CC BY-ND-NC 4.0 · Synlett 2019; 30(04): 483-487
DOI: 10.1055/s-0037-1610384
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Catalytic Enantioselective Synthesis of 4-Amino-1,2,3,4-tetrahydropyridine Derivatives from Intramolecular Nucleophilic Addition Reaction of Tertiary Enamides

Shuo Tong*
,
MOE Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. of China   Email: tongshuo@mail.tsinghua.edu.cn   Email: wangmx@mail.tsinghua.edu.cn
› Author Affiliations
We thank the National Natural Science Foundation of China (No. 21320102002, 91427301) for financial support.
Further Information

Publication History

Received: 30 September 2018

Accepted after revision: 22 October 2018

Publication Date:
15 November 2018 (eFirst)

 

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

A general and efficient method for the synthesis of highly enantiopure 4-amino-1,2,3,4-tetradydropyridine derivatives based on chiral phosphoric acid catalyzed intramolecular nucleophilic addition of tertiary enamides to imines has been developed. We have also demonstrated a substrate engineering strategy to significantly improve the enantioselectivity of asymmetric catalysis


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Chiral six-membered N-heterocyclic compounds such as functionalized 4-aminopiperidines are used extensively in the study of synthetic pharmaceutics and drug discovery.[1] (2S,4R)-1-(3,5-dimethylbenzoyl)-2-benzyl-4-((quinolin-3-ylmethyl)amino) piperidine CGP 49823, for instance, is an orally and centrally active nonpeptide NK1 antagonist[2] while carmegliptin is a potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type II diabetes.[3] Synthesis of functionalized 4-aminopiperidine requires multistep reactions[4] or reductive amination of prefunctionalized piperidine-4-one derivatives.[5] The documented methods suffer, however, from drawbacks such as tedious stepwise chemical manipulations or low chemical yields. The development of general and asymmetric catalytic methods for the synthesis of highly enantiopure diverse 4-aminopiperidine derivatives is therefore highly desirable.

Tertiary enamides are variants of enamines in which one of the N-alkyl groups is replaced by an electron-attracting moiety such as carbonyl. Various synthetic methods have been established allowing facile accesses to tertiary enamides.[6] Unfortunately, due to the electronic effect of carbonyl group, tertiary enamides show much diminished enaminic activity and had been noted for a long time as inert and not useful chemical entities in organic synthesis.[7] [8] [9] [10] However, we envisioned that tertiary enamides would be a type of shelf-stable nucleophiles with tunable reactivity based on the fluxional cross-conjugational system comprising carbon–carbon double bond, lone-pair electrons on nitrogen atom and carbonyl group (C=C–N–C=O). We have demonstrated in recent years that tertiary enamides behave indeed as unique and invaluable synthons in chemical synthesis. They are able to undergo stereoselective nucleophilic addition reactions to epoxides,[11] carbonyls,[12] iminiums,[13] nitriliums,[14] and activated alkynes,[15] furnishing diverse nitrogen-containing heterocyclic compounds which are not easily obtained by other means. To further explore the synthetic applications of tertiary enamides and to develop new methods for the construction of chiral 4-aminopiperidines,[16] we have undertaken the current study of catalytic asymmetric cyclization reactions of tertiary enamides. We disclose herein a chiral phosphoric acid catalyzed intramolecular nucleophilic addition of tertiary enamides to imines and a substrate engineering strategy to achieve high enantioselectivity in the synthesis of diverse 4-aminopiperidine derivatives.

