Enantioselective Synthesis of Metathesis-Derived Ureapeptoid Macrocycles

Xiang-Zhu Wang; Terrence R. Burke Jr

doi:10.1055/s-2004-815425

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Synlett 2004(3): 469-472
DOI: 10.1055/s-2004-815425

LETTER

Enantioselective Synthesis of Metathesis-Derived Ureapeptoid Macrocycles

Xiang-Zhu Wang, Terrence R. Burke Jr.*
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NCI-Frederick, Frederick, MD 21702-1201, USA
Fax: +1(301)8466033; e-Mail: tburke@helix.nih.gov;

Further Information

Publication History

Received 1 December 2003
Publication Date:
26 January 2004 (online)

Abstract
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Abstract

Ring-closing metathesis (RCM) was used for the preparation of the first member of a new class of ureapeptoid-containing macrocycles. Key to the approach was the enantioselective synthesis of functionalized carbamoyl alkenylglycine equivalents using (-)-B-allyldiisopinocampheylborane [(-)-d-Ipc₂ Ball]-mediated asymmetric allylation.

Key words

asymmetric synthesis - macrocycles - metathesis - ring closure - stereoselective

References

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12

Compound 11: bp 142 °C (0.04 Torr). ¹H NMR (400 MHz, CDCl₃): δ = 9.97 (s, 1 H, CHO), 7.79 (d, J = 7.9 Hz, 2 H), 7.42 (d, J = 7.9 Hz, 2 H), 3.99 (m, 4 H), 3.19 (d, J = 22.4 Hz, 2 H), 1.18 (t, J = 7.2 Hz, 6 H). IR (neat): 1696, 1605, 1246, 1020, 961, 850 cm^-1. FABMS: m/z = 257 [MH⁺].

14

Commercially available from Sigma-Aldrich Chemical Corp.

15

Compound 12: ¹H NMR (400 MHz, CDCl₃): δ = 8.57 (s, 1 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 2 H), 4.03 (m, 4 H), 3.20 (d, J = 22.3 Hz, 2 H), 1.25 (m, 15 H). IR (neat): 2980, 1598, 1247, 1021 cm^-1. FABMS: m/z = 360 [MH⁺]. Anal. Calcd for C₁₆H₂₆NO₄PS: C, 53.47; H, 7.29; N, 3.90. Found: C, 53.21; H, 7.58; N, 3.78.

19

Compound 14: [α]_D = -36.9 (c 1.02 CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.21 (m, 4 H), 5.71 (ddt, J = 7.0, 10.2, 17.2 Hz, 1 H), 5.02 (m, 2 H), 4.65 (t, J = 6.4 Hz, 1 H), 3.92 (m, 4 H), 3.05 (d, J = 21.7 Hz, 2 H), 2.73 (br s, 1 H, OH), 2.42 (t, J = 7.4 Hz, 2 H), 1.16 (t, J = 7.0 Hz, 6 H). IR (neat): 3376, 2980, 1228, 1021, 962 cm^-1. FABMS: m/z = 299 [MH⁺]. Anal. Calcd for C₁₅H₂₃O₄P·0.2H₂O: C, 59.67; H, 7.81. Found: C, 59.69; H, 7.83.

24

Compound 15: [α]_D = +65.9 (c 1.22 CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.31 (m, 2 H), 7.23 (m, 2 H), 5.70 (ddt, J = 6.9, 10.4, 17.2 Hz, 1 H), 5.07 (m, 2 H), 4.45 (t, J = 7.2 Hz, 1 H), 3.97 (m, 4 H), 3.13 (d, J = 21.7 Hz, 2 H), 2.51 (m, 2 H), 1.20 (t, J = 7.0 Hz, 6 H). IR (neat): 2095 (N₃), 1246, 1022, 958 cm^-1. FABMS: m/z = 324 [MH⁺].

25

Compound 16: [α]_D = +14.8 (c 1.19 CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.23 (m, 4 H), 5.67 (m, 1 H), 5.04 (m, 2 H), 3.95 (m, 5 H, 2 × OCH₂ + CHN), 3.07 (d, J = 21.7 Hz, 2 H), 2.38 (m, 1 H), 1.18 (t, J = 7.0 Hz, 6 H). IR (neat): 3368, 3291, 2978, 1731, 1632, 1051 cm^-1. FABMS: m/z = 298 [MH⁺]. Anal. Calcd for C₁₅H₂₄NO₃P: C, 60.59; H, 8.14; N, 4.71. Found: C, 60.14; H, 8.11; N, 4.69.

