CC BY-ND-NC 4.0 · Synlett 2019; 30(04): 488-492
DOI: 10.1055/s-0037-1611642
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Copyright with the author

Direct Catalytic Asymmetric Mannich-Type Reaction of an α-CF3 Amide to Isatin Imines

Jin-Sheng Yu
,
Hidetoshi Noda
,
Naoya Kumagai*
,
This work was financially supported by the ACT-C program (JPMJCR12YO) from JST and KAKENHI (17H03025, JP18K14878, and 18H04276 in Precisely Designed Catalysts with Customized Scaffolding) from JSPS and MEXT. J.-S.Y. was supported by a JSPS International Research Fellowship.
Further Information

Publication History

Received: 31 October 2018

Accepted after revision: 03 December 2018

Publication Date:
18 December 2018 (eFirst)

 

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

Abstract

An α-CF3 amide underwent direct asymmetric Mannich-type reaction to isatin imines in the presence of a chiral catalyst comprising a soft Lewis acid Cu(I), a chiral bisphosphine ligand, and Barton’s base. The Mannich adduct was converted in one step into a unique tricycle bearing a trifluoromethylated chiral center and an α-tertiary amine moiety.


#

Organofluorine compounds generally exhibit distinctive chemical properties compared to their corresponding nonfluorinated analogues owing to the strong C–F bond and high electronegativity of fluorine.[1] The altered attributes are often beneficial for medicinal and agrochemical applications.[2] Therefore, the incorporation of fluorine and perfluoroalkyl groups such as CF3 into organic molecules has been a topic of the intensive research.[3] In addition to fluorinated aromatics, recent effort has also been dedicated to the preparation of fluorine-containing aliphatic compounds in enantioenriched form.[4] Two strategies exist for this purpose: fluorination/fluoroalkylation and building block approaches. Given the broad utility of enolate-based chemical transformations, α-CF3 enolates would seem one of the most ideal building blocks for the construction of a trifluoromethylated stereogenic carbon. Nevertheless, only limited chemistry has been explored with this class of nucleo­philes due to their notorious instability associated with the high aptitude for β-fluoride elimination from the corresponding metal enolates (Scheme [1, a]).[5] [6]

Zoom Image
Scheme 1 (a) Known decomposition pathway for α-CF3 metal enolates. (b) Our chelated amide strategy.

As a part of our research program in direct enolization chemistry,[7] we have recently devised a chelated enolate strategy to tame otherwise unstable α-CF3 metal enolates (Scheme [1, b]).[8] The designed pronucleophile[9] contains a 7-azaindoline amide as a bidentate chelating unit that prevents unfavorable metal–fluorine interactions. The thus generated α-CF3 enolate has proven effective in the construction of CF3-containing stereogenic carbons in a wide range of Cu(I)-catalyzed asymmetric transformations.[10] The applications have, however, been limited to the construction of trisubstituted stereocenters at the β-position of the amide carbonyl group.[11] [12] Facile Mannich addition of the α-CF3 amide to Boc-aldimines[8] prompted us to examine activated ketimines as potential reaction partners. Herein, we report the successful implementation of this strategy for the preparation of tetrasubstituted carbons by means of a direct catalytic asymmetric Mannich-type reaction to isatin imines. [13]

Our experience with 7-azaindoline amides has established a combined soft Lewis acid/Brønsted base system comprising Cu(I)/chiral bisphosphine ligand/Barton’s base as a particularly effective catalyst for direct enolization chemistry.[8] [14] A recent systematic study has also found that the Ph-BPE ligand exhibits consistently high catalytic competency for a broad range of α-substituents of the amides including N3, Cl, and alkyl groups, but not fluoroalkyl groups such as CF3; biaryl-type phosphine ligands are preferred for the α-CF3 amide.[15] With these factors in mind, our optimization studies for the Mannich-type reaction of amide 2 to isatin imine 1a commenced with screening various biaryl-type ligands (Table [1]). A quick examination revealed that the desired product was indeed formed in the presence of 5 mol% Cu(I)/chiral biaryl ligand complex, although the enantioselectivities were low to moderate (Table [1], entries 1–4). Hence, we turned our attention to different ligand backbones, and surprisingly, Ph-BPE (L8) was found to perform the best among the ligands evaluated (Table [1], entries 5–8). The catalyst loading was reduced to as little as 1 mol% without sacrificing the reactivity and selectivities (Table [1], entry 9).

