Synthesis of Majusculamides A and B

Abstract

The synthesis of two marine lipodipeptides, majusculamides A and B, is described. The key feature of this synthesis is the stereoselective construction of an α-methyl-β-keto-carboxamide moiety.

Key words

marine natural products - peptides - polyketides - β-ketoamide - asymmetric aldol reaction

• References and Notes

• 1a Molinski TF, Dalisay DS, Lievens SL, Saludes JP. Nat. Rev. Drug Discov. 2009; 8: 69
• 1b Montaser R, Luesch H. Future Med. Chem. 2011; 3: 1475
• 1c Blunt JW, Copp BR, Keyzers RA, Munro MH. G, Prinsep MR. Nat. Prod. Rep. 2017; 34: 235
• 1d Blunt JW, Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR. Nat. Prod. Rep. 2018; 35: 8
• 1e Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR. Nat. Prod. Rep. 2019; 36: 122
• 2 Marner F.-J, Moore RE, Hirotsu K, Clardy J. J. Org. Chem. 1977; 42: 2815
• 3 Majusculamides A and B were also recently isolated by us from the marine cyanobacterium Moorea producens collected from the coast of Bise Okinawa.
• 4 No isomerization was observed in ¹H NMR spectra of the pure amides in DMSO-d ₆ at 140 °C after heating for 10 minutes.

The α-methyl-β-keto-carboxamide moiety is observed in the macrocyclic systems of some natural products. For synthetic studies toward such natural products, see:
• 5a Rinehart KL, Kishore V, Nagarajan S, Lake RJ, Gloer JB, Bozich FA, Li K.-M, Maleczka RE, Todsen WL, Munro MH. G, Sullins DW, Sakai R. J. Am. Chem. Soc. 1987; 109: 6846
• 5b Plaza A, Garcia R, Bifulco G, Martinez JP, Hüttel S, Sasse F, Meyerhans A, Stadler M, Müller R. Org. Lett. 2012; 14: 2854
• 5c Ghosh AK, Rao KV, Akasapu S. Tetrahedron Lett. 2014; 55: 5191
• 5d Qi N, Allu SR, Wang Z, Liu Q, Guo J, He Y. Org. Lett. 2016; 18: 4718
• 5e Revu O, Prasad KR. J. Org. Chem. 2017; 82: 438
• 5f Seo C, Yim JH, Lee HK, Park SM, Sohn J.-H, Oh H. Tetrahedron Lett. 2008; 49: 29
• 5g Ghosh AK, Xu C.-X. Org. Lett. 2009; 11: 1963
• 5h Reddy KM, Shashidhar J, Pottireddygari GR, Ghosh S. Tetrahedron Lett. 2011; 52: 5987
• 5i Kaneda M, Inuki S, Ohno H, Oishi S. J. Org. Chem. 2018; 83: 3047
• 6 Evans DA, Ennis MD, Le T, Mandel N, Mandel G. J. Am. Chem. Soc. 1984; 106: 1154

Tertiary amides are essential for the stereochemical stabilities of β-keto-carboxamides. For examples of isomerization of secondary amides, see:
• 7a Satoh N, Yokoshima S, Fukuyama T. Org. Lett. 2011; 13: 3028
• 7b Sun Y, Ding Y, Li D, Zhou R, Su X, Yang J, Guo X, Chong C, Wang J, Zhang W, Bai C, Wang L, Chen Y. Angew. Chem. Int. Ed. 2017; 56: 14627

In the case of N,O-dimethylhydroxamic acids, also known as Weinreb amides, α-methyl-β-keto compounds could be employed in further transformation under the appropriate conditions without isomerization, whereas the α-methyl-β-keto compounds could be used as substrates for asymmetric transfer hydrogenation with dynamic kinetic resolution. For examples, see:
• 8a Takamura H, Kadonaga Y, Kadota I, Uemura D. Tetrahedron 2010; 66: 7569
• 8b Kumaraswamy G, Narayanarao V, Shanigaram P, Balakishan G. Tetrahedron 2015; 71: 8960
• 9 The structure of the α-methyl-β-keto-carboxamide moiety was supported by DFT calculations and NOESY experiments of simplified molecules. For details, see Supporting Information.
• 10 Glucose uptake enhancement activity was also investigated. Both compounds had no effect on the glucose uptake up to a concentration of 30 μM in cultured L6 myotubes.

