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

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Synlett 2007(11): 1656-1662
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;

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Publikationsverlauf

Received 2 April 2007
Publikationsdatum:
25. Juni 2007 (online)

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

References and Notes

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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]⁺.

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.