Dieter Hoppe

Generation of a configurationally stable, enantioenriched α-oxy-α-methylbenzyllithium: Stereodivergence of its electrophilic substitution

Abstract The deprotonation of (R)- or (S)-1-phenylethyl N,N-diisopropylcarbamate with s-butyllithium/TMEDA in unpolar solvents (e.g. ether or hexane) at −78°C produces configurationally stable ion pairs which are substituted stereospecifically by different electrophiles. In several examples, complete stereoretention or inversion, respectively, was achieved. Electrophiles, which have an energetically low LUMO, such as acid chlorides, heterocumulenes and trialkyltin chlorides prefer antarafacial attack. If the leaving group has a high tendency to interact with the lithium cation, such as in esters, suprafacial substitution with retention takes place.

Enantioselective synthesis via sparteine-induced asymmetric deprotonation

The deprotonation of achiral akyl carbamates with sec-butyllithium/(-)sparteine proceeds with a high degree of chiral recognition to form substituted alcohols usually with 2 95 76 ee after reaction with electrophiles followed by deprotection. The stereoselection is kinetically controlled and a qualitative transition state model is proposed. Some studies, concerning the discrimination between both enantiomers of stereogenic akyl carbamates and on its utilization for the kinetic resolution are reported. The competition between external and internal competition was investigated in few cases. Finally, we disclose a short report on the enantioselective electrophilic substitution of 1-methylindene; here the origin of stereoselection is an thermodynamically driven epimerization of diastereomeric indenyllithium sparteine complexes. INTRODUCTION Many methods for the enantioselective synthesis are based on the selection of a chiral reagent or of a reagent under the influence of a chiral catalyst between the enantiotopic faces of a trigonal carbon moiety. In only a few cases, an efficient selection between enantiotopic groups at a tetragonal carbon atom has been verified (Scheme 1). Scheme 1 Select ion between Enant iotopic Faces Select ion between Enant io top ic Groups Widely used in synthesis Impressive examples of the latter type have been reported (ref. 1) independently by the research groups of Koga and Simpkins: CSubstituted cyclohexanones are deprotonated by chiral lithium amides, derived from

Sparteine complexes of lithiated primary O-2-alkenyl carbamates stereochemistry of the lithium-titanium exchange and application for the synthesis of enantiomerically enriched γ-lactones

Abstract The preferentially formed (−)-sparteine complex from 1-lithio-2-butenyl N,N -diisopropylcarbamate has ( S )-configuration at the metal bearing carbon atom, in contrary to our previous assumption. Transmetallation with titanium tetraisopropoxide and the carboxylation proceed with inversion. The addition of aldehydes occurs in a anti -S E′ -process. The enantioselective synthesis of homoaldol adducts and some corresponding γ-lactones is reported.

Highly diastereoslective synthesis of di- and trisubstituted 4-butanolides from aldehydes and ketones via three-carbon-extension by allylic homoenolate reagents

Abstract Lithiated or titanated O -allyl carbamates 7 or 8 add to aldehydes and ketones regio- and diastereoselectively to yield O -(4-hydroxy-1-alkenyl) carbamates 9 , which are converted to λ-lactones 12 with an one-pot procedure.

Reagent-controlled enantioselective homoaldol reaction with chiral 1-oxyallyllithium derivatives. Enantio-divergent tuning by achiral titanium reagents

Abstract Optically active 2-alkenyl carbamates are deprotonated by n-butyllithium with retention of configuration. Lithium titanium exchange by Ti(O i Pr)4 proceeds with retention and by ClTi(NEt2)3 with inversion of configuration. The stereochemical course of addition to aldehydes is mainly determined by the chiral center of the metal allyl reagents to offer a flexible route to both enantiomers of highly substituted ketones.

Metallated 2-alkenyl carbamates: chiral homoenolate reagents for asymmetric synthesis

Nonracemic chiral 1-lithio-2-alkenyl carbamates are generated by stereospecific deprotonation of optically active 2-alkenyl carbamates, by kinetic resolution with sec-butyllithium/(-)-sparteine, or by preferential crystallisation of one of the diastereo- meric complexes. After stereospecific lithium titanium exchange, the addition reaction to aldehydes proceeds with a high degree of chirality transfer to yield diastereomerically pure, enantiomerically enriched 4-hydroxy-1-alkenyl carbamates. Some simple trans- formations giving rapid access to methyl furanosides of methyl-branched 3,6-dideoxy aldohexoses, 4-butanolides and 3-acyl-tetrahydrofuranes are discussed. New reagents for asymmetric nucleophilic alkenoylation (substrate-controlled) or a-(hydroxy)alkylation (reagent-controlled) are introduced.

