Stereoselective Synthesis of 5-7 membered Cyclic Ethers by Deiodonative Ring-Enlargement Using Hypervalent Iodine Reagents

Stereoselective synthesis of 5-7 membered cyclic ethers was achieved by deiodonative ring-enlargement of cyclic ethers having an iodoalkyl substituent. The reaction took place readily under mild conditions using hypervalent iodine compounds and an acetoxy or a trifluoroacetoxy group was introduced into the rings depending on the hypervalent iodine reagent employed. The use of hexafluoroisopropanol (HFIP) as solvent is critical.


Introduction
Recently, we found that 5-7 membered fluoro cyclic ethers 2 can be stereoselectively prepared from 4-6 membered ones having an iodoalkyl substituent at the 2-position, 1, by the fluorinative ring-enlargement reaction induced by iodotoluene difluoride [1]. During our continued study of ring-enlargement reaction of cyclic ethers 1 using hypervalent iodine compounds, we found that cyclic ether having an acetoxy or a trifluoroacetoxy group, key intermediates for the synthesis of cyclic polyether natural compounds [2][3][4][5], can be stereoselectively synthesized by the reaction with (diacetoxyiodo)toluene (DIT)

Results and Discussion
When 2-(2-iodononyl)tetrahydrofuran (1a), obtained as a single stereoisomer by the iodocyclization reaction of (E)-4-methyl-4-tridecen-1-ol [6][7][8][9][10][11][12], was treated with DIT and acetic acid in a mixture of CH 2 Cl 2 and hexafluoroisopropanol (HFIP) at room temperature, the acetoxylated tetrahydropyran derivative 3a was obtained as a main product, along with an acetoxy group-substituted tetrahydrofuran derivative 5a as a minor product (Table 1, Entries 2-4). The use of HFIP as solvent was critical [13] and without it, the reaction was sluggish (Entry 1). The best result was obtained by carrying out the reaction at room temperature in a 1:1 mixture of CH 2 Cl 2 and HFIP without AcOH, and 3a was isolated in 80 % yield with high selectivity (3a:5a = 34:1) (Entry 5). A commercially available (diacetoxyiodo)benzene showed a similar reactivity as DIT (Entry 7). When BTI was used instead of DIT, the starting material 1a was consumed quickly, but a mixture of unidentifiable products was formed.  The ring-enlargement reaction steroselectively proceeded to provide 3a as a single stereoisomer and its stereochemistry was determined from NOESY experiment.
As shown in Table 2, various 2,5-substituted tetrahydrofuran derivatives 1b-d could be converted to the corresponding 2,5-disubstituted tetrahydropyran derivatives 3b-d, which can be key intermediates for the synthesis of natural products [2]. The reaction proceeded stereospecifically and the trans-3c or cis-2,5-disubstituted tetrahydropyran derivative 3d was obtained selectively from trans-1c or the cis-disubstituted derivative 1d, respectively. A 7-membered cyclic ether, 3g, could also be prepared stereoselectively from a tetrahydropyran derivative, 1g, using DIT.  Table 2. Acyloxy ring-enlargement of cyclic ethers by DIT and BTI a a If otherwise not mentioned, the reaction was carried out using 1.1 eq of DIT to 1 in a mixture of CH 2 Cl 2 and HFIP (1:2). b Isolated yield based on 1. Yield of 5 was determined by GC. c the reaction was carried out using 2 eq of DIT in HFIP. d BTI was used instead of DIT.
On the other hand, the reaction of 4-membered cyclic ethers 1e,f with DIT was sluggish and the starting materials remained even after 24 h. Ring-enlargement of 1e,f could be achieved by using BTI instead of DIT and the corresponding tetrahydrofuran derivatives 3e,f having a trifluoroacetoxy group could be obtained stereospecifically .
The reaction must proceed as follows: the oxidation of 1 by ArIX 2 gives an unstable hypervalent iodine intermediate 6 [14], which decomposes to an oxonium ion intermediate 7. The attack of an acyloxy group at the internal carbon of 7 provides the ring-enlarged product 3. On the other hand, an attack of an acyloxy group on the terminal carbon of 7 gives simple substituted product 5. As the bond cleavage between oxygen and the internal carbon in 7 generates a more stable carbocation, the formation of 3 takes place predominantly (Scheme 1).

Conclusions
We have succeeded in the stereoselective synthesis of 5-7 membered cyclic ethers by deiodonative ring-enlargement of cyclic ethers having an iodoalkyl substituent using hypervalent iodine compounds. According to the method, an acyloxy group-substituted cyclic ethers could be readily prepared under mild conditions. prepared from iodotoluene according to the literature [14]. BTI was obtained from Sigma-Aldrich Co. and used without further purification.