Table 1 Optimization Studiesa

Entry

Ligand

x (mol%)

y (mol%)

Yield (%)b

drb

ee (%)c

1

L1

5

5

93

 91:9

–69

2

L2

5

5

70

 60:40

 21

3

L3

5

5

90

 92:8

–49

4

L4

5

5

80

 90:10

–23

5

L5

5

5

59

 89:11

–95

6

L6

5

5

95

 94:6

–70

7d

L7

5

5

88

 88:12

 31

8d

L8

5

5

98

>95:5

 99

9d

L8

1

2

98

>95:5

 99

a Reaction conditions: 1a (0.10 mmol), 2 (0.11 mmol), THF (0.1 M).

b Yield and diastereomeric ratio were determined by 1H NMR analysis of the unpurified reaction mixture using 3,4,5-trichloropyridine as an internal standard.

c Enantiomeric excess of (S,S)-isomer was determined with normal-phase HPLC on a chiral support.

d The reaction was performed on a 0.2 mmol scale in THF (0.2 M), and isolated yield was reported.

After the identification of a highly selective ligand for this transformation, a series of isatin imines 1 was evaluated with either 1 mol% or 3 mol% Cu catalyst (Table [2]). The Cbz-protected imine also proved suitable for this catalytic system, affording the corresponding product with almost the same level of selectivities (Table [2], entries 1, 2). Both electron-donating and electron-withdrawing substituents at the 5-position were tolerated (Table [2], entries 3–7). Positional isomers of 3d bearing a chlorine atom at different positions were obtained in comparable diastereo- and enantioselectivities (Table [2], entries 8, 9). Substituents on the oxindole nitrogen other than Me were also examined. While the PMB-protected substrate exhibited slightly lower reactivity and selectivities (Table [2], entry 10), the allyl-protected compound afforded results close to those of the Me-substituted one (Table [2], entry 11). The relative and absolute configurations of 3e were determined by X-ray diffraction, and those of the other compounds were assigned by analogy.[16]

Table 2 Substrate Scope of the Mannich-Type Reaction of α-CF3 Amide 2 a

Entry

R1

R2

PG

Product

Yield (%)b

erc

ee (%)d

 1

H

Me

Boc

3a

98

>95:5

99

 2

H

Me

Cbz

3b

91

>95:5

99

 3

5-F

Me

Boc

3c

86

 94:6

99

 4

5-Cl

Me

Boc

3d

89

 92:8

99

 5

5-Br

Me

Boc

3e

90

>95:5

99

 6

5-Me

Me

Boc

3f

99

>95:5

98

 7

5-MeO

Me

Boc

3g

81

>95:5

99

 8

6-Cl

Me

Boc

3h

86

>95:5

99

 9

7-Cl

Me

Boc

3i

90

>95:5

96

10

H

PMB

Boc

3j

66

 86:14

92

11

H

Allyl

Boc

3k

97

>95:5

97

a Reaction conditions: 1 (0.20 mmol), 2 (0.22 mmol), THF (0.2 M). For entries 1–4, [Cu(CH3CN)]PF6 (1.0 mol%), L8 (1.2 mol%), Barton’s base (2.0 mol%). For entries 5–11, [Cu(CH3CN)]PF6 (3.0 mol%), L8 (3.6 mol%), Barton’s base (3.0 mol%).

b Yield values refer to isolated yield.

c Diastereomer ratio was determined by 1H NMR and 19F NMR analysis of the unpurified reaction mixture.

d Enantiomeric excess of (S,S)-isomer was determined with normal-phase HPLC on a chiral support.

The reaction proceeded smoothly on a 3.0 mmol scale, producing 1.46 g of Mannich adduct 3a with almost perfect stereoselectivities, albeit a slightly higher catalyst loading was necessary for full consumption of the substrates (Scheme [2]).[17] [18] We have previously shown that 7-azaindoline amides can provide an in situ chelating group when treated with an organometallic reagent in a manner similar to Weinreb amides, and thus prevent further sequential addition of the reagent.[8b,9,11b,14b] Mannich adduct 3a was reduced by the action of DIBALH to form a masked aldehyde accompanied by the formation of an aluminum alkoxide derived from reduction of the oxindole moiety, which cyclized presumably during the workup. This triple-bond-forming process (two reductions and one cyclization) furnished highly decorated tricycle 4 in 46% yield with excellent diastereoselectivity.[19]

Zoom Image
Scheme 2 A large scale reaction and the transformation of its product into a tricyclic skeleton.

