HETEROCYCLES
An International Journal for Reviews and Communications in Heterocyclic ChemistryWeb Edition ISSN: 1881-0942
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Received, 2nd August, 2008, Accepted, 7th October, 2008, Published online, 9th October, 2008.
DOI: 10.3987/COM-08-S(F)91
■ Synthesis of Annulated 1,4-Dioxanes and Perhydro-1,4-oxazines by Domino-Wacker-Carbonylation and Domino-Wacker-Mizoroki-Heck Reactions
Lutz F. Tietze,* Arne Heins, Mohammad Soleiman-Beigi, and Christian Raith
Institute of Organic and Biomolecular Chemistry, Georg-August-University, Tammannstr. 2, D-37077 Göttingen, Germany
Abstract
Palladium(II)-catalyzed domino reactions for the formation of 1,4-dioxanes and perhydro-1,4-oxazines starting from hydroxy alkenes are described. The domino-Wacker-carbonylation comprises a Wacker oxidation, subsequent CO-insertion and a nucleophilic substitution of the intermediately formed Pd-species. The domino-Wacker-Mizoroki-Heck reaction proceeds via a Wacker oxidation, subsequent insertion into the olefinic π-bond of α,β-unsaturated carbonyl compounds and β-hydride elimination.INTRODUCTION
The domino-Wacker-carbonylation and the domino-Wacker-Mizoroki-Heck reaction are versatile methods for the synthesis of chromanes.1 The procedure has been used by us not only for the preparation of natural products and analogues as vitamin E (1)2 and 4-dehydroxydiversonol (3),3 but also for the production of different heterocycles.4
In these transformations a phenol as 3 containing an unsaturated side chain is treated with Pd(OTFA)2 and an α,β-unsaturated carbonyl compound or an alcohol under a CO-atmosphere. Thus, reaction of 3 with methyl vinyl ketone (4) in the presence of a catalytic amount of the (S,S)-Bn-BOXAX ligand (5)5 led to chroman 6 in up to 86% yield with 97% ee, which was transformed in a few steps into 1.
However, as described in this article, these domino reactions can not only be performed using phenols but also alicyclic alcohols as substrates to give 1,4-dioxanes. Moreover, it also allows the synthesis of perhydro-1,4-oxazines.
RESULTS AND DISCUSSION
The synthesis of 1,4-dioxanes and perhydro-1,4-oxazines using a Pd-catalyzed domino-Wacker-carbonylation and a domino-Wacker-Mizoroki-Heck reaction, respectively, requires the use of mono-O-allylated aliphatic 1,2-diols or N-allylated 2-aminoalcohols as substrates. The synthesis of these compounds can efficiently be accomplished by a selective allylation of one of the two hydroxy groups of the 1,2-diols or the nitrogen of N-Boc protected 2-aminoalcohols by a nucleophilic substitution with allyl halides 7 or 8. The further transformation of these compounds to give the desired products is accomplished using a catalytic amount of Pd(OTFA)2 or PdCl2, equimolar amounts of p-benzoquinone for reoxidizing the in situ formed Pd0 species and either CO and an alcohol usually MeOH or a α,β-unsaturated carbonyl compound 9 or 10 (Scheme 3).
SYNTHESIS OF THE SUBSTRATES FOR DOMINO-REACTIONS
The substrates 22–29 for the domino-Wacker-carbonylation reactions and the domino-Wacker-Mizoroki-Heck reactions were prepared by allylation of either mono- or unprotected 1,2-diols 11–18 with β-methallyl bromide (7) or chloride (8) and sodium hydride as base (Scheme 4). Using β-methally chloride (8) as reagent TBAI had to be added to allow a reasonable transformation.
The enantiomerically pure dihydroxy-compounds 11 and 12 were obtained via an epoxidation of cyclohexene and 1,4-dihydronaphthalene, respectively followed by an enantioselective opening of the meso-compounds using an enantiopure Co-salene complex and benzoate.6 Enantiopure compound 13 was synthesized using a Sharpless-dihydroxylation of indene and selective TBS protection.7 Allylation of these compounds with 7 or 8 followed by removal of the protecting groups led to 22, 23 and 24 in 40–50% yield over two steps.
The substrates rac 25–rac 29 were prepared directly from the corresponding 1,2-diols rac-14–rac-15 and the meso compounds 16–18 by monoallylation in 35–60% yield together with the bisallylated compounds and starting material.
As the domino-transformations did not tolerate basic amino functionalities, N-Boc protected substrates rac-30, 31 and 32 were prepared from rac-19, enantiopure 20 and 21. To assure a selective N-allylation, the employed corresponding 2-aminoalcohols were transformed into the N-Boc amides, then the hydroxy group was protected as silyl ether. The allylation with 7 or 8 and the following silyl ether cleavage led to rac-30 as well as enantiopure 318 and 32 in 49–68% yield over two steps.
DOMINO-WACKER-CARBONYLATION REACTION
The domino-Wacker-carbonylation reaction of enantiopure 22 and 23 as well as of rac-22, rac-27 and rac-30 using palladium(II)chloride in methanol under an atmosphere of CO for 1.5–4 h at 60 °C led to the desired compounds 31–38 in 72–90% yield. As expected two diastereomers were obtained in a 19:81 to 34:66 ratio (Table 1).
Interestingly, the cis-1,2-disubstituted cyclohexane derivative rac 28 and the trans-1,2-disubstituted cyclopentane derivative rac-25 did not react under these conditions. The reaction of the N-Boc protected compound rac 30 gave a mixture of rac 37 and rac 38 in 79% yield in a ratio of 22:78 after a reaction time of 4 h, which is probably due to a strong steric hindrance caused by the BOC-group.
For comparison we also used achiral 32 which could be transformed in an asymmetric reaction in the presence of the BOXAX ligand 5 to give 39 in 70% yield and 87% ee. We have also tried to perform a kinetic resolution using rac-22 and rac-27 in the presence of BOXAX ligand 5. However, under these conditions the reaction slowed down considerably, that even after 10 days less than 10% of the desired product was formed.
DOMINO-WACKER-MIZOROKI-HECK REACTION
For the domino-Wacker-Mizoroki-Heck reactions of the alkenyl phenols we used d(OTFA)2 and equimolar amounts of p-benzoquinone in the presence of methyl acrylate (9), acrolein (10a), methyl vinly ketone (10b) and ethyl vinyl ketone (10c) in CH2Cl2 as solvent at rt. These conditions had also been used in the already described transformations using phenols.2,4a Thus, reaction of the trans- and cis-cyclopentanediol and cis-tetrahydrofuran-3,4-diol derivatives rac-25, rac-27 and rac-29 led to the 1,4-dioxanes rac-40–rac-54 in yields of 33 to 77%. The lowest yield was obtained using acrolein (10a), whereas the highest yield was observed using methyl acrylate (9). However, methyl and ethyl vinyl ketone (10b and 10c) gave comparable yields. Interestingly, using the domino-Wacker-Mizoroki-Heck reaction also the trans-disubstituted cyclopentane derivative rac-25 reacted though in only 39% yield, whereas in the domino-Wacker-carbonylation reaction a transformation could not be achieved with this substrate. On the other hand, the usage of methyl crotylate as a more hindered α,β-unsaturated carbonyl compound failed since only traces of the desired product were formed within five days. Also, a kinetic resolution starting with racemic substrates in the presence of the (S,S)-Bn-BOXAX (5) ligand was not possible due to a strong reduction of the reaction rate. However, enantiopure 1-(methallyloxy)indane-2-ol (24) and N-Boc-protected 1-(methallylamino)indane-2-ol 31 provided the annulated tricyclic 1,4-dioxans 54 and 55 and the perhydro-1,4-oxazines 56 and 57 in 56 and 91% yield, respectively. In all transformations, diastereomers were formed as expected ranging from 50:50 to 70:30.
It should be noted that there is a main difference between the domino-Wacker-carbonylation reaction and the domino-Wacker-Heck-Mizoroki reaction, which concerns the reaction rate. Whereas using the first procedure a full transformation is accomplished within a few hours, the second procedure usually needs a few days.
STRUCTURE DETERMINATION
The relative configuration of the obtained diastereomers could be determined for 31, 32, 37 and 38 using NOESY experiments. In all other cases a differentiation employing NMR spectroscopy was not possible.
CONCLUSION
We have reported on a new and operationally simple methods for the preparation of 1,4-dioxanes and perhydro-1,4-oxazines starting from rapidly available precursors. The methodology is based on an efficient palla¬dium-catalyzed domino-reaction, initiated by a Wacker oxidation and subsequent insertion of the Pd-species formed into the π-bonds of CO or α,β-unsaturated carbonyl compounds.
EXPERIMENTAL
General Procedure A: Allylation using NaH: The substrate, dissolved in dry DMF (3 mL/mmol), was carefully treated with NaH (1.00 eq.) at 0 °C. After warming up to rt and the end of gas release, the allyl hallide 7 or 8 as well as TBAI (cat.) in the case of using 8 were added and the reaction mixture stirred for 2–24 h at 60 °C (TLC-Control). Then H2O (5 mL/mmol) was added, the solution neutralized with 1 n HCl and the aqueous phase extracted with Et2O (3 × 5 mL/mmol). The combined organic layers were washed with H2O (15 mL/mmol) and brine, dried over MgSO4 and the solvent removed in vacuo. The crude product was purified by column chromatography on silica gel.
General Procedure B: Domino-Wacker-carbonylation reaction: A mixture of palladium(II)chloride (0.10 eq.), p-benzoquinone (4.00 eq.) and the substrate in MeOH (2 mL) was stirred at 60 °C for 1–4 h under a CO-atmosphere using a balloon filled with carbon monoxide. Then the reaction mixture was treated with 1 n HCl (50 mL) and the aqueous phase extracted with Et2O (3 × 50 mL). The combined organic phases were washed with 1 n NaOH (3 × 10 mL), brine and dried over MgSO4. The solvent was removed in vacuo and the crude product purified by column chromatography on silica gel.
General Procedure C: Domino-Wacker-Mizoroki-Heck reaction: A mixture of palladium trifluoroacetate (0.032 mmol) and p-benzoquinone (1.29 mmol) in CH2Cl2 (0.5 mL) was stirred at rt for 30 min. Afterwards the substrate (0.320 mmol) and the α,β-unsaturated carbonyl compound 9 or 10 (0.96 mmol) were added as solution in CH2Cl2 (0.5 mL) and the mixture was stirred at rt. After complete conversion (TLC-control, typically several days) the mixture was treated with 1n HCl (5 mL) and the aqueous phase extracted with Et2O (3 × 5 mL). The combined organic phases were washed with 1n NaOH solution (3 × 5 mL) and brine and dried over MgSO4. The solvent was removed in vacuo and the crude product purified by column chromatography on silica gel.
