Science of Synthesis

Parrain, J.-L.; Thibonnet, J., Science of Synthesis, (2005) 26, 834.

Monosubstituted dithianes are very useful since their anions can be coupled with a variety of electrophiles,[‌359‌,‌481‌] and many total syntheses of natural products involve 1,3-dithiane linchpins.[‌482‌–‌485‌] Deprotonation of 2-substituted dithianes often requires stronger bases, solvent additives, and a myriad of time and temperature regimes.[‌486‌] Owing to the great stability of the α-sulfanyl anion, the hydrogen atom at C2 of the 1,3-dithianes is easily removed by hard bases (alkyllithium or lithium diisopropylamide) (‌Scheme 119‌). The lithium reagent generated can be acylated with a variety of electrophiles, such as acyl chlorides[‌487‌,‌488‌] or esters,[‌489‌] to give the corresponding α,α-disulfanyl ketones. For example, 2-ethyl-1,3-dithiane (‌302‌) is lithiated with butyllithium and the resulting anion can be trapped with methyl esters ‌303‌ to give α,α-disulfanyl ketones ‌304‌.[‌489‌] The total synthesis of chiral difluorinated [6]-gingerol via this approach was achieved using a similar addition to the key intermediates, (R)-(+)- and (S)-(–)-ethyl 2,2-difluoro-3-hydroxyoctanoates.[‌490‌] Similarly, the preparation of the “tricarbonyl region” of FK-506 was achieved via the dithiane route.[‌491‌,‌492‌] The reactivity of 2-acyl-2-lithio-1,3-dithianes has been described, and shows a great dependence on the nature of the electrophiles used.[‌493‌] Using α-chloro-β,γ-unsaturated esters ‌305‌ as electrophiles, the acylation of dithiane anions can be combined with a formal SN2′ substitution, affording functionalized cyclopentenones ‌307‌.[‌494‌] It was proposed that the final step was an intramolecular attack by the sulfur atom on the allylic carbon to give a stable sulfonium ylide ‌306‌, followed by [1,2]-sigmatropic rearrangement to give the observed product. This strategy was also applied to the synthesis of cis-jasmone and dehydrojasmone.[‌495‌] A sulfur-substituted allylcopper species can be generated, at low temperature, by reaction of a ketene dithioacetal ‌308‌, bearing a chlorine atom at an al­lylic position with organocuprate reagents. These α,α-disulfanyl copper reagents react with esters to afford the corresponding disulfanyl ketones ‌309‌ in fair yields (‌Scheme 120‌).[‌496‌] (Methylsulfanyl)methyl 4-tolyl sulfone (‌310‌) has been proposed in place of 1,3-dithiane in the synthesis of the title compounds. For example, sulfone ‌310‌ is easily metalated with sodium hydride in tetrahydrofuran at 0°C and the resulting anion is condensed onto alkoxyacetic esters ‌311‌ to give the sulfones ‌312‌ (‌Scheme 121‌).[‌497‌] Treatment of an alkoxyacetyl derivative ‌312‌ with a base such as triethylamine or 1,4-diazabicyclo[2.2.2]octane affords 3-(methylsulfanyl)-2-oxopropanal acetals.

‌Meeeee 888‌ Meeeeeee ee 8-Meeeee-8,8-eeeeeeee eeee Meeeee[‌888‌]

‌Meeeee 888‌ Meeee α,α-Meeeeeeeee Meeeeeeeeeee Meeeeeee[‌888‌]

‌Meeeee 888‌ Meeeeeee ee (Meeeeeeeeeeeee)eeeeee Meeeeee Meeeee eeee Meeeee[‌888‌]

Meeeeeeeeeee Meeeeeeee

8-(8-eeee-Meeeeeeeeee)-8-(8-eeeee-8,8-eeeeeee-8-ee)eeeeeeee (‌888‌, M8 = 8-e-Me); Meeeeee Meeeeeeee:[‌888‌]

Me e eeeeeee eeee ee 8-eeeee-8,8-eeeeeeee (‌888‌; 8.88 e, 88.8 eeee) ee MMM (888 eM) ee −88°M, 8.8 M MeMe ee eeeeeee (88.88 eM, 88.8 eeee) eee eeeee. Meeee 8 e, eeeeee 8-eeee-eeeeeeeee­eeeeeeeee (‌888‌, M8 = e-Me; 8.88 e, 88.8 eeee) ee MMM (88 eM) eee eeeee eee eee eeeeeee eeeeeee ee eeee ee ee eeee 88 e. Meeeee eeeeee eeeeeeee ee eeeeeeeeeee eeee eeeeeeeee eeeee eeee eee eeeeeee ee ee eee-eeeee eeeeeeeeeee eeeee; eeeee: 8.88 e (88%); ee 888–888°M.

8-Meeee-8,8-eee(eeeeeeeeeeeeee)eeee-8-ee-8-eee (‌888‌, M8 = Me; M8 = Me); Meeeeee Meeeeeeee:[‌888‌]

Me eee eeee ee eee eeeeeee (8.88 eeee), eeeeeeee ee eeeeee e eeee ee 8.88 M MeMe ee Me8M (8.8 eM, 8.88 eeee) ee e eeeeeeeeee ee MeMM (88 ee, 8.88 eeee) ee Me8M (8 eM) ee −88°M, eee eeeee e eeee ee 8-(eeeeeeeeeeee)-8,8-eee(eeeeeeeeeeeeee)eee-8-eee (‌888‌, M8 = Me; 88 ee, 8.8 eeee) ee Me8M (8 eM) ee e eeeeeee ee −88°M. Mee eeeeeee eee eeeeeee eee 88 eee ee eee eeee eeeeeeeeeee. Meeee eeeeeeeee (8.88 eM, 8.8 eeee) eee eeeee eee eee eeeeeee eee eeeeeee ee eeee ee eeeeeeeeeee ee −88°M eeee 8 e. Mee eeeeeeee eee eeeeeeee eeee eee. ee MM8Me eee eeeeeeeee eeee Me8M. Meeee eeeeee eee eeeeeeeeeee ee eee eeeeeeee, eee eeeee eeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee, eeeeee/MeMMe); eeeee: 888 ee (88%).

8-(Meeeeeeee)-8-(eeeeeeeeeeeeee)-8-eeeeeeeeeee-8-eee (‌888‌, M8 = Me); Meeeeee Meeeeeeee:[‌888‌]

Me e eeee ee 8-eeeee (eeeeeeeeeeeeee)eeeeee eeeeeee (‌888‌; 8.88 e, 88.8 eeee) ee MMM (88 eM) eeee eeeeeeeeeeee eeeee 88% MeM ee eeeeeee eee (8.8 e, 88.88 eeee) eee eeeeee (eeeeee­eee)eeeeeee (‌888‌, M8 = Me; 8.88 e, 88.88 eeee) eeeee eee eeeeeee. Mee eeee eee eeeeeee ee eeee ee ee eee eeeeeee eee 88 e. Mee eeeee eeeeee eee eeeeeeeeeeeeeeeee (eeeeee/eeeeeee) (MMMMMMM: eeeeeeeeee) eeeeeeee eee eeeeeee; eeeee: 8.88 e (88%).

References

Meeeeee Meeeeeeeeee

• 8.Meeeee-Meee, (8888) M 88-8, 888.
• 8.Meeeee-Meee, (8888) M 88-8, 8888.
• 8.Meeeee-Meee, (8888) M 88e8, 888.
• 8.Meeeee-Meee, (8888) M 88e8, 8888.
• 8.Meeeee-Meee, (8888) M 88e, 888.
• 8.Meeeee-Meee, (8888) M 88e, 8888.