anti‐Selective Asymmetric Michael Reactions of Aldehydes and Nitroolefins Catalyzed by a Primary Amine/Thiourea

Abstract

In the last decade, remarkable progress has been made toward direct catalytic asymmetric assembly of simple and readily available precursor molecules into stereochemically complex products under operationally simple and environmentally friendly conditions. [1] In enamine catalysis, significant effort has focused on understanding the origin of diastereo-and enantioselectivity in organocatalysis. These studies have facilitated the design of syn-selective aldol and anti-selective Mannich reactions not originally addressed by organocatalytic methods. [2][3][4][5] The organocatalytic Michael reaction is often regarded as one of the most efficient and broadly applicable carbon-carbon bond-forming reactions known because a wide variety of acceptors can be employed and high stereoselectivity has been realized. [6] Although a large number of reports on the organocatalytic Michael reaction of aldehydes have been published, to the best of our knowledge, all of these reactions are syn selective. [7] Several studies, however, have reported success in the anti-selective organocatalytic Michael reaction of ketones. [8] Herein, we report the first highly anti-selective asymmetric Michael reactions of aldehydes and nitroolefins using a strategy designed to control the configuration of the reacting enamine.The predominant stereochemical outcome of the enamine-based Michael reaction was first explained in the classic studies of Seebach and co-workers. [9] Seebach deduced that high syn selectivity can be explained by an acyclic synclinal transition-state model (Scheme 1 a). [9a] In this transition state, the thermodynamically stable E enamine reacts with E nitroolefins in a synclinal arrangement, in which the actual donor and acceptor atoms are situated close to each other (see NO 2 and NR'R'' in Scheme 1 a).We have explored two routes for control of the overall diastereoselectivity of organocatalytic enamine reactions: 1) controlling the face selectivity of the reactive enamine to affect anti-Mannich reactions [2] and 2) controlling the E/Z configuration of the reactive enamine to affect anti-Mannich and syn-aldol reactions (Scheme 1 b). [3] For the anti-Michael reactions described herein, we have taken the latter approach.The classic organocatalytic Michael reaction of aldehydes and ketones utilizes pyrrolidine-based catalysts which react via E-enamine intermediates with nitroolefins and other Michael acceptors in synclinal transition states to provide predominately syn-configured Michael products. The Z-enamine intermediate formed using secondary amine catalysts are significantly less favored. Movement from a secondary amine catalyst to a primary amine catalyst provides steric latitude which enables Z-enamine formation with ketones. A caveat, however, is that Z-enamine formation from aldehydes is likely to be more difficult than that from ketones since the E-configured enamine derived from an aldehyde minimizes steric conflicts between the catalyst and Scheme 1. a) Synclinal transition-state model, b) anti-Mannich and synaldo...

Organocatalytic asymmetric assembly reactions for the syntheses of carbohydrate derivatives by intermolecular Michael-Henry reactions

“…Heteroaromatic substrates were also good candidates for this reaction: 2-(2-Nitrovinyl)thiophene 2f was converted to the product 6f in good yield and selectivity (entry 6). Enantiomeric excess of products 6 was comparable to that of Michael products 4 we reported previously (24). When nitrodiene 2g was used, alkenyl-substituted dideoxytalose derivative 6g formed with acceptable ee (entry 7).…”

“…Stereoselectivity at C2 and C3 positions is explained by our anti-Michael reaction design as reported previously (24). Meanwhile, asymmetric induction at C4 and C5 positions occurred in the consecutive Henry reaction catalyzed by achiral bases.…”

“…Recently, we reported highly selective anti-Michael reactions of (tert-butyldimethylsilyloxy)acetaldehyde 1 to form γ-nitroaldehydes 4 catalyzed by primary amine-thiourea 3 (24). This type of catalyst provides for enamine-based activation of the aldehyde while enforcing configurational control of enamine geometry.…”

Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis

“…Interestingly, the observed sense of relative stereoinduction is not common in the corresponding enamine-catalyzed Michael addition of carbonyls to nitroalkenes, which generally leads to a syn-relationship (55,56).…”

Primary Amino Acid Lithium Salt-Catalyzed Asymmetric Michael Addition of Carbon Nucleophiles to Enones

“…As for a silyl group, the triisopropylsilyl (TIPS) group was chosen as a protective group of the hydroxyl group of L-serine, since Ser(O-TIPS)-OLi (1d) gave a better enantioselectivity than did the TBS-protected catalyst 1a and also gave a much better yield of 4a than did a tert-butyldiphenylsilylated catalyst, Ser(O-TBDPS)-OLi (1e) ( Table 2, entries 1, 4 and 5). Finally, we examined the effects of alkali metals of Ser(O-TIPS)-OM (1f-j) and found that the lithium salt catalyst 1d gave the best enantioselectivity as was found in our previous studies (Table 2, entries 4, 6-10) [33, [41][42][43][44]. Since the Michael adduct 4a was obtained with high enantioselectivity in a moderate yield, catalyst 1d was chosen as a catalyst.…”