We started our study with the examination of the cyclization of tertiary enamide 3aa, which was obtained quantitatively from the reaction of aldehyde 1a with benzylamine 2a (see Supporting Information for details), under asymmetric catalysis. Chiral Lewis acids catalysts such as BINOL-Ti/spiro-Ti complex, Salen-AlCl, Pybox/Sn(OTf)2, Brønsted acids such as camphorsulphonic acid and a chiral thiourea were found to be able to effect the transformation of 3aa to afford 4-aminopiperide product 4aa in good to excellent yields. Disappointedly, the enantiomeric excess values obtained were very low in all cases (Supporting Information).[17] We then focused on chiral phosphoric acids (CPA) as they were renowned catalysts to activate imine functionality enantioselectively.[18] [19] [20] A series of 17 chiral BINOL-derived phosphoric acids CC1CC17 (Supporting Information), which have fine-tuned electronic and steric effects, were tested as catalysts in the transformation of 3aa into 4ab. All chiral phosphoric acids showed appallingly low activity and enantioselectivity (Supporting Information) except 2,2′-bis(2,4,6-triisopropylpohenyl)-substituted chiral phosphoric acid CC8 which produced 4aa in 91% yield with 48.3% ee after 18 h in dichloromethane (DCM, Table [1]). Unfortunately, further optimization of reaction conditions by screening reaction media, temperature, and reaction time did not lead to the improvement of enantiocontrol, with ee values never exceeding 48.3% (Supporting Information).

Table 1 Development of Catalytic Enantioselective Nucleophilic Addition of Tertiary Enamides to Imines by Means of a Substrate Engineering Strategy

Entry

2

CC8 (mol%)

Solvent

Temp (°C)

Time

Yield (%)b

ee (%)c

 1

2a

10

DCM

rt

18 h

91

48.3

 2

2a

10

CCl4

rt

48 h

88

35.2

 3d

2a

20

CCl4

reflux

 7 h

92

33.1

 4

2b

10

DCM

rt

 2 h

97

41.1

 5

2b

10

CCl4

rt

 8 h

99

77.8

 6

2b

10

CCl4

0

48 h

trace

n.d.

 7

2b

10

CCl4

40

 1.5 h

95

80.5

 8

2b

10

CCl4

reflux

10 min

98

84.6

 9

2b

 5

CCl4

reflux

30 min

96

72.9

10

2b

20

CCl4

reflux

 5 min

98

87.2

11d

2b

20

CCl4

reflux

10 min

98

88.8

12d

2c

20

CCl4

reflux

10 min

97

87.1

13d

2d

20

CCl4

reflux

 5 min

99

94.0

14d

2e

20

CCl4

reflux

 5 min

97

60.0

a Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), solvent, rt, 5–10 min, then CPA CC8, c 10 mM.

b Isolated yield.

c Enantiomeric excess of 4 was determined by HPLC analysis on chiral stationary phase.

d The reaction was carried out in the concentration of c 2.5 mM.

Although extensive examination of catalysts fabricated from different chiral scaffolds and of various reaction parameters may probably result in a better enantioselective reaction, we adopted completely a different approach to achieve efficient synthesis of highly enantiopure 4-aminopiperidine structures. In biocatalysis and biotransformation, substrate engineering, namely, structural modification of the reactants in order to best-fit the active site of enzymes, is a powerful strategy to realize high enzymatic activity and selectivity. In comparison to protein engineering, substrate engineering is generally easy-to-handle, time-saving, and cost-effective.[21] For example, we have demonstrated previously the dramatic improvement of enantioselectivity in enzyme-catalyzed hydrolysis of β-hydroxy and β-amino nitriles and carboxamides simply by protecting hydroxyl or amino with a benzyl group.[22]

Based on the assumption of effective recognition of a larger chiral pocket of CC8 toward imine moiety through both steric and electronic (π/π and C–H/π) interactions, imine substrates bearing N-diphenylmethyl (DPM, 3ab), N-di(4-methoxyphenyl)methyl (DMPM, 3ac), 10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl (DHDBA, 3ad) and 5H-dibenzo[a,d][7]annulen-5-yl (DBA, 3ae) were designed and synthesized from the condensation reaction between aldehyde and the corresponding amines (Supporting Information). Their intramolecular cyclization reactions were investigated under the catalysis of CC8. To our delight, substrate engineering led to significant improvement of both efficiency and enantioselectivity of the catalytic transformation. As indicated in Table [1], under the identical conditions such as using CCl4 as solvent, the ee values obtained from the reaction of 3ab and of 3aa were 77.8% and 35.2%, respectively, although comparable enantioselectivity was observed when reactions were performed in DCM (Table [1], entries 1, 2, 4, and 5). After further examining catalyst loading, reaction temperature and substrate concentration (Table [1], entries 6–10), an ee value of 88.8% was achieved for product 4ab (Table [1], entry 11). On contrary, under such optimized conditions, namely, refluxing reactant (2.5 mM) with chiral catalyst (20 mol%) in CCl4, reaction of 3aa afforded product 4aa with only 33.1% ee (Table [1], entry 3). Increasing the bulkiness of N-substituent by replacing DPM (3ab) with DMPM (3ac) caused slight decrease of enantioselectivity (Table [1], entry 12). After locking the conformation of two phenyl substituents by forming a fused carbocyclic structure, the resulting DHDBA-bearing substrate 3ad underwent a remarkably high enantioselective cyclization reaction to afford 4ad in an almost quantitative yield with 94.0% ee (Table [1], entry 13). Further rigidification of the carbocyclic ring substituent, however, had a detrimental effect on enantioselectivity of chiral catalysis. This has been exemplified by the drastic erosion of ee from 94.0% for the reaction of DHDBA-substituted imine 3ad to 60.0% for the reaction of DBA-substituted imine analogue 3ae (Table [1], entries 13 and 14).

Zoom Image
Scheme 1 Catalytic enantioselective synthesis of 4-amino-1,2,3,4-tetrahydropyridine derivatives from tertiary enamides. a Reflux in CCl4. b Room temperature in CCl4.

Since N-DPM- and N-DHDBA-substituted imines exhibited high level of enantiocontrol under catalysis of chiral phosphoric acid CC8, the scope of intramolecular nucleophilic addition of tertiary enamides to imines was then surveyed on substrates derived from amines 2b and 2d. The reactions were conveniently conducted using imines formed in situ. The results summarized in Scheme [1] show clearly that tertiary enamides undergo generally efficient cyclization reaction to produce 4-amino-1,2,3,4-tetrahydropyridine derivatives irrespective of the nature of the substituents. For example, reaction of all aryl-substituted tertiary enamides in which phenyl group contains either electron-withdrawing or electron-donating group(s) at different position(s) went completion within 0.5 h to generate heterocyclic products in high yields. Only in the case of N-acetyl-substituted enamide 3ib and cyclohexanone-derived enamide 3jb, a long reaction time (ca. 24–36 h) was required due to their lower enaminic reactivity. Good to excellent enantioselectivity was achieved using either DPM or DHDBA substituent on imine moiety. It is worth noting that, however, DPM outweighed DHDBA in a number of cases in the control of enantioselectivity of chiral phosphoric acid catalyzed transformation. It implied that the enantioselectivity of intramolecular nucleophilic addition of enamide moiety to chiral phosphoric acid activated imine moiety is governed by both the N-substituent on imine and the variation of steric and electronic effects of substituents bonded to enamide segment. The outcomes manifested again the potential of substrate engineering strategy in the synthesis of a targeted enantiopure 4-amino-1,2,3,4-tetrahydropyridine compound under the catalysis of chiral phosphoric acid.[23]

Advantage of substrate engineering protocol was further demonstrated by easy removable of the N-protection group. Treatment of 4ca with trifluoroacetic acid at ambient temperature thus gave product 5 (Scheme [2]). Derivatization of free amino group would therefore feasibly permit the generation of diverse compounds. To determine the absolute configuration of the product 4, an authentic sample of (S)-4-hydroxy-1,2,3,4-tetrahydropyridine 6 [11b] was converted into (R)-4-amino-1,2,3,4-tetrahydropyridine (R)-5 through azide intermediate 7 (Scheme [3]). The absolute S-configuration was assigned to products 4ac on the basis of the comparison of specific rotation values between (S)-5 (Scheme [2]) and (R)-5 (Scheme [3]).

