The Total Synthesis of Trungapeptin A

Abstract

Trungapeptin A, a novel cyclodepsipeptide isolated from a marine cyanobacterium (Lyngbya majuscula), has been synthesised and its structure unambiguously confirmed.

Key words

marine cyanobacterium - Lyngbya majuscule - cyclo­depsipeptide - total synthesis - lactamisation

References and Notes

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• 2 Newman DJ. Cragg GM. J. Nat. Prod.  2004,  67:  1216 
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• 5 Gennari C. Mielgo A. Potenza D. Scolastico C. Piarulli U. Manzoni L. Eur. J. Org. Chem.  1999,  379 
• 6 Kunishima M. Kawachi C. Morita J. Terao K. Iwasaki F. Tani S. Tetrahedron  1999,  55:  13159 
• 7 Inanaga J. Hirata K. Saeki H. Katsuki T. Yamaguchi M. Bull. Chem. Soc. Jpn.  1979,  52:  1989 
• 8 Fernández R. Rodríguez J. Quiñoá E. Riguera R. Muñoz L. Fernández-Suárez M. Debitus C. J. Am. Chem. Soc.  1996,  118:  11635 
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• 13 Saigo K. Usui M. Kikuchi K. Shimada E. Mukaiyama T. Bull. Chem. Soc. Jpn.  1977,  50:  1863 
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10

All new compounds gave spectroscopic data in agreement with the assigned structures. Data for compound 13: [α]_D ^²²
-63.2 (c 0.5, MeOH). R _f  = 0.4 (cyclohexane-EtOAc, 5:5). ^¹H NMR (300 MHz, CDCl₃): δ = 0.11 (s, 6 H, SiMe₂), 0.05 (s, 9 H, SiMe₃), 0.79-0.95 (m, 18 H, CH₃ Val, CH₃ NMeVal, CH₃ alloIle), 0.95 (s, 9 H, SitBu), 0.95-1.39 (m, 7 H, CH₂Si, CH₃, CH₂ alloIle), 1.40-1.62 (m, 4 H, CH₂CH₂, H-4, H-5), 1.90-2.22 (m, 9 H, CH_β NMeVal, CH_β Val, CH_β alloIle, CH₂ Pro, ≡CH, CH₂, H-6), 2.35-2.40 (m, 1 H, CH₂ Pro), 2.47-2.52 (m, 1 H, CH, H-2), 3.03 (s, 3 H, NMe), 3.06-3.08 (m, 2 H, CH₂-Ph), 3.28-3.33 (m, 1 H, NCH₂), 3.58-3.66 (m, 1 H, NCH₂), 3.70-3.75 (m, 1 H, CH, H-3), 4.22 (dd, J = 7.1, 8.6 Hz, 2 H, OCH₂), 4.55 (dd, J = 4.1, 8.5 Hz, 1 H, CH_α alloIle), 4.61-4.64 (m, 2 H, CH_α Val, CH_α Pro), 5.08 (d, J = 10.3 Hz, 1 H, CH_α NMeVal), 5.19-5.20 (m, 1 H, CH_α Pla), 6.93 (d, J = 9.0 Hz, 1 H, NH Val), 7.14 (d, J = 8.4 Hz, 1 H, NH alloIle), 7.23-7.33 (m, 5 H, Ar-H). ^¹³C NMR (75 MHz, CDCl₃): δ = -4.5 (SiMe₂), -1.5 (SiMe₃), 11.7 (CH₃ alloIle), 13.7 (CH₃), 14.6 (CH₃ alloIle), 17.3 (CH₂Si), 18.0 (Cq-tBu), 18.3 (CH₂, C-6), 18.4 (CH₃ Val), 18.8 (CH₃ NMeVal), 19.2 (CH₃ Val), 19.5 (CH₃ NMeVal), 24.8 (CH₂, C-5), 25.2 (CH₂ Pro), 25.8 (SitBu), 26.2 (CH₂ alloIle), 26.8 (CH₂ Pro), 27.3 (CH_β NMeVal), 31.4 (CH_β Val), 31.4 (NMe), 31.6 (CH₂, C-4), 37.2 (CH₂-Ph), 37.4 (CH_β alloIle), 45.8 (CH, C-2), 47.0 (NCH₂ Pro), 53.7 (CH_α Val), 55.7 (CH_α alloIle), 59.9 (CH_α Pro), 60.9 (CH_α NMeVal), 63.5 (OCH₂), 68.4 (≡CH), 73.3 (CH_α Pla), 74.6 (CH, C-3), 84.0 (Cq, C-7), 128.9 (CH), 129.1 (CH), 129.1 (CH), 129.4 (CH), 129.4 (CH), 135.8 (Cq), 168.9 (C=O Pla), 170.5 (C=O NMeVal), 170.6 (C=O Pro), 172.0 (C=O alloIle), 172.8 (C=O Val), 173.9 (C=O, C-1). HRMS: m/z calcd for C₅₁H₈₇N₄O₉Si₂: 955.6012; found: 955.6008. MALDI-TOF MS (LD+): m/z (%) = 978.1 (100) [M + 23]^{+ ˙} , 811.9 (57), 689.7 (17), 499.5 (47), 381.6 (28).