(1R,2R)-2-Hydroxycyclohexyl benzoate (11): A solution of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicyliden)-1,2-cyclohexanediaminocobalt (31.0 mg, 51.0 μmol) and benzoic acid (680 mg, 5.60 mmol) in TBME (2 mL) was stirred under O2 for 30 min. Volatile materials were removed in vacuo. The flask was recharged with nitrogen, i-Pr2NEt (724 mg, 976 µL, 5.60 mmol) was added, and the stirred mixture was cooled to 4 °C. Cyclohexene oxide (500 mg, 5.09 mmol) was added and the resulting dark brown solution was stirred at 4 °C for 5 d. The product mixture was diluted with Et2O (10 mL), washed with 1 n aq. HCl (5 × 2 mL) and saturated aq. NaHCO3 (2 × 2 mL), dried over MgSO4, and filtered. The solution was concentrated in vacuo and the resulting solid was recrystallized four times from CH2Cl2/heptane to afford the product 11 (567 mg, 2.62 mmol, 51%) as colorless crystals. 1H-NMR (300 MHz, CDCl3): δ = 1.21–2.20 (m, 8 H, 3-H2, 4-H2, 5-H2, 6-H2), 2.39 (d, J = 3.7 Hz, 1 H, OH), 3.65–3.75 (m, 1 H, 2-H), 4.79 (mc, 1 H, 1-H), 7.38–7.45 (m, 2 H, Ph-Hm), 7.54 (tt, J = 7.4, 2.2 Hz, 1 H, Ph-Hp), 8.00–8.07 (m, 2 H, Ph-Ho). 13C-NMR (50.3 MHz, C6D6): δ = 23.67 (C-4), 23.83 (C-5), 29.94 (C-6), 32.94 (C-3), 72.70 (C-2), 77.21 (C-1), 128.31 (Ph-CHm), 129.61 (Ph-CHo), 130.28 (Ph-Ci), 132.98 (Ph-CHp), 166.38 (Ph-CO2). IR (KBr): ν (cm-1) = 3533, 2936, 2860, 1692, 1454, 1323, 1279, 1133, 1071, 995, 917, 850, 711. UV (CH3CN): λmax (lg ε) = 192.5 nm (4.5717), 197.5 (4.5997), 227.5 (4.1039), 272 (2.9441), 279.5 (2.8488). MS (DCI, 200 eV): m/z (%) = 458 (15) [2M+NH4]+, 255 (10) [M+NH3+NH4]+, 238 (100) [M+NH4]+.
(2R,3R)-(3-Hydroxy-1,2,3,4-tetrahydronaphthalene-2-yl)(phenyl)methanone 12: A solution of 1,4-dihydronaphthalene (779 mg, 5.98 mmol) in CH2Cl2 (11 mL) was cooled to 0 °C and mCPBA (2.21 g, 8.97 mmol) was added. The mixture was stirred at rt for 16 h, then aq. NaHCO3 (10 mL) was added and stirring was continued for another 30 min. The organic layer was washed with aq. NaHCO3 (2 ×10 mL), dried over MgSO4 and the solvent removed in vacuo to provide meso-1a,2,7,7a-tetrahydronaphtho[2,3-b]oxirene (873 mg, 5.97 mmol, quant.) after column chromatography on silica gel (P/Et2O = 8:1) as a colourless solid. 1H-NMR (300 MHz, CDCl3): δ = 3.18 (d, J = 17.6 Hz, 2 H, 2-Ha, 7-Ha), 3.31 (d, J = 17.6 Hz, 2 H, 2-Hb, 7-Hb), 3.47 (dd, J = 2.4, 1.3 Hz, 2 H, 1a-H, 7a-H), 7.04 (dd, J = 5.6, 3.5 Hz, 2 H, 4-H, 5-H), 7.14 (dd, J = 5.6, 3.5 Hz, 2 H, 3-H, 6-H). 13C-NMR (75.5 MHz, CDCl3): δ = 29.66 (C-2, C-7), 51.69 (C-1a, C-7a), 126.48 (C-4, C-5), 129.20 (C-5, C-8), 131,42 (C-2a, C-6a). IR (film): ν (cm-1) = 3343, 3004, 2909, 2247, 1498, 1456, 1422, 1062, 1043, 818, 746. UV (CH3CN): λmax (lg ε) = 194.5 nm (4.5457), 264 (2.4285), 271 (2.4009). MS (DCI, 200 eV): m/z (%) = 181 (12) [M+NH3+NH4]+, 164 (100) [M+NH4]+. A solution of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicyliden)-1,2-cyclohexanediaminocobalt (62.0 mg, 103 µmol,) and benzoic acid (276 mg, 2.26 mmol) in TBME (2 mL) was stirred under O2 for 30 min. Volatile materials were removed in vacuo. The flask was recharged with nitrogen, i-Pr2NEt (292 mg, 393 µL, 2.26 mmol) and meso-1a,2,7,7a-tetrahydronaphtho[2,3-b]oxirene (300 mg, 2.05 mmol) was added (300 mg, 2.05 mmol) and the resulting dark brown solution stirred at rt for 3 d. The product mixture was diluted with Et2O (10 mL), washed with 1 n aq. HCl (5 ×2 mL) and saturated aq. NaHCO3 (2 × 2 mL), dried over MgSO4, and filtered. The solution was concentrated in vacuo and the resulting solid was recrystallized 4 times from CH2Cl2/heptane to afford the product 12 (386 mg, 1.43 mmol, 70%) as a colourless solid. 1H-NMR (300 MHz, CDCl3): δ = 2.93 (dd, J = 16.1, 8.8 Hz, 1 H, 4-Ha), 2.99 (dd, J = 16.1, 8.6 Hz, 1 H, 1-Ha), 3.28 (dd, J = 16.5, 5.7 Hz, 1 H, 4-Hb), 3.41 (dd, J = 16.5, 5.8 Hz, 1-H, 4-Hb), 4.24 (ddd, J = 8.8, 8.4, 5.7 Hz, 1 H, 3-H), 5.29 (ddd, J = 8.6, 8.4, 5.8 Hz, 1 H, 2-H), 7.13 (mc, 4 H, 5-H, 6-H, 7-H, 8-H), 7.44 (mc, 2 H, Ph-Hm), 7.57 (mc, 1 H, Ph-Hp), 8.05 (mc, 2 H, Ph-Ho). 13C-NMR (125 MHz, CDCl3): δ = 33.31, 36.08 (C-1, C-4), 69.59 (C-3), 75.25 (C-2), 126.48, 126.53 (C-6, C-7), 128.44 (Ph-CHm), 128.67, 128.87 (C-5, C-8), 129.69 (Ph-CHo), 129.95 (Ph-Ci), 132.99, 133.34 (C-4a, C-8a), 133.24 (Ph-CHp), 166.65 (CO2Ph). IR (pellet): ν (cm-1) = 3517, 2933, 2901, 2851, 1692, 1452, 1278, 1124, 1028, 991, 713, 438. UV (CH3CN): λmax (lg ε) = 192.5 nm (4.9177), 194.5 (4.9452), 216.5 (4.1612), 228 (4.1613), 265 (3.1388), 272 (3.1773), 279.5 (2.9243). MS (DCI, 200 eV): m/z (%) = 554 (15) [2M+NH4]+, 286 (100) [M+NH4]+, 269 (10) [M+H]+.
tert-Butyl rac-trans-2-(triisopropylsilyloxy)cyclohexylcarbamate rac-19: A suspension of 2-aminocyclohexanol hydrochloride (1.00 g, 6.60 mmol) in THF (30 mL) was treated with NaH (60% in mineral oil, 264 mg, 6.60 mmol) and stirred at rt for 1.5 h. Afterwards di-tert-butyl dicarbonate (1.51 g, 6.93 mmol) was added, and the mixture was stirred at rt for 4 h. The solvent was removed in vacuo, H2O (10 mL) was added and the aqueous phase was extracted with Et2O (3 × 30 mL). The solvent was removed under reduced to provide rac-tans-tert-butyl 2-hydroxycyclohexylcarbamate (940 mg, 4.37 mmol, 66%) as a colourless solid. 1H-NMR (300 MHz, CDCl3): δ = 1.45 (s, 9 H, C(CH3)3), 1.67 (s, 1 H, OH), 1.06–1.37 (m, 4 H, 4-H2, 5-H2), 1.64–1.76 (m, 2 H, 3-Ha, 6-Ha), 1.91–2.09 (m, 2 H, 3-Hb, 6-Hb), 3.21–3.39 (m, 2 H, 1-H, 2-H), 4.54 (sbr, 1 H, NH). 13C-NMR (125 MHz, CDCl3): δ = 24.00, 24.68 (C-4, C-5), 28.32 (C(CH3)3), 31.74, 34.13 (C-3, C-6), 56.35 (C-1), 75.35 (C-2), 79.93 (C(CH3)3), 157.20 (CO2C(CH3)3). IR (pellet): ν (cm-1) = 3329, 2932, 1681, 1535, 1449, 1363, 1240, 1176, 1125, 1068, 1016, 854, 645. MS (ESI): m/z (%) = 238 (100) [M+Na]+, 453 (8) [2M+Na]+. To a solution of rac-tans-tert-butyl 2-hydroxycyclohexylcarbamate (940 mg, 4.37 mmol) and imidazole (446 mg, 6.55 mmol) in CH2Cl2 (20 mL) was added Chlorotriisopropylsilane (1.26 g, 1.40 mL, 6.55 mmol). The mixture was stirred at rt for 3 d, H2O (10 mL) was added. The aqueous phase was extracted with CH2Cl2 (3 × 20 mL), dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (P/Et2O = 20:1) to provide rac-19 (1.16 g, 3.14 mmol, 72 %) as a colourless solid. 1H-NMR (300 MHz, CDCl3): δ = 1.07 (s, 18 H, 3 × CH(CH3)2), 1.43 (s, 9 H, C(CH3)3), 0.84–1.57 (m, 7 H, 3 × CH(CH3)2, 4-H2, 5-H2), 1.63–1.90 (m, 3 H, 3-H2, 6-Ha), 2.02–2.14 (m, 1 H, 6-Hb), 3.34–3.64 (m, 2 H, 1-H, 2-H), 4.55 (mc, 1 H, NH). 13C-NMR (150 MHz, CDCl3): δ = 12.55 (CH(CH3)2), 18.16 (CH(CH3)2), 23.13, 23.45 (C-4, C-5), 28.40 (C(CH3)3), 30.45, 33.69 (C-3, C-6), 55.23 (C-1), 72.80 (C-2), 82.18 (C(CH3)3), 155.51 (CO2(C(CH3)3). IR (pellet): ν (cm-1) = 3368, 2943, 2866, 1686, 1532, 1462, 1366, 1321, 1179, 1107, 1045, 1023, 883, 779, 678. MS (ESI): m/z (%) = 372 (100) [M+H]+. HRMS (ESI): calcd for [C20H41NO3Si + Na]+: 371.286; confirmed.
