5. IR (thin film): 3035 (w), 2972 (w), 1777 (s), 1685 (m), 1626 (m), 1385 (s) cm^-1. MS (APCI): m/z (%) = 274 (8) [M + H]⁺, 248 (100), 230 (53), 111 (92). MS: (MALDI) m/z calcd for C₁₆H₁₉NO₃Na: 296.1257; found: 296.1265.
22a: R _f 0.41 (33% EtOAc-hexanes); clear oil; [α]_D ²⁵ +88.4 (c = 1.81, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃; major): δ = 1.94 (m, 2 H), 2.28-2.34 (m, 2 H), 2.36 (m, 2 H), 4.17 (dd, J = 6.8, 8.8 Hz, 1 H), 4.69 (dd, J = 8.8, 8.8 Hz, 1 H), 4.91 (dddd, J = 2.0, 2.0, 2.0, 2.0 Hz, 1 H), 4.99 (dd, J = 6.8, 8.8 Hz, 1 H), 6.07 (s, 1 H), 7.15 (tt, J = 1.2, 7.2 Hz, 1 H), 7.22-7.26 (m, 2 H), 7.30-7.40 (m, 7 H). ¹H NMR (400 MHz, CDCl₃; minor): δ = 5.95 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.5, 29.0, 30.8, 59.3, 70.1, 102.7, 111.7, 126.9, 127.3, 128.47, 128.53, 129.2, 129.3, 133.6, 138.0, 139.4, 154.2, 155.9. IR (neat): 3063 (w), 2958 (w), 1761 (s), 1651 (m), 1391 (m), 1364 (m), 1341 (m) cm^-1. MS (APCI): m/z (%) = 348 (3) [M + H]⁺, 296 (100). MS: (MALDI): m/z calcd for C₂₂H₂₁NO₃Na: 370.1414; found: 370.1394.
22b: R _f 0.36 (33% EtOAc-hexanes); clear oil; [α]_D ²⁵ +174 (c = 1.92, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃; major): δ = 1.49-1.56 (m, 2 H), 1.60-1.78 (m, 4 H), 2.06 (m, 2 H), 2.31 (m, 1 H), 2.38 (m, 1 H), 4.16 (dd, J = 6.8, 8.8 Hz, 1 H), 4.67 (dd, J = 8.8, 8.8 Hz, 1 H), 4.98 (dd, J = 6.8, 8.8 Hz, 1 H), 5.75 (dd, J = 6.4, 6.4 Hz, 1 H), 6.08 (s, 1 H), 7.14 (tt, J = 1.2, 6.4 Hz, 1 H), 7.21-7.25 (m, 2 H), 7.29-7.40 (m, 7 H). ¹H NMR (400 MHz, CDCl₃; minor): δ = 5.71 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 25.3, 26.0, 27.8, 31.6, 31.8, 59.1, 70.0, 106.9, 112.3, 126.8, 127.1, 128.39, 128.41, 129.1, 129.3, 134.0, 138.0, 138.1, 155.3, 155.9. IR (neat): 2981 (w), 1761 (s), 1672 (m), 1391 (m), 1345 (m) cm^-1. MS (APCI): m/z (%) = 376 (10) [M + H]⁺, 296 (100). MS (MALDI): m/z calcd for C₂₄H₂₅NO₃Na: 398.1727; found: 398.1709.
23: R _f 0.33 (33% EtOAc-hexanes); clear oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.13 (t, J = 7.6 Hz, 3 H), 1.59 (d, J = 6.8 Hz, 3 H), 2.23 (dq, J = 7.2, 14.8 Hz, 1 H), 2.30 (dq, J = 7.6, 14.8 Hz, 1 H), 4.12 (dd, J = 6.8, 8.8 Hz, 1 H), 4.66 (dd, J = 8.8, 8.8 Hz, 1 H), 4.89 (q, J = 6.8 Hz, 1 H), 4.93 (dd, J = 6.8, 8.8 Hz, 1 H), 6.12 (s, 1 H), 7.12-7.16 (m, 1 H), 7.20-7.26 (m, 2 H), 7.28-7.40 (m, 7 H). ¹H NMR (400 MHz, CDCl₃; minor): δ = 0.93 (t, J = 7.2 Hz, 3 H), 1.71 (dt, J = 1.6, 6.8 Hz, 3 H), 2.01-2.20 (m, 2 H), 4.17 (dd, J = 5.6, 8.8 Hz, 1 H), 4.67 (dd, J = 8.8, 8.8 Hz, 1 H), 4.80 (qt, J = 1.2, 6.8 Hz, 1 H), 5.06 (dd, J = 5.6, 8.8 Hz), 5.96 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 11.8, 12.3, 22.2, 58.9, 70.1, 98.5, 113.4, 126.7, 127.2, 128.38, 128.41, 129.0, 129.3, 133.9, 137.7, 138.0, 152.5, 156.1. IR (neat): 3062 (w), 2980 (w), 1762 (s), 1661 (w), 1391 (m) cm^-1. MS (APCI): m/z (%) = 350 (5) [M + H]⁺, 296 (100). MS (MALDI): m/z calcd for C₂₂H₂₃NO₃Na: 372.1570; found: 372.1566.
