Facile Synthesis of 3-Amido-Dienynes via a Tandem α-Propargylation–Isomerization of Chiral Allenamides and their Applications in Diels–Alder Cycloadditions

With deep respect and admiration, this paper is dedicated to Professor Victor Snieckus on the special occasion of his 80^th birthday

Abstract

A series of interesting 3-amido-dienynes was synthesized via tandem α-propargylation–isomerization of chiral allenamides with moderate E/Z ratio. Reactivities of E and Z isomers were examined.

Key words

allenamide - tandem - 3-amido-dienyne - propargylation - Diels–Alder reaction - Pauson–Khand reaction - electrocyclization

• References and Notes

• 1 New address: China Novartis Institutes for BioMedical Research, Shanghai, P. R. of China.
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• 5 In terms of 3-amidotrienes/dienynes, those with alkenes as part of an aromatic system were not considered here.
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• 9 Sometimes a trace amount of the starting allenamide was detected after the reaction, which implies deprotonation by the α-deprotonated allenamide.
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• 14 General Procedures for the Propargylation/1,3-H-Shift Sequence of Allenamides To a solution of allenamide 6 (1.0 equiv) and HMPA (1.5 equiv) in THF (0.1 M) was added dropwise n-BuLi (2.5 M in hexanes, 1.5 equiv) at –78 °C. After stirring for 45 min, propargyl bromide 7 (1.5 equiv) was added dropwise. The resulting solution was stirred at –78 °C for 1 h and then at rt for overnight. The reaction mixture was quenched with sat. aq NH₄Cl solution, and the separated aqueous phase was extracted with EtOAc (3 times). The combined organic phases were washed with sat. aq NaCl solution, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford a crude product which was purified via silica gel flash column chromatography [gradient eluent: EtOAc in hexane with 1% Et₃N added] to afford the desired products 4 and E/Z -5.
• 15 Characterization of α-Propargyl Allenamide Product 4 and 3-Amidodienynes 5 Compounds 4a (77 mg, 34%), E-5a (34 mg, 15%), and Z-5a (59 mg, 26%) were obtained from allenamide 6a (172 mg) according to the general procedure. Compound 4a: pale yellow oil; R_f = 0.45 (hexane–EtOAc = 2:1); [α]_D ²⁵ 27.2 (c 2.40, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.89 (d, J = 7.0 Hz, 3 H), 0.93 (d, J = 7.0 Hz, 3 H), 1.78 (t, J = 3.0 Hz, 3 H), 2.16 (dqq, J = 3.5, 7.0, 7.0 Hz, 1 H), 3.35 (ABMNX₃, J _AM = J _BM = J _MX = 2.5 Hz, J _MN = 18 Hz, 1 H), 3.45 (ABMNX₃, J _NX = 2.5 Hz, J _AN = J _BN = 3.5 Hz, J _MN = 18 Hz, 1 H), 3.91 (ddd, J = 3.5, 5.5, 9.0 Hz, 1 H), 4.12 (dd, J = 6.0, 8.5 Hz, 1 H), 4.28 (dd, J = 9.0, 9.0 Hz, 1 H), 5.19 (ABMN, J _AM = 2.5 Hz, J _AN = 3.5 Hz, J _AB = 10.5 Hz, 1 H), 5.31 (ABMN, J _BM = 2.5 Hz, J _BN = 3.5 Hz, J _AB = 10.