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Synlett 2004(15): 2647-2669  
DOI: 10.1055/s-2004-836029
ACCOUNT
© Georg Thieme Verlag Stuttgart · New York

Planar and Central Chiral [2.2]Paracyclophanes as Powerful Catalysts for Asymmetric 1,2-Addition Reactions

Stefan Bräse*a, Stefan Dahmen*b, Sebastian Höfenera, Frank Lauterwassera, Michael Kreisa, Robert E. Ziegertc
a Institut für Organische Chemie, Universität Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
b cynora GmbH, Kaiserstr. 100, 52134 Herzogenrath, Germany, www.cynora.de
c Kekulé-Institut für Organische Chemie und Biochemie, Rheinischen Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany
Fax: +49(721)6088581; e-Mail: braese@ioc.uka.de;
Further Information

Publication History

Received 15 June 2004
Publication Date:
25 November 2004 (online)

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Abstract

Planar and central chiral [2.2]paracyclophane ligands have been designed and used in the highly enantioselective addition of alkyl, alkenyl, alkynyl and aryl zinc reagents to aldehydes and imines.

1 Why Use [2.2]Paracyclophanes as Chiral Ligands?

2 Synthesis of [2.2]Paracyclophane Ligands

2.1 Preparation and Resolution of FHPC, AHPC and BHPC-Based Imines

2.2 Synthesis of Further Imines Based on FHPC and AHPC

2.3 Synthesis of Chiral Amine Ligands

2.4 1,2-Addition to Imines

2.5 Reductive Amination

2.6 Structural Information on AHPC-Based Imines

2.7 Synthesis of Enantiomerically Pure Thio-Substituted ­Paracyclophanes

2.8 Other Cyclophane-Based Ligands Used for Asymmetric 1,2-Addition Reactions

3 Asymmetric 1,2-Addition Reactions to Aryl Aldehydes

3.1 Initial Considerations

3.2 Mechanistic Investigations

3.3 Reactivity of [2.2]Paracyclophane Ligands

3.4 Asymmetric Addition Reactions to Aromatic Aldehydes: Scope of Substrates

4 Asymmetric Addition Reactions to Aliphatic Aldehydes

5 Addition of Alkenyl Zinc Reagents to Aldehydes

6 Addition of Alkynyl Zinc Reagents to Aldehydes

7 Addition of Phenylzinc to Aldehydes

8 Asymmetric Addition Reactions to Imines

9 Asymmetric Addition Reactions on Solid Supports

10 Conclusions and Outlook

11 Abbreviations

Key words

asymmetric catalysis - ligands - paracyclophanes - zinc - nucleophilic additions

25

Kreis, M. unpublished results.

31

The transfer of the planar cylopentadienyl moiety of the ferrocene to benzenederivatives as done by Bolm et al. is risky, because of the change of the ortho-angle from 72° for the ferrocene to 60° for the benzenederivatives. These changes in the molecule geometry make it extremely difficult to derive the exact nature of the transition state from the one of the ferrocene.

32

To give the reader the opportunity to compare the results of the catalysis directly with the ligand structure, we do this without a detailed summary of the reactions. Further in this chapter, we will only show the catalyst and its results in the diethylzinc addition to benzaldehyde with the conditions as shown in Scheme [12] .

34

Lauterwasser, F. unpublished results.

35

Energy minimization of the corresponding conformers were done with Chem3D Pro and CS MOPAC Pro.

36

In a PM3 calculation of the conformers done by J. Rudolph with the program Spartan 2001 (Wavefunction Inc., California) the results of the MNDO-analysis werde confirmed, resulting in conformer A as the conformer with the lowest energy. Although the differences in energy by this method are only 5 kcal/mol and therefore a bit lower as with MNDO, they are still high enough to make any consideration of the conformer B superfluous. (1 kcal = 4.1868 kJ).

37

The energy differences of the µ-O structures are only between 1-3 kcal/mol.

45

Allyl alcohols are substrates for, e.g., cyclopropanation reactions, aziridination reactions, ene-reactions, epoxidations, dihydroxylations, methoxy selenations, iodo hydroxylations, brominations, and allylic substitution reactions.

52

Using these modifications, the aldehyde could be added in one portion, which is a significant practical improvement over the original Oppolzer protocol, where the aldehyde had to be added over a period of 20 min to obtain high enantioselectivities.

53

The absolute configuration was assigned by comparison of the optical rotation with the literature known compounds (S)-1-(4-chlorophenyl)hept-2-en-1-ol and (S)-1-phenylnon-2-en-1-ol, respectively, and the assumption of a unanimous reaction pathway for all other aldehyde substrates. The absolute configuration of the allyl alcohol products 51 is consistent with the induction observed in the diethylzinc addition to aldehydes with the ligands 5a and 6a.

61

Zn(OTf)2 is ten times more expensive than diethylzinc: Zn(OTf)2: 10 g 46.80 $ ( = 1 $/mmol), Et2Zn in hexane: 100 g (810 mmol) 80.90 $ (= 0.1 $/mmol). Prices taken from Acros Organics.

64

This behavior is untypical for mixed zinc species. The equilibrium could be influenced by the very low solubility of the dialkynylzinc reagents.

65

The clear supernant solution gives rise to the ethylation product in >80% yield.

73

Bräse, S.; Dahmen, S.; Vogt, H. to be submitted.