First Total Synthesis of (+)-Sparteine and

Gram-Scale Synthesis of (-)-Sparteine

Literature Report 5

Reporter

Checker

Date

: Fan-Jie Meng

: Lei Shi

: 2018-05-09

Firth, J. D.; Canipa, S. J.; Ferris, L.; O’Brien, P. Angew. Chem. Int. Ed. 2018, 57, 223

CV of Peter O'Brien

Education:

19XX-1995 Ph.D., University of Cambridge

1995-2002 Lecturer, University of York

2002-2005 Senior Lecturer, University of York

2005-2007 Reader, University of York

2007-Now Professor, University of York

2

Research:

Bioinorganic chemistry

Medicinal chemistry

Organic chemistry

Organometallic chemistry

Contents

3

1

2

Introduction

3

4

First Asymmetric Total Synthesis of (+)-Sparteine

Gram-Scale Synthesis of (-)-Sparteine

Summary

Introduction

They rely on natural product extractions and this can lead to

supply issues over the last few years;

The natural product sparteine and the sparteine surrogate are

widely used chiral ligands in asymmetric synthesis.

4

Introduction

5

Lete, E.; Martínez-Estíbalez, U.; Sotomayor, N. Org. Lett. 2009, 11, 1237

Introduction

6

Marek, I.; Normant, J.-F. et al. J. Am. Chem. Soc. 1995,117, 8853

O’Brien, P.; Dearden, M. J.; McGrath, M. J. Org. Chem. 2004, 69, 5789

Introduction

7

Aggarwal, V. K. et al. Nature 2014, 513, 183

8

Mitsunobu, O.; Masaaki, Y. Bull. Chem. Soc. Japan 1967, 40, 935

Mitsunobu Azidation

9

Aube, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965

Schmidt Reaction

10

Retrosynthetic Analysis of (+)-Sparteine and (-)-Sparteine

11

Retrosynthetic Analysis of (+)-Sparteine

Aubé, J.; Smith, B. T.; Wendt, J. A. Org. Lett. 2002, 4, 2577

12

First Asymmetric Total Synthesis of (+)-Sparteine

Hayashi, T. Acta Chem. Scand. 1996, 50, 259

13

First Asymmetric Total Synthesis of (+)-Sparteine

14

First Asymmetric Total Synthesis of (+)-Sparteine

15

First Asymmetric Total Synthesis of (+)-Sparteine

16

Retrosynthetic Analysis of (-)-Sparteine

Firth, J. D.; Canipa, S. J.; Ferris, L.; O’Brien, P. Angew. Chem. Int. Ed. 2018, 57, 223

17

Gram-Scale Synthesis of (-)-Sparteine

Pousset, C. et al. Tetrahedron: Asymmetry 2004, 15, 3407

18

Gram-Scale Synthesis of (-)-Sparteine

19

Gram-Scale Synthesis of the (-)-Sparteine Surrogate

Summary

20

15 steps and 16% overall yield;

The key steps were two ring-expansion reactions;

Schmidt reaction;

Photo-Beckmann rearrangement.

10 steps and 31% overall yield;

Gram-scale synthesis of (-)-sparteine;

Synthesis of enantiopure (-)-sparteine from a

simple racemic starting material.

The First Paragraph

21

The natural product sparteine and its structurally

related cousin, the sparteine surrogate, which was

developed in our laboratory, are widely used chiral

ligands in asymmetric synthesis. In particular, these

diamines are the “go-to” chiral ligands for organolithium

bases such as sec-Butyllithium for use in reactions

pioneered in the 1990s by Hoppe and Beak. The more

recent work from the Aggarwal group on programmable

assembly-line synthesis using chiral boron reagents has

significantly expanded the synthetic potential offered by

sparteine and the sparteine surrogate.

In summary, we have presented a unified strategy for

the gram-scale synthesis of the (-)-sparteine surrogate

and the lupin alkaloid (-)-sparteine, with full control over

relative and absolute stereo-chemistry. The modular

nature of the routes facilitates the synthesis of either

antipode of the sparteine surrogate and sparteine and

thus addresses any long-term supply issues relating to

these synthetically useful chiral ligands.

The Last Paragraph

22

Acknowledgement

23

Thanks for your attention