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 3.7, 14.6, 17.9, 21.7, 28.2, 60.9, 63.3, 74.7, 78.2, 84.5, 105.5, 156.4, 204.4. IR (thin film): 3391 (br s), 2966 (w), 1748 (s), 1638 (w), 1452 (w), 1405 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₁₃H₁₈NO₂ [M + H]⁺: 220.1332; found: 220.1328. Compound E-5a: pale yellow oil; R_f = 0.42 (hexane–EtOAc = 2:1); [α]_D ²⁵ 174.3 (c 0.88, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.86 (d, J = 6.8 Hz, 3 H), 0.88 (d, J = 6.8 Hz, 3 H), 1.91 (dqq, J = 4.0, 6.8, 6.8 Hz, 1 H), 2.03 (d, J = 2.4 Hz, 3 H), 4.01 (ddd, J = 4.0, 5.6, 8.8 Hz, 1 H), 4.15 (dd, J = 7.0, 9.2 Hz, 1 H), 4.35 (dd, J = 8.8, 8.8 Hz, 1 H), 5.29–5.41 (m, 2 H), 5.67 (s, 1 H), 6.77 (dd, J = 11.2, 17.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 4.96, 14.8, 18.0, 29.0, 61.2, 63.5, 75.3, 96.9, 111.8, 117.8, 129.7, 141.9, 156.8. IR (thin film): 3483 (br s), 2964 (w), 1747 (s), 1623 (w), 1576 (w), 1485 (w), 1402 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₁₃H₁₈NO₂ [M + H]⁺: 220.1332; found: 220.1329. Compound Z-5a: pale yellow oil; R_f = 0.40 (hexane–EtOAc = 2:1); [α]_D ²⁵ –24.3 (c 0.85, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.91 (d, J = 7.0 Hz, 3 H), 0.97 (d, J = 7.0 Hz, 3 H), 1.90–1.98 (m, 1 H), 2.03 (d, J = 2.5 Hz, 3 H), 4.19–4.21 (m, 1 H), 4.35–4.41 (m, 2 H), 5.25 (d, J = 10.5 Hz, 1 H), 5.41 (d, J = 17.5 Hz, 1 H), 5.69 (q, J = 2.5 Hz, 1 H), 6.29 (dd, J = 10.5, 17.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 5.1, 16.0, 18.7, 29.7, 61.2, 64.7, 75.9, 97.8, 110.7, 117.2, 133.2, 142.6, 156.2. IR (thin film): 3422 (br s), 2966 (w), 1749 (s), 1485 (w), 1406 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₁₃H₁₈NO₂ [M + H]⁺: 220.1332; found: 220.1330. Compound E-5b (165 mg, 15%) and Z-5b (285 mg, 26%) were obtained from allenamide 6a (912 mg) according to the general procedure. Compound E-5b: pale yellow oil; R_f = 0.35 (hexane–EtOAc = 2:1); [α]_D ²⁵ 88.0 (c 1.21, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.88 (d, J = 7.0 Hz, 3 H), 0.89 (d, J = 6.5 Hz, 3 H), 1.94 (dqq, J = 3.5, 7.0, 7.0 Hz, 1 H), 3.43 (d, J = 2.5 Hz, 3 H), 4.06 (ddd, J = 3.5, 5.0, 8.5 Hz, 1 H), 4.18 (dd, J = 5.5, 9.0 Hz, 1 H), 4.37 (dd, J = 8.5, 9.0 Hz, 1 H), 5.46 (d, J = 11.0 Hz, 1 H), 5.51 (d, J = 17.5 Hz, 1 H), 5.72 (s, 1 H), 6.78 (dd, J = 11.0, 17.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.7, 18.0, 29.0, 61.2, 63.5, 79.1, 87.3, 108.7, 119.7, 129.5, 144.7, 156.5. IR (thin film): 3303 (w), 3018 (w), 1748 (s), 1573 (w), 1485 (w), 1402 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₁₂H₁₆NO₂ [M + H]⁺: 206.1176; found: 206.1174. Compound Z-5b: pale yellow oil; R_f = 0.31 (hexane–EtOAc = 2:1); [α]_D ²⁵ –5.6 (c 1.62, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.91 (d, J = 7.0 Hz, 3 H), 0.95 (d, J = 6.5 Hz, 3 H), 1.95 (dqq, J = 4.0, 7.0, 7.0 Hz, 1 H), 3.46 (d, J = 2.5 Hz, 1 H), 4.19 (dd, J = 6.0, 8.5 Hz, 1 H), 4.40 (dd, J = 8.5, 9.0 Hz, 1 H), 4.47 (ddd, J = 4.0, 6.0, 8.5 Hz, 1 H), 5.34 (d, J = 10.5 Hz, 1 H), 5.52 (d, J = 17.0 Hz, 1 H), 5.69 (d, J = 2.5 Hz, 1 H), 6.31 (dd, J = 10.5, 17.