Letter pubs.acs.org/OrgLett
Enantioselective Synthesis of α‑Acetal-β′-Amino Ketone Derivatives by Rhodium-Catalyzed Asymmetric Hydrogenation Quentin Llopis,†,‡ Gérard Guillamot,‡ Phannarath Phansavath,*,† and Virginie Ratovelomanana-Vidal*,† †
PSL Research University, Chimie ParisTech-CNRS, Institut de Recherche de Chimie Paris, 11 rue Pierre et Marie Curie, 75005 Paris, France ‡ PCAS, 2-8 rue de Rouen, ZI de Limay-Porcheville, 78440 Porcheville, France S Supporting Information *
ABSTRACT: A range of β-keto-γ-acetal enamides has been synthesized and transformed into the corresponding enantioenriched α-acetal-β′-amino ketones with enantioinductions of up to 99% by using rhodium/QuinoxP*-catalyzed enantioselective hydrogenation under mild conditions. This method also proved to be highly chemoselective toward the reduction of the C−C double bond. Scheme 1. Asymmetric Hydrogenation of β-Keto Enamides
B
ecause of their wide range of applications in the pharmaceutical industry or biomedical research,1 enantiomerically pure β-amino ketones2 are of increasing interest, and numerous syntheses of these compounds have been developed in recent years. Furthermore, postfunctionalization of β-amino ketones can lead to β-amino acids,3 amino alcohols,4 1,3diamines, or γ-aryl amines.5 Hetero-Michael addition reactions catalyzed by Lewis acids,6 Mannich-type reactions,7 and other methods have been reported to access racemic β-amino ketones, whereas the first example of an enantioselective synthesis has been developed by Davis’ group using sulfinimines.8 Transition-metal-catalyzed asymmetric reduction of β-keto enamides would constitute an elegant and efficient method to access these enantiomerically enriched β-amino ketones. However, although the asymmetric hydrogenation of simple enamides is well described,9 only a few examples of asymmetric hydrogenation of β-keto enamides can be found. Zhang and co-workers reported the first rhodium-catalyzed asymmetric hydrogenation of β-keto enamides using DuanPhos10 or ZhangPhos ligands.11 His group also described the synthesis of cyclic chiral β-amino ketones via rutheniumcatalyzed asymmetric hydrogenation.12 (Z)-N-(4-Oxo-4-phenylbut-2-en-2-yl)acetamide was successfully reduced to the corresponding β-amino ketone with excellent enantioselectivities using P-chiral ligands such as QuinoxP*, BenzP*, DioxyBenzP,*13 and MaxPhos.14 In all of these cases, the substrate scope was limited to alkyl-substituted enamides bearing aryl-substituted ketones (Scheme 1, previous work). Following our continued interest in transition-metal-catalyzed asymmetric reduction,15 we herein describe the first highly enantioselective and chemoselective asymmetric hydrogenation of β-keto-γ-acetal enamides (Scheme 1, this work). © 2017 American Chemical Society
For the sake of this study, a range of β-keto-γ-acetal enamides 1a−u were prepared in four steps from chloroximes 2a−u (Scheme 2). A [3 + 2] cycloaddition with bromovinyl acetal 3 in the presence of potassium carbonate provided the corresponding isoxazoles 4a−u.16 The latter were diastereoselectively converted into the (Z)-β-keto-γ-acetal enamines 5a−u by either reductive ring opening with molybdenum hexacarbonyl and water17 or PtO2-catalyzed hydrogenation.18 Internal Scheme 2. Synthesis of β-Keto-γ-Acetal Enamides 1a−u
Received: October 25, 2017 Published: November 20, 2017 6428
DOI: 10.1021/acs.orglett.7b03332 Org. Lett. 2017, 19, 6428−6431
Letter
Organic Letters
Zhang’s ligand, DuanPhos, led to the hydrogenated product with 90% yield and 86% ee (Table 1, entry 13). Finally, Imamoto’s QuinoxP*,21 a rigid P-chiral and air-stable ligand, offered the best result (Table 1, entry 14). In this case, the αacetal-β′-amino ketone 6a was obtained in quantitative yield and with an excellent enantiomeric excess of 96%. The catalyst loading and temperature effect were then investigated (Table 2).
