Eva Bednářová

David Nečas

Ivana Císařová

Michal Dušek

Frédéric Lamaty
email: frederic.lamaty@umontpellier.fr

ORIGINAL Martin Kotora
email: martin.kotora@natur.cuni.cz

Eva Bedna ´r ˇova ´1

David Nec ˇas

Ivana Cı ´sar ˇova ´3 •

Michal Dus ˇek

Fre ´de ´ric Lamaty

Synthesis of new

Keywords: Cyclotrimerization, Catalysis, N,N 0 -Dioxides, Silicon compounds, Enantioselective synthesis

come

Introduction

Chiral pyridine N-oxides and bipyridine N,N 0 -dioxides are an important class of heteroaromatic compounds with interesting chemical properties. Polarization of the N-O bond results in their electron-donation activity and makes them rather strong Lewis bases, which are able to activate Lewis acids such as trichlorosilanes. Therefore, they can catalyze a number of various reactions such as allylation and crotylation of aldehydes, aldol reactions, ring-opening of epoxides, and cyanosilylation of ketones and imides [START_REF] Koukal | Pyridine N-Oxides and Derivatives Thereof in Organocatalysis[END_REF][2][3][4][5][6][7][8][9][10]. Due to the general high interest in the development of new Lewis basic chiral organocatalysts, synthetic approaches providing new chiral compounds possessing the pyridine N-oxide moiety are desirable.

Results and discussion

Ligand design

We designed new types of bipyridine N,N 0 -dioxides with the C2 symmetry (Fig. 1) which possess centers of chirality in the side chains. The pyridine cores are connected in positions 2 and 2 0 . In addition, the presence of two substituents in position 3 and 3 0 together with two oxygen atoms of the N-oxides should cause restricted rotation of the C2-C2 0 bond between the two pyridine rings, thus, to generate dynamic axial chirality [11] in the molecule.

Generally, there are two possible pathways of synthesis of these types of N,N-dioxides (Scheme 1). The first approach (A) is based on the following retrosynthetic analysis: (i) oxidation of a bipyridine to a bipyridine N,N 0dioxide, (ii) reductive homocoupling of a 2-halopyridine that could be prepared by (iii) catalytic cyclotrimerization of a 1-halodiyne with a nitrile. In the second approach (B) is a bipyridine N,N 0 -dioxide synthesized by (i) oxidative dimerization of a pyridine N-oxide prepared by (ii) oxidation of a bicyclic pyridine and (iii) catalytic cyclotrimerization of an unsubstituted diyne with a nitrile.

Synthesis of bipyridine N,N 0 -dioxides Approach A Synthesis of desired bipyridine N,N 0 -dioxides started with monolithiation of hepta-1,6-diyne (1a, Y=CH 2 ) or propargyl ether (1b, Y=O) with LiHMDS followed by reactions with trimethylsilyl chloride (Scheme 2). Then the formed diynes 2a and 2b underwent bromination with NBS providing 1-bromodiynes 3a and 3b at isolated yields of 52% and 65% after two steps. The subsequent cyclotrimerization of 3a and 3b with pivaloyl cyanide under the standard condition developed in our group (Cp*RuCl(cod) (10 mol%), dichloroethane, 20 °C) [12] proceeded with the preferential formation of 2-bromopyridines 4a and 4b in both cases. Thus, in each case, mixtures of both possible regioisomers 4a and 5a, and 4b and 5b were obtained at high isolated yields (4a 56%, 5a 15%; 4b 60%, 5b 12%). The TMS group of 4a was then removed using tetrabutylammonium fluoride (TBAF) yielding ketone 6a at 94% yield. In the case of 4b it was necessary to use potassium carbonate and the deprotected ketone 6b was obtained at 93% yield. It should be mentioned that deprotection with TBAF was not reproducible and intractable reaction mixtures were obtained, probably as a result of low stability of either the starting material or the product. Ketones 6a and 6b were then reduced by enantioselective Ru-catalyzed transfer hydrogenation to chiral alcohols 7a and 7b in quantitative yields and with excellent enantioselectivity of 94% and 90% ee, respectively [13]. S configuration of both alcohols 7a and 7b was unequivocally confirmed by a single-crystal X-ray analysis (for 7a, see Ref. [14], for 7b, see Fig. 2).

After protection of the free hydroxyls with the acetyl group, the pyridines 8a and 8b were dimerized using in situ-generated Ni(0) species in 68% and 62%,

Scheme 1

Fig. 1 Newly designed bipyridine N,N 0 -dioxide respectively (Scheme 3). Surprisingly, deprotection of the acetyl groups in bipyridines 9a and 9b under the standard conditions (K 2 CO 3 , MeOH, 20 °C) resulted in different outcomes. Whereas the reaction with 9a proceeded without any problems and provided pyridine 10a at 96% yield as an optically pure compound, deprotection of 9b produced an insoluble material, which we were not able to characterize and identify. Although a full consumption of the starting material and formation of monodeprotected species was observed using different deprotection conditions such as 4A ˚MS in MeOH or NH 3 in MeOH, the same insoluble material was formed at the end of the reaction. Some of the aspects of the synthesis of bipyridine 10a are discussed in detail in our recent report, where this chiral 2,2 0 -bipyridine was efficiently used as a ligand in metal-catalyzed reactions [14].

The reaction of bipyridine 10a with methyl iodide formed bipyridine 11a which was then oxidized with MCPBA to furnish the desired bipyridine N,N 0 -dioxide 12a at 93% isolated yield (Scheme 4). Although formation of two atropoisomers of 12a could have been expected, only one diastereoisomer was detected and isolated and its aR configuration was determined by the single-crystal X-ray analysis (Fig. 3).

Unsatisfactory result of the attempt to synthesize N,N 0dioxide bearing oxygen in the 5-membered ring resulted in invention of a new synthetic approach. As we were suspicious that our problems could originate in the presence of free hydroxyl groups in bipyridine 10b, we tested the possibility to convert the OH groups to methyl ethers prior to dimerization. In addition, this pathway would also Scheme 2

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shorten the synthesis of N,N 0 -dioxide by making the steps of protection and deprotection with acetyl groups obsolete.

We were pleased that treatment of chiral alcohols (S)-7a and (S)-7b with methyl iodide furnished pyridines 13a and 13b at 87% and almost quantitative yield, respectively.

They were afterwards successfully dimerized to bipyridines 11a and 11b at 68% and 78% isolated yields (Scheme 5). Surprisingly, oxidation of bipyridine 11b with MCPBA provided a complex mixture of products. The LC-MS analysis of the mixture detected the formation of other products as cyclic lactones formed by oxidation of benzylic CH 2 groups in the five-membered ring. Unfortunately, also other oxidizing agents (other peroxides, percarbonate, TEMPO, perruthenate, nitrite, oxaziridines, etc.) did not improve the selectivity of the reaction towards selective formation of N,N 0 -dioxide 12b. Author's personal copy

Approach B

As we did not find a way for the synthesis of bipyridine N,N 0 -dioxide 12b using approach A and as it would be convenient to prepare also the second atropoisomer (S,S,aS)-12b with the opposite chirality, we turned our attention to approach B described in Scheme 1. We started our synthesis with cyclotrimerization of hepta-1,6-diyne (1a) and propargyl ether (1b) with pivaloyl cyanide (Table 1). The original conditions developed by Yamamoto [15] for similar substrates provided desired products 14a and 14b at 44% moderate and 58% isolated yield, respectively (entries 1 and 2). Gratifyingly, optimization of reaction conditions comprising increase of the catalyst loading to 10 mol % and slow addition of diyne by a syringe pump resulted in increased yields of 75% and 89%, respectively (entries 4 and 5).

Reduction of the starting ketone 14a with (-)-Ipc 2 BCl brought about no conversion (Table 2, entry 1). Its Rucomplex catalyzed transfer hydrogenation under the standard conditions (RuCl[(S,S)-Tsdpen](p-cymene), HCOOH/ Et 3 N, 20 °C) [13] turned out to be very slow and, in addition, the required chiral alcohol 15a was formed with moderate enantioselectivity: 47% yield, 55% ee after 12 days (entry 2). Increasing the temperature to 40 °C improved not only the rate of the reaction, the yield, but surprisingly also enantioselectivity (88% yield, 74% ee; entry 3). The rate of the reaction together with its yield was further improved by refluxing of the reaction mixture; unfortunately, a significant drop of enantioselectivity to 67% ee was observed (entry 4). Ketone 14b was reduced under optimized conditions yielding alcohol 15b in quantitative yield and 89% ee (entry 5). In addition, after recrystallization from hexanes, the enantiomeric purity of both of the alcohols 15a and 15b was further improved. As a result, both compounds were obtained as optically pure compounds. S configuration of 15a was unequivocally confirmed by a single-crystal X-ray analysis (Fig. 4).

Alcohols (S)-15a and (S)-15b were in the next step treated under basic conditions with methyl iodide to provide the corresponding methyl ethers 16a and 16b at 94% and the quantitative yield, respectively (Scheme 6). Their oxidation by MCPBA proceeded smoothly to furnish pyridine N-oxides 17a and 17b in quantitative yield without any sign of oxidation of benzylic CH 2 positions as was observed in the case of bipyridine 11b. Ensuing oxidative dimerization using LiTMP and iodine furnished both atropoisomers of the target compounds (S,S,aS)-12a and (S,S,aR)-12a at 28% and 59% isolated yields, and (S,S,aS)-12b and (S,S,aR)-12b at 11% and 60% isolated yields.

Interestingly, our levels of selectivity in the last steps of approaches A and B are completely opposite to the observation reported by Denmark [16]. While we observed in approach A formation of only atropoisomer (S,S,aR)-12b by oxidation of bipyridine 11b to N,N 0 -dioxide 12b, Denmark described formation of both isomers (R,R,aS) and (R,R,aR) in 5/2 ratio when a structurally similar compound is oxidized. On the other hand, in the last step in approach B, the oxidative dimerization of a pyridine N-oxide to an N,N 0 -dioxide in the Denmark's case only (R,R,aS)-isomer was obtained, the same type of reaction in our hands furnished both (S,S,aR) and (S,S,aS) atropoisomers in 2/1 ratio for 12a and 6/1 ratio for 12b.

Application of bipyridine N,N 0 -dioxide in organocatalytic reactions

Lewis base-catalyzed asymmetric allylation of benzaldehyde 18 with allyltrichlorosilane 19 has become the testing ground of the new N-oxide catalyst. For testing, we used all four of our newly prepared bipyridine N,N 0 -dioxide (S,S,aS)-12a, (S,S,aR)-12a, (S,S,aS)-12b, (S,S,aR)-12b, and N,N 0 -dioxide 20 (Fig. 5) derived from Bolm's 2,2 0 -bipyridine which possesses no axial chirality because of the lack of substituent in the positions 3 and 3 0 and which was prepared following a slightly modified published procedure [17].