In summary, we developed the direct catalytic Mannich-type reaction of an α-CF3 amide to isatin imines. Enolization was promoted without decomposition by a proficient soft Lewis acidic Cu(I)/bisphosphine/Barton’s base catalytic system, and the generated enolate underwent a highly stereoselective addition, producing an α-tertiary amine with an adjacent trifluoromethylated stereogenic carbon. The Mannich adduct was smoothly transformed into a tricyclic framework by harnessing a unique property of the 7-azaindoline as a chelating unit in the reduction step.


#

Acknowledgment

We are grateful to Dr. Tomoyuki Kimura for X-ray crystallographic analysis of 3e, Dr. Ryuichi Sawa, Yumiko Kubota, Dr. Kiyoko Iijima, and Yuko Takahashi for NMR and MS analyses.

Supporting Information

  • References and Notes

    • 1a Mikami K, Itoh Y, Yamanaka M. Chem. Rev. 2004; 104: 1
    • 1b O’Hagan D. Chem. Soc. Rev. 2008; 37: 308
    • 1c Hunter L. Beilstein J. Org. Chem. 2010; 6: 38
    • 2a Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
    • 2b Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
    • 2c Fujiwara T, O’Hagan D. J. Fluorine Chem. 2014; 167: 16
    • 2d Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J. Med. Chem. 2015; 58: 8315
    • 2e Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
    • 2f Meanwell NA. J. Med. Chem. 2018; 61: 5822
    • 3a Kirk KL. Org. Process Res. Dev. 2008; 12: 305
    • 3b Tomashenko OA, Grushin VV. Chem. Rev. 2011; 111: 4475
    • 3c Furuya T, Kamlet AS, Ritter T. Nature 2012; 473: 470
    • 3d Campbell MG, Ritter T. Chem. Rev. 2015; 115: 612
    • 3e Champagne PA, Desroches J, Hamel J.-D, Vandamme M, Paquin J.-F. Chem. Rev. 2015; 115: 9073
    • 4a Billard T, Langlois BR. Eur. J. Org. Chem. 2007; 891
    • 4b Cahard D, Xu X, Couve-Bonnaire S, Pannecoucke X. Chem. Soc. Rev. 2010; 39: 558
    • 4c Nie J, Guo H.-C, Cahard D, Ma J.-A. Chem. Rev. 2011; 111: 455
    • 4d Yang X, Wu T, Phipps RJ, Toste FD. Chem. Rev. 2015; 115: 826
    • 4e Noda H, Kumagai N, Shibasaki M. Asian J. Org. Chem. 2018; 7: 599
    • 4f Zhu Y, Han J, Wang J, Shibata N, Sodeoka M, Soloshonok VA, Coelho JA. S, Toste FD. Chem. Rev. 2018; 118: 3887
    • 5a Uneyama K, Katagiri T, Amii H. Acc. Chem. Res. 2008; 41: 817

    • For early contributions, see:
    • 5b Yokozawa T, Nakai T, Ishikawa N. Tetrahedron Lett. 1984; 25: 3987
    • 5c Yokozawa T, Nakai T, Ishikawa N. Tetrahedron Lett. 1984; 25: 3991
    • 5d Yokozawa T, Ishikawa N, Nakai T. Chem. Lett. 1987; 16: 1971

      Aldol reactions:
    • 6a Itoh Y, Yamanaka M, Mikami K. Org. Lett. 2003; 5: 4807
    • 6b Itoh Y, Yamanaka M, Mikami K. J. Am. Chem. Soc. 2004; 126: 13174
    • 6c Franck X, Meniel BS, Figadère B. Angew. Chem. Int. Ed. 2006; 45: 5174
    • 6d Shimada T, Yoshioka M, Konno T, Ishihara T. Org. Lett. 2006; 8: 1129
    • 6e Ramachandran PV, Parthasarathy G, Gagare PD. Org. Lett. 2010; 12: 4474

