HETEROCYCLES

Paper | Regular issue | Vol. 81, No. 7, 2010, pp. 1669-1688
Received, 30th April, 2010, Accepted, 8th June, 2010, Published online, 9th June, 2010.
DOI: 10.3987/COM-10-11967

■ Asymmetric 1,3-Dipolar Cycloaddition Reactions of Azomethine Imines with Acrolein Catalyzed by L-Proline and Its Derivatives

Hiroyuki Suga,* Tadashi Arikawa, Kennosuke Itoh, Yukihisa Okumura, Akikazu Kakehi, and Motoo Shiro

Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, 4-17-1 Wakasato, Nagano 380-8553, Japan

Abstract

1,3-Dipolar cycloadditions between acrolein and various N,N’-cyclic azomethine imines in the presence of L-proline and its derivatives as organocatalysts were investigated. Reactions that were catalyzed by (S)-indline-2-carboxylic acid (30 mol%) in CHCl3/MeOH 97:3 (v/v) showed high exo-selectivities (exo/endo 91:9 ~ 99:1) and enantioselectivities (75 ~ 98% ee). In contrast, reactions catalyzed by L-proline (30 mol%) under similar conditions favored the endo-cycloadduct (83:27 ~ 99:1) with modest to good enantioselectivities (31 ~ 83% ee). Based on our studies, the diastereoselective mechanism of the L-proline-catalyzed reaction was found to involve the isomerization of the exo- to the endo-cycloadduct in the presence of L-proline.

INTRODUCTION
1,3-Dipolar cycloadditions have served as powerful and effective reactions in the construction of five-membered heterocyclic compounds, commonly found within the fundamental frameworks of numerous biologically important natural products.1, 2c During the past two decades, various catalytic asymmetric 1,3-dipolar cycloadditions that are catalyzed by chiral Lewis acids and organocatalysts have been developed.2 For the contribution of such asymmetric dipolar cycloaddition chemistry, we have recently reported on chiral Ni(II) complexes of binaphthyldiimine (BINIM) as highly effective catalysts for providing high levels of asymmetric induction for the cycloadditions of nitrones,3 azomethine imines,4 nitrile oxides,5 and carbonyl ylides.6 For the reactions between N,N’-cyclic azomethine imines and 3-acryloyl-2-oxazolidinone, the catalytic effects of the BINIM-Ni(II) complexes were also evident in terms of rate acceleration with high endo- and enantioselectivity of the cycloadducts.4 Upon further investigations using 1H NMR, the BINIM-Ni(II) complex was found to be predominantly coordinated to the azomethine imine rather than 3-acryloyl-2-oxazolidinone during the reaction. In contrast to the BINIM-Ni(II)-catalyzed reactions, the use of aminoindanol-derived bis(oxazoline)-Cu(OTf)2 as the catalyst resulted in high exo- and enantioselectivities for similar cycloadditions involving N,N’-cyclic azomethine imines and 2-acryloyl-3-pyrazolidinones.7 However, for such chiral Lewis acid-catalyzed reactions, good reactivities with high enantioselectivities were limited to acrylic acid derivatives as the dipolarophiles, presumably due to the relatively basic nature of the N,N’-cyclic azomethine imines.8 High levels of asymmetric induction have been reported for the organocatalytic [3+2] cycloadditions of N,N’-cyclic azomethine imines catalyzed by α,α-bis-[3,5-di(trifluoromethyl)phenyl]prolinol9 (exo-selectivity) and 9-amino-9-deoxyepiquinine derivatives10 (endo-selectivity). For these reactions, the disubstituted alkenes, which possess an aldehyde or ketone moiety, were effectively activated as the dipolarophiles – specifically, the above organocatalytic cycloadditions involve β-substituted-α,β- unsaturated aldehydes and cyclohexenone, respectively. Acrolein, however, remained to be employed as a dipolarophile for these organocatalytic cycloadditions of N,N’-cyclic azomethine imines. In this paper, we describe the cycloadditions between acrolein and N,N’-cyclic azomethine imines that are catalyzed by either L-proline to selectively give the corresponding endo-cycloadducts with good enantioselectivity, or by (S)-indoline-2-carboxylic acid to give the exo-cycloadducts with extremely high diastereo- and enantioselectivities.

RESULTS AND DISCUSSION
Cycloadditions of azomethine imines catalyzed by L-proline

Initially, the cycloaddition between azomethine imine 1aa and acrolein (2) was carried out in the presence

of L-proline (30 mol%) as the catalyst (Scheme 1, Table 1). Although the reaction in CH2Cl2 was unsuccessful,11 presumably due to the insolubility of L-proline, the reaction in CHCl3 (commercial grade) at 25 oC for 17 h gave the cycloadducts in high yield with an endo/exo ratio of 88:12 (entry 1).12 The cycloadducts were isolated, after reduction with NaBH4, as the corresponding alcohols. Enantiomeric excesses of the endo- (78% ee) and exo-cycloadducts (74% ee) were determined using HPLC analysis of the corresponding alcohols. Interestingly, under similar conditions, the use of purified CHCl3 (dried over CaCl2, followed by distillation over P2O5) resulted in a lower yield with decreased diastereo- and enantioselectivity (entry 2). Because commercial grade CHCl3 contains 0.3 ~ 1.0% (v/v) EtOH as a stabilizer, we decided to examine the inclusion of alcohols such as EtOH, i-PrOH, and MeOH as additives of dried and purified CHCl3. Among the three alcohols (entries 4, 5, and 8), the addition of MeOH was found to give the highest diastereo- and enantioselectivity of the endo-cycloadduct (entry 8), in which an amount of 3.0% (v/v) MeOH gave the optimal diastereo- (endo/exo 94:6) and enantio- selectivity (83% ee) (entry 10). Finally, a lower catalyst loading (10 mol%) resulted in slightly lower diastereo- (endo/exo 73:27) and enantioselectivity (79% ee) of the endo-cycloadduct (entry 13). Although a precise role of MeOH is not clear, an addition of MeOH presumably increases solubility of L-proline and accelerates the formation of an active iminium ion. An amount of the solvent (CHCl3/MeOH 97:3 (v/v), 42 mL for 0.5 mmol scale) is also important factor for the reaction rate probably because of solubility of L-proline.

Next, the cycloadditions were carried out under the optimized conditions using azomethine imines 1ba and 1ca, which possess dimethyl substituents at their pyrazolidinone ring (Table 2, entries 2 and 3, respectively), to afford the corresponding endo-cycloadducts with relatively good enantioselectivities. The scope of the R3-substituent was investigated using azomethine imines with p- and o-substituted phenyl, 2-naphthyl, and alkyl substituents. As shown in entries 4 – 9, the reactions exhibited good to high endo-selectivities. Although the imines with p-substituted phenyl and 2-naphthyl substituents showed relatively good enantioselectivities, the o-chlorophenyl- and alkyl-substituted imines resulted in merely moderate enantioselectivities.