We started our study with conditions (0.5 mol% of the catalyst, 1.5 eq. of base, THF, -78 °C, Table 3) that turned out to be optimal in our previous study of allylation of aldehydes using bipyridine N,N 0 -dioxide catalysts [18]. Unfortunately, only catalysts 20 and (S,S,aR)-12a turned out to be active providing allyl alcohol 21 at low yield and moderate to high enantioselectivity in the range of 0-69% ee (entries 1-5). Elevation of the reaction temperature to -40 °C improved the yield but the enantioselectivity Author's personal copy noticeably dropped (entries 6-10). Increasing the amount of the base to 5 eq. caused the drop of both yield and ee (entries 11-15). A higher loading of the catalyst (1.5 mol %) improved the yield of the reaction but the change of enantioselectivity was marginal if any (entries [16][17][18][19][20]. Although the use of acetonitrile notably improved the yields, the enantioselectivity remained moderate (entries 21-25). On the other hand, using DCM brought rise of enantioselectivity (entries 26-30) keeping the catalyst 20 the most active (76% yield, 82% ee). Increasing of the amount of the base as well as loading of the catalyst did not improve the results of the reaction (entries 31 and 32). Generally, it can be stated that in most cases the N,N 0dioxide 20 without element of axial chirality provided allylic alcohol 21 in the best yields and enantioselectivity. Among the atropoisomeric N,N 0 -dioxides, (R)-atropoisomers ((S,S,aR)-12a and (S,S,aR)-12b) provided the higher yield of alcohol 21 while the higher ee could be obtained using (aS)-isomers ((S,S,aS)-12a and (S,S,aS)-12b). Comparing N,N 0 -dioxides 12a (Y = CH 2 ) and 12b (Y=O), the more selective were catalysts 12b bearing the oxygen atom in the five-membered ring, whereas catalysts 12a bearing all-carbon ring gave better enantioselectivity.

Catalytic activity of the abovementioned N,N 0 -dioxides was then studied in aldolization reaction of acetophenone (22) with trichlorosilyl ketene acetal of methyl acetate (23) to tertiary alcohol 24 (Table 4). Despite its synthetic potential, the enantioselective variant of the aldol reaction is rather scarce. In 2002, Denmark et al. found out that the reaction can be catalyzed by bipyridine N,N 0 -dioxides of a similar structure to ours and they obtained the required alcohol 24 at 91% isolated yield and 87% ee, which has not been surpassed yet [17,19]. For our study, we used Denmark's reaction conditions without any further optimization (10 mol % of the catalyst, DCM, -20 °C).

The use of (S,S,aS)-12a furnished (S)-24 at 93% yield and 60% ee (entry 1), while utilization of the opposite atropoisomer (S,S,aR)-12a provided the desired product with the opposite stereochemistry, however, with low enantioselectivity (entry 2). On the other hand, using the atropoisomers (S,S,aS)-12b and (S,S,aR)-12b, the desired alcohol 24 was obtained with the same R configuration and quantitative yields with 57% and 78% ee, respectively (entries 3 and 4). Since Denmark et al. in their studies found that the N,N 0 -dioxides possessing 2,4,6-trimethylbenzyl (TMB) substituent instead of the methyl group in the etheric part of the catalysts provided the best results [17,19], we synthesized new dioxides (S,S,aS)-25b and (S,S,aR)-25b (Fig. 6) following approach B. Using catalyst (S,S,aS)-25b alcohol (S)-24 was formed at 67% yield with 24% ee (entry 5), while using catalyst (S,S,aR)-25b, alcohol 24 was obtained in 56% yield and 70% ee (entry 6) giving no advantage in use of N,N 0 -dioxide (S,S,aR)-25b instead of (S,S,aR)-12b.

The N,N 0 -dioxides (R,aS)-26 and (R,aR)-26, which were previously developed in our group [20] (Fig. 6) and gave us the best results in allylation reactions, were studied as

Scheme 6

Fig. 5 Structure of N,N 0 -dioxide 20 catalysts in aldolization reaction as well. Catalyst (R,aS)-26 provided alcohol (S)-24 in 86% and 40% ee; on the other hand, alcohol (R)-24 was obtained using (R,aR)-26 in 93% yield and 65% ee (entries 7 and 8).

Unfortunately, the most promising results with catalysts (S,S,aR)-12b and (R,aR)-26 were not further improved by decrease of the reaction temperature to -50 °C (entries 9 and 10). The replacement of DCM by THF, which revealed to be essential in allylation reaction with catalyst (R,aR)-26 [20], caused the formation of opposite major enantiomer, however, with low selectivity (entry 11).

S configuration in all cases

Synthesis of new bipyridine N,N 0 -dioxides and their application in asymmetric allylation of… 123

Author's personal copy

Conclusion

We have developed two new pathways for the synthesis of six axially chiral N,N 0 -dioxides based on catalytic [2?2?2] cyclotrimerization of diynes with nitriles. These two approaches differ in the dimerization method-while in approach A, the N,N 0 -dioxide was prepared by oxidation of a bipyridine, which is formed by reductive dimerization of 2-bromopyridine, approach B is based on oxidative dimerization of a pyridine N-oxide. While only one atropoisomer of the desired N,N 0 -dioxide is formed selectively in approach A, approach B provides both the atropoisomers. The utility of all six newly formed N,N 0dioxides was proved in asymmetric reactions, namely allylation of aldehydes and aldol addition to acetophenone.

Experimental

All chemicals were purchased from common commercial sources-Sigma-Aldrich, Acros Organics, Alfa Aesar, Strem chemicals and PENTA. Dry solvents for reactions were purified and dried by distillation from sodium/benzophenone (THF, Et 2 O), CaH 2 (DCM, DCE), or by standing over molecular sieves (DMF, ACN). For degassing the solvents, freeze-pump-thaw technique or sonication with argon bubbling was used. Solvents for column chromatography were distilled prior to use. Benzaldehyde (18), acetophenone (22), tetrachlorosilane, diisopropylamine, N,N-diisopropylethylamine, and tributyltin chloride were purified by distillation prior to use. Other solvents and chemicals were used without any purification. Argon or nitrogen was used as an inert gas. Silica gel 60 (0.040-0.063 mm) was used for column chromatography, TLC was performed on aluminum sheets with a layer of silica gel 60 F 254 , both purchased from MERCK. Spots on TLC plates were detected using UV lamp (k = 254 nm), basic permanganate solution or acidic p-anisaldehyde solution.

NMR spectra were recorded on Varian VNMRS 300 (m( 1 H) = 299.94 MHz, m( 13 C) = 75.43 MHz), on Bruker Avance III (400 MHz) (m( 1 H) = 400.13 MHz, m( 13 C) = 100.61 MHz), or on Bruker Avance III (600 MHz) (m( 1 H) = 600.17 MHz, m( 13 C) = 150.04 MHz) in deuterated chloroform and referenced to residual solvent peak ( 1 H: 7.26 ppm, 13 C: 77.16 ppm). Chemical shifts are given in d scale; coupling J constants are given in Hz.

Mass spectra were recorded on VG-Analytical ZAB-SEQ and Synapt G2-S. Infrared spectra were recorded in KBr and measured on spectrometer Hermo Nicolet AVA-TAR 370 FT-IR. All melting points were determined on Kofler apparatus. Optical rotations were measured on automatic polarimeter Autopol III and are given in THF was used as a solvent deg cm 3 g -1 dm -1 with accuracy ± 2 and the mass concentrations in g/100 cm 3 . HPLC analyses of chiral products were done on Shimadzu chromatograph with Daicel Chiralpak Ò and Lux Columns. Compounds 2a, 2b, 3a, 3b, 4a, 5a, 6a, 7a, 8a, 9a, 10a, (R,aS)-26, (R,aR)-26, 27, and pivaloyl cyanide were prepared according to the previously published procedures [12,14,20].

1-[4-Bromo-7-(trimethylsilyl)-1,3-dihydrofuro[3,4-c]pyridin- 6-yl]-2,2-dimethylpropan-1-one (4b, C 14 H 20 BrNO 2 Si) and 1-[7-bromo-4-(trimethylsilyl)-1,3-dihydrofuro[3,4-c]pyridin- 6-yl]-2,2-dimethylpropan-1-one (5b, C 14 H 20 BrNO 2 Si)
To a dry-argon-flushed 5-cm 3 Schlenk flask were added 9 mg of Cp*RuCl(cod) (0.02 mmol), 1 cm 3 of DCE and 60 mm 3 of pivaloyl cyanide (0.5 mmol). Then 60 mg of diyne 3b (0.25 mmol) dissolved in 2 cm 3 of DCE was added slowly by a syringe pump during the course of 1 h. The reaction mixture was stirred at 20 °C until 3b was fully consumed (disappearance of the respective spot on TLC). Then volatiles were evaporated under reduced pressure. Column chromatography of the residue on silica gel (gradient 50/ 1 ? 40/1 cyclohexane/EtOAc) provided 52 mg (60%) of 4b and 10 mg (12%) of 5b as colorless oils. 4b: 1 H NMR (300 MHz, CDCl 3 ): d = 5.23-5.20 (m, 2H, CH 2 ), 5.06-5.03 (m, 2H, CH 2 ), 1.41 (s 9H, 3 9 CH 3 ), 0.27 (s, 9H, 3 9 CH 3 ) ppm; 13

(S,S)-(1,1 0 ,3,3 0 -Tetrahydro[4,4 0 -bifuro[3,4-c]pyridine]-6,6 0 - diyl)bis(2,2-dimethylpropane-1,1-diyl) diacetate (9b, C 28 H 36 N 2 O 6 )
To a dry-argon-flushed 100-cm 3 flask with 193 mg of NiCl 2 (1.5 mmol), dry degassed 5 cm 3 of DMF was added. The mixture was heated to 70 °C, then 1.53 g of PPh 3 (5.8 mmol) and 105 mg of Zn (1.6 mmol) were added. The reaction mixture was stirred at 70 °C for 1 h, then 400 mg of 8b (1.2 mmol) in dry degassed 4 cm 3 of DMF was added. After stirring for 13 h at 70 °C, the reaction mixture was quenched with 10 cm 3 of water and extracted with 3 9 30 cm 3 of Et 2 O. The combined organic fractions were washed with 20 cm 3 of brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 4/1 ? 3/1 hexanes/EtOAc) furnished 187 mg (62%) of the title compound as a colorless solid. M.p.: 176.4 °C; 1 H NMR (300 MHz, CDCl 3 ): d = 7.14 (s, 2H, 2 9 Ar-H), 5.75 (dt, J = 14.6, 1.9 Hz, 2H, CH 2 ), 5.62-5.53 (m, 2H, CH 2 ), 5.55 (s, 2H, 2 9 CH), 5.14-5.09 (m, 4H, 2 9 CH 2 ), 2.15 (s, 6H, 2 9 CH 3 ), 1.01 (s, 18H, 6 9 CH 3 ) ppm; 13

3,3 0 -Bis((S)-1-methoxy-2,2-dimethylpropyl)-6,6 0 ,7,7 0 -te- trahydro-5H,5 0 H-1,1 0 -bi(cyclopenta[c]pyridine) (11a, C 28 H 40 N 2 O 2 )
Method A: To a suspension of 30 mg of NaH (60% w/w suspension in mineral oil, 0.73 mmol) in 1 cm 3 of THF in 10-cm 3 Ar-flushed flask, a solution of 100 mg of 10a (0.25 mmol) in 4 cm 3 of THF was added slowly. Mixture was stirred at 20 °C for 30 min, then 124 mm 3 of MeI (3.0 mmol) was added slowly. After stirring at 50 °C for 24 h, the reaction mixture was quenched by addition of 2 cm 3 of water and extracted with 3 9 10 cm 3 of DCM. Combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 30/1 ? 20/1) yielded 89 mg (83%) of the title compound as a colorless solid.

Method B: To a dry-argon-flushed 5-cm 3 vial with 48 mg of NiCl 2 (0.36 mmol), dry degassed 2 cm 3 of DMF was added. The reaction mixture was heated to 70 °C, then 380 mg of PPh 3 (1.45 mmol) and 26 mg of Zn (0.39 mmol) were added. The reaction mixture was stirred at 70 °C for 1 h, then 90 mg of 13a (0.30 mmol) in 2 cm 3 of dry degassed DMF was added. After stirring for 12 h at 70 °C, DMF was distilled off under the reduced pressure, the residue was suspended in 10 cm 3 of DCM and filtered through Celite Ò . Filtrate was washed with 5 cm 3 of NaHCO 3 (sat. aq. solution) and the aqueous phase was then washed with 2 9 15 cm 3 of DCM. The combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 100/1 ? 12/1 hexanes/ EtOAc) furnished 45 mg (68%) of the title compound as colorless crystals. M.p.: 199. 6,6 0 -Bis((S)-1-methoxy-2,2-dimethylpropyl)-1,1 0 ,3,3 0 -tetrahydro-4,4 0 -bifuro[3,4-c]pyridine (11b, C 26 H 36 N 2 O 4 ) To a dry-argon-flushed 5-cm 3 vial with 80 mg of NiCl 2 (0.6 mmol), dry degassed 1.5 cm 3 of DMF was added. The reaction mixture was heated to 70 °C, then 630 mg of PPh 3 (2.4 mmol) and 43 mg of Zn (0.65 mmol) were added. The reaction mixture was stirred at 70 °C for 1 h, then 150 mg of 13b (0.50 mmol) in dry degassed 2 cm 3 of DMF was added. After stirring for 12 h at 70 °C, DMF was distilled off under the reduced pressure; the residue was suspended in 15 cm 3 of DCM and filtered through Celite Ò . Filtrate was washed with 10 cm 3 of NaHCO 3 (sat. aq. solution) and the aqueous phase was then washed with 2 9 30 cm 3 of DCM. The combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 30/1 ? 18/1 hexanes/EtOAc) furnished 86 mg (78%) of the title compound as colorless crystals. M.p.: 215.0 °C; 1 H NMR (400 MHz, CDCl 3 ): d = 7.26 (s, overlapping with CDCl 3 , 2 9 Ar-H), 5.73 (dt, J = 14.5, 2.0 Hz, 2H, 2 9 CH), 5.61 (dt, J = 14.6, 1.9 Hz, 2H, 2 9 CH), 5.17-5.13 (m, 4H, 2 9 CH 2 ), 4.05 (s, 2H, 2 9 CH), 3.23 (s, 6H, 2 9 CH 3 ), 0.96 (s, 18H, 6 9 CH 3 ) ppm; 13 (S,S,aS)-3,3 0 -Bis((S)-1-methoxy-2,2-dimethylpropyl)-6,6 0 ,7,7 0tetrahydro-5H,5 0 H-[1,1 0 -bi(cyclopenta[c]pyridine)] 2,2 0 -dioxide ((S,S,aS)-12a, C 28 H 41 N 2 O 4 ) and (S,S,aR)-3,3 0 -bis((S)-1methoxy-2,2-dimethylpropyl)-6,6 0 ,7,7 0 -tetrahydro-5H,5 0 H-[1,1 0 -bi(cyclopenta[c]pyridine)] 2,2 0 -dioxide ((S,S,aR)-12a, C 28 H 41 N 2 O 4 ) Method A: To a solution of 60 mg of 11a (0.14 mmol) in 4.5 cm 3 of DCM cooled down to 0 °C (icewater) was added 90 mg of MCPBA (0.41 mmol) in six portions during 5 h. After stirring for 2 h at 20 °C, 11a was fully consumed (disappearance the respective spot on TLC), the reaction was quenched by addition of 3 cm 3 of NaOH (40% aq. solution) and stirred for 1 h. The phases were separated and the aqueous phase was washed with 3 9 15 cm 3 of DCM. Combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 20/1 ? 5/1 CHCl 3 /acetone) furnished 60 mg (93%) of (S,S,aR)-12a as a colorless solid.

Method B: To a solution of 273 mg of 17a (1.16 mmol) in 5 cm 3 of Et 2 O cooled to -73 °C in 25-cm 3 Ar-flushed flask, freshly prepared solution of LiTMP (1.27 mmol) in 3.5 cm 3 of dry THF was added dropwise. Mixture was stirred at -73 °C for 16 h, then solution of 330 mg of I 2 (1.3 mmol) in 2.5 cm 3 of dry THF was added in two portions in 1 h. The reaction mixture was let to warm up to 20 °C during the period of 3 h, then it was quenched by addition of 5 cm 3 of Na 2 S 2 O 3 (sat. aq. solution) and extracted with 5 9 15 cm 3 of DCM. Combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 90/1/1 ? 90/30/1 DCM/ acetone/EtOH) furnished 75 mg (28%) of (S,S,aS)-12a and 160 mg (59%) of (S,S,aR)-12a as yellowish solids. (S,S,aS)-12a: M.p.: 210.6 °C; 1 Racemic (S,S,aS)-3,3 0 -bis(1-methoxy-2,2-dimethylpropyl)-6,6 0 ,7,7 0 -tetrahydro-5H,5 0 H-[1,1 0 -bi(cyclopenta[c]pyridine)] 2,2 0 -dioxide ((rac)-12a 1 , C 28 H 41 N 2 O 4 ), racemic (S,S,aR)-3,3 0bis(1-methoxy-2,2-dimethylpropyl)-6,6 0 ,7,7 0 -tetrahydro-5H, 5 0 H-[1,1 0 -bi(cyclopenta[c]pyridine)] 2,2 0 -dioxide ((rac)-12a 2 , C 28 H 41 N 2 O 4 ), racemic (S,R,aR)-3,3 0 -bis(1-methoxy-2,2-dimethylpropyl)-6,6 0 ,7,7 0 -tetrahydro-5H,5 0 H-[1,1 0 -bi(cyclopenta-[c]pyridine)] 2,2 0 -dioxide ((rac)-12a 3 , C 28 H 41 N 2 O 4 ), and racemic (S,R,aR)-3,3 0 -bis(1-methoxy-2,2-dimethylpropyl)-6, 6 0 ,7,7 0 -tetrahydro-5H,5 0 H-[1,1 0 -bi(cyclopenta[c]pyridine)] 2,2 0 -dioxide ((rac)-12a 4 , C 28 H 41 N 2 O 4 ) By approach B using racemic alcohol (rac)-15a were prepared products (rac)-12a 1 and (rac)-12a 2 and as well 50/50 mixture of (rac)-12a 3 and (rac)-12a 4 . Spectral data of products (rac)-12a 1 and (rac)-12a 2 were in agreement with chiral products (S,S,aS)-12a and (S,S,aR)-12a. HPLC of (rac)-12a 1 : Lux Columns-Lux Cellulose-1, n-heptane/IPA 99.5/0.5, 1 cm 3 /min, 254 nm, t S,S,aS = 13.6 min, t R,R,aR = 16.1 min. HPLC of (rac)-12a 2 : Lux Columns-Lux Cellulose-1, nheptane/IPA 95/5, 1 cm 3 /min, 254 nm, t S,S,aR = 4.1 min, t R,R,aS = 5.4 min.

(rac)-12a (S,S,aS)-3,3 0 -6,6 0 -Bis((S)-1-methoxy-2,2-dimethylpropyl)-1,1 0 ,3,3 0 -tetrahydro[4,4 0 -bifuro [3,4-c]pyridine] 5,5 0 -dioxide ((S,S,aS)-12b, C 26 H 37 N 2 O 6 ) and (S,S,aR)-3,3 0 -6,6 0 -bis((S)-

1- methoxy-2,2-dimethylpropyl)-1,1 0 ,3,3 0 -tetrahydro[4,4 0 -bi- furo[3,4-c]pyridine] 5,5 0 -dioxide ((S,S,aR)-12b, C 26 H 37 N 2 O 6 )
To a solution of 163 mg of 17b (0.7 mmol) in 4 cm 3 of Et 2 O cooled to -73 °C in 25-cm 3 Ar-flushed flask, freshly prepared solution of LiTMP (0.76 mmol) in 1.4 cm 3 of dry THF was added dropwise. Mixture was stirred at -73 °C for 16 h, then solution of 191 mg of I 2 (1.3 mmol) in 2 cm 3 of dry THF was added in two portions in 2 h. The reaction mixture was let to warm up to 20 °C during the period of 3 h, then it was quenched by addition of 5 cm 3 of Na 2 S 2 O 3 (sat. aq. solution) and extracted with 5 9 15 cm 3 of DCM. Combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 90/1/ 1 ? 100/20/1 DCM/acetone/EtOH) furnished 18 mg (11%) of (S,S,aS)-12b and 97 mg (60%) of (S,S,aR)-12b as yellowish solids. (S,S,aS)-12b: M.p.: 205.0 °C; 1 20 = ? 296.3°(c = 0.37, CHCl 3 ); HPLC of (S,S,aR)-12b: Lux Columns-Lux Cellulose-4, n-heptane/IPA 90/10, 1 cm 3 /min, 254 nm, t R,R,aS = ND, t S,S,aR = 20.4 min.

Racemic

(S,S,aS)-3,3 0 -6,6 0 -bis(1-methoxy-2,2-dimethylpropyl)-1,1 0 ,3,3 0 -tetrahydro[4,4 0 -bifuro [3,4-c]pyridine] 5,5 0dioxide ((rac)-12b 1 , C 26 H 37 N 2 O 6 ), racemic (S,S,aR)-3,3 0 -6,6 0bis(1-methoxy-2,2-dimethylpropyl)-1,1 0 ,3,3 0 -tetrahydro[4,4 0 -bifuro [3,4-c]pyridine] 5,5 0 -dioxide ((rac)-12b 2 , C 26 H 37 N 2 O 6 ), racemic (S,R,aS)-3,3 0 -6,6 0 -bis(1-methoxy-2,2dimethylpropyl)-1,1 0 ,3,3 0 -tetrahydro[4,4 0 -bifuro[3,4-c]pyridine] 5,5 0 -dioxide ((rac)-12b 3 , C 26 H 37 N 2 O 6 ), and racemic (S,R,aR)-3,3 0 -6,6 0 -bis(1-methoxy-2,2-dimethylpropyl)-1,1 0 ,3,3 0 -tetrahydro[4,4 0 -bifuro[3,4-c]pyridine] 5,5 0 -dioxide ((rac)-12b 4 , C 26 H 37 N 2 O 6 ) By approach B using racemic alcohol (rac)-15b were prepared products (rac)-12b 1 and (rac)-12b 2 and as well 50/50 mixture of (rac)-12b 3 and (rac)-12b 4 . Spectral data of products (rac)-12b 1 and (rac)-12b 2 were in agreement with chiral products (S,S,aS)-12b and (S,S,aR)-12b. HPLC of (rac)-12b 1 : Lux Columns-Lux Cellulose-2, n-heptane/IPA 80/20, 1 cm 3 /min, 254 nm, t S,S,aS = 7.0 min, t R,R,aR = 28.2 min. HPLC of (rac)-12b 2 : Lux Columns-Lux Cellulose-4, n-heptane/ IPA 90/10, 1 cm 3 /min, 254 nm, t R,R,aS =9.7 min, t S,S,aR- = 20.5 min. (rac)-12b 3 ? (rac)-12b 4 : M.p.: 232.8 °C; 1 H NMR (400 MHz, CDCl 3 ): d = 7.37 (s, 2H, 2 9 Ar-H), 7.36 (s, 2H, 2 9 Ar-H), 5.36-5.30 (m, 2H, 2 9 CH), 5.29- BrNO) To a cooled (ice water) suspension of 28 mg of NaH (60% w/w suspension in mineral oil, 0.70 mmol) in 2 cm 3 of THF in 25cm 3 argon-flushed flask, a solution of 131 mg of 7a (0.46 mmol) in 4 cm 3 of THF was added slowly. Mixture was stirred at 20 °C for 30 min, then 58 mm 3 of MeI (0.92 mmol) was added slowly to the cooled reaction mixture. After stirring at 20 °C for 2 h, the reaction mixture was quenched by addition of 5 cm 3 of water and extracted with 3 9 15 cm 3 of DCM. Combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 30/1 ? 20/1 hexanes/ EtOAc) yielded 119 mg (87%) of the title compound as a colorless solid. M.p.: 113.4 °C; 1 H NMR (400 MHz, CDCl 3 ): d = 7.19 (s, 1H, Ar-H), 3.96 (s, 1H, CH), 3.22 (s, 3H, CH 3 ), 3.02 (t, J = 7.6 Hz, 2H, CH 2 ), 2.93 (t, J = 7.6 Hz, 2H, CH 2 ), 2.13 (p, J = 7.7 Hz), 0.89 (s, 9H, 3 9 CH 3 ) ppm; 13 ) 320.06205, found 320.06203; R f = 0.47 (20/1 hexanes/EtOAc).

(S)-1-Bromo-3-(1-methoxy-2,2-dimethylpropyl)-6,7-dihydro- 5H-cyclopenta[c]pyridine (13a, C 14 H 20
(S)-4-Bromo-6-(1-methoxy-2,2-dimethylpropyl)-1,3-dihydro- furo[3,4-c]pyridine (13b, C 13 H 18 BrNO 2 )
To a cooled (ice water) suspension of 130 mg of NaH (60% w/w suspension in mineral oil, 3.2 mmol) in 9 cm 3 of THF in 50-cm 3 argon-flushed flask, a solution of 630 mg of 7b (2.14 mmol) in 17 cm 3 of THF was added slowly. Mixture was stirred at 20 °C for 10 min, then 270 mm 3 of MeI (4.3 mmol) was added slowly to the cooled reaction mixture. After stirring at 20 °C for 2 h, the reaction mixture was quenched by addition of 10 cm 3 of water and extracted with 3 9 30 cm 3 of DCM. Combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 30/1 ? 20/1 hexanes/EtOAc) yielded 622 mg (97%) of the title compound as a colorless solid. M.p.: 47.3 °C; 1 H NMR (400 MHz, CDCl 3 ): d = 7.24 (s, 1H, Ar-H), 5.21-5.17 (m, 2H, CH 2 ), 5.08-5.04 (m, 2H, CH 2 ), 4.00 (s, 1H, CH), 3.23 (s, 3H, CH 3 ), 0.90 (s, 9H, 3 9 CH 3 ) ppm; 13

; R f = 0.42 (5/1 hexanes/ EtOAc). 1-(6,7-Dihydro-5H-cyclopenta[c]pyridin-3-yl)-2,2-dimethyl- propan-1-one (14a, C 13 H 17 NO)
To a dry-argon-flushed 100-cm 3 flask were added 126 mg of Cp*RuCl(cod) (0.33 mmol), 12 cm 3 of DCE and 0.60 cm 3 of pivaloyl cyanide (90% purity, 4.9 mmol). Then 310 mg of hepta-1,6-diyne 1a (3.3 mmol) dissolved in 18 cm 3 of DCE was added slowly by a syringe pump during the course of 10 h. The reaction mixture was stirred at 20 °C for 5 h and then volatiles were evaporated under reduced pressure. Column chromatography of the residue on silica gel (gradient 50/ 1 ? 40/1 hexanes/EtOAc) provided 499 mg (75%) of the title compound as colorless crystals. M.p.: 25.7 °C; 1 H NMR (400 MHz, CDCl 3 ): d = 8.44 (s, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 2.99-2.90 (m, 4H, 2 9 CH 2 ), 2.12 (p, J = 7.5 Hz, 2H, CH 2 ), 1.44 (s, 9H, 3 9 CH 3 ) ppm; 13

R f = 0.61 (10/1 hexanes/EtOAc). 1-(1,3-Dihydrofuro[3,4-c]pyridin-6-yl)-2,2-dimethylpropan- 1-one (14b, C 12 H 15 NO 2 )
To a dry-argon-flushed 250-cm 3 flask were added 282 mg of Cp*RuCl(cod) (0.73 mmol), 50 cm 3 of DCE and 1.35 cm 3 of pivaloyl cyanide (90% purity, 10.9 mmol). Then 770 mm 3 of propargyl ether 1b (7.3 mmol) dissolved in 20 cm 3 of DCE was added slowly by a syringe pump during the course of 10 h. The reaction mixture was stirred at 20 °C for 3 h and then volatiles were evaporated under reduced pressure. Column chromatography of the residue on silica gel (gradient 20/1 ? 8/1 hexanes/EtOAc) provided 1327 mg (89%) of the title compound as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ): d = 8.52 (d, J = 0.8 Hz, 1H, Ar-H), 7.82 (d, J = 0.8 Hz, 1H, Ar-H), 5.19-5.15 (m, 2H, CH 2 ), 5.13-5.09 (m, 2H, CH 2 ), 1.44 (s, 9H, 3 9 CH 3 ) ppm; 13 (S)-1-(6,7-Dihydro-5H-cyclopenta[c]pyridin-3-yl)-2,2dimethylpropan-1-ol (15a, C 13 H 19 NO) To a dry-argonflushed 20-cm 3 vial with a solution of 498 mg of 14a (2.45 mmol) and 86 mg of RuCl[(S,S)-Tsdpen](p-cymene) (0.12 mmol) in 5 cm 3 of DCM, 4 cm 3 of a mixture of Et 3 N/HCOOH (2/1) was added. After stirring for 6 days at 40 °C, the reaction mixture was quenched with 5 cm 3 of NaHCO 3 (sat. aq. solution) and extracted with 3 9 15 cm 3 of DCM. The combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 5/2 ? 2/1 hexanes/EtOAc) furnished 442 mg (88%, 74% ee) of the title compound as a colorless solid. By recrystallization from excess of hexanes was obtained 240 mg (48%, [ 99% ee) of the title compound. M.p.: 93. After 1 h at 20 °C, the reaction mixture was quenched with 5 cm 3 of water and extracted with 3 9 15 cm 3 of DCM. The combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Filtration of the residue through silica gel pad (1/1 hexanes/ EtOAc) provided 152 mg (99%) of the title compound as an amorphous solid. All the spectral data were in agreement with the chiral product 15a. HPLC of (rac)-15a: Daicel Chiralpak IA, n-heptane/IPA 80/20, 1 cm 3 /min, 208 nm, t S =6.3 min, t R = 7.7 min.

(S)-1-(1,3-Dihydrofuro [3,4-c]pyridin-6-yl)-2,2-dimethylpropan-1-ol (15b, C 12 H 17 NO 2 ) To a dry-argon-flushed 50cm 3 flask with a solution of 1327 mg of 14b (6.47 mmol) and 227 mg of RuCl[(S,S)-Tsdpen](p-cymene) (0.32 mmol) in 7 cm 3 of DCM, 10 cm 3 of a mixture of Et 3 N/HCOOH (2/1) was added. After stirring for 2 days at 40 °C, the reaction mixture was quenched with 10 cm 3 of NaHCO 3 (sat. aq. solution) and extracted with 3 9 30 cm 3 of DCM. The combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 2/1 ? 2/3 hexanes/EtOAc) furnished 1317 mg (98%, 89% ee) of the title compound as an amorphous solid. By recrystallization from excess of hexanes was obtained 909 mg (68%, [ 99% ee) of the title compound. M.p.: 101.9 °C; 1 Mixture was stirred at 20 °C for 30 min, then 160 mm 3 of MeI (2.5 mmol) was added slowly to the cooled reaction mixture. After stirring at 20 °C for 1 h, the reaction mixture was quenched by addition of 10 cm 3 of water and extracted with 3 9 30 cm 3 (S)-3-(1-Methoxy-2,2-dimethylpropyl)-6,7-dihydro-5H-cyclopenta[c]pyridine 2-oxide (17a, C 14 H 21 NO 2 ) To a solution of 262 mg of 16a (1.2 mmol) in 15 cm 3 of DCM under Ar atmosphere cooled down to 0 °C (ice water) was added 408 mg of MCPBA (1.8 mmol). After stirring at 20 °C for 1 h, the reaction mixture was quenched by addition of 10 cm 3 of K 2 CO 3 (sat. aq. solution) and stirred for 10 min. The phases were separated and the aqueous phase was washed with 3 9 30 cm 3 of DCM. Combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 2/1 ? 1/1 CHCl 3 /acetone) furnished 278 mg (99%) of title compound as a colorless oil. 1 (20) To a solution of 384 mg of 28 (1.1 mmol) in 20 cm 3 of DCM cooled down to 0 °C (ice water) was added 724 mg of MCPBA (3.2 mmol) and after stirring for 2 h at 20 °C, the second portion of 727 mg of MCPBA (3.2 mmol) was added to the cooled reaction mixture. After stirring at 20 °C for 19 h, the reaction mixture was quenched by addition of 5 cm 3 of NaOH (40% aq. solution) and stirred for 1 h. The phases were separated and the aqueous phase was washed with 3 9 20 cm 3 of DCM. Combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 40/1 ? 10/1 CHCl 3 /acetone) and recrystallization from hexanes furnished 294 mg (70%) of title compound as a colorless solid. The recorded spectral data (SI) were in agreement with the published data [19].