    • Allylic alkylations:
    • 6f Komatsu Y, Sakamoto T, Kitazume T. J. Org. Chem. 1999; 64: 8369
    • 6g Shibata N, Suzuki S, Furukawa T, Kawai H, Tokunaga E, Yuan Z, Cahard D. Adv. Synth. Catal. 2011; 353: 2037

    • Conjugate additions:
    • 6h Wang Q, Huan F, Shen H, Xiao J.-C, Gao M, Yang X, Murahashi S.-I, Chen Q.-Y, Guo Y. J. Org. Chem. 2013; 78: 12525
    • 6i Foster RW, Lenz EN, Simpkins NS, Stead D. Chem. Eur. J. 2017; 23: 8810

    • α-Sulfenylation:
    • 6j Yuan T, Yin L, Xu Y. Tetrahedron Lett. 2017; 58: 2521
    • 7a Yamada YM. A, Yoshikawa N, Sasai H, Shibasaki M. Angew. Chem., Int. Ed. Engl. 1997; 36: 1871
    • 7b Yoshikawa N, Yamada YM. A, Das J, Sasai H, Shibasaki M. J. Am. Chem. Soc. 1999; 121: 4168
    • 8a Yin L, Brewitz L, Kumagai N, Shibasaki M. J. Am. Chem. Soc. 2014; 136: 17958
    • 8b Brewitz L, Arteaga FA, Yin L, Alagiri K, Kumagai N, Shibasaki M. J. Am. Chem. Soc. 2015; 137: 15929
  • 9 Weidner K, Kumagai N, Shibasaki M. Angew. Chem. Int. Ed. 2014; 53: 6150
    • 10a Saito A, Kumagai N, Shibasaki M. Angew. Chem. Int. Ed. 2017; 56: 5551
    • 10b Sun Z, Sun B, Kumagai N, Shibasaki M. Org. Lett. 2018; 20: 3070

      In Cu(I)-catalyzed aldol reactions, the reactivity of the α-CF3 enolate is somewhat lower than those with other substituents: While α-alkyl, vinyl, and N3 7-azaindoline amides smoothly undergo aldol additions to simple aldehydes, α-CF3 amide 2 only reacts with activated arylglyoxal hydrates.
    • 11a Weidner K, Sun Z, Kumagai N, Shibasaki M. Angew. Chem. Int. Ed. 2015; 54: 6236
    • 11b Liu Z, Takeuchi T, Pluta R, Arteaga FA, Kumagai N, Shibasaki M. Org. Lett. 2017; 19: 710
    • 11c Takeuchi T, Kumagai N, Shibasaki M. J. Org. Chem. 2018; 83: 5851
    • 11d Matsuzawa A, Noda H, Kumagai N, Shibasaki M. J. Org. Chem. 2017; 82: 8304
  • 12 For the construction of a tetrasubstituted carbon by aldol reaction of an α-N3 amide to CF3 ketones, see: Noda H, Amemiya F, Weidner K, Kumagai N, Shibasaki M. Chem. Sci. 2017; 8: 3260