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 16.0, 18.5, 29.6, 61.0, 64.7, 79.4, 88.2, 107.7, 119.0, 132.9, 145.3, 155.9. IR (thin film): 3301 (w), 3016 (w), 2970 (w), 1749 (s), 1585 (w), 1485 (w), 1406 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₁₂H₁₆NO₂ [M + H]⁺: 206.1176; found: 206.1174. Compounds 4c (244 mg, 38%), E-5c (89 mg, 14%), and Z-5c (151 mg, 23%) were obtained from allenamide 6b (518 mg) according to the general procedure. Compound 4c: pale yellow oil; R_f = 0.60 (hexane–EtOAc = 2:1); [α]_D ²⁵ 24.4 (c 0.95, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.81 (t, J = 2.5 Hz, 3 H), 2.71 (dd, J = 9.0, 14.0 Hz, 1 H), 3.27 (dd, J = 3.5, 14.0 Hz, 1 H), 3.42 (ABMNX₃, J _AM = J _BM = J _MX = 2.5 Hz, J _MN = 18 Hz, 1 H), 3.48 (ABMNX₃, J _NX = 2.5 Hz, J _AN = J _BN = 3.0 Hz, J _MN = 18 Hz, 1 H), 4.81 (dd, J = 5.5, 8.0 Hz, 1 H), 4.14–4.20 (m, 1 H), 4.23 (dd, J = 8.0, 8.0 Hz, 1 H), 5.29 (ABMN, J _AM = 1.5 Hz, J _AN = 3.0 Hz, J _AB = 10.5 Hz, 1 H), 5.40 (ABMN, J _BM = 2.0 Hz, J _BN = 3.0 Hz, J _AB = 10.5 Hz, 1 H), 7.16–7.18 (m, 2 H), 7.25–7.28 (m, 1 H), 7.31–7.34 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 3.6, 21.8, 38.6, 58.2, 67.1, 74.6, 78.3, 85.0, 105.8, 127.3, 129.1, 129.3, 135.9, 155.8, 204.3. IR (thin film): 3369 (br s), 3027 (w), 2920 (w), 1749 (s), 1604 (w), 1497 (w), 1479 (w), 1453 (m), 1402 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₁₇H₁₈NO₂ [M + H]⁺: 268.1332; found: 268.1328. Compound E-5c: pale yellow solid, mp 46–47 °C; R_f = 0.55 (hexane–EtOAc = 2:1); [α]_D ²⁵ 70.0 (c 0.91, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 2.07 (d, J = 2.5 Hz, 3 H), 2.59 (dd, J = 10.0, 13.5 Hz, 1 H), 3.07 (dd, J = 3.5, 13.5 Hz, 1 H), 4.11–4.15 (m, 1 H), 4.22–4.30 (m, 2 H), 5.41 (d, J = 10.5 Hz, 1 H), 5.43 (d, J = 17.5 Hz, 1 H), 5.74 (m, 1 H), 6.88 (dd, J = 11.0, 17.5 Hz, 1 H), 7.10–7.12 (m, 2 H), 7.24–7.27 (m, 1 H), 7.30–7.32 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 5.0, 39.0, 58.5, 67.3, 75.2, 97.2, 112.5, 117.9, 127.4, 129.1, 129.2, 135.5, 141.7, 156.3. IR (thin film): 3405 (br s), 3016 (w), 2918 (w), 1753 (s), 1624 (w), 1497 (w), 1479 (w), 1454 (w), 1403 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₁₇H₁₈NO₂ [M + H]⁺: 268.1332; found: 268.1327. Compound Z-5c: pale yellow oil; R_f = 0.52 (hexane–EtOAc = 2:1); [α]_D ²⁵ –57.6 (c 1.09, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 2.06 (d, J = 2.5 Hz, 3 H), 2.67 (dd, J = 10.5, 13.5 Hz, 1 H), 3.11 (dd, J = 4.0, 13.5 Hz, 1 H), 4.18 (dd, J = 7.0, 9.0 Hz, 1 H), 4.32 (dd, J = 