Stereoselective Synthesis of Hexahydroisobenzofuran‐4(1H)‐ones from Chiral Substituted Cyclohex‐2‐enyl Carbamates via Asymmetric Homoaldol Reaction and THF Cyclocondensation

Abstract

Keywords: Asymmetric synthesis / Heterocycles / Metallated allyl carbamates / Homoaldol reactions / Tetrahydrofuran synthesisThe diastereofacial selectivity of the homoaldol reaction of metalated substituted cyclohex-2-enyl carbamates with aldehydes is controlled by the nature of the metal complex. Allyllithiums yield syn-configured products whereas transmetallation to Ti(NEt 2 ) 3 gives access to anti-configured 3-(1-hydroxyalkyl)cyclohexenes. The syn-configured homoaldol products were transformed into annulated all-cis-tetrahydrofurans by Lewis acid-mediated cyclocondensation with

Asymmetric Homoaldol Reactions with Cyclohex‐2‐enyl N,N‐Diisopropylcarbamate: Kinetic Resolution, Elucidation of the Stereochemical Course and Applications in the Synthesis of Hexahydroisobenzofuran‐4‐(1H)‐ones

“…In the subsequent paper we report on the enantioselective synthesis of higher substituted hexahydroisobenzofuran-4(1H)-ones. [20] Experimental Section General Remarks: All solvents were dried and purified prior to use: toluene and Et 2 O were distilled from sodium benzophenone ketyl, THF was distilled from potassium benzophenone ketyl and CH 2 Cl 2 was distilled from powdered CaH 2 . N,N,NЈ,NЈ-Tetramethylethylenediamine (TMEDA) was distilled from powdered CaH 2 and stored under Ar in the dark.…”

DNA‐Regulated Micro‐ and Nanoparticle Assembly

“…Die Ketofunktion sollte sich im letzten Schritt leicht in die exocyclische Methylengruppe überführen lassen. Unsere konvergente Strategie zur Synthese des Tricyclus 4 umfasst drei Schlüsselschritte: eine asymmetrische Homoaldolreaktion12 des Carbamats 6 10b mit dem α‐stereogenen Enal 7 , eine nachfolgende Krämersche THF‐Synthese13 mit dem Acetal 8 14 sowie eine Ringschlussmetathese des Diens 5 15. ( R )‐4‐Isopropylcyclohex‐2‐enon ( 9 ) [( R )‐(−)‐Crypton)]16 wurde für die Synthese von 6 verwendet.…”

“…Durch LiAlH 4 ‐Reduktion der Mischung wurde das Cycloalkenol 11 21 (d.r.=84:16) erhalten, das durch einfache Chromatographie an Kieselgel vom Sesquiterpen getrennt wurde (Schema ). Carbamoylierung von 11 und Trennen der Diastereomere lieferte (1 S ,4 R )‐ 6 10b mit 97 % ee .…”

α-Metallated O-2-Alkenyl Carbamates: Synthetic Equivalents of Chiral Homoenolates and Materials for Asymmetric Homoaldol Reaction

“…Similar to the lithium compounds derived from secondary 2-alkenyl carbamates, those obtained from 2-cycloalkenyl carbamates proved to be configurationally stable at -70°C. [43][44][45] However, there are limitations as the possibility of deprotonation is concerned: Only if a good overlap between the developing carbanionic lone pair and the porbitals of the C=C bond is given in the transition state (according to f between 90° and 110° in the starting carbamate), a deprotonation by means of sec-butyllithium was feasible (Scheme 15). 44…”

“…58c Finally, as mentioned before for few special cases, the cyclocondensation of the 4-hydroxy-1-alkenyl carbamates 71 with aldehydes or ketones generally provides diastereomerically pure tetrasubstituted tetrahydrofurans (see Scheme 14). 41,42,45 Simpler vinyl carbamates 80 are converted into lithium enolates 81 59 or silyl enol ethers 82, 60 or to vinyl triflates 83. 60 The 2-alkenyl carbamates have been applied to completed or attempted total syntheses of natural compounds by P. J. Kocienski, M. Julia, J. Ardisson, A. Pancrazi, Y. Férézou, I. E. Markó et al, and others.…”