hydrogen bonding between the hydrogen on the nitrogen atom and the oxygen of the carbonyl group probably allowed the preferential formation of the (Z)-enamine. Finally, acetylation of 5a−u led to the desired enamides 1a−u. Subsequently, various conditions for the rhodium-catalyzed hydrogenation of β-keto-γ-acetal enamides were initially tested on 1a as the standard substrate (Table 1). DuPhos ligands gave the Table 1. Ligand Screening for the Asymmetric Hydrogenation of 1aa
Table 2. Optimization of the Reaction Conditions for the Asymmetric Hydrogenationa
entry amt (mol %) product 1 2 3 4 5 6 7 8 9 10 11
10 5 2.5 2 1 2 2 2.5 2 2.5 2
6a 6a 6a 6a 6a 6a 6a 6e 6e 6l 6l
temp (°C)
time (h)
30 30 30 30 30 40 50 30 40 30 40
0.5 6 24 24 24 3 1 24 4 24 6
yield (%)b
83 75 60
36 35
100 100 (84) (76) (63) 100 100 (40) 95 (38) 90
ee (%)c 96 97 96 97 96 95 93 92 92 97 97
a
entry
ligand
time (h)
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14
(R,R)-Me-DuPhos (R,R)-Et-DuPhos (R,R)-i-Pr-DuPhos (R,R)- i-Pr-BPE (R)-Synphos (R)-Difluorphos (S)-Binapine (+)-DIOP (S)-SiPhos-PE (R)-Me-MonoPhos (S)-PhanePhos (S)-Tol-SDP (SP,RC)-DuanPhos (R,R)-QuinoxP*
0.5 3.5 24 7 7 24 7 0.5 24 24 24 24 5 0.5
100 100 38 (48) 30 (38) 100 50 (69) 32 (47) 100 42 24 (33) 68 no conversn 90 100
90 90 93 0 50 25 0 10 71 24 36
All reactions were carried out on 0.35 mmol of 1 in MeOH under 1 atm of H2. bConversions are given in parentheses if incomplete. c Determined by SFC analysis.
Gradually decreasing the catalyst loading from 10 to 1 mol % caused a drop in conversion from 100% to 63%, with no alteration of the asymmetric induction (Table 2, entries 1−5). Increasing the temperature from 30 to 40 and then 50 °C while maintaining a substrate/catalyst ratio of 100/2 improved the rate of the reaction, whereas slightly lower enantioselectivities were observed (Table 2, entries 4, 6, and 7). Additional experiments carried out with substrates 1e,l showed that a reaction temperature of 40 °C was required to reach full conversion within a short reaction time and with no loss of enantioselectivity (Table 2, entries 8−11). On the basis of these results, the optimized reaction conditions that allowed a good compromise between fast conversion and good enantioselectivity were defined as follows: a catalyst loading of 2 mol %, an atmospheric pressure of hydrogen, MeOH as the solvent, and a reaction temperature of 40 °C. With these optimized conditions in hand, we further explored the substrate scope and limitations of the hydrogenation reaction (Scheme 3). The presence of a methyl group in the para or meta position on the phenyl ring of the enamide did not affect the stereoselectivity of the reaction (compounds 6b,c), whereas the more sterically demanding ortho-substituted analogue led to a slight decrease in the enantioselectivity (compound 6d). We found the reaction to be efficient with either electron-donating or electron-withdrawing groups, and compounds 6e−j were obtained with good to excellent enantioinductions. On the other hand, no reaction occurred under the standard reaction conditions for compound 1k bearing a nitro group on the aryl ring, whereas only traces of
86 96
a All reactions were carried out on 0.35 mmol of 1a with a catalyst loading of 10 mol % at 30 °C in MeOH under 1 atm of H2. bIsolated yields. Conversions are given in parentheses if incomplete. c Determined by SFC analysis.
corresponding α-acetal-β′-amino ketone 6a with enantioselectivities up to 93% under an atmospheric pressure of hydrogen, in MeOH, at 30 °C with a catalyst loading of 10 mol % (Table 1, entries 1−3). Nevertheless, increasing the steric hindrance on the DuPhos ligand led to a dramatic decrease in the conversion (Table 1, entry 3). Poor conversion and no enantioinduction were observed with the i-Pr-BPE ligand (Table 1, entry 4). Synphos19 and Difluorphos,20 developed in house, or other commercially available ligands such as Binapine, DIOP, SiPhosPE, Me-MonoPhos, PhanePhos, and Tol-SDP were tested under these conditions, but none of them enabled access to 6a with good yields or enantioselectivities (Table 1, entries 5−12). 6429
DOI: 10.1021/acs.orglett.7b03332 Org. Lett. 2017, 19, 6428−6431
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Organic Letters Scheme 3. Scope and Limitations of the Rh-Catalyzed AHa
formed stereocenter. By analogy, we supposed that the remainder of products 6 followed the same trend.
Figure 1. X-ray crystallographic structures of 6f,h.
Furthermore, scale-up experiments were performed on 1a (3.8 mmol, 1.0 g) and 1r (1.92 mmol, 600 mg), and no diminution of yield or enantioselectivity was observed (Scheme 4).22 Finally, postfunctionalization of (−)-6r was studied, and a Scheme 4. Scale-up Experiments and Postfunctionalization Reaction
Suzuki-Miyaura cross-coupling reaction with phenylboronic acid in the presence of 5 mol % of Pd(PPh3)4 in toluene/water (20/1) allowed the formation of 7 in good yield. In conclusion, we have developed a highly enantio- and chemoselective rhodium-catalyzed hydrogenation of a series of β-keto-γ-acetal enamides using the air-stable ligand QuinoxP* under an atmospheric pressure of hydrogen. This method allowed access to a wide range of α-acetal-β′-amino ketones under mild conditions with high yields and enantioselectivities up to 99%. The reaction tolerated a diverse set of acetals as well as aryl groups on the enamide functional group and could be readily transposed to gram scale, attesting to the usefulness of this reduction.
a
Unless specified otherwise, reactions were carried out on 0.35 mmol of 1 with a catalyst loading of 2 mol % at 40 °C in MeOH under 1 atm of H2. The ee values were determined by SFC analysis. bReaction carried out with a catalyst loading of 5 mol % at room temperature in MeOH under 10 atm of H2.
the reduced product 6k appeared when the reaction was carried at room temperature using a catalyst loading of 5 mol % under a hydrogen pressure of 10 bar. A substrate with a naphthyl group was also effectively reduced with a high 97% ee (compound 6l). The keto enamide 1m bearing a thienyl substituent could be converted into the corresponding amido ketone 6m with an excellent enantioselectivity of 96%, although higher hydrogen pressure (10 bar) and catalyst loading (5 mol %) were required. Finally, we showed that other acetals, such as dioxanyl and diethoxy compounds, were also suitable for this reaction and allowed the formation of the corresponding αacetal-β′-amino ketones with excellent yields and enantioinductions up to 99% (compounds 6n−u). It should be pointed out that, for all substrates, neither the carbonyl reduction nor the degradation of the acetal moiety were observed, demonstrating the high efficiency of this method. X-ray crystallographic analysis of compounds 6f,h (Figure 1) allowed determination of the absolute configuration of the newly
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications Web site. (PDF) Crystallographic data for 6f (CIF), Crystallographic data for 6f (CIF) Crystallographic data for 6h (CIF), Crystallographic data for 6h (CIF) The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03332. Experimental procedures, compound characterization data, and NMR, HPLC, or SFC spectra for all new compounds (PDF) 6430
DOI: 10.1021/acs.orglett.7b03332 Org. Lett. 2017, 19, 6428−6431
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Organic Letters Accession Codes
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CCDC 1559274−1559275 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail for P.P.:
[email protected]. *E-mail for V.R.-V.:
[email protected]. ORCID
Virginie Ratovelomanana-Vidal: 0000-0003-1167-1195 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Q.L. is grateful to the PCAS for a grant (2014-2017). We thank L.-M. Chamoreau and G. Gontard for the X-ray analysis (UPMC Sorbonne Universités, Paris).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03332 Org. Lett. 2017, 19, 6428−6431