tert-Butyl 2-(triisopropylsilyloxy)phenylcarbamate 21: 2 Aminophenol (2.00 g, 18.3 mmol) in THF (20 mL) was treated with di-tert-butyl dicarbonate (4.20 g, 19.2 mmol) and stirred at rt for 13 h. Afterwards the solvent was removed unter reduced pressure, H2O (50 mL) was added and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over MgSO4, the solvent was removed in vacuo and the resulting solid washed with CCl4 (4 × 50 mL) to give tert-butyl 2-hydroxyphenylcarbamate (2.98 g, 14.2 mmol, 78%) as a colourless solid. 1H-NMR (300 MHz, CD3OD): δ =1.53 (s, 9 H, C(CH3)3), 6.52–6.90 (m, 4 H, 3-H, 4-H, 5-H, 6-H), 7.62 (d, J = 7.9 Hz, 1 H, NH). 13C-NMR (125 MHz, CD3OD): δ =28.64 (C(CH3)3), 81.27 (C(CH3)3), 116.12, 120.67, 121.03, 124.69, 127.69 (C-1, C-3, C-4, C-5, C-6), 148.19 (C-2), 155.48 (CO2C(CH3)3). IR (pellet): ν (cm-1) = 3427, 3292, 2986, 1691, 1614, 1522, 1456, 1326, 1227, 1151, 1054, 927, 842, 777, 750, 735, 611. UV (CH3CN): λmax (lg ε) = 204.5 nm (4.6047), 235.0 (4.0397), 281.5 (3.5691). MS (ESI): m/z (%) = 232 (100) [M+Na]+. To a solution of tert-butyl 2-hydroxyphenylcarbamate (2.00 g, 9.56 mmol) and imidazole (977 mg, 14.3 mmol) in CH2Cl2 (30 mL) was added Chlorotriisopropylsilane (2.76 g, 14.3 mmol). The mixture was stirred at rt for 20 h, H2O (15 mL) was added. The aqueous phase was extracted with CH2Cl2 (3 × 40 mL), dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (P/Et2O = 100:1) to provide 21 (2.86 g, 7.82 mmol, 82%) as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ = 1.12 (d, J = 7.3 Hz, 18 H, 3 × CH(CH3)2), 1.24–1.41 (m, 3 H, 3 × CH(CH3)2), 1.51 (s, 9 H, C(CH3)3), 6.78–6.89 (m, 2 H, 3-H, 5-H), 6.93 (dt, J = 6.9, 2.2 Hz, 1 H, 4-H), 7.11 (sbr, 1 H, NH), 7.99 (d, J = 8.0 Hz, 1 H, 6-H). 13C-NMR (125 MHz, CDCl3): δ = 12.71 (3 × CH(CH3)2), 17.89 (3 × CH(CH3)2), 28.30 (C(CH3)3), 80.00 (C(CH3)3), 117.31, 118.54, 121.53, 122.18 (C-3, C-4, C-5, C-6), 129.83 (C-1), 143.92 (C-2), 152.75 (CO2C(CH3)3). IR (film): ν (cm-1) = 3438, 2946, 2869, 1735, 1598, 1520, 1450, 1392, 1367, 1328, 1265, 1234, 1158, 1113, 1049, 998, 916, 883, 828, 749, 707, 683. UV (CH3CN): λmax (lg ε) = 206.5 nm (4.6141), 237 (4.155), 280 (3.493). MS (DCI, 200 eV): m/z (%) = 749 (53) [2M+NH4]+, 383 (100) [M+NH4]+, 367 (35) [M+H]+.
SYNTHESIS OF MONOALLYL ETHERS
(1R,2R)-trans-2-(2-Methallyloxy)cyclohexanol (22): According to general procedure A, 11 (551 mg, 2.50 mmol) was reacted with β-methallyl chloride (8) (451 mg, 488 μL, 5.00 mmol) within 24 h at 60 °C to provide (1R,2R)-2-(2-methallyloxy)cyclohexyl benzoate (612 mg, 2.23 mmol, 89%) as a colorless liquid after column chromatography on silica gel (P/Et2O = 20:1). 1H-NMR (300 MHz, CDCl3): δ = 1.65 (s, 3 H, 2'-CH3), 1.16–2.12 (m, 8 H, 3-H2, 4-H2, 5-H2, 6-H2), 3.44–3.53 (m, 1 H, 1-H), 3.94 (d, J = 12.4 Hz, 1 H, 1'-Ha), 4.02 (d, J = 12.4 Hz, 1 H, 1'-Hb), 4.78 (mc, 1 H, 3'-Ha), 4.96 (mc, 1 H, 3'-Hb), 5.01– 5.11 (m, 1 H, 2-H), 7.33–7.49 (m, 2 H, Ph-Hm), 7.51–7.60 (m, 1 H, Ph-Hp), 8.02–8.10 (m, 2 H, Ph-Ho). 13C-NMR (125 MHz, CDCl3): δ = 13.41 (2'-CH3), 23.03, 23.11 (C-4, C-5), 29.58, 29.62 (C-3, C-6), 68.10 (C-1'), 73.47 (C-1), 78.02 (C-2), 111.92 (C-3'), 128.25 (Ph-Cm), 129.54 (Ph-Co), 129.60 (Ph-Ci), 132.70 (Ph-Cp), 142.63 (C-2'), 166.22 (CO2Ph). UV (CH3CN): λmax (lg ε) = 192.5 nm (4.6262), 194.5 (4.6446), 228.0 (4.1016), 272 (2.9359), 279.5 (2.8395). MS (ESI): m/z (%) = 297 (100) [M+Na]+, 275 (5) [M+H]+. A solution of (1R,2R)-2-(2-methallyloxy)cyclohexyl benzoate (612 mg, 2.23 mmol) in MeOH (36 mL) was cooled to 0 °C, and a 0.5 m NaOMe-solution was added dropwise. The mixture was stirred at rt for 3.5 d, aq. saturated NH4Cl (10 mL) was added and the aqueous phase was extracted with Et2O (3 × 30 mL). The combined organic phases were dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (P/Et2O = 5:1) to provide 22 (169 mg, 995 µmol, 45%) as a colorless liquid. 1H-NMR (300 MHz, C6D6): δ = 1.73 (s, 3 H, 2'-CH3), 1.04–2.09 (m, 8 H, 3-H2, 4-H2, 5-H2, 6-H2), 2.69 (s, 1 H, OH), 3.05 (ddd, J = 10.5, 8.7, 4.4 Hz, 1 H, 2-H), 3.44 (mc, 1 H, 1-H), 3.85 (d, J = 12.3 Hz, 1 H, 1'-Ha), 4.02 (d, J = 12.3 Hz, 1 H, 1'-Hb), 4.86 (mc, 1 H, 3'-Ha), 4.95 (mc, 1 H, 3'-Hb). 13C-NMR (125 MHz, CDCl3): δ = 19.61 (2'-CH3), 23.93, 24.19 (C-4, C-5), 29.04 (C-6), 31.98 (C-3), 72.64 (C-1'), 73.84 (C-2), 83.21 (C-1), 112.07 (C-3'), 142.55 (C-2'). IR (film): ν (cm-1) = 3442, 3075, 2934, 2861, 1656, 1373, 1233, 1082, 997, 898, 848. MS (DCI, 200 eV): m/z (%) = 188 (100) [M+NH4]+. GC: temperature: 90 °C, pressure: 65 kPa, column: heptakis(6-O-TBDMS-2,3-di-O-methyl)-β-cyclodextrin (50% in OV 1701), tR = 19.865 min (E1), 20.687 (E2); ee = 86%.
rac-trans-2-(2-Methallyloxy)cyclohexanol (rac 22): According to general procedure A, rac-trans-cyclohexane 1,2 diol (15, 2.00 g, 17.2 mmol) was reacted with β-methallyl chloride (8) (1.87 g, 2.02 mL, 20.7 mmol) within 12 h at 60 °C to provide rac 22 (1.45 g, 8.55 mmol, 50%) as a colorless liquid after column chromatography on silica gel (P/Et2O = 4:1). 1H-NMR (300 MHz, CDCl3): δ = 1.75 (s, 3 H, 2'-CH3), 1.04-2.14 (m, 8 H, 3-H2, 4-H2, 5-H2, 6-H2), 2.73 (s, 1 H, OH), 3.08 (mc, 1 H, 2-H), 3.45 (mc, 1 H, 1-H), 3.87 (d, J = 12.3 Hz, 1 H, 1'-Ha), 4.05 (d, J = 12.3 Hz, 1 H, 1'-Hb), 4.88 (mc, 1 H, 3'-Ha), 4.94 (mc, 1 H, 3'-Hb). 13C-NMR (125 MHz, CDCl3): δ = 19.61 (2'-CH3), 23.93, 24.19 (C-4, C-5), 29.04 (C-6), 31.98 (C-3), 72.64 (C-1'), 73.84 (C-2), 83.21 (C-1), 112.07 (C-3'), 142.55 (C-2'). IR (film): ν (cm-1) = 3418, 3076, 2934, 2861, 1725, 1656, 1451, 1373, 1234, 1082, 997, 899, 849. MS (DCI, 200 eV): m/z (%) = 188 (100) [M+NH4]+. HRMS (ESI): calcd for [C10H18O2 + Na]+: 193.1204; confirmed.
(2R,3R)-3-(2-Methallyloxy)-1,2,3,4-tetrahydronaphthalen-2-ol 23: According to general procedure A, 12 (234 mg, 870 μmol) was reacted with β-methallyl bromide (7) (235 mg, 175 μL, 1.74 mmol) within 20 h at rt to provide (2R,3R)-3-(2-methallyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl benzoate (127 mg, 395 µmol, 45%) as a colourless solid after column chromatography on silica gel (P/Et2O = 10:1). 1H-NMR (300 MHz, CDCl3): δ = 1.69 (s, 3 H, 2'-CH3), 2.94 (t, J = 6.1 Hz, 1 H, 4-Ha), 2.99 (t, J = 6.2 Hz, 1 H, 1-Ha), 3.22 (dd, J = 16.8, 5.0 Hz, 1 H, 1-Hb), 3.39 (dd, J = 17.0, 5.0 Hz, 1 H, 4-Hb), 3.96 (ddd, J = 6.6, 6.5, 5.1 Hz, 1 H, 3-H), 4.06 (s, 1 H, 1'-H2), 4.85 (mc, 1 H, 3'-Ha), 4.95 (mc, 1 H, 3'-Hb), 5.51 (dd, J = 12.0, 6.0 Hz, 1 H, 2-H). 7.13 (mc, 4 H, 5-H, 6-H, 7-H, 8-H), 7.40 (mc, 2 H, Ph-Hm), 7.53 (mc, 1 H, Ph-Hp), 7.98 (mc, 2 H, Ph-Ho). 13C-NMR (125 MHz, CDCl3): δ = 19.52 (2'-CH3), 32.45, 32.71 (C-1, C-4), 71.67 (C-2), 73.64 (C-1'), 74.31 (C-3), 112.50 (C-3'), 126.27, 126.30 (C-6, C-7), 128.39 (Ph-CHm), 128.84, 128.97 (C-5, C-8), 129.68 (Ph-CHo), 130.39 (Ph-Ci), 133.03 (Ph-CHp), 133.14, 133.41 (C-4a, C-8a), 142.31 (C-2'), 166.04 (CO2Ph). IR (film): ν (cm-1) = 3414, 3065, 3023, 2929, 1719, 1602, 1584, 1494, 1451, 1350, 1272, 1176, 1110, 1026, 904, 743, 711. UV (CH3CN): λmax (lg ε) = 192.5 nm (4.7873), 195.5 (4.8457), 216.5 (4.1586), 228 (4.1696), 265 (3.1466), 272 (3.1821), 280 (2.9322). MS (DCI, 200 eV): m/z (%) = 357 (54) [M+NH3+NH4]+, 340 (100) [M+NH4]+, 323 (10) [M+H]+. A solution of (2R,3R)-3-(2-methallyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl benzoate (120 mg, 372 µmo) in MeOH (6 mL) was cooled to 0 °C, and a 5.4 m NaOMe-solution (7.50 µL, 37.2 µmol) was added dropwise. The mixture was stirred at rt for 3.5 d, saturated aq. NH4Cl (5 mL) was added and the aqueous phase was extracted with Et2O (3 × 15 mL). The combined organic phases were dried over MgSO4, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (P/Et2O = 5:1) to provide 23 (169 mg, 995 µmol, 45%) as a colorless liquid. 1H-NMR (300 MHz, CDCl3): δ = 1.79 (s, 3 H, 2'-CH3), 2.73 (dd, J = 16.2, 10.0 Hz, 1 H, 4-Ha), 2.82 (dd, J = 16.4, 10.1 Hz, 1 H, 1-Ha), 2.87 (s, 1 H, OH), 3.20 (dd, J = 10.8, 5.6 Hz, 1 H, 1-Hb), 3.25 (dd, J = 10.5, 5.6 Hz, 1 H, 4-Hb), 3.57 (ddd, J = 9.8, 9.1, 5.5 Hz, 1 H, 3-H), 3.96 (mc, 1 H, 2-H), 3.99 (d, J = 12.3 Hz, 1 H, 1'-Ha), 4.14 (d, J = 12.3 Hz, 1-H, 1'-Hb), 4.92 (mc, 1 H, 3'-Ha), 5.01 (mc, 1 H, 3'-Hb), 7.11 (mc, 4 H, 5-H, 6-H, 7-H, 8-H). 13C-NMR (125 MHz, CDCl3): δ = 19.63 (2'-CH3), 33.74 (C-4), 36.03 (C-1), 70.54 (C-2), 73.27 (C-1'), 79.19 (C-3), 112.62 (C-3'), 126.16, 126.27 (C-6, C-7), 128.89, 128.92 (C-5, C-8), 133.63, 133.85 (C-4a, C-8a), 142.21 (C-2'). IR (film): ν (cm-1) = 3440, 3065, 3021, 2907, 1655, 1494, 1454, 1373, 1216, 1112, 902, 744. UV (CH3CN): λmax (lg ε) = 265 nm (2.7335), 272 (2.7432). MS (DCI, 200 eV): m/z (%) = 253 (12) [M+NH3+NH4]+, 236 (100) [M+NH4]+. HPLC (Chiralcel OD): Wavelength: 211 nm, Eluent: n-hexane / iso-propanol = 98:1, Flow: 0.8 mL/min, tR = 9.64 min , ee > 99.99 %.
rac-trans-2-(2-Methallyloxy)cyclopentanol (rac 25): According to general procedure A, rac-trans-cyclopentane 1,2 diol (14, 1.00 g, 9.79 mmol) was reacted with β-methallyl chloride (8) (974 mg, 1.05 mL, 10.8 mmol) within 3 h at 60 °C to provide rac 25 (666 mg, 4.27 mmol, 44%) as a pale yellow oil after column chromatography on silica gel (P/Et2O = 3:1). 1H-NMR (300 MHz, CDCl3): δ = 1.75 (s, 3 H, 2'-CH3), 1.80 (d, J = 2.9 Hz, 1 H, OH), 1.50–2.16 (m, 6 H, 3-CH2, 4-H2, 5-H2), 3.66–3.72 (m, 1 H, 2-H), 3.89 (d, J = 12.6 Hz, 1 H, 1'-Ha), 3.94 (d, J = 12.6 Hz, 1 H, 1'-Hb), 4.14 (mc, 1 H, 1-H), 4.88 (mc, 1 H, 3'-Ha), 4.97 (mc, 1 H, 3'-Hb). 13C-NMR (150 MHz, CDCl3): δ = 19.54 (2'-CH3), 20.43, 29.22, 32.05 (C-3, C-4, C-5), 73.23 (C-1'), 76.79 (C-1), 86.23 (C-2), 111.93 (C-3'), 142.54 (C-2'). IR (film): ν (cm-1) = 3383, 3076, 2966, 1657, 1453, 1348, 1099, 898. MS (DCI, 200 eV): m/z (%) = 191 (60) [M+NH3+NH4]+, 174 (100) [M+NH4]+. HRMS (ESI): calcd for [C9H16O2 + Na]+: 179.1043; confirmed.
rac-cis-2-(2-Methallyloxy)cyclopentanol (rac 27): According to general procedure A, meso-cyclopentane 1,2 diol (16, 1.10 g, 10.8 mmol) was reacted with β-methallyl chloride (8) (1.07 g, 1.16 mL, 11.9 mmol) within 2 h at 60 °C to provide rac 27 (1.01 g, 6.49 mmol, 60%) as a colorless liquid after column chromatography on silica gel (P/Et2O = 3:1). 1H-NMR (300 MHz, CDCl3): δ = 1.42–1.91 (m, 6 H, 3-H2, 4-H2, 5-H2), 1.76 (s, 3 H, 2'-CH3), 2.50 (d, J = 4.0 Hz, 1 H, OH), 3.69–3.77 (m, 1 H, 2-H), 3.94 (mc, 2 H, 1'-H2), 4.06–4.12 (m, 1 H, 1-H), 4.89 (mc, 1 H, 3'-Ha), 4.98 (mc, 1 H, 3'-Hb). 13C-NMR (150 MHz, CDCl3): δ = 19.50 (2'-CH3), 19.65, 27.81, 31.14 (C-3, C-4, C-5), 72.16 (C-1), 73.29 (C-1'), 80.95 (C-2), 112.11 (C-3'), 142.12 (C-2'). IR (film): ν (cm-1) = 3461, 3076, 2968, 1656, 1450, 1335, 1098, 899. MS (DCI, 200 eV): m/z (%) = 174 (100) [M+NH4]+. HRMS (ESI): calcd for [C9H16O2 + Na]+: 179.1043; confirmed.
rac-cis-2-(2-Methallyloxy)cyclohexanol (rac 28): According to general procedure A, meso-cyclohexane 1,2 diol (17, 1.00 g, 8.61 mmol) was reacted with β-methallyl chloride (8) (857 mg, 926 μL, 9.47 mmol) within 4 h at 60 °C to provide rac-28 (519 mg, 3.03 mmol, 35%) as a colorless liquid after column chromatography on silica gel (P/Et2O = 5:1). 1H−NMR (300 MHz, CDCl3): δ = 1.75 (s, 3 H, 2'-CH3), 1.20–1.88 (m, 8 H, 3-H2, 4-H2, 5-H2, 6-H2), 2.28 (s, 1 H, OH), 3.42 (mc, 1 H, 1-H), 3.83 (mc, 1 H, 2-H), 3.88 (d, J = 12.5 Hz, 1 H, 1'-Ha), 3.97 (d, J = 12.5 Hz, 1 H, 1'-Hb), 4.88 (mc, 1 H, 3'-Ha), 4.96 (mc, 1 H, 3'-Hb); 13C−NMR (125 MHz, CDCl3): δ = 19.52 (2'-CH3), 21.18, 22.12 (C-4, C-5), 26.49 (C-6), 30.42 (C-3), 68.69 (C-1'), 72.04 (C-1), 77.81 (C-2), 111.84 (C-3'), 142.50 (C-2'); IR (film): ν (cm-1) = 3410, 3076, 2936, 2861, 1726, 1449, 1368, 1249, 1080, 985, 910, 848; MS (DCI, 200 eV): m/z (%) = 188 (100) [M+NH4]+. HRMS (ESI): calcd for [C10H18O2 + Na]+: 193.1204; confirmed.
(rac)-cis-4-(2-Methallyloxy)tetrahydrofuran-3-ol (rac-29): According to general procedure A cis-tetrahydrofuran-3,4-diol (18, 2.08 g, 20.0 mmol)) was reacted in dry DMF (60 mL) with β-methallyl chloride (7,1.99 g, 22.0 mmol) for 6.5 h at rt. After work-up and column chromatography (silica gel, n-pentane/Et2O = 1 / 1) rac-29 (1.54 g, 9.6 mmol, 48%) was provided as colorless oil. 1H NMR (300 MHz, CDCl3) δ = 1.76 (sbr, 3 H, 3’-CH3), 2.86 (d, J = 5.7 Hz, 1 H, OH), 3.73–3.80 (m, 2 H, 5-Ha, 5-Hb), 3.88–3.93 (m, 2 H, 2-Ha, 2-Hb), 3.99–4.03 (m, 3 H, 4 –H, 1’-Ha, 1’-Hb), 4.28 (ddd, J = 10.5, 5.30, 5.30 Hz, 1 H, 3-H), 4.95 (sbr, 1 H, 3’-Ha), 5.00 (sbr, 1 H, 3’-Hb) ppm; 13C NMR (75 MHz, CDCl3): δ = 19.37 (2’-CH3), 69.93 (C-5), 70.23 (C-3), 73.33, 74.21 (C-2, C-1’), 77.79 (C-4), 113.01 (C-3’), 141.23 (C-2’) ppm; IR (Film): [イメージ] = 2941 cm-1, 2870, 1656, 1455, 1409, 1375, 1334, 1261, 1215, 1193, 1132, 1071, 1008, 905.6, 824.1, 731.4; MS (70 eV, EI): m/z (%) = 158.2 (12) [M]+, 103.1 (8) [M – C4H7]+, 87.1 (16) [M – OC4H7]+, 72.1 (48) [C4H7O]+, 55.1 (100) [C4H7]+; HRMS (ESI): calcd for [C8H14O3 + Na]+: 181.0841; confirmed.
tert-Butyl rac-trans-2-hydroxycyclohexyl(2-methallyl)carbamate rac-30: According to general procedure A, rac 19 (1.15 g, 3.11 mmol) was reacted with β-methallyl bromide (7) (1.26 g, 940 μL, 9.33 mmol) within 24 h at 60 °C to provide rac-trans-tert-butyl 2-methallyl-(2-(triisopropylsilyloxy)cyclohexyl)carbamate (1.02 g, 2.41 mmol, 77%) as a colorless liquid after column chromatography on silica gel (P/Et2O = 100:1). 1H-NMR (300 MHz, CDCl3): δ = 1.03 (s, 18 H, 3 × CH(CH3)2), 1.39 (s, 9 H, 3 × C(CH3)2), 1.68 (s, 3 H, 2'-CH3), 1.10–2.06 (m, 11 H, CH(CH3)3, 3-H2, 4-H2, 5-H2, 6-H2), 3.47–4.23 (m, 4 H, 1-H, 2-H, 1'-H2), 4.78 (mc, 2 H, 3'-H2). 13C-NMR (150 MHz, CDCl3): δ = 12.89 (3 × CH(CH3)2), 18.29 (3 × CH(CH3)2), 20.19 (2'-CH3), 24.48, 24.64 (C-4, C-5), 28.38 (C(CH3)3), 25.60, 36.47 (C-3, C-6), 64.64 (C-1'), 71.43 (C-1), 78.81 (C-2), 79.24 (C(CH3)3), 110.86 (C-3'), 143.15 (C-2'), 155.57 (CO2C(CH3)3). IR (film): ν (cm-1) = 2941, 2866, 1693, 1365, 1325, 1172, 1110, 989, 883, 775, 678. MS (ESI): m/z (%) = 448 (100) [M+Na]+. To a solution of rac-trans-tert-butyl 2-methallyl(2-(triisopropylsilyloxy)cyclohexyl)carbamate (1.02 g, 2.41 mmol) in THF (25 mL) was added TBAF · 3 H2O (1.14 g, 3.61 mmol). The mixture was stirred at rt for 1 h, the solvent removed in vacuo to provide rac-30 (405 mg, 1.50 mmol, 63 %) as a colorless liquid after column chromatography on silica gel (P/Et2O = 1:1). 1H-NMR (300 MHz, CDCl3): δ = 1.42 (s, 9 H, C(CH3)3), 1.71 (s, 3 H, 2'-CH3), 1.10–1.33 (m, 4 H, 4-H2, 5-H2), 1.61–2.08 (m, 4 H, 3-H2, 6-H2), 2.40 (sbr, 1 H, OH), 3.70 (sbr, 2 H, 1'-H2), 3.43–3.78 (m, 2 H, 1-H, 2-H), 4.82 (mc, 2 H, 3'-H2). 13C-NMR (150 MHz, CDCl3): δ = 20.26 (2'-CH3), 24.35, 25.35 (C-4, C-5), 29.30, 35.07 (C-3, C-6), 28.31 (C(CH3)3), 49.13 (C-1'), 61.82, 71.43 (C-1, C-2), 79.96 (C(CH3)3), 110.57 (C-3'), 143.34 (C-2'), 157.03 (CO2C(CH3)3). IR (film): ν (cm-1) = 3438, 2934, 2860, 1692, 1454, 1365, 1246, 1170, 977, 882, 768. MS (ESI): m/z (%) = 561 (11) [2M+Na]+, 292 (100) [M+Na]+. HRMS (ESI): calcd for [C15H27NO3 + Na]+: 292.1883; confirmed.
tert-Butyl 2-hydroxyphenyl(2-methallyl)carbamate 32: According to general procedure A, 21 (2.84 g, 7.77 mmol) was reacted with β-methallyl bromide (7) (3.15 g, 2.35 mL, 23.3 mmol) within 18 h at rt to provide tert-butyl 2-methallyl (2-(triisopropylsilyloxy)phenyl)carbamate (2.53 g, 6.02 mmol, 77 %) as a colorless solid after column chromatography on silica gel (P/Et2O = 50:1). 1H-NMR (300 MHz, DMSO-d6): δ = 1.15 (d, J = 7.1 Hz, 18 H, 3 × CH(CH3)2), 1.27–1.42 (m, 3 H, 3 × CH(CH3)2), 1.33 (s, 9 H, C(CH3)3), 1.71 (s, 3 H, 2'-CH3), 2.99 (s, 2 H, 1'-H2), 4.68 (mc, 1 H, 3'-Ha), 4.75 (mc, 1 H, 3'-Hb), 6.82–6.92 (m, 2 H, 3-H, 5-H), 7.08 (dd, J = 8.2, 1.8 Hz, 1 H, 6-H), 7.14 (ddd, J = 8.3, 7.3, 1.8 Hz, 1 H, 4-H). 13C-NMR (75.5 MHz, DMSO-d6): δ = 11.88 (3 × CH(CH3)2), 17.21 (3 × CH(CH3)2), 19.38 (2'-CH3), 27.39 (C(CH3)3), 78.29 (C(CH3)3), 111.52 (C-3'), 118.27, 119.85, 127.28, 130.21 (C-3, C-4, C-5, C-6), 130.21 (C-1), 141.17 (C-2'). IR (pellet): ν (cm-1) = 2967, 2946, 2867, 1693, 1599, 1581, 1499, 1381, 1365, 1346, 1300, 1284, 1254, 1206, 1173, 1142, 1116, 1057, 1040, 999, 939, 908, 881, 868, 801, 756, 719, 683, 669, 620, 582, 517, 441. UV (CH3CN): λmax (lg ε) = 272.5 nm (3.2899), 278 (3.2546). MS (EI, 70 eV): m/z (%) = 419 (47) [M]+, 346 (100) [M-C4H9O]+. To a solution of tert-butyl 2-methallyl-(2-(tri-isopropylsilyloxy)phenyl)carbamate (2.53 g, 6.02 mmol) in THF (50 mL) was added TBAF · 3 H2O (2.85 g, 9.02 mmol). The mixture was stirred at rt for 1 h, the solvent was removed in vacuo to provide 32 (1.19 g, 4.52 mmol, 75%) as a colourless solid after column chromatography on silica gel (P/Et2O = 10:1). 1H-NMR (300 MHz, CDCl3): δ = 1.49 (s, 9 H, C(CH3)3), 1.72 (s, 3 H, 2'-CH3), 4.16 (s, 2 H, 1'-H2), 4.87 (mc, 2 H, 3'-H2), 6.90 (dt, J = 7.4, 1.5 Hz, 1 H, 5-H), 7.01 (dd, J = 8.2, 1.2 Hz, 1 H, 3-H), 7.10–7.19 (m, 2 H, 4-H, 6-H). 13C-NMR (125 MHz, CDCl3): δ = 20.12 (2'-CH3), 28.17 (C(CH3)3), 56.79 (C-1'), 82.06 (C(CH3)3), 111.54 (C-3'), 119.5 (C-3), 121.06 (C-5), 127.69 (C-4, C-6), 130.90 (C-1), 141.25 (C-2'), 150.99 (C-2), 155.53 (CO2C(CH3)3). IR (pellet): ν (cm-1) = 3247, 2972, 1650, 1596, 1513, 1403, 1366, 1321, 1293, 1241, 1158, 1109, 1056, 902, 861, 759. UV (CH3CN): λmax (lg ε) = 194 nm (4.6041), 274.5 (3.4139). MS (EI, 70 eV): m/z (%) = 263 (6) [M]+, 207 (66) [M-C4H7]+, 57 (100) [tBu]+.
DOMINO-WACKER-CARBONYLATION REACTION
Methyl rac-2-(2-methyloctahydrobenzo[b][1,4]dioxin-2-yl)acetate (rac 31) and (rac 32): According to general procedure B, rac 22 (50.7 mg, 298 μmol) was reacted with p benzoquinone (129 mg, 1.19 mmol) and PdCl2 (5.28 mg, 29.8 µmol) within 2 h to provide a mixture of rac-31 and rac-32 (59.7 mg, 262 µmol, 88%, 19:81) as a pale yellow liquid after column chromatography on silica gel (P/Et2O = 5:1). 1H-NMR (300 MHz, C6D6): δ = 1.21 (s, 2.4 H, 2'-CH3), 1.49 (s, 0.6 H, 2'-CH3), 0.92–1.86 (m, 8 H, 5'-H2, 6'-H2, 7'-H2, 8'-H2), 2.32 (d, J = 14.4 Hz, 0.2 H, 2-Ha), 2.40 (d, J = 14.4 Hz, 0.2 H, 2-Hb), 2.51 (d, J = 13.5 Hz, 0.8 H, 2-Ha), 2.89 (ddd, J = 11.2, 9.2, 4.3 Hz, 1 H, 4a'-H), 3.04 (d, J = 13.5 Hz, 0.8 H, 2-Hb), 3.26 (s, 0.6 H, OCH3), 3.27 (dd, J = 11.5, 0.7 Hz, 0.8 H, 3'-Ha), 3.32 (s, 2.4 H, OCH3), 3.87 (ddd, J = 11.1, 9.0, 4.2 Hz, 0.2 H, 8a'-H), 3.54 (ddd, J = 11.0, 9.1, 4.6 Hz, 0.8 H, 8a'-H), 3.64 (dd, J = 11.3, 0.9 Hz, 0.2 H, 3'-Ha), 3.69 (dd, J = 11.5 Hz, 0.8 H, 3'-Hb), 3.83 (d, J = 11.3 Hz, 0.2 H, 3'-Hb). 13C-NMR (150 MHz, C6D6): δ = 19.80, 23.66 (2'-CH3), 24.42, 24.43, 24.52, 24.53 (C-6', C-7'), 30.36, 30.38, 30.97 (C-5', C-8'), 38.86, 44.76 (C-2), 50.96, 51.00 (OCH3), 71.90, 72.03 (C-2'), 73.62, 73.75 (C-8a'), 74.24, 74.37 (C-3'), 80.61, 80.77 (C-4a'), 170.17, 170.91 (CO2CH3). IR (film): ν (cm-1) = 2939, 2864, 1738, 1513, 1322, 1227, 1095, 1020, 853. UV (CH3CN): λmax (lg ε) = 286 nm (2.2717). MS (DCI, 200 eV): m/z (%) = 246 (100) [M+NH4]+, 229 (45) [M+H]+. HRMS (ESI): calcd for [C12H20O4 + Na]+: 251.2746; confirmed.