    • For recent reviews on the use of isatin imines in asymmetric catalysis, see:
    • 13a Pellissier H. Beilstein J. Org. Chem. 2018; 14: 1349
    • 13b Kaur J, Chimni SS. Org. Biomol. Chem. 2018; 16: 3328
    • 14a Sun Z, Weidner K, Kumagai N, Shibasaki M. Chem. Eur. J. 2015; 21: 17574
    • 14b Arteaga FA, Liu Z, Brewitz L, Chen J, Sun B, Kumagai N, Shibasaki M. Org. Lett. 2016; 18: 2391
  • 15 Li Z, Noda H, Kumagai N, Shibasaki M. Tetrahedron 2018; 74: 3301
  • 16 See the Supporting Information for details. CCDC 1874483 contains the supplementary crystallographic data for 3e. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 17 With 1 mol% catalyst, 3a was obtained in 55% yield with the high selectivities retained (dr >95:5, 98% ee).
  • 18 Compound 3a A flame-dried 30 mL flask equipped with a magnetic stirring bar and 3-way glass stopcock were charged with imine 1a (781 mg, 3.0 mmol, 1.0 equiv), and α-CF3 amide 2 (760 mg, 3.3 mmol, 1.1 equiv), followed by the addition of anhydrous THF (9.6 mL, 0.2 M) via syringe with a stainless steel needle under an Ar atmosphere. After being stirred at 25 °C for 5 min, a solution of the catalyst in THF (4.5 mL) containing a chiral copper(I) complex (0.090 mmol, 3.0 mol%), which was prepared from [Cu(CH3CN)4]PF6 (33.5 mg, 0.090 mmol) and (R,R)-Ph-BPE L8 (54.7 mg, 0.11 mmol, 3.6 mol%), and a solution of Barton’s base (0.1 M in THF, 0.90 mL, 0.09 mmol, 3.0 mol%) were sequentially added via a syringe with a stainless steel needle. After stirring at 25 °C for 12 h, the reaction mixture was filtered through a pad of silica gel and washed with EtOAc, then concentrated in vacuo to afford the crude residue. 1H NMR analysis of the crude residue showed that the dr was >95:5. The combined crude residue was then purified by silica gel column chromatography (5% to 80% EtOAc in hexane) to afford product 3a (1.46 g, 99% yield). IR (thin film): ν = 3371, 2943, 1721, 1653, 1426, 1256, 1164, 754 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.93–7.92 (m, 1 H), 7.51–7.49 (m, 1 H), 7.44 (d, J = 7.2 Hz, 1 H), 7.35–7.31 (m, 1 H), 7.08–7.04 (m, 2 H), 6.91 (dd, J = 7.6 Hz, 5.2 Hz, 1 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.31 (q, J = 8.8 Hz, 1 H), 4.31–4.10 (m, 2 H), 3.15–2.99 (m, 2 H), 2.96 (s, 3 H), 1.20 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 174.6, 163.4, 154.8, 153.8, 145.2, 143.2, 134.3, 129.3, 127.2, 126.8, 125.4 (d, J = 2.5 Hz), 124.3 (q, J = 281.1 Hz), 122.2, 119.0, 108.1, 80.0, 61.2, 48.9 (q, J = 26.1 Hz), 46.0, 27.9, 26.1, 23.7. 19F NMR (376 MHz, CDCl3): δ = –57.98 (d, J = 8.5 Hz). HRMS (ESI): m/z calcd for C24H25O4N4F3Na [M + Na]+: 513.1720; found: 513.1724. [α]D 24 –48.0 (c = 1.00, CHCl3). Enantiomeric excess of the product was determined to be 98% by chiral stationary phase HPLC analysis (CHIRALPAK AD-H (φ 0.46 cm × 25 cm), 2-propanol/n-hexane = 1:4, flow rate 1.0 mL/min, detection at 254 nm, t R = 5.9 min (major), 13.2 min (minor)).
  • 19 The stereochemistry of 4 was assigned by NOE analysis. See the Supporting Information for details.

  • References and Notes

    • 1a Mikami K, Itoh Y, Yamanaka M. Chem. Rev. 2004; 104: 1
    • 1b O’Hagan D. Chem. Soc. Rev. 2008; 37: 308
    • 1c Hunter L. Beilstein J. Org. Chem. 2010; 6: 38
    • 2a Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
    • 2b Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
    • 2c Fujiwara T, O’Hagan D. J. Fluorine Chem. 2014; 167: 16
    • 2d Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J. Med. Chem. 2015; 58: 8315
    • 2e Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
    • 2f Meanwell NA. J. Med. Chem. 2018; 61: 5822
    • 3a Kirk KL. Org. Process Res. Dev. 2008; 12: 305
    • 3b Tomashenko OA, Grushin VV. Chem. Rev. 2011; 111: 4475
    • 3c Furuya T, Kamlet AS, Ritter T. Nature 2012; 473: 470
    • 3d Campbell MG, Ritter T. Chem. Rev. 2015; 115: 612
    • 3e Champagne PA, Desroches J, Hamel J.-D, Vandamme M, Paquin J.-F. Chem. Rev. 2015; 115: 9073
    • 4a Billard T, Langlois BR. Eur. J. Org. Chem. 2007; 891
    • 4b Cahard D, Xu X, Couve-Bonnaire S, Pannecoucke X. Chem. Soc. Rev. 2010; 39: 558
    • 4c Nie J, Guo H.-C, Cahard D, Ma J.-A. Chem. Rev. 2011; 111: 455
    • 4d Yang X, Wu T, Phipps RJ, Toste FD. Chem. Rev. 2015; 115: 826
    • 4e Noda H, Kumagai N, Shibasaki M. Asian J. Org. Chem. 2018; 7: 599
    • 4f Zhu Y, Han J, Wang J, Shibata N, Sodeoka M, Soloshonok VA, Coelho JA. S, Toste FD. Chem. Rev. 2018; 118: 3887
    • 5a Uneyama K, Katagiri T, Amii H. Acc. Chem. Res. 2008; 41: 817

