Supplementary Material

Transcription

1 ARKIVC 0 (iii) S-S9 Supplementary Material Lewis acid-catalyzed Diels-Alder reaction of -cyclopentenones with Danishefsky s diene: double bond isomerization of tetrahydro-hindene-,(7ah)-diones, and attempts on an asymmetric catalysis Michael Krebs and Sabine Laschat* Institut für rganische Chemie, Universität Stuttgart, Pfaffenwaldring, D-709 Stuttgart, Germany sabine.laschat@oc.uni-stuttgart.de Dedicated to Prof. Rainer Beckert on the occasion of his 0th birthday Contents NMR spectroscopic analysis of double bond isomers 0, Details on the isolation of ketals, Synthesis of the proline-based oxazaborolidines a-d S S S9 Page S

2 ARKIVC 0 (iii) S-S9 NMR-spectroscopic analysis of the inseparable double bond isomers 0, The NMR-spectroscopic analysis of the isolated mixture of double bond isomers 0 and is discussed in the following: Initially we expected the two compounds to be the two regioisomers 0 and as shown below. 7 7a a 7 7a a 0 Scheme S If indeed the regioisomers 0 and were formed, we should have found a multiple degenerated doublet in the range of and 7 ppm in the H-NMR spectrum for each of the vinylic protons -H and 7-H (regioisomer 0) and -H und -H (regioisomer ) respectively. As shown in the enlargement of the olefinic part of the H-NMR spectrum between.80 and. ppm in Figure S, the NMR experiment provided a doublet of doublets (J = 0. Hz, J =. Hz) at.8 ppm and a doublet of doublets of doublets (J = 0. Hz, J =. Hz, J = 0.7 Hz) at. ppm. The third multiplet at. ppm was identified to be a triplet of doublets of doublets (J =.7 Hz, J =. Hz, J = 0.7 Hz). The integration of the triplet of doublets of doublets showed a value of one whereas the doublet of doublets of doublets and the doublet of doublets contained an integration of 0.7 each. This and the fact that both had an identical coupling constant (0. Hz) led us to the assumption that these two protons are located in the same molecule. The triplet of doublets of doublets was then inevitably assigned to the second compound. n closer examination of the integration we found a ratio of 0.7:.7 or 0.:0.7 of the two isomers that is attended by GC analysis (cf. Table ). Conflicting our first theory of the two regioisomers 0 and was the fact that we found only three signals for the four expected vinylic protons and the presence of nearly equimolar mixtures made us suspicious of the supposed structure of the two isolated products. Page S

3 ARKIVC 0 (iii) S-S9 tdd (J =.7 Hz, J =. Hz, J = 0.7 Hz). ppm H dd (J = 0. Hz, J =. Hz).8 ppm 0.7 H ddd (J = 0. Hz, J =. Hz, J = 0.7 Hz). ppm 0.7 H Figure S H-NMR spectrum of the inseparable mixture of double bond isomers 0, In order to explore the real structures of the two compounds the HSQC spectrum of the mixture was examined carefully. A sector of the HSQC spectrum is shown in Figure S. ne of the carbon atoms (9. ppm) in the vinylic part of the spectrum shows no cross peak to any of the protons. Therefore it was assigned as a quaternary carbon. This assumption was confirmed in a DEPT-spectrum that is not shown here. Page S

4 ARKIVC 0 (iii) S-S9 Figure S HSQC spectrum of the inseparable mixture of double bond isomers 0, At this point it was clear that one of the compounds had a quaternary olefinic carbon atom and owing to the two olefinic protons the other compound had to be one of the two initially expected ones. Altogether there were four possible isomers (Scheme S). 7a a 7 7a a 7 7a a 7 7a a 7 0 0' ' Schema S The next issue was the position of the double bond. In order to solve that problem, the HMBC spectrum was investigated more closely. Possible correlations between the olefinic protons -H and 7-H (isomers 0, 0 ) and -H, -H (isomers, ) respectively, and the carbonyl carbon atoms C-, C- (isomers 0, 0 ) and C-, C- (isomers, ) respectively, should be observed in that spectrum and so the problem of the position of the double bond Page S