Cycloaddition of azomethine imine 1aa catalyzed by other L-proline derivatives
In attempts to improve the enantioselectivity, several other L-proline derivatives were evaluated as organocatalysts, as shown in Table 3 (Scheme 1). The use of L-proline derivative 4 (entry 2), which possesses a bulky TBDMSO-substituent at the 4-position of the pyrrolidine ring, failed to improve the enantioselectivity of the endo-cycloadduct. The use of L-proline methyl ester hydrochloride (5) resulted in a reversal of the facial selectivity, albeit with only slight asymmetric induction (entry 3). Although the combination of L-prolinol 6 and p-nitrobenzoic acid as catalysts resulted in a low-yielding reaction with only slight exo- and enantioselectivity (entry 4), the combination of TMS ether 7 and p-nitrobenzoic acid gave the endo-cycloadduct selectively in a high yield (entry 5), thus providing a complimentary enantioselectivity of the endo-cycloadduct to that of L-proline with the opposite facial selectivity. Surprisingly, the reaction catalyzed by (S)-indoline-2-carboxylic acid selectively gave the exo-cycloadduct in a high yield with good enantioselectivity (entry 6). Finally, although a longer reaction time was necessary, lowering the reaction temperature to 0 oC helped improve the exo/endo- (91:1) and enantioselectivity (94% ee) (entry 7).

Cycloadditions of azomethine imines catalyzed by (S)-indoline-2-carboxylic acid
The reaction of azomethine imine 1aa with acrolein (2) in the presence of 10 mol% (S)-indoline-2-carboxylic acid under similar conditions resulted in decreased yield and exo-selectivity with good enantioselectivity of exo-adduct (Table 4, entry 2). The cycloadditions between acrolein (2) and dimethyl-substituted azomethine imines 1ba and 1ca proceeded smoothly in the presence of (S)-indoline-2-carboxylic acid (30 mol%) in CHCl3/MeOH 97:3 (v/v) at 0 oC to selectively give the corresponding exo-cycloadducts in high yields with high enantioselectivities (entries 3 and 4, respectively). In particular, the highest exo- (> 99:1) and enantioselectivy (96% ee) were obtained using azomethine imine 1ca. Subsequently, dimethyl-substituted azomethine imines 1cb – 1ce and 1cg – 1ch,

which possess p-substituted phenyl groups as the R3–substituent, were examined under similar conditions. As shown in entries 5 – 10, relatively good to excellent enantioselectivies (98 ~ 75% ee) along with extremely high exo-selectivities (> 99:1) were observed, regardless of the electronic character of the p-susbstituents. However, in the case of o-chlorophenyl derivative 1cf (R1 = H, R2 = Me, R3 = o-ClC6H4), the reaction did not give cycloadducts under similar conditions. The use of 2-naphthyl derivative 1ci (R1 = H, R2 = Me, R3 = 2-naphthyl) also gave the exo-cycloadduct as the sole product with high enantioselectivity (entry 11). Although the reaction of cyclohexyl derivative 1cj (R1 = H, R2 = Me, R3 = cyclohecyl) also showed good enantioselectivity with high exo-selectivity, the yield was unsatisfactory (entry 12).

Isomerization of the exo- to the endo-cycloadduct

To gain insight into the reaction mechanisms causing opposite diastereoselectivities exhibited by the L-proline and the (S)-indoline-2-carboxylic acid catalyts, an exo-enriched (exo/endo 92:8) mixture of diastereomers 3aa was treated with L-proline (30 mol%) in CHCl3/MeOH 97:3 (v/v) at 25 oC (Scheme 2). Surprisingly, after stirring for 65 h, the exo/endo ratio indicated an endo-enriched (exo:endo 6:94) mixture, which strongly suggests that the exo-cycloadduct isomerizes to the endo-cycloadduct under our reaction conditions. To further investigate the endo-selectivity of the L-proline-catalyzed reactions, the rate of the endo/exo–isomerization was determined, under a catalyst loading of 30 mol% (Table 5, Scheme 1). After a reaction time of 1 h, the cycloadducts were obtained with an endo/exo ratio of 47:53 (27% yield, entry 1). Longer reaction times resulted in higher endo/exo ratios (entries 2 – 5), ending with an endo/exo ratio of 94:4 after 24 h (87% yield, entry 5). The enantioselectivities of the endo- and exo-cycloadducts were 83% ee and 84% ee, respectively. These results indicate that the exo-cycloadduct isomerizes to the endo-cycloadduct in the presence of L-proline as the catalyst.

Absolute configuration of exo-3cc with reaction mechanism for the asymmetric induction
To gain insight into the mechanism behind the asymmetric induction, X-ray crystal analysis was carried out using the corresponding alcohol derived from exo-3cc via NaBH4 reduction. For the (S)-indoline-2-carboxylic acid-catalyzed reaction, the resulting alcohol obtained via NaBH4 reduction possesses a (5S,6R)-configuration (Figure 1). As shown in Scheme 3, the high exo-selectivity can be attributable to the selective formation of a sterically-favorable Z-iminium ion that is susceptible to the cycloaddition by the azomethine imine via an exo-approach. The selectivity is further assisted by favorable interactions between the negative charge of the carboxylate ion and the positive charge of the azomethine imine from the upper side of the olefin moiety. The configuration obtained from this facial selectivity (upper side approach) is consistent with that observed by X-ray analysis, as shown in Figure 1.

On the other hand, for the L-proline-catalyzed reactions, although the initial diastereoselectivity remains unclear, the exo-cycloadduct readily epimerizes at the aldehyde-substituted stereogenic center, under the reaction conditions, to the more thermodynamically stable endo-cycloadduct. The facial selectivity during the asymmetric induction would be similar to that of the (S)-indoline-2-carboxylic acid-catalyzed reactions. In contrast to these organocatalysts that possess a carboxylic acid moiety, the L-prolininol-derived TMS ether catalyst 7 exhibited the opposite facial selectivity (Table 3, entry 4), which can be attributed to the effective shielding of the upper side by the sterically hindered TMS ether moiety thus blocking the interactions of the positive charge of azomethine imine.

