SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2015, 26, 111–115 111 letter Syn lett K. P. Stockton et al. Letter Nucleophilic Trapping of Alkoxy-Stabilized Oxyallyl Systems Gen- erated from Inosose 2-O-Mesylates Kieran P. Stockton O O O RO Stephen A. Glover RO OH RO ROH RO Ben W. Greatrex* 1. MsCl, Et3N RO OR 2. Et N, ROH RO OR School of Science and Technology, University of New England, 3 RO OR Armidale, 2351, Australia OR OR OR [email protected] up to 64% yield tolerant of stereochemistry Received: 07.09.2014 some addition products,13 trapping reactions,14 as well as Accepted after revision: 13.10.2014 reaction rates for alcoholysis reactions15 have been used as Published online: 14.11.2014 DOI: 10.1055/s-0034-1379490; Art ID: st-2014-d0743-l evidence for the oxyallyl intermediate 3, while stereospecif- ic examples of the rearrangement provide evidence for di- Abstract Protected inosose 2-O-mesylates generate oxyallyl systems rect synchronous cyclopropanone formation.9,16 by elimination of the mesylate group after enolization. The reaction is promoted by weak bases such as triethylamine and azide, and the oxy- O O O allyl systems are then trapped by nucleophilic alcohols or azide. Compu- tations using DFT/B3LYP confirm that the singlet planar oxyallyl is stabi- Br RONa RONa OR lized by the exocyclic alkoxy group. ROH Key words nucleophilic addition, carbocycle, carbohydrates, rear- rangement, carbocation 1 2 4 The oxyallyl system is a transient reactive group often – O used in [4+3]-cycloaddition reactions to form seven-mem- O OR bered and bicyclic structures.1–3 Macmillan et al. has re- RONa cently expanded their use as electrophiles that react with + ROH heteroatoms and soft π-systems when generated in the sol- 4 vent 2,2,2-trifluoroethanol. Stabilization of the oxyallyl 3 5 5–7 system can be promoted by heteroatoms such as nitrogen Scheme 1 General form of the Favorskii reaction and oxygen,1b,2 and a methoxy-stabilized oxyallyl was re- cently proposed as an intermediate following a cyclopro- pane ring-opening reaction.8 We have recently observed nucleophilic addition to 2- Oxyallyls have most notably been implicated as inter- O-alkyl-6-O-mesylinosose derivatives through an oxyallyl mediates in the Favorskii rearrangement which transforms intermediate without ring contraction and now detail our cyclic α-halo ketones into ring-contracted cycloalkanecar- findings, mechanistic investigations and the scope of the This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. boxylic acids and acyclic alkanones into chain-extended reaction. carboxylic acids or derivatives (Scheme 1).9,10 Evidence sug- In a recent report, we described the synthesis of a series gests that the reaction proceeds by the intramolecular cy- of tetra-O-alkylinosose derivatives from tetra-O-alkyldial- clization of an enolate generated from an α-halo ketone 1 to doses using organocatalysis and converted the products give a cyclopropanone 2, in equilibrium with the oxyallyl into allo- and epi-inositol.17 To examine the utility of the intermediate 3 (Scheme 1).10–12 The cyclopropanone inter- primary products of cyclization such as 6a described in this mediate is attacked by alcohol or water giving a hemiacetal report, we attempted the synthesis of some aminodeoxy- which then undergoes cyclopropane ring opening affording inositols. Thus, allo-inosose derivative 6a was converted the final product 4. The rearrangement is usually conducted into mesylate 6b using mesyl chloride and an equivalent of using alkoxide or hydroxide as both base and nucleophile, triethylamine in good yield (Scheme 2). Treating the affording esters or acids, respectively. When conformation- mesylate with sodium azide in DMF did not give the ex- ally constrained α-halo ketones are used, both ring-con- pected 6-azido-6-deoxyinosose, rather two diastereomers tracted products 4 and alkoxide α-addition products 5 can of azidoketal 7a and 7b were isolated in a 1:1 ratio in excel- be observed.10 The retention of stereochemistry observed in lent yield. An evaluation of the reaction outcome suggested © Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 111–115 112 Syn lett K. P. Stockton et al. Letter that the products arose from a Favorskii-type process with ant to stereochemistry and good yields of ketal 8, 13, and 15 opening of the cyclopropanone or direct formation of a di- were obtained from 9b, 12b, and 14b, respectively. The polar alkoxy-stabilized oxyallyl intermediate. If this was the product isolated from the reaction of 9b was