Recent years have witnessed an unthinkable upsurge in potential utility of asymmetric organocatalysis as a tool for the synthesis of enantiopure molecules under mild,environmentally benign conditions ^[1]. Readily,available cinchona alkaloids, namely cinchonidine (CD),cinchonine (CN),quinine (QN) and quinidine (QD),enjoyed much interest as privileged organocatalysts effective in numerous mechanistically diverse enantioselective transformations ^[2]. The resulting (8S,9S) and (8R,9R)-9- amino-(9-deoxy) cinchona alkaloids are employed as attractive and efficient organocatalysts with excellent catalytic properties in asymmetric Aldol addition ^[3],Diels-Alder reaction ^[4],Friedel- Crafts reaction ^[5],Henry reaction ^[6],Mannich reaction ^[7], Michael addition ^[8],hydrogenation ^[9],epoxidation ^[10],1,3- dipolar cycloaddition ^[11],decarboxylation ^[12] and methanolytic desymmetrization ^[13]. In the aforementioned organocatalytic asymmetric reactions,the stereochemistry of catalytic products,to a great extent,generally depended on the configurations of the 8- and 9-stereogenic centers in 9-amino-(9-deoxy) cinchona alkaloids, although the experimental observations occasionally revealed the unexpected hint of enantioselectivity ^[14]. Considering the influence of stereochemical diversity of the organocatalyst on the stereochemistry of the products,(8S,9R) and (8R,9S)-9-amino-(9-deoxy) cinchona alkaloids possibly play the different and unthinkable role in determining the spatial structures of catalytic products. However,until now,(8S,9R) and (8R,9S)-9-amino-(9-deoxy) cinchona alkaloids have not been developed or received considerable attention. Based on the Mitsunobu reaction,in this report,four exotic pseudoenantiomers of (8S,9R) and (8R,9S)-9-amino-(9-deoxy) cinchona alkaloids were conveniently synthesized for the first time through the two conversions of the configurations at the 9-stereogenic centers in commercially available cinchona alkaloids (Scheme 1).

Scheme 1

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Scheme 1.The synthetic route to 9-amino-(9-deoxy) cinchona alkaloids through the two inversions of configuration.

General procedure for 9-amino(9-deoxy) cinchona alkaloids: The epi-cinchona alkaloids (epi-CD,CN,QN and QD) (1.63 mmol) and triphenylphosphine (520 mg,1.95 mmol) were dissolved in 6 mL of anhydrous THF under an argon atmosphere and added dropwise 2 mL of diisopropyl azidocarboxylate (DIAD) (0.38 mL, 1.95 mmol) and 1 mL THF solution of diphenylphosphoryl azide (DPPA) (0.42 mL,1.95 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h and 50 °C for 2 h and then triphenylphosphine (563 mg,2.12 mmol) added in one portion. After the gas evolution had ceased (about 2 h),the reaction mixture was cooled to room temperature,added 0.3 mL of water,stirred for another 3 h and evaporated under reduced pressure. The residue was dissolved in 10 mL of CH₂Cl₂ and added 5 mL of diluted hydrochloric acid (10%). The aqueous phase was washed with CH₂Cl₂ (3 × 10 mL),alkalinized with an excess of concentrated ammonia and extracted with CH₂Cl₂ (3 × 30 mL). The organic phase was dried over anhydrous Na₂SO₄. The concentrated organic phase was purified by silica gel column chromatography using CHCl₃-MeOH (40:1,v/v) as an eluent to afford the title compounds as yellowish viscous oils.