    • For early contributions, see:
    • 5b Yokozawa T, Nakai T, Ishikawa N. Tetrahedron Lett. 1984; 25: 3987
    • 5c Yokozawa T, Nakai T, Ishikawa N. Tetrahedron Lett. 1984; 25: 3991
    • 5d Yokozawa T, Ishikawa N, Nakai T. Chem. Lett. 1987; 16: 1971

      Aldol reactions:
    • 6a Itoh Y, Yamanaka M, Mikami K. Org. Lett. 2003; 5: 4807
    • 6b Itoh Y, Yamanaka M, Mikami K. J. Am. Chem. Soc. 2004; 126: 13174
    • 6c Franck X, Meniel BS, Figadère B. Angew. Chem. Int. Ed. 2006; 45: 5174
    • 6d Shimada T, Yoshioka M, Konno T, Ishihara T. Org. Lett. 2006; 8: 1129
    • 6e Ramachandran PV, Parthasarathy G, Gagare PD. Org. Lett. 2010; 12: 4474

    • Allylic alkylations:
    • 6f Komatsu Y, Sakamoto T, Kitazume T. J. Org. Chem. 1999; 64: 8369
    • 6g Shibata N, Suzuki S, Furukawa T, Kawai H, Tokunaga E, Yuan Z, Cahard D. Adv. Synth. Catal. 2011; 353: 2037

    • Conjugate additions:
    • 6h Wang Q, Huan F, Shen H, Xiao J.-C, Gao M, Yang X, Murahashi S.-I, Chen Q.-Y, Guo Y. J. Org. Chem. 2013; 78: 12525
    • 6i Foster RW, Lenz EN, Simpkins NS, Stead D. Chem. Eur. J. 2017; 23: 8810

    • α-Sulfenylation:
    • 6j Yuan T, Yin L, Xu Y. Tetrahedron Lett. 2017; 58: 2521
    • 7a Yamada YM. A, Yoshikawa N, Sasai H, Shibasaki M. Angew. Chem., Int. Ed. Engl. 1997; 36: 1871
    • 7b Yoshikawa N, Yamada YM. A, Das J, Sasai H, Shibasaki M. J. Am. Chem. Soc. 1999; 121: 4168
    • 8a Yin L, Brewitz L, Kumagai N, Shibasaki M. J. Am. Chem. Soc. 2014; 136: 17958
    • 8b Brewitz L, Arteaga FA, Yin L, Alagiri K, Kumagai N, Shibasaki M. J. Am. Chem. Soc. 2015; 137: 15929
  • 9 Weidner K, Kumagai N, Shibasaki M. Angew. Chem. Int. Ed. 2014; 53: 6150
    • 10a Saito A, Kumagai N, Shibasaki M. Angew. Chem. Int. Ed. 2017; 56: 5551
    • 10b Sun Z, Sun B, Kumagai N, Shibasaki M. Org. Lett. 2018; 20: 3070

      In Cu(I)-catalyzed aldol reactions, the reactivity of the α-CF3 enolate is somewhat lower than those with other substituents: While α-alkyl, vinyl, and N3 7-azaindoline amides smoothly undergo aldol additions to simple aldehydes, α-CF3 amide 2 only reacts with activated arylglyoxal hydrates.
    • 11a Weidner K, Sun Z, Kumagai N, Shibasaki M. Angew. Chem. Int. Ed. 2015; 54: 6236
    • 11b Liu Z, Takeuchi T, Pluta R, Arteaga FA, Kumagai N, Shibasaki M. Org. Lett. 2017; 19: 710
    • 11c Takeuchi T, Kumagai N, Shibasaki M. J. Org. Chem. 2018; 83: 5851
    • 11d Matsuzawa A, Noda H, Kumagai N, Shibasaki M. J. Org. Chem. 2017; 82: 8304
  • 12 For the construction of a tetrasubstituted carbon by aldol reaction of an α-N3 amide to CF3 ketones, see: Noda H, Amemiya F, Weidner K, Kumagai N, Shibasaki M. Chem. Sci. 2017; 8: 3260