Methyl 2-((4aR,10aR)-2-methyl-2,3,4a,5,10,10a-hexahydronaphtho[2,3-b][1,4]dioxin-2-yl)acetate (33) and (34): According to general procedure B, 23 (45.0 mg, 206 μmol) was reacted with p-benzoquinone (89.1 mg, 825 µmol) and PdCl2 (3.62 mg, 22.9 µmol) within 90 min to provide a mixture of 37 and 38 (41.0 mg, 148 µmol, 72%, 34:64) as a colorless liquid after column chromatography on silica gel (P/Et2O = 5:1). 1H-NMR (300 MHz, CDCl3): δ = 1.28 (s, 2 H, 2'-CH3), 1.50 (s, 1 H, 2'-CH3), 2.51 (s, 0.7 H, 2-H2), 2.68 (d, J = 13.7 Hz, 0.7 H, 2-Ha), 2.81 (mc, 2 H, 10'-Ha, 5'-Ha), 2.96 (dd, J = 16.0, 5.9 Hz, 1 H, 5'-Hb), 3.07 (d, J = 13.7 Hz, 0.7 H, 2-Hb), 3.06, 3.12 (2 x dd, J = 6.0, 2.5 Hz, 1 H, 10'-Hb), 3.49 (d, J = 11.8 Hz, 1 H, 3'-Ha), 3.50 (mc, 1 H, 4a' H), 3.68 (s, 3 H, OCH3), 3.82 (d, J = 11.8 Hz, 1 H, 3'-Hb), 3.92 (ddd, J = 10.8, 9.8, 5.8 Hz, 0.66 H, 10a'-H), 4.00 (ddd, J = 10.8, 9.9, 5.9 Hz, 0.34 H, 10a'-H), 7.10 (mc, 4 H, 6'-H, 7'-H, 8'-H, 9'-H). 13C-NMR (125 MHz, CDCl3): δ = 19.54, 23.33 (2'-CH3), 34.33, 34.34 (C-5'), 35.01, 35.03 (C-10'), 38.54, 44.54 (C-2), 51.60 (OCH3), 69.95, 70.12 (C-10a'), 73.48, 73.72 (C-3'), 76.43, 76.60 (C-4a'), 126.22, 126.24, 126.26, 128.96, 128.99 (C-6', C-7', C-8', C-9'), 133.48, 133.56 (C-5a'), 133.76, 133.80 (C-9a'), 170.47, 171.16 (CO2CH3). MS (DCI, 200 eV): m/z (%) = 574 (10) [2M+Na]+, 299 (100) [M+Na]+. HRMS: calcd for [C16H20O4 + Na]+: 299.1259; confirmed.
Methyl rac-2-(2-methyl-hexahydro-2H-cyclopenta[b][1,4]dioxin-2-yl)acetate (rac 35) and (rac 36): According to general procedure B, rac-27 (49.7 mg, 318 μmol) was reacted with p benzoquinone (127 mg, 1.27 mmol) and PdCl2 (5.65 mg, 31.8 µmol) within 75 min to provide a mixture of rac-35 and rac-36 (58.7 mg, 274 µmol, 86%, 29:71) as a pale yellow liquid after column chromatography on silica gel (P/Et2O = 8:1). 1H-NMR (600 MHz, CDCl3): δ = 1.21 (s, 2.1 H, 2'-CH3), 1.35 (s, 0.9 H, 2'-CH3), 1.41–2.03 (m, 6 H, 5'-H2, 6'-H2, 7'-H2), 2.46 (d, J = 14.1 Hz, 0.3 H, 2-Ha), 2.52 (d, J = 14.1 Hz, 0.3 H, 2-Hb), 2.66 (d, J = 13.8 Hz, 0.7 H, 2-Ha), 2.85 (d, J = 13.8 Hz, 0.7 H, 2-Hb), 3.29 (d, J = 11.7 Hz, 0.3 H, 3'-Ha), 3.41 (d, J = 11.8 Hz, 0.7 H, 3'-Ha), 3.53 (d, J = 11.8 Hz, 0.7 H, 3'-Hb), 3.65 (s, 0.9 H, OCH3), 3.66 (s, 2.1 H, OCH3), 3.81 (d, J = 11.7 Hz, 0.3 H, 3'-Hb), 3.96 (dt, J = 7.8, 4.5 Hz, 0.3 H, 4a'-H), 4.01 (dt, J = 8.4, 4.5 Hz, 0.7 H, 4a'-H), 4.04 (dd, J = 4.7, 2.3 Hz, 0.3 H, 7a'-H), 4.12 (dt, J = 4.8, 1.7 Hz, 0.7 H, 7a'-H). 13C-NMR (125 MHz, CDCl3): δ = 20.12, 23.70 (2'-CH3), 20.39, 20.51, 24.49, 25.75, 30.76, 30.93 (C-5', C-6', C-7'), 38.93, 44.18 (C-2), 51.46, 51.52 (OCH3), 66.19, 66.59 (C-3'), 69.94, 70.21 (C-7a'), 70.59, 70.69 (C-2'), 76.29, 76.91 (C-4a'), 170.77, 171.28 (CO2CH3). IR (film): ν (cm-1) = 2953, 1737, 1437, 1316, 1223, 1131, 1024, 969, 914. UV (CH3CN): λmax (lg ε) = 288 nm (1.6481). MS (DCI, 200 eV): m/z (%) = 249 (5) [M+NH3+NH4]+, 232 (100) [M+NH4]+, 215 (75) [M+H]+. HRMS (ESI): calcd for [C11H18O4 + Na]+: 237.1103; confirmed.
tert-Butyl rac-2-(2-methoxy-2-oxoethyl)-2-methyloctahydrobenzo[b][1,4]oxazine-4-carboxylate (rac 37) and (rac 38): According to general procedure B, rac 30 (49.0 mg, 181 μmol) was reacted with p-benzoquinone (78.6 mg, 728 µmol) and PdCl2 (3.23 mg, 18.1 µmol) within 4 h to provide a mixture of rac-37 and rac-38 (47.3 mg, 144 µmol, 79%, 22:78) as a colorless liquid after column chromatography on silica gel (P/Et2O = 5:1). 1H-NMR (600 MHz, CDCl3): δ = 1.12 (ddd, J = 23.5, 12.0, 3.4 Hz, 1 H, 5a-Ha), 1.21 (s, 2.3 H, 2-CH3), 1.27 (s, 0.7 H, 2-CH3), 1.24–1.32 (m, 3 H, 6-Ha, 7-Ha, 8-Ha), 1.42 (s, 2 H, C(CH3)3), 1.43 (s, 7 H, C(CH3)3), 1.64 (mc, 1 H, 7-Hb), 1.72 (mc, 1 H, 6-Hb), 1.86 (mc, 1 H, 8-Hb), 2.18 (dd, J = 10.3, 2.3 Hz, 1 H, 5-Hb), 2.42 (d, J = 15.9 Hz, 0.2 H, 1'-Ha), 2.46 (d, J = 14.1 Hz, 0.8 H, 1'-Ha), 2.53 (d, J = 14.1 Hz, 0.8 H, 1'-Hb), 3.09 (d, J = 14.6 Hz, 0.2 H, 3-Ha), 3.26 (ddd, J = 10.8, 10.7, 3.4 Hz, 1 H, 4a-H), 3.43 (d, J = 14.3 Hz, 0.8 H, 3-Ha), 3.48 (ddd, J = 10.7, 8.4, 4.0 Hz, 1 H, 8a-H), 3.63 (s, 0.7 H, OCH3), 3.65 (s, 2.3 H, OCH3), 3.78 (d, J = 14.3 Hz, 0.8 H, 3-Hb), 4.06 (d, J = 14.6 Hz, 0.2 H, 3-Hb). 13C-NMR (125 MHz, CDCl3): δ = 23.37, 25.67 (2-CH3), 24.40, 24.57, 24.62 (C-6, C-7), 28.30, 28.38 (C(CH3)3), 29.31, 29.56 (C-5), 31.98, 32.03 (C-8), 43.09, 44.00 (C-1), 45.77, 45.89 (C-3), 51.34, 51.58 (OCH3), 60.21, 60.28 (C-4a), 71.78, 72.68 (C-8a), 75.47, 75.73 (C-2), 79.69 (C(CH3)3), 155.36, 155.72 (CO2C(CH3)3), 170.65, 170.78 (CO2OCH3). IR (Film): ν (cm-1) = 2935, 1740, 1695, 1407, 1366, 1157, 1016, 862. HRMS (ESI): calcd for [C17H29NO5 + Na]+: 350.1943; confirmed.
tert-Butyl 2-(2-methoxy-2-oxoethyl)-2-methyl-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxylate 39: A mixture of Pd(OTFA)2 (3.21 mg, 9.65 µmol) and (S,S)-Bn-BOXAX (16.6 mg, 28.9 µmol) in MeOH (2 mL) was stirred at rt for 10 min. Afterwards p-benzochinone (83.3 mg, 772 µmol) and 32 (50.8 mg, 193 µmol) were added and the mixture stirred under CO-atmosphere at 60 °C for 6 h. After workup according to general procedure B and column chromatography on silica gel (P/Et2O = 5:1) 30 was obtained as a yellow liquid (43.1 mg, 134 µmol, 70%). 1H-NMR (300 MHz, C6D6): δ = 1.30 (s, 3 H, 2-CH3), 1.41 (s, 9 H, C(CH3)3), 2.38 (d, J = 15.4 Hz, 1 H, 1'-Ha), 2.44 (d, J = 15.4 Hz, 1 H, 1'-Hb), 3.23 (s, 3 H, OCH3), 3.52 (d, J = 13.5 Hz, 1 H, 3-Ha), 3.94 (d, J = 13.5 Hz, 1 H, 3-Hb), 6.84 (mc, 2 H, 6-H, 7-H), 6.95 (mc, 8 H), 8.07 (mc, 1 H, 5-H). 13C-NMR (125 MHz, C6D6): δ = 22.40 (2-CH3), 28.11 (C(CH3)3), 41.26 (C-1'), 48.93 (C-3), 51.10 (OCH3), 74.67 (C-2), 80.94 (C(CH3)3), 117.68 (C-8), 124.87, 127.92 (C-6, C-7), 128.29 (C-5), 145.49 (CO2C(CH3)3), 169.77 (CO2OCH3). IR (film): ν (cm-1) = 2978, 1784, 1704, 1586, 1495, 1372, 1151, 1020, 927, 861. UV (CH3CN): λmax (lg ε) = 211 nm (4.5992), 239.5 (3.9811), 281.5 (3.5323). MS (EI, 70 eV): m/z (%) = 344 (100) [M+Na]+, 665 (11) [2M+Na]+. HRMS (ESI): calcd for [C17H23NO5 + Na]+: 344.3580; confirmed.
