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Carbene-catalyzed activation of cyclopropylcarbaldehydes for mannich reaction and δ-lactam formation: remote enantioselecitvity control and dynamic kinetic asymmetric transformation

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  • ReceivedJan 20, 2021
  • AcceptedMar 22, 2021
  • PublishedMay 18, 2021

Abstract


Funded by

the National Natural Science Foundation of China(21772029,21801051,21961006,22071036,82360589,81360589)

The 10 Talent Plan(Shicengci)

the Guizhou Province Returned Oversea Student Science and Technology Activity Program [(2014)

the Science and Technology Department of Guizhou Province([2018]2802,[2019]1020)

the Program of Introducing Talents of Discipline to Universities of China(111,Program,D20023)

Frontiers Science Center for Asymmetric Synthesis and Medicinal Molecules

Department of Education

Guizhou Province [Qianjiaohe KY(2020)

the Guizhou Province First-Class Disciplines Project [(Yiliu,Xueke,Jianshe,Xiangmu)


Acknowledgment

This work was supported by the National Natural Science Foundation of China (21772029, 21801051, 21961006, 22071036, 82360589, 81360589), The 10 Talent Plan (Shicengci) of Guizhou Province ([2016]5649), the Guizhou Province Returned Oversea Student Science and Technology Activity Program [(2014)-2], the Science and Technology Department of Guizhou Province ([2018]2802, [2019]1020), the Program of Introducing Talents of Discipline to Universities of China (111 Program, D20023) at Guizhou University, Frontiers Science Center for Asymmetric Synthesis and Medicinal Molecules, Department of Education, Guizhou Province [Qianjiaohe KY (2020)004], the Guizhou Province First-Class Disciplines Project [(Yiliu Xueke Jianshe Xiangmu)-GNYL(2017)008], Guizhou University of Traditional Chinese Medicine (China), and Guizhou University.


Interest statement

The authors declare no conflict of interest.


Supplement

Supporting information

The supporting information is available online at http://chem.scichina.com and http://link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.


References

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  • Scheme 1

    Scope of the 1-alkyl-1-cyclopropylcarbaldehydes 1. Reaction conditions as stated in Table 1, entry 6. Yields are isolated yields of 3a+3a1 to 3r+3r1 after purification by column chromatography. dr values of the substrates 1 varied from 3:1 to 12:1, see Supporting Information online for details. er values of 3a to 3r were determined via HPLC on chiral stationary phase. dr values indicate the ratios of 3a:3a1 to 3r:3r1, determined via 1H NMR on the crude reaction mixture. The absolute configurations of the major diastereomers were estimated based on the X-ray analysis on the single crystals of 3a, and the relative configurations of the minor diastereomers were determined based on the X-ray analysis on the single crystals of 3f2, 3a3.

  • Figure 1

    NHC-catalyzed reactions of cyclopropylcarbaldehydes (color online).

  • Scheme 2

    Scope of the cyclic N-sulfonyl α-iminoester substrate 2. Reaction conditions as stated in Table 1, entry 6. Yields are isolated yields of 4a+4a1 to 4n+4n1 after purification by column chromatography. er values of 4a to 4n were determined via HPLC on chiral stationary phase. dr values indicate the ratios of 4a:4a1 to 4n:4n1, which were determined via 1H NMR on the crude reaction mixture.

  • Figure 2

    Control experiments for mechanistic investigations.

  • Figure 3

    Proposed chirality induction process (color online).

  • Figure 4

    Synthetic transformations of 3a.

  • Table 1   Optimization of reaction conditions a)

    Entry

    NHC

    Base

    Solvent

    3a:3a1:3a2:3a3

    Yield (%) b)

    er c)

    1

    A

    Cs2CO3

    THF

    0

    2

    B

    Cs2CO3

    THF

    0

    3

    C

    Cs2CO3

    THF

    4.1:1.0:0.7:0.3

    36

    95:5

    4

    D

    Cs2CO3

    THF

    7.1:1.0:1.1:0.7

    72

    97:3

    5

    E

    Cs2CO3

    THF

    0

    6

    D

    K2CO3

    THF

    8.1:1.0:0.8:0.5

    84

    98:2 d)

    7

    D

    DBU

    THF

    9.6:1.0:1.5:1.0

    72

    98:2

    8

    D

    TEA

    THF

    6.1:1.0:0.9:0.9

    48

    98:2

    9

    D

    K2CO3

    EtOAc

    8.8:1.0:1.7:1.5

    66

    98:2

    10

    D

    K2CO3

    dioxane

    6.5:1.0:0.9:0.9

    70

    98:2

    11

    D

    K2CO3

    CHCl3

    3.0:1.0:0.6:0.6

    43

    97:3

    Unless otherwise specified, the reactions were carried out using 1a(0.125 mmol), 2a (0.1 mmol), NHC (0.02 mmol), base (0.02 mmol), 4 Å MS (50 mg) and tetrahydrofuran (THF, 1.0 mL) at 25 °C for 15 h; b) isolated yield of 3a+3a1; c) the er values of 3a were determined via high performance liquid chromatography (HPLC) on chiral stationary phase; d) the er values of the other diastereomers are: 3a1 (62:38), 3a2 (90:10), and 3a3 (71:29).

  • Table 2   Yields of 3a, 3a1, 3a2, 3a3 after different reaction time a)

    Entry

    Reaction time (h)

    3a (%) b)

    3a1 (%) b)

    3a:3a1

    3a2 (%) c)

    3a3 (%) c)

    1

    15

    74.1

    9.9

    7:1

    7.2

    4.8

    2

    24

    70.9

    9.1

    8:1

    8.8

    6.2

    3

    48

    69.8

    8.2

    9:1

    9.8

    8.2

    4

    72

    68.1

    6.9

    10:1

    12.4

    9.6

    The reactions were carried out using 1a (0.125 mmol), 2a (0.1 mmol), NHC D (0.02 mmol), K2CO3 (0.02 mmol), 4 Å MS (50 mg) and THF (1.0 mL) at 25 °C for certain reaction time; b) yields of 3a and 3a1 were calculated based on the isolated yields of 3a+3a1 and their dr values from 1H NMR; c) yields of 3a2 and 3a3 were calculated based on the isolated yields of 3a2+3a3 and their dr values from 1H NMR.

  • Table 3   Relationships between the dr values of the substrates and the products a)

    dr of 1o

    1:1

    5:1

    9:1

    total yield of 3o+3o1+3o2+3o3 b)

    81%

    87%

    94%

    3o:3o1:3o2:3o3 c)

    66:18:10:6

    72:13:8:6

    72:12:9:7

    yield of 3o d)

    54%

    63%

    68%

    er of 3o e)

    98:2

    98:2

    98:2

    The reactions were carried out using 1o (0.125 mmol), 2a (0.1 mmol), NHC D (0.02 mmol), K2CO3 (0.02 mmol), 4 Å MS (50 mg) and THF (1.0 mL) at 25 °C for 15 h. b) Total yield of 3o, 3o1, 3o2 and 3o3 were calculated based on the isolated yields of 3o+3o1 and 3o2+3o3. c) The values of 3o:3o1:3o2:3o3 were calculated based on the isolated yields of 3o+3o1 and 3o2+3o3 and their dr values from 1H NMR. d) Yields of 3o were calculated based on the isolated yields of 3o+3o1 and their dr values from 1H NMR. e) The er values of 3o were determined via HPLC on chiral stationary phase.

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