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Synlett 2010(17): 2667-2671  
DOI: 10.1055/s-0030-1258773
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Dimeric Fischer Carbenes: A Bidirectional Dötz Benzannulation and oxa-Pictet-Spengler Strategy for the Synthesis of the Regioisomeric Core of Cardinalin 3

Rodney A. Fernandes*, Sandip V. Mulay
Department of Chemistry, Indian Institute of Technology Bombay, Powai 400076 Mumbai, Maharashtra, India
Fax: +91(22)25767152; e-Mail: rfernand@chem.iitb.ac.in;
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Publication History

Received 2 August 2010
Publication Date:
30 September 2010 (online)

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Abstract

An efficient, asymmetric synthesis of the regioisomeric dimeric pyranonaphthoquinone core structure of cardinalin 3 is presented. The strategy involves the synthesis of dimeric Fischer carbene, bidirectional Dötz benzannulation, and oxa-Pictet-Spengler reactions as the key steps. The synthesis is achieved in six steps and 7.4% overall yield.

Key words

dimeric Fischer carbene - Dötz benzannulation - oxa-Pictet-Spengler reaction - asymmetric synthesis - pyranonaphthoquinones - cardinalins

    References and Notes

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8

Compound 10 was prepared starting from commercially available ethyl (S)-3-hydroxybutyrate (99%, 96% ee, Aldrich).4b

9

Data for 12: Yellow solid; mp 150-151 ˚C; [α]D ²5 -13.1 (c 0.46, CHCl3). IR (CHCl3): 3269, 2955, 2931, 2901, 2858, 1666, 1634, 1601, 1514, 1471, 1464, 1406, 1372, 1324, 1300, 1257, 1217, 1123, 1112, 1042, 990, 939, 838, 778, 759, 725, 667 cm-¹. ¹H NMR (400 MHz, CDCl3/TMS): δ = 0.00 (s, 6 H), 0.09 (s, 6 H), 0.93 (s, 18 H), 1.23 (d, J = 6.1 Hz, 6 H), 2.90 (dd, J = 14.7, 7.0 Hz, 2 H), 3.07 (dd, J = 14.5, 2.3 Hz, 2 H), 3.97 (s, 6 H), 4.33-4.36 (m, 2 H), 6.47 (s, 2 H), 7.89 (dd, J = 8.5, 2.1 Hz, 2 H), 8.24 (d, J = 8.6 Hz, 2 H), 8.37 (s, 2 H, OH), 8.61 (d, J = 1.2 Hz, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = -5.0 (2 × SiCH3), -4.7 (2 × SiCH3), 18.0 {2 × Si[C(CH3)3]}, 22.7 (2 × CHCH3), 25.8 {2 × Si[C(CH3)3]}, 42.1 (2 × CH2), 55.9 (2 × OCH3), 71.5 (2 × CHCH3), 108.0 (2 × CAr), 117.5 (2 × CAr), 120.6 (2 × CAr), 122.0 (2 × CAr), 124.5 (2 × CAr), 125.0 (2 × CAr), 126.8 (2 × CAr), 138.6 (2 × CAr), 145.2 (2 × CAr), 148.7 (2 × CAr). HRMS (ESI-TOF): m/z [M + H]+ calcd for C40H59O6Si2: 691.3850; found: 691.3855