-Bis((S)-1-methoxy-2,2-dimethylpropyl)-[2,2 0 -bipyridine] 1,1 0 -dioxide
(S)-1-Phenylbut-3-en-1-ol (21) To a solution of 50 mm 3 of benzaldehyde (18, 0.50 mmol), N,N 0 -dioxide (0.0025 mmol), and 130 mm 3 of DIPEA (0.75 mmol) in 2 cm 3 of DCM cooled to -78 °C, 115 mm 3 of allyltrichlorosilane (0.75 mmol) was added. The mixture was stirred at -78 °C for 16 h, then the reaction mixture was quenched with 1 cm 3 of NaHCO 3 (sat. aq. solution) and extracted with 3 9 5 cm 3 of DCM. The combined organic fractions were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The yield was determined by 1 H NMR analysis with 1,2,4,5-tetramethylbenzene as an internal standard. Analytically pure product 21 was obtained by column chromatography on silica gel (gradient 30/1 ? 20/1 hexanes/EtOAc). (S)-Configuration was determined by comparison of data with the literature [20]. The recorded analytical data (SI) were in agreement with the published data [18].

(rac)-1-Phenylbut-3-en-1-ol ((rac)-21) To a solution of 13 mg of Fe(ClO 4 ) 2 Á6H 2 O (0.035 mmol) in 10 cm 3 of ACN were added 100 mm 3 of allylboronic acid pinacol ester (0.52 mmol) and 35 mm 3 of benzaldehyde (18, 0.35 mmol). The reaction mixture was stirred at 20 °C for 5 h, then quenched with 3 cm 3 of water, and extracted with 3 9 10 cm 3 of DCM. The combined organic fractions were dried over MgSO 4 , filtered, and concentrated under the reduced pressure. Column chromatography of the residue on silica gel (gradient 30/1 ? 20/1 hexanes/ EtOAc) furnished 50 mg (97%) of the title compound as a colorless oil. All spectral data were in agreement with the chiral product 21.

Trichloro[(1-methoxyvinyl)oxy]silane (23) To the vigorously stirred 10.0 cm 3 of SiCl 4 (85 mmol) in two-neck 100-cm 3 flask was slowly added 4.1 g of 29 (11.3 mmol) followed by 0.6 cm 3 of (Bu 3 Sn)O (1.1 mmol). Mixture was stirred until the starting 29 was fully consumed (12 h, determined by 1 H NMR), then mixture of SiCl 4 and product 23 was distilled to 50-cm 3 three-neck flask connected with dry-ice condenser (50 °C, 2-5 mbar). Then SiCl 4 was slowly distilled off (20 °C, 80 mbar) using the vacuum regulator to another flask. The purity (48%) of the title compound was determined by the amount of created aldol product in the reaction of a small sample of the oily residue with the excess of benzaldehyde in DCM-d 2 and with 1,2,4,5-tetramethylbenzene as an internal standard. Because of its instability, the product 23 was able to be characterized only by 1 H NMR. The recorded analytical data (SI) were in agreement with published data [17].

(R)-Methyl 3-hydroxy-3-phenylbutanoate (24) A solution of 23 mm 3 of acetophenone (22, 0.20 mmol) and N,N 0dioxide (0.02 mmol) in 1 cm 3 of DCM was cooled to -20 °C, then 100 mm 3 of 23 (48% purity, 0.3 mmol) was added. The reaction mixture was stirred at -20 °C for 18 h, then quenched with 1 cm 3 of NaHCO 3 (sat. aq. solution), filtered through Celite Ò , and extracted with 3 9 5 cm 3 of DCM. The combined organic fractions were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The yield was determined by 1 H NMR analysis with 1,2,4,5-tetramethylbenzene as internal standard. Analytically pure product 24 was obtained by column chromatography on silica gel (gradient 20/1 ? 7/1 cyclohexane/EtOAc). (R)-configuration was determined by comparison of data with the literature [17]. It should be also noted that because of the difficulty in the preparation and handling of the starting silyl ketene acetal 23, the yields of 24 (namely in Table 4, entries 5, 6, and 11) could be influenced by changing the batch of this compound. But we truly believe that the purity of 23 is not influencing the enantioselectivity of the reaction. The recorded analytical data (SI) were in agreement with published data [17].

(rac)-Methyl 3-hydroxy-3-phenylbutanoate ((rac)-24) The racemic product was prepared by the same procedure as chiral product 24 using trimethylamine N-oxide as catalyst. All spectral data were in agreement with the chiral product 24. 3 Ar-flushed flask was dropwise added freshly prepared solution of LiTMP (0.46 mmol) in 0.9 cm 3 of THF. Mixture was stirred at -73 °C for 16 h, then a solution of 119 mg of I 2 (0.46 mmol) in 1 cm 3 of dry THF was added in two portions in 2 h. The reaction mixture was let to warm up to 20 °C during the period of 3 h, then it was quenched by addition of 5 cm 3 of Na 2 S 2 O 3 (sat. aq. solution), and extracted with 5 9 15 cm 3 of DCM. Combined organic phases were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 10/1 ? 3/ 1 hexanes/EtOAc) furnished 19 mg (13%) of (S,S,aS)-25b as an amorphous solid and 63 mg (42%) of (S,S,aR)-25b as yellowish crystals. (S,S,aS)-25b: 1

1 2 3

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Fig. 2

 2 Fig.2ORTEP drawing of (S)-7b

Fig. 3

 3 Fig.3ORTEP drawing of (S,S,aR)-12a

Fig. 4

 4 Fig.4ORTEP drawing of (S)-15a

  (S)-1-(4-Bromo-1,3-dihydrofuro[3,4-c]pyridin-6-yl)-2,2dimethylpropan-1-ol (7b, C 12 H 16 BrNO 2 ) To a dry-argonflushed 10-cm 3 flask with a solution of 270 mg of 6b (0.95 mmol) and 34 mg of RuCl[(S,S)-Tsdpen](p-cymene) (0.05 mmol) in 2 cm 3 of DCM, 1.5 cm 3 of a mixture of Et 3 N/HCOOH (2/1) was added. After stirring for 17 h at 20 °C, the reaction mixture was quenched with 5 cm 3 of water and extracted with 3 9 20 cm 3 of EtOAc. The combined organic fractions were dried over MgSO

  = 0.32 (2/1 hexanes/EtOAc); [a] D 20 = --30.1°(c = 0.38, CHCl 3 ); HPLC of 15a: Daicel Chiralpak IA, n-heptane/IPA 80/20, 1 cm 3 /min, 208 nm, t S = 6.3 min, t R = ND. (rac)-1-(6,7-Dihydro-5H-cyclopenta[c]pyridin-3-yl)-2,2dimethylpropan-1-ol ((rac)-15a, C 13 H 19 NO) To a solution of 153 mg of 14a (0.75 mmol) in 3 cm 3 of dry MeOH in 25-cm 3 flask, 43 mg of NaBH 4 (1.1 mmol) was added.

(

  rac)-1-(1,3-Dihydrofuro[3,4-c]pyridin-6-yl)-2,2-dimethylpropan-1-ol ((rac)-15b, C 12 H 17 NO 2 ) To a solution of 150 mg of 14b (0.73 mmol) in 4 cm 3 of dry MeOH in 25-cm 3 flask, 41 mg of NaBH 4 (1.1 mmol) was added. After 1.5 h at 20 °C, the reaction mixture was quenched with 5 cm 3 of water and extracted with 3 9 15 cm 3 of DCM. The combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Filtration of the residue through silica gel pad (1/2 hexanes/ EtOAc) provided 145 mg (96%) of the title compound as an amorphous solid. All the spectral data were in agreement with the chiral product 15b. HPLC of (rac)-15b: Daicel Chiralpak IC, n-heptane/IPA 80/20, 1 cm 3 /min, 207 nm, t S =7.5 min, t R = 11.0 min.(S)-3-(1-Methoxy-2,2-dimethylpropyl)-6,7-dihydro-5H-cyclopenta[c]pyridine (16a, C 14 H 21 NO) To a cooled (ice water) suspension of 80 mg of NaH (60% w/w suspension in mineral oil, 2.0 mmol) in 8 cm 3 of dry THF in 50-cm 3 argon-flushed flask, a solution of 259 mg of 15a (1.26 mmol) in 8 cm 3 of dry THF was added slowly.

