The chemistry of lithium enolates is used to demonstrate that complex structures held together by noncovalent bonds (“supramolecules”) may dramatically influence the result of seemingly simple standard reactions of organic synthesis. Detailed structural data have been obtained by crystallographic investigations of numerous Li enolates and analogous derivatives. The most remarkable features of these structures are aggregation to give dimers, tetramers, and higher oligomers, complexation of the metal centers by solvent molecules and chelating ligands, and hydrogen-bond formation of weak acids such as secondary amines with the anionoid part of the enolates. The presence in nonpolar solvents of the same supramolecules has been established by NMR-spectroscopic, by osmometric, and by calorimetric measurements. The structures and the order of magnitude of the interactions have also been reproduced by ab-initio calculations. Most importantly, supramolecules may be product-forming species in synthetic reactions of Li enolates. A knowledge of the complex structures of Li enolates also improves our understanding of their reactivity. Thus, simple procedures have been developed to avoid complications caused by secondary amines, formed concomitantly with Li enolates by the common methods. Mixtures of achiral Li enolates and chiral Li amides can give rise to enantioselective reactions. Solubilization by LiX is observed, especially of multiply lithiated compounds. This effect is exploited for alkylations of N-methylglycine (sarcosine) CH2 groups in open-chain oligopeptides. Thus, the cyclic undecapeptide cyclosporine, a potent immunosuppressant, is converted into a THF-soluble hexalithio derivative (without epimerization of stereogenic centers) and alkylated by a variety of electrophiles in the presence of either excess lithiumdiisopropyl amide or of up to 30 equivalents of lithium chloride. Depending on the nature of the LiX additive, a new stereogenic center of (R) or (S) configuration is created in the peptide chain by this process. A structure-activity correlation in the series of cyclosporine derivatives thus available is discussed.

Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C‐Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures

The first enantioselective aldehyde α-benzylation using electron-deficient aryl and heteroaryl substrates has been accomplished. The productive merger of a chiral imidazolidinone organocatalyst and a commercially available iridium photoredox catalyst in the presence of household fluorescent light directly affords the desired homobenzylic stereogenicity in good to excellent yield and enantioselectivity. The utility of this methodology has been demonstrated via rapid access to an enantioenriched drug target for angiogenesis suppression.

Enantioselective α-benzylation of aldehydes via photoredox organocatalysis.

The Michael-additions of aliphatic, alicyclic, and arylsubstituted nitroolefins and enamines lead to γ-nitroketones 3 in good chemical and excellent (> 90%) diastereomeric yields (see Table 1).



The known threo-configuration of one type of adducts 3 (entries 8, 10, and 11 of Table 1) can be arrived at by assuming the approach 8 of the Michael-acceptor and -donor; the reaction follows a topological rule, which is formulated and which is applicable to such diverse reactions as the diene synthesis, cyclopropanations, carbonyl olefinations and methylenations, aldol- and nitroaldol-type additions, as well as additions of lithium, boron, and chromium derivatives to aldehydes (see 9, 10, 11, and Table 2).

Synthesis of Open-Chain 2,3-Disubstituted 4-nitroketones by Diastereoselective Michael-addition of (E)-Enamines to (E)-Nitroolefins. A topological rule for C, C-bond forming processes between prochiral centres. Preliminary communication

uous specification of the steric course and the product configuration of diastereoselective reactions. The reflection-invariant relative topicity of approach of reactants is defined as like {Ik) and unlike (ul) if the corresponding descriptor pairs are Re*,Re*. or R*,Re*, and Re*,Si* or R*,Si*, respectively. The descriptor pair notations (Ik and uc) of reactants disclose related steric courses of reactions more often than do the relative configurations of their products, for which the configurational notation I= R*,R* and u= R*,S* is proposed. The advantage of specifying the relative topicity is demonstrated by means of a series of recent examples of importance to the synthetic organic chemist taken from the literature and from our own work. 1. Introduction-The Problem Complex natural products such as macrolides, ionophores, and related compounds have recently become target molecules for synthetic organic chemists[’]. The often formidable array of asymmetric carbon atoms in the structures of these compounds[21 has stimulated the development of highly stereoselective asymmetric syntheses. Foremost amongst these are the ald~l[~-~], nitr~aldoF“~], and Michael additions[81. In all these reactions two planar trigonal carbon atoms are linked together to create a pair of asymmetric tetrahedral carbon atoms [route (a) in Scheme 11. Stereoselective additions to 01efins[~] and to trigonal carbon atoms a to an asymmetric carbon [routes (b) and (c), respectively, in Scheme 11, give the same type of products 1L7.9-121

The Unambiguous Specification of the Steric Course of Asymmetric Syntheses

Synthesis of optically active pheromones

Preparation for erythro-2-Hydroxy-succinic Acid Derivatives from Malic Esters



As a contribution to the much discussed diastereoselective synthesis of enantiomers of open chain compounds, > 90% erythro-selective branching of malic esters by alkylation of the doubly deprotonated derivative 2 (alkoxide-enolate) with methyl, allyl, and benzyl halides in THF at −78° ( 3aa, 3ba, 3bb, 3bc, Table 1) is described. A second alkylation ( 4) and addition of 2 to acetone ( 5) are also possible. Cyclization of 2 to the enantiomerically pure trans-epoxides 6 is achieved by treatment with iodine. Cuprate opening of 6b furnishes the same product 3ba obtained from the methylation of 2b, establishing the configurational assignment.

