Reagent-Controlled Stereoselective Iodolactonizations

Abstract

[reaction: see text] Iodocyclizations are important transformations and among stereocontrolled iodocyclizations mostly substrate-controlled versions using a chiral auxiliary have been successfully investigated. This work reports on stereoselective reagent-controlled iodolactonizations applying a new method using a combination of ICl and a primary amine leading to the highest selectivities known so far.

Iodine Monochloride–Amine Complexes: An Experimental and Computational Approach to New Chiral Electrophiles

“…5-Iodomethyl-5-phenyl-dihydrofuran-2-one (2): For spectral data, see Supporting Information of reference [7].…”

“…The racemate was separated by subjecting it to preparative HPLC (Daicel Chiracel OD, 21 mm 250 mm, 5 mL min 4-(4-Chlorophenyl)-4-pentenoic acid (16 c): 4-(4-Chlorophenyl)-4-pentenoic acid tert-butyl ester (2 mmol, 500 mg) and silica (10 g) were refluxed in toluene (5 mL) for 2 h. [36] After filtration over celite, a basic extraction with 1 n NaOH and extraction with CH 2 Cl 2 after acidification with 1 n HCl yielded 250 mg (60 %). For spectral data, see Supporting Information of reference [7]. Methyl 5-methyl-4-phenylhex-4-enoate: 2-Methyl-3-phenylbut-3-en-2-ol [37] (799 mg, 4.9 mmol), trimethyl orthoformate (5.88 g, 49 mmol), and acetic acid (30 mg, 0.5 mmol) were heated to 125 8C for 2 h. The temperature was increased to 1408 for a further 6 h and the reaction mixture was then concentrated under reduced pressure.…”

“…Although it is known that oxygencontaining compounds like carbonyl compounds, [4] ethers, [5] and nitrogen-containing molecules [6] can form 1:1 complexes with ICl, we found that complexes of enantiomerically pure primary amines are suitable reactive and selective electrophilic species for iodolactonizations. Recently, we reported preliminary results on stereoselective iodolactonizations of 4-phenyl-4-pentenoic acid 1 and other substrates by employing mixtures of enantiomerically pure amines with ICl as reagents [7] (Scheme 1). (R)-1,2,3,4-Tetrahydro-1-naphthylamine 3 and other amines with similar structure, such as (R)-1-phenyl-1-ethylamine 4, were found to be efficient amines for the iodolactonization, yielding lactones 2 with up to 45 % ee.…”

“…Experimentally, we found that the second equivalent of amine can be replaced by another base. [7] The second molecule of ICl that is necessary to form 7 or 8 must originate from 5, as all of the ICl is assumed to be used initially in the formation of 5. This means that the reactions leading to 7 and 8 are side reactions.…”

“…tert-Butyl ester 18 ( Figure 8) could be cyclized only with ICl, but the expected lactone 2 was not formed by using the amine-ICl complex of the stereoselective protocol described above. [7] The reactivity of the 2:1 amine-ICl complex is too low for the conversion of 18 into lactone 2, but by changing to an amine:ICl ratio of 1:1.5, 2 was obtained in 66 % yield with 34 % ee. Only amide 19 a (Figure 8) was reactive when the stereoselective lactonization protocol was used (amine:ICl ratio of 2:1) to give 2 in 37 % ee, albeit in a low yield (43 %), which might be due to the low solubility of 19 a in dichloromethane.…”