Letter Cite This: Org. Lett. 2018, 20, 4811−4814
pubs.acs.org/OrgLett
Dynamic Kinetic Resolution of Azlactones by a Chiral N,N‑Dimethyl4-aminopyridine Derivative Containing a 1,1′-Binaphthyl Unit: Importance of Amide Groups Hiroki Mandai,* Kohei Hongo, Takuma Fujiwara, Kazuki Fujii, Koichi Mitsudo, and Seiji Suga* Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan Org. Lett. 2018.20:4811-4814. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 08/17/18. For personal use only.
S Supporting Information *
ABSTRACT: A dynamic kinetic resolution (DKR) of azlactones in the presence of benzoic acid and a binaphthyl-based N,N-4dimethylaminopyridine (DMAP) derivative 1i having two amide groups at the 3,3′-positions of a binaphthyl unit is developed. The reaction proceeded smoothly with a wide range of azlactones to provide α-amino acid derivatives with good to high enantiomeric ratios (er’s). A multigram-scale reaction (2.5 g) for the DKR of azlactone 2d was also demonstrated, and the resulting product was converted to unnatural α-amino acid 6d′. rearrangement,4 the kinetic resolution of benzylic carbinols5 and d,l-1,2-diols,6 and the desymmetrization of meso-1,2-diols7 (Figure 1b−d). According to various control experiments and DFT calculations, tert-alcohol units [-C(OH)Ar2] were responsible for the high catalytic activity and enantioselectivity as a result of hydrogen bonding interaction between the reaction substrate and tert-alcohol unit(s) of the catalyst.4 These enantioselective acyl transfer reactions developed by our group required only an achiral acylating agent (e.g., (iPrCO)2O) with a prochiral or racemic nucleophile, while the reactions of a racemic acylating agent (not an achiral variant) and an achiral nucleophile have not been examined. To further explore the utility of binaphthyl-based chiral DMAP derivatives in enantioselective transformations, we sought to elucidate their roles in different modes of the reaction (i.e., other than the enantioselective acylation of alcohol). We thought that the dynamic kinetic resolution (DKR) of azlactones, which gives an α-amino acid derivative, is a benchmark reaction for evaluating the catalyst capability. With regard to such transformations, several organocatalytic approaches to the DKR of azlactones have been reported (using a planar chiral DMAP derivative,8 benzotetramisole,9 urea-based bifunctional catalysts,10,11 chiral phosphoric acid,12 a peptide catalyst,13 and a chiral bisguanidinium salt catalyst14), but some of the reported methods resulted in only moderate enantioselectivity (24 h). Thus, there is still room for improvement regarding increased enantioselectivity (>95:5 er) and reduced catalyst loading (98 >98 >98 77 >98 >98 >98 90 28
72:28 82:18 82:18 94:6 83:17 72.5:27.5 70:30 75:25 82:18
a
Reactions were performed on a 0.1 mmol scale in toluene (0.2 M) under an argon atmosphere. bConversion was determined by 1H NMR analysis based on consumption of the starting material. c Enantioselectivities were determined by HPLC analysis.
accelerate the DKR of 2a. Furthermore, the use of a bulkier αbranched alcohol, benzhydryl alcohol, resulted in significant decreases in conversion and enantioselectivity (28% conv., 82.5:17.5 er, entry 9). Accordingly, we selected isopropyl alcohol as the optimal nucleophile in terms of high enantioselectivity of desired product 6a. Next, we screened various solvents for the DKR of 2a with 1i at 25 °C for 15 h (Table 2). The reactions in common organic Table 2. Screening of Solvent in the DKR of 2aa
entry d
1 2 3 4 5 6 7
Figure 2. Initial screening of catalyst for the DKR of azlactone 2a.
with 3 mol % of catalysts 1a−d, which have alkyl ethers or ethyl esters at the 3,3′-positions of the binaphthyl unit, led to a nearly racemic mixture of 3a (up to 53:47 er), and those with 1e−h, which have tert-alcohol units,16 resulted in a slight improvement in the enantioselectivity of 3a (up to 39:61 er). On the other hand, catalysts 1i−l having amide groups afforded 3a with moderate enantioselectivity (up to 72:28 er). Based on these results, 1i was selected as an optimal catalyst for further optimization of the reaction conditions. To verify the effect of the nucleophile on the DKR of 2a, reactions with various alcohols were carried out in the presence of 3 mol % of 1i at 25 °C for 15 h (Table 1). Although most of the tested alcohols showed >98% conversion (conv.) with moderate enantioselectivities of the products (entries 1−3 and 5−8), isopropyl alcohol (α-branched alcohol) gave the highest enantioselectivity (entry 4, 77% conv., 94:6 er). Although isopropyl alcohol is a less reactive nucleophile in the DKR of azlactones (48 h),8−11 it is worth noting that the amide catalyst 1i showed excellent catalytic activity (3 mol % of 1i and reaction time of 99:1 er). Deprotection of the resulting product 6d was successively achieved by treatment of
high enantioselectivity according to our previous studies.4−7 After taking into account these results and extensive screening of the reaction conditions (reaction temperature, concentration of substrate, acid additive, equivalents of nucleophile, and catalyst 4813
DOI: 10.1021/acs.orglett.8b01960 Org. Lett. 2018, 20, 4811−4814
Letter
Organic Letters HBr aq in refluxed acetic acid to give the desired unnatural αamino acid salt 6d′ in 43% yield without a decrease in the enantiomeric ratio. To gain further insight into the high catalytic activity of 1i having two amide units, we conducted additional control experiments using other pyridine-based nucleophilic catalysts (Figure 3). DKR of 2a with C1-symmetric catalyst 1m (lack of
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Experimental procedures and copies of 1H and 13C NMR spectra for substrates and products (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Hiroki Mandai: 0000-0001-9121-3850 Koichi Mitsudo: 0000-0002-6744-7136 Seiji Suga: 0000-0003-0635-2077 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was partially supported by a Grant-in-Aid for Young Scientists (B) (17K17903) from JSPS, a Grant-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts,” and the JGC-S Scholarship Foundation.
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Figure 3. Effects of amide group(s) of the catalyst in the DKR of 2a.
one amide group) gave 6a in 78% conv. with 91.5:8.5 er. The yield and enantioselectivity of 6a were somewhat lower than those from 1i (an optimal catalyst) having two amide groups (87% conv., 94:6 er). The reaction with catalyst 1n without amide groups at the 3,3′-positions of the binaphthyl unit resulted in 51% conv. with 45.5:54.5 er, and the catalytic activity of 1n was almost identical to that of DMAP (51% conv. vs 56% conv.). Although at least one amide group is required for enantioselective transformation, two amide groups play important roles in acceleration of the rate of the reaction and achieving high enantioselectivity. In conclusion, we have developed a dynamic kinetic resolution of azlactones using a binaphthyl-based DMAP derivative 1i having two amide groups. As little as 3 mol % of the catalyst facilitates the reactions within a relatively short reaction time (