8.5, 8.5 Hz, 1 H), 4.63 (dddd, J = 4.0, 8.0, 9.0, 11.0 Hz, 1 H), 5.29 (d, J = 10.5 Hz, 1 H), 5.44 (d, J = 17.0 Hz, 1 H), 5.77 (q, J = 2.0 Hz, 1 H), 6.37 (dd, J = 10.5, 17.0 Hz, 1 H), 7.14–7.15 (m, 2 H), 7.24–7.27 (m, 1 H), 7.30–7.33 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 5.2, 39.2, 58.1, 68.3, 75.8, 98.0, 111.8, 117.2, 127.3, 129.1, 129.2, 133.3, 135.9, 141.9, 155.8. IR (thin film): 3406 (br s), 3017 (w), 1752 (s), 1498 (w), 1405 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₁₇H₁₈NO₂ [M + H]⁺: 268.1332; found: 268.1328. Compounds 4d (142 mg, 41%), E-5d (40 mg, 12%), and Z-5d (66 mg, 19%) were obtained from allenamide 6c (291 mg) according to the general procedure. Compound 4d: pale yellow oil; R_f = 0.45 (hexane–EtOAc = 2:1); [α]_D ²⁵ –70.1 (c 1.10, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.76 (t, J = 2.5 Hz, 3 H), 3.05 (ABMNX₃, J _AM = J _MX = 2.5 Hz, J _BM = 3.5 Hz, J _MN = 18.5 Hz, 1 H), 3.28 (ABMNX₃, J _NX = J _AN = J _BN = 2.5 Hz, J _MN = 18.5 Hz, 1 H), 4.17 (dd, J = 5.0, 9.0 Hz, 1 H), 4.40 (d, J = 9.0 Hz, 1 H), 4.42 (d, J = 6.0 Hz, 1 H), 4.77 (ddd, J = 5.0, 6.5, 11.5 Hz, 1 H), 5.05 (ABMN, J _AM = J _AN = 3.0 Hz, J _AB = 10.5 Hz, 1H), 5.31 (ABMN, J _BN = 3.0 Hz, J _BM = 3.5 Hz, J _AB = 10.5 Hz, 1 H), 7.19–7.20 (m, 4 H), 7.23–7.26 (m, 2 H), 7.29–7.34 (m, 4 H). ¹³C NMR (125 MHz, CDCl₃): δ = 3.7, 21.7, 53.5, 59.4, 65.8, 74.3, 78.5, 84.6, 105.5, 127.3, 127.6, 128.5, 128.9 (2 C), 129.0, 139.4, 140.7, 156.2, 205.2. IR (thin film): 3397 (br s), 3017 (w), 2920 (w), 1750 (s), 1495 (w), 1452 (w), 1405 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₂₃H₂₂NO₂ [M + H]⁺: 344.1645; found: 344.1636. Compound E-5d: yellow solid, mp 52–53 °C; R_f = 0.40 (hexane–EtOAc = 2:1); [α]_D ²⁵ 1.5 (c 0.72, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.96 (d, J = 2.5 Hz, 3 H), 4.14 (d, J = 8.0 Hz, 1 H), 4.20 (dd, J = 5.0, 9.0 Hz, 1 H), 4.39 (dd, J = 9.0, 9.0 Hz, 1 H), 4.93 (ddd, J = 5.0, 8.5, 8.5 Hz, 1 H), 5.28 (d, J = 10.0 Hz, 1 H), 5.30 (d, J = 17.5 Hz, 1 H), 5.33 (m, 1 H), 6.48 (dd, J = 11.0, 17.5 Hz, 1 H), 7.15–7.32 (m, 10 H). ¹³C NMR (125 MHz, CDCl₃): δ = 5.0, 55.6, 59.1, 66.3, 75.1, 96.7, 113.4, 116.9, 127.4, 127.7, 128.4 (2 C), 128.8, 129.3, 130.0, 139.8, 140.4, 141.6, 156.7. IR (thin film): 3398 (br s), 3018 (w), 1751 (s), 1495 (w), 1453 (w), 1403 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₂₃H₂₂NO₂ [M + H]⁺: 344.1645; found: 344.1639. Compound Z-5d: yellow solid, mp 54–55 °C; R_f = 0.38 (hexane–EtOAc = 2:1); [α]_D ²⁵ –82.0 (c 0.76, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 2.12 (d, J = 2.5 Hz, 3 H), 4.11 (dd, J = 7.0, 9.0 Hz, 1 H), 4.15 (d, J = 10.0 Hz, 1 H), 4.35 (dd, J = 9.0 Hz, 9.0 Hz, 1 H), 5.05 (d, J = 11.0 Hz, 5.25–5.30 (m, 2 H), 5.41 (ddd, J = 7.0, 8.5, 10.0 Hz, 1 H), 5.82 (dd, J = 10.5, 17.0 Hz, 1 H), 7.14–7.31 (m, 10 