1-Oxaspiro[4.4]nonan-6-ones. Synthetic Access via Oxonium Ion Technology, Optical Resolution, and Conversion into Enantiopure Spirocyclic α,β-Butenolides

Abstract

A general approach to the synthesis of enantiomerically pure spirocyclic alpha,beta-butenolides is presented where the fundamental framework is rapidly elaborated by acid- or bromonium ion-induced rearrangement of the carbinol derived by addition of 2-lithio-4,5-dihydrofuran to cyclobutanone. Subsequent resolution of the resulting ketones by either sulfoximine or mandelate acetal technology has been applied effectively. The availability of these building blocks makes possible in turn the acquisition of the enantiomers of dihydrofurans typified by 17, 35, and 38 and lactones such as 25 and 31, as well as the targeted title compounds. Complementary reductions of the early intermediates provide the added advantage that the alpha- and beta-stereoisomeric carbinol series can be obtained on demand. These capabilities have been coordinated to allow the crafting of any member of the series in relatively few steps.

The Julia Reaction

“…Unfortunately, coupling between optically pure a-lithiated sulfoximines and aldehydes or ketones generally leads to 1:1 mixtures of syn/anti adducts [156,[158][159][160][161]. Despite this shortcoming, chiral sulfoximines have found widespread application in a number of useful synthetic transformations, including resolution [162][163][164][165][166][167][168][169][170][171][172][173][174].…”

Brønsted Acid Catalyzed Enantioselective Semipinacol Rearrangement for the Synthesis of Chiral Spiroethers

“…Good enantioselectivities (about 90 % ee ) were achieved at 0 °C with the less acidic ( R )‐ 2 f catalyst, whilst only about 50 % ee could be obtained for the reaction of 1 h using the phosphoric acid catalyst ( R )‐ 2 e . It should be noted that the low yield in the reaction of 1 h (51 %; Table 2, entry 9) was due to the volatility of the product 3 h and its undesired dimerization 3a. In order to investigate the enantioselectivity of this reaction, the absolute configuration of 3 h is further unambiguously assigned as “ S ” by the comparison of its optical rotation with the literature data 3a…”

“…If silver phosphate ( R )‐ 2 f was used as precatalyst in the reaction of 1 f and 1 g , the desired rearrangement proceeded very slowly, and did not go to completion, even after 8 days. We also examined two substrates with dihydrofuranyl moieties ( 1 h and 1 i ; Table 2, entries 9 and 10), which are highly acid–sensitive 3a. Good enantioselectivities (about 90 % ee ) were achieved at 0 °C with the less acidic ( R )‐ 2 f catalyst, whilst only about 50 % ee could be obtained for the reaction of 1 h using the phosphoric acid catalyst ( R )‐ 2 e .…”

Stereocontrolled Synthesis and Functionalization of Cyclobutanes and Cyclobutanones

“…Tu and co-workers, also developed an interesting enantioselective organocatalyzed semipinacolic rearrangement of cyclobutanol allylic alcohols 123 [107]. This reaction represents a catalytic Paquette-type [108,109] cyclobutanol ring expansion, through the enantioselective protonation of dihydropyranyl- or furanyl double bonds, followed by a cyclobutanol sigmatropic 1,2-shift [110].…”