DOMINO-WACKER-MIZOROKI-HECK REACTION
rac-trans-(E)-Methyl 4-(2-methylhexahydro-2H-cyclopenta[b][1,4]dioxin-2-yl)but-2-enoate (rac 40) and (rac 41): Ac¬cording to ge¬ne¬ral procedure C rac-25 (50.0 mg, 0.330 mmol) was reacted with methyl acrylate (9, 78.0 mg, 0.96 mmol) for 3 d at rt. After work-up and column chromatography (silica gel, n-pentane/EtOAc = 4 / 1) rac-40 and rac-41 (30.0 mg, 0.125 mmol, 39%, 50:50 mixture) were provided as yellow oil. 1H-NMR (300 MHz, CDCl3, * indicates the minor epimer ): δ = 1.12*, 1.39 (s, 1.8 H, 2'-CH3), 1.39–1.92 (m, 6 H, 5'-H2, 6-H2, 7'-H2), 2.35 (m, 2 H, 4-H2), 3.05–3.30 (m, 1 H, 4'a-H), 3.22–3.72 (m, 3 H, 3-H2, 7'a-H), 3.74 (s, 3 H, OCH3), 5.90 (m, 1 H, 2-H), 7.00 (m, 1 H, 3-H). 13C-NMR (125 MHz, CDCl3): δ = 16.25, 20.43 (2-CH3), 23.14, 23.85, 23.88, 24.46, 24.48(C-5', C-6', C-7'), 36.22, 42.35 (C-4), 51.42, 51.44 (OCH3), 73.00, 73.17 (C-3'), 74.21, 74.42 (C-7a'), 74.54, 74.72 (C-2'), 81.39, 81.68(C-4a'), 123.93, 123.97 (C-2), 143.61, 144.15 (C-3), 166.55 (CO2CH3). IR (film): ν (cm-1) = 2973, 2881, 1724, 1657, 1436, 1384, 1274, 1127, 1022, 984, 895. UV (CH3CN): λmax (lg ε) = 206 nm (4.0901). MS (DCI, 200 eV): m/z (%) = 258 (100) [M+NH4]+.
rac-cis-(E)-5-(2-Methylhexahydro-2H-cyclopenta[b][1,4]dioxin-2-yl)pent-3-en-2-one (rac 42) and (rac 43): Ac¬cording to ge¬ne¬ral procedure C rac-27 (50.0 mg, 0.330 mmol) was reacted with methyl vinyl ketone (10b, 67.3 mg, 0.96 mmol) for 2 d at rt. After work-up and column chromatography (silica gel, n-pentane/EtOAc = 4 / 1) rac-42 and rac-43 (51.0 mg, 0.228 mmol, 70%, 50:50 mixture) were provided as yellow oil. 1H-NMR (300 MHz, CDCl3, * indicates the minor epimer ): δ = 1.09, 1.24 (s, 3 H, 2'-CH3), 1.44–2.12 (m, 6 H, 5'-H2, 6'-H2, 7'-H2), 2.25–2.50 (m, 2 H, 4-H2), 2.25 (s, 3 H, 1-CH3), 3.19, 3.26 (d, J = 11.7 Hz, 1 H, 3'-Ha), 3.57 (d, J = 11.7 Hz, 1 H, 3'-Hb), 4.03 (m, 2 H, 4'a-H, 7'a-H), 6.13 (m, 1 H, 2-H), 6.85 (m, 1 H, 3-H). 13C-NMR (150 MHz, CDCl3): δ = 20.24, 23.57 (2'-CH3), 20.27, 20.57, 24.34, 25.84, 30.65, 30.98 (C-5', C-6', C-7'), 26.70, 26.88 (1-CH3), 36.61, 42.80 (C-4), 66.55, 67.29 (C-3'), 69.79, 70.17 (C-7a'), 71.34, 71.40 (C-2'), 76.21, 76.96 (C-4a'), 133.71, 133.90 (C-2) 143.25, 143.38 (C-3), 198.39 (COCH3). IR (film): ν (cm-1) = 2968, 1697, 1673, 1628, 1435, 1361, 1254, 1130, 1057, 981. UV (CH3CN): λmax (lg ε) = 221 nm (1.1073). HRMS (ESI): calcd for [C13H20O3 + Na]+: 247.13047; confirmed.
Methyl rac-cis-(E)-4-(2-methyl-hexahydro-2H-cyclopenta[b][1,4]dioxin-2-yl)but-2-enoate rac 44 and rac 45: According to general procedure C rac-27 (50.0 mg, 0.330 mmol) was reacted with methyl acrylate (57, 78.0 mg, 0.96 mmol) for 3 d at rt. After work-up and column chromatography (silica gel, n-pentane/EtOAc = 4 / 1) rac-44 and rac-45 (47.0 mg, 0.196 mmol, 61%, 50:50 mixture) were provided as yellow oil. 1H-NMR (300 MHz, CDCl3): δ = 1.09 (s, 1.5 H, 2'-CH3), 1.24 (s, 1.5 H, 2'-CH3), 1.41–2.12 (m, 6 H, 5'-H2, 6'-H2, 7'-H2), 2.25–2.45 (m, 2 H, 4-H2), 3.18 (d, J = 11.6 Hz, 0.5 H, 3'-Ha), 3.25 (d, J = 11.7 Hz, 0.5 H, 3'-Ha), 3.55 (d, J = 11.7 Hz, 0.5 H, 3'-Hb), 3.57 (d, J = 11.6 Hz, 0.5 H, 3'-Hb), 3.74 (s, 3 H, OCH3), 4.03 (m, 2 H, 4'a-H, 7'a-H), 5.90 (m, 1 H, 2-H), 7.00 (m, 1 H, 3-H). 13C-NMR (125 MHz, CDCl3): δ = 20.09, 23.64 (2'-CH3), 20.37, 20.59, 24.53, 25.73, 30.78, 30.99 (C-5', C-6', C-7'), 36.51, 42.55 (C-4), 51.45 (OCH3), 66.58, 67.27 (C-3'), 69.85, 70.24 (C-7a'), 71.39, 71.42 (C-2'), 76.87(C-4a'), 123.71, 123.90 (C-2) 144.36, 144.59 (C-3), 166.66 (CO2CH3). IR (film): ν (cm-1) = 2953, 1724, 1657, 1436, 1274, 1198, 1131, 1091, 1057. UV (CH3CN): λmax (lg ε) = 206 nm (4.0711). MS (EI): m/z (%) = 141 (100) [M–C4H7O2]+. HRMS (ESI): calcd for [C13H20O4 + Na]+: 263.12538; confirmed.
(rac)-4-(2-Methylhexahydro-(cis-furo[3,4-b][1,4]dioxin)-2-yl)but-2-enal (rac-46) and (rac-47): According to general procedure C rac-29 (51.0 mg, 0.320 mmol) was reacted with acrolein (10a, 54.0 mg, 0.960 mmol) for 2 d at rt. After work-up and column chromatography (silica gel, n-pentane/EtOAc = 2 / 1) rac-46 and rac-47 (22.6 mg, 0.106 mmol, 33%, 65:35 mixture) were provided as yellow oil. 1H NMR (300 MHz, CDCl3, * indicates the minor epimer): δ = 1.23*, 1.26 (s, 3 H, 2’-CH3), 2.38–2.63, 2.98–3.06* (m, 2 H, 4-Ha, 4-Hb), 3.23, 3.30* (d, J = 11.9 Hz, 1 H, 3’-Ha), 3.59, 3.60* (d, J = 11.9 Hz, 1 H, 3’-Hb), 3.79–4.04 (m, 4 H, 5’-Ha, 5’-Hb, 7’-Ha, 7’-Hb), 4.14–4.35 (m, 2 H, 4a’-H, 7a’-H), 6.14, 6.21* (dddd, J = 15.7, 7.8, 1.3, 1.3 Hz, 1 H, 2-H), 6.85*, 6.94 (ddd, J = 15.7, 7.7, 6.9 Hz, 1 H, 4-H), 9.53, 954* (d, J 7.8 Hz, 1 H, 1-H) ppm; 13C NMR (75 MHz, CDCl3, * indicates the minor epimer): δ = 20.25, 23.55* (2’-CH3), 37.18*, 42.84 (C-4), 66.25*, 67.55*, 67.71, 68.26, 68.57*, 68.93, 73.02*, 73.13, 73.47*, 74.62 (C-3’, C-4a’, C-5’, C-7’, C-7a’), 71.36*, 71.53 (C-2’), 135.6, 135.8* (C-2), 152.5*, 152.9 (C-3), 193.5*, 193.7 (C-1) ppm; MS (ESI): m/z (%) = 251.1 (50) [M + K]+, 235.1 (100) [M + Na]+; HRMS (ESI): calcd for [C11H16O4 + Na]+: 235.0946; confirmed.
(rac)-5-(2-Methylhexahydro(cis-furo[3,4-b][1,4]dioxin)-2-yl)pent-3-en-2-one (rac-48) and (rac-49):
According to general procedure C rac-29 (51.0 mg, 0.320 mmol) was reacted with methyl vinyl ketone (10b, 78.0 mg, 0.960 mmol) for 2 d at rt. After work-up and column chromatography (silica gel, n-pentane/EtOAc = 2 / 1) rac-48 and rac-49 (49.0 mg, 0.220 mmol, 68%, 55:45 mixture) were provided as yellow oil. 1H NMR (300 MHz, CDCl3, * indicates the minor epimer): δ = 1.17*, 1.27 (s, 3 H, 2’-CH3), 2.27*, 2.28 (s, 3 H, 1-H3), 2.31–2.54, 2.85–2.96* (m, 1 H, 5-Ha), 3.21–3.33, 3.58–3.62* (m, 1 H, 3’-Hb), 3.81–4.06 (m, 4 H, 5’-Ha, 5’-Hb, 7’-Ha, 7’-Hb), 4.18–4.35 (m, 2 H, 4a’-H, 7a’-H), 6.12*, 6.20 (ddd, J = 15.9, 1.2, 1.2 Hz, 1 H, 3-H), 6.79, 6.87* (ddd, J = 15.9, 8.0, 6.9 Hz, 1 H, 4-H) ppm; 13C NMR (75 MHz, CDCl3, * indicates the minor epimer): δ = 20.12, 23.56* (2’-CH3), 26.86, 27.10* (C-1), 37.01, 42.68 (C-5), 66.27*, 68.19 (C-3’), 67.49*, 67.59, 73.04*, 73.13 (C-5’, C-7’), 68.49*, 68.81 (C-4a’), 71.40, 71.56 (C-2’), 73.48*, 74.56 (C-7a’), 134.1, 134.2* (C-3), 142.3, 142.7* (C-4), 198.1*, 198.4 (C-2) ppm; IR (Film): [イメージ] = 2955 cm-1, 2926, 2872, 1697, 1673, 1628, 1461, 1428, 1363, 1256, 1186, 1132, 1079, 984.5, 951.0, 897.3, 870.1, 831.3, 789.6, 716.6; UV (CH3CN): λmax (lg ε) = 222.0 (4.058) nm; MS (ESI): m/z (%) = 265.1 (15) [M + K]+, 249.1 (100) [M + Na]+, 244.2 (60) [M + NH4]+, 227.1 (50) [M + H]+; HRMS (ESI): calcd for [C12H18O4 + Na]+: 249.1103; confirmed.