H). ¹³C NMR (125 MHz, CDCl₃): δ = 5.2, 56.7, 58.8, 67.5, 76.2, 97.6, 111.3, 116.6, 127.3, 127.6, 128.0, 128.3 (2 C), 129.3, 133.0, 140.5, 140.7, 143.1, 156.3. IR (thin film): 3375 (br s), 3018 (w), 1753 (s), 1641 (w), 1494 (w), 1403 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₂₃H₂₂NO₂ [M + H]⁺: 344.1645; found: 344.1639. Compound E-5e (37 mg, 13%) and Z-5e (63 mg, 22%) were obtained from allenamide 6c (206 mg) according to the general procedure. Compound E-5e: yellow solid, mp 57–58 °C; R_f = 0.40 (hexane–EtOAc = 2:1); [α]_D ²⁵ 19.8 (c 0.44, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 4.19 (d, J = 8.5 Hz, 1 H), 4.22 (dd, J = 5.0, 9.0 Hz, 1 H), 4.42 (dd, J = 9.0, 9.0 Hz, 1 H), 4.99 (ddd, J = 5.0, 8.5, 8.5 Hz, 1 H), 5.36 (d, J = 11.0 Hz, 1 H), 5.41 (d, J = 17.5 Hz, 1 H), 5.60 (s, 1 H), 6.55 (dd, J = 11.0, 17.5 Hz, 1 H), 7.17–7.20 (m, 3 H), 7.23–7.28 (m, 6 H), 7.31–7.34 (m, 4 H), 7.37–7.39 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 55.7, 59.3, 66.4, 84.8, 99.4, 112.0, 118.0, 123.3, 127.5, 127.7, 128.4, 128.5 (2 C), 128.7, 128.9, 129.3, 130.1, 131.5, 139.7, 140.3, 142.3, 156.6. IR (thin film): 3424 (br s), 3017 (w), 2920 (w), 1753 (s), 1599 (w), 1490 (w), 1453 (m), 1402 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₂₈H₂₄NO₂ [M + H]⁺: 406.1802; found: 406.1794. Compound Z-5e: yellow solid, mp 65–66 °C; R_f = 0.36 (hexane–EtOAc = 2:1); [α]_D ²⁵ –100.4 (c 0.53, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 4.15 (dd, J = 6.5, 9.0 Hz, 1 H), 4.20 (d, J = 10.0 Hz, 1 H), 4.40 (dd, J = 9.0, 9.0 Hz, 1 H), 5.13 (d, J = 10.5 Hz, 1 H), 5.37 (d, J = 17.0 Hz, 1 H), 5.49–5.54 (m, 2 H), 5.91 (dd, J = 10.5, 17.0 Hz, 1 H), 7.16–7.21 (m, 4 H), 7.24–7.29 (m, 6 H0, 7.38–7.40 (m, 3 H), 7.47–7.50 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 56.8, 59.1, 67.5, 85.9, 100.4, 110.3, 117.4, 123.1, 127.4, 127.6, 128.0, 128.3, 128.4, 128.8, 129.2, 129.4, 131.7, 133.0, 140.4, 140.6, 144.0, 156.2. IR (thin film): 3398 (br s), 3019 (w), 1753 (s), 1490 (w), 1403 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₂₈H₂₄NO₂ [M + H]⁺: 406.1802; found: 406.1795.
• 16 General Procedures for the Diels–Alder Reaction of (Z)-3-Amidodienynes To a solution of diene Z-5 (1.0 equiv) in toluene (3 mL) in a sealed tube was added 8 (10.0 equiv) and BHT (2.0 equiv) at rt, and the reaction vessel was well sealed and heated to 130 °C overnight. After cooling to rt, the reaction mixture was concentrated under reduced pressure, and the resulting crude residue was directly used for crude ¹H NMR analysis to determine the isomer ratio by comparing the integrations of C–H proton adjacent to either the triple bond or the carbonyl group. Then the mixture was purified via silica gel flash column chromatography (gradient eluent: EtOAc in hexane) to afford the desired Diels–Alder product 9.