5 ARKIVC 0 (iii) S-S9 should be resolved unambiguously. In the case of isomer 0 there should be a cross peak of the protons -H and 7-H to both of the carbonyl C-atoms C- and C- whereas in the case of isomer the olefinic protons -H and -H should correlate only to one of the carbonyl C-atoms, namely C-. The same applies for the isomers 0 and. A correlation of the olefinic proton 7-H to both of the carbonyl carbons should be detected in the case of isomer 0 and only one cross peak should be seen in the case of isomer. A part of the HMBC spectrum is shown in Figure S. Figure S HMBC spectrum of the inseparable mixture of double bond isomers 0, The olefinic protons at. ppm (ddd) and. ppm (tdd) are unambiguously correlated to two C-atoms. This verifies the structure of the two double bond isomers, that is about the two compounds 0 and 0 (= ) (Scheme S). It is not uncommon that there is no correlation in the HMBC-spectrum between the dd at.8 ppm and the carbonyl C-atoms, since such two-bondcouplings are not always visible in these HMBC spectra. Page S

6 ARKIVC 0 (iii) S-S9 + Me SiMe ) LA ) H + + 9a 0 0' = Scheme S This result also explains why there was obtained only one product in the selective reduction of the enone moiety. Details on the isolation of ketals, In the following the isolation of the pure monoketal and diketal and their NMR spectroscopic analysis is specified: As described in the main part the obtained monoketal and the bisketal could not be separated by chromatography (Scheme S). But initially the structure of the two isolated products (one with m/z 9, the other with m/z ) was not confirmed at least four different monoketals d and two different diketals, b were possible (Scheme S). b + 0 Ethylenglycol PPTS benzene 00 C, h c m/z 9 d b m/z 8 Scheme S Page S

7 ARKIVC 0 (iii) S-S9 We felt confident that after reduction of the enone moiety of the monoketal to the corresponding alcohol, the remaining diketal could be separated from the resulting alcohol. The mixture of the monoketal and diketal was reduced with equiv. NaBH in the presence of 0. equiv. LiCl in CH CN. Actually we obtained after reduction a mixture of diketal and diasteriomeric allylic alcohols (Scheme S). The desired diketal could then be separated via preparative HPLC and analyzed in NMR experiments. The NMR sample, dissolved in CDCl, was subjected to another GC-MS analysis and we found out that the compound was not the same anymore than before the NMR experiment: Under the slightly acid conditions of CDCl one of the ketal protecting groups was cleaved off. This resulting monoketal showed exactly the same retention time as the monoketal gained during the first ketalization and so we assumed that the two monoketals had the same structure. There is shown the olefinic section of the resulting H-NMR of the obtained monoketal in Figure S. ddd (J = 0. Hz, J =. Hz, J = 0.9 Hz).8 ppm H dd (J = 0. Hz, J =. Hz).7 ppm H Figure S H-NMR spectrum of the obtained monoketal Comparison of the NMR spectrum with the starting material 0, revealed that the ketalization took exclusively place with the C/C7 double bond isomer rather than the C7/C7a isomer. There are visible two signals: ne doublet of doublets (.7 ppm, J = 0. Hz, J =. Hz) and one doublet of doublets of doublets (.8 ppm, J = 0. Hz, J =. Hz, J = 0.9 Hz). The Page S7

