Direct Catalytic Enantio‐ and Diastereoselective Ketone Aldol Reactions of Isocyanoacetates

Abstract

Ac atalytic asymmetric aldol addition/cyclization reaction of unactivated ketones with isocyanoacetate pronucleophiles has been developed. Aquinine-derived aminophosphine precatalyst and silver oxide were found to be an effective binary catalyst system and promoted the reaction to afford chiral oxazolines possessing af ully substituted stereocenter with good diastereoselectivities and excellent enantioselectivities.The aldol reaction is one of the most powerful methods for the construction of b-hydroxy carbonyl compounds.[1] The importance of these building blocks,c ontained in aw ide variety of biologically relevant compounds,has promoted the development of several catalytic asymmetric methods for their production.[2] However, despite enormous progress in the aldol addition arena, its application to the synthesis of tertiary alcohols still remains am ajor challenge,p rincipally owing to al ack of reactivity and the fact that the differentiation of the enantiotopic faces is more difficult with ketone electrophiles than with the corresponding aldehydes. Furthermore,d eleterious side reactions,s uch as retro-aldol reactions,c an predominate when ak etone moiety is involved.[3] Although af ew catalytic asymmetric aldol reactions with unactivated ketones have been reported, [4] the development of new and efficient catalytic asymmetric methods to access chiral tertiary alcohols remains an important goal in modern asymmetric catalysis. [5] Along these lines,w er ecognized that the catalytic asymmetric ketone aldol reaction of isocyanoacetate pronucleophiles [6] could be as ynthetically powerful approach.Isocyanoacetate ester addition reactions to carbonyl [7] or imine electrophiles [8,9] directly afford the respective oxazoline or imidazoline heterocycles,which can be ring-opened under mild hydrolytic conditions to yield b-substituted a-amino acids.A lthough the catalytic asymmetric version of this reaction has been widely studied using aldehydes, [7] to date, no enantioselective example using unactivated ketones has been reported despite its potential to provide an elegant asymmetric route to a-amino acid derivatives possessing ac hiral tertiary alcohol in the b-position (Scheme 1).[10] In ar elated study,t he asymmetric aldol addition reaction of isothiocyanato esters and unactivated ketones,w hich afforded oxazolidinethione products with af ully substituted b-stereocenter,w as described.[11]Forpromoting and controlling various addition reactions, our group has developed an effective binary catalyst system comprising a" soft" metal ion, such as as ilver (I) ion, and ac inchona-derived aminophosphine precatalyst of type 1. This system promotes the highly diastereo-and enantioselective aldol reaction of isocyanoacetates with aldehydes, [7l] and Mannich reactions of aldimines [8e] and ketimines.[9a] The precatalyst is equipped with Brønsted basic and Lewis basic sites and also possesses ahydrogen-bond donor group located in the proximity of the chiral pocket that is created by the cinchona scaffold (Scheme ...

Recent Developments in Enantioselective Transition Metal Catalysis Featuring Attractive Noncovalent Interactions between Ligand and Substrate

“…In a closely related system, an enantioselective aldol reaction with ketone substrates was also achieved ( Figure 4 e). 38 Further examples using this methodology to construct challenging quaternary carbon centers have been described. For example, the group reported a catalytic asymmetric Mannich-type addition to N -diphenylphosphinoyl (DPP) protected imine electrophiles to form imidazolines bearing a quaternary carbon stereocenter at the β-position ( Figure 4 d).…”

Catalytic Atropenantioselective Heteroannulation between Isocyanoacetates and Alkynyl Ketones: Synthesis of Enantioenriched Axially Chiral 3‐Arylpyrroles

“…Thep rotodemetallation and [1,5]-H shift of C would then furnish the polysubstituted pyrrole 3.W ehypothesized that if R 2 was an aryl bearing ortho-substituents that could hinder the free rotation of the newly formed aryl-pyrrole bond, the resulting C3 aryl substituted pyrrole would be axially chiral. In connection with our interest in the isocyanide chemistry, [14] we became interested in developing ac atalytic enantioselective version of Yamamoto-de Meijere pyrrole synthesis.W e report herein that the reaction of 1 and alkynyl ketones 2 (EWG = COR 2 )i nt he presence of Ag 2 Oa nd aD ixon-type amino phosphine ligand 4 [15] is highly atropenantioselective to afford axially chiral 3-arylpyrroles 3 in good yields with excellent enantiomeric excesses (Scheme 1c).…”

“…Catalytic enantioselective addition of isocyanoacetate 1 to carbonyls, [15,16] imines, [17] electron-deficient alkenes, [18] and allenes [19] are well documented in the literature.Itis therefore interesting to note that enantioselective addition of isocyanoacetate 1 to alkynoates which constitutes the key step in our planned asymmetric synthesis of 3-arylpyrroles remains unknown at the outset of this work. Using Dixonsconditions developed for the aldol reaction of isocyanoacetate 1, [15] we began our studies by examining the reaction between ethyl aisocyanoacetate 1aand ethyl 3-(2-methoxynaphthyl-1-yl)propiolate 5a (Scheme 2). Performing the reaction of 1a and 5a at room temperature in the presence of Ag 2 O(10 mol %) and the chiral phosphine 4 (20 mol %), the reaction proceeded cleanly to afford the desired arylpyrrole 6a,a lbeit in moderate conversion (< 20 %) and low enantioselectivity.…”

“…To our delight, the reaction between 1a and 2a in chloroform in the presence of Ag 2 O( 10 mol %) and the phosphine 4 (20 mol %) proceeded smoothly to afford the axially chiral 3-arylpyrrole 3a (67 %y ield, 65 % ee,e ntry 1, Table 1), together with two side products 8 and 9 (Figure 1) resulting from the aldol reaction. [15] Thes olvent has ad ramatic effect on the outcome of the reaction (entries 1-8) and the higher enantioselectivity was observed in etheric solvents (entries [5][6][7][8]. Adding K 3 PO 4 accelerated the reaction without having significant impact on the enantioselectivity (entry 5v s. 9, Table 1).…”

“…As tereochemical model implicating a( Z)-enolate of aisocyanoacetate was proposed (Scheme 4). [15][16][17][18] Thec oordination of amide nitrogen, phosphorous,carbonyl oxygen, and the divalent isocyanide carbon atoms to silver would define the positioning of the two reactants.The additional hydrogen bond between the protonated quinuclidine and ketone oxygen could further refine the stereochemical environment 1C HCl 3 -R T6 76 5 2D CM -R T5 76 3 3T oluene -R T4 57 9 4E tOAc -R T4 67 7 5T HF -R T4 68 0 6D ioxane -R T3 57 9 7E t 2 O-RT 37 85 8T BME -R T4 28 7 9 [d] THF -R T5 57 8 10 [d] THF 4 MS RT 76 80 11 [d] THF 4 MS 06 48 7 12 [d] TBME 4 MS 01 49 1 13 [d] THF/TBME(1:1) 4 MS 05 38 9 14 [d] THF/TBME (1:4) 4 MS 04 59 2 15 [d] THF/TBME (1:4) 3 MS 05 09 0 16 [d] THF/TBME (1:4)…”