• 17 Characterization of the Diels–Alder Products 9 Compound 9a was obtained (15 mg, 58%) on a 20.0 mg scale reaction as a pale yellow oil according to the general procedure; R_f = 0.20 (hexane–EtOAc = 2:1); [α]_D ²⁵ 182.7 (c 0.33, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.89 (d, J = 7.0 Hz, 3 H), 0.91 (d, J = 7.0 Hz, 3 H), 1.62–1.68 (m, 1 H), 1.73 (d, J = 2.5 Hz, 3 H), 2.01–2.08 (m, 2 H), 2.10–2.18 (m, 1 H), 2.26 (s, 3 H), 2.30–2.37 (m, 1 H), 2.96 (ddd, J = 3.0, 10.0, 10.0 Hz, 1 H), 3.57–3.60 (m, 1 H), 4.06–4.13 (m, 2 H), 4.29 (dd, J = 8.5, 8.5 Hz, 1 H), 5.84 (m, 1H). ¹³C NMR (125 MHz, CDCl₃): δ = 3.7, 14.9, 18.0, 23.3, 23.6, 29.1, 29.3 (2 C), 53.4, 59.1, 63.1, 78.3, 123.7, 130.8, 157.3, 209.6. IR (thin film): 3404 (br s), 2963 (w), 2922 (w), 1746 (s), 1712 (m), 1670 (w), 1485(w), 1411 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₁₇H₂₄NO₃ [M + H]⁺: 290.1751; found: 290.1750. Compound 9b was obtained (12 mg, 20%) on a 45.0 mg scale reaction as a pale yellow oil according to the general procedure; R_f = 0.40 (hexane–EtOAc = 1:1); [α]_D ²⁵ 110.6 (c 1.60, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.88 (d, J = 7.0 Hz, 3 H), 0.91 (d, J = 7.5 Hz, 3 H), 1.65–1.72 (m, 1 H), 2.04–2.18 (m, 3 H), 2.08 (d, J = 3.0 Hz, 1 H), 2.26 (s, 3 H), 2.31–2.38 (m, 1 H), 3.00 (ddd, J = 3.5, 7.0, 10.0 Hz, 1 H), 3.68–3.70 (m, 1 H), 4.06–4.12 (m, 2 H), 4.29 (dd, J = 8.5, 8.5 Hz, 1 H), 5.85–5.87 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 1.2, 14.9, 18.0, 23.1, 23.4, 28.9, 29.0, 53.0, 59.0, 63.0, 70.8, 82.4, 124.1, 129.6, 157.1, 208.8. IR (thin film): 3302 (br s), 2963 (w), 1746 (s), 1712 (m), 1671 (w), 1485 (w), 1411 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₁₆H₂₂NO₃ [M + H]⁺: 276.1594; found: 276.1594. Compounds 9c (67 mg, 59%) and 9′c were obtained on a 90 mg scale reaction according to the general procedure. Compound 9c: R_f = 0.40 (hexane–EtOAc = 1:1); [α]_D ²⁵ 40.0 (c 0.77, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.64–1.71 (m, 1 H), 1.75 (d, J = 2.0 Hz, 3 H), 2.02–2.16 (m, 2 H), 2.26 (s, 3 H), 2.28–2.35 (m, 1 H), 2.70 (dd, J = 4.0, 14.0 Hz, 1 H), 2.94 (ddd, J = 3.5, 6.5, 9.0 Hz, 1 H), 3.19 (dd, J = 4.5, 13.5 Hz, 1 H), 3.61–3.63 (m, 1 H), 4.09 (dd, J = 5.0, 8.5 Hz, 1 H), 4.28 (dd, J = 8.5, 8.5 Hz, 1 H), 4.33–4.39 (m, 1 H), 5.85 (ddd, J = 2.0, 4.0, 4.0 Hz, 1 H), 7.16–7.21 (m, 2 H), 7.24–2.27 (m, 1 H), 7.31–7.34 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 3.8, 22.8, 23.3, 28.8, 29.3, 39.4, 53.3, 56.5, 67.0, 77.3, 78.5, 123.8, 127.3, 129.0, 129.5, 130.7, 136.2, 156.6, 209.2. IR (thin film): 3417 (br s), 2921 (w), 2850 (w), 1750 (s), 1711 (m), 1671 (w), 1497 (w), 1480 (w), 1454 (w), 1407 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₂₁H₂₄NO₃ [M + H]⁺: 338.1751; found: 