8 ARKIVC 0 (iii) S-S9 position of the ketal was determined by comparison of the chemical shifts of the carbonyl carbon in the C-NMR spectrum with the C-NMR spectrum of the double bond isomer 0. It is well known that carbonyl carbons in -membered rings are detected at lower field (approx. 0-0 ppm) whereas conjugated carbonyl carbons are detected at higher field (approx ppm). The double bond isomer 0 shows the carbonyl C-atom in the -membered ring at. ppm whereas the conjugated carbonyl carbon in the -membered ring shows up at 9. ppm. The carbonyl C-atom in the described monoketal shows one signal at 9.9 ppm. We concluded that the carbonyl carbon must be the one conjugated in the -membered ring (Scheme S). CDCl Ethylenglycol PPTS + benzene 00 C, h 0 NaBH,LiCl CH CN, rt, min H H H H H H a b Scheme S The olefinic part of the H-NMR spectrum of the diketal, dissolved in benzene-d is shown in Figure S. Again a doublet of doublets (.7 ppm, J = 0. Hz, J =. Hz) and a doublet of doublets of doublets (. ppm, J = 0. Hz, J =. Hz, J = 0.7 Hz) was observed. Since the difference of the chemical shifts (v v ) J, the two signals are distorted. Again the similarity of the spectrum to the one of double bond isomer 0 is evident. Thus the structures of the resulting monoketal and the diketal could be established. Page S8

9 ARKIVC 0 (iii) S-S9 dd (J = 0. Hz, J =.).7 ppm H ddd (J = 0. Hz, J =. Hz, J = 0.7 Hz). ppm H Figure S H-NMR spectrum of the obtained diketal Synthesis of the proline-based oxazaborolidines a-d : (S)-N-(Ethoxycarbonyl)-proline methyl ester (7) N 7 L-Proline (.00 g,. mmol) was dissolved in 8 ml of methanol. Potassium carbonate (.97 g,. mmol) was added and the mixture was cooled to 0 C. Then 9 ml (0. g, 9.0 mmol) ethyl chloroformate were added slowly. The resulting solution was allowed to warm up to room temperature and was stirred for further h. The resulting colorless solid was filtered off, the solvent was reduced in vacuo and the remaining colorless oil was transferred to 0 ml of H. Then ml of CH Cl were added and the layers were separated. The aqueous layer was extracted with x 0 ml CH Cl and the combined Page S9

10 ARKIVC 0 (iii) S-S9 organic layers were dried over MgS. Concentration under reduced pressure afforded the product as colorless oil (7. g, 8 mmol, 87%). A mixture of rotamers was obtained. H-NMR (00 MHz, CDCl ): δ =.0 (t, J = 7. Hz, H, CH CH ),.7 (t, J = 7. Hz, H, CH CH ),.8 -. (m, 8H, -H, -H), (m, H, -H),.7 (s, H, CH ),.7 (s, H, CH ),.0. (m, H, CH CH ),. (dd, J =., J = 8. Hz, H, -H),.7 (dd, J =., J = 8. Hz, H, -H) ppm. C-NMR (7 MHz, CDCl ): δ =. (CH CH ),.7 (CH CH ),.,., 9.9, 0.9 (C-, C- ),.,.7 (C-),.,. (CH ), 8.8, 9.0 (C-),.,. (CH ),.,. (C-), 7., 7. (C-) ppm. Spectroscopic data were consistent with previously reported data for this compound. (S)-N-Ethoxy-α,α-diphenyl--pyrrolidinemethanol (8) N 8 H In an oven dried Schlenk flask 7. g (0.0 mol) magnesium turnings were covered with 7 ml of THF. A small amount of bromobenzene ( ml, 0.0 mol) was added to the mixture and the reaction was started using a heat gun. Then a mixture of.8 ml (0.7 g, 0. mol) bromobenzene and ml of THF was added dropwise and after complete addition the grey solution was refluxed for further 0 min. Under an inert gas atmosphere (S)-N-(ethoxcarbonyl)proline methyl ester (7) (7. g, 7.8 mmol) was dissolved in 7 ml THF and cooled to 0 C. The Grignard-solution was added slowly over a period of one hour and the resulting solution was stirred for further 0 h at room temperature. The reaction was hydrolyzed using 0 ml sat. NaHC solution. After the addition of 00 ml of dichloromethane the layers were separated and the aqueous layer was extracted with x ml CH Cl. The combined organic layers were dried over MgS and concentrated in vacuo. Purification by flash chromatography (: hexanes/ethyl acetate) afforded the product as a colorless solid (.0 g,. mmol, 0%). Page S0

11 ARKIVC 0 (iii) S-S9 H-NMR (00 MHz, CDCl ): δ = 0.8 (b, H, -H a ),. (t, J = 7. Hz, H, CH CH ),.. (m, H, -H a ), (m, H, -H b ),.0. (m, H, -H b ),.9 (m, H, -H a ),..7 (m, H, -H b ),.0.8 (m, H, CH CH ),.9 (dd, J =.8, J = 8.8 Hz, H, - H), (m, 0H, Ph) ppm. C-NMR (7 MHz, CDCl ): δ =. (CH CH ),.0, 9.7 (C-, C-), 7.7 (C-),.9 (CH CH ),.9 (C-), 8. (C-), 7., 7., 7., 7., 7.9, 8. (Ph),.7 (ArC),. (C-) ppm. Spectroscopic data were consistent with previously reported data for this compound. (S)-α,α-Diphenyl--pyrrolidinemethanol (9) NH 9 H (S)-N-Ethoxy-α,α-diphenyl--pyrrolidinemethanol (8) (.0 g,. mmol) was dissolved in ml of methanol. Potassium hydroxide (7.0 g, 0. mol) was added and the resulting solution was refluxed for 0 h. After concentration the resulting yellow oil was transferred to 0 ml H and 0 ml of dichloromethane were added. The layers were separated and the aqueous layer was extracted with x 0 ml CH Cl. The combined organic layers were washed with brine, dried over MgS and concentrated in vacuo. After recrystallization from ml of heptane.0 g (0.00 mol, 8%) of a colorless solid were obtained. H-NMR (00 MHz, CDCl ): δ =.0.8 (m, H, -H, -H), (m, H, -H),. (t, J = 7. Hz, H, -H), (m, 0H, Ph) ppm. C-NMR (7 MHz, CDCl ): δ =.,. (C-, C-),.8 (C-),. (C-), 77. (C-),.,.9,.,., 8.0, 8. (Ph),. (ArC), 8. (ArC) ppm. [α] D 0 = -. (c = 0., MeH) [Lit.: -. (c = 0., MeH)] Spectroscopic data were consistent with previously reported data for this compound. Page S

12 ARKIVC 0 (iii) S-S9 (S)-Ethyl -(hydroxydinaphthalen--ylmethyl)pyrrolidine--carboxylate (0), (S)-,-Di(naphthalen--yl)tetrahydropyrrolo[,-c]oxazol-(H)-one () In an oven dried Schlenk flask 0.0 g (.7 mmol) magnesium turnings were covered with 0 ml of THF. A small amount of -bromonaphthalene (0.0 g,.0 mmol) in ml of THF was added to the reaction mixture. The reaction was started using one crystal of iodine. Then a mixture of.99 g (9. mmol) -bromonaphthalene and 8 ml of THF was added dropwise and after complete addition the grey solution was refluxed for further three hours. Then 0. g (.0 mmol) (S)-N-(ethoxycarbonyl)proline methyl ester (7) were dissolved in 0 ml of THF and cooled to 0 C. Since the Grignard-solution was poorly soluble in cold THF, it was dissolved in hot benzene. The addition of the Grignard-solution was completed after one hour and the mixture was stirred for further 0 h at room temperature. The reaction was hydrolyzed using 0 ml sat. NaHC solution. After the addition of 0 ml of dichloromethane the layers were separated and the aqueous layer was extracted with x ml CH Cl. The combined organic layers were dried over MgS and concentrated in vacuo. Purification by flash chromatography (: hexanes/ethyl acetate) afforded 0.0 g (%) of a mixture (:) of desired product 0 and the cyclic carbamate. H N 0 R f = 0. (: hexanes/ethyl acetate, anisaldehyde) H-NMR (00 MHz, CDCl ): δ = 0.79 (b, H, -H a ),.0 (t, J =.8 Hz, H, CH CH ),.0. (m, H, -H a ),.0.9 (m, H, -H b, -H b ),.90.0 (m, H, -H a ),..0 (m, H, -H b ),.0.8 (m, H, CH CH ),. (dd, J =.0, J = 8.7 Hz, H, -H), (m, H, Ar), (m, 8H, Ar) ppm. C-NMR (7 MHz, CDCl ): δ =.8 (CH CH ),., 0.0 (C-, C-), 8.0 (C-),. (CH CH ),. (C-), 8. (C-),.,.,.,.,., 7., 7., 7., 7.7, 8.0, 8.7, 8.9 (Ph),.78,.8,.0,. (ArC),.8 (C-) ppm. Spectroscopic data were consistent with previously reported data for this compound. Page S

13 ARKIVC 0 (iii) S-S9 N R f = 0. (: hexanes/ethyl acetate, anisaldehyde) H-NMR (00 MHz, CDCl ): δ =.. (m, H, -H a ),.7.78 (m, H, -H b ),.8.9 (m, H, -H a ),.9.0 (m, H, H b ),.7. (m, H, -H a ),.7.80 (m, H, - H b ),.77 (dd, J =., J = 0. Hz, H, -H), 7. (dd, J =.9, J = 8. Hz, H, Ar), (m, H, Ar), 7. (dd, J =., J = 8. Hz, H, Ar), (m, H, Ar), 8.0 (d, J =. Hz, H, Ar), 8.0 (d, J =. Hz, H, Ar) ppm. C-NMR (7 MHz, CDCl ): δ =.0, 9. (C-, C-),. (C-), 8.7 (C-), 8. (C-),.8,.0,.,.,.9,.,.,.7, 7., 7., 8., 8., 8., 8.7 (Ph),.,.8,.9,.0, 7., 0. (ArC), 0. (C-) ppm. Spectroscopic data were consistent with previously reported data for this compound. (S)-α,α-Di--naphthyl--pyrrolidinemethanol () NH H The mixture of (S)-,-di(naphthalen--yl)tetrahydropyrrolo[,-c]oxazol-(H)-one and (S)-ethyl -(hydroxydinaphthalen--ylmethyl)pyrrolidine--carboxylate 0 (0.8 g,. mmol) was dissolved in 0 ml of methanol and an excess of potassium hydroxide (.0 g, 0.0 mol) was added. The mixture was stirred for h at room temperature, methanol was distilled off and the residue was dissolved in ml of dichloromethane. Water was added ( ml), the layers were separated and the organic layer was dried over MgS. After concentration in vacuo 0.7 g (0.7 mmol, 80%) of desired product was isolated as a colorless solid. Page S

14 ARKIVC 0 (iii) S-S9 H-NMR (00 MHz, CDCl ): δ =.0.8 (m, H, -H, -H, NH),.97. (m, H, -H),. (t, J = 7., H, -H), (br, H, H), (m, H, Ar), 7.8 (dd, J =.8, J = 8.7 Hz, H, Ar), (m, H, Ar), (m, H, Ar), (m, H, Ar) ppm. C-NMR (7 MHz, CDCl ): δ =.,. (C-, C-),.9 (C-),.0 (C-), 77. (C-),.8,.0,.,.,.,.8,.9,., 7., 7.7, 8., 8., 8., (Ph),.0,.,.,.,.,., (ArC) ppm. Spectroscopic data were consistent with previously reported data for this compound. 7 (S)-Ethyl -(-naphthoyl)pyrrolidine--carboxylate () N In an oven dried Schlenk flask. g (0.8 mol) magnesium turnings were covered with 0 ml of THF. A small amount of -bromonaphthalene (0. g,. mmol) in ml of THF was added to the reaction mixture. The reaction was started using one crystal of iodine. Then a mixture of 7.8 g (8.0 mmol) -bromonaphthalene and 0 ml of THF was added drop wise and after complete addition the grey solution was refluxed for further three hours. Then. g (.0 mmol) (S)-N-(ethoxycarbonyl)proline methyl ester 7 were dissolved in 0 ml of THF and cooled to 0 C. Since the obtained Grignard-solution was poorly soluble in cold THF, it was dissolved in hot benzene. The addition of the Grignard-solution was completed after one hour and the mixture was stirred for further h at room temperature. The reaction was hydrolyzed using 00 ml sat. NaHC solution. After the addition of 00 ml of dichloromethane the layers were separated and the aqueous layer was extracted with x ml CH Cl. The combined organic layers were dried over MgS and concentrated in vacuo. Purification by flash chromatography (: hexanes/ethyl acetate) afforded. g (%) of monoarylated product. R f = 0. (: hexanes/ethyl acetate, anisaldehyde) btained was a mixture of two rotamers. Page S

15 ARKIVC 0 (iii) S-S9 H-NMR (00 MHz, CDCl ): δ =. (t, J = 7. Hz, H, CH CH ),. (t, J = 7. Hz, H, CH CH ),.88.7 (m, 8H, -H, -H),.. (m, H, -H),.7.8 (m, H, -H),. (q, J = 7. Hz, H, CH CH ),.0 (q, J = 7. Hz, H, CH CH ),. (dd, J =.7, J = 8.9 Hz, H, -H),. (dd, J =.7, J = 8.9 Hz, H, -H), (m, H, Ar), (m, H, Ar), 8.0 (d, J = 8. Hz, H, Ar), 8. (d, J = 8. Hz, H, Ar) ppm. C-NMR (7 MHz, CDCl ): δ =.,.8 (CH CH ),.,., 9., 0. (C-, C-),.8, 7. (C-),.,. (CH CH ),.0,. (C-),.,.,.,.,.,.7, 7.0, 7., 7.9, 8.0, 8., 8., 0.,.,.,.8,.9,.8,. (Ar),.,. (C-), 0., 0. (C-) ppm. HRMS (ESI): calcd. for C 8 H 9 N Na +, 0. found 0.7. MS (APCI) m/z: 98. [M + H] +,. [M C H ],. [M CC H ], 08.,.0,., 7.0,.0, 98.0, 70.. FT-IR (ATR): ν = 979 (w), 8 (s), 9 (m), 80 (w), (m), (w), 7 (m), 0 (m), 00 (w), 98 (m), 887 (m), 777 (m), 70 (m) cm -. [α] D 0 = -.0 (c =.0, CH Cl ) (7aS)--(naphthalen--yl)--phenyltetrahydropyrrolo[,-c]oxazol-(H)-one () N In an oven dried Schlenk flask 88. mg (. mmol) magnesium turnings were covered with 0 ml of THF. A small amount of bromobenzene (0.0 ml, 0.0 g, 0.0 mmol) in ml of THF was added to the reaction mixture. The reaction was started using one crystal of iodine. In the following a mixture of 0. ml (0. g,.0 mmol) bromobenzene and ml of THF was added dropwise and after complete addition the grey solution was refluxed for further three hours. Then 0.7 g (0.9 mmol) (S)-Ethyl -(-naphthoyl)pyrrolidine--carboxylate were dissolved in ml of THF and cooled to 0 C. The obtained Grignard-solution was added slowly over a period of one hour and the resulting solution was stirred for further 0 h at room temperature. Page S

