Science of Synthesis

Scott, P. J. H., Science of Synthesis Knowledge Updates, (2013) 4, 249.

Many of the early methods of synthesizing macrocyclic ketones described above, such as the Thorpe reaction, the Ziegler condensation, and the cyclization of diketenes developed by Blomquist and Spencer, require high-dilution conditions to favor intramolecular cyclization. This is impractical, especially on an industrial scale, but was overcome by the groups of Prelog[‌53‌] and Stoll[‌54‌] through use of the acyloin cyclization. The acyloin condensation (‌Scheme 1‌ and ‌Table 6‌), originally developed by Hansley,[‌55‌] and extensively reviewed by the groups of Bloomfield[‌56‌] and Finley,[‌57‌] is a reductive coupling of two carboxylic esters (although acid chlorides and anhydrides have also been utilized)[‌56‌] using metallic sodium to yield an α-hydroxy ketone, also known as an acyloin. High-dilution conditions are not required because the reaction actually proceeds under pseudodilute conditions on the surface of finely divided sodium. Macrocyclic acyloins can then readily be converted into the corresponding ketones by zinc/hydrochloric acid reduction,[‌58‌] or oxidized to the diketone using, for example, copper(II) acetate or bismuth(III) oxide (‌Scheme 1‌).[‌59‌,‌60‌]

‌Meeeee 8‌ Meeeeeee Meeeeeeeee eeee eee Meeeeee Meeeeeee[‌88‌,‌88‌]

Meeeeeee eee Meeeeee eeeeeeeeeee (Meeeeee ‌88.88.8.8.8‌) eeeeeee ee eeeeeee eee eeeeeee eeeeee ee eeeeeeeeeeeeeee eee eeeeeeeeeeeeee,[‌88‌,‌88‌] eee eeeeeee eeeeeeeeeee eee ee eeee ee eeeeeeee eeee eeeee (‌Meeee 8‌, eeeee 8),[‌88‌] eee ee eeeeeeee eeeeee e eeee eeeeeeeee eeeeee eee eeeeeeeee eeeeeeeeeeeee (eeeee 8), eeeeeeeeeeeee (eeeee 8), eeeeeeeeeeeeeee (eeeee 8), eeeeeeeeeeeeeee (eeeee 8), eeeeeeeeeeeeeeee (eeeee 8), eee eeeeeeeeeeeeeeeeee (eeeee 8) (eee eee[‌88‌] eee eeeeeeeeee eeeee eeeeeee). Mee eeeeeeee eee eeeeee eeeee eeeeeeeee, eeeeee eeee eeeeeeee ee eeeeeee ee ee 88-eeeeeeee eeeeeeee. Mee eeeeeee, 88-eeeeeeee eeeeeeee ee eee ee eee eeee eeeeeeeeeeeee eeeeeeeeeee eeeeeeeeeee eeeee. Meeee eeeeeeeee[‌88‌,‌88‌] eeeeeeeeeeee ee eeeeeeeeeeeeee eeeeeeeeeee ee eeeee-eeeeeeeee eeee eee ee eeeeeeeeee eeeeeeee ee eeee eeeeeeee. Meee eeeeeeee, eeeeeee, e eeeeee ee eeeeeeeee eee eee eeeeeee eeeeeeeeeeee (eee eeeeeeeeee eeee eeeeeeeeeee) ee eeeeeeeee eeee (8,88-eeeeeeeeeeeee­eeeeeeeeeee eeee),[‌88‌,‌88‌] eee eeeee eeeeeee eeeeeee,[‌88‌] eeee eeee eeeeeeee. Meeee eeeeeeeeeeee ee eee eeeeeee eeeeeeee ee eeeeeeeeee eeeee-ee eeeeeee eee eeeee eeeeeeeeee eeeeeeeee ee eeeeeee (8-eeeeeeeeeeeeeeeeeeeeeeee) eee eeeeeeee (eeeeeeeeeeeeeeeeee).[‌88‌,‌88‌,‌88‌] Me eeeeeeeeeee eeeeeeeeeeeeee eeeeeee eee eeee eeeeeeee ee Meeeee‘e eeeee, eee eeee eeee ee eeeeee e eee-eeeeee eeee eeeeeeeeeee ee 88-, 88-, eee 88-eeeeeeee eeeee ee eeeeeeee eee eee eeeeeee eeeeeeeeeeee ee eee eeeeeeee ee eeeeeeeeeeeeeeeeeeeee ee eeeeeeee 88-, 88-, eee 88-eeeeeeee eeeeee eeeeeee, eeeeeeeeeeee.[‌88‌]

‌Meeee 8‌ Meeeeee Meeeeeeeeeee Meeeeeeee ee Meeeeeee[‌88‌,‌88‌]

Meeee	Meeeeeee Meeeeeee	Meeeeeeeee	Meeeeee	Meeee (%)	Mee
8		Me		88	[‌88‌]
8		8. Me 8. Me/MMe		88	[‌88‌]
8		8. Me 8. Me/MMe		88	[‌88‌]
8		8. Me 8. Me/MMe		88	[‌88‌]
8		8. Me 8. Me/MMe		88	[‌88‌]
8		8. Me 8. Me/MMe		88	[‌88‌]
8		8. Me 8. Me/MMe		88	[‌88‌]

Meeeeeeeeeee Meeeeeeee

8-Meeeeeeeeeeeeeeeeeeee (‌Meeee 8‌, Meeee 8); Meeeeee Meeeeeeee:[‌88‌]

Me e eeeeeeeee eeee ee Me (88 e) ee eeeee eeeeee (8 M), ee e 8-M eeeee eeeeee eeee e eeeeeeee eeeeee ee eeee e eee eeee eeeeeeee eeeee eeee eee eeeeeeee eeeeee eee eeeeeee eeee eeeeeeeee eeeeeee eeee e eeeeeeeee, eee eeeee e eeee ee eeeeeee eeeeeeeeeeeee (88 e) ee eeeeee (8 M) eeee e eeeeee ee 88 e. Meeee eeeee eeeeeeee, eee eeeeeee eee eeeeeee eee ee eeeeeeeeee 88 eee, eeeeee eeeeeee eeee eee eee eeeeeeeee eeee 88 eee eeee e eeee ee eeeeeee MeMM (88.8 eM) ee eeeee Me8M (888 eM). Mee eeeeeeeee MeMMe eee eeeeeee ee eeeeeeeeee eee eeeeee eeee Me8M, eee eee eeeeeeee eeeeeeeee eeee eeeeeeeeeeee eee eeeeeeee ee eeeeeeeeeeee ee eeeee eee eeeee eeeeeeee; eeeee: 88 e (88%).

References