10

Data for 14b: White solid; mp 250-251 ˚C; [α]D ²5 +24.9 (c 0.8, CHCl3). IR (CHCl3): 3055, 2972, 2932, 2841, 1625, 1595, 1449, 1359, 1332, 1219, 1139, 1102, 1071, 1011, 972, 825, 757 cm-¹. ¹H NMR (400 MHz, CDCl3/TMS): δ = 1.42 (d, J = 5.9 Hz, 6 H), 1.65 (d, J = 6.7 Hz, 6 H), 2.64 (dd, J = 16.8, 10.9 Hz, 2 H), 3.15 (dd, J = 16.6, 3.2 Hz, 2 H), 3.94 (s, 6 H), 3.96 (s, 6 H), 4.13-4.21 (m, 2 H), 5.37 (q, J = 6.7 Hz, 2 H), 7.89 (dd, J = 8.7, 2.0 Hz, 2 H), 8.14 (d, J = 8.7 Hz, 2 H), 8.38 (d, J = 1.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 20.7 (2 × CHCH3), 22.1 (2 × CHCH3), 30.8 (2 × CH2), 61.0 (2 × OCH3), 61.6 (2 × OCH3), 62.6 (2 × CHCH3), 68.8 (2 × CHCH3), 120.3 (2 × CAr), 123.0 (2 × CAr), 124.2 (2 × CAr), 125.4 (2 × CAr), 126.2 (2 × CAr), 127.9 (2 × CAr), 129.3 (2 × CAr), 138.4 (2 × CAr), 147.6 (2 × CAr), 149.5 (2 × CAr). HRMS (ESI-TOF): m/z [M + H]+ calcd for C34H39O6: 543.2747; found: 543.2745. Data for 14c: White solid; mp 231-232 ˚C; [α]D ²5 +56.4 (c 0.42, CHCl3). IR (CHCl3): 2970, 2932, 2852, 1659, 1625, 1597, 1450, 1404, 1360, 1334, 1289, 1223, 1192, 1137, 1107, 1074, 1038, 1013, 971, 891, 850, 757 cm-¹. ¹H NMR (400 MHz, CDCl3/TMS): δ = 1.32 (d, J = 6.1 Hz, 3 H), 1.41 (d, J = 6.1 Hz, 3 H), 1.43 (d, J = 6.1 Hz, 3 H), 1.66 (d, J = 6.7 Hz, 3 H), 2.62 (d, J = 11.0 Hz, 1 H), 2.66 (dd, J = 13.0, 2.0 Hz, 1 H), 3.13 (dd, J = 15.9, 1.8 Hz, 1 H), 3.15 (dd, J = 16.8, 3.2 Hz, 1 H), 3.67-3.73 (m, 1 H), 3.92 (s, 3 H), 3.94 (s, 3 H), 3.955 (s, 3 H), 3.96 (s, 3 H), 4.14-4.21 (m, 1 H), 5.21-5.39 (m, 1 H), 5.37 (q, J = 6.6 Hz, 1 H), 7.87 (dd, J = 8.7, 1.9 Hz, 1 H), 7.89 (dd, J = 8.7, 1.9 Hz, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 8.17 (d, J = 8.8 Hz, 1 H), 8.38 (d, J = 1.5 Hz, 1 H), 8.39 (d, J = 1.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 19.3 (CHCH3), 20.6 (CHCH3), 21.9 (CHCH3), 22.1 (CHCH3), 30.7 (CH2), 32.0 (CH2), 61.0 (OCH3), 61.1 (OCH3), 61.5 (OCH3), 61.6 (OCH3), 62.6 (CHCH3), 68.8 (CHCH3), 69.4 (CHCH3), 72.1 (CHCH3), 120.2 (CAr), 120.3 (CAr), 123.0 (2 × CAr), 124.2 (CAr), 125.4 (2 × CAr), 126.2 (2 × CAr), 126.5 (CAr), 127.7 (CAr), 127.8 (CAr), 128.2 (CAr), 129.2 (CAr), 138.4 (CAr), 138.4 (CAr), 147.6 (CAr), 148.3 (CAr), 149.0 (CAr), 149.4 (CAr). HRMS (ESI-TOF): m/z [M + H]+ calcd for C34H39O6: 543.2747; found: 543.2744

