Mannich cyclization, diastereoselective

Davis and coworkers have exploited the reactions of chiral JV-sulfinyl-amines in the synthesis of numerous alkaloids. Their route to (—)-epimyr-tine (1098) began with the diastereoselective addition of the enolate anion of methyl acetate to the (Ss)-(4-)-sulfmimine (+)-1128, from which the (Ss,S)-p-amino ester derivative (- -)-1129 was obtained in better than 97% de (Scheme 144). After Claisen condensation of 1129 with ierf-butyl acetate, the sulfmyl group was removed from the resulting P-keto ester (4-)-1130 by treatment with acid, the desuhinylated product then undergoing Mannich cyclization with acetaldehyde. The relative stereochemistry of the sole product, 2,6-a5-disubstituted piperidine (4-)-1131, was corroborated by nOe experiments, which indicated that no epimerization at the stereogenic centers had occurred. After hydrolysis and decarboxylation of... 

Padwa A, Danca MD, Hardcastle KI, McClure MS. A short diastereoselective synthesis of the putative alkaloid jamtine, using a tandem Pummerer/Mannich cyclization sequence. J. Org. Chem. 2003 68(3) 929-941. 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

Optimization of the previously reported Mannich-type reaction of trimethyl (pent-2-en-3-yloxy)silane with the sulfone Is derived from phenyl acetaldehyde (Table 5, entry 11) led to the corresponding (3-amino ketone in a good yield with moderate diastereoselectivity (2 mol% Bi(0Tf)3-4H20, yield = 84%, 24v/24v syn/anti = 72 28) (Scheme 8). Reduction of the major diastereoisomer 24v with lithium tri-ferf-butoxyaluminohydride afforded 25 as the only one diastereoisomer. Further cyclization of the latter with NaH afforded 4-benzyl-6-ethyl-5-methyl-l,3-oxazinan-2-one 26. The relative configuration of the six-membered carbamate was established as cis-cis by NMR analysis. 

Reductive coupling of acrylates 521 and imines in the presence of iridium provides azetidin-2-ones bearing aromatic, alkenyl, and alkynyl side chains, with high diastereoselection (Equation 213) <2002OL2537>. The reaction has been proposed to occur through a reductive Mannich addition-cyclization mechanism. 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

Reaction with inUnes derived from a-amino esters. In the presence of ZnCh (1 equiv.) the imine 1 derived from L-valine reacts with this diene to form 6-substituted 2,3-didehydro-4-piperidinones 2 and 3 with high diastereoselectivity (92 8). This reaction is believed to involve a Mannich reaction to form a, which undergoes Michael cyclization to form 2 and 3 in the ratio 92 8. 

Remuson and coworkers reported that highly diastereoselective synthesis of 2,6-cis-disubstituted-4-methylenepiperidines based on a Mannich type intramolecular cyclization of allylsilane [37]. Reaction of p-aminohydroxysilane 116 with carbonyl derivative in the presence of TFA in a mixture of H2O-THF (1 1) led to 4-methylenepiperidine 117. Oxidation with osmium tetraox-ide in the presence of Na3H3lOe in AcOH led to piperidin-4-one followed by the stereoselective reduction with NaBH4 afforded (- -)-241D (13) and its C-4 epimer 118 in a ratio of 83 17 (Scheme 20). 

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