Zoom Image
Scheme 2 Synthesis of (S)-5 from 4ac through deprotection of DMPM group
Zoom Image
Scheme 3 Synthesis of (R)-5 from authentic sample (S)-6

In conclusion, we have shown a general and efficient method for the synthesis of highly enantiopure 4-amino-1,2,3,4-tetrahydropyridine derivatives based on intramolecular nucleophilic addition of tertiary enamides to imines. We have also demonstrated a substrate engineering strategy enabling significant improvement of the enantioselectivity of chiral phosphoric acid catalyzed reaction.


#

Supporting Information

  • References and Notes

  • 1 Watson PS, Jiang B, Scott B. Org. Lett. 2000; 2: 3679
    • 2a Ofner S, Hauser K, Schilling W, Vassout A, Veenstra SJ. Bioorg. Med. Chem. Lett. 1996; 6: 1623
    • 2b Veenstra SJ, Hauser K, Schilling W, Betschart C, Ofner S. Bioorg. Med. Chem. Lett. 1996; 6: 3029
  • 3 Patrizio M, Markus B, Patrick DG, Holger F, Michael H, Joerg H, Buelent K, Bernd K, Bernd ML, Alexander M, Robert N, Etienne R, Elena S, Urs S. Bio. Med. Chem. Lett. 2010; 20: 11009
    • 4a Van Niel MB, Collins I, Beer MS, Broughton HB, Cheng SK. F, Goodacre SC, Heald A, Locker KL, MacLeod AM, Morrison D, Moyes CR, O’Connor D, Pike A, Rowley M, Russell MG. N, Sohal B, Stanton JA, Thomas S, Verrier H, Watt AP, Castro JL. J. Med. Chem. 1999; 42: 2087
    • 4b Lübbers T, Böhringer M, Gobbi L, Hennig M, Hunziker D, Kuhn B, Löffler B, Mattei P, Narquizian R, Peters J.-U, Ruff Y, Wessel HP, Wyss P. Bioorg. Med. Chem. Lett. 2007; 17: 2966
    • 4c Benmehdi H, Lamouri A, Serradji N, Pallois F, Heymans F. Eur. J. Org. Chem. 2008; 299
    • 4d Barluenga J, Mateos C, Aznar F, Valdés C. Org. Lett. 2002; 4: 3667
    • 4e Badorrey R, Portaña E, Díaz-de-Villegas MD, Gálvez JA. Org. Biomol. Chem. 2009; 7: 2912
    • 5a Sun H, Scott DO. ACS Med. Chem. Lett. 2011; 2: 638 ; and references cited therein
    • 5b Manetti D, Martini E, Ghelardini C, Dei S, Galeotti N, Guandalini L, Romanelli MN, Scapecchi S, Teodori E, Bartolini A, Gualtieri F. Bioorg. Med. Chem. Lett. 2003; 13: 2303

      For reviews of enamide syntheses, see:
    • 6a Dehli JR, Legros J, Bolm C. Chem. Commun. 2005; 973
    • 6b Tracey MR, Hsung RP, Antoline J, Kurtz KC, Shen L, Slafer BW, Zhang Y. Category 3, Compounds with Four and Three Carbon Heteroatom Bonds . In Science of Synthesis . Vol. 21 Weinreb SM. Thieme; Stuttgart: 2005: 387
  • 7 For an overview, see: Wang M.-X. Chem Commun. 2015; 51: 6039
  • 8 Carbery DR. Org. Biomol. Chem. 2008; 6: 3455
  • 9 Gopalaiah K, Kagan HB. Chem. Rev. 2011; 111: 4599

    • Secondary enamides are active aza-ene components to undergo aza-ene addition reactions with highly electron-deficient unsaturated compounds. For reviews, see:
    • 10a Matsubara R, Kobayashi S. Acc. Chem. Res. 2008; 41: 292
    • 10b Bernadat G, Masson G. Synlett 2014; 25: 2842
    • 11a Yang L, Deng G, Wang D.-X, Huang Z.-T, Zhu J, Wang M.-X. Org. Lett. 2007; 9: 1387
    • 11b Yang L, Zheng Q.-Y, Wang D.-X, Huang Z.-T, Wang M.-X. Org. Lett. 2008; 10: 2461
    • 11c Yang L, Lei C.-H, Wang D.-X, Huang Z.-T, Wang M.-X. Org. Lett. 2010; 12: 3918
    • 12a Yang L, Wang D.-X, Huang Z.-T, Wang M.-X. J. Am. Chem. Soc. 2009; 131: 10390
    • 12b Tong S, Wang D.-X, Zhao L, Zhu J, Wang M.-X. Angew. Chem. Int. Ed. 2012; 51: 4417
    • 12c He L, Zhao L, Wang D.-X, Wang M.-X. Org. Lett. 2014; 16: 5972
    • 12d Zhu W, Zhao L, Wang M-X. J. Org. Chem. 2015; 80: 12047
    • 12e Xu X.-M, Zhao L, Zhu J, Wang M.-X. Angew. Chem. Int. Ed. 2016; 55: 3799
    • 12f Xu X.-M, Lei C.-H, Tong S, Zhu J, Wang M.-X. Org. Chem. Front. 2018; 5: 3138
    • 13a Shono T, Matsumura Y, Tsubata K, Sugihara Y, Yamane S, Kanazawa T, Aoki T. J. Am. Chem. Soc. 1982; 104: 6697
    • 13b Andan L, Miesch L. Org. Lett. 2018; 20: 3430
    • 14a Lei C.-H, Wang D.-X, Zhao L, Zhu J, Wang M.-X. J. Am. Chem. Soc. 2013; 135: 4708
    • 14b Lei C.-H, Wang D.-X, Zhao L, Zhu J, Wang M.-X. Chem. Eur. J. 2013; 19: 16981
  • 15 Zhang X.-Y, Xu X.-M, Zhao L, You J, Zhu J, Wang M.-X. Tetrahedron Lett. 2015; 56: 3898
  • 16 Tong S, Yang X, Wang D.-X, Zhao L, Zhu J, Wang M.-X. Tetrahedron 2012; 68: 6492
  • 17 Zhou Q.-L. Privileged Chiral Ligands and Catalysts . Wiley-VCH; Weinheim: 2011
    • 18a Akiyama T, Itoh J, Fuchibe K. Angew. Chem. Int. Ed. 2004; 43: 1566
    • 18b Yamanaka M, Itoch J, Fuchibe K, Akiyama T. J. Am. Chem. Soc. 2007; 129: 6756
  • 19 Uraguchi D, Terada M. J. Am. Chem. Soc. 2004; 126: 5356

    • For recent reviews on chiral phosphoric acids, see:
    • 20a Parmar D, Sugiono E, Raja S, Rueping M. Chem. Rev. 2014; 114: 9047
    • 20b Lv J, Luo S. Chem. Commun. 2013; 49: 847
    • 20c Li P, Yamamoto H. Top. Curr. Chem. 2011; 37: 161
    • 20d Yu J, Shi F, Gong LZ. Acc. Chem. Res. 2011; 44: 1156
    • 20e Kampen D, Reisinger CM, List B. Top. Curr. Chem. 2010; 291: 395
    • 20f Mahlan M, List B. Angew. Chem. Int. Ed. 2013; 52: 518
    • 20g Terada M. Synthesis 2010; 1929
    • 20h Hatano M, Ishihara K. Synthesis 2010; 3785
    • 20i Zamfir A, Schenker S, Freund M, Tsogoeva SB. Org. Biomol. Chem. 2010; 8: 5262
    • 20j Yu X, Wang W. Chem. Asian J. 2008; 3: 516
    • 20k Akiyama T. Chem. Rev. 2007; 107: 5744

      For select examples about substrate engineering in biocatalytic transformations, see:
    • 22a Braunegg G, De Raadt A, Feichtenhofer S, Griengl H, Kopper I, Lehmann A, Weber H.-J. Angew. Chem. Int. Ed. 1999; 38: 2763
    • 22b De Raadt A, Griengl H, Weber H. Chem. Eur. J. 2001; 7: 27
    • 22c Ma D.-Y, Zheng Q.-Y, Wang D.-X, Wang M.-X. Org. Lett. 2006; 8: 3231
    • 22d Ma D.-Y, Wang D.-X, Pan J, Huang Z.-T, Wang M.-X. J. Org. Chem. 2008; 73: 4087
  • 23 General Reaction Procedure A mixture of enamides 1a (0.5 mmol) and amines 2b (0.5 mmol) in dry CCl4 (25 mL) was stirred at ambient temperature for 5 min. Chiral phosphoric acid catalyst CC8 (75 mg, 0.1 mmol, 0.2 equiv) was added to the reaction system. Upon completion of the reaction, which was monitored by TLC, the reaction mixture was quenched with 10 mL sat. NaHCO3 solution, then extracted with 3 × 10 mL CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel to yield pure product 4ab. Oil (98% yield); ee 88.8% (chiral HPLC analysis). IR (KBr): 3422, 1723, 1656, 1601 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.21–7.44 (m, 17 H), 6.99 (br s, 2 H), 5.50 (br s, 1 H), 5.08 (s, 1 H), 4.05 (br s, 1 H), 3.74 (br s, 1 H), 3.41 (br s, 1 H), 2.00 (br s, 2 H), 1.62 (br s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 170.9, 144.0, 143.8, 140.6, 137.8, 136.2, 131.2, 130.7, 128.7, 128.6, 128.3, 128.1, 127.5, 127.34, 127.27, 127.2, 121.3, 118.6, 64.4, 48.8, 44.1, 31.2. HRMS (ESI): m/z calcd for C31H27BrN2O [M + Na]+, [M + 2 + Na]+: 521.1229, 523.1213; found: 521.1226, 523.1216.

  • References and Notes

  • 1 Watson PS, Jiang B, Scott B. Org. Lett. 2000; 2: 3679
    • 2a Ofner S, Hauser K, Schilling W, Vassout A, Veenstra SJ. Bioorg. Med. Chem. Lett. 1996; 6: 1623
    • 2b Veenstra SJ, Hauser K, Schilling W, Betschart C, Ofner S. Bioorg. Med. Chem. Lett. 1996; 6: 3029
  • 3 Patrizio M, Markus B, Patrick DG, Holger F, Michael H, Joerg H, Buelent K, Bernd K, Bernd ML, Alexander M, Robert N, Etienne R, Elena S, Urs S. Bio. Med. Chem. Lett. 2010; 20: 11009
    • 4a Van Niel MB, Collins I, Beer MS, Broughton HB, Cheng SK. F, Goodacre SC, Heald A, Locker KL, MacLeod AM, Morrison D, Moyes CR, O’Connor D, Pike A, Rowley M, Russell MG. N, Sohal B, Stanton JA, Thomas S, Verrier H, Watt AP, Castro JL. J. Med. Chem. 1999; 42: 2087
    • 4b Lübbers T, Böhringer M, Gobbi L, Hennig M, Hunziker D, Kuhn B, Löffler B, Mattei P, Narquizian R, Peters J.-U, Ruff Y, Wessel HP, Wyss P. Bioorg. Med. Chem. Lett. 2007; 17: 2966
    • 4c Benmehdi H, Lamouri A, Serradji N, Pallois F, Heymans F. Eur. J. Org. Chem. 2008; 299
    • 4d Barluenga J, Mateos C, Aznar F, Valdés C. Org. Lett. 2002; 4: 3667
    • 4e Badorrey R, Portaña E, Díaz-de-Villegas MD, Gálvez JA. Org. Biomol. Chem. 2009; 7: 2912
    • 5a Sun H, Scott DO. ACS Med. Chem. Lett. 2011; 2: 638 ; and references cited therein
    • 5b Manetti D, Martini E, Ghelardini C, Dei S, Galeotti N, Guandalini L, Romanelli MN, Scapecchi S, Teodori E, Bartolini A, Gualtieri F. Bioorg. Med. Chem. Lett. 2003; 13: 2303

      For reviews of enamide syntheses, see:
    • 6a Dehli JR, Legros J, Bolm C. Chem. Commun. 2005; 973
    • 6b Tracey MR, Hsung RP, Antoline J, Kurtz KC, Shen L, Slafer BW, Zhang Y. Category 3, Compounds with Four and Three Carbon Heteroatom Bonds . In Science of Synthesis . Vol. 21 Weinreb SM. Thieme; Stuttgart: 2005: 387
  • 7 For an overview, see: Wang M.-X. Chem Commun. 2015; 51: 6039
  • 8 Carbery DR. Org. Biomol. Chem. 2008; 6: 3455
  • 9 Gopalaiah K, Kagan HB. Chem. Rev. 2011; 111: 4599

    • Secondary enamides are active aza-ene components to undergo aza-ene addition reactions with highly electron-deficient unsaturated compounds. For reviews, see:
    • 10a Matsubara R, Kobayashi S. Acc. Chem. Res. 2008; 41: 292
    • 10b Bernadat G, Masson G. Synlett 2014; 25: 2842
    • 11a Yang L, Deng G, Wang D.-X, Huang Z.-T, Zhu J, Wang M.-X. Org. Lett. 2007; 9: 1387
    • 11b Yang L, Zheng Q.-Y, Wang D.-X, Huang Z.-T, Wang M.-X. Org. Lett. 2008; 10: 2461
    • 11c Yang L, Lei C.-H, Wang D.-X, Huang Z.-T, Wang M.-X. Org. Lett. 2010; 12: 3918
    • 12a Yang L, Wang D.-X, Huang Z.-T, Wang M.-X. J. Am. Chem. Soc. 2009; 131: 10390
    • 12b Tong S, Wang D.-X, Zhao L, Zhu J, Wang M.-X. Angew. Chem. Int. Ed. 2012; 51: 4417
    • 12c He L, Zhao L, Wang D.-X, Wang M.-X. Org. Lett. 2014; 16: 5972
    • 12d Zhu W, Zhao L, Wang M-X. J. Org. Chem. 2015; 80: 12047
    • 12e Xu X.-M, Zhao L, Zhu J, Wang M.-X. Angew. Chem. Int. Ed. 2016; 55: 3799
    • 12f Xu X.-M, Lei C.-H, Tong S, Zhu J, Wang M.-X. Org. Chem. Front. 2018; 5: 3138
    • 13a Shono T, Matsumura Y, Tsubata K, Sugihara Y, Yamane S, Kanazawa T, Aoki T. J. Am. Chem. Soc. 1982; 104: 6697
    • 13b Andan L, Miesch L. Org. Lett. 2018; 20: 3430
    • 14a Lei C.-H, Wang D.-X, Zhao L, Zhu J, Wang M.-X. J. Am. Chem. Soc. 2013; 135: 4708
    • 14b Lei C.-H, Wang D.-X, Zhao L, Zhu J, Wang M.-X. Chem. Eur. J. 2013; 19: 16981
  • 15 Zhang X.-Y, Xu X.-M, Zhao L, You J, Zhu J, Wang M.-X. Tetrahedron Lett. 2015; 56: 3898
  • 16 Tong S, Yang X, Wang D.-X, Zhao L, Zhu J, Wang M.-X. Tetrahedron 2012; 68: 6492
  • 17 Zhou Q.-L. Privileged Chiral Ligands and Catalysts . Wiley-VCH; Weinheim: 2011
    • 18a Akiyama T, Itoh J, Fuchibe K. Angew. Chem. Int. Ed. 2004; 43: 1566
    • 18b Yamanaka M, Itoch J, Fuchibe K, Akiyama T. J. Am. Chem. Soc. 2007; 129: 6756
  • 19 Uraguchi D, Terada M. J. Am. Chem. Soc. 2004; 126: 5356

