Amino acids spirocyclic

The regio- and stereochemical outcome of the intermolecular 1,3-dipolar cycloaddition of an azomethine ylide generated by the decarboxylative condensation of an isatin with an a-amino acid was unambiguously determined by a single-crystal X-ray study of the spirocyclic heterocycle 49 (R1 =4-Br, R2 = H, X = CH2) <1998TL2235>. 

Tetramethylpiperidinomethyltrimehtoxysilane 816 and the corresponding 2,2,6,6-tetramethyl-piperidinomethylsilane 817 are the precursors for another family of spirocyclic silicates 818-824, which are accessible upon reaction with a-hydroxy acids, a-amino acids, o-benzene dithiol, and dithioglycol (Scheme 109).821 822... 

The first cyclization of a-hydroxyalkoxyallenes goes back to the pioneering experiments of Brandsma, Hoff and Arens, who found that dihydrofuran derivatives 102 are formed by treatment of 101 with KOtBu in DMSO (Scheme 8.26) [12c], This reaction protocol was successfully applied by others [61, 63, 64, 80-83], for example in the preparation of spiro compound 104 (Eq. 8.19) [83] and in the cyclization of 64 leading to a-amino acid-derived dihydrofurans 105 (Scheme 8.27) [61, 63], Acidic hydrolysis of dihydrofurans furnished 3(2H)-dihydrofuranones, which could be used again as carbonyl components in the repetitive addition of lithiated methoxyal-lene 42. This concept was employed in syntheses of racemic [82] and enantiomeri-cally pure [64] primary helical spirocycles. 

The diastereofacial selective imine-ene reactions with a-imino esters prepared from (—)-8-phenylmenthyl glyoxylate have provided an efficient entry to the asymmetric synthesis of a-amino acids, and a Lewis acid-mediated intramolecular imine-ene reaction has been used for the key spirocyclization step in a recent synthesis of (—)-perhydrohistrionicotoxin. Asymmetric azo-ene reactions have been effected using the chiral azo-enophile, di-(—)-(lR,2S)-2-phenyl-l-cyclohexyldiazenedicarboxylate. ... 

Since the migrating group retains its configuration, the use of enantiomerically enriched oximes provides a direct entry to enantiomerically pure lactams. These lactams may be used as a key building block for the synthesis of diverse compounds. Westermann and Gedrath applied this strategy to the stereoselective synthesis of enantiomerically pure o-.a-disubstituted a-amino acids (equation 135), bicyclic lactams and the spirocyclic framework of Histrionicotoxins (equation 136). 

Benkovic and co-workers also isolated spirocyclic 2-amino-4(5/7)-oxazolones during their studies on pterin-dependent amino acid hydroxylases (Scheme 6.24). Reaction of 91 with 0-methyl hydroxylamine or semicarbazide at pH 4.8 yielded 92a and 92b, respectively. The authors showed that 92 does not simply result from reaction of the corresponding oxazolidinedione with either reagent. Further, by using H2 0 as the solvent they demonstrated that there was no incorporation into the product. Two different but precedented mechanisms were proposed to account for this rearrangement. The stereochemistry of 92b was confirmed by single-crystal X-ray. 

In addition, there are many important nonantibiotic uses of 2-azetidinones in fields ranging from enzyme inhibition [15-21] to gene activation [22], Systems containing one carbon atom common to two rings, spirocyclic compounds, represent an important structural organization. Spirocyclic p-lactams (Fig. 3) behave as p-tum mimetics [23-26] as well as enzyme inhibitors [27, 28], they are precursors of a,a-disubstituted p-amino acids [29-32], and the spiranic p-lactam moiety is present in chartellines and chartelamides [33-38], a family of marine natural products. Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C have been described [38],... 

In conclusion, the CAI activity of spiro-(3-lactams, their antiviral and antibacterial properties, their potential as efficient (3-tum nucleators and (3-tum mimetics, and their application as synthons for a,a-disubstituted (3-amino acids motivated synthetic and medicinal chemists to design novel spirocyclic (3-lactams. Several approaches to the stereoselective synthesis of spiro-(3-lactams have been described in this review. However, ketene-imine cycloaddition (Staudinger Reaction) shows much versatility for the access to diversely functionalized spiro-(3-lactams. In addition, we have developed a facile route to novel spiro-(3-lactams by using... 

Merck has used a diastereoselective double RCM in the synthesis of NK-1 receptor antagonists (Scheme 28.3).33 Previously reported studies by the same group showed that amino acid-derived tetraene 12 smoothly underwent ring closure in a diastereoselective fashion to give the corresponding spirocyclic compounds 13 in excellent diastereoselectivity.34 An extension of this work to the tetraene system derived from phenylglycine gave the desired spirocycle in 86% yield and 70% ds. 

R,R-diphenyl ethylene carbonate CR,R-DPEC)) with a racemic zirconaaziridine. (C2-symmetric, cyclic carbonates are attractive as optically active synthons for C02 because optically active diols are readily available through Sharpless asymmetric dihydroxylations [67].) Reaction through diastereomeric transition states affords the two diastereomers of the spirocyclic insertion product protonolysis and Zr-mediated transesterification in methanol yield a-amino acid esters. As above, the stereochemistry of the new chiral center is determined by the competition between the rate of interconversion of the zirconaaziridine enantiomers and the rate of insertion of the carbonate. As the ratio of zirconaaziridine enantiomers (S)-2/(R)-2 is initially 1 1, a kinetic quench of their equilibrium will result in no selectivity (see Eq. 32). Maximum diastereoselec-tivity (and, therefore, maximum enantioselectivity for the preparation of the... 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cycloaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the l-oxa-1,3-butadiene moiety in 2-816. The formed spirocyclic ketones 2-818/2-819 can be used in natural products synthesis and in medicinal chemistry [410]. They have also been used in the preparation of exotic amino acids these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

Decarboxylative condensation of N-unsubstituted tx-amino acids with benzaldehyde as an aromatic aldehyde requires somewhat harsher conditions. Benzaldehyde and oc-amino acids are heated under reflux in DMF together with N-phenylmaleimide. The azomethine ylides 108 generated can be captured as mixtures of several stereoisomeric cycloadducts (84CC180). 1-Aminocyclopentane-l-carboxylic acid undergoes a similar reaction with pyridine-3-carbaldehyde in the presence of N-phenylmaleimide to afford a spirocyclic cycloadduct, the maleimide cycloadduct of azomethine ylide 109 (84CC182). 

The enantioselective alkylation of A-protected a-amino esters has been studied with many chiral catalysts, including spirocyclic ammonium salt 10A, while (lOB) containing two binaphthyl components is an effective mediator for alkylation of protected glycine under phase-transfer conditions.p-f-Boc-amino acid derivatized with (-l-)-pseu-doephedrine enables enantioselective alkylation of the ensuing amides. - Note the enolate derived from 11 remains chiral, alkylation products are produced in high ee. ... 

Tri- and tetra-peptide analogues incorporating an a-atnino acid at the anomeric position, e.g. 33, were synthesized by way of a novel oxidative ting contraction of 2-amino-2-deoxy-heptonic acid derivative 31 to give heptulosonic acid glycosylamine 32 and its anomer (Scheme 6). The spirocyclic diketopiperazine 35 was obtained from 34 it could be 0-deprotected under acidic conditions then anomerized to the thermodynamically favoured C-2 q>imer with strong base. See also reference 3 for a general route to anomeric a-amino acids. 

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