CN-NH²: Yellowish viscous oil,α²⁰_D = -56.0 (c 0.30,EtOH). 1H NMR (300 MHz,CDCl3,Me₄Si): d 8.89 (d,1 H,³J = 6.0 Hz,H-2'),8.21 (d,1 H,³J = 6.0 Hz,H-5'),8.12 (d,1 H,³J = 6.0 Hz,H-8'),7.70 (t,1 H, ³J = 6.0 Hz,H-7'),7.57 (t,1 H,³J = 6.0 Hz,H-60),7.41 (d,1 H, ³J = 3.0 Hz,H-3'),5.93-6.05 (m,1 H,H-10),5.12 (d,1 H,³J = 6.0 Hz, H-11a),5.08 (d,1 H,³J = 6.0 Hz,H-11b),4.81 (d,1 H,³J = 9.0 Hz,H- 9),3.18 (q,1 H,³J = 9.0 Hz,H-8),2.66-2.88 (m,4 H,H-6a,H-2-exo, H-6β,H-2-endo),2.25 (q,1 H,³J = 9.0 Hz,H-3),1.90-1.95 (m,3 H, NH₂,H-4),1.80 (d,2 H,³J = 9.0 Hz,H-7a,H-7β),1.62 (q,2 H, ³J = 9.0 Hz,H-5). 13CNMR(75 MHz,CDCl3): d 150.0 (C-20),148.3 (C- 100),139.3 (C-4'),130.2 (C-10),129.1 (C-7'),128.8 (C-8'),126.5 (C- 90),126.3 (C-60),122.6 (C-5'),117.6 (C-3'),114.9 (C-11),60.4 (C-8), 52.1 (C-9),49.1 (C-2),48.1 (C-6),38.8 (C-3),29.4 (C-7),27.5 (C-4), 25.6 (C-5). Anal. Calcd. for C₁₉H₂₃N₃: C,77.78; H,7.90; N,14.32. Found: C,77.75; H,9.93; N,14.27. MS: m/z 293.8 [M+H]⁺. QD-NH₂: Yellowish viscous oil,α²⁰_D = -106.7 (c 0.79,EtOH). 1H NMR (300 MHz,CDCl3,Me₄Si): d 8.72 (d,1 H,³J = 6.0 Hz,H-2'),8.01 (d,1 H,³J = 9.0 Hz,H-8'),7.42 (s,1 H,H-5'),7.31-7.37 (m,2 H,H-7', H-3'),5.93-6.04 (m,1 H,H-10),5.04-5.12 (m,2 H,H-11),4.73 (d,1 H,³J = 9.0 Hz,H-9),3.95 (s,3H,H-110),3.13 (q,1 H,³J = 9.0 Hz,H-8), 2.65-2.92 (m,4 H,H-6a,H-2-exo,H-6β,H-2-endo),2.24 (q,1 H, ³J = 9.0 Hz,H-3),2.13 (s,2 H,NH₂),1.86 (s,1 H,H-4),1.77 (q,2 H, ³J = 6.0 Hz,H-7a,H-7β),1.60 (q,2 H,³J = 9.0 Hz,H-5). ¹³C NMR (75 MHz,CDCl₃): δ 157.5 (C-60),149.3 (C-20),147.6 (C-100),144.4 (C-1'),140.2 (C-4'),131.6 (C-8'),127.6 (C-9'),121.2 (C-3'),118.0 (C-7'),114.5 (C-11),101.0 (C-5'),60.6 (C-8),55.4 (C-2),52.8 (C-11'), 49.3 (C-9),48.4 (C-6),39.2 (C-3),27.7 (C-7),26.1 (C-5),25.2 (C-4). Anal. Calcd. for C₂₀H₂₅N₃O: C,74.27; H,7.79; N,12.99; O,4.95. Found: C,74.34; H,7.81; N,12.96; O,4.96. MS: m/z 324.7 [M+H]⁺.

CD-NH₂: Yellowish viscous oil,α²⁰_D = -55.6 (c 1.63,EtOH). 1H NMR (300 MHz,CDCl₃,Me₄Si): δ 8.89 (d,1 H,³J = 6.0 Hz,H-2'),8.22 (d,1 H,³J = 6.0 Hz,H-5'),8.13 (d,1 H,³J = 9.0 Hz,H-8'),7.70 (t,1 H, ³J = 6.0 Hz,H-7'),7.57 (t,1 H,³J = 6.0 Hz,H-60),7.42 (1 d,H, ³J = 6.0 Hz,H-3'),5.86-5.98 (m,1 H,H-10),5.03-5.09 (m,2 H,H- 11),4.76 (d,1 H,³J = 9.0 Hz,H-9),3.23 (q,1 H,³J = 9.0 Hz,H-8), 2.96-3.07 (m,2 H,H-6a,H-2-exo),2.66 (d,1 H,³J = 15.0 Hz,H-6β), 2.55 (td,1 H,³J ₁= 12.0 Hz,³J ₂= 6.0 Hz,H-2-endo),2.28 (s,3 H,NH₂, H-3),2.16 (m,1 H,H-4),1.90 (d,1 H,H-7β),1.68 (td,1 H, ³J ₁= 12.0 Hz,³J ₂= 3.0 Hz,H-7a),1.50-1.56 (q,2 H,³J = 9.0 Hz,H-5). ¹³C NMR (75 MHz,CDCl₃): δ 150.3 (C-20),148.6 (C-100),141.7 (C- 40),130.5 (C-10),129.3 (C-7'),128.9 (C-8'),126.6 (C-9'),126.5 (C- 60),122.6 (C-5'),118.0 (C-3'),114.5 (C-11),60.6 (C-8),56.1 (C-2), 53.4 (C-9),41.8 (C-6),39.6 (C-3),27.7 (C-7),27.6 (C-4),26.4 (C-5). Anal. Calcd. for C₁₉H₂₃N₃: C,77.78; H,7.90; N,14.32. Found: C, 77.72; H,9.98; N,14.29. MS: m/z 293.7 [M+H]⁺.