11

Data for 14a: Yellow solid; mp 245-247 ˚C; [α]D ²5 +36.9 (c 0.64, CHCl3). IR (CHCl3): 2971, 2934, 2895, 2847, 1625, 1594, 1449, 1404, 1344, 1333, 1288, 1218, 1177, 1162, 1137, 1111, 1074, 1059, 1014, 990, 969, 825, 757 cm-¹. ¹H NMR (400 MHz, CDCl3/TMS): δ = 1.45 (d, J = 6.1 Hz, 6 H), 1.73 (d, J = 6.4 Hz, 6 H), 2.67 (dd, J = 16.1, 10.8 Hz, 2 H), 3.13 (dd, J = 16.1, 1.6 Hz, 2 H), 3.71-3.79 (m, 2 H), 3.91 (s, 6 H), 3.97 (s, 6 H), 5.26 (q, J = 6.3 Hz, 2 H), 7.90 (dd, J = 8.8, 1.8 Hz, 2 H), 8.17 (d, J = 8.7 Hz, 2 H), 8.40 (d, J = 1.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 21.8 (2 × CHCH3), 22.4 (2 × CHCH3), 32.0 (2 × CH2), 61.1 (2 × OCH3), 61.4 (2 × OCH3), 69.6 (2 × CHCH3), 71.3 (2 × CHCH3), 120.2 (2 × CAr), 122.9 (2 × CAr), 125.4 (2 × CAr), 125.9 (2 × CAr), 126.6 (2 × CAr), 127.7 (2 × CAr), 129.4 (2 × CAr), 138.5 (2 × CAr), 148.5 (2 × CAr), 149.2 (2 × CAr). HRMS (ESI-TOF): m/z [M + H]+ calcd for C34H39O6: 543.2747; found: 543.2749

12

Data for 7: Yellow solid; mp 237-238 ˚C; [α]D ²5 +261.8 (c 0.24, CHCl3). IR (CHCl3): 2978, 2932, 2855, 1730, 1660, 1617, 1599, 1452, 1408, 1385, 1312, 1295, 1218, 1186, 1163, 1125, 1102, 1054, 915, 881, 850, 757, 734 cm-¹. ¹H NMR (400 MHz, CDCl3/TMS): δ = 1.39 (d, J = 6.3 Hz, 6 H), 1.56 (d, J = 6.3 Hz, 6 H), 2.30 (ddd, J = 18.4, 10.2, 3.9 Hz, 2 H), 2.82 (dt, J = 18.4, 2.4 Hz, 2 H), 3.60-3.65 (m, 2 H), 4.85-4.89 (m, 2 H), 8.0 (dd, J = 7.9, 1.6 Hz, 2 H), 8.16 (d, J = 8.1 Hz, 2 H), 8.33 (d, J = 2.0 Hz, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 20.8 (2 × CHCH3), 21.2 (2 × CHCH3), 30.5 (2 × CH2), 68.7 (2 × CHCH3), 70.0 (2 × CHCH3), 124.9 (2 × CAr), 127.2 (2 × CAr), 132.0 (2 × 2CAr), 132.3 (2 × CAr), 142.9 (2 × CAr), 143.9 (2 × CAr), 147.1 (2 × CAr), 183.4 (2 × C=O), 183.5 (2 × C=O). HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H27O6: 483.1808; found: 483.1801

13

Data for 15: Yellow solid; mp 160 ˚C (dec.); [α]D ²5 +9.7 (c 0.5, CHCl3). IR (CHCl3): 2976, 2935, 2855, 1723, 1661, 1622, 1600, 1455, 1386, 1348, 1293, 1185, 1162, 1124, 1099, 1055, 968, 917, 854, 816, 755, 734 cm-¹. ¹H NMR (400 MHz, CDCl3/TMS): δ = 1.38 (d, J = 6.1 Hz, 6 H), 1.57 (d, J = 6.7 Hz, 6 H), 2.31 (ddd, J = 18.8, 9.9, 1.9 Hz, 2 H), 2.78 (dd, J = 18.8, 2.6 Hz, 2 H), 4.13-4.21 (m, 2 H), 5.05 (q, J = 6.7 Hz, 2 H), 8.03 (dd, J = 8.1, 1.7 Hz, 2 H), 8.2 (d, J = 7.9 Hz, 2 H), 8.39 (d, J = 1.8 Hz, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 19.7 (2 × CHCH3), 21.5 (2 × CHCH3), 29.9 (2 × CH2), 62.6 (2 × CHCH3), 67.3 (2 × CHCH3), 125.0 (2 × CAr), 127.4 (2 × CAr), 131.7 (2 × CAr), 132.1 (2 × CAr), 132.4 (2 × CAr), 141.9 (2 × CAr), 144.1 (2 × CAr), 146.8 (2 × CAr), 182.8 (2 × C=O), 183.7 (2 × C=O). HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H27O6: 483.1808; found: 483.1806