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Synlett 2014; 25(07): 1014-1018
DOI: 10.1055/s-0033-1340872
DOI: 10.1055/s-0033-1340872
letter
Total Synthesis of the Proposed Structure for Itralamide B
Further Information
Publication History
Received: 28 December 2013
Accepted after revision: 05 February 2014
Publication Date:
14 March 2014 (online)
![](https://www.thieme-connect.de/media/synlett/201407/lookinside/thumbnails/10.1055-s-0033-1340872-1.jpg)
Abstract
A stereocontrolled total synthesis of the cyclodepsipeptide, itralamide B, has been achieved. Both R- and S-stereoisomers of the side chain were attached to the macrocyclic ring, however, the synthesized structure appears to be different from that of the marine natural product.
Key words
natural products - total synthesis - macrolactonization - configuration determination - stereoselectivitySupporting Information
- for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
- Supporting Information
-
References and Notes
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- 25 Synthesis of Itralamide B (1): Compound 18 (23.0 mg, 0.03 mmol, 1.0 equiv) was dissolved in CH2Cl2 (1.0 mL) at 0 °C, and BF3·OEt2 (34 μL, 0.3 mmol, 10.0 equiv) was added dropwise to the solution at 0 °C. The reaction solution was allowed to warm to r.t. and stirred for 0.5–1.0 h (reaction monitored by TLC). The reaction was quenched by the addition of saturated NH4Cl (2 mL) and diluted with CH2Cl2 (60 mL). The organic phase was washed with saturated NH4Cl (3 × 20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford the crude hydroxy acid. A solution of this hydroxy acid in THF–PhMe (10 mL, 1:1) was slowly added to a solution of DMAP (33 mg, 0.3 mmol, 10.0 equiv) and MNBA (47 mg, 0.14 mmol, 5.0 equiv) in PhMe (10 mL) at 0 °C. The reaction mixture was warmed to r.t., then stirred and heated to 60 °C for 2 d. The reaction mixture was diluted with EtOAc (100 mL) and washed successively with saturated NH4Cl (3 × 20 mL) and brine (2 × 20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc) to afford (S)-itralamide B (1; 5.0 mg, 21%). (S)-Itralamide B (1): [α]D 25 –44.63 (c 0.4, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.45–7.12 (m, 5 H), 6.90 (d, J = 9.6 Hz, 1 H), 6.47 (d, J = 8.0 Hz, 1 H), 5.99 (d, J = 2.9 Hz, 1 H), 5.75–5.65 (m, 2 H), 5.53–5.43 (m, 1 H), 5.08 (q, J = 6.8 Hz, 1 H), 4.98 (dd, J = 7.9, 4.2 Hz, 1 H), 4.71 (dd, J = 9.4, 4.1 Hz, 1 H), 4.62 (q, J = 7.6 Hz, 1 H), 3.66 (dd, J = 15.5, 4.9 Hz, 1 H), 3.33 (d, J = 23.6 Hz, 3 H), 3.19 (d, J = 7.1 Hz, 3 H), 3.17–3.07 (m, 3 H), 3.07–2.94 (m, 3 H), 2.87 (dd, J = 15.6, 12.1 Hz, 1 H), 2.80 (d, J = 4.0 Hz, 1 H), 2.76–2.65 (m, 1 H), 2.46 (dd, J = 16.5, 7.5 Hz, 1 H), 2.28–2.21 (m, 1 H), 2.06–1.99 (m, 1 H), 1.29 (d, J = 2.0 Hz, 3 H), 1.26 (d, J = 2.8 Hz, 3 H), 1.20 (dd, J = 6.6, 3.5 Hz, 3 H), 1.08–1.01 (m, 6 H), 0.92 (dd, J = 9.4, 7.2 Hz, 6 H), 0.80 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 174.89, 172.84, 172.53, 170.65, 170.17, 169.90, 169.47, 137.35, 128.54, 128.34, 126.48, 78.18, 69.62, 56.92, 56.75, 54.69, 54.68, 53.98, 51.43, 40.65, 35.75, 33.92, 33.77, 32.15, 31.83, 31.12, 31.00, 30.54, 19.90, 19.63, 17.82, 17.10, 15.61, 15.35, 14.10, 13.82. HRMS (ESI): m/z [M+Na]+ calcd for C38H58Cl2N6NaO8 +: 819.3585; found: 819.3587. (R)-Itralamide B (1): [α]D 25 –42.33 (c 0.2, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.24–7.16 (m, 5 H), 6.89 (d, J = 9.1 Hz, 1 H), 6.48 (d, J = 7.8 Hz, 1 H), 6.04 (d, J = 2.9 Hz, 1 H), 5.78–5.63 (m, 1 H), 5.49 (dd, J = 6.6, 3.2 Hz, 1 H), 5.45–5.35 (m, 1 H), 5.12–5.02 (m, 1 H), 4.98 (dd, J = 7.8, 4.2 Hz, 1 H), 4.71 (dd, J = 9.3, 4.0 Hz, 1 H), 4.67–4.55 (m, 1 H), 3.66 (dd, J = 15.3, 5.1 Hz, 1 H), 3.28 (d, J = 63.9 Hz, 3 H), 3.18 (s, 3 H), 3.13 (d, J = 23.1 Hz, 3 H), 3.01 (d, J = 11.3 Hz, 3 H), 2.93 (d, J = 15.7 Hz, 1 H), 2.90–2.78 (m, 1 H), 2.78–2.67 (m, 1 H), 2.43 (dd, J = 16.7, 6.0 Hz, 1 H), 2.25 (dd, J = 11.9, 5.9 Hz, 1 H), 2.04 (d, J = 9.5 Hz, 1 H), 1.38 (dd, J = 18.4, 7.2 Hz, 3 H), 1.30 (d, J = 6.7 Hz, 3 H), 1.20 (d, J = 6.6 Hz, 3 H), 1.06 (d, J = 6.8 Hz, 6 H), 0.92 (dd, J = 11.7, 7.0 Hz, 6 H), 0.80 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 174.88, 172.83, 172.56, 170.68, 170.17, 169.85, 169.51, 137.37, 128.55, 128.34, 126.48, 78.02, 69.64, 56.88, 56.75, 54.75, 54.22, 53.99, 51.47, 40.45, 35.98, 33.97, 33.78, 32.18, 31.85, 31.12, 31.02, 30.55, 19.89, 19.63, 17.82, 17.09, 17.07, 15.60, 15.05, 13.83 ppm. HRMS (ESI): m/z [M+Na]+ for C38H58Cl2N6NaO8 +: 819.3585; found: 819.3589.
- 26 See the Supporting Information for detailed analyses.
Lyngbyabellin A was isolated from marine cyanobacterium Lyngbya majuscule, see:
Its structure and absolute stereochemistry were confirmed by total syntheses, see: