SEARCH

SEARCH BY CITATION

Keywords:

  • asymmetric synthesis;
  • diastereoselectivity;
  • enantioselectivity;
  • Michael addition;
  • phase-transfer catalysis

Conjugate addition of glycine-derived imine esters (1) to Michael acceptors can generate highly functionalized molecules with up to three contiguous stereogenic centers (Scheme 1), which is an attractive strategy for assembling molecular complexity from achiral precursors in a single step without byproducts.1

thumbnail image

Scheme 1. Conjugate addition of glycine imine esters (1) to α,β-unsaturated carbonyl compounds.

Download figure to PowerPoint

Presently, nonmetal-based phase-transfer catalysts (PTCs) and organocatalysts2 have been deployed to great effect for these reactions.3 Corey et al. first reported the conjugate addition of 1 to acrylates and enones with notable enantioselectivity (>90 % ee) in the presence of an N-alkylated cinchonidine salt.4 Subsequently, the scope of the reaction was expanded with other modified cinchona alkaloids5 as well as new catalysts, comprising largely of quaternary bis(ammonium) and N-spiro ammonium moieties derived from tartrates,6 axially-chiral 1,1′-biaryl units,5f, 7 inositol-derived crown ethers,8 and a calix[4]arene amino acid.9 The use of these pH-neutral catalysts requires strong bases to generate the nucleophile, thus very low temperatures (typically −40 to −78 °C) were necessary to suppress competitive reactions.

In contrast, deployment of catalysts containing planar nitrogen entities received far less attention. In 2001, Ishikawa et al. showed that the modified guanidine derivative 2 (Figure 1) can be employed as a chiral Brønsted superbase for Michael reactions.10 The basicity of the catalyst allowed reactions to proceed under ambient conditions in good enantioselectivities, but reactions were sluggish. They required days to complete even without using any solvents, which may account for the lack of development of this type of catalyst in the ensuing decade. However, two recent breakthroughs have rekindled interest in this area, with independent reports of the pentanidium derivative 311 and cyclopropenimine 412 (Figure 1), which can deliver very favorable catalytic turnovers and enantioselectivities between room temperature and −20 °C.

thumbnail image

Figure 1. Effective catalysts containing planar nitrogen atoms for asymmetric Michael reactions.

Download figure to PowerPoint

Herein, we describe the preparation of a family of structurally novel 2-oxopyrimidinium salts (5), and their performance as asymmetric PTCs in the conjugate addition of the glycine imine ester 1 a (R1=tBu) to vinyl ketone and chalcone derivatives.

The structure of 5 is derived from chiral methylene-bridged bis(imidazolines) (MBI), previously reported by Pfaltz and co-workers as a variant of bisoxazoline ligands for asymmetric catalysis.13 The C2-symmetrical architecture was assembled in five steps from the N-Boc-protected amino acids 6 ac (Scheme 2): the MBIs 10 aj were prepared by a modified literature procedure, and subsequently treated with triphosgene to afford the 2-oxo-pyrimidinium salts 5. Single-crystal X-ray diffraction analysis of the n-butyl-substituted derivative 5 b (Figure 2) revealed planar fused rings, corroborating a highly mesomeric tricyclic system.

thumbnail image

Figure 2. Structure of (R,R)-5 b as determined by single-crystal X-ray crystallography (nonstereogenic hydrogen atoms omitted).17

Download figure to PowerPoint

thumbnail image

Scheme 2. Synthesis of chiral 2-oxopyrimidinium salts (5) from the N-Boc amino acids 6 ac: a) N-methylmorpholine, ClCO2iBu, R′NH2 (74–96 %). b) AcCl, MeOH, 0 °C[RIGHTWARDS ARROW]RT. c) LiAlH4, THF, reflux (73–98 % over 2 steps). d) CH2(C(=NH)OEt)22 HCl (9), CH2Cl2, RT[RIGHTWARDS ARROW]reflux, (65–100 %). e) 10 % aq. NaOH/CH2Cl2. f) triphosgene, CH2Cl2, NEt3, 0 °C[RIGHTWARDS ARROW]RT (84–93 % over 2 steps). Boc=tert-butoxycarbonyl.

Download figure to PowerPoint

The addition of the tert-butyl ester glycinate benzophenone Schiff base (1 a; Table 1) to MVK (11 a) in the presence of 5 a was chosen for reaction optimization, including extensive screening of solvent, dilution, inorganic base, catalyst loading, and stoichiometry (see Tables S1–S6, in the Supporting Information). Under phase-transfer conditions, the solvent exerts an important effect. When using Cs2CO3 as a base at a 5 mol % catalyst loading, the reaction was complete within an hour at ambient temperature in toluene or xylene, furnishing the Michael adduct 12 a with greater than 80 % ee (Table 1, entries 1 and 2). In comparison, the use of dichloromethane was detrimental for both productivity and enantiodiscrimination (entry 3).

Table 1. Conjugate addition of tert-butyl glycinate benzophenone Schiff base (1 a) to MVK (11 a).[a] inline image
EntryCatalyst[b] (mol %)SolventT [°C]t [min]Yield [%][c]ee [%][d]
  1. [a] Reactions were performed using 1 a (0.05 mmol), 11 a (0.1 mmol), and Cs2CO3 (0.075 mmol) in 0.5 mL of solvent. [b] Catalyst loading is indicated within parentheses. [c] Yield of the isolated product after purification by column chromatography. Reactions were complete (TLC), unless otherwise indicated. [d] Determined by HPLC using a chiral stationary phase. Absolute configuration assigned by comparison with literature data. [e] 97 % conversion (1H NMR spectroscopy).

15 a (5)tolueneRT658281 (S)
25 a (5)o-xyleneRT457882 (S)
35 a (5)CH2Cl2RT120852 (S)
45 b (5)tolueneRT658884 (S)
55 c (5)tolueneRT658588 (S)
65 d (5)tolueneRT658424 (R)
75 e (5)tolueneRT65876 (S)
85 f (5)tolueneRT358279 (S)
95 g (5)tolueneRT458735 (R)
105 h (5)tolueneRT458632 (R)
115 i (5)tolueneRT658016 (S)
125 j (5)tolueneRT459048 (R)
135 c (2)toluene03008593 (S)
145 c (2)toluene−20144076[e]93 (S)
155 c (2)o-xylene03007993 (S)

As might be expected, variations in the structure of the catalyst have a profound effect on the reaction outcome. Extending the N-alkyl chain (from methyl to n-butyl and neopentyl) led to an increase in the product ee value to 88 % (Table 1, entries 4 and 5), whereas the substitution with phenyl and bulky tert-butyl groups has the opposite effect (entries 6 and 7). The level of enantioselectivity was restored with the N-benzyl derivative 5 f, which also afforded a faster reaction (entry 8). In contrast, attempts to replace the phenyl substituents on the stereogenic centers of the catalyst with isopropyl (entries 9–11) or benzyl (entry 12) groups did not lead to any improvement. Concurrently, the study also revealed a highly synergistic relationship between the N and C substituents in determining the stereochemical outcome. For catalysts containing phenyl substituents at the stereogenic centers, the selectivity for the S isomer can be overturned by changing the N-alkyl substituent to a phenyl group (Table 1, entry 6 versus entries 1, 4, 5, 7, and 8). The same effect was also observed for the isopropyl-substituted series (entry 11 versus entries 9 and 10).

Eventually, the best yield and ee value were attained with 2 mol % of 5 c within 2 hours at 0 °C in toluene or o-xylene (Table 1, entries 13 and 15). Additional lowering of temperature led only to a slower reaction with no detectable improvement in the product ee value (entry 14). With these optimized reaction conditions in hand, five additional vinyl ketone substrates (11 bf) were evaluated (Table 2). In all cases, the product can be obtained with good to excellent yields and enantioselectivities, which compare favorably with previously reported systems.

Table 2. Addition of 1 a to vinyl ketones catalyzed by 5 c.[a] inline image
EntryRProductt [h]Yield [%][b]ee [%][c]
  1. [a] Reactions were performed using 1 a (0.05 mmol), 11 (0.1 mmol), 5 c (1 μmol), and Cs2CO3 (0.075 mmol) in toluene (0.5 mL) at 0 °C. [b] Yield of the isolated product after purification by column chromatography. [c] Determined by HPLC using a chiral stationary phase. Absolute stereochemistry established by comparison with literature data.

1Me12 a58593
2Et12 b109290
3nPr12 c39592
4CH2CH2Ph12 d29485
5Ph12 e128280
62-naphthyl12 f247683

Chalcone derivatives are a particularly challenging class of Michael acceptors. To date, only two catalysts have been reported to have broad generality for these substrates: a dimeric binol-derived (binol=2,2′-dihydroxy-1,1′-binaphthyl) N-spiroammonium salt (≤96 % de, 93 % ee),7e and the pentanidium derivative 3 (100 % de, ≤94 % ee).11a Hence, we were delighted to find that 5 c is not only catalytically active, but furnishes the Michael adducts as single diastereoisomers with excellent yields and enantioselectivities (Table 3) under adjusted reaction conditions (see Table S7 in the Supporting Information). In terms of reaction scope, a variety of aryls and heteroaryls can be accommodated within the Michael acceptor. Reactions catalyzed by the 2-oxopyrimidinium salt 5 c appeared to be faster than those mediated by the pentanidium catalyst 3. Under practically identical reaction conditions, reactions were complete within 6 hours, compared to the 10 or more hours provided in the earlier report.

Table 3. Conjugate addition of 1 a to chalcone derivatives 13.[a] inline image
EntryArR1Productt [h]Yield [%][b]ee [%][c]
  1. [a] Reactions were performed using 1 a (0.05 mmol), 13 (0.051 mmol), 5 c (1 μmol) and Cs2CO3 (0.25 mmol) in mesitylene (0.5 mL) at −20 °C for the indicated time. [b] Yield of the isolated product after purification by column chromatography. [c] HPLC using a chiral stationary phase. Absolute stereochemistry established by comparison with literature data.

1PhPh14 a39893
24-NO2C6H4Ph14 b29690
34-ClC6H4Ph14 c49491
42-F-5-BrC6H3Ph14 d59493
54-CF3C6H4Ph14 e29291
62-naphthylPh14 f49685
72-pyridylPh14 g39693
83-pyridylPh14 h39893
9Ph4-BrC6H414 i68885
10Ph2-naphthyl14 j69286
11Ph4-ClC6H414 k29087
12Ph2-furyl14 l38790
13Ph2-thienyl14 m29385
14Ph4-CF3C6H414 n29083
15Ph4-pyridyl14 o39688

As the Michael adduct of the methoxy-substituted chalcone 13 p was prone to retro-Michael reaction at ambient temperature, it was subjected to deprotection/cyclization to afford the dihydropyrrole derivative 15 a prior to analysis [Scheme 3, Eq. (1)]. This strategy was employed to achieve an expedient synthesis of a dihydropyrrole derivative on a semipreparative scale [Eq. (2)]. Using a catalytic loading of 0.5 mol %, a telescoped Michael addition/deprotection/cyclization sequence furnished the product 15 b within a reasonable timescale in high yields and enantiopurity, without the need for column chromatography.

thumbnail image

Scheme 3. Synthesis of chiral dihydropyrrole derivatives 15.

Download figure to PowerPoint

The synthetic utility of the methodology was further demonstrated by the preparation of the novel proline/nicotine hybrid molecule (2S,3R,5S)-16,14 containing three well-defined stereogenic centers, in just three steps (Scheme 4). Following the previous procedure, the dihydropyrrole intermediate 15 c was obtained in good yield and selectivity. Reduction of the imine moiety with sodium borohydride furnished (2S,3R,5S)-16 as a single diastereoisomer with excellent optical purity (94 % ee).15

thumbnail image

Scheme 4. Synthesis of the novel nicotine/proline hybrid (2S,3R,5S)-16: a) 1 a, 5 c (2 mol %), mesitylene, −20 °C, 3 h. b) 1 N HCl, THF, 0 °C, 1.5 h. c) NaBH4, MeOH, 0 °C[RIGHTWARDS ARROW]RT, 24 h. THF=tetrahydrofuran.

Download figure to PowerPoint

In conclusion, a new family of 2-oxopyrimidinium salts has been shown to be highly effective catalysts for the asymmetric Michael addition of a glycine imine ester to vinyl ketones and chalcones under synthetically practical conditions. Although these catalysts contain only planar nitrogen moieties (Figure 2), they are entirely devoid of Brønsted basicity.16 Thus, it is tantalizing to suggest that these first-in-class compounds may offer a greater reaction scope, particularly towards substrates with base-labile moieties. Future work will include delineating the mechanism of these reactions, and applications in other asymmetric processes.

Supporting Information

  1. Top of page
  2. Supporting Information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

FilenameFormatSizeDescription
anie_201300614_sm_miscellaneous_information.pdf9724Kmiscellaneous_information

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.