(rac)-6-(2-Methylhexahydro(cis-furo[3,4-b][1,4]dioxin)-2-yl)hex-4-en-3-one (rac-50) and (rac-51):
According to general procedure C rac-29 (51.0 mg, 0.320 mmol) was reacted with ethyl vinyl ketone (10c, 80.1 mg, 0.960 mmol) for 3 d at rt. After work-up and column chromatography (silica gel, n-pentane/EtOAc = 2 / 1) rac-50 and rac-51 (52.0 mg, 0.220 mmol, 62%, 70:30 mixture) were provided as yellow oil. 1H NMR (300 MHz, CDCl3, * indicates the minor epimer) δ = 1.02*, 1.02 (t, J = 7.3 Hz, 3 H, 1-H3), 1.08, 1.17* (s, 3 H, 2’-CH3), 2.22–2.43, 2.74–2.80* (m, 2 H, 6-Ha, 6-Hb), 2.25 (q, J = 7.30 Hz, 2-H2), 3.13–3.25 (m, 1 H, 3’-Ha), 3.48–3.54 (m, 1 H, 3’-Hb), 3.71–3.96 (m, 4 H, 5’-Ha, 5’-Hb, 7’-Ha, 7’-Hb), 4.10–4.25 (m, 2 H, 4a’-H, 7a’-H), 6.05*, 6.13 (ddd, J = 15.9, 1.4, 1.4 Hz, 1 H, 4-H), 6.74, 6.80* (ddd, J = 15.9, 8.1, 6.9 Hz, 1 H, 5-H) ppm; 13C NMR (75 MHz, CDCl3, * indicates the minor epimer): δ = 7.86, 7.92* (C-1), 19.94*, 23.43 (2’-CH3), 32.96*, 33.28 (C-2), 36.87, 42.51* (C-6), 66.12, 67.31, 67.34*, 67.98*, 68.35, 68.67* 69.98*, 71.45, 72.91, 72.98*, 73.35, 74.36* (C-2’, C-3’, C-4a’, C-5’, C-7’, C-7a’), 132.9*, 132.9 (C-4), 140.9*, 141.1 (C-5), 200.4, 200.7* (C-3) ppm; MS (ESI): m/z (%) = 481.28 [2M + H]+, 265.1 (100) [M + Na]+, 241.1 (6) [M + H]+; HRMS (ESI): calcd for [C13H20O4 + Na]+: 263.1259; confirmed.
(rac)-4-(2-Methylhexahydro(cis-furo[3,4-b][1,4]dioxin)-2-yl)but-2-enoic acid methyl ester (rac-52) and (rac-53): According to general procedure C rac-29 (51.0 mg, 0.320 mmol) was reacted with methyl acrylate (9, 78.0 mg, 0.960 mmol) for 2 d at rt. After work-up and column chromatography (silica gel, n-pentane/EtOAc = 7 / 1 → 4 / 1) rac-52 and rac-53 (60.0 mg, 0.230 mmol, 77%, 60:40 mixture) were provided as yellow oil. 1H NMR (300 MHz, CDCl3, * indicates the minor epimer) δ = 1.12, 1.22* (s, 3 H, 2’-CH3), 2.25–2.47, 2.74–2.84* (m, 2 H, 4-Ha, 4-Hb), 3.17–3.28 (m, 1 H, 3’-Ha), 3.51–3.57 (m, 1 H, 3’-Hb), 3.70*, 3.70 (s, 3 H, OCH3), 3.75–4.01 (m, 4 H, 5’-Ha, 5’-Hb, 7’-Ha, 7’-Hb), 4.13–4.29 (m, 2 H, 4a’-H, 7a’-H), 5.85*, 5.91 (ddd, J = 15.7, 1.4, 1.4 Hz, 1 H, 2-H), 6.87–6.96 (m, 1 H, 3-H) ppm; 13C NMR (75 MHz, CDCl3, * indicates the minor epimer): δ = 19.80*, 23.47 (2’-CH3), 36.68, 42.18* (C-4), 51.46*, 51.50 (OCH3), 66.10, 67.14*, 67.29, 67.98*, 68.39, 68.72*, 69.98*,71.33*, 71.47, 73.02, 73.39, 74.25* (C-2’, C-3’, C-4a’, C-5’, C-7’, C-7a’), 125.1*, 124.2 (C-2), 143.6*, 143.7 (C-3), 166.5, 166.5* (C-1) ppm; IR (Film): [イメージ] = 2952 cm-1, 2874, 1723, 1657, 1460, 1437, 1276, 1201, 1133, 1079, 987.2, 950.6, 906.7, 853.0, 791.1, 731.8; UV (CH3CN): λmax (lg ε) = 207.0 (4.058) nm; MS (ESI): m/z (%) = 506.9 (12) [2M + Na]+, 265.1 (100) [M + Na]+, 243.1 (6) [M + H]+; HRMS (ESI): calcd for [C11H18O5 + Na]+: 265.1052; confirmed.
4-(2-Methyl-2,3,9,9a-tetrahydro-4aH-1,4-dioxafluoren-2-yl)but-2-enoic acid methyl ester (54) and (55): According to general procedure C 24 (68.4 mg, 0.320 mmol) was reacted with methyl acrylate (9, 78.0 mg, 0.960 mmol) for 2 d at rt. After work-up and column chromatography (silica gel, n-pentane/EtOAc = 7 / 1) 54 and 55 (51.8 mg, 0.180 mmol, 56%, 60:40 mixture) were provided as pale yellow oil. 1H NMR (300 MHz, CDCl3, * indicates the minor epimer): δ = 1.38, 1.81* (s, 3 H, 2’-CH3), 2.05 (ddd, J = 14.1, 8.4, 1.3 Hz, 1 H, 4-Ha), 2.17 (ddd, J = 14.1, 7.0, 1.4 Hz, 1 H, 4-Hb), 2.48* (ddd, J = 14.1, 8.4, 1.3 Hz, 1 H, 4-Ha), 2.72* ddd, J = 14.1, 7.0, 1.4 Hz, 1 H, 4-Hb), 2.95–3.11 (m, 2 H, 9-Ha, 9-Hb), 3.24–3.47 (m, 2 H, 3’-Ha, 3’-Hb), 3.69*, 3.75 (s, 3 H, OCH3), 4.56 (mc, 1 H, 9a’-H), 5.04–5.08 (m, 1 H, 4a’-H), 5.76*, 5.98 (ddd, J = 15.6, 1.4, 1.4 Hz, 1 H, 2-H), 6.84*, 7.01 (ddd, J = 15.6, 8.4, 7.0 Hz, 1 H, 3-H), 7.23–7.39 (m, 4 H, 5-H, 6-H, 7-H, 8-H) ppm; 13C NMR (75 MHz, CDCl3, * indicates the minor epimer): δ = 18.73, 19.57* (2’-CH3), 35.76, 37.67*, 37-73, 41.84* (C-4, C9’), 51.37*, 51, 45 (OCH3),66.74, 67.35* (C-3’), 70.53, 70.75* (C9a’), 71.17*, 71.30 (C-2’), 77.95, 78.31* (C-4a’), 123.8*, 124.1 (C-2), 125.5*, 125.5, 125.5*, 125.6, 126.6, 128.1*, 128.1, 128.9* (C-5’, C-6’, C-7’, C-8’), 138.9, 139.0* (C-4b’), 140.8, 140.9* (C-8a’), 143.5*, 144.5 (C-3), 166.5*, 166.6 (C-1) ppm; MS (ESI): m/z (%) = 311.1 (100) [M + Na]+, 289.1 (25) [M + H]+; HRMS (ESI): calcd for [C17H20O4 + Na]+: 311.1259; confirmed.
2-(3-Methoxycarbonylallyl)-2-methyl-2,3,9,9a-tetrahydro-4aH-1-oxa-4-azafluorene-4-carboxylic acid tert-butyl ester (56) and (57): According to general procedure C 21 (106.0 mg, 0.320 mmol) was reacted with methyl acrylate (9, 78.0 mg, 0.960 mmol) for 4 d at rt. After work-up and column chromatography (silica gel, n-pentane/EtOAc = 7 / 1) 56 and 57 (117 mg, 0.300 mmol, 91%, 60:40 mixture) were provided as pale yellow oil. 1H NMR (300 MHz, DMSO, 100°C, * indicates the minor epimer): δ = 0.92, 1.21* (s, 3 H, 2’-CH3), 1.51, 1.52* (s, 9 H, OC(CH3)3), 2.24–2.16 (m, 1 H, 1’-Ha), 2.49 (mc, 1 H, 1-’Hb), 2.46–2.71 (m, 2 H, 3-Ha, 3-Hb), 2.76 (d, J = 15.6 Hz, 1 H, 9-Ha), 3.09 (dd, J = 15.6, 4.3 Hz, 9-Hb), 3.63, 3.69* (s, 3 H, OCH3), 4.53–4.58 (m, 1 H, 9a-H), 5.32 (sbr, 1 H, 4a-H), 5.83, 6.00* (ddd, J = 15.6, 1.3, 1.3 Hz, 1 H, 3’-H), 6.74, 6.88* (ddd, J = 15.6, 7.6, 7.6 Hz, 1 H, 2’-H), 7.04–7.07 (m, 1 H), 7.19–7.28 (m, 4 H, 5-H, 6-H, 7-H, 8-H) ppm; 13C NMR (75 MHz, CDCl3, * indicates the minor epimer): δ = 17.88, 23.49* (2-CH3), 27.51*, 27.55 (C(CH3)3), 34.62, 37.35, 37.42*, 41.57 (C-3, C-9, C-1’), 50.31, 50.40* (OCH3), 70.91*, 71.04 (C-9a), 71.34*, 71.56 (C-2), 79.06, 79.19* (OC(CH3)3), 122.4, 124.6, 124.6*, 125.9, 125.9*, 126.9, 126.9* (C-5, C-6, C-7, C-8), 123.1, 123.3* (C-3’), 138.7*, 138.7, 140.5, 140.5* (C-4b, C-8a), 142.8, 143.4* (C-2’), 154.1, 154.3 (C=O), 165.1, 165.2* (C-1’) ppm; IR (Film): [イメージ] = 2977 cm-1, 2931, 1724, 1694, 1417, 1393, 1366, 1320, 1276, 1219, 1198, 1169, 1131, 1100, 1084, 1065, 1019, 991.1, 957.4, 927.2, 910.0, 880.6, 862.8, 851.0, 823.7, 746.2; UV (CH3CN): λmax (lg ε) = 264.5 (3.014), 271.0 (3.017), 257.5 (2.92,) nm; MS (ESI): m/z (%) = 426.2 (25) [M + K]+, 410.2 (100) [M + Na]+, 405.2 (90) [M + NH4]+, 388.2 (20) [M + H]+; HRMS (ESI): calcd for [C22H29NO5 + Na]+: 410.1943; confirmed.
ACKNOWLEDGEMENTS
This work was supported by the Deutsche Forschungs¬gemeinschaft (DFG) and the Fonds der Chemischen
Industrie (VCI). C.R. thanks the Fonds der Chemischen Industrie for a Ph.D. scholarship. Generous gifts of chemicals by BASF, Bayer-Schering, and Wacker Chemie are greatly appreciated.
Dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday
References
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