Synthesis of Functionalized Alkylidenecyclopropanes by Ireland–Claisen Rearrangement of Cyclopropenylcarbinyl Esters

Abstract

Glycolates or glycinates derived from diversely substituted secondary cyclopropenylcarbinols have been involved for the first time in an Ireland-Claisen rearrangement. This reaction allows an efficient and stereoselective access to highly functionalized alkylidenecyclopropanes possessing an α-hydroxy or α-amino acid subunit, which in turn are valuable precursors of substituted cyclopropanes by diastereoselective hydrogenation of the exocyclic alkene.

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

“…The ( Z )-silyl ketene acetals 68a and 68b were generated, in agreement with previous results disclosed by Carbery et al with allylic N , N -diBoc glycinates [69], and underwent a Ireland–Claisen rearrangement to afford N , N -diBoc α-amino esters 69a (78%) and 69b (91%) in good yields and with high diastereoselectivity [61]. Although cleavage of the two Boc groups could not be achieved cleanly upon exposure of 69b to a large excess of trifluoroacetic acid, this operation could be accomplished in a sequential manner by addition of trifluoroacetic acid (2 equiv, CH 2 Cl 2 , 0 °C) and then by treatment of the resulting N -Boc carbamate 70 (97%) with trimethylsilyl triflate in the presence of 2,6-lutidine to generate α-amino ester 71 (99%, Scheme 24) [61].…”

“…More sterically hindered substituents were tolerated at C3, as illustrated with the isolation of the spirocyclic compounds 58j (60%) and 58k (77%), and alkylidenecyclopropane 58l possessing a fully substituted three-membered ring was also formed in excellent yield (96%). That the Ireland–Claisen rearrangement of cyclopropenylcarbinyl glycolates proceeded with chirality transfer was also verified in the case of alkylidenecyclopropanes 58a and 58i which were obtained with optical purities (ee = 87% and ee = 97%, respectively) identical to those of the corresponding enantioenriched precursors ( R )- 56a and ( R )- 56i (Scheme 21) [61].…”

“…The resulting silyl ketene acetals of ( Z )-configuration 57a – l , arising from O-silylation of the corresponding chelated potassium enolates [60], underwent an efficient [3,3]-sigmatropic rearrangement upon warming to room temperature. After an acidic work-up and treatment of the crude carboxylic acids with trimethylsilyldiazomethane, the resulting α-alkoxy methyl esters 58a – l , incorporating an alkylidenecyclopropane moiety, were obtained as single detectable diastereomers [61]. As in the previously discussed [3,3]-sigmatropic rearrangements, the observed stereochemical outcome was in agreement with a six-membered chair-like transition state model TS6 in which the substituent at the α-position of the oxygen atom (C4) preferentially occupies a pseudo-equatorial position.…”

“…Because the gem -diester substitution at C3 increased the acidity of the proton at C2 in substrate 61 [64], silylation of that position took place under the reaction conditions prior to the Ireland–Claisen rearrangement which eventually produced alkylidenecyclopropane 62 (56%) with high diastereoselectivity. The trimethylsilyl substituent at C2 could then be easily removed by treatment of 62 with tetrabutylammonium fluoride under buffered conditions (AcOH, THF, 0 °C) to afford alkylidenecyclopropane 63 (92%, Scheme 22) [61].…”

Synergistic NaBH4 Reduction/Cyclization of 2‐Aroylcyclopropane‐1‐carboxylates: Synthesis of 3‐Oxabicyclo[3.1.0]hexane Derivatives

“…The great pharmaceutical potential of this scaffold prompted us to search for new and efficient methods that would provide diversified structures in a minimum number of steps. As a result of their biological importance, many methods for the construction of 3‐oxabicyclo[3.1.0]hexanes have been developed 3‐Oxabicyclo[3.1.0]hexanes can be synthesized by various strategies, such as the Ireland–Claisen rearrangement procedure,, intramolecular cyclization reactions of aryldiazoacetates, Ru‐catalysed annulations, Pd‐promoted [2+1] cycloaddition reactions between dihydrofuran derivatives and alkynes, or Au‐catalysed cyclopropanation reactions of substituted (allyloxy)sulfonium ylides . Another interesting synthetic pathway, reported by Pathak and co‐worker, is based on the formation of single diastereomers of substituted 3‐oxabicyclo[3.1.0]hexanes through the reaction of the corresponding vinyl selenone with nitromethane, malononitrile, and dimethyl malonate in the presence of t BuOK in THF at room temperature .…”