(

  S,S,aS)-6,6 0 -Bis[(S)-2,2-dimethyl-1-[(2,4,6-trimethylbenzyl)oxy]propyl]-1,1 0 ,3,3 0 -tetrahydro[4,4 0 -bifuro[3,4-c]pyridine] 5,5 0 -dioxide ((S,S,aS)-25b, C 44 H 56 N 2 O 6 ) and (S,S,aR)-6,6 0 -bis[(S)-2,2-dimethyl-1-[(2,4,6-trimethylbenzyl)oxy]propyl]-1,1 0 ,3,3 0 -tetrahydro[4,4 0 -bifuro[3,4-c]pyridine] 5,5 0 -dioxide ((S,S,aR)-25b, C 44 H 56 N 2 O 6 ) To a solution of 150 mg of 32b (0.42 mmol) in 1.7 cm 3 of Et 2 O cooled to -73 °C in 25-cm

  ) 709.42111, found 709.42122; R f- = 0.33 (3/1 hexanes/EtOAc); [a] D 20 = --35.0°(c = 0.34, CHCl 3 ). (S,S,aR)-25b: M.p.: 143.7 °C; 1 H NMR (400 MHz, CDCl 3 ): d = 7.48 (s, 2H, 2 9 Ar-H), 6.85 (s, 4H, 4 9 Ar-H), 5.38-5.31 (m, 2H, CH 2 ), 5.25 (s, 2H, 2 9 CH), 5.18-5.07 (m, 4H, 2 9 CH 2 ), 4.67-4.61 (m. 2H,

Table 1

 1 Cyclotrimerization of 1a and 1b with pivaloyl nitrile

	Entry	Y	Diyne	[Ru]/mol% a	T/°C	Time/h	Pyridine	Yield/% b
	1	C H 2	1a	5	20 then 60	2.5	14a	44
	2	O	1b	5	20 then 60	2.5	14b	58
	3 c	CH 2	1a	10	60	12	14a	70
	4 c	CH 2	1a	10	20	15	14a	75
	5 c	O	1b	10	20	13	14b	89
	a [Ru]-Cp*RuCl(cod)
	b Isolated yield
	c Diyne was added slowly by a syringe pump

Table 2

 2 Chiral reduction of 14a and 14b

	Synthesis of new bipyridine N,N 0 -dioxides and their application in asymmetric allylation of…
	Entry	Y	Ketone	Catalyst a	Reductant	Solvent	T/°C	Time/d	Alcohol	Yield/% b	ee/% c
	1	C H 2	14a	-	(-)-Ipc 2 BCl	THF	20	2	15a	NR	-
	2	C H 2	14a	[Ru]	HCOOH, Et 3 N	DCM	20	12	15a	47	55
	3	C H 2	14a	[Ru]	HCOOH, Et 3 N	DCM	40	6	15a	88 (48) d	74 ([ 99) d
	4	C H 2	14a	[Ru]	HCOOH, Et 3 N	DCM	reflux	0.5	15a	98	67
	5	O	14b	[Ru]	HCOOH, Et 3 N	DCM	40	2	15b	98 (68) d	89 ([ 99) d
	a [Ru]-(RuCl[(S,S)-Tsdpen](p-cymene) (5 mol%)
	b Isolated yield. NR no reaction
	c Determined by HPLC with a chiral stationary phase
	d Recrystallization from hexanes in parenthesis

Table 3

 3 Allylation of benzaldehyde 18 with allyltrichlorosilane 19

	Entry	N,N 0 -Dioxide	Mol%	DIPEA/eq.	Solvent	T/°C	Time/h	Yield/% a	ee/% b,c
	1	20	0.5	1.5	THF	-78	13	17	69
	2	( S,S,aS)-12a	0.5	1.5	THF	-78	13	NR	-
	3	( S,S,aR)-12a	0.5	1.5	THF	-78	13	14	48
	4	( S,S,aS)-12b	0.5	1.5	THF	-78	13	NR	-
	5	( S,S,aR)-12b	0.5	1.5	THF	-78	13	NR	-
	6	20	0.5	1.5	THF	-40	13	40	21
	7	( S,S,aS)-12a	0.5	1.5	THF	-40	13	NR	-
	8	( S,S,aR)-12a	0.5	1.5	THF	-40	13	57	10
	9	( S,S,aS)-12b	0.5	1.5	THF	-40	13	NR	-
	10	(S,S,aR)-12b	0.5	1.5	THF	-40	13	NR	-
	11	20	0.5	5	THF	-78	15.5	18	47
	12	(S,S,aS)-12a	0.5	5	THF	-78	15.5	NR	-
	13	(S,S,aR)-12a	0.5	5	THF	-78	15.5	10	43
	14	(S,S,aS)-12b	0.5	5	THF	-78	15.5	NR	-
	15	(S,S,aR)-12b	0.5	5	THF	-78	15.5	NR	-
	16	20	1.5	1.5	THF	-78	12	27	70
	17	(S,S,aS)-12a	1.5	1.5	THF	-78	12	6	68
	18	(S,S,aR)-12a	1.5	1.5	THF	-78	12	42	49
	19	(S,S,aS)-12b	1.5	1.5	THF	-78	12	NR	-
	20	(S,S,aR)-12b	1.5	1.5	THF	-78	12	NR	-
	21	20	0.5	1.5	ACN	-40	13.5	93	54
	22	(S,S,aS)-12a	0.5	1.5	ACN	-40	13.5	11	40
	23	(S,S,aR)-12a	0.5	1.5	ACN	-40	13.5	96	33
	24	(S,S,aS)-12b	0.5	1.5	ACN	-40	13.5	39	51
	25	(S,S,aR)-12b	0.5	1.5	ACN	-40	15.5	93	45
	26	20	0.5	1.5	DCM	-78	15.5	76	82
	27	(S,S,aS)-12a	0.5	1.5	DCM	-78	15.5	NR	-
	28	(S,S,aR)-12a	0.5	1.5	DCM	-78	15.5	77	46
	29	(S,S,aS)-12b	0.5	1.5	DCM	-78	15.5	NR	-
	30	(S,S,aR)-12b	0.5	1.5	DCM	-78	15.5	27	72
	31	20	0.5	1.5	DCM	-78	17	40	83
	32	20	1.5	5	DCM	-78	17	73	81

a1 H NMR yield, NR no reaction b Determined by HPLC with a chiral stationary phase c

Table 4

 4 Aldol reaction of acetophenone 22 with trichlorosilyl ketene acetal 23

		N,N 0 -Dioxide	T/°C	Time/h	Yield/% a	ee/% b
	1	( S,S,aS)-12a	-20	18	93	60 (S)
	2	( S,S,aR)-12a	-20	18	87	15 (R)
	3	( S,S,aS)-12b	-20	18	[ 96	57 (R)
	4	( S,S,aR)-12b	-20	18	[ 96	78 (R)
	5	( S,S,aS)-25b	-20	18	67	24 (S)
	6	( S,S,aR)-25b	-20	18	56	70 (R)
	7	( R,aS)-26	-20	18	86	40 (S)
	8	( R,aR)-26	-20	18	93	65 (R)
	9	( S,S,aR)-12b	-50	36	81	75 (R)
	10	(R,aR)-26	-50	36	81	68 (R)
	11 c	(R,aR)-26	-50	36	42	9 (S)
	a1 H NMR yield

b

Determined by HPLC with a chiral stationary phase c

  -one (6b, C 12 H 14 BrNO 2 ) To a solution of 3.27 g of 4b (9.24 mmol) in 80 cm3 of MeOH was added 1.3 g of K 2 CO 3(9.4 mmol). After stirring at 60 °C for 10 h, the reaction mixture was quenched by addition of 30 cm 3 of water and extracted with 3 9 100 cm 3 of DCM. Combined organic fractions were dried over Na 2 SO 4 , filtered, and concentrated under the reduced pressure. Column chromatography of the residue on silica gel (gradient 30/1 ? 20/1) yielded 2415 mg (93%) of the title compound as colorless crystals. M.p.: 112.9 °C;1 H NMR (300 MHz, CDCl 3 ): d = 7.79 (s, 1H, Ar-H), 5.23-5.19 (m, 2H, CH 2 ), 5.11-5.08 (m, 2H, CH 2 ), 1.44 (s, 9H, 3 9 CH 3 ) ppm; 13 C NMR (75 MHz, CDCl 3 ): d = 204.87, 154.44, 151.86, 139.84, 132.80, 116.21, 74.38, 73.41, 44.46, 27.59 ppm; IR (drift KBr): m = 2973, 2959, 1679, 1550, 1281, 1191, 1127, 1049, 996, 910, 855 cm -1 ; HRMS (ESI): m/z calcd. for C 12 H 15 BrNO 2 ([M?H] 1 ) 284.0286, found 284.0288; R f = 0.23 (10/1 hexane/EtOAc).

	C NMR (75 MHz, CDCl 3 ): d = 208.84,
	160.81, 156.96, 136.02, 132.71, 127.25, 74.99, 71.90,
	43.26, 27.18, 0.29 ppm; IR (drift KBr):	m = 2956, 1693,
	1541, 1241, 1050, 1009, 931, 846 cm -1 ; HRMS (ESI): m/z
	calcd. for C 14 H 21 BrNO 2 Si ([M?H] ? ) 342.0525, found
	342.0524; R f = 0.40 (10/1 hexane/EtOAc). 5b: 1 H NMR
	(300 MHz, CDCl 3 ): d = 5.27 (t, J = 2.1 Hz, 2H, CH 2 ),
	5.06 (t, J = 2.1 Hz, 2H, CH 2 ), 1.33 (s 9H, 3 9 CH 3 ), 0.29
	(s, 9H, 3 9 CH 3 ) ppm; 13 C NMR (75 MHz, CDCl 3 ): d =
	211.31, 159.66, 157.34, 149.89, 143.85, 111.99, 75.90,
	75.47, 46.16, 28.81, 0.00 ppm; IR (drift KBr):	m = 2966,
	1704, 1249, 1057, 1013, 942, 895, 845 cm -1 ; HRMS
	(ESI): m/z calcd. for C 14 H 21 BrNO 2 Si ([M?H] ? ) 342.0525,
	found 342.0524; R f = 0.31 (10/1 hexane/EtOAc).
	1-(4-Bromo-1,3-dihydrofuro[3,4-c]pyridin-6-yl)-2,2-
	dimethylpropan-1

  Daicel Chiralpak IA, n-heptane/IPA 98/2, 1 cm 3 / min, 207 nm, t S = 17.8 min (major), t R = 18.8 min (minor). -ol ((rac)-7b, C 12 H 16 BrNO 2 ) To a solution of 16 mg of 6b (0.06 mmol) in 0.4 cm 3 of dry MeOH in 4 cm 3 vial, 3 mg of NaBH 4 (0.08 mmol) was added. After 3 h at 20 °C, the reaction mixture was quenched with 2 cm 3 of water and the mixture was extracted with 3 9 5 cm 3 of Et 2 O. The combined organic fractions were washed with 5 cm 3 of brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (5/1 hexanes/ EtOAc) provided 15 mg (93%) of the title compound as an amorphous solid. All the spectral data were in agreement with the chiral product 7b. HPLC of (rac)-7b: Daicel Chiralpak IA, n-heptane/IPA 98/2, 1 cm 3 /min, 207 nm, t S = 17.7 min, t R = 18.7 min. C 14 H 18 BrNO 3 ) To a cooled solution (ice-water) of 198 mg of 7b (0.69 mmol) in 150 mm 3 of pyridine (1.7 mmol) in 10-cm 3 flask, 200 mm 3 of acetic anhydride (1.9 mmol) was added dropwise. After stirring at 20 °C for 16 h, the reaction mixture was quenched with 5 cm 3 of NaHCO 3 (sat. aq. solution) and extracted with 3 9 15 cm 3 of DCM. The combined organic fractions were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.