    • For recent reviews on chiral phosphoric acids, see:
    • 20a Parmar D, Sugiono E, Raja S, Rueping M. Chem. Rev. 2014; 114: 9047
    • 20b Lv J, Luo S. Chem. Commun. 2013; 49: 847
    • 20c Li P, Yamamoto H. Top. Curr. Chem. 2011; 37: 161
    • 20d Yu J, Shi F, Gong LZ. Acc. Chem. Res. 2011; 44: 1156
    • 20e Kampen D, Reisinger CM, List B. Top. Curr. Chem. 2010; 291: 395
    • 20f Mahlan M, List B. Angew. Chem. Int. Ed. 2013; 52: 518
    • 20g Terada M. Synthesis 2010; 1929
    • 20h Hatano M, Ishihara K. Synthesis 2010; 3785
    • 20i Zamfir A, Schenker S, Freund M, Tsogoeva SB. Org. Biomol. Chem. 2010; 8: 5262
    • 20j Yu X, Wang W. Chem. Asian J. 2008; 3: 516
    • 20k Akiyama T. Chem. Rev. 2007; 107: 5744

      For select examples about substrate engineering in biocatalytic transformations, see:
    • 22a Braunegg G, De Raadt A, Feichtenhofer S, Griengl H, Kopper I, Lehmann A, Weber H.-J. Angew. Chem. Int. Ed. 1999; 38: 2763
    • 22b De Raadt A, Griengl H, Weber H. Chem. Eur. J. 2001; 7: 27
    • 22c Ma D.-Y, Zheng Q.-Y, Wang D.-X, Wang M.-X. Org. Lett. 2006; 8: 3231
    • 22d Ma D.-Y, Wang D.-X, Pan J, Huang Z.-T, Wang M.-X. J. Org. Chem. 2008; 73: 4087
  • 23 General Reaction Procedure A mixture of enamides 1a (0.5 mmol) and amines 2b (0.5 mmol) in dry CCl4 (25 mL) was stirred at ambient temperature for 5 min. Chiral phosphoric acid catalyst CC8 (75 mg, 0.1 mmol, 0.2 equiv) was added to the reaction system. Upon completion of the reaction, which was monitored by TLC, the reaction mixture was quenched with 10 mL sat. NaHCO3 solution, then extracted with 3 × 10 mL CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel to yield pure product 4ab. Oil (98% yield); ee 88.8% (chiral HPLC analysis). IR (KBr): 3422, 1723, 1656, 1601 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.21–7.44 (m, 17 H), 6.99 (br s, 2 H), 5.50 (br s, 1 H), 5.08 (s, 1 H), 4.05 (br s, 1 H), 3.74 (br s, 1 H), 3.41 (br s, 1 H), 2.00 (br s, 2 H), 1.62 (br s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 170.9, 144.0, 143.8, 140.6, 137.8, 136.2, 131.2, 130.7, 128.7, 128.6, 128.3, 128.1, 127.5, 127.34, 127.27, 127.2, 121.3, 118.6, 64.4, 48.8, 44.1, 31.2. HRMS (ESI): m/z calcd for C31H27BrN2O [M + Na]+, [M + 2 + Na]+: 521.1229, 523.1213; found: 521.1226, 523.1216.

  
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Scheme 1 Catalytic enantioselective synthesis of 4-amino-1,2,3,4-tetrahydropyridine derivatives from tertiary enamides. a Reflux in CCl4. b Room temperature in CCl4.
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Scheme 2 Synthesis of (S)-5 from 4ac through deprotection of DMPM group
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Scheme 3 Synthesis of (R)-5 from authentic sample (S)-6