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20.5.10.1.2.1.3 Method 3: Alkylation Utilizing Chiral Phase-Transfer Reagents

DOI: 10.1055/sos-SD-020-01043

Garbaccio, R. M.; Wolkenberg, S. E.Science of Synthesis, (2007201141.

The first reports of asymmetric phase-transfer catalysis (PTC) appeared in 1984, when the Merck process group discovered that a 2-phenylindan-1-one could be alkylated at the C2 position in high enantiomeric excess (92%) using cinchona-derived catalysts.[‌50‌,‌51‌] Since O'Donnell's disclosure[‌52‌] five years later that these same catalysts mediate the enantioselective alkylation of glycine imines in a two-phase solvent system, intense effort has been devoted to developing general, highly selective catalysts 2931 (Scheme 9).[‌53‌,‌54‌] Early reports showed that tert-butyl esters of the benzophenone imine 32 provide the highest enantiomeric excesses of imines 33, and this has become the standard substrate for all catalysts developed to date. The original cinchona-based catalysts provide alkylated products with moderate enantioselectivity (4566% ee), and the utility of these modest selectivities was demonstrated by recrystallization procedures to upgrade enantiomeric excesses to >95%.[‌52‌] An important early observation was that alkyl, allyl, and benzylic halides provide products with similar levels of enantioselection. In the initial Merck report, the importance of electron-withdrawing substituents on the catalyst N-benzyl substituent for high enantioselectivity was noted,[‌51‌] and this electronic effect on enantioselectivity has been observed with newer catalysts as well,[‌55‌‌57‌] presumably due to adjustment of the ion pair distance.

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Meeeeeee M8 M Meee M+ ee (%) Meeee (%) ee 88 Mee
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88 (M8=8-eeeeeee) M Me 88% ee MMM M8M=MMMM8Me 88 88 [‌88‌]
88 (M8=8-eeeeeee) eeeee Me MeMMM8M M8M=MMMM8Me 88 88 [‌88‌]
88 Me 88% ee MMM M8M=MMMM8Me 88 88 [‌88‌]
88 (M8=Me) M Me 88% ee MeMM MeMe 88 88 [‌88‌]
88 (M8=8-eeeeeee) M Me 88% ee MMM MeMe 88 88 [‌88‌]
88 (M8=8-eeeeeee) eeeee Me MeMMM8M MeMe 88 88 [‌88‌]
88 Me 88% ee MMM MeMe 88 88 [‌88‌]
88 (M8=Me) M Me 88% ee MeMM MeMe 88 88 [‌88‌]
88 (M8=8-eeeeeee) M Me 88% ee MMM MeM 88 88 [‌88‌]
88 (M8=8-eeeeeee) eeeee Me MeMMM8M MeM 88 88 [‌88‌]
88 Me 88% ee MMM MeM 88 88 [‌88‌]
88 (M8=Me) M Me 88% ee MeMM MeMe 88 88 [‌88‌]
88 (M8=8-eeeeeee) M Me 88% ee MMM MeM 88 88 [‌88‌]
88 (M8=8-eeeeeee) eeeee Me MeMMM8M MeM 88 88 [‌88‌]
88 Me 88% ee MMM MeM 88 88 [‌88‌]

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(8M)-8-Meeeeeeeeeeee Meee (88, M=Me); Meeeeee Meeeeeeee:[‌88‌]

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Mee eeeeeeeeeeeeeeeeee eee eeeeeeeeee ee eeeeee MMMM. Mee eeeeeeee eeeeeeeeeeeee eee eeeeeeeeee ee eeeeeeeeee ee eee eeeee eee eeeee eeeeee (eeeeeeeee 8M MMe, 8e) eeeeeeee ee eeeeeeeeeeeeee ee eee eeeee eeeeeeeeeeeee eeeee eeeeeee eeeee ee MeMM, ee eeeeee (M)-(+)-8-eeeeeeeeeeeee eeee (88, M=Me); eeeee: 88%; [α]M88 +88.8 {e 8.88, 8M MMe; eee. [α]M88 +88.8 (e 8, 8M MMe)}.

Mee eeeeeeee eeeeeeee eeeeeeee 88 (M8=8-eeeeeee) eee eeeeeeeee ee eeeeeeeeee eee eeeeeee eeeeee eeee MM8Me8 (8 × 88eM). Mee eeeeeeee eeeeeee eeeeee eeee eeee eeeeee eeee eeeee (8 × 88eM), eeeee (MeMM8), eeeeeeee, eee eeeeeeeeeeee eeeee eeeeeee eeeeeeee ee eeeeee eeeeeeee ee eee eeeeeeee eeee eee Me eeeeeeeeee eeeeeeeee eee Me eee ee eee eeeee eeee; eeeee: 8ee (88%). Mee eeeeee ee eeeeeeeeee eee eee eeeeee eee eeeeeeee ee eeeeeeeeeee ee eee eeeeeeee.

References


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