ASAP report

Reporter: Xiaoyun Liao

Supervisors: Prof. Tao Ye

Dr. Yian Guo

Sep. 21st, 2020

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A brief introduction to a total synthesis

Part Ⅰ :Total synthesis of Thromboxane B2

Varinder K. Aggarwal, et. al, Org. Lett. 2020, 22, 6505−6509

TxB2 is a metabolite of thromboxane A2, play a role in the immun and vascular systems, employed TxB2 as a synthetic precursor to the biologically active TxA2.

3Benjamin List, et. al, Chem. Rev. 2007, 107, 12, 5471–5569.Aggarwal, V. K., et al, Nature 2012, 489, 278−281.

Gong, Chen, et. al, Org. Lett. 2020, 22, 6879−68834

Part ⅠI: Construction of Cyclophane-Braced Peptide Macrocycles via Palladium-Catalyzed Picolinamide-Directed Intramolecular C(sp2)−H Arylation

A brief introduction to a methodology

Part ⅠI: Peptide Macrocyclization of Aryl C−H Bonds

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A brief introduction to a methodology

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Part ⅠI: Peptide Macrocyclization of Aryl C−H Bonds

A brief introduction to a methodology

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Part ⅠI: Peptide Macrocyclization of Vinyl C−H Bonds

A brief introduction to a methodology

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A brief introduction to a separation of natural products

Sergey B. Zotchev, et. al, J. Nat. Prod. 2020, 83, 2381−2389

Part Ⅲ: Next-Generation Total Synthesis of Vancomycin

Dale L. Boger, et. al. J. Am. Chem. Soc. 2020, asap.9

The introduction of author

Boger, Dale Professor

Richard and Alice Cramer Professor of Chemistry

The Scripps Research Institute Department of Chemistry

Tel : (858) 784-7522

E-mail: boger@scripps.edu

Research interests1. Synthetic Organic And Bioorganic Chemistry2. Synthetic Methodology 3. Natural Products Total Synthesis 4. Bioorganic Chemistry

Experiences1975 B.S. University of Kansas1980 Ph.D. Harvard University1979-85 Assistant/Associate Professor of Medicinal Chemistry, University of Kansas1985-91 Associate Professor/Professor of Chemistry, Purdue University1991-present Professor, The Scripps Research Institute

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Challenges for chemical synthesis:1. highly functionalized and rigid

tricyclic heptapeptide core2. unusual centers of axial or planar

chirality (atropisomers)3. glycosylation

Introduction

Atroposelectivity

Total syntheses LLS Overall Yield

AB CD DE

Evans (1998) 32 0.4% <1:20 5:1 5:1

Nicolaou (1998) 24 0.05% 2:1 1:1 1:3

Boger (1999) 25 0.2% 1:1 1:1 8:1

This Work (2020)

17 5% >20:1 8:1 14:111

Vancomycin: one of the clinically most effective and important antibiotics

Introduction

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Previous work: Total Synthesis of the Vancomycin Aglycon

Dale L. Boger, et. al. J. Am. Chem. Soc. 1999, 121, 10004-10011

LLS: 25 steps, overall yield: 0.2%, Atroposelectivity: AB(1:1), CD(1:), DE(8:1), lack of kinetic atroposelectivity in the construction of the AB and CD ring systems.

Retrosynthetic analysis

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This Work:

C-H activation (chiral pool)

Synthesis of A ring amino acid

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Previous work:key reaction-Sharpless asymmetric AA> 10 g scale, 20% 6 steps, 90% ee, 3:1 rr

Dale L. Boger, et. al. J. Am. Chem. Soc. 1999, 121, 10004-10011

Synthesis of D ring amino acid

chiral pool

15Dale L. Boger, et. al. J. Am. Chem. Soc. 1999, 121, 10004-10011

Previous work: key reaction-Sharpless asymmetric AA, 69% 9 steps, 96% ee, 7:1 regioselectivity

Synthesis of C ring amino acid

Michael T. Crimmins, et. al, J. Org. Chem. 2001, 66, 894-90216Dale L. Boger, et. al. J. Am. Chem. Soc. 1999, 121, 10004-10011

Previous work: ① zirconium-mediated addition of a Schöllkopf reagent (commercially available for >$100/g;② 4 steps from D-valine, proceeding in 5:1 dr (syn:anti) and 50% yield (syn isomer).

Diastereoselective synthesis of AB axis of chirality

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Synthesis of the AB ring system

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R dr yield

a H 2:1 50%

b TBS 3:1 84%

c TBDPS 5:1 50%

d TIPS 7:1 80%

With preorganization- CD ring closure

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Completion of Formal Total Synthesis

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Completed formal total synthesis: 26 steps from amino acide subunits 0.7% overall yield.A ring amine protecting group-it introduced an inefficient deprotection− oxidation sequence

Dale L. Boger, et. al, J. Am. Chem. Soc. 1999, 121, 10004-10011

Completion of Formal Total Synthesis

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Next-Generation Vancomycin Total Synthesis

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Next-Generation Vancomycin Total Synthesis

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Next-Generation Vancomycin Total Synthesis

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Summary

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Atroposelectivity

Total syntheses LLS Overall Yield AB CD DE

Boger (1999) 25 0.2% 1:1 1:1 8:1

This Work (2020) 17 5% >20:1 8:1 14:1

Vancomycin aglycon

1999 2020

precatalysts:[Ir(COD)Cl]2 ligand:tmphen

Milton R. Smith, III, et. al. J. Am. Chem. Soc. 2013, 135, 7572−758226

Mechanism of the Chan-Lam Coupling

The reaction with a stoichiometric amount of copper(II) is also facilitated by oxygen, because reductive elimination from a copper(III) species is faster.

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Miyaura Borylation Reaction VS Suzuki Coupling

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Milorad M. Rogic, et. al, J. Org. Chem. 1981, 46, 4489-4493 29

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Staudinger Reaction

Triphenylphosphine reacts with the azide to generate a phosphazide, which loses N2 to form an iminophosphorane. Aqueous work up leads to the amine and the very stable phosphine oxide.

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Suzuki cross-coupling.

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DEPBT-mediated coupling.

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Sandmeyer chlorination

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D. H. O' Donovan et al./Tetrahedron Letters 57 (2016) 2962–2964 38

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Mechanism of the Baeyer-Villiger Oxidation