12

Unfortunately, we were unable to control this reaction; coupling of Boc-Val-CO-NMe-Val-OH (17) with 7 under Yamaguchi’s conditions often afforded a mixture of diastereoisomers.

14

Data for compound 24: [α]_D ^²5 -81.6 (c 0.5, MeOH). R _f  = 0.28 (cyclohexane-EtOAc, 7:3). ^¹H NMR (300 MHz, CDCl₃): δ = 0.03 (s, 9 H, SiMe₃), 0.80-1.02 (m, 20 H, CH₃ Val, CH₃ NMeVal, CH₃ alloIle, CH₂Si), 1.19-1.21 (m, 4 H, CH₃, CH₂ alloIle), 1.38-1.62 [m, 12 H, C(CH₃)₃, CH₂ alloIle, CH₂, H-5], 1.65-1.75 (m, 2 H, CH₂, H-4), 1.80-2.05 (m, 6 H, CH_β Val, CH_β alloIle, CH₂-CH₂ Pro, ºCH), 2.10-2.20 (m, 3 H, CH_β NMeVal, CH₂, H-6), 2.30-2.40 (m, 1 H, CH₂ Pro), 2.62-2.67 (m, 1 H, CH, H-2), 2.95-3.10 (m, 5 H, NMe, CH₂-Ph), 3.21-3.32 (m, 1 H, NCH₂), 3.55-3.62 (m, 1 H, NCH₂), 4.15 (dd, J = 7.1, 8.6 Hz, 2 H, OCH₂), 4.32-4.36 (m, 1 H, CH_α Val), 4.53-4.62 (m, 2 H, CH_α alloIle, CH_α Pro), 4.95 (d, J = 10.3 Hz, 1 H, CH_α NMeVal), 5.15-5.21 (m, 3 H, CH_α Pla, CH, H-3, NH Val), 7.15-7.30 (m, 6 H, Ar-H, NH alloIle). ^¹³C NMR (75 MHz, CDCl₃): δ = -1.5 (SiMe₃), 11.7 (CH₃ alloIle), 12.5 (CH₃), 14.4 (CH₃ alloIle), 17.2 (CH₂Si), 17.5 (CH₃ Val), 18.0 (CH₂, C-6), 18.6 (CH₃ NMeVal), 19.3 (CH₃ Val), 19.6 (CH₃ NMeVal), 24.0 (CH₂, C-5), 25.2 (CH₂ Pro), 26.3 (CH₂ alloIle), 26.6 (CH₂ Pro), 27.3 (CH_β NMeVal), 28.1 [C(CH₃)₃], 30.9 (CH_β Val), 30.9 (CH₂, C-4), 31.6 (NMe), 37.1 (CH₂-Ph), 37.1 (CH_β alloIle), 43.3 (CH, C-2), 47.0 (NCH₂ Pro), 55.2 (CH_α Val), 55.7 (CH_α alloIle), 59.8 (CH_α Pro), 61.5 (CH_α NMeVal), 62.9 (OCH₂), 68.7 (≡CH), 73.2 (CH_α Pla), 74.7 (CH, C-3), 79.4 [Cq, C(CH₃)₃], 83.4 (Cq, C-7), 127.0 (CH), 128.5 (CH), 128.5 (CH), 129.0 (CH), 129.0 (CH), 135.6 (Cq), 155.9 (Cq), 168.9 (C=O Pla), 170.4 (C=O NMeVal), 170.5 (C=O Pro), 171.2 (C=O alloIle), 173.4 (C=O Val), 173.5 (C=O, C-1). HRMS: m/z calcd for C₅₀H₈₀N₄O₁₁NaSi: 963.5491; found: 963.5499. MALDI-TOF MS (LD+): m/z (%) = 963.4 (100) [M + 23]^{+ ˙} , 872.3 (48), 863.4 (23), 575.0(13), 463.6 (18), 447.5 (67).