CONCLUSION
We have demonstrated that (S)-indoline-2-carboxylic acid (30 mol%) can serve as an efficient organocatalyst for the asymmetric cycloadditions between N,N’-cyclic azomethine imines and acrolein to afford the corresponding exo-cycloadducts with high diastereo- (91:1 ~ > 99:1) and enantioselectivities (75 ~ 98% ee). In contrast, the L-proline catalyst (30 mol%) afforded the endo-cycloadducts selectively (83:27 ~ > 99:1) with modest to good enantioselectivities (31 ~ 83% ee). The contrasting diastereoselectivites can be explained based on our studies that showed the isomerization of the exo-cycloadduc into the endo-cycloadduct in the presence of L-proline. The solvent system of CHCl3/MeOH 97:3 (v/v) was also essential for optimizing the cycloadditions.

EXPERIMENTAL
Melting points are uncorrected. IR spectra were taken with FT/IR spectrophotometer. 1H NMR spectra were run at 400 MHz. Chemical shifts are expressed in parts per million downfield from tetramethylsilane as an internal standard. 13C NMR spectra were recorded at 100 MHz using broadband proton decoupling. Chemical shifts are expressed in parts per million downfield from tetramethylsilane, using the middle resonance of CDCl3 (77.0 ppm) as an internal standard. For preparative column chromatography, Wakogel C-300HG was employed. All reactions were carried out under an argon atmosphere in dried glassware. L-Proline, L-proline methyl ester hydrochloride (5), (S)-indoline-2-carboxylic acid (8), and acrolein (2) are commercially available and used without further purification. (4R)-4-(t-Butyldimethylsilyloxy)-L-proline (4),13 L-prolinol 6,14 and TMS ether 715 were prepared according to the procedure reported previously. Azomethine imines were prepared according to the procedure reported by Fu.16 CHCl3 was purified by distillation first from CaCl2 and then P2O5 under argon. CH2Cl2 was purified by distillation first from CaCl2 and then CaH2 under argon. MeOH and ethanol were purified by distillation from the corresponding magnesium alkoxide.

General procedure for the asymmetric cycloaddition reaction of azomethine imine with acrolein was exemplified by the reaction of azomethine imine 1ca in the presence of (S)-indoline-2-carboxylic acid.
Azomethine imine 1ca (101.1 mg, 0.50 mmol) was added to a solution of acrolein (66.7 µl, 1.0 mmol) and (S)-indoline-2-carboxylic acid (24.5 mg, 0.15 mmol) in CHCl3 (40.7 mL) and MeOH (1.3 mL) at 0 oC. After stirring the mixture for 36 h at the same temperature, a solution of NaBH4 (75.7 mg, 2.0 mmol) in EtOH (5.0 mL) was added, and then the stirring was continued for 1 h. The reaction was quenched with saturated aqueous NH4Cl solution (5.0 mL) and water (10.0 mL), and then the mixture was extracted with CHCl3 (10.0 mL x 3). The combined extracts were dried over Na2SO4 and evaporated in vacuo. The residue was chromatographed on silica gel with EtOAc and EtOAc-MeOH (30 : 1 v/v) as an eluent to give the corresponding alcohol derived from exo-3ca’ (exo : endo = >99 : 1, 106.4 mg, 82%). The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 0.5 mL/min, 35 oC, tmajor = 47.0 min (exo), tminor = 62.4 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-phenyltetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3ca’): Colorless plates; mp 223-224 oC (MeOH-Et2O); [α]D26 -60.5 o (c 1.0, MeOH, exo : endo = >99 : 1, 96% ee).; IR (KBr) 3367, 2964, 2926, 2879, 2359, 1678, 1601, 1473, 1432, 1398, 1370, 1296, 1222, 1177, 1113, 1047, 970, 912, 868, 758, 707, 683, 625, 507 cm-1; 1H NMR (CDCl3) δ = 1.06 (3H, s), 1.26 (3H, s), 1.60 (1H, brs), 2.46 (1H, d, J = 16.1 Hz), 2.68 (1H, d, J = 16.1 Hz), 2.83 (1H, m), 3.30 (1H, ddd, J = 1.2 Hz, 3.9 Hz, 11.7 Hz), 3.35-3.47 (2H, m), 4.00 (1H, dd, J = 8.5, 11.7 Hz), 4.17 (1H, d, J = 7.3 Hz), 7.30-7.45 (5H, m); 13C NMR (CDCl3) δ = 22.5 (CH3), 29.1 (CH3), 43.2 (CH2), 47.7 (CH2), 48.2 (CH), 60.2 (C), 62.6 (CH2), 64.5 (CH), 127.7 (CH), 127.9 (CH), 128.5 (CH), 136.7 (C), 168.7 (C); Mass (EI) m/z 260 (M+), 201, 91, 77, 56. Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76%. Found: C, 69.17; H, 7.82; N, 10.72%.
(5R,6R)-6-Hydroxymethyl-5-phenyltetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3aa’): Colorless plates; mp 111.5-112.5 oC (benzene); [α]D26 -147.3 o (c 1.0, CHCl3, exo : endo = 94 : 6, 94% ee (exo), 20% ee (endo)).; IR (KBr) 3424, 2947, 2847, 2360, 1664, 1470, 1426, 1213, 1139, 1041, 990, 749, 704, 601, 551 cm-1; 1H NMR (CDCl3) δ = 1.79 (1H, brs), 2.69 (1H, ddd, J = 6.3 Hz, 9.3 Hz, 16.6 Hz), 2.80 (1H, m), 2.85-2.95 (2H, m), 3.33 (1H, m), 3.37-3.43 (2H, m), 3.63 (1H, ddd, J = 6.3 Hz, 9.3 Hz, 11.0 Hz), 3.79 (1H, d, J = 7.1 Hz), 4.05 (1H, dd, J = 8.5 Hz, 11.7 Hz), 7.29-7.55 (5H, m); 13C NMR (CDCl3) δ = 32.8 (CH2), 43.9 (CH2), 47.7 (CH), 48.0 (CH2), 62.2 (CH2), 71.6 (CH), 127.1 (CH), 127.9 (CH), 128.7 (CH), 134.7 (C), 170.5 (C).; MS (EI) m/z 232 (M+), 173, 117, 91, 78, 49; HRMS (EI) Calcd for C13H16N2O2: (M+), 232.1236. Found: 232.1236. Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.04%. Found: C, 67.46; H, 6.95; N, 11.82%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, Flow rate = 0.5 mL/min, 35 °C, tminor = 36.8 min (endo), tmajor = 44.1 min (endo), tmajor = 88.6 min (exo), tminor = 136.5 min (exo)).
(5R,6R)-6-Hydroxymethyl-2,2-dimethyl-5-phenyltetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3ba’): Colorless prisms; mp 57.5-59.0 oC (CH2Cl2-hexane); [α]D26 -117.7 o (c 1.0, CHCl3, exo : endo = 92 : 8, 93% ee (exo), 6% ee (endo)); IR (KBr) 3423, 2965, 2362, 1670, 1457, 136,5 1047, 757, 705, 498 cm-1; 1H NMR (CDCl3) δ = 1.21 (3H, s), 1.34 (3H, s), 2.04 (1H, brs), 2.55 (1H, d, J = 9.5 Hz), 2.94 (1H, m), 3.31-3.42 (3H, m), 3.45 (1H, dd, J = 2.7 Hz, 11.6 Hz), 3.66 (1H, d, J = 6.6 Hz), 4.00 (1H, dd, J = 8.3 Hz, 11.6 Hz), 7.28-7.48 (5H, m); 13C NMR (CDCl3) δ = 23.7 (CH3), 24.1 (CH3), 42.9 (CH2), 46.0 (C), 47.7 (CH), 61.8 (CH2), 64.9 (CH2), 72.7 (CH), 126.9 (CH), 127.7 (CH), 128.4 (CH), 134.5 (C), 170.7 (C); Mass (EI) m/z 260 (M+), 201, 117, 92, 78. Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76%. Found: C, 69.21; H, 7.78; N, 10.72%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, Flow rate = 1.0 mL/min, 35 °C, tminor = 16.3 min (endo), tmajor = 19.0 min (endo), tmajor = 29.1 min (exo), tminor = 39.1 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-(4-chlorophenyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3cb’): Colorless prisms.; mp. 184-184.5 oC (benzene); [α]D25 -67.6 o (c 1.0, MeOH, exo : endo = >99 : 1, 94% ee (exo)).; IR (KBr) 3396, 2974, 2927, 2854, 1670, 1488, 1469, 1411, 1399, 1382, 1372, 1325, 1289, 1250, 1225, 1198, 1173, 1123, 1104, 1086 cm-1; 1H NMR (CDCl3) δ = 1.05 (3H, s), 1.23 (3H, s), 1.68 (1H, brs), 2.47 (1H, d, J = 16.3 Hz), 2.67 (1H, d, J = 16.3 Hz), 2.80 (1H, m), 3.26-3.36 (2H, m), 3.41 (1H, dd, J = 6.6, 11.0 Hz), 4.00 (1H, dd, J = 8.2, 11.0 Hz), 4.14 (1H, d, J = 7.6 Hz), 7.30-7.43 (4H, m); 13C NMR (CDCl3) δ = 22.3 (CH3), 28.9 (CH3), 43.3 (CH2), 47.7 (CH2), 47.8 (CH), 60.3 (C), 62.2 (CH2), 63.3 (CH), 128.6 (CH), 129.0 (CH), 133.5 (C), 135.4 (C), 168.4 (C); Mass (EI) m/z 294 (M+), 151, 126, 111, 92, 83, 56. Anal. Calcd for C15H19ClN2O2: C, 61.12; H, 6.50; N, 9.72%. Found: C, 60.83; H, 6.57; N, 9.72%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak IA, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 1.0 mL/min, 35 oC, tminor = 24.7 min (endo), tmajor = 27.5 min (endo), tmajor = 52.0 min (exo), tminor = 67.3 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-(4-bromophenyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3cc’): Colorless plates; mp 202-203 oC (benzene); [α]D23 -63.6 o (c 0.80, MeOH, exo : endo = >99 : 1, 93% ee (exo)); IR (KBr) 3370, 2967, 2941, 2910, 2876, 1665, 1486, 1449, 1427, 1407, 1387, 1370, 1351, 1294, 1220, 1205, 1177, 1162, 1122, 1111, 1072, 1049, 1010 cm-1; 1H NMR (CDCl3) δ = 1.05 (3H, s), 1.24 (3H, s), 1.58 (1H, brs), 2.45 (1H, d, J = 16.3 Hz), 2.66 (1H, d, J = 16.3 Hz), 2.80 (1H, m), 3.29 (1H, ddd, J = 1.5 Hz, 4.4 Hz, 11.7 Hz), 3.31-3.47 (2H, m), 4.01 (1H, dd, J = 8.5, 11.7 Hz), 4.13 (1H, d, J = 7.3 Hz), 7.27-7.33 (2H, m), 7.46-7.54 (2H, m); 13C NMR (CDCl3) δ = 22.5 (CH3), 29.0 (CH3), 43.3 (CH2), 47.6 (CH2), 47.8 (CH), 60.4 (C), 62.4 (CH2), 63.6 (CH), 121.7 (C), 129.4 (CH), 131.5 (CH), 136.0 (C), 168.7 (C); Mass (EI) m/z 338 (M+), 138, 126, 111, 83, 56. Anal. Calcd for C15H19BrN2O2: C, 53.11; H, 5.65; N, 8.26%. Found: C, 53.03; H, 5.65; N, 8.26%.; The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 1.0 mL/min, 35 oC, tminor = 9.1 min (endo), tmajor = 11.4 min (endo), tmajor = 20.3 min (exo), tminor = 26.9 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-(4-cyanophenyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3cd’): Colorless needles; mp 163-164.5 oC (benzene); [α]D23 -98.4 o (c 1.0, MeOH, exo : endo = >99 : 1, 96% ee (exo)); IR (KBr) 3379, 2976, 2953, 2934, 2911, 2892, 2225, 1671, 1605, 1504, 1474, 1443, 1421, 1371, 1294, 1252, 1229, 1181, 1157, 1122, 1111, 1075, 1051, 1018 cm-1; 1H NMR (CDCl3) δ = 1.04 (3H, s), 1.25 (3H, s), 1.68 (1H, brs), 2.46 (1H, d, J = 16.4 Hz), 2.66 (1H, d, J = 16.4 Hz), 2.87 (1H, m), 3.24 (1H, m), 3.28 (1H, ddd, J = 1.2, 4.6, 11.7 Hz), 3.36 (1H, dd, J = 7.5 Hz, 10.7 Hz), 4.05 (1H, dd, J = 8.5 Hz, 11.7 Hz), 4.21 (1H, d, J = 7.8 Hz), 7.50 – 7.61 (2H, m), 7.63 – 7.73 (2H, m); 13C NMR (CDCl3) δ = 22.3 (CH3), 28.7 (CH3), 43.4 (CH2), 47.2 (CH2), 47.5 (CH), 60.4 (C), 61.7 (CH2), 63.0 (CH), 111.3 (C), 118.2 (C), 128.4 (CH), 131.8 (CH), 142.9 (C), 168.7 (C).; Mass (EI) m/z 285 (M+), 111, 83, 56. Anal. Calcd for C16H19N3O2: C, 67.35; H, 6.71; N, 14.73%. Found: C, 67.15; H, 6.89; N, 14.75%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak IA, hexane : 2-PrOH = 5 : 1 v/v%, detector: UV 254 nm, flow rate = 0.4 mL/min, 35 oC, tminor = 22.4 min (endo), tmajor = 25.0 min (endo), tmajor = 37.0 min (exo), tminor = 46.0 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-(4-nitrophenyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3ce’): Pale yellow leaflets; mp 161.5-163 oC (benzene); [α]D23 -55.3 o (c 0.80, MeOH, exo : endo = >99 : 1, 75% ee (exo)).; IR (KBr) 3384, 2976, 2963, 2944, 2897, 1646, 1597, 1525, 1465, 1421, 1385, 1370, 1345, 1314, 1296, 1228, 1108, 1074, 1053, 1035 cm-1; 1H NMR (CDCl3) δ = 1.05 (3H, s), 1.25 (3H, s), 2.20 (1H, brs), 2.46 (1H, d, J = 16.8 Hz), 2.67 (1H, d, J = 16.3 Hz), 2.90 (1H, m), 3.20 (1H, dd, J = 5.4, 10.5 Hz), 3.29 (1H, ddd, J = 1.2, 4.6, 12.0 Hz), 3.37 (1H, dd, J = 7.8, 10.5 Hz), 4.04 (1H, dd, J = 8.3, 12.0 Hz), 4.27 (1H, d, J = 8.1 Hz), 7.56-7.71 (2H, m), 8.14-8.34 (2H, m); 13C NMR (CDCl3) δ = 22.8 (CH3), 29.1 (CH3), 43.5 (CH2), 47.1 (CH2), 47.8 (CH), 60.4 (C), 62.1 (CH2), 63.4 (CH), 123.5 (CH), 128.7 (CH), 145.1 (C), 147.3 (C), 169.6 (C); Mass (EI) m/z 305 (M+), 111, 78. Anal. Calcd for C15H19N3O4: C, 59.01; H, 6.27; N, 13.76%. Found: C, 59.21; H, 6.17; N, 13.66%.; The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 1.0 mL/min, 35 oC, tminor = 18.1 min (endo), tmajor = 24.8 min (endo), tmajor = 37.3 min (exo), tminor = 64.1 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-p-toyltetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3cg’): Colorless needles; mp 187-187.5 oC (benzene); [α]D23 -67.7 o (c 0.80, MeOH, exo : endo = >99 : 1, 97% ee (exo)); IR (KBr) 3368, 3094, 3060, 3028, 3010, 2963, 2926, 2875, 1685, 1632, 1515, 1474, 1449, 1431, 1398, 1371, 1297, 1256, 1222, 1205, 1182, 1167, 1125, 1078, 1053 cm-1; 1H NMR (CDCl3) δ = 1.06 (3H, s), 1.23 (3H, s), 1.71 (1H, brs), 2.35 (3H, s), 2.46 (1H, d, J = 16.3 Hz), 2.68 (1H, d, J = 16.3 Hz), 2.79 (1H, m), 3.28 (1H, dd, J = 3.7 Hz, 11.7 Hz), 3.38 – 3.46 (2H, m), 3.97 (1H, dd, J = 8.5 Hz, 11.7 Hz), 4.14 (1H, d, J = 7.3 Hz), 7.14 – 7.20 (2H, m), 7.27 – 7.34 (2H, m); 13C NMR (CDCl3) δ = 21.2 (CH3), 22.1 (CH3), 28.7 (CH3), 42.9 (CH2), 47.9 (CH2), 47.9 (CH), 60.3 (C), 62.5 (CH2), 64.1 (CH), 127.5 (CH), 129.0 (CH), 133.3 (C), 137.4 (C), 167.9 (C); Mass (EI) m/z 274 (M+), 131, 111, 83, 56; Anal. Calcd for C16H22N2O2: C, 70.04; H, 8.08; N, 10.21%. Found: C, 70.04; H, 8.07; N, 10.23%.; The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak IA, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 0.5 mL/min, 35 oC, tminor = 21.5 min (endo), tmajor = 23.7 min (endo), tmajor = 39.6 min (exo), tminor = 47.3 min (exo)).