16 ARKIVC 0 (iii) S-S9 The reaction was hydrolyzed using 0 ml sat. NaHC solution. After the addition of 0 ml of dichloromethane the layers were separated and the aqueous layer was extracted with x ml CH Cl. The combined organic layers were dried over MgS and concentrated in vacuo. Purification by flash chromatography (: hexanes/ethyl acetate) afforded the product as a colorless solid (0.0 g, 0.0 mmol, %). R f = 0. (: hexanes/ethyl acetate, anisaldehyde) H-NMR (00 MHz, CDCl ): δ = (m, H, -H a ),.8.0 (m, H, -H b ),.7.9 (m, H, -H),.. (m, H, -H a ),.7.8 (m, H, -H b ),.9 (dd, J =., J = 0.9 Hz, H, -H), (m, H, Ar), (m, H, Ar), 7.7 (dd, J = 7., J = 8. Hz, H, Ar), (m, H, Ar), 8.0 (d, J =. Hz, H, Ar), 8.08 (dd, J =., J = 7. Hz, H, Ar) ppm. C-NMR (7 MHz, CDCl ): δ =., 8. (C-, C-),. (C-), 9. (C-), 8. (C-),.,.,.,.,.9, 7.0, 8.8, 8.9, 9., 9. (Ar), 9.,.,.,. (ArC), 0. (C-) ppm. HRMS (ESI): calcd. for C H 9 N Na +., found.. MS (ESI) m/z:. [M + Na] +, 0. [M + H] +, 8., 9., 9.,.. FT-IR (ATR): ν = 09 (w), 97 (w), (w), 78 (s), 98 (w), 09 (w), 8 (w), 7 (m), 0 (m), 09 (m), 9 (m), 80 (m), 778 (m) cm -. [α] D 0 = -8. (c = 0.8, CH Cl ) (S)-α,α-(-Naphthyl)-phenyl--pyrrolidinemethanol () NH H (7aS)--(Naphthalen--yl)--phenyltetrahydropyrrolo[,-c]oxazol-(H)-one (0.07 g, 0. mmol) was dissolved in ml of methanol and an excess of potassium hydroxide (0.0 g, 9.00 Page S

17 ARKIVC 0 (iii) S-S9 mmol) was added. The mixture was refluxed for h, methanol was distilled off and the residue was dissolved in ml of dichloromethane. Water was added ( ml), the layers were separated and the organic layer was dried over MgS. After concentration in vacuo 0.0 g (0.0 mmol, 9%) of desired product was isolated as a yellow oil. H-NMR (00 MHz, CDCl ): δ =..0 (m, H, -H, -H),.8.9 (m, H, -H a ),.0 -. (m,h, -H b ),.0.9 (m, H, -H), (m, H, Ar), (m, H, Ar), (m, H, Ar), (m, H, Ar), 8.0 (br, H, Ar) ppm. C-NMR (7 MHz, CDCl ): δ =.8, 7. (C-, C-),. (C-),.8 (C-), 79. (C-),.,.,.,.,.9,., 7.9, 8., 8.0 (Ph),.7,.8, 0., 7.7 (ArC) ppm. HRMS (ESI): calcd. for C 8 H 9 N, 0.70 found 0.9 [M + H] +. MS (ESI) m/z: 0.7 [M + H] +, 8. [M H]. FT-IR (ATR): ν = 89 (s), 0 (s), 08 (m), 90 (s), 70 (m), 0 (w), 7 (m) cm -. [α] D 0 = -0.0 (c = 0.0, CH Cl ) mp.: C (S)-N-Ethoxy-α,α-dimethyl--pyrrolidinemethanol () H N In an oven dried Schlenk flask.9 g (0.08 mol) magnesium turnings were covered with 0 ml of diethyl ether. A small amount of methyl iodide (0. ml, 0.7 g,.00 mmol) was added to the mixture and the reaction was started using a heat gun. In the following a mixture of.8 ml (.97 g,.0 mol) methyl iodide and ml of Et was added drop wise and after complete addition the colorless solution was refluxed for further 0 minutes. Under an inert gas atmosphere (S)-N-(ethoxcarbonyl)proline methyl ester 7 (.00 g,.9 mmol) was dissolved in 0 ml Et and cooled to 0 C. The obtained Grignard-solution was added slowly over a period of one hour and the resulting solution was stirred for further 0 h at room temperature. The reaction was hydrolyzed using 0 ml sat. NaHC solution. After the addition of 0 ml of dichloromethane the layers were separated and the aqueous layer was extracted with Page S7

