Catalytic Asymmetric Synthesis of Ketene Heterodimer β-Lactones: Scope and Limitations

Abstract

In this article we describe extensive studies of the catalytic asymmetric heterodimerization of ketenes to give ketene heterodimer β-lactones. The optimal catalytic system was determined to be a cinchona alkaloid derivative (TMS-quinine or Me-quinidine). The desired ketene heterodimer β-lactones were obtained in good to excellent yields (up to 90%), with excellent levels of enantioselectivity (≥90% ee for 33 Z- and E-isomer examples), good to excellent Z-olefin isomer selectivity (≥90:10 for 20 examples), and with excellent regioselectivity (only one regioisomer formed). Full details of catalyst development studies, catalyst loading investigations, substrate scope exploration, protocol innovations (including double in situ ketene generation for 7 examples), and an application to a cinnabaramide A intermediate are described. The addition of lithium perchlorate (1-2 equiv) as an additive to the alkaloid catalyst system was found to favor formation of the E-isomer of the ketene heterodimer. 10 examples were formed with moderate to excellent E-olefin isomer selectivity (74:25 to 97:3) and with excellent enantioselectivity (84-98% ee).

Mechanistic Investigations of the Pd‐Catalyzed Hydrogenolysis of Ketene Heterodimer β‐Lactones

“…Both enantiomers of ketene heterodimers 2a-2n were prepared in moderate to good yields through the alkaloid-catalyzed reaction of propionyl chloride (methylketene) with various methylarylketenes. [12,13] The desired ketene heterodimers were formed with excellent enantioselectivity (Table 1), and generally with excellent Z-isomer selectivity (entries 1-12). The only examples where poor Z/E-selectivity was observed was with examples bearing a 2-F substituent on the aryl ring of the methyl aryl ketene -in those cases, the desired heterodimers were obtained in poor to moderate yield (11-45 %), albeit with excellent enantioselectivity (entries 13 and 14).…”

“…R 1 Catalyst Yield Z/E [b] ee 2 [%] [a] [%] [c] entries 5 and 6), implicating reaction of ammonium enolate (Intermediate I) with alkylarylketene 1 as the slow step in the reaction (Scheme 2). [13] Scheme 2. Proposed mechanism for alkaloid-catalyzed ketene heterodimerization.…”

“…[29] Ketene heterodimers 2a, 2b, Z-2o, E-2o and 2p, acids 3a and 3b, and -lactone 5o were prepared and characterized as described previously. [12][13][14][15] NMR spectra were recorded on a 400 spectrometer (400 MHz for 1 H and 100 MHz for 13 C). NMR chemical shifts were reported relative to TMS (0 ppm) for 1 H and to CDCl 3 (77.23 ppm) for 13 C spectra.…”

“…General Procedure for Ketene Heterodimerization: [12,13] Acyl chloride in dichloromethane was added over the indicated time via syringe pump to a solution of ketene, Hünig′s base and alkaloid catalyst in dichloromethane at -25°C, and stirred for the indicated time.…”

“…[10][11][12][13][14][15] This sequential process represents a very efficient, atom economical direction, as it entails the coupling of two catalytic processes, one of which is enantioselective, the second of which is diastereoselective. [12][13][14][15] The employment of just one chiral catalyst (an alkaloid derivative) for the overall creation of two stereocenters sets this process apart from other methodologies, which generally require two steps involving chiral catalysts/reagents/auxiliaries to establish the two asymmetric centers found in the deoxypropionate unit. The desired products were obtained in moderate to excellent diastereoselectivity (dr ca.…”