338.1749. Compound 9′c: R_f = 0.35 (hexane–EtOAc = 1:1); [a]_D ²⁵ –110.4 (c 0.45, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.77 (d, J = 2.5 Hz, 3 H), 1.80–1.86 (m, 1 H), 2.02 (dd, J = 6.0, 14.0 Hz, 1 H), 2.20–2.27 (m, 1 H), 2.24 (s, 3 H), 2.34 (td, J = 5.0, 14.0 Hz, 1 H), 2.61 (dd, J = 11.0, 13.5 Hz, 1 H), 2.77 (ddd, J = 2.5, 5.0, 12.0 Hz, 1 H), 3.32 (dd, J = 3.5, 13.5 Hz, 1 H), 3.76 (s, 1 H), 4.05 (dd, J = 6.0, 8.5 Hz, 1 H), 4.22 (t, J = 8.5 Hz, 1 H), 5.52–5.58 (m, 1 H), 5,90 (dd, J = 2.5, 5.0 Hz, 1 H), 7.15–7.17 (m, 2 H), 7.24–7.27 (m, 1 H), 7.30–7.33 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 3.8, 18.7, 24.5, 28.2, 31.5, 39.3, 51.9, 58.7, 67.7, 76.8, 80.0, 127.3, 128.9, 129.1 (2 C), 131.1, 135.9, 157.0, 207.6; IR (thin film): 3018 (w), 1745 (m), 1711 (m), 1671 (w), 1407 (m), 1216 (s) cm^–1. Compound 9d was obtained (26 mg, 72%) on a 30.0 mg scale reaction as a yellow oil according to the general procedure; R_f = 0.30 (hexane–EtOAc = 1:1); [α]_D ²⁵ 14.8 (c 0.93, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.91 (dddd, J = 5.5, 11.0, 11.0, 13.0 Hz, 1 H), 1.70–1.74 (m, 1 H), 1.75 (d, J = 2.5 Hz, 3 H), 1.78–1.85 (m, 1 H), 2.06–2.15 (m, 1 H), 2.19 (s, 3 H), 2.72 (ddd, J = 3.0, 9.0, 12.0 Hz, 1 H), 3.20–3.22 (m, 1 H), 4.07 (dd, J = 5.0, 9.0 Hz, 1 H), 4.25 (d, J = 9.0 Hz, 1 H), 4.39 (dd, J = 9.0 Hz, 1 H), 4.88 (ddd, J = 5.0, 9.0, 9.0 Hz, 1 H), 5.57 (ddd, J = 2.5, 2.5, 5.0 Hz, 1 H), 7.16–7.33 (m, 10 H). ¹³C NMR (125 MHz, CDCl₃): δ = 3.7, 23.5, 23.9, 29.4, 29.7, 53.4, 56.3, 57.8, 66.6, 76.8, 78.7, 126.4, 127.3, 127.5, 128.3, 128.8, 128.9, 129.2, 130.6, 140.3, 141.2, 157.5, 209.5. IR (thin film): 3403 (br s), 3061 (w), 3029 (w), 2921 (w), 1751 (s), 1711 (m), 1674 (w), 1600 (w), 1494 (w), 1477 (w), 1452 (w), 1408 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₂₇H₂₈NO₃ [M + H]⁺: 414.2064; found: 414.2063. Compound 9e was obtained (17 mg, 61%) on a 24.0 mg scale reaction as a yellow solid according to the general procedure, mp 82–83 °C; R_f = 0.35 (hexane–EtOAc = 1:1); [α]_D ²⁵ 50.8 (c 0.87, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.92–1.00 (m, 1 H), 1.74–1.79 (m, 1 H), 1.83–1.88 (m, 1 H), 2.11–2.19 (m, 1 H), 2.24 (s, 3 H), 2.85 (ddd, J = 3.0, 9.0, 12.0 Hz, 1 H), 3.49–3.51 (m, 1 H), 4.05 (dd, J = 5.0, 9.0 Hz, 1 H), 4.25 (d, J = 9.0 Hz, 1 H), 4.38 (dd, J = 9.0, 9.0 Hz, 1 H), 4.94 (ddd, J = 5.0, 9.0, 9.0 Hz, 1 H), 5.63 (ddd, J = 2.5, 5.0, 5.0 Hz, 1 H), 7.18–7.33 (m, 13 H), 7.36–7.38 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 23.5, 23.9, 29.6, 30.5, 53.0, 56.6, 57.9, 66.7, 83.2, 87.1, 122.8, 127.1, 127.4, 127.5, 128.2, 128.4, 128.5, 128.8, 128.9, 129.2, 130.1, 131.8, 140.3, 141.3, 157.6, 209.2. IR (thin film): 3405 (br s), 3059 (w), 2923 (w), 1754 (s), 1713 (m), 1675 (w), 1599 (w), 1491 (w), 1452 (w), 1408 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₃₂H₃₀NO₃ [M + H]⁺: 476.2220; found: 476.2220. Compound 9f was obtained (27 mg, 72%) on a 30.0 mg scale reaction as a yellow solid according to the general procedure, mp 82–83 °C; R_f = 0.40 (hexane–EtOAc = 2:1); [α]_D ²⁵ 6.9 (c 0.71, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.94 (ddd, J = 5.5, 10.5, 10.5 Hz, 1 H), 1.65 (d, J = 2.5 Hz, 3 H), 1.68–1.70 (m, 1 H), 1.78–1.84 (m, 1 H), 2.14–2.22 (m, 1 H), 3.39–3.41 (m, 1 H), 3.56 (ddd, J = 2.5, 9.0, 12.0 Hz, 1 H), 4.07 (dd, J = 4.5, 9.0 Hz, 1 H), 4.23 (d, J = 9.5 Hz, 1 H), 4.40 (dd, J = 9.0, 9.0 Hz, 1 H), 4.91 (ddd, J = 4.5, 9.0, 9.0 Hz, 1 H), 5.61 (ddd, J = 2.5, 2.5, 5.0 Hz, 1 H), 7.17–7.20 (m, 1 H), 7.23–7.35 (m, 9 H), 7.62 (d, J = 8.5 Hz, 2 H), 7.81 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 3.7, 24.1, 25.0, 30.6, 48.0, 56.8, 57.9, 66.9, 76.6, 79.2, 126.9, 127.4, 127.5, 128.3, 128.7, 128.8, 129.0, 129.3, 130.2, 130.9, 132.2, 135.0, 140.5, 141.3, 157.7, 200.5. IR (thin film): 3398 (br s), 2922 (w), 1752 (s), 1681 (m), 1585 (m), 1494 (w), 1452 (w), 1409 (m) cm^–1. HRMS (QTOF MS ESI): m/e calcd for C₃₂H₂₉BrNO₃ [M + H]⁺: 554.1325; found: 554.1329.
• 18 Procedure of Pauson–Khand Reaction To a solution of E-5a (44 mg, 0.2 mmol) in toluene (4.0 mL) was added Co₂(CO)₈ (82 mg, 0.24 mmol) under Ar. The mixture was stirred at rt until the starting material was completely consumed as indicated by TLC (ca 3 h), then norbornene (56.5 mg, 0.6 mmol) and NMO (117 mg, 1.0 equiv) were added successively, and the mixture was further stirred at 110 °C overnight. The reaction mixture was concentrated under reduced pressure to afford a crude mixture which was further purified via silica gel flash column chromatography (gradient eluent: EtOAc in hexane) to afford product 11 (19 mg, 28%) as a pale yellow oil. R_f  = 0.40 (hexane–EtOAc = 2:1). ¹H NMR (500 MHz, CDCl₃): δ = 0.89 (d, J = 7.0 Hz, 3 H), 0.96 (d, J = 7.0 Hz, 3 H), 1.00–1.01 (m, 1 H), 1.02 (m, 1 H), 1.25–1.36 (m, 2 H), 1.57–1.64 (m, 1 H0, 1.67–1.74 (m, 1 H), 1.99–2.07 (m, 1 H), 2.05 (s, 3 H), 2.24 (d, J = 5.5 Hz, 1 H), 2.33 (dd, J = 4.0, 15.0 Hz, 1 H), 2.44 (dd, J = 5.0, 5.0 Hz, 1 H), 2.57 (d, J = 5.0 Hz, 1 H), 4.04 (dddd, J = 2.0, 4.0, 5.5, 5.5 Hz, 1 H), 4.19 (dd, J = 5.5, 8.5 Hz, 1 H), 4.36 (dd, J = 9.0, 9.0 Hz, 1 H), 5.28–5.34 (m, 2 H), 6.05 (dd, J = 11.0, 17.5 Hz, 0.5 H), 6.08 J = 10.5, 17.5 Hz, 0.5 H), 6.12 (d, J = 8.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.8/14.9, 18.1, 18.2, 28.7, 28.9, 29.3, 31.8, 38.0, 39.2, 53.5/53.8, 54.2/54.3, 60.9/61.0, 63.5/63.5, 117.2/117.3, 122.2, 129.9/130.0, 135.4, 138.8/138.9, 157.3, 175.7, 208.2/208.5. HRMS (QTOF MS ESI): m/e calcd for C₂₁H₂₈NO₃ [M + H]⁺: 359.2330; found: 359.2334.