(5R,6R)-6-Hydroxymethyl-5-(4-methoxyphenyl)-3,3-dimethyltetrahydropyrazolo[1,2-a]pyrazol-1- one (exo-3ch’): Colorless needles; mp 192 oC (benzene); [α]D26 -70.5 o (c 0.80, MeOH, exo : endo = >99 : 1, 98% ee (exo)).; IR (KBr) 3344, 2989, 2972, 2951, 2892, 2878, 2834, 1683, 1632, 1615, 1583, 1516, 1473, 1465, 1443, 1431, 1402, 1369, 1296, 1256, 1221, 1204, 1170, 1126, 1109, 1078, 1053, 1036, cm-1; 1H NMR (CDCl3) δ = 1.07 (3H, s), 1.21 (3H, s), 1.77 (1H, brs), 2.44 (1H, d, J = 16.3 Hz), 2.68 (1H, d, J = 16.3 Hz), 2.77 (1H, m), 3.29 (1H, dd, J = 3.7 Hz, 11.7 Hz), 3.39 – 3.50 (2H, m), 3.82 (3H, s), 3.97 (1H, dd, J = 8.5 Hz, 11.7 Hz), 4.13 (1H, d, J = 7.3 Hz), 6.84 – 6.96 (2H, m), 7.28–7.38 (2H, m); 13C NMR (CDCl3) δ = 22.0 (CH3), 28.7 (CH3), 43.0 (CH2), 48.0 (CH2), 47.8 (CH), 55.1 (CH3), 60.2 (C), 62.2 (CH2), 63.3 (CH), 113.6 (CH), 128.0 (C), 128.7 (CH), 158.8 (C), 167.5 (C); Mass (EI) m/z 290 (M+), 147, 111, 83, 56. Anal. Calcd for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65%. Found: C, 66.07; H, 7.99; N, 9.41%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak IA, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 0.5 mL/min, 35 oC, tminor = 30.8 min (endo), tmajor = 33.5 min (endo), tmajor = 60.4 min (exo), tminor = 70.6 min (exo)).
(5R,6R)-6-Hydroxymethyl-3,3-dimethyl-5-(2-naphthyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3ci’): Pale red prisms; mp 260-261 oC (MeOH); [α]D26 -43.7 o (c 0.40, MeOH, exo : endo = >99 : 1, 95% ee (exo)).; IR (KBr) 3351, 2990, 2970, 2925, 2877, 1671, 1632, 1599, 1507, 1473, 1446, 1428, 1402, 1388, 1365, 1306, 1294, 1252, 1221, 1202, 1174, 1124, 1109, 1079, 1050 cm-1; 1H NMR (CDCl3) δ = 1.09 (3H, s), 1.27 (3H, s), 1.60 (1H, brs), 2.49 (1H, d, J = 16.4 Hz), 2.71 (1H, d, J = 16.4 Hz), 2.90 (1H, m), 3.36 (1H, m), 3.39 (1H, dd, J = 5.6 Hz, 11.2 Hz), 3.46 (1H, dd, J = 6.3 Hz, 11.2 Hz), 4.05 (1H, dd, J = 8.1 Hz, 11.2 Hz), 4.35 (1H, d, J = 7.3 Hz), 7.46 – 7.61 (3H, m), 7.77 – 7.96 (4H, m); 13C NMR (CDCl3) δ = 22.8 (CH3), 29.2 (CH3), 43.2 (CH2), 47.7 (CH2), 48.3 (CH), 60.3 (C), 62.7 (CH2), 64.7 (CH), 125.3 (CH), 126.2 (CH), 126.4 (CH), 126.8 (CH), 127.6 (CH), 127.7 (CH), 128.2 (CH), 132.9 (C), 133.0 (C), 134.3 (C); Mass (EI) m/z 310 (M+), 167, 111, 83, 56. Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14; N, 9.03%. Found: C, 73.39; H, 7.33; N, 8.97%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak IA, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 0.5 mL/min, 35 oC, tminor = 26.2 min (endo), tmajor = 31.1 min (endo), tmajor = 55.2 min (exo), tminor = 74.1 min (exo)).
(5R,6R)-5-Cyclohexyl-6-hydroxymethyl-3,3-dimethyltetrahydropyrazolo[1,2-a]pyrazol-1-one (exo-3cj’): Pale yellow oil; [α]D23 +40.6 o (c 0.60, MeOH, exo : endo = >99 : 1, 88% ee (exo)).; IR (neat) 2984, 2932, 2856, 2361, 1680, 1452, 1371, 1113 cm-1; 1H NMR (CDCl3) δ = 1.15 – 1.70 (11H, m), 1.26 (6H, s), 2.17 (1H, d, J = 14.9 Hz), 2.62 (1H, m), 2.79 (1H, d, J = 14.9 Hz), 2.99 – 3.09 (2H, m), 3.81-3.84 (2H, m), 3.99 (1H, dd, J = 8.3 Hz, 11.2 Hz), The signal of OH could not be identified; Mass (EI) m/z 266 (M+), 141; HRMS (EI) Found: m/z 266.1950. Calcd for C15H26N2O2 (M+): 266.1994. Anal. Calcd for C15H26N2O2: C, 67.63; H, 9.84; N, 10.52%. Found: C, 68.21; H, 9.85; N, 9.93% (Satisfactory elemental analysis was not obtained). The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak IA, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, flow rate = 0.5 mL/min, 35 oC, tminor = 19.6 min (endo), tmajor = 20.1 min (endo), tmajor = 31.2 min (exo), tminor = 34.0 min (exo)).
(5R,6S)-6-Hydroxymethyl-5-phenyl-tetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3aa’): Pale orange leaflets; mp 142-143 oC (benzene-hexane); [α]D26 -14.1 o (c 1.0, CHCl3, endo : exo = 94 : 6, 83% ee (endo), 84% ee (exo)).; IR (KBr) 3387, 3028, 2935, 2852, 2356, 1680, 1471, 1411, 1306, 1251, 1200, 1160, 1129, 1060, 1019, 837, 797, 754, 699, 610, 581 cm-1; 1H NMR (CDCl3) δ = 2.52 (1H, brs), 2.69–2.77 (3H, m), 2.93 (1H, dt, J = 11.2 Hz, 8.8 Hz), 3.41 (1H, d, J = 9.3 Hz), 3.45 (1H, dt, J = 11.2 Hz, 7.8 Hz), 3.52 (1H, dd, J = 9.8 Hz, 11.2 Hz), 3.61 (1H, dd, J = 5.0 Hz, 11.5 Hz), 3.71 (1H, dd, J = 3.8 Hz, 11.5 Hz), 3.82 (1H, dd, J = 6.6 Hz, 11.2 Hz), 7.32-7.41 (5H, m); 13C NMR (CDCl3) δ = 32.8 (CH2), 43.2 (CH2), 47.5 (CH2), 52.7 (CH), 60.0 (CH2), 71.0 (CH), 127.6 (CH), 128.0 (CH), 128.8 (CH), 137.1 (C), 170.3 (C); MS (EI) m/z 232 (M+), 173, 117, 91, 78, 56; HRMS (EI) Calcd for C13H16N2O2: (M+), 232.1212. Found: 232.1236. Anal. Calcd for C19H20N4O4: C, 67.22; H, 6.94; N, 12.04%. Found: C, 67.99; H, 7.39; N, 10.61% (Satisfactory elemental analysis was not obtained). The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, Flow rate = 0.5 mL/min, 35 oC, tminor = 35.0 min (endo), tmajor = 41.9 min (endo), tmajor = 84.3 min (exo), tminor = 130.0 min (exo)).