16

Spectroscopic data of synthetic trungapeptin A (1): [α]_D ^²²
-45 (c 0.37, MeOH). ^¹H NMR (300 MHz, CDCl₃): δ = 0.85 (m, 6 H, CH₃ alloIle), 0.92 (d, J = 6.7 Hz, 3 H, CH₃ Val), 0.95 (m, 1 H, CH₂ Pro), 0.96 (d, J = 6.7 Hz, 3 H, CH₃ Val), 1.06 (d, J = 6.5 Hz, 3 H, CH₃ NMeVal), 1.12 (m, 1 H, CH₂ alloIle), 1.19 (d, J = 7.1 Hz, 3 H, CH₃), 1.31 (m, 1 H, CH₂ alloIle), 1.38 (d, J = 6.5 Hz, 3 H, CH₃ NMeVal), 1.41 (m, 1 H, CH₂, H-5), 1.45 (m, 1 H, CH₂ Pro), 1.52 (m, 1 H, CH₂, H-5), 1.70 (m, 1 H, CH₂ Pro), 1.85 (m, 1 H, CH₂, H-4), 1.88 (m, 1 H, CH_β alloIle), 1.99 (t, J = 2.4 Hz, 1 H, ≡CH), 1.99 (m, 1 H, CH₂, H-4), 2.05 (m, 1 H, CH_β Val), 2.14 (dd, J = 6.2, 12.5 Hz, 1 H, CH₂ Pro), 2.22 (td, J = 2.7, 6.7 Hz, 2 H, CH₂, H-6), 2.41 (m, 1 H, CH_β NMeVal), 2.49 (dd, J = 3.3, 7.1 Hz, 1 H, CH, H-2), 2.99 (s, 3 H, NMe), 3.18 (dd, J = 10.7, 12.7 Hz, 1 H, CH₂-Ph), 3.30 (d, J = 7.6 Hz, 1 H, CH_α Pro), 3.34 (m, 1 H, CH₂Ph), 3.39 (m, 1 H, NCH₂ Pro), 3.50 (m, 1 H, NCH₂ Pro), 4.25 (t, J = 8.1 Hz, 1 H, CH_α alloIle), 4.44 (d, J = 9.6 Hz, 1 H, CH_α NMeVal), 4.63 (t, J = 9.5 Hz, 1 H, CH_α Val), 4.95 (dt, J = 3.0, 9.9 Hz, 1 H, CH, H-3), 5.06 (dd, J = 5.5, 10.5 Hz, 1 H, CH_α Pla), 5.96 (d, J = 9.5 Hz, 1 H, NH Val), 7.24-7.36 (m, 5 H, Ar-H), 7.84 (d, J = 8.3 Hz, 1 H, NH alloIle). ^¹³C NMR (75 MHz, CDCl₃):
δ = 11.2 (CH₃, alloIle), 12.9 (CH₃), 15.4 (CH₃, alloIle), 17.9 (CH₂, C-6), 18.7 (CH₃ Val), 19.7 (CH₃ Val), 20.1 (CH₃ NMeVal), 21.3 (CH₃ NMeVal), 21.8 (CH₂ Pro), 24.3 (CH₂, C-5), 26.2 (CH₂, alloIle), 28.7 (CH₂, C-4), 29.5 (CH_β NMeVal), 30.5 (NMe), 30.6 (CH₂ Pro), 31.7 (CH_β Val), 35.0 (CH_β alloIle), 38.2 (CH₂-Ph), 43.2 (CH, C-2), 46.5 (NCH₂ Pro), 53.7 (CH_α Val), 57.3 (CH_α alloIle), 61.0 (CH_α Pro), 65.5 (CH_α NMeVal), 69.3 (≡CH), 74.7 (CH, C-3), 75.0 (CH_α Pla), 83.7 (Cq, C-7), 127.9 (CH), 129.2 (CH), 129.8 (CH), 134.2 (Cq), 169.1 (C=O Pla), 170.3 (C=O, alloIle), 170.4 (C=O Pro), 171.8 (C=O NMeVal), 172.8 (C=O, C-1), 173.6 (C=O Val). MALDI-TOF MS (LD+): m/z (%) = 745.2 (100) [M + 23]^{+ ˙} , 723.2 (25) [M]^{+ ˙} , 340.5 (33). IR (film): 734, 912, 1149, 1194, 1248, 1374, 1451, 1518, 1649, 1658, 1730, 2848, 2873, 2923, 2957, 3354 cm^-¹.