Herstellung von erythro-2-Hydroxybernsteinsäure-Derivaten aus Äpfelsäureester. Vorläufige Mitteilung

Enantiomerically Pure Synthetic Building Blocks with Four C-Atoms and Two or Three Functional Groups from β-Hydroxy-butanoic, Malic, and Tartaric Acid

The pool of chiral, non-racemic electrophilic building blocks, which are available from simple natural products in both enantiomeric forms is enlarged by the epoxides 3, 5, and 10, by the tosylate 12a, and by the aldehydes 18 (cf. symbols A-D, 14, and Scheme 1). Key steps of the conversions leading from hydroxyacids to the building blocks are: epoxide-opening by triethylborohydride (1 → 2a) and tosylate reduction (12a → 12b); the Mitsunobu inversion (2a → 4a); the reduction of (R, R)-tartaric ester to (R)-malic ester by NBS (N-bromosuccinimide) opening of the benzaldehyde acetal 8 and tin hydride reduction (6c → 7c); the enantiomer enrichment of optically active ethyl β-hydroxy-butanoate through the crystalline dinitrobenzoate 21b. Detailed procedures are given for large scale preparations of the key intermediates. The enantiomeric purities of the building blocks are secured by correlations.

Doppelt und dreifach funktionalisierte, enantiomerenreine C4‐Synthesebausteine aus β‐Hydroxybuttersäure, Äpfelsäure und Weinsäure

(+)-Pantolactone1 (13) has been synthesized from (−)-(S)-dimethyl malate (7) in 40% yield in a short sequence involving double alkylation (7 10 11), selective hydrolysis (11 12) and subsequent reduction (12 13). Through variation of the alkylating agents and preparation of the two diastereomeric 3-ethyl-3-methyl malates 14 and 15 it was possible to show that the diastereoselectivity of the second alkylation step is brought about by preferential attack from the Re-face of the critical enolate (9, see also Scheme 1). This knowledge, in turn, has been exploited for the synthesis of a sample of pantolactone specifically enriched with 13C in its Si-methyl group. Analysis of the 13C-NMR. spectrum of this sample together with the results of biosynthetic experiments previously reported by Aberhart demonstrates that the biological hydroxymethylation of 2-oxoisovaleric acid (3) to 2-oxopantoic acid (4), an important step in the biosynthesis of pantothenic acid, takes place in a retention mode (of. Scheme 2).

Zum stereochemischen Verlauf der Biosynthese von 2-Oxo-pantolacton: Synthese von stereospezifisch indiziertem Pantolacton aus Äpfelsäure†

Synthesis of Optically Active 2-Methyl- and 2-Ethyl-1, 6-dioxaspiro [4.4]nonane- and -[4.5]decane Pheromones from a Common Chiral Precursor



The versatility of the bromoepoxide 6 as chiral building block, which is readily available in both enantiomeric forms from malic acid, and which has previously been used for a vermiculine synthesis, is further demonstrated by the preparation of the title compounds 1, 3, 4 and 5. Alkylation of 1,3-dithiane, first with the 1-ethoxyethyl-protected ω-chloroalcohols 8b or 9b and then with the (S)-(−)-bromoepoxide 6, followed by oxirane opening with Selectride or methyl Gilman-reagent creates the desired carbon skeletons and functionality patterns 14–17, in overall yields of 60–80%. Acetal and thioacetal hydrolyses directly furnish the spiroacetal target structures 1 and 3–5 as 3:2-diastereomeric mixtures; the E/Z-epimers 3 are separated by preparative GC. (Fig.).

Daniel Wasmuth

Papers

Herstellung von erythro-2-Hydroxybernsteinsäure-Derivaten aus Äpfelsäureester. Vorläufige Mitteilung

Doppelt und dreifach funktionalisierte, enantiomerenreine C4‐Synthesebausteine aus β‐Hydroxybuttersäure, Äpfelsäure und Weinsäure

Zum stereochemischen Verlauf der Biosynthese von 2-Oxo-pantolacton: Synthese von stereospezifisch indiziertem Pantolacton aus Äpfelsäure†

Synthese optisch aktiver 2-Methyl- und 2-Äthyl-1, 6-dioxaspiro [4.4]-nonan- und -[4.5]decan-Pheromone aus einem gemeinsamen chiralen Vorläufer

Alkylierung von Aminosäuren ohne Verlust der optischen Aktivität: α‐ und β‐Alkylierung eines Asparaginsäure‐Derivates