(5R,6S)-6-Hydroxymethyl-2,2-dimethyl-5-phenyltetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3ba’): Colorless prisms; mp 129-130.5 oC (CH2Cl2-hexane); [α]D26 -27.6 o (c 0.80, CHCl3, endo : exo = 87 : 13, 78% ee (endo), 83% ee (exo)).; IR (KBr) 3440, 3031, 2971, 2927, 2838, 2360, 1694, 1469, 1405, 1367, 1345, 1306, 1254, 1191, 1127, 1074, 1038, 995, 949, 839, 775, 744, 697, 602, 556 cm-1; 1H NMR (CDCl3) δ = 1.21 (3H, s), 1.29 (3H, s), 2.59 (1H, brs), 2.62 (1H, d, J = 9.5 Hz), 2.75 (1H, m), 3.21 (1H, d, J = 9.5 Hz), 3.37 (1H, d, J = 9.3 Hz), 3.53-3.65 (2H, m), 3.72 (1H, dd, J = 3.6 Hz, 11.2 Hz), 3.83 (1H, dd, J = 8.0 Hz, 11.2 Hz), 7.23-7.45 (5H, m); 13C NMR (CDCl3) δ = 23.8 (CH3), 24.1 (CH3), 42.4 (CH2), 52.6 (CH), 59.8 (CH2), 64.5 (CH2), 72.4 (CH), 127.6 (CH), 128.0 (CH), 128.5 (CH), 137.0 (C), 170.7 (C); Mass (EI) m/z 260 (M+), 201, 117, 91, 56. Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76%. Found: C, 68.88; H, 7.97; N, 10.86%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, Flow rate = 0.5 mL/min, 35 oC, tminor = 16.4 min (endo), tmajor = 18.9 min (endo), tmajor = 29.1 min (exo), tminor = 39.2 min (exo).
(5R,6S)-6-Hydroxymethyl-3,3-dimethyl-5-phenyltetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3ca’): Colorless leaflets; mp 142-143 oC (CH2Cl2-hexane); [α]D26 +23.6 o (c 1.0, CHCl3, endo : exo = 90 : 10, 79% ee (endo), 69% ee (exo)); IR (KBr) 3437, 3029, 2970, 2935, 2872, 2360, 1687, 1461, 1379, 1292, 1252, 1229, 1177, 1060, 817, 753, 701, 594, 543 cm-1; 1H NMR (CDCl3) δ = 1.01 (6H, s), 1.97 (1H, brs), 2.47 (1H, d, J = 16.6 Hz), 2.63 (1H, d, J = 16.6 Hz), 2.67 (1H, m), 3.50-3.63 (2H, m), 3.64-3.76 (2H, m), 3.78 (1H, d, J = 9.3 Hz), 7.27-7.44 (5H, m); 13C NMR (CDCl3) δ = 22.7 (CH3), 28.6 (CH3), 42.5 (CH2), 47.8 (CH2), 53.7 (CH), 59.9 (CH2), 63.2 (CH), 127.6 (CH), 127.7 (CH), 128.4 (CH), 139.4 (C), 168.1 (C); Mass (EI) m/z 260 (M+), 201, 138, 117, 91, 56. Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76%. Found: C, 69.17; H, 7.82; N, 10.72%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak IA, CH2Cl2 : hexane : 2-PrOH = 20 : 10 : 1 v/v%, detector: UV 254 nm, flow rate = 0.3 mL/min, 25 oC, tmajor and tminor = 40.5 min (exo), tmajor = 44.0 min (endo), tminor = 47.4 min (endo)).
(5R,6S)-5-(4-Chlorophenyl)-6-hydroxymethyltetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3ab’): Colorless needles; mp 200.5-201 oC (benzene); [α]D26 -17.5 o (c 0.80, MeOH, endo : exo = 99 : 1, 74% ee (endo)); IR (KBr) 3289, 3041, 2972, 2945, 2928, 2888, 2865, 1645, 1498, 1460, 1419, 1380, 1347, 1303, 1204, 1182, 1119, 1090 cm-1; 1H NMR (CDCl3) δ = 2.22 (1H, brs), 2.60-2.79 (3H, m), 2.92 (1H, dt, J = 11.2, 8.4 Hz), 3.40 (1H, d, J = 8.8 Hz), 3.43-3.56 (2H, m), 3.60 (1H, dd, J = 5.4, 11.2 Hz), 3.70 (1H, dd, J = 3.9, 11.2 Hz), 3.81 (1H, dd, J = 6.1, 11.2 Hz), 7.35 (5H, brs); 13C NMR (CDCl3) δ = 32.8 (CH2), 43.2 (CH2), 47.4 (CH2), 53.0 (CH), 59.9 (CH2), 70.3 (CH), 128.8 (CH), 129.0 (CH), 133.9 (C), 135.9 (C), 170.9 (C); Mass (EI) m/z 266 (M+), 151, 115, 98, 56. Anal. Calcd for C13H15ClN2O2: C, 58.54; H, 5.67; N, 10.50%. Found: C, 58.61; H, 5.63; N, 10.47%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 20 : 1 v/v%, detector: UV 254 nm, Flow rate = 0.5 mL/min, 35 °C, tminor = 65.0 min (endo), tmajor = 70.2 min (endo)).
(5R,6S)-5-(2-Chlorophenyl)-6-hydroxymethyltetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3af’): Pale yellow oil; [α]D24 +1.1 o (c 0.80, MeOH, endo : exo = 88 : 12, 50% ee (endo)).; IR (KBr) 3354, 2990, 2943, 2916, 2884, 1653, 1569, 1471, 1422, 1373, 1312, 1272, 1200, 1161, 1139, 1115, 1091, 1053, 1033 cm-1; 1H NMR (CDCl3) δ = 2.17 (1H, brs), 2.63-2.83 (3H, m), 3.00 (1H, ddd, J = 7.8. 9.0, 11.2 Hz), 3.43 (1H, ddd, J = 7.3, 9.3, 11.2 Hz), 3.54 (1H, m), 3.68 (1H, dd, J = 5.4, 11.2 Hz), 3.74 (1H, dd, J = 4.4, 11.2 Hz), 3.85 (1H, dd, J = 6.1, 11.2 Hz), 4.02 (1H, d, J = 9.0 Hz), 7.20-7.40 (3H, m), 7.63-7.71 (1H, m); 13C NMR (CDCl3) δ = 32.5 (CH2), 44.0 (CH2), 47.3 (CH2), 53.4 (CH), 60.9 (CH2), 66.4 (CH), 127.2 (CH), 128.9 (CH), 129.0 (CH), 129.3 (CH), 133.9 (C), 135.0 (C), 171.3 (C); Mass (EI) m/z 266 (M+), 151, 125, 84, 77, 56. Anal. Calcd for C13H15ClN2O2: C, 58.54; H, 5.67; N, 10.50%. Found: C, 58.66; H, 5.76; N, 10.30%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 12 : 1 v/v%, detector: UV 254 nm, Flow rate = 1.0 mL/min, 35 oC, tminor = 20.4 min (endo), tmajor = 35.4 min (endo)).