QN-NH₂: Yellowish viscous oil,α²⁰_D = -42.3 (c 1.76,EtOH). 1HNMR (300 MHz,CDCl₃,Me₄Si): δ 8.74 (d,1 H,³J = 6.0Hz,H-2'),8.02 (d,1 H,³J = 12.0 Hz,H-8'),7.44 (d,1 H,³J = 3.0Hz,H-5'),7.38 (1 H,d, ³J = 3.0Hz,H-7'),7.35 (d,1H,³J = 6.0Hz,H-3'),5.87-5.99 (1 H,m,H- 10),5.03-5.09 (m,2 H,H-11),4.63 (d,1 H,³J = 9.0 Hz,H-9),3.96 (s,3 H,H-110),3.21 (q,1 H,³J = 9.0 Hz,H-8),2.95-3.07(m,2 H,H-6a,H-2- exo),2.66 (d,1 H,³J = 12.0 Hz,H-6β),2.56 (1 H,td,³J ₁= 12.0Hz, ³J ₂= 3.0 Hz,H-2-endo),2.28 (s,1 H,H-3),2.15 (td,1 H,³J ₁= 9.0Hz ³J ₂= 3.0 Hz,H-4),1.90 (s,3 H,NH₂,H-7β,),1.67 (td,1H,³J ₁= 15.0Hz, ³J ₂= 3.0Hz,H-7a),1.52 (2 q,H,³J = 9.0Hz,H-5). ¹³C NMR (75MHz, CDCl3): d 157.7 (C-60),149.2 (C-20),147.8 (C-100),144.7 (C-10),141.8 (C-4'),131.9 (C-8'),127.6 (C-9'),121.1 (C-3'),118.3 (C-7'),114.4 (C- 11),101.1 (C-5'),60.5 (C-8),56.1 (C-2),55.6 (C-11'),53.7 (C-9),41.9 (C-6),39.6 (C-3),27.8 (C-7),27.7 (C-4),26.5 (C-5). Anal. Calcd. for C₂₀H₂₅N₃O: C,74.27; H,7.79; N,12.99; O,4.95. Found: C,74.32; H, 7.80; N,12.97; O,4.98. MS: m/z 324.9 [M+H]⁺. 3. Results and discussion

The first conversion of cinchona alkaloids to 9-epimers of cinchona alkaloids was achieved through one-pot inversion of Mitsunobu esterification-saponification ^[15]. Four cinchona alkaloids (CD,CN,QN and QD) were esterified with 4-nitrobenzoic acid (NBA) and subsequently treated in situ with aqueous lithium hydroxide solution. The corresponding 9-epi-cinchona alkaloids (epi-CD,CN,QN and QD) were easily purified by flash column chromatography using CHCl₃/t-BuOMe (3:1,v/v) as an eluent to remove Ph3PO and diethyl hydrazine-1,2-dicarboxylate,and then CHCl₃/MeOH/Et3N (40:1:1,v/v/v) to obtain the target compounds of analytical purity in 51%-83% yield,which were identified by 1H- NMR,¹³C NMR,α²⁰_D and Rf (Table 1).

Table 1

Table 1 Inversion of cinchona alkaloids by Mitsunobu esterification/saponification.a

Table 1 Inversion of cinchona alkaloids by Mitsunobu esterification/saponification.a

According to the reported synthetic procedure ^[16],four (8S,9R) and (8R,9S)-9-amino(9-deoxy) cinchona alkaloids (CD-NH₂,CN-NH²,QN-NH₂,QD-NH₂) were conveniently prepared in good yields (53%-87%) ^[17]. The key step was the Mitsunobu reaction that led to the C₉-azido compound by an ^SN² mechanism. The reduction is performed in situ by adding triphenylphosphane. Hydrolysis of the intermediate aminophosphorane yielded free amine. The pure 9-amino(9-deoxy) cinchona alkaloids (CD-NH₂, CN-NH²,QN-NH₂ and QD-NH₂) were easily separated by silica gel flash column chromatography using CHCl₃/MeOH (40:1,v/v) as an eluent to afford yellowish viscous oils,whose structures were identified by 1H NMR,¹³C NMR,1H COSY 2D NMR,¹H NOESY 2D NMR,α²⁰_D and Rf (Table 2). It is noteworthy that the α²⁰_D values of CD-NH₂,CN-NH²,QN-NH₂ and QD-NH₂ were converted from positive to negative due to the inversions of the configurations at the 9-hydroxyl groups of epi-CD,CN,QN and QD.

Table 2

Table 2 IInversion of epi-cinchona alkaloids to 9-amino(9-deoxy) cinchona alkaloids by Mitsunobu reaction.

Table 2 IInversion of epi-cinchona alkaloids to 9-amino(9-deoxy) cinchona alkaloids by Mitsunobu reaction.

Herein,we provided the direct evidence for conformational preference of 9-amino(9-deoxy) cinchona alkaloids (CD-NH₂,CNNH₂, QN-NH₂ and QD-NH₂) through a combination of ¹H NOESY 2D NMR and computational methods. Full geometric optimization calculations were performed in chloroform using the polarized continuum model (PCM) with B3LYP functional and 6-31G(d) basis set,and their minimum energy structures were shown in the Supporting information. For the identification of conformers,the interring NOEs between the quinoline and quinuclidine protons and NOEs involving H8 and H9 are most useful. Pointedly,four 9- amino(9-deoxy) cinchona alkaloids appeared to exhibit the hindered rotations around the C_4'-C₉ and C₉-C₈ bonds and to favor only a narrow range of the available conformational space of the molecule. The ¹H NOESY 2D NMR of CN-NH² displayed only three cross-peaks related to aromatic hydrogen,indicating close interactions between the H_5'-H₉,H_5'-H₈,and H_3'-H₆ pairs of atoms. These data mainly supported the minimum energy conformation of CN-NH²,and elucidated that CN-NH² favored the open conformation (Fig. 1). Although the NOESY spectrum of CD-NH₂,QN-NH₂ and QD-NH₂ did not directly support their minimum energy conformations,but the favored conformations could be obtained through molecular rotations around the C_4'-C₉ and C₉-C₈ bonds from their minimum energy structures,in which the H_5'-H₉ and H_3'-H₈ pairs of atoms showed close NOE interactions with the closed conformations ^[18]. Furthermore, 1H NMR and 13CNMR spectra of (8S,9R)-CD-NH₂ differed from that of (8S,9S)-9-amino-(9-deoxy) cinchona alkaloids (epi-CD-NH₂) because of their opposite configurations of carbon atoms at C9-position. The mixture of 50 wt% (8S,9R)-CD-NH₂ and 50 wt% (8S,9S)-epi-CD-NH₂ showed the more sophisticated 1H NMR and ¹³C NMR spectra than their own shown in the Supporting information,which provided the indirect evidence to elucidate the different configurations at the C9-position between (8S,9R)- CD-NH₂ and (8S,9S)-epi-CD-NH₂.

Fig. 1

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Fig. 1.1H NOESY 2D NMR and minimum energy conformation of CN-NH2.

In summary,four exotic (8S,9R) and (8R,9S)-9-amino(9-deoxy) cinchona alkaloids were conveniently synthesized for the first time through the two conversions of the configurations at the 9- stereogenic centers of commercially available cinchona alkaloids. Their catalytic performances in various asymmetric reactions are under investigation. Acknowledgments

Research support from the National Science Foundation of China (No. 21071116) and Chongqing Scientific Foundation,China (No. 2010BB4126). Appendix A. Supplementary data Supplementary data associated with this article can be found,in the online version,at