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An efficient and operationally simple strategy for the stereoselective synthesis of novel C-3 functionalized 3-sulfonyl-β-lactam heterocycles is described. The C-3 functionalized 3-phenyl/benzylsulfonyl-β-lactams 3/3′, 5/5′ has been synthesized via Michael addition using different Michael acceptors on trans-3-phenyl/benzylsulfonyl-β-lactams 2(a–f) using K2CO3as a base and acetonitrile/DMF as solvents. The reaction furnished exclusively cis-β-lactam adducts 3(a–r) using sterically less hindered Michael acceptors. Further, the effect of steric bulk and chiralilty of Michael acceptors was explored to achieve target C-3 functionalized β-lactams 3(s-u)/3′(s-u) and 5(a–c)/5′(a–c). The structural and stereochemical analysis of novel β-lactams were carried out using FT-IR, NMR (1H,13C,1H-1H COSY,1H-13C COSY and13C DEPT-135), elemental analysis (CHNS), mass spectrometry (EIMS and LCMS) in representative cases and single crystal X-ray crystallographic studies (3e). The cis or trans configuration of the Michael acceptor (E) at C-3 was assigned with respect to C4-H.

Enantiopure 4-oxo-pipecolic acid derivatives were obtained by double asymmetric induction aza-Diels-Alder reactions between chiral glyoxylate N-phenylethylimines and Danishefsky's diene mediated by zinc iodide. The key to success was the use of iminoacetates possessing two chiral auxiliaries, N-(S)- or N-(R)-1-phenylethyl and (-)-8-phenylmenthyl or (+)-8-phenylneomenthyl. Adducts were formed in good yields (78-81%), with complete regioselectivity and high diastereoselectivity (87-96%). The absolute configuration of the adducts formed was unequivocally assigned through NMR, specific optical rotation and X-ray data of appropriated derivatives. These cycloadducts can serve as precursors for bioactive piperidinic azasugars and pipecolic acid derivatives.

A structural study of three synthesized stereoisomeric oximes, (-)-8-phenylmenthyl glyoxylate oxime (8-PMGO), (+)-8-phenylneomenthyl glyoxylate oxime (8-PnMGO), and (-)-8-phenylisoneomenthyl glyoxylate oxime (8-PinMGO), was performed by means of variable temperature 1H NMR spectroscopy, X-ray crystallography, and ab initio calculations. It was found that in 8-PMGO a conformation where the phenyl and oxime moieties are stacked is significantly favored, whereas in the other stereoisomers this preference was not so evident. The conformational differences found between the isomers were used to rationalize the outcome of the reaction (simultaneous 1,3-cycloaddition and aza-Diels-Alder reaction) between the referred oximes and cyclopentadiene, in which the stereoselectivity was evaluated and found to be nicely reproduced by a simple conformational analysis. The global results indicate that the stereoselectivity of the studied oximes, a bit higher for 8-PMGO, originates from their particular conformational distribution, in which the phenyloxime aromatic interaction plays a decisive role.

The cycloaddition between protonated glyoxylate imines possessing two chiral auxiliaries, N-(S)- or N-(R)-1-phenylethyl and (-)-8-phenylmenthyl or (+)-8-phenylneomenthyl, and cyclopentadiene is described. The absolute configuration of all adducts formed was unequivocally assigned through NMR, specific optical rotation, and X-ray data of appropriated derivatives. Experimental results confirm the highly exo-selectivity for these aza-Diels-Alder reactions, single adducts being obtained from combinations of (8PM)-(R-PEA) and (8PNM)-(S-PEA).

The cyclic somatostatin analogue cyclo[Pro1-Phe 2-D-Trp3-Lys4-Thr5-Phe6] (L-363,301) displays high biological activity in inhibiting the release of growth hormone, insulin, and glucagon. According to the sequence of L-363,301, we synthesized a number of cyclic hexa- and pentapeptides containing nonnatural α- and β-amino acids. The N-fluorenylmethoxycarbonyl protected cyclic β-amino acid [1S, 2S, 5R]-2-amino-3,5-dimethyl-2-cyclohex-3-enecarboxylic acid (cβAA), for the replacement of the Phe6-Pro1 moiety of L-363,301, was synthesized in two steps by an enantioselective multicomponent reaction using (-)-8-phenylmenthol as a chiral auxiliary. The resulting peptide cyclo[cβAA1-Tyr2-D-Trp 3-Nle4-Thr(Trt)5] (Trt = triphenylmethyl) shows high antiproliferative effects in an in vitro assay with A431 cancer cells. The same peptide without the Trt group does not reveal any biological activity, whereas L-363,301 and closely related hexapeptides show only minor activity. By comparison of the solution structure of cyclo[cβAA1-Tyr 2-D-Trp3-Nle4-Thr(Trt)5] with the structure of L-363,301, a nearly perfect match of the βII′-turn region with D-Trp in the i + 1 position was observed. The cyclic β-amino acid cβAA is likely needed for the bioactive conformation of the peptide.