Partial formation of an N,O-bis(Boc) product was observed under those conditions. The Boc group on the phenolic hydroxy group was easily cleaved during the ensuing methylation. For related reports, see:
• 11a Nakamura K, Nakajima T, Kayahara H, Nomura E, Taniguchi H. Tetrahedron Lett. 2004; 45: 495
• 11b Nishiyama Y, Ishizuka S, Shikama S, Kurita K. Chem. Pharm. Bull. 2001; 49: 233
• 12 Boger DL, Yohannes D. J. Org. Chem. 1988; 53: 487
• 13 Malkov AV, Vranková K, Černý M, Kočovský P. J. Org. Chem. 2009; 74: 8425
• 14 Lim HJ, Gallucci JC, RajanBabu TV. Org. Lett. 2010; 12: 2162
• 15 El-Faham A, Funosas RS, Prohens R, Albericio F. Chem. Eur. J. 2009; 15: 9404
• 16 Crimmins MT, King BW, Tabet EA. J. Am. Chem. Soc. 1997; 119: 7883
• 17a Evans DA, Sjogren EB, Bartroli J, Dow RL. Tetrahedron Lett. 1986; 27: 4957
• 17b Evans DA, Britton TC, Ellman JA. Tetrahedron Lett. 1987; 28: 6141
• 18a Carpino LA. J. Am. Chem. Soc. 1993; 115: 4397
• 18b Carpino LA, Imazumi H, El-Faham A, Ferrer FJ, Zhang C, Lee Y, Foxman BM, Henklein P, Hanay C, Mügge C, Wenschuh H, Klose J, Beyermann M, Bienert M. Angew. Chem. Int. Ed. 2002; 41: 441
• 19 (2R,3S)-N-[(R)-1-{[(S)-1-amino-3-methyl-1-oxobutan-2-yl](methyl)amino}-3-(4-methoxyphenyl)-1-oxopropan-2-yl]-3-hydroxy-N,2-dimethyldecanamide (15) To a solution of carboxylic acid 14 (51.0 mg, 0.252 mmol) and i-Pr₂NEt (0.048 mL, 0.28 mmol) in DMF (1.62 mL) was added HATU (106 mg, 0.278 mmol) at 0 °C. After stirring for 30 min, a solution of amine hydrochloride 10 (90.3 mg, 0.252 mmol) and i-Pr₂NEt (0.097 mL, 0.56 mmol) in DMF (1.54 mL) was added dropwise at 0 °C. After the resulting mixture was stirred for 4 h at 25 °C, the reaction was quenched with NaCl solution (10%) in water. The resulting mixture was extracted three times with AcOEt. The combined organic phases were washed with aqueous NaHCO₃, dried with Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (AcOEt–n-hexane 1:5 to 1:0) to give 15 (91.4 mg, 0.181 mmol, 72%) as a colorless oil. [α]_D ²³ −1.78 (c 0.310, CHCl₃). IR (film): 3397, 3205, 2929, 2856, 1691, 1627, 1514, 1466, 1405, 1301, 1249, 1178, 1095, 1036, 824 cm^–1. ¹H NMR (400 MHz, CDCl₃, mixture of rotamers): δ = [7.14 (d, J = 8.8 Hz), 7.10 (d, J = 8.8 Hz), all sum to 2 H), [6.81 (d, J = 8.8 Hz), 6.79 (d, J = 8.8 Hz), all sum to 2 H], [6.71 (br s), 6.13 (br s), all sum to 1 H], [5.70 (dd, J = 8.0, 7.6 Hz), 5.68 (dd, J = 8.0, 7.6 Hz), all sum to 1 H], [5.58 (br s), 5.35 (br s), all sum to 1 H], [4.50 (d, J = 10.8 Hz), 3.72 (d, J = 10.4 Hz), all sum to 1 H], 3.80–3.60 (m, 1 H), 4.15–4.06 (br s, 1 H), [3.76 (s), 3.76 (s), all sum to 3 H], 3.18–2.84 (m, 2 H), [some signals including the following: 3.06 (s), 2.99 (s), 2.96 (s), 2.91 (s), all sum to 6 H], [2.57 (qd, J = 7.2, 2.0 Hz), 2.48 (qd, J = 7.2, 2.0 Hz), 1 H], 2.34–2.15 (m, 1 H), 1.48 (m, 2 H), 1.34–1.17 (m, 10 H), [0.97 (d, J = 6.4 Hz), 0.74 (d, J = 6.4 Hz), all sum to 3 H], [0.93–0.81 (m), 0.65 (d, J = 6.4 Hz), 0.63 (d, J = 6.4 Hz), 6 H], 0.89 (t, J = 7.7 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃, mixture of rotamers): δ = 178.6 (C), 178.1 (C), 172.1 (C), 171.8 (C), 171.6 (C), 169.1 (C), 158.6 (C), 158.5 (C), 130.3 (CH), 130.1 (CH), 128.2 (C), 128.0 (C), 113.9 (CH), 113.8 (CH), 71.2 (CH), 70.8 (CH), 63.5 (CH), 62.4 (CH), 55.3 (CH₃), 54.3 (CH), 53.9 (CH), 39.4 (CH), 39.0 (CH), 34.7 (CH₂), 34.6 (CH₂), 33.9 (CH₂), 33.5 (CH₂), 31.8 (CH₂), 31.1 (CH₃), 31.0 (CH₃), 30.7 (CH₃), 30.4 (CH₃), 29.6 (CH₂), 29.2 (CH₂), 27.3 (CH), 26.0 (CH₂), 25.9 (CH₂), 25.4 (CH), 22.6 (CH₂), 19.7 (CH₃), 19.3 (CH₃), 19.2 (CH₃), 18.3 (CH₃), 14.1 (CH₃), 9.3 (CH₃), 8.5 (CH₃). HRMS (ESI+): m/z calcd for C₂₈H₄₇N₃NaO₅: 528.3413; found: 528.3427.
• 20a Dess DB, Martin JC. J. Org. Chem. 1983; 48: 4155
• 20b Dess DB, Martin JC. J. Am. Chem. Soc. 1991; 113: 7277
• 21 Majusculamide A (1)To a solution of β-hydroxy amide 15 (26.1 mg, 0.0517 mmol) in CH₂Cl₂ (0.344 mL), were added NaHCO₃ (8.15 mg, 0.0971 mmol) and Dess–Martin periodinane (32.9 mg, 0.0775 mmol) at 0 °C. After stirring for 1 h at 25 °C, NaHCO₃ aq and Na₂S₂O₃ aq were added to the reaction mixture. The resulting solution was extracted three times with AcOEt. The combined organic layer was dried with Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by preparative TLC (AcOEt–n-hexane 5:1) to give 1 (13.3 mg, 0.0264 mmol, 51%) as a colorless oil. [α]_D ²³ +33.2 (c 0.715, EtOH). IR (film): 3335, 3208, 2930, 2863, 1688, 1635, 1510, 1463, 1400, 1297, 1250, 1178, 1107, 1040, 829 cm^–1. ¹H NMR (400 MHz, CDCl₃, mixture of rotamers): δ [7.14 (d, J = 8.4 Hz), 7.08 (d, J = 8.4 Hz), all sum to 2 H], [7.01 (br s), 6.16 (br s), all sum to 1 H], [6.80 (d, J = 8.4 Hz), 6.79 (d, J = 8.4 Hz), all sum to 2 H], [5.71 (dd, J = 8.0, 8.0 Hz), 5.65 (dd, J = 9.2, 6.0 Hz), all sum to 1 H], [5.50 (br s), 5.27 (br s), all sum to 1 H], [4.54 (d, J = 10.8), 3.71 (d, J = 10.8 Hz), all sum to 1 H], 3.77 (s, 3 H), [3.59 (q, J = 7.0 Hz), 3.44 (q, J = 7.2 Hz), all sum to 1 H], 3.20–2.85 (m, 2 H), [some signals including the following: 3.08 (s), 3.00 (s), 2.94 (s), 2.91 (s), all sum to 6 H], 2.48–2.30 (m, 2 H), [2.34–2.24 (m), 2.26–2.14 (m), all sum to 1 H], 1.51 (m, 2 H), 1.35–1.10 (m, 8 H), [1.00–0.91 (m), 0.90–0.78 (m) 0.59 (d, J = 6.4 Hz), all sum to 6 H], [1.22 (d, J = 7.0 Hz), 0.93 (d, J = 7.0 Hz), all sum to 3 H] 0.85 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃, mixture of rotamers): δ = 206.9 (C), 206.7 (C), 172.5 (C), 172.0 (C), 171.7 (C), 171.6 (C), 171.2 (C), 169.3 (C), 158.5 (C), 130.3 (CH), 130.1 (CH), 128.3 (C), 128.2 (C), 113.9 (CH), 113.8 (CH), 63.7 (CH), 62.5 (CH), 55.7 (CH), 55.3 (CH₃), 54.3 (CH), 51.2 (CH), 50.6 (CH), 40.5 (CH₂), 40.1 (CH₂), 34.9 (CH₂), 34.6 (CH₂), 31.6 (CH₂), 31.2 (CH₃), 30.9 (CH₃), 30.7 (CH₃), 29.6 (CH₃), 29.1 (CH₂), 27.6 (CH), 25.5 (CH), 23.5 (CH₂), 23.3 (CH₂), 22.6 (CH₂), 19.9 (CH₃), 18.8 (CH₃), 18.6 (CH₃), 18.4 (CH₃), 14.1 (CH₃), 13.4 (CH₃). HRMS (ESI+): m/z calcd for C₂₈H₄₅N₃NaO₅: 526.3257; found: 526.3252.
• 22 Majusculamide B (2) To a solution of β-hydroxy amide (17.6 mg, 0.0348 mmol), prepared by condensation of ent-14 with 10, in CH₂Cl₂ (0.232 mL), were added NaHCO₃ (4.8 mg, 0.0568 mmol) and Dess–Martin periodinane (19.2 mg, 0.0453 mmol) at 0 °C. After stirring for 1 h at 25 °C, NaHCO₃ aq and Na₂S₂O₃ aq were added to the reaction mixture. The resulting solution was extracted three times with AcOEt. The combined organic layer was dried with Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by preparative TLC (AcOEt–n-hexane 5:1) to give 2 (10.8 mg, 0.0215 mmol, 62%) as a colorless oil. [α]_D ²³ +25.5 (c 0.580, EtOH). IR (film): 3336, 3209, 2958, 2931, 2856, 1722, 1691, 1633, 1514, 1467, 1400, 1301, 1249, 1178, 1128, 1101, 1073, 1038, 825 cm^–1. ¹H NMR (400 MHz, CDCl₃, mixture of rotamers): δ = [7.16 (d, J = 8.6 Hz), 7.12 (d, J = 8.6 Hz), all sum to 2 H], [6.80 (d, J = 8.6 Hz), 6.78 (d, J = 8.4 Hz), all sum to 2 H], [6.74 (br s), 6.09 (br s), all sum to 1 H], [5.77 (dd, J = 7.4, 7.4 Hz), 5.73 (dd, J = 8.8, 6.4 Hz), all sum to 1 H], [5.48 (br s), 5.32 (br s), all sum to 1 H], [4.48 (d, J = 10.8 Hz), 3.62 (d, J = 10.8 Hz), all sum to 1 H], [3.76 (s), 3.75 (s), all sum to 3 H], 3.61–3.43 (m, 1 H), 3.18–2.85 (m, 2 H), [some signals including the followings: 3.04 (s), 3.04 (s), 3.02 (s), 2.91 (s), all sum to 6 H], 2.32–2.15 (m, 1 H), [1.99 (dt, J = 17.6, 7.2 Hz), 1.93 (dt, J = 17.6, 7.2 Hz), 1.65–1.53 (m), all sum to 2 H], 1.50–1.32 (m, 2 H), 1.32–1.06 (m, 8 H), 1.28 (d, J = 7.2 Hz, 3 H), [0.97 (d, J = 6.4 Hz), 0.92 (d, J = 6.4 Hz), 0.91–0.84 (m), 0.75 (d, J = 6.8 Hz), 0.63 (d, J = 6.8 Hz), all sum to 6 H], 0.88 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃, mixture of rotamers): δ = 206.6 (C), 205.5 (C), 172.2 (C), 171.8 (C), 171.5 (C), 171.4 (C), 171.0 (C), 169.2 (C), 158.5 (C), 130.3 (CH), 130.1 (CH), 128.3 (C), 113.9 (CH), 63.7 (CH), 62.4 (CH), 55.1 (CH₃), 55.0 (CH₃), 54.9 (CH), 54.3 (CH), 51.4 (CH), 50.7 (CH), 39.4 (CH₂), 39.3 (CH₂), 34.8 (CH₂), 34.6 (CH₂), 31.2 (CH₂), 31.6 (CH₃), 30.9 (CH₃), 30.5 (CH₃), 29.5 (CH₃), 29.2 (CH₂), 29.1 (CH₂), 29.0 (CH₂), 28.9 (CH₂), 27.4 (CH), 25.4 (CH), 23.4 (CH₂), 23.4 (CH₂), 22.6 (CH₂), 19.7 (CH₃), 19.2 (CH₃), 19.2 (CH₃), 18.3 (CH₃), 14.1 (CH₃), 13.7 (CH₃), 13.6 (CH₃). HRMS (ESI+): m/z calcd for C₂₈H₄₅N₃NaO₅: 526.3257; found: 526.3278.