Chiral superbase organocatalysts

Chiral Iminophosphoranes—An Emerging Class of Superbase Organocatalysts

Referred to: Krawczyk et al., 2015

• The application of organosuperbases, namely cyclopropenimines, guanidines, and iminophosphoranes, • particular, asymmetric organocatalysis in which simple chiral organic molecules are employed as promoters of various enantiodifferentiating transformations • chiral Brønsted bases ocatalytic cycle of these reactions proceeds via formation of the intimate ion pair with the chiral cation being responsible for the stereochemical reaction outcome • cyanohydrine formation employing simple cinchona alkaloids as catalysts.

• The main challenge related to this issue was the basicity of the catalyst as too strong an organic base can lead to the racemization of the enantiomerically enriched product formed. • catalyst turnover was problematic as for the very strong bases protonation can become irreversible. • Chiral bases with the guanidine, cyclopropenimine, and iminophosphorane structural motifs incorporated turned out to be a solution to the above-stated challenges, opening new opportunities in asymmetric synthesis (Scheme 1).

Scheme 1. From traditional Brønsted base catalysis to organosuperbases in organocatalysis. pKBH+ (MeCN) values of selected tertiary amines and organosuperbases are given.

Iminophosphorane • Iminophosphoranes constitute a group of very strong nonionic bases. • chiral iminophosphoranes can be classified into three main groups based on their structure (Scheme 2).

● Type 1 ○ The compounds with the iminophosphorane phosphorus atom being a central atom of the spirocyclic system ○ is available either directly as the corresponding iminophosphoranes or formed in situ from the corresponding salts in the presence of strong inorganic bases by N-H deprotonation. ○ precursor ■ Are used for: ● salts

● Type 2 ○ Bifunctional systems possessing an additional functional group capable of H-bonding interactions. ○ allows for the independent activation of both pronucleophile (via deprotonation) and electrophile (via H-bonding interactions). ○ it positions the two reactants in a close proximity allowing for a smooth and selective conversion of the reactants.

● Type 3 ○ stereodifferentiating group is present in the amide moieties of the catalysts (P-N single bonds). ○ The basicity of these systems was estimated approximately as pKBH+ =35–37. ○ Disappointingly, no information on their applications as chiral bases in asymmetric synthesis exists in the literature.

The authors proposed that the reaction was initiated by the formation of the iminophosphorane 7 by the N-H deprotonation of the salt 3 by potassium tert-butoxide (Scheme 5). Subsequent deprotonation of nitroalkane 5 with iminophosphorane 7 thus obtained yielded nitronate anion 8 that was involved in the interactions with the phosphonium cation 3 by a double H-bonding. In such a manner a chiral environment of the reaction was provided and the addition of 5 to aldehyde 4 to give 6 proceeded in a highly enantio- and diastereoselective fashion.

Superbases for Organic Synthesis Referred to: Ishikawa, 2009 introduction ● imine function (=NH) to the a-carbon of amines affords more basic amine species, amidines, which correspond structurally to amine equivalents of carboxylic esters (carboxylic acid imidates). Älä ota näitä tarkemmin esitkseen

● (The corresponding phosphonium salts formed by protonation on the phosphorus atom are stabilized through effective trans-annular N-P bond formation, to which the fourth nitrogen atom located at the alternative bridge head position participates;) ● Organic chemists often use the words ‘ strong’ or ‘ super’ as the intensive expression of basic property; however, the criteria are ambiguous and dependent upon the chemists who use the expression. ● Caubere: “The term “superbases” should only be applied to bases resulting from a mixing of two (or more) bases leading to new basic species possessing inherent new properties. The term “superbase” does not mean a base is thermodynamically and/or kinetically stronger than another, instead it means that a basic reagent is created by combining the characteristics of several different bases.” -> superbases in general applies to ionic metalcontaining bases acting under irreversible proton abstraction.

● One of important and beneficial characteristics of an organic base, especially from the viewpoint of environmental aspects, is the ability of recycling use in repeated reaction, in which reversible proton transfer occurs between the base and a substrate, an acidic counterpart. Guanidines ● Guanidines, which carry three nitrogen functions (one amine and two imines) and correspond to amine equivalents of ortho esters (carbonimidic diamides), show the strongest Brønsted basicity among these amine derivatives ○ basicity is comparable to the hydroxyl ion (OH-) ○ categorized as organic superbases [1] due to the resonance stability of their conjugated acids (s93), are expected to catalyse various types of baseparticipated organic reactions ● typical and fundamental guanidine 1,1,3,3-tetramethylguanidine (or N,N,N0,N0-tetramethylguanidine; TMG) ● ‘ Barton’ s bases =sterically-hindered organic bases ● Bicyclic guanidines 3, 1,5,7-triazabicycle[4.4.0]dec-5-ene (TBD) and the N-methyl analogue (MTBD) were introduced by Schwesinger [4] (Figure 4.1). ● classified into two types of reactions: catalytic and stoichiometric

s94 three types, dependent upon whether the guanidinyl function is incorporated into ring systems or not.

Ei näitä! 3.4 Amidinium Salts: Design and Synthesis 3.4.1 Catalyst A novel C2-chiral bis(amidinium) salt can be synthesized from 5-(tert-butyl)isophthalic acid. The salt [tetrakis(3,5-bistrifluoromethylphenyl)borate (TFPB)] contributes to not only rate acceleration but also asymmetric induction in the Diels–Alder reaction of 1-vinyl- 3,4-dihydronaphthalene and cylopentendione, owing to hydrogen bond mediated association of chiral auxiliary with dienophile [91] (Scheme 3.NaN). s82

s83

4.3 Guanidines as Synthetic Tools (s99) addition, catalytic reaction

s101

Reference:

Ishikawa, T., 2009. Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes and Related Organocatalysts. https://doi.org/10.1002/9780470740859

Krawczyk, H., Dzięgielewski, M., Deredas, D., Albrecht, A., Albrecht, Ł., 2015. Chiral Iminophosphoranes - An Emerging Class of Superbase Organocatalysts. Chem. - A Eur. J. 21, 10268–10277. https://doi.org/10.1002/chem.201500481