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Synlett 2019; 30(20): 2279-2284
DOI: 10.1055/s-0037-1610736
letter
© Georg Thieme Verlag Stuttgart · New York

Total Synthesis of Endolides A and B

Langlang Liu
a   State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Xili, Shenzhen, 518055, P. R. of China   Email: yet@pkusz.edu.cn
b   Department of Pharmaceutical Engineering, Northwest University, 229 Taibai North Road, Xi’an, Shaanxi, 710069, P. R. of China
,
Yian Guo
a   State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Xili, Shenzhen, 518055, P. R. of China   Email: yet@pkusz.edu.cn
,
Qingchao Liu∗
b   Department of Pharmaceutical Engineering, Northwest University, 229 Taibai North Road, Xi’an, Shaanxi, 710069, P. R. of China
,
Ranjala Ratnayake
c   Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL 32610, USA
,
Hendrik Luesch
c   Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL 32610, USA
,
Tao Ye  ∗
a   State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Xili, Shenzhen, 518055, P. R. of China   Email: yet@pkusz.edu.cn
› Author AffiliationsWe acknowledge financial support from the Shenzhen Peacock Plan (KQTD2015071714043444), the National Natural Science Foundation of China (21772009), the Shenzhen Science and Technology Innovation Commission (JCYJ20170818090017617 and JCYJ20170818090238288), the Guangdong Natural Science Foundation (2014B030301003), and the China Postdoctoral Science Foundation (2018M641059 for Y.G.). H.L. thanks the National Institutes of Health (NCI grant R01CA172310), and the Debbie and Sylvia DeSantis Chair professorship. R.R. thanks the NCI for a Research Specialist Award (R50CA211487).
Further Information

Publication History

Received: 17 September 2019

Accepted after revision: 01 November 2019

Publication Date:
14 November 2019 (online)

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‡ These authors contributed equally to this work.

Abstract

The total synthesis of endolides A and B has been achieved in a concise and highly stereoselective fashion (12 steps; 16.2 and 16.0% overall yield, respectively). Key features of the route include a modified Negishi coupling between 3-bromofuran and an organozinc reagent derived from an iodoalanine derivative for the synthesis of a 3-(3-furyl)alanine derivative, and a judicious choice of reaction conditions to overcome the conformational constraints placed by converting a linear peptide into the corresponding macrocycle.

Key words

total synthesis - endolides - Negishi coupling - furylalanine - Buchwald phosphine ligands - peptide macrocycles

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610736.
  • Supporting Information
 

  • References and Notes

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  • 14 Endolide A (1) White solid; yield: 44.0 mg (45% for 2 steps); Rf = 0.40 (EtOAc–hexanes, 1:1); [α]24 D –181.9 (c 1.0, CHCl3). 1H NMR (400 MHz, acetone-d 6): δ = 7.89 (d, J = 9.6 Hz, 1 H), 7.80 (d, J = 8.6 Hz, 1 H), 7.53 (t, J = 1.7 Hz, 2 H), 7.44 (s, 1 H), 7.43 (s, 1 H), 6.39 (s, 1 H), 6.37 (s, 1 H), 4.68 (td, J = 8.8, 5.7 Hz, 1 H), 4.39 (dd, J = 11.7, 3.3 Hz, 1 H), 4.40–4.34 (m, 1 H), 4.31 (dd, J = 11.6, 3.2 Hz, 1 H), 3.40 (dd, J = 11.4, 2.9 Hz, 1 H), 3.37 (dd, J = 11.4, 2.9 Hz, 1 H), 2.96 (t, J = 11.6 Hz, 1 H), 2.92 (t, J = 11.6 Hz, 1 H), 2.79 (s, 3 H), 2.75 (s, 3 H), 2.21–2.07 (m, 1 H), 1.75–1.63 (m, 1 H), 1.62–1.47 (m, 1 H), 1.36–1.23 (m, 1 H), 0.89 (d, J = 7.0 Hz, 3 H), 0.87 (d, J = 7.2 Hz, 3 H), 0.85 (d, J = 6.7 Hz, 6 H). 13C NMR (101 MHz, acetone-d 6): δ = 172.9, 172.1, 170.7, 170.3, 144.4, 144.3, 141.0, 141.0, 122.0, 121.9, 110.9, 110.8, 62.8, 62.6, 56.2, 49.2, 41.9, 30.5, 30.3, 30.1, 25.0, 24.4, 24.4, 23.2, 22.5, 20.7, 18.4. HRMS: m/z [M + Na]+ Calcd for C27H38N4NaO6: 537.2689; found: 537.2679. Endolide B (2) White solid; yield: 44 mg (43% for 2 steps); Rf = 0.35 (EtOAc–hexanes, 1:1); [α]24 D –180.8 (c 1.0, CHCl3). 1H NMR (400 MHz, acetone-d 6): δ = 7.92 (d, J = 9.7 Hz, 1 H), 7.80 (d, J = 9.6 Hz, 1 H), 7.52 (t, J = 1.7 Hz, 1 H), 7.47 (t, J = 1.8 Hz, 1 H), 7.42–7.40 (m, 3 H), 7.28 (s, 1 H), 6.36 (d, J = 0.9 Hz, 1 H), 6.34 (d, J = 1.0 Hz, 1 H), 6.30 (d, J = 1.0 Hz, 1 H), 4.86 (dt, J = 9.6, 6.7 Hz, 1 H), 4.41–4.32 (m, 2 H), 4.30 (dd, J = 11.7, 3.3 Hz, 1 H), 3.38 (dd, J = 15.2, 2.9 Hz, 1 H), 3.31 (dd, J = 15.6, 2.6 Hz, 1 H), 2.97 (d, J = 15.2 Hz, 1 H), 2.95 (dd, J = 15.0, 5.5 Hz, 1 H), 2.86 (d, J = 11.8 Hz, 1 H), 2.81 (s, 3 H), 2.73 (s, 3 H), 2.61 (dd, J = 14.8, 6.7 Hz, 1 H), 2.18–2.07 (m, 1 H), 0.85 (d, J = 7.0 Hz, 3 H), 0.84 (d, J = 6.7 Hz, 3 H). 13C NMR (101 MHz, acetone-d 6): δ = 172.5, 172.1, 170.7, 170.1, 144.4, 144.4, 143.2, 141.3, 141.0, 141.0, 122.0, 122.0, 121.7, 112.8, 111.0, 110.9, 62.8, 62.6, 56.2, 51.4, 30.6, 30.3, 30.1, 28.0, 24.7, 24.4, 20.8, 18.4. HRMS: m/z [M + Na]+ Calcd for C28H34N4NaO7: 561.2325; found: 561.2306.