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DOI: 10.1055/s-0037-1611805
Synthesis of Majusculamides A and B
This work was financially supported by JSPS KAKENHI (Grant Numbers 17H01523 and 18H04399) and by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research; BINDS) from the Japan Agency for Medical Research and Development (AMED) under Grant Number JP18am0101099.
Publication History
Received: 28 February 2019
Accepted after revision: 02 April 2019
Publication Date:
12 April 2019 (online)
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.
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Key words
marine natural products - peptides - polyketides - β-ketoamide - asymmetric aldol reactionMarine natural products show a wide range of biological activities because of their structural diversity, which offers a rich source of biological tools as well as new drugs.[1] Although the evaluation of their biological activities is sometimes restricted by their limited natural supply, chemical synthesis can provide sufficient amounts of samples and might expand the possibility of identifying the potencies of the molecules. In connection with our campaign to discover biologically active molecules, we developed syntheses of the marine natural products, majusculamides A and B (Figure [1]).


The first isolation of the majusculamides from cyanobacteria, Lyngbya majuscula, and their structural elucidation were reported by Moore, Clardy, and co-workers in 1977.[2] [3] These natural products feature a dipeptide moiety comprising N,O-dimethyl-d-tyrosine and N-methyl-l-valine, with a C-terminal primary amide. The α-methyl-β-keto-decanoyl group is bonded to the N terminus of the dipeptide to form a tertiary amide. The methyl group in the decanoyl group generates two diastereomers, and the (R) and (S) diastereomers are majusculamides A (1) and B (2), respectively.
Although the α-methyl-β-keto-carboxamide moiety appears to be stereochemically labile, these two isomers could be separated. Isomerization of either isomer under heating in dimethyl sulfoxide at 140 °C was reported to be slow.[4] [5] Conformational insights into the α-methyl-β-keto-imide moiety by Evans and coworkers explain the stereochemical stability of the system,[6] in which the C–H bond at the α position is arranged almost coplanar with the plane of the amide so as to minimize the 1,3-allylic strain of the amide moiety (Figure [2]).[7] [8] This insight also suggests that the alkyl chains of the decanoyl groups in majusculamides A and B are oriented in different directions relative to the dipeptide core in preferable conformations, thereby differentiating the shapes of the two molecules.[9] The structural differences might confer distinct biological activities. In fact, a difference in cell cytotoxicity measured with an MTT assay was observed between majusculamides A and B. Majusculamide A showed cytotoxicity at 10 μM in cultured Hela S3 cells, while majusculamide B showed no cytotoxicity under the same conditions.[10]
The synthesis of majusculamides A and B began with the preparation of methylated amino acid units (Scheme [1]). Protection of d-tyrosine (3) with a Boc group,[11] followed by methylation with iodomethane in the presence of sodium hydride in tetrahydrofuran afforded N,O-dimethyl-N-Boc-tyrosine (4).[12] After protecting l-valine (5) with a Boc group, N-methylation was conducted under the same conditions.[13] The carboxylic acid moiety in 6 was then activated by treatment with isobutyl chloroformate and N-methylmorpholine in diethyl ether, and the resulting mixed anhydride was treated with ammonia gas to furnish carboxamide 7.[14] Compound 7 was subjected to deprotection by treatment with methanolic hydrogen chloride, giving the hydrogen chloride salt of N-methylvaline carboxamide 8. Condensation of these amino acid units thus obtained could be successfully carried out by using (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) to give dipeptide 9 in 74% yield.[15] Employing other condensation reagents such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU) or EDCI–HOBt (EDCI = ethyl-3-(3-dimethylaminopropyl)carbodiimide) resulted in a lower yield because of the steric hindrance at the units. The Boc group in 9 was cleaved with methanolic hydrogen chloride to give 10.




The decanoic acid unit was prepared by an asymmetric aldol reaction (Scheme [2]). Sequential treatment of (R)-propanoyloxazolidinone 11 with titanium(IV) chloride, TMEDA, and then octanal (12) afforded β-hydroxy-imide 13,[16] which was hydrolyzed with lithium hydroperoxide to give carboxylic acid 14.[17] Condensation of 14 with dipeptide 10 was conducted by using HATU to furnish 15 in 72% yield.[18] [19] Since the primary carboxamide moiety in 10 was affected by HATU, premixing 14 and HATU before adding 10 effectively improved the yield. Finally, oxidation of the secondary alcohol moiety with Dess–Martin periodinane[20] in the presence of sodium bicarbonate produced majusculamide A (1).[21] Starting from (S)-propanoyloxazolidinone 16, majusculamide B (2) could be obtained according to the same procedure.[22] The spectral data of the synthetic materials were identical to those of the natural samples.


In summary, we achieved syntheses of majusculamides A and B with a longest linear sequence of eight steps in 13 and 18% overall yields, respectively. The characteristic α-methyl-β-keto-carboxamide moiety could be constructed in a two-step sequence, which includes condensation of the amine moiety in the peptide unit and the β-hydroxy-carboxylic acid units, followed by oxidation of the hydroxy group. The sequence can be used to synthesize analogues of majusculamides. Other biological evaluation of the natural products and the analogues is currently underway and will be reported in due course.
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Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0037-1611805.
- Supporting Information
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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.
- 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
- 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
- 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.
- 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.
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:
Tertiary amides are essential for the stereochemical stabilities of β-keto-carboxamides. For examples of isomerization of secondary amides, see:
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:
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:
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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.
- 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
- 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
- 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.
- 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.
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:
Tertiary amides are essential for the stereochemical stabilities of β-keto-carboxamides. For examples of isomerization of secondary amides, see:
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:
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:







