Angew. Chem. Int. Ed., 2013, 52, 10060-10063.

A Rapid Route to Aminocyclopropanes via Carbamatoorganozinc Carbenoids

S. Ishikawa, T.D. Sheppard, J.M. D’Oyley, A.Kamimura, and W.B. Motherwell

Sylvain TaillemaudCharette Group

Charette/Collins Litterature meeting

October 2nd, 2013

Pr. William B. Motherwell• University College London

• B.Sc : Glasgow University• Ph.D : Glasgow University (1972)

• 1975 : Postdoc at the Imperial College London, with Pr. Sir Derek Barton.• Went together at the Institut de Chimie des Subtances Naturelles (CNRS,

France) as a « chargé de recherche » for six years.• 1983 : Back at the ICL, first as a Lecturer and then as a Reader in

Chemistry.• 1993 : Alexander Williamson Chair of Chemistry, University College

London.

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Pr. William B. Motherwell• Reasearch Interests

– Free radical chemistry

– Selective Fluorination

– Transition Metal catalysed reactions

– Chemistry of Organozinc Carbenoïds

– Multicomponent / Tandem reactions

– Artificial enzymes

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Aminocyclopropanes : What for ?• Tranylcypromine (GSK)1

– Antidepressant– Anti-anxiety

• Ticagrelor/Brilique (AZD6140, AZ)2

– Anti-aggregant at the blood platelets level

• Synthetic aminoacid derivatives (here Cytotrienin A)3

– Anti-tumor

1. López-Muñoz, F.; Alamo, C. Curr. Pharm. Des. 2009, 15, 1563. 2. Hubert, K.; Hamad, B.; Kirkpatrick, P. Nat. Rev. Drug Discovery, 2011, 10, 255. 3. Zhang, H.P.; Kakeya, H.; Osada, H. Tetrahedron Lett. 1997, 38, 1789.General references on aminocyclopropyl derivatives : Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603 ;Brackmann, F.; de Meijere, A. Chem. Rev. 2007, 107, 4493.

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Aminocyclopropanes : How to synthetize them ?

• Curtius rearrangement1

• Nitrocyclopropanes reduction2

1. Charette A.B.; Côté B. J. Am. Chem. Soc. 1995, 117, 12721 ; Pietruszka J., Solduga G. Eur. J. Org. Chem. 2009, 5998.2. Moreau, B.; Charette, A.B. J. Am. Chem. Soc. 2005, 127, 18014. 5

Aminocyclopropanes : How to synthetize them ?

• Reductive amination1

• Cyclopropychloroboranes intermediaries2

• Enamine/Enamide cyclopropanation3

1. Kang, J.; Kim, K.S. J. Chem. Soc. Chem. Commun. 1987, 897.2. Pietruszka J., Solduga G. Eur. J. Org. Chem. 2009, 5998.3. Song, Z.; Lu, T.; Hsung, R.P.; Al-Rashid, Z.F.; Ko, C.; Tang, Y. Angew. Chem. Int. Ed. 2007, 46, 4069.

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Aminocyclopropanes : How to synthetize them ?

• Kulinkovich-type reaction from amides1

• Kulinkovich-type reaction from nitriles2

1. de Meijere, A.; Chaplinski, V.; Winsel, H.; Kordes, M.; Stecker, B.; Gazizova, V.; Savchenko,A.I.; Boese, R.; Schill, F. Chem. Eur. J. 2010, 16, 13862.2. Bertus, P.; Menant, C.; Tanguy, C.; Szymoniak, J. Org. Lett. 2008, 10, 777.

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Aminocyclopropanes : Motherwell’s approach

• Two reported examples with carbenes– Hegedus1

– Barluenga2

• Use a protected amino-carbenoid to react with a conventionnal alkene

1.Merino, I.; Hegedus, L. S. Organometallics 1995, 14, 2522.2. Barluenga, J.; Aznar, F.; Gutirrez, I.; Garca-Granda, S.; Llorca-BaragaÇo, M.A. Org. Lett. 2002, 4, 4273.

Simmons Smith type ?

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Motherwell’s work• Organozinc carbenoïd from carbonyls or orthoesters

Motherwell, W. B. J. Organomet. Chem. 2001, 41.

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Motherwell’s work• Cyclopropanation

– Intermolecular

– Intramolecular

• Alkoxy-cyclopropanation

Motherwell, W. B. J. Organomet. Chem. 2001, 41.

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Motherwell’s work• Access to amidocyclopropanes1

1. W. B. Motherwell, G. Bégis, D. E. Cladingboel, L. Jerome, T. D. Sheppard, Tetrahedron 2007, 6462 ; L. Jerome, T. D. Sheppard, A. E. Aliev, W. B. Motherwell, Tetrahedron Lett. 2009, 3709. 11

Motherwell’s work• Use of chiral oxazolidinones

– Synthesis 2005 1

G. Bégis, T. D. Sheppard, D. E. Cladingboel, W. B. Motherwell,D. A. Tocher, Synthesis 2005, 3186.12

Motherwell’s work• Use of chiral oxazolidinones

– JOC 2009 1

The deprotection remains a problem, with no good enough yields

Moreover, hydrogenation as a deprotection step is not recomanded when an aryl substituant is on the cyclopropane

G. Bgis, D. E., Cladingboel, L. Jerome, W. B. Motherwell, T. D. Sheppard, Eur. J. Org. Chem. 2009, 1532. 13

This paper• The best way to avoid hydrogenolysis : removing the C-N bond !

• The plan

Angew. Chem. Int. Ed., 2013, 52, 10060.

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This paper• First try

• After optimisation

Angew. Chem. Int. Ed., 2013, 52, 10060-10063.15

This paper• Scope

Large scale

Angew. Chem. Int. Ed., 2013, 52, 10060-10063.16

CisStereochemistry

!

This paper• Explanation to the stereochemistry

• Trans examples

Angew. Chem. Int. Ed., 2013, 52, 10060-10063.17

This paper• The final step : deprotection

Angew. Chem. Int. Ed., 2013, 52, 10060-10063.18

AZD6140