18 ARKIVC 0 (iii) S-S9 x 0 ml CH Cl. After drying over MgS concentration afforded.00 g (.9 mmol, 00%) of the desired product as yellow oil. H-NMR (00 MHz, CDCl ): δ =.07 (s, H, Me),.7 (s, H, Me),.7 (t, J = 7., H, CH CH ),.9.0 (m, H, -H, -H),..7 (m, H, -H a ),..79 (m, H, - H b ),.89 (t, J = 7., H, -H),. (q, J = 7., H, CH CH ),.7 (br, H, H) ppm. C-NMR (7 MHz, CDCl ): δ =.8 (CH CH ),.,. (C-, C-), 7.8, 9. (Me), 8. (C-),.9 (CH CH ), 7.9 (C-), 7.8 (C-), 8. (C-) ppm. Spectroscopic data were consistent with previously reported data for this compound. 8 (S)-α,α-Dimethyl--pyrrolidinemethanol (7) H NH 7 (S)-N-Ethoxy-α,α-dimethyl--pyrrolidinemethanol (0.0 g,.8 mmol) was dissolved in 0 ml of methanol and an excess of potassium hydroxide (.8 g, 0.08 mol) was added. The mixture was refluxed for h, methanol was distilled off and the residue was dissolved in ml of dichloromethane. Water was added ( ml), the layers were separated and the organic layer was dried over MgS. After concentration in vacuo 0.0 g (0.77 mmol, %) of desired product was isolated as a yellow oil. H-NMR (00 MHz, CDCl ): δ =.09 (s, H, Me),. (s, H, Me), (m, H, -H, -H),.8.0 (m, H, -H, -H) ppm. C-NMR (7 MHz, CDCl ): δ =.9,.9 (C-, C-),., 7. (Me),.8 (C-),. (C-), 9. (C-) ppm. Spectroscopic data were consistent with previously reported data for this compound. 9 Tri(o-tolyl)boroxin (8) o-tolylboronic acid (0.9 g,.80 mmol) was dissolved in 0 ml of toluene, heated to 0 C and was directly distilled off via a claisen bridge. This procedure was repeated three times. The favored product was obtained as a colorless solid (0. g,.8 mmol, 8%). Page S8

19 ARKIVC 0 (iii) S-S9 B B B 8 H-NMR (00 MHz, CDCl ): δ =.8 (s, H, Me) (m, H), 7. (td, J = 7., J =. Hz, H), 8.0 (dd, J = 7., J =. Hz, H) ppm. C-NMR (7 MHz, CDCl ): δ =.,., 0.,., 7.,. ppm. Spectroscopic data were consistent with previously reported data for this compound. 0. Nyberg, N. T.; Duus, J. Ø.; Sorensen,. W. J. Am. Chem. Soc ,.. Halimjani, A. Z.; Saidi, M. R. Synth. Commun. 00,, 7.. Kalinowski, H.; Berger, S.; Braun, S. C-NMR-Spektroskopie, Georg Thieme Verlag, Stuttgart, Germany 98,.. Gautier, F. M.; Martin, S. J.; Jones, S. rg. Biomol. Chem. 009, 7, 9.. Mathre, D. J.; Jones, T. K.; Xavier, L. C. ; Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Turner Jones, E. T.; Hoogsteen, K.; Baum, M. W.; Grabowsky E. J. J. J. rg. Chem. 99,, 7.. Ho, C.-Y.; Chen, Y.-C.; Wong, M.-K.; Yang D. J. rg. Chem. 00, 70, Corey, E. J.; Link, J.. Tet. Lett. 989, 0, Sibi, M. P.; Manyem, S. rg. Lett. 00,, Sibi, M. P.; Zhang, R.; Manyem, S. J. Am. Chem. Soc. 00,, (a) Corey, E. J.; Loh, T. P. J. Am. Chem. Soc. 99,, 89; (b) Corey, E.J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 00,, 808. Page S9