spectroscopi- case, then other nucleophiles might also be used to trap the cally identical to the product obtained from the reaction of intermediate formed in the reaction. Thus, mesylate 6b was 6b as both of the epimeric α-centers are eliminated in the stirred with triethylamine in benzyl alcohol which fulfilled rearrangement. Attempted isolation of the mesylate from the role of solvent and nucleophile and to our delight af- 10 was unsuccessful and so the crude mesylate obtained af- forded a good yield of ketal 8. ter precipitating ammonium salts using ethyl acetate was treated with benzyl alcohol and triethylamine which af- OBn OBn forded minor amounts of ketal 11. Inosose 10 was a difficult 2 NaN3 R1 O 4 3 3 OBn DMF 2 substrate, prone to decomposition, especially on silica BnO 5 1 BnO 1 6 BnO which may have contributed to the low yield of 11. Confor- 82% 5 6 OR O 2 OBn 4 R mations of the products were assigned on the basis of cou- 1 2 6a R = H MsCl 7a R = N3, R = OBn pling constants which indicated that the products 11, 13, 81% 1:1 6b R = Ms Et3N 1 2 and 15 were ring-flipped relative to the starting materials. 7b R = OBn, R = N3 Et3N OBn OBn O OBn O OBn BnOH BnO 1 Et3N, BnOH 6b BnO 2 BnO BnO OR 8 65% 6 65% OBn 9a R = H MsCl 8 66% 9b R = Ms Et3N Scheme 2 Rearrangement of mesylate 6b OBn MsCl, Et3N OBn O BnOBnO 2 OBn The observed reaction outcome is similar to the Mattox 2 then OBn 1 BnO rearrangement which converts a steroidal dihydroxyace- Et N, BnOH OBn HO 3 6 18 1 tone motif into an enol aldehyde under acidic conditions. 6 17% O OBn A base-promoted variant of this rearrangement on beta- 10 11 methasone dipropionate has been reported by Li et al. who proposed hydrolysis and rearrangement of an intermediate OBn O OBn enol.19 OBn 2 BnO 1 Et3N, BnOH BnO 2 OBn The characterization of ketal 8 was performed using 1D OR BnO 6 and 2D 1H and 13C NMR spectroscopy. A methylene group, 6 52% 1 OBn OBn O not present in the starting material, was assigned on the basis of two upfield resonances at δ = 2.87 and 2.73 ppm in 12a R = H MsCl 13 Et N 99% the 1H NMR spectrum. Assignment of protons around the 12b R = Ms 3 ring was straightforward using the COSY spectrum, and the OMe O relative stereochemistry of the product was found to match OMe OMe MeO 1 Et3N, MeOH 2 2 MeO OMe the starting material although the conformation was ring- OR MeO flipped, on the basis of the trans-diaxial coupling constant 6 85% 6 1 (J = 8.8 Hz) observed between H-3 and H-4 and a gauche H- OMe OMe O 14a R = H 4 to H-5 coupling. Ketal 8 exhibited both ketone (δ = 202 MsCl 15 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 61% ppm) and ketal (δ = 102 ppm) resonances in the 13C NMR 14b R = Ms Et3N spectrum consistent with the proposed structure. Scheme 3 Synthesis and rearrangements of 9b, 10, 12b, and 14b Many reactions on carbohydrates and inositols show showing conformations of the products dependence on the stereochemistry of the substrate. In ad- dition, the Favorskii reaction on cyclohexyl substrates is in- All mesylates underwent varying degrees of decomposi- fluenced by the relative geometry of both the acidic proton tion on silica so we applied our chromatography-free pro- and the leaving group.10 To examine the scope of the reac- cedure for 10 to the other hydroxy ketones (Table 1). tion and the effect of stereochemistry, a series of inososes The yields obtained from 6a and 12a were superior us- were subjected to the reaction conditions (Scheme 3). ing this chromatography-free methodology, however, both Mesylation of the alcohols under standard conditions af- 9a and 14a afforded inferior isolated yields of ketals. Appli- forded 9b, 12b, and 14b which were then treated with tri- cation of the conditions to the methyl ether 16 afforded a ethylamine in benzyl alcohol or in the case of 14b with tri- poor yield of ketal 17. ethylamine in methanol. The reaction was generally toler- © Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 111–115 113 Syn lett K. P. Stockton et al. Letter Table 1 Chromatography-Free Rearrangement Starting with Hydroxy OBn H Ketonea OBn BnO Yield Entry Starting material Product OMs O (%) OBn 1 6a 8 58 6b 2 9a 8 30 + Et3N – H 4 12a 13 64 5 14a 15 45 OBn OBn OBn OBn – OMe OMe O – MsO H OMe OMe MeO BnO BnO 6 27 BnO OMs O– MeO MeO BnO O O OMe OH OMe 16a 17 16 17 a Reactions were performed on 40–60 mg of hydroxy ketone using 2 equiv of MsCl and Et3N and once complete, amine salts were precipitated using ring-flip EtOAc, the mixture filtered, concentrated, and BnOH or MeOH (2 mL) and – Et3N (4 equiv) were added.