The diamination of certain olefins bearing electron-withdrawing substituents proceeds with well-defined bisimido and trisimido complexes of osmium. The products are obtained as osmaimidazolidines which are of unprecedented stability with regards to olefin functionalisation. Osmium complexes from related dihydroxylation or amino-hydroxylation are significantly less stable and thereby promote catalytic reactions. This difference in reaction profile has been investigated and chiral osmium heterocycles obtained from olefin difunctionalisation were characterised by X-ray analysis for the first time. Kinetic studies on the reaction profile have also been carried out. An asymmetric version of this reaction is based on chiral non-racemic auxiliaries and leads to diastereomerically enriched osmaimidazolidines with up to 90% de. This sequence represents the first asymmetric diamination of olefins. Attempts on the use of chiral ligands for direct asymmetric diamination as well as the consequences of osmaimidazolidine properties for a catalytic reaction are discussed.

Asymmetric Diels-Alder reactions with 2H-azirines as dienophiles have been studied. Diastereoselective reactions with an enantiopure azirine 1b, bearing a chiral auxiliary, gave substituted bi- and tricyclic tetrahydropyridines in high yield and stereoselectivity, under the influence of a Lewis acid. The novel enantioselective [4+2] cycloaddition reaction of 3-benzyl-2H-azirine carboxylate with cyclopentadiene was investigated with various chiral Lewis acid complexes and provided the corresponding tetrahydropyridines in moderate to low yield and enantioselectivity.

The silylated telluronium allylide 4, generated in situ from the corresponding telluronium salt in the presence of LiTMP, reacted with (-)-8-phenylmenthyl α,β-unsaturated esters to afford trans-2-silylvinyl-trans-3-substituted cyclopropyl esters with high diastereoselectivity in high yields. The absolute configuration was determined by chemical transformation. A mechanistic rationale is proposed.

A number of mixed ligand η6 arenechromium carbonyl complexes have been prepared and investigated for their ability to effect electronic modulation of arene chemistry. In the case of an aniline-derived system, the arenechromium carbonyl complex is able to modulate the inductive capacity of the aniline nitrogen atom and thus, regulate its anchimeric ability. In the case of 8-phenylmenthol and benzyloxazolidinone derivatives, modulation of arene π basicity is achieved, and results suggest that important vinylarene π-π interactions exist in acrylate derivatives of these chiral auxiliary systems.

An asymmetric Diels-Alder reaction between ketene acetal 2 and the 3-nitropropenoate 10, derived from (-)-8-phenyl-menthol, affords the optically pure adduct 15, which can be converted into either enantiomer of calicheamicinone 1.

(1R,4aS,8S,8aS)-8-(5'-Methoxy-2'-methylphenyl)-8-methyldecahydro-1-nap hthalenol 3a is a highly efficient chiral auxiliary in the Diels-Alder addition of its acrylate ester 5 and in the DIBAL-H and Grignard reactions of its phenylglyoxylate ester 7.

The nickel(0)-catalyzed codimerisation of methylenecyclopropane 1a or 2,2-dimethylmethylenecyclopropane (1b) with the chiral derivatives of acrylic acid 2a-2f leads to the optically active 3-methylenecyclopentanecarboxylic esters 3a, 3c-3f, 4a, and 4c, or amides 3b and 4b in good yields.The diastereomeric excess accesible depends on the steric demand of the chiral auxiliaries, de values up to 98percent can be achieved.Some improvements of the preparation of optically pure auxiliaries are also described.

We recently communicated (J.K.Whitesell, A.Bhattacharya, D.A.Aguilar and K.Henke, J.Chem.Soc.Chem.Commun. 989 (1982)) a highly efficient and effective method for the control of absolute stereochemistry through asymmetric induction in the ene reaction the chiral glyoxylate 1 with alkenes.We now have accumulated sufficient information on this process in terms of both its mechanistic details as well as its scope and applicability to a variety of situations that warrants a more complete presentation of these reactions.