26

Compound 8: [α]_D = +69.5 (c 0.53, CHCl₃); mp 56-57 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.27 (m, 6 H), 7.12 (m, 1 H), 7.05 (m, 2 H), 5.70 (m, 2 H), 5.05 (m, 2 H), 4.78 (dt, J = 7.0 Hz, 7.2 Hz, 1 H), 3.97 (m, 4 H), 3.10 (d, J = 21.7 Hz, 2 H), 2.55 (m, 2 H), 1.19 (t, J = 7.4 Hz, 6 H). IR (neat): 3240, 1737, 1200 cm^-1. FABMS: m/z = 418 [MH⁺]. Anal Calcd for C₂₂H₂₈NO₅P: C, 63.30; H, 6.76; N, 3.36. Found: C, 63.15; H, 6.55; N, 3.49.

28

Compound 18: mp 69-71 °C. ¹H NMR (400 MHz, MeOH-d): δ = 8.08 (d, J = 8.8 Hz, 1 H), 7.89 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 6.93 (m, 2 H), 6.79 (m, 2 H), 5.88 (ddt, J = 6.8 Hz, 10.2 Hz, 17.0 Hz, 1 H), 5.62 (ddt, J = 6.8 Hz, 10.2 Hz, 17.2 Hz, 1 H), 5.06 (m, 4 H), 4.56 ( dd, J = 4.9 Hz, 6.9 Hz, 1 H), 4.51 (t, J = 7.0 Hz, 1 H), 4.0 (m, 4 H), 3.22 (dd, J = 8.0 Hz, 13.1 Hz, 1 H), 3.10-3.02 (m, 3 H), 2.93 (dd, J = 7.2 Hz, 13.9 Hz, 1 H), 2.67 (m, 2 H), 2.34 (m, 3 H), 2.16 (m, 3 H), 1.98 (m, 1 H), 1.88(m, 1 H), 1.79 (m, 1 H), 1.66 (m, 4 H), 1.57 (m, 1 H), 1.43 (m, 1 H), 1.32 (m, 1 H), 1.28 (t, J = 7.0 Hz, 6 H). FABMS; m/z = 788 [MH⁺]. Anal Calcd for C₄₃H₅₈N₅O₇P·0.5H₂O: C, 64.65; H, 7.31; N, 8.77. Found: C, 64.80; H, 7.42; N, 8.75.

44

Compound E -5: mp 182-184 °C (dec.). ¹H NMR (400 MHz, MeOH-d): δ = 8.08 (m, 1 H), 7.83 (m, 1 H), 7.70 (dd, J = 2.3 Hz, 7.0 Hz, 1 H), 7.44 (m, 4 H), 7.32 (m, 2 H), 7.11 (d,
J = 8.0 Hz, 2 H), 5.68 [q(apparent), J = 8.5 Hz, 16.7 Hz, 1 H], 5.12 (ddd, J = 4.3 Hz, 10 Hz, 16.7 Hz, 1 H), 4.51 (m, 1 H), 4.37 (dd, J = 4.3 Hz, 10.7 Hz, 1 H), 3.45 (m, 1 H), 3.36 (dd, J = 5.3 Hz, 13.9 Hz, 1 H), 3.11 (d, J = 21.5 Hz, 2 H), 2.98 (m, 2 H), 2.80 (m, 3 H), 2.60 (m, 1 H), 2.50 (m, 1 H), 2.12 (m, 1 H), 1.98 (m, 1 H), 1.70 (m, 3 H), 1.53 (m, 4 H), 1.47 (m, 1 H), 1.35 (m, 1 H), 1.19 (m, 1 H).

45

Compound Z -5: mp 214-216 °C. ¹H NMR (400 MHz, MeOH-d): δ = 7.96 (d, J = 8.6 Hz, 1 H), 7.74 (d, J = 7.2 Hz, 1 H), 7.60 ( d, J = 7.6 Hz, 1 H), 7.41 (m, 1 H), 7.37 (m, 1 H), 7.28 (m, 2 H), 7.19 (m, 2 H), 7.12 (m, 2 H), 5.60 (m, 1 H), 5.14 (m, 1 H), 4.82 (m, 1 H), 4.61 (m, 1 H), 3.74 (d, J = 12.8 Hz, 1 H), 3.31 (d, J = 12.8 Hz, 1 H), 3.05 (m, 1 H), 2.99 (d, J = 21.7 Hz, 2 H), 2.86 (dd, J = 6.6 Hz, 15.6 Hz, 1 H), 2.74 (m, 2 H), 2.17 (m, 3 H), 1.94 (m, 3 H), 1.74 (m, 2 H), 1.53 (m, 4 H), 1.40 (m, 1 H), 1.20 (m, 3 H).