24: characterized as an inseparable mixture; R _f 0.49 (25% EtOAc in hexanes); [α]_D ²⁰ -80.6 (c = 1.95, CHCl₃). ¹H NMR (500 MHz, CDCl₃; E-isomer): δ = 1.16 (t, J = 7.5 Hz, 3 H), 2.14 (s, 3 H), 2.29 (q, J = 7.5 Hz, 2 H), 4.26 (dd, J = 4.0, 8.5 Hz, 1 H), 4.72 (t, J = 9.0 Hz, 1 H), 5.54 (dd, J = 4.0, 8.5 Hz, 1 H), 7.01-7.03 (m, 1 H), 7.34-7.39 (m, 3 H), 7.40-7.45 (m, 2 H). ¹H NMR (500 MHz, CDCl₃; Z-isomer): δ = 1.07 (t, J = 7.5 Hz, 3 H), 2.01 (s, 3 H), 2.48-2.56 (m, 1 H), 2.56-2.64 (m, 1 H), 4.24-4.29 (m, 1 H), 4.71 (t, J = 9.0, 1 H), 5.52-5.56 (m, 1 H), 6.97 (br s, 1 H), 7.34-7.39 (m, 3 H), 7.40-7.45 (m, 2 H). IR (neat): 1774 (s), 1684 (m), 1627 (w), 1606 (m) cm^-1. MS (APCI): m/z (%) = 260.1 (100) [M + H]⁺.
25: R _f 0.17 (10% EtOAc in hexanes); [α]_D ²³ -102.5 (c = 0.80, CHCl₃). ¹H NMR (400 MHz, CDCl₃; E-isomer): δ = 1.22-1.32 (m, 4 H), 1.52-1.82 (m, 6 H), 2.02-2.10 (m, 1 H), 2.07 (s, 3 H), 4.20 (dd, J = 4.0, 8.8 Hz, 1 H), 4.66 (dd, J = 8.8, 8.8 Hz, 1 H), 5.49 (dd, J = 4.0, 8.8 Hz, 1 H), 6.97 (br s, 1 H), 7.28-7.34 (m, 3 H), 7.35-7.40 (m, 2 H). ¹H NMR (500 MHz, CDCl₃; Z-isomer): δ = 1.22-1.32 (m, 4 H), 1.52-1.82 (m, 7 H), 1.89 (s, 3 H), 4.20 (dd, J = 4.0, 8.8 Hz, 1 H), 4.66 (dd, J = 8.8, 8.8 Hz, 1 H), 5.49 (dd, J = 4.0, 8.8 Hz, 1 H), 6.81 (br s, 1 H), 7.28-7.34 (m, 3 H), 7.35-7.40 (m, 2 H). IR (film): 2926 (m), 2852 (w), 1772 (s), 1680 (m), 1618 (w), 1383 (w) cm^-1. MS (APCI): m/z (%) = 314.2 (100) [M + H]⁺.
26: R _f 0.41 (25% EtOAc in hexanes); [α]_D ²³ -56.3 (c = 1.45, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 4.31 (dd, J = 4.0, 8.8 Hz, 1 H), 4.73 (d, J = 11.6 Hz, 1 H), 4.74 (d, J = 8.8 Hz, 1 H), 5.03 (d, J = 11.6 Hz, 1 H), 5.55 (dd, J = 4.0, 8.8 Hz, 1 H), 7.33-7.38 (m, 3 H), 7.39-7.44 (m, 5 H), 7.54 (s, 1 H), 7.60-7.64 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 40.0, 58.0, 70.3, 119.8, 126.2, 127.3, 129.1, 129.1, 129.5, 130.2, 138.5, 139.1, 153.6, 153.8, 163.9. IR (film): 2923 (w), 1775 (s), 1681 (m), 1615 (w), 1451 (m), 1384 (m) cm^-1. MS (APCI): m/z (%) = 342.1 (100) [M + H]⁺.

15a Kirmse W. Rondan NG. Houk KN. J. Am. Chem. Soc. 1984, 106: 7989

15b Kallel EA. Wang Y. Spellmeyer DC. Houk KN. J. Am. Chem. Soc. 1990, 112: 6759

15c Dolbier WR. Koroniak H. Houk KN. Sheu C. Acc. Chem. Res. 1996, 29: 471

15d Lee PS. Zhang X. Houk KN. J. Am. Chem. Soc. 2003, 125: 5072

16a Murakami M. Miyamoto Y. Ito Y. Angew. Chem. Int. Ed. 2001, 40: 189

16b Murakami M. Miyamoto Y. Ito Y. J. Am. Chem. Soc. 2001, 123: 6441

16c Murakami M. Hasegawa M. Igawa H. J. Org. Chem. 2004, 69: 587

16d Hasegawa M. Murakami M. J. Org. Chem. 2007, 72: in press

17

We did not rigorously assign the E and Z stereochemistries for the trisubstituted acrylic amides 23, 24 and 25 because of the low ratio and/or yield.

18

Authors appreciate the suggestion made by one of the referees to attempt homologations with these unsymmetrical ketones.