(5R,6S)-6-Hydroxymethyl-5-p-tolyltetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3ag’): Colorless needles; mp 189-190 oC (benzene); [α]D27 -6.6 o (c 0.80, MeOH, endo : exo = 99 : 1, 74% ee (endo)); IR (KBr) 3343, 3026, 2949, 2926, 2889, 2868, 1661, 1518, 1458, 1418, 1381, 1303, 1256, 1215, 1205, 1186, 1108, 1086, 1024 cm-1; 1H NMR (CDCl3) δ = 1.90 (1H, brs), 2.36 (3H, s), 2.65-2.79 (3H, m), 2.93 (1H, dt, J = 11.2, 8.4 Hz), 3.33 (1H, d, J = 9.5 Hz), 3.43 (1H, dt, J = 11.2, 7.7 Hz), 3.53 (1H, m), 3.61 (1H, m), 3.70 (1H, m), 3.78 (1H, dd, J = 6.8, 9.0 Hz), 7.16-7.21 (2H, m), 7.26-7.32 (2H, m); 13C NMR (CDCl3) δ = 21.2 (CH3), 32.8 (CH2), 43.2 (CH2), 47.5 (CH2), 52.7 (CH), 60.0 (CH2), 70.9 (CH), 127.5 (CH), 129.2 (CH), 133.9 (C), 137.7 (C), 170.3 (C); Mass (EI) m/z 246 (M+), 131, 98, 56. Anal. Calcd for C14H18N2O2: C, 68.27; H, 7.37; N, 11.37%. Found: C, 68.35; H, 7.41; N, 11.25%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 20 : 1 v/v%, detector: UV 254 nm, Flow rate = 0.5 mL/min, 35 oC, tminor = 51.3 min (endo), tmajor = 55.9 min (endo)).
(5R,6S)-6-Hydroxymethyl-5-(2-naphthyl)tetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3ai’): Pale yellow prisms; mp 196-197 oC (benzene-MeOH); [α]D24 -13.7 o (c 0.80, MeOH, endo : exo = 99 : 1, 82% ee (endo)).; IR (KBr) 3463, 3402, 3384, 2932, 2888, 2853, 2811, 1671, 1598, 1509, 1472, 1408, 1380, 1349, 1247, 1205, 1127, 1097, 1085, 1064, 1041, 1019 cm-1; 1H NMR (CDCl3) δ = 1.96 (1H, brs), 2.70-2.83 (2H, m), 2.85 (1H, m), 2.99 (1H, dt, J = 11.2, 8.5 Hz), 3.47 (1H, ddd, J = 7.3, 8.5, 11.2 Hz), 3.59 (1H, m), 3.65 (1H, m), 3.75 (1H, m), 3.85 (1H, dd, J = 6.6, 11.2 Hz), 7.43-7.63 (3H, m), 7.78-7.92 (4H, m); 13C NMR (CDCl3) δ = 32.8 (CH2), 43.4 (CH2), 47.5 (CH2), 52.8 (CH), 60.2 (CH2), 71.3 (CH), 124.9 (CH), 126.1 (CH), 126.2 (CH), 127.3 (CH), 127.5 (CH), 127.6 (CH), 128.5 (CH), 133.0 (C), 133.1 (C), 134.6 (C), 171.0 (C); Mass (EI) m/z 282 (M+), 167, 78, 56. Anal. Calcd for C17H18N2O2: C, 72.32; H, 6.43; N, 9.92%. Found: C, 72.52; H, 6.20; N, 9.95%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak OD-H, hexane : 2-PrOH = 20 : 1 v/v%, detector: UV 254 nm, Flow rate = 1.0 mL/min, 35 oC, tminor = 72.9 min (endo), tmajor = 85.7 min (endo)).
(5R,6S)-5-Cyclohexyl-6-hydroxymethyltetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3aj’): Colorless oil; [α]D23 -12.4 o (c 0.60, MeOH, endo : exo = 99 : 1, 31% ee (endo)); IR (neat) 3374, 3018, 2930, 2856, 2401, 2361, 2339, 1669, 1451, 1426, 1215, 1045 cm-1; 1H NMR (CDCl3) δ = 0.87-1.82 (11H, m), 1.86 (1H, brs), 2.18 (1H, m), 2.51 (1H, m), 2.65 (1H, ddd, J = 4.9, 9.5, 14.4 Hz), 2.77 (1H, m), 2.94 (1H, m), 3.15 (1H, m), 3.46 (1H, dd, J = 7.8, 10.7 Hz), 3.56-3.70 (2H, m), 3.84 (1H, m); 13C NMR (CDCl3) δ = 26.2 (CH2), 26.4 (CH2), 29.79 (CH2), 29.85 (CH2), 34.0 (CH2), 41.2 (CH), 42.5 (CH2), 46.9 (CH), 52.0 (CH2), 63.6 (CH2), 73.4 (CH), 167.6 (C); Mass (EI) m/z 238 (M+), 156, 55. Anal. Calcd for C13H22N2O2: C, 65.51; H, 9.30; N, 11.75%. Found: C, 65.27; H, 9.52; N, 11.71%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak OD-H, hexane : 2-PrOH = 20 : 1 v/v%, detector: UV 254 nm, Flow rate = 1.0 mL/min, 35 oC, tmajor = 22.2 min (endo), tminor = 27.6 min (endo)).
(5R,6S)-6-hydroxymethyl-5-Isobutyltetrahydropyrazolo[1,2-a]pyrazol-1-one (endo-3ak’): Colorless oil; [α]D23 -18.4 o (c 0.80, MeOH, endo : exo = 83 : 17, 32% ee (endo)); IR (KBr) 3282, 3000, 2954, 2913, 2905, 2866, 1671, 1470, 1426, 1377, 1366, 1328, 1319, 1253, 1226, 1191, 1165, 1150, 1109, 1091 cm-1; 1H NMR (CDCl3) δ = 0.94 (3H, d, J = 6.6 Hz), 0.95 (3H, d, J = 6.6 Hz), 1.33-1.58 (2H, m), 1.61-1.83 (2H, m), 2.43 (1H, m), 2.50 (1H, m), 2.66 (1H, ddd, J = 5.1, 9.3, 14.4 Hz), 2.77 (1H, m), 2.99 (1H, q, J = 9.3 Hz), 3.32 (1H, m), 3.54-3.65 (2H, m), 3.66-3.77 (2H, m); 13C NMR (CDCl3) δ = 22.7 (CH3), 23.4 (CH3), 25.4 (CH), 33.9 (CH2), 34.0 (CH2), 42.5 (CH2), 42.5 (CH2), 50.4 (CH), 62.2 (CH2), 65.4 (CH), 167.9 (C).; Mass (EI) m/z 212 (M+), 156, 125, 81, 55; HRMS (EI) Calcd for C11H20N2O2: (M+), 212.1215. Found: 212.1551. Anal. Calcd for C11H20N2O2: C, 62.23; H, 9.50; N, 13.20%. Found: C, 61.92; H, 9.90; N, 13.11%. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD-H, hexane : 2-PrOH = 20 : 1 v/v%, detector: UV 254 nm, Flow rate = 1.0 mL/min, 35 oC, tmajor = 17.3 min (endo), tminor = 21.2 min (endo), tmimor = 36.2 min (exo), tmajor = 41.0 min (exo)).

ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research (nos. 17550097, 20550094, and 20200052) from the Ministry of Education, Science and Culture, Japan.

References

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