	Author's personal copy
	of 7b: (rac)-1-(4-Bromo-1,3-dihydrofuro[3,4-c]pyridin-6-yl)-2,2-
	4 , fil-tered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 7/ 1 ? 4/1 hexanes/EtOAc) furnished 270 mg (99%, 90% ee) of the title compound as an amorphous solid. Optically pure compound could be obtained by recrystallization from CHCl 3 by slow evaporation of solvent. M.p.: 49.2 °C; 1 H NMR (400 MHz, CDCl 3 ): d = 7.08 (s, 1H, Ar-H), 5.18-5.16 (m, 2H, CH 2 ), 5.05 (t, J = 2.2 Hz, 2H, CH 2 ), 4.35 (s, 1H, CH), 0.92 (s, 9H, 3 9 CH 3 ) ppm; 13 C NMR (100 MHz, CDCl 3 ): d = 161.70, 151.05, 136.04, 133.60, 114.75, 80.77, 74.16, 73.15, 36.43, 25.97 ppm; IR (drift KBr): m = 2955, 2867, 1607, 1556, 1364, 1051, 1016, 906 cm Fig. 6 Structure of N,N 0 -dioxides 25b and 26 dimethylpropan-1(S)-1-(4-Bromo-1,3-dihydrofuro[3,4-c]pyridin-6-yl)-2,2-dimethylpropyl acetate (8b, Column chromatog-raphy of the residue on silica gel (gradient 6/1 ? 5/1 hexanes/EtOAc) furnished 225 mg (99%) of the title compound as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ): d = 7.11 (s, 1H, Ar-H), 5.52 (s, 1H, CH), 5.19-5.14 (m, 2H, CH 2 ), 5.06-5.01 (m, 2H, CH 2 ), 2.13 (s, 3H, CH 3 ), 0.97 (s, 9H, 3 9 CH 3 ) ppm; 13 C NMR (75 MHz, CDCl 3 ): d = 170.34, 159.36, 151.07, 136.10, 133.85, 114.10, 82.89, 74.24, 73.27, 35.17, 26.22 ppm; IR (drift KBr): m = 2968, 1371, 1240, 1201, 1051, 1027, 911 cm -1 ; HRMS (ESI): m/ z calcd. for C 14 H 19 BrNO 3 ([M?H] 1 ) 328.0548, found 328.0552; R f = 0.50 (3/1 hexane/EtOAc).
	123

-1 ; HRMS (ESI): m/z calcd. for C 12 H 17 BrNO 2 ([M?H] 1 ) 286.04372, found 286.04381; R f = 0.30 (4/1 hexane/EtOAc); [a] D 20 = ? 2.58°(c = 2.7, CHCl 3 ). HPLC

  C NMR (75 MHz, CDCl 3 ): d = 170.47, 156.58, 150.72, 149.45, 133.95, 114.74, 83.76, 75.18, 72.36, 35.23, 26.46, 21.24 ppm; IR (drift KBr): m = 2959, 2929, 2869, 1739, 1592, 1568, 1371, 1242, 1042, 1024, 902 cm -1 ; HRMS (ESI) m/z calcd. for C 28 H 37 N 2 O 6 ([M?H] 1 ) 497.2652, found 497.2654; R f = 0.34 (3/1 hexane/EtOAc).

  2 °C; 1 H NMR (400 MHz, CDCl 3 ): d = 7.27 (s, overlapping with CDCl 3 ), 4.05 (s, 2H, 2 9 CH), 3.44-3.33 (m, 2H, 2 9 CH), 3.18 (s, 6H, 2 9 CH 3 ), 3.01-2.93 (m, 4H, 2 9 CH 2 ), 2.75-2.65 (m, 2H, 2 9 CH), 2.23-2.11 (m, 2H, 2 9 CH), 2.05-1.19 (m, 2H, 2 9 CH), 0.96 (s, 18H, 9 9 CH 3 ) ppm; 13 C NMR (100 MHz, CDCl 3 ): d = 157.67, 155.51, 152.50, 138.13, 117.66, 92.93, 57.77, 35.80, 33.13, 31.92, 26.66, 25.06 ppm; IR (drift KBr): m = 2983, 2962, 2926, 2869, 2815, 1248, 1231, 1183, 1105, 973 cm -1 ; HRMS (ESI): m/ z calcd. for C 28 H 41 N 2 O 2 ([M?H] 1 ) 437.31626, found 437.31570; R f = 0.48 (5/1 hexanes/EtOAc).

  H NMR (400 MHz, CDCl 3 ): d = 7.36 (s, 2H, 2 9 Ar-H), 5.29-5.22 (m, 2H, 2 9 CH), 5.13-5.08 (m, 4H, 2 9 CH 2 ), 4.97 (s, 2H, 2 9 CH), 4.73-4.66 (m, 2H, 2 9 CH), 3.21 (s, 6H, Lux Columns-Lux Cellulose-2, nheptane/IPA 80/20, 1 cm 3 /min, 254 nm, t S,S,aS = 7.1 min, t R,R,aR = ND. (S,S,aR)-12b: M.p.: 180.7 °C; 1 H NMR (600 MHz, CDCl 3 ): d = 7.36 (s, 2H, Ar-H), 5.25-5.20 (m, 2H, 2 9 CH), 5.14-5.09 (m, 4H, 2 9 CH 2 ), 4.98 (s, 2H, 2 9 CH), 4.64-4.60 (m, 2H, 2 9 CH), 3.21 (s, 6H, 2 9 CH 3 ), 0.99 (s, 18H, 6 9 CH 3 ) ppm; 13 C NMR (150 MHz, CDCl 3 ): d = 150.84, 139.15, 136.46, 135.92, 118.14, 82.95, 73.17, 72.25, 58.48, 37.41, 25.79 ppm; IR (drift KBr): m = 1260, 1201, 1183, 1102, 1096, 1078, 1048, 1033, 973, 914, 899 cm -1 ; HRMS (ESI): m/z calcd. for C 26 H 37 N 2 O 6 ([M?H] ? ) 473.26461, found 473.26462; R f- = 0.17 (60/1 DCM/MeOH); [a] D

	2 9 CH 3 ), 0.96, (s, 18H, 6 9 CH 3 ) ppm; 13 C NMR
	(100 MHz, CDCl 3 ): d = 150.82, 139.00, 136.31, 135.85,
	118.14, 83.35, 73.13, 72.18, 58.21, 37.41, 25.79 ppm; IR
	(drift KBr):	m = 1260, 1198, 1186, 1099, 1075, 1048, 1033,
	908 cm -1 ; HRMS (ESI): m/z calcd. for C 26 H 36 N 2 NaO 6
	([M ? Na] ? ) 495.24656, found 495.24652; R f = 0.20 (60/
	1 DCM/MeOH); [a] D 20 = -393.4°(c = 0.24, CHCl 3 );
	HPLC of (S,S,aS)-12b:

  C NMR (100 MHz, CDCl 3 ):

	d = 162.08, 151.17, 135.68, 133.52, 113.93, 91.95, 74.34,
	73.24, 58.16, 35.85, 26.20 ppm; IR (drift KBr):	m = 2974,
	2959, 1380, 1242, 1189, 1099, 1054, 908, 860 cm -1 ;
	HRMS (ESI): m/z calcd. for C 13 H 18 BrNNaO 2 ([M?Na] 1 )
	322.04131, found 322.04140

  C NMR (100 MHz, CDCl 3 ): d = 206.64, 153.92, 149.60, 140.77, 137.57, 116.71, 73.08, 71.86, 44.31, 27.63 ppm; IR (drift KBr): m = 3482, 3422, 3402, 2968, 2956, 2926, 2863, 1688, 1272, 1189, 1147, 1123, 1048, 1003, 985, 899, 881 cm -1 ; HRMS ESI): m/z calcd. for C 12 H 15 NO 2 (M ? ) 205.1103, found 205.1105; R f = 0.46 (5/1 hexanes/EtOAc).

	Author's personal copy
	123

(

  2 °C; 1 H NMR (400 MHz, CDCl 3 ): d = 8.36 (s, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 4.40 (rs, 1H, OH), 4.29 (s, 1H, CH), 2.98-2.84 (m, 4H, 2 9 CH 2 ), 2.19-2.03 (m, 2H, CH 2 ), 0.90 (s, 9H, 3 9 CH 3 ) ppm; 13 C NMR (100 MHz, CDCl 3 ): d = 157.48, 153.68, 143.46, 139.11, 119.03, 80.44, 36.40, 32.71, 30.02, 26.07, 25.27 ppm; IR (drift KBr) m = 3264, 3246, 3210, 2974, 2953, 2902, 2872, 1344, 1296, 1072, 1018, 884 cm -1 ; HRMS (ESI): m/z calcd. for C 13 H 20 NO ([M?H] 1 ) 206.15394, found 206.15395; R f-

  Daicel Chiralpak IC, n-heptane/IPA 80/20, 1 cm 3 /min, 207 nm, t S = 7.4 min, t R = ND.

	H NMR (400 MHz, CDCl 3 ): d = 8.45, (s, 1H,
	Ar-H), 7.10 (s, 1H, Ar-H), 5.18-5.03 (m, 4H, 2 9 CH 2 ),
	4.36 (s, 1H, CH), 4.21 (brs, 1H, OH), 0.91 (s, 9H,
	3 9 CH 3 ) ppm; 13 C NMR (100 MHz, CDCl 3 ): d = 159.09,
	148.82, 140.77, 134.34, 115.49, 80.69, 72.90, 71.59, 36.43,
	26.00 ppm; IR (drift KBr):	m = 3249, 2959, 2932, 2869,
	1341, 1075, 1048, 1021, 902, 878 cm -1 ; HRMS (ESI): m/
	z calcd. for C 12 H 18 NO 2 ([M?H] 1 ) 208.13321, found
	208.13322; R f = 0.11 (2/1 hexanes/EtOAc); [a] D 20 = --
	20.9°(c = 0.31, CHCl 3 ); HPLC of 15b:

  °C; 1 H NMR (400 MHz, CDCl 3 ): d = 8.36 (s, 1H, Ar-H), 7.20 (s, 1H, Ar-H), 3.92 (s, 1H, CH), 3.19 (s, 3H, CH 3 ), 2.89 (t, J = 7.5 Hz, 4H, 2 9 CH 2 ), 2.08 (p, J = 7.5 Hz, 2H, CH 2 ), 0.88 (s, 9H, 3 9 CH 3 ) ppm;13 C NMR (100 MHz, CDCl 3 ): d = 157.79, 153.66, 144.11, 138.76, 118.16, 92.87, 57.80, 35.60, 32.81, 30.08, 26.36, 25.16 ppm; IR (drift KBr): m = 2974, 2955, 2904, 1366, 1359, 1233, 1198, 1179, 1154, 1097, 1103, 1046, 973, 951, 900 cm -1 ; HRMS (ESI): m/z calcd. for C 14 H 22 NO ([M?H]1 ) 220.16959, found 220.16979; R f = 0.43 (3/1 hexanes/EtOAc). To a cooled (ice water) suspension of 42 mg of NaH (60% w/w suspension in mineral oil, 1.1 mmol) in 3 cm 3 of THF in 50-cm 3 argon-flushed flask, a solution of 145 mg of 15b (0.7 mmol) in 6 cm 3 of THF was added slowly. Mixture was stirred at 20 °C for 20 min, then 90 mm 3 of MeI (1.4 mmol) was added slowly to the cooled reaction mixture. After stirring at 20 °C for 2 h, the reaction mixture was quenched by addition of 6 cm 3 of water and extracted with 3 9 20 cm 3 of DCM. Combined organic phases were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 3/1 ? 2/1 hexanes/EtOAc) yielded 150 mg (97%) of the title compound as a colorless solid. M.p.: 81.6 °C;1 H NMR (400 MHz, CDCl 3 ): d = 8.45 (s, 1H, Ar-H), 7.26 s, overlapping with CDCl 3 , Ar-H), 5.15-5.11 (m, 2H, CH 2 ), 5.11-5.07 (m, 2H, CH 2 ), 3.99 (s, 1H, CH), 3.21 (s, 3H, CH 3 ), 0.89 (s, 9H, 3 9 CH 3 ) ppm; 13 C NMR (100 MHz, CDCl 3 ): d = 159.54, 148.92, 141.27, 134.04, 114.71,

	of DCM. Combined organic phases were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (10/1 hexanes/EtOAc) yielded 259 mg (94%) of the title compound as a colorless solid. M.p.: 38.0 (S)-6-(1-Methoxy-2,2-dimethylpropyl)-1,3-dihydrofuro[3,4-c]pyridine (16b, C 13 H 19 NO 2 ) 92.70, 73.07, 71.69, 57.96, 35.71, 26.30 ppm; IR (drift KBr): m = 2977, 2953, 2923, 2869, 1180, 1114, 1087, 1048, 970, 905, 881 cm -1 ; HRMS (EI): m/z calcd. for C 13 H 19 NO 2 (M ? ) 221.1416, found 221.1418; R f = 0.20 (3/ 1 hexanes/EtOAc).

  calcd. for C 13 H 19 NO 3 (M ? ) 237.1365, found 237.1366; R f = 0.33 (50/1 DCM/MeOH).

		1248, 1219, 1189, 1147, 1096, 1066, 967 cm -1 ; HRMS
		(ESI): m/z calcd. for C 14 H 21 NO 2 (M ? ) 235.1572, found
		235.1570; R f = 0.35 (50/1 DCM/MeOH).
		(S)-6-(1-Methoxy-2,2-dimethylpropyl)-1,3-dihydrofuro[3,4-
		c]pyridine 5-oxide (17b, C 13 H 19 NO 3 ) To a solution of
		147 mg of 16b (0.66 mmol) in 9 cm 3 of DCM under Ar
		atmosphere cooled down to 0 °C (ice water) was added
		225 mg of MCPBA (1.0 mmol). After stirring at 20 °C for
		1 h, the reaction mixture was quenched by addition of
		6 cm 3 of K 2 CO 3 (sat. aq. solution) and stirred for 10 min.
		The phases were separated and the aqueous phase was
		washed with 3 9 20 cm 3 of DCM. Combined organic
		fractions were dried over MgSO 4 , filtered, and concen-
		trated under reduced pressure. Column chromatography of
		the residue on silica gel (gradient 2/1 ? 3/2 CHCl 3 /ace-
		tone) furnished 156 mg (99%) of title compound as a
		colorless oil. 1 H NMR (400 MHz, CDCl 3 ): d = 8.17 (s, 1H,
		Ar-H), 7.28 (s, 1H, Ar-H), 5.07 (s, 4H, 2 9 CH 2 ), 4.97 (s,
		1H, CH), 3.18 (s, 3H, CH 3 ), 0.96 (s, 9H, 3 9 CH 3 ) ppm;
		13 C NMR (100 MHz, CDCl 3 ): d = 150.61, 137.95, 137.07,
		133.45, 117.77, 82.72, 72.86, 71.29, 58.25, 37.37,
		25.70 ppm; IR (drift KBr):	m = 2968, 2956, 1272, 1245,
		1195, 1180, 1153, 1096, 1051, 1033, 902 cm -1 ; HRMS
		(ESI): m/z 6,6 0
	H NMR (400 MHz, CDCl 3 ): d = 8.11 (s,
	1H, Ar-H), 7.22 (s, 1H, Ar-H), 4.98 (s, 1H, CH), 3.17 (s,
	3H, CH 3 ), 2.90 (t, J = 7.5 Hz, 4H, 2 9 CH 2 ), 2.16 (p,
	J = 2H, CH 2 ), 0.97 (s, 9H, 3 9 CH 3 ) ppm; 13 C NMR
	(100 MHz, CDCl 3 ): d = 148.93, 143.70, 141.47, 135.14,
	120.59, 82.69, 58.11, 37.23, 32.29, 30.61, 25.78,
	25.55 ppm; IR (drift KBr):	m = 2968, 2953, 1305, 1263,

  H NMR (400 MHz, CDCl 3 ): d = 7.46 (s, 2H, 2 9 Ar-H), 6.86 (s, 4H, 4 9 Ar-H), 5.32-5.25 (m, 2H, CH 2 ), 5.21 (s, 2H, 2 9 CH), 5.18-5.04 (m, 4H, 2 9 CH 2 ), 4.80-4.70 (m, 2H, CH 2 ), 4.44 (d, J = 10.8 Hz, 2H, 2 9 CH), 4.33 (d, J = 10.8 Hz, 2H, 2 9 CH), 2.31 (s, 12H, 6 9 CH 3 ), 2.28 (s, 6H, 2 9 CH 3 ), 0.97 (s, 9H, 3 9 CH 3 ) ppm; 13 C NMR (100 MHz, CDCl 3 ): d = 151.41, 138.99, 137.94, 137.88, 136.02, 135.76, 131.20, 139.07, 118.58, 81.13, 73.14, 72.22, 66.64, 37.58, 25.88, 21.13, 19.73 ppm; IR (drift KBr): m = 2953, 2920, 2872, 2860, 1613, 1395, 359, 1263, 1219, 1192, 1087, 1042, 908, 854, 785 cm -1 ; HRMS (ESI): m/z calcd. for C 44 H 57 N 2 O 6 ([M?H] ?

Acknowledgements E. B. and M. K. would like to acknowledge financial support from the Czech Science Foundation (Grant no. 17-07707S) and French embassy in Prague. E. B. and F. L. would like to thank Universite ´de Montpellier, CNRS and French Ministry of Higher Education and Research for funding.

CH 2 ), 4.35 (s, 4H, 2 9 CH 2 ), 2.29 (s, 12H, 4 9 CH 3 ), 2.27 (s, 6H, 2 9 CH 3 ), 1.01 (s, 18H, 6 9 CH 3 ) ppm; 13 3 of dry THF cooled to 0 °C. Mixture was stirred for 20 min at 0 °C and then cooled down to -78 °C. Then 3.4 cm 3 of MeOAc (42.9 mmol) was added slowly and the mixture was stirred for 1 h at -78 °C. The solution was then added via a cannula to a solution of 10 cm 3 of Bu 3 SnCl (35.4 mmol) in 50 cm 3 of dry THF cooled to -78 °C during the course of 30 min. The reaction mixture was stirred at -78 °C for 10 min, then it was let to warm up to 20 °C during the course of 3 h, and then stirred at 20 °C for 30 min. Volatiles were evaporated under reduced pressure and then 150 cm 3 of hexane was added. White precipitate was removed by filtration through Celite Ò and the filtrate was concentrated under reduce pressure. Filtration through the short silica gel column (90/10/1 hexanes/EtOAc/Et 3 N) and Kugelrohr distillation (175 °C, 2 mbar) provided 11.9 g (93%) of the title compound as a colorless oil. The recorded analytical data (SI) were in agreement with the published data [17].

2-(Bromomethyl)-1,3,5-trimethylbenzene (30) [22] To a cooled (ice water) solution of 998 mg of 2,4,6-trimethylbenzyl alcohol (6.6 mmol) in 45 cm 3 of THF in dry-argonflushed 100-cm 3 flask, 0.25 cm 3 of PBr 3 (2.6 mmol) was added slowly. The reaction mixture was stirred at 20 °C for 2 h, quenched by addition of 20 cm 3 of water, extracted with 3 9 60 cm 3 of DCM, dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient hexanes ? 20/1 hexanes/EtOAc) provided 1103 mg (78%) of the title compound as a colorless solid. The recorded analytical data (SI) were in agreement with the published data [23].

To a suspension of 15 mg of NaH (60% w/w suspension in mineral oil, 0.36 mmol) and 37 mg of NaI (0.25 mmol) in 1.5 cm 3 of THF in 25-cm 3 argon-flushed flask, a solution of 50 mg of 15b (0.24 mmol) in 1.5 cm 3 of THF was added slowly. Mixture was stirred at 20 °C for 30 min, then 107 mg of 30 (0.50 mmol) was added slowly. After stirring at 20 °C for 20 h, the reaction mixture was quenched by addition of 3 cm 3 of water and extracted with 3 9 10 cm 3 of DCM. Combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 10/1 ? 5/1 hexanes/EtOAc) yielded 39 mg (48%) of the title compound as colorless oil. 1 H NMR (400 MHz, CDCl 3 ): d = 8.49 (s, 1H, Ar-H), 7.39 (s, 1H, Ar-H), 6.84 (s, 2H, 2 9 Ar-H), 5.20-5.16 (m, 2H, CH 2 ), 5.16-5.04 (m, 2H, CH 2 ), 4.33 (d, J = 10.5 Hz, 1H, CH), 4.29 (d, J = 10.5 Hz, 1H, CH), 4.24 (s, 1H, CH), 2.28-2.24 (m, 9H, 3 9 CH 3 ), 0.91 (s, 9H, CH 3 ) ppm; 13 To a solution of 141 mg of 31b (0.42 mmol) in 7 cm 3 of DCM under Ar atmosphere cooled down to 0 °C (ice water) was added 140 mg of MCPBA (0.63 mmol). After stirring at 20 °C for 2 h, the reaction mixture was quenched by addition of 5 cm 3 of K 2 CO 3 (sat. aq. solution) and stirred for 10 min. The phases were separated and the aqueous phase was washed with 3 9 15 cm 3 of DCM. Combined organic fractions were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Column chromatography of the residue on silica gel (gradient 2/ 1 ? 3/2 CHCl 3 /acetone) furnished 146 mg (99%) of title compound as a colorless oil. 1