Asymmetric total synthesis and X-ray crystal structure of the cytotoxic marine diterpene (+)-vigulariol.

belongs to the impressively large class of the cladiellin (eunicellin) diterpenes, of which many bear interesting biological activities. (+)-1 has shown to exhibit cyctotoxity against A 549 (human lung adenocarcinoma) cell culture at an IC50 of 18.33 mgmL . Two other soft-coral diterpenes sclerophytin A (2) and polyanthellin A (3) have shown high cytotoxicity and antimalarial activity, respectively. Their attractive molecular architectures and their diverse biological activities previously led to several ingenious total syntheses of some members of this natural product family by the research groups of Paquette, Overman, Crimmins, and Kim. (+)-1 was formed as a by-product during Paquette and coworkers3 synthesis of 2 before it was known to be natural product and was therefore not fully characterized. The total synthesis of rac-1 over 20 linear steps was quite recently published by Clark et al. Herein we present a short and efficient total synthesis and, in addition, the solid-state structure of enantiomerically pure (+)-vigulariol (1), by applying our previous synthetic and mechanistic investigations. As depicted in Scheme 1, (+)-vigulariol (1) could be elaborated by stereoselective epoxidation of the C=C double bond of tricycle 4. Deprotection of the hydroxy group was

The Configurational Stability of an Enantioenrichedα-Thiobenzyllithium Derivative and the Stereochemical Course of Its Electrophilic Substitution Reactions; Synthesis of Enantiomerically Pure, Tertiary Benzylic Thiols[1,2]

The lithium compound (S)-7, formed by deprotonation of the (S)-S-1-phenylethyl thiocarbamate (S)-10, is configurationally stable at -70 degrees C. Even at elevated temperatures it racemizes only very slowly. It represents the first essentially enantiopure alpha-thiocarbanion derivative and can be utilized in asymmetric synthesis. Most electrophiles (except proton acids) add to (S)-7 with complete stereoinversion. Cleavage of the substitution products leads to practically enantiopure, tertiary 1-phenylalkanethiols.

Enantioselective Synthesis by Lithiation Adjacent to Oxygen and Electrophile Incorporation

Enantioenriched sp 3-hybridized 1-oxy-alkyllithium compounds are accessible by lithiodestannylation of the appropriate chiral stannanes or by deprotonation of 1-alkyl carbamates by means of sec-butyllithium/(-)-sparteine. These are usually configurationally stable at temperatures below-40°C and are substituted by a wide array of electrophiles with strict stereoretention. When applying chiral substrates, bearing an adjacent stereogenic center, often a high internal chiral induction occurs, being the basis for an efficient kinetic resolution in the deprotonation step. α-Oxybenzyllithium derivatives are usually more easily accessible due to mesomeric stabilization, but most of these compounds undergo facile racemization or epimerization at temperatures around-70 to -78°C. The sense of stereospecificity of the electrophilic substitution is less predictable: both — retention or inversion — are common, depending on the individual situation. 1-Oxy-2-alkenyllithium reagents have similar stereochemical properties. In a number of cases configurational stability is recorded. Procedures for efficient dynamic kinetic resolution, involving a crystallization step, have been developed. In particular, 1-lithio-2-alkenyl carbamates — after titanation — are valuable homoenolate reagents for achieving highly stereoselective homoaldol reactions. Chiral 1-oxy-2-alkynyllithium derivatives allow for a facile entry to enantioenriched allenes.

Enantiomerically enriched 1-(N,N-diisopropylcarbamoyloxy)-1,3-dimethylallyllithium : stereochemistry of the stannylation, titanation, and the homoaldol reaction

Abstract Contrarely to our former assumption 1,3 , the title compounds 3 and 9 [(2 E )- and (2 Z )-isomer, (−)-sparteine or TMEDA complex] are substituted by means of trialkyltin halides in an anti -S E ′ process. The optically active allylstannanes, thus produced, and aldehydes undergo a stereospecific homoaldol reaction under the influence of TiCl 4 which involves a second anti -S E ′ transmetallation.