    • For recent reviews on the use of isatin imines in asymmetric catalysis, see:
    • 13a Pellissier H. Beilstein J. Org. Chem. 2018; 14: 1349
    • 13b Kaur J, Chimni SS. Org. Biomol. Chem. 2018; 16: 3328
    • 14a Sun Z, Weidner K, Kumagai N, Shibasaki M. Chem. Eur. J. 2015; 21: 17574
    • 14b Arteaga FA, Liu Z, Brewitz L, Chen J, Sun B, Kumagai N, Shibasaki M. Org. Lett. 2016; 18: 2391
  • 15 Li Z, Noda H, Kumagai N, Shibasaki M. Tetrahedron 2018; 74: 3301
  • 16 See the Supporting Information for details. CCDC 1874483 contains the supplementary crystallographic data for 3e. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 17 With 1 mol% catalyst, 3a was obtained in 55% yield with the high selectivities retained (dr >95:5, 98% ee).
  • 18 Compound 3a A flame-dried 30 mL flask equipped with a magnetic stirring bar and 3-way glass stopcock were charged with imine 1a (781 mg, 3.0 mmol, 1.0 equiv), and α-CF3 amide 2 (760 mg, 3.3 mmol, 1.1 equiv), followed by the addition of anhydrous THF (9.6 mL, 0.2 M) via syringe with a stainless steel needle under an Ar atmosphere. After being stirred at 25 °C for 5 min, a solution of the catalyst in THF (4.5 mL) containing a chiral copper(I) complex (0.090 mmol, 3.0 mol%), which was prepared from [Cu(CH3CN)4]PF6 (33.5 mg, 0.090 mmol) and (R,R)-Ph-BPE L8 (54.7 mg, 0.11 mmol, 3.6 mol%), and a solution of Barton’s base (0.1 M in THF, 0.90 mL, 0.09 mmol, 3.0 mol%) were sequentially added via a syringe with a stainless steel needle. After stirring at 25 °C for 12 h, the reaction mixture was filtered through a pad of silica gel and washed with EtOAc, then concentrated in vacuo to afford the crude residue. 1H NMR analysis of the crude residue showed that the dr was >95:5. The combined crude residue was then purified by silica gel column chromatography (5% to 80% EtOAc in hexane) to afford product 3a (1.46 g, 99% yield). IR (thin film): ν = 3371, 2943, 1721, 1653, 1426, 1256, 1164, 754 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.93–7.92 (m, 1 H), 7.51–7.49 (m, 1 H), 7.44 (d, J = 7.2 Hz, 1 H), 7.35–7.31 (m, 1 H), 7.08–7.04 (m, 2 H), 6.91 (dd, J = 7.6 Hz, 5.2 Hz, 1 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.31 (q, J = 8.8 Hz, 1 H), 4.31–4.10 (m, 2 H), 3.15–2.99 (m, 2 H), 2.96 (s, 3 H), 1.20 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 174.6, 163.4, 154.8, 153.8, 145.2, 143.2, 134.3, 129.3, 127.2, 126.8, 125.4 (d, J = 2.5 Hz), 124.3 (q, J = 281.1 Hz), 122.2, 119.0, 108.1, 80.0, 61.2, 48.9 (q, J = 26.1 Hz), 46.0, 27.9, 26.1, 23.7. 19F NMR (376 MHz, CDCl3): δ = –57.98 (d, J = 8.5 Hz). HRMS (ESI): m/z calcd for C24H25O4N4F3Na [M + Na]+: 513.1720; found: 513.1724. [α]D 24 –48.0 (c = 1.00, CHCl3). Enantiomeric excess of the product was determined to be 98% by chiral stationary phase HPLC analysis (CHIRALPAK AD-H (φ 0.46 cm × 25 cm), 2-propanol/n-hexane = 1:4, flow rate 1.0 mL/min, detection at 254 nm, t R = 5.9 min (major), 13.2 min (minor)).
  • 19 The stereochemistry of 4 was assigned by NOE analysis. See the Supporting Information for details.

  
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Scheme 1 (a) Known decomposition pathway for α-CF3 metal enolates. (b) Our chelated amide strategy.
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Scheme 2 A